189453-43-8Relevant articles and documents
Synthesis of epothilones, intermediates thereto, analogues and uses thereof
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Page column 40, (2010/01/31)
The present invention provides convergent processes for preparing epothilone A and B, desoxyepothilones A and B, and analogues thereof. Also provided are analogues related to epothilone A and B and intermediates useful for preparing same. The present invention further provides novel compositions based on analogues of the epothilones and methods for the treatment of cancer and cancer which has developed a multidrug-resistant phenotype.
Total Synthesis of Epothilones A and B
Dongfang, Meng,Bertinato, Peter,Balog, Aaron,Su, Dai-Shi,Kamenecka, Ted,et al.
, p. 10073 - 10092 (2007/10/03)
Convergent, stereocontrolled total syntheses of the microtubule-stabilizing macrolides epothilones A (2) and B (3) have been achieved. Four distinct ring-forming strategies were pursued (see Scheme 1). Of these four, three were reduced to practice. In one approach, the action of a base on a substance possessing an acetate ester and a nonenolazable aldehyde brought about a remarkably effective macroaldolization see (89 -> 90 + 91; 99 -> 100 + 101), simultaneously creating the C2-C3 bond and the hydroxyl-bearing stereocenter at C-3. Alternatively, the 16-membered macrolide of the epothilones could be fashioned through a C12-C13 ring-closing olefin metathesis (e.g. see 111 -> 90 + 117; 122 -> 105 + 123) and through macrolactonization of the appropriate hydroxy acid (e.g. see 88 -> 93). The application of a stereospecific B-alkyl Suzuki coupling strategy permitted the establishment of a cis-C12-C13 olefin, thus setting the stage for an eventual site- and diastereoselective epoxidation reaction (see 96 -> 2; 106 -> 3). The development of a novel cyclopropane solvolysis strategy for incorporating the geminal methyl groups of the epothilones (see 39 -> 40 -> 41), and the use of Lewis acid catalyzed diene-aldehyde cyclocondensation (LACDAC) (see 35 + 36 -> 37) and asymmetric allylation (see 10 -> 76) methodology are also noteworthy.
