Ir and NHC Dual Chiral Synergetic Catalysis: Mechanism and Stereoselectivity in γ‑Butyrolactone Formation

Cooperative dual catalysis is a powerful strategy for
achieving
unique reactivity by combining catalysts with orthogonal modes of
action. This approach allows for independent control of the absolute
and relative stereochemistry of the product. Despite its potential
utility, the combination of N-heterocyclic carbene (NHC) organocatalysis
and transition metal catalysis has remained a formidable challenge
as NHCs readily coordinate metal centers. This characteristic also
makes it difficult to rationalize or predict the stereochemical outcomes
of these reactions. Herein, we use quantum mechanical calculations
to investigate formation of γ-butyrolactones from aldehydes
and allyl cyclic carbonates by means of an NHC organocatalyst and
an iridium catalyst. Stereoconvergent activation of the racemic allyl
cyclic carbonate forms an Ir-π-allyl intermediate and activation
of an unsaturated aldehyde forms an NHC enolate, the latter of which
is rate-limiting. Union of the two fragments leads to stereodetermining
C–C bond formation and ultimately ring closure to generate
the product lactone. Notably, CO2 loss occurs after formation
of the C–C bond and Et3NH+ plays a key
role in stabilizing carboxylate intermediates and in facilitating
proton transfer to form the NHC enolate. The computed pathways agree
with the experimental findings in terms of the absolute configuration,
the enantiomer excess, and the different diastereomers seen with the
(R)- and (S)-spiro-phosphoramidite combined with the NHC catalyst. Calculations reveal
the lowest energy pathway includes both an NHC ligand and a phosphoramidite
ligand on the iridium center. However, the stereochemical features
of this Ir-bound NHC were found to not contribute to the selectivity
of the process.