Aldol with silyl enolates

Scheme 2.2 illustrates several examples of the Mukaiyama aldol reaction. Entries 1 to 3 are cases of addition reactions with silyl enol ethers as the nucleophile and TiCl4 as the Lewis acid. Entry 2 demonstrates steric approach control with respect to the silyl enol ether, but in this case the relative configuration of the hydroxyl group was not assigned. Entry 4 shows a fully substituted silyl enol ether. The favored product places the larger C(2) substituent syn to the hydroxy group. Entry 5 uses a silyl ketene thioacetal. This reaction proceeds through an open TS and favors the anti product. 

More recently, asymmetric Mannich-type reactions have been studied in aqueous conditions. Barbas and co-worker reported a direct amino acid catalyzed asymmetric aldol and Mannich-type reactions that can tolerate small amounts of water (<4 vol%).53 Kobayashi found that a diastereo- and enantioselective Mannich-type reaction of a hydrazono ester with silyl enol ethers in aqueous media has been successfully achieved with ZnF2, a chiral diamine ligand, and trifluoromethanesul-fonic acid (Eq. 11.31).54 The diastereoselective Mannich-type reaction... 

Sc(OTf)3 is effective in aldol reactions in aqueous media (water-THF, Scheme 15).49 Direct treatment of aqueous solutions of water-soluble formaldehyde and chloroacetaldehyde with silyl enol ethers affords the corresponding aldol adducts in good yields. Water-sensitive silicon enolates can be used in aqueous solutions in the presence of a catalytic amount of Sc(OTf)3. 

Mukaiyama aldol reactions of aldehydes with silyl enol ethers are amongst the most widely used Lewis-acid-mediated or -catalyzed reactions. However, trimethylsilyl triflate is not active enough to promote these reactions,66 and more active silicon-based Lewis acids have been developed. One example is the species generated by mixing trimethylsilyl triflate (or chloride) and B(OTf)3,319,320 for which the formulation R3Si + [B(OTf)4] is suggested by NMR experiments. Only a catalytic amount of this was needed to complete Mukaiyama aldol reactions of... 

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. 

Activities of various metallosilicates for Mukaiyama aldol reaction of benzaldehyde with silyl enol ether... 

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. 

On the other hand, Ln(OTf)3 compounds, which were found to be effective catalysts for the hydroxy-methylation in aqueous media, also activate aldehydes other than formaldehyde in aldol reactions with silyl enol ethers in aqueous solvents.1121 One feature of the present reactions is that water-soluble... 

Judging from these findings, the mechanism of Lewis acid catalysis in water (for example, aldol reactions of aldehydes with silyl enol ethers) can be assumed to be as follows. When metal compounds are added to water, the metals dissodate and hydration occurs immediatdy. At this stage, the intramolecular and intermolecular exchange reactions of water molecules frequently occur. If an aldehyde exists in the system, there is a chance that it will coordinate to the metal cations instead of the water molecules and the aldehyde is then activated. A silyl enol ether attacks this adivated aldehyde to produce the aldol adduct. According to this mechanism, it is expected that many Lewis acid-catalyzed reactions should be successful in aqueous solutions. Although the precise activity as Lewis acids in aqueous media cannot be predicted quantitatively... 

The cationic iridium complex [Ir(cod)(PPh3)2]OTf, when activated by H2, catalyzes the aldol reaction of aldehydes 141 or acetal with silyl enol ethers 142 to afford 143 (Equation 10.37) [63]. The same Ir complex catalyzes the coupling of a, 5-enones with silyl enol ethers to give 1,5-dicarbonyl compounds [64]. Furthermore, the alkylation of propargylic esters 144 with silyl enol ethers 145 catalyzed by [Ir(cod)[P(OPh)3]2]OTf gives alkylated products 146 in high yields (Equation 10.38) [65]. An iridium-catalyzed enantioselective reductive aldol reaction has also been reported [66]. 

Lewis acids are quite often used as catalysts in organic synthesis. Although most Lewis acids decompose in water, it was found that rare earth triflates such as Sc(OTf)3, Yb(OTf)3, etc. can be used as Lewis acid catalysts in water or water-containing solvents (water-compatible Lewis acids) [6-9]. For example, the Mukaiyama aldol reactions of aldehydes with silyl enol ethers were catalyzed by Yb(OTf)3 in water-THF (1 4) to give the corresponding aldol adducts in high yields [10, 11]. Interestingly, when the reactions were carried out in dry THF (without water), the yield of the aldol adducts was very low (ca. 10%). Thus, this catalyst is not only compatible with water but also is activated by water, probably due to dissociation of the counteranions from the Lewis acidic metal. Furthermore, the catalyst can be easily recovered and reused. 

Bismuth triflate has been reported by Dubac as an efficient catalyst for the Mukaiyama aldol reaction with silyl enol ethers [27] and was recently used with a chiral ligand, as reported by Kobayashi in an elegant hydroxymethylation reaction... 

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). ° ... 

Organoaluminum reagents, 202 1,1,1-Trifluoroacetone, 323 Trityllithium, 338 Zinc chloride, 349 Stereoselective aldol reactions With boron enolates Boron trichloride, 43 Chlorodimethoxyborane, 73 9-(Phenylseleno)-9-borabicyclo-[3.3.1]nonane, 245 With silyl enol ethers... 

Aldol reactions.2 This combination of catalysts is effective for promoting reaction of acetals with silyl enol ethers and ketene silyl acetals. It can also promote reaction of aldehydes or imines with ketene silyl acetals. The reactions occur in high yield at 25° either CH3CN or THF can be used as the solvent. 

Carbonyl activation and deactivation.1 Aldehydes, but not ketones, undergo aldol condensation with silyl enol ethers at —78° in the presence of dibutyltin bistriflate. In contrast, the dimethyl acetals of ketones, but not of aldehydes, can undergo this condensation (Mukaiyama reaction) with silyl enol ethers at -78° with almost complete discrimination, which is not observed with the usual Lewis-acid catalysts. Thus dibutyltin bistriflate activates aldehydes, but deactivates acetals of... 

Diastereoselective aldol coupling of alkynyl aldehydes.3 The Co2(CO)6 complexes (2) of alkynyl aldehydes react with silyl enol ethers to form aldols with... 

Aldol reactions1 (15, 314-315). In the presence of a complex (1) obtained from a chiral diamine such as (S)-l-ethyl-2-[(piperidinyl)methyl]pyrrolidine (13, 302), and Sn(OTf)2 and Bu2Sn(OAc)2, aldehydes react with silyl enol ethers of a-benzy-loxy thioesters to form anti-a,P-dihydroxy thioesters in high diastereoselectivity. 

Chiral N-oxides have also been employed as catalysts to promote aldol addition [62], but their true potential remains to be realized. Catalysis by N-oxides follows the same general trends that were established for the phosphoramide activators, though with reduced enantioselectivity. Thus, Nakajima [62] has demonstrated that the reaction of aldehydes 1 with silyl enol ethers 55, catalyzed by bidentate... 

Hoveyda and coworkers reported that the silver complex generated from AgF2 and an amino acid-based ligand could be used for the asymmetric aldol reaction with silyl enol ethers and a-ketoesters (Table 9.11).23... 

In 2002, Yamamoto and Momiyama reported an unusual aldol-like reaction with silyl enol ethers and nitrosobenzene in the presence of a catalytic amount of TESOTf (nitrosoaldol reaction).29 Usually, nucleophiles react with nitrosobenzene without Lewis acid to give the N adduct predominantly. In contrast, they reported that the reaction of silyl enol ethers and nitrosobenzene catalyzed by TESOTf afforded the... 

Aldol reaction. Silyl enol ethers react with aldehydes at 25° to give aldols - the presence of BiCl, (5 mole %). The classical version (Mukaiyama, 6, 590- 11 of this reaction usually requires a full equivalent of TiCl4 as the promotor. 7>,e BiCl, version permits use of ketones as well as aldehydes in reactions carried ut at 25°, but a longer time is required and yields are only moderate (20-65%). Both versions show only slight diastereoselectivity. 

We have also developed a new catalytic system for aldol reactions in water. The reaction of benzaldehyde with silyl enol ether 2 was catalysed by a combination of diphenylborinic acid (PhjBOH), benzoic acid and SDS in water to give the aldol adduct in high yield with high syn/anti ratio (Equation (6)) [30,31]. All of the three components in the catalyst combination were indispensable for the high yield and selectivity. This... 

The Mukaiyama aldol reaction of carbonyl substrates with silyl enol ethers is the most widely accepted of Lewis acid-promoted reactions. Many Lewis acids for the reaction have been developed and used enantioselectively and diastereoselectively. In 1980, catalytic amounts of la were found by Noyori et al. to effect aldol-type condensation between acetals and a variety of silyl enol ethers with high stereoselectivity [2c,20]. Unfortunately, la has poor Lewis acidity for activation of aldehydes in Mukaiyama s original aldol reaction [21]. Hanaoka et al. showed the scope and limitation of 11-cat-alyzed Mukaiyama aldol reaction, by varying the alkyl groups on the silicon atom of silyl enol ethers [22]. Several efforts have been since been made to increase the reactivity and/or the Lewis acidity of silicon. One way to enhance the catalyst activity is to use an additional Lewis acid. 

The importance of aqueous reactions is now generally recognized, and development of carbon-carbon bond-forming reactions that can be performed in aqueous media is now one of the most challenging topics in organic synthesis [59]. It has been found that Sc(OTf)3 was effective in aldol reactions of silyl enolates with aldehydes in aqueous media (water-THF Eq. 16) [4]. Reaction between aromatic and aliphatic aldehydes such as benzaldehyde and 3-phenylpropionaldehyde and silyl enolates have been performed successfully in aqueous solvents. In addition, direct treatment of aqueous solutions of water-soluble formaldehyde and chloroacetaldehyde with silyl enolates affords the corresponding aldol adducts in good yields. Water-sensitive silyl enolates could be used in aqueous solutions with Sc(OTf)3 as catalyst. 

Several examples of Sc(OTf)3-catalyzed aldol reactions in micellar systems are shown in Table 4. Not only aromatic, but also aliphatic and a,j8-unsaturated aldehydes react with silyl enol ethers to afford the corresponding aldol adducts in high yields. Aqueous formaldehyde solution also worked well. Even the ketene silyl acetals, which readily hydrolyze in the presence of a small amount of water, reacted with aldehydes... 

The same group described the Yb(OTf)3 catalyzed Mukaiyama aldol reaction of aldehyde 43 with silyl enol ether 435 in an aqueous medium [161] (O Scheme 88). This results in the formation of two non-separable diastereomeric aldols 436 and 437 in a 95% combined yield. Finally, NaBH4 reduction leads to isolation of pure 440 and a mixture of 438 and 439. 

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