Enantioselective ketones reduction, hydrogenation

Achiral polymers synthesized from achiral monomers have been modified after polymerization using asymmetric catalysts to yield optically active polymers. For example, enantioselective ketone reduction, hydrogenation, olefin epoxida-tion, and olefin hydroxylation have been carried on the functional groups of achiral polymers [111, 112]. Such functionalizations, however, are often incomplete or occur with a low degree of asymmetric control. 

The hydrogen transfer reaction (HTR), a chemical redox process in which a substrate is reduced by an hydrogen donor, is generally catalysed by an organometallic complex [72]. Isopropanol is often used for this purpose since it can also act as the reaction solvent. Moreover the oxidation product, acetone, is easily removed from the reaction media (Scheme 14). The use of chiral ligands in the catalyst complex affords enantioselective ketone reductions [73, 74]. 

Many of the chiral bidentate phosphines synthesized in the last years have also been tested for enantioselective ketone reduction. Some of the results achieved are compiled in Table 2. The influence of phosphine structure on optical selectivity and catalytic activity is considerable, but a reliable correlation could not yet be found. It seems that chiral bidentate 6w(diphenyl)phosphines, like prophos forming 5-membered chelate rings with the rhodium atom and used with great success for the hydrogenation of dehydroaminoacids, are not suitable for ketone reduction because of very low reaction rates. 

Chart 1.2 Practical hydrogenation catalysts for enantioselective ketones reduction. 

Far more ruthenium-complex-catalyzed enantioselective hydrogenation has been directed towards ketone reduction rather than alkene reduction. Recent studies carried out on the mechanism of C=C hydrogenation has been rather limited. 

The TEAF system can be used to reduce ketones, certain alkenes and imines. With regard to the latter substrate, during our studies it was realized that 5 2 TEAF in some solvents was sufficiently acidic to protonate the imine (p K, ca. 6 in water). Iminium salts are much more reactive than imines due to inductive effects (cf. the Stacker reaction), and it was thus considered likely that an iminium salt was being reduced to an ammonium salt [54]. This explains why imines are not reduced in the IPA system which is neutral, and not acidic. When an iminium salt was pre-prepared by mixing equal amounts of an imine and acid, and used in the IPA system, the iminium was reduced, albeit with lower rate and moderate enantioselectivity. Quaternary iminium salts were also reduced to tertiary amines. Nevertheless, as other kinetic studies have indicated a pre-equilibrium with imine, it is possible that the proton formally sits on the catalyst and the iminium is formed during the catalytic cycle. It is, of course, possible that the mechanism of imine transfer hydrogenation is different to that of ketone reduction, and a metal-coordinated imine may be involved [55]. 

Evans et al.106 report an asymmetric transfer hydrogenation of ketones using samarium(III) complex (108) as the catalyst at ambient temperature in 2-propanol. The products showed ee comparable with those obtained through enantioselective borane reduction (Scheme 6-48). 

An enantioselective organocatalytic reductive amination has been achieved using Hantzsch ester for hydrogen transfer and compound (21) as catalyst. This mild and operationally simple fragment coupling has been accomplished with a wide range of ketones in combination with aryl and heterocyclic amines.359... 

Highly enantioselective conjugate reductions of substituted cyclopentenones and cyclohexenones were reported by Kergomard using Beauveria sulfurescens (ATCC 7159) under anaerobic conditions. The reaction takes place only with substrates containing a small substituent in the a-position and hydrogen in the -position. The saturated ketones obtained were, in some cases, accompanied by saturated alcohols. 

Hydrogen transfer to ketones from 2-propanol was developed into an extremely efficient method of obtaining secondary alcohols [256,257] and the use of chiral N-(p-tolylsulfonyl)diamines allow the reduction of prochiral ketones with extraordinary stereoselectivity [257-259], In general, water is not well tolerated in such processes, and several studies showed that both the rate and the enantioselectivity of transfer hydrogenations from 2-propanol decrease substantially in increasingly aqueous mixtures even in the presence of water soluble catalysts [260,261], However, in a recent study the opposite effect was found. Using the water soluble Rh- and Ir-complexes... 

Ketone reductions. For the asymmetric hydrogenation of functionalized ketones, a team led by Noyori in Nagoya and Akutagawa in Tokyo introduced ruthenium(II) BINAP catalysts that produce excellent enantioselectivities for a number of functionalized ketones [69-75] (review [76] for a recent reference to a more reactive catalyst see ref. [77]). The topicity of the reduction is illustrated in Scheme... 

Reduction of carbonyl groups. Aldehydes and ketones are subjected to enantioselective reduction. Hydrogenation of benzaldehyde-a-d, a-alkoxyketones " or )3-ketoesters can be accomplished using either the Ru dihalide complexes or some modified forms. a-Ketoesters are also similarly reduced. 

Only little information is available on asymmetric ketone reduction using hydrogen transfer. With secondary alcohols or indoline as hydrogen donors, optical yields up to 9.9% were obtained in the presence of H4Ru4(CO)8[(-)DIOP]2 as a catalyst. Iridium compounds like [Ir(C0D)(PPEI)] C104 proved to be more enantioselective in the presence of Reducing propiophenone 30% e.e. was observed at 50%... 

Concerning the nature of the nitrogen-containing ligand itself, immobilized derivatives of DPEN revealed to be the most efficient in the reduction of prochiral ketones by catalytic hydrogenation in the presence of BINAP or by HTR and CBS-supported ligands for the enantioselective hydride reduction. 

It has been pointed out that trichloromethyl ketones are generally available by the reaction of aldehydes with nucleophilic trichloromethide reagents followed by oxidation as well as in other ways. So, as shown in Scheme 12.60, when the trichloromethyl ketone is reduced with catecholborane in the presence of the (S)-oxazaborolidine catalyst, the corresponding (i )-secondary alcohol is produced in high enantioselectivity. Then, when the alcohol is treated with sodium hydroxide and sodium azide, the corresponding (5)-a-azidocarboxylic acid results and reduction (hydrogen [H2] in the presence of a palladium [Pd] catalyst) produces the amino acid. 

Ketone reduction The enantioselective hydrogenation of vicinal diketones such as l-phenylpropane-l,2-dione over cinchonidine-modifled Pt gave the (R)-enantiomers in excess. Faster reaction of (S)-hydroxyketone to the diols, contributed to an increase in enantioselective excess (ee) [41]. 

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