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 HAliBu 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 sixmembered exocyclic alkenylsulfoximine afforded the corresponding sulfoximine-substituted β-amino alcohol with a ketal-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

Synthesis, Reactivity and Application of Vinyl Sulfoximines and Vinyl Aminosulfoxonium Salts

“…In a search of mimics of the aggrecanase inhibitor 208 (Figure 12), [98] analogs 209 a-d, bearing a sulfonimidoyl group, a halogen atom, a sulfonyl group and a double bond in addition to an octahydropentalene and octahydroindene skeleton, were targeted. [99] To access the bicyclic amino alcohols required for Scheme 61. Proposed mechanistic scheme of the ACCR of vinyl sulfoximines and α-lithiovinyl sulfoximines with lithium cuprates.…”

“…The oxidative hydrolysis of sulfoximine 211 a with metachloroperbenzoic acid gave sulfone 224 in high yield (Scheme 65). [99,100] The elimination of the hydroxy sulfoximine 211 a with diethyl azodicarboxylate (DEAD) and PPh 3 furnished the vinyl sulfoximine 225 in high yield.…”