The stereoselective formation of carbon-carbon bonds through the process of conjugate addition has proven to be a very important methodology in synthetic organic chemistry. We became interested in exploring the potential utility of oxadiazinones in asymmetric conjugate addition applications. In this context, oxadiazinones (1) are chiral auxiliaries that have been applied in the asymmetric aldol addition reaction. 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 Tolterodine. Our preliminary efforts focused on using an N4-p-methoxyphenyl substituted oxadiazinone. This oxadiazinone was acylated with trans-cinnamic acid via the Steglich reaction with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and catalytic N,N’-dimethylamino pyridine (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 reaction was carried out in diethyl ether and in tetrahydrofuran. While tetrahydrofuran gave the superior result, still the diastereoselectivity of the conjugate addition was determined by 500 MHz NMR spectroscopy to be no greater than 3:1, a value unsuitable for meaningful asymmetric synthesis. This observation was in contrast to higher stereoselectivities observed in the asymmetric aldol reaction with Ephedra based oxadiazinones 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 series of oxadiazinones were prepared, namely N4-2-naphthylmethyloxadiazinone and N4-p-methoxybenzyloxadiazinone, 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 synthesis of the medicinally valuable target compound, tolterodine.

Oxadiazinones as chiral auxiliaries: Asymmetric conjugate addition reactions with Ephedra based oxadiazinones

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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