Enolizable enones

In this sequence the new ring is built onto the side of an old ring but this is not necessary. Any combination of an easily enolizable compound and an enone may give a Robinson annelation product. A simple example combines a non-enolizable enone with ethyl aceto-acetate to give an excellent yield of a cyclohexenone. As these compounds are so robust a stronger base can be used. 

Scheme 5.6 Enantioselective dimerization of enolizable enones catalyzed by 103b.

In a completely different context, an A-protected version of the amino acid cysteine has been found to be an excellent promoter for the intramolecular Rauhut-Currier reaction (Scheme 6.20)," in which an enolizable enone played the role of the Michael acceptor, adding to another a,p-unsaturated ketone moiety in already present at the substrate structure. The mechanism of the reaction involved the activation of the enone which has to play the role of the donor by the catalyst via sulfa-Michael addition through the mercapto functionality of the A-protected cysteine derivative. The formed enolate... 

However, it is in this context where the use of primary amines as catalysts demonstrates the high performance of this concept. As has already been mentioned in Chapter 2, primary amines are much more efficient catalysts for the activation of ketones than the corresponding secondary amines due to the formation of a less sterically congested enamine or iminium ion and also because of the more efficient geometry control in their formation. For example, primary amine 28a was found to be able to activate a-enolizable enones toward... 

A series of chalcone derivatives and enolizable enones were reacted, affording the Michael adducts with excellent results. Finally, to obtain the fluoromethyl-ated compound, the authors proposed a short sequence of three steps, consisting of reduction of the carbonyl moiety, reductive desuUbnylation using Mg/ MeOH, and oxidation with PCC. Desulfonylated products were obtained without racemization. 

The group of Melchiorre expanded the nature of donors to y-enolizable enones [27], usually considered in organocatalysis as electrophiles, using dienamine activation. Indeed (i-substituted cyclohexenones were activated by chiral primary amine 19 derived from cinchona alkaloid to become a dienamine nucleophilic species that could react with nitroolefins. Among the three dienamines that could be formed after iminium generation (Scheme 34.2), the conditions described by Melchiorre et al. selectively favored thermodynamically the exo dienamine 20. 

Scheme 34.2 Possible functionalizations of y-enolizable enone by dienamine activation.

Note. This sequence succeeds with both aldehydes and ketones, but fails with readily enolizable ketones and enones. 

Three-component aldol synthesis.1 This rhodium carbonyl can promote aldol coupling of enol silyl ethers with aldehydes or ketones. It can also effect coupling of an enone, an aldehyde, and a trialkylsilane to provide a silyl aldol. In the case of an enolizable aldehyde, yields are improved by addition of a phosphine ligand such as... 

The use of silyl enol ethers can be illustrated in a synthesis of manicone, a conjugated enone that ants use to leave a trail to a food source. It can be made by an aldol reaction between the pentan-3-one (as the enol component) and 2-methylbutanal (as the electrophile). Both partners are enolizable so we shall need to form a specific enol equivalent from the ketone. The silyl enol ether works well. 

A simple example from the first report of this reaction by Gilbert Stork and his group in 1974 is the condensation of pentan-2-one with butanal to give the aldol and then the enone oct-4-en-3-one by acid-catalysed dehydration. The yields may seem disappointing, but this was the first time anyone had carried out a crossed aldol reaction like this with an unsymmetrical ketone and an enolizable aldehyde and got just one aldol product in any reasonable yield at all. 

The essential requirement for a Robinson annelation is a Michael addition of an enolate to an enone that has a second enolizable group on the other side of the ketone. The classic enone is butenone (methyl vinyl ketone) and the classic Robinson annelation is the synthesis of rings A and B of the steroid nucleus. 

In a recent pubhcation the nitrile (EWG = CN) variant [ 126] of this chemistry was performed in water by applying N,N-diethylaminopropylated sihca gel as heterogeneous catalyst [ 128]. Another variant of this reaction sequence, leading to chiral sulfinylated enones, has been developed by Llera [ 129] employing the enantiomerically pure geminal bis(sulfoxide) 208 (Scheme 54). This bis(sulfoxide) was prepared from (-)-p-toluenesulfinic acid menthyl ester [100], as described by Kunieda [130]. Later this procedure was improved to increase the yield from 35 to 91% [13,131]. Treatment of 208 with enolizable aldehydes or ketones, in the presence of piperidine as a base and thiophile, initiated a reaction cascade involving a condensation step (to 210), a proton shift to allylic sulfoxide 211, and a [2,3]-0-shift followed by a piperidine-mediated desulfuration delivering the alcohols 212 as isomeric mixtures. Oxidation of the latter compounds (one of the R = H) led to enantiomerically pure E-y-oxo vinyl sulfoxides 213. 

Suzuki et al. found that a-trimethylsilylvinylcerium reagents add to readily enolizable p, y-enones. The method has been employed in the syndiesis of (-)-eldanolide, as shown in Scheme 16. ... 

A mild base such as diisopropylethylamine or DBU can be used for the Homer-Wads worth-Emmons reaction in the presence of a complexing agent such as lithium chloride. These conditions are useful for sensitive substrates, such as chiral compounds with an enolizable stereocentre. For example, the enone 66 is formed in high optical purity under these conditions (2.81), whereas use of the base potassium tert-butoxide gives the product as a racemic mixture. 

It has to be pointed out that simple enolizable aldehydes and ketones, which are not acidic enough compounds to be directly used as pro-nucleophiles in this context, can nevertheless be employed as Michael donors in the reaction with enals or enones, which have been previously activated as the corresponding iminium ion, but their use requires prior activation via enamine activation. In these cases, it is usually proposed that the amine catalyst is involved in a dual activation profile interacting with both the Michael donor and the acceptor, although the enamine activation of the pro-nucleophile is mandatory for the reaction to occur, the activation of the acceptor being of less relevance in most cases. For these reasons, this chemistry has been covered in Chapter 2. 

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