Amino Acid Bromides: A Convenient Choice for Very Difficult Couplings

During the synthesis of pseudopeptides, many difficulties can be encountered for introduction of very hindered pseudoamino acids into a peptide chain. In the case of α-trifluoromethyl or difluoromethyl amino acids (α-Tfm or Dfm-AA), all methods known in modern peptide chemistry fail to afford peptides in significant yields. In fact, besides the steric hindrance, the polarizing effect of fluorine renders the amino function totally unreactive. We and others have obtained some peptides containing the least bulky α-Tfm-alanine, although the yields were low [1], Moreover, it was possible to prepare peptides bearing an α-Tfm-amino acid at the N-terminal position [2], but the problem of chain elongation by derivatization of the amino group was not yet resolved until recently. We have successfully synthesized peptides containing different extremely hindered amino acids via amino acid bromides, prepared from N-protected amino acids and l-bromo-N, N-2-trimethyl-l-propenylamine, a reagent proposed in the literature for the synthesis of some simple acylbromides. The resulting bromides were used in situ for the coupling reactions, affording a number of di- or tripeptides containing fluoroalkyl residues, in very high yields and without racemiz-ation [3]. We then extended the series of N-protected amino acid bromides, with the purpose to verify the general applicability of our method.