Synthesis of Some Novel D-Dihomo-aza- and D-Dihomo-oxa-steroid Derivatives in the Estrone Series

Éva Frank; Gyula Schneider; Josef Messinger; Hubert Thole; János Wölfling

doi:10.1055/s-2005-918940

LETTER

Synthesis of Some Novel D-Dihomo-aza- and D-Dihomo-oxa-steroid Derivatives in the Estrone Series

Éva Frank^a, Gyula Schneider^a, Josef Messinger^b, Hubert Thole^b, János Wölfling*^a
^a Department of Organic Chemistry, University of Szeged, Dóm tér 8., 6720 Szeged, Hungary
Fax: +36(62)544200; e-Mail: wolfling@chem.u-szeged.hu;
^b Solvay Pharmaceuticals Research Laboratories, Hans-Boeckler-Allee 20, 30173 Hannover, Germany

Abstract

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Abstract

New heteroestrone derivatives with a seven-membered ring D were efficiently synthesized from unsaturated carboxylic estrone-secoaldehyde 1 via multistep reactions.

Key words

Michael addition - condensation - cyclization - lactams - D-dihomoestrone derivatives

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Referenzen

References

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Compound 19 (C₂₇H₄₄N₂O₃): colorless oil; R _f = 0.26 (MeOH). ¹H NMR (500 MHz, MeOD): δ = 0.96 (t, 3 H, J = 7.4 Hz) and 1.00 [t, 3 H, J = 7.4 Hz, 2 × propyl-CH₃], 1.07 (s, 3 H, 18-H₃), 2.80 (m, 2 H, 6-H₂), 3.72 (s, 3 H, 3-OMe), 6.57 (d, 1 H, J = 2.5 Hz, 4-H), 6.66 (dd, 1 H, J = 8.6 Hz, J = 2.5 Hz, 2-H), 7.15 (d, 1 H, J = 8.6 Hz, 1-H). ¹³C NMR (125 MHz, MeOD): δ = 11.7 and 12.1 (2 × propyl-CH₃), 16.9 (C-18), 21.2, 23.6, 28.3, 28.7, 31.3, 34.0, 36.6 (C-16), 39.0, 44.1, 44.9, 46.3, 48.9 (C-13), 50.6 (N-CH₂), 51.9 (N-CH₂), 54.0 (N-CH₂), 55.7 (3-OMe), 55.8 (N-CH₂), 112.9 (C-2), 114.4 (C-4), 127.8 (C-1), 133.6 (C-10), 138.7 (C-5), 159.0 (C-3), 187.4 (C-17).

Compound 24 (C₂₄H₃₃NO₂): colorless crystals, mp 178-180 °C. R _f = 0.57 (MeOH). ¹H NMR (500 MHz, DMSO-d ₆): δ = 0.91 (t, 3 H, J = 7.4 Hz, propyl-CH₃), 1.07 (s, 3 H, 18-H₃), 2.71 (m, 2 H, 6-H₂), 3.50 (m, 2 H, 16a′-H₂), 3.68 (s, 3 H, 3-OMe), 5.24 (s, 1 H) and 5.26 (s, 1 H): 16a-H₂, 6.58 (d, 1 H, J = 2.5 Hz, 4-H), 6.66 (dd, 1 H, J = 7.6 Hz, J = 2.5 Hz, 4-H), 7.15 (d, 1 H, J = 7.6 Hz, 1-H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 11.0 (propyl-CH₃), 15.0 (C-18), 18.6, 25.6, 27.0, 29.8, 35.9, 36.3, 41.4, 42.4, 42.5, 46.5 (C-13), 48.0 and 50.8 (propyl N-CH₂ and C-16a′), 54.8 (3-OMe), 111.6 (C-2), 113.0 (C-4), 115.8 (C-16a), 126.3 (C-1), 131.7 (C-10), 137.3 (C-5), 140.4 (C-16), 157.0 (C-3), 179.4 (C-17).

Compound 28 (C₂₇H₄₂N₂O₂): colorless oil; R _f = 0.24 (MeOH-CH₂Cl₂ = 5:95). ¹H NMR (500 MHz, DMSO-d ₆): δ = 0.81 (t, 3 H, J = 7.4 Hz) and 0.87 (t, 3 H, J = 7.4 Hz, 2 × propyl-CH₃), 1.13 (s, 3 H, 18-H₃), 2.74 (m, 2 H, 6-H₂), 3.67 (s, 3 H, 3-OMe), 6.60 (d, 1 H, J = 2.5 Hz, 4-H), 6.67 (dd, 1 H, J = 8.6 Hz, J = 2.5 Hz, 2-H), 7.16 (d, 1 H, J = 8.6 Hz, 1-H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 11.2 and 11.5 (2 × propyl-CH₃), 15.8 (C-18), 20.4, 21.6, 25.4, 27.2, 29.6, 33.5, 37.5, 39.8, 41.2, 42.1, 43.7, 45.1 (C-13), 50.7, 50.9, 52.3 and 52.9 (2 × propyl N-CH₂, C-16a and C-16a′), 54.8 (3-OMe), 111.4 (C-2), 112.7 (C-4), 125.8 (C-1), 132.6 (C-10), 137.4 (C-5), 157.1 (C-3), 177.2 (C-17).

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Compound 37 (C₂₁H₂₆O₃): colorless crystals, mp 135-137 °C. R _f = 0.39 (CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 1.20 (s, 3 H, 18-H₃), 2.86 (m, 2 H, 6-H₂), 3.77 (s, 3 H, 3-OMe), 4.56 (d, 1 H, J = 10.9 Hz) and 4.69 (d, 1 H, J = 10.9 Hz): 16a′-H₂, 5.20 (s, 1 H) and 5.25 (s, 1 H): 16a-H₂, 6.63 (d, 1 H, J = 2.3 Hz, 4-H), 6.72 (dd, 1 H, J = 8.6 Hz, J = 2.3 Hz, 2-H), 7.19 (d, 1 H, J = 8.6 Hz, 1-H). ¹³C NMR (125 MHz, CDCl₃): δ = 15.6 (C-18), 26.1, 26.5, 29.9, 37.0, 38.8, 40.2, 42.3, 43.3, 47.8 (C-13), 55.1 (3-OMe), 72.2 (C-16a′), 111.6 (C-2), 113.3 (C-4), 120.2 (C-16a), 126.2 (C-1), 131.9 (C-10), 137.4 (C-5), 141.8 (C-16), 157.6 (C-3), 181.2 (C-17).

Compound 38 (C₂₁H₂₆O₃): colorless crystals, mp 190-192 °C. R _f = 0.45 (CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 1.22 (s, 3 H, 18-H₃), 1.82 (s, 3 H, 16a-H₃), 2.83 (m, 2 H, 6-H₂), 3.78 (s, 3 H, 3-OMe), 4.80 (d, 1 H, J = 10.8 Hz, 15-H), 5.16 (s, 1 H) and 5.26 (s, 1 H): 16a′-H₂, 6.61 (d, 1 H, J = 2.5 Hz, 4-H), 6.72 (dd, 1 H, J = 8.7 Hz, J = 2.5 Hz, 4-H), 7.18 (d, 1 H, J = 8.7 Hz, 1-H). ¹³C NMR (125 MHz, CDCl₃): δ = 15.2 (C-18), 16.5 (C-16a), 25.5, 26.0, 29.3, 31.9, 36.5, 43.0 (C-13), 43.7, 51.4, 55.2 (3-OMe), 85.5 (C-15), 111.7 (C-2), 113.8 (C-4), 118.7 (C-16a′), 126.3 (C-1), 131.0 (C-10), 137.2 (C-5), 141.7 (C-16), 157.7 (C-3), 180.1 (C-17). The compounds give correct elemental analyses.