Aldol reactions Lewis acid

Danshefsky s diene [19] is the 1,3-butadiene with amethoxy group at the 1-position and a trimethylsiloxy group at the 3-position (Scheme 18). This diene and Lewis acids extended the scope of hetereo-Diels-Alder reactions with aldehydes [20], This diene reacts with virtually any aldehyde in the presence of Lewis acids whereas dienes usually react with only selected aldehydes bearing strongly electron accepting a-substituents. There are two (Diels-Alder and Mukaiyama aldol) reaction pathways (Scheme 18) identified for the Lewis acids catalyzed reactions of Danishefsky diene with aldehydes [21, 22]. The two pathways suggest that these reactions occur on the boundary between the delocahzation band (the pericyclic... 

The Mukaiyama aldol reaction refers to Lewis acid-catalyzed aldol addition reactions of silyl enol ethers, silyl ketene acetals, and similar enolate equivalents,48 Silyl enol ethers are not sufficiently nucleophilic to react directly with aldehydes or ketones. However, Lewis acids cause reaction to occur by coordination at the carbonyl oxygen, activating the carbonyl group to nucleophilic attack. 

Indium trichloride349-351 is a mild Lewis acid that is effective for various kinds of Lewis-acid-catalyzed reactions such as Diels-Alder reactions (Scheme 85), aldol reactions, and Friedel Crafts reactions. Since indium trichloride is stable in water, several aqueous reactions have been investigated (Scheme 85) indium(III) triflate is also used as a Lewis acid. 

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... 

Fig. 13). The cross-linked scandium-modified dendrimer was tested in a number of Lewis acid-catalyzed reactions, including Mukaiyama aldol additions to aldehydes and aldimines, Diels-Alder reactions, and Friedel-Crafts acylations. The dendritic catalyst was recovered by a simple filtration. The Mukaiyama aldol... 

The Lewis acid-mediated reactions of 2-aza-l,3-dienes and aldehydes, resulting in tetrahydro-l,3-oxazin-4-one derivatives, were explained in terms of the competitive existence of two reaction pathways a [4+2] hetero-Diels-Alder cycloaddition reaction and a Mukaiyama aldol reaction <2001TA439>. 

Chlorodifluoromethylketones underwent aldol reactions (Eq. 124) via zinc enolates, to afford good yields of a,a-difluoro-/ -hydroxy ketones, in a study by the Kyoto group [327]. Copper(I) or silver salt catalysis was essential and boron-trifluoride additive appeared to exert a key role in the conversion to the enolate. Earlier [328], chlorodifluoromethyl ketones had been converted to the di-fluoroenoxy silanes by the action of zinc in the presence of chlorotrimethyl silane. A difluoroenoxy silane was used by McCarthy and co-workers [329] to synthesise a kynureninase inhibitor (Eq. 125) Lewis acid-mediated reaction with a chloroglycinate installed the key carbon-carbon bond. 

Formyl hydrogen bonds, in which die C—H bond of a formyl group acts as an acceptor (typically to oxygen), have recently been identified in Lewis acid-catalysed reactions of aldehydes.523 An X-ray crystal structure of such a complex has been reported.5213 This type of hydrogen bond is now suggested as a likely organizing stereochemical element in a variety of enantioselective aldol, allylation, and Diels-Alder reactions catalysed by Lewis acids reported in the literature.520 Further examples of such reactions are also discussed.53... 

Dihydropyran-4-ones are formed with good enantiomeric excess by a chiral Lewis acid catalysed reaction of aldehydes with Danishefsky s diene and cyclisation of the initial aldol product. The overal process equates to a hetero-Diels-Alder cycloaddition (95JOC5998). Lactams also react with the electron rich diene under the influence of a Lewis acid, yielding 7-aza-l-oxaspiroalkenones (95JOC7724). 

Trimethylsilyl enolates of aldehydes and ketones are now established as highly useful synthetic intermediates.2 In particular, their Lewis acid-catalyzed reactions - e.g., alkylation 1 and mild, regiospecific aldol... 

Good yields of 2-alkylidene or 2-benzylidene ketones are readily achieved by condensation of enamines of cyclic ketones with aldehydes146-148. Except for the reaction with chloral149,150, where the intermediate carbinolamine (65) was isolated and hydrolysed to the /Miydroxyketone (66), the corresponding aldol intermediates formed in these reactions could not be isolated (Scheme 54). However, it has recently been shown that in the presence of a slight excess of Lewis acid the reaction can be carried out under very mild conditions and high yields of the crossed aldol products can be obtained from... 

While the Lewis acid-catalysed aldol reactions in water-containing solvents described above were catalysed by several metal salts, a certain amount of organic solvents such as THF and ethanol still had to be combined with water to dissolve organic substrates and promote the reactions efficiently. However, it is desirable to avoid the use of harmful organic solvents. Therefore, we initiated investigations to develop a new system for Lewis acid-catalysed reactions in water without using any organic solvents. 

The use of Al(III) complexes as catalysts in Lewis acid mediated reactions has been known for years. However, recent years have witnessed interesting developments in this area with the use of ingeiuously designed neutral tri-coordinate Al(lll) chelates. Representative examples involving such chelates as catalysts include (1) asymmetric acyl halide-aldehyde cyclocondensations, " (2) asymmetric Meerwein-Schmidt-Ponndorf-Verley reduction of prochiral ketones, (3) aldol transfer reactions and (4) asymmetric rearrangement of a-amino aldehydes to access optically active a-hydroxy ketones. It is important to point out that, in most cases, the use of a chelating ligand appears critical for effective catalytic activity and enantioselectivity. 

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. 

There are two different modes of cyclizations in hetero [4+2] cycloadditions involving Danishefsky s diene 1) concerted (pericyclic) and 2) stepwise. When carbonyl compounds are reacted with Danishefsky s diene, the stepwise pathway is often referred to as the Mukaiyama aldol reaction pathway. The concerted process is called the Diels-Alder pathway. The mode of cyclization in the case of Lewis acid catalyzed reactions depends on the Lewis acid itself and whether it is present in stoichiometric or catalytic amounts. The Mukaiyama aldol pathway has been... 

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-... 

Lewis acid catalysis in micellar systems [33] was first found in the model reaction in Table 14-6 [34]. While the reaction proceeded sluggishly in the presence of 0.2 eq. Yb(OTf)3 in water, remarkable enhancement of the reactivity was observed when the reaction was carried out in the presence of 0.2 eq. Yb(OTf)3 in an aqueous solution of sodium dodecyl sulfate (SDS, 0.2 eq., 35 mM), and the corresponding aldol adduct was obtained in 50% yield. In the absence of the Lewis acid and the surfactant (water-promoted conditions), only 20% yield of the aldol adduct was isolated after 48 h, while 33% yield of the aldol adduct was obtained after 48 h in the absence of the Lewis acid in an aqueous solution of SDS. The amount of the surfactant also influenced the reactivity, and the yield was improved when Sc(OTf)3 was used as a Lewis acid catalyst. Judging from the critical micelle concentration, micelles would be formed in these reactions, and it is noteworthy that the Lewis acid-catalyzed reactions proceeded smoothly in micellar systems [35]. It was also found that the surfactants influenced the yield, and that Triton X-100 was effective in the aldol reaction (but required long reaction time), while only a trace amount of the adduct was detected when using cetyltri-methylammonium bromide (CTAB) as a surfactant. 

In the Lewis acid-catalyzed reaction of a Danishefsky diene (102 or 102 ) with a carbonyl dienophile, two different reaction paths, the Mukaiyama aldol path and the concerted DA path, are available for formation of the cychc producL depending on the Lewis acid used (Scheme 10.119) [331]. Strictly speaking, the former path is not that of DA reaction, but the stepwise reaction also is generally classified as an HDA reaction. The B(III)- and Ti(IV)-catalyzed HDA reactions probably proceed through the Mukaiyama aldol path [318, 320]. The concerted path has been positively identified in reactions catalyzed by Lewis acids based on Al(III) [319], Cr(III) [323], Co(III) [324], Zn(II) [331], Rh(II) [327], and Eu(III) [294, 317]. 

Me2AlCl has unique character in the discrimination of reaction pathways in Lewis acid-promoted reactions of aldehydes with organosilicon reagents (Scheme 10.235) [609]. The Me2AlCl-promoted reaction of benzaldehyde and cyclohexanecarbalde-hyde with a ketene silyl acetal and TMSCN affords the corresponding aldol adduct of benzaldehyde and the cyanohydrin TMS ether of cyclohexanecarbaldehyde, exclusively. 

Anti-aldols by Lewis acid-catalysed reactions with Evans oxazolidinones Chiral Auxiliaries... 

Lewis-acid-catalyzed reactions of enoxysilanes with aldehydes and ketones have been developed by Mukaiyama and coworkers [832], The Lewis acid activates the C=0 group of the electrophile. The O-Si bond of the reaction product is usually cleaved by a nucleophile or during hydrolytic workup. However, aldol silylethers are obtained under carefully controlled conditions [1296]. It has been... 

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