Asymmetric synthesis of unsaturated, fused bicyclic proline analogues through amino alkylation of cyclic bis(allylsulfoximine)titanium complexes and migratory cyclization of delta-amino alkenyl aminosulfoxonium salts.
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.
Institut für Organische Chemie der Rheinisch-Westfälischen Technischen Hochschule (RWTH) Aachen, Prof.-Pirlet-Strasse 1, D-52056 Aachen, Germany.
Stefan
S
Koep
Hans-Joachim
HJ
Gais
Gerhard
G
Raabe
D000478:Alkylation; D000596:Amino Acids / Q000737:chemistry*; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis; D018360:Crystallography, X-Ray; D003500:Cyclization; D003622:Dapsone / Q000031:analogs & derivatives* / Q000737:chemistry*; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D014025:Titanium / Q000737:chemistry*
D000596:Amino Acids; D001643:Bridged Bicyclo Compounds; C036115:sulfoxone; D003622:Dapsone; D011392:Proline; D014025:Titanium