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The total synthesis of (-)-cyanthiwigin F by means of double catalytic enantioselective alkylation

Nature volume 453, pages 1228–1231 (2008)Cite this article

Abstract

Double catalytic enantioselective transformations are powerful synthetic methods that can facilitate the construction of stereochemically complex molecules in a single operation1,2. In addition to generating two or more stereocentres in a single reaction, multiple asymmetric reactions also impart increased enantiomeric excess to the final product in comparison with the analogous single transformation3,4,5,6. Furthermore, multiple asymmetric operations have the potential to independently construct several stereocentres at remote points within the same molecular scaffold, rather than relying on pre-existing chiral centres that are proximal to the reactive site1. Despite the inherent benefits of multiple catalytic enantioselective reactions, their application to natural product total synthesis remains largely underutilized2. Here we report the use of a double stereoablative7 enantioselective alkylation reaction in a concise synthesis of the marine diterpenoid (-)-cyanthiwigin F (ref. 8). By employing a technique for independent, selective formation of two stereocentres in a single stereoconvergent operation, we demonstrate that a complicated mixture of racemic and meso diastereomers may be smoothly converted to a synthetically useful intermediate with exceptional enantiomeric excess. The stereochemical information generated by means of this catalytic transformation facilitates the easy and rapid completion of the total synthesis of this marine natural product.

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Figure 1
Figure 2: Synthesis of diketone 6.
Figure 3: Synthesis of cyanthiwigin F.

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Acknowledgements

The authors wish to thank NIH-NIGMS (R01GM080269-01), Amgen, Abbott, Boehringer Ingelheim, Merck and Bristol-Myers Squibb for financial support. We also wish to thank M. W. Day and L. M. Henling for X-ray crystallographic expertise, S. Virgil, A. Harned, D. White, D. Caspi and J. T. Mohr for helpful discussions, and M. T. Hamann for an authentic sample and spectra of cyanthiwigin F. We thank E. J. Corey for guidance and mentorship, on the occasion of his 80th birthday.

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Authors and Affiliations

  1. Division of Chemistry and Chemical Engineering, The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, California Institute of Technology, 1200 East California Boulevard, MC164-30, Pasadena, California 91125, USA,

    John A. Enquist Jr & Brian M. Stoltz

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  1. John A. Enquist Jr
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  2. Brian M. Stoltz
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Correspondence to Brian M. Stoltz.

Additional information

Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK, and copies can be obtained on request, free of charge, by quoting the publication citation and the deposition number 664430.

Supplementary information

Supplementary Information

The file contains Supplementary Methods, Supplementary Tables 1 – 7, Supplementary Figures 1 – 5, and Supplementary Notes. This file contains detailed data on experimental procedures, characterization of new chemical compounds, X-ray crystal structure, and comparisons between synthetic and natural samples of cyanthiwigin F. (PDF 1503 kb)

Supplementary Zip file

This folder contains Crystal Structure CIF File. This file is a properly formatted representation of the crystal structure data reported in the Supplementary Information. (ZIP 5 kb)

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Enquist Jr, J., Stoltz, B. The total synthesis of (-)-cyanthiwigin F by means of double catalytic enantioselective alkylation. Nature 453, 1228–1231 (2008). https://doi.org/10.1038/nature07046

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