Nickel/photoredox-catalyzed three-component silylacylation of acrylates via chlorine photoelimination.

The extensive utility of organosilicon compounds across a wide range of disciplines has sparked significant interest in their efficient synthesis. Although catalytic 1,2-silyldifunctionalization of alkenes provides a promising method for the assembly of intricate organosilicon frameworks with atom and step economy, its advancement is hindered by the requirement of an external hydrogen atom transfer (HAT) agent in photoredox catalysis. Herein, we disclose an efficient three-component silylacylation of α,ß-unsaturated carbonyl compounds, leveraging a synergistic nickel/photoredox catalysis with various hydrosilanes and aroyl chlorides. This method enables the direct conversion of acrylates into valuable building blocks that contain both carbonyl and silicon functionalities through a single, redox-neutral process. Key to this reaction is the precise activation of the Si-H bond, achieved through chlorine radical-induced HAT, enabled by the photoelimination of a Ni-Cl bond. Acyl chlorides serve a dual role, functioning as both acylating agents and chloride donors. Our methodology is distinguished by its mild conditions and extensive substrate adaptability, significantly enhancing the late-stage functionalization of pharmaceuticals.

Concurrent Optimizations of Efficacy and Blood-Brain Barrier Permeability in New Macrocyclic LRRK2 Inhibitors for Potential Parkinson's Disease Therapeutics.

The elevated activity of leucine-rich repeat kinase 2 (LRRK2) is implicated in the pathogenesis of Parkinson's disease (PD). The quest for effective LRRK2 inhibitors has been impeded by the formidable challenge of crossing the blood-brain barrier (BBB). We leveraged structure-based de novo design and developed robust three-dimensional quantitative structure-activity relationship (3D-QSAR) models to predict BBB permeability, enhancing the likelihood of the inhibitor's brain accessibility. Our strategy involved the synthesis of macrocyclic molecules by linking the two terminal nitrogen atoms of HG-10-102-01 with an alkyl chain ranging from 2 to 4 units, laying the groundwork for innovative LRRK2 inhibitor designs. Through meticulous computational and synthetic optimization of both biochemical efficacy and BBB permeability, 9 out of 14 synthesized candidates demonstrated potent low-nanomolar inhibition and significant BBB penetration. Further assessments of in vitro and in vivo effectiveness, coupled with pharmacological profiling, highlighted 8 as the promising new lead compound for PD therapeutics.

Unraveling the Potential of Vinyl Ether as an Ethylene Surrogate in Heteroarene C─H Functionalization via the Spin-Center Shift.

Despite the simplicity and abundance of ethylene, its practical application presents significant hurdles due to its nature as a highly flammable gas. Herein, a strategic use of easily handled vinyl ether is reported as a latent ethylene surrogate achieved via a spin-center shift (SCS) pathway, enabling the successful three-component reaction that bridges heteroarenes and various coupling partners, including sulfinates, thiols, and phosphine oxides. Through a photoredox catalytic process, α-oxy radicals are generated by combining various radicals with phenyl vinyl ether, which are subsequently added to N-heteroarenes. Subsequently, the radical-mediated SCS pathway serves as the driving force for C─O bond cleavage, effectively engaging the phenoxy group as a leaving group. In addition, by broadening the utility of the method, a valuable synthon is provided for efficient C─H vinylation of N-heteroarenes following sulfonyl group elimination. This approach not only enriches the toolbox of synthetic methodology but also provides a more streamlined alternative, circumventing the challenges associated with direct ethylene gas usage. The versatility of the method, particularly evident in late-stage functionalizations of medicinally relevant molecules and peptides, underscores its capability to produce invaluable three-component compounds and vinylated N-heteroarene derivatives.

Nickel-Catalyzed Hydrofluorination in Unactivated Alkenes: Regio- and Enantioselective C-F Bond Formation.

Catalytic formation of a regio- and enantioselective C-F bond chiral center from readily available alkenes is a crucial goal, yet it continues to pose significant challenges in organic synthesis. Here, we report the regioselective formation of C-F bonds facilitated by NiH catalysis and a coordination directing strategy that enables precise hydrofluorination of both terminal and internal alkenes. Notably, we have optimized this methodology to achieve high enantioselectivity in creating aliphatic C-F stereogenic centers especially with ß,γ-alkenyl substrates, using a tailored chiral Bn-BOx ligand. Another pivotal finding in our research is the identification of the (+)-nonlinear effect under optimized conditions, allowing for high enantioselectivity even with moderately enantiomerically enriched chiral ligands. Given the significant role of fluorine in pharmaceuticals and synthetic materials, this research offers essential insights into the regioselective and enantioselective formation of C-F bond chiral centers, paving the way for the efficient production of valuable fluorinated compounds.

NiH-catalyzed C-N bond formation: insights and advancements in hydroamination of unsaturated hydrocarbons.

The formation of C-N bonds is a fundamental aspect of organic synthesis, and hydroamination has emerged as a pivotal strategy for the synthesis of essential amine derivatives. In recent years, there has been a surge of interest in metal hydride-catalyzed hydroamination reactions of common alkenes and alkynes. This method avoids the need for stoichiometric organometallic reagents and overcomes problems associated with specific organometallic compounds that may impact functional group compatibility. Notably, recent developments have brought to the forefront olefinic hydroamination and hydroamidation reactions facilitated by nickel hydride (NiH) catalysis. The inclusion of suitable chiral ligands has paved the way for the realization of asymmetric hydroamination reactions in the realm of olefins. This review aims to provide an in-depth exploration of the latest achievements in C-N bond formation through intermolecular hydroamination catalyzed by nickel hydrides. Leveraging this innovative approach, a diverse range of alkene and alkyne substrates can be efficiently transformed into value-added compounds enriched with C-N bonds. The intricacies of C-N bond formation are succinctly elucidated, offering a concise overview of the underlying reaction mechanisms. It is our aspiration that this comprehensive review will stimulate further progress in NiH-catalytic techniques, fine-tune reaction systems, drive innovation in catalyst design, and foster a deeper understanding of the underlying mechanisms.

Photocatalytic Enantioselective Hydrosulfonylation of α,ß-Unsaturated Carbonyls with Sulfonyl Chlorides.

This research explores the enantioselective hydrosulfonylation of various α,ß-unsaturated carbonyl compounds via the use of visible light and redox-active chiral Ni-catalysis, facilitating the synthesis of enantioenriched α-chiral sulfones with remarkable enantioselectivity (exceeding 99 % ee). A significant challenge entails enhancing the reactivity between chiral metal-coordinated carbonyl compounds and moderate electrophilic sulfonyl radicals, aiming to minimize the background reactions. The success of our approach stems from two distinctive attributes: 1) the Cl-atom abstraction employed for sulfonyl radical generation from sulfonyl chlorides, and 2) the single-electron reduction to produce a key enolate radical Ni-complex. The latter process appears to enhance the feasibility of the sulfonyl radical's addition to the electron-rich enolate radical. An in-depth investigation into the reaction mechanism, supported by both experimental observations and theoretical analysis, offers insight into the intricate reaction process. Moreover, the versatility of our methodology is highlighted through its successful application in the late-stage functionalization of complex bioactive molecules, demonstrating its practicality as a strategy for producing α-chiral sulfones.

Nucleophilic C4-selective (hetero) arylation of pyridines for facile synthesis of heterobiaryls.

The synthesis of heterobiaryl compounds holds significant value in organic chemistry due to their extensive range of applications. Herein, we report a highly efficient strategy for conducting C4-selective (hetero) arylation of pyridines using N-aminopyridinium salts. The reaction proceeds readily at room temperature in the presence of a base, thus eliminating the requirement for catalysts or oxidants. This method allows for the installation of various electron-rich (hetero) aryl groups on pyridines, resulting in the streamlined synthesis of highly valuable C4-(hetero) aryl pyridine derivatives, which are otherwise challenging to acquire via conventional methods. This simple and straightforward method will facilitate access to a range of heterobiaryl compounds thereby promoting their application in various scientific disciplines.

Regio- and Enantioselective Catalytic δ-C-H Amidation of Dioxazolones Enabled by Open-Shell Copper-Nitrenoid Transfer.

Controlling regio- and enantioselectivity in C-H functionalization reactions is of paramount importance due to their versatile synthetic utilities. Herein, we describe a new approach for the asymmetric δ-C(sp3)-H amidation catalysis of dioxazolones using a Cu(I) precursor with a chiral bisoxazoline ligand to access six-membered lactams with high to excellent regio- and enantioselectivity (up to >19:1 rr and >99:1 er). Combined experimental and computational mechanistic studies unveiled that the open-shell character of the postulated Cu-nitrenoids enables the regioselective hydrogen atom abstraction and subsequent enantio-determining radical rebound of the resulting carbon radical intermediates. The synthetic utility of this asymmetric cyclization was demonstrated in the diastereoselective introduction of additional functional groups into the chiral δ-lactam skeleton as well as in the rapid access to biorelevant azacyclic compounds.

Penile length and circumference: are they related to nose size?

Background: We investigated the relationship between the size of the penis and that of the nose. Methods: We retrospectively analyzed 1,160 patients whose nose and penis sizes were measured. These participants were selected from a subset of 1,531 patients who visited the Dr. JOMULJU Urology Clinic between March and October 2022. Patients aged <20 years and those who underwent surgery for the nose and penis were excluded. Nose size was determined by measuring the length, width, and height of the nose, which were used to calculate the volume of the triangular pyramid. Stretched penile length (SPL) and penile circumference before erection were measured. The participants' height, weight, foot size, and serum testosterone levels were measured. Testicular size was measured using ultrasonography. Predictors of penile length and circumference were assessed using linear regression analysis. Results: The participants' average age was 35.5 years, mean SPL was 11.2 cm, and mean penile circumference was 6.8 cm. Univariate analysis revealed that body weight, body mass index (BMI), the serum testosterone level, and nose size were associated with SPL. Multivariable analysis revealed that BMI (P=0.001) and nose size (P=0.023) were significant predictors of SPL. Univariate analysis revealed that penile circumference was related to an individual's height, weight, BMI, nose size, and foot size. Multivariable analysis revealed that body weight (P=0.008) and testicular size (P=0.002) were significant predictors of penile circumference. Conclusions: Nose size was a significant predictor of penile size. The sizes of the penis and nose increased with a decrease in BMI. This interesting study confirms the truth of an erstwhile myth about penis size.

Photoinduced Electron Transfer from Xanthates to Acyl Azoliums: Divergent Ketone Synthesis via N-Heterocyclic Carbene Catalysis.

Considering the prevalence of alcohols and carboxylic acids, their fragment cross-coupling reactions could hold significant implications in organic synthesis. Herein, we report a versatile method for synthesizing a diverse range of ketones from alcohols and carboxylic acid derivatives via N-heterocyclic carbene (NHC) catalysis. Mechanistic investigations revealed that photoexcited xanthates and acyl azoliums undergo single electron transfer (SET) under photocatalyst-free conditions, generating NHC-derived ketyl radicals and alkyl radicals. These open-shell intermediates subsequently undergo the radical-radical cross-coupling reaction, yielding valuable ketones. Furthermore, this approach can be employed in three-component reactions involving alkenes and enynes, resulting in structurally diverse cross-coupled ketones. The unified strategy offers a unique opportunity for the fragment coupling of a diverse range of alcohols and carboxylic acid derivatives, accommodating diverse functional groups even in complex settings.

Unlocking the Potential of ß-Fragmentation of Aminophosphoranyl Radicals for Sulfonyl Radical Reactions.

Exploiting ß-scission in aminophosphoranyl radicals for radical-mediated transformations has been a longstanding challenge. In this study, we investigated the untapped potential of ß-fragmentation in aminophosphoranyl radicals by leveraging the unique properties of the P-N bond and the substituents of P(III) reagents. Our approach carefully considers factors such as cone angle and electronic properties of phosphine and employs density functional theory (DFT) calculations to probe structural and molecular orbital influence. We successfully induced ß-fragmentation through N-S bond cleavage of aminophosphoranyl radicals under visible light and mild conditions, generating a range of sulfonyl radicals derived from pyridinium salts via the photochemical activity of electron donor-acceptor (EDA) complexes. This innovative synthetic strategy exhibits broad applicability, including late-stage functionalization, and paves the way for valuable sulfonyl radical-mediated reactions, such as alkene hydrosulfonylation, difunctionalization, and pyridylic C-H sulfonylation.

Energy-transfer-induced [3+2] cycloadditions of N-N pyridinium ylides.

Photocycloaddition is a powerful reaction to enable the conversion of alkenes into high-value synthetic materials that are normally difficult to obtain under thermal conditions. Lactams and pyridines, both prominent in pharmaceutical applications, currently lack effective synthetic strategies to combine them within a single molecular structure. Here we describe an efficient approach to diastereoselective pyridyl lactamization via a photoinduced [3+2] cycloaddition, based on the unique triplet-state reactivity of N-N pyridinium ylides in the presence of a photosensitizer. The corresponding triplet diradical intermediates allow the stepwise radical [3+2] cycloaddition with a broad range of activated and unactivated alkenes under mild conditions. This method exhibits excellent efficiency, diastereoselectivity and functional group tolerance, providing a useful synthon for ortho-pyridyl γ- and δ-lactam scaffolds with syn-configuration in a single step. Combined experimental and computational studies reveal that the energy transfer process leads to a triplet-state diradical of N-N pyridinium ylides, which promotes the stepwise cycloaddition.

Deconstructive Pyridylation of Unstrained Cyclic Amines through a One-Pot Umpolung Approach.

A one-pot umpolung method for the ring-opening pyridylation of unstrained cyclic amines was developed using N-amidopyridinium salts. This process involves the formation of electron donor-acceptor complexes between bromide and N-amidopyridinium salts, ultimately leading to the functionalization of pyridines. This protocol is compatible with a range of 5- or 6-membered cyclic amines and pyridines, thereby providing a powerful synthon for preparing C4-functionalized pyridines under visible-light conditions in the absence of an external photocatalyst.

A dynamic in vitro developing testis model reflects structures and functions of testicular development in vivo.

To better define appropriate applications of our 3-dimensional testicular co-culture as a model for reproductive toxicology, we evaluated the ability of the model to capture structural and functional elements that can be targeted by reproductive toxicants. Testicular co-cultures were prepared from postnatal day 5 male rats and cultured with a Matrigel overlay. Following a 2-day acclimation period, we characterized functional pathway dynamics by evaluating morphology, protein expression, testosterone concentrations, and global gene expression at a range of timepoints from experimental days 0-21. Western blotting confirmed expression of Sertoli cell, Leydig cell, and spermatogonial cell-specific protein markers. Testosterone detected in cell culture media indicates active testosterone production. Quantitative pathway analysis identified Gene Ontology biological processes enriched among genes significantly changing over the course of 21 days. Processes enriched among genes significantly increasing through time include general developmental processes (morphogenesis, tissue remodeling, etc.), steroid regulation, Sertoli cell development, immune response, and stress and apoptosis. Processes enriched among genes significantly decreasing over time include several related to male reproductive development (seminiferous tubule development, male gonad development, Leydig cell differentiation, Sertoli cell differentiation), all of which appear to peak in expression between days 1 and 5 before decreasing at later timepoints. This analysis provides a temporal roadmap for specific biological process of interest for reproductive toxicology in the model and anchors the model to sensitive phases of in vivo development, helping to define the relevance of the model for in vivo processes.

Nickel-Catalyzed Kinetic Resolution of Racemic Unactivated Alkenes via Enantio-, Diastereo-, and Regioselective Hydroamination.

Kinetic resolution is a powerful strategy for the isolation of enantioenriched compounds from racemic mixtures, and the development of selective catalytic processes is an active area of research. Here, we present a nickel-catalyzed kinetic resolution of racemic α-substituted unconjugated carbonyl alkenes via the enantio-, diastereo-, and regioselective hydroamination. This protocol affords both chiral α-substituted butenamides and syn-ß2,3 -amino acid derivatives with high enantiomeric purity (up to 99 % ee) and selectivity factor up to >684. The key to the excellent kinetic resolution efficiency is the distinctive architecture of the chiral nickel complex, which enables successful resolution and enantioselective C-N bond construction. Mechanistic investigations reveal that the unique structure of the chiral ligand facilitates a rapid migratory insertion step with one enantiomer. This strategy provides a practical and versatile approach to prepare a wide range of chiral compounds.

Visible-Light-Active Coumarin- and Quinolinone-Based Photocatalysts and Their Applications in Chemical Transformations.

Organic dyes have been actively studied as useful photocatalysts because they allow access to versatile structural flexibility and green synthetic applications. The identification of a new class of robust organic chromophores is, therefore, in high demand to increase structural diversity and variability. Although coumarins and quinolinones have long been acknowledged as organic chromophores, their ability to participate in photoinduced transformations is somewhat less familiar. Fascinated by their chromophoric features and adaptable platform, our group is interested in the identification of fluorescent bioactive molecules and in the development of new photoinduced synthetic methods using coumarins and quinolinones as photocatalysts. This account provides an overview of our recent progress in the discovery and application of light-absorbing coumarin and quinolinone derivatives in photochemistry and medicinal chemistry.

Alteration of oral microbiome composition in children living with pesticide-exposed farm workers.

Our prior work shows that azinphos-methyl pesticide exposure is associated with altered oral microbiomes in exposed farmworkers. Here we extend this analysis to show the same association pattern is also evident in their children. Oral buccal swab samples were analyzed at two time points, the apple thinning season in spring-summer 2005 for 78 children and 101 adults and the non-spray season in winter 2006 for 62 children and 82 adults. The pesticide exposure for the children were defined by the farmworker occupation of the cohabitating household adult and the blood azinphos-methyl detection of the cohabitating adult. Oral buccal swab 16S rRNA sequencing determined taxonomic microbiota proportional composition from concurrent samples from both adults and children. Analysis of the identified bacteria showed significant proportional changes for 12 of 23 common oral microbiome genera in association with azinphos-methyl detection and farmworker occupation. The most common significantly altered genera had reductions in the abundance of Streptococcus, suggesting an anti-microbial effect of the pesticide. Principal component analysis of the microbiome identified two primary clusters, with association of principal component 1 to azinphos-methyl blood detection and farmworker occupational status of the household. The children's buccal microbiota composition clustered with their household adult in ∼95% of the households. Household adult farmworker occupation and household pesticide exposure is associated with significant alterations in their children's oral microbiome composition. This suggests that parental occupational exposure and pesticide take-home exposure pathways elicit alteration of their children's microbiomes.

C4-Selective C-H Borylation of Pyridinium Derivatives Driven by Electron Donor-Acceptor Complexes.

The photoinduced C4-selective C-H borylation of pyridines was achieved using electron donor-acceptor complexes derived from a Lewis base and N-amidopyridinium salts under external oxidant- and photocatalyst-free conditions. Notably, the nucleophilic character of phosphite-ligated boryl radicals enables addition of a radical to position C4 of pyridinium salts to afford C4-borylated heteroarenes that are otherwise difficult to obtain. This approach provides a versatile platform for the installation of both phosphite- and amine-coordinated boron groups on a series of pyridines under mild conditions, demonstrating excellent C4-positional selectivity for the pyridine scaffolds.

Structure-Based Virtual Screening and De Novo Design to Identify Submicromolar Inhibitors of G2019S Mutant of Leucine-Rich Repeat Kinase 2.

Missense mutations of leucine-rich repeat kinase 2 (LRRK2), including the G2019S mutant, are responsible for the pathogenesis of Parkinson's disease. In this work, structure-based virtual screening of a large chemical library was carried out to identify a number of novel inhibitors of the G2019S mutant of LRRK2, the biochemical potencies of which ranged from the low micromolar to the submicromolar level. The discovery of these potent inhibitors was made possible due to the modification of the original protein-ligand binding energy function in order to include an accurate ligand dehydration energy term. The results of extensive molecular docking simulations indicated that the newly identified inhibitors were bound to the ATP-binding site of the G2019S mutant of LRRK2 through the multiple hydrogen bonds with backbone amide groups in the hinge region as well as the hydrophobic interactions with the nonpolar residues in the P-loop, hinge region, and interdomain region. Among 18 inhibitors derived from virtual screening, 4-(2-amino-5-phenylpyrimidin-4-yl)benzene-1,3-diol (Inhibitor 2) is most likely to serve as a new molecular scaffold to optimize the biochemical potency, because it revealed submicromolar inhibitory activity in spite of its low molecular weight (279.3 amu). Indeed, a highly potent inhibitor (Inhibitor 2n) of the G2019S mutant was derived via the structure-based de novo design using the structure of Inhibitor 2 as the molecular core. The biochemical potency of Inhibitor 2n surged to the nanomolar level due to the strengthening of hydrophobic interactions in the ATP-binding site, which were presumably caused by the substitutions of small nonpolar moieties. Due to the high biochemical potency against the G2019S mutant of LRRK2 and the putatively good physicochemical properties, Inhibitor 2n is anticipated to serve as a new lead compound for the discovery of antiparkinsonian medicines.

Oxidatively induced reactivity in Rh(iii)-catalyzed 7-azaindole synthesis: insights into the role of the silver additive.

A typical synthetic protocol for preparing 7-azaindoles involves the coupling of 2-aminopyridine and alkyne substrates using a Rh(iii)-catalyst. The catalysis requires the assistance of an external Ag+ oxidant that is thought to regenerate the catalyst and increase the turnover efficiency. Density functional theory (DFT) simulations confirm that Ag+ can oxidize various neutral Rh(iii) intermediates encountered at different stages of the catalysis. Among them, the catalytically relevant species is a cationic Rh(iii)-pyridyl+ complex (2A), which undergoes C-H activation of pyridine and couples an internal alkyne substrate into the pyridyl ligand to form the desired 7-azaindole product. Computations reveal that the oxidation also accelerates the reaction steps, including C-H activation via concerted metalation deprotonation (CMD), 1,2-alkyne insertion, and reductive elimination, thus highlighting the role of Ag+ as a catalytic promoter for the oxidatively induced reactivity of the Rh-catalyst in 7-azaindole synthesis. DFT calculations show that the catalysis is inefficient without invoking an oxidatively induced reaction pathway.