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Site-selective and stereoselective functionalization of non-activated tertiary C–H bonds

Nature volume 551, pages 609–613 (2017)Cite this article

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Abstract

The synthesis of complex organic compounds usually relies on controlling the reactions of the functional groups. In recent years, it has become possible to carry out reactions directly on the C–H bonds, previously considered to be unreactive1,2,3. One of the major challenges is to control the site-selectivity because most organic compounds have many similar C–H bonds. The most well developed procedures so far rely on the use of substrate control, in which the substrate has one inherently more reactive C–H bond4 or contains a directing group5,6 or the reaction is conducted intramolecularly7 so that a specific C–H bond is favoured. A more versatile but more challenging approach is to use catalysts to control which site in the substrate is functionalized. p450 enzymes exhibit C–H oxidation site-selectivity, in which the enzyme scaffold causes a specific C–H bond to be functionalized by placing it close to the iron–oxo haem complex8. Several studies have aimed to emulate this enzymatic site-selectivity with designed transition-metal catalysts but it is difficult to achieve exceptionally high levels of site-selectivity9,10,11. Recently, we reported a dirhodium catalyst for the site-selective functionalization of the most accessible non-activated (that is, not next to a functional group) secondary C–H bonds by means of rhodium-carbene-induced C–H insertion12. Here we describe another dirhodium catalyst that has a very different reactivity profile. Instead of the secondary C–H bond12, the new catalyst is capable of precise site-selectivity at the most accessible tertiary C–H bonds. Using this catalyst, we modify several natural products, including steroids and a vitamin E derivative, indicating the applicability of this method of synthesis to the late-stage functionalization of complex molecules. These studies show it is possible to achieve site-selectivity at different positions within a substrate simply by selecting the appropriate catalyst. We hope that this work will inspire the design of even more sophisticated catalysts, such that catalyst-controlled C–H functionalization becomes a broadly applied strategy for the synthesis of complex molecules.

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Figure 1: Catalyst-controlled site-selective C–H functionalization.
Figure 2: Catalyst optimization for site-selective functionalization of tertiary C–H bonds.
Figure 3: Substrate scope of the Rh2(S-TCPTAD)4-catalysed C–H functionalization.
Figure 4: Exploration of the site-selectivity of Rh2(S-TCPTAD)4-catalysed and Rh2(R-TCPTAD)4-catalysed C–H functionalization in complex substrates.
Figure 5: Computational study of Rh2(S-TCPTAD)4 and the corresponding carbene structures.

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Acknowledgements

Financial support was provided by the NSF under the CCI Center for Selective C–H Functionalization (CHE-1700982). We thank Novartis and AbbVie for supporting our research in C–H functionalization. D.G.M. gratefully acknowledges NSF MRI-R2 grant (CHE-0958205) and the use of the resources of the Cherry L. Emerson Center for Scientific Computation. The NMR and X-ray instruments used in this work were supported by the National Science Foundation (CHE 1531620 and CHE 1626172).

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Authors and Affiliations

  1. Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, 30322, Georgia, USA

    Kuangbiao Liao, Thomas C. Pickel, Vyacheslav Boyarskikh, John Bacsa & Huw M. L. Davies

  2. Cherry L. Emerson Center for Scientific Computation, Emory University, 1521 Dickey Drive, Atlanta, 30322, Georgia, USA

    Djamaladdin G. Musaev

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  1. Kuangbiao Liao
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  6. Huw M. L. Davies
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Contributions

K.L. performed the synthetic experiments. V.B. and D.G.M. conducted the computational studies. T.P. and J.B. conducted the X-ray crystallographic studies. K.L. and H.M.L.D. designed and analysed the synthetic experiments and K.L., D.G.M. and H.M.L.D. prepared the manuscript.

Corresponding author

Correspondence to Huw M. L. Davies.

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Competing interests

H.M.L.D. is a named inventor on a patent entitled “Dirhodium Catalyst Compositions and Synthetic Processes Related Thereto” (US 8,974,428, issued 10 March 2015). The other authors have no competing financial interests.

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Reviewer Information Nature thanks M. Doyle and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Liao, K., Pickel, T., Boyarskikh, V. et al. Site-selective and stereoselective functionalization of non-activated tertiary C–H bonds. Nature 551, 609–613 (2017). https://doi.org/10.1038/nature24641

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