Practical Asymmetric Synthesis of a γ-Secretase Inhibitor Exploiting Substrate-Controlled Intramolecular Nitrile Oxide−Olefin Cycloaddition

A practical asymmetric synthesis of the γ-secretase inhibitor (−)-1 is described. As the key transformation, a highly diastereoselective intramolecular nitrile oxide cycloaddition forms the hexahydrobenzisoxazole core of 3 in four operations. Other aspects of the route include a highly stereoselective reduction of an isoxazole to form a cis-γ-amino alcohol, an efficient chemical resolution, a dianion cyclization to construct a sultam ring, and the α-alkylation of a sultam with excellent diastereoselectivity. In each instance, the relative stereochemistry was evolved by way of substrate-based induction with ≥96% ds. Kilogram quantities of the targeted drug candidate (−)-1 were obtained, without recourse to chromatography, by way of 10 isolated intermediates and in 13% overall yield.