Biology-Oriented Synthesis of Decahydro-4,8-epoxyazulene Scaffolds

Dedicated to Victor Snieckus on the occasion of his 80^th birthday

Abstract

Guided by the principle of biology-oriented synthesis, a collection of compounds with decahydro-4,8-epoxyazulene scaffold occurring in bioactive natural products was synthesized by the rhodium(II)-catalyzed 1,3-dipolar cycloaddition reaction of pentafulvenes and carbonyl ylides. The products can be obtained in moderate to high yields, with moderate enantioselectivity and excellent diastereoselectivity and regioselectivity.

Key words

biology-oriented synthesis - azulene - cycloaddition - rhodium - carbonyl ylides

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• 14 Dirhodium(II)-Catalyzed 1,3-Dipoar Cycloaddition of Fulvenes 1 and Diazo Derivatives 2 A typical procedure is given for the reaction of fulvene 1a and diazo derivative 2a (Table 1, entry 5). A flame-dried Schlenk tube was charged with Rh₂(S-TCPTTL)₄ (1.96 mg, 0.001 mmol, 1 mol%) and 4 Å MS (20 mg). Under argon flow, a solution of fulvene 1a (14.62 mg, 0.1 mmol, 1 equiv) in 0.5 mL of α,α,α-trifluorotoluene was added, followed by a solution of the corresponding diazo compound 2a (36.03 mg, 0.15 mmol, 1.5 equiv) in 0.5 mL α,α,α-trifluorotoluene. The reaction mixture was allowed to stir for an additional 1 h. Upon completion monitored by thin-layer chromatography (TLC), the reaction mixture was directly loaded on the silica gel column and was purified by using EtOAc/PE mixture as an eluent to afford the desired compound 3a in 92% yield. ¹H NMR (500 MHz, CD₂Cl₂): δ = 6.59 (dd, J = 5.7, 2.0 Hz, 1 H), 5.72 (dd, J = 5.7, 2.3 Hz, 1 H), 3.73 (d, J = 6.9 Hz, 1 H), 3.47 (d, J = 6.9 Hz, 1 H), 2.72 (ddd, J = 16.5, 11.9, 8.2 Hz, 1 H), 2.45 (dd, J = 16.5, 5.8 Hz, 1 H), 2.42–2.33 (m, 1 H), 2.28 (dd, J = 9.1, 3.2 Hz, 1 H), 2.22–2.12 (m, 2 H), 2.12–1.99 (m, 2 H), 1.68–1.56 (m, 4 H), 1.56–1.43 (m, 11 H), 1.27 (s, 3 H) ppm. ¹³C NMR (126 MHz, CD₂Cl₂): δ = 203.38, 166.32, 136.24, 135.29, 134.97, 131.18, 91.02, 84.52, 82.85, 57.77, 49.74, 40.32, 34.31, 33.66, 32.12, 28.44, 28.37, 28.12, 27.10, 22.68 ppm. FT-IR: ν = 2982, 2929, 2855, 2161, 1745, 1722, 1448, 1160 cm^–1. HRMS: m/z calcd for [M + Na]⁺ C₂₂H₃₀O₄Na: 381.2036; found: 381.2023. HPLC conditions: CHIRAPAK IC column, (CH₂Cl₂/EtOH = 100:2)/i-hexane = 30:70, flow rate = 0.5 mL min^–1, major enantiomer: t _R = 61.3 min; minor enantiomer: t _R = 28.2 min, 59% ee.
• 15 Reaction-conditions screening including adding the diazo substrate by syringe pump over 1 h, temperature, solvents, and the ratio of fulvene and diazo substrate.
• 16 The structure was confirmed by X-ray crystallographic analysis. CCDC 1552869 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures. Please see the Supporting Information for details.
• 17 See details in Supporting Information.
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