Total synthesis of (-)-2-epi-peloruside A

Area of Science:

• Organic Synthesis
• Natural Product Chemistry
• Medicinal Chemistry

Background:

• Peloruside A is a marine natural product with significant biological activity.
• The total synthesis of complex natural products presents considerable challenges.
• Developing efficient synthetic routes is crucial for further biological evaluation and analog development.

Purpose of the Study:

• To achieve a convergent synthesis of (-)-2-epi-peloruside A.
• To explore the utility of anion relay chemistry (ARC) in constructing complex molecular architectures.
• To investigate the macrolactonization step and potential stereochemical outcomes.

Main Methods:

• Implementation of multicomponent type I anion relay chemistry (ARC) to couple a dithiane with two epoxides.
• A late-stage dithiane union to assemble the complete carbon backbone.
• Yamaguchi macrolactonization for macrocycle formation.

Main Results:

• Successful construction of the eastern hemisphere of (-)-2-epi-peloruside A using ARC.
• Assembly of the fully functionalized carbon backbone through a late-stage dithiane coupling.
• Formation of (-)-2-epi-peloruside A via Yamaguchi macrolactonization, accompanied by an unexpected epimerization at the C(2) position.

Conclusions:

• A convergent and efficient synthetic route to (-)-2-epi-peloruside A has been established.
• Anion relay chemistry proved effective for assembling key fragments of the molecule.
• The study highlights an unexpected stereochemical outcome during macrolactonization, providing insights into reaction mechanisms.