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Synlett 2015; 26(04): 547-551
DOI: 10.1055/s-0034-1379700
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© Georg Thieme Verlag Stuttgart · New York

Construction of a Bicyclo[3.2.1]octane System Carrying the (R)-Carvone Core under Oxidative Radical Conditions: Synthetic Access to (+)-Miroestrols

Mizuna Hamano
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan   Email: n-suzuki@chiba-u.jp
,
Mayuko Akimoto
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan   Email: n-suzuki@chiba-u.jp
,
Keiko Funada
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan   Email: n-suzuki@chiba-u.jp
,
Natsuko Kagawa
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan   Email: n-suzuki@chiba-u.jp
,
Noriyuki Suzuki*
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan   Email: n-suzuki@chiba-u.jp
,
Tsutomu Ishikawa*
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan   Email: n-suzuki@chiba-u.jp
› Author Affiliations
Further Information

Publication History

Received: 25 October 2014

Accepted: 11 November 2014

Publication Date:
03 February 2015 (online)

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Abstract

Bicyclo[3.2.1]octane systems carrying an (R)-carvone core were successfully constructed by 5-exo-cyclization between a β-keto ester function and a 3,3-dimethylallyl group under oxidative radical conditions.

Key words

natural products - asymmetric synthesis - cyclization - radical reaction - bicyclic compounds

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0034-1379700.
  • Supporting Information
 

  • References and Notes

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  • 11 Melting points were determined on a micro melting point hot-stage instrument (Yanagimoto) and are uncorrected. IR spectra were recorded on a JASCO IR-300E spectrophotometer. NMR spectra were recorded in CDCl3 with tetramethylsilane as internal reference on JEOL JNM ECP 400 (400 MHz for 1H NMR, 100 MHz for 13C NMR), and ECA 600 and ECP 600 (600 MHz for 1H NMR, 150 MHz for 13C NMR) spectrophotometers unless otherwise stated; dif. = diffused. FABMS and ESIMS were recorded on JMX-HX 110A and JMS-T100LP spectrophotometer, respectively, with a direct inlet system. Optical rotations ([α]D) were measured on a JASCO P-1020 polarimeter. Anhydrous CH2Cl2 was purchased from Kanto Chemicals. Anhydrous THF was purchased from Wako Pure Chemicals. For column chromatography, Silica Gel 60 (spherical) or Silica Gel 60N (spherical, neutral) purchased from Kanto Chemicals were used. Organic extracts were dried over MgSO4 unless otherwise stated. (1S,3R,4R,6R)-Methyl 3,4-Bis(methoxymethoxy)-3-(3-methylbut-2-enyl)-2-oxo-6-(propen-2-yl)cyclohexanecarboxylate (5a) and (3R,4R,6S)-Methyl 3,4-Bis(methoxymethoxy)-2-hydroxy-3-(3-methylbut-2-enyl)-6-(propen-2-yl)cyclohex-1-enecarboxylate (5b) A 2.25 M solution of n-BuLi in hexane (0.22 mL, 0.48 mmol) was slowly added to a stirred solution of DIPA (0.10 mL, 0.71 mmol) in THF (1.0 mL) at –78 °C under Ar. After 1.5 h, a solution of 19 (105 mg, 0.32 mmol) in THF (1.5 mL) was added dropwise and then stirring was continued at –78 °C for 1 h. To the reaction mixture was added HMPA (0.06 mL, 0.35 mmol) and methyl cyanoformate (0.05 mL, 0.63 mmol), and the whole was stirred at –78 °C for 1.5 h, quenched with H2O (5 mL), and extracted with Et2O (3 × 10 mL). The combined organic solutions were washed with brine (10 mL), dried, and evaporated. The residue was purified by column chromatography (silica gel; hexane–EtOAc, 8:1) to give 5a (57 mg, 46%) and 5b (51 mg, 41%). 5a: Colorless oil. [α]D 23 +122.4 (c 1.07, CHCl3). IR (neat): 1748, 1724 cm–1. 1H NMR (400 MHz): δ = 1.67 [3 H, s, CH=C(CH3)2], 1.74 [3 H, s, CH=C(CH3)2], 1.78 [3 H, s, C(=CH2)CH3], 1.88 (1 H, ddd, J = 14.8, 12.4, 2.0 Hz, C5-H), 2.14 (1 H, dt, J = 14.8, 4.4 Hz, C5-H), 2.60 (2 H, br d, J = 6.4 Hz, C3-CH2), 3.32 (1 H, td, J = 12.0, 4.8 Hz, C6-H), 3.40 (3 H, s, CH2OCH3), 3.43 (3 H, s, CH2OCH3), 3.68 (1 H, d, J = 12.0 Hz, C1-H), 3.73 (3 H, s, CO2CH3), 4.09 (1 H, dd, J = 4.0, 1.6 Hz, C4-H), 4.68 (1 H, d, J = 7.2 Hz, OCH2O), 4.80 (1 H, d, J = 7.2 Hz, OCH2O), 4.81 [1 H, br s, C(=CH2)CH3], 4.85 [1 H, br s, C(=CH2)CH3], 4.90 (1 H, d, J = 7.2 Hz, OCH2O), 4.95 (1 H, d, J = 7.2 Hz, OCH2O), 5.17 [1 H, m, CH=C(CH3)2]. 13C NMR (100 MHz): δ = 18.2, 20.2, 26.0, 32.4, 32.5, 42.2, 52.1, 55.8, 55.9, 58.7, 80.2, 86.2, 93.0, 97.5, 112.0, 116.1, 135.2, 145.0, 169.0, 204.2. HRMS (ESI): m/z calcd for C20H32NaO7 ([M + Na]+): 407.20457; found: 407.20400. 5b: Colorless oil. [α]D 22 +106.7 (c 1.59, CHCl3). IR (neat): 1655 cm–1. 1H NMR (400 MHz): δ = 1.65 [6 H, s, CH=C(CH3)2], 1.83 [3 H, s, C(=CH2)CH3], 1.85–1.89 (1 H, m, C5-H), 2.13 (1 H, td, J = 12.6, 6.4 Hz, C5-H), 2.68 (1 H, dd, J = 13.8, 8.2 Hz, C3-CH), 2.93 (1 H, dif. dd, J = 13.8, 5.6 Hz, C3-CH), 3.17 (1 H, d, J = 6.0 Hz, C6-H), 3.39 (3 H, s, CH2OCH3), 3.42 (3 H, s, CH2OCH3), 3.72 (3 H, s, CO2CH3), 3.75 (1 H, dd, J = 12.6, 3.4 Hz, C4-H), 4.45 (1 H, s, C(=CH2)CH3], 4.61 (1 H, d, J = 6.8 Hz, OCH2O), 4.70 (1 H, d, J = 6.8 Hz, OCH2O), 4.78 [1 H, s, C(=CH2)CH3], 4.89 (1 H, d, J = 6.8 Hz, OCH2O), 4.94 [1 H, dif. t, J = 7.2 Hz, CH=C(CH3)2], 5.05 (1 H, d, J = 6.8 Hz, OCH2O). 13C NMR (100 MHz): δ = 18.2, 22.5, 25.9, 26.5, 29.6, 38.7, 51.8, 55.5, 55.7, 73.9, 79.1, 92.7, 96.7, 102.8, 110.7, 118.6, 134.9, 147.0, 169.2, 172.9. HRMS (ESI): m/z calcd for C20H32NaO7 ([M + Na]+): 407.20457; found: 407.20619.
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  • 13 (4R,5R,7R,8R,10S)-7,8-Bis(methoxymethoxy)-3,3-dimethyl-4,7-methylene-2-oxa-10-(propen-2-yl)spiro[4.5]decan-1,6-dione (21), (1R,2S,4R,5R)-methyl 4,5-bis(methoxymethoxy)-2,7-di(propen-2-yl)-8-oxobicyclo[3.2.1]octane-1-carboxylate (22), and (1R,2S,4R,5R,7R)-methyl 4,5-bis(methoxy­methoxy)-7-(2-hydroxypropan-2-yl)-8-oxo-2-(propen-2-yl)-bicyclo[3.2.1]octane-1-carboxylate (23) A solution of 5 (41 mg, 0.11 mmol) in AcOH (0.9 mL) was added to a stirred suspension of Mn(OAc)3·2H2O (55 mg, 0.20 mmol) and Cu(OAc)2 (21 mg, 0.11 mmol) in AcOH (1.5 mL) at r.t. under Ar. The reaction mixture was stirred at r.t. for 23 h, quenched with aq 10% NaHSO3 solution (5 mL), and extracted with CH2Cl2 (3 × 20 mL). The combined organic solutions were washed with aq sat. NaHCO3 solution (20 mL) and brine (20 mL), dried, and evaporated. The residue was purified by column chromatography (silica gel; hexane– EtOAc, 2:1 → 1:1) to give 21 (9 mg, 22%), 22 (4 mg, 9%), and 23 (3 mg, 6%). 21: Colorless needles; mp 105–109 °C. [α]D 26 +112.6 (c 0.36, CHCl3). IR (ATR): 1788, 1749 cm–1. 1H NMR (400 MHz): δ = 1.28 (3 H, s, C3-CH3), 1.48 (3 H, s, C3-CH3), 1.84 [3 H, s, C(=CH2)CH3], 1.95 (1 H, ddd, J = 13.2, 13.2, 3.2 Hz, C9-H), 2.07 (1 H, dd, J = 14.8, 10.8 Hz, C4-CH2-C7), 2.12 (1 H, ddd, J = 15.2, 4.8, 2.4 Hz, C9-H), 2.48 (1 H, dd, J = 14.4, 3.6 Hz, C4-CH2-C7), 3.02 (1 H, dd, J = 10.4, 3.4 Hz, C4-H), 3.22 (1 H, dd, J = 13.2, 4.6 Hz, C10-H), 3.37 (3 H, s, OCH3), 3.41 (3 H, s, OCH3), 4.17 (1 H, dd, J = 2.8, 2.8 Hz, C8-H), 4.69 (1 H, d, J = 7.0 Hz, OCH2O), 4.78 (1 H, d, J = 7.0 Hz, OCH2O), 4.85 (1 H, d, J = 7.6 Hz, OCH2O), 4.89 [1 H, s, C(=CH2)CH3], 4.92 (1 H, d, J = 7.6 Hz, OCH2O), 4.96 [1 H, s, C(=CH2)CH3]. 13C NMR (100 MHz): δ = 23.9, 25.0, 26.9, 29.9, 32.0, 42.4, 45.8, 55.8, 63.4, 81.3, 84.9, 87.3, 93.1, 96.9, 113.1, 143.4, 169.2, 203.2. HRMS (ESI): m/z calcd for C19H28NaO7 ([M + Na]+): 391.17327; found: 391.17079. 22: Colorless oil. [α]D 26 +126.1 (c 0.29, CHCl3). IR (ATR): 1770, 1739 cm–1. 1H NMR (400 MHz): δ = 1.63 [3 H, s, C(=CH2)CH3], 1.79 [3 H, s, C(=CH2)CH3], 1.98 (1 H, ddd, J = 14.8, 4.4, 2.4 Hz, C3-H or C6-H), 2.12–2.20 (3 H, m, C3-H, C6-H), 3.30–3.36 (2 H, m, C2-H, C7-H), 3.37 (3 H, s, CH2OCH3), 3.39 (3 H, s, CH2OCH3), 3.67 (3 H, s, CO2CH3), 4.17 (1 H, dd, J = 2.8, 2.4 Hz, C4-H), 4.70 (1 H, d, J = 6.8 Hz, OCH2O), 4.70–4.72 [2 H, m, C7-C(=CH2)CH3], 4.80 (1 H, d, J = 6.8 Hz, OCH2O), 4.83–4.84 [2 H, m, C(=CH2)CH3], 4.87 (2 H, s, OCH2O). 13C NMR (100 MHz): δ = 19.5, 21.4, 30.5, 32.4, 40.9, 51.2, 51.7, 55.7, 63.1, 81.9, 85.0, 92.9, 96.9, 111.7, 114.3, 143.7, 147.6, 168.0, 204.5. HRMS (ESI): m/z calcd for C20H30NaO7 ([M + Na]+): 405.18892; found: 405.18607. 23: Colorless oil. [α]D 26 +90.4 (c 0.14, CHCl3). IR (ATR): 3437, 1770, 1712 cm–1. 1H NMR (600 MHz): δ = 1.14 [3 H, s, C(CH3)2O], 1.23 [3 H, s, C(CH3)2O], 1.80[3 H, s, C(=CH2)CH3], 2.03–2.08 (4 H, m, C3-H, C6-H), 2.83 (1 H, t, J = 8.7 Hz, C7-H), 3.38–3.40 (1 H, m, C2-H), 3.39 (3 H, s, OCH3), 3.40 (3 H, s, OCH3), 3.80 (3 H, s, CO2CH3), 4.17 (1 H, br s, C4-H), 4.70 (1 H, d, J = 7.2 Hz, OCH2O), 4.79 (1 H, d, J = 7.2 Hz, OCH2O), 4.84–4.87 [3 H, m, OCH2O, C(=CH2)CH3], 5.02 [1 H, s, C(=CH2)CH3]. 13C NMR (100 MHz): δ = 22.2, 23.2, 29.3, 30.6, 31.2, 45.8, 50.9, 53.0, 55.7, 55.8, 64.2, 72.6, 81.6, 84.6, 92.9, 96.9, 113.9, 143.6, 172.6, 204.3. HRMS (ESI): m/z calcd for C20H32NaO8 ([M + Na]+): 423.19949; found: 423.19675.