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
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- 作者：Christina R. Harris ; Scott D. Kuduk ; Aaron Balog ; Ken Savin ; Peter W. Glunz ; and Samuel J. Danishefsky
- 刊名：Journal of the American Chemical Society
- 出版年：1999
- 出版时间：August 4, 1999
- 年：1999
- 卷：121
- 期：30
- 页码：7050 - 7062
- 全文大小：423K
- 年卷期：v.121,no.30(August 4, 1999)
- ISSN：1520-5126
文摘
The epothilones are naturally occurring cytotoxic molecules that possess the remarkable ability toarrest 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 curativeagainst a variety of sensitive and resistant xenograft tumors in animal models. In light of these discoveries, wesought a chemical synthesis of dEpoB that would be able to support a serious and substantial discovery researchprogram directed toward the clinical development of this molecule. The overall strategy for this endeavorassumed the ability to synthesize dEpoB from three constructs which include an achiral 
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-diketo ester constructA, an (S)-2-methylpentenal moiety B, and the thiazoyl-containing vinyl iodide moiety C. We envisioned thata diastereoselective aldol condensation between an achiral C5-C6 (Z)-metalloenolate derived from constructA and an (S)-2-methylalkanal fragment, B, would generate the desired C6-C7 bond. Second, a B-alkyl Suzukicoupling 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 wouldpermit us to introduce the ,-diketo ester fragment A, into the synthesis as a readily accessible achiral buildingblock. The governing concepts for our new synthesis are described herein.
,-diketo ester constructA, an (S)-2-methylpentenal moiety B, and the thiazoyl-containing vinyl iodide moiety C. We envisioned thata diastereoselective aldol condensation between an achiral C5-C6 (Z)-metalloenolate derived from constructA and an (S)-2-methylalkanal fragment, B, would generate the desired C6-C7 bond. Second, a B-alkyl Suzukicoupling 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 wouldpermit us to introduce the ,-diketo ester fragment A, into the synthesis as a readily accessible achiral buildingblock. The governing concepts for our new synthesis are described herein.