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Synlett 2005(20): 3131-3135  
DOI: 10.1055/s-2005-921933
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Concise Approach to Benzoic Acid Derivatives Bearing an α,β-Unsaturated Ketone Substituent: Synthesis of Methyl Taboganate

Anastasia Detsia, Vassilios Roussisb, Andrew Tsotinisc, Christos Roussakisd, Theodora Calogeropoulou*a
a Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., 116 35 Athens, Greece
Fax: +30(210)7273831; e-Mail: tcalog@eie.gr;
b University of Athens, Faculty of Pharmacy, Dept. of Pharmacognosy and Chemistry of Natural Products, Panepistimiopoli Zografou, 15771 Athens, Greece
c University of Athens, Faculty of Pharmacy, Dept. of Pharmaceutical Chemistry, Panepistimiopoli Zografou, 15771 Athens, Greece
d Laboratoire de Pharmacologie Marine, Faculté de Pharmacie, 1 rue G. Veil, 44035 Nantes, France
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Publication History

Received 12 October 2005
Publication Date:
28 November 2005 (online)

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Abstract

A concise route to benzoic acid derivatives bearing an α,β-unsaturated ketone moiety and its application to the synthesis of the natural product methyl taboganate (1) is described. The methodology is based on the addition of a Grignard reagent to an appropriately substituted salicylaldehyde followed by oxidation of the resulting allylic alcohol to the corresponding α,β-unsaturated ketone. The new compounds were tested for their cytotoxic activity.

Key words

methyl taboganate - α,β-unsaturated ketones - cytotoxicity

    References

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    General Procedure for the Synthesis of Allylic Alcohols 19-21.
    To a 0.07 M solution of 3-formyl-4-hydroxy-benzoic acid methyl ester (15, 1 equiv) in THF was added dropwise a solution of the appropriate Grignard reagent 16-18 (0.5 M in THF, 5 equiv) at -78 °C over a period of 10 min. After stirring for 1 h, the reaction was quenched with sat. NH4Cl at -78 °C, the mixture was extracted with EtOAc (3 × 15 mL), dried (Na2SO4) and the solvents were evaporated in vacuo. The yellowish oily crude product was used for the next reaction without purification. 4-Hydroxy-3-(1-hydroxy-3-methylbut-2-enyl)benzoic Acid Methyl Ester ( 19). 1H NMR (300 MHz, CD3COCD3): δ = 7.91 (d, J = 2.40 Hz, 1 H), 7.79-7.76 (m, 1 H), 6.88 (d, J = 8.50 Hz, 1 H), 5.79 (d, J = 9.15 Hz, 1 H), 5.41 (d, J = 9.15 Hz, 1 H), 3.83 (s, 3 H), 1.81 (s, 3 H), 1.73 (s, 3 H). 4-Hydroxy-3-(1-hydroxybut-2-enyl)benzoic Acid Methyl Ester ( 20).
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7

1-(2-Methoxy-5-carboxymethylphenyl)-1-trimethyl-silyloxyethylene ( 11). 3-Acetyl-4-methoxybenzoic acid methyl ester (10, 4.16 g, 0.02 mol) was dissolved in Et3N (3.8 mL, 0.027 mol) followed by the addition of TMSCl (3.4 mL, 0.027 mol) and the resulting solution was heated at 35 °C. A solution of NaI (4.05 g, 0.027 mol) in MeCN (25 mL) was added at such a rate to keep the temperature at 35-40 °C without external heating. After completion of the addition, the mixture was stirred at r.t. for 2 h and was subsequently poured onto cold H2O (350 mL) and extracted with Et2O. The organic layer was dried (K2CO3) and the solvent was evaporated in vacuo to afford 1-(2-methoxy-5-carboxymethylphenyl)-1-trimethylsilyloxyethylene (11) as an oil (5.13 g, 92%). 1H NMR (300 MHz, CDCl3): δ = 8.18 (d, J = 2.14 Hz, 1 H), 7.92 (dd, J = 8.73, 2.17 Hz, 1 H), 6.89 (d, J = 8.71 Hz, 1 H), 4.98 (s, 1 H), 4.68 (s, 1 H), 3.90 (s, 3 H), 3.85 (s, 3 H), 0.25 (s, 9 H).
1-(2-Methoxy-5-carboxymethylphenyl)-3-hydroxy-3-methyl-1-butanone ( 12). TiCl4 (2 mL, 0.018 mol) was added to ice-chilled CH2Cl2 (26 mL) followed by the dropwise addition of a solution of CH3COCH3 (1.5 mL, 0.021 mol) in CH2Cl2 (5.5 mL). Upon completion of the addition a solution of 1-(2-methoxy-5-carboxymethylphenyl)-1-trimethylsilyloxyethylene (11, 5.13 g, 0.018 mol) in CH2Cl2 (2.5 mL) was added and the resulting solution was stirred for 15 min. The reaction mixture was poured onto ice water with vigorous stirring and the organic layer was separated. The aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with a 1:1 mixture of sat. aq NaHCO3 and H2O, brine and were dried (Na2SO4). The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (PE-EtOAc, 1:1) to afford 1-(2-methoxy-5-carboxymethylphenyl)-3-hydroxy-3-methyl-1-butanone (12) as a viscous oil (3.35 g, 69%). 1H NMR (300 MHz, CDCl3): δ = 8.31 (d, J = 2.14 Hz, 1 H), 8.15 (dd, J = 8.73, 2.18 Hz, 1 H), 6.99 (d, J = 8.71 Hz, 1 H), 3.96 (s, 3 H), 3.90 (s, 3 H), 3.15 (s, 2 H), 1.31 (s, 6 H).
Methyl 4-Methoxy-3-(3-methyl-2-butenoyl)benzoate ( 13). To an ice-cold solution of 1-(2-methoxy-5-carboxymethyl-phenyl)-3-hydroxy-3-methyl-1-butanone (12, 2.85 g, 0.012 mol) in Et3N (5.3 mL, 0.038 mol) and CH2Cl2 (5.3 mL) was added dropwise SO2Cl (1.60 mL, 0.022 mol) during 30 min. The mixture was then stirred for 2 h, poured onto 53 g of crushed ice and extracted with EtOAc. The combined organic extracts were washed with 1 M HCl, H2O, sat. aq NaHCO3, brine, then dried (Na2SO4), and concentrated under vacuum. The crude product was purified by flash column chromatography (PE-EtOAc, 85:15) as eluent to give the title compound (2.53 g, 90%) as an off-white solid; mp 47-48 °C. Anal. Calcd for C14H16O4: C, 67.73; H, 6.50. Found: C, 68.01; H, 6.64. 1H NMR (300 MHz, CDCl3): δ = 8.19 (d, J = 2.20 Hz, 1 H), 8.08 (dd, J = 8.70, 2.20 Hz, 1 H), 6.95 (d, J = 8.75 Hz, 1 H), 6.53 (d, J = 2.50 Hz, 1 H), 3.91 (s, 3 H), 3.88 (s, 3 H), 2.21 (s, 3 H), 1.96 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 191.8, 166.3, 161.0, 156.1, 133.8, 131.8, 131.1, 124.9, 122.8, 111.3, 56.0, 51.9, 27.9, 21.3.

18

General Procedure for the Synthesis of α,β-Unsaturated Ketones. The crude allylic alcohols 19-21 were dissolved in dry MeCN (1.3% w/v), activated MnO2 85% (5-fold w/w) was added in one portion. After stirring the reaction mixture at r.t. overnight, it was filtered through Celite, which was washed with EtOAc (4 × 20 mL). Evaporation of the solvents followed by purification by flash column chromatography afforded pure α,β-unsaturated ketones 1, 22 and 23, respectively.
4-Hydroxy-3-(3-methylbut-2-enoyl)benzoic Acid Methyl Ester (Methyl Taboganate, 1).
According to the general procedure from 62 mg of crude allylic alcohol 19 (obtained from 50 mg, 0.28 mmol of aldehyde 15), 1 was obtained (25 mg, 40% overall yield, after purification by flash column chromatography using PE-EtOAc, 92:8) as a light yellow crystalline solid; mp 92-94 °C (lit. [2] mp 91-95 °C). 1H NMR (300 MHz, CDCl3): δ = 13.30 (s, 1 H), 8.46 (d, J = 1.83 Hz, 1 H), 8.04 (dd, J = 8.80, 2.10 Hz, 1 H), 6.94 (d, J = 8.50 Hz, 1 H), 6.84 (s, 1 H), 3.87 (s, 3 H), 2.21 (s, 3 H), 2.05 (s, 3 H).
3-But-2-enoyl-4-hydroxybenzoic Acid Methyl Ester ( 22).
Following the general procedure, from 220 mg of crude alcohol 20 (obtained from 150 mg, 0.83 mmol of aldehyde 15), 22 was obtained as a yellow solid [90 mg, 50% overall yield after purification by flash column chromatography (PE-EtOAc, 90:10)]. Anal. Calcd for C12H12O4: C, 65.45; H, 5.49. Found: C, 65.42; H, 5.33. Ratio of cis:trans = 9:1. 1H NMR (300 MHz, CDCl3): δ = 13.18 (s, 0.9 H), 13.07 (s, 0.1 H), 8.55 (d, J = 1.83 Hz, 0.9 H), 8.50 (d, J = 2.43 Hz, 0.1 H), 8.10 (dd, J = 8.85, 2.13 Hz, 1 H), 7.33-7.11 (m, 1.8 H), 7.04-6.94 (m, 0.1 H), 6.98 (d, J = 8.55 Hz, 1 H), 6.61-6.52 (m, 0.1 H), 3.93 (s, 2.7 H), 3.90 (s, 0.3 H), 2.18 (dd, J = 7.32, 1.83 Hz, 0.3 H), 2.06 (d, J = 6.09 Hz, 2.7 H). 13C NMR (75 MHz, CDCl3): δ = 193.8, 167.2, 166.1, 147.3, 136.9, 132.6, 132.4, 125.0, 124.9, 123.5, 120.8, 118.8, 118.7, 52.2, 18.8.
4-Hydroxy-3-(3-phenylacryloyl)benzoic Acid Methyl Ester ( 23).
According to the general procedure from 200 mg of crude allylic alcohol 21 (obtained from 60 mg, 0.33 mmol of aldehyde 15), the α,β-unsaturated ketone 23 was obtained as a bright yellow solid [38 mg, 41% overall yield after purification by flash column chromatography (PE-EtOAc, 95:5)]. Anal. Calcd for C17H14O4: C, 72.33; H, 5.00. Found: C, 72.05; H, 5.21. Ratio of trans:cis = 3:1. 1H NMR (300 MHz, CDCl3): δ = 13.32 (s, 0.75 H), 12.68 (s, 0.25 H), 8.67 (d, J = 1.83 Hz, 0.75 H), 8.49 (d, J = 2.43 Hz, 0.25 H), 8.15 (dd, J = 8.55, 1.83 Hz, 0.75 H), 8.10 (dd, J = 8.55, 2.13 Hz, 0.25 H), 7.98 (d, J = 15.00 Hz, 0.75 H), 7.76 (d, J = 15.00 Hz, 0.75 H), 7.73-7.71 (m, 2 H), 7.47-7.45 (m, 2 H), 7.29-7.27 (m, 1 H), 7.13 (d, J = 12.81 Hz, 0.25 H), 7.05 (d, J = 8.52 Hz, 0.75 H), 7.01 (d, J = 8.55 Hz, 0.25 H), 6.73 (d, J = 12.81 Hz, 0.25 H), 3.94 (s, 2.25 H), 3.88 (s, 0.75 H). 13C NMR (75 MHz, CDCl3): δ = 193.5, 167.2, 146.7, 166.1, 137.0, 134.3, 132.2, 131.3, 129.4, 129.1, 129.0, 128.4, 120.9, 119.4, 118.8, 52.2.

19

trans -4-Hydroxy-3-(3-phenylacryloyl)benzoic Acid Methyl Ester.
Separated from the trans-cis mixture 25, using HPLC (column DAICEL-CHIRACEL OD, 254 nm, 1.2 mL/min, hexane-2-PrOH, 80:20, t R = 28 min). 1H NMR (300 MHz, CDCl3): δ = 13.31 (s, 1 H), 8.67 (d, J = 2.50 Hz, 1 H), 8.17 (dd, J = 9.15, 1.83 Hz, 1 H), 7.99 (d, J = 16.00 Hz, 1 H), 7.73 (d, J = 16.00 Hz, 1 H), 7.73-7.70 (m, 2 H), 7.48-7.45 (m, 3 H), 7.06 (d, J = 9.15 Hz, 1 H), 3.94 (s, 3 H).

20

Hydroxy-3-(3-methylbutyryl)benzoic Acid Methyl Ester ( 26).
To a solution of 1 (20 mg, 0.085 mmol) in EtOAc (2 mL) was added 10% Pd/C (2 mg). The suspension was stirred under 1 atm of H2 for 1 h. The reaction mixture was filtered through Celite, which was washed with EtOAc, and the filtrate was concentrated in vacuo to afford compound 26 (17 mg, 85%) as an off-white solid; mp 43-44 °C. Anal. Calcd for C13H16O4: C, 66.09; H, 6.83. Found: C, 66.12; H, 6.89. 1H NMR (300 MHz, CDCl3): δ = 12.88 (s, 1 H), 8.49 (d, J = 1.83 Hz, 1 H), 8.11 (dd, J = 8.83, 2.14 Hz, 1 H), 7.00 (d, J = 8.55 Hz, 1 H), 3.91 (s, 3 H), 2.91 (d, J = 6.69 Hz, 2 H), 2.34-2.27 (m, 1 H), 1.02 (d, J = 6.72 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 206.7, 166.2, 166.0, 136.9, 132.6, 120.9, 119.1, 118.7, 52.2, 30.9, 25.3, 22.7.