Enantioselective Synthesis of Arylglycines via Pd‐Catalyzed Coupling of Schöllkopf Bis‐Lactim Ethers with Aryl Chlorides

Arylglycines are important pharmacophores present in several top‐selling drugs. This compound class has now been made accessible from abundant aryl chlorides by a Pd‐catalyzed Schöllkopf‐type amino acid synthesis. In the presence of the catalyst methylnaphthyl(XPhos)‐palladium bromide, the base lith...

Full description

Saved in:
Bibliographic Details
Published in:Angewandte Chemie International Edition 2023-12, Vol.62 (49), p.e202309868-n/a
Main Authors: Prendes, Daniel Sowa, Papp, Florian, Sankaran, Nagesh, Sivendran, Nardana, Beyer, Frederike, Merten, Christian, Gooßen, Lukas J.
Format: Article
Language:English
Subjects:
Amino Acids
Aromatic compounds
Arylation
Catalysis
Catalysts
Chemical synthesis
Chlorides
Diastereoselectivity
Enantiomers
Ethers
Leucine
Lithium
Palladium
Pharmacophores
Room temperature
Zinc chloride
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Arylglycines are important pharmacophores present in several top‐selling drugs. This compound class has now been made accessible from abundant aryl chlorides by a Pd‐catalyzed Schöllkopf‐type amino acid synthesis. In the presence of the catalyst methylnaphthyl(XPhos)‐palladium bromide, the base lithium 2,2,6,6‐tetramethylpyrrolidide and the additive ZnCl2, tert‐leucine‐derived bis‐lactim ethers were efficiently arylated at room temperature, reaching yields of 95 % and diastereoselectivities of 98 : 2. Hydrolysis gave the corresponding arylglycines in high enantiomeric excess. Catalytic methylnaphthyl(XPhos)‐palladium bromide promotes the coupling of chiral tert‐leucine‐derived Schöllkopf bis‐lactim ether with cheap aryl chlorides at room temperature in yields up to 95 % and >25 : 1 dr. This enables a convenient access to non‐natural tertiary arylglycines, which are key structural motifs in several top‐selling drugs. This protocol is also suitable for the late‐stage functionalization of common pharmaceuticals.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202309868