Synthesis of an Oxidation‐Stable Analogue of Cyclic Pyranopterin Monophosphate (cPMP)

Abstract

AbstractMolybdenum cofactor (Moco) deficiency is a lethal hereditary metabolic disease. A recently developed therapy requires continuous intravenous supplementation of the biosynthetic Moco precursor cyclic pyranopterin monophosphate (cPMP). The limited stability of the latter natural product, mostly due to oxidative degradation, is problematic for oral administration. Therefore, the synthesis of more stable cPMP analogues is of great interest. In this context and for the first time, the synthesis of a cPMP analogue, in which the oxidation‐labile reduced pterin unit is replaced by a pyrazine moiety, was achieved starting from the chiral pool materials D‐galactose or D‐arabitol. Our synthesis, 13 steps in total, includes the following key transformations: i) pyrazine lithiation, followed by acylation; ii) closure of the pyrane ring by nucleophilic aromatic substitution; and iii) introduction of phosphate.