The reaction of 1,6-anhydro-beta-D-glucopyranose (I) with tosyl chloride in pyridine gives 1,6-anhydro-2,4-di-O-(p-toluenesulfonyl)-beta-D-glucopyranose (II), which is oxidized with NaBrO3 and RuCl3 in acetonitrile/water yielding 1,6-anhydro-2,4-di-O-(p-toluenesulfonyl)-beta-D-glucopyranos-3-ulose (III). Finally, the deoxygenation of the ditosylate (III) to the desired intermediate (IV) is performed with Zn dust and NH4OAc in THF. The 1,6-anhydro-2,4-di-O-(p-toluenesulfonyl)-beta-D-glucopyranose (II) obtained before can be reduced with Super-hydride in THF yielding the bicyclooctanol (V), which is finally oxidized to the target ketone (IV) by means of pyridinium chlorochromate (PCC) in dichloromethane. The treatment of D-glucose (VI) successively with TsCl and pyridine, with DBU and finally again with TsCl gives the previously reported 1,6-anhydro-2,4-di-O-(p-toluenesulfonyl)-beta-D-glucopyranose (II), which is reduced to the previously reported bicyclooctanol (V) with LiEt3BH. Finally, this compound is oxidized with PCC as before to the target ketone (IV).
The target compound has been obtained as follows: The condensation of 3-furoic acid (XV) with ethyl 3-iodopropionate (XVI) by means of Zn-Cu and Pd(PPh3)4 in hot benzene, followed by hydrolysis with NaOH in methanol/THF/water gives 4-(3-furyl)-4-oxobutyric acid (XVII), which is condensed with 3-methoxybenzaldehyde (XVIII) by means of NaOAc in hot Ac2O yielding the lactone (XIX). The cyclization of (XIX) by means of H2SO4 in methanol or HCl/methanol/AcOH affords 4-(3-furyl)-7-methoxynaphthalene-2-carboxylic acid methyl ester (XX), which is converted into the 7-hydroxy-4-(3-furyl)naphthalene-2-carbonitrile (XXI) by reaction with (Me)2Al-NH2 in refluxing toluene, followed by demethylation with pyridine and TFAA or HCl in dioxane. Finally, the condensation of naphthol (XXI) with benzyl alcohol derivative (XXII) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) or di-tert-butyl azodicarboxylate (DBAD) in THF affords the target product. The benzyl alcohol derivative (XXII) has been obtained as follows: The condensation of the bicyclic ketone intermediate (IV) with the 3-(tert-butyldiphenylsilyloxymethyl)phenyllithium (XXIII) gives the silylated benzyl alcohol (XXIV), which is finally deprotected with TBAF to afford the intermediate (XXII).
The esterification of L-malic acid (VII) with methanol in acidic medium gives the dimethyl ester (VIII), which is chemoselectively reduced with BH3, Me2S and NaBH4 yielding the diol (IX). The reaction of (IX) with trimethyl orthoformate affords the cyclic orthoester (X), which is reduced with DIBAL to the aldehyde (XI). The methylation of (XI) with MeLi provides the isopropanol derivative (XII), which is submitted to a Swern oxidation to afford the corresponding ketone (XIII). The enolization of (XIII) with TBDMS-OTf and DIEA gives the silylated enol ether (XIV), which is finally cyclized to the target ketone (IV) by means of Lewis acids such as TiCl4, BF3.Et2O, SnCl4 or Et2AlCl, the best yields being obtained with the last mentioned reagent.