Andrew McCabe

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.

Described herein is a strategy for preparing 3° and 4° carbon-containing 3-alkylquinolones: molecules previously inaccessible and/or underexplored in synthetic- and medicinal chemistry. It was found that ~equimolar amounts of 4-(arylsulfonyl) quinolones and 2° allyl alcohols can react via nucleophilic aromatic substitution and allyl quinolyl ether Claisen rearrangement to yield the targeted quinolones. Key findings are fundamental and applied, including optimization of conditions and substrate for mild and high yielding [3,3] rearrangement, transition state analysis and enantiospecificity of the [3,3] step, and scope and limitations for the sequence. The work culminates in the synthesis of unique and previously unexplored antiparasitic endochin-like quinolones (ELQs) bearing 4°-carbons.