First Total Synthesis of N-Oxido-3-aza-1,3,5(10)-trieno Steroids

Abstract

An efficient synthesis of 3-aza-steroids bearing a pyridine as an A ring was achieved via intramolecular cycloaddition of orthoquinodimethanes, which were generated from a 3-azabicy­clo[4.2.0]octa-1,3,5-trien-7-one ketal.

Key words

aza-steroid - pyridine - intramolecular Diels-Alder reaction - Wacker oxidation

References

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22

The crystallographic data (CCDC 272301) can be obtained free of charge from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; e-mail: [e-mail].

27

All compounds showed satisfactory spectroscopic data as well as microanalytical data. Diastereomeric ratios were established from the ¹H NMR spectrum of the crude product.
Experimental procedure for the preparation of 11: A solution of 10 (0.75 g, 2.53 mmol) in 1,2,4-trichlorobenzene (50 mL) was stirred under argon at 200 °C for 24 h. After cooling, the solvent was removed under reduced pressure (0.2 Torr). The resulting oil was purified by flash chromatography on silica gel (EtOAc-Et₂O, 2:8 to 5:5) to afford compounds 11a (0.336 g; 41%), 11b (0.232 g; 29%), and 11c (0.12 g; 15%) in 85% overall yield.
11a: White solid; mp 146-147 °C. IR (film): 3083, 2932, 1773, 1610 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.30 (d, J = 11.9 Hz, 1 H), 1.52 (m, 3 H), 1.92 (m, 3 H), 2.14 (m, 3 H), 2.73 (d, J = 3.8 Hz, 1 H), 2.76 (m, 1 H), 2.84 (dt, J = 8.5 Hz, J = 12.4 Hz, 1 H), 3.23 (m, 1 H), 3.34 (m, 1 H), 4.98 (m, 2 H), 5.42 (m, 1 H), 7.06 (d, J = 5.3 Hz, 1 H), 8.35 (m, 2 H). ¹³C NMR (250 MHz, CDCl₃): δ = 21.6, 23.8, 27.5; 28.9, 34.2, 35.1, 37.0, 43.2, 44.8, 49.1, 96.7, 116.6, 121.3, 132.7, 137.2, 144.1, 147.5, 151.0, 177.2. Anal. Calcd for C₁₉H₂₁NO₂: C, 77.26; H, 7.17. Found: C, 77.48; H, 7.26.
11b: Oil. IR (film): 2930, 2880, 1762, 1550 cm^-1. ¹H NMR (500 MHz, CDCl₃) : δ = 1.49 (m, 1 H), 1.62 (m, 1 H), 1.64 (m, 1 H), 1.69 (m, 1 H), 1.71 (m, 1 H), 1.80 (d, J = 11.8 Hz, 1 H), 2.03 (m, 1 H), 2.12 (m, 1 H), 2.26 (m, 1 H), 2.52 (dd, J = 5.4, 11.8 Hz, 1 H), 2.65 (d, J = 10.5 Hz, 1 H), 2.89 (m, 1 H), 3.44 (d, J = 5.4 Hz, 1 H), 5.11 (d, J = 9.5 Hz, 1 H), 5.14 (d, J = 17.0 Hz, 1 H), 5.64 (dt, J = 9.9, 17.2 Hz, 1 H), 7.32 (d, J = 5.0 Hz, 1 H), 8.34 (s, 1 H), 8.39 (d, J = 5.0 Hz, 1 H). ¹³C NMR (250 MHz, CDCl₃): δ = 25.8, 27.0, 27.1, 29.5, 38.9, 40.4, 41.7, 43.8, 49.1, 49.4, 96.3, 116.7, 119.8, 132.0, 137.2, 144.4, 147.1, 150.4, 175.5. HRMS (EI): m/z calcd for C₁₉H₂₁NO₂ [M⁺]: 295.1572; found: 295.1571.
11c: Oil. IR (film): 2928, 1771, 1609 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.09 (qd, J = 5.7, 12.2 Hz, 1 H), 1.49 (qd, J = 2.7, 11.1 Hz, 1 H), 1.59 (m, 1 H), 1.91 (m, 2 H), 2.01 (d, J = 12.2 Hz, 1 H), 2.07 (dd, J = 4.2, 12.2 Hz, 1 H), 2.08 (m, 1 H), 2.12 (qd, J = 5.4, 11.9 Hz, 1 H), 2.12 (m, 1 H), 2.45 (td, J = 7.6, 11.3 Hz, 1 H), 2.90 (m, 1 H), 5.09 (m, 1 H), 5.88 (m, 1 H), 7.18 (d, J = 5.1 Hz, 1 H), 8.32 (s, 1 H), 8.37 (d, J = 5.1 Hz, 1 H). ¹³C NMR (250 MHz, CDCl₃): δ = 25.7, 26.7, 29.8, 31.6, 32.9, 39.5, 39.8, 41.0, 51.4, 51.9, 94.3, 116.7, 119.0, 132.4, 135.4, 147.2, 147.5, 150.3, 179.7. HRMS (EI): m/z calcd for C₁₉H₂₁NO₂ [M⁺]: 295.1572; found: 295.1569.