Investigations of Thioether Generation for S-D-Ribosyl-L-homocysteine Synthesis

Abstract

Creation of the thioether linkage is a fundamental step for the chemical preparation of the bacterial quorum sensing molecule S-D-ribosyl-L-homocysteine (SRH). Although previous preparations of SRH and its analogues have been reported in the literature, they employ assorted methods with varied results. Therefore, a reassessment of the methodology used for synthetic preparation of the thioether bond in SRH-like molecules is here considered. This work examines four methods of thioether generation following two mechanisms, bimolecular nucleophilic substitution (SN2) and radical-initiated thiol-ene coupling, in an attempt to generate SRH in a more efficient and reproducible manner. Both mechanisms address key objectives for SRH preparation: consistent production of the target compound in an analytically pure form, synthesis from easily obtained commodity materials, and improved understanding of each variable involved in creating the thioether bond in this molecule. One application of the thiol-ene coupling reaction generates the SRH thioether at a trial scale with a much-improved yield (93% over 70%) when compared to the most successful reported method to date. Other observations include improved understanding of steric effects involved in both mechanisms, optimization of conditions, assessment of electrophile choice, and the synthesis of a diastereomer of SRH, which may be considered for use in competitive inhibition assays