page_title: Epothilone
section_title: Total synthesis
hierarchical_section_title: Epothilone / Total synthesis
caption_attribution_description: English: Retrosynthetic analysis to epothilone B. This retrosynthesis was outlined by Kyriacos Nicolaou et al. in 1997. The file was made by ChemBioDraw Ultra 13. As a reference, the digital object identifier is https://dx.doi.org/10.1021/ja971110h. This image replaces the original one (https://commons.wikimedia.org/wiki/File:Epoth_Retrosyth.gif) made by Cuigy because this original version is in graphics interchange format having lower quality. In addition, the retrosynthetic arrows, both in the scholarly paper and in the original image, are incorrect.
context_page_description: The epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials epothilones have better efficacy and milder adverse effects than taxanes.
  As of September 2008, epothilones A to F have been identified and characterised.
  Early studies in cancer cell lines and in human cancer patients indicate superior efficacy to the taxanes. Their mechanism of action is similar, but their chemical structure is simpler. Due to their better water solubility, cremophors are not needed.
  Endotoxin-like properties known from paclitaxel, like activation of macrophages synthesizing inflammatory cytokines and nitric oxide, are not observed for epothilone B.
  Epothilones were originally identified as metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum.
context_section_description: Due to the high potency and clinical need for cancer treatments, epothilones have been the target of many total syntheses.  The first group to publish the total synthesis of epothilones was S. J. Danishefsky et al. in 1996.  This total synthesis of epothilone A was achieved via an intramolecular ester enolate-aldehyde condensation.  Other syntheses of epothilones have been published by Nicolaou, Schinzer, Mulzer, and Carreira.  In this approach, key building blocks aldehyde, glycidols, and ketoacid were constructed and coupled to olefin metathesis precursor via an aldol reaction and then an esterification coupling.  Grubbs' catalyst was employed to close the bis terminal olefin of the precursor compound.  The resulting compounds were cis- and tran-macrocyclic isomers with distinct stereocenters.  Epoxidation of cis- and trans-olefins yield epothilone A and its analogues.
  One of total syntheses of epothilone B is outlined below and was described by the laboratory of K. C. Nicolaou. The retrosynthetic analysis revealed 1, 2, and 3 as the building blocks (Figure 1).
  As seen in Figure 2, keto acid 1 was generated from the keto aldehyde that was converted to the silyl ether via asymmetric allylboration and silylation of the resulting alcohol. Ozonolysis of the silyl ether and Lindgren–Pinnick oxidation of the aldehyde afforded the keto acid. Ketone 2 was constructed via Enders alkylation starting from the hydrazone. Ozonolysis, the last step of the Enders alkylation, was followed by reduction of the aldehyde and silylation of the resulting alcohol. Hydrogenolysis of the benzyl ether gave the alcohol, which was oxidized under Swern condition and alkylated with the Grignard reagent to yield the secondary alcohol. Oxidation of this alcohol with the Ley–Griffith reagent gave the desired ketone. Thiazole 3 was synthesized from the ester, which was reduced with diisobutylaluminium hydride, and the aldehyde was reacted with the stabilized ylide in Wittig reaction. Asymmetric allylboration of the α,β-unsaturated aldehyde and protection of the hydroxy group gave the silyl ether, whose the terminal olefin was reacted with osmium tetroxide to a diol that was cleaved with lead tetraacetate to furnish the aldehyde. Reduction, iodination, and treatment with triphenylphosphine led to the phosphonium salt.
  Fragments 1, 2, and 3 were reacted with each other to deliver epothilone B in an approach including Wittig reaction, aldol reaction, and Yamaguchi esterification (Figure 3). Preparative thin-layer chromatography was used to separate the diastereomers.
caption: Figure 1
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