Origin of Stereoselectivity in Cooperative Asymmetric Catalysis

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Origin of Stereoselectivity in Cooperative Asymmetric Catalysis Involving N-Heterocylic Carbenes and Lewis Acids toward the Synthesis of Spirooxindole Lactone Yernaidu Reddi, and Raghavan B. Sunoj ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03026 • Publication Date (Web): 06 Dec 2016 Downloaded from http://pubs.acs.org on December 6, 2016

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Origin of Stereoselectivity in Cooperative Asymmetric Catalysis Involving N-Heterocyclic Carbenes and Lewis Acids toward the Synthesis of Spirooxindole Lactone Yernaidu Reddi and Raghavan B. Sunoj* Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076 [email protected]

LiCl activation THF O

Li

Cooperative catalysis N

O Me

C-Hπ

O

Ph

Cl Ph

N

NHC activation

Me

O Li

H H O THF

Et N H

H Et

Et

Cl

H

Et N

H N

HO

N O

C-HO

N

H N O

O O

(S) (R)

experiment %ee = 96 computed %ee = >99 Ph (SMD (THF) /B3LYP-D3/6-31G**) O

N Me

Abstract: Increasing number of examples are now being reported that use chiral Nheterocyclic carbenes (NHCs) in conjunction with Lewis acids to enhance its catalytic potential. Herein, we provide molecular insights into NHC catalyzed stereoselective annulation reaction between N-methyl isatin and an enal leading to spirooxindole lactone in the presence of LiCl as the Lewis acid. Mechanistic features as well as the origin of enantioand diastereo-selectivities of the catalytic reaction have been unravelled using density functional theory (B3LYP-D3) method. The key mechanistic steps of the reaction are identified to proceed through the formation of a Breslow intermediate between the chiral NHC catalyst and the enal, an enantioselective addition of the re face of this intermediate to the re face of the carbonyl group of N-methyl isatin, an intramolecular proton transfer and lactonization that eventually provide access to (2S,3R) spirooxindole lactone as the final 1

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product. In the most preferred pathway, the Lewis acid is bound to the carbonyl group of the substrate in the form of LiCl(THF). We note that both DBU and LiCl(THF) employed in the reaction play a crucial role respectively in the formation of the initial Breslow intermediate (between the enal and NHC) and in the stereocontrolling C–C bond formation as well as in an ensuing intramolecular proton transfer. The explicit participation of LiCl(THF) is found to lower the activation barriers by 6.4 kcal/mol and 8 kcal/mol respectively for the stereoselective C–C bond formation and an ensuing intramolecular proton transfer, as compared to the pathway devoid of the Lewis acid. The predicted enantio- and diastereoselectivities using the LiCl(THF) bound transition state models have been in good agreement with the experimental observations. A number of weak interactions such as C−H···O, C−H···π, Cl···π and lone pair···π have been identified as playing a vital role in offering additional stabilization to the transition state that corresponds to the major stereoisomer of the spirocyclic product. Key words: N-heterocyclic carbene, Lewis acid, cooperative catalysis, density functional theory, transition state, non-covalent interactions, asymmetric catalysis Introduction In the last couple of decades N-heterocyclic carbenes (NHCs) have found increasing number of applications as a Lewis base and as a nucleophilic organocatalysts in a range of stereoselective C–C and C–heteroatom bond formation reactions.1 The ability of NHC in imparting umpolung reactivity to carbonyls, in the form of nucleophilic homoenolate2 and enolate,3 gave rise to a considerable number of nucleophilic addition reactions with a range of electrophilic partners. This important feature of NHC resulted organocatalytic access to an impressive set of reactions such as annulation, benzoin, Stetter, Mannich, Michael, Claisen rearrangement, C–H activation, C–C bond activation, and cycloaddition.4 While the early reports employed NHC as the sole catalyst in a given reaction, the current practices indicate 2


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the simultaneous use of NHCs alongside other catalysts in a cooperative manner. In fact, NHCs are used in conjunction with other organo or metal catalysts in asymmetric synthesis.5 In 2010, Scheidt and co-workers created a powerful platform involving NHC and Lewis acid such as Mg(OtBu)2 which cooperatively promotes homoenolate addition to hydrazones to generate highly stereoselective γ-lactams.6 Since then, several cooperative asymmetric reactions involving NHCs were developed by the groups of Scheidt, Rovis, Chi, and others. For instance, NHCs have been used cooperatively with Lewis acids (such as Ti(OiPr)4, LiCl, Sc(OTf)3 and La(OTf)3),7 Brønsted acid,8 cinchona,9 and amines.10 Scheidt and co-workers have recently reported an interesting cooperative asymmetric catalytic route towards spirooxindole lactone (Scheme 1).11 The reaction between cinnamaldehyde and isatin could be effectively catalyzed by using the triazole family of chiral NHC and LiCl as the cooperative catalytic dyad. The reaction offered high yields, enantio-, and diastereo-selectivities. The yields and stereoselectivities were lower in the absence of the Lewis acid, suggesting that the Lewis acid plays an important role in the mechanism of the reaction. Spirooxindole lactones with a quaternary carbon center are architecturally important structural motifs present in a number of complex and biologically active natural products.11 There have been a number of computational studies focusing on the mechanism and origin of stereoselectivities of different NHC-catalyzed reactions.12 However, analogous studies on cooperative multi-catalytic reactions involving NHC remained rather scarce.13 In continuation of our research efforts in the understanding of stereoinduction and cooperativity in asymmetric catalysis, we became interested in the NHC catalyzed reaction between isatin and an enal in the presence of LiCl as shown in Scheme 1. It was surmised that NHC activates the aldehydes in the form of a nucleophile while the coordination of LiCl to N-methyl isatin activates the electrophile through the lowering of LUMO energy. Therefore, the catalytic 3


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ability of NHC appears to get modulated by the cooperative participation of the Lewis acid in this reaction.

Scheme 1. Cooperativity of NHC/Lewis acid catalyzed annulation reaction. To the best of our knowledge, no evidence exists as to how the transition states responsible for the formation of stereoisomers interact with the Lewis acid. In this article, we focus on the mechanism and origin of stereoinduction in chiral NHC catalyzed stereoselective synthesis of spirooxindole lactone. We wish to disclose the stereoelectronic factors operating in the diastereomeric transition states for the C–C bond formation in the absence and presence of LiCl in THF solvent. More importantly, we wanted to shed light on how the use of LiCl enhances the enantioselectivity as compared to its absence.

Computational Methods All calculations were carried out using the Gaussian09 suite of quantum chemical program.14 Geometry optimization of reactants, intermediates and transition states were performed using the B3LYP-D3 density functional theory15 functional in conjunction with basis set 6-31G** in the solvent phase. The effect of continuum solvation was incorporated by using the Truhlar-Cramer SMD solvation model wherein the full solute electron density is employed without defining the partial atomic charges.16 The model is developed and tested for charged or uncharged solute in any solvent or liquid medium. Since the experimental studies employed tetrahydrofuran (THF) as the solvent, we have employed the continuum dielectric 4


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of THF (ε=7.4257) in our computations. Fully optimized geometries of all the stationary points were characterized by frequency calculations in order to verify that (a) the transition states have one and only one imaginary frequency representing the desired reaction coordinate, and (b) all minimum energy structures have only positive Hessian index. The Intrinsic Reaction Coordinate (IRC) calculations were performed to further authenticate that the transition states on the potential energy surfaces connect to the desired minima on either side of the first order saddle point. The enthalpy and Gibbs free energy in the solvent phase for all stationary points were obtained by adding the zero point vibrational energy (ZPVE) and thermal energy corrections obtained by using standard statistical mechanics approximations at 298.15K and 1 atm pressure in the condensed phase. The calculation of molecular entropy is done using translational, rotational, electronic and vibrational partition functions.17 Further, we have also evaluated the entropic corrections to the Gibbs free energies using Truhlar’s quasiharmonic approximation.18 We have also carried out single point calculations at the M06-2X-D3/6-31G** level of theory in THF continuum using the optimized geometries at the SMD(THF)/B3LYP-D3 level of theory. The relative Gibbs free energies at the SMD(THF)/B3LYP-D3/6-31G** with respect to the separated reactants are employed for discussions in the manuscript. Topological analysis of the electron density distribution was performed using Bader’s atoms in molecule (AIM) by using AIM2000 software19 using the wave function generated at the SMD(THF)/B3LYP-D3/6-31G** level of theory. This analysis is used for the determination of weak inter-atomic interactions within a molecule for the diastereomeric transition states involved in the stereocontrolling C–C bond formation step of the reaction. We have also considered non-covalent interaction (NCI) analysis to analyze the weak interactions in the lower energy diastereomeric transition states.20 Additionally, we have used distortioninteraction model21 to examine the origin of the difference in energies between 5


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diastereomeric transition states. In the distortion-interaction model, the activation energy (∆E‡) is equated to the sum of distortions in the reactant geometries (∆Ed‡) as noted in the transition state structures as compared to the respective undistorted ground state geometries and the interaction energy (∆Ei‡) between the distorted fragments in the transition state geometries. The activation barrier is therefore written as ∆E‡ = ∆Ed‡ + ∆Ei‡ We have also applied energetic span model developed by Shaik and Kozuch to the computed catalytic cycle.22 In this model, the turn over frequency (TOF) of a catalytic cycle is expressed using the energetics of different stationary points. In many catalytic processes, one can identify two states, such as intermediate and transition state, which determine the TOF of the catalytic cycle. Therefore, the TOF of the cycle depends on TOF-determining intermediate (TDI) and TOF-determining transition state (TDTS). The energetic span of the cycle δE can be calculated as δE = TTDTS- ITDI

----(1),

δE = TTDTS- ITDI + ∆Grx ----(2),

if the TDTS is after the TDI if the TDTS is before the TDI (where ∆Grx is the Gibbs free

energy of the reaction)

Results and Discussion We investigated the key mechanistic steps involved in NHC-LiCl cooperative asymmetric catalysis in an annulation reaction, as shown in Scheme 2. Initially, the NHC adds to the electrophilic aldehydic carbon of the substrate enal (1) to generate a zwitterionic intermediate 3, which subsequently forms Breslow intermediate 4. The formation of Breslow intermediate (an eneaminol intermediate) is a key event in NHC catalyzed reactions. The energetics of formation has been studied under different conditions and its reactivity has been explored towards different electrophiles using both experimental and computational methods.1,2,12 In the next step, which is the stereocontrolling C–C bond formation step, the Breslow 6


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intermediate adds to N-methyl isatin 2 to generate intermediate 5. Although, the addition of the Breslow intermediate in the C–C bond formation may be considered either at the amidic C-2 or at C-3 positions of N-methyl isatin, the C-3 addition is found to be more preferred than that at C-2 position.23 The C–C bond formation is accompanied by a concomitant transfer of the enol proton to the developing alkoxide of the isatin moiety. Another intramolecular proton transfer from the carbinol oxygen to the enolate carbon gives intermediate 6. In the last important step of the catalytic cycle, an intramolecular lactonization furnishes the spirooxindole lactone 7 as the final product and helps in the release of free NHC.

Scheme 2. The key steps involved in cooperative NHC/LiCl catalyzed reaction. 7


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The Gibbs free energy profile for the catalytic cycle at the SMD(THF)/B3LYP-D3/6-31G** level of theory has been analysed (vide infra). The relative Gibbs free energies of catalytic cycle is calculated with respect to the separated reactants, NHC, and 1/2[Li2Cl2(THF)4].24 In the initial step, the C–C bond formation takes place through a nucleophilic addition of the NHC to electrophilic carbonyl carbon of cinnamaldehyde. The relative Gibbs free energy of transition state (1-3)‡ is found to be 13.7 kcal/mol. It is of interest to note that the transition state for the formation of Breslow intermediate 4, through a direct proton transfer via a three membered ring transition state (3-4)‡ is as high as 46.4 kcal/mol. The higher energy of the direct proton transfer transition state is due to the high strain associated with the threemembered ring. Earlier reports suggested that the formation of Breslow intermediate could be an assisted process, such as the one that involves explicit participation of a base, water, or an acid available under the given reaction condition.12,13,25 In the present example, DBU was used as a base,11 prompting us to consider a DBU-assisted pathway for the formation of the Breslow intermediate. The relative Gibbs free energy of the DBU-assisted proton transfer transition state, as shown in Figure 1, is found to be about 24 kcal/mol (Figure 3). The question of whether this proton transfer occurs in a concerted or stepwise manner is addressed by performing extended intrinsic reaction coordinate (IRC) calculations.26 It is identified that the deprotonation of the C2-H by the basic nitrogen atom of DBU and protonation of the enolate oxygen is a concerted process. In another possibility, wherein the role of LiCl(THF)2 is considered in the Breslow intermediate formation, a similar Gibbs free energy as that with the DBU-assisted pathway is noticed.27 The relative Gibbs free energy for the formation of Breslow intermediate 4 is found to be exergonic by 1.9 kcal/mol (Figure 3). (a)

(b)

8


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(1-3)‡ (3−4)dbu‡ Figure 1. The optimized geometries of the transition states obtained at the SMD(THF)/B3LYPD3/6-31G** level of theory for the C–C bond formation (a) and DBU assisted proton transfer (b) involved in the formation of Breslow intermediate. Distances are in Å. (C = black, N = cyan, O = red, H = gray). Only select hydrogen atoms are shown for improved clarity. The most crucial step in the catalytic cycle is the stereoselective C–C bond formation, wherein a nucleophilic addition of 4 to the more electrophilic C-3 carbonyl carbon of Nmethyl isatin takes place. A total of 16 stereochemically distinct transition states are considered for the C–C bond formation. The key differences between these transition states originate from the identities of the prochiral faces and the conformational differences. These differences are (i) re or si prochiral faces of the enol carbon of 4 and the C-3 carbonyl carbon of 2 involved in the bond formation, (ii) the ring conformation of the triazole fused morpholine subunit of the NHC framework, and (iii) relative orientation between the reacting species 2 and 4 as indicated by the change in O1-C2-C3-N4 dihedral angle along the incipient bond. The notations cis and trans represent the orientation of the morpholine oxygen relative to the indane ring. When the morpholine oxygen is oriented in a downward position toward the indane ring it is termed as cis, whereas the upward orientation away from the indane ring

9


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is designated as trans. Different conformations and configurations of transition states for the stereocontrolling C–C bond formation are shown in Figure S4 in the Supporting Information. In addition to the stereochemically different possibilities, we have also considered two sets of transition state models for stereocontrolling C–C bond formation, with and without the explicit inclusion of the Lewis acid. Two likely situations, one with just the LiCl and another model with LiCl(THF) are considered as involved in the activation of the substrate. Since we found that LiCl(THF) pathway is energetically lower in energy than with LiCl, the discussions here focus only on the former.28 We describe the stereoselective C–C bond formation both in the presence of a bound LiCl(THF) and also in its absence.29 In the absence of the Lewis acid, trans-(si,si) transition state is found to be the lowest energy among all the stereochemical modes. However, this mode of addition would lead to a spirooxindole lactone with a configuration (2R,3S), which is at variance with the experimentally observed configuration.11 The difference in Gibbs free energy of the diastereomeric transition states trans-(si,si) and cis-(re,re) is precariously low (0.1 kcal/mol), which corresponds to an ee of 8% with an inverted configuration of the product. The experimental enantioselectivity without the use of Lewis acid was 34% in favor of (2S,3R) stereoisomer.11 In the case of the transition state model with LiCl(THF) binding, a total of nine stereochemical modes are considered for the C–C bond formation between the Breslow intermediate and isatin.30 The transition state for the addition of the re-face of phenyl bearing carbon atom of 4 to the re-face of the carbonyl carbon of 2, denoted as cis-(re,re)lt, is found to be of the lowest energy. Such a mode of addition leads to the desired lactone with the (2S,3R) configuration. Here, the subscript ‘lt’ represents the presence of an explicit LiCl bound to a molecule of solvent THF. The Gibbs free energy of the transition state for the si-si mode of addition, i.e., cis-(si,si)lt is about 6.8 kcal/mol higher than cis-(re,re)lt. Such an energy difference corresponds to an enantiomeric excess of >99%, which is in excellent 10


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agreement

with

the

earlier

experimental

observation

of

96%.11

However,

the

diastereoselectivity is overestimated as compared to the earlier experimental report.11,31 The key geometric features of the stereocontrolling C–C bond formation transition states (4−5)lt‡ are provided in Figure 2.

(4−5)cis-(re,re)lt‡ (0.0)

(4−5)cis-(si,si)lt‡ (6.8)

11


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Figure 2. The optimized geometries of the stereocontrolling C–C bond formation transition states with a bound LiCl(THF) at the SMD(THF)/B3LYP-D3/6-31G** level of theory. The distances are in Å. The electron densities (ρx10-2) at the bond critical points along the bond paths and relative Gibbs free energies (kcal/mol) with respect to the lowest energy transition state are given in parentheses. (C = black, N = cyan, O = red, Cl = green, H = gray, Li = light yellow). A number of interesting non-covalent interactions are noticed in the stereocontrolling transition states as depicted using the optimized geometries in Figure 2. These interactions are further analysed by using topological features such as the bond paths and the value of the electron densities at various bond critical points within the AIM formalism. Various interactions are denoted using alphabets a to q in the figure. While there are a few common and similar interactions (denoted as g – j) in both cis-(re,re)lt and cis-(si,si)lt, the number of unique interactions are different in these transition states. In general, Li tends to maintain a tetrahedral coordination environment. It can be noticed from the geometries of the stereocontrolling transition states as shown in Figure 2 that the coordinating ligands on lithium, except for the chloride and THF, are not the same in cis-(re,re)lt and cis-(si,si)lt. For instance, in the lower energy transition state cis-(re,re)lt the enolate oxygen and only one of the isatin carbonyl interacts with Li whereas in cis-(si,si)lt both the carbonyl oxygen atoms of isatin binds to Li. A somewhat direct role of Lewis acid coordination is noticeable in the lower energy transition state cis-(re,re)lt where LiCl(THF) coordinates to the enolate oxygen (Li-O distance, e = 2.11 Å). This interaction is absent in the higher energy in cis-(si,si)lt. An effective coordination of Li to the isatin carbonyl is noticed in the higher energy cis-(si,si)lt (1.98 Å) which is absent in cis-(re,re)lt. Some of the common weak interactions present in both diastereomeric transition states cis(re,re)lt and cis-(si,si)lt are (i) C−H···Cl interactions (g and h), (ii) Cl···π interaction (i), and 12


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(iii) C−H···O hydrogen bonding (j).32 The weak interaction between the Cl of LiCl and the traizole π framework (i),33 although present in both transition state geometries, it appears to be relatively weaker in cis-(re,re)lt (3.67 Å) than in cis-(si,si)lt (3.41 Å). The C−H···Cl interactions (g and h) in both the diastereomeric transition states cis-(re,re)lt and cis-(si,si)lt are found to be quite similar with a contact distance in the range of 2.82 Å to 2.87 Å. Apart from these common interactions there are a few unique interactions that manifest in only one of the two transition states. For instance, the C−H···O type of interactions a, c, j, k, and l are found in the lower energy cis-(re,re)lt with a contact distances in the range of 2.28 Å to 2.73 Å. Only lesser number of same type of interactions (m and o) are noted in cis-(si,si)lt. Among these C−H···O interactions, the one between the enolate oxygen and the morpholine hydrogen (a) and also with one of the methylene hydrogen atoms of the THF (l), are present in cis-(re,re)lt but not in cis-(si,si)lt. On the other hand, the C−H···O interaction between the carbonyl oxygen of isatin with the morpholine hydrogen (m) is present in cis-(si,si)lt whereas it is absent in cis-(re,re)lt. In other words, the C−H···O interaction that contribute toward the stabilization of the transition state is more in cis-(re,re)lt than in cis-(si,si)lt. The C−H···π interactions between the π cloud of 2,6-diethylbenzene with the α-C−H of the alkene (b) and with the phenyl C−H of cinnamaldehyde (d) are noted in cis-(re,re)lt which are absent in cis(si,si)lt. Another set of C−H···π interactions32 are noted between the methylene hydrogen of THF and π cloud of isatin (p) and α-C−H alkene with the π cloud of indane ring (q) in cis(si,si)lt whereas these are absent in cis-(re,re)lt. Overall, the efficiency of the C−H···π interactions appears to be slightly better in the lower energy cis-(re,re)lt transition state than the diastereomeric cis-(si,si)lt. Another weak interaction, namely, lone pair···π interaction (n)34 is present in cis-(si,si)lt whereas it is absent in cis-(re,re)lt. Through the transition state models for the stereoselective bond formation step presented herein, it is evident that a set of non-covalent interactions, such as C−H···O, Cl···π, C−H···π, and lone pair···π are the most 13


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important factors that help accomplish high levels of stereoinduction. We have also examined the presence of these weak non-covalent interactions using the NCI plot. The NCI analysis also revealed similar features of intramolecular interactions in these transition states.35 An alternative method for the analysis of transition states that will help gain insights into the origin of the energy difference between the diastereomeric transition states is the activation strain model.36 We have performed activation strain analysis on four of the lower energy C–C bond formation transition states that control the stereoselectivity of this reaction.37 The total destabilizing distortion and interaction energies is about 4.0 kcal/mol lower for the lower energy transition state cis-(re,re)lt in comparison with the higher energy cis-(si,si)lt. The stabilizing interaction energy in cis-(re,re)lt is 17.58 kcal/mol lower than that in cis-(si,si)lt. But the destabilizing distorted energy in cis-(re,re)lt is found to be 13.54 kcal/mol higher than that in cis-(si,si)lt. Total activation energy as obtained using the activation strain analysis for cis-(re,re)lt is 4.04 kcal/mol lower than with cis-(si,si)lt.

Figure 3. Gibbs free energy (kcal/mol) profile at the SMD(THF)/B3LYP-D3/6-31G** level of theory for the formation of spirooxindole lactone catalyzed by cooperative action of NHC and LiCl. 14


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The overall energetic features of the catalytic cycle can be gleaned from the Gibbs free energy profile given in Figure 3. There are three important events in the mechanism, namely, the activation of the pro-nucleophile in the form of Breslow intermediate 4, the stereoselective C–C formation via (4-5)‡, and the catalyst regeneration and product release via (6-7)‡. The most striking aspect worth noting at this juncture is that the explicit inclusion of LiCl(THF) provides access to a lower energy pathway owing to the enhanced stabilization of various transition states and intermediates. For instance, the relative Gibbs free energies of the C–C formation transition states (4-5)‡, with and without LiCl(THF) are respectively -10.5 and 1.1 kcal/mol. Similarly, the activation barrier for this elementary step with LiCl(THF) is 6.4 kcal/mol lower than without the Lewis acid. The proton transfer from the carbinol oxygen to the nucleophilic α-carbon in intermediates 5’ and 5lt can take place to give an alkoxide intermediate 6 and 6lt respectively. The relative Gibbs free energies for the proton transfer through five membered transition state (5’-6)‡ is 22.6 kcal/mol in the absence of LiCl(THF) whereas it is found to be -3.4 kcal/mol for (5-6)lt‡ with LiCl(THF).38 The activation barrier of this proton transfer is about 8 kcal/mol lower in LiCl(THF) compared to the corresponding event in the absence of the Lewis acid. The relative Gibbs free energies without and with LiCl(THF) for the regeneration of NHC and formation of spirooxindole lactone transition state (6-7)‡ from intermediate 6 are found to be 2.9 and -8.7 kcal/mol respectively. The optimized transition state geometries for the five membered proton transfer step as well as that for the regeneration of NHC are shown in Figure 4. The formation of lactone product with (2S,3R) configuration is found to be exergonic by 19.5 kcal/mol. The results show that LiCl in the presence of THF solvent stabilizes the transition states and intermediates through non-covalent interactions such as C−H···O, Cl···π, and C−H···Cl.

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(5−6)lt‡ (6-7)lt‡ Figure 4. The optimized geometries for the five membered ring proton transfer step and NHC regeneration transition states in the presence of LiCl(THF) at the SMD(THF)/B3LYPD3/6-31G** level of theory. The bond lengths are in Å. (C = black, N = cyan, O = red, Cl = green, H = gray, Li = light yellow). A few more pertinent aspects of the catalytic pathway are worth noting at this point. In the first phase of the reaction, the explicit participation of DBU as well as LiCl(THF)2 evidently results in a reduction of the barrier for the formation of Breslow intermediate. The binding of LiCl(THF) to the substrate provides additional stabilization to the key mechanistic steps such as in the stereoselectivity determining C–C formation step, proton transfer step, and in the regeneration of the free NHC catalyst. We have compared the efficiencies of the computed catalytic cycle by using the energetic span model as described in the computational section. In the absence of the Lewis acid, the TDI and TDTS are respectively found to be intermediate 4···2 and (5-6)‡ respectively. The energetic span δE for this pathway is 29 kcal/mol. Interestingly, the pivotal role played by the Lewis acid leads to noticeable change in the energetic course of the catalytic cycle. In the presence of LiCl(THF), intermediate 5 becomes the TDI while TDTS is (5-6)‡. The δE is found to be about 21 kcal/mol. On the basis of the energetic span model, it is clear that explicit participation of LiCl(THF) in the mechanism offers a more efficient lower energy pathway toward spirooxindole lactone. 16


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Conclusion Mechanistic insights into the cooperative action of chiral NHC catalyst and lithium chloride as gathered using the DFT(B3LYP-D3) computational tools revealed that the Lewis acid additive plays a vital role in modulating the catalytic activity of NHC. Three of the most important steps in this reaction, between an enal and N-methyl isatin leading to spirooxindole lactone, involve explicit participation of a base (DBU) or the Lewis acid (LiCl). The formation of the Breslow intermediate between the chiral NHC and enal has been found to be effectively assisted by DBU. Similarly, LiCl(THF) has been noted to help in lowering the barrier for stereoselective C−C bond formation between the Breslow intermediate and Nmethyl isatin as well as in an intramolecular proton transfer transition state involved in the catalytic cycle. The transition state models for the C−C bond formation, devoid of LiCl(THF), have remained inadequate as it led to incorrect prediction of the enantioselectivity. Refined transition state models with an explicitly included LiCl(THF) has been effective toward rationalizing the origin of stereoselectivity in the formation of the annulated spirooxindole lactone as the product, in line with the experimental observations. The cooperative action of Lewis acid in modulating the catalytic efficiency of NHC has thus been made established. Overall, the coordination of lithium to the enolate oxygen, C−H···O, C−H···π, Cl···π and lone pair···π interactions in the transition states have been identified as the stereocontrolling factors responsible for high enantioselectivity. Aided by the knowledge of these weak interactions as important control elements in the stereocontrolling transition states, modification on the catalyst and even the choice of the reacting substrates could be made more rational.

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Supporting Information Optimized geometries, additional schemes, figures, tables, and Cartesian coordinates are provided. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *Email: [email protected] ACKNOWLEDGMENT We acknowledge the high performance computing resources at IIT Bombay. Y.R. is grateful to IIT Bombay for providing a research associateship. References (1) (a) Ryan, S. J.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42, 4906-4917. (b) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606-5655. (c) Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37, 2691-2698. (d) Phillips, E. M.; Chan, A.; Scheidt, K. A. Aldrichimica Acta 2009, 42, 55-83. (e) Vora, H. M.; Rovis, T. Aldrichimica Acta 2011, 44, 3-11. (f) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307−9387. (g) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511−3522. (h) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature 2014, 510, 485−496. (2) (a) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205-6208. (b) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 14370-14371. (c) Nair, V.; Menon, R. S.; Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.; Sreekumar, V. Chem. Soc. Rev. 2011, 40,

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Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian09, Revision D.01; Gaussian, Inc.: Wallingford CT, 2013. (15) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104. (16) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378. (17) Ochterski, J. W. Thermochemistry in Gaussian; Gaussian Inc.: Wallingford, CT, 2000. (18) (a) Ribeiro, R. F.; Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2011, 115, 14556−14562. (b) Ayala, P. Y.; Schlegel, H. B. J. Chem. Phys. 1998, 108, 2314−2325. (19) (a) AIM2000 Version 2.0; Buro fur Innovative Software, SBK-Software, Bielefeld, Germany, 2002. (b) Bader, R. F. W. Chem. Rev. 1991, 91, 893−928. (c) Biegler-Konig, F.; Schonbohm, J.; Bayles, D. J. Comput. Chem. 2001, 22, 545-559. (20) Contreras-Garcia, J.; Johnson, E. R.; Keinan, S.; Chaudret, R.; Piquemal, J.-P.; Beratan, D. N.; Yang, W. J. Chem. Theory Comput. 2011, 7, 625–632. (21) (a) Bickelhaupt, F. M. J. Comput. Chem. 1999, 20, 114. (b) van Zeist, W.-J.; Bickelhaupt, F. M. Org. Biomol. Chem. 2010, 8, 3118−3127. (c) Zheng, C.; Zhuo, C.-X.; You, S.-L. J. Am. Chem. Soc. 2014, 136, 16251−16259. (22) (a) Kozuch, S.; Shaik, S. Acc. Chem. Res. 2011, 44, 101−110. (b) Kozuch, S.; Shaik, S. J. Phys. Chem. A. 2008, 112, 6032−6041. (c) Kozuch, S.; Shaik, S. J. Am. Chem. Soc. 2006, 128, 3355−3365. (23) The addition of re face of Breslow intermediate with re face of C-2 of N-methyl isatin is found to be about 10 kcal/mol higher than the addition of re face of Breslow intermediate with re face of C-3 of N-methyl isatin. The optimized geometry of diastereomeric transition state cis-(re,re) at C-2 of N-methyl isatin as shown in Figure S5 in Supporting Information.

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(24) Details of solvation of LiCl in THF is provided in Figure S1 in the Supporting Information (page no. S4-S5). (25) Verma, P.; Patni, P. A.; Sunoj, R. B. J. Org. Chem. 2011, 76, 5606−5613. (26) The extended IRC plot of DBU assisted proton transfer transition state is provided in the Supporting Information (see Figure S3). (27) In the case of LiCl(THF)2 assisted pathway, chloride helps in proton transfer from enolate carbon to enolate oxygen as shown in Figure S2 in Supporting Information. (28) Details of pathway involving LiCl is provided in the Figures S8-S9 and Tables S1 and S3 in Supporting Information. (29) The computed relative Gibbs free energies of sixteen stereochemical possibilities and the corresponding optimized transition state geometries for the new C–C bond formation in the absence of Lewis acid at the SMD(THF)/B3LYP-D3/6-31G** and SMD(THF)/M06-2X-D3/631G**//SMD(THF)/B3LYP-D3/6-31G** levels of theory are provided in Table S1, Figures S4 and Figure S6 in Supporting Information. (30) A full set of transition states in the presence of LiCl(THF) is given in Table S1 and Figure S10 in Supporting Information. (31) (a) The difference in Gibbs free energy of lower energy diastereomeric transition state cis-(re,re)lat and its higher energy diastereomeric transition state cis-(si,re)lat is about 4.8 kcal/mol and 5.0 kcal/mol and their corresponding diastereomeric excesses are >99% and >99%

at

the

SMD(THF)/B3LYP-D3/6-31G**

and

SMD(THF)/M06-2X-D3/6-

31G**//SMD(THF)/B3LYP-D3/6-31G** respectively which is found to be higher than experimental selectivity. (b) Johnston, R. C.; Cohen, D. T.; Eichman, C. C.; Scheidt, K. A.; Cheong, P. H.-Y. Chem. Sci. 2014, 5, 1974-1982.

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(32) (a) Sunoj, R. B. Acc. Chem. Res. 2016, 49, 1019-1028. (b) Wheeler, S. E.; Seguin, T. J.; Guan, Y.; Doney, A. C. Acc. Chem. Res. 2016, 49, 1061-1069. (c) Wheeler, S. E.; Bloom, J. W. G. J. Phys. Chem. A 2014, 118, 6133−6147. (d) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 5062−5075. (33) (a) Imai, Y. N.; Inoue, Y.; Nakanishi, I.; Kitaura, K. Protein Science 2008, 17, 11291137. (b) Bhaskararao, B.; Sunoj, R. B. J. Am. Chem. Soc. 2015, 137, 15712-15722. (34) Das, D.; Choudhury, S. R.; Dey, B.; Yalamanchili, S. K.; Helliwell, M.; Gamez, P.; Mukhopadhyay, S.; Estarellas, C.; Frontera, A. J. Phys. Chem. B 2010, 114, 4998-5009. (35) NCI plots for the lower energy stereocontrolling transition states are provided in Figure S12. (36) (a) Hong, X.; Liang, Y.; Griffith, A. K.; Lambert, T. H.; Houk, K. N. Chem. Sci. 2014, 5, 471-475. (b) Jindal, G.; Sunoj, R. B. Angew. Chem., Int. Ed. 2014, 53, 4432-4435. (c) Diefenbach, A.; Bickelhaupt, F. M. J. Phys. Chem. A 2004, 108, 8460-8466. (d) Legault, C. Y.; Garcia, Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 12664-12665. (37) The computed distortion and interaction energies of the transition states are provided in Table S2. (38) (a) The formation of intermediate 5 is found to exoergic due to a relatively strong hydrogen bonding between O-H of the carbinol moiety of the isatin and the enolate oxygen. This intermediate is likely to remain as the non-reactive conformer for further steps in the absence of LiCl(THF), as implied by the higher activation barrier (33 kcal/mol) for the ensuing proton transfer. In the mechanism devoid of LiCl(THF), another reactive conformer 5’ is identified without the above-mentioned hydrogen bonding interaction. (b) In an alternative mode, we considered a DBU-assisted two-step mechanism wherein the DBU first abstract the proton from the carbinol oxygen and deliver the same to the enolate carbon. This 24


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mode of proton transfer involves higher energy transition states. Optimized geometries of intermediate 5 and 5’ are provided in Figure S13 in Supporting Information.

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Origin of Stereoselectivity in Cooperative Asymmetric Catalysis

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