4.2.2. General Procedure for the Synthesis of Homodrimanyl Aliphatic Amides (4–16): Aminolysis Reaction from Amines
According to a published procedure [
21] with little modifications, a solution of (+)-sclareolide (100 mg, 0.4 mmoL, 1.0 eq.) and the opportune amine in dry THF (1.5 mL) was stirred at 45 °C for 48–72 h. The reaction mixture was then concentrated under reduced pressure and dispersed in water (15 mL). The inorganic phase was extracted twice with EtOAc (15 mL), and the collected organic layers were washed with brine (15 mL), dried over anhydrous Na
2SO
4 and filtered. The solvent was removed under vacuum, and the crude product was purified by flash chromatography using a mixture of PE/EtOAc as eluent to give the homodrimanyl aliphatic amide in good yield.
N-benzyl-2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)acetamide (4)
The product was purified by column chromatography using PE/EtOAc (1.5/1) as eluent to give the compound as a colorless oil. Yield 98%. IR ν (cm−1): 3014, 2926, 1650, 1214, 748, 666. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.28-7.14 (m, 4H, Ar), 6.92 (t, J = 12.1 Hz, 1H, Ar), 4.38-4.21 (m, 2H, CH2NH), 3.53 (s, 1H, OH), 2.36 (dd, J1 = 15.2 Hz, J2 = 4.5 Hz, 1H, CH2CO), 2.09 (dd, J1 = 15.5 Hz, J2 = 4.7 Hz, 1H, CH2CO), 1.83 (dt, J1 = 12.1 Hz, J2 = 2.7 Hz, 1H), 1.68 (t, J = 4.7 Hz, 1H), 1.62-1.08 (m, 9H, CH2), 1.02 (s, 3H, CH3), 0.94-0.85 (m, 1H, CH), 0.80 (s, 3H, CH3), 0.71 (s, 6H, CH3). 13C NMR (75 MHz, CDCl3) δ (ppm): 175.6, 138.4, 129.1, 128.6, 128.3, 128.1, 72.9, 57.3, 56.6, 55.1, 43.5, 41.7, 38.8, 34.1, 33.2, 32.5, 24.4, 22.9, 22.2, 20.5, 18.3, 16.2, 14.6. Anal. Calcd. for C23H35NO2: C, 77.27; H, 9.87; N, 3.92. Found: C, 77.38; H, 9.90; N, 3.93.
N-(4-chlorobenzyl)-2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)acetamide (5)
The product was purified by column chromatography using PE/EtOAc (2/1) as eluent to give the compound as a white solid, mp 154–155 °C (G). Yield 70%. IR ν (cm−1): 3279, 2924, 1642, 1492, 1387, 1091, 1015, 938, 800. 1H NMR (300 MHz, CDCl3) δ: 7.25-7.23(m, 2H, Ar), 7.15-7.13 (m, 2H, Ar), 4.35-4.21 (m, 2H, CH2NH), 3.69 (brs, 1H, OH), 2.42 (dd, J1 = 15.4 Hz, J2 = 4.5 Hz, 1H, CH2CO), 2.16 (dd, J1 = 15.4 Hz, J2 = 4.6 Hz, 1H, CH2CO), 1.90-1.85 (m, 1H, CH), 1.71-1.20 (m, 10H), 1.07 (s, 3H, CH3), 0.94-0.90 (m, 1H, CH), 0.86 (s, 3H, CH3), 0.77 (s, 3H, CH3), 0.74 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3) δ: 175.8, 137.1, 132.9, 128.8 (×2), 128.6 (×2), 72.9, 57.9, 55.9, 44.1, 42.8, 41.7, 39.2, 38.7, 33.3, 33.2, 32.5, 23.7, 21.4, 20.4, 18.3, 15.4. Anal. Calcd. for C23H34ClNO2: C, 70.48; H, 8.74; N, 3.57. Found: C, 70.22; H, 8.77; N, 3.56.
N-(3,4-dichlorobenzyl)-2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)acetamide (6)
The product was purified by column chromatography using PE/EtOAc (1/1.5) as eluent to give the compound as a white solid, mp 149-150 °C (G). Yield 83%. IR ν (cm−1): 3298, 2926, 1642, 1548, 1470, 1388, 1082, 1032, 754. 1H NMR (400 MHz, DMSO) δ (ppm): 8.23 (t, 1H, J = 6.1 Hz, NH), 7.51 (d, J = 8.3 Hz, 1H, Ar), 7.44 (d, J = 1.8 Hz, 1H, Ar), 7.20 (dd, J1 = 8.3 Hz, J2 = 1.8 Hz, 1H, Ar), 4.26 (dd, J1 = 15.5 Hz, J2 = 6.2 Hz, 1H, CH2NH), 4.15 (dd, J1 = 15.5 Hz, J2 = 5.8 Hz, 1H, CH2NH), 2.34 (dd, J1 = 15.4 Hz, J2 = 2.8 Hz, 1H, CH2CO), 2.05 (dd, J1 = 15.4 Hz, J2 = 7.1 Hz, 1H, CH2CO), 1.76-1.66 (m, 2H), 1.54-1.02 (mm, 8H), 0.93 (s, 3H, COH(CH3)), 0.87-0.82 (m, 2H), 0.80 (s, 3H, CH3), 0.72 (s, 6H, CH3). 13C NMR (100 MHz, DMSO) δ (ppm): 174.6 (C=O), 141.7 (CqAr), 131.3 (CqAr), 130.8 (CHAr), 129.6 (CHAr + CqAr), 128.1 (CHAr), 71.6 (Cq-OH(CH3)), 56.8 (CH), 56.0 (CH), 44.2, 42.0, 41.6, 39.2, 38.7, 33.7, 33.3, 31.6, 24.6, 21.8, 20.5, 18.3, 15.5. Anal. Calcd. for C23H32Cl2NO2: C, 64.78; H, 7.80; N, 3.28. Found: C, 65.02; H, 7.77; N, 3.29.
N-(4-fluorobenzyl)-2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)acetamide (7)
The product was purified by column chromatography using PE/EtOAc (1.5/1) as eluent to give the compound as a white solid, mp 135-136 °C (G). Yield 97%. IR ν (cm−1): 3675, 2987, 2907, 1510, 1214, 1057, 742, 666. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.22-7.19 (m, 2H, Ar), 6.97 (t, J = 8.6 Hz, 2H, Ar), 6.38 (brs, 1H, NH), 4.37 (dd, J1 = 15.0 Hz, J2 = 6.0 Hz, 1H, CH2-NH), 4.31 (dd, J1 = 15.0 Hz, J2 = 5.9 Hz, 1H, CH2-NH), 2.46 (brs, 1H, OH), 2.39 (dd, J1 = 15.4 Hz, J2 = 5.2 Hz, 1H, CH2CO), 2.14 (dd, J1 = 15.4 Hz, J2 = 4.1 Hz, 1H, CH2CO), 1.90 (dt, J1 = 12.5 Hz, J2 = 3.0 Hz, 1H, -CH2-COH(CH3)), 1.76 (t, J = 4.6 Hz, 1H, -CH-COH(CH3)), 1.68-1.52 (m, 2H), 1.50-1.32 (m, 4H), 1.29-1.12 (m, 2H), 1.10 (s, 3H, COH(CH3)), 0.97-0.88 (m, 2H), 0.85 (s, 3H, CH3), 0.76 (s, 3H, CH3), 0.75 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ (ppm): 175.2 (C=O), 162.1 (d, J = 267 Hz, Cq-F), 134.3 (CqAr), 129.4 (×2, J = 7.9 Hz, CHAr), 115.5 (×2, J = 21.3 Hz, CHAr), 73.2 (Cq-OH(CH3)), 57.9 (CH), 56.0 (CH), 44.3, 43.0, 41.8, 39.4, 38.8 (Cq-(CH3)2), 33.3, 32.6, 29.7, 23.8, 21.4, 20.5, 18.4, 15.5. Anal. Calcd. for C23H24FNO2: C, 73.56; H, 9.13; N, 3.73. Found: C, 73.76; H, 9.09; N, 3.72.
2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)-N-(4-methoxybenzyl)acetamide (8)
The product was purified by column chromatography using PE/EtOAc (1/1) as eluent to give the compound as a yellow oil. Yield 78%. IR ν (cm−1): 3675, 3289, 2920, 1512, 1214, 1038, 748, 666. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.17 (d, 2H, J = 8.4 Hz, Ar), 6.83 (d, 2H, J = 8.6 Hz, Ar), 6.23 (brs, 1H, NH), 4.34 (dd, J1 = 14.8 Hz, J2 = 5.8 Hz, 1H, CH2NH), 4.29 (dd, J1 = 14.8 Hz, J2 = 5.6 Hz, 1H, CH2NH), 3.77 (s, 3H, OCH3), 2.47 (brs, 1H, OH), 2.39 (dd, J1 = 15.4 Hz, J2 = 5.2 Hz, 1H, CH2CO), 2.12 (dd, J1 = 15.4 Hz, J2 = 4.0 Hz, 1H, CH2CO), 1.90 (dt, J1 = 9.6 Hz, J2 = 2.9 Hz, 1H, -CH2-COH(CH3)), 1.78 (t, J = 4.5 Hz, 1H, -CH-COH(CH3)), 1.68-1.45 (mm, 4H), 1.42-1.12 (mm, 4H), 1.10 (s, 3H, COH(CH3)), 0.97-0.93 (m, 2H), 0.85 (s, 3H, CH3), 0.76 (s, 3H, CH3), 0.75 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ (ppm): 175.1 (C=O), 159.0 (CqAr), 130.5 (CqAr), 129.1 (×2, CHAr), 114.1 (×2, CHAr), 73.1 (Cq-OH(CH3)), 57.8 (CH), 56.0 (CH), 55.3 (OCH3), 44.3, 43.3, 41.8, 39.4, 38.8 (Cq-(CH3)2), 33.3, 33.2, 32.5, 23.7, 21.4, 20.5, 18.4, 15.5. Anal. Calcd. for C24H37NO3: C, 74.38; H, 9.62; N, 3.61. Found: C, 74.42; H, 9.66; N, 3.62.
2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)-N-(3 methoxybenzyl)acetamide (9)
The product was purified by column chromatography using PE/EtOAc (1/1) as eluent to give the compound as a yellow oil. Yield 85%. IR ν (cm−1): 3291, 2945, 1642, 1264, 1214, 1051, 746, 666. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.15-7.07 (m, 1H, Ar), 6.74-6.68 (m, 3H, Ar), 4.30-4.17 (m, 2H, CH2NH), 3.68 (s, 3H, CH3O), 2.36 (dd, J1 = 15.4 Hz, J2 = 4.4 Hz, 1H, CH2CO), 2.09 (dd, J1 = 15.3 Hz, J2 = 4.7 Hz, 1H, CH2CO), 1.95-1.79 (m, 1H, CH), 1.67 (t, J = 4.5 Hz, 1H), 1.57-1.03 (m, 9H, CH2), 1.00 (s, 3H, CH3), 0.87-0.81 (m, 1H, CH), 0.78 (s, 3H, CH3), 0.69 (s, 6H, CH3). 13C NMR (75 MHz, CDCl3) δ (ppm): 178.9, 159.6, 140.1, 129.5, 119.7, 112.9, 112.7, 72.9, 57.8, 55.9, 44.1, 43.4, 41.7, 39.2, 38.7, 33.3, 33.2 (×2), 32.4, 23.6, 21.4, 20.4, 18.3, 15.3. Anal. Calcd. for C24H37NO3: C, 74.38; H, 9.62; N, 3.61. Found: C, 74.48; H, 9.65; N, 3.60.
2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)-N-phenethylacetamide (10)
The product was purified by column chromatography using PE/EtOAc (1/1) as eluent to give the compound as a light yellow oil. Yield 95%. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.29-7.19 (m, 2H, Ar), 7.18-7.10 (m, 2H, Ar), 6.60-6.51 (m, 1H, Ar), 3.54 (s, 1H, OH), 3.48-3.32 (m, 2H, CH2NH), 2.74 (t, J = 6.6 Hz, 2H, CH2Ar), 2.02 (dd, J1 = 14.5 Hz, J2 = 3.4 Hz, 1H, CH2CO), 1.85 (dd, J1 = 12.3 Hz, J2 = 5.0 Hz, 1H, CH2CO), 1.91-1.80 (m, 1H), 1.65-1.10 (m, 10H), 1.04 (s, 3H, CH3), 0.92-0.85 (m, 1H, CH), 0.80 (s, 3H, CH3), 0.70 (s, 6H, CH3). 13C NMR (75 MHz, CDCl3) δ (ppm): 175.6, 139.0, 129.8, 129.6, 127.8, 127.5, 125.3, 72.9, 57.2, 55.1, 40.7, 38.7, 35.5, 33.2, 32.6, 24.5, 23.1, 22.2, 20.5, 19.8, 19.1, 18.3, 16.2, 14.6. IR ν (cm−1): 3021, 2930, 1655, 1214, 748, 666. Anal. Calcd. for C24H37NO2: C, 77.58; H, 10.04; N, 3.77. Found: C, 77.60; H, 10.07; N, 3.77.
N-(4-chlorophenethyl)-2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)acetamide (11)
The product was purified by column chromatography using PE/EtOAc (1/1) as eluent to give the compound as a white solid, mp 168 °C (G). Yield 75%. IR ν (cm−1): 3298, 2977, 2914, 1634, 1214, 1056, 749, 666. 1H NMR (400 MHz, DMSO) δ (ppm): 7.68 (m, 1H, NH), 7.31-7.28 (m, 2H, Ar), 7.22-7.19 (m, 2H, Ar), 4.23 (s, 1H, OH), 3.27-3.20 (m, 2H, CH2NH), 2.69-2.64 (m, 2H, CH2-Ar), 2.21 (d, J = 15.4 Hz, 1H, CH2CO), 1.95 (dd, J1 = 15.3 Hz, J2 = 6.1 Hz, 1H, CH2CO), 1.71-1.60 (m, 4H), 1.53-1.40 (m, 2H), 1.37-1.12 (m, 4H), 1.08-1.01 (m, 2H), 0.93 (s, 3H, COH(CH3)), 0.82 (s, 3H, CH3), 0.73 (s, 3H, CH3), 0.69 (s, 3H, CH3). 13C NMR (100 MHz, DMSO) δ (ppm): 174.4 (C=O), 139.1 (CqAr), 131.0 (×2, CHAr + CqAr), 128.6 (×2, CHAr), 71.6 (Cq-OH(CH3)), 56.8 (CH), 56.0 (CH), 44.2, 42.0, 39.4 (under DMSO), 38.9, 38.7 (Cq-(CH3)2), 34.7, 33.8, 33.3, 31.8, 24.6, 21.8, 20.5, 18.4, 15.5. Anal. Calcd. for C24H36ClNO2: C, 71.00; H, 8.94; N, 3.45. Found: C, 71.12; H, 8.97; N, 3.46.
N-(4-fluorophenethyl)-2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)acetamide (12)
The product was purified by column chromatography using PE/EtOAc (1/1) as eluent to give the compound as a white solid, mp 114–115 °C (G). Yield 83%. IR ν (cm−1): 3298, 2970, 2933, 1642, 1509, 1215, 1057, 748, 666. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.15-7.12 (m, 2H, Ar), 6.96 (t, 2H, J = 8.2 Hz, Ar), 6.03 (brs, 1H, NH), 3.52-3.37 (m, 2H, CH2NH), 2.76 (t, J = 6.1 Hz, 2H, CH2-Ar), 2.47 (brs, 1H, OH), 2.29 (dd, J1 = 15.3 Hz, J2 = 5.2 Hz, 1H, CH2CO), 2.04 (dd, J1 = 15.3 Hz, J2 = 3.9 Hz, 1H, CH2CO), 1.89 (dt, J1 = 12.5 Hz, J2 = 3.1 Hz, 1H, -CH2-COH(CH3)), 1.68-1.62 (m, 1H), 1.56-1.51 (m, 2H), 1.42-1.32 (m, 4H), 1.27-1.14 (m, 2H), 1.09 (s, 3H, COH(CH3)), 0.93-0.90 (m, 2H), 0.85 (s, 3H, CH3), 0.75 (s, 3H, CH3), 0.73 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ (ppm): 175.4 (C = O), 161.6 (d, J = 244 ppm, Cq-F), 134.7 (CqAr), 130.3 (×2, J = 7.5 Hz, CHAr), 115.4 (×2, J = 21.2 Hz, CHAr), 73.1 (Cq-OH(CH3)), 57.9 (CH), 56.0 (CH), 44.3, 41.8, 40.7, 39.3, 38.7 (Cq-(CH3)2), 34.8, 33.3, 33.2, 32.6, 23.8, 21.4, 20.5, 18.3, 15.4. Anal. Calcd. for C24H36FNO2: C, 74.00; H, 9.32; N, 3.60. Found: C, 73.88; H, 9.36; N, 3.59.
N-(3-fluorophenethyl)-2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)acetamide (13)
The product was purified by column chromatography using PE/EtOAc (1/1) as eluent to give the compound as an amorphous solid. Yield 72%. IR ν (cm−1): 3685, 3310, 2977, 1642, 1215, 1057, 747, 666. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.27-7.18 (m, 1H, Ar), 7.00-6.84 (m, 2H, Ar), 6.66 (t, J = 5.4 Hz, 1H, Ar), 3.53-3.32 (m, 2H, CH2NH), 2.77 (t, J = 6.9 Hz, 2H, CH2), 2.34 (dd, J1 = 15.3 Hz, J2 = 4.6 Hz, 1H, CH2), 2.06 (dd, J1 = 15.3 Hz, J2 = 5.3 Hz, 1H, CH2), 1.91-1.86 (m, 1H, CH), 1.65-1.10 (m, 10H), 1.07 (s, 3H, CH3), 0.95-0.87 (m, 1H, CH), 0.85 (s, 3H, CH3), 0.73 (s, 6H, CH3). 13C NMR (75 MHz, CDCl3) δ (ppm): 175.8, 164.5, 161.2, 141.6, 128.9, 125.6, 123.5, 114.8, 112.3, 72.9, 57.2, 56.6, 55.1, 40.5, 38.7, 35.2, 32.6, 31.7, 23.3, 20.9, 18.2, 16.2, 14.9, 14.5. Anal. Calcd. for C24H36FNO2: C, 74.00; H, 9.32; N, 3.60. Found: C, 73.90; H, 9.34; N, 3.61.
N-(furan-2-ylmethyl)-2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)acetamide (14)
The product was purified by column chromatography using PE/EtOAc (1/1) as eluent to give the compound as a yellow oil. Yield 95%. IR ν (cm−1): 3306, 2926, 1648, 1214, 746, 666. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.31 (s, 1H, Fur), 6.32 (brs, 1H, NH), 6.28 (t, J = 1.3 Hz, 1H, Fur), 6.18 (d, J = 2.7 Hz, 1H, Fur), 4.40 (dd, J1 = 15.5 Hz, J2 = 5.5 Hz, 1H, CH2NH), 4.36 (dd, J1 = 15.5 Hz, J2 = 5.4 Hz, 1H, CH2NH), 2.92 (brs, 1H, OH), 2.38 (dd, J1 = 15.4 Hz, J2 = 5.1 Hz, 1H, CH2CO), 2.12 (dd, J1 = 15.4 Hz, J2 = 4.2 Hz, 1H, CH2CO), 1.90 (d, J = 12.5 Hz, 1H, -CH2-COH(CH3)), 1.76 (t, J = 4.5 Hz, 1H, -CH-COH(CH3)), 1.67-1.51 (m, 2H), 1.49-1.31 (m, 4H), 1.29-1.19 (m, 2H), 1.10 (s, 3H, COH(CH3)), 0.98-0.89 (m, 2H), 0.84 (s, 3H, CH3), 0.76 (s, 6H, CH3). 13C NMR (100 MHz, CDCl3) δ (ppm): 175.1 (C=O), 151.5 (CqAr), 142.1 (CHFur), 110.4 (CHFur), 107.2 (CHFur), 73.2 (Cq-OH(CH3)), 57.8 (CH), 55.9 (CH), 44.3, 41.8, 39.3, 38.7 (Cq-(CH3)2), 36.8, 33.3, 33.2, 32.5, 23.7, 21.4, 20.5, 18.4, 15.5. Anal. Calcd. for C21H33NO3: C, 72.58; H, 9.57; N, 4.03. Found: C, 72.70; H, 9.61; N, 4.03.
N-((1,1′-biphenyl)-4-ylmethyl)-2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)acetamide (15)
The product was purified by column chromatography using PE/EtOAc (2/1) as eluent to give compound as an amorphous solid. Yield 40%. IR ν (cm−1): 3288, 2924, 1637, 1548, 1386, 1123, 938, 759, 696. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.58-7.52 (m, 4H, Ar), 7.46-7.41 (m, 2H, Ar), 7.37-7.31 (m, 2H, Ar), 6.60 (t, J = 5.2 Hz, 1H, Ar), 4.5-4.36 (m, 2H, CH2NH), 3.15 (brs, 1H, OH), 2.46 (dd, J1 = 15.4 Hz, J2 = 4.9 Hz, 1H, CH2CO), 2.17 (dd, J1 = 15.4 Hz, J2 = 4.3 Hz, 1H, CH2CO), 1.94-1.89 (m, 1H), 1.81 (t, J = 4.6 Hz, 1H), 1.73-1.21 (m, 9H, CH2), 1.12 (s, 3H, CH3), 1.00-0.96 (m, 1H), 0.86 (s, 3H, CH3), 0.77 (s, 6H, CH3). 13C NMR (75 MHz, CDCl3) δ (ppm): 175.4, 140.7, 140.2, 137.5, 128.8 (×2), 128.1, 127.3 (×2), 127.0, 73.1, 57.8, 55.9, 44.2, 43.4, 41.7, 39.3, 38.7, 33.3, 33.2, 32.6, 31.6, 23.7, 22.7, 21.4, 20.5, 18.4, 15.5, 14.2. Anal. Calcd. for C29H39NO2: C, 80.33; H, 9.07; N, 3.23. Found: C, 80.55; H, 9.11; N, 3.24.
N-(3-(1H-imidazol-1-yl)propyl)-2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)acetamide (16)
Without any further purification, the product was obtained as a light yellow solid, mp 83-84 °C (G). Yield 93%. IR ν (cm−1): 3291, 2926, 1644, 1390, 1214, 1082, 747, 666. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.47 (s, 1H, imid), 7.00 (s, 1H, imid), 6.90 (s, 1H, imid), 6.79 (brt, J = 5.3 Hz, 1H, NH), 3.95 (t, J = 6.9 Hz, 2H, CH2-Nimid), 3.23-3.11 (m, 2H, CH2-NH), 2.72 (brs, 1H, OH), 2.34 (dd, J1 = 15.2 Hz, J2 = 5.3 Hz, 1H, CH2CO), 2.12 (dd, J1 = 15.2 Hz, J2 = 4.0 Hz, 1H, CH2CO), 1.97-1.88 (m, 3H), 1.69 (t, J = 4.6 Hz, 1H, -CH-COH(CH3)), 1.66-1.32 (mm, 6H), 1.28-1.18 (m, 2H), 1.12 (s, 3H, COH(CH3)), 0.95-0.89 (m, 2H), 0.84 (s, 3H, CH3), 0.75 (s, 3H, CH3), 0.74 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ (ppm): 175.9 (C=O), 137.2 (CHimid), 129.2 (CHimid), 119.0 (CHimid), 73.3 (Cq-OH(CH3)), 58.2 (CH), 56.1 (CH), 44.6, 44.3, 41.8, 39.5, 38.8 (Cq-(CH3)2), 36.6, 33.3, 33.2, 32.7, 31.0, 23.8, 21.4, 20.5, 18.4, 15.4. Anal. Calcd. for C22H37N3O2: C, 70.36; H, 9.93; N, 11.19. Found: C, 70.24; H, 9.97; N, 11.24.
4.2.4. General Procedure for the Synthesis of Homodrimanyl Diol Esters (22–24)
According to a published procedure with some modifications, homodrimanyl diol 21 (80 mg, 0.31 mmol, 1.0 eq.) was dissolved in anhydrous DCM (2 mL) under an inert atmosphere. The appropriate carboxylic acid (0.34 mmol, 1.1 eq.), 1-etil-3-(3-dimetilaminopropil) carbodiimide (EDCI) (0.37 mmol, 1.2 eq.), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (DMAP) (0.031 mmol, 0.1 eq.) was added under stirring to the solution. The mixture was stirred at rt, checking the reaction by TLC, until the starting material disappeared (48–72 h). The reaction was quenched by the addition of water (5 mL) and the inorganic layer was extracted with DCM (2 × 10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na
2SO
4, and filtered. The solvent was removed under reduced pressure, and the resulting residue was purified by flash chromatography on silica gel using the mixture PE/EtOAc as eluent to give final ester in good yield [
26].
2-((1R,2R,4aS,8aS)-2-Hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)ethyl Benzo[d][1,3]dioxole-5-carboxylate (22)
The product was purified by column chromatography using PE/EtOAc (4/1) as eluent to give the compound as a white solid, mp 155-156 °C (G). Yield 59%. IR ν (cm−1): 3675, 2977, 2901, 1705, 1441, 1258, 1214, 1076, 1041, 750, 666. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.63 (d, J = 8.0 Hz, 1H, Ar), 7.45 (s, 1H, Ar), 6.81 (d, J = 8.1 Hz, 1H, Ar), 6.01 (s, 2H, OCH2O), 4.36-4.29 (m, 2H, CH2-OCO), 1.91-1.81 (m, 2H), 1.77-1.59 (m, 4H), 1.45-1.34 (m, 3H), 1.31-1.10 (mm, 7H), 0.97-0.90 (m, 2H), 0.85 (s, 3H, CH3), 0.79 (s, 3H, CH3), 0.78 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ (ppm): 166.1 (C=O), 151.5 (CqAr), 147.7 (CqAr), 125.3 (CHAr), 124.6 (CqAr), 109.6 (CHAr), 108.0 (CHAr), 101.8 (OCH2O), 73.7 (Cq-OH(CH3)), 67.1 (CH2-O), 58.1 (CH), 56.1 (CH), 44.5, 41.9, 39.8, 38.8 (Cq-(CH3)2), 33.4, 33.3, 24.7, 24.0, 21.5, 20.5, 18.4, 15.3. Anal. Calcd for C24H34O5: C, 71.61; H, 8.51. Found: C, 71.87; H, 8.55.
2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)ethyl (E)-3-(benzo[d][1,3]dioxol-5-yl)acrylate (23)
The product was purified by column chromatography using PE/EtOAc (4/1) as eluent to give the compound as a white solid, mp 115–116 °C (G). Yield 65%. IR ν (cm−1): 2983, 2901, 1214, 1057, 744, 668. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.57 (d, J = 15.9 Hz, 1H, CH=CH-Ar), 7.00 (s, 1H, Ar), 6.98 (d, J = 8.0 Hz, 1H, Ar), 6.78 (d, J = 8.0 Hz, 1H, Ar), 6.22 (d, J = 15.9 Hz, 1H, CH=CH-Ar), 5.98 (s, 2H, OCH2O), 4.28-4.17 (m, 2H, CH2-OCO), 1.88 (dt, J = 12.3 Hz, J = 2.9 Hz, 1H, -CH2-COH(CH3)), 1.83-1.53 (m, 4H), 1.46-1.34 (m, 4H), 1.31-1.20 (m, 2H), 1.16 (s, 3H, COH(CH3)), 1.14-1.09 (m, 2H), 0.95-0.90 (m, 2H), 0.85 (s, 3H, CH3), 0.79 (s, 3H, CH3), 0.77 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ (ppm): 167.3 (C=O), 149.6 (CqAr), 148.4 (CqAr), 144.5 (=CH-Ar), 128.9 (CqAr), 124.4 (CHAr), 116.2 (CH=CHAr), 108.6 (CHAr), 106.6 (CHAr), 101.6 (OCH2O), 73.6 (Cq-OH(CH3)), 66.6 (CH2-O), 58.1 (CH), 56.1 (CH), 44.4, 41.9, 39.7, 38.8 (Cq-(CH3)2), 33.4, 33.3, 24.7, 24.0, 21.5, 20.5, 18.4, 15.3. Anal. Calcd for C26H36O5: C, 72.87; H, 8.47. Found: C, 73.01; H, 8.49.
2-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)ethyl 4-(thiophen-2-yl)butanoate (24)
The product was purified by column chromatography using PE/EtOAc (3/1) as eluent to give the compound as a colorless oil. Yield 70%. IR ν (cm−1): 3675, 2958, 1724, 1390, 1214, 1082, 748, 692, 667. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.10 (d, J = 5.0 Hz, 1H, thienyl), 6.90 (t, J = 4.2 Hz, 1H, thienyl), 6.78 (d, J = 2.4 Hz, 1H, thienyl), 4.17-4.06 (m, 2H, CH2-OCO), 2.86 (t, J = 7.5 Hz, 2H, COCH2-CH2-CH2), 2.34 (t, J = 7.5 Hz, 2H, COCH2-CH2-CH2), 2.03-1.95 (m, 2H, COCH2-CH2-CH2), 1.87 (d, J = 12.3 Hz, 1H, -CH2-COH(CH3)), 1.77-1.69 (m, 1H), 1.67-1.52 (mm, 6H), 1.43-1.35 (m, 3H), 1.30-1.19 (m, 1H), 1.14 (s, 3H, COH(CH3)), 1.12-1.07 (m, 1H), 0.92-0.88 (m, 2H), 0.86 (s, 3H, CH3), 0.77 (s, 6H, CH3). 13C NMR (100 MHz, CDCl3) δ (ppm): 173.4 (C=O), 144.1 (Cqthienyl), 126.8 (CHthienyl), 124.5 (CHthienyl), 123.2 (CHthienyl), 73.6 (Cq-OH(CH3)), 66.6 (CH2-O), 58.0 (CH), 56.1 (CH), 44.4, 41.9, 39.7, 38.8 (Cq-(CH3)2), 33.5, 33.4, 33.3, 29.2, 26.8, 24.5, 24.0, 21.5, 20.5, 18.4, 15.3. Anal. Calcd for C24H38O3S: C, 70.89; H, 9.42. Found: C, 70.75; H, 9.44.
Synthesis of (1R,2R,4aS,8aS)-1-(2-((3-Chlorobenzyl)oxy)ethyl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol (homodrimanyl diol ether) (25)
Homodrimanyl diol 20 (90 mg, 0.35 mmol, 1.0 eq.) was dissolved in anhydrous THF (10 mL) under argon atmosphere and NaH, previously purified, (67.0 mg, 0.4 mmol, 1.2eq) was added. The reaction mixture was refluxed for 30 min and then, after cooling at rt, 3-chlorobenzyl bromide (67.6 mg, 0.42 mmol, 1.2 eq.) was added. The mixture was still heated to reflux for 48 h, cooled to rt and quenched with water and saturated NH4Cl solution (pH 7). Afterward, the aqueous layer was extracted with EtOAc (3 × 15 mL) and the combined organic phases were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness to obtain the final homodrimanyl diol ether. Column chromatography with PE/EtOAc (8/1) as eluent gave the pure compound as a light yellow oil. Yield 27%. IR ν (cm−1): 2926, 1214, 1077, 750, 667. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.39-7.18 (m, 4H), 4.49 (s, 2H, CH2-Ar), 3.68-3.57 (m, 1H), 3.41-3.30 (m, 1H), 3.19 (brs, 1H, OH), 1.96-1.85 (m, 1H), 1.83-1.70 (m, 1H), 1.69-1.48 (m, 3H), 1.44-1.17 (m, 8H), 1.14 (s, 3H, CH3), 0.96-0.90 (m, 1H), 0.88 (s, 3H, CH3), 0.78 (s, 6H, CH3). 13C NMR (75 MHz, CDCl3) δ (ppm): 139.9, 129.8, 127.8, 127.8, 126.5, 125.7, 72.5, 72.3, 72.2, 59.0, 56.0, 43.9, 41.8, 39.5, 38.9, 33.4, 33.2, 25.2, 24.3, 21.5, 20.4, 18.4, 15.3. Anal. Calcd for C23H35ClO2: C, 72.89; H, 8.31. Found: C, 72.56; H, 8.34.