Lewis acids Mukaiyama aldol reaction

The role of the ligand has been found to be crucial in the silyl Lewis acid Mukaiyama aldol reaction, which opens interesting applications for synthetic organic chemistry. When TMSOTf induces the reaction, the silyl group of TMSOTf remains in the product and that of the silyl enol ether becomes the catalyst for the next catalytic cycle however, if the reaction is promoted by TMSNTf2, the silyl group of the catalyst is not released from... 

The stereochemical outcome of the Mukaiyama reaction can be controlled by the type of Lewis acid used. With bidentate Lewis acids the aldol reaction led to the anti products through a Cram chelate control [366]. Alternatively, the use of a monoden-tate Lewis acid in this reaction led to the syn product through an open Felkin-Anh... 

Attention now turned to the aldol reaction of methyl ketone 27 with chiral aldehyde 9d. Motivated by our previous success with a Mukaiyama aldol reaction (see Section 2.3), we aimed to employ an analogous procedure with methyl ketone 27. Formation of silyl enol ether 37 was achieved by treatment with tri-methylsilyl triflate and triethylamine. The Lewis acid-mediated aldol reaction proceeded smoothly once more, although full conversion to aldol 26 could not be attained. Reaction of 37 with aldehyde 9d at -78 °C in the presence of boron trifluoride diethyl etherate provided aldol 26 in 58% yield over two steps together with 38% recovered methyl ketone 27 (Scheme 12). In an effort to improve the yield, the reaction time was extended to 3 h. Interestingly, this did not result in any significant increase in the yield of aldol 26 (56% yield). 

Eor the application of C2-symmetric bis-oxazoline-Lewis acids in other catalytic reactions (a) Mukaiyama-aldol reactions see, e.g., D.A. Evans, M.C. Kozlowski,... 

For example in the so-called Mukaiyama aldol reaction of an aldehyde R -CHO and a trimethylsilyl enol ether 8, which is catalyzed by Lewis acids, the required asymmetric environment in the carbon-carbon bond forming step can be created by employing an asymmetric Lewis acid L in catalytic amounts. 

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... 

Asymmetric Mukaiyama aldol reactions have also been performed in the presence of Lewis-acid lanthanoid complexes combined with a chiral sulfonamide ligand. Similar enantioselectivities of about 40% ee were obtained for all... 

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. 

Quite a number of other Lewis acids can catalyze the Mukaiyama aldol reaction, including Bu2Sn(03SCF3)2,51 Bu3SnC104,52 Sn(03SCF3)2,53 Zn(03SCF3)2,54 and... 

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. 

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... 

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... 

A Lewis acid-catalyzed vinylogous Mukaiyama aldol reaction between 2-trialkylsilyloxyfurans and a-substituted ketones proceeded diastereoselectively... 

The aldol reactions introduced thus far have been performed under basic conditions where enolate species are involved as the reactive intermediate. In contrast to the commonly accepted carbon-anion chemistry, Mukaiyama developed another practical method in which enol species can be used as the key intermediates. He is the first chemist to successfully demonstrate that acid-catalyzed aldol reactions using Lewis acid (such as TiCU) and silyl enol ether as a stable enol equivalent can work as well.17 Furthermore, he developed the boron tri-fluoromethane sulfonate (triflate)-mediated aldol reactions via the formation of formyl enol ethers. 

Silyloxy)alkenes were first reported by Mukaiyama as the requisite latent enolate equivalent to react with aldehydes in the presence of Lewis acid activators. This process is now referred to as the Mukaiyama aldol reaction (Scheme 3-12). In the presence of Lewis acid, anti-aldol condensation products can be obtained in most cases via the reaction of aldehydes and silyl ketene acetals generated from propionates under kinetic control. 

The addition of an enolsilane to an aldehyde, commonly referred to as the Mukaiyama aldol reaction, is readily promoted by Lewis acids and has been the subject of intense interest in the field of chiral Lewis acid catalysis. Copper-based Lewis acids have been applied to this process in an attempt to generate polyacetate and polypropionate synthons for natural product synthesis. Although the considerable Lewis acidity of many of these complexes is more than sufficient to activate a broad range of aldehydes, high selectivities have been observed predominantly with substrates capable of two-point coordination to the metal. Of these, benzy-loxyacetaldehyde and pyruvate esters have been most successful. 

Based on these results, Kalesse et al. applied the vinylogous Mukaiyama aldol reaction in their total synthesis of ratjadone [33, 34]. In the synthesis of the C14-C24 segment (A-fragment), the vinylogous aldol reaction was used together with different Lewis acids to achieve the addition of this diacetate syn-thon in a diastereoselective manner under Felkin control (Scheme 23). 

Table 12 Vinylogous Mukaiyama aldol reaction using different Lewis acids... 

In order to enhance the catalytic activity of a carbocationic center, the novel Lewis acid 54 was designed by Mukaiyama [149-152]. The 1-oxoisoindolium-based carbenium salt 54 [149], possessing a weak coordinating borate counter anion, proved to be a very active catalyst in the aldoUzation (Scheme 58) [150]. The Mukaiyama aldol reaction was catalyzed by 1 mol% of salt 54 and proceeded in up to 97% yield in 30 min. 

The Mukaiyama aldol reaction is one of the most important means for C-C bond formation. Silyl end ethers react with aldehydes in the presence of Lewis acids to give (3-hydroxy carboxylates. 

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. 

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>. 

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