Synthetic Routes of Patupilone, (-)-Epothilone B, Epothilone B, EPO-906,152044-5

【Name】Patupilone, (-)-Epothilone B, Epothilone B, EPO-906

【Chemical】

      (4S,7R,8S,9S,13R,14S,16S)-13,14-Epoxy-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2(E)-(2-methylthiazol-4-yl)vinyl]-1-oxacyclohexadecane-2,6-dione; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-4-thia

【CAS】152044-54-7

【Structure Formula】

【Molecule Formula】C27-H41-N-O6-S

【Molecule Weight】507.6879

【Use】Oncolytic Drugs, Solid Tumors Therapy, Antimitotic Drugs, Epothilones, Microtubule-Stabilizing Agents

【Status】Phase II

〖Synthetic Routes〗

〖Title〗Total syntheses of epothilones A and B via a macrolactonization-based strategy

〖Synthetic Method〗

      The synthesis of the intermediate chiral aldehyde (XVIII) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid methyl ester (I) with DIBAL in dichloromethane gives the aldehyde (II), which by condensation with phosphorane (III) in refluxing benzene yields the unsaturated aldehyde (IV). The condensation of (IV) with the chiral borane (V) in ethyl ether affords the chiral unsaturated alcohol (VI), which is treated with Tbdms-Cl and imidazole to provide the sill ether (VII). The oxidation of the terminal double bond of (VIII) with OsO4 and Pb(OAc)4 in THF/tBuOH/water gives the aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the carboxylic acid (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is reduced by reaction with CCl4 and PPh3, followed by a reductive dechlorination with LiBHEt3, to furnish the dimethylated olefin (XII). Hydroxylation of the terminal double bond of (XII) with 9-BBN in THF gives the primary alcohol (XIII), which is treated with I2 and PPh3 in ethyl ether/CH3CN to yield the iodo derivative (XIV). The condensation of (XIV) with the chiral 1-(propylideneamino)pyrrolidine (XV) by means of LDA in THF affords intermediate (XVI), which is converted into the nitrile (XVII) by reaction with monoperoxyphthalic acid magnesium salt (MMPP) in MeOH. Finally this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).

〖author〗Nicolaou, K.C.; et al.

〖Refer〗Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974

   J Am Chem Soc1997,119,(34):7974