Automated iterative C sp 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 C sp 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 C sp 2 –C sp 2 bonds and were effective building blocks for automating the synthesis of many small molecules 2 , but they are incompatible with stereospecific C sp 3 –C sp 2 and C sp 3 –C sp 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 C sp 3 boronate building blocks to be assembled using automated synthesis, including the preparation of natural products through automated stereospecific C sp 3 –C sp 2 and C sp 3 –C sp 3 bond formation. These findings will enable increasingly complex C sp 3 -rich small molecules to be accessed via automated assembly.