Preparation of N-Fmoc-protected β2- and β3-amino acids and their use as building blocks for the solid-phase synthesis of β-peptides

N-Fmoc-Protected (Fmoc = (9H-fluoren-9-ylmethoxy)carbonyl) beta-amino acids are required for an efficient synthesis of beta-oligopeptides on solid support. Enantiomerically pure Fmoc-beta(3)-amino acids (beta(3): Side chain and NH2 at C(3)(= C(beta))) were prepared from Fmoc-protected (S)- and (R)-alpha-amino acids with aliphatic, aromatic, and functionalized side chains. using the standard or an optimized Arndt-Eistert reaction sequence. Fmoc-beta(2) Amino acids (beta(2) side chain at C(2), NH2 at C(3)(= C(beta))) configuration bearing the side chain of Ala, Val, Leu, and Phe were synthesized eia the Evans' chiral auxiliary methodology. The target beta(3)-heptapeptides 5-8, a beta(3)-pentadecapeptide 9 and a beta(2)-heptapeptide 10 were synthesized on a manual solid-phase synthesis apparatus using conventional solid-phase peptide synthesis procedures (Scire,ne 3). In the case of beta(3)-peptides, two methods were used to anchor the first beta-amino acid: esterification of the ortho-chlorotrityl chloride resin with the first Fmoc-beta-amino acid 2 (Method I, Scheme 2) or acylation of the 4-(benzyloxy)benzyl alcohol resin (Wang resin) with the ketene intermediates from the Wolff rearrangement of amino-acid-derived diazo ketone 1 (Method II, Scheme 2). The former technique provided better results, as exemplified by the synthesis of the heptapeptides 5 and 6 (Table 2). The intermediate from the Wolff rearrangement of diazo ketones 1 was also used for sequential peptide-bond formation on solid support (synthesis of the tetrapeptides 11 and 12). The CD spectra of the beta(2)- and beta(3)-peptides 5, 9, and 10 show the typical pattern previously assigned to an (M) 3(1) helical secondary structure (Fig.). The most intense CD absorption was observed with the pentadecapeptide 9 (strong broad negative Cotton effect at ca. 213 nm): compared to the analogous heptapeptide 5, this corresponds to a 2.5 fold increase in the molar ellipticity per residue!