Heterocyclic Assembly: An Underutilized Disconnection with Potential to Maximize High Fsp³ Chemical Space Exploration

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Heterocyclic cores are essential in medicinal chemistry, but their synthesis and functionalization present challenges.
• Current methods often limit access to diverse chemical structures, particularly those with high Fsp3 character.

Purpose of the Study:

• To present a novel strategy for the synthesis of heterocyclic cores using readily available building blocks.
• To demonstrate the library-friendly nature of this approach for medicinal chemistry applications.
• To compare the efficiency of this method with existing state-of-the-art techniques.

Main Methods:

• Utilizing carboxylic acids and amines as ubiquitous building blocks for heterocyclic core formation.
• Developing a library-friendly format for efficient synthesis.
• Adapting and miniaturizing the synthesis for micro-scale parallel medicinal chemistry (PMC).

Main Results:

• The developed strategy enables access to a wider chemical space, including analogs with higher Fsp3 values.
• Successful synthesis of N2-indazoles and C2-benzimidazoles using the new method.
• Achieved an 80% success rate in PMC libraries, comparable to established Suzuki and Buchwald-Hartwig couplings.

Conclusions:

• This novel heterocycle synthesis strategy offers a powerful tool for medicinal chemists.
• The approach facilitates rapid access to diverse heterocyclic libraries, accelerating drug discovery programs.
• The method's efficiency and scalability make it a valuable alternative to current functionalization techniques.