Preparation of <i>N</i>‐Fmoc‐Protected β²‐ and β3‐Amino Acids and their use as building blocks for the solid‐phase synthesis of β‐peptides

Abstract

Abstract N ‐Fmoc‐Protected (Fmoc = (9 H ‐fluoren‐9‐ylmethoxy)carbonyl) β‐amino acids are required for an efficient synthesis of β‐oligopeptides on solid support. Enantiomerically pure Fmoc‐β 3 ‐amino acids β 3 : side chain and NH 2 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‐β 2 ‐ Amino acids (β 2 side chain at C(2), NH 2 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 β 3 ‐heptapeptides 5–8 , a β 3 ‐ pentadecapeptide 9 and a β 2 ‐heptapeptide 10 were synthesized on a manual solid‐phase synthesis apparatus using conventional solid‐phase peptide synthesis procedures ( Scheme 3 ). In the case of β 3 ‐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 β 2 ‐ and β 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!