Expanding the Medicinal Chemist Toolbox: Comparing Seven C(sp²)-C(sp³) Cross-Coupling Methods by Library Synthesis

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Advances in C(sp2)-C(sp3) cross-coupling reactions have increased.
• Selecting appropriate methods for highly functionalized intermediates in medicinal chemistry remains challenging.

Purpose of the Study:

• To compare the efficacy of seven distinct cross-coupling methods for direct alkyl group installation.
• To evaluate these methods using diverse, "drug-like" aryl structures via parallel synthesis.

Main Methods:

• Parallel library synthesis was employed to screen seven different C(sp2)-C(sp3) cross-coupling methodologies.
• A diverse set of alkyl groups was tested for installation onto various aryl substrates.

Main Results:

• Each method demonstrated unique strengths, excelling with specific substrate types.
• An overall reaction success rate of 50% was observed across all tested methods.
• Challenges remain, particularly in the direct installation of sterically hindered tertiary alkyl groups.

Conclusions:

• The findings provide valuable data for selecting optimal C(sp2)-C(sp3) cross-coupling strategies.
• Current methods have limitations, indicating a need for further development, especially for tertiary alkyl installations.
• Medicinal chemists are encouraged to broaden their synthetic approaches using these insights.