Synlett 2017; 28(14): 1758-1762
DOI: 10.1055/s-0036-1588560
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© Georg Thieme Verlag Stuttgart · New York

Efforts Toward a Synthesis of Crotogoudin and Crotobarin

Duy N. Mai, Dmitriy Uchenik, Christopher D. Vanderwal*
  • Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, CA 92697-2025, USA   Email: cdv@uci.edu
We thank the UC Cancer Research Coordinating Committee for funding initial phases of this research with grant CRC-15-380750 and the NSF for continued funding (CHE-1564340)
Further Information

Publication History

Received: 11 July 2017

Accepted after revision: 07 August 2017

Publication Date:
16 August 2017 (eFirst)

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.

Supporting Information

 
  • References and Notes

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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.