A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Chemical Biology

Background:

• Drug discovery and chemical genetics rely on diverse compound libraries.
• Diversity-oriented synthesis (DOS) is key for generating these libraries.
• The build/couple/pair (B/C/P) algorithm is a common DOS strategy.

Purpose of the Study:

• To develop an advanced B/C/P strategy for generating structurally diverse compound libraries.
• To incorporate multidimensional coupling into the B/C/P approach.
• To create a library of macrocyclic compounds with varied molecular shapes.

Main Methods:

• Developed an advanced B/C/P strategy incorporating multidimensional coupling.
• Applied this strategy to diversity-oriented synthesis (DOS).
• Synthesized a library of 73 macrocyclic compounds based on 59 scaffolds.

Main Results:

• The advanced B/C/P strategy increased structural diversity by varying linking motifs.
• A library of 73 macrocyclic compounds was successfully prepared.
• Principal moment-of-inertia analysis confirmed a broad range of molecular shapes.

Conclusions:

• The advanced B/C/P strategy with multidimensional coupling is effective for generating structurally diverse compound collections.
• This approach enhances the utility of DOS for drug discovery and chemical genetics.
• The method offers a step-efficient route to complex macrocyclic structures.