A Concise and Flexible Synthesis of the Core Structure of Pinnaic Acid

Abstract

An efficient and flexible approach to the core structure of pinnaic acid has been developed that centres on the microwave-induced 1,3-dipolar cycloaddition of a novel spirocyclic nitrone 5 with alkene 7. The application of this nitrone to the synthesis of a diverse set of C5-substituted analogues of pinnaic acid is also de­monstrated.

pinnaic acid - nitrones - cycloadditions - isoxazolidine - oxidative ring opening

References and Notes

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10

A solution of MCPBA (70%, 5.70 g, 33.0 mmol) in CH₂Cl₂ (130 mL) was added to a solution of isoxazolidine 8 (3.80 g, 22.7 mmol) in CH₂Cl₂ at 0 °C over 7 h. After the addition was complete the mixture was warmed to r.t. and stirred for a further 20 h. Then, sat. aq Na₂S₂O₃ (60 mL) and sat. NaHCO₃ (60 mL) were added and the mixture extracted with CH₂Cl₂ (3 × 30 mL). The combined organic extracts were dried over anhyd MgSO₄, concentrated and purified by column chromatography on silica gel using CH₂Cl₂-MeOH (9.5:0.5) as eluent to give nitrone 5 as a yellow solid (3.72 g, 89%); mp 70-73 °C. IR (neat): 3410, 2961, 1642 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.30-2.10 (m, 10 H), 2.45-2.52 (m, 2 H), 2.70-2.85 (m, 1 H), 3.65-3.80 (m, 2 H), 7.34 (t, 1 H, J = 4.0 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 15.4, 24.0, 26.3, 28.3, 37.0, 38.5, 52.7, 61.1, 76.5, 142.0. HRMS (EI): m/z calcd for [C₁₀H₁₇NO₂]⁺: 183.1253; found: 183.1259.

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20

A 10 mL microwave reaction vessel was charged with ester 7 (0.62 g, 3.27 mmol), nitrone 5 (0.30 g, 1.63 mmol) and toluene (5 mL). The vial was sealed with a cap containing a silicon septum, loaded into the cavity of a focussed micro-wave oven (Discover^® CEM, 250 W) and heated for 1 h at 165 °C. The reaction mixture was cooled to r.t., concentrated and purified by column chromatography on silica gel using EtOAc-hexane (3:7) as eluent to give isoxazolidine 17 as two diastereomers as colourless oils (0.48 g, 80%; dr = 1:1; diastereomers unassigned).
Diastereomer A: IR (neat): 3443, 2958, 1728 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.25 (d, 3 H, J = 7.1 Hz), 1.30-1.63 (m, 8 H), 1.64-1.93 (m, 3 H), 1.94-2.08 (m, 2 H), 2.09-2.12 (m, 2 H), 2.66 (dq, 1 H, J = 7.9, 7.1 Hz), 3.45 (d, 1 H, J = 5.8 Hz), 3.56-3.65 (m, 2 H), 4.12 (td, 1 H, J = 7.9, 5.7 Hz), 5.11 (d, 2 H, J = 7.4 Hz), 7.30-7.38 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.5, 19.2, 21.2, 26.4, 27.8, 30.2, 38.2, 40.0, 45.3, 45.4, 57.8, 65.4, 66.1, 69.2, 76.0, 128.0, 128.1, 128.5, 135.9, 174.3. HRMS (EI): m/z = calcd for [C₂₂H₃₁NO₄]⁺: 373.2253; found: 373.2253.
Diastereomer B: IR (neat): 3448, 2958, 2931, 1727 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.11 (d, 3 H, J = 7.0 Hz), 1.23-1.68 (m, 10 H), 1.69-1.96 (m, 2 H), 1.97-2.08 (m, 2 H), 2.09-2.15 (m, 2 H), 2.70 (dq, 1 H, J = 8.5, 7.1 Hz), 3.45 (d, 1 H, J = 6.3 Hz), 3.54-3.64 (m, 2 H), 4.20 (td, 1 H, J = 8.5, 6.0 Hz), 5.14 (d, 2 H, J = 4.9 Hz), 7.29-7.36 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 12.7, 19.2, 21.1, 26.4, 27.7, 29.6, 38.0, 39.1, 45.2, 45.4, 57.9, 65.4, 66.0, 69.1, 76.3, 127.9, 128.0, 128.4, 136.1, 174.5. HRMS (EI): m/z calcd for [C₂₂H₃₁NO₄]⁺: 373.2253; found: 373.2256.