Asymmetric Enamine Catalysis with β‑Ketoesters by Chiral Primary Amine: Divergent Stereocontrol Modes

α-Branched ketones remain a
challenging type of substrates
in aminocatalysis due to their congested structures as well as the
associated difficulties in controlling chemo- and stereoselectivity.
In this work, we have explored asymmetric aminocatalysis with α-substituted
β-ketoesters. A simple chiral primary amine catalyst was identified
to enable unprecedentedly effective catalysis of β-ketoesters
in α-hydrazination and Robinson annulation reaction with good
yields and high enantioselectivities. Stoichiometric experiments with
preformed enamine ester intermediates revealed their enamine-catalytic
nature as well as the critical roles of acidic additives in facilitating
catalytic turnovers and in tuning the chemo- and stereoselectivity.
With the identical catalytic system, the two reactions demonstrated
opposite chiral inductions in terms of the absolute configurations
of the newly formed stereogenic centers. Investigations into this
intriguing issue by DFT have revealed divergent stereocontrol modes.
For α-hydrazination, H-bonding-directed facial attack determines
the stereoselectivity, whereas a steric model is applied to the Robinson
annulation where dual activations of both β-ketoester and vinyl
ketone/aldehyde are involved.