Efficient Access to Novel Furanofurone Compounds from Quinic Acid: Studies of Inter-and Intramolecular Wittig Reactions on Lactones

Abstract

(-)-Quinic acid has been converted into derivatives of a furo[3,2-b]furan-2-one system using Wittig olefination reactions of lactones. Studies for this transformation included the use of microwave-assisted reactions.

Key words

quinic acid - furanofurone systems - Wittig olefination reactions on lactones - microwave-assisted reactions - heterocycles

References and Notes

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• Cytotoxic compounds isolated from plants of Goniothala mus species. See:
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• 7 Isolated from plants of Scrophularia species and used in Asian herbal medicine. See: Han JS. Lowary TL. J. Org. Chem.  2003,  68:  4116 
• 8 Isolated from Stemona species, which present insecticidal activities. See: Kaltenegger E. Brem B. Mereiter K. Kalchhauser H. Kählig H. Hofer O. Vajrodaya S. Greger H. Phytochemistry  2003,  63:  803 
• 9 A potent enzyme activator used for cardiac irregularities, isolated from Caribbean sponges of the genus Plakortis. See: Hayes PY. Kitching W. J. Am. Chem. Soc.  2002,  124:  9718 
• 10 Compounds found in braconid wasps. See: Mereyala HB. Gadikota RR. Tetrahedron: Asymmetry  2000,  11:  743 
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• 12 Sabitha G. Reddy MM. Srinivas D. Yadov JS. Tetrahedron Lett.  1999,  40:  165 
• 17 Desmaële D. Tetrahedron Lett.  1996,  37:  1233 
• 18 Bittner C. Burgo A. Murphy PJ. Sung CH. Thornhill AJ. Tetrahedron Lett.  1999,  40:  3455 
• 20 Small signals, always presented on the spectral data of crude 19, were attributed to the C7-epimer of 19 (less than 8% yield). This compound probably arises from a minor C7-epimer of the dialdehyde 18. A seven-membered lactone, possible by intramolecular transesterification reaction of 19, was not observed.

13

Microwave labstation MicroSYNTH (Millestone) operating at 2.45 GHz, dual magnetron system with delivered microwave power of 1000 W (pulsed irradiation), equipped with a thermocouple temperature control system. All experiments were conduced in sealed vessels (20 mL - the volume of the reactions were no more than 10% of this) with magnetic stirring.

14

The lactone 3 was recovered intact when treated, with or without the assistance of microwaves, with diethylphosphonoacetate and bases (Horner-Wadsworth-Emmons olefinations).

15

Batches of several reaction mixtures were combined for chromatographic purification.

16

Reaction of Lactone 3 with Ph ₃ PCHCOOEt under Microwave Irradiation A 20 mL microwave vessel (for reactions up to 4 bar) containing a mixture of 3 (200 mg, 0.93 mmol), freshly distilled chlorobenzene (2 mL), and ethoxycarbonyl-methylene(triphenyl) phosphorane (5, 500 mg, 1.43 mmol) was connected to a temperature sensor, and the apparatus was irradiated for 1 h in a microwave equipment programmed for temperature control: 15 min to reach 180 °C and then 1 h at this temperature. After cooling, the mixture was evaporated. The residue was purified by silica gel column chromatography (hexane-EtOAc 15%) to give 6 (39%) and 8 (46%), besides unchanged lactone 3 (10%). When batches of several reaction mixtures were combined for chromatographic purification, compounds 7 (7%), 9 (1%), and 10 (4%) were also isolated.
Compound 6: [α]_D ²⁰ 47.6 (c 0.58, CHCl₃). IR (film): ν_max = 3392, 1687, 1650 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.24 (t, 3 H, J = 7.0 Hz), 1.28 and 1.48 (2 × s, 2 × 3 H), 2.08 (dd, 1 H, J = 4.3, 13.7 Hz), 2.11 (dddd, 1 H, J = 1.0, 2.6, 6.1, 11.5 Hz), 2.27 (ddd, 1 H, J = 2.6, 8.2, 13.7 Hz), 2.38 (d, 1 H, J = 11.5 Hz), 3.35 (br s, 1 H), 4.11 (q, 2 H, J = 7.0 Hz), 4.28 (ddd, 1 H, J = 1.0, 2.9, 6.2 Hz), 4.38 (ddd, 1 H, J = 4.3, 6.2, 8.2 Hz), 4.82 (dd, 1 H, J = 2.9, 6.1 Hz), 5.05 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.2, 24.7, 27.3, 36.0, 42.0, 59.8, 71.7, 72.6, 76.2, 79.8, 86.7, 110.0, 166.4, 174.6. HRMS (EI): m/z calcd for C₁₄H₂₀O₆: 284.12598; found: 284.12726.
Compound 8: mp 77.5-78.1 °C. [α]_D ²⁰ -135.5 (c 0.34, CHCl₃). IR (KBr): ν_max = 1767, 1664 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.32 and 1.51 (2 × s, 2 × 3 H), 2.10 (ddd, 1 H, J = 2.1, 7.1, 15.1 Hz), 2.18 (dddd, 1 H, J = 1.9, 2.1, 6.3, 11.4 Hz), 2.59 (dd, 1 H, J = 1.6, 15.1 Hz), 2.74 (d, 1 H, J = 11.4 Hz), 4.36 (dt, 1 H, J = 1.9, 7.1 Hz), 4.61 (tdd, 1 H, J = 1.0, 1.6, 7.1 Hz), 4.87 (s, 1 H) 5.03 (ddd, 1 H, J = 1.0, 1.9, 6.3 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 24.0, 26.8, 32.7, 35.9, 71.8, 73.1, 82.4, 84.0, 89.2, 109.7, 173.4, 187.7. HRMS (EI): m/z calcd for C₁₂H₁₄O₅: 238.08412; found: 238.08394.
Compound 7: [α]_D ²⁰ -47.7 (c 0.28, CHCl₃). IR (film): ν_max = 3268, 1685, 1676 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.29 (t, 3 H, J = 7.1 Hz), 1.32 and 1.51 (2 × s, 2 × 3 H), 2.09 (dd, 1 H, J = 4.9, 13.4 Hz), 2.27 (dddd, 1 H, J = 1.2, 2.5, 6.0, 11.7 Hz), 2.46 (d, 1 H, J = 11.7 Hz), 2.60 (ddd, 1 H, J = 2.5, 8.2, 13.4 Hz), 4.18 (m, 2 H), 4.21 (m, 1 H), 4.35 (ddd, 1 H, J = 4.9, 6.3, 8.2 Hz), 4.78 (dd, 1 H, J = 3.0, 6.0 Hz), 5.30 (s, 1 H), 7.03 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.1, 24.9, 27.3, 37.1, 41.6, 60.6, 71.9, 73.0, 76.3, 79.6, 90.5, 110.0, 170.2, 180.2. HRMS (EI): m/z calcd for C₁₄H₂₀O₆: 284.12598; found: 284.12315.
Compound 9: IR (film): ν_max = 1802, 1748 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.33 and 1.52 (2 × s, 2 × 3 H), 2.12 (s, 3 H) 2.31 (dd, 1 H, J = 3.0, 14.5 Hz), 2.45 (ddd, 1 H, J = 2.1, 7.3, 14.5 Hz), 2.54 (d, 1 H, J = 11.3 Hz), 3.05 (dddd, 1 H, J = 1.2, 2.1, 6.2, 11.3 Hz), 4.32 (ddd, 1 H, J = 1.2, 2.4, 7.3 Hz), 4.53 (td, 1 H, J = 3.0, 7.3 Hz), 4.78 (dd, 1 H, J = 2.4, 6.2 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 24.3, 26.9, 30.3, 35.5, 71.0, 72.4, 75.3, 76.0, 109.9, 169.2, 173.5. HRMS (EI): m/z calcd for C₁₂H₁₆O₆: 256.09468; found: 256.09362.
Compound 10: IR (film): ν_max = 1791 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.24 (t, 1 H, J = 7 Hz) 1.32 and 1.51 (2 × s, 2 × 3 H), 2.17 (m, 1 H), 2.39 (dd, 1 H, J = 1.8, 13.0 Hz), 2.42 (m, 2 H), 3.57 and 3.63 (2 × m, 2 × 1 H), 4.28 (dd, 1 H, J = 1.8, 6.8 Hz), 4.51 (td, 1 H, J = 2.5, 6.8 Hz), 4.67 (dd, 1 H, J = 2.5, 5.5 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 15.5, 24.3, 27.0, 30.3, 36.0, 60.2, 71.4, 72.3, 74.9, 76.5, 109.6, 175.9. HRMS (EI): m/z calcd for C₁₂H₁₈O₅: 242.11543; found: 242.11399.

19

Preparation of 8 via the Bromoacetyl Derivative 12
1) A solution of 3 (200 mg, 0.93 mmol) in anhyd Et₂O (15 mL), under argon atmosphere, was stirred at 0 °C, and anhyd pyridine (100 µL, 1.2 mmol) was added, followed by bromoacetyl bromide (100 µL, 1.15 mmol). The solution was slowly warmed to r.t., in the absence of light, and the stirring was maintained for 2 h. Then, H₂O (15 mL) was added and the aqueous layer was separated and extracted two more times with Et₂O (15 mL). The combined organic layers were washed sequentially with H₂O (25 mL), sat. CuSO₄ solution (25 mL), H₂O (25 mL) and brine (25 mL), separated, and dried (MgSO₄). After filtration, the solvent was concentrated to give crude 12 in 89% yield (278 mg), used without purification in the next step. For characterization, a small sample was purified by flash chromatography (hexane-EtOAc 20%), to give 12 as white crystals; mp 85.0-87.5 °C. [α]_D ²⁰ 1.69 (c 1.4, CHCl₃). IR (KBr): ν_max = 2809, 1759 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.34 and 1.53 (2 × s, 2 × 3 H), 2.37 (dd, 1 H, J = 3.3, 14.6 Hz), 2.50 (ddd, 1 H, J = 2.4, 7.2, 14.6 Hz), 2.63 (d, 1 H, J = 11.4 Hz), 3.02 (dddd, 1 H, J = 1.3, 2.4, 6.2, 11.4 Hz), 3.88 (s, 2 H) 4.33 (ddd, 1 H, J = 1.3, 2.5, 7.2 Hz), 4.55 (td, 1 H, J = 3.3, 7.2 Hz), 4.80 (dd, 1 H, J = 2.5, 6.2 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 24.3, 25.2, 26.9, 30.3, 35.3, 71.0, 72.3, 75.4, 77.6, 110.1, 165.4, 172.6. HRMS (EI): m/z calcd for C₁₂H₁₅BrO₆: 335.00862; found: 320.9851 [M - CH₃]. 2) Triphenylphosphine (188 mg, 0.72 mmol) was added to a solution of 12 (200 mg, 0.6 mmol) in anhyd MeCN (2 mL) at r.t.; and the resulting mixture was warmed to 50 °C and maintained for 2 h. After cooling (-15 °C), DBU (73 mg, 0.48 mmol) was slowly added. The mixture was stirred at this temperature for 10 min and then warmed to 50 °C for 15 min. The reaction was then cooled (0 °C), diluted with Et₂O (30 mL), and filtered through a short silica column, which was washed with further Et₂O. Evaporation of the solvent and flash chromatography (hexane-EtOAc 15%) of the crude residue gave 8 as a white crystalline solid in 92% yield (131 mg).

21

Data for Compound 21 - [(4 S ,5 S ,7 S )-7-(2-Phenylethyl)-5-(3-phenylpropyl)tetrahydrofuro[3,2- b ]furan-2 (3 H )-one] [α]_D ²⁰ -14.5 (c 0.27, CHCl₃). IR (film): ν_max = 1779 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.59 (dd, 1 H, J = 10.3, 13.4 Hz), 1.70-1.97 (m, 6 H), 2.37 (dd, 1 H, J = 4.6, 13.4 Hz), 2.61-2.79 (m, 4 H), 2.65 (d, 1 H, J = 18.8 Hz), 2.79 (dd, 1 H, J = 6.2, 18.8 Hz), 4.46 (d, 1 H, J = 6.2 Hz), 4.73 (m, 1 H), 7.16-7.34 (m, 10 H). ¹³C NMR (125 MHz, CDCl₃): δ = 26.0, 32.2, 35.6, 36.2, 36.3, 37.0, 42.8, 77.7, 80.7, 96.5, 125.9, 126.0, 128.2, 128.3, 128.4, 141.2, 141.3, 175.5. HRMS (EI): m/z calcd for C₂₃H₂₆O₃: 350.45094; found: 350.45186.