Stereoselective syntheses of substituted succinic acid derivatives of the iron chiral auxiliary [(η5-C5H5)Fe(CO)(PPh3)]

© 2014 Elsevier Ltd. A range of alkyl- or aryl-substituted iron succinoyl complexes, incorporating the iron chiral auxiliary [(η5-C5H5)Fe(CO)(PPh3)], were prepared in high regio- and diastereoselectivities by employing four successful strategies: (i) the alkylation of chiral enolate equivalents with tert-butyl bromoacetate; (ii) the mutual kinetic resolution of tert-butyl α-bromoacetate with a chiral acetate enolate equivalent; (iii) the alkylation of chiral succinoyl enolate equivalents; (iv) the conjugate addition of organolithium reagents or lithium amide reagents to chiral fumaroyl derivatives. Oxidative cleavage of the iron chiral auxiliary was shown to occur without compromising the stereochemical integrity of the succinoyl fragments

Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 1: Quaternary amines

We report the identification of a novel series of human epithelial sodium channel (ENaC) blockers that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride. Following a rational design hypothesis a series of quaternary amines were prepared and evaluated for their ability to block ion transport via ENaC in human bronchial epithelial cells (HBECs). Compound 11 has an IC50 of 200 nM and is efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED50 of 44 μg kg−1 at 1 h. As such, pyrazinoyl quaternary amines represent the first examples of a promising new class of human ENaC blockers