Exploring the combinatorial explosion of amine-acid reaction space via graph editing

Rui Zhang; Babak Mahjour; Andrew Outlaw; Andrew McGrath; Tim Hopper; Brian Kelley; W Patrick Walters; Tim Cernak

doi:10.1038/s42004-024-01101-w

Exploring the combinatorial explosion of amine-acid reaction space via graph editing

Commun Chem. 2024 Feb 3;7(1):22. doi: 10.1038/s42004-024-01101-w.

Authors

Rui Zhang¹, Babak Mahjour², Andrew Outlaw², Andrew McGrath², Tim Hopper³, Brian Kelley³, W Patrick Walters³, Tim Cernak^{4

5}

Affiliations

¹ Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.
² Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA.
³ Relay Therapeutics, Cambridge, MA, USA.
⁴ Department of Chemistry, University of Michigan, Ann Arbor, MI, USA. tcernak@med.umich.edu.
⁵ Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA. tcernak@med.umich.edu.

Abstract

Amines and carboxylic acids are abundant chemical feedstocks that are nearly exclusively united via the amide coupling reaction. The disproportionate use of the amide coupling leaves a large section of unexplored reaction space between amines and acids: two of the most common chemical building blocks. Herein we conduct a thorough exploration of amine-acid reaction space via systematic enumeration of reactions involving a simple amine-carboxylic acid pair. This approach to chemical space exploration investigates the coarse and fine modulation of physicochemical properties and molecular shapes. With the invention of reaction methods becoming increasingly automated and bringing conceptual reactions into reality, our map provides an entirely new axis of chemical space exploration for rational property design.