Discovery of Orally Bioavailable and Liver-Targeted Hypoxia-Inducible Factor Prolyl Hydroxylase (HIF-PHD) Inhibitors for the Treatment of Anemia.

We report herein the design and synthesis of a series of orally active, liver-targeted hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors for the treatment of anemia. In order to mitigate the concerns for potential systemic side effects, we pursued liver-targeted HIF-PHD inhibitors relying on uptake via organic anion transporting polypeptides (OATPs). Starting from a systemic HIF-PHD inhibitor (), medicinal chemistry efforts directed toward reducing permeability and, at the same time, maintaining oral absorption led to the synthesis of an array of structurally diverse hydroxypyridone analogues.

An efficient method for construction of the angularly fused 6,3,5-tricyclic skeleton of mycorrhizin A and its analogues.

The angularly fused 6,3,5-tricyclic system is readily generated via a cascade cyclization under acid promotion. The reaction proceeds at room temperature with high stereochemical fidelity from the electrophilic center of the epoxide to the cyclopropane product. This methodology provides a potentially useful approach for the synthesis of mycorrhizin A and its analogues.

The first asymmetric total syntheses and determination of absolute configurations of xestodecalactones B and C.

The first efficient asymmetric total syntheses of xestodecalactones B and C have been accomplished in 10 steps with an overall yield of 22 and 20.2%, respectively. The key steps involve the utility of Evans oxazolidinone-mediated syn-aldol condensations to establish the C-9 configuration and the macrolide ring formation by intramolecular acylation.