Aug. 20, 1958
4423
COMMUNICATIONS T O T H E EDITOR N,N'-CARBONYLDIIMIDAZOLE, A NEW REAGENT FOR PEPTIDE SYNTHESIS
Sir: Wieland and Schneiderl showed in 1953 that peptide derivatives could be synthesized via acylation of the imidazole ring of methyl N-benzoyl-Lhistidinate, but their procedure was not suitable for general use. I n seeking a simple method for making N-acylimidazoles, i t occurred t o us that N,N'carbonyldiimidazole should be ideal, since elimination of carbon dioxide would be a driving force 0
0
65% yield, m.p. 98-99', [ a ] " D -21.7 h0.5' (c 5, EtOH).6 Possible racemization was investigated in the reaction of carbobenzoxyglycyl-L-phenylalaninewith ethyl glycinate, a sensitive case.' The acylimidazole was formed a t - 10' in dimethylforniamide (a better solvent than T H F a t low temperatures) in order to minimize racemization, and the reaction solution was allowed to warin to room temperature after the addition of ethyl glycinate. A crude yield of 96y0 of tripeptide, m.p. 115.5-117', was obtained and recrystallization from a 2% solution in absolute ethanol gave 0.5% containing some DL form, m.p. 119-133.5', and 87% of the L form, m.p. ~ j=1.25" ( c 2, ethanol). 119.8-120.3O, [ a I z 5-12.2 Approximately 5% of DL form was obtained when both reactions were carried out a t room temperature in THF.
Staab2 has shown recently that N,N'-carbonyldiimidazole is highly reactive to amines and alco(6) M. Bergmann, el al., J . B d . Chenz., 109, 325 (1935). hols. We now have found that this compound re(7) G. W. Anderson and F. M. Callahan, THISJOURNAL, 80, 2902 acts readily with carboxylic acids to form acyl (1958). imidazoles, and subsequent reaction with amines to CONTRIBUTION FROM THE GEORGE W. ANDERSON form amides goes smoothly. Application to pep- ORGANIC CHEMICAL RESEARCH DEPARTMENT tide synthesis has been highly successful. We en- RESEARCH DIVISION,AMERICAN CYANAMID COMPANY ROLFPAUL RIVER,NEWYORK countered difficulties in following Staab's proce- PEARL RECEIVED JULY 24, 1958 dure for the preparation of the reagent. These were overcome by preparing the reagent from phosgene and imidazole in rigorously dried benzene. STEROIDS. CIII.1 A NEW CLASS OF POTENT The crude reagent was assayed for carbon dioxide CORTICAL HORMONES, 6a-FLUOROCORTICOIDS on hydrolysis; the purity was usually 98-100% and the m.p. 113-115'. Adjusting the quantity Sir: We wish to report the synthesis of a series of 6ato give 0.10 mole, the reagent was added to 0 10 mole of an acylamino acid in dry tetrahydrofuran fluorocortical hormones which we have found to be (THF) a t room temperature. When the efferves- powerful corticoids. Peracid oxidation of A5-pregnene-30,17a,21-triolcence stopped, the desired amino acid or peptide ester in 0.010 mole quantity then was added, and the 20-one-17,21-diacetate (I) gave the 5a,6a-epoxide reaction was allowed to proceed for 15 minutes or (11) (m.p. 198-200°, [a]D -54°)3 which underwent more a t room temperature. The product was iso- fission with boron trifluoride4 to the corresponding lated by removal of the solvent under vacuum fol- 5a-hydroxy-6P-fluoro compound (111) (m.p. 176lowed by washing with N acid, saturated bicar- 178') [ a ] D -10"). Oxidation of 111 gave the corbonate and water. Ester hydrochlorides may be responding 3-ketofluorohydrin (IV) (m.p. 227used in this reaction as may aqueous solutions of 22S0, [ a ] D fO") whence acid catalyzed dehydration amino acid salts. I n the latter case the yields are and concomitant inversion of the fluorine atom, lower. Examples are ethyl carbobenzoxyglycyl- yielded 6a-fluor0 compound "S" 17,21-diacetate L-tyrosinate, 3*4 obtained in 83% yield (recrys- (v) (m.p. 241-242', [ a ] D $53"; Xmax 236 mp, log tallized) m.p. 126-127', [(YI2'D + I 8 =kl.oo (c 5 , E 4.17). Under milder conditions the principal EtOH) ; ethyl t-butyloxycarbonyl-L-phenylalanyl- product was 60-fluor0 "S" diacetate (VI) (m.p. Amax 233 mp, log E 4.05). 187-189") [ a ] D -114'; glycinate' 78y0 yield, m.p. 88-89.5', [ a ] % -4.2 ~ . ~led , ~ to . ~ the A l f1.2 O (c 2, EtOH) ; carbobenzoxyglycyl-L-leuci- Selenium dioxide ~ x i d a t i o n ~of~ V nate, via ethyl L-leucinate hydrochloride followed derivative (VII) (m.p. 247-249', [ a ] D *oo, Xmax by saponification of the peptide ester (an oil), 68% (1) Paper CII, J. S. Mills, H. J. Ringold and C. Djerassi, TAIS over-all yield, m.p. 103-104", [CX)~'D - 18.2 10.5' JOURNAL,80, Oct. (1958). (2) H. J. Ringold, G.Rosenkranz and F. Sondheimer, ibid., 78, 820 (c 5, N NaOH) ; carbobenzoxyglycyl-L-phenylalanine via the sodium salt of phenylalanine, 40% (1956). (3) All new compounds described had correct analytical data. yield, m.p. 126.5-127.5", [cY]'~D +40.7 a1.7' (c Unless stated otherwise rotations were measured in chloroform and 3, EtOH) ; ethyl carbobenzoxy-L-alanylglycinate, ultraviolet spectra in 96% ethanol. (1) T . Wieland and G. Schneider, Ann., 680, 159 (1953). (2) H . A. Staab, i b i d . , 609, 75 (1957). (3) We thank Mr. L. Brancone and staff for analysis, and Mr. W.
Fulmor and staff for optical rotations. (4) J. R. Vaughan, Jr., and R. L. Osato, THISJOURNAL, 74, 676 (1952). ( 5 ) G. W. Anderson and A. C. McGregor, ibid., 79, 6180
(1957).
(4) (a) H. B. Henbest and T. I. Wrigley, J . Chem. SOC.,4765 (1957). (b) A. Bowers and H. J. Ringold, Tetrahedron, S, 14 (1958). (5) (a) H . J. Ringold, G. Rosenkraoz and F. Sondheimer, J . Org. C h e n . , 21, 239 (1956). (b) Ch. Meystre, H. Frey, W. Voser and A. Wettstein, Helo. Chim. A d a , S9, 734 (1956). ( c ) S. A. Szpilfogel, T.A. P. Posthumus, M. S. De Winter and D. A. Van Dorp, Rec. Trav. Chim., 76, 475 (1956). (d) K. Florey and A. R. Restivo, J . Ovg. Chem. 2 2 , 406 (1957).
