Synthesis of Combinatorial Libraries of Vinylogous Sulfonamidopeptides (vs-Peptides)

Abstract

Chiral vinylogous sulfonamidopeptides (vs-peptides) were synthesized on TentaGel resin employing (S)- and (R)-N-Boc-vinylogous sulfonyl chlorides 2a–i as building blocks. Glycine and two different photocleavable molecules were used as linkers, and the corresponding cleavage conditions were optimized. According to preliminary studies in solution and on solid phase, three libraries were synthesized with the “split-mix synthesis” method. Taking advantage of the acidic character of the sulfonamides (RSO2–NHR: pKa = 10-11), mild conditions were developed to alkylate the sulfonamide nitrogen atom so as to reduce the acidity of the monomers and of the oligomers and increase their in vivo bioavailability. This synthetic methodology was employed to increase the diversity in a library of di-N-alkylated vs-dipeptides 26. The electron-withdrawing capability of the sulfonamido group pointed to the use of vinylogous sulfonamidopeptides as Michael acceptors. The sodium enolate of dimethyl malonate was used as nucleophile to obtain N-Boc-γ-lactams 35 in moderate yields and good diastereoselectivity.