Silyl ketene acetals conjugate addition reactions

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. 

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. 

A recent synthesis of P-D lactone (Scheme 13.51) used an enantioselective catalytic approach. A conjugate addition of a silyl ketene acetal derived from an unsaturated ester gave an unsaturated lactone intermediate. The catalyst is CuF-(S )-tol-BINAP.30 The catalytic cycle for the reaction is shown below. 

Intermolecular addition of carbon nucleophiles to the ri2-pyrrolium complexes has shown limited success because of the decreased reactivity of the iminium moiety coupled with the acidity (pKa 18-20) of the ammine ligands on the osmium, the latter of which prohibits the use of robust nucleophiles. Addition of cyanide ion to the l-methyl-2//-pyr-rolium complex 32 occurs to give the 2-cyano-substituted 3-pyrroline complex 75 as one diastereomer (Figure 15). In contrast, the 1-methyl-3//-pyrrolium species 28, which possesses an acidic C-3-proton in an anti orientation, results in a significant (-30%) amount of deprotonation in addition to the 2-pyrroline complex 78 under the same reaction conditions. Uncharacteristically, 78 is isolated as a 3 2 ratio of isomers, presumably via epimerization at C-2.17 Other potential nucleophiles such as the conjugate base of malononitrile, potassium acetoacetate, and the silyl ketene acetal 2-methoxy-l-methyl-2-(trimethylsiloxy)-l-propene either do not react or result in deprotonation under ambient conditions. 

It is even possible to use a silyl enol ether to create a new C-C bond that joins two new quaternary centres. In this example the silyl ketene acetal does conjugate addition on an unsaturated ketone catalysed by the usual Lewis acid (TiCl4) for such reactions. 

The silyl enol ether that is the initial product from conjugate addition of a silyl enol ether or silyl ketene acetal need not be hydrolysed but can also be used in aldol reactions. This example uses trityl perchlo-... 

First, chemoselective (Chapter 24) conjugate addition of the silyl ketene acetal on the enone is preferred to direct aldol reaction with the aldehyde. Then an aldol reaction of the intermediate silyl enol ether on the benzaldehyde follows. The stereoselectivity results, firstly, from attack of benzalde-hyde on the less hindered face of the intermediate silyl enol ether, which sets the two side chains trans on the cyclohexanone, and, secondly, from the intrinsic diastereoselectivity of the aldol reaction (this is treated in some detail in Chapter 34). This is a summary mechanism. 

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. 

Conjugate additions. Efficient reaction between silyl ketene acetals and conjugated carbonyl compounds in nonpolar aprotic solvents (such as toluene, while containing TMEDA) is possible when catalyzed by LiAl[OC(CF3)2Ph]. The catalyst is derived from LiAlH and HOC(CF3)2Ph. 

Conjugate additions. Cuprate addition to ynoate esters and trapping with aldehydes (in the presence of EtjAlCl) provide special analogs of Baylis-Hillman reaction products. Trapping with phosphonoacetatic esters is another synthetically valuable variation. Silyl ketene acetals derived from 1,6-addition to allyl alk-4-yn-2-enoates undergo Claisen... 

Conjugate additions. Cyclopentaneacetic esters are readily prepared by cyclization of -iodo-a,P-unsaturated esters. The Michael reaction of silyl ketene acetals with enones (and Mukaiyama aldol reaction) can be promoted by Sml,. " However, thermodynamic enolsilylation of carbonyl compounds under similar conditions is noted. 

A similar conjugate addition- silyl group transfer process was reported later by Danishefsky and co-workers for the synthesis of PGF2a (Scheme 52) (103). In this case, the silyl ketene acetal adds, under Hgl2 promotion, cis to the OTBS group in the optically pure enone 52.1 to provide silyl enol ether 52.2 as the exclusive product. The indicated aldol products are obtained from 52.2 in subsequent reactions with ( )- and (Z)-octenal using TiCl4 catalysis. 

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,... 

Denmark SE, Heemstra JR (2006) Lewis base activatimi of Lewis acids. Vinylogous aldol addition reactions of conjugated N,0-silyl ketene acetals to aldehydes. J Am Chem Soc 128 1038-1039... 

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