Enantioselective hydrogenation of isophorone

Highly mesoporous carbon supported Pd catalysts were prepared using sodium formate and hydrogen for the reduction of the catalyst precursors. These catalysts were tested in the enantioselective hydrogenation of isophorone and of 2-benzylidene-l-benzosuberone. The support and the catalysts were characterized by different methods such as nitrogen adsorption, hydrogen chemisorption, SEM, XPS and TPD. 

In the enantioselective hydrogenation of isophorone in the presence of (-)-DHVIN modifier the best optical purity was afforded by small dispersion (<0,05) Pd black catalyst (up to 55%) (7). The influence of the preparation method of Pd black on the optical yield was reported (8). A correlation was found between the oxidation state of the metal surface and the enantioselectivity, the catalyst having more oxidised species on its surface giving higher enantiomeric excess, while the Pd black with lower surface area was more enantioselective. 

Table 4 Enantiomeric excesses in the enantioselective hydrogenation of isophorone and 2-benzyl- 1-benzosuberone on highly mesoporous carbon supported Pd catalysts.

Scheme 10.9 Enantioselective hydrogenation of isophorone over ethyl dihydroapovincaminate-modified palladium black, and the best product ee-value.

Hydrogenation reactions studied have been those of benzene [92], cyn-namaldehyde [93], and the enantioselective hydrogenation of isophorone and... 

Sipos and co-workers studied enantioselective hydrogenation of isophorone and 2-benzylidene-l-benzosuberone using Pd catalysts supported on mesoporous carbon xerogels [94]. Enantioselective hydrogenation reactions can be strongly affected by the type of support and catalyst [97,98]. A carbon xerogel and its... 

Farkas and Tungler et al. studied the support effects in the enantioselective hydrogenation of isophorone over Pd catalysts prepared on different carbon supports with different specific surface areas and on activated carbons with different surface chemistries. The Pd catalysts, obtained by different reduction methods of the catalyst precursors had different dispersions, and the... 

S)-Proline based chiral modifier esters and amides containing aromatic rings were used in the enantioselective hydrogenation of isophorone and EtPy (Sipos et al. ). 

Sipos et al. " considered the characteristics of Pd-titania catalysts modified with (-)-DHVin in the enantioselective hydrogenation of isophorone. They used supports that were different in crystalline forms and in surface areas. 

Table 5.9. A comparison of enantioselective hydrogenation of isophorone (reaction 1) on Pd and ethyl pyruvate (reaction 2) on Pt catalysts modified with DHVin isomers and DHCnd (according to Tungler, Sheldon...

Farkas, G, Hegedus, L., Tungler, A., Mathe, T., Figueiredo, J.L., Freitas, M. (2000) Effect of carbon support properties on enantioselective hydrogenation of isophorone over palladium catalysts modified with (-)-dihydroapovincaminic acid ethyl ester, J. Mol Catal A Chem. 153, 215-219. 

In the hydrogenation of isophorone the catalyst type 1 of smaller dispersion resulted in higher enantiomeric excesses especially with DPPM modifier. In the hydrogenation of 2-benzylidene-l-benzosuberone the catalyst type 2 of higher dispersion was more enantioselective. These reverse tendencies or smaller relative difference in e.e. for the latter reaction can be attributed to the use of modifiers with totally different structure and working mode. 

New modifiers have traditionally been discovered by the trial-and-error method. Many naturally occurring chiral compounds (the chiral pool38) have been screened as possible modifiers. Thus, the hydrogenation product of the synthetic drug vinpocetine was discovered to be a moderately effective modifier of Pt and Pd for the enantioselective hydrogenation of ethyl pyruvate and isophorone.39 Likewise, ephedrine, emetine, strychnine, brucine, sparteine, various amino acids and hydroxy acids, have been identified as chiral modifiers of heterogeneous catalysts.38... 

The hydrogenation of isophorone and acetophenone in the presence of (S )-proline shows some similarities. The effect of Pd-C-(5 )-prohne system is based on the addition reaction of the reactants and (S)-proline in solution and on the chemoselectivity of Pd. Both hydrogenations should be termed diastereoselective rather than enantioselective, since the asymmetric induction takes place in the adduct molecules. 

Enantioselective hydrogenation of ethyl pyruvate and isophorone over modified Pt and Pd catalysts... 

A vinca-type alkaloid, (-)-dihydroapovincaminic acid ethyl ester (Fig. 8) afforded up to 55 % ee in the hydrogenation of isophorone to the corresponding cyclic ketone [46]. The authors assumed that a H-bond between the protonated N atom of the alkaloid and the carbonyl O atom of isophorone was responsible for the enantioselectivity [47]. 

The apolar toluene and the acetic acid were found to be unfavourable both in the hydrogenation of ethyl pyravate and in the hydrogenation of isophorone. It is interesting that adding water to methanol led to increase in the optical purity of dihydro-isophorone, but resulted in the conplete loss of enantioselectivity in the case of etiiyl pyravate. The possible explanation may be that considerable... 

In order to verify the existence of a chiral intermediate with kinetic methods too, we studied the effect of concentration of the chiral auxiliary on rate and enantioselectivity in hydrogenation of isophorone and acetophenone with Pd/C-(S)-proline. 

Nitta, Y., Kubota, T., Okamoto, Y. (2000) Preparation of cinchonidine-modified Palladium catalysts for the enantioselective hydrogenation of ( )-fl// /ifl-Phenylcinnamic acid. Bull. Chem. Soc. Jpn., 73,2635-2641. Tungler, A., Nitta, Y., Fodor, K., Farkas, G., Mathe, T. (1999) Comparison of chiral modifiers in the Pd catalysed hydrogenation of phenylcinnamic acid and isophorone, J. Mol. Catal. A. Chem. 149, 135-MO. 

Fodor, K., Timgler, A., Mathe, T., Szabo, S., Sheldon, R.A. (1998) Effect of poisoning and metal adsorption on the enantioselective heterogeneous catalytic hydrogenation of isophorone and ethyl pyruvate. Chemical Industries Series Catalysis of Organic Reactions, Herkes F.E., ed.),((Dekker) 75,115-127. 

The enantioselective reduction of a prochiral substrate to produce a nomacemic chiral product is of cracial importance in organic synthesis. One way to achieve this goal is by using an asymmetric catalyst. For example, the asymmetric hydrogenation of isophorone was achieved in 80% ee by using (,S)-proline as a chiral ligand. Thus, the enantioselective reduction of isophorone was achieved in the presence of Pd/C with stoichiometric amounts of the chiral ligand in methanol at room temperature (Scheme... 

Enantioselection in the proline-modified asymmetric hydrogenation of isophorone on supported Pd catalysts can serve as an example of such cascade (Fig. 8.34). 

Fig. 8.34 The general scheme and major products of proline-modified Pd-catalyzed hydrogenation of isophorone. (From C Schafer, S.C Mhadgut, N. Kugyela, M. Torok, B. Torok, Proline-induced enantioselective heterogeneous catalytic hydrogenation of isophorone on basic polymer-supported Pd catalysts, Catal. Sci. Technol. 5 (2015) 716-723. Copyright 2015 Royal Society of Chemistry).

The type of catalyst strongly influences the enantioselectivity of heterogeneous catalytic hydrogenations (1). In the enantioselective saturation of the C=C bond of isophorone over (-)-dihydroapovincaminic acid ethyl ester ((-)-DHVIN) modified Pd catalysts (scheme 1) the optical purity strongly depended on the type and properties of the support used (2, 3, 4). 

Reduction of C=C Bonds. The reduction of the C=C double bond of isophorone (26) with Pd/C in the presence of (S)-proline yields the saturated ketone (27) with 60% optical purity (eq 10). - With (S)-proline ester/Pd (or Pt) systems the hydrogenation of ethyl pyruvate, an a-keto ester, was investigated, but only insignificant enantioselectivities were reached. ... 

The present study aimed at revealing the mode of enantiodifferentiation in the asymmetric hydrogenation of ethyl pyruvate and isophorone over platinum and palladium catalysts. The effect of adding the modifier after an initial phase of racemic hydrogenation and the combined use of different vinca and cinchona type modifiers on enantioselectivity and activity were studied. A mechanistic rationale is proposed to account for the experimental observations. 

Kinetic investigation of the Pd/carbon-(S)-proline system in reduction of isophorone and acetophenone and comparison with known enantioselective hydrogenations were carried out. An addition reaction of (S)-proline with the substrates, and the selective hydrogenation of this adduct results in the optically active products, the kinetic analysis verified this mode of action these are rather diastereoselective reactions. 

Recently we published about enantioselective hydrogenations with palladium on carbon catalysts where (S)-proline i was the chiral auxiliary. C=C double bond (isophorone 3,3,5-trimethyl-l-oxo-2-cyclohexene) and carbonyl-group (acetophenone) were reduced with ee s enantiomeric excess (ee) [%]= ([R]-[S])/([R]+[S])xl00 up to 80% [9-12]. An addition and/or condensation between (S)-proline 1 and the unsaturated reactants 2 was proved, the chemo and diastereoselective hydrogenation of this adduct 3, 4 results in the optically active products (Scheme 1.). 

Vinpocetine is a synthetic medicine which is used in the treatment of oxygen-deficiency of the brain and is quite available (trade mark "Cavintone"). DHVin was prepared by hydrogenation of vinpocetine and consisted of a mixture of diastereomers at the C14 centers (-)- and (+)-stereoisomers in the ratio of 91 8. The catalytic system of 5% Pd-C-DHVin proved to be enantioselective in the hydrogenation of the C=C bond in isophorone and the C=0 bond in methyl pyruvate, which also was enantioselectively hydrogenated on Pt-alumina-DHVin catalyst. 

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