Enantioselective hydrogenation cinchona alkaloids

Not so long ago, the general opinion was that high enantioselectivity can only be achieved with natural, structurally unique, complex modifiers as the cinchona alkaloids. Our results obtained with simple chiral aminoalcohols and amines demonstrate the contrary. With enantiomeric excesses exceeding 80%, commercially available naphthylethylamine is the most effective chiral modifier for low-pressure hydrogenation of ethyl pyruvate reported to... 

The hydrogenation of methyl pyruvate proceeded over 4% Pd/Fe20 at 293 K and 10 bar when the catalyst was prepared by reduction at room temperature Racemic product was obtained over utunodified catalyst, modification of the catalyst with a cinchona alkaloid reduced reaction rate and rendered the reaction enantioselective. S-lactate was formed in excess when the modifier was cinchonidine, and R-lactate when the modifier was cinchonine... 

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. 

Pt/Al2C>3-cinchona alkaloid catalyst system is widely used for enantioselective hydrogenation of different prochiral substrates, such as a-ketoesters [1-2], a,p-diketones, etc. [3-5], It has been shown that in the enantioselective hydrogenation of ethyl pyruvate (Etpy) under certain reaction conditions (low cinchonidine concentration, using toluene as a solvent) achiral tertiary amines (ATAs triethylamine, quinuclidine (Q) and DABCO) as additives increase not only the reaction rate, but the enantioselectivity [6], This observation has been explained by a virtual increase of chiral modifier concentration as a result of the shift in cinchonidine monomer - dimer equilibrium by ATAs [7],... 

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],... 

As mentioned, the most studied reaction using these modified catalysts is the enantioselective hydrogenation of MP or ethyl pyruvate to the corresponding lactates using cinchona alkaloids... 

The best studied systems are the Raney Ni/tartaric acid/NaBr combination, for the hydrogenation of / -functionalized ketones, and the Pt- and Pd-on-support/cinchona alkaloid systems for the enantioselective hydrogenation of a-functionalized ketones. 

Much work [42] has been devoted to cinchona alkaloid modified Pd and Pt catalysts in the enantioselective hydrogenation of a-keto esters such as ethyl pyruvate (Scheme 5.11). Optimal formulation and conditions include supported Pt, the inexpensive (—)-cinchonidine, acetic acid as solvent, 25 °C and 10-70 bar H2. Presently, the highest e.e. is 97.6% [to (R)-ethyl lactate]. 

Enantioselective hydrogenation of a-ketoesters on cinchona alkaloid-modified Pt/Al203 is an interesting system in heterogeneous catalysis [143-146], The key feature is that on cinchonidine-modified platinum, ethyl pyruvate is selectively hydrogenated to R-ethyl lactate, whereas on einchonine-modified platinum, S-ethyl pyruvate is the dominant product (Figure 16) [143]. 

Figure 16. Main features in enantioselective hydrogenation of a-ketoesters on cinchona alkaloid-modified metal catalysts [ 143]. [Reproduced with permission of Elsevier from Baiker, A. J. Mol. Catal. A 1997,115, 473-493.]...

A new cinchona alkaloid-derived catalyst has been developed for the enantioselective Strecker reaction of aryl aldimines via hydrogen-bonding activation. For reference, see Huang, J. Corey, E. J. Org. Lett. 2004, 6, 5027-5029. 

New catalyst design further highlights the utility of the scaffold and functional moieties of the Cinchona alkaloids. his-Cinchona alkaloid derivative 43 was developed by Corey [49] for enantioselective dihydroxylation of olefins with OsO. The catalyst was later employed in the Strecker hydrocyanation of iV-allyl aldimines. The mechanistic logic behind the catalyst for the Strecker reaction presents a chiral ammonium salt of the catalyst 43 (in the presence of a conjugate acid) that would stabilize the aldimine already activated via hydrogen-bonding to the protonated quinuclidine moiety. Nucleophilic attack by cyanide ion to the imine would give an a-amino nitrile product (Scheme 10). 

The modification of platinum-group metals by adsorbed chiral organic modifiers has emerged as an efficient method to make catalytic metal surfaces chiral. The method is used to prepare highly efficient catalysts for enantioselective hydrogenation of reactants with activated C = O and C = C groups. The adsorption mode of the chiral modifier is crucial for proper chiral modification of the active metal surfaces. The most efficient chiral modifiers known today are cinchona alkaloids, particularly CD, which yields more than 90% enantiomeric excess in the hydrogenation of various reactants. 

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],... 

A highly enantioselective direct Mannich reaction of simple /V-Boc-aryl and alkyl- imines with malonates and /1-kclo esters has been reported.27 Catalysed by cinchona alkaloids with a pendant urea moiety, bifunctional catalysis is achieved, with the urea providing cooperative hydrogen bonding, and the alkaloid giving chiral induction. With yields and ees up to 99% in dichloromethane (DCM) solvent, the mild air- and moisture-tolerant method opens up a convenient route to jV-Boc-amino acids. 

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

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