Indole type akuammiline from Vinca erecta: Crystal structure of 10-OAc-Akuammine European Journal of Chemistry 10 (4) (2019) 345-349 European Journal of Chemistry View Journal Online View Article Online Indole type akuammiline from Vinca erecta: Crystal structure of 10-OAc-Akuammine Shahobiddin Adizov 1,* and Bakhodir Tashkhodjaev 2 1 Laboratory of High-Molecular Plant Substances and Physical Methods of Research, Institute of the Chemistry of Plant Substances, Academy of Sciences, 100170, Tashkent, Uzbekistan adizovsh@gmail.com (S.A.) 2 Physical Methods of Research, Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Tashkent 100170, Uzbekistan tashkhodjaev@rambler.ru (B.T.) * Corresponding author at: Laboratory of High-Molecular Plant Substances and Physical Methods of Research, Institute of the Chemistry of Plant Substances, Academy of Sciences, 100170, Tashkent, Uzbekistan. Tel: +998.71.2625913 Fax: +998.71.2627348 e-mail: adizovsh@gmail.com (Sh. Adizov). 10.5155/eurjchem.10.4.345-349.1898 Received: 24 May 2019 Received in revised form: 21 August 2019 Accepted: 24 August 2019 Published online: 31 December 2019 Printed: 31 December 2019 Single crystal X-ray diffraction has established the absolute configuration of the indole alkaloids from Vinca erecta such as akuammiline-o-acyl derivative of akuammine with a 3D stable polycyclic framework. Crystal data for C24H28N2O5: orthorhombic, space group P212121 (no. 19), a = 7.349(3) Å, b = 16.099(5) Å, c = 17.323(5) Å, V = 2049.5(12) Å3, Z = 4, T = 293(2) K, μ(CuKα) = 0.789 mm-1, Dcalc = 1.376 g/cm3, 1742 reflections measured (7.496° ≤ 2Θ ≤ 119.792°), 1742 unique (Rsigma = 0.0374) which were used in all calculations. The final R1 was 0.0608 (I > 2σ(I)) and wR2 was 0.1680 (all data). The polycyclic framework of the well-known picrinine and akuammine is compared. The ether bridges located in different positions of the framework and forming five-membered cycles do not change the conformation of the polycyclic akuammiline framework. In V. erecta alkaloids, the exomethylene fragment (C18-C19=C20-C21) of the polycyclic backbone always takes on the E-condition. Chirality Akuammine Akuammiline Indole alkaloids Absolute configuration Single crystal structure Cite this: Eur. J. Chem. 2019, 10(4), 345-349 Journal website: www.eurjchem.com 1. Introduction Vinca erecta Rgl. et Schmalh. (fam. Apocynaceae) perennial herb spread in the mountainous and foothill regions of Central Asia [1,2], and this plant contains a large number of indole alkaloids [3,4]. Plant alkaloids are biologically active substan- ces and are used in medicine as important medicines [5]. The handbook [4] notes the isolation from V. erecta of five indoline alkaloids such as akuammiline (according to the systematics of Lee Men [6]): picrinine (1) [7,8], vincaricine (2) [9,10], vinkarinine (3) [11], akuammine (4) [12], 10-o- methylakuammine (5) [13], which differs in the location of the ether bridge in the akuammiline skeleton (Figure 1). Essential oxygen atoms in the case of 1-3 bind the atoms of the polycyclic framework C2 and C5, and in the case of 4,5-C2 and C22. In compound 1 and 2, the carbon atom C22 is absent, but the polycyclic skeleton of akuammiline is preserved. In order to compare the conformations of the akuammiline polycyclic skeleton and unambiguously determine the abso- lute configuration (the values of R and S chirality descriptors), X-ray structural analysis (XRD) of the indoline alkaloid 10- OAc-akuammine molecule (6) was carried out. Compound 6 is formed by processing the amount of alkaloids with 5% acetic acid in the process of isolating them from the plant. 2. Experimental 2.1. Materials and apparatus Plants of V. erecta were grown in natural conditions in the mountain of Piskent, Tashkent region, Uzbekistan. Dried material was powdered and kept in a desiccator at room temperature, in the dark, until the analysis. Compound 6 is formed as a result of processing the amount of alkaloids with 5% acetic acid in the process of isolating them from the plant, V. erecta. Single-crystal X-ray diffraction data were collected on a STOE Stadi-4 four-circle diffractometer using CuKα- radiation (λ = 1.54184 Å) (T =293 K, θ/2θ-scan) equipped with a graphite monochromator. ABSTRACT RESEARCH ARTICLE KEYWORDS European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2019 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. http://dx.doi.org/10.5155/eurjchem.10.4.345-349.1898 http://dx.doi.org/10.5155/eurjchem.10.4.345-349.1898 https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.10.4.345-349.1898&domain=pdf&date_stamp=2019-12-31 http://www.eurjchem.com/ http://dx.doi.org/10.5155/eurjchem.10.4.345-349.1898 mailto:adizovsh@gmail.com mailto:tashkhodjaev@rambler.ru mailto:adizovsh@gmail.com http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.10.4.345-349.1898&domain=pdf&date_stamp=2019-12-31� 346 Adizov and Tashkhodjaev / European Journal of Chemistry 10 (4) (2019) 345-349 Table 1. Crystal data and details of the structure refinement for compound 6. Parameters Compound 6 Empirical formula С24Н28N2О5 Formula weight 423.47 Temperature (K) 293.15 Crystal system Orthorhombic Space group P212121 a, (Å) 7.349(3) b, (Å) 16.099(5) c, (Å) 17.323(5) Volume (Å3) 2049.5(12) Z 4 ρcalc (g/cm3) 1.376 μ (mm1) 0.789 F(000) 904.0 Crystal size (mm3) 0.2 × 0.3 × 0.7 Radiation CuKα (λ = 1.54184) 2Θ range for data collection (°) 5.1 to 119.8 Index ranges 0 ≤ h ≤ 8, 0 ≤ k ≤ 18, 0 ≤ l ≤ 19 Reflections collected 1742 Independent reflections 1403 [Rint = 0.00, Rsigma = 0.0374] Data/restraints/parameters 1742/0/282 Goodness-of-fit on F2 1.130 Final R indexes [I≥2σ (I)] R1 = 0.0608, wR2 = 0.1438 Final R indexes [all data] R1 = 0.0841, wR2 = 0.1690 Largest diff. peak/hole (e.Å-3) 0.194/-0.304 Flack parameter 0.3(8) N N COOCH3 H O 1 2 16 3 5 21 15 Picrinine (Vincaridine) (1) 2S,3S,5S,7R,15S,16S N N COOCH3 H OH3CO H 1 2 16 3 5 21 15A B C D E Vincaricine (2) 2S,3S,5S,7R,15S,16S N N COOCH3 OH3CO C O H 1 2 16 3 5 21 15 H Vincarinine (3) 2S,3S,5S,7S,15S,16R Akuammine (4) 2R,3S,7S,15S,16S 10-ОMe akuammine (5) 2R,3S,7S,15S,16S 10- ОAc-akuammine (6) 2R,3S,7S,15S,16S Figure 1. The structure of akuammine alkaloids from Vinca erecta. 2.2. X-ray crystal structure determination of compound 6 Single-crystal X-ray diffraction experiment of compound 6 was performed on a STOE Stadi-4 four-circle diffractometer using CuKα-radiation. The unit cell parameters of the crystal were determined and refined on this diffractometer. The crystals possessed rhombic space group P212121, Z = 4. A three-dimensional set of reflections for crystal was obtained on this diffractometer. Table 1 shows the main parameters of X-ray diffraction experiments and calculations of the refinement of the crystal structure of compound 6. The structural parameters including bond distances and bond angles for compound 6 are listed in Table 2. The structure was deciphered by direct methods within the SHELXS-97 program [14], calculations to refine the struc- ture were performed using the SHELXL-2014/7 program [15]. All non-hydrogen atoms were refined by the least squares method (F2) in the full-matrix anisotropic approximation. Hydrogen atoms at carbon atoms are set geometrically and refined according to the rider’s scheme with fixed isotropic displacement parameters Uiso=nUeq, where n = 1.5 for methyl groups and 1.2 for the others (Ueq is the equivalent isotropic parameter for the displacement of the corresponding carbon atoms). 3. Results and discussion 3.1. Crystal structure of compounds 6 Indoline alkaloids 1, 2, and 3 are of the type of the skeleton of akuammiline. Alkaloid 2 differs from compound 1 by the presence of the 10-exo OCH3-group in the position, and in compound 3 the aldehyde CHO-group is added to the position C16. The spatial structure of compound 1 was previously defined by the single crystal X-ray diffraction analysis [16]. The CCDC base contains its 3D structure, where all six- membered boat-shaped cycles, ring C (C2-C3-N4-C5-C6-C7) is divided by the ether bridge into two five-membered cycles, the C/D-cis junction (C3-C14-C15-C20-C21-N4). Only the six- membered cycle formed by the C2-C3-C14-C15-C16-C7 links exists in the form of a chair. Ring B (C2-C7-C8-C13-N1) takes the form of a 2α envelope. Nitrogen atoms N1 and N4 in sp3 hybridization. Molecule of compound 1 forms a three- dimensional rigid framework, and it is possible that, in the natural derivatives 2 and 3, the stereochemistry of the polycyclic framework remains. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.4.345-349.1898 Adizov and Tashkhodjaev / European Journal of Chemistry 10 (4) (2019) 345-349 347 Table 2. Bond lengths and angles for compound 6. Atom-Atom Bond length (Å) Atom-Atom Bond length (Å) O1-C25 1.300(9) C6-C7 1.541(8) O1-C10 1.420(8) C7-C8 1.516(8) O2-C25 1.150(9) C7-C16 1.541(8) O3-C22 1.444(7) C8-C9 1.373(8) O3-C2 1.475(8) C8-C13 1.392(8) O4-C17 1.196(7) C9-C10 1.388(9) O5-C17 1.343(8) C10-C11 1.361(9) O5-C26 1.441(8) C11-C12 1.390(9) N1-C13 1.395(8) C12-C13 1.372(9) N1-C2 1.438(8) C14-C15 1.537(9) N1-C23 1.442(8) C15-C20 1.529(9) C2-C7 1.525(8) C15-C16 1.575(8) C2-C3 1.529(9) C16-C17 1.483(8) C3-N4 1.500(9) C16-C22 1.532(8) C3-C14 1.527(10) C18-C19 1.464(11) N4-C5 1.447(8) C19-C20 1.321(9) N4-C21 1.468(9) C20-C21 1.510(9) C5-C6 1.511(8) C24-C25 1.424(10) Atom-Atom-Atom Bond angles (°) Atom-Atom-Atom Bond angles (°) C25-O1-C10 124.0(6) C11-C10-C9 122.4(6) C22-O3-C2 108.4(4) C11-C10-O1 123.3(6) C17-O5-C26 116.8(6) C9-C10-O1 114.1(6) C13-N1-C2 105.3(5) C10-C11-C12 119.2(6) C13-N1-C23 120.9(6) C13-C12-C11 119.0(6) C2-N1-C23 120.6(6) C12-C13-C8 121.3(6) N1-C2-O3 106.8(4) C12-C13-N1 128.7(6) N1-C2-C7 104.5(5) C8-C13-N1 110.0(5) O3-C2-C7 103.6(5) C3-C14-C15 107.6(6) N1-C2-C3 120.6(5) C20-C15-C14 104.5(6) O3-C2-C3 108.2(5) C20-C15-C16 116.8(5) C7-C2-C3 111.9(5) C14-C15-C16 110.4(5) N4-C3-C14 109.7(6) C17-C16-C22 112.9(5) N4-C3-C2 111.6(5) C17-C16-C7 113.7(5) C14-C3-C2 105.6(6) C22-C16-C7 100.3(5) C5-N4-C21 110.1(5) C17-C16-C15 111.0(5) C5-N4-C3 113.5(5) C22-C16-C15 105.8(5) C21- N4-C3 112.7(6) C7-C16-C15 112.4(5) N4-C5-C6 112.8(5) O4-C17-O5 122.3(6) C5-C6-C7 109.8(5) O4-C17-C16 125.7(6) C8-C7-C2 98.4(5) O5-C17-C16 111.9(6) C8-C7-C6 108.6(5) C20-C19-C18 130.0(7) C2-C7-C6 113.1(5) C19-C20-C21 121.9(6) C8-C7-C16 118.5(5) C19-C20-C15 124.3(6) C2-C7-C16 97.4(5) C21-C20-C15 113.4(6) C6-C7-C16 118.3(5) N4-C21-C20 116.8(5) C9-C8-C13 119.7(6) O3-C22-C16 104.4(5) C9-C8-C7 131.8(6) O2-C25-O1 119.3(8) C13-C8-C7 108.0(5) O2-C25-C24 124.6(8) C8-C9-C10 118.3(6) O1-C25-C24 116.0(7) Table 3. Intra- and inter-molecular interactions on the crystal structure 6. D—H…A d(D—H), Å d(H…A), Å d(D…A), Å ∠(DHA), ° Symmetry С5-Н5A…N1 0.970 2.460 2.989(8) 114.0 - C9-H9A…O4 0.930 2.580 3.244(8) 129.0 - C11-H11A...O2 0.930 2.540 2.860(11) 101.0 - C14-H14A…O2 0.970 2.560 3.126(15) 118.0 1-x, -1/2+y, 1/2-z C14-H14B…O3 0.970 2.220 2.585(9) 101.0 - This assumption confirms the spatial structure of compound 2 (S)-cathafoline (1’) [17], where the ether bridge is absent in the polyamine framework of akuammiline, but the conformation of the polycyclic framework remains (Figure 2). Structure of the compound 4 and its 10-OMe derivative 5 was established on the basis of spectral data and an absolute configuration was proposed [12,13,18]. The spatial structure of compounds 4 and 5 is determined by single crystal XRD on the basis of its 10-OAc derivative (6), which is shown in Figure 2. The five-membered heterocyclic of the indoline core B (C13- N1-C2-C7-C8) and E (C2-O3-C22-C16-C7) take the 2β- and 7β- envelope form, respectively, and the six-membered cycles C (C2-C3-N4-C5-C6-C7) and D (C3-C14-C15-C20-C21-N4) take the boat conformation and they are cis-articulated. The flat (with an accuracy of ±0.04 Å) 10-O-acetyl group in the exo- position is slightly rotated by 14.1° relative to the benzene ring (±0.01 Å) and does not significantly affect the stereochemical parameters of the akuammine polycycle. Atom O2 of the carbonyl group has an abnormally large thermal parameter in the direction perpendicular to the plane of the OAc group, which is explained by the free oscillation of this atom in this direction. N1 nitrogen atoms (the sum of the internal valent angles is 347.7°) and N4 (336.1°) in sp3 hybridization and the methyl group with N4β is oriented similarly to that observed in picrinine. In akuammine and picrinine (skeletons that differ in the location of the ether bridge), the conformation of the cycles (polycyclic framework) is practically the same. In indolines of V. erecta, the skeletons of the akuammiline type are observed in the Z-states of the exomethylene group (fragment C18- C19=C20-C15). However, in the CCDC database there are examples of indolines (the same types of skeletons) isolated from other plants with E-states of the exomethyl fragment [16]. In the crystal structure of compound 6, the molecules are connected via weak non classic hydrogen bonds (Table 3). 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.4.345-349.1898 348 Adizov and Tashkhodjaev / European Journal of Chemistry 10 (4) (2019) 345-349 Picrinine (Vincaridine) (1) Picrinine 2(S)-cathafoline (1’) 10-ОAc-akuammine (6) Figure 2. The crystal structure of compounds 1, 1’ and 6. 4. Conclusion The ether bridges located in different positions and forming five-membered cycles do not change the conformation of the polycyclic akuammiline framework. In indolines of V. erecta, skeletons of the akuammiline type are observed in the Z-states of the exomethylene group. Acknowledgements The work was carried out according to the fundamental research projects №PZ-20170929764, №Т.4-18 and ВА-ФА- Ф6-010 S. Yunusov Institute of the Chemistry of Plant Substances Academy of Sciences Republic of Uzbekistan. Supporting information CCDC-1038564 contains the supplementary crystal- lographic data for this paper. These data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/, or by e-mailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. Author contributions: All authors contributed equally to this work. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. ORCID Shahobiddin Adizov http://orcid.org/0000-0002-8902-7466 Bakhodir Tashkhodjaev http://orcid.org/0000-0003-3027-9893 References [1]. Kurmukov, A. G.; Zakirov, U. B. Alkaloids and medicinal herb preparations, First edition, Ibn Sina Publ. , Tashkent, Uzbekistan, 1992. [2]. Sadriddinov, F. S.; Kurmukov, A. G. Pharmacology of plant alkaloids and their use in medicine, Tashkent, Medicina, 1980. [3]. Aripov, Kh. N., Results of the study of alkaloid plants, Edition FAN, Tashkent, 1993. [4]. Azimova, S. S.; Yunusov, M. S. Natural Compounds: Alkaloids. Plant Sources, Structure and Properties; Springer, Science & Business Media: New York, NY, USA, 2013. [5]. Mashkovskiy, M. D. Medical product. Abu Ali Ibn Sina Publ., Tashkent, Uzbekistan, 1998. [6]. Le-Men J.; Taylor, W. I. J. Cellular Mol. Life Sci. Exp. 1965, 21, 508- 510. [7]. Rakhimov, D. A.; Il’yasova, Kh. T.; Malikov, V. M.; Yunusov, S. Yu. Chem. Nat. Comp. 1969, 5, 440-445. [8]. Chatterjee, A.; Mukherjee, B.; Ray, A. Tetrahedron Lett. 1965, 41, 3633-3637. [9]. Yagudaev, M. R. Chem. Nat. Comp. 1985, 21, 131-135. [10]. Il’yasova, Kh. T.; Malikov, V. M.; Yunusov, S. Y. Chem. Nat. Comp. 1968, 4, 278-278. [11]. Il’yasova, Kh. T.; Malikov, V. M.; Yunusov, S. Y. Chem. Nat. Comp. 1971, 7, 155-156. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.4.345-349.1898 https://www.ccdc.cam.ac.uk/structures/ mailto:data_request@ccdc.cam.ac.uk http://orcid.org/0000-0002-8902-7466 http://orcid.org/0000-0003-3027-9893 Adizov and Tashkhodjaev / European Journal of Chemistry 10 (4) (2019) 345-349 349 [12]. Abdurakhimova, N.; Yuldashev, P. Kh.; Yunusov, S. Y. Dan. UzSSR 1964, 4, 33-37. [13]. Rakhimov, D. A.; Sharipov, M. R.; Malikov, V. M.; Yunusov, S. Y. Chem. Nat. Comp. 1971, 7, 663-663. [14]. Sheldrick, G. M. Acta Cryst. C 2015, 71, 3-8. [15]. Sheldrick, G. M. Acta Cryst. A 2008, 64, 112-122. [16]. Ghosh, R.; Roychowdhury, P.; Chattopadhyay, D.; Iitaka, Y. Acta Crystallogr. C 1988, 44, 2151-2154. [17]. Lim, S. H.; Low, Y. Y.; Sinniah, S. K.; Yong, K. T.; Sim, K. S.; Kam, T. S. Phytochemistry 2014, 98, 204-215. [18]. Buckingham, J.; Baggaley, K. H.; Roberts, A. D.; Szabo L. F. Second Edition, Dictionary of alkaloids, CRC Press, London, UK, 2010. Copyright © 2019 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.4.345-349.1898 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Materials and apparatus 2.2. X-ray crystal structure determination of compound 6 3. Results and discussion 3.1. Crystal structure of compounds 6 4. Conclusion Acknowledgements Supporting information Disclosure statement ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: