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 direct, by-product–free conversion of basic feedstocks to products of medicinal and agricultural relevance is a broad goal of chemical research. Butadiene is a product of petroleum cracking and is produced on an enormous scale (about 12 × 106 metric tons annually). Here, with the use of a ruthenium catalyst modified by a chiral phosphate counterion, we report the direct redox-triggered carbon-carbon coupling of alcohols and butadiene to form products of carbonyl crotylation with high levels of anti-diastereoselectivity and enantioselectivity in the absence of stoichiometric by-products.

The ruthenium catalyst generated in situ from H2Ru(CO)(PPh3)3, (S)-SEGPHOS and a TADDOL-derived phosphoric acid promotes butadiene hydrohydroxyalkylation to form enantiomerically enriched products. Notably, the observed diastereo- and enantioselectivity is opposite of that observed using BINOL-derived phosphate counterions in combination with (S)-SEGPHOS, the same enantiomer of chiral ligand. Match-mismatch effects between chiral ligand and chiral TADDOL-phosphate counterion are described. For the first time, single crystal X-ray diffraction data is reported for a ruthenium complex modified by a chiral phosphate counterion.

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Under the conditions of ruthenium(0) catalyzed hydrohydroxyalkylation, vicinal diols 1a–1l and methyl acrylate 2a are converted to the corresponding lactones 3a–3l in good to excellent yield. The reaction of methyl acrylate 2a with hydrobenzoin 1f, benzoin didehydro-1f, and benzil tetradehydro-1f form the same lactone 3f product, demonstrating that this process may be deployed in a redox level-independent manner. A variety of substituted acrylic esters 2a–2h participate in spirolactone formation, as illustrated in the conversion of N-benzyl-3-hydroxyoxindole 1o to cycloadducts 4a–4h. Hydrohydroxyalkylation of hydroxyl-substituted methacrylate 2i with diols 1b, 1f, 1j and 1l forms α-exo-methylene-γ-butyrolactones 5b, 5f, 5j and 5l in moderate to good yield. A catalytic cycle involving 1,2-dicarbonyl-acrylate oxidative coupling to form oxaruthenacyclic intermediates is postulated. A catalytically competent mononuclear ruthenium(II) complex was characterized by single crystal X-ray diffraction. The influence of electronic effects on regioselectivity in reactions of nonsymmetric diols were probed using para-substituted 1-phenyl-1,2-propanediols 1g, 1m and 1n and density functional theory (DFT) calculations.

Under the conditions of ruthenium catalyzed transfer hydrogenation, 1,1-disubstituted allenes 1a-1c and alcohols 2a-2g engage in redox-triggered generation of allylruthenium-aldehyde pairs to form products of hydrohydroxyalkylation 3a-3g, 4a-4g and 5a-5g with complete branched regioselectivity. By exploiting Curtin-Hammett effects, good to excellent levels of antidiastereoselectivity (4:1 ->20:1) are obtained. Thus, all carbon quaternary centers are formed in a diastereoselective fashion upon carbonyl addition from the alcohol oxidation level in the absence of pre-metallated nucleophiles or stoichiometric byproducts. Exposure of allene 1b to equimolar quantities of alcohol 2a and aldehyde 6b under standard reaction conditions delivers adducts 4a and 4b in a 1:1 ratio. Similarly, exposure of allene 1b to equimolar quantities of aldehyde 6a and alcohol 2b provides adducts 4a and 4b in an identical equimolar ratio. Exposure of allene 1b to d 2 -para-nitrobenzyl alcohol, deuterio-2a, under standard reaction conditions delivers the product of hydrohydroxymethylation deuterio-4a, which incorporates deuterium at the carbinol position (>95% 2 H) and the interior vinylic position (34% 2 H). Competition experiments involving exposure of allene 1b to equimolar quantities of benzylic alcohols 2a and deuterio-2a reveal no significant kinetic effect. The collective data corroborate rapid, reversible alcohol dehydrogenation, allene hydrometallation and (E)-, (Z)-isomerization of the transient allylruthenium in advance of turn-over limiting carbonyl addition. Notably, analogous allenealdehyde reductive C-C couplings employing isopropanol as the terminal reductant display poor levels of anti-diastereoselectivity, suggesting carbonyl addition is not turn-over limiting in reactions conducted from the aldehyde oxidation level.

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 39 new chemical entities approved for the first time globally in 2018.

New drugs introduced to the market are privileged structures having affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody–drug conjugates, provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This review is part of a continuing series presenting the most likely process-scale synthetic approaches to 40 NCEs approved for the first time anywhere in the world in 2019.