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 the 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 trans-macrocyclic isomers with distinct stereocenters.  Epoxidation of cis- and trans-olefins yield epothilone A and its analogs.
One of the 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 the Wittig reaction. Asymmetric allylboration of the α,β-unsaturated aldehyde and protection of the hydroxy group gave the silyl ether, whose 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 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.