Treatment of 1,2,4-butanetriol (I) with acetone and p-toluenesulfonic acid gave the isopropylidene ketal (II). Subsequent Swern oxidation of the unprotected alcohol group of (II) produced aldehyde (III), which was condensed with phosphorane (IV) to afford unsaturated ester (V). Ketal hydrolysis of (V) gave ethyl 5,6-dihydroxy-2-hexenoate (VI), which was cyclized by means of iodine and NaHCO3 to produce the (tetrahydrofuranyl)-2-iodoacetate (VII). Further oxidation of the hydroxyl group of (VII) by means of Jones reagent yielded iodoketone (VIII). This was cyclized in the presence of DBU to generate the bicyclic compound (IX). The Bucherer-Bergs reac-tion of (IX) with potassium cyanide and ammonium carbonate produced the spiro hydantoin (X). Resolution of (X) was then achieved by ethyl ester hydrolysis, followed by recrystallization of the corresponding diastereomeric salt with (R)-2-phenylglycinol. Basic hydrolysis of the hydantoin ring of the required isomer (XII) then yielded the title compound.
Cycloaddition of ethyl diazoacetate to furan (XXII) in the presence of dirhodium tetraacetate gave bicyclic compound (XXIII). Hydroboration of the olefin group of (XXIII) with tert-hexylborane, followed by oxidative treatment with hydrogen peroxide provided alcohol (XXIV), which was oxidized to ketone (IX) under Swern conditions. The title compound was then obtained as above by formation of hydantoin (X), ester hydrolysis, resolution as before, and hydrolysis of the hydantoin.
Cycloaddition of ethyl diazoacetate to thiophene (I) in the presence of dirhodium tetraacetate gave bicyclic compound (II). Hydroboration of the olefin double bond of (II), followed by oxidative treatment with hydrogen peroxide provided alcohol (III), which was oxidized to ketone (IV) under Swern conditions. The Bucherer-Bergs reaction of (IV) with potassium cyanide and ammonium carbonate produced the spiro hydantoin (V). Hydrolysis of the hydantoin ring in boiling aqueous NaOH then yielded the title compound.
In a related procedure, the chiral triol (XIII) was protected as the ketal (XIV), and then oxidized to aldehyde (XV). Subsequent Wittig condensation of (XV) with phosphorane (IV) afforded unsaturated ester (XVI). After ketal hydrolysis of (XVI), cyclization by means of I2 and NaHCO3 yielded cyclic ether (XVIII). Oxidation of (XVIII) to ketone (XIX) and cyclization in the presence of DBU produced bicyclic compound (XX). This was converted to the chiral spiro hydantoin (XXI) with KCN and (NH4)2CO3 and finally hydrolyzed with NaOH to give the corresponding dicarboxylic acid.