A Tandem In Situ Peptide Cyclization through Trifluoroacetic Acid Cleavage†
Dr. Koushik Chandra
Institute of Chemistry, Edmond J. Safra campus The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904 (Israel) http://chem.ch.huji.ac.il/∼assaf
Search for more papers by this authorDr. Tapta Kanchan Roy
Institute of Chemistry, Edmond J. Safra campus The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904 (Israel) http://chem.ch.huji.ac.il/∼assaf
Search for more papers by this authorDr. Deborah E. Shalev
The Wolfson Centre for Applied Structural Biology, The Hebrew University of Jerusalem (Israel)
Search for more papers by this authorProf. Abraham Loyter
Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem (Israel)
Search for more papers by this authorProf. Chaim Gilon
Institute of Chemistry, Edmond J. Safra campus The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904 (Israel) http://chem.ch.huji.ac.il/∼assaf
Search for more papers by this authorProf. R. Benny Gerber
Institute of Chemistry, Edmond J. Safra campus The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904 (Israel) http://chem.ch.huji.ac.il/∼assaf
The Fritz Haber Centre, The Hebrew University of Jerusalem (Israel)
Department of Chemistry, University of Helsinki, P.O. Box 55, 00014 Helsinki (Finland)
University of California, Irvine, CA 92697 (USA)
Search for more papers by this authorCorresponding Author
Prof. Assaf Friedler
Institute of Chemistry, Edmond J. Safra campus The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904 (Israel) http://chem.ch.huji.ac.il/∼assaf
Institute of Chemistry, Edmond J. Safra campus The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904 (Israel) http://chem.ch.huji.ac.il/∼assafSearch for more papers by this authorDr. Koushik Chandra
Institute of Chemistry, Edmond J. Safra campus The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904 (Israel) http://chem.ch.huji.ac.il/∼assaf
Search for more papers by this authorDr. Tapta Kanchan Roy
Institute of Chemistry, Edmond J. Safra campus The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904 (Israel) http://chem.ch.huji.ac.il/∼assaf
Search for more papers by this authorDr. Deborah E. Shalev
The Wolfson Centre for Applied Structural Biology, The Hebrew University of Jerusalem (Israel)
Search for more papers by this authorProf. Abraham Loyter
Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem (Israel)
Search for more papers by this authorProf. Chaim Gilon
Institute of Chemistry, Edmond J. Safra campus The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904 (Israel) http://chem.ch.huji.ac.il/∼assaf
Search for more papers by this authorProf. R. Benny Gerber
Institute of Chemistry, Edmond J. Safra campus The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904 (Israel) http://chem.ch.huji.ac.il/∼assaf
The Fritz Haber Centre, The Hebrew University of Jerusalem (Israel)
Department of Chemistry, University of Helsinki, P.O. Box 55, 00014 Helsinki (Finland)
University of California, Irvine, CA 92697 (USA)
Search for more papers by this authorCorresponding Author
Prof. Assaf Friedler
Institute of Chemistry, Edmond J. Safra campus The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904 (Israel) http://chem.ch.huji.ac.il/∼assaf
Institute of Chemistry, Edmond J. Safra campus The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904 (Israel) http://chem.ch.huji.ac.il/∼assafSearch for more papers by this authorA.F. was supported by the European Research Council (FP7/2007-2013)/ERC Grant agreement n° 203413 and the Minerva Center for Bio-Hybrid complex systems. K.C. and T.K.R. are supported by a PBC fellowship, Council of Higher Education, Israel. T.K.R. thanks the CSC-IT Center for Science, Finland, for computational resources and Dr. S. Saha for fruitful discussions. R.B.G. thanks the Academy of Finland in the framework of the FiDiPro program.
Abstract
We present a new approach for peptide cyclization during solid phase synthesis under highly acidic conditions. Our approach involves simultaneous in situ deprotection, cyclization and trifluoroacetic acid (TFA) cleavage of the peptide, which is achieved by forming an amide bond between a lysine side chain and a succinic acid linker at the peptide N-terminus. The reaction proceeds via a highly active succinimide intermediate, which was isolated and characterized. The structure of a model cyclic peptide was solved by NMR spectroscopy. Theoretical calculations support the proposed mechanism of cyclization. Our new methodology is applicable for the formation of macrocycles in solid-phase synthesis of peptides and organic molecules.
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