SYNTHESIS OF CHIRAL VINYLOGOUS SULFONAMIDOPEPTIDES (VS-PEPTIDES)

Chiral vinylogous amino sulfonic acids (vs-amino acids) were synthesiz ed starting from either L-or D-alpha-amino acids via N-Boc-alpha-amino aldehydes. Wittig-Homer reaction with methyl (or ethyl) diethylphosph oryl methanesulfonate and nBuLi gave the corresponding alpha,beta-unsa turated sulfonates in high yield and complete (E) stereoselectivity. C leavage of the methyl (ethyl) ester was effected by treatment of the s ulfonates with nBu(4)NI in refluxing acetone. Treatment of the nBu(4)N (+) sulfonate salts with SO2Cl2/PPh3/CH2Cl2 gave the corresponding sul fonyl chlorides as stable chromatographable compounds. The synthetic s equence proved successful not only starting from alpha-amino acids car rying unfunctionalized side-chains (Ala, Val, Phe, Leu, Pro), but also with functionalized alpha-amino acids (Ser, Tyr, Gin) provided that t he side chains were suitably protected. The sulfonyl chlorides were co upled with the amine salts to give vs-dipeptides. Amine hydrochlorides were prepared from N-Boc derivatives by treatment with HCl in methano l or ethyl acetate. The process was further iterated to give vs-tripep tides and vs-tetrapeptides. The above procedure was also used to synth esize ''mixed'' peptides, which incorporate both proteinogenic alpha-a mino acids and vs-amino acids. Proteinogenic alpha-amino acids were in corporated at both the C-terminal and the N-terminal position.