Mechanistic study on the Knorr pyrazole synthesis-thioester generation reaction. Issue 30 (25th July 2019)

• Record Type: Journal Article
• Authors: Du, Yijun; Xu, Yanyan; Qi, Chenze; Wang, Chen
• Is Part Of: Tetrahedron letters. Volume 60:Issue 30(2019)
• Page Start: 1999
• Page End: 2004
• Publication Date: 2019-07-25
• Subjects: Knorr pyrazole synthesis -- Thioester -- Native chemical ligation -- Mechanism -- Theoretical calculations; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tetlet.2019.06.053
• Languages: English
• ISSNs: 0040-4039

Abstract

Graphical abstract: Highlights: Mechanism of Knorr pyrazole synthesis-thioester generation reaction was studied. DFT calculations show that the thioester formation occurs easily. Both hydrazone and pyrazole formation is sensitive to solution acidity. Some steps in the reaction require protonation of oxygen atoms. Low pH favors protonation of O atoms, thus increasing the reaction efficiency. Abstract: A novel Fmoc-SPPS compatible peptide thioester generation method leveraging Knorr pyrazole synthesis was reported recently. C-terminal peptide hydrazides, pentane-2, 4-dione and excess arylthiol were added in one-pot to efficiently produce peptide thioesters in acidic aqueous solution at room temperature. To elucidate the detailed mechanism of this reaction and the origin of the effect of solution acidity, a theoretical investigation on the Knorr pyrazole synthesis-thioester generation reaction was carried out. Our computational results suggest that the reaction generally proceeds through three stages: hydrazone formation, pyrazole formation and thioester formation. The rate-determining step is the CO bond cleavage step in the pyrazole formation stage. The formed pyrazole is readily converted to thioester in the presence of excess thiophenol. The effect of solution acidity originates from the need for protonation of oxygen atoms to increase the electrophilicity of carbonyl group or the leaving ability of hydroxyl group.