Catalyst-control over sixfold stereogenicity
Governing higher-order stereogenicity is a long-standing goal in stereoselective catalysis, because it allows to achieve selectivity for more than a twofold number of stereoisomers per stereogenic unit. Current methods warrant control over the power of two stereoisomers and the configurations are routinely assigned using the descriptors (R ) and (S ), or related binary codes. In contrast, conformational analysis ranges beyond this dualistic treatment of stereoisomerism, which constitutes an unmet challenge for catalyst stereocontrolled processes. Herein, we now report that sixfold stereogenicity can be governed by stereoselective catalysis. By controlling a configurationally stable stereogenic axis with six large rotational barriers, a catalytic [2+2+2]-cyclotrimerization selectively governs the formation of one out of six stereoisomers with up to 0:0:2:98:0:0 stereocontrol. The underpinnings of conformational analysis and stereoselective catalysis are thereby conceptually reunited. Novel molecular architectures featuring distinct chemical topologies and unexplored chemical designs are anticipated from catalystcontrol over higher-order stereogenicities.Stereogenic units typically spawn a twofold number of possible stereoisomers and their configurations are assigned with binary stereochemical descriptors such as (R ) and (S ). The overall number of possible stereoisomers is thus commonly predicted by the Le Bel-Van 't Hoff rule, as two raised to the power of the number of stereogenic units (2 n ), while the symmetrical meso compounds are subtracted. This binary stereochemical conception of stereoisomerism represents the current realm of stereoselective catalysis and a wide range of bioactive compounds critical for our healthcare are elegantly prepared by controlling the configuration of the desired stereoisomers (1 ). Also atropisomeric compounds, stereoisomers that result from the restricted rotation about a single bond, are accounted for by the two different enantio-or diastereoisomeric states that provide unique utility in organic synthesis (Fig. 1A) (2-9 ). For instance, prototypical ortho-substituted biaryls are characterized by two elevated rotational barriers that differentiate the structurally well-defined (Ra)-and (Sa)-configured atropisomers under synthetically meaningful conditions (10)(11)(12)(13)(14). Nevertheless, at extremely low temperatures, the shallow barriers arising from π-conjugation result in further differentiation of the conformational states, similar to n -butane that displays three conformational stereoisomers which would otherwise rapidly interconvert (Fig. 1B) (15)(16)(17). Interestingly, unusual atropisomeric natural products, such as the cordypyridones, with rotationally restricted stereogenic C(sp 2 )-C(sp 3 ) axes were found to be sufficiently stable also under ambient conditions (Fig. 1C) (18,19 ). Archetypical C(sp 2 )-C(sp 3 )-atropisomers with suitably high barriers, as the ones pioneered by Ōki, feature six stereoisomers from the restricted rotation about a single bond, which were distinguished and influenced by other stereogenic units (Fig. 1D) (20-25 ). The Ōki atropisomers, which are reminiscent to molecular motors (26,27 ), epitomize compounds with higher-order stereogenicity for which stereoselective strategies are markedly required. Herein, we present that catalyst-control over sixfold stereogenicity can be governed in interlocked atropisomers with rotationally restricted C(sp 2 )-C(sp 3 ) axes by means of Rh-catalyzed [2+2+2]-cyclotrimerizations (28-32 ).
<p>We initiated our study by preparing trialkyne ethenoanthracene substrate 1a bearing a bulky adamantyl group to give an interlocked molecular system 2a in an ensuing cyclotrimerization (Fig. 2A and Table S1). Intriguingly, three racemic diastereoisomers emerged from the stereogenic C(sp 2 )-C(sp 3 ) axis with the racemic rhodium/SEGPHOS catalyst. A diastereomeric ratio of 1:1.3:1.5 was observed by nuclear magnetic resonance (NMR) spectroscopy, corresponding to a 13:17:20:20:17:13 distribution of the six stereoisomers. Remarkably, the three diastereomers could be separated by thin layer chromatography and were assigned to the synperiplanar (sp ), clinal (c ) and antiperiplanar (ap ) configurations (33,34 ).</p><p>The three pairs of enantiomers were consequently resolved by high-performance liquid chromatography (HPLC) on a chiral stationary phase. However, over the course of 2-16 hours, slow interconversion of the isomers was observed at room temperature, indicating an equilibration with (+ap )⇆(+c )⇆(+sp )⇆(-sp ) directionality and vice versa. In contrast, a direct enantiomerization of (+ap )⇆(-ap )-isomers, requiring the adamantyl group to travers over the inner carbonyl group, was not detected (Figs. S1-S3). These observations were substantiated by NMR studies (Fig. S4-S8), which established bond rotational barriers in the range of 73-110 kJmol -1 (Fig. 2B). At temperatures relevant for organic synthesis, the rotation about the stereogenic axis is hence slowed but not prevented in this six-step molecular system. Nevertheless, correlating the bond rotational profile with the ortho-aryl substituents interlocked into the three ethenoanthracene segments allowed to recognize, that pronounced configurationally stability of the rotationally restricted C(sp 2 )-C(sp 3 ) axis is reached when an interdigitating carbonyl function is introduced to significantly increase all six bond rotational barriers of the atropisomer 2b to >120 kJmol -1 (Fig. 2C).   The unique configurational stability of product 2b relieved from obstructing atropisomerization processes provides a means to address selectivity over the sixfold stereogenicity with catalyst control. We thus first examined how the stereoselectivity is influenced for [2+2+2]-cyclotrimerizations by the choice of catalysts that select one out of six possible isomers (Fig. 3). Notably, the reaction with (Sa)-SEGPHOS (L1) afforded two diastereoisomers with antiperiplanar (ap)-2b and clinal (c)-2b configurations in 92:8:0 selectivity and without detectable synperiplanar isomers (sp)-2b (entry 1). However, both pairs of enantiomers were obtained in racemic form. When a neutral rhodium catalyst and the chiral ligand (Ra)-DM-BINAP (L2) were employed, a modest enantioselectivity was observed for both the (ap)-and (c)- stereoisomers (entry 2). Notably, only one pair of enantiomers (ap) was observed when decreasing the reaction temperature (entries 3-5) and a broad range of catalysts and conditions were consequently explored to control the selective formation of a specific stereoisomer by diminishing the pathways to the other five atropisomers (Tables S2-S4). Gratifyingly, the use of the bisphosphine ligand (Sa)-xyl-SDP (L4) (35 ) ultimately allowed an excellent stereoselectivity of 0:0:7:93:0:0 for the (+ap)-configured stereoisomer, which was isolated in 75% yield (entry 5).  S2-S4). Isolated yields. Diastereomeric ratios were determined by NMR measurements of crude material and enantiomeric ratios by high-performance liquid chromatography on a chiral stationary phase.</p><p>With the optimal conditions in hand, the generality of catalyst-control over sixfold stereogenicity was explored (Fig. 4A). With trialkynes possessing a variety of substituents on the C(sp 3 ) component, the corresponding cyclized products were obtained in high yields (2b-2h). Interestingly, the N-aryl groups showed a remarkable effect on the enantioselectivity of the reactions. The para-bromophenyl product 2c</p><p>was obtained with excellent selectivity for one of the six atropisomers (0:0:2:98:0:0), while substrates bearing a more electron-rich group afforded products with lower enantiomeric ratios. We next investigated the influence of variations at the C(sp 2 ) component on reactivity and selectivity by introduction of different tether moieties between the triple bonds (Fig. 4B). Substrates with tosylamide linkages provided good yields and selectivities (2i-2k) and also the diethyl malonate tether was tolerated (2l). While sixfold stereogenicity results from the restricted rotation about the stereogenic C(sp 2 )-C(sp 3 ) axis, compound 2e further includes a stereogenic C-N axis. Intriguingly, this scaffold represents an atropisomeric two-axis system where the six-and twofold stereogenicities give rise to twelve stereoisomers. Nevertheless, a 2:1 equilibrium of rapidly interconverting C-N atropisomers was observed, and a barrier of 70 kJmol -1 was determined by NMR measurements (Figs. S9-S12). Moreover, the resulting C(sp 2 )-C(sp 3 ) atropisomers 2 are competent of undergoing a photochemical di-π-methane rearrangement to a semibullvalenes 3 when irradiated by blue LED light (Fig. 4C) (36 ). The radical cascade process was found to occur with excellent stereospecificity, thereby governing the configuration of four stereocenters and one stereogenic axis (e.r. 93:7 for 3b), which establishes the transformability of the stereochemical features of C(sp 2 )-C(sp 3 ) atropisomers. We have demonstrated the feasibility of catalyst-control over higher-order stereogenicities by a Rhcatalyzed-[2+2+2]-cyclotrimerization, governing the formation of one out of six stereoisomers emerging from a single stereogenic unit. Based on studies of a transitionally stereodynamic ortho-substituted aryl ethenoanthracene with a restricted rotation about a C(sp 2 )-C(sp 3 ) axis, interlocked and thereby configurationally stable atropisomers with six pronounced rotational barriers were assembled and examined. The choice of a suitable ligand furnished a catalytic system that selectively provides enantioand diastereoisomerically enriched atropisomers resembling a halted molecular six-step motor that could otherwise adopt five additional conformational states. We therefore anticipate that catalyst-control over higher-order stereogenicities opens new avenues for the design of functional molecular systems and imparts broad implementations in stereoselective catalysis.</p>