Synthesis of β-Hexa- and β-Heptapeptides Containing Novel β2,3-Amino Acids with Two Serine or Two Cysteine Side Chains - CD- and NMR-Spectroscopic Evidence for 314-Helical Secondary Structures in Water

Abstract

Two representatives of a new type of β-amino acids, carrying two functionalized side chains, one in the 2- and one in the 3-position, have been prepared stereoselectively: a β-Ser derivative with an additional CH2OH group in the 2-position (for β-peptides with better water solubility; Scheme 2) and a β-HCys derivative with an additional CH2SBn group in the 2-position (for disulfide formation and metal complexation with the derived β-peptides; Scheme 3). Also, a simple method for the preparation of α-methylidene-β-amino acids is presented (see Boc-2-methylidene-β-HLeu-OH, 8 in Scheme 3). The two amino acids with two serine or two cysteine side chains are incorporated into a β-hexa- and two β-heptapeptides (18 and 23/24, resp.), which carry up to four CH2OH groups. Disulfide formation with the β-peptides carrying two CH2SH groups generates very stable 1,2-dithiane rings in the centre of the β-heptapeptides, and a cyclohexane analog was also prepared (cf. 27 in Scheme 6). The CD spectra in H2O clearly indicate the presence of 314-helical structures of those β-peptides (18, 23, 24, 27b) having the `right' configurations at all stereogenic centers (Fig. 2). NMR Measurements (Tables 1 and 2, and Fig. 4) in aqueous solution of one of the new β-peptides (24) are interpreted on the assumption that the predominant secondary structure is the 314-helix, a conformation that has been found to be typical for β-peptides in MeOH or pyridine solution, according to our previous NMR investigations.