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A Reinvestigation of the Mixed Carbonic Anhydride Method of Peptide Synthesis


The modern era of custom peptide synthesis began in 1932 with the introduction by B ergmann and Z ervas of the carbobenzoxy derivative for the protection of the &-amino group of amino acids and peptides [91]. Before that time some peptides had been synthesized by methods that were laborious and very limited in their application.

The introduction of the carbobenzoxy group provided protection for the amino function that could be removed under very mild conditions (catalytic hydro- genolysis), conditions which left the peptide bond unaffected. Today we have numerous other very useful protecting agents, and new and widely applicable coupling methods have been developed, but peptide synthesis is essentially the same procedure it was in 1932. The carbobenzoxy group is still one of the most widely used groups for protection of the amino function.

The factors which affect yield and racemization in custom peptide synthesis by the mixed carbonic anhydride method have been investigated. Good results in test cases were obtained when the tertiary amine necessary for formation of the mixed anhydride contained at least one N-methyl group, and it was not used in excess, indicating the importance of steric factors. Reduction of "basicity" of the amine was found to be favorable; complete racemization was found with an excess of trimethylamine as the tertiary base, and none with an excess of N-methyl-morpholine in the test Z-Gly-Phe-Gly-OEt synthesis in ethyl acetate or tetrahydrofuran. The more sensitive Bz-Leu-Gly-OEt synthesis gave no racemate with 1 equiv of N-methylmorpholine but some racemate with 2 equiv. The effects on racemization of change of solvent, temperature, time allowed for mixed anhydride formation, and several anions are reported. Evidence for racemization via oxazolones is given. Best yields were obtained with isobutyl chloroformate as the reagent. The principles disclosed here should be useful in improving other acylations.
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