摘要:
490 J.C.S. Perkin ITransfer Hydrogenation ; a Convenient Method for Removal of SomeCommonly Used Protecting Groups in Peptide SynthesisBy Gattadahalli M. Anantharamaiah and Kadlebal M. Sivanandaiah,' Department of Chemistry, CentralN-Benzyloxycarbonyl and benzyl ester groups in peptides can be conveniently removed by transfer hydrogenationwith cyclohexene and 10% palladium-carbon catalyst. If freshly prepared palladium black catalyst is used, othercommonly used protecting groups like NT-benzyl (histidine), benzyl ether (tyrosine, serine), and nitro (arginine) canalso be removed much more rapidly than in the case of the usually employed catalytic hydrogenation.College, Bangalore University, Bangalore 560001, IndiaTHE reduction of mono- and poly-nitro-aromatic com-pounds rapidly, selectively, and in high yield by transferof hydrogen from cyclohexene in the presence of palla-dium-charcoal was reported recent1y.l We report herethat transfer hydrogenation is also very useful for theremoval of several protecting groups commonly used inpeptide synthesis. Groups like N-benzyloxycarbonyl,C-terminal benzyl ester, nitro of nitroarginine, NT-benzyl of NT-benzylhistidine, and O-benzyl ether ofO-benzyl-tyrosine or -seine are usually removed bycatalytic hydrogenation over palladium-charcoal orpalladium black.This method, though satisfactory inthe case of N-benzyloxycarbonyl and benzyl ester groups ,takes longer for the removal of other protecting groups.Indeed, hydrogenation for 2-3 days over palladiumblack may be necessary for the removal of the nitro-group from nitroarginyl residues in peptides, and eventhen the reaction may not be complete.Further,conversion of a nitroarginyl residue into an aminoguan-idino-derivative 2 and reduction of the aromatic ring of aphenylalanine residueJ3 if present, are other compli-cating aspects of this procedure. The final product maytherefore need extensive purification. Our own experi-ence of catalytic hydrogenation of several nitroarginylpeptides has shown that the product is invariably con-taminated with closely related impurities.Transfer hydrogenation is a simple and convenient1 I. D. Entwistle, R. A. W. Johnstone, and T. J. Povall,J.C.S. Pevki.n I , 1976, 1300.method for removal of all protecting groups that arenormally removed by catalytic hydrogenation.Theprotected peptide is dissolved in a mixture of ethanol andcyclohexene (acetic acid may be added to assist dissolu-tion) and the solution is refluxed with stirring in thepresence of palladium-charcoal or palladium black.The reaction may be followed by t.1.c.; after completionthe catalyst is filtered off and washed with ethanol. Ifthe product is a free peptide, it generally stays on thecatalyst, from which it can be collected by repeatedwashing with water and evaporation of the washings ircvacuo at 40 "C. If acetic acid is used for dissolutionthen the product will be an acetate, which stays insolution in the ethanol, from which it can be recoveredby evaporation. In either case the product needsminimal purification.Experimental details for twotypical cases are described in the Experimental section,and relevant data concerning other peptides are incor-porated in the Table.These results demonstrate that N-benzyloxycarbonyland C-terminal benzyl ester groups can be removedeasily in the presence of 10% palladium-charcoal. Thequantity of catalyst required is quite large but thecatalyst can be re-used. In case of Z-Gly-Gly we carriedout four hydrogenations with the same catalyst beforeC. Gross, M. P. de Garilhe, A. Costopanagiotis, and R.3 D. J. Schafer, G. T. Young, D. F. Elliott, and R. Wade, J .Schwyzer, Helv. Chim. Acta, 1961, 44. 2042.Chem. Soc. (C), 1971, 461977its efficiency decreased. 10% Palladium-charcoal canalso be used for the removal of N7-benzyl and benzylether groups, but the reaction time is longer.However,this can be considerably reduced by using freshly pre-pared palladium black catalyst, which must also be usedfor the removal of the nitro-group from a nitroarginylpeptide. The time required for this last reaction is muchless than that for the usual catalytic hydrogenation, andthe product is of greater purity. Indeed, for the removalof a nitro-group, transfer hydrogenation appears vastlysuperior to catalytic hydrogenation. This was evidentQuantities of(1) substrate (mg),(2) catalyst (mg),(3) cyclohexene +(1) 150, (2) 75,: (3) 3 + 6(1) 180, (2) 90,: (3) 4 + 8Substrate * ethanol (ml)Z-Gl y-GlyZ-Ser-Gly-OBzl aZ-Pro-Val-Gly-OEtZ-Ala-Asp(OBz1) -Ser-Gly CBOC-LYS (2)Boc-Phe-Arg(N0,)-Trp-Gly *Boc-His(N7-Bzl)B~C-TJT (Bzl)Z- P-Ala-Tyr-Ser-Met-OMe 6Asn-Glu (0Bzl)-Glu(OBz1)-Gly-Leu-Phe-Cly-Gly-Arg(N0,)-OBzl efor 1.5 h.During this period the product Ser-Gly precipi-tated out. This was filtered off along with the catalyst, andthe solid was washed with ethanol ( 1 x 10 ml) and water(3 x 10 ml). The aqueous washings were collected andevaporated in vacuo at 40 "C to yield Ser-Gly (100 mg, 90%)m.p. 208-210" (lit.,4 204-206").Boc-Phe-Arg-Trp-Gly,AcOH from Boc-Phe-Arg( NO,)-Trp-G2y.-To Boc-Phe-Arg(N0,)-Trp-Gly (745 mg) in cyclo-hexene (14 ml) was added ethanol (28 ml); only a portionof the peptide dissolved and glacial acetic acid (3 ml) wasintroduced to effect complete dissolution. To the resultingsolution was added freshly prepared palladium black (75Reactiontime21.51.520.751.5246837316(h)Yield(%)GIy-Gly 80Ser-Gly 90ProductPro -Val-Gl y- OE t 84 } ~~G-p-Ser-Gly, 93BOC-LYS 95 } BTc;hg-Arg-Trp-Gly 7788Boc-His 1 91.597jBOC-TF 9093a-Ala-Tyr-Ser-Met- 90Asn-Glu-Glu-Gly- 83OMeLeu-Phe-G1 y-Gly-Arg-2AcOH t t(Fibrinopep tideB of greenmonkey)M.p.("C)Found(Reported)t208-210(204-206)125-128(127-128) '192-196(190-194)199-200(200-201) d175-180 **190-192(191.5) f135-1 37(1 36-1 38) g128-130 **t "* Except for glycine, the amino-acids in these peptides are of the L-variety. t Identical with an authentic sample.f 10% ** Satisfactory elemental analyses have t t For the removal of ammonium acetate formed during the hydrogenation,C G. M. Anantharamaiah and K. M. Sivanandaiah,f B. 0.g G. W. Anderson and A. C. McGregor, J .Pd-C.been obtained for peptides not previously reported.gel filtration of this peptide over LH-20 was carried out.Current Sci., 1974, 43, 245.Handford, T. A. Hylton, K. T. Wang, and B. Weinstein, J . Org. Chem., 1968,33,4251.Amer. Chem. Soc., 1957, 79, 6180.TI Freshly prepared palladium black. § Acetic acid added until dissolution.Ref. 4. R. Schwyzer and W. Rittel, Helv. Chim. Acta, 1961, 44, 159.d R. Schwyzer, A. Costopanagiotis, and P. Sieber, Helv. Chim. Acta, 1963, 46, 870. C Ref. 5.from the hydrogenation of nitroarginyl peptides otherthan those listed in the Table. This method, unlikecatalytic hydrogenation, is also useful for the removal ofN-benzyloxycarbonyl group from peptides havingsulphur-containing amino-acids. The t-butoxycar-bony1 group is unaffected under these conditions.EXPERIMENTALSer-Gly from Z-Ser-Gly-0BzZ.-A mixture of Z-Ser-Gly-OBzl (180 mg), 10% palladium-charcoal (90 mg), cyclo-hexene (4 ml), and ethanol (8 ml) was refluxed with stirringK.Noda, M. Besho, T. Kato, and N. Izumiya, Bull. Chem.SOC. Japan. 1970, 48, 1834.mg) and the mixture was refluxed with stirring until theprotected compound had disappeared (t.1.c.) (ca. 6 h). Themixture was then filtered and the filtrate evaporated invacuo at 40 "C. The residue was washed with water (toremove ammonium acetate), dried, and reprecipitated frommethanol-ethyl acetate to yield Boc-Phe-Arg-Trp-Gly, AcOH(670 mg, 88%), m.p. 175-180°.5We thank the Council of Scientific k Industrial Research,Government of India, for financial support.[6/1214 Received, 22nd June, 197615 G. M. Anantharamaiah and K. M. Sivanandaiah, unpub-lished work
ISSN:1472-7781
DOI:10.1039/P19770000490
出版商:RSC
年代:1977
数据来源: RSC