A Convergent Approach to the Forskolin Skeleton

Abstract

A convergent approach to the forskolin skeleton is described. Assembly of a simplified tricyclic framework is achieved in a single step via the dihydropyrone Diels–Alder reaction. Selective manipulation of the resulting cycloadduct, in conjunction with an unusual equilibration of the C8 stereocenter, provides access to scaffolds that differ in relative stereochemistry at both the A/B and B/C ring junctions.

Key words

Diels–Alder reaction - fused ring systems - regioselectivity - diastereoselective synthesis - equilibration - forskolin - natural product analogues

Publication History

Received: 06 March 2024

Accepted after revision: 23 April 2024

Article published online:
06 May 2024

• References and Notes

• 1 Bhat SV, Bajwa BS, Dornauer H, de Souze NJ, Fehlhaber H.-W. Tetrahedron Lett. 1977; 1669
• 2a Seamon KB, Padgett W, Daly JW. Proc. Natl. Acad. Sci. U.S.A. 1981; 78: 3363
• 2b Insel PA, Ostrom RS. Cell. Mol. Neurobiol. 2003; 23: 305
• 2c Alasbahi RH, Melzig MF. Pharmazie 2012; 67: 5
• 3 Bhat SV, Dohndwalla AN, Bajwa BS, Dadkar NK, Dornauer H, de Souza NJ. J. Med. Chem. 1983; 26: 486
• 4a Lichey J, Friedrich T, Priesnitz M, Biamo G, Usinger P, Huckauf H. Lancet 1984; 324: 167
• 4b Kreuter W, Chapman RW, Gulbenkian A, Tozzi S. Eur. J. Pharm. 1985; 111: 1
• 5a Owana BA, Zug C, Schluesener H, Zhang Z.-Y. J. Neuropathol. Exp. Neurol. 2016; 75: 618
• 5b Ivanova MA, Sitnikova LS, Karelina TV. Neurosci. Behav. Physiol. 2019; 49: 1096
• 6a Sapio L, Gallo M, Illiano M, Chiosi E, Naviglio D, Spina A, Naviglio S. J. Cell. Physiol. 2016; 232: 922
• 6b Salzillo A, Ragone A, Spina A, Naviglio S, Sapio L. Eur. J. Cell Biol. 2023; 102: 151292
• 7 Pullaiah T. Forskolin: Natural Sources, Pharmacology and Biotechnology. Springer; Singapore: 2022
• 8a Ziegler FE, Jaynes BH, Saindane MT. J. Am. Chem. Soc. 1987; 109: 8115
• 8b Hashimoto S, Sakata S, Sonegawa M, Ikegami S. J. Am. Chem. Soc. 1988; 110: 3670
• 8c Corey EJ, da Silva Jardine P, Rohloff JC. J. Am. Chem. Soc. 1988; 110: 3672
• 9a Delpech B, Calvo D, Lett R. Tetrahedron Lett. 1996; 37: 1015
• 9b Delpech B, Calvo D, Lett R. Tetrahedron Lett. 1996; 37: 1019
• 9c Calvo D, Port M, Delpech B, Lett R. Tetrahedron Lett. 1996; 37: 1023
• 10a Hylse O, Maier L, Kučera R, Perečko T, Svobodová A, Kubala L, Paruch K, Švenda J. Angew. Chem. Int. Ed. 2017; 56: 12586
• 10b Thomas WP, Schatz DJ, George DT, Pronin SV. J. Am. Chem. Soc. 2019; 141: 12246
• 11a Hagiwara H, Takeuchi F, Kudou M, Hoshi T, Suzuki T, Hashimoto T, Asakawa Y. J. Org. Chem. 2006; 71: 4619
• 11b Hagiwara H, Tsukagoshi M, Hoshi T, Suzuki T, Hashimoto T, Asakawa Y. Synlett 2008; 929
• 12a Chen D, Wang J, Totah NI. J. Org. Chem. 1999; 64: 1776
• 12b Seth PP, Totah NI. J. Org. Chem. 1999; 64: 8750
• 12c Seth PP, Totah NI. Org. Lett. 2000; 2: 2507
• 13 Ireland RE, Thompson WJ. J. Org. Chem. 1979; 44: 3583
• 14 Totah NI, Chen D. Tetrahedron Lett. 1998; 39: 213
• 15 CCDC 2336906 and 2336894 contain the supplementary crystallographic data for compounds 18 and 41, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 16 Sharpless KB, Young MW, Lauer RF. Tetrahedron Lett. 1973; 1979
• 17a Reich HJ, Renga JM, Reich IL. J. Org. Chem. 1974; 39: 2133
• 17b Reich HJ, Renga JM, Reich IL. J. Am. Chem. Soc. 1975; 97: 5434
• 18 Approach of the electrophile occurs from the convex face of the intermediate silyl enol ether to give the alpha (axial) silyl ether at C7 (cf. Scheme 4). Under Rubottom conditions, isomerization occurs to give the corresponding beta (equatorial) silyl ether (not shown).
• 19 Oxidation of a secondary, propargylic alcohol to the corresponding ketone with Martin sulfurane has been reported: Wensley AM, Hardy AO, Gonsalves KM, Koviach JL. Tetrahedron Lett. 2007; 48: 2431
• 20 Arhart RJ, Martin JC. J. Am. Chem. Soc. 1972; 94: 5003
• 21 Lu Y, Nguyen PL, Levaray N, Lebel H. J. Org. Chem. 2013; 78: 776
• 22 Johnson WS. J. Am. Chem. Soc. 1953; 75: 1498
• 23 Diels–Alder Adduct 12 A solution of KHMDS (35 mL of an 0.5 M solution in toluene, 17.5 mmol) in 20 mL THF was cooled to –78 °C. Acetyl cyclohexene (2.00 g, 16.0 mmol) in 20 mL THF was added dropwise via cannula, and the resulting mixture was allowed to warm slowly to –30 °C, then cooled back to –78 °C. TBSCl (4.82 g, 32.0 mmol) in 20 mL THF was then added dropwise. After 1 h, the mixture was warmed slowly to room temperature and stirred for an additional hour. Anhydrous diethyl ether (150 mL) was added, and the resulting mixture was filtered through a bed of Celite. The filtrate was concentrated in vacuo to give the diene 10 as a colorless oil that was used without further purification. ¹H NMR (400 MHz, CDCl₃): δ = 6.26 (1 H, m), 4.34 (1 H, s), 4.18 (1 H, s), 2.14 (4 H, m), 1.67 (2 H, m), 1.58 (2 H, m), 0.98 (9 H, s), 0.18 (6 H, s). A solution of the crude diene 10 (16.0 mmol) and dihydropyrone 11 (4.75 g, 24.0 mmol) in 60 mL CH₂Cl₂ was cooled to 0 °C. A freshly prepared solution of zinc chloride (2.20 g, 16.0 mmol in 20 mL THF) was then added dropwise. The resulting mixture was warmed slowly to room temperature and stirred for 10 h, then quenched with saturated aqueous NaHCO₃ and extracted with CH₂Cl₂ (3×). The combined organics were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO₂, hexanes:EtOAc, 20:1) to afford the Diels–Alder adduct 12 as a pale yellow oil (5.91 g, 85%). ¹H NMR (CDCl₃, 300 MHz): δ = 4.72 (1 H, d, J = 5.3 Hz), 4.17 (2 H, m), 3.00 (1 H, m), 2.92 (1 H, m), 2.57 (1 H, d, J = 17.5 Hz), 2.39 (1 H, d, J = 17.5 Hz), 2.36 (1 H, m), 2.22 (1 H, d, J = 18.1 Hz), 1.82 (1 H, m), 1.72 (1 H, m), 1.58 (3 H, m), 1.37 (3 H, s), 1.34 (2 H, m), 1.32 (3 H, s), 1.25 (3 H, t, J = 7.1 Hz), 0.92 (9 H, s), 0.10 (3 H, s), 0.07 (3 H, s). ¹³C NMR (CDCl₃, 75 MHz): δ = 207.2, 170.0, 136.2, 116.8, 73.1, 69.1, 62.8, 61.6, 51.1, 40.7, 33.3, 33.1, 31.0, 27.8, 27.6, 27.1, 26.9, 25.8, 18.2, 14.0, -4.1. IR (neat): 2931, 2857, 1746, 1707, 1668, 1253, 1191, 1071, 1030 cm^–1. HRMS (ESI): m/z calcd for C₂₄H₄₀O₅Si [M + Na]⁺: 459.2537; found: 459.2517.