Date of Award
Master of Science (MS)
Department of Chemistry
Shawn R. Hitchcock
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. In this context, 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. This thesis describes efforts that were directed towards employing oxadiazinones as chiral scaffolds for the process of asymmetric conjugate addition with the ultimate objective of using this methodology in the preparation of medicinal agents such as Tolterodine. Preliminary efforts focused on using an N4-p-methoxybenzyl substituted oxadiazinone to achieve these goals. 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 diastereoselectivity of the conjugate addition product was determined by analysis of the 500 MHz 1H NMR spectrum 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. To resolve this issue, a new series of oxadiazinones were designed, namely N4-isopropyloxadiazinone and N4-p-diphenylmethyloxadiazinone. The observed diastereoselectivity of the asymmetric conjugate addition for the N4-isopropyloxadiazinone was lower. This reinforced the idea that the diastereoselectivity was being influenced by the conformational dynamics of the ring system and not just the N4-substituent. This thesis 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 (Detrol).
Obe, Fatima Olayemi, "Oxadiazinones as Chiral Auxiliaries: Chiral Templates for Asymmetric Conjugate Addition in the Synthesis of ( R )-( + )-Tolterodine" (2020). Theses and Dissertations. 1301.