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Two-Component Redox Organocatalyst for Peptide Bond Formation
journal contribution
posted on 2022-02-21, 15:34 authored by Handoko, Nihar R. Panigrahi, Paramjit S. AroraPeptides are fundamental therapeutic
modalities whose sequence-specific
synthesis can be automated. Yet, modern peptide synthesis remains
atom uneconomical and requires an excess of coupling agents and protected
amino acids for efficient amide bond formation. We recently described
the rational design of an organocatalyst that can operate on Fmoc
amino acidsthe standard monomers in automated peptide synthesis
(J. Am. Chem. Soc. 2019, 141, 15977).
The catalytic cycle centered on the conversion of the carboxylic acid
to selenoester, which was activated by a hydrogen bonding scaffold
for amine coupling. The selenoester was generated in situ from a diselenide catalyst and stoichiometric amounts of phosphine.
Although the prior system catalyzed oligopeptide synthesis on solid
phase, it had two significant requirements that limited its utility
as an alternative to coupling agentsit depended on stoichiometric
amounts of phosphine and required molecular sieves as dehydrating
agent. Here, we address these limitations with an optimized method
that requires only catalytic amounts of phosphine and no dehydrating
agent. The new method utilizes a two-component organoreductant/organooxidant-recycling
strategy to catalyze amide bond formation.
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required molecular sievesprotected amino acidshydrogen bonding scaffoldnew method utilizescatalytic cycle centeredtwo significant requirementscoupling agents component redox organocatalystcoupling agentsoptimized methodcomponent organoreductantcatalytic amountsamine couplingstoichiometric amountsstandard monomersspecific synthesissolid phasesoc .situ recycling strategyrecently describedrational designdiselenide catalystdehydrating agentcarboxylic acid15977 ).