Synthesis of Tri‐, Penta‐, and Heptapeptides Containing and (R)‐2‐alkyl‐2‐amino‐3‐(methylamino)‐propionic acid residue in the central position

Abstract

AbstractBy conventional peptide‐coupling methods (C to N direction; mixed anhydride, bis(2)‐oxooxazolidin‐3‐yl)phosphinoyl chloride (Bop‐Cl), or dicyclohexylcarbodiimide (DCC), 2‐amino‐2‐methyl‐3‐(methylamino)‐propionic acid and 2‐amino‐2‐ethyl‐3‐(methylamino)propionic acid ( = 2‐amino‐2‐[(methylamino)methyl]butanoic acid) are incorporated in the central position of tri‐, penta‐, and heptapeptides (see 3–7, 21, and 22). The fragment coupling of the β ‐amino group of the diamino‐acid moiety in a tetrapeptide led to partial epimerization, and thus, two epimeric heptapeptide derivatives were actually obtained (7 and epi‐7). The final deprotection to the free heptapeptide (involving a Me3SiI cleavage of BocNH and MeOCONH, a saponification with NaOH, and HPLC purification) gave both the desired product (isopeptide 21), with the β ‐amino group inside the peptide backbone, and a product (peptide 22) of transpeptidation, with the α‐amino group of the diamino acid incorporated and a (methylamino)methyl group as the side chain. Peptide 22 is completely converted to the isopeptide 21 by prolonged treatment with base. The heptapeptide 21 was analyzed by elaborate 2QF‐COSY and NOESY NMR measurements in H2O/CD3OD at −5° (Table, Fig.); there is no indication for β ‐sheet or helical structures, a fact which was also confirmed by CD measurements.