Benzazetidines and Related Compounds: Synthesis and Potential.

Benzazetidines are a class of N-heterocycles potentially very interesting for a variety of purposes, including biological applications and drug design. In the past, their high ring strain has hampered the development of trustable, general, and efficient synthetic methodologies for their preparation. In this review article, the aim is to disclose all the literature contributions about the synthesis of these compounds and the study of their reactivity, from the early examples to the most recent synthetic approaches. Recently, there has been a growth of interest for this heterocycle, driven by the publication of novel synthetic methodologies based on palladium-catalyzed intramolecular C-H amination and organocatalyzed ring-closure of 2-(N-Boc-anilino)-α-ketoesters/amides.

Organocatalytic Synthesis of Benzazetidines by Trapping Hemiaminals with Protecting Groups.

Benzazetidines are highly strained and inherently unstable heterocycles. There are only few methodologies for assembling these compounds. Here, a protocol is presented to trap an elusive cyclic, four-membered hemiaminal structure. This method affords several benzazetidines in moderate to good yields (up to 81%), and it uses inexpensive materials and does not require catalysts based on transition metals. The high ring strain energy of these benzazetidine systems was estimated by density functional theory calculations to be about 32 kcal mol-1. This synthesis can be applied also on gram scale with reaction yield essentially unchanged.

Synthesis of Benzofuranones via Malonates Desymmetrization: Yield Increase by the Portion-wise Addition of Quinones.

The organocatalyzed addition of several malonates to 1,4-benzoquinones affords benzofuranones bearing a quaternary stereocenter with good enantioselectivity. This reaction is an intramolecular desymmetrization since it proceeds through the formation of an arylated achiral malonate that cyclizes to give the reaction product. The addition rate of the quinone dramatically affects the reaction yield which was originally low. The yield was considerably increased, in some cases, from less than 20 % to over 95 %, by adding the quinone in portions rather than at once, keeping similar enantioselectivity. A possible rationalization for the preferential formation of the indicated enantiomer has been investigated by DFT calculations.

Organocatalysis and catalyst aggregation: a study using the asymmetric synthesis of benzofuranones as a test reaction.

A common problem encountered in enantioselective organocatalysis is the aggregation of the catalyst, which can result in a relevant decrease of the efficiency and selectivity of the process. In the asymmetric synthesis of chiral benzofuranones, recently reported by us, we noted a remarkable increase of the reaction yield upon the addition of one of the reagents in a portionwise manner rather than in a single addition. We investigated this phenomenon by several experimental techniques such as 1D and 2D NMR experiments, UV-Vis spectroscopy, circular dichroism and dynamic light scattering. In addition, we studied the kinetic profile of this reaction using a simple numerical model and carried out in silico investigations. All these different approaches point to the conclusion that in the reaction medium a supramolecular polymerization/aggregation phenomenon, based on weak interactions, occurs and such a process is promoted by a quinone, which is one of the reagents of the benzofuranone synthesis. The portionwise mode of addition is a known strategy which can improve the performance of many synthetic procedures and this strategy is commonly adopted on account of empirical experience. However, our results provide an explanation, based on a chemical kinetic model, of the reason why the portionwise addition affects in such a dramatic way the yield of the benzofuranone synthesis catalyzed by Cinchona alkaloids.

Quinine-Catalyzed Asymmetric Synthesis of 2,2'-Binaphthol-Type Biaryls under Mild Reaction Conditions.

Simple quinine as an organocatalyst mediates the addition of various naphthols to halogenated quinones to afford non-C2 -symmetrical, axially chiral biaryl products, which are promising compounds as chiral ligands and organocatalysts. The rotational barrier required to have two distinct atropisomers has been evaluated in the products generated from the addition of naphthols to various quinones by means of DFT calculations and HPLC. The use of halogenated quinones as reagents was necessary to have configurationally stable enantiomeric products which can be obtained in good yield and stereoselectivity. These compounds have also been prepared in gram quantities and recrystallized to near enantiopurity.

Cross-Aldol Reaction of Isatin with Acetone Catalyzed by Leucinol: A Mechanistic Investigation.

Comprehensive mechanistic studies on the enantioselective aldol reaction between isatin (1 a) and acetone, catalyzed by L-leucinol (3 a), unraveled that isatin, apart from being a substrate, also plays an active catalytic role. Conversion of the intermediate oxazolidine 4 into the reactive syn-enamine 6, catalyzed by isatin, was identified as the rate-determining step by both the calculations (ΔG(≠) =26.1 kcal mol(-1) for the analogous L-alaninol, 3 b) and the kinetic isotope effect (kH /kD =2.7 observed for the reaction using [D6 ]acetone). The subsequent reaction of the syn-enamine 6 with isatin produces (S)-2 a (calculated ΔG(≠) =11.6 kcal mol(-1) ). The calculations suggest that the overall stereochemistry is controlled by two key events: 1) the isatin-catalyzed formation of the syn-enamine 6, which is thermodynamically favored over its anti-rotamer 7 by 2.3 kcal mol(-1) ; and 2) the high preference of the syn-enamine 6 to produce (S)-2 a on reaction with isatin (1 a) rather than its enantiomer (ΔΔG(≠) =2.6 kcal mol(-1) ).

Kinetic resolution of oxazinones: rational exploration of chemical space through the design of experiments.

The organocatalytic kinetic resolution of 4-substituted oxazinones has been optimised (selectivity factor S up to 98, chiral oxazinone ee values up to 99.6 % (1 a-g) and product ee values up to 90 % (3 a-g)) in a rational way by applying the Design of Experiments (DoE) approach.

Dietary combination of linseed and hazelnut skin as a sustainable strategy to enrich lamb with health promoting fatty acids.

This study investigated the effect of the inclusion of extruded linseed and hazelnut skin on fatty acid (FA) metabolism in finishing lambs. Forty lambs were divided into 4 groups and fed for 60 d with: a conventional cereal-based diet, or the same diet with 8% of extruded linseed, or 15% of hazelnut skin, or 4% of linseed plus 7.5% of hazelnut skin as partial replacement of maize. Dietary treatments did not affect growth performances, carcass traits, and ruminal fermentation. The combined effect of linseed and hazelnut skin enriched the intramuscular fat with health promoting FA. Particularly, increases in α-linolenic acid (3.75-fold), and very long-chain n-3 poly-unsaturated FA (+ 40%) were attributed to the supplementation with linseed, rich in α-linolenic acid. In addition, increases in rumenic (+ 33%), and vaccenic (+ 59%) acids were attributed to hazelnut skin tannins modulating ruminal biohydrogenation and accumulating intermediate metabolites. The simultaneous inclusion of linseed and hazelnut skin can be a profitable strategy for enriching the intramuscular fat of lambs with health promoting FA, without adverse effects on ruminal fermentation and animal performance.

Effects of Bergamot (Citrus bergamia Risso) By-Product on Growth Performance and Meat Quality of Growing Rabbits.

This study aimed to investigate the effects of feeding dried bergamot pulp to rabbits on animal performance and meat quality. Thirty rabbits were assigned to two groups (balanced for body weight, 804.4 ± 2.35 g) and fed individually for 60 days a basal diet (control) or the basal diet in which part of the cereals was replaced with 10% of dried bergamot pulp (DBP). There were no effects of DBP on growth performance, carcass yield, or the crude protein and ether extract composition of meat. The concentrations of α-linolenic acid (C18:3 n-3) and eicosapentaenoic acid (C20:5 n-3) increased in the longissimus thoracis et lumborum muscle (p < 0.01 and p = 0.021, respectively) after integrating dried bergamot pulp into the diet, leading to higher levels of total of ω-3 fatty acids (p < 0.01) compared to the control treatment. The inclusion of dried bergamot pulp improved the oxidative stability in meat (p < 0.001), where TBARS values were lower after 4 and 7 days of refrigerated storage (p < 0.001) in the DBP group than in the control group. Finally, feeding dried bergamot pulp to rabbits improves meat quality without negatively influencing growth performance.

Determination of enantioselectivity and enantiomeric excess by mass spectrometry in the absence of chiral chromatographic separation: an overview.

This review describes the principles and instrumentation for the screening of asymmetric reactions by mass spectrometry. These techniques witnessed a significant advancement in the last few years. Although some of them are still at the proof-of-concept development stage, several applications might be foreseen in the field of combinatorial, high-throughput parallel catalyst screening.

Enantioselective aza-Michael addition of imides by using an integrated strategy involving the synthesis of a family of multifunctional catalysts, usage of multiple catalysis, and rational design of experiment.

A challenging asymmetric reaction (aza-Michael addition of imides to enones) has been optimized through an integrated approach involving the synthesis of a family of organocatalysts, multiple catalysis (usage of additives), and finally with rational exploration of the chemical space by the application of the experiment design.

The Rabe amination after a century: direct addition of N-heterocycles to carbonyl compounds.

A catalytic version of the Rabe electrophilic amination is presented. This kind of reaction was originally employed in 1918 in a key step for the conversion of quinotoxine to quinine. Ketones and α-substituted aldehydes give the corresponding α-aminated carbonyl compounds in moderate yield. α,α-Unsubstituted aldehydes give rise to amino ketones via a novel rearrangement.

Effect of dietary magnolia bark extract supplementation in finishing pigs on the oxidative stability of meat.

BACKGROUND: Magnolia bark extract (MBE) is a natural supplement with antioxidant, anti-inflammatory, and antimicrobial activities. Its properties suggest that the dietary supplementation in livestock could improve the quality of products. Therefore, the aim of this study was to investigate, for the first time, the effect of dietary MBE supplementation (0.33 mg/kg) in finishing pigs on the oxidative stability of meat. Oxidative stability is of paramount importance for pork, as it affects storage, retail, and consumer acceptance. For the purpose, the fatty acid profile, cholesterol, fat-soluble vitamins, antioxidant enzymes (catalase, glutathione peroxidase, and superoxide dismutase), non-enzymatic antioxidant capacity (TEAC, FRAP, and Folin-Ciocalteu assays), color stability, and lipid stability of pork were assessed. RESULTS: Concerning carcass characteristics, dietary MBE did not affect cold carcass yield, but reduced (P = 0.040) the chilling weight loss. The meat from pigs fed MBE had a lower (P = 0.031) lightness index than the control meat. No effect on intramuscular fat, cholesterol, and fatty acid profile was observed. Dietary MBE did not affect the content of vitamin E (α-tocopherol and γ-tocopherol) in pork, whereas it reduced (P = 0.021) the retinol content. The catalase activity was 18% higher (P = 0.008) in the meat from pigs fed MBE compared with the control group. The MBE supplementation reduced (P = 0.039) by 30% the thiobarbituric acid reactive substances (TBARS) in raw pork over 6 d of aerobic refrigerated storage. Instead, no effect on lipid oxidation was observed in cooked pork. Last, the meat from pigs fed MBE reduced Fe3+-ascorbate catalyzed lipid oxidation in muscle homogenates, with a lower (P = 0.034) TBARS value than the control group after 60 min of incubation. CONCLUSIONS: Dietary MBE supplementation in finishing pigs delayed the lipid oxidation in raw meat. This effect was combined with an increased catalase concentration. These results suggest that dietary MBE could have implications for improving the shelf-life of pork.

Influence of Dietary Inclusion of Exhausted Bergamot By-Product in Pigs on Animal Performance, Fatty Acid Profile and Oxidative Stability of Meat and Meat Products.

An investigation was carried out on the effect in pig diet of supplementation with exhausted bergamot by-product, stemming from pharmaceutical industry after extraction of phenolic compounds, on growth performance and on the quality of meat and meat products. Twenty pigs were assigned to two dietary treatments and fed a conventional concentrate (control) or a concentrate including exhausted bergamot by-product at the level of 15% on a DM basis (EB). No significant differences between dietary treatments were found for final weight (p = 0.243), carcass weight (p = 0.679), dry matter intake (p = 0.321). In EB pork, the proportion of docosapentaenoic acid was significantly increased (p < 0.05); it tended to have a greater proportion of n-3 PUFA (p = 0.09), and the n-6/n-3 PUFA ratio was lower in EB treatment (p = 0.01). In salami from EB pigs fed, the proportion of α-linolenic acid and the total n-3 PUFA were higher than in the control group (p < 0.001). In salami, the TBARS value was lower after 5 days of storage (p < 0.001) in the EB group. Therefore, the present results suggest that the inclusion of exhausted bergamot by-product in pig diet resulted in a qualitative improvement of meat and meat products.

Multiple catalysis with two chiral units: an additional dimension for asymmetric synthesis.

This Minireview focuses on asymmetric reactions mediated by two distinct chiral catalysts (chiral multiple catalysis). Initially, this approach appears unconventional, but indeed it allows a fast multidimensional optimization and fine-tuning of the catalytic system required to perform a given transformation. Herein, this emerging concept is presented and its potential applications are highlighted.

Multicomponent asymmetric reactions mediated by proline lithium salt.

The multicomponent reaction between proline lithium salt, 2-cyclohexen-1-one and aliphatic aldehydes affords the 4-alkylidene-2-cyclohexen-1-ones, which are interesting fragrances, and bicyclic amino acids that bear four additional stereocenters, obtained as single stereoisomer.

Synergic asymmetric organocatalysis (SAOc) of Cinchona alkaloids and secondary amines in the synthesis of bicyclo[2.2.2]octan-2-ones.

A synergistic effect between chiral secondary and tertiary amines gives access to bicyclo[2.2.2]octan-2-ones with up to 90% ee and >10 : 1 dr.

Characterization of foxing stains in early twentieth century photographic and paper materials.

The subject of this present work is a group of nine historical pictures shot in Palermo by the Sicilian photographer E. Interguglielmi in 1912. They are nine matte-collodion prints mounted on the original cardboard supports and all of them show foxing stains affecting the paper surface. In order to characterise the chemical composition of the supports and investigate foxing spots, non-destructive and micro-destructive analysis were carried out. X-rays fluorescence (XRF) analysis was used to characterise the elemental composition of all the mounting boards, allowing a comparison between the foxing spots and non-affected areas. Laser-Induced Breakdown Spectroscopy was used to investigate the presence of lower atomic number elements, not detectable by XRF, while SEM imaging allowed the investigation of surface appearance and nature of original paper samples from the cardboards.

Dietary Pomegranate Pulp: Effect on Ewe Milk Quality during Late Lactation.

Pomegranate pulp, a by-product of the pomegranate juice industry, contains a remarkable quantity of bioactive compounds that can favorably affect ruminant metabolism and milk quality. The present paper investigated the effect of dietary pomegranate pulp on milk yield and quality during late lactation in grazing ewes. Twenty Comisana ewes (150 ± 10 days in milk) were subdivided into control (CTRL) and pomegranate (PP) groups. The CTRL group received a corn-barley based concentrate, while the PP group received a concentrate containing 64.8% pomegranate pulp. Dietary treatment did not affect milk yield. CTRL milk had a greater percentage of ß-casein and total casein, while αs1-casein percentage tended to be greater in the PP group. The PP milk showed a lower percentage of 14:0, 16:0, but a greater percentage of vaccenic, rumenic, and α-linolenic acid. Punicic acid was detected only in the PP milk. Total antioxidant capacity (ORAC) was greater in the CTRL milk as compared with the hydrophilic ORAC. Dietary pomegranate pulp increased milk health quality with no detrimental effects on milk yield. Therefore, pomegranate pulp could represent a strategy for improving milk quality and reducing feeding cost during a less profitable phases such as late lactation. Also, dietary pomegranate pulp, as an alternative to traditional feedstuffs, may lower feed-to-food competition in livestock production.

Characterisation of the ruminal fermentation and microbiome in lambs supplemented with hydrolysable and condensed tannins.

This study characterised the response of ruminal fermentation and the rumen microbiome in lambs fed commercial vegetal sources of hydrolysable tannins (HT) and condensed tannins (CT). Forty-four lambs (19.56 ± 2.06 kg) were randomly assigned to either a concentrate diet (CON, n = 8) or CON supplemented with 4% of two HT [chestnut (Castanea sativa, HT-c) and tara (Caesalpinia spinosa, HT-t)] and CT [mimosa (Acacia negra, CT-m) and gambier (Uncaria gambir, CT-g)] extracts (all, n = 9) for 75 days pre-slaughter. Tannin supplementation did not influence ruminal fermentation traits. Quantitative PCR demonstrated that tannins did not affect the absolute abundance of ruminal bacteria or fungi. However, CT-m (-12.8%) and CT-g (-11.5%) significantly reduced the abundance of methanogens, while HT-t (-20.7%) and CT-g (-20.8%) inhibited protozoal abundance. Ribosomal amplicon sequencing revealed that tannins caused changes in the phylogenetic structure of the bacterial and methanogen communities. Tannins inhibited the fibrolytic bacterium, Fibrobacter and tended to suppress the methanogen genus, Methanosphaera. Results demonstrated that both HT and CT sources could impact the ruminal microbiome when supplemented at 4% inclusion level. HT-t, CT-m and CT-g extracts displayed specific antimicrobial activity against methanogens and protozoa without compromising ruminal fermentation in a long-term feeding trial.