SYNTHESIS OF PROTEINS 11 



impossible. Moreover the anhydride-ring is in many cases (e.g., 

 leucin anhydride) very difficult to break up when it has once 

 been formed. 



In the search for methods of overcoming these difficulties, 

 Fischer found that the instability of the amino-acids could be 

 eliminated by the introduction of radicals into the NH 2 group, 

 and he and Fourneau synthesized phenyl-cyanate-glycyl-glycin 

 and carboxyethyl-glycyl-glycin ester (C 2 H 5 O.OC.NH.CH 2 .CO.- 

 NH.CH 2 .CO.OC 2 H 5 ) which are both chemically stable* bodies. 

 In subsequent investigations Fischer found that by gentle heat- 

 ing, combination between the esters of the carboxyethyl amino- 

 acids and other ammo-acid esters could be directly brought about 

 (25); in this way carboxyethyl-diglycyl-leucin ester was formed 

 (C 2 H 5 O.OC.NH.CH 2 CO.NH.CH 2 .CO.NH.CH.C4H 9 .CO.OC 2 H5). 



The difficulty was here encountered, however, that the car- 

 boxyethyl group, once introduced, cannot be eliminated again. 



The method which Fischer devised to overcome this difficulty 

 (25) was extremely ingenious. The introduction of a radical into 

 the NH 2 group appeared to be a necessity, forced upon us by 

 the impossibility of otherwise securing simple anhydrides of the 

 acids. It occurred to Fischer, however, that the radical thus 

 introduced into the NH 2 group might itself be made a carrier of 

 amino-acid groups into the molecule. This anticipation proved 

 to be correct. The radical which Fischer first utilized was the 

 chloracetyl group (C1CH 2 .CO ); when chloracetyl is allowed to 

 act upon glycyl-glycin ester (obtained by the methods described 

 above) chloracetyl-glycyl-glycin ester is obtained : 



C1.CH 2 .COC1 + NH 2 .CH 2 .CO.NH.CH 2 .COOC 2 H 5 



(Chloracetyl chloride) (Glycyl-glycin ester) 



= C1CH 2 CO.NH.CH 2 .CO.NH.CH 2 .COOC 2 H 5 + HC1. 



(Chloracetyl glycyl-glycin ester) 



By saponification of this ester, free chloracetyl-glycyl-glycin is 

 obtained; on now treating this with a concentrated aqueous 

 solution of ammonia, the Cl atom in the chloracetyl group be- 

 comes replaced by an NH 2 group and diglycyl-glycin is obtained : 



C1CH 2 .CO.NH.CH 2 .CO.NH.CH 2 .COOC 2 H 5 + 2NH 3 



(Chloracetyl-glycyl-glycin ester) 



= NH 2 .CH 2 .CO.NH.CH 2 CO.NH.CH2.COOC 2 H5 + NH 4 C1. 



(Diglycyl-glycin ester) 



