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Synlett 2007(2): 0333-0335  
DOI: 10.1055/s-2007-967996
LETTER
© Georg Thieme Verlag Stuttgart · New York

Preparation of the Geranyl-α-pyrone (±)-Aurantiacone via a New Pyrone Synthesis

Dietmar Schmidt, Jürgen Conrad, Iris Klaiber, Sabine Mika, Uwe Beifuss*
Bioorganische Chemie, Institut für Chemie, Universität Hohenheim, Garbenstraße 30, 70599 Stuttgart, Germany
Fax: +49(711)45922951; e-Mail: ubeifuss@uni-hohenheim.de;
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Publication History

Received 25 September 2006
Publication Date:
24 January 2007 (online)

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Abstract

The structure of the leaf resin geranyl-α-pyrone aurantiacone isolated from Mimulus ( = Diplacus) aurantiacus (Curtis) Jeps. (Scrophulariaceae) was confirmed through synthesis. The key step is lactonization of the sensitive 5-hydroxy-3-oxopent-4-enoic acid under mild conditions, which can be released from the corresponding bispotassium salt. The latter is accessible in a few steps from an N-acyl aziridine and an ethyl acetoacetate.

Key words

hydrolyses - cyclizations - lactones - heterocycles - ­natural products

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Selected data for 3a (mixture of two diastereomers D1 and D2): IR (ATR): 2957, 2929, 2856, 1696, 1471, 1405, 1374, 1255, 1179, 1134, 1076, 1002, 832, 810, 774 cm-1. UV (MeCN): λmax (log ε) = 243 (2.55) nm. 1H NMR (500 MHz, CDCl3): δ = 0.01 (s, 3 H, SiCH3),* 0.02 (s, 3 H, SiCH3),* 0.07 (s, 6 H, 2 × SiCH3),* 0.858 [s, 9 H, SiC(CH3)3],* 0.861 [s, 9 H, SiC(CH3)3],* 1.197 (d, 3 J = 6.1 Hz, 3 H, 4-H3),* 1.202 (d, 3 J = 6.1 Hz, 3 H, 4-H3),* 1.31 (d, 3 J = 5.3 Hz, 3 H, 2′-CH3, D1), 1.32 (d, 3 J = 5.2 Hz, 3 H, 2′-CH3, D2), 1.917 (d, 3 J = 3.1 Hz, 1 H, 3′-HA, D2), 1.925 (d, 3 J = 2.9 Hz, 1 H, 3′-HA, D1), 2.37 (d, 3 J = 5.9 Hz, 1 H, 3′-HB, D2), 2.38 (d, 3 J = 6.2 Hz, 1 H, 3′-HB, D1), 2.43 (dd, 2 J = 9.7 Hz, 3 J = 5.3 Hz, 1 H, 2-HA),* 2.45 (dd, 2 J = 9.3 Hz, 3 J = 5.0 Hz, 1 H, 2-HA),* 2.53 (overlapped, 2′-H, D1), 2.56 (overlapped, 2-H′, D2), 2.59 (overlapped, 2-HB),* 2.61 (dd, 2 J = 10.1 Hz, 3 J = 7.7 Hz, 1 H, 2-HB),* 4.29-4.37 (m, 1 H, 3-H). 13C NMR (125 MHz, CDCl3): δ = -4.79 (2 × SiCH3),* -4.73 (SiCH3),* -4.71 (SiCH3),* 17.72, 17.79 (2′-CH3),* 17.92, 17.94 [SiC(CH3)3],* 23.92, 23.96 (C-4),* 25.79 [SiC(CH3)3], 31.12 (C-3′, D1), 31.69 (C-3′, D2), 32.18 (C-2′, D2), 32.72 (C-2′, D1), 47.44, 47.23 (C-2),* 66.09, 66.17 (C-3),* 183.68, 183.71 (C-1).* MS (EI, 70 eV): m/z (%) = 257.0 (<1%) [M+], 242.0 (7) [M+ -CH3], 199.9 (100) [M+ - C4H9], 142.9 (20) [M+ - C6H14Si], 113.9 (35) [C6H17Si+], 74.9 (30) [C2H7OSi+]. * Unambiguous assignment was not possible.

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Selected data for 5a (mixture of four isomers; for details see Figure [2] ): IR (ATR): 2928, 2856, 1738, 1601, 1444, 1375, 1255, 1132, 1096, 997, 834, 810, 775 cm-1. UV (MeOH): λmax (log ε) = 280 (3.92) nm. Tautomer T1: 1H NMR (500 MHz, CDCl3): δ = 0.002 (s, 6 H, 2 × SiCH3),* 0.04 (s, 6 H, 2 × SiCH3),* 0.855 [s, 9 H, SiC(CH3)3],* 0.858 [s, 9 H, SiC(CH3)3],* 1.19 (d, 3 J = 6.1 Hz, 3 H, 3′′-H3), 1.25 (t, 3 J = 7.1 Hz, 3 H, CO2CH2CH3),* 1.27 (t, 3 J = 7.1 Hz, 3 H, CO2CH2CH3),* 1.59 (s, 3 H, 7′-CH3), 1.63 (s, 3 H, 3′-CH3), 1.68 (s, 3 H, 8′-H3), 1.94-2.00 (m, 2 H, 4′-H2), 2.01-2.08 (m, 2 H, 5′-H2), 2.34 (dd, 2 J = 13.5 Hz, 3 J = 5.0 Hz, 1 H, 1′′-HA),* 2.35 (dd, 2 J = 13.5 Hz, 3 J = 5.0 Hz, 1 H, 1′′-HA),* 2.40 (dd, 2 J = 13.7 Hz, 3 J = 7.8 Hz, 1′′-HB),* 2.46-2.53 (overlapped, m, 1 H, 1′-HA), 2.59-2.67 (overlapped, m, 1 H, 1′-HB), 3.26 (dd, 3 J = 4.3 Hz, 3 J = 6.8 Hz, 1 H, 2-H),* 3.27 (dd, 3 J = 4.3 Hz, 1 H, 3 J = 6.8 Hz, 1 H, 2-H)*, 4.14-4.20 (overlapped, 2 H, OCH2), 4.18-4.30 (m, 1 H, 2′′-H), 5.02-5.09 (m, 2 H, 2′-H, 6′-H), 5.621 (s, 1 H, 4-H),* 5.623 (s, 1 H, 4-H),* 15.19 (br s, 1 H, enolic H). 13C NMR (125 MHz, CDCl3): δ = -5.11 (2 × SiCH3), -4.71 (SiCH3), -4.69 (SiCH3), 14.09 (CO2CH2CH3), 16.10 (3′-CH3), 17.60 (7′-CH3), 17.96 [SiC(CH3)3], 24.10, 24.12 (C-3′′)*, 25.60 (C-8′), 25.72 [SiC(CH3)3], 26.57 (C-5′), 27.84, 28.00 (C-1′)*, 39.67 (C-4′), 47.79, 47.83 (C-1′′),* 55.97, 56.03 (C-2),* 61.21, 61.23 (OCH2),* 66.21 (C-2′′), 100.47, 100.54 (C-4),* 119.78, 119.83 (C-2′)*, 123.97, 124.01 (C-6′),* 131.44, 131.50 (C-7′),* 138.28, 138.31 (C-3′),* 169.87, 169.88 (C-1),* 188.87, 189.06 (C-5),* 192.3 (C-3). Tautomer T2: 1H NMR (500 MHz, CDCl3): δ = 2.52 (overlapped, 1′′-HA), 2.57 (overlapped, 2 H, 1′-H2), 2.69 (overlapped, 1′′-HB), 3.56 (t, 3 J = 7.5 Hz, 1 H, 2-H),* 3.57 (t, 3 J = 7.5 Hz, 1 H, 2-H),* 3.61 (d, 2 J = 15.8 Hz, 1 H, 4-HA, D3), 3.70 (s, 2 H, 4-H2, D4), 3.77 (d, 2 J = 15.8 Hz, 1 H, 4-HB, D3), 4.28 (overlapped, 2′′-H). 13C NMR (125 MHz, CDCl3): δ = 26.82 (C-1′), 39.64 (C-4′), 57.32, 57.36 (C-4),* 52.83 (C-1′′), 59.49, 59.47 (C-2),* 65.38 (C-2′′), 119.34, 119.36 (C-2′),* 138.34 (C-3′), 169.57 (C-1), 199.03 (C-3), 202.73 (C-5). MS (EI, 70 eV): m/z (%) = 466.0 (15) [M+]. HRMS: m/z calcd for C26H46O5Si: 466.31027; found: 466.30818. * Unambiguous assignment was not possible.

9

Synthesis of 9a from 5a: A solution of 5a (3.46 g, 7.43 mmol) in EtOH (15 mL) was treated with a solution of KOH (2.43 g, 41.0 mmol) in anhyd EtOH (30 mL) at r.t. and the resulting mixture was stirred for 3 h at r.t. The volatiles were removed in vacuo, the residue dissolved in distilled H2O (ca. 30 mL) and then poured into a vigorously stirred mixture of CH2Cl2 (300 mL at -20 °C) and aq tartaric acid solution (10%, 200 mL at 4 °C). The reaction mixture was stirred for 10 min and the precipitated potassium hydrogen tartrate was filtered off. The filter cake was washed with CH2Cl2 (100 mL at -20 °C), the filtrates were combined and the organic phase was separated. The aqueous phase was saturated with solid NaCl and extracted twice with cold CH2Cl2. The organic phases were combined and dried over MgSO4 and the volatiles were removed in vacuo (heating bath temperature: max. 5 °C). The crude product was immediately dissolved in cold Ac2O (30 mL at -20 °C). Then pyridine (1 mL) was added and the resulting mixture was stirred for 2 h at 0 °C. The excess Ac2O was removed in vacuo without heating and the residue was dissolved in MeOH (50 mL). After addition of K2CO3 (5.67 g, 41.0 mmol) the mixture was stirred for 2 h at r.t. The volatiles were removed in vacuo and the residue was dissolved in distilled H2O (200 mL). The mixture was acidified with glacial AcOH to pH 3, saturated with solid NaCl and extracted with CH2Cl2 (3 ×). The combined organic phases were washed twice with H2O and dried over MgSO4. The volatiles were removed in vacuo (traces of AcOH were removed azeotropically with toluene) and the residue was submitted to flash chromatography (SiO2; PE-EtOAc, 8:2). Pyrone 9a (2.38 g, 76%) was obtained as a colorless oil that solidified on storage at -20 °C.

10

Selected data for 2: IR (ATR): 2965, 2913, 2726, 1667, 1579, 1431, 1409, 1273 cm-1. UV (MeOH): λmax (log ε) = 224 (4.21), 335 (4.40) nm. 1H NMR (500 MHz, CD3OD): δ = 1.23 (d, 3 J = 6.2 Hz, 3 H, 3′′-H3), 1.58 (s, 3 H, 7′-CH3), 1.64 (s, 3 H, 8′-H3), 1.73 (s, 3 H, 3′-CH3), 1.94-1.99 (m, 2 H, 4′-H2), 2.03-2.10 (m, 2 H, 5′-H2), 2.53 (dd, 2 J = 14.4 Hz, 3 J = 7.7 Hz, 1 H, 1′′-HA), 2.58 (dd, 2 J = 14.5 Hz, 3 J = 5.3 Hz, 1 H, 1′′-HB), 3.08 (d, 3 J = 7.2 Hz, 2 H, 1′-H2), 4.08-4.15 (m, 1 H, 2′′-H), 5.07 (br t, 3 J = 7.0 Hz, 1 H, 6′-H), 5.17 (br t, 3 J = 7.0 Hz, 1 H, 2′-H), 6.06 (s, 1 H, 5-H). 13C NMR (125 MHz, CD3OD): δ = 16.27 (3′-CH3), 17.71 (7′-CH3), 22.79 (C-1′), 23.39 (C-3′′), 25.86 (C-8′), 27.68 (C-5′), 40.84 (C-4′), 44.01 (C-1′′), 66.19 (C-2′′), 102.92 (C-5), 103.63 (C-3), 122.44 (C-2′), 125.38 (C-6′), 132.08 (C-7′), 136.54 (C-3′), 162.29 (C-6), 167.41 (C-4), 168.62 (C-2). MS (EI, 70 eV): m/z (%) = 306 (41) [M+], 237 (28) [M+ - C4H5O], 183 (36) [M+ - C4H15], 139 (80) [M+ - C10H15O2], 123 (52) [C9H15 +], 69 (100) [C4H3O+], 41 (90) [C3H6 +].