Enantioselective copper-catalysed reductive coupling of alkenylazaarenes
Chiral azaarene-containing molecules, tertiary alcohols and α-stereogenic amines are ubiquitous structures in pharmaceuticals, agrochemicals and natural products. The development of new catalytic enantioselective methods to construct molecules containing these chemotypes is of significant utility. Recent efforts within the Lam group have targeted the development of processes that exploit the embedded imine functionality within an azaarene to activate adjacent alkenes towards nucleophilic additions. Chapter 1 reviews the current state of the art with respect to nucleophilic additions of alkenylazaarenes and catalytic conjugate reduction reactions. Chapter 2 describes a catalytic, enantioselective reductive coupling of 2- alkenylazaarenes with ketones using chiral CuH-bisphosphine complex in the presence of PhSiH3 as a hydride source. The scope of this process is broad, with eleven different types of azaarenes and a range of acyclic and cyclic ketones demonstrated as effective coupling partners. β-Substitution on the alkene is tolerated, and the reactions proceed under mild conditions to deliver products with good to high levels of diastereo- and enantio- selection. Chapter 3 describes, further investigation of the scope of enantioselective reductive coupling, using N-Boc aldimines as electrophiles. This process is tolerant of a variety of vinylazaarenes and N-Boc aldimines, and provides aromatic heterocycles bearing α-stereogenic amines with good to moderate yields and good to excellent levels of diastereo- and enantio- selection.