An aerobic dehydrogenation of nitrogen‐containing heterocycles catalyzed by Grubbs catalyst is developed. The reaction is applicable to various nitrogen‐containing heterocycles. The exceptionally high functional group compatibility of this method was confirmed by the oxidation of an unprotected dihydroindolactam V to indolactam V. Furthermore, by taking advantage of the oxygen‐mediated structural change of the Grubbs catalyst, we integrated ring‐closing metathesis and subsequent aerobic dehydrogenation to develop the novel assisted‐tandem catalysis using molecular oxygen as a chemical trigger. The utility of the assisted‐tandem catalysis was demonstrated by the concise synthesis of N‐containing fused heteroarenes including a natural antibiotic, pyocyanine.
Inhibition
of hypoxia-inducible factor prolyl hydroxylase domain
(HIF-PHD) promotes erythropoietin (EPO) production by stabilizing
the HIFα subunit. Thieno[2,3-d]pyrimidine 8 identified based on X-ray crystal structure analysis was
optimized to lead to the discovery of pyrazolo[4,3-d]pyrimidine 13 as the lead compound of orally bioavailable
HIF-PHD inhibitors. Conversion of the benzyl moiety in 13 gave pyrazolopyrimidine 19 with high solubility and
bioavailability, which increased hemoglobin levels in anemic model
rats after repeated oral administration. It was shown that pyrazolo[4,3-d]pyrimidine derivatives are promising therapeutic agents
for renal anemia through the inhibition of HIF-PHD.
A practical method for the synthesis of 1,3-aminohydroxyacetone synthons was developed, and their utility in the organocatalytic asymmetric aldol reaction was demonstrated in a short synthesis of aza-sugars.
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