Asymmetric Synthesis of Functionalized Bicyclic β‐Amino Alcohols by Cascade Hydrometallation–Cyclization–Reduction of Glycinyl‐Substituted Alkenylsulfox­imines – Application to the Synthesis of an Aggrecanase Inhibitor Mimic

Abstract The treatment of exocyclic alkenylsulfoximines, which carry an α‐glycinyl group at the allylic position, with HAl i Bu 2 caused cascade hydroalumination–cyclization–reduction and delivered the corresponding enantio‐ and diastereopure sulfoximine‐substituted bicyclic β‐amino alcohols with a bicyclo[3.3.0]octane and bicyclo[4.3.0]nonane skeleton in high yields. Three consecutive stereogenic C atoms of the bicyclic β‐amino alcohols were generated in the cascade reactions with high diastereoselectivities. Application of the hydroalumination–cyclization–reduction to a ketal‐substituted six‐membered exocyclic alkenylsulfoximine afforded the corresponding sulfoximine‐substituted β‐amino alcohol with aketal‐functionalized bicyclo[4.3.0]nonane skeleton. Reduction of a sulfoximine‐substituted β‐amino alcohol gave the parent β‐amino alcohol, whereas its oxidative deamination afforded the corresponding sulfonyl‐substituted β‐amino alcohol. The treatment of a sulfoximine‐substituted β‐amino alcohol with chloro‐ and iodoformates stereoselectively furnished the corresponding chloro‐ and iodo‐substituted β‐amino alcohols. Finally, the feasibility of a dehydration and elimination of sulfoximine‐substituted β‐amino alcohols with formation of the corresponding amino‐substituted alkenylsulfoximine and allylic amine was demonstrated. An enantio‐ and diastereopure protected aggrecanase inhibitor mimic was synthesized in high yield starting from the sulfoximine‐substituted bicyclic β‐amino alcohol with a bicyclo[4.3.0]nonane skeleton and ( R )‐2‐(3‐benzyloxy)benzyl‐4‐ tert ‐butoxy‐4‐oxobutanoic acid. Coupling of both building blocks gave the corresponding succinamide, the tert ‐butoxycarbonyl group of which was converted into the corresponding O ‐benzyl‐hydroxycarbamoyl group.