Leveraging the Knorr Pyrazole Synthesis for the Facile Generation of Thioester Surrogates for use in Native Chemical Ligation |
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Authors: | Dillon T. Flood Jordi C. J. Hintzen Michael J. Bird Philip A. Cistrone Jason S. Chen Dr. Philip E. Dawson |
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Affiliation: | 1. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA;2. Automated Synthesis Facility, The Scripps Research Institute, La Jolla, CA, USA |
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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. |
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Keywords: | chemoselective ligation native chemical ligation peptide hydrazides protein synthesis pyrazoles |
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