Crystal structure of the Ate1 arginyl-tRNA-protein transferase and arginylation of N-degron substrates.

N-degron pathways are proteolytic systems that target proteins bearing N-terminal (Nt) degradation signals (degrons) called N-degrons. Nt-Arg of a protein is among Nt-residues that can be recognized as destabilizing ones by the Arg/N-degron pathway. A proteolytic cleavage of a protein can generate Arg at the N terminus of a resulting C-terminal (Ct) fragment either directly or after Nt-arginylation of that Ct-fragment by the Ate1 arginyl-tRNA-protein transferase (R-transferase), which uses Arg-tRNAArg as a cosubstrate. Ate1 can Nt-arginylate Nt-Asp, Nt-Glu, and oxidized Nt-Cys* (Cys-sulfinate or Cys-sulfonate) of proteins or short peptides. Ate1 genes of fungi, animals, and plants have been cloned decades ago, but a three-dimensional structure of Ate1 remained unknown. A detailed mechanism of arginylation is unknown as well. We describe here the crystal structure of the Ate1 R-transferase from the budding yeast Kluyveromyces lactis. The 58-kDa R-transferase comprises two domains that recognize, together, an acidic Nt-residue of an acceptor substrate, the Arg residue of Arg-tRNAArg, and a 3'-proximal segment of the tRNAArg moiety. The enzyme's active site is located, at least in part, between the two domains. In vitro and in vivo arginylation assays with site-directed Ate1 mutants that were suggested by structural results yielded inferences about specific binding sites of Ate1. We also analyzed the inhibition of Nt-arginylation activity of Ate1 by hemin (Fe3+-heme), and found that hemin induced the previously undescribed disulfide-mediated oligomerization of Ate1. Together, these results advance the understanding of R-transferase and the Arg/N-degron pathway.

On variance estimation of the inverse probability-of-treatment weighting estimator: A tutorial for different types of propensity score weights.

Propensity score methods, such as inverse probability-of-treatment weighting (IPTW), have been increasingly used for covariate balancing in both observational studies and randomized trials, allowing the control of both systematic and chance imbalances. Approaches using IPTW are based on two steps: (i) estimation of the individual propensity scores (PS), and (ii) estimation of the treatment effect by applying PS weights. Thus, a variance estimator that accounts for both steps is crucial for correct inference. Using a variance estimator which ignores the first step leads to overestimated variance when the estimand is the average treatment effect (ATE), and to under or overestimated estimates when targeting the average treatment effect on the treated (ATT). In this article, we emphasize the importance of using an IPTW variance estimator that correctly considers the uncertainty in PS estimation. We present a comprehensive tutorial to obtain unbiased variance estimates, by proposing and applying a unifying formula for different types of PS weights (ATE, ATT, matching and overlap weights). This can be derived either via the linearization approach or M-estimation. Extensive R code is provided along with the corresponding large-sample theory. We perform simulation studies to illustrate the behavior of the estimators under different treatment and outcome prevalences and demonstrate appropriate behavior of the analytical variance estimator. We also use a reproducible analysis of observational lung cancer data as an illustrative example, estimating the effect of receiving a PET-CT scan on the receipt of surgery.

Comparison of two propensity score-based methods for balancing covariates: the overlap weighting and fine stratification methods in real-world claims data.

BACKGROUND: Two propensity score (PS) based balancing covariate methods, the overlap weighting method (OW) and the fine stratification method (FS), produce superb covariate balance. OW has been compared with various weighting methods while FS has been compared with the traditional stratification method and various matching methods. However, no study has yet compared OW and FS. In addition, OW has not yet been evaluated in large claims data with low prevalence exposure and with low frequency outcomes, a context in which optimal use of balancing methods is critical. In the study, we aimed to compare OW and FS using real-world data and simulations with low prevalence exposure and with low frequency outcomes. METHODS: We used the Texas State Medicaid claims data on adult beneficiaries with diabetes in 2012 as an empirical example (N = 42,628). Based on its real-world research question, we estimated an average treatment effect of health center vs. non-health center attendance in the total population. We also performed simulations to evaluate their relative performance. To preserve associations between covariates, we used the plasmode approach to simulate outcomes and/or exposures with N = 4,000. We simulated both homogeneous and heterogeneous treatment effects with various outcome risks (1-30% or observed: 27.75%) and/or exposure prevalence (2.5-30% or observed:10.55%). We used a weighted generalized linear model to estimate the exposure effect and the cluster-robust standard error (SE) method to estimate its SE. RESULTS: In the empirical example, we found that OW had smaller standardized mean differences in all covariates (range: OW: 0.0-0.02 vs. FS: 0.22-3.26) and Mahalanobis balance distance (MB) (< 0.001 vs. > 0.049) than FS. In simulations, OW also achieved smaller MB (homogeneity: <0.04 vs. > 0.04; heterogeneity: 0.0-0.11 vs. 0.07-0.29), relative bias (homogeneity: 4.04-56.20 vs. 20-61.63; heterogeneity: 7.85-57.6 vs. 15.0-60.4), square root of mean squared error (homogeneity: 0.332-1.308 vs. 0.385-1.365; heterogeneity: 0.263-0.526 vs 0.313-0.620), and coverage probability (homogeneity: 0.0-80.4% vs. 0.0-69.8%; heterogeneity: 0.0-97.6% vs. 0.0-92.8%), than FS, in most cases. CONCLUSIONS: These findings suggest that OW can yield nearly perfect covariate balance and therefore enhance the accuracy of average treatment effect estimation in the total population.

Motor unit firing rates during slow and fast contractions in boys and men.

BACKGROUND: Motor unit (MU) activation during maximal contractions is lower in children compared with adults. Among adults, discrete MU activation differs, depending on the rate of contraction. We investigated the effect of contraction rate on discrete MU activation in boys and men. METHODS: Following a habituation session, 14 boys and 20 men completed two experimental sessions for knee extension and wrist flexion, in random order. Maximal voluntary isometric torque (MVIC) was determined before completing trapezoidal isometric contractions (70%MVIC) at low (10%MVIC/s) and high (35%MVIC/s) contraction rates. Surface electromyography was captured from the vastus lateralis (VL) and flexor carpi radialis (FCR) and decomposed into individual MU action potential (MUAP) trains. RESULTS: In both groups and muscles, the initial MU firing rate (MUFR) was greater (p < 0.05) at high compared with low contraction rates. The increase in initial MUFR at the fast contraction in the VL was greater in men than boys (p < 0.05). Mean MUFR was significantly lower during fast contractions only in the FCR (p < 0.05). In both groups and muscles, the rate of decay of MUFR with increasing MUAP amplitude was less steep (p < 0.05) during fast compared with slow contractions. CONCLUSION: In both groups and muscles, initial MUFRs, as well as MUFRs of large MUs were higher during fast compared with slow contractions. However, in the VL, the increase in initial MUFR was greater in men compared with boys. This suggests that in large muscles, men may rely more on increasing MUFR to generate torque at faster rates compared with boys.

Tuning NaCo(II) Bimetallic Cooperativity to Perform Co-H Exchange / C-F Bond Activation Processes in Polyfluoroarenes.

Recent advances in cooperative chemistry have shown the potential of heterobimetallic complexes combining an alkali-metal with an earth abundant divalent transition metal for the functionalisation of synthetically relevant aromatic molecules via deprotonative metalation. Pairing sodium with cobalt (II), here we provide an overview of the reactivity of bimetallic [NaCo(HMDS)3] [HMDS = N(SiMe3)2] towards C-H and C-F functionalisation of a wide range of perfluorinated molecules. These studies also uncover the enormous potential of this heterobimetallic base to perform Co-H exchanges with excellent selectivity and exceptional stoichiometric control as well as shedding light on the key role played by the alkali-metal.

Controllable Regiodivergent Alkynylation of 1,3-Bis(Boronic) Esters Activated by Distinct Organometallic Reagents.

1,3-Bis(boronic) esters can be readily synthesized from alkylBpin precursors. Selective transformations of these compounds hold the potential for late-stage functionalization of the remaining C-B bond, leading to a diverse array of molecules. Currently, there are no strategies available to address the reactivity and, more importantly, the controllable regiodivergent functionalization of 1,3-bis(boronic) esters. In this study, we have achieved controllable regiodivergent alkynylation of these molecules. The regioselectivity has been clarified based on the unique chelation patterns observed with different organometallic reagents. Remarkably, this methodology effectively addresses the low reactivity of 1,3-bis(boronic) esters and bridges the gap in radical chemistry, which typically yields only the classical products formed via stable radical intermediates. Furthermore, the compounds synthesized through this approach serve as potent building blocks for creating molecular diversity.

Ir-Catalyzed Enantioselective Synthesis of gem-Diborylalkenes Enabled by 1,2-Boron Shift.

Asymmetric cross-couplings based on 1,2-carbon migration from B-ate complexes have been developed efficiently to access valuable organoboronates. However, enantioselective reactions triggered by 1,2-boron shift have remained to be unaddressed synthetic challenge. Here, Ir-catalyzed asymmetric allylic alkylation enabled by 1,2-boron shift was developed. In this reaction, we disclosed that excellent enantioselectivities were achieved through an interesting dynamic kinetic resolution (DKR) process of allylic carbonates at the elevated temperature. Notably, the highly valuable (bis-boryl)alkenes have enabled an array of diversifications to access versatile molecules. Extensive experimental and computational studies were conducted to elucidate the reaction mechanism of DKR process and clarify the origin of excellent enantioselectivities.

Evaluating sensitivity to classification uncertainty in latent subgroup effect analyses.

BACKGROUND: Increasing attention is being given to assessing treatment effect heterogeneity among individuals belonging to qualitatively different latent subgroups. Inference routinely proceeds by first partitioning the individuals into subgroups, then estimating the subgroup-specific average treatment effects. However, because the subgroups are only latently associated with the observed variables, the actual individual subgroup memberships are rarely known with certainty in practice and thus have to be imputed. Ignoring the uncertainty in the imputed memberships precludes misclassification errors, potentially leading to biased results and incorrect conclusions. METHODS: We propose a strategy for assessing the sensitivity of inference to classification uncertainty when using such classify-analyze approaches for subgroup effect analyses. We exploit each individual's typically nonzero predictive or posterior subgroup membership probabilities to gauge the stability of the resultant subgroup-specific average causal effects estimates over different, carefully selected subsets of the individuals. Because the membership probabilities are subject to sampling variability, we propose Monte Carlo confidence intervals that explicitly acknowledge the imprecision in the estimated subgroup memberships via perturbations using a parametric bootstrap. The proposal is widely applicable and avoids stringent causal or structural assumptions that existing bias-adjustment or bias-correction methods rely on. RESULTS: Using two different publicly available real-world datasets, we illustrate how the proposed strategy supplements existing latent subgroup effect analyses to shed light on the potential impact of classification uncertainty on inference. First, individuals are partitioned into latent subgroups based on their medical and health history. Then within each fixed latent subgroup, the average treatment effect is assessed using an augmented inverse propensity score weighted estimator. Finally, utilizing the proposed sensitivity analysis reveals different subgroup-specific effects that are mostly insensitive to potential misclassification. CONCLUSIONS: Our proposed sensitivity analysis is straightforward to implement, provides both graphical and numerical summaries, and readily permits assessing the sensitivity of any machine learning-based causal effect estimator to classification uncertainty. We recommend making such sensitivity analyses more routine in latent subgroup effect analyses.

R-catcher, a potent molecular tool to unveil the arginylome.

Protein arginylation is a critical regulator of a variety of biological processes. The ability to uncover the global arginylation pattern and its associated signaling pathways would enable us to identify novel disease targets. Here, we report the development of a tool able to capture the N-terminal arginylome. This tool, termed R-catcher, is based on the ZZ domain of p62, which was previously shown to bind N-terminally arginylated proteins. Mutating the ZZ domain enhanced its binding specificity and affinity for Nt-Arg. R-catcher pulldown coupled to LC-MS/MS led to the identification of 59 known and putative arginylated proteins. Among these were a subgroup of novel ATE1-dependent arginylated ER proteins that are linked to diverse biological pathways, including cellular senescence and vesicle-mediated transport as well as diseases, such as Amyotrophic Lateral Sclerosis and Alzheimer's disease. This study presents the first molecular tool that allows the unbiased identification of arginylated proteins, thereby unlocking the arginylome and provide a new path to disease biomarker discovery.

Functional Interplay between Arginyl-tRNA Synthetases and Arginyltransferase.

Protein arginylation, mediated by arginyltransferase ATE1, is a post-translational modification of emerging biological importance that consists of transfer of the amino acid Arg to protein and peptide substrates. ATE1 utilizes charged tRNAArg as the donor of the arginyl group, which depends on the activity of Arg-tRNA synthetases (RARS) and is also utilized in translation. The mechanisms that regulate the functional balance among ATE1, RARS and translation are unknown. Here, we addressed the question of how these two enzymes can partition Arg-tRNAArg to functionally distinct pathways using an intracellular arginylation sensor in cell lines with overexpression or deletion of ATE1 and RARS isoforms. We found that arginylation levels depend on the physiological state of the cells but are not directly affected by translation activity or the availability of RARS isoforms. However, displacement of RARS from the multi-synthetase complex leads to an increase in intracellular arginylation independently of RARS enzymatic activity. This effect is accompanied by ATE1's redistribution into the cytosol. Our results provide the first comprehensive analysis of the interdependence among translation, arginyl-tRNA synthesis and arginylation.

Alkali Metal Metal(ates) Containing Divalent Earth Abundant Transition Metals.

Recent advances in cooperative chemistry have shown the enormous potential of main group heterobimetallic complexes for the functionalisation of aromatic molecules. Going beyond main group metal chemistry, here we provide an overview on the synthesis, structure and reactivity of bimetallic complexes which combine an alkali-metal (AM= Li, Na) with a divalent earth-abundant transition metal (M= Mn, Fe, Co, Ni), containing the utility silyl amide HMDS (HMDS = N(SiMe3)2). Advancing the understanding on how cooperative effects operate in these bimetallic (ate) systems, selected examples of their applications in deprotonative metalation are also discussed with special emphasis on the constitution of the metalated intermediates.

Immune checkpoint inhibitors and potential risk of thromboembolic events: Analysis of the WHO global database of individual case safety reports.

Introduction: Thromboembolic events with the use of immune checkpoint inhibitors (ICIs) in patients with cancer have been reported in few studies. However, the detailed profile of these cases remains mostly uncertain. Method: A descriptive analysis of Thromboembolic events associated with ICIs retrieved from the VigiBase, between 1967 to November 2020. We extracted the data using the terms of 'pulmonary embolism' OR 'deep vein thrombosis' OR 'acute coronary syndrome' OR 'myocardial infarction' OR 'ischemic stroke' (preferred term (PT) (MedDRA). Results: We included 161 cases from 26 countries in our descriptive analysis. Patients' ages were reported in 141 (87.6%) cases, with a median of 68 years (interquartile range 61-74), and 63.4% of the patients were male. Indications for ICIs were reported in 151 (93.8%) cases, as follows: lung cancer (n = 85, 52.8%), renal cell carcinoma (n = 24, 14.9%), melanoma (n = 20, 12.4%), urethral carcinoma (n = 12, 7.45%), breast cancer (n = 4, 2.48%), adenocarcinoma of the gastroesophageal junction (n = 3, 1.9%), gastric cancer (n = 2, 1.24%), and skin cancer (n = 1, 0.62%). Nivolumab was reported as a suspected drug in 76 cases (47%), pembrolizumab in 46 cases (28.5%), atezolizumab in 21 cases (13%), durvalumab in 14 cases (8.6%), and avelumab in four cases (2.4%).The time to onset of thromboembolic events was reported in 127 (78.8%) cases. Most of these patients (n = 109, 85.8%) reported thromboembolic events within the first six months. The causality assessment of included cases showed that 50.3% of reported thromboembolic events were possibly related to the suspected reported medication, 13.7% were probably related, 13% were unlikely to be related, and 23% were not assessable due to insufficient information. Conclusion: This study demonstrates a possible association between the use of ICIs and thromboembolic events. Further epidemiological studies are needed to assess this association and to elucidate the underlying mechanism.

Increasing confidence in waiving dermal toxicity studies: A comparison of oral and dermal acute data with alternative approaches for agrochemicals and products.

The refinement of OECD 402 study design and criteria under which the study can be waived has been welcomed in some regulatory regions but met with uncertainty in others. To address these human safety concerns, previously available in vivo acute oral and acute dermal toxicity data was evaluated from a total of 597 agrochemical active ingredients and products. It was identified that all active ingredients and 99.6% of products had an acute dermal classification equal to or less toxic than their acute oral classification, confirming that waiving the acute dermal study and basing the outcome on the acute oral toxicity result has no impact on human health assessment. Additionally, automated Acute Toxicity Estimate (ATE) calculations were conducted on 440 products to evaluate if the predicted dermal toxicity resulted in the same in vivo classification. 93% of ATE predictions provided excellent correlation to the in vivo result and 6.4% resulted in a more conservative prediction. It is therefore clear that the results of this investigation, should remove any regulatory concerns and that OECD 402 can be confidently eliminated in its entirety from testing requirements globally.

N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis.

The conjugation of amino acids to the protein N termini is universally observed in eukaryotes and prokaryotes, yet its functions remain poorly understood. In eukaryotes, the amino acid l-arginine (l-Arg) is conjugated to N-terminal Asp (Nt-Asp), Glu, Gln, Asn, and Cys, directly or associated with posttranslational modifications. Following Nt-arginylation, the Nt-Arg is recognized by UBR boxes of N-recognins such as UBR1, UBR2, UBR4/p600, and UBR5/EDD, leading to substrate ubiquitination and proteasomal degradation via the N-end rule pathway. It has been a mystery, however, why studies for the past five decades identified only a handful of Nt-arginylated substrates in mammals, although five of 20 principal amino acids are eligible for arginylation. Here, we show that the Nt-Arg functions as a bimodal degron that directs substrates to either the ubiquitin (Ub)-proteasome system (UPS) or macroautophagy depending on physiological states. In normal conditions, the arginylated forms of proteolytic cleavage products, D101-CDC6 and D1156-BRCA1, are targeted to UBR box-containing N-recognins and degraded by the proteasome. However, when proteostasis by the UPS is perturbed, their Nt-Arg redirects these otherwise cellular wastes to macroautophagy through its binding to the ZZ domain of the autophagic adaptor p62/STQSM/Sequestosome-1. Upon binding to the Nt-Arg, p62 acts as an autophagic N-recognin that undergoes self-polymerization, facilitating cargo collection and lysosomal degradation of p62-cargo complexes. A chemical mimic of Nt-Arg redirects Ub-conjugated substrates from the UPS to macroautophagy and promotes their lysosomal degradation. Our results suggest that the Nt-Arg proteome of arginylated proteins contributes to reprogramming global proteolytic flux under stresses.

Protective effect of Aster tataricus extract on NLRP3-mediated pyroptosis of bladder urothelial cells.

Aster tataricus L.f. is a traditional Eastern Asian herbal medicine used for the relief of uroschesis-related illnesses and has been demonstrated clinically to exert satisfied effects. However, the mechanism of its therapeutic action remains unclear. The present study aimed to evaluate the protective mechanism of Aster tataricus extract (ATE) on CYP or LPS + ATP-induced interstitial cystitis (IC), we successfully constructed the induced IC Sprague-Dawley (SD) rat model and IC human urothelium cell (SV-HUC-1) model. The main compounds of ATE were determined by LC-MS. After intervention, the changes on the bladder wall morphology and inflammation were observed in each group. SV-HUC1 cell viability was measured by MTT and double stained with Hoechst 33342 and propidium iodide (PI). The expression levels of NLRP3, Pro-caspase-1, Caspsae-1 p20, GSDMD, GSDMD-N and Cleave-IL-1ß in vivo and in vitro in different groups were detected by Western blotting. ATE significantly alleviated oedema and haemorrhage and reduced the inflammation index and histopathological score in SD rat bladder. The results of cell revealed that ATE could improve cell viability and decrease pyroptosis ratio. The expression of NLRP3 and other pyroptosis-related protein was remarkably decreased by ATE both in vivo and in vitro. ATE may be used as an inhibitor of NLRP3 in treating IC. The discovery of NLRP3/Caspase-1/GSDMD-N as a new protective pathway provides a new direction for protecting cell against IC.

Radical-Induced 1,2-Migrations of Boron Ate Complexes.

1,2-Boron ate rearrangements represent a fundamental class of transformations to establish new C-C bonds while retaining the valuable boron moiety in the product. In established ionic processes, the boron ate complex is activated by an external electrophile to induce a 1,2-migration from boron to an adjacent sp 3 or sp 2 carbon atom. Recently, two complementary radical polar crossover approaches have been explored for both classes, 1,2-migrations to sp 2 and sp 3 carbon centers. This review describes the general concepts in this emerging research field and summarizes recent developments of radical-induced 1,2-migrations from boron to carbon.

Cross-cultural comparison of symptom networks in late-life major depressive disorder: Yoruba Africans and the Spanish Population.

BACKGROUND: The concept of European psychologisation of depression versus somatisation in non-European populations has been the basis of several studies of cultural psychopathology in the general population. Little is currently known about cross-cultural differences and similarities in late-life depression symptom reporting. We cross-culturally compared symptom reporting in the context of Major Depressive Disorder (MDD) among community-dwelling older adults from Spain and Nigeria. METHODS: We relied on data from two household multistage probability samples comprising 3,715 persons aged 65 years or older in the Spanish and Nigerian populations. All participants underwent assessments for MDD using the World Mental Health Survey version of the Composite International Diagnostic Interview. Cross-cultural comparison of broad somatic and psychological categories as well as relationship and influence of individual symptoms were analysed using the Symptom Network Analysis approach. RESULTS: Current MDD was diagnosed in 232 and 195 older persons from Spain and Nigeria, respectively. The symptom network of the two samples were invariant in terms of global strength, S(GSPAIN , GNIGERIA ) = 7.56, P = .06, with psychological and somatic symptoms demonstrating centrality in both countries. However, country-specific relationships and influence of individual symptoms were found in the network structure of both samples, M(GSPAIN , GNIGERIA ) = 2.95, P < .01. CONCLUSION: Broad somatic and psychological symptoms categories contributed to the structural network of older Africans and their peers from the Spanish population. Variations in the relationship and influence of individual symptoms suggests that the functional and "communicative" role of individual symptoms may be differentiated by context specific imperatives. J Am Geriatr Soc 68:-, 2020.

Vasopressor treatment and mortality following nontraumatic subarachnoid hemorrhage: a nationwide electronic health record analysis.

OBJECTIVE: Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular condition, not only due to the effect of initial hemorrhage, but also due to the complication of delayed cerebral ischemia (DCI). While hypertension facilitated by vasopressors is often initiated to prevent DCI, which vasopressor is most effective in improving outcomes is not known. The objective of this study was to determine associations between initial vasopressor choice and mortality in patients with nontraumatic SAH. METHODS: The authors conducted a retrospective cohort study using a large, national electronic medical record data set from 2000-2014 to identify patients with a new diagnosis of nontraumatic SAH (based on ICD-9 codes) who were treated with the vasopressors dopamine, phenylephrine, or norepinephrine. The relationship between the initial choice of vasopressor therapy and the primary outcome, which was defined as in-hospital death or discharge to hospice care, was examined. RESULTS: In total, 2634 patients were identified with nontraumatic SAH who were treated with a vasopressor. In this cohort, the average age was 56.5 years, 63.9% were female, and 36.5% of patients developed the primary outcome. The incidence of the primary outcome was higher in those initially treated with either norepinephrine (47.6%) or dopamine (50.6%) than with phenylephrine (24.5%). After adjusting for possible confounders using propensity score methods, the adjusted OR of the primary outcome was higher with dopamine (OR 2.19, 95% CI 1.70-2.81) and norepinephrine (OR 2.24, 95% CI 1.80-2.80) compared with phenylephrine. Sensitivity analyses using different variable selection procedures, causal inference models, and machine-learning methods confirmed the main findings. CONCLUSIONS: In patients with nontraumatic SAH, phenylephrine was significantly associated with reduced mortality in SAH patients compared to dopamine or norepinephrine. Prospective randomized clinical studies are warranted to confirm this finding.

Iron-Catalyzed Cross-Coupling of Bis-(aryl)manganese Nucleophiles with Alkenyl Halides: Optimization and Mechanistic Investigations.

Various substituted bis-(aryl)manganese species were prepared from aryl bromides by one-pot insertion of magnesium turnings in the presence of LiCl and in situ trans-metalation with MnCl2 in THF at -5 °C within 2 h. These bis-(aryl)manganese reagents undergo smooth iron-catalyzed cross-couplings using 10 mol% Fe(acac)3 with various functionalized alkenyl iodides and bromides in 1 h at 25 °C. The aryl-alkenyl cross-coupling reaction mechanism was thoroughly investigated through paramagnetic 1H-NMR, which identified the key role of tris-coordinated ate-iron(II) species in the catalytic process.

Synthesis of 1,3-Bis-(boryl)alkanes through Boronic Ester Induced Consecutive Double 1,2-Migration.

A general and efficient approach for the preparation of 1,3-bis-(boryl)alkanes is introduced. It is shown that readily generated vinylboron ate complexes react with commercially available ICH2 Bpin to valuable 1,3-bis-(boryl)alkanes. The introduced transformation, which is experimentally easy to conduct, shows broad substrate scope and high functional-group tolerance. Mechanistic studies reveal that the reaction does not proceed via radical intermediates. Instead, an unprecedented boronic ester induced sequential bis-1,2-migration cascade is suggested.