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Enhanced reactivity of decarboxylative cross-coupling using a new parallel photoreactor.

Pharmaceutical and agrochemical discovery efforts rely on robust methods for chemical synthesis that rapidly access diverse molecules. Cross-coupling reactions are the most widely used synthetic methods, but these methods typically form bonds to C(sp2)-hybridized carbon atoms (e.g., amide coupling, biaryl coupling) and lead to a prevalence of "flat" molecular structures with suboptimal physicochemical and topological properties. Benzylic C(sp3)–H cross-coupling methods offer an appealing strategy to address this limitation by directly forming bonds to C(sp3)-hybridized carbon atoms, and emerging methods exhibit synthetic versatility that rivals conventional cross-coupling methods to access products with drug-like properties. Here, we use a virtual library of >350,000 benzylic ethers and ureas derived from benzylic C–H cross-coupling to test the widely held view that coupling at C(sp3)-hybridized carbon atoms affords products with improved three-dimensionality. The results show that the conformational rigidity of the benzylic scaffold strongly influences the product dimensionality. Products derived from flexible scaffolds often exhibit little or no improvement in three-dimensionality, unless they adopt higher energy conformations. This outcome introduces an important consideration when designing routes to topologically diverse molecular libraries. The concepts elaborated herein are validated experimentally through an informatics-guided synthesis of selected targets and the use of high-throughput experimentation to prepare a library of three-dimensional products that are broadly distributed across drug-like chemical space.

C(sp3)–H functionalization methods provide an ideal synthetic platform for medicinal chemistry; however, such methods are often constrained by practical limitations. The present study outlines a C(sp3)–H isocyanation protocol that enables the synthesis of diverse, pharmaceutically relevant benzylic ureas in high-throughput format. The operationally simple C–H isocyanation method shows high site selectivity and good functional group tolerance, and uses commercially available catalyst components and reagents [CuOAc, 2,2′-bis(oxazoline) ligand, (trimethylsilyl)isocyanate, and N-fluorobenzenesulfonimide]. The isocyanate products may be used without isolation or purification in a subsequent coupling step with primary and secondary amines to afford hundreds of diverse ureas. These results provide a template for implementation of C–H functionalization/cross-coupling in drug discovery., A copper-based catalyst system composed of commercially available reagents enables C–H isocyanation with exquisite (hetero)benzylic site selectivity, enabling high-throughput access to pharmaceutically relevant ureas via coupling with amines.

The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds

A guide for catalyst choice in the forest Chemists often discover reactions by applying catalysts to a series of simple compounds. Tweaking those reactions to tolerate more structural complexity in pharmaceutical research is time-consuming. Ahneman et al. report that machine learning can help. Using a high-throughput data set, they trained a random forest algorithm to predict which specific palladium catalysts would best tolerate isoxazoles (cyclic structures with an N–O bond) during C–N bond formation. The predictions also helped to guide analysis of the catalyst inhibition mechanism. Science , this issue p. 186

Over the past two decades, there have been major developments in transition metal-catalyzed aminations of aryl halides to form anilines, a common structure found in drug agents, natural product isolates, and fine chemicals. Many of these approaches have enabled highly efficient and selective coupling through the design of specialized ligands, which facilitate reductive elimination from a destabilized metal center. We postulated that a general and complementary method for carbon-nitrogen bond formation could be developed through the destabilization of a metal amido complex via photoredox catalysis, thus providing an alternative approach to the use of structurally complex ligand systems. Here, we report the development of a distinct mechanistic paradigm for aryl amination using ligand-free nickel(II) salts, in which facile reductive elimination from the nickel metal center is induced via a photoredox-catalyzed electron-transfer event., National Institutes of Health (U.S.) (Award GM58160), National Institutes of Health (U.S.) (Award RO1-GM078201-05), National Institutes of Health (U.S.) (Award GM113311)

High-throughput experimentation (HTE) offers means to allow medicinal chemists to synthesize a variety of pharmaceutically active compounds in an ultra-high throughput fashion, which also requires the development of an ultra-fast analytical method in order to reduce the bottleneck of post-reaction data analysis. We recently demonstrated MALDI-TOF-MS as an ultra-fast screening tool for the profiling of nano-mole C–N coupling reactions in a 1536 well plate at the rate of 0.3–0.4 s per sample. This work will cover MALDI method development steps including determination and optimization of sample concentration, spotting and drying methods, matrix selection, and quantitation approaches for high throughput pharmaceutical reaction profiling. The purpose of this work is to serve as a practical guide for organic and medicinal chemists to quickly develop a high throughput MALDI-TOF-MS method for routine screening of multi-well plate based chemical reactions without any MALDI plate modification or product tagging.

INTRODUCTION The invention of new chemical reactions provides new bond construction strategies for improved access to diverse regions of structural space. However, a pervasive, long-standing bias toward reporting successful results means that the shortcomings of even mature reaction methods remain poorly defined, making practical syntheses of structurally diverse targets far from certain. Distinct tools and experimental approaches are required to expose and record the problematic structural elements that limit different synthetic methods. The experimental space required to systematically survey reaction failure is vast, and existing ultrahigh-throughput (uHT) reaction screening approaches are inadequate for exploring the diversity of conditions pertaining in modern synthetic methods. Additionally, analytical approaches must continuously improve to meet the throughput demands of this expansive reaction screening. RATIONALE We report a nanomole-scale screening protocol that can be used to execute heterogeneous reactions with heating and agitation, use of volatile solvents, and capacity for photoredox chemistry. These advances in miniaturized chemistry screening were combined with the use of matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry (MALDI-TOF MS), enabling analysis of 1536 reactions in ~10 min. Together, these advances create a platform that can enable systematic reaction evaluation and data capture to survey the dark space of chemical reactions. RESULTS Using the Buchwald-Hartwig C–N coupling reaction to exemplify this process, an uHT Glorius fragment additive poisons diagnostic approach was first applied to demonstrate that MALDI-MS could provide adequate data quality to monitor the formation of a single product under a wide variety of different synthetic conditions. Four catalytic methods—Ir/Ni and Ru/Ni dual-metal photoredox catalysis, as well as heterogeneous and high-temperature Cu and Pd catalysis—with extended nanomole chemistry requirements were evaluated for the synthesis of a single product in the presence of 383 structurally diverse simple and complex potential poisons. Using a normalizing internal standard that was closely related to the product and optimized operating parameters, MALDI-MS provided good correlation with existing ultra performance liquid chromatography (UPLC)–MS approaches (coefficient of determination R2 up to 0.85), allowing correct binning of “hits” and “misses” (defined as >50% product signal knockdown) up to 95% of the time. Next, the more challenging goal of exploring diverse whole-molecule C–N couplings was explored. In this case, it was not practical to have either product standards or closely related internal standards to enable analytical quantitation. A “simplest-partner test” was employed, in which 192 aryl bromides and 192 secondary amines were each coupled with a MS-active “simplest partner,” guaranteeing a somewhat normalized MS response for all products. The formation of 384 different products using the four aforementioned synthetic methods was monitored by MALDI-MS, with pass-fail binning of results correlating well with UPLC-MS in the identification of common structural elements (such as functional group counts, H-bond donors and acceptors, and polar surface area) that lead to reaction failure. CONCLUSION In the near future, each problematic structural element that is identified through systematic dark-space exploration can be promoted for in-depth examination to precisely define the specific parameters that determine reaction outcome at the atomic and quantum molecular level. Predictive machine learning models will use this focused data to enable synthetic practitioners to select the most appropriate reactions for use in a particular synthetic setting. In addition, functionality that persistently fails across synthetic methods can sharply define important challenges for the invention of improved chemical reactions.

PURPOSE To assess the repeatability and reproducibility of corneal power values obtained by a Fourier-domain optical coherence tomography (FD-OCT) system (RTVue) and to compare them with the values obtained by a Scheimpflug camera system (Pentacam HR) and by automated keratometry (IOL Master). METHODS Thirty-two eyes from 32 healthy subjects were included in this prospective study. Two experienced observers measured each eye 3 consecutive times with the Pentacam, IOLMaster, and RTVue centered on either the pupil or corneal vertex. The conventional keratometry equivalent (CKE) and anterior (Ka), posterior (Kp), and net (Kn) corneal power values were determined. RESULTS The corneal power values obtained by the RTVue showed high repeatability (all intraclass correlation coefficient >0.96) and reproducibility (coefficient of variation

The incorporation of an easily oxidized arylsulfide moiety facilitates the photocatalytic generation of alkene radical cations that undergo a variety of cycloaddition reactions with electron-rich reaction partners. The sulfide moiety can subsequently be reductively cleaved in a traceless fashion, affording products that are not otherwise directly accessible using photoredox catalysis. This approach constitutes a novel oxidative “redox auxiliary” strategy that offers a practical means to circumvent a fundamental thermodynamic limitation facing photoredox reactions.

Over the past two decades, there have been major developments in transition metal–catalyzed aminations of aryl halides to form anilines, a common structure found in drug agents, natural product isolates, and fine chemicals. Many of these approaches have enabled highly efficient and selective coupling through the design of specialized ligands, which facilitate reductive elimination from a destabilized metal center. We postulated that a general and complementary method for carbon–nitrogen bond formation could be developed through the destabilization of a metal amido complex via photoredox catalysis, thus providing an alternative approach to the use of structurally complex ligand systems. Here, we report the development of a distinct mechanistic paradigm for aryl amination using ligand-free nickel(II) salts, in which facile reductive elimination from the nickel metal center is induced via a photoredox-catalyzed electron-transfer event.

Shenzhen was a famous typical rapid-urbanization city in China, and this study compares plant species diversity in urban parks from the start of urbanization through 2011. Results show that the plant species biodiversity increased rapidly: the rate changed from 140% to 980% and the average increasing rate was 406.90%, but only 12.59% of plants spread into the park naturally. Shrubs had the highest rate; with change increasing from 20.70% to 43.54%, they replaced trees to become the dominant type. The biodiversity of native plants also increased, but their proportion relative to all species had declined. The homogenization of plant species in the parks increased; more than half of the plant species (62.24%) are located in 5–7 parks at once now, compared with 65.52% of species located in only 2–3 parks at the start of the study. The increase of species was faster than the increase of families; many new species planted belong to a few specific families. The ratio of species to families declined from 0.40 to 0.32. Results indicate that the rapid increase of plant species diversity as well as their homogenization happened in the initial stage of urbanization, and so rapid urbanization might be the major factor in the changes in plant species diversity in municipal parks. Rapid urbanization was an important cause of change in plant species diversity.

Ruthenium(II) polypyridyl complexes promote the efficient radical cation Diels-Alder cycloaddition of electron-rich dienophiles upon irradiation with visible light. These reactions enable facile [4 + 2] cycloadditions that would be electronically mismatched under thermal conditions. Key to the success of this methodology is the availability of ligand-modified ruthenium complexes that enable rational tuning of the electrochemical properties of the catalyst without significantly perturbing the overall photophysical properties of the system.

Bicyclic guanidines are able to catalyze the protonation reactions of 2-phthalimidoacrylates with thiols in excellent yields and enantioselectivities. The protonation reaction of itaconimides with secondary phosphine oxides is also known. Herein, the tandem conjugate addition-enantioselective protonation of N-substituted itaconimides with thiols catalyzed by chiral bicyclic guanidine is investigated. The rotational barrier of the C-N axis of N-2-tert-butyl phenylitaconimide is also studied, both experimentally and computationally.

Purpose To establish a normative database for corneal elevation in Chinese myopic patients who underwent refractive surgery, and analyze the association of corneal elevation with sex, age, and ocular parameters. Methods A total of 3000 eyes in 1500 patients were evaluated with the Pentacam. Anterior and posterior elevations were measured at the apex and thinnest point. Normative thresholds were defined according to the Tukey method. Univariate and multivariate analyses were performed to assess the association of corneal elevation with sex, age, and ocular parameters. Results Normal upper limits for corneal elevation in adult Chinese were 4.95 μm, 5.25 μm, 6.2 μm, and 11.0 μm at the anterior apex, anterior thinnest point, posterior apex, and posterior thinnest point, respectively. Thinner corneal pachymetry at the apex and greater anterior corneal astigmatism tended to show greater anterior corneal elevation values. Younger age, greater anterior corneal astigmatism, lower anterior and posterior keratometry, and shallower anterior chamber depth resulted in greater posterior corneal elevation values. Conclusions Locally derived thresholds may offer higher sensitivity and specificity when screening eyes for myopic refractive surgery, and keratoconic and post-orthokeratology eyes. Anterior and posterior corneal elevation at the apex and thinnest point were associated significantly with anterior corneal astigmatism, showing a positive correlation.

Purpose To evaluate axial length (AL) measurement failure rate with the IOLMaster (Carl Zeiss AG, Germany) and Lenstar LS 900 (Haag-Streit AG, Switzerland) in eyes with cataract. Methods Two hundred and ninety-six eyes of 170 patients with cataract were enrolled. Cataract type and severity were graded using the Lens Opacities Classification System III (LOCS III) and AL measurements were attempted with IOLMaster (version 5.4) and Lenstar LS 900 (version 1.1). Chi-squared analysis was used to assess if the difference in AL measurement acquisition rate was statistically significant between the two devices. The association of the different cataract types and severity with the AL measurement acquisition rate was evaluated with logistic regression analysis. Results AL measurements were obtained in 184 eyes (62.16%) using the IOLMaster and 191 eyes (64.53%) using the Lenstar, which corresponds to a failure rate of 37.84% and 35.47% respectively. Chi-square analysis indicated no significant difference between the Lenstar and IOLMaster for AL measurement failure rate (x2 = 0.356, P = 0.550). Logistic regression analysis indicated no association between acquisition rates and cortical or nuclear cataracts with either device. There was a statistically significant association between acquisition rates and increasing severity of posterior subcapsular cataracts with the IOLMaster (β = -1.491, P

To compare anterior eye segment measurements obtained using low optical coherence reflectometry (LENSTAR LS900, Haag-Streit), autokeratometry (RC-5000, Tomey) and corneal topography (Topolyzer, Wavelight).In 46 healthy subjects, flat keratometry (Kf), steep keratometry (Ks), mean keratometry (Km) and white-to-white (WTW) distance were measured by Lenstar, Tomey RC-5000 and Topolyzer.Kf and Km measurements of Lenstar were significantly steeper than Tomey RC-5000 (both p0.001), but the 95% LoA of them were narrow (-0.22 to 0.46D, -0.16 to 0.36D, respectively). There were no significant differences between the Kf and Km measurements of Lenstar and Topolyzer, with a narrow 95% LoA. There were no significant differences between the Ks measurements of Lenstar and Tomey RC-5000, and Lenstar and Topolyzer. A good agreement was found between them with 95% LoA of -0.40 to 0.56D, and -0.56 to 0.64D, respectively. WTW measurements with Lenstar were greater than those with Tomey RC-5000 and Topolyzer (p=0.042, p0.01, respectively). A good agreement existed between the WTW obtained by Lenstar and Topolyzer, Tomey RC-5000, with 95% LoA ranging from -0.13 to 0.74mm and -0.33 to 0.51mm.Generally good agreement was found between the Lenstar and Tomey RC-5000, Topolyzer for K and WTW measurements. In clinical practice, K and WTW measurements obtained by Lenstar and Tomey RC-5000, Topolyzer can be used interchangeably.

Intramolecular radical cation Diels–Alder reactions can be conducted under photocatalytic conditions using visible light irradiation. The photocatalyst system involves the use of a Ru ( bpy ) 3 2 + chromophore and methyl viologen as a co-oxidant. These reactions enable the cycloaddition of substrates whose thermal Diels–Alder cycloadditions are electronically mismatched and thus require forcing conditions. Nevertheless, the radical cation cycloadditions can be conducted on gram scale using ambient sunlight as the only source of irradiation.

Ruthenium(II) polypyridyl complexes promote the efficient radical cation Diels–Alder cycloaddition of electron-rich dienophiles upon irradiation with visible light. These reactions enable facile [4 + 2] cycloadditions that would be electronically mismatched under thermal conditions. Key to the success of this methodology is the availability of ligand-modified ruthenium complexes that enable rational tuning of the electrochemical properties of the catalyst without significantly perturbing the overall photophysical properties of the system.