Studies Towards the Synthesis of Crotogoudin

Abstract

An effective synthesis of the tricyclic core structure of the new diterpene crotogoudin was achieved. The synthesis features an intermolecular domino Michael reaction to construct a bicyclo[2.2.2]octane motif and an aldol condensation to close ring B. Stork reductive alkylation with allyl bromide proceeded from the β side, resulting in the wrong stereochemistry at C-10.

Key words

crotogoudin - atisane - diterpene - domino Michael reaction - Stork reductive alkylation

• References and Notes

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• 17 Enedione 14 Pd(OH)₂/C (Pearlman’s catalyst, 20%, 1.1 g, 2.0 mmol) was added to a stirred suspension of enone 10 (10.0 g, 43.0 mmol), K₂CO₃ (1.5 g. 10.0 mmol) in CH₂Cl₂ (200 mL), followed by addition of TBHP (5.0–6.0 M in decaline, 43 mL, 215.0 mmol) at r.t. The resulting mixture was stirred overnight at r.t. The reaction mixture was then filtered through a short pad of silica gel, washed with CH₂Cl₂, and concentrated in vacuo at r.t. The residue was purified by flash chromatography (PE–EtOAc, 1:1) to give 1,4-diketone 12 (8.3 g, 78%) as a colorless oil. R_f  = 0.40 (PE–EtOAc, 1:1). ¹H NMR (400 MHz, CDCl₃, atoms numbered according to the naphthalene system): δ = 1.74–1.79 (m, 1 H, 10-H), 1.84–1.99 (m, 4 H, 5-H, 10-H, 2 × 9-H), 2.11–2.21 (m, 3 H, 2 × 3-H, 5-H), 2.30 (ddd, J = 16.8, 7.3, 5.3 Hz, 1 H, 6-H), 2.45 (ddd, J = 16.7, 9.9, 5.8 Hz, 1 H, 6-H), 2.60 (ddd, J = 5.8, 3.0, 3.0 Hz, 1 H, 2-H), 2.79 (dd, J = 9.6, 6.1 Hz, 1 H, 4-H), 3.63 (s, 3 H, OCH₃), 6.50 (s, 1 H, 8-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 22.7 (C-9), 28.0 (C-3), 29.8 (C-5), 31.1 (C-10), 34.4 (C-6), 38.6 (C-4a), 40.4 (C-2), 46.7 (C-4), 52.2 (OCH₃), 125.4 (C-8), 152.4 (C-8a), 174.3 (ester), 198.8 (C-7), 201.8 (C-1) ppm. ESI-HRMS: m/z [M + Na]⁺ calcd for C₁₄H₁₆O₄Na: 271.094080; found: 271.094073.
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• 19 Enedione 5 A solution of diazomethane in Et₂O (200 mL) was added to a stirred solution of enedione 14 (4.7 g, 0.019 mol) in CHCl₃ (150 mL) at 0 °C. The mixture was allowed to warm to r.t. and stirred for 6 h before the solvents were removed with a flow of nitrogen. The residue was purified by flash chromatography (PE–EtOAc, 4:1 to 1:1) to give enedione 5 (3.9 g, 78%) as white crystals (mp 97–98.5 °C). R_f  = 0.45 (PE–EtOAc, 1:1). ¹H NMR (400 MHz, CDCl₃): δ = 1.61–1.68 (m, 1 H, 10-H), 1.78–2.00 (m, 4 H, 5-H, 10-H, 2 × 9-H), 2.06–2.14 (m, 3 H, 2 × 3-H, 5-H), 2.17 (s, 3 H, 8-CH₃) 2.34 (ddd, J = 16.4, 6.8, 5.0 Hz, 1 H, 6-H), 2.49 (ddd, J = 16.4, 10.9, 5.8 Hz, 1 H, 6-H), 2.55 (ddd, J = 6.1, 3.0, 3.0 Hz, 1 H, 2-H), 2.69 (dd, J = 8.6, 7.3 Hz, 1 H, 4-H), 3.60 (s, 3 H, OCH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 12.0 (CCH₃), 22.6 (C-9), 28.1 (C-3), 29.8 (C-5), 31.1 (C-10), 34.0 (C-6), 39.8 (C-4a), 42.2 (C-2), 47.2 (C-4), 52.0 (OCH₃), 138.2 (C-8), 144.6 (C-8a), 174.6 (ester), 199.6 (C-7), 204.7 (C-1) ppm. ESI-HRMS: m/z [M + Na]⁺ calcd for C₁₅H₁₈O₄Na: 285.109730; found: 285.109658.

For a review, see:
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• 22 Allylation of Dienolate of Enedione 5 to 15: Methyl (2S,4S,4aS,8S)-8-Allyl-1-(allyloxy)-8-methyl-7-oxo-3,4,5,6,7,8-hexahydro-2H-2,4a-ethanonaphthalene-4-carboxylate (15) Lithium (60 mg, 8.82 mmol) was added in small portions to stirred liquid NH₃ (10 mL) at –78 °C. The resulting blue solution was stirred for 1 h before it was treated with a solution of diketone 5 (50 mg, 0.19 mmol) in THF (4 mL). After complete addition stirring was continued for 2 h at the same temperature. Then, allyl bromide (1.6 mL, 18.90 mmol) was added dropwise at –78 °C and the mixture stirred for 30 min before the cooling bath was removed and the NH₃ was allowed to evaporate. The resulting white suspension was diluted with H₂O (20 mL) and extracted with Et₂O (3 × 10 mL). The combined organic layers were washed with sat. NaCl solution (20 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (PE–EtOAc, 4:1) to give ketone 15 (41 mg, 63%) as a colorless oil. R_f  = 0.64 (PE–EtOAc = 1:1). ¹H NMR (400 MHz, CDCl₃): δ = 1.29–1.76 (m, 7 H, 2 × 3-H, 5-H, 2 × 9-H, 2 × 10-H), 1.33 (s, 3 H, 8-CH₃), 1.85 (ddd, J = 12.6, 9.7, 2.8 Hz, 1 H, 3-H), 2.01–2.08 (m, 1 H, 5-H), 2.25 (ddd, J = 8.5, 5.1, 2.9 Hz, 2 H, 2 × 6-H), 2.45 (dd, J = 9.8, 5.8 Hz, 1 H, 4-H), 2.51 [dd, J = 13.1, 7.6 Hz, 1 H, 8-(CH ₂CH=CH₂)], 2.80–2.86 [m, 2 H, 2-H, 8-(CH ₂CH=CH₂)], 3.60 (s, 3 H, OCH₃), 4.30–4.39 [m, 2 H, 1-(OCH ₂CH=CH₂)], 4.87–4.89 [m, 2 H, 8-(CH₂CH=CH ₂)], 5.22 [ddd, J = 12.1, 1.5, 1.5 Hz, 1 H, 1-(OCH₂CH=CH ₂)], 3.56 [ddd, J = 17.2, 3.3, 1.6 Hz, 1 H, 1-(OCH₂CH=CH ₂)], 5.55 [dddd, J = 17.2, 10.0, 7.4, 7.4 Hz, 1H, 8-(CH₂CH=CH₂)], 5.99 [dddd, J = 17.2, 10.4, 5.2, 5.0 Hz, 1 H, 1-(OCH₂CH=CH₂)] ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 24.8 (8-CH₃), 26.1 (C-9), 30.4 (C-2), 30.8 (C-5), 32.4 (C-3), 34.7 (C-10), 37.3 (C-6), 41.0 (C-4a), 42.9 [8-(CH₂CH=CH₂)], 49.2 (C-4), 51.6 (OCH₃, C-8), 68.8 [1-(OCH₂CH=CH₂)], 116.8 [8-(CH₂CH=CH₂), 1-(OCH₂CH=CH₂)], 118.5 (C-8a), 134.2 [1-(OCH₂ CH=CH₂)], 136.1 [(8-(CH₂ CH=CH₂)], 154.5 (C-1), 175.9 (ester), 215.2 (C-7) ppm. ESI-HRMS: m/z [M + Na]⁺ calcd for C₂₃H₃₀O₄Na: 393.203631; found: 393.203799.