Enantioselective Synthesis and Biological Evaluation of Pyrrolidines Bearing Quaternary Stereogenic Centers.

Molecular complexity plays an increasingly important role in the modern pharmaceutical industry. Setting up multiple stereogenic centers in privileged substructures may give rise to improved or even unprecedented bioactivities; however, this area remains largely unexplored due to the tremendous synthetic challenges. Herein, we report a series of multisubstituted pyrrolidines with four continuous stereogenic centers, including up to two aza-QSCs (quaternary stereogenic centers). Systematic evaluations, including phenotypic screening, molecular docking, molecular dynamics, bioinformatics, and bioactivity analysis, have been performed to screen entities with pharmacological properties of interest. Among them, compound 4m with two QSCs was identified to be a potent antiproliferation agent through disturbing mitosis exit, and the presence of QSCs was found to be crucial for anticancer efficacy. This work illustrates that the introduction of QSCs in privileged scaffolds not only helps to expand the unpatented chemical space but also provides new opportunities for the discovery of novel therapeutic agents.

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.