How does the Achiral Base Decide the Stereochemical Outcome in the Dynamic Kinetic Resolution of Sulfinyl Chlorides? A Computational Study

Abstract

Abstract:The dynamic kinetic resolution of sulfinyl chlorides by addition of the optically active alcohol DAGOH (diacetone d-glucose) in the presence of non-chiral bases was theoretically studied at the ONIOM (Becke3LYP:UFF) level. The dependence of the stereochemical outcome on the nature of the base observed in this reaction was explored considering two electronically similar bases, pyridine and collidine, that are experimentally known to promote opposite diastereoselectivities. Our calculations reproduced the experimental result that the absolute configuration of sulfur in the major reaction product is R with pyridine but S with collidine. The analysis of the optimized geometries revealed that the most sterically active substituent around sulfur is the methyl of the substrate with pyridine but the base itself with collidine. This leads to an inversion of the chiral distribution of steric hindrance around sulfur that induces the reversal of the stereochemical outcome.

Sulforaphane homologues: Enantiodivergent synthesis of both enantiomers, activation of the Nrf2 transcription factor and selective cytotoxic activity

“…In this regard, the "DAG-methodology" [54], developed in our group, seems the method of choice as it is able to give a diasteromerically pure sulfinate ester with a non-hindered alkyl chain at the sulfinyl sulfur. Additionally, based on our experimental and theoretical studies [55], both epimers at sulfur should be accessible in an enantiodivergent manner, by a simple change of the base used to catalyse the reaction, from the corresponding sulfinyl chlorides [56].…”

DMAP‐Catalysed Sulfinylation of Diacetone‐D‐Glucose: Improved Method for the Synthesis of Enantiopure tert‐Butyl Sulfoxides and tert‐Butanesulfinamides

“…Analysis of the optimized geometries revealed that the most sterically relevant substituent around the sulfur is the R group of the substrate when pyridine is used as the base, but it is the base itself when DIPEA (diisopropylethylamine) is used. This leads to an inversion of the chiral distribution of steric hindrance around the sulfur, and that in turn induces a reversal of the stereochemical outcome and results in the the observed enantiodivergence 28c…”

Mechanistic studies of desaturase-mediated oxidations

“…The formation of the DAG sulfinate ester is thought to occur through the addition of the alcohol moiety of DAGOH to the sulfur centre of a sulfinyl chloride via an H-bonded trigonal bipyramidal transition state (Figure 2.7). [31] A tertiary amine base is thought to participate through the formation of an N-H bond with the hydrogen atom being transferred (Figure 2.7). The sulfinyl chloride is proposed to undergo pyramidal inversion in the presence of the tertiary base allowing for high reaction yields of diastereomerically enriched product from this racemic starting material.…”

“…[26] ci When a less sterically active base, such as pyridine is used, the reaction proceeds to give the (R) sulfinate; when a bulkier base, such as diisopropylethyl amine or collidine is used, the pathway yielding the (5) sulfinate is preferred. [31] Steric interactions have been studied computationally for transition states of each of the four cases and the proposed rationalization for the observed diastereoselectivity is shown in Figure 2.8. [31] The upper half of the figure shows the most stable transitions states for the formation of the R-(left) and the 5-(right) diastereomers when pyridine is used.…”

“…[31] Steric interactions have been studied computationally for transition states of each of the four cases and the proposed rationalization for the observed diastereoselectivity is shown in Figure 2.8. [31] The upper half of the figure shows the most stable transitions states for the formation of the R-(left) and the 5-(right) diastereomers when pyridine is used. The base is coplanar with the H-O-S-0 plane.…”