Asymmetrical ketones

20 Aromatic Ketones Containing Only Acetyl Groups 

The structure of Cynandione A, previously designated as 3, 4-diacetyl-2,2, 3,6 -tetrahydroxy-biphenyl [5855], has been revised as 2,3 -diacetyl-2, 3,6,6 -tetrahydroxybiphenyl [5859] in 1997. 

OCH3 CH3O biphenyl with acetyl chloride in the 

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The aziridine carbinols are also effective ligands in the preparation of oxazaborolidine catalysts for the asymmetric ketone reduction with borane (Fig. 4) [551. 

Schroer, K., Mackfeld, U., Tana, I.A.W. et al. (2007) Continuous asymmetric ketone reduction processes with recombinant Escherichia coli. Journal of Biotechnology, 132 (4), 438 AAA. 

Enantiometrically pure alcohols are important and valuable intermediates in the synthesis of pharmaceuticals and other fine chemicals. A variety of synthetic methods have been developed to obtain optically pure alcohols. Among these methods, a straightforward approach is the reduction of prochiral ketones to chiral alcohols. In this context, varieties of chiral metal complexes have been developed as catalysts in asymmetric ketone reductions [ 1-3]. However, in many cases, difficulties remain in the process operation, and in obtaining sufficient enantiomeric purity and productivity [2,3]. In addition, residual metal in the products originating from the metal catalyst presents another challenge because of the ever more stringent regulatory restrictions on the level of metals allowed in pharmaceutical products [4]. An alternative to the chemical asymmetric reduction processes is biocatalytic transformation, which offers... 

In summary, ketoreductases have emerged as valuable catalysts for asymmetric ketone reductions and are preparing to enter the mainstream of synthetic chemistry of chiral alcohols. These biocatalysts are used in three forms wild-type whole-cell microorganism, recombinant... 

Zhu, D., Malik, H.T. and Hua, L. (2006) Asymmetric ketone reduction by a hyperthermophilic alcohol dehydrogenase. The substrate specificity enantioselectivity and tolerance of organic solvents. Tetrahedron Asymmetry, 17 (21), 3010-3014. 

Scheme 18. Ru-catalyzed asymmetric ketone reduction used by Schreiber in the total syntheses of immunosuppressive agents FK506 and rapamycin (1990, 1993).

The acylation of asymmetrical ketones takes place mainly at the more unsubstituted position. 

In the case of asymmetrical ketones, two different modes of a-cleavage can occur, with the major products being formed via the more stable pair of initially-formed radicals. For alkyl radicals, the stability of the radical increases as its complexity increases and radical stabilities are tertiary > secondary > primary. 

Figure 18.18. Diphosphines used in asymmetric ketone hydrosilylation...

The electrolysis of asymmetric ketones 43 led to the formation of isomers and stereoisomers. Kinetic measurements for the formation of ketimine 43 in saturated ammoniacal methanol indicated that at least 12 h of the reaction time were required to reach the equilibrium in which approximately 40% of 42 was converted into the ketimine 43. However, the electrolysis was completed within 2.5 h and the products 44 were isolated in 50-76% yields. It seems that the sluggish equilibrium gives a significant concentration of ketimine 43 which is oxidized by the 1 generated at the anode, and the equilibrium is shifted towards formation of the product 44. 2,5-Dihydro-IH-imidazols of type 44, which were unsubstituted on nitrogen, are rare compounds. They can be hydrolyzed with hydrochloric acid to afford the corresponding a-amino ketones as versatile synthetic intermediates for a wide variety of heterocyclic compounds, that are otherwise difficult to prepare. 

Biocatalysis is still an emerging field hence, some transformations are more established than others.Panke et alP have performed a survey of patent applications in the area of biocatalysis granted between the years 2000 and 2004. They found that although hydrolases, which perform hydrolyses and esterifications, still command widespread attention and remain the most utilized class of enzyme (Figure 1.5), significant focus has turned towards the use of biocatalysts with different activities and in particular alcohol dehydrogenases (ADHs) - also known as ketoreductases (KREDs) - used for asymmetric ketone reduction. 

Microbial reduction has been recognized for decades as a laboratory method of preparing alcohols from ketones with exquisite enantioselectivity. The baker s yeast system represents one of the better known examples of biocatalysis, taught on many undergraduate chemistry courses. Numerous other microorganisms also produce the ADH enzymes (KREDs) responsible for asymmetric ketone reduction, and so suitable biocatalysts have traditionally been identified by extensive microbial screening. Homann et have... 

The coupled substrate method is perhaps the simplest approach to asymmetric ketone reduction, using a single recombinant ADH to perform the oxidation of a cheap auxiliary... 

In asymmetric ketone hydrosilylation, axially chiral bidentate N-heterocyclic carbene ligands derived from BINAM proved to be moderately effective when bound to iridium, but less so with rhodium (Scheme 3.19) [44]. 

ASYMMETRIC KETONE FORMATION FROM CARBON-CARBON... 

A benzophenone-based ruthenium complex (15) afforded high enantioselectivity in the catalytic asymmetric ketone hydrogenation (up to 99% ee, >99% yield). It was found that chirality of benzophenone complexes can be controlled even in the solution phase.332... 

Aldehydes, symmetric and asymmetric ketones, such as formaldehyde, acetaldehyde, substituted benzaldehydes and cyclic ketones, were introduced into the reaction along with acetone. The reaction is reversible azirenoimidazoles undergo reverse transformation forming tnms-aziridinyl ketones in acetic acid. 

The chemoenzymatic synthesis of chiral alcohols is a field of major interest within biocatalytic asymmetric conversions. A convenient access to secondary highly enan-tiomerically enriched alcohols is the usage of alcohol dehydrogenases (ADHs) (ketoreductases) for the stereoselective reduction of prochiral ketones. Here, as in many other cases in asymmetric catalysis, enzymes are not always only an alternative to chemical possibilities, but are rather complementary. Albeit biocatalysts might sometimes seem to be more environmentally friendly, asymmetric ketone reduction... 

The asymmetric hydrogenation of enol esters is an alternative to asymmetric ketone hydrogenation. The precursors can be prepared from the ketones but also via ruthenium-catalyzed addition of the carboxylic acids to the 2-postion of terminal alkynes. This latter method allows the study of the effect of the carboxylate on the enantioselectivity of the asymmetric hydrogenation. A remarkable study by Reetz and colleagues established that it is possible to hydrogenate enolate... 

Fig. 9.30. Regioselective formation of an enamine from an asymmetrical ketone.

Fig. 17.32. Oxidative cleavage of an asymmetric ketone with complementary regiose-lectivities. Lactone A is obtained by Baeyer-Villiger oxidation of menthone [2-methyl-5-(l- methylethyl)cyclo-hexanone]. Alternatively, one may first convert menthone into the silylenol ether B and cleave its C=C double bond with ozone to obtain a silyl ester containing an a-methoxyhydroperoxide group as a second functional group (which resembles the unstable structural element of the so-called ether peroxides cf. Figure 1.38). The latter is reduced with NaBH4tothe hydroxylated silyl ester C. The hydroxycarboxylic acid is obtained by acid-catalyzed hydrolysis. It cyclizes spontaneously to give lactone D.

For asymmetric ketones, such as methylethyl ketone, there are two possible bond cleavages, producing different sets of free radicals [6] ... 

The deprotonation of an iminium ion (formula A in Figure 7.27) to give an enam-ine is reversible under the usual reaction conditions. Therefore, the most stable enam-ine possible is produced preferentially. Figure 7.28 emphasizes this using the example of an enamine formation from a-methylcyclohexanone (i.e., from an asymmetrical ketone). The enamine with the trisubstituted double bond is produced regioselectively and not the enamine with the tetrasubstituted double bond. Since the stability of olefins usually increases with an increasing degree of alkylation, this result is at first... 

An asymmetric ketone may even lead to the generation of one enolate in a selective fashion if the asymmetry is caused by the substitution patterns in the f3 rather than a positions. The difference in the fi positions may be due to the number or the kind of substituents there. This point is emphasized in Figure 10.10 with cyclohexanones that contain one (D) or two (A) p substituents. In this case, deprotonation occurs preferentially on the side opposite to the location of the extra substituent that is, the ster-ically less hindered acidic H atom is attacked. 

Fig. 11.31. Regioselective and stereoselective Baeyer-Villiger rearrangement of an asymmetric ketone with magnesium monoperoxophthalate hexahydrate (in the drawing, Mg2+ is omitted for clarity).

Fig. 11.32. Regioselective Baeyer-Villiger rearrangement of an asymmetric ketone with MCPBA (meta-chloroperbenzoic acid). The aryl group is [1,2]-shifted in all cases and irrespective of whether the acetophenone is electron rich or electron poor.

Fig. 14.26. Oxidative cleavage of an asymmetric ketone with complementary regioselectivities. Lactone A is obtained by...

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