Ketone lithium enolates diastereoselective alkylation

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

A study of the alkylation of the trimethylsilyl enol ether of octahydro-1 (2//)-naphthalenone reveals that the diastereoselectivity of the reaction is similar to that of the methylation of the corresponding lithium enolate (see Section 1.1.1.3.1.1.2 1.)89. Lewis acid cataly2ed phenyl-thioalkylations of the type indicated (i.e., 3 -> 4) have been used for a-alkylations of several cyclic and acyclic ketones, as well as aldehydes89. The easy removal of the phenylthio group by catalytic hydrogenation completes this convenient procedure for a-alkylation of carbonyl compounds89. 

After reaction of the excess lithium with isoprene the enolate is alkylated with allyl bromide diastereoselectively from the less hindered face, opposite to the axial methyl group at the bridge head, to provide allyl ketone 3 as the single diastereomer. 

Enol stannanes of cyclohexanone and propiophenone have been indicated to take part in r/treo-selective aldol reactions with benzaldehyde at low temperatures e.g. —78 °C), but to be erythro-seAsciiwe at higher temperatures ca 45 °C). Two complementary methods have been described for stereoselection in aldol-type reactions. Whilst a-mercurio-ketones show eryr/wo-selection in their reactions with aldehydes in the presence of boron trifluoride diethyl etherate, pre-formed lithium enolates and aldehydes, in the presence of simple trialkyl-boranes, lead to mixtures that are rich in the more stable threo-d do product. Aldol-type products arise from 1,3-alkyl migrations of alk-l-enyl alkyl acetals and ketals, in a reaction that is catalysed by boron trifluoride diethyl etherate (Scheme 52). Diastereoselection is possible, since (.E)-alkenyl acetals give the... 

Scheme 5.10 Regioselective, diastereoselective, and enantioselective palladium

Silyl enol ethers have also been used as a trap for electrophilic radicals derived from a-haloesters [36] or perfluoroalkyl iodides [32]. They afford the a-alkylated ketones after acidic treatment of the intermediate silyl enol ethers (Scheme 19, Eq. 19a). Similarly, silyl ketene acetals are converted into o -pcriluoroalkyl esters upon treatment with per fluoro alkyl iodides [32, 47]. The Et3B/02-mediated diastereoselective trifluoromethylation [48,49] (Eq. 19b) and (ethoxycarbonyl)difluoromethylation [50,51] of lithium eno-lates derived from N-acyloxazolidinones have also been achieved. More recently, Mikami [52] succeeded in the trifluoromethylation of ketone enolates... 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

In the research groups of Seebach [67, 153] and Tidwell [154], alkyl and aryl lithium compounds were found to add readily to ketenes 153 that are accessible by various methods, as, for example, treatment of acid chlorides with triethy-lamine or acid bromides with zinc. As a result, ketone enolates 154 are formed. Due to the high reactivity of the ketenes, the protocol permits to access even sterically hindered trisubstituted enolates, the configuration of which depends on the steric demand of the substituents and R. Thus, alkyllithium reagents add from the sterically less hindered side, so that enolates 154 form with high diastereoselectivity. Of course, the ketone enolates thus generated are pure regioisomers. 

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