Isocomplestatin: total synthesis and stereochemical revision

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Methodology

Background:

• Complestatins are complex macrocyclic compounds with demonstrated anti-HIV activity.
• The precise stereochemical configuration and natural occurrence of complestatin and its isomers have been subjects of investigation.
• Previous reports identified a compound as isocomplestatin, necessitating clarification of its identity and origin.

Purpose of the Study:

• To develop a palladium-catalyzed synthetic route for the strained macrocyclic core of complestatins.
• To establish the stereochemical identity of the anti-HIV agent complestatin through stereoselective synthesis.
• To resolve the identity of the compound previously designated as isocomplestatin.

Main Methods:

• Palladium-mediated cross-coupling reactions for macrocycle formation.
• Stereoselective synthesis of model macrocyclic compounds.
• Synthesis and characterization of the S atropisomer of complestatin.

Main Results:

• A novel Pd-catalyzed method was successfully developed for preparing the strained macrocyclic moiety of complestatins.
• Stereoselective synthesis confirmed the structure and configuration of the S atropisomer of complestatin.
• The compound previously identified as isocomplestatin was shown to be identical to complestatin.

Conclusions:

• The S atropisomer of complestatin is the true isocomplestatin.
• Isocomplestatin has not been isolated as a natural product.
• The developed Pd-mediated synthesis offers a viable route to complestatin analogs.