Epothilones side chain-modified

Scheme 9. Synthesis of epothilone E and side-chain modified epothilones via RCM and Stille coupling, (a) 0.1 equiv of RuCl2(=CHPh)(PCy3)2 (3), CH2C12,0.004 M, 25°C, 20 h, 65% (41a 41b=1.8 l) (b) HF Py, THF,43 (84%) 44 (85%) (c) R13Sn(Aro), Pd(PPh3)4 or Pd(MeCN)2Cl2, 55-90% (d) H202, CH3CN, KHC03, 65%. Aro=aromatic (Nicolaou et al.) [20]...

Out of 350 epothilone analogs produced at Schering AG (now Bayer) by total synthesis up to 2006, the side chain-modified analog sagopilone (also known as ZK-EPO, 3 Figure 3.2) was chosen as a clinical candidate, since it combined high activity and efficacy with fast and efficient cellular uptake and... 

In addition to the examples discussed above, many other potent side chain-modified epothilone analogs have been reported in the literature. Major advances in this area have resulted from the collaborative work between the Nicolaou group at the TSRI and the group at Novartis. For example, these groups discovered that pyridine-based analog 22 (Figure 3.5) is equipotent... 

In NRPS, the cyclization domain catalyzes cyclization of the side-chain nucleophile from a dipeptide moiety such as AA-Ser or AA-Cys (AA = amino acids) to form a tetrahedral intermediate, followed by dehydration to form oxazolines and thiazolines (Scheme 7.1) [20]. The synthesis of a 2-methyl oxazoline from threonine follows a similar mechanism. Once a heterocycle is formed, it can be further modified by reductase to form tetrahydro thiazolidine in the case of pyochelin biosynthesis. Conversely, oxidation of the dehydroheterocycles lead to heteroaro-mahc thiazoles or oxazoles as in the case of epothilone D (Figure 7.2) [21]. 

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