Secondary Reactions of Mixed Anhydrides Urethane Formation

4 SECONDARY REACTIONS OF MIXED ANHYDRIDES URETHANE FORMATION 

There have been reports that urethane was produced when the mixed-anhydride method was employed for the coupling of segments. However, studies on urethane formation during the aminolysis of mixed anhydrides of peptides have never been carried out. The anhydrides are too unstable to be isolated. The activated moiety of the peptide cyclizes too quickly to the 2,4-dialkyl-5(4//)-oxazolonc (see Section 2.23), and since the time allowed to generate the anhydride in segment couplings is always limited to avoid epimerization, one cannot exclude the possibility that the urethane that was produced originated by aminolysis of unconsumed chloroformate. 

FIGURE 7.5 Preparation of a protected dipeptide by the mixed-anhydride method, employing a chloroformate that generates a cleavable urethane.13 The urethane impurity is destroyed by a P-elimination reaction. NMM = A-methylmorpholine, Msc = methane-sulfonylethoxycarbonyl. 

In fact, recent work indicates that less urethane is formed by aminolysis of an activated peptide than by aminolysis of an activated /V-al ko x y carbon y I am ino acid. Such results are consistent with the postulate that the intermediate undergoing aminolysis during the mixed anhydride reaction of a segment is the 2,4-dialkyl-5(4//)-oxazolonc, a tenet that is indicated by the high rate at which the activated peptide is converted to the oxazolone.10 13 

M Bodanszky, JC Tolle. Side reactions in peptide synthesis. V. A reexamination of the mixed anhydride method. Ini Pept Prot Res 10, 380, 1977. 

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