Cinchona modifiers

The molecular modelling approach, taking into account the pyruvate—cinchona alkaloid interaction and the steric constraints imposed by the adsorption on the platinum surface, leads to a reasonable explanation for the enantio-differentiation of this system. Although the prediction of the complex formed between the methyl pyruvate and the cinchona modifiers have been made for an ideal case (solvent effects and a quantum description of the interaction with the platinum surface atoms were not considered), this approach proved to be very helpful in the search of new modifiers. The search strategy, which included a systematic reduction of the cinchona alkaloid structure to the essential functional parts and validation of the steric constraints imposed to the interaction complex between modifier and methyl pyruvate by means of molecular modelling, indicated that simple chiral aminoalcohols should be promising substitutes for cinchona alkaloid modifiers. Using the Sharpless symmetric dihydroxylation as a key step, a series of enantiomerically pure 2-hydroxy-2-aryl-ethylamines... 

Although cinchona-modified Pd showed no enantioselectivity in the hydrogenation of the methyl esters of the unsaturated acids, the hydrogenation of methyl pyruvate occurred with a modest enantiomeric excess... 

Since the initial work of Onto et al. (1) a considerable amount of work has been performed to improve our understanding of the enantioselective hydrogenation of activated ketones over cinchona-modified Pt/Al203 (2, 3). Moderate to low dispersed Pt on alumina catalysts have been described as the catalysts of choice and pre-reducing them in hydrogen at 300-400°C typically improves their performance (3, 4). Recent studies have questioned the need for moderate to low dispersed Pt, since colloidal catalysts with Pt crystal sizes of <2 nm have also been found to be effective (3). A key role is ascribed to the effects of the catalyst support structure and the presence of reducible residues on the catalytic surface. Support structures that avoid mass transfer limitations and the removal of reducible residues obviously improve the catalyst performance. This work shows that creating a catalyst on an open porous support without a large concentration of reducible residues on the Pt surface not only leads to enhanced activity and ee, but also reduces the need for the pretreatment step. One factor... 

Starting from the Pt-cinchona modified system, more recently an interesting concept has been developed by Feast and coworkers [144], A chiral acidic zeolite was created by loading one molecule of iM,3-dithianc-l-oxide per supercage of zeolite Y, either during or after the zeolite synthesis. Other chiral zeolites were formed by adsorbing ephedrine as a modifier on zeolites X and Y for the Norrish-Yang reaction [145],... 

Cinchona-modified platinum catalysts received special interest mainly because of to the results obtained for the hydrogenation of methyl pyruvate (MP) or ethyl pyruvate. E.e. s up to 80% or even higher (98% for ethyl pyruvate) made this system one of the most interesting ones from the application point of view. At present, 5% Pt/alumina with low dispersion (metal particles > 2 nm) and a rather large pore volume constitutes one of the best catalysts commercially available. 

Scheme 14.9 Main features of cinchona-modified metal systems [35],...

The chapter Chiral Modification of Catalytic Surfaces [84] in Design of Heterogeneous Catalysts New Approaches based on Synthesis, Characterization and Modelling summarizes the fundamental research related to the chiral hydrogenation of a-ketoesters on cinchona-modified platinum catalysts and that of [3-ketoesters on tartaric acid-modified nickel catalysts. Emphasis is placed on the adsorption of chiral modifiers as well as on the interaction of the modifier and the organic reactant on catalytic surfaces. 

Enantioselective synthesis is a topic of undisputable importance in current chemical research and there is a steady flow of articles, reviews and books on almost every aspect involved. The present overview will concentrate on the application of solid chiral catalysts for the enantioselective synthesis of chiral molecules which are a special class of fine chemicals. Included is an account on our own work with the cinchona-modified Pt catalysts. Excluded is the wide field of immobilized versions of active homogeneous complexes or of bio-catalysts. During the preparation of this survey, several reviews have been found to be very informative [1-14]. 

This section will be organized according to catalyst systems a) Tartrate modified catalysts, b) Cinchona modified catalysts and c) Electrochemical systems. We are aware of no other reaction types where systematic investigations have been reported. 

The next example originates from our own laboratory Two potential intermediates for the angiotensin-converting enzyme inhibitor benazepril can be synthesized using cinchona modified noble metal catalysts (3). While the hydrogenation of the a-ketoester has been developed and scaled-up into a production process (10-200 kg scale, chemical yield >98%, ee 79-82%), the novel enantioselective hydrodechlorination reaction (see Section in) could be a potential alternative to the established synthesis where the racemic a-bromobenzazepinon is used [75]. At the moment both selectivity and productivity of the catalyst are too low and substitution reactions occur less readily with the chloro analog. 

MASS TRANSFER CONSIDERATIONS FOR THE ENANTIOSELECTIVE HYDROGENATION OF a-KETO ESTERS CATALYZED BY CINCHONA MODIFIED Pt/Al203... 

Recently, the enantioselective hydrogenation of ethyl pyruvate catalyzed by cinchona modified Pt/Al203 (ref. 1) was shown to be a ligand accelerated reaction (ref. 2). The rate of reaction for the fully modified system is more than 10 times faster than the racemic hydrogenation using unmodified catalyst. Under certain reaction conditions, this liquid phase hydrogenation exhibits a turn-over frequency of up to 50 s 1 (3.4 mol/kg-cat s). Emphasis until now has been directed at empirically increasing optical yields (ref. 3,4). 

The transformations that use asymmetric heterogeneous catalysis will be highlighted P-keto esters and diketone reductions by Raney nickel catalyst modified with R,R-tartaric acid and NaBr. a-Keto acid reductions with cinchona modified Pt catalysts are discussed in Chapter 18. 

The stereoselective reduction of a-keto acid derivatives at a preparative scale is performed with cinchona-modified Pt catalyst (see Chapter 18). Enantioselectivities range from 57-95% for the reduction of a-keto acid derivatives5 and is dependent on the preparation of the Pt catalyst.5 22 205 206... 

Novartis (Ciba Geigy) has reported the synthesis of Benazepril (163) (Scheme 12.63), an angiotensin-converting enzyme inhibitor, via an intermediate prepared by cinchona-modified Pt asymmetric hydrogenation (10-200-kg scale, >98%, 79-82% ee).5 The low optical purities can be tolerated because enantio-enrichment is relatively easy in the latter stages of the synthesis.22... 

Novartis (Ciba Geigy) has implemented a cinchona-modified Pt/Al203 catalyst in the asymmetric hydrogenation of a-keto esters for the industrial preparation of Benzaprin. 

The hydrogenation of 2,4-diketo acid derivatives 6-9 to the corresponding 2-hydroxy compounds with cinchona-modified Pt catalysts as depicted in Scheme 18.1 can be carried out with chemoselectivities... 

Substituted aliphatic and aromatic a-keto ethers (Scheme 18.5) are also amenable to enantioselective hydrogenation catalyzed by cinchona-modified Pt catalysts.25 However, as opposed to the prochiral ketones discussed earlier, kinetic resolution is observed for these chiral substrates. At conversions of 20A2%, ee s of 91-98% were obtained when starting with a racemic substrate (see Table 18.5). It is somewhat surprising that a-keto ethers without substituent in the a-position, such as methoxy acetone, reacted very slowly or not at all and led to very low enantioselectivities,6 and from the results described earlier for a-ketoacetals, the same is expected if 2 substituents are present. 

FIGURE 18.6 Structures of good, medium, and bad substrates for cinchona-modified Pt catalysts. 

Systematic investigation of the Pt - cinchona alkaloid system, discovered by Orito et al. in 19797, has led to a better understanding of the a-ketoester-modifier-Pt interaction. It has been therefore possible to increase the enantioselectivities of the original reaction and, more importantly, to broaden the application range of cinchona-modified platinum. 

Several zeolites have been used as supports for cinchona modified Pt in the enantioselective hydrogenation of a-ketoesters such as ethyl pyruvate ... 

Blaser HU, Jalett HP, Muller M, Studer M (1997) Enantioselective hydrogenation of a-Ketoesters using cinchona modified platinum catalysts and related systems. Catal Today 37 441... 

In this chapter, we do not attempt to give a comprehensive overview of the field, but we would rather concentrate on results where both enantioselectivity and catalyst activity are relevant to preparative application. In the first section, results obtained with cinchona-mediated homogeneous systems for the reduction of ketones are briefly reviewed. Then, heterogeneous cinchona-modified Pt catalysts applied to the hydrogenation of a-functionalized ketones and cinchona-modified Pd catalysts for the hydrogenation of activated C=C bonds are discussed from a synthetic point... 

The hydrogenation of 2,4-diketo acid derivatives to the corresponding 2-hydroxy compounds with cinchona-modified Pt catalysts as depicted in Figure 2.4 can be carried out with chemoselectivities more than 99% and enantioselectivities up to 87% (R) and 68% (S), respectively [30a]. Enrichment to more than 98% ee was possible for several substrates by recrystallization, giving rise to an efficient technical synthesis of (R)-2-hydroxy-4-phenyl butyric acid ethyl ester [30b], a building block for several ACE (angiotensin-converting enzyme) inhibitors, as well as some enantio-merically enriched a-hydroxy and a-amino acid esters (see below) [30c]. 

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