Asymmetric Total Synthesis of (-)-Verrucarol

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Asymmetric Synthesis

Background:

• Trichothecene natural products, such as verrucarins A and J, exhibit significant bioactivity.
• The 12,13-epoxytrichothec-9-ene (EPT) core presents a synthetic challenge due to its intricate 6/6/5 ring system.
• Enantioselective construction of this core is crucial for accessing bioactive trichothecenes.

Purpose of the Study:

• To develop a concise and asymmetric synthesis of (-)-verrucarol.
• To establish an enantioselective route to the challenging EPT core.
• To investigate the mechanism of key synthetic transformations.

Main Methods:

• Chiral Lewis acid-catalyzed enantioselective [4+2] cycloaddition for A/B ring formation.
• Diastereoselective modifications including silylative generation and addition to a vinyl oxocarbenium.
• Diastereoselective 5-endo-trig cyclization for C-ring closure, achieving formal [3+2] annulation.
• Density functional theory (DFT) for mechanistic studies of the cycloaddition.

Main Results:

• Successful construction of the 6/6/5 ring system of the EPT core.
• Efficient synthesis of (-)-verrucarol, a key precursor to bioactive trichothecenes.
• Elucidation of the mechanism for the pivotal [4+2] cycloaddition through experimental and computational methods.

Conclusions:

• The developed synthetic strategy provides an efficient route to (-)-verrucarol.
• This work overcomes significant challenges in the enantioselective synthesis of trichothecene natural products.
• The mechanistic insights gained can inform future synthetic endeavors in this area.