Conjugate addition of silyl enol ethers

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. 

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 ... 

Conjugate addition of silyl enol ethers to a,/3-unsaturated ketones proceeds regio-selectively in the presence of 2 mol % B(C6Fs)3 (not anhydrous grade) [151a,c]. The product can be isolated as a synthetically valuable silyl enol ether when the crude product is worked-up without exposure to acid (Eq. 93). 

The Lewis acid-catalyzed conjugate addition of silyl enol ethers to a,y3-unsaturated carbonyl derivatives, the Mukaiyaraa Michael reaction, is known to be a mild, versatile method for carbon-cabon bond formation. Although the development of catalytic asymmetric variants of this process provides access to optically active 1,5-dicarbonyl synthons, few such applications have yet been reported [108], Mukiyama demonstrated asymmetric catalysis with BINOL-Ti oxide prepared from (/-Pr0)2Ti=0 and BINOL and obtained a 1,4-adduct in high % ee (Sch. 43) [109]. The enantioselectiv-ity was highly dependent on the ester substituent of the silyl enol ether employed. Thus the reaction of cyclopentenone with the sterically hindered silyl enol ether derived from 5-diphenylmethyl ethanethioate proceeds highly enantioselectively. Sco-lastico also reported that reactions promoted by TADDOL-derived titanium complexes gave the syn product exclusively, although with only moderate enantioselectiv-ity (Sch. 44) [110]. 

Conjugate addition of silyl enol ethers leads to the silyl enol ether of the product... 

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,... 

Scheme 5.105 Conjugate addition of silyl enol ethers 405 to crotonylphosphonates 406, mediated by aluminum complex 407.

In some instances, particularly when a dependence of the stereochemistry on the double-bond geometry of either the acceptor or donor is observed, it appears likely that the stereochemistry-determining step is the initial conjugate addition. The stereochemical consequences of Lewis-acid-mediated additions of silyl enol ethers (116) and allylsilanes (117,118) have frequently been rationalized by open-extended transition states. Similar pathways seem likely with the Mukaiyama-Michael addition (vide infra) (77,79). 

Conditions for effecting conjugate addition of neutral enolate equivalents such as silyl enol ethers in the presence of Lewis acids have been developed and are called Mukaiyama-Michael reactions. Trimethylsilyl enol ethers can be caused to react with electrophilic alkenes by use of TiCl4. These reactions proceed rapidly even at -78° C.308... 

Annelation-ring cleavage.1 A bifunctional reagent with an acetal and an allylsi-lane group can be used for annulation of silyl enol ethers to six- and seven-membered carbocycles (equation I).2 The reaction involves conjugate addition to give an adduct that undergoes intramolecular cyclization. 

If the 1,5-diearbonyl compound is required, then an aqueous work-up with either acid or base cleaves the silicon-oxygen bond in the product but the value of silyl enol ethers is that they can undergo synthetically useful reactions other than just hydrolysis. Addition of the silyl enol ether derived from aeetophenone (PhCOMe) to a disubstituted enone promoted by titanium tetrachloride is very rapid and gives the diketone product in good yield even though a quaternary carbon atom is created in the conjugate addition, This is a typical example of this very powerful class of conjugate addition reactions. 

The Michael addition (1,4-conjugate addition) of an enolate to an ot, -unsaturated carbonyl system is another prevalent reaction for carbon-carbon bond formation (75, 76). However, its use in organic syntheses is occasionally restricted owing to a concurrent 1,2-addition reaction and polymerization of a, -unsaturated carbonyl compounds. A new methodology to overcome these problems has been devised by the use of lithium enolates (77-79). Another approach is to use silyl enol ethers and silyl ketene acetals as enolates. 

Finally, the Lewis acid activation of a,)6-unsaturated carbonyl compounds and Q -nitroalkenes is sufficient to induce productive Sr reactions with allenylstannanes (Scheme 5.2.70). Haruta and Kita have successfully achieved condensation reactions with 326 and 328 in the presence of TiCU, and cyclo-hexenones 330 and 332 also serve as synthetically effective substrates for the 1,4-conjugate addition. In the case of enone 332, activation with TBSOTf led to the isolation of silyl enol ether 333. ... 

First attempts to achieve silyl enol ethers ) are known since the late 195O s when hydrosilylation-type procedures were applied to a,d-unsaturated ketones is—i is) based upon the observation by Duffaut and Galas ) that simple ketones are able to add trichlorosilane (2) under UV irradiation. These hydrosilylation reactions were widely expanded and intensively studied ). a,/3-unsaturated ketones react via 1,4-addition ) to silyl enol ethers ) affecting only the conjugated double bonds. It is worth mentioning that the employment of chiral catalysts induces an asymmetrical reaction " ) (Scheme 24). 

As will be shown, the stereochemistry of Mukaiyama-Michael additions is in many instances insensitive to the stereochemistry of the silyl enol ether used. This method is potentially advantageous relative to the direct conjugate addition of ketone enolates when it is impossible to obtain the enolate or silyl enol ethers in a stereoisomerically pure form. 

The preparation of silyl enol ethers from carbonyl compounds represents one of the major uses of TMSOTf. Recently, the stereochemistry and regiospeciflcity of such transformation has been addressed for aldehydes and Q -(lV-alkoxycarbonylamino) ketones, respectively. On the other hand, enantiopure silyl enol ethers can be formed by addition of TMSOTf to zinc enolates, which are obtained from the copper-catalyzed enantioselective conjugate addition of dialkyIzinc reagents to cyclic (eq 36) and acyclic enones. ... 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

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