Mechanistic investigation on the remote stereocontrol in the chiral Lewis base-catalyzed, SiCl₄-promoted kinetic resolution of chlorinated cis-vinyl epoxides

Highlights

• The remote stereocontrol in the kinetic resolution of chlorinated vinyl epoxide was investigated.

• The role of the β-chlorine-bearing stereocenter has been elucidated by DFT calculation of transition state.

• Non-covalent interactions including C–H/π hydrogen bonding are proposed as key stereodetermining factors.

Abstract

It has been known that the enantioselectivity of the chiral Lewis base-catalyzed, SiCl₄-promoted kinetic resolution of α,β-dichloro cis-vinyl epoxide is highly influenced by the configuration of the distal β-chlorine-bearing stereocenter. In this report, the precise nature of this unusual remote stereocontrol was investigated both experimentally and theoretically. Upon examination of a substrate that has an alkyl group in place of the β-chlorine substituent, the spatial location of major catalyst-substrate interaction was determined. Subsequently, through computational analysis of transition states, the steric repulsion by the β-substituents as well as the additional C–H/π hydrogen bond by the alkyl substituent were proposed as the crucial stereo-determining factors.

Introduction

Epoxide is one of the most versatile functional groups in organic synthesis, and thus a number of synthetic methods have been developed for the enantioselective formation of chiral epoxide [1]. Enantioenrichment can also be achieved by the enantioselective opening of optically inactive epoxide via either desymmetrization of meso-epoxide [2] or kinetic resolution of racemic epoxide [3], typically in the presence of chiral Lewis acid. Denmark and coworkers developed a chiral Lewis base catalysis for the generation of highly active chiral silicon Lewis acids by taking advantage of Lewis base activation of Lewis acids phenomenon [4], and the utility of such catalytic system was demonstrated in the desymmetrization of meso-epoxide with chiral phosphoramide catalyst and silicon tetrachloride [5]. Since this seminal report, various types of chiral Lewis base including N-oxides [6], phosphines [7], and phosphine oxides [8] were developed by several research groups, and highly selective epoxide desymmetrization was accomplished, illustrating the efficiency of the Lewis base-SiCl₄ system [9]. Later, the scope of Denmark’s chiral phosphoramide-catalyzed, enantioselective epoxide opening has been successfully extended to the kinetic resolution of racemic cis-vinyl epoxide (1) by Vanderwal and coworkers during the enantioselective total synthesis of chlorosulfolipids (Fig. 1A) [10]. In this case, the dimeric bisphosphoramide 2 performed better than the monomeric catalyst even though it was an inferior catalyst for desymmetrization. Interestingly, the selectivity of the kinetic resolution is highly affected by the configuration of a relatively remote β-stereocenter. Under the identical catalytic conditions with 2, anti-α,β-dichloride (R = n-C₆H₁₃) was resolved much more effectively than the related syn-α,β-dichloride (R = n-C₈H₁₇). Recently, a preliminary mechanistic study on the stereo-controlling effect of these chlorine-bearing stereocenters was reported by our group (Fig. 1B) [11]. Through a systematic examination of α- or β-monochlorinated substrates 4–6, we have demonstrated that both α- and β-chlorine substituents are required for the high level of enantio-differentiation. In addition, computational analysis was performed for the aliphatic side chain conformation of α,β-dichlorinated vinyl epoxide in order to rationalize the cooperative action of the two stereocenters. It was suggested that the allylic 1,3-like strain at the α-stereocenter as well as the preferred gauche conformation between the α- and β-chlorine-bearing carbons result in a fairly well-defined spatial arrangement of the substituents. Then, upon examination of the ground state of a representative catalyst-substrate complex, it was proposed that the dichloroalkyl side chain could be placed near the chiral catalyst pocket depending on the epoxide configuration, and the conformationally rigid α-center would direct the aliphatic residue toward the catalyst. Thus, the enantiomer with its alkyl side chain in a less crowded space (i) is likely to be activated preferentially to result in the selective epoxide opening whereas the other enantiomer-catalyst complex (ii) is energetically less favorable because of the destabilizing steric interaction between the β-substituents of the side chain and the catalyst. The degree of such interaction appears to be finely controlled by the position and property of the substituents at the β-center. In the current study, the influence of the remote site was further evaluated by employing a substrate with two β-alkyl groups (Fig. 1C). This type of substrate can be considered as an alkyl analog of α,β-dichloro cis-vinyl epoxide, in which the β-chlorine is replaced by an alkyl group. Then, a more precise computational analysis was conducted via transition state calculation to support our stereochemical model and to rationalize the observed remote configuration-dependency. Herein, we describe the results from these mechanistic investigations that led to a plausible proposal on the nature of the catalyst-substrate interaction.