Preparation of N-Fmoc-Protected β2- and β3-Amino Acids and their use as building blocks for the solid-phase synthesis of β-peptides†‡

摘要: 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 β3: side chain and NH2 at C(3)(= C(β)) were prepared from Fmoc-protected (S)- (R)-α-amino with aliphatic, aromatic, functionalized chains, using the standard or optimized Arndt-Eistert reaction sequence. Fmoc-β2- Amino (β2 C(2), C(β))) configuration bearing Ala, Val, Leu, Phe synthesized via Evans' chiral auxiliary methodology. The target β3-heptapeptides 5–8, a β3- pentadecapeptide 9 β2-heptapeptide 10 manual solid-phase apparatus conventional peptide procedures (Scheme 3). In case β3-peptides, two methods used to anchor first acid: esterification ortho-chlorotrityl chloride resin Fmoc-β-amino acid 2 (Method I, Scheme 2) acylation 4-(benzyloxy)benzyl alcohol (Wang resin) ketene intermediates Wolff rearrangement amino-acid-derived diazo ketone 1 II, 2). former technique provided better results, as exemplified by heptapeptides 5 6 (Table intermediate ketones was also sequential peptide-bond formation support (synthesis tetrapeptides 11 12). CD spectra β2- β3-peptides 5, 9, show typical pattern previously assigned (M) 31 helical secondary structure (Fig.). most intense absorption observed (strong broad negative Cotton effect ca. 213 nm); compared analogous heptapeptide this corresponds 2.5 fold increase in molar ellipticity per residue!