Mechanistic, crystallographic, and computational studies on the catalytic, enantioselective sulfenofunctionalization of alkenes

Abstract

The stereocontrolled introduction of vicinal heteroatomic substituents into organic molecules is one of the most powerful ways of adding value and function. Although many methods exist for the introduction of oxygen- and nitrogen-containing substituents, the number of stereocontrolled methods for the introduction of sulfur-containing substituents pales by comparison. Previous reports from our laboratories have described sulfenofunctionalizations of alkenes that construct carbon-sulfur bonds vicinal to carbon-oxygen, carbon-nitrogen or carbon-carbon bonds with high levels of diastereospecificity and enantioselectivity. This process is enabled by the concept of Lewis-base activation of Lewis acids, which provides activation of Group 16 electrophiles. To provide a foundation for the expansion of substrate scope and improved selectivities, we have undertaken a comprehensive study of the catalytically active species. Insights gleaned from kinetic, crystallographic and computational methods have led to the introduction of a new family of sulfenylating agents that provide significantly enhanced selectivities.

Figure 1. Lewis base catalysed, enantioselective sulfenofunctionalisation of unactivated alkenes

a, A generic reaction pathway of the 1,2-sulfenofunctionaliaztion of alkenes is presented. Initial formation of an enantiomerically enriched thiiranium ion is followed by the stereospecific (invertive) capture with a nucleophile in an intra- or intermolecular fashion. b, The substrate and nucleophile scope of the Lewis base catalysed, enantioselective sulfenofunctionalisation is shown.

Figure 2. Kinetic study of the Lewis base catalysed sulfenofunctionalisation

The model reaction for the kinetic analysis of the Lewis base catalysed sulfenofunctionalisation is presented.

Figure 3. Synthesis of the catalytically active species (±)-5b and its X-ray crystal structure

a, The catalytically active species (±)-5b was prepared from 3b, PhSCl and NaBArF₂₄. Its sulfenylating potential is demonstrated by the reaction with alkene 1b. b, Ortep plot of (±)-5b X-ray crystal structure (35% thermal ellipsoids, BArF₂₄⁻ counter anion omitted for clarity). S(2)-S(1)-P(1) = 103.5°, C(1)-S(2)-S(1) = 104.1°, P(1)-S(1)-S(2)-C(1) = 96.0°, N(3)-P(1)-S(1)-S(2) = 175.1°.

Figure 4. Proposed catalytic cycle of the Lewis base catalysed sulfenofunctionalisation

The catalytic cycle commences with the sulfenylation of Lewis base 3 mediated by MsOH to generate the catalytically active species 5 which is the resting state of the catalyst with a diagnostic ³¹P NMR chemical shift at 59.9 ppm for 5c. Subsequently, in the turnover-limiting and stereodetermining step, the arylsulfenyl group is transferred to the alkene forming the enantiomerically enriched thiiranium ion. Its stereospecific capture by an internal or external nucleophile delivers the sulfenofunctionalised product and regenerates catalyst 3.

Figure 5. Calculations of the transition states leading to the formation of the thiiranium ion

a, Limiting transition state geometries are shown wherein the spiro transition state is favored over the planar transition state due to stabilizing interaction of a sulfur lone pair with π*-orbital of the alkene in the former. b, Free energies of the four transition states with two different arylsulfenyl groups are given for the reaction at −20 °C. c, Three transition states are presented to illustrate the steric interactions between the alkene and the catalytically active species during thiiranium ion formation. Both of the transition states that lead to the respective minor enantiomer (H-TS-minor1 and Me-TS-minor1, respectively) suffer from destabilising repulsions between the binaphthyl rings and alkene substituents.