Total Synthesis of (−)-Blepharocalyxin D and Analogues

An efficient strategy for the total synthesis of (−)-blepharocalyxin D and an analogue is described. The key step involves an acid-mediated cascade process in which reaction of methyl 3,3-dimethoxypropanoate with γ,δ-unsaturated alcohols possessing diastereotopic styrenyl groups gives <i>trans</i>-fused bicyclic lactones with the creation of two rings and four stereocenters in one pot

Silyl Migrations in d‑Xylose Derivatives: Total Synthesis of a Marine Quinoline Alkaloid

A versatile method for the synthesis of orthogonally protected d-xylose 1-thioethers is described using unusual silyl group migrations which were pivotal in the synthesis of 4,8-dimethyl-6-<i>O</i>-(2′,4′-di-<i>O</i>-methyl-β-d-xylopyranosyl)hydroxyquinoline confirming the structure and absolute configuration of the natural product

Design and Nuclear Magnetic Resonance (NMR) Structure Determination of the Second Extracellular Immunoglobulin Tyrosine Kinase A (TrkAIg2) Domain Construct for Binding Site Elucidation in Drug Discovery

The tyrosine kinase A (TrkA) receptor is a validated therapeutic intervention point for a wide range of conditions. TrkA activation by nerve growth factor (NGF) binding the second extracellular immunoglobulin (TrkAIg2) domain triggers intracellular signaling cascades. In the periphery, this promotes the pain phenotype and, in the brain, cell survival or differentiation. Reproducible structural information and detailed validation of protein–ligand interactions aid drug discovery. However, the isolated TrkAIg2 domain crystallizes as a β-strand-swapped dimer in the absence of NGF, occluding the binding surface. Here we report the design and structural validation by nuclear magnetic resonance spectroscopy of the first stable, biologically active construct of the TrkAIg2 domain for binding site confirmation. Our structure closely mimics the wild-type fold of TrkAIg2 in complex with NGF (1WWW.pdb), and the ¹H–¹⁵N correlation spectra confirm that both NGF and a competing small molecule interact at the known binding interface in solution