F-ketoester

A constant interest in the development of new rapid methodologies for the preparation of oxazole hbraries is motivated by their presence in numerous biologically active natural products. Janda and coworkers were hrst to show that oxazoles can be obtained by microwave-assisted treatment of polymer-bound a-acylamino-/f-ketoesters with Burgess reagent [68]. Hydroxybutyl-functionalized /anda/el resin was used for this investigation, with key steps being monitored by on-bead FT-IR. First, a resin-bound acetoacetate was pre-... 

Diketones and /f-Ketoesters from Reactions of Imidazolides with Lithium Enolates... 

The group of Janda has presented a microwave-mediated oxazole synthesis utilizing /3-ketoestcrs bound to a novel polymeric resin [57]. The desired polymer support was prepared by transesterification reactions of tert-butyl /f-ketoesters and hydroxy-butyl-functionalized JandaJel resin and subsequent standard diazo transfer. The resulting a-diazo /f-ketoesters were employed for the synthesis of an array of oxa-zoles (Scheme 7.41). 

In addition to j6-diketones, /f-ketoacids and /f-ketoesters, cyanoacetic ester and related compounds are suitable starting materials. The arylhydrazones 4 thus obtained are of great importance as starting materials for the Fischer indole synthesis, as well as for the preparation of other fV-heterocycles. ... 

The most common group G is an ester function (aldiougli many odier groups have been employed as well). The starting /f-ketoester, which can be prepared easily by a Claisen-type reaction of an ester enolate and an acid chloride, has a... 

Interesting alternative biselectrophiles are /f-ketoesters which react in the presence of molecular sieves with aminocrotonate esters to give pyridones67 (equation 49). 

Dynamic kinetic resolution is well known in pure chemical synthesis, as illustrated by work by Noyori et al. on the asymmetric hydrogenation of a-substituted /f-ketoesters. Noyori et al. [5], Ward [6] and Caddick et al. [7] have reviewed the chemical syntheses, and biocatalytic routes have been discussed by Faber et al. [8]. 

Also, dianions derived from y-substituted /f-ketoesters engage in condensations with oxiranes, to afford 2-carbomethoxyethylidene-tetrahydrofurans in a stereospecific manner <92SL529>. In certain cases these types of reactions can be effected on an alumina surface without solvent. In a base-catalyzed tandem nitroaldol cyclization process <90JOC78l>, 2-isoxazoline-2-oxides are formed in... 

Several strategies for the synthesis of polymer-bound enones have been described. One way is to start from immobilized [f-ketoesters, which can be prepared via transesterfica-tion of Wang resin with alkyl fl-keto carboxylates [31], or by treatment with diketene [16]. Knoevenagel reactions of these polymer-bound [f-ketoesters with aldehydes led to the formation of 2-alkylidene- or arylidene-P-ketoesters (Fig. 6.19 (A)). 

Tab. 10.11. Reaction of/f-ketoesters with Michael acceptors (E = C02Et) [41],...

Benzopyranone synthesis from phenols and f) ketoesters or unsaturated acids... 

In the same way, reaction of glyoxal mono-l,l-dimethylhydrazone (70) with f-ketoesters 67 in the absence of solvent [64] gave 1-aminopyrroles 73 and other nitrogen heterocycles 71 and 72. The selectivity was found to depend on a variety of conditions, for example temperature, time, and mode of heating (Scheme 5.20). 

Scheme 5.2 Typical reagents and chiral modifiers for the enantioselective hydrogenation of a-ketoesters and f-ketoesters. (With kind permission from Springer Science and Business Media [54].)...

Juvabione is a terpene-derived ketoester that has been isolated from various plant sources. There are two stereoisomers, both of which occur naturally with R-configuration at C(4) of the cyclohexene ring and are referred to as erythro- and f/trao-juvabione. The 7(.S )-cnan(iomcr is sometimes called epijuvabione. Juvabione exhibits juvenile hormone activity in insects that is, it can modify the process of metamorphosis.18... 

Carpentier and coworkers studied the asymmetric transfer hydrogenation of /f-keloeslers using chiral ruthenium complexes prepared from [(// -p-cyrriene)-RuC12]2 and chiral aminoalcohols based on norephedrine. During this study, these authors became aware of substrate inhibition when ketoesters carrying 4-halo-substituents were used. It transpired that this was caused by formation of a complex between the substrate and the catalyst [28]. 

A closely related reaction of ketones and ketoesters with chiral f-butyl (+)-(i )-p-toluenesulfinylacetate 50 was utilized for the synthesis of chiral (3-hydroxy acids as shown in Scheme 32 (317). The optical purities of the final reaction products varied from 8.5 to 91%. 

CJ Sih, BN Zhou, AS Gopalan, WR Shieh, CS Chen, G Girdaukas, F vanMiddles-worth. Enantioselective reduction of P-ketoesters by Baker s yeast. Ann NY Acad Sci 434 186-193, 1984. 

The direct enantioselective organocatalytic a-fluorination can also be performed with cinchona alkaloid derivatives as catalyst under phase-transfer reaction conditions [25]. The fluorination reaction by NFSI of / -ketoesters 21, readily enolizable substrates, generated a stereogenic quaternary C-F bond in high yields and with enantioselectivities up to 69% ee for the optically active products 26 (Eq. 6). 

The butylated /J-ketoester C of Figure 13.26 is not the final synthetic target of the acetoacetic ester synthesis of methyl ketones. In that context, the /J-ketoester C is converted into the corresponding /J-ketocarhoxylic acid via acid-catalyzed hydrolysis (Figure 13.27 for the mechanism, see Figure 6.22). This /i-ketocarboxylic acid is then heated either in the same pot or after isolation to effect decarboxylation. The /f-ketocarboxylic acid decarboxylates via a cyclic six-membered transition state in which three valence electron pairs are shifted at the same time. The reaction product is an enol, which isomerizes immediately to a ketone (to phenyl methyl ketone in the specific example shown). 

Functionalized P-hydroxy esters 64 e,f,g,h were obtained quantitatively with excellent enantiomeric excesses (> 98 %) by hydrogenation of p-ketoesters in the presence of chiral ruthenium catalysts. This convenient methodology gives both optical antipodes with equal ease using (/ ) or (5) atropoisomer ligand for the metal complex. 

The asymmetric variant of a-oxybenzoylation makes use of lithioenamines. Lithioena-mines formed with / -ketoesters and ( S)-valine f-butyl ester were in fact easily oxidized with benzoyl peroxide53 with high enantioselectivity (78-92% e.e.) to give, after hydrolysis, the corresponding protected tertiary a-ketols having (i ) configuration (Scheme 36). 

Exploitation of the synthetic route in solution to 3.25 The diversification of the 2,2-dimethylbicyclo[3.3.1]nonan-9-one scaffold using the same synthetic route, as intended by general structure 3.28 (Fig. 3.17), was done by preparing 16 tricyclic analogues. Their general structures (3.44-3.59) and their synthesis from the appropriate P-ketoesters (3.40a-d, 3.41a-d, 3.42a,b, 3.43a-f) are reported in Fig. 3.22 yields... 

Exploitation of the SP route The SP endocyclization of P-ketoesters 3.43a-f was abandoned due to results in solution. Six condensation products 3.60-3.65 were obtained from the reaction of P-ketoesters 3.30, 3.40a, 3.41a, 3.41c, 3.42a and 3.42b with bromide 3.37 with similar yields and purities than their solution counterparts (Fig. 3.23) the same experimental protocol seen for 3.38 (Fig. 3.21) was applied. 

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