Stereocontrolled Routes to 4-Methoxypentadienoates for Use in Natural Product Synthesis

Abstract

Mild and efficient routes to (E,E)- and (E,Z)-4-methoxypentadienoic acid esters from readily accessible γ,δ-epoxydienoates are described. The crucial epoxide methanolysis can be carried out in stereocomplementary ways by the use of either acid-mediated or palladium-catalysed procedures, the latter procedure proving ­preferable in most cases.

Key words

epoxides - stereoselective synthesis - palladium ­catalysis - acid catalysis - diene synthesis

• References and Notes

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• 8 General Procedure for the Acid-Promoted Epoxide Ring Opening To a stirred solution of epoxide (1.0 equiv) in MeOH (0.1 M) was added a catalytic amount of concd H₂SO₄. The resulting solution was stirred at r.t. until complete as monitored by TLC. After this time, the reaction mixture was quenched with brine and extracted with EtOAc. The combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo. The resulting crude material was purified by flash column chromatography to afford the desired alcohol.
• 9 General Procedure for the Pd(0)-Mediated Epoxide Ring Opening To a stirred solution of epoxide (1.0 equiv) and B(OMe)₃ (1.2 equiv) in THF (0.2 M) at r.t. was added Pd(PPh₃)₄ (10 mol%). The resulting solution was stirred at r.t. until complete as monitored by TLC. After this time, the reaction mixture was quenched with NaHCO₃ (sat. aq solution) and diluted with EtOAc. The aqueous layer was extracted with EtOAc (3 ×). The combined organics were washed with brine, dried (MgSO₄), filtered, and concentrated in vacuo. The resulting crude material was purified by flash column chromatography to afford the desired alcohol.
• 10 General Procedure for the Mesylation and Elimination Sequence To a stirred solution of alcohol (1.0 equiv) in CH₂Cl₂ (0.15 M) at r.t. was added MsCl (1.5 equiv) followed by Et₃N (3.0 equiv). The resulting solution was stirred at r.t. for 2 h. After this time, the reaction mixture was diluted with brine (20 mL). The aqueous layer was extracted with CH₂Cl₂ (2×). The combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo. The resulting crude mesylate (1.0 equiv) was redissolved in CH₂Cl₂ (0.1 M), and DBU (1.2 equiv) was added at r.t. The resulting solution was stirred at r.t. until complete as monitored by TLC. After this time, the reaction mixture was quenched with 10% HCl and diluted with H₂O and CH₂Cl₂, and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ (2 ×). The combined organic layers were washed with brine, dried (MgSO₄), filtered, and concentrated in vacuo. The resulting crude material was purified by flash column chromatography to afford the desired diene.
• 11 Methyl (2E,4E)-4-Methoxyhepta-2,4-dienoate [(E,E)-13a] IR (film): ν_max = 1712 (C=O), 1645 (C=C) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.03 (3 H, t, J = 7.5 Hz), 2.20–2.28 (2 H, m), 3.57 (3 H, s), 3.74 (3 H, s), 4.98 (1 H, t, J = 7.9 Hz), 6.21 (1 H, d, J = 15.0 Hz), 7.45 (1 H, d, J = 15.0 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.2, 19.7, 54.3, 59.8, 111.9, 117.6, 135.0, 150.0, 167.4 ppm. MS: m/z = 171 [MH]⁺, 193 [MNa]⁺. ESI-HRMS: m/z calcd for C₉H₁₅O₃: 171.1016; found [MH⁺]: 171.1013 (1.5 ppm error).
• 12 Methyl (2E,4Z)-4-Methoxyhepta-2,4-dienoate [(E,Z)-13a] IR (film): ν_max = 1715 (C=O), 1639 (C=C) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.04 (3 H, t, J = 7.6 Hz), 2.26 (2 H, q, J = 7.6 Hz), 3.62 (3 H, s), 3.76 (3 H, s), 5.39 (1 H, t, J = 7.6 Hz), 6.02 (1 H, d, J = 15.5 Hz), 7.03 (1 H, d, J = 15.5 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 13.4, 19.3, 51.4, 59.8, 116.0, 130.3, 140.9, 152.7, 167.4 ppm. MS: m/z = 171 [MH]⁺, 193 [MNa]⁺. ESI-HRMS: m/z calcd for C₉H₁₅O₃: 171.1016; found [MH⁺]: 171.1013 (1.5 ppm error).