crystal structure of de-oxy corticosterone-21-hemisuccinate

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Journal of Chemical Crystallography, Vol. 29, No. 12, 1999 Structure of de-oxy corticosterone-21-hemisuccinate Raja Dey, (1) Sandhya Roychowdhury, (2) P. Roychowdhury (1) * Received November 10, 1999 Synthetic glucocorticoid de-oxy corticosterone-21-hemisuccinate crystallizes in the monoclinic space group C2, with a 21.896(2), b 7.596(3) and c 14.291(3) Å, Z 4. Ring A is a distorted half chair, ring B and C are in the chair configuration and ring D is in the 14 -half chair configuration. The ring junctions B/C and C/D are both trans. The molecule as a whole is slightly convex towards the -side, with an angle of 18.4(2) between the C(10)UC(19) and C(13)UC(18) vectors. In addition to packing and stacking interaction, intermolecular hydrogen bonding plays an important role in structural association. The X- ray structure determination of the title compound was undertaken to study its high binding affinity to serum protein like globulin. KEY WORDS: Crystal structure; corticosteroid; de-oxy corticosterone-21-hemisuccinate. Introduction Steroid antibodies can be produced by immunizing animals with steroid-protein conjugate. 1 We have undertaken the X-ray analysis of a series of corticosteroids to resolve their structures in 3D and use the structural information to suggest an ideal steroidprotein complex by computer modelling methods. In this paper we have confined our discussion to the crystal structure of de-oxy corticosterone-21-hemisuccinate with the view to understanding the chemical coupling of the steroid to protein. The substitution O3 on this steroid nucleus unquestionably contributes to its biological properties. The 3-one A-ring of this corticoid is the area of greatest conformational flexibility, which facilitates its highly specific interaction with globulin protein. 2 Experimental The compound de-oxy corticosterone-21-hemisuccinate (C 25 H 34 O 6 ) crystallizes from ethanol in the (1) X-ray laboratory, Department of Physics, University College of Science, Technology and Agriculture, University of Calcutta, 92 A.P.C. Road, Calcutta 700009. (2) X-ray laboratory, Department of Physics, Presidency College, Calcutta 700073. * To whom correspondence should be addressed. monoclinic space group C2. The crystals are colorless and transparent and are quite stable at room temperature. The crystal parameters are given in Table 1. The structure was solved by direct methods using SHELX-86. 3 All non hydrogen atoms were refined anisotropically using 2161 reflections by full-matrix least-squares method (F 2 ) using SHELX-93. 4 All the hydrogen atoms were generated and allowed to ride with the associated non-hydrogen atoms. The geometrical parameters of the molecule were calculated by PARST-93. 5 Results and discussion The title compound is represented by a schematic diagram (Fig. 1(a)). The asymmetric carbon atoms are indicated by asterisk. The PLUTO plot (Fig. 1(b)) gives a view of the entire molecule (including hydrogen atoms) in perspective. Ring A is a distorted half chair. 6 Rings B and C are both in the chair configuration and the five member ring D is in the 14 -half chair conformation. 6 The 3D stereo OR- TEP 7 of the molecule is shown in Fig. 2. The endocyclic torsion angles C7UC8UC9U C10 and C14UC8UC9UC11 about the ring junction B/C are respectively 53.7(3) and 55.6(3), whereas the endocyclic torsion angles C12UC13UC14UC8 1265 1074-1542/99/1200-1265$16.00/0 1999 Plenum Publishing Corporation

1266 Dey, Roychowdhury, and Roychowdhury Table 1. Crystal Data and Structure Refinement Parameters Compound De-oxy corticosterone-21- hemisuccinate CCDC deposit no. CCDC-1003/5711 Color/shape colorless/needle shape Chemical formula C 25 H 34 O 6 Formula weight 430.52 Temperature, K 293(2) Crystal system Monoclinic Space group C2 Unit cell dimensions a 21.896(2) Å 90.00 (2224 reflections in b 7.596(3) Å 105.94 full range) c 14.291(3) Å 90.00 Volume, Å 3 2285.5(11) Z 4 Density (calculated), mg/m 3 1.251 Absorption coefficient, mm 1 0.088 Diffractometer/scan CAD4/ -2 range for data collection, deg 2.09 to 24.99 Reflections measured 2224 Independent/observed reflections 2161 [R(int) 0.0128] Data/restraints/parameters 2161/1/283 Extinction Coefficient none Absolute Structure Parameter 2(2) Goodness-of-fit on F 2 1.067 Final R indices [I 2 (I)] R1 0.0447, wr2 0.1090 R indices (all data) R1 0.0575, wr2 0.1160 from head to tail is determined by the pseudo torsion angle C(19)UC(10) C(13)UC(18). This torsion angle was found to be 8.4(3), which implies that the tail of the molecule is twisted clockwise by that amount. The molecule is slightly convex towards the -side with an angle of 18.4(2) between the vectors C(10)UC(19) and C(13)UC(18). Final fractional coordinates with equivalent thermal parameters are given in Tables 2 and 3. The esd s for the bond lengths and angles lie within the range 0.004 Å to 0.007 Å and 0.2 to 0.5, respectively. The torsion angle C13UC17UC20UO20 of 118.5(4) suggests that the oxygen O20 is in the anticlinal position with respect to C13 whereas the torsion angle O20UC20UC21UO21 of 7.6(6) implies that the conformation of O21 relative to O20 is assigned by the qualitative descriptor synperiplanar. 9 The geometry of the side chain at C(17) of the title compound is compared with six other corticosteroid structures. This comparison is shown clearly in Table 4 and in the Newman projection shown in Fig. 3. The side chain conformation seen in the Newman projection down the C(17)UC(20) bond, agrees qualitatively in all cases with the conformation assigned by Wellman and Djerassi 10 on the basis of and C17UC13UC14UC15 about the ring junction C/D are respectively 59.1(3) and 47.2(3). These conformations imply that the ring junctions B/C and C/D are both trans. 8 The twist of the molecule about its length seen Fig. 1(A). A schematic diagram of de-oxy corticosterone-21-hemisuccinate. Fig. 1(B). A perspective view of de-oxy corticosterone-21-hemisuccinate.

De-oxy corticosterone-21-hemisuccinate 1267 Table 2. Atomic Coordinates ( 10 4 ) and Equivalent Isotropic Displacement Parameters (Å 2 10 3 ) x y z U(eq) a Fig. 2. A stereo ORTEP plot of de-oxy corticosterone-21- hemisuccinate. the optical rotatory dispersion and circular dichroism measurements. The exact orientations of the side chains in deoxy corticosterone-21-hemisuccinate and 6 -fluorocortisol are somewhat different from what is observed in all the other five structures. The torsion angles for de-oxy corticosterone-21-hemisuccinate differ by about 28, whereas those for 6 -fluorocortisol differ by about 10 from the other five, which agree fairly well. This conformational difference is probably because O(20) serves as an acceptor in a hydrogen bond in the two disagreed structures. The change in sidechain orientation in these two structures also induces the D ring to adopt a half-chair conformation although the D ring has a -envelope conformation in the other five structures. The crystal structure appears to have stabilized through hydrogen bonding and stacking interactions. The PLUTO 11 packing showing the stacking of the title compound (in an extended environment) is given in Fig. 4(a) and (b). The hydrogen bonding network is shown in this figure by broken lines. Molecules are connected by means of intermolecular hydrogen bonds formed between the hydroxyl groups at C25 C(1) 3562(2) 375(6) 3507(3) 63(1) C(2) 4281(2) 413(7) 3951(3) 72(1) C(3) 4568(1) 2097(7) 3744(4) 62(1) C(4) 4161(2) 3638(6) 3633(2) 56(1) C(5) 3560(1) 3611(5) 3676(2) 43(1) C(6) 3204(2) 5293(5) 3661(3) 64(1) C(7) 2544(2) 5239(5) 2943(3) 55(1) C(8) 2161(1) 3676(5) 3129(2) 37(1) C(9) 2524(1) 1967(5) 3101(2) 37(1) C(10) 3214(1) 1933(5) 3791(2) 40(1) C(11) 2128(2) 381(5) 3246(3) 54(1) C(12) 1467(2) 320(5) 2513(3) 55(1) C(13) 1105(1) 2028(5) 2529(2) 41(1) C(14) 1519(1) 3558(5) 2367(2) 40(1) C(15) 1073(2) 5141(6) 2176(3) 58(1) C(16) 436(2) 4357(6) 1598(3) 70(1) C(17) 514(1) 2344(5) 1640(2) 51(1) C(18) 900(1) 2195(7) 3470(2) 59(1) C(19) 3214(2) 1800(7) 4865(2) 63(1) C(20) 86(2) 1355(7) 1625(3) 63(1) C(21) 57(2) 635(7) 1619(3) 67(1) C(22) 1034(1) 1574(6) 585(2) 54(1) C(23) 1671(2) 2271(6) 563(3) 62(1) C(24) 2124(2) 2251(7) 438(3) 71(1) C(25) 2800(2) 2470(6) 461(2) 58(1) O(3) 5115(1) 2173(6) 3694(2) 90(1) O(20) 573(1) 2108(7) 1628(3) 105(1) O(21) 672(1) 1395(5) 1490(2) 77(1) O(22) 856(1) 1203(7) 98(2) 98(1) O(25A) 2990(1) 2567(10) 210(2) 147(2) O(25B) 3177(1) 2585(7) 1339(2) 93(1) a U(eq) is defined as one third of the trace of the orthogonalized U ij tensor. and the oxygen of the keto group involving C20, the hydroxyl group being the donor and the keto oxygen the acceptor, O25B O20 I 2.665(3), O25BU H25B 0.82(3), O20 I H25B 1.90(2), O25BU H O20 I 156(2), where I stands for the symmetry operator x 0.5, y 0.5, z. Table 3. Hydrogen Coordinates ( 10 4 ) and Isotropic Displacement Parameters (Å 2 10 3 ) x y z U(eq) H(1A) 3474(2) 346(6) 2804(3) 76 H(1B) 3396(2) 702(6) 3708(3) 76 H(2A) 4375(2) 255(7) 4650(3) 86 H(2B) 4471(2) 559(7) 3691(3) 86 H(4) 4331(2) 4716(6) 3524(2) 68 H(6A) 3444(2) 6251(5) 3486(3) 77 H(6B) 3162(2) 5527(5) 4308(3) 77 H(7A) 2319(2) 6319(5) 2998(3) 66 H(7B) 2585(2) 5170(5) 2285(3) 66 H(8) 2090(1) 3802(5) 3774(2) 44

1268 Dey, Roychowdhury, and Roychowdhury Table 3. (Continued) x y z U(eq) H(9) 2566(1) 1869(5) 2437(2) 44 H(11A) 2079(2) 419(5) 3900(3) 64 H(11B) 2356(2) 690(5) 3186(3) 64 H(12A) 1512(2) 128(5) 1864(3) 66 H(12B) 1228(2) 657(5) 2670(3) 66 H(14) 1614(1) 3312(5) 1749(2) 48 H(15A) 1217(2) 6033(6) 1800(3) 70 H(15B) 1040(2) 5657(6) 2782(3) 70 H(16A) 328(2) 4762(6) 929(3) 84 H(16B) 101(2) 4710(6) 1883(3) 84 H(17) 636(1) 1992(5) 1056(2) 61 H(18A) 640(12) 3224(23) 3435(10) 88 H(18B) 1269(2) 2294(42) 4016(3) 88 H(18C) 662(13) 1170(20) 3548(12) 88 H(19A) 2955(13) 2723(26) 5013(7) 95 H(19B) 3640(2) 1913(44) 5274(2) 95 H(19C) 3045(14) 678(18) 4979(6) 95 H(21A) 116(2) 1021(7) 1097(3) 80 H(21B) 225(2) 1042(7) 2229(3) 80 H(23A) 1847(2) 1572(6) 995(3) 74 H(23B) 1626(2) 3470(6) 806(3) 74 H(24A) 2077(2) 1144(7) 749(3) 85 H(24B) 2008(2) 3187(7) 818(3) 85 H(25B) 3528(11) 2923(103) 1315(4) 140 Table 4. Torsion angles O(20)UC(20)UC(21)UO(21) in the Corticosteroid Structures Structure O(20)UC(20)UC(21)UO(21) De-oxy corticosterone-21-7.6 Hemisuccinate 6 -Fluorocortisol 12 6.7 Cortisol 13 10.6 9 -Fluorocortisol 14 15 2.1 6 -Methylprednisolone 16a 8.8 Cortisone 16b 0.6 4-Chlorocortisone 17 8.8 Fig. 3. Torsion angles about C(17)UC(20) bond in the corticosteroid structures Fig. 4. A PLUTO packing of de-oxy corticosterone-21-hemisuccinate showing the stacking and hydrogen bonding network (indicated by broken lines) in an extended environment. (a) with packing range a 0 to 1.5, b 1 to 2.5 and c 0 to 0.5. (b) with packing range a 0.5 to 1, b 1.5 to 2, and c 0.5 to 1. References 1. King, R.J.B. Steroid-Cell Interaction; Butterworth: London, 1974; pp 383 384. 2. Roberts, P.J.; Coppola, J.C.; Isaacs, N.W.; Kennard, O. J.C.S. Parkin II 1973, pp 774 781. 3. Sheldrick, G.M. SHELX86, Program for Crystal Structure Solution; University of Gottingen: Germany, 1990. 4. Sheldrick, G.M. SHELX93, Program for Crystal Structure Determination; University of Cambridge: England, 1993. 5. Nardelli, M. J. Comput. Chem. 1983, 7, 95 98. 6. Cremer, D.; Pople, J.A. Contribution from the Department of Chemistry, Carnegie-Mellon University, Pittsburgh, Pennsylvania 15213. Received May 20, 1974. 7. Johnson, C.K. ORTEP II. Report ORNL-5138; Oak Ridge National Laboratory: TN, 1976. 8. Bucourt, R. In Topics in Stereochemistry, Vol. 8; Eliel, E.L.; Allinger, N.L., Eds.; Interscience.: New York, 1974; p 159. 9. Klyne, W.; Prelog, V. Experientia. 1960, 16, 152. 10. Wellman, K.M.; Djerassi, C. J. Amer. Chem. Soc. 1965, 87, 60. 11. Motherwell, W.D.S. PLUTO, Program for Plotting Molecular and Crystal Structures; University of Cambridge: England, 1992.

De-oxy corticosterone-21-hemisuccinate 1269 12. Weeks, C.M.; Duax, W.L.; Wolff, M.E. J. Amer. Chem. Soc. 1973, 95, 9. 13. Roberts, P. University Chemical Laboratory, Cambridge, England, Private communication. 14. Weeks, C.M.; Duax, W.L. American Crystallography Association Meeting, Albuquerque, N.M., 1972, Abstract M5. 15. Dupout, L.; Dideberg, O.; Campsteyn, H. Cryst. Struct. Commun. 1972, 1, 177. 16(a). Declercq, J.P.; Germain, G.; Van Meerssche, M. ibid. 1972, 1, 5.; (b) ibid. 1972, 1, 13. 17. Duax, W.L.; Cooper, A.; Norton, D.A. Acta Crystallogr. Sect. B. 1971, 27, 1.

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