J . Am. Chem. SOC.1982, 104, 7626-7630
7626
separated, the aqueous layer was extracted with additional ether, and the combined ethereal extracts were dried (MgS04) and concentrated. The crude product was crystallized from petroleum ether/methylene chloride to yield 4 mg (40%) of chuangxinmycin: mp 145-145.5 OC; ’HNMR (CDCI,) 8 1.36 (d, 3 H J = 7 Hz), 3.80 (d of q, 1 H, J = 7, 3.5 Hz), 4.30 (d, 1 H, J = 3.5 Hz), 6.9-7.3 (m, 4 H), 8.6 (br s, 1 H). Exact mass calcd for C,2HI,NO2S: 233.051 1. Found: 233.0507.
technical assistance of Scott Gordon is also acknowledged.
Acknowledgment. We are indebted to the National Institutes of Health ( G r a n t R 0 1 HL 20579) for support of these investigations. W e are grateful to Dr. Zhi-Ping Zhang of the Institute of Materia Medica for generous samples of chuangxinmycin. The
Supplementary Material Available: X-ray structure and listings of atomic coordinates, temperature parameters, bond distances, and bond angles (6 pages). Ordering information is given on any current masthead page.
Registry No. cis-(-)-], 63339-68-4; 4, 83561-15-3; 7, 73363-65-2; 10, 606-20-2; 11, 73363-64-1; 13, 83561-16-4; 15, 78283-22-4; 15 diethyl acetal, 83561-17-5; 16, 83561-18-6; 17, 73363-63-0; 19, 83602-19-1; 20, 83602-20-4; HSCH2C0,CH3, 2365-48-2; N,N-dimethylformamide dimethyl acetal, 4637-24-5; triethyl orthoformate, 122-51-0.
Structure and Conformation of the Antiviral Nucleoside 2’-Fluoro-5-iodoarabinosylcytosine(FIAC). The Gauche Effect in Nucleosides’ George I. Birnbaum,*zaMiroslaw Cygler,” Kyoichi A. Watanabe,2band Jack J. FoxZb Contribution from the Department of Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada K1A OR6,and the Sloan-Kettering Institute for Cancer Research, New York, New York 10021. Received April 15. 1982
Abstract: The three-dimensional structure of 2’-fluoro-5-iodoarabinosylcytosine(FIAC), an inhibitor of herpes simplex and herpes zoster viruses, was determined by X-ray crystallography. The crystals belong to the monoclinic space group P2,, and the cell dimensions are a = 4.747 (2), b = 14.017 (2), and c = 18.514 (3) A, 6 = 90.28O. Intensity data were measured with a diffractometer, and the structure was solved by the heavy-atom method. Least-squares refinement, which included the coordinates of the hydrogen atoms, converged at R = 4.8%. In the asymmetric unit there are two crystallographically independent molecules of FIAC that are related by a pseudo-2-fold screw axis. The conformation about the glycosidic bond is anti, xCN having the rather low value of 19.1’. Contrary to expectations based on the substituent effect, the furanose ring adopts the C(3’) e n d d ( 2 ’ ) exo (type N) pucker. The influence of electronegative substituents on the ring conformation is being discussed in terms of the gauche effect. The -CHIOH side chain is disordered, giving rise to equal populations of the gauche’ and trans rotamers.
The antiviral activities of some arabinonucleosides as well a s of some 5-substituted 2’-deoxyribonucleosides have been known for several years.3 Recently, Watanabe et aL4synthesized a new series of variously 5-substituted 2’-deoxy-2’-fluoroarabinofuranosylpyrimidines, several of which exhibited marked antiherpetic activity. One of these, 1-(2’-deoxy-2’-fluoro-P-~arabinofuranosyl)-5-iodocytosine(also called 2’-fluoro-5-iodoarabinosylcytosine or F I A C ) was found4s5to be especially capable of suppressing the replication of various strains of herpes simplex virus types 1 and 2, as well as of herpes zoster and cytomegalovirus. Continuing our structural studies of chemotherapeutic nucleosides,6 we decided to carry out an X-ray analysis of FIAC. In particular, we wished to compare t h e conformation in t h e solid state with ~
~~
(1) Issued as NRCC No. 20495.
(2) (a) National Research Council. (b) Sloan-Kettering Institute for Cancer Research. (3) For a recent review, see: De Clercq, E.; Descamps, J.; Verhelst, G.; Walker, R. T.; Jones, A. S.;Torrence, P. F.; Shugar, D. J. Infect. Dis. 1980, 141, 563-574. (4) Watanabe, K. A.; Reichman, A.; Hirota, K.; Lopez, C.; Fox, J. J. J . Med. Chem. 1979, 22, 21-24. ( 5 ) (a) Lopez, C.; Watanabe, K. A.; Fox, J. J. Antimicrob. Agents Chemother. 1980, 17, 803-806. (b) Fox, J. J.; Lopez, C.; Watanabe, K. A. In ‘Medicinal Chemistry Advances”; De las Heras, F. G.; Vega, S., Eds.; Pergamon Press: New York, 1981; pp 27-40. (6) (a) Birnbaum, G. I.; Lin, T.-S.; Shiau, G . T.; Prusoff, W. H. J . A m . Chem. SOC.1979, 101, 3353-3358. (b) Bimbaum, G. I.; Deslauriers, R.; Lin, T.-S.; Shiau, G. T.;Prusoff, W. H. Ibid. 1980,102, 4236-4241. (c) Birnbaum, G. I.; Watanabe, K. A.; Fox, J. J. Can. J . Chem. 1980, 58, 1633-1638. (d) Birnbaum, G. I.; Cygler, M.; Kusmierek, J. T.; Shugar, D. Biochem. Biophys. Res. Commun. 1981, 103, 968-974.
0002-7863/82/ 1504-7626$01.25/0
that determined in solution’ and with the conformations of other arabinonuclmsides. The effect of electronegative ring substituents on the conformation of the furanose ring in nucleosides has been the subject of some discussion in recent Since no fluoroarabinonucleoside has ever been subjected to an X-ray analysis, the crystal structure determination of FIAC was considered to be particularly valuable.
Experimental Section 2’-Fluoro-5-iodoarabinosylcytosine (FIAC), C9Hl,N30,FI,was prepared as described by Watanabe et aL4 and crystallized from methanol. Systematic absences and the symmetry of reflection intensities on precession photographs indicated the orthorhombic space group P2,2,2,. All crystals in our possession were rather mosaic (0.849’); nevertheless we collected data with molybdenum radiation on a CAD-4 diffractometer. The cell dimensions were as follows: a = 4.742 (4), b = 14.012 (9,and c = 18.504 (6) A. The angles a,@, and y were 90°,within experimental error (&0.2’). The data were corrected for Lorentz and polarization factors and for absorption. The structure was determined by the heavy-atom method and refined by block-diagonal least squares with anisotropic temperature parameters for non-hydrogen atoms. The refinement converged at R = 0.069 (R’ = 0.077) for 1464 observed re(7) Lipnick, R. L.; Fissekis, J. D.Biochim. Biophys. Acfa 1980, 608, 96-102. ( 8 ) Uesugi, S.; Miki, H.; Ikehara, M.; Iwahashi, H.; Kyogoku, Y. Tetrahedron Lett. 1979, 4073-4076. (9) Klimke, G.; Cuno, I.; Liidemann, H.-D.; Mengel, R.; Robins, M. J. Z . Naturforsch., C Biosci. 1980, 35C. 853-864. (10) (a) Guschlbauer, W.; Jankowski, K. Nucleic Acids Res. 1980, 8, 1421-1433. (b) HaertlE, T.; Wohlrab, F.; Guschlbauer, W. Eur. J. Biochem. 1979, 102, 223-230.
0 1982 American Chemical Society
Conformation of 2'- Fluoro-5-iodoarabinosylcytosine NH2 11.332
OH
Figure 1. Average bond lengths and some torsion angles in FIAC. The disorder of O(5') is indicated by dashed bonds. flections. However, we were suspicious of the results because of unusually high discrepancies between observed and calculated structure factors for = 4.46, many reflections, both weak and strong. For instance, 1 1 11 (IFo[ lFcl = 30.33), 0 1 14 (7.98, 27.36), 1 2 14 (4.90, 22.86), 0 1 15 (8.41, 26.00), 2 1 3 (89.56, 70.24). Consequently, we decided to recrystallize our sample of FIAC, and we managed to obtain crytstals that, although smaller, were much less mosaic (0.3"). One of these crystals, measuring 0.05 X 0.10 X 0.26 mm, was mounted on the CAD-4 diffractometer, and the dimensions of the unit cell were determined from a least-squares refinement of the angular settings of 22 reflections. These reflections, located in four different octants, had medium intensities and were in the mid range of the molybdenum sphere (27 < 28 < 34"). The new cell parameters showed that the space group is, in fact, monoclinic, F2,.The following crystal data were obtained: a = 4.747 (2), b = 14.017 (2), and c = 18.514 (3) A, @ = 90.28 (2)"; V = 1229.5 A', d, = 2.01 g cm-', Z = 4, F(000) = 720, p (Mo K a ) = 26.6 cm-I. The intensity data were measured (w/28 scans) at room temperature (20 "C) with monochromatized Mo K a radiation (A = 0.71069 A). Three reflections were monitored at intervals of 100 min; their intensities showed variations of f2.5%. Of the 3848 reflections with 28 5 60", there were 2636 reflections with I > 1,5u(I). The intensities were corrected for Lorentz and polarization factors. An analytical absorption correction was also applied, varying in the range 1.14-1.30. Refinement was resumed with the atomic parameters previously obtained, and the second molecule in the asymmetric unit was found on a weighted Fourier map. The two independent molecules are related to each other by a pseudo-2-fold screw axis, making the structure pseudoorthorhombic. In each molecule, the oxygen atom in the side chain was found in two equally populated positions. Consequently, O(5') and O(5") were refined with occupancy factors of 0.5. The refinement was by block-diagonal least squares. All scattering factors were taken from the 'International Tables for X-ray Crystallography"," and the iodine curve was corrected for anomalous dispersion (AJ' = -0.726, Af" = 1.812). The hydrogen atoms were located on difference Fourier maps, and their coordinates were also refined. Each hydrogen atom was assigned a temperature parameter corresponding to that of the heavy atom to which it is bonded. Throughout the refinement the function x:w(lFol - lFC1)*was minimized and a factor of 0.8 applied to all shifts. The following weighting scheme was used during the final stages: w = (F01/27 for IFoI 5 27, w = 27/IF01 for lFol > 27. This weighting scheme made the average values of w(@) fairly independent of IFo[and sin2 8. After the final cycle, the average parameter shift equaled 0.1 u and the largest 0 . 5 ~ The . conventional residual index R is 0.048, and the weighted index R'is 0.049 for 2636 reflections. The observed and calculated structure factors of the previously mentioned reflections are as follows: 1 1 11 (30.68, 30.28) , 0 1 14 (27.61, 27.63), 1 2 14 (23.65, 23.50), 0 1 15 (24.78, 25.65), 2 1 3 (66.10, 64.49). There are many sjgnificant differences in the calculated structure factors of hkl and hkl pairs: e.g., 2 1 1 (51.91,41.85), 4 2 1 (18.27, 11.42), 2 4 1 (27.70, 21.41), 2 8 1 (17.71, 9.08), 2 1 2 (48.12, 38.56). A final difference Fourier map showed no significant features. The final atomic coordinates of the non-hydrogen atoms and their equivalent isotropic B values are given in Table I.
Results and Discussion T h e chemical structure of FIAC is illustrated in Figure 1, which also shows t h e averaged bond lengths a n d some torsion angles. (1 1) 'International Tables for X-ray Crystallography", Ibers, J. A., Hamilton, W . C., Eds.; Kynoch Press: Birmingham, England, 1974; Vol. IV.
J . Am. Chem. Soc.. Vol. 104, No. 26, 1982 1621 Table I. Final Atomic Parameters and Their Standard Deviation@ atom
X
J)
Z
Beav
3189 (14) 11743 (14) 4007 (18) 10977 (18) 3001 (14) 12001 (13) 5731 (15) 9233 (16) 6755 (16) 8160 (16) 8638 (21) 6271 (21) 5915 (20) 9039 (20) 7324.6 (17) 7587.5 (18) 4162 (17) 10815 (20) 1312 (18) 13675 (17) 2981 (17) 11993 (17) 5397 (11) 9613 (11) 3671 (16) 11290 (16) 4315 (15) 10691 (15) 975 (17) 13973 (15) 30(12) 14942 (12) 1239 (22) 13666 (22) 332 (3) 1161 (3) -147 (3) 1628 (3)
4493 (4) 5521 (5) 3538 (6) 6467 (6) 2936 (4) 7086 (4) 3301 (5) 671 1 ( 5 ) 3963 (6) 6030 (6) 3695 (6) 6305 (6) 4938 (6) 5061 (6) 6008.0 (5) 4000.0 5152 (5) 4836 (6) 4733 (5) 5286 (6) 4834 (6) 5154 (6) 4286 (4) 5730 (4) 5905 (5) 4118 (6) 6196 (4) 3821 (4) 6309 (6) 3701 (6) 56 12 (4) 4391 (4) 7275 (7) 2733 (7) 7305 (10) 2691 (8) 7694 (9) 2317 (9)
3825 (3) 8829 (3) 3737 (4) 8739 (4) 4160 (3) 9154 (3) 3194 (4) 8198 (4) 2758 (4) 7762 (3) 2269 (4) 7269 (4) 2820 (4) 7840 (4) 2133.6 (4) 7140.9 (4) 3367 (4) 8368 (4) 4438 (4) 9451 (4) 5138 (4) 10153 (4) S I 6 2 (3) 10175 (3) 5150 (4) 10158 (4) 5852 (3) 10868 (3) 4842 (4) 9853 (5) 4314 (3) 9326 (3) 4493 (6) 9499 (6) 3865 (7) 8876 (7) 4481 (6) 9468 (7)
1.8 (1) 2.0 (1) 2.3 (2) 2.3 (2) 3.1 (2) 2.7 (1) 2.4 (2) 2.4 (2) 2.1 (2) 2.2 (2) 3.7 (2) 4.0 (2) 2.5 (2) 2.6 (2) 4.37 (2) 4.52 (2) 2.0 (2) 2.5 (2) 2.1 (2) 2.1 (2) 2.0 (2) 2.3 (2) 3.0 (1) 3.1 (1) 1.9 (2) 2.1 (2) 3.2 (2) 3.2 (2) 2.3 (2) 2.1 (2) 2.3 (1) 2.5 (1) 3.4 (2) 3.5 (3) 3.0 (3) 2.6 (3) 2.8 (3) 3.3 (3)
a The top and bottom values refer to molecules A and B, respectively. T h e x coordinates of O(5') and O(5") were multiplied by 10'; all other coordinates by l o 4 .
Table 11. Bond Lengths (A) in Molecules A and Ba molecule
N( 1)-C( 2) N(l)-C(6) N( 1)-C( 1') C( 2)-N( 3) C(2)-0(2) N(3)-C(4) C( 4) -C( 5 ) C(4)-N(4) C(51436) c(5)-1(5) C( l')-C( 2') C( 1')-O( 4') C(2')-C( 3') C( 2')-F( 2') C(3')-C(4') C( 3')-O( 3') C( 4')-O( 4') C(4')-C(S') C(5')-O(5') C(5')-0(5")
A
B
1.404 1.338 1.486 1.341 1.249 1.324 1.428 1.329 1.348 2.079 (8) 1.522 1.393 1.537 1.381 1.510 1.395 (9) 1.451 1.505 (13) 1.529 (17) 1.414 (17)
1.384 1.357 1.506 1.341 1.254 1.348 1.428 1.334 1.325 2.087 (8) 1.540 1.410 1.490 1.389 1.5 13 1.410 (9) 1.45 0 1.514 (13) 1.510 (17) 1.371 (18)
a Estimated standard deviations are 0.010-0.012 A unless otherwise indicated.
T h e bond lengths and bond angles of t h e independent molecules A and B a r e given in Tables I1 a n d 111. S o m e selected torsion angles a r e listed in Table IV. T h e precision of the results is not as high as one attains with structures without heavy atoms, but quite respectable when one considers the presence of two iodine
Birnbaum et al.
7628 J . Am. Chem. SOC.,Vol, 104, No. 26, 1982
6 Figure 2. Stereoscopic view of FIAC; the thermal ellipsoids correspond to 50% probability. Table IV. Selected Torsion Angles (deg)
Table 111. Bond Angles (deg) in Molecules A and Ba
molecule
molecule
C(2)-N(l)-C(6) C(2)-N( 1)-C( 1’) C(6)-N(l)-C( 1’) N(l)-C(2)-N(3) N( 1)-C ( 2)-0( 2) N( 3)-C( 2)-0(2) C( 2)-N( 3)-C(4) N(3)-C(4)-C(5) N( 3)-C(4)-N(4) C(5)-C(4)-N(4) C(4)-C( 5)-C(6) C( 4) -C(5 )-I( 5 ) C(6)-C(5)-1(5) C(5)-C(6)-N( 1) N( 1)-C( 1 -C( 2’) N( l)-C( 1’)-0(4’) O(4’)-C( 1’)-C(2‘) C( 1’)-C( 2’)-C(3’) C(l‘)-C( 2’)-F( 2’) C( 3‘)-C( 2’)-F( 2’) C(2‘)-C( 3’)-C(4‘) C( 2 ’ ) C (3’)-O( 3’) C(4’)-C(3’)-O( 3’) C( 3’)-C(4’)-0(4’) C(3’)-C(4’)-C(5’) 0(4’)-C(4’)-C(5’) C(4’)-0(4’)-C( 1’) C(4’)-C(S’)-O(S‘) C(4’)4(5’)-0(5”) 0(5’)-C(5’)-0(5”) I )
A
B
119.3 118.2 122.6 120.7 117.7 122.7 120.7 121.2 117.9 120.9 116.6 123.4 120.0 122.6 111.1 109.7 106.5 102.3 113.9 111.5 100.4 110.2 115.2 105.2 115.3 110.1 110.6 114.0 (9) 107.6 (9) 124 (1)
121.2 117.4 121.4 119.8 119.2 121.1 119.8 120.2 117.2 122.6 119.0 121.3 119.7 120.0 110.8 109.2 104.8 103.8 112.3 112.6 100.7 109.8 114.1 105.3 115.4 109.7 110.2 115.3 (9) 108.3 (9) 122 (1)
C(6)-N( l)-C( l’)-C(2’) C(6)-N( l)-C( 1’)-0(4’) C( 2)-N( 1)-C( l’)-C(2’) C( 2)-N( l)-C( 1’)-O(4’) N( 1)-C( l’)-C(2’)4(3’) N( l)-C( 1’)-C( 2’)-F( 2’) 0(4’)-C( l’)-C(2’)-C(3’) 0(4’)-C( lf)-C(2’)-F(2’) C( l’)-C( 2‘)-C( 3’)-C(4‘) C( l’)-C(2’)-C( 3’)-O( 3’) F( 2’)-C( 2’)-C( 3’)-C(4’) F( 2’)-C( 2’)-C(3’)-O( 3’) C( 2’)-C( 3’)-c(4’)-0(4’) C( 2’)-C( 3’)-C(4’)-C(5’) O( 3‘)-C( 3’)-C(4‘)-0(4’) O( 3’)-C( 3’)-C(4’)-C(5‘) C(3‘)-C(4‘)-0(4‘)-C(1’) C(S’)-C(4’)-0(4’)-C(1’) C(4’)-0(4’)-C(l’)-N( 1) C(4’)-0(4’)-C( l’)-C(2’) C( 3’)
