Regioselective Alkynylation and Alkenylation at the More Hindered C-B Bond of 1,2-Bis(Boronic) Esters.

Selective transformations at the more sterically hindered sites of organic molecules represent a frontier in the ability to precisely modify molecules. The lack of effective synthetic methods stands in stark contrast to the large number of encumbered sites encountered in molecules of interest. Here, we demonstrate that 1,2-bis(boronates) undergo selective alkynylation and alkenylation at the more sterically hindered C-B bond. Our preliminary mechanistic studies disclosed that this reaction can proceed through two convergent pathways involving direct coupling of sterically encumbered site versus 1,2-boron migratory coupling. Notably, this method facilitated convenient access to alkenyl and alkynyl boron products, which can be diversified by an array of transformations.

Asymmetric Synthesis of Chiral 1,2-Bis(Boronic) Esters Featuring Acyclic, Non-Adjacent 1,3-Stereocenters.

The construction of acyclic, non-adjacent 1,3-stereogenic centers, prevalent motifs in drugs and bioactive molecules, has been a long-standing synthetic challenge due to acyclic nucleophiles being distant from the chiral environment. In this study, we successfully synthesized highly valuable 1,2-bis(boronic) esters featuring acyclic and nonadjacent 1,3-stereocenters. Notably, this reaction selectively produces migratory coupling products rather than alternative deborylative allylation or direct allylation byproducts. This approach introduces a new activation mode for selective transformations of gem-diborylmethane in asymmetric catalysis. Additionally, we found that other gem-diborylalkanes, previously challenging due to steric hindrance, also successfully participated in this reaction. The incorporation of 1,2-bis(boryl)alkenes facilitated the diversification of the alkenyl and two boron moieties in our target compounds, thereby enabling access to a broad array of versatile molecules. DFT calculations were performed to elucidate the reaction mechanism and shed light on the factors responsible for the observed excellent enantioselectivity and diastereoselectivity. These were determined to arise from ligand-substrate steric repulsions in the syn-addition transition state.

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.

A Polyketide Cyclase That Forms Medium-Ring Lactones.

Medium-ring lactones are synthetically challenging due to unfavorable energetics involved in cyclization. We have discovered a thioesterase enzyme DcsB, from the decarestrictine C1 (1) biosynthetic pathway, that efficiently performs medium-ring lactonizations. DcsB shows broad substrate promiscuity toward linear substrates that vary in lengths and substituents, and is a potential biocatalyst for lactonization. X-ray crystal structure and computational analyses provide insights into the molecular basis of catalysis.

Cascade CuH-Catalysed Conversion of Alkynes to Enantioenriched 1,1-Disubstituted Products.

Enantioenriched α-aminoboronic acids play a unique role in medicinal chemistry and have emerged as privileged pharmacophores in proteasome inhibitors. Additionally, they represent synthetically useful chiral building blocks in organic synthesis. Recently, CuH-catalyzed asymmetric alkene hydrofunctionalization has become a powerful tool to construct stereogenic carbon centers. In contrast, applying CuH cascade catalysis to achieve reductive 1,1-difunctionalization of alkynes remains an important, but largely unaddressed, synthetic challenge. Herein, we report an efficient strategy to synthesize α-aminoboronates via CuH-catalyzed hydroboration/hydroamination cascade of readily available alkynes. Notably, this transformation selectively delivers the desired 1,1-heterodifunctionalized product in favor of alternative homodifunctionalized, 1,2-heterodifunctionalized, or reductively monofunctionalized byproducts, thereby offering rapid access to these privileged scaffolds with high chemo-, regio- and enantioselectivity.

Catalytic, Enantioselective α-Alkylation of Azlactones with Nonconjugated Alkenes by Directed Nucleopalladation.

A palladium(II)-catalyzed enantioselective α-alkylation of azlactones with nonconjugated alkenes is described. The reaction employs a chiral BINOL-derived phosphoric acid as the source of stereoinduction, and a cleavable bidentate directing group appended to the alkene to control the regioselectivity and stabilize the nucleopalladated alkylpalladium(II) intermediate in the catalytic cycle. A wide range of azlactones were found to be compatible under the optimal reaction conditions to afford products bearing α,α-disubstituted α-amino-acid derivatives with high yields and high enantioselectivity.

Direct Access to Versatile Electrophiles via Catalytic Oxidative Cyanation of Alkenes.

Nucleophilic attack on carbon-based electrophiles is a central reactivity paradigm in chemistry and biology. The steric and electronic properties of the electrophile dictate its reactivity with different nucleophiles of interest, allowing the opportunity to fine-tune electrophiles for use as coupling partners in multistep organic synthesis or for covalent modification of proteins in drug discovery. Reactions that directly transform inexpensive chemical feedstocks into versatile carbon electrophiles would therefore be highly enabling. Herein, we report the catalytic, regioselective oxidative cyanation of conjugated and nonconjugated alkenes using a homogeneous copper catalyst and a bystanding N-F oxidant to furnish branched alkenyl nitriles that are difficult to prepare using existing methods. We show that the alkenyl nitrile products serve as electrophilic reaction partners for both organic synthesis and the chemical proteomic discovery of covalent protein ligands.

Catalytic, Enantioselective Synthesis of Allenyl Boronates.

A method to achieve enantioselective 1,4-hydroboration of terminal enynes to access allenyl boronates under CuH catalysis is described. The reaction typically proceeds in a highly stereoselective manner and tolerates an array of synthetically useful functional groups. The utility of the enantioenriched allenyl boronate products is demonstrated through several representative downstream derivatizations.

Tridentate Directing Groups Stabilize 6-Membered Palladacycles in Catalytic Alkene Hydrofunctionalization.

Removable tridentate directing groups inspired by pincer ligands have been designed to stabilize otherwise kinetically and thermodynamically disfavored 6-membered alkyl palladacycle intermediates. This family of directing groups enables regioselective remote hydrocarbofunctionalization of several synthetically useful alkene-containing substrate classes, including 4-pentenoic acids, allylic alcohols, homoallyl amines, and bis-homoallylamines, under Pd(II) catalysis. In conjunction with previous findings, we demonstrate regiodivergent hydrofunctionalization of 3-butenoic acid derivatives to afford either Markovnikov or anti-Markovnikov addition products depending on directing group choice. Preliminary mechanistic and computational data are presented to support the proposed catalytic cycle.

Clinical characteristics, target organ damage and associate risk factors of resistant hypertension determined by ambulatory blood pressure monitoring in patients aged ≥ 80 years.

OBJECTIVES: To investigate clinical characteristics, target organ damage, and the associated risk factors of the patients aged ≥ 80 years with true resistant hypertension (RH). METHODS: Patients aged ≥ 80 years with hypertension (n = 1163) were included in this study. The included participants attended a structured clinical examination and an evaluation of RH was carried out. The prevalence, clinical characteristics and target organ damage of patients with RH were assessed. The associated clinical risk factors were analyzed by using logistic regression. RESULTS: The prevalence of RH diagnosis by 24-h ambulatory blood pressure monitoring assessment was 21.15%. End-diastolic left ventricular internal dimension, left ventricular mass index as well as prevalence of left ventricular hypertrophy were significantly greater in patients with RH than in control group. The common carotid artery intimal media thickness, carotid walls thickness, common carotid artery diameter and relative wall thickness were significant greater in RH group than in control. A relatively higher level of creatinine, estimated glomerular filtration rate, microalbuminuria and retinal changes was found in RH group than in control. A multivariate analysis showed that patients with a history of diabetes, higher body mass index (BMI) and lipid profiles were independent risk factors of RH. CONCLUSIONS: The prevalence of RH in patients aged ≥ 80 years was within the range of reported rates of the general population. Subjects with RH diagnosis showed a higher occurrence of target organ damage than patients with well controlled blood pressure. Patients with diabetes, higher BMI and serum lipid profiles were independent risk factors for RH in patients aged ≥ 80 years.

Assessment of complications after liver surgery: Two novel grading systems applied to patients undergoing hepatectomy.

Although quality assessment is gaining increasing attention, there is still no consensus on how to define and grade postoperative complications. The absence of a definition and a widely accepted ranking system to classify surgical complications has hampered proper interpretation of the surgical outcome. This study aimed to define and search the simple and reproducible classification of complications following hepatectomy based on two therapy-oriented severity grading system: Clavien-Dindo classification of surgical complications and Accordion severity grading of postoperative complications. Two classifications were tested in a cohort of 2008 patients who underwent elective liver surgery at our institution between January 1986 and December 2005. Univariate and multivariate analyses were performed to link respective complications with perioperative parameters, length of hospital stay and the quality of life. A total of 1716 (85.46%) patients did not develop any complication, while 292 (14.54%) patients had at least one complication. According to Clavien-Dindo classification of surgical complications system, grade I complications occurred in 150 patients (7.47%), grade II in 47 patients (2.34%), grade IIIa in 59 patients (2.94%), grade IIIb in 13 patients (0.65%), grade IVa in 7 patients (0.35%), grade IVb in 1 patient (0.05%), and grade V in 15 patients (0.75%). According to Accordion severity grading of postoperative complications system, mild complications occurred in 160 patients (7.97%), moderate complications in 48 patients (2.39%), severe complications (invasive procedure/no general anesthesia) in 48 patients (2.39%), severe complications (invasive procedure under general anesthesia or single organ system failure) in 20 patients (1.00%), severe complications (organ system failure and invasive procedure under general anesthesia or multisystem organ failure) in 1 patient (0.05%), and mortality was 0.75% (n=15). Complication severity of Clavien-Dindo system and Accordion system were all correlated with the length of hospital stay, the number of hepatic segments resected, the blood transfusion and the Hospital Anxiety and Depression Scale-Anxiety (HADS-A). The Clavien-Dindo classification system and Accordion classification system are the simple ways of reporting all complications following the liver surgery.

Synthesis of Planar Chiral Ferrocenes via Transition-Metal-Catalyzed Direct C-H Bond Functionalization.

Ferrocenes are of great interest in the fields of materials science, organic synthesis, and biomedical research. Of particular significance is the fact that ferrocenes bearing planar chirality have been demonstrated to be highly efficient ligands or catalysts in asymmetric catalysis, some of which have been employed in the industrial synthesis of pharmaceuticals and agrochemicals. So far, the main methods for the synthesis of planar chiral ferrocenes involve diastereoselective directed ortho-metalation (DoM), enantioselective DoM, and chiral resolution. Despite the fact that these approaches are well developed and widely applied, the use of chiral auxiliaries or external stoichiometric chiral bases is required in most cases. Additionally, the practicality of these processes is hampered by the requirement of sensitive organometallic reagents, the poor compatibility with functional groups, and the low atom economy in some cases. Therefore, the development of highly efficient strategies to introduce planar chirality on the backbone of ferrocene that do not possess these limitations is highly desirable. Meanwhile, transition-metal-catalyzed asymmetric C-H bond functionalization reactions have attracted much attention over the past few years owing to their emerging potential for providing a straightforward approach for the preparation of chiral molecules. In addition to the majority of the work focusing on the installation of central chirality, methods for the catalytic asymmetric synthesis of planar chiral compounds via C-H bond functionalization have also been explored. In this Account, we summarize our recent efforts aimed at the development of novel methods to synthesize planar chiral compounds via asymmetric C-H bond functionalization and also highlight related achievements by other groups. First, we briefly introduce the precedent examples of diastereoselective and enantioselective synthesis of planar chiral ferrocenes. Subsequently, asymmetric syntheses of structurally diverse planar chiral ferrocenes via Pd [Pd(II), Pd(0)]-, Ir-, Rh-, Au-, and Pt-catalyzed C-H bond functionalization are described. These methods have impressive advantages over traditional approaches for the synthesis of functionalized planar chiral ferrocenes in terms of both step- and atom-economies. Notably, the products of these processes are easily transformed into a variety of new catalysts or ligands, which have been demonstrated to promote efficient asymmetric reactions. Moreover, DFT calculations have been conducted to explore the origin of the excellent enantioselectivity of Pd-catalyzed enantioselective C-H bond functionalization reactions. Progress made in the area of asymmetric C-H bond functionalization provides an effective platform for the design and synthesis of planar chiral ferrocenes.

Assessment of Complications after Liver Surgery: Two Novel Grading Systems Applied to Patients Undergoing Hepatectomy / 华中科技大学学报（医学）（英德文版）

Although quality assessment is gaining increasing attention,there is still no consensus on how to define and grade postoperative complications.The absence of a defimition and a widely accepted ranking system to classify surgical complications has hampered proper interpretation of the surgical outcome.This study aimed to define and search the simple and reproducible classification of complications following hepatectomy based on two therapy-oriented severity grading system:Clavien-Dindo classification of surgical complications and Accordion severity grading of postoperative complications.Two classifications were tested in a cohort of 2008 patients who underwent elective liver surgery at our institution between January 1986 and December 2005.Univariate and multivariate analyses were performed to link respective complications with perioperative parameters,length of hospital stay and the quality of life.A total of 1716 (85.46％) patients did not develop any complication,while 292 (14.54％)patients had at least one complication.According to Clavien-Dindo classification of surgical complications system,grade Ⅰ complications occurred in 150 patients (7.47％),grade Ⅱ in 47 patients (2.34％),grade Ⅲa in 59 patients (2.94％),grade Ⅲb in 13 patients (0.65％),grade Ⅳa in 7 patients (0.35％),grade Ⅳb in 1 patient (0.05％),and grade Ⅴ in 15 patients (0.75％).According to Accordion severity grading of postoperative complications system,mild complications occurred in 160 patients (7.97％),moderate complications in 48 patients (2.39％),severe complications (invasive procedure/no general anesthesia) in 48 patients (2.39％),severe complications (invasive procedure under general anesthesia or single organ system failure) in 20 patients (1.00％),severe complications (organ system failure and invasive procedure under general anesthesia or multisystem organ failure) in 1 patient (0.05％),and mortality was 0.75％ (n=15).Complication severity of Clavien-Dindo system and Accordion system were all correlated with the length of hospital stay,the number of hepatic segments resected,the blood transfusion and the Hospital Anxiety and Depression Scale-Anxiety (HADS-A).The Clavien-Dindo classification system and Accordion classification system are the simple ways of reporting all complications following the liver surgery.

Impact of operative and peri-operative factors on the long-term prognosis of primary liver cancer patients undergoing hepatectomy.

This study examined the impact of the operative and peri-operative factors on the long-term prognosis of patients with primary liver cancer undergoing hepatectomy. A total of 222 patients with primary liver cancer who underwent hepatectomy were followed up from January 1986 to December 2010 at Chinese PLA General Hospital. The post-operative complication rate was 14.0% for all cases, 13.7% for hepatocellular carcinoma (HCC), 10.0% for cholangiocarcinoma. The 1-, 3-, 5- and 10-year overall survival rates in patients with primary liver cancer after resection were 76.6%, 57.6%, 41.4%, and 21.0%. The survival rates were significantly higher in the HCC group than in the cholangiocarcinoma group (P=0.000), in the non-anatomical resection group than in the anatomical resection group (P=0.005), in the female group than in the male group (P=0.002), in patients receiving no blood transfusion than in those who were given intra-operative blood transfusion (P=0.000), in patients whose intra-operative blood loss was less than 400 mL than in those who intra-operatively lost more than 400 mL (P=0.000). No significant difference was found in the survival rate between the HBsAg-positive group and the HBsAg-negative group (P=0.532). Our study showed that anatomical resection, blood loss and blood transfusion were predictors of poor survival after hepatectomy for primary liver cancer patients, and concomitant hepatitis B virus infection bore no relation with the post-resection survival.

An Enantioselective Oxidative C-H/C-H Cross-Coupling Reaction: Highly Efficient Method To Prepare Planar Chiral Ferrocenes.

A Pd-catalyzed, asymmetric oxidative cross-coupling reaction between ferrocenes and heteroarenes is described. The process, which takes place via a twofold C-H bond activation pathway, proceeds with modest to high efficiencies (36-86%) and high levels of regio- and enantioselectivity (95-99% ee). In the reaction, air oxygen serves as a green oxidant and excess amounts of the coupling partners are not required. The process is the first example of a catalytic asymmetric biaryl coupling reaction that occurs via double C-H bond activation. Finally, the generated coupling products can be readily transformed into chiral ligands and catalysts.

Organocatalytic asymmetric chlorinative dearomatization of naphthols.

An organocatalytic asymmetric chlorinative dearomatization of naphthols was realized for the first time, providing chiral naphthalenones with a Cl-containing all-substituted stereocenter in excellent yields and enantioselectivity (up to 97% yield and 96% ee). The reaction features mild reaction conditions, good tolerance of diverse functional groups and simple reaction operation.

Enantioselective synthesis of planar chiral ferrocenes via Pd(0)-catalyzed intramolecular direct C-H bond arylation.

A highly efficient synthesis of planar chiral ferrocenes by enantioselective Pd(0)-catalyzed direct C-H arylation from readily available starting materials under mild reaction conditions was developed (up to 99% yield, 99% ee). The products can be easily transformed to the highly efficient planar ferrocene ligands, which have demonstrated high efficiency in Pd-catalyzed asymmetric allylic alkylation and amination reactions.

Enantioselective synthesis of planar chiral ferrocenes via palladium-catalyzed annulation with diarylethynes.

When Boc-L-Val-OH was used as a ligand for the enantioselective Pd(II)-catalyzed annulation of N,N-substituted aminomethyl ferrocene derivatives with diarylethynes, ferrocenes with planar chirality could be achieved with excellent enantioselectivity (up to 99% ee).

Enantioselective synthesis of planar chiral ferrocenes via palladium-catalyzed direct coupling with arylboronic acids.

Enantioselective Pd(II)-catalyzed direct coupling of aminomethylferrocene derivatives with boronic acids was realized. With commercially available Boc-L-Val-OH as a ligand, planar-chiral ferrocenes could be synthesized in yields of 14-81% with up to 99% ee under mild conditions.