High-throughput experimentation (HTE) has revolutionized the pharmaceutical industry, most notably allowing for rapid screening of compound libraries against therapeutic targets. The past decade has also witnessed the extension of HTE principles toward the realm of small-molecule process chemistry. Today, most major pharmaceutical companies have created dedicated HTE groups within their process development teams, invested in automation technology to accelerate screening, or both. The industry's commitment to accelerating process development has led to rapid innovations in the HTE space. This review will deliver an overview of the latest best practices currently taking place within our teams in process chemistry by sharing frequently studied transformations, our perspective for the next several years in the field, and manual and automated tools to enable experimentation. A series of case studies are presented to exemplify state-of-the-art workflows developed within our laboratories.

The stereochemical course of the 1,2-addition of several allylmetal reagents and of the Normant Grignard [ClMgO(CH2)3MgCl] to 2-methoxycyclohexanone and tetrahydrofuranspiro-(2-cyclohexanone) has been determined. In four of the six substrates examined, a 4-tert-butyl group is present to serve as a conformational anchor. The neighboring methoxyl substituent is shown to be capable of engaging effectively in chelation, although special circumstances can dictate otherwise. Experiments involving the allylindium reagent as the nucleophile in aqueous solution reveal that the presence of water does not inhibit the operation of chelation control, which often exceeds that attainable with the corresponding magnesium, cerium, and chromium reagents in anhydrous media by significant margins. The extent to which cooperation between the α-oxygen atom and control of π-facial nucleophilic attack reaches a maximum (>97:3) is when the system is conformationally rigid and the 2-methoxy and 4-tert-butyl groups are both oriented equatorially. As the steric bulk about the oxygen is increased, the ability of indium to anchor onto the heteroatom is significantly lessened. The results of competition experiments are detailed. The prospects for useful synthetic applications of indium catalysis in water or water/THF mixtures appear to be very promising.

A strategy to prepare compounds with multiple chirality axes, which has led to a concise total synthesis of compound 1A with complete stereocontrol, is reported.

The unprotected 2- and 3-hydroxycyclohexanones 1−8 were prepared by methods that skirted as much as possible their proclivity for α-ketol rearrangement (where the possibility for such isomerization exists). The diastereofacial selectivity of their reaction with the allylindium reagent in water, 50% aqueous THF, and anhydrous THF is described. The neighboring α-hydroxyl substituent is construed to be capable of engaging in chelation, thereby controlling the stereochemical outcome of the coupling process. When the hydroxyl substituent is oriented in the equatorial plane, kinetic acceleration accompanies exclusive entry of the allyl group from the equatorial direction. Steric congestion in the vicinity of the binding hydroxyl and ketonic centers is well tolerated. Alternative projection of the OH group into the more crowded axial region may not curtail chelation. For coordination to occur, however, a twist-boat conformation must initially be adopted. While the evidence suggests that this may indeed occur in water, the necessity of crossing the added energy barrier precludes the attainment of rates that are competitive with those exhibited by the equatorial epimers (competition experiments). Placement of the hydroxyl group at C-3 provides no evident opportunity for chelation control. However, excellent stereoselectivity is seen upon axial orientation of the 3-OH group. This phenomenon is attributed to steric and/or electronic effects alone or in combination.

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.