Synthesis of (3S)-Hydroxyandrosta-5,7-diene-17-ones via Intramolecular Cobalt-Mediated [2+2+2] Cycloaddition [1]

Abstract

A new method for the synthesis of lumisterin-type steroids following the DÆABCD approach is reported. A key step is the cobalt-induced cyclization of a cyclopentanoid enediyne, which was prepared via thioalkylation of the zinc enolate of a 2,3-substituted cyclopentanone with α-chlorosulfides.

Key words

cobalt - cycloaddition - cyclopentanones - steroids - vitamins

References and Notes

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Cobalt-mediated [2+2+2] cycloaddition: A solution of enediyne 14 (200 mg, 0.54 mmol) in toluene (80 mL) was cooled to -70 °C and the apparatus was evacuated for 3 min (0.5 Torr). The flask was allowed to warm to r.t. and the apparatus was filled with argon. The solution of enediyne in toluene was cooled to -70 °C and the above procedure was repeated twice. CpCo(CO)₂ (117 mg, 0.65 mmol) was added and the reaction mixture was refluxed under radiation with visible light until no starting material could be detected by TLC analysis. The reaction mixture was cooled to r.t. and volatile components were removed in vacuo (20 °C/0.1 Torr). The residue was dissolved in degassed Et₂O-pentane (1:4, 10 mL) and filtered through celite under an argon atmosphere. FeCl₃·H₂O (0.49 g, 1.8 mmol) was dissolved in MeCN (20 mL), pentane (20 mL) was added and the mixture cooled to -20 °C. At this temperature the filtrate was added under stirring, and stirring was continued for 30 min. The reaction mixture was cooled to -60 °C and the pentane layer was removed from the frozen MeCN layer. The MeCN layer was allowed to warm to -20 °C, pentane (15 mL) was added, and the above procedure was repeated four times. The pentane layers were combined, the solvent was removed in vacuo (30 °C/18 Torr), and the residue purified by chromatography on silica gel (Et₂O-pentane, 1:1) to afford steroids 15 (66.65 mg, 0.18 mmol, 33%).
Compound 15a/15′a (signals of the major diastereomeric pair): R _f = 0.27 (Et₂O-PE, 1:1). ¹H NMR (250 MHz, CDCl₃): δ = 0.76 and 0.84 (2 s, 6 H, 2 × CH₃), 1.20-2.80 (m, 16 H, CH₂, CH), 3.40 (s, 3 H, OCH₃), 3.50-3.64 and 3.66-3.79 (2 × m, 5 H, OCH₂CH₂O, OCH), 4.78 (dd, J = 6 Hz, 6 Hz, 2 H, OCH₂O), 5.47-5.68 (m, 2 H, C=CHC=CH). ¹³C NMR (50.3 MHz, CDCl₃): δ = 13.66 and 13.81 (C-18), 18.05, 18.38, 20.20, 20.23, 26.17, 28.80, 29.06, 33.96, 35.78, 35.85, 35.93, 36.12, 37.08, 38.03, and 38.28 (C-1, C-2, C-4, C-10, C-11, C-12, C-15, C-16), 20.30 (C-19), 46.27 and 46.58 (C-9), 46.77 (C-13), 59.04 (C-23), 66.78 and 71.79 (C-21, C-22), 70.74 and 75.81 (C-3), 93.35 and 93.73 (C-20), 116.50, 116.57, 119.66 and 119.99 (C-6, C-7), 137.46, 137.94, 140.82 and 142.15 (C-5, C-8), 220.97 and 221.15 (C-17). MS (70 eV): m/z (%) = 374 (2) [M⁺], 268 (100) [M - C₄H₁₀O₃]⁺, 89 (35) [C₄H₁₀O₃ ⁺], 59 (60) [C₃H₇O⁺]. HRMS: m/z calcd C₂₃H₃₄O₄ for 374.2457; found: 374. 2459.

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Purchased from Aldrich.