Synthesis of S-Containing Maleopimaric Acid Derivatives

New S-containing maleopimaric acid derivatives were synthesized. The structures of all synthesized compounds were elucidated using NMR spectroscopy and elemental analyses.

S-Containing organic compounds are widely used in industry, agriculture, and medicine. For example, vitamins (biotin, thiamine, coenzyme A, lipoic acid), amino acids (cystine, cysteine, methionine), and alkaloids (peptides isolated from EtOH extract of Amanita phalloides mushroom, Cruciferae plants, Nymphaeaceae water lilies, etc.) are notable natural compounds with pharmacological activity. S-Containing modern drugs are used as antibacterial, antituberculosis, and anti-inflammatory medicines [1]. The presence of S atoms in organic molecules is well-known to be responsible for their high physiological activity and to reduce their toxicity [2].

Levopimaric acid occurs in resins of many conifer species and has recently been used as a scaffold for synthesizing biologically active compounds [3]. Diene adducts of levopimaric acid and maleic anhydride, i.e., maleopimaric acid (MPA, 1) derivatives, are highly interesting because of their antibacterial, anti-inflammatory, and antiulcer properties [3]. Several S-containing levopimaric acid derivatives (quinopimaric acid framework derivatives) showed antihypoxic activity [4]. New S-containing MPA derivatives were synthesized by us to expand the repertoire of levopimaric acid derivatives and to discover new derivatives with valuable pharmacological properties.

S-Containing MPA derivatives were prepared in two steps using acid chlorides. First, the reaction of SOCl₂ and MPA (1) gave acid chloride 2, which then was reacted with mercaptans. The thiols were methyl and ethyl mercaptoacetates, 2-furylmethylthiol, thiophenol, 2-mercaptothiazoline, and 4,4′-thiodiphenol. The reactions were performed at room temperature in CH₂Cl₂ with added Et₃N. Carbothioates 3–8 were obtained in 74–99% yields.

The reaction with 4,4′-thiodiphenol gave carbothioate 8 and a small amount (4%) of dimer 9. Weak-field shifts of the carbonyl singlet (δ 185.54 ppm for MPA and 201–206 ppm for 3–9) and the C-6 singlet (δ 46.85 ppm for MPA and 54 for 3–6, 8) and a strong-field shift of C-6 in 7 (δ_C 46.79 ppm) confirmed that carbothioates 3–9 had formed.

Thus, MPA carbothioates were synthesized for the first time by us by reacting MPA chloride with mercaptans.

Experimental

General comments were published [4].

R_f values were determined using CHCl₃–MeOH (10:1).

MPA chloride (2) was synthesized as before [5]. All physicochemical properties of MPA chloride agreed with the literature.

Synthesis ofS-Containing MPA Derivatives. MPA chloride (2, 0.7 g, 1.67 mmol) in anhydr. CH₂Cl₂ (30 mL) was stirred at room temperature and treated with mercaptan (1.75 mmol) and then Et₃N (0.23 mL, 1.67 mmol). When the reaction was finished (TLC monitoring), the solvent was evaporated at reduced pressure. The residue was treated with anhydr. Me₂CO (25 mL). The precipitate was filtered off and rinsed with anhydr. Me₂CO (10 mL). The filtrate was evaporated at reduced pressure. The solid was dried under vacuum and ground. If necessary, the product was purified by column chromatography over SiO₂ (eluents CHCl₃ and CHCl₃–MeOH gradient, 100:1, 50:1, 10:1).

Methyl {[{(6R,9aR)-12-Isopropyl-6,9a-dimethyl-1,3-dioxotetradecahydro-1H-3b,11-ethenophenanthro[1, 2-c]furan-6-yl}carbonyl]thio}acetate (3). C₂₇H₃₆O₆S. Yield 87%, R_f 0.61, mp 45–48°C, ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ –4.4° (c 5.7, CHCl₃). IR spectrum (ν, cm^–1): 1842, 1779, 1744, 1681, 1463, 1385, 1297, 1232, 1159, 1084, 1003, 946, 918, 854. ¹³C NMR spectrum (CDCl₃, δ, ppm): 15.80 (CH₃, C-6), 16.83 (CH₃, C-9a), 17.07 (CH₂, C-8), 19.96 (CH₃, C-14), 20.57 (CH₃, C-14), 21.18 (CH₂, C-5), 27.28 (CH₂, C-10), 31.32 (CH₂, C-1′), 32.76 (CH, C-14), 34.69 (CH₂, C-4), 35.64 (CH, C-11), 37.62 (CH₂, C-7), 37.88 (CH₂, C-9), 37.96 (C, C-9a), 40.39 (C, C-3b), 45.67 (CH, C-11a), 50.22 (CH, C-5a), 52.75 (CH₃, COOMe), 53.05 (CH, C-3a), 53.31 (CH, C-9b), 54.35 (C, C-6), 125.16 (CH, C-13), 148.15 (C, C-12), 169.45 (C, COO), 170.92 (C, C-1), 172.71 (C, C-3), 206.32 (C, COS). Found, %: C 66.01; H 7.09; S 6.74. Calcd, %: C 66.37, H 7.43, S 6.56.

Ethyl {[{(6R,9aR)-12-Isopropyl-6,9a-dimethyl-1,3-dioxotetradecahydro-1H-3b,11-ethenophenanthro[1, 2-c]furan-6-yl}carbonyl]thio}acetate (4). C₂₈H₃₈O₆S. Yield 98%, R_f 0.68, mp 34–37°C, ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ –42° (c 0.9166, CHCl₃). IR spectrum (ν, cm^–1): 1842, 1778, 1733, 1682, 1464, 1377, 1297, 1232, 1155, 1083, 946, 917. ¹³C NMR spectrum (CDCl₃, δ, ppm): 14.12 (CH₃, Me in Et), 15.79 (CH₃, C-6), 16.82 (CH₃, C-9a), 17.07 (CH₂, C-8), 19.95 (CH₃, C-14), 20.56 (CH₃, C-14), 21.17 (CH₂, C-5), 27.25 (CH₂, C-10), 31.57 (CH₂, C-1′), 32.74 (CH, C-14), 34.66 (CH₂, C-4), 35.63 (CH, C-11), 37.65 (CH₂, C-7), 37.84 (CH₂, C-9), 37.93 (C, C-9a), 40.38 (C, C-3b), 45.64 (CH, C-11a), 50.16 (CH, C-5a), 53.02 (CH, C-3a), 53.26 (CH, C-9b), 54.31 (C, C-6), 61.77 (CH₂, OCH₂), 125.14 (CH, C-13), 148.16 (C, C-12), 168.96 (C, COO), 170.96 (C, C-1), 172.75 (C, C-3), 206.39 (C, COS). Found, %: C 70.01; H 7.77; S 6.50. Calcd, %: C 66.90, H 7.62, S 6.38.

S-(2-Furylmethyl) (6R,9aR)-12-Isopropyl-6,9a-dimethyl-1,3-dioxotetradecahydro-1H-3b,11-ethenophenanthro[ 1,2-c]furan-6-carbothioate (5). C₂₉H₃₆O₅S. Yield 99%, R_f 0.77, mp 154–157°C, ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ –54.7 ± 0.1° (c 1.01, CHCl₃). IR spectrum (ν, cm^–1): 1840, 1768, 1713, 1657, 1652, 1464, 1456, 1377, 1235, 1227, 1158, 1087, 1011, 945, 918, 854, 754. ¹³C NMR spectrum (CDCl₃, δ, ppm): 15.79 (CH₃, C-6), 16.83 (CH₃, C-9a), 17.11 (CH₂, C-8), 19.96 (CH₃, C-14), 20.56 (CH₃, C-14), 21.17 (CH₂, C-5), 25.92 (CH₂, C-1′), 27.26 (CH₂, C-10), 32.76 (CH, C-14), 34.69 (CH₂, C-4), 35.65 (CH, C-11), 37.66 (CH₂, C-7), 37.91 (CH₂, C-9), 37.96 (C, C-9a), 40.40 (C, C-3b), 45.65 (CH, C-11a), 50.18 (CH, C-5a), 53.04 (CH, C-3a), 53.32 (CH, C-9b), 54.41 (C, C-6), 104.92 (CH, C-4′′), 110.61 (CH, C-3′′), 125.17 (CH, C-13), 142.14 (CH, C-5′′), 148.17 (C, C-12), 150.65 (C, C-2′′), 170.94 (C, C-1), 172.70 (C, C-3), 206.73 (C, COS). Found, %: C 70.21; H 7.23; S 6.74. Calcd, %: C 70.13, H 7.31, S 6.46.

S-Phenyl (6R,9aR)-12-Isopropyl-6,9a-dimethyl-1,3-dioxotetradecahydro-1H-3b,11-ethenophenanthro[1, 2-c]furan-6-carbothioate (6). C₃₀H₃₆O₄S. Yield 74%, R_f 0.71, mp 186–188°C, ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ –61.4 ± 0.1° (c 1.01, CHCl₃). IR spectrum (ν, cm^–1): 1834, 1775, 1682, 1533, 1464, 1377, 1226, 1084, 945, 928, 915, 747. ¹³C NMR spectrum (CDCl₃, δ, ppm): 15.82 (CH₃, C-6), 17.01 (CH₃, C-9a), 17.16 (CH₂, C-8), 19.97 (CH₃, C-14), 20.57 (CH₃, C-14), 21.36 (CH₂, C-5), 27.26 (CH₂, C-10), 32.76 (CH, C-14), 34.73 (CH₂, C-4), 35.66 (CH, C-11), 37.71 (CH₂, C-7), 37.93 (CH₂, C-9), 37.99 (C, C-9a), 40.40 (C, C-3b), 45.65 (CH, C-11a), 50.15 (CH, C-5a), 53.06 (CH, C-3a), 53.31 (CH, C-9b), 54.93 (C, C-6), 125.15 (CH, C-13), 128.35 (C, C-1′), 129.13 (CH, C-2′, 6′), 129.21 (CH, C-4′), 135.13 (CH, C-3′, 5′), 148.21 (C, C-12), 171.07 (C, C-1), 172.77 (C, C-3), 205.98 (C, COS). Found, %: C 73.22; H 7.40; S 6.33. Calcd, %: C 73.14, H 7.37, S 6.51.

S-(4,5-Dihydro-1,3-thiazol-2-yl) (6R,9aR)-12-Isopropyl-6,9a-dimethyl-1,3-dioxotetradecahydro-1H-3b,11- ethenophenanthro[1,2-c]furan-6-carbothioate (7). C₂₇H₃₅NO₄S₂. Yield 99%, R_f 0.51, mp 63–67°C, ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ –2.6° (c 5.6, CHCl₃). IR spectrum (ν, cm^–1): 3142, 1841, 1778, 1693, 1519, 1464, 1377, 1299, 1231, 1088, 1053, 947, 924. ¹³C NMR spectrum (CDCl₃, δ, ppm): 15.51 (CH₃, C-6), 16.51 (CH₃, C-9a), 17.29 (CH₂, C-8), 19.97 (CH₃, C-14), 20.57 (CH₃, C-14), 21.67 (CH₂, C-5), 27.22 (CH₂, C-10), 32.76 (CH, C-14), 33.66 (CH₂, C-5′), 34.80 (CH₂, C-4), 35.69 (CH, C-11), 36.77 (CH₂, C-7), 37.57 (C, C-9a), 37.99 (CH₂, C-9), 40.45 (C, C-3b), 45.69 (CH, C-11a), 46.79 (C, C-6), 49.09 (CH, C-5a), 51.44 (CH₂, C-4′), 53.12 (CH, C-3a), 53.30 (CH, C-9b), 125.17 (CH, C-13), 148.17 (C, C-12), 171.07 (C, C-1), 172.83 (C, C-3), 184.29 (C, C-2′), 201.85 (C, COS). Found, %: C 64.84; H 7.29; N 3.03; S 12.74. Calcd, %: C 64.64, H 7.03, N 2.79, S 12.78.

S-[4-(4-Mercaptophenoxy)phenyl] (6R,9aR)-12-Isopropyl-6,9a-dimethyl-1,3-dioxotetradecahydro-1H-3b,11- ethenophenanthro[1,2-c]furan-6-carbothioate (8). C₃₆H₄₀O₅S₂. Yield 96%, obtained together with dimer 9, 8–9 ratio 96:4. Isolated pure by column chromatography. R_f 0.79, mp 151–154°C, ${\left[\alpha \right]}_{\mathrm{D}}^{20}$ –36.7 ± 0.1° (c 1.01, CHCl₃). IR spectrum (ν, cm^–1): 1848 br.s, 1778, 1697, 1581, 1483, 1456, 1377, 1238, 1167, 1083, 1013, 947, 914. 13C NMR spectrum (CDCl₃, δ, ppm): 15.54 (CH₃, C-6), 17.03 (CH₃, C-9à), 17.17 (CH₂, C-8), 19.99 (CH₃, C-14), 20.61 (CH₃, C-14), 21.41 (CH₂, C-5), 27.27 (CH₂, C-10), 32.79 (CH, C-14), 34.76 (CH₂, C-4), 35.65 (CH, C-11), 37.58 (CH₂, C-7), 37.91 (CH₂, C-9), 38.01 (C, C-9a), 40.43 (C, C-3b), 45.64 (CH, C-11a), 50.18 (CH, C-5a), 52.86 (CH, C-3a), 53.36 (CH, C-9b), 54.92 (C, C-6), 119.72 (CH, C-2′′, 6′′), 119.87 (CH, C-3′, 5′), 125.11 (CH, C-13), 131.05 (C, C-4′′), 131.76 (C, C-1′), 136.89 (CH, C-2′, 6′), 138.80 (CH, C-3′′, 5′′), 148.23 (C, C-12), 156.56 (C, C-1′′), 157.82 (C, C-4′), 171.05 (C, C-1), 172.74 (C, C-3), 206.44 (C, COS). Found, %: C 70.09; H 6.43; S 10.52. Calcd, %: C 70.10, H 6.54, S 10.40.

S,S′-[Oxy-bis(4,1-phenylene)]bis-[(6R,9aR)-12-Isopropyl-6,9a-dimethyl-1,3-dioxotetradecahydro-1H-3b,11- ethenophenanthro[1,2-c]furan-6-carbothioate] (9). Yield 4% (according to spectral data), obtained together with carbothioate 8, 8–9 ratio 96:4, not isolated pure. Characteristic resonances in the ¹³C NMR spectrum (CDCl₃, δ, ppm): 124.98 (CH, C-13), 131.08 (CH, C-2′, 6′), 154.80 (C, C-12), 206.41 (C, C=S).