Solid-Phase Total Synthesis of Yaku'amide B Enabled by Traceless Staudinger Ligation

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Natural Product Synthesis

Background:

• Yaku'amide B is a peptidic natural product with demonstrated antiproliferative activity against cancer cells.
• The complex structure of yaku'amide B, featuring four β,β-dialkylated α,β-dehydroamino acid residues, presents significant synthetic challenges.
• Existing solid-phase synthesis methods are insufficient for constructing such intricate peptide structures.

Purpose of the Study:

• To develop a novel Fmoc-based solid-phase strategy for the total synthesis of yaku'amide B.
• To establish new methodologies for key synthetic steps including enamide formation, deprotection, and C-terminal modification.
• To achieve efficient and high-yield synthesis of yaku'amide B.

Main Methods:

• Development of a traceless Staudinger ligation for enamide formation using sterically hindered precursors.
• Application of a novel chemoselective deprotection strategy using Eu(OTf)3 for Boc groups without resin cleavage.
• Simultaneous resin cleavage and C-terminal modification via ester-amide exchange using CTA and AlMe3.

Main Results:

• Successful total synthesis of yaku'amide B (1) using the developed solid-phase strategy.
• Achieved an overall yield of 9.1% over 24 steps from the resin.
• Demonstrated the efficacy of new methods for enamide formation, deprotection, and C-terminal modification in complex peptide synthesis.

Conclusions:

• The reported solid-phase strategy provides an efficient route for the total synthesis of yaku'amide B.
• The developed synthetic methodologies are applicable to other complex peptidic natural products containing dehydroamino acid residues.
• This work facilitates further investigation into the anticancer potential of yaku'amide B and related compounds.