3 years ago

Enantioselective Silver and Amine Co-catalyzed Desymmetrizing Cycloisomerization of Alkyne-Linked Cyclohexanones

Enantioselective Silver and Amine Co-catalyzed Desymmetrizing Cycloisomerization of Alkyne-Linked Cyclohexanones
Darren J. Dixon, Swarup Datta, Rubén Manzano, Robert S. Paton
A silver(I) and amine co-catalyzed desymmetrization of 4-propargylamino cyclohexanones for the direct enantioselective synthesis of 2-azabicyclo[3.3.1]nonanes is described. Exploiting reactivity arising from dual activation of the pendant terminal alkyne by silver(I) and the ketone moiety through transient enamine formation, this synthetically relevant transformation is easy to perform, efficient and broad in scope. High enantioselectivity (up to 96 % ee) was achieved by exploiting a significant matching effect between the chirality of a cinchona alkaloid-derived aminophosphine ligand for the silver(I) salt and the 2-bis(aryl)methylpyrrolidine catalyst which was rationalized by DFT calculations. This allowed for the preparation of both enantiomers of the bicyclic product with near-identical stereocontrol. A matching effect between a chiral aminocatalyst and a chiral ligand for silver is exploited in the title reaction of 4-propargylamino cyclohexanones for the direct enantioselective synthesis of 2-azabicyclo[3.3.1]nonanes. The reaction is efficient, broad in scope and proceeds with high enantioselectivity.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/anie.201612048

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