Synthesis of Novel Tetranorlabdane Derivatives with Unprecedented Carbon Skeleton

 

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Abstract

Synthesis of novel tetranorlabdane derivatives including hybride with terpeno-(1,2)-diazine units and dimers with an unprecedented carbon skeleton, was performed based on methyl 7-oxo-13,14,15,16-tetranorlabd-8-en-12-oate intermediate. The structures of the synthesized compounds have been fully confirmed, including by X-ray diffraction, and their antifungal and antibacterial activity was tested. A possible mechanistic pathway of the cycloaddition reaction is considered.

• References and Notes

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• 21 Dye-Sensitized Photooxygenation of Diene 13 meso-Tetraphenylporphyrin (TPP, 2 mg) was added to a stirred solution of diene 13 (0.24 g, 0.92 mmol) in CH₂Cl₂ (25 mL). The resulting mixture was irradiated with two 100 W lamps while oxygen was passed through the solution with stirring for 5 h at 5 °C. Evaporation of the solvent at the reduced pressure and chromatography of the residue (0.311 g) on SiO₂ (16 g, eluent: PE–EtOAc, 9:1) gave endoperoxide 14 (0.057 g, 21%), dioxine 15 (0.019 g, 7%), and dienone 16 (0.137 g, 54%).Analytical Data for Endoperoxide 14 White crystals; mp 68–69 °С (from PE–EtOAc, 9:1). [α]_D ²³ +12.0 (c 0.21, CHCl₃). IR (film): ν_max = 2924, 1730, 1427, 1356, 1198, 1167, 1107 cm^–1. ¹H NMR (400.13 MHz, CDCl₃): δ = 6.36 (1 H, d, J = 6.0 Hz, H-7), 4.52 (1 H, d, J = 6.0 Hz, H-6), 3.68 (3 H, s, CO₂CH₃), 2.84 (1 H, d, J = 16.0 Hz, H-11), 2.62 (1 H, d, J = 16.0 Hz, H-11), 2.06 (1 H, m, H-5), 2.02 (3 H, s, H-17), 1.06 (3 H, s, H-20), 0.92 (3 H, s, H-18), 0.79 (3 H, s, H-19). ¹³C NMR (100.61 MHz, CDCl₃): δ = 169.9 (C-12), 141.8 (C-8), 125.7 (C-7), 86.3 (C-9), 72.3 (C-6), 51.9 (C-5), 51.7 (CO₂ CH₃), 45.3 (C-10), 38.8 (C-3), 32.2 (C-4), 31.8 (C-19), 32.0 (C-11), 30.5 (C-1), 24.3 (C-18), 21.3 (C-17), 20.1 (C-20), 18.6 (C-2). MS: m/z (%) = 262 (10) [(M⁺ –32], 205 (3), 193 (18), 187 (19), 173 (29), 151 (10), 133 (20), 119 (44), 109 (95), 95 (57), 81 (54), 69 (78), 55 (54), 41 (100). HRMS (EI): m/z calcd for C₁₇H₂₆O₄: 294.18311; found: 294.18231 [M⁺– 32]. Analytical Data for Dioxine 15 Oil; [α]_D ²⁷ –15.5 (c 0.4, CHCl₃). IR (film): ν_max = 2951, 1738, 1672, 1436, 1335, 1262, 1172, 1155, 1025, 905 cm^–1. ¹H NMR (400.13 MHz, CDCl₃) δ = 3.67 (3 H, s, CO₂CH₃), 3.15 (1 H, d, J = 4.0 Hz, H-6), 2.85 (1 H, d, J = 4.0 Hz, H-7), 2.83 (1 H, d, J = 16.0 Hz, H-11), 2.56 (1 H, d, J = 16.0 Hz, H-11), 1.49 (1 H, d, J = 4.0 Hz, H-5), 1.62 (3 H, s, H-17), 1.03 (3 H, s, H-19), 1.01 (3 H, s, H-18), 0.97 (3 H, s, H-20). ¹³C NMR (100.61 MHz, CDCl₃): δ = 170.8 (C-12), 68.4 (C-9), 58.5 (C-8), 52.9 (C-6), 51.9 (CO₂ CH₃), 49.1 (C-7), 45.5 (C-5), 40.5 (C-3), 39.7 (C-10), 33.9 (C-1), 33.2 (C-11), 32.7 (C-4), 32.6 (C-19), 22.1 (C-18), 19.3 (C-17), 18.5 (C-2), 17.9 (C-20). MS: m/z (%) = 293 (18) [M⁺ – 33], 194 (5), 167 (10), 159 (8), 133 (20), 124 (6), 109 (24), 85 (22), 81 (16), 69 (43), 55 (35), 41 (48). HRMS (EI): m/z calcd for C₁₇H₂₆O₆: 326.19248; found: 293.17408 [M⁺ – 32]. Analytical data for dienone 16 were consistent with those reported in literature.^4,9
• 22 Balci M. Chem. Rev. 1981; 81: 91
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• 23 Garlaschelli L, Vidari G. Tetrahedron 1989; 45: 7371
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• 24 Bromination of Ketoester 6 NBS (0.819 g, 5.38 mmol) was added to a solution of ketoester 6 (1.0 g, 3.59 mmol) in dry CCl₄ (27 mL), and the mixture was heated to reflux for 2 h. After cooling, the reaction mixture was filtered and the solvent removed under reduced pressure. The resulting crude product (1.4 g) was purified by column chromatography on silica gel (7.0 g, eluent: PE–EtOAc, 95.5:0.5), to give bromide 22 (0.13 g, 10%) and bromide 21 (1.15 g, 90%). Analytical Data for Bromide 21 Colorless crystals; mp 101–102 °C (from PE). Anal. Calcd (%) for C₁₇H₂₇O₃Br: C, 56.82; H, 7.57; Br, 22.24. Found: C, 56.97; H, 7.62; Br, 22.13. [α]_D ²⁰ –123.1 (c 1.9, CHCl₃). IR (CCl₄): ν_max = 2949, 2928, 2870, 2849, 1738, 1714, 1460, 1436, 1391, 1373, 1230, 1260, 1193, 1171, 1115, 1097, 1066, 1035, 992, 880, 833, 792, 772, 626, 527, 480 cm^–1. ¹H NMR (400.13 MHz, CDCl₃): δ = 3.71 (3 H, s, CO₂CH₃), 3.03 (1 H, dd, J = 16.0, 4.0 Hz, H-11), 2.64 (1 H, d, J = 16.0 Hz, H-6), 2.60 (1 H, d, J = 16.0 Hz, H-6), 2.46 (1 H, dd, J = 16.0, 4.0 Hz, H-11), 2.05 (1 H, d, J = 4.0 Hz, H-9), 1.70 (3 H, s, H-17), 1.28 (1 H, dd, J = 16.0, 4.0 Hz, H-5), 1.17 (3 H, s, H-19), 0.90 (3 H, s, H-18), 0.87 (3 H, s, H-20). ¹³C NMR (100.61 MHz, CDCl₃): δ = 202.8 (C-7), 173.8 (C-12), 69.5 (C-8), 56.4 (C-9), 53.9 (C-5), 52.1 (CO₂ CH₃), 41.4 (C-3), 39.1 (C-1), 38.9 (C-10), 34.5 (C-11), 33.7 (C-4), 33.1 (C-6), 32.7 (C-19), 27.3 (C-17), 21.1 (C-18), 17.7 (C-2), 14.4 (C-20). Analytical Data for Bromide 22 Colorless crystals, mp 107–108 °C (from PE). Anal. Calcd (%) for C₁₇H₂₅O₃Br: C, 57.14; H, 7.05; Br, 22.37. Found: C, 57.17; H, 6.91; Br, 22.21. [α]_D ²⁰ +30.5 (c 6.2, CHCl₃). IR (CCl₄): ν_max = 2933, 2867, 2855, 1771, 1741, 1668, 1614, 1457, 1443, 1434, 1424, 1389, 1377, 1366, 1339, 1330, 1323, 1257, 1214, 1199, 1168, 1158, 1168,1038, 1014, 982, 929, 886, 823, 786, 759, 737, 704, 688 cm^–1. ¹H NMR (400.13 MHz, CDCl₃): δ = 4.41 (1 H, d, J = 9.6 Hz, H-17), 3.95 (1 H, d, J = 9.6 Hz, H-17), 3.74 (3 H, s, CO₂CH₃), 3.54 (1 H, d, J = 16.4 Hz, H-11), 3.39 (1 H, d, J = 16.4 Hz, H-11), 2.59 (1 H, dd, J = 17.6, 3.2 Hz, H-6), 2.43 (1 H, dd, J = 17.6, 14.4 Hz, H-6), 1.78 (1 H, d, J = 3.2 Hz, H-5), 1.19 (3 H, s, H-19), 1.09 (3 H, s, H-18), 0.93 (3 H, s, H-20). ¹³C NMR (100.61 MHz, CDCl₃): δ = 196.9 (C-7), 169.8 (C-12), 164.1 (C-9), 134.0 (C-8), 52.6 (CO₂ CH₃), 49.5 (C-5), 41.1 (C-10), 40.8 (C-3), 35.1 (C-1), 34.9 (C-6), 34.1 (C-11), 33.2 (C-4), 32.3 (C-19), 24.6 (C-17), 21.3 (C-18), 18.4 (C-2), 17.5 (C-20).
• 25 Synthesis of Dimer 23 KOAc (0.64 g, 6.44 mmol) was added to a solution of bromide 21 (1.15 g, 3.22 mmol) in dry DMSO (23 mL), and the reaction mixture was stirred overnight at r.t. Then it was diluted with water (50 mL) and extracted with Et₂O (3 × 20 mL). The combined organic phases were washed with water (3 × 30 mL) and dried. After solvent removal in vacuo, the crude reaction product (1.2 g) was subjected to column chromatography on silica gel (36 g, eluent: PE–EtOAc, 95:5), to give dimer 23 (1.54 g, 86%) and acetate 24 (0.14 g, 14%). Analytical Data for Dimer 23 Colorless crystals; mp 223-224 °C (from PE). [α]_D ²⁰ –26.8 (c 18.4, CHCl₃). IR (CCl₄): ν_max = 3435, 2958, 2300, 1728, 1704, 1669, 1618, 1458, 1433, 1381, 1368, 1255, 1192, 1159, 1069, 1043, 1024, 839, 799 cm^–1. ¹H NMR (400.13 MHz, CDCl₃): δ (unit A) = 3.58 (3 H, s, CO₂CH₃), 3.23 (1 H, s, H-11), 1.20–2.80 (11 H, overlapped signals, H-1, H-3, H-5, H-6, H-17), 0.95 (6 H, s, H-18 and H-19), 0.78 (3 H, s, H-20); δ (unit B) = 3.80 (1 H, s, H-11′^¢), 3.57 (3 H, s, CO₂CH₃), 1.20–2.80 (11 H, overlapped signals, H-1′, H-3′, H-5′, H-6′, H-17′), 1.01 (3 H, s, H-19′), 0.95 (3 H, s, H-18′), 0.92 (3 H, s, H-20′). ¹³C NMR (100.61 MHz, CDCl₃): δ (unit A) = 210.7 (C-7), 172.3 (C-12), 69.9 (C-9), 57.6 (C-8), 53.4 (C-11), 51.9 (CO₂ CH₃), 44.6 (C-5), 40.6 (C-3), 40.4 (C-10), 36.6 (C-6), 34.6 (C-1), 34.2 (C-4), 33.2 (C-18), 21.5 (C-18), 20.6 (C-17), 18.4 (C-2), 15.8 (C-20); δ (unit B) = 213.9 (C-7′), 169.9 (C-12′), 72.3 (C-9′), 51.9 (CO₂ CH₃), 51.8 (C-8′), 45.9 (C-11′), 41.8 (C-5′), 41.6 (C-3′), 39.1 (C-10′), 39.1 (C-6′), 38.2 (C-1′), 33.0 (C-19′), 30.0 (C-4′), 27.1 (C-17′), 22.6 (C-18′), 20.4 (C-20′),18.6 (C-2′). MS: m/z (%) = 552 (35) [M⁺], 5520 (37), 492 (15), 488 (18), 461 (32), 445 (6), 396 (7), 364 (5), 336 (5), 304 (5), 288 (6), 276 (34), 264 (4), 217 (14), 195 (5), 175 (8), 147 (12), 133 (9), 109 (31), 97 (12), 81 (34), 73 (11), 69 (73), 57 (28), 43 (67). HRMS (EI): m/z C₃₄H₄₈O₆: 552.74404; found: 552.34628 [M⁺]. Analytical Data for Acetate 24 Oil. Anal. Calcd (%) for C₁₈H₂₈O₅: C, 64.26; H, 8.38. Found: C, 64.13; H, 8.40. [α]_D ²⁴ +31.9 (c 0.2, CHCl₃). IR (film): ν_max = 3457, 2954, 1930, 1870, 1739, 1673, 1613, 1461, 1434, 1380, 1365, 1335, 1234, 1199, 1163, 1072, 1024, 963, 830, 786, 745, 624, 421 cm^–1. ¹H NMR (400.13 MHz, CDCl₃): δ = 4.83 (1 H, d, J = 12.0 Hz, H-17), 4.79 (1 H, d, J = 12.0 Hz, H-17), 3.71 (3 H, s, CO₂CH₃), 3.55 (1 H, d, J = 16.0 Hz, H-11), 3.37 (1 H, d, J = 16.0 Hz, H-11), 2.58 (1 H, dd, J = 17.6, 3.6 Hz, H-6), 2.42 (1 H, dd, J = 17.6, 14.4 Hz, H-6), 2.02 (3 H, s, OAc), 1.79 (1 H, m, H-5), 1.12 (s, 3 H, H-19), 0.93 (3 H, s, H-18), 0.91 (3 H, H-20); ¹³C NMR (100.61 MHz, CDCl₃): δ = 198.4 (C-7), 171.0 (OAc), 170.4 (C-12), 165.3 (C-9), 131.9 (C-8), 58.0 (C-17), 52.5 (CO₂ CH₃), 49.6 (C-5), 41.0 (C-10), 40.9 (C-3), 35.2 (C-1), 34.9 (C-6), 33.9 (C-11), 33.2 (C-4), 32.3 (C-19), 21.3 (C-18), 20.9 (OAc), 18.4 (C-2), 18.1 (C-20).
• 26 Kuchkova K, Aricu A, Barba A, Vlad P, Shova S, Secara E, Ungur N, Zbancioc G, Mangalagiu II. Synlett 2013; 24: 697
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• 27 Kuchkova K, Aricu A, Secara E, Barba A, Vlad P, Ungur N, Tuchilus C, Shova S, Zbancioc G, Mangalagiu II. Med. Chem. Res. 2014; 23: 1559
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• 28 Mantu D, Moldoveanu C, Nicolescu A, Deleanu C, Mangalagiu I. Ultrason. Sonochem. 2009; 16: 452
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• 29 Synthesis of Terpeno-Heterocycle 29 and Dimer 26d K₂CO₃ (0.042 g, 0.3 mmol) was added to a solution of 3(2H)-piridazinone (27) or 4,5-dihydro-3(2H)-piridazinone (28, 0.02 g, 0.1 mmol) in dry DMAA (3 mL). A solution of bromide 21 (0.072 g, 0.2 mmol) in dry DMAA (1 mL) was added dropwise (30 min, stirring) to the resulting mixture. The mixture was stirred at r.t. for 48 h, then filtered, and the residue was washed with Et₂O (2 × 10 mL). After solvent removal under reduced pressure, the crude reaction product was dissolved in a small volume of acetone, adsorbed on SiO₂, and eluted with mixture of PE–EtOAc (1:1) to give N-substituted terpeno-pyridazinone derivative 29 (0.07 g, 75% yield) and dimer 26d (0.078 g, 70%). Analytical Data for Terpeno-Heterocycle 29 Oil. [α]_D ²⁴ +145.9 (c 0.4, CHCl₃). IR (film): ν_max = 2949, 2930, 1736, 1662, 1590, 1254, 1198, 1160, 1115, 818 cm^–1. ¹H NMR (400.13 MHz, CDCl₃): δ = 7.61 (1 H, d, J = 10.0 Hz, H-4′), 7.56 (2 H, d, J = 10.0 Hz, H-2′′ and H-6′′), 7.21 (2 H, d, J = 10.0 Hz, H-3′′ and H-5′′), 6.96 (1 H, d, J = 10.0 Hz, H-3′), 5.22 (1 H, d, J = 15.0 Hz, H-17), 4.95 (1 H, d, J = 15.0 Hz, H-17), 3.66 (1 H, d, J = 20.0 Hz, H-11), 3.58 (3 H, s, CO₂CH₃), 3.39 (1 H, d, J = 20.0 Hz, H-11), 2.63 (1 H, dd, J = 25.0, 5.0 Hz, H-6), 2.46 (1 H, dd, J = 25.0, 15.0 Hz, H-6), 2.38 (3 H, s, H-7′′), 1.91 (1 H, dd, J = 15.0, 5.0 Hz, H-5), 1.14 (3 H, s, H-19), 0.92 (6 H, both s, H-18 and H-20). ¹³C NMR (100.61 MHz, CDCl₃): δ = 198.3 (C-7), 170.3 (C-12), 164.0 (C-9), 159.7 (C-2′), 143.9 (C-5′), 139.3 (C-4′′), 132.3 (C-8), 132.1 (C-1′′), 129.6 (C-3′, C-3′′ and 5′′), 129.5 (C-4′), 125.5 (C-2′′ and 6′′), 52.4 (CO₂ CH₃), 49.5 (C-5), 45.9 (C-17), 41.1 (C-10), 40.9 (C-3), 35.2 (C-6), 35.1 (C-1), 34.7 (C-11), 33.2 (C-4), 32.4 (C-19), 21.3 (C-7′′), 18.4 (C-18), 18.2 (C-20). MS: m/z (%) = 462 (7) [M⁺], 276 (55), 261 (34), 245 (4), 173 (12), 151 (9), 139 (8), 118 (4), 102 (4), 95 (6), 93 (7), 79 (9), 69 (17), 57 (8), 53 (9), 41 (33). HRMS (EI): m/z calcd for C₂₈H₃₅O₄N₂: 462.5876; found: 337.20026. Analytical Data for Dimer 26d White crystals; mp 147–148 °C (from PE). [α]_D ²⁵ –63.5 (c 0.5, CHCl₃). IR (CCl₄): ν_max = 2950, 2928, 1725, 1710, 1662, 1606, 1457, 1434, 1392, 1369, 1215, 1158, 1148, 1066, 1026, 980 cm^–1. ¹H NMR (400.13 MHz, CDCl₃): δ (unit A) = 4.23 (2 H, d, J = 1.4 Hz, H-11), 3.59 (3 H, s, CO₂CH₃), 2.15 (1 H, t, J = 9.0 Hz, H-5), 1.20–2.80 (10 H, overlapped signals, H-1, H-2, H-3, H-6, H-17), 1.15 (3 H, s, H-20), 0.95 (3 H, s, H-18), 0.92 (3 H, s, H-19); δ (unit B) = 6.0 (1 H, s, H-11′), 3.65 (3 H, s, CO₂CH₃), 2.05 (2 H, m, H-17′), 1.82 (1 H, dd, J = 13.3, 6.0 Hz, H-5′), 1.20–2.80 (10 H, overlapped signals, H-1′, H-2′, H-3′, H-6′, H-17′), 1.06 (3 H, s, H-20′), 0.92 (3 H, s, H-18′), 0.90 (3 H, s, H-19′). ¹³C NMR (100.61 MHz, CDCl₃): δ (unit A) = 200.8 (C-7), 172.9 (C-12), 161.0 (C-9), 132.7 (C-8), 53.2 (C-11), 52.0 (CO₂ CH₃), 49.6 (C-5), 41.0 (C-3), 40.5 (C-10), 35.7 (C-6), 34.4 (C-1), 33.3 (C-4), 32.9 (C-19), 21.8 (C-18), 20.6 (C-17), 20.1 (C-20), 18.5 (C-2); δ (unit B) = 209.9 (C-7′), 175.8 (C-9′), 166.5 (C-12′), 114.5 (C-11′), 56.6 (C-8′), 51.4 (CO₂ CH₃), 44.3 (C-5′), 42.8 (C-10′), 41.2 (C-3′), 40.3 (C-1′), 37.6 (C-6′), 33.9 (C-4′), 32.2 (C-19′), 31.3 (C-17′), 22.1 (C-20′), 21.9 (C-18′), 19.0 (C-2′). MS: m/z (%) = 552 (5) [M⁺], 261 (11), 205 (11), 189 (5), 165 (7), 152 (12), 149 (20), 137 (11), 125 (13), 109 (28), 97 (37), 82 (14), 79 (13), 59 (11), 56 (19), 44 (31). HRMS (EI): m/z C₃₄H₄₈O₆: 552.7496; found: 552.34571 [M⁺ – 30].

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