N‐Acylamino Acids and Peptides. VII. Synthesis of Oxygen‐Sensitive N‐Acylglycines (N‐Caffeoylglycine, N‐Protocatechuoylglycine and N‐Galloylglycine) and a N‐Acyldipeptide (N‐Caffeoylglycyl‐L‐Phenylalanine)

Abstract

The synthesis of N-caffeoylglycine (6) , N-protocatechuoylglycine (16) , N-galloylglycine (El and N-caffeoylglycyl-L-phenylalanine (1) by means of the active ester method is described. IntrodbctionAs a result of studies of the natural occurrence in the plant world of N-acylamino acids and peptides of the benzoyl and cinnamoyl type, the synthesis of a variety of such compounds (reference substances) has become an interest of this laboratory. In the past different methods have been used for the synthesis of the pseudopeptide bond between the carboxylic function of a phenolic acid and an amino function of an amino acid or peptide. In this connection reference can be made to the acid-chloride method" '''5) , the dicyclohexylcarbodiimide (DCCD) method"), the mixed anhydride meth~d("~'~) and the active ester method(6).While the first three methods must be considered as being rather tedious, the active ester method, using N-hydroxysuccinimide as a reagent, is far more elegant. Indeed, the reaction with N-hydroxysuccinimide which was introduced by Anderson et alJ7) , can easily be effected.In addition, it is frequently possible to omit several of the usual protection and deprotection reactions while at the same time the yields are usually high(6). However, in the case of the oxygen sensitive N-caffeoylglycine (6) the above mentioned active ester method gave rise to poor yields ( 2 0 % over two steps) ( 6 ) . Even more difficulties were encountered when the Nhydroxysuccinimide method was employed for the preparation of N-caffeoylglycyl-L-phenylalanine (1).Moreover, the latter compound, which could not be crystallized was also not sufficiently pure.The employment of the other active esters such as p.nitrophenylesters and 2,4-dinitrophenylesters did not overcome the above difficulties(*).A possible reason for the poor results could be formation of undesired side products, which easily arise by oxidation of the oxygen-sensitive ortho-phenolic groups from the caffeoyl moieties. Similar or even greater difficulties were encountered with protocatechuic (8, and gallic acid ( 9 , . For this reason, the phenolic groups in caffeic, protocatechuic or gallic acid were first protected with ethylchloroformate to form 0-(ethoxycarbonyl) phenolic acids and the title compounds could then be prepared in higher yields by the active ester method using N-hydroxysuccinimide. SynthesisThe synthesis of the N-acylglycines and the N-acyldipeptide under discussion is shown in scheme 1.The phenolic acids, caffeic acid (I), protocatechuic acid (8) and gallic acid (9, were allowed to react with ethylchloroformate and sodium hydroxide to yield the corresponding -1029 -

New Multifunctional Surfactants from Natural Phenolic Acids

“…Several amides synthesized by coupling hydroxycinnamic acids with amino acids have been described, such as N -feruloyl-glycine, − N -caffeoyl-glycine, ,, and N -feruloyl-glutamate, but none shows surfactant activity. The aim of the present study was to synthesize new multifunctional molecules of natural origin to be used in cosmetics.…”