Relevant articles and documents
Novel syn intramolecular pathway in base-catalyzed 1,2-elimination reactions of β-acetoxy esters
Mohrig, Jerry R. Carlson, Hans K. Coughlin, Jane M. Hofmeister, Gretchen E. McMartin, Lea A. Rowley, Elizabeth G. Trimmer, Elizabeth E. Wild, Andrew J. Schultz, Steve C.
(Chemical Equation Presented) As part of a comprehensive investigation of electronic effects on the stereochemistry of base-catalyzed 1,2-elimination reactions, we observed a new syn intramolecular pathway in the elimination of acetic acid from β-acetoxy esters and thioesters. 1H and 2H NMR investigation of reactions using stereospecifically labeled tert-butyl (2R*,3R*)-3-acetoxy-2,3-2H2- butanoate (1) and its (2R*,3S*) diastereomer (2) shows that 23 ± 2% syn elimination occurs. The elimination reactions were catalyzed with KOH or (CH3)4-NOH in ethanol/water under rigorously non-ion-pairing conditions. By contrast, the more sterically hindered β-trimethylacetoxy ester produces only 6 ± 1% syn elimination. These data strongly support an intramolecular (Ei) syn path for elimination of acetic acid, most likely through the oxyanion produced by nucleophilic attack at the carbonyl carbon of the β-acetoxy group. The analogous thioesters, S-tert-butyl (2R*,3R*)-3-acetoxy-2,3- 2H2-butanethioate (3) and its (2R*,3S*) diastereomer (4), showed 18 ± 2% syn elimination, whereas the β-trimethylacetoxy substrate gave 5 ± 1% syn elimination. The more acidic thioester substrates do not produce an increased amount of syn stereoselectivity even though their elimination reactions are at the Elcb interface.
Stereospecificity of the reaction catalyzed by enoyl-CoA hydratase
Wu, Wen-Jin Feng, Yuguo He, Xiang Hofstein, Hilary A. Raleigh, Daniel P. Tonge, Peter J.
Enoyl-CoA hydratase catalyzes the stereospecific hydration of α,β- unsaturated acyl-CoA thiolesters. Hydration of trans-2-crotonyl-CoA to 3(S)- hydroxybutyryl-CoA proceeds via the syn addition of water and thus the pro-2R proton of 3(S)-hydroxybutyryl-CoA is derived from solvent. Incubation of 3(S)-hydroxybutyryl-CoA with enzyme in D2O results in the slow exchange of the pro-2S proton with solvent deuterium, in addition to the anticipated rapid exchange of the pro-2R proton. Further experiments have shown that the exchange of the pro-2S proton occurs in concert with the formation of the incorrect 3(R)-hydroxybutyryl-CoA enantiomer. The rate of 3(R)- hydroxybutyryl-CoA formation is 4 x 105-fold slower than the normal hydration reaction, but at least 1.6 x 106-fold faster than the non-enzyme- catalyzed reaction. This has allowed us to determine that the absolute stereospecificity for the enzyme-catalyzed reaction is 1 in 4 x 105. The initial formation of 3(R)-hydroxybutyryl-CoA is hypothesized to occur via the incorrect hydration of trans-2-crotonyl-CoA. Once formed, the 3(R)- hydroxybutyryl-CoA dehydrates to give cis-2-crotonyl-CoA. While the equilibrium constant for the hydration of trans-2-crotonyl-CoA to 3(S)- hydroxybutyryl-CoA is 7.5, the equilibrium constant for the hydration of cis- 2-crotonyl-CoA to 3(R)-hydroxybutyryl-CoA is estimated to be ~1000. To validate this reaction scheme, cis-2-crotonyl-CoA has been synthesized and characterized. These studies demonstrate that the enzyme is capable of catalyzing the epimerization of hydroxybutyryl-CoA.
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