Abstract:The conformational preferences of chiral vinylogous aminosulfonic acids (vs-amino acids) and of the corresponding oligomers (vs-peptides) were investigated by a combination of X-ray crystallography, variable-temperature (VT) 'H NMR spectroscopy, FT-IR spectroscopy, and NOE experiments. The major source of conformational freedom in the monomers is the rotation around the C-C bond connecting the double bond with the allylic stereocenter (N-C*-C=C). The allylic conformational preferences can be altered in the oligomers by the formation of secondary structures enforced by hydrogen bonding. Twelve-membered-ring hydrogen bonding is detected in the crystal structure of vs-dipeptide 9, while fourteen-membered-ring hydrogen bonding is the most common folding pattern for the peptides oligomers in chloroform solution. The experimental results are complemented by computer modeling: suitable force-field (FF) parameters for the unsaturated sulfonamide group were developed from ab initio calculations. A Goodman-Still systematic pseudo-Monte-Carlo search was used for the conformational search. The conformers were minimized in chloroform with the GBjSA model. The calculations correctly predicted both the size of the hydrogen-bonded ring and its relative importance, in agreement with the experimental data in solution.

No abstract

No abstract

No 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.