Total synthesis of biologically active natural products toward elucidation of the mode of action

Masahito Yoshida

Research output: Contribution to journalReview articlepeer-review

Abstract

Total synthesis of biologically active cyclodepsipeptide destruxin E using solid- and solution-phase synthesis is described. The solid-phase synthesis of destruxin E was initially investigated for the efficient synthesis of destruxin analogues. Peptide elongation from polymer-supported β-alanine was efficiently performed using DIC/HOBt or PyBroP/ DIEA, and subsequent cleavage from the polymer-support under weakly acidic conditions furnished a cyclization precursor in moderate yield. Macrolactonization of the cyclization precursor was smoothly performed using 2-methyl-6- nitrobenzoic anhydride (MNBA)/4-(dimethylamino)pyridine N-oxide (DMAPO) to afford macrolactone in moderate yield. Finally, formation of the epoxide in the side chain via three steps provided destruxin E, and the stereochemistry of the epoxide was determined to be S. Its diastereomer, epi-destruxin E, was also synthesized in the same manner used to synthesize the natural product. The stereochemistry of the epoxide was critical for the V-ATPase inhibition; natural product destruxin E exhibited 10-fold more potent V-ATPase inhibition than epi-destruxin E. Next, the scalable synthesis of destruxin E for in vivo study was also performed via solution-phase synthesis. The scalable synthesis of a key component, (S)-HA-Pro-OH, was achieved using osmium-catalyzed diastereoselective dihydroxylation with (DHQD)2 PHAL as a chiral ligand; peptide synthesis using Cbz-protected amino acid derivatives furnished the cyclization precursor on a gram-scale. Macrolactonization smoothly provided the macrolactone without forming a dimerized product, even at 6 mM, and the synthesis of destruxin E was achieved via three steps on a gram scale in high purity (>98%).

Original languageEnglish
Pages (from-to)1099-1108
Number of pages10
JournalYakugaku Zasshi
Volume135
Issue number10
DOIs
Publication statusPublished - 2015 Oct 1

Keywords

  • Cyclodepsipeptide
  • Macrolactonization
  • Natural product
  • Solid-phase synthesis
  • Total synthesis

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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