Lewis asymmetric aldol reactions

Asymmetric reactions using chiral copper Lewis acids are also performed in aqueous media. It has been reported that an asymmetric Diels-Alder reaction proceeds smoothly in water using Cu(OTf)2 and abrine as a chiral ligand (Scheme 49).214 The Cu -bis(oxazoline) system is effective in asymmetric aldol reactions in an aqueous solvent such as water/ethanol and even in pure water.215... 

Sn(OTf)2 can function as a catalyst for aldol reactions, allylations, and cyanations asymmetric versions of these reactions have also been reported. Diastereoselective and enantioselective aldol reactions of aldehydes with silyl enol ethers using Sn(OTf)2 and a chiral amine have been reported (Scheme SO) 338 33 5 A proposed active complex is shown in the scheme. Catalytic asymmetric aldol reactions using Sn(OTf)2, a chiral diamine, and tin(II) oxide have been developed.340 Tin(II) oxide is assumed to prevent achiral reaction pathway by weakening the Lewis acidity of Me3SiOTf, which is formed during the reaction. 

A lead(II) triflate-crown ether complex functions as a chiral Lewis-acid catalyst for asymmetric aldol reactions in aqueous media (Scheme 86).352 This is the first example of a chiral crown-based Lewis acid that can be successfully used in catalytic asymmetric reactions. 

This method has been applied in the enantioselective synthesis of d-erythro-sphingosine and phytosphingosine. Sphingosine became an important substance for studying signal transduction since the discovery of protein kinase C inhibition by this compound.48 Many efforts have been made to synthesize sphingosine and its derivatives.49 Kobayashi et al. reported another route to this type of compound in which a Lewis acid-catalyzed asymmetric aldol reaction was a key step. 

Asymmetric Aldol Reactions Catalyzed by Chiral Lewis Acids... 

The aldol reaction between enolsilanes and aldehydes mediated by chiral Lewis acids may be considered the most notable achievement in the area of asymmetric aldol reactions. However, the design of new catalyst systems to tolerate... 

Several other chiral Lewis acids have also been reported to effect asymmetric aldol reactions. Kruger and Carreira59 reported a catalytic aldol addition of silyl dienolate to a range of aldehydes in the presence of a bisphosphanyl-Cu(II) fluoride complex generated in situ from (iS )-Tol-BINAP, Cu(OTf)2, and (Bu4N)Ph3SiF2. Aromatic, heteroaromatic, and a,/ -unsaturated aldehydes provided the aldol adducts with up to 95% ee and 98% yield (Scheme 3-33). 

Lewis acids as water-stable catalysts have been developed. Metal salts, such as rare earth metal triflates, can be used in aldol reactions of aldehydes with silyl enolates in aqueous media. These salts can be recovered after the reactions and reused. Furthermore, surfactant-aided Lewis acid catalysis, which can be used for aldol reactions in water without using any organic solvents, has been also developed. These reaction systems have been applied successfully to catalytic asymmetric aldol reactions in aqueous media. In addition, the surfactant-aided Lewis acid catalysis for Mannich-type reactions in water has been disclosed. These investigations are expected to contribute to the decrease of the use of harmful organic solvents in chemical processes, leading to environmentally friendly green chemistry. 

The catalytic asymmetric aldol reaction has been applied to the LASC system, which uses copper bis(-dodecyl sulfate) (4b) instead of CufOTf. 1261 An example is shown in Eq. 6. In this case, a Bronsted add, such as lauric add, is necessary to obtain a good yield and enantioseledivity. This example is the first one involving Lewis acid-catalyzed asymmetric aldol reactions in water without using organic solvents. Although the yield and the selectivity are still not yet optimized, it should be noted that this appredable enantioselectivity has been attained at ambient temperature in water. 

These first examples of the catalytic asymmetric aldol reaction not only provided first results that could be utilized for such transformations but also highlighted the problems that had to be overcome in further elaborations of this general method. It was shown that truly catalytic systems were required to perform an enantioselective and diastereoselective vinylogous aldol reaction, and it became obvious that y-substituted dienolates that serve as propionate-acetate equivalents provide an additional challenge for diastereoselective additions. To date, the latter problem has only been solved for diastereoselective additions under Lewis acid catalysis (vide infra) (Scheme 4, Table 3). 

A review of enantioselective aldol additions of latent enolate equivalents covers a variety of Sn", boron, Ti, Cu, lanthanide, and Lewis base catalysts. Asymmetric aldol reactions using boron enolates have been reviewed (401 references). ... 

In the following a few examples of the asymmetric aldol reaction are given. Silyl enol ethers (0-Si) resemble very much allylsilanes (C-Si) in terms of structure and mode of action. That is why Lewis base catalyzed aldol reactions of silyl enol ethers have been extensively studied. The first example of Lewis base catalyzed asymmetric aldol reaction of trichlorosilyl enol ether with chiral phosphoramide [80-91] was reported by Denmark et al. (Scheme 24). 

Several methods for the anti-selective, asymmetric aldol reaction recorded in the literature include (i) the use of boron, titanium, or tin(ll) enolate carrying chiral ligands, (ii) Lewis acid-catalyzed aldol reactions of a metal enolate of chiral carbonyl compounds, and (iii) the use of the metal enolate derived from a chiral carbonyl compound. Although many of these methods provide anti-aldols with high enantioselectivities, these methods are not as convenient or widely applicable as the method reported here, because of problems associated with the availability of reagents, the generality of reactions, or the required reaction conditions. 

Fluoral hydrate and hemiacetals are industrial products. They are stable liquids that are easy to handle, and they react as fluoral itself in many reactions. Thus, in the presence of Lewis acids, they react in Friedel-Crafts reactions. They also react very well with organometallics (indium and zinc derivatives) and with silyl enol ethers.Proline-catalyzed direct asymmetric aldol reaction of fluoral ethyl hemiac-etal with ketones produced jS-hydroxy-jS-trifluoromethylated ketones with good to excellent diastereo- (up to 96% de) and enantioselectivities. With imine reagents, the reaction proceeds without Lewis acid activation. The use of chiral imines affords the corresponding 8-hydroxy ketones with a 60-80% de (Figure 2.49). ° ... 

Studies of catalytic asymmetric Mukaiyama aldol reactions were initiated in the early 1990s. Until recently, however, there have been few reports of direct catalytic asymmetric aldol reactions [1]. Several groups have reported metallic and non-metallic catalysts for direct aldol reactions. In general, a metallic catalysis involves a synergistic function of the Bronsted basic and the Lewis acidic moieties in the catalyst (Scheme 2). The Bronsted basic moiety abstracts an a-pro-ton of the ketone to generate an enolate (6), and the Lewis acidic moiety activates the aldehyde (3). 

B1.4. LEWIS ACID CATALYZED ASYMMETRIC ALDOL REACTION... 

The asymmetric aldol reaction is one of the most important topics in modern catalytic synthesis [54]. The products, namely />-hydroxy carbonyl compounds, have a broad range of applications and play a key role in the production of pharmaceuticals [55], Since the discovery of the catalytic asymmetric aldol reaction with enolsi-lanes by Mukaiyama et al. [56], steady improvements of the metal-catalyzed asymmetric aldol reaction have been made by many groups [57]. For this type of aldol reaction a series of chiral metal catalysts which act as Lewis acids activating the aldol acceptor have been shown to be quite efficient. It was recently shown by the Shibasaki group that the asymmetric metal-catalyzed aldol reaction can be also performed with unmodified ketones [57a], During the last few years, several new concepts have been developed which are based on use of organocatalysts [58], Enolates and unmodified ketones can be used as aldol donors. 

The mechanism A very detailed mechanistic study of this phosphoramide-catalyzed asymmetric aldol reaction was conducted by the Denmark group (see also Section 6.2.1.2) [59, 60], Mechanistically, the chiral phosphoramide base seems to coordinate temporarily with the silicon atom of the trichlorosilyl enolates, in contrast with previously used chiral Lewis acids, e.g. oxazaborolidines, which interact with the aldehyde. It has been suggested that the hexacoordinate silicate species of type I is involved in stereoselection (Scheme 6.15). Thus, this cationic, diphosphoramide silyl enolate complex reacts through a chair-like transition structure. 

Kiyooka S-i (1997) Development of a chiral lewis acid-promoted asymmetric aldol reaction using oxaborolidinone. Rev Heteroatom Chem 17 245-270... 

Asymmetric aldol reactions promoted by chiral oxazaborolidinones can achieve high ee with critical quantities of THF, typically a 4-5-fold excess over the borane.117 Ah initio calculations on Lewis acid-aldehyde-solvent complexes have been used to rationalize such results extended hydrogen bonding networks have been identified. 

Asymmetric aldol reactions.4 The borane complex 3 can also serve as the Lewis acid catalyst for the aldol reaction of enol silyl ethers with aldehydes (Mukaiyama reactions).5 Asymmetric induction is modest (80-85% ee) in reactions of enol ethers of methyl ketones, but can be as high as 96% ee in reactions of enol ethers of ethyl ketones. Moreover, the reaction is syn-selective, regardless of the geometry of the enol. However, the asymmetric induction is solvent-dependent, being higher in nitroethane than in dichloromethane. 

Shibasaki and coworkers have conducted extensive research on the use of hetero-bimetallic complexes as catalysts for asymmetric synthesis [11]. The reactions are catalyzed by heterobimetallic complexes that function as both a Lewis acid and a Bronsted base. Among these, LaLi3tris(binaphthoxide) catalyst 1 (LLB) was proven to be an effective catalyst in direct asymmetric aldol reactions (Fig. 1) [12]. On the basis of this research, Shibasaki et al. reported the first report of a direct catalytic asymmetric Mannich reaction [13],... 

The design for a direct catalytic asymmetric aldol reaction of aldehydes and unmodified ketones with bifunctional catalysts is shown in Figure 36. A Brpnsted basic functionality (OM) in the heterobimetallic asymmetric catalyst (I) could deprotonate the a-proton of a ketone to generate the metal enolate (II), while at the same time a Lewis acidic functionality (LA) could activate an aldehyde to give (III), which would then react with the metal enolate (in a chelation-controlled fashion) in an asymmetric environment to afford a P-keto metal alkoxide (IV). 

Scheme 3. Catalytic asymmetric aldol reaction with aluminum- and tin-containing chiral Lewis acids a) Reetz and b) Mukaiyama.

Scheme 4. Catalytic, asymmetric aldol reaction with boron-containing Lewis acids a) Masamune, b) Corey and c) Yamamoto.

C2-Symmetric tridentate bis(oxazolinyl)pyri-dine-Cu(Il) complexes, introduced by Evans et al., can function as effective chiral Lewis acid catalysts in the Diels-Alder reaction [15a]. When applied to catalytic asymmetric aldol reactions [15], remarkable results were achieved (Scheme 8) [15a]. Only 0.5 mol % of catalyst 48 was needed for the reaction of 30 with the silylketene thioacetal 47 to yield after deprotection 49 in 99 % chemical yield. The ee values were determined to be 99 %. Today, catalysts... 

Compared to the great variety of Lewis acid catalysts for the catalytic asymmetric aldol reaction the field of nucleophilic (Lewis base) catalysts is less explored. This strategy involves the transient activation of the latent enolate equivalent via Lewis base coordination to the silyl enol ether (Scheme 9) [3], For instance the tri-chlorosilyl enol ether 50 is able to expand its valency at the silicon atom from four to five and six. It reacts with an aldehyde (51), proceeding through a closed Zimmerman-Traxler-like transition state (54), to give 53 after quenching with saturated aqueous NaHCO, [16]. 

Scheme 9. Lewis base-promoted catalytic asymmetric aldol reaction according to Denmark.

Catalytic asymmetric aldol reactions in water have been attained by a combination of Cu(DS)2 and chiral bis(oxazoline) ligand 4. In this case, addition of a Br0sted acid, especially a carboxylic acid such as lauric acid, is essential for good yield and enantioselectivity (Equation (5)) [29]. This is the first example of Lewis acid-catalysed asymmetric aldol reactions in water without using organic solvents. Although the yield and the selectivities have not yet been optimized, it is noted that this enantioselectivity has been achieved at ambient temperature in water. 

Optically active 1,2-diol units are often observed in nature as carbohydrates, macrolides or polyethers, etc. Several excellent asymmetric dihydroxylation reactions of olefins using osmium tetroxide with chiral ligands have been developed to give the optically active 1,2-diol units with high enantioselectivities. However, there still remain some problems, for example, preparation of the optically active anti-1,2-diols and so on. The asymmetric aldol reaction of an enol silyl ether derived from a-benzyloxy thioester with aldehydes was developed in order to introduce two hydroxyl groups simultaneously with stereoselective carbon-carbon bond formation by using the chiral tin(II) Lewis acid. For example, various optically active anti-a,p-dihydroxy thioester derivatives are obtained in good yields with excellent diastereo-... 

Although the asymmetric aldol reaction of benzaldehyde and di ketene has been reported with a catalyst generated from di-iso-propyl tartrate and iso-propanol, low induction and low yields were observed for the d-hydroxyl-y5-keto ester 27 [8], Low induction was also observed for aldol reactions mediated by chiral aluminum catalysts generated from a-amino acids [9]. These types of catalyst have been very successful when employing boron as the Lewis acid, as illustrated in the aldol reaction of ketene acetal 10 with the boron catalyst 31 derived from (5)-valine (Sch. 4) [9,10]. Catalysts derived from A-tosyl-(5 )-valine and Et2AlCl and i-BuyAl were relatively ineffective (< 15 % ee) [9]. 

The BINAP silver(I) complex can be further applied as a chiral catalyst in the asymmetric aldol reaction. Although numerous successful methods have been developed for catalytic asymmetric aldol reaction, most are the chiral Lewis acid-catalyzed Mukaiyama aldol reactions using silyl enol ethers or ketene silyl acetals [32] and there has been no report which includes enol stannanes. Yanagisawa, Yamamoto, and their colleagues found the first example of catalytic enantioselective aldol addition of tributyltin enolates 74 to aldehydes employing BINAP silver(I) complex as a catalyst (Sch. 19) [33]. 

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