Structure epothilones

Suzuki couplings have been used in the synthesis of complex molecules. For example, coupling of two large fragments of the epothilone A structure was accomplished in this way.229... 

The epothilones are natural products containing a 16-membered lactone ring that are isolated from mycobacteria. Epothilones A-D differ in the presence of the C(12)-C(13) epoxide and in the C(12) methyl group. Although structurally very different from Taxol, they have a similar mechanism of anticancer action and epothilone A and its analogs are of substantial current interest as chemotherapeutic agents.36 Schemes 13.59 to 13.66 summarize eight syntheses of epothilone A. Several syntheses of epothilone B have also been completed.37... 

Epothilones A, B and E (4,5 and 6) (Fig. 2) are representative members of a new class of bacterially derived natural products which exhibit potent biological activity. Isolated by Hofle and coworkers [6] from a soil sample collected near the Zambesi river, the compounds have provided a great deal of excitement in the scientific community due to their potent cytotoxicity against a number of multiple drug-resistant tumor cell lines and because of the mechanism by which they exert this effect. Like Taxol [7], the epothilones promote the combination of a- and 3-tubulin subunits and stabilize the resulting microtubule structures. This mode of action inhibits the cell division process and is, therefore, an attractive strategy for cancer chemotherapy [7,8]. 

With the synthesis of epothilones A and B secured, subsequent studies concentrated on the preparation of analogs of the natural molecules. In addition to providing structure-activity relationships, it was anticipated that these studies would provide a further test for the generality of the RCM process. In this context, a general strategy was developed by Nicolaou et al. [20] to investigate the... 

Fig. 2.1 Structures of the naturally occurring mictrotubule stabilizing compounds paclitaxel, epothilones A and B, discodermolide, and eleutherobin.

Although the epothilones are structurally less complex that the taxanes, we foresaw several synthetic issues concerning this venture that would require careful attention. The structures of the epothilones invite retrosynthetic dissection into two regions. The polypropionate domain of the epothilones constitutes carbons C1-C8, while the... 

Scheme 2.1 outlines the synthetic strategies pursued in our laboratory towards the total synthesis of the epothilones. Although the structural issues addressed above were not insurmountable, several obstacles were encountered during the course of our pursuit. In nearly each instance, the two sectors containing the stereochemical information were prepared independently and then assembled in a late stage merger. 

First we consider the acyl sector of the epothilones, which proved to be intolerant of modification. For example, inversion of stereochemistry at C3 (S toR), or reduction at C5 results in serious arrest of activity. Analogs with functionality at C3, C5, C6, C7 and C8 removed demonstrate both diminished tubulin-binding activity and cytotoxidty (structures not shown). Ddetion of the single methyl group at C8 has a highly pronounced deleterious effect on activity. Removal of the C9 methylene group resulting in a 15-membered macrolide, 87, results in a major loss of activity in tubulin polymerization/depolymerization assays. 

Tab. 2.2 Structure-activity relationships for epothilone and various epothilone analogs.

In the past few years the total synthesis of a number of quite complex natural products with many different structures have been achieved on solid supports (Fig. 3.3), for example Verrucine A and B (195, 196) [292], Trypostatin B (197) [97] Epothilone A (198) [181] Deglycobleomycin A5 (194) [293] and Oscillamide Y (199)... 

Hofle G Bedorf N, Steinmertz H, Schomburg D, Gerth K, Reichenach H. (1996) Epothilone A and B — novel 16-membered macrolides with cytotoxic activity Isolation, crystal structure, and conformation in solution. Angew Chem 35 1567-1569. 

The extraordinary biological activity of epothilones has spurred interest of scientists around the world. Indeed, several epothilones and many derivatives are currently in different phases of clinical trials for the treatment of various forms of cancer. Also the synthetic community has given a great deal of attention to these remarkable compounds, probably more than to any other compound in the last ten years. This is not very surprising, because in comparison to paclitaxel (which until recently was one of the main success stories of natural products research), the epothilones have a relatively simple structure, which allows easier modification, and they display higher in vitro activity as well as better pharmacokinetic properties. 

Altmann KH, Wartmann M, O Reilly T. Epothilones and related structures—anew class of microtubule inhibitors with potent in vivo antitumor activity. Biochim Biophys Acta 2000 1470(3) M79-91. 

This total synthesis is the first of three preparations of macrocycles that will be described (epothilone A, zearalenone, and muscone). All feature cycli-zation/release strategies that involve carbon-carbon bond formation.18 These efforts illustrate how the research on supported syntheses of highly complex structures has inspired the use of creative linker strategies for attachment to a solid phase. 

The natural products epothilone A and B are structurally different from taxol but have similar anticancer activity. Significantly, they have been reported to be much more active against cell lines exhibiting multiple-drug resistance [26], Taylor and co-workers at the University of Notre Dame have recently published an elegant, formal total synthesis of epothilone A [27], In this work, the authors used the CLC form of Burkholderia cepacia (formerly Pseudomonas cepacia) lipase (ChiroCLEC -PC) to resolve a key alcohol intermediate by selective acylation with vinyl acetate in /-butyl methyl ether (Fig. 6). The enantioselectivity was >20 1 at 47% conversion and efficiently provided gram quantities of the desired (R) alcohol. Since the unreacted (S) alcohol can easily be epimerized by a simple oxidation-reduction sequence and the catalyst reused without significant loss in activity, the method is ideally suited for scale-up. 

The natural product eleutherobin (1) was isolated in 1994 by Fenical et al. from a marine soft coral from an Eleutherobia species and its structure was elucidated shortly afterwards (Figure 1) [1]. Eleutherobin is a diterpene glycoside that possesses remarkable cytotoxicity against a wide variety of cancer cells, which is likely to be based on binding to tubulin and stabilization of microtubules [2, 3]. Mitosis is interrupted and the cell division cycle is terminated. The mechanism of action of eleutherobin is comparable to that of highly potent cytostatic agents such as paclitaxel (Taxol), nonataxel, epothilones, and discodermolide. 

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