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Guided desaturation of unactivated aliphatics

Nature Chemistry volume 4, pages 629–635 (2012)Cite this article

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Abstract

The excision of hydrogen from an aliphatic carbon chain to produce an isolated olefin (desaturation) without overoxidation is one of the most impressive and powerful biosynthetic transformations for which there are no simple and mild laboratory substitutes. The versatility of olefins and the range of reactions they undergo are unsurpassed in functional group space. Thus, the conversion of a relatively inert aliphatic system into its unsaturated counterpart could open new possibilities in retrosynthesis. In this article, the invention of a directing group to achieve such a transformation under mild, operationally simple, metal-free conditions is outlined. This ‘portable desaturase’ (TzoCl) is a bench-stable, commercial entity (Aldrich, catalogue number L510092) that is facile to install on alcohol and amine functionalities to ultimately effect remote desaturation, while leaving behind a synthetically useful tosyl group.

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Figure 1: Pioneering studies for alkane desaturation.
Figure 2: Design of a directing group for desaturation.
Figure 3: Applications of the guided desaturation reaction on complex substrates.
Figure 4: Mechanistic investigations and proposed reaction mechanism.

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Acknowledgements

We thank D-H. Huang and L. Pasternack for NMR spectroscopic assistance, A. Rheingold and C. Moore for X-ray crystallographic analysis, M. Wasa for assistance with chiral high performance liquid chromatography and L. Leman for assistance with the peptide synthesis. Financial support for this work was provided by the National Institute of General Medical Sciences, National Institute of Health (GM-097444), Spanish Ministry of Education and Science (MEC)–Fulbright Program (postdoctoral fellowship for A.M.), National Science Foundation (predoctoral fellowship for W.R.G.), the Spanish MEC (predoctoral grant for J.O.F.) and Bristol-Myers Squibb (unrestricted research support).

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Author notes

  1. Abraham Mendoza and Will R. Gutekunst: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Ana-Florina Voica, Abraham Mendoza, Will R. Gutekunst, Jorge Otero Fraga & Phil S. Baran

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  1. Ana-Florina Voica
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Contributions

A-F.V. and P.S.B. conceived the original concept for the desaturation reaction, A-F.V., A.M., W.R.G. and J.O.F. conducted the experimental work and analysed the results, A-F.V., W.R.G., A.M. and P.S.B. co-wrote the manuscript.

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Correspondence to Phil S. Baran.

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Supplementary information

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Experimental procedures and characterization data (PDF 1718 kb)

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NMR spectra (PDF 2912 kb)

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Crystallographic data for compound 21 (CIF 16 kb)

Supplementary information

Crystallographic data for compound 33 (CIF 13 kb)

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Crystallographic data for compound 39 (CIF 13 kb)

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Crystallographic data for compound 41 (CIF 17 kb)

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Crystallographic data for compound 43 (CIF 19 kb)

Supplementary information

Crystallographic data for compound 44 (CIF 19 kb)

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Voica, AF., Mendoza, A., Gutekunst, W. et al. Guided desaturation of unactivated aliphatics. Nature Chem 4, 629–635 (2012). https://doi.org/10.1038/nchem.1385

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