Cinchonine catalysis

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],... 

Epoxidation is another important area which has been actively investigated on asymmetric phase transfer catalysis. Especially, the epoxidation of various (i.)-a,p-unsaturated ketones 68 has been investigated in detail utilizing the ammonium salts derived from cinchonine and cinchonidine, and highly enantioselective and diastereoselective epoxidation has now been attained. When 30 % aqueons H202 was utilized in the epoxidation of various a, 3-unsaturated ketones 68, use of the 4-iodobenzyl cin-choninium bromide 7 (R=I, X=Br) together with LiOH in Bu20 afforded the a,p-epoxy ketones 88 up to 92% ee,1641 as shown in Table 5. The O-substituted... 

In 1992, O Donnell succeeded in obtaining optically active a-methyl-a-amino acid derivatives 49 in a catalytic manner through the phase-transfer alkylation of p-chlorobenzaldehyde imine of alanine tert-butyl ester 48 with cinchonine-derived la as catalyst (see Scheme 4.16) [46]. Although the enantioselectivities are moderate, this study is the first example of preparing optically active a,a-dialkyl-a-amino acids by chiral phase-transfer catalysis. 

BQC is derived from quinine, which is a member of the cinchona family of alkaloids. Ammonium salts derived from quinidine, a diastereomer of (1) at the hydroxyl substituent, have been used less frequently in catalysis than BQC. Quini-dinium salts often give rise to products with enantioselectivity opposite to that from (1). Other related compounds, such as those derived from cinchonine and cinchonidine (which lack the methoxy substituent on the quinoline nucleus), have found application in organic synthesis. The cinchona alkaloids, as well as salt derivatives in which the benzyl group bears various substituents, have also been studied. Results from polymer-bound catalysts have not been promising. ... 

As mentioned in the previous section, nowadays, readily available and inexpensive cinchona alkaloids with pseudoenantiomeric forms, such as quinine and quinidine or cinchonine and cinchonidine, are among the most privileged chirality inducers in the area of asymmetric catalysis. The key feature responsible for their successful utility in catalysis is that they possess diverse chiral skeletons and are easily tunable for diverse types of reactions (Figure 1.2). The presence of the 1,2-aminoalcohol subunit containing the highly basic and bulky quinuclidine, which complements the proximal Lewis acidic hydroxyl function, is primarily responsible for their catalytic activity. 

On the basis of the significant kinetic isotope effect (kMeOH/ MeOD = 2.3) in the cinchonine (1, 10 mol%)-catalyzed ring opening of cis-2,4-dimethylglutaric anhydride by methanol (20 equiv) in toluene, Oda proposed the general base catalysis mechanism depicted in Scheme 11.5 [3a, b]. Another comparative study on the reaction rates (k0bs) obtained with different bases (cinchonidine (2.26 x 10-3), quinuclidine (2.26 x 10 3), and quinoline (4.34 x 10-5)) and with different... 

Another well-known example of catalytic asymmetric hydrogenation is the synthesis of L-Dopa (an anti-Parkinson drug) developed by Monsanto [315], which is schematically reported in Figure 2.56, where the role of the chiral phosphine ligand is also highlighted. Various attempts have been also reported to use heterogeneous asymmetric catalysis (cinchonine modified Pd/C) to produce L-Dopa, although the results are still unsatisfactory [316]. 

The mechanism of enamine catalysis has been established the enamine is the active form of nucleophile. Other modes of activation are less developed and are limited to a certain group of donors and acceptors. Quinidine was found to catalyze the reaction of hydroxyacetone with aldehydes to yield the desired 5y -aldols with moderate diastereoselectivity and low enantioselectivity [169]. This represents the first example of a tertiary amine catalyzing the direct aldol reaction. Even (3, y-unsaturated a-keto ester 154 was successfidly coupled with protected hydroxyacetone 51 in the presence of 20 mol% of 9-amino-9-deoxy-cpi-cinchonine 155 and a small amount of TEA (Scheme 3.27). 

A vinylogous Michael addition of Q, j0-unsaturated y-butyrolactams (175) to a,p-unsaturated ketones has been shown to produce (176) (>30 1 dr, <99% ee) when catalysed by the triamine derivative (177). Catalysis by the cinchonine-derived thiourea (166b) afforded its diastereoisomer (>40 1 dr, <99% ee) ... 

Another novel extension of asymmetric organocatalysis was reported by Hintermann and Schmitz towards the successful development of an organo-catalytic enantioselective double-bond isomerisation, which has been previously associated with the field of metal catalysis. Therefore, an asymmetric synthesis of the 2,5-diphenylphosphol-2-ene fragment was achieved via the enantioselective cinchonine-catalysed double-bond isomerisation of a wc50-2,5-diphenyl-phosphol-3-ene amide into a 2,5-diphenylphosphol-2-ene amide with an enantioselectivity of up to 83% ee (Scheme 10.10). This new asymmetric concept opened the way to a catalytic enantioselective synthesis of 2,5-diarylphospho-lane building blocks for many applications in transition metal catalysis. 

Iminium ion catalysis was demonstrated by Deng and coworkers for the conjugate addition of a,a-dicyanoalkenes to benzylideneacetone with the use of a TFA salt of 36 [100] and by Chen and coworkers for the Friedel-Crafts reaction of indoles with a, 3-unsaturated ketones [101] as catalyzed by the C9 amino derivative of cinchonine 42 (Scheme 6.47). 

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