The compounds mentioned in the title were prepared via debenzylation and subsequent cyclization of &alpha;-succinimido- and &alpha;-(p-toluenesulfonamido)-&beta;-benzylthiopropionyl chlorides with aluminum bromide in benzene at room temperature

A. Markovac-Prpić

D. Fleš

M. Milohnoja

V. Tomašić

English

Hrčak - Portal of scientific journals of Croatia

C R 0 A TI C A C H E M I C A A C TA 30 (1958) 167 C CA - 131 547.473 Studies in the Propiothiolactone Series. II.* .Preparation of DL_o;_Succinimido- and L_o;_(p-Toluenesulfonamido).,. · -~-propiothiolactone D. Fles, A. Markovac-Prpic, V. Tomasic and M. Milohnoja Department of Biochemistry, Institute »Ru<ler Boskovic«, Zagreb, and Research Department, »Pliva« Pharmaceuticai and Chemicai Works , Zagreb, Croatia, Yugosiavia • Received July 31, 1958 The compounds mentioned in the title were prepared via debenzylation and subsequent cyclization of a -succinimido- and a- (p-toluenesulfonamido)-~-benzylthiopropionyl chlorides with alu-minum bromide in benzene at room temperature. The reaction of S-benzyl-N-phthaloyl-L-cysteinyl chloride with two moles -0f aluminum halides in benzene has been shown by work in labora-tories to yield L-o;-phthalimido-~-propiothiolactone.1 The formation of propio-thiolactone presumably proceeds through the intermediate formation of the betaine structure I, in which the zwitterion character of the betaine leads to the internal approach of the reactive centres and thus to the formation of propiothiolactone. This reaction seems to be a general method for the preparation of propiothiolactone derivatives. In continuation of this work we have prepared: DL-o;-succinimido-~­propiothiolactone (II) and L-o;-(p-toluenesulfonamido)-~-propiothiolactone (III). These compounds were prepared by debenzylation and subseqent cyclization of the corresponding ~-benzylthiopropionyl chloride with aluminum bromide in benzene at room temperature. The reaction was accomplished after 30 minutes and propiothiolactones were isolated as crystalline products after the removal of diphenylmethane with petroleum ether. XaAl- · S · CH2 I I (AlX4)- +co . CH . R S---CH2 I I II R = (CH2C0)2N I I III R = p-CH3 · CsH 4 · S02NH O = C--CH · R The hitherto undescribed S-benzyl-N-succinoyl-DL-cysteine was synthesized from S-benzyl-L-cysteine and succinic acid anhydride following essentially the method described by Scheiber and Reckleben for the preparation of N-succinoyl-glycine.2 N-Succinoyl derivative was isolated in a yield of 21 O/o and was racemic. No attempt was made so far to prepare the optically active S-benzy 1-N -succinoy lcysteine. * Paper I , D. Fles, A. Markovac-Prpic and V. Tomasic, J. Am. Chern Soc. n~ (1958) 4654. 168 D. FLES, A. MARKOVAC-PRPIC, V. TOMASIC AND M. MILOHNOJA The compounds II and III are rather stable and can be crystallized from the common organic solvents. The N-tosyl derivative III was however very sensitive toward the action of dilute alkalies and formed a white, insoluble precipitate when a benzene solution was treated with 5°/o bicarbonate solution. On the basis of elementar analysis it was supposed the most probable structure to be the one corresponding to a linear polythioester, similar to the one obtained in the series of N-phthaloyl derivative. 1 The phthalimido-polythioester was obtained by debenzylation of S-benzyl-N-phthaloyl-L-cysteinyl chloride with one mole of aluminum chloride. It is worthwhile to note that thermal · polymerization of ~-propiolactone gave a similar polyester.3 Wave number in crri' 5000 4000 3000 2500 2000 150014001300 1200 1100 1000 950 900 850 800 750 700 100 ~ 90 ~ 80 1§ 70 g 60 .!:: 50 ~o 30 20 10 r /'"\ r IT \ ~ 100 0: 90 g 60 n- f(-"" ~ 70 g 60 ~ ~o 10 JO 20 10 \. I" ~+cL 40 JO 20 10 02 -~-r-1 --\ J1 \ ( ---- __ j _ _!__ ~ ~ ,!'\ r ii ~ I ! ., tf ~ ~--- ~ --·-1---'\( .I I Al I/ /I ( I u f\/ r-V--l ----~  v- I/ I II v \I v ' I .l-PHTf .ALIMIOC -1.J · PRO t-IOTHIOI ~CTO•E ,...I( ( II I \ · I I ( (\ ( \ I I ~~ .I I \ A r I - --I I Ii I ·-- ----.t -SUC l~IMIOO V-J- PROF OTH I OL~CTO•E I ! -- _ __j_t-j-1' ' -1 I \n v I I ' it~-/ !l~i- ---~ . 1 ' =- l,I ~ -- 1 1_1 __ t- . ----1-rl~, ~---' I I •/ \I - 1--u-1----I' - . : ___ J - --- ---~ __ 1_ _ _ L-~~~T~~b~~~:~~~~~~;, D0\-13 ·1 10 "" 12 13 14 1~ Wove length in_µ Fig. 1. The infra red absorption spectra The infrared spectra of ci-phthalimido-1, cr.-succinimido- and ci-(p-toluene-sulfonamido)-~-propiothiolactones were recorded on a Perkin-Elmer Mod. 21 spectrophotometer, using KBr pelleting technique (Fig. 1). The limited number of the compounds examined does not allow for a more detailed search for bands due to the thiolactone ring vibrations, but it appears interesting to note the frequency of the C-0 stretching pand. With propiothiolactone III, it is possible to locate easily this band at 1780 cm- 1, whereas with the other t wo STUDIES IN THE PROPIOTHIOLACTONE SERIES 169 "Compounds this region of the spectrum is obscured by the imide carbonyl bands. Nevertheless, by comparing the spectra of the two propiothiolactones with the spectra of phthalimide and with succinimide respectively, it is. pos-~ible to locate the thiolactone carbonyl bands at 1770 cm-1 (phthalimido-propiothiolactone) and at 1762 cm-1 (succinimidopropiothiolactone). Hence, the -carbonyl band in the propiothiolactone system seems to appear between 1760 ·ond 1780 cm-1. This range has been found to be characteristic of the five ·membered lactones4 whereas the carbonyl of the ~-lactones should absorb at higher frequencies. The replacement of the oxygen atom by sulfur seems to result in a lowering of the carbot:iyl frequency, perhaps through a reduction ·of the ting strain. There is another band in the spectra of the propiothiolactones which does ·not appear with related amides and imides. It is near 1000 cm-1 and may be 'brought in connection with the C<tactonerN stretching vibration, in agreement with the assignments in the. spectra of some amines and amides.5 EXPERIMENTAL• :S-Benzyl-N-succinoyl-DL-cysteine A well powdered mixture of 4 g. (0.019 mole) of S-benzyl-L-cysteine and 2 g. '(0.02 mole) of succinic anhydride was placed in a round-bottomed flask equipped with a thermometer, p.nd the reaction mixture was immersed into an oil bath heated to 190°. When inside temperature reached 180° the heating was disconnected and the temperature of the reaction mixture kept for 2'0 minutes at 160-70°. The ·dark-brown mass was treated with 5 ml. of ethyl acetate, 100 ml. of benzene fol-lowed by 30 ml. of petroleum ether (b. p. 40~60°) was added, and the reaction mixture kept overnight in a refrigerator. The solvent was decanted, evaporated in vacua., and the residue crystallized from, 5 ml. of benzene to give 1.4 g. of white crystalline product melting at 120°. The crude product was recrystallized from 4 ml. of benzene and a yield of 1.2 g. (210/o) was obtained; m. p. 127-130°. An analy-tical sample was recrystallized from benzene to a melting point of 129-130° Ju]~ O' (c. 1.6650/o in EtOH). . Anal. 13.63 mg. subst.: 28.60 mg. C02, 5.98 mg. H20 2.38 mg. subst.: 0.98 ml. N2 (25°, 75·9 mm.) C41H15N04S (W3.27) calc'd: C 57,33; H 5.16; N 4.780/o. found: C 57.25; H 4,91 ; N 4.710/o, :S-Benzyl-N-succinoyl-cysteinyl chloride S-Benzyl-N-succinoyl-cysteine (2 g., 0.007 mole) was refluxed one hour with 20 ml. of thionyl chloride. The excess of thionyl chloride was removed in vacua, the residue repeatedly treated with benzene and finally dissolved in 10 ml. of benzene. The impurities were precipitated with 20 ml. of petroleum ether and the clear solution decanted and evaporated in vacua gave 2.0 g. (94.50/o) of a crystal-line product. A sample for analysis was purified by crystallization from benzene-petroleum ether (4 :3) in needles, m. p . 73-75°. Anal. 9.84 mg. subst.: 19.56 mg. C02, 3.90 mg. H20 C14H 14ClN03S (311.78) calc'd. : C 53.93 ; H 4.530/o found : C 54.24 ; H 4.430/o ·oL-a-Succinimido-~-propothiolactone (II) u-Succinimido-~-benzylthiopropionyl chloride (2 g., 0.0064 mole) dissolved in 250 ml. of benzene was added at once into a solution of 5.6 g. (0.021 mole) of AlBra in 50, ml. of benzene. The reaction mixture was kept for one hour at room tempe-r ature and was hydrolyzed with 30 g. of ice and 6 ml. of concentrated hydrochloric • Melting points are uncorrected. 170 D. FLES, A. MARKOV AC-PRPIC, V. TOMASIC AND M. MILOHNOJ A acid. The aqueous layer was separated and extracted with two 20-ml. portions of benzene, the combined benzene layers were washed with two 20 ml. portions of water and dried over magnesium sulfate. The benzene was removed under reduced pressure and the residue (2.2 g.). triturated with two 10-ml. portions of petroleum · ether (b. p. 40-60°). Evaporation of petroleum ether gave 0.47 g. (44°/o) of diphenyl-· _met)lane. The residue obtained after trituration with petroleum ether (1.7 g.) was rdissolved in 2 ml. of ethyl acetate and 1 ml. of petroleum ether, and after standing overnight in a refrigerator 0.71 g. (600/o) of crystaline propiothiolactone II was col-lected, m . p. 93-95°. A sample for analysis was recrystallized from methanol and finally from ethanol to _a melting point .of 9•5-97°. Anai. 8.64 mg. subst.: 14.48 mg. C02, 2.85 mg. H20 C7H7N03S (185.13) calc'd.: C 45..41; H 3.81 O/o found: C 45.73; H 3.680/o L-a-(p-Toluenesulfonamido)-~-propiothiolactone (III) . S-Benzyl-N-(p-toluenesulfonyl)-L-cysteinyl chloride6 (4.9 g., 0~013 mole) in. 80 ml. benzene was treated with 15 g. (0.056 mole) of A1Br3 in 80 ml. of benzene, and the reaction mixture worked up as before. The residue after trituration with pe-troleum' ether was dissolved in 13 ml. benzene and 5 ml. petroleum ether, yielding 2.2 g, (670/o) of propiothiolactone III, m. p. 99-101°. A sample was recrystallized for analysis from a mixture of benzene-petroleum ether; needles melting at 101-102·\ [a]~ -5.2° (c 6.2850/o in dioxane). AnaL. 1°4.50 mg. subst.: 24.87 mg. C02; 5.20 mg. H20 C10HuN03S2 (257 .20) calc'd.: C 46.70; H 4.31 O/o found: C 46.80; H 4.010/o ·Conversion of the propiothiolactone III to · L-cystine The propiothiolactone III (0.2 g., 0.00078 mole) was refluxed for 4 hours with 2 ml. of glacial acetic acid and 2 ml. of hydriodic acid, and the reaction mixture was kept overnight at room temperature. The mixture of acids was evaporated ·'hi vacua, the last traces of acids removed by successive treatment with water, the· ' residue dissolved in 10 ml. of water, extracted with ether, water evaporated t o dryness, the residue dissolved in 2 ml. of water and adjusted to pH 4.5 with a saturated sodium · acetate solution. The solution was exposed to air and after several days 46 mg. (4'9.50/o) of L-cystine separated; m . p. 25·2' (decompn.) , [a]~ -2010 (c 2.3250/o in N-HCJ) . Reported m. p. 258-2610 (decompn.)7 [aJi5·910 -212.9<> (c 0.99470/o in 1.02N-HC1).B Paper chromatography of the compound gave the same· spot with ninh:y:drine as the authentic specimen of L-cystine. Reaction of the propiothiolactone III with sodium bicarbonate The propiothiolactone III (0.2 g., 0.00078 mole) was dissolved in 15 ml. of ben-zene and treated in a separatory funnel with 10 ml. of an aqueous 5°/o sodium bicar-bonate solution. A white precipitate which was formed instantaneously was filtered off, washed with water, extracted with 15 ml. of boiling benzene, the insoluble part was filtered off and dried on air, yielding 0.15 g. of white powder melting at 175-180° (decompn. under sintering at 165°). The product was insoluble in common organic solvents, but was very soluble in dimethylformamide. The »polymer« was insoluble in melted camphor and m-dinitrobenzene. AnaL 9'.93 mg. subst.: 17.10 mg. C02, 3.75 mg. H20 (C10H11NOsS2)x calc'd.: C 46.70; H 4;/31 O/o found: C 46.99; H 4.220/o A sample of the »polymer« (50 mg.) was refluxed for 24 hours with 2 ml. of glacial acetic acid and 2 ml. of hydriodic acid, and the reaction mixture worked up. as it was described for the hydrolysis of the propiothiolactone III. Cystine which was obtained gave on paper chromatography the same spot with ninhydrine as the authentic sample of L-cystine. M. p. 253° (decompn.). STUDIES IN THE PROPIOTHIOLACTONE SERIES 171 Bis(N-p-toluenesulfonyl)-L-cystinyl-diglycine dimethyl ester A solution of 0.5 g. (0.002 mole) of the propiothiolactone III and 0.49 g. (0.00;';.fi mole) of glycine methyl ester in 4 ml. dioxane was kept overnight at room tempe -· rature. The solvent was evaporated under reduced pressure, the residue dissolved. in 50 ml. ethyl acetate, washed with two 10-ml. of water, dried over m agnesium . sulfate, and the solvent was evaporated in vacuo. The crystaline residue (0.4 g.) w as recrystallized three times from ethyl acetate to a melting point of 177-178.5° (Kofler microscopic method), [a]~ 47.5° (c 1.8200/o in dioxane). Anal. 10.19 mg. subst.: 16.92 mg. 002, 4.32 mg. T20 C26H34N4010S4 (690.82) calc'd.: C 45.20; H 4.960/o found: C 45.31; H 4.740/o ' Acknowledgments. We wish to express our indebtedness to Professor D. Hadzi from the University Chemical Laboratory, Ljubljana, for measurements and inter-pretation of infrared spectra. Thanks are also due to Mr. V. Cakara for micro-analysis and to Miss S. Iskric for paper chromatograms. REFERENCES 1. D. Fles, A. Markovac-Prpic and V. Tomasic, J. Am. Chem. Soc. 86' (1958) 4654. 2. I. Scheib 1 er and H. Reck 1 e be n, Ber. 46 (1913) 2412. 3. T. L . Gresham and J. E. Jansen, U. S. pat. 2, 526', 554, Oct. 17, 1950; T . L . Gresham, J. E. Jansen and F. W. Shaver, J. Am. Chem. Soc. 70 (1948) 998. 4. R. S. R as mu s s en and R. R. B rat a in, J. Am. Chem. Soc. 71 (1949) In73 . 5. D . Had z i, J. Chem. Soc. (1957) 843 and 847. 6. J. Hon z 1 and J . Rudin g er, Collection Czechoslov. Chem. Commun. 20 (1955) 1190. 7. M. S. Dunn and T . W. Brophy, J. Biol. Chem. 99 (1933) 221 . 8. G . Toe n n i e s and T . F . Lavine, J . Biol. Chem. 89 (1930) 153. IZVOD Studije u redu propiotiolaktona II. Sinteza DL-a-sukcinimido-i L-a-(p-toluensulfonamido)-~-propiotiolaktona D. Fles, A. Markovac-Prpic, V . Tomasic i M. Milohnoja U r anijem je radul pokazano, da debenziliranj e S-benzil-N-ftaloil-L-cisteiniI klorida s jednim molom aluminijskoga triklorida daje opticki aktivni ftalimid o-politioester, a sa dva mola aluminijskog triklorida da nasta je L-a-ftalimido-~­propiotiolakton. Predlozen je reakcioni mehanizam, koji pretpostavlja nastajanje-intermedijarne betainske strukture I. Primjenom iste metode priredeni su u okviru ovoga rada, DL-a-sukcinimido-~-propiotiolakton (II) i L-a-(p-toluensulfonamido)-~­propiotiolakton (III). Sinteza ovih spojeva provedena je u benzenu, kod sobne tem -perature, uz upotrebu aluminijskoga tribromida. Propiotiolakton III l agano se poli -merizira u kontaktu s natrijskim bikarbonatom. Aciliranjem metilnog estera glicina ,. pomoeu propiotiolaktona III, prireden je dimetilni ester bis(N-p-toluensulfonil)-L-cistinil-diglicina. INSTITUT »RUDER BOSKOVIC« III. BIOKEMIJSKA GRUPA I ISTRAZIV ACK! INSTITUT _.PLIVA« TVORNICA FARMACEUTSKIH I KEMIJSKIH PROIZVODA ZAGREB Primljeno 31. srpnja 1953 . 

Studies in the Propiothiolactone Series. II.* Preparation of DL-α-Succinimido- and L-α-(p-Toluenesulfonamido)-β-propiothiolactone

Abstract

Similar works

Full text

Available Versions

Hrčak - Portal of scientific journals of Croatia

Studies in the Propiothiolactone Series. II.* Preparation of DL-&alpha;-Succinimido- and L-&alpha;-(p-Toluenesulfonamido)-&beta;-propiothiolactone

Abstract

Similar works

Full text

Available Versions

Hrčak - Portal of scientific journals of Croatia

Studies in the Propiothiolactone Series. II.* Preparation of DL-α-Succinimido- and L-α-(p-Toluenesulfonamido)-β-propiothiolactone