Acetoacetate aldol reaction

Moreover, the protocol could be used for a vinylogous Mukaiyama aldol addition and offered a solution to the problem of the asymmetric acetoacetate aldol reaction. Thus, 2 mol% of the catalyst 198 is enough to promote the addition of silyl dienolate 214 to various aldehydes to give, after desilylation, O-protected P-keto-5-hydroxy esters [113]. The protocol is illustrated for an addition to P-stannylpropenal 213. Depending on the enantiomer of the catalyst 198 or ent-198 chosen to mediate the aldol addition, enantiomeric products 215 and ent-215 were obtained in 92% ee. In an elegant convergent total synthesis, both enantiomers were incorporated into macrolactin A, as shown in Scheme 5.65 [114,115]. 

The mechanism of the Feist-Benary reaction involves an aldol reaction followed by an intramolecular 0-alkylation and dehydration to yield the furan product. In the example below, ethyl acetoacetate (9) is deprotonated by the base (B) to yield anion 10 this carbanion reacts with chloroacetaldehyde (8) to furnish aldol adduct 11. Protonation of the alkoxide anion followed by deprotonation of the [i-dicarbonyl in 12 leads to... 

Pyrimidinopyrazines related to folic acid have been investigated in some detail for their antimeta-bolic and antineoplastic activities. A related compound, which lacks one nitrogen atom, has been described as an antiproliferative agent, indicating it too has an effect on cell replication. Aldol condensation of the benzaldehyde 99 with ethyl acetoacetate gives the cinnamate 100. This is then reduced catalytically to the acetoacetate 101. Reaction of that keto ester with 2,4,6- triami-nopyrimidine gives the product 102 which is subsequently chlorinated (103) and subjected to hydrogenolysls. There is thus formed piritrexim (104) [17]. 

G If one of the carbonyl partners is much more acidic than the other and so is transformed into its enolate ion in preference to the other, then a mixed aldol reaction is likely to be successful. Ethyl acetoacetate, for instance, is completely converted into its enolate ion in preference to enolate ion formation from monocarbonyl partners. Thus, aldol condensations of monoketones with ethyl acetoacetate occur preferentially to give the mixed product. 

The situation can be summarized by saying that a mixed aldol reaction leads to a mixture of products unless one of the partners either has no a hydrogens but is a good electrophilic acceptor (such as benzaldehyde) or is an unusually acidic nucleophilic donor (such as ethyl acetoacetate). 

One significant difference from the simple aldol reaction, however, is that the original adduct (113) now possesses a good leaving group (OEt) thus instead of adding a proton, as in the aldol reaction proper (p. 224), eOEt is lost to yield a /1-ketoester, ethyl 3-ketobutanoate (ethyl acetoacetate, 114). This is finally converted by base (eOEt) into its stabilised (delocalised) carbanion, (115). 

An example of the Knorr pyrrole synthesis is provided by the formation of 3,5-diethoxycarbonyl-2,4-dimethylpyrrole (55). Overall ring construction in this case may be related to (46) above. A retrosynthetic analysis involving disconnection of the N—C2 bond, appropriate prototropic shifts, and finally a retro-aldol reaction to effect disconnection of the C3—C4 bond, reveals ethyl acetoacetate and ethyl a-aminoacetoacetate (ethyl 2-amino-3-oxo-butanoate) (56) as reagents. An FGI transform on this latter compound generates the corresponding nitroso (oximino) compound which may also be derived from ethyl acetoacetate. 

Sato/Kaneko [104] and Carreira [105] have independently employed acetoacetate-derived O-silyl dienolates as Si-substituted nucleophiles in asymmetric catalytic aldol reactions. The aldol products, d-hydroxy-/3-ketoesters, and the derived syn- and anti-yS,d-diol esters are ubiquitous structural subunits in biologically active natural products such as the polyene macrolide antibiotics. These structural subunits are also found in chemotherapeutics, most notably compactin analogs [106] that have been studied as... 

The aldol reaction is a carbonyl condensation that occurs between two aldehyde or ketone molecules. Aldol reactions are reversible, leading first to j3-hydroxy aldehydes/ketones and then to a,jS unsaturated products. Mixed aldol condensations between two different aldehydes or ketones generally give a mixture of all four possible products. A mixed reaction can be successful, however, if one of the two partners is an unusually good donor (ethyl acetoacetate, for instance) or if it can act only as an acceptor (formaldehyde and benzaldehyde, for instance). Intramolecular aldol condensations of 1,4- and 1,5-diketones are also successful and provide a good way to make five- and six-membered rings. 

The catalytic system using 62 is applicable to highly enantioselective preparation of acetoacetate aldol adducts (Scheme 10.55) [152]. The use of 1-3 mol% 62 and 0.4 equiv. 2,6-lutidine promotes the aldol reaction of a variety of aldehydes with silyl dienolate 64 in good to high optical yields. The dienolate addition provides a convergent and enantioselective route to 1,3-polyols by appending a protected acetoacetate in a single step. The 62-catalyzed aldol reactions of methyl acetate TMS enolate and dienolate 64 have been used in the total syntheses of Rofla-mycoin [153] and Macrolactin A [154], respectively. In the latter both enantiomers... 

We referred above to a synthesis of bryostatin that contained a reduction controlled by a 1,3-relationship. Evans synthesis34 contains a 1,3-selective aldol as well as a 1,3-controlled reduction The aldehyde 202, made by an asymmetric aldol reaction, was combined with the double silyl enol ether of methyl acetoacetate to give, as expected, the anti-aldol 203. However, the only Lewis acid that gave this good result was (<-PrO)2TiCl2 and not BF3 thus emphasising the rather empirical aspect of this type of control. Evans s own 1,3-controlled reduction gave the anti,anti-triol 204 that was incorporated into bryostatin. 

Aldol reactions, usually followed by dehydration, of /3-dicarbonyl compounds with the aldehyde forms of substituted nonnitrogenous monosaccharides are also known. 2,3-0-Isopropylidene-D-glyceraldehyde condenses with ethyl acetoacetate in the presence of piperidine, giving the 1,3-dideoxy-3-(ethoxycarbonyl)-5,C-0-isopropyIidenehexulose (54), presumably as a mixture of diastereoisomers, and 1,3,4-trideoxy-3-(ethoxy-carbonyl)-5,6-0-isopropylidene-D-gfi /cero-hex-3-enulose (55). Reaction of... 

Hagiwara, H., K. Kimura, and H. Uda High Diastereoselection in the Aldol Reaction of the Bistrimethylsilyl Enol Ether of Methyl Acetoacetate with 2-Benzyloxy-hexanal Synthesis of (-)-Pestalotin. J. Chem. Soc. (London) Perkin Trans. 1, 693 (1992). 

Claisen reaction is a carbonyl condensation that occurs between two ester components and gives a p-keto ester product. The reaction has a mechanism similar to that of the aldol reaction. The difference from aldol condensation is the expulsion of an alkoxide ion from the tetrahedral intermediate of the initial Claisen adduct. This adduct is not stable and expels the ethoxide ion to give the new carbonyl compound ethyl acetoacetate (p-keto ester). Claisen products can be easily hydrolyzed and decarboxylated (Figure 1.19). There are also many examples of retro-Claisen... 

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