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The Zn(II)/UCD-Imphanol-catalyzed highly endo -selective [3 + 2] asymmetric cycloaddition of acyclic enones and azomethine ylides has been developed. Moderate to high yields (up to 94%) with excellent endo / exo selectivities (99 : 1) and enantioselectivities up to 96.5 : 3.5 er were obtained.

The Pd-catalysed decarboxylative asymmetric allylic alkylation (DAAA) has been applied to the enantioselective synthesis of sterically hindered benzofuran-3(2H)-one-derived α-aryl-β-keto esters employing the (R,R)-ANDEN phenyl Trost ligand. A range of substrates were synthesised, employing previously developed aryllead triacetate methodology to install various aryl groups. The resulting α-aryl-α-allyl benzofuran-3(2H)-one DAAA products were obtained in moderate to high yields and in enantioselectivities of up to 96 % ee, with the best results observed for substrates containing a di-ortho-substitution pattern on the aryl ring as well as naphthyl-containing substrates., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

This review article assembles key recent advances in the synthetic chemistry and biology of specialised pro-resolving mediators (SPMs). The major medicinal chemistry developments in the design, synthesis and biological evaluation of synthetic SPM analogues of lipoxins and resolvins have been discussed. These include variations in the top and bottom chains, as well as changes to the triene core, of lipoxins, all changes intended to enhance the metabolic stability whilst retaining or improving biological activity. Similar chemical modifications of resolvins are also discussed. The biological evaluation of these synthetic SPMs is also described in some detail. Original investigations into the biological activity of endogenous SPMs led to the pairing of these ligands with the FPR2/LX receptor, and these results have been challenged in more recent work, leading to conflicting results and views, which are again discussed.

While ion current rectification (ICR) in aprotic solvent has been fundamentally studied, its application in sensing devices lacks exploration. The development of sensors operable in these solvents is highly beneficial to the chemical industry, where polar aprotic solvents, such as acetonitrile, are widely used. Currently, this industry relies on the use of inductively coupled plasma mass spectrometry (ICP-MS) and optical emission spectroscopy (OES) for the detection of metal contamination in organic products. Herein, we present the detection of trace amounts of Pd 2+ and Co 2+ using ion current rectification, in cyclam-functionalized quartz nanopipettes, with tetraethylammonium tetrafluoroborate (TEATFB) in MeCN as supporting electrolyte. This methodology is employed to determine the concentration of Pd in organic products, before and after purification by Celite filtration and column chromatography, obtaining comparable results to ICP-MS within minutes and without complex sample preparation. Finite element simulations are used to support our experimental findings, which reveal that the formation of double-junction diodes in the nanopore enables trace detection of these metals, with a significant response from baseline even at picomolar concentrations.

Herein we report a catalytic enantioselective alkynylation of quinolones. In this reaction, quinolones are silylated to form a quinolinium ion which then undergoes an enantioselective attack by a copper acetylide, templated by ( S , S , R a )-UCD-Phim. This gives alkynylated products (24 examples) in yields of up to 92% and enantioselectivities of up to 97%. This methodology has been applied to the synthesis of two natural products, (+)-cuspareine and (+)-galipinine.

Lipoxins are an important class of pro-resolving mediators that play a crucial role in the resolution of inflammation. Thus, the synthesis of more chemically and metabolically stable synthetic lipoxin analogues is an area of significant interest. Whereas synthetic analogues of lipoxin A 4 (LXA 4 ) have been well studied, analogues of lipoxin B 4 (LXB 4 ) have been the focus of considerably less attention. Herein we report the asymmetric synthesis of a focused library of LXB 4 mimetics in which the triene core of the molecule has been replaced with different aromatic and heteroaromatic rings. The synthesis of each of these analogues was achieved by a general strategy in which the key steps were a Suzuki cross coupling between a common upper chain fragment and an aromatic lower chain, followed by a stereoselective ketone reduction.

Bismacycles featuring a sulfone-bridged scaffold have recently been developed as versatile and convenient electrophilic arylating agents. Here, we report that the exocyclic aryl group, which is ultimately transferred to a nucleophilic coupling partner, can be functionalized through cross-coupling, heteroatom substitutions, oxidations and reductions, and protecting group manipulations. This "postsynthetic modification" approach provides concise and divergent access to complex aryl bismacycles. The utility of the functionalized bismacycles in electrophilic arylation of C-H and O-H bonds is demonstrated.

Asymmetric [3+2] cycloaddition reactions are fascinating and powerful methods for the synthesis of enantioenriched pyrrolidines up to four stereocentres. Pyrrolidines are important compounds for both biology and organocatalytic applications. This review summarizes the most recent advances in the enantioselective synthesis of pyrrolidines by [3+2] cycloadditions of azomethine ylides using metal catalysis. It has been organized by the type of metal catalysis used and further arranged by the complexity nature of dipolarophile. The presentation of each reaction type highlights their advantages and limitations., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Diol scaffolds have been utilized as highly effective catalysts and ligands in a wide range of catalytic asymmetric transformations. For scaffolds to be successful as broadly used motifs, they should be prepared cheaply through facile routes and be easily handled. Herein, the synthesis of a family of planar chiral diols based on a modular and robust three-step route is described, which yields catalytically active diols in >99 % de and >99 % ee, with up to seven different chiral elements. These diols have been characterized by X-ray crystallographic analysis, which provides clear evidence for the likely transition state when applied in the asymmetric hetero-Diels-Alder reaction. Without altering the stereochemistry of the catalyst backbone, it is possible to access both enantiomers of the product by varying the substitution of the catalyst at the α-position., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Herein, we report the design and synthesis of a series of chiral pyrrolidine-substituted ferrocene-derived ligands. The proficiency of this novel structural motif was demonstrated in the Rh-catalyzed asymmetric hydrogenation of dehydroamino acid esters and α-aryl enamides. The products were obtained with full conversions and excellent levels of enantioselectivities of up to >99.9% ee and 97.7% ee, respectively, using a BINOL-substituted phosphine-phosphoaramidite ligand which possesses planar, central, and axial chirality elements.

Lipoxins are important drivers of inflammation resolution, suggesting a potential therapeutic benefit. Bicyclo[1.1.1]pentanes (BCPs) are potential isosteric replacements for arenes and/or alkyl groups within drug candidates. We carried out an asymmetric synthesis of four BCP-containing synthetic lipoxin A 4 mimetics (BCP-sLXms) in which the key steps were a Suzuki coupling, an asymmetric ketone reduction, and a triethylborane-initiated radical bicyclopentylation. These mimetics were screened for their impact on inflammatory responses, and one imidazolo-BCP-sLXm ( 6a ) was found to possess high anti-inflammatory activity.

We present a facile synthetic route toward a novel series of imidazolinyl-[2.2]paracyclophanol (UCD-Imphanol) ligands possessing central and planar chirality. Both sets of diastereomeric ligands were successfully purified by column chromatography. The preliminary application of this family of ligands showed excellent activities in the asymmetric Zn-catalyzed azomethine ylide cycloaddition. Enantioenriched pyrrolidines, in a substrate scope of 20 examples, were accessed in high levels of endo/exo ratios (up to >99/1) and enantioselectivities (up to >99 % ee) with excellent yields (up to 99 %) by using (S,S,S P )-UCD-Imphanol/(S,S,R P )-UCD-Imphanol, respectively., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Failure to resolve inflammation underlies many prevalent pathologies. Recent insights have identified lipid mediators, typified by lipoxins (LXs), as drivers of inflammation resolution, suggesting potential therapeutic benefit. We report the asymmetric preparation of novel quinoxaline-containing synthetic-LXA 4 -mimetics (QNX-sLXms). Eight novel compounds were screened for their impact on inflammatory responses. Structure-activity relationship (SAR) studies showed that ( R )- 6 (also referred to as AT-02-CT) was the most efficacious and potent anti-inflammatory compound of those tested. ( R )- 6 significantly attenuated lipopolysaccharide (LPS)- and tumor-necrosis-factor-α (TNF-α)-induced NF-κB activity in monocytes and vascular smooth muscle cells. The molecular target of ( R )- 6 was investigated. ( R )- 6 activated the endogenous LX receptor formyl peptide receptor 2 (ALX/FPR2). The anti-inflammatory properties of ( R )- 6 were further investigated in vivo in murine models of acute inflammation. Consistent with in vitro observations, ( R )- 6 attenuated inflammatory responses. These results support the therapeutic potential of the lead QNX-sLXm ( R )- 6 in the context of novel inflammatory regulators.

Herein, we report antibacterial and antifungal evaluation of a series of previously prepared (+)-tanikolide analogues. One analogue, (4 S ,6 S )-4-methyltanikolide, displayed promising anti-methicillin-resistant Staphylococcus aureus activity with a MIC of 12.5 µg/mL. Based on the antimicrobial properties of the structurally related (-)-malyngolide, two further analogues (4 S ,6 S )-4-methylmalyngolide and (4 R ,6 S )-4-methylmalyngolide bearing a shortened n -nonyl alkyl side chain were prepared in the present study using a ZrCl 4 -catalysed deprotection/cyclisation as the key step in their asymmetric synthesis. When these were tested for activity against anti-methicillin-resistant Staphylococcus aureus , the MIC increased to 50 µg/mL.

The chiral oxazoline motif is present in many ligands that have been extensively applied in a series of important metal-catalyzed enantioselective reactions. This Review aims to provide a comprehensive overview of the most significant applications of oxazoline-containing ligands reported in the literature starting from 2009 until the end of 2018. The ligands are classified not by the reaction to which their metal complexes have been applied but by the nature of the denticity, chirality, and donor atoms involved. As a result, the continued development of ligand architectural design from mono(oxazolines), to bis(oxazolines), to tris(oxazolines) and tetra(oxazolines) and variations thereof can be more easily monitored by the reader. In addition, the key transition states of selected asymmetric transformations will be given to illustrate the features that give rise to high levels of asymmetric induction. As a further aid to the reader, we summarize the majority of schemes with representative examples that highlight the variation in % yields and % ee s for carefully selected substrates. This Review should be of particular interest to the experts in the field but also serve as a useful starting point to new researchers in this area. It is hoped that this Review will stimulate both the development/design of new ligands and their applications in novel metal-catalyzed asymmetric transformations.

This Review compiles the evolution, mechanistic understanding, and more recent advances in enantioselective Pd-catalyzed allylic substitution and decarboxylative and oxidative allylic substitutions. For each reaction, the catalytic data, as well as examples of their application to the synthesis of more complex molecules, are collected. Sections in which we discuss key mechanistic aspects for high selectivity and a comparison with other metals (with advantages and disadvantages) are also included. For Pd-catalyzed asymmetric allylic substitution, the catalytic data are grouped according to the type of nucleophile employed. Because of the prominent position of the use of stabilized carbon nucleophiles and heteronucleophiles, many chiral ligands have been developed. To better compare the results, they are presented grouped by ligand types. Pd-catalyzed asymmetric decarboxylative reactions are mainly promoted by PHOX or Trost ligands, which justifies organizing this section in chronological order. For asymmetric oxidative allylic substitution the results are grouped according to the type of nucleophile used.

Oxa- and azabicyclic alkenes can be readily activated by transition-metal complexes with facial selectivity, because of the intrinsic reactivity of strained bicyclic structures. Synthetically, these compounds are important synthons that offer an important platform for the construction of biologically/medicinally significant compounds with two or more stereocenters. This Review comprehensively compiles the diverse catalytic processes involving the enantioselective transformations of oxa- and azabicyclic alkenes. It has been organized according to reaction type, including asymmetric ring opening (ARO) reactions, hydrofunctionalizations, cycloadditions and C-H activation reactions. The ARO section has been subdivided based on the type of nucleophiles employed, and further subdivided based on the metal used, with a separate topic dedicated to asymmetric ring-opening metathesis. Lastly, the presentation of each method/group of reactions is accompanied by concise discussions on their advantages and limitations.

The resolution of inflammation is a dynamic process, characterized by the biosynthesis of pro-resolving mediators, including the lipid Lipoxin A4 (LXA 4 ). LXA 4 acts on the N-formyl peptide receptor 2 (FPR2/ALX) to mediate anti-inflammatory and pro-resolving effects. In order to exploit the therapeutic potential of endogenous LXA 4 in the context of inflammation we have recently developed synthetic LXA 4 mimetics (sLXms) including a dimethyl-imidazole-containing FPR2/ALX agonist designated AT-01-KG. Here, we have investigated the effect of treatment with AT-01-KG in established models of articular inflammation. In a model of gout, mice were injected with MSU crystals and treated with AT-01-KG at the peak of inflammatory response. The treatment decreased the number of neutrophils in the knee exudate, an effect which was accompanied by low levels of myeloperoxidase, CXCL1 and IL-1β in periarticular tissue. AT-01-KG treatment led to reduced tissue damage and hypernociception. The effects of AT-01-KG on neutrophil accumulation were not observed in MSU treated FPR2/3 -/- mice. Importantly, AT-01-KG induced resolution of articular inflammation by increasing neutrophil apoptosis and subsequent efficient efferocytosis. In a model of antigen-induced arthritis, AT-01-KG treatment also attenuated inflammatory responses. These data suggest that AT-01-KG may be a potential new therapy for neutrophilic inflammation of the joints., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

With the ever-present need for novel asymmetric methodologies in organic synthesis to allow chemists to access enantiopure compounds, so too is there a need for new chiral ligands and organocatalysts to affect these transformations. Due to the unique properties of ferrocene and its derivatives, ferrocenyl compounds are unsurprisingly considered privileged structures in asymmetric catalysis. The versatility of the ferrocene moiety gives rise to a vast range of diverse ligand and catalyst motifs which are successful in broad ranges of mechanistically distinct reactions. This review details recent advances in the application of ferrocenyl mono-, bi- and tridentate-ligands and ferrocene-derived organocatalysts in asymmetric catalysis. Given the necessity for the development of new approaches to expand the scope of ferrocenyl ligands and catalysts, this review also illustrates the development of elegant and novel methodologies for the synthesis of ferrocenyl compounds.

The design and first enantioselective synthesis of a series of chiral ferrocifens and ferrociphenols was realised by enantioselective palladium-catalysed intramolecular direct C-H bond activation followed by McMurry coupling. Biological evaluation revealed moderate anticancer activities on breast cancer cells and evidence of chiral discrimination between enantiomers. Treatment of the novel ferrocifens with Ag 2 O revealed that these systems are unable to form a neutral quinone methide, yet still demonstrate marked antiproliferative properties against both the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 cell lines. This bioactivity arises from two mechanisms: Fenton-type chemistry and the anti-estrogenic activity associated with the tamoxifen-like structure., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The propargyl electrophile has proven to be a versatile reactant when coupled with palladium catalysis. Its versatility is owed to the several reaction pathways that the palladium-propargyl intermediate can proceed by, and the outcome can be predictably controlled by varying several factors. The tunable nature of the propargyl electrophile along with its versatility are detailed herein. The initial reports for each of the pathways are highlighted along with a discussion of more recent developments in the field.

α-Aryl oxindoles are accessed from isatin via a two-step procedure involving a phospha-Brook rearrangement and a Friedel-Crafts alkylation in a one-pot procedure. The use of 1,1,1,3,3,3-hexafluoro-2-propanol as solvent significantly extended the reaction substrate scope to include relatively less electron-rich arenes including benzene. This new alkylation method is fast and straightforward and allows for the direct introduction of the oxindole moiety onto a range of aromatic compounds including phenols. Additionally, the application of arylated products was shown in decarboxylative asymmetric allylation and protonation.

A catalytic method to synthesize 1,3,-dienes from propargylic precursors is reported. This palladium-catalyzed carbon-nitrogen bond-forming reaction furnishes 2-amino-1,3-dienes in excellent yields (up to 98%) and shows a broad tolerance to functional group diversity. The reaction has been demonstrated for over 30 amine substrates, including anilines and indoles, and proceeds under mild neutral conditions. The resulting 1,3-dienes are of great synthetic interest because of their further reaction potential.

Asymmetric A3 coupling has emerged as an important class of reactions to synthesise chiral propargylamines. In this tutorial review, an up to date progress of this reaction, with significant recent advancements in terms of ligand development, is presented. Applications of asymmetric A3 coupling in natural product synthesis and in tandem processes are also discussed.

A method for the construction of chiral quaternary stereocenters has been accomplished via decarboxylative palladium-catalyzed propargylic alkylation. Both pressurized sealed tubes and microwave irradiation have proven successful for this transformation, yet despite these forcing conditions a range of α-aryl,α-propargyl, and α-alkyl,α-propargyl containing all-carbon quaternary products have been synthesized in good yields and high enantioselectivities (up to 92:8 er). While palladium-catalyzed decarboxylative allylic alkylation has been well studied, this work represents the furthest advancement for the propargylic variant to date.

A practical application of the UCD-PHIM ligand in the copper-catalyzed asymmetric A3 coupling is reported for aromatic, alkenylic, and alkynylic aldehydes under mild reaction conditions, low catalytic loading, and at ambient temperature. A broad range of aldehydes, secondary amines with a cheaper ethyne equivalent, 2-methyl-3-butyn-2-ol, was explored and enantioselectivities of up to 99% ee were obtained. The importance of (i) axial chirality and central chirality, (ii) imidazoline moiety over oxazoline moiety, and (iii) phosphine unit is investigated for A3 coupling by synthesizing and testing a series of related ligands to UCD-PHIM.

Decarboxylative asymmetric protonation (DAP) is a mild and efficient synthetic tool for the catalytic asymmetric formation of tertiary stereocenters adjacent to a carbonyl group. The development of the methodology from the initial racemic report to recent asymmetric examples is summarized. The discovery of an enantiodivergent Pd-catalyzed DAP, in which the choice of the achiral proton source determines the stereochemical outcome, is highlighted. Furthermore, the mechanism of Pd-catalyzed DAP, investigated since the initial report, is also discussed.

Lipoxins (LXs) are endogenously generated eicosanoids with potent bio-actions consistent with attenuation of inflammation. The costly synthesis and metabolic instability of LXs may limit their therapeutic potential. Here we report the synthesis and characterization of novel imidazole-/oxazole-containing synthetic-LX-mimetics (sLXms). The key steps of asymmetric synthesis of putative sLXms include a Suzuki reaction and an asymmetric ketone reduction. The effect of the novel compounds on inflammatory responses was assessed using a human monocyte cell line stably expressing a Nuclear Factor Kappa B (NFkB) reporter gene, by investigating downstream cytokine secretion. The potential interaction of the imidazoles/oxazoles with the molecular target of LXs, i.e. G-protein coupled receptor (GPCR) Formyl Peptide Receptor 2 (ALX/FPR2) was investigated using a cell system where ALX/FPR2 is coupled to the Gα q subunit and receptor interaction determined by mobilisation of intracellular calcium. In vivo anti-inflammatory effects were assessed using a murine zymosan-induced peritonitis model. Overall, structure-activity relationship (SAR) studies demonstrated that the (R)-epimer of 6C-dimethyl-imidazole (1R)-11 was the most potent and efficient anti-inflammatory agent, among the ten compounds tested. This molecule significantly attenuated LPS-induced NFkB activity, reduced the release of several pro-inflammatory cytokines and inhibited peritonitis-associated neutrophil infiltration in vivo. The underlying mechanism for those actions appeared to be through FPR2 activation. These data support the therapeutic potential of imidazole-containing sLXms in the context of novel inflammatory regulators., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Increasing evidence points to the fact that defects in the resolution of inflammatory pathways predisposes individuals to the development of chronic inflammatory diseases, including diabetic complications such as accelerated atherosclerosis. The resolution of inflammation is dynamically regulated by the production of endogenous modulators of inflammation, including lipoxin A4 (LXA 4 ). Here, we explored the therapeutic potential of LXA 4 and a synthetic LX analog (Benzo-LXA 4 ) to modulate diabetic complications in the streptozotocin-induced diabetic ApoE -/- mouse and in human carotid plaque tissue ex vivo. The development of diabetes-induced aortic plaques and inflammatory responses of aortic tissue, including the expression of vcam-1 , mcp-1 , il-6 , and il-1β , was significantly attenuated by both LXA 4 and Benzo-LXA 4 in diabetic ApoE -/- mice. Importantly, in mice with established atherosclerosis, treatment with LXs for a 6-week period, initiated 10 weeks after diabetes onset, led to a significant reduction in aortic arch plaque development (19.22 ± 2.01% [diabetic]; 12.67 ± 1.68% [diabetic + LXA 4 ]; 13.19 ± 1.97% [diabetic + Benzo-LXA 4 ]). Secretome profiling of human carotid plaque explants treated with LXs indicated changes to proinflammatory cytokine release, including tumor necrosis factor-α and interleukin-1β. LXs also inhibited platelet-derived growth factor-stimulated vascular smooth muscle cell proliferation and transmigration and endothelial cell inflammation. These data suggest that LXs may have therapeutic potential in the context of diabetes-associated vascular complications., (© 2018 by the American Diabetes Association.)

Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation. Methods We investigated the potential of LXA 4 and a synthetic LX analog (Benzo-LXA 4 ) as therapeutics in a murine model of diabetic kidney disease, ApoE -/- mice treated with streptozotocin. Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10 weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P ≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renal proinflammatory/profibrotic signals (TNF- α , IL-1 β , NF- κ B). In diabetic mice, we identified 20 and 51 transcripts regulated by LXA 4 and Benzo-LXA 4 , respectively, and pathway analysis identified established (TGF- β 1, PDGF, TNF- α , NF- κ B) and novel (early growth response-1 [EGR-1]) networks activated in diabetes and regulated by LXs. In cultured human renal epithelial cells, treatment with LXs attenuated TNF- α -driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF- β 1 and TNF- α Conclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation., (Copyright © 2018 by the American Society of Nephrology.)

The highly enantioselective synthesis of sterically hindered α-allyl-α-aryl oxindoles possessing an all-carbon quaternary stereocenter at the oxindole 3-position has been developed. The key step in the synthetic route employed was a novel one-pot, two-step synthesis of α-aryl-β-amido allyl ester substituted oxindoles in good yields of 41-75% (13 examples) by interception of an unstable allyl ester intermediate through reaction with aryllead triacetate reagents. Pd-Catalyzed decarboxylative asymmetric allylic alkylation (DAAA) was optimized with 2,4,6-trimethoxyphenyl as the aryl-containing substrate. A screen of chiral P,N- and P,P-based ligands showed that the ANDEN-phenyl Trost ligand was the most effective, affording the corresponding α-allyl-α-aryl oxindole product in 96% yield and 99% ee. A substrate scope of a further 12 α-aryl-β-amido allyl ester substituted oxindoles showed that products containing bulky di-ortho-methoxy substituted arenes and naphthyl groups were formed in very high ee's (94-98%), whereas those lacking this substitution pattern were formed in more moderate levels of enantioselectivities (56-63% ee). Surprisingly, the 2,6-dimethylphenyl-substituted substrate afforded the O-allylated product in contrast to the expected C-allylated product. A crystal structure was obtained of the 2,4,6-trimethoxyphenyl-substituted α-allyl-α-aryl oxindole product which enabled us to identify the absolute stereochemistry of the quaternary stereocenter formed. A plausible explanation to rationalise the sense of enantioselection observed in these DAAA transformations is also proposed.

Herein, we describe a study into the scope and origin of an enantiodivergent effect in the palladium-catalyzed decarboxylative asymmetric protonation. By switching the achiral proton source, both enantiomers of a series of tertiary α-aryl-1-indanones are readily accessed from the corresponding α-aryl-β-keto allyl esters. In this example of dual stereocontrol, enantioselectivities up to 94% (S) and 92% (R) were achieved using Meldrum's acid and formic acid, respectively. In an attempt to rationalize this switch in absolute configuration an investigation of the ambiguous mechanism of the decarboxylative asymmetric protonation was conducted. A novel catalytic cycle for the reaction with formic acid is proposed and subjected to a variety of experimental studies.

Excess blood vessel growth contributes to the pathology of metastatic cancers and age-related retinopathies. Despite development of improved treatments, these conditions are associated with high economic costs and drug resistance. Bevacizumab (Avastin®), a monoclonal antibody against vascular endothelial growth factor (VEGF), is used clinically to treat certain types of metastatic cancers. Unfortunately, many patients do not respond or inevitably become resistant to bevacizumab, highlighting the need for more effective antiangiogenic drugs with novel mechanisms of action. Previous studies discovered quininib, an antiangiogenic small molecule antagonist of cysteinyl leukotriene receptors 1 and 2 (CysLT 1 and CysLT 2 ). Here, we screened a series of quininib analogues and identified a more potent antiangiogenic novel chemical entity (IUPAC name ( E )-2-(2-quinolin-2-yl-vinyl)-benzene-1,4-diol HCl) hereafter designated Q8. Q8 inhibits developmental angiogenesis in Tg( fli1 :EGFP) zebrafish and inhibits human microvascular endothelial cell (HMEC-1) proliferation, tubule formation, and migration. Q8 elicits antiangiogenic effects in a VEGF-independent in vitro model of angiogenesis and exerts an additive antiangiogenic response with the anti-VEGF biologic bevacizumab. Cell-based receptor binding assays confirm that Q8 is a CysLT 1 antagonist and is sufficient to reduce cellular levels of NF-κB and calpain-2 and secreted levels of the proangiogenic proteins intercellular adhesion molecule-1, vascular cell adhesion protein-1, and VEGF. Distinct reductions of VEGF by bevacizumab explain the additive antiangiogenic effects observed in combination with Q8. In summary, Q8 is a more effective antiangiogenic drug compared with quininib. The VEGF-independent activity coupled with the additive antiangiogenic response observed in combination with bevacizumab demonstrates that Q8 offers an alternative therapeutic strategy to combat resistance associated with conventional anti-VEGF therapies., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

An enantioselective Pd-catalyzed DAAA of α-aryl-β-oxo esters has been developed employing the (R,R)-ANDEN-phenyl Trost ligand to prepare a series of α-aryl-α-allyldihydrocoumarins and 3-isochromanones. A variety of aryl groups were successfully employed to afford the dihydrocoumarin and 3-isochromanone products in high yields up to 95% and ee's up to 96%. Under these conditions, substrates containing di- and mono-ortho-substituted aryl groups gave the highest levels of enantioselectivities. This work represents the first example of the enantioselective preparation of all-carbon quaternary α-allyl-α-aryl dihydrocoumarins and 3-isochromanones.

Readily available chiral diol scaffolds are useful as sources of chirality for asymmetric synthesis, however, few such scaffolds are readily available in enantiopure form. Reported herein is a cheap and modular synthesis of a novel family of chiral ferrocenyl diols in excellent yields with excellent enantio- and diastereoselectivity (>99 % ee and 99 % de). These diols possess not only planar and central chirality, but also axial chirality around the central iron atom. Characterization of these diols by X-ray crystallography revealed intra- and intermolecular hydrogen-bond networks depending on substitution at the carbinol positions. The potential of these diols as catalysts was subsequently demonstrated in an asymmetric hetero-Diels-Alder reaction which provided cycloadducts in up to 84 % yield with ee values ranging from -92 to +72 %., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A highly enantioselective Pd-catalysed decarboxylative asymmetric allylic alkylation of cyclopentanone derived α-aryl-β-keto esters employing the (R,R)-ANDEN-phenyl Trost ligand has been developed. The product (S)-α-allyl-α-arylcyclopentanones were obtained in excellent yields and enantioselectivities (up to >99.9 % ee). This represents one of the most highly enantioselective formations of an all-carbon quaternary stereogenic center reported to date. This reaction was demonstrated on a 4.0 mmol scale without any deterioration of enantioselectivity and was exploited as the key enantioselective transformation in an asymmetric formal synthesis of the natural product (+)-tanikolide., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The synthesis of a range of novel gem-disubstituted and electronically varied thiophene-oxazoline (HetPHOX) ligands and ferrocene-oxazoline (FcPHOX) ligands and their application in the Pd-catalyzed intermolecular asymmetric Heck reaction (IAH) is described. These investigations show that gem-disubstitution of i-Pr-PHOX-type ligands can lead to effective and cost-efficient alternatives to the corresponding t-Bu-PHOX systems. The Pd complexes of these ligands were very effective in the IAH, providing phenylated products in up to 100% conversion with up to 97% ee.

The synthesis of a range of novel gem-disubstituted ferrocene-oxazoline ligands and their application in both the asymmetric ethyl- and phenylzinc additions to aldehydes is reported. These studies reveal that gem-disubstitution of i-Pr-containing ferrocene oxazoline ligands results in increased enantioselectivity compared to their unsubstituted counterparts. Utilizing zinc catalysis, these ligands provided a wide range of secondary alcohols in yields of up to 93% with ee's of up to >99%. An interesting crystal structure of a ferrocene oxide-lithium tetramer showing lithium-nitrogen coordination in the solid state is also presented.

A series of eight novel bis(oxazoline) ligands incorporating gem-disubstitution on one of the oxazoline rings were prepared from (S)-valine. These ligands are designed as a cost-effective alternative to similar ligands possessing an oxazolinyl C(5)-tert-butyl group derived from expensive (S)-tert-leucine. Four of the ligands possess a C(4)-gem-dimethyl group and four a C(4)-gem-diphenyl group adjacent to the C(5)-isopropyl substituent. Zinc complexes of ligands 11a-h, along with non-C(4)-gem-disubstituted analogues 1a-g, were effective in the Friedel-Crafts alkylation of both indole (up to 74% ee) and 2-methoxyfuran (up to 95% ee) with a series of nitroalkenes. Three of the ligands (11a-c), an iron dichloride complex of ligand 11d and two zinc dichloride complexes, were characterized by X-ray crystallography, one with ligand 11d and the second a bis-tert-butyl-substituted N-methylamine ligand. A direct comparison of the latter structures clearly illustrates the gem-dimethyl effect.

The role of inflammation in obesity-related pathologies is well established. We investigated the therapeutic potential of LipoxinA4 (LXA4:5(S),6(R),15(S)-trihydroxy-7E,9E,11Z,13E,-eicosatetraenoic acid) and a synthetic 15(R)-Benzo-LXA4-analog as interventions in a 3-month high-fat diet (HFD; 60% fat)-induced obesity model. Obesity caused distinct pathologies, including impaired glucose tolerance, adipose inflammation, fatty liver, and chronic kidney disease (CKD). Lipoxins (LXs) attenuated obesity-induced CKD, reducing glomerular expansion, mesangial matrix, and urinary H2O2. Furthermore, LXA4 reduced liver weight, serum alanine-aminotransferase, and hepatic triglycerides. LXA4 decreased obesity-induced adipose inflammation, attenuating TNF-α and CD11c(+) M1-macrophages (MΦs), while restoring CD206(+) M2-MΦs and increasing Annexin-A1. LXs did not affect renal or hepatic MΦs, suggesting protection occurred via attenuation of adipose inflammation. LXs restored adipose expression of autophagy markers LC3-II and p62. LX-mediated protection was demonstrable in adiponectin(-/-) mice, suggesting that the mechanism was adiponectin independent. In conclusion, LXs protect against obesity-induced systemic disease, and these data support a novel therapeutic paradigm for treating obesity and associated pathologies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A modular six-step asymmetric synthesis of two naturally occurring and three non-natural isoflavanones containing tertiary α-aryl carbonyls is reported. This synthetic route, utilising a Pd-catalyzed decarboxylative asymmetric protonation, produces isoflavanones in excellent enantioselectivities from 76-97 %. A switch in the sense of stereoinduction was observed when different H(+) sources were employed, showing the first example of dual stereocontrol in an asymmetric protonation reaction. The first enantioselective synthesis of the naturally occurring isoflavanones sativanone and 3-o-methylviolanone has been accomplished., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The catalytic asymmetric synthesis of a series of tertiary α-aryl cyclopentanones and cyclohexanones has been accomplished via a Pd-catalyzed decarboxylative protonation of the corresponding α-aryl-β-keto allyl esters. Enantioselectivities of up to 92% ee and 74% ee were achieved for cyclopentanone and cyclohexanone substrates, respectively. The route described gives access to these important structural motifs in moderate to high levels of enantioselectivity. In particular, this is only the second direct approach for the preparation of tertiary α-aryl cyclopentanones. The synthetic approach allows for simple modification of the aryl group. Significantly, substrates containing sterically hindered aryl groups gave the highest levels of enantioselectivity, and these aryl groups were readily installed by a Pb-mediated arylation of a β-keto allyl ester.

Among the range of P,N-chelating ligands that have been employed in asymmetric catalysis, those relying on atropisomerism for the stability of individual enantiomers form a definable class. These APN (atropos P,N) ligands require a specific type of biaryl, with one component carrying a pendant phosphine unit, most commonly diaryl substituted, and the other bearing an sp(2)-nitrogen adjacent to the biaryl link. When substituents in the biaryl inhibit rotation about the linking bond, stable nonracemizing six-membered ring chelates can be formed. This Perspective relates the background to the initial synthesis in 1993 of Quinap, the original member of the series, and initial observations on its effectiveness in asymmetric catalysis. The current state of play in development of syntheses of this and other members of the APN ligand family is assessed, and their applications in asymmetric catalysis are presented. These include hydroboration and diboration of alkenes, 1,3-dipolar cycloadditions, alkynylation of iminium salts in a three-component (A(3)) condensation, and conjugate additions of Cu acetylides.

P,N ligands are an important class of ligands for asymmetric catalysis. In this tutorial review an up to date account of recent applications of these ligands in asymmetric catalysis is presented. A special focus is given to newer classes of ligands and the application of more established P,N ligands in novel reactions.

All X-ray structures of PN ligands forming 6-ring metal complex chelates have been retrieved from the CDS database, and those lacking chelate chirality filtered out. Many of the remainder fit naturally into four main families (PPFA, FcPhox, Phox and Quinap), which have been widely applied to asymmetric catalysis in diverse ways. It is known through experimental observation that certain of these ligand structures are more effective for specific classes of reaction but there has been little by way of explanation for their divergent behaviour. In this paper we examine the wide variation of conformations within individual families of PN complexes in the solid state, establish common features, and make cross-correlations with their effectiveness in specific catalytic asymmetric reactions. The extent of rigidity in the chelate varies widely and yet flexible complexes may be extremely effective in asymmetric catalysis. These observations emphasise the importance of induced fit between reactants and catalyst and militate against over-reliance on rigid lock-and-key models.

1-(3,4-Dihydroxyphenyl) ethanol was produced biocatalytically for the first time using mushroom tyrosinase. 4-Ethylphenol at 1 mM was consumed over 12 min giving 0.23 mM 4-ethylcatechol and 0.36 mM (R/S)-1-(3,4-dihydroxyphenyl) ethanol (ee 0.5 %). Mushroom tyrosinase consumed 4-ethylphenol at 6.7 μmol min(-1) mg protein(-1) while the rates of formation of 4-ethylcatechol and 1-(3,4-dihydroxyphenyl) ethanol were 1.1 and 1.9 μmol min(-1) mg protein(-1). Addition of the ascorbic acid, as a reducing agent to biotransformation reactions, increased 4-ethylcatechol formation by 340 %. However, accumulation of 1-(3,4-dihydroxyphenyl) ethanol was not observed in the presence of ascorbic acid. While the 1-(3,4-dihydroxyphenyl) ethanol was racemic, it is the first chiral product produced by tyrosinase starting from a non-chiral substrate.

Lipoxins, which are endogenously produced lipid mediators, promote the resolution of inflammation, and may inhibit fibrosis, suggesting a possible role in modulating renal disease. Here, lipoxin A4 (LXA4) attenuated TGF-β1-induced expression of fibronectin, N-cadherin, thrombospondin, and the notch ligand jagged-1 in cultured human proximal tubular epithelial (HK-2) cells through a mechanism involving upregulation of the microRNA let-7c. Conversely, TGF-β1 suppressed expression of let-7c. In cells pretreated with LXA4, upregulation of let-7c persisted despite subsequent stimulation with TGF-β1. In the unilateral ureteral obstruction model of renal fibrosis, let-7c upregulation was induced by administering an LXA4 analog. Bioinformatic analysis suggested that targets of let-7c include several members of the TGF-β1 signaling pathway, including the TGF-β receptor type 1. Consistent with this, LXA4-induced upregulation of let-7c inhibited both the expression of TGF-β receptor type 1 and the response to TGF-β1. Overexpression of let-7c mimicked the antifibrotic effects of LXA4 in renal epithelia; conversely, anti-miR directed against let-7c attenuated the effects of LXA4. Finally, we observed that several let-7c target genes were upregulated in fibrotic human renal biopsies compared with controls. In conclusion, these results suggest that LXA4-mediated upregulation of let-7c suppresses TGF-β1-induced fibrosis and that expression of let-7c targets is dysregulated in human renal fibrosis.

A method for the catalytic asymmetric α-arylation of ketones bearing very sterically hindered aryl rings has been developed. This reaction occurs under mild conditions, in short reaction times and has been applied to the first catalytic asymmetric synthesis of isoflavanones.

Leukotriene B(3) and B(4) are part of an important class of signaling molecules - the leukotrienes, implicated in the inflammation process. Their pro-inflammatory effects have been widely recognized for almost three decades but it is only recently that their benefit in host defense has begun to be acknowledged. Their use as therapeutic agents is, unfortunately, limited by rapid metabolism. However, over the past 25 years, a number of stable leukotriene B(3) and B(4) analogues have been produced. In this review, we examine their medicinal chemistry and biological evaluation.