Convergent and Efficient Total Synthesis of (+)-Heilonine Enabled by C-H Functionalizations

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Steroidal alkaloids are a class of natural products with diverse biological activities.
• The C-nor D-homo steroid skeleton presents significant synthetic challenges.
• (+)-Heilonine is a complex steroidal alkaloid with a unique hexacyclic ring system.

Purpose of the Study:

• To develop a convergent and efficient total synthesis of (+)-heilonine.
• To establish novel synthetic methodologies for constructing complex steroidal alkaloids.
• To explore the utility of C-H functionalization and cross-coupling reactions in complex molecule synthesis.

Main Methods:

• Convergent synthesis strategy.
• Four selective C-H functionalizations for C-C bond and stereocenter formation.
• Stille carbonylative cross-coupling for AB and DEF ring system connection.
• Nazarov cyclization for C ring construction.

Main Results:

• Successful total synthesis of (+)-heilonine.
• Construction of a hexacyclic ring system with nine stereocenters.
• Formation of a trans-hydrindane moiety.
• Delivery of (+)-heilonine in 11 or 13 longest linear sequence (LLS) steps.

Conclusions:

• The developed synthetic route is efficient and convergent.
• The employed methodologies, including C-H functionalization and Stille coupling, are effective for complex steroidal alkaloid synthesis.
• This synthesis provides a valuable route to (+)-heilonine and related compounds.