Preparation of N-Fmoc-Protected β2- and β3-Amino Acids and Their Use as Building Blocks for the Solid-Phase Synthesis of β-Peptides

Article abstract of DOI:10.1002/hlca.19980810202

N-Fmoc-Protected (Fmoc = (9H-fluoren-9-ylmethoxy)carbonyl) β-amino acids are required for an efficient synthesis of β-oligopeptides on solid support. Enantiomerically pure Fmoc-β³-amino acids (β³: side chain and NH₂ at C(3)(=C(β))) were prepared from Fmoc-protected (S)- and (R)-α-amino acids with aliphatic, aromatic, and functionalized side chains, using the standard or an optimized Arndt-Eistert reaction sequence. Fmoc-β²-Amino acids (β² side chain at C(2), NH₂ at C(3)(=C(β))) configuration bearing the side chain of Ala, Val, Leu, and Phe were synthesized via the Evans' chiral auxiliary methodology. The target β³-heptapeptides 5-8, a β³- pentadecapeptide 9 and a β²-heptapeptide 10 were synthesized on a manual solid-phase synthesis apparatus using conventional solid-phase peptide synthesis procedures (Scheme 3). In the case of β³-peptides, two methods were used to anchor the first β-amino acid: esterification of the ortho-chlorotrityl chloride resin with the first Fmoc-β-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 β²- and β³-peptides 5, 9. and 10 show the typical pattern previously assigned to an (M) 3₁ 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!