ABSTRACT
Previous syntheses of the biologically active 2-aminated benzoxazoles have relied on forcing thermal conditions to generate the products directly from the corresponding thiols. The resulting yields have ranged from moderate to poor. A mild and high-yielding alternative one-pot chlorination-amination procedure is described. Compounds with a variety of substitution patterns are reported and the methodology has been successfully extended to benzothiazoles. Palladium catalysis on suitably activated examples has been employed to generate the desired compounds of interest.
Subject(s)
Benzothiazoles/chemical synthesis , Benzoxazoles/chemical synthesis , Hydrocarbons, Halogenated/chemistry , Amination , Benzothiazoles/chemistry , Benzoxazoles/chemistry , Catalysis , Magnetic Resonance Spectroscopy/methods , Molecular Structure , Structure-Activity Relationship , Sulfhydryl Compounds/chemistry , TemperatureABSTRACT
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.
