op6b00320_si_001.pdf (1.09 MB)
Practical Synthesis of MDM2 Antagonist RG7388. Part 1: A Cu(II)-Catalyzed Asymmetric [3 + 2] Cycloaddition
journal contribution
posted on 2016-10-31, 00:00 authored by Lianhe Shu, Chen Gu, Dan Fishlock, Zizhong LiAn efficient asymmetric
synthesis of MDM2 antagonist RG7388 is
reported. The highly functionalized chiral pyrrolidine carboxamide
was assembled via a Cu(OAc)2/(R)-BINAP
catalyzed asymmetric [3 + 2] cycloaddition, which gave the exo and
endo adducts in a ratio of 10:1, with high enantiomeric excess for
the exo isomer. A one-pot hydrolysis and retro-Mannich/Mannich isomerization
of the cycloaddition adducts in the presence of aqueous sodium hydroxide
afforded RG7388 in high chemical and enantiomeric purities and 69%
overall yield.