Substituent effects in carbon-nitrogen cleavage of thiamin derivatives. Fragmentation pathways and enzymic avoidance of cofactor destruction.
The combination of thiamin and benzaldehyde can produce benzoin but also destroys thiamin. The destruction comes from fragmentation of the conjugate of thiamin and benzaldehyde undergoing a process that produces a phenyl thiazole ketone and pyrimidine. The key step in this process is cleavage of the C-N bond between the heterocycles, which occurs by an unknown mechanism. Enzymes that utilize similar intermediates do not fragment the cofactor although fragmentation is inherent to the structure. To analyze the nature of the C-N cleavage step, the rates of fragmentation of a series of phenyl-substituted N1'-methyl-2-(1-hydroxybenzyl)thiamin derivatives were determined under two sets of conditions: (1) where proton transfer in the step prior to C-N bond breaking is rate-determining and (2) where C-N bond breaking is rate-determining. The resulting rho values are 1.6 and 1.8, respectively, leading to the conclusion that C-N cleavage is insensitive to substituent effects. On the basis of these results, we conclude that cleavage occurs by a facile process that resembles the outcome of a [1,5] sigmatropic rearrangement. An enzyme may avoid the fragmentation by holding the intermediate in a conformation that prevents such a process, allowing the normal catalytic process to proceed.
Moore
Ian F
IF
Davenport Chemical Research Building, Department of Chemistry, University of Toronto, Toronto, Ontario, Canada M5S 3H6.
Kluger
Ronald
R
D003374:Coumarins / Q000138:chemical synthesis*; D007700:Kinetics; D013329:Structure-Activity Relationship; D013831:Thiamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
C453561:2-aminophenyl 6-chloro-7-hydroxycoumarin-4-acetamidophenyl phosphoric acid; D003374:Coumarins; D013831:Thiamine