N-(p-Toluenesulfonyl)- and N-benzyloxycarbonyl-L-cysteine
were converted to the corresponding propiothiolactones by cyclization
with diisopropyl- and dicyclohexylcarbodiimide in dioxane
at room temperature. The propiothiolactones were condensed
with esters of amino acids to the following protected dipeptides:
bis-(N-p-toluenesulfonyl) - L - cystinyl- di-B-alanine diethyl ester,
bis-(N-p-toluenesulfonyl)-L-cystinyl-diglycine dimethyl ester and
bis-(N -benzy loxycar bony 1)-L-cystiny 1-diglycine dime thy 1 ester

A. Markovac-Prpić

D. Fleš

M. Dadić

English

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CR 0 AT IC A CHEMIC A ACT A 33 (1961) 73 CCA-213 547.473:547.491.6 Studies in the Propiothiolactone Series.* III. Preparation of L-ix-Acylamino-~-Propiothiolactones via Carbodiimide Method M . Dadic**, D. Fles*** and A. Markovac-Prpic Pharmaceutical Faculty, University of Zagreb, and »Pliva«, Pharmaceutical and Chemical Works, Zagreb, Croatia, Yugoslavia Received June 23, 1961 N-(p-Toluenesulfonyl)- and N-benzyloxycarbonyl-L-cysteine were converted to the corresponding propiothiolactones by cycli-zation with diisopropyl- and dicyclohexylcarbodiimide in dioxane at room t emperature. The propiothiolactones were condensed with esters of amino acids to the following protected dipeptides: bis-(N-p-toluenesulfonyl) - L - cystinyl- di-B-alanine diethyl ester, bis-(N-p-toluenesulfonyl)-L-cystinyl-diglycine dimethyl ester and bis-(N -benzy loxycar bony 1)-L-cystiny 1-diglycine dime thy 1 ester. In the previous communications1•2 we have described the preparation of N-phtaloyl, N-succinoyl- and N-tosyl-ix-amino-~-propiothiolactones by deben-zylation and cyclization of corresponding N-acyl-S-benzyl-cysteinyl chlorides with aluminum halides. The propiothiolactones were successfully used for the preparation of cysteine and cystine containing polypeptides3• Although the method for the preparation of propiothiolactones via aluminum chloride seems to be applicable to various N-acylderivatives of S-benzyl-cysteine, its use for the preparation of thiolactones has been limited to the compounds containing the acyl groups not sensitive to aluminum halides and hydrochloric acid which is formed during the course of debenzylation and cyclization. In the search for a more general method for the preparation of propiothio-lactones derived from cysteine, the cyclization of N-acyl-L-cysteine has been performed with substituted carbodiimides. The reactions were carried out in dioxane at room temperature and N,N'-diisopropylcarbodiimide+ and N,N'-dicyclohexylcarbodiimide were used for the elimination of water. L-ix-benzyloxycarbonyl-amino-~-propiothiolactone was isolated in crystalline form, whereas the crude N-tosyl++-derivative was used directly in the peptide synthesis. The dipeptides of glycine and ,~-alanine were prepared from the corresponding ethyl or methyl esters with thiolactones in dioxane at room temperature following the method described by Fles et al.2 *Paper II. D. Fles, A. Markovac-Prpic, V. Tomasic, and M. Mi-lo h no j a, Croat. Chem. Acta 30 (1'95!8) 167. ** Taken from the thesis submitted by M. Dadic in partial fulfilment of the requirements for the degree of Doctor of Chemistry (Ph. D.) at the University of Zagreb. *** Present address: Organsko-kemijska industrija, Zagreb + The same reagent was used by Sheehan et aL4 for the prearation of a-trityl-amino-B-propiolactone from the corresponding derivative of serine. ++ Tosyl = p-toluenesulfonyl. 74 . M. DADIC, D . FLES, AND A . MARKOV AC-PR~IC The m ethod described iri t h is pap e r r ep resen ts a very convenient route fo r the prep a r a tion of a-acylamino-~-propiothiolactones under very mild condit ions. EXPERIMENTAL N-(p-Toluenesulfon yl)-L-cysteine A m ixture of 3 g. (0.0055 m ole) of N,N'-ditosyl-L- cystine, 1.4 g. of p owder ed zinc, 20 ml. of m eth anol and 20 ml. of 2N sulfuric acid was heated on a water bath for 1.5 hour. Zin c was removed by filtration and the solution evaporated in vacuo. The residue was extracted w ith ether, extr act dr ied over magnesium sulfate and ether evaporated yielding 1.25 g. (41.50/o) of sulfonamide derivative which upon recrystal-lization from a m ixture of 5 ml. of benzene and 10 ml. of petroleum eth er (b. p . 40-f:lOOC) melted at 157- 1580, [a]~ 31.20 (c, 3.070 in dioxane). A nal. C10H 13N04S2 (275 .34) calc'd. : C 43.62; H 4.760/o found: C 43.91 ; H 4.57°/~ L - o:-( p-To 7, v,en esu l f ona m ido )-{3 -propioth io lactone N-Tosyl-L-cysteine (0.75 g., 0.0027 mole) was dissolved in 5 m l. of dry dioxane and 0.40 g. (0.0032 mole) of N,N' -diisopropylcarbodiimide6 added. The reaction mixture was k ept for 1.5 hour at room temperature and the crystals r emo·ved by suction filtration yielding 0·4 g. of diisopropylurea. The filtrate was evaporated in vacuo at room temperature and a yellow oil (0 .75 g.) was obtained. The crude product was used directly in the next step, since it polymer ized during an attempt to purify it by aluminum oxide chromato-graphy. A sample was t reated with an aqueous solution of sodium bicarb on ate an d gave a polymer identical with the one pr eviously described2. Bis (N-p-Toluenesulfonyl)-L-cystinyl- di-~- alanine-Diethyl Ester A solution of 1.5 g. (0.0128 mole) of B- alanine ethyl est er and 0.5 g. (0.0019 m ole) of crude L- a-(p - tolu enesulfonamido)-B-propiothiolactone in 8 ml. of dioxan e was kept overnight at room temperature. The solvent was evaporated under reduced pressure and the residue dissolved in 50 ml. of ethyl acetate, washed with two 10 ml. portions of 50/o hydr ochloric acid , followed by 10 ml· of wat er , dried over magnesium sulfate and the solvent evaporated in v acuo yielding 0.8 g. of a crystallin e product . After two r ecrystallizations from absolute eth anol 0.3 g. (41.70/o) of the product was obta ined, m. p. 171- 1730, [a] "f} 48.20 (c, 0.166 in dioxan e). Sodium nitro-prusside t est was negative. Anal. CaoH42N40 10S4 (746.93) calc 'd .: C 48.23; H 5.670/o found: C 48.10; H 5.570/o Bis (N-p-Toluenesulfonyl)-L-cystinyl-diglycine Dim ethyl Ester Similarly 0.5 g. (0 .002 mole) of L-a-(p-toluen esulfonamido)-B-propiothiolactone and 0.49 g. (0.0056 mole) of m ethyl glycinate were converted to the corresponding dipeptide. The crude oily product (0.7 g.) obtained upon evaporation of dioxane was d issolved in ethyl acetate, poured on a column of 0.7 g. of n eutral aluminum oxide, eluted w ith 25 ml. of ethyl acetate and the solvent evap or ated. The crude dipeptide (0.35 g.) w as recrystallized from 3 ml· of ethanol, yielding 0.12 g. (17.90/o), m. p. 171-1720, [a] "fJ 57,20 (c, 0.940 in dioxane) of the analytically pure product. Sodium nit roprusside test was negative. In admixture with an authentic specimen of bis (N-p-- toluen esulfonyl)-L-cystinyl-diglycine dimethyl ester2 the melting point was undepressed. Anal. C25H34N4010S4 (690.82) calc'd.: C 45.20 ; H 4.960/o found: C 45.47; H 5.1270/o STUDIES IN THE PROPIOTHIOLACTONE SERIES 15 L-1X-Benzyloxyc,arbonylamino-·~-propiothiolactone N-Benzyloxycarbonyl-L-cysteines (1.95 g., 0.00'78 mole) was dissolved in 5 ml. of dioxane and 1.6 g. (0.0078 mole) of N,N' -dicyclohexylcarbodiimide was added with .shaking. White crystals precipitated immediately. The reaction mixture was kept for 1.5 hour at room temperature and the crystals removed by suction filtration yielding 1.60 g. of dicyclohexylurea. The filtrate was evapor ated and the semi-crystaline residue (0.75 g.) was crystallized from a mixture of 2 ml. of methylene-dichloride and 3 ml. of petroleum ether (b. p. 40-600). Yield: 0.2 g. (140/o), m . p. 1wo (with softening at 1150), [a] fjl -500 (c, 1 in chloroform). Anal. C11H11N03S (236.27) calc'd. : C 55.69; H 4.670/o found : C 56.12; H 5.380/o Bis (N-Benzyloxycarbonyl)-L-cystinyl-diglycine Dimethyl Ester A solution of 0.25 g. (0.00'1 mole) of L-a-benzyloxycarbonylamino-~-propiothio­lactone and 0.25 g. (0.0G28 mole) of glycine methyl ester in 4 ml. of dioxane was kept overnight at room temperature and worked up as previously described. Yield -0f pure dipeptide was 0.34 g. (86.8-0/o), m. p. 143-1450, [a] iJ -340 (c, 0.672 in dioxane). Anal. C28H 34N4010S2 (650.71) calc'd.: C 51.69; H 5.270/o found: C 51.93; H 5.22°/o REFERENCES 1. D. Fl es, A. Markovac-Prpic, and V. Tomasic, J. Am. Chem. Soc. 80 (1958) 4654. 2. D. F 1 e s, A· Ma r k ova c - Pr pi c, V. Tom as i c, and M. Mi 1 oh no j a, Croat. Chem. Acta 30 (1958) 167. 3. A. Markov a c - Pr pi c and D. F 1 es, IV. International Congress of Biochem., Vienna 195'8., Section I, p . 2. 4. J. C. Sheehan, K. Hass pa ch er, and Lien Yeh, J. Am. Chem. Soc. 81 (1959) 6086. 5. W. Foye and M. Verderame, J. Am. pharm. Assoc. 46 (1957) 273. B. E. S c h mid t und W. S tr i e w sky, Ber. 74 (1941) 1285. IZVOD Studlje u redu proplotiolaktona. III. Priprava L-a-acllamino-~-propiotiolaktona primjenom karbodiimidske metode M. Dadic, D. Fles i A. Markovac-Prpic N-(p-Toluensulfonil)- i N-benzilok~ikarbonil-L-cistein prevedeni su u odgova-rajuce propiotiolaktone ciklizacijom pomoeu diizopropil- i dicikloheksilkarbodiimida u dioksanu kod sobne temperature. Nastali propiotiolaktoni kondenzirani su sa este-rima amino kiselina u slijedeee zasticene dipeptide: bis (N-p - toluensulfonil)-L-cistinil--di-B-alanin dietil ester, bis (N-p-toluensulfonil)-L-cistinil-diglicin dimetil ester i bis (N-benziloksikarbonil)-L-cistinil-diglicin dimetil ester. FARMACEUTSKIFAKULTET I •PLIVA« TVORNICA FARMACEUTSKIH I KEMIJSKIH PROIZVODA ZAGREB Primljeno 23 . lipnja 1961. 

Studies in the Propiothiolactone Series. III. Preparation of L-a-Acylamino-B-Propiothiolactones via Carbodiimide Method

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