Stereoselective Synthesis of Condensed Aza-d-homo-estrone Derivatives by 1,3-Dipolar Cycloaddition

Abstract

The halogen-induced intramolecular formation of 13α- and 13β-estrone nitrones, followed by 1,3-dipolar cycloaddition reactions with N-phenylmaleimide (NPM) stereoselectively furnished halogen-containing condensed heterocyclic d-homosteroids.

Estrone - d-homosteroids - 1,3-dipolar cycloadditions - stereoselective synthesis - halogenation

References

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7

General Procedure for the Synthesis of 16-Bromomethyl Cycloadducts (7a, 8a).
Compound 3 or 4 (100 mg, ca. 0.33 mmol) was dissolved in CH₂Cl_2, and DDH (50 mg, ca. 0.17 mmol) or NBS (60 mg, 0.33 mmol) was added. The mixture was then stirred at r.t. for 0.5 h and the solvent was evaporated off. The crude product was dissolved in benzene (5 mL), NPM (58 mg, ca. 0.33 mmol) was added and the solution was stirred at 50 °C for 2 h. After evaporation of the solvent, purification by column chromatography with tert-butyl-methyl ether (30%)-hexane (70%) as eluent yielded 145 mg (81%) of 7a: mp 132-137 °C; R _f = 0.33 (CH₂Cl₂). ¹H NMR (CDCl₃): δ = 1.38 (s, 3 H, 18-H₃), 2.87 (m, 2 H, 6-H₂), 3.42 (dd, 1 H, J = 9.9 Hz, J = 8.0 Hz, 16a-H), 3.80 (dd, 1 H, J = 9.9 Hz, J = 2.2 Hz, 16a-H), 3.44 (d, 1 H, J = 8.0 Hz, 17a-H), 3.78 (s, 3 H, 3-OMe), 4.33 (t, 1 H, J = 8.0 Hz, 4′-H), 5.09 (d, 1 H, J = 8.0 Hz, 3′-H), 6.64 (d, 1 H, J = 2.4 Hz, 4-H), 6.73 (dd, 1 H, J = 8.6 Hz, J = 2.4 Hz, 2-H), 7.23-7.26 and 7.46 (overlapping multiplets, 5 H, 1-, 2′′-, 3′′-, 5′′-, 6′′-H), 7.40 (t, 1 H, J = 7.3 Hz, 4′′-H) ppm. ¹³C NMR (CDCl₃): δ = 26.4, 27.4, 27.7, 29.8, 34.3 (C-18), 34.9, 36.4, 36.6, 38.3, 42.0, 45.0, 50.3, 55.2, 55.6, 74.6 (C-17a), 77.3 (C-3′), 111.9 (C-2), 113.4 (C-4), 126.4 and 129.2 (2 × 2 C, C-2′′, -3′′, -5′′, -6′′), 126.7 (C-1), 129.0 (C-4′′), 131.1 and 132.3 (2 ¥ l C, C-1′′ and C-10), 137.6 (C-5), 157.8 (C-3), 170.8 and 173.6 (2 ¥ l C, C-2′ and C-5′) ppm. Compound 8a was purified by chromatography with CH₂Cl₂ as eluent, yielding 120 mg (67%) of the pure product: mp 155-158 °C; R _f = 0.25 (CH₂Cl₂). ¹H NMR (CDCl₃): δ = 1.22 (s, 3 H, 18-H₃), 2.78 (m, 1 H, 4′-H), 2.88 (m, 2 H, 6-H₂), 3.52 (dd, 1 H, J = 10.1 Hz, J = 7.3 Hz, 16a-H), 3.74 (m, 1 H, 16a-H), 3.54 (d, 1 H, J = 9.2 Hz, 17a-H), 3.77 (s, 3 H, 3-OMe), 5.20 (d, 1 H, J = 8.0 Hz, 3′-H), 6.64 (d, 1 H, J = 2.2 Hz, 4-H), 6.72 (dd, 1 H, J = 8.6 Hz, J = 2.2 Hz, 2-H), 7.20 (d, 1 H, J = 8.6 Hz, 1-H), 7.29 (d, 2 H, J = 7.8 Hz, 2′′-, 6′′-H), 7.41 (t, 1 H, J = 7.8 Hz, 4′′-H), 7.48 (t, 2 H, J = 7.8 Hz, 3′′-, 5′′-H). ¹³C NMR (CDCl₃): δ = 21.3 (C-18), 25.3, 26.5, 28.2, 29.8, 35.4, 37.2, 37.4, 38.4, 41.1, 43.2, 48.5 (C-4′), 55.2 (3-OCH₃), 61.2 (C-16), 77.3 (C-17a), 77.9 (C-3′), 111.7 (C-2), 113.5 (C-4), 126.2 and 128.9 (2 × 1 C, C-1 and C-4′′), 126.3 and 129.2 (2 × 2 C, C-2′′, -3′′, -5′′, -6′′), 131.1 and 131.9 (2 ¥ l C, C-1′′ and C-10), 137.5 (C-5), 157.6 (C-3), 170.9 and 173.2
(2 ¥ l C, C-2′and -5′).