Stereocenter

Organic chemistry

Combinatorial chemistry

Desymmetrization

Maleimide

Palladium

Stereochemistry

Enantioselective synthesis

Catalysis

Medicinal chemistry

Alkylation

Chemistry

Amide

Pyridine

Cycloaddition

Journal of the American Chemical Society

Cycloaddition reactions provide an expeditious route to construct ring systems in a highly convergent and stereoselective manner. For a typical cycloaddition reaction to occur, however, the installation of multiple reactive functional groups (π-bonds, leaving group, etc.) is required within the substrates, compromising the overall efficiency or scope of the cycloaddition reaction. Here, we report a palladium-catalyzed [3 + 2] reaction that utilizes twofold C(sp3)–H activation to generate the three-carbon unit for formal cycloaddition. The initial β-C(sp3)–H activation of aliphatic amide, followed by maleimide insertion, triggers a relayed, second C(sp3)–H activation to complete a formal [3 + 2] cycloaddition. The key to success was the use of weakly coordinating amide as the directing group, as previous studies have shown that Heck or alkylation pathways are preferred when stronger-coordinating directing groups are used with maleimide coupling partners. To promote the amide-directed C(sp3)–H activation step, the use of pyridine-3-sulfonic acid ligands is crucial. This method is compatible with a wide range of amide substrates, including lactams, which lead to spiro-bicyclic products. The [3 + 2] product is also shown to undergo a reductive desymmetrization process to access chiral cyclopentane bearing multiple stereocenters with excellent enantioselectivity.

Palladium-Catalyzed [3 + 2] Cycloaddition via Twofold 1,3-C(sp<sup>3</sup>)–H Activation

Palladium-Catalyzed [3 + 2] Cycloaddition via Twofold 1,3-C(sp3)–H Activation

Palladium-Catalyzed [3 + 2] Cycloaddition via Twofold 1,3-C(sp³)–H Activation