Solid phase synthesis of the protected 43–55 tridecapeptide of the heavy chain of myeloma immunoglobin M603, employing cyclohexyl ester protection for glutamic acid

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Abstract
A protected tridecapeptide of the sequence Boc‐Lys(2ClZ)‐Arg(Tos)‐Leu‐Glu(OcHex)‐Trp(For)‐Ile‐Ala‐Ala‐Ser(Bzl)‐Arg(Tos)‐Asn‐Lys(2ClZ)‐Gly‐OH, representing residues 43–55 of the variable region of the heavy chain of mouse myeloma protein M603, was synthesized. It was assembled by a stepwise solid phase method designed to give a fully protected peptide in high yield and purity with minimal side reactions. Thus, the peptide chain was attached as an α‐methyl phenacyl ester to a 2‐bromopropionyl‐resin. After the synthesis the protected peptide fragment was obtained in 89% yield by photolytic cleavage from the resin. The peptide was purified by multiple precipitation and column chromatography. It was shown to be homogeneous by reverse phase high pressure liquid chromatography, and it had the correct amino acid composition and sequence. In the course of this work it was shown that tert.‐butyloxycarbonyl‐amino acids caused the formation of significant amounts of pyrrolidone carboxylic acid residues during the coupling reaction when a γ‐benzyl glutamyl residue was NH2‐terminal. Other weak‐acid additives also caused this chain terminating side reaction. The cyclization was markedly suppressed by protection of the glutamyl side chain as a cyclohexyl ester. With this protecting group, no evidence of pyrrolidone carboxylic acid formation could be detected in the tridecapeptide 43–55.