Dual NHC/HAT-Promoted Esterification to Access α-Aryl Glycines
Matthew J McGill1, Adam X Wayment1, Cullen R Schull1
1Department of Chemistry, Northwestern University, Silverman Hall, Evanston, Illinois 60208, USA.
Advanced Synthesis & Catalysis
|May 11, 2026
Summary
This study introduces a new dual catalysis method for synthesizing aryl glycines, important compounds in pharmaceuticals. The novel approach efficiently creates these valuable nonproteinogenic amino acids using radical chemistry.
Area of Science:
- Organic Chemistry
- Catalysis
- Medicinal Chemistry
Background:
- α-aryl glycines are crucial nonproteinogenic amino acids found in many pharmacophores.
- Existing synthetic strategies for α-aryl glycines are limited, especially direct carboxylation methods.
Purpose of the Study:
- To develop an efficient method for synthesizing α-aryl glycines using a novel dual catalysis strategy.
- To explore the scope and limitations of the new methodology for various substrates.
Main Methods:
- Utilized a dual N-heterocyclic carbene (NHC)/photocatalysis approach.
- Generated 2-azaallyl radicals which coupled with ester azolium radical intermediates.
- Employed base-mediated collapse of tetrahedral intermediates for product formation.
Main Results:
- Successfully synthesized a variety of aryl substituted glycine derivatives.
- Demonstrated the esterification of allylic and benzylic sites.
- Mechanistic studies indicated operation under both oxidative and reductive radical quenching cycles.
- Preliminary experiments showed modest enantioselectivity using a chiral NHC and Lewis acid.
Conclusions:
- The developed dual NHC/HAT catalysis strategy provides a new route to α-aryl glycines.
- The methodology is versatile, applicable to various aryl substituted glycines and other functional groups.
- Further research can optimize enantioselectivity for broader pharmaceutical applications.
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