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

Rubén Manzano; Swarup Datta; Robert S Paton; Darren J Dixon

doi:10.1002/anie.201612048

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

Angew Chem Int Ed Engl. 2017 May 15;56(21):5834-5838. doi: 10.1002/anie.201612048. Epub 2017 Apr 21.

Authors

Rubén Manzano¹, Swarup Datta¹, Robert S Paton¹, Darren J Dixon¹

Affiliation

¹ Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.

PMID: 28429384
DOI: 10.1002/anie.201612048

Abstract

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.

Keywords: aminocatalysis; asymmetric catalysis; cycloisomerization; morphan core; silver catalysis.