Palladium-catalyzed regio- and enantioselective migratory allylic C(sp3)-H functionalization

Ye-Wei Chen; Yang Liu; Han-Yu Lu; Guo-Qiang Lin; Zhi-Tao He

doi:10.1038/s41467-021-25978-6

Palladium-catalyzed regio- and enantioselective migratory allylic C(sp³)-H functionalization

Nat Commun. 2021 Sep 24;12(1):5626. doi: 10.1038/s41467-021-25978-6.

Authors

Ye-Wei Chen^#^{1

2}, Yang Liu^#¹, Han-Yu Lu^{1

2}, Guo-Qiang Lin^{3

4}, Zhi-Tao He⁵

Affiliations

¹ CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, China.
² School of Physical Science and Technology, ShanghaiTech University, Shanghai, China.
³ CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, China. lingq@sioc.ac.cn.
⁴ School of Physical Science and Technology, ShanghaiTech University, Shanghai, China. lingq@sioc.ac.cn.
⁵ CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, China. hezt@sioc.ac.cn.

^# Contributed equally.

Abstract

Transition metal-catalyzed asymmetric allylic substitution with a suitably pre-stored leaving group in the substrate is widely used in organic synthesis. In contrast, the enantioselective allylic C(sp³)-H functionalization is more straightforward but far less explored. Here we report a catalytic protocol for the long-standing challenging enantioselective allylic C(sp³)-H functionalization. Through palladium hydride-catalyzed chain-walking and allylic substitution, allylic C-H functionalization of a wide range of acyclic nonconjugated dienes is achieved in high yields (up to 93% yield), high enantioselectivities (up to 98:2 er), and with 100% atom efficiency. Exploring the reactivity of substrates with varying pK_a values uncovers a reasonable scope of nucleophiles and potential factors controlling the reaction. A set of efficient downstream transformations to enantiopure skeletons showcase the practical value of the methodology. Mechanistic experiments corroborate the PdH-catalyzed asymmetric migratory allylic substitution process.

Abstract

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