Stability and reactivity of alkylidene dihydropyridines.

Alkylidene dihydropyridines (ADHPs) are electron-rich nucleophilic intermediates that can be readily prepared by dearomatization of 4-alkylpyridines using chloroformate reagents and mild base. Their stability and reactivity can be tuned with the chloroformate reagent used as evidenced by NMR chemical shifts and oxidation potentials. ADHPs prepared with ethyl, allyl and trichloroethyl chloroformate undergo decomposition under an oxygen atmosphere at different rates (ethyl > allyl > trichloroethyl), predominantly to the corresponding 4-acylpyridine. The ADHPs derived from benzyl chloroformate are stable towards oxidation, and those derived from phenyl chloroformate hydrolyze readily.

Enantioselective Synthesis of 7(S)-Hydroxydocosahexaenoic Acid, a Possible Endogenous Ligand for PPARα.

We report the first total synthesis of the polyunsaturated fatty acid 7-hydroxydocosahexaenoic acid (7-HDHA) in racemic form and the enantioselective synthesis of 7-(S)-HDHA. Both syntheses follow a convergent approach that unites the C1-C9 and C10-C22 fragments using Sonogashira coupling and Boland reduction as key steps. These syntheses enabled the unambiguous characterization of this natural product for the first time and helped establish 7(S)-HDHA as a possible endogenous ligand for peroxisome proliferator-activated receptor alpha.

Convenient Access to meta-Substituted Phenols by Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling and Oxidation.

We report a new approach to the synthesis of meta-substituted phenols in which a single palladium catalyst accomplishes a Suzuki-Miyaura cross-coupling between a ß-chlorocyclohexenone and an arylboronic acid, and oxidation of the resulting cyclohexenone to the corresponding phenol upon introduction of a terminal oxidant and electron transfer mediator. Notably, this method also allows ready access to ortho, meta-disubstituted phenols, sterically congested biaryl phenols, and more highly substituted phenols.

Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice.

AIMS/HYPOTHESIS: Liver X receptors (LXRs) α and ß are nuclear hormone receptors that are widely expressed in the kidney. They promote cholesterol efflux from cells and inhibit inflammatory responses by regulating gene transcription. Here, we hypothesised (1) that LXR deficiency would promote renal decline in a mouse model of diabetes by accelerating intraglomerular cholesterol accumulation and, conversely, (2) that LXR agonism would attenuate renal decline in diabetes. METHODS: Diabetes was induced with streptozotocin (STZ) and maintained for 14 weeks in Lxrα/ß (+/+) (Lxrα, also known as Nr1h3; Lxrß, also known as Nr1h2) and Lxrα/ß (-/-) mice. In addition, STZ-injected DBA/2J mice were treated with vehicle or the LXR agonist N,N-dimethyl-hydroxycholenamide (DMHCA) (80 mg/kg daily) for 10 weeks. To determine the role of cholesterol in diabetic nephropathy (DN), mice were placed on a Western diet after hyperglycaemia developed. RESULTS: Even in the absence of diabetes, Lxrα/ß (-/-) mice exhibited a tenfold increase in the albumin:creatinine ratio and a 40-fold increase in glomerular lipid accumulation compared with Lxrα/ß (+/+) mice. When challenged with diabetes, Lxrα/ß (-/-) mice showed accelerated mesangial matrix expansion and glomerular lipid accumulation, with upregulation of inflammatory and oxidative stress markers. In the DN-sensitive STZ DBA/2J mouse model, DMHCA treatment significantly decreased albumin and nephrin excretion (by 50% each), glomerular lipids and plasma triacylglycerol (by 70%) and cholesterol (by 48%); it also decreased kidney inflammatory and oxidative stress markers compared with vehicle-treated mice. CONCLUSIONS/INTERPRETATION: These data support the idea that LXR plays an important role in the normal and diabetic kidney, while showing that LXR, through its inhibitory effect on inflammation and cholesterol accumulation in glomeruli, could also be a novel therapeutic target for DN.

Mild and catalytic electrocyclizations of heptatrienyl anions.

We report the synthesis of functionalized cycloheptanes by thermal electrocyclization of heptatrienyl anions under mild conditions. In addition, we disclose the first examples of this electrocyclization manifold conducted under catalytic conditions. Previously, electrocyclization of heptatrienyl systems required formation of anions with a strong base, resulting in limited functional group compatibility. We demonstrate that polarization of heptatrienyl anions using strategically positioned electron-withdrawing groups lowers the energy landscape of the reaction by stabilizing both the acyclic heptatrienyl anion and cycloheptadienyl product. Divergent reactivity is observed between aliphatic and aromatic substrates, with the latter requiring only catalytic amounts of base for complete conversion. This can be rationalized by the relative stability of the acyclic and cyclic anions and their ability to participate in a chain reaction process.

Measuring kinetic isotope effects in enzyme reactions using time-resolved electrospray mass spectrometry.

Kinetic isotope effect (KIE) measurements are a powerful tool for studying enzyme mechanisms; they can provide insights into microscopic catalytic processes and even structural constraints for transition states. However, KIEs have not come into widespread use in enzymology, due in large part to the requirement for prohibitively cumbersome experimental procedures and daunting analytical frameworks. In this work, we introduce time-resolved electrospray ionization mass spectrometry (TRESI-MS) as a straightforward, precise, and inexpensive method for measuring KIEs. Neither radioisotopes nor large amounts of material are needed and kinetic measurements for isotopically "labeled" and "unlabeled" species are acquired simultaneously in a single "competitive" assay. The approach is demonstrated first using a relatively large isotope effect associated with yeast alcohol dehydrogenase (YADH) catalyzed oxidation of ethanol. The measured macroscopic KIE of 2.19 ± 0.05 is consistent with comparable measurements in the literature but cannot be interpreted in a way that provides insights into isotope effects in individual microscopic steps. To demonstrate the ability of TRESI-MS to directly measure intrinsic KIEs and to characterize the precision of the technique, we measure a much smaller (12)C/(13)C KIE associated specifically with presteady state acylation of chymotrypsin during hydrolysis of an ester substrate.

Mild Installation of Piperidines on 4-Alkylpyridines.

We report a mild method for the synthesis of scaffolds bearing 4-pyridine and 4-piperidine moieties joined by a substituted methylene group. The method exploits the latent nucleophilicity of 4-alkylpyridines and the inherent electrophilicity of pyridines. 4-Alkylpyridines are transformed into nucleophilic alkylidene dihydropyridines (ADHPs) through a soft enolization approach using triethyl amine and chloroformate reagents. HCl is used to promote the addition of ADHPs to pyridine, yielding an adduct bearing pyridine and protected dihydropyridine fragments. Transfer hydrogenation delivers the desired compounds in good yields.

Soft Fluorination of 4-Alkylpyridines.

We report the mild and selective mono- and difluorination of 4-alkylpyridines. The process involves soft-dearomatization of pyridines to the corresponding alkylidene dihydropyridines and treatment with Selectfluor. The reaction tolerates a broad range of functional groups, including those bearing acidic and weak C-H bonds. In addition, selective fluorination of 4-alkylpyridines attached to 2-alkylpyridines and 2-alkylpyrimidines can be achieved in good yields, but a 4-alkylpyridine tethered to a 4-alkylpyrimidine is fluorinated at both heterobenzylic positions.

Rain Cover and Netting Materials Differentially Affect Fruit Yield and Quality Traits in Two Highbush Blueberry Cultivars via Changes in Sunlight and Temperature Conditions.

The use of covers to protect blueberry orchards from adverse weather events has increased due to the variability in climate patterns, but the effects of rain covers and netting materials on yield and fruit quality have not been studied yet. This research evaluated the simultaneous effect of an LDPE plastic cover, a woven cover, and netting material on environmental components (UV light, PAR, NIR, and growing degree days (GDDs)), plant performance (light interception, leaf area index, LAI, yield, and flower development), and fruit quality traits (firmness, total soluble solids, and acidity) in two blueberry cultivars. On average, UV transmission under the netting was 11% and 43% higher compared to that under woven and LDPE plastic covers, while NIR transmission was 8-13% higher with both types of rain covers, with an increase in fruit air temperature and GDDs. Yield was 27% higher under the woven cover with respect to netting, but fruit firmness values under the netting were 12% higher than those of the LDPE plastic cover. Light interception, LAI, and flower development explained 64% (p = 0.0052) of the yield variation due to the cover material's effect. The obtained results suggest that the type of cover differentially affects yield and fruit quality in blueberries due to the specific light and temperature conditions generated under these materials.

Synthesis of acyl pyrroles via palladium-catalyzed carbonylative amination of aryl and alkenyl iodides.

A palladium-catalyzed synthesis of acyl pyrroles from aryl and alkenyl iodides is reported. This carbonylative amination requires only atmospheric (balloon) pressure of carbon monoxide and proceeds with Pd(PPh(3))(4) and Pd-NHC catalysts. Aryl and heteroaryl iodides give the corresponding acyl pyrroles in good to excellent yields, while alkenyl iodides provide the corresponding acyl pyrroles in low to moderate yields.

A Diels-Alder-based total synthesis of (-)-kainic acid.

An efficient synthesis of (-)-kainic acid, through a high-pressure-promoted Diels-Alder cycloaddition of a vinylogous malonate derived from 4-hydroxyproline, is described. The bicyclic adduct could be converted into the natural product with complete stereocontrol.

Alkylidene Dihydropyridines Are Surrogates for Pyridylic Anions in the Conjugate Addition to α,ß-Unsaturated Ketones.

We show that alkylidene dihydropyridines, readily prepared from 4-alkylpyridines, behave as soft nucleophiles toward a range of α,ß-unsaturated ketones under the influence of silyl Lewis acids to give the products of conjugate addition. In contrast to existing methods, which use strongly basic pyridylic anions, this reaction tolerates a wide array of functional groups, providing access to useful heterocyclic scaffolds.

The omega-3 hydroxy fatty acid 7(S)-HDHA is a high-affinity PPARα ligand that regulates brain neuronal morphology.

The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) is emerging as an important target in the brain for the treatment or prevention of cognitive disorders. The identification of high-affinity ligands for brain PPARα may reveal the mechanisms underlying the synaptic effects of this receptor and facilitate drug development. Here, using an affinity purification-untargeted mass spectrometry (AP-UMS) approach, we identified an endogenous, selective PPARα ligand, 7(S)-hydroxy-docosahexaenoic acid [7(S)-HDHA]. Results from mass spectrometric detection of 7(S)-HDHA in mouse and rat brain tissues, time-resolved FRET analyses, and thermal shift assays collectively revealed that 7(S)-HDHA potently activated PPARα with an affinity greater than that of other ligands identified to date. We also found that 7(S)-HDHA activation of PPARα in cultured mouse cortical neurons stimulated neuronal growth and arborization, as well as the expression of genes associated with synaptic plasticity. The findings suggest that this DHA derivative supports and enhances neuronal synaptic capacity in the brain.

Palladium-catalyzed selective carboelimination and cross-coupling reactions of benzocyclobutenols with aryl bromides.

The palladium-catalyzed selective ß-carboelimination and cross-coupling chemistry of benzocyclobutenols is described. In contrast to the base-mediated ring-opening reactions of benzocyclobutenols, this variant proceeds with exclusive cleavage of the proximal bond.

Pyridylic anions are soft nucleophiles in the palladium-catalyzed C(sp3)-H allylation of 4-alkylpyridines.

We report a mild palladium-catalyzed method for the selective allylation of 4-alkylpyridines in which highly basic pyridylic anions behave as soft nucleophiles. This method exploits alkylidene dihydropyridines, which are semi-stable intermediates readily formed using a 'soft-enolization' approach, in a new mechanistic manifold for decarboxylative allylation. Notably, the catalytic generation of pyridylic anions results in a substantially broader functional group tolerance compared to other pyridine allylation methods. Experimental and theoretical mechanistic studies strongly suggest that pyridylic anions are indeed the active nucleophiles in these reactions, and that they participate in an outer-sphere reductive elimination step. This finding establishes a new pK a boundary of 35 for soft nucleophiles in transition metal-catalyzed allylations.

The Transaction Costs of Government Responses to the COVID-19 Emergency in Latin America.

The COVID-19 pandemic has created a crisis that is challenging national and local governments to innovate in their responses to novel problems. Despite similarities to the challenges confronted in developed countries, for Latin American governments, these problems are amplified by structural obstacles such as social inequalities. These countries must respond with capacities and resources that are often limited by spoils systems and by social and political polarization. This essay provides an overview of some innovative practices in Argentina, Brazil, Chile, Colombia, and Mexico. In particular, this essay concentrates on some salient collaborative efforts in the region. To draw lessons from these practices, the authors focus on the formal and informal institutions that facilitate or obstruct collaboration across jurisdictions. The findings are discussed in terms of the transaction costs of collaboration identified in these experiences.

Towards the total synthesis of FD-838: modular enantioselective assembly of the core.

A rapid assembly of the tetracyclic core of FD-838, featuring a catalytic asymmetric Stetter reaction, is described.

The Acid-Free Cyclopropanol-Minisci Reaction Reveals the Catalytic Role of Silver-Pyridine Complexes.

A well-defined homogeneous silver precatalyst can be utilized for the direct C-H functionalization of a wide range of aromatic nitrogen heterocycles with cyclopropanols under acid-free conditions. This reaction can be conducted on gram-scale and with low catalyst loadings (as low as 1%), which is rare for silver-catalyzed Minisci-type reactions. Moreover, reactivity trends, as well as steric and calculated electronic properties of the heterocycles, strongly suggest that silver-heterocycle complexes formed in situ behave as redox active catalysts and as Lewis acid activators of the heterocycle and that the electronic nature of the heterocyclic substrates tunes the reactivity of the resulting complexes.

Separating the Anti-Inflammatory and Diabetogenic Effects of Glucocorticoids Through LXRß Antagonism.

Synthetic glucocorticoids (GCs), including dexamethasone (DEX), are powerful anti-inflammatory drugs. Long-term use of GCs, however, can result in metabolic side effects such as hyperglycemia, hepatosteatosis, and insulin resistance. The GC receptor (GR) and liver X receptors (LXRα and LXRß) regulate overlapping genes involved in gluconeogenesis and inflammation. We have previously shown that Lxrß-/- mice are resistant to the diabetogenic effects of DEX but still sensitive to its immunosuppressive actions. To determine whether this finding could be exploited for therapeutic intervention, we treated mice with GSK2033, a pan-LXR antagonist, alone or combined with DEX. GSK2033 suppressed GC-induced gluconeogenic gene expression without affecting immune-responsive GR target genes. The suppressive effect of GSK2033 on DEX-induced gluconeogenic genes was specific to LXRß, was liver cell autonomous, and occurred in a target gene-specific manner. Compared with DEX treatment alone, the coadministration of GSK2033 with DEX decreased the recruitment of GR and its accessory factors MED1 and C/EBPß to the phosphoenolpyruvate carboxykinase promoter. However, GSK2033 had no effect on DEX-mediated suppression of inflammatory genes expressed in the liver or in mouse primary macrophages stimulated with lipopolysaccharides. In conclusion, our study provides evidence that the gluconeogenic and immunosuppressive actions of GR activation can be mechanistically dissociated by pharmacological antagonism of LXRß. Treatment with an LXRß antagonist could allow the safer use of existing GC drugs in patients requiring chronic dosing of anti-inflammatory agents for the treatment of diseases such as rheumatoid arthritis and inflammatory bowel disease.

High-pressure Diels-Alder approach to natural kainic acid.

The first Diels-Alder based synthesis of (-)-kainic acid is described. Danishefsky's diene and a vinylogous malonate derived from 4-hydroxyproline combine under high pressure to afford a key bicyclic intermediate with virtually no loss of enantiopurity. This adduct can be converted into the natural product with complete stereocontrol. [reaction: see text].