Enol ethers, addition ketenes

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. 

Lewis acids such as TiCl4 and SnCl4 induce addition of both silyl enol ethers and ketene silyl acetals to aldehydes.49... 

A number of other chiral catalysts can promote enantioselective conjugate additions of silyl enol ethers, silyl ketene acetals, and related compounds. For example, an oxazaborolidinone derived from allothreonine achieves high enantioselectivity in additions of silyl thioketene acetals.323 The optimal conditions for this reaction also include a hindered phenol and an ether additive. 

The use of oxygen-containing dienophiles such as enol ethers, silyl enol ethers, or ketene acetals has received considerable attention. Yoshikoshi and coworkers have developed the simple addition of silyl enol ethers to nitroalkenes. Many Lewis acids are effective in promoting the reaction, and the products are converted into 1,4-dicarbonyl compounds after hydrolysis of the adducts (see Section 4.1.3 Michael addition).156 The trimethylsilyl enol ether of cyclohexanone reacts with nitrostyrenes in the presence of titanium dichloride diisopropoxide [Ti(Oi-Pr)2Cl2], as shown in Eq. 8.99.157 Endo approach (with respect to the carbocyclic ring) is favored in the presence of Ti(Oi-Pr)2Cl2. Titanium tetrachloride affords the nitronates nonselectively. 

Aldol additions of silyl enol ethers and ketene silyl acetals can be catalyzed by (Cp)2Zr2+ species, including [(Cp)2ZrO-/-Bu]+ and (Cp)2Zr(03SCF3)2.39... 

The BINAP silver(I) complex can be further applied as a chiral catalyst in the asymmetric aldol reaction. Although numerous successful methods have been developed for catalytic asymmetric aldol reaction, most are the chiral Lewis acid-catalyzed Mukaiyama aldol reactions using silyl enol ethers or ketene silyl acetals [32] and there has been no report which includes enol stannanes. Yanagisawa, Yamamoto, and their colleagues found the first example of catalytic enantioselective aldol addition of tributyltin enolates 74 to aldehydes employing BINAP silver(I) complex as a catalyst (Sch. 19) [33]. 

Tab. 8.27 Michael addition of silyl enol ethers and ketene silyl enol acetals...

Protic-acid-catalyzed Michael additions (59) are subject to most of the limitations of base-catalyzed Michael additions (regioselectivity and stereoselectivity of enol generation, polyaddition, etc.), and hence, the stereochemistry has been little studied (60). At low temperatures silyl and stannyl enol ethers,+ ketene acetals, and allyl species are unreactive to all but the most reactive activated olefins. However, it was discovered by Mukaiyama and co-workers that enol ethers and ketene acetals react with a,/f-unsaturated carbonyl compounds in the presence of certain Lewis acids (4,61,62). Sakurai, Hosomi, and co-workers found that allylsilanes behave similarly (5,63,64). 

Lewis-acid-promoted Michael additions complement the enolate (2) and enamine reactions (vide supra). Since a variety of methods exist for the generation of enol ethers and ketene acetals, often with good stereochemical and regiochemical control (vide infra), the Mukaiyama-Michael reaction often permits a degree of stereochemical and regiochemical control that is not easily possible in enolate and enamine reactions. Additionally, the reaction occurs under formally acidic conditions, so it can be used with base-sensitive substrates. 

N, P ] and [P, P ] Aldehydes with an a-stereocenter exhibit unusually high diastereofacial preferences for the addition of silyl enol ethers and ketene acetals with Lewis acid assistance (81). Heathcock and Uehling found good levels of facial discrimination in the addition of silyl enol ethers to chiral enones (Scheme 38, Table 11) (82). With the more substituted silyl enol ether, only one diastereomeric addition product is obtained (Eq. [1], Scheme 38). Use of a prostereogenic silyl enol ether allows control over the relative... 

Potassium terf-butoxide,1-5-32 sodium hydride,6 butyllithium1 have all been used for this purpose. The alkyl(aryl)sulfanylcarbene (carbenoid) thus generated undergoes addition, often effectively, across the double bond of alkenes,1,25 enol ethers,6 ketene acetals1 and enamines.3,4 The use of chloromethyl phenyl sulfide, oxirane, tetraethylammonium bromide as a catalyst and an alkene gave phenylsulfanylcyclopropanes in rather low yield.7 For the synthesis of... 

It can be taken as a measnre of the low intrinsic aromaticity associated with fused pyrone rings, that 3-acyl-chromones undergo hetero-Diels-Alder additions with enol ethers," and ketene acetals, 3-formylchromone reacting the most readily. 

Increasing the oxidation state from enol ether to ketene acetal allows one to gain access to syn-P,y-dihydroxy esters (522) when the aldol addition is carried out under chelation control (Table 1.3). An excellent replacement for the standard Lewis acids in this type of reaction is Eu(fod)3 [92]. 

Michael Reactions. The Michael reactions of silyl enol ethers or ketene silyl acetals with a,/3-unsaturated carbonyl compounds are catalyzed by Sc(OTf)3 to give the corresponding 1,5-dicarbonyl compounds in high yields after acid work-up (eq 5). When the crude adducts were worked up without acid, the synthetically valuable silyl enol ethers could be isolated. The catalyst can be recovered almost quantitatively and reused. Sc(OTf)3 also catalyzes 1,4-addition of PhMe2Si-ZnMe2Li to enones in the presence of 3 mol % of Me2Cu(CN)Li2. ... 

This reaction was first reported by Mukaiyama et al. in 1974. It is a Lewis acid-catalyzed Michael conjugate addition of silyl enol ether to o ,/3-unsaturated compounds. Therefore, it is generally referred to as the Mukaiyama-Michael reaction. Because this reaction is essentially a conjugate addition, it is also known as the Mukaiyama-Michael addition or Mukaiyama-Michael conjugate addition. This reaction is a mechanistic complement for the base-catalyzed Michael addition, j and often occurs at much milder conditions and affords superior regioselectivity. s Besides silyl enol ether, silyl ketene acetals are also suitable nucleophiles in this reaction.For the hindered ketene silyl acetals, the Lewis acid actually mediates the electron transfer from the nucleophiles to o ,/3-unsaturated carbonyl molecules.On the other hand, the Q ,j8-unsaturated compounds, such as 3-crotonoyl-2-oxazolidinone, alkylidene malonates, and a-acyl-a,/3-unsaturated phosphonates are often applied as the Michael acceptors. It has been found that the enantioselectivity is very sensitive to the reactant structures —for example, Q -acyl-Q ,j8-unsaturated phosphonates especially prefers the unique syn- vs anft-diastereoselectivity in this reaction. In addition,... 

Lewis acid promoted reactions of silicon enolates, /.e., silyl enol ethers and ketene silyl acetals with various electrophiles have yielded a wealth of novel and selective synthetic methods. This combination of reagents has been used in the past to perform such reactions as aldol-condensations with aldehydes and acetals, imine-condensations, conjugate additions to a,P-enones, alkylations, electrophilic aminations, and Diels-Alder/cyclocondensations. Our own interest in this field has involved the use of titanium tetrachloride to promote the reaction of ketene silyl acetals with non-activated imines as an efficient route to P-lactams. This reaction has been applied to the asymmetric synthesis of P-lactams via a chiral imine-titanium tetrachloride template. We have also found that both ketene silyl acetals and vinylketene silyl acetals oxidativelly dimerize or cross-couple, in the presence of titanium tetrachloride to conveniently yield various diesters . Our present study concerns reactions of vinylketene silyl acetals with non-activated imines and vinylimines promoted by titanium and zirconium tetrachlorides. 

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... 

Carbon-carbon bonds can be similarly formed at the anomeric centerof carbohydrates. Oxonium ions, formed by the treatment of l-(2 -thiopyridyl)glycosides v/ith Silver(I) Trifluoromethanesul-fonate, can be trapped with silyl enol ethers, silyl ketene acetals, and reactive aromatic compounds, where the stereoselectivity of the addition is determined by solvent and nucleophile choice. The intramolecular version of this process has also been examined (eq 5). Similarly, bicyclic piperazinediones are available by the intramolecular trapping of iminium ions, generated from the appropriate thiopyridyl derivatives with PhHgC104 (eq 6). ... 

Conjugate addition of allylsilanes to enones results in regiospe-cific introduction of the allyl group (eq 34). The reaction can be intramolecular (eq 35). TiCU or SnCU activates nitro alkenes for Michael addition with silyl enol ethers or ketene silyl acetals. The silyl nitronate product is hydrolyzed to a 1,4-diketone or -y-keto ester (eq 36). ... 

Activation of C=X Bonds. The mild Lewis acid character of ZnCl2 is frequently exploited to promote the addition of various nucleophiles to carbon-heteroatom double bonds. The well-established Knoevenagel condensation and related reactions have been effectively catalyzed by ZnC (eq 26). " The addition of enol ethers and ketene acetals to aldehydes and ketones has been noted (eq 27), though ZnCl2 has been used less widely in these aldol-type condensations than other Lewis acids, including TiCU,... 

The addition of water to enol ethers causes hydrolysis to aldehydes or ketones (10-6). Ketenes add water to give carboxylic acids in a reaction catalyzed by acids " ... 

Addition of silyl enol ethers or silyl ketene acetals to unsaturated ketones or esters... 

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. 

The scope of the conjugate addition reaction can be further expanded by use of Lewis acids in conjunction with enolate equivalents, especially silyl enol ethers and silyl ketene acetals. The adduct is stabilized by a new bond to the Lewis acid and products are formed from the adduct. 

As expected, other enol ethers work well in these procedures. For example, Jones and Selenski find that implementation of method F, which occurs by addition of MeMgBr to benzaldehyde 5 in the presence of dihydropyran (DHP) at 78 °C affords a 66% yield of the corresponding tricyclic ketal 59 with better than 50 1 endo diastereoselectivity (Fig. 4.31).27 On the contrary, Lindsey reports use of method H with the benzyl alcohol 35 and diethylketene acetal. The cycloaddition reaction occurs almost instantaneously upon deprotonation of the benzyl alcohol 35 by f-butyl-magnesium bromide in the presence of the ketene acetal and yields the corresponding benzopyran ortho ester 60 in a 67% yield.29... 

In aldol reactions, especially Mukaiyama aldol reactions, TiIV compounds are widely employed as efficient promoters. The reactions of aldehydes or ketones with reactive enolates, such as silyl enol ethers derived from ketones, proceed smoothly to afford /3-hydroxycarbonyl compounds in the presence of a stoichiometric amount of TiCl4 (Scheme 17).6, 66 Many examples have been reported in addition to silyl enol ethers derived from ketones, ketene silyl acetals derived from ester derivatives and vinyl ethers can also serve as enolate components.67-69... 

Dialkyl(trimethylsilyl)phosphines undergo 1,4-addition to a,/3-unsaturated ketones and esters to give phosphine-substituted silyl enol ethers and silyl ketene acetals, respectively. A three-component coupling reaction of a silylphosphine, activated alkenes, and aldehydes in the presence of a catalytic amount of GsF affords an aldol product (Scheme 76).290 291... 

Reaction of 4a with TiCl4 was carried out in the presence of siloxyalkene 3 as nucleophile and the results are summarized in Table III. In the reaction with ketene silyl acetals 3a and 3e at -78 °C, y-ketoesters 15a and 15e were obtained instead of chloride product 8 which is a major product in the absence of 3. Formation of product 15 is likely to result from trapping of alkylideneallyl cation 5 with 3 at the sp2 carbon. In contrast, the reactions with silyl enol ethers 3f and 3g gave no acyclic product 15, but gave cyclopentanone derivatives 16-18. The product distribution depends on the mode of addition of TiCl4 (entries 4-7). 

The reactions proceeded efficiently under mild conditions in short time. The silyl enol ethers reacted with the activated acetals or aldehydes at -78 °C to give predominant erythro- or threo-products [136, 137] respectively. In the same manner, the aldol reaction of thioacetals, catalyzed by an equimolar amount of catalyst, resulted in <-ketosulfides [139] with high diastereoselectivity. In the course of this investigation, the interaction of silyl enol ethers with a,]3-unsaturated ketones, promoted by the trityl perchlorate, was shown to proceed regioselec-tively through 1,2- [141] or 1,4-addition [138]. The application of the trityl salt as a Lewis acid catalyst was spread to the synthesis of ]3-aminoesters [142] from the ketene silyl acetals and imines resulting in high stereoselective outcome. 

Recent investigations have demonstrated that electron withdrawing substituents at the a-position increase the rate of this reaction strongly (12.). This reaction would have great potential for natural product syntheses provided that additional electron donating functional substituents could be introduced in the p- and a-positions, that enol ethers, enediol ethers, ketene acetals could react as dienophiles (see route E in Scheme 1). In addition. 

Other Lewis acids can also effect conjugate addition of silyl enol ethers to electrophilic alkenes. For example, Mg(C104)2 catalyzes addition of ketene silyl acetals ... 

Cerium, samarium, and other lanthanide halides promote addition of ketene silyl enol ethers to aldehydes.54 Imines react with ketene silyl acetals in the presence of Yb(03SCF3)3. Preferential addition to the imine occurs even in the presence of aldehyde... 

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