Aldol with Lewis acids

Aldol reactions with specific enol equivalents Contrast with equilibrium methods Aldols with Lewis acid catalysis silyl enol ethers Application to the synthesis of gingerol Reaction at O or C Silylation, Acylation and Alkylation Naked enolates... 

Aldols with Lewis acid catalysis silyl enol ethers... 

The authors apphed this new concept to chemoselective functionalization of carbonyls rather than acetals [194], which is usually quite difficult to achieve because of the high reactivity of the acetal counterparts with Lewis acids. Reaction of a mixture of 1 equiv. each of acetophenone and its dimethyl acetal with ketene silyl acetal 191 under the influence of bidentate aluminum Lewis acid 188 in CH2CI2 at -78 °C for 3 h afforded aldol products 195 exclusively (88 % yield). It is worth noting that employment of dibutyltin bis(triflate) (DBTT) (10 mol%) as catalyst [195], which is quite useful for activation of aldehyde carbonyls rather than acetals, gave unsatisfactory results, producing the y3-methoxy ester preferentially (Sch. 147). 

The silyl enol ethers of esters, e.g. Ill and lactones, e.g. 114 similarly take part in efficient aldol reactions with enolisable aldehydes and ketones with Lewis acid catalysis, again with complete regioselectivity. Example 113 is particularly impressive as the very enolisable ketone gives a high yield of an aldol product with two adjacent quaternary centres.21... 

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

Condensation reactions of simple carboxylic acids with imines are of intense interest because of their applications to 3-lactam synthesis. Activation of the carboxylic acid derivative is accomplished by preforming the enolate in situ or by using a silyl ketene acetal derivative with Lewis acid catalysis. The first example of an enolate-imine condensation of this type can be attributed to Gillman and Speeter, who in 1943 reported the synthesis of 3-lactams from Reformatsky reagents and Schiff bases. Subsequently, other workers have investigated the mechanism and syn-anti selectivity of this reaction. A review of these studies by Evans et al. covering work through 1980 has appeared in their review, Stereoselective Aldol Condensations . ... 

FIGURE 19.68 Two reactions of the weakly nucleophilic enol with Lewis acids. In the first case, it is protonated to regenerate acetaldehyde in the second, the enol adds to the strongly Lewis acidic protonated carbonyl group to give aldol. 

New challenges were then made to develop useful Lewis base-catalyzed aldol reactions of trimethylsilyl enolates, simple and the most popular silicon enolates. It has recently been found that aldol reactions of trimethylsilyl enolates with aldehydes proceed smoothly under the action of a catalytic amount of lithium diphenylamide or lithium 2-pyrrilidone in DMF or pyridine (Eq. (38)) [57]. This Lewis base-catalyzed aldol reaction of trimethylsilyl enolates [58] has an advantage over acid-catalyzed reactions in that aldol reaction of carbonyl compounds with highly-coordinative functional groups with Lewis acid catalysts are smoothly catalyzed by Lewis bases to afford the desired aldol adducts in high yields. 

A slightly different sitrration is observed if Lewis adds ate required for the nucleophilic attack. The Mukaiyama aldol reaction is such an example. Here silyl enol ethers or ketene acetals are used in combination with Lewis acids. Recently an excellent analysis for the observed selectivities and transition state models was proposed by Wrest and Helquist [5]. In addition to the anti transition state, they could... 

In 1973, Mukaiyama et al. established the aldol reaction using enol silanes with Lewis acids (Scheme 8.21). ... 

Lewis acid promoted condensation of silyl ketene acetals (ester enolate equiv.) with aldehydes proceeds via "open" transition state to give anti aldols starting from either E- or Z- enolates. 

A regioselective aldol condensation described by Biichi succeeds for sterical reasons (G. Biichi, 1968). If one treats the diaidehyde given below with acid, both possible enols are probably formed in a reversible reaaion. Only compound A, however, is found as a product, since in B the interaction between the enol and ester groups which are in the same plane hinders the cyclization. BOchi used acid catalysis instead of the usual base catalysis. This is often advisable, when sterical hindrance may be important. It works, because the addition of a proton or a Lewis acid to a carbonyl oxygen acidifies the neighbouring CH-bonds. 

The mechanism of the cycloaddition reaction of benzaldehyde 2a with Danishefsky s diene 3a catalyzed by aluminum complexes has been investigated theoretically using semi-empirical calculations [14]. It was found that the reaction proceeds as a step-wise cycloaddition reaction with the first step being a nucleophilic-like attack of Danishefsky s diene 2a on the coordinated carbonyl compound leading to an aldol-like intermediate which is stabilized by interaction of the cation with the oxygen atom of the Lewis acid. The next step is the ring-closure step, giving the cycloaddition product. 

An enantioselective aldol reaction may also be achieved with non-chiral starting materials by employing an asymmetric Lewis acid as catalyst ... 

A syn-selective asymmetiic nih o-aldol reaction has been reported for structurally simple aldehydes using a new catalyst generated from 6,6-bis[(tiiethylsilyl)ethynyl]BINOL (g in Scheme 3.18). The syn selectivity in the nitro-aldol reaction can be explained by steric hindrance in the bicyclic transition state as can be seen in Newman projection. In the favored h ansition state, the catalyst acts as a Lewis acid and as a Lewis base at different sites. In conbast, the nonchelation-controlled transition state affords anti product with lower ee. This stereoselective nitro-aldol reaction has been applied to simple synthesis of t/ireo-dihydrosphingosine by the reduction of the nitro-aldol product with H2 and Pd-C (Eq. 3.79). 

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... 

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