First synthesis of (±)-halichonadins A-D

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Marine Natural Products

Background:

• Marine natural products, such as halichonadins, exhibit unique chemical structures and biological activities.
• The total synthesis of complex molecules like (±)-halichonadin C presents significant chemical challenges.
• Isocyanide functional groups are rare in natural products and their synthetic introduction is often difficult.

Purpose of the Study:

• To achieve the first total synthesis of the marine isocyanide terpene (±)-halichonadin C.
• To develop a novel synthetic strategy for constructing the isocyanide moiety.
• To explore the biosynthetic pathways of halichonadins A-D.

Main Methods:

• Total synthesis of (±)-halichonadin C.
• Nitrile-to-isocyanide interconversion using hypervalent iodine-promoted Hofmann rearrangement.
• Transformation of (±)-halichonadin C to related natural products.

Main Results:

• Successful first total synthesis of (±)-halichonadin C.
• Efficient construction of the isocyanide group at a sterically hindered position (C-6).
• Conversion of (±)-halichonadin C to halichonadins A and B via a proposed biosynthetic intermediate.

Conclusions:

• The developed synthetic strategy is effective for accessing complex isocyanide-containing natural products.
• The synthesis provides insights into the biosynthesis of the halichonadin family.
• This work expands the synthetic toolbox for incorporating isocyanide functionalities.