untitled European Journal of Chemistry 8 (3) (2017) 248‐251 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2017 Atlanta Publishing House LLC ‐ All rights reserved ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.8.3.248-251.1602 European Journal of Chemistry Journal webpage: www.eurjchem.com Synthesis and X‐ray crystallography of (1R,3aR,7aR)‐1‐((S)‐1‐((2R,5S)‐5‐(3‐ hydroxypentan‐3‐yl)tetrahydrofuran‐2‐yl)ethyl)‐7a‐methyloctahydro‐4H‐ inden‐4‐one Modou Lo 1, Andrea Martínez 2, Hugo Santalla 2, Fátima Garrido 2, Aliou Hamady Barry 3 and Mohamed Gaye 1,* 1 Department of Chemistry, University Cheikh Anta Diop, Dakar, 10700, Senegal 2 Dipartamento Química Orgínica, Facultade de Química, Universidade de Vigo, Vigo, 36310, Spain 3 Department of Chemistry, University of Nouakchott, Nouakchott, 130301, Mauritania * Corresponding author at: Department of Chemistry, University Cheikh Anta Diop, Dakar, 10700, Senegal. Tel.: +221.77.5555891. Fax: +221.33.8246318. E‐mail address: mohamedl.gaye@ucad.edu.sn (M. Gaye). ARTICLE INFORMATION ABSTRACT DOI: 10.5155/eurjchem.8.3.248-251.1602 Received: 21 June 2017 Received in revised form: 12 July 2017 Accepted: 15 July 2017 Published online: 30 September 2017 Printed: 30 September 2017   The crystal of the title compound, C21H36O3 contains an oxolane ring, and six defined stereocenters which are unambigously established by the crystallography study. A three dimensional supramolecular architecture is ensured by hydrogen bonds from the hydroxy group which is both engaged in inter (O‐H···O2) and intramolecular C‐H···O‐H) hydrogen bonds. Weak C‐H···O=C hydrogen bonds are involved also into the consolidation of the network. KEYWORDS Calcitriol Vitamin D Crystal structure NMR spectroscopy Pyridinium dichromate Heterocycle compounds Cite this: Eur. J. Chem. 2017, 8(3), 248‐251 1. Introduction Our constant interest in the chemistry of heterocyclic compounds and particularly in the synthesis of vitamin D analogues, has led us to develop several methods for the synthesis of these compounds [1,2]. We also considered their biological activities which are studied in the literature [3]. Recently, we reported the synthesis of a new vitamin D2 analogue and the evaluation of its biological activity on colon cancer [4]. In the continuation of our work on the analogues of vitamin D, we synthesized two new molecules of calcitriol from an oxolane ring and its side chains [5]. In this study, we present the structure of a new analog of calcitriol with six stereo centers. The crystal structure allowed elucidating the absolute configuration of the stereo centers. 2. Experimental 2.1. Materials and physical methods Diol and pyridinium dichromate (PDC) were purchased from Aldrich and used without further purification. The IR spectrum was recorded as KBr discs on a Bruker IFS‐66 V spectrophotometer (4000‐400 cm‐1). Mass spectrometry was carried out with a Hewlett Packard 5988A spectrometer. The 1H and 13C NMR spectra of the compound 1 were recorded in CDCl3 on a BRUKER 500 MHz spectrometer at room tempera‐ ture using TMS as internal reference. 2.2. Crystal structure determination Crystallographic data were collected at room temperature using a Bruker Smart 6000 CCD detector and Cu‐Kα radiation ( = 1.54178 Å) generated by a Incoatec microfocus sour‐ ce equipped with Incoatec Quazar MX optics. The software APEX3 [6] was used for collecting frames of data, indexing reflections and the determination of lattice parameters, SAINT [6] for integration of intensity of reflections, and SADABS [6] for scaling and empirical absorption correction. The structure was solved by dual‐space methods using the program SHELXT [7]. Lo et al. / European Journal of Chemistry 8 (3) (2017) 248‐251 249 Scheme 1 Figure 1. Crystal structure of the compound 1. All non‐hydrogen atoms were refined with anisotropic thermal parameters by full‐matrix least‐squares calculations on F2 using the program SHELXL [8]. Hydrogen atoms were inserted at calculated positions and constrained with isotropic thermal parameters except for the hydrogen atom of the hydroxyl group. Drawings were produced with PLATON [9]. 2.3. Synthesis of compound 1 To a solution of diol (2) (0.18 mmol) in CH2Cl2 (5 mL), pyridinium dichromate (PDC) (0.37 mmol) was added and the mixture stirred at room temperature for 12 h, then the solvent was evaporated and the residue was chromatographed on sılica gel using (10%, EtOAc:hexane, v:v) to afford ketone (1) (Scheme 1). The title compound was recrystallized using a mixture of hexane:ethyl ether (1:1, v:v). (1R, 3aR, 7aR)‐1‐((S)‐1‐((2R, 5S)‐5‐(3‐hydroxypentan‐3‐ yl)tetrahydrofuran‐2‐yl)ethyl)‐7a‐methyloctahydro‐4H‐inden‐ 4‐one (1): Color: White solid. M.p: 80‐82 °C. Yield: 88%. Rf: 0.42 (30%, EtOAc:hexane, v:v). [α]D19 = +26.27 (c 1.0, CDCl3). 1H NMR (250 MHz, CDCl3, δ, ppm): 3.99 (1H, td, J = 10.1, 5 Hz, H‐ 5'), 3.81 (1H, dd, J = 9.8, 5.7 Hz, H‐2'), 2.42 (1H, dd, J = 11.2, 7.4 Hz, H‐3a), 2.37‐1.70 (12H, m, 6 x CH2) , 1.69‐1.24 (9H, m, 3 x CH2 + H‐1 + H‐1' + HO), 0.93 (3H, d, J = 6.7 Hz, CH3‐21), 0.87 (6H, td, J = 7.5, 5.3 Hz, CH3‐Et ), 0.66 (3H, s, CH3‐18). 13C NMR (62.5 MHz, CDCl3, δ, ppm): 211.91 (C=O), 83.49 (CH‐2'), 81.78 (CH‐5'), 74.76 (C‐3''), 61.43 (CH‐14), 54.23 (CH‐17), 50.30 (CH‐13), 41.02 (CH2), 38.94 (CH2), 38.93 (CH‐20), 28.79 (CH2), 26.91 (CH2), 26.35 (CH2), 25.92 (CH2), 25.89 (CH2), 24.05 (CH2), 19.26 (CH2), 12.69 (CH3‐21), 12.50 (CH3‐18), 7.99 (CH3‐ Et), 7.60 (CH3‐Et). IR (NaCl, ν, cm‐1): 3491, 3361, 2964, 2879, 2347, 1713, 1460, 1381, 1245, 1145, 958, 890, 755. MS (ESI+) (m/z, (%)): 359.25 ((M+Na)+, 47), 319.26 ((M‐OH)+, 100). HRMS (ESI+): Calculated for C21H36NaO3, 359.25567 g/mol; Found: 359.25562 g/mol. 3. Results and discussion The compound 1 was prepared by a facile oxidation of compound 2 with pyridinium dichromate in dichloromethane (Scheme 1). Suitable X‐ray crystals diffraction was obtained after recrystallization of compound 1 in a mixture of hexane:ethyl ether (1:1, v:v). The afforded compound is soluble in common organic solvent such as chloroform. The mass spectrum of the compound 1 present a peak at 359.25562 amu corresponding to the molecular ion of [1+Na]+. The infrared spectrum of the compound shows absorption band pointed at 1713 cm‐1 which is assigned to the ν(C=O) vibration confirming the oxidation of the secondary alcohol function of compound 2. In addition the 13C NMR spectrum recorded in deuterated chloroform shows a characteristic signal at δ 211.91 ppm which is assigned to the C=O. The molecular structure of the title compound is shown in Figure 1. Crystallographic data, selected bond lengths and angles, hydrogen‐bond geometry and atomic displacement parameters are listed respectively in Table 1‐4. The compound crystallizes in the non‐centrosymmetric space group P21 and the absolute structure was unambiguously established. The molecule contains a cyclopentane ring trans‐fused to a cyclohexanone ring. The lateral chain contains an oxolane ring. The cyclohexanone ring adopts a chair conformation. The cyclopentane ring is an envelope (Flap atom = C5) and the tetrahydrofuran ring is twisted about C13‐O2. The configure‐ tions of the stereogenic centres are C5(R), C6(R), C9(R), C11(S), C13(R) and C16(R). There is an intramolecular O‐H···O hydrogen bond involving the hydroxyl group (O3‐H3) and an oxolane O atom (O2), generating an S(5) ring motif (Figure 1 and Table 4). The bond lengths and angles are normal and comparable to those observed in compounds containing the bicyclic moiety fragment (1S,3aR,7aR)‐1‐ethyl‐7a‐methyl‐ octahydroinden‐4‐one); specially in our recent work [10], which concerns an isomer of the title compound, adopting a very similar crystal structure. In the crystal, weak C2‐H2B···O1=C hydrogen bonds (Table 4, Figure 2) link the molecules into C(4) chains, which propagate parallel to [101]. The chains are linked through extremely weak hydrogen bonds. Comparison of the crystal structure with that of the recent isomer we reported [10], shows that the two isomers adopt similar supramolecular architecture: hydrogen bonds linking molecules into chains, which propagate parallel to [101]. In both structures, the chains are linked by very weak H bonds. 250 Lo et al. / European Journal of Chemistry 8 (3) (2017) 248‐251 Table 1. Crystal data and structure refinement for compound 1. Empirical formula C21H36O3 Formula weight 336.50 Temperature (K) 296(2) Crystal shape / color Block/Colorless Crystal system Monoclinic Space group P21 a (Å) 12.4156(19) b (Å) 6.3672(6) c (Å) 12.7186(12) α (°) 90 β (°) 90.509(5) γ (°) 90 Volume (Å3) 1005.4(2) Z 2 ρcalc (g/cm3) 1.112 μ (mm‐1) 0.562 F(000) 372.0 Crystal size (mm3) 0.111 × 0.107 × 0.053 Radiation CuKα (λ = 1.54178) 2Θ range for data collection (°) 6.95 to 143.848 Index ranges ‐15 ≤ h ≤ 15, ‐7 ≤ k ≤ 7, ‐15 ≤ l ≤ 15 Reflections collected 12352 Independent reflections 3777 [Rint = 0.0296, Rsigma = 0.0278] Data/restraints/parameters 3777/1/221 Goodness‐of‐fit on F2 1.065 Final R indexes [I≥2σ (I)] R1 = 0.0370, wR2 = 0.1009 Final R indexes [all data] R1 = 0.0384, wR2 = 0.1039 Largest diff. peak/hole (e Å‐3) 0.18/‐0.13 Table 2. Bond lengths for compound 1. Atom Atom Length (Å) Atom Atom Length (Å) O1 C1 1.213(3) C7 C8 1.542(3) O2 C16 1.437(2) C8 C9 1.551(3) O2 C13 1.447(3) C9 C11 1.538(3) O3 C17 1.431(3) C11 C12 1.522(4) C1 C6 1.501(3) C11 C13 1.540(3) C1 C2 1.504(3) C13 C14 1.528(3) C2 C3 1.519(4) C14 C15 1.525(3) C3 C4 1.531(3) C15 C16 1.519(3) C4 C5 1.532(3) C16 C17 1.529(3) C5 C10 1.539(3) C17 C20 1.528(3) C5 C9 1.551(3) C17 C18 1.531(3) C5 C6 1.553(3) C18 C19 1.506(4) C6 C7 1.514(3) C20 C21 1.522(4) Table 3. Bond angles for compound 1. Atom Atom Atom Angle (°) Atom Atom Atom Angle (°) C16 O2 C13 109.87(16) C5 C9 C8 103.55(16) O1 C1 C6 123.5(2) C12 C11 C9 114.17(19) O1 C1 C2 123.2(2) C12 C11 C13 111.22(18) C6 C1 C2 113.3(2) C9 C11 C13 109.33(17) C1 C2 C3 113.63(19) O2 C13 C14 105.57(17) C2 C3 C4 113.8(2) O2 C13 C11 110.18(18) C3 C4 C5 111.88(19) C14 C13 C11 116.21(18) C4 C5 C10 110.61(19) C15 C14 C13 102.53(19) C4 C5 C9 117.21(17) C16 C15 C14 101.03(18) C10 C5 C9 111.04(17) O2 C16 C15 104.17(17) C4 C5 C6 106.79(17) O2 C16 C17 107.87(16) C10 C5 C6 111.02(18) C15 C16 C17 118.20(19) C9 C5 C6 99.50(15) O3 C17 C20 106.00(18) C1 C6 C7 119.95(19) O3 C17 C16 109.04(17) C1 C6 C5 111.81(17) C20 C17 C16 109.75(19) C7 C6 C5 105.13(17) O3 C17 C18 108.45(18) C6 C7 C8 103.97(17) C20 C17 C18 112.73(19) C7 C8 C9 107.11(16) C16 C17 C18 110.69(18) C11 C9 C5 119.18(17) C19 C18 C17 116.4(2) C11 C9 C8 112.71(17) C21 C20 C17 114.7(2) The title isomer is characterized by the presence of an intramolecular hydrogen bond and the molecules in the chains are linked by weak H bonds. On the contrary, in the previously reported isomer, there is no intramolecular H bond and the molecules in the chains are strongly linked. It should be mentioned that the crystal structure change between the two isomers affected mainly the unit cell lattice, but not the crystal system (monoclinic), nor the space group symmetry (P21). Indeed, the unit cell volume expands from the precedent isomer to the title isomer (979.3 to 1005.3 Å3). This expansion resulted from contraction in the c parameter and the increase of the a parameter, so that the c/a ratio and the β angle decreased from 1.8° to 1.0° and 104.2 to 90.5 °, respectively. The b parameter remains almost unchanged. 4. Conclusion The titled compound having an oxolane moiety in his side chain was synthesized successfully and its structure has been determined by X‐ray single crystallography. One of his stereo‐ isomer was previously synthetized and reported by our group. Lo et al. / European Journal of Chemistry 8 (3) (2017) 248‐251 251 Table 4. Anisotropic displacement parameters (Å2×103) for compound 1. The Anisotropic displacement factor exponent takes the form: ‐2π2[h2a*2U11+2hka*b*U12+…]. Atom U11 U22 U33 U23 U13 U12 O1 84.8(11) 73.9(11) 58.6(9) 5.9(8) 7.4(8) ‐0.2(9) O2 79.6(10) 49.9(8) 55.5(8) 10.5(7) 15.0(7) 10.9(7) O3 54.1(8) 99.9(14) 69.2(9) ‐1.4(10) ‐7.4(7) ‐4.6(9) C1 64.2(12) 50.8(12) 60.3(12) ‐0.1(10) 10.6(10) 2.5(9) C2 55.6(12) 72.6(15) 80.1(15) 2.6(13) 14.0(11) ‐3.9(11) C3 51.9(12) 77.9(16) 90.0(17) ‐3.0(14) 3.0(11) ‐13.8(12) C4 53.3(11) 69.7(14) 65.3(12) ‐1.8(11) ‐4.6(9) ‐7.1(11) C5 47.8(10) 46.6(10) 53.4(10) 1.5(9) 0.0(8) ‐1.7(9) C6 51.2(10) 51.5(11) 55.2(11) ‐0.5(9) 2.6(8) ‐1.2(9) C7 55.7(12) 91.1(18) 54.4(11) ‐8.7(12) 0.9(9) ‐8.4(12) C8 49.1(10) 72.7(14) 58.0(11) ‐1.3(11) 1.9(8) ‐6.4(10) C9 49.4(10) 43.7(10) 51.7(10) 1.9(8) 0.3(8) ‐1.2(8) C10 75.8(15) 50.5(12) 72.4(14) 6.3(10) 10.3(12) 2.8(11) C11 61.9(12) 45.8(10) 54.2(10) 1.6(9) 6.5(9) ‐1.7(9) C12 87.3(17) 81.1(18) 61.6(13) ‐13.9(13) 5.7(12) ‐24.3(14) C13 58.9(11) 53.9(12) 52.3(10) 2.6(10) 5.4(9) 1.4(9) C14 68.5(13) 47.4(11) 65.8(13) ‐4.0(9) 6.2(11) ‐2.6(10) C15 74.0(14) 47.5(11) 62.8(12) 4.5(10) 4.6(10) ‐6.5(10) C16 55(1) 45.3(10) 55.5(10) 7.5(8) ‐1.9(8) ‐1.2(8) C17 50.7(10) 52.7(11) 53.2(10) 5.7(9) ‐2.6(8) ‐4.3(9) C18 63.8(12) 52.2(11) 63.2(12) 6.4(10) 8(1) 2.4(10) C19 81.3(17) 70.5(16) 92.6(19) ‐22.7(15) ‐2.2(14) ‐9.7(14) C20 82.4(16) 56.4(13) 64.6(13) 10.5(11) 5.7(12) ‐12.0(12) C21 116(2) 91(2) 71.2(16) 7.6(16) 25.6(16) ‐26.4(19) Table 5. Hydrogen bonds for compound 1. D H A d(D‐H) (Å) d(H‐A) (Å) d(D‐A) (Å) D‐H‐A (°) O3 H3 O2 0.82 2.34 2.766(2) 112.6 C2 H2B O11 0.97 2.55 3.267(4) 130.7 1 1‐x, ‐1/2+y, ‐z. Figure 2. Three dimensional network of compound 1. In future, the biological activities of these two calcitriol analogues will be studied. Acknowledgements The authors thank the University of Vigo (Spain) and the Sonatel Fondation for his financial support. Supplementary material Crystallographic data for the structure reported in this article have been deposited with Cambridge Crystallographic Data Center, CCDC‐1555293. The data can be obtained free of charge at http://www.ccdc.cam.ac.uk/const/retrieving.html or from the Cambridge Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223‐ 336033 or e‐mail: deposit@ccdc.cam.ac.uk. References [1]. Fernandez, C.; Santalla, H.; Garrido, F.; Gomez, G.; Fall, Y. Tetrahedron Lett. 2016, 57, 2790‐2792. [2]. 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