Automated iterative Csp³-C bond formation.

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Chemical Engineering

Background:

• Automated synthesis offers on-demand access to small molecules, but current methods are limited.
• Automating stereospecific Csp³-C bond formation is crucial for accessing diverse functional organic molecules.
• Previous methyliminodiacetic acid (MIDA) boronates are unsuitable for stereospecific Csp³-C bond-forming reactions.

Purpose of the Study:

• To develop a new class of boronates compatible with automated stereospecific Csp³-C bond formation.
• To overcome the limitations of existing MIDA boronates in complex molecule synthesis.

Main Methods:

• Development of tetramethyl N-methyliminodiacetic acid (TIDA) boronates through hyperconjugative and steric tuning.
• Charge density analysis to understand N-B bond stability and hydrolysis.
• Steric shielding of carbonyl π-faces to control reactivity.

Main Results:

• TIDA boronates exhibit enhanced stability against hydrolysis and reduced reactivity towards nucleophiles.
• The iminodiacetic acid cage features essential for automated synthesis are preserved in TIDA boronates.
• Automated synthesis of Csp³ boronate building blocks and natural products via stereospecific Csp³-Csp² and Csp³-Csp³ bond formation was achieved.

Conclusions:

• TIDA boronates represent a significant advancement in automated synthetic chemistry.
• This new class of boronates enables the synthesis of complex Csp³-rich small molecules.
• The findings pave the way for broader applications of automated synthesis in organic chemistry.