Keto esters aldol reactions

The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a /3-keto ester, an enamine, or a /3-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

Aldol-type reactions of nitrones (303) occur with electron-deficient ketones, such as a-keto esters, a, 3-diketones, and trifluoromethyl ketones. These reactions are catalyzed by secondary amines. The use of chiral cyclic amines A1-A7 leads to a-(2-hydroxyalkyl)nitrones (304) in moderate yields and rather high optical purity (Scheme 2.120) (381). The mechanism of the nitrone-aldol reaction of iV-methyl-C-ethyl nitrone with dimethyl ketomalonate in the absence and presence of L- proline has been studied by using density functional theory (DFT) (544). 

Catalyst 86a also catalyzed the enantioselective aldol reaction between a-keto esters and silylketene acetals or enolsilanes with high ee (ranging from 93% to 99%).58... 

Unlike the corresponding reaction of p-keto esters with a,p-unsaturated aldehydes, which produce Michael adducts, a-cyanoacetic esters undergo the aldol reaction forming a-cyanodienoic esters [17]. 

P-keto esters with a,p-unsaturated aldehydes liquidrliquid two-phase conditions [20] but, in contrast, under analogous conditions a-cyanoacetic esters produce aldol adducts with a,p-unsaturated aldehydes [20], Ethyl acetoacetate undergoes a catalysed Michael reaction addition with trans but-2-en-l,4-diones the products are generally insufficiently stable for isolation, but can be converted into furans [21 ]. 

Optically active 4-alkoxycarbonyl-3-hydroxycyclohexanones (formed in highly enantio- and diastereoselective organocatalytic asymmetric domino Michael aldol reaction of / -keto esters and a,/ -unsaturated ketones) are transformed into corresponding chiral oxepanones under the action of urea-hydrogen peroxide and trifluoroacetic anhydride <2004AGE1272>. 

The third molecule of acetyl CoA also functions as a nucleophilic enol and attacks the keto group of acetoacetyl CoA. This is not a Claisen ester condensation—it is an aldol reaction between the enol of a thiol ester and an electrophilic ketone. 

When you need to synthesize a p-hydroxy ketone or aldehyde or an a,p-unsaturated ketone or aldehyde, use an aldol reaction. When you need to synthesize a p-diketone or p-keto ester, use a Claisen reaction. When you need to synthesize a 1,5-dicarbonyl compound, use a Michael reaction. The Robinson annulation is used to synthesize polycyclic molecules by a combination of a Michael reaction with an aldol condensation. 

Cyclizations of hydroxy esters under basic conditions have been achieved." Aldol reactions of a-keto esters with aldehydes give unsaturated lactones." The photocatalytic addition of alcohols 17 to a,/f-unsaturated acids (e.g., 18) or esters is an example of a radical... 

The gold(I) complex is prepared in situ by the reaction of (1) with bis(cyclohexyl isocyanide)gold(I) tetrafluoroborate (2), typically in anhydrous dichloromethane. The dihydrooxazolines obtained provide a ready access to enantiomerically pure p-hydroxy-a-amino acid derivatives. High diastereo- and enantios-electivity are generally maintained with a wide variety of substituted aldehydes, and a-isocyanoacetate esters. N,N-Dimethyl-a-isocyanoacetamides and a-keto esters have been substituted for the a-isocyanoacetate ester and aldehyde component, respectively, sometimes with improved stereoselectivity. The effect of both the central and planar chirality of (1) on the diastereo- and enantioselectivity of the gold(I)-catalyzed aldol reaction has been studied. The modification of the terminal di-alkylamino group of (1) can lead to improvements in the stereos-... 

Unlike the aldol reaction, which is base-catalyzed, a full equivalent of base is needed to deprotonate the P-keto ester formed in Step [3] of the Claisen reaction. 

This reagent is the best promoter of the aldol reaction of 2-(trimethylsiloxy)acry-late esters, prepared by the silylation of pyruvate esters, to afford y-alkoxy-a-keto esters (Eq. 80) [135] These esters occur in a variety of important natural products. 

Although the asymmetric aldol reaction of benzaldehyde and di ketene has been reported with a catalyst generated from di-iso-propyl tartrate and iso-propanol, low induction and low yields were observed for the d-hydroxyl-y5-keto ester 27 [8], Low induction was also observed for aldol reactions mediated by chiral aluminum catalysts generated from a-amino acids [9]. These types of catalyst have been very successful when employing boron as the Lewis acid, as illustrated in the aldol reaction of ketene acetal 10 with the boron catalyst 31 derived from (5)-valine (Sch. 4) [9,10]. Catalysts derived from A-tosyl-(5 )-valine and Et2AlCl and i-BuyAl were relatively ineffective (< 15 % ee) [9]. 

Nucleophilic addition to less reactive ketone carbonyls by Lewis acid activation is also possible. Evans and co-workers have reported enol silane addition to pyruvate esters mediated by chiral copper Lewis acids (Sch. 36) [72]. The aldol reactions proceed with high facial selectivity to provide the tertiary alcohol products 153. The chemical efficiency is, however, reduced when a bulky alkyl group is present at the ketone carbonyl. Addition of more functionalized enol silanes (155) to keto esters enables the establishment of two contiguous chiral centers, a substitution pattern present in a variety of natural products. The stereochemistry of the major product is syn, irrespective of the enol silane geometry. Once again, bidentate coordination of the substrate to the Lewis acid was essential for obtaining high selectivity. 

This enantioselective aldol reaction employing isocyanoacetate 27 is quite effective for aromatic aldehydes or tertiary alkyl aldehydes, but not for sterically less hindered aliphatic aldehydes as described above. Ito and coworkers found that very high enantioselectivity is obtained even for acetaldehyde (R = Me) in the aldol reaction with Af,A -dimethyl-a-isocyanoacetamide (95) (Sch. 25) [47]. Use of a-keto esters in place of aldehydes also results in moderate to high enantioselectivity of up to 90 % ee [48]. 

The gold-catalyzed aldol reaction of a-keto esters gives the corresponding oxazolines with up to 90% ee, which are converted into optically actice ) -alkyl-) -hydroxyaspartic acid derivatives (Scheme 2-55) [77]. 

Akiyama, Y, Ishikawa, K, OzaM, S, Asymmetric synthesis of functionalized tertiary alcohols by diastereoselective aldol reaction of silyl enol ether and ketene silyl acetals with a-keto esters bearing an optically active cyclitol as a chiral auxihary, Synlett, 275-276, 1994. 

This adduct is in equilibrium with the stable enolate from the keto-ester and elimination now gives an unsaturated carbonyl compound. Such chemistry is associated with the aldol reactions we discussed in Chapter 27. The new enone has two carbonyl groups at one end of the double bond and is therefore a very good Michael acceptor (Chapter 29). A second molecule of enolate does a conjugate addition to complete the carbon skeleton of the molecule. Now the ammonia attacks either of... 

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