Exploring the Mechanism and Stereoselectivity in Chiral Cinchona

Article Cite This: J. Org. Chem. 2017, 82, 13449−13458

pubs.acs.org/joc

Exploring the Mechanism and Stereoselectivity in Chiral CinchonaCatalyzed Heterodimerization of Ketenes Bangaru Bhaskararao,† Garima Jindal,‡ and Raghavan B. Sunoj*,† †

Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India Department of Chemistry, University of Southern California, 3620 McClintock Avenue, Los Angeles, California 90089, United States

‡

S Supporting Information *

ABSTRACT: Catalytic heterodimerization of ketenes can lead to important four-membered β-lactones. A recent asymmetric organocatalytic [2 + 2] cycloaddition between methylketene (MK) and methylphenylketene (MPK) in the presence of pseudoenantiomeric cinchona catalysts (trimethylsilylquinine (TMSQ) or methylquinidine (MeQd)) provided β-lactones with high enantio- and diastereoselectivities. We employ DFT(M06-2X) computations to understand the mechanism and the origin of stereoselectivity in this ketene heterodimerization. The mechanism is found to involve the formation of an ammonium enolate first, by the action of the quinuclidine tertiary amine of the cinchona catalyst on MK. A stepwise pathway wherein the MK-cinchona enolate (enolate-A) adds to MPK in the selectivity-determining C−C bond formation step leading to the R-Z and S-Z product respectively with TMSQ and MeQd catalysts is predicted. The inclusion of LiClO4 is found to favor the C−C bond formation transition state to the S-E isomer in the case of MeQd and the R-E isomer with TMSQ catalysts. In the most preferred transition states, more effective C−H···π (between the phenyl ring of the EPK and the catalyst) and C−H···O interactions (between the catalyst and LiClO4) are noticed than that in the higher energy analogues, underscoring the importance of noncovalent interactions in enantio- and diastereocontrol.

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INTRODUCTION Lactones are important functional and structural motifs present in biologically active molecules, of which β-lactones are included and are composed of a strained four-membered ring.1 Owing to the high strain in β-lactone rings, stereoselective synthesis of such structural motifs is generally regarded as a difficult task. However, their presence in several drugs such as orlistat (obesity) and obafluorin (antibiotic) as well as in other materials makes them an attractive target for chemical synthesis.2 One of the prime methods currently employed in the synthesis of β-lactones involves the use of a reactive species such as a ketene.3 Ketenes have played an important role in the development of new asymmetric reactions, in particular by making use of [2 + 2] and [4 + 2] cycloaddition reactions.4 One of the earliest reactions that employed ketenes for the synthesis of β-lactone was the Staudinger reaction that involves the [2 + 2] cycloaddition of a ketene to an imine.5 Although the use of ketenes in asymmetric synthesis of β-lactones was demonstrated more than three decades ago, several challenges arising due to the instability of monosubstituted ketenes hampered their further developments.6 Calter and co-workers accomplished the formation of β-lactones from monosubstituted ketenes using cinchona-based quinidine (Qd) as the chiral catalyst.7 Since then, cinchonabased chiral catalysts that act as nucleophilic amines have played an important role in ketene chemistry.8 While homodimerization of ketenes has been achieved with moderate © 2017 American Chemical Society

success, heterodimerization that would result in a range of different products is far more daunting and only select examples exist on this front.9 The main challenge associated with heterodimerization is to selectively activate one of the ketenes so as to minimize the formation of homodimers. Kerrigan and co-workers recently reported an efficient asymmetric synthesis of β-lactones using a heterodimerization strategy, building upon two key observations: (a) methylphenylketenes (MPK) do not undergo dimerization in the presence of trimethylsilylquinine (TMSQ); (b) methylketenes (MK) dimerize in the presence of cinchona-based catalysts.10 They were able to develop an effective method for the predominant formation of the heterodimer. The heterodimerization between the more reactive MK as the donor ketene and the less reactive MPK as the acceptor ketene could be accomplished in the presence of TMSQ or methylquinidine (MeQd) as the catalyst (Scheme 1). There are several intriguing features underlying this heterodimerization of ketenes to β-lactones. The reaction is highly enantioselective and diastereoselective toward the formation of the heterodimer. Here the enantioselectivity pertains to the new chiral center in the β-lactone, and diastereoselectivity is that of the exocyclic double bond. More importantly, the olefin configuration in the final lactone could Received: October 4, 2017 Published: November 17, 2017 13449

DOI: 10.1021/acs.joc.7b02517 J. Org. Chem. 2017, 82, 13449−13458

Article

The Journal of Organic Chemistry

Scheme 1. β-Lactone Formation via a [2 + 2] Cycloaddition Reaction between MK (generated in situ by the action of diisopropylethylamine (DIPEA) base on the substrate) and MPK in the Presence of Chiral Cinchona Alkaloids

Figure 1. Different conformers and the corresponding relative Gibbs free energies (kcal/mol) for the chiral cinchona catalyst MeQd. Similar conformational features are also noticed for TMSQ as well (see Tables S1 and S2 of Supporting Information for additional details). geometries were additionally optimized using a higher basis set (6311++G**). We noticed that in the absence of LiClO4 the use of a lower basis set such as 6-31G** could not provide a firmer answer to whether the preferred pathway involves a stepwise or a concerted mechanism. With the higher basis set, a stepwise mechanism was predicted for heterodimerization.16 Mechanisms in the presence of LiClO4 are reported at the SMD(DCM)/M06-2X/6-311++G**// SMD(DCM)/M06-2X/6-31G** level of theory. To characterize the stationary points as a minimum or a first-order saddle point, Hessian indices were evaluated. Additionally, the presence of a unique imaginary frequency along with the intrinsic reaction coordinate (IRC) calculations was used to verify the transition state (TS).17 The geometries corresponding to the end points of the IRC trajectories were subjected to full geometry optimization using the “opt = calcfc” keyword (as implemented in Gaussian 09) in both forward and backward directions from the TS so as to connect to the reactant and product. Vibrational frequencies were calculated to estimate the zeropoint energies and entropies, which were subsequently used in the calculation of the Gibbs free energies. The zero-point energies at the M06-2X level were added to the bottom-of-the-well energies obtained using single-point calculations. The Gibbs free energies reported in the text are obtained at the M06-2X level of theory unless specified, and the basis set is indicated in each case. The activation strain analysis of the stereocontrolling transition states were carried out to gain additional details on the origin of stereoselectivity.18

be inverted from Z in the absence of LiClO4 additive to E in the presence of LiClO4, thereby widening the scope of the reaction. Only a few mechanistic studies on [2 + 2] cycloaddition of ketenes are reported, some with Lewis acids such as AlCl3 while others without any additives or catalyst.11 A qualitative working hypothesis by Kerrigan and co-workers suggested a concerted [2 + 2] cycloaddition as the stereoselectivity-determining step (vide infra).12 In this article, we aim to present some valuable molecular insights as obtained through a thorough mechanistic investigation by using DFT(M06-2X) calculations. In particular, we wish to (i) identify the key intermediates and transition states involved in the catalytic cycle so as to understand the most likely mechanism, (ii) compare between stepwise and concerted heterodimerization pathways to β-lactones, (iii) establish factors governing enantio- and diastereoselectivities, and (iv) probe the origin of inversion in diastereoselectivity of the exocyclic olefin effected by LiClO4.

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COMPUTATIONAL METHODS

Computations were carried out using the Gaussian 09 (rev D.01) suite of the quantum chemical program.13 The geometries were optimized in the solvent phase (dichloromethane, DCM, with a dielectric ε of 8.93) using the solvation model density (SMD) module in conjunction with the M06-2X functional.14 For all preliminary studies (conformational analysis of cinchona catalysts and those species involved in the catalytic cycle), geometry optimizations were performed using Pople’s 6-31G(d,p) basis set in the solvent phase.15 For the stereodetermining transition states and for the generation of Gibbs free energy profile,

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RESULTS AND DISCUSSION Prior to investigating the mechanistic steps of the reaction, it is important to examine various conformers of the chiral catalysts, namely TMSQ and MeQd. The importance of the conforma13450


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Scheme 2. Mechanism of TMSQ-Catalyzed β-Lactone Formation from Methylketene (MK) and Methylphenylketene (MPK)

Figure 2. Optimized geometries of TSs [1−2]‡ for the formation of enolates of methylketene with TMSQ and MeQd and the corresponding relative Gibbs free energies (kcal/mol, given in parentheses) obtained at the M06-2X(SMD)/6-311++G**//M06-2X(SMD)/6-31G** level of theory. Ed and Ei are respectively the distortion and interaction energies in kcal/mol. Only select hydrogen atoms are shown for improved clarity.

Subsequent addition of quinuclidine nitrogen to this donor ketene yields enolate-A (2) via [1−2]‡.22 Alternatively, TMSQ might also add to the acceptor ketene MPK. However, the transition state for the formation of the enolate-A from MPK is found to be 5.1 kcal/mol higher than the corresponding transition state with MK. This prediction is in line with the expected higher reactivity of a more reactive MK. As can be noted from Figure 2, the TS for the formation of the Z isomer [1−2]z‡ is 5.8 kcal/mol more preferred than that for the E isomer, indicating a stereoselective formation the Z isomer.23 It appears that the orientation of the methyl group of MK away from the line of approach of the quinuclidine nitrogen is more preferred, leading to the formation of a Z-selective enolate-A from MK. The activation strain analysis on [1−2]‡, the transition state for the formation enolate-A, revealed a lower distortion in the reactants in the case of Z enolate than that involved in the formation of the corresponding E isomer (Figure 2). Specifically, the methylketene fragment exhibits a relatively lower distortion in the transition state for the Z enolate formation. This can also be gleaned from the geometric parameters, such as the Ca−Cb−Oc angle, as given in Figure 2.

tional features of cinchona catalysts has been previously demonstrated in several asymmetric reactions.19 Different conformers that can arise due to the flexibility of the C9− C4′ and C8−C9 bonds are shown in Figure 1, for MeQd as a representative example. The open and closed conformers are defined by the position of the quinuclidine N with respect to the quinoline ring. In the closed form, the N atom points toward the ring, whereas in the open form it points away from the quinoline ring. Additional conformers exist due to the orientation of the methoxy group, resulting in a total of 16 key conformers for each catalyst. The geometries of the lowest energy conformer (open-3) for both catalysts are employed in the study of the mechanism and stereocontrolling step in greater detail.20 Results of conformational analyses are in line with previous reports on chiral cinchona catalysts.21 The mechanistic routes toward the formation of β-lactone with TMSQ as the catalyst are shown in Scheme 2. We noted that MeQd follows a catalytic cycle similar to that for TMSQ. The reaction begins with the in situ generation of the more reactive methylketene from the corresponding acyl chloride precursor. The initial interaction of MK with the chiral TMSQ, as shown in Scheme 2, leads to prereacting complex 1. 13451


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Figure 3. Free energy profiles (kcal/mol) for the heterodimerization of ketenes with TMSQ and MeQd as the catalysts obtained using the SMD(DCM)/M06-2X/6-311++G** method. The computed and experimental (in parentheses) ee’s are provided in the inset. Details for the formation of the final product (from 4 to 5) are shown only for the lowest energy pathway.

The Ca−Cb−Oc angle in the Z enolate pathway of MK is 165.7° whereas it is 150.0° for the E enolate formation, when TMSQ is the catalyst. Thus, the deviation from the initial value of 180.0° in MK is larger in the transition state leading to the E enolate, which is in line with the predicted lower energy of the Z enolate transition states. A similar trend is also noticed in the formation of enolate-A intermediates with MeQd as the catalyst. Further mechanistic steps are studied only with the Z isomer of enolate-A, unless specified otherwise. The catalytic activation of the donor ketene (MK) in the form of enolate-A (2) is followed by its reaction with the less reactive acceptor ketene (MPK) via [3−4]‡ to yield an aldoltype product 4, which subsequently lactonizes to yield the catalyst−product complex 5 (Scheme 2). Alternatively, 3 could directly form intermediate 5 through a [2 + 2] cycloaddition with the acceptor ketene (MPK) without the involvement of enolate-B intermediate 4. The intrinsic reaction coordinate (IRC) calculations and subsequent optimization of the geometries obtained as the end points of the IRC trajectory in both reverse and forward directions from [3−4]‡, respectively, resulted in intermediates 3 and 4. Identification of enolate-B (4) suggests that a stepwise mechanism is more likely involved in this reaction. Interestingly, earlier mechanistic studies that employed a lower basis set12 on other related systems proposed a concerted mechanism.24 The free energy profiles for the formation of β-lactone 6 in the presence of TMSQ and MeQd are given in Figure 3. It can be noticed that the overall energetic features for both catalysts are quite similar. A closer inspection of these profiles reveals that the stereoselectivity-determining step involving [3−4]‡ itself is the rate-determining step of the reaction. The lactonization via [4−5]‡ also poses a reasonable barrier, lending further credence to our proposal that a stepwise mechanism is likely in the catalytic heterodimerization between MK and MPK. Formation of enolate-B, via [3−4]‡, is one of the most important steps in this reaction, as it controls enantioselectivity at the one and only chiral center of the developing β-lactone and also the E/Z diastereoselectivity of the exocyclic olefin. The acceptor ketene, MPK can approach the si and re prochiral faces of Z enolate-A (derived from methylketene (2)), which would respectively lead to the R and S enantiomers of the product. To identify the energetically preferred modes of addition of the Z

enolate to MPK, we have considered different transition state possibilities for the C−C bond formation, denoted as R-E, R-Z, S-E, and S-Z (where R/S is the configurational descriptor at the developing chiral center and E/Z is the configuration of the exocyclic double bond). For each transition state type, different geometric approaches of MPK to the prochiral faces of the enolate-A (2) that differ in terms of the C1−C2−C3−O4 (3) dihedral are considered (Scheme 2). During the course of geometry optimization, we noted that several initial-guess geometries with varying dihedral angles reverted to a previous conformer, overall resulting in a rather limited set of conformers for this transition state. Optimized geometries of the stereocontrolling transition states are provided in Figure 4.25 The ee calculated on the basis of the energy difference between R-Z and S-Z transition states (as shown in the inset of Figure 4) is in good agreement with the experimental values.10a While the R enantiomer is predominantly formed with TMSQ as the catalyst, the pseudoenantiomer MeQd steers the reaction to the S isomer. The predicted configuration of the exocylic olefin in the case of TMSQ is Z, which is in line with the experimental observation. However, for MeQd catalyst, the configuration of the exocylic olefin is predicted as E as opposed to the Z isomer noted in 1H NMR.10,12 In the case of MeQd, the transition state for the addition of enolate-A (3) to MPK, leading to the formation of the E isomer, is found to be 0.8 kcal/mol lower energy than the corresponding transition state for the Z isomer. Activation strain analysis on the stereocontrolling transition states is carried out to probe the likely factors that affect their energy difference. In Figure 4, the distortion energies of the reacting partners and the interaction energies between the distorted reactants are compiled, along with a set of important geometric parameters. All the transition states can be noted to exhibit weak C−H···π (denoted as a1, a2,...) and C−H···O (b1, b2,...) noncovalent interactions. However, the differences in such interactions between the two transition states (R-Z and SZ in the case of TMSQ catalyst) are found to be very minimal, implying that these interactions are unlikely to act as the differentiating factor. Hence, we probed the origin of stereoselectivity, applying the activation strain model on R-Z and S-Z transition states. Although the R-Z mode of C−C bond formation transition state is the most preferred in terms of the 13452


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Figure 4. Optimized geometries of stereocontrolling C−C bond formation transition states [3−4]‡ for TMSQ- and MeQd-catalyzed pathways obtained at the M06-2X(SMD)/6-311++G** level of theory. Note that the distortion/interaction energies are electronic energies while the values in parentheses are relative Gibbs free energies (in kcal/mol). Distances are in angstroms and angles in degrees. Relative Ed (distortion energy) and Ei (interaction energy) are with respect to the lowest energy R-Z (for TMSQ) and S-Z (for MeQd) transition states. Notations a1, a2,... and b1, b2,... are respectively C−H···π and C−H···O interactions.

the S-Z isomer. Such energy difference corresponds to a % ee of 96.5, in concert with the experimental value of 94.0. In the case of MeQd-catalyzed heterodimerization, the transition state for the S-Z isomer is 1.8 kcal/mol lower than that of the R-Z isomer, indicating that % ee is 90.8, again in line with experimental % ee of 98.0 (Figure 4). Next we investigated the E/Z selectivity in the formation of the exocyclic double bond of the β-lacone product. In other words, we focused on the energetic origin of why the Z isomer of intermediate 4 is preferred over the E isomer. The conformational features of the lowest energy diastereomeric transition states, as noticed in the R-Z (0.0) mode, are adopted in the corresponding transition states for the R-E (2.0) mode in the case of TMSQ. Similarly, the most preferred conformer of the transition state leading to the S-Z (0.0) product in the case of MeQd catalyst is maintained in S-E (−0.8) mode as well.25 The Gibbs free energy of the transition state leading to the R-Z

Gibbs free energies, the interaction energy (Ei) between the enolate-A and the acceptor is not the best. This feature suggests that the distortion is a more likely factor that influences the relative Gibbs free energies of the stereocontrolling transition states. From the energies provided in Figure 4, it is evident that distortion energy outweighs the effect of interactions in the transition states leading to the major isomer (S-Z). More specifically, the distortion in enolate-A moiety of [3−4]‡ exhibits differences and could thus be regarded as critical to the stereochemical outcome. For catalyst MeQd, the distortion in enolate-A for the transition state leading to the minor isomer (R-Z) is 4.1 kcal/mol higher than that in the major isomer S-Z. A similar trend is also noticed with TMSQ. For MeQd catalyst, distortion in the enolate-A correlates well with the predicted relative energy order and hence the stereoselectivity.26 The Gibbs free energy of the transition state leading to the R-Z isomer with TMSQ catalyst is 2.4 kcal/mol lower than that for 13453


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The Journal of Organic Chemistry isomer with TMSQ catalyst is 2.0 kcal/mol lower than that of the R-E isomer (Figure 4). Such energy difference corresponds to a % de of 93.3, which is in line with an experimental value of 94.0. The better interaction energy between the distorted reactants (Ei) in the R-E transition state is outweighed by the destabilizing distortion (Ed), making this mode of C−C bond formation less favorable than the R-Z mode in the TMSQcatalyzed pathway. In other words, the lower distortion of the TMSQ−enolate-A fragment in the R-Z transition state makes it the lower one, thereby leading to the Z diastereomer of βlactone. The predicted diastereoselectivity in the case of MeQd is found to be in favor of the E isomer, which is in contrast with the experimentally noted Z isomer.27 Role of LiClO4. Lewis acids (LiClO4, EtAlCl2, BF3·Et2O, etc.) have been known to exhibit significant impact on the cycloaddition of ketenes.28 The multiple advantages of these additives include, but are not limited to, increased reactivity, improved control over diastereo- and regioselectivities, and even an inversion of diastereoselectivity, in certain cases. An interesting observation by Kerrigan and co-workers relates to the formation of the E isomer when the reaction is carried out in the presence of LiClO4, in the absence of which Z isomer was the major product (Scheme 3), with both TMSQ and MeQd catalysts.12,29

The elementary steps involved in the mechanism are similar to that in the absence of the lithium salt as presented in the preceding sections (Scheme 4). Shown in Scheme 4 are various steps involved in TMSQ-catalyzed heterodimerization in the presence of LiClO4. The Li can coordinate to two oxygen atoms, one from methylketene and the other from the TMS group. Interaction of substrate/catalyst with the Lewis acid can affect the energetic course of the reaction and hence the stereochemical outcome. In the following section, we highlight the key features of the ketene heterodimerization reaction with an explicitly included LiClO4. The free energy profiles for both TMSQ and MeQd catalytic systems are shown in Figure 5. For [1−2]‡, the transition state for the formation of Z enolate has a lower barrier (as well as relative energy), suggesting a predominant formation of the Z isomer. We also note that the stereoselectivity-determining C− C bond formation transition state [3−4]‡ between enolate-A and EPK exhibits the highest barrier and hence can be regarded as the rate-limiting step. Interestingly, the general features of the free energy profile with inclusion of LiClO4 remained similar to that without LiClO4. It is also noticed that both enantioselectivity (R/S) of the newly formed chiral carbon center and diastereoselectivity (E/Z) of the exocyclic olefin predicted using our transition state models are in qualitative agreement with experimental results (Figure 5). The ee, which depends on the free energy difference between the diastereomeric transition states for the R-E and S-E modes in the case of TMSQ and S-E and R-E modes for MeQd, is predicted to be >99%, in line with the experimental values of 85.0% and 94.0%, respectively. The inversion in the olefin diastereoselectivity from Z to E in the presence of LiClO4 can be noticed from the lower energy of the diastereomeric transition state leading to the formation of the R-E isomer of the product in comparison to the transition state for the R-Z (0.8) isomer. The de predicted using the Gibbs free energy difference between these two transition states is 76.6%, which is quite comparable with the experimental value of 74.0% in the case of TMSQ. On the other hand, the computed de (94.3%) in the case of MeQd is found to be higher than the experimental value (68.0%) (Figure 5). The factors controlling the enantio- and diastereoselectivities are elaborated below.

Scheme 3. Heterodimerization of Ketenes Catalyzed by Chiral Cinchona Catalysts (MeQd and TMSQ) in the Presence of LiClO4

Scheme 4. Mechanism of Heterodimerization of Substituted Ketenes with TMSQ in the Presence of LiClO4

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Figure 5. Free energy profiles (kcal/mol) for TMSQ- and MeQd-catalyzed heterodimerization of ketenes in the presence of LiClO4 at the M062X(SMD)/6-311++G**//M06-2X(SMD)/6-31G** level of theory. The calculated and experimental ee’s and E:Z ratio are provided in the inset (experimental values are in parentheses). Details for the formation of the final product (from 4 to 5) are shown only for the lowest energy pathway.

Figure 6. Optimized geometries of the selectivity-determining C−C bond formation transition states [3−4]‡ for catalysts TMSQ and MeQd obtained at the M06-2X(SMD)/6-311++G**//M06-2X(SMD)/6-31G** level of theory. The relative free energies (kcal/mol) are provided in parentheses. The relative Ei (interaction energy) and Ed (distortion energy) in kcal/mol are with respect to the most preferred R-E mode for TMSQ and S-E for MeQd transition states. Distances are in angstroms. Notations a1, a2,... and b1, b2,... are respectively C−H···π and C−H···O interactions.

We have performed activation strain analysis to ascertain what factors could possibly contribute to the origin of the predicted enantio- and diastereoselectivities. Interesting insights are obtained by comparing the distortion and interaction energies in each transition state. In the case of TMSQ-catalyzed heterodimerization, the lower energy transition state leading to the E diastereomer of the product (R-E) is found to exhibit

relatively improved interaction energy than that in the transition state for the R-Z product. Although the distortion in the reacting partners (particularly in EPK) is higher in the transition state for the E isomer, better stabilization due to improved interaction between the reactants appears to compensate (Figure 6). 13455


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undergoes a ring closure to the β-lactone with a concomitant expulsion of the TMSQ catalyst.34 Because we could characterize (a) an intermediate such as enolate-B (4) as a genuine minimum on the lowest energy pathway, and (b) the transition state for lactonization, a stepwise heterodimerization mechanism is proposed in this study. We have also evaluated the effect of the C9 substituent of the cinchona framework in both the quinine and the quinidine systems by interchanging the TMS and Me groups. The predicted diastereoselectivities are found to be slightly lower in the case of the C9-O-methylquinine (MeQ) and C9-Otrimethylsilyl ether quininidine (TMSQd) as compared to the corresponding TMSQ and MeQd catalysts, The enantioselectivities remained identical for both modified catalysts.35 In addition, the effect of another Lewis acid additive, namely EtAlCl2 instead of LiClO4, is evaluated for a representative system with TMSQ catalyst. With EtAlCl2, diastereoselectivity is predicted to be moderately lower as compared to when LiClO4 is used as the Lewis acid.36

In asymmetric catalysis, the interactions between the chiral catalyst and the reactants in the stereocontrolling transition state are critical to successful stereoinduction.30 Analysis of transition state geometries revealed the presence of a number of noncovalent interactions, which can be gleaned from the optimized geometries as given in Figure 6. The R-E transition state evidently exhibits more C−H···π (a1, a2,...) and C−H···O (b1, b2,...) noncovalent interactions in comparison to that in the R-Z transition state. In particular, interesting substrate− catalyst interactions are noticed. The phenyl ring of EPK engages in C−H···π (a1, a2, a3, a4) interactions with the quinuclidine ring of the cinchona catalyst in the R-E transition state, which is an interaction that is absent in the R-Z transition state. The catalyst−substrate interaction of this sort would help in generating the vital energy differences desirable for good diastereoselectivity in the exocyclic double bond of the product β-lactone. Similar geometric features are also noticed in the stereocontrolling transition states in the case of MeQdcatalyzed pathway. The Lewis acid LiClO4 is noted to play an anchoring role through improved C−H···O and Li···O interactions between the chiral catalyst and the reactants in the transition states. Additionally, the enantioselectivity that depends on the energy difference between the S-E and R-E transition states is also governed by the differences in the noncovalent interactions in these stereocontrolling transition states. For TMSQ catalyst, the distortion in the transition states leading to R-E and S-E isomers is found to be similar. In the lower energy R-E transition state, LiClO4 is better positioned to interact with the chiral catalyst. In the case of the lower energy S-E transition state with MeQd catalyst, the substrate EPK is oriented suitably to participate in multiple noncovalent interactions. Thus, the origin of enantio- as well as diastereoselectivities can be regarded as arising due to a concerted action of multiple weak noncovalent interactions for both TMSQ and MeQd catalysts (Figure 6). Interestingly, in the absence of LiClO4, the noncovalent interactions are found to be nearly the same in the enantiocontrolling and diastereocontrolling pairs of transition states (vide supra, Figure 4). We note that the inclusion of LiClO4 generally lowers the relative free energy of various transition states well as the intermediates, including the C−N bond formation transition state leading to the Z enolate-A, for which the lowering is 5.0 kcal/mol. More importantly, the formation of the Z enolate is favored by 3.5 kcal/mol over the E enolate, similar to the trend found in the absence of LiClO4.31 In the steps subsequent to the formation of enolate-A, the involvement of the acceptor ketene EPK leads to additional coordination for LiClO4 and thus facilitates improved interaction with the substrates. For instance, an important transition state such as [3−4]‡ for the C−C bond formation between the enolate-A and EPK is expected to receive additional stabilization through an ion− dipole type interaction between the developing charge on the ketene moiety and LiClO4.32 We note that [3−4]‡ in the case of TMSQ-catalyzed heterodimerization leading to the R-E product is about 16 kcal/mol lower with an explicit LiClO4 as compared to the corresponding possibility without the LiClO4. A similar trend in additional stabilization (∼20 kcal/mol) due to the inclusion of LiClO4 is found with MeQd as well for the S-E stereoisomer of the product. The other transition states and intermediates in the catalytic cycle are also found to be of lower energy when LiClO4 is present.33 In the last step of the catalytic cycle, via a low energy transition state [4−5]‡, enolate-B

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CONCLUSIONS In summary, the heterodimerization of ketenes catalyzed by pseudoenantiomeric trimethylsilylquinine (TMSQ) or methylquinidine (MeQd) has been found to exhibit similar mechanistic features and energetics. The formation of a fourmembered lactone ring between the donor methylketene and an acceptor ketene (methylphenylketene or ethylphenylketene) takes place via a stepwise process as opposed to a concerted pathway proposed previously. The enantioselectivity at the newly formed chiral center is primarily controlled by lower distortion of the reactants in the most preferred transition state as compared to the higher distortion in the transition state that corresponds to the less preferred product isomer. The Z:E ratio in favor of the Z isomer is also found to be governed by the higher distortion in the E isomer. The transition state models with an explicit molecule of Lewis acid LiClO4 reveal that the additive plays a major role in the formation of Z enolate-A (generated by the action of the chiral cinchona catalyst on methylketene) as well as in the stereodetermining transition state wherein the Z enolate-A adds to the ethylphenylketene. Moreover, the diastereoselectivity of the exocyclic olefin as well as the enantioselectivity of the new chiral center on the βlactone in the case of the Lewis acid-assisted pathway is controlled by weak noncovalent interactions such as C−H···π and C−H···O operating between the catalyst and substrate as well as the additive. These noncovalent interactions remained virtually the same in the stereocontrolling transition states in the absence of the Lewis acid, where the origin of stereoselectivity has been traced to differential distortion in the reactants (enolate-A and MPK). The predicted enantio- and diastereoselectivities are in good agreement with the experimental observations. The molecular insights presented in this article might help to exploit the potential of cinchona-catalyzed asymmetric heterodimerization of ketene toward various βlactone frameworks.

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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/acs.joc.7b02517. Optimized geometries and additional schemes, figures, and tables (PDF) 13456


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Cartesian coordinates of all the stationary points (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Raghavan B. Sunoj: 0000-0002-6484-2878 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The SpaceTime supercomputing facility at IIT Bombay is acknowledged for computing time. B.B. is grateful to UGC New Delhi for a Senior Research Fellowship.

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REFERENCES

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The Journal of Organic Chemistry state and also quasi-harmonic and RRHO approximations at the M062X level of theory. All these methods have conveyed trends similar to that obtained at the M06-2X level of theory. See Table S8 and Figure S3 of Supporting Information for complete details. (28) (a) Rasik, C. M.; Hong, Y. J.; Tantillo, D. J.; Brown, M. K. Org. Lett. 2014, 16, 5168. (b) Rasik, C. M.; Brown, M. K. J. Am. Chem. Soc. 2013, 135, 1673. (c) Rigsbee, E. M.; Zhou, C.; Rasik, C. M.; Spitz, A. Z.; Nichols, A. J.; Brown, M. K. Org. Biomol. Chem. 2016, 14, 5477. (d) Wei, D. H.; Zhang, W. J.; Zhu, Y. Y.; Tang, M. S. J. Mol. Catal. A: Chem. 2010, 326, 41. (e) Wang, Y.; Wei, D. H.; Li, Z. Y.; Zhu, Y. Y.; Tang, M. S. J. Phys. Chem. A 2014, 118, 4288. (f) Hao, X.; Liu, X.; Li, W.; Tan, F.; Chu, Y.; Zhao, X.; Lin, L.; Feng, X. Org. Lett. 2014, 16, 134. (g) Hao, X.; Lin, L.; Tan, F.; Yin, C.; Liu, X.; Feng, X. ACS Catal. 2015, 5, 6052. (29) Experimental studies in the presence of LiClO4 were carried out with ethylphenylketene (EPK) as the acceptor and not MPK. (30) Sunoj, R. B. Acc. Chem. Res. 2016, 49, 1019. (31) Optimized geometries of formation of enolate-A in presence of LiClO4 of TMSQ and MeQd catalyst combinations are shown Table S9 and Figure S4 of Supporting Information. (32) (a) Baboul, A. G.; Redfern, P. C.; Sutjianto, A.; Curtiss, L. A. J. Am. Chem. Soc. 1999, 121, 7220. (b) Eilmes, A.; Kubisiak, P. J. Phys. Chem. B 2011, 115, 14938. (c) Reddi, Y.; Sunoj, R. B. ACS Catal. 2017, 7, 530. (33) A comparison of the relative energies in the presence and absence of LiClO4 with EPK is provided in Table S10 of Supporting Information. (34) The optimized geometries of O−C bond formation transition state [4−5]‡, both in the absence and in the presence of LiClO4, is provided in Figure S5 of Supporting Information. (35) (a) Full details of substitution effect at the C9 position of cinchona catalysts are provided in Tables S12 and S13 of Supporting Information. (b) The predicted % de for MeQ and TMSQ is found to be in line with the earlier experimental observation (ref 10a). (36) Full details of additive effects (LiClO4 and EAlCl2) are provided in Table S14 of Supporting Information.

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Exploring the Mechanism and Stereoselectivity in Chiral Cinchona

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