Enols problems with silylation

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

You might think that the presence of the acidic proton in a carboxylic acid would present an insuperable barrier to the formation and use of any enol derivatives. In fact, this is not a problem with either the lithium enolates or the silyl enol ethers. Addition of BuLi or LDA to a carboxylic acid... 

The answer is both For the Li enolate, the usual rule makes OU of lower priority than oMe, so it s E, while the silyl enol ether (or silyl ketene acetal ) has OSi of higher priority than OMe, so it s Z. This is merely a nomenclature problem, but it would be irritating to have to reverse all our arguments for lithium enolates simply because lithium is of lower atomic number than carbon. So, for the sake of consistency, it is much better to avoid the use of Eand Z with enolates and instead use cis and trans, which then always refer to the relationship between the substituent and the anionic oxygen (bearing the metal). 

Unfortunately, the usual routes to a-PhS ketones 94, from the parent ketone33 6i, 62) by sulphenylation or halogenation, themselves require a solution of the specific enol problem This can be found if silyl enol ethers are combined with PhSCl63). 

In ether and THF, 0-alkylation is a much less serious problem in reactions with alkyl halides. With the possible exception of iodomethane, the use of lithium enolates in ether solvents leads to C-alkylation as the major product in virtually all cases. When the enolate carbanion center is sterically hindered, however, O-alkylation can be a problem, even in THF or ether. There are some reagents that prefer 0-alkylation, with silyl halides, and anhydrides being the most common. Both of these O-alkylation reactions will be discussed in Section 9.3.C. 

One problem with the Robinson annulation is the reversible nature of the initial Michael addition. One solution is to use a conjugated system that is particularly prone to Michael addition and forms the product, essentially irreversibly. a-Silyl vinyl ketones have been shown to be powerful Michael acceptors.The lithium enolate of cyclohexanone reacted with conjugated ketone 559 to produce the Michael product. 560.304b jn this case, the initially formed Michael adduct was stabilized by the presence of the silyl group at the a-position, driving the reaction toward the product. Hydrolysis produced 561, which was converted to the Robinson product (562) in 80% overall yield by treatment with NaOMe/MeOH under the requisite thermodynamic conditions.304b Pq,. this sequential process is justified when compared with normal treatment... 

Some solutions to the problem of the formation of a specific enolate from an unsymmetrical ketone were discussed above. Another solution makes use of the structurally specific enol acetates or enol silanes (silyl enol ethers). Treatment of a trimethylsilyl enol ether with one equivalent of methyllithium affords the corresponding lithium enolate (along with inert tetramethylsilane). Equilibration of the... 

The treatment of a,p-unsaturated ketones with organocopper reagents provides another method to access specific enolates of unsymmetrical ketones. Lithium dialkylcuprates (see Section 1.2.1) are used most commonly and the resulting enolate species can be trapped with different electrophiles to give a,p-dialkylated ketones (1.27). Some problems with this approach include the potential for the intermediate enolate to isomerize and the formation of mixtures of stereoisomers of the dialkylated product. The intermediate enolate can be trapped as the silyl enol ether and then regenerated under conditions suitable for the subsequent alkylation. Reaction of the enolate with phenylselenyl bromide gives the a-phenylseleno-ketone 12, from which the p-alkyl-a,p-unsaturated ketone can be obtained by oxidation and selenoxide elimination (1.28). 

There is also a problem with i-PrCl it is a secondary hahde and chloride is the worst leaving group among the halogens Cl, Br, I—it is prone to ehmination rather than substitution reactions. To make the required product, an aza-enolate (p. 593 in the textbook) or a silyl enol ether (p. 595 in the textbook) would be a better bet. 

Mukaiyama aldol reactions of various silyl enol ethers or ketene silyl acetals with aldehydes or other electrophiles like chloromethyl methyl ether and trimethylorthoformate proceed smoothly in the presence of 2 mol% of 1 (eq 1) (3, 5). These reactions can be carried out in aqueous media, so that the reaction of silyl enol ethers with an aqueous solution of formaldehyde does not present any problems. Triphenylboron catalyzes no aldol-type reactions. 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

In contrast to these transformations, Michael additions of simple enolates to acceptor-substituted dienes often yield mixtures of 1,4- and 1,6-addition products27-30. For example, a 70 30 mixture of 1,4- and 1,6-adducts was isolated from the reaction of the lithium enolate of methyl propionate with methyl sorbate30. This problem can be solved by using the corresponding silyl ketene acetal in the presence of clay montmorillonite as acidic promoter under these conditions, almost exclusive formation of the 1,4-addition product (syn/anti mixture) was observed (equation ll)30. Highly regioselective 1,4-additions... 

Lithium Enolates. The control of mixed aldol additions between aldehydes and ketones that present several possible sites for enolization is a challenging problem. Such reactions are normally carried out by complete conversion of the carbonyl compound that is to serve as the nucleophile to an enolate, silyl enol ether, or imine anion. The reactive nucleophile is then allowed to react with the second reaction component. As long as the addition step is faster than proton transfer, or other mechanisms of interconversion of the nucleophilic and electrophilic components, the adduct will have the desired... 

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