DEVELOPING A CHIRAL AUXILIARY OXADIAZINONE PLATFORM FOR THE ASYMMETRIC SYNTHESIS OF GAMMA-AMINO ACIDS: OXADIAZINONES AS CHIRAL TEMPLATES FOR ASYMMETRIC CONJUGATE ADDITION REACTIONS

Publication Date

4-5-2019

Document Type

Poster

Degree Type

Undergraduate

Department

Chemistry

Mentor

Shawn Hitchcock

Mentor Department

Chemistry

Abstract

Oxadiazinones are chiral auxiliaries that have been applied in the asymmetric aldol addition reaction to synthesize valuable synthetic fragments such as the aldol side chain of the multi-drug resistance medicinal agent hapalosin. We seek to expand the catalog of reactions that the oxadiazinones can be employed in. Our current efforts are directed towards employing these compounds as chiral scaffolds for the process of asymmetric conjugate addition with the ultimate objective of using this methodology in the preparation of gamma-amino acids such as lyrica. Our preliminary efforts focused on the use of an N4-p-methoxyphenyl substituted oxadiazinone as the chiral scaffold. This oxadiazinone was acylated at the N3-nitrogen with trans-cinnamic acid via the Steglich reaction with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and catalytic N,N'-dimethylaminopyridine (DMAP). This substrate was then reacted with a Normant reagent, a mixture of the Grignard reagent methylmagnesium bromide and copper (I) bromide-dimethylsulfide complex. The addition reaction was carried out in diethyl ether and in tetrahydrofuran. While tetrahydrofuran gave the superior result, the diastereoselectivity of the conjugate addition was determined by 500 MHz NMR spectroscopy to be no greater than 3:1 ratio of diastereomers, a value unsuitable for meaningful asymmetric synthesis. This observation was in contrast to higher stereoselectivities observed in the asymmetric aldol reaction where ratios of 95:5 are commonly observed. It was reasoned that the electrophilic site of the conjugate addition was further away from the stereodirecting group at the N4-position than the aldol reactive site. To resolve this issue, a new system, namely the more sterically demanding N4-2-naphthylmethyloxadiazinone, was designed and prepared and used in the asymmetric conjugate addition process. This poster will describe the chemistry that has been accomplished to this point, and make projections for future efforts in the effort to synthesize the medicinally valuable target compound lyrica.

This document is currently not available here.

Share

COinS