Cooperative Asymmetric Catalysis by N-Heterocyclic Carbenes and

Research Article pubs.acs.org/acscatalysis

Cooperative Asymmetric Catalysis by N‑Heterocyclic Carbenes and Brønsted Acid in γ‑Lactam Formation: Insights into Mechanism and Stereoselectivity Monika Pareek and Raghavan B. Sunoj* Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India S Supporting Information *

ABSTRACT: Current developments in the burgeoning area of cooperative asymmetric catalysis indicate the use of Nheterocyclic carbenes (NHCs) in conjunction with other catalysts such as a Brønsted acid. Herein, mechanistic insights derived through a comprehensive DFT (M06-2X) computational study on a dual catalytic reaction between an enal and an imine leading to trans-γ-lactams, catalyzed by a chiral NHC and benzoic acid, is presented. In the most preferred pathway, we note that the NHC catalyst activates one of the reactants (enal) in the form of a Breslow intermediate, whereas the electrophilic partner (imine) is activated by the benzoic acid through protonation of the imino nitrogen. In this article, we focus on the origin of cooperative action of both catalysts as well as on the stereoselectivity by identifying the stereocontrolling transition states. The explicit and cooperative participation of the Brønsted acid and NHC lowers the energetic barrier both in the Breslow intermediate formation and in the stereocontrolling step through a number of C−H···π, N−H···O, and π···π noncovalent interactions. The enantio- and diastereoselectivities computed using the transition state models with an explicit benzoic acid are in good agreement with the earlier experimental reports. KEYWORDS: cooperative catalysis, N-heterocyclic carbenes, Brønsted acid, transition state, asymmetric induction

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The reaction, as shown in Scheme 1, constitutes the first asymmetric synthesis of trans-γ-lactams using an NHC−

INTRODUCTION The use of N-heterocyclic carbenes (NHCs) as organocatalysts has become quite widespread in recent years.1 While the ability of NHCs to impart umpolung reactivity to ubiquitous aldehydes continues to provide newer avenues in a range of asymmetric reactions, the most recent strides appear to devote increasing attention to multicatalytic approaches.2 NHCs are now being employed in cooperative catalytic protocols in conjunction with other organo and metal catalysts. Two different catalysts could operate sequentially or concurrently in such reactions.3 Recent demonstrations that NHCs can partner with other catalysts such as Lewis acid,4 cinchona,2d,5 amine,6 and Brønsted acids7,8 are indeed promising. The elucidation of the origin of cooperativity between two or more catalysts is of high contemporary significance. The general strategy in NHC catalysis has been to generate homoenolates through a Breslow intermediate and intercept the same with suitable electrophiles such as a Michael acceptor. In an interesting conceptual advancement, Rovis and coworkers have reported a dual role for the base, which is typically used in the in situ generation of a free NHC catalyst from its precursor.8 For instance, the conjugate acid formed through the deprotonation of the NHC precursor can subsequently activate an electrophilic acceptor such as an imine, thereby setting the stage for a potentially cooperative dual catalytic mechanism. © XXXX American Chemical Society

Scheme 1. Formation of trans-γ-Lactams using Chiral NHC and Brønsted Acid Cooperative Catalysis

Brønsted acid cooperative catalytic dyad. It is interesting to note that γ-lactams are important structural motifs found in a number of natural products as well as in medicinally active compounds.9 There have been recent studies that reported improved yield and enantioselectivities by using Brønsted acids as additives.7,8 However, the exact mode of participation of Received: January 13, 2016 Revised: April 6, 2016

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DOI: 10.1021/acscatal.6b00120 ACS Catal. 2016, 6, 3118−3126

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Scheme 2. Key Mechanistic Steps in the Reaction between β-Ester Enal and Imine Catalyzed by NHC and Brønsted Acid (BA) Cooperative Catalysis Leading to trans-γ-Lactamsa

a

Shown in the inset are the notations used for the reaction without (BA = 0) and with the involvement (BA = 1) of benzoic acid.

the catalytic cycle and selected lower energy stationary points involved in the stereoselective C−C bond were reoptimized in the solvent phase. The effect of continuum solvation was incorporated by using the SMD model developed by Truhlar and Cramer.14 Since the experimental studies employed acetonitrile as the solvent, we have employed the continuum dielectric of acetonitrile (ε = 35.688) in our computations. The discussions are presented on the basis of the Gibbs free energies obtained at the SMDCH3CN/M06-2X/6-31G** level of theory. Partition functions are evaluated using Truhlar’s quasiharmonic approximation wherein the vibrational frequencies lower than 100 cm−1 are raised to 100 cm−1, so as to correct for the breakdown of the harmonic oscillator model. The free energies are reported using the corrected lowfrequency vibrational modes.15 The single-point energies of additional conformational possibilities have been computed in the solvent phase using the gas-phase optimized geometries obtained at the M06-2X/6-31G** level of theory. The extent of enantioselectivity, in terms of enantiomeric excess (% ee), is calculated by using the Boltzmann distribution of diastereomeric transition states with the expression

such Brønsted acids in the reaction has not yet been established. Although this dual catalytic approach represents an important methodological progress, molecular-level details of its mechanism as well as the origin of enantio- and diastereoselectivities still remains to be understood. The present study provides the first molecular insight into NHC− Brønsted acid cooperative asymmetric catalysis. In a continuation of our efforts toward understanding the mechanistic features of NHC-catalyzed asymmetric reactions,10 we became interested in examining the origin of cooperativity in this dual catalytic reaction. In particular, we intend to establish the role of the in situ generated benzoic acid in the mechanistic course of the reaction and to probe whether or not it has any direct role in the stereodetermining step(s). The discussions are presented on the basis of the Gibbs free energies obtained at the SMDCH3CN/M06-2X/6-31G** level of theory.

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COMPUTATIONAL METHODS All calculations were carried out using the Gaussian09 suite of quantum chemical programs.11 Geometry optimizations of all stationary points were performed using the M06-2X density functional in conjunction with the 6-31G** basis set.12 Fully optimized geometries of all stationary points were characterized by frequency calculations in order to verify that the transition states (TSs) have one and only one imaginary frequency for the desired reaction coordinate. The intrinsic reaction coordinate (IRC) calculations13 were performed using the same level of theory to further verify that the TS on the potential energy surface connects to the desired minima on either side of the first-order saddle point. The important mechanistic events in

% ee =

1 − e−ΔG

⧧

R / S / RT

1 + e−ΔG

⧧

R / S / RT

× 100

where ΔG⧧ is the difference in the Gibbs free energies between the competing diastereomeric transition states. Additional analysis of the transition states has been performed by examining the topological distribution of electron density. The atoms in molecules (AIM) formalism16 and noncovalent interaction (NCI) analysis17 have been employed to gain more insights into the important noncovalent 3119


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Figure 1. Lower energy transition states and corresponding relative Gibbs free energies (in kcal/mol) with respect to the separated reactants for (a) C−C bond formation between NHC and enal, and (b) Breslow intermediate formation obtained at the SMDCH3CN/M06-2X/6-31G** level of theory. Distances are given in Å.

compete with potential side reactions such as enal dimerization.21 The important steps in the mechanism of NHCcatalyzed formation of γ-lactams are provided in Scheme 2. The catalytic cycle can be considered to begin with the nucleophilic addition of the chiral NHC to the electrophilic enal 1, leading to the zwitterionic intermediate 2 (Scheme 2). While one can envisage multiple mechanistic avenues for this intermediate to convert to the Breslow intermediate 3, we present only the most preferred one here. The zwitterionic species 2 is noted to exhibit a distinct preference for a benzoic acid assisted proton transfer to give the dienaminol intermediate 3. The next important step is stereoselective C− C bond formation, wherein the nucleophilic Breslow intermediate adds to the electrophilic imine. In this step, the benzoic acid present in the medium can either engage directly by activating the electrophile through a hydrogen-bonding interaction or can remain passive without any significant participation. In the ensuing step, a proton transfer from the imino nitrogen to the α-carbon of the enal moiety can provide intermediate 6. Again, benzoic acid could play an active role in this step as well. The most favored proton transfer mode from the imino nitrogen to the enolate carbon is found to be that with the assistance of the explicit benzoic acid. Next, an intramolecular C−N bond formation through the addition of the nucleophilic nitrogen to the carbonyl group results in intermediate 7, which upon expulsion of NHC can provide the desired γ-lactam product 8. Each step described in the overall catalytic cycle, as given in Scheme 2, is examined in greater detail to identify the most preferred mechanism of this reaction. For instance, in the nucleophilic addition of NHC to enal 1, a total of eight possibilities differing in terms of (i) which one of the prochiral faces of enal 1 (si or re) participates in the C−C bond formation, (ii) the relative orientation of the cyclohexyl substituent on the chiral center of NHC with respect to the incoming enal moiety, and (iii) within a given mode of approach additional possibilities arising due to the rotations along the incipient C−C bond are examined.22 Among all of the possibilities, the addition of NHC to the si face of the enal (Figure 1) is found to be the most preferred mode. The alkoxide intermediate 2 thus formed by the addition of NHC to enal can now be converted to the Breslow intermediate 3 via multiple pathways. It is identified that the

interactions present in the stereocontrolling transition states. Topological analysis of the electron density distribution is performed using the wave function generated at the SMDCH3CN/M06-2X/6-31G** level of theory. An interacting pair of atoms is characterized by the presence of a bond path and a bond critical point (bcp) along the bond path. The shared electron density shows a minimum at the bcp. The value of the electron density at such bcps can be regarded as proportional to the strength of the interaction. In addition, activation strain analysis18 has been carried out on the stereocontrolling transition states. The overall Gibbs free energy profile was analyzed using the Shaik−Kozuch energetic span model.19 According to this model, the energetic span (δE) for a catalytic cycle is calculated first by identifying the turnover frequency (TOF) determining transition state (TDTS) and the TOF determining intermediate (TDI). The lowest energy intermediate in the energy profile is considered as the TDI, and the TDTS is the transition state which maximizes the energetic span (δE), calculated using the equations δE = TTDTS − ITDI

if TDTS appears after TDI

δE = TTDTS − ITDI + ΔGr

(1)

if TDTS appears before TDI (2)

where ΔGr is the free energy of the reaction.

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RESULTS AND DISCUSSION The reported experimental approach involved the combination of an enal, an imine, a Brønsted acid, and a nucleophilic catalyst (NHC), all under one-pot reaction conditions. In such a situation, the formation of the active catalyst, i.e., free NHC, can take place by the action of sodium benzoate on the triazolium salt precursor. The abstraction of the acidic proton of triazolium by the benzoate is found to be a facile process. This process is exergonic by 2.0 kcal/mol (see Scheme S1 and Figure S1 in the Supporting Information). The literature precedence indicates the use of sodium salts of carboxylic acids for the deprotonation of triazolium salts to release free carbene and the corresponding conjugate acid.20 The active catalyst can then enter the catalytic cycle through its reaction with the reactant enal. The Brønsted acid is used to increase the electrophilicity of the imine such that the desired reaction can 3120


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Figure 2. Generalized representation for the approach of electrophile to the Breslow intermediate.

Figure 3. Optimized diastereomeric transition states for the stereoselective C−C bond formation at the SMDCH3CN/M06-2X/6-31G** level of theory. Distances are given in Å. The electron densities (ρ × 10−2 au) at the bond critical points along the bond paths and relative Gibbs free energies (kcal/mol) are given in parentheses. The red and blue dotted lines respectively represent the reaction coordinate and other interactions.

proton transfer is favored over the direct proton transfer pathway.10b,23 The benzoic acid assists the transfer of the proton from the carbon to the oxygen of the alkoxide moiety

explicit participation of benzoic acid is vital to this step, as the activation barrier for the formation 3 is 27 kcal/mol higher than that without an active participation of benzoic acid. The relay 3121


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Figure 4. Noncovalent interaction (NCI) plots for diastereomeric transition states. The blue, green, and red regions respectively represent strong, weak, and repulsive interactions. The values in parentheses are the relative Gibbs free energies (in kcal/mol) with respect to the lowest energy transition state.

via the seven-membered transition state (2-3)BA‡, as shown in Figure 1. Alternative modes of benzoic acid assistance such as the involvement of only the O−H group of the carboxylic acid are noted to be of higher energy (see Scheme S2 and Table S2 in the Supporting Information). The formation of a Breslow intermediate is found to be exergonic by about 5 kcal/mol. We further note that different configurations around both the double bonds of the Breslow intermediate have very similar energies (see Figure S3 and Table S3 in the Supporting Information). Hence, all such configurations are considered in the subsequent stereoselective C−C bond formation between the homoenolate (Michael donor) and electrophilic imine (Michael acceptor). The addition between different prochiral faces of the reactants in this step can result in different stereoisomeric products.24 Different possible configurations and conformations of the nucleophile and of the electrophile and the role of benzoic acid are examined to identify the lowest energy transition state. As shown in Figure 2, the most preferred prochiral face of the Breslow intermediate accessible for the incoming electrophile is directly influenced by the

orientation of the cyclohexyl group on the chiral center of the NHC. The electrophile will approach (using either its si or re face) from the direction opposite to the cyclohexyl group to minimize any unfavorable steric interaction. Interestingly, the benzoic acid is noted to play two vital roles in the stereocontrolling step. First, it activates the imine through a hydrogen-bonding interaction, and second, it offers additional stabilization through a cooperative participation with the NHC catalyst toward imparting the desired stereoselectivity. Examination of the lower energy transition state structures, as shown in Figure 3, reveals that the benzoic acid interacts both with the enol oxygen of the Breslow intermediate as well as with the imino nitrogen of the electrophile. In other words, the participation of benzoic acid appears to help bring the reacting partners into a well-defined orientation. A facile proton transfer from the enol to benzoate in all of the diastereomeric transition states is identified. The addition of the si face of the homoenolate carbon to the re face of the imine is found to be the most preferred C−C bond formation mode. Such an approach between the prochiral 3122


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ACS Catalysis faces of the reactants will lead to the final product with the configuration 2S,3R. At this juncture, an interesting side reaction wherein a combination of two molecules of aldehyde occurs is also considered. However, the barrier for this potentially competitive aldehyde dimerization, as reported by Bode and co-workers,14 is found to be 5.5 kcal/mol higher than the addition to the activated imine that is the focus of our study.25 On the other hand, the re−si addition would lead to the enantiomeric product with a 2R,3S configuration at the new chiral centers. The re−si transition state is 3.9 kcal/mol higher in energy than the lowest energy si−re transition state. A Boltzmann distribution analysis of these stereochemically distinct transition states on the basis of their energies indicates an enantiomeric excess of 99.7%. This predicted value of enantiomeric excess compares well with the experimentally reported value of 93%. Similarly, the transition state for another stereochemical mode of addition wherein the re face of the homoenolate adds to the re face of the imine resulting in a 2S,3S configuration is found to be 2.8 kcal/mol higher in energy than the lowest energy C−C bond formation transition state. This energy difference translates to a diastereomeric excess of 98.2%, again in concert with the experimentally determined de of 91%.26 Hence, these transition state models could successfully reproduce the experimental stereochemical outcome. After identifying the preferred stereochemical modes of approach between the reactants on the basis of the energies of the corresponding transition states, we turned our attention toward rationalizing the origin of the predicted energy differences. Typically the factors responsible for the vital energy difference between the stereocontrolling transition states are traced to the differences in the stereoelectronic features. In the following section, we present additional insights into the origin of stereoselecitivity gained through the analysis of such stereoelectronic features. It can be noted, from the optimized geometries of the stereocontrolling transition states presented in Figure 3, that the number and the nature of weak interactions are different depending on the prochiral faces involved in the C−C bond formation. To analyze these weak interactions, we have employed two widely accepted methods based on the topological distribution of electrons. The presence of a bond path and a bond critical point between a pair of atoms is generally regarded as an early indicator of an interatomic interaction. The topological maps have been carefully analyzed, and the corresponding values of the electron densities at the bond critical points are provided in parentheses beside the corresponding interatomic contact distances in Figure 3. In the lower energy transition state (3-5)si‑re‡, C−H···π (shown as d, e, f in Figure 3) and π···π (g) are found to be more effective than in (3-5)re‑si‡. The number of C−H···π interactions is greater in (3-5)si‑re‡ than in the diastereomeric higher energy (3-5)re‑si‡. The N−H···O interaction is also found to be stronger in (35)si‑re‡ than in (3-5)re‑si‡. In addition, other kinds of weak interactions such as C−H···O and C−H···F also contribute to the energy differences between the lowest and higher energy transition states. There have been an increasing number of reports in the recent literature on the role of N−H···O and C− H···π interactions in asymmetric catalysis.27 The ρbcp values for the C−H···π interactions are found to be in the range of 0.0051−0.0085 au, and those for the N−H···O interactions fall in the range of 0.045−0.057 au.28 After having identified a number of important interatomic noncovalent interactions through the AIM analysis, we

examined the details of noncovalent interactions in these transition states. Recently proposed noncovalent interaction index (NCI) plots offer a qualitative mapping of the regions of noncovalent interaction present in a molecule in real space. NCI plots for the stereocontrolling transition states are provided in Figure 4. In the graphical depiction of NCI, strong attractive interactions appear as blue regions, dispersion or weak noncovalent interactions as green regions, and repulsive interactions as red regions. The nature of these contacts can be further distinguished by the sign of the second eigenvalue (λ2) of the Hessian of the density matrix used in the AIM analysis.18,29 Ideally, the bond critical points obtained through AIM topological analysis should have a corresponding distinguishable color gradient in an NCI plot. However, the regions of noncovalent interactions usually remain quite dispersed. The noncovalent interaction is most prominent in the lowest energy transition state involving the si−re mode of addition. For instance, green color patches that characterize weak noncovalent interaction can be noticed between the aromatic π face offered by the catalyst (through (a) an Nphenyl group and (b) a triazole moiety) and the aryl groups of the substrate as well as that of the explicit benzoic acid. Such π···π interactions are less prominent in the higher energy transition states. In addition, other weak interactions such as C−H···π and C−H···O and a relatively stronger (within the domain of weak interaction) N−H···O interactions can also be noted in the NCI plots. It is interesting to note that the largest value of electron density at the bond critical point noted for the N−H···O interaction between the benzoic acid and the substrate in the lowest energy transition state ((3-5)si‑re‡; Figure 3) exhibits a good correlation with the NCI plot, wherein a blue region is noticeable (Figure 4). The other interactions are too weak, as indicated by the lower values of ρbcp in the AIM analysis, and appear in the form of a larger green region in the NCI plot. This suggests that a relatively stronger interaction is required to be able to note a distinguishable color gradient in an NCI plot, whereas much weaker interactions are captured in AIM analysis. The differential noncovalent interactions that are present in these stereocontrolling transition states can be regarded as the most important contributing factors to the energy difference between them. When reactants combine together to form a product through a transition state, the structure of each reactant becomes distorted in comparison to its native ground state geometry. Similar distortions are also likely in the catalyst framework in a catalyzed reaction. There are some useful methods to gain a semiquantitative idea about such distortions and how these distortions vary between the stereocontrolling transition states. One such method is activation strain analysis.30 In this approach, the activation barrier (ΔE‡⧧) is partitioned into (i) destabilizing distortion of the reactants (ΔE⧧d) and (ii) the stabilizing interaction energy between such distorted reactants (ΔE⧧i). ΔE⧧d is calculated as the difference in energies between the ground state geometries of undistorted reactants and the corresponding distorted structures as noted in the transition states. In other words, the activation barrier can be expressed as ΔE⧧ = ΔE⧧d + ΔE⧧i. It is noted that the total distortion in the reactants is about 3.7 kcal/mol lower for the lower energy (35)si‑re‡ mode of addition in comparison to the diastereomeric higher energy species (3-5) re‑si ‡. In other words, the destabilization due to distortion of the reactants is greater in (3-5)re‑si‡ than that in (3-5)si‑re‡. The interaction energies 3123


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Figure 5. (A) Gibbs free energy (kcal/mol) profile obtained at the SMDCH3CN/M06-2X/6-31G** level of theory for the formation of the trans-γlactam product from enal and imine catalyzed by chiral NHC and benzoic acid. The pathways shown in red and blue are respectively in the absence and in the presence of benzoic acid. (B) Important intermediates and transition states considered in the computation of the energetic span for the catalytic cycle.

lowest energy intermediate (TDI) in the absence of benzoic acid is the Breslow intermediate 3. It is interesting to note that the detection and isolation of different Breslow intermediates in NHC-catalyzed reactions have recently been reported.31 The proton transfer transition state (5-6)‡ is the TDTS. On the other hand, in the most preferred pathway with an explicit benzoic acid, the low-lying enolate intermediate 5 is the TDI and the subsequent proton transfer transition state (5-6)‡ is the TDTS. The energetic span, i.e., δE, for the benzoic acid assisted pathway is 13.6 kcal/mol, and that for the unassisted pathway is 27.7 kcal/mol.32 These species maximize the energetic span and can be considered as rate-determining transition states of the catalytic process. It is interesting to note that the stereoselectivity-determining TS is not the rate-determining transition state in this reaction. Similar observations are also reported wherein a proton transfer step is found to be the ratedetermining step, whereas the selectivity is controlled by other steps of the reaction.33 Thus, the explicit participation of benzoic acid lowers the activation barrier, which is also in line with the fact that the use of benzoic acid is vital to the success of this reaction. The turnover limiting step of the reaction, as per the energetic span analysis, involves the protonation of the enolate intermediate 5 by benzoic acid. The elementary step barrier for

between the distorted reactants, namely the Breslow intermediate and the imine, are nearly the same in both TSs. All of the aforementioned tools helped us develop valuable insights into the process of stereoinduction in the vital C−C bond formation step. Equally important an analysis of the energetic features of the catalytic cycle. In the next section, we have provided an overall analysis of the Gibbs free energy profile of the title reaction. A few interesting energetic features of the catalytic cycle become apparent from the Gibbs free energy profile, as provided in Figure 5. It is evident that the explicit participation of benzoic acid provides access to a lower energy pathway (shown in blue) in comparison to that in its absence (shown in red). The effect is more pronounced in the formation of the Breslow intermediate. We have also analyzed the overall Gibbs free energy profile using the energetic span model proposed by Shaik and Kozuch.20 In this approach, the turnover frequency (TOF) of the catalytic cycle can be determined by calculating the energetic span (δE) of the reaction. The energetic span is the difference in energies between the TDI (TOF determining intermediate) and TDTS (TOF determining transition state). The TDI is the lowest energy intermediate in the energy profile, and the TDTS is the transition state that provides a maximum energetic span (δE) for the catalytic reaction. The 3124


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established through this study and the accompanying mechanistic insights, would help encourage considering the explicit role of protic additives in asymmetric catalysis. The insight that both chiral NHC and achiral benzoic acid simultaneously participate in the stereocontrolling event could be helpful in developing newer methodologies wherein an achiral NHC and chiral amino acid (or other axially chiral Brønsted acid) is used as a cooperative catalytic dyad.

this protonation (13.6 kcal/mol) is coherent with the reaction conditions, such as the temperature, employed in the title reaction. The formation of the final product is exoergic by more than 30 kcal/mol, indicating a thermodynamic drive for the reaction, both toward the product formation and for the release of free NHC for the catalytic cycle to continue. It can be noted from the Gibbs free energy profile that a relatively low lying enolate intermediate (5) is involved in the catalytic cycle. This prediction could become amenable to experimental detection through careful studies. An interesting question at this stage relates to how different the energetics is when different substrates are involved in the reaction. To examine the nature of the substrate, we have evaluated the barriers for a relatively less electron deficient enal: cinnamaldehyde. The barrier for the attack of the NHC to cinnamaldehyde is found to be higher by 3.2 kcal/mol in comparison to the ester enal. The predicted enantio- and diastereoselectivities are in agreement with the earlier experimental report, which noted a relatively lower yield with cinnamaldehyde without much erosion in the stereoselectivity.34 The present investigation has been able to shed light on the origin of asymmetric induction in the formation of trans-γlactam. A series of noncovalent interactions between the reactants and the chiral catalyst as well as between the reacting partners are noted. The vital energy difference is traced to the differential in these interactions. Without the insights into the stereoelectronic features of the transition states, the origin of selectivity would have invariably been attributed to the “bulky” cyclohexyl group at the chiral center of the NHC. While the guided approach of the incoming electrophile (activated imine) to the face opposite to the cyclohexyl group is an important control element, the effect of the differential in the noncovalent interactions when different prochiral faces are exposed to the nucleophile (Breslow intermediate) is even more important. In other words, the interactions within a given mode of approach, i.e., away from the directing cyclohexyl group, is vital. These insights are expected to serve as valuable inputs in the design of newer catalysts and choice of substrates and/or its modifications such that noncovalent interactions could be exploited more as a control element.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.6b00120. Cartesian coordinates of all the transition states and other relevant information (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail for R.B.S.: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Computing time from the IITB Computer Center is acknowledged. M.P. acknowledges the CSIR (New Delhi) for a junior research fellowship. We thank Y. Reddi and C. Patel (IIT Bombay) for valuable discussions during the course of this work.

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CONCLUSION In summary, DFT (M06-2X) computations helped us gain interesting mechanistic insights into an NHC−Brønsted acid cooperative asymmetric catalytic system leading to a trans-γlactam with high enantio- and diastereoselectivities. The participation of in situ generated benzoic acid has been found to be vital both in the generation of the Breslow intermediate and in the stereoselectivity-determining transition state. The activation barriers for the Breslow intermediate formation and the stereoselective C−C bond formation are much lower in the presence of Brønsted acid. The streoselectivities computed using our transition state models with an explicitly included benzoic acid are found to be in very good agreement with the experimentally known enantioselectivity (predicted 99%, experimental 93%) as well as diastereoselectivity (predicted 98.2%, experimental 91%) in favor of the trans isomer. The origin of high stereoselectivity is traced to a series of more effective noncovalent interactions (such as C−H···π, C−H···O, C−H···F, N−H···O, and π···π) between the Breslow intermediate and the activated imine, in the lower energy transition state. The dual role of the Brønsted acid, as 3125


Research Article

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(23) Other examples of relay proton transfer have been reported. See: (a) Sunoj, R. B.; Anand, M. Phys. Chem. Chem. Phys. 2012, 14, 12715−12736. (b) Ortuño, M. A.; Lledós, A.; Maseras, F.; Ujaque, G. ChemCatChem 2014, 6, 3132−3138. (c) Bhaskararao, B.; Sunoj, R. B. J. Am. Chem. Soc. 2015, 137, 15712−15722. (d) Monot, J.; Brunel, P.; Kefalidis, C. E.; Espinosa-Jalapa, N. A.; Maron, L.; Martin-Vaca, B.; Bourissou, D. Chem. Sci. 2016, 7, 2179−2187. (e) Bach, R. D. J. Org. Chem. 2012, 77, 6801−6815. (f) Allen, S. E.; Hsieh, S.-Y.; Gutierrez, O.; Bode, J. W.; Kozlowski, M. C. J. Am. Chem. Soc. 2014, 136, 11783− 11791. (24) See Figures S5 and S6 and Tables S4 and S5, respectively, in the Supporting Information. (25) The details of side reactions are provided in Scheme S3 and Table S7 in the Supporting Information. (26) (a) Although there are no experimental results known in the absence of benzoic acid, we note that the diastereoselectivity is very low in this case. (b) Further energetic details are provided in Figure S10 and Tables S11 and S12 in the Supporting Information. (27) (a) Allen, S. E.; Mahatthananchai, J.; Bode, J. W.; Kozlowski, M. C. J. Am. Chem. Soc. 2012, 134, 12098−12103. (b) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 5062−5075. (c) Krenske, E. H.; Houk, K. N. Acc. Chem. Res. 2013, 46, 979−989. (d) Jindal, G.; Sunoj, R. B. Angew. Chem., Int. Ed. 2014, 53, 4432−4436. (e) Johnston, R. C.; Cheong, P. H.-Y. Org. Biomol. Chem. 2013, 11, 5057−5064. (28) All of the noncovalent interactions have been analyzed by AIM, and details are given in Figure S8 and Table S8 in the Supporting Information. (29) (a) Wagner, J. P.; Schreiner, P. R. J. Chem. Theory Comput. 2016, 12, 231−237. (b) Gonzalez, J.; Baños, I.; Leon, I.; ContrerasGarcía, J.; Cocinero, E. J.; Lesarri, A.; Fernandez, J. A.; Millań, J. J. Chem. Theory Comput. 2016, 12, 523−534. (c) Hennum, M.; Fliegl, H.; Gundersen, L.-L.; Eisenstein, O. J. Org. Chem. 2014, 79, 2514− 2521. (d) Castro, B.; Chaudret, R.; Ricci, G.; Kurz, M.; Ochsenbein, P.; Kretzschmar, G.; Kraft, V.; Rossen, K.; Eisenstein, O. J. Org. Chem. 2014, 79, 5939−5947. (e) Wu, P.; Chaudret, R.; Hu, X.; Yang, W. J. Chem. Theory Comput. 2013, 9, 2226−2234. (30) The details of activation strain analysis on the stereoselective transition states are provided in Figure S9 and Table S9 in the Supporting Information. (31) (a) Berkessel, A.; Elfert, S.; Yatham, V. R.; Neudörfl, J.-M.; Schlörer, N. E.; Teles, J. H. Angew. Chem., Int. Ed. 2012, 51, 12370− 12374. (b) Berkessel, A.; Yatham, V. R.; Elfert, S.; Neudörfl, J.-M. Angew. Chem., Int. Ed. 2013, 52, 11158−11162. (c) Paul, M.; Breugst, M.; Neudörfl, J.-M.; Sunoj, R. B.; Berkessel, A. J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.5b13236. (32) (a) Here, TDTS appears after TDI, the calculated δE for the catalytic cycle: δE = −1.8 − (−15.4) = 13.6 kcal/mol in the presence of benzoic acid and δE = −9.3 − (−18.4) = 27.7 kcal/mol in the absence of benzoic acid (Figure 5). (b) The details of the energetic span model are provided in Figure S11 and Table S13 in the Supporting Information. (33) (a) Stegelmann, C.; Andreasen, A.; Campbell, C. T. J. Am. Chem. Soc. 2009, 131, 8077−8082. (b) Ajitha, M. J.; Suresh, C. H. Tetrahedron Lett. 2013, 54, 7144−7146. (c) Domingo, L. R.; Saéz, J. A.; Arnó, M. RSC Adv. 2012, 2, 7127−7134. (d) Moore, J. L.; Silvestri, A. P.; Read de Alaniz, J.; DiRocco, D. A.; Rovis, T. Org. Lett. 2011, 13, 1742−1745. (e) Domingo, L. R.; Zaragozá, R. J.; Arnó, M. Org. Biomol. Chem. 2011, 9, 6616−6622. (34) The details of this reaction are provided in Scheme S4 and Table S14 in the Supporting Information.

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Cooperative Asymmetric Catalysis by N-Heterocyclic Carbenes and

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