J. Org. Chem. 1982,47,474-482
474
Syntheses and Structure Assignments of Six Azolinone Ribonucleosides David R. Haines, Nelson J. Leonard,* and David F . Wiemer Roger Adams Laboratory, School of Chemical Sciences, University of Illinois, Urbana, Illinois 61801 Received August 5, 1981
N-Ribosidation of a series of azolinones was achieved via silylation and SnCll catalysis. N-Ribosidation of of 1,2,4-triazolin-3-onegave 2-and 4-8-D-ribo4-imidazolin-2-onegave l-8-~-ribofuranosyl-4-imidazolin-2-one; furanosyl-1,2,4-triazolin-3-one, and 2,4-di-~-D-ribofuranosyl-1,2,4-triazolin-3-one; and of 2-tetrazolin-5-one gave l-@-~-ribofuranosyl-2-tetrazolin-5-one and 1,4-di-@-D-ribofuranosyl-2-tetrazolin-5-one. Structure assignments were based on NMR and mass spectra, microanalytical data, and interconversions. The triazolinone monoriboside isomer structures were differentiated by '% N M R long-range coupling patterns, and the assignmentswere confirmed by X-ray crystallography. New syntheses were developed for several of the ribonucleosides by fashioning the azolinone rings from 2,3,5-tri-O-benzoylribofuranosyl isocyanate. The imidazolidin-2-one nucleus appears in products of the y-radiolysis of cytosine2 and of the oxidation of uric acid.3 The 4-imidazolin-2-one nucleus (l),through 1carbamoyl-4-imidmh-2-0ne,s e r ~ e e das a precursor for the synthesis of the m i n e radiolysis products! It is possible that the y-radiolysis producta of cytidine2 will include, by analogy, cis- and trans-l-carbamoyl-3-~-D-ribofuranosyl4,5-dihydroxyimidazolidin-2-oneand, by facile hydrolysis of the carbamoyl group, the corresponding l-P-D-ribofuranosyl-4,5-dihydroxyimidazolidin-2-one (2). Because of our interest in these compounds, we have directed attention first to the synthesis of the N-ribosyl derivatives of 4-imidazolin-2-one (1) and the related 1,2,4-triazolin3-one (3) and 2-tetrazolin-5-one (4). Interest is also
growth of Candida albicans and vaccinia virus, is cytotoxic to lymphoma cell line L5178Y, and is an immunosuppressive agent; and the synthetic broad-spectrum antiviral compound ribavirin (virazole, 8).16-19 Other N-ribosyl derivatives that have been synthesized include those of the five-membered-ring imidazoles,20s21t r i a z o l e ~ , ~tetra~-~~ ~ 0 l e ~ and , ~ ~ 1 ~ ~ thiazole^.^^^^^ 0 H , N ~ \
HOC&r
8
H
HO I
OH
HO
5
H H
,
HO
OH 6
H
OH
2
3
4
stimulated in these compounds by the existence of biologically and therapeutically active ribonucleosides that contain five-membered-ring heterocycles. These include the natural antibiotics pyrazofurin (pyrazomycin, which has antiviral and antitumor activity; showdomycin (6),*12 an antibacterial agent and an inhibitor of Ehrlich ascites tumor cells; and bredinin (7),'"15 which inhibits the (1) This work was supported by Research Grants CHE-76-23543and CHE79-22001 from the National Science Foundation. (2) Hahn, B. S.; Wang, S. Y.; Flippen, J. L.; Karle, I. L. J. Am. Chem. SOC. 1973,95, 2711. (3) Poje, M.; Paulus, E. F.; RoEiC, B. J. Org. Chem. 1980, 45, 65. (4) Leonard, N. J.; Wiemer, D. F. J. Am. Chem. SOC.1976,98,8218. (5) Gerzon, K.; Williams, R. H.; Hoehn, M.; Gorman, M.; Delong, D. C. 2nd International Congress of Heterocyclic Chemistry, Montpellier, France, 1969, Abstract C-30. (6) Streightoff, F.; Nelson, J. D.; Cline, J. C.; Gerzon, K.; Williams, R. H.; Delong, D. C. 9th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 1969, p 18. (7) Sweeney, M. J.; Davis, F. A.; Cutowski, G. E.; Hamill, R. L.; Hoffman, D. H.; Poore, G. A. Cancer Res. 1973, 33, 2619. (8) Gutowski, G. E.; Sweeney, M. J.; DeLong, D. C.; Hamill, R. L.; Cerzon, K.; Dyke, R. W. Ann. N.Y. Acad. Sci. 1975, 255, 544. (9) Niehimura, H.; Mayama, M.; Komatau, Y.; Kat4 H.; Shimaoka,N.; Tanaka, Y. J. Antibiot., Ser. A 1964, 17, 148. (10) Darnall, K. R.; Townsend, L. B.; Robins, R. K. h o c . Natl. Acad. Sci. U.S.A. 1967, 57, 548. (11) Nakagawa, Y.; KanB, H.; Tsukuda, Y.; Koyama, H. Tetrahedron Lett. 1967, 4105. (12) Shionogi & Co., Ltd. Shionogi Kenkyusho Nempo 1968,18, 2, 10, 13, 23, 33, 38, 42, 47, 52. (13) Mizuno, K.; Tsujino, M.; Takada, M.; Hayashi, M.; Ataumi, K.; Asano, K.; Matsuda, T. J. Antibiot. 1974, 27, 775. (14) Sakaguchi, K.; Tsujino,M.; Yoshizawa, M.; Mizuno, K.; Hayano, K. Cancer Res. 1975, 35, 1643.
OH
HO
7
HO
OH
6
(15) Sakaguchi, K.; Tsujino, M.; Mizuno, K.; Hayano, K.; Ishida, N. J. Antibiot. 1975. 28. 798. (16) Sidwell, R. W.; Huffman, J. H.; Khare, G. P.; Allen, L. B.; Witkowski, J. T.; Robins, R. K. Science 1972,177, 705. (17) Witkowski, J. T.; Robins, R. K.; Sidwell, R. W.; Simon, L. N. J . Med. Chem. 1972,15,1150. (18) Streeter, D. G.; Witkowski, J. T.; Khare, G. P.; Sidwell, R. W.; Bauer. R. J.: Robins. R. K.: Simon. L. N. h o c . Natl. Acad. Sci. U.S.A. 1973, 70, 1174. (19) Revankar, G. R.; Robins, R. K. Ann. N.Y. Acad. Sci. 1975,255, 166. (20) Srivastava, P. C.; Ivanovica, G. A.; Rousseau, R. J.; Robins, R. K. J. Org. Chem. 1975,40, 2920. (21) Srivastava, P. C.; Streeter, D.G.; Matthews, T. R.; Allen, L. B.; Sidwell, R. W.; Robins, R. K. J.Med. Chem. 1976,19, 1020. (22) Witkowski, J. T.; Robins, R. K.; Khare, G. P.; Sidwell, R. W. J. Med. Chem. 1973, 16,935. (23) Narang, A. S.; Vince, R. J.Med. Chem. 1977,20, 1684. (24) Huynh-Dinh, T.; Igolen, J.; Bieagni, E.; Marquet, J. P.; Civier, A. J. Chem. SOC.,Perkin Tram. 1 1977,761. (25) Vanik, T.; Farkari, J.; Gut, J. Collect. Czech. Chem. Commun. 1979,44, 1334. (26) Poonian, M. S.; Nowoswiat, E. F. J. Org. Chem. 1977,42, 1109. (27) Ogura, H.; Takahashi, H.; Sato, 0. Nucleic Acid Res., Symp. Ser. 1979, 6, 813. (28) Poonian, M. S.; Nowoswiat, E. F.; Blount, J. F.; Williams, T. H.; Pitcher, R. G.; Kramer, M. J. J. Med. Chem. 1976,19, 286. (29) Poonian, M. S.; Nowoswiat, E. F.; Blount, J. F.; Kramer, M. J. J Med. Chem. 1976,19, 1017. (30) Srivastava, P. C.; Pickering, M. V.; Allen, L. B.; Streeter, D.G Camobell. M. T.: Witkowski. J. T.: Sidwell. R. W.; Robins, R. K. J. Me, Cheh. 1977, 20,'256.
0022-326318211947-0474$01.25/00 1982 American Chemical Society
Azolinone Ribonucleosides Among t h e five-membered-ring heterocycles, 4imidazolin-2-one (11, 1,2,4-triazolin-3-one (3),and 2-tetrazolin-Bone (4) bear close resemblance to the pyrimidinones, and pyrimidinones have been N-ribosidated efficiently by the Vorbriiggen which accordingly directed our course of synthesis.% Trimethylsilylation of 4-imidazolin-2-one (1) with hexamethyldisilazane and trimethylsilyl chloride in anhydrous pyridine yielded a sublimable solid, identified as 1-(trimethylsily1)-2-[(trimethylsilyl)oxy]imidazole (9). Reaction of 9 with 1-0-
J. Org. Chem., Vol. 47,No. 3, 1982
475
N-Ribosidation of 1,2,4-triazolin-3-one (3)was carried out by the same procedure t h a t was used for 4imidazolin-&one (1). Trimethylsilylation of 3 gave a lowmelting, distillable solid consisting, on the basis of comparison with 9, of 2- and 4-(trimethylsilyl)-3-[ (trimethylsilyl)oxy]-1,2,4-triazole(12 + 13) and possibly the third, the 1-trimethylsilyl, isomer. N-Ribosidation, followed by
s
13
vu
workup and column chromatography, yielded three ribonucleoside products consisting of one diribonucleoside and Rb 6R two monoribonucleosides. The relative proportions of these products were highly variable, depending upon the reaction conditions. A diribonucleoside has been reported b , R = -H as an attendant product with 11 in the N-ribosidation of 4-imida~oline-2-thione.~ We could assign the structure acetyl-2,3,5-tri-O-betlzoyl-@-~-ribofuranose in 1,2-diof the deprotected diribonucleoside from the trimethylchloroethane/acetonitrile with SnC14 as catalyst gave 1silylated 1,2,4-triazolin-3-one (3) as 2,4-di-p-~-ribo(2,3,5-tri-O-benzoyl-~-~ribofuranosyl)-4-imidazolin-2-one furanosyl-l,2,4-triazolin-3-one (14b)on the basis of ele(loa)as the major ribonucleoside product. Deprotection mental analysis, mass spectrum, and a comparison of its with methanolic ammonia furnished 1-0-D-ribofuranosyl13C NMR spectrum with the spectra of the two mono-N4-imidazolin-2-one (lob). Analysis of the 13C NMR ribosyl derivatives. When the 13C NMR spectrum of 14b spectrum of lob was useful in assigning N-ribosidation was determined in (CD&SO, the proton-coupled resonance sites of other products in this series. The resonances for of C5 appeared as a doublet of doublets due to one-bond the ribosyl carbons were in the expected range.*@ For and three-bond coupling a t 134.2 ppm, whereas in D20, the imidazolidinone ring, the C4 and C5 resonances were the C5 resonance disappeared in the fourier transform in close proximity, 110.2 and 109.1 ppm from tetrapulsed spectrum, which indicated that exchange of deumethylsilane in the decoupled spectrum, but were easily terium for hydrogen had occurred a t C5.41 Confirmation distinguishable in the proton-coupled l3C spectrum. In the of the assigned structure was obtained by N-ribosidation latter, the 110.2-ppm resonance appeared as a doublet of of 13a to give 14a in good yield. If the possibility of 0doublets, J = 199.7 and 9.3 Hz, due to coupling with H4 ribosidation is rejected, as indicated by the close proximity and H5, respemively, whereas the 109.1-ppm resonance was of the two 1’-carbons in the 13C NMR spectrum of 14b in split by H 5 and H4 (J = 199.7 and 10.2 Hz) and also (CD3)$0, the only site on 15a which is available for rishowed three-bond coupling, J = 4.8 Hz, to the anomeric bosidation is the N2 position. proton of the sugar attached to the adjacent nitrogen. The RO OR 13C assignments are therefore in the order listed above. Compound 10b is of ancillary interest due to the recent finding that a substituted glycosyl-4-imidazolin-2-one makes up part of the structure of the antibiotic nikkomycin X.39 The synthesis of l-&~-ribofuranosy1-4-imidazolineRO OR 2-thione (1-~-~-ribofuranosylimidazole-2-thione) (11) by the Vorbriiggen method has also been described.40
o< j;
~
H
p
H
(311 VanBk. T.: FarkaB., J.:. Gut,. J. Collect. Czech. Chem. Commun. 1979, 1339. ’ (32) Niedballa, U.; Vorbriiggen, H.J. Org. Chem. 1974,39,3664,3660, 3664,3688. (33) Vorb-en, H.;Krolikiewicz, K. Angew. Chem. 1975, 87, 417. (34) VorbrQgen, H.; Bennua, B. Tetrahedron Lett. 1978,1339. (36) Wiemer, D. F.; Ph.D. Thesis, Univereity of Illinois, 1976. (36) Doman, D.E.;Roberta, J. D.Proc. Natl. Acad. Sci. U.S.A. 1970, 65,19. (37) Jones, A. J.; Winkley, M. W.; Grant, D. M.; Robins, R. K. Proc. Natl. Acad. Sci. U.S.A. 1970, 66,27. (38) Jonea, k J.; Grant, D. M.; Winkley, M. W.; Robins, R. K. J. Am. Chem. SOC.1970,92,4079. (39) Hegenmaier, H.; Keckeisen, A.; Eihner, H.; Khig, W. A. Liebigs 4nn. Chem. 1979,1494.
A,
(40) Goaselin, G.;Imbach, J. L.; Townsend, L. B.; Panzica, R. P. J. ‘eterocycl. Chem. 1979,16, 1186.
!! Of the N-tribenzoylribosidated triazolinones, the isomer of highest Rf on thin-layer chromatography (silica, 5 % EtOH/CHCI3) was deprotected to yield the N-ribmidated triazolinone that showed C5 in the 13CNMR spectrum in D 2 0 as a doublet of doublets, J = 221 and 6 Hz. These values correspond to one-bond and three-bond couplings. The carbonyl carbon showed coupling to more than one proton a t three-bond distance. These coupling patterns identify this N-ribosyl derivative as 4-/3-~-ribofuranoeyl(41) Gribble, G. W.; Nelson,R. B.; Levy, G . C.; Nelson, G. L.J . Chem. SOC.,Chem. Commun. 1972, 703.
476 J. Org. Chem., Vol. 47, No. 3, 1982
Haines, Leonard, and Wiemer
Figure 1. Stereoscopic view of a single molecule of 4-p-D-ribofuranosyl-l,2,4-triazolin-3-one (15b).
Figure 2. Stereoscopic view of the packing of 4-p-D-ribofuranosy~-l,2,4-triazo~in-3-one (15b).
Figure
Stereoscoi
view of a single molecule of 2-p-~-ribc ranosyl-1,2,4-triazolin-3-one (16b).
Table I. Best Planes Calculations for 1,2,4triazolin-3-one (15b), in a singular solution to the 4-~D-Ribofuranosyl-1,2,4-triazolin-3one (15h) structure problem, since only in 15b are both C3 and C5 coupled to the anomeric proton three bonds distant. The deviation deviation "C NMR of the second deprotected mono-N-ribosyl deatomsin from atoms in from olane olane, dane dane, A rivative showed C5 as a doublet, J = 219 Hz, due to one. . A .~ bond coupling, and C3 as a multiplet, leading to assignN1 -0.0075 N1 0.0005 ment of its structure as 2-B-~-ribofuranosyl-1,2,4-triazoN2 0.0096 N2 0.0022 c3 0.0113 C3 -0.0044 lin-3-one (16b). The structure assignments of these two N4 0.0084 N4 0.0033 isomers were verified by X-ray crystallography. Slow -0.0042 c5 -0.0129 C5 crystallization from CH,CN/CH,OH gave X-ray quality 03 -0.0109 other atoms crystals of both 15b and 16b. 03 -0:0405 X-ray crystallography of the compound assigned structure 15b confirms both the position of N-ribosidation and x' = 7.35 x* = 94.58 the configuration at C1' (B). A stereoscopic view of the molecule is given in Figure 1, together with the atom Table 11. Intermolecular Hydrogen Bonds in numbering used in the analysis. The atoms of the nitro4p~-Ribofuranosyl-1,2,4-triazolin-3-one (15b) gen-containing heterocyclic ring are coplanar and show
