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Synlett 2006(18): 3073-3076  
DOI: 10.1055/s-2006-951533
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Attempted Cascade Radical-Mediated Cyclisation Approach to Ring-D Aromatic Steroids

Gerald Pattenden*, Alexander J. Blake, L. Krishnakanth Reddy, Davey A. Stoker
School of Chemistry, The University of Nottingham, Nottingham, England, NG7 2RD, UK
Fax: +44(115)9513535; e-Mail: gp@nottingham.ac.uk;
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Publication History

Received 18 May 2006
Publication Date:
25 October 2006 (online)

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Abstract

A synthetic approach to ring-D aromatic steroids, viz. 5, based on a cascade of radical-mediated cyclisations from the ortho-aryl-substituted iododienynones 12 and 13, instead led to the macrocyclic ketone 16 or to the novel bridged tricycle 17, respectively, as the major products.

Key words

radical reactions - steroids - polycycles - cascade reactions - nicandrenones

    References

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8

Typical Experimental Procedure for the Synthesis of Polycycles 17a and 17b.Polycycle 17a.
A solution of tri-n-butyltin hydride (170 µL, 0.61 mmol) and 2,2′-azobis(isobutyronitrile) (AIBN; 25 mg, 0.15 mmol) in degassed benzene (20 mL) was added dropwise over 8 h by syringe pump to a stirred solution of the iodide 12a (200 mg, 0.51 mmol) and AIBN (50 mg, 0.30 mmol) in degassed benzene (200 mL) under reflux and an argon atmosphere. The mixture was heated under reflux for a further 12 h, then allowed to cool to r.t. and concentrated in vacuo. The residue was purified by column chromatography on silica, using a gradient of 2-10% Et2O in light PE (bp 40-60 °C) as eluent, to give the bridged tricyclic ketone 17a (45 mg, 30%) as an inseparable mixture of diastereoisomers in a 2:1 ratio as a colourless oil.
IR (film): 1693, 1612 cm-1. 1H NMR (400 MHz): δ (major diastereoisomer) = 1.39 (3 H, s, CH 3), 1.47-1.63 (3 H, m), 1.69-1.85 (3 H, m), 2.01-2.19 (3 H, m), 2.67 (1 H, app td, J = 15.5, 2.9 Hz, ArCH aHb), 2.89 (1 H, app dt, J = 15.5, 3.4 Hz, ArCHa H b), 3.21 (1 H, ddd, J = 8.1, 3.0, 2.4 Hz, C=OCH), 3.32 (1 H, dd, J = 10.1, 3.0 Hz, ArCH), 3.80 (3 H, s, OCH 3), 6.69 (1 H, d, J = 2.7 Hz, MeOCCHC), 6.77 (1 H, dd, J = 8.6, 2.7 Hz, MeOCCHCH), 6.87 (1 H, s, PhCH), 7.17 (1 H, d, J = 8.6 Hz, MeOCCHCH), 7.26-7.44 (5 H, m, PhH); δ (minor diastereoisomer) = 1.27 (3 H, s, CH 3), 1.51-1.82 (6 H, m), 1.96-2.19 (3 H,m), 2.81 (1 H, app d, J = 8.7 Hz, C=OCH), 3.00 (2 H, app t, J = 8.4 Hz, ArCH 2), 3.29 (1 H, dd, J = 8.7, 1.6 Hz, ArCH), 3.79 (3 H, s, OCH 3), 6.68 (1 H, d, J = 2.9 Hz, MeOCCHC), 6.71 (1 H, s, PhCH), 6.78 (1 H, dd, J = 8.4 and 2.9 Hz, MeOCCHCH), 7.00 (1 H, d, J = 8.4 Hz, MeOCCHCH), 7.26-7.38 (5 H, m, PhH). 13C NMR (100.6 MHz): δ (major diastereoisomer) = 21.4 (t), 24.7 (t), 24.8 (t), 27.6 (q), 31.2 (t), 36.1 (d), 36.9 (t), 43.4 (s), 45.7 (d), 52.6 (d), 55.2 (q), 112.4 (d), 113.3 (d), 127.8 (2 C d), 127.9 (d), 128.5 (d), 128.7 (s), 129.0 (2 C d), 135.3 (d), 136.9 (s), 140.7 (s), 144.0 (s), 157.4 (s), 205.8 (s); δ (minor diastereoisomer) = 21.8 (t), 23.7 (t), 24.2 (q), 25.9 (t), 29.1 (t), 40.7 (s), 42.9 (d), 46.0 (t), 46.7 (d), 47.3 (d), 55.2 (q), 110.6 (d), 114.4 (d), 124.2 (d), 127.7 (2 C d), 127.8 (d), 129.0 (2 C d), 131.6 (s), 135.0 (d), 136.6 (s), 138.7 (s), 142.6 (s), 158.0 (s), 206.1 (s). ESI-MS: m/z calcd for: 373.2162; found: 373.2155 [MH+].
Polycycle 17b.
Boron tribromide (50 µL, 0.53 mmol) was added dropwise to a stirred solution of the tricycle 17a (50 mg, 0.13 mmol) in anhyd CH2Cl2 (10 mL), at -78 °C under a nitrogen atmosphere. The solution was warmed to r.t. slowly over 13 h, and then quenched with H2O (50 mL). The separated aqueous phase was extracted with CH2Cl2 (3 × 50 mL) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography, using 10% Et2O in light PE (bp 40-60 °C) as eluent, to give a 2:1 mixture of diastereoisomers of the phenol 17b (23 mg, 48%) as a viscous liquid solid. Crystallisation from Et2O and pentane gave the major diastereoisomer as colourless crystals; mp 195-196 °C. IR (film): 3597, 1693, 1608 cm-1. 1H NMR (400 MHz): δ (major diastereoisomer) = 1.39 (3 H, s, CH 3), 1.46-1.62 (3 H, m), 1.69-1.85 (3 H, m), 2.01-2.20 (3 H, m), 2.63 (1 H, app td, J = 15.6, 3.4 Hz, ArCH aHb), 2.85 (1 H, app dt, J = 15.6, 3.2 Hz, ArCHa H b), 3.19 (1 H, app d, J = 10.1 Hz, C=OCH), 3.31 (1 H, dd, J = 10.1, 3.0 Hz, ArCH), 4.71 (1 H, br s, OH), 6.62 (1 H, d, J = 2.5 Hz, HOCCHC), 6.66 (1 H, dd, J = 8.3, 2.5 Hz, HOCCHCH), 6.89 (1 H, s, PhCH), 7.11 (1 H, d, J = 8.3 Hz, HOCCHCH), 7.27-7.36 (3 H, m, PhH), 7.42 (2 H, app d, J = 7.3 Hz, PhH); δ (minor diastereoisomer) = 1.26 (3 H, s, CH 3), 1.47-1.81 (6 H, m), 1.95-2.13 (3 H, m), 2.79 (1 H, app d, J = 10.2 Hz, C=OCH), 2.93-2.99 (2 H, m, ArCH 2), 3.30 (1 H, dd, J = 10.2, 1.9 Hz, ArCH), 5.25 (1 H, br s, OH), 6.59 (1 H, d, J = 2.6 Hz, HOCCHC), 6.65 (1 H, dd, J = 8.4, 2.6 Hz, HOCCHCH), 6.71 (1 H, s, PhCH), 6.92 (1 H, d, J = 8.4 Hz, HOCCHCH), 7.25-7.39 (5 H, m, PhH). 13C NMR (100.6 MHz): δ (major diastereoisomer) = 21.4 (t), 24.7 (t), 24.9 (t), 27.6 (q), 31.0 (t), 36.1 (d), 37.0 (t), 43.5 (s), 45.7 (d), 52.6 (d), 113.7 (d), 114.8 (d), 127.8 (d), 127.9 (d), 128.7 (d), 128.8 (s), 129.0 (d), 135.4 (d), 137.0 (s), 141.0 (s), 144.0 (s), 153.3 (s), 205.9 (s); δ (minor diastereoisomer) = 21.8 (t), 23.8 (t), 24.3 (q), 25.9 (t), 28.9 (t), 40.7 (s), 43.0 (d), 46.0 (t), 46.8 (t), 47.3 (d), 112.3 (d), 115.7 (d), 127.7 (s), 127.8 (d), 128.0 (d), 128.7 (d), 128.9 (d), 135.3 (d), 138.1 (s), 139.3 (s), 144.5 (s), 154.1 (s), 206.7 (s); ESI-MS: m/z calcd for C25H27O2: 359.2006; found: 359.1999 [MH+].

9

Crystal Data.
C25H26O2, M = 358.46, monoclinic, a = 8.7699 (9), b = 22.255 (2), c = 9.7402 (10) Å, β = 95.633 (2)°, V = 1891.9 (5) Å3, T = 150 (2) K, space group ‘Ia’ (No. 9), Z = 4, D calcd = 1.259 g cm-3, µ(Mo-Ka) = 0.078 mm-1, 2181 unique reflections measured and used in all calculations. Final R1 [2066 F > 4σ(F)] = 0.0401 and wR2 [all F 2] was 0.0994. Data have been deposited with the Cambridge Crystallographic Data Centre as CCDC 601625; they are available free of charge via www.ccdc.cam.ac.uk/data_request/cif.

10

An identical 2:1 mixture of diastereoisomers of desmethoxy bridged tricycle, corresponding to 17a, was obtained (ca. 30%) when the E-isomer 12b was treated similarly with Bu3SnH-AIBN.
Spectroscopic Data for Desmethoxy 17a. IR (film): 1694, 1614 cm-1. 1H NMR (400 MHz): δ (major diastereoisomer) = 1.40 (3 H, s, CH 3), 1.48-1.89 (6 H, m), 1.98-2.24 (3 H, m), 2.68 (1 H, app td, J = 15.6, 2.6 Hz, ArCH aHb), 2.94 (1 H, app dt, J = 15.6, 3.5 Hz, ArCHa H b), 3.28 (1 H, app dt, J = 8.0, 3.0 Hz, C=OCH), 3.38 (1 H, dd, J = 10.0, 3.0 Hz, ArCH), 6.89 (1 H, s, PhCH), 7.08-7.43 (9 H, m, ArH); δ (minor diastereoisomer) = 1.27 (3 H, s, CH 3), 1.48-1.89 (6 H, m), 1.98-2.24 (3 H, m), 2.86 (1 H, app d, J = 10.3 Hz, C=OCH), 2.99-3.05 (2 H, m, ArCH 2), 3.34 (1 H, app dd, J = 10.3, 1.6 Hz, ArCH), 6.71 (1 H, s, PhCH), 7.08-7.43 (9 H, m, ArH). 13C NMR (100.6 MHz): δ (major diastereoisomer) = 21.4 (t), 24.7 (t), 25.0 (t), 27.6 (q), 30.9 (t), 36.8 (d), 37.1 (t), 43.5 (s), 45.7 (d), 52.4 (d), 55.2 (q), 125.7 (d), 126.4 (d), 127.5 (d), 127.9 (2 C d), 128.0 (d), 129.0 (d), 129.1 (d), 135.4 (d), 136.8 (s), 137.0 (s), 139.6 (s), 144.1 (s), 205.7 (s); δ (minor diastereoisomer) = 21.8 (t), 24.0 (t), 24.3 (q), 25.8 (t), 28.7 (t), 40.7 (s), 43.6 (d), 46.0 (t), 46.5 (d), 47.2 (d), 123.3 (d), 125.4 (d), 126.2 (d), 127.8 (2 C d), 128.6 (2 C d), 128.9 (d), 135.1 (d), 136.6 (s), 137.4 (s), 139.5 (s), 142.6 (s), 206.1 (s). ESI-MS: m/z calcd for C25H27O: 343.2056; found: 343.2053 [MH+].