Automated iterative Csp³-C bond formation

Fully automated synthetic chemistry would substantially change the field by providing broad on-demand access to small molecules. However, the reactions that can be run autonomously are still limited. Automating the stereospecific assembly of Csp ³–C bonds would expand access to many important types of functional organic molecules ¹. Previously, methyliminodiacetic acid (MIDA) boronates were used to orchestrate the formation of Csp ²–Csp ² bonds and were effective building blocks for automating the synthesis of many small molecules ², but they are incompatible with stereospecific Csp ³–Csp ² and Csp ³–Csp ³ bond-forming reactions ^3–10. Here we report that hyperconjugative and steric tuning provide a new class of tetramethyl N-methyliminodiacetic acid (TIDA) boronates that are stable to these conditions. Charge density analysis ^11–13 revealed that redistribution of electron density increases covalency of the N–B bond and thereby attenuates its hydrolysis. Complementary steric shielding of carbonyl π-faces decreases reactivity towards nucleophilic reagents. The unique features of the iminodiacetic acid cage ², which are essential for generalized automated synthesis, are retained by TIDA boronates. This enabled Csp ³ boronate building blocks to be assembled using automated synthesis, including the preparation of natural products through automated stereospecific Csp ³–Csp ² and Csp ³–Csp ³ bond formation. These findings will enable increasingly complex Csp ³-rich small molecules to be accessed via automated assembly.