SYNTHESIS OF LABELED PRECURSORS

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A major goal of our renewal proposal was to develop efficient routes to synthetically useful precursors at the oxidation state of [ 13C]formaldehyde. As described below, we have developed efficient generation of three important new precursors. First using diethyl ether as a solvent, we have developed conditions for the generation of the potassium anion of t-butyl [ 3C]methyl ether (II) which can act as a nucleophilic formaldehyde equivalent. For example, the anion can be trapped withC02 to yield the t-butyl protected derivative of glycolic acid in just two steps with an overall yield of 70%. As diagrammed below, we have developed a two step route to chloro[13C]methyl t-butyl ether (overall 80% yield) which can serve as an electrophilic formaldehyde equivalent. Finally, we have treated the anion t-butyl [13C]methyl ether with phenyl disulfide to yield t-butoxy [13C]methyl phenyl sulfide (85% yield). This compound is the synthetic equivalent of Corey's dithiane reagent and provide a direct route to labeling aldehydes and ketones. The availability of these [13C]fonnaldehyde can significantly shorten synthetic routes to biornedically important compounds. For example, the availability of t-butyl [13C]methyl ether has allowed us to shorten the synthesis of [13C31glycerol to 4 steps from 13CO.