Stereoselective Approach to some Novel 16-Methylated and 16-Halomethylated Tetrahydropyran and δ-Lactone Derivatives in both the Normal and the 13α-Estrone Series

Abstract

Intramolecular cyclizations of the 3-methyl ether of an unsaturated d-secoestrone alcohol and secoestrone carboxylic acid in both the normal and the 13α-estrone series are reported. The ring-closure reactions furnished substituted, new oxa-d-homoestrone derivatives stereoselectively.

cyclizations - etherification - esterification - diastereo­selectivity - estrone derivatives

References

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General Procedure for the Synthesis of 16-Methyl Tetrahyropyrans: Compound 3 or 4 (300 mg, 1.00 mmol) was dissolved in CH₂Cl₂ (5 mL) and BF₃·OEt₂ (48% solution in Et₂O, 0.47 mL, 1.5 mmol) was added drop wise during stirring of the mixture under reflux for 72 h. The solution was then diluted with water (10 mL) and extracted with CH₂Cl₂ (3 × 10 mL), and the combined organic phases were dried over Na₂SO₄. Evaporation in vacuo and purification by column chromatography (silica gel, CH₂Cl₂) afforded 5 (261 mg, 87%) or 9 (168 mg, 56%) and 10 (90 mg, 30%). 5: A colorless oil; R_f = 0.43 (CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 1.15 (s, 3 H, 18-H₃), 1.16 (d, 3 H, J = 6.8 Hz, 16a-H₃), 2.83 (m, 2 H, 6-H₂), 3.15 (d, 1 H, J = 11.3 Hz, one of 17-H₂), 3.54 (m, 1 H, 16α-H), 3.76 (s, 3 H, 3-OMe), 3.81 (d, 1 H, J = 11.3 Hz, the other17-H₂), 6.63 (d, 1 H, J = 2.3 Hz, 4-H), 6.70 (dd, 1 H, J = 8.6 Hz, J = 2.3 Hz, 2-H) and 7.18 (d, 1 H, J = 8.6 Hz, 1-H). ¹³C NMR (125 MHz, CDCl₃): δ = 22.1 (C-16a), 26.8, 27.3, 27.8 (C-18), 30.2, 30.7, 32.6 (C-13), 37.0, 37.6, 43.0, 45.0, 55.2 (3-OMe), 68.1 (C-16), 71.6 (C-17), 111.6 (C-2), 113.4 (C-4), 126.4 (C-1), 132.8 (C-10), 138.1 (C-5) and 157.6 (C-3). MS (EI): m/z (relative intensity) = 300 (M⁺, 100). - C₂₀H₂₈O₂. 9: Mp 99-101 °C.
R_f = 0.47 (CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 0.98 (s, 3 H, 18-H₃), 1.22 (d, 3 H, J = 6.0 Hz, 16a-H₃), 2.84 (m, 2 H, 6-H₂), 3.22 (d, 1 H, J = 10.6 Hz, one 17-H₂), 3.46 (m, 1 H, 16α-H), 3.47 (d, 1 H, J = 10.6 Hz, the other 17-H₂), 3.78 (s, 3 H, 3-OMe), 6.62 (d, 1 H, J = 2.4 Hz, 4-H), 6.72 (dd, 1 H, J = 8.6 Hz, J = 2.4 Hz, 2-H) and 7.21 (d, 1 H, J = 8.6 Hz, 1-H). ¹³C NMR (125 MHz, CDCl₃): δ = 16.7 (C-18), 22.1 (C-16a), 25.6 (C-11), 25.7 (C-7), 30.0 (C-6), 32.3, 34.0 (C-13), 35.4, 38.6 (C-8), 43.8 (C-9), 47.7 (C-14), 55.2 (3-OMe), 74.9 (C-16), 80.0 (C-17), 111.6 (C-2), 113.6 (C-4), 126.1 (C-1), 132.8 (C-10), 137.9 (C-5), 157.5 (C-3). IR (KBr): 1080, 1238, 1502, 1606, 2864, 2922, 2940 cm^-1. MS (EI): m/z (relative intensity) = 300 (M⁺, 100), 173(27). - C₂₀H₂₈O₂. 10: A colorless oil. R_f = 0.42 (CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 1.02 (s, 3 H, 18-H₃), 1.29 (d, 3 H, J = 6.9 Hz, 16a-H₃), 2.84 (m, 2 H, 6-H₂), 3.15 (d, 1 H, J = 11.0 Hz) and 3.40 (d, 1 H, J = 11.0 Hz, 17-H₂), 3.78 (s, 3 H, 3-OMe), 4.30 (m, 1 H, 16β-H), 6.63 (d, 1 H, J = 2.5 Hz, 4-H), 6.72 (dd, 1 H, J = 8.6 Hz, J = 2.5 Hz, 2-H) and 7.21 (d, 1 H, J = 8.6 Hz, 1-H). ¹³C NMR (125 MHz, CDCl₃): δ = 16.2 and 17.3
(C-16a and C-18), 25.6 (C-11), 25.8 (C-7), 28.6, 30.0, 34.5 (C-13), 35.8, 38.6 (C-8), 41.5 (C-9), 43.8 (C-14), 55.2 (3-OMe), 69.3 (C-16), 72.2 (C-17), 111.6 (C-2), 113.6 (C-4), 126.1 (C-1), 132.9 (C-10), 137.9 (C-5), 157.6 (C-3).
- C₂₀H₂₈O₂. The compounds give correct elemental analyses.

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