合成路线1

The desepoxidation of epothilone B (I) by means of WCl6 and n-BuLi in THF gives the target epothilone D.

合成路线2

Deoxygenation of epothilone B (I) by means of tungsten hexachloride and butyllithium produced the olefin epothilone D (II). After protection of (II) as the bis-O-silylated derivative (III), cyclopropanation with chloroiodomethane and diethylzinc afforded the cyclopropane adduct (IV). A higher yield procedure to prepare (IV) involved addition of dibromocarbene, generated from bromoform and NaOH under phase-transfer conditions, to olefin (II), followed by reduction of the resulting dibromocyclopropane (V) with azobisisobutyronitrile. Finally, desilylation employing trifluoroacetic acid furnished the title compound.

合成路线3

The cleavage of the lactone group of epothilone B (I) by means of Na-N3 and tetrakis triphenylphosphine palladium (0) in THF gives the azido carboxylic acid (II), which is reduced with polymer-supported PPH3 (or in solution) or with H2 over PtO2 in ethanol to yield the amino acid (III). Finally, this compound is cyclized by means of diphenylphosphoryl azide (DPPA) in DMF.

合成路线4

The reaction of epothilone B (I) with MCPBA in dichloromethane gives the N-oxide (II), which is treated with trifluoroacetic anhydride and 2,6-lutidine in dichloromethane at 70 C in a sealed tube to yield the hydroxymethyl derivative (epothilone F) (III). The reaction of (III) with diphenylphosphoryl azide (DPA) and DBU in THF affords the azidomethyl compound (IV), which is reduced with PMe3 in THF or with H2 and Lindlar catalyst in ethanol to provide the target amino epothilone. Alternatively, the hydroxymethyl derivative (epothilone F) (III) can be obtained by biochemical hydroxylation of epothilone B (I) with Actinomyces sp. strain PTA-XXX.

合成路线5