Highly substituted ketone substrates

A novel synthetic route for the preparation of unsymmetrically substituted benzophenones was developed in the laboratory of C.-M. Andersson utilizing an iron-mediated aromatic substitution as one of the key steps. The power of this method was demonstrated by the formal synthesis of the benzophenone moiety of the protein kinase C inhibitor balanol. In the late stages of the synthesis, it became necessary to convert the aromatic methyl ketone functionality of the highly substituted benzophenone substrate to the corresponding carboxylic acid. Bromine was added to sodium hydroxide solution, and the resulting sodium hypobromite solution was slowly added to the substrate at low temperature. Upon acidification the desired carboxylic acid was obtained in fair yield. 

They have developed direct asymmetric synthesis of quaternary carbon centers via addition-elimination process. The reactions of chiral nitroenamines with zinc enolates of a-substituted-8-lactones afford a,a-disubstituted-6-lactones with a high ee through addition-elimination process, in which (5)-(+)-2-(methoxy methy l)pyrrolidine (SMP) is used as a chiral leaving group (Eq. 4.96).119 Application of this method to other substrates such as a-substituted ketones, esters, and amides has failed to yield high ee. 

A large number of diaryl ketone substrates, including those listed in Table 9.3, have been reduced with high enantioselectivity with the protocol described here. Unlike analogous chemical catalysts, the commercially available biocatalysts displayed no dependence on ortho substitutions or electronic dissymmetry, and produced diaryl methanols with good to excellent ee values in nearly all cases. 

An intramolecular reductive coupling of ketones with nitriles has been reported for acyclic and monocyclic substrates y9-amino nitriles were isolated from acyclic malononitrile adducts [87]. The Sml2-initiated reductive cyclization of cyclic a-cyanoalkyl-substituted ketones leads to acyloin products in high yields. In this instance further irradiation of the reaction mixtures was performed to afford complete conversion (Scheme 27) [88]. More applications have been collected in several excellent reviews [89-92]. 

The base catalyzed decomposition of arylsulfonylhydrazones of aldehydes and ketones to provide alkenes is called the Bamford-Stevens reaction. When an organolithium compound is used as the base, the reaction is termed the Shapiro reaction. The most synthetically useful protocol involves treatment of the substrate with at least two equivalents of an organolithium compound (usually MeLi or BuLi) in ether, hexane, or tetramethylenediamine. The in s/ft formed alkenyllithium is then protonated to give the alkene. The above procedure provides good yields of alkenes without side reactions and where there is a choice, the less highly substituted alkene is predominantly formed. Under these reaction conditions tosylhydrazones of a,(3-unsaturated ketones give rise to conjugated dienes. It is also possible to trap the alkenyllithium with electrophiles other than a proton. 

The second classical reaction mentioned above is the acetoacetic ester synthesis. this reaction, an ester of acetoacetic acid (3-oxobutanoic acid) such as ethyl acetoacetate is treated with base under thermodynamic control conditions and alkylated, as with the malonic ester synthesis. Reaction with sodium ethoxide in ethanol (since an ethyl ester is being used) generated the enolate and quenching with benzyl bromide led to 84. Saponification and decarboxylation (as above) gave a substituted ketone (85). Although the malonic ester synthesis and the acetoacetic ester synthesis are fundamentally similar, the different substrates lead to formation of either a highly substituted acid or a ketone. The reaction is not restricted to acetoacetate derivatives, and any p-keto-ester can be used (ethyl 3-oxopentanoate for example). ... 

Several highly substituted pyrroles 284 were produced by Kaupp et al. by mechano-chemical one-pot reaction of the enamine ketones 282 with fran -l,2-dibenzoylethene 280 (Scheme 3.75) [50], Depending on the reactivity of substrate, different milling temperatures were applied. In addition, ball milhng of enamine cyclohexenone 281 under same reaction conditions produced tetrahydroindolone 283 in quantitative yield. Quantitative yields of aU products were obtained by heating of reaction mixture after milling for removal of water. In solution, these reactions afforded moderate yields at much higher tanperatuies (Table 3.38). 

DKR of racemic ketones via the BV oxidation is very rare. Notably, the CHMO-containing (CHMO = cyclohexanone monooxygenase) recombinant E. coli sp. was found to be highly efficient in the DKR of 2-substituted cyclopentanone rac-105 at pH 9. The ketone substrate 105 underwent facile racemization via keto-enol tautomerism, and the lactone product (R)-106 was isolated in 85% yield and 96% ee (Scheme 2.24)." ... 

S.2.2.3. a, -Unsaturated Sulfones, Malononitriles, and Maleimides as Acceptors, Base on their previous achievements on the asymmetric Michael addition of aldehydes [24], Lu and co-workers [55] developed the first enantiose-lective conjugate addition of cyclic ketones to vinyl sulfone catalyzed by a primary amine 57 (Scheme 5.28). Various cyclic ketones could be applied, affording the corresponding adducts in good yields and with high to excellent enantioselectivities. However, linear ketones were not suitable substrates for this catalytic system. Performing the desulfonylation procedure on a-substituted ketones and in combination... 

Diastereoselective Reduction of Ketones by Baker s Yeast. Asymmetric microbial reduction of oc-substituted ketones leads to the formation of diastereomeilc syn-and anh -products. Because the chiral center on the a-position of the ketone is stereochemically labile, rapid in-situ racemization of the substrate enantiomers occurs via enolization ° - leading to dynamic resolution [67, 895, 896]. Thus, the ratio between the diastereomeric syn- and anti-products is not 1 1, but is determined by the selectivities of the enzymes involved in the reduction process [897]. Under optimal conditions it can even be as high as 100 0 [898]. 

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