Retro-aza-Michael reaction of an o-aminophenol adduct in protic solvents inspired by natural products

?,13-Unsaturated carbonyls are reactive group often found in bioactive small molecules. Their non-specific reaction with biomolecules can be the cause of the low efficacy and unexpected side-effects of the molecule. Accordingly, unprotected ?,13-unsaturated carbonyls are not often found in drugs. Here, we report that o-aminophenol is a new masking group of ?,13-unsaturated ketone, which is inspired by natural products saccharothriolides. o-Aminophenol adduct of ?,13-unsaturated ketone, but not those of ?,13-unsaturated amide or ester, undergoes a retro-Michael reaction to yield o-aminophenol and the Michael acceptor. This reaction was observed only in protic solvents, such as MeOH and aqueous MeOH. In contrast, o-anisidine was not eliminated from its Michael adduct. o-Aminophenol may be a promising masking tool of highly-reactive bioactive ?,13-unsaturated carbonyl compounds.

Automated summary

Unsaturated carbonyls are commonly found in bioactive small molecules and their non-specific reactions with biomolecules can lead to low efficacy and unexpected side effects of drugs. A new masking group, o-aminophenol, was discovered for ?,13-unsaturated ketones, which may be a promising tool for masking highly-reactive bioactive unsaturated carbonyl compounds.