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We developed performant in situ hypohalite, especially hypobromite, catalysis for the oxidative dearomatization of low-reactivity electron-deficient arenols. The reaction scope encompasses inter- and intramolecular oxidative dearomative C-O, C-N, and C-C coupling reactions. Notably, using a chiral ammonium countercation, we achieved enantioselective hypobromite catalysis for oxidative dearomative coupling reactions. Mechanistic studies revealed that the reaction mechanisms might differ depending on the halide identity.
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Here, we report a highly effective dearomative (3 + 2) cycloaddition reaction between isoquinolinium ylides and α,ß-enamides, α,ß-γ,δ-dienamides, or an α,ß-γ,δ-ε,ζ-trienamide, which is catalyzed by a chiral π-Cu(ii) complex (1-10 mol%) and proceeds in a site-selective, exo/endo-selective, and enantioselective manner. The (3 + 2) cycloaddition involving the α,ß-enamides proceeds with high exo-selectivity and enantioselectivity. This method is applicable to various substrates including α-substituted, α,ß-disubstituted, or ß,ß-disubstituted α,ß-enamides, which are compounds with an intrinsically low reactivity. This method provides synthetic access to pyrroloisoquinoline derivatives with up to three chiral carbon centers, including those featuring fluorine and trifluoromethyl groups, as well as quaternary carbon centers. The (3 + 2) cycloaddition involving α,ß-γ,δ-dienamides proceeds with high γ,δ-site-selectivity and enantioselectivity, whereby the exo/endo-selectivity depends on the substrates and ligands. Remarkably, the (3 + 2) cycloaddition of δ-phenyl-α,ß-γ,δ-dienamide proceeds with high α,ß-site-selectivity, exo-selectivity, and enantioselectivity. In a manner similar to the reaction with the α,ß-γ,δ-dienamides, α,ß-γ,δ-ε,ζ-trienamide furnishes a (3 + 2) cycloadduct with good ε,ζ-site-selectivity, endo-selectivity, and enantioselectivity.
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The clinical course of residual ventricular septal defects after congenital heart disease repair is not completely elucidated in the medical literature. This study assessed the incidence, size, and clinical course of residual defects.This single-center retrospective study included 132 patients who survived after ventricular septal defect patch closure (n = 107) and intracardiac repair of double-outlet right ventricle (n = 16) and tetralogy of Fallot (n = 9). Residual defect was evaluated on transthoracic echocardiogram upon hospital discharge and at outpatient clinic visits.The median age at surgery was 1.2 (0.3-13.9) years. In total, 45 (34.1%) patients presented with residual defects upon hospital discharge. The residual defects were within 2 mm (n = 27), 2-3 mm (n = 15), and > 3 mm (n = 3), and the median size was 1.5 (0.5-3.8) mm. There was no late mortality during a median follow-up of 5.4 years. Among 42 residual defects measuring < 3 mm upon hospital discharge, 37 (82.2%) spontaneously closed. Further, five defects decreased in size (1.8 ± 0.6 mm upon hospital discharge vs1.2 ± 0.8 mm at the latest visits, p = 0.15). However, the size of three residual defects measuring > 3 mm upon hospital discharge increased, and two patients required re-surgery for residual defect.Significant residual defect requiring reoperation was rare. In most cases, residual defects measuring < 3 mm upon hospital discharge spontaneously closed within 5 years, and the size of the other defects decreased.
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The effect of the U-shaped cavity of conformationally flexible chiral Lewis acidic boron-based catalysts in multiselective Diels-Alder reactions was investigated. The U-shaped catalysts can recognize substituents at the terminal acetylene moiety of propynal based on steric factors and can also recognize alkyne and alkene substrates based on the match/mismatch between the catalysts and substrates. Moreover, even in a mixture of different catalysts and substrates, the desired competitive reactions can proceed multiselectively. This proof-of-concept study should contribute to the development of artificial enzyme-like catalysis in vitro.
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BACKGROUND: Diabetic retinopathy (DR) is the leading cause of visual impairment and blindness. Consequently, numerous deep learning models have been developed for the early detection of DR. Safety-critical applications employed in medical diagnosis must be robust to distribution shifts. Previous studies have focused on model performance under distribution shifts using natural image datasets such as ImageNet, CIFAR-10, and SVHN. However, there is a lack of research specifically investigating the performance using medical image datasets. To address this gap, we investigated trends under distribution shifts using fundus image datasets. METHODS: We used the EyePACS dataset for DR diagnosis, introduced noise specific to fundus images, and evaluated the performance of ResNet, Swin-Transformer, and MLP-Mixer models under a distribution shift. The discriminative ability was evaluated using the Area Under the Receiver Operating Characteristic curve (ROC-AUC), while the calibration ability was evaluated using the monotonic sweep calibration error (ECE sweep). RESULTS: Swin-Transformer exhibited a higher ROC-AUC than ResNet under all types of noise and displayed a smaller reduction in the ROC-AUC due to noise. ECE sweep did not show a consistent trend across different model architectures. CONCLUSIONS: Swin-Transformer consistently demonstrated superior discrimination compared to ResNet. This trend persisted even under unique distribution shifts in the fundus images.
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Alkynyl addition to carbonyl compounds is a valuable synthetic method for the preparation of versatile chiral alcohols that are widely found in pharmaceuticals and natural products. Although a variety of enantioselective variations have been reported, alkynyl addition to simple ketones remains an unmet challenge due to their low reactivity and difficult enantiofacial discrimination. Here, we report a method for the catalytic enantioselective addition of lithium acetylide to a variety of ketones using macrocyclic lithium binaphtholates as catalysts. These reactions generally suffer from facile aggregation of lithium species, which leads to less active and selective catalysts. The macrocyclic structure designed in this study prevents such aggregation, affording a monomeric and highly active catalyst that can furnish enantioenriched tertiary alcohols from a variety of ketones within 5-30 min. Moreover, the confined cavity and lipophilicity of the macrocycle confer substrate specificity on the system, demonstrating a multiselectivity similar to that of enzymatic reactions. Thus, these findings offer new insights into the rational design of small-molecule artificial enzymes that exhibit high levels of reactivity and multiselectivity.
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Allenes are important building blocks, and derivatization of products via cycloadditions of allenes could become a powerful strategy for constructing carbocyclic and heterocyclic rings. However, the development of catalytic site-selective and enantioselective cycloaddition reactions of allenes still presents significant challenges. Here, we report chiral π-Cu(II)-complex-catalyzed isomerization of N-(3-butynoyl)-3,5-dimethyl-1H-pyrazole to generate N-allenoylpyrazole in situ and subsequent α,ß-site-selective and enantioselective [3 + 2], [4 + 2], or [2 + 2] cycloaddition or conjugate addition reactions. The asymmetric environment created by the intramolecular π-Cu(II) interactions provides the corresponding adducts in moderate to high yield with excellent enantioselectivity. To the best of our knowledge, this is the first successful method for chiral-Lewis-acid-catalyzed tandem isomerization/α,ß-site-selective and enantioselective cycloaddition or conjugate addition reactions of latent non-γ-substituted allenoyl derivative.
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Radical cations show a unique reactivity that is fundamentally different from that of conventional cations and have thus attracted considerable attention as alternative cationic intermediates for novel types of organic reactions. However, asymmetric catalysis to promote enantioselective radical cation reactions remains a major challenge in contemporary organic synthesis. Here, we report that the judicious design of an ion pair consisting of a radical cation and a chiral counteranion induces an excellent level of enantioselectivity. This strategy was applied to enantio-, diastereo-, and regioselective [2 + 2] cycloadditions, as well as enantio-, diastereo-, and regioselective [4 + 2] cycloadditions, by using chiral iron(III) photoredox catalysis. We anticipate that this strategy has the potential to expand the use of several mature chiral anions to develop numerous unprecedented enantioselective radical cation reactions.
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The first catalytic enantioselective aromatic Claisen rearrangement of allyl 2-naphthyl ethers using 5-10 mol% of π-copper(ii) complexes is reported. A Cu(OTf)2 complex with an l-α-homoalanine amide ligand gave (S)-products in up to 92% ee. Conversely, a Cu(OSO2C4F9)2 complex with an l-tert-leucine amide ligand gave (R)-products in up to 76% ee. Density-functional-theory (DFT) calculations suggest that these Claisen rearrangements proceed stepwise via tight-ion-pair intermediates, and that (S)- and (R)-products are enantioselectively obtained via the staggered transition states for the cleavage of the C-O bond, which is the rate-determining step.
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Catalyst design has traditionally focused on rigid structural elements to prevent conformational flexibility. Ishihara's elegant design of conformationally flexible C2-symmetric iodoarenes, a new class of privileged organocatalysts, for the catalytic asymmetric dearomatization (CADA) of naphthols is a notable exception. Despite the widespread use of the Ishihara catalysts for CADAs, the reaction mechanism remains the subject of debate, and the mode of asymmetric induction has not been well established. Here, we report an in-depth computational investigation of three possible mechanisms in the literature. Our results, however, reveal that this reaction is best rationalized by a fourth mechanism called "proton-transfer-coupled-dearomatization (PTCD)", which is predicted to be strongly favored over other competing pathways. The PTCD mechanism is consistent with a control experiment and further validated by applying it to rationalize the enantioselectivities. Oxidation of the flexible I(I) catalyst to catalytic active I(III) species induces a defined C2-symmetric helical chiral environment with a delicate balance between flexibility and rigidity. A match/mismatch effect between the active catalyst and the substrate's helical shape in the dearomatization transition states was observed. The helical shape match allows the active catalyst to adapt its conformation to maximize attractive noncovalent interactions, including I(III)···O halogen bond, N-H···O hydrogen bond, and π···π stacking, to stabilize the favored transition state. A stereochemical model capable of rationalizing the effect of catalyst structural variation on the enantioselectivities is developed. The present study enriches our understanding of how flexible catalysts achieve high stereoinduction and may serve as an inspiration for the future exploration of conformational flexibility for new catalyst designs.
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We serendipitously found an unprecedented 5-to-7-membered ring expansion of 2-alkylspiroindolenines to azepinoindoles mediated by n-tetrabutylammonium fluoride. The starting materials can be easily prepared by the hypoiodite-catalyzed oxidative dearomative spirocyclization of indole derivatives. Mildly basic conditions and electron-deficient protecting groups for the amines were found to be crucial to promoting chemoselective reactions. Moreover, the ring expansion of aniline-derived spiroindolenines proceeds smoothly under much milder conditions using only a catalytic amount of cesium carbonate.
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Given the industrial importance of (meth)acrylate esters, various groups have devoted considerable effort to investigating their chemoselective transesterification. In 2021, we developed magnesium(ii) and sodium(i) complexes derived from 2,6-di-tert-butyl-p-cresol (BHT-H) as chemoselective catalysts for the transesterification of methyl acrylate (MA) and methyl methacrylate (MMA), respectively. Based on our results, we report the discovery of magnesium(ii) and sodium(i) salts derived from 6,6'-(propane-2,2'-diyl)bis(2,4-di-tert-butylphenol) (PBTP-H2), i.e. Mg(PBTP) and Na2(PBTP), which are 41 and 81 times more effective catalysts than Mg(BHT)2 and Na(BHT) for the transesterification of MA and MMA, respectively. These new catalysts are highly effective across an extensive range of alcohols, including primary and secondary alcohols, diols, and triols. Overall, this efficient transesterification technology can be expected to find practical applications in industrial process chemistry.
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A chiral amidophosphate-N-iodosuccinimide cooperative catalysis has been developed for the site-, diastereo-, and enantioselective iodocyclization of 2-geranylarenols with molecular iodine to give the corresponding iodo-containing polycyclic compounds with good levels of selectivity. This is the first example of a catalytic enantioselective iodocarbocyclization. A reactive chiral iodonium species is generated from molecular iodine via the dual halogen-bonding interactions with a chiral Lewis base and Lewis acid. The sterically demanding 3,3'-substituents of the chiral BINOL-derived amidophosphate are critical to induce the site-selective iodination at the less-hindered terminal alkenyl moiety of 2-geranylarenols.
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We report the highly enantioselective α-amination of N-acyl-3,5-dimethylpyrazoles with dialkyl azodicarboxylates, catalyzed by in situ generated π-Cu(II) complexes that consist of Cu(OTf)2 and N-(5H-dibenzo[a,d][7]annulen-5-yl)-l-alanine-derived amides, to give the corresponding products as d-α-amino acid derivatives (up to >99% yield and 99% ee). The site-selectivity and enantioselectivity can be satisfactorily explained by the coordination of dialkyl azodicarboxylate with π-Cu(II) complex. The synthetic potential of this one-pot transformation to the α-amino ester is also described.
Assuntos
Amidas , Aminoácidos , Aminação , Estereoisomerismo , Catálise , Aminoácidos/química , AlaninaRESUMO
A multiselective Diels-Alder (DA) reaction of α-arylacroleins with cyclopentadiene using BBr3-assisted chiral BINOL-derived phosphoric acid catalysts has been developed. This unusual exo- and enantioselective DA reaction can be multicontrolled by the chiral cavity of the in situ-formed acid-base cooperative catalysts, in particular, suppressing the competitive hetero Diels-Alder (HDA) reaction effectively.
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Here we report the oxidative umpolung of 2,3-disubstituted indoles toward enantioselective dearomative aza-spirocyclization to give the corresponding spiroindolenines using chiral quaternary ammonium hypoiodite catalysis. Mechanistic studies revealed the umpolung reactivity of C3 of indoles by iodination of the indole nitrogen atom. Moreover, the introduction of pyrazole as an electron-withdrawing auxiliary group at C2 suppressed a competitive dissociative racemic pathway, and enantioselective spirocyclization proceeded to give not only spiropyrrolidines but also four-membered spiroazetidines that are otherwise difficult to access.
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Indóis , Estresse Oxidativo , Catálise , Compostos de Iodo , EstereoisomerismoRESUMO
We report the hypoiodite-catalyzed oxidative C-C homocoupling of arenols to biarenols or biquinones using aqueous hydrogen peroxide as an oxidant. In addition, by combining hypoiodite catalysis and lipophilic Lewis acid-assisted Brønsted acid catalysis under aqueous conditions, we achieved a tandem oxidation/cross-coupling reaction of hydroquinones with electron-rich arenes. These results highlight the substantial scope of hypoiodite/acid co-catalysis for use in oxidative coupling reactions.
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Insight into the mechanism of a safe, simple, and inexpensive phosphoric acid (H3PO4)-catalyzed acylation of alcohols with acid anhydrides is described. The corresponding in situ-generated diacylated mixed anhydrides, unlike traditionally proposed monoacylated mixed anhydrides, are proposed as the active species. In particular, the diacylated mixed anhydrides act as efficient catalytic acyl transfer reagents rather than as Brønsted acid catalysts simply activating acid anhydrides. Remarkably, highly efficient phosphoric acid (1-3 mol %)-catalyzed acylation of alcohols with acid anhydrides was achieved and a 23 g scale synthesis of an ester was demonstrated. Also, phosphoric acid catalyst was effective for synthetically useful esterification from carboxylic acids, alcohols, and acid anhydride. Moreover, with regard to recent developments in chiral 1,1'-bi-2-naphthol (BINOL)-derived phosphoric acid diester catalysts toward asymmetric kinetic resolution of alcohols by acylation, some phosphate diesters were examined. As a result, a 31P NMR study and a kinetics study strongly supported not only the acid-base cooperative mechanism as previously proposed by other researchers but also the mixed anhydride mechanism as presently proposed by us.