Elson Santiago de Alvarenga^a*, and John Mann^b

a Departamento de Química, Universidade Federal de Viçosa 36571-000 Viçosa - Minas Gerais, Brazil

^b Chemistry Department, Reading University, Whiteknights, Reading, RG6 6AD, England

Ácido orselínico é benzilado e 4-benziloxi-2-hidroxi-6-metilbenzoato de benzila (7) é então convertido no composto desejado (2), o qual é o constituinte aromático de calicheamicin g₁^I.

 

Orsellinic acid (6) was benzylated, and the benzyl 4-benzyloxy-2-hydroxy-6-methylbenzoate (7) was then elaborated into the title compound (2), which is the aromatic constituent of calicheamicin g₁I.

Keywords: calicheamicin g₁^I, antitumour, orsellinic acid

In this work we describe the synthesis of benzyl 4-hydroxy-5-iodo-2,3-dimethoxy-6-methylbenzoate (2) from the readily available 3,5-dimethoxytoluene (3).

Benzyl 4-benzyloxy-2-hydroxy-6-methylbenzoate (7) and Benzyl 2,4-dibenzyloxy-6-methylbenzoate (8)

To a mixture of orsellinic acid (6) (5.0 g, 29.7 mmoles) and anhydrous potassium carbonate (15.0 g, 108.5 mmoles) in dry acetone (150 mL) was added benzyl bromide (14.0 g, 81.9 mmoles). The mixture was stirred under reflux in an atmosphere of argon for 7 h. The heating was removed and the mixture was poured into 2 M hydrochloric acid (500 mL). The mixture was extracted with petrol-diethyl ether 4:6 (4 x 200 mL) and the combined organic layers dried (MgSO₄), filtered and evaporated to dryness. The white crystalline residue was mixed with silica gel and purified by column chromatography eluting with petrol-diethyl ether 8:2. The dibenzyl compound was obtained as white crystalline needles (4.3 g, MW 348.398, 42%) and the tribenzyl as white crystalline plates (7.6 g, 58%).

Compound 7

Compound 8

Benzyl 4-benzyloxy-2-hydroxy-3-formyl-6- methylbenzoate (9)

A 1.0 M dichloromethane solution of titanium (IV) chloride (75 mL, 75 mmoles) was added dropwise to a vigorously stirred cooled (-10 °C) solution of the dibenzyl (7) (10.37 g, 29.8 mmoles) and dichloromethyl methyl ether^# (7.5 g, 65.2 mmoles) in dry dichloromethane (150 mL) under argon atmosphere. Stirring was continued for a further 3 h at 0 °C, and then poured into ice-cold hydrochloric acid (500 mL). The resulting suspension was transferred to a separating funnel and the layers separated. The aqueous layer was extracted with diethyl ether-petrol 6:4 (3 x 350 mL). The dichloromethane was evaporated under vacuum and the residue was combined with the ether-petrol layers. The organic mixture was washed with water (2 x 100 mL), filtered through a pad of silica gel, and the silica washed with diethyl ether (500 mL). The solvent was removed on the rotary evaporator and the residue dried under high vacuum to give a red solid which was used without any further purification (10.0 g, 89%).

Benzyl 4-benzyloxy-2,3-dihydroxy-6-methylbenzoate (10)

A solution of the aldehyde (9) (9.5 g, 25.2mmoles) in a mixture of dioxane (150 mL) and 40% sodium hydroxide (7 mL) was stirred and cooled in an ice bath under argon atmosphere. Hydrogen peroxide (30%, 60 mL) in dioxane (120 mL) was added dropwise using a pressure equalizer dropping funnel. The cooling bath was removed and after stirring for a further 1 h the solution was poured into ice-cold 2 M hydrochloric acid (250 mL) and extracted with diethyl ether (3 x 200 mL). The combined ether layers were washed with water (2 x 100 mL) and brine (2 x 100 mL) and dried (MgSO₄). The solvent was removed and the oily residue filtered through a pad of silica gel to give a yellow oil (8.8 g, 96%).

Benzyl 4-benzyloxy-2,3-dimethoxy-6-methylbenzoate (11)

A mixture of potassium carbonate (14.0 g, 102.8 mmoles), the catechol (10) (8.6 g, 23.6mmoles) and dimethyl sulphate (10.0 g, 79.3mmoles) in dry acetone (250 mL) was refluxed for 5 h under argon atmosphere. The heating was removed and after 10 min it was filtered under vacuum using a sinter funnel and the solid was washed with acetone. The filtrate was evaporated to dryness in the rotary evaporator and the residue was dissolved in diethyl ether-petrol 2:8. The solution was loaded onto a column with silica gel and eluted with the same solvent mixture to give the title compound as a crystalline solid (7.7 g, 83%).

4-Hydroxy-2,3-dimethoxy-6-methylbenzoic acid (12)

A mixture of the dibenzyl (11) (4.5 g, 11.5 mmoles) and 5% palladium on carbon (0.7) in ethyl acetate (100 mL) under an atmosphere of hydrogen was stirred overnight. The mixture was filtered and the palladium washed with ethyl acetate. The combined organic washings were evaporated under vacuum to give a yellow oil (2.33 g, 96%).

Benzyl 4-hydroxy-2,3-dimethoxy-6-methylbenzoate (13)

A mixture of the acid-phenol (12) (0.48 g, 2.26 mmoles), anhydrous potassium carbonate (0.40 g, 2.89 mmoles) and benzyl bromide (0.40 g, 2.34 mmoles) in dry acetone (20 mL) was stirred overnight at room temperature under argon atmosphere. The mixture was poured into ice cold 2 M hydrochloric acid (40 mL) and was extracted with diethyl ether (3 x 50 mL). The combined organic layers were washed with water (2 x 50 mL) and brine (1 x 50 mL) and dried (MgSO₄). The ether was removed under vacuum and the residue purified by column chromatography eluting with petrol-diethyl ether 7:3 to give the benzyl ester as an oil (0.15 g, 22%).

Methyl 4-hydroxy-2,3-dimethoxy-6-methylbenzoate (16)

A mixture of the acid-phenol (2.0 g, 9.42 mmoles), anhydrous potassium carbonate (1.5 g, 10.85 mmoles) and dimethyl sulphate (1.2 g, 9.51 mmoles) in dry acetone (50 mL) was stirred overnight at room temperature under argon atmosphere. The mixture was poured into ice cold 2 M hydrochloric acid (80 mL) and was extracted with diethyl ether (3 x 80 mL). The combined organic layers were washed with water (2 x 50 mL) and brine (1 x 50 mL) and dried (MgSO₄). The organic mixture was filtered through a pad of silica and the silica was rinsed with a further 100 mL of diethyl ether-petrol 1:1. The solvent was removed under vacuum to give (16) as a solid (1.8 g, 84%).

Methyl 4-hydroxy-5-iodo-2,3-dimethoxy-6-methylbenzoate (1)

1.0 M solution of iodine chloride in dry dichloromethane (15.0 mL) was added dropwise to a stirred solution of the methyl benzoate (16) (2.55 g, 11.3 mmoles) in dry dichloromethane (50 mL). The mixture was stirred for 5 h, diluted with dichloromethane (100 mL) and washed with aqueous Na₂S₂O₃ (2 x 30 mL), and water (1 x 30 mL). The organic layer was dried (MgSO₄) and the solvent evaporated. The residue was dissolved in petrol-ethyl acetate 1:2 (100 mL), filtered over a short column of silica gel and washed with petrol-ethyl acetate 1:2 (100 mL). The solvent was evaporated and the residue recrystallized from toluene-petrol to afford (1) as a white crystalline solid (2.56 g, 64%). The solvent of the filtrate was removed and the residue purified by column chromatography to give a further (0.80 g, 20%) of the iodo methyl ester.

4-Hydroxy-5-iodo-2,3-dimethoxy-6-methylbenzoic acid (17)

A solution of the iodo methyl ester (1) (0.4 g, 1.136 mmoles) in 2.5 M aqueous sodium hydroxide (20 mL) was refluxed for 3 h. The reaction mixture was poured into ice-cold 2 M hydrochloric acid (50 mL) and then extracted with diethyl ether (3 x 50 mL). The combined organic layers were washed with water (2 x 50 mL) and dried (MgSO₄). The solvent was evaporated under vacuum and the residue was left under high vacuum for 6 h to give the free acid as a white crystalline solid (0.35 g, 91%).

Benzyl 5-iodo-4-hydroxy-2,3-dimethoxy-6-methylbenzoate (2)

Benzyl bromide (0.2 g, 1.17 mmoles) was added by pipette to a stirred mixture of the iodo-carboxylic acid (17) (0.34 g, 1.01 mmoles) and anhydrous potassium carbonate (0.2 g, 1.45 mmoles) in dry acetone (20 mL) under argon atmosphere. The mixture was stirred overnight and was poured into ice-cold 2 M hydrochloric acid (50 mL). The mixture was extracted with diethyl ether (4 x 50 mL), dried (MgSO₄), evaporated to dryness under vacuum and the residue purified by column chromatography eluting with petrol-diethyl ether 7:3 to give the iodo benzyl ester as an oil (0.3 g, 70%).

Orsellinic acid (6) was prepared in three steps in high yield from the readily available 3,5-dimethoxytoluene (3) following the literature procedure⁴.

Benzylation of orsellinic acid with benzyl bromide in the presence of anhydrous potassium carbonate in dry acetone under reflux gave the di (7) and tribenzylated (8) adducts in 42% and 58% yield respectively.

The tribenzylated compound (8) can be converted quantitatively back into starting material (6) by hydrogenation in the presence of palladium on carbon.

Benzyl 4-benzyloxy-2-hydroxy-6-methylbenzoate (7) was selectively formylated with dichloromethyl methyl ether and titanium tetrachloride in the ortho position in 89% yield⁵. The aldehyde (9) was oxidised to the corresponding catechol (10) with hydrogen peroxide (96% yield)^6,7. Methylation of (10) with dimethyl sulphate gave the dimethoxy compound (11) in 83% yield.

The two benzyl groups were removed by catalytic hydrogenation in quantitative yield. Compound (12) was then monobenzylated with benzyl bromide at room temperature in the presence of the free phenol. Nevertheless attempts to iodinate the benzyl esters (compounds 11 and 13) with iodine chloride to produce compounds (14 and 15) failed.

Methylation with dimethyl sulphate in dry acetone in the presence of anhydrous potassium carbonate of (12) gave the methyl ester (16). The literature procedure was followed to iodinate and hydrolyse the methyl ester (16) to produce (17)⁸. Finally, compound (17) was benzylated with benzyl bromide in dry acetone in the presence of potassium carbonate in 70% yield to give the title compound (2).

E.S. de Alvarenga thanks the Yamanouchi Research Institute for a Research Fellowship.

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