Synthesis of stable isotope‐labeled epothilone D using a degradation–reconstruction approach. (8th July 2015)

• Record Type: Journal Article
• Authors: Burrell, Richard C.; Turley, Wesley A.; Bonacorsi, Samuel J.
• Is Part Of: Journal of labelled compounds & radiopharmaceuticals. Volume 58:Number 9(2015)
• Page Start: 361
• Page End: 369
• Publication Date: 2015-07-08
• Subjects: Tracers (Chemistry) -- Periodicals; Radiopharmaceuticals -- Periodicals; 615.8424
• DOI: 10.1002/jlcr.3312
• Languages: English
• ISSNs: 0362-4803

Abstract

<abstract abstract-type="main" id="jlcr3312-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p id="jlcr3312-para-0001">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.</p> <p id="jlcr3312-para-0002">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. <italic>Bis</italic>(triethylsilyl) protection produced (4S, 7R, 8S, 9S, 16S, Z)‐16‐acetyl‐5, 5, 7, 9, 13‐pentamethyl‐4, 8‐<italic>bis</italic>(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 <sup>13</sup>C<sub>5</sub>, <sup>15</sup>N‐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 <sup>13</sup>C<sub>5</sub>, <sup>15</sup>N‐labeled epothilone D was prepared in an 8% overall yield from <sup>13</sup>C<sub>2</sub>, <sup>15</sup>N‐labeled thioacetamide and <sup>13</sup>C<sub>3</sub>‐labeled ethyl bromopyruvate.</p> </abstract>