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Chiral Lewis acid catalysts are widely used in organic synthesis due to their diverse applications. However, their high Lewis acidity makes them susceptible to deactivation by basic Lewis reagents and water. Here, we present a novel strategy for mitigating this deactivation using small molecules. By incorporating weakly coordinating anions into the secondary coordination sphere of the metal center, we designed a highly reusable chiral Lewis acid complex. This complex exhibits excellent thermal stability and allows for the use of electron-poor nucleophiles in the reactions. Spectroscopic and titration studies confirmed the robustness of the optimized complex. This work provides valuable insights for overcoming the limitations of chiral Lewis acids in Lewis basic environments, expanding their potential for chemical synthesis.
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This work demonstrates the effectiveness of vigorously stirred lanthanum oxide (La2O3) suspensions in catalyzing Michael additions in water. These surfactant-free suspensions offer a counterintuitive yet highly efficient approach compared to traditional methods. Notably, the reactions are ineffective in the absence of water, suggesting a crucial role for the aqueous environment.
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This work presents an acid-free method for aromatic nitrosation using 2-methoxyethyl nitrite (MOE-ONO). While originally developed as a NOx radical source in our group, we demonstrate the utility of MOE-ONO as a NO cation source for aromatic electrophilic nitrosation. This method successfully nitrosates phenols, naphthols, and other pronucleophiles, completely suppressing undesired nitration by NOx radicals. Notably, it enables nitrosation of acid-sensitive substrates, which has been difficult to achieve with existing protocols.
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Nowadays, stereoselective control over the sheer variety of chemical transformations benefits from the multipotency of chiral Lewis acids. Their use under biocompatible conditions has long posed a challenge because profuse amounts of biogenic nucleophiles readily deactivate them. To bridge the gap between chiral Lewis acid catalysis and biocompatible chemistry, the conversion of UiO(BPY)-type nanosized metal-organic frameworks (NMOFs) into chiral variants was herein exemplified. The combination of an elongated 2,2'-bipyridyl linker and scandium salt with a hydrophobic anion proved essential to implement traits such as robustness, biocompatibility, and catalytic activity. The catalyst could construct sufficiently hydrophobic environments sequestered within the framework, catalyzing asymmetric ring-opening reactions of meso-epoxide with low catalyst loading to afford ß-amino acid alcohols in high yield (up to >99%) with high enantioselectivity (up to 88%). Most impressively, it exhibited a tolerance to the ex vivo poisoning of chiral Lewis acid catalysis by biogenic nucleophiles in sharp contrast to conventional water-compatible Lewis acids.
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Alkylation reactions are fundamental carbon-carbon bond-forming reactions in synthetic organic chemistry. Among them, intermolecular α-alkylation reactions of carbonyl compounds with alkenes are important because they are more atom-economical than the equivalent processes using alkyl halides. However, intermolecular reactions with nonactivated alkenes such as 1-hexene, which can allow the use of a wide range of valuable substrates, have been considered to be very challenging for a long time. In this review, radical-mediated intermolecular α-alkylation reactions of carbonyl compounds with nonactivated alkenes are discussed. The examples are grouped into three types of reactions: peroxide-mediated reactions, metal-oxidant-mediated reactions, and photoactivated reactions. Photoredox-catalyzed alkylation reactions under visible-light irradiation are discussed as a particularly promising recent hot topic. This review provides brief history and new prospects on the α-alkylation process with nonactivated alkenes using α-carbonyl radical species.
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Catalytic enantioselective Mannich reactions of simple nonactivated esters proceeded using a chiral potassium strong base catalyst prepared from a chiral bisoxazoline and potassium hexamethyldisilazide. Alkyl acetates, alkyl propionates, and an alkyl butyrate were employed as the simple esters, and the desired reactions proceeded smoothly to afford Mannich products in good to high yields with high enantioselectivities. One of the products was successfully employed in the asymmetric total synthesis of Maraviroc.
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Water is not a good solvent for most organic compounds, yet water can offer many benefits to some organic reactions, hence enriching organic chemistry. Herein, the unique divergent reactivity of 2-substituted indoles with â NO sources is presented. The amount of water solvent was harnessed for a scalable, benign, and expedient synthesis of indolenine oximes, albeit with water's inability to dissolve the reactants. 2-Methoxyethyl nitrite, which has been tailored for reactions in water, empowered this protocol by enhancing the product selectivity. We further report on chemoselective transformations of the products that rely on their structural features. Our findings are expected to offer access to an underexplored chemical space. The platform is also applicable to oximinomalonate synthesis. Mechanistic studies revealed the important role of water in the reversal of stability between oxime and nitroso compounds, promoting the proton transfer.
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In catalytic α-alkylation reactions of carbonyl compounds, although SN2-type substitution reactions of enolates with alkyl halides are a conventional methodology, addition reactions with alkenes are more desirable because of their atom-economical character; however, reactions with nonactivated alkenes are challenging. Here, we developed highly efficient catalytic α-alkylation reactions of active methylene and methine compounds with nonactivated alkenes such as 1-decene using an organophotocatalyst and lithium thiophenoxide as a Lewis acid/Brønsted base/hydrogen atom transfer (HAT) multifunctional catalyst under blue-light irradiation. The reaction was also performed with a higher degree of efficiency under a continuous-flow system to obtain the products in multigram scales. The present reaction system enables highly efficient and practical α-alkylation reactions of active methylene and methine compounds to be achieved.
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Catalytic asymmetric direct-type aldol reactions of ketones with aldehydes are a perennial puzzle for organic chemists. Notwithstanding the emergence of a myriad of chiral catalysts to address the inherent reversibility of the aldol products, a general method to access acyclic α-chiral ketones from prochiral aryl ketones has remained an unmet synthetic challenge. The approach outlined herein is fundamentally different to that used in conventional catalysis, which typically commences with an α-proton abstraction by a Brønsted base. The use of a chiral 2,2'-bipyridine scandium complex enabled the hydroxymethylation of propiophenone to be run under base-free conditions, which avails effectual suppression of hydrolytic deactivation of the Lewis acid catalyst. Intriguingly, the use of water as a reaction medium had an overriding effect on the progress of the reaction. The sagacious selection of sodium dodecyl sulfate and lithium dodecyl sulfate as surfactants allowed a variety of propiophenone derivatives to react in a highly enantioselective manner.
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Cetonas , Propiofenonas , Agua , Estereoisomerismo , CatálisisRESUMEN
We studied the friction coefficient between the polymer gel network and water f for thermoreversible agarose gels under various conditions of agarose concentration and gelation temperature. Since agarose gels exhibit phase separation below the gelation temperature, f strongly depends on the thermal history. We found that the friction coefficient of the phase-separated agarose gel normalized by the water viscosity, f/η, is expressed as f/η = S/ξνSD where ξSD is the frictional pore size and ν and S are constant parameters. ξSD corresponds to the correlation length of the frozen density fluctuations of the polymers via spinodal decomposition determined from small-angle light scattering. The least-squares analysis of the results shows that the exponent is ν ≃ 2 with the numerical constant of S ≃ 105/2π. The results suggest that the frictional properties of phase-separated agarose gels are dominated by the dilute regions of the bicontinuous gel structure.
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Organometallic reagents are effective for carbon-carbon bond formation; however, consumption of stoichiometric amounts of metals is problematic. We developed electrochemical allylation reactions of imines catalyzed by nitrogen-doped carbon-supported single-atom zinc, which were fixed on a cathode to afford a range of homoallylic amines efficiently. The system could suppress generation of metallic waste, and the catalyst electrode showed advantages over bulk zinc in terms of activity and robustness. An electrochemical flow reaction was also successfully performed to produce the homoallylic amine continuously with minimum amounts of waste.
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A metal-free, heterogeneous acid catalyst, trifluoromethanesulfonic acid-immobilized nitrogen-doped carbon catalyst, was developed for Povarov reactions. This catalyst exhibited excellent catalytic activity, achieving high turnover frequency (>400 h-1) and good cis-selectivity of the desired 1,2,3,4-tetrahydroquinoline products. The reaction had a broad substrate scope, and the multicomponent Povarov reaction proceeded smoothly with readily accessible aldehydes and anilines. The heterogeneity and reusability of this catalytic system were confirmed. The catalyst was characterized by spectroscopic and microscopic analysis studies.
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BACKGROUND/AIM: Radium-223 (Ra-223) therapy provides a survival benefit for castration-resistant prostate cancer (CRPC) patients with bone metastasis. The optimal timing of using Ra-223 has not been determined. We evaluated the efficacy and safety of Ra-223 before and after docetaxel (DOC) therapy. PATIENTS AND METHODS: We retrospectively reviewed 36 CRPC patients with bone metastasis who were treated with Ra-223 in our institution and satellite hospitals. Ra-223 was used before DOC (pre-DOC group) in 17 patients (47%) and after DOC (post-DOC group) in 19 patients (53%). The treatment completion rate of 6 cycles, progression-free survival (PFS), cause-specific survival (CSS) and occurrence rate of adverse events were compared between the groups. RESULTS: The median follow-up duration was 45 months. In the pre-DOC compared with the post-DOC group, treatment completion rate was significantly higher (94% vs. 52%, p<0.01), PFS was significantly longer (median: 8 vs. 5 months, p=0.024) and CSS was significantly longer (median: 32 vs. 15 months, p=0.028). The difference in CSS was significant in multivariate analysis. In the pre-DOC compared with the post-DOC group, the occurrence rate of grade ≥3 adverse events tended to be lower (6% vs. 36%, p=0.322), and the CSS tended to be longer (median: not reached vs. 45 months, p=0.208). CONCLUSION: Ra-223 could be used more safely and more effectively for CRPC patients with bone metastasis before than after DOC therapy.
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Neoplasias Óseas , Neoplasias de la Próstata Resistentes a la Castración , Radio (Elemento) , Neoplasias Óseas/inducido químicamente , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/radioterapia , Docetaxel/efectos adversos , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Radio (Elemento)/efectos adversos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Although the use of molecular sieves for imine synthesis is a common protocol, there have been no comprehensive studies on heat-drying methods. This can be crucial for reproducibility. It was found that molecular sieve 5A dried at 160 °C for 5 h under vacuum efficiently promoted the condensation of various ketones and amines to afford even relatively bulky ketimines. Several control experiments and analyses revealed that only a small amount of Brønsted acid sites was important for the activity, rather than dehydration ability. Other types of molecular sieves could be utilized for the reaction after treatment with water followed by heat drying. A continuous-flow acetalization reaction of alcohols using the activated molecular sieve 5A was also demonstrated.
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Addition reactions of ketene silyl acetals with alkenes that do not have an electron-withdrawing group are generally difficult because the nucleophilicity of ketene silyl acetals and the electrophilicity of alkenes are not sufficient. Herein, we report photocatalytic addition reactions of ketene silyl acetals with alkenes that proceed through formation of α-carbonyl radicals. In the presence of an appropriate protic additive, the reactions proceeded smoothly under blue-light irradiation to afford the desired products in moderate to high yields.
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Acetales , Alquenos , Etilenos , CetonasRESUMEN
An on-water approach has been developed that allows a nitration of tyrosines and phenols under mild conditions. We envisioned that the assembly of tyrosine/tyrosyl radical couples with interfacial water molecules would realize a biomimetic stacking hydrogen atom transfer (HAT) transition state to facilitate the electron-transfer process. The optimal organic nitrite, 2-methoxyethyl nitrite, resulted in rapid coupling of the tyrosyl radicals with â NO2 at the oil-water interface to afford the nitrated phenols. Many characteristics found in our on-water strategy are distinct from other complementary systems that include radical nitration. These enticing roles of water in the reaction process introduce new avenues to explore in the design of synthetic organic chemistry systems.
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Nitritos , Agua , Indicadores y Reactivos , Nitritos/química , Óxidos de Nitrógeno , Fenoles/químicaRESUMEN
Bioinspired supramolecular architectures were used to compartmentalize highly charged aqua scandium ions into chiral hydrophobic scaffolds for Lewis acid-catalyzed asymmetric reactions. Recycling without significant loss in catalytic performance is a formidable task, especially for Lewis acid-catalyzed reactions. This is because Lewis basic impurities derived from starting materials, products, and water are highly competitive ligands for both substrate binding and metal complexation, thus poisoning the Lewis acids and leading to their leaching. Even when basic aniline is used, the architecture allowed for effective suppression of Sc3+ leaching and for reuse of solvent-catalyst couples in asymmetric ring-opening reactions without deactivation. Application to asymmetric thia-Michael addition and hydroxymethylation was also demonstrated. The successful recycling in highly Lewis basic environments underpins the exceptionally high robustness of the chiral Lewis acid catalyst.
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Electrochemical allylation reactions of carbonyl compounds using cathodes prepared from nitrogen-doped carbon (NDC)-incarcerated zinc catalysts have been developed. A range of aldehydes and ketones afforded the desired allylic alcohols in high yields with <10 mol % zinc leaching, and the heterogeneous nature of the active species was suggested. Compared with bulk zinc electrodes, NDC-stabilized zinc nanoparticle species were compatible with a broader range of heteroaromatic substrates and enabled the use of an undivided cell.
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Catalytic imino-ene-type allylation reactions of unactivated allyl compounds were achieved. In the presence of a catalytic amount of a strongly basic KOtBu-LiTMP or NaOtBu-LiTMP mixed system, the desired reactions proceeded smoothly at low temperature. Notably, a gaseous alkene, propylene, could also be used in this reaction system.
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Chiral alkaline metal Brønsted bases are traditional and reliable promoters in enantioselective catalysis. Here, new chiral potassium strong base catalysts were developed for enantioselective carbon-carbon bond-forming reactions of weakly acidic carbon pronucleophiles. Chiral potassium amide or alkyl potassium catalyzed enantioselective addition reactions to imines or α,ß-unsaturated amides with good to high enantioselectivities. The good potential of chiral potassium Brønsted bases to act as proton transfer catalysts has been shown.