N-nitrosamine Mitigation with Nitrite Scavengers in Oral Pharmaceutical Drug Products.

N-nitrosamines are likely human carcinogens. After N-nitrosamine contaminants were detected in pharmaceutical products in 2018, regulatory authorities set a framework for the risk assessment, testing and mitigation of N-nitrosamines in drug products. One strategy to inhibit the formation of N-nitrosamines during the manufacture and storage of drug products involves the incorporation of nitrite scavengers in the formulation. Diverse molecules have been tested in screening studies including the antioxidant vitamins ascorbic acid and α-tocopherol, amino acids, and other antioxidants used in foods or drugs, for inclusion into drug products to mitigate N-nitrosamine formation. This review article outlines key considerations for the inclusion of nitrite scavengers in oral drug product formulations.

Organophotocatalytic Aerobic Oxygenation of Phenols in a Visible-Light Continuous-Flow Photoreactor.

A mild photocatalytic phenol oxygenation enabled by a continuous-flow photoreactor using visible light and pressurized air is described herein. Products for wide-ranging applications, including the synthesis of vitamins, were obtained in high yields by precisely controlling principal process parameters. The reactor design permits low organophotocatalyst loadings to generate singlet oxygen. It is anticipated that the efficient aerobic phenol oxygenation to benzoquinones and p-quinols contributes to sustainable synthesis.

Nutritional strategies in ruminants: A lifetime approach.

This review examines the role of nutritional strategies to improve lifetime performance in ruminants. Strategies to increase ruminants' productive longevity by means of nutritional interventions provide the opportunity not only to increase their lifetime performances and their welfare, but also to decrease their environmental impact. This paper will also address how such nutritional interventions can increase herd efficiency and farm profitability. The key competencies reviewed in this article are redox balance, skeletal development and health, nutrient utilization and sustainability, which includes rearing ruminants without antibiotics and methane mitigation. While the relationships between these areas are extremely complex, a multidisciplinary approach is needed to develop nutritional strategies that would allow ruminants to become more resilient to the environmental and physiological challenges that they will have to endure during their productive career. As the demand of ruminant products from the rapidly growing human world population is ever-increasing, the aim of this review is to present animal and veterinary scientists as well as nutritionists a multidisciplinary approach towards a sustainable ruminant production, while improving their nutrient utilization, health and welfare, and mitigation of their carbon footprint at the same time.

Mode of action uncovered for the specific reduction of methane emissions from ruminants by the small molecule 3-nitrooxypropanol.

Ruminants, such as cows, sheep, and goats, predominantly ferment in their rumen plant material to acetate, propionate, butyrate, CO2, and methane. Whereas the short fatty acids are absorbed and metabolized by the animals, the greenhouse gas methane escapes via eructation and breathing of the animals into the atmosphere. Along with the methane, up to 12% of the gross energy content of the feedstock is lost. Therefore, our recent report has raised interest in 3-nitrooxypropanol (3-NOP), which when added to the feed of ruminants in milligram amounts persistently reduces enteric methane emissions from livestock without apparent negative side effects [Hristov AN, et al. (2015) Proc Natl Acad Sci USA 112(34):10663-10668]. We now show with the aid of in silico, in vitro, and in vivo experiments that 3-NOP specifically targets methyl-coenzyme M reductase (MCR). The nickel enzyme, which is only active when its Ni ion is in the +1 oxidation state, catalyzes the methane-forming step in the rumen fermentation. Molecular docking suggested that 3-NOP preferably binds into the active site of MCR in a pose that places its reducible nitrate group in electron transfer distance to Ni(I). With purified MCR, we found that 3-NOP indeed inactivates MCR at micromolar concentrations by oxidation of its active site Ni(I). Concomitantly, the nitrate ester is reduced to nitrite, which also inactivates MCR at micromolar concentrations by oxidation of Ni(I). Using pure cultures, 3-NOP is demonstrated to inhibit growth of methanogenic archaea at concentrations that do not affect the growth of nonmethanogenic bacteria in the rumen.

Total synthesis of (R,R,R)-α-tocopherol through asymmetric Cu-catalyzed 1,4-addition.

By introducing a disposable activating substituent at C-3, the asymmetric 1,4-addition to a notoriously unreactive 2-substituted chromenone was achieved with high levels of (2R)-stereoselectivity in the presence of a chiral Cu(I)-phosphoramidite complex as a catalyst. This paved the way for an efficient and conceptually novel synthesis of (R,R,R)-α-tocopherol from readily available starting materials.

Large-scale production of bioactive ingredients as supplements for healthy human and animal nutrition.

In this review, synthetic strategies and the development of environmentally benign methods for the production of economically important vitamins, carotenoids, and nutraceuticals used as food and feed supplements are illustrated by selected examples. The application of efficient catalytic transformations in multi-step chemical syntheses of such natural products enables technically feasible and cost-effective processes. For the preparation of fat-soluble (isoprenoid) vitamins A and E and the water-soluble vitamin (+)-biotin, homogeneous metal catalysis, including enantioselective transformations, heterogeneous and enzymatic catalysis serve as key methodologies. In the area of carotenoids, general building concepts and coupling methods for the total synthesis of beta-carotene and astaxanthin are discussed. Biotechnological methods and isolation from natural sources are also employed successfully, as exemplified for the xanthophyll lutein and the antioxidant (-)-epigallocatechin gallate. Lastly, key steps of the chemical synthesis of the polyphenol resveratrol are highlighted.

Highly efficient, facile, room temperature intermolecular [5 + 2] cycloadditions catalyzed by cationic rhodium(I): one step to cycloheptenes and their libraries.

A cationic rhodium(I) complex--[(C(10)H(8))Rh(cod)](+) SbF(6)(-)--catalyzes the remarkably efficient intermolecular [5 + 2] cycloaddition of vinylcyclopropanes (VCPs) and various alkynes, providing cycloheptene cycloadducts in excellent yields in minutes at room temperature. The efficacy and selectivity of this catalyst are also shown in a novel diversification strategy, affording a cycloadduct library in one step from nine commercially available components.

A metal-catalyzed intermolecular [5+2] cycloaddition/Nazarov cyclization sequence and cascade.

The bicyclo[5.3.0]decane skeleton is one of the most commonly encountered bicyclic subunits in nature and the core scaffold of a wide range of targets of structural, biological, and therapeutic importance. Prompted by the interest in such structures, we report the first studies of metal-catalyzed [5+2] cycloadditions of vinylcyclopropanes (VCPs) and enynones. The resultant efficiently formed dienone cycloadducts serve as substrates for subsequent Nazarov cyclizations and as intermediates for single-operation [5+2]/Nazarov serial reactions and catalytic cascades. In many cases the one-flask process can be carried out in shorter reaction times and with comparable or superior yields to the two-flask procedure. Significantly, a single catalyst can be used to mediate both transformations. These [5+2]/Nazarov reaction sequences and cascades collectively provide strategically novel and facile access to the bicyclo[5.3.0]decane skeleton from simple and readily available components.

Catalytic asymmetric approaches towards enantiomerically enriched diarylmethanols and diarylmethylamines.

Enantiopure diarylmethanols and diarylmethylamines are important intermediates for the synthesis of pharmaceutically relevant products with antihistaminic, antiarrhythmic, diuretic, antidepressive, laxative, local-anesthetic and anticholinergic properties. Furthermore, they have been used as precursors for 1,1-diarylalkyl moieties, which occur in other antidepressants as well as in antimuscarinics and endothelin antagonists. In this critical review catalytic strategies towards enantioenriched diarylmethanols and diarylmethylamines are discussed, including methods for asymmetric carbon-carbon bond formations by aryl transfer reactions to aldehydes and arylimines, respectively, and enantioselective reductions of diarylketones.

Planar-chiral cyrhetrenes for the rhodium-catalyzed asymmetric 1,4-addition and the hydrogenation of enamides.

[reaction: see text] The syntheses of novel cyrhetrenes 7a-c and 8a,b are described. These planar-chiral, mono- and diphosphines have been applied as ligands in the Rh-catalyzed 1,4-addition reaction to activated olefins and in the Rh-catalyzed hydrogenation of enamide 12, giving the corresponding products with up to 97 and 93% ee, respectively.