Quaternary Azetidines, Oxetanes, and Cyclobutanes via Allylic Allylation – Cope Rearrangement: Synthesis of linked heterocycles.

Aliphatic 4-membered (hetero)cycles, such as cyclobutanes and azetidines, are becoming more prevalent as structural features on pharmaceutical leads and drugs. In particular, their rigidity and favorable physicochemical properties allow them to serve as bioisosteric replacements for common drug motifs. Substitution of (hetero)cyclobutanes in stereocontrolled fashion with pharmaceutically relevant functionality is still a modern challenge. Described herein is a method for constructing quaternary (hetero)cyclobutanes and linking them to other (hetero)cycles via an allylic alkylation/exocyclic strain-release Cope rearrangement. The one- or two- step sequence can yield uniquely linked heterocycles bearing an alkylidenemalononitrile functional group, which can be readily transformed into amides diastereoselectively. This study includes optimization and scope studies of the allyic alkylation/[3,3] sequence, enantioselective optimization using asymmetric allylic alkylation, and functional group interconversion studies to yield densely substituted drug-like scaffolds.