Automated Iterative N─C and C─C Bond Formation

Area of Science:

• Organic Chemistry
• Chemical Engineering
• Medicinal Chemistry

Background:

• Small molecule discovery is crucial for societal challenges but hindered by manual synthesis.
• Current automated methods like block chemistry excel at C-C bond formation but not nitrogen incorporation.
• A need exists for versatile automated synthesis platforms that can handle diverse chemical structures.

Purpose of the Study:

• To develop a novel chemical strategy for automated, modular small molecule synthesis.
• To introduce a new iteration-enabling group for incorporating nitrogen atoms into automated synthesis.
• To demonstrate the utility of this new method in synthesizing a clinically relevant drug.

Main Methods:

• Development and application of the CbzT (p-TIDA boronate-substituted carboxybenzyl) group.
• Iterative synthesis utilizing both C-C and N-C bond formations.
• Automated modular assembly of building blocks.
• Catch-and-release purification enabled by the CbzT group.

Main Results:

• The CbzT group was successfully synthesized and characterized.
• Automated modular synthesis of Imatinib (Gleevec) was achieved using iterative N-C and C-C bonds.
• The CbzT group enabled reversible attenuation of nitrogen reactivity and facilitated purification.
• The methodology expands the scope of automated small molecule synthesis.

Conclusions:

• The CbzT group significantly advances automated modular synthesis by enabling nitrogen incorporation.
• This approach facilitates the generalized and automated preparation of diverse small molecules.
• The work supports the development of machine-amenable chemical synthesis strategies.