Diversity-oriented synthesis of biaryl-containing medium rings using a one bead/one stock solution platform

Area of Science:

• Organic Chemistry
• Chemical Biology
• Medicinal Chemistry

Background:

• Exploring cellular pathways requires diverse small molecules with natural product-like structures.
• Efficient and stereoselective synthesis methods are crucial for generating these molecules.
• Diversity-oriented synthesis (DOS) is a key strategy for discovering new biologically active compounds.

Purpose of the Study:

• To develop and investigate the oxidation of organocuprates for atropdiastereoselective synthesis of biaryl-containing medium rings.
• To apply this methodology to a diversity-oriented synthesis platform for generating a library of complex small molecules.
• To establish a systematic chemical genetics approach for biological pathway exploration.

Main Methods:

• Developed an oxidation method for organocuprates, focusing on atropdiastereoselective synthesis of medium-sized biaryl rings.
• Performed synthesis on high-capacity polystyrene beads using metalation, transmetalation, and oxidation steps.
• Utilized a one bead/one stock solution technology for library generation and subsequent phenotypic and protein-binding assays.

Main Results:

• Successfully synthesized biaryl-containing medium rings (9-, 10-, and 11-membered) with atropdiastereoselectivity.
• Generated a library of 1412 theoretically diverse compounds using the developed bead-based DOS platform.
• Demonstrated the utility of the generated compound library in biological assays.

Conclusions:

• The developed organocuprate oxidation methodology is effective for synthesizing complex biaryl structures.
• The bead-based DOS platform enables efficient generation of large, diverse compound libraries for chemical genetics.
• This approach provides a systematic pathway for exploring biological functions through small molecule screening.