Automated iterative Csp-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-C bonds would expand access to many important types of functional organic molecules. Previously, methyliminodiacetic acid (MIDA) boronates were used to orchestrate the formation of Csp-Csp bonds and were effective building blocks for automating the synthesis of many small molecules, but they are incompatible with stereospecific Csp-Csp and Csp-Csp bond-forming reactions. 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 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, which are essential for generalized automated synthesis, are retained by TIDA boronates. This enabled Csp boronate building blocks to be assembled using automated synthesis, including the preparation of natural products through automated stereospecific Csp-Csp and Csp-Csp bond formation. These findings will enable increasingly complex Csp-rich small molecules to be accessed via automated assembly.