RESUMO
This paper describes a remarkably efficient process for the preparation of gamma-secretase inhibitor 1. The target is synthesized in only five steps with an overall yield of 58%. The key operation is a highly selective and practical, crystallization-driven transformation for the conversion of a mixture of tertiary benzylic alcohols into the desired sulfide diastereomer with 94:6 dr. This unprecedented process is based upon a reversible carbon-sulfur bond formation under acidic conditions.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Carbono/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Enxofre/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Cristalização , Flúor/química , Cetoácidos/síntese química , Cetoácidos/química , Magnésio/química , Estrutura Molecular , Oxirredução , Inibidores de Proteases/química , Solubilidade , Estereoisomerismo , Sulfetos/química , TemperaturaRESUMO
Intramolecular nitrile oxide-olefin cycloaddition to form hexahydrobenzisoxazole 14, which engenders a phenylsulfonyl, 2,5-difluorophenyl geminally substituted carbon substructure, proceeds with up to 99% ds. A rationalization of the high level of substrate-based stereo-induction observed in this and related ketone and acrylonitrile metallohydride reductions, supported by single crystal X-ray crystallography, is presented.
Assuntos
Hidrocarbonetos Aromáticos/química , Alcenos/química , Cristalografia por Raios X , Conformação Molecular , Sulfonas/químicaRESUMO
A practical asymmetric synthesis of the gamma-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-gamma-amino alcohol, an efficient chemical resolution, a dianion cyclization to construct a sultam ring, and the alpha-alkylation of a sultam with excellent diastereoselectivity. In each instance, the relative stereochemistry was evolved by way of substrate-based induction with > or = 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.