Taku Kitanosono

Chiral Copper(II)‐Catalyzed Enantioselective Boron Conjugate Additions to α,β‐Unsaturated Carbonyl Compounds in Water

Organic reactions are usually carried out in organic solvents in modern organic chemistry, and it is very rare to use water as the reaction medium despite water being safe, benign, environmentally friendly, and inexpensive compared with organic solvents. In organic reactions in aqueous media, there are two major obstacles to be surmounted. First, many reactive substrates, reagents, and catalysts are decomposed or deactivated by water. Second, most organic substances are insoluble in water. On the other hand, we have investigated organic reactions in water from the standpoint that the most ideal reactions, enzymatic reactions in vivo, are carried out in water, and have found unique reactivity and selectivity in aqueous media, which are not observed in organic solvents where water plays key roles. a-Chiral boron derivatives are an important class of compounds, because the C B linkage can be transferred into C O, C N, and C C bonds through 1,2-migration of intermediary ate complexes with appropriate nucleophiles, with retention of stereogenic centers. Enantioselective boron conjugate addition to a,b-unsaturated carbonyl and related compounds provides one of the most efficient routes to achiral boron compounds. Based on seminal reports of Cucatalyzed conjugate borylation, Yun et al. reported an enantioselective method for Cu-catalyzed conjugate borylation. After that, several catalytic asymmetric borylations using Cu with chiral ligands were reported. Furthermore, other metal-catalyzed and metal-free enantioselective boron conjugate additions to a,b-unsaturated carbonyl and related compounds have also been reported. In all of those cases, the reactions were carried out in organic solvents, and to the best of our knowledge, there has been no report of this conjugate addition in water. In previous papers, we have shown that addition reactions of allylboronates and allenylboronates to aldehydes and acylhydrazones proceeded smoothly in the presence of metal hydroxides such as Zn(OH)2, Cu(OH)2, Bi(OH)3, and others in aqueous media. In these reactions, metal hydroxides that had not been used as catalysts in organic synthesis were shown to be suitable and stable catalysts in aqueous media, and that exchange processes from boron to the second elements were crucial to promote the reactions. Based on a hint obtained from this work, we assumed a similar exchange process from the B atom of bis(pinacolato)diboron (B2(pin)2) to a second element. Herein, we report enantioselective boron conjugate additions to various a,b-unsaturated carbonyl compounds and nitrile in water catalyzed by Cu(OH)2 with a chiral ligand. Very rare chiral Cu II catalysis in water is also described. 12] First, we conducted the reaction of B2(pin)2 with chalcone in water in the presence of several promising metal hydroxides that were expected to work well in water. It was found that some metal hydroxides worked well with ligands. For example, when Cu(OH)2 was combined with dibenzylamine (DBA), the desired 1,4-addition product 1a was obtained in 88% yield (Table 1, entry 1). Zn(OH)2 showed inferior reactivity (entry 2). We then investigated several chiral ligands in an attempt to produce enantioselective reactions. Asymmetric catalysis in water is extremely difficult to achieve because many chiral catalysts decompose rapidly in the presence of water. We have already investigated watercompatible Lewis acidic metals (cations), in which Cu and Zn are involved. We have also demonstrated that combinations of Cu and Zn with chiral 2,2’-bipyridine ligand L1 were effective for enantioselective ring-opening reactions of meso-epoxides and allylation reactions of aldehydes, respectively, in aqueous media. It was found that Cu(OH)2-L1 showed very promising results; namely, the desired addition product was obtained in 83% yield with a 90.5:9.5 enantiomeric ratio (e.r.) in the presence of Cu(OH)2 (10 mol%) with L1 (12 mol%) at RT in water for 12 h (entry 3). Whereas Zn(OH)2-L1 showed lower yield and enantioselectivity (entry 4), combinations of Cu(OH)2 with chiral ligands L2 and L3 gave high yields with moderate enantioselectivities (entries 5 and 6). The use of water as a solvent is essential for reactivity and selectivity; the reactions did not proceed at all or proceeded very sluggishly in typical organic solvents such as THF, toluene, CH2Cl2, DMF, DMSO, MeOH, and EtOH (entries 7–13). With 5 mol% catalyst loading, the enantioselectivity decreased slightly (entry 14). We then examined several reaction conditions to further improve the yield and the enantioselectivity, and found that some additives were effective for that purpose. Among them, the use of acetic acid (entry 16) or trifluoroacetic acid (entry 17) were found to be the most effective to improve both yield and enantioselectivity. Boronic acid was also effective as an additive (entry 19). Finally, the desired product was obtained in 95% yield with 99.5:0.5 e.r. when the reaction was conducted at 5 8C (entry 21). It was also confirmed that the product was isolated [*] Prof. Dr. S. Kobayashi, P. Xu, T. Endo, Dr. M. Ueno Department of Chemistry, School of Science The University of Tokyo Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan) E-mail: shu_kobayshi@chem.s.u-tokyo.ac.jp

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

Heterogeneous versus Homogeneous Copper(II) Catalysis in Enantioselective Conjugate‐Addition Reactions of Boron in Water

We have developed Cu(II)-catalyzed enantioselective conjugate-addition reactions of boron to α,β-unsaturated carbonyl compounds and α,β,γ,δ-unsaturated carbonyl compounds in water. In contrast to the previously reported Cu(I) catalysis that required organic solvents, chiral Cu(II) catalysis was found to proceed efficiently in water. Three catalyst systems have been exploited: cat. 1: Cu(OH)2 with chiral ligand L1; cat. 2: Cu(OH)2 and acetic acid with ligand L1; and cat. 3: Cu(OAc)2 with ligand L1. Whereas cat. 1 is a heterogeneous system, cat. 2 and cat. 3 are homogeneous systems. We tested 27 α,β-unsaturated carbonyl compounds and an α,β-unsaturated nitrile compound, including acyclic and cyclic α,β-unsaturated ketones, acyclic and cyclic β,β-disubstituted enones, acyclic and cyclic α,β-unsaturated esters (including their β,β-disubstituted forms), and acyclic α,β-unsaturated amides (including their β,β-disubstituted forms). We found that cat. 2 and cat. 3 showed high yields and enantioselectivities for almost all substrates. Notably, no catalysts that can tolerate all of these substrates with high yields and high enantioselectivities have been reported for the conjugate addition of boron. Heterogeneous cat. 1 also gave high yields and enantioselectivities with some substrates and also gave the highest TOF (43,200 h(-1) ) for an asymmetric conjugate-addition reaction of boron. In addition, the catalyst systems were also applicable to the conjugate addition of boron to α,β,γ,δ-unsaturated carbonyl compounds, although such reactions have previously been very limited in the literature, even in organic solvents. 1,4-Addition products were obtained in high yields and enantioselectivities in the reactions of acyclic α,β,γ,δ-unsaturated carbonyl compounds with diboron 2 by using cat. 1, cat. 2, or cat. 3. On the other hand, in the reactions of cyclic α,β,γ,δ-unsaturated carbonyl compounds with compound 2, whereas 1,4-addition products were exclusively obtained by using cat. 2 or cat. 3, 1,6-addition products were exclusively produced by using cat. 1. Similar unique reactivities and selectivities were also shown in the reactions of cyclic trienones. Finally, the reaction mechanisms of these unique conjugate-addition reactions in water were investigated and we propose stereochemical models that are supported by X-ray crystallography and MS (ESI) analysis. Although the role of water has not been completely revealed, water is expected to be effective in the activation of a borylcopper(II) intermediate and a protonation event subsequent to the nucleophilic addition step, thereby leading to overwhelmingly high catalytic turnover.

Iron‐ and Bismuth‐Catalyzed Asymmetric Mukaiyama Aldol Reactions in Aqueous Media

We have developed asymmetric Mukaiyama aldol reactions of silicon enolates with aldehydes catalyzed by chiral Fe(II) and Bi(III) complexes. Although previous reactions often required relatively harsh conditions, such as strictly anhydrous conditions, very low temperatures (-78 °C), etc., the reactions reported herein proceeded in the presence of water at 0 °C. To find appropriate chiral water-compatible Lewis acids for the Mukaiyama aldol reaction, many Lewis acids were screened in combination with chiral bipyridine L1, which had previously been found to be a suitable chiral ligand in aqueous media. Three types of chiral catalysts that consisted of a Fe(II) or Bi(III) metal salt, a chiral ligand (L1), and an additive have been discovered and a wide variety of substrates (silicon enolates and aldehydes) reacted to afford the desired aldol products in high yields with high diastereo- and enantioselectivities through an appropriate selection of one of the three catalytic systems. Mechanistic studies elucidated the coordination environments around the Fe(II) and Bi(III) centers and the effect of additives on the chiral catalysis. Notably, both Brønsted acids and bases worked as efficient additives in the Fe(II) -catalyzed reactions. The assumed catalytic cycle and transition states indicated important roles of water in these efficient asymmetric Mukaiyama aldol reactions in aqueous media with the broadly applicable and versatile catalytic systems.

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.

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.

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.

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.

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.

Toward Chemistry-Based Design of the Simplest Metalloenzyme-Like Catalyst That Works Efficiently in Water

Enzymes exhibit overwhelmingly superior catalysis compared with artificial catalysts. Current strategies to rival enzymatic catalysis require unmodified or minimally modified structures of active sites, gigantic molecular weight, and sometimes the use of harsh conditions such as extremely low temperatures in organic solvents. Herein, we describe a design of small molecules that act as the simplest metalloenzyme-like catalysts that can function in water, without mimicking enzyme structures. These artificial catalysts efficiently promoted enantioselective direct-type aldol reactions using aqueous formaldehyde. The reactions followed Michaelis-Menten kinetics, and heat-resistant asymmetric environments were constructed in water.