Synthesis of BACE Inhibitor LY2886721. Part I. An Asymmetric Nitrone Cycloaddition Strategy

A scalable, asymmetric synthesis of (3aS,6aS)-6a-(5-bromo-2-fluorophenyl)-1-((R)-1-phenylpropyl)tetrahydro-1H,3H-furo[3,4-c]isoxazole, a key intermediate in the synthesis of LY2886721, is reported. Highlights of the synthesis include the development of an asymmetric [3 + 2] intramolecular cycloaddition facilitated by trifluoroethanol, and the development of a new synthesis of (R)-N-(1-phenylpropyl)hydroxylamine tosylate which proceeds through a p-anisaldehyde imine and avoids the formation of toxic hydrogen cyanide gas as a byproduct. The synthesis proceeds over four steps and provides the product in 36% overall yield.