A description is given of the reaction products of p-benzoquinone with glycine benzyl ester [lc], with B-alanine ethyl ester [Id] and with glycylglycine ethyl ester [le]

K. Balenović

Ž. Fuks

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AR H I V Z A K E M I J U 26 (1954) Preparation of Peptide-like 2,5-Disubstituted p-Benzoquinone Derivatives. Peptide-like Polyoxo Compounds*. lr':· K. Balenovic and Z. Fuks**~· Chemicai Institute, Facuity of Science, University of Zagreb, Croatia, Yugosiavia Received August 25, 1954. A de:>cr ipt1on is given of the reaction producb of p-bcnzo-quinone with glycine benzyl ester [le], with ~-alanine ethyl ester [Id] and with glycylglycine ethyl ester [le]. 229 The bacteriostatic activity of quinones is very well known1• There are :severail theories of the mechanism of this activity, lbased on the fact that quinones show an inhibitive action on certain enzymes. H has been shown later that p-benzoquinone, ais well as other substituted benzoquinones and naphthoquinones, inhibit the action of some enzymes2• 3, and that this inhi-bitive action is not in correlation with their redox potential, .or with their .antibacterial activity. The antibacterial action of certa1in quinones has been interpreted as being due to their interaction with v~tal thiol groups4• 5 and .amino groups6 of p-aminoibenzoic acid. Following Cooper and coworkers7, the germicidic action of quinones is dtie more to the 1reaction of quinones with individual amino acids than wii.ith proteins. The first qualitative investigation of the reaction of quinones with amino acids and proteins was carried out by Raciborski8• Later Su1da9 showed that in the dyeing of animal tissues with quinones, the amino groups are also involved. The qu:iJnones which have dyeing properties must have the unchanged and unsubstituted -CO. CH : CH. CO-_group. In these circumstances it seemed to be of some interest to investigate the .a ction of quinones on amino acids and peptides. Fi1scher has shown10 that glycine ethyl ester and DL-alanine ethyl ester react with benzoquinone to give 2,5-disubstituted p~benzoquinones [Ia-b]. We have, therefore, as the first step in the investigatiom. of these reactions, prepared condensation products of p-benzoquinone with glycine benzyl ester [le], with ~-alanine ethyl ester [Id], and with glycyl glycine ethyl ester [le]. In every instance intensively red * This series of papers deals with colored compounds, cyclic or acyclic, containing at least one -CO· NH- group and a chromophore system with two or . more >C=O groups. To a certain extent this series of compounds corresponds, by definition, to Brockmann's definition of »chromopeptides« [Angew. Chem. 66 (1954) 1]. . . . . - .. . . . .. . . ** Paper I, N. A 11 egret t'i, K. B a I en o.v i c, V. Fist er and R. Munk, Expe -rientia 9 (1953) 416. ·**' Predodorate Fellow (Army Health Service). Present address: V. p. 4295 -Sarajevo. 230 K: BALENOVIC AND 2. FUKS colored compounds of qui.nonoid charncter were obtained. If vital amino groups inactivate quinones as antibacterial agents, we can expect that corn-. pounds of the formula [I] will probably be of low antibacterial activity, as compared with other quinones. Further dnvestigation of this series of compounds is in progress, inter alia of their antibacterial activity. OO , NH·R RNH 0 la, R = CH2COOC2Hs lb, R = CH (CHa) COOC2Hs le, R = CH2COOCH2CuHs Id, R = CH2CH2COOC2Hs l e, R = CH2CONHCH2COOC2H ;, EXPERIMENT AL* 2,5-Diglycinoquinone dibenzyl ester [le] Glycine benzyl ester hydrochloride prepared according to ~rlanger and Brcmdll (14.6 g. , 0.072 mole) was suspended in chloroform (100 ml.) and saturated with dry ammonia. The ammonium chloride was filtered off and washed with chloroform. The combined filtrates were evaporated in vacuo. The residual glycine benzyl ester was dissolved :in ai])solute ethanol (20 ml.) .in a flask fitted with a dropping funn el with a mercury sealed stirrer and calcium chloride tube. At _5oc a solution of p-benzoquinone (13.9 g., 0.128 mole) in absolute ethanol (200 ml.) was gradually added during half an hour with stirring. After stirring the mixture for two hours, the red crystalline precipitate of 2,5-diglycinoquinone dibenzyl ester was filtered off and washed with 10-15 ml. of cold ethanol. Yield 16.3 g. (51.60/o) of red needles, m. p. 201-2{).40. After several recrystallizations from ethyl acetate, m. p . 2140 (corr.). Froni the mother liquor, quinhydrone (4.1 g.) was isolated. Anal. 9,97 mg subst.: 24.30 mg. C02, 4,62 mg H20 C24H22N206 (434.43) calc'd: C 66.35 ; H 5.1 00/o found : C 66.51; H 5.190/o. 2,5-Di- .~-alaninoquinone diethyl ester [Id]. ~-Alanine ethyl ester hydrochloride prepared according to Hoogewerff and Van Dorp12 was converted to the free base as described in the preparation of glycine benzyl ester. To a solution of B-alanine ethyl ester (10 g., 0.085 mole) in ethanol (10 ml.), a solution of quinone (14 g., 0.129 mole) .in ether (175 ml.) was added, and the mixture left at room temperature overnight. After cooling to -120, the crystals were collected and extracted with hot chloroform. The chloroform extracts were evaporated to dryness under reduced pressure, and the r esidue dissolved in the minimum quantity of methanol. After cooling the crude 2,5-di-~ -alaninoquinone diethyl ester separated, yield 7.5 g. (52,10/o), m. p . 1380. Repeated recrystallization from methanol gave red needles, m . p. 144-1450. Anal. 9.10 mg. subst.: 19.05 mg. C02, 5,35 mg. H20 C1aHl22N20a (388.35) callc'd: C 56.79; H 6.550/o found: C 57.13; H 6.58°/o. From the ethereal mother liquor quinhydrone could be isolated in the usual manner. Di[glycyl-glycino]quinone diethyl ester [le]. Glycylglycine hydrochloride monohydrate was prepared according to Sheehan and Frank.13 From this compound glycylglycine ethyl ester was prepared according to * The melting points are uncorrected., unless otherwise stated. PEPTIDE-LIKE POL YOXO COMPOUNDS 231 Fischer and Fourneau14 and Dunn and coworkers15. A suspension of glycylglyci.ne ethyl ester (1.64 g., ·0.010 mole) in absolute ethanol (10 ml.) was cooled to oo, and a solution of p-benzoquinone (1.62 g., 0.0.15 mole) in absolute ethanol (25 ml.) gradually· added during 20 minutes. The mixture was left overnight at -100, and then the crystals collected. Yield of crude di[glycylglycino]quinone diethyl ester 1.58 g., (36.30/o), m . p. 210.5-211.50. After repeated recrystallization from 700/o ethanol, red needles with the m. p. 230 .20 were obtained. Anal. 9.70 mg subst.: 18.20 mg. C02, 4.95 mg. H20 C1sH24N40s (424.4-0) calc'd: C 50.94; H 5.700/o found: C 51.20 ; H 5.710/o REFERENCES l. cf. e. g. W. A. Sexton, Chemical Constitution and Biological Activity, Van Nostrand, .:-Jew York, 1950, pp. 189-209. 2. 0. Hoffmann - 0 s ten ho f and W . H. Lee, Monatsh. 76 (1946) 180. 3. 0. Hoffmann - 0 s ten ho f and E. Bi a c h, Experientia 2 (1946) 405. 4. C. J. Cava 11 it o and J. H. Bai 1 e y, Science 100 (1944) 390. 5. W. B. Geiger and J. E. Conn, J. Am. Chem. Soc. 67 (1945) 112. 6. H . . N. Green and F . Bi e 1 s chows k i, Brit. J. Exp. Path. 23 (1942) 13. 7. E. A. Cooper and n. B. Haines, Biochem. J . 22 (1928) 317; E. A . Coope r and S. D. N ·i c ho 1 as, J. Soc. Chem. Ind. (London) 46, T 59-60. 8. M. Ra c i b ors k i, Anzeiger Akad. Wiss. Krakow 1906, 553; cit. from Chem. Z entr. 1907, I, 1595. 9. W. ·S u id a, Z. physiol Chem . 85 (1913) 308. 10. E. F is c her and H. S c h rad e r, Ber. 43 (191•0) 525. 11 . B. F. Er 1 anger and E . Brand, J. Am. Chem. Soc. 73 (1951) 3508. 12. S. Ho o g ewer ff and W. A_ Van D or p, Ree. trav. chim. 9 (1890) 54. 13. J. C. Sheehan and V. S. Frank, J . Am. Chem. Soc. 71 (1949) 1856. 14. E. Fis -c her and E. Four n ea u , Ber. 34 (1901) 2868. 15. H. F. Schott, J. B . Larkin, L. B . Rock 1 and and M. S. Dunn, J. Org. Chem. 12 (1947) 490. IZVOD Preparacija 2,5-disupstituiranih derivata p-benzokinona peptidnog karaktera. Poliokso spojevi peptidnog karaktera. II K. Balenovic i Z. Fuks Opisani su reakcioni produkti p-benzokinona s glicinbenzil esterom [IcJ , s P-alanin etil ester.am [Id] i s glicilglicin etil esterom [le]. KEMIJSKI INSTITUT PRIRODOSLOVNO-MA TEMATIC:KI F AKULTET ZAGREB Primljeno 25. augusta 1954.. 

Preparation of Peptide-like 2,5-Disubstituted p-Benzoquinone Derivatives. Peptide-like Polyoxo Compounds

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