Rearrangement of 3-deoxy-D-erythro-hexos-2-ulose in aqueous solution: NMR evidence of intramolecular 1,2-hydrogen transfer.

Selective (13)C- and (2)H-labeling, and (13)C NMR spectroscopy, have been used to show that the 1,2-dicarbonyl compound (osone), 3-deoxy-D-erythro-hexos-2-ulose (3-deoxy-D-glucosone) (1; 3DG), degrades to 3-deoxy-D-ribo-hexonic acid 2 and 3-deoxy-D-arabino-hexonic acid 3 exclusively via an intramolecular 1,2-hydrogen transfer mechanism in aqueous phosphate buffer at pH 7.5 at 37 °C. Acids 2 and 3 are produced in significantly different amounts (1:6 ratio) despite the prochiral C3 in 1, and two potential reaction mechanisms are considered to explain the observed stereoselectivity. One mechanism involves acyclic forms of 1 as reactants, whereas the other assumes cyclic pyranose reactants. In the former (2-keto-hydrate or 2KH mechanism), putative transition state structures based on density functional theory (DFT) calculations arise from the C1 hydrate form of acyclic 1 having the C1-H1 bond roughly orthogonal to the C2 carbonyl plane. The relative orientation of the alkoxide oxygen atom at C1 and the C2 carbonyl oxygen, and H-bonding between C(1)OH and the C2 carbonyl oxygen, contribute to the stability of the transition state. DFT calculations of the natural charges on individual atoms in the transition state show the migrating hydrogen to have an almost neutral charge, implying that it may more closely resemble a hydrogen atom than a hydride anion during transfer from C1 to C2. A second mechanism (2-keto-pyranose or 2KP mechanism) involving the cyclic 2-keto-pyranoses of 1 as reactants aligns the C1-H1 bond orthogonal to the C2 carbonyl plane in different ring conformations of both anomers, with the β-pyranose giving 3 and the α-pyranose giving 2. While both the 2KH and 2KP mechanisms are possible, the latter readily leads to a prediction of the reaction stereospecificity that is consistent with the experimental data.