Meso-Ketones

Toda and Akai49 reported that compound 48 reacted with the stable solid state inclusion compound of chiral host 46 and meso-ketone 47, providing alkene 49 in 57% ee. 

SCHEME 170. Pt-catalyzed enantioselective Baeyer-Villiger oxidation of cyclic meso-ketones with H2O2 using chiral diphosphine hgands... 

Asymmetric enolates of meso-ketones.1 The ketal 1, formed from 4-ethyl-cyclohexanone and (2R,4R)-2,4-pentanediol, when treated with triisobutylalu-minum in CH2C12 at -78° gives the enol ethers (S)-2 and (R)-2 in the ratio 6 1. Somewhat superior selectivity obtains by use of a dialkylaluminum amide such as 3.8... 

While this example of the Robinson annulation is clearly not enantioselec-tive, the same antibody converts the meso-ketone [120] into the Wieland-Miescher (WM) decalenedione product kcat = 0.086 min-1 and Km = 2.34 mM at 25°C, parameters that give an impressive ER of 3.6 X 106. Good evidence suggests that the mechanism of the reaction involves the formation of a ketimine with the e-amino group of a buried lysine residue in the antibody, as shown in Fig. 39. Most significantly, the reaction delivers the (5)-(+)-WM product in 96% ee (by polarimetry) and in 95% ee by nmr and hplc analysis for a 100 mg scale reaction. A recent report tells that this antibody is to be made commercially available at a cost of 100 for 10 mg. The realization of that objective would mark the start of a new era of application of abzymes to organic stereoselective synthesis. 

Elimination of Acetals. Treatment of 2,4-pentanediol acetals of meso ketones with Triisobutylaluminum gives enol ethers with high diastereoselectivities (eq 3). ... 

Honda et al. have utilized acid-catalyzed lactonization of a 5-hydroxy ester in an enantioselective synthesis of the lactone moiety of HMG CoA reductase inhibitor [52] (Scheme 15). An enantioselective deprotonation reaction of meso-ketone 75 with lithium (5,5)-a,a -dimethyldibenzylamide as the chiral base in the presence of... 

The study of optical isomers has shown a similar development. First it was shown that the reduction potentials of several meso and racemic isomers were different (Elving et al., 1965 Feokstistov, 1968 Zavada et al., 1963) and later, studies have been made of the ratio of dljmeso compound isolated from electrolyses which form products capable of showing optical activity. Thus the conformation of the products from the pinacolization of ketones, the reduction of double bonds, the reduction of onium ions and the oxidation of carboxylic acids have been reported by several workers (reviewed by Feokstistov, 1968). Unfortunately, in many of these studies the electrolysis conditions were not controlled and it is therefore too early to draw definite conclusions about the stereochemistry of electrode processes and the possibilities for asymmetric syntheses. 

Various biocatalytic options have been presented for the desymmetrization of meso-diols to chiral hydroxyl-ketones. A particularly facile system is represented by... 

R)-l results in the (R)-hydroxy ketone (3) as expected. Further hydrogenation with the same catalyst gives R,R-4 and meso-4 in the ratio 99 1. In contrast, hydrogenation of 3 catalyzed by Ru-(S)-1 gives the same diols, but in the ratio... 

The chiral substrate trans- stilbene oxide (10.121) behaved differently, yielding meso-l,2-diphenylethane-l,2-diol (meso-10.122) [183], This means that, in both enantiomeric substrates, the enzyme does not discriminate between the two oxirane C-atoms, bringing about inversion of configuration at the C-atom attacked. Interestingly, the various stereoisomers of 1,2-diphenylethane-l, 2-diol can be interconverted metabolically by alcohol/ketone equilibria catalyzed by alcohol dehydrogenases. 

For further contributions on the dia-stereoselectivity in electropinacolizations, see Ref. [286-295]. Reduction in DMF at a Fig cathode can lead to improved yield and selectivity upon addition of catalytic amounts of tetraalkylammonium salts to the electrolyte. On the basis of preparative scale electrolyses and cyclic voltammetry for that behavior, a mechanism is proposed that involves an initial reduction of the tetraalkylammonium cation with the participation of the electrode material to form a catalyst that favors le reduction routes [296, 297]. Stoichiometric amounts of ytterbium(II), generated by reduction of Yb(III), support the stereospecific coupling of 1,3-dibenzoylpropane to cis-cyclopentane-l,2-diol. However, Yb(III) remains bounded to the pinacol and cannot be released to act as a catalyst. This leads to a loss of stereoselectivity in the course of the reaction [298]. Also, with the addition of a Ce( IV)-complex the stereochemical course of the reduction can be altered [299]. In a weakly acidic solution, the meso/rac ratio in the EHD (electrohy-drodimerization) of acetophenone could be influenced by ultrasonication [300]. Besides phenyl ketone compounds, examples with other aromatic groups have also been published [294, 295, 301, 302]. 

These tautomeric equilibria support the view that in enamino-aldehyde, -ketone and -ester systems generally the relative basicities of the C- and O-protonation sites are comparable, whereas N-protonation is encountered only when steric hindrance to meso-merism is present and, exceptionally, in some solid salts. 

Enantioselective deprotonations of meso substrates such as ketones or epoxides are firmly entrenched as a method in asymmetric synthesis, although the bulk of this work involves stoichiometric amounts of the chiral reagent. Nevertheless, a handful of reports have appeared detailing a catalytic approach to enantioselective deprotonation. The issue that ultimately determines whether an asymmetric deprotonation may be rendered catalytic is a balance of the stoichiometric base s ability... 

The deprotonation of meso oxiranes 144 and 145 by the system alkyllithium/diamine leads to the enantiomeric ketones (S)- and (R)-146 (Scheme 63). Due to the general propensity of these systems to achieve deprotonation at the R carbon of the oxirane ring, it was then concluded that this rearrangement follows exclusively a 1,2-H shift. 

Representatives of this new type of meso-ionic system (502) have been prepared by cyclodehydration of the acid derivatives 503 using trifluoroacetic anhydride. For example, the acid 503, R = p.ClCgH4, gave the red crystalline meso-ionic l,3-oxathiol-5-one (502, R =p.Cl.CgH4, R = CF3.CO) which is readily hydrolysed to the ketone (504, R = j3.Cl.CgH4). The trifluoroacetyl group in the 4-position appears to be essential for the stability of the meso-ionic system (502). 

Reaction of the chiral lithium enolate of meso-2,6-dimethylcyclohexanone (6), generated by deprotonation with (R)-l-phenylethylamine and (/ )-camphor/(R)-l-phenylethylaniine derived chiral lithium amides (Table 1, entries 17 and 64) with 3-bromopropene, leads to homoallyl ketones of opposite absolute configuration in acceptable yield with poor to modest enantiomeric excess14, which can be determined directly by H-NMR spectroscopy in the presence of tris [3-(heptafluorohydroxymethylene)-D-camphorato]europium(III) [Eu(hfc)3]. 

I, 5-dithioniabicyclo[3.3.0]octane bis(trifluoromethanesulfonate) 7 in acetonitrile at 50°C. The salt promotes pinacol coupling of aromatic ketones even at —40 °C. In addition, the diastereoselectivity dl meso) of the coupling reaction of acetophenone in acetonitrile at —40°G is 94 6. "... 

Application of the Pd-catalyzed alkylation of hydrogencarbonate to the meso-biscarbonate 29 gave the allylic alcohol 30 in 87% yield with 96% ee (Scheme 2.1.4.31). Alcohol 30 has been converted via the silyl ether 31 and alcohol 32 to ketone 33, the enantiomer of which is an important building block for the synthesis of prostaglandins [40]. Since both BPA and mt-BPA are readily available, access to ent-33 is also provided. 

Pentadienone (divinyl ketone) was epoxidized55 by means of hydrogen peroxide in alkaline solution, to give a mixture of DL- and me.so-l,2 4,5-dianhydro-3-pentanones in the ratio of 13 7. Reduction of the ketone group in the DL-diepoxide with sodium horohvdride, followed by alkaline hydrolysis in dimethyl sulfoxide, was fully stereo-specific, and afforded DL-arabinitol. The same reaction-sequence performed on the meso-diepoxide led to a mixture of ribitol and xylitol. 

---