Diastereoselective Self‐Condensation of Dihydroxyfumaric Acid in Water: Potential Route to Sugars

Abstract

Dihydroxyfumaric acid (DHF, 1, Scheme 1) has a long history since the days of its synthesis and extensive studies by Fenton in the 1890s. [1] The chemistry of DHF and that of its corresponding ester derivatives in organic solvents has been investigated. [2] However, studies of the (non-enzymatic) aqueous chemistry of DHF have been sparse, perhaps as result of a) its perceived "instability" in aqueous solutions owing to its oxidative transformation into dioxosuccinic acid [3] and its more widely known decarboxylative conversion into glycolaldehyde [4] (Scheme 1), and b) the sparing solubility not only of the parent acid, but also of its Na + , K + , and NH 4 + salts, in water. [4b,c] Our investigation into the aqueous chemistry of DHF was initiated in the context of the proposals of Eschenmoser that DHF is a molecule of interest [5] in the search for primordial metabolism, wherein DHF and glyoxylate could serve as source molecules for the formation of organic building blocks by reactions deemed to be compatible with the constraints of prebiotic chemistry ("glyoxylate scenario"). [6] We report herein the discovery of uncharted reactivity of water-soluble Li, Cs, and Mg salts of DHF. Our findings show that it is possible to expand the scope and spectrum of the chemical reactivity of DHF to include carbon-carbon bondforming reactions, which exemplify its capacity to act both as a nucleophile and as an electrophile.In our preliminary investigations we found that we could handle DHF as its lithium and cesium salts with ease. Our studies began with the monitoring of degassed aqueous solutions of the dilithium salt of DHF (0.45 m, pH 8-9) at room temperature and 4 8C by 13 C NMR spectroscopy (Figure 1), which initially showed signals that corresponded only to the enolic form; no signals corresponding to the keto form were seen. [7] Within 30 min (at room temperature), much to our surprise, we observed the appearance of eight new signals and a concomitant decrease in the intensity of the two DHF signals, which disappeared after 6 h. Continued monitoring showed that these eight signals were slowly replaced by six different signals over a period of 24-72 h; after this time the spectrum remained unchanged at room temperature.The observations by 13 C NMR spectroscopy suggested the following reaction pathway (Scheme 2): DHF (1) condenses with itself (via its putative keto form) by intermolecular dimerization to yield a (presumed) linear dimer intermediate 2, which immediately undergoes ring closure to form the cyclic dimer 3. This cyclic dimer undergoes successive decarboxylation (perhaps via intermediate 2) to form the final compound, pentulosonic acid (4). The 13 C NMR spectrum indicates that predominantly one diastereomer of 3 and essentially one diastereomer of 4 are formed. At the lower temperature of 4 8C, the reaction was slower, and the DHF signals persisted for up to 24 h. Reactions at 0.9 and 1.8 m concentrations of 1 at room temperature resulted in the formation of a 1:3-1:4 anomeric/diastereomeric mixture of 3; ...