Flow Photo-Oxidative Dearomative Cyclization Enables Unified Asymmetric Synthesis of Trichodermamides A-F

Area of Science:

• Organic Synthesis
• Natural Product Chemistry
• Medicinal Chemistry

Background:

• Fungal secondary metabolites, such as trichodermamides, possess complex structures and potential biological activities.
• Previous synthetic routes for trichodermamides were limited, necessitating the development of efficient and versatile methods.
• Asymmetric synthesis is crucial for obtaining enantiomerically pure compounds with defined biological functions.

Purpose of the Study:

• To develop a unified and divergent asymmetric synthesis for fungal secondary metabolites trichodermamides A-F.
• To establish the first asymmetric synthesis for trichodermamides C, D, E, and F.
• To enable efficient access to optically active trichodermamide D for further derivatization.

Main Methods:

• A novel gas-liquid two-phase continuous flow photo-oxidation process for rapid construction of the optically active *cis*-1,2-oxazadecalin core.
• Tandem oxidative dearomatization/stereoselective cyclization of a tyrosine-derived hydroxylamine.
• A one-pot dimethyldioxirane and *i*Bu₂AlH-mediated oxidation and reduction process for assembling the oxazadecalin skeleton.

Main Results:

• Successful development of a unified approach for the divergent asymmetric synthesis of trichodermamides A-F.
• Achieved multigram preparation of optically active trichodermamide D.
• Elucidated a revised structure for trichodermamide E.
• Enabled late-stage divergent transformation into a series of trichodermamides.

Conclusions:

• The developed synthetic strategy provides efficient access to optically active trichodermamides.
• The novel continuous flow photo-oxidation process is key to constructing the core oxazadecalin structure.
• This work significantly advances the synthesis of complex fungal metabolites and aids in structural elucidation.