Synthesis of Leiodolide A Macrolactone

Area of Science:

• Organic Synthesis
• Medicinal Chemistry
• Natural Product Synthesis

Background:

• Leiodolide A is a marine natural product with potential biological activity.
• Previous synthetic routes to leiodolide A have been reported.
• A convergent synthesis offers advantages in efficiency and flexibility.

Purpose of the Study:

• To develop a novel convergent synthetic route toward leiodolide A.
• To investigate the stereochemical outcomes of key reactions.
• To synthesize and characterize the macrolactone core.

Main Methods:

• Indium chloride-induced transmetalation of allylic stannane.
• Nucleophilic addition with a nonracemic aldehyde.
• In situ isomerization to a Z-allylindium reagent.
• Anti-Felkin addition.
• Pi-allyl Stille cross-coupling.
• Horner-Wadsworth-Emmons macrolactonization.

Main Results:

• Stereoselective formation of an all-syn stereotriad was achieved.
• Z-allylindium reagent facilitated anti-Felkin addition.
• Effective pi-allyl Stille cross-coupling was performed.
• Macrolactone 37 was synthesized via Horner-Wadsworth-Emmons reaction.
• The synthesized macrolactone exhibited discrepancies in NMR data compared to reported leiodolide A.

Conclusions:

• A convergent synthesis of leiodolide A was successfully developed.
• The stereochemical control in key steps was rationalized.
• The synthesized macrolactone structure requires further investigation due to NMR data discrepancies.