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Ferroptosis is a caspase-independent, iron-dependent form of regulated necrosis extant in traumatic brain injury, Huntington disease, and hemorrhagic stroke. It can be activated by cystine deprivation leading to glutathione depletion, the insufficiency of the antioxidant glutathione peroxidase-4, and the hemolysis products hemoglobin and hemin. A cardinal feature of ferroptosis is extracellular signal-regulated kinase (ERK)1/2 activation culminating in its translocation to the nucleus. We have previously confirmed that the mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor U0126 inhibits persistent ERK1/2 phosphorylation and ferroptosis. Here, we show that hemin exposure, a model of secondary injury in brain hemorrhage and ferroptosis, activated ERK1/2 in mouse neurons. Accordingly, MEK inhibitor U0126 protected against hemin-induced ferroptosis. Unexpectedly, U0126 prevented hemin-induced ferroptosis independent of its ability to inhibit ERK1/2 signaling. In contrast to classical ferroptosis in neurons or cancer cells, chemically diverse inhibitors of MEK did not block hemin-induced ferroptosis, nor did the forced expression of the ERK-selective MAP kinase phosphatase (MKP)3. We conclude that hemin or hemoglobin-induced ferroptosis, unlike glutathione depletion, is ERK1/2-independent. Together with recent studies, our findings suggest the existence of a novel subtype of neuronal ferroptosis relevant to bleeding in the brain that is 5-lipoxygenase-dependent, ERK-independent, and transcription-independent. Remarkably, our unbiased phosphoproteome analysis revealed dramatic differences in phosphorylation induced by two ferroptosis subtypes. As U0126 also reduced cell death and improved functional recovery after hemorrhagic stroke in male mice, our analysis also provides a template on which to build a search for U0126's effects in a variant of neuronal ferroptosis.SIGNIFICANCE STATEMENT Ferroptosis is an iron-dependent mechanism of regulated necrosis that has been linked to hemorrhagic stroke. Common features of ferroptotic death induced by diverse stimuli are the depletion of the antioxidant glutathione, production of lipoxygenase-dependent reactive lipids, sensitivity to iron chelation, and persistent activation of extracellular signal-regulated kinase (ERK) signaling. Unlike classical ferroptosis induced in neurons or cancer cells, here we show that ferroptosis induced by hemin is ERK-independent. Paradoxically, the canonical MAP kinase kinase (MEK) inhibitor U0126 blocks brain hemorrhage-induced death. Altogether, these data suggest that a variant of ferroptosis is unleashed in hemorrhagic stroke. We present the first, unbiased phosphoproteomic analysis of ferroptosis as a template on which to understand distinct paths to cell death that meet the definition of ferroptosis.

An enantioselective carbene‐catalyzed radical‐radical coupling of acyl imidazoles and racemic Hantzsch esters is disclosed. This method involves the coupling of an N‐heterocyclic carbene‐derived ketyl radical and a secondary sp3‐carbon radical and allows access to chiral α‐aryl aliphatic ketones in moderate‐to‐good yields and enantioselectivities without any competitive epimerization. The utility of this protocol is highlighted by the late‐stage functionalization of various pharmaceutical compounds and is further demonstrated by the transformation of the enantioenriched products to biologically relevant molecules. Computational investigations reveal the N‐heterocyclic carbene controls the double‐facial selectivity of the ketyl radical and the alkyl radicals, respectively. [ABSTRACT FROM AUTHOR]

Keywords: potassium trifluoroborate; photoredox catalysis; organophotocatalysis; acyl azolium compounds; radical-radical coupling; ketones EN potassium trifluoroborate photoredox catalysis organophotocatalysis acyl azolium compounds radical-radical coupling ketones 2175 2180 6 10/31/23 20231127 NES 231127 Graph Organoboron compounds have long been recognized for providing chemists with unique strategies for carbon-carbon bond formation. [41] Shortly after, we reported the applications of isolated acyl azoliums and expanded our methods to include both stoichiometric ester azoliums and three-component radical-relay reactions, which employed potassium trifluoroborates as radical precursors in the photoredox-mediated alkoxycarbonylation of trifluoroborates and synthesis of -aryloxy ketones. [33] However, under appropriate conditions radical-radical coupling is favored when (a) radicals are generated at equivalent rates, such as in photoredox-mediated reactions, and (b) the radicals exhibit different lifetimes, with one radical being persistent and the other transient. Potassium trifluoroborate, photoredox catalysis, acyl azolium compounds, radical-radical coupling, organophotocatalysis, ketones. [Extracted from the article]

A mild photocatalyzed approach to achieve the α‐alkylation of esters via formation of an α ‐radical is disclosed here. Cesium enolates of esters were generated in situ using Cs2CO3 as a base. A subsequent photocatalyzed oxidation at the α‐carbon of these enolates produced an α‐radical that was added into activated alkenes. This is the first example accessing the α‐carbon radical of esters in photoredox catalyed transformations. [ABSTRACT FROM AUTHOR]

The C(1)-(C11) fragment of apoptolidin A is synthesized by using a convergent route. This convergent route has involved the stereoselective glycosidation of porpargyl alcohol and the Suzuki cross-coupling reaction of bromodienoate and the vinylborane generated via chemoselective hydroboration of diyne with diisopinocampheylborane.

N-acyl 3,4-disubstituted pyrroles are synthesized directly from hydrazine and an aldehyde via a Piloty-Robinson pyrrole synthesis. The free N-H pyrroles are accessed after the Piloty-Robinson reaction and they are used in the synthesis of octaethylprophyrin and octaethyltetraphenylporphyrin.

The total synthesis of bioactive alkaloids is an enduring challenge and an indication of the state of the art of chemical synthesis. With the explosion of catalytic asymmetric methods over the past three decades, these compelling targets have been fertile proving grounds for enantioselective bond forming transformations. These activities are summarized herein both to highlight the power and versatility of these methods and to instill future inspiration for new syntheses of these privileged natural products. 1 Introduction 2 Monoterpenoid Indole Alkaloids 2.1 Corynanthe-Type MIAs 3 Biosynthesis 4 Biological Activity 5 Scope 6 Strategies in Yohimbine Alkaloid Synthesis 6.1 Momose's Formal Synthesis of (+)-Yohimbine 6.2 Jacobsen's Synthesis of (+)-Yohimbine 6.3 Hiemstra's Synthesis of (+)-Yohimbine 6.4 Qin's Synthesis of (–)-Yohimbine 6.5 Tan's Synthesis of (+)-Rauwolscine 6.6 Jacobsen's Synthesis of (+)-Reserpine 6.7 Chen's Synthesis of (+)-Reserpine 6.8 Riva's Synthesis of (–)-Alloyohimbane 6.9 Katsuki's Synthesis of (–)-Alloyohimbane 6.10 Ghosh's Synthesis of (–)-Yohimbane and (–)-Alloyohimbane 6.11 Hong's Synthesis of (–)-Yohimbane 6.12 Gellman's Synthesis of (–)-Yohimbane 6.13 Scheidt's Synthesis of (–)-Rauwolscine and (–)-Alloyohimbane 7 Conclusion [ABSTRACT FROM AUTHOR]

N‐heterocyclic carbenes (NHCs) have emerged as catalysts for the construction of C−C bonds in the synthesis of substituted ketones under single‐electron processes. Despite these recent reports, there still remains a need to increase the utility and practicality of these reactions by exploring new radical coupling partners. Herein, we report the synthesis of γ‐aryloxyketones via combined NHC/photoredox catalysis. In this reaction, an α‐aryloxymethyl radical is generated via oxidation of an aryloxymethyl potassium trifluoroborate salt, which is then added into styrene derivatives to provide a stabilized benzylic radical. Subsequent radical‐radical coupling reaction with an azolium radical affords the γ‐aryloxy ketone products. [ABSTRACT FROM AUTHOR]

Research has been conducted on the beta-hydroxy ketone stereochemistry. The results of the (super)1H NMR analysis of this stereochemistry which allows to inspect alpha-methylene unit of the beta-hydroxy ketone in (super)1H NMR spectra are reported.

Research has been conducted on the aldols which correspond to the C(13)-C(25) segment of bafilomycin A (sub)1. The development of the stereoselective syntheses of these aldols via the chiral aldehyde's fragment assembly aldol reactions is discussed.

Single‐electron N‐heterocyclic carbene (NHC) catalysis has gained attention recently for the synthesis of C−C bonds. Guided by density functional theory and mechanistic analyses, we report the light‐driven synthesis of aliphatic and α‐amino ketones using single‐electron NHC operators. Computational and experimental results reveal that the reactivity of the key radical intermediate is substrate‐dependent and can be modulated through steric and electronic parameters of the NHC. Catalyst potential is harnessed in the visible‐light driven generation of an acyl azolium radical species that undergoes selective coupling with various radical partners to afford diverse ketone products. This methodology is showcased in the direct late‐stage functionalization of amino acids and pharmaceutical compounds, highlighting the utility of single‐electron NHC operators. [ABSTRACT FROM AUTHOR]

Background: There is no consensus on postoperative rotator cuff repair protocols in orthopedic or physical therapy literature. Despite surgical management, the frequency of rotator cuff retears continues to be high. Objectives: This study is designed to investigate the current concepts of postoperative rehabilitation and to evaluate the state of communication between referring surgeons and treating physical therapists. Methods: A survey was conducted over a 2-year period, performed by an online survey company. Results: Six hundred responses were obtained from physical therapists. Most rehab protocols were based on size of tear, tissue quality, and open versus arthroscopic repair. Current intervention concepts and professional experience guided protocol development. Thirty-three percent of therapists receive operative notes ≤ 25% of the time. Sixteen percent reported not receiving operative notes and not having access to the physician >50% of the time. Most patients were seen within 2 weeks, with passive range of motion started in 83% of cases. Sixty percent started active-assist range of motion at ≤ 4 weeks. Sixty-four percent of therapy was continued for 12 to 16 weeks. Patient compliance, poor tissue quality, and rapid rehab progression were reported as common causes of failure. Conclusion: Most rehabilitation programs follow protocols developed by surgeons and physical therapists. Tissue quality, size of tear, and repair type are usually documented in the operative report, and are rarely conveyed to the therapist. This study highlights the lack of communication between the physician and the therapist. Improving communication regarding the findings at surgery, opening lines of communication, and making alterations to the protocol may improve patient outcomes. [ABSTRACT FROM AUTHOR]

As a key element in the construction of complex organic scaffolds, the formation of C−C bonds remains a challenge in the field of synthetic organic chemistry. Recent advancements in single‐electron chemistry have enabled new methods for the formation of various C−C bonds. Disclosed herein is the development of a novel single‐electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium in situ followed by a radical–radical coupling was made possible merging N‐heterocyclic carbene (NHC) and photoredox catalysis. The utility of this protocol in synthesis was showcased in the late‐stage functionalization of a variety of pharmaceutical compounds. Preliminary investigations using chiral NHCs demonstrate that enantioselectivity can be achieved, showcasing the advantages of this protocol over alternative methodologies. [ABSTRACT FROM AUTHOR]

Combining biological and small‐molecule catalysts under a chemoenzymatic manifold presents a series of significant advantages to the synthetic community. We report herein the successful development of a two‐step/single flask synthesis of γ‐lactones through the merger of Umpolung catalysis with a ketoreductase‐catalyzed dynamic kinetic resolution, reduction, and cyclization. This combined approach delivers highly enantio‐ and diastereoenriched heterocycles and demonstrates the feasibility of integrating NHC catalysis with enzymatic processes. [ABSTRACT FROM AUTHOR]

Chemical transformations that install heteroatoms into C−H bonds are of significant interest because they streamline the construction of value‐added small molecules. Direct C−H oxyfunctionalization, or the one step conversion of a C−H bond to a C−O bond, could be a highly enabling transformation due to the prevalence of the resulting enantioenriched alcohols in pharmaceuticals and natural products,. Here we report a single‐flask photoredox/enzymatic process for direct C−H hydroxylation that proceeds with broad reactivity, chemoselectivity and enantioselectivity. This unified strategy advances general photoredox and enzymatic catalysis synergy and enables chemoenzymatic processes for powerful and selective oxidative transformations. [ABSTRACT FROM AUTHOR]