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

Abstract

Described is an asymmetric synthesis of new Delta(3a,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, delta-sulfoximine substituted, cyclic gamma,delta-unsaturated alpha-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 Me(3)OBF(4) 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 > or =99% ee was obtained in good yield as a further reaction product. Conversion of the sulfinamide to N,S-dimethyl-S-phenylsulfoximine of > or =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.

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

“…Diisobutylaluminumhydride was selected as the reagent because of its ability to perform hydroaluminations of both C=C and C=O double bonds. [16] Model experiments with alkenylsulfoximines 1 [17] and 3 [5] (Scheme 5) were performed in order to seek answers to the following questions: 1) do the double bonds of alkenylsulfoximines react with HAliBu 2 ? 2) is hydroalumination of the C=C double bond with HAliBu 2 faster than that of the C=O double bond?…”

“…The similar treatment of cyclopentanoid alkenylsulfoximine 16 [5] with 5.0 equiv. of HAliBu 2 afforded β-amino alcohol 17 with Ն 98 % de (NMR) in 50 % yield and the diastereomeric alcohol 18 with Ն 98 % de (NMR) in 21 % yield (Scheme 9).…”

“…[5] Having the isomers 27 and 29 in hand, it was of interest to study their reactivity towards HAliBu 2 . Surprisingly, the treatment of 27 with 5.0 equiv.…”

“…We have previously described an asymmetric synthesis of glycinylsubstituted alkenylsulfoximines II through γ-aminoalkylation of the allylic sulfoximines V with the imino ester VI (Scheme 2). [5,6] Although several methods have been devel- 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.…”

Modular Asymmetric Synthesis of Functionalized Azaspirocycles Based on the Sulfoximine Auxiliary

“…Using the same procedure seven-membered (n=3) and eight-membered (n=4) rings have also been successfully prepared (Scheme 6). 34 …”