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

Publikationsverlauf

Eingereicht: 25. Februar 2021

Angenommen nach Revision: 12. April 2021

Accepted Manuscript online:
12. April 2021

Artikel online veröffentlicht:
29. April 2021

• References and Notes

• 1a Witzman RF. Steroids. Keys to Life . Van Nostrand Reinhold; New York: 1981
• 1b Lednicer D. Steroid Chemistry at a Glance . John Wiley & Sons; Hoboken: 2011
• 2a Fieser L, Fieser M. Steroids 1959
• 2b Woodward RB, Sondheimer F, Taub D, Heusler K, McLamore WM. J. Am. Chem. Soc. 1952; 74: 4223
• 2c Barton DH. R. J. Chem. Soc. 1953; 1027
• 2d Barton DH. R. Science 1970; 169: 539
• 2e Eder U, Sauer G, Wiechert R. Angew. Chem., Int. Ed. Engl. 1971; 10: 496
• 2f Yoder RA, Johnston JN. Chem. Rev. 2005; 105: 4730

See, for instance:
• 3a Duecker FL, Heinze RC, Heretsch P. J. Am. Chem. Soc. 2020; 142: 104

For recent reviews, see:
• 3b Duecker FL, Reuß F, Heretsch P. Org. Biomol. Chem. 2019; 17: 1624
• 3c Mousavizadeh F, Meyer D, Gianni A. Synthesis 2018; 50: 1587
• 3d Indu S, Kaliappan KP. Org. Biomol. Chem. 2020; 18: 3965
• 4 Amagata T, Amagata A, Tenney K, Valeriote FA, Lobkovsky E, Clardy J, Crews P. Org. Lett. 2003; 5: 4393
• 5a El Sheikh S, Meier zu Greffen A, Lex J, Neudörfl J.-M, Schmalz H.-G. Synlett 2007; 1881
• 5b Plummer CW, Wei CS, Yozwiak CE, Soheili A, Smithback SO, Leighton JL. J. Am. Chem. Soc. 2014; 136: 9878
• 6a Liu J, Wu J, Fan JH, Yan X, Mei G, Li C.-C. J. Am. Chem. Soc. 2018; 140: 5365
• 6b Wang Y, Ju W, Tian H, Tian W, Gui J. J. Am. Chem. Soc. 2018; 140: 9413
• 7a Taspinar Ö, Wilczek T, Erver J, Breugst M, Neudörfl J.-M, Schmalz H.-G. Chem. Eur. J. 2020; 26: 4256
• 7b Kranz DP, Chiha S, Meier zu Greffen A, Neudörfl JM, Schmalz HG. Org. Lett. 2012; 14: 3692
• 8 Wang W, Lee TG, Patil RS, Mun B, Yang I, Kim H, Hahn D, Won DH, Lee J, Lee Y, Choi H, Nam S.-J, Kang H. J. Nat. Prod. 2015; 78: 368
• 9 A related structure was proposed for a weakly characterized byproduct of a radical transformation of a 4β,5β-epoxysteroid. See: Barton DH. R, Motherwell RS. H, Motherwell WB. J. J. Chem. Soc., Perkin Trans. 1 1981; 2363
• 10a Criegee R. Ber. Dtsch. Chem. Ges. B 1931; 64: 260
• 10b Criegee R, Marchand B, Wannowius H. Justus Liebigs Ann. Chem. 1942; 550: 99
• 11 Duecker FJ, Heinze RC, Müller M, Zhang S, Heretsch P. Org. Lett. 2020; 22: 1585
• 12 Kirihara M, Osugi R, Saito K, Adachi K, Yamazaki K, Matsushima R, Kimura Y. J. Org. Chem. 2019; 84: 8330

For early reports on the oxidative cleavage of the Δ⁵,⁶-double bond of ergosterol, see:
• 13a Heilbron IM. A. L, Morrison Simpson JC. E. J. Chem. Soc. 1933; 302
• 13b Huang-Minlon, Chem. Ber. 1939; 72: 854
• 13c For the first configurational assignment of an intermediate (related to cis- 5) see ref. 10b.
• 14 Michaud DP, Nashed NT, Jerina DM. J. Org. Chem. 1985; 50: 1835
• 15 Goldstein AS. J. Med. Chem. 1996; 39: 5092
• 16a Madaio A, Notaro G, Piccialli V, Sica D. J. Nat. Prod. 1990; 53: 565
• 16b Madaio A, Piccialli V, Sica D. Tetrahedron Lett. 1988; 29: 5999
• 17 According to ref. 16, compounds related to (Z)-4 can be converted into the more stable (E)-isomer by exposing a CHCl₃ solution to light, but not vice versa.
• 18 For a review, see: Mukherjee S, Yang JW, Hoffmann S, List B. Chem. Rev. 2007; 107: 5471
• 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