Synthesis of beta-hexa- and beta-heptapeptides containing novel beta(2,3)-amino acids with two serine or two cysteine side chains - CD- and NMR-spectroscopic evidence for 3(14)-helical secondary structures in water

Two representatives of a new type of beta-amino acids, carrying two functio nalized side chains, one in the 2- and one in the 3-position, have been pre pared stereoselectively: a beta-Ser derivative with an additional CH2OH gro up in the 2-position (for beta-peptides with better water solubility; Schem e 2) and a beta-HCys derivative with an additional CH2SBn group in the 2-po sition (for disulfide formation and metal complexation with the derived bet a-peptides; Scheme 3). Also, a simple method for the preparation of alpha-m ethylidene-beta-amino acids is presented (see Boc-2-methylidene-beta-HLeu-O H, 8 in Scheme 3). The two amino acids with two serine or two cysteine side chains are incorporated into a beta-hexa- and two beta-heptapeptides (18 a nd 23/24, resp.), which carry up to four CH2OH groups. Disulfide formation with the beta-peptides carrying two CH2SH groups generates very stable 1,2- dithiane rings in the centre of the beta-heptapeptides, and a cyclohexane a nalog was also prepared (cf. 27 in Scheme 6). The CD spectra in H2O clearly indicate the presence of 3(14)-helical structures of those beta-peptides ( 18, 23, 24, 27b) having the 'right' configurations at all stereogenic cente rs (Fig. 2). NMR Measurements (Tables I and 2, and Fig. 4) in aqueous solut ion of one of the new beta-peptides (24) are interpreted on the assumption that the predominant secondary structure is the 3(14)-helix, a conformation that has been found to be typical for beta-peptides in MeOH or pyridine so lution, according to our previous NMR investigations.