How to stabilize or break beta-peptidic helices by disulfide bridges: Synthesis and CD investigation of beta-peptides with cysteine and homocysteine side chains

all-L-beta(3)-Penta-, hexa-, and heptapeptides with the proteinogenic side chains of valine, leucine, serine, cysteine, and methionine have been prepa red by previously described procedures (12, 13, 14, 15; Schemes 2-5). Thioe ther cleavage with Na/NH3 in beta-HMet residues has also provided a beta(3) -hexapeptide with homocysteine (CH2CH2S) side chains (13e). The HS-(CH2)(n) groups were positioned on the beta-peptidic backbone in such a way that, u pon disulfide-bridge formation, the corresponding beta-peptide was expected to maintain either a 3(1)-helical secondary structure (1, 2) (Fig. 1) or t o be forced to adopt another conformation (3, 4). The 13-, 17-, 19-, and 21 -membercd-ring macrocyclic disulfide derivatives and their open-chain precu rsors, as well as all synthetic intermediates, were purified (crystallizati on, flash or preparative HPL chromatography; Fig. 5) and fully characterize d (m.p., [alpha](D), to, IR, NMR, FAB or ESI mass spectroscopy, and element al analysis, whenever possible; Fig. 2 and Exper. Part). The structures in MeOH and H2O of the new beta-peprides were studied by CD spectroscopy (Figs . 3 and 4), where the characteristic 215-nm-trough/200-nm-peak pattern was used as an indicator for the presence or absence of (M)-3(1)-helical confor mations. A CH2-S-2-CH2 and, somewhat less so, a (CH2)(2)-S-2-(CH2)(2) brack et between residues i and i + 3 (1 vs. 12d. and 2 vs. 13e in Fig. 3) give r ise to CD spectra which are compatible with the presence of 3(1)-helical st ructures, while CH2-S-2-CH2 brackets between residues i and i+2 (3 vs. 14c) or i and i+4 (4 vs. 15c in Fig. 4) do not.