This project proposes research at the chemistry-biology interlace. It focuses on the stereochemistry of addition and elimination reactions involving n-substituted esters and thioesters of butyric acid and the related aldehydes and ketones. The objective of the research program is a comprehensive understanding of the stereochemical consequences of the carbonyl group and substituents at C-on the stereochemistry of addition-elimination and proton-transfer reactions involving acyclic B-substituted carbonyl compounds. Conjugate addition-elimination reactions of carbonyl substrates are fundamental processes in biochemical pathways. They are important from fatty acid metabolism to glycolysis and the citric acid cycle, from terpene biosynthesis to the shikimic acid pathway. This project will study the stereochemistry of 1,2-elimination reactions of B-hydroxybutyric acid derivatives, since these provide the best model systems for the enoyl-CoA hydratase reaction found in fatty acid metabolism. It is designed to be able to assess the inherent electronic factors that control the reactions of simple B-substituted acyclic carbonyl compounds. The study is important for three major reasons. Earlier work by the principal investigator has shown that the base-catalyzed addition of D20 to a conjugated thioester substrate of enoyl-CoA hydratase favors the anti pathway, even though the enzyme itself catalyzes the addition of water with synstereochemistry. This can be taken as direct evidence for the importance of evolutionary history, rather than chemical efficiency, in this enzymatic catalysis. Because enoyl-CoA hydratase apparently uses the synpathway for reasons of other than chemical efficiency, this evidence is relevant to the question of whether some natural enzymatic processes may represent local rather than global optima. It is important to assess the validity of our enzyme models as completely as possible. In the second place, understanding and control of the stereochemistry of conformationally-mobile, acyclic molecules remains an important challenge in organic chemistry, and base-catalyzed 1,2-elimination reactions and the related question of proton transfer to enols and enolates occupy an important position within its fundamental framework. Thirdly, B-hydroxybutyric acid is the second most abundant organic monomer on earth, but it and its derivatives have received much less study by chemists than they deserve. The project is divided into five specific research areas. The first one assesses the validity of our enzyme model systems. Two others relate to the stereochemistry of base-catalyzed 1,2-elimination reactions that produce conjugated carbonyl compounds. These will investigate the importance of the substrate acidity and the leaving group upon the stereoselectivity of these reactions. The last two research areas concern the stereochemistry of electrophilic attack at enolate anions. The experimental methods will be those of organic chemistry, in particular nuclear magnetic resonance (NMR) spectroscopy, chromatography, and organic synthesis. Carleton College undergraduate chemistry majors will carry out the research. The principal investigator has had substantial experience in crafting successful undergraduate research experiences over his teaching career.
| Mohrig, Jerry R; Beyer, Brandon G; Fleischhacker, Angela S et al. (2012) Does activation of the anti proton, rather than concertedness, determine the stereochemistry of base-catalyzed 1,2-elimination reactions? Anti stereospecificity in E1cB eliminations of ?-3-trifluoromethylphenoxy esters, thioesters, and ketones. J Org Chem 77:2819-28 |
