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Scalable enantioselective total synthesis of taxanes

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Abstract

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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Figure 1: Retrosynthetic analysis of Taxol (1) and other members of the taxane family.
Figure 2: Enantioselective synthesis of key taxane 6.
Figure 3: Elaboration of (+)-taxadienone (6) to (+)-taxadiene (7) by a three-step reduction–deoxygenation sequence.
Figure 4: Initial synthetic investigations towards the synthesis of taxadienone (6).

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Acknowledgements

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).

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Contributions

A.M., Y.I. and P.S.B. conceived the synthetic route, conducted the experimental work, analysed the results and wrote the manuscript.

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Correspondence to Phil S. Baran.

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The authors declare no competing financial interests.

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Supplementary information (PDF 1248 kb)

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Supplementary information, NMR spectra (PDF 1371 kb)

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Crystallographic data for compound 6 (CIF 12 kb)

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Crystallographic data for compound S2 (CIF 15 kb)

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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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