What are cookies? Sign up for PNAS Online eTocs
Link: Info for AuthorsLink: SubscribeLink: AboutLink: Editorial BoardLink: ContactLink: Site Map Link: PNAS Home
Proceedings of the National Academy of Sciences
Link: Current Issue "" Link: Archives "" Link: Online Submission ""  Link: Advanced Search

Institution: NIH Library Sign In as Member / Individual


This Article
Full Text
Services
Alert me to new issues of the journal
Request Copyright Permission

Supporting Methods

3-(2-Iodophenyl)acrylic Acid Ethyl Ester 15a. Manganese dioxide (18.6 g, 0.2 mol) was added in one portion to a stirred solution of 2-iodobenzyl alcohol (5.0 g, 21.0 mmol) in dichloromethane (200 ml), at room temperature, under nitrogen. The mixture was stirred at room temperature for 16 h and then filtered through a pad of Celite. The filtrate was concentrated in vacuo to leave a yellow oil, which was purified by column chromatography on silica, using 10% diethyl ether in light petroleum (bp 40–60°C) as eluent, to give 2-iodobenzaldehyde (4.6 g, 96%) as a colorless oil; n max (film)/cm–1 1698, 1643, 1582; 1H NMR (360 MHz) d = 7.29 (1H, t, J = 7.5 Hz, ArH), 7.47 (1H, t, J = 7.5 Hz, ArH), 7.88 (1H, d, J = 7.5 Hz, ArH), 7.95 (1H, d, J = 7.5 Hz, ArH), 10.08 (1H, s, CHO); 13C NMR (90.6 MHz) d = 100.7 (s), 128.7 (d), 130.2 (d), 135.1 (s), 135.4 (d), 140.6 (d), 195.7 (d); m/z [electron impact (EI)] 231.9385 (M+ C7H5IO requires 231.9385).

Triethyl phosphonoacetate (4.7 ml, 23.3 mmol) was added dropwise over 5 min to a stirred suspension of NaH (0.9 g, 23.3 mmol of a 60% suspension in paraffin) in THF (190 ml), at room temperature, under nitrogen. The mixture was stirred at room temperature for 30 min and then cooled to 0°C. A solution of 2-iodobenzaldehyde (4.5 g, 19.4 mmol) in THF (10 ml) was added dropwise over 5 min and the yellow/green solution was then stirred at 0°C for 30 min. The solution was allowed to warm to room temperature over 12 h, then diethyl ether (100 ml) and saturated aqueous ammonium chloride solution (100 ml) were added. The organic layer was separated and the aqueous layer was extracted with diethyl ether (2 Χ 10 ml). The combined organic extracts were washed with brine, dried, and concentrated in vacuo. The residue was purified by column chromatography on silica, using 10% diethyl ether in light petroleum (bp 40–60°C) as eluent, to give the ester (5.4 g, 92%) as a colorless oil; (found: C, 43.9; H, 3.7%; C11H11IO2 requires C, 43.7; H, 3.7%); l max (EtOH)/nm 226 (15,060), 276 (15,770); n max (film)/cm–1 1713, 1635, 1581, 1558; 1H NMR (360 MHz) d = 1.35 (3H, t, J = 7.1 Hz, OCH2CH3), 4.28 (2H, q, J = 7.1 Hz, OCH2CH3), 6.32 (1H, d, J = 15.8 Hz, CH=CHCO2Et), 7.05 (1H, td, J = 7.7 and 1.6 Hz, ArH), 7.36 (1H, td, J = 7.7 and 1.8 Hz, ArH), 7.56 (1H, dd, J = 7.7 and 1.6 Hz, ArH), 7.89 (1H, dd, J = 7.7 and 1.6 Hz, ArH), 7.90 (1H, d, J = 15.8 Hz, ArCH=CH); 13C NMR (90.6 MHz) d = 14.3 (q), 60.6 (t), 101.1 (s), 121.2 (d), 127.3 (d), 128.5 (d), 131.1 (d), 137.8 (s), 139.9 (d), 147.6 (d), 166.2 (s); m/z (EI) 301.9811 (M+ C11H11IO2 requires 301.9804).

3[2-(3-Oxoprop-1-yl)phenyl]acrylic Acid Ethyl Ester 16a. Palladium(II) acetate (185 mg, 0.8 mmol) was added in one portion to a stirred solution of the iodide 15a (5.0 g, 16.5 mmol), allyl alcohol (3.4 ml, 49.7 mmol), tetra-n-butylammonium chloride (5.6 g, 16.5 mmol) and sodium bicarbonate (3.5 g, 41.4 mmol) in dimethylformamide (DMF) (17 ml), at room temperature, under nitrogen. The mixture was heated at 45–50°C for 15 h and then allowed to cool to room temperature. Diethyl ether (50 ml) was added, the solution was washed with water (3 Χ 20 ml), and the combined aqueous extracts were then extracted with diethyl ether (2 Χ 10 ml). The combined ether extracts were washed with brine, dried, and concentrated in vacuo. The residue was purified by column chromatography on silica, using 40% diethyl ether in light petroleum (bp 40–60°C) as eluent, to give the aldehyde (3.1 g, 81%) as a colorless oil; n max (film)/cm–1 2980, 1710; 1H NMR (360 MHz) d = 1.35 (3H, t, J = 7.2 Hz, OCH2CH3), 2.75 (2H, td, J = 7.5 and 1.2 Hz, ArH), 3.10 (2H, t, J = 7.5 Hz, ArH), 4.28 (2H, q, J = 7.2 Hz, OCH2CH3), 6.38 (1H, d, J = 15.8 Hz, CH), 7.22–7.34 (3H, m, 3xArH), 7.56 (1H, dd, J = 7.7 and 1.2 Hz, ArH), 7.96 (1H, d, J = 15.8 Hz, CH), 9.81 (1H, t, J = 1.2 Hz, CHO); 13C NMR (90.6 MHz) d = 14.3 (q), 25.4 (t), 44.9 (t), 60.6 (t), 120.3 (d), 126.9 (d), 127.0 (d), 129.8 (d), 130.2 (d), 133.1 (s), 139.8 (s), 141.3 (d), 166.8 (s), 200.7 (d); m/z [chemical ionization (CI)] 255.0996 (M+ C14H16O3Na requires 255.0997).

(E)-3-{2-[(Z)-6-(tert-Butyldimethylsilyloxy)hex-3-enyl]phenyl}acrylic Acid Ethyl Ester 17a. A solution of potassium bis(trimethylsilyl)amide in toluene (27.4 ml, 0.5 M, 13.7 mmol) was added dropwise over 5 min to a stirred suspension of triphenyl-(tert-butylsilyloxy)propylphosphonium iodide (cf. ref. 1) (7.1 g, 13.7 mmol) in THF (120 ml) at –78°C under an atmosphere of nitrogen. The mixture was stirred at –78°C for 20 min, then allowed to warm to 0°C over 40 min and again recooled to –78°C. A solution of the aldehyde 16a (3 g, 11.4 mmol) in THF (10 ml) was added dropwise over 10 min and the mixture was then allowed to warm to room temperature over 2 h. Water (60 ml) was added and the separated aqueous layer was then extracted with diethyl ether (3 Χ 20 ml). The combined organic extracts were dried and concentrated in vacuo and the residue was purified by column chromatography on silica, eluting with 8% diethyl ether in light petroleum to give the alkene (3.4 g, 77%) as a colorless oil; (found: C, 71.5, H, 9.5%. C23H36O3Si requires C, 71.1, H, 9.3%); n max (CHCl3)/cm–1 2859, 1716, 1634; 1H NMR (360 MHz, CDCl3) d = 8.03 (1H, d, J = 15.7 Hz, ArCH=CH), 7.57 (1H, d, J = 8.6 Hz, ArH), 7.33–7.16 (3H, m, 3 Χ ArH), 6.38 (1H, d, J = 15.7 Hz, ArCH=CH), 5.54–5.39 (2H, m, Z CH=CH), 4.28 (2H, q, J = 7.1 Hz, OCH2CH3), 3.53 (2H, t, J = 7.2 Hz, CH2OTBS), 2.82 (2H, t, J = 6.9 Hz, ArCH2CH2), 2.33 (2H, app. q, J = 7.1 Hz, CH2CH2OTBS), 2.19 (2H, app. q, J = 6.9 Hz, ArCH2CH2), 1.34 (3H, t, J = 7.5 Hz, OCH2CH3), 0.89 (9H, s, SiCMe3), 0.04 (6H, s, SiMe2); 13C NMR (90.5 MHz, CDCl3) d = 166.9 (s), 142.2 (d), 141.5 (s), 132.9 (s), 130.1 (d), 129.8 (d), 127.0 (d), 2 Χ 126.5 (d), 126.4 (d), 119.5 (d), 62.8 (t), 60.3 (t), 33.1 (t), 30.9 (t), 29.1 (t), 25.9 (q), 18.3 (s), 14.4 (q), –5.3 (q); m/z (EI) 388.2435 (M+, C23H36O3Si requires 388.2434).

(E)-3-[2-(Z)-6-Chlorohex-3-enyl)phenyl]acrylic Acid, Ethyl Ester 18a. A solution of tetra-n-butylammonium fluoride (7.6 ml) in THF (1.0 M, 7.61 mmol) was added dropwise over 5 min to a stirred solution of the silyl ether 17a (2.5 g, 6.34 mmol) in THF (60 ml), at 0°C, under an atmosphere of nitrogen. The solution was allowed to warm to room temperature where it was stirred for 5 h. Diethyl ether (20 ml) and water (50 ml) were added and the separated aqueous layer was then extracted with diethyl ether (2 Χ 10 ml). The combined organic extracts were washed with brine, dried and concentrated in vacuo. The residue was purified by chromatography on silica, using 50% diethyl ether in light petroleum (bp 40–60°C) as eluent, to give the corresponding alcohol (1.6 g, 90%) as a pale yellow oil; (found: C, 73.8; H, 7.9%; C17H22O3 requires C, 74.4; H, 8.1%); n max (film)/cm–1 3623, 3514, 1698, 1633, 1571; 1H NMR (360 MHz) d = 1.35 (3H, t, J = 7.1 Hz, OCH2CH3), 2.26–2.37 (5H, m), 2.81 (2H, t, J = 8.0 Hz, ArCH2CH2), 3.61 (2H, t, J = 6.6 Hz, CH2OH), 4.28 (2H, q, J = 7.1 Hz, OCH2CH3), 5.43 (1H, dm, J = 10.8 Hz, CH), 5.61 (1H, dm, J = 10.8 Hz, CH), 6.40 (1H, d, J = 15.8 Hz, ArCH=CH), 7.16–7.25 (2H, m, ArH), 7.31 (1H, td, J = 7.4 and 1.3 Hz, ArH), 7.58 (1H, d, J = 7.8 Hz, ArH), 8.07 (1H, d, J = 15.8 Hz, CHCO2Et); 13C NMR (90.6 MHz) d 14.2 (q), 29.6 (t), 31.1 (t), 33.7 (t), 60.6 (t), 62.1 (t), 119.1 (d), 126.4 (d), 126.6 (d), 126.8 (d), 130.1 (d), 130.2 (d), 130.9 (d), 132.8 (s), 141.6 (s), 142.4 (d), 167.4 (s); m/z (EI) 274.1564 (M+, C17H22O3 requires 274.1569).

N-Chlorosuccinimide (1.13 g, 8.8 mmol) was added in one portion to a stirred solution of the alcohol (1.6 g, 5.7 mmol) and triphenylphosphine (2.2 g, 8.5 mmol) in DMF (55 ml), at 0°C, under a nitrogen atmosphere. The mixture was stirred at 0°C for 30 min, then methanol (2 ml) was added, and the mixture was again stirred at 0°C for a further 15 min. Diethyl ether (20 ml) was added and the mixture was washed with water (3 Χ 10 ml). The combined aqueous extracts were washed with diethyl ether (2 Χ 5 ml) and the separated organic layers were then washed with brine, dried, and evaporated in vacuo. The residue was purified by chromatography on silica, using 10% diethyl ether in light petroleum (bp 40–60°C) as eluent, to give the chloride (1.40 g, 84%) as a pale yellow oil; (found: C, 69.9; H, 7.1%; C17H21ClO2 requires C, 69.7; H, 7.2%); n max (film)/cm–1 2940, 2906, 1704, 1633, 1600, 1571; 1H NMR (360 MHz) d = 1.36 (3H, J = 7.1 Hz, OCH2CH3), 2.34 (2H, app. q, J = 7.5 Hz, CH2CH=CH), 2.40 (2H, app. q, J = 7.1 Hz, CH=CHCH2), 2.84 (2H, app. t, J = 7.4 Hz, ArCH2), 3.37 (2H, t, J = 7.0 Hz, CH2Cl), 4.29 (2H, q, J = 7.1 Hz, OCH2CH3), 5.42 (1H, dm, J = 10.8 Hz, CH), 5.59 (1H, dm, J = 10.8 Hz, CH), 6.39 (1H, d, J = 15.8 Hz, CH), 7.16–7.26 (2H, m), 7.32 (1H, td, J = 7.4 and 1.2 Hz, ArH), 7.57 (1H, d, J = 7.8 Hz, ArH), 8.02 (1H, d, J = 15.8 Hz, CH); 13C NMR (90.6 MHz) d = 14.3 (q), 29.2 (t), 30.5 (t), 32.9 (t), 43.9 (t), 60.4 (t), 119.7 (d), 126.2 (d), 126.6 (2 Χ d), 129.9 (d), 130.1 (d), 131.1 (d), 132.9 (s), 141.2 (s), 141.9 (d), 166.9 (s); m/z (EI) 293.1272 (M+, C17H21ClO2 requires 293.1308).

(E)-3-[2-(Z)-6-Chlorohex-3-enyl)phenyl]-propenal 19a. A solution of iBu2AlH (8.3 ml) in toluene (1.5 M, 12.0 mmol) was added dropwise over 10 min to a stirred solution of the ester 18a (1.66 g, 5.66 mmol) in dichloromethane (60 ml) at –78°C, under a nitrogen atmosphere. The solution was stirred at –78°C for 30 min then quenched with methanol (2 ml) and allowed to warm to room temperature. The mixture was poured into a saturated aqueous solution of Rochelle salt (100 ml) and stirred for 10 h. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3 Χ 20 ml). The combined organic extracts were washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica, using 40% diethyl ether in light petroleum (bp 40–60°C) as eluent, to give the corresponding allylic alcohol (1.15 g, 81%) as a colorless oil; n max (film)/cm–1 3612, 2937, 1652, 1601; 1H NMR (360 MHz) d = 1.59 (1H, br. s, OH), 2.32 (2H, q, J = 6.9 Hz, CHCH2), 2.43 (2H, qd, J = 6.8 and 1.4 Hz, CHCH2), 2.76 (2H, t, J 7.5 Hz, ArCH2), 3.38 (2H, t, J = 7.1 Hz, CH2Cl), 4.37 (2H, dd, J = 5.7 and 1.6 Hz, CH2OH), 5.40 (1H, dm, J = 10.8 Hz, CH), 5.60 (1H, dm, J = 10.8 Hz, CH), 6.28 (1H, dt, J = 15.7 and 5.6 Hz, CH), 6.90 (1H, dt, J = 15.7 and 1.5 Hz, ArCH=CH), 7.13–7.15 (1H, m, ArH), 7.16–7.22 (2H, m, 2xArH), 7.47–7.49 (1H, m, ArH); 13C NMR (90.6 MHz) d = 28.8 (t), 30.6 (t), 33.1 (t), 44.1 (t), 63.8 (t), 125.8 (d), 126.2 (d), 126.4 (d), 127.6 (d), 128.5 (d), 129.7 (d), 130.3 (d), 131.7 (d), 135.4 (s), 139.1 (s); m/z (EI) 250.1121 (M+, C15H19ClO requires 250.1124).

Manganese oxide (4.0 g, 45.9 mmol) was added in one portion to a stirred solution of the alcohol (1.15 g, 4.6 mmol) in dichloromethane (50 ml), at room temperature, under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 h, then filtered through a pad of Celite, which was washed with dichloromethane (10 ml). The solvent was evaporated in vacuo to leave a yellow oil, which was purified by column chromatography on silica, using 10% diethyl ether in light petroleum (bp 40–60°C) as eluent, to give the aldehyde (940 mg, 82%) as a colorless oil; (found: C, 72.0; H, 6.8%; C15H17ClO requires C, 72.4; H, 6.9%); n max (film)/cm–1 2741, 1672, 1621, 1600; 1H NMR (360 MHz) d = 2.34–2.44 (4H, m), 2.88 (2H, t, J = 7.3 Hz, ArCH2), 3.39 (2H, t, J = 6.8 Hz, CH2Cl), 5.43 (1H, dm, J 10.8 Hz, CH), 5.59 (1H, dm, J = 10.8 Hz, CH), 6.69 (1H, dd, J = 15.8 and 7.7 Hz, ArCH=CH), 7.25–7.31 (2H, m, 2xArH), 7.38 (1H, td, J = 7.4 and 1.3 Hz, ArH), 7.62 (1H, dd, J = 7.6 and 0.9 Hz, ArH), 7.84 (1H, d, J = 15.8 Hz, CH), 9.76 (1H, d, J = 7.7 Hz, CHO); 13C NMR (90.6 MHz) d = 29.4 (t), 30.5 (t), 32.9 (t), 43.9 (t), 126.5 (d), 126.9 (2 Χ d), 129.9 (d), 130.4 (d), 130.9 (d), 131.0 (d), 132.4 (s), 141.6 (s), 149.9 (d), 193.8 (s); m/z (EI) 248.0962 (M+ C15H17ClO requires 248.0968).

(1E,3Z)-3-[2-(6-Chlorohex-3-enyl)phenyl]penta-1,4-dien-3-ol 20a. A solution of vinylmagnesium bromide (2.27 ml) in THF (1 M, 2.27 mmol) was added dropwise over 5 min to a stirred solution of the aldehyde 19a (470 mg, 1.9 mmol) in THF (20 ml), at –78°C, under a nitrogen. The solution was allowed to warm to room temperature where it was stirred for one hour. Diethyl ether (20 ml) and saturated aqueous ammonium chloride solution (20 ml) were added, and the separated aqueous layer was extracted with diethyl ether (2 Χ 5 ml). The combined organic extracts were washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica, using 20% diethyl ether in light petroleum (bp 40–60°C) as eluent, to give the alcohol (459 mg, 88%) as a colorless oil; n max (film)/cm–1 3597, 2936, 2870, 1642; 1H NMR (360 MHz) d = 1.79 (1H, d, J = 4.2 Hz, OH), 2.33 (2H, app. q, J = 7.7 Hz, CHCH2), 2.43 (2H, qd, J = 7.1 and 1.4 Hz, CHCH2), 2.76 (2H, t, J = 7.2 Hz, ArCH2), 3.38 (2H, t, J = 7.1 Hz, CH2Cl), 4.85–4.87 (1H, m, CHOH), 5.22 (1H, dt, J 10.3 and 1.3 Hz, CHH), 5.37 (1H, dt, J = 17.2 and 1.3 Hz, CHH), 5.38–5.44 (1H, dm, J = 10.8 Hz, CH), 5.56–5.63 (1H, dm, J = 10.8 Hz, CH), 6.01 (1H, ddd, J = 17.2, 10.3 and 5.8 Hz, CH), 6.15 (1H, dd, J = 15.7 and 6.3 Hz, CH), 6.90 (1H, dd, J 15.7 and 1.1 Hz, CH), 7.13–7.16 (1H, m, ArH), 7.17–7.21 (2H, m, 2xArH), 7.46–7.48 (1H, m, ArH); 13C NMR (90.6 MHz) d = 28.8 (t), 30.6 (t), 33.1 (t), 44.1 (t), 73.9 (d), 115.4 (t), 125.8 (d), 126.2 (d), 126.4 (d), 127.7 (d), 128.3 (d), 129.7 (d), 131.7 (d), 132.1 (d), 135.3 (s), 139.2 (s), 139.3 (d); m/z (EI) 276.1274 (M+, C17H21ClO requires 274.1125).

(1E,3Z)-3-[2-(6-Iodohex-3-enyl)phenyl]penta-1,4-dien-3-one 8a. Barium manganate (851 mg, 3.3 mmol) was added in one portion to a stirred solution of the alcohol 20a (459 mg, 1.7 mmol) in dichloromethane (15 ml), at room temperature, under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 h, then filtered through a pad of Celite, which was washed with dichloromethane (10 ml). The solvent was evaporated in vacuo to leave a pale yellow oil, which was purified by column chromatography on silica, using 10% diethyl ether in light petroleum (bp 40–60°C) as eluent, to give the corresponding ketone (419 mg, 92%) as a yellow oil; (found: C, 74.2; H, 6.9%; C17H19ClO requires C, 74.3; H, 7.0%); n max (film)/cm–1 1660, 1620; 1H NMR (360 MHz) d = 2.32–2.43 (4H, m), 2.86 (2H, t, J = 7.3 Hz, ArCH2), 3.36 (2H, t, J = 6.9 Hz, CH2Cl), 5.41 (1H, dm, J = 10.8 Hz, CH), 5.58 (1H, dm, J = 10.8 Hz, CH), 5.91 (1H, dd, J = 10.6 and 1.2 Hz, CHH), 6.40 (1H, dd, J = 17.5 and 1.2 Hz, CHH), 6.70 (1H, dd, J = 17.4 and 10.6 Hz, COCH=CH2), 6.98 (1H, d, J = 15.7 Hz, CH), 7.21–7.28 (2H, m, 2xArH), 7.34 (1H, td, J = 7.4 and 1.4 Hz, ArH), 7.64 (1H, dd, J = 7.6 and 1.2 Hz, ArH), 8.03 (1H, d, J = 15.7 Hz, CH); 13C NMR (90.6 MHz) d = 29.3 (t), 30.5 (t), 33.0 (t), 44.0 (t), 125.2 (d), 126.3 (d), 126.6 (d), 126.7 (d), 128.6 (d), 130.3 (d), 130.4 (d), 131.1 (d), 133.2 (s), 135.8 (d), 141.2 (d), 141.8 (s), 189.4 (s); m/z (EI) 274.1118 (M+, C17H19ClO requires 274.1125).

Sodium iodide (225 mg, 1.50 mmol) was added in one portion to a stirred mixture of the chloride (82 mg, 0.30 mmol) and potassium carbonate (4 mg, 0.03 mmol) in butan-2-one (5 ml), at room temperature, under nitrogen. The mixture was heated at reflux for 16 h then allowed to cool to room temperature. The solvent was evaporated in vacuo to leave a residue and diethyl ether added. The solution was filtered and the solvent evaporated in vacuo to leave a yellow oil. The oil was purified by column chromatography on silica, using 10% diethyl ether in light petroleum (bp 40–60°C) as eluent, to give the iodide (110 mg, 99%) as a pale yellow oil; (found: C, 56.2; H, 5.1%; C17H19IO requires C, 55.8; H, 5.2%); n max (film)/cm–1 1660, 1621, 1592; 1H NMR (360 MHz) d = 2.33 (2H, app. q, J = 7.4 Hz, CHCH2), 2.49 (2H, qd, J = 7.3 and 1.3 Hz, CHCH2), 2.87 (2H, t, J = 7.3 Hz, ArCH2), 2.94 (2H, t, J = 7.3 Hz, CH2I), 5.32–5.38 (1H, dm, J = 10.8 Hz, CH), 5.54–5.61 (1H, dm, J = 10.8 Hz, CH), 5.92 (1H, dd, J = 10.6 and 1.2 Hz, CHH), 6.40 (1H, dd, J = 17.4 and 1.2 Hz, CHH), 6.70 (1H, dd, J = 17.5 and 10.6 Hz, COCH=CH2), 6.98 (1H, d, J = 15.7 Hz, CH), 7.21–7.28 (2H, m, 2xArH), 7.34 (1H, td, J = 7.4 and 1.4 Hz, ArH), 7.64 (1H, dd, J = 7.7 and 1.2 Hz, ArH), 8.01 (1H, d, J = 15.7 Hz, ArCH=CH); 13C NMR (90.6 MHz) d = 5.1 (t), 29.3 (t), 31.3 (t), 32.9 (t), 125.3 (d), 126.6 (d), 126.7 (d), 128.6 (t), 129.1 (d), 130.3 (d), 130.4 (d), 130.5 (d), 133.3 (s), 135.9 (d), 141.2 (d), 141.8 (s), 189.3 (s); m/z (EI) 366.0489 (M+, C17H19IO requires 366.0481).

2-Iodo-4-methoxycinnamic Acid Ethyl Ester 15b. Triethyl phosphonoacetate (1.4 ml, 7 mmol) was added dropwise over 5 min to a stirred solution of n-butyllithium in pentane (2.6 ml, 2.50 M, 6.5 mmol) and THF (45 ml) at room temperature under an atmosphere of nitrogen. The mixture was stirred at room temperature for 30 min and then cooled to 0°C. A solution of 2-iodo-4-methoxy benzaldehyde (ref. 2) (1.6 g, 6.2 mmol) in THF (5 ml) was added dropwise over 5 min and the resulting yellow solution was allowed to warm to room temperature over 12 h. Saturated aqueous ammonium chloride (25 ml) was added and the separated aqueous layer was then extracted with diethyl ether (2 Χ 5 ml). The combined organic extracts were washed with brine (2 Χ 10 ml), then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 20% diethyl ether in light petroleum to give the ester (1.48 g, 72%) as colorless crystals; mp 76–78°C (from Et2O); (found: C, 43.3, H, 3.9, I, 38.0%; C12H13IO3 requires C, 43.4, H, 3.9, I, 38.2%). n max (CHCl3)/cm–1 1698, 1629, 1590, 1557, 1492; 1H NMR (360 MHz, CDCl3) d = 7.85 (1H, d, J = 15.7 Hz, ArCH=CH), 7.49 (1H, d, J = 8.7 Hz, ArH), 7.40 (1H, d, J = 2.6 Hz, ArH), 6.89 (1H, dd, J = 8.7 and 2.6 Hz, ArH), 6.21 (1H, d, J = 15.7 Hz, ArCH=CH), 4.26 (2H, q, J = 7.2 Hz, OCH2CH3), 3.80 (3H, s, OMe), 1.34 (3H, t, J = 7.2 Hz, OCH2CH3); 13C NMR (90.5 MHz, CDCl3) d = 166.7 (s), 160.0 (s), 147.2 (d), 130.2 (s), 127.8 (d), 124.8 (d), 118.9 (d), 115.2 (d), 102.2 (s), 60.4 (t), 55.7 (q), 14.3 (q); m/z (EI) 331.9912 (M+, C12H13IO3 requires 331.9909).

(E)-3-[4-Methoxy-2-(3-oxopropyl)phenyl]acrylic Acid Ethyl Ester 16b. Palladium(II) acetate (50 mg, 0.23 mmol) was added in one portion to a stirred solution of the iodide 15b (1.48 g, 4.4 mmol), allyl alcohol (0.9 ml, 13.5 mmol), tetra-n-butylammonium chloride (1.5 g, 4.5 mmol) and sodium bicarbonate (0.94 g, 11.5 mmol) in DMF (5 ml), at room temperature under an atmosphere of nitrogen. The mixture was heated at 38°C for 4 h and then allowed to cool to room temperature. Diethyl ether (25 ml) and water (10 ml) were added and the separated aqueous layer was then extracted with diethyl ether (2 Χ 5 ml). The combined organic extracts were washed with brine (10 ml), then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, using 50% diethyl ether in light petroleum as eluent to give the aldehyde (1.01 g, 87%) as a colorless oil. n max (CHCl3)/cm–1 2982, 1730, 1714, 1603; 1H NMR (360 MHz, CDCl3) d = 9.81 (1H, t, J = 1.2 Hz, CHO), 7.88 (1H, d, J = 15.7 Hz, ArCH=CH), 7.54 (1H, d, J = 8.6 Hz, ArH), 6.78 (1H, dd, J = 8.6 and 2.6 Hz, ArH), 6.74 (1H, d, J = 2.6 Hz, ArH), 6.28 (1H, d, J = 15.7 Hz, ArCH=CH), 4.26 (2H, q, J = 7.1 Hz, OCH2CH3), 3.81 (3H, s, OMe), 3.08 (2H, t, J = 7.7 Hz, ArCH2CH2), 2.74 (2H, dt, J = 7.7 and 1.2 Hz, ArCH2CH2), 1.33 (3H, t, J = 7.1 Hz, OCH2CH3); 13C NMR (90.5 MHz, CDCl3)d = 200.6 (d), 167.1 (s), 161.1 (s), 141.9 (s), 140.8 (d), 128.4 (d), 125.6 (s), 117.6 (d), 115.1 (d), 112.6 (d), 60.4 (t), 55.3 (q), 44.9 (t), 25.6 (t), 14.3 (q); m/z (EI) 262.1211 (M+, C15H18O4 requires 262.1205).

(E)-3-{2-[(Z)-6-(tert-Butyldimethylsilyloxy)hex-3-enyl]-4-methoxyphenyl}acrylic Acid Ethyl Ester 17b. A solution of potassium bis(trimethylsilyl)amide in toluene (4.6 ml, 0.5 M, 2.3 mmol) was added dropwise over 5 min to a stirred suspension of triphenyl(tert-butylsilyloxy)propylphosphonium iodide (ref. 1) (1.2 g, 2 mmol) in THF (8 ml) at –78°C under an atmosphere of nitrogen. The mixture was stirred at –78°C for 20 min, then allowed to warm to 0°C over 40 min and again recooled to –78°C. A solution of the aldehyde 16b (510 mg, 1.9 mmol) in THF (10 ml) was added dropwise over 10 min and the mixture was then allowed to warm to room temperature over 1 h and 45 min. Water (5 ml) was added and the separated aqueous layer was then extracted with diethyl ether (3 Χ 10 ml). The combined organic extracts were dried and concentrated in vacuo and the residue was purified by column chromatography on silica, eluting with 5% ethyl acetate in light petroleum to give the alkene (750 mg, 92%) as a colorless oil; (found: C, 68.9, H, 9.3%; C24H38O4Si requires: C, 68.9, H, 9.2%); n max (CHCl3)/cm–1 2955, 1703, 1602, 835; 1H NMR (360 MHz, CDCl3) d = 7.96 (1H, d, J = 15.7 Hz, ArCH=CH), 7.55 (1H, d, J = 8.6 Hz, ArH), 6.77 (1H, dd, J = 8.6 and 2.6 Hz, ArH), 6.72 (1H, d, J = 2.6 Hz, ArH), 6.28 (1H, d, J = 15.7 Hz, ArCH=CH), 5.54–5.39 (2H, m, Z CH=CH), 4.26 (2H, q, J = 7.1 Hz, OCH2CH3), 3.83 (3H, s, OMe), 3.54 (2H, t, J = 7.5 Hz, CH2OTBS), 2.79 (2H, t, J = 7.3 Hz, ArCH2CH2), 2.33 (2H, app. q, J = 7.1 Hz, CH2CH2OTBS), 2.19 (2H, app. q, J = 7.3 Hz, ArCH2CH2), 1.34 (3H, t, J = 7.5 Hz, OCH2CH3), 0.88 (9H, s, SiCMe3), 0.04 (6H, s, SiMe2); 13C NMR (90.5 MHz, CDCl3) d = 167.3 (s), 160.9 (s), 143.6 (s), 141.5 (d), 129.8 (d), 128.1 (d), 127.1 (d), 125.6 (s), 116.9 (d), 115.2 (d), 112.2 (d), 62.8 (t), 60.3 (t), 55.2 (q), 38.3 (t), 30.9 (t), 29.1 (t), 25.9 (q), 18.3 (s), 14.4 (q), –5.3 (q); m/z [fast atom bombardment (FAB)] 441.2440 ([M+ + Na], C24H38O4SiNa requires 441.2437).

(E)-3-[2-((Z)-6-Chlorohex-3-enyl)-4-methoxyphenyl]acrylic Acid Ethyl Ester 18b. A solution of tetra-n-butylammonium fluoride in THF (6.9 ml, 1 M, 6.9 mmol) was added dropwise over 5 min to a stirred solution of the silyl ether 24a (2.3 g, 5.35 mmol) in THF (90 ml) at 0°C under an atmosphere of nitrogen and the solution was then allowed to warm gradually to room temperature over 3 h. Diethyl ether (20 ml) and water (20 ml) were added and the separated aqueous layer was extracted with diethyl ether (2 Χ 20 ml). The combined organic extracts were washed with brine (10 ml), then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 50% diethyl ether in light petroleum to give the corresponding alcohol (1.3 g, 80%) as a colorless oil. n max (CHCl3)/cm–1: 3623, 1693, 1631, 1368; 1H NMR (360 MHz, CDCl3) d = 8.00 (1H, d, J = 15.8 Hz, ArCH=CH), 7.57 (1H, d, J = 8.6 Hz, ArH), 6.77 (1H, dd, J = 8.6 and 2.6 Hz, ArH), 6.74 (1H, d, J = 2.6 Hz, ArH), 6.30 (1H, d, J = 15.8 Hz, ArCH=CH), 5.64–5.38 (2H, m, Z CH=CH), 4.26 (2H, q, J = 7.1 Hz, OCH2CH3), 3.83 (3H, s, OMe), 3.63 (2H, t, J = 6.7 Hz, ArCH2CH2), 2.77 (2H, m, CH2OH), 2.28–2.34 (4H, m, CH2CH=CHCH2), 1.33 (3H, t, J = 7.1 Hz, OCH2CH3); 13C NMR (90.5 MHz, CDCl3) d = 167.8 (s), 161.1 (s), 143.8 (s), 141.9 (d), 130.9 (d), 127.9 (d), 126.9 (d), 125.4 (s), 116.4 (d), 115.2 (d), 112.3 (d), 62.2 (t), 60.5 (t), 53.3 (q), 34.1 (t), 31.2 (t), 29.7 (t), 14.3 (q); m/z (EI) 304.1679 (M+, C18H24O4 requires 304.1674).

N-Chlorosuccinimide (809 mg, 6.1 mmol) was added in one portion to a stirred solution of the alcohol (1.3 g, 4.3 mmol) and triphenylphosphine (1.5 g, 5.6 mmol) in dichloromethane (80 ml) at 0°C under an atmosphere of nitrogen. The mixture was stirred at 0°C for 30 min and then methanol (10 ml) and diethyl ether (20 ml) were added. Water (20 ml) was added and the separated aqueous layer was then extracted with diethyl ether (2 Χ 20 ml). The combined organic extracts were washed with brine (10 ml), then dried and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 10% diethyl ether in light petroleum to give the chloride (1.2 g, 87%) as a pale yellow oil. n max (CHCl3)/cm–1 1698, 1631, 1368; 1H NMR (360 MHz, CDCl3) d = 7.94 (1H, d, J = 15.8 Hz, ArCH=CH), 7.56 (1H, d, J = 8.6 Hz, ArH), 6.77 (1H, dd, J = 8.6 and 2.6 Hz, ArH), 6.72 (1H, d, J = 2.6 Hz, ArH), 6.29 (1H, d, J = 15.8 Hz, ArCH=CH), 5.60–5.41 (2H, m, Z CH=CH), 4.26 (2H, q, J = 7.1 Hz, OCH2CH3), 3.83 (3H, s, OMe), 3.39 (2H, t, J = 7.1 Hz, CH2Cl), 2.81 (2H, t, J = 7.3 Hz, ArCH2CH2), 2.45–2.31 (4H, m, CH2CH=CHCH2), 1.34 (3H, t, J = 7.1 Hz, OCH2CH3); 13C NMR (90.5 MHz, CDCl3) d = 167.3 (s), 160.9 (s), 143.3 (s), 141.4 (d), 131.1 (d), 128.2 (d), 126.3 (d), 125.6 (s), 117.1 (d), 115.4 (d), 112.3 (d), 60.3 (t), 53.3 (q), 40.0 (t), 33.2 (t), 30.5 (t), 29.2 (t), 14.4 (q); m/z (EI) 322.1337 (M+, C18H23ClO3 requires 322.1336).

(E)-3-[2-((Z)-6-Chlorohex-3-enyl)-4-methoxyphenyl]propenal 19b. A solution of iBu2AlH in toluene (5.3 ml, 1.5 M, 8 mmol) was added dropwise over 10 min to a stirred solution of the ester 18b (1.3 g, 4 mmol) in dichloromethane (80 ml) at –78°C under an atmosphere of nitrogen. The solution was stirred at –78°C for 1 h, then methanol (10 ml) was added and the solution was allowed to warm to room temperature. The solution was poured into a saturated aqueous solution of Rochelle salt (25 ml) and stirred for a further 12 h. The separated aqueous layer was then extracted with dichloromethane (3 Χ 20 ml). The combined organic extracts were washed with brine (20 ml), then dried and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 50% diethyl ether in light petroleum to give the corresponding allylic alcohol (1.0 g, 89%) as a yellow oil. n max (CHCl3)/cm–1 3610, 1606, 835; 1H NMR (360 MHz, CDCl3) d = 7.41 (1H, d, J = 8.6 Hz, ArH), 6.81 (1H, d, J = 15.7 Hz, ArCH=CH), 6.75 (1H, dd, J = 8.6 and 2.6 Hz, ArH), 6.69 (1H, d, J = 2.7 Hz, ArH), 6.22–6.14 (1H, m, ArCH=CH), 5.62–5.38 (2H, m, Z CH=CH), 4.32 (2H, dd, J = 5.9 and 1.5 Hz, CH2OH), 3.81 (3H, s, OMe), 3.40 (2H, t, J = 7.1 Hz, CH2Cl), 2.71 (2H, t, J = 7.3 Hz, ArCH2CH2), 2.45 (2H, app. q, J = 7.1 Hz, ArCH2CH2), 2.34 (2H, app. q, J = 7.5 Hz, CH2CH2Cl), 1.46 (1H, br s, OH); 13C NMR (90.5 MHz, CDCl3) d = 159.1 (s), 140.6 (s), 131.7 (d), 128.4 (d), 128.3 (d), 128.1 (s), 127.4 (d), 125.9 (d), 115.0 (d), 111.8 (d), 64.0 (t), 55.2 (q), 44.1 (t), 33.3 (t), 30.6 (t), 28.7 (t); m/z (EI) 280.1235 (M+, C16H21ClO2 requires 280.1230).

Pyridinium dichromate (2.9 g, 7.7 mmol) was added in one portion to a stirred solution of the alcohol (1.4 g, 5 mmol) in dichloromethane (80 ml) at 0°C under an atmosphere of nitrogen and the mixture was then allowed to warm gradually to room temperature over 16 h. The mixture was filtered through a pad of Celite, which was washed with dichloromethane (20 ml). The filtrate was concentrated in vacuo to leave the aldehyde (984 mg, 71%) as a pale yellow oil, which solidified on standing. The crude aldehyde was used in the next step without further purification. n max (CHCl3)/cm–1 2744, 1672, 1597, 969; 1H NMR (360 MHz, CDCl3) d = 9.70 (1H, d, J = 7.7 Hz, CHO), 7.74 (1H, d, J = 15.6 Hz, ArCH=CH), 7.61 (1H, d, J = 8.7 and 2.7 Hz, ArH), 6.83 (1H, dd, J = 8.7 and 2.7 Hz, ArH), 6.77 (1H, d, J = 2.7 Hz, ArH), 6.61 (1H, dd, J = 15.6 and 7.7 Hz ArCH=CH), 5.62–5.42 (2H, m, Z CH=CH), 3.84 (3H, s, OMe), 3.42 (2H, t, J = 6.8 Hz, CH2Cl), 2.85 (2H, t, J = 7.4 Hz, ArCH2CH2), 2.46–2.33 (4H, m, CH2CH=CHCH2); 13C NMR (90.5 MHz, CDCl3) d = 193.7 (d), 161.9 (s), 149.6 (d), 143.9 (s), 130.9 (d), 128.8 (d), 127.6 (d), 126.6 (d), 124.9 (s), 115.6 (d), 112.5 (d), 64.0 (t), 55.4 (q), 43.9 (t), 33.1 (t), 30.6 (t), 29.3 (t); m/z (EI) 278.1076 (M+, C16H19ClO2 requires 278.1074).

(1E,3Z)-3-[2-(6-Chlorohex-3-enyl)-4-methoxyphenyl]penta-1,4-dien-3-ol 20b. A solution of vinylmagnesium bromide (1.77 ml) in THF (1 M, 1.77 mmol) was added dropwise over 2 min to a stirred solution of the aldehyde 19b (405 mg, 1.47 mmol) in THF (15 ml), at –78°C, under nitrogen atmosphere. The solution was allowed to warm to room temperature, where it was stirred for 30 min. Diethyl ether (10 ml) and saturated aqueous ammonium chloride solution (20 ml) were added and the separated aqueous layer was extracted then with diethyl ether (2 Χ 5 ml). The combined organic extracts were washed with brine, dried, and concentrated in vacuo. The residue was purified by column chromatography on silica, using 40% diethyl ether in light petroleum (bp 40–60°C) as eluent, to give the alcohol (400 mg, 89%) as a colorless oil; n max (film)/cm–1 3631, 2943, 1607, 1571, 1H NMR (360 MHz) d = 1.77 (1H, d, J = 4.2 Hz, OH), 2.33 (2H, app. q, J = 7.6 Hz, CH2CH=CH), 2.46 (2H, dq, J = 7.1 and 1.4 Hz, CH=CHCH2), 2.72 (2H, t, J = 7.4 Hz, ArCH2), 3.41 (2H, t, J = 7.0 Hz, CH2Cl), 3.81 (3H, s, OCH3), 4.80–4.84 (1H, m, CHOH), 5.20 (1H, dt, J = 10.4 and 1.3 Hz, CHH), 5.35 (1H, dt, J = 17.2 and 1.4 Hz, CHH), 5.39–5.43 (1H, dm, J = 10.4 Hz, CH), 5.54–5.66 (1H, dm, J = 10.4 Hz, CH), 6.01 (1H, dd, J = 8.5 and 2.7 Hz, ArH), 6.62 (1H, dd, J = 15.7 and 7.7 Hz, CH), 6.77 (1H, d, J = 2.7 Hz, ArH), 6.82 (1H, J = 15.6 and 0.9 Hz, CH), 7.42 (1H, d, J = 8.6 Hz, ArH); 13C NMR (90.6 MHz) d = 28.8 (t), 30.6 (t), 33.3 (t), 44.1 (t), 55.2 (q), 74.1 (d), 111.8 (d), 115.1 (d), 115.2 (t), 125.9 (d), 127.4 (d), 127.9 (s), 130.2 (d), 131.7 (d), 139.5 (d), 140.8 (s), 159.2 (s); m/z (EI) 306.1384 (M+, C18H23ClO2 requires 306.1387).

(1E,3Z)-3-[2-(6-Iodohex-3–enyl)-4-methoxyphenyl]penta-1,4-dien-3-one 8b. Barium manganate (1.7 g, 6.5 mmol) was added in one portion to a stirred solution of the alcohol 20b (400 mg, 1.30 mmol) in dichloromethane (15 ml), at 0°C, under a nitrogen atmosphere. The mixture was allowed to warm to room temperature over 16 h, then filtered through a pad of Celite, which was washed with dichloromethane (10 ml). The solvent was evaporated in vacuo to leave a yellow oil, which was purified by column chromatography on silica, using 20% diethyl ether in light petroleum (bp 40–60°C) as eluent, to give the corresponding ketone (310 mg, 78%) as a pale yellow oil; n max (film)/cm–1 1658, 1587; 1H NMR (360 MHz) d = 2.35 (2H, q, J = 7.4 Hz, CHCH2), 2.42 (2H, app. q, J = 7.0 Hz, CHCH2), 2.84 (2H, t, J = 7.3 Hz, ArCH2), 3.39 (2H, t, J = 6.9 Hz, CH2Cl), 3.85 (3H, s, OCH3), 5.41–5.46 (1H, dm, J = 10.8 Hz, CH), 5.55–5.59 (1H, dm, J = 10.8 Hz, CH), 5.87 (1H, dd, J = 10.6 and 1.3 Hz, CHH), 6.38 (1H, dd, J = 17.4 and 1.3 Hz, CHH), 6.70 (1H, dd, J = 17.4 and 10.6 Hz, CH), 6.74 (1H, d, J = 2.7 Hz, ArH), 6.80 (1H, dd, J = 8.6 and 2.6 Hz, ArH), 6.87 (1H, d, J = 15.7 Hz, CH), 7.64 (1H, d, J = 8.7 Hz, ArH), 7.98 (1H, d, J = 15.6 Hz, CH); 13C NMR (90.6 MHz) d = 29.3 (t), 30.6 (t), 33.2 (t), 44.0 (t), 55.3 (q), 112.4 (d), 115.5 (d), 123.1 (d), 125.7 (s), 126.4 (d), 128.1 (t), 128.2 (d), 131.0 (d), 135.9 (d), 140.8 (d), 144.1 (s), 161.4 (s), 189.3 (s); m/z (EI) 304.1239 (M+, C18H21ClO2 requires 304.1230).

Sodium iodide (763 mg, 5.09 mmol) was added in one portion to a stirred mixture of the chloride (310 mg, 1.02 mmol) and potassium carbonate (14 mg, 0.10 mmol) in butan-2-one (20 ml), at room temperature, under a nitrogen atmosphere. The mixture was heated under reflux for 12 h and then allowed to cool to room temperature. The solvent was evaporated in vacuo to leave a residue. Diethyl ether was added and the solution was filtered. The filtrate was evaporated in vacuo to leave a yellow oil, which was purified by column chromatography on silica, using 30% diethyl ether in light petroleum (bp 40–60°C) as eluent, to give the iodide (400 mg, 99%) as a clear yellow oil; n max (film)/cm–1 1680, 1589, 1492; 1H NMR (360 MHz) d = 2.33 (2H, app. q, J = 6.9 Hz, CHCH2), 2.51 (2H, app. q, J = 7.2 Hz, CHCH2), 2.85 (2H, t, J = 7.3 Hz, ArCH2), 2.98 (2H, t, J = 7.2 Hz, CH2I), 3.85 (3H, s, OCH3), 5.34–5.39 (1H, dm, J = 10.8 Hz, CH), 5.54–5.59 (1H, dm, J = 10.8 Hz, CH), 5.87 (1H, dd, J = 10.6 and 1.3 Hz, CHH), 6.38 (1H, dd, J = 17.4 and 1.3 Hz, CHH), 6.69 (1H, dd, J 17.7 and 10.8 Hz, COCH=CH2), 6.74 (1H, d, J = 2.8 Hz, ArH), 6.81 (1H, dd, J = 8.6 and 2.8 Hz, ArH), 6.89 (1H, d, J = 15.6 Hz, CH), 7.64 (1H, d, J = 8.7 Hz, ArH), 7.97 (1H, d, J = 15.6 Hz, ArCH=CH); 13C NMR (90.6 MHz) d = 5.2 (t), 29.3 (t), 31.3 (t), 33.1 (t), 55.3 (q), 112.4 (d), 115.6 (d), 123.0 (d), 125.7 (s), 128.1 (t), 128.2 (d), 129.2 (d), 130.4 (d), 135.9 (d), 140.8 (d), 144.0 (s), 161.3 (s), 189.3 (s); m/z (EI) 396.0587 (M+, C18H21IO2 requires 396.0586).

(5aa ,7b ,8a ,9ab )-5,6,7,8,9,10,5a,9a-Octahydrocyclopenta[a]phenanthren-6-one 21a. A solution of tri-n-butyltin hydride (88 m l, 0.33 mmol) and 2,2'-azobis(isobutyronitrile) (AIBN; 2 mg, 0.01 mmol) in degassed benzene (5 ml) was added over 6 h, by syringe pump, to a stirred solution of the iodide 8a (100 mg, 0.27 mmol) and AIBN (2 mg, 0.01 mmol) in degassed benzene (85 ml), at reflux, under an argon atmosphere. The mixture was heated under reflux for a further 10 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica, using a gradient of 10–20% diethyl ether in light petroleum (bp 40–60°C) as eluent, to give (i) the 12-ketosteroid (17.5 mg, 27%) as a colorless solid; n max (film)/cm–1 1651, 1627; 1H NMR (360 MHz) d = 1.25–1.46 (2H, m), 1.48–1.62 (2H, m), 1.64–1.89 (4H, m), 2.03–2.16 (2H, m), 2.40 (2H, t, J = 12.5 Hz), 2.85 (1H, td, J = 13.8 and 3.9 Hz), 2.91–2.99 (2H, m), 3.14 (1H, dd, J = 13.4 and 4.6 Hz, H-11a or H-11b), 7.15 (4H, m, 4 ´ ArH); 13C NMR (90.6 MHz) d = 21.7 (t), 22.7 (t), 27.5 (t), 29.6 (t), 30.0 (t), 44.8 (d), 45.5 (d), 46.2 (t), 52.8 (d), 57.8 (d), 125.2 (d), 125.9 (d), 126.2 (d), 129.1 (d), 136.5 (s), 138.6 (s), 210.4 (s); m/z (EI) 240.1508 (M+, C17H20O requires 240.1514); and (ii) a diastereoisomeric tetracyclic ketone (15 mg, 24%); n max (film)/cm–1 1651, 1627; 1H NMR (360 MHz) d = 1.36 (1H, m, H-15b), 1.52–1.67 (3H, m, H-7 + H-14), 1.68–1.79 (3H, m, H-6 + H-17a), 2.02 (2H, m, H-15a + H-17b), 2.25 (1H, m, H-8), 2.48 (1H, m, H-13), 2.69 (1H, ddd, J = 15.6, 5.6 and 0.7 Hz, H-11a), 2.74–2.82 (2H, m, H-16), 2.94 (1H, dd, J = 15.6 and 6.3 Hz, H-11b), 3.53 (1H, q, J = 5.9 Hz, H-9), 7.08–7.19 (3H, m, 3 ´ ArH), 7.28 (1H, d, J = 7.6 Hz, ArH); 13C NMR (90.6 MHz) d = 21.9 (t), 22.4 (t), 26.0 (t), 27.3 (t), 30.6 (t), 39.7 (d), 39.9 (d), 44.6 (t), 47.3 (d), 55.5 (d), 125.9 (d), 126.2 (d), 127.6 (d), 128.8 (d), 137.1 (s), 137.4 (s), 211.2 (s); m/z (EI) 240.1519 (M+, C17H20O requires 240.1514).

(5aa ,7b ,8a ,9ab )-2-Methoxy-5,6,7,8,9,10,5a,9a-Octahydrocyclopenta[a ]phenanthren-6-one 21b. The iodide 8b (100 mg) was treated with Bu3SnH/AIBN under the same conditions as those described for the iodide 8a and gave (i) the 12-ketosteroid (16 mg, 24%) as a colorless solid; n max (film)/cm–1 1651, 1627, 1H NMR (360 MHz) d = 1.25 (1H, qd, J = 11.2 and 2.5 Hz), 1.38–1.50 (2H, m), 1.52–1.63 (1H, m), 1.72–1.83 (1H, m), 1.84–2.01 (3H, m), 2.12 (1H, dq, J = 16.4 and 2.8 Hz), 2.22 (1H, m), 2.29 (1H, dd, J = 16.6 and 12.0 Hz), 2.78–2.86 (3H, m), 2.96–3.12 (2H, m), 3.79 (3H, s, OMe), 6.65 (1H, d, J = 2.8 Hz, H-4), 6.75 (1H, dd, J = 8.6 and 2.8 Hz, H-2), 7.09 (1H, d, J 8.5 Hz, H-1); 13C NMR (90.6 MHz) d = 24.8 (t), 27.5 (t), 28.2 (t), 30.2 (t), 31.6 (t), 40.0 (d), 42.3 (d), 45.4 (t), 47.4 (d), 51.0 (d), 55.2 (q), 112.3 (d), 113.6 (d), 127.5 (d), 130.8 (s), 138.0 (s) 157.7 (s), 214.3 (s); m/z (EI) 270.1623 (M+, C18H22O2 requires 270.1619) and (ii) a diastereoisomeric tetracyclic ketone (15 mg, 22%); 1H NMR (360 MHz) d = 1.36 (1H, m, H-15b), 1.55–1.65 (3H, m, H-7 + H-14), 1.66–1.80 (3H, m, H-17a + H-6), 1.99-2.03 (2H, m, H-15a + H-17b), 2.19-2.24 (1H, m, H-8), 2.45-2.51 (1H, m, H-13), 2.67 (1H, dd, J = 15.5 and 5.6 Hz, H-11b), 2.73–2.79 (2H, m, H-16), 2.91 (1H, dd, J = 15.5 and 6.1 Hz, H-11a), 3.48 (1H, q, J = 5.7 Hz, H-9), 3.78 (3H, s, OMe), 6.63 (1H, d, J = 2.7 Hz, H-4), 6.73 (1H, dd, J = 8.6 and 2.8 Hz, H-2), 7.20 (1H, d, J = 8.4 Hz, H-1); 13C NMR (90.6 MHz) d = 21.8 (t), 22.4 (t), 25.9 (t), 27.5 (t), 30.5 (t), 39.6 (d), 39.9 (d), 44.8 (t), 47.0 (d), 55.2 (q), 55.6 (d), 111.9 (d), 113.8 (d), 128.6 (d), 129.4 (s), 138.2 (s), 157.6 (s), 211.3 (s); m/z (EI) 270.1623 (M+, C18H22O2 requires 270.1619).

(E)-1-[2-((Z)-6-Chlorohex-3-enyl)-4-methoxyphenyl]pent-1-en-4-yn-3-ol 22. A solution of ethynylmagnesium bromide in THF (12.9 ml, 0.5 M, 6.5 mmol) was added dropwise over 5 min to a stirred solution of the aldehyde 19b (1.2 g, 4.3 mmol) in THF (30 ml) at 0°C under an atmosphere of nitrogen and the solution was then allowed to warm to room temperature over 12 h. Diethyl ether (20 ml) and saturated aqueous ammonium chloride (20 ml) were added and the separated aqueous layer was extracted with diethyl ether (3 Χ 20 ml). The combined organic extracts were washed with brine (10 ml), then dried and concentrated in vacuo. The residue which was purified by column chromatography on silica, eluting with 20% diethyl ether in light petroleum to give the alcohol (1.3 g, 99%) as a yellow oil. n max (CHCl3)/cm–1 3550, 3289, 3010, 2955, 2115, 1606, 967; 1H NMR (360 MHz, CDCl3) d = 7.42 (1H, d, J = 8.6 Hz, ArH), 7.02 (1H, d, J = 15.5 Hz, ArCH=CH), 6.75 (1H, dd, J = 8.6 and 2.5 Hz, ArH), 6.69 (1H, d, J = 2.5 Hz, ArH), 6.12 (1H, dd, J = 15.5 and 5.9 Hz, ArCH=CH), 5.61–5.39 (2H, m, Z CH=CH), 5.02 (1H, br s, OH), 3.81 (3H, s, OMe), 3.40 (2H, t, J = 7.0 Hz, CH2Cl), 2.73 (2H, t, J = 7.4 Hz, ArCH2CH2), 2.66 (1H, s, C≡CH), 2.44 (2H, app. q, J = 7.0 Hz, CH2CH2Cl), 2.32 (2H, app. q, J = 7.4 Hz, ArCH2CH2), 2.14 (1H, d, J = 5.9 Hz, CHOH); 13C NMR (90.5 MHz, CDCl3) d = 159.5 (s), 141.2 (s), 131.6 (d), 129.5 (d), 127.6 (d), 127.4 (s), 127.3 (d), 126.0 (d), 115.2 (d), 111.9 (d), 83.1 (s), 74.6 (d), 63.0 (d), 55.3 (q), 44.2 (t), 33.4 (t), 30.7 (t), 28.9 (t); m/z (EI) 304.1232 (M+, C18H21O2Cl requires 304.1230).

(E)-1-[2-((Z)-6-Iodohex-3-enyl)-4-methoxyphenyl]pent-1-en-4-yn-3-one 23. Activated manganese dioxide (10 g, 115 mmol) was added in one portion to a stirred solution of the alcohol 22 (1.3 g, 4.3 mmol) in dichloromethane (120 ml) at room temperature under an atmosphere of nitrogen and the mixture was stirred at room temperature for 6 h. The mixture was filtered through a pad of Celite, which was washed with dichloromethane (50 ml). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica, eluting with 20% diethyl ether in light petroleum to give the corresponding chloroketone (996 mg, 77%) as a yellow oil. n max (CHCl3)/cm–1 2954, 2096, 1632, 975; 1H NMR (360 MHz, CDCl3) d = 8.20 (1H, d, J = 15.9 Hz, ArCH=CH), 7.61 (1H, d, J = 8.7 Hz, ArH), 6.82 (1H, dd, J = 8.7 and 2.7 Hz, ArH), 6.77 (1H, d, J = 2.7 Hz, ArH), 6.69 (1H, d, J = 15.9 Hz, ArCH=CH), 5.61–5.39 (2H, m, Z CH=CH), 3.86 (3H, s, OMe), 3.41 (2H, t, J = 7.0 Hz, CH2Cl), 3.33 (1H, s, C≡CH), 2.86 (2H, t, J = 7.4 Hz, ArCH2CH2), 2.46–2.43 (4H, m, CH2CH=CHCH2); 13C NMR (90.5 MHz, CDCl3) d = 177.7 (s), 162.2 (s), 146.8 (d), 144.7 (s), 131.0 (d), 128.8 (d), 126.8 (d), 126.6 (d), 124.9 (d), 115.9 (d), 112.7 (d), 80.3 (s), 78.9 (d), 55.5 (q), 44.1 (t), 33.4 (t), 30.7 (t), 29.6 (t); m/z (EI) 302.1071 (M+, C18H19O2Cl requires 302.1074).

Sodium iodide (683 mg, 4.60 mmol) was added in one portion to a stirred solution of the chloroketone (692 mg, 2.30 mmol) in 2-butanone (38 ml) at room temperature under an atmosphere of nitrogen. The solution was heated under reflux for 24 h and then allowed to cool to room temperature. The solvent concentrated in vacuo and the residue was purified by flash chromatography on silica, eluting with 10% diethyl ether in light petroleum to give the iodide (765 mg, 85%) as a yellow oil that solidified on standing; mp 103–105°C (from pentane); (found: C, 54.7; H, 4.9. C18H19O2I requires C, 54.8, H 4.9%); n max (CHCl3)/cm–1 2945, 2095, 1629, 974; 1H NMR (360 MHz, CDCl3) d = 8.20 (1H, d, J = 15.9 Hz, ArCH=CH), 7.61 (1H, d, J = 8.7 Hz, ArH), 6.82 (1H, dd, J = 8.7 and 2.7 Hz, ArH), 6.77 (1H, d, J = 2.7 Hz, ArH), 6.70 (1H, d, J = 15.9 Hz, ArCH=CH), 5.61–5.30 (2H, m, Z CH=CH), 3.86 (3H, s, OMe), 3.41 (2H, t, J = 7.0 Hz, CH2Cl), 3.32 (1H, s, C≡CH), 2.99 (2H, t, J = 7.4 Hz, ArCH2CH2), 2.89–2.30 (4H, m, CH2CH=CHCH2); 13C NMR (90.5 MHz, CDCl3) d = 177.7 (s), 162.2 (s), 146.7 (d), 144.7 (s), 131.9 (d), 130.3 (d), 129.4 (d), 128.8 (d), 126.7 (d), 126.6 (d), 124.8 (s), 115.7 (d), 112.7 (d), 80.2 (s), 79.0 (s), 55.4 (q), 44.1 (t), 33.4 (t), 30.7 (t), 29.6 (t); m/z (EI) 395.0511 (M+, C18H19O2I requires 395.0508).

3-Methoxy-6,7,8,9,11,14,15,16-octahydrocyclopenta[a]phenanthren-12-one 24. A solution of Bu3SnH (81 m l, 0.3 mmol) and AIBN (25 mg, 0.15 mmol) in dry degassed benzene (10 ml) was added dropwise over 8 h by syringe pump to a refluxing solution of the iodide 23 (100 mg, 0.25 mmol) and AIBN (8.3 mg, 0.05 mmol) in dry degassed benzene (100 ml) under an atmosphere of argon. The mixture was heated under reflux for a further 6 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with diethyl ether (25 ml) and the solution was stirred over 12 h with 5% aqueous potassium fluoride (25 ml). The separated aqueous layer was extracted with diethyl ether (3 Χ 10 ml) and the combined organic extracts were dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 5–30% diethyl ether in pentane to give the steroid (32.8 mg, 48%) as a colorless oil, which crystallized from ether/light petroleum as colorless crystals, mp 96–97°C; (CHCl3)/cm–1 3056, 2923, 2852, 1682, 1609, 1501; d H (500 MHz; CDCl3) 7.14 (1H, d, J = 8.6 Hz, H-1), 6.74 (1H, dd, J = 8.6 Hz, H-2), 6.67 (1H, dd, J = 5.6 and 3.0 Hz, H-17), 6.65 (1H, d, J = 2.8 Hz, H-4), 3.79 (3H, s, OMe), 3.29 (1H, m, H-14), 3.07 (1H, dd, J = 18.2 and 3.4 Hz, H-11a ), 2.95-2.82 (3H, m, 2 Χ H-6 and H-9), 2.49–2.36 (2H, m, H-16), 2.23 (1H, dd, J 18.2 and 12.7 Hz, H-11b ), 2.18 (1H, m, H. dddd, J 11.6, 6.5, 6.3 and 1.3 Hz, H-15b ), 2.06 (1H, dddd, J 12.0, 11.9, 9.1 and 2.7 Hz, H-8), 1.96 (1H, dddd, J 12.8, 5.0, 2.7 and 2.4 Hz, H-7b ), 1.79 (1H, dddd, J 11.7, 11.7, 11.2 and 8.6 Hz, H-15a ), 1.61 (1H, dddd, J 12.8, 12.6, 12.0 and 5.4 Hz, H-7a ); 13C NMR (90 MHz, CDCl3) d = 200.6 (C12), 157.8 (C3), 146.6 (C13), 140.2 (C17), 138.3 (C5*), 130.0 (C10*), 128.3 (C1), 113.9 (C4), 112.3 (C2), 55.3 (MeO), 47.4 (C11), 44.6 (C14), 39.7 (C8), 35.3 (C9), 32.0 (C16), 31.7 (C15), 30.9 (C6), 25.4 (C7); m/z (EI) 268.1460 (M+, C18H20O2 requires 268.1463).

*These signals may be interchanged.

In other experiments, using an excess of Bu3SnH (» 0.4 mmol), in addition to forming 24 (44%) the reduced steroidal product 25 (23%) was also obtained as colorless needles, mp 106–107°C (from MeOH); n max/cm–1 2918, 2866, 1702, 1609, 1572, 1499, 1452, 1282, 1253, 1132, 1033, 866, 795; d H (360 MHz; CDCl3) 7.12 (1H, d, J = 8.6, H-1), 6.74 (1H, dd, J = 8.6 and 2.7 Hz, H-2), 6.66 (1H, d, J = 2.7 Hz, H-4), 3.79 (3H, s, MeO), 3.08 (1H, dd, J = 13.7 and 3.6 Hz, H-11a ), 3.00-2.84 (3H, m, 2 Χ H-6 and H-9), 2.75 (1H, br t, J = 8.0 Hz, H-13), 2.53 (1H, m, H-14), 2.37 (1H, m, H-17b ), 2.28 (1H, dd, J = 13.7 and 9.8 Hz, H-11b ), 2.15 (1H, dddd, J = 16.4, 11.7, 4.7 and 2.5 Hz, H-8), 1.92 (1H, dddd, J = 12.7, 7.9, 4.7 and 3.2 Hz, H-7b ), 1.75-1.50 (5H, m, H-7a ,, 2 Χ H-16, H-15b , H-17a ), 1.19 (1H, dddd, J = 12.3, 12.0, 8.8 and 3.6 Hz, H-15a ); d C (90 MHz; CDCl3) 212.6 (C12), 157.8 (C3), 137.9 (C5*), 130.8 (C10*), 127.1 (C1), 114.0 (C4), 112.1 (C2), 55.3 (MeO), 53.3 (C13), 47.9 (C14), 47.0 (C11), 40.3 (C8), 36.7 (C9), 30.7 (C6), 27.9 (C7), 24.7 (C15), 24.5 (C17), 22.9 (C16); m/z (EI), 270.1620 (M+, C18H22O2 requires 270.1621).

*These signals may be interchanged.

(E)-1-[2-((Z)-6-Chlorohex-3-enyl)-4-methoxyphenyl]-4-methylpenta-1,4-dien-3-ol 26. A solution of isopropenylmagnesium bromide in THF (0.6 ml, 0.5 M, 0.3 mmol) was added dropwise over 5 min to a stirred solution of the aldehyde 19b (60 mg, 0.2 mmol) in THF (4 ml) at –78°C under an atmosphere of nitrogen and the solution was then allowed to warm to room temperature over 4 h. Diethyl ether (10 ml) and saturated aqueous ammonium chloride (5 ml) were added, and the separated aqueous layer was extracted with diethyl ether (3 Χ 5 ml). The combined organic extracts were washed with brine (5 ml), then dried and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 20% diethyl ether in light petroleum to give the alcohol (58 mg, 84%) as a yellow oil. n max (CHCl3)/cm–1 3421, 1654, 967, 902; 1H NMR (360 MHz, CDCl3) d = 7.41 (1H, d, J = 8.5 Hz, ArH), 6.84 (1H, d, J = 15.6 Hz, ArCH=CH), 6.75 (1H, dd, J = 8.5 and 2.6 Hz, ArH), 6.67 (1H, d, J = 2.6 Hz, ArH), 6.05 (1H, dd, J = 15.6 and 4.2 Hz, ArCH=CH), 5.63–5.37 (2H, 2 Χ m, Z CH=CH), 5.14 (1H, s, (CH3)C=CH2), 4.97 (1H, s, (CH3)C=CH2) 4.73 (1H, d, J = 6.6 Hz, CHOH) 3.80 (3H, s, OMe), 3.39 (2H, t, J = 7.0 Hz, CH2Cl), 2.73 (2H, t, J = 7.3 Hz, ArCH2CH2), 2.45–2.33 (4H, m, CH2CH=CHCH2), 2.20 (1H, br s, OH), 1.80 (3H, s, CH3); 13C NMR (90.5 MHz, CDCl3) d = 159.1 (s), 146.5 (s), 140.7 (s), 131.7 (d), 130.1 (d), 128.2 (d), 128.1 (s), 127.4 (d), 125.9 (d), 115.1 (d), 118.8 (d), 110.0 (t), 76.7 (d), 55.3 (q), 44.1 (t), 33.4 (t), 28.8 (t), 18.4 (q); m/z (EI) 320.1546 (M+, C19H25ClO2 requires 320.1543).

(E)-1-[2-((Z)-6-Iodohex-3-enyl)-4-methoxyphenyl]-4-methylpenta-1,4-dien-3-one 27a. Activated manganese dioxide (606 mg, 6.9 mmol) was added in one portion to a stirred solution of the alcohol 26 (58 mg, 0.18 mmol) in dichloromethane (5 ml) at room temperature under an atmosphere of nitrogen and the mixture was stirred at room temperature for 6 h. The mixture was filtered through a pad of Celite, which was washed with dichloromethane (10 ml). The filtrate was concentrated in vacuo and the residue was then purified by flash chromatography on silica, eluting with 30% diethyl ether in light petroleum to give the corresponding ketone (56 mg, 97%) as a pale yellow oil. n max (CHCl3)/cm–1 1660, 1620, 984, 874; 1H NMR (360 MHz, CDCl3) d = 7.95 (1H, d, J = 15.6 Hz, ArCH=CH), 7.61 (1H, d, J = 8.6 Hz, ArH), 7.13 (1H, d, J = 15.6 Hz, ArCH=CH), 6.80 (1H, dd, J = 9.0 and 2.6 Hz, ArH), 6.76 (1H, d, J = 2.6 Hz, ArH), 6.01 (1H, s, (CH3)C=CH2), 5.80 (1H, s, (CH3)C=CH2), 5.62–5.37 (2H, 2 Χ m, Z CH=CH), 3.89 (3H, s, OMe), 3.40 (2H, t, J = 6.8 Hz, CH2Cl), 2.84 (2H, t, J = 7.4 Hz, ArCH2CH2), 2.40 (4H, m, CH2CH=CHCH2), 2.03 (3H, s, -CH3); 13C NMR (90.5 MHz, CDCl3) d = 191.8 (s), 161.1 (s), 145.8 (s), 144.0 (s), 140.5 (d), 131.2 (d), 128.1 (d), 126.3 (d), 126.2 (s), 123.9 (t), 120.5 (d), 115.5 (d), 112.4 (d), 55.4 (q), 44.1 (t), 33.2 (t), 30.6 (t), 29.3 (t), 18.3 (q); m/z (FAB) 319.1464 ([M+ + H], C19H24ClO2 requires 319.1465).

Sodium iodide (164 mg, 1.1 mmol) was added in one portion to a stirred mixture of the chloride (70 mg, 0.22 mmol) and potassium carbonate (3 mg, 0.02 mmol) in 2-butanone (5 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux for 16 h and then allowed to cool to room temperature. The solvent was concentrated in vacuo and the residue was then purified by flash chromatography on silica, eluting with 20% ethyl acetate in light petroleum to give the iodide (60 mg, 66%) as a yellow oil. n max (CHCl3)/cm–1 1660, 1594, 980, 873; 1H NMR (360 MHz, CDCl3) d = 7.98 (1H, d, J = 15.4 Hz, ArCH=CH), 7.65 (1H, d, J = 8.6 Hz, ArH), 7.16 (1H, d, J = 15.4 Hz, ArCH=CH), 6.84 (1H, dd, J = 8.6 and 2.7 Hz, ArH), 6.78 (1H, d, J = 2.7 Hz, ArH), 6.06 (1H, s, (CH3)C=CH2), 5.84 (1H, s, (CH3)C=CH2), 5.63–5.29 (2H, 2 Χ m, Z CH=CH), 3.90 (3H, s, OMe), 2.96 (2H, t, J = 7.3 Hz, CH2I), 2.84 (2H, t, J = 7.3 Hz , ArCH2CH2), 2.52 (2H, app. q, J = 7.1 Hz, CH2CH2I), 2.33 (2H, app. q, J = 6.9 Hz, ArCH2CH2), 2.02 (3H, s, CMe); 13C NMR (90.5 MHz, CDCl3) d = 191.8 (s), 161.1 (s), 143.9 (s), 140.5 (d), 130.6 (d), 129.2 (d), 128.1 (d), 126.2 (s), 123.9 (t), 120.5 (d), 115.6 (d), 112.4 (d), 55.4 (q), 33.2 (t), 31.4 (t), 29.4 (t), 18.3 (q), 5.5 (t); m/z (FAB) 411.0849 ([M+ + H], C19H24IO2 requires 411.0821).

(E)-1-2-[(Z)-6-Hex-3-enyl)-4-methoxyphenyl]-4-methylpenta-1,4-dien-3-one 27b. A solution of Bu3SnH (69 m l, 0.26 mmol) and AIBN (2 mg, 0.01 mmol) in degassed benzene (5 ml) was added dropwise over 10 h by syringe pump to a refluxing solution of the iodide 27a (100 mg, 0.24 mmol) and AIBN (2 mg, 0.01 mmol) in degassed benzene (80 ml) under an atmosphere of argon. The mixture was heated under reflux for a further 6 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with diethyl ether (10 ml) and the solution was stirred over 12 h with 5% aqueous potassium fluoride (15 ml). The separated aqueous layer was extracted with diethyl ether (3 Χ 10 ml) and the combined organic extracts were dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 0–10% diethyl ether in light petroleum to give the hydrocarbon (42 mg, 62%) as a colorless oil. n max (CHCl3)/cm–1 2943, 1660, 1621, 985; 1H NMR (360 MHz, CDCl3) d = 7.90 (1H, d, J = 15.4 Hz, ArCH=CH), 7.6 (1H, d, J = 8.3 Hz, ArH), 7.10 (1H, d, J = 15.4 Hz, ArCH=CH), 6.84 (1H, dd, J = 8.5 and 2.7 Hz, ArH) 6.78 (1H, d, J = 2.6 Hz, ArH), 5.95 (1H, s, (CH3)C=CH2), 5.65 (1H, s, (CH3)C=CH2), 5.60–5.32 (2H, 2 Χ m, Z CH=CH), 3.80 (3H, s, OMe), 2.68 (2H, t, J = 7.3 Hz, ArCH2CH2), 2.60 (2H, m, CH2CH3), 2.30 (2H, app. q, J = 7.0 Hz, ArCH2CH2), 2.03 (3H, s, CMe), 0.94 (3H, t, J = 7.3 Hz, CH2CH3); 13C NMR (90.5 MHz, CDCl3) d = 191.6 (s), 162.0 (s), 145.7 (s), 143.2 (s), 140.5 (d), 130.6 (d), 129.4 (d), 128.2 (d), 126.2 (s), 123.8 (t), 120.6 (d), 115.7 (d), 112.4 (d), 55.3 (q), 33.2 (t), 30.9 (t), 29.6 (t), 18.3 (q), 12.7 (q); m/z (EI) 283.1699 (M+, C19H23O2 requires 283.1698).

1-tert-Butyldimethylsilyloxy-3-propyl-1-sulfonyl)-2-phenyl-2H-tetrazole 28. A solution of 3-(tert-butyldimethylsilyloxy)propan-1-ol (1 g, 5.26 mmol) in THF (30 ml) was added dropwise over 5 min to a stirred solution of 1-phenyltetrazole-5-thiol (1.9 g, 10.5 mmol) and triphenylphosphine (2 g, 7.9 mmol) in THF (30 ml) at 0°C under an atmosphere of nitrogen. Diethyl azodicarboxylate (1.6 ml, 10 mmol) was added dropwise over 5 min and the mixture was then heated to room temperature for 3 h. The mixture was diluted with diethyl ether (50 ml), and then water (20 ml) and brine (20 ml) were added. The separated aqueous layer was extracted with ethyl acetate (2 Χ 50 ml) and the combined organic extracts were then dried and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 5% ethyl acetate in light petroleum to give 1-tert-butyldimethylsilyoxy-3-propylsulfanyl-2-phenyl-2H-tetrazole (1.82 g, 99%) as a colorless oil; (found: C, 55.0; H, 7.4%. C16H26N4OSSi requires C, 54.8, H 7.5%); n max (CHCl3)/cm–1 2953, 2930, 1598; 1H NMR (360 MHz, CDCl3) d = 7.60–7.50 (5H, m, ArH), 3.78 (2H, t, J = 5.9 Hz, CH2OTBS), 3.48 (2H, t, J = 6.9 Hz, CH2SAr), 2.05 (2H, tt, J = 5.9 and 6.8 Hz, CH2CH2OTBS), 0.96 (9H, s, SiCMe3), 0.08 (6H, s, OSiMe2); 13C NMR (90.5 MHz, CDCl3) d = 154.6 (s), 133.8 (s), 130.1 (d), 129.8 (d), 123.9 (d), 61.3 (t), 32.0 (t), 30.2 (t), 25.9 (q), 18.3 (s), –5.3 (q); m/z (EI) 373.1493 ([M+ + Na], C16H26N4OSSiNa requires 373.1494).

A solution of m-chloroperbenzoic acid (0.59 g, 2.38 mmol) in dichloromethane (9 ml) was added dropwise over 2 min to a stirred solution of the sulfide (333 mg, 0.95 mmol) and sodium hydrogen carbonate (328 mg, 4.78 mmol) in dichloromethane (9 ml) at room temperature under an atmosphere of nitrogen. The mixture was stirred at room temperature for 72 h and then quenched by the addition of saturated sodium thiosulfate solution (20 ml). The separated aqueous layer was extracted with dichloromethane (3 Χ 40 ml), and the combined organic extracts were then washed with brine (40 ml), dried, and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 5% ethyl acetate in light petroleum to give the sulfone (302 mg, 88%) as a colorless oil. n max (CHCl3)/cm–1 2955, 1769, 1596; 1H NMR (360 MHz, CDCl3) d = 7.70–7.57 (5H, m, ArH), 3.85 (2H, m, CH2SO2Ar), 3.78 (2H, t, J = 5.7 Hz, CH2OTBS), 2.16 (2H, tt, J = 5.7 and 7.7 Hz, CH2CH2OTBS), 0.90 (9H, s, SiCMe3), 0.07 (6H, s, OSiMe2). 13C NMR (90.5 MHz, CDCl3) d = 153.5 (s), 133.1 (s), 131.5 (d), 129.8 (d), 125.1 (d), 60.4 (t), 53.4 (t), 25.9 (q), 25.6 (t), 18.3 (s), –5.4 (q); m/z (EI) 383.1577 (M+, C16H26N4O3Si requires 383.1573).

(E)-3-{2-[(E)-6-(tert-Butyldimethylsilyloxy)-hex-3-enyl]-4-methoxyphenyl}acrylic Acid Ethyl Ester 29. A solution of potassium bis(trimethylsilyl)amide in toluene (3.2 ml, 0.5 M, 1.6 mmol) was added dropwise over 5 min to a stirred solution of the sulfone 28 (529 mg, 1.38 mmol) and the aldehyde 16b (259 mg, 0.99 mmol) in THF (15 ml) at –78°C under an atmosphere of nitrogen and the mixture was stirred at –78°C for 3 h. The mixture was allowed to warm to room temperature over 1 h, then quenched with saturated aqueous ammonium chloride (5 ml) and diluted with diethyl ether (20 ml). The separated aqueous layer was extracted with ethyl acetate (3 Χ 30 ml) and the combined organic extracts were then dried and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 3% ethyl acetate in light petroleum to give the E-alkene (320 mg,77%) (containing » 15% of the Z isomer) as a colorless oil. n max (CHCl3)/cm–1 2930, 1699, 1631, 1603, 980; 1H NMR (360 MHz, CDCl3) d = 7.94 (1H, d, J = 15.7 Hz, ArCH=CH), 7.55 (1H, d, J = 8.5 Hz, ArH), 6.76 (1H, dd, J = 8.5 and 2.6 Hz, ArH), 6.72 (1H, d, J = 2.6 Hz, ArH), 6.27 (1H, d, J = 15.7 Hz, ArCH=CH), 5.57–5.39 (2H, m, Z CH=CH), 4.26 (2H, q, J = 7.1 Hz, OCH2CH3), 3.83 (3H, s, OMe), 3.58 (2H, t, J = 7.0 Hz, CH2OTBS), 2.79 (2H, t, J = 7.8 Hz, ArCH2CH2), 2.30–2.16 (4H, m, CH2CH=CHCH2), 1.34 (3H, t, J = 7.1 Hz, OCH2CH3), 0.89(9H, s, Me3CSi), 0.06 (6H, s, Me2Si); 13C NMR (90.5 MHz, CDCl3) d = 167.5 (s), 161.3 (s), 144.2 (s), 142.0 (d), 131.2 (d), 128.0 (d), 127.9(d), 125.5 (s), 117.1 (d), 115.0 (d), 112.5 (d), 63.9 (t), 60.2 (t), 55.2 (q), 36.5 (t), 34.9 (t), 34.1 (t), 26.1 (q), 18.5 (s), 14.8 (q), –5.1 (q); m/z (EI) 419.2620 (M+, C24H39O4Si requires 419.2618).

(E)-3-{2-[(E)-6-Chlorohex-3-enyl]-4-methoxyphenyl}acrylic Acid Ethyl Ester 30. A solution of tetra-n-butylammonium fluoride in THF (295 m l, 1 M, 295 m mol) was added dropwise over 1 min to a stirred solution of the silyl ether 29 (95 mg, 0.23 mmol) in THF (5 ml) at 0°C under an atmosphere of nitrogen and the solution was then allowed to warm gradually for to room temperature for 1 h. Water (20 ml) and diethyl ether (50 ml) were added and the separated aqueous layer was extracted with diethyl ether (3 Χ 40 ml). The combined organic extracts were washed with brine (50 ml), then dried and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 40% ethyl acetate in petroleum to give the corresponding alcohol (59 mg, 84%) as a colorless oil. n max (CHCl3)/cm–1 2930, 2904, 1699, 1631, 1603, 980; 1H NMR (360 MHz, CDCl3) d = 7.92 (1H, d, J = 15.8 Hz, ArCH=CH), 7.53 (1H, d, J = 8.7 Hz, ArH), 6.75 (1H, dd, J = 8.7 and 2.4 Hz, ArH), 6.69 (1H, d, J = 2.4 Hz, ArH), 6.26 (1H, d, J = 15.8 Hz, ArCH=CH), 5.60–5.35 (2H, m, Z CH=CH), 4.24 (2H, q, J = 7.1 Hz, OCH2CH3), 3.81 (3H, s, OMe), 3.59 (2H, t, J = 6.4 Hz, ArCH2CH2), 2.79 (2H, t, J = 7.5 Hz, CH2OH), 2.33–2.18 (4H, m, CH2CH=CHCH2), 1.32 (3H, t, J = 7.1 Hz, OCH2CH3); 13C NMR (90.5 MHz, CDCl3) d = 171.2 (s), 161.0 (s), 143.6 (s), 141.7 (d), 132.1 (d), 128.0 (d), 127.4(d), 125.5 (s), 116.8 (d), 115.2 (d), 112.4 (d), 61.9 (t), 60.4 (t), 55.3 (q), 35.9 (t), 34.4 (t), 33.4 (t), 14.2 (q); m/z (EI) 304.1676 (M+, C18H24O4 requires 304.1675).

N-Chlorosuccinimide (36 mg, 0.27 mmol) was added in one portion to a stirred solution of the alcohol (59 mg, 0.19 mmol), triphenylphosphine (66 mg, 0.25 mmol) and anhydrous potassium carbonate (5.4 mg, 38.7 m mol) in dichloromethane (5 ml) at 0°C under an atmosphere of nitrogen. The mixture was stirred at 0°C for 30 min and then concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 10% diethyl ether in light petroleum to give the chloride (58 mg, 95%) as a colorless oil. n max (CHCl3)/cm–1 2941, 1703, 1631, 1603, 980; 1H NMR (360 MHz, CDCl3) d = 7.92 (1H, d, J = 15.7 Hz, ArCH=CH), 7.54 (1H, d, J = 8.7 Hz, ArH), 6.77 (1H, dd, J = 8.7 and 2.5 Hz, ArH), 6.72 (1H, d, J = 2.5 Hz, ArH), 6.28 (1H, d, J = 15.7 Hz, ArCH=CH), 5.63–5.37 (2H, 2 Χ m, Z CH=CH), 4.25 (2H, q, J = 7.2 Hz, OCH2CH3), 3.82 (3H, s, OMe), 3.49 (2H, t, J = 7.0 Hz, CH2Cl), 2.81 (2H, t, J = 7.5 Hz, ArCH2CH2), 2.44 (2H, app. q, J = 6.8 Hz, CH2CH2Cl), 2.30 (2H, app. q, J = 7.3 Hz, ArCH2CH2), 1.34 (3H, t, J = 7.2 Hz, OCH2CH3); 13C NMR (90.5 MHz, CDCl3) d = 167.4 (s), 161.1 (s), 143.5 (s), 141.6 (d), 132.3 (d), 128.1 (d), 126.9 (d), 125.6 (s), 116.9 (d), 115.2 (d), 112.3 (d), 60.4 (t), 55.3 (q), 44.3 (t), 35.8 (t), 34.3 (t), 33.3 (t), 14.4 (q); m/z (EI) 322.1337 (M+, C18H23O3Cl requires 322.1336).

(E)-3-{2-[(E)-6-Chlorohex-3-enyl]-4-methoxyphenyl}propenal 31. A solution of iBu2AlH in toluene (0.7 ml, 1.5 M, 1.1 mmol) was added dropwise over 10 min to a stirred solution of the ester 30 (150 mg, 0.46 mmol) in THF (3.5 ml) at –78°C under an atmosphere of nitrogen. The solution was stirred at –78°C for 30 min and diluted with diethyl ether (20 ml) and saturated aqueous solution of Rochelle salt (6 ml). The mixture was stirred at room temperature for a further 12 h, and the separated aqueous layer was extracted with dichloromethane (2 Χ 50 ml). The combined organic extracts were dried and concentrated in vacuo to leave the corresponding alcohol (140 mg, » 80%), which was used in the next step without further purification.

Activated manganese dioxide (1.00 g, 12.7 mmol) was added in one portion to a stirred solution of the alcohol (127 mg, 0.450 mmol) in dichloromethane (5 ml) at 0°C under an atmosphere of nitrogen and the mixture was stirred at 0°C for 3 h. The mixture was filtered through a pad of Celite, which was washed with dichloromethane (20 ml). The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica, eluting with 20% diethyl ether in light petroleum to give the aldehyde (108 mg, 86%) as a colorless oil, which partially solidified on standing. n max (CHCl3)/cm–1 2942, 1732, 1673, 970, 908; 1H NMR (360 MHz, CDCl3) d = 9.68 (1H, d, J = 7.7 Hz, CHO), 7.70 (1H, d, J = 15.7 Hz, ArCH=CH), 7.59 (1H, d, J = 8.6 Hz, ArH), 6.82 (1H, dd, J = 8.6 and 2.6 Hz, ArH), 6.76 (1H, d, J = 2.6 Hz, ArH), 6.60 (1H, dd, J = 15.7 and 7.7 Hz, ArCH=CH), 5.63–5.41 (2H, 2 Χ m, Z CH=CH), 3.84 (3H, s, OMe), 3.50 (2H, t, J = 6.8 Hz, CH2Cl), 2.84 (2H, t, J = 7.5 Hz, ArCH2CH2), 2.48–2.42 (2H, m, CH2CH2Cl), 2.35–2.28 (2H, m, ArCH2CH2); 13C NMR (90.5 MHz, CDCl3) d = 193.8 (s), 161.9 (s), 149.7 (d), 144.0 (s), 132.0 (d), 128.8 (d), 127.5 (d), 127.1 (d), 124.9 (s), 115.5 (d), 112.6 (d), 55.4 (q), 44.3 (t), 35.7 (t), 34.3 (t), 33.2 (t); m/z (EI) 278.1070 (M+, C16H19O2Cl requires 278.1074).

(E)-3-{2-[(E)-6-Chlorhex-3-enyl]-4-methoxyphenyl}pent-1-en-4-yn-3-ol 32. A solution of ethynylmagnesium bromide in THF (1 ml, 0.5 M, 0.5 mmol) was added dropwise over 5 min to a stirred solution of the aldehyde 31 (95 mg, 0.34 mmol) in THF (1.6 ml) at 0°C under an atmosphere of nitrogen and the solution was then allowed to warm to room temperature over 16 h. Saturated aqueous ammonium chloride (5 ml) and diethyl ether (50 ml) were added and the separated aqueous layer was extracted with diethyl ether (3 Χ 40 ml). The combined organic extracts were washed with brine (20 ml), then dried and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 30% ethyl acetate in light petroleum to give the alcohol (67 mg, 62%) as an orange oil. n max (CHCl3)/cm–1 3594, 3306, 2942, 2839, 1731, 1607, 976, 908; 1H NMR (360 MHz, CDCl3) d = 7.42 (1H, d, J = 8.6 Hz, ArH), 7.00 (1H, d, J = 15.6 Hz, ArCH=CH), 6.74 (1H, dd, J = 8.6 and 2.6 Hz, ArH), 6.68 (1H, d, J = 2.6 Hz, ArH), 6.11 (1H, dd, J = 15.6 and 6.0 Hz, ArCH=CH), 5.63–5.40 (2H, 2 Χ m, Z CH=CH), 5.07 (1H, dd, J = 6.0 and 2.2 Hz, CHOH), 3.81 (3H, s, OMe), 3.50 (2H, t, J = 7.0 Hz, CH2Cl), 2.73 (2H, t, J = 7.5 Hz, ArCH2CH2), 2.65 (1H, d, J = 2.2 Hz, C≡CH), 2.48–2.42 (2H, m, CH2CH2Cl), 2.32–2.25 (2H, m, ArCH2CH2), 2.24 (1H, br s, OH); 13C NMR (90.5 MHz, CDCl3) d = 159.5 (s), 141.3 (s), 132.6 (d), 129.6 (d), 127.5 (d), 127.2 (s), 127.0 (d), 126.6 (d), 115.0 (d), 111.9 (d), 83.1 (s), 74.6 (d), 63.1 (d), 55.3 (q), 44.4 (t), 35.8 (t), 33.9 (t), 33.4 (t); m/z (EI) 318.1389 (M+, C19H23O2Cl requires 318.1387).

(E)-3-{2-[(E)-6-Iodohex-3-enyl]-4-methoxyphenyl}pent-1-en-4-yn-3-one 33. Activated manganese dioxide (629 mg, 7.23 mmol) was added in one portion to a stirred solution of the alcohol 32 (63 mg, 0.21 mmol) in dichloromethane (3 ml) at room temperature under an atmosphere of nitrogen and the mixture was stirred at room temperature for 3 h. The mixture was filtered through a pad of Celite, which was washed with dichloromethane (100 ml). The filtrate was then removed in vacuo and the residue was purified by column chromatography on silica, eluting with 20% diethyl ether in light petroleum to give the corresponding ketone (53 mg, 79%) as a colorless oil. n max (CHCl3)/cm–1 3297, 2929, 2854, 2101, 1631, 1598, 974; 1H NMR (360 MHz, CDCl3) d = 8.19 (1H, d, J = 15.8 Hz, ArCH=CH), 7.60 (1H, d, J = 8.7 Hz, ArH), 6.80 (1H, dd, J = 8.7 and 2.6 Hz, ArH), 6.75 (1H, d, J = 2.6 Hz, ArH), 6.68 (1H, d, J = 15.8 Hz, ArCH=CH), 5.63–5.42 (2H, 2 Χ m, Z CH=CH), 3.84 (3H, s, OMe), 3.50 (2H, t, J = 6.8 Hz, CH2Cl), 3.33 (1H, s, C≡CH), 2.85 (2H, t, J = 7.6 Hz, ArCH2CH2), 2.48–2.42 (2H, m, CH2CH2Cl), 2.37–2.29 (2H, m, ArCH2CH2); 13C NMR (90.5 MHz, CDCl3) d = 177.1 (s), 162.2 (s), 146.8 (d), 144.7 (s), 132.0 (d), 128.7 (d), 127.2 (d), 126.5 (d), 124.8 (s), 115.6 (d), 112.7 (d), 80.2 (s), 78.9 (d), 55.4 (q), 35.7 (t), 34.6 (t), 33.6 (t); m/z (EI) 302.1079 (M+, C18H19O2Cl requires 302.1074).

Sodium iodide (148 mg, 0.99 mmol) was added in one portion to a stirred solution of the chloroketone (60 mg, 0.2 mmol) in 2-butanone (3.5 ml) at room temperature under an atmosphere of nitrogen. The solution was heated under reflux for 18 h and then allowed to cool to room temperature. The solvent was concentrated in vacuo and the residue was purified by flash chromatography on silica; eluting with 20% ethyl acetate in light petroleum gave the iodide (64 mg, 82%) as a yellow solid; mp 107–109°C (Et2O); (found: C, 54.6; H, 4.8. C18H19O2I requires C, 54.7, H 4.8%); n max (CHCl3)/cm–1 3297, 2942, 2840, 2102, 1631, 1598, 974. 1H NMR (360 MHz, CDCl3) d = 8.19 (1H, d, J = 15.8 Hz, ArCH=CH), 7.61 (1H, d, J = 8.7 Hz, ArH), 6.80 (1H, dd, J = 8.7 and 2.6 Hz, ArH), 6.76 (1H, d, J = 2.6 Hz, ArH), 6.68 (1H, d, J = 15.8 Hz, ArCH=CH), 5.61–5.36 (2H, 2 Χ m, Z CH=CH), 3.85 (3H, s, OMe), 3.29 (1H, s, C≡CH), 3.12 (2H, t, J = 7.0 Hz, CH2I), 2.86 (2H, t, J = 7.5 Hz, ArCH2CH2), 2.57–2.50 (2H, m, CH2CH2I), 2.37–2.27 (2H, m, ArCH2CH2) (irradiation of the multiplet centered at d 2.31 ppm resulted in collapse of the multiplet centered at d = 5.55 ppm to a doublet, Jtrans = 15.3 Hz); 13C NMR (90.5 MHz, CDCl3) d = 177.7 (s), 162.1 (s), 146.9 (d), 144.7 (s), 131.6 (d), 129.9 (d), 128.8 (d), 126.5 (d), 124.8 (s), 115.7 (d), 112.7 (d), 80.2 (s), 79.0 (d), 55.4 (q), 36.5 (t), 34.6 (t), 33.6 (t), 6.0 (t); m/z (EI) 395.0512 (M+, C18H19O2I requires 395.0508).

3-Methoxy-6,7,8,9,11,14,15,16-octahydrocyclopenta[a]phenanthren-12-one 35. A solution of Bu3SnH (45 m l, 0.17 mmol) and AIBN (13.8 mg, 0.09 mmol) in dry degassed benzene (7 ml) was added over 10 h by syringe pump to a refluxing solution of the iodide 33 (55 mg, 0.14 mmol) and AIBN (4.6 mg, 0.02 mmol) in dry degassed benzene (63 ml) under an atmosphere of argon. The mixture was heated under reflux for a further 6 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with diethyl ether (25 ml) and stirred at room temperature over 12 h with 5% aqueous potassium fluoride (25 ml). The separated aqueous layer was extracted with diethyl ether (3 Χ 10 ml) and the combined organic extracts were dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 5–15% ethyl acetate in light petroleum to give the cis, anti 12-ketosteroid (5 mg, 13%) as a colorless crystalline solid; mp 98–99°C (3:1 vol/vol CH3CN/hexane). n max (CHCl3)/cm–1 2927, 2855, 1682, 1614, 1041, 985; 1H NMR (360 MHz, CDCl3) d = 7.11 (1H, d, J = 8.6 Hz, H-1), 6.72 (1H, dd, J = 8.6 and 2.7 Hz, H-2), 6.66 (2H, d, J = 2.7 Hz, H-4 and H-17), 3.78 (3H, s, OMe), 3.28–3.23 (1H, m, H-14), 2.94 (1H, dd, J = 16.6 and 7.4 Hz, H-11a ), 2.90–2.73 (3H, m, H-6 and H-9), 2.63 (1H, dd, J = 16.6 and 4.8 Hz, H-11b ), 2.53–2.47 (1H, m), 2.44–2.30 (2H, m), 2.06–1.98 (2H, m), 1.89–1.80 (1H, m), 1.60 (1H, m); 13C NMR (120.5 MHz, CDCl3) d = 199.1 (s), 157.9 (s), 143.6 (s), 138.8 (d), 138.3 (s), 130.1 (s), 128.6 (d), 113.9 (d), 112.0 (d), 55.3 (q), 45.9 (d), 45.1 (t), 41.1 (d), 37.3 (d), 32.7 (t), 32.1 (t), 27.6 (t), 25.9 (t); m/z (EI) 268.1465 (M+, C18H20O2 requires 268.1463).

3-Methoxy-7,8,9,11,14,15,16,17-octahydro-6H-20-oxa-cyclopropa[13,17]cyclopenta [a]phenanthren-12-one 36. Hydrogen peroxide (634 m l, 560 m mol) was added dropwise over 5 min to a stirred solution of the 12-ketoestrane 24 (15 mg, 55.9 m mol) in THF (1.5 ml) and t-BuOH (1.5 ml) at 0°C. Aqueous NaOH (112 m l, 5 M, 560 m mol) was added dropwise over 5 min and the stirred mixture was then allowed to warm to room temperature over 18 h. Ethyl acetate (40 ml) and 5% aqueous sodium sulfite (10 ml) were added and the separated aqueous layer was then extracted with ethyl acetate (3 Χ 10 ml). The combined organic extracts were dried and concentrated in vacuo and the residue was purified by column chromatography on silica, eluting with 20% ethyl acetate in light petroleum to give one diastereoisomer of the epoxyketone (6.4 mg, 40%) as a yellow oil. n max (CHCl3)/cm–1 2934, 2863, 1714, 1609, 1504, 1436; 1H NMR (360 MHz, CDCl3) d = 7.10 (1H, d, J = 8.6 Hz, H-1), 6.77 (1H, dd, J = 8.6 and 2.7 Hz, H-2), 6.66 (1H, d, J = 2.7 Hz, H-4), 3.80 (3H, s, OMe), 3.74 (1H, d, J = 1.9 Hz, H-17), 3.23 (1H, dd, J = 18.7 and 4.2 Hz, H-11a ), 3.19–3.10 (1H, m, H-14), 2.91–2.84 (2H, m, H2-6), 2.83–2.73 (1H, m), 2.35 (1H, dd, J = 12.2 and 18.7 Hz, H-11b ), 2.26–2.09 (2H, m), 2.01–1.85 (3H, m), 1.66–1.49 (2H, m); 13C NMR (120.5 MHz, CDCl3) d = 205.9 (s), 157.8 (s), 137.9 (s), 129.3 (s), 128.4 (d), 113.7 (d), 112.6(d), 71.8 (s), 71.1 (d), 55.2 (q), 47.4 (t), 41.7 (d), 40.9 (d), 33.8 (d), 30.4 (t), 28.9 (t), 28.3 (t), 25.9 (t); m/z (EI) 284.1408 (M+, C18H20O3 requires 284.1412).

3-Methoxy-7,8,9,11,14,15,16,17-octahydro-6H-cyclopenta[a]phenanthren-17-ol 37. A solution of hydrazine monohydrate (2.11 m l, 67.6 m mol) in MeOH (0.4 ml) was added dropwise over 5 min to a stirred solution of the epoxide 36 (6.4 mg, 22.6 m mol) in methanol (1.6 ml) at room temperature under an atmosphere of nitrogen. A solution of acetic acid (one drop) in MeOH (0.16 ml) was added and the mixture was stirred at room temperature for 5 h. Ethyl acetate (5 ml) and water (5 ml) were added and the separated aqueous layer was extracted with ethyl acetate (3 Χ 5 ml). The combined organic extracts were washed with brine (3 ml), then dried and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 50% ethyl acetate in light petroleum to give one diastereoisomer of the allylic alcohol (1.8 mg, 30%) as a yellow oil. n max (CHCl3)/cm–1 3690, 3606, 2930, 1603, 1502, 1435; 1H NMR (360 MHz, CDCl3) d = 7.23 (1H, d, J = 8.6 Hz, H-1), 6.77 (1H, dd, J = 8.5 and 2.8 Hz, H-2), 6.66 (1H, d, J = 2.8 Hz, H-4), 5.89 (1H, d, J = 7.2 Hz, H-12), 4.48 (1H, dd, J = 6.8 and 2.0 Hz, H-17), 3.79 (3H, s, OMe), 2.94 (1H, app. dt, J = 12.3 and 5.0 Hz, H-9a ), 2.84-2.77 (2H, m, H2-6), 2.75–2.71 (1H, m), 2.39–2.35 (1H, m), 2.20–2.13 (1H, m), 1.97–1.88 (3H, m), 1.86–1.79 (1H, m), 1.67–1.55 (11H, m), 1.28–1.15 (2H, m); 13C NMR (120.5 MHz, CDCl3) d = 147.7 (s), 138.5 (s), 128.0 (d), 121.3 (d), 113.7 (d), 112.0 (d), 73.5(d), 55.3 (q), 40.6 (d), 38.7 (d), 34.9 (d), 30.0 (t), 31.8 (t), 31.0 (t), 27.1 (t), 24.7 (t); m/z (EI) 270.1609 (M+, C18H22O2 requires 270.1619).

3-Methoxy-6,7,8,9,11,14,15,16-octahydrocyclopenta[a]phenanthren-17-one 38. Tetrapropylammonium perruthenate (15 mg, 43.0 m mol) was added to a stirred mixture of the alcohol 37 (11.6 mg, 43 m mol), N-methylmorpholine N-oxide (7.6 g, 64.6 m mol), and 4-Å molecular sieves (21.6 mg, 500 mg/mmol) in dichloromethane at room temperature under an atmosphere of nitrogen. The mixture was stirred at room temperature for 17 h and then concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 20% ethyl acetate in light petroleum to give the enone (6.2 mg, 54%) as colorless crystals; mp 156–158°C (from Et2O). n max (CHCl3)/cm–1 3057, 2934, 2851, 1660, 1607; 1H NMR (360 MHz, CDCl3) d = 7.25 (1H, d, J = 8.6 Hz, H-1), 6.81 (1H, app. dt, J = 7.7 and 2.8 Hz, H-12), 6.76 (1H, dd, J = 2.4 and 8.6 Hz, H-2), 6.65 (1H, d, J = 2.4 Hz, H-4), 3.79 (3H, s, OMe), 3.06–2.84 (4H, m), 2.44–2.29 (3H, m), 2.14–1.96 (4H, m), 1.74–1.61 (2H, m); 13C NMR (120.5 MHz, CDCl3) d = 200.9 (s), 148.0 (s), 138.5 (s), 137.4 (d), 121.3 (d), 115.8 (d), 114.4(d), 55.4 (q), 41.6 (d), 38.7 (d), 34.6 (d), 33.8 (t), 32.1 (t), 30.0 (t), 27.4 (t), 24.7 (t); m/z (EI) 268.1468 (M+, C18H20O2 requires 268.1463).

14-Epiestrone-3-methyl Ether 39. A solution of methyllithium in diethyl ether (1.4 m l, 1.6 M, 2.24 m mol) was added dropwise over 1 min to a stirred suspension of copper iodide (0.49 mg, 2.57 m mol) in THF (2 ml) at –10°C under an atmosphere of argon. Hexamethylphosphoric triamide (18.2 m l, 104 m mol) was added dropwise over 5 min and the mixture was then stirred at –10°C for 10 min. The mixture was cooled to –50°C and a solution of iBu2AlH in hexane (52 m l, 1 M, 52 m mol) was added dropwise over 15 min. The mixture was stirred at –50°C for a further 30 min, and then a solution of the enone 38 (14 mg, 52.2 m mol) in THF (1 ml) was added dropwise over 5 min. The mixture was stirred at –50°C for 1 h and a solution of methyllithium in diethyl ether (52 m l, 1.6 M, 83.2 m mol) was added dropwise over 5 min followed, after 15 min, by methyl iodide (137 m l, 217 m mol) over 5 min. The mixture was allowed to warm to room temperature over 3 h, then HCl (2 M, 4 ml) and diethyl ether (6 ml) were added. The separated organic layer was dried and concentrated in vacuo and the residue was purified by column chromatography on silica, eluting with 5% diethyl ether in light petroleum to give the steroid (9.8 mg, 66%) as a yellow oil, which crystallized from methanol and recrystallized from 1:1 vol/vol methanol/hexane mixture as colorless crystals; mp 112–114°C (from MeOH, refs. 3 and 4, 114–115°C). n max (CHCl3)/cm–1 1732, 1610, 1575; 1H NMR (360 MHz, CDCl3) d = 7.19 (1H, d, J = 8.6 Hz, H-1), 6.91 (1H, dd, J = 8.6 and 2.3 Hz, H-2), 6.80 (1H, d, J = 2.3 Hz, H-4), 3.54 (3H, s, OMe), 2.90–2.72 (2H, m, H2-6), 2.36–2.29 (2H, m, H-9a and H-16b ), 2.08–2.03 (1H, app. dq, J = 7 and 2 Hz, H-11b ), 1.97–1.86 (1H, m, H-16a ), 1.66–1.52 (2H, m, H-14b and H-8b ), 1.49–1.37 (4H, m, H2-7 and H2-15), 1.35–1.26 (2H, m, H2-12), 1.22–1.13 (1H, m, H-11a ), 1.18(3H, s, -CH3); 13C NMR (120.5 MHz, C6D6) d = 219.9 (C-17), 158.5 (C-3), 138.1 (C-5), 128.5 (C-10), 127.3 (C-1), 114.4 (C-4), 112.4(C-2), 55.0 (OMe), 48.9 (C-14), 47.8 (C-13), 37.7 (C-8), 36.5 (C-9), 36.1 (C-16), 31.0 (C-6), 29.0 (C-12), 28.0 (C-7), 26.9 (C-11), 19.4 (C-15), 19.4 (C-18); m/z (EI) 284.1773 (M+, C19H24O2 requires 284.1778).

14-Epiestrone 40. A solution of boron tribromide in dichloromethane (98.0 m l, 1 M, 98 m mol) was added dropwise over 5 min to a stirred solution of the methyl ether 39 (8 mg, 28.1 m mol) in dichloromethane at –78°C under an atmosphere of nitrogen. The mixture was allowed to warm gradually to room temperature overnight and then cooled to 0°C. Water (4 ml) was added and the mixture was stirred for a further 30 min and then brine (2 ml) was added. The separated aqueous layer was extracted with dichloromethane (3 Χ 2 ml), and the combined organic extracts were then dried and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 30% diethyl ether in hexane to give 14-epiestrone (6 mg, 79%) as colorless crystals; mp 214–215°C (1:1 vol/vol methanol/hexane mp 215.8–216.8°C reported in refs. 5 and 6); (found: C, 80.2; H, 8.2%; calculated for C18H22O2 requires C, 80.2, H 8.5%); n max (CHCl3)/cm–1 3597, 2935, 2861, 1732, 1612, 1585; 1H NMR (360 MHz, CDCl3) d = 7.09 (1H, d, J = 8.4 Hz, H-1), 6.66 (1H, dd, J = 8.4 and 2.7 Hz, H-2), 6.49 (1H, d, J = 2.7 Hz, H-4), 4.38 (1H, br s, -OH), 2.81–2.68 (2H, m, H2-6), 2.36-2.24 (2H, m, H-9a and H-16b ), 2.01–1.86 (2H, m, H-11b and H-16a ), 1.61–1.49 (2H, m, H-14b and H-8b ), 1.43–1.35 (4H, m, H2-7 and H2-15), 1.33–1.15 (4H, m, H2-12 and H-11a ), 1.18(3H, s, H3-18); 13C NMR (90.5 MHz, C6D6) d = 220.4 (C-17), 154.5 (C-3), 138.2 (C-5), 132.0 (C-10), 127.3 (C-1), 115.7 (C-4), 113.4(C-2), 48.7 (C-14), 47.7 (C-13), 37.6 (C-8), 36.4 (C-9), 36.0 (C-16), 30.7 (C-6), 29.0 (C-12), 27.8 (C-7), 26.7 (C-11), 19.3 (C-15), 19.3 (C-18); m/z (EI) 270.1621 (M+, C18H22O2 requires 270.1619).

(E)-3-{2-[(Z)-6-(tert-Butyldimethylsilyloxy)-hex-3-enyl]phenyl}prop-2-en-1-ol 46a. A solution of iBu2AlH in toluene (14.3 ml, 1.5 M, 21.5 mmol) was added dropwise over 10 min to a stirred solution of the ester 17a (3 g, 7.7 mmol) in dichloromethane (100 ml) at –78°C under an atmosphere of nitrogen. The solution was stirred at –78°C for 2 h, then methanol (3 ml) was added and the solution was allowed to warm to room temperature. The solution was poured into a saturated aqueous solution of Rochelle salt (100 ml) and stirred for a further 8 h. The separated aqueous layer was extracted with dichloromethane (3 Χ 30 ml). The combined organic extracts were washed with brine (30 ml), then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 40% diethyl ether in light petroleum to give the allylic alcohol (2.4 g, 90%) as a colorless oil; found: C, 72.7, H, 9.9%, C21H34O2Si requires: C, 72.8, H, 9.9%. n max (CHCl3)/cm–1 3380, 1652, 835; 1H NMR (360 MHz, CDCl3) d = 7.47–7.44 (1H, m, ArH), 7.22–7.14 (3H, m, 3 Χ ArH), 6.92 (1H, dt, J = 15.6 and 1.6 Hz, ArCH=CH), 6.26 (1H, dt, J = 15.6 and 5.7 Hz, ArCH=CH), 5.53–5.37 (2H, m, Z CH=CH), 4.35 (2H, td, J = 5.7 and 1.5 Hz, CH2OH), 3.58 (2H, t, J = 7.1 Hz, CH2OTBS), 2.72 (2H, t, J = 7.7 Hz, ArCH2CH2), 2.34–2.24 (4H, m, CH2CH=CHCH2), 2.07 (1H, s, OH), 0.91 (9H, s, SiCMe3), 0.07 (6H, s, SiMe2); 13C NMR (90.5 MHz, CDCl3) d = 139.4 (s), 135.6 (s), 130.5 (d), 129.6 (d), 128.4 (d), 127.5 (d), 126.4 (d), 126.2 (d), 63.7 (t), 63.0 (t), 33.6 (t), 31.0 (t), 28.9 (t), 25.9 (q), 18.4 (s), –5.3 (q); m/z (EI) 346.2326 (M+, C21H34SiO2 requires 346.2328).

1-{2-[(Z)-6-(tert-Butyldimethylsilyloxy)hex-3-enyl]phenyl}-trans-cyclopropyl Carbaldehyde 47a. Diethylzinc (0.8 ml, 7.3 mmol) was added dropwise over 10 min to a stirred solution of the E-allylic alcohol 46a (2.3 g, 6.6 mmol) in toluene (60 ml) at room temperature under an atmosphere of nitrogen. Diiodomethane (1.6 ml, 13.8 mmol) was added dropwise over 5 min and the mixture was then stirred at room temperature for 2 h. Saturated aqueous ammonium chloride (30 ml) and diethyl ether (20 ml) were added and the separated organic layer was then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 30% diethyl ether in light petroleum to give the corresponding trans-cyclopropylmethanol (2.8 g, 82%) as a colorless oil; (found: C, 73.8; H, 10.0%; C22H36SiO2 requires C, 73.3; H, 10.1%); n max (film)/cm–1 3364, 3062; d H (360 MHz) 0.11 (6H, s, SiMe2), 0.89–0.99 (11H, m, SiCMe3 + CH2CHCHO), 1.42–1.48 (1H, m, CHCHO), 1.69 (1H, t, J 5.6 Hz, OH), 1.92 (1H, dt, J 8.6 and 5.2 Hz, ARCH), 2.26 (2H, app. q, J 7.2 Hz, ArCH2CH2), 2.40 (2H, app. q, J = 7.2 Hz, CH2CH2OH), 2.84 (2H, J = 7.2 Hz, ArCH2), 3.55 (2H, t, J = 7.5 Hz, CH2OTBS), 3.65–3.73 (2H, m, CH2OH), 5.4–5.6 (2H, m, Z CH=CH), 6.95 (1H, m, Ar-H), 7.11–7.17 (3H, m, 3 Χ ArH); 13cnmr (90.6 MHz) –5.3 (q), 12.3 (t), 18.3 (s), 18.5 (d), 23.7 (d), 25.9 (q), 28.4 (t), 30.9 (t), 32.9 (t), 62.9 (t), 66.2 (t), 125.3 (d), 125.7 (d), 125.9 (d), 126.2 (d), 128.9 (d), 130.8 (d), 139.4 (s), 140.9 (s); m/z (CI) 383.2394 ([C22H36SiO2 + Na]+ requires 383.2382).

Pyridinium dichromate (3.8 g, 9.8 mmol) was added in one portion to a stirred solution of the cyclopropylmethanol (2.8 g, » 5.9 mmol) in dichloromethane (20 ml) at room temperature under an atmosphere of nitrogen and the mixture was stirred at room temperature for 16 h. The mixture was filtered through a pad of Celite, which was washed with dichloromethane (100 ml). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica, eluting with 20% diethyl ether in light petroleum to give the aldehyde (1.5 g, 63% over two steps) as a colorless oil. n max (CHCl3)/cm–1 3007, 1709, 1610, 835; 1H NMR (360 MHz, CDCl3) d = 9.38 (1H, d, J = 4.7 Hz, CHO), 7.19–7.15 (3H, m, 3 Χ ArH), 6.99 (1H, d, J = 7.4 Hz, ArH), 5.54–5.39 (2H, m, Z CH=CH), 3.54 (2H, t, J = 7.3 Hz, CH2OTBS), 2.78 (2H, t, J = 7.4 Hz, ArCH2CH2), 2.73–2.68 (1H, m, ArCHCH2CH), 2.38 (2H, app. q, J = 7.4 Hz, CH2CH2OTBS), 2.21 (2H, app. q, J = 7.4 Hz, ArCH2CH2), 2.05–2.01 (1H, m, ArCHCH2CH), 1.72–1.67 (1H, m, ArCHCH2CH), 1.53–1.48 (1H, m, ArCHCH2CH), 0.89 (9H, s, SiCMe3), 0.05 (6H, s, SiMe2); 13C NMR (90.5 MHz, CDCl3) d = 199.9 (d), 141.1 (s), 136.2 (s), 130.2 (d), 129.0 (d), 127.0 (d), 126.8 (d), 126.2 (d), 125.7 (d), 62.8 (t), 32.8 (t), 32.6 (d), 31.0 (t), 28.2 (t), 25.9 (q), 24.2 (d), 18.3 (s), 15.5 (t), –5.3 (q); m/z (CI) 358.2332 (M+, C22H34O2Si requires 358.2328).

1-{2-[(Z)-6-(tert-Butyldimethylsilyloxy)hex-3-enyl]phenyl}-trans-cyclopropyl Ethanone 48a. A solution of methylmagnesium bromide in THF (2.4 ml, 3.0 M, 7.2 mmol) was added dropwise over 5 min to a stirred solution of the aldehyde 47a (2.1 g, 5.8 mmol) in THF (60 ml) at 0°C under an atmosphere of nitrogen and the solution was then allowed to warm to room temperature over 1 h. Diethyl ether (50 ml) and saturated aqueous ammonium chloride (50 ml) were added and the separated aqueous layer was extracted with diethyl ether (3 Χ 25 ml). The combined organic extracts were washed with brine (30 ml), then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 20% diethyl ether in light petroleum to give the intermediate tertiary alcohol as a yellow oil.

Pyridinium dichromate (3.8 g, 9.8 mmol) was added in one portion to a stirred solution of the alcohol (2.8 g, » 5.9 mmol) in dichloromethane (30 ml) at room temperature under an atmosphere of nitrogen and the mixture was stirred at room temperature for 16 h. The mixture was filtered through a pad of Celite, which was washed with dichloromethane (100 ml). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica, eluting with 20% diethyl ether in light petroleum to give the methyl ketone (1.3 g, 60%) as a colorless oil; (found: C, 74.2; H, 9.8%; C23H36O2Si requires: C, 74.1; H, 9.7%). n max (CHCl3)/cm–1 3007, 1693, 1609; 1H NMR (360 MHz, CDCl3) d = 7.17–7.12 (3H, m, 3 Χ ArH), 7.01–6.96 (1H, m, ArH), 5.58–5.39 (2H, 2 Χ m, Z CH=CH), 3.55 (2H, t, J = 7.5 Hz, CH2OTBS), 2.85 (2H, t, J = 7.1 Hz, ArCH2CH2 ), 2.34–2.38 (2H, m), 2.24 (2H, app. q, J = 7.1 Hz, ArCH2CH2), 2.11 (1H, dt, J = 8.4 and 3.1 Hz, ArCHCH2CH), 1.76 (3H, s, CH3), 1.64–1.59 (1H, m, ArCHCH2CH), 1.21–1.12 (2H, m, ArCHCH2CH), 0.91 (9H, s, SiCMe3), 0.06 (6H, s, SiMe2); 13C NMR (90.5 MHz, CDCl3) d = 145.2 (s), 140.9 (s), 139.8 (s), 131.9 (d), 128.9 (d), 126.0 (d), 125.8 (d), 125.7 (d), 125.2 (d), 108.6 (t), 61.9 (t), 32.9 (t), 30.7 (t), 28.6 (d), 28.4 (t), 25.9 (q), 21.0 (d), 20.3 (q), 13.5 (t), 18.3 (s), –5.3 (q); m/z (EI) 372.2489 (M+, C23H36O2Si requires 372.2485).

1-((Z)-6-Iodohex-3-enyl)-2-(2-isopropenyl-trans-cyclopropyl)benzene 49a. A solution of n-butyllithium in hexane (1.7 ml, 1.6 M, 2.7 mmol) was added dropwise over 10 min to a stirred suspension of methyltriphenylphosphonium bromide (1.6 g, 4.5 mmol) in THF (30 ml) at 0°C under an atmosphere of nitrogen. The orange solution was stirred at 0°C for 20 min, then allowed to warm to room temperature over 30 min and again recooled to 0°C. A solution of the ketone 48a (1.1 g, 3 mmol) in THF (2 ml) was added dropwise over 5 min and the resulting yellow solution was then allowed to warm to room temperature over 12 h. Diethyl ether (30 ml) and water (30 ml) were added and the separated aqueous layer was then extracted with diethyl ether (3 Χ 20 ml). The combined organic extracts were washed with brine (20 ml), then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 5% diethyl ether in light petroleum to give the vinylcyclopropane (900 mg, 81%) as a yellow oil. n max (CHCl3)/cm–1 3063, 1635, 938; 1H NMR (360 MHz, CDCl3) d = 7.17–7.12 (3H, m, 3 Χ ArH), 7.01–6.96 (1H, m, ArH), 5.58–5.39 (2H, 2 Χ m, Z CH=CH), 4.79 (2H, m, C=CH2), 3.55 (2H, t, J = 7.5 Hz, CH2OTBS), 2.85 (2H, t, J = 7.1 Hz, ArCH2CH2), 2.38 (2H, app. q, J = 7.5 Hz, CH2CH2OTBS), 2.24 (2H, app. q, J = 7.1 and 1.3 Hz, ArCH2CH2), 2.11 (1H, dt, J = 8.5 and 3.1 Hz, ArCHCH2CH), 1.76 (3H, s, CH3), 1.65–1.59 (1H, m, ArCHCH2CH), 1.21–1.12 (2H, m, ArCHCH2CH), 0.91 (9H, s, SiCMe3), 0.06 (6H, s, SiMe2); 13C NMR (90.5 MHz, CDCl3) d = 145.2 (s), 140.9 (s), 139.8 (s), 131.9 (d), 128.9 (d), 126.0 (d), 126.0 (d), 125.8 (d), 125.7 (d), 125.2 (d), 108.6 (t), 61.8 (t), 32.9 (t), 30.6 (t), 28.6 (d), 28.4 (t), 25.8 (q), 21.0 (d), 20.3 (q), 18.3 (s), 13.5 (t), –5.3 (q); m/z (EI) 370.2693 (M+, C24H38OSi requires 370.2692).

A solution of tetra-n-butylammonium fluoride in THF (1.4 ml, 1.0 M, 1.4 mmol) was added dropwise over 5 min to a stirred solution of the above silyl ether (777 mg, 2.1 mmol) in THF (20 ml) at 0°C under an atmosphere of nitrogen and the solution was allowed to warm gradually to room temperature over 3 h. Diethyl ether (20 ml) and water (20 ml) were added and the separated aqueous layer was extracted with diethyl ether (3 Χ 10 ml). The combined organic extracts were washed with brine (20 ml), then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 40% diethyl ether in light petroleum to give the corresponding alcohol (443 mg, 82%) as a colorless oil. n max (CHCl3)/cm–1 3359, 3074, 1634. 1H NMR (360 MHz, CDCl3) d = 7.24–7.17 (3H, m, 3 Χ ArH), 7.06–7.01 (1H, m, ArH), 5.71–5.43 (2H, 2 Χ m, Z CH=CH), 4.84 (2H, app d, C=CH2), 3.59 (2H, t, J = 7.7 Hz, CH2OTBS), 2.88 (2H, t, J = 7.4 Hz, ArCH2CH2), 2.46 (2H, app. q, J = 7.5 Hz, CH2CH2OTBS), 2.31 (2H, app. q, J = 7.4 and 1.3 Hz, ArCH2CH2), 2.19–2.14 (1H, m, ArCHCH2CH), 1.81 (3H, s, CH3), 1.70–1.65 (1H, m, ArCHCH2CH), 1.26–1.18 (2H, m, ArCHCH2CH); 13C NMR (90.5 MHz, CDCl3) d = 145.2 (s), 140.9 (s), 139.8 (s), 131.9 (d), 128.9 (d), 126.0 (d), 125.8 (d), 125.7 (d), 125.2 (d), 108.6 (t), 61.9 (t), 32.9 (t), 30.6 (t), 28.6 (d), 28.4 (t), 21.0 (d), 20.3 (q), 13.5 (t); m/z (EI) 256.1829 (M+, C18H24O requires 256.1827).

A solution of iodine (879 mg, 3.5 mmol) in dichloromethane (10 ml) was added dropwise over 5 min to a stirred solution of the alcohol (443 mg, 1.7 mmol), imidazole (247 mg, 3.6 mmol) and triphenylphosphine (1.5 g, 5.8 mmol) in dichloromethane (20 ml) at room temperature under an atmosphere of nitrogen. The reaction flask was covered with aluminum foil and the mixture was then stirred in the dark for 12 h. Water (20 ml) was added and the separated organic layer was washed successively with aqueous sodium bicarbonate (20 ml) and 5% aqueous sodium sulfite (20 ml). The organic layer was dried and concentrated in vacuo and the residue was purified by column chromatography on silica, eluting with 1% diethyl ether in pentane to give the iodide (587 mg, 93%) as a yellow oil. n max (CHCl3)/cm–1 3064, 1634, 987, 951. 1H NMR (360 MHz, CDCl3) d = 7.17–7.11 (3H, m, 3 Χ ArH), 7.01–6.96 (1H, m, ArH), 5.62–5.33 (2H, 2 Χ m, Z CH=CH), 4.84 (2H, app d, J = 11.2 Hz, C=CH2), 2.96 (2H, t, J = 7.3 Hz, CH2I), 2.85 (2H, t, J = 7.6 Hz, ArCH2CH2), 2.55 (2H, app. q, J = 7.3 Hz, CH2CH2OTBS), 2.37 (2H, app. q, J = 7.6 and 1.3 Hz, ArCH2CH2), 2.14–2.08 (1H, m, ArCHCH2CH), 1.77 (3H, s, CH3), 1.66–1.16 (1H, m, ArCHCH2CH), 1.22–1.16 (2H, m, ArCHCH2CH); 13C NMR (90.5 MHz, CDCl3) d = 145.3 (s), 140.8 (s), 139.9 (s), 131.5 (d), 129.1 (d), 128.5 (d), 126.2 (d), 125.8 (d), 125.3 (d), 108.8 (t), 32.9 (t), 28.8 (d), 28.6 (t), 21.1 (d), 20.8 (q), 13.8 (t), 5.2 (t); m/z (EI) 366.0843 (M+, C18H23I requires 366.0845).

(E)-3-{2-[(Z)-6-(tert-Butyldimethylsilyloxy)-hex-3-enyl]-4-methoxyphenyl}prop-2-en-1-ol 46b. A solution of iBu2AlH in toluene (4.3 ml, 1.50 M, 6.5 mmol) was added dropwise over 10 min to a stirred solution of the ester 17b (1.2 g, 3.04 mmol) in dichloromethane (30 ml) at –78°C under an atmosphere of nitrogen. The solution was stirred at –78°C for 2 h, then methanol (3 ml) was added and the solution was allowed to warm to room temperature. The solution was poured into a saturated aqueous solution of Rochelle salt (50 ml) and stirred for a further 6 h. The separated aqueous layer was extracted with dichloromethane (3 Χ 10 ml). The combined organic extracts were washed with brine (10 ml), then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 40% diethyl ether in light petroleum to give the allylic alcohol (1 g, 87%) as a colorless oil. n max (CHCl3)/cm–1 3611, 3443; 1H NMR (360 MHz, CDCl3) d = 7.40 (1H, d, J = 8.5 Hz, ArH), 6.83 (1H, d, J = 15.6 Hz, ArCH=CH), 6.74 (1H, dd, J = 8.5 and 2.7 Hz, ArH), 6.70 (1H, d, J = 2.7 Hz, ArH), 6.17 (1H, dt, J = 15.6 and 5.9 Hz, ArCH=CH), 5.53–5.41 (2H, 2 Χ m, Z CH=CH ), 4.32 (2H, app. td, J = 5.9 and 1.5 Hz, CH2OH), 3.81 (3H, s, OMe), 3.58 (2H, t, J = 7.1 Hz, CH2OTBS), 2.69 (2H, t, J = 7.7 Hz, ArCH2CH2), 2.34–2.24 (4H, m, CH2CH=CHCH2), 1.96 (1H, s, OH), 0.90 (9H, s, SiCMe3), 0.07 (6H, s, SiMe2); 13C NMR (90.5 MHz, CDCl3) d = 159.1 (s), 140.9 (s), 130.5 (d), 128.6 (d), 128.3 (d), 128.2 (d), 127.4 (s), 126.5 (d), 114.8 (d), 111.7 (d), 63.9 (t), 62.9 (t), 55.2 (q), 33.8 (t), 31.1 (t), 28.8 (t), 25.6 (q), 18.4 (s), –5.3 (q); m/z (FAB) 399.2340 ([M + Na]+, C22H36SiO3Na requires 399.2331).

1-{2-[(Z)-6-(tert-Butyldimethylsilyloxy)-hex-3-enyl]-4-methoxyphenyl}-trans-cyclopropyl Carbaldehyde 47b. Diethylzinc (3 ml, 30 mmol) was added dropwise over 10 min to a stirred solution of the allylic alcohol 46b (1.9 g, 5 mmol) in toluene (74 ml) at room temperature under an atmosphere of nitrogen. Diiodomethane (4.8 ml, 59.4 mmol) was added dropwise over 5 min and the mixture was then stirred at room temperature for 1 h 30 min. Saturated aqueous ammonium chloride (28 ml) and diethyl ether (25 ml) were added and the separated organic layer was then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 30–50% diethyl ether in light petroleum to give the corresponding cyclopropylmethanol (1.4 g, 72%) as a colorless oil; (found: C, 70.9; H, 9.9%; C23H38O3Si requires C, 70.7; H, 9.8%). n max (CHCl3)/cm–1 3616, 3006; 1H NMR (360 MHz, CDCl3) d = 6.94 (1H, d, J = 8.4 Hz, ArH), 6.74 (1H, dd, J = 8.4 and 2.7 Hz, ArH), 6.67 (1H, m, ArH), 5.58–5.39 (2H, m, Z CH=CH), 3.79 (3H, s, OMe), 3.69 (2H, t, J = 6.9 Hz, CH2OTBS), 3.65 (2H, m, CH2OH), 3.58 (2H, t, J = 6.9 Hz, ArCH2CH2), 2.40 (2H, app. q, J = 7.3 Hz, CH2CH2OTBS), 2.27 (2H, app. q, J = 7.6 Hz, ArCH2CH2), 1.97–1.93 (1H, m, ArCHCH2CH), 1.85–1.79 (1H, m, ArCHCH2CH), 1.76–1.70 (2H, m, ArCHCH2CH), 1.42–1.32 (1H, m, ArCHCH2CH), 0.91 (9H, s, SiCMe3), 0.07 (6H, s, SiMe2); 13C NMR (90.5 MHz, CDCl3) d = 157.9 (s), 142.5 (s), 131.6 (s), 130.7 (d), 127.1 (d), 126.4 (d), 114.7 (d), 110.8 (d), 66.7 (t), 63.0 (t), 55.3 (q), 33.1 (t), 31.0 (t), 28.4 (t), 26.0 (q), 23.3 (d), 18.4 (s), 15.3 (d), 11.8 (t), –5.3 (q); m/z (EI) 390.2595 (M+, C23H38O3Si requires 390.2590).

Pyridinium dichromate (1.8 g, 4.8 mmol) was added in one portion to a stirred solution of the alcohol (900 mg, 2.3 mmol) in dichloromethane (20 ml) at room temperature under an atmosphere of nitrogen and the mixture was stirred at room temperature for 16 h. The mixture was filtered through a pad of Celite, which was washed with dichloromethane (50 ml). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica, eluting with 20% diethyl ether in light petroleum to give the aldehyde (827 mg, 93%) as a colorless oil. n max (CHCl3)/cm–1 3007, 2990, 2856, 2735, 2238, 1702, 1610; 1H NMR (360 MHz, CDCl3) d = 9.36 (1H, d, J = 4.7 Hz, CHO), 6.94 (1H, d, J = 8.5 Hz, ArH), 6.75 (1H, d, J = 2.7 Hz, ArH), 6.69 (1H, dd, J = 8.5 and 2.7 Hz, ArH), 5.54–5.39 (2H, m, Z CH=CH), 3.79 (3H, s, OMe), 3.56 (2H, t, J = 7.6 Hz, CH2OTBS), 2.74 (2H, t, J = 7.4 Hz, ArCH2CH2), 2.66–2.62 (1H, m, ArCHCH2CH), 2.38–2.23 (4H, 2 Χ app. q, J = 7.4 Hz, CH2CH=CHCH2), 2.05–2.01 (1H, m, ArCHCH2CH), 1.72–1.67 (1H, m, ArCHCH2CH), 1.53–1.48 (1H, m, ArCHCH2CH), 0.89 (9H, s, SiCMe3), 0.05 (6H, s, SiMe2); 13C NMR (90.5 MHz, CDCl3) d = 200.0 (d), 158.6 (s), 142.8 (s), 130.1 (d), 128.4 (s), 127.3 (d), 126.8 (d), 114.9 (d), 110.9 (d), 62.8 (t), 55.1 (q), 32.8 (t), 32.6 (d), 31.0 (t), 27.9 (t), 25.9 (q), 23.9 (d), 18.3 (s), 15.3 (t), –5.3 (q); m/z (CI) 388.2439 (M+, C23H36O3Si requires 388.2434).

1-{2-[(Z)-6-(tert-Butyldimethylsilyloxy)-hex-3-enyl]-4-methoxyphenyl}-trans-cyclopropyl Ethanone 48b. A solution of methylmagnesium bromide in THF (0.200 ml, 3.00 M, 0.600 mmol) was added dropwise over 5 min to a stirred solution of the aldehyde 47b (192 mg, 0.490 mmol) in THF (6 ml) at 0°C under an atmosphere of nitrogen and the solution was then allowed to warm to room temperature over 1 h. Diethyl ether (10 ml) and saturated aqueous ammonium chloride (10 ml) were added and the separated aqueous layer was extracted with diethyl ether (3 Χ 5 ml). The combined organic extracts were washed with brine (10 ml), then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 20% diethyl ether in light petroleum to give the corresponding tertiary alcohol (190 mg, 95%) as a yellow oil; (found: C, 71.1; H, 9.9. C24H4O3Si requires C, 71.2, H 9.9%); n max (CHCl3)/cm–1 3606, 2955, 2930, 2857, 1607; 1H NMR (360 MHz, CDCl3) d = 6.91 (1H, d, J = 8.4 Hz, ArH), 6.73 (1H, d, J = 2.7 Hz, ArH), 6.68 (1H, dd, J = 8.4 and 2.7 Hz, ArH), 5.58–5.42 (2H, m, Z CH=CH), 3.80 (3H, s, OMe), 3.58 (2H, t, J = 7.8 Hz, CH2OTBS), 3.47–3.40 (1H, m, -(CH3)CHOH) 2.80 (2H, t, J = 7.4 Hz, ArCH2CH2 ), 2.39–2.22 (4H, m, CH2CH=CHCH2), 1.86–1.80 (1H, m, ArCHCH2CH), 1.64–1.45 (2H, m, br s, CHOH and ArCHCH2CH) , 1.39 (3H, m, CHCH3), 1.32–1.20 (2H, m, ArCHCH2CH), 0.90 (9H, s, SiCMe3), 0.07 (6H, s, SiMe2); 13C NMR (90.5 MHz, CDCl3) d = 158.4 (s), 142.8 (s), 132.4 (s), 131.6 (d), 128.4 (d), 127.8 (d), 115.0 (d), 110.8 (d), 62.8 (t), 55.3 (q), 38.9 (s), 32.7 (t), 31.6 (d), 31.0 (t), 30.8 (q), 28.2 (t), 26.5 (d), 26.0 (q), 18.1 (t), –5.3 (q); m/z (EI) 404.2746 (M+, C24H40O3Si requires 404.2748).

Dess–Martin periodinane (299 mg, 0.71 mmol) was added in one portion to a stirred solution of the cyclopropylmethanol (190 mg, 0.47 mmol) in dichloromethane (6 ml) at 0°C and the mixture was allowed to warm to room temperature over 16 h. Diethyl ether (20 ml) and saturated aqueous sodium thiosulfate (20 ml) were added. The separated organic layer was washed with brine (10 ml), then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 10% diethyl ether in light petroleum to give the methyl ketone (174 mg, 91%) as a brown oil. n max (CHCl3)/cm–1 1693, 1609; 1H NMR (360 MHz, CDCl3) d = 6.90 (1H, d, J = 8.5 Hz, ArH), 6.76 (1H, d, J = 2.7 Hz, ArH), 6.65 (1H, dd, J = 8.5 and 2.7 Hz, ArH), 5.58–5.42 (2H, m, Z CH=CH), 3.78 (3H, s, OMe), 3.56 (2H, t, J = 7.8 Hz, CH2OTBS), 2.78 (2H, t, J = 7.1 Hz, ArCHCH2CH2), 2.38–2.29 (4H, m, CH2CH=CHCH2), 2.08–2.03 (1H, m, ArCHCH2CH), 1.64–1.60 (1H, m, ArCHCH2CH), 1.57 (3H, s, CH3), 1.38–1.34 (1H, m, ArCHCH2CH), 0.90 (9H, s, SiCMe3), 0.06 (6H, s, SiMe2); 13C NMR (90.5 MHz, CDCl3) d = 208.3 (s), 158.4 (s), 144.2 (s), 130.4 (d), 130.3 (d), 129.8 (s), 126.8 (d), 115.0 (d), 111.1 (d), 62.8 (t), 55.3 (q), 38.9 (s), 32.7 (t), 31.6 (d), 31.0 (t), 30.8 (q), 28.2 (t), 26.5 (d), 26.0 (q), 18.1 (t), –5.1 (q); m/z (EI) 402.2593 (M+, C24H38O3Si requires 402.2590).

2-((Z)-6-Iodohex-3-enyl)-1-(2-isopropenyl-trans-cyclopropyl)-4-methoxybenzene 49b. A solution of n-butyllithium in hexane (242 m l, 2.5 M, 0.62 mmol) was added dropwise over 10 min to a stirred suspension of methyltriphenylphosphonium bromide (231 mg, 0.65 mmol) in THF (5 ml) at 0°C under an atmosphere of nitrogen. The orange solution was stirred at 0°C for 20 min, then allowed to warm to room temperature over 30 min and again recooled to 0°C. A solution of the ketone 48b (174 mg, 0.430 mmol) in THF (4 ml) was added dropwise over 5 min and the resultant yellow solution was then allowed to warm to room temperature over 12 h. Diethyl ether (20 ml) and water (20 ml) were added and the separated aqueous layer was then extracted with diethyl ether (3 Χ 10 ml). The combined organic extracts were washed with brine (10 ml), then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 5% diethyl ether in light petroleum to give the corresponding vinylcyclopropane (110 mg, 64%) as a yellow oil. n max (CHCl3)/cm–1 3063, 1635, 986, 938. 1H NMR (360 MHz, CDCl3) d = 6.90 (1H, d, J = 8.5 Hz, ArH), 6.72 (1H, d, J = 2.4 Hz, ArH), 6.67 (1H, dd, J = 8.5 and 2.4 Hz, ArH), 5.62–5.31 (2H, m, Z CH=CH), 4.73 (2H, m, C=CH2), 3.79 (3H, s, OMe), 3.54 (2H, t, J = 7.5 Hz, CH2OTBS), 2.72 (2H, t, J = 7.1 Hz ArCH2CH2), 2.66–2.61 (1H, m, ArCHCH2CH), 2.38 (2H, app. q, J = 7.6 Hz, CH2CH2OTBS), 2.23 (2H, app. q, J = 7.4 Hz, ArCH2CH2), 2.08–2.03 (1H, m, ArCHCH2CH), 1.70–1.48 (2H, m, ArCHCH2CH), 1.39 (3H, s, -CH3), 0.89 (9H, s, SiCMe3), 0.05 (6H, s, SiMe2); 13C NMR (90.5 MHz, CDCl3) d = 157.7 (s), 146.4 (s), 142.4 (s), 132.3 (s), 131.6 (d), 128.4 (d), 127.0 (d), 116.2 (d), 110.8 (d), 108.7 (t), 55.5 (q), 32.8 (t), 32.6 (d), 31.0 (t), 27.9 (t), 25.9 (q), 23.9 (d), 18.3 (s), 15.3 (t), –5.3 (q); m/z (EI) 400.2799 (M+, C25H40O2Si requires 400.2798).

A solution of tetra-n-butylammonium fluoride in THF (0.4 ml, 1 M, 0.4 mmol) was added dropwise over 5 min to a stirred solution of the silyl ether (110 mg, 0.28 mmol) in THF (6 ml) at 0°C under an atmosphere of nitrogen, and the solution was then allowed to warm gradually to room temperature over 3 h. Diethyl ether (20 ml) and water (20 ml) were added and the separated aqueous layer was extracted with diethyl ether (2 Χ 10 ml). The combined organic extracts were washed with brine (6 ml), then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 20% diethyl ether in light petroleum to give the corresponding alcohol (70 mg, 89%) as a colorless oil. n max (CHCl3)/cm–1 3359, 3074, 1634. 1H NMR (360 MHz, CDCl3) d = 6.92 (1H, d, J = 8.3 Hz, ArH), 6.72 (1H, d, J = 2.4 Hz, ArH), 6.67 (1H, dd, J = 8.3 and 2.4 Hz, ArH), 5.62–5.31 (2H, m, Z CH=CH), 4.78 (2H, app. d, J = 11.0 Hz, C=CH2), 3.80 (3H, s, OMe), 3.54 (2H, t, J = 7.5 CH2OH), 2.81 (2H, t, 7.1 Hz, ArCH2CH2), 2.57 (2H, app. q, J = 7.2 Hz, CH2CH2OH), 2.53 (2H, app. q, J = 7.4 Hz, ArCH2CH2), 2.14–2.19 (1H, m, ArCHCH2CH), 1.81 (3H, s, CH3), 1.70–1.65 (1H, m, ArCHCH2CH), 1.26–1.18 (2H, m, ArCHCH2CH); 13C NMR (120.5 MHz, CDCl3) d = 157.8 (s), 146.2 (s), 142.4 (s), 132.3 (s), 131.6 (d), 128.4 (d), 127.0 (d), 115.0 (d), 110.9 (d), 108.7 (t), 55.5 (q), 38.4 (t), 31.6 (d), 29.4 (t), 27.9 (t), 28.5 (d), 20.7 (d), 20.6 (q), 18.3 (s), 13.3 (t), 5.6 (t); m/z (EI) 286.1930 (M+, C19H26O2 requires 286.1932).

A solution of iodine (244 mg, 0.96 mmol) in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of the alcohol (212 mg, 0.73 mmol), imidazole (151 mg, 2.22 mmol) and triphenylphosphine (252 mg, 0.96 mmol) in dichloromethane (10 ml) at room temperature under an atmosphere of nitrogen. The reaction flask was covered with aluminum foil and the mixture was then stirred in the dark for 12 h. Water (10 ml) was added and the separated organic layer was washed successively with aqueous sodium bicarbonate (10 ml) and 5% aqueous sodium sulfite (10 ml). The organic layer was dried and concentrated in vacuo and the residue was then purified by column chromatography on silica, eluting with 2% diethyl ether in pentane to give the iodide (178 mg, 61%) as a yellow oil. n max (CHCl3)/cm–1 3064, 1634, 987, 951; 1H NMR (360 MHz, CDCl3) d = 6.95 (1H, d, J = 8.4 Hz, ArH), 6.73 (1H, d, J = 2.4 Hz, ArH), 6.68 (1H, dd, J = 8.4 and 2.4 Hz, ArH), 5.62–5.30 (2H, 2 Χ m, Z CH=CH), 4.78 (2H, app. d, J = 11.2 Hz, –C=CH2), 3.80 (3H, s, OMe), 2.98 (2H, t, J = 7.5 Hz, CH2I), 2.80 (2H, t, J = 7.1 Hz, ArCH2CH2), 2.56 (2H, app. q, J = 7.2 Hz, CH2CH2I), 2.38 (2H, app. q, J = 7.1 Hz, ArCH2CH2), 2.06–1.98 (1H, m, ArCHCH2CH), 1.73 (3H, s, -CH3), 1.18–1.08 (1H, m, ArCHCH2CH), 0.91–0.85 (2H, m, ArCHCH2CH); 13C NMR (90.5 MHz, CDCl3) d = 157.8 (s), 145.5 (s), 142.4 (s), 132.1 (s), 131.5 (d), 128.6 (d), 127.0 (d), 115.0 (d), 110.9 (d), 108.7 (t), 55.3 (q), 33.3 (t), 31.5 (t), 28.6 (t), 28.5 (d), 20.8 (d), 20.7 (q), 13.4 (t), 5.3 (t); m/z (EI) 396.0943 (M+, C19H25IO2 requires 396.0950).

10-Methyl-6,6a,6b,7,8,9,10,10a,11,11a-decahydro-5H-benzo[a]fluorine 51a. A solution of Bu3SnH (87 m l, 0.33 mmol) and AIBN (2 mg, 0.01 mmol) in degassed benzene (5 ml) was added over 6 h, by syringe pump, to a refluxing solution of the iodide 49a (100 mg, 0.27 mmol) and AIBN (2 mg, 0.01 mmol) in degassed benzene (90 ml) under an atmosphere of argon. The mixture was heated under reflux for a further 8 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 5–30% diethyl ether in hexane to give the 6,6,5,6-tetracycle (15.0 mg, 23%) as a colorless oil. n max (CHCl3)/cm–1 2958, 1651, 1486, 778; 1H NMR (360 MHz, CDCl3) d = 7.20–7.07(4H, m, 4 Χ ArH), 3.02–2.92 (1H, m), 2.58–2.46 (1H, m), 2.17 (1H, m), 2.17–2.03 (1H, m), 1.82–1.09 (12H, m), 1.00–0.84 (5H, m, -CH3 and 2 Χ CH); 13C NMR (120.5 MHz, CDCl3) d = 142.3 (s), 136.9 (s), 128.4 (d), 125.6 (d), 125.4 (d), 125.3 (d), 46.9 (d), 44.6 (d), 44.0 (d), 43.5 (d), 37.2 (d), 34.5 (t), 34.1 (t), 29.8 (t), 26.8 (t), 24.7 (t), 21.8 (t), 20.8 (q); m/z (EI) 240.1881 (M+, C18H24 requires 240.1878).

3-Methoxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a] phenanthrene 50b. A solution of Bu3SnH (80 m l, 0.3 mmol) and AIBN (25 mg, 0.15 mmol) in degassed toluene (10 ml) was added over 10 h by syringe pump to a refluxing solution of the iodide 49b (100 mg, 0.25 mmol) and AIBN (8 mg, 0.05 mmol) in degassed toluene (120 ml) under an atmosphere of argon. The mixture was heated under reflux for a further 4 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with diethyl ether (10 ml) and the solution was stirred overnight with 5% aqueous potassium fluoride. The separated aqueous layer was extracted with diethyl ether (3 Χ 10 ml) and the combined organic extracts were dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 0–20% diethyl ether in hexane to give the steroid (8.3 mg, 12%) as a colorless oil. n max (CHCl3)/cm-1 2928, 2871, 1608, 1576; 1H NMR (360 MHz, CDCl3) d = 7.25 (1H, d, J = 8.6 Hz, H-1), 6.73 (1H, dd, J = 8.6 and 2.7 Hz, H-2), 6.65 (1H, d, J = 2.7 Hz, H-4), 3.78 (3H, s, OMe), 2.97–2.79 (2H, m, H2-6), 2.32–2.18 (2H, m, H-11a and H-9a ), 1.96–1.82 (2H, m, H-7b and H-12b ), 1.80–1.64 (3H, m, H2-16 and H-15a ), 1.56–1.48 (2H, m, H-7a and H-17), 1.44–1.10 (6H, m, H-17, H-12a , H-11b , H-8b , H-15b and H-14a ), 0.75 (3H, s, H3-18); 13C NMR (120.5 MHz, CDCl3) d = 157.4 (C-3), 138.2 (C-5), 133.2 (C-10), 126.4 (C-1), 113.8 (C-4), 111.5 (C-2), 55.3 (OMe), 53.6 (C-14), 44.1 (C-9), 41.1 (C13), 40.6 (C17), 39.3 (C-8), 38.9 (C-12), 30.1 (C-6), 28.2 (C-7), 26.9 (C-11), 25.2 (C-15), 20.7 (C-16) 17.6 (C-18); m/z (EI) 270.1981 (M+, C19H25O requires 270.1984).

1-{2-[(Z)-6-tert-Butyldimethylsilyloxy)hex-3-enyl]-4-methoxyphenyl}-2-methoxyvinyl-trans-cyclopropane 54. Diisopropylamine (0.2 ml, 0.39 mmol) was added dropwise over 5 min to a stirred solution of n-butyllithium in hexane (0.2 ml, 2.5 M, 0.39 mmol) and THF (2 ml) at –78°C under an atmosphere of nitrogen. The solution was stirred at –78°C for 15 min and then allowed to warm to room temperature over 30 min. The solution was added dropwise via cannula over 15 min to a stirred solution of methoxymethyldiphenylphosphine oxide (98 mg, 0.39 mmol) in THF (2 ml) at –78°C under an atmosphere of nitrogen. The resulting red solution was stirred at –78°C for 10 min and then a solution of the ketone 48 (80 mg, 0.19 mmol) in THF (3 ml) was added dropwise over 10 min. The mixture was stirred at –78°C for 10 min and then allowed to warm to room temperature over 16 h. Ethyl acetate (4 ml) and brine (2 ml) were added and the separated aqueous layer was extracted with ethyl acetate (3 Χ 3 ml). The combined organic extracts were washed with brine (8 ml), then dried and concentrated in vacuo to leave a yellow oil.

Sodium hydride (25 mg, 0.62 mmol, 60% suspension in oil) was added in one portion to a stirred solution of the yellow oil in THF (5 ml) at room temperature under an atmosphere of nitrogen. The mixture was stirred at room temperature for 52 h and then water (2 ml) and diethyl ether (3 ml) were added. The separated aqueous layer was extracted with diethyl ether (3 Χ 5 ml) and the combined organic extracts were then dried and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 5% diethyl ether in light petroleum to give a mixture of E and Z isomers of the enol ether (72 mg, 90%) as a colorless oil. n max (CHCl3)/cm–1 3004, 2935, 2881, 2836, 1671, 1608; 1H NMR (360 MHz, CDCl3) d = 6.99–6.87 (1H, m, ArH), 6.73–6.70 (1H, m, ArH), 6.69–6.65 (1H, m, ArH), 5.95, 5.94 (1H, br s, CHOMe), 5.66–5.37 (2H, m, Z CH=CH), 3.79, 3.78 (3H, s, OMe), 3.59, 3.58 (3H, s, =CHOMe), 3.57–3.54 (2H, m, CH2OH), 2.83–2.77 (2H, m, ArCH2CH2), 2.40–2.37 (2H, app. q, J = 7.3 Hz, ArCH2CH2), 2.29–2.25 (2H, m, CH2CH2OH), 2.08–2.00 (1H, m, ArCHCH2CH), 1.91–1.89 (1H, m, ArCHCH2CH), 1.73–1.70 (2H, m, ArCHCH2CH), 1.14–1.04 (1H, m, ArCHCH2CH), 0.99–0.95 (1H, m, ArCHCH2CH), 0.82–0.79 (2H, m, ArCHCH2CH), 0.91 (9H, s, SiCMe3), 0.06 (6H, s, SiMe2); 13C NMR (90.5 MHz, CDCl3) d = 157.7 (s), 142.8 (d), 142.5 (d), 142.2 (s), 132.5 (s), 132.4 (d), 132.2 (d), 127.0 (d), 126.8 (d), 125.9 (d), 125.8 (d), 115.0 (d), 114.9 (d), 114.9 (s), 110.9 (d), 110.8 (d), 110.6 (s), 62.3 (t), 59.4 (q), 59.4 (q), 55.2 (q), 33.2 (t), 33.1 (t), 30.9 (t), 30.8 (t), 28.5 (t), 28.2 (t), 25.3 (d), 21.0 (d), 18.8 (d), 18.1 (d), 13.5 (d), 11.6 (t), 11.4 (t); m/z (EI) 400.6772 (M+, C23H36O3Si requires 400.6769).

2-((Z)-6-Iodohex-3-enyl)-4-methoxy-1-[2-((E)-2-methoxy-1-methylvinyl)-trans-cyclopropyl]benzene 55. A solution of tetra-n-butylammonium fluoride in THF (0.4 ml, 1 M, 0.36 mmol) was added dropwise over 5 min to a stirred solution of the silyl ether 54 (75 mg, 0.19 mmol) in THF (8 ml) at 0°C under an atmosphere of nitrogen and the solution was then allowed to warm gradually to room temperature over 3 h. Diethyl ether (20 ml) and water (20 ml) were added and the separated aqueous layer was extracted with diethyl ether (2 Χ 10 ml). The combined organic extracts were washed with brine (4 ml), then dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 50% diethyl ether in light petroleum to give a mixture of E- and Z-enol ether isomers of the corresponding alcohol (58 mg, 98%) as a colorless oil. n max (CHCl3)/cm–1 3621, 3004, 1608, 1574; 1H NMR (360 MHz, CDCl3) d = 6.99–6.87 (2H, m, 2 Χ ArH), 6.73–6.70 (2H, m, 2 Χ ArH), 6.69–6.65 (2H, m, 2 Χ ArH), 5.95, 5.94(2H, br s, 2 Χ CHOMe), 5.66–5.37 (4H, 2 Χ m, Z CH=CH), 3.79, 3.78 (6H, s, 2 Χ OMe), 3.59, 3.58 (3H, s, 2 Χ =CHOMe), 3.57–3.54 (4H, m, 2 Χ CH2OH), 2.83–2.77 (4H, m, ArCH2CH2), 2.40–2.37 (4H, app. q, J = 14.6 and 7.3 Hz, ArCH2CH2), 2.29–2.25 (4H, m, CH2CH2OH), 2.08–2.00 (1H, m, ArCHCH2CH), 1.91–1.89 (1H, m, ArCHCH2CH), 1.73–1.70 (2H, m, ArCHCH2CH), 1.14–1.04 (1H, m, ArCHCH2CH), 0.99–0.95 (1H, m, ArCHCH2CH), 0.82–0.79 (2H, m, ArCHCH2CH), 0.91 (9H, s, SiCMe3), 0.06 (6H, s, SiMe2); 13C NMR (90.5 MHz, CDCl3) d = 157.7 (s), 142.8 (d), 142.5 (d), 142.2 (s), 132.5 (s), 132.4 (d), 132.2 (d), 127.0 (d), 126.8 (d), 125.9 (d), 125.8 (d), 115.0 (d), 114.9 (d), 114.9 (s), 110.9 (d), 110.8 (d), 110.6 (s), 62.3 (t), 59.4 (q), 59.4 (q), 55.2 (q), 33.2 (t), 33.1 (t), 30.9 (t), 30.8 (t), 28.5 (t), 28.2 (t), 25.3 (d), 21.0 (d), 18.8 (d), 18.1 (d), 13.5 (d), 11.6 (t), 11.4 (t); m/z (EI) 316.2041 (M+, C20H28O3 requires 316.2039).

A solution of iodine (62 mg, 0.24 mmol) in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of the alcohol (58.0 mg, 0.18 mmol), imidazole (37 mg, 0.55 mmol) and triphenylphosphine (62 mg, 0.24 mmol) in dichloromethane (5 ml) at 0°C under an atmosphere of nitrogen. The reaction flask was then covered with aluminum foil and the mixture was then stirred at room temperature in the dark for 12 h. Water (10 ml) was added and the separated organic layer was washed successively with aqueous sodium bicarbonate (5 ml) and 5% aqueous sodium sulfite (5 ml). The organic layer was dried and concentrated in vacuo and the residue was purified by column chromatography on silica, eluting with 2% diethyl ether in pentane to give a mixture of E- and Z-enol ether isomers of the iodide (63 mg, 80%) as a yellow oil. (Data reported for E-isomer). n max (CHCl3)/cm–1 1722, 1672, 1609, 1574; 1H NMR (360 MHz, CDCl3) d = 6.98 (1H, d, J = 2.4 Hz, ArH), 6.72 (1H, d, J = 8.6 Hz, ArH), 6.69 (1H, dd, J = 8.6 and 2.4 Hz, ArH), 5.95 (1H, br s, =CHOMe), 5.64–5.53 (2H, 2 Χ m, Z CH=CH), 3.79 (3H, s, OMe), 3.58 (3H, s, =CHOMe), 3.02–2.97 (2H, m, ArCH2CH2), 2.84–2.78 (2H, m, CH2I), 2.58–2.54 (2H, app. q, CH2CH2I), 2.38–2.33 (2H, m, ArCH2CH2), 2.06–1.70 (3H, m, ArCHCH2CH), 1.56 (3H, s, -CH3); 13C NMR (90.5 MHz, CDCl3) d = 157.7 (s), 143.0 (s), 142.5 (s), 132.6 (d), 131.8 (d), 128.5 (d), 126.9 (d), 115.1 (d), 110.9 (d), 59.5 (q), 55.3 (q), 33.3 (t), 30.8 (t), 28.4 (t), 11.8 (t), 25.6 (d), 17.4 (d), 13.6 (q), 11.8 (t), 5.4 (t); m/z (EI) 426.1043 (M+, C20H27O2I requires 426.1045).

3,17-Dimethoxyestra-1,3,5(10)-triene 56. A solution of Bu3SnH (50 m l, 188 m mol) and AIBN (18.5 mg, 113 m mol) in degassed toluene (10 ml) was added over 8 h by syringe pump to a refluxing solution of the iodide 55 (80 mg, 188 m mol) and AIBN (6 mg, 37.6 m mol) in degassed toluene (75 ml) under an atmosphere of argon. The mixture was heated under reflux for a further 4 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with diethyl ether (10 ml) and the solution was stirred overnight with 5% aqueous potassium fluoride. The separated aqueous layer was extracted with diethyl ether (3 Χ 10 ml) and the combined organic extracts were dried and concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with 0–20% diethyl ether in hexane to give a mixture of diastereoisomers of the dimethoxy steroid (7 mg, 12%) as an oil, which was induced to crystallize from 1:1 vol/vol acetonitrile/hexane to give colorless crystals; mp 160–161°C (ref. 7 mp 161–163°C for 17b -OMe); (found: C, 79.5, H, 9.1%; calculated for C20H28O2: C, 79.9, H, 9.4%); n max (CHCl3)/cm–1 1608, 1500, 1237, 1118, 1034; 1H NMR (360 MHz, CDCl3) d = 7.21 (1H, d, J = 8.4 Hz, H-1), 6.72 (1H, dd, J = 8.4 and 2.8 Hz, H-2), 6.63 (1H, d, J = 2.8 Hz, H-4), 3.78 (3H, s, OMe), 3.38 (3H, s, CHOMe) 3.32 (1H, app. t, J = 8.0 Hz, H-17), 2.88–2.84 (2H, m, H2-6), 2.31–2.26 (1H, m, H-9a ), 2.24–2.18 (1H, m, H-11a ), 2.11–2.02 (2H, m, H-7b and H-12b ), 1.90–1.86 (1H, m), 1.74–1.66 (1H, m), 1.56–1.19 (12H, m), 0.79 (3H, s, H3-18); 13C NMR (120.5 MHz, CDCl3) d = 157.5 (C-3), 138.0 (C-5), 132.8 (C-10), 126.4 (C-1), 113.8 (C-4), 111.5 (C-2), 90.9 (C-17), 58.0 (ArOMe), 55.3 (CHOMe), 50.4 (C-14), 44.0 (C-9), 43.3 (C13), 38.7 (C-8), 38.1 (C-12), 29.9 (C-6), 27.8 (C-7), 27.3 (C-11), 26.5 (C-15), 23.1 (C-16) 11.6 (C-18); m/z (EI) 300.2083 (M+, C20H28O2 requires 300.2089).

3-Methoxyestrone 57. Chromium trioxide (15 mg, 0.14 mmol) was added in one portion to a stirred solution of the methyl ether 56 (11.0 mg, 0.04 mmol) in acetone (5 ml) at 0°C. A solution of H2SO4 (10 drops) in acetone (1 ml) was added and that the mixture was stirred at room temperature for 12 h. The mixture was diluted with diethyl ether (2 ml) and water (2 ml) and the separated aqueous layer was extracted with diethyl ether (3 Χ 5 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (5 ml), then dried and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 5% diethyl ether in hexane to give the estrone (9.8 mg, 94%) as colorless crystals; mp 140–141°C (from CH3CN) (refs. 8 and 9 mp 143–144°C). n max (CHCl3)/cm–1 1732, 1607; 1H NMR (360 MHz, CDCl3) d = 7.21 (1H, d, J = 8.6 Hz, H-1), 6.74 (1H, dd, J = 8.6 and 2.8 Hz, H-2), 6.66 (1H, d, J = 2.8 Hz, H-4), 3.79 (3H, s, OMe), 2.93–2.90 (2H, m, H2-6), 2.51 (1H, m, H-16b ), 2.44–2.39 (1H, m, H-11a ), 2.27 (1H, ddd, J = 10.3, 6.4 and 3.9 Hz, H-9a ), 2.16 (1H, m, H-12b ), 2.10–2.01 (2H, m, H-16a and 7b ), 2.00–1.96 (1H, m, H-15a ), 1.67–1.40 (8H, m, H-12a , H-11b , H-8b , H-7a , H-15b and H-14a ), 0.92 (3H, s, H3-18); 13C NMR (90.5 MHz, CDCl3) d = 221.0 (s), 157.6 (s), 137.8 (s), 132.1 (s), 126.4 (d), 113.9 (d), 111.6(d), 55.3 (q), 50.5 (d), 48.1 (s), 44.0 (d), 38.4 (d), 35.9 (t), 31.6 (t), 29.7 (t), 26.6 (t), 26.0 (t), 21.6(t), 13.9 (q); m/z (EI) 284.1774 (M+, C19H24O2 requires 284.1776).

(±)-Estrone 1. A solution of boron tribromide in dichloromethane (93 m l, 1 M, 93 m mol) was added dropwise over 5 min to a stirred solution of the methyl ether 57 (8 mg, 28.1 m mol) in dichloromethane (5 ml) at –78°C under an atmosphere of nitrogen. The solution was allowed to warm gradually to room temperature overnight and then cooled to 0°C. Water (4 ml) was added and the mixture was stirred for a further 30 min and then brine (2 ml) was added. The separated aqueous layer was extracted with dichloromethane (3 Χ 2 ml) and the combined organic extracts were then dried and concentrated in vacuo. The residue was purified by flash chromatography on silica, eluting with 30% diethyl ether in hexane to give estrone (6 mg, 79%) as colorless crystals; mp 253–255°C (from MeOH) (refs. 8 and 9 mp 252.8–255.7°C). n max (CHCl3)/cm–1 3688, 3596, 1731, 1611; 1H NMR (360 MHz, CDCl3) d = 7.18 (1H, d, J = 8.4 Hz, H-1), 6.63 (1H, dd, J = 8.4 and 2.8 Hz, H-2), 6.59 (1H, d, J = 2.8 Hz, H-4), 4.61 (1H, s, -OH), 2.92–2.86 (2H, m, H2-6), 2.46 (1H, dd, J = 19.0 and 8.2 Hz, H-16b ), 2.42–2.36 (1H, m, H-11a ), 2.28–2.20 (1H, m, H-9a ), 2.16–2.07 (2H, m, H-12b and 16a ), 2.06–1.94 (2H, m, H-7b and H-15a ), 1.67–1.40 (8H, m, H-12a , H-11b , H-8b , H-7a , H-15b and H-14a ), 0.91 (3H, s, H3-18). 13C NMR (120.5 MHz, CDCl3) d = 221.0 (s), 153.5 (s), 138.1 (s), 132.2 (s), 126.6 (d), 115.3 (d), 112.8 (d), 50.4 (d), 48.1 (s), 44.0 (d), 38.3 (d), 35.9 (t), 31.6 (t), 29.5 (t), 26.6 (t), 26.5 (t), 22.9 (t), 21.6 (t), 13.9 (q); m/z (EI) 270.1630 (M+, C18H22O2 requires 270.1612).

1. Nyström, J. E., McCanna, T. D., Helquist, P. & Amouroux, R. (1988) Synthesis, 56–58.

2. Karl, J., Gust, R., Engel, J., Wrobel, K. H., Lux, F., Haeberlin, S. T., Spruss, T., Schneider, M. R. & Schoenenberger, H. (1988) J. Med. Chem. 31, 72–83.

3. Johns, W. F. & Johnson, W. S. (1957) J. Am. Chem. Soc. 79, 2005–2009.

4. Prousa, R., Schonecker, B., Tresselt, D. & Ponsold, K. (1986) J. Prakt. Chem. 328, 55–70.

5. Node, M., Hori, H. & Fujita, E. (1976) J. Chem. Soc. Perkin Trans. 1, 2237–2240.

6. Johnson, W. S., Christiansen, R. G. & Ireland, R. E. (1957) J. Am. Chem. Soc. 79, 1995–2005.

7. Ciuffreda, P., Ferraboschi, P., Verza, E. & Manzocchi, A. (2001) Magn. Reson. Chem. 39, 648–650.