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- Title
Leveraging the Knorr Pyrazole Synthesis for the Facile Generation of Thioester Surrogates for use in Native Chemical Ligation.
- Authors
Flood, Dillon T.; Hintzen, Jordi C. J.; Bird, Michael J.; Cistrone, Philip A.; Chen, Jason S.; Dawson, Philip E.
- Abstract
Abstract: Facile synthesis of C‐terminal thioesters is integral to native chemical ligation (NCL) strategies for chemical protein synthesis. We introduce a new method of mild peptide activation, which leverages solid‐phase peptide synthesis (SPPS) on an established resin linker and classical heterocyclic chemistry to convert C‐terminal peptide hydrazides into their corresponding thioesters via an acyl pyrazole intermediate. Peptide hydrazides, synthesized on established trityl chloride resins, can be activated in solution with stoichiometric acetyl acetone (acac), readily proceed to the peptide acyl pyrazoles. Acyl pyrazoles are mild acylating agents and are efficiently exchanged with an aryl thiol, which can then be directly utilized in NCL. The mild, chemoselective, and stoichiometric activating conditions allow this method to be utilized through multiple sequential ligations without intermediate purification steps.
- Subjects
CHEMICAL reagents; THIOESTERS; HETEROCYCLIC chemistry; PEPTIDES; PYRAZOLES
- Publication
Angewandte Chemie, 2018, Vol 130, Issue 36, p11808
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201805191