Synthesis of Cyclic Pyranopterin Monophosphate, a Biosynthetic Intermediate in the Molybdenum Cofactor Pathway

Cyclic pyranopterin
monophosphate (1), isolated from
bacterial culture, has previously been shown to be effective in restoring
normal function of molybdenum enzymes in molybdenum cofactor (MoCo)-deficient
mice and human patients. Described here is a synthesis of 1 hydrobromide (1·HBr) employing in the key step
a Viscontini reaction between 2,5,6-triamino-3,4-dihydropyrimidin-4-one
dihydrochloride and d-galactose phenylhydrazone to give the
pyranopterin (5aS,6R,7R,8R,9aR)-2-amino-6,7-dihydroxy-8-(hydroxymethyl)-3H,4H,5H,5aH,6H,7H,8H,9aH,10H-pyrano­[3,2-g]­pteridin-4-one
(10) and establishing all four stereocenters found in 1. Compound 10, characterized spectroscopically
and by X-ray crystallography, was transformed through a selectively
protected tri-tert-butoxycarbonylamino intermediate
into a highly crystalline tetracyclic phosphate ester (15). The latter underwent a Swern oxidation and then deprotection to
give 1·HBr. Synthesized 1·HBr
had in vitro efficacy comparable to that of 1 of bacterial
origin as demonstrated by its enzymatic conversion into mature MoCo
and subsequent reconstitution of MoCo-free human sulfite oxidase–molybdenum
domain yielding a fully active enzyme. The described synthesis has
the potential for scale up.