Total Synthesis of (-)-Rauvomine B via a Strain-Promoted Intramolecular Cyclopropanation

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• Indole alkaloids represent a significant class of natural products with diverse biological activities.
• (-)-Rauvomine B is an unusual cyclopropane-containing indole alkaloid whose total synthesis has not been previously reported.
• Developing efficient synthetic routes to complex natural products is crucial for their further study and potential therapeutic applications.

Purpose of the Study:

• To achieve the first total synthesis of the indole alkaloid (-)-rauvomine B.
• To develop a novel synthetic strategy centered on intramolecular cyclopropanation.
• To investigate the factors influencing the key cyclopropanation step through computational studies.

Main Methods:

• The synthesis employed a multi-step approach involving palladium-catalyzed stereospecific allylic amination.
• Key reactions included a cis-selective Pictet-Spengler reaction and ring-closing metathesis for constructing the tetracyclic core.
• The final step involved intramolecular cyclopropanation of an N-sulfonyltriazole precursor.

Main Results:

• The total synthesis of (-)-rauvomine B was successfully accomplished in 11 steps with an overall yield of 2.4%.
• The key intramolecular cyclopropanation step's efficiency was found to be highly dependent on the precursor's structure and conformational strain.
• Density Functional Theory (DFT) studies were performed to explore the origins of this dependency.

Conclusions:

• This study reports the first total synthesis of (-)-rauvomine B, establishing a viable route to this complex natural product.
• The developed strategy highlights the utility of intramolecular cyclopropanation for constructing cyclopropane-containing alkaloids.
• Computational insights provide a deeper understanding of the stereochemical outcomes in the cyclopropanation reaction.