Carboxamide protection in peptide synthesis

Abstract

In the first part the use of 4-methoxy-2- -methylbenzyl and 4-methoxy-l-naphthalenemethyl as protecting groups for the amide side chain of glutamine and asparagine during peptide synthesis is demonstrated. The second part involves the hydration of some cyano containing model compounds (cyano group is an undesired functional group formed ty the dehydration of the unprotected carboxamide group when N,N"':'dicyclohexylcarbodiimide is used as the coupling reagent in the course of peptide synthesis) under mild conditions to the corresponding carboxamide containing products. 4-Methoxy-2-met-bylbenzonitrile and 4-methoxy-lnaphthonitrile were reduced to 4-methoxy-2-methylbenzylamine and 4-methoxy-l-naphthalenemethylamine respectively using lithium aluminium hydride in ether. These groups were then used to prepare the carboxamide CA protected derivatives viz. Carbobenzoxy-N -4-methoxy- CA -2-methylbenzylleucinamide; carbobenzoxyleucyl-N -4- -methoxy-2-methylbenzylglycinamide; tert-butyloxycarbonylphenylalanyl- a-benzyl-N CA-4-methoxy-2-methylbenzylasparaginate; tert-butyloxycarbonylglycyl- -phenylalanyl-a-benzyl-NCA-4-methOxy-2-methylbenzyl- -asparaginate; carbobenzoxy-NCA-4-methoxy-l-naphthal- -enemethylleucinamide; carbobenzoxy-NCA-4-methoxy-l- naphthalenemethylglycinamide; tert-butyloxycarbonylphenylalanyl- a-benzyl-N CA -4-methoxy-I-naphthalenemethylasparaginate; and tert-butyloxycarbonylglycyl- phenylalanyl-a-benzyl-N CA -4-methoxy-I-naphthalenemethylasparaginate. Cleavage of all protecting groups (i.e. Carboxamide, Carboxyl, and Amino) is carried out using boron trifluoride with acetic acid complex (B7FA) to obtain the fully deprotected products i.e. leucinamide; leucylglycinamide; phenylalanylasparagine and glycylphenylalanylasparagine. In the second part, model studies on the hydration of nitrile to the amide using (i) hydrogen peroxide in a base (Radziszenwskis reaction) and (ii) 33% hydrogen bromide in glacial acetic acid were carried out. The nitrile model compounds used for the study include, benzonitrile; 4-methoxy-l- -naphthonitrile; carbobenzoxy-S-cyanoalanine; carbobenzoxy-y-cyano-a-aminobutyric acid; carbobenzoxy- S-cyanoalanylglycine methyl ester and carbobenzoxy-y-cyano-a-aminobutylglycine methyl ester. Carbobenzoxyasparagine and carbobenzoxyglutamine were dehydrated to their corresponding cyano derivatives using N,N~-dicyclohexylcarbodiimide in pyridine at a-~emperature of 16oC. The synthesis of the cyano dipeptides was carried out using N-hydroxysuccinimide coupling procedure.