Unraveling the Cleavage Reaction of Hydroxylamines with Cyclopropenones Considering Biocompatibility

Abstract

We develop a latent biocompatible cleavage reaction involving the hitherto unexplored interaction between hydroxylamines and cyclopropenones. Our study addresses the regioselectivity challenges commonly observed in asymmetric cyclopropenone transformations, substantiated by variations in substrate, Density Functional Theory calculations, and in situ NMR analysis. This reaction is characterized by high efficiency, broad substrate scope, stability, latent biocompatibility, and mild reaction conditions. Significantly, it facilitates fluorescence activation and functions as a controlled release mechanism for prodrugs, showing great promise in biological assays. Our success in achieving the controlled release of nitrogen mustard in HeLa cells underscores its potential application in cellular contexts. Additionally, we introduce a simple and highly efficient method for synthesizing α, β-substituted pentenolides, applicable to a variety of substrates. Moreover, we extend this cleavage reaction to the CRISPR-Cas9 system, achieving precise, on-demand regulation of guide RNA activity. The introduction of this cleavage reaction offers a promising tool for biochemical research and biotechnological applications.