Total Synthesis of (+)-Isolysergol

Area of Science:

• Organic Synthesis
• Medicinal Chemistry

Background:

• (+)-isolysergol is a valuable ergot alkaloid with potential therapeutic applications.
• Efficient and stereoselective synthetic routes are crucial for accessing complex natural products.

Purpose of the Study:

• To develop a novel, enantioselective synthesis of (+)-isolysergol.
• To establish key synthetic transformations for constructing the ergot alkaloid core structure.

Main Methods:

• Utilized a chiral pool approach starting from (2R)-(+)-phenyloxirane.
• Employed a stereoselective intramolecular 1,3-dipolar cycloaddition of a nitrone with a terminal olefin.
• Incorporated a Cope elimination for D-ring formation.
• Developed a late-stage rhodium-catalyzed intramolecular [3 + 2] annulation for the 3,4-fused indole scaffold.

Main Results:

• Achieved a total synthesis of (+)-isolysergol in 18 steps.
• Obtained an overall yield of 11% for the enantioselective synthesis.
• Successfully constructed the tetracyclic ergot alkaloid core with defined stereochemistry.

Conclusions:

• The developed synthetic strategy provides an efficient route to (+)-isolysergol.
• The key transformations, particularly the nitrone cycloaddition and rhodium-catalyzed annulation, are valuable for constructing complex indole-containing natural products.