Application of an Intramolecular Stetter Reaction to Access trans,syn,trans-Fused Pyrans

Abstract

The use of a commercially available thiazolium salt facilitated an intramolecular Stetter reaction between an aliphatic aldehyde and an acrylate unit, which delivered a trans,syn-fused bicyclic pyranone in high yield as a single diastereomer. The pyranone was used to synthesize a trans,syn,trans-fused polycyclic ether array and was ring expanded to give the corresponding oxepanone.

carbenes - diastereoselectivity - fused-ring systems - ring closure - umpolung

References and Notes

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<A NAME="RD33108ST-17">17</A>

Synthesis of Compound 8
To a solution of aldehyde 7 (58 mg, 0.24 mmol) in THF (2 mL) was added thiazolium salt 11 (90 mg, 0.36 mmol) and DBU (54 µL, 0.36 mmol). The mixture was stirred under reflux for 16 h, poured onto H₂O (30 mL), and extracted with EtOAc (4 × 10 mL). The combined organic phases were dried over Na₂SO₄, the solvent was evaporated, and the residue was subjected to flash chromatography, eluting with 10% EtOAc in hexanes, to give 8 (57 mg, 98%) as a clear oil. IR (CHCl₃): ν_max = 3093, 2977, 2931, 1735, 1720, 1450, 1396, 1288, 1172, 1103, 1026 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 4.29 (1 H, dd, J = 6.0, 5.7 Hz), 4.14 (2 H, q, J = 7.2 Hz), 3.36 (1 H, ddd, J = 9.9, 9.9, 4.5 Hz), 2.87 (1 H, dd, J = 16.5, 5.4 Hz), 2.62 (1 H, dd, J = 16.5, 6.3 Hz), 2.55 (1 H, dd, J = 15.5, 4.5 Hz), 2.15 (1 H, dd, J = 15.5, 12.3 Hz), 2.05-1.99 (1 H, m), 1.85-1.62 (4 H, m), 1.37-1.06 (4 H, m), 1.25 (3 H, t, J = 7.2 Hz). ^¹³C NMR (75.4 MHz, CDCl₃): δ = 206.6 (C), 171.0 (C), 80.5 (CH), 79.7 (CH), 60.7 (CH₂), 45.1 (CH₂), 42.9 (CH), 35.3 (CH₂), 32.0 (CH₂), 31.7 (CH₂), 24.9 (CH₂), 24.6 (CH₂), 14.2 (CH₃). HRMS: m/z calcd for C₁₃H₂₁O₄ [M + H⁺]: 241.14344; found: 241.14383.

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<A NAME="RD33108ST-19A">19a</A>

For the synthesis of compound 13 see Supporting Information.

<A NAME="RD33108ST-19B">19b</A>

CCDC 702838 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/data_request/cif.

<A NAME="RD33108ST-20A">20a</A>

A crystalline p-bromobenzoate derivative of a similar fused bicyclic system has been reported. [²0b] Therefore, alcohol 12 was converted into the corresponding p-bromo-benzoate but that compound failed to provide crystals suitable for X-ray crystallographic analysis.

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