Epothilone - Total Synthesis

Total Synthesis

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.

The particular synthetic method determined by the laboratories of K.C Nicolaou, described the synthesis of appropriate building blocks 9, 11, and 12, derived from the retrosynthetic analysis of epothilone B (Figure 1), both diastereoisomers and the geometrical isomers at C6-C7 and C12-C13, can be obtained to give a diverse molecular product. The synthesis of required building blocks 9, 11 and 12, were obtained in a maximum of 4 steps for each building block as seen in Figure 2. With fragments 9, 11 and 12 in hand, these intermediates can then react with one another via Wittig olefination, aldol reaction, macrolactonization, and epoxidation to give the various epothilone B as seen in Figure 3.

• epothilone total synthesis

• Figure 1: Retrosynthetic analysis of epothilone B to obtain the intermediates 9, 11, and 12.

• Figure 2: Synthesis of the intermediates: a) keto acid, 9 b) thiazole containing fragment with phosphonium salt, 12 and c) ketone, 11.

• Figure 3: Total synthesis of Epothilone B and Analogues. This was obtained by coupling all the intermediates (Figure 1 and 2) together through various reactions.