Systematic Synthesis of Chiral CAACs with Three Independent Stereogenic Centers for Enantioselective Copper-Catalyzed Conjugate Borylation of Michael Acceptors

Chiral cyclic alkyl amino carbenes (CAACs), an intriguing
subclass
of N-heterocyclic carbenes, hold promising potential in asymmetric
catalysis. Yet, synthetic hurdles and a lack of understanding of dominant
selectivity-inducing design elements prevent the development of widespread
applications. We report the systematic synthesis of a chiral CAAC
ligand family featuring a chiral backbone and a total of three independently
controllable stereogenic centers. An enantioselective DAP-catalyzed
Eschenmoser–Claisen rearrangement selectively delivered both
diastereomers of the pivotal methallyl aldehydes with two vicinal
stereogenic centers. Condensation with chiral primary amines enabled
the selective synthesis of all possible α,β,β-chiral
CAAC ligand diastereomers. The corresponding copper complexes provided
structural insights and were assessed for their catalytic performance
in benchmarking enantioselective 1,4-borylations of α,β-unsaturated
esters. One ligand diastereomer displayed synergism of the three stereogenic
centers, showing superior enantioselectivities and reactivity at a
low catalyst loading. Highlighting the interplay of the stereocenters,
the other three diastereomers suffered from various degrees of mismatched
effects with poor catalytic outcomes. Crystallographic data analysis
provided insights into the role of the ligand’s chiral backbone
in enhancing selectivity and reactivity. The best performing catalyst
was exploited with an array of β,β-disubstituted Michael
acceptors including unsaturated esters, thioesters, amides, and ketones,
providing enantioselectivities of up to 98:2 er for the addition products.
This work highlights the potential of introducing a stereogenic center
in the backbone of the CAACs as a strategy to optimize both reactivity
and selectivity in enantioselective CAAC-transition-metal catalysis.