合成路线1

A new procedure for the synthesis of acivicin has been reported: The photochlorination of L-glutamic acid (I) gives 3-chloroglutamic acid (II); the corresponding diastereomers were separed by ion-exchange chromatography over Dowex-50 (H+). The reaction of (II) with benzyl chloroformate (III) affords N-carbobenzoxy-3-chloroglutamic acid (IV), which is anhydrized with dicyclohexylcarbodiimide to the corresponding protected anhydride (V). The reaction of (V) with lithium N-hydroxyphthalimide (VI) yields the phthalimidoxy derivative (VII), which is converted to the protected hydroxamic acid (VIII) by a treatment with hydroxylamine. The cyclization of (VIII) with triethylamine affords N-carbobenzoxytricholomic acid (IX), which is esterified with diphenyldiazomethane (X) giving the corresponding protected benzhydryl ester (Xl). The reaction of (XI) with dichloro-trisdimethylaminophosphorane (XII) yields the deprotected final compound (XIII), which is finally treated with trifluoroacetic acid and thioanisole (A).

合成路线2

7) The Friedel-Crafts condensation of thioanisole (XX) with acetyl chloride (XXI) by means of AlCl3 in dichlorobenzene gives the corresponding acetophenone (X), which is oxidized with H2O2/WO4Na2 to the ketosulfone (XI). The bromination of (XI) with Br2 in acetic acid/48% HBr affords the phenacyl bromide (XII), which is condensed with phenylacetic acid sodium salt (XXIII) in DMF, giving the phenacyl ester (XXII). Finally, this compound is cyclized by means of diisopropylamine in DMF.

合成路线3

The Friedel Crafts acylation of thioanisole (I) with acetyl chloride (II) and AlCl3 in chloroform gives 4-(methylsulfanyl)acetophenone (III), which is oxidized with monoperoxyphthalic acid (MMPP) in methanol/dichloromethane to yield 4-(methylsulfonyl)acetophenone (IV). The bromination of (IV) with Br2 and AlCl3 in chloroform affords 4-(methylsulfonyl)phenacyl bromide (V), which is finally cyclized by means of DBU and TEA in acetonitrile to provide the target furanone derivative.

合成路线4

Friedel-Crafts acylation of thioanisole (I) with isobutyryl chloride (II) in the presence of AlCl3 gave ketone (III), which was hydroxylated with NaOH and a phase-transfer agent in CCl4-toluene to provide hydroxyketone (IV). Subsequent oxidation of the sulfide group employing Oxone(tm) gave rise to sulfone (V) (1). Further esterification of (V) with chloroacetyl chloride (VI) and pyridine yielded chloroacetate ester (VII), which was cyclized to the epoxy lactone (VIII) by treatment with DBU in acetonitrile. Finally, epoxide opening with the potassium salt of 5-bromo-2-hydroxypyridine (IX) produced the title (pyridyloxy)furanone.

合成路线5