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(1RS,2RS,6RS)-2-(6-Amino-9H-purin-9-yl)-8-azaspiro[5.6]dodec-10-en-1-ol Dihydrochloride

Chemistry Department, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia
*
Author to whom correspondence should be addressed.
Molbank 2022, 2022(4), M1495; https://doi.org/10.3390/M1495
Received: 18 October 2022 / Revised: 4 November 2022 / Accepted: 11 November 2022 / Published: 15 November 2022
(This article belongs to the Section Organic Synthesis)

Abstract

:
The title compound (1RS,2RS,6RS)-2-(6-Amino-9H-purin-9-yl)-8-azaspiro[5.6]dodec-10-en-1-ol dihydrochloride was synthesized for the first time in two steps, the first of which was a regioselectivity of epoxide ring-opening reaction under the action of adenine, yielding N-tert-butoxycarbonyl-((1RS,2RS,6RS)-2-(6-amino-9H-purin-9-yl)-8-azaspiro[5.6]dodec-10-en-1-ol. By treating the latter with a saturated methanolic solution of hydrogen chloride, it was possible to obtain ((1RS,2RS,6RS)-2-(6-Amino-9H-purin-9-yl)-8-azaspiro[5.6]dodec-10-en-1-ol dihydrochloride. The features of the molecular and crystal structure of ((1RS,2RS,6RS)-2-(6-Amino-9H-purin-9-yl)-8-azaspiro[5.6]dodec-10-en-1-ol dihydrochloride are discussed based on X-ray diffraction studies. The product overall yield was 40% out of two steps and after purification by column chromatography and recrystallization. The product was characterized by 1H-NMR, 13C-NMR, IR spectroscopy, HRMS and X-ray.

1. Introduction

The development of new synthetic methodologies for the generation of biologically active compounds is a crucial tool for medicinal and organic chemists [1]. This is a complex and multifaceted process that requires deep knowledge, initiative and creativity. Recently, the synthesis of saturated heterocyclic compounds has gained attention, since these structures are most often found in natural products and their synthetic methods are of high interest for producing new attractive chemical scaffolds for the development of new therapeutic molecules [2]. Spirocyclic compounds occupy an important place among saturated heterocyclic compounds [3,4,5]. In fact, spirocyclic compounds are notable for their unique three-dimensional structures, conformational rigidity, as well as their broad biological activity [6,7,8,9]. In particular, azaspirocyclic systems characterized by varied spiro-rings fused at the C3 position of the derivative of the piperidine core represent privileged scaffolds with prevalence in numerous natural products (polyzonimine, nitropolyzonamine, horsfiline, (+)-nitramine, (+)-isonitramine, (−)-isonitramine and (−)-sibirine et al.) [6,7,10] and pharmacologically relevant drugs (for example, vesamicol binds with high affinity to the allosteric binding site of the vesicular acetylcholine transporter (VAChT) [8,9,11,12]. Interestingly, some synthetic spiro compounds have found applications as chiral ligands and chiral catalysts, such as SPINOL and SPRIX [13,14]. Their conformational restriction, imparted by the spiro-carbon, provides an excellent strategy to not only imprint the desired conformation for ligand–protein binding, therefore increasing the specificity and potency, but also for enhancing the molecular complexity and potentially to reduce the P450 inhibition, rendering a better bioavailability and metabolic stability of the target compound [15,16]. An interesting expansion of the chemical space of these spiro systems can be achieved by conjugating them with different nucleobases. Nucleosides are fundamental building blocks of biological systems that show a wide range of biological activity. Thus, the chemistry behind them has been extensively explored and developed. Particularly, part of this nucleoside chemistry has been dedicated to modifications for avoiding their metabolic degradation due to enzymatic attacks either on the heterocyclic base and/or on the sugar moiety. A key strategy to avoid such metabolic degradations exploits the replacement of oxygen in the sugar portion of the nucleoside with a methylene unit, resulting in carbocyclic nucleoside analogues which are highly resistant to phosphorylases. Therefore, we focused on developing new nucleoside-like compounds based on this approach.
Earlier, while studying the regioselectivity of the epoxide ring-opening reaction of the derivative of oxaspiro[bicyclo[4.1.0]heptane-2,3′-oxepine] under the action of adenine (100 °C, DMF), we obtained only one regiosisomer of adeninospirane [17]. Herein, by extending this methodology to include the fragment of the analogue of (−)-sibirine, we report the efficient synthesis and structural characterization of (1RS,2RS,6RS)-2-(6-Amino-9H-purin-9-yl)-8-azaspiro[5.6]dodec-10-en-1-ol dihydrochloride.

2. Results

Epoxide 1 was synthesized according to previously developed procedures [18,19]. Hydrochloride 3 was synthesized in two stages (Scheme 1). Epoxide 1 interacts with adenine when heated in a closed vessel, which leads to the formation of amino alcohol 2 in a 42% yield. When the unsymmetrical epoxides open, the SN2 nucleophilic substitution mechanism takes place, which implies the formation of two possible isomeric alcohols during the reaction. In our case, during the opening of the neopentyl fragment containing epoxide 1, only one from two regioisomers was formed. The resulting alcohol 2 was treated with a methanolic solution of hydrogen chloride at room temperature; as a result, we isolated the target product-((1RS,2RS,6RS)-2-(6-Amino-9H-purin-9-yl)-8-azaspiro[5.6]dodec-10-en-1-ol dihydrochloride (3). The synthesized hydrochloride 3 was isolated as a light brown powder.
The structure of the target product 3 was confirmed by 1H, 13C, HR-MS and IR spectroscopy (see Supplementary Materials). The 1H, HR-MS, HMBC, HSQC, ROESY and COSY NMR and IR spectroscopy established the chemical formula of compound 2. The 13C-NMR spectrum of 2 showed signals of carbamate rotamers around the N-Boc group. The 1H-NMR spectrum of 3 showed signals of an olefinic protons at 5.60–5.68 ppm and 5.87–5.96 ppm, signals of protons in the adenine (two C-H signals) fragment at 8.51 ppm and at 8.63 ppm, respectively. The characteristic signals of the C=C double bond in the 13C-NMR spectrum were 123.2 ppm and 131.2 ppm, and the CH-OH carbon’s signal in the carbocyclic fragment was 78.7 ppm.
The IR spectrum reveals that there were characteristic bands of the amino group of the purine fragment (3304 and 3144 cm−1), OH group (1689 cm−1) and C=N, C=C double bonds (1510–1605 cm−1).
The molecular structure of compound 3 is illustrated in Figure 1 according to the X-ray diffraction data. The X-ray profiling showed that the compound crystallized as a dichloride salt and contained one molecule of water. A deep analysis of the long bonds and the Fourier synthesis difference showed that the protonation in the crystal is observed for both the nitrogen atom of the spirocycle and for the nitrogen atom N(1). In this particular case, a very unusual supramolecular organization was observed in the crystal: the formation of a tetracationic dimer.
This centrosymmetric dimer, evidently unfavorable from an electrostatic point of view, is stabilized by two OH…N(7) hydrogen bonds (2.908(2)Å) and two intermolecular H-bonds N(10)-H…O(1) (N...O 2.872(2) Å) (Figure 2). Taking into account that the hydroxyl group acts in this supramolecular system as both a donor and an acceptor of a proton, it is logical to assume that, due to cooperative effects, the O–H…N hydrogen bond will be additionally strengthened.
In addition to the H-bonds, this dimer is also stabilized due to stacking interactions. Although the overlapping area of the purine rings is not large, the distance between the parallel planes of the purine rings is only 3Å, and the shortest N(7)…C(8) contacts are 3.077(2) Å. Evidently, for a given tetracationic dimer, it is impossible to estimate the stabilization energy by standard methods of quantum chemistry, since for charged supramolecular associates formed by fragments with the same charges, the dimer is inevitably unstable in the gas phase. Therefore, to assess its stabilization, we used an approach based on the use of a topological analysis of the electron density distribution function, in combination with the Espinosa–Lecomte empirical correlation [20,21]. The electron density distribution function (ρ(r)) was obtained for the experimental geometry, for which the optimization of the positions of the hydrogen atoms was carried out in the framework of the PBE1PBE/def-2-TZVP calculation. According to the topological analysis of ρ(r) in the framework of the “Atoms in the Molecule” theory, the critical points (3,−1) were localized both for all hydrogen bonds and for the stacking interaction. All of these nonvalent interactions in the dimer correspond to interactions of the closed shell type. The energy of the O-H…N bonds is 6.6 kcal/mol, and for N-H…O it is 9.8 kcal/mol. The stacking interaction is expectedly weaker and its total energy is 3.8 kcal/mol. Thus, the total stabilization of the dicationic dimer will be 36 kcal/mol. It seems that such a high stabilization energy is sufficient to stabilize the dimer despite the significant positive charge of the supramolecular associate.

3. Materials and Methods

3.1. General

Reagents were purchased at the highest commercial quality and used without further purification unless otherwise stated. Reactions were monitored by thin-layer chromatography (TLC) carried out on Merck TLC (Moscow, Russia) Silica gel plates (60F254), using UV light for visualization and basic aqueous potassium permanganate or iodine fumes as developing agents. 1H and 13C NMR spectra were recorded on Bruker Avance 400 instrument (Moscow, Russia) with an operating frequency of 400 and 100 MHz, respectively, and calibrated using residual undeuterated chloroform (δH = 7.26 ppm) and CDCl3 (δC = 77.16 ppm), or undeuterated DMSO (δH = 2.50 ppm) and DMSO-d6 (δC = 39.51 ppm) as internal references. The following abbreviations are used to set multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, br. = broad. For structure determination and NMR signal assignment in 2 2D correlation spectra, 1H-1H (COSY, ROESY) and 1H-13C (HSQC, HMBC) were used. IR spectra were recorded on Thermo Nicolet IR-200 in KBr, nujol or neat. High-resolution mass spectra (HRMS) were recorded on a TripleTOF 5600 mass spectrometer (AB Sciex, Concord, ON, Canada) equipped with a DuoSpray ion source. Low-resolution mass spectra were recorded on Finnigan MAT mass spectrometer using electron ionization (direct inlet) and an ITD-700 detector with the ionizing electron energy being 70 eV and the mass range being m/z 35–400. Elemental analysis was performed on EURO EA CHN Elemental Analyzer. The melting points (m.p.) were measured in open capillaries and presented without correction.

3.2. Synthesis of Tert-butyl (1RS,2RS,6RS)-2-(6-Amino-9H-purin-9-yl)-1-hydroxy-8-azaspiro[5.6]dodec-10-ene-8-carboxylate (2)

Epoxide 1 (0.50 g, 1.79 mmol, 1 eq) was dissolved in abs. DMF (18 mL, 0.1 M) and K2CO3 (0.741 g, 5.37 mmol, 3 eq) and adenine (0.484 g, 3.58 mmol, 2 eq) were added. The reaction mixture was heated at 110–120 °C for 30 h until complete disappearance of the starting epoxide by TLC (usually 25–30 h). The reaction mixture was cooled to room temperature, poured into water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The resulting substance was purified by flash chromatography (gradient elution with CH2Cl2-MeOH systems from 20:1 to 10:1). Yield 0.31 g (42%), beige crystals (yellow oil, crystallizing on storage), m.p. 220–225 °C (octane). Rf = 0.4 in CH2Cl2-MeOH (10:1). 1H-NMR (DMSO-d6, δH): 1.03–1.15 (m, 1H), 1.41 (d, J = 13.4 Hz, 9H), 1.47–1.62 (m, 1H), 1.68–2.02 (m, 4H), 2.06–2.25 (m, 1H), 2.34–2.69 (m, 1H), 3.38–4.42 (m, 6H), 4.89 (dd, J = 23.0, 7.6 Hz, 1H), 5.58–5.78 (m, 2H), 7.11 (d, J = 2.3 Hz, 2H), 8.10 (s, 1H), 8.13 (d, J = 6.7 Hz, 1H). 13C-NMR (mixture of rotamers), δC: (20.1, 20.5), (28.1, 28.2, 3 C), (31.0, 31.3), (32.1, 32.9), (37.6, 38.8), (44.3, 44.7), (46.7, 46.9), (47.5, 47.9), (56.6, 56.8), (77.1, 77.7), (79.2, 79.2), 119.2, (126.9, 127.6), (129.3, 129.6), 140.7, 149.8, 152.0, (155.1, 155.4), 156.0. IR νmax (cm−1): 3123, 2931, 2882, 2851, 1695, 1666, 1596, 1572, 1480, 1453, 1412, 1366, 1303, 1248, 1207, 1170, 1142, 1114, 1071, 892, 883, 798, 789, 767, 756, 653, 623, 602. HR-MS (ESI-TOF): 415.2458 ([M + H]+, C21H31N6O3; calcd 415.2452). Copies of 1H-NMR, 13C-NMR, 2D correlation spectra 1H-1H (COSY, ROESY) and 1H-13C (HSQC, HMBC) and mass spectra of 2 are presented in Supplementary Materials.

3.3. Synthesis of Dihydrochloride of (1RS,2RS,6RS)-2-(6-Amino-9H-purin-9-yl)-8-azaspiro[5.6]dodec-10-en-1-ol (3)

To alcohol 2 (0.20 g, 0.482 mmol, 1.0 eq) in MeOH (5 mL) was added a methanolic solution of hydrogen chloride (20 mL, 1M HCl, the solution was preliminarily prepared by adding acetyl chloride to methanol dropwise with cooling). The reaction mixture was allowed to stir at room temperature for 30 min and then rotary evaporated. Et2O (40 mL) was added, the precipitate was filtered off and air dried. Yield 0.18 g (96%), light brown crystals, m.p. 300–305 °C (methanol). 1H-NMR (DMSO-d6, δH): 1.16–1.31 (m, 1H), 1.43–1.67 (m, 2 H), 1.86–2.20 (m, 4 H), 2.93 (d, J = 13.3 Hz, 1H), 3.26–3.41 (m, 2H), 3.54–3.73 (m, 2H), 3.86 (d, J = 10.5 Hz, 1H), 4.45–4.55 (m, 1H), 5.60–5.68 (m, 1H), 5.87–5.96 (m, 1H), 8.51 (s, 1H), 8.63 (s, 1H), 8.72–9.55 (m, 4 H). 13C-NMR, δC: 19.6, 30.6, 32.0, 36.6, 42.5, 46.0, 47.9, 57.2, 76.7, 118.0, 123.2, 131.2, 143.4, 144.5, 148.7, 150.5. IR νmax (cm−1): 3304, 3144, 3052, 2943, 2788, 2659, 1689, 1605, 1584, 1510, 1469, 1459, 1417, 1382, 1306, 1206, 1060, 886, 784, 695, 678, 637, 619. HR-MS (ESI-TOF): 315.1932 ([M-2HCl + H]+, C16H23N6O; calcd 315.1928).

3.4. Crystallography Details

X-ray crystallography study of the crystals were carried out on a Bruker Quest D8 diffractometer equipped with a Photon-III detector using ϕ,ϖ-scans of narrow (0.5°) frames with Mo Kα radiation (λ = 0.71073 Å) and a graphite monochromator. The structure was solved by direct methods using the SHELXT-2014/5 [22] and was refined by the full-matrix least-squares method against all F2 in anisotropic approximation using the SHELXL-2018/3 [23]. The hydrogen atom positions were calculated with the riding model. Absorption corrections were applied using the empirical multi-scan method with the SADABS program [24]. The hydrogen atoms of the NH and OH groups are localized from Fourier electron density syntheses. All other hydrogen atoms were placed in the calculated positions and refined according to the rider model. An analysis of the difference syntheses of electron density and atomic displacement parameters showed that the solvate water molecule is disordered over two positions with occupancies 0.548(7) and 0.452(7). The compound was triclinic, space group P-1, a = 7.3638(4), b = 10.7327(6), c = 13.0314(8)Å, α = 110.036(2)°, β = 105.026(2)°, γ = 92.097(2)°, V = 925.53(9) Å3, Z = 2, C16H26Cl2N6O2, Dc = 2.230 r/cm3, µ = 1.454 mm−1, F(000) = 428, independent reflections 5382, wR2 = 0.1513, S = 1.04 for all reflections (R = 0.0589 for 3921 I > 2σ). Tables listing detailed crystallographic data, atomic positional parameters and bond lengths and angles are available as CCDC 2122336 from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif (accessed on 16 November 2021).

4. Conclusions

The interaction of adenine with spirocycle 1 in DMF led to the epoxide ring-opening product 2 upon treatment of it with a saturated methanolic solution of hydrogen chloride. We successfully obtained the target compound ((1RS,2RS,6RS)-2-(6-Amino-9H-purin-9-yl)-8-azaspiro[5.6]dodec-10-en-1-ol dihydrochloride in gram quantitates, good purity and with a 40% preparative yield in two steps.

Supplementary Materials

The following data are available online. 1H-NMR, 13C-NMR, 2D correlation spectra 1H-1H (COSY, ROESY), 1H-13C (HSQC, HMBC) and HR-MS of 2 and 3.

Author Contributions

I.R.I. performed the chemical synthesis. The registration and interpretation of the NMR data and structure characterization of both compounds were conducted by I.R.I. and A.A. X-ray crystallography study of the crystals was carried out by K.A.L. The manuscript was written by A.V.K., A.A. and K.A.L. All authors have read and agreed to the published version of the manuscript.

Funding

The current work was financially supported by the Russian Foundation for Basic Research (Grant No. 20-33-90036).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The study was performed using equipment purchased at the expense of the Development Program of Moscow State University. High-resolution mass spectra were recorded at the Department of Structural Studies, N.D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences, Moscow.

Conflicts of Interest

The authors declare no conflict of interest.

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Scheme 1. The opening of epoxide 1 with adenine and synthesis of ((1RS,2RS,6RS)-2-(6-Amino-9H-purin-9-yl)-8-azaspiro[5.6]dodec-10-en-1-ol dihydrochloride (3).
Scheme 1. The opening of epoxide 1 with adenine and synthesis of ((1RS,2RS,6RS)-2-(6-Amino-9H-purin-9-yl)-8-azaspiro[5.6]dodec-10-en-1-ol dihydrochloride (3).
Molbank 2022 m1495 sch001
Figure 1. The molecular structure of dication 3. Displacement ellipsoids are shown at a 50% probability level.
Figure 1. The molecular structure of dication 3. Displacement ellipsoids are shown at a 50% probability level.
Molbank 2022 m1495 g001
Figure 2. Centrosymmetric tetracationic dimer in crystal 3 (hydrogen atoms of C-H groups are not shown).
Figure 2. Centrosymmetric tetracationic dimer in crystal 3 (hydrogen atoms of C-H groups are not shown).
Molbank 2022 m1495 g002
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Iusupov, I.R.; Lyssenko, K.A.; Altieri, A.; Kurkin, A.V. (1RS,2RS,6RS)-2-(6-Amino-9H-purin-9-yl)-8-azaspiro[5.6]dodec-10-en-1-ol Dihydrochloride. Molbank 2022, 2022, M1495. https://doi.org/10.3390/M1495

AMA Style

Iusupov IR, Lyssenko KA, Altieri A, Kurkin AV. (1RS,2RS,6RS)-2-(6-Amino-9H-purin-9-yl)-8-azaspiro[5.6]dodec-10-en-1-ol Dihydrochloride. Molbank. 2022; 2022(4):M1495. https://doi.org/10.3390/M1495

Chicago/Turabian Style

Iusupov, Ildar R., Konstantin A. Lyssenko, Andrea Altieri, and Alexander V. Kurkin. 2022. "(1RS,2RS,6RS)-2-(6-Amino-9H-purin-9-yl)-8-azaspiro[5.6]dodec-10-en-1-ol Dihydrochloride" Molbank 2022, no. 4: M1495. https://doi.org/10.3390/M1495

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