Indole alkaloids from Vinca erecta type of sarpagine and ajmaline European Journal of Chemistry 10 (4) (2019) 409-416 European Journal of Chemistry View Journal Online View Article Online Indole alkaloids from Vinca erecta type of sarpagine and ajmaline 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.10.4.409-416.1907 Received: 20 June 2019 Received in revised form: 20 October 2019 Accepted: 26 October 2019 Published online: 31 December 2019 Printed: 31 December 2019 The single crystal X-ray diffraction method established the absolute configuration of the Vinca erecta indole alkaloids of the akuammidine sarpagine type (3S, 5S, 15R, 16R) and its o- acyl derivative, as well as the type of ajmaline, quebrachidine (2S, 3S, 5S, 7R, 15S, 16R, 17S) and majoridine (2R, 3S, 5S, 7R, 15R, 16S, 17R). Crystal data for C21H24N2O3 (1): orthorhombic, space group P212121 (no. 19), a = 6.3949(5) Å, b = 13.5009(10) Å, c = 22.461(3) Å, Z = 4, 7694 reflections measured (7.64° ≤ 2Θ ≤ 152.294°), 3813 unique (Rint = 0.0798) which were used in all calculations. The final R1 was 0.0680 (I > 2σ(I)) and wR2 was 0.1650 (all data). Crystal data for C23H26N2O4 (2): orthorhombic, space group P212121 (no. 19), a = 9.9730(13) Å, b = 10.2090(10) Å, c = 20.409(3) Å, Z = 4, 7959 reflections measured (8.666° ≤ 2Θ ≤ 151.998°), 4212 unique (Rint = 0.0386) which were used in all calculations. The final R1 was 0.0477 (I > 2σ(I)) and wR2 was 0.1171 (all data). Crystal data for C42H48N4O6 (3): monoclinic, space group P21 (no. 4), a = 8.9320(10) Å, b = 21.515(5) Å, c = 9.5420(10) Å, β = 97.103(10)°, Z = 2, 16677 reflections measured (9.34° ≤ 2Θ ≤ 151.836°), 7393 unique (Rint = 0.0278) which were used in all calculations. The final R1 was 0.0366 (I > 2σ(I)) and wR2 was 0.1037 (all data). Crystal data for C23H28N2O3 (4): orthorhombic, space group P212121 (no. 19), a = 10.636(2) Å, b = 11.208(12) Å, c = 16.725(13) Å, Z = 4, 1650 reflections measured (9.498° ≤ 2Θ ≤ 119.97°), 1650 unique (Rint = 0.0436) which were used in all calculations. The final R1 was 0.0608 (I > 2σ(I)) and wR2 was 0.1720 (all data). In alkaloids such as sarpagine and ajmaline exo, the substituents of alkaloids do not lead to conformational changes of a stable polycyclic framework. In the series of sarpagine, alkaloids form mono-salts in the tetrahedral nitrogen N4, and in indolines of the ajmaline type, the tetrahedral hybridization of the N1 and N4 atoms favors the formation of disols. In V. erecta alkaloids, the exomethylene fragment (C18-C19=C20-C21) of the polycyclic backbone always takes on the E-state. Chirality Majoridine Quebrachidine Akuammidine Indole alkaloids Single crystal X-ray diffraction Cite this: Eur. J. Chem. 2019, 10(4), 409-416 Journal website: www.eurjchem.com 1. Introduction Vinca erecta Rgl. et Schmalh. (сем. Apocynaceae)-Perennial herbaceous plant is common in the mountainous and foothill regions of Central Asia [1,2], and contains a large number of indole alkaloids [3-5]. Plant alkaloids are biologically active substances and have been used in medicine as important medicines [2,6]. The reference book [5] notes the isolation of five indole alkaloids of the sarpagine type from V. erecta (according to the systematics of Lee Men [7]): tombosine [8], 6-hydroxy- tombosine (ervincidine) [9], o-benzoyl-tombosine [10], 10- methoxy-alkyllosimine [11] and akuammidine [12], which differ in exo-substituents in the sarpagine skeleton (Figure 1). In tombosine, the carbon atom C22 is absent, but the polycyclic skeleton of sarpagin remains. Its structure was determined by X-ray diffraction method (XRD) in the form of an ethanol solvate called (+)-normacusine B [13]. V. erecta has been isolated four indolines with the ajmaline skeleton of a polycyclic skeleton [5]. The alkaloids vincamajine [14], vincamedine [15], quebrachidine [16] and majoridine (majdinine) [17] differ in substituents in the ajmaline skeleton, their structures are studied by various spectral methods [18,19]. The sarpagine and ajmaline groups have a 3D polycyclic framework and a two-dimensional representation of the structure, indicating the relative α- or β-orientation of the substituent is difficult. For example, due to the fuzzy reduction of the chemical structure of ervincidine [9], it was mistakenly accepted as 16-epi-6-hydroxy tombosine in the 2010 reference book [20], although later its structure was corrected for 6- hydroxy tombosine [5]. For this reason, in determining the absolute configuration, the values of the chirality descriptors R, S are the main addition in the description of the asymmetric center. 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.10.4.409-416.1907 http://dx.doi.org/10.5155/eurjchem.10.4.409-416.1907 https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.10.4.409-416.1907&domain=pdf&date_stamp=2019-12-31 http://www.eurjchem.com/ http://dx.doi.org/10.5155/eurjchem.10.4.409-416.1907 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.10.4.409-416.1907&domain=pdf&date_stamp=2019-12-31� 410 Adizov and Tashkhodjaev / European Journal of Chemistry 10 (4) (2019) 409-416 Sarpagines Ajmalines 10 11 12 9 8 13 N H 1 2 7 3 N 5 6 14 15 20 21 16 CH2OH 17 4 19 18 H A B C D 3S,5S,15R,16R Tombosine (Tombosine, Normacusine) 12 8 13 N 1 2 7 3 N 4 5 6 14 15 21 1617 19 18 H COOCH3HO CH3 A D C D 2S,3S,5S,7R,15S,16R,17S Vincamajine 10 11 12 9 8 13 N H 1 2 7 3 N 5 6 14 15 20 21 16 CH2OH 17 4 19 18 H OH A B C D 3S,5S,15R,16R 6-Hydoxytombosine (Ervincidine) 12 8 13 N 1 2 7 3 N 4 5 6 14 15 21 1617 19 18 H COOCH3O CH3 C CH3 O 2S,3S,5S,7R,15S,16R,17S Vincamedine N H N CH2OCOC6H5 4 H OH 1 3S,5S,15R,16R o-Benzoyle-tombosine 12 8 13 N H 1 2 7 3 N 4 5 6 14 15 21 1617 19 18 H COOCH3HO 2S,3S,5S,7R,15S,16R,17S Quebrachidine (Vincarine) N H N CHO H OH H3CO 10-Methoxyvellosimine 12 8 13 N 1 2 7 3 N 4 5 6 14 15 21 1617 19 18 H O CO CH3 CH3 H3CO 2R,3S,5S,7R,15R,16S,17R Majoridine (Majdine) N H N CH2OH H H3COOC 3S,5S,15S,16S, Akuammidine Figure 1. The structure of sarpagines and ajmaline alkaloids from Vinca erecta. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.4.409-416.1907 Adizov and Tashkhodjaev / European Journal of Chemistry 10 (4) (2019) 409-416 411 Table 1. Crystal data and details of the structure refinement for compounds 1-4. Structures 1 2 3 4 Empirical formula С21Н24N2О3 С23Н26N2О4 С46Н48N4О6 С23Н28N2О3 Formula weight 352.42 394.46 704.84 380.47 Temperature (K) 290.15 293.15 293.15 293.15 Crystal system Orthorhombic Orthorhombic Monoclinic Orthorhombic Space group P212121 P212121 P21 P212121 a (Å) 6.3949(5) 9.973(1) 8.932(1) 10.636(2) b (Å) 13.5009(1) 10.209(1) 21.515(5) 11.208(12) c (Å) 22.461(3) 20.409(3) 9.542(1) 16.725(13) β (°) 90 90 97.103(10) 90 Volume (Å3) 1939.2(3) 2078.0(4) 1819.6(5) 1994(3) Z 4 4 2 4 ρcalc (g/cm3) 1.207 1.261 1.286 1.268 μ (mm1) 0.652 0.702 0.695 0.671 F(000) 752 840 752 816 Crystal size (mm3) 0.30 × 0.50 × 0.60 0.30 × 0.50 × 0.70 0.30 × 0.40 × 0.60 0.26 × 0.30 × 0.54 Radiation CuKα (λ = 1.54184 Å) CuKα (λ = 1.54184 Å) CuKα (λ = 1.54184 Å) CuKα (λ = 1.54184 Å) 2Θ range for data collection (°) 3.82 to 76.147 4.333 to 75.999 4.670 to 75.918 4.749 to 59.985 Index ranges -7≤ h ≤ 4 -16 ≤ k ≤ 15 -26 ≤ l ≤ 28 -12≤ h ≤ 11 -12 ≤ k ≤ 8 -25 ≤ l ≤ 25 -9≤ h ≤ 11 -26 ≤ k ≤ 27 -11 ≤ l ≤ 11 0≤ h ≤ 11 0 ≤ k ≤ 12 0≤ l ≤ 18 Reflections collected 7694 7959 16677 1650 Independent reflections 3813 [Rint = 0.0798, Rsigma =0.1337] 4212 [Rint = 0.0386, Rsigma =0.0534] 7393 [Rint = 0.0278, Rsigma = 0.0291] 1202 [Rint = 0.0436, Rsigma = 0.0] Data/restraints/parameters 3813/2/241 4212/0/267 7393/1/486 1650/0/258 Goodness-of-fit on F2 0.998 0.940 0.980 1.243 Final R indexes [I≥2σ (I)] R1 = 0.068, wR2 = 0.098 R1 = 0.0477, wR2 = 0.0999 R1 = 0.0366, wR2 = 0.1005 R1 = 0.0608, wR2 = 0.1326 Final R indexes [all data] R1 = 0.1969, wR2 = 0.1650 R1 = 0.0776, wR2 = 0.1171 R1 = 0.0417, wR2 = 0.1037 R1 = 0.1013, wR2 = 0.1720 Largest diff. peak/hole (e.Å-3) 0.173/-0.148 0.182/-0.146 0.208/-0.168 0.206/-0.212 Flack parameter 0.1(4) -0.1(2) 0.17(7) 1.6(1) CCDC 1897669 1897666 1897662 978765 In order to unambiguously determine the absolute configuration (the values of the chirality descriptors R, S), X- ray structural analysis of the molecule of the indole alkaloid akuammidine (1) and its OAc-derivative (2), as well as the indolines of quebrachidine (3) and majoridine (4) was performed. The absolute configurations of alkaloids such as sarpagine and ajmaline V. erecta are clarified. 2. Experimental 2.1. Materials and apparatus Plants of V. erecta were grown in natural conditions in the mountain of Alai, Fergana valley, Uzbekistan. Dried material was powdered and kept in a desiccator at room temperature, in the dark, until the analysis. Samples of alkaloids 1-4 were obtained from The Collection of the Laboratory of Chemistry of Alkaloids, Institute of the Chemistry of Plant Substances Academy of Sciences of Republic Uzbekistan. 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), or CCD Xcalibur Ruby diffractometer (Oxford Diffraction) diffractometer equipped with a graphite monochromatic CuKα radiation (λ = 1.54184 Å) 2.2. X-ray crystal structure determination of compounds 1-4 The unit cell parameters of the crystal of compounds 1, 2, and 3 were determined and refined on a CCD Xcalibur Ruby diffractometer (Oxford Diffraction) using CuKα radiation [21]. The X-ray diffraction experiment of the crystal of compound 4 was performed on a STOE Stadi-4 four-circle diffractometer using CuKα radiation. A three-dimensional set of reflections for crystals was obtained on these diffractometers, respect- tively. The absorption correction was introduced using the SADABS program [22]. Table 1 shows the main parameters of X-ray diffraction experiments and calculations of the refinement of the structures of crystals 1-4. The structures were deciphered by direct methods within the SHELXS-97 program complex [23], calculations to refine the structures were performed using the SHELXL-2014/7 program [24]. All non-hydrogen atoms were refined by the least squares method in the full-matrix anisotropic approxi- mation. 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 of displacement of the corresponding carbon atoms). The hydrogen atoms of the NH and OH groups were detected from difference syntheses of electron density (EP) and refined isotropically. 3. Results and discussion The structure of alkaloids 1 and 2 of sarpagine type according to XRD data is shown in Figure 2, the Flack para- meters for the two of them are -0.1(2) and 0.1(3), respectively, which allow determining the absolute configuration of four chiral centers as 3S, 5S, 15S and 16S. In the above example, tombosine in exo position 22 contains an H atom (unlike akuammidine), which leads to a change in the chirality of the 16 center-3S, 5S, 15S, 16R. Earlier, the spatial structure in the akuammidine crystal was established by XRD in the form of methyl iodide monohydrate [24]. However, the authors did not define the absolute configuration, and the optical antipode of alkaloid is given in the Cambridge Crystallographic Data Centre (CCDC) database. Figure 2 shows its inverted enantiomer, that is, the corrected structure. The structural parameters including bond distances and bond angles for compounds 1-4 are listed in Table 2-5, respectively. In sarpagines 1 and 2, the nitrogen atoms N1 and N4 adopt the planar sp2 and pyramidal-tetrahedral sp3-configuration, respectively. In these molecules, the indole core is planar, cycle C (for compound 1 and 2; C2, C3, N4, C5, C6, C7, Figure 2) takes a half-seat conformation with the release of N4 and C5 atoms in different directions, and the remaining six-membered cycles (atoms N4, C5, C16, C15, C20, C21) form a bicyclo [2.2.2]octane a heterosystem where the cycles take on the conformation of a slightly distorted bath. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.4.409-416.1907 412 Adizov and Tashkhodjaev / European Journal of Chemistry 10 (4) (2019) 409-416 Table 2. Selected bond lengths and angles for compound 1. Atom-Atom Bond length (Å) Atom-Atom Bond length (Å) O3-C17 1.424(8) C16-C15 1.539(10) O2-C22 1.289(13) C16-C17 1.542(9) O2-C23 1.642(12) C16-C5 1.585(9) N1-C2 1.377(10) C20-C19 1.305(13) N1 C13 1.399(12) C20-C15 1.469(12) O1-C22 1.243(12) C20-C21 1.508(12) C22-C16 1.534(13) C2-C7 1.370(11) N4-C21 1.482(10) C15-C14 1.553(9) N4-C3 1.498(9) C5-C6 1.514(10) N4-C5 1.505(8) C8-C7 1.415(12) C3-C2 1.459(11) C7-C6 1.489(10) C3-C14 1.567(10) C19-C18 1.539(15) Atom-Atom-Atom Bond angles (°) Atom-Atom-Atom Bond angles (°) C22-O2-C23 99.0(9) C15-C20-C21 111.0(9) C2-N1-C13 107.3(8) C7-C2-N1 110.4(9) O1-C22-O2 123.8(12) C7-C2-C3 125.0(9) O1-C22-C16 120.5(12) N1-C2-C3 124.1(9) O2-C22-C16 115.5(11) C20-C15-C14 105.0(7) C21-N4-C3 109.5(7) C16-C15-C14 110.7(7) C21-N4-C5 109.6(7) N4-C5-C6 108.2(7) C3-N4-C5 108.2(7) N4-C5-C16 109.5(6) C2-C3-N4 108.8(8) C6-C5-C16 117.3(7) C2-C3-C14 113.4(7) C12-C13-N1 126.5(13) N4-C3-C14 109.2(7) C12-C13-C8 125.7(13) C22-C16-C15 110.0(8) C15-C14-C3 108.3(6) C22-C16-C17 105.1(7) C2-C7-C8 107.2(9) C15-C16-C17 112.2(7) C2-C7-C6 121.0(10) C22-C16-C5 116.3(8) C8-C7-C6 131.6(9) C15-C16-C5 108.3(6) C7-C6-C5 109.1(7) C17-C16-C5 104.9(6) N4-C21-C20 111.2(8) C19-C20-C15 127.9(12) O3-C17-C16 112.4(6) C19-C20-C21 127.9(12) C20-C19-C18 126.8(14) Compound 1 Compound 2 Akuammidine [20] Figure 2. Spatial structure of compounds 1 and 2; and quaternary salt of akuammidine [20] (The corrected enantiomer and directions of intermolecular H- bonds are shown). 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.4.409-416.1907 Adizov and Tashkhodjaev / European Journal of Chemistry 10 (4) (2019) 409-416 413 Table 3. Selected bond lengths and angles for compounds 2. Atom-Atom Bond length (Å) Atom-Atom Bond length (Å) O3-C23 1.310(6) C16-C15 1.561(6) O3-C22 1.459(5) C16-C5 1.596(6) N1-C13 1.378(6) C13-C8 1.407(6) N1-C2 1.379(6) O4-C23 1.193(6) N4-C21 1.463(6) C7-C8 1.434(6) N4-C5 1.470(5) C7-C6 1.494(6) N4-C3 1.477(5) C14-C15 1.526(6) O2-C17 1.344(5) C14-C3 1.557(5) O2-C25 1.441(7) C21-C20 1.513(7) O1-C17 1.199(5) C15-C20 1.517(6) C2-C7 1.356(6) C5-C6 1.540(6) C2-C3 1.490(5) C23-C24 1.472(7) C16-C17 1.524(6) C20-C19 1.322(7) C16-C22 1.530(6) C19-C18 1.491(9) Atom-Atom-Atom Bond angles (°) Atom-Atom-Atom Bond angles (°) C23-O3-C22 117.8(4) N4-C3-C2 106.8(3) C13-N1-C2 108.3(4) N4-C3-C14 110.7(3) C21-N4-C5 109.9(4) C2-C3-C14 113.5(3) C21-N4-C3 109.1(3) O3-C22-C16 107.7(3) C5-N4-C3 109.1(3) O1-C17-O2 122.0(4) C17-O2-C25 117.4(4) O1-C17-C16 126.5(4) C7-C2-N1 110.3(4) O2-C17-C16 111.4(4) C7-C2-C3 125.3(4) N4-C21-C20 111.6(4) N1-C2-C3 124.4(4) C20-C15-C14 107.0(4) C17-C16-C22 106.7(4) C20-C15-C16 107.0(3) C17-C16-C15 110.3(3) C14-C15-C16 111.8(3) C22-C16-C15 111.5(3) N4-C5-C6 108.9(3) C17-C16-C5 115.4(3) N4-C5-C16 111.2(3) C22-C16-C5 106.7(3) C6-C5-C16 117.4(3) C15-C16-C5 106.3(3) C7-C6-C5 108.4(3) N1-C13-C12 129.9(5) O4-C23-O3 122.6(5) N1-C13-C8 107.7(4) O4-C23-C24 124.2(5) C12-C13-C8 122.4(4) O3-C23-C24 113.2(4) C2-C7-C8 106.7(4) C19-C20-C15 126.6(5) C2-C7-C6 121.4(4) C19-C20-C21 123.8(5) C8-C7-C6 131.9(4) C15-C20-C21 109.6(3) C15-C14-C3 108.1(3) C20-C19-C18 129.0(6) Table 4. Selected bond lengths and angles for compounds 3. Atom-Atom Bond length (Å) Atom-Atom Bond length (Å) O1-C17 1.422(3) C3-C2 1.517(4) O1-C17 1.418(3) C3-C14 1.536(4) O3-C22 1.330(3) C17-C7 1.558(3) O3-C23 1.439(3) C17-C7 1.556(3) O3-C22 1.334(3) C22-C16 1.516(3) O3-C23 1.444(3) C6-C7 1.522(3) O2-C22 1.200(3) C15-C20 1.511(4) N4-C21 1.477(4) C15-C14 1.539(3) N4-C5 1.493(3) C15-C16 1.560(3) N4-C3 1.496(3) C6-C7 1.526(3) N4-C21 1.477(4) C6-C5 1.529(4) N4-C5 1.493(3) C16-C5 1.563(3) N4-C3 1.497(3) C7-C8 1.508(4) O2-C22 1.194(3) C7-C2 1.548(3) C16-C22 1.519(3) C9-C8 1.379(4) C16-C15 1.556(3) C13-C12 1.390(4) C16-C17 1.567(3) C3-C14 1.539(4) C16-C5 1.575(3) C21-C20 1.530(4) N1-C13 1.406(4) C21-C20 1.523(4) N1-C2 1.470(4) C20-C19 1.326(4) C15-C20 1.514(4) C20-C19 1.323(4) C15-C14 1.537(3) C19-C18 1.498(5) C2-N1 1.460(3) C9-C10 1.387(5) C2-C3 1.525(4) C19-C18 1.494(6) C2-C7 1.549(3) C10-C11 1.374(5) N1-C13 1.395(4) C12-C11 1.393(5) C5-C6 1.532(4) C11-C10 1.381(5) Atom-Atom-Atom Bond angles (°) Atom-Atom-Atom Bond angles (°) C22-O3-C23 117.0(2) C15-C16-C17 112.52(18) C22-O3-C23 116.3(2) C5-C16-C17 104.0(2) C21-N4-C5 107.3(2) C8-C7-C6 124.8(2) C21-N4-C3 108.6(2) C8-C7-C2 99.02(19) C5-N4-C3 109.38(19) C6-C7-C2 106.3(2) C21-N4-C5 107.0(2) C8-C7-C17 112.79(19) C21-N4-C3 108.7(2) C6-C7-C17 100.14(18) C5-N4-C3 109.86(19) C2-C7-C17 114.2(2) C22-C16-C15 111.1(2) C12-C13-N1 128.4(2) C22-C16-C17 108.77(19) C12-C13-C8 120.9(3) C15-C16-C17 113.30(19) N1-C13-C8 110.7(2) 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.4.409-416.1907 414 Adizov and Tashkhodjaev / European Journal of Chemistry 10 (4) (2019) 409-416 Table 4. Continued. Atom-Atom-Atom Bond angles (°) Atom-Atom-Atom Bond angles (°) C22-C16-C5 111.3(2) O2-C22-O3 123.5(2) C15-C16-C5 108.39(19) O2-C22-C16 125.7(2) C17-C16-C5 103.79(19) O3-C22-C16 110.8(2) C13-N1-C2 104.3(2) N4-C3-C2 106.7(2) C20-C15-C14 106.4(2) N4-C3-C14 110.4(2) C20-C15-C16 107.4(2) C2-C3-C14 115.1(2) C14-C15-C16 109.1(2) N1-C2-C3 116.6(2) N1-C2-C3 116.9(2) N1-C2-C7 102.2(2) N1-C2-C7 102.15(19) C3-C2-C7 115.1(2) C3-C2-C7 114.77(19) C8-C7-C6 126.4(2) C13-N1-C2 105.2(2) C8-C7-C2 99.51(18) N4-C5-C6 111.6(2) C6-C7-C2 107.20(19) N4-C5-C16 108.76(19) C8-C7-C17 111.01(19) C6-C5-C16 103.69(19) C6-C7-C17 101.57(19) N4-C3-C2 106.4(2) C2-C7-C17 110.92(19) N4-C3-C14 111.1(2) C9-C8-C13 120.0(3) C2-C3-C14 113.9(2) C9-C8-C7 132.8(2) O1-C17-C7 110.93(19) C13-C8-C7 107.1(2) O1-C17-C16 111.84(19) N4-C21-C20 110.9(2) C7-C17-C16 103.61(18) N4-C21-C20 110.9(2) O1-C17-C7 108.06(19) N4-C5-C6 111.6(2) O1-C17-C16 110.24(18) N4-C5-C16 109.09(19) C7-C17-C16 103.36(18) C6-C5-C16 104.5(2) O2-C22-O3 123.8(2) C19-C20-C15 126.6(3) O2-C22-C16 124.0(2) C19-C20-C21 124.0(3) O3-C22-C16 112.2(2) C15-C20-C21 109.4(2) C7-C6-C5 99.70(19) C19-C20-C15 126.7(3) C20-C15-C14 106.4(2) C19-C20-C21 123.7(3) C20-C15-C16 107.4(2) C15-C20-C21 109.5(2) C14-C15-C16 108.4(2) C3-C14-C15 107.90(19) C7-C6-C5 99.19(19) C12-C13-N1 128.4(3) C22-C16-C15 112.2(2) C8-C13-N1 110.7(2) C22-C16-C5 110.04(19) C3-C14-C15 107.7(2) C15-C16-C5 108.12(19) C20-C19-C18 127.1(3) C22-C16-C17 109.6(2) C20-C19-C18 127.3(4) Table 5. Selected bond lengths and angles for compounds 4. Atom-Atom Bond length (Å) Atom-Atom Bond length (Å) O1-C10 1.369(9) C3-C14 1.540(10) O1-C23 1.409(9) C5-C6 1.517(9) O2-C24 1.359(9) C5-C16 1.548(9) O2-C17 1.439(7) C7-C8 1.509(9) O3-C24 1.175(9) C7-C17 1.526(9) N1-C13 1.404(9) C14-C15 1.515(10) N1-C22 1.469(9) C15-C20 1.492(10) N1-C2 1.469(8) C15-C16 1.526(9) N4-C3 1.465(9) C16-C17 1.549(9) N4-C5 1.475(9) C18-C19 1.496(13) N4-C21 1.481(9) C19-C20 1.340(11) C2-C3 1.523(10) C20-C21 1.521(11) C2-C7 1.538(9) C24-C25 1.480(10) Atom-Atom-Atom Bond angles (°) Atom-Atom-Atom Bond angles (°) C10-O1-C23 116.8(6) C6-C7-C2 107.5(6) C24-O2-C17 116.2(6) C17-C7-C2 109.2(5) C13-N1-C22 116.7(7) C12-C13-N1 130.0(7) C13-N1-C2 103.1(6) N1-C13-C8 111.6(7) C22-N1-C2 116.0(6) C15-C14-C3 108.1(5) C3-N4-C5 109.7(5) C20-C15-C14 106.0(6) C3-N4-C21 108.2(6) C20-C15-C16 105.2(6) C5-N4-C21 106.1(6) C14-C15-C16 109.6(6) N1-C2-C3 119.4(6) C15-C16-C5 107.7(6) N1-C2-C7 101.3(5) C15-C16-C17 114.0(5) C3-C2-C7 114.6(6) C5-C16-C17 105.8(5) N4-C3-C2 111.9(6) O2-C17-C7 106.7(5) N4-C3-C14 109.9(6) O2-C17-C16 111.4(5) C2-C3-C14 108.9(6) C7-C17-C16 103.0(5) N4-C5-C6 107.5(6) C20-C19-C18 125.2(9) N4-C5-C16 110.2(5) C19-C20-C15 126.7(8) C6-C5-C16 104.1(5) C19-C20-C21 122.4(8) C5-C6-C7 100.9(5) C15-C20-C21 110.5(7) C8-C7-C6 112.4(5) N4-C21-C20 108.8(6) C8-C7-C17 123.8(6) O3-C24-O2 122.3(8) C6-C7-C17 102.7(5) O3-C24-C25 127.4(8) C8-C7-C2 100.5(5) O2-C24-C25 110.3(8) The realized conformations of the cycles do not differ from those observed in the akuammidine cation [25], as well as in the bases of 19(Z)-akuammidine isolated from Gelsemium elegans [26] and normacusine B [13]. Thus, the conformation of the sarpagine polycyclic framework in various natural derivatives is preserved.In the indoles of V. erecta with sarpagine skeletons, the E-states of the exomethylene group (C18-C19=C20-C21 atoms) are observed in the C20 position, in contrast to the 19(Z)-akuammidine. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.4.409-416.1907 Adizov and Tashkhodjaev / European Journal of Chemistry 10 (4) (2019) 409-416 415 Table 6. Intermolecular H-bonds in structures of compounds 1-4 (d: distance, D: donor, А: acceptor). Compound Structure d(N1···O3), Å d(Н···A), Å ∠(DHA), ° Symmetry 1 N1-H···O3 2.825(10) 1.98 165 -1/2+x, -1/2-y, -1-z O3-H···N4 2.768(9) 1.98 161 1/2+x, -1/2-y, -1-z 2 N1-H···O4 2.917(6) 2.19(4) 145(4) 1+x, y, z 3 O1-H···N4’ 2.938 (3) 2.12(6) 167(4) x, y, z О1’-H···N4 2.788(3) 1.99(4) 162(5) x, y, -1+z N1-H···O2 2.953(3) 2.17(4) 166(3) x, y, z N1’-H···O2’ 3.156(3) 2.32(4) 165(3) 1+x, y, z Compound 3 Compound 4 Figure 3. Spatial structure of ajmaline 3 (one of two asymmetric molecules is shown) and 4. Comparison of the molecular structure of the quaternary salt and the base of akuammidine shows the difference in the position of the flat COOCH3-group at position 22 relative to the sarpagine skeleton. The value of the torsion angle C15-C16- C22-O1 is an indicator of this difference. In compounds 1 and 2, it is equal to 2.9 and 5.1°, respectively, in 19(Z)-akuammidine, this angle is 5.4° [26], and in the quaternary alkaloid salt, the similar angle takes (opposite) 171.2°. Although the -СООСН3- group in these compounds does not participate in intra- and inter-molecular weak interactions (H-bonds), which indicates the possibility of two (alternative) energetically close conditions. The spatial structure of alkaloids of the type of ajmaline, quebrachidine (3) and majoridine (4) according to XRD data is shown in Figure 3. The Flack parameter (0.17(7)) allows determining the absolute configuration of the seven chiral centers of molecule 3 as 2S, 3S, 5S, 7R, 15S, 16R, 17S. The absolute configuration of V. erecta alkaloids of vincamajine and vincamedine is identical with that observed in compound 3. Although earlier their spatial structure was established by PCA [27,28], but the absolute configuration is not determined, optical antipodes are given in the CCDC database. In alkaloid 4, the H atom of the chiral center C2 is β-directed, unlike other ajmalines V. erecta. For compound 4, the chiral centers have the following meanings 2R, 3S, 5S, 7R, 15R, 16S, 17R. In alkaloids 3 and 4, the nitrogen atoms N1 and N4 are in the tetrahedral sp3-hybridization. The H atom at N1 in 3α-is similar to that observed in vincamajine and vincamedine [29], but in compound 4, nitrogen N1 is inverted and the methyl group has β-direction. In the molecular structures of the ajmalines, the atoms N4, C5, C16, C15, C20, C21 also form a rigid bicycle[2.2.2]octane system, in which six-membered cycles are in the form of a slightly distorted bath (Figure 3). A visual comparison of compounds 3 and 4 shows that the ajmaline skeleton is rigid and there are no differences in exo- substituents for conformational changes. In addition to the ring B (for compound 3 and 4; N1, C2, C7, C8, C13; Figure 3), which in compound 3 takes the 2α-envelope form, and in the compound 4 2β-envelope. In molecule 3, there is a difference (rotational) in the location of the flat COOCH3-group (at position 16) relative to the ajmaline skeleton compared to that realized in vincamajine and vincamedine [29]. The C15-C16-C22-O1 torsion angle in compound 3 for two independently found molecules is 134.3 and 130.2°, and in vincamajine and vincamedine the similar angle is -42.8 and -51.1° [29], respectively. Such a difference in torsion angles is probably due to the nature of the intermolecular H-bonds and the packing factor. In the indoles and V. erecta indolines with the skeletons of sarpagine and ajmaline, the E-condition of the exomethylene group (C18-C19=C20-C21) are observed in position C20. However, in the 19(Z)-akummidine, the Z-condition of this exomethylene group is realized [28]. In this case, the conformation of the polycyclic frame is the same, that is, different exo skeleton substituents and their location do not affect the conformation of the polycyclic frame. In crystal of compound 1, the OH group of the initial and N1H groups transformed along the a and b axes of the molecules form an H-bond of the type N1-H···O3 and O3- H···N4 (Table 6). In crystal of compound 1, weak H-bonds like C5-H···O1 can be observed. These H-bonds form a two- dimensional grid in the plane of the axes a and b. In crystal of compound 2, due to the intermolecular H-bond of type N1- H···O4, between the translated molecules along the a axis, a chain is formed. In crystal of compound 2, there are also weak H-bonds of the type C6-H···O4 and C25-H···O1. In crystal cell of compound 3, there are two asymmetric alkaloid molecules that are linked by the O1-H···N1 H-bond. This pair, trans- formed by the symmetry element 21 along the b axis, forms a chain along the helical axis. Other intermolecular H-bonds of the N1-H···O2 type are formed due to the translation element along the a axis (Table 6). As a result, a network is formed in the crystal in the ab plane. In crystal of compound 4, the molecules are located at van der Waals interactions. Until present time usually do not always noted the obtaining of mono- and disols from isolated alkaloids. However, an analysis of the literature [4,19] shows that disols of alkaloids were obtained only for indoline alkaloids. It is possible that in indolines the tetrahedral hybridization of the N1 and N4 atom favors the formation of disol (disalt). That is, under normal conditions, salt formation depends on the coordination of the nitrogen atoms N1 and N4, and they, due to 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.4.409-416.1907 416 Adizov and Tashkhodjaev / European Journal of Chemistry 10 (4) (2019) 409-416 the absence of the neighboring double bond, accept the sp3 hybridization. 4. Conclusion In alkaloids such as sarpagine and ajmaline exo, the substituents of alkaloids do not lead to conformational changes of a stable polycyclic framework. In the series of sarpagine, alkaloids form mono-salts in the tetrahedral nitrogen N4, and in indolines of the ajmaline type, tetrahedral hybridization of the N1 and N4 atoms favors the formation of disols. In V. erecta alkaloids, the exomethylene fragment (C18- C19=C20-C21) of the polycyclic backbone always takes on the E-condition. Acknowledgements The work was carried out according to the fundamental research projects ПЗ-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-1897669 (Akuammidine), CCDC-1897666 (OAc- Akuammidine), CCDC-1897662 (Quebrachidine) and CCDC- 978765 (Majoridine) contain 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]. Vvedenskiy, A. I.; Korovin, E. P. Flora of Uzbekistan, Edit. FAN, Tashkent, 1953, 5, 110-111. [2]. Kurmukov, A. G.; Zakirov, U. B. Alkaloids and medicinal herb preparations, First edition, Publisher: Ibn Sina, Tashkent, Uzbekistan, 1992. [3]. Sadriddinov, F. S.; Kurmukov, A. G. Pharmacology of plant alkaloids and their use in medicine, Tashkent, Medicina, 1980. [4]. Aripov, Kh. N.; Results of the study of alkaloid plants, Edition FAN, Tashkent, 1993. [5]. Azimova, S. S.; Yunusov, M. S. Natural Compounds: Alkaloids. Plant Sources, Structure and Properties; Springer, Science & Business Media: New York, NY, USA, 2013. [6]. Mashkovskiy, M. D. Medical product. Abu Ali Ibn Sina Publ. Tashkent, Uzbekistan, 1998. [7]. Le-Men, J.; Taylor, W. I. J. Cellular Mol. Life Sci. 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L.; Mariezcurrena, R.; Gomes, O. Acta Crystallogr. C 1987, 43, 1981-1983. [29]. Yagudaev, M. R. Chem. Nat. Comp. 1982, 18, 693-696. 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.10.4.409-416.1907 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 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 compounds 1-4 3. Results and discussion 4. Conclusion Acknowledgements Supporting information Disclosure statement ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: