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

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.

hydrolyses - cyclizations - lactones - heterocycles - ­natural products

References and Notes

1a Lincoln DE. Biochem. Syst. Ecol.  1980,  8:  397 

1b Hare JD. Biochem. Syst. Ecol.  2002,  30:  281 

1c Hare JD. Biochem. Syst. Ecol.  2002,  30:  709 

2a Lincoln DE. J. Chem. Ecol.  1985,  11:  1459 

2b Lincoln DE. Newton TS. Ehrlich PR. Williams KS. Oecologia  1982,  52:  216 

3a Wollenweber E. Schober I. Schilling G. Arriaga-Giner FJ. Roitman JN. Phytochemistry  1989,  28:  3493 

3b Lincoln DE. Walla MD. Biochem. Syst. Ecol.  1986,  14:  195 

4 Hare JD. Borchardt DB. Phytochemistry  2002,  59:  375 

5 Schmidt D. Conrad J. Klaiber I. Beifuss U. Chem. Commun.  2006,  4732 

6 Lygo B. Tetrahedron  1995,  51:  12859 

7

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): λ_max (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′-H_A, D2), 1.925 (d, ³ J = 2.9 Hz, 1 H, 3′-H_A, D1), 2.37 (d, ³ J = 5.9 Hz, 1 H, 3′-H_B, D2), 2.38 (d, ³ J = 6.2 Hz, 1 H, 3′-H_B, D1), 2.43 (dd, ² J = 9.7 Hz, ³ J = 5.3 Hz, 1 H, 2-H_A),^* 2.45 (dd, ² J = 9.3 Hz, ³ J = 5.0 Hz, 1 H, 2-H_A),^* 2.53 (overlapped, 2′-H, D1), 2.56 (overlapped, 2-H′, D2), 2.59 (overlapped, 2-H_B),^* 2.61 (dd, ² J = 10.1 Hz, ³ J = 7.7 Hz, 1 H, 2-H_B),^* 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.

8

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): λ_max (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′′-H_A),^* 2.35 (dd, ² J = 13.5 Hz, ³ J = 5.0 Hz, 1 H, 1′′-H_A),^* 2.40 (dd, ² J = 13.7 Hz, ³ J = 7.8 Hz, 1′′-H_B),^* 2.46-2.53 (overlapped, m, 1 H, 1′-H_A), 2.59-2.67 (overlapped, m, 1 H, 1′-H_B), 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′′-H_A), 2.57 (overlapped, 2 H, 1′-H₂), 2.69 (overlapped, 1′′-H_B), 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-H_A, D3), 3.70 (s, 2 H, 4-H₂, D4), 3.77 (d, ² J = 15.8 Hz, 1 H, 4-H_B, 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): λ_max (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′′-H_A), 2.58 (dd, ² J = 14.5 Hz, ³ J = 5.3 Hz, 1 H, 1′′-H_B), 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 ⁺].