Silyl enol ethers, aldol condensation

This review covers the catalytic literature on condensation reactions to form ketones, by various routes. The focus is on newer developments from the past 15 years, although some older references are included to put the new work in context. Decarboxylative condensations of carboxylic acids and aldehydes, multistep aldol transformations, and condensations based on other functional groups such as boronic acids are considered. The composition of successful catalysts and the important process considerations are discussed. The treatment excludes enantioselective aldehyde and ketone additions requiring stoichiometric amounts of enol silyl ethers (Mukaiyama reaction) or other silyl enolates, and aldol condensations catalyzed by enzymes (aldolases) or catalytic antibodies with aldolase activity. It also excludes condensations catalyzed at ambient conditions or below by aqueous base. Recent reviews on these topics are those of Machajewski and Wong, Shibasaki and Sasai, and Lawrence. " The enzymatic condensations produce mainly polyhydroxyketones. The Mukaiyama and similar reactions require a Lewis acid or Lewis base as catalyst, and the protecting silyl ether or other group must be subsequently removed. However, in some recent work the silane concentrations have been reduced to catalytic amounts (or even zero) this work is discussed. 

For some condensations with silylated substrates as starting compounds, trimethylsilyl inflate can be used as a catalyst [103, 104, 105] Atypical example of such a reaction is the aldol type condensation of silyl enol ethers and acetals catalyzed by 1-5 mol% of trimethylsilyl inflate [103] (equation 53)... 

Aldol condensation of silyl enol ethers 213 with 214 provided in good yields the condensation products 215 which on treatment with concentrated hydrochloric acid in methanol gave derivatives 216 (Scheme 51) (88S381). 

Conjugate reduction.1 This stable copper(I) hydride cluster can effect conjugate hydride addition to a,p-unsaturated carbonyl compounds, with apparent utilization of all six hydride equivalents per cluster. No 1,2-reduction of carbonyl groups or reduction of isolated double bonds is observed. Undesirable side reactions such as aldol condensation can be suppressed by addition of water. Reactions in the presence of chlorotrimethylsilane result in silyl enol ethers. The reduction is stereoselective, resulting in hydride delivery to the less-hindered face of the substrate. 

Fluoride-catalysed aldol condensation of silyl enol ethers... 

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... 

Lewis acid-catalyzed aldol condensation of aldehyde and silyl enol ether. 

Mukiayama aldol reactions between silyl enol ethers and various carbonyl containing compounds is yet another reaction whose stereochemical outcome can be influenced by the presence of bis(oxazoline)-metal complexes. Evans has carried out a great deal of the work in this area. In 1996, Evans and coworkers reported the copper(II)- and zinc(II)-py-box (la-c) catalyzed aldol condensation between benzyloxyacetaldehyde 146 and the trimethylsilyl enol ether [(l-ferf-butylthio)vinyl]oxy trimethylsilane I47. b82,85 Complete conversion to aldol adduct 148 was achieved with enantiomeric excesses up to 96% [using copper(II) triflate]. The use of zinc as the coordination metal led to consistently lower selectivities and longer reaction times, as shown in Table 9.25 (Eig. 9.46). 

Vinyloxyboranes (boron enolates) are obtained in quantitative yield by reaction of silyl enol ethers with dialkylboron triflates in CH2C12 at —22 . The products can be used for stereoselective aldol condensations.3 Example ... 

Aldol condensation. The aldol condensation of silyl enol ethers with an aldehyde in the presence of 1 (0.1 5 equivalents) results mainly or even exclusively in erythro-adducts (equations I and II) regardless of the stereochemistry of the cnolatc. 

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... 

Recently, Yamamoto et al. have shown that the chiral acyloxyborane complex 31 is an excellent catalyst for the asymmetric Mukaiyama condensation of simple silyl enol ethers (Scheme 8B1.19 Table 8B1.11 entries 1-7) [43], The syn-aldol adducts are formed preferentially with high enantiomeric excess regardless of the stereochemistry (EI7) of the silyl enol ethers, suggesting an extended transition state (entries 4, 7). This methodology has been... 

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. 

Mukaiyama found that Lewis acids can induce silyl enol ethers to attack carbonyl compounds, producing aldol-like products.22 The reaction proceeds usually at -78 °C without selfcondensation and other Lewis acids such as TiCl4 or SnCI4 are commonly used. The requisite silyl enol ether 27 was prepared by treatment of ketone 13 with lithium hexamethyl disilazide (LiHMDS) and trapping the kinetic enolate with chlorotrimethylsilane. When the silyl enol ether 27 was mixed with aldehyde 14 in the presence of BF3-OEt2 a condensation occurred via transition state 28 to produce the product 29 with loss of chlorotrimethylsilane. The induced stereochemistry in Mukaiyama reactions using methylketones and a, -chiral aldehydes as substrates... 

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... 

In Equation Si3.7 conversion of cyclohexanone to its silyl enol ether ensures that only acetone acts as the electrophilic partner in a reaction which is equivalent to an aldol condensation of two ketones. 

The silyl enol ether is not isolated but reacted immediately with the aldehyde to give an excellent yield of the aldol. Dehydration in acid solution with toluene sulfonic acid (TsOH) gives the enone. You can see by the high yield in the aldol reaction that there is no significant self-condensation of either partner in the aldol reaction. 

These silyl enol ethers are probably the best way of carrying out crossed aldol reactions with an aldehyde as the enol partner. An example is the reaction of the enol of the not very enolizable iso-butyraldehyde with the very enolizable 3-phenylpropanal. Mixing the two aldehydes and adding base would of course lead to an orgy of self-condensation and cross-couplings. 

When the acetal and the silyl enol ether are mixed with the same Lewis acid catalyst, Noyori found that an efficient aldol-style condensation takes place with the acetal providing the electrophile. The reaction is successful at low temperatures and only a catalytic amount of the Lewis acid is needed. Under these conditions, with no acid or base, few side-reactions occur. Notice that the final desilylation is carried out by the triflate anion to regenerate the Lewis acid Me3Si-OTf. Triflate would be a very poor nucleophile for saturated carbon but is reasonable for silicon because oxygen is the nucleophilic atom. 

Condensation of 1,2-dielectrophiles with a component that serves as a l,3-C,0-nucleophile is the underlying principle of a number of improved methods for furan synthesis. Bis-silyl enol ethers are suitable enol equivalents for the condensation with dielectrophiles to produce furans. Langer and co-workers have made use of this concept in the synthesis of annulated furans with l-chloro-2,2-dimethoxyethane as electrophile <2005EJ02074>. In a stepwise reaction comprising TMS triflate-assisted aldol reaction and cyclization with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base, 3-methoxy exomethylene tetrahydrofurans are obtained, which finally yield the furan reaction products upon treatment with trifluoroacetic acid (Scheme 18). 

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). 

For example, condensation of silyl enol ether (3.21) of 3-pentanone with 2-methylbutanal in the presence of TiC gives the Ti-complex 3.22, which on hydrolysis yields an aldol product, manicone (4,6-dimethyl-4-octen-3-one) (3.23), an alarm pheromone. Treatment of 3-pentanone with LDA results in the formation of an enolate, which is trapped with chlorotrimethylsilane to give 3.21. Other Lewis acids such as tin tetrachloride (SnCU) and boron trifluoride etherate (BF3-OEt2) can also be used. 

Aldol Condensations. The rhodium complex has been utilized as a catalyst in aldol condensation of silyl enol ethers and... 

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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