Generation of Oxyphosphonium Ions by Photoredox/Cobaloxime Catalysis for Scalable Amide and Peptide Synthesis in Batch and Continuous‐Flow

Phosphine‐mediated deoxygenative nucleophilic substitutions, such as the Mitsunobu reaction, are of great importance in organic synthesis. However, the conventional protocols require stoichiometric oxidants to trigger the formation of the oxyphosphonium intermediates for the subsequent nucleophilic...

Full description

Saved in:
Bibliographic Details
Published in:Angewandte Chemie International Edition 2022-01, Vol.61 (5), p.e202112668-n/a
Main Authors: Su, Junqi, Mo, Jia‐Nan, Chen, Xiangyang, Umanzor, Alexander, Zhang, Zheng, Houk, Kendall N., Zhao, Jiannan
Format: Article
Language:English
Subjects:
Catalysis
computational chemistry
Computer applications
Deoxygenation
Intermediates
Ions
Oxidants
Oxidizing agents
Peptide synthesis
Peptides
Phosphine
Phosphines
redox chemistry
visible-light chemistry
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:Phosphine‐mediated deoxygenative nucleophilic substitutions, such as the Mitsunobu reaction, are of great importance in organic synthesis. However, the conventional protocols require stoichiometric oxidants to trigger the formation of the oxyphosphonium intermediates for the subsequent nucleophilic additions. Through dual catalysis of photoredox and cobaloxime, we realized a radical strategy for the catalytic formation of acyloxyphosphonium ions that enables direct amidation. The deoxygenative protocol exhibits a broad scope and has been used in the late‐stage amidation of drug molecules. In addition to batch reactions, a continuous‐flow reactor was developed, enabling rapid peptide synthesis on gram scale. The successful assembly of a tetrapeptide on the solid support further demonstrated the versatility of this photocatalytic system. Moreover, experimental and computational studies are consistent with the hypothesis of acyloxyphosphonium ions being formed as the key intermediates. A photocatalytic method for the synthesis of amides and peptides is reported. Synergistic cooperation between a cobaloxime and a photoredox catalyst removes the elements of H2O through the use of PPh3 as a gentle organic reductant. The deoxygenative method is compatible with gram‐scale peptide synthesis and applicable to peptide fragment condensation and SPPS, which may find applications in both organic synthesis and pharmaceutical production.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202112668