A modular lead-oriented synthesis of diverse piperazine, 1,4-diazepane and 1,5-diazocane scaffolds.

Piperazines are found widely in commercially-available compounds and bioactive molecules (including many drugs). However, in the vast majority of these molecules, the piperazine ring is isolated (i.e. not fused to another ring) and is not substituted on any of its carbon atoms. A modular synthetic approach is described in which combinations of cyclic sulfamidate and hydroxy sulfonamide building blocks may be converted into piperazines and related 1,4-diazepine and 1,5-diazocane scaffolds. By variation of the combinations of building blocks used, it was possible to vary the ring size, substitution and configuration of the resulting heterocyclic scaffolds. The approach was exemplified in the synthesis of a range of heterocyclic scaffolds that, on decoration, would target lead-like chemical space. It was demonstrated that lead-like small molecules based on these scaffolds would likely complement those found in large compound collections.

Asymmetric synthesis of tertiary thiols and thioethers.

Enantiomerically 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.

Tertiary thiols from allylic thiocarbamates by tandem enantioselective [3,3]-sigmatropic rearrangement and stereospecific arylation.

The synthesis of tertiary thiols in enantiomerically enriched form is accomplished by lithiation of enantiomerically enriched N-aryl allylic thiocarbamates. Formation of an allyllithium derivative promotes intramolecular N to C aryl migration to the position α to sulfur, generally with good stereospecificity. The substrates may themselves be obtained by Pd-catalyzed enantioselective [3,3]-sigmatropic rearrangement of N-aryl O-allyl thiocarbamates. Solvolysis of the product thiocarbamates yields tertiary thiols, which may be converted to sulfide derivatives.

A conceptual framework for analysing and planning synthetic approaches to diverse lead-like scaffolds.

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.

Enantioselective synthesis of tertiary thiols by intramolecular arylation of lithiated thiocarbamates.

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.