Well-Designed Phosphine–Urea Ligand for Highly Diastereo- and Enantioselective 1,3-Dipolar Cycloaddition of Methacrylonitrile: A Combined Experimental and Theoretical Study

A novel chiral phosphine–urea
bifunctional ligand has been
developed for Cu-catalyzed asymmetric 1,3-dipolar cycloaddition of
iminoesters with methacrylonitrile, a long-standing challenging substrate
in asymmetric catalysis. Distortion–interaction energy analysis
based on density functional theory (DFT) calculations reveals that
the distortion energy plays an important role in the observed enantioselectivity,
which can be attributed to the steric effect between the phosphine
ligand and the dipole reactant. DFT calculations also indicate that
nucleophilic addition is the enantioselectivity-determining step and
hydrogen bonding between the urea moiety and methacrylonitrile assists
in control of the diastereo- and enantioselectivity. By a combination
of metal catalysis and organocatalysis, excellent diastereo- and enantioselectivities
(up to 99:1 diastereomeric ratio, 99% enantiomeric excess) as well
as good yields are achieved. A wide range of substitution patterns
of both iminoester and acrylonitrile is tolerated by this catalyst
system, providing access to a series of highly substituted chiral
cyanopyrrolidines with up to two quaternary stereogenic centers. The
synthetic utility is demonstrated by enantioselective synthesis of
antitumor agent ETP69 with a pivotal nitrile pharmacophore
and an all-carbon quaternary stereogenic center.