A Concise Synthesis of 24,25-Dihydro-6-epi-Monanchosterol A

Abstract

We report the first synthetic entry to a steroid with an unusual bicyclo[4.3.1]dec-3-en-10-one A/B ring substructure as a close structural analogue of the anti-inflammatory monanchosterols. Under optimized conditions, regioselective cis-dihydroxylation of the Δ⁵-double bond of 7-dehydrocholesterol and subsequent Criegee oxidation yields the corresponding 5,6-seco-steroid as a pure Z-isomer which upon treatment with K₂CO₃ in MeOH diastereoselectively affords 24,25-dihydro-6-epi-monanchosterol A through intramolecular aldol addition (cyclization). The developed three-step sequence proceeds in 17% overall yield without the need of any protecting group. The title compound was characterized by X-ray crystallography.

Key words

steroids - natural products - intramolecular aldol addition - olefin cis-dihydroxylation - oxidative glycol cleavage

Publication History

Received: 25 February 2021

Accepted after revision: 12 April 2021

Accepted Manuscript online:
12 April 2021

Article published online:
29 April 2021

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• 19 Detailed experimental procedures and characterization data are given in the Supporting Information. Synthesis of 24,25-Dihydro-6-epi-monanchosterol A (6-epi-3) Compound (Z)-4 (15 mg, 0.04 mmol, 1.0 equiv) was dissolved in methanol (8 mL) and K₂CO₃ (5 mg, 0.04 mmol, 1.0 equiv) was added. The mixture was stirred at ambient temperature for 20 h. After completion of the reaction (TLC), the solvent was removed, and the residue was purified by silica gel chromatography (c-Hex/EtOAc, 2:1 to 1:2) to give 24,25-dihydro-6-epi-monanchosterol A (11 mg, 0.03 mmol, 73%) as a white solid; mp 65–68 °C. ¹H NMR (500 MHz, CD₃OD): δ = 5.19 (s, 1 H, H-7), 4.47 (s, 1 H, H-6), 4.34 (d, 1 H, H-3), 2.94 (d, 1 H, H-4), 2.42–2.34 (m, 1 H, H-2α), 2.15 (ddd, 2 H, H-1, H-14), 2.04 (d, 1 H, H-9), 1.98–1.12 (m, 19 H), 1.09 (s, 3 H, H-19), 0.91 (d, 3 H, H-21), 0.88 (dd, 6 H, H-26, H-27), 0.47 (s, 3 H, H-18) ppm. ¹³C NMR (125 MHz, CD₃OD): δ = 215.5 (C-5), 142.1 (C-8), 123.2 (C-7), 70.1 (C-6), 69.5 (C-3), 65.3 (C-4), 61.2 (C-14), 59.8 (C-9), 57.9 (C-17), 50.7 (C-10), 49.1 (C-13), 42.4 (C-12), 40.7 (C-16), 37.7 (C-1), 37.5 (C-20), 37.2 (C-22), 29.6 (C-11), 29.2 (C-2), 29.2 (C-25), 28.0 (C-23), 25.0 (C-24), 24.6 (C-19), 23.2 (C-27), 23.0 (C-15), 22.9 (C-26), 19.1 (C-21), 12.5 (C-18) ppm. HRMS (ESI): m/z [M + Na]⁺ calcd: 439.31827; found: 439.31874.
• 20 CCDC 2065067 (6-epi-3) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures