ON THE BOND BETWEEN DIKETOPIPERAZINES AND AMINO ACIDS

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• Collection: General CIA Records
• Document Number (FOIA) /ESDN (CREST): CIA-RDP80-00809A000600370826-4
• Release Decision: RIPPUB
• Original Classification: C
• Document Page Count: 6
• Document Creation Date: December 22, 2016
• Document Release Date: September 27, 2011
• Sequence Number: 826
• Publication Date: February 9, 1951
• Content Type: REPORT

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INFORMATION FROM
FOREIGN DOCUMENTS OR RADIO BR0ADCP.STS CD NO,
CLASSIFICATION COV?DENTIAL C", av 10
CENTRAL INTELLIGENCE AGENCY REPORT
COUNTRY USSR
SUBJECT Scientific - Chemistry, Amino Acids
DATE
PUBLISHED 11 Sep 1950
DATE OF
INFORMATION
DATE DIST. 9 Feb 1951
THE ,I STOOL ON`T 0OIITA
1O
STATSSS W THIIN ATNS MRANIN0 S01 ISSI0NA0lDEFENSE
Y. S. C.. SI AND )1, AS AYIN0[0., ITS TRANSMISSION OR TNS NSVACTSLATION
R PI MAN
SROHISIITIO? IS PRO'
UNAUTH N"INIT&OI ITS ST TLAW. IN RSSROOV MR TO Of THIS FORM OSIZKO
NO. OF PAGES
SUPPLEMENT TO
REPORT NO.
THIS IS UNEVALUATED INFORMATION
SOURCE Dokl&dy..Akademli .Nauk 'SSSR, Vol 74, No 2, 1950, pp 251254.
ON THE BOND BETWEEN DIKETOPIPEItAZIN1S AND AMINO ACIDS
L. N. Akimova and N. I. Gavrilov
Submitted 23 May 1950
Presented by Academician
N. D. Zelinskiy, 18 July, 1950
After the natural origin of cyclic forms of bendingas proved by N. D.
,elinski , V. S. Sadikov ?1>, N. I. Gavrilov C2-7, and the school [3 7, the question arose in regard to the-structure of more complicated
;ompounds, particularly derivatives of diketopiperazine and peptides or amino
acids, the'more so since a series of compounds consisting of 3-5 amino acids
and possessing a cyclic anhydride CamideJ structure were isolated by N. D.
Zelinskiy and V. S. Sadikov Zr14J as well as Abderbalden and his co-workers
[5]. The first steps in this direction were taken by Maillard Z"6,].
Abderhalden and Schwab C7_7 conducted systematic investigations Bon the
synthesis of N-ami.noacyl derivatives of diketopiperazines C8-13]
not one case did the obtain individual, well defined compounds. The works
of M. Berman rmj, N. I. Gavrilov and Kh. N. Lerman [11], ?
Akimova t 15_7-showed the fundamental impossibility of the course chosen by
Abderhalden for the synthesis of N-aminoacyldiketopiperazines. Thus to this
time no one has succeeded in obtaining N-aminoacyl derivatives of diketopipe-
razines.
The synthesis of acylamine compounds from enols of diketopiperazines also
led Karrer (16j to no positive results.
0
I! N~C-OH H2el --C-OA[; 2C18LH2! TIC C6H5
1:02~ ~tI bH2 N /b 2
STATE
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The greatest interest was elicited by Abderhalden's work with chloracyl
derivatives of diketopiperizines. In our preceding article (20] were shown
the specific reactive properties of N-acyl compounds which led us to methods
of obtaining: 1) exo-acyl amino acid (piperazine) amidines, 2) their esters,
3) hydrates of these esters, and 4) free amidines.
Moreover, we worked out a method for obtaining piperazines and dihydro-
pyrazines which are connected through an amidine bond with amino acids and
peptides; in this way the possibility of a fourth form of bond between diketopipe-
razines and ami.r;oacyls has been demonstrated
,,CHrf-N~~
...HNO00H2H - CA N-CH2 ~C NCH2CONH.... H
In spite of Abderhalden's and our failure to obtain aminoacyl derivatives,
we still consider it exceptionally important to synthesize these compounds,
which may be found in the structure of a micromolecule of protein. This form
of binding has also been accomplished by us.
Proceeding from the ease of acylating diketopiperazines with acid chlorides,
we obtained chlorides of glycine, protecting the amino group with phthalyl,
toluene sulfonyl and benzylsulfonyl groups.
We combined N, NI-diphathalylglycinediketopiperazine with the ester of
glycine by our methods for the synthesis of exo-acylamidinesand obtained
two phthalylglycylglyciripeptides joined by means ofvdihydropiperazine bridge.
The proof of the structure of this compound is its hydrolysis to phthalylglycine
iA solution-
.
ac
I. 1.4-diphthalylglycine-2.5-di '.ketopiperazine. l.9 g of phthalylglycinch-
loride (17 7, carefully ground together with 0.48 g of diketopiperazingeun er
were heated in 2.5 ml of xylene for 20 minutes in a water bath oilin ),
and then for 5 hours in Wood's alloy at 142?. The precipitate was washed with
benzene and treated with boiling water to remove diketopiperazine. The residue,
insoluble in water, was washed with alcohol and ether. The melding point was
385? under decomposition. The yield was 83%. The product was partially sol-
uble in boiling xylene and methyl acetate, as well as acetone. The picrin and
ninhydrin reactions were negative. It was recrystallized from nitrobenzene.
CONFIDENTIAL
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CONFIDENT 1d.
II. 1.4-ditoluenesulfonylglycine-2.5-diketoEliLierazine. 3.7 g of tolub.sulfo+NC
glycinchloride [18], dissolved in 50 ml of nitrobenzene, were heated with
0.85 g of diketopiperazine at 140? for 2 hours. To the hot filtered solution
was added absolute ether. The precipitate was filtered off and washed with
alcohol and ether. The melting'point was 220?. The product gives a positive
anhydride reaction. From the analysis it appears to be a monoacylated
diketopiperazine.
Found %: C 117.85; H 14.51; N 13.21
c131i5O5N5s. Calculated : c 48.0; H 11.61; N 12.92
III. 1.4-dibenzylsulfonylglycine-2.5-diketopiperazine. 1.3 g of
benzylsulfonylglycinechloride [19], dissolved in 30 ml of nitrobenzene,
were heated with 0.3 g of diketopiperazine at VIC? for 30 minutes. The hot
solution, filtered through a glass filter, was precipitated witH absolute
etther. The precipitate, which settled on standing, was filtered out and
washed with alcohol. Then it was recrystallized from nitrobenzene. The boil-
ing point was 226?, accompanied by decomposition. The anhydride reaction was-
positive, and the ninhydrin reaction negative.
Found %: C 49.18; H 4.51; N 10.58
Calculated %: C 49.25; H 4.47; N 10.45
IV. Di-exo-N-phthalylglyc?.lglycineethyl ester hydrate-215-dihydro-
pyrazineamidine. To 5 g of diphthalylglycine-2.5-diketopiperazine in 25 ml
of absolutet?ether are added 2.1 g (2 moles) of ethyl ester of glycine. The
ablution was agitated on a rocking device for a week. A stream of dry H01
was passed into the filtrate separated from precipitate 1. The precipitate
forming here represented a hydrochloride of the glycine ester. Precipitate
1 was treated with chloroform at a low temperature. The precipitate which
formed when the chloroform filtrate was concentrated wns treated with methyl
acetate. A small portion was dissolved and when concentrated gave a pre-
cipitate with a melting point of 183?. The greater portion was not dissolved
and represented a substance with a melting point of 145? and with a crystal
form resembling leaves. On analysis the substance with a melting point of
145? appeared to be an amidine. Ninhydrin and picrin reactions were negative.
Found %: C 55.10; H 4.95; N 11.84
Calculated A: C 55.33; H 4.89; N 12.11
C32H~1012N6? Found (Solution) : M - 678.7
Calculated : 14 - 694
For evidence as to the regrouping of the phthalylglyeine group from the
exo-position of nitrogen in the pi.perazine ring to the exo-position of nitrogen
in the side chain amino acid, this compound was hydrolyzed with 1% HC1 with
and without ferment. After standing for 2.days in a constant-temperature chamber
a precipitate which seemed to be phthalylglycylglycine formed in?both solutions.
For analysis this substance was recrystallized from water. The melting point
of 229.5?, the crystal form (needles) under the-microscope, and the complete
absence of an anhydride reaction and a biuret?~,~`` reaction carried out with both
CuC12 and Co(NO33)2, demonstrate that the substance we isolated is actually
phthalylglycylgiycine. The synthetic phthalylglycylglycine melts at 230? and
gives no depression with the substance obtained above.
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rJ: /
.t !
-N
Scheme of the Decomposition of Amidine in 1% HCl
H ~'. Uri }I
L I /
G, t "ZFt~.C1!1
1 ' ` h! t , CU , i J - : F i ~ l r- 1
We did not succeed in finding diketopiperazine. Its presence in this
compound was proved by the appearance of the ninhydrin reaction in the filtrate
after neutralization with HCl. The assumption made earlier as to the location
of the phthalylglycine group at the nitrogen of the side chain 'was verified
by this experiment.
1. The synthesis of doubly'N-aminoacylated diketopiperazine was carried -
out by acylation with chlorides of glycine under protection of the lattera'
amine group with!phthalyl, toluene sulfonyl, and benzylsulfonyl residues..
2. The phthalylglycine group at the nitrogen of diketopiperazine possesses
the properties of a mobile acyl group and with glycine, E)ster forms the exo-acyl-
(phthalylglycil)-glycine amidine of dihydropiperazine.
3, By the synthesis of this compound was shown the possibility of the
structure put forward by N. I. Gavrilov for the complex (peptone) micromolecule
of protein.
1:4r E~Nr: CC;~!f~!I`.Or1:.1;,!.2iNN'6fC.NCUNfiCh!`C.Odhf
CGNFIDEP:IV,dL
~! r /. !,.
l i ', ,.' I r' C II,S }cif
hNcrrtnn:N~i cl -I~
The central fragment of this structure has been realized.
I. N-acylamine groups are easily rearranged to the exo-position if the
carbonyl is replaced by en aminoacy) iesidue, and furthermore they can serve
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as*a model (in agreement
`20 7) Of t(ie synthesis
with ?1. Bergmann's reaction, which we have interpreted
of the peptide link.
1. N. D. Zelinskiy and V. S. Sadikov, Biochem. Zs., 136, 241; 137, 397, 401;
138, 156 (1923)-
2. N. I. Gavrilov and N. D. Zelinskiy, Vestn. MGU; No. 7 (1947).
3. E. Abderhalden and H. Mahn, Zs. phys. Chem., 169, 211 (1927)1,E. Abder-
halden and E. Schwab, Ibid, 11,8, 256 (1925); 134, 121 (1924); 139, 147 (1924).
4. N. D. Zelinskiy and V. S. Sadikov, Bioch.?Zs., 179, 326 (1926).
5. E. Abderhalden and E. Schwab, Ber., 40, 3541, (1907).
6. M. L. Maillard, Ann. Chim., (9), 2, 210 (1914).
7. E. Abderhalden and E. Schwab, Zs. f. phys. Chem., 139, 169 (1924)?
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12.
13.
8. E. Abderhalden and E. Schwab, Ibi.d., 3119, 298 (1925).
9. E. kbderhalden and E. Schwab, Ibid, 158, 66 (1926).
10. E. Abderhalden and E. Schwab, Ibid, 164, 271, 274 (1927).
11. N. I. Gavrilov and Kh. N. Lerman, Zh. 0. Kh, 11, 127 (19b1).
E. Abderhaiden and E. Schwab, Zs. f. phys. Chem., 148,
263
(1925).
E. Abderhalden and E. Klarmann, Ibid, 129, 323 (1923);
135,
199 (19210).
M. Bergmann,'Ibid, 62, 315 (1909); M. Bergmann and L. Zervas, Ibid, 175,
1145 (1928); M. Bergmann, F. Stern, and Ch. Witta, Lieb. Ann., 449,277
(1926); M. Bergmann and J. E. Tietzman, Jourrn, biol. Chem., 155, 535 (1944).
15. L N. Akimova, Dissertation cpissertatsiyaj, MGU [Moscow State Univer-
sity,, 1949.
16. P. Karrer, Ch. Graenacher, and A. Schlosser, Holy. chim. acta, 6, 1108
(1923).
17. Journ. prakt. Chem., (2), 27, 418 (1883); Journ, Am. Chem. Soc., 71,
No. 5, 1856 (1949).
18. E. Fischer, Untershchungen uber Aminosauren, Polypeptide u.-Proteine, II,
1907-1919, S. 198.
19. E. Fischer and M. Bergmann, Ber., 37, 4101 (190)4),
20. L. N. Akva and N. I. Gavrilov, Dok, A. Nauk., 73, No, 6 (1950).
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