pH‐controlled reaction divergence of decarboxylation versus fragmentation in reactions of dihydroxyfumarate with glyoxylate and formaldehyde: parallels to biological pathways

Abstract

The reactions of dihydroxyfumarate with glyoxylate and formaldehyde exhibit a unique pH‐controlled mechanistic divergence leading to different product suites by two distinct pathways. The divergent reactions proceed via a central intermediate (2,3‐dihydroxy‐oxalosuccinate, 3, in the reaction with glyoxylate and 2‐hydroxy‐2‐hydroxymethyl‐3‐oxosuccinate, 14, in the reaction with formaldehyde). At pH 7–8, products (7, 8, and 15) exclusively from a decarboxylation of the intermediate are observed, while at pH 13–14, products (9, 10, and 16) solely derived from a hydroxide‐promoted fragmentation of the intermediate are formed. The decarboxylative and fragmentation pathways are mutually exclusive and do not appear to coexist under the range of pH (7–14) conditions investigated. Herein, we employ a combination of quantitative 13C NMR measurements and density functional theory calculations to provide a rationale for this pH‐driven reaction divergence. These rationalizations also hold true for the reactions of dihydroxyfumarate produced in situ by the catalytic cyanide‐mediated dimerization of glyoxylate. In addition, the non‐enzymatic decarboxylation and fragmentation transformations of these central intermediates (3 and 14) appear to have intriguing parallels to the enzymatic reactions of oxalosuccinate and formation of glyceric acid derivatives in extant metabolism – the high and low pH mimicking the precise control exerted by the enzymes over reaction pathways. Copyright © 2016 John Wiley & Sons, Ltd.

Base-Mediated Cascade Aldol Addition and Fragmentation Reactions of Dihydroxyfumaric Acid and Aromatic Aldehydes: Controlling Chemodivergence via Choice of Base, Solvent, and Substituents

“…meso -Tartrate was determined by comparison to the known literature. Pure glycolate was added to the NMR sample to confirm its location, and tartronate was assigned by comparison to previously published results …”

“…Deprotonation effectively minimizes the orbital overlap between the delocalized carboxylate anions and the electron-rich ene-diol portion of the molecule. To the best of our knowledge, in cases where DHF behaves as an electrophile, the carboxylic acids of DHF existed as alkyl esters, − whereas when the reacted as a nucleophile the carboxylic acid groups of DHF were always ionized using basic media. − Even with this clear trend in the literature there has been no focused study on why seemingly minor changes to the carboxylic acid moieties of DHF have a profound effect on its reactivity. The relative stabilities of the DHF derivatives, especially toward reaction with atmospheric oxygen (to form dioxosuccinic acid) and self-condensation (via the putative keto form of DHF 2– to form sugar acid 5 , Scheme ) also seem to be affected by state of ionization of DHF versus its ester derivatives.…”

“…To test that hypothesis, we exposed DHF to the deoxalation reaction conditions in the absence of benzaldehyde (Figure A). Through spiking studies as well as a comparison to literature precedent, we determined that the signal at 174.3 ppm is glycolic acid ( 13 ), the pair of peaks at 173.3 and 172.8 ppm are the two diastereomers ( d / l and meso ) of tartaric acid ( 6 ), and the peak at 170.8 ppm is tartronic acid ( 12 ). 2-D NMR experiments and DEPT further confirm these identifications.…”

“…Conducting the reaction at pH 13–14 produces tartrate ( 6 ) and oxalate ( 7 ) via a hydroxide-mediated deoxalation of the same intermediate 3 . The divergent product formation based on the different pH has been rationalized based on the proclivity of decarboxylation pathway at lower pH versus the dominance of the deoxalation pathway at high pH . The reaction of glycolaldehyde and glyceraldehyde as electrophiles, in place of glyoxylate, with DHF at pH 7–8 was found to produce efficiently the corresponding ketoses, tetrulose and pentulose, respectively …”

Anchimeric‐Assisted Spontaneous Hydrolysis of Cyanohydrins Under Ambient Conditions: Implications for Cyanide‐Initiated Selective Transformations

“…Recently, we reported that reaction of glyoxylate 1 with catalytic cyanide at pH 13 led to the production tartrate 2 and oxalate 3 in high yields in a novel deoxalation reaction (Scheme a) . Within a prebiotic context, however, such a high pH could be considered problematic.…”