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Synlett 2017; 28(05): 565-571
DOI: 10.1055/s-0036-1588651
DOI: 10.1055/s-0036-1588651
letter
Synthesis of Novel Tetranorlabdane Derivatives with Unprecedented Carbon Skeleton
Further Information
Publication History
Received: 17 October 2016
Accepted after revision: 19 October 2016
Publication Date:
18 November 2016 (online)
![](https://www.thieme-connect.de/media/synlett/201705/lookinside/thumbnails/st-2016-d0475-l_10-1055_s-0036-1588651-1.jpg)
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.
Key words
(–)-sclareol - (+)-sclareolide - methyl 7-oxo-13,14,15,16-tetranorlabd-8-en-12-oate - cycloaddition - dimer - terpeno-(1,2)-diazineSupporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0036-1588651.
- Supporting Information
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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): νmax = 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): νmax = 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
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- 23 Garlaschelli L, Vidari G. Tetrahedron 1989; 45: 7371
- 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): νmax = 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): νmax = 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): νmax = 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): νmax = 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
- 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
- 28 Mantu D, Moldoveanu C, Nicolescu A, Deleanu C, Mangalagiu I. Ultrason. Sonochem. 2009; 16: 452
- 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): νmax = 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): νmax = 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].