Since their discovery in 1997, iridium-catalysed asymmetric allylic substitutions have been developed into a broadly applicable tool for the synthesis of chiral building blocks via C-C and C-heteroatom bond formation. The remarkable generality of these reactions and the high levels of regio- and enantioselectivity that are usually obtained in favour of the branched products have been made possible by a thorough investigation of the catalyst system and its mode of action. Therefore, today the Ir-catalysed asymmetric allylic substitution is a powerful reaction in the organic chemist's repertoire and has been used extensively for several applications. This article aims to provide an overview of the development of iridium catalysts derived from an Ir salt and a chiral phosphoramidite and their application to the enantioselective synthesis of natural products and biologically relevant compounds.

Controlling the properties of lead molecules is critical in drug discovery, but sourcing large numbers of lead-like compounds for screening collections is a major challenge. A unified synthetic approach is described that enabled the synthesis of 52 diverse lead-like molecular scaffolds from a minimal set of 13 precursors. The divergent approach exploited a suite of robust, functional group-tolerant transformations. Crucially, after derivatisation, these scaffolds would target significant lead-like chemical space, and complement commercially-available compounds.

The synthesis of enantioenriched molybdenum precatalysts for the asymmetric hydrogenation of substituted quinolines and naphthalenes is described. Three classes of pincer ligands with chiral substituents were evaluated as supporting ligands in the molybdenumcatalyzed hydrogenation reactions, where oxazoline imino(pyridine) chelates were identified as optimal. A series of 2,6-disubstituted quinolines was hydrogenated to enantioenriched decahydroquinolines with high diastereo-and enantioselectivities. For quinoline derivatives, selective hydrogenation of both the carbocycle and heterocycle was observed depending on the ring substitution. Spectroscopic and mechanistic studies established molybdenum η 6 -arene complexes as the catalyst resting state and that partial hydrogenation arises from dissociation of the substrate from the coordination sphere of molybdenum prior to complete reduction. A stereochemical model is proposed based on the relative energies of the respective coordination of the prochiral faces of the arene determined by steric interactions between the substrate and the chiral ligand, rather than through precoordination by a heteroatom.

Abstract:The combination of an air-stable iridium catalyst and the dipolar aprotic solvent dimethyl sulfoxide (DMSO) allowed, for the first time, the systematic exploitation of highly polar, functionalized amines in asymmetric allylic substitutions: low molecular weight, sp 3 -rich chiral building blocks were obtained with physicochemical properties that will be valuable in the synthesis of lead-like small molecules.

Catalytic static mixer (CSM) technology is presented as an industrially viable solution for aromatic nitro group reduction in the synthesis of fenebrutinib. Factors affecting catalyst inhibition could be rapidly understood and mitigated by the use of real-time analytics (FT-IR and UHPLC). This facilitated the development of stable and optimal conditions in a system with four CSMs positioned inside a thermostated shell-and-tube reactor. Additional care was taken to ensure the control of three key impurities to low levels (<0.10 area% by offline UHPLC analysis). The optimal conditions (0.4 M concentration, 20 bar, 120 °C, 3.3 equiv H 2 ) were then scaled up to a reactor with eight CSMs, whereby an improvement in the space−time yield was achieved. Over 16 h of processing, a stable impurity profile was observed, without metal leaching. Finally, the reaction was performed in a system with 16 CSMs, which also provided an increase in the space−time yield (to 26.2 mol L −1 h −1 or 6.5 kg L −1 h −1 ), resulting in 174 g h −1 throughput, while maintaining an excellent impurity profile.