Ketone Hydroxylation, enantioselective

Ketones can be converted to dioxiranes by Oxone (2KHSO5 KHSO4 K2SO4) under shghtly alkaline conditions (pH 7-8) (400). The dioxirane of 1,1,1-trifluoroacetone is a powerful yet selective oxidant under mild conditions, typically at temperatures below 313 K (10). Exemplary reactions are stereospecific olefin epoxidation and hydroxylation of tertiary C-H groups, or ketonization of CH2 groups. With chiral ketones, even enantioselective reactions are possible (401). Although the reactions are often performed in excess ketone, it is actually possible to use the ketone in a catalytic fashion, for example, for 1,1,1-trifluoroacetone (Scheme 5). 

Mechanistic studies103 revealed that chiral ketone-mediated asymmetric epoxidation of hydroxyl alkenes is highly pH dependent. Lower enantioselectivity is obtained at lower pH values at high pH, epoxidation mediated by chiral ketone out-competes the racemic epoxidation, leading to higher enantioselectivity. (For another mechanistic study on ketone-mediated epoxidation of C=C bonds, see Miaskiewicz and Smith.104)... 

Asymmetric Hydrogenation of Enol Esters. Prochiral ketones represent an important class of substrates. A broadly effective and highly enantioselective method for the asymmetric hydrogenation of ketones can produce many useful chiral alcohols. Alternatively, the asymmetric hydrogenation of enol esters to yield a-hydroxyl compounds provides another route to these important compounds. 

Moreover, Soai et al.53c found that the enantioselective addition of Reformatsky reagents to prochiral ketones proceeds well when N,N-dialkylnorephedine 59 is used as the chiral ligand. When (15, 2R)-59a is used, the //-hydroxyl ester is obtained in 74% ee and 65% yield with ( -configuration predominant. When (lR,25,)-59a is used, the product is obtained in 74% ee and at 47% yield with (R)-configuration prevailing. 

Asymmetric a-hydroxylation of ketones 97 through phase transfer catalysis under alkaline conditions was realized by use of the Merck catalyst 7 (R=4-CF3, X=Br)[721 as well as the chiral azacrown ether 98[731 in conjunction with molecular oxygen, as shown in Scheme 30. The highest enantioselectivity of 79% ee was attained in the a-hydroxylation of the tetralone 100 by use of the Merck cata-... 

Enantioselective a-hydroxylotion of carbonyl compounds. The lithium enolates of the SAMP-hydrazones of ketones undergo facile and diastereoselective oxidation with 2-phenylsulfonyl-3-phenyloxaziridine (13, 23-24) to provide, after ozonolysis, (R)-a-hydroxy ketones in about 95% ee. High enantioselectivity in hydroxylation of aldehydes requires a more demanding side chain on the pyrrolidine ring such as —QCjHOjOCH, which also results in reversal of the configuration. 

This is the first time that the biotransformation of a-bromo and a,a -dibromo ketone using S. platensis has been successfully accomplished. Although enantioselective a-hydroxy ketones were not obtained, it was found that the hydroxylative biotransformation of a-bromo and o ,Q -(jibromo alkanones using S. platensis affords a new synthetic method, which is more convenient, cleaner, and of lower energy than the chemical method used heretofore (see Tables 12.7 and 12.8). Biotransformation for a-hydroxy ketone from a-bromo ketone is no doubt attributable to the special properties of S. platensis system. 

Racemic warfarin (65), a vitamin K antagonist, has been used for decades both as an oral anticoagulant in man and as a rodenticide. The metabolism of this drug has been found to be substrate-enantioselective 9S-warfarin is considered as more active than the 9R-antipode. In mammalian systems, warfarin undergoes a stereoselective reduction of the ketonic side chain [176,177], affording mainly the 9R,llS-alcohol (71), but the major biotransformation route involves substrate-enantioselective aromatic hydroxylations at 4 -, 6-, 7- or 8-positions... 

The remaining chapters deal with a variety of catalysts for effecting oxidation reactions. Chapter 5 describes three simple protocols for the controlled oxidation of primary or secondary alcohols. The importance of stereocontrolled epoxidation and hydroxylation reactions is reflected by the fact that Chapter 6, directed at this field, is one of the most extensive sections of the book. An interesting example of an enantioselective Baeyer-Villiger reaction is featured in Chapter 7, together with an industrially important ketone to enone conversion. Oxidative carbon-carbon... 

Ketones can be a hydroxylated in good yields, without conversion to the enolates, by treatment with the hypervalent iodine reagents162 o-iodosobenzoic acid163 or phenyliodoso acetate PhI(OAc)2 in methanolic NaOH.164 The latter reagent has also been used on carboxylic esters.165 02 and a chiral phase transfer catalyst gave enantioselective a hydroxylation of ketones, if the a position was tertiary.166... 

Trost et al. [11] reported another impressive example of bimetallic catalysts in which a Zn-Zn homobimetallic complex (17, Scheme 7) serves as an effective catalyst for direct aldol reactions [11-13]. The proposed structure of the catalyst was verified by mass spectrometry and the best ratio of Et2Zn and the ligand. The chemical yield was moderate in the reaction of methyl ketones (1) (Scheme 7, top) [11,12], but a highly atom-economic system was achieved when a-hydroxylated ketones (10) were used as a substrate (Scheme 7, bottom) [13]. Excellent diastereo- and enantioselectivity were obtained under mild conditions. In contrast to the case of Shibasaki s heteropolymetallic catalyst, syn-1,2-diols (syn-11) were obtained as the major diastereomers. 

Enantioselective a-hydroxylation of carbonyl compounds,2 Useful enantiose-lectivity (60-95% ee) obtains in the oxidation of enolates of a number of carbonyl compounds (ketones, esters, amides) with the simplest member of this series, ( + )-or (— )-l. This reagent, however, is not useful for enantioselective oxidations resulting in tertiary a-hydroxyl ketones. For this purpose, the 8,8-dichloro derivative (2) of ( + )-l is markedly superior, as shown in equation (I). This derivative can also be... 

Either or both myrcene and 5-hydroxygeranyl diphosphate are then converted to ipsdienol, or 5-hydroxygeranyl diphosphate is converted to ipsdienone via a ketone (5-keto-geranyl diphosphate) intermediate. As outlined in Vanderwel (1991), ipsdienol can be converted directly or via other ketone intermediates to ipsenol. Note that the ultimate enantiomeric composition of ipsdienol may result from the enantioselective insertion of a hydroxyl group at C5 of geranyl diphosphate or from an enantioselective interconversion of ipsdienol and ipsdienone (modified from Fish etal., 1984 Vanderwel, 1991). For intermediates in this pathway, OPP denotes a diphosphate moiety. Figure adapted from Seybold et al. (2000). 

The direct enantioselective a-hydroxylation of activated ketones [22], specifically cyclic / -dicarbonyl compounds, can be performed using dihydroquinine as the chiral catalyst and simple commercially available peroxides as the oxidant. The use of cumyl hydroperoxides led to the a-hydroxylation of / -ketoesters 21 in high yields and moderate to good enantioselectivities (66-80% ee) (Eq. 5). These optically active alcohols (22) undergo a diastereoselective reaction to anti-diols with excellent diastereoselectivity (99 1) using BH3-4-ethylmorpholine as the reducing agent. 

The epihydrin has an hydroxyl group that allows /w/ramolecular chelation of the anion, thus enabling one to bring a chiral nucleophile, that is responsible for the enantioselective synthesis, to the reaction center. The increase in the size of the cation from Li+ to Mg++ raises the optical purity of the product, whereas the decomposition to ketone causes some racemization. 

Over the past 25 years, biomimetic model systems have been extensively studied and a wide variety of interesting oxidation processes such as the epoxidation of olefins, the hydroxylation of aromatics and alkanes, the oxidation of alcohols to ketones, etc., have been accomplished some of these are also known in enantioselective versions with spectacular ee s. The vast majority of these transformations were obtained using monooxygen donors such as those mentioned above as primary oxidants. The complexity of the catalysts and the practical impossibility to use dioxygen as the terminal oxidant have so far prevented the use of such systems for large industrial applications, but some small applications in the synthesis of chiral intermediates for pharmaceuticals and agrochemicals, are finding their way to market. 

There is however a second phenomenon decisively influencing the optical purities of the alcohols formed in the course of Penicillium citrinum catalyzed reduction.The formed alcohols are metabolized again this metabolization proceeds enantioselectively. The preferentially formed (S)-enantiomer is preferentially metabolized. As shown in Table III the optical purity (% enantiomeric excess, e.e.) of nonan-2-ol decreases from 92% e.e.(S) to 12% e.e. (S). Heptan-2-ol is finally present mainly as (R)-enantiomer. The metabolization steps are currently under investigation one of the pathways is a hydroxy-lation leading to hydroxy ketones and diols. Figure 5 presents structures of hydroxylated metabolites obtained from nonan-2-one. 

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