108 SCIENCE PROGRESS 
temperature produced the same result in fifteen to twenty 
minutes. The diketopiperazines of alanine, leucine, pheny]l- 
alanine, tyrosine are thus easily prepared, as also the corre- 
sponding dipeptide. As yet the dipeptides of the diamino 
acids, lysyllysine and histidylhistidine and serylserine, have 
only been obtained by this method by Fischer and Suzuki; 
in these cases the methyl ester of the amino acid was more 
easily converted into the diketopiperazine. The method does not 
lend itself to the preparation of mixed diketopiperazines. These 
are obtained by the action of ammonia on the a-halogenacyl 
derivative of the amino acid ester, e.g. glycylalanine anhydride, 
Cl. CH,. CO. NH. CH(CH,). COOC;H; + 2NH, = NH,Cl + C,H;OH + 
CH,. CO 
NHS >NH 
CO. CH CEH. 
The simple method of combining the acid chloride of an 
amino acid with another amino acid for the synthesis of 
polypeptides could not be employed, as these derivatives 
were unknown and impossible to prepare. The carbethoxy 
derivative, however, of the amino acid, or polypeptide, when 
warmed with thionylchloride, was found to give the acid 
chloride, and this compound reacted with the esters of amino 
acids or polypeptides to form the carbethoxy derivates of 
polypeptides, thus carbethoxyglycylglycine on treatment with 
thionylchloride yielded the acid chloride which reacted with 
glycylglycinester to form the carbethoxy derivative of tri- 
glycylglycinester. The conversion of this compound into the 
true tetrapeptide, owing to the firm union of the COOH group, 
was not possible, and a third method, which reminds us of 
the preparation of the amino acids, was attempted, and proved 
most fruitful. 
This method consists in introducing an a-halogenacyl residue 
into the molecule of an-amino acid or polypeptide, and then 
treating this compound with ammonia, whereby the Cl is 
exchanged for NH,; thus chloracetyl tyrosine, obtained from 
chloracetyl chloride and tyrosine, on treatment with ammonia 
gives glycyltyrosine, 
CH,Cl. COC] + HOOC. CH(NH,).CH,. C,H,OH = HCl] + 
HOOC. CH(NH. CO. CH,Cl). CH,.C,H,OH 
. HOOC. CH(NH.CO.CH,Cl). CH,.C,H,OH + NH; = HCl + 
HOOC.CH(NH.CO.CH,. NH,). CH,.C,H,OH 
