Enantiomerically Pure and Highly Substituted Alicyclic α,α‐Difluoro Ketones: Potential Inhibitors for Malarial Aspartic Proteases, the Plasmepsins

The design and synthesis of novel fluorinated building blocks is of major interest in the development of new pharmaceuticals and agrochemicals. A quantitative search in the Protein Data Bank (PDB) manifests the use of di‐ and trifluoro hydrates for binding to hydrophilic enzyme active sites. Hydrated alicyclic α,α‐difluorinated ketones attract attention since they provide suitable functionalities for binding to the pair of catalytically active aspartate (Asp) side chains at the active site of aspartic proteases. This article expands the synthetic availability of this novel class of binding elements. Enantiomerically pure alicyclic α,α‐difluoro ketones are efficiently accessed by a straightforward route involving the separation of diastereoisomeric Mosher esters. The transformation into Mosher esters also enables the determination of the absolute configuration of the enantiomeric α,α‐difluoro ketones. The synthetic protocol was further expanded to the preparation of highly substituted cyclohexyl‐based α,α‐difluoro ketones bearing two exit vectors to fill the corresponding side pockets in the malarial aspartic proteases, the plasmepsins. Moderate biological activities toward these enzymes were determined, with IC 50 (median inhibitory concentration) values in the lower micromolar range.