Lewis acids catalyzing asymmetric aldol reaction

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. 

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. 

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

In contrast with the above Lewis acid-catalyzed asymmetric aldol reactions, chiral Pd and Pt cationic complexes have been found to catalyze the asymmetric process by a transmetalation mechanism involving a metal enolate intermediate (Section 10.2.1.3). 

Lewis acid-catalyzed asymmetric aldol reactions of silyl enol ethers with aldehydes are among the most powerful carbon-carbon bond-forming methods aprotic anhydrous solvents and low reaction temperatures are, however, usually needed for successful reaction. To perform the catalytic asymmetric aldol reaction in aqueous media a chiral crown ether-Pb(OTf)2 complex was employed as a chiral catalyst stable in water-ethanol [9]. Good to high yields and high levels of diastereo-and enantioselectivity were obtained at 0°C in aqueous media (Scheme 13.64). 

The aldol reachon is one of the most efficient methods for extending the carbon framework of an organic synthon. Since the discovery of the Lewis acid-catalyzed asymmetric aldol reaction of silyl enol ethers by Mukaiyama, numerous variations of this type of reaction have been reported [80]. Recently, more attention has been focused on the development of new organocatalysts for the asymmetric direct aldol... 

SCHEME 120. Lewis acid-catalyzed asymmetric aldol-type reaction of enol silyl ethers. 

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]. 

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. 

At this point, one can see the impact of the chiral Lewis acid catalysis in the indirect small-molecule-catalyzed asymmetric aldol reactions. More examples together with exhaustive discussions about the stereochemical... 

The Lewis-acid-catalyzed carbonyl-ene reaction represents an important alternative method for the addition of an allyl group to a carbonyl group (Equation 23). The resulting secondary homoallylic alcohols are amenable to a number of structural modifications and constitute useful synthetic building blocks. Because the olefin of the products can be a surrogate for a carbonyl functionality, these homoallylic alcohol are formally the synthetic equivalent of aldol addition products. Powerful asymmetric versions of the carbonyl-ene reaction [196, 197] provide an important alternative to the more traditional allylation methods, which primarily employ silanes, boranes, or stannanes (see Chapter 5). 

Asymmetric Lewis-Acid Catalyzed. Another important advance in aqueous Mukaiyama aldol reaction is the recent success of asymmetric catalysis.283 In aqueous ethanol, Kobayashi and co-workers achieved asymmetric inductions by using Cu(OTf)2/chiral >A(oxazoline) ligand,284 Pb(OTf)2/chiral crown ether,285 and Ln(OTf)3/chiral Mv-pyridino-18-crown-6 (Eq. 8.105).286... 

Asymmetric Aldol Reactions Catalyzed by Chiral Lewis Acids... 

Next to the above presented use of SiCl for the in situ preparation of a Lewis acid catalyst with a Lewis base for the aldol reaction, it is possible to apply this compound as a reagent in the ring opening of epoxides leading to chlorinated alcohols. Denmark [104] reported that the chiral phosphoramide 38 catalyzed the asymmetric ring opening reaction of meso-epoxides in the presence of tetrachlo-rosilane. Similar examples were provided by Hashimoto in 2002 [105], applying the A -oxide 39 as catalyst (Scheme 30). 

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). ° ... 

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],... 

Catalyzed enantioselective Mukaiyama-aldol reactions have been developed extensively [101] and chiral polymer-supported Lewis acids are the catalysts of choice. Polymer-supported chiral A(-sulfonyloxazaborohdinones 86 and 87, prepared by copolymerization of styrene, divinylbenzene, and chiral monomers derived from L-valine and L-glutamic acid, respectively, have been used for aldol reactions [102]. The rates of reaction using the polymeric catalysts were slow and enantioselectivity was lower than was obtained by use of the low-molecular-weight counterpart (88). The best ee obtained by use of the polymeric catalyst was 90 % ee with 28 % isolated yield in the asymmetric aldol reaction of benzaldehyde with 89 (Eq. 27). 

Catalytic asymmetric aldol reactions provide one of the most powerful carbon-carbon bond-forming processes affording synthetically useful chiral )ff-hydroxy ketones and esters [25]. Chiral Lewis acid-catalyzed reactions of silyl enol ethers with aldehydes (the Mukaiyama reaction) [3] are among the most convenient and promising, and several successful examples have been reported since the first chiral tin(II)-cat-alyzed reactions appeared in 1990 [26]. Some common characteristics of these cat-... 

Chiral auxiliary-bound substrates have also been used for the asymmetric process. The aldol reaction of chiral pyruvates such as 46 is a reliable method for highly enantioselective synthesis of functionalized tertiary alcohols (Scheme 10.38) [112]. The Lewis acid-catalyzed aldol-type reactions of chiral acetals with silyl enolates are valuable for the asymmetric synthesis of -alkoxy carbonyl compounds ]113, 114]. 

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