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Pd(II)-Catalyzed Enantioselective C(sp3)-H Arylation of Cyclopropanes and Cyclobutanes Guided by Tertiary Alkylamines.


ABSTRACT: Strained aminomethyl-cycloalkanes are a recurrent scaffold in medicinal chemistry due to their unique structural features that give rise to a range of biological properties. Here, we report a palladium-catalyzed enantioselective C(sp3)-H arylation of aminomethyl-cyclopropanes and -cyclobutanes with aryl boronic acids. A range of native tertiary alkylamine groups are able to direct C-H cleavage and forge carbon-aryl bonds on the strained cycloalkanes framework as single diastereomers and with excellent enantiomeric ratios. Central to the success of this strategy is the use of a simple N-acetyl amino acid ligand, which not only controls the enantioselectivity but also promotes γ-C-H activation of over other pathways. Computational analysis of the cyclopalladation step provides an understanding of how enantioselective C-H cleavage occurs and revealed distinct transition structures to our previous work on enantioselective desymmetrization of N-isobutyl tertiary alkylamines. This straightforward and operationally simple method simplifies the construction of functionalized aminomethyl-strained cycloalkanes, which we believe will find widespread use in academic and industrial settings relating to the synthesis of biologically active small molecules.

SUBMITTER: Rodrigalvarez J 

PROVIDER: S-EPMC9097487 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Pd(II)-Catalyzed Enantioselective C(sp<sup>3</sup>)-H Arylation of Cyclopropanes and Cyclobutanes Guided by Tertiary Alkylamines.

Rodrigalvarez Jesus J   Reeve Luke A LA   Miró Javier J   Gaunt Matthew J MJ  

Journal of the American Chemical Society 20220225 9


Strained aminomethyl-cycloalkanes are a recurrent scaffold in medicinal chemistry due to their unique structural features that give rise to a range of biological properties. Here, we report a palladium-catalyzed enantioselective C(sp<sup>3</sup>)-H arylation of aminomethyl-cyclopropanes and -cyclobutanes with aryl boronic acids. A range of native tertiary alkylamine groups are able to direct C-H cleavage and forge carbon-aryl bonds on the strained cycloalkanes framework as single diastereomers a  ...[more]

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