Structure and absolute configuration of versiol, a metabolite fromAspergillus versicolor

摘要

1978 683 Structure and Absolute Configuration of Versiol, a Metabolite from Aspergillus versicolor By Keiichi Fukuyama," Yukiteru Katsube, Takashi Hamasaki, and Yuichi Hatsuda, Faculty of Engineering, Tottori University, Koyama, Tottori 680, Japan X-Ray analysis has established the structure and absolute configuration of versiol (I ), a metabolite isolated from Aspergillus versicolor. Crystals are orthorhombic, space group P212121, with a = 9.1 40(3), b = 6.1 18(2), c = 25.201 (7) 8,Z = 4. The structure was solved by direct methods and refined by least-squares techniques to R 0.048 for 1 249 reflections. The absolute configuration determined by the Bijvoet method has verified that assigned by application of the Horeau asymmetric synthesis, but shown that that assigned by taking into account the Cotton effect was incorrect.Intermolecular hydrogen bonds link the molecules into infinite chains along the a axis. DURINGan investigation of the metabolites of the genus his co-workers isolated from Sporormia aflnis a rneta- Aspergillzts,l a new metabolite named versiol (1) was bolite named LL N313C whose structure was identical isolated from a strain of Aspergillus versicolor (Vuille-with that of versiol, except in its stereochemistry. min) Tiraboschi NI 5 346. The physical properties and Recently both metabolites were found to be identical by relative configuration of versiol determined by X-ray comparison of their X-ray diffraction patterns. This diffraction were reported briefly,2 while McGahren and fact prompted us to investigate further the absolute 1 T.Hamasaki, T. Nakagomi, Y. Hatsuda, K. Fukuyama, W. J. McGahren, G. A. Ellestad, J. E. Lancaster, G. 0. and Y. Katsube, Tetrahedron Letters, 1977, 2765. Morton, and M. P. Kunstmann, J. Amer. Chem. Soc., 1974, 96, 2 K. Fukuyama, T. Tsukihara, Y.Katsube, T. Hamasaki, and 1616; W. J. McGahren, G. A. Ellestad, G. 0.Morton, and M. P. Y. Hatsuda, Tetrahedron Letters, 1976, 189. Kunstmann, J. Org. Cltem., 1976, 41, 66. configuration of versiol in order to ascertain whether the application of Horeaursquo;s asymmetric synthesis or of Beechamrsquo;s idea,5 which took into account the Cotton effect due to the diene system with allylic oxygen, had led to an incorrect result. Since a crystal of a heavy-atom derivative was not available, we utilized the small anomalous scattering of light atoms for the determin- (1 1 ation of the absolute configuration.697 We now describe the absolute stereochemistry of versiol elucidated by X-ray diffraction. EXPERIMENTAL The isolation and n.m.r.data are described in ref. 2. The compound was crystallized from acetone as colourless prisms elongated along the b axis. Crystal Datu.-C,,H,,O,, M =262.35. Orthorhonibic, u = 9.140(3), b =6.118(2), G =25.201(7) A, U = 1409.2 A3,Z =4, D = 1.24 g ~m-~.Cu-K, radiation, h = 1.541 8A; p(Cu-K,) = 6.8 cm-l. Space group P212,2, from systematic absences. Crystallographic Measurements.-Preliminary unit-cell data were obtained from Weissenberg photographs. Accurate cell constants were determined by the least-squares treatment of the angular settings of 13 reflections.Intensities were initially measured up to sinO/A 0.53 with Ni-filtered Cu-K, radiation on a Toshiba four-circle diffracto- meter by means of the stationary-crystal-stationary-counter method, with a counting time of 30 s. Since it was desirable to obtain a more accurate molecular structure, the inten- sities were remeasured, after the structure determination,* on a Rigaku computer-controlled four-circle diffractometer using Ni-filtered Cu-K, radiation. The 8-28 scan tech-nique was used with a scan speed of 2rsquo; min-l in 8, and back- grounds were measured for 8 s at both the start and end points of a scan. A total of 1 250 independent intensities were measured in the range, 0 sinO/h 5 0.56.The intensities of three reference reflections measured every sixty reflections showed no significant variation during data collection. The crystal used was so small (ca. 0.10 x 0.30 x 0.15 mm) that no absorption correction was con-sidered necessary. Intensities were corrected for the Lorentz and polarization factors. Structure Determination and Refinement.-The structure was solved by use of 232 reflections with El 2 1.2 by the multiple-solution weighted-tangent formula procedure.* The set with the highest figure-of-merit yielded an E map revealing the positions of all non-hydrogen atoms. At an early stage of refinement, the co-ordinates and isotropic temperature factors were refined by a block-diagonal *In the preliminary communication, only the first set of inten-sities was used.* A. Horeau and H. B. Kagan, Tetrahedron, 1964, 20, 2431. ,4. F. Beecham, A. M. Mathieson, S. R. Johns, J. A. Lam-herton, A. A. Sioumis, T. J. Batterham, and I. G. Young, Tetra-hedvon, 1971, 27, 3725. D. W. Engel, Acta Cryst., 1972, B28,1496. J.C.S. Perkin 11 least-squares method by use of the carbon-atom scattering factors. The atoms were identified and the types of bonds assigned on the basis of temperature factors and bond lengths and angles. All twenty-two hydrogen atoms were located in a difference-Fourier synthesis after anisotropic refinement, so that the structure of versiol was determined unambiguously. The refinement, including hydrogen atoms TABLE1 Final atomic parameters *(x lo4),with estimated standard deviations in parentheses, for non-hydrogen atoms X Y z 3 962(3) 5(5) 1176(1)2 485(4) -20(6) 887(1)1446(3) 156416) 1 157(1)1 158(4) 969(6) 1736(1)2 575(4) 499(7) 2 014( 1)3 794(4) -116(6) 1774(1)5 l67(4) -401 (6) 2 060( 1)6 442(4) -723(6) 1 828(1) 6 631(4) -1 002(6) 1239(1)5 128(3) -1 673(5) 977(1)5 326(3) -1 442(6) 384(1)5 917(4) 726(6) 191(1) 7 294(4) 1292(6) 497(1)297(5) 2 757(8) 2 012(2) 7 836(4) -2 660(6) 1122(2)4 741(4) -4 046(5) 1124(1)1864(3) -2 169(4) 881(1)5 099( 3) -2 949(5) 78P)7 058(2) 1155(4) 1052(1) TABLE 2 Fractional co-ordinates (x 103) for hydrogen atoms Distance1 X Y z A H(C1) 442(5) 159(7) 109(1) 1.08 H(C2) 266(4) 44(6) 4W) 1.07 H(C3) 47(4) 154(7) 94P) 1.04 H(C3) 188(5) 312(7) 115(1) 1.03 H(C4) 48(4) -50(7) 175(2) 1.09 H(C5) 257(4) 56(6) 242(1) 1.02 euro;3 (C7) 513(5) -34( 6) 248(2) 1.06 743(5) -94( 7) 206 (2) 1.08FgL) 512(4) 200(6) 24(1) 1.08 H(C12) 614(4) 65(7) -21(1) 1.03 H(C13) 763(4) 288(7) 40(1) 1.05 H(C13) 808(4) 15(7) 38(1) 1.04 H(C14) W5) 230(7) 237(2) 0.96 H(C14) -57(5) 319(8) 183(2) 0.95 H(C14) 97(5) 416(8) 199(2) 1.05 H(C15) 766(4) -398(7) 135(1) 1.00 H(C15) 795(5) -307(7) 73(2) 1.03 H(C15) 880(4) -198(7) 122(2) 1.00 H(C16) 458(5) -413(7) 150(1) 0.97 H(C16) 561(5) -497 (7) 104(1) 1.00 H(C16) 382(5) -463(8) 91(2) 1.06 H(01) 121(4) -225(7) 64(2) 0.86 with isotropic temperature factors, reduced R to 0.08 for 996 reflections.The structure was further refined by use of the recollected data. The strongest reflection, 012, was omitted from subsequent calculation. A weighting scheme, with w = 0.3 for F, =0, w = 1.0 for 0 F, 5 17, and w =1.0 +0.25 (F, -17)I-l for 17 F,, was used in the final refinement. The final R was 0.048 for 1 249 reflections (R 0.040 for non-zero reflections). Final atomic parameters K. Fukuyama, K. Hamada, T. Tsukihara, and Y. Katsube, Bull. Chew. Soc. Japan, 1978, 51,37. G. Germain, P. Main, and M. M. Woolfson, Acta Cryst., 1971,A27,368. T. Ashida, HBLS V, The Osaka Universal Crystallographic Computing System, The Computation Center, Osaka UniGersity, 1973, p. 55. are given in Tables 1 and 2. Observed and calculated structure factors and atom thermal parameters are listed in Supplementary Publication No.SUP 22234 (11 pp., 1 microfiche).* Absolute Configuration.-The absolute configuration was determined by the Bijvoet method with the technique described by EngeL6 The Bijvoet differences were cal-culated with Af1'0:~== 0.02, and seventeen sets of Bijvoet pairs and reference-reflection pairs were chosen by hand. A specimen of size ca. 0.20 x 0.30 x 0.15 mm was mounted a L 6 RESULTS AND DISCUSSION The present X-ray crystallographic analysis has established the structure and absolute configuration of versiol as in (1). The absolute configuration is correctly TABLE3 Bond lengths (A) and angles (O), with estimated standard deviations in parentheses (a) Bond lengths :;j:E;L)C(2)-0(1) c(4)-c (5)C(5)-C(6)C(7)-C(8)c(9)-c (10) C(9)-0(3)C( 10)-C (16)C(l1)-O(2)C(13)-0 (3) (b) Bond angles C (2)-C ( 1)-C ( 6)C(6)-C( 1)-C( 10) c( 1)-c(2)-0 ( 1)c(2)-c (3)-c (4) c(3)-c(4)-c (14)C (4)-C (5)-C (6) C(1)-C (6)-C (7)C( 6)-C (7)-C (8)C(S)-C(S)-C( 10) C( 8)-C(9)-0( 3) C(10)-C (9)-0 (3) C( 1)-C( 1O)-C(9) C( 1)-C( 10)-C( 16) C (9)-C (10)-C ( 16)c(10)-C( 11)-C( 12) c( 12)-c ( 11)-0(2)C( 12)-C( 13)-O( 3) 1.535(5)1.562 (4) 1.432(5)1.501 (6) 1.323(6) 1.318(5)1.577( 4) 1.455( 4) 1.540(5)1.219( 4) 1.419(4) 112.5(3)110.9(3)111.2 (3) 112.6(3) 110.8(3)124.5 (4) 114.2(3)124.0( 4) 110.0(3) 104.3 (3) 109.6 (3) 106.8( 2) 112.6( 3) 110.2( 3) 116.3 (3) 12 1.3 (3) 111.2(3) 1.515(5) 1.518(5) 1.527(5)1.517 (6) 1.458(5)1.506(5)1.525(5)1.512(5)1.513(5) 1.516(5) c(2)-c (1)-c(10) 116.2(3)C( 1)-C(2)-C(3) 109.3( 3) C(3)-C( 2)-O( 1) 110.O(3)c(3)-c (4)-c (5) 110.1(3)C(5)-C(4)-C( 14) 111.8(3)C( 1)-C (6)-C (5) 12 1.8 (4) C( 5)-C( 6)-C( 7) 122.1(4) c(7)-c( 8)-c (9) 123.8(4)c(8)-C (9)-c ( 15) 110.4(3)c( 10)-c (9)-c(15) 112.O( 3)C(15)-C (9)-0 (3) 110.3(3)c(l)-c(lo)-c(ll) 109.7 (3) c(9)-c (10)-c (11) 106.5 (3) C(11)-C( 10)-C( 16) 110.7(3) c( 10)-c (11)-0(2) 122.3 (3) C(11)-C( 12)-c ( 13) 109.4(3)C(9)-0 (3)-C (13) 114.4(3) a FIGURE Crystal structure of versiol, viewed along the b axis.1 Broken lines indicate hydrogen bonds.Hydrogen atoms are omitted for clarity with its b axis parallel to the C$ axis of a Rigaku off-line four- circle diffractometer. The intensities of the Bijvoet pair, h1F2,Z, and h,h,Z,, and its reference-reflection pair, h,K,Z, and h,h,Z,, were measured alternately 10 times by use of Ni- filtered Cu-K, radiation. The 6-26 scan technique was applied with a scan speed of 0.5"min-l in 8, and backgrounds were counted for 26 s at each end of the scan range. The results are also deposited in the Supplementary Publication, and clearly indicate the correct enantiomer. The prob- ability that the absolute configuration of versiol shown as (1) is wrong may be estimated by assuming t-distribution of DELA'sJ6and is calculated to be 0.01.Atomic scattering factors were taken from ref. 10. Computations were carried out on a TOSRAC 3400computer at the Tottori University Computing Centre, and on an NEAC 2200 N700 computer at the Computation Centre of Osaka University. * See Notice to Authors in J.C.S. Pevkin II,1977, Index issue. lo ' International Tables for X-Ray Crystallography,' vol. 111, Kynoch Press, Birmingham 1962, p. 202. TABLE4 Selected torsion angles (") C (6)-C (1)-C (2)-C (3) 46.1 c(2)-c (3)-c (4)-c (5) 47.6 C(4)-C (5)-C (6)-C ( 1) 11.9 C( 10)-C ( 1)-C (6)-C (7) 40.0 c(q-c(7)-C( 8)-C( 9) -4.6 c(8)-c ( 9)-c (10)-c ( 1) 50.8 0(3)-C(9)-C(lO)-C(11) 54.0 c( 10)-c ( 11)-c( 12)-c (13) 51.2 C( 12)-C( 13)-0(3)-C( 9) 60.7 C(5)-C( 6)-C( 7)-C( 8) -170.5 C( 1)-C( 2)-C( 3)-C( 4) -60.6 C (3)-C (4)-C (5)-C (6) -23.4 C (5)-C (6)-C (1)-C (2) -23.2 C( 1 )-C (6)-C (7)-C (8) -5.7 c(7)-c (8)-C (9)-C( 10) -19.7 C (9)-C ( 10)-C ( 1)-C( 6) -62.2 c(9)-c ( 10)-c ( 11)-c(1 2) -51.9 c( 11)-c( 12)-C ( 13)-0 (3) -51.7 c( 13)-0 (3)-c (9)-C( 10) -62.0 c( 7)-c (8)-c(9)-0 (3) 97.7 represented by the atomic parameters in Tables 1 and 2, if the right-handed co-ordinate system is adopted.The arrangement of molecules in the crystal and scheme of atomic numbering used in this paper are shown in Figure 1, and a stereoscopic view of the molecule plotted by a local version of PLUTO l1 in Figure 2. Bond lengths and angles are given in Table 3, selected torsion angles in Table 4, and intermolecular distances (3.8 A in Table 5.11 S. Motherwell, PLUTO, Cambridge Crystallographic File User Manual, May 1976. McGahren and his co-workers assigned the configur- ation at C(2) by application of Horeau's asymmetric synthesis, and on the basis of that assigned the con-figurations at C(1) and C(4) : these have been verified by TABLE5 Intermolecular distances 3.8 A C(2) ' * * O(2I) 3.494 0(1)* * * C(11') 3.587 O(1) ' * C(12') 3.575 O(1) * O(29 2.907 * O(2)* * * C(13I) 3.585 O(2) * -* C(151) 3.684 C(15) -* * O(lI1) 3.744 C(l) * * * C(16III) 3.711 O(3) * * * C(161'I) 3.625 C(7) * * * C(7Iv) 3.791 * Hydrogen bond. Roman numeral superscripts refer to the following transformations of the co-ordinates relative to the reference molecule at x,y,z: I -4 + x, -h -y, -2 11 1 4 x, y, z I11 x, 1 +y, 2 IV 1-xx,~+y,4-z the present analysis.They also assigned the configur- ation at the C(9) atom according to Beecham's method. They interpreted the diene system with an allylic oxygen as being of left-handed helicity, since it showed a nega- tive Cotton effect in c.d. and 0.r.d. ~pectra.~ However, the present crystallographic analysis has contradicted the spectroscopic assignment : the helical sense of C(7)-C(8)-C(9)-0(3) is right-handed (the torsion angle is 97.7" in the crystalline state). The pyranone ring adopts a chair conformation. The C(9)-C(15) bond is axial, while C(lO)-C(16) is equatorial with respect to the ring. The ring composed of atoms C(1)-(6) has a half-chair conformation; atoms C(2) and C(3) deviate by 0.39 and 0.33 A respectively on opposite sides of the plane through atoms C(1), and C(4)-(6).As predicted by spectro~copy,~ the atom H(C4) is 1,3-diaxal relative to the hydroxy-group. J.C.S. Perkin 11 An intermolecular hydrogen bond between the hydroxy-group and the carbonyl oxygen links the mole- cules into infinite chains along the a axis. The distance HO(l) * O(2) is 2.07 A, and the angles O(1)- HO(l) O(2) and HO(l) -* O(2)-C(l1) are 164 FIGURE 2 Stereoscopic view of versiol, showing the correct absolute configuration and 115". The difference between the i.r. absorption bands due to the carbonyl group for KBr (1680 cm-l) and chloroform (1700 cm-1) samples, and the band due to its acetyl derivative (1 703 cm-l) are explicable in terms of the intermolecular hydrogen bond. Other intermole- cular distances require no special comment. We thank the staff of the Institute for Protein Research of Osaka University for the use of a Rigaku computer-controlled four-circle diffractometer, and Drs. W. J . McGahren and E. L. Patterson of the Cyanamid Company for supplying crystals of LL N313C. 7/ 1740 Received, 3rd October, 19771