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

Mizuna Hamano; Mayuko Akimoto; Keiko Funada; Natsuko Kagawa; Noriyuki Suzuki; Tsutomu Ishikawa

doi:10.1055/s-0034-1379700

Synlett, Table of Contents

Synlett 2015; 26(04): 547-551
DOI: 10.1055/s-0034-1379700

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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

Abstract

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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

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References

References and Notes

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4 Ito, F.; Kumamoto, T.; Ishikawa, T. unpublished results.
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8 Batey RA, Harling JD, Motherwell WB. Tetrahedron 1996; 52: 11421
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10 Ho T, Jitsukawa K, Kaneda K, Teranishi S. J. Am. Chem. Soc. 1979; 101: 159
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.
12 Snider BB. Chem. Rev. 1996; 96: 339
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.

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