Synthesis of Benzyl 4-Hydroxy-5-iodo-2 , 3-dimethoxy-6-methylbenzoate-The Aromatic Unit of Calicheamicin

Calicheamicin γ1 is a highly sophisticated molecule that displays high antitumour and antibiotic potency and an unusual mode of action. Nicolaou et al. used compound (1) as an intermediate in the synthesis of calicheamicin γ1. Nevertheless after coupling the monossacaride to the free hydroxyl of (1), they needed three steps to convert the methyl ester into the corresponding carboxylic 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). The benzyl ester (2) should be a better intermediate for the synthesis of calicheamicin γ1 than the methyl ester (1), as the benzyl group can be easily removed by hydrogenation without deprotecting the carbohydrate bound to the free oxygen.


Introduction
Calicheamicin γ1 I is a highly sophisticated molecule that displays high antitumour and antibiotic potency and an unusual mode of action 1 .
Nicolaou et al. 2 used compound (1) as an intermediate in the synthesis of calicheamicin γ1 I .Nevertheless after coupling the monossacaride to the free hydroxyl of (1), they needed three steps to convert the methyl ester into the corresponding carboxylic acid.
The benzyl ester (2) should be a better intermediate for the synthesis of calicheamicin γ1 I than the methyl ester (1), as the benzyl group can be easily removed by hydrogenation without deprotecting the carbohydrate bound to the free oxygen.

Experimental
Reagents and solvents were purified when necessary according to the usual procedures described in the literature 3 .Flash column chromatography was performed using Crosfield Sorbil C60 (32-63 µm).Rfs were determined by Analytical Thin Layer Chromatography on a 0.25 mm film of silica gel containing fluorescent indicator UV254 sup-ported on a plastic sheet (CamLab plc.).The melting points were determined on an Electrothermal digital apparatus without correction.Infrared Spectra were recorded on a Perkin Elmer 881 grating spectrometer, scanning from 625 to 4000 cm -1 .The samples were run as nujol mull.Mass Spectra were recorded on a MICROMASS 7070F. 1 H and 13 C-NMR spectra were recorded on a JEOL JNM-EX400 (400 and 100.53MHz) and on a Bruker WH250 (250 and 62.89 MHz).They were recorded in CDCl3 and tetramethylsilane was used as the internal standard.

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

Results and Discussion
The benzyl group is easily removed by hydrogenation in the presence of palladium on carbon.We envisaged the synthesis of benzyl 4-hydroxy-5-iodo-2,3-dimethoxy-6methylbenzoate (2) as a potential intermediate for the synthesis of calicheamicin γ1 I .Orsellinic acid (6) was prepared in three steps in high yield from the readily available 3,5-dimethoxytoluene (3) following the literature procedure 4 .
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.
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).