Efficient Syntheses of Pyrofolic Acid and Pteroyl Azide, Reagents for the Production of Carboxyl-Differentiated Derivatives of Folic Acid

Reaction of folic acid (<b>1</b>) with excess trifluoroacetic anhydride provides access to both the previously unknown <i>N</i>¹⁰-(trifluoroacetyl)pyrofolic acid (<b>8) </b>and pyrofolic acid (<b>9</b>). Reaction of either of these materials with hydrazine selectively affords pteroyl hydrazide (<b>13</b>), which may be oxidized to pteroyl azide (<b>27) </b>on a large scale (62% overall from <b>1</b> without the need for chromatography). Treatment of <b>27</b> with differentially protected glutamates provides a convenient and high-yielding synthesis of differentially protected, optically pure folates.