Enantioselective Construction of α-Quaternary Cyclobutanones by Catalytic Asymmetric Allylic Alkylation

No strain, no gain! The first transition metal-catalyzed enantioselective α-alkylation of cyclobutanones is reported. This method employs palladium catalysis and an electron-deficient PHOX-type ligand to afford all-carbon α-quaternary cyclobutanones in good to excellent yields and enantioselectivities (see scheme)

Controls on boron incorporation in cultured tests of the planktic foraminifer Orbulina universa

Culture experiments with living planktic foraminifers reveal that the ratio of boron to calcium (B/Ca) in Orbulina universa increases from 56 to 92 μmol mol−1 when pH is raised from 7.61+/–0.02 to 8.67+/–0.03 (total scale). Across this pH range, the abundances of carbonate, bicarbonate, and borate ions also change (+530, −500, and +170 μmol kg−1, respectively). Thus specific carbonate system control(s) on B/Ca remain unclear, complicating interpretation of paleorecords. B/Ca in cultured O. universa also increases with salinity (55–72 μmol mol−1 from 29.9–35.4‰) and seawater boron concentration (62–899 μmol mol−1 from 4–40 ppm B), suggesting that these parameters may need to be taken into account for paleorecords spanning large salinity changes (~ 2‰) and for samples grown in seawater whose boron concentration ([B]SW) differs from modern by more than 0.25 ppm. While our results are consistent with the predominant incorporation of the charged borate species B(OH)4−into foraminiferal calcite, the behavior of the partition coefficient KD (defined as [B/Ca]calcite/[B(OH)4−/HCO3−]seawater) cannot be explained by borate incorporation alone, and suggests the involvement of other pH-sensitive ions such as CO3 2− For a given increase in seawater B(OH)4−, the corresponding increase in B/Ca is stronger when B(OH)4− is raised by increasing [B]SW than when it is raised by increasing pH. These results suggest that B incorporation controls should be reconsidered. Additional insight is gained from laser-ablation ICP-MS profiles, which reveal variable B/Ca distributions within individual shells

Enantioselective construction of quaternary N-heterocycles by palladium-catalysed decarboxylative allylic alkylation of lactams

The enantioselective synthesis of nitrogen-containing heterocycles (N-heterocycles) represents a substantial chemical research effort and resonates across numerous disciplines, including the total synthesis of natural products and medicinal chemistry. In this Article, we describe the highly enantioselective palladium-catalysed decarboxylative allylic alkylation of readily available lactams to form 3,3-disubstituted pyrrolidinones, piperidinones, caprolactams and structurally related lactams. Given the prevalence of quaternary N-heterocycles in biologically active alkaloids and pharmaceutical agents, we envisage that our method will provide a synthetic entry into the de novo asymmetric synthesis of such structures. As an entry for these investigations we demonstrate how the described catalysis affords enantiopure quaternary lactams that intercept synthetic intermediates previously used in the synthesis of the Aspidosperma alkaloids quebrachamine and rhazinilam, but that were previously only available by chiral auxiliary approaches or as racemic mixtures

Effects of Gluten Intake on Risk of Celiac Disease: a case-control study on a Swedish birth cohort.

It is not clear how intake of gluten during infancy affects subsequent risk of celiac disease. We investigated whether gluten intake before 2 years of age increases risk for celiac disease in genetically susceptible children

Viloxazine, a Non-stimulant Norepinephrine Reuptake Inhibitor, for the Treatment of Attention Deficit Hyperactivity Disorder: A 3 Year Update.

Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in childhood. Current treatment options for ADHD include pharmacological treatment (stimulants, non-stimulants, anti-depressants, anti-psychotics), psychological treatment (behavioral therapy with or without parent training, cognitive training, neurofeedback), and complementary and alternative therapies (vitamin supplementation, exercise). Central nervous system (CNS) stimulants are the primary pharmacological therapy used in treatment; however, these stimulant drugs carry a high potential for abuse and severe psychological/physical dependence. Viloxazine, a non-stimulant medication without evidence of drug dependence, is a selective norepinephrine reuptake inhibitor that has historically been prescribed as an anti-depressant medication. The extended-release (ER) form was approved by the US Food and Drug Administration (FDA) in April 2021 for the treatment of ADHD in pediatric patients aged 6-17 years. Phase 2 and 3 randomized control trials have demonstrated significant efficacy of viloxazine in improving ADHD symptoms versus placebo. Related to its long-standing use as an antidepressant, the safety profile and pharmacokinetics of viloxazine are well understood. Viloxazine appears to be a suitable alternative to current standard-of-care pharmacotherapy for ADHD, but the further investigation remains to be done in comparing its efficacy to that of current treatments

Expanding Insight into Asymmetric Palladium-Catalyzed Allylic Alkylation of N-Heterocyclic Molecules and Cyclic Ketones

Eeny, meeny, miny … enaminones! Lactams and imides have been shown to consistently provide enantioselectivities substantially higher than other substrate classes previously investigated in the palladium-catalyzed asymmetric decarboxylative allylic alkylation. Several new substrates have been designed to probe the contributions of electronic, steric, and stereoelectronic factors that distinguish the lactam/imide series as superior alkylation substrates (see scheme). These studies culminated in marked improvements on carbocyclic allylic alkylation substrates

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

Pd-catalyzed enantioselective alkylation in conjunction with further synthetic elaboration enables the formal total syntheses of a number of “classic” natural product target molecules. This publication highlights recent methods for setting quaternary and tetrasubstituted tertiary carbon stereocenters to address the synthetic hurdles encountered over many decades across multiple compound classes spanning carbohydrate derivatives, terpenes, and alkaloids. These enantioselective methods will impact both academic and industrial settings, where the synthesis of stereogenic quaternary carbons is a continuing challenge

Flatworm-specific transcriptional regulators promote the specification of tegumental progenitors in Schistosoma mansoni

Schistosomes infect more than 200 million people. These parasitic flatworms rely on a syncytial outer coat called the tegument to survive within the vasculature of their host. Although the tegument is pivotal for their survival, little is known about maintenance of this tissue during the decades schistosomes survive in the bloodstream. Here, we demonstrate that the tegument relies on stem cells (neoblasts) to specify fusogenic progenitors that replace tegumental cells lost to turnover. Molecular characterization of neoblasts and tegumental progenitors led to the discovery of two flatworm-specific zinc finger proteins that are essential for tegumental cell specification. These proteins are homologous to a protein essential for neoblast-driven epidermal maintenance in free-living flatworms. Therefore, we speculate that related parasites (i.e., tapeworms and flukes) employ similar strategies to control tegumental maintenance. Since parasitic flatworms infect every vertebrate species, understanding neoblast-driven tegumental maintenance could identify broad-spectrum therapeutics to fight diseases caused by these parasites

Depleting inositol pyrophosphate 5-InsP7 protected the heart against ischaemia–reperfusion injury by elevating plasma adiponectin

Aims Adiponectin is an adipocyte-derived circulating protein that exerts cardiovascular and metabolic protection. Due to the futile degradation of endogenous adiponectin and the challenges of exogenous administration, regulatory mechanisms of adiponectin biosynthesis are of significant pharmacological interest. Methods and results Here, we report that 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP7) generated by inositol hexakisphosphate kinase 1 (IP6K1) governed circulating adiponectin levels via thiol-mediated protein quality control in the secretory pathway. IP6K1 bound to adiponectin and DsbA-L and generated 5-InsP7 to stabilize adiponectin/ERp44 and DsbA-L/Ero1-Lα interactions, driving adiponectin intracellular degradation. Depleting 5-InsP7 by either IP6K1 deletion or pharmacological inhibition blocked intracellular adiponectin degradation. Whole-body and adipocyte-specific deletion of IP6K1 boosted plasma adiponectin levels, especially its high molecular weight forms, and activated AMPK-mediated protection against myocardial ischaemia–reperfusion injury. Pharmacological inhibition of 5-InsP7 biosynthesis in wild-type but not adiponectin knockout mice attenuated myocardial ischaemia–reperfusion injury. Conclusion Our findings revealed that 5-InsP7 is a physiological regulator of adiponectin biosynthesis that is amenable to pharmacological intervention for cardioprotection