An Efficient Approach for the Total Synthesis of C

Authors: Sungkyu Park Sunithi Gunasekera Teshome Leta Aboye Ulf Göransson

Publish Date: 2010/07/21

Volume: 16, Issue: 3, Pages: 167-176

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Abstract

Cyclotides are miniproteins of approximately 30 amino acid residues that have a unique structure consisting of a headtotail cyclized backbone and a knotted arrangement of three disulfide bonds This unique cyclotide structure provides exceptional stability to chemical enzymatic and thermal treatments and has been implicated as an ideal drug scaffold for the development into agricultural and biotechnological agents In the current work we present the first method for microwave assisted FmocSPPS of cyclotides This protocol adopts a strategy that combines optimized microwave assisted chemical reactions for FmocSPPS of the peptide backbone the cleavage of the protected peptide and the introduction of a thioester at the Cterminal carboxylic acid to obtain the headtotail cyclized cyclotide backbone by native chemical ligation To exemplify the utility of this protocol in the synthesis of a wide array of different cyclotide sequences we synthesized representative members from the three cyclotide subfamilies—the Möbius kalata B1 the bracelet cycloviolacin O2 and the trypsin inhibitory MCoTIII In addition a “one pot” reaction promoting both cyclization and oxidative folding of crude peptide thioester was adapted for kalata B1 and MCoTIII

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