Synlett 2021; 32(03): 309-315
DOI: 10.1055/s-0040-1706545
letter

BF3·OEt2-Catalyzed Rearrangement of Epoxy-Himachalenes: Access to New Biosourced N-Acetamide-Based Himachalenes

a   Laboratoire de Chimie des Substances Naturelles, Faculté des Sciences Semlalia, Université Cadi Ayyad, B.P. 2390, Marrakech, Morocco   mustapha.aitelhad@gmail.com
b   Laboratoire de Chimie Bioorganique et Macromoléculaire, Faculté des Sciences et Techniques de Marrakech (FSTGM), Université Cadi Ayyad, 40000 Marrakech, Morocco
,
Mohamed Zaki
b   Laboratoire de Chimie Bioorganique et Macromoléculaire, Faculté des Sciences et Techniques de Marrakech (FSTGM), Université Cadi Ayyad, 40000 Marrakech, Morocco
,
Moha Taourirte
b   Laboratoire de Chimie Bioorganique et Macromoléculaire, Faculté des Sciences et Techniques de Marrakech (FSTGM), Université Cadi Ayyad, 40000 Marrakech, Morocco
,
Ahmed Benharref
a   Laboratoire de Chimie des Substances Naturelles, Faculté des Sciences Semlalia, Université Cadi Ayyad, B.P. 2390, Marrakech, Morocco   mustapha.aitelhad@gmail.com
,
Martine Urrutigoïty
c   Laboratoire de Chimie de Coordination (LCC), Université de Toulouse, CNRS, 31030 Toulouse Cedex4, France   Email: abdelouahd.oukhrib@lcc-toulouse.fr
,
Abdelouahd Oukhrib
a   Laboratoire de Chimie des Substances Naturelles, Faculté des Sciences Semlalia, Université Cadi Ayyad, B.P. 2390, Marrakech, Morocco   mustapha.aitelhad@gmail.com
c   Laboratoire de Chimie de Coordination (LCC), Université de Toulouse, CNRS, 31030 Toulouse Cedex4, France   Email: abdelouahd.oukhrib@lcc-toulouse.fr
› Author Affiliations


Abstract

Biosourced N-acetamide-based himachalenes were synthesized by Lewis acid catalyzed rearrangement of epoxy-himachalene derived from α-cis- and β-himachalenes, the main component of essential oil of Atlas cedar (Cedrus atlantica). Several new chiral polycyclic N-acetamide compounds were obtained with different selectivities depending on the acid used. Among the Lewis acids used, BF3·OEt2 under catalytic and mild conditions is efficient and selective affording the formation of chiral N-acetamides in good yields. Otherwise, using acetonitrile as solvent and reagent was proved as an efficient tool giving access to new N-acetamide-based himachalenes. A mechanism to explain the formation of the different compounds observed in the reaction mixture has also been proposed.

Supporting Information



Publication History

Received: 07 July 2020

Accepted after revision: 22 September 2020

Article published online:
28 October 2020

© 2020. Thieme. All rights reserved

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  • 23 All purchased solvents and chemicals were of analytical grade and used without further purification. Thin-layer chromatography (TLC) was performed using F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching and phosphomolybdic acid solution staining. Flash chromatography was performed on silica gel (230–400 mesh). Chromatography separations were carried out by a conventional column on silica gel 60 (230–400 mesh), using hexanes–EtOAc (EtOAc–hexane) mixtures of increasing polarity. 1H NMR and 13C NMR spectra were recorded at 600 and 500 MHz, and at 150 and 125 MHz, respectively in CDCl3. Chemical shifts (δH) are quoted in parts per assigned utilizing DEPT experiments and based on heteronuclear correlations. Infrared spectra (IR) were recorded as thin films or as solids on a FTIR spectrophotometer with samples frequency of absorption (cm–1). [α]D 25 measurements were carried out in a polarimeter; utilizing a 1 dm length cell and CHCl3 as a solvent. Concentration is expressed in mg/mL. Epoxidation of α-cis- and β-Himachalene – General Procedure m-Chloroperbenzoic acid (1 equiv, 1.7 g, 10 mmol) is added to a stirred mixture of α-cis and β-himachalene (2.1 g, 10 mmol) in CH2Cl2 (30 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Then, the mixture was quenched with saturated solution of NaHCO3 (20 mL) and washed with water (2 × 30 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The two epoxides 1 and 2 were separated by chromatography on silica gel with EtOAc/hexane (2:98) as eluent. (1S,2S,3R,6R)-2,3-Epoxy-3,7,11,11-tetramethylbicyclo[5,4,0]-undec-7,13-ene (1) Oily; Rf = 0.5 (EtOAc/hexane, 2:98). 1H NMR (500 MHz, CDCl3): δ = 0.95 (3 H, s), 1.1 (3 H,s), 1.65–1.45 (2 H, m), 1.35–1.55 (2 H, m), 1.72 (2 H, m), 1.75 (3 H, s), 2.41 (1 H, q), 2.66 (1 H, dd, J = 4.0, 11.0 Hz), 2.95 (1 H, d, J = 4.5 Hz), 4.78 (2 H, d, J = 6.5 Hz) ppm. 13C NMR (126 MHz, CDCl3): δ = 22.71 (CH3), 23.20 (CH3), 24.8 (CH2), 26.60 (CH2), 28.11 (CH2), 30.8 (CH2), 32.09 (CH3), 36.9 (C), 37.80 (C), 39.31 (CH2), 47.50 (C), 58.8 (C), 62.59 (CH), 111.90 (CH2), 155.61 (C) ppm. MS (DCI, NH3): m/z (%) = 221 (100%) [M + H]+. IR (film): 890 (C–O–C) cm–1. (1S,6S,7R)-6,7-Epoxy-3,7,11,11-tetramethylbicyclo[5,4,0]-undec-2-ene (2) Oily; Rf = 0.4 (EtOAc/hexane, 2:98). 1H NMR (500 MHz, CDCl3): δ = 0.98 (3 H, s), 1.35 (3 H, s), 1.65 (3 H, s), 1.53 (2 H, m), 1.75 (3 H, s), 1.97 (2 H, dt), 2.2–1.95 (2 H, m), 2.01 (1 H, d, J = 4.5 Hz), 4.41 (1 H, d, J = 4.5 Hz) ppm. 13C NMR (126 MHz, CDCl3): δ = 18.30 (CH2), 20.71 (CH2), 23.82 (CH3), 24.80 (CH3), 25.39 (CH3), 27.58 (CH2), 29.91 (CH3), 36.30 (CH2), 36.52 (CH2), 44.11 (C), 48.81 (CH), 65.0 (C), 65.15 (C), 124.32 (CH), 134.81 (C) ppm. MS (DCI, NH3): m/z (%) = 220 (100%) [M + H]+. IR (film): 1034 (C–O–C) cm–1. Diepoxy β-Himachalene (3) – General Procedure Epoxy-β-himachalene (2, 1 g, 45 mmol) dissolved in CH2Cl2 (15 mL) and stirred at 0 °C. Then, one equivalent of m-chloroperbenzoic acid (780 mg, 45 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was quenched with saturated solution of NaHCO3 (10 mL) and then washed with water (2 × 30 mL). The organic layer was combined, dried over sodium sulfate, and then concentrated under reduced pressure. The diepoxide 3 was separated by chromatography on silica gel with EtOAc/hexane (4:96) as eluent. (1S,2R,3S,6S,7R)-2,3,6,7-Diepoxy-3,7,11,11 tetramethylbicyclo[5,4,0]undecane (3) White solid; mp 68–69 °C; Rf = 0.4 (EtOAc/hexane, 4:96). 1H NMR (500 MHz, CDCl3): δ = 1.01 (3 H, s), 1.09 (3 H, s), 1.24 (3 H, s), 1.37 (3 H, s), 3.01 (1 H, d, J = 2.0 Hz) ppm. 13C NMR (126 MHz, CDCl3): δ = 60.38 (C), 60.36 (C), 59.62 (C), 55.45 (C), 47.01 (CH), 28.5 (CH2), 24.5 (CH2), 21.32 (CH2), 43.40 (CH2), 27.0 (C), 23.6 (CH2), 20.61 (C), 27.29 (2 × CH2) ppm. MS (DCI, NH3): m/z (%) = 236 (100%) [M + H]+. Rearrangement Reaction of Epoxides – General Procedure Epoxy-himachalene (1 mmol) was dissolved in CH3CN (15 mL) and stirred at the desired temperature. Then, the acid (20%) was gently added to the solution. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was quenched with NaHCO3 (10 mL) saturated solution, and then brine (9ml) was added, the resulting aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The organic layer was combined, dried over sodium sulfate, and then concentrated under reduced pressure. The crude was separated by chromatography on silica gel with EtOAc/hexane as eluent. (1S,3R,7S) 3,11,11-Trimethyltricyclo [5.4.1(3,7).0]dodecan-2-one (4) Oily; [α]D 25 = + 9.1 (c 3.8, CHCl3); Rf = 0.6 (EtOAc/hexane, 5:95). 1H NMR (500 MHz, CDCl3): δ = 1.03 (s, 3 H), 1.07 (s, 3 H), 1.12 (td, J = 13.6, 1.43 Hz, 2 H), 1.22 (s, 3 H), 1.24 (td, J = 13.4 Hz, 1 H), 1.32 (d, J = 13.0 Hz, 1 H), 1.38 (d, J = 11.3 Hz, 1 H), 1.41 and 1.71 (m, 2 H), 1.44 and 1.59 (m, 2 H), 1.53–1.69 (m, 2 H), 1.62 (d, J = 11.3 Hz, 1 H), 1.63 (s, 1 H), 1.76 (d, J = 13.0 Hz, 1 H), 2.14 (m, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 19.39 (CH2), 20.47 (CH2), 20.69 (CH3), 21.59 (CH3), 31.89 (CH3), 32.63 (CH2), 33.25 (C), 38.88 (CH2), 39.51 (CH2), 40.82 (C), 43.34 (CH2), 48.23 (C), 53.21 (CH2), 66.68 (CH), 220.70 (C=O) ppm. IR (film): 2923, 2854, 1730, 1699, 1454, 1384, 1363, 1350, 1109, 962, 909, 893, 771, 744 cm–1. N-[(1R,2S,3S)-1,4,4-Trimethyltricyclo[6.3.1.03,9]dodec-8(12)-en-2-yl]acetamide (5) White solid; mp 145–146 °C; [α]D 25 + 6.4 (c 1.5, CHCl3); Rf = 0.3 (EtOAc/hexane, 15:85). 1H NMR (500 MHz, CDCl3): δ = 0.80 (s, 3 H), 0.82–0.95 (m, 1 H), 0.96 (s, 3 H), 0.99 (m, 1 H), 1.02 (s, 3 H), 1.10 (m, 1 H), 1.26 (s, 1 H), 1.34 (m, 1 H), 1.44–1.55 (m, 2 H), 1.56–1.64 (m, 2 H), 1.96 (dd, J = 8.2, 4.6 Hz,1 H), 1.99 (s, 3 H), 2.30 (m, 1 H), 2.42 (dq, J = 3.1, 1.5 Hz, 1 H), 3.53 (ddd, J = 10.2, 4.9, 2.0 Hz, 1 H), 5.40 (br, 1 H), 5.58 (s, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 19.96 (CH2), 21.91 (CH2), 23.70 (CH3), 26.22 (CH2), 26.27 (CH2), 27.50 (CH3), 28.23 (CH3), 32.40 (CH3), 34.65 (CH2), 34.79 (CH), 36.83 (C), 39.40 (C), 55.47 (CH), 56.72 (CH), 131.47 (CH), 145.76 (C), 169.09 (C=O) ppm. HRMS (ES+/TOF): m/z calcd for C17H27NO [M + H+]: 262.2171; found: 262.2168. IR (film): 3293, 2927, 2866, 1648, 1552, 1464, 1370, 805, 771, 606, 513, 475 cm–1. N-{(3aR*,3bS*)-1,3b,7,7-Tetramethyl-3a,3b,4,5,6,7,7a,7b-octahydro-3H-cyclopenta[3,4]-cyclobuta[1,2]benzen-3a-yl}acetamide (6) White solid; mp 158–159 °C; [α]D 25 –41.9 (c 1.4, CHCl3); Rf = 0.3 (EtOAc/hexane, 10:90). 1H NMR (500 MHz, CDCl3): δ = 0.82 (s, 3 H), 0.89 (s, 3 H), 1.10–1.28 (m, 3 H), 1.32 (s, 3 H), 1.37–1.56 (m, 4 H), 1.71 (m, 3 H), 1.91 (s, 3 H), 2.27–2.35 (m, 1 H), 2.50 (ddd, J = 17.7, 2.7, 1.8 Hz, 1 H), 2.99 (d, J = 2.8 Hz, 1 H), 5.43 (dt, J = 2.6, 1.6 Hz, 1 H), 5.79 (br, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 15.82 (CH3), 18.28 (CH2), 23.19 (CH3), 23.50 (CH3), 28.67 (CH3), 29.72 (CH3), 29.73 (C), 31.36 (CH2), 36.85 (CH2), 40.71 (CH2), 41.23 (C), 53.94 (CH), 57.30 (CH), 66.09 (C), 127.96 (CH), 141.94 (C), 169.38 (C=O) ppm. HRMS (ES+/TOF): m/z calcd for C17H27NO [M + H+]: 262.2171; found: 262.2169. IR (film): 3287, 3034, 2953, 2917, 1635, 1542, 1441, 1368, 1318, 1300, 1253, 1212, 1012, 790, 598, 536 cm–1. N-{(1R,3aR,3bS,7aR,7bS)-1-Hydroxy-1,3b,7,7-tetramethyldecahydro-3aH-cyclopenta[3,4]cyclobuta[1,2]benzen-3a-yl}acetamide (7) White solid; mp 163–164 °C; [α]D 25 –19.3 (c 1.1, CHCl3); Rf = 0.2 (EtOAc/hexane, 15:85). 1H NMR (600 MHz, CDCl3): δ = 0.83 (s, 3 H), 0.91 (s, 3 H), 1.10 (s, 3 H), 1.18 (d, J = 8.4 Hz, 1 H), 1.22 (s, 3 H), 1.28 (t, J = 6.3 Hz, 2 H), 1.55–1.41 (m, 3 H), 1.65–1.58 (m, 1 H), 1.91–1.78 (m, 2 H), 1.97 (s, 3 H), 2.17–2.10 (m, 2 H), 2.53 (d, J = 8.4 Hz, 1 H), 5.99 (s, 1 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 18.18 (CH2), 23.88 (CH3), 24.17 (CH3), 24.23 (CH3), 29.68 (CH3), 30.30 (C), 31.03 (CH2), 31.22 (CH3), 32.25 (CH2), 36.48 (CH2), 39.23 (C), 40.56 (CH2), 49.11 (CH), 55.89 (CH), 66.63 (C), 80.67 (C), 170.15 (C=O) ppm. HRMS (ES+/TOF): m/z calcd for C17H29NO2 [M + H+]: 279.2198; found: 279.2193. IR (film): 3283, 3075, 2945, 2865, 1626, 1546, 1460, 1369, 1301, 1276, 1224, 1190, 1147, 1111, 912, 769, 691, 593 cm–1. Arylhimachalene (8) Oily; [α]D 25 +0.4 (c 1.6, CHCl3). Rf = 0.7 (hexane). 1H NMR (600 MHz, CDCl3): δ = 1.22 (s, 3 H), 1.24 (s, 3 H), 1.31 (d, J = 6.8 Hz, 3 H), 2.23 (s, 3 H), 3.18 (m, 1 H), 6.82 (d, J = 7.9 Hz, 2 H), 6.91 (d, 7.9 Hz, 1 H), 7.04 (s, 1 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 22.09 (CH3), 22.14 (CH3), 25.97 (CH3), 30.03 (CH3), 33.27 (CH2), 33.36 (CH2), 3966 (C), 37.55 (CH2), 41.24, 126,65 (CH), 126.30 (CH), 127.50 (CH), 134.76 (C), 140.70 (C), 147.36 (C) ppm. (1R,2R,7S,8R,9R)-N-{2-Hydroxy-2,6,6,9-tetramethyl-12-oxatricyclo[7.2.1.01,7] dodecan-8-yl}- acetamide (9) White solid; mp 181–182 °C; [α]D 25 –56.5 (c 0.3, CHCl3); Rf = 0.2 (EtOAc/hexane, 20:80). 1H NMR (500 MHz, CDCl3): δ = 0.96 (s, 3 H), 1.13 (s, 3 H), 1.24 (m, 1 H), 1.31 (s, 3 H), 1.31 (s, 3 H), 1.35 (m, 1 H), 1.55 (dd, J = 14.4, 8.7 Hz, 1 H), 1.69 (m, 1 H), 1.97–1.78 (m, 5 H), 2.06 (s, 3 H), 2.77 (dd, J = 11.7, 2.4 Hz, 1 H), 4.44 (td, J = 11.5, 1.8 Hz, 1 H), 5.53 (d, J = 11.2 Hz, 1H ) ppm. 13C NMR (126 MHz, CDCl3): δ = 17.90 (CH2), 19.62 (CH3), 24.11 (CH3), 26.17 (CH3), 27.26 (CH3), 29.01 (CH2), 32.33 (CH3), 32.63 (CH2), 33.47 (C), 41.66 (CH2), 45.60 (CH), 47.32 (CH2), 58.01 (CH), 73.50 (C), 82.90 (C), 94.65 (C), 169.49 (C=O) ppm. HRMS (ES+/TOF): m/z calcd for C17H29NO3 [M + H+]: 296.2226; found: 296.2224. IR (film): 3291, 2918, 2853, 1657, 1546, 1472, 1452, 1378, 1317, 1297, 1219, 1131, 1064, 1048, 911, 772 cm–1.