Practical, catalytic, asymmetric synthesis of beta-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-beta-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-beta-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-beta-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 alpha-epimerization and alpha-alkylation or acylation led to trans-beta-lactones and beta-lactones bearing alpha-quaternary carbons, respectively. Several of the ketene dimers and beta-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-beta-lactone 3d, displayed an apparent Ki (2.5 +/- 0.5 microM) of only approximately 10-fold lower than that of orlistat (0.28 +/- 0.06 microM). In addition, mechanistic studies of the ketene dimerization process by ReactionView infrared spectroscopy support previous findings that ketene formation is rate determining.
Purohit
Vikram C
VC
Department of Chemistry, Texas A & M University, P.O. Box 30012, College Station, Texas 77842-3012, USA.
Richardson
Robyn D
RD
Smith
Jeffrey W
JW
Romo
Daniel
D
D000475:Alkenes / Q000737:chemistry; D002384:Catalysis; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D006865:Hydrogenation; D007659:Ketones / Q000737:chemistry; D007783:Lactones / Q000138:chemical synthesis*; D010170:Palmitoyl-CoA Hydrolase / Q000037:antagonists & inhibitors*
D000475:Alkenes; D004791:Enzyme Inhibitors; D007659:Ketones; D007783:Lactones; D064429:Fatty Acid Synthases; D010170:Palmitoyl-CoA Hydrolase