Abstract
The synthetic utility of pterins is often hampered by the notorious insolubility of this heterocycle, slowing the development of medicinally relevant pteridine derivatives. Reactions which expedite the development of new pterins are thus of great importance. Through a dual role of diazabicycloundecene (DBU), 7-carboxymethylpterin is converted to the soluble DBU salt, with additional DBU promoting an ester-to-amide transformation. We have explored this reaction to assess its scope and identify structural features in the amines which significantly affect success, monitored the reaction kinetics using a pseudo-first order kinetics model, and further adapted the reaction conditions to allow for product formation in as little as 5 min, with yields often >80%.
Highlights
Pteridines are a class of fused bicyclic heterocycles with significant biological relevance
In addition to pteridine derivatives being used as inhibitors of dihydrofolate reductase and dihydropteroate synthase, pterins have been a useful scaffold in the development of inhibitors of ricin [3,4], methionine synthase [5], nitric oxide synthase [6], shigella [7], and aldose reductase [8], as well as for treatment of leishmaniosis [9]
The general procedure for the DBU-promoted amidation involved the initial suspension of 7-CMP (1) in a small quantity of anhydrous methanol, followed by the addition of 2 equiv DBU resulting in the full dissolution of the pterin ester, whereupon 2 equiv of the amine of interest were added and the reaction was stirred until complete (Scheme 1)
Summary
Pteridines are a class of fused bicyclic heterocycles with significant biological relevance. In addition to this improvement in solubility, we can further take advantage of a mechanistic role of DBU, as it catalyzes the ester-to-amide transformation, allowing for 7-methoxycarbonylpterin (7-CMP, 1) to smoothly generate new pterin amides (Figure 1) [14,17]. The benefit of DBU as an additive in these previous reports was largely empirical, and reaction times were still in the order of several hours.
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