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Synlett 2007(18): 2847-2850  
DOI: 10.1055/s-2007-990837
LETTER
© Georg Thieme Verlag Stuttgart · New York

Straightforward Introduction of Side Chains on the Estrane Skeleton - Convenient Synthesis of a 19-Norcholestane

Rajamalleswaramma Jogireddya, Jürgen Rullkötterb, Jens Christoffers*a
a Institut für Reine und Angewandte Chemie, Universität Oldenburg, Carl-von-Ossietzky-Str. 9-11, 26111 Oldenburg, Germany
Fax: +49(441)7983873; e-Mail: jens.christoffers@uni-oldenburg.de;
b Institut für Chemie und Biologie des Meeres, Universität Oldenburg, Carl-von-Ossietzky-Str. 9-11, 26111 Oldenburg, Germany
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Publication History

Received 9 August 2007
Publication Date:
12 October 2007 (online)

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Abstract

Organocerium compounds are the reagents of choice for the introduction of side chains onto estrone methyl ether. A 19-norcholestane derivative was prepared as a model for a geochemical biomarker by subsequent dehydration and C-C double-bond hydrogenation.

Key words

geochemistry - biomarkers - steroids - organometallic ­reagents - steric hindrance - 19-norcholestane

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3-Methoxy-17-(5-methyl-1-methylene-4-hexen-1-yl)estra-1,3,5(10)-triene-17-ol (3a) t-BuLi (6.80 mL, 11.5 mmol, c = 1.7 M in pentane) was added dropwise to a solution of vinylic bromide 6 (1.20 g, 6.35 mmol) in abs. THF (15 mL) over a period of 30 min at -78 °C. The resulting yellow solution was stirred for another 20 min at the same temperature before it was added to a precooled solution of anhyd CeCl3 (1.67 g, 6.81 mmol) in abs. THF (17 mL) at -78 °C. After the resulting orange solution was stirred for 45 min, estrone methyl ether (2, 490 mg, 1.72 mmol) in abs. THF (15 mL) was added dropwise, and the reaction mixture was then allowed to stir for 5 h at -78 °C. Subsequently, it was treated with sat. aq NH4Cl solution (5 mL). The resulting biphasic mixture was filtered through Celite (washing with EtOAc). The organic layer was dried over Na2SO4, filtered, and evaporated in vacuo. Afterwards, the residue was purified by column chromatography [SiO2, hexane-EtOAc (4:1), R f = 0.48] to obtain alcohol 3a (544 mg, 1.38 mmol, 80%) as a colorless solid, mp 90-92 °C. 1H NMR (500 MHz, CDCl3): δ = 0.99 (s, 3 H), 1.23 (dt, J = 4.1, 12.7 Hz, 1 H), 1.32-1.43 (m, 1 H), 1.44-1.52 (m, 3 H), 1.59-1.67 (m, 2 H), 1.68 (s, 3 H), 1.70-1.78 (m, 2 H), 1.75 (s, 3 H), 1.90-1.96 (m, 2 H), 2.10-2.22 (m, 4 H), 2.25-2.35 (m, 3 H), 2.84-2.94 (m, 2 H), 3.80 (s, 3 H), 4.88 (s, 1 H), 5.14 (s, 1 H), 5.24-5.28 (m, 1 H), 6.66 (d, J = 2.7 Hz, 1 H), 6.73 (dd, J = 2.8, 8.5 Hz, 1 H), 7.20 (d, J = 8.6 Hz, 1 H) ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ = 14.38 (CH3), 17.70 (CH3), 23.46 (CH2), 25.64 (CH3), 26.43 (CH2), 27.36 (CH2), 28.79 (CH2), 29.77 (CH2), 33.05 (CH2), 33.55 (CH2), 38.48 (CH2), 39.45 (CH), 43.41 (CH), 46.92 (C), 47.33 (CH), 55.04 (CH3), 87.45 (C), 111.31 (CH), 111.67 (CH2), 113.67 (CH), 124.38 (CH), 126.11 (CH), 131.96 (C), 132.63 (C), 137.81 (C), 154.37 (C), 157.30 (C) ppm. IR (ATR): ν = 3550 (m), 2975 (m), 2932 (s), 2918 (s), 2879 (m), 2864 (m), 2847 (m), 1612 (s), 1505 (vs), 1465 (m), 1442 (s), 1323 (m), 1289 (m), 1242 (vs), 1038 (vs), 991 (vs), 904 (vs), 823 (vs), 790 (m), 743 (m) cm-1. GC-MS (EI, 70 eV): m/z (%) = 394 (12) [M+], 325 (36), 307 (23), 240 (57), 227 (85), 173 (100), 147 (100), 121 (25). HRMS (EI, 70 eV): m/z calcd for C27H38O2: 394.2872; found: 394.2872 [M+].

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3-Methoxy-17-(5-methyl-1-methylene-4-hexen-1-yl)estra-1,3,5(10),16-tetraene (4a) Phosphoroxidchloride (304 mg, 1.98 mmol) was added to a stirred solution of alcohol 3a (130 mg, 0.329 mmol) in pyridine (1 mL) at -5 °C. After stirring for 3 d at 23 °C, all volatile materials were evaporated in vacuo. The residue was purified by column chromatography [SiO2, hexane-EtOAc (5:1), R f = 0.45] to obtain olefin 4a (89 mg, 0.236 mmol, 72%) as a light yellow oil. 1H NMR (500 MHz, CDCl3): δ = 0.89 (s, 3 H), 1.32-1.42 (m, 1 H), 1.49-1.61 (m, 4 H), 1.53 (s, 3 H), 1.62 (s, 3 H), 1.83-1.93 (m, 2 H), 2.05-2.11 (m, 2 H), 2.12-2.21 (m, 5 H), 2.24-2.29 (m, 1 H), 2.77-2.88 (m, 2 H), 3.70 (s, 3 H), 4.82 (s, 1 H), 5.03 (s, 1 H), 5.05-5.08 (m, 1 H), 5.69 (t, J = 2.7 Hz, 1 H), 6.57 (d, J = 2.4 Hz, 1 H), 6.64 (dd, J = 2.6, 8.5 Hz, 1 H), 7.13 (d, J = 8.6 Hz, 1 H) ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ = 16.26 (CH3), 17.77 (CH3), 25.71 (CH3), 26.81 (CH2), 27.52 (CH2), 27.70 (CH2), 29.76 (CH2), 30.88 (CH2), 35.90 (CH2), 36.01 (CH2), 37.24 (CH), 44.05 (CH), 47.24 (C), 55.19 (CH3), 56.58 (CH), 110.42 (CH2), 111.39 (CH), 113.82 (CH), 124.34 (CH), 126.01 (CH), 126.79 (CH), 131.41 (C), 132.97 (C), 137.99 (C), 143.54 (C), 154.31 (C), 157.42 (C) ppm. IR (ATR): ν = 3033 (w), 2925 (vs), 2853 (s), 1610 (s), 1574 (m), 1499 (vs), 1452 (s), 1373 (m), 1281 (s), 1254 (vs), 1237 (vs), 1153 (m), 1050 (s), 1036 (s), 882 (s), 818 (s), 624 (s) cm-1. GC-MS (EI, 70 eV): m/z (%) = 376 (7) [M+], 361 (7), 333 (100), 265 (8), 227 (12), 186 (16), 173 (55), 159 (42), 147 (55), 115 (12), 105 (11), 91 (14). HRMS (EI, 70 eV): m/z calcd for C27H36O: 376.2766; found: 376.2766 [M+].

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3-Methoxy-19- nor -cholesta-1,3,5(10)-triene (1a) A solution of compound 4a (50 mg, 0.133 mmol) and 10% Pd/C (150 mg) in EtOAc (1 mL) and EtOH (9 mL) was degassed (freeze, pump, thaw) and stirred under 1 atm of H2 at 23 °C for 3 d. Subsequently, the mixture was filtered through a pad of Celite (washing with 10 mL CH2Cl2) and the solvent was removed in vacuo. The residue was purified by column chromatography [SiO2, hexane-EtOAc (10:1), R f = 0.42] to obtain compound 1a (50 mg, 0.131 mmol, 98%) as a colorless oil and as two diastereoisomers (ratio 2.5:1 by 1H NMR). 1H NMR (500 MHz, CDCl3): δ (major diastereoisomer) = 0.62 (s, 3 H), 0.77 (d, J = 6.6 Hz, 3 H), 0.81 (d, J = 6.6 Hz, 3 H), 0.81 (d, J = 6.5 Hz, 3 H), 1.00-1.18 (m, 6 H), 1.21-1.34 (m, 6 H), 1.37-1.51 (m, 4 H), 1.57-1.63 (m, 1 H), 1.73-1.81 (m, 2 H), 2.00-2.20 (m, 3 H), 2.72-2.83 (m, 2 H), 3.70 (s, 3 H), 6.55 (d, J = 2.7 Hz, 1 H), 6.63 (dd, J = 2.8, 8.6 Hz, 1 H), 7.12 (d, J = 8.5 Hz, 1 H) ppm; δ (minor diastereoisomer) = 0.62 (s, 3 H), 0.80 (d, J = 6.3 Hz, 3 H), 0.80 (d, J = 6.6 Hz, 3 H), 0.87 (d, J = 6.5 Hz, 3 H), 1.00-1.18 (m, 6 H), 1.21-1.34 (m, 6 H), 1.37-1.51 (m, 4 H), 1.57-1.63 (m, 1 H), 1.73-1.81 (m, 2 H), 2.00-2.20 (m, 3 H), 2.72-2.83 (m, 2 H), 3.70 (s, 3 H), 6.55 (d, J = 2.7 Hz, 1 H), 6.63 (dd, J = 2.8, 8.6 Hz, 1 H), 7.12 (d, J = 8.5 Hz, 1 H) ppm. 13C{1H}-NMR (125 MHz, CDCl3): δ (major diastereoisomer) = 12.25 (CH3), 18.71 (CH3), 22.66 (CH3), 22.76 (CH3), 23.87 (CH2), 24.02 (CH2), 26.82 (CH2), 27.73 (CH2), 28.08 (CH), 28.15 (CH2), 29.93 (CH2), 35.28 (CH), 35.66 (CH2), 38.84 (CH), 39.46 (CH2), 39.90 (CH2), 42.88 (C), 43.77 (CH), 55.18 (CH3), 55.50 (CH), 56.04 (CH), 111.38 (CH), 113.75 (CH), 126.24 (CH), 133.08 (C), 138.06 (C), 157.36 (C) ppm; δ (minor diastereoisomer) = 12.01 (CH3), 18.70 (CH3), 22.57 (CH3), 22.82 (CH3), 23.84 (CH2), 23.95 (CH2), 26.80 (CH2), 27.73 (CH2), 28.02 (CH), 28.30 (CH2), 29.93 (CH2), 35.81 (CH), 36.20 (CH2), 38.84 (CH), 39.54 (CH2), 39.99 (CH2), 42.82 (C), 43.75 (CH), 55.18 (CH3), 55.46 (CH), 56.40 (CH), 111.38 (CH), 113.75 (CH), 126.24 (CH), 133.08 (C), 138.06 (C), 157.36 (C) ppm. IR (ATR): ν = 2929 (vs), 2868 (s), 1611 (m), 1501 (vs), 1466 (s), 1381 (m), 1281 (m), 1257 (s), 1238 (s), 1154 (m), 1043 (s), 1036 (s), 811 (m), 818 (s), 782 (m), 726 (w) cm-1. GC-MS (EI, 70 eV): m/z (%) = 382 (95) [M+], 242 (11), 227 (100), 199 (39), 186 (47), 173 (95), 160 (55), 147 (74), 121 (21), 95 (11). HRMS (CI, isobutane): m/z calcd for C27H43O: 383.3314; found: 383.3314 [M+ + H].