(2aR,2a¹S,5aR,9bR)-4-Isopropyl-7,8-dimethoxy-2a¹-methyl-2,2a,2a¹,3,5a,9b-hexahydrofluoreno[9,1-bc]furan

Abstract

The development of highly efficient methods for the synthesis of chemical products by using renewable raw materials is one of the topical areas of medicinal chemistry. The paper presents the synthesis of (2aR,2a¹S,5aR,9bR)-4-isopropyl-7,8-dimethoxy-2a¹-methyl-2,2a,2a¹,3,5a,9b-hexahydrofluoreno[9,1-bc]furan. The title compound was obtained through Prins–Friedel–Crafts cascade reactions of trans-4-hydroxymethyl-2-carene, which was synthesized from 3-carene, one of the main components of gum turpentine. The product yield after purification was 48%. The compound’s structure was confirmed by X-ray diffraction analysis.

1. Introduction

Monoterpenes and their derivatives are valuable renewable raw materials in organic chemistry. Renewability, availability, enantiomeric purity, and variable reactivity make monoterpenes an attractive foundation for various transformations, including the production of new chiral heterocyclic biologically active compounds [1,2,3,4,5]. Reactions of monoterpenes with carbonyl compounds, primarily aldehydes, are important approaches for synthesizing oxygen-containing heterocycles. This approach has enabled the creation of compounds with previously unknown types of carbon skeletons, which exhibit a high biological activity [4].

One of the important methods for modifying monoterpenes is by obtaining their hydroxymethyl derivatives by Prins reaction. The addition of a hydroxymethyl fragment to the molecule opens up new possibilities for chemical modifications. Thus, when such hydroxymethyl derivatives interact with aldehydes, the formation of chiral heterocyclic compounds, promising for the study of their biological activity, often occurs [3,4].

One of the most widespread monoterpenes in nature is (+)-3-carene 1, which is the main constituent of gum turpentine and has a high optical purity. It is known that reactions of (+)-3-carene 1 with aldehydes (such as salicylic or vanillin) lead to the formation of 3-oxobicyclo[3.3.1]nonanes 2 and isobenzofurans 3, but with low yields (Scheme 1) [6]. It is worth noting that some isobenzofurans synthesized based on 3-carene have neuroprotective properties [3,4] and are also powerful inhibitors of the TDP1 enzyme, showing promise for use in complex cancer treatment [7]. A number of 3-oxabicyclo[3.3.1]nonenes act as antileishmanial agents [8,9] or estrogen receptor agonists [10,11,12,13], including in in vivo experiments [10].

In contrast to 3-carene 1, its hydroxymethyl derivative, trans-4-hydroxymethyl-2-carene 4 synthesized by Prins reaction with formaldehyde in acetic acid [14,15], readily reacts with aromatic aldehydes in the presence of montmorillonite clays, yielding a variety of heterocyclic products whose structure depends on the structures of the starting aldehyde [4,15]. For instance, the reaction of alcohol 4 and benzaldehyde results in the formation of isobenzofurans 5, while its reaction with salicylic aldehydes leads to a cascade Prins reaction, yielding compounds with a hexahydrofuro[4,3,2-kl]xanthenes 6 backbone (Scheme 2) [4,15,16]. When aldehydes containing electron-donating groups (-OH and -OMe) are used, a cascade reaction consisting of Prins cyclization and subsequent intramolecular Friedel−Crafts cyclization takes place, affording hexahydrofluoreno[9,1-bc]furans 7 (Scheme 2) [4,15,16,17]. Cascade transformations are an effective method for the synthesis of polycyclic compounds, allowing one to avoid the stage of isolation and purification of intermediates [16,18,19,20]. It should be noted that compound 7 with a hexahydrofluoreno[9,1-bc]furan skeleton exhibits a high cytotoxic effect (CTD₅₀ 0.9 µM) causing apoptosis in the MT-4 human lymphoblastoid cell line [16]. Therefore, the synthesis of new compounds with a hexahydrofluoreno[9,1-bc]furan skeleton is an important task.

2. Results

In the present work, the synthesis of hexahydrofluoreno[9,1-bc]furan 7a starting from trans-4-hydroxymethyl-2-carene 4 and 3,4-dimethoxybenzaldehyde 8 was carried out for the first time. The reaction proceeded in a single preparative step at room temperature without the use of a solvent, employing montmorillonite K10 as a catalyst, following the procedure previously described [15]. Montmorillonite K10 is an aluminosilicate with both Brønsted and Lewis acidic centers and is widely used as an acidic catalyst for reactions between monoterpenes and aldehydes [4,15,16]. The polycyclic compound 7a was obtained with a yield of 49%. The formation of hexahydrofluoreno[9,1-bc]furans 7 is characterized by high regio- and stereoselectivity, and no other products with skeleton type 7 were identified. Additionally, a complex mixture of compounds with m/z = 314 (probably alcohol 4 dimerization products and compound 7a isomers) was formed during the reaction, but we were unable to separate this mixture using column chromatography.

Despite a sufficient number of hexahydrofluoreno[9,1-bc]furans 7 obtained by the reaction of alcohol 4 and aromatic aldehydes being described in the literature [15,16], their structures, including the relative arrangement of substituents and ring coupling, were previously established based only on NMR spectra. In this work, we successfully isolated a new hexahydrofluoreno[9,1-bc]furan 7a in the form of crystals through recrystallization from ethyl acetate. We confirmed the structure of compound 7a by the results of X-ray diffraction analysis (Figure 1). The geometry of the fluorenofuran skeleton of compound 7a is close to the analogous 5a-methoxy-3-oxo-2-phenyl-2,2a,3,5a,9b,9c-hexahydrofluoreno[9,1-bc]furan-2-carboxylate [21].

3. Materials and Methods

3.1. General

All reagents and solvents were purchased from commercial suppliers and used as received. As the catalyst, we used montmorillonite K10 clay (Aldrich (St. Louis, MO, USA)). The clay was calcinated at 105 °C for 3 h immediately before use. CH₂Cl₂ was passed through calcined Al₂O₃. Analytical and spectral measurements were acquired at the Multi-Access Chemical Research Center SB RAS, located in Novosibirsk, Russia. Column chromatography (CC): silica gel (SiO₂; 60–200 μm; Macherey-Nagel (Dueren, Germany)); hexane/EtOAc 100:0 → 50:50. GC/MS for purity control and product analysis involved the use of an Agilent 7890A gas chromatograph (Agilent Technologies, Santa Clara, CA, USA) equipped with a quadrupole mass spectrometer Agilent 5975C as a detector. A HP-5MS quartz column measuring 30,000 × 0.25 mm was employed, and helium (1 atm) served as the carrier gas. Optical rotation measurements were conducted using a polarimetric spectrometer, namely, the polAAr 3005 spectrometer from Optical Activity Ltd. (Huntingdon, UK), with a CHCl₃ solution. High-resolution mass spectrometry (HR-MS) data were acquired using a DFS-Thermo-Scientific spectrometer (Thermo Fisher Scientific, Waltham, MA, USA) operating in full scan mode (15–500 m/z) with 70 eV electron-impact ionization and direct sample introduction. ¹H- and ¹³C-NMR: Bruker Avance-III 600 (Bruker Corporation, Karlsruhe, Germany) apparatus at 600.30 MHz (¹H) and 150.95 MHz (¹³C) in CDCl₃; chemical shifts δ in ppm rel. to residual CHCl₃ (δ (H) 7.24, δ (C) 76.90 ppm), J in Hz. Structural elucidation was achieved through a comprehensive analysis of ¹H and ¹³C NMR spectra, including two-dimensional homonuclear ¹H-¹H correlation spectra (COSY); ¹³C NMR spectra recorded in the J-modulation (JMOD) mode, and ¹³C-¹H 2D heteronuclear correlation on direct and long-range spin-spin coupling constants (C-H COSY, ¹J(C,H) = 135 Hz; HSQC, ¹J(C,H) = 145 Hz; HMBC, ^2,3J(C,H) = 7 Hz). Note that numeration of atoms of 7a (see Scheme 3) is given to assign the signals in the NMR spectra and does not coincide with that for the names according to the nomenclature of compounds. Trans-4-hydroxymethyl-2-carene 4 was synthesized according to [10] from 3-carene 1 (Acros Organics, 98%). (Copies of ¹H and ¹³C NMR Spectra and HR-MS spectrum can be found in the Supplementary Materials).

3.2. Synthesis of (2aR,2a¹S,5aR,9bR)-4-Isopropyl-7,8-dimethoxy-2a¹-methyl-2,2a,2a¹,3,5a,9b-hexahydrofluoreno[9,1-bc]furan 7a

To the suspension of K10 (2.0 g) in CH₂Cl₂ (10 mL), 3,4-dimethoxybenzaldehyde (0.500 g, 3.01 mmol, 1 eq.) and solution of trans-4-hydroxymethyl-2-carene 2 (0.500 g, 3.01 mmol, 1 eq.) in CH₂Cl₂ (5 mL) were added. The solvent was evaporated, and the reaction mixture was allowed to stand at room temperature for 2 h. Following this, 20 mL of ethyl acetate was added, the catalyst was separated by filtration, and the resulting filtrate was subjected to evaporation. The residue was purified by column chromatography on SiO₂ with EtOAc/hexane gradient (0–50%) to obtain compound 7a (465 mg, 49%).

(2aR,2a¹S,5aR,9bR)-4-Isopropyl-7,8-dimethoxy-2a¹-methyl-2,2a,2a¹,3,5a,9b-hexahydrofluoreno[9,1-bc]furan 7a. White powder; mp = 159.0–159.5 °C (from EtOAc); ${\left[\alpha \right]}_D^{26}$ = 48 (c 0.3, CHCl₃). NMR ¹H (600 MHz, CDCl₃, δ, ppm, J/Hz): 0.96 (3H, d, J_18,16 = 6.8 Hz, Me-18), 0.97 (3H, d, J_17,16 = 6.8 Hz, Me-17), 1.34 (3H, s, Me-19), 1.87 (1H, dd, J_{10,10`</sub> = 16.6, J<sub>10,1</sub> = 3.2 Hz, H-10), 2.17 (1H, dm, J<sub>10`,10} = 16.6 Hz, H-10`), 2.18-2.28 (2H, m, H-1, H-16), 3.17-3.21 (2H, m, H-2, H-7), 3.76 (1H, dd, J_2′,2 = 8.3, J_2′,1 = 6.8 Hz, H-2’), 3.85 (3H, s, Me-20), 3.88 (3H, s, Me-21), 5.00 (1H, s, H-4), 5.63-5.65 (1H, m, H-8), 6.68 (1H, s, H-15), 6.85 (1H, s, H-14). NMR ¹³C (151 MHz, CDCl₃, δ, ppm): 20.71 (q, C-17), 20.89 (q, C-18), 23.18 (t, C-10), 26.73 (q, C-19), 34.95 (d, C-16), 45.35 (d, C-1), 50.05 (s, C-11), 50.12 (d, C-7), 55.74 (q, C-20), 55.85 (q, C-21), 70.91 (t, C-2), 94.35 (d, C-4), 105.58 (d, C-15), 107.56 (d, C-12), 120.01 (d, C-8), 131.93 (s, C-5), 138.55 (s, C-6), 140.13 (s, C-9), 148.86 (s, C-13), 150.32 (d, C-14). HR-MS: 314.1872 (M⁺, C₂₀H₂₆O₃; calc. 314.1877).

3.3. X-ray Diffraction Analysis

Single crystals of 3 were obtained by slow evaporation of its EtOAc solution at room temperature. The X-ray diffraction of compound 7a was carried out on a Bruker KAPPA APEX II CCD diffractometer with graphite monochromated MoKα (0.71073 Å) radiation at room temperature. Absorption corrections were applied using SADABS. The structure was resolved by the direct method. The positions and temperature factors of the non-hydrogen atoms were refined with anisotropic parameters using the full-matrix least-squares technique. The hydrogen atoms were refined in the riding model. All computations were conducted using SHELXT and SHELXL programs. Some crystal data for 7a: the crystal system is orthorhombic, space group is P2₁2₁2₁, C₂₀H₂₆O₃, M 314.41, a 6.3419(3), b 9.6339(6), c 28.5594(14) Å, V 1744.90(16) ų, Z 4, d_calc 1.197 g/cm³, μ 0.079 mm⁻¹, 9650 collected reflections, 2θ < 52°. Final R 0.0476 [2879 with I > 2σ(I)], wR₂ 0.1162 [3408 I], S 1.045. The isopropyl group is disordered (rotation by 155° around the bond C9-C16) in the ratio 0.66(2):0.34(2). The atom coordinates and their temperature parameters were deposited in the Cambridge Structural Database, CCDC 2294387.

4. Conclusions

Starting from 3-carene 1, a new oxygen heterocyclic compound, (2aR,2a¹S,5aR,9bR)-4-isopropyl-7,8-dimethoxy-2a¹-methyl-2,2a,2a¹,3,5a,9b-hexahydrofluoreno[9,1-bc]furan 7a, was synthesized. Its structure was determined by 1D and 2D NMR experiments (HSQC, HMBC, COSY), HR-MS and X-ray diffraction analysis.