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, , in the reaction with glyoxylate and 2-hydroxy-2-hydroxymethyl-3-oxosuccinate, , in the reaction with formaldehyde). At pH 7–8, products ( , , and ) exclusively from a decarboxylation of the intermediate are observed, while at pH 13–14, products ( , , and ) 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 13 C 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 ( and ) 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. A simple pH switch causes a strict divergence of decarboxylation or fragmentation reaction of a common intermediate, leading to distinct classes of products. Such a strict control exerted by a change of pH over reaction pathways and the nature of product formation seems to parallel the precise control exhibited by enzymes over analogous metabolic reactions.
Chemistry and Pharmacology