Practical, Catalytic, Asymmetric Synthesis of β-Lactones via a Sequential Ketene Dimerization/Hydrogenation Process: Inhibitors of the Thioesterase Domain of Fatty Acid Synthase

The recent finding that the FDA-approved antiobesity agent orlistat (tetrahydrolipstatin, Xenical) is a
potent inhibitor of the thioesterase domain of fatty acid synthase (FAS) led us to develop a concise and
practical asymmetric route to pseudosymmetric 3,4-dialkyl-cis-β-lactones. The well-documented up-regulation of FAS in cancer cells makes this enzyme complex an interesting therapeutic target for cancer.
The described route to 3,4-dialkyl-β-lactones is based on a two-step process involving Calter's catalytic,
asymmetric ketene dimerization of acid chlorides followed by a facial-selective hydrogenation leading
to cis-substituted-β-lactones. Importantly, the ketene dimer intermediates were found to be stable to flash
chromatography, enabling opportunities for subsequent transformations of these optically active, reactive
intermediates. Subsequent α-epimerization and α-alkylation or acylation led to trans-β-lactones and
β-lactones bearing α-quaternary carbons, respectively. Several of the ketene dimers and β-lactones
displayed antagonistic activity (apparent Ki in the low micromolar range) in competition with a fluorogenic
substrate toward a recombinant form of the thioesterase domain of fatty acid synthase. The best antagonist,
a simple phenyl-substituted cis-β-lactone 3d, displayed an apparent Ki (2.5 ± 0.5 μM) of only ∼10-fold
lower than that of orlistat (0.28 ± 0.06 μM). In addition, mechanistic studies of the ketene dimerization
process by ReactionView infrared spectroscopy support previous findings that ketene formation is rate
determining.