Ligand-switchable directing effects of tethered alkenes in nickel-catalyzed additions to alkynes

Nickel-catalyzed reductive couplings of aldehydes with alkynes that contain tethered olefins are described, in which the degree and sense of regioselectivity are controlled by the length of the tether and the presence or absence of an additive. When the alkyne and alkene are separated by four bonds, very high (>95:5) regioselectivities are observed. Use of a monodentate phosphine as an additive leads to formation of the opposite regioisomer in equal and opposite selectivity (5: >95). These results provide strong evidence for an interaction between the remote alkene and the metal center during the regioselectivity-determining step and suggest that reactions with and without an additive proceed via fundamentally distinct mechanisms.     

Nickel‐Catalyzed Mizoroki–Heck Reaction of Aryl Sulfonates and Chlorides with Electronically Unbiased Terminal Olefins: High Selectivity for Branched Products

Achieving high selectivity in the Heck reaction of electronically unbiased alkenes has been a longstanding challenge. Using a nickel‐catalyzed cationic Heck reaction, we were able to achieve excellent selectivity for branched products (≥19:1 in all cases) over a wide range of aryl electrophiles and aliphatic olefins. A bidentate ligand with a suitable bite angle and steric profile was key to obtaining high branched/linear selectivity, whereas the appropriate base suppressed alkene isomerization of the product. Although aryl triflates are traditionally used to access the cationic Heck pathway, we have shown that, by using triethylsilyl trifluoromethanesulfonate, we can effect a counterion exchange of the catalytic nickel complex, such that cheaper and more stable aryl chlorides, mesylates, tosylates, and sulfamates can be used to yield the same branched products with high selectivity.     

A Three‐Minute Synthesis and Purification of Ibuprofen: Pushing the Limits of Continuous‐Flow Processing

In a total residence time of three minutes, ibuprofen was assembled from its elementary building blocks with an average yield of above 90 % for each step. A scale‐up of this five‐stage process (3 bond‐forming steps, one work‐up, and one in‐line liquid–liquid separation) provided ibuprofen at a rate of 8.09 g h^?1 (equivalent to 70.8 kg y^?1) using a system with an overall footprint of half the size of a standard laboratory fume hood. Aside from the high throughput, several other aspects of this synthesis expand the capabilities of continuous‐flow processing, including a Friedel–Crafts acylation run under neat conditions and promoted by AlCl₃, an exothermic in‐line quench of high concentrations of precipitation‐prone AlCl₃, liquid–liquid separations run at or above 200 psi to provide solvent‐free product, and the use of highly aggressive oxidants, such as iodine monochloride. The use of simple, inexpensive, and readily available reagents thus affords a practical synthesis of this important generic pharmaceutical.     

CHARMM additive all-atom force field for carbohydrate derivatives and its utility in polysaccharide and carbohydrate-protein modeling

Monosaccharide derivatives such as xylose, fucose, N-acetylglucosamine (GlcNAc), N-acetylgalactosamine (GlaNAc), glucuronic acid, iduronic acid, and N-acetylneuraminic acid (Neu5Ac) are important components of eukaryotic glycans. The present work details development of force-field parameters for these monosaccharides and their covalent connections to proteins via O-linkages to serine or threonine sidechains and via N-linkages to asparagine sidechains. The force field development protocol was designed to explicitly yield parameters that are compatible with the existing CHARMM additive force field for proteins, nucleic acids, lipids, carbohydrates, and small molecules. Therefore, when combined with previously developed parameters for pyranose and furanose monosaccharides, for glycosidic linkages between monosaccharides, and for proteins, the present set of parameters enables the molecular simulation of a wide variety of biologically-important molecules such as complex carbohydrates and glycoproteins. Parametrization included fitting to quantum mechanical (QM) geometries and conformational energies of model compounds, as well as to QM pair interaction energies and distances of model compounds with water. Parameters were validated in the context of crystals of relevant monosaccharides, as well NMR and/or x-ray crystallographic data on larger systems including oligomeric hyaluronan, sialyl Lewis X, O- and N-linked glycopeptides, and a lectin:sucrose complex. As the validated parameters are an extension of the CHARMM all-atom additive biomolecular force field, they further broaden the types of heterogeneous systems accessible with a consistently-developed force-field model.     

Simple alkenes as substitutes for organometallic reagents: nickel-catalyzed, intermolecular coupling of aldehydes, silyl triflates, and alpha olefins

A nickel-catalyzed method for the three-component coupling of alkenes (ethylene and alpha olefins), aldehydes, and silyl triflates is described, and this process represents the first catalytic method for coupling aldehydes and alkenes to give allylic alcohol derivatives. Conceptually, the alkene functions as a replacement for an alkenylmetal reagent.     

Catalytic Addition of Simple Alkenes to Carbonyl Compounds Using Group 10 Metals

Recent advances using nickel complexes in the activation of unactivated monosubstituted olefins for catalytic intermolecular carbon-carbon bond-forming reactions with carbonyl compounds, such as simple aldehydes, isocyanates, and conjugated aldehydes and ketones, are discussed. In these reactions, the olefins function as vinyl- and allylmetal equivalents, providing a new strategy for organic synthesis. Current limitations and the outlook for this new strategy are also discussed.