4.8 Article

Catalytic asymmetric synthesis of enantioenriched α-deuterated pyrrolidine derivatives

Journal

CHEMICAL SCIENCE
Volume 13, Issue 14, Pages 4041-4049

Publisher

ROYAL SOC CHEMISTRY
DOI: 10.1039/d2sc00826b

Keywords

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Funding

  1. NSFC [220711186, 22101216]
  2. Hubei Province Natural Science Foundation [2020CFA036]
  3. China Postdoctoral Science Foundation [2021M702514]
  4. Program of Introducing Talents of Discipline to Universities of China (111 Program)

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This article introduces an efficient method for synthesizing pharmaceutical compounds with deuterium labels, which addresses the challenge of building deuterium-containing stereogenic centers in organic synthesis. By combining H/D exchange and 1,3-dipolar cycloaddition in a catalytic asymmetric strategy, bioactive alpha-deuterated pyrrolidine derivatives were constructed with high yields and excellent stereoselectivities.
The recent promising applications of deuterium-labeled pharmaceutical compounds have led to an urgent need for the efficient synthetic methodologies that site-specifically incorporate a deuterium atom into bioactive molecules. Nevertheless, precisely building a deuterium-containing stereogenic center, which meets the requirement for optimizing the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of chiral drug candidates, remains a significant challenge in organic synthesis. Herein, a catalytic asymmetric strategy combining H/D exchange (H/D-Ex) and azomethine ylide-involved 1,3-dipolar cycloaddition (1,3-DC) was developed for the construction of biologically important enantioenriched alpha-deuterated pyrrolidine derivatives in good yields with excellent stereoselectivities and uniformly high levels of deuterium incorporation. Directly converting glycine-derived aldimine esters into the deuterated counterparts with D2O via Cu(i)-catalyzed H/D-Ex, and the subsequent thermodynamically/kinetically favored cleavage of the alpha-C-H bond rather than the alpha-C-D bond to generate the key N-metallated alpha-deuterated azomethine ylide species for the ensuing 1,3-DC are crucial to the success of alpha-deuterated chiral pyrrolidine synthesis. The current protocol exhibits remarkable features, such as readily available substrates, inexpensive and safe deuterium source, mild reaction conditions, and easy manipulation. Notably, the synthetic utility of a reversed 1,3-DC/[H/D-Ex] protocol has been demonstrated by catalytic asymmetric synthesis of deuterium-labelled MDM2 antagonist idasanutlin (RG7388) with high deuterium incorporation.

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