Automated iterative Csp3-C bond formation – Nature

Fully automated synthetic chemistry would significantly change the field by providing access to small molecules for any lab with the right equipment. However, the reactions that can be run autonomously are still somewhat limited. Automating the stereospecific assembly of Csp³–C bonds would significantly expand access to functional organic molecules¹. Previously, methyliminodiacetic acid (MIDA) boronates were used to orchestrate the formation of Csp²-Csp² bonds and were effective building blocks for automating the synthesis of many small molecules², but are incompatible with stereospecific Csp³-Csp² and Csp³-Csp³ bond forming reactions^3–10. Here we report that hyperconjugative and steric tuning gave a new class of tetramethyl N-methyliminodiacetic acid (TIDA) boronates that are stable to these conditions. Charge density analysis^11–13 revealed 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 toward nucleophilic reagents. The unique features of the iminodiacetic acid cage² essential for generalized automated synthesis are retained by TIDA boronates. This allowed Csp³ boronate building blocks to be assembled using automated synthesis, including the preparation of natural products through automated stereospecific Csp³-Csp² and Csp³-Csp³ bond formation. These findings will enable increasingly complex Csp³-rich small molecules to be accessed via automated assembly.