Catalysts Modified with Cinchona Alkaloids

Since these are the only heterogeneous enantioselective catalysts with significant synthetic and industrial apphcation, a somewhat more detailed description of their scope and hmitations is provided. For recent updates, the reader is referred to Ref. [19]. 

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Enantioselective Hydrogenation of Activated Ketones Using Heterogeneous Pt Catalysts Modified with Cinchona Alkaloids... 

Heterogeneous Pt and Pd Catalysts Modified with Cinchona Alkaloids 15... 

Studer, M. and Blaser, H.U. (2005) Enantioselective hydrogenation of activated ketones using heterogeneous Pt catalysts modified with cinchona alkaloids, in Handbook of Chiral Chemicals, 2nd edn, CRC Press LLC, Boca Raton, pp. 345-57. 

Salen palladium(II) complexes have been reported to be effective homogeneous, or when immobilized, to be active heterogeneous catalysts for the hydrogenation of alkenes [1,2]. It is also known that platinum(O) catalysts modified with cinchona alkaloids catalyze the enantioselective hydrogenation of a-ketoesters to the corresponding a-hydroxyesters[3]. The platinum(O) catalyst is attached to AI2O3 [4] or to zeolites [5,6]. 

Following on from the Orito work [20], Wells and co-workers studied the hydrogenation of metl pyruvate (MeOO.CXX)Me) to methyl lactate (MeCH(OH)OOOMe) over supported platinum catalysts modified with cinchona alkaloids. 

ENANTIOSELECTIVE HYDROGENATION OF a-KETOACIDS USING PLATINUM CATALYSTS MODIFIED WITH CINCHONA ALKALOIDS. 

Niwa, S., Imai, S., Onto, Y. (1980) As5Tnmetric hydrogenation of alpha-keto esters using platinum-alumina catalyst modified with cinchona alkaloid, J. Chem. Soc. Jpn. Nippon Kagaku Kaishi) N4, 670-672. 

Blaser, H.U., Boyer, S.K., Pittelkow, U. (1991) The heterogeneous enantioselective hydrodehalogenation of alpha, alpha-dichlorobenzazepinone-2 a unique case of substrate specificity. Tetrahedron Asymm. 2, 721-732. Blaser, H.U., Jalett, H.P. (1993) Enantioselective hydrogenation of alpha-keto acids using Platinum catalysts modified with cinchona alkaloids. Stud. Surf. Sci. Catal. 78, 139-146. 

The enantioselective hydrogenation of prochiral substances bearing an activated group, such as an ester, an acid or an amide, is often an important step in the industrial synthesis of fine and pharmaceutical products. In addition to the hydrogenation of /5-ketoesters into optically pure products with Raney nickel modified by tartaric acid [117], the asymmetric reduction of a-ketoesters on heterogeneous platinum catalysts modified by cinchona alkaloids (cinchonidine and cinchonine) was reported for the first time by Orito and coworkers [118-121]. Asymmetric catalysis on solid surfaces remains a very important research area for a better mechanistic understanding of the interaction between the substrate, the modifier and the catalyst [122-125], although excellent results in terms of enantiomeric excesses (up to 97%) have been obtained in the reduction of ethyl pyruvate under optimum reaction conditions with these Pt/cinchona systems [126-128],... 

In fact, there are only two heterogeneous catalysts that reliably give high enantioselectivities (e.s. s) (90% e.e. or above). These are Raney nickel (or Ni/Si02) system modified with tartaric acid (TA) or alanine for hydrogenation of /(-kctocstcrs [12-30], and platinum-on-charcoal or platinum-on-alumina modified with cinchona alkaloids for the hydrogenation of a-ketoesters [31-73],... 

In contrast to Raney nickel catalysts ( 3.4.1), heterogeneous hydrogenation catalysts based on Pt, Rh or Pd do not induce asymmetry in the presence of tartaric acid [113, 578], Platinum catalysts modified by cinchona alkaloids 3.1 and 3.2 cause asymmetric hydrogenation of the carbonyl group of a-ketoesters with a high enantiomeric excess (> 90%). From other types of ketones, the enantioselectivities are lower. 

Alternatively, the surface of a metal can be modified with an enantiomerically pure additive. For example, in 1956 palladium metal/silk fibroin was used for the hydrogenation of alkenes with moderate enantioselectivity. However, most success with modified metal siufaces has been achieved in the hydrogenation of ketones. The reduction of 3-keto esters with a Raney nickel/tartaric acid/sodium bromide catalyst provides good enantioselectivities. For example, P-keto ester (3.108) affords the P-hydroxy ester (3.109). Platinum metal modified with cinchona alkaloids has been successfully used with a-keto esters. The reaction yields product with up to 90% ee in the reduction of a-keto ester (3.110). ... 

Catalytic asymmetric hydrogenation is a relatively developed process compared to other asymmetric processes practised today. Efforts in this direction have already been made. The first report in this respect is the use of Pd on natural silk for hydrogenating oximes and oxazolones with optical yields of about 36%. Izumi and Sachtler have shown that a Ni catalyst modified with (i ,.R)-tartaric acid can be used for the hydrogenation of methylacetoacetate to methyl-3-hydroxybutyrate. The group of Orito in Japan (1979) and Blaser and co-workers at Ciba-Geigy (1988) have reported the use of a cinchona alkaloid modified Pt/AlaO.i catalyst for the enantioselective hydrogenation of a-keto-esters such as methylpyruvate and ethylpyruvate to optically active (/f)-methylacetate and (7 )-ethylacetate. 

Okamura and Nakatani [65] revealed that the cycloaddition of 3-hydroxy-2-py-rone 107 with electron deficient dienophiles such as simple a,p-unsaturated aldehydes form the endo adduct under base catalysis. The reaction proceeds under NEtj, but demonstrates superior selectivity with Cinchona alkaloids. More recently, Deng et al. [66], through use of modified Cinchona alkaloids, expanded the dienophile pool in the Diels-Alder reaction of 3-hydroxy-2-pyrone 107 with a,p-unsaturated ketones. The mechanistic insight reveals that the bifunctional Cinchona alkaloid catalyst, via multiple hydrogen bonding, raises the HOMO of the 2-pyrone while lowering the LUMO of the dienophile with simultaneous stereocontrol over the substrates (Scheme 22). 

Most of the studies of Pt catalysts with cinchona alkaloids have focused on the hydrogenation of a-keto esters, especially ethyl pyruvate, as shown above, However, enantioselective hydrogenation of ketopantolactone and l-ethyl-4,4-dimethylpyrrolidine-2,3,5-trione is attainable with a Pt catalyst modified by cinchonidine, giving the corresponding R alcohols with 92% ee and 91% ee, respectively (Scheme 1.40) [213]. These reactions can be performed with an S/C of up to 237,000 [213a],... 

Consequently, Dehmlow and coworkers modified the cinchona alkaloid structure to elucidate the role of each ofthe structural motifs of cinchona alkaloid-derived chiral phase-transfer catalysts in asymmetric reactions. Thus, the quinoline nucleus of cinchona alkaloid was replaced with various simple or sterically bulky substituents, and the resulting catalysts were screened in asymmetric reactions (Scheme 7.2). The initial results using catalysts 8-11 in the asymmetric borohydride reduction of pivalophenone, the hydroxylation of 2-ethyl-l-tetralone and the alkylation of SchifF s base each exhibited lower enantiomeric excesses than the corresponding cinchona alkaloid-derived chiral phase-transfer catalysts [14]. 

Platinum catalysts modified with members of the cinchona alkaloids are effective enantioselective catEilysts for the hydrogenation of a keto esters giving the chiral a hydroxy esters with ee s as high as 95%. >72 of the cinchona alkaloids, cinchonidine (30) and cinchonine (31) appear to be more effective than quinine (32) and quinidine (33). With cinchonidine the (R) lactate, 34, is... 

Other transition metal catalysts modified with tartaric acid have been used. Tartaric acid is not a good modifier with Pt. Cinchona alkaloids efficiently modify Pt, Pd, Rh, and reduce the carbonyl group of a-ketoesters ... 

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