Total Synthesis of Tetrahydrolipstatin and Stereoisomers via a Highly Regio- and Diastereoselective Carbonylation of Epoxyhomoallylic Alcohols

ABSTRACT: A concise enantioselective synthesis of tetrahy-drolipstatin (THL) and seven stereoisomers has been achieved. The synthesis of THL was accomplished in 10 steps and 31 % overall yield from an achiral ynone. Key to the success of the approach is the use of a bimetallic [Lewis acid]+[Co(CO)4] − catalyst for a late-stage regioselective carbonylation of an enantiomerically pure cis-epoxide to a trans-β-lactone. The success of this route to THL and its stereoisomers also demonstrated the practicality of the carbonylation catalyst for complex molecule synthesis as well as its functional group compatibility. Tetrahydrolipstatin (THL, 1) is an over-the-counter anti-obesity drug that acts by inhibiting the absorption of dietary fats. THL is the saturated form of lipstatin (2), a natura