Controlling Pd(iv) reductive elimination pathways enables Pd(ii)-catalysed enantioselective C(sp3)−H fluorination

Abstract

The development of a Pd(ii)-catalysed enantioselective fluorination of C(sp3)−H bonds would offer a new approach to making chiral organofluorines. However, such a strategy is particularly challenging because of the difficulty in differentiating prochiral C(sp3)−H bonds through Pd(ii)-insertion, as well as the sluggish reductive elimination involving Pd−F bonds. Here, we report the development of a Pd(ii)-catalysed enantioselective C(sp3)−H fluorination using a chiral transient directing group strategy. In this work, a bulky, amino amide transient directing group was developed to control the stereochemistry of the C−H insertion step and selectively promote the C(sp3)−F reductive elimination pathway from the Pd(iv)–F intermediate. Stereochemical analysis revealed that while the desired C(sp3)−F formation proceeds via an inner-sphere pathway with retention of configuration, the undesired C(sp3)−O formation occurs through an SN2-type mechanism. Elucidation of the dual mechanism allows us to rationalize the profound ligand effect on controlling reductive elimination selectivity from high-valent Pd species.

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Fig. 1: Enantioselective C(sp3)−H fluorination.
Fig. 2: Experimental evidence for the dual mechanism of Pd(iv) reductive elimination.
Fig. 3: Controlling reductive elimination pathways from putative Pd(iv) intermediates.
Fig. 4: Access to diverse chiral organofluorines.

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Acknowledgements

The authors acknowledge financial support from The Scripps Research Institute, the National Institutes of Health (NIGMS, 2R01GM084019) and Shanghai RAAS Blood Products Co. H.P. thanks the Korea Foundation for Advanced Studies and Eli Lilly for graduate fellowship.

Author information

H.P. developed the enantioselective fluorination reaction. H.P. and K.H. expanded the substrate scope. P.V. conducted the computational studies. J.-Q.Y. conceived and supervised the project.

Correspondence to Jin-Quan Yu.

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Supplementary information

Supplementary information

Supplementary experimental data, synthetic procedures and chemical compound characterization data

Crystallographic data

CIF for compound 5a; CCDC reference: 1556389

Crystallographic data

CIF for compound 6; CCDC reference: 1556390

Crystallographic data

CIF for compound 8; CCDC reference: 1577327

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Park, H., Verma, P., Hong, K. et al. Controlling Pd(iv) reductive elimination pathways enables Pd(ii)-catalysed enantioselective C(sp3)−H fluorination. Nature Chem 10, 755–762 (2018). https://doi.org/10.1038/s41557-018-0048-1

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