Small-Molecule-Based Strategy for Mitigating Deactivation of Chiral Lewis Acid Catalysis.

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.

Highly enantioselective hydroxymethylation of unmodified α-substituted aryl ketones in water.

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.

Efficient Recycling of Catalyst-Solvent Couples from Lewis Acid-Catalyzed Asymmetric Reactions in Water.

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.

Hydrogen-Bonding-Assisted Cationic Aqua Palladium(II) Complex Enables Highly Efficient Asymmetric Reactions in Water.

Metal-bound water molecules have recently been recognized as a new facet of soft Lewis acid catalysis. Herein, a chiral palladium aqua complex was constructed that enables carbon-hydrogen bonds of indoles to be functionalized efficiently. We embraced a chiral 2,2'-bipyridine as both ligand and hydrogen-bond donor to configure a robust, yet highly Lewis acidic, chiral aqua complex in water. Whereas the enantioselectivity could not be controlled in organic solvents or under solvent-free conditions, the use of aqueous environments allowed the σ-indolylpalladium intermediates to react efficiently in a highly enantioselective manner. This work thus describes a potentially powerful new approach to the transformation of organometallic intermediates in a highly enantioselective manner under mild reaction conditions.

Reactions in Water Involving the "On-Water" Mechanism.

Ever-evolving catalyst advances in synthetic protocols using water as a reaction medium have enriched the understanding of sustainable organic chemistry. Because conventional classification and definitions were ambivalent, it is proposed here that catalytic reactions using water be collectively called to be "in water", with further classification into seven types. When accelerated in water as heterogeneous mixtures, the reactions can be regarded as following an "on-water" mechanism. The original term "on water" coined by Sharpless is incongruous with catalytic reactions, whereas on-water used in this review covers all the interfaces involving water where chemical reactions are accelerated. As a result of the unconcluded dispute on the antiquated catalyst-free "on water" model, the modified model defines three water layers: water molecules that are oriented to extrude protons toward the oil phase in the inner layer, those enwrapped by a secondary layer, and finally the bulk water layer. In light of the latitudinous outlook on the role of water at the interface, selected examples of reactions, in particular those reported over the past decade, that follow an "on-water" mechanism are reviewed herein.

Catalytic Organic Reactions in Water toward Sustainable Society.

Traditional organic synthesis relies heavily on organic solvents for a multitude of tasks, including dissolving the components and facilitating chemical reactions, because many reagents and reactive species are incompatible or immiscible with water. Given that they are used in vast quantities as compared to reactants, solvents have been the focus of environmental concerns. Along with reducing the environmental impact of organic synthesis, the use of water as a reaction medium also benefits chemical processes by simplifying operations, allowing mild reaction conditions, and sometimes delivering unforeseen reactivities and selectivities. After the "watershed" in organic synthesis revealed the importance of water, the development of water-compatible catalysts has flourished, triggering a quantum leap in water-centered organic synthesis. Given that organic compounds are typically practically insoluble in water, simple extractive workup can readily separate a water-soluble homogeneous catalyst as an aqueous solution from a product that is soluble in organic solvents. In contrast, the use of heterogeneous catalysts facilitates catalyst recycling by allowing simple centrifugation and filtration methods to be used. This Review addresses advances over the past decade in catalytic reactions using water as a reaction medium.

Catalytic enantioselective aldol reactions.

Recent developments in catalytic asymmetric aldol reactions have been summarized. Enantioselective aldol reactions are important methods to synthesize ß-hydroxy carbonyl compounds in optical pure form, and as such, numerous successful chiral catalysts were designed and applied for asymmetric aldol reactions. This review article is organized under the categories of: (1) catalytic enantioselective aldol reactions of preformed enolates, (2) catalytic enantioselective direct-type aldol reactions using chiral metal catalysts, (3) catalytic enantioselective direct-type aldol reactions using organocatalysts, (4) catalytic enantioselective aldol reactions in aqueous media. Examples of the aldol reactions that employ simple carbonyl compounds will be also the focus of this review.

Upregulation of an Artificial Zymogen by Proteolysis.

Regulation of enzymatic activity is vital to living organisms. Here, we report the development and the genetic optimization of an artificial zymogen requiring the action of a natural protease to upregulate its latent asymmetric transfer hydrogenase activity.

An Insoluble Copper(II) Acetylacetonate-Chiral Bipyridine Complex that Catalyzes Asymmetric Silyl Conjugate Addition in Water.

Acicular purplish crystals were obtained from Cu(acac)2 and a chiral bipyridine ligand. Although the crystals were not soluble, they nevertheless catalyzed asymmetric silyl conjugate addition of lipophilic substrates in water. Indeed, the reactions proceeded efficiently only in water; they did not proceed well either in organic solvents or in mixed water/organic solvents in which the catalyst/substrates were soluble. This is in pronounced contrast to conventional organic reactions wherein the catalyst/substrates tend to be in solution. Several advantages of the chiral Cu(II) catalysis in water over previously reported catalyst systems have been demonstrated. Water is expected to play a prominent role in constructing and stabilizing sterically confined transition states and accelerating subsequent protonation to achieve high yields and enantioselectivities.

The Mechanism of Iron(II)-Catalyzed Asymmetric Mukaiyama Aldol Reaction in Aqueous Media: Density Functional Theory and Artificial Force-Induced Reaction Study.

Density functional theory (DFT), combined with the artificial force-induced reaction (AFIR) method, is used to establish the mechanism of the aqueous Mukaiyama aldol reactions catalyzed by a chiral Fe(II) complex. On the bases of the calculations, we identified several thermodynamically stable six- or seven-coordinate complexes in the solution, where the high-spin quintet state is the ground state. Among them, the active intermediates for the selectivity-determining outer-sphere carbon-carbon bond formation are proposed. The multicomponent artificial force-induced reaction (MC-AFIR) method found key transition states for the carbon-carbon bond formation, and explained the enantioselectivity and diastereoselectivity. The overall mechanism consists of the coordination of the aldehyde, carbon-carbon bond formation, the rate-determining proton transfer from water to aldehyde, and dissociation of trimethylsilyl group. The calculated full catalytic cycle is consistent with the experiments. This study provides important mechanistic insights for the transition metal catalyzed Mukaiyama aldol reaction in aqueous media.

Chiral Cu(II)-catalyzed enantioselective ß-borylation of α,ß-unsaturated nitriles in water.

The promising performance of copper(II) complexes was demonstrated for asymmetric boron conjugate addition to α,ß-unsaturated nitriles in water. The catalyst system, which consisted of Cu(OAc)2 and a chiral 2,2'-bipyridine ligand, enabled ß-borylation and chiral induction in water. Subsequent protonation, which was accelerated in aqueous medium, led to high activity of this asymmetric catalysis. Both solid and liquid substrates were suitable despite being insoluble in water.

Development of chiral catalysts for Mukaiyama aldol reactions in aqueous media.

Since the discovery of the Mukaiyama aldol reaction in 1973, tremendous efforts have been made to develop a definitive catalyst that catalyzes asymmetric Mukaiyama aldol reactions under mild conditions with broad substrate tolerance. Forty years later, an exhaustive search for a water-compatible Lewis acid was able to uncover the hidden potential of iron(II) and bismuth(III), leading to the establishment of broadly applicable and versatile catalytic systems for asymmetric Mukaiyama aldol reactions in aqueous media. The ternary catalytic system was able to expand the substrate generality considerably as the most distinguished catalyst ever reported. The superiority of this methodology over conventional methods has also been demonstrated in terms of high catalytic activity, simplicity of experimental procedures, and a wide substrate range including aqueous aldehydes, for which the stereochemistry had been regarded as difficult to control. Furthermore, a facile synthesis of the chiral ligand underscores its versatility. The reaction did not proceed at all without use of water. In the postulated mechanism, water plays prominent roles in: (1) producing the active metal complexes with a high water-exchange rate constant (3.2 × 10(6)) to activate substrates effectively and to catalyze the reaction through a rapid proton transfer on the order of picoseconds; (2) facilitating the catalytic turnover with simultaneous desilylation as direct access to aldol adducts or facile recovery of active metal complexes; and (3) stabilizing rigid transition states composed of metal complexes and reactants through entropy-driven aggregation derived from the highest cohesive energy density.

Water vs. Organic Solvents: Water-Controlled Divergent Reactivity of 2-Substituted Indoles.

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 ⋅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.

Nanoscale and chiral metal-organic frameworks for asymmetric reactions in water: bridging Lewis acid catalysis and biological systems.

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.

Direct Aromatic Nitrosation Using 2-Methoxyethyl Nitrite as a NO Cation Source.

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.

Mukaiyama Aldol Reactions in Aqueous Media.

Mukaiyama aldol reactions in aqueous media have been surveyed. While the original Mukaiyama aldol reactions entailed stoichiometric use of Lewis acids in organic solvents under strictly anhydrous conditions, Mukaiyama aldol reactions in aqueous media are not only suitable for green sustainable chemistry but are found to produce singular phenomena. These findings led to the discovery of a series of water-compatible Lewis acids such as lanthanide triflates in 1991. Our understanding on these beneficial effects in the presence of water will be deepened through the brilliant examples collected in this review. 1 Introduction 2 Rate Enhancement by Water in the Mukaiyama Aldol Reaction 3 Lewis Acid Catalysis in Aqueous or Organic Solvents 3.1 Water-Compatible Lewis Acids 4 Lewis-Base Catalysis in Aqueous or Organic Solvents 5 The Mukaiyama Aldol Reactions in 100% Water 6 Asymmetric Catalysts in Aqueous Media and Water 7 Conclusions and Perspective.

Bismuth catalysts in aqueous media.

Several bismuth-catalyzed synthetic reactions, which proceed well in aqueous media, are discussed. Due to increasing demand of water as a solvent in organic synthesis, catalysts that can be used in aqueous media are becoming more and more important. Although bismuth Lewis acids are not very stable in water, it has been revealed that they can be stabilized by basic ligands. Chiral amine and related basic ligands combined with bismuth Lewis acids are particularly useful in asymmetric catalysis in aqueous media. On the other hand, bismuth hydroxide is stable and works as an efficient catalyst for carbon-carbon bond-forming reactions in water.

Chiral-Sc catalyzed asymmetric Michael addition/protonation of thiols with enones in water.

Asymmetric Michael reactions and enantioselective protonations between enones and thiols were catalyzed by a Sc(OTf)(3)-chiral 2,2'-bipyridine complex in water. The remarkable governing of the enantioselectivity for simple introduction of protons despite their abnormally high mobility in water may provide us with new synthetic opportunities as well as significant chemical advances.

2-Methoxyethyl Nitrite as a Reagent for Chemoselective On-Water Nitration.

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 ⋅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.

Chiral Sc-catalyzed asymmetric Michael reactions of thiols with enones in water.

Asymmetric Michael reactions of thiols with enones were catalyzed by a Sc(OTf)(3)-chiral bipyridine complex at room temperature in water without using any organic solvents, to afford the desired sulfides in high yields with high enantioselectivities.