Concise Synthesis of (±)-Stephadiamine via Vinylogous Wenker Cyclization

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Natural Product Synthesis

Background:

• Stephadiamine is a complex alkaloid with a challenging aza[4.3.3]propellane framework.
• Efficient and diastereoselective synthetic routes are crucial for accessing such complex natural products.

Purpose of the Study:

• To develop a short and diastereoselective synthesis of stephadiamine.
• To establish key synthetic methodologies for constructing the aza[4.3.3]propellane core and syn-diamine motif.

Main Methods:

• Homoconjugate addition-Wittig olefination cascade using a modified Schweizer-Fuchs cyclopropyl phosphonium salt.
• Vinylogous substitution to install the aza[4.3.3]propellane system.
• Diastereoselective Strecker reaction for syn-diamine formation.
• Azide masking strategy to circumvent retro-Strecker degradation during lactonization.

Main Results:

• A 12-step synthesis of stephadiamine was successfully completed.
• The synthesis features a novel cascade reaction for carbocyclic framework construction.
• The challenging aza[4.3.3]propellane core and syn-diamine motif were efficiently installed with high diastereoselectivity.

Conclusions:

• The developed synthetic strategy provides an efficient route to stephadiamine.
• The novel methodologies employed are valuable for the synthesis of complex alkaloids and related structures.
• This work highlights the utility of cascade reactions and diastereoselective transformations in natural product synthesis.