Synthesis of N,N,O-Trisubstituted Hydroxylamines (Hydroxalogs) and Other Projects

There has been a continuous need to enrich small molecule libraries with underrepresented functional groups to increase the chance of finding potential drug candidates. N,N,O-trisubstituted hydroxylamine is such a functional group that has been underrepresented in drug discovery due to concerns about its stability and mutagenicity. However, the trisubstituted hydroxylamine functionality has multiple features that make it suitable as a drug candidate including low basicity, relative stability at ambient temperatures and being inert towards a variety of acetylating and sulfonylating enzymes. Additionally they have the potential to replace stereogenic centers while increasing the traction of sp³ centers. Here, the first operationally simple method for the direct synthesis of a series N,N,O-trisubstituted hydroxylamines utilizing 2-methyl-tetrahydropyranyl (MTHP) monoperoxy acetals as a suitable “R-O⁺” reagent is presented.

The new method has been applied to the synthesis of 35+ structurally diverse N,N,O-trisubstituted hydroxylamines and is generally applicable for a wide range of magnesium amide nucleophiles  derived from N,N-disubstituted amines with simple and complex alcohols. This development was used to synthesize trisubstituted hydroxylamine-based analog or hydroxalog of a known potential drug candidate in order to reduce it’s associated toxicity.

Further, there are few known methods to gain direct access to N,N-disubstituted O-glycosyl hydroxylamines. Here we present a novel synthetic method for O-glycosyl N,N-disubstituted hydroxylamines via acid catalyzed rearrangement of N-glycosidyl amine oxides. Glycosylation of N,N-disubstituted hydroxylamines using 1,2-anhydro sugar donors led to the formation of the kinetically more favorable glycosylamine N-oxides as the major product, which then rearranged to the more thermodynamically stable O-glycosyl hydroxylamines.

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