Atropisomerism, biphenyls and the Suzuki coupling: peptide antibioticsAbbreviations: Bn = benzyl; Boc = tert-butoxycarbonyl; dba = dibenzylideneacetone; Ddm = 4,4′-dimethoxydiphenylmethyl; DMSO = dimethylsulfoxide; FDPP = pentafluorophenyl diphenylphosphinate; MEM = methoxyethoxymethyl; Ms = methylsulfonyl; Piv = pivaloyl; TBS = tert-butyldimethylsilyl; Tf = trifluoromethanesulfonyl; Tfa = trifluoroacetyl; TFA = trifluoroacetic acid; Z = benzoxycarbonyl.

Abstract

The formidable synthetic challenge posed by the vancomycin class of glycopeptide antibiotics has only recently been met. Foremost among the difficulties associated with the synthesis of these molecules is the control of non-conventional stereochemical issues. These are a consequence of the molecules possessing biphenyl and biaryl ether linkages between amino acid residues situated within the constituent macrocycles. Among the keys to success is the availability of methods that allow the efficient formation of biaryl linkages between amino acid derivatives under mild conditions. Recent progress in the chemistry of the Suzuki coupling suggests that this constitutes a very powerful and general method for the synthesis of peptide biphenyls.