Synthesis of Panal Terpenoid Core

Abstract

Panal is a natural bicyclic cadalane-type sesquiterpenoid with an unusual combination of stereocenters. It was isolated in 1988 as an alleged biosynthetic precursor of luciferin (a light-emitting molecule) in a bioluminescent fungus Panellus stipticus. Herein we present the first approach to the synthesis of the terpenoid skeleton of panal, which includes construction of five stereocenters, one of which is easily epimerizable. The key steps in the synthetic approach presented are high-pressure Diels–Alder reaction disobeying the ‘endo rule’, Barbier reductive allylation, and cyclization of trans-decalin ring via ring-closing metathesis.

Key words

panal - cadinane - cadalane - fungal bioluminescence - terpenoid

• References and Notes

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• 13 General Procedure for Silylation HMPA (300 mL) was mixed with THF (150 mL) under inert atmosphere. The mixture was cooled to –78 °C, and the solution of LiHMDS (1 M in THF, 60 mL, 60 mmol) was added. The solution of ketone (9.9 g, 50 mmol) in THF (75 mL) was added dropwise, and the mixture was stirred for 30 min. The solution of chlorosilane (55 mmol) in THF (35 mL) was added slowly, and the mixture was stirred for 1 h at –78 °C and gently warmed to the r.t. (1–2 h). The mixture was dissolved in hexane (1000 mL), washed with brine (3 × 100 mL), and dried over sat. Na₂SO₄. The solvents were evaporated, and the product was purified by column chromatography (EtOAc–hexane, 1:10). Representative Analytical Data tert-Butyl{[(1Z,3E)-1-(2,2-dimethyl-1,3-dioxan-5-yl)penta-1,3-dien-2-yl]oxy}diphenylsilane (IVa) White solid, mp 96–98 °С, yield: 14.1 g (64%). ESI-HRMS: m/z calcd for C₂₇H₃₇O₃Si⁺ [M + H]⁺: 437.2512; found: 437.2495. ¹H NMR (700 MHz, CDCl₃): δ = 7.73 (4 H, d, J = 8.1 Hz), 7.44 (1 H, t, J = 7.1 Hz), 7.39 (1 H, t, J = 7.2 Hz), 5.89 (1 H, dq, J = 15.2, 6.8 Hz), 5.70 (1 H, dq, J = 15.2, 1.5 Hz), 4.50 (1 H, d, J = 10.0 Hz), 3.40 (2 H, dd, J = 4.7, 11.5 Hz), 3.27 (2 H, dd, J = 11.5, 8.1 Hz), 2.718–2.67 (1 H, m), 1.57 (3 H, dd, J = 6.8, 1.5 Hz), 1.35 (3 H, s), 1.27 (3 H, s), 1.08 (9 H, s). ¹³C NMR (176 MHz, CDCl₃): δ = 17.6 (CH₃), 19.8, 21.7, 26.1, 26.7 (3 × CH₃), 32.3, 63.8, 97.2, 106.3, 126.3, 127.6, 129.5, 129.8, 133.3, 135.3, 150.3. tert-Butyl{[(1Z,3E)-1-(2,2-dimethyl-1,3-dioxan-5-yl)penta-1,3-dien-2-yl]oxy}dimethylsilane (IVb) Colorless liquid, yield: 13.6 g (87%). ESI-HRMS: m/z calcd for C₁₇H₃₃O₃Si⁺ [M + H]⁺: 313.2199; found: 313.2188. ¹H NMR (700 MHz, CDCl₃): δ = 5.85–5.81 (2 H, m), 4.41 (1 H, d, J = 9.6 Hz), 3.80 (2 H, dd, J = 4.9, 12.0 Hz), 3.59 (2 H, dd, J = 11.1, 11.5 Hz), 2.98–2.92 (1 H, m), 1.75 (3 H, d, J = 4.9 Hz), 1.45 (3 H, s), 1.41 (3 H, s), 1.01 (9 H, s), 0.13 (6 H, s). ¹³C NMR (176 MHz, CDCl₃): δ = –4.7, 17.5, 19.2, 21.1, 25.9, 27.8, 32.4, 63.9, 64.1, 97.3, 107.4, 125.8, 129.5, 150.5.
• 14 CCDC 1492233 (IVa) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
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• 16 General Procedure for the Diels–Alder Reaction The mixture of alkene (24.6 g, 100 mmol), diene (105 mmol), and ionol (2,6-di-tert-butyl-4-methylphenol; 1 g, 4.5 mmol) was dissolved in 50 mL of dry CH₂Cl₂ and degassed upon freezing. The mixture was heated in an autoclave to 100 °C under high pressure (1 GPa) for 1 week. The solvent was evaporated, and the product was purified by column chromatography (EtOAc–hexane, 1:4). Representative Analytical Data (1S,2S,5R,6R)-Ethyl 6-[2-(Benzyloxy)ethyl]-4-[(tert-butyldiphenylsilyl)oxy]-5-(2,2-dimethyl-1,3-dioxan-5-yl)-2-methylcyclohex-3-enecarboxylate (6a) Colorless liquid, yield: 37.7 g (55%). ESI-HRMS: m/z calcd for C₄₁H₅₅O₆Si⁺ [M + H]⁺: 671.3768; found: 671.3761. ¹H NMR (700 MHz, CDCl₃): δ = 7.67 (2 H, d, J = 6.6 Hz), 7.57 (2 H, d, J = 6.8 Hz), 7.39–7.20 (11 H, m), 4.48 (1 H, d, J = 11.3 Hz), 4.37 (1 H, d, J = 11.3 Hz), 4.36 (1 H, br s), 4.08–4.00 (4 H, m), 3.71 (1 H, dd, J = 11.3, 3.2 Hz), 3.56 (1 H, dd, J = 11.3, 3.0 Hz), 3.31 (2 H, br t, J = 7.3 Hz), 2.21–2.18 (1 H, m), 2.03–2.01 (1 H, m), 2.00–1.93 (1 H, m), 1.86 (1 H, dd, J = 11.5, 10.3 Hz), 1.82–1.78 (1 H, m), 1.68–1.63 (1 H, m), 1.55–1.51 (1 H, m), 1.40 (3 H, s), 1.34 (3 H, s), 1.17 (3 H, t, J = 7.3 Hz), 1.00 (9 H, s), 0.62 (3 H, d, J = 6.8 Hz). ¹³C NMR (176 MHz, CDCl₃): δ = 14.3, 18.8, 19.2, 20.3, 26.7, 29.5, 29.7, 32.3, 33.6, 38.6, 40.0, 50.6, 60.3, 64.6, 65.8, 68.0, 73.0, 97.7, 111.2, 127.5, 127.6, 127.7, 127.8, 128.9, 129.8, 129.9, 132.0, 133.5, 135.4, 138.2, 148.8, 175.4. (1S,2S,5R,6R)-Ethyl 6-[2-(Benzyloxy)ethyl]-4-[(tert-butyldimethylsilyl)oxy]-5-(2,2-dimethyl-1,3-dioxan-5-yl)-2-methylcyclohex-3-enecarboxylate (6b) Colorless solid, mp 67–69 °С, yield: 25.3 g (45%). ESI-HRMS: m/z calcd for C₃₁H₅₀NaO₆Si⁺ [M + Na]⁺: 569.3274; found: 569.3271. ¹H NMR (700 MHz, CDCl₃): δ = 7.36–7.28 (5 H, m), 4.66 (1 H, br s), 4.48 (1 H, d, J = 12.0 Hz), 4.37 (1 H, d, J = 12.0 Hz), 4.18–4.12 (2 H, m), 4.00 (1 H, t, J = 11.5 Hz), 3.90 (1 H, t, J = 11.5 Hz), 3.71 (1 H, br d, J = 11.8 Hz), 3.56 (1 H, br d, J = 11.8 Hz), 3.41 (2 H, br t, J = 6.4 Hz), 2.61–2.58 (1 H, m), 2.20–2.17 (1 H, m), 2.06–2.03 (1 H, m), 1.99 (1 H, dd, J = 11.3, 11.8 Hz), 1.75–1.71 (2 H, m), 1.65–1.62 (1 H, m), 1.45 (3 H, s), 1.39 (3 H, s), 1.27 (3 H, t, J = 7.3 Hz), 0.96 (9 H, s), 0.93 (3 H, d, J = 6.8 Hz), 0.18 (3 H, s), 0.14 (3 H, s). ¹³C NMR (176 MHz, CDCl₃): δ = –4.6, –4.2, 14.3, 17.9, 18.7, 20.7, 25.8, 29.5, 29.7, 31.9, 33.8, 38.4, 40.1, 50.8, 60.4, 64.4, 65.6, 67.9, 73.0, 97.7, 109.2, 127.6, 127.7, 138.3, 149.3, 175.6.
• 17 CCDC 1492234 (6b) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
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• 21 General Procedure for RCM Reaction The alkene (1.77 g, 3 mmol) was dissolved in dry DCE (50 mL), and the Grubbs II catalyst (255 mg, 0.3 mmol) was added under inert atmosphere. The mixture was heated to 80 °C for 8 h, the solvent was evaporated, and the product was purified by column chromatography (EtOAc–hexane, 1:1). Representative Analytical Data (1R,4aR,5S,8S,8aS)-6-[(tert-Butyldiphenylsilyl)oxy]-5-(2,2-dimethyl-1,3-dioxan-5-yl)-3-(hydroxymethyl)-8-methyl-1,2,4a,5,8,8a-hexahydronaphthalen-1-ol (11a) White powder, yield: 540 mg (32%). ESI-HRMS: m/z calcd for C₃₄H₄₇O₅Si⁺ [M + H]⁺: 563.3193; found: 563.3197. ¹H NMR (700 MHz, CDCl₃): δ = 7.75 (2 H, d, J = 6.6 Hz), 7.65 (2 H, d, J = 6.6 Hz), 7.46–7.40 (4 H, m), 7.36 (2 H, t, J = 7.5 Hz), 5.49 (1 H, br s), 4.49 (1 H, d, J = 3.0 Hz), 4.16 (1 H, t, J = 11.5 Hz), 4.03 (1 H, t, J = 11.3 Hz), 4.14–4.10 (1 H, m), 4.04–3.96 (2 H, m), 3.76 (1 H, ddd, J = 11.5, 4.9, 1.9 Hz), 3.73 (1 H, ddd, J = 11.3, 4.9, 1.9 Hz), 2.52–2.48 (1 H, m), 2.38 (1 H, br d, J = 11.5 Hz), 2.36–2.31 (1 H, m), 2.27–2.20 (1 H, m), 2.07–2.03 (1 H, m), 2.02–1.96 (1 H, m), 1.92 (1 H, br t, J = 3.3 Hz), 1.86 (1 H, br d, J = 3.5 Hz), 1.47 (3 H, s), 1.39 (3 H, s), 1.08 (9 H, br s), 1.04 (1 H, br t, J = 11.1 Hz), 0.75 (3 H, d, J = 6.8 Hz). ¹³C NMR (176 MHz, CDCl₃): δ = 18.8, 19.2, 19.4, 26.8, 29.5, 30.0, 34.3, 34.6, 36.8, 42.2, 42.5, 64.3, 64.6, 66.0, 66.7, 97.8, 113.2, 124.4, 127.6, 127.6, 129.8, 132.3, 133.5, 135.4, 135.8, 148.7. (1S,4aR,5S,8S,8aS)-6-[(tert-Butyldiphenylsilyl)oxy]-5-(2,2-dimethyl-1,3-dioxan-5-yl)-3-(hydroxymethyl)-8-methyl-1,2,4a,5,8,8a-hexahydronaphthalen-1-ol (11b) White powder, yield: 420 mg (25%). ESI-HRMS: m/z calcd for C₃₄H₄₇O₅Si⁺ [M + H]⁺: 563.3193; found: 563.3200. ¹H NMR (700 MHz, CDCl₃): δ = 7.75 (2 H, d, J = 6.7 Hz), 7.65 (2 H, d, J = 6.7 Hz), 7.46–7.41 (4 H, m), 7.36 (2 H, t, J = 7.5 Hz), 5.35 (1 H, br s), 4.42 (1 H, d, J = 3.1 Hz), 4.11 (1 H, t, J = 11.6 Hz), 4.04 (1 H, t, J = 11.6 Hz), 4.06–3.97 (2 H, m), 3.85 (1 H, ddd, J = 11.6, 4.9, 2.0 Hz), 3.74 (1 H, ddd, J = 11.4, 5.1, 1.8 Hz), 3.64–3.58 (1 H, m), 2.38 (1 H, br dd, J = 16.7, 4.4 Hz), 2.25–2.19 (1 H, m), 2.12–2.05 (1 H, m), 2.05–2.01 (1 H, m), 2.00–1.96 (2 H, m), 1.85 (1 H, br t, J = 3.5 Hz), 1.70 (1 H, br d, J = 3.8 Hz), 1.49 (3 H, s), 1.40 (3 H, s), 1.17 (1 H, br q, J = 9.5 Hz), 1.07 (9 H, br s), 1.00 (3 H, d, J = 6.7 Hz). ¹³C NMR (176 MHz, CDCl₃): δ = 18.8, 19.1, 23.4, 26.7, 29.4, 33.9, 34.1, 36.9, 42.5, 43.1, 44.9, 64.5, 65.8, 66.0, 74.1, 97.7, 113.8, 124.3, 127.6, 127.7, 129.8, 132.3, 133.5, 135.4, 137.5, 148.8.
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