A Droplet Flow Platform with Multiple Process Analytics Facilitates Flexible Reaction Optimization

Flow processing offers many opportunities to optimize reactions in a rapid and automated manner, yet often requires relatively large quantities of input materials. To combat this, we report the use of a flexible droplet flow reactor, equipped with two analytical instruments, for low-volume optimization experiments. A Buchwald-Hartwig amination toward the drug olanzapine, with 6 independent optimizable variables, was optimized using three different automated approaches: self-optimization, design of experiments and kinetic modeling. These approaches are complementary and provide differing information on the reaction: pareto optimal operating points, response surface models and mechanistic models, respectively. The results were achieved using <10% of the material that would be required for standard flow operation. Finally, a chemometric model was built utilizing automated data handling and three subsequent validation experiments demonstrated good agreement between the droplet flow reactor and a standard (larger scale) flow reactor

Addressing the Configuration Stability of Lithiated Secondary Benzylic Carbamates for the Development of a Noncryogenic Stereospecific Boronate Rearrangement

A practical noncryogenic process for the Aggarwal stereospecific boronate rearrangement with chiral secondary benzylic carbamates has been developed. The use of LDA instead of <i>sec</i>-BuLi combined with an <i>in situ</i> trapping of the unstable lithiated carbamate was critical to success. Furthermore, this new process increased the substrate scope to include the versatile aryl iodide and bromide substrates. The methodology was applied to a diverse array of substrates and was demonstrated on multikilogram scale

Development of an Asymmetric Synthesis of a Chiral Quaternary FLAP Inhibitor

A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor

Sequential C–H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11β-HSD‑1 Inhibitor

A concise asymmetric synthesis of an 11β-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of <b>1</b> was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C–H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir­(COD)­Cl]₂

Expression of Interest for a Phase-II LHCb Upgrade: Opportunities in flavour physics, and beyond, in the HL-LHC era

https://cds.cern.ch/record/224431