POLYPEPTIDES 41 



By applying this method of preparing the acid chlorides to the 

 amino acids themselves, Fischer ultimately succeeded in obtaining the 

 amino acid chlorides, so that he was enabled to combine together any 

 two amino acids in any order, without the necessity of preparing the 

 corresponding halogen derivative. Polypeptides containing the natural 

 optically active amino acids can thus be synthesised with ease, since 

 the natural compound obtained by hydrolysis can be again used di- 

 rectly in the synthesis, and very often it is easier to prepare the natural 

 compound than the synthetical one, which also requires, separation into 

 its stereoisomers. 



This method cannot be used directly for the introduction of 

 tyrosine and other oxyamino acids on account of the reactivity of 

 the hydro xyl group with phosphorus pentachloride. If, however, the 

 hydroxyl group be protected by combination with the carbomethoxyl 

 group, the acid chloride can be prepared and used for synthesis. The 

 carbomethoxyl group is subsequently readily removed by saponification. 

 In this way Fischer, in 1908, prepared glycyl-tyrosyl-glycyl-alanine : 

 chloracetyl-1-tyrosine was shaken in alkaline solution with methyl 

 chlorocarbonate, when chloracetyl-carbomethoxy-1-tyrosine, 

 Cl . CH, . CO NH . CH . COOH 



CH, . C 6 H 4 . O . COOCHj 

 was obtained. 



Treatment of this compound with acetyl chloride and phosphorus 

 pentachloride gave the corresponding acid chloride, which on com- 

 bination with glycine ester yielded chloracetyl-carbomethoxy-tyrosyl- 

 glycine ester, 



Cl . CH, . CO NH . CH . CO NH . CH, . COOC,H 5 



CH, . C,H 4 . O . COOCH, 



Complete saponification occurred on shaking the ester with dilute 

 alkali ; the carbomethoxy group was eliminated as methyl alcohol and 

 carbon dioxide and chloracetyl-tyrosyl-glycine, 



Cl . CH, . CO NH . CH . CO NH . CH, . COOH 

 CH, . C 8 H 4 . OH 



was formed. 



Glycyl-tyrosyl-glycine resulted on treatment with ammonia. 



The tetrapeptide, glycyl-tyrosyl-glycyl-alanine, was prepared in 

 the same way by employing glycyl-d-alanine ester instead of glycine 

 ester. Racemisation unfortunately occurred in the process : the chlor- 

 acetyl-carbomethoxy-tyrosyl-glycine was optically inactive and also 



