Stereochemical Control via a 1,3-dithiane Group: Auxiliary Performance and Removal

Indianapolis, IN

Due to the chiral nature of enzymes in the body, the biological activity of any given molecule is often highly dependent its stereochemical configuration. As chemists seek to synthesize biologically active molecules from scratch, it is imperative to adequately control their stereochemistry as they go. A common way to exert such control is to exploit the inherent shape of an existing portion of a molecule to help control the shape of a new portion being added, which is known as substrate control. A number of natural products contain a motif most logically derived from (S)-2-methylbutanal, which is a readily accessible chiral building block. However, this substrate is notoriously unable to offer any significant stereocontrol over its reactions. The goal of this research project is to develop a surrogate for (S)-2-methylbutanal. A 1,3-dithiane auxiliary has been explored to that end; it was anticipated to control the stereochemistry of nucleophilic addition reactions, and there is precedent that the dithiane group can easily be removed. Our research has in fact shown that the 1,3-dithiane is able to adequately control the relative stereochemical configuration of the newly formed chiral centers during the nucleophilic addition of various organometallic reagents. Stereochemical proof (in the form of 1– and 2–D NMR data) of the relative configuration of the stereocenters resulting from nucleophile addition has been established. We have also demonstrated single–step desulfurization for a variety of nucleophile adducts, validating the approach.