Asymmetric Synthesis of Unsaturated, Fused Bicyclic Proline Analogues through Amino Alkylation of Cyclic Bis(allylsulfoximine)titanium Complexes and Migratory Cyclization of δ-Amino Alkenyl Aminosulfoxonium Salts

Described is an asymmetric synthesis of new Δ3a,4-unsaturated, fused bicyclic proline analogues
from cyclic bis(allylsulfoximine)titanium complexes and N-tert-butylsulfonyl imino ethyl ester. Treatment of
the enantiomerically pure five-, six-, seven-, and eight-membered cyclic bis(allylsulfoximine)titanium
complexes with the imino ester gave mixtures of the corresponding (E,syn)- and (Z,syn)-configured,
δ-sulfoximine substituted, cyclic γ,δ-unsaturated α-amino acid esters with high regio- and diastereoselectivities in good yields. Activation of the N-methyl sulfoximine group of these amino acid derivatives through
methylation with Me3OBF4 afforded in nearly quantitative yields the corresponding (dimethylamino)sulfoxonium salts. A novel migratory cyclization of these salts with DBU gave via an isomerization to the
corresponding allylic (dimethylamino)sulfoxonium salts and an intramolecular substitution of the (dimethylamino)sulfoxonium group the enantio- and diastereomerically pure, bicyclic, N-tert-butylsulfonyl protected
proline analogues having a six- and eight-membered unsaturated carbocyclic ring. Cyclization of the alkenyl
(dimethylamino)sulfoxonium salts was independent of the configuration of the double bond. N,N-Dimethylphenylsulfinamide of ≥99% ee was obtained in good yield as a further reaction product. Conversion
of the sulfinamide to N,S-dimethyl-S-phenylsulfoximine of ≥99% ee, the starting material for the synthesis
of the allylic sulfoximines, had been accomplished previously. Finally, cleavage of the tert-butylsulfonyl
protecting group with anhydrous acid furnished the fused bicyclic proline analogue containing an unsaturated
six-membered ring in high yield.