Desymmetrization of N-Cbz glutarimides through N-heterocyclic carbene organocatalysis

Desymmetrization of achiral building blocks is one of the most efficient ways to access enantiopure compounds of synthetic relevance. Here, the authors desymmetrize glutarimides with alcohols via an imide C-N bond cleavage under NHC organocatalysis. Over the past decade, the catalysis of N-heterocyclic carbenes has achieved significant advances. In this area, aldehydes, enals, and esters, are commonly employed as starting materials through various catalytic activation modes. However, NHC-activated strategy of amide and its derivatives remains elusive. Described herein is the realization of asymmetric desymmetrization of N-Cbz glutarimides with alcohols through an imide C-N bond cleavage under NHC organocatalysis. A structurally diverse set of enantioenriched 4-amido esters is generated with acceptable yields and high enantioselectivities. This method features mild reaction conditions, excellent substrate scope, and excellent atom economy. DFT calculations have been performed to explore the detailed reaction mechanism and the origin of the enantioselectivity, which indicate that the strength of the C-H center dot center dot center dot O hydrogen bond and C-HMIDLINE HORIZONTAL ELLIPSIS pi interactions should be responsible for the stereoselectivity. The current strategy could open a door for efficient construction of (R)-Rolipram with excellent stereoselectivity.

Automated summary

This paper describes a method for the asymmetric desymmetrization of amides using NHC organocatalysis, resulting in the generation of a diverse set of enantioenriched 4-amido esters with mild reaction conditions, wide substrate scope, and excellent atom economy.