Efforts Toward a Synthesis of Crotogoudin and Crotobarin

^◊ These authors contributed equally

Published as part of the ISHC Conference Special Section

Abstract

Two synthesis designs for the diterpenoid crotogoudin are discussed, and efforts to achieve each are described. First, a Cope rearrangement/intramolecular Diels–Alder cascade reaction was investigated. Second, a bioinspired sequence of cationic bicyclization and A-ring oxidative fragmentation set-up for a lactonization induced by a phenolic oxidation, ultimately providing a tricyclic intermediate that required only installation of the bridging ring of the salient bicyclo[2.2.2]octane system. This last endeavor was fraught with difficulty, but did lead to the development of conditions for cyclization of related keto-alkenes via manganese(III)-based radical chemistry.

Key words

diterpenoid - cascade - cationic cyclization - phenolic oxidation - dearomatization - Birch reduction - Diels–Alder cycloaddition - radical cyclization

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• 28 Representative Experimental Procedure and Characterization Data Compound 26: Phenol 19 (1.48 g, 5.39 mmol) was dissolved in CF₃CH₂OH (50 mL) assisted by sonication. The open flask was cooled to 0 °C. A solution of diacetoxyiodobenzene (1.82 g, 5.66 mmol) in CF₃CH₂OH (4 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 2 h, diluted with water (100 mL), and extracted with CH₂Cl₂ (3 × 100 mL). The combined organic extracts were dried with MgSO₄, filtered, and concentrated in vacuo. The resultant crude dark red oil was purified by column chromatography (20% EtOAc in hexanes) to give 26 as a white solid (0.96 g, 66% yield; mp 105–107 °C. ¹H NMR (500 MHz, CDCl₃): δ = 6.86 (d, J = 10.2 Hz, 1 H), 6.33 (d, J = 10.2 Hz, 1 H), 6.16 (s, 1 H), 5.02 (s, 1 H), 4.82 (s, 1 H), 2.88–2.71 (m, 4 H), 2.42 (d, J = 13.3 Hz, 1 H), 2.02–1.83 (m, 4 H), 1.77 (s, 3 H), 0.89 (s, 3 H).¹³C NMR (125 MHz, CDCl₃): δ = 184.8, 169.9, 156.7, 144.1, 143.6, 131.1, 126.2, 116.3, 82.8, 44.0, 41.1, 31.8, 28.6, 28.0, 26.0, 23.3, 17.5. IR (thin film): 3077, 3053, 2969, 2949, 1741, 1674, 1640, 1615 cm^–1. ESI-HRMS (MeOH): m/z calcd for C₁₇H₂₀O₃Na [M + Na]⁺: 295.1310; found: 295.1311. Compound 35: Mn(OAc)₃·2H₂O (0.316 g, 1.18 mmol) and Cu(OTf)₂ (0.195 g, 0.539 mmol) were added to a flame-dried vial, degassed in triplicate (backfilling with argon), and suspended in DMSO (5.4 mL). Ketone 34 (0.103 g, 0.533 mmol) was added neat, via syringe, and the reaction mixture was heated to 80 °C in a preheated aluminum block for 36 h. The brown suspension was cooled to r.t., diluted with water (2 mL), extracted with CH₂Cl₂ and Et₂O (2 × 2 mL). The combined organic extracts were washed with NaHCO₃, water, brine, dried over Na₂SO₄, filtered through SiO₂, and concentrated in vacuo. The resultant crude material was purified by column chromatography (1–3% EtOAc in hexanes) to give 35 as a yellow oil (0.070 g, 69% yield). ¹H NMR (600 MHz, CDCl₃): δ = 4.92 (d, J = 0.7 Hz, 1 H), 4.81 (d, J = 1.0 Hz, 1 H), 2.85 (dd, J = 3.6, 2.2 Hz, 1 H), 2.69 (dd, J = 19.1, 3.2 Hz, 1 H), 2.23 (dd, J = 17.1, 2.3 Hz, 1 H), 2.18–2.12 (m, 2 H), 1.74 (dd, J = 19.2, 1.4 Hz, 1 H), 1.73–1.62 (m, 2 H), 1.60–1.48 (m, 3 H), 1.37–1.16 (m, 4 H), 1.08 (ddd, J = 35.7, 13.0, 3.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 212.7, 143.3, 110.6, 55.0, 44.0, 42.9, 37.5, 36.3, 36.1, 32.9, 31.2, 26.2, 21.8. HRMS (CI/CH₂Cl₂): m/z calcd for C₁₃H₁₈ONH₄ [M + NH₄]⁺: 208.1701; found: 208.1703.