The Benzyl and p-Nitrobenzyl Esters of L-Glutamine and L-Asparagine¹

Abstract

The p-nitrobenzyl esters and benzyl esters of L-glutamine and L-asparagine have been prepared. The use of the benzyl esters in the synthesis of carboxyl-terminal glutamine and asparagine peptides is illustrated.Normally, treatment of A-acylamino acid esters with alkali yields the alcohol and a salt of the acyl amino acid. However, the alkaline hydrolysis of A-acylasparagine and Ar-acylglutamine methyl esters under the conditions normally used in peptide synthesis is complicated by imide formation, isomerization due to hydrolysis of the imides, and in the case of the glutamine derivatives by partial racemization.2 Therefore, the synthesis of peptides with carboxyl-terminal glutamine or asparagine groups requires methods in which these side reactions are avoided. One way of accomplishing this is to use methods that do not require a protected amino acid. Thus, Hoffman, Thompson, and E. T. Schwartz3 prepared L-methionyl-L-glutamine by coupling carbobenzoxy-L-methionine and glutamine by the mixed anhydride method. Presumably this technique would also be suitable for the preparation of carboxyl-terminal asparagine peptides. This approach is limited to those coupling procedures which permit the use of unprotected amino acids and peptides with the component that has the activated carboxyl group. The availability of glutamine and asparagine derivatives with carboxyl-masking groups that can be removed innocuously, would greatly increase the number of applicable coupling procedures. Recently, Anderson and Callahan4 prepared a number of ¿-butyl esters of amino acids, including that of L-glutamine.The chief advantages of these esters lie in the ease of decsterification by mild acid catalysts, and in their stability as the free bases. In this paper we wish to report the preparation of the benzyl and p-nitrobenzyl esters of glutamine and asparagine. The use of the benzyl esters in peptide syntheses is also demonstrated. Schwarz and Arakawa5 have described a procedure for the synthesis of amino acid p-nitrobenzyl esters in which a carbobenzoxy amino acid(1) This investigation was supported in part by a research grant RG-5492 from the

Exploration of Routes Leading to Derivatives of α‐Hydroxyalanine and its Precursors

“…f a s t evolution of nitrogen, the appearance in the IR of the isocyanate peak at 4.41.~ and its subsequent disappearance, concurrently with the appearance of a new peak at 6.71.1 indicating the formation of the benzyloxycarbonyl group. In VI all functional groups are selectively protected [6,9,23,32]. Shemyakin found [29] that the e s t e r function of N-acetyl and N-benzoyl derivatives of 0-alkyl cy -hydroxy-a-amino acids could be saponified by aqueous alkali at temperatures up to 50°C without attacking the N-acyl and the 0-alkyl bonds.…”