Peptide formation in the presence of a metal ion protecting group. 4. Synthesis of penta- and hexapeptide sequences with the pentaamminecobalt(III) complex

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Kinetically inert metal ion protecting groups provide radically different approaches to the protection of the terminals and side chains of amino acids and peptides. Pentaamminecobalt(III) is a useful C-terminal protecting group for sequential peptide synthesis. This is demonstrated by the synthesis of a number of amino acid complexes of the type NH 3x yc CH x O-Co(NH 3 )5 (cofAA),) where R = hydrophilic, hydrophobic, aliphatic, and aromatic amino acid side chains. The reaction of these complexes with Boc-amino acid active esters or Boc symmetric anhydrides results in the formation of (Co(AA) 1(AA)2 BoC). The Boc group is removed with 95% trifluoroacetic acid to form (Co(AA)1(AA)2), which is further used for sequential peptide synthesis. Alternatively, the ((NH3)5Com-) group is selectively removed by rapid reduction with NaBH4 or NaHS to form the N-protected peptide fragment, ((AA)1(AA)2BoC), under extremely mild conditions. Tests for racemization of the amino acid directly bound to cobalt showed no detectable loss of chirality of ((AA) 1). The detailed synthesis, monitoring, purification, and analysis of cobalt pentaammine derivatives of Leu-enkephalin (TyrGlyGlyPheL eu), Met-enkephalin (TyrGlyGlyPheMet), and the hexapeptide sequence HisGlyHisGlyHisGly are described and so is a general procedure for peptide synthesis with the cobalt(III) protecting group. The individual fragments of these peptide sequences are characterized by HPLC. The attractive features of the ((NH3)5Conl-) protecting group include its color, tripositive charge, ease of introduction, and removal. Such properties are invaluable in the purification of synthetic peptides.