Article pubs.acs.org/JPCB

Asymmetric Phase-Transfer Catalysis with Homo- and Heterochiral Quaternary Ammonium Salts: A Theoretical Study Galina P. Petrova,† Hai-Bei Li,†,‡ Keiji Maruoka,§ and Keiji Morokuma*,† †

Fukui Institute for Fundamental Chemistry, Kyoto University, Kyoto 606-8103, Japan School of Ocean, Shandong University, Weihai 264209, China § Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan ‡

S Supporting Information *

ABSTRACT: A thorough theoretical study of phase-transfer quaternary ammonium catalysts designed by the Maruoka group has been performed in an attempt to gain better understanding of the properties and catalytic behavior of the homo- and heterochiral forms of these systems. The conformationally flexible analogue is found to easily undergo interconversion from the homo- to the heterochiral form driven by the higher thermodynamic stability of the heterochiral isomer and resulting in alternation in catalytic behavior. Theoretical calculations of 1H NMR spectra of the two isomers for different model systems are in good agreement with the experimental data, allowing us to conclude that the upfield shift of signals for the benzylic protons in the heterochiral form could be explained by an increase in the shielding effect of the aromatic parts of the system around these protons due to the conformational changes. By applying the automated transition state (TS) search procedure for the alkylation of glycine derivatives catalyzed by the homo-/heterochiral form of a conformationally rigid analogue, we were able to locate more than 40 configurations of the TS structures. In brief, the homochiral form was theoretically confirmed to catalyze the formation of the predominant R-product, while for the heterochiral form the catalytic activity is found to depend on two factors: (i) formation of a tight ion pair between the catalyst and the glycine derivative, which results in a decrease in the reaction rate, in agreement with the experimental data, and formation of only the R-product, and (ii) the possibility that the reaction occurs without the initial formation of the ion pair or after its dissociation, in which case the formation of an S-product is predominant. The combined effects of both factors would explain the lower reaction rate and the poor enantioselectivity observed experimentally for the heterochiral form.

1. INTRODUCTION In the past several decades phase-transfer catalysis (PTC) has developed into a widespread methodology for organic synthesis expanding from the sphere of pure scientific research to industry mainly due, on one hand, to the simplicity of experimental procedures, its mild conditions, and the usage of relatively inexpensive and environmentally friendly reagents and solvents and, on the other, to the possibility of easy transfer of these laboratory procedures to large-scale synthesis.1−6 The use of chiral quaternary ammonium salts (quats) as chiral phase-transfer catalysts has proven to be a unique and reliable technique for catalytic synthesis in numerous valuable chemical reactions for preparation of chiral, nonracemic organic compounds from prochiral substrates.4,7−13 The approach has been successfully used in numerous organic reactions of scientific and industrial interest such as alkylation, conjugate addition, Mannich reaction, Aldol reaction, cyclization, ringopening reactions, and hydrolysis, etc. Practical aspects of asymmetric PTC and very recent advances in the field have been thoroughly presented and discussed in numerous review papers and references therein.1−6,14 Because our theoretical study was mainly concentrated with catalysts designed and synthesized by the Maruoka group, hereby several important © 2014 American Chemical Society

aspects of their essential contribution in this fast developing field of organic synthesis are listed: (i) design of a series of C2symmetric spirobinaphthyl quaternary ammonium bromides, analogous to model systems I and II adopted in the current theoretical study (see Scheme 1);15−17 (ii) testing their catalytic performance in the stereoselective functionalization of protected glycine derivatives under different conditions, aiming at developing an effective catalyst and experimental procedure for preparation of both natural and unnatural α-amino acids;18−21 (iii) studying the dependence of catalytic activity on the conformation and flexibility of the catalyst16 and showing that homochiral isomers of the studied catalysts have better performance in terms of both rate and enantioselectivity than heterochiral isomers; and (iv) investigating the interconversion of several conformationally flexible species via variable-temperature (VT) 1H NMR, in order to explain how the catalyst performance is affected by reaction conditions and under what conditions a flexible catalyst may still be applied with the desired stereoselectivity. Theoretical approaches at Received: February 12, 2014 Revised: April 4, 2014 Published: April 10, 2014 5154

dx.doi.org/10.1021/jp501520g | J. Phys. Chem. B 2014, 118, 5154−5167

The Journal of Physical Chemistry B

Article

In the present work, we report a thorough theoretical study on catalysts experimentally synthesized and studied by the Maruoka group, aiming at providing further insights on the properties and behavior of the catalytic system. Toward this goal, we modeled the interconversion of the homo-/ heterochiral forms of conformationally flexible catalysts and simulated and analyzed the 1H NMR spectra of chiral forms of several different quaternary ammonium salts as well as their performance in asymmetric catalysis for the interaction of the glycine imine ester and benzyl bromide (Scheme 1b,c). Considering the complexity of the system and its flexibility as well as the fact that the catalyst does not participate actively in the catalyzed process but only provides the local asymmetric environment via electrostatic and short-range interactions, we used the artificial force induced reaction (AFIR) method recently developed by us,32−34 in order to find all possible conformations of the transition state (TS) structures without prejudice.

Scheme 1. Schematic Representation of (a) the Homo- (S,S) and Heterochiral (R,S) Forms of Two Systems, I and II, Chosen for the Current Study; (b) Asymmetric Alkylation of Glycine Schiff Base as a Model Reaction; and (c) Reaction Mechanism under Phase-Transfer Catalytic Condition

2. RESEARCH METHODOLOGY 2.1. Model Systems. In the current study we considered two catalysts, developed and studied by the Maruoka group (see Scheme 1a): the interconversion equilibrium was studied using catalyst I, while the reaction mechanism of stereoselective functionalization of the glycine derivative (reactant A) with benzyl bromide (reactant B) was modeled with catalyst II. NMR is among the simplest experimental techniques for structural analysis of organic molecules, and better understanding of the NMR spectrum of catalytic systems may be of great importance. Very recently Mori et al.35 demonstrated the power of the 1H NMR method for catalyst screening on the example of chiral phosphoric acid-catalyzed asymmetric bromination. 1H NMR spectra were modeled for both systems and were compared with the available experimental data. The biphenyl derivative, model system I, was found to go through easy interconversion, as studied experimentally by a variabletemperature 1H NMR (VT-NMR).15,16 It is, however, interesting to point out that a plausible reaction mechanism, catalyzed by model system I, is ambiguous due to the system flexibility. According to the experimental data at 273 K in toluene, the reaction provided high-yield, 95%, and enhanced enatioselectivity, 92% ee forming an R-product.15,16 The high enantioselectivity was explained by the predominant presence of the catalyst homochiral form under the reaction conditions (similar observations were previously made by Vial and Lacour29 for highly symmetric spirobi[dibenzazepinium] cations). Rapid interconversion of the homochiral isomer and shifting the equilibrium toward the heterochiral form would lead to lower rates and loss of the enantioselectivity. In VTNMR experiments (CH2Cl2), the interconversion of homochiral bromide salt was observed at even lower temperatures. The interconversion process under reaction conditions may be delayed due to many factors such as the presence of water, formation of ion pairs with the reactants, and so on. Due to the conformational flexibility of model system I, we chose the conformationally rigid model system II, for which experimental data are available for the catalytic performance of both homo- and heterochiral forms. Under the same reaction conditions as for model system I, the homochiral (S,S)_II catalyst resulted in 91% yield with 94% ee R-selectivity, while the heterochiral (R,S)_II form led to much lower yield, 47%, even after longer reaction time and only 11% ee with respect to the R-product (see Scheme 1b).18 The studied reaction itself is

different levels have been successfully applied to studies of asymmetric reactions giving insights both on the effect of catalyst on the enantioselectivity and on the detailed reaction mechanism.22−25 A full quantum-mechanical modeling, taking properly into account the weak dispersion interactions typical for these systems at the M06-2X level, was reported quite recently by Cook et al.26 Of course, some aspects of the system under discussion have been previously approached and experimentally studied on similar or simpler systems with analogous behavior. Thus, conformations and energy barriers for conformational inversion of bridged biphenyls/binaphthyls have been of considerable interest. Experimentally energy barriers for the interconversion as well as the ratio of stereoisomers could be estimated with high precision on the basis of 1H NMR data, as the benzylic methylene groups of bridged biphenyls in different forms of compounds are magnetically nonequivalent due to their differing geometrical relationship to the aromatic rings.27−31 5155

dx.doi.org/10.1021/jp501520g | J. Phys. Chem. B 2014, 118, 5154−5167

The Journal of Physical Chemistry B

Article

considering a bigger fragment of reactant A, >CN−CH−− CO2−. As will be seen in the discussion that follows, both approaches provided valuable results. All approximate intermediates and TS structures, obtained by AFIR search at the relatively low ONIOM(B3LYP/3-21G*:PM6)52 level (level A) without taking into account the effect of the solvent, were fully optimized (without force) at the same level. The most stable approximate TS structures and the corresponding reaction paths were further reoptimized at ONIOM(B3LYP/631G*:PM6)|PCM(toluene) (level B) and ONIOM(M06−2x/ 6-31G*:PM6)|PCM(toluene) (level M)53 in order to improve the computational accuracy and include the implicit solvent effect. Considering the fact that the reactant complex for this reaction is an ion pair, the solvent effect is important for proper stabilization of the system. Reported free energy values, ΔG, are calculated at the default for Gaussian 09 (temperature, 298 K; pressure, 1 atm). Frequency calculations were performed for all local minima and saddle points to check the nature of the structures. IRC calculations confirmed the connectivity of all of the TS structures. Reported relative energies were calculated with respect to the sum of the energies of the most stable ion pair, (R,S)_II_01, and the alkyl bromide (reactant B) (unless specified otherwise) at the corresponding levels. In the discussion the energy values are given in the format ΔE(ΔG) in kilocalories per mole at level B. In order to obtain reliable initial structures of the ion pair consisting of the catalyst and reactant A (the mechanism proposed in Scheme 1 supposes formation of such a pair in advance to the SN2 reaction with reactant B), we performed docking simulations by using MGL tools 1.5.4 with AutoGrid4 and AutoDock4.54,55 The structures of the two receptors (the homo and hetero forms of the catalyst in this case) and the ligand (reactant A) for the docking were initially optimized at the PM6 level. All bonds in the reactant molecule excluding the aromatic bonds in the phenyl substituents were considered rotatable in order to account for the possibility of formation of both E- and Z-enolate complexes; the potential grid was built on the rigid structure of the receptor. During the docking procedure the catalyst molecule is enclosed in a box with 100 × 100 × 100 grid points in x × y × z directions, at grid spacing of 0.2 Å. The docking calculations were performed by applying Lamarckian genetic algorithm, as implemented in AutoDock. The clustering analysis was based on 150 runs at population size 150 with a single survivor.

a one-step SN2 alkylation of benzyl bromide, in which reactant A (initial structures of the ion pair consisting of the catalyst and reactant A) plays the role of a nucleophile, while bromine atom is released as an anion. Under phase-transfer catalytic conditions, the whole catalytic process proceeds in several stages (see Scheme 1c):2,36 (i) interaction of the glycine derivative with inorganic base at the interface of the two phases as the obtained metal enolate remains entrapped at the interface due to its polar character; (ii) exchange of the metal cation with the ammonium catalyst resulting in formation of lipophilic onium enolate easily solvated in the organic phase; (iii) interaction between the onium salt and the alkyl halide to release the product of the reaction and to regenarate the onium halide closing the catalytic cycle (an SN2 type reaction). Considering that the structure of the onium enolate ion pair and the step of interaction with the alkyl halide are the enantioselective stages of the process, the formation of the ion pair and its further interaction with halide were modeled in the reaction mechanism study. 2.2. Theoretical Approach. All calculations were performed by using the Gaussian 09 program37 at the ONIOM(B3LYP/6-31G*:PM6) level38−41 in dichloromethane (CH2Cl2) or toluene, described implicitly by the PCM model.42,43 The high-level quantum-mechanical (QM) model includes the >CN−CH−−CO2− fragment of reactant A, the −CH2Br group of reactant B, and the N+(CH2

Asymmetric phase-transfer catalysis with homo- and heterochiral quaternary ammonium salts: a theoretical study.

A thorough theoretical study of phase-transfer quaternary ammonium catalysts designed by the Maruoka group has been performed in an attempt to gain be...
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