Practical Asymmetric Synthesis of a γ-Secretase Inhibitor Exploiting Substrate-Controlled Intramolecular Nitrile Oxide−Olefin Cycloaddition
Citations Over TimeTop 13% of 2006 papers
Abstract
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.
Related Papers
- → Intramolecular 1,3-Dipolar Cycloaddition Strategy for Enantioselective Synthesis of FR-900482 Analogues(2001)50 cited
- → Catalytic Enantioselective [3 + 2] Cycloaddition of α-Keto Ester Enolates and Nitrile Oxides(2017)45 cited
- → Synthesis of Assemblies of Isoxazole and Azoles Based on 1,3-Dipolar Cycloaddition Reaction of Enamines with Nitrile Oxides(2016)11 cited
- → Synthesis of Pyrrolo[3,4-c]pyrazole Derivatives by Intramolecular Cycloaddition of Nitrile Imines(1976)12 cited
- → Functionalized g-Lactones via Intramolecular Nitrile Oxide Cycloaddition(1993)10 cited