Practical, Catalytic, Asymmetric Synthesis of -Lactones via a Sequential Ketene Dimerization/Hydrogenation Process: Inhibitors of the Thioesterase Domain of Fatty Acid Synthase Vikram C. Purohit, ² Robyn D. Richardson, ‡ Jeffrey W. Smith,* ,‡ and Daniel Romo* ,² Department of Chemistry, Texas A & M UniVersity, P.O. Box 30012, College Station, Texas 77842-3012 and Cell Adhesion and Extra Cellular Matrix Biology, Burnham Institute for Medical Research, Infectious and Inflammatory Disease Center, La Jolla, California 92037 romo@mail.chem.tamu.edu; jsmith@burnham.org ReceiVed February 24, 2006 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--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--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--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 R-epimerization and R-alkylation or acylation led to trans--lactones and -lactones bearing R-quaternary carbons, respectively. Several of the ketene dimers and -lactones displayed antagonistic activity (apparent K i 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--lactone 3d, displayed an apparent K i (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. Introduction The development of synthetic processes that deliver optically active products from achiral starting materials in a practical and catalytic manner continues to be a vital area of research in organic synthesis. 1 In the area of -lactone synthesis, the Wynberg process continues to be a benchmark for further developments in this area. 2 Several groups have recently developed various catalytic, asymmetric routes to -lactones involving nucleophile-catalyzed aldol-lactonizations and Lewis- acid-catalyzed [2+2] cycloadditions. 3 With regard to the former route, we recently reported an intramolecular, nucleophile- catalyzed aldol-lactonization process building on the work of Wynberg that effectively joins catalytic, asymmetric carbocycle synthesis with -lactone synthesis employing organocatalysis. 4 This was the first example of this process with highly electro- philic (e.g., non-R-chlorinated) aldehydes. More recently, this * To whom correspondence should be addressed. ² Texas A & M University. ‡ Burnham Institute for Medical Research. (1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York, 1994. (b) Williams, J. M. J. Catalysis in Asymmetric Synthesis; Sheffield Academic Press: Sheffield, England, 1999. (2) (a) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166. (b) Wynberg, H.; Staring, E. G. J. Top. Stereochem. 1986, 16, 87. (3) For reviews describing asymmetric routes to -lactones, see: (a) Yang, H. W.; Zhao, C.; Romo, D. Tetrahedron 1997, 53, 16471. (b) Wang, Y.; Tennyson, R. L.; Romo, D. Heterocycles 2004, 64, 605. (4) (a) Cortez, G. S.; Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001, 123, 7945. (b) Cortez, G. S.; Oh, S. H.; Romo, D. Synthesis 2001, 1731. (c) Oh, S.; Cortez, G.; Romo, D. J. Org. Chem. 2005, 70, 2835. 10.1021/jo060392d CCC: $33.50 © 2006 American Chemical Society J. Org. Chem. 2006, 71, 4549-4558 4549 Published on Web 05/18/2006