Reaction of (I) with acetic anhydride-sulfuric acid in methylene chloride provided the sulfonic acid in 98% yield. Conversion to the sulfonyl chloride with phosphorous pentachloride in methylene chloride followed by treatment with aqueous ammonia gave the sulfonamide (II). Reduction of the carbonyl function with sodium borohydride and oxidation of the thiopyran sulfur with Oxone(R) yielded (IV). The 4-hydroxy substituent was converted to the acetylamino functionality under Ritter conditions. Reduction of (V) with borane-dimethylsulfide complex yielded (VI) as a mixture of diasteriomers. Chromatography on silica gel gave the trans-racemate, which was resolved into its individual enantiomers through the di-p-toluoyl-L-tartaric acid salt. The absolute configuration of the S,S-enantiomer, MK-507, was established by single crystal X-ray analysis.

Reaction of (I) with acetic anhydride-sulfuric acid in methylene chloride provided the sulfonic acid in 98% yield. Conversion to the sulfonyl chloride with phosphorous pentachloride in methylene chloride followed by treatment with aqueous ammonia gave the sulfonamide (II). Reduction of the carbonyl function with sodium borohydride and oxidation of the thiopyran sulfur with Oxone(R) yielded (IV). The 4-hydroxy substituent was converted to the acetylamino functionality under Ritter conditions. Reduction of (V) with borane-dimethylsulfide complex yielded (VI) as a mixture of diasteriomers. Chromatography on silica gel gave the trans-racemate, which was resolved into its individual enantiomers through the di-p-toluoyl-L-tartaric acid salt. The absolute configuration of the S,S-enantiomer, MK-507, was established by single crystal X-ray analysis.

Reaction of (I) with acetic anhydride-sulfuric acid in methylene chloride provided the sulfonic acid in 98% yield. Conversion to the sulfonyl chloride with phosphorous pentachloride in methylene chloride followed by treatment with aqueous ammonia gave the sulfonamide (II). Reduction of the carbonyl function with sodium borohydride and oxidation of the thiopyran sulfur with Oxone(R) yielded (IV). The 4-hydroxy substituent was converted to the acetylamino functionality under Ritter conditions. Reduction of (V) with borane-dimethylsulfide complex yielded (VI) as a mixture of diasteriomers. Chromatography on silica gel gave the trans-racemate, which was resolved into its individual enantiomers through the di-p-toluoyl-L-tartaric acid salt. The absolute configuration of the S,S-enantiomer, MK-507, was established by single crystal X-ray analysis.

A new synthesis of MK-0507 has been described: The condensation of 3(R)-(tosyloxy)butyric acid methyl ester (I) with lithium 2-thienylmercaptide (II) in formamide-THF gives 3(S)-(2-thienylthio)butyric acid methyl ester (III), which is hydrolyzed with aqueous HCl to the corresponding free acid (IV). The intramolecular Friedel-Crafts'cyclization of (IV) with trifluoroacetic anhydride yields 6(S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one (V), which is reduced with LiAlH4 in toluene to afford 4(R)-hydroxy-6(S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran (VI). Epimerization of (VI) with sulfuric acid gives the alcohol (VII) in a cis:trans ratio of 24:76%. Oxidation of (VII) with H2O2 and sodium tungstate yields the 7,7-dioxide (VIII; cis-trans mixture), which is acetylated with acetic anhydride to the acetate (IX). The reaction of (IX) with acetonitrile and sulfuric acid affords N-[6(S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl]acetamide 7,7-dioxide (X; cis-trans mixture), which is sulfonated with chlorosulfonic acid and then treated with SOCl2 to give 4-acetamide-6(S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonyl chloride 7,7-dioxide (XI; cis-trans mixture). The reaction of (XI) with concentrated aqueous NH4OH in THF yields the corresponding sulfonamide (XII), which by reduction with BH3-dimethylsulfide in THF affords 4-(ethylamino)-6(S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide (XIII; cis-trans mixture). Finally, this mixture is treated with maleic acid in acetone and the resulting maleates are submitted to fractionated crystallization, giving the maleate of the (4S,6S)-isomer, which is treated first with NaHCO3 and then with HCl to give MK-0507; [alpha](25)589 -17.1 C (c 1, H2O).