Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Sep 2;353(6303):1023-1027.
doi: 10.1126/science.aaf4434.

Ligand-accelerated enantioselective methylene C(sp3)-H bond activation

Gang Chen  1 , Wei Gong  1 , Zhe Zhuang  1 , Michal S Andrä  1 , Yan-Qiao Chen  1 , Xin Hong  2 , Yun-Fang Yang  2 , Tao Liu  1 , K N Houk  2 , Jin-Quan Yu  1
Affiliations

Ligand-accelerated enantioselective methylene C(sp3)-H bond activation

Gang Chen et al. Science. .

Abstract

Effective differentiation of prochiral carbon-hydrogen (C-H) bonds on a single methylene carbon via asymmetric metal insertion remains a challenge. Here, we report the discovery of chiral acetyl-protected aminoethyl quinoline ligands that enable asymmetric palladium insertion into prochiral C-H bonds on a single methylene carbon center. We apply these palladium complexes to catalytic enantioselective functionalization of β-methylene C-H bonds in aliphatic amides. Using bidentate ligands to accelerate C-H activation of otherwise unreactive monodentate substrates is crucial for outcompeting the background reaction driven by substrate-directed cyclopalladation, thereby avoiding erosion of enantioselectivity. The potential of ligand acceleration in C-H activation is also demonstrated by enantioselective β-C-H arylation of simple carboxylic acids without installing directing groups.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1. Enantioselective methylene C–H activation reactions
(A) Desymmetrization of prochiral C(sp3)–H bonds on the two different carbon centers. (B) Two synthetic disconnections. (C) Differentiating methylene C(sp3)–H bond on the same carbon center. DG, directing group; PG, protecting group; OTf, trifluoromethanesulfonate; Ar, aryl group; Ac, acetyl group; Et, ethyl group; Bu, butyl group.
Fig. 2
Fig. 2. Ligand development for enantioselective methylene C–H arylation
The yields were determined by 1H NMR analysis of the crude product using CH2Br2 as an internal standard. Enantiomeric ratios (er) were determined by chiral high-performance liquid chromatography. The absolute configurations of L13, L21, L35 and L40b were determined by X-ray crystallography (see supplementary material). HFIP, hexafluoro-2-propanol; Me, methyl group; Pr, propyl group; Bn, benzyl group; Ph, phenyl group.
Fig. 3
Fig. 3. Scope of coupling partners in enantioselective C–H arylation
Isolated yield of purified compounds. The absolute configuration was determined by X-ray crystallography.
Fig. 4
Fig. 4. Enantioselective methylene C–H arylation of aliphatic amides
Isolated yield of purified compound. The absolute configuration was determined by X-ray. *Compounds 4t–w were obtained using 1.5 equiv. Ag2CO3, 2.5 equiv. aryl iodide and L32 as ligand. Phth, phthalimido group.
See this image and copyright information in PMC

References

    1. Giri R, Shi BF, Engle KM, Maugel N, Yu JQ. Transition metal-catalyzed C–H activation reactions: diastereoselectivity and enantioselectivity. Chem Soc Rev. 2009;38:3242–3272. - PubMed
    1. Doyle MP, Duffy R, Ratnikov M, Zhou L. Catalytic carbene insertion into C–H bonds. Chem Rev. 2010;110:704–724. - PubMed
    1. Reddy RP, Davies HML. Dirhodium tetracarboxylates derived from adamantylglycine as chiral catalysts for enantioselective C–H aminations. Org Lett. 2006;8:5013–5016. - PubMed
    1. Liang C, Robert-Peillard F, Fruit C, Muller P, Dodd RH, Dauban P. Efficient diastereoselective intermolecular rhodium-catalyzed C–H amination. Angew Chem Int Ed. 2006;45:4641–4644. - PubMed
    1. Zalatan DN, Du Bois J. A chiral rhodium carboxamidate catalyst for enantioselective C–H amination. J Am Chem Soc. 2008;130:9220–9221. - PMC - PubMed

Publication types