Selective small molecule probes for the hypoxia inducible factor (HIF) prolyl hydroxylases.

The hypoxia inducible factor (HIF) system is central to the signaling of low oxygen (hypoxia) in animals. The levels of HIF-α isoforms are regulated in an oxygen-dependent manner by the activity of the HIF prolyl-hydroxylases (PHD or EGLN enzymes), which are Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases. Here, we describe biochemical, crystallographic, cellular profiling, and animal studies on PHD inhibitors including selectivity studies using a representative set of human 2OG oxygenases.

Asymmetric synthesis of N,O,O,O-tetra-acetyl d-lyxo-phytosphingosine, jaspine B (pachastrissamine), 2-epi-jaspine B, and deoxoprosophylline via lithium amide conjugate addition.

The highly diastereoselective anti-aminohydroxylation of (E)-gamma-tri-iso-propylsilyloxy-alpha,beta-unsaturated esters, via conjugate addition of lithium (S)-N-benzyl-N-(alpha-methylbenzyl)amide and subsequent in situ enolate oxidation with (+)-(camphorsulfonyl)oxaziridine, has been used as the key step in the asymmetric synthesis of N,O,O,O-tetra-acetyl d-lyxo-phytosphingosine (20% yield over 7 steps), the anhydrophytosphingosine jaspine B (10% yield over 9 steps), 2-epi-jaspine B (14% yield over 9 steps), and the Prosopis alkaloid deoxoprosophylline (26% yield over 7 steps).

An efficient one-pot approach to bridged bicyclic ring-systems through consecutive hetero-domino transformations: a mechanistic rationale and further rearrangements.

This article describes the design of olefin-generated/reagent-modulated consecutive hetero-domino reactions of 1,2-unsaturated bicyclic diols, which are potentially of great use, initiated by PhI(OAc)(2), continued by [Pb(OAc)(4)], and completed by use of a mild base (K(2)CO(3)). Inversion of a quaternary center has been achieved through a three-reaction sequence: a domino transformation followed by an m-CPBA-mediated Baeyer-Villiger oxidation and subsequent reductive lactone ring opening.