Our previously reported chiral silane‐promoted enol ether‐acylhydrazone 3+2 cycloaddition reaction has been applied to a brief and efficient synthesis of the neuroprotective agent MS‐153. ...Unsatisfactory and variable levels of efficiency and enantioselectivity with the requisite acetaldehyde‐derived acylhydrazone occasioned a modification to the chiral silane Lewis acid, which led to the key cycloaddition step proceeding with excellent efficiency (85 % yield) and enantioselectivity (≥98 % ee).
A catalytic, enantioselective γ-alkylation of α,β-unsaturated malonates and ketoesters is reported. This strategy entails a highly regio- and enantioselective iridium-catalyzed α-alkylation of an ...extended enolate, and a subsequent translocation of chirality to the γ-position via a Cope rearrangement.
High-throughput (HT) techniques built upon laboratory automation technology and coupled to statistical experimental design and parallel experimentation have enabled the acceleration of chemical ...process development across multiple industries. HT technologies are often applied to interrogate wide, often multidimensional experimental spaces to inform the design and optimization of any number of unit operations that chemical engineers use in process development. In this review, we outline the evolution of HT technology and provide a comprehensive overview of how HT automation is used throughout different industries, with a particular focus on chemical and pharmaceutical process development. In addition, we highlight the common strategies of how HT automation is incorporated into routine development activities to maximize its impact in various academic and industrial settings.
In the pharmaceutical industry, high throughput (HT) technology is well developed and routinely utilized in chemical process development for reaction optimization and isolations via crystallization. ...However, fewer HT technologies have been employed in the development of workup procedures, bridging optimized reaction and isolations. Frequently, extensive workups involving numerous unit operations are required to remove reaction stream components, such as impurities, solvent, and catalyst, prior to isolation. Herein, we describe a systematic yet flexible approach using designed experimentation, laboratory automation, and parallel experimentation to quickly and efficiently optimize unit operations that are required post reaction to remove reaction stream components (e.g., impurities, metal catalysts, solvent). This novel high throughput extraction (HTEx) platform has shown potential to broadly impact development by faster and more robustly improving process greenness, process mass intensity (PMI), cycle time, and ease of operation.
The development of an improved short and efficient commercial synthesis of the JAK2 inhibitor, a complex pyrrolopyridine, BMS-911543, is described. During the discovery and development of this ...synthesis, a Pd-catalyzed C–H functionalization was invented which enabled the rapid union of the key pyrrole and imidazole fragments. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only six steps (longest linear sequence) from readily available materials.
Two efficient asymmetric routes to γ-secretase modulator BMS-932481, under investigation for Alzheimer’s disease, have been developed. The key step for the first route involves a challenging ...enantioselective hydrogenation of an unfunctionalized trisubstituted alkene to establish the benzylic stereocenter, representing a very rare case of achieving high selectivity on a complex substrate. The second route demonstrates the first example of a vinylogous dynamic kinetic resolution (VDKR) ketone reduction, where the carbonyl and the racemizable stereocenter are not contiguous, but are conjugated through a pyrimidine ring. Not only did this transformation require both catalyst and substrate control to correctly establish the two stereocenters, but it also necessitated that the nonadjacent benzylic center of the ketone substrate be more acidic than that of the alcohol product to make the process dynamic. DFT computations aided the design of this novel VDKR pathway by reliably predicting the relative acidities of the intermediates involved.
BMS-911543 is a complex pyrrolopyridine investigated as a potential treatment for myeloproliferative disorders. The development of a short and efficient synthesis of this molecule is described. ...During the course of our studies, a Ni-mediated C–N bond formation was invented, which enabled the rapid construction of the highly substituted 2-aminopyridine core. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only eight steps starting from readily available materials.
The development of a diastereoselective nucleoside phosphorylation is described, which produces a single isomer of a complex nucleoside monophosphate pro-drug. A stable phosphoramidic acid derivative ...is coupled to the nucleoside, in a process mediated by HATU and quinine, to deliver the coupled product in high chemical yield and good diastereoselectivity. This unusual process was shown to proceed through a dynamic kinetic resolution of a 1:1 mixture of activated phosphonate ester diastereoisomers. The optimized conditions afforded the product with a combined S,S(P) and S,R(P) in-process yield of 89% and a ∼7:1 S,S(P):S,R(P) diastereomeric ratio. Isolation of the major isomer was facilitated by single crystallization from anisole, where the product was obtained in 57% isolated yield, excellent purity (>95%), and a high diastereomeric ratio (>50:1).
A brief synthesis of manzacidin C based on a chiral silane-promoted diastereo- and enatioselective acylhydrazone-alkene 3 + 2 cycloaddition reaction has been achieved. This synthesis is the first ...synthesis of any of the manzacidins wherein the C(4) and C(6) stereocenters are established in a single highly stereoselective step.
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) in which neuropathic pain is now recognized as a major symptom. To date, few studies have examined ...the underlying mechanisms of neuropathic pain in MS. Recently we showed that in a chronic-relapsing animal model of MS, experimental autoimmune encephalomyelitis (EAE), characteristic neuropathic behaviours develop. However, responses to persistent noxious stimuli in EAE remain unexplored. We, therefore set out to characterize the changes in pain sensitivity in our EAE model to subcutaneous injection of formalin. We show here that female C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG
35–55) display a significant decrease in elicited pain behaviours in response to formalin injection. These effects were found to involve dysregulation of the glutamatergic system in EAE. We show here that these effects are mediated by decreased glutamate transporter expression associated with EAE. Our findings demonstrate that dysregulation of glutamate transporter function in EAE mice is an important mechanism underlying the abnormal pain sensitivity in response to persistent noxious stimulation of mice with EAE and also sheds light on a potential mechanism underlying neuropathic pain behaviours in this model.
PDF
