Synthesis of stable isotope‐labeled epothilone D using a degradation–reconstruction approach |
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| Authors: | Richard C. Burrell Wesley A. Turley Samuel J. Bonacorsi Jr. |
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| Affiliation: | 1. Bristol‐Myers Squibb Research and Development, Discovery Chemistry Platforms, Wallingford, CT, USA;2. Bristol‐Myers Squibb Research and Development, Discovery Chemistry Platforms, Princeton, NJ, USA |
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| Abstract: | The stabilization of microtubules using epothilones represents a novel mechanism of action to treat Alzheimer's disease. Epothilone D is one such microtubule‐stabilizing drug that has been investigated by Bristol‐Myers Squibb. An important step in the development process was the synthesis of a stable isotope‐labeled analog for use in bioanalytical assays to accurately quantify the concentration of the drug in biological samples. A novel synthetic route to stable isotope‐labeled epothilone D is described. The synthetic route was based on a strategy to degrade epothilone B and then use that key intermediate to reconstruct stable isotope‐labeled epothilone D. Epothilone B was treated with potassium osmate and sodium periodate. The thiazole moiety in epothilone B was efficiently cleaved to give (1S,3S,7S,10R,11S,12S,16R)‐3‐acetyl‐7,11‐dihydroxy‐8,8,10,12,16‐pentamethyl‐4,17‐dioxabicyclo[14.1.0]heptadecane‐5,9‐dione. The epoxide in the macrocyclic ring of that intermediate was cleanly removed by treatment with tungsten hexachloride and n‐butyllithium to give the corresponding olefin (4S,7R,8S,9S,16S,Z)‐16‐acetyl‐4,8‐dihydroxy‐5,5,7,9,13‐pentamethyloxacyclohexadec‐13‐ene‐2,6‐dione. Bis(triethylsilyl) protection produced (4S,7R,8S,9S,16S,Z)‐16‐acetyl‐5,5,7,9,13‐pentamethyl‐4,8‐bis(triethylsilyloxy)‐oxacyclohexadec‐13‐ene‐2,6‐dione. This intermediate was coupled to a stable isotope‐labeled thiazole using a Wittig reaction as the key step to provide 13C5, 15N‐labeled epothilone D. In summary, the synthesis was completed in nine total steps, only six of which involved isotopically labeled reagents. A total of 168 mg of 13C5, 15N‐labeled epothilone D was prepared in an 8% overall yield from 13C2, 15N‐labeled thioacetamide and 13C3‐labeled ethyl bromopyruvate. |
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| Keywords: | stable isotope labeling degradation of epothilone B epothilone D Alzheimer's disease |
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