Bi (DHM-3 Dimer). A Water-Soluble, One-Electron Reducing Agent

Article abstract of DOI:10.1021/jo00390a020

The synthesis and reactivity of the water-soluble, one-electron reducing agent bi<3.5-dimethyl-5-(hydroxymethyl)-2-oxomorpholin-3-yl> (DHM-3 dimer, 8) are described.DHM-3 dimer was formed as a mixture of diastereoisomers from the photoreduction of 5,6-dihydro-3,5-dimethyl-5-(hydroxymethyl)-2H-1,4-oxazin-2-one (3A) in 2-propanol, and a major diastereoisomer 8A was isolated in pure form.Oxazinone 3A, which exists in equilibrium with a ring-chain tautomer, 3,5-dimethyl-8-aza-3,7-dioxabicyclo<3.2.1>octan-2-one (3B), was obtained from condensation of 2-amino-2-methyl-1,3-propanediol (1) with ethyl pyruvate (2).DHM-3 diastereoisomeric dimers equilibrate through facile bond homolysis via captodative radical 3,5-dimethyl-5-(hydroxymethyl)-2-oxomorpholin-3-yl (DHM-3).In the presence of an easily reducible substrate, DHM-3 reacts as a one-electron-reducing agent.Reductions of ferriin (an Fe³⁺-1,10-phenanthroline complex), methylviologen (paraquat), 1,1-diphenyl-2-picryljydrazyl (DPPH), potassium ferricyanide, molecular oxygen, and daunomycin by DHM-3 are described.The rates of these reductions, with the exception of the rates of reduction of molecular oxygen and daunomycin, are the rates of bond homolysis of DHM-3 dimer.The rate constant is solvent dependent and is highest in the most polar solvent, water, a result consistent with captodative resonance stabilization of the DHM-3 radical.Reduction of oxygen gives hydrogen peroxide less rapidly than bond homolysis, and reduction of daunomycin (11) gives 7-deoxydaunomycinone (13) via a consecutive first-order rate law.In the absence of a reducible substrate, DHM-3 dimer undergoes slow disproportionation to a mixture of 3A, 3B, and the two stereoisomers of 3,5-dimethyl-5-(hydroxymethyl)-2-oxomorpholine (4A, 4B).The products of oxidation or disproportionation of DHM-3 hydrolyze in water: 3A and 3B give 2-amino-2-methyl-1,3-propanediol (1), pyruvic acid, and the two diastereoisomers of 2-carboxy-2,4-dimethyl-4-(hydroxymethyl)oxazolidine (9A, 9B); 4A and 4B give d,l-N-alanine (10).Because of its water solubility, redox activity, and low animal toxicity, DHM-3 dimer is proving to be a useful antidote for some quinone antitumor drugs such as daunomycin