Mechanism and Origins of Stereoinduction in Natural Cinchona

Research Article Cite This: ACS Catal. 2017, 7, 7977-7986

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Mechanism and Origins of Stereoinduction in Natural Cinchona Alkaloid Catalyzed Asymmetric Electrophilic Trifluoromethylthiolation of β‑Keto Esters with N‑Trifluoromethylthiophthalimide as Electrophilic SCF3 Source Man Li,† Xiao-Song Xue,*,† and Jin-Pei Cheng†,‡ †

State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, People’s Republic of China ‡ Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100084, People’s Republic of China S Supporting Information *

ABSTRACT: The trifluoromethylthio (SCF3) group enjoys a privileged role in the field of drug discovery because its incorporation into a drug molecule often leads to significantly improved pharmacokinetics and efficacy. In spite of its prime importance in drug discovery, the stereospecific introduction of the SCF3 group into target molecules has remained an unmet challenge. A major breakthrough was made in 2013 when Rueping and Shen simultaneously and independently disclosed natural Cinchona alkaloid catalyzed asymmetric electrophilic trifluoromethylthiolation of β-keto esters. However, two key issues remain obscure. (a) What is the preferred mode of catalysis? (b) How is asymmetric induction accomplished? Here we report an in-depth computational exploration into the mechanism and origin of stereoinduction in Cinchona alkaloid catalyzed trifluoromethylthiolation of β-keto esters with N-trifluoromethylthiophthalimide as electrophilic SCF3 source. Three mechanistic possibilities, i.e., (a) the transfer-trifluoromethylthiolation, (b) the Wynberg ion pair-hydrogen bonding model, and (c) the Houk−Grayson bifunctional Brønsted acid-hydrogen bonding model, were evaluated with density functional theory (B3LYP-D3 and M06-2X functionals). Our calculations suggest that, in contrast to Cinchona alkaloid catalyzed conjugate additions, the most preferred mode for the title reaction is not the Houk−Grayson bifunctional Brønsted acid-hydrogen bonding model but instead the Wynberg ion pair-hydrogen bonding model, wherein the SCF3 transfer proceeds via an SN2-like mechanism. Consequently, although the Houk−Grayson bifunctional Brønsted acid−hydrogen bonding model has recently been demonstrated to be a general mechanistic model for Cinchona alkaloid catalyzed asymmetric Michael additions, this catalysis mode cannot be simply extended to an asymmetric SN2-type of reaction. The predicted enantioselectivities based on the Wynberg ion pair-hydrogen bonding model are in good agreement with experimental data, lending strong support to the plausibility of this mode of catalysis. Noncovalent interaction (NCI) analysis of the stereocontrolling transition state structures reveals that the enantioselectivity is mainly induced by the concerted action of multiple weak noncovalent substrate−catalyst interactions, such as C−H···O, C−H··· S, C−H···π, and π···π interactions. Not only has this contribution provided insights into the mechanistic model and principles of stereocontrol by Cinchona alkaloids but also it should offer help in the future design of catalysts and asymmetric electrophilic trifluoromethylthiolation reactions. KEYWORDS: trifluoromethylthiolation, asymmetric catalysis, Cinchona alkaloid, density functional calculation, noncovalent interaction the field of asymmetric catalysis has witnessed an explosive growth in the past decades.3 Because of its unique properties, fluorine has become a “magic” element,4 and molecular editing with fluorine and fluorinated groups has emerged as a powerful and widely

1. INTRODUCTION The chirality of drug molecules often has a profound effect on their functions.1 The thalidomide tragedy provided an important lesson about how different enantiomers of a given biomolecule can exhibit dramatically different pharmacological activities.2 Thus, single-enantiomer biological compounds are much desired in life science. Indeed, the majority of new drugs on the market are enantiomerically pure,2 and consequently, © 2017 American Chemical Society

Received: September 3, 2017 Revised: October 1, 2017 Published: October 11, 2017 7977

DOI: 10.1021/acscatal.7b03007 ACS Catal. 2017, 7, 7977−7986

Research Article

ACS Catalysis employed tactic to modulate the bioavailability, lipophilicity, metabolic stability, or other desirable properties of drug candidates.5 Among many fluorinated groups, the trifluoromethylthio group (SCF3) has attracted special interest due to its remarkable lipophilicity (Hansch constants 1.44 for SCF3 and 0.88 for CF3).6 This could be particularly beneficial in modulating the pharmacokinetic properties of lead compounds.7 It is not surprising, therefore, that tremendous efforts have been devoted to developing efficient methodologies for the incorporation of the SCF3 group into desired scaffolds.8,9 Despite the fact that significant advances have been achieved for the synthesis of achiral SCF3-containing molecules, the stereospecific introduction of the SCF3 group into target molecules has remained an unmet challenge.8f,10,11 Remarkable progress was made in 2013 when Rueping11a and Shen11b simultaneously and independently disclosed natural Cinchona alkaloid catalyzed asymmetric electrophilic trifluoromethylthiolation of β-keto esters. They utilized similar Cinchona alkaloid catalysts but used different electrophilic SCF3 sources. In both cases, high yields and excellent enantioselectivities were obtained. These studies provided an efficient access to optically pure SCF3-containing compounds and laid important groundwork for subsequent advances.11c−l However, two key issues remain unclear. (a) What is the preferred mode of catalysis? (b) How is chirality transfer accomplished? The lack of knowledge of such mechanistic details seriously hampers the rational design and optimization of new reactions and also limits new catalyst exploration in this highly important field of catalysis. Quantum chemistry calculation has become a powerful and successful tool in the chemist’s arsenal for the elucidation of the detailed reaction mechanisms and the origins of various selectivities, such as chemo-, regio-, and stereoselectivities.12,13 Indeed, it has been applied extensively to a wide variety of catalytic systems and has provided vast amounts of new insights into the mechanisms of catalytic processes and their selectivities for various products, which, in turn, has greatly facilitated the design of new catalysts and reactions.12 In a continuation of our research efforts in understanding the origin of chiral induction by Cinchona alkaloids14 as well as in understanding the reactivities and mechanisms of fluoroalkylating reagents,15 we report herein the first computational study on the mechanism and stereoselectivity of Cinchona alkaloid catalyzed trifluoromethylthiolation reactions of β-keto esters with N-trifluoromethylthiophthalimide (Munavalli reagent16) as an electrophilic SCF3 source (Scheme 1a). Three mechanistic possibilities, (a) the transfer-trifluoromethylthiolation, (b) the Wynberg ion pair-hydrogen bonding model (dual activation of trifluoromethylthiolating reagent and β-keto ester by the catalyst’s hydroxyl group and the quinuclidine nitrogen, respectively), and (c) the Houk−Grayson bifunctional Brønsted acid-hydrogen bonding model (the trifluoromethylthiolating reagent is activated by the protonated quinuclidine nitrogen and the enolate is directed by the catalyst’s hydroxyl group), were evaluated (Scheme 1b). Calculations reveal that, in contrast to recently proposed mechanisms for Cinchona alkaloids13o and Cinchona alkaloid derived urea-13p and squaramide-promoted13q,r asymmetric conjugate additions, the most preferred mode for the title reaction is not the Houk− Grayson bifunctional Brønsted acid-hydrogen bonding model (pathway C) but instead the Wynberg ion pair-hydrogen bonding model (pathway B). In the Wynberg ion pairhydrogen bonding model, the SCF3 transfer from trifluoromethylthiolating reagent to β-keto esters proceeds via an SN2-

Scheme 1. (a) Rueping’s Asymmetric Electrophilic Trifluoromethylthiolation and (b) Possible Pathways for QD-Catalyzed Asymmetric Trifluoromethylthiolation

like mechanism. Therefore, although the Houk−Grayson bifunctional Brønsted acid-hydrogen bonding model has been demonstrated to be a general mechanistic model for Cinchona alkaloid derivative promoted asymmetric conjugate additions,13o−r this catalysis mode should not be simply extended to an asymmetric SN2 type of reaction. The enantioselectivities predicted on the basis of the Wynberg ion pair-hydrogen bonding model are in good agreement with experimental data, offering strong support to the plausibility of this pathway. In addition, we explored the origin of enantioselectivity in these important reactions. Noncovalent interaction (NCI) analysis of the stereocontrolling transition state (TS) structures reveals that the Cinchona alkaloid catalyst employs a combination of multiple weak noncovalent interactions, including C−H···O, C−H···S, C−H···π, and π···π interactions, to achieve the high levels of enantioinduction. Not only has this study provided new insights into the mechanistic model and asymmetric induction by Cinchona alkaloids but also it should offer help in the design of novel catalysts and new asymmetric electrophilic trifluoromethylthiolation reactions.

2. COMPUTATIONAL METHODS Quantum chemistry calculations were conducted by using Gaussian 09.17 Geometry optimizations and frequency computations were performed using the M06-2X18 density functional in conjunction with the 6-31G(d) basis set and an ultrafine integration grid. The SMD19 model was used to account for the solvation effects of dichloromethane (CH2Cl2), the solvent used experimentally.11a All of the optimized geometries were characterized as minima or transition state structures by frequency calculations. Thermal free energy corrections were obtained at 198.15 K to match the experimental conditions. To obtain more accurate electronic 7978


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Figure 1. Transfer-trifluoromethylthiolation (pathway A) versus the dual activation (pathway B) mechanism calculated at the (SMD)-B3LYPD3(BJ)/6-311++G(2d,p)//(SMD)-M06-2X/6-31G(d) level of theory. All energies are in kcal mol−1, and bond lengths are in Å.

the Supporting Information for the detailed conformational studies).

energies, single-point energy calculations were performed at the (SMD)-B3LYP-D3(BJ)20/6-311++G(2d,p) and (SMD)-M062X/6-311++G(2d,p) level with the (SMD)-M06-2X/6-31G(d) optimized structures. To further test the possible influence of the basis set superposition error, single-point energy calculations for key intermediate and transition state structures were also conducted at the (SMD)-B3LYP-D3(BJ)/TZVP level of theory.21 The discussion in the main text employs the Gibbs free energies calculated at the (SMD)-B3LYP-D3(BJ)/6-311+ +G(2d,p)//(SMD)-M06-2X/6-31G(d) level of theory, while the (SMD)-M06-2X/6-311++G(2d,p)//(SMD)-M06-2X/631G(d) and (SMD)-B3LYP-D3(BJ)/TZVP//(SMD)-M062X/6-31G(d) levels of theory yield identical tendencies and similar magnitudes of relative activation free energies (ΔΔG⧧) of the stereoisometric TSs as the former (see Figures S1−S3 and section 4 in the Supporting Information). NCIPLOT22 and Multiwfn23 were employed for the visualization of noncovalent interactions and topology analysis, respectively. The quantitative description of the strength of hydrogen bonds in transition state structures was obtained according to Espinosa’s equation.24 Structures were generated using CYLview25 and VMD.26 All energies reported throughout the text are in kcal mol−1, and bond lengths are in angstroms (Å). The anti-open and syn-open conformations of the catalyst in TSs have been thoroughly considered because these two conformations were found to be strongly preferred over the anti-closed and syn-closed conformations.13 The calculations reveal that the anti-open conformation of the catalyst is favored over the syn-open conformation in TSs in most cases. Moreover, the conformation of the methoxy and vinyl groups of the catalyst has also been studied. In most cases, the methoxy group anti to the N atom of the quinoline ring is the favored conformation, which is consistent with the observation of Houk and co-workers.13p The conformation of the catalyst’s vinyl group has a minimal effect on the TS energies (see Figure S3 in

3. RESULTS AND DISCUSSION 3.1. Mechanism Study of Rueping’s Asymmetric Electrophilic Trifluoromethylthiolation. Rueping’s quinidine (QD) catalyzed asymmetric electrophilic trifluoromethylthiolation of indanone-derived β-keto ester (S) by Ntrifluoromethylthiophthalimide (R)11a (Scheme 1a) was treated as the model reaction for exploring possible modes of catalysis. Three possible mechanistic scenarios can be envisioned (Scheme 1b): pathway A, the transfer-trifluoromethylthiolation, involves “+SCF3” transfer from reagent R to the quinuclidine nitrogen of Cinchona alkaloid catalyst to generate the new electrophilic species R′, which then delivers the “+SCF3” intermolecularly to the enolized β-keto ester to furnish the desired product. A similar mechanism has been reported to operate for Cinchona alkaloid catalyzed asymmetric electrophilic fluorination reactions.13k,t,27 Pathway B, the Wynberg ion pair-hydrogen bonding model,13o−r,28 features dual activation of electrophilic trifluoromethylthiolating reagent (electrophile E) and β-keto esters (nucleophile Nu) by the catalyst’s hydroxyl group and the quinuclidine nitrogen, respectively. The SCF3 transfer from the trifluoromethylthiolating reagent to β-keto esters proceeds via an SN2-like mechanism. Indeed, Shen proposed this model for quinine (QN) catalyzed trifluoromethylthiolation of β-keto esters.11b In contrast with pathway B, the electrophilic trifluoromethylthiolating reagent is activated by the protonated quinuclidine nitrogen in pathway C (the Houk−Grayson bifunctional Brønsted acid-hydrogen bonding model) and the enolate is directed by the catalyst’s hydroxyl group. Notably, the Houk−Grayson bifunctional Brønsted acidhydrogen bonding model has recently been demonstrated to be a general mechanistic model for Cinchona alkaloid derivative catalyzed asymmetric conjugate additions.13o−r 7979


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ACS Catalysis Calculated potential energy profiles for the transfertrifluoromethylthiolation (pathway A) and the dual activation (pathway B) mechanisms are presented in Figure 1. In the dual activation mechanism, the formation of hydrogen-bonded complex CP3 between the enol form of β-keto ester and catalyst is exergonic by 1.5 kcal mol−1. The proton transfer from the coordinated enol to the quinuclidine nitrogen of the catalyst leads to the ion pair complex CP4, which is 3.3 kcal mol−1 below CP3. The coordination of trifluoromethylthiolating reagent to CP4 through an O−H···O hydrogen-bonding interaction yields CP5, which is located 5.3 kcal mol−1 below the reactants and 0.5 kcal mol−1 below CP4. The overall activation free energy (ΔG⧧) for the Wynberg ion pairhydrogen bonding model (pathway B) is calculated to be only 8.2 kcal mol−1. On the other hand, the putative active intermediate CP2 on the transfer-trifluoromethylthiolation pathway (pathway A) lies 22.8 kcal mol−1 above the intermediate CP1.29 Thus, the free energy of activation required for pathway A is at least 14.6 kcal mol−1 higher than that for pathway B, indicating that the transfer-trifluoromethylthiolation pathway is highly unfavorable and should be unlikely to occur.30 The mechanism of QD catalyzed asymmetric electrophilic trifluoromethylthiolation is hence different from that of the Cinchona alkaloid derived primary amine catalyzed asymmetric electrophilic fluorination,13k,t,27 where the preferred pathway involves fluorine transfer from electrophilic fluorinating reagent to the quinuclidine nitrogen of Cinchona alkaloid (Scheme 2). The rationalization for the

Figure 2. Lowest-lying TSs for C−SCF3 bond formation of pathways B and C along with their relative free energies calculated at the (SMD)-B3LYP-D3(BJ)/6-311++G(2d,p)//(SMD)-M06-2X/631G(d) level of theory. All energies are in kcal mol−1, and bond lengths are in Å.

Scheme 2. Asymmetric Electrophilic Fluorination versus Trifluoromethylthiolation Catalyzed by Cinchona Alkaloids

TS(S) (major), leading to the S stereoisomer of trifluoromethylthiolated product, is lower in energy than B1-TS(R) (minor) by 4.3 kcal mol−1. This yields a computed ee of >99% in favor of the S enantiomer, which agrees well with the level and sense of enantioselectivity observed experimentally (98% S ee). B1-TS(S) was found to be 8.0 and 8.4 kcal mol−1 more stable than C1-TS(S) and C1-TS(R), respecitvely, suggesting that the Wynberg ion pair-hydrogen bonding model is preferred over the Houk−Grayson Brønsted acid-hydrogen bonding model by around 8 kcal mol−1. Therefore, although the Houk−Grayson bifunctional Brønsted acid-hydrogen bonding model has been found to operate for Cinchona alkaloids13o and Cinchona alkaloid derived urea-13p and squaramide-promoted13q,r conjugate additions, this catalysis mode cannot account for the asymmetric electrophilic trifluoromethylthiolation being similarly successful, however. As shown in Figure 1, the barrier for the C−SCF3 formation via the dual activation mode (pathway B) is relatively low, and this step is highly exergonic. This suggests that B1-TS(S) is an early transition state,31 resembling the reactant complex (CP5). Because the transition state is early, the charge distribution in the transition state structure should resemble the reactant complex (CP5), i.e., the enolate has most of the negative charge (see Figure S4 in the Supporting Information), which can be stabilized to a greater extent by the quinuclidinium ion in model B relative to the hydroxyl group in model C. This may be the reason why B1-TS(S) is more stable than C1-TS(S). In addition, this is the difference with the Houk−Grayson model, in which the transition state has a charge distribution like that of the product.13o−r 3.2. Origin of Enantioselectivity. After establishing the preferred dual activation mode (i.e., the Wynberg ion pair-

dichotomy of the mechanism between electrophilic fluorination and trifluoromethylthiolation is that the transfer-fluorination is a thermodynamically favored process,15c,27 whereas the transfer-trifluoromethylthiolation in the present study is, however, a thermodynamically very unfavorable process. Having ruled out the transfer-trifluoromethylthiolation pathway, we then evaluated the two possible bifunctional activation models, namely the Wynberg ion pair-hydrogen bonding model (pathway B in Scheme 1b) and the Houk− Grayson Brønsted acid-hydrogen bonding model (pathway C in Scheme 1b). Following an extensive search of low-lying transition state structures for the C−SCF3 formation step in the QD catalyzed asymmetric electrophilic trifluoromethylthiolation, we identified the lowest-lying TSs leading to the major and minor products for pathways B and C, as shown in Figure 2 (for other TSs and detailed conformational studies, see section 2 in the Supporting Information). For pathway B, the B17980


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Scheme 3. (a) Enantiocontrolling TSs and the Staggered Conformation Adopted by the Substrates in B1-TS(S) versus the Eclipsed Conformation in B1-TS(R), (b) Schematic Diagram for Energy Decomposition Analysis (EDA) for the Lowest Energy TSs, and (c) EDA for the Lowest Energy TSs (B1-TS(S) and B1-TS(R)) Calculated at the (SMD)-B3LYP-D3(BJ)/6-311+ +G(2d,p)//(SMD)-M06-2X/6-31G(d) Level of Theorya

a A(sub) and B(cat) are respectively the substrates and the protonated catalyst at the TS. A0 is the optimized structure of the substrates, and B0 is the optimized structure of protonated catalyst. All energies are in kcal mol−1 and bond lengths are in Å.

conformation about the developing C−S bond in comparison to the eclipsed conformation in B1-TS(R) (the C−S−C−C dihedral angles in B1-TS(S) and B1-TS(R) are 53.0 and −14.3°, respectively; Scheme 3a). To reveal the difference in interaction energies between the substrates and the catalyst (ΔΔEint), the NCI analysis of the TS structures was conducted, which enables the visualization of noncovalent interactions.22 The results are shown in Figure 3. The NCI analysis of B1-TS(S) and B1-TS(R) reveals that, in addition to the strong conventional N+-H···O and O−H···O hydrogen bonding interactions, several weak nonconventional C−H···O,35 C−H···S,13o and C−H···π36 interactions are present within. Most interestingly, there is a favorable π···π stacking36a,37 interaction between the quinoline of the catalyst and the aromatic ring of reagent R that should also contribute to the stabilization of both B1-TS(S) and B1-TS(R) (Figure 3).38 As the substrates interact with the catalyst through a network of hydrogen bonding interactions as well as a π···π stacking interaction, it is still not easy to figure out which factors are the major ones contributing to ΔΔEint. To accomplish this, quantification of these weak interactions in transition state structures is required. For a better understanding of the contributions of individual noncovalent interactions to ΔΔEint, we applied Espinosa’s equation24 (eq 1) to quantify the strength of hydrogen bonds in the hydrogen-bond network and employed Wheeler’s strat-

hydrogen bonding model) that could well reproduce the observed stereoselectivity, we subsequently explored the origin of stereoinduction in Rueping’s asymmetric electrophilic trifluoromethylthiolation. To shed light on the source of energy differences between B1-TS(S) and B1-TS(R), we performed a simple form of energy decomposition analysis (EDA)32−34 for the two TS structures (Scheme 3). The activation energy ΔE⧧ of the TSs can be written as ΔE⧧ = ΔEdef + ΔEint, where the terms ΔEdef and ΔEint are the deformation and interaction energies, respectively. The deformation energy ΔEdef is the energy difference that arises from structural changes toward the TS formation. The interaction energy ΔEint corresponds to the energy difference between the catalyst plus the substrates and the complex at the TS structure. The results are presented in Scheme 3c. Clearly, the large energy separation between B1-TS(S) and B1-TS(R) mainly arises from differences in interaction energy (ΔΔEint = 3.8 kcal mol−1) and substrate deformation energy (ΔΔEdef(sub) = 1.0 kcal mol−1). Both ΔΔEint and ΔΔEdef(sub) are positive, meaning that the two components contribute synergistically to the overall energy difference between B1-TS(S) and B1TS(R). In other words, the substrates in B1-TS(S) are not only more stable but also interact more favorably with the catalyst than do those in B1-TS(R). Inspection of the TS geometries reveals that the more stable of the substrates in B1-TS(S) presumably arises from the more favorable staggered 7981


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Figure 3. NCI analysis of enantiocontrolling TSs (blue, strongly attractive; green, weakly attractive; red, strongly repulsive) calculated at the (SMD)B3LYP-D3(BJ)/6-311++G(2d,p)//(SMD)-M06-2X/6-31G(d) level of theory. Key noncovalent interactions between substrates and catalyst are denoted with dashed lines. ΔΔEπ‑stacking represents the energy difference of the π···π interaction between B1-TS(S) and B1-TS(R). All energies are in kcal mol−1, and bond lengths are in angstroms (Å).

of B1-TS(S) but only 5.6 kcal mol−1 (1.9 + 1.9 + 1.8 = 5.6 kcal mol−1) to the stabilization of B1-TS(R). Additionally, the π···π interaction is 0.2 kcal mol−1 stronger in B1-TS(S) than in B1TS(R) (Figure 3). As a result, these noncovalent interactions contribute 4.3 kcal mol−1 to ΔΔEint, preferentially stabilizing B1-TS(S) over B1-TS(R). Notably, the difference in the summations of these weak interactions between B1-TS(S) and B1-TS(R) corresponds well with the difference in interaction energies ΔΔEint (4.3 vs 3.8 kcal mol−1). Therefore, one can reasonably conclude that the origins of stereoinduction in this reaction are twofold: (i) the more favorable staggered conformation of substrates in B1-TS(S) in comparison to the eclipsed conformer in B1-TS(R) and (ii) the noncovalent interactions, including hydrogen bonds and π···π stacking

egy33h (using a truncated model system; for details, see Figure S5 in the Supporting Information) to estimate the strength of π···π stacking interactions in transition state structures. The estimated EHB and ΔΔEπ‑stacking values are also summarized in Figure 3 (various interactions are denoted using labels a−k). It was found that the strong conventional O−H···O hydrogen bond (a) contributes identically to the stabilization of the two TS structures. On the other hand, the N+-H···O hydrogen bonds (b and c) contribute 11.8 kcal mol−1 (4.8 + 7.0 = 11.8 kcal mol−1) to the stabilization of B1-TS(S) but only 10.2 kcal mol−1 (5.4 + 4.8 = 10.2 kcal mol−1) to the stabilization of B1TS(R). Moreover, the total of weak nonconventional C−H···O, C−H···S, and C−H···π interactions contributes 8.1 kcal mol−1 (2.2 + 1.5 + 1.5 + 2.0 + 0.9 = 8.1 kcal mol−1) to the stabilization 7982


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4. CONCLUSION In summary, we have performed an in-depth density functional theory study to gain insights into the mechanism and origins of stereoselectivity of Rueping’s landmark discovery from 2013 that natural Cinchona alkaloid catalyzed electrophilic trifluoromethylthiolation of β-keto esters with N-trifluoromethylthiophthalimide as an electrophilic SCF3 source. We have evaluated three mechanistic possibilities: i.e., (a) the transfertrifluoromethylthiolation, (b) the Wynberg ion pair-hydrogen bonding model, and (c) the Houk−Grayson bifunctional Brønsted acid−hydrogen bonding model. The calculations show that the most preferred model of catalysis is the Wynberg ion pair-hydrogen bonding model in which the SCF3 transfer from trifluoromethylthiolating reagent to β-keto ester proceeds via an SN2-like transition state. This finding has an important consequence for the mechanistic model of Cinchona alkaloid catalysis: although the Houk−Grayson bifunctional Brønsted acid-hydrogen bonding model has recently been demonstrated to be a general mechanistic model for Cinchona alkaloid derivative catalyzed asymmetric conjugate additions, this catalysis mode should not be applied directly to an asymmetric SN2 type of reaction. The enantioselectivities predicted on the basis of the Wynberg ion pair-hydrogen bonding model are in good agreement with experimental data, lending strong support to the plausibility of this pathway. NCI analysis of the stereocontrolling transition state structures reveals that the enantioselectivity is mainly induced by the concerted action of multiple noncovalent substrate−catalyst interactions such as C−H···O, C−H···S, C−H···π, and π···π interactions. Of special interest is the observation of a favorable π···π stacking interaction between the quinoline of catalyst and the aromatic ring of trifluoromethylthiolating reagent that preferentially stabilizes the TS leading to the observed major product. It should be noted that the quinoline motif of Cinchona alkaloid catalyst acting as a π-donor participating in stereocontrol has been largely ignored in mechanistic studies of reactions catalyzed by natural Cinchona alkaloids,12a,13b,38 although π···π interactions have been recognized as important design elements for enantioselective catalysis. An enhanced understanding of noncovalent interactions40 underlying asymmetric induction is of great value for future catalyst design.41 The results reported herein are expected to inspire future rational design of novel catalysts and new asymmetric electrophilic trifluoromethylthiolation reactions, a field that is in a relatively early stage of development.8f

interactions, preferentially stabilizing B1-TS(S) over B1TS(R). 1 E HB = V (rcp) (1) 2 3.3. Application of the Wynberg Ion Pair-Hydrogen Bonding Model. To address the predictive ability of the Wynberg ion pair-hydrogen bonding model (the most preferred dual activation mode), we further applied it to explain the effect of structural changes in substrate and catalyst on the stereoselectivities. On the basis of the enantiodetermining TS structures, it follows that substituents on the aromatic ring of the β-keto ester would hardly influence the stereoselectivities because they are incapable of interacting with the catalyst (see Figure 3). Indeed, the calculated ΔΔG⧧ values for the reactions of cyclic five-membered-ring β-keto esters bearing substituents of the aromatic ring are nearly constant (entries 1− 3 in Table 1), agreeing well with experimental observations. Table 1. Experimental and Theoretical ee Values and Corresponding ΔΔG⧧ values in kcal mol−1 Calculated at the (SMD)-B3LYP-D3(BJ)/6-311++G(2d,p)//(SMD)-M06-2X/ 6-31G(d) Level of Theory

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ASSOCIATED CONTENT

S Supporting Information *

Moreover, Rueping’s observation that replacing the tert-butyl group of the β-keto ester with a methyl group leads to only a slight reduction in ee value is also reproduced by the Wynberg ion pair-hydrogen bonding model (ΔΔG⧧ = 4.3 kcal mol−1 vs ΔΔG⧧ = 3.8 kcal mol−1; see entries 1 and 4 in Table 1).13p,36d,39 Furthermore, the established preferred dual activation mode was applied to explain the effect of structural changes in the catalyst. Calculation predicted that quinine catalysis of the same reaction leads to >99% ee in favor of the R enantiomer, consistent with the sense and level of enantioselectivity experimentally observed, 96% ee (entry 5 in Table 1).11a Obviously, these cases well verified the reliability and feasibility of the Wynberg ion pair-hydrogen bonding model in predicting the enatioselectivity of Cinchona alkaloid catalyzed asymmetric electrophilic trifluoromethylthiolation reactions.

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.7b03007. Figures S1−S5 and optimized geometries of all species (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail for X.-S.X.: [email protected]. ORCID

Xiao-Song Xue: 0000-0003-4541-8702 Jin-Pei Cheng: 0000-0001-8822-1577 Notes

The authors declare no competing financial interest. 7983


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ACKNOWLEDGMENTS We are grateful for financial support from the Natural Science Foundation of China (NSFC, Grant Nos. 21390400, 21402099, and 21772098), the Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), the State Key Laboratory on Elemento-organic Chemistry, and the Fundamental Research Funds for the Central Universities. The very valuable and insightful comments of the reviewers are gratefully acknowledged.

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Mechanism and Origins of Stereoinduction in Natural Cinchona

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