Deactivation of Secondary Amine Catalysts via Aldol Reaction–Amine Catalysis under Solvent-Free Conditions

Despite intense interest
in amine-catalyzed stereoselective reactions,
high catalyst loadings of ≥10 mol % are still common and either
due to low reactivity or catalyst deactivation. Yet, few deactivation
pathways are well understood. Here, we unraveled the deactivation
of secondary amines by undesired aldol reaction. Mechanistic studies
with peptide and prolinol silyl ether catalysts showed the generality
of this so-far underappreciated catalyst deactivation pathway. The
insights enabled conjugate addition reactions between aldehydes and
nitroolefins on a multigram scale in the absence of solventconditions
that are attractive as environmentally benign processeswith
excellent product yields and stereoselectivities in the presence of
as little as 0.1 mol % of a chemoselective peptidic catalyst.