Date of Award
Doctor of Philosophy (PhD)
This research effort dealt primarily with the synthesis of nicotinic acid derivatives, either incorporated into crown ether frameworks via 2,6-methylene bridges, or as appendage groups on nitrogen or carbon pivot lariat ethers. These crown ethers were also investigated as possible NADH mimics. During the course of this study three different types of nicotinic acid crown ethers were prepared: (1) 2,6-Methylene bridged nicotinic acid crown ethers, (2) 6-Methylene bridged nicotinic acid lariat ethers, (3) N-bridged nicotinic acid pyridinium salt lariat ethers. Various 1:1 and 2:2 isomeric macrocyclic 2,6-methylene bridged-(5,5-dimethyloxazolyl)pyridines were generated by treatment of 2,6-bis bromomethyl-3-(5,5-dimethyloxazolyl)pyridine , prepared from ethyl 2,6-dimethylnicotinate, with cesium dibenzo-tetraethylene glycolate or a variety of sodium polyethylene glycolates. Ethyl 2,6-bis(bromomethyl)nicotinate, also prepared from ethyl 2,6-dimethylnicotinate, was converted to the corresponding 1:1-dibenzo-18-crown-6 macrocyclic analog. NMR and mass spectral data were used to ascertain the macrocyclic structures. Reduction of the 2,6-methylene bridged 3-oxazolylpyridine dibenzo 18-crown-6 macrocycle with ethylmagnesium bromide afforded, after oxidation, the corresponding 4-substituted pyridino macrocycle in high yield. However, under identical conditions, the analogous non-oxazoline macrocycle was recovered in toto. 6-Methylene bridged nicotinic acid lariat ethers were prepared incorporating a chiral oxazoline which assisted in both stereospecific reductive metallation of the pyridine moiety and imparted asymmetry to the reactive site for NADH model reductions of suitable electrophiles. A chiral 6-methyl-3-oxazolylpyridine was converted to 6-methylene bridged 18-crown-6 and 15-crown-5 lariat ethers via conversion to the corresponding chiral 6-hydroxymethyl-3-oxazolylpyridine, followed by reaction with various electrophilic monoaza lariat ethers. One such lariat was converted to an enantiomerically enriched N-magnesio-1,4-dihydropyridine by stereoselective addition of methylmagnesium bromide. This N-metallo NADH mimic, along with its non-lariat analogue, was subsequently employed in the biomimetic reduction of (alpha),(alpha),(alpha)-trifluoroacetophenone to give the first reported stereospecific reductions by N-metallo-1,4-dihydropyridines. The third type of NADH model, the N-bridged pyridinium salt lariat, was synthesized by treatment of chiral (S)-proline nicotinamide derivatives with tosylated hydroxymethyl-15-crown-5. Attempted reductions of such "classical" models are described here.
Marston, Charles Ray, "Nicotinic Acid Crown Ethers: Syntheses, Characterization, Complexation, and Nadh Model Reaction (Lariat Ether, Enzyme Model)." (1985). LSU Historical Dissertations and Theses. 4062.