Steven Malcolmson

New Strategies for the Catalytic Enantioselective Synthesis of Chiral Amines and Other Challenging Scaffolds

The development of new methods for the stereoselective synthesis of chiral amines is a compelling objective in organic synthesis as these structures are found in a large number of biologically active compounds.  Yet many amine motifs remain difficult to prepare in an efficient manner, especially through complexity-building carbon–carbon bond-forming reactions and/or in atom economical ways.  In this lecture, I will describe our work in two areas of enantioselective catalysis to prepare chiral amines: 1) carbon–carbon bond formations via electrophilic additions to 2-azadienes, which act as enamine umpolung reagents, and 2) nucleophilic additions of aliphatic amines and anilines to acyclic 1,3-dienes and enynes (hydroamination).

In the former area, Cu-catalyzed reductive couplings of azadienes—virtually unexplored reagents—with ketones and imines has enabled the synthesis of challenging, sterically congested vicinal amino alcohols and diamines, while Pd-catalyzed fluoroarylation of difluoroazadienes has permitted access to alpha-trifluoromethyl benzylic amines.  In the latter, the development of a family of electron deficient Pd–PHOX catalysts for hydrofunctionalization has enabled regio- and enantioselective addition of highly Lewis basic amines to dienes, furnishing allylic amines with a variety of allylic and olefin substituents.  Hydroaminations of enynes has led to the isolation of chiral di- and trisubstituted allenes.  Extension to diene hydroalkylation with beta-dicarbonyl-like pronucleophiles delivers myriad unsaturated carbonyl products in atom economical carbon–carbon bond-forming transformations.