Iodomethane in C1 chemistry: application in palladium-catalyzed [2 + 2 + 1] annulation.

An efficient palladium-catalyzed [2 + 2 + 1] annulation of 3-iodochromones, bridged olefins, and iodomethane is described, affording a range of chromone-containing polycyclic compounds. Additionally, the corresponding deuterated products were smoothly obtained with iodomethane-d3 instead of iodomethane. Moreover, the synthetic utility of this method is further substantiated by gram scale preparation and application to late-stage modification of estrone.

Trifluoromethyl Rhodium-Carbynoid in [2+1+2] Cycloadditions.

Trifluoromethyl cationic carbyne (CF3 C+ :) possessing dual carbene-carbocation behavior emulated as trifluoromethyl metal-carbynoid (CF3 C+ =M) has not been explored yet, and its reaction characteristics are unknown. Herein, a novel α-diazotrifluoroethyl sulfonium salt was prepared and used in Rh-catalyzed three-component [2+1+2] cycloadditions for the first time with commercially available N-fused heteroarenes and nitriles, yielding a series of imidazo[1,5-a] N-heterocycles that are of interest in medicinal chemistry, in which the insertion of trifluoromethyl Rh-carbynoid (CF3 C+ =Rh) into C=N bonds of N-fused heteroarenes was involved. This strategy demonstrates synthetic applications in late-stage modification of pharmaceuticals, construction of CD3 -containing N-heterocycles, gram-scale experiments, and synthesis of phosphodiesterase 10A inhibitor analog. These highly valuable and modifiable imidazo[1,5-a] N-heterocycles exhibit good antitumor activity in vitro, thus demonstrating their potential applications in medicinal chemistry.

Biocatalytic Synthesis of Metaxalone and Its Analogues.

A biocatalytic approach for the synthesis of metaxalone and its analogues was developed based on the reaction of epoxides and cyanate catalyzed by halohydrin dehalogenase. Gram-scale synthesis of chiral and racemic metaxalone was achieved with 44% (98% ee) and 81% yields, respectively, by protein engineering of the halohydrin dehalogenase HHDHamb from Acidimicrobiia bacterium. Additionally, various metaxalone analogues were synthesized at 28-40% yields (90-99% ee) for chiral forms and 77-92% yields for racemic forms.

Early Diastolic Peak Velocity of Mitral Valve Annulus and Right Ventricular Systolic Tricuspid Annular Velocity as Predictors in Assessing Prognosis of Patients with Sepsis.

Objective: To analyze the epidemiological data of patients with septic cardiomyopathy and investigate the relationship between ultrasonic parameters and prognosis of patients with sepsis. Methods: In this study, we enrolled patients with sepsis who were treated at the Department of Critical Care Medicine in the Beijing Electric Power Hospital (No.1 Taipingqiao Xili, Fengtai District, Beijing) from January 2020 to June 2022. All patients received standardized treatment. Their general medical status and 28-day prognosis were recorded. Transthoracic echocardiography was performed within 24 hours after admission. We compared the ultrasound indexes between the mortality group and the survival group at the end of 28 days. We included parameters with significant difference in the logistic regression model to identify the independent risk factors for prognosis and evaluated their predictive value using receiver operating characteristic (ROC) curve. Results: We included 100 patients with sepsis in this study; the mortality rate was 33% and the prevalence rate of septic cardiomyopathy was 49%. The peak e' velocity and right ventricular systolic tricuspid annulus velocity (RV-Sm) of the survival group were significantly higher than those of the mortality group (P < 0.05). Results of logistic regression analysis showed that the peak e' velocity and RV-Sm were independent risk factors for prognosis. The area under curve of the peak e' velocity and the RV-Sm was 0.657 and 0.668, respectively (P < 0.05). Conclusion: The prevalence rate of septic cardiomyopathy in septic patients is high. In this study, we found that the peak e' velocity and right ventricular systolic tricuspid annulus velocity were important predictors of short-term prognosis.

Cooperative Tertiary Amine/Palladium-Catalyzed Sequential [4 + 3] Cyclization/[1,3]-Rearrangement for Stereoselective Synthesis of Spiro [Methylenecyclopentane-1,3'-oxindolines].

A cooperative tertiary amine/palladium-catalyzed sequential reaction process, proceeding via a [4 + 3] cyclization of isatin-derived Morita-Baylis-Hillman Expansion (MBH) carbonates and tert-butyl 2-(hydroxymethyl)allyl carbonates followed by a [1,3]-rearrangement, has been found and developed. A range of structurally diverse spiro[methylene cyclopentane-1,3'-oxindolines] bearing two adjacent ß,γ-acyl quaternary carbon stereocenters, which are difficult to obtain by conventional strategies, were obtained in good yields. Further synthetic utility of this protocol is highlighted by its excellent regio- and stereocontrol as well as the large-scale synthesis and diverse functional transformations of the synthetic compounds. Moreover, the control experiments probably established the plausible mechanism for this sequential [4 + 3] cyclization/[1,3]-rearrangement process.

Palladium-Catalyzed Domino Reaction for the Assembly of Norbornane-Containing Chromones with Dimethyl Squarate as the Solid C1 Source.

Reported herein is a novel palladium-catalyzed [2 + 2 + 1] domino annulation of 3-iodochromones, bridged olefins, and dimethyl squarate allowing the construction of chromone-containing polycyclic compounds in good to high yields. Importantly, dimethyl squarate is first employed as the solid C1 source in organic synthesis. Gram-scale experiments, late-stage modification of natural products, as well as transformations of products show potential for further synthetic elaborations.

Biocatalytic Thionation of Epoxides for Enantioselective Synthesis of Thiiranes.

Expanding the enzymatic toolbox for the green synthesis of valuable molecules is still of high interest in synthetic chemistry and the pharmaceutical industry. Chiral thiiranes are valuable sulfur-containing heterocyclic compounds, but relevant methods for their enantioselective synthesis are limited. Herein, we report a biocatalytic thionation strategy for the enantioselective synthesis of thiiranes, which was developed based on the halohydrin dehalogenase (HHDH)-catalyzed enantioselective ring-opening reaction of epoxides with thiocyanate and a subsequent nonenzymatic rearrangement process. A novel HHDH was identified and engineered for enantioselective biocatalytic thionation of various aryl- and alkyl-substituted epoxides on a preparative scale, affording the corresponding thiiranes in up to 43 % isolated yield and 98 % ee. Large-scale synthesis and useful transformations of chiral thiiranes were also performed to demonstrate the utility and scalability of the biocatalytic thionation strategy.

Cu-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of N-2,2,2-Trifluoroethylisatin Ketimines Enables the Desymmetrization of N-Arylmaleimides: Access to Enantioenriched F3C-Containing Octahydropyrrolo[3,4-c]pyrroles.

With a Cu(OTf)2/chiral ferrocenyl P,N-ligand complex as a catalyst, the enantioselective desymmetrization of N-arylmaleimides was successfully realized by taking advantage of the asymmetric 1,3-dipolar cycloaddition reaction of N-2,2,2-trifluoroethylisatin ketimines. A series of structurally diverse F3C-containing octahydropyrrolo[3,4-c]pyrroles, bearing four contiguous carbon stereocenters and one stereogenic chiral C-N axial bond, were obtained with excellent results (≤99% yield, >20:1 dr, and 99% ee).

Copper-Catalyzed [5 + 1] Cyclization of o-Pyrrolo Anilines and Heterocyclic N-Tosylhydrazones for Access to Spiro-dihydropyrrolo[1,2-a]quinoxaline Derivatives.

An inexpensive copper-catalyzed sequential reaction process, proceeding via a nucleophilic attack of amine to Cu-carbene generated in situ from heterocyclic N-tosylhydrazone precursors followed by a 1,2-H shift/oxidative cyclization cascade of N-ylides, has been described, smoothly generating the corresponding structurally various spiro-dihydropyrrolo[1,2-a]quinoxaline derivatives. Furthermore, the significance of this protocol can be also highlighted by its diverse conversions of the synthetic compounds to the potentially bioactive molecules such as the 2-substituted pyrrolo[1,2-a]quinoxalins.

Diazotrifluoroethyl Radical: A CF3-Containing Building Block in [3 + 2] Cycloaddition.

We present herein a visible-light-induced [3 + 2] cycloaddition of a hypervalent iodine(III) reagent with α-ketoacids for the construction of 5-CF3-1,3,4-oxadiazoles that are of importance in medicinal chemistry. The reaction proceeds smoothly without a photocatalyst, metal, or additive under mild conditions. Different from the well-established trifluorodiazoethane (CF3CHN2), the diazotrifluoroethyl radical [CF3C(·)N2], a trifluoroethylcarbyne (CF3CC:) equivalent and an unusual CF3-containing building block, is involved in the present reaction system.

Regiodivergent and stereoselective hydroxyazidation of alkenes by biocatalytic cascades.

Asymmetric functionalization of alkenes allows the direct synthesis of a wide range of chiral compounds. Vicinal hydroxyazidation of alkenes provides a desirable path to 1,2-azidoalcohols; however, existing methods are limited by the control of stereoselectivity and regioselectivity. Herein, we describe a dual-enzyme cascade strategy for regiodivergent and stereoselective hydroxyazidation of alkenes, affording various enantiomerically pure 1,2-azidoalcohols. The biocatalytic cascade process is designed by combining styrene monooxygenase-catalyzed asymmetric epoxidation of alkenes and halohydrin dehalogenase-catalyzed regioselective ring opening of epoxides with azide. Additionally, a one-pot chemo-enzymatic route to chiral ß-hydroxytriazoles from alkenes is developed via combining the biocatalytic cascades and Cu-catalyzed azide-alkyne cycloaddition.

Palladium-catalyzed asymmetric allylic alkylation of 3-aminooxindoles to access chiral homoallylic aminooxindoles.

An organometal catalytic conversion of 3-aminooxindoles for the diastereo- and enantioselective synthesis of homoallylic aminooxindoles has been described. The asymmetric allylic alkylation of 3-aminooxindoles with allyl carboxylates proceeded smoothly to afford a series of chiral 3-allyl-3-aminooxindoles. This work offers an alternative route to build these scaffolds. The application of this protocol is also highlighted by a significant conversion of products to the potential applicable spiro[indoline-3,2'-pyrrolidin]-2-one derivatives.

Synthesis of chromone-containing polycyclic compounds via palladium-catalyzed [2 + 2 + 1] annulation.

A palladium-catalyzed [2 + 2 + 1] domino annulation of 3-iodochromones, α-bromo carbonyl compounds, and tetracyclododecene (TCD) is described. This approach provides a facile, efficient and atom-economical route to a variety of chromone-containing polycyclic compounds bearing fused/bridged-ring systems in good yields (up to 81%) with excellent diastereoselectivities (99 : 1 dr in all cases).

Ex Situ Generation of Difluorodiazoethane (CF2HCHN2): Application in the Regioselective Synthesis of CF2H-Containing Pyrazoles.

A new method for the ex situ generation of difluorodiazoethane (CF2HCHN2) and a procedure for its efficient use in [3 + 2] cycloaddition with nitroolefins by the AcOH/O2 catalyst system were developed by using a simple two-chamber system. The method provides a facile and straightforward access to a series of 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazoles that are of interest in medicinal chemistry. Interestingly, the key factor for the success of this method is the efficient preparation of CF2HCHN2 by an ex situ process.

2,2-Bifunctionalization of Norbornene in Palladium-Catalyzed Domino Annulation.

A palladium-catalyzed three-component [2 + 3 + 1] domino annulation among 3-iodochromones, α-bromoacetophenones, and norbornene is presented, affording various chromone-containing polycyclic compounds bearing fused/spiro/bridged-ring systems. For the first time, the 2,2-bifunctionalization of norbornene was realized in palladium-catalyzed domino reaction. This cyclization characterizes three new bonds (two C-C and one C-O) in a single operation and produces nontrivial spiro-norbornane fragments in comparison with a traditional palladium-catalyzed process involving norbornene.

Asymmetric [3 + 2] Cycloaddition Reaction of Isatin-Derived MBH Carbonates with 3-Methyleneoxindoles: Enantioselective Synthesis of 3,3'-Cyclopentenyldispirooxindoles Incorporating Two Adjacent Quaternary Spirostereocenters.

A highly regio- and stereoselective [3 + 2] cycloaddition reaction for constructing novel 3,3'-cyclopentenyldispirooxindoles incorporating two adjacent quaternary spirostereocenters is reported. Under the mild conditions, the asymmetric annulation of isatin-derived MBH carbonates with 3-methyleneoxindoles involving a chiral tertiary amine catalyst provides the corresponding dispirooxindole frameworks with an extraordinary level of enantioselective control. Further synthetic utility of this method was demonstrated by the gram-scale experiment and simple transformation of the obtained product. Moreover, a plausible mechanism for this annulation reaction was also proposed on the basis of the control experiments.

A Protocol for the Synthesis of CF2H-Containing Pyrazolo[1,5- c]quinazolines from 3-Ylideneoxindoles and in Situ Generated CF2HCHN2.

Herein is disclosed a selective and facile approach for the construction of CF2H-containing pyrazolo[1,5- c]quinazolines from easily accessible 3-ylideneoxindoles and in situ generated CF2HCHN2. The reaction involving a [3 + 2] cycloaddition/1,3-H shift/rearrangement/dehydrogenation cascade proceeded smoothly at room temperature in the absence of catalyst and additive. Moreover, this metal-free process along with mild conditions is desirable and valuable for the pharmaceutical industry. Importantly, this reaction features a broad substrate scope, good functional group tolerance, and gram-scale synthesis.

Diastereoselective [3 + 2] cycloaddition of 3-ylideneoxindoles with in situ generated CF2HCHN2: syntheses of CF2H-containing spirooxindoles.

An efficient [3 + 2] cycloaddition of 3-ylideneoxindoles with in situ generated CF2HCHN2 for the syntheses of spirooxindoles has been developed. This methodology gives access to a range of relatively complex spirooxindoles featuring a CF2H group and three contiguous stereogenic centers in up to 84% yield and 99 : 1 trans/cis.

[Anesthesia and perioperative management for cesarean section in patient with factor XI deficiency: a case report].

Factor XI deficiency is a hereditary blood coagulation disorders. Puerpera with factor XI deficiency is exceedingly rare. A case of a 28-year-old woman who was found to have factor XI deficiency coagulopathy at the end of 33 weeks of gestation was presented here, and was admitted to Peking University Third Hospital at the end of 38 weeks of gestation. The doctors from several departments conducted cooperative management, and prepared with supplement of the coagulant factor and fresh frozen plasma before operation. The woman had general anesthesia, the baby was delivered successfully and the mother's condition was kept stable. The amount of bleeding of puerpera was not much perioperation. Yet the management of cesarean section with factor XI deficiency at home and abroad is still lack of standard guideline by now.

Asymmetric synthesis of ß-hydroxy-α-amino phosphonic acid derivatives via organocatalytic direct aldol reaction of α-isothiocyanato phosphonates with aldehydes.

α-Isothiocyanato phosphonates are first used as nucleophiles to react with aldehydes for the asymmetric synthesis of ß-hydroxy-α-amino phosphonic acid derivatives. The process is catalyzed by a quinine-derived thiourea via cascade aldol/cyclization reaction, affording a wide range of protected ß-hydroxy-α-amino phosphonates containing adjacent quaternary-tertiary stereocenters in up to 93% yield, up to 81% ee, and >99:1 dr. This work represents the first example of α-isothiocyanato phosphonates serving as nucleophiles that are used in the catalytic asymmetric synthesis.