Ketene acetals, aldol condensations

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. 

Ketene acetals prepared from fluorinated esters by trimethylsilylation undergo Lewis acid-promoted aldol condensations giving satisfactory yields but low diastereoselectivity [27] (equation 22). 

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. 

Moreover, this two-step equivalent of an aldol condensation can proceed with high enantioselectivity in the presence of a chiral auxiliary. Thus reaction of the enolate of chiral silyl ketene acetal (5) with isobutyryl chloride gives 6 in 89% yield and 94% ee after reduction of the intermediate. 

Silyloxy esters.l Silyl ketene acetals are known to undergo aldol condensation with carbonyl compounds in the presence of TiCl4 (12,268) to afford (3-silyloxy esters. The same products can be obtained in a one-step reaction of an a,p-unsaturated ester with trimethylsilane and a carbonyl compound in the presence of RhCl3H20. 

Aldol condensation of a-amino silyl ketene acetals (l).10 2-Dibenzylami-noketene trimethylsilyl acetals (1) react with aldehydes premixed with TiCl4 to give a-amino-p-hydroxy carboxylic esters (2) with moderate to high syn-selectivity. Surprisingly, TiCl4-catalyzed reaction of 1 with a chiral a-alkoxy aldehyde proceeds with low asymmetric induction. 

It has been reported that the chiral NMR shift reagent Eu(DPPM), represented by structure 19, catalyzes the Mukaiyama-type aldol condensation of a ketene silyl acetal with enantiose-lectivity of up to 48% ee (Scheme 8B1.13) [29-32]. The chiral alkoxyaluminum complex 20 [33] and the rhodium-phosphine complex 21 [34] under hydrogen atmosphere are also used in the asymmetric aldol reaction of ketene silyl acetals (Scheme 8BI. 14), although the catalyst TON is quite low for the former complex. 

In other studies, analysis of the products of reaction between formaldehyde and guanosine at moderate pH shows a new adduct—formed by condensing two molecules of each reactant—which has implications for the mechanism of DNA cross-linking by formaldehyde,17 while the kinetics of the mutarotation of N-(/ -chlorophcnyl)-//-D-glucopyranosylamine have been measured in methanolic benzoate buffers.18 For a stereoselective aldol reaction of a ketene acetal, see the next section. 

Scheme 7.13 Aldol-type condensation of aldehydes with TBS ketene acetals.

Intramolecular Mukaiyama aldol condensation.5 The silyl ketene acetal 1 cyclizes to the tetrahydrofuran 2 in 32% yield on exposure to TiCl4 (1 equiv.) in CH2C12 at 0°. The product is convertible into 3, an analog of cycloleucine. 

Mukaiyama Aldol Condensation. The BINOL-derived titanium complex BINOL-T1CI2 is an efficient catalyst for the Mukaiyama-type aldol reaction. Not only ketone silyl enol ether (eq 25), but also ketene silyl acetals (eq 26) can be used to give the aldol-type products with control of absolute and relative stereochemistry. 

An important variation of the aldol condensation involves treatment of an aldehyde or ketone with a silyl ketene acetal R2C=C(OSiMe3)OR ° in the presence of TiCl4 ° , to give 38. The silyl ketene acetal can be considered a preformed enolate that gives aldol product... 

Applying an analogous method, Kobayashi and Kawasuji [37] have prepared L-fucose from (C)-crotonaldehyde and the ketene acetal 83 in four steps and 49% overall yield (Scheme 13.34). The asymmetric aldol condensation is catalyzed by a complex made of Sn(OTf)2 and chiral diamine 84. 

Aldol reactions. The enantioselectivity in condensations involving silyl enol ethers and silyl ketene acetals (also thioacetals) has been actively pursued. Valuable catalysts include 102, 103. Subsequent to the development of Cj-symmetric... 

Condensations. Reaction of tertiary alcohols with cyclic anhydrides, Baylis-Hillman reaction, aldol reaction involving bis(trimethylsilyl) ketene acetals, reaction of R(XIH(CN)2 with activated imines, and the [2+2]cycloaddition between isocyanates and enol ethers are assisted by high pressure. 

Dumas et al. noted the good yields and syn diastereoselectivities obtained in a high-pressure aldol reaction of bis-silyl ketene acetals 154 with benzaldehyde (155) (Scheme 7.39). The syn aldol 156 was obtained with a diastereoselectivity that was significantly correlated with the steric bulkiness of the R-substituent in the acetals 154. The preference for syn bis-silyl aldols 156 has been attributed to the reaction pathway that involves compact transition states in which steric interactions between the R substituent of 154 and the phenyl group of benzaldehyde are minimized. The authors also studied the condensation of unsaturated bis-silyl ketene acetal as a model for the synthesis of retinoid compounds. ... 

Two synthetic approaches to Al-(l -alkylthioglucop3Tanosyl)indoles were developed <05TL8117>. Radical reduction of the thiol group of the orthothioamides preferentially gave the P-A-glycoside indoles. Treatment of p-carboline-l-carboxaldehydes with lithium ketene acetal provided canthin-6-ones by an intramolecular amidation of the aldol condensation intermediates <05S28>. 

The condensation of an enol silyl ether with an aldehyde or ketone usually requires Lewis acid catalyzed conditions (vide infra). However, under high pressure, the reaction can be induced to proceed in the absence of catalyst (Scheme 32). ° Silyl ketene acetals, on the other hand, can react with aldehydes to give the aldol products by heating in the absence of Lewis acid. ° ... 

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