Reactions of Allylmagnesium Reagents with Carbonyl Compounds and\nCompounds with C=N Double Bonds: Their Diastereoselectivities Generally Cannot\nBe Analyzed Using the Felkin\xe2\x80\x93Anh and Chelation-Control\nModels
This review describes the additions of allylmagnesium reagents to carbonyl compounds and to imines, focusing on the differences in reactivity between allylmagnesium halides and other Grignard reagents. In many cases, allylmagnesium reagents either react with low stereoselectivity when other Grignard reagents react with high selectivity, or allylmagnesium reagents react with the opposite stereoselectivity. This review collects hundreds of examples, discusses the origins of stereoselectivities or the lack of stereoselectivity, and evaluates why selectivity may not occur and when it will likely occur.
Allylmagnesium Reagents Exhibit Unique Reactivities<!>Purpose of the Review<!>Experimental Details<!>How to Use this Review<!>Current Understanding of the Mechanism of Additions of Allylmagnesium\nReagents to Carbonyl Compounds<!>Diffusion-Controlled Additions<!>Reversibility of Addition Reactions<!>Importance of Reaction Rate to Understanding Stereoselectivity<!>Additions to Imines<!>Caveats Regarding Stereochemical Models<!>Stereochemical Control by the Chelation-Control Model<!>Additions of Allylmagnesium Reagents to \xce\xb1-Substituted Carbonyl\nCompounds Capable of Chelation<!>Additions to \xce\xb1-Alkoxy Ketones<!>Use of Non-Coordinating Solvents to Improve Selectivities of\nAllylations of \xce\xb1-Alkoxy Ketones<!>Additions to \xce\xb1-Alkoxy Acyl Silanes<!>Additions to \xce\xb2-Alkoxy Ketones<!>Additions to \xce\xb1-Substituted Aldehydes<!>Use of Other Metals to Increase Selectivity of Allylation<!>Use of Non-Coordinating Solvents and Salts to Improve Selectivities\nof Allylation<!>Allylations of \xce\xb1-Alkoxy Aldehydes<!>Allylations of \xce\xb1-Nitrogen Atom-Substituted Aldehydes<!>Additions to \xce\xb2-Alkoxy Aldehydes<!>Additions to \xce\xb2-Silyloxy Aldehydes<!>Additions to \xce\xb2-Nitrogen-substituted Aldehydes<!>Additions to Aldehydes with Distant Chelating Groups<!>Alkoxy-substituted Cyclic Ketones<!>\xce\xb1-Oxygenated Six-Membered-Ring Ketones<!>Additions to \xce\xb2-Hydroxycyclohexanones<!>Additions to \xce\xb3-Substituted Cyclohexanones<!>Additions to Alkoxy-substituted Five-membered Ring Ketones<!>Additions to Alkoxy-substituted Four-membered Ring Ketones<!>Additions of Allylmagnesium Halides to Cyclic Hemiacetals<!>Felkin\xe2\x80\x93Anh Stereoselectivity<!>Additions to \xce\xb1-Chiral Acyclic Ketones<!>Additions to Chiral Exocyclic Ketones and Aldehydes<!>Additions of Allylmagnesium Halides to Chiral Cyclic Ketones Controlled by\nFelkin\xe2\x80\x93Anh Selectivity<!>Additions of Allylmagnesium Halides to Chiral Acyclic Aldehydes<!>Steric Approach Control and Stereoselectivity<!>Additions of Allylmagnesium Halides to Six-membered Ring Ketones<!>Additions to 4-Substituted Six-membered Ring Ketones<!>Additions to 3-Substituted Six-membered Ring Ketones<!>Additions to 2-Substituted Six-membered Ring Ketones<!>Additions to Six-membered Ring Ketones with Multiple\nStereocenters<!>Additions to 2-Substituted Five-membered Ring Ketones<!>Additions to 3-Substituted Five-membered Ring Ketones<!>Additions to Five-membered Ring Ketones with Multiple\nStereocenters<!>Additions to Four-membered Ring Ketones<!>Additions to Seven-membered Ring Ketones<!>Additions to Eight-membered Ring Ketones<!>Additions to Nine-membered Ring Ketones<!>Additions to Cyclic Ketones with Other Rings<!>Additions to Fused Six-membered Ring Ketones<!>Additions to Fused Five-membered Ring Ketones<!>Additions to Bridged Bicyclic Ketones<!>Additions to Bridged Bicyclic Ketones with the Carbonyl Group in the\nOne-Carbon Bridge<!>Additions to Bridged Bicyclic Ketones with the Carbonyl Group in the Two-\nor Three-Carbon Bridge<!>Additions to Bridged Bicyclic Ketones with Carbonyl Groups in the Larger\nBridge<!>Additions to Multicyclic Ketones<!>Multicyclic Ketones with Carbonyl Group in Fused Ring<!>Multicyclic Ketones with the Carbonyl Group in a Bridging Ring<!>Multicyclic Ketones with the Carbonyl Group in a Spiro Ring<!>Additions to Carbonyl Groups Attached to Rings<!>Additions to Other Acyclic Carbonyl Compounds<!>Comparisons between Reactions of Imines and Reactions of Carbonyl\nCompounds<!>Mechanism of Additions of Allylmagnesium Reagents to the\nCarbon\xe2\x80\x93Nitrogen Double Bond<!>Additions to Acyclic Imines Capable of Chelation<!>Additions to Acyclic Imines Not Capable of Chelation<!>Additions of Allylmagnesium Reagents to Exocyclic Imines<!>Additions of Allylmagnesium Reagents to Endocyclic Imines<!>Additions of Allylmagnesium Reagents to Iminium Ions<!>Additions of Allylmagnesium Reagents to Complexes of Imines with Lewis Acids\nand Metal Complexes<!>Additions to Oximes<!>Additions to Amidines<!>Additions to Hydrazones<!>Additions to Nitrones<!>Additions to Sulfinyl Imines<!>Additions to Imines with Other Chiral Auxiliaries on Nitrogen<!>Conclusions
<p>The additions of allylic nucleophiles to carbonyl compounds are powerful
transformations because they form synthetically useful homoallylic alcohols.
Although allylmetal reagents containing zinc, cerium, boron, titanium, and tin
groups can be used in many instances,1 synthetic strategies often depend upon commercially
available allylmagnesium reagents to introduce the synthetically useful allyl
group (Scheme 1).2</p><p>The reactions of allylmagnesium reagents, unfortunately, do not always
follow models normally used to predict and explain the stereochemical outcomes
of additions to carbonyl compounds. The Felkin–Anh or related models (for
example, Scheme 23) and the chelation-control model (for example,
Scheme 34) often fail to rationalize the product obtained
in these transformations, although they can explain selectivities observed for
additions of other organometallic nucleophiles. In some cases, allylmagnesium
reagents react with opposite selectivity to other Grignard reagents5–7 (for example, Scheme
4).8 These problems
can hinder efforts to develop stereoselective syntheses of natural products
using allylmagnesium reagents, as illustrated for additions to structurally
similar substrates 109 and 12,(Iwasaki et al. 2006, #301) which occur
with contrasting selectivities (Scheme 5).
Synthetic chemists often use allylation reactions because of the operational
simplicity of the transformation, the commercial availability of the reagent,
and the synthetic utility of the products,10–14 even
when these reactions are not stereoselective or their outcome cannot be
predicted.15,16</p><!><p>This review documents the additions of allylmagnesium nucleophiles to
chiral carbonyl compounds, imines, and related electrophiles to provide a guide
to understanding when these reactions will likely occur with stereoselectivity
and when they will likely not. The outcomes of the reactions described herein
are analyzed using common stereochemical models and analysis of possible
transition states. Because these models often fall short of explaining the
outcomes of additions of allylmagnesium reagents, in some cases the analysis
provided in the original papers will be supplemented with an analysis guided by
our recent studies of the unusual reactivity of these reagents.17,18 The review focuses on examples reported since this
topic was reviewed in 197119,
although additions to chiral carbonyl compounds were not discussed in that
review. The present review will emphasize more recent examples through 2018,
particularly those applying to complex target synthesis, although some older
work will be discussed for context. Comparisons to either different
organomagnesium reagents or different allylmetal reagents have been provided in
many cases to illustrate the unusual behavior of allylmagnesium reagents.
Considering that other allylmetal reagents and their reactivities have been
reviewed recently,20,21 that material will not be covered in
depth. Generally, reactions that use allylmagnesium reagents directly, without
transmetallation to other organometallic species, will be discussed, although
some examples of such reactions will be included for comparison.</p><p>The purpose of this review is several-fold. It should inform chemists who
see unexpected results with allylmagnesium reagents that their observations are
not unique: many authors see divergent results for these reagents compared to
other organomagnesium reagents. This review is also intended to explain why the
selectivities might be different based upon the latest understanding of the
mechanism of these reactions and the implications of that mechanism. With that
information available, researchers should be able to report their results using
mechanistically sound arguments and by comparing their observations to related
work. Furthermore, the review intends to show that mechanistic arguments using
transition state models are not infallible, and that the underlying assumptions
governing their application must be considered thoughtfully. It is necessary, in
light of mechanistic information about how additions of allylmagnesium reactions
occur,18 that
stereochemical analyses use the most recent and relevant information.
Consequently, many stereochemical outcomes are reconsidered here based on those
insights. This review is also intended to help synthetic chemists predict what
might happen in planned reactions, so that synthetic approaches can be devised
with the highest probability of success. Finally, this review pays respect to
the contributions of the authors who are cited because they have contributed to
our understanding of the important synthetic reactions that use allylmagnesium
reagents.</p><!><p>The experimental details of these reactions are important to consider.
Information such as solvents and temperatures are provided to facilitate
comparisons, considering the influence that some solvents22 and temperature23 can have on the outcomes of additions of
allylic organomagnesium reagents. In most cases, such details were available
either in the text or Supporting Information of any article, but, on occasion,
such information was unavailable. Other cases clearly document that allylations
and other types of additions were performed, but no details such as
diastereoselectivity were provided, so no specific insight could be
gleaned.24 When
temperatures were not listed, it was assumed that the reactions were conducted
at room temperature if that were implied; otherwise, temperatures were not
listed. Yields are reported as greater than some value if a yield were reported
over multiple steps that include the addition reaction (in most cases, only the
addition reaction was shown for clarity). Diastereomeric ratios are provided,
although in some cases authors only note a single product, so that fact is
indicated in the Scheme. In several cases, the text, figures, and experimental
results reported deviate slightly in issues such as solvent, temperature,
product ratios, and yields. In such cases, the values from the experimental
sections were used, although it should be stressed that such differences are
minor and do not affect conclusions. Finally, stereochemical assignments in all
cases are based upon the analysis provided by the authors of the individual
papers and are assumed to be correct.</p><!><p>Although it would be ideal to read this review in its entirety, that
idealistic view will only be possible for a reader with a considerable amount of
time to devote to this subject. A reader could still appreciate the topic by
selecting a specific topic from the Table of Contents and focusing on the
examples therein. As the reader then generates questions regarding reaction
mechanisms and reasons for stereochemical outcomes, then the introductory
sections might be more useful.</p><!><p>Recent studies provided insight into the mechanism of additions of
allylmagnesium reagents to carbonyl compounds.18 Computational25 and experimental23 studies suggest that a concerted,
six-membered-ring transition state is most likely responsible for the addition
(i.e., 14, Scheme 6). This
pathway, which was proposed many years ago based upon mechanistic studies with
substituted allylic organomagnesium reagents,26 is unique among pathways for additions
of organomagnesium reagents to carbonyl compounds. Non-allylic Grignard reagents
react through different types of transition states, including four-center
transition states and six-membered-ring transition states involving dimers of
the reagents (i.e., 15).27 Considering the differences in addition mechanisms
between allylic and non-allylic organomagnesium reagents, it may not be
surprising that the stereochemical outcomes of addition reactions are
different.</p><!><p>The most important mechanistic consequence of the six-membered-ring
transition states through which allylmagnesium halides react is that these
addition reactions proceed unusually quickly. Anecdotally, researchers noted the
high reactivity of allylmagnesium reagents, a fact established carefully decades
ago.28,29 This high reactivity allows
allylmagnesium reagents to add to ketones for which no other organometallic
nucleophile will add (Scheme 7)30 or to ketones that generally
only undergo enolization (Scheme
8).31,32 In particular, additions of allylic
Grignard reagents to unhindered carbonyl compounds likely occur at rates
approaching the diffusion rate limit,28 although rates would be slower for additions to
particularly hindered carbonyl compounds.17 This high reactivity can be synthetically useful and
provides a strongly compelling reason to continue to use these reagents.</p><p>The high reactivity of allylmagnesium reagents comes at a cost of
decreased stereoselectivity. This problem is best illustrated by considering the
key steps involved in addition to a carbonyl compound (Scheme 9). Before the new carbon–carbon bond is
formed, the nucleophile and electrophile must diffuse toward each other and form
an encounter complex (i.e., 22) with a rate constant of
kon. At that point, the nucleophile can attack
the prochiral carbonyl compound (21) from either the top or bottom
face, two processes that are competitive with the separation of encounter
complex (the path labeled koff). As addition to the
carbonyl group becomes faster with more reactive reagents, eventually the rates
of ktop and kbottom
become faster than the rate at which the two reaction partners can dissociate
from each other (that is, ktop,
kbottom >>
koff). In this case of high reactivity, the
transition state for bond formation no longer exclusively determines the
selectivity of a reaction, but the manner in which the two components diffuse to
one another (i.e., kon) will also influence
diastereoselectivity. This change of the selectivity-controlling step from bond
formation to diffusion has been documented for chemoselective additions to
carbocations33 and
stereoselective reactions of oxocarbenium ions.34–37 Therefore, as the rates of carbon–carbon bond
formation approach the diffusion rate limit, the stereochemistry-determining
step can be the approach of the reagents to each other (i.e., the step
corresponding to kon), as illustrated in Scheme 9. Stereochemical models do not hold
in this scenario because facial selectivity is determined before the
carbon–carbon bond forming step.38 Therefore, any analysis of stereoselectivity must first
consider whether these reactions might be diffusion-controlled or not. If the
reaction were under diffusion control, then the diffusion step must be analyzed,
not the bond-forming step.</p><p>Recent studies suggest that additions of allylmagnesium reagents to
aldehydes and most ketones occur at the diffusion rate limit.17,18 While most other organomagnesium reagents (and
methyllithium) show dramatically different rates of addition to acetophenone and
benzaldehyde, allylmagnesium reagents react with both at the same rate (Scheme 1017).28 These facts lead to the conclusion that many reactions
of allylmagnesium reagents with ketones cannot be analyzed using transition
state models, but, instead, must be analyzed by considering the diffusion step.
Only in the case of highly hindered ketones, such as
di-tert-butyl ketone (27), camphor
(28), and fenchone (29, Scheme 11), do rates likely fall below the diffusion rate
limit.17,23 The much slower addition of allylic
Grignards to these hindered ketones is consistent with the fact that the
reduction of di-tert-butyl ketone (27) by
NaBH4 at 0 °C is over 5,000 times slower than the
reduction of acetone.39 The
rapid rate of addition of allylmagnesium reagents to most carbonyl compounds
suggests that these reactions cannot be made faster by catalysis.40,41</p><p>The lack of chemoselectivity resulting from the high rates at which
allylmagnesium halides react presents a problem for multiply-substituted
electrophiles commonly encountered in synthesis. Scheme 12 illustrates the problematic behavior of allylmagnesium
bromide compared to vinylmagnesium bromide in such a system.42 Addition of vinylmagnesium bromide to
compound 30, which contains both carbonyl and carboethoxy groups,
resulted in addition to the carbonyl group followed by transesterification.
Conversely, allylmagnesium bromide added to both the carbonyl and carboethoxy
groups of compound 30 at comparable rates. Alternatively, the rate
of addition to the carboethoxy group could be comparable to the rate of the
intramolecular transesterification. Other evidence of the similar rates of
additions of allylmagnesium reagents to aldehydes and esters have been
reported.17 The
ability of allylmagnesium reagents to add to esters rapidly can be useful for
the analysis of triacylglyerols by facilitating deprotection of multiple ester
groups,43 although it
can complicate their application in natural product synthesis.44</p><p>The high reactivity of allylmagnesium reagents even extends to the
carboxamide functional group. In the addition to cyclic amide 34
(Scheme 13), allylmagnesium bromide
reacted at room temperature, whereas higher temperatures were required to
generate product 35 in good yield with the methyl and phenyl
Grignard reagents.45 Multiple
additions to amides are also not uncommon for allylmagnesium reagents, as
illustrated in Scheme 14.46 It is notable that one of the
two carboxamide groups of 36 does not react with the reagent,
suggesting that chemoselectivity in allylic Grignard additions to complex
molecules is possible. Other authors have noted similar behavior of
allylmagnesium reagents with amides.47</p><p>Even for reactions with seemingly simple electrophiles, the reactivity
of allylmagnesium reagents can be quite useful (Scheme 15).48
Addition to aromatic aldehyde 38 using allylmagnesium bromide
occurred in high yields, but efforts to achieve this allylation with
allyltrimethylsilane and Lewis acids either gave no reaction or resulted in
decomposition. This example illustrates the value of allylmagnesium reagents
among the many reagents used to form allylated products.</p><!><p>For highly hindered carbonyl compounds, additions of some
organomagnesium reagents can be reversible. The reversibility of additions of
allylic magnesium reagents was first examined by Benkeser and co-workers, who
monitored the isomerization of homoallylic magnesium alkoxides formed after
addition of a crotyl Grignard reagent (Scheme
16).49,50 The observation of reversible reactions
was established with sterically hindered ketones and long reaction times to
achieve complete equilibration. In the case of addition of the smaller reagent,
allylmagnesium bromide, to di-tert-butyl ketone
(27), the reverse reaction required heating to reflux in
THF.51 Other
reversible additions are also slow: the reverse of the additions of
benzylmagnesium reagents were performed at 140 °C for three to ten
days.52 As a result,
reversibility is not likely to occur, even in hindered systems, if reactions
were quenched after the addition reaction.23 This protocol is normally followed by synthetic
chemists.</p><!><p>Competition experiments provide important insights into if and when
stereoselectivity should be expected from reactions. Because the rate at which
allylmagnesium nucleophiles react with carbonyl compounds approaches the
diffusion limit, traditional rate measurements (or even stopped-flow
measurements) cannot provide rate constants for these reactions.28,29 Such competition experiments can provide insight not
only into chemoselectivity (Scheme 10
above) but also can reveal why, in some cases, additions of allylmagnesium
reagents may not be diastereoselective. For example, competition experiments
suggest why additions of allylmagnesium halides to α-alkoxy ketones in
ethereal solvents are not generally diastereoselective (Scheme 17).22 Considering that addition through a chelated transition
state should be faster than additions through a non-chelated transition
state,53–55 the fact that addition of an
allylmagnesium reagent to a chelating ketone is not faster than addition to a
non-chelating ketone22
suggests that any explanations for stereochemical control involving chelation
should be considered with some skepticism. Consequently, additions that can be
analyzed using Felkin–Anh, Cieplak, Cornforth, and related
models56,57 would also need to be evaluated as to
whether or not the stereochemical outcome arises instead from
diffusion-controlled behavior. Such studies would be relatively simple to
perform in cases where sufficient quantities of the carbonyl compound were
available, as is often the case in methodological studies. Information about
relative reaction rates of reactions can be obtained using carefully controlled
competition experiments.17 As
a result of the recent relative rate studies of allylic Grignard reagents, the
analyses reported in this review will necessarily make assumptions about
relative rates based upon reasonable comparisons, as will be described
below.</p><!><p>Although this review will focus on reactions of ketones and aldehydes,
reactions of allylmagnesium reagents with imines and related electrophilic
carbon–nitrogen double bonds will be discussed to provide comparisons.
Much less is known about the mechanism of additions of allylmagnesium reagents
to imines and other electrophiles with carbon–nitrogen double bonds. It
is reasonable to assume that the six-membered ring transition state suggested
above (14, Scheme 6) operates
for additions of allylmagnesium reagents to imines. The rates of the reactions,
however, must be considerably slower than additions to carbon–oxygen
double bonds, although additions to activated imines such as
N-sulfonylimines, could be even faster.58 As a result, stereochemical models such
as the Felkin–Anh model may operate, so there may not be the same
unpredictability or loss of stereoselectivity as observed with ketones and
aldehydes. For example, addition of allylmagnesium bromide to chiral
α-alkoxy aldimine 45 proceeded with high diastereoselectivity (Scheme 1859), as compared to the additions of
allylmagnesium reagents to α-alkoxy aldehydes and ketones (as illustrated
in Scheme 3).</p><!><p>Stereochemical models are powerful tools that help organic chemists
rationalize and predict the stereochemical outcomes of reactions, but they need to
be used wisely. Many stereochemical models are predicated on the assumption that the
carbon–carbon bond-forming step is also the stereochemistry-determining step.
As the rates of bond formation approach the diffusion limit, however, the
bond-forming step may no longer determine the stereochemical outcome, and thus the
model would no longer apply. Similarly, in some cases, reactions are
diastereoselective, but it is not a difference in enthalpy that determines
selectivity; differences in entropy in the corresponding transition states control
diastereoselectivity.60–62</p><p>The failures of stereochemical models due to rapid reaction rates have been
documented for the reactions of a family of electrophiles closely related to
carbonyl compounds, namely oxocarbenium ions. The standard stereochemical models can
fail to explain the outcomes of reactions of these electrophiles with some of the
most reactive π-nucleophiles, Me3SiCN, and alcohols.34–37 When nucleophiles become more reactive, additions to these
highly reactive oxocarbenium ions occur with decreased stereoselectivity (Scheme 19) likely because these reactions occur
at rates approaching the diffusion limit and, therefore, the addition step is no
longer the stereochemistry-determining step.36 While in this situation the electrophile is the highly
reactive partner, the reactions of highly reactive allylmagnesium reagents with
carbonyl compounds are likely to be analogous.22 As a result, stereochemical models need to be used wisely
to prevent their being applied in settings in which their necessary conditions are
not met. Such precise thinking requires discipline on the part of both authors and
readers.</p><p>It is also imperative that any explanation of reactivity is logically sound.
An example is illustrated for additions of nucleophiles to prochiral carbonyl
compounds (Scheme 20). In this case, only two
possible stereochemical products can be formed. Each of these products (resulting
from addition to the Re or Si face) is generally
ascribed to one of two different stereochemical models. The Cram chelate model can
be used to explain how one product is formed, whereas the Felkin–Anh model
would explain how the opposite stereoisomer would be formed.57 Haphazard use of these models can perpetuate
a logical fallacy that confuses cause and effect. One could assume that if the
product of chelation-control were favored, then the reaction must have proceeded
through a transition state involving chelation-control. Conversely, if the
diastereomer expected from the Felkin–Anh model were formed in excess, it
could be proposed that the transition state for this reaction would involve the
types of conformational preferences and interactions stipulated by that model.
Although these explanations are consistent with the outcomes, they
do not require that the particular mechanistic pathway described by
the stereochemical model is operating.</p><p>This point is particularly clear for reactions generally analyzed using the
Felkin–Anh model. This model is not the only explanation for formation of
products with the same configuration. The original Felkin model,63 without the benefit of the insights applied
by Anh and Eisenstein,64 also
explained the formation of the same diastereomer (and other models have analyzed the
same transition state differently65). The Felkin transition state, however, is just one of a number
of possible transition states leading to the same product, and, in some cases, other
models might be more consistent with the results, even though the same diastereomer
of the product was formed.66 As a
result, simply because a reaction yields the product expected from the proposed
transition state model, that is insufficient to prove that this reaction proceeded
through that transition state. Instead, the outcome is merely consistent with that
transition state; other transition states could have led to the same outcome.</p><p>This issue is also relevant to product ratios. It is common in papers for
authors to discuss the origin of the major product of a reaction, but a more
sophisticated argument would need to explain the formation of minor products as
well. If the major product were formed by, for example, a Felkin–Anh-like
transition state, then application of the false logic described above would require
that the minor product would necessarily arise from a chelation-controlled
transition state. But such an argument is not universally applicable, particularly
in cases where chelation would not be possible. Thus, it makes more sense that the
minor product occurs from some higher-energy, Felkin–Anh-like transition
state or possibly a completely different type of transition state altogether. It is
conceivable that the final product ratio might be the result of a statistical
average of several different pathways, based on their relative energies, as has been
argued for additions to chiral carbonyl compounds67 and oxocarbenium ions68 and for the asymmetric hydrogenation of
alkenes using chiral catalysts.69</p><p>These arguments would also apply to many other modes of stereochemical
control. For the purposes of this review, we have analyzed the results of reactions
of allylmagnesium halides with chiral carbonyl compounds and imines using four
distinct models: the Cram chelation model (as formulated by Eliel and
Frye,53–55 although with caveats obtained from more
recent results22,70), the Felkin–Anh model, the torsional
strain model71 associated with
additions to cyclic ketones, and the concept of steric approach control.</p><p>This last model deserves additional introduction. Steric approach control
addresses which face of a carbonyl group is attacked strictly based upon which face
is more sterically accessible.72
What sets this model apart is that it is not analyzed in the same way as the other
stereochemical models. Other models consider a number of possible transition states,
analyze which transition state would have the lowest energy, and conclude that the
reaction occurred through the lowest-energy transition state. Those models, by
definition, assume a Curtin–Hammett kinetic scenario73 in which a number of different intermediates
(such as encounter complexes and conformational isomers) are rapidly interconverting
but the major fraction of molecules follows the lowest-energy pathway among all
possible pathways.</p><p>Steric approach control, however, does not assume a Curtin–Hammett
kinetic scenario. Instead, it focuses on what steric interactions develop upon
bringing a reagent close to the starting material.74,75
Such steric interactions in the transition state can be sufficient to define
selectivity. It is correct that steric approach is involved in the other modes of
stereocontrol as well (as in determining which face is attacked once chelation had
occurred or what interactions occur in the Felkin–Anh transition state once
orbital interactions are optimized), but steric approach control requires only
steric factors developing between the components of a reaction to explain
selectivity. For example, additions to ketone 56 (Scheme 21) have been argued to be the result of steric approach
control: the face of the carbonyl group that is preferentially attacked is
determined by balancing the steric destabilization that would occur from attack of
the opposing faces.76 This balance
shifts as the size of the substituent on the nearby aromatic ring increases in
size.</p><p>Although, on one level, it may be a semantic point to discuss steric
approach as a separate mode of stereochemical control, it is a useful mode of
thinking that enables different possibilities for analyzing stereochemistry.
Analysis of the results in Scheme 21
illustrates how steric approach control can be used. Neither the Felkin–Anh
model nor the chelation control model can explain these results adequately. It is
also difficult to analyze these experiments by considering torsional effects in the
transition states of addition, which should be similar for the three
halogen-containing substrates. It is reasonable, however, to argue that the
exo face of the carbonyl group becomes less accessible as the
halogen atom increases in size, causing attack from that face to be slower.</p><p>Steric approach control can be a powerful mode of controlling
stereochemistry, and it is worth acknowledging it as a possibility with the same
importance as Felkin–Anh or chelation control models. A classic example of
steric approach control involves the commonly used arguments to analyze approach to
a π-system from the convex face of a bicyclic (or multicyclic) system. This
"convex vs. concave" mode of analysis is an important stereochemical
controlling element with a long history in organic chemistry.83,84</p><p>It should not be construed that steric approach control does not consider
differences in energies of competing transition states. Rather, it evaluates which
face of a molecule is more accessible to reagents. Those interactions are among the
many factors that influence selectivity. Steric approach control, such as evaluating
convex vs. concave faces, can be of secondary importance compared to other
stereochemical control elements.85–87
Nevertheless, the analysis of which face of a π-system is more easily
approached by a reagent can be useful when considering reactions in which the
approach of the reagents (i.e., diffusion), and not the transition state for bond
formation, is important for stereoselectivity. It is precisely this situation that
may occur in the case of additions of allylmagnesium reagents to carbonyl compounds.
The stereoselectivity of these reactions is no longer controlled by transition
states that include bond formation, so, as rates approach the diffusion limit,
transition-state models will no longer operate.38</p><!><p>Chelation control is a commonly used method for controlling the
stereochemistry of additions to carbonyl compounds. This approach is most useful
in the case of α-substituted carbonyl compounds (particularly
α-alkoxy ketones), but chelation can be observed with more remotely
substituted substrates. In comparison, α-alkoxy aldehydes react with
lower selectivity than ketones do, likely because of the generally higher
reactivity of the aldehyde functional group.17,28,88</p><p>Chelation-controlled selectivity was not intended to denote an
electronic difference between chelated and non-chelated transition states. As
originally formulated, the model explained the high selectivity based upon the
presence of a rigid intermediate with sterically differentiated faces in which
the α-heteroatom and the carbonyl group are chelated to the
organometallic reagent (Scheme
22).67 Approach
to one face of the chelate 55 is sterically blocked by a larger
substituent (in this case, Rl), so attack occurs from the
less sterically hindered face. As a result, chelation control is a form of
steric approach control: the difference in energy between the transition states
of addition to one side of the chelated intermediate compared to the other is
caused by the different steric destabilizations that develop between the
incoming nucleophile and the substrate.</p><p>Chelation-controlled selectivity is not so simple to analyze, however.
The contributions of Eliel, Frye, and co-workers are particularly important to
the understanding of this model.53–55 Their
studies revealed that chelated intermediate 58 is likely not the
major intermediate present in solution in THF, one of the most common solvents
used for reactions involving organomagnesium reagents. 1H NMR
spectroscopy of ketones in the presence of
MgBr2•(OEt2)2 (as a surrogate for
the organomagnesium nucleophile) demonstrated that the chelated intermediate is
a minor component in ethereal solution (Scheme
23).</p><p>Solvent choice can make a significant difference in the quantity of the
chelated intermediate. For example, complexation was much more pronounced in
CD2Cl2 compared to THF-d8,
as evidenced by the significant differences in chemical shifts observed upon
addition of MgBr2 to an α-alkoxy ketone (Scheme 23).22 Other metal salts, such as EtZnCl, also formed significant
quantities of chelated species with α-silyloxy ketones in
CD2Cl2.89</p><p>The origin of stereoselectivity in systems where chelation is possible
is more complex than just recognizing that chelation can occur. The difficulty
is caused by the fact that many intermediates could be present in solution, such
as those shown in Scheme 24, but the
chelated intermediate, a minor component, must be more reactive than other
species. Eliel, Frye, and co-workers measured reaction rates for additions of
Me2Mg to ketones that could and could not form chelated
intermediates.53,54 For α-methoxy ketones,
reaction rates were up to 2,000 times higher than for ketones without a
chelating group (Scheme 25).53 As a result, the
chelation-control model is an example of a Curtin–Hammett kinetic
scenario:73 a minor
amount of a highly reactive species (i.e., the chelate 60) must
undergo reaction with the organometallic reagent faster than any other species
in solution reacts. Furthermore, the chelated carbonyl compound must react much
faster considering the generally high stereoselectivities observed. It was
suggested that the chelated carbonyl compound was more reactive because the
carbon–carbon bond formation is unimolecular instead of
bimolecular,54 a
suggestion that has been supported computationally.90</p><p>This conclusion, however, may only be the case for the monomeric
dialkylmagnesium species examined in those studies. The structures of the more
commonly used organomagnesium halides are likely to be more complicated (Scheme 26). The Schlenk equilibrium, which
exchanges ligands on magnesium atoms, enables different types of organomagnesium
reagents to be the nucleophilic species.91 Grignard reagents also readily form aggregates,
depending on the solvent, concentration, halide, and nature of the organic
group, all of which would complicate this picture significantly.91,92 Although the aggregation state of organomagnesium
halides vary widely, multimeric species are plausible intermediates in which
there is a synergy between the complexation of the carbonyl compound to one
equivalent of a magnesium species and a second magnesium species.93–95 This type of mechanism parallels
observations with organozinc reagents, which show chelation-controlled
selectivity in the presence of dimeric zinc species.96</p><p>As suggested above, the use of non-ethereal solvents can change the
stereochemical outcome dramatically. For example, whereas addition of
methylmagnesium halides followed the chelation-control mode in ethereal
solvents, addition of allylmagnesium reagents were generally poorly selective,
as would be expected from a reaction whose stereochemistry-determining step was
diffusion (Scheme 27).22 By contrast, additions in the
non-complexing solvent CH2Cl2 were highly
diastereoselective. In non-ethereal solvents such as
CH2Cl2, the chelated form of the carbonyl compound was
demonstrated to be more favored compared to ethereal solvents (Scheme 23),22 which might be expected to increase the
amount of product formed from this intermediate.</p><p>Other experiments, however, show that the observation of highly
diastereoselective reactions with allylmagnesium halides in
CH2Cl2 cannot be explained by the chelation control
model as currently defined. That model includes the stipulation that chelation
is accompanied by acceleration of the reaction rate,53,54 but no chelation-induced rate acceleration was observed for
allylmagnesium halides (Scheme
28).22 The
chelation-control model describing additions of Grignard reagents to
α-alkoxy ketones can therefore be broadened to state that the product
arising from addition to the favored face of the chelated intermediate should be
the major product of a reaction in either of two scenarios: a small amount of
the chelated intermediate is the most reactive species in solution, or the
chelated intermediate must be the major species in solution. Therefore, the
nature of the solvent needs to be considered in any analysis of additions of
organometallic nucleophiles to ketones capable of chelation.</p><p>The nature of stereocontrol through chelation is likely even more
complicated. One final example reinforces the general caveats noted about the
stereochemical models used by organic chemists (Section 3). In studies of hydride reduction reactions, it was
demonstrated that the product expected from chelation control was formed without
any evidence that it was either a result of a highly reactive chelated
intermediate or that the major species in solution was a chelated
intermediate.70
Therefore, it is important to remember that all that is required for
stereoselectivity is that the diastereotopic faces of the carbonyl compound are
sufficiently differentiated.</p><!><p>Among the more consistent problems in using allylmagnesium reagents is
their general reluctance to engage in chelation-controlled additions. This point
is illustrated in Scheme 3 in the
Introduction section. The striking difference in diastereoselectivity can be
attributed to the high rates of additions of allylmagnesium reagents, which
approach the diffusion rate limit. In this section, examples of
chelation-controlled and non-chelation-controlled additions are documented.
These examples will focus on reactions of allylmagnesium reagents; the studies
of chelation-controlled additions by other organometallic reagents such as
organotitanium or organozinc reagents have been reported elsewhere.97–100</p><!><p>As noted in the Introduction section (Section 1), additions of allylmagnesium reagents to
chiral, α-alkoxy ketones are generally unselective. The examples
shown in Scheme 29 below are
illustrative.4,101 Addition of an
alkyllithium reagent preferentially gave the Felkin–Anh product
(albeit with low selectivity), likely because chelation to the lithium
atom is generally weaker.102,103 On
the other hand, most organomagnesium reagents reacted with high
chelation-controlled stereoselectivity. Among the organomagnesium
reagents investigated, however, only allylmagnesium bromide reacted with
no stereoselectivity. Similar observations were made using other
protecting group schemes.104</p><p>The contrasting reactivity of allylmagnesium reagents compared
to other organomagnesium reagents is a general observation. Among
several Grignard reagents examined for additions to ketone
69 and related substrates, allylmagnesium bromide was
notable for its lack of chelation-controlled diastereoselectivity (Scheme 30).105</p><p>Even in conformationally controlled systems, these reactions are
not generally stereoselective (Scheme
31).101 In
this case, the low stereoselectivity was not a problem because the
authors were interested in exploring the biological activity of
different stereoisomers of the final product. That advantage does not
apply to most situations, however.</p><p>In some cases, addition of an allylmagnesium reagent occurred
with the opposite stereoselectivity from what was expected (Scheme 32).106 Whereas addition of MeMgCl to
the ketone 73 occurs with some selectivity for the product
expected from chelation control, addition of allylmagnesium chloride to
ketone 75 provided similar selectivity but for the opposite
stereoisomer (i.e., the product of addition consistent with the
Felkin–Anh model).</p><p>The importance of the overall structure of a compound and not
just the potentially chelating α-stereocenter is illustrated by
comparing the results shown in Scheme
32 to studies of a related ketone 76, Scheme 33 based upon the figure
drawn in the paper and its conversion to a cyclic acetal).107 Addition to this
ketone, the diastereomer of 75, gave much higher
selectivity, but that reaction also did not form the chelation-control
product: the transformation was highly Felkin–Anh selective. This
reaction may be an example of a reaction selective for the
Felkin–Anh product that does not proceed through a
Felkin–Anh transition state, as discussed in Section 3. It is likely that the ketone exists
predominantly in the conformation 78, which would minimize
dipole interactions and avoid a potential
syn-pentane-like interaction between the
β-methyl group on the ring and the methyl group on the carbonyl
carbon atom. Addition from the more accessible face would then give the
observed product. This analysis also makes it easier to rationalize the
fact that addition of a different organomagnesium reagent to ketone
76 occurred with the opposite sense of facial
selectivity, giving the product expected from chelation control as a
single stereoisomer (Scheme
34).108 The rate acceleration required of chelation
control53,54 could be necessary for
addition of an alkylmagnesium reagent to this hindered ketone. Addition
of allylmagnesium halide would not need such rate acceleration for the
reaction to proceed;22
addition could occur from the lowest-energy conformer.</p><p>A similar comparison could be made with the addition to an
imine, although these reactions will be discussed in more detail in a
later section (Section 7).
Addition of an allylzinc reagent to imine 80 gave the
product expected from chelation control, whereas addition of the
allylmagnesium reagent gave the Felkin–Anh product (Scheme 35).109</p><p>High selectivity for allylation can be observed in the case of
α-hydroxy ketones, where the chelating group may be an OMgX
group, not an OR group. The addition of an excess of allylmagnesium
chloride to ketone 83 gave high selectivity for the product
anticipated from chelation to the α-OMgCl group (Scheme 36).106 This type of addition has been
seen previously (for example, with ketone 85, Scheme 37).110</p><p>Analyzing these selectivities by assuming that deprotonation of
the hydroxyl group occurred first followed by chelation-controlled
addition may or may not be logical. The rate of deprotonation of an
alcohol by an alkylmagnesium reagent is much faster than addition, but
for allylmagnesium reagents, the rate of addition to a carbonyl group is
competitive with proton transfer from a relatively acidic OH
group.111
Consequently, it cannot be assumed that the nearby OH group has been
converted to OMgX prior to addition to the carbonyl group for every
molecule of the reaction mixture.</p><p>Evidence supporting the chelating ability of the OMgX group is
illustrated by a comparison using prenylmagnesium chloride, a
substituted allylmagnesium reagent (Scheme 38).23 Addition of one equivalent of prenylmagnesium
chloride to the α-hydroxy ketone 87 gave high
selectivity for the diol 88, which would be anticipated
from chelation control (Scheme
38). The low yield of the product could result from competitive
deprotonation of the hydroxyl group. A control experiment indicated that
chelation to an OMgCI group is most likely responsible for selectivity.
Initial deprotonation of the OH group was performed with MeMgCI. No
addition of a methyl group occurred under these conditions, which is
consistent with the fact that proton transfer should be much faster with
an alkylmagnesium reagent.111 Subsequent addition of prenylmagnesium
chloride to the resulting alkoxide gave the chelation-control product
with similar selectivity and yield as in the original experiment. By
comparison, prenylation of the corresponding α-methoxy ketone
89 occurred with low stereoselectivity.</p><p>These experiments also suggest a reason why additions to
α-hydroxy ketones are more stereoselective than to
α-alkoxy ketones. It is likely that with a negative charge
present on the molecule, addition to the carbonyl group could be
relatively slow (that is, with a rate constant that is slower than the
rate of separation of the encounter complex, as discussed in Section 2.2). Additionally, with the
magnesium atom now tightly bound to the α-oxygen atom,
complexation of the carbonyl group to the metal atom becomes a
unimolecular process, not a bimolecular one. That chelation should lead
to faster addition54
to the magnesium alkoxide and therefore stereoselectivity. It is also
worth noting that the general regioselectivity exhibited by
prenylmagnesium reagents and the presence of this functional group in
natural products make this reagent an attractive nucleophile for use in
synthesis (for example, Scheme
39112). Oxidation of alcohol 92, followed by
asymmetric reduction of the ketone provided the stereoisomer needed for
the synthetic route.</p><p>Addition of an allylmagnesium reagent to a more structurally
complex α-hydroxy ketone also resulted in high stereoselectivity
(Scheme 40).113 The
stereoselectivity can again be rationalized by considering chelation to
an α-OMgX group (as in 95).</p><!><p>As noted above (Section
4.1), the use of non-ethereal solvents in reactions with
allylmagnesium halides can give rise to more stereoselective reactions.
Strictly speaking, however, these selectivities cannot be explained
using the chelation-control model under Curtin-Hammett kinetics, as
formulated by Eliel and Frye.53–55 Instead, stereoselectivity could arise because the
major species in solution is the chelated intermediate.22 Allylations that are
not selective in ethereal solvents show some improvement using
halogenated solvents (Scheme
41).114 The selectivity for allylation of ketone
96 can be improved under carefully controlled
conditions.22
The presence of additional magnesium salts under these conditions can
improve the selectivity further, likely by increasing the proportion of
a chelated species in solution compared to unchelated substrate. The
selectivities under these conditions are comparable to those observed
for the addition of allylstannanes with chelating Lewis acids.114 This combination of
non-coordinating solvents and additional magnesium salts also can
increase the stereoselectivity of additions of other organomagnesium
reagents to α-alkoxy ketones.115</p><p>The use of halogenated solvents, although it should be
considered as a possible solution, cannot solve all selectivity issues.
For example, in a study using a chiral auxiliary to control
selectivities for additions to a carbonyl group, additions of a number
of organomagnesium reagents in CH2Cl2 with excess
magnesium salts led to highly diastereoselective reactions (Scheme 42). Only in the case of
allylmagnesium halides was this reaction unselective, even under these
optimized conditions (the counterion was not specified in all
cases).114
Another example of the failure of non-complexing solvents to solve the
issues of low selectivity is illustrated for ketone 100,
where allylmagnesium reagents once again reacted with uniquely low
stereoselectivity (Scheme
43).116</p><p>Related additions to an α-keto amide gave little
diastereoselectivity for reactions of allylmagnesium halides (Scheme 44).117 Whereas selectivity could be
achieved in some additions of allylmetal reagents in halogenated
solvents, the addition of allylmagnesium bromide in Et2O was
unselective (the other diastereomer was somewhat favored). Reactions of
methylmagnesium and methyllithium reagents in Et2O with a
similar substrate were similarly unselective, reacting with the same
sense of selectivity as the allylmagnesium reagent (Scheme 45).118</p><!><p>Just as with additions to α-alkoxy ketones, additions of most
organomagnesium halides to α-alkoxy acyl silanes can also be achieved
with chelation control (Scheme
46).119
The additions of allylmagnesium reagents, however, proceeded with little
stereoselectivity. In this case, use of a different allylmetal reagent
formed product 107 selectively. These results demonstrate that
although acyl silanes are more electrophilic than the corresponding
ketones,120 they
appear to follow similar trends of diastereoselectivity.</p><!><p>Additions of nucleophiles to β-alkoxy ketones using
chelation control can be stereoselective. A particularly useful example
is the stereoselective reductions of β-hydroxy ketones (Scheme 47).121 This reaction involves
chelation of a boron reagent to the β-hydroxyl and carbonyl
groups followed by reduction of the chelate 109 from the
stereoelectronically favored face.122,123
Methods for performing chelation-controlled reductions of
β-alkoxy ketones have also been reported.124</p><p>As a general rule, additions of Grignard reagents to
β-alkoxy ketones are much less selective than the corresponding
reactions of α-alkoxy ketones.100 Nevertheless, attempts to
obtain the β-chelation product have been successful in some
cases.125 In
the presence of lanthanum salts, additions of organomagnesium reagents
can be stereoselective in some cases (Scheme 48). Selectivity was also higher in mixtures of THF
and CH2Cl2 instead of THF alone. No information
was provided regarding the selectivities without the use of the metal
salt and whether these conditions resulted in transmetallation to form
an organolanthanum intermediate. The higher selectivity of the
allylation reaction in this case may also reflect the fact that this
ketone is highly hindered, so it should undergo additions more slowly,
possibly below the diffusion rate limit.</p><p>Attempts to achieve chelation-controlled addition using an OMgX
group at the β-position were not selective (Scheme 49).126,127
Additions of allylmagnesium halides to β-hydroxy ketones
113 and 115 resulted in low selectivity.
This lack of selectivity appears to be general.128</p><p>In more complex settings, however, there have been examples of
remote complexation of an alkoxide anion (Scheme 50).129 In the case of hindered ketone 117,
treatment with allylmagnesium bromide gave a complicated mixture of
products, likely because the carbonyl and carboxyl groups reacted with
allylmagnesium reagents at competitive rates.17 Deprotonation of the hydroxyl
group also likely occurred at a similar rate.111 Transmetallation to zinc did
allow for a stereoselective addition reaction, which the authors
attributed to chelation of the remote alkoxy group of compound
117.129 It is also likely that the ketone adopts a
conformation resembling 119 to minimize destabilizing
steric interactions (i.e., allylic strain130) between the two carbonyl
groups.</p><p>A case of β-chelation controlled addition was reported in
the context of a chromium-mediated transformation (Scheme 51).131 This reaction incorporates the allyl fragment
into the ring by an addition reaction onto β-alkoxy-substituted
ketone 122. The product of that step, alkoxide
123, was attributed by the authors to be formed through
the chelated transition state 126, where the nucleophile
was delivered to the external face of carbonyl group, which faces away
from the ring. Further transformations that close the ring to the five-
and six-membered rings involve reactions of chromium carbenes.</p><!><p>Generally, additions to chiral aldehydes are much less
stereoselective than the corresponding additions to ketones, even for
non-allylic Grignard reagents 22,132–134.This difference in
selectivity likely relates to the significantly higher electrophilicity of
aldehydes compared to ketones.17,135 The
difference in selectivity can be illustrated by several examples using
Grignard reagents. For example, Felkin–Anh selective additions to
aldehydes are generally poorly selective, but additions to the corresponding
ketones can be highly stereoselective (Scheme
52).136</p><p>A more complicated example is illustrated in Scheme 53.137 Addition of racemic alkyl Grignard reagent
129 to racemic aldehyde 130 (shown as only one
enantiomer to simplify the discussion) gave a mixture of four diastereomeric
products (each as its racemate). This lack of selectivity shows that the
BnOCH2– protecting group, though capable of chelation,
could not control the stereoselectivity of addition to the aldehyde. Upon
oxidation to ketone 132, one of the stereocenters was removed,
leaving only two diastereomers detectable by NMR spectroscopy. Addition of
MeMgCl to ketone 132 formed only two detectable stereoisomers,
which indicates that the new stereocenter was formed with high
stereoselectively. The relative configuration of this product, which is
consistent with chelation-controlled addition to the ketone directed by the
α-BnOCH2O group, was established upon conversion of
tertiary alcohol 133 into the natural product zoapatanol. The
stereoselectivity of the third step (132 →
133) was not an artifact of the order of addition:
reversing the order of the synthetic steps in which the Grignard reagents
were added gave the tertiary alcohol 133 with the opposite
configuration at the newly formed stereogenic center. That result arose from
chelation-controlled alkylation of a methyl ketone intermediate (not shown).
These results demonstrate that, even for alkylmagnesium reagents,
chelation-controlled additions to ketones can be stereoselective while
additions to aldehydes are not.</p><p>The above results reinforce observations involving allylmagnesium
reagents (Scheme 54).138 Regardless of the
substitution pattern on the aldehyde, stereoselectivity of addition to the
α-alkoxy aldehyde was poor. The diastereoselectivity was comparable
to that of a simple ketone that did not contain a chelating group
(R1 = Ph, R2 = Me). Other examples confirm that
additions of allylmagnesium reagents to α-alkoxy aldehydes proceed
with low stereoselectivity (Scheme
55).139</p><p>Recent experiments suggest a possible explanation for why
α-alkoxy aldehydes are not generally able to undergo chelation
control with any Grignard reagent. Competition experiments using THF as
solvent revealed that no rate acceleration occurred for additions to an
aldehyde capable of forming a chelated intermediate (138)
versus an aldehyde that cannot (139) for either allyl- or
methylmagnesium chloride (Scheme 56).
As discussed in Section 4.1, the rate
acceleration observed for additions to β-alkoxy ketones was essential
for diastereoselectivity because these systems operate under
Curtin–Hammett control, where the majority of the product is formed
through the lower-energy, chelated transition state. If rate acceleration
were not present, the chelated transition state would no longer be favored,
so addition could occur to any of the many forms of the aldehyde in solution
(i.e., not complexed to RMgX (58), complexed to RMgX but not
chelated (59), and chelated to RMgX (60), as
illustrated in Scheme 24), resulting
in low stereoselectivity.22 It is possible that, because reactions of
allylmagnesium halides with α-alkoxy ketones are not
chelation-controlled due to the high rate constants associated with addition
reactions, reactions involving all organomagnesium halides with
α-alkoxy aldehydes are generally not amenable to chelation control
due to the higher reactivity of aldehydes compared to ketones.17,88</p><!><p>A commonly used strategy to solve the problem of low
stereoselectivity for allylation of aldehydes using allylmagnesium
halides is to use other allylmetal reagents. Considering that this topic
was reviewed in considerable detail,1,20 only
some foundational studies will be described here. The high
diastereoselectivity that can sometimes be obtained in reactions of
α-alkoxy aldehydes with a number of different allylmetal reagents
is illustrated in Scheme
57.97,138,140,141 Transmetallation can be effective for
providing products with high chelation-controlled diastereoselectivity,
and the use of allylsilanes or allylstannanes in the presence of Lewis
acids provides another alternative. This solution can be general (Scheme 58).142 The preference for the
Felkin–Anh product in the case of the allylboron nucleophile (pin
= OCMe2CMe2O) reflects the fact that the boron
atom cannot accommodate the extra coordination required for observing
chelation-controlled addition.</p><p>Related studies show that the use of other allylmetal reagents
can be effective to control the diastereoselectivity of additions to
α-alkoxy aldehydes (Scheme
59).143
Allylmagnesium bromide added to aldehyde 144, but the
product was formed with little stereoselectivity (reaction conditions
were not provided). Attempts at allylation using allyltrimethylsilane
gave no reaction, but addition of allyltributylstannane with
AlMe3 as a Lewis acid gave good diastereoselectivity. A
common method to performing stereoselective allylations involves using a
chiral boron reagent,144 but in this case that reagent did not add
efficiently.</p><!><p>As with ketones, non-coordinating solvents such as
CH2Cl2 can be used to obtain the
chelation-controlled product in the absence of chelation-induced rate
acceleration (Scheme
60).22
Addition of a suspension of allylmagnesium bromide in
CH2Cl2 to aldehyde 146 was able
to form alcohol 147, the product expected by chelation
control, as a single diastereomer. By comparison, the addition in THF
gave a mixture of diastereomers. As with α-alkoxy ketones,
however, this protocol is not always successful (Scheme 61).145</p><p>Other examples of highly selective additions to α-alkoxy
aldehydes using CH2Cl2 as the solvent have been
reported. For both additions of vinyl- and allylmagnesium bromide to
aldehyde 151, chelation-control products were formed
stereoselectively (Scheme
62).146 Changing the protecting group on the hydroxyl
group of 150 to a non-coordinating silyl ether led to high
diastereoselectivity favoring the product with the opposite
configuration (Scheme 121, Section 5.3).</p><p>As with ketones, when an α-alkoxy aldehyde is already in
a noncoordinating solvent, the addition of metal salts can increase the
diastereoselectivity of reactions with allylmagnesium halides.147 Whereas addition to
140 gave low selectivity without additives, the authors
report high selectivity in the presence of a magnesium salt (Scheme 63).114,147 It should be noted that for the more hindered
aldehyde 146 with an α-benzyloxy group (Scheme 60), the addition of
magnesium salts were not necessary to observe high selectivity, but the
use of CH2Cl2 as solvent was.</p><!><p>A common example of a substrate that is reluctant to undergo
chelation-controlled, stereoselective additions by Grignard reagents is
protected glyceraldehyde acetonide (154). Although a useful
protecting group for 1,2- and 1,3-diols, the acetonide is not generally
optimal for obtaining chelation-controlled addition products from
α-alkoxy aldehydes (Scheme
64).99,148 Addition of a
variety of Grignard reagents, including allylmagnesium bromide, to
aldehyde 154 proceeded with low diastereoselectivity. This
lack of selectivity was attributed to the presence of the second oxygen
atom at the β-position, which could chelate through a
six-membered ring transition state. As a result, better selectivities
are usually observed with different protection schemes, particularly
with a benzyl group at the α-oxygen atom.149,150 Additions to a more elaborated version of this
aldehyde (157) were also unselective (Scheme 65).151</p><p>It is possible to observe highly stereoselective reactions of
glyceraldehyde acetonide (159). Whereas no selectivity was
observed above with allylmagnesium bromide (Scheme 64),148 additions of an allylzinc reagent to aldehyde
159 proceeded with high diastereoselectivity, favoring
the product expected had Felkin–Anh control operated (Scheme 66).152</p><p>Generally, however, allylmagnesium reagents add to acetonide
derivatives with low diastereoselectivity (Scheme 67).107 Regardless of the relative stereochemistry of
the starting material, additions are unselective.</p><p>With other types of ketal-protected α,β-dihydroxy
aldehydes, stereoselectivities were also low (Scheme 68).153. Despite this low stereoselectivity, the
allylation reaction of aldehyde 165 has been used in
natural product synthesis after separation of the desired stereoisomer
from the undesired one.154,155</p><p>In some cases with potentially chelating alkoxy groups,
allylation gave unexpected products (Scheme 69).156 Instead of forming the product expected from
chelation control, addition to 167 resulted in low
stereoselectivity in favor of the Felkin–Anh product. As noted
earlier (Section 3), the formation
of the Felkin–Anh product need not be the result of a
Felkin–Anh transition state; other transition states could be
responsible for formation of this product. Ultimately, achieving the
desired stereochemical outcome required using organoindium reagents,
which are generally useful for achieving chelation-controlled
additions.157
A similar observation was made with aldehyde 170, which
underwent allylation with allylmagnesium bromide unselectively (Scheme 70).158 The opposite diastereomer was
obtained using an organozinc reagent.</p><p>Other cyclic ethers bearing formyl groups also reacted
unselectively. Additions to furanose-derived aldehyde 174
gave an inseparable mixture of diastereomers, which were carried on in a
subsequent ring-closing metathesis reaction to prepare nucleoside
analogues (Scheme 71).159 This type of furan
generally gives low stereoselectivity for additions of
nucleophiles.160,161
Low selectivity was also observed in the pyran series (Scheme 72).162 The pyran-substituted aldehyde
176 can react diastereoselectively: addition of
methylmagnesium bromide was moderately diastereoselective (the
stereochemistry of the major product was not assigned),163 and addition of an
alkenyllithium reagent was highly stereoselective (Scheme 73).164</p><p>Addition of allylmagnesium halides to aldehydes derived from
pyranosides show lower diastereoselectivities than additions of other
organomagnesium reagents. Allylation of aldehyde 180 was
not stereoselective (Scheme
74).165 Addition of methylmagnesium iodide to related
aldehyde 183 gave product 184 in higher
diastereoselectivity, however (Scheme
75).166
The difference in stereoselectivity was attributed to the difference in
counterion for magnesium and for the difference in solvent. Comparing
the results in Scheme 76 to the
examples discussed in this review, however, suggest that the difference
in selectivity for forming 184 is more likely the result of
the nature of the nucleophile, with allylmagnesium reagents generally
giving poor stereoselectivity in cases when other organomagnesium
reagents are selective. Additionally, it has been demonstrated that the
counterion and ethereal solvent does not significantly affect the
diastereoselectivity of a reaction between Grignard reagents and
α-alkoxy carbonyl compounds.22</p><!><p>Similar efforts to achieve chelation-controlled addition of an
allylmetal reagent using a nitrogen atom were met with limited success.
Attempted allylation of a chiral aldehyde with a potentially chelating
carbamoyl group (185) led to no selectivity (Scheme 76).167 Similarly, additions of either
allylmagnesium or allylzinc reagents gave chelation-control product
188 in low diastereoselectivity (Scheme 77).168 In the case of diastereomeric ketone
189, the product expected by the chelation-control
model (190) was formed with slightly higher
stereoselectivity. In both of these examples, the allylmagnesium reagent
formed the product more diastereoselectively than the allylzinc reagent,
which is atypical (Scheme 70).
These diastereoselectivities do not seem to be restricted to allylmetal
reagents: additions of other organometallic reagents also proceeded with
low diastereoselectivity (Scheme
78).169
Related reactions also occurred with low stereoselectivity.170, 171</p><p>Reactions of amino sugars behaved much as additions with pyrans
related to sugars (Scheme 79). Low
selectivity was observed upon addition of allylmagnesium chloride to
aldehyde 192.172 By contrast, allylation using
allyltrimethylsilane with TiCl4 gave high
diastereoselectivity. Reactivity of that nucleophile, however, depended
upon the choice of Lewis acid.</p><!><p>Similar to the additions to β-alkoxy ketones discussed in
Section 4.2.3.1, additions to
β-alkoxy aldehydes generally proceed with little
diastereoselectivity. For example, with or without a fully substituted
α-carbon atom, which would cause considerable steric hindrance
towards nucleophilic attack, stereoselectivity was low (Scheme 80).173 Low stereoselectivity was also
observed for another sterically congested aldehyde (Scheme 81).174.</p><p>The challenges associated with allylation and the efforts to
correct undesired configurations are illustrated for the β-alkoxy
aldehyde 198 (Scheme
82).175,176 In the course of a
natural product synthesis, it was necessary to achieve a
diastereoselective synthesis of polyoxygenated products such as
199. The addition reactions of allylmagnesium halides
were efficient, but they were not stereoselective. Efforts to repair
this stereochemical course by oxidation of both diastereomers followed
by hydride reduction were also ineffective, forming allylic alcohol
199 as an 80:20 mixture of diastereomers. The only
reasonable solution was to employ chiral allyl silane reagents177 to control the new
stereogenic center efficiently. Other authors have observed similarly
low stereoselectivity in related systems, which could be repaired by an
oxidation-reduction sequence.178 Stereochemical inversion through further
elaboration to correct issues of stereochemistry is a common course of
action made to remedy the low diastereoselectivity in reactions of
allylmagnesium halides.</p><p>An aldehyde with a β-tetrahydropyranyl group also reacted
with little selectivity in the presence of allylmagnesium bromide (Scheme 83).179 In the course of this
synthesis, it was important to obtain this diastereomer selectively, but
the authors note that efforts using chiral reagents to control the
stereoselectivity were unsuccessful. In the end, a circuitous repair
involved isolating the minor diastereomer and inverting the homoallylic
configuration using a Mitsunobu reaction.180</p><p>In the course of a natural product synthesis, it was shown that
the allylation of a β-alkoxy aldehyde 202 by
allylmagnesium chloride was unselective (Scheme 84).181 The undesired diastereomer was recycled to the
desired diastereomer through a two-step sequence which inverted the
configuration at the homoallylic position. Low diastereoselectivity was
also observed in the addition of allylmagnesium bromide to a similar
β-alkoxy aldehyde (204, Scheme 85).182 Although the use of chiral reagents
(allylboranes, in this case) were effective at controlling the
stereochemistry, the authors found it operationally easier, considering
the scales of their reactions, to use the readily available
allylmagnesium bromide despite the low diastereoselectivity that
resulted. The two diastereomeric alcohols of 205 were first
separated, and then the undesired stereoisomer was converted to the
desired alcohol by a Mitsunobu inversion followed by ester
hydrolysis.</p><p>Chelation-controlled additions to β-substituted aldehydes
can be achieved using other metal salts as additives.183 The addition of
ZnCl2 to the addition of aldehyde 206 led to
a completely stereoselective reaction (Scheme 86). No experiment without the use of zinc salts was
reported, so the outcome of addition of the magnesium reagent is not
known. Although the authors did not comment on the origin
diastereoselectivity, it is consistent with addition through a
transition state resembling 208 where chelation occurs to
the carbonyl oxygen atom in the β-position rather than the
β-alkoxy group.</p><!><p>Efforts toward the synthesis of a natural product and its
analogues led to investigations of methods to obtain the product
expected by chelation-control in the allylation of β-silyloxy
aldehydes (Scheme 87).184 Chelation-controlled
selectivity could not be achieved with the β-silyloxy aldehyde
210 using allylmagnesium or allylzinc reagents. By
contrast, additions to aldehyde 212 were
diastereoselective. The reaction with allylmagnesium chloride formed the
diastereomer of product 213. This diastereomer is formally
the product of addition through a Felkin–Anh transition state.
Instead, this product was likely formed through a transition state
resembling 214, which is consistent with the modified
Cornforth model.185
This model is justified because aldehydes 210 and
212 resemble aldehydes investigated by Evans to
understand how substituents at the α- and β-positions of
carbonyl compounds influence the diastereoselectivities of addition
reactions.186
Alternatively, in the presence of zinc salts, a chelate resembling
215 would be favored, leading to the illustrated
product.</p><p>Addition to aldehyde 212 formed the desired
diastereomer of 213 expected by the chelation-control model
in the presence of ZnCl2. This reaction may or not involve
transmetallation from magnesium to zinc, considering that the zinc salt
was first combined with the aldehyde followed by addition of the
organomagnesium reagent. As a result, transmetallation would need to
compete with addition to the carbonyl group. Because complexation of
alkylzinc halides to α-silyloxy ketones has been
established,89,187 it is possible that
product 213 could be obtained by chelation, as illustrated
in transition state 214.</p><p>Additional experiments provide added justification for the above
analysis. When a group is not present at the α-position to
reinforce stereochemistry, as depicted with aldehyde 216
below (Scheme 88), allylation was
less selective than the "matched" case (212)
but more selective than the "mismatched" case
(210) shown in Scheme
87.188 It
is also worth noting that in this system the use of a chiral allylborane
reagent or an allylstannane reagent in the presence of a Lewis acid also
did not afford product 217 with high stereoselectivity.</p><!><p>An example of β-chelation was observed in the case of
aldehyde 219, which contains a β-nitrogen atom
capable of metal complexation (Scheme
89).189,190 Additions of both
MeMgBr and allylmagnesium bromide led to low stereoselectivity. In
contrast to reactions with simpler systems,191 the methyl cuprate reagent gave
low diastereoselectivity. Selectivities for the allylation reaction
could be improved by transmetallation to zinc. The stereochemical
outcome for addition of the β-chelation product was different
than for addition of an allylzinc reagent to a β-alkoxy carbonyl
compound, however.192
It was argued that a boat-like chelate was favored in this system
because the nitrogen atom is trigonal planar. Subsequent intramolecular
delivery of the nucleophilic group would occur as illustrated in
transition state 220. By comparison, the aluminate complex
would react through a more standard cyclic chelating transition state,
thus favoring the opposite product.</p><!><p>Groups other than alkoxy substituents can be used to control the
stereoselectivity of addition to carbonyl compounds from remote positions
using chelation. Axially chiral aldehyde 221 underwent
diastereoselective reactions with a number of different nucleophiles (Scheme 90).193 In the case of organolithium
reagents, it was believed that chelation was not possible, but in the
presence of magnesium ions, chelation could occur (as illustrated in
transition structure 224), leading to the diastereoselective
formation of alcohol 222. Selectivity was moderate with methyl-
and n-butylmagnesium reagents, but phenylmagnesium bromide
formed 223 with a diastereomeric ratio of 97:3. As with other
reactions, allylmagnesium reagents underwent this reaction with low
diastereoselectivity.</p><!><p>The stereochemical outcome for nucleophilic addition to cyclic
ketones is often influenced by distinct factors from their acyclic
counterparts. Although they were among the early examples studied when
stereochemical models such as the work of Felkin were originally
formulated,194
these systems are more complicated than those of acyclic ketones. Bond
rotation is restricted in acyclic ketones, and torsion angles and torsional
strain exert strong influences upon the preferences for nucleophilic
attack.71 Approach
of the nucleophile to one face of the carbonyl could be favored judging by
the steric environment, but torsional strain in the transition state could
favor the opposing side. Also, distinct electronic effects can operate,
leading to selectivities that need to be analyzed separately.65,195 It is not essential to master these subtleties to
notice the disparate reactivity profile of allylmagnesium reagents compared
to other Grignard reagents.</p><!><p>In some cases, the diastereoselectivities for allylations of
alkoxy-substituted cyclohexanones can be quite high using Grignard
reagents. Nucleophilic addition to highly substituted α-alkoxy
ketone 225 proceeded with high selectivity for addition
anti to the alkoxy group (Scheme 91).196 Whether this reaction is the result of
chelation-controlled addition or simply addition to the lowest-energy
conformer (227) from the sterically more accessible side
cannot be established. Nevertheless, this example provides a good
comparison for other highly functionalized, six-membered-ring
ketones.</p><p>The presence of an α-alkoxy group is not sufficient to
observe selectivity, however. Addition to substituted cyclohexenone
228 occurred with low selectivity for addition
anti to the α-benzyloxy group, at the same
time removing the benzoyl protecting group (Scheme 92).197 Nevertheless, the major isomer could be
converted to a substrate that underwent an efficient intramolecular
Diels–Alder reaction leading to the scaffold of a natural
product.</p><p>Another example suggests that allylation with
chelation-controlled selectivity should not be expected in cyclic
ketones. Ketone 230 (Scheme
93).198
contains an α-hydroxyl group that might be expected to undergo
highly stereoselective reactions considering that the presence of
hydroxyl groups can lead to high selectivity for the chelation-control
product in acyclic systems (as illustrated by, for example, Scheme 36). Instead, low selectivity
was observed. By comparison, additions of phenyl and methyl Grignard
reagents to α-hydroxy ketone 232 were highly
stereoselective (Scheme
94).199 likely by formation of chelate 234
and addition from the face not blocked by the axial phenyl group.</p><p>Although the examples shown in Schemes 91 and 92 did
not include a direct comparison between an allylmagnesium reagent and
other organomagnesium reagents, it appears that, just as for acyclic
systems, allylmagnesium reagents add to cyclic ketones with low
selectivity (Scheme 95).200 Additions of several
organomagnesium bromides to ketone 235 occurred with high
stereoselectivity, favoring a product that could arise through addition
to the more accessible face of the multicyclic chelate 237.
On the other hand, allylmagnesium bromide added with no
stereoselectivity. This difference in selectivity mirrors other losses
of diastereoselectivity with allylic organomagnesium reagents compared
to nonallylic organomagnesium reagents.17,22,23
Considering that this cyclohexadienone structure is likely to be highly
flattened, it might be anticipated that the two faces of the carbonyl
group should show little stereochemical differentiation without
chelation. Therefore, the allylmagnesium reagent, which does not benefit
from rate acceleration conferred by chelation,22 added with little stereochemical
discrimination.</p><p>Chelation in bridged six-membered ring ketones has been invoked
both to explain stereoselectivity and reactivity of ketones.201. For the bicyclic
ketones 238 and 240, attack of allylmagnesium
bromide occurred at the conjugated carbonyl group instead of the
hindered carbonyl group on the one-atom bridge (Scheme 96). It was suggested that the addition to
the conjugated carbonyl group was the result of chelation to the nearby
alkoxy group, which would be consistent with the kinetic acceleration
conferred by chelation.54 The authors did not discuss why HMPA was used as
the solvent, which should complex tightly to magnesium, likely breaking
up dimeric species202
and disrupting chelation.</p><p>An alternative explanation for the chemoselectivity and
stereoselectivity of this addition relies on the overall structure of
this bicyclic ketone. The carbonyl group on the three-carbon bridge
appears to be more sterically accessible than the carbonyl group on the
one-carbon bridge (the reactions of allylmagnesium reagents with ketones
with the carbonyl group in a bridge will be discussed in Section 6.8). Addition to the bottom
face of this ketone, which should be less hindered considering that
longer bridge with the additional ring occupies the top face, should
lead to stereoselectivity (Scheme
97).</p><!><p>The highly stereoselective additions of allylmagnesium chloride
to cyclohexanones with β-hydroxyl groups illustrates that
chelation by a hydroxyl group is possible (Scheme 98).203 The planned synthetic route required that the
allyl groups were installed stereoselectivity so that subsequent
ring-closing metathesis reactions of the two allyl groups could form
additional rings. In general, these additions of allylmagnesium halides
to the hindered cyclohexanones were stereoselective. It is possible that
addition of an allylmagnesium reagent to the highly hindered
cyclohexanone 244 is slower than diffusion and possibly
slower than deprotonation of the hydroxyl group. While the reaction
rates of allylmagnesium reagents with sterically crowded carbonyl
compounds has been observed to decrease,17 competitive deprotonation versus
addition has only been examined for relatively unhindered aldehydes and
ketones.111
In the case of cyclohexanone 244, the strongly chelating
OMgX group could control selectivity (as discussed in Section 4.2.1.1) through transition
state 246. Addition of a substituted allylic
organomagnesium reagent, crotylmagnesium chloride, to cyclohexanone
244 in the presence of CeCI3 (Scheme 99)203,204 also occurred with high stereoselectivity with
respect to which face of the carbonyl group the reagent reacted,
although control of the configuration at the exocyclic position was low
(as observed in other systems and discussed in Section 6.2.1.4). With epimeric ketone
248, the reaction also showed high selectivity for
addition anti to the hydroxyl group, which can be
explained by chelation to this β-oxygen in the axial position
(250, Scheme
100). It was also noted that addition to benzoate
251 favored the same diastereomer of product (Scheme 101),204 although with lower selectivity
(and the acyl group had been removed in the reaction, which is
consistent with the competitive rates of addition of allylmagnesium
reagents to ketones and esters17).</p><p>The high selectivity obtained in the examples shown above would
be particularly surprising if controlled by chelation, considering that
chelation would require a bridged bicyclic structure as an intermediate.
It is not clear that a chelate can be formed considering that
complexation would have to occur on the π-face of the carbonyl
group, not in the σ-plane. It may be that the role of the OMgCl
group is more electrostatic: in the transition state, partial negative
charge on the carbonyl oxygen atom may be electrostatically stabilized
by the nearby magnesium atom, lowering the energy of this transition
state. Nevertheless, these examples illustrate that remote chelation may
be possible.</p><!><p>The idea of remote chelation is not general. A remote amido
group in an unhindered cyclohexanone could not control selectivity by
chelation (Scheme 102).205 The low selectivity
observed for addition to ketone 252 is similar to what was
observed for 4-tert-butylcyclohexanone194 (which will be
discussed in Section 6.2.1).</p><!><p>As with highly substituted cyclohexanones bearing α-alkoxy
groups (Scheme 91), additions of
organomagnesium reagents to α-alkoxycyclopentanones occurred
anti to the alkoxy group. In the case of ketone
254 (Scheme 103),
only one diastereomer of product was observed upon additions of both vinyl-
and allylmagnesium chloride.206 If the transformation shown below were controlled by
chelation, it is not clear whether chelation using the α-benzyloxy or
α-methoxy group would be more favorable. This stereoselective
addition reaction was used in the development of a synthesis of nucleoside
inhibitors (Scheme 104).207 This example provides
additional evidence that stereochemical outcomes do not depend upon whether
Et2O or THF is employed or what the counterion is for the
organomagnesium reagent.22</p><p>The stereochemical outcome is more difficult to explain in the case
of a more highly substituted cyclopentanone, which was an intermediate in
the synthesis of a carbohydrate (Scheme
105).208
Ketone 257 possesses an α-hydroxyl group, which should
provide an effective chelating group (OMgX), but the diastereoselectivity
for the addition to 257 using an allylmagnesium reagent was
low. High selectivity was obtained using an allylic silane in the presence
of a Lewis acid, which may chelate the carbonyl group and the hydroxyl
group.</p><!><p>Additions of allylmagnesium reagents to substituted cyclobutanones
do not appear to follow a consistent trend. Addition to cyclobutanone
259, which contains a naphthylamido group, proceeded with
low stereoselectivity (Scheme 106),
which is similar to the selectivity observed for reactions of 4-substituted
cyclohexanones (Scheme
102).205
In a later paper from the same team, the product of addition to carbamate
analogue 261 was identified as a single stereoisomer (Scheme 107).209 This seeming contradiction may not
be chemically significant. In the latter paper, unlike the former one,
diastereoselectivity was not discussed explicitly, and the analytical data
provided may describe only the desired stereoisomer, and not the
stereoisomeric product.</p><!><p>Reactions of cyclic acetals add a mechanistic ambiguity to the general
difficulties of analyzing addition reactions of allylic Grignard reagents.
Hemiacetals exist in an equilibrium between the ring-closed form
263, which should be the favored structure,210 and ring-opened form
264, an aldehyde with a remote alkoxide group (Scheme 108). Although there might only be a
small amount of the aldehyde form in solution, this intermediate would likely be
the electrophile reacting with the Grignard reagent.</p><p>Experiments with a six-membered ring acetal are consistent with this
analysis.211 For
stereoselectivity to occur, addition to the ring-opened aldehyde form of
265 would need to be controlled by either a β-alkoxy
group or a δ-OMgCl group. The β-alkoxy group would not be expected
to control stereoselectivity (as discussed in Sections 4.2.5.1), and the more distant group could not, either.</p><p>Hemiacetals also undergo reactions faster with allylmagnesium halides
than other reagents (Scheme
110).212
Attempts to open acetal 267 with either vinylmagnesium chloride or
vinyllithium failed to give any product. By contrast, addition of allylmagnesium
chloride gave a high yield of addition product 268, although with
low diastereoselectivity. It is possible that only a small amount of the
hindered aldehyde 269 is present, and thus the overall rate of
addition would include both the rate constant for the carbon–carbon bond
formation and the concentration of the electrophile, which would be quite low.
The observation of any addition products would require a highly reactive
nucleophile to trap the small amount of the aldehyde electrophile. The authors
also note that the same reaction for a less hindered acetal (270)
was successful with allylmagnesium chloride, but diastereoselectivity was again
low for adduct 271 (Scheme
111).</p><p>In more structurally rigid electrophiles, however, acetal substitution
reactions with allylmagnesium reagents can be highly stereoselective (Scheme 112).213 Ring-opening of acetal 272
occurred with high stereoselectivity for several organomagnesium reagents,
including allylmagnesium bromide. In this case, the bridged hemiacetal alkoxide
may open more readily than for the acetal in Scheme 110 because of ring strain. The increased concentration of
the electrophilic aldehyde form would then allow for additions of alkyl- and
alkenylmagnesium reagents to proceed. Subsequent chelation through an
intermediate resembling 274 may control the stereochemistry of the
observed product. Such an intermediate bears some structural characteristics of
the putative remote chelation by OMgX substituents discussed above (Section 4.2.1.1).</p><!><p>The use of Felkin–Anh-type stereochemical models to explain
selectivity must be accompanied by a similar level of analysis as was applied to
the use of the chelation-control model (Section
4.1). The "anti-Felkin–Anh" product is, in a
sense, the chelation-controlled product, so determining which model correctly
describes the pathway through which a particular product is formed can be a
subjective decision. Some assumptions upon which transition state models such as
the Felkin–Anh model rely have been discussed in detail in Section 3 above, so they will not be
elaborated here. In this section, reactions of α-chiral carbonyl
compounds will be analyzed using the Felkin–Anh model, which will also
include the polar Felkin–Anh variant (where RL is an
electron-withdrawing group, not simply a sterically large group). These
reactions could be analyzed differently using a myriad of the existing variants
of the Felkin–Anh and related models,56,57 but the
specific origin of selectivity will be less the focus than the similarities and
differences exhibited by allylic and nonallylic organomagnesium reagents. As
will emerge, the specific transition state determining the favored
stereochemical outcome can be difficult to ascertain for many reactions. This
section also focuses on reactions that likely do not involve chelation control,
although, at times, the choice of stereochemical model to explain a reaction
outcome can appear arbitrary.</p><p>Just as with chelation control, the Felkin–Anh model considers
the influence of steric destabilization on which transition state is favored. In
examples that do not include α-heteroatom-substituted carbonyl compounds,
the group that occupies the RL position is determined by steric
effects. In that case, the incoming nucleophile will approach the electrophile
as far away from RL as possible to minimize steric destabilization in
the transition state. Consequently, nucleophilic attack occurs from the face
away from RL (Scheme
113).63 Two
possible configurations place RL opposite the approach of the
nucleophile (275 and 276). The lower energy transition
state, 275, places the least sterically encumbered group in the
RS position because the nucleophile will attack near that group,
developing interactions that are somewhere between gauche and
eclipsed.214
Consequently, steric approach considerations also play a significant role in
determining which of the two diastereotopic faces of the carbonyl group is most
reactive.</p><p>The transition state proposed by Felkin was confirmed by Anh and
Eisenstein, who proposed that alignment of the π-system of the carbonyl
group with the σ*C-RL orbital lowered the energy of
the lowest unoccupied molecular orbital, thus favoring the Felkin transition
state 277.64
These studies also provided insight into how the electronic nature of
substituents can influence stereoselectivity. Electronic interactions involving
the developing bond between the nucleophile and the carbon atom and orbitals
associated with the C–X bond lead to transition states with different
energies due to how favorable certain filled–unfilled orbitals
interactions are in each potential transition state. For substrates containing a
heteroatom at the α-chiral position, these orbital interactions define
which group resides in the RL position.</p><!><p>One example of stereoselective addition of an allylmagnesium
nucleophile to a chiral ketone can be attributed to a Felkin–Anh-type
transition state. Allylation of ketone 279 using allylmagnesium
chloride formed homoallylic alcohol 280 with high stereoselectivity
(Scheme 114).215 The selectivity can be understood by
examining transition state 281, with the phenyl group serving as
the large group (RL). The selectivity of this reaction may not be
exclusively due to 281 serving as the lowest energy transition
state, however. The presence of two sterically large aromatic rings on both
sides of the ketone likely causes the conformer 281 to be the
lowest energy conformer in solution, resulting in only one available site of
attack even at the diffusion rate limit. The idea that this conformation is
favored is supported by X-ray crystal structures of α-phenyl-substituted
phenyl ketones that adopt conformers resembling 281.216–220</p><p>Analysis of another highly stereoselective reaction illustrates the
subjectivity of interpreting stereochemical outcomes. Addition of allylmagnesium
chloride to α-fluoroketone 282 proceeded with high
stereoselectivity (Scheme 115).221 Similar selectivity was
reported for addition of an aryllithium reagent to ketone 282.
These examples could be analyzed only considering the steric size of the
substituents, just as Scheme 114 was. The
phenyl group could serve as RL, with attack over the small fluorine
atom leading to the major product through transition state 285.
Alternatively, the F substituent could adopt the position of RL (as
in the polar Felkin–Anh model), leading to attack over the smaller benzyl
group, as shown in transition state 286. The ability of a fluorine
atoms to serve as the RL group in the polar Felkin–Anh model
(by virtue of the relatively low energy of σ*C-F) may be
operative, although other effects could operate as well.185,222–224 The
results of the additions reported in Scheme
115 cannot distinguish between transition states 285 and
286 because both pathways would lead to the major product
observed in these reactions.</p><p>Less sterically congested substrates, however, underwent less
stereoselective addition reactions of allylmagnesium reagents compared to
additions of other organomagnesium reagents. For most organomagnesium reagents,
addition to methyl ketone 287 was stereoselective, except for the
addition of phenylmagnesium bromide, which was considered to be a small
nucleophile (Scheme 116).136,225 The stereoselectivities of these reactions are
consistent with the transition state 289. Additions of
allylmagnesium reagents to methyl ketone 287 and trifluoromethyl
ketone 291, however, were less stereoselective (Scheme 117; the use of ultrasound was
likely employed to blend the reaction mixture).226 The presence of the reduction product
293 in the case of the trifluoromethyl ketone 291
was considered carefully. The authors provided evidence that these allylation
reactions did not proceed by a single-electron transfer mechanism, a mechanism
that is also unlikely based on mechanistic studies using radical clock
substrates.227
Instead, they suggest that the reduction product emerges from a β-hydride
transfer reaction from the allyl group, although this process was not observed
in the reaction of the simple methyl ketone substrate.</p><!><p>Additions of allylmagnesium halides to exocyclic chiral ketones can be
diastereoselective (Scheme
118).228,229 The major product can be
formed from a Felkin–Anh-like transition state resembling
296. It may be possible that the ketone adopts this
conformation in the ground state to minimize steric interactions, just as
observed in Scheme 114. In this
conformation, only one face of the carbonyl group is more accessible. The
stereoselectivity was responsive to solvents. Selectivity was generally higher
in coordinating solvents (like DME and THF) and less selective in
non-coordinating solvents (like toluene). The presence of excess magnesium salts
resulted in only a modest increase in diastereoselectivity. The highest
selectivities were achieved in the presence of
Ti(Oi-Pr)4, which could involve transmetallation
to form an allyltitanium reagent. Nevertheless, an advantage of the use of the
Grignard reagent was that the presence of titanium salts complicated
workup.228</p><p>Addition of allylmagnesium halides to aldehyde 297 under
conditions expected to favor chelation control instead gave the opposite
stereoselectivity (Scheme 119).230 In general, additions of
Grignard reagents to tetrahydrofuran-substituted aldehydes are not
stereoselective unless chelation is suppressed, such as when non-coordinating
solvents are used.231 In this
case, Felkin–Anh selectivity can be high.232 In the example shown in Scheme 119, transmetallation to zinc did
not result in a chelation-controlled addition, although it did mitigate the
competing addition to the ester carbonyl group17 observed in the addition of
allylmagnesium bromide to aldehyde 297. The use of an allyl silane
as the nucleophile was ineffective, highlighting an important advantage of the
more reactive allylmagnesium reagents. As with other examples, a circuitous
repair was required to obtain the desired configuration. Alcohol
298 was oxidized to the corresponding ketone and then reduced
with LiBH4 to give the desired diastereomer of alcohol
298.</p><p>A selective addition to a bicyclic system substituted with a formyl
group was reported, which demonstrates that selective additions can occur in
these type of aldehydes (Scheme
120).11 This
addition occurred to give magnesium alkoxide 300 with reasonable
diastereoselectivity (86:14) after an intramolecular Diels–Alder
reaction. The selectivity of this addition is consistent with what would be
expected from the Felkin–Anh model (transition state 303,
assuming that the tetrasubstituted carbon atom serves as RL). The
configuration at this carbon atom proved to be a challenge that needed to be
addressed. A subsequent reaction involved a Grob fragmentation, but the
secondary hydroxyl group was in the wrong orientation for optimal orbital
alignment. The configuration was inverted by a process of oxidation and
reduction, which itself was not highly stereoselective, although further
recycling was possible.</p><p>Felkin–Anh control can operate in formyl-substituted oxazolines.
Although the oxazoline group can engage in chelation (Scheme 89), it can also serve as an electron-withdrawing
group, as illustrated in Scheme
121.233,234 The major product in this
reaction can be understood using the polar Felkin–Anh model where the
nitrogen atom adopts the position of RL (306). Addition
to hindered aldehyde 304 occurred with high diastereoselectivity
only at low temperatures: at −50 °C, selectivity dropped
precipitously to 70:30.</p><!><p>Although many examples of additions of allylmagnesium reagents to
cyclic ketones have been reported, this section will focus on the few examples
of Felkin–Anh selectivity (or lack thereof) where there is not a strong
steric bias to determine diastereoselectivity. The examples noted here are
striking because of the differences between the selectivities observed with
allylmagnesium reagents and other organomagnesium nucleophiles. A more inclusive
discussion of additions to cyclic ketones will be presented in Section 6.</p><p>Additions of organomagnesium reagents to α-trifluoromethylthio
ketones illustrate the unique reactivity of allylmagnesium halides (Scheme 122; Ad = adamantyl).235 Addition of methylmagnesium
bromide to ketone 307 proceeded with high stereoselectivity,
favoring the product where the nucleophile added anti to the sulfur substituent,
which would be expected based upon previous studies of Felkin–Anh
selectivity.222
Allylation, on the other hand, proceeded with little stereoselectivity. This
result is consistent with the argument that Felkin–Anh selectivity, which
relies on a lower transition state energy for the Felkin–Anh pathway than
for others, should be difficult to achieve if reaction rates approach the
diffusion limit.</p><p>Reactions of the hindered ketone 309 provide more
contrasts between allylic and nonallylic organomagnesium reagents (Scheme 120).5,6
Addition of allylmagnesium chloride provided a product that could be consistent
with chelation control (i.e., addition of the allyl group anti to the
potentially chelating α-methoxy group). Chelation in this substrate would
be difficult, however, due to the axial orientation of the OMe group (as
illustrated in structure 313). As a result, the preference for
formation of diastereomer 310 could be interpreted as the result of
Felkin–Anh-controlled addition anti to the axial α-methoxy group.
On the other hand, addition of vinylmagnesium chloride occurred to the opposite
face, which would require the endocyclic oxygen atom to control
Felkin–Anh selectivity. By contrast, the less substituted ketone
311 reacted with both reagents with high diastereoselectivity
anti to the axial α-methoxy group. These examples serve as a reminder
that stereoselectivity can be controlled by a number of factors.</p><!><p>As noted above, sometimes it is arbitrary to decide what constitutes
Felkin–Anh versus chelation-controlled selectivity, so this section
focuses on reactions that are unlikely to involve chelation. As discussed in the
Introduction (Section 1.1, Scheme 2), carbonyl compounds generally
capable of reacting selectively through a Felkin–Anh transition state (as
illustrated with alkylmetal nucleophiles) typically react with allylmagnesium
reagents to give products with low diastereoselectivity.</p><p>The difference in selectivity when using an alkenylmagnesium reagent
compared to an allylmagnesium reagent is illustrated by addition reactions to
the simple aldehyde 314 (Scheme
124).146 Addition
of vinylmagnesium bromide occurred with 89:11 diastereoselectivity, favoring the
product expected from addition through Felkin–Anh transition state
316, where RL is the silyloxy group. By contrast,
addition of allylmagnesium bromide gave low stereoselectivity (the configuration
was determined after conversion to a cyclic product). Chelated transition states
are unlikely, considering that, for most organometallic reagents, chelation to a
bulky silyloxy group is normally disfavored236 (although chelation can be favored with zinc
reagents98,187).</p><p>Two other examples confirm the generally low stereoselectivity of
additions of allylmagnesium halides to substrates capable of reacting through a
Felkin–Anh transition state. Addition of allylmagnesium bromide to
aldehyde 317 provided a mixture of products, with a similar level
of selectivity to that obtained in the addition to aldehyde 314
(Scheme 125).237 Similarly low stereoselectivity was
observed for aldehyde 319 (Scheme
126).238 In both
of these cases, the configuration of the major product can be considered to
arise from a transition state resembling 316 above, with the
branched alkyl group serving as RL. Although the diastereoselectivity
for the Felkin–Anh isomer (320) was low, the reaction
proceeded in high yield.238
The stereoisomers were separated, and the minor isomer was oxidized to the
corresponding ketone, which was reduced by borane in the presence of a chiral
oxazaborolidine catalyst to provide more of the desired diastereomer
320.239</p><p>This protocol of oxidation of a mixture of stereoisomeric homoallylic
alcohols followed by reduction is a general route to convert chiral aldehydes to
homoallylic alcohols with high stereoselectivity. In the course of preparing the
desired homoallylic alcohol 324 in a synthesis of a natural
product, allylation of aldehyde 321 was performed (Scheme 127).240 This reaction provided the undesired
stereoisomer 322 in high yield but with low diastereoselectivity.
The diastereomers were separated, and the major, undesired stereoisomer
(322) was oxidized to form ketone 323. Reduction
of this ketone proceeded with stereoselectivity that would be predicted using
the Felkin–Anh model to give the desired stereoisomer (324).
It is unlikely that reduction of ketone 323 could occur by a
β-chelation-controlled reduction with NaBH4 because this
reagent does not generally conform to the chelation-control model.70</p><p>In the case of an α-amino aldehyde, addition of an
allylmagnesium reagent occurred with high diastereoselectivity (Scheme 128).241 Addition to aldehyde 325
provided homoallylic alcohol 326, likely through a transition state
resembling 327, where the NBn2 group adopts the position
expected for RL.</p><p>The high selectivity of the above reaction contrasts with the generally
low diastereoselectivity observed for similar reactions of α-amino
aldehydes. In the course of developing methodology for obtaining
Felkin–Anh-selective additions to α-amino aldehydes, Reetz and
coworkers observed that allylmagnesium reagents were particularly unselective
compared to other reagents (Scheme
129).242 Low
selectivity was attributed to the high reactivity of allylmagnesium reagents
without additional discussion.243 It should be noted, however, that an inverse correlation
between reactivity and selectivity can only be expected when reaction rates
approach the diffusion rate limit.244</p><p>A similar trend of low Felkin–Anh selectivity for reactions of
allylmagnesium reagents was observed with an Fmoc-protected α-amino
aldehyde (Scheme 130).245 The selectivity was
attributed to the large ortho ester group serving as RL in a
Felkin–Anh type transition state. For several of the nucleophiles,
selectivities for the Felkin–Anh product were improved by either lowering
the temperature of the reaction or using a different solvent, but no
improvements to the selectivity of the allylic nucleophile were demonstrated. It
is also worth noting that control experiments showed that the carbamoyl group
did not engage in chelation.</p><p>A related system highlighting the unusual reactivity profile of
allylmagnesium halides involves the reactions of highly substituted aldehyde
332 (Scheme
131).246,247 In the course of
synthesizing fluorinated peptide isosteres, the stereoselectivity of addition
reactions of organomagnesium reagents were examined. Use of only one equivalent
of a Grignard reagent such as methylmagnesium chloride generated none of product
333, which suggests that deprotonation of the carbamate group
was faster than addition to the carbonyl group. Upon addition of an excess of
Grignard reagent, selectivity was observed, which would be expected to result
from chelation between the formyl group and the deprotonated carbamate, as
illustrated in transition state 334. The authors optimized this
reaction as an "inverse addition," in which the aldehyde was added
to the Grignard reagent.</p><p>The results with allylmagnesium chloride differed from the results
obtained with alkyl and alkenyl Grignard reagents. Use of only one equivalent of
allylmagnesium chloride generated product with 50% conversion (as compared to no
conversion). The major product, however, had the opposite configuration (i.e.,
the Felkin–Anh product). The yield was improved somewhat upon addition of
excess allylmagnesium reagent (Scheme
131). The favored diastereomer formed in the allylation reaction is
consistent with addition through a Felkin–Anh transition state resembling
(335, in which the carbamoyl group may or may not be
deprotonated. The fact that substantial product was formed with only one
equivalent of the reagent suggests that addition may occur to either the
protonated or deprotonated form of the electrophile, as also observed for a
simple α-hydroxy ketone (Section
4.2.1.1). Instead of being controlled by chelation, the
stereochemical outcome may be governed by the nature of the lowest energy
conformer, with hyperconjugation stabilizing the conformer that maximizes
overlap of the σC-S bond with the π-system of the
carbonyl group.222,248. The anomalously low selectivity
exhibited by allylmagnesium reagents was also illustrated in reactions of
difluoromethyl aldehyde 336 with various organomagnesium reagents
(Scheme 132).246,249</p><p>Achieving high Felkin–Anh selectivity can be challenging with
many carbon nucleophiles. For example, addition to aldehyde 338
gave generally low Felkin–Anh selectivity (Scheme 133),250, presumably through a transition state where the
dimethylamino-substituted carbon atom served as RL
(340). With phenylmagnesium bromide, however, the chelation-control
product was formed. Use of organozinc reagents instead of organomagnesium
reagents with aldehyde 338 generally gave higher selectivity for
the desired anti product through chelation.</p><p>High selectivity for the product consistent with the Felkin–Anh
model can be observed in a highly biased system, even with allylmagnesium
reagents (Scheme 134).251 Addition of organomagnesium
reagents to aldehyde 341 proceeded with high diastereoselectivity.
It was argued that Felkin–Anh transition state 343 was
responsible for selectivity.</p><p>An alternative explanation of the observed stereochemical outcome can
be made based upon consideration of the X-ray crystallographic analysis of
addition product 342 (R = Et). The conformation of that adduct
closely resembles the transition state 344, with the alkyl group
that was introduced pointing away from the ring system. The aldehyde may
therefore adopt a ground-state conformation resembling the conformation of the
electrophile in transition state 344 (Scheme 135), only allowing a nucleophilic attack from the
opposite direction of the multicyclic ring system. This steric approach control
argument, which may be required to explain the diastereoselectivity observed for
allylmagnesium reagents despite their high reactivity, may be more general (as
discussed in Section 6).</p><p>Less hindered aldehydes displayed lower Felkin–Anh selectivity
in additions of allylmagnesium reagents. In the case of aldehyde
345, addition of allylmagnesium bromide formed product
346 as a 50:50 mixture of diastereomers (Scheme 136).252 The configuration that was required for a planned
synthesis was achieved by oxidation of the product to form the cyclopropyl
ketone, followed by reduction with a hindered borohydride reagent (which
occurred with 90:10 stereoselectivity).</p><p>The previous discussion of chelation-controlled reactions (Section 4.2.4.3) established that additions
to a formyl group attached to a cyclic ether ring did not benefit from chelation
(Scheme 71).160 Instead, the major product for
additions to substrates such as 347 is more consistent with the
Felkin–Anh model, although the selectivity is low (Scheme 137). Related systems also show low selectivity,
although a different explanation was provided.253 Similar low selectivity was observed
for tetrahydrothiophene analogue (Scheme
138).254</p><p>In the course of a planned synthesis of a natural product,
stereoselective formation of homoallylic alcohol 352 was attempted
by additions of a carbon nucleophile to the formyl pyrrolidine 351
(Scheme 139).255 Improved but not optimal selectivity
could be achieved using an organozinc reagent. The observed major product did
not appear to arise from a Felkin–Anh transition state: instead, it
likely reflects the fact that the substrate adopted a low-energy conformation
that would minimize syn-pentane-like interactions between the
two oxygen atoms as illustrated in transition state 353. This
conformation is adopted in the solid state by an aldehyde resembling
351.256</p><p>Additions to aldehydes bearing 2-pyrrolidine rings generally exhibit
Felkin–Anh type selectivity, but not with allylmagnesium reagents.
Additions to the triphenylmethyl-protected amine 3 gave high
selectivity for additions of most organomagnesium reagents (Scheme 140).3 Stereoselectivity was markedly lower for addition of
allylmagnesium bromide. For these reactions, the nitrogen atom should adopt the
RL position, both electronically and sterically. Because of the
constraints of the pyrrolidine ring, the carbonyl oxygen atom would need to
either point over the ring (354) or away from it
(355). Transition state 355 would normally not be
favored because steric interactions develop between the nucleophile and the ring
as it approaches along the Bürgi–Dunitz angle.257 Nevertheless, this
conformation already possesses syn-pentane-like interactions
between the group on the nitrogen atom and the carbonyl oxygen atom, which
should further favor reaction through alternative transition state
355.</p><p>Additions of most organomagnesium reagents to the similar aldehyde
356 were also highly stereoselective (Scheme 141).258 The reaction of 356 with allylmagnesium
bromide, however, occurred with lower selectivity. The authors invoked a
chelated transition state between the oxygen atoms in the sulfonyl and carbonyl
groups to explain the resulting stereoselectivity. Such chelation, however, is
not required to explain this selectivity when one considers this example along
with the work illustrated in Scheme 140.
In that case, there is no sulfonyl group, and the diastereoselectivity is
comparable.</p><p>Other N-tosylpyrrolidine derivatives show similarly
low selectivity for additions of allylmagnesium reagents. The synthesis of
homoallylic alcohol 359 was pursued towards the synthesis of a
pyrrolizidine alkaloid (Scheme
142),259 but
the diastereoselectivity for addition of allylmagnesium bromide was low. The
desired stereoisomer, formally the isomer expected from chelation control, was
obtained with some selectivity using an allylstannane reagent.</p><p>The preference for forming Felkin–Anh products in reactions of
aldehydes bearing hindered pyrrolidines is also generalizable to substituted
piperidines (Scheme 143).260 The same explanation as
detailed above can be used to explain the highly selective stereochemical
outcome in forming 361. These hindered carbonyl compounds may have
strong conformational preferences in the ground state. It is likely that the
formyl group adopts an axial orientation to minimize allylic strain with the
substituent on nitrogen, and that a chair conformation such as 363
would be disfavored because it would create 1,3-diaxial interactions, leading to
a more boat-like structure 362 being favored. The resulting axial
formyl group is likely favored in a conformation that puts the hydrogen atom
closer to the more sterically demanding ring. Attack from over the ring would be
disfavored because that face would be sterically congested.</p><p>Steroids bearing acyloxy groups (20-keto steroids) generally undergo
highly stereoselective additions of Grignard reagents (Scheme 144).261"263 Additions of allylmagnesium reagents were somewhat
selective in this series, but selectivity could be improved by the use of
allyltitanium reagents.263
The stereoselectivities of these reactions can be considered to arise from
attack anti to the sterically large quaternary carbon atom using the
Felkin–Anh model (366).</p><p>Other examples of additions of allylic magnesium reagents to related
ketones have been reported. Addition of allyl- and methallylmagnesium halides to
ketone 367 gave products with high stereoselectivity (Scheme 145).264 Additions of other reagents, such as
heteroaryllithium reagents, were also highly stereoselective (for example, to
form the furyl adduct). For many of these reagents, TMEDA was used because,
without it, mixtures of products were formed, but it was not indicated whether
these mixtures included other stereoisomers or only other products. Similarly,
en route to vitamin D derivatives, addition of allylmagnesium bromide to ketone
369 occurred to form one major product (Scheme 146).265 Additions to related ketones with methylmagnesium
reagents also proceed with high diastereoselectivity.262</p><!><p>As noted in the previous section, the developing steric interactions
that occur upon approach of a nucleophile to an electrophile (i.e., steric
approach control) play an important role in determining the stereoselectivity of
nucleophilic attack onto carbonyl compounds. The case of chelation control
provides a logical starting point for illustrating this concept. The fundamental
role of chelation in heteroatom-substituted carbonyl compounds is to define a
conformation. Once that conformation is defined, then steric approach control
determines which face of the carbonyl group is attacked: the nucleophile will
approach from the side that minimizes the number of steric interactions (Scheme 147). For chelation-controlled
additions in non-coordinating solvents, chelation need play no other role than
to differentiate the diastereotopic faces of the carbonyl compound.22 Conversely, chelates formed in
coordinating solvents must be more reactive than non-chelated forms, because the
chelate species is in such low abundance.53–55) One
face of the chelate, however, must be more sterically accessible than the other
to observe any stereoselectivity.</p><p>This last statement raises the prospect for another form of
stereocontrol. Conformational bias of reactive intermediates arising from
sources other than complexation of metals might also lead to sterically
differentiated faces. For example, hydrogen-bonding has been used to define the
conformation of a reactant that in turn can lead to stereoselective
reactions.266–268 Additionally, understanding
stereochemical control can focus on considerations of what conformational isomer
might be favored by allylic strain, and then consideration of the steric
accessibility of the two faces of the molecule.130 The overall topography of a molecule,
such as differentiation between convex versus concave faces of multicyclic
molecules77,79–82 or the steric differences observed in double bonds
contained within medium-ring systems,269 can control stereoselectivity. These effects have been
used to control selectivity for a diverse range of reactions, including
reactions of electrophiles,270 nucleophiles,271 and radicals272 (Scheme 148).
Conformational analysis of a reactive species is a form of steric approach
control: only one face of a prochiral functional group is sterically accessible
to a reagent. The same analysis would hold to explain why large nucleophiles add
to cyclohexanones from the equatorial position: although torsionally this
conformational preference is disfavored, it would minimize steric interactions
between the nucleophile and electrophile that would develop in the transition
state of the reaction (for example, Scheme
149273).</p><p>Steric approach control of stereoselectivity, combined with the
emerging picture of how one can observe chelation control even without rate
acceleration,22,70 suggests a way to understand
why allylmagnesium reagents can sometimes react with carbonyl compounds with
high stereoselectivity. As observed with chelation-controlled additions of
allylmagnesium reagents to chiral α-alkoxy ketones in non-polar solvents,
if the electrophile preferentially adopts a conformation where steric effects
are different enough between the two faces of the electrophile, then a highly
stereoselective reaction can ensue. It is precisely that issue that is explored
in this section, where stereoselectivity cannot be analyzed neatly using either
chelation control or Felkin–Anh control.</p><!><p>Additions of nucleophiles to six-membered ring ketones have been
analyzed extensively, and differing explanations of the origin of
stereoselectivity have been proposed. With small nucleophiles, both
torsional and electronic factors seem to contribute to that
selectivity.195
With larger nucleophiles, however, these reactions are dominated by steric
approach control issues.</p><p>Considering that allylmagnesium halides are better described as
large nucleophiles (in line with other organomagnesium and organolithium
reagents) and not small nucleophiles (like LiAlH4), torsional
analysis need not be the first concern. With the additions occurring at
rates approaching the diffusion limit, steric approach control may be
responsible for these additions. The following sections organize these
reactions according to the type of ring and its substitution pattern.</p><!><p>A formative examination of additions to 4-substituted
cyclohexanones included the additions of allylmagnesium reagents to
4-tert-butylcyclohexanone (381)
compared to additions of other organomagnesium reagents (Scheme 150).194 Addition of propylmagnesium
bromide proceeded with moderate stereoselectivity for attack from the
equatorial face, as illustrated in transition state 383.
This mode of attack was favored because of fewer developing steric
interactions; axial attack would incur two gauche interactions. Smaller
reagents (like LiAlH4), however, tend to add from the axial
face, a preference that has been attributed, among other reasons, to
torsional selectivity.195 The lower selectivity for allylmagnesium bromide
was originally attributed to its smaller size compared to
propylmagnesium reagents.</p><p>Fifty years of accumulated knowledge of these reactions suggest
that this conclusion should be reevaluated. First, the difference in
energy that corresponds to this selectivity is less than 1 kcal/mol,
which could arise from many different factors. Second, based upon more
recent results,17 the
reaction of the ketone with allylmagnesium bromide likely occurs at
rates approaching the diffusion rate limit. Consequently, almost no
stereoselectivity would be expected because the two diastereotopic faces
of the cyclohexanone would not be significantly sterically
differentiated in the carbon–carbon bond-formation
step.17
Furthermore, the mechanism of addition of allylmagnesium reagents to
ketones is likely to be different than for other organomagnesium
reagents,23,25 so direct comparisons
between reactions are likely to be imperfect.</p><p>The advantages of using
4-tert-butylcyclohexanone (381) as a model
ketone have led to the development of numerous variants of nucleophilic
additions, including allylations. For example, other Grignard reagents
have been examined, and those reactions also exhibit little
diastereoselectivity (Scheme
151).274 Other authors have confirmed this low
stereoselectivity with allylmagnesium halides and other Grignard
reagents.275,276</p><p>Additions of substituted allylmetal reagents to 4-substituted
cyclohexanones also occur with little facial stereoselectivity (Scheme 152).277 Although both
methallylmagnesium and methallyllithium reagents reacted with little
stereoselectivity, methallylzinc reagents exhibited somewhat higher
selectivity for addition from the equatorial face. These results could
be interpreted as indicating that both the methallylmagnesium and
methallyllithium reagents reacted at the diffusion rate limit, but the
methallylzinc reagent reacted more slowly.</p><p>The additions of other substituted allylmagnesium reagents
provide additional support for the generally low stereoselectivity of
these reactions.277
Addition of crotylmagnesium and crotyllithium reagents to ketone
381 proceeded with low facial selectivity, just as the
corresponding methallyl reagents had (Scheme 153). The regioisomeric alcohols 386
were formed in small quantities (values were not given). Similar
selectivities were observed for cinnamylmetal reagents (not shown). The
regioselectivity of these reactions is consistent with what is known
about the reactions of methallyl and cinnamyl nucleophiles. Typically,
allylic magnesium reagents, such as crotylmagnesium reagents (Scheme 154),278 add to ketones and aldehydes to
provide the product resembling 388, not
386.278,279' The origin of the selectivity for the product
resembling 388 is preferential reaction through a
six-membered transition state involving allylic transposition (i.e.,
transition state 14 in the Introduction, Section 2.1).18,23 This selectivity even holds for reactions of
more highly substituted allylic magnesium reagents such as
prenylmagnesium halides with relatively unhindered carbonyl
compounds.23</p><p>Addition of a tert-butyl-substituted allylic
magnesium reagent also showed little facial selectivity (Scheme 155).280,281 These reactions showed some selectivity for
addition at the less substituted end of the allylic magnesium reagent.
The regiochemistry of the major product of addition (389)
is consistent with the reagent reacting through the same type of
transition state that would be expected for any organomagnesium reagent
(i.e., transition states 391 and 392, without
allylic transposition).23 In that respect, this allylic magnesium reagent
behaves more like any other organomagnesium reagent: it should react at
rates below the rate of diffusion. The minor regioisomer
390 would be formed through a cyclic transition state
with allylic transposition resembling 393. The addition of
this substituted allylic Grignard reagent through the cyclic transition
state was highly stereoselective, potentially due to steric interactions
between the two tert-butyl groups that arise in cyclic
transition state 394.</p><p>As a general rule, it is difficult to obtain high
stereoselectivity for additions of organometallic reagents to
4-substituted cyclohexanones. For example, additions to the
phenyl-substituted cyclohexanone 395 proceeded with low
stereoselectivity regardless of the metal (Scheme 156).276,282 As
noted earlier (Scheme 102, Section 4.3.1.3), the presence of a
4-NHCOR group also resulted in low stereoselectivity.205</p><p>One possible exception to this general rule appears in the
addition to 4-carbomethoxycyclohexanone (397) to form
product 398 (Scheme
157).283
Only one stereoisomer of the product was depicted in the paper, but no
specific comment was made about the diastereoselectivity of its
formation. No stereochemical proof for the structure of the product was
included, nor was there any characterization of the product beyond a
1H NMR spectrum. The low yield for this reaction is
consistent with the above analysis (Section 2.2) that the rates of addition to esters are
comparable to those of aldehydes and ketones. A number of products may
have been formed in this reaction, but only the desired product was
isolated.</p><p>Additions to a 4,4-disubstituted cyclohexanone were also
unselective (Scheme
158).284 This example illustrates not only the generally
low selectivity of this family of cyclohexanones, but also the somewhat
counterintuitive conformational preferences of geminally substituted
six-membered rings,285 which might result in this ketone existing as a
mixture of conformational isomers.</p><p>In contrast to the above examples, additions of allylmagnesium
reagents to 4-substituted enones proceed with higher
diastereoselectivity (Scheme
159).286 These reactions are likely to proceed by addition
from the axial orientation because this approach permits appropriate
orbital overlap with the carbonyl group, as shown in 403.
Although this preference is not high, the selectivity of addition of
allylmagnesium bromide is slightly higher than for addition of
methyllithium.287</p><!><p>Like the 4-substituted systems, cyclohexanones substituted at
C-3 generally do not react with Grignard reagents with high selectivity
(Scheme 160).274 The low selectivity
for the reactions of this substrate may reflect both the low bias of the
cyclohexanone group to selectivity and the fact that both axial- and
equatorial conformers should be present in solution.288 Consequently,
multiple pathways could lead to each diastereomer of product. In the
case of the allylmagnesium reagent, addition might also not be
stereoselective because addition occurs at the diffusion rate limit:
there might not be enough steric destabilization from the nucleophilic
approach to decrease the rate constants for addition from either
face.</p><p>The importance of conformational control and reaction rate are
supported by observations of the addition to hindered ketone
406 (Scheme
161).289 With the additional substituents compared to
ketone 404, the conformational preference would be biased
toward the conformer depicted in transition state 408 to
minimize syn-pentane interactions. This conformer would
then be likely to be attacked only from the equatorial face because of
developing syn-pentane interactions in a transition
state involving axial attack. Attack at this hindered axial face could
occur at a rate below the diffusion rate limit, so stereoselectivity
could result even if attack from one face were particularly
fast.17,22</p><p>A similar explanation could hold for reactions of the geminally
substituted tetrahydropyranone 409 (Scheme 162).290 The preferred conformation likely positions
the alkyl group equatorial considering the high preference for the alkyl
group to be in the equatorial position at C-2 of the pyranone291 as well as an
anomeric effect with the axial methoxy group.292,293 There is also little steric penalty for
placing an alkoxy group axial in the axial position on a
3-alkoxycyclohexanone.294 Attack from the axial face would develop a
destabilizing syn-pentane-like 1,3-diaxial steric
interaction,295 so attack would occur from the equatorial face. It
should also be noted that this relative stereochemistry was observed for
3-OMgX-substituted cyclohexanones, which was attributed to chelation
(Section 4.3.1.2, Schemes 98 and 100).</p><p>In the case of 3-substituted enone, diastereoselectivities can
be quite high. In a study comparing the efficacy of different allylmetal
reagents, it was shown that carvone (411) underwent highly
selective allylation with allylmagnesium bromide (Scheme 163).286 No conditions for this reaction were given,
but it is likely to similar to conditions employed with related
substrates (Scheme 160).</p><p>A detailed study of the additions of allylic organomagnesium
reagents to pulegone (413) also provides similar high
selectivity (Scheme
164).296 With several of the reagents examined, the
reactions were diastereoselective, favoring a 1,3-trans relationship
between the nucleophile and the substituent on the
β-stereocenter. Furthermore, most of the substituted allylic
organomagnesium reagents reacted to give the products expected for
reactions through a six-membered ring intermediate with allylic
transposition (transition state 14, Section 2.1). Addition of the highly hindered
reagent prenylmagnesium bromide, however, gave not only low
diastereoselectivity for the γ-product 415 (Scheme 165), but also a significant
number of products formed from conjugate addition. This result is not
unique: another hindered allylic Grignard reagent gave similar results
(Scheme 166). Computational
studies of this reaction have been conducted.297</p><p>Additions to monosubstituted tetrahydropyranone derivatives are
not generally diastereoselective for any organometallic agents. Addition
of allylmagnesium bromide to ketone 419 proceeded with low
1,3-cis diastereoselectivity (Scheme
167).298
Addition of an aryllithium reagent to a similar ketone,
421, also proceeded with low stereoselectivity.299 By contrast, high
1,3-trans selectivity is expected for additions of alkylmetal reagents
to dihydropyranones (that is, the unsaturated ketone) with this
substitution pattern.300–302</p><!><p>As a general rule, additions of nucleophiles such as
organomagnesium halides to 2-substituted cyclohexanones are more
selective than for the other substituted cyclohexanones.71 Additions occur
anti to the substituent to minimize steric
interactions that develop in the transition state (Scheme 168).303 It should be noted, however, that additions of
allylmagnesium halides occur with lower selectivity, which is consistent
with their reactivity with other ketones and aldehydes.</p><p>The difference in selectivity between different reagents is
also illustrated by additions to other 2-substituted cyclohexanones
(Scheme 169).304 Whereas addition of
a vinylmetal reagent occurs with high selectivity, the lower selectivity
observed for allylation is similar to what was observed with the simple
ethyl substituent in the previous case (Scheme 168).</p><p>The modest diastereoselectivity for the allylation reactions of
2-substituted cyclohexanones has been confirmed for a number of
substrates (Scheme
170).305 In particular, these studies indicate that the
presence of a methoxy group does not alter the selectivity. This result
is consistent with the generally low chelation-controlled selectivity
observed by allylmagnesium reagents, as discussed in Section 2.2. For organomagnesium
reagents, additions to 2-alkoxycyclohexanones are stereoselective, while
additions of organolithium and organotitanium reagents are less
selective (Scheme 171).306 Low selectivity was
also observed in a case where there was potential for β-chelation
(Scheme 172),307 although simple
Grignard reagents did not react selectively either.308</p><p>The low selectivity exhibited for additions of allylmagnesium
reagents may or not be problematic to synthetic chemists. In the case of
addition to ketone 436 (Scheme 173), the stereochemical consequence of this low
selectivity was irrelevant, considering that both stereoisomers could be
converted to the final target by an elimination reaction.309 In other cases, the
diastereomeric addition products needed to be separated (Scheme 174).310</p><p>Additions to 2,2-disubstituted cyclohexanones also illustrate a
dramatic difference in reactivity for allylmagnesium reagents compared
to other Grignard reagents (Scheme
175).311 A
variety of organomagnesium reagents added to ketone 442
with high stereoselectivity, but additions of allylmagnesium did not. It
is worth noting that a crystal structure of a related ketone where the
propargyl group was replaced by a benzylic group (shown as
"R") favored the conformation 444 where the
carboxyethyl group adopted an axial orientation.312 The major addition products
would arise from axial attack considering how hindered equatorial attack
would be.</p><p>The above observation of low stereoselectivity for addition of
allylmagnesium halides is not general, however. Additions of both vinyl-
and allylmetal reagents to ketone 445 were highly
stereoselective (Scheme
176).313 The addition of homoallylic magnesium reagents,
however, were unsuccessful. This example might be more selective because
the two substituents are larger than those in Scheme 175, with the larger group occupying the
equatorial orientation. Approach of the nucleophile from the equatorial
position would develop gauche interactions with both substituents, which
could be avoided upon attack from the axial orientation, as shown in
transition state 447.</p><p>The additions to 2-substituted cyclohexanones with geminal
substituents at the adjacent carbon atom were also highly
stereoselective (Scheme
177).314 It was noted later that additions of homoallylic
magnesium reagents were also highly stereoselective, but those reactions
required the addition of CeCl3 to facilitate
addition.315
Generally, CeCl3 is used to assist additions of
alkylmagnesium reagents, particularly in the case of readily enolizable
ketones.316
Just as with the 3,5,5-trisubstituted cyclohexanones (Scheme 161), the presence of an
axial substituent at the geminally substituted carbon atom likely
decreases the rate of addition from that face, so addition from the
equatorial face would be favored (as illustrated in transition state
452). Similar highly selective reactions were observed
in a related system (Scheme
178).313</p><!><p>As with earlier examples, additions of allylmagnesium reagents
to more sterically congested or conformationally constrained carbonyl
compounds tend to give higher diastereoselectivity. This similarity
between reactions of different types of organomagnesium reagents may
occur because the rates of addition of allylmagnesium halides may be
below the diffusion rate limit, at least for the diastereotopic face
that leads to the minor product.</p><p>Menthone (455) is the canonical example of a
multiply substituted six-membered ring where additions of various types
of organomagnesium reagents, including allylmagnesium reagents, are
highly stereoselective (Scheme
179).317
These results contrast with observations in the additions to simple
2-substituted ketones described above (Section 6.2.1.3). Other authors have also noted the highly
stereoselective additions of allylic organomagnesium reagents to
menthone.282,318,319 The high selectivity of these
reactions may result from the influence of the isopropyl group. Two
possible modes of approach to the carbonyl group (transition state
457) can be considered for attack on what is likely the
lowest energy conformer.320 If the nucleophile attacked from the bottom face
of the carbonyl group, the transition state would be destabilized by
interactions between the ring and a methyl group, which would develop a
syn-pentane interaction. Conversely, approach from
the top face is less hindered. Crotylation is also highly
stereoselective for addition to the carbonyl group. The moderate
diastereoselectivity observed is a result of reaction through a
six-membered transition state leading to a mixture of diastereomers at
the exocyclic stereogenic center (Scheme
180).318</p><p>In the case of a more substituted cyclohexanone related to
menthone, additions of allylmagnesium and aryllithium reagents were also
highly diastereoselective, although reaction conditions were not
provided (Scheme 181).321 The illustrated
conformation of 459 could be favored, and developing
1,3-diaxial interactions with the axial methyl group and the isopropyl
group would develop upon addition to the axial face of this
conformer.</p><p>Conformational constraints imposed by other substituents on
2-alkoxycyclohexanones exert strong influences on chelation (Scheme 182).322 As noted previously (Scheme 171), chelation can play a
large role in additions of some Grignard reagents to simple
α-alkoxy cyclohexanones. When a chelating group is constrained to
an axial position (as in 461), chelation is unlikely, so no
selectivity was observed unless strongly chelating indium reagents were
used (Scheme 182).157 By contrast, when
the chelating group was fixed to be equatorial (as in 464),
the additions of allylmagnesium reagents and alkylmagnesium reagents,
among others, were highly stereoselective (Scheme 183). The additions of the allylindium
reagents also appear to benefit from chelation-induced rate
acceleration, which would be consistent with the standard view of
chelation control (Section
4.1).53–55</p><p>It should not be concluded that addition to a cyclohexanone
with an axial group at C-2 leads to low stereoselectivity and addition
to a cyclohexanone with an equatorial group leads to high selectivity,
however. Addition of methyllithium to the cyclohexanone with an axial
methyl group (467) gave predominantly one stereoisomer of
adduct (Scheme 184).323 By contrast,
addition of an alkynyllithium species to the compound with the
equatorial methyl group (i.e., 469) gave a mixture of
products.324</p><p>An inherent difference in selectivities between different types
of Grignard reagents was noted for a number of cyclohexanones with a
potential chelating group at C-2 (Scheme
185).322,325 The alkoxyalkyl
Grignard reagent gave selectivity for what is argued to be the
non-chelation product, whereas allylmagnesium reagents gave low
selectivity. Ultimately, the use of the chelating allylindium reagent
provided the solution for obtaining the chelation product as the
complementary diastereomer to 472.</p><p>Chelation to a β-alkoxy group, however, is not a
defining mode of selectivity, at least in a highly substituted
cyclohexanone. Additions of organomagnesium reagents to a mixture of
ketones 473 and 474 occur at the equatorial
face of each conformationally constrained ketone, regardless of the
presence of a chelating oxygen atom at the β-position (Scheme 186).326</p><p>In the case of a β-hydroxy substituted variant,
allylation also favored addition from the equatorial face (Scheme 187).326 As noted above (Scheme 186), the hydroxyl group is
not necessary to encourage this mode of stereocontrol. It is worth
noting, however, that chelation appeared to be important in the case of
a different cyclohexanone (Scheme
99, Section
4.3.1.2).203</p><p>The relative orientation of substituents in a multiply
substituted cyclohexanone can influence the stereoselectivities of
additions to ketones (Scheme
188).327 For additions to a 2,3-trans-disubstituted
cyclohexanone, addition of the homoallylic reagent was employed using a
cerium salt (the counterion was not specified) to minimize enolization,
but addition was faster than enolization with allylmagnesium reagents,
as discussed in Section 2. The
diastereoselectivities for both reactions, however, were modest. By
contrast, addition of allylmagnesium bromide to the
2,3-cis-disubstituted ketone occurred with high diastereoselectivity,
likely because the conformational preferences of the ketone magnify the
differences between the diastereotopic faces. The conformer of
482 likely places the allyl group equatorially as
shown.328
Addition to the axial position is now slower because of the presence of
the axial ethyl group at C-3, leading to preferential equatorial
attack.</p><p>A highly substituted cyclohexenone also reacted with
allylmagnesium with high selectivity (Scheme 189).329 Although the authors note that the product was
formed with high stereoselectivity, the configuration was not assigned
because it was not critical to the synthetic plan. It is likely that the
major stereoisomer was formed upon attack as shown for 486,
in analogy to observations with another cyclohexenone (Scheme 159).</p><p>Additions to ketones with a number of alkoxy groups led to
divergent diastereoselectivities depending upon the nucleophile that was
employed (Scheme 190).330 Addition of
methyllithium to ketone 487 occurred from the axial
orientation to give exclusively alcohol 488. By contrast,
addition of allylmagnesium bromide occurred with little selectivity. The
same observation was made for a different ketone under similar
conditions, forming alcohols 490 with the selectivity
depending upon the nucleophile (Scheme
191).</p><p>Another example illustrates the importance of steric size of
the substituent on stereoselectivity (Scheme 192). Unlike in other cases (Section 4.3.1.2), 203,204 addition of allylmagnesium bromide to the free
β-hydroxy ketone 491 occurred with low
diastereoselectivity.331 When the hydroxyl group was protected as the
sterically large pivaloyloxy group, the addition occurred with high
diastereoselectivity. It is likely that the conformation
493 is favored in the hindered carbonyl compound, and
equatorial attack occurs to minimize developing 1,3-diaxial interactions
that would occur upon attack from the axial orientation.</p><p>The difference in selectivity of additions of Grignard
additions to a highly substituted cyclohexenone is striking (Scheme 193).7 This enone is likely to adopt the
conformation 497 that minimizes 1,2-allylic strain by
placing the oxygen atoms equatorial (a similar enone adopts this type of
conformation in the solid state332). Whereas attack from the top face might be
torsionally favored, it should be disfavored by a developing 1,3-diaxial
interaction, whereas attack from the bottom face is more sterically
accessible. It is possible that the more reactive allyl reagent responds
only to the steric effects, whereas the other reagent is aided by
chelation to the nearby oxygen atom.</p><p>High selectivities were observed for additions to other
cyclohexanones with an exocyclic alkylidene substituent. Additions of
allylmagnesium reagents to ketone 498 occurred with the
highest stereoselectivities of the nucleophiles examined (Scheme 194).333 The low yields observed for the
other reagents reflect significant amounts of 1,4-addition, which was
not observed for allylmagnesium reagents. Allylmagnesium reagents are
generally more prone than other organomagnesium reagents to 1,2-addition
than conjugate addition to unsaturated systems,19,334–336 which is consistent with the mechanistic analysis
that they undergo addition through six-membered ring transition states
with allylic transposition.18 The favored mode of addition in these cases was
attributed to the goal of minimizing torsional strain upon nucleophilic
attack (transition state 500), and it was argued that the
six-membered ring transition state for allylation minimized the steric
size of the allyl group. A related unsaturated cyclohexanone was also
observed to react with high diastereoselectivity with allylmagnesium
reagents with a similar sense of selectivity (Scheme 195).337 The ring likely adopts the conformer
503 to minimize allylic strain interactions that would
be found in conformer 504, and addition to minimize
torsional interactions would occur from the axial face.</p><!><p>The literature on additions to five-membered ring ketones with
substituents at C-2 is somewhat inconsistent. Cyclopentanones are
considerably puckered,338 so controlling diastereoselectivity is possible by
differentiating the two faces of the carbonyl group should be possible,
just as it is for cyclohexanones. Additions of some nucleophiles to
2-methylcyclopentanone (505) can be selective, whereas
others may not be (Scheme
196).71,339–341</p><p>Chelation-controlled additions also seem to proceed with little
selectivity (Scheme
197).341,342
More recent examples show that methylation306 proceeded with lower
selectivity than allylation (Scheme
198).343
Nevertheless, some additions of vinyllithium reagents to five-membered
ketones can be diastereoselective, even in highly functionalized
systems.344</p><p>Additions to cyclopentanone derivative 513
illustrate some general trends (Scheme
199).313
Additions can be highly stereoselective, but they often need to be
optimized for the appropriate choice of metal nucleophile. On the other
hand, allylmagnesium reagents add readily with high stereoselectivity.
Some Grignard reagents required transmetallation with CeCl3
to afford product. Similar cyclopentanones with pendant aryl-substituted
alkyl groups show similar trends.315 A 2-aryl-substituted cyclopentanone has been
shown to undergo highly stereoselective allylation (Scheme 200).345</p><p>The additions of nucleophiles to ketone 517
illustrate how phosphoryl groups can be used to obtain high
diastereoselectivity in some cases (Scheme 201).346 Yields could be improved by first pre-mixing the
Grignard reagent with BF3•Et2 prior to
adding the ketone or using an allylzinc reagent, but, in the case of the
cyclopentanone 517, addition of allylmagnesium itself was
efficient. The steric influence of the phosphoryl group was also
observed for six-membered ring ketones, forming products
519 and 520 as the major diastereomers. As
an indication of the atypical reactivity of allylic organomagnesium
reagents, the less reactive methyl, phenyl, and vinyl Grignard reagents
only gave the products in small amounts under any conditions.
Benzylmagnesium bromide also underwent addition, but not as efficiently
as allylmagnesium chloride did.</p><p>The selectivity for additions of allylmagnesium reagents to
2-substituted cyclopentanones is evident in more complex settings.
Geminally substituted ketone 521 reacted stereoselectively
with allylmagnesium bromide to give alcohol 522 (Scheme 202).347 This compound was used in a
synthesis of a natural product. Addition likely occurred from the more
accessible face of the equatorial conformer, as illustrated in
transition state 523.</p><p>The presence of geminal stereocenters at C-2, however, can lead
to low selectivity (Scheme
203).311 This trend is similar to what had been observed in
the six-membered ring analogue of ketone 524 (i.e., ketone
442, Scheme
175), in which most organomagnesium reagents reacted with high
selectivity, but allylmagnesium reagents showed lower selectivity.</p><p>A benzo-fused cyclopentanone with a geminally substituted
stereocenter underwent highly selective additions with alkyl- and
allylmagnesium halides (Scheme
204).348
It was suggested that the stereoselectivity arose from chelation between
the ketone carbonyl group and the hindered carboalkoxyl group, so
nucleophilic attack occurred from the face opposite the CF3
group. This selectivity, however, should be compared to the
Felkin–Anh-selective additions to similar indanone derivatives
with an SCF3 group, in which allylation proceeded with low
diastereoselectivity (Scheme 122,
Section 5.4).</p><!><p>The few reports available for additions of allylmagnesium
nucleophiles to 3-substituted cyclopentanones show little selectivity
for these reactions (Scheme
205).349,350
Similarly, additions of propylmagnesium bromide yielded a 55:45 mixture
of stereoisomers.274
Additions of alkyllithium reagents to related substrates were also
unselective.351 More highly substituted cyclopentanones with only
one stereogenic center also did not undergo highly stereoselective
additions (Scheme 206).352</p><p>In the case of a cyclopentanone fused to an aromatic ring,
stereoselectivity depended upon the nucleophile (Scheme 207).353 Addition of vinylmagnesium bromide occurred
with high diastereoselectivity, presumably because the diastereotopic
faces were significantly differentiated because of the ring fusion.
Allylmagnesium bromide, however, added with little
stereoselectivity.</p><!><p>Selectivity tends to be higher in cases where the ketone is
more substituted, regardless of ring size. For example, addition of
allylmagnesium chloride to a cyclopentanone with several potentially
chelating groups occurred with high stereoselectivity (Scheme 103 and 104, Section
4.3.2). Another example of the reactivity of allylmagnesium
reagents to a highly substituted cyclopentanone is illustrated by
reactions of ketone 534, which were examined in the course
of a synthesis of diterpenes (Scheme
208).354
Addition of an excess of allylmagnesium chloride formed the diol
535 as a mixture of diastereomers. The authors remarked
that 10–20% of other compounds were separated from the major
products, and these compounds were suspected to possess different
configurations at the tertiary hydroxyl group (i.e., not complete
selectivity of addition of the allylmagnesium reagent to the ketone
functional group). It is worth noting, however, that other authors had
difficulty even adding other types of carbon nucleophiles to ketones
resembling 534, being successful only with sterically small
alkynylcerium reagents.355</p><p>Selective allylations can be complicated when taking into
account the similar reactivity of allylmagnesium reagents with
electrophiles such as esters, aldehydes, and ketones.17 This selectivity has
been achieved in carbohydrate systems with the use of a cerium reagent
(Scheme 209).356 The similarity in
outcome to the previously described system is notable (Scheme 103, Section 4.3.2), but no experiments without cerium
salts were reported using ketone 536. The benzoyl group at
the anomeric center migrated to the newly formed tertiary hydroxyl
group, which resulted in having to re-protect the now epimerized
anomeric center.</p><p>A reaction with a highly hindered five-membered ring ketone
illustrates the utility of the high reactivity of allylmagnesium
reagents (Scheme 210).357 Attempted additions
of other carbon nucleophiles under a variety of conditions gave no
addition products. Addition of allylmagnesium chloride, however,
occurred at −78 °C to give the adduct as a single
stereoisomer. The selectivity can be understood as involving
nucleophilic attack from the top face of a low energy conformer of the
ketone similar to that illustrated in Scheme 202 above.</p><!><p>As noted in the section describing chelation-controlled additions in
cyclobutanones (Section 4.3.3), additions
of allylmagnesium reagents to 3-substituted cyclobutanones proceed with low
stereoselectivity. When a stereocenter is adjacent to the carbonyl group,
however, these reactions can be stereoselective. For example, addition of
allylmagnesium reagents to cyclobutanone 540 occurred with high
anti selectivity (Scheme 211).358 This stereoselectivity is
not general, however: related examples proceed with low diastereoselectivity
(Scheme 212).359 Other authors report mixtures of
stereoisomers upon additions of Grignard and organolithium reagents to such
cyclobutanones.360
Some additions of Grignard reagents, however, proceeded with high
diastereoselectivity provided that the two groups on the ring are sufficiently
different in size (Scheme 213).361</p><p>Reactions of cyclobutanediones proceed with some stereoselectivity. In
the course of developing routes to terpene natural products, addition of
allylmagnesium bromide to dione 547, prepared in situ from diol
546, gave mostly the cis-substituted products 548
and 549 (Scheme
214).362 The
major adduct involved addition of the two allyl groups anti to the alkoxymethyl
groups but syn to each other. This outcome could result from the conformational
preferences of the starting ketone. The initial cyclobutanedione might be
expected to adopt a conformation where a resident alkoxy group is positioned
near the carbonyl group to maximize electrostatic effects.363 This hypothesis is supported by X-ray
crystal structures of alkoxyalkyl-substituted cyclobutanones, which adopt
conformations where the alkoxy groups approach the carbonyl carbon
atoms.364–366 As a result, addition should
occur from the face that is more exposed (i.e., away from the alkoxyalkyl group)
as illustrated for transition structure 551 (Scheme 215). Once the first addition occurred, the
resulting OMgBr group could form a chelate with the second carbonyl group
(552). Addition to the second carbonyl group in the molecule
would now be slower, considering that the molecule has negative charge. This
addition could be slower than the diffusion rate limit, which would then allow
the chelation to accelerate the addition (Section
4.1). That chelation would give the cis relationship between the two
allyl groups. In the course of using these reactions in target-directed
synthesis, it was noted that diastereoselectivity was higher using a substituted
benzyl protecting group (Scheme
216).367</p><!><p>In general, additions of Grignard and alkyllithium reagents to
2-substituted cycloheptanones are highly stereoselective.368 This selectivity arises because
additions avoid developing torsional strain in the transition state.368 Steric effects might also
discourage attack from the face nearer to a substituent.</p><p>Allylmagnesium reagents also add to cycloheptanones with high
diastereoselectivity. The results in Schemes
217315 and 218313 contrast with the low stereoselectivities observed for
some additions of allylmagnesium reagents to 2-substituted five- and
six-membered ring ketones (Sections
6.2.1.3 and 6.2.2.1,
respectively). As with those other types of ketones, allylmagnesium reagents
generally added more smoothly without the need to transmetallate to other metals
such as cerium.</p><p>In contrast to additions to monosubstituted cycloheptanones, additions
of Grignard reagents to 2,2-disubstituted cycloheptanones proceeded with
generally low stereoselectivity, not just for allylmagnesium reagents (Scheme 219).311 Selectivities for additions to ketone
561 are lower than for the analogous six- and five-membered
ring (Schemes 175, 176 and 203,
respectively). The added flexibility of the seven-membered ring might contribute
to this decreased selectivity.</p><p>A geminally disubstituted cycloheptanone fused to an aromatic ring,
however, underwent highly stereoselective allylation (Scheme 220).369 No explanation was given for why this reaction was
stereoselective, nor was a comment made regarding why cerium salts were used,
which are often used to suppress enolization or conjugate addition.370 The X-ray crystal structure
of alcohol 564, however, provides some insight into the overall
structure of this ring system. The lowest energy conformation of the ketone
563 likely resembles 565, where the branched group
blocks the lower face. Nucleophilic attack from the more exposed top face would
lead to the observed product.</p><p>Additions of allylmagnesium reagents to disubstituted cycloheptanones
can show some selectivity. The allylation of 2,3-disubstituted isomer
566 (Scheme
221)327 formed
the product expected for additions to a 2-substituted cycloheptanone.368 The magnitude of the
diastereoselectivity matches the selectivity observed for additions to a similar
trans-substituted cyclohexanone (Scheme
188).</p><p>Addition of allylmagnesium bromide to a cis-2,7-disubstituted
cycloheptanone was diastereoselective (Scheme
222).371 Ketone
568 was isolated as a mixture of diastereomers (80:20), with
the major isomer characterized as the cis isomer. Addition of allylmagnesium
bromide to that mixture gave one major isomer of product, identified by the
authors as 569 because the allyl group should have added opposite
to the two methyl groups. The minor isomer, 570, was assigned as
the product arising from the minor amount of trans-substituted ketone present in
the starting material.</p><p>As observed for a geminally substituted seven-membered ring ketone
fused to an aromatic ring (Scheme 220),
addition of allylmagnesium chloride to a vicinally substituted cycloheptanone
fused to an aromatic ring occurred with high diastereoselectivity (Scheme 223).372 By comparison, addition to a related
five-membered ring ketone exhibited low stereoselectivity (Scheme 207).</p><p>The reactivity of a highly substituted seven-membered ring ketone
illustrates the high selectivity that can be observed with allylmagnesium
reagents even when other reagents do not add (Scheme 224).373
Addition of allylmagnesium chloride to ketone 573 at −98
°C gave predominately one stereoisomer of tertiary alcohol
574. The selectivity can be explained by considering the X-ray
crystal structure of ketone 573, which resembles conformer
575. The one face is blocked by one of the large
tert-butyl groups, so attack occurred from the other face.
It was noted that other Grignard reagents did not react with ketone
573; only reactions of allylmagnesium and LiAlH4
were observed, which is in accordance with the high reactivity of allylmagnesium
reagents.</p><!><p>Nucleophilic additions to substituted cyclooctanones are not common
reactions. Felkin–Anh type additions of organometallic reagents have been
observed for cyclooctanones with α-SPh groups,374 but few examples of additions to
alkyl-substituted cyclooctanones have been reported.375,376 Such reactions can be stereoselective: addition of an
alkenyllithium reagent to a 2-substituted cyclooctanone proceeded with high
selectively, although the yield was not reported (Scheme 225).377</p><p>Few examples of allylations of substituted cyclooctanones have been
reported. Addition of allylmagnesium chloride to a 2,3-disubstituted
cyclooctanone gave low stereoselectivity, (Scheme 226), which was slightly lower selectivity than observed for
the seven-membered ring system (Scheme
221).327 Across
this series of six- to seven- to eight-membered rings, the selectivity for
allylation gradually decreased.327 Similarly, reactions of 3-alkoxy-substituted
cyclooctanones were not selective with any nucleophile, including allylmagnesium
halides (Scheme 227).378 The generally low
stereoselectivity in these substrates may reflect the number of potential
conformers of a substituted cyclooctanone,379 which could allow nucleophiles to approach both faces
of the carbonyl group.</p><p>Reactions of conformationally constrained eight-membered ring ketones
illustrate the relationship between the topography of an electrophile and the
stereoselectivities of its reactions (Scheme
228).380 Two
related ketones, 584 and 586, differing only in a
substituent on an sp2-hybridized carbon atom, gave products with the
opposite configuration upon exposure to nucleophiles. The difference in
stereochemical outcomes can be traced to the conformational preferences of the
starting ketone, as determined by X-ray crystallography. In the case of ketone
584, the conformer 588 with the Ph group
equatorial was favored. Increasing the steric size of the group from
SiMe3 to tert-butyl, however, changed the
conformational preference to favor the pseudoaxial ketone 589 to
minimize allylic strain. In both cases, nucleophilic attack from the more
exposed convex face would lead to the observed products. The additions of the
nucleophiles, therefore, involve identifying which face of the ketone is more
exposed, as required by a steric approach control argument. The results with
allylmagnesium halide can be explained by considering that even particularly
fast reactions should also be governed by the relative ability of the
nucleophile to approach the carbonyl group from the different faces.</p><p>Additions to another eight-membered ring electrophile emphasize the
importance of the conformation of a medium-sized ring and the stereochemical
courses of its reactions.269
Although not an addition to a ketone, addition of allylmagnesium halides to the
eight-membered ring bis(imine) 590 was controlled by the ability of
the nucleophile to approach the electrophile (Scheme 229). The low energy conformation of the ring of
590 differentiates the faces of the ring, and nucleophiles can
only add from the convex face.381 This substrate was prone to additions under
single-electron additions, which could be operative in this case. It is worth
noting, however, that addition of tert-butylmagnesium halides
led to no reaction, but allylation was clean and highly diastereoselective.</p><!><p>The same conformational control of stereoselective allylation can be
observed in a conformationally constrained nine-membered ring
trans-alkene with an endocyclic carbonyl group (Scheme 226).382 Addition of allylmagnesium chloride to
either chiral, optically active alkene 592 or its derived epoxide
594 occurred with high diastereoselectivity. This
stereochemical course can be explained by involving addition to the more exposed
convex face of the chiral ketone. Reduction with NaBH4 also occurred
from the same face.</p><!><p>As substrates become more complex by involving more rings, it becomes
more difficult to categorize the type of substrate involved. The following
sections focus on reactions of cyclic ketones where another ring is fused to it
adjacent to the carbonyl group, where the ring is bridged, or where there are
multiple rings involved. Readers wishing to know whether a planned addition of
allylmagnesium to a cyclic ketone bearing other rings might be stereoselective
should consult all sections to identify the best analogies to any proposed
system.</p><!><p>Reactions of a cyclohexanone with a fused epoxide ring (i.e., a
fused [4.1.0]-bicyclic system) can lead to high diastereoselectivity for
additions of various organometallic reagents (Scheme 231).383 With all nucleophiles examined, including
allylmagnesium bromide, a single stereoisomer of product was formed.
Other authors have observed similar selectivities with additions of
nucleophiles to other epoxy ketones,384 although reactions of other
epoxy ketones show low diastereoselectivity.385 This phenomenon was also
observed for fused cyclopentanones (as will be shown in Section 6.7.1.2). The selectivity
could result from attack from the more exposed convex face of the highly
substituted fused bicyclic ring system. Electronic influences of the
nearby epoxide ring cannot be discounted, although in general
α,β-epoxy carbonyl compounds do not undergo highly
diastereoselective addition reactions.386,387</p><p>Addition of an excess of allylmagnesium bromide to the highly
substituted epoxy ketone 598 gave a single stereoisomer of
the adduct 599 (Scheme
232).388.
As with the above example (Scheme
231), the nucleophile added from the convex face. The authors
proposed that a chelating interaction resembling 600 was
responsible for selectivity. Such a chelated intermediate need not be
invoked to explain the observed stereochemistry, however, considering
the results shown in Scheme
231.</p><p>Additions to ketones residing in a cis-fused decalin-like ring
system gave high stereoselectivity (Scheme 233).389 Addition occurred exclusively from the more
accessible convex face of the fused system.</p><p>Additions of organometallic reagents to trans-fused
decalin-derived ketones generally occur from the equatorial face. For
example, addition of allylmagnesium bromide to the simple decalinone
603 gave the equatorial addition product as the major
product (Scheme 234).282 The magnitude of
this selectivity is not significantly different from selectivities
observed for additions of methyllithium and methylmagnesium iodide
(Scheme 235), showing a
general preference for equatorial attack.390 The same preference for
equatorial attack on a trans-decalin system was observed for addition of
allylmagnesium bromide in a more highly substituted case (Scheme 236).391</p><p>Attempts to obtain chelation-controlled allylation of a fused
six-membered ring ketone were particularly difficult (Scheme 237).392 It was noted that the
selectivity was sensitive to the amount of the ether that was present in
the solutions of Grignard reagent employed. The reaction was optimized
by removing all ether and performing the reaction in a mixture of
toluene and CH2Cl2. Even so, only modest
stereoselectivity was observed. The stereochemical outcome of this
reaction was explained by considering a fused-ring chelate
610. As noted in Section
4.1, however, control of addition of allylmagnesium reagents
by chelation is not as straightforward as chelation-controlled additions
for other organomagnesium reagents.</p><p>The stereoselectivities of allylations of related fused
six-membered ring ketones are highly sensitive to the precise structure
of the fused ring (Schemes
238–240).10,392
With the cis ring fusion in acetonide 611, addition gave
high selectivity for addition from the convex face by transition state
613 (Scheme
238). In the case of another highly substituted fused
cyclohexanone, additions were generally highly stereoselective for all
organomagnesium reagents examined (Scheme 239). This selectivity was independent of protecting
group at the adjacent α-oxygen atom (Scheme 240).</p><p>Allylation of a simple fused enone 618 shows the
utility of allylmagnesium reagents in certain settings (Scheme 241).393 Initially, this reaction was
attempted using allylsilanes or allylstannanes in the presence of a
Lewis acid. Those efforts, however, led only to deprotection of the
acetal. Addition of allylmagnesium chloride, however, proceeded in high
yield with a level of diastereoselectivity that allowed for completion
of the synthesis of a natural product.</p><p>Additions to other fused cyclohexenones gave similar
stereoselectivities, even with other organometallic reagents. For
example, allylation of cholest-3-one (620) gave the
β-allylated product with 86:14 selectivity, although no reaction
conditions were provided (Scheme
242).286
Addition of a vinyl anion derived from a glucal gave similar
selectivities for alcohol 622 (the figure in this paper
shows the opposite configuration C-14, but this figure is likely to be a
typographical error considering that 4-cholestene-3-one 620
was used as the starting material for the synthesis of
622).394</p><p>Reactions of a fused-ring vinylogous amide illustrate the high
reactivity of allylmagnesium reagents (Scheme 243).395 Whereas additions of allyltrimethylsilane and
allyltributylstannane in the presence of Lewis acids resulted in no
reaction, addition of allylmagnesium reagents were successful, although
details of this experiment were not provided. The use of allylic
cuprates gave the 1,4-products as a mixture of diastereomers. Conjugate
addition was ultimately successful using the more reactive396
methallyltributylstannane reagent with the iminium ion 625
generated in situ.</p><p>A related highly conjugated fused cyclohexanone underwent
highly stereoselective additions with all organometallic reagents,
including allylmagnesium halides (Scheme
244).397
This stereoselectivity can be attributed to the steric congestion at the
carbonyl group so that additions of allylmagnesium reagents are unlikely
to occur at rates approaching the diffusion rate limit. Attack from the
more accessible face of the ketone, as illustrated in transition state
629, would lead to the observed product.</p><p>Reactions of a series of highly substituted steroid derivatives
with the carbonyl group in the B ring occurred with high
stereoselectivity. With a relatively simple ketone, addition from the
more accessible α-face proceeded with modest selectivity (Scheme 245).398 Under these conditions,
addition to the acetoxy group likely also occurred to remove the
protecting group, considering that additions of allylmagnesium reagents
to ketones and esters occur at competitive reaction rates (Scheme 12, Section 2.2). With the more substituted ketone
632, however, addition was more stereoselective (Scheme 246).399 The origin of this increased
stereoselectivity is not obvious considering the structural similarity
between the two compounds. Similar diastereoselectivities were reported
for the formation of products 634 and 635.</p><p>Fusion of a six-membered ring ketone to a six-membered ring
does not guarantee a stereoselective addition, however (Scheme 247).400 It is likely that ketone
636 is too flat to provide much differentiation between
its diastereotopic faces. Conversely, addition to the ketone
638 was highly stereoselective at the newly formed
stereogenic center. The carbonyl group that was attacked in this
substrate is considerably more sterically congested, as evidenced by the
low conversion to product upon addition of the nucleophile. This steric
congestion likely prevents attack from the top face of the carbonyl
group, leading to high diastereoselectivity.</p><!><p>In contrast to reactions of fused six-membered ring ketones,
additions of allylmagnesium reagents to fused five-membered ring systems
have been studied less. One example, shown in Scheme 248,384 is analogous to observations for a
six-membered ring fused system (Schemes
231–232, Section 6.7.1.1). Reactions of other
Grignard reagents with ketone 640 gave similar
diastereoselectivities.</p><p>In the case of a multiply fused system, addition of
allylmagnesium bromide was highly stereoselective (Scheme 249).401 The nucleophile approached ketone
642 from the side opposite to the fusion with the
five-membered ring compared to the fusion with the four-membered ring,
as illustrated in transition state 644. It is worth noting
that the acyloxy group was also attacked by the reagent, as expected
based upon the similar rates of additions of allylmagnesium reagents to
ketones and esters (Scheme 12,
Section 2.2).</p><p>Cis-fused cyclopentanone 645 underwent additions
with generally low diastereoselectivity for a number of organometallic
reagents (Scheme 250).402 Computational
studies suggested that lack of stereoselectivity in this case was the
result of two modes of attack that could occur with similar rate
constants. Attack from the exposed convex top face was expected for
ketone 645 considering the highly stereoselective addition
to fused cyclopentanone 647, which cannot chelate (Scheme 251). For ketone
645, however, it is possible that chelation to the
methoxy group would promote addition from the more congested concave
face. This chelation would involve a group at the γ-position,
which is an unusual mode of chelation control that does not generally
proceed with high stereoselectivity with magnesium reagents.403 Nevertheless, this
mode of chelation might compete with the inherent preference for
addition from the convex face, leading to an unselective reaction.</p><p>Steroid-derived fused cyclopentanones underwent highly
diastereoselective reactions. Addition of allylmagnesium reagents
occurred in a 1,2-fashion to enone 649 to give the
α-allylated product 650 (Scheme 252).404 In later studies, it was found that
selectivities for the 1,2-addition products were higher when these
reagents were transmetallated to form the allylaluminum reagents (Scheme 253).405 High diastereoselectivity was
observed for addition of these reagents from the α-face. These
selectivities can be understood by examining the conformation about the
enone ring. Attack from the β-face is blocked by the axial methyl
group, so attack should be favored from the α-face (as
illustrated by transition state 655, Scheme 254).</p><!><p>Additions of allylmagnesium nucleophiles to bridged bicyclic ketones
are generally diastereoselective. Because of the bridges of these compounds,
they tend to be more sterically crowded than other ketones, with interactions
resembling eclipsed or syn-pentane interactions developing upon
addition from any face. These reactions are also not likely to occur at rates
approaching the diffusion rate limit considering how sterically congested they
are.17,23 The stereochemical preferences in these
cases are relatively easy to predict and explain as occurring by preferential
attack from what appears, at first glance, to be the more sterically accessible
diastereotopic face.</p><!><p>Additions to ketone 656 illustrate the generally high
selectivity observed for additions of allylmagnesium halides to bridged
bicyclic ketones with the carbonyl group in the one-carbon bridge (Scheme 255). In the course of a natural
product synthesis, the allylation of ketone 656 was shown to
proceed with preferential addition over the more flattened, less sterically
encumbered face bearing the carbon–carbon double bond.406 It was essential in this
case to install an allyl group, which was later elaborated to a
tetrahydrofuran moiety by a hydroboration and oxidation sequence.</p><p>Similar additions to hindered bicyclic ketone 658 gave
highly diastereoselective additions (Scheme
256).13 Under
these conditions, the ester group was also removed, as would be expected
from rapid addition also to this carbonyl group, as discussed in Section 2.2. Just as for ketone
656, attack occurred over the less hindered, more flattened
bridge bearing one trigonal carbon atom. Similar observations were made with
a related ketone 660 (Scheme
257).</p><p>Experiments conducted in the course of developing a library
synthesis using microfluidics technology provide valuable insight into
reactions of bicyclic ketones and illustrate the unique reactivity of
allylmagnesium reagents (Scheme
258).12
Addition of alkyl-, alkenyl-, or arylmagnesium bromides to dione
662 gave only addition to the enone portion of the
molecule. Addition occurred from the face with the smaller, less sterically
demanding bridge (additions to ketones in longer bridges will be discussed
in detail in the next section). No addition occurred at the bridging
carbonyl group, however, indicating that additions to this carbonyl group
are relatively slow.</p><p>When a smaller nucleophile, an alkynylmagnesium reagent, was
employed, addition to ketone 662 occurred to one or the other
but not both of the two carbonyl groups (Scheme 259). This result suggests that steric approach had
determined the diastereoselectivity. It is worth noting that the
alkynylmagnesium reagent added only to one of the carbonyl groups of
662 and that addition occurred to the bridging carbonyl
group from the less sterically encumbered face, again on the side with the
trigonal planar carbon atoms. It is likely that once addition occurred to
the bridging carbonyl group, it is not possible to add a second equivalent
of reagent to the enone portion of the magnesium alkoxide 666
because both faces are sterically congested.</p><p>Addition of allylmagnesium bromide to ketone 662 gave
completely different results (Scheme
260). This reaction gave diol 667, which resulted
from addition to both carbonyl groups. Allylmagnesium bromide was the only
nucleophile that added to both carbonyl groups. The configuration of
667, particularly on the one-carbon bridge, suggests that
addition occurs in a specific order. Addition must first occur to the enone
functional group from the less hindered face to give alkoxide
668. The subsequent step would involve allylation at the
bridgehead carbonyl group. That the second addition does not occur near the
trigonal planar atoms, as it had with the propargyl nucleophile (Scheme 259), may result because of the
added hindrance of the endo allyl group. This argument is
supported by the observation that addition of allylmagnesium bromide to
ketone 669 (Scheme 261)
occurred with the same sense of stereoselectivity as the second addition
illustrated in Scheme 260.</p><p>Not all additions to bridging carbonyl groups are stereoselective.
In the course of a synthesis of an alkaloid, addition to ketone
671 was observed to occur with low stereoselectivity (Scheme 262).16 No comment was made regarding the
choice of CH2Cl2 as the solvent, although the use of a
non-coordinating solvent suggests that the authors were attempting to
encourage chelation control.22 The low stereoselectivity observed is likely due to the
fact that the two faces are not sterically strongly differentiated. Despite
the low stereoselectivity, the allyl group was essential to the synthesis
because it was converted to a carbonyl group that could be used for fragment
coupling.</p><p>Similar issues of stereoselectivity were observed for bicyclic
ketone 673, which also point to an issue of the heightened
reactivity of allylmagnesium reagents (Schemes 263 and 264).407
Addition of ethylmagnesium bromide occurred slowly at low temperatures
(−65 °C), so the reaction mixture needed to be warmed (Scheme 263). This higher temperature,
however, caused some reduction to form alcohol 675, presumably
by β-hydrogen atom transfer from the ethylmagnesium bromide, which
can be a common pathway with hindered ketones and in certain
solvents.408,409 The presence of the
reduced products attests to the hindrance of the carbonyl group. The major
product was formed by addition over the more flattened fused aromatic ring.
By contrast, addition of allylmagnesium chloride occurred at
−78°C with relatively low diastereoselectivity (Scheme 264), a point the authors
suggest may be due to its enhanced reactivity (as noted in Section 2.2, reactivity-selectivity
correlations can only be expected as reaction rates approach the diffusion
limit244). The
temperature needed to be controlled carefully with allylmagnesium reagents,
however. If the reaction mixture were warmed to −25 °C, the
product 677 was formed. This product results from both addition
to the carbonyl group and addition to the pyridine ring, resulting in a
nucleophilic aromatic substitution. As with the previous example, the allyl
group was necessary to complete the synthesis, because it was used to form a
ring to the nitrogen atom attached at the bridgehead carbon atom.</p><p>A similar substrate with a saturated ring also exhibited similar
low stereoselectivity.(Scheme
265).410
The allyl group was used for a similar annulation protocol to form an
additional ring.</p><p>The reactions of the highly hindered bridged ketone
680 provide other examples of the dramatic differences of
reactions with allylmagnesium halides compared to other reagents (Scheme 266).411 Addition of the Grignard reagent
substituted with the OMgCl group gave preferential attack from the face
bearing the two oxygen atoms poised to engage in chelation. Allylmagnesium
bromide, on the other hand, added from the more accessible face that would
develop fewer 1,3-diaxial interactions, as might be expected from such a
highly reactive reagent. It should be noted that hydride reagents, including
Zn(BH4)2, attacked from the same face as
allylmagnesium bromide. The lack of chelation control with the zinc reducing
reagent is different than its usual reactivity.412,413</p><!><p>The archetypal bridged bicyclic system is the
[2.2.1]-bicycloheptane system possessed by compounds such as camphor. The
inherent selectivity of this system, however, is best illustrated by
norcamphor (683), without the additional steric hindrance found
in the terpene. In this case, addition occurred with high
diastereoselectivity from the shorter, less sterically imposing bridge
(Scheme 267).414 That this reaction is
stereoselective argues that it is also not a reaction under diffusion
control. This view is supported by the observation that this mode of
stereoselectivity can be seen for additions of other organomagnesium
reagents (Scheme 268).415</p><p>The same sense of diastereoselectivity was observed for a
derivative of norcamphor (686, Scheme 269).416 The addition of these two methyl groups had no
influence on the sense of stereoselectivity</p><p>Additions to the even more hindered ketone fenchone
(29) provide useful information. In this case,
allylmagnesium reagents added again from the face opposite to the small
bridge, as observed for norcamphor (Scheme
270).417,418 In this case, reactions
of allylmagnesium operate at rates below the diffusion rate limit17,23 through the six-membered ring transition state with
allylic transposition (i.e., 14, Section 2.1).23 On the other hand, addition of prenylmagnesium chloride
occurred with high regioselectivity, favoring the product of addition at the
α-carbon atom of the reagent, likely because addition at the
γ-carbon atom is too sterically hindered (Scheme 271).23</p><p>Nucleophilic additions to camphor occur with the opposite
stereoselectivity, and this trend is general for a number of organometallic
reagents (Scheme 272).419 In the original paper,
the identity of the halide ion used was not given, but that has not
generally been seen to affect selectivity even for phenomena such as
chelation control, which might be more sensitive to the
counterion.22 The
high selectivity for the allylation of camphor has been confirmed by many
researchers, even for substituted allylic organomagnesium reagents (for
example, Scheme 273418).17,23,282,319,420,421 The selectivity for this addition is the opposite
to that observed for norcamphor (Scheme
267–268). That
difference is likely because the one-carbon atom bridge is now sterically
demanding with the geminal substitution at this center. Control experiments
demonstrate that these reactions are not occurring at rates that approach
the diffusion rate limit,17 but still likely proceed through the six-membered ring
transition state with allylic transposition (i.e., 14, Section 2.1).23 Addition of a particularly large
organometallic nucleophile (Scheme
274) proceeded with lower diastereoselectivity,422 although with the same
sense as observed for additions of phenyl and naphthyl Grignard
reagents.423</p><p>The reactions of camphorthione 693 illustrate a unique
reactivity of allylmagnesium reagents compared to other organomagnesium
reagents (Scheme 275).424 Addition of
allylmagnesium bromide to thione 693 gave the
exo-allylated isomer, which appears to involve addition
from the more sterically hindered face. The mechanism of this reaction,
however, is different than additions to ketones. Addition appears to first
occur at the sulfur atom to form the anion 695, which then
undergoes a [2,3]-sigmatropic rearrangement leading to the final
product.425
Similarly, additions to thiofenchone (697) also occurred with
allylmagnesium reagents, whereas no reaction was observed with
isoprenylmagnesium bromide (Scheme
276). This observation is similar to the observation that
additions to thionolactones were much faster and cleaner with allylmagnesium
reagents than with other Grignard reagents.426</p><p>The selectivity for attack away from the geminally substituted
bridge of camphor is also manifested in homologated versions of camphor.
Addition of allylmagnesium chloride to homocamphor (699)
occurred with high diastereoselectivity (Scheme 277).427 The same stereochemical course was observed for its
hydroxylated variant (Scheme 278),
suggesting that chelation in this case does not play a significant role in
selectivity.428
That stereochemical course is also consistent for other organomagnesium
reagents and alkyllithium reagents.</p><p>Even when the carbonyl group is not adjacent to the bridgehead
atoms, additions can be highly stereoselective, even with allylmagnesium
reagents. This point is illustrated with the bridged bicyclic ketones
703 (Scheme
279).429
In all cases, addition occurred from the exo face, on the
side of the shorter bridge, with high stereoselectivity. The stereochemical
courses of these reactions likely arise from preferential addition from the
face that minimizes developing syn-pentane interactions
with the bridges. The authors failed to observe additions of a number of
organometallic reagents, including alkyllithium reagents and organomagnesium
reagents, without the presence of CeCl3 as an additive, so these
additives were used in all cases. It should be noted that other
nucleophiles, such as allylstannanes, allylsilanes, allylindium reagents,
and Reformatsky reagents, failed to add to these ketones.</p><p>Other results indicate that addition of allylmagnesium reagents to
these bicyclic ketones are unlikely to require CeCl3 to observe
addition. For example, addition to the nitrogen-containing variant of these
compounds can be achieved with just allylmagnesium reagents, in high
stereoselectivity and in high yield (Scheme
280).430 The
introduction of an allyl group was necessary because it was subsequently
converted into a tetrahydrofuran ring. Other researchers have also used
additions of allylmagnesium reagents to ketones such as 707
because the products can be elaborated to form compounds related to natural
products (Scheme 281)431 or to pharmaceutical
agents.432</p><p>Several oxygen-containing bicyclic systems also underwent additions
of allylmagnesium reagents with high stereoselectivity. Addition to bicyclic
ketone 709 occurred from the same less-encumbered face (Scheme 282).433 Similar selectivity was observed
for bicyclic ketone 711 (Scheme
283).434</p><!><p>A family of oxygen-atom bridged bicyclic ketones was employed to
prepare a system of stabilized carbocations (Scheme 284).435 Because of the subsequent steps involved, the
configurations of the addition products were not described in detail.
Nevertheless, additions of allylmagnesium bromide occurred efficiently in a
number of cases. Addition of homoallylmagnesium bromide, unlike addition of
allylmagnesium bromide, was accomplished in the presence of a lanthanide
salt. Although no experiments were provided showing that these salts were
necessary, they are often used to improve the efficiency of additions to
hindered and enolizable ketones. 436</p><p>A multiply bridged system also gave reasonable selectivity for
additions, even with allylmagnesium reagents (Scheme 285).437 In this system, the nucleophile added from the
less sterically encumbered face away from the three-membered ring, as
illustrated in transition state 719. It is worth comparing the
selectivity in this series to the epoxide-fused ketones discussed earlier
(Schemes 231, 232, and 248), which occur with similar senses of
stereoselectivity.</p><!><p>This section collects examples that do not fit neatly into other cases.
These are multicyclic ketones where the carbonyl group may be considered simply
part of a fused ring or is part of a spiro ring, in a bridge of a series of
bicyclic rings, or even in an acyclic chain attached to a multicyclic framework.
As a result, these examples tend to be more associated with natural product
synthesis, so there may be fewer comparisons between additions of allyl groups
versus additions of alkyl groups if the allyl group were necessary for the
synthesis. These systems also tend to be highly sterically hindered, so rates of
reaction with allylmagnesium reagents are likely to be below the diffusion
limit, leading to stereoselective reactions.</p><!><p>Reactions of a hindered androstenone derivative with various
allylic organomagnesium reagents provide interesting mechanistic information
(Schemes 286–288).438 Addition of allylmagnesium reagents
occurred only from the relatively unhindered bottom face (as illustrated by
transition state 722, Scheme
286) compared to the top face, where addition would develop
syn-pentane interactions.</p><p>Additions of substituted allylic organomagnesium reagents give an
indication of how hindered even the bottom face is (Scheme 287).438 Addition of crotylmagnesium reagents occurred
exclusively from the bottom face, just as for allylmagnesium bromide. With
this reagent, however, reasonable selectivity was observed for the anti
stereoisomer 723. Normally, ketones need to be relatively
hindered and the two groups well differentiated to see high anti:syn
selectivity,278
suggesting that the bottom face is still sterically hindered. Upon
increasing the steric size of the group on the nucleophile to a phenyl
group, addition was slow and inefficient (Scheme 288). The major product, however, was the
α-isomer, 725. Experiments with prenylmagnesium bromide
(Me2C=CHCH2MgBr) showed similar trends of
increasing amounts of the α-isomer as steric hindrance
increases23 (as
illustrated in Scheme 271). Those
results were interpreted as reactions no longer following the six-membered
ring transition state with allylic rearrangement (i.e., they would follow
the same transition state as any other Grignard reagent, as discussed in
Section 2.1).23</p><p>Because alcohol 727 was an important precursor in the
pursuit of a natural product synthesis, efforts were focused on developing a
stereoselective addition of an allyl nucleophile to ketone 726
(Scheme 289).439 Inspection of molecular
models suggested that attack should occur from the more easily approached
bottom face. Allylmagnesium bromide, however, added with little selectivity,
although little experimental detail was provided. Ultimately, a chiral
organozinc reagent was employed to obtain the desired stereochemistry to
complete the synthesis (Scheme
290).440
As noted earlier (Section 4.2.5.1),
this strategy of using a chiral reagent is often the best solution in
difficult allylations. The use of an allylmetal reagent here was critical
because the allyl group was necessary for a subsequent anionic oxy-Cope
rearrangement,441
a powerful synthetic transformation in natural product synthesis.442</p><p>Cis-fused rings gave high selectivity for additions should the
carbonyl group be near the ring fusion. This point is illustrated for a
cyclohexanone fused to a five- and a seven-membered ring, which gave high
stereoselectivity for addition of allylmagnesium bromide from the more
accessible convex face (Scheme
291).443
This example also suggests that addition of allylmagnesium halides to
carbon–nitrogen double bonds are much slower than additions to
carbon–oxygen double bonds. A cycloheptanone fused cis to a
five-membered ring also reacted with high stereoselectivity (Scheme 292).16 Alcohol 731 was
prepared as part of a stereochemical proof of how all of the rings of a
natural product had been joined. Because alcohol 731 was not a
synthetic intermediate on the way to the final target, no details about this
reaction were given.</p><p>A cyclopentanone with sterically differentiated faces also
exhibited high stereoselectivity in the additions of allylmagnesium reagents
(Scheme 293).444 Stereoselective addition
to ketone 732 and subsequent intramolecular acyl transfer
formed carbamate 733 as a single stereoisomer. Addition was
completely stereoselective to the convex face, even with the free amino
group (734), as illustrated for the formation of alcohol
735. This allyl group was then used to anneal a
six-membered ring onto the five-membered ring in the context of a synthesis
of an alkaloid.</p><p>The reactions of a series of highly substituted ketones illustrate
the powerful influence of a cis fused ring to control additions of
allylmagnesium reagents from the convex face (Scheme 294).445 For enediones 736 and
738, addition of allylmagnesium bromide occurred opposite
to the cis-fused bicyclic system. It should be noted that, even after the
addition of the first allyl group, addition occurred from the same face (the
new OMgBr group did not provide enough impetus for chelation to occur). On
the other hand, for the more hindered dione 740, attack
occurred from the face opposite the more sterically demanding bicyclic
system. The authors used the combination of alkenes present in these diols
to perform ring-closing metathesis reactions to form multicyclic
products.</p><!><p>Multicyclic diones 742 and 744 are so
sterically congested that their reactions exhibit distinct selectivities
(Scheme 295).446 Addition to the
symmetric diketone 742 occurred to only one of the two carbonyl
groups even with an excess of reagent. The product was formed with high
diastereoselectivity, indicating that attack occurred from the face away
from the acetonide moiety at the top of the molecule. This stereochemical
course, however, was undesired for the intended application in
target-directed synthesis. Radical allylation was ultimately used to install
this allyl group with the correct configuration. At a later point in the
synthesis, the dione 744 was formed after introduction of the
2-propenyl group by addition of the corresponding organolithium reagent to a
ketone, and then 744 was subjected to allylation. This reaction
also involved attack away from the acetonide group, resulting in the
formation of diol 745. In a later key step, the two vicinal
allyl groups were subjected to ring-closing metathesis followed by
hydrogenation to form a fused cyclohexane ring.</p><p>Other multicyclic ketones underwent highly stereoselective
additions of nucleophiles, including allylmagnesium halides. Addition to
ketone 746 occurred from the convex face of this bicyclic
system (Scheme 296).434 A similar highly
substituted bridged system also gave high stereoselectivity (Scheme 297).447 The use of CeCl3 in this
reaction was not explained, although presumably it was employed to improve
the selectivity for 1,2-addition.316</p><p>A series of highly substituted bridged bicyclic compounds was
prepared that underwent highly stereoselective additions of allylmagnesium
reagents (Scheme 298).448 In all cases, addition
occurred from the more accessible face. The allyl groups were introduced
because subsequent ring-closing metathesis reactions led to highly caged
final products. It is worth noting the similarity in these structures
compared to other highly caged carbonyl compounds (Scheme 4, Section
1.1).8</p><!><p>Hindered spirocyclic ketones generally undergo highly
diastereoselective reactions because the carbonyl group is sterically
hindered. This hindrance leads to additions that are likely to occur at
rates that are below the diffusion limit. An example of this mode of attack
is shown in Scheme 299.449 Addition of
allylmagnesium bromide to the cyclopentanone 756 occurred with
complete stereoselectivity from the face opposite the
N–OBn group. Presumably the six-membered ring adopts
a conformation that places the silyloxyethyl side chain in an equatorial
position to minimize 1,3-diaxial interactions, which would position the
carbonyl group such that one face is blocked by the substituted nitrogen
atom (as in 758). The high selectivity in this case was
important to the synthesis of an alkaloid because the allyl group was needed
to close a five-membered ring with the nitrogen atom.</p><p>Reactions of the spirobicyclic ketone 759 illustrate
the unique reactivity of organomagnesium reagents (Scheme 300).450. Addition of allylmagnesium reagents to ketone
759 proceed with low selectivity, presumably from the face
away from any deprotonated nitrogen atom. Addition of the acetylide anion,
however, gave high stereoselectivity for addition to the opposite face of
the carbonyl group (i.e., from the same side as the nitrogen atom). This
change in selectivity was explained as due to the size of the reagents, but
the outcome may be the result of other factors. Addition of
2-propenylmagnesium bromide (or the corresponding organolithium reagent),
also a large reagent, occurred with the same stereoselectivity as observed
for the alkynyl anion, providing alcohol 761. These results may
implicate chelation between the reagent and the nitrogen atom in the case of
the alkynyl and propenyl reagents. As discussed in Section 4.1, allylmagnesium reagents are less
susceptible to stereochemical control by chelation.</p><p>A hindered spirocyclic cyclopentanone underwent highly
stereoselective allylation with allylmagnesium bromide (Scheme 301).451 The authors indicate that one stereoisomer of
product was formed in this reaction, but they do not indicate the
configuration. Conformational analysis for the ketone suggests that the
product should be formed by attack from the back side of the conformation
764, where the front face is blocked by the substituted
pyrrolidine. The carbonyl group of ketone 762 must be
particularly sterically hindered: it underwent a total of 17 synthetic steps
without need for protection. Among the conditions that this carbonyl group
survived included exposure to phosphonate anions, hindered borohydride
reducing agents, amines under reductive amination conditions, thiolate
anions, and MCPBA. Even with the highly reactive allylmagnesium reagent,
only slow conversion to the addition product was observed. Enolization,
however, could be a competitive process.</p><p>The selective additions of allylmagnesium reagents to spirocyclic
ketones is useful in natural product synthesis (Scheme 302).14 Addition of allylmagnesium bromide to ketone
765 formed a single stereoisomer of adduct
766, with addition occurring from the face opposite to the
nearby vinyl group. The allyl group was subsequently shortened to a
two-carbon tether by ozonolysis, and this tether was then used to form the
bridged bicyclic amine framework of the target molecules.</p><p>For the spirocyclic ketone 767, the carbonyl group is
hindered enough that it might be anticipated that additions would be
stereoselective (Scheme
303).452
Addition might be expected to occur from the face opposite to the
substituted carbon atom of the spirocyclic six-membered ring. In this case,
however, the ketone also contained a fused five-membered ring that will
exert strong control on selectivity, just as it did with the other
five-membered ring systems discussed above (Section 6.7.1.2). This effect appeared to be stronger: addition
occurred with complete stereoselectivity to form the product where addition
occurred from the face opposite to the adjacent fused ring, and thus toward
the more substituted carbon atom of the adjacent spiro ring. As with other
cases, the presence of an allyl group was required for the synthesis. It was
shortened by one atom by ozonolysis then connected to the protected
cyclohexanone ring by an intramolecular aldol addition.</p><p>Additions of Grignard reagents to a family of spirocyclic diones
raises questions about stereoselectivity that are difficult to address with
the available information (Scheme
304).453
Allylation of dione 769 provided a mixture of 1,3-diols
770 and 771. Previous experiments reported by
this group showed that the presence of the two trigonal carbon atoms in a
spirocyclic ring could influence stereoselectivity of additions of
methyllithium to ketones to moderate levels (approximately 85:15).454 This stereoselectivity,
however, did not hold true for the more complex double-addition of the
latter report. The reaction of the mono-addition product 773
appears to be contradictory (Scheme
305). This ketone, which was isolated from a mixture formed by
adding fewer equivalents of the reagent to ketone 769 and
isolating a small amount of it, gave, upon addition of the nucleophile,
exclusively 771, and not 770, after column
chromatography. This result indicates that diol 770, the
1,3-syn isomer, must come from the diastereoisomer of
773. That prediction is supported by a related system:
addition to vinylated ketone 774 gave the
1,3-syn product 775. The same low
selectivity observed with 769 was also observed with
776 and 779 (Scheme 306). These results reinforce the authors'
suggestion that electronic effects control addition to these
rings,454 but
they suggest that they operate only for the second addition and not for the
first addition, which occurred unselectively. It is also worth mentioning
that when vinylmagnesium bromide was added to the hindered mono-ketones,
CeCl3 needed to be added. These additions were not
diastereoselective (Scheme 307).</p><!><p>Although some examples of additions to carbonyl groups attached to
rings can be stereoselective, it is not clear that general trends can be
established. The difficulty in obtaining stereoselective additions to exocyclic
carbonyl groups is illustrated by additions explored in the course of a
synthesis of a terpene natural product.455 Model aldehyde 784 underwent additions of
allylmagnesium reagents with low stereoselectivity, but at least in the desired
sense (Scheme 308). The low selectivity
is consistent with the generally low stereoselectivity observed for additions to
aldehydes, which is the result of reaction rates approaching the diffusion limit
(as noted in Section 2.2). Addition of
allylzinc bromide gave the undesired stereochemical outcome, which was the only
product formed when an allyl silane was used as the nucleophile. Although the
use of the allylmagnesium reagent would have been ideal, the sensitivity of the
protecting scheme of the compound 787 used for the application in
synthesis (Scheme 309) required the use
of the zinc reagent (deprotection of the acetate would likely occur with
allylmagnesium halides, as discussed in Section
2.2). The low diastereoselectivity for this allylation was repaired
by subsequent oxidation of the resulting alcohol and reduction with
LiAlH4, which occurred with 81:19 diastereoselectivity.</p><p>A related substrate also showed little diastereoselectivity upon
addition of allylmagnesium bromide (Scheme
310).48 Whereas the
mixture of alcohols 790 could be separated chromatographically, the
authors found that it was easiest to separate diastereomeric alcohols
792 by silylation of the mixture of products. Only one of the
two diastereomers was silylated, leading to simple separation by
chromatography.</p><p>Generally, the additions of allylmagnesium reagents to such
cyclohexyl-substituted aldehydes are not stereoselective. For example, in the
process of developing potential drugs for the treatment of African sleeping
sickness, routes to prepare cyclic peroxides and related structures as libraries
of compounds were examined (Scheme
311).15 The
synthetic route included the additions of allylic magnesium reagents to
aldehydes such as 793 and 796. These reactions
proceeded with little stereoselectivity.</p><p>A comparison between different nucleophilic additions to an exocyclic
aldehyde is informative. Addition of vinylmagnesium chloride to an aldehyde
formed the allylic alcohol 13 as a single diastereomer (Scheme 312).456 That selectivity was explained by
invoking a long-range chelation with an OMgCl group, a species that, as
discussed above, can be effective in chelation (as discussed in Section 4.2.1.1). Chelation may not even be
necessary when considering that the low-energy conformation could be locked into
a conformer resembling 799 (Scheme
313) to avoid eclipsing interactions and
syn-pentane-like interactions. Regardless of the reason,
however, it is notable that addition of allylmagnesium bromide to a similar
aldehyde gave little selectivity for the desired isomer of alcohol
11 (Scheme
314).9
Selectivity was slightly improved by changing the solvent, but the ratios are
nevertheless much lower than for formation of 13. The difference
could result from the different sizes of the two groups (i.e., the
silyloxymethyl group in 13 compared to the alkynyl group in
(11). The relative populations of the two conformers could be
different considering the small size of the alkyne group.9 Nevertheless, addition of allylmagnesium
bromide did proceed with lower selectivity, thus complicating a synthetic
scheme.</p><p>Understanding whether a selective nucleophilic addition results from
chelation control or conformational control can be difficult. This issue is
illustrated by additions to the chiral glyceraldehyde derivative
801 (Scheme
315).457 As
noted in Section 4.2.4.3, additions to
glyceraldehyde derivatives are not particularly selective. Additions to aldehyde
801, however, were highly stereoselective for a number of
different organometallic reagents. The selectivity was attributed to chelation
to the endocyclic oxygen atom through a chelate resembling 803.
Such chelation should be enhanced considering that the non-polar solvent used
would not compete with the chelation structure, as discussed previously (Section 4.2.4.2).</p><p>An alternative argument, based upon steric approach control, can be
considered. The X-ray crystal structure of aldehyde 801 was
reported, and the aldehyde's conformation resembles the chelated form
803. This conformation is likely favored to minimize
destabilizing interactions between the nearby axial methoxy group and the
carbonyl oxygen atom (as shown in 804, Scheme 316). If this conformation were favored in
solution, even a diffusion-controlled reaction like addition of allylmagnesium
reagents should be highly stereoselective. The results with a related system
support this analysis. Additions to the acetal 806 proceeded with
generally lower stereoselectivity (Scheme
317).458 These
acetals lacked the axial OMe groups present in aldehyde 801. The
resulting stereoselectivities were somewhat lower, even under conditions
optimized for chelation. It is likely that even though chelation should be
favored using zinc atoms, the ring is less sterically constrained than for the
ketal illustrated in Scheme 315.</p><p>A chiral aldehyde with the formyl group appended to a spirobicyclic
system showed low stereoselectivity for allylation (Scheme 318).459 The stereoisomers could be separated, and the major
isomer underwent an arene-olefin photocycloaddition to construct much of the
core structure of a natural product. Recycling of the minor isomer was planned
using an inversion sequence after this step.</p><p>A ketone where the carbonyl group was exocyclic to a five-membered ring
also underwent addition with low stereoselectivity, although reaction conditions
were not provided (Scheme 319).460 The presence of the mixture
was unimportant considering that this stereocenter was later removed by
elimination.</p><p>Two related aldehydes appended to six-membered rings also underwent
reaction with allylmagnesium reagents with low stereoselectivity (Scheme 320).461 The lack of selectivity in the
allylation of aldehyde 812 was irrelevant because both isomers were
converted to the same final product with high stereoselectivity through an
anionic oxy-Cope rearrangement 441,442</p><p>Additions to cyclopropyl-substituted aldehydes also indicate the
difficulty of such additions (Scheme
321).462 The
low selectivity in this case is general for a number of different Grignard
reagents in both coordinating and non-coordinating solvents. The lack of
stereoselectivity can be explained by the competing transition states
illustrated in Scheme 322. Because the
group cis to the carbonyl group is small, diastereoselectivity is low because
both s-cis and s-trans-conformers are
populated, and they undergo additions to the carbonyl group from each face.
56</p><p>Additions to aldehydes appended to bridged systems generally do not
show high degrees of selectivity. For example, additions to α-bromo
aldehyde 820 were unselective (Scheme 323).463
Felkin–Anh selectivity was expected in this case due to the general
behavior of α-bromocarbonyl compounds.464,465 Instead, no selectivity was observed for the additions of
organomagnesium or organolithium reagents. The significantly different time
courses of the two experiments may suggest that the addition of allylmagnesium
bromide was faster, as would be expected (Section
2.2).</p><p>Even in a hindered exocyclic aldehyde, diastereoselectivity was modest
(Scheme 324).466 Addition to the hindered
β-alkoxy aldehyde 822 occurred with low
diastereoselectivity, which was established after conversion to the resulting
cyclic products by ring-closing metathesis. The aldehyde 822
resembles an aldehyde discussed earlier (Scheme
120). The resulting spirobicyclic compounds were designed to be
analogues of paclitaxel, and some analogues showed promising biological
activity.</p><p>A related bicyclic ketone also underwent allylation with modest
stereoselectivity, although the stereochemistry of the major isomer was not
determined (Scheme 325).467 As with the system described
in Scheme 324, the allyl group was used
in a fragmentation reaction. This reaction broke the bridged bicyclic system to
form a radical that closed on the allyl group, forming another ring.</p><!><p>An important example in additions to acyclic carbonyl compounds
underscores the importance of looking at the three-dimensional structure of a
carbonyl compound to determine which face may be more prone to attack by
nucleophiles (Scheme 326).468 This study showed that the
diastereoselectivities of additions of organometallic reagents to a family of
related ketones did not follow a simple pattern. Attempts to control the
stereoselectivity on a protected, acyclic, polyoxygenated ketone
(828) using chelation did not give good diastereoselectivity
for any reagent except the hindered reagent 2-propenylmagnesium bromide. Upon
changing the terminal protecting groups to acetonides, which were earlier shown
to give poor chelation-controlled selectivity in this system, and incorporating
an α-methoxy group adjacent to the carbonyl group (830),
poor selectivity was observed for all reagents (Scheme 327). Simply changing the protecting group at the
α-hydroxyl group to a benzyl group led to high stereoselectivity for all
reagents examined except allylmagnesium bromide (Scheme 328). This pattern of high selectivity for other Grignard
reagents but low selectivity for allylmagnesium halides is common, which, as
discussed in Section 2.2, may result
because the additions of this reagent occur near the diffusion rate limit and
thus are unlikely to occur diastereoselectively.</p><p>The results shown in Scheme 329,
however, complicate the analysis. With the progressively larger groups on the
α-oxygen atom of ketone 834, selectivity was high with every
reagent examined. It was necessary to have two acetonide protecting groups to
observe high selectivity with allylmagnesium bromide, but not for the other
Grignard reagents, which likely under went chelation-controlled additions to
α-alkoxy ketone 836 (Scheme
330).</p><p>The authors noted that their studies on this class of substrates
provided evidence that transition state models such as Felkin–Anh and
chelation-control do not entirely govern the stereoselectivity of reactions.
Instead, they interpreted the stereochemical course of these reactions to be
governed by the ground state conformations of each substrate and steric approach
control. This conclusion was supported by careful conformational analysis.
Benzoyl-protected ketone 834 adopts a rigid conformation, the same
in solution and in the solid phase, as illustrated in Scheme 331. That conformation exposes only one face of the
carbonyl group to nucleophilic attack. Consequently, high stereoselectivity was
observed for all nucleophiles, even for allylmagnesium bromide. This example
illustrates that the high reactivity of allylmagnesium reagents is not
incompatible with high selectivity.</p><p>Conformational effects and steric approach control could also operate
in reactions of an acyclic aldehyde (Schemes
332–333).469 Addition of allylmagnesium
bromide to the aldehyde 839 occurred with only modest
diastereoselectivity (Scheme 332).
Efforts to improve this stereoselectivity by using a chiral reagent were
modestly successful. By contrast, addition of allylmagnesium bromide to the
diastereomeric aldehyde 842 gave the product 843 as a
single diastereomer (Scheme 333). This
result cannot be readily accommodated by either the Felkin–Anh model or
the chelation-control model, which would depend principally upon the neighboring
stereocenters to control stereochemistry (and chelation-controlled additions of
allylmagnesium reagents with aldehydes are unlikely to be successful22).</p><p>Just as with the examples illustrated in Schemes 326–330, the analysis of the conformational preferences of these
aldehydes provides insight. Aldehyde 839, which reacts
unselectively, likely adopts a conformation resembling 844, with
the larger group placed in the position expected for a Felkin–Anh type
transition state (Scheme 334). This
conformation would also place the silyloxy group in the expected anti alignment
to minimize destabilizing dipole interactions,186 but that orientation places the large
alkyl group bearing R1 in the path of nucleophilic attack. The
alternative Felkin–Anh type transition state would minimize that
interaction but would not permit the minimization of unfavorable dipole
interactions. On the other hand, the other diastereomer of aldehyde
(842) would likely adopt a conformation resembling
845, which more closely resembles a Felkin–Anh
transition state and minimizes both unfavorable steric interactions and dipole
interactions. Support for this analysis can be found by analyzing an X-ray
crystal structure of a chiral β-silyloxy aldehyde with similar
substitution pattern (although different relative configuration at the
β-carbon atom); that aldehyde adopts a conformation resembling
845.470</p><p>Another reaction that might be governed by conformational preferences
and steric approach control is the addition of allylmagnesium bromide to ketone
846 (Scheme
335).471 The
identity of the solvent appears to influence the propensity of the magnesium
alkoxide intermediate to undergo an intramolecular nucleophilic substitution
reaction, but it does not affect the diastereoselectivity.</p><p>An analysis of the conformational preferences of this ketone suggest an
explanation for the diastereoselectivity. Silyl ethers often prefer different
conformations than alkyl ethers,472 and the presence of vicinal silyloxy groups could cause
them to orient themselves anti to each other.473–475 This strong conformational preference would control
the overall conformation of the molecule and thus the diastereoselectivity of
its addition reactions. Based on the crystal structure of an
α,β-bis(tert-butyldimethylsilyloxy)-substituted
ketone,476 a
conformation can be assigned to ketone 846 that minimizes steric
interactions (Scheme 336). Attack on
849 would be blocked from the front face by the silyloxy
groups, so attack from the more accessible back face would be favored, which
would form the observed product. Similar selectivities have been observed with a
related
α,β-bis(tert-butyldimethylsilyloxy)-substituted
ketone (850), including with methallylmagnesium reagents (Scheme 337), which were also attributed to
strong conformational control exerted by the vicinal silyloxy groups.477</p><p>Simple β-substituted ketones generally do not react with
stereoselectivity. For example, allylation of hindered ketone 852
was not diastereoselective (Scheme
338).478 It
was not important to the synthetic endeavor, however: this stereocenter was
destroyed in a subsequent SN1-like ring closure.</p><p>Addition of allylmagnesium halides to β-methyl-substituted
ketones are generally not diastereoselective. Addition to 854 gave
homoallylic alcohol 855 with low stereoselectivity (Scheme 339).479 Higher selectivity (75:25) could be
achieved using chiral reagents, but, in either case, the isomers needed to be
separated to complete the desired synthesis using electrochemical methods. Low
stereoselectivity was also observed for addition of allylmagnesium reagents to
β-methyl-substituted ketone 856 (Scheme 340).480</p><p>Another example of the significant difference between allylmagnesium
reagents and other Grignard reagents was noted in the course of developing
chiral auxiliaries for performing additions to aldehydes (Scheme 341).481 Whereas additions of reagents such as organomagnesium,
organolithium, and Reformatsky reagents all gave the product with high
diastereoselectivity, additions of allylmagnesium reagents gave low selectivity.
The selectivity could be improved somewhat by changing the solvent or by first
transmetallating to zinc.</p><p>Even with allylic strain constraints, additions to enals with a
γ-stereogenic center occurred with low diastereoselectivity. Additions of
allylmagnesium bromide to aldehyde 860 gave a mixture of isomeric
products (Scheme 342).482 Although control of the
absolute stereochemistry could be achieved using reagent-based methods,
purification was difficult. The most effective course of action was to use the
commercially available allylmagnesium reagent, separate the diastereomeric
alcohols 861, and convert the undesired isomer into the desired one
using the Mitsunobu inversion protocol followed by hydrolysis.</p><p>Similar substrates with sulfoximine chiral auxiliaries, however, show
higher selectivity (Scheme
343).483,484 Additions to the carbonyl
group of ketone 862 occurred with high diastereoselectivity. On the
other hand, additions of allylmagnesium bromide to aldehyde 864
occurred with lower diastereoselectivity than additions of other organomagnesium
reagents (Scheme 344).</p><p>Substituted enals also did not react stereoselectively with
allylmagnesium reagents (Scheme 345).
Nevertheless, these unselective reactions were used in efforts to establish the
configurations of natural products. The diastereomers of the addition products
867485 and
869486 were
separated and individually converted to advanced intermediates that could be
compared spectroscopically to natural products.</p><p>In the course of synthesizing new vitamin D derivatives, additions to
hindered enone 870 were explored (Scheme 346).487
Although selectivity with allylmagnesium reagents was low, somewhat higher
selectivity was observed with alkylmagnesium reagents. The authors attribute the
facial selectivity to the conformational preferences of the ground state, as
determined using molecular mechanics calculations. It is possible that
conducting these additions at lower temperatures could have improved
selectivity.</p><p>Additions of allylmagnesium halides to chiral aldehydes may not be
stereoselective, but they can nevertheless be synthetically useful. Addition of
allylmagnesium bromide to a mixture of diastereomeric aldehydes 872
led to a mixture of diastereomeric alcohols (Scheme 347).488
Neither of the stereocenters on this side-chain were important for the synthetic
plan. After ring-closing metathesis involving the new allyl group, the secondary
homoallylic hydroxyl group was oxidized to the give the corresponding ketone,
and the stereocenter adjacent to that new carbonyl group was isomerized under
basic conditions.</p><p>Two additional examples from the steroid literature also occur with
similar low selectivity.489
Ketoaldehyde 874 reacted with prenylmagnesium chloride only at the
formyl group to give a mixture of products. The regioselectivity of addition of
the prenyl group contrasts with the general preference for prenylmagnesium
reagents to give the γ-isomer, not the α-isomer.23 Similarly, additions to the
α-hydroxyaldehyde 876, which is a mixture of diastereomers
at the A-B ring fusion, also gave a mixture of stereoisomeric products.
Evidently, the α-OMgX substituent did not control stereochemistry by
chelation.</p><p>Additions of allylmagnesium reagents to aldehyde 878, with
a complex side chain, occurred with low diastereoselectivity (Scheme 349).490 It was possible to obtain the product
with the desired configuration by separating the stereoisomers of
879 and recycling the undesired one, through a sequence of
oxidation and reduction. For aldehyde 880 (Scheme 350), however, addition was not stereoselective,
and efforts to convert the mixture into the desired stereoisomer were
unsuccessful.</p><p>Additions of allylmagnesium bromide to the related chiral aldehyde
882 also were not stereoselective (Scheme 351).491 The challenge of establishing the desired stereoisomer
was eventually solved using chiral enolate chemistry.</p><!><p>The analysis of reactions of imines and related substrates with
allylmagnesium reagents provide useful comparisons to the related reactions of
carbonyl compounds. Although both the carbon–oxygen and
carbon–nitrogen double bonds are polarized bonds, the stereoselectivities
of their reactions with carbon nucleophiles492 and the mechanisms of addition may or may not be the
same. For example, in the case of iminium ions as electrophiles, any mechanism
involving complexation of an organometallic nucleophile to the nitrogen atom is
not possible considering that the nitrogen atom is positively charged. The
additions of alkyl- and arylmagnesium reagents to simple imines are also likely
to be slow.493–495 The reactivity of imines is
also strongly influenced by the substituent on the nitrogen atom, which makes
transition states more crowded. These groups can exert strong influences on the
reactivity of the carbon–nitrogen double bond,58 and the stereochemical outcomes of the
reactions, as illustrated for reactions with imines bearing chiral auxiliaries
(Section 7.7). Considering that
additions are generally slow, reactions with allylmagnesium reagents with imines
may not be diffusion-controlled, although they are much faster than additions of
alkylmagnesium reagents.336
Even with these differences, it is instructive to consider the reactions of
compounds with carbon–nitrogen double bonds to provide comparisons to the
reactions of carbon–oxygen double bonds discussed above.</p><p>This review will not cover all additions to imines. Instead, it will
discuss the behavior of the carbon–nitrogen double bond with
allylmagnesium reagents as a contrast to other reactions of this reagent. In
general, reactions with imines do not show as dramatic differences in reaction
outcomes as observed for reactions of carbonyl compounds with allylmagnesium
reagents versus other Grignard reagents. As a result, only representative
examples of additions will be presented. Other reviews have discussed in detail
the diastereoselective reactions of imines with nucleophiles,492,496,497 including
allyl nucleophiles.20,21</p><!><p>In contrast to studies of the mechanism of additions of allylmagnesium
reagents to carbon–oxygen double bonds,18 the mechanism of addition to
carbon–nitrogen double bonds has not been examined in detail. Like the
reactions of carbonyl compounds, however, these reactions may proceed with
allylic transposition through a transition state resembling 884
(Scheme 352).498 This mechanism is supported by
observations of additions of prenylmagnesium bromide to an activated imine,
which gave preferentially the γ-product (Scheme 353),498
just as for additions to most aldehydes and ketones.23</p><p>One study suggests that single-electron transfer pathways are unlikely,
just as they are for most carbonyl compounds. A radical clock experiment,
illustrated in Scheme 354,499 does not show evidence for
radical intermediates (a similar experiment performed for additions of
allylmagnesium reagents to alkyl aldehydes also showed no evidence for radical
intermediates227).
Addition of allylmagnesium bromide to imine 887 formed an amide
intermediate, which eliminated the cyanide ion to form a new imine
(888). This reaction occurred without ring-opening, which the
authors suggest disproves the presence of radical intermediates. Addition of a
second equivalent of the allylmagnesium reagent to imine 888 gave a
diastereomeric mixture of products.</p><!><p>Additions of Grignard reagents to imines with an
α-alkoxy group can give products expected from chelation control.
For example, additions of allylmagnesium reagents to simple imines
proceed with chelation-controlled diastereoselectivity, as noted earlier
(Scheme 18, Section 2.5).59 This observation, however, does
not seem to be general. Additions to imine 890 occurred
with high diastereoselectivity for most organomagnesium reagents (Scheme 355).500–504 Just as with α-alkoxy
aldehydes, however (Section
4.2.4.3), additions of allylmagnesium reagents with imine
890 gave low stereoselectivity.503 No allylmetal reacted with high
diastereoselectivity, however (Scheme
356).</p><p>Installation of a group that should be more prone to chelation
did not lead to high chelation-controlled diastereoselectivity (Scheme 357).505 The addition of allylmagnesium
and allylzinc reagents gave moderate stereoselectivity for the chelation
product. Additions of allyltitanium reagents were modestly selective for
the Felkin–Anh product, which was strongly favored for the
non-chelating boron reagent.</p><p>Addition of allylmagnesium bromide to more highly substituted
substrates occurred with high diastereoselectivity (Scheme 358).506 This reaction was a key step in the synthesis
of a conformationally constrained sialic acid derivative.</p><p>Additions of allylmetal nucleophiles to α-alkoxy and
α-silyloxy imines behaved similarly (Scheme 359).507 Although the product from chelation control
was favored, stereoselectivity was not particularly high, even with
allylzinc reagents.</p><p>Additions of carbon nucleophiles to α-silyloxy
silylimines, however, occurred with significantly different
stereochemical outcomes depending upon the reagent used (Scheme 360).508 Imine 900
possesses a silyloxy group, which should not engage in
chelation.236
Nevertheless, additions of alkylmetals like
n-Bu–Li and PhCH2–MgCl both
gave the product expected from chelation control. By contrast, additions
of allylmagnesium reagents gave the Felkin–Anh product, even in
the presence of zinc salts that would be expected to be favor
chelation.</p><p>Allylations of imines with α-alkoxy groups as part of a
ring gave only modest stereoselectivity (Scheme 361).509,510
Allylmagnesium reagents favored the expected chelation-controlled
product, but the zinc reagents gave the opposite selectivity. These
differences could involve chelation through different oxygen atoms,
which might alter the outcome of addition.</p><p>Additions to more highly substituted exocyclic imines, however,
were highly diastereoselective. In contrast to additions to exocyclic
aldehydes (for example, Scheme 71,
Section 4.2.4.3), additions to
exocyclic imines favored the product expected from chelation control
with high stereoselectivity (Scheme
362).511
These reactions, which were used to prepare glycosidase inhibitors,
parallel similar observations for additions of other organometallic
nucleophiles to a related electrophile512</p><p>Reactions with another related substrate gave similar results
(Scheme 363).513 Additions of both
allyl- and homoallylmagnesium reagents gave the product as a single
stereoisomer. Additions of vinylmagnesium reagents were reported to
proceed with lower diastereoselectivity, although the selectivity was
not given. Instead, addition of the vinyl nucleophile was conducted in
the presence of a Lewis acid, which led to the opposite diastereomer,
the product expected by considering the Felkin–Anh model (Scheme 364). This reversal of
selectivity in the presence of BF3·Et2 was
also observed with the aldimine 906 (Scheme 362).511</p><p>Chelation from a carbonyl group can also be used to control the
stereoselectivity of additions to imines. Additions to the chiral
α-imino ester 911, which was generated in situ from
an α-bromo amine, proceeded with generally good
diastereoselectivity (Scheme
365).514 Upon chelation between the imine nitrogen atom and
the carbonyl group, attack would need to occur from the face away from
the cumyl group. As observed for carbonyl compounds, however, addition
of allylmagnesium reagents were much less stereoselective.</p><p>Just as with ketones and aldehydes (Sections 4.2.3.1 and 4.2.5.1, respectively), additions of carbon nucleophiles to
imines with β-chelating groups did not lead to generally high
stereoselectivity (Scheme
366).505 Among all the allylating reagents examined,
allylmagnesium chloride gave the highest selectivity.</p><!><p>The additions of allylmetal reagents to chiral imines with a
stereocenter provide a clear comparison with reactions of related
carbonyl compounds (Scheme
367).1,515 The
stereoselectivity of allylations of imine 915 with
allylmagnesium reagents was low. Addition of an allylboron reagent,
however, proceeded with high diastereoselectivity.</p><p>The analyses of the stereochemical courses of these reactions
illustrate how the reactions of imines must be considered differently
than reactions of aldehydes. At first analysis, the stereoselectivity
observed for the addition of allylmagnesium halide is quite similar to
the selectivity observed for addition to the corresponding aldehyde
(Scheme 52). If these
reactions proceed through a cyclic transition state with allylic
transposition, as likely operates for additions to carbonyl compounds
(i.e., 14, Section
2.1), the transition states develop other steric interactions
with the substituent on the imine. The cyclic transition state with
allylic transposition is illustrated by 884 (Scheme 352), assuming that the
metal atom (boron or magnesium) possesses two groups, which could be
substituents or solvent. In the case of the imine, the substituents must
adopt axial orientations because the lone pair on the nitrogen atom
would be complexed to the metal atom. This requirement brings the
branched substituent close to the ligands on the metal center. The
stereogenic center could adopt a conformation to minimize steric
interactions with the groups on the metal, as illustrated for transition
state 917 (Scheme
368). The larger ligands on the boron center likely
contribute to the higher selectivity in that case.516 Transition state
917, is not, strictly speaking, a Felkin–Anh
transition state, however, because of the arrangement of the atoms on
the stereogenic center. To adopt a transition state more resembling the
Felkin–Anh transition state (i.e., 918), steric
interactions would develop with the axial group on the metal atom. This
example provides an important caveat regarding stereochemical models:
observation of a product expected from the Felkin–Anh model does
not require that the transition state fits that model precisely. This
point is discussed in detail in Section
3.</p><p>Additions to a family of N-tosylimines
occurred with different stereoselectivity depending upon the nature of
the organomagnesium reagent (Scheme
369).517
For both imine 919 and 921, additions of
vinyl- and homoallylmagnesium reagents occurred with high
diastereoselectivity that can be explained by invoking the
Felkin–Anh-like transition state where the OR group adopts the
RL position (923). Additions of
allylmagnesium reagents, however, occurred with low
diastereoselectivity.</p><!><p>The low selectivity observed upon additions of Grignard reagents to
4-tert-butylcyclohexanone (Section 6.2.1.1) was also observed for their derived
imines (Scheme 370).518 This example illustrates
the challenges associated with reactions of imines and the utility of
allylmagnesium reagents. Additions of other allylmetal reagents, including
allylsilanes, allylstannanes, and allylzinc reagents, occurred only slowly
or not at all. Furthermore, attempted additions of other organomagnesium
reagents gave only products resulting from deprotonation of the imine.</p><p>The enhanced reactivity of allylmagnesium reagents compared to most
other Grignard reagents is also illustrated for reactions of cyclohexanone
sulfoximine 926 (Scheme
371).519
Benzyl- and allylmagnesium reagents were the only Grignard reagents that
would add to this electrophile. It should be noted, however, that these
reaction mixtures contained residual titanium salts because of how the
sulfoximines were prepared. Consequently, the involvement of organotitanium
reagents cannot be discounted.</p><p>Just as with five-membered ring ketones with highly differentiated
faces (Section 6.2.2.3), the exocyclic
amine 928 underwent highly diastereoselective addition
reactions with allylmagnesium chloride (Scheme 372).520 The allyl group attacked from the face opposite the
two alkyl groups, which could adopt pseudoaxial orientations to minimize
allylic strain with the carbamoyl group.521 Attack on the
carbon–nitrogen double bond from the more exposed face, as shown in
930, would form the observed product.</p><!><p>Additions to cyclic imines are more easily analyzed than additions
to acyclic ones. For example, addition to imine 931, formed in
situ, resulted in high selectivity for the product 932 (Scheme 373).522 This outcome can be understood as
arising from addition to the half-chair conformation of the imine along a
trajectory that converts the half-chair into the chair form (i.e.,
933→934, Scheme 374). This model follows the stereoelectronic
and torsional model originally formulated to understand the reactions of
iminium ions,122 which
was later extended to reactions of oxocarbenium ions.123 The allyl group was cyclized onto
the nitrogen atom to form the core structure of indolizidine natural
products.</p><p>The utility of allylmagnesium reagents was demonstrated in the
course of optimizing a method for the synthesis of quinolizidine alkaloids
(Scheme 375).523 Addition of
allylmagnesium chloride to imine 935, formed in situ, occurred
with the same sense of stereoselectivity expected from Scheme 374. The use of allylmagnesium reagents in the
presence of small quantities (as low as 23 mol%) of ZnCl2 gave
slightly improved yields, but generating the allylzinc reagent
stoichiometrically led to no reaction. Whereas the use of allylboranes gave
similar yields, no allylation was observed using allylsilanes or
allylstannanes in the presence of Lewis acids. Under the optimized
conditions, crotylation with the zinc reagent, which likely proceeded
through a cyclic transition state with allylic transposition similar to
884 (Scheme 352),
also controlled stereoselectivity at the exocyclic stereocenter (Scheme 376). The configuration at the
ring for 937 can be explained by assuming that the alkyl group
adopts an equatorial orientation, leading to the cis-disubstituted ring;
this selectivity is the same for the related oxocarbenium ions.524 Pyrrolidine
938 was converted to the alkaloid target by fusing a new
ring onto the six-membered ring.</p><p>A more constrained six-membered ring imine reacted with lower
stereoselectivity, however (Scheme
377).525 In
the course of preparing potential anti-depressant drugs, additions of
allylmetals to imine 939 were examined. Additions with
allyllithium and allylmagnesium reagents were unselective, but addition of
allylzinc bromide gave useful stereoselectivity. The allyl group was needed
to form a fused pyrrolidine ring onto the tetrahydroisoquinoline
framework.</p><p>Addition of allylmagnesium chloride to a spirocyclic six-membered
ring imine (941) occurred with high stereoselectivity (Scheme 378).526 This selectivity can be understood
as the reaction occurring through a transition state resembling
933 (Scheme 374)
with the more substituted atom of the cyclohexyl group adopting an
equatorial position. Attack to the only accessible face along an axial
trajectory would form the observed product.</p><p>Additions to five-membered ring imines are also highly
stereoselective, but the stereochemical outcomes of these reactions are
somewhat difficult to reconcile. Addition of allylmagnesium chloride to
imine 943 occurred with high diastereoselectivity for addition
opposite the substituent (Scheme
379).527
Other additions of allylmagnesium halides to five-membered ring imines give
similar stereoselectivities (Scheme
380).528 The
stereochemical outcome is what might be expected by considering the
substituent blocking one face so attack must occur from the other face.
Additions to five-membered ring electrophiles with two trigonal atoms in the
ring cannot be analyzed steric effects alone, however529,530.</p><p>The difficulty of analysis of the outcomes in Schemes 379 and 380 emerges by comparison to the results in Scheme 81.531 Addition of allylmagnesium bromide to imine
947 gave good selectivity for addition syn
to the substituent, not anti to it. The selectivity of this
reaction can be considered to involve addition to the lowest-energy
conformer of the imine from the stereoelectronically favored direction
(i.e., from inside the envelope) through transition state 949
to give the major product (Scheme
382). This mode of attack is similar to the one that occurs for
additions to five-membered ring oxocarbenium ions530,532 and iminium ions.533,534 It is not clear why this example proceeds with
opposite stereoselectivity compared to Schemes 379 and 380.</p><p>A similar syn-selective addition was observed in a
related imine (Scheme 383).535 This example provides
evidence that addition to imine 947 (Scheme 381) cannot involve chelation, because
chelation of the reagent to the silyloxy group of imine 950 is
unlikely.236
Nevertheless, the experiments shown in Schemes 381 and 383 are
in conflict with those shown in Schemes
379 and 380.</p><p>Additions to a fused bicyclic five-membered ring imines were also
highly diastereoselective (Scheme
384).536
These reactions required an excess of the organomagnesium reagent to
generate the imine. Formation of the sulfonyl-stabilized carbanion caused a
ring-opening reaction to generate the imine 955 (Scheme 385). This elimination resembles
the decomposition of THF by alkyllithium reagents.537 The resulting imine was then
trapped by the organometallic reagent from the convex face with high
stereoselectivity.</p><p>Additions to the indole derivative 957 provided an
outcome that is difficult to accommodate by consideration of steric effects
alone (Scheme 386).538 Addition to the indoline
957 occurred smoothly with allylmagnesium iodide to give
the adduct 958. By contrast, additions of methylmagnesium
iodide to indolines of this type were slow and occurred with low yields, and
additions of benzylmagnesium reagents formed a number of products. Reactions
with Grignard reagents with β-hydrogen atoms, such as ethyl, propyl,
or butylmagnesium halides, did not give products. These results were
explained as involving radical intermediates, a mechanism that has been
discounted for additions of organomagnesium reagents, including
allylmagnesium halides, to alkyl aldehydes.227 The configuration of the product
involves coupling from the more hindered face. The stereochemical
assignment, however, may be considered tentative: the two isomers were
differentiated based upon their splitting patterns in their 1H
NMR spectra, which may not be completely diagnostic.</p><p>Additions to the seven-membered ring imine generated from
N,O-acetal 960 led to different
stereochemical preferences depending upon the reagent (Scheme 387).539 Reactions with allyl and phenylmagnesium reagents
gave one stereoisomer of product, while the use of other Grignard reagents
gave the opposite stereoisomer. The preferential formation of the isomer
from a reagent such as methylmagnesium bromide could be argued to arise from
chelation-controlled addition through magnesium alkoxide 961.
The origin of the other stereoisomer was not explained, however. The sense
of selectivity is similar to that observed for reactions of structurally
similar seven-membered ring oxocarbenium ions,540 whose reactions are likely
controlled by stereoelectronic and torsional effects.541</p><!><p>A series of iminium ions, generated from the dihydropyridine
964, could be trapped with nucleophiles with good selectivity
(Scheme 388).542,543 The iminium ion was generated by alkylating the enamine.
Addition of an organometallic reagent then occurred with high
diastereoselectivity, likely by minimizing torsional strain in the first-formed
products.544 The
allylcerium reagent derived from the allylmagnesium halide was employed to favor
addition over proton transfer543</p><p>Fused bicyclic iminium ions also undergo stereoselective allylations
(Scheme 389).545 The iminium ion 968, which
was generated by abstraction of the cyano group with silver ion, could be
observed spectroscopically. Trapping of the iminium ion with organometallic
reagents, including allylmagnesium reagents, occurred from the convex face with
high stereoselectivity. Additions of alkyllithium reagents were
unsuccessful.</p><p>Additions to the fused bicyclic iminium 971 also occurred
with high stereoselectivity (Scheme
390).546 The
iminium ion was prepared in situ by first reduction of the bicyclic acetal to
yield the hemiacetal followed by warming in the presence of the nucleophile.
Only allylmagnesium bromide was examined because this group was essential to
perform a subsequent ring closure to make the desired core structure of an
alkaloid.</p><p>Additions of allylmagnesium reagents to multicyclic iminium ions can be
highly stereoselective (Scheme
391).547
Addition of methallylmagnesium chloride occurred from the convex face to
establish stereochemistry at a tetrasubstituted carbon stereocenter. This
four-carbon chain was essential for the subsequent steps of a synthesis of an
alkaloid natural product.</p><p>Additions to pyridinium ions can also be stereoselective with some
organometallic nucleophiles, but not allylmagnesium halides (Scheme 392).548 Addition can form mixtures of
regioisomers and stereoisomers. The use of methyllithium exhibited neither
regio- nor stereoselectivity, but the use of alkylmagnesium bromides were both
regio- and stereoselective. Additions of allylmagnesium bromide, however, were
not highly regioselective. The major regioisomer (i.e., the regioisomer that
formed faster), was the product of 1,4-addition, 976. This product
was obtained with low stereoselectivity. By contrast, the minor regioisomer, the
1,2-addition product 977, was formed with high
diastereoselectivity. This trend, in which the faster-formed regioisomer was
made without diastereoselectively but the slower-formed regioisomer was made
stereoselectively, was also observed for additions of allylic organomagnesium
reagents to hindered ketones.23</p><p>Five-membered ring iminium ions also underwent reactions with
allylmagnesium reagents with some diastereoselectivity (Scheme 393).549 The only nucleophile that was used to trap these
iminium ions was allylmagnesium bromide. The relative configuration of the
product was not given.</p><p>In the course of the synthesis of alkaloids that could be used for the
treatment of cancer, the reactions of the five-membered ring iminium ion
982 were examined (Scheme
394).550 Whereas
vinylmagnesium reagents reacted with high diastereoselectivity, allylmagnesium
reagents reacted with a only a modest preference for the desired product.
Because a two-carbon atom chain was needed for the proposed synthesis, use of
the adduct 983 with the vinyl group would have been ideal. It was
not possible to functionalize the double bond of 983 (R =
CH=CH2) to obtain the desired product, however. As a result, the
allylated compound 983 (R = CH2CH=CH2) was
used to complete the synthesis. A carbon atom needed to be removed from the
allyl chain by dihydroxylation and oxidative cleavage of the resulting diol.
This chain was then used to close additional rings, which enabled the synthesis
of the target molecule.</p><!><p>A transformation that is closely related to the reactions of
nucleophiles with iminium ions are the reactions of nucleophiles with imines
complexed to Lewis acids. Boron-containing Lewis acids have been employed
commonly for reactions with organomagnesium reagents. For example, the reaction
of 984, the boron complex of an imine, was highly
diastereoselective for addition from the convex face (Scheme 395).551 The use of a chiral boron Lewis acid reagent
(986) was capable of conferring high diastereoselectivity to
additions of allylmagnesium bromide (Scheme
396), a transformation that enabled the enantioselective synthesis of
pyrrolidines.552</p><p>The use of complexation to a boron Lewis acid can change the
stereoselectivity of an addition reaction. As discussed above (Scheme 381, Section 7.3.3), addition of allylmagnesium bromide to the imine
947 occurred with high stereoselectivity favoring addition from
the face bearing the benzyloxymethyl group. After complexation to
BF3•OEt2, however, the sense of
diastereoselectivity was reversed (Scheme
397).531 It is
likely that the Lewis acid-base complex adopts a conformation resembling
989 (Scheme 398) to
minimize allylic strain, as has been observed for other nitrogen-containing
five-membered ring species.521 Stereoelectronically favored attack from inside the
envelope530,532,534 would lead to the observed product.</p><p>Additions of allylmagnesium reagents to complexes of amines with boron
Lewis acids are also stereoselective with multicyclic imines (Scheme 399).553 The imine 990 was first
complexed with the Lewis acid at −30 °C for 30 minutes, then
allylmagnesium chloride was added to provide amine 991 a single
stereoisomer. The product forms the cis-fused pyrrolidine ring
by attack from the more exposed convex face.</p><p>Transition metal complexes can also be used to activate imines for
attack by carbon nucleophiles. The metal complex of an isoquinoline,
992, reacted with different diastereoselectivity depending upon
the nucleophile employed (Scheme
400).554 Among
the several organometallic reagents examined, including both Grignard reagents
and organolithium reagents, allylmagnesium reagents gave the lowest
stereoselectivity.</p><!><p>Although additions of allylmagnesium reagents to oxime derivatives
are not common transformations, these reactions can be stereoselective. For
example, addition to α-alkoxy oxime 994 proceeded with
high stereoselectivity (Scheme
401).555
This stereochemical course can be understood by considering chelation
between the OMe group and the oxime nitrogen (as illustrated in transition
state 996). This degree of stereoselectivity is higher than
generally seen with imines with α-alkoxy groups (Section 7.3.1.1).</p><p>An oxime ether with the stereocenter more remote did not react as
stereoselectively with allylmagnesium reagents, however (Scheme 402).556 Addition of allyllithium was
stereoselective. The major product could be formed by addition to chelate
999 from the more exposed back face. Addition of
allylmagnesium bromide, however, was unselective, and addition of a cerium
reagent proceed with the opposite sense of selectivity.</p><p>Addition of allylmagnesium to the oxime ether 1000
with a nearby 8-phenmenthol ester group proceeded with low
diastereoselectivity (Scheme
403).557
This result is similar to the observation of low selectivity for addition of
allylmagnesium to the corresponding N-acylimine (Scheme 365, Section 7.3.1.1).514 In the presence of zinc salts, however, high
diastereoselectivity, which is consistent with a chelate, was observed. In
general, additions of organomagnesium reagents did not occur or occurred in
low yields unless the zinc salts were employed.557</p><p>Additions of organometallic nucleophiles to five-membered cyclic
oximes (i.e., isoxazolines), provided a stereoselective method for preparing
β-amino acid analogues (Scheme
404).558,559 The oxime ethers were
complexed to BF3 before addition of the nucleophile, as discussed
in Section 7.5. These reactions were
successful with allyl and benzylic Grignard reagents, but other Grignard
reagents (i.e., alkyl and aromatic Grignard reagents) would not add. If the
free hydroxyl group were protected, however, alkyllithium reagents could be
employed to achieve the addition reaction (Scheme 405).</p><p>Addition of allylmagnesium bromide to a related isoxazoline
proceeded with low stereoselectivity (Scheme
406).560 The
low selectivity in this case may arise from the similar sizes between the
geminal phenyl and trifluorethyl groups that do not differentiate between
the faces. The configuration depicted for 1006 was provided in
the Supporting Information of this paper, although it was not clear how this
configuration was assigned.</p><p>An unusual rearrangement was observed in the case of addition to
cyclic oxime 1008 (Scheme
407).561
Addition occurred at the carbon–nitrogen double bond, but then a
ring-opening reaction occurred. It was speculated that a proton-transfer
reaction must occur from anion 1010 to form the allylic
carbanion 1011 (Scheme
408). The addition to the oxime must be diastereoselective.
Subsequent nucleophilic substitution at the nitrogen atom would form the
resulting aziridine. Conversions of oximes into aziridines have been
observed under similar conditions, although the mechanism is likely to be
different.562</p><!><p>Additions to amidines have not been examined extensively. Upon
addition of allylmagnesium reagents to amidine 1012, an
intramolecular nucleophilic displacement occurred to form aziridine
1013 as a single diastereomer (Scheme 409).233 Methylmagnesium iodide, however, did not add. This
result underscores the difference in reactivity between allylmagnesium
reagents and other Grignard reagents.</p><!><p>Additions of organomagnesium reagents to hydrazone
1014 with allylmagnesium reagents were developed as a
method to prepare chiral α-amino aldehydes (Scheme 410).563 The diastereoselectivity of the reaction was
highly dependent upon the solvent. Nevertheless, the selectivities with
allylmagnesium reagents were low; only upon transmetallation to the
allyltitanium reagent could stereoselectivity be achieved. The authors
ascribed the selectivity to a chelation-controlled addition through a
transition state resembling 1016 (Scheme 411).</p><!><p>Nitrones possess strongly electrophilic C=N double bonds by virtue
of the substituents on the nitrogen atom,495 so it is not surprising that
organomagnesium reagents add to nitrones at low temperature. Depending upon
the substitution pattern, these reactions can be highly stereoselective.
Additions of allylmagnesium or allyllithium reagents to the glyceraldehyde
acetonide-derived nitrones were not stereoselective (Scheme 412).564 Transmetallation or addition of Lewis acids
changed the sense of diastereoselectivity. By comparison, additions to the
α-amino analogue 1020 (Scheme 413) occurred with high diastereoselectivity. These
selectivities have been explained as the result of additions to the top face
of a chelate resembling 1023 (Scheme 414).565</p><p>Additions of alkylmagnesium reagents to cyclic nitrone
1024 were generally highly diastereoselective (Scheme 415).566 Additions occurred anti to the
large silyloxy group with complete diastereoselectivity. By contrast,
addition of allylmagnesium bromide was less stereoselective. This low
stereoselectivity could reflect the high electrophilicity of the nitrones,
which possess relatively low-energy unoccupied orbitals.567 Consequently, reaction
rates could approach the diffusion rate limit, thus diminishing
diastereoselectivity.22,23</p><p>Additions to five-membered ring nitrones, on the other hand, were
highly diastereoselective. Additions to highly substituted nitrone
1026 occurred from the α-face (Scheme 416).568 This sense of selectivity is similar to what was
observed for additions of Grignard reagents to the related imine, although
that imine did not react with consistently high stereoselectivity (Scheme 417).569</p><p>Additions to bicyclic nitrones, however, were generally highly
diastereoselective. In the case of a fused bicyclic nitrone, addition
occurred from the more accessible convex face (Scheme 418).570 The addition product was subsequently converted to
an aza-sugar analogue. Similar outcomes were observed with a structurally
related bicyclic nitrone (Scheme
419).571</p><p>In the process of developing inhibitors of glycosyl transferases,
the allylations of nitrones 1034 were examined (Scheme 420).572 In all cases, additions were highly
stereoselective, even for monocyclic nitrones.</p><p>Additions to all five-membered ring nitrones, however, are not
stereoselective with allylmagnesium reagents. Addition to nitrone
1039, which resembles nitrone 1036 above,
proceeded with high selectivity with vinylmagnesium bromide, but not
allylmagnesium bromide (Scheme
421).573</p><p>Additions to exocyclic nitrones occurred with different
stereochemical outcomes depending upon which reagent was used.574 These addition reactions
occurred twice to form two new stereogenic centers adjacent to the nitrogen
atom (Scheme 422). Addition of a
nucleophile to nitrone 1041 generates a second nitrone,
1043. That nitrone can be trapped by second equivalent of
the nucleophile to form the final product 1044. With most
organomagnesium reagents, the reaction gave three stereoisomers of product,
with the major products having the same relative configurations (Scheme 423). Additions of
allylmagnesium reagents, however, resulted in only two isomers of products
with the opposite relative stereochemical outcome. The selectivity for only
two isomers is caused by the highly stereoselective addition of the second
equivalent of the allylmagnesium reagent, whereas the other Grignard
reagents reacted less selectively.</p><!><p>Among the methods developed to install chiral auxiliaries on
nitrogen atoms to control the stereoselectivities of addition
reactions,492
sulfinyl imines have proven to be the most broadly applicable (Scheme 424).498 This method represents a useful
application of allylmagnesium reagents. Additions of allylmagnesium bromide
to aryl-substituted sulfinyl imines gave high diastereoselectivity.
Additions of reagents such as n-butyllithium or
vinylmagnesium bromide were unsuccessful, however, because those reagents
deprotonated the carbon atom adjacent to the imine. These results led the
authors to suggest that the additions of allylmagnesium reagents must follow
a different mechanism than for other organometallic reagents. They proposed
that addition of allylmagnesium bromide occurred through a six-membered ring
transition state with allylic transposition like 1051, but with
complexation to the oxygen atom of the sulfinyl imine (Scheme 425). Others researchers have also found
additions of allylmagnesium reagents to these arylsulfinyl imines to be
useful for the synthesis of chiral amines.575</p><p>Nucleophilic addition to camphor-based sulfinyl imines was also
found to be a useful method for the synthesis of chiral amines (Scheme 426).576 Of all the nucleophiles examined,
among the most stereoselective was allylmagnesium bromide. It was suggested
that methylmagnesium iodide was behaving as a larger nucleophile by
aggregation, and that addition of allylmagnesium halides added by a
mechanism involving allylic transposition, as observed for the other
systems.</p><p>The tert-butyl variant of the sulfinyl imine has
been used more frequently.577 This system also gives high selectivity for allylation
(Scheme 427).578 The allylation reaction
is a generally useful reaction for preparing homoallylic amines, as
evidenced by its application to the synthesis of potential drug candidates
(Scheme 428).579</p><p>A practical and useful modification of this allylation has also
been developed (Scheme
429).580
The cumyl sulfinyl imine enables purification simply by extraction. For this
substrate, stereoselectivity for allylation is considerably higher at room
temperature than it is at −78 °C, which suggests a difference
in entropy between the transition states leading to the different
products.581</p><p>Some discrepancies in the literature about outcomes of allylation
reactions of sulfinyl imines suggest that one should study the reported
examples carefully before using this transformation. In the course of a
synthesis of lactam derivatives, the allylation of sulfinimides was used to
prepare starting materials with high optical purity (Scheme 430).582 Other authors had performed the same reaction with
the enantiomeric starting material and reported the opposite stereochemical
outcome (Scheme 431).583 It is likely that the
structure of 1063 had been misassigned.582 The discrepancy in the level of
stereoselectivity, however, is harder to explain, although it should be
noted that the reaction conditions are quite different.</p><p>Analysis of the stereochemical outcome of addition to the
ketone-derived sulfinyl imine is also not necessarily straightforward.
Addition to imine 1064 was reported to proceed with modest
stereoselectivity (Scheme
432).584
The two different enantiomers of 1064 were also reported to
give different isomeric mixtures of 1065, although that
discrepancy was attributed to changes to the isolation step for the
products. Different results had been reported by other researchers (Scheme 433).583</p><p>The additions to chiral sulfinyl imines have been applied to the
synthesis of fluorinated amines. In the course of the synthesis of
fluorinated amino acids, it was discovered that N,O-acetal
precursors were superior for these reactions compared to the unstable
fluorinated imine (Scheme
434).585
Additions of allylic organomagnesium reagents exhibited higher
diastereoselectivity than additions of other organometallic agents, which
was attributed to a chelated transition state similar to 1051
(Scheme 425).498,577,586 In a system with enolizable protons, addition was
accompanied by small amounts of a condensation product, 1073
(Scheme 435). Addition to the
chiral sulfinyl imine 1074 were not particularly
diastereoselective, however (Scheme
436).587</p><p>Chiral sulfinyl imines can also be used to prepare monofluorinated
amines (Scheme 437).588 The method involved
diastereoselective fluorination of anions of sulfinyl imidates followed by
reduction to form sulfinyl imines such as 1076. Addition of the
allylzincate reagent was highly stereoselective. In the absence of the zinc
reagent, the diastereoselectivity was lower (dr = 83:17).</p><p>The allylation of sulfinyl imines can be useful in target-directed
synthesis. For example, allylation of 1078 formed the amine
1079 after deprotection (Scheme 438).589 Synthesis of precursors to alkaloids can also be
achieved using this reaction (Scheme
439).590,591 In both of these cases,
the allyl group was used to form a six-membered ring with the homoallylic
nitrogen atom by ring-closing metathesis. The allylation reaction has also
been used to prepare amines that have been examined for their use for the
synthesis of macrolide antibiotic analogues (Scheme 440).592 Allylations of an aromatic aldehyde progressed with
good stereoselectivity (Scheme
441).593,594 The resulting amino
group can then be cyclized by displacement of the chloride to form
enantiomerically enriched tetrahydroisoquinolines, where the allyl group can
be elaborated to close additional rings. This variant of the reaction has
also proven to be useful for the preparation of precursors to alkaloids
(Scheme 442).595 Addition of
allylmagnesium bromide to 1088 in the presence of magnesium
bromide provided reasonable selectivity for the desired product
1089. A simple purification by trituration enabled the
isolation of the product with high selectivity (dr > 98:2).</p><!><p>Although the sulfinyl imines have emerged as the most common chiral
auxiliaries for the additions of allylmagnesium reagents to imines (Section 7.7.1), other auxiliaries have
been used in different cases. Imines derived from chiral amines have been
used extensively for the stereoselective additions of allylmagnesium
reagent. One example demonstrates a contrast with an experiment discussed in
the context of the mechanism of addition (Scheme 354, Section 7.2).
Whereas addition to the cyclopropyl-substituted imine gave poor
diastereoselectivity for the double-addition reaction (Scheme 354), addition to the corresponding isopropyl
derivative 1090 gave high stereoselectivity (Scheme 443).499 Additional experiments with the
putative imine intermediate 1092 provided evidence for the
presence of this intermediate. No explanation for the differences in
selectivity for an isopropyl group and a cyclopropyl group was provided.</p><p>Other approaches have been developed to refine the stereoselective
additions to the carbon–nitrogen double bond. One set of chiral
auxiliaries that was employed involves the readily available
α-methylbenzyl imine 1093 (Scheme 444).516 As with the additions to simple imines of
α-chiral aldehydes (Scheme
367, Section 7.3.1.2),
additions of allylboron reagents proceeded in generally higher selectivity
than addition of allylmagnesium reagents. A transition state resembling
1095 was suggested, presumably with addition to the imine
through a six-membered ring transition state 884 (Scheme 352). Other types of
organometallic reagents can also be useful (Scheme 445).596</p><p>A modification of this method was introduced with a methoxy group
on the aromatic ring (Scheme
446).597
The methoxy group was intended to provide another point of contact for the
metal to reinforce the preference for a conformation resembling
1095 (Scheme 444).
This modification allowed for the reactions of allylic organomagnesium
reagents to be highly diastereoselective. It should be noted that the
addition of the prenyl reagent gave the product with high
γ-selectivity, suggesting that these reactions proceed by a
transition state involving allylic transposition, as observed for additions
to sulfinyl imines (Scheme 425, Section 7.7.1). This reaction has also
been applied to the synthesis of 1,2-diamines (Scheme 447).598,599</p><p>The presence of the chiral auxiliary on nitrogen, however, may not
override substrate control (Scheme
448).600
Regardless of the configuration of the auxiliary, the stereoselectivity of
addition to an α-epoxy imine was dominated by the chelating effect of
the epoxide functional group. This stereochemical course can be reversed in
the presence of BF3•Et2, which cannot engage in
chelation (Scheme 449).</p><p>In other cases, the sense of the substrate control can be either
matched or mismatched601
with the control exerted by the reagents. There are other cases where the
stereochemical control elements, along with the preferences of reagents, are
more in balance. With the imine 1107 with a potentially
chelating α-alkoxy group, addition of allylmagnesium reagents were
unselective, whereas additions of allylboranes were selective (Scheme 450).503 With the other diastereomer,
however, the allylmagnesium reagents added stereoselectively, but the borane
did not (Scheme 451). These
selectivities can be explained by considering the two modes of stereocontrol
(Scheme 452). Chelation would be
most stereoselective when the larger benzyloxymethyl group and the phenyl
group would occupy the same face (as illustrated by 1111);
addition would occur away from these groups. Conversely, using the borane
reagent, the reaction would proceed by a Felkin–Anh type transition
state, and selectivity would be maximized when the larger phenyl group would
be oriented away from the approaching nucleophile (as illustrated by
1112).503</p><p>Additional results with chiral imines also indicate the high
reactivity of allylmagnesium reagents. Upon addition of allylmagnesium
chloride to the imine 1113 containing also ester and pyridine
functional groups, modest diastereoselectivity for addition to the imine was
observed (Scheme 453).602 Addition to the
heteroaromatic ring and the ester functional group were also observed. The
diastereoselectivity observed with the magnesium and zinc reagents was
argued to involve a transition state (1115) where the metal
atom was complexed to the imine nitrogen atom, the pyridine nitrogen atom,
and the ester group (Scheme 454).
Opposite diastereoselectivity was observed with an allyltin reagent, which
should not engage the carboxyl group in chelation, as illustrated in
transition state 1116.</p><p>Other chiral imines also underwent stereoselective additions with a
number of organomagnesium reagents. Addition to chiral imine
1117 gave high selectivity for amine 1118
(Scheme 455).603 It is likely that the
difficulty of addition of some Grignard reagents could result from
competitive deprotonation of the starting material. The presence of
magnesium salts was not necessary to observe high stereoselectivity,
although they did increase it somewhat. The selectivities of these reactions
can be considered to occur through chelate 1119, which would
minimize allylic strain. Addition from the face opposite the larger phenyl
group would lead to the observed product.</p><p>Chiral hydrazones have also been examined for their applications
for preparing chiral amines (Scheme
456).604
Organocerium reagents were used in this case because of a general lack of
success with reagents such as Grignard reagents.605</p><p>Efforts to use a chiral diol-derived auxiliary illustrate the
differences between other Grignard reagents and allylmagnesium halides
(Scheme 457).606 Alkyllithium reagents
added to imine 1122 in high yields, but other reagents, such as
organomagnesium, organocerium, organozinc, and organocopper reagents, would
not add. Only one Grignard reagent added: allylmagnesium bromide. The
diastereoselectivity of this reaction was low, however.</p><p>Additions of allylmagnesium halides to oxime ethers were less
stereoselective than additions of alkyllithiums (Scheme 458).607 Although a direct comparison to other
organomagnesium reagents was not made with this substrate, additions to a
related substrate, unsaturated oxime 1126, also showed lower
diastereoselectivity for the Grignard reagents, but not as low as for
allylmagnesium bromide with oxime 1124.</p><p>Sulfenimines can also be useful chiral auxiliaries for preparing
chiral amines (Scheme 459).576 Diastereoselectivity was
sensitive to the nature of the group on the camphor-based auxiliary, with
the free alcohol giving the product with the highest diastereoselectivity.
This stereoselectivity was attributed to complexation of the magnesium atom
to both the sulfur atom and the anionic oxygen atom, as illustrated in
1130. The higher selectivity may be attributable to the
strong complexation with the OMgBr group, as was observed for chelation in
α-hydroxy ketones (Section
4.2.1.1). No other organometallic nucleophiles were examined with
this auxiliary; more studies were made on the sulfinyl imines, as discussed
in Section 7.7.1.</p><p>An alternative chiral auxiliary for imines involves a
phosphorus-based auxiliary (Scheme
460).608
Earlier studies with this auxiliary employed isolated imines,609 but this study used an
N,O-acetal prepared in situ. Additions occurred with
several organomagnesium reagents, but only with allylmagnesium bromide were
these reactions highly diastereoselective, likely due to the cyclic
transition state of allylation. This transition state allows for
complexation to the oxygen atom on the phosphorous atom, as illustrated in
1133. The reaction mixture likely contains
Ti(Oi-Pr)4 or other titanium salts because
of the two-step, one-flask method for the synthesis of the imine. It is
unlikely that the salts are important in the case of allylmagnesium reagents
because the results are similar to those obtained using an earlier
protocol.609</p><p>Additions to nitrones with chiral substituents on the nitrogen atom
were also stereoselective (Schemes
461 and 462).610 In the case of additions
of most Grignard reactions, additions to chiral nitrones 1134
were highly stereoselective. Addition of allylmagnesium reagents, however,
proceeded with low diastereoselectivity. The stereoselectivity patterns,
however, were odd: Addition of methylmagnesium reagents to nitrone
1136, however, gave products with the opposite
stereoselectivity compared to the reactions of other reagents (Scheme 462). No explanation for this
phenomenon was reported.</p><!><p>Allylmagnesium nucleophiles are useful reagents for introducing the allyl
functional group into a variety of organic compounds. They are inexpensive,
convenient to use, and highly reactive. It is this reactivity, however, that renders
them unpredictable in synthetic endeavors. This review collected and analyzed
hundreds of examples of the additions of these reagents to C=O and C=N double bonds,
highlighting under what circumstances additions may be stereoselective, and when
they may not.</p><p>Although in some cases allylmagnesium reagents react much as other
organomagnesium reagents do, most often, they react differently. For example,
chelation control cannot be expected for allylmagnesium reagents in ethereal
solvents because they do not conform to the formal chelation-control model.
Therefore, even when the product expected from chelation control is the major
product, that does not mean that the reaction proceeded by the chelation control
model as rigorously formulated by Eliel.53,54 Instead, other
factors may be responsible for selectivity.</p><p>To be able to use allylmagnesium reagents more effectively, it is important
to know why they react the way they do. A picture to explain that reactivity is
emerging.18 While the
details of transition state structure and possible intermediates provide some
insight into the different patterns of reactivity exhibited by allylmagnesium
reagents compared to other organomagnesium compounds, those details are not the most
important factor underlying the difference in reactivity. The most important factor
is that, for most aldehydes and ketones (unless they are unusually sterically
hindered), the rate constants for addition of allylmagnesium reagents appear to be
so fast that the carbon–carbon bond forming step is not the
stereochemistry-determining step. Instead, it is the step that brings the
nucleophile and electrophile together (i.e., diffusion, as discussed in Section 2.2 and Scheme 9) that determines the stereoselectivity. If the reagent
approaches the carbonyl compound from the Re face, for example, the
new bond will be formed on the Re face. For many carbonyl
compounds, this diffusion step is random: both faces will be approached with equal
probability, so diastereoselectivity will be low. On the other hand, for some
carbonyl compounds where the faces are highly differentiated (such as for
multicyclic ketones where the carbonyl group is embedded in a fused, bridged, or
spirocyclic ring), the rate constants for approach to the different faces could be
quite different, leading to diastereoselectivity. Even some acyclic compounds can
exist in conformations that bury a carbonyl group, so that only one face of the
carbon–oxygen double bond might be accessible, again resulting in
diastereoselective reactions of allylmagnesium reagents. These cases underscore the
point that careful consideration of the conformational preferences of the substrate,
and how approach of the nucleophile may be faster on one face than the other, can
give insight into how reactions might occur. Finally, in systems that are so
hindered (such as carbonyl compounds flanked by tetrasubstituted carbon
atoms17,23), rates of carbon–carbon bond
formation can be below the diffusion rate limit. In these cases, again,
diastereoselectivity will be observed because reaction outcomes can be determined by
the relative energies of competing transition states, which is central to models
such as the chelation-control model and the Felkin–Anh and related
models.</p><p>Arriving at some of the conclusions regarding the reactivity of
allylmagnesium reagents described in this article has taken assembling a
considerable amount of information from disparate sources with different levels of
detail. For example, sometimes additives such CeCl3 or ZnCl2
were used in reactions without any comment, so it is not possible to know what
happens in the absence of these reagents. In other cases, non-ethereal solvents were
used in reactions without any indication of what happened in ethereal solvents.
Sometimes, stereochemical information was not provided. Stereochemical assignments
can also be misleading, even in cases of well-studied reactions such as reductions
of 2-substituted cyclohexanones, where different papers might suggest different
stereochemical outcomes (as illustrated by comparing the following two papers
discussing a different type of reaction than discussed here611,612). It would have been helpful for researchers to provide that
information, or in other cases, when an allylmagnesium compound was used, to provide
insight into what happened (if anything) with other reagents. Nevertheless, even
without ideal information of that kind, a picture emerges of the unique reactivity
of allylmagnesium reagents.</p><p>A question that might be raised is whether these reagents, given their
unpredictability, are useful in modern organic synthesis. We believe that the answer
is yes, as evidenced by the hundreds of creative applications of it in this Review.
In many cases, they are the only reagents that are capable of reacting with highly
hindered carbonyl compounds, and it is in just those cases, where the selectivity
can be predicted to be the highest. Researchers should be aware of the details about
the unusually high rates of reactions of allylmagnesium reagents, however, and
consider carefully the implications of that rate.</p>