Catalytic Enantiodivergent Michael Addition by Subtle Adjustment of Achiral Amino Moiety of Dipeptide Phosphines.

Youshao Tu,Xiuzheng Li,Huamin Wang,Junliang Zhang

doi:10.1016/j.isci.2020.101138

Abstract

SummaryOver the past decades, asymmetric catalysis has been intensely investigated as a powerful tool for the preparation of numerous chiral biologically active compounds. However, developing general and practical strategies for preparation of both enantiomers of a chiral molecule via asymmetric catalysis is still a challenge, particularly when the two enantiomers of a chiral catalyst are not easily prepared from natural chiral sources. Inspired by the biologic system, we report herein an unprecedented catalytic enantiodivergent Michael addition of pyridazinones to enones by subtle adjustment of achiral amino moiety of dipeptide phosphine catalysts. These two dipeptide phosphine catalysts, P5 and P8, could deliver both enantiomers of a series of N2-alkylpyridazinones in good yields (up to 99%) with high enantioselectivities (up to 99% ee) via the catalyst-controlled enantiodivergent addition of pyridazinones to enones.

Highlights

The development of efficient methods to synthesize both enantiomers of a chiral molecule is of great significance, because drug candidates and their isomers may have distinct therapeutic properties or adverse effects (Wermuth, 2008; Jozwiak et al, 2012)
Inspired by the biologic system, we report an unprecedented catalytic enantiodivergent Michael addition of pyridazinones to enones by subtle adjustment of achiral amino moiety of dipeptide phosphine catalysts
Sickle cell anemia is an autosomal recessive genetic disease, caused by a single-base mutation in the beta gene of globin causing glutamate mutated to proline. This sickling leads to the RBC membrane damage and increases the likelihood of rupture and anemia (Gyang et al, 2011). Inspired by this intriguing biological process, we hypothesized that some small structural modifications in conformationally flexible chiral organocatalysts without changing any stereocenter might allow to obtain both stereoisomers in the individual form in asymmetric catalysis as well

Summary

Introduction

The development of efficient methods to synthesize both enantiomers of a chiral molecule is of great significance, because drug candidates and their isomers may have distinct therapeutic properties or adverse effects (Wermuth, 2008; Jozwiak et al, 2012). Sickle cell anemia is an autosomal recessive genetic disease, caused by a single-base mutation in the beta gene of globin causing glutamate mutated to proline. This sickling leads to the RBC membrane damage and increases the likelihood of rupture and anemia (Gyang et al, 2011). Inspired by this intriguing biological process, we hypothesized that some small structural modifications in conformationally flexible chiral organocatalysts without changing any stereocenter might allow to obtain both stereoisomers in the individual form in asymmetric catalysis as well

Methods

Results

Conclusion