SummaryEnantiomerically pure tertiary thiols provide a major synthetic challenge, and despite the importance of chiral sulfur-containing compounds in biological and medicinal chemistry, surprisingly few effective methods are suitable for the asymmetric synthesis of tertiary thiols. This review details the most practical of the methods available.

A modular synthetic approach is described in which combinations of cyclic sulfamidate and hydroxy sulfonamide building blocks may be converted into piperazine, 1,4-diazepine and 1,5-diazocane scaffolds.

Lithiation of N-aryl S-α-alkylbenzyl thiocarbamates leads to rearrangement with migration of the N-aryl ring to the anionic centre α to S, a process which generally proceeds with ca. 98% retention of stereochemistry and returns chiral benzylic tertiary thiols in high enantiomeric ratios.

Historically, chemists' exploration of chemical space has been exceptionally uneven and unsystematic.This feature article outlines a comprehensive conceptual framework that may be used to capture, analyse and plan synthetic approaches that may address this historically uneven exploration. Illustrative examples of synthetic approaches that target, or have potential to target, broad tracts of lead-like chemical space are presented within the context of this conceptual framework. Particular emphasis is placed on synthetic approaches that enable the combinatorial variation of molecular scaffold, particularly within the boundaries of lead-like chemical space.