Preparation of Activated Esters Using Carbodiimides and Associated Secondary Reactions

7 PREPARATION OF ACTIVATED ESTERS USING CARBODIIMIDES AND ASSOCIATED SECONDARY REACTIONS 

Activated esters of A-alkoxycarbonylamino acids are prepared by two approaches, activation of the acid followed by reaction with the hydroxy compound, and trans-esterification. Most of the products are stable enough to be purified by washing a solution of the ester in an organic solvent with aqueous solutions. A few that are not crystalline are purified by passage through a column of silica. The commonly used method for their preparation is addition of dicyclohexylcarbodiimide to a cold mixture of the reactants in dimethylformamide or ethyl acetate. The first Boc-amino acid nitrophenyl esters were obtained using pyridine as solvent. Pyridine generates the nitrophenoxide ion that is more reactive. For one type of ester, 2-hydroxypyridino 

FIGURE 7.10 Formation of the succinimido ester of IV-succinimidoxycarbonyl-P-alanine by reaction of three molecules of IV-hydroxysuccinimide (HONSu) with one molecule of dicy-clohexylcarbodiimide.25 The first molecule (N1) reacts to form the O-succinimido-isourea. The second molecule (N2) ruptures the ring by attack at the carbonyl, generating a nitrene that rearranges to the esterified carboxyalkyl isocyanate. The third molecule (N3) attacks the carbonyl of the latter. R3 = R4 = cyclohexyl SuN- = succinimido. 

FIGURE 7.11 Formation of 4-oxo-3,4-dihydrobenzotriazine-3-yl 2 -azidobenzoate by reaction of one molecule of dicyclohexylcarbodiimide with two molecules of 3-hydroxyM-oxo-3,4-dihydrobenzotriazine (HOObt).26 The intermediate is the equivalent of the O-acylisourea. R3 = R4 = cyclohexyl. 

M Bodanszky, V duVigneaud. A method of synthesis of long peptide chains using a synthesis of oxytocin as an example. J Am Chem Soc 81, 5688, 1959. 

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