Acyclic 3-ketoesters

Isocupreidine ((3-ICD, 19), another compound in the cinchona alkaloid family, can also catalyze the a-amination of 1,3-dicarbonyl compounds enantioselectively [37]. The reaction of a-substituted 1,3-dicarbonyl compounds, including cyclic and acyclic (3-ketoesters and 1,3-diketones with di-tert-butyl azodicarboxylate, proceeded with high yield and enantioselectivity. 

The asymmetric bromination of (3-dicarbonyl compounds was accomplished using a catalytic amount of a chiral primary amine catalyst, with pyridine dicarboxylic acid (PDA) as the co-catalyst and 3,3-dibromo-5,5-dimethylcyclo-hexa-l,3-dione as the bromine source (Scheme 13.25) [55]. The substrate scope was quite broad and included cyclic and acyclic (3-ketoesters, acycfic p-diketones, and the cyclic ketones cyclopentanone and cyclohexanone. Additionally, the conditions for chlorination of (3-dicarbonyl compounds using the benzoylquinidine catalyst depicted in Scheme 13.15 were adapted for the bromination of two substrates [35]. 

Chiral bidentate bis(oxazoline)-metal complexes (metal = Cu, Ni, Mg, Zn, Sc, La) were also studied, with preference for copper (II) trifiate- and nickel (II) per-chlorate-bis(oxazolines). It was found that as little as 1 mol% of catalyst is adequate for the enantioselective electrophilic fluorination of both cyclic and acyclic (3-ketoest-ers (Scheme 44.22). NFSI was preferred to Selectfiuor or A-fluoropyridinium trifiate to produce higher enantiomeric excesses. Importantly, the use of HFIP as additive greatly improved the ee-values in all the reactions by ca. 15%. An important finding in NFSI mediated fluorination is that the (5,5)-Ph-BOX-Ni(II) complex provides the fiuorinated product with opposite configuration to that obtained with the (5,S)-Ph-BOX-Cu(ll) complex (Scheme 44.22). The origin of the reversed sense of stereoinduction could be a consequence of a change in the metal-center geometry from distorted square-planar (Cu complex) to square-pyramidal (Ni complex) in the reactive intermediates. 

The rhenium catalyst also allows the alkyne Insertion into acyclic ketoester 47, delivering 5-keto ester 48 and its isomers, based on the position and geometry of the alkene moiety (Scheme 6.9) [24]. The product mixture can be converted into a sole compound, 2-pyranone 49 by heating or treatment with tetrabutylam-monium fluoride (TBAF) via loss of EtOH. An analogous insertion into C-C=0 bonds of 1,3-dicarbonyls was reported to proceed without transition metal catalysts when an activated alkyne [25] or aryne [26] was used. 

Organo copper and lithium enolates of cyclic ketones, lactones, and lactams or acyclic ketones are converted with acylimidazoles or imidazole-N-carboxylates into the corresponding / -diketones or / -ketoesters ... 

Inspired by the proline-catalyzed Robinson annulation pioneered by Wiechert, Hajos, Parrish and coworkers [39], they were able to construct cyclohexanones of type 2-107 with up to four stereogenic centers with excellent enantio- and di-astereoselectivity from unsaturated ketones 2-104 and acyclic (l-ketoesters 2-105 in the presence of 10 mol% phenylalanine-derived imidazohdine catalyst 2-106. The final products can easily be converted into useful cyclohexanediols, as well as y- and e-lactones. 

In the Diels-Alder reaction with inverse electron demand, the overlap of the LUMO of the 1-oxa-l,3-butadiene with the HOMO of the dienophile is dominant. Since the electron-withdrawing group at the oxabutadiene at the 3-position lowers its LUMO dramatically, the cycloaddition as well as the condensation usually take place at room or slightly elevated temperature. There is actually no restriction for the aldehydes. Thus, aromatic, heteroaromatic, saturated aliphatic and unsaturated aliphatic aldehydes may be used. For example, a-oxocarbocylic esters or 1,2-dike-tones for instance have been employed as ketones. Furthermore, 1,3-dicarbonyl compounds cyclic and acyclic substances such as Meldmm s acid, barbituric acid and derivates, coumarins, any type of cycloalkane-1,3-dione, (1-ketoesters, and 1,3-diones as well as their phosphorus, nitrogen and sulfur analogues, can also be ap-... 

Reaction of 4a with TiCl4 was carried out in the presence of siloxyalkene 3 as nucleophile and the results are summarized in Table III. In the reaction with ketene silyl acetals 3a and 3e at -78 °C, y-ketoesters 15a and 15e were obtained instead of chloride product 8 which is a major product in the absence of 3. Formation of product 15 is likely to result from trapping of alkylideneallyl cation 5 with 3 at the sp2 carbon. In contrast, the reactions with silyl enol ethers 3f and 3g gave no acyclic product 15, but gave cyclopentanone derivatives 16-18. The product distribution depends on the mode of addition of TiCl4 (entries 4-7). 

The first organocatalyzed conjugate addition of a-substituted p-ketoester to a,P-unsaturated ketones was presented by Deng et al. [42] (Scheme 3). Although traditional Cinchona alkaloids were efficient catalysts for conjugate addition of carbon nucleophiles to nitroalkenes and sulfones, replacement of the C(9)-OH with an ester group (Q-7b) showed great improvement in stereoselectivity. The reaction is applicable to a variety of cyclic and acyclic enones (16,18). 

Neither starting material need be cyclic. Combination of the acyclic enone 14 and P-ketoester 15 with an amine catalyst gives high yields of 16 and good (>97 3) stereoselectivity.3 Both 13 and 16 can easily be dehydrated to the enones 1 or 17. 

The enol acetate moiety in diketene can be utilized for cyclopropane formation. Unfortunately, with most diazo compounds, yields are rather moderate 29), and therefore the synthetic value of methods developed on this basis is restricted. As exemplified by the ethyl diazoacetate adduct 44 (Scheme 4) the ring opening of this masked tricarbonyl compound can lead to different classes of acyclic or cyclic products. The outcome of these reactions depends on the conditions employed. They simultaneously transform the P-ketoester unit present in 44 29b). 

Considerable work was done to induce chirality via chiral auxiliaries. Reac tions with aromatic a-ketoesters like phenylglyoxylates 21 and electron-rich al kenes like dioxoles 22 and furan 23 were particularly efficient (Scheme 6). Yield up to 99% and diastereoselectivities higher than 96% have been observed whet 8-phenylmenthol 21a or 2-r-butylcyclohexanol 21b were used as chiral auxiliarie [14-18]. It should be noted that only the exoisomers 24 and 25 were obtained from the reaction of dioxoles 22. Furthermore, the reaction with furan 23 wa regioselective. 24 were suitable intermediates in the synthesis of rare carbohydrate derivatives like branched chain sugars [16], Other heterocyclic compounds liki oxazole 28 [19] and imidazole 29 [20] derivatives as well as acyclic alkenes 3fl 31, and 32 [14,15,21,22] were used as olefinic partners. Numerous cyclohexane derived alcohols [18,21-24] and carbohydrate derivatives [25] were used as chiri... 

Enantioselective fluorination reactions catalyzed by chiral palladium enolate complexes have been the subject of considerable research . For instance, the fluorination of acyclic /S-ketoester (88, equation 24) using Af-fluorobenzenesulfonimide (NFSI) gave product 89 in high yields and with excellent enantioselectivity (ee up to 94%) . This reaction can be carried out in environmentally benign alcoholic solvents and provides valuable synthetic building blocks that find applications in medicinal chemistry, chemical biology and material sciences. 

Trost was able to extend the scope of this reaction by investigating use of acyclic (Z)-enolate starting materials, such as compound 31 in equation 12.35.72 Again, both yield and % ee were quite good. Stoltz expanded his work to determine that (3-ketoesters also give ketones with highly enantioenriched quaternary centers at the a-position (equation 12.36).73... 

Scheme 7.22 Comparative performances of (5-amino alcohols for the palladium-catalyzed tandem debenzylation/EDP of acyclic (5-ketoesters [28].

The reaction did not require dry solvents or inert atmosphere and afforded the desired adducts in 42-98% yield. As expected, the more reactive acrolein and methyl vinyl ketone gave very good results with both acyclic and cyclic p-ketoesters and p-diketones and, surprisingly, acrylonitrile and methyl acrylate, reported to be totally inactive under Lewis acid catalysis, " afforded the corresponding adducts with a-acetylbutyrolactone in high yield (77 and 98% respectively). In the reaction with crotonaldehyde, a 1 1 mixture of... 

Acyclic P-ketoesters are generally less predictable as substrates than their cyclic counterparts, with the selectivity depending on the nature of the groups attached to the dicarbonyl moiety (Fig. 9-29). 

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