On the Mechanism of the Asymmetric Aldol Addition of Chiral N-Amino Cyclic Carbamate Hydrazones: Evidence of Non-Curtin-Hammett Behavior
The mechanistic details of the aldol addition of N-amino cyclic carbamate (ACC) hydrazones is provided herein from both an experimental and computational perspective. When the transformation is carried out at room temperature the anti-aldol product is formed exclusively. Under these conditions the anti- and syn-aldolate intermediates are in equilibrium and the transformation is under thermodynamic control. The anti-aldolate that leads to the anti-aldol product was calculated to be 3.7 kcal/mole lower in energy at room temperature than that leading to the syn-aldol product, which sufficiently accounts for the exclusive formation of the anti-aldol product. When the reaction is conducted at \xe2\x80\x9378 \xc2\xb0C it is under kinetic control and favors formation of the syn-aldol addition product. In this case, it was found that a solvent separated azaenolate anion and aldehyde form a \xcf\x83-intermediate in which the lithium cation is coordinated to the aldehyde. The \xcf\x83-intermediate collapses with a very small activation barrier to form the \xce\xb2-alkoxy hydrazone intermediate. The chiral nonracemic lithium azaenolate discriminates between the two diastereotopic faces of the pro-chiral aldehyde, and there is no rapid direct pathway that interconverts the two diastereomeric intermediates. Consequently, the reaction does not follow the Curtin-Hammett principle and the stereochemical outcome at low temperature instead depends on the relative energies of the two \xcf\x83-intermediates.
Introduction<!>Results and Discussion<!>Conclusions<!>General Experimental Considerations<!>Synthesis of ACC 3-pentanone hydrazone (9).<!>Synthesis of ACC (1S,2R)-1-hydroxy-2-methyl-1-(4-trifluoromethyl)phenyl)pentan-3-one (10a).<!>Synthesis of ACC (1R,2R)-1-hydroxy-2-methyl-1-(4-trifluoromethyl)phenyl)pentan-3-one (10b).<!>Synthesis of ACC (1S,2R)-1-hydroxy-2-methyl-1-phenylpentan-3-one (11a).<!>ACC (1R,2R)-1-hydroxy-2-methyl-1-phenylpentan-3-one (11b).<!>ACC (1R,2R)-1-hydroxy-2-methyl-1-(4-methyl)phenylpentan-3-one (15).<!>Kinetic vs. thermodynamic control 4-triflurobenzaldehyde/2-naphthaldehyde rt cross-over experiment (Scheme 3a).<!>Kinetic vs. thermodynamic control 4-tolualdehyde/2-naphthaldehyde rt cross-over experiment (Scheme 3b).<!>Kinetic vs. thermodynamic control 4-triflurobenzaldehyde/4-tolualdehyde \xe2\x80\x9378 \xc2\xb0C cross-over experiment (Scheme 4a).<!>Syn-10a to anti-10b conversion (Scheme 4b).<!>Computational Details
<p>The asymmetric aldol addition of ketone donors and aldehyde acceptors is a significant and important challenge.1 Both syn-selective2 and anti-selective3 versions of this reaction are known. One of the latter was recently reported by us and is the first method that offers a broadly applicable way of conducting the anti-aldol addition that is not significantly limited by the structure of the ketone.4 This approach uses chiral N-amino cyclic carbamate (ACC) hydrazones, formed by the condensation of ACC auxiliaries and ketones,5 to enable regioselective deprotonation and asymmetric induction, and delivers a single anti-aldol product with essentially perfect stereoselectivity. ACC hydrazones derived from symmetrical ketones can be used directly to obtain the anti-aldol product (1 → 2, Scheme 1). Alternatively, by coupling our ACC α,α-bisalkylation method5e with this anti-aldol method, it is possible to access aldol products corresponding to those formally obtained by the regiocontrolled addition of nonsymmetrical ketones having both α- and α'-protons (e.g., 3-hexanone) to aldehydes (3 → 4, Scheme 1). Based on our preliminary studies, this anti-selective transformation, which is conducted at room temperature, seemed to be under thermodynamic control. Confirmation of this has been obtained both experimentally and computationally, as outlined below. To our knowledge, this is the first report of a thermodynamically controlled ketone-based aldol addition involving a chiral auxiliary.6 When the reaction was conducted at –78 °C, conditions favoring kinetic control, the syn-aldol addition product was formed predominantly. Mechanistic details of the low temperature reaction were elucidated experimentally and computationally. It was found that the selectivity at low temperature was based on the relative energies of two σ-intermediates that are in equilibrium with one another, but which go on to form products in a way that does not adhere to the Curtin-Hammett principle. In what follows we describe mechanistic details of both the syn- and anti-selective ACC aldol addition reactions, which includes an analysis of the stereochemical course of the reactions.</p><!><p>As mentioned above, we have previously reported an approach to the asymmetric α-alkylation of ketones using N-amino cyclic carbamate (ACC) auxiliaries (Scheme 2a).5a The introduction of the auxiliary is achieved in excellent yield by acid mediated condensation with a ketone to give the corresponding ACC hydrazone. Treatment of the hydrazone with LDA generates its azaenolate in a kinetically controlled fashion, which when treated with an alkyl halide provides the α-alkylated hydrazone in excellent yield and diastereoselectivity. Removal of the auxiliary from this compound proceeds under mild conditions that do not compromise the integrity of the newly formed stereogenic center and that allow for recycling of the auxiliary. Given the effectiveness of this enantioselective alkylation method, we recently set out to examine ACC auxiliaries in the context of the asymmetric aldol addition of ketone-donors and aldehyde acceptors (Scheme 2b).4</p><p>As we began this work, we had only limited knowledge of what the stereochemical outcome of the proposed aldol addition might be (vide infra). However, we initially tried the reaction4a using hydrazone 9 and 4-(trifluoromethyl)benzaldehdye under kinetically controlled conditions, as is typically done to maximize asymmetric induction in aldol additions (Table 1, entry 1).7, 8 Disappointingly this led to only an approximately 2.5:1 mixture of syn-diastereomer 10a to anti-diastereomer 10b. However, we were encouraged by the fact that the reaction did not produce either diastereomer 10c or 10d.9 Standard modifications to the reaction conditions4a gave no significant improvement until the temperature of the reaction was increased (entries 2 and 3). Not only did these higher temperature conditions, which are unusual in asymmetric aldol chemistry, produce a single diastereomeric product, but the product had the anti-stereochemistry. The low and high temperature reactions were also tried using benzaldehyde in place of 4-(trifluoromethyl)benzaldehdye, with the same outcome (entries 4 and 5).</p><p>Given these interesting results, we undertook an investigation into the mechanism of the reaction. Since the high anti-selectivity correlated with an increase in temperature and prolonged reaction time (see Table 1, entries 2–4), we suspected that the transformation might be under thermodynamic control. A series of experiments was conducted to test this. First, the reaction between hydrazone 9 and 4-(trifluoromethyl)benzaldehyde was carried out under the conditions corresponding to Table 1, entry 3, but with a slight modification. In this case, instead of quenching the reaction after 2 h, 2-naphthaldehyde was added (Scheme 3a). The mixture was allowed to stir for an additional 2 h and was then quenched with saturated aqueous NH4Cl. If aldolate intermediate 12 were undergoing a retro-aldol reaction at room temperature to reform the azaenolate species, then the product (13) of addition of the azaenolate to 2-naphthaldehyde should also have been observed. However, this was not the case. While this suggested that 12 was being formed in an irreversible manner, another possibility was that 12 was undergoing the retro-aldol reaction, but that the trifluoromethyl group was simply biasing the system toward the formation of 10b over the corresponding 2-naphthadlehyde derived aldolate (not shown) by enhancing the stability of 10b. Additionally, or as an alternative, the observed outcome could be the result of the enhanced reactivity of 4-(trifluoromethyl)benzaldehyde over 2-naphthaldehyde in the azaenolate addition step. To rule out these possibilities, a similar transformation was conducted using p-tolualdehyde in place of 4-(trifluoromethyl)benzaldehyde. Thus, aldolate 14 was formed as shown in Scheme 3b and 2-naphthaldehyde was then added to the reaction mixture. As with aldolate 12 above, no 2-naphthaldehyde-based aldol product (13) was formed from aldolate 14; 15 was obtained as the sole product after workup. On the basis of these experiments we could reasonably conclude that the anti-aldolate intermediates (cf. 12 and 14) form irreversibly and lead to the corresponding anti-β-hydroxy hydrazones upon workup.</p><p>Despite the above evidence for irreversible formation of the anti-aldolate intermediates, there remained a strong indication that the net transformation was under thermodynamic control. In particular, as shown in Table 1 (entries 1 and 5), when the reaction was conducted at –78 °C a 2.5:1 mixture of syn-product 10a/11a to anti-product 10b/11b was generated. If, however, the reaction mixture was allowed to warm to room temperature, only anti-product 10b/11b was obtained (Table 1, entries 3 and 4). A plausible explanation for this was that only the syn-aldolate that formed at –78 °C was sufficiently unstable that the retro-aldol reaction could proceed. The anti-aldolate intermediate, on the other hand, being relatively stable, did not undergo the reverse reaction. Thus, when the 2.5:1 mixture of syn- to anti-aldolates that was generated at –78 °C was removed from the cold bath and allowed to warm to room temperature (cf. Table 1, entries 3 and 4), the anti-aldolate was unaffected, but the less stable syn-aldolate underwent the retro-adol process. Over time, all of the less stable syn-aldolate could be converted (irreversibly) to the anti-aldolate, ultimately giving exclusively the anti-aldol addition product upon workup.</p><p>To test this theory 4-(trifluoromethyl)benzaldehyde was added to a solution of the azaenolate generated at –78 °C (Scheme 4a). After 5 min, p-tolualdehyde was added, the cold bath was removed and the mixture was allowed to stir for 2 h while warming to room temperature. A mixture of the two anti-aldol products 10b and 15 was obtained from this transformation in a ratio of approximately 3:1.10 These data support our assumption that once formed the anti-aldolate does not undergo the retro-aldol reaction due to its relatively high stability, and instead remains in the reaction mixture until it is quenched with NH4Cl, producing the corresponding anti-β-hydroxy hydrazone. In contrast, the less stable syn-aldolate does undergo retro-aldol addition, providing a pathway for it to be converted to the more stable anti-form (12), leading to anti-β-hydroxy hydrazone upon workup.</p><p>To gain further evidence for the reversible formation of the syn-adolate in these reactions, pure syn-aldol product 10a was dissolved in THF and added to a solution of LDA at –78 °C (Scheme 4b). The mixture was allowed to stir for 5 min, the cold bath was removed, and stirring was continued for 2 h while warming to room temperature. Upon work up only anti-aldol product 10b was obtained. The most likely pathway for the conversion of 10a to 10b would begin with deprotonation of the β-hydroxyl group of 10a by LDA, giving the corresponding syn-aldolate (16). This species would then undergo retro-aldol addition to provide the corresponding azaenolate (17) and aldehyde. Some portion of this mixture would recombine in an irreversible fashion to produce the anti-aldolate (12), with the remainder reforming the syn-aldolate, reversibly. Over time, all of the syn-aldolate would be converted to the more stable anti-aldolate, ultimately giving 10b upon workup.11</p><p>Taken collectively the above data are consistent with a mechanism (Scheme 5) wherein the azaenolate (19) and aldehyde react in an irreversible manner at –78 °C to give the syn-(R,S)-aldolate (20) and the anti-(R,R)-aldolate (21) in a ratio favoring the syn-intermediate. Upon warming to room temperature, the syn-intermediate undergoes retro-aldol addition to reform the azaenolate (19) and the aldehyde. In contrast, anti-aldolate (21) is stable and does not undergo the retro-aldol reaction. Some portion of the azaenolate and aldehyde generated from the breakdown of 20 goes on to irreversibly produce anti-aldolate 21, with the remainder reverting back to the syn-aldolate. Eventually, all of the syn-adolate is converted to the anti-aldolate by repetition of this process. Protonation of 21 upon workup provides exclusively the anti-β-hydroxy hydrazone (22). Alternatively, (not shown) direct alkylation of aldolate 21 upon addition of BnI prior to workup gives the corresponding anti-β-benzyloxy hydrazone.4</p><p>With regard to the stereochemical outcome of this transformation, two factors must be addressed. The first is why the syn-(R,S)-aldol (cf. 10a/11a, Table 1) and the anti-(R,R)-aldol (cf. 10b/11b) products are produced in these reactions, whereas the syn-(S,R)-aldol (cf. 10c/11c) and the anti-(S,S)-aldol (cf. 10d/11d) are not. The second factor is why the anti-(R,R)-aldolate (21) (Scheme 5) is significantly more stable than the syn-(R,S)-aldolate (20).</p><p>The first of these two issues can be explained by reference to the stereochemical model that we have developed for alkylation of ACC hydrazone-derived azaenolates with alkyl halides.5a,c As shown in Scheme 6, the generalized ACC hydrazone (23) exists preferentially in the conformation depicted as 23b, where steric interactions between R1 and R2 and the larger substituent (L) on the auxiliary are minimized. Coordination of LDA to the carbonyl group then leads to complex induced syn-deprotonation (CIS-D),5a,c,e giving the ECC/ZCN-azaenolate 24 as a five-membered chelate. In this form the bottom (re) face of 24 is blocked causing alkylation to take place selectively at the top (si) face,12 which leads to the R-configuration at the stereogenic center α-to the hydrazone. The requirement of top (si) face alkylation of the azaenolate, therefore, precludes the possibility of generating the syn-(S,R)-aldolate (26) and the anti-(S,S)-aldolate (27). Consequently 20 and 21 are the only aldolates that are accessible from addition of an aldehyde to azaenolate 19.</p><p>Further investigations of this aspect of the reaction mechanism were carried out computationally on 19, R1 = R2 = Me for the azaenolate, R3 = Ph for the aldehyde. Unless otherwise indicated, all calculations were carried out at the M06–2X/6–311+G(d,p)//ωB97XD/6–31+G(d) level using the IEF-PCM solvent model to simulate the bulk THF solution.13 Full details are reported in the Computational Details section. The free energy differences are initially reported to be those calculated at 200K. The optimized structure for the azaenolate is shown in Figure 1. Here, the lithium cation is coordinated to two THF ligands yielding a tetrahedral four-coordinate environment, which is typical for this cation.14 The computed Li-O distances average 1.96 Å, which is identical to the average bond lengths found for lithium coordinated ethers.15 Attack from the bottom face (orange arrow in 19) is blocked by the dimethylnorbornyl unit. The aldehyde must, therefore, approach from the top side of the azaenolate (green arrow in 19). Using benzaldehyde to approach the azaenolate produced two minima corresponding to 28 and 29, which lead to the syn- and anti-products, respectively (vide infra). In both cases a lone pair on the carbonyl oxygen is used to form a σ-dative bond with the lithium cation. The O-Li distance was computed to be 2.02 Å and 1.99 Å for 28 and 29, respectively, which are typical14 for compounds of this type. Of particular importance is that the syn-σ–intermediate (28) is 0.6 kcal/mol more stable than the anti-species (29). The reason for this is that in 29 the phenyl group is folded towards the coordinated THF and dimethylnorbornyl regions, whereas in 28 it is extended away from these regions. As a consequence, in 29 there is a close contact between the hydrogen on the ortho-carbon of the phenyl group and an oxygen atom, along with a hydrogen atom in the THF. (Illustrated in blue on the right side of Figure 1.) The formation of a four-coordinate lithium cation in 28 and 29 requires that one bound THF ligand (presumably the one on the side opposite to the incoming benzaldehyde ligand) be displaced. The complication here is that loss of one THF molecule need not occur. Optimization of the resultant five-coordinate species produced two structures that are also minima on the potential energy surface (Figure 2). The geometry around the lithium cation in both cases is close to an ideal trigonal bipyramid with benzaldehyde occupying an equatorial site. Importantly, the syn-structure (30) is again 0.9 kcal/mol more stable than the anti-species (31). Bond length metrics in 30 and 31 are not much different than their four-coordinate counterparts. Structures 30 and 31 are 5.5 and 5.2 kcal/mol, respectively, below the energy of their four-coordinate counterparts. It is expected that a facile equilibrium16 will exist between the four and five coordinate σ–intermediates. In fact, while the preponderance of crystal structures for this type of structure contain four-coordinate lithium, five-coordinate structures are also plentiful.17 This presents a problem in our theoretical analysis of the reaction mechanism.</p><p>Figure 3 illustrates the computed reaction potential energy surface, in implicit THF solvent at 200K, for both the syn (in red) and the anti (in green) addition pathway. Notice that the five-coordinate intermediates (30 and 31) are illustrated in this Figure. Recall that the four-coordinate intermediates (28 and 29) lie respectively 5.5 and 5.2 kcal/mol higher in energy than their five-coordinate analogs. The next step in the mechanism forms a C–C bond between the carbonyl carbon of benzaldehyde and the α-carbon of the azaenolate, leading to the anti-21 or syn-20 product. As shown in Figure 3 the barriers here are minuscule. The N–Li bond length stretches from 2.18 Å in 30 to 2.42 Å in the associated transition state where the (THF)O–Li distances are 2.12 Å and 2.07 Å. Transition states where the four coordinate σ-intermediates lead to products 20 and 21 were not located. Notice that the lone pair on the nitrogen atom coordinated to the lithium cation is broken. The resultant structure, upon forming the C–C bond from the four-coordinate 28 and 29, would possess a three-coordinate lithium cation, which is quite unusual.17,18 Our hypothesis is that the C–C coupling steps occur via the five coordinate σ-intermediates. As shown in Figures 1 and 2, the C–C distances between the carbonyl and the α-azaenolate carbons are quite short in the σ-intermediates. The steric factors mentioned previously push the carbonyl carbon closer to the azaenolate for the anti-isomer and create a barrier that is smaller. The low barrier in this step for both isomers is reflected in the HOMO as shown in Figure 4 for the anti σ-intermediate (29). The filled middle π orbital of the azaenolate interacts with the π* carbonyl orbital in a bonding fashion. Notice that there is also a small in-phase interaction between the aza-nitrogen and carbonyl oxygen. This also serves to anchor the benzaldehyde in the correct position to form the C–C bond. The small barriers in the C–C coupling step suggested that quantum mechanical tunneling might also be operative. Several approaches have been used19 to gauge the importance of a tunneling mechanism. Here we have used a semi-classical approach developed by Miller and coworkers.20 At 200 K the estimated rate constant with tunneling was 8.5 × 108 sec−1 and 7.6 × 108 sec−1 without the tunneling correction. Thus, quantum mechanical tunneling is not expected to have a significant effect on the reaction dynamics. Notice in Figure 3 that while the syn σ-intermediate (30) is more stable than the anti (31) the opposite is true for the associated transition states, TS(2). We will return to this issue shortly. The required number of THF molecules to solvate a lithium cation has been explored in the past18 and, in general, this has been found to range from three to five. Molecular dynamics simulations have been used21 to address these facile lithium–ether solvation equilibria. This would be the proper way to address the solvation issue here, but the required dynamic simulations presently lie well beyond our computational abilities.</p><p>Two transition states were located that connect azaenolate 19 and benzaldehyde to 30 and 31. The structure of one of the transition states, 32, which leads to intermediate 31 is shown on the left side of Figure 5. The two nearly identical (THF)O–Li distances clearly indicate that an associative rather than dissociative mechanism occurs for the addition of benzaldehyde to precursor 19. The long (benzaldehyde)O–Li distance of 3.28Å indicates an early transition state. Furthermore, very similar metrical details are associated with TS(1) for the syn isomer. Consequently, the two isomers for TS(1) lie at essentially the same relative energy. Three minima were found (and there are probably more) which correspond to weak dipole-dipole complexes between 19 and benzaldehyde. Two were located on the face of 19 aligned with the orange arrow shown in Figure 1. In the third isomer (33) the benzaldedyde is positioned along the green arrow in Figure 1 and, therefore, serves as the intermediate which leads to TS(1). The structure of this complex is shown on the right side of Figure 5. Here the (benzaldehyde)O–Li distance is 5.38Å. The other two intermediates lie 0.2 and 1.7 kcal/mol above the energy of 33.</p><p>The next issue with regard to the stereochemical course of the reaction is why the anti-(R,R)-aldolate (21) is thermodynamically more stable than the syn-(R,S)-aldolate 20. The theoretical calculations (Figure 3) show that 21 becomes lower in energy than 20 by ΔΔG = 3.7 kcal/mol at 200K. This is due to the existence of fewer gauche interactions across the formed C–C bond in 21 as shown in Figure 6. The steric situation here is analogous to a syn-pentane interaction.22</p><p>It is known that under reversible, thermodynamically-controlled conditions, simple aldolates obtained from the addition of ketone-derived enolates to aldehydes are more stable in their anti- rather than syn-form.7,8 This can be explained by assuming that the six-membered aldolate adopts a chair-like conformation (Scheme 7a). In this form the anti-aldolate (34/36) is lower in energy than its syn-counterpart (35/37) due to a minimization of diaxial steric interactions. For the present ACC aldol addition, a simple six-membered chair chelate is not possible and, therefore, cannot be used to account for the enhanced stability of the anti-aldolate (21) over the syn-aldolate (20). The inability to form a six-membered chelate results from the fact that the Z-configuration of the hydrazone renders the nitrogen lone pair physically inaccessible. In contrast, a nine membered chelate in which the lone pair of the auxiliary carbonyl interacts with the lithium ion is reasonable (cf. 38 and 39). Indeed, it is the interaction of this lone pair with the lithium cation from LDA that forms the basis of CIS-D, enabling regioselective formation of the azaenolate.5a,c,e A representation of an energetically-minimal nine-membered chelate corresponding to the anti-aldolate intermediate is shown in Scheme 7b (38). In comparison to this species, the corresponding syn-aldolate intermediate (39) suffers from a significant steric interaction between R1 and R3, as further demonstrated for the computed structures in Figure 5, highlighting its relative instability in comparison to 38. As previously mentioned, the ΔΔG at 200 K was computed to be 3.7 kcal/mol. Such an energy difference is sufficient to account for the exclusive formation of the anti-aldol product even if the syn- and anti-aldolate intermediates were in equilibrium with one another.</p><p>The notion of a nine-member chelated anti-aldolate intermediate is also supported by observations from the 1H NMR spectra and X-ray crystal structures. The 1H NMR spectrum of the anti-product 10b and 11b (Table 1) each display a hydroxyl resonance (5–6 ppm) as a doublet. This is indicative of an intramolecular hydrogen bond, which according to molecular models could reasonably exist between the β-hydroxyl group and the carbonyl of the ACC chiral auxiliary. Such an interaction occurs via a nine-membered ring. The existence of this hydrogen bond is also supported by the X-ray crystal structure of aldol product 11b (Figure 7).23 By analogy to the hydrogen bond of 10b it stands to reason that the anti-aldolate intermediates (21) could chelate lithium between the alkoxide and the auxiliary carbonyl via a nine-membered ring as a stabilizing factor. Neither the 1H NMR spectra of syn-aldol products 10a and 11a, nor the X-ray structure of 11a (Figure 7) support the existence of an intramolecular hydrogen bond.</p><p>Recalculating the free energies of the reaction at room temperature does not introduce much change in the relative energies. At 298 K the syn-σ-intermediate is again more stable than the anti by a smaller amount, 0.5 kcal/mol. The four-coordinate intermediates are now only 1.6 kcal/mol above their five-coordinate counterparts and, therefore, become energetically viable where again the syn isomer is 0.5 kcal/mol more stable than the anti. Finally the energy difference between products 20 and 21 has increased to 3.7 kcal/mol. The relative energies of the remaining stationary points lie within 0.2 kcal/mol of their 200K counterparts.</p><p>We believe that are two possible scenarios that can be used to describe the reaction mechanism. The first, and simpler, is that TS(1) is the rate determining transition state for the reaction sequence. The lower barrier for the syn isomer then is consistent with favoring the kinetic product (20) at low temperatures. Thermodynamic control operates at room temperature and the anti-diastereomer (21) becomes the exclusive product. The problem with this explanation is that TS(1) occurs very early along the reaction path. It is understandable that the energy difference between the two transition states (0.2 kcal/mol) is so small that even the relative energy ordering is suspect. Furthermore in a multistep reaction such as this, the control of the overall rate is not straightforward.24 An alternative hypothesis for the full reaction mechanism may be detailed as follows: Referring back to Figure 3 at 200 K, at low temperature the syn- and anti-σ-intermediates (30 and 31) (in rapid equilibrium with 28 and 29), may either with essentially no activation barrier pass on to products 20 and 21, or revert back to 33. The Curtin-Hammett principle25 would predict that the observed product ratio should be a reflection of the relative energies of the transition states in the rate-determining step. This is only true if there is a rapid equilibrium between the syn- and anti-intermediates.26 Here, there is a significant barrier for rotation around the phenyl–carbonyl carbon bond going from the syn- to anti-σ-intermediate. Rigid rotation around this bond by 40° requires 6.4 kcal/mol. A transition state for isomer interconversion would require a rotation of about 90°. The ACC auxiliary very effectively encapsulates benzaldehyde in the σ-intermediates. This is demonstrated by plots of the van der Waals surface, which are given in the Supplementary Materials. The ultimate product ratio is then determined by the energy difference of the σ-intermediates.26,27 A ΔG of 0.9 kcal/mol translates into a product ratio for 20:21 of 9:1. The experimental ratio of 2.5:1 would correspond to a ΔG of 0.4 kcal/mol. Given our level of theory and the approximations involved [the ΔG associated with the four coordinate intermediates (28 and 29) is 0.6 kcal/mol], we consider that the agreement between experiment and theory is satisfactory. The data are consistent with a mechanism that does not follow the Curtin-Hammett principle. Instead our hypothesis is that the product ratio at low temperature is given by the relative energies of the intermediates. Calculations on the stationary points from the σ-intermediates to products were also carried out with the ωBP97XD, B3LYP and PBE0 functionals at the same basis set levels. For all four functionals the relative level ordering of syn versus anti was the same, which leads credence to the results in Figure 3. We are aware of a number of other cases where this "feed-in"27,28 or "fast-trapping"29 reaction sequence has been shown to be operative. At room temperature there is enough kinetic energy to return the products to 33 for the syn-isomer. The free energy for return from the syn-product, 20, was calculated to be 13.7 kcal/mol as opposed to 18.1 kcal/mol for the anti-product, 21. Therefore, the thermodynamically favored anti-product is formed exclusively. While the basis set used is large and a number of density functionals have been employed, we do acknowledge that further theoretical work on this reaction mechanism should, as mentioned earlier, include a molecular dynamics treatment with the explicit involvement of THF solvent molecules. We look forward to this work in the future.</p><p>There does not appear to be anything special with the benzaldehyde framework. Computations using acetaldehyde reveal a very similar pattern to that just presented. The five-coordinate syn-σ-intermediate is 0.8 kcal/mol more stable than the anti (the difference is 1.4 kcal/mol for the four-coordinate species). The two five-coordinate σ-intermediates are now 0.7 kcal/mol more stable than the four-coordinate analogs. This is presumably a result of more efficient packing in the ACC pocket by acetaldehyde compared with benzaldehyde. At 200K the anti product is 2.1 kcal/mol more stable than the syn, in keeping with one more gauche interaction with a methyl group. Full details of the computational results are given in the Supporting Information section. Unfortunately, this prediction cannot be tested. Alkyl substituted aldehydes with an α-proton lead to polymerization products under the above reaction conditions. This is presumably due to the reversibility of the transformation and the lower pKa of the aldehyde α-protons compared to those of the hydrazone, which favors formation of the aldehyde-derived enolate.</p><!><p>In conclusion, we have investigated the mechanisms of the anti- and syn-selective ACC aldol addition reactions. Under kinetically controlled conditions (–78 °C), the reaction proceeds such that the syn-aldolate is formed preferentially. Interestingly, theoretical calculations for this reaction are most consistent with a mechanism that does not follow the Curtin-Hammett principle. Instead the product ratio at low temperature is given by the relative energies of the intermediates. In this instance the intermediate leading to the syn-product is sterically favored over that leading to the anti-isomer. In contrast, at room temperature the reaction is under thermodynamic control and gives a single anti-aldol addition product. This is due to the syn-aldolate undergoing a retro-aldol reaction, upon warming to room temperature, as a means of equilibrating to the thermodynamically more stable (approximately 3.7 kcal/mol by theoretical calculations at 298 K) anti-aldolate, which upon work up provides the observed anti-aldol product.</p><!><p>Unless stated to the contrary, where applicable, the following conditions apply: Reactions were carried out using dried solvents (see below) and under a slight static pressure of Ar (pre-purified quality) that had been passed through a column (5 × 20 cm) of Drierite. Glassware was dried in an oven at 180 °C for at least 12 h prior to use and then either cooled in a desiccator cabinet over Drierite or assembled quickly while hot, sealed with rubber septa, and allowed to cool under a stream of Ar. Reactions were stirred magnetically using Teflon-coated magnetic stirring bars. Teflon-coated magnetic stirring bars and syringe needles were dried in an oven at 180 °C for at least 12 h prior to use. Hamilton microsyringes were dried in an oven at 60 °C for at least 12 h prior to use and cooled in the same manner. Commercially available Norm-Ject disposable syringes were used. Dry benzene, toluene, Et2O, CH2Cl2, THF, MeCN and DME were obtained using an Innovative Technologies solvent purification system. All other dry solvents were of anhydrous quality purchased from Aldrich. Commercial grade solvents were used for routine purposes without further purification. Et3N, pyridine, i-Pr2NEt, 2,6-lutidine, i-Pr2NH, TMEDA were distilled over CaH2 under a N2 atmosphere prior to use. Flash column chromatography was performed on silica gel 60 (230–400 mesh) or, where indicated, high-grade silica gel (5–20 mesh). 1H and 13C NMR spectra were recorded on a JOEL-ECA-600, JEOL ECA-500 or ECX-400P spectrometer at ambient temperature. High-resolution Mass Spectrometry was acquired using an Agilent Technologies 6530 Accurate Mass Q-T of LC/MS for electrospray ionization (ESI), or a Micromass Autospec Ultima for chemical ionization (CI). The syn-anti ratios reported were computed from the 1H NMR spectrum of the crude material. Reactions were visualized on TLC plates using uv detection of Cerium-ammonium-molybdate (CAM) stain.</p><!><p>This compound was prepared by a known literature procedure, and the spectral data was identical to that reported therein.5a</p><!><p>This compound was prepared by a known literature procedure, and the spectral data was identical to that reported therein.4a</p><!><p>This compound was prepared by a known literature procedure, and the spectral data was identical to that reported therein.4a</p><!><p>This compound was prepared by a known literature procedure, and the spectral data was identical to that reported therein.4a</p><!><p>This compound was prepared by a known literature procedure, and the spectral data was identical to that reported therein.4a</p><!><p>n-Butyllithium (2.5 M in hexanes, 0.095 mL, 0.236 mmol) was added dropwise over ~2 min to a stirred and cooled (–78 °C) solution of i-Pr2NH (0.033 mL, 0.236 mmol) and THF (1.5 mL) (Ar atmosphere). The mixture was transferred to an ice-H2O bath, stirred for 30 min, and then cooled to –78 °C. A solution of 9 (0.050 g, 0.189 mmol) in THF (1.0 mL) was added and the mixture was stirred for 45 min. 4-CH3PhCHO (0.023 mL, 0.198 mmol) was added and the mixture was warmed to rt over 2 h. The reaction was then quenched with saturated NH4Cl(aq) (2.0 mL) with vigorous stirring. The mixture was partitioned between Et2O (10 mL) and H2O (10 mL) and the aqueous phase was extracted with Et2O (2 × 10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Flash chromotography over silica gel using 10:90 EtOAc/hexanes (v/v) gave 15 as a pure, colorless solid. 1H NMR (CDCl3, 600 MHz): δ 7.20 (d, 2H, J = 7.6 Hz), 7.13(d, 2H, J = 7.6 Hz), 5.34 (d, OH, J = 10.3 Hz), 4.41 (app. t, 1H, J = 10.3 Hz), 4.28 (dd, 1H, J = 4.1 Hz, 8.3 Hz), 3.20 (dq, 1H, J = 6.9 Hz, 11.0 Hz), 2.72 (dq, 1H, J = 7.6 Hz, 17.9 Hz), 2.54 (dq, 1H, J = 6.9 Hz, 17.9 Hz), 2.35–2.3 [m,4H, containing a s at 2.32 (3H)], 2.04–1.92 (m, 2H), 1.87 (dd, 1H, J = 8.3 Hz, 13.8 Hz), 1.80 (apparent t, 1H, J = 4.1Hz), 1.30–1.26 [m, 4H, containing a s at δ 1.26 (3H)], 1.21–1.16 [6H, containing a t at δ 1.19 (3H), J = 6.9 Hz and a s at δ 1.16 (3H)], 1.07 (m, 1H), and 0.80 (d, 3H, J = 6.9 Hz); 13C NMR (CDCl3, 100 MHz): 182.08,156.34, 140.76, 137.19, 129.04, 126.98, 83.58, 76.24, 73.81, 47.99,44.08, 42.98, 35.37, 26.42, 25.64, 24.18, 21.36, 21.25, 19.21, 15.88, and 10.10. HRMS (CI) calcd. for C23H32N2O3(M+Na)+: 407.2305, found: 407.2317. Melting point: 131–133 °C. [α]D22 = +163° in CHCl3 at a concentration of 1.5 (g/100mL).</p><!><p>n-Butyllithium (2.5 M in hexanes, 0.095 mL, 0.236 mmol) was added dropwise over ~2 min to a stirred and cooled (–78 °C) solution of i-Pr2NH (0.033 mL, 0.236 mmol) and THF (1.5 mL) (Ar atmosphere). The mixture was transferred to an ice-H2O bath, stirred for 30 min, and then cooled to –78 °C. A solution of 9 (0.050 g, 0.189 mmol) in THF (1.0 mL) was added and the mixture was stirred for 45 min. 4-CF3PhCHO (0.029 mL, 0.195 mmol) was added and the mixture was warmed to rt over 2 h. 2-naphthaldehyde (0.030g, 0.195 mmol) was added and the mixture was stirred for 2 h. The reaction was then quenched with saturated NH4Cl(aq) (2.0 mL) with vigorous stirring. The mixture was partitioned between Et2O (10 mL) and H2O (10 mL), and the aqueous phase was extracted with Et2O (2 × 10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. 1H NMR analysis of the crude material indicated 10b was the sole product. Spectral data was identical to that reported previously.4a</p><!><p>n-Butyllithium (2.5 M in hexanes, 0.095 mL, 0.236 mmol) was added dropwise over ~2 min to a stirred and cooled (–78 °C) solution of i-Pr2NH (0.033 mL, 0.236 mmol) and THF (1.5 mL) (Ar atmosphere). The mixture was transferred to an ice-H2O bath, stirred for 30 min, and then cooled to –78 °C. A solution of 9 (0.050 g, 0.189 mmol) in THF (1.0 mL) was added and the mixture was stirred for 45 min. 4-CH3PhCHO (0.023 mL, 0.195 mmol) was added and the mixture was warmed to rt over 2 h. 2-naphthaldehyde (0.030g, 0.195 mmol) was added and the rmixture was stirred for 2 h. The reaction was then quenched with saturated NH4Cl(aq) (2.0 mL) with vigorous stirring. The mixture was partitioned between Et2O (10 mL) and H2O (10 mL), and the aqueous phase was extracted with Et2O (2 × 10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. 1H NMR analysis of crude material indicated 15 was the sole product. Spectral data was identical to that given above.</p><!><p>n-Butyllithium (2.5 M in hexanes, 0.095 mL, 0.236 mmol) was added dropwise over ~ 2 min to a stirred and cooled (–78 °C) solution of i-Pr2NH (0.033 mL, 0.236 mmol) and THF (1.5 mL) (Ar atmosphere). The mixture was transferred to an ice-H2O bath, stirred for 30 min, and then cooled to –78 °C. A solution of 9 (0.050 g, 0.189 mmol) in THF (1.0 mL) was added and the mixture was stirred for 45 min. 4-CF3PhCHO (0.029 mL, 0.195 mmol) was added, the mixture was stirred for 5 min, and 2-CH3PhCHO (0.023 mL, 0.195 mmol) was added. The mixture was stirred for 5 min and then warmed to rt over 2 h. The reaction was then quenched with saturated NH4Cl(aq) (2.0 mL) with vigorous stirring. The mixture was partitioned between Et2O (10 mL) and H2O (10 mL) and the aqueous phase was extracted with Et2O (2 × 10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. 1H NMR analysis of the crude material indicated a 3:1 mixture of 10b to 15. Spectral data was identical to identical to that reported previously.4a</p><!><p>n-Butyllithium (2.5 M in hexanes, 0.108 mL, 0.271 mmol) was added dropwise over ~2 min to a stirred and cooled (–78 °C) solution of i-Pr2NH (0.033 mL, 0.236 mmol) and THF (1.5 mL) (Ar atmosphere). The mixture was transferred to an ice-H2O bath, stirred for 30 min, and then cooled to –78 °C. A solution of 10a (0.095 g, 0.217 mmol) in THF (1.0 mL) was added and the mixture was stirred for 45 min and warmed to rt over 2 h. The reaction was then quenched with saturated NH4Cl(aq) (2.0 mL) with vigorous stirring. The mixture was partitioned between Et2O (10 mL) and H2O (10 mL) and the aqueous phase was extracted with Et2O (2 × 10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Analysis of the crude material indicated 10b was the sole product. Spectral data was identical to identical to that reported previously.4a</p><!><p>All computations were performed with Gaussian09.30 Geometries were optimized at the IEFPCM31-ωB97X-D32/6–31+G(d)33 level (R1 = R2 = Me for the azaenolate, R3 = Ph for the aldehyde) using THF as the solvent. The nature of each optimized structure was verified by calculation of the vibrational frequencies and the transition states were checked by calculation of the IRC.34 Single point calculations with a 6–311+G(d,p) basis35 used the M06–2X density functional36 and the reported relative energies all include thermal free energy corrections from the lower level. Computation of the entropy of solvation has proven to be a very difficult issue.37,38 The free energies reported in this work correspond to the ΔG50% scheme by Plata and Singleton.37 M06–2X was chosen as the functional because it has been shown to be more reliable than ωB97X-D39 and in particular for the relative energies associated with isomeric aldol reactions.40 In our case the results using ωB97X-D were not substantially different from those using M06–2X. Results based on single point calculations at the ωB97X-D/6–311+G(d,p) level, as well as those using acetaldehyde are given in the Supplementary Materials section. Molecular graphics were produced using the CYLview program.41 The Multiwell package42 was used to calculate the rate constants. Tunneling contributions here were estimated using the approach by Miller and coworkers.20 With 80 atoms harmonic rather than anharmonic frequencies were employed in the calculations due to computational limitations.</p>