Ketone hydrogenation optically active alcohols

Iridium(I) complexes with Schiff base ligands effectively transfer hydrogenate ketones. Use of optically active ligands allows asymmetric reduction of prochinal ketones to optically active alcohols ... 

Compound A, C H O, was found to be an optically active alcohol. Despite its apparent unsaturation, no hydrogen was absorbed on catalytic reduction over a palladium catalyst. On treatment of A with dilute sulfuric acid, dehydration occurred and an optically inactive alkene B, Q iH14, was produced as the major product. Alkene B, on ozonolysis, gave two products. One product was identified as propanal, CH3CH2CHO. Compound C, the other product, was shown to be a ketone, CgHgO. How many degrees of unsaturation does A have Write the reactions, and identify A, B, and C. 

As outlined in Section II,E, ketone and imine groups are readily hydrogenated via a hydrosilylation-hydrolysis procedure. Use of chiral catalysts with prochiral substrates, for example, R,R2C=0 or R,R2C=N— leads to asymmetric hydrosilylation (284, 285 Chapter 9 in this volume) and hence optically active alcohols [cf. Eq. (41)]. 

Supported cationic rhodium(I) phosphine complexes, chiral at a men-thyl moiety, effected hydrogenation of ketones, but the 2-butanol produced from methylethylketone was optically inactive (348). Polystyrene-or silica gel-supported DIOP systems, however, are particularly effective for production of optically active alcohols (up to 60% ee) via asymmetric hydrosilylation of ketones (10, 284, 296, 366, 368 see also Section III, A,4). 

It is possible to use isolated, partially purified enzymes (dehydrogenases) for the reduction of ketones to optically active secondary alcohols. However, a different set of complications arises. The new C H bond is formed by delivery of the hydrogen atom from an enzyme cofactor, nicotinamide adenine dinucleotide (phosphate) NAD(P) in its reduced form. The cofactor is too expensive to be used in a stoichiometric quantity and must be recycled in situ. Recycling methods are relatively simple, using a sacrificial alcohol, or a second enzyme (formate dehydrogenase is popular) but the real and apparent complexity of the ensuing process (Scheme 8)[331 provides too much of a disincentive to investigation by non-experts. 

The hydrogenation of various ketones with heterogeneous Palladium on Carbon or Raney Nickel catalysts in the presence of (S)-proline proceeds to produce the corresponding optically active alcohols with low optical yields (up to 23%). ... 

Various ketones have been converted to optically active alcohols with high optical purity and in high yield using alcohol dehydrogenases. In addition, successful reductions have been performed by catalytic hydrogenation, over Adams catalyst, " Raney nickel, and palladium on carbon, and lithium in tcrf-butyl alcohol/ammonia, and in one case even with lithium dibutylcuprate. ... 

After hydrogen evolution has subsided, the solution is refluxed for 2 hrs. The complex has been shown to eifect asymmetric reduction of ketones optically active alcohols of up to 40% optical purity have been obtained and they all have the (S)-configuration. On the other hand, if increasing quantities of ethanol are added to the lithium aluminum hydride complex, the configuration of the secondary alcohol formed changes from (S) to (R). Thus the stereoselectivity increases to a maximum and then decreases as more ethanol is added. Furthermore, maximum selectivities are substantially increased... 

Asymmetric hydrogenation. The ligand enables the Ru-catalyzed hydrogenation of ketones to afford optically active alcohols (7 examples, -99% yield, ee 91-96%). 

Osawa, T., and Harada, T. (1984) The enantioface-differentiating hydrogenation of the C=0 double bond with asymmetrically modified Raney nickel, XXXVIII. The hydrogenation of methyl ketones to optically active secondary alcohols. Bull. Chem. Soc. Jpn. 57, 1518 -1521. 

Figure 15.16 summarizes a series of optically active alcohols and amines reported (in a review by Blacker at Avecia ) to be produced by the CATHy catalysts. These include the types of products described for the different classes of hydrogenations described in the previous sections. These products include those from the reduction of alkyl aryl ketones, a-ketoesters, aliphatic ketones, a,(3-unsaturated ketones, cyclic ketones, and a-hydroxy ketones. In addition, transfer hydrogenation allows for the asymmetric formation of amines by the reduction of N-diphenylphosphinylimines. These transfer hydrogenations... 

Bodendorf and Krieger (12) established the presence of a ketonic carbonyl group from the IR spectrum of mesembrine hydrochloride which contains a carbonyl absorption at 1715 cm this assignment was confirmed by the conversion of mesembrine to an oxime. Analysis of the alkaloid indicted two methoxyls and a tertiary iV-methyl group. Catalytic hydrogenation of 1 gave a crystalline optically active alcohol, mesembranol (2). 

In addition methyl isobutyl ketone, which could be regarded as a hydrogenation intermediate, does not give an optically active alcohol. Furthermore, the authors were able to find traces of 2-methyl-2 pentene-4-ol in the reaction mixture. Consequently, the authors concluded that a bidentate coordination of both and groups is essential for the asymmetric hydrogenation of mesityl oxide. 

As already mentioned, the secondary alcohols that are obtained are optically active. It should be stressed that the reduction of ketones to carbinols by means of fermenting yeast is completely different from the method of resolution of racemic alcohols by treatment with living microorganisms (Pasteur). In the latter case one of the enantiomorphs is removed by oxidation during metabolism in the former it is produced by true asymmetric hydrogenation, without the intermediate formation of the inactive form, (Cf. Mayer and Levene and Walti. )... 

The procedure for getting the polymer-bound ligands is very easy to reproduce. Three jS-functionalized aromatic ketones were successfully reduced to the corresponding alcohols by heterogeneous asymmetric hydrogen transfer reaction with formic acid-triethylamine azeotrope as the hydrogen donor. One of the product alcohols (19c) is an intermediate for the synthesis of optically active fluoxetine. 

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