Automated iterative Csp3–C bond formation

Daniel J. Blair (), Sriyankari Chitti, Melanie Trobe, David M. Kostyra, Hannah M. S. Haley, Richard L. Hansen, Steve G. Ballmer, Toby J. Woods, Wesley Wang, Vikram Mubayi, Michael J. Schmidt, Robert W. Pipal, Greg. F. Morehouse, Andrea M. E. Palazzolo Ray, Danielle L. Gray, Adrian L. Gill and Martin D. Burke ()
Additional contact information
Daniel J. Blair: University of Illinois at Urbana-Champaign
Sriyankari Chitti: University of Illinois at Urbana-Champaign
Melanie Trobe: University of Illinois at Urbana-Champaign
David M. Kostyra: University of Illinois at Urbana-Champaign
Hannah M. S. Haley: University of Illinois at Urbana-Champaign
Richard L. Hansen: REVOLUTION Medicines, Inc.
Steve G. Ballmer: REVOLUTION Medicines, Inc.
Toby J. Woods: University of Illinois at Urbana-Champaign
Wesley Wang: University of Illinois at Urbana-Champaign
Vikram Mubayi: University of Illinois at Urbana-Champaign
Michael J. Schmidt: University of Illinois at Urbana-Champaign
Robert W. Pipal: University of Illinois at Urbana-Champaign
Greg. F. Morehouse: University of Illinois at Urbana-Champaign
Andrea M. E. Palazzolo Ray: University of Illinois at Urbana-Champaign
Danielle L. Gray: University of Illinois at Urbana-Champaign
Adrian L. Gill: REVOLUTION Medicines, Inc.
Martin D. Burke: University of Illinois at Urbana-Champaign

Nature, 2022, vol. 604, issue 7904, 92-97

Abstract: Abstract 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 Csp3–C bonds would expand access to many important types of 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 they are incompatible with stereospecific Csp3–Csp2 and Csp3–Csp3 bond-forming reactions3–10. 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 analysis11–13 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 cage2, which are essential for generalized automated synthesis, are retained by TIDA boronates. This enabled 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.

Date: 2022
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DOI: 10.1038/s41586-022-04491-w

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