Divergent Total Syntheses of Rearranged Steroids Swinhoeisterols A-C

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Natural Products Chemistry

Background:

• Swinhoeisterols A-C are complex natural products with a unique 6/6/5/7 tetracyclic core.
• These steroids exhibit potent inhibitory activity against histone acetyltransferase p300, a key epigenetic regulator.

Purpose of the Study:

• To report the divergent total syntheses of Swinhoeisterols A-C.
• To establish efficient synthetic routes from readily available starting materials.

Main Methods:

• Development of a tandem Negishi/Heck cross-coupling reaction to install a methylenecyclopentene motif.
• Utilized a silyl-tethered homoallylic zinc reagent to control reactivity during cross-coupling.
• Employed Baran reductive olefin coupling for simultaneous seven-membered ring construction and stereocenter formation.

Main Results:

• Successful divergent total syntheses of Swinhoeisterols A-C were achieved.
• The synthetic strategy efficiently constructed the intricate tetracyclic framework.
• Key steps included novel cross-coupling and reductive olefin coupling methodologies.

Conclusions:

• The developed synthetic routes provide access to Swinhoeisterols A-C and analogs.
• These syntheses highlight innovative methods for constructing complex polycyclic structures.
• The findings contribute to the understanding of steroid biosynthesis and potential therapeutic applications.