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Elucidating the biosynthetic pathway of taxol




Rubenstein, Steven Marc, author
Williams, Robert M., advisor

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The total synthesis of (±)-taxa-4(5),11(12)-diene, (±)-taxa-4(20),11(12)-diene, (±)-taxa-4(20), 11(12)-diene-5(β)-ol, and (±)-taxa-4(20),11(12)-diene-5(α)-ol is described. The syntheses rely upon selenium-based methodology developed by Krief for the introduction of the tetrasubstituted double bond in diene 201 and an intramolecular Diels-Alder reaction, methodology developed by Shea and Jenkins, to form the AB ring system of taxol in compound 208. The synthetic route was used to introduce stable and radiolabeled atoms into the target compounds. The incubation of 13C labeled (±)-taxa-4(20),11(12)-diene with taxadiene synthase has helped confirm the first committed biosynthetic step to taxol, in Taxus brevifolia, as being the direct cyclization of geranylgeranyl diphosphate to taxa-4(5),11(12)-diene. The incubation of tritium labeled (±)-taxa-4(5),11(12)-diene with a cytochrome P-450 microsomal cell-free extract produced a new mono-oxygenated product that had the same g.l.c. retention time and mass spectral fragmentation pattern as taxa-4(20),11(12)-diene-S(α)-ol. Taxa-4(20),11(12)-diene-5(β)-ol could not be found in this assay. Tritium labeled taxa-4(20),11(12)-diene-S(a)-ol was subsequently incubated with Taxus brevifolia stem discs and was incorporated into taxol. In addition, taxa-4(20),11(12)-diene-S(α)-acetate acted as a better substrate than taxa-4(20),11(12)-diene-5(α)-ol in the conversion to the more polar product(s) when incubated with the cytochrome P-450 microsomal cell-free extract. The more polar product(s) is/are presumed to be more highly hydroxylated biosynthetic intermediates enroute to taxol.


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