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

Photo of speaker Asiri Hettikankanamalage Don
Asiri Hettikankanamalage Don
Graduate Student, Department of Chemistry
University of Georgia
iSTEM Building 2, Room 1218
Organic Seminar

Diagram illustrating the synthesis of N,N,O-Trisubstituted Hydroxylamines (Hydroxalogs)

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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