Keto esters aldol-type reactions

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). 

Aldol-type reactions. Chiral dioxinone derivatives and a-amino y-keto esters are readily obtained. 

Aldol-type reactions. The highest anti selectivity is observed with BINAP complex of Pd(OTf)j in the aldol reaction of tin enolate of cyclohexanone. The condensation of silyl enol ethers with imines provides y-keto a-amino esters. ... 

Although ketones are not generally considered to be reactive carbonyl partners in MBH reactions (except under high pressure), the enhanced reactivity of certain a-diketones towards aldol-type reactions make them suitable partners for reaction with MBH-type vinyl carbanion equivalents. Indeed, a-keto esters have been found to possess the requisite reactivity and are very reactive electrophiles for the MBH reaction of acrylate, methyl vinyl ketone, acrylonitrile and acrolein in the presence of a tertiary amine, such as DABCO (Scheme 1.66). " ... 

Aldol-type reaction of a-keto esters with 5-methyleneoxazolines in... 

Silver(I) complexes with Tol-BINAP (270) were used by Yamamoto and coworkers for mediating diastereoselective and enantioselective Mukaiyama aldol additions. According to the authors conclusion, the mechanism does not involve transmetallation to silver enolates but follows the usual carbonyl group activation [135]. Hoveyda and coworkers used silver(II) fluoride in the presence of a dipeptide-type ligand for enantioselective additions of silyl enol ethers to a-keto esters [136]. The reaction of 2-trimethylsilyloxyfuran with aromatic and aliphatic aldehydes was catalyzed with chromium salen complex in the presence of protic additives like isopropanol [137]. Various protocols of enantioselective Mukaiyama aldol reactions that use water as cosolvent have been elaborated ... 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

This reaction is quite special in that it is an aldol-type addition in which a thioester is the donor (nucleophile) and a keto acid is the acceptor (electrophile). From the discussion in Section 18-8E, you will see that reactions of this kind involving an ester as the donor and an aldehyde or ketone as the acceptor can be achieved in the laboratory only under rather special conditions. For the thioester to function as a nucleophile at the a carbon under the restraints imposed by having the reaction occur at the physiological pH, the catalyzing enzyme almost certainly must promote formation of the enol form of the thioester. The enol then could add to the ketone carbonyl with the assistance of a basic group on the enzyme. This kind of catalysis by enzymes is discussed in Section 25-9C. 

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]. 

In the reaction of y -keto esters with a-halo ketones, the possible competition between C-alkylation (followed by reaction of the Paal-Knorr type) and aldol addition (followed by reaction of the Feist-Benary type) can result in mixtures of isomeric fiirans. Regioselectivity can, however, sometimes be controlled by the reaction conditions, as for instance in the interaction of chloroacetone with an aceto-acetic acid ester, leading to the furan-3-carboxylates 18/19 ... 

TMG (1) is used favourably for tandem reactions of Michael and aldol additions [93,94] (Scheme 4.37). Bicyclic furanopyran [93a] and a nucleotide derivative [93b] were synthesized from the corresponding a,p-unsaturated systems in one-pot reaction. A [3.3.1]bicyclic ring system, leading to huperzine A [94a], a candidate drug for Alzheimer decease, and its spirocyclopropyl derivative [94b], is efficiently constructed by Robinson-type annulation from (3-keto ester and methacrolein in the presence of TMG (1) [94] (Scheme 4.37c). 

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