Automated iterative Csp 3 -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.