A deconstruction-reconstruction strategy for pyrimidine diversification

Benjamin J H Uhlenbruck; Celena M Josephitis; Louis de Lescure; Robert S Paton; Andrew McNally

doi:10.1038/s41586-024-07474-1

A deconstruction-reconstruction strategy for pyrimidine diversification

Nature. 2024 May 2. doi: 10.1038/s41586-024-07474-1. Online ahead of print.

Authors

Benjamin J H Uhlenbruck¹, Celena M Josephitis¹, Louis de Lescure¹, Robert S Paton², Andrew McNally³

Affiliations

¹ Department of Chemistry, Colorado State University, Fort Collins, Colorado, USA.
² Department of Chemistry, Colorado State University, Fort Collins, Colorado, USA. Robert.paton@colostate.edu.
³ Department of Chemistry, Colorado State University, Fort Collins, Colorado, USA. andy.mcnally@colostate.edu.

PMID: 38697196
DOI: 10.1038/s41586-024-07474-1

Abstract

Structure-Activity Relationship (SAR) studies are fundamental to drug and agrochemical development, yet only a few synthetic strategies apply to the nitrogen heteroaromatics frequently encountered in small molecule candidates.^1-3 Here, we present an alternative approach where we convert pyrimidine-containing compounds various other nitrogen heteroaromatics. Transforming pyrmidines into their corresponding N-arylpyrimidinium salts enables cleavage into a three-carbon iminoenamine building block, used for various heterocycle-forming reactions. This deconstruction-reconstruction sequence diversifies the initial pyrimidine core and enables access to various heterocycles, such as azoles.⁴ In effect, this approach allows heterocycle formation on complex molecules, resulting in analogs that would be challenging to obtain by other methods. We anticipate this deconstruction-reconstruction strategy will extend to other heterocycle classes.