New chemical synthesis of the promising cancer chemotherapeutic agent 12,13-desoxyepothilone B: Discovery of a surprising long-range effect on the diastereoselectivity of an aldol condensation Journal Article
| Authors: | Harris, C. R.; Kuduk, S. D.; Balog, A.; Savin, K.; Glunz, P. W.; Danishefsky, S. J. |
| Article Title: | New chemical synthesis of the promising cancer chemotherapeutic agent 12,13-desoxyepothilone B: Discovery of a surprising long-range effect on the diastereoselectivity of an aldol condensation |
| Abstract: | The epothilones are naturally occurring cytotoxic molecules that possess the remarkable ability to arrest cell division through the stabilization of microtubule assemblies. Our in vivo studies with 12,13-desoxyepothilone B (dEpoB), have established that the desoxy compound is well tolerated and virtually curative against a variety of sensitive and resistant xenograft tumors in animal models. In light of these discoveries, we sought a chemical synthesis of dEpoB that would be able to support a serious and substantial discovery research program directed toward the clinical development of this molecule. The overall strategy for this endeavor assumed the ability to synthesize dEpoB from three constructs which include an achiral β,δ-diketo ester construct A, an (S)-2-methylpentenal moiety B, and the thiazoyl- containing vinyl iodide moiety C. We envisioned that a diastereoselective aldol condensation between an achiral C5-C6 (Z)-metalloenolate derived from construct A and an (S)-2-methylalkanal fragment, B, would generate the desired C6-C7 bond. Second, a B-alkyl Suzuki coupling between the vinyl iodide construct C and an alkyl borane would form the C11-C12 bond. Finally, a late-stage reduction of the C3 ketone to the requisite C3 alcohol with high asymmetric induction would permit us to introduce the β,δ-diketo ester fragment A, into the synthesis as a readily accessible achiral building block. The governing concepts for our new synthesis are described herein. |
| Keywords: | unclassified drug; polymerization; microtubule assembly; synthesis; stereochemistry; proton nuclear magnetic resonance; epothilone b; carbon nuclear magnetic resonance; diastereoisomer; hydrogenation; chirality; 12,13 desoxyepothilone b; article |
| Journal Title: | Journal of the American Chemical Society |
| Volume: | 121 |
| Issue: | 30 |
| ISSN: | 0002-7863 |
| Publisher: | American Chemical Society |
| Date Published: | 1999-08-04 |
| Start Page: | 7050 |
| End Page: | 7062 |
| Language: | English |
| DOI: | 10.1021/ja991189l |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 16 August 2016 -- Source: Scopus |
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