Taxanes form a large family of terpenes comprising over 350 members, the most famous of which is Taxol (paclitaxel), a billion-dollar anticancer drug. Here, we describe the first practical and scalable synthetic entry to these natural products via a concise preparation of (+)-taxa-4(5),11(12)-dien-2-one, which has a suitable functional handle with which to access more oxidized members of its family. This route enables a gram-scale preparation of the ‘parent’ taxane—taxadiene—which is the largest quantity of this naturally occurring terpene ever isolated or prepared in pure form. The characteristic 6-8-6 tricyclic system of the taxane family, containing a bridgehead alkene, is forged via a vicinal difunctionalization/Diels–Alder strategy. Asymmetry is introduced by means of an enantioselective conjugate addition that forms an all-carbon quaternary centre, from which all other stereocentres are fixed through substrate control. This study lays a critical foundation for a planned access to minimally oxidized taxane analogues and a scalable laboratory preparation of Taxol itself.
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The authors dedicate this manuscript to K.C. Nicolaou on the occasion of his 65th birthday. The authors thank D-H. Huang and L. Pasternack for NMR spectroscopic assistance, A. Rheingold for X-ray crystallographic analysis and M. Wasa for chiral HPLC assistance. N. Wilde is thanked for valuable technical assistance. Special thanks go to G. Stephanopoulos for providing a bioengineered sample of taxadiene. Financial support for this work was provided by the National Institutes of Health/National Institute of General Medical Sciences (GM-097444), Ministerio de Educación y Ciencia-Fulbright programme (postdoctoral fellowship for A. M.), Natural Sciences and Engineering Research Council of Canada (doctoral fellowship for Y. I.) and Bristol-Myers Squibb (unrestricted research support).
The authors declare no competing financial interests.
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Mendoza, A., Ishihara, Y. & Baran, P. Scalable enantioselective total synthesis of taxanes. Nature Chem 4, 21–25 (2012). https://doi.org/10.1038/nchem.1196
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