Biology-oriented combined solid- and solution-phase synthesis of a macroline-like compound collection

Area of Science:

• Natural Product Synthesis
• Organic Chemistry
• Medicinal Chemistry

Background:

• Macrolines are a large class of natural products (>100 members) with significant biological activities.
• The cycloocta[b]indole scaffold is a key structural motif in macrolines, making it an attractive target for synthesis.

Purpose of the Study:

• To develop a robust solid-phase synthesis for isomerically pure cycloocta[b]indoles.
• To explore diversification strategies for generating novel cycloocta[b]indole derivatives.

Main Methods:

• Solid-phase synthesis utilizing Pictet-Spengler and Dieckmann cyclization as key steps.
• Palladium-catalyzed cross-coupling reactions (Sonogashira, Suzuki) on solid phase for diversification.
• Solution-phase modifications including reduction and saponification.

Main Results:

• Successful synthesis of isomerically pure cycloocta[b]indoles.
• Demonstrated scope expansion through solid-phase cross-coupling, enabling 10-substituted derivatives.
• Evaluated solution-phase functionalization for further structural elaboration.

Conclusions:

• The developed solid-phase synthesis provides efficient access to diverse cycloocta[b]indole structures.
• This methodology is valuable for biology-oriented synthesis (BIOS) and drug discovery efforts.
• The combination of solid-phase and solution-phase strategies enhances the utility of this synthetic route.