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Synthesis of Piperazic Acid-Containing Cyclodepsipeptide Core of Verucopeptin
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  • Yuanjun Sun,
  • Wenhao Tang,
  • Mei Wang,
  • Huxin Ni,
  • Ya-Qiu Long
Yuanjun Sun
Soochow University
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Wenhao Tang
Soochow University
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Mei Wang
Soochow University
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Huxin Ni
Soochow University
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Ya-Qiu Long
Soochow University

Corresponding Author:[email protected]

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Abstract

Chemically, N1 nitrogen of piperazic acid is more nucleophilic than N2 nitrogen, but amide bonds predominantly formed at N2 nitrogen are prevalent in piperazic acid-containing natural products, with only one exception of sanglifehrin. Thus two orthogonal protecting groups of nitrogen are often employed to realize selective coupling of N2 nitrogen, resulting in increased synthetic steps and low synthetic efficiency. However, we developed selective deprotection of N2-Cbz from the N1,N2-diCbz piperazic acid-containing peptide to form the N2 amide exclusively, avoiding the tedious orthogonal protection strategy commonly applied to the easily-accessible N1,N2-diCbz piperazic acid as the building block. We employ this method to achieve an efficient synthesis of piperazic acid-containing cyclodepsipeptide core of verucopeptin with an overall yield of 21%. The key steps include late stage coupling of piperazic acid with 3-hydroxyleucine derivatives, and HATU-mediated macrolactamization of 19-membered macrocycle at N9 and C10. The selective deprotection of N2-Cbz from the N1,N2-diCbz-piperazic acid at late-stage would greatly facilitate the total syntheses of piperazic acid-containing cyclodepsipeptides of biological interest.
31 Mar 20231st Revision Received
03 Apr 2023Submission Checks Completed
03 Apr 2023Assigned to Editor
03 Apr 2023Review(s) Completed, Editorial Evaluation Pending
03 Apr 2023Editorial Decision: Accept