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Synlett 2007(8): 1219-1222  
DOI: 10.1055/s-2007-977446
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Sung-Hyun Yang, Vittorio Caprio*
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
Fax: +64(9)3737422; e-Mail: v.caprio@auckland.ac.nz;
Further Information

Publication History

Received 25 January 2007
Publication Date:
18 April 2007 (online)

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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.

Key words

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

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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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.