Pro-chiral ketones

As a consequence of the wide choice of hydride reagents the classical methods such as reduction with sodium in ethanol almost fell into oblivion [579, 520]. Nevertheless some old reductions were resuscitated. Sodium di-thionite was found to be an effective reducing agent [262], and the reduction by alcohols [309] was modified to cut down on the temperature [755] or the time required [527], or to furnish chiral alcohols ( in good yields and excellent optical purity ) by using optically active pentyl alcohol and its aluminum salt [522]. Formation of chiral alcohols by reduction of pro-chiral ketones is... 

This obviously is unlikely for the given example because there is no reason for cyanide ion to have anything other than an exactly equal chance of attacking above or below the plane of the ethanal molecule, producing equal numbers of molecules of the enantiomers, 21 and 22. However, when a chiral center is created through reaction with a dissymmetric (chiral) reagent, we should not expect an exactly 1 1 mixture of the two possible isomers. For example, in an aldol-type addition (Section 18-8E) of a chiral ester to a pro-chiral ketone the two configurations at the new chiral center in the products 23 and 24 are not equally favored. That is to say, asymmetric synthesis is achieved by the influence of one chiral center (R ) on the development of the second ... 

The 1,2-addition of chiral aluminum ate complexes to various aldehydes and ketones has been re-viewed and, generally, this protocol produces very disappointing results with respect to the overall stereospecificity of the process as compared to other organometallics however, the recent extension of this methodology to the preparation of chiral a-hydroxy esters and acids, via 1,2-additions to the pro-chiral ketone moieties of a-keto esters, " has renewed interest in this area. TTie transformation outlined in equation (8) proceeds in excellent overall yield with exclusive selectivity for the ketone functionality unfortunately, the stereospecificity is not as impressive. 

Rhodium-phosphine complexes are usually active and effective in the asymmetric hydrosilylation of olefins, ketones, and aldehydes, allowing for the virtual synthesis of optically active alkoxysilanes and organic compounds of high purity. Chiral rhodium-phosphine catalysts predominate in the hydrosilylation of pro-chiral ketones. This subject has been comprehensively reviewed by several authors who have made major contributions to this field [52-54]. A mechanism for the hydrosilylation of carbonyl groups involving the introduction of asymmetry is shown in Scheme 3 [55]. 

The specific example of sugar hydrogenation (e. g. glucose to sorbitol) has warranted an individual chapter in this book and so is excluded here. Reference to enantioselective hydrogenation of pro-chiral ketones is only included where appropriate, for the same reason. 

The enantiomers of this complex catalyse the asymmetric hydrogenation of pro-chiral ketones and olefins in high yields and ee values. [Ohta, Takaya and Noyori Inorg Chem 27 566 1988, Kumbobyashi et al. Symlett 1055 200L RhBINAP complexes with ligands other than acetate, e.g. CI2, C6H6, (OCO-t-Bu)2,... 

There are also a variety of asymmetric catalytic reactions which may produce optically active alcohols. Metalo-organic compounds have been reported to play an essential role in some of them. One of these reactions is enantioselective reduction of pro-chiral ketones with borane in which BHj-SMe adduct are used as reductant. It also needs a chiral ligand along with aluminum isopropoxide to prepare enantioenrich compounds (reaction 7.7). Fu and Uang used (R)-binaphthol as chiral ligand and without use of AKOTrlj, reached 50% yield with no enantioselectivity in production of phenyl ethanol 63, from acetophenone 62, by BH -SMe even after 24 hours [54]. But in the presence of both, at 40°C, 96% yield with 74%... 

A series of new chiral Cs-symmetric tris(P-hydroxy phosphoroamide) ligands have been synthesized. Structurally well-defined, recoverable Cs-symmetric ligand (105) was used as an efiicient catalyst in the enantioselective borane reduction of pro-chiral ketones containing electron-withdrawing or electron-donating groups... 

Synthetic strategy C2-Symmetric copper-bound A -heterocyclic carbene (NHC) catalyzed enantioselective hydrosilylation of pro-chiral ketones Catalyst (R, / )-CuPhEt (I)/KO Bu... 

The principal aim in the development of the modern aldol reaction vas stereochemical control, a field that has been treated in a series of review articles [46, 48-60]. In stereochemical terminology, the topic is discussed in the terms of simple diastereoselectivity and induced stereoselectivity [61]. Except for relatively rare examples w hen is identical w ith R and R is identical w ith R, all aldol additions are stereogenic. If the carbonyl-active compound is either an aldehyde (except formaldehyde - R = H) or a pro-chiral ketone (R R ), addition of the enolate leads to formation of either... 

An NADH-dependent reductase (ScCR) was identified by genome mining studies of Streptomyces coelicolor. This dehydrogenase showed broad tolerance to pro-chiral ketones including aryl ketones, a- and 3-ketoesters and had particularly high activity and excellent enantioselectivity (>99% ee) for the last substrate type For example the enzyme reduced ethyl 4-chloro-3-oxobutanoate (CORE)... 

While enantioenriched diols have been broadly used for generating epoxides and a-hydro qr carbonyl compounds, these chiral synthons have been used to generate a number of other useful functional groups. Researchers at Lilly used SAD to generate diol 173 which, upon acidification, condensed on a pendent pro-chiral ketone to generate the enantioenriehed ketal 174 (Scheme 14.65). This intramolecular reaction provided rapid access to the 6,8-dioxabicyclo[3.2.l]octane skeleton of (-)-frontalin and brevieomin. Whilst enantioselectivities were modest in this case (60-70%), the sealemie mixtures still proved useful for the purposes of their research. 

Further evidence of the mechanism in which both the alcohol and ketone are simultaneously coordinated to a Lewis acid metal center was obtained from the reduction of the pro-chiral phenylacetone with (S)-2-butanol.76 A nearly identical enantiomeric excess (e.e.) of 34% was observed over both the Al- and Ti-Beta. 

Enantioselective epoxidation of pro-chiral alkenes with dioxiranes generated from optically active ketones affords optically active epoxides with enantiomeric excesses (ee) in the 9-12.5% range <84CC155>. In the late 1980s values up to 24% have been observed when employing 4,4,4-trifluoro-3-phenyl-3-methoxybutan-2-one as the ketone <89ACR205>. 

Industry is very interested in chiral cyanohydrins because they are valuable starting materials for several classes of polyfunctional molecules that are useful in the synthesis of agrochemicals and pharmaceuticals. By use of a chiral catalyst the pro-chiral aldehydes or ketones, a large number of which are readily available, are... 

Lithium borohydride, 92 (lR,2S)-N-Methylephedrine-0-pro-pionate, 308 Norephedrine, 200 2-Oxazolidones, chiral, 225 (2R,4R)-Pentanediol, 237 Potassium triethylborohydride, 260 Other hydroxy carbonyl compounds (R)-( + )- and (S)-( - )-2,2 -Bis-(diphenylphosphine)-1,1 -binaphthyl, 36 Ketones... 

By means of a chiral base the compound shown below can be converted enantioselectively into its lithium enolate which can be transformed into an a,p-unsaturated ketone in two subsequent steps. If deprotonation of the initial ketone occurs preferentially at the pro-R group to the extent of 92 %, what is the configuration and the enantiomeric excess of the resulting a,p-unsaturated ketone ... 

Our research group developed catalytic enantioselective protonations of preformed enolates of simple ketones with (S,S)-imide 23 or chiral imides 25 and 26 based on a similar concept [29]. For catalytic protonation of a lithium eno-late of 2-methylcyclohexanone, chiral imide 26, which possesses a chiral amide moiety, was superior to (S.S)-imide 23 as a chiral acid and the enolate was pro-tonated with up to 82% ee. 

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