Timothy D. Neubert

Identification of Novel HSP90α/β Isoform Selective Inhibitors Using Structure-Based Drug Design. Demonstration of Potential Utility in Treating CNS Disorders such as Huntington’s Disease

A structure-based drug design strategy was used to optimize a novel benzolactam series of HSP90α/β inhibitors to achieve >1000-fold selectivity versus the HSP90 endoplasmic reticulum and mitochondrial isoforms (GRP94 and TRAP1, respectively). Selective HSP90α/β inhibitors were found to be equipotent to pan-HSP90 inhibitors in promoting the clearance of mutant huntingtin protein (mHtt) in vitro, however with less cellular toxicity. Improved tolerability profiles may enable the use of HSP90α/β selective inhibitors in treating chronic neurodegenerative indications such as Huntingtons disease (HD). A potent, selective, orally available HSP90α/β inhibitor was identified (compound 31) that crosses the blood-brain barrier. Compound 31 demonstrated proof of concept by successfully reducing brain Htt levels following oral dosing in rats.

Radical Mediated C–H Functionalization of 3,6-Dichloropyridazine: Efficient Access to Novel Tetrahydropyridopyridazines

A radical mediated C-H functionalization of 3,6-dichloropyridazine using primary alcohols, t-BuOOH, and TiCl3 to access alkoxy pyridazines is described. This transformation is conducted open to air and on gram scale. A subsequent cyclization step can then be employed to efficiently access diversely substituted tetrahydropyridopyridazines with multiple functional handles.

Chapter 11 The enantioselective synthesis of morphine

Publisher Summary This chapter focuses on the enantioselective synthesis of morphine. Each of the pathways discussed in the chapter has contributed to the area of morphine synthesis. Even though similar tactics appear in several of these approaches, each presents a unique solution to the problem, with varying degrees of elegance and efficiency and their differences imply diverse possibilities for analog synthesis. While the morphine structure appears relatively simple by the standards of many natural products being studied today, the unique challenges posed by the string of five contiguous stereocenters and the relative dearth of active functionality present in the target combine to test synthetic chemists imagination and capacity for clever strategy. Morphine is the principal alkaloid of the pharmacologically active substance opium, which is derived from the poppy Papaver somniferum L. or P. album Mill, Papaveraceae. The major alkaloids comprising the morphine family, represented by (–)-morphine, (–)-codeine, and (–)-thebaine, still hold important positions in modern pharmacopias. The medicinal importance of these compounds and their analogs is coupled with the formidable synthetic challenges implicit in the pentacyclic morphinan skeleton—five contiguous stereogenic centers at C-6, C-5, C-13, C-14, and C-9, one of which, C-13, is both benzylic and quaternary.

Diastereoselective one-pot Knoevenagel condensation/Corey-Chaykovsky cyclopropanation.

Efforts to substitute the cyclopropane ring in a series of aryl cyclopropylnitriles led to the discovery of an operationally simple one-pot method for Knoevenagel condensation and subsequent Corey-Chaykovsky cyclopropanation giving diastereomerically pure products as a racemic mixture of enantiomers. Method development and results for variably substituted aryl acetonitriles and aldehydes in the reaction are reported. A concise synthesis of (±)-bicifadine in two steps is provided to demonstrate the utility of the method.