Mukaiyama aldol condensations

A series of chiral binaphthyl ligands in combination with AlMe3 has been used for the cycloaddition reaction of enamide aldehydes with Danishefsky s diene for the enantioselective synthesis of a chiral amino dihydroxy molecule [15]. The cycloaddition reaction, which was found to proceed via a Mukaiyama aldol condensation followed by a cyclization, gives the cycloaddition product in up to 60% yield and 78% ee. 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

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. 

An exceptionally mild procedure for the cross-condensation of aldimines and enolsilanes has been described (eq. [67]) (80). This titanium tetrachloride-mediated reaction is predicated on the previous analogies provided by Mukaiyama for related aldol condensations (73a). Depending on aldimine structure and reaction time, either -lactams or their penultimate amino esters may be isolated from the reaction. The authors postulate that these reactions are proceeding via titanium enolates derived from ligand exchange by... 

Although in the recent years the stereochemical control of aldol condensations has reached a level of efficiency which allows enantioselective syntheses of very complex compounds containing many asymmetric centres, the situation is still far from what one would consider "ideal". In the first place, the requirement of a substituent at the a-position of the enolate in order to achieve good stereoselection is a limitation which, however, can be overcome by using temporary bulky groups (such as alkylthio ethers, for instance). On the other hand, the ( )-enolates, which are necessary for the preparation of 2,3-anti aldols, are not so easily prepared as the (Z)-enolates and furthermore, they do not show selectivities as good as in the case of the (Z)-enolates. Finally, although elements other than boron -such as zirconium [30] and titanium [31]- have been also used succesfully much work remains to be done in the area of catalysis. In this context, the work of Mukaiyama and Kobayashi [32a,b,c] on asymmetric aldol reactions of silyl enol ethers with aldehydes promoted by tributyltin fluoride and a chiral diamine coordinated to tin(II) triflate... 

Amino-3-tetrahydrofurancarboxylic acid 17, an oxygen cycloleucine analog, has been synthesized from D,L-homoserine by an intramolecular Mukaiyama aldol condensation in six steps (89TL1181). From o-Thr, l-muscarine 18 was synthesized in eight steps. The synthesis is highly stereoselective (85T5321). 

A recent approach toward ( )-guanacastepene (rac-187) published by Kwon in 2003 employed a sequential methyl cuprate 1,4-addition to the en-one 281 followed by an intramolecular Mukaiyama aldol condensation to construct the B ring (Eq. 9) [142, 143] ... 

The synthesis of Taxol completed by a group led by the Japanese chemist Teruaki Mukaiyama and shown in Scheme 13.46 takes a rather different approach. Much of the stereochemistry is built into the B ring by a series of acyclic aldol condensations in steps A-D. The ring is closed by a samarium-mediated cyclization at step E-3. 

Mukaiyama aldol condensation (6, 590-591).8 This reaction can be effected in the absence of a Lewis acid catalyst under high pressure (10 kbar). Surprisingly the stereoselectivity is the reverse of that of the TiCl4-catalyzed reaction (equation I). The reaction can also be effected in water with the same stereoselectivity, but the yield is low because of hydrolysis of the silyl enol ether. Yields are improved by use of water-oxolane (1 1) and by sonication.9... 

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. 

The Mukaiyama reaction is a versatile crossed-aldol reaction that uses a silyl enol ether of an aldehyde, ketone, or ester as the carbon nucleophile and an aldehyde or ketone activated by a Lewis acid as the carbon electrophile. The product is a /1-hydroxy carbonyl compound typical of an aldol condensation. The advantages to this approach are that it is carried out under acidic conditions and elimination does not usually occur. 

Vankar and co-workers709 have shown that Nafion-H can catalyze the hetero Diels-Alder reaction between the Danisefsky diene 164 and aromatic imines to form 2,3-dihydro-y-pyridones (Scheme 5.69). The reaction with aromatic aldehydes, however, yields only the Mukaiyama aldol condensation products. 

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... 

Carboxonium/oxocarbenium ions emerging from the reaction of an electrophile towards an enol ether are encountered less frequently. Figure 12.23 shows an important, since gener-alizable example (a Mukaiyama aldol condensation) Figure 12.25 contains a special example which, however, leads to an important reagent. 

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. 

Intramolecular Mukaiyama aldol condensation. This reaction can be used to obtain six-, seven-, and eight-membered rings. Thus the reaction of the r /.v-dioxolanc la with TiCL (1-2 equiv.) gives 2a as the exclusive product. The isomeric /ran.v-dioxolane lb under similar conditions gives a I I mixture of 2a and 2b (72% yield). No cyclization products are obtained with SnCL or ZnCL. 

The aldol condensation of aldehyde and silyl enol ether in the presence of a catalyst such as TiCU is called the Mukaiyama aldol condensation (Scheme 3.7). 

Stereoselective aldot condensations. Mukaiyama et al. have reported that ketones are converted into vinyloxyboranes by reaction with dialkylboron triflates and a tertiary amine and that these enolates undergo regioselective aldol reactions with aldehydes (equation I). Mukaiyama used di-n-butylboryl triflate in combination... 

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. 

Mukaiyama Aldol Condensation. As expected, the chiral titanium complex is also effective for a variety of carbon-carbon bond forming processes such as the aldol and the Diels-Alder reactions. The aldol process constitutes one of the most fundamental bond constructions in organic synthesis. Therefore the development of chiral catalysts that promote asymmetic aldol reactions in a highly stereocontrolled and truly catalytic fashion has attracted much attention, for which the silyl enol ethers of ketones or esters have been used as a storable enolate component (Mukaiyama aldol condensation). The BINOL-derived titanium complex BINOL-TiCl2 can be used as an efficient catalyst for the Mukaiyama-ty pe aldol reaction of not only ketone si ly 1 enol ethers but also ester silyl enol ethers with control of absolute and relative stereochemistry (eq 11). ... 

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