Alkaloids as Chirality Transmitters in Asymmetric Catalysis

Choong Eui Song    Division of Applied Science Korea Institute of Science and Technology P.O.Box 131, Cheongryang, Seoul 130-650, Korea

I Introduction

During the last decade a number of powerful catalytic asymmetric reactions have emerged as a result of the growing need to develop more efficient and practical synthetic methods for biologically active compounds. A wide variety of chiral ligands and chiral catalysts have been designed and their catalytic efficiency has been investigated. Especially, since the pioneering work (1) of Wynberg, naturally occurring alkaloids have been extensively utilized in asymmetric catalysis as chiral ligands or as chiral catalysts themselves. The parent alkaliods (Figure 1) possess nitrogen surrounded by highly asymmetric environment. They are also inexpensive and readily available in both enantiomeric forms in most cases, and can easily be modified to a variety of different derivatives. A number of processes have gained wide acceptance, and some are even used on an industrial scale, e.g. heterogeneous hydrogenation of α-ketoesters catalyzed by cinchona alkaloid-modified Pt (CibaGeigy) (section II.A.1.), Sharpless asymmetric dihydroxylation of olefins (Chirex Ltd.) (section III.A.1.), asymmetric alkylation of indanones using cinchona alkaloidderived chiral phase-transfer catalysts (Merck) (section IV.A.), and cinchona alkaloid-catalyzed 2,2-cycloaddition of ketene and chloral or trichloroacetone (Lonza) (section IV.I.), etc. This research area has been very fast growing, nevertheless there has been no review, since 1986 when the first review (1) by Wynberg was published. This review is an overview of recent activities in this area.

II Enantioselective Carbon-Hydrogen Bond Formation

A ASYMMETRIC CATALYTIC HYDROGENATION

1 Heterogeneous Asymmetric Carbonyl Hydrogenation

a Asymmetric hydrogenation of α-ketoesters using cinchona alkaloid-modified Pt/Al2O3(or Pt/C) catalysts

Asymmetric hydrogenation of α-ketoesters using cinchona alkaloid-modified Pt/Al2O3(or Pt/C) catalysts (2,3), which was initially developed by Orito (4-7), is one of the most intensively studied areas in asymmetric catalysis, in which alkaloids are used as chirality transmitters. Over the last few years, Blaser (8-15) has made extensive studies of this reaction. Enantioselectivities up to 95% (14) were obtained by optimizing the catalyst, modifier, solvent, and reaction conditions (4-15) (Table I). Pretreatment of platinum on Al2O3 with hydrogen at high temperature (ca. 400 °C) is essential for high optical yields. Increasing the size of platinum particles by increasing the temperature with hydrogen led to more active and enantioselective catalysts (8). Hydrogenation of ethyl 2-oxo-2-phenylethanoate with unpretreated Pt/Al2O3 gave ethyl (-)-2-hydroxy-2-phenylethanoate in only 34% ee. After thermal treatment of the catalyst with hydrogen the ee increased to 84% ee.

The practical utility was demonstrated in the synthesis of ethyl (R)-2-hydroxy-4-phenylbutanoate, an ACE-inhibitor intermediate (16). The reaction with Pt/Al2O3 modified by dihydrocinchonidine can be carried out on 10-200 kg scale in greater than 98% chemical yield and in 79-82% optical yield (2) (Scheme 1).

In the hydrogenation of α-ketoesters in the presence of cinchona alkaloid-modified Pt, alkaloid adsorption leads to a marked increase in reaction rate (15). Accordingly, this reaction can be classified as “ligand-accelerated catalysis (LAC)” (17). The initial rate for the enantioselective hydrogenation of α-ketoesters over chirally modified Pt catalysts is usually 5-20 times higher than that of the unmodified (racemic) reaction. The actual hydrogenation involves two kinds of reaction sites, chirally modified Pt(Ptm) and unmodified Pt(Ptu). Accordingly, the reaction is analyzed in term of a general two-cycle mechanism (Scheme 2). The first cycle is ligand-accelerated catalysis, which exhibits excellent enantioselectivity; the other cycle is a slow, chirally unmodified cycle to produce the racemic product. Both rate and product ee reach a maximum at extremely low concentration of alkaloid, corresponding to an alkaliod/Ptsurf ratio of 0.5 in toluene and 1 in ethanol (15). These data suggest that adsorption of the alkaloid on the metal surface is reasonably strong and/or only a small fraction of the surface is modifiable. A modified ensemble consists of one adsorbed alkaloid and 10-20 Pt atoms.

However, unfortunately, the highly selective reaction is restricted to α-keto esters as substrates. Despite many efforts to broaden the application range of this reaction, the results have been disappointing. Only 20% ee or below, was obtained in the enantioselective hydrogenation of β-diketones, β-ketoesters, aryl alkyl ketones and α-methoxy ketones (18,19). Better enantioselectivities were achieved in the hydrogenation of α-diketones (33-38% ee) (20), 2,2,2-trifluoroacetophenone (56% ee) (21). cyclic ketoamide (47% ee) (22) and α-ketoamides (up to 60% ee) (23).

b Asymmetric hydrogenation of α-ketoesters using cinchona alkaloid-modified Pt/silica (EUROPT-1) catalysts

The well characterized 6.3% Pt/silica (EUROPT- 1) (24-27) catalyst was also developed to be an enantioselective catalyst (28,29) by modifying with alkaloids. The rate for the hydrogenation of α-ketoesters over chirally modified EUROPT-1 catalyst is 25 times higher than that of the unmodified reaction. Modification with alkaloid can be best carried out in ethanol solution in the presence of air using a pre-reduced Pt/silica. Before modification, Pt/silica should be pre-reduced with H2 (1bar) at 100 °C for 1h. This exposure to air confers on the catalysts a high hydrogenation rate and enantioselectivity. In the hydrogenation of α- ketoesters, the highest optical yields exceeded 80% ee when dihydrocinchonidine was used as a chiral modifier. Cinchonidine gave lower enantioselectivity. The superiority of the dihydrocinchonidine modifier, compared to cinchonidine, was ascribed to a different adsorption behavior. Whereas cinchonidine might bond to the surface either with the quinoline ring system or the vinylic double bond, the adsorption of dihydrocinchonidine is only possible by the quinoline ring system (28,29).

Other alkaloids such as codeine, 7,8-dihydrocodeine, brucine and strychnine, adsorbed on Pt/silica (EUROPT-1) also enhanced the rate of hydrogenation of methyl pyruvate and butane-2,3-dione, however, exhibited very low enantioselectivities (1-21% ee) (30).

c Asymmetric hydrogenation of α-ketoesters using cinchona alkaloid-modified finely dispersed polyvinylpyrrolidine(PVP)-stabilized platinum clusters

Very recently, Liu and co workers reported that finely dispersed polyvinylpyrrolidine(PVP)-stabilized platinum clusters modified with cinchonidine catalyzed the asymmetric hydrogenation of α-ketoesters, giving enantiomeric excesses in favor of (R)-(+)-methyl lactate up to 97.6% (31). The cinchonidine-modified PVP-Pt cluster immobilized onto alumina and a cross-linked polystyrene (PS) support also showed high enantioselectivities (91.3% ee for PVP-Pt/Al2O3 and 88.9% ee for PVP-Pt/PS, respectively) for the hydrogenation of methyl pyruvate (31). The reaction runs best over a tiny cluster with a mean size of 1.4 nm (Scheme 4), which is quite different from Pt catalysts supported on aluminium oxide or carbon. As mentioned in section A.1.a., the activity and enantioselectivity of cinchona alkaloid-modified Pt/Al2O3 (or Pt/C) increased by increasing particle size (8). When the particle size of cinchona alkaloid-modified Pt/Al2O3 (or Pt/C) is below 3.0 nm, both the activity and enantioselectivity decreased significantly.

It is also noteworthy that the protonated dihydrocinchonidine also functioned as the stabilizer of the Pt colloid (32). With excessive dihydrocinchonidine added into the reaction mixture to prevent agglomeration of the colloid, the hydrogenation of ethyl pyruvate was conducted at atmospheric pressure, and yielded products with an enantioselectivity of up to 78%. The activity of dihydrocinchonidine-stabilized platinum colloids decreases with increasing particle sizes as a result of decreasing dispersion.

2 Co-Catalyzed Hydrogenation of 1,2-Diketones

Cinchona alkaloids were also used as chirality transmitters in the Co-catalyzed hydrogenation of...