Switchable Chemo-, Regio- and Pseudo-Stereodivergence in Palladium-Catalyzed Cycloaddition of Allenes.

Here, we report a strategy enabling triple switchable chemo-, regio-, and stereodivergence in newly developed palladium-catalyzed cycloadditions of allenes. An asymmetric pseudo-stereodivergent cycloaddition of allenes bearing a primary leaving group at the α-position, where a dynamic kinetic asymmetric hydroalkoxylation of racemic unactivated allenes was the enantio-determining step, is realized, providing four stereoisomers [(Z,R), (Z,S), (E,S), and (E,R)] containing a di-substituted alkene scaffold and a stereogenic center. By tuning reaction conditions, a mechanistically distinctive cycloaddition is uncovered selectively with the same set of substrates. By switching the position of the leaving group of allenes, a cycloaddition involving an intermolecular O-attack is disclosed. Diverse mechanisms of the cycloaddition reactions of allenes enable rapid access to structurally and stereochemically diverse 3,4-dihydro-2H-1,4-benzoxazines in high efficiency and selectivity.

Catalytic Enantioselective Desymmetrization of Prochiral Triacylamines via Pseudopeptidic Guanidine-Guanidinium Catalysis.

Triacylamines with Cs symmetry have been explored in asymmetric organocatalysis, leading to the development of a novel catalytic enantioselective desymmetrization of prochiral triacylamines by methanolysis under the catalysis of chiral pseudopeptidic guanidine-guanidinium salt having a weakly coordinating anion. This organocatalytic methodology provides an effective approach to the synthetically useful chiral imide-esters with a 1,5-dicarbonyl moiety, and its synthetic potential has been manifested in the asymmetric synthesis of two GABA analogue drugs, (R)-Baclofen·HCl and (S)-Pregabalin.

Analysis of healthcare-associated infection in patients with pulmonary arterial hypertension associated with congenital heart disease in PICU: Evidence from a tertiary hospital in western China.

Objective: The present study intends to analyze the targeted surveillance and risk factors for healthcare-associated infection (HAI) in patients with pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) in a Pediatric intensive care unit (PICU), and provide basis for formulating relevant prevention and control measures of HAI. Methods: Children (≤14 years old) who were admitted to the PICU for ≥2 calendar days from January 2018 to December 2021 were included. Targeted surveillance of HAI was described. Results: A total of 7,828 patients in PICU were monitored, and the total hospitalization days of the patients were 36,174. 108 cases of HAI occurred, with a per-case infection rate of 1.38% and a per-thousand day infection rate of 2.99. 1,129 patients with CHD-PAH were included, among which the total hospitalization days were 1,483. In this subpopulation, 38 cases of HAI were diagnosed, with a per-case infection rate of 3.37% and a per-thousand day infection rate of 25.62. The main site of HAI was lower respiratory tract (43.51%), followed by blood infection (34.26%) and surgical site infection (9.26%). 36 strains of pathogenic bacteria were detected from patients with HAI. The top three pathogens with the highest detection rate were Klebsiella pneumoniae (6 episodes, 16.67%), Enterococcus faecium (6 episodes, 16.67%) and Acinetobacter baumannii (4 episodes, 11.11%). The incidence of VAP, CAUTI and CLABSI was 2.78, 0.08 and 1.66 per 1,000 catheter days respectively. Analysis revealed that patients with CHD-PAH were younger and prone to receive surgical corrections. CHD-PAH could significantly increase the length of ICU stay, ventilator days, times of central venous catheterization and central venous catheterization days. The choice of different central venous catheter types differed significantly between the two groups. Conclusion: Patients with CHD-PAH are characterized with excessive central venous catheterization operations, prolonged indwelling time, and more types of catheterization, which are considered to be risk factors for HAI, thus increasing the length of hospital stay. The clinical etiology is mainly G-bacteria, which requires reasonable selection of antibiotics and strict aseptic operation. Limiting unnecessary invasive procedures is helpful for reducing the incidence of postoperative HAI in PICU.

Tandem (2 + 2) Annulation/Retro-4π Electrocyclization/Imino-Nazarov Cyclization Reaction of p-Quinone Methides with Ynamides: Expeditious Construction of Functionalized Aminoindenes.

A new tandem annulation of p-quinone methides (p-QMs) with ynamides is described. This cascade reaction features a unique combination of (2 + 2) annulation, retro-4π electrocyclization, and imino-Nazarov cyclization, wherein vinyl p-quinone methides (p-VQMs) as one of the key intermediates have been identified chemically. Significantly, an unusual structural reconstruction of p-QMs involving the cleavage of the C5-C6 bond and the late-stage formation of the C4-C6 bond is involved, leading to a methodology development for the construction of functionalized aminoindenes.

Palladium-Catalyzed Asymmetric (4 + 2) Annulation of γ-Methylidene-δ-valerolactones with Alkenes: Enantioselective Synthesis of Functionalized Chiral Cyclohexyl Spirooxindoles.

An unprecedented asymmetric catalytic (4 + 2) annulation reaction of aryl-substituted γ-methylidene-δ-valerolactones (GMDVs) with isatin-derived para-quinone methides (p-QMs) has been developed under the catalysis of palladium(0) and (S,S,S)-(-)-Xyl-SKP, offering a new approach for the diastereo- and enantioselective synthesis of chiral cyclohexadienone-fused cyclohexyl spirooxindoles. Significantly, three highly congested contiguous tetrasubstituted carbon atoms embedded in bispirocyclic skeleton, of which two are vicinal quaternary stereogenic centers, are forged in an effective and selective manner (up to 99% yield, up to 95% ee, >20/1 dr). The current reaction represents the first exploration of enantioselective catalytic (4 + 2) annulation forming the six-membered carbocycles in the chemistry of both GMDVs and p-QMs.

Palladium-Catalyzed Asymmetric Direct Intermolecular Allylation of α-Aryl Cyclic Vinylogous Esters: Divergent Synthesis of (+)-Oxomaritidine and (-)-Mesembrine.

We demonstrate that α-aryl cyclic vinylogous esters are competent substrates in the direct intermolecular Pd-catalyzed asymmetric allylic alkylation, enabling a straightforward enantioselective synthesis of 6-allyl-6-aryl-3-ethoxycyclohex-2-en-1-ones, common motifs embedded in numerous structurally diverse natural products. As an initial demonstration of the utility of this protocol, the first catalytic enantioselective total synthesis of (+)-oxomaritidine and an improved five-step catalytic enantioselective synthesis of (-)-mesembrine have been completed divergently.

P(NMe2)3-Mediated Umpolung Spirocyclopropanation Reaction of p-Quinone Methides: Diastereoselective Synthesis of Spirocyclopropane-Cyclohexadienones.

An unprecedented umpolung spirocyclopropanation reaction of p-quinone methides and α-keto carbonyls is described. Our umpolung strategy based on 1,6-conjugate addition and intramolecular nucleophilic substitution offers a new method for effective access to a series of highly functionalized spirocyclohexadienonyl cyclopropanes having two vicinal quaternary carbons in ≤98% yield and >20:1 dr. Significantly, cyclic and acyclic topological structures of α-keto carbonyls as 1,1-dipole one-carbon synthons have a distinct influence on the stereochemistry of products, showing a reversal of diastereoselectivity in this P(NMe2)3-mediated umpolung spirocyclopropanation.

Palladium-Catalyzed Asymmetric (2+3) Annulation of p-Quinone Methides with Trimethylenemethanes: Enantioselective Synthesis of Functionalized Chiral Spirocyclopentyl p-Dienones.

A novel asymmetric catalytic (2+3) annulation of p-quinone methides with CN-substituted trimethylenemethane is described under palladium catalysis, providing an alternative approach for the enantioselective construction of highly functionalized chiral spirocyclopentyl p-dienones. Driven by the significant improvement in the reactivity and enantioselectivity, a novel type of non-C2-symmetric phosphoramidite ligand from the chirality-matched combination of (S)-BINOL and sterically demanding amine derived from l-hydroxyproline is evolved and explored for the protocol presented here.

Enantioselective synthesis of chiral α-alkynylated thiazolidones by tandem S-addition/acetalization of alkynyl imines.

A SPINOL-derived chiral phosphoric acid catalyzed asymmetric formal [2 + 3]-annulation of in situ generated alkynyl imines and 1,4-dithiane-2,5-diol has been developed to afford enantiopure α-alkynylated thiazolidones with up to 72% yield and 98.5 : 1.5 er. This tandem annulation involved a tandem S-addition of alkynyl imines/intramolecular acetalization, followed by PDC-mediated oxidation. The α-alkynylated thiazolidones could facilely afford the corresponding chiral α-alkynylated or α-alkenylated cyclic sulfoxides via further elaboration.

Catalytic Asymmetric [4 + 2] Cycloaddition of ortho-Alkenyl Naphthols/Phenols with ortho-Quinone Methides: Highly Stereoselective Synthesis of Chiral 2,3,4-Trisubstituted Chromans.

Chiral phosphoric acid-catalyzed biomimetic asymmetric [4 + 2] cycloaddition of ortho-alkenyl naphthols/phenols and ortho-quinone methides (o-QMs) has been demonstrated to afford various important 2,3,4-trisubstituted chromans in high yields with excellent enantio- and diastereoselectivities (up to 99% yield, 99% ee, >20:1 dr). Notably, this methodology not only enabled access to the trans-cis chiral trisubstituted chromans from 1-alkenyl 2-naphthols but also is compatible with 2-alkenyl 1-naphthols and phenols to deliver trans-trans chiral trisubstituted chromans.

Enantioselective Synthesis of Functionalized 4-Aryl Hydrocoumarins and 4-Aryl Hydroquinolin-2-ones via Intramolecular Vinylogous Rauhut-Currier Reaction of para-Quinone Methides.

A novel strategy for the asymmetric construction of functionalized 4-aryl-3,4-dihydrocoumarins and 4-aryl-3,4-dihydroquinolin-2-ones via an intramolecular vinylogous Rauhut-Currier reaction of para-quinone methides (p-QMs) under the bifunctional catalysis of chiral amine-phosphine is described. This intramolecular mode for the catalytic enantioselective 1,6-conjugate addition of p-QMs has been explored for the first time, delivering two types of synthetically important heterocycles in high yields and enantioselectivites.

Au-Catalyzed [2 + 3] Annulation of Enamides with Propargyl Esters: Total Synthesis of Cephalotaxine and Cephalezomine H.

A novel Au-catalyzed [2 + 3] annulation reaction of enamides with propargyl esters has been developed, providing a new method for expeditious assembly of synthetically useful functionalized 1-azaspiro[4.4]nonane building blocks. Based on this key annulation, strategic installation of the pivotal azaspirocyclic core, followed by constructing the benzazepine unit via Witkop cyclization, led to the divergent total syntheses of cephalotaxine and cephalezomine H.

Cinchona Alkaloid Catalyzed Enantioselective [4 + 2] Annulation of Allenic Esters and in Situ Generated ortho-Quinone Methides: Asymmetric Synthesis of Functionalized Chromans.

A novel enantioselective [4 + 2] annulation of the allenoates having a unique positive ortho-effect with in situ generated ortho-quinone methides has been developed under the catalysis of Cinchona alkaloid. This chiral amine-catalyzed reaction provides an alternative route to asymmetric catalytic construction of synthetically interesting, highly functionalized chiral chromans in good to excellent enantioselectivities (up to 97% ee).

Total Synthesis of (±)-Lycojaponicumin D and Lycodoline-Type Lycopodium Alkaloids.

Lycopodium alkaloids with structural diversity and biological significance have been stimulating an increasing interest in the synthetic and medicinal communities, in which inspiration and exploration of their related biogenetic relationship generally constitute one of the major concerns. Driven by the plausible biogenetic entry to lycojaponicumin D as the first member of Lycopodium alkaloids having a structurally unusual C3-C13-linked scaffold, a new connection with lycodoline has been proposed and discovered on the basis of the design of an unprecedented bioinspired tandem fragmentation/Mannich reaction. Initiated by expeditious assembly of bridgehead heterofunctionalization in the [3.3.1] bicyclic system of lycodoline, a novel tandem palladium-mediated oxidative dehydrogenation/hetero-Michael reaction has been developed for the strain-driven formation of the C-heteroatom bond, leading to a new approach to conformationally rigid bridgehead heteroquaternary carbons. The present unified strategy provides a scenario for the divergent total syntheses of nine natural Lycopodium alkaloids and four unnatural C12 epimers, wherein (±)-lycojaponicumin D and six lycodoline-type alkaloids have been synthetically achieved for the first time.

Tandem Spirocyclopropanation/Rearrangement Reaction of Vinyl p-Quinone Methides with Sulfonium Salts: Synthesis of Spirocyclopentenyl p-Dienones.

A novel base-mediated tandem spirocyclopropanation/rearrangement reaction of vinyl p-quinone methides (p-VQMs) with sulfonium salts is described. The unprecedented reactivity of p-VQMs was explored for the first time in the spiroannulation cascade, providing a stereoselective approach to the construction of synthetically interesting, densely functionalized spirocyclopentenyl p-dienones.

Diastereoselective and Enantioselective Synthesis of Unsymmetric ß,ß-Diaryl-α-Amino Acid Esters via Organocatalytic 1,6-Conjugate Addition of para-Quinone Methides.

A novel strategy based on phase transfer catalysis for the diastereoselective and enantioselective direct assembly of unsymmetric ß,ß-diaryl-α-amino acid esters via 1,6-conjugate addition of para-quinone methides and glycine derivatives is described. This protocol also provides an alternative route to the synthetically interesting functionalized chiral tetrahydroisoquinoline and its analogues.

Spirocyclopropanation Reaction of para-Quinone Methides with Sulfonium Salts: The Synthesis of Spirocyclopropanyl para-Dienones.

A novel DBU-mediated stereoselective spirocyclopropanation of para-quinone methides with sulfonium salts has been developed on the basis of the mode involving a 1,6-conjugate addition/intramolecular dearomatizing cyclization cascade. This reaction provides a mild and effective method for the assembly of synthetically and structurally interesting spirocyclopropanyl para-dienones. The feasibility for the enantioselective access to such functionalized para-dienones has also been explored by using the axially chiral sulfonium salt. Importantly, the regioselective ring openings of the related spirocyclopropanyl para-dienones have been achieved divergently.

Bifunctional tertiary amine-squaramide catalyzed asymmetric catalytic 1,6-conjugate addition/aromatization of para-quinone methides with oxindoles.

The asymmetric catalytic 1,6-addition of p-QMs with racemic oxindoles under the bifunctional catalysis of C2-symmetric dimeric Cinchona-derived squaramide is described. This tertiary amine-squaramide catalyzed reaction provides a diastereoselective and enantioselective approach to the effective assembly of diverse diarylmethine-substituted oxindoles having vicinal tertiary and quaternary stereocenters.

Highly enantioselective aldol reactions between acetaldehyde and activated acyclic ketones catalyzed by chiral primary amines.

Highly enantioselective cross-aldol reactions between acetaldehyde and activated acyclic ketones are reported for the first time. Various acyclic ketones, such as saturated and unsaturated keto esters, reacted with acetaldehyde in the presence of a chiral primary amine and a Brønsted acid to afford optically enriched tertiary alcohols in good yields and with excellent enantioselectivities. Trifluoromethyl ketones were tolerable under the reaction conditions, thereby affording the trifluoromethyl carbinol in good-to-excellent yields and enantioselectivities. Structural modification of the chiral amines from the same chiral source switched the stereoselectivity of the products. The utility of aldol chemistry was demonstrated in the brief synthesis of functionally enriched δ-lactones. Theoretical calculations on the transition-state structure indicated that the protonated tertiary amine could effectively activate the carbonyl group of a keto ester to promote the addition process through hydrogen-bonding interaction and, simultaneously, provide an appropriate attacking pattern for the approach of the keto ester to the enamine, which is formed from acetaldehyde and the chiral catalyst, on a particular face, resulting in high enantioselectivity.

Combinatory effects of hepatic CD8+ and NK lymphocytes in bile duct injury from biliary atresia.

INTRODUCTION: To our knowledge, elucidating the immune pathogenesis of disease, especially characteristic T-cell and natural killer (NK) cell expansions, has not been performed before now. We investigated the role of T lymphocytes and NK lymphocytes in the destruction of extrahepatic bile ducts of patients with biliary atresia. METHODS: Lymphocytes from the liver and extrahepatic bile duct remnants of patients with biliary atresia were characterized by immunofluorescence staining, fluorescence-activated cell sorter analysis, and real-time reverse-transcriptase PCR. Cholangiocyte lysis assays were performed to confirm cytotoxicity of activated hepatic NK lymphocytes or CD8(+) cells. RESULTS: The inflammatory milieu from portal tracts and/or biliary remnants consisted of greater numbers of Kupffer cells, T lymphocytes, and NK lymphocytes in the patients with biliary atresia as compared with the cholestatic and noncholestatic controls. In patients with biliary atresia, expression of NK or CD8+ costimulatory molecules was upregulated as compared with controls. Hepatic NK lymphocytes or CD8(+) cells from patients with biliary atresia were demonstrated to be cytotoxic to the duct epithelium. DISCUSSION: Specific immune responses from NK and CD8(+) cells were involved in the injury to the duct epithelium and play a significant role in the phenotype of experimental biliary atresia.