P-Ketoester moieties

Stoltz et al. reported enantioselective synthesis of (—)-cyanthiwigin F via double decarboxylative asymmetric allylation of bis(allyl P-ketocarboxylates) (Scheme 8.10) [34]. Initially, two molecules of diallyl succinate (57) was condensed under basic conditions to give a cyclic bis(P-ketoester), which was then methylated to afford an isomeric mixture of 58. Subsequent treatment with a chiral palladium catalyst induced double decarboxylation of those allyl P-ketoester moieties to afford a chiral cyclohexan-l,4-dione 59 (99% ee) along with its meso isomer. The enantiomeric excess of the product was enhanced through the double asymmetric allylation reaction. The cyclo-hexanedione 59 was converted into (-)-cyanthiwigin F through further six steps. 

The stereoselective formation of 9 can be explained by assuming that transition states A and B, as shown in Fig. 7, are involved in this cyclization. If the nucleophilic displacement of the n-allylpaUadium intermediate with the anion of the p-ketoester moiety proceeds through a product-like transition state, transition state A, which should lead to the more stable product 9 with a pseudoequatorial C-6 unit and a pseudoaxial methyl group, probably favors over transition state B, producing a less stable product with the opposite stereochemistry at the quaternary center. 

Padwa and co-workers (60,106,107) have been highly active in using carbonyl ylides for the synthesis of a number of bioactive alkaloids (Scheme 4.51). In an approach to the aspidosperma alkaloids, a push-pull carbonyl ylide was used to generate a bicyclic ylide containing a tethered indole moiety. This strategy ultimately allowed for the synthesis of the dehydrovindorosin skeleton (108). Starting from a quaternary substimted piperidone (200), elaboration of the 3-carboxylic acid provided p-ketoester amide 201. Addition of the indole tethered side chain provided a very rapid and efficient method to generate the cycloaddition precursor 203. 

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). 

After formation of the enolate by deprotonation with LiHMDS, the ester moiety is introduced by reaction with methyl cyanoformate to give P-ketoester 20 in 70 % yield over three steps. Structure 20 represents a 1,3-dicarbonyl compound that preferentially exists in the enol form. 

The transformation of P-ketoester 20 into a,P-unsaturated ester 21 requires the reduction of the ketone chemoselectively in the presence of the ester. Sodium borohydride (NaBH4) is the standard reagent for this type of transformation. Subsequent reaction of the sterically hindered secondary alcohol with benzoyl triflate " provides a good leaving group in P-position to the ester moiety. Elimination under basic conditions provides the a,p-unsaturated ester 21 in 50 % yield over three steps. 

In 2006, Deng and coworkers reported that quinine/quinidine-derived catalysts (64a,b) bearing a free OH group at the C6 -position and bulky phenanthryl moiety at the 9( Opposition quite efficiently promoted the Michael addition of the a-substituted P-ketoesters 65 to the a,P-unsaturated ketones 66 (Scheme 9.21) [18]. The reaction with as little as 1.0mol% of catalyst 64 afforded excellent stereoselectivity and chemical yields (up to 98% ee with quantitative yield) for a wide range of both donors and acceptors. 

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). 

The behavior of a-keto-a,p-unsaturated esters is slightly different. The Michael reaction between aldehydes and these kinds of doubly activated olefins proceeded smoothly in the presence of 31a as catalyst but the conjugate addition products underwent spontaneous intramolecular hemiacetalization via the corresponding enol form of the a-ketoester moiety. Consequently, this reactivity was exploited for setting up a very efficient and simple protocol for the enantioselective synthesis of highly substituted dihydropyrones by carrying out the in situ oxidation of these Michael adducts (Scheme 2.30). ° The final heterocyclic derivatives were obtained in excellent overall yield and outstanding enantioselectivity. Moreover, the reaction could also be carried out in water as solvent. 

There is also a modified version of Takemoto s catalyst, which incorporates a benzimidazole heterocycle as the H-bonding donor site in place of the thiourea moiety." This catalyst 82 has been tested with success in several Michael-type reactions of 1,3-dicarbonyl compounds to nitroalkenes, in particular focused on the use of malonates as donors (Scheme 4.20), providing the corresponding adducts in excellent yields and enantioselectivities. p-Ketoesters have also been tested, although in this case the performance of the catalyst was found to be highly dependent on the structure of the p-ketoester employed. It has also to be pointed out that the reaction required the incorporation of a Bronsted acid cocatalyst such as TFA for achieving the best enantioselectivity, although the presence of this co-catalyst did not have any influence in the catalytic activity. 

A first approach described the use of catalyst 106a in the Michael reaction of a cyclic p-ketoester with acrolein (Scheme 5.28). ° The reaction proceeded satisfactorily, furnishing quantitatively the desired conjugate addition product in excellent enantioselectivity, requiring the in situ protection of the formyl moiety as the corresponding cyclic acetal derivative. However, the authors reported the need of a 9-fluorenyl ester Michael donor and the reaction was not studied further, with no data reported about the scope and limitations of the methodology. 

Highly substituted cyclohexanes and cyclopentanes have been prepared by means of a cascade process involving the use of a nitroalkene as Michael acceptor and an a-substituted p-ketoester incorporating a lateral p-substituent with a terminal methyl ketone moiety at the convenient position, ready to... 

Use of the methoxyphenyl group as a latent P-ketoester represents the combined protection of two functional groups (ketone and ester) in a single moiety. It is very common to combine the protection of neighboring alcohol functions as henzylidene acetal, as an acetonide, or as a siladioxane (Scheme 7.12). Of these, the henzylidene acetals are most versatile, as they allow the selective deprotection of either the sterically more encumbered or less encumbered hydroxyl function [1,2]. 

A diastereo- and enantioselective Michael addition combined with a Darzens condensation reaction can be used to form two products of interest in the field of medicinal and natural products chemistry [60]. Additionally, depending on the workup conditions, an optically active epoxycyclohexanone, 92, can be prepared through an Sf 2 reaction, or the ElcB reaction pathway to 91 can be accessed (Scheme 7.17). In the early stages of the proposed mechanism, a planar iminium ion is suggested between the 2-[bis(3,5-bistrifluoromethylphenyl) trimethylsilany-loxymethyljpyrrolidine 61 and the aldehyde moiety of compound 88, which is subsequently attacked by the P-ketoester 89. For the synthesis of the epoxide, a... 

A novel approach to the asymmetric Mannich reaction with a wide range of malonates and p-ketoesters under phase-transfer catalytic conditions was performed by Ricci and Bernadi. The authors found that catalysts derived from quinine with a free C(9)-OH group and an o/tAo-substituted aromatic group at the N-benzylic moiety of the quinuclidine, such as 48f and 48g, afforded consistently better results in terms of chemical yield and enantioselectivity with low catalytic loading (1 mol%) (Scheme 16.30). ... 

These observations have led to the construction of a simple model which allows one to predict the diastereoselectivity (i.e., the syn/anfi-ratio) of yeast-catalyzed reductions of cx-substituted p-ketoesters (Fig. 2.17) [903]. Thus, when cx-substitu-ents are smaller than the carboxylate moiety, they fit well into the small pocket (S), with L being the carboxylate, but substrates bearing space-filling groups on the... 

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