Access to unsaturated bicyclic lactones by overriding conventional C(sp3)–H site selectivity

Access to unsaturated bicyclic lactones by overriding conventional C(sp3)–H site selectivity

Nature Chemistry

10.1038/s41557-023-01295-x

http://dx.doi.org/10.1038/s41557-023-01295-x

Jayabrata Das, Wajid Ali, Animesh Ghosh, Tanay Pal, Astam Mandal, Chitrala Teja, Suparna Dutta, Rajagopal Pothikumar, Haibo Ge, Xinglong Zhang, Debabrata Maiti

10 August 2023

Das, J., Ali, W., Ghosh, A., Pal, T., Mandal, A., Teja, C., Dutta, S., Pothikumar, R., Ge, H., Zhang, X., & Maiti, D. (2023). Access to unsaturated bicyclic lactones by overriding conventional C(sp3)–H site selectivity. Nature Chemistry, 15(11), 1626–1635. https://doi.org/10.1038/s41557-023-01295-x

AbstractTransition metal catalysis plays a pivotal role in transforming unreactive C–H bonds. However, regioselective activation of distal aliphatic C–H bonds poses a tremendous challenge, particularly in the absence of directing templates. Activation of a methylene C–H bond in the presence of methyl C–H is underexplored. Here we show activation of a methylene C–H bond in the presence of methyl C–H bonds to form unsaturated bicyclic lactones. The protocol allows the reversal of the general selectivity in aliphatic C–H bond activation. Computational studies suggest that reversible C–H activation is followed by β-hydride elimination to generate the Pd-coordinated cycloalkene that undergoes stereoselective C–O cyclization, and subsequent β-hydride elimination to provide bicyclic unsaturated lactones. The broad generality of this reaction has been highlighted via dehydrogenative lactonization of mid to macro ring containing acids along with the C–H olefination reaction with olefin and allyl alcohol. The method substantially simplifies the synthesis of important bicyclic lactones that are important features of natural products as well as pharmacoactive molecules.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the A*STAR - Career Development Fund
Grant Reference no. : C210812008

This research / project is supported by the A*STAR - MTC Young Individual Research Grants (YIRG)
Grant Reference no. : M22K3c0091

https://oar.a-star.edu.sg/communities-collections/articles/19983

1755-4349
1755-4330
1755-4349

Institute of High Performance Computing 

https://doi.org/10.1038/s41557-023-01295-x