Mulzer M, Tiegs BJ, Wang Y, Coates GW, * O'Doherty GA. * Northeastern University,
Boston and Cornell University, Ithaca, USA
Total Synthesis of Tetrahydrolipstatin and Stereoisomers via a Highly Regio- and Diastereoselective
Carbonylation of Epoxyhomoallylic Alcohols.
J. Am. Chem. Soc. 2014;
136: 10814-10820
Key words
tetrahydrolipstatin - pancreatic lipase inhibitors - epoxide carbonylation - epoxyhomoallylic
alcohols
Significance
Tetrahydrolipstatin (Xenical®) is a pancreatic lipase inhibitor that is marketed as a treatment for obesity. The
eleven-step small-scale synthesis depicted (31% overall yield) features the regioselective
carbonylation of the cis-epoxide I using the bimetallic [Lewis acid]+[Co(CO)4]– catalyst J to give the trans-β-lactone.
Comment
Seven diastereoisomers of tetrahydrolipstatin were also prepared by this epoxide carbonylation
route. Attempts to synthesize epoxide I via the direct DCC coupling of N-formyl-l-leucine with G occurred with appreciable amounts of epimerization.
