Desymmetrization of the anti-meso-Acetylmethyldivinylcyclopentane by ­Directed Epoxidation and its Application to the Synthesis of a ­Polyfunctionalized trans-Hydrindane Unit

Abstract

Desymmetrization of the anti-meso-acetylmethyldivinyl cyclopentane was realized through a three-step sequence involving reduction of the ketone moiety, bishomoallylic alcohol-directed epoxidation and Dess-Martin oxidation leading to the epoxy ketone as a single diastereoisomer. The epoxy ketone was efficiently converted to a trans-hydrindane unit, which constitutes an excellent precursor for the preparation of steroids and their seco-B analogues such as vitamin D₃ and its metabolites.

desymmetrization - directed epoxidation - trans-hydrindane - steroids - vitamin D₃

References and Notes

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First, we considered a ketone-directed epoxidation of 5. Various attempts performed with meta-chloroperbenzoic acid at r.t. led to a 50:50 mixture of two monoepoxide diastereoisomers, resulting from a total lack of facial selectivity.

<A NAME="RG36105ST-9">9</A>

To a stirred solution of VO(acac)₂ (95 mg, 0.36 mmol) in dry CH₂Cl₂ (15 mL) was added dropwise a solution of (±)-7 (640 mg, 3.56 mmol) in dry CH₂Cl₂ (15 mL) under argon at r.t. After 15 min stirring was slowly added a 5 M tert-butyl-hydroperoxide/nonane solution (1.06 mL, 5.32 mmol) and the resulting solution was stirred 16 h at certain temperatures (15 °C and 25 °C). The reaction was monitored by TLC analysis. The yellow mixture was quenched with a sat. Na₂S₂O₃ solution (30 mL) and was stirred 30 min at r.t. The aqueous layer was extracted with CH₂Cl₂ (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO₄, filtered and concentrated under vacuum. The yellow oil obtained was purified by flash silica gel chromatography [(30-40) PE-EtOAc, 90:10] to provide a mixture [dr = 88:12 at T = 15 °C and 82:18 at T = 25 °C from chiral GC analysis] of two diastereoisomers (±)-11a and (±)-11b as a colorless oil (301 mg, 43%, corrected yield 63%) with a recovered amount of starting material (204 mg, 32%). R _f = 0.3 [(30-40) PE-EtOAc, 80:20). IR (NaCl; mixture of isomers): ν_max = 3459, 3074, 3048, 2973, 2873, 1735, 1637, 1473, 1449, 1415, 1402, 1379, 1259, 1063, 1001, 919, 872 cm^-1. ¹H NMR for the major isomer (±)-11a (300 MHz, CDCl₃): δ = 0.92 (3 H, s), 1.15 (3 H, d, J = 6.5 Hz), 1.51-1.63 (2 H, m), 1.71-1.81 (2 H, m), 2.34-2.43 (1 H, m), 2.56 (1 H, dd, J = 4.5, 3.0 Hz), 2.84-2.90 (2 H, m), 2.94 (1 H, br s), 3.54 (1 H, q, J = 6.5 Hz), 4.95-5.01 (2 H, m), 5.77 (1 H, dt, J = 18.0, 9.0 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 10.4, 18.4, 25.8, 29.8, 48.7, 51.5, 51.9, 52.2, 52.7, 75.1, 115.5, 139.7. MS (FAB+): m/z 197 [M + H]⁺. Representative signals for the minor isomer (±)-11b: ¹H NMR (300 MHz, CDCl₃): δ = 0.99 (3 H, s), 1.14 (3 H, d, J = 6.5 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 13.1, 17.9, 24.7, 28.3, 46.5, 48.8, 50.7, 51.8, 52.6, 72.6, 115.8, 139.0.

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CCDC reference number: CCDC 272821.

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Compound (±)-10 was recrystallized from hexane. Mp 67-68 °C; R _f = 0.3 [ (30-40) PE-EtOAc, 70:30). IR (NaCl): ν_max = 3447, 3055, 2961, 2879, 1703, 1265, 738, 704 cm^-1. ¹H NMR (300 MHz, CDCl₃) δ = 1.17 (3 H, s), 1.57-1.97 (6 H, m), 2.03 (1 H, br s), 2.09 (1 H, ddd, J = 14.0, 5.5, 2.5 Hz), 2.16 (1 H, ddt, J = 14.5, 6.5, 2.5 Hz), 2.67 (1 H, ddd, J = 14.5, 8.5, 6.0 Hz), 2.94 (1 H, td, J = 14.5, 6.5 Hz), 4.17 (1 H, br s), 5.04 (1 H, dt, J = 11.0, 2.0 Hz), 5.05 (1 H, dt, J = 16.5, 2.0 Hz), 5.93 (1 H, ddd, J = 16.5, 11.0, 6.0 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 14.8, 21.9, 24.1, 34.4, 35.7, 46.6, 53.7, 56.0, 67.2, 115.3, 138.8, 215.5. MS (FAB+): m/z = 195 [M + H]⁺. CCDC reference number: CCDC 272822.