Transition State Models for Understanding the Origin of Chiral

Apr 21, 2016 - At the heart of all such manifestations of asymmetric catalysis, ... Biying ZhouMoriana K. HajEric N. JacobsenK. N. HoukXiao-Song Xue...
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Transition State Models for Understanding the Origin of Chiral Induction in Asymmetric Catalysis Published as part of the Accounts of Chemical Research special issue “Computational Catalysis for Organic Synthesis”. Raghavan B. Sunoj* Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India

CONSPECTUS: In asymmetric catalysis, a chiral catalyst bearing chiral center(s) is employed to impart chirality to developing stereogenic center(s). A rich and diverse set of chiral catalysts is now available in the repertoire of synthetic organic chemistry. The most recent trends point to the emergence of axially chiral catalysts based on binaphthyl motifs, in particular, BINOLderived phosphoric acids and phosphoramidites. More fascinating ideas took shape in the form of cooperative multicatalysis wherein organo- and transition-metal catalysts are made to work in concert. At the heart of all such manifestations of asymmetric catalysis, classical or contemporary, is the stereodetermining transition state, which holds a perennial control over the stereochemical outcome of the catalytic process. Delving one step deeper, one would find that the origin of the stereoselectivity is delicately dependent on the relative stabilization of one transition state, responsible for the formation of the predominant stereoisomer, over the other transition state for the minor stereoisomer. The most frequently used working hypothesis to rationalize the experimentally observed stereoselectivity places an undue emphasis on steric factors and tends to regard the same as the origin of facial discrimination between the prochiral faces of the reacting partners. In light of the increasing number of asymmetric catalysts that rely on hydrogen bonding as well as other weak non-covalent interactions, it is important to take cognizance of the involvement of such interactions in the sterocontrolling transition states. Modern density functional theories offer a pragmatic and effective way to capture non-covalent interactions in transition states. Aided by the availability of such improved computational tools, it is quite timely that the molecular origin of stereoselectivity is subjected to more intelligible analysis. In this Account, we describe interesting molecular insights into the stereocontrolling transition states of five reaction types, three of which provide access to chiral quaternary carbon atoms. While each reaction has its own utility and interest, the focus of our research has been on the mechanism and the origin of the enantio- and diastereoselectivity. In all of the examples, such as asymmetric diamination, sulfoxidation, allylation, and Wacker-type ring expansion, the role played by non-covalent interactions in the stereocontrolling transition states has been identified as crucial. The transfer of the chiral information from the chiral catalyst to the product is identified as taking place through a series of non-covalent interactions between the catalyst and a given position/ orientation of the substrate in the chiral environment offered by the axially chiral catalyst. The molecular insights enunciated herein allude to abundant opportunities for rational modifications of the present generation of catalysts and the choice of substrates in these as well as related families of reactions. It is our intent to propose that the domain of asymmetric catalysis could enjoy additional benefits by having knowledge of the vital stereoelectronic interactions in the stereocontrolling transition states.

1. INTRODUCTION The importance of transition states (TSs) in chemical catalysis has long been recognized. A catalyzed process follows a lowerenergy pathway due to the involvement of lower-energy TSs compared with the corresponding uncatalyzed pathway, resulting in rate enhancements.1 The literature, spanning both chemistry © XXXX American Chemical Society

and molecular biology, routinely makes reference to TSs, albeit with varying connotations. In experimental organic chemistry, structural and electronic features of TSs are often invoked to Received: January 31, 2016

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highly likely that the preferences for the addition to the si and re prochiral faces are not equal. In fact, the difference in the Gibbs free energies of the TSs for the si and re face additions, denoted as ΔG⧧, is a desirable feature for enhanced stereocontrol (Figure 2).

rationalize rate enhancement as well as product selectivity in reactions.2 What is intriguing is that although the transitory TSs remain elusive to experimental observation, they enjoy ubiquitous acceptance in the rationalization of experimental observations. In particular, concepts such as kinetic and thermodynamic control of product distributions are omnipresent. One of the didactic examples of TSs that makes its earliest appearance in organic chemistry textbooks is when one tries to rationalize endo/exo product selectivity in a Diels−Alder reaction. While there have been alternative views on the origins of endo selectivity, the most widely used interpretation relies on additional stabilization due to secondary orbital interactions in the endo TS. In this Account, the importance of transition state models in asymmetric catalysis is highlighted by using a select set of recent examples from our laboratory. It is implicitly proposed that the overemphasis on steric arguments in interpreting observed stereochemical outcomes be subjected to a timely refinement. With the advent of affordable density functional theory (DFT) methods that can capture dispersive and long-range interactions,3 computational tools have become increasingly more reliable in addressing real-life problems in asymmetric catalysis. Many of the chosen examples are from the domain of rapidly emerging multicatalytic protocols in asymmetric synthesis. The discussions revolve around the stereocontrolling TSs and are intended to shed light on the origins of stereoselectivity and illustrate how such insights could help further developments in the design of asymmetric catalysts.

Figure 2. Illustration of ΔG⧧ and the Boltzmann distribution for the calculation of enantiomeric excess (% ee). ΔG⧧R/S denotes the free energy difference between the pro-R and pro-S transition states.

The stereochemical relationship between these two TSs is diastereomeric. The Boltzmann distribution of these competing diastereomeric TSs would determine the extent of enantioselectivity. The larger the value of the free energy difference between the pro-R and pro-S transition states (ΔG⧧R/S), the greater is the enantioselectivity, and thus, this is regarded as one of the most important control elements in asymmetric catalysis. Computational methods offer an effective tool to locate such stereocontrolling TSs on the respective free energy surfaces.

2. ASYMMETRIC INDUCTION The process of transfer of chiral information from the catalyst to the product is termed asymmetric induction. The chiral catalyst usually forms a catalyst−substrate complex via either a covalent or non-covalent activation mode. Two such examples of catalyst− substrate complexes are given in Figure 1. The catalyst proline

3. COMPUTATIONAL PROTOCOLS IN THE STUDY OF STEREOSELECTIVITY The identification of the energetically most preferred TS is vital to the development of a robust stereoelectronic model. A detailed search through a plethora of mechanistic possibilities might be required, first to identify the lower-energy pathway. Within the lower-energy pathway, far more careful analyses of the conformational features of the TSs are equally important. Such rigor can engender a greater degree of confidence in the computation of a delicate quantity such as ΔG⧧. An immediately accompanying question on the stereocontrolling TSs pertains to the very origin of this energy difference. There are a few contemporary recipes for unraveling the origin of the vital energy difference ΔG⧧. In one such method, known as the activation−strain model (synonymous to the distortion−interaction model), the activation energy is partitioned as the difference between the attractive interaction between the distorted reactants in the TS and the sum of distortions in each reactant when they go from the reactant geometry to the TS geometry.6 Analysis of weak interactions in the TSs also offers more insights into the origin of the energy difference. The electron density distributions in the TSs can be examined by using topological analysis within the Atoms-in-Molecules framework.7 Identification of bond paths between the interacting atoms as well as the electron densities at the corresponding bond critical points (ρbcp) provides useful indicators of intramolecular interactions in a TS. ρbcp is proportional to the strength of the interaction, while the Laplacian as well as the total energy density at a bcp (H) can ascertain whether the interaction is covalent or ionic.8 A similar recent approach, known as the non-covalent interaction index (NCI), is based on the reduced density gradient and electron density.9 NCI can provide a qualitative picture of the regions of attractive non-covalent interactions, hydrogen bonding, and repulsive steric interactions in a TS.

Figure 1. Examples of (a) covalent activation and (b) non-covalent activation of substrates by chiral catalysts.

combines with a ketone to provide a more reactive nucleophilic enamine through covalent bond formation in the first example4 (Figure 1a), whereas hydrogen-bond activation of the electrophile takes place prior to the reaction in the second case (Figure 1b).5 In several instances, a chiral catalyst can exhibit a modest preference for the formation of an interaction complex with one of the possible orientations of the prochiral substrate, rendering one of its prochiral faces more amenable to the incoming reacting partner. An early inception of chiral induction can be regarded as occurring in the initial “chiral recognition” complex, which gets modulated at the TS. Certain basic premises involved in the computational study of asymmetric catalysis deserve mention here. The actual chiral induction takes place in the stereocontrolling TS. When a nucleophile adds to the prochiral faces of an electrophile in the presence of a chiral catalyst (or other source of chirality), it is B

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followed by the C1−N8 bond formation, which is the stereocontrolling event wherein the chirality at the developing stereogenic carbon is decided. The addition of the aziridinone nitrogen to the re face of the diene is 3.3 kcal/mol more preferred than that to the si face. The preference for cis or trans diastereoselectivity of the final product would depend on the second C2−N6 bond formation through the reductive elimination step. The formation of the trans product is noted as energetically more favorable, which is in line with the experimentally observed diastereomer. The enantiocontrolling C−N bond formation TS structures suggest that the facial discrimination between the si and re faces of the incoming diene does not appear to emanate from steric differential (Figure 3). However, the non-covalent interactions in the si and re face approaches exhibit notable differences. The number of C−H···π, C−H···O, and anagostic interactions is much more pronounced when the re face of the diene approaches the nitrogen of the palladated diaziridinone. The key interactions such as C−H···O and C−H···π can be noted as missing in the TS for the si face addition, resulting in some destabilization compared with the corresponding re face addition. The insights into the process of stereoinduction as described above could in principle be exploited as a tool for predicting new catalysts or substrates for the same and related class of reactions. On an optimistic ground, the idea of in silico catalyst design appears to hold promise.14 However, the challenges in the experimental verification of such predictions could be formidable. There have been efforts to design newer catalysts for different types of reactions.15 We have employed DFT computations to design of a series of phosphoramidites by way of fine-tuning the vital interactions in the TSs.16 Among the designed ligands shown in Figure 4, the first two were earlier reported to yield good enantioselectivities whereas the remaining ones are yet to be tested experimentally.11 A comparison of the computed ee values for 1 and 2 indicates good agreement with the experimental enantioselectivities. Two hot spots for modifications are the BINOL 3,3′-positions and the substituents on the amido nitrogen. It can be noted that the position of the gem-dimethyl group is important (1 vs 5), although the nature of the chiral center on the amido substituent does not seem to have a large impact (2−4). Suitable decorations, such as the introduction of an aryl group, can be beneficial as well (8). Stereoinversion without altering the axial chirality of the BINOL backbone is also likely by installation of an extended aromatic arm (7). A balance of the natures of the substituents on the amido and the BINOL is suggested as a potentially good strategy for catalyst design for the asymmetric diamination reaction.

These topological methods should be considered suitable for the purpose of comparison of the intramolecular interactions between two diastereomeric TSs, although they might not offer quantitative accuracies. In the following sections, some representative recent examples of asymmetric catalysis are employed to delineate the process of chiral induction in stereocontrolling TSs. The source of chirality in these examples is axially chiral phosphoramidite(s) as ligand(s) bound to a suitable transition metal or an axially chiral BINOL phosphoric acid.

4. CHIRAL INDUCTION BY AXIALLY CHIRAL PHOSPHORAMIDITES A large number of organic reactions make use of axially chiral compounds as a source of chirality. In one such recent example from the domain of palladium catalysis, an interesting strategy for introducing two nitrogen atoms across a double bond is reported. This approach, which came to be known as asymmetric diamination, stands out as an exclusive example in comparison with a gamut of other double-bond functionalization reactions.10 In another study, Shi and co-workers reported a palladiumcatalyzed asymmetric diamination of butadiene derivatives (Scheme 1a).11 We examined the mechanism and origin of the Scheme 1. (a) Pd−Phosphoramidite-Catalyzed Asymmetric Diamination; (b) Mechanism of Diamination of a Conjugated Diene by Di-tert-butyldiaziridinone

5. CHIRAL INDUCTION BY AXIALLY CHIRAL PHOSPHORIC ACIDS The use of BINOL-derived axially chiral phosphoric acids is one of the prototypical examples of Brønsted acid catalysis.17 A range of substituents that can be introduced at the 3,3′-positions of the BINOL framework enhance the diversity of BINOL phosphoric acids.18 While the catalytic ability of such phosphoric acids can readily be attributed to the Brønsted acidity, deeper understanding of the origin of the stereoselectivity requires knowledge of the TSs. In recent years we have examined a number of interesting reactions wherein the source of chirality stems from the axially chiral BINOL phosphoric acid or its variants.

stereoselectivity to gain insights into the chiral induction provided by the axially chiral ligands. It can be noticed that the source of chirality in this reaction is the phosphoramidite ligand, which is used in a gamut of recent reactions.12 The mechanism can be broadly viewed as involving activation of the diaziridinone by oxidative addition of palladium, leading to a palladacycle intermediate.13 Uptake of the diene would then be C

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Figure 3. Stereocontrolling C−N bond formation transition states for the addition of diene to the palladated diaziridinone obtained at the M06/6-31G*,LANL2DZ(Pd) level of theory. The numbers in parentheses are the relative Gibbs free energies (in kcal/mol).

Figure 4. Computationally designed phosphoramidites and the corresponding enantioselectivities (calculated at the M06/6-31G**//B3LYP/6-31G* level of theory) for asymmetric diamination. Numbers in parentheses refer to experimental % ee, wherever available.

5.1. Asymmetric Sulfoxidation

The two arms of the thioanisole through which it can interact with the catalyst are the aryl ring and the S-Me group. Evidently, these groups are not capable of engaging in stronger interactions with the catalyst framework. In other words, the incipient chiral recognition of the prochiral substrate and the developing chirality in the TSs are expected to be very similar for both the si and re face approaches of the thioanisole to the chiral pocket of the H2O2−catalyst complex. More interesting features became evident in the case of catalyst II, which has more aromatic decorations at the 3,3′-positions. With a larger π face, the substrate can develop more C−H···π interactions with the catalyst. Each such weak contact is likely to improve the chirality transfer, as the cumulative effect could be in just the right proportion for high levels of stereoinduction. The differential in such multipoint contacts holds the key to stereoinduction. The action of one chiral catalyst in a given reaction has been the focus of discussions until now. Perusal of the recent literature conveys an increasingly widespread use of multiple catalysts under one-pot reaction conditions.22 As with many other developmental strides in synthetic methodologies, mechanistic clarity in multicatalytic reactions continues to remain vague. Taking cognizance of these lacunae, we have examined the mechanistic intricacies of a number of cooperative asymmetric multicatalytic reactions.23 In the following sections, the origin of

Motivated by the importance of chiral sulfur-atom-containing compounds as pharmaceuticals, we examined an asymmetric sulfoxidation reaction wherein chirality transfer from an axially chiral phosphoric acid to a center of chirality in the product occurs (Scheme 2a). It can be noticed that catalyst II is quite effective in imparting high enantiocontrol whereas catalyst I yields surprisingly poor enantioselectivity.19 However, in reactions other than asymmetric sulfoxidation, catalyst I generally offers high enantioselectivity.20 Knowledge of the enantiocontrolling TS helped us decipher the origin of these contrasting abilities of BINOL phosphoric acids in asymmetric sulfoxidation. The reaction involves Brønsted acid activation of H2O2 and oxygenation of the sulfur center of the incoming thioanisole (a representative substrate here), which is then followed by the release of a molecule of water to yield the sulfoxidated product (Scheme 2b). In the stereocontrolling event, the oxygen of the activated H2O2 adds to the sulfur center. It can be noticed from Figure 5 that the oxygenation of the re face is only marginally more favorable than that to the si face in the case of catalyst I.21 The weak interactions that help hold the thioanisole in a desirable orientation for the oxygen transfer in these two TSs are quite similar, leading only to a modest energy differential between the diastereomeric TSs. D

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chiral induction in some of the most recent multicatalytic reactions is described.

Scheme 2. Phosphoric Acid-Catalyzed Asymmetric Sulfoxidation and the Mechanism

5.2. Asymmetric Allylation

A well-known challenge in asymmetric catalysis is to construct quaternary carbon centers. Some elegant solutions have recently emerged that could effectively address this issue.24 Similar to the earlier examples involving axially chiral phosphoric acids, we have probed the mechanism of a Tsuji−Trost asymmetric allylation (Scheme 3). Jiang and List25 showed that a combination of three catalysts such as benzhydrylamine, Pd(PPh3)4, and (S)-TRIP can provide access to quaternary chiral carbon atoms. The mechanism has been identified to involve an enamine nucleophile (derived from the secondary amine and the aldehyde) and a Pd−π-allyl electrophile (generated by the action of the phosphoric acid on the palladium-bound allyl alcohol).26 The bulkier triphenyl groups on the palladium precursor Pd(PPh3)4 should make way for the incoming reactants. The computed energies of the Pd−π-allyl intermediates with two or one PPh3 on the metal did not offer much clarity as to what could potentially be the active electrophile. Hence, we addressed this problem in greater detail to compare two fundamentally distinct modes of chiral induction by the chiral (S)-TRIP phosphate. Two modes of participation of the chiral phosphate, either as a ligand directly bound to the palladium (Figure 6a) or as a counterion that remains in the outer sphere (Figure 6b), were considered. Both of these TS models offered the correct sense of the enantioselectivity, in line with the experimentally observed major stereoisomer. Akin to the other examples in this Account,

Figure 5. Transition state geometries for S−O bond formation obtained at the M06-2X/6-31G** level of theory. The numbers in parentheses are the relative Gibbs free energies (in kcal/mol). E

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Accounts of Chemical Research Scheme 3. (a) A Triple-Catalytic Tsuji−Trost Asymmetric Allylation; (b) Two Types of Transition State Models for the Stereocontrolling C−C Bond Formation

Figure 6. Stereocontrolling C−C bond formation transition states when the chiral phosphate acts as (a) a ligand or (b) a counterion, obtained at the M06/6-31G**,LANLD2Z(Pd) level of theory. The numbers in parentheses are the relative Gibbs free energies (in kcal/mol) in the SMD(toluene) solvation model at the same level of theory with thermal and entropic corrections from the gas phase. F

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the palladium-bound acetate and dislodge it in the form of acetic acid while itself occupying the coordination site as a phosphate ligand.28 The computed energetics conveyed that two phosphate ligands, a molecule of water, and the substrate are the most preferred ligands for the initial Wacker-type ring expansion, as shown in Figure 7. An alternative model, with the native acetate ligands on palladium and the chiral phosphoric acid bound through hydrogen bonding (with the acetate and the OH group of the substrate), was found to be of much higher energy. Interestingly, this prediction is in contrast to the earlier example of the (S)-TRIP−Pd-catalyzed asymmetric Tsuji−Trost allylation, wherein the chiral phosphate was found to be a counterion in the enantiocontrolling TS. In the formation of the spirocyclic ring junction, the stereocontrolling event is a semipinacol-type rearrangement. Depending on the prochiral face to which the cyclobutanol carbon atom migrates, two configurations at the spiro ring junction can be created, as depicted in Figure 7.29 In the ring expansion TSs, two chiral phosphates are nearly orthogonal in the lower-energy TS-si, whereas a coplanar orientation is noticed in the higher energy TS-re (Figure 7). The BINOL 3,3′ substituents exhibit a pronounced spatial spread and provide a chiral environment for the substrate. A larger number of relatively shorter C−H···π interactions can be identified in TS-si compared with the higher-energy diastereomeric TS. It is important to note that C−H···π interactions between the substrate and the catalyst arm (denoted as c, d, e, and f) are more prominent in TS-si compared with TS-re (only c). In this chiral environment, the substrate is positioned in such a way that the ring expansion to the si face of the palladated indenyl framework is noted as more favored. A nearly square-planar geometry around

we note that the differential C−H···π interaction and ionic N−H···O hydrogen bonding contribute to the energy differences between the additions to the re and si faces of the enamine. The most important aspect of these two modes of C−C bond formation is that the TS for the counterion mode of stereoinduction is about 8 kcal/mol lower in energy than the TS for the ligand mode. 5.3. Asymmetric Wacker-Type Ring Expansion Reaction

Methods for the generation of spirocyclic ring systems have been in recent focus in asymmetric catalysis. In particular, spirooxindoles and spiroindenes received considerable attention because of their potential biological applications. The mode of chirality transfer becomes an intriguing question when the source of chirality is not from the native ligands on the transition metal. In the example shown in Scheme 4, the acetate ligands would Scheme 4. Cooperative Dual Catalysis Leading toward a Spirocyclic Ring with a Quaternary Ring Junction

have to be displaced by the chiral phosphate derived from (S)-TRIP.27 In our recent study, dynamic ligand exchange was considered as a viable possibility, first by computing the energetic feasibility of the exchange of the native acetate ligands with various ligands potentially available under the reaction conditions. For instance, the stronger phosphoric acid can protonate

Figure 7. Stereocontrolling transition states for the ring expansion, obtained at the M06/6-31G**,LANL2DZ(Pd) level of theory. The numbers in parentheses are relative Gibbs free energies (in kcal/mol) in the SMD(toluene) solvation model at the same level of theory using the thermal and entropic corrections from the gas phase. G

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Accounts of Chemical Research palladium (as indicated by the distortion coordinates θ1−θ4 and the dihedral angles ϕ1 and ϕ2) indicated less distortion in TS-si. Although the predicted sense of the selectivity is in agreement with the experimentally observed stereoisomer, the extent of selectivity at the M06 level is overestimated.30 We believe the source of additional stabilization of the lower-energy TS, which exhibits a greater number of C−H···π contacts, stems from an inherent geometric feature noted for the M06 functional wherein such interactions tend to be stickier. The example presented here constitutes an interesting illustration of how the axial chirality emanating from the BINOL framework gets effectively transmitted through the aryl substituents.

Ir−π-allyl intermediate [Ir(Cl)(π-allyl)(PR)2] with the bis-(R)phosphoramidite as the chiral ligand are provided in Figure 8.32 The lowest-energy TS involves the addition of the re face of the enamine to the si face of the Ir-π-allyl intermediate, which would result in the (2R,3R) product. The TSs for the si−si and si−re modes of addition are respectively about 3.3 and 7.6 kcal/mol higher in energy, indicating very high enantio- and diastereoselectivity. These predictions are in agreement with the experimentally observed high enantio- and diastereoselectivity. The lowest-energy TS is richly dominated by weak non-covalent interactions such as π−π stacking, C−H···π, lone pair···π, N···H, and Cl···H. In the higher-energy TS, the number and strength of these interactions are found to be lower. Among these interactions, the π stacking between the quinoline arm of the cinchona and the phenyl ring of the allylic substrate (denoted as a, b, and c in Figure 8) is found to be the most important control element. Similarly, a couple of crucial C−H···π contacts between the olefinic C−H of the azepine and the phenyl ring of the enamine (e and f) can be identified as well. It is noted that the orientations of the quinoline ring in the higher-energy si−si and si−re TSs are not conducive for this π stacking. Again, these molecular insights, as with the other examples described, could be further exploited in making suitable modifications to the chiral ligands and in the choice of the substrates.

6. ASYMMETRIC ALLYLATION USING TWO CHIRAL CATALYSTS UNDER ONE-POT CONDITIONS In the general practice of multicatalytic one-pot reactions, only one of the catalysts is chiral. As a natural progression, it is of inherent interest to ask how the chirality transfer would be accomplished when both catalysts are chiral. The Carreira group recently reported an exemplary dual-catalytic reaction with chiral iridium phosphoramidites and the cinchona family of chiral amines.31 The reaction makes use of an Ir−π-allyl complex (derived from an allyl alcohol by the action of trichloroacetic acid in the presence of a chiral phosphoramidite ligand) and an enamine (obtained from the aldehyde and the cinchona primary amine catalyst, again in the presence of trichloroacetic acid) (Scheme 5). An interesting feature of this reaction is that the configuration at each chiral center could be altered by employing a catalyst with the opposite configuration. For instance, when the (R)-phosphoramidite is used in conjunction with the (R,R)-cinchona, the product has the 2R,3R configuration. The configuration at the α stereocenter can be inverted by using the (S,S)-cinchona to produce the 2S,3R product. Similarly, the configuration at the β stereocenter could be inverted by using the (S)-phosphoramidite ligand on the Ir−π-allyl species. The stereocontrolling C−C bond formation TSs were located and helped us establish the origin of this stereodivergence for different combinations of chiral catalysts. The optimized geometries of the TSs for the C−C bond formation between the (8R,9R)-cinchona enamine and the

7. CONCLUSIONS AND OUTLOOK Transition state models for the stereocontrolling bond formation step developed by using modern DFT computations have helped us gain valuable molecular insights into the process of chiral induction. The most recent examples from the domain of asymmetric catalysis encompassing (a) axially chiral phosphoramidites, (b) BINOL-derived phosphates as ligands on transition metals, and (c) Brønsted acid catalysis by BINOL phosphoric acids have been detailed in order to shed light on the control elements in chirality transfer. The central theme fortifying these examples has been the significance of non-covalent interactions in asymmetric induction. How the cumulative effect of weak non-covalent interactions dictates the relative energies of transition states that differ in the prochiral faces involved in the stereodetermining bond formation step has been delineated through this Account.

Scheme 5. Cooperative Dual-Catalytic Asymmetric α-Allylation of an Aldehyde Leading to Two New Chiral Centers, Including a Quaternary α-Carbon

H

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Indian Institute of Technology Bombay. He was promoted to full professor in 2012. He is an elected member of the board of the World Association of Theoretical and Computational Chemists (WATOC). His research interests are in the domain of computational studies of transition states in asymmetric catalysis, mechanisms of multicatalytic reactions, and catalyst design.



ACKNOWLEDGMENTS I acknowledge the present and past members of the RBS group at IIT Bombay. Special thanks are extended to Dr. Garima Jindal (University of Southern California) and Bangaru Bhaskararao (IIT Bombay) for their efforts in pursuing increasingly complex problems in transition state modeling and chiral induction.



Figure 8. Stereocontrolling transition states for C−C bond formation obtained at the B3LYP-D3/6-31G**,LANL2DZ(Ir) level of theory. The numbers in parentheses are relative Gibbs free energies of solvation (in kcal/mol) at the SMD(toluene)/B3LYP-D3/6-311G**, def2-TZVP(Ir) level using the gas-phase geometries.

Beyond the inherently interesting rationalization of the origin of the stereoselectivity and chirality transfer is the message that non-covalent interactions should be exploited more in asymmetric catalysis. While our study has been inspired by past experiments, the results are expected to inspire future experiments. We believe that increasing synergism between theory and experiments is more likely in asymmetric catalysis in the years to come.



REFERENCES

(1) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric Catalysis; University Science Books: Sausalito, CA, 2008. (2) (a) Cheong, P. H.-Y.; Legault, C. Y.; Um, J. M.; Ç elebi-Ö lçüm, N.; Houk, K. N. Quantum Mechanical Investigations of Organocatalysis: Mechanisms, Reactivities and Selectivities. Chem. Rev. 2011, 111, 5042− 5137. (b) Sunoj, R. B. Proline-Derived Organocatalysis and Synergism between Theory and Experiments. WIREs Comput. Mol. Sci. 2011, 1, 920−931. (3) Wagner, J. P.; Schreiner, P. London Dispersion in Molecular Chemistry − Reconsidering Steric Effects. Angew. Chem., Int. Ed. 2015, 54, 12274−12296. (4) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N. Theory of Asymmetric Organocatalysis of Aldol and Related Reactions: Rationalizations and Predictions. Acc. Chem. Res. 2004, 37, 558−569. (5) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. Enantioand Diastereoselective Michael Reaction of 1,3-Dicarbonyl Compounds to Nitroolefins Catalyzed by a Bifunctional Thiourea. J. Am. Chem. Soc. 2005, 127, 119−125. (6) (a) Legault, C. Y.; Garcia, Y.; Merlic, C. A.; Houk, K. N. Origin of Regioselectivity in Palladium-Catalyzed Cross-Coupling Reactions of Polyhalogenated Heterocycles. J. Am. Chem. Soc. 2007, 129, 12664. (b) Fernandez, I.; Bickelhaupt, F. M. The Activation Strain Model and Molecular Orbitals Theory: Understanding and Designing Chemical Reactions. Chem. Soc. Rev. 2014, 43, 4953−4967. (7) Bader, R. F. W. A Quantum Theory of Molecular Structure and its Applications. Chem. Rev. 1991, 91, 893−928. (8) Grabowski, S. J. What is the Covalency of Hydrogen Bonding? Chem. Rev. 2011, 111, 2597−2625. (9) Contreras-Garcia, J.; Johnson, E. R.; Keinan, S.; Chaudret, R.; Piquemal, J. P.; Beratan, D. N.; Yang, W. J. NCIPLOT: A Program for Plotting Noncovalent Interaction Regions. J. Chem. Theory Comput. 2011, 7, 625−632. (10) Cardona, F.; Goti, A. Metal-Catalyzed 1,2-Diamination Reactions. Nat. Chem. 2009, 1, 269−275. (11) Du, H.; Zhao, B.; Shi, Y. A Facile Pd(0)-Catalyzed Regio- and Stereoselective Diamination of Conjugated Dienes and Trienes. J. Am. Chem. Soc. 2007, 129, 762−763. (12) Teichert, J. F.; Feringa, B. L. Phosphoramidites: Priviledged Ligands in Asymmetric Catalysis. Angew. Chem., Int. Ed. 2010, 49, 2486− 2528. (13) Jindal, G.; Sunoj, R. B. Mechanistic Insights into the Role of Chiral Ligands in Asymmetric Diamination Reactions. Chem. - Eur. J. 2012, 18, 7045−7049. (14) Houk, K. N.; Cheong, P. H.−Y. Computational Prediction of Small-Molecule Catalysts. Nature 2008, 455, 309−313. (15) Rooks, B. J.; Haas, M. R.; Sepúlveda, D.; Lu, T.; Wheeler, S. E. Prospects for the Computational Design of Bipyridine N,N′-Dioxide Catalysts for Asymmetric Propargylation Reactions. ACS Catal. 2015, 5, 272−280.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biography Raghavan B. Sunoj received his Ph.D. from the Indian Institute of Science Bangalore under the tutelage of Jayaraman Chandrasekhar. After a couple of years of postdoctoral research with Christopher Hadad at the The Ohio State University (Columbus, OH, USA), he returned to India in 2003 to join the faculty of the Department of Chemistry at I

DOI: 10.1021/acs.accounts.6b00053 Acc. Chem. Res. XXXX, XXX, XXX−XXX

Article

Accounts of Chemical Research (16) Jindal, G.; Sunoj, R. B. Rational Design of Catalysts for Asymmetric Diamination Reaction using Transition State Modeling. Org. Biomol. Chem. 2014, 12, 2745−2753. (17) (a) Terada, M. Binaphthol-derived Phosphoric Acid as a Versatile Catalyst for Enantioselective Carbon-Carbon Bond Formating Reactions. Chem. Commun. 2008, 4097−4112. (b) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chiral Brønsted Acids in Enantioselective Carbonyl Activations − Activation Modes and Applications. Chem. Soc. Rev. 2011, 40, 4539−4549. (c) Akiyama, T.; Mori, K. Stronger Brønsted Acids: Recent Progress. Chem. Rev. 2015, 115, 9277−9306. (18) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Complete Field Guide to Asymmetric BINOL-Phosphate Derived Bronsted Acid and Metal Catalysis: History and Classificaiton by Mode of Activation; Bronsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates. Chem. Rev. 2014, 114, 9047−9153. (19) Liao, S.; Č orić, I.; Wang, Q.; List, B. Activation of H2O2 by Chiral Confined Bronsted Acids: A Highly Enantioselective Catalytic Sulfoxidation. J. Am. Chem. Soc. 2012, 134, 10765−10768. (20) Terada, M. Chiral Phosphoric Acids as Versatile Catalysts for Enantioselective Transformations. Synthesis 2010, 2010, 1929−1982. (21) Jindal, G.; Sunoj, R. B. Axially Chiral Imidodiphosphoric Acid Catalyst for Asymmetric Sulfoxidation Reaction: Insights on Asymmetric Induction. Angew. Chem., Int. Ed. 2014, 53, 4432−4436. (22) (a) Chen, D.−F.; Han, Z.−Y.; Zhou, Z.−L.; Gong, L.−Z. Asymmetric Organocatalysis Combined with Metal Catalysis: Concept, Proof of Concept, and Beyond. Acc. Chem. Res. 2014, 47, 2365−2377. (b) Park, Y. J.; Park, J.−W.; Jun, C.−H. Metal-Organic Cooperative Catalysis in C−H and C−C Bond Activation and Its Concurrent Recovery. Acc. Chem. Res. 2008, 41, 222−234. (23) Jindal, G.; Kisan, H. K.; Sunoj, R. B. Mechanistic Insights on Cooperative Catalysis through Computational Quantum Chemical Methods. ACS Catal. 2015, 5, 480−503. (24) Liu, Y.; Han, S.−J.; Liu, W.−B.; Stoltz, B. M. Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules. Acc. Chem. Res. 2015, 48, 740−751. (25) Jiang, G.; List, B. Direct Asymmetric α-allylation of Aldeydes with Simple Allylic Alcohols Enabled by the Concerted Action of Three Different Catalysts. Angew. Chem., Int. Ed. 2011, 50, 9471−9474. (26) Jindal, G.; Sunoj, R. B. Mechanistic Insights on Cooperative Asymmetric Multicatalysis using Chiral Counterions. J. Org. Chem. 2014, 79, 7600−7606. (27) Chai, Z.; Rainey, T. J. Pd(II)/Brønsted Acid Catalyzed Enantioselective Allylic C-H Activation for the Synthesis of Spirocyclic Rings. J. Am. Chem. Soc. 2012, 134, 3615−3618. (28) Jindal, G.; Sunoj, R. B. Importance of Ligand Exchanges in Pd(II)Brønsted Acid Cooperative Catalytic Approach to Spirocylic Rings. J. Am. Chem. Soc. 2014, 136, 15998−16008. (29) Jindal, G.; Sunoj, R. B. Deciphering the Origin of Stereoinduction in Cooperative Asymmetric Catalysis Involving Pd(II) and a Chiral Brønsted Acid. Org. Lett. 2015, 17, 2874−2877. (30) Krenske, E. H.; Houk, K. N.; Lohse, A. G.; Antoline, J. E.; Hsung, R. P. Stereoselectivity in Oxyallyl-furan (4 + 3) Cycloadditions: Control of Intermediate Conformations and Dispersive Stabilization in Cycloadditions Involving Oxazolidinone Auxiliaries. Chem. Sci. 2010, 1, 387. (31) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Enantio- and Diastereodivergent Dual Catalysis: α-Allylation of Branched Aldehydes. Science 2013, 340, 1065−1068. (32) Bhaskararao, B.; Sunoj, R. B. Origin of Stereodivergence in Cooperative Asymmetric Catalysis with Simultaneous Involvement of Two Chiral Catalysts. J. Am. Chem. Soc. 2015, 137, 15712−15722.

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DOI: 10.1021/acs.accounts.6b00053 Acc. Chem. Res. XXXX, XXX, XXX−XXX