Cinchona alkaloids cinchonine

Catalytic enantioselective nucleophilic addition of nitroalkanes to electron-deficient alke-nes is a challenging area in organic synthesis. The use of cinchona alkaloids as chiral catalysts has been studied for many years. Asymmetric induction in the Michael addition of nitroalkanes to enones has been carried out with various chiral bases. Wynberg and coworkers have used various alkaloids and their derivatives, but the enantiomeric excess (ee) is generally low (up to 20%).199 The Michael addition of methyl vinyl ketone to 2-nitrocycloalkanes catalyzed by the cinchona alkaloid cinchonine affords adducts in high yields in up to 60% ee (Eq. 4.137).200... 

The use of compounds with activated methylene protons (doubly activated) enables the use of a mild base during the Neber reaction to 277-azirines. Using ketoxime 4-toluenesulfonates of 3-oxocarboxylic esters 539 as starting materials and a catalytic quantity of chiral tertiary base for the reaction, moderate to high enantioselectivity (44-82% ee) was achieved (equation 240). This asymmetric conversion was observed for the three pairs of Cinchona alkaloids (Cinchonine/Cinchonidine, Quinine/Quinidine and Dihydro-quinine/Dihydroquinidine). When the pseudoenantiomers of the alkaloid bases were used, opposite enantioselectivity was observed in the reaction. This fact shows that the absolute configuration of the predominant azirine can be controlled by base selection. 

Cincholoipon ethyl ester (168), available from the commercial Cinchona alkaloid (+)-cinchonine in 50% overall yield according to the classical... 

Modifier The effect of the modifier structure is also quite similar to that found for a-ketoesters [7]. Cinchonidine derivatives and quinine lead to an excess of the (R)-hydroxy-acid while the pseudo-enantiomeric cinchona alkaloids (cinchonine and quinidine) give preferentially (S)-product but with much lower enantioselecdvity. Changing the substituent Y at C9 has only an effect on the degree of asymmetric induction but not its direction. OMe and OH are more effective than OAc or H. An interesting exception are the Nj alkylated Cd derivatives which are completely ineffective in the case of the ester. Here, N-methyl-Cd+Cr gives a small excess of the R-enantiomer while N-benzyl-Cd Cl leads an 33% excess of (S)-4-phenyl-2-hydroxybutyric acid ... 

The reversibility problem in 1,2-additions is alleviated when imines bearing an electron-poor protecting group at nitrogen (sulfonyl, aeyl, ear-bamoyl) are employed as aeceptor partners, rendering possible even the use of 1,3-dicarbonyl compounds as donors. For example, Sehaus and eoworkers reported the highly enantioselective Mannich reaction of acetoacetates and cyclic 1,3-dicarbonyl compounds with N-carbamoyl imines derived from benzaldehydes and cinnamaldehydes catalysed by the natural Cinchona alkaloid cinchonine (CN) (Scheme 14.15). On the basis of the obtained results they developed a model that accounts for the observed diastereo- and enantioselectivity based on the bifunctional nature of the catalyst, which acts simultaneously as a hydrogen-bond donor and acceptor. 

In addition to flavone synthesis, Hintermann also studied the kinetics and mechanism of natural Cinchona alkaloids (cinchonine and cinhonidine) catalysed oxa-Michael cyclisation of 4-(2-hydroigratyl)-2-hutenoates. Various henzodihydrofuranyl acetates and related products were obtained in up to 99% yield and with 91% ee. ... 

The cinchona alkaloids of practical importance are quinine, quinidine, cinchonine and cinchonidine, but, in addition, over twenty others have been isolated from cinchona and cuprea species. Their names and formulae are as follows ... 

Numerous new salts and additive compounds of cinchona alkaloids, and especially of quinine, have been described, of which only a few can be mentioned as examples quinine additive compounds with sulph-anilamide, t quinine salts of (+) and (—)-pantothenic acid, °( > quinine sulphamate and disulphamate, °( organo-mercury compounds of quinine and cinchonine such as quinine-monomercuric chloride. Various salts and combinations of quinine have also been protected by patent, e.g., ascorbates and nicotinates. 

On these results the primary cinchona alkaloids and their dihydroderivatives arrange themselves in the following descending order of activity (1) dihydroquinine, (2) quinine, (3) dihydroquinidine, (4) cincho-nidine and quinidine, (5) cinchonine, dihydrocinchonidine and dihydrocinchonine. 

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... 

Cinchona alkaloids have been used as drugs for the treatment of several diseases. Quinine is very popular as an antimalarial drug against the erythrocyte stage of the parasite [34]. Recently, Shibuya et al. (2003) reported the microbial transformation of four Cinchona alkaloids (quinine, quini-dine, cinchonidine, and cinchonine) by endophytic fungi isolated from Cin-... 

Fig. 3 Structiu-es of Cinchona alkaloids (quinine, quinidine, cinchonidine, and cinchonine) transformed into their corresponding 1-N-oxide derivatives [34]...

Figure 3.59. Chiral quats derived from cinchona alkaloids R = H, derived from cinchonine, or MeO, derived from quinidine a and b are diastereomers aminoalcohol parts are enantiomeric.

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],... 

The most successful modifier is cinchonidine and its enantiomer cinchonine, but some work in expanding the repertoire of substrate/modifier/catalyst combinations has been reported (S)-(-)-l-(l-naphthyl)ethylamine or (//)-1 -(I -naphth T)eth Tamine for Pt/alumina [108,231], derivatives of cinchona alkaloid such as 10,11-dihydrocinchonidine [36,71], 2-phenyl-9-deoxy-10, 11-dihydrocinchonidine [55], and O-methyl-cinchonidine for Pt/alumina [133], ephedrine for Pd/alumina [107], (-)-dihydroapovincaminic acid ethyl ester (-)-DHVIN for Pd/TiOz [122], (-)-dihydrovinpocetine for Pt/alumina [42], chiral amines such as 1 -(1 -naphtln I)-2-(I -pyrro 1 idiny 1) ethanol, l-(9-anthracenyl)-2-(l-pyrrolidinyl)ethanol, l-(9-triptycenyl)-2-(l-pyrrol idi nyl)cthanol, (Z )-2-(l-pyrrolidinyl)-l-(l-naphthyl)ethanol for Pt/alumina [37,116], D- and L-histidine and methyl esters of d- and L-tryptophan for Pt/alumina [35], morphine alkaloids [113],... 

The structures of quinine, cinchonidine, quinidine, and cinchonine are shown in Figure 3. Other workers (16,17) have discussed these alkaloids and their use as catalysts in some detail. An excellent discussion of cinchona-alkaloid-catalyzed reactions prior to 1968 was given by Pracejus (18). In this section we discuss only four aspects of these reactions. 

These reactions, performed many times, show, in addition to the reversal of the absolute configuration of the product with the change in the configuration at C-8 and C-9 of the alkaloids, a small but reproducible difference in the e.e. of the product. It is evident that the diastereomeric nature of quinine vs. quinidine and cinchonidine vs. cinchonine expresses itself via small but important energy differences in the best fits of the transition states. Noteworthy in this respect is the fine work of Kobayashi (20), who observed larger differences (in the e.e. s of products) when the diastereomeric cinchona alkaloids were used as catalysts after having been copolymerized with acrylonitrile (presumably via the vinyl side chain of the alkaloids). 

FIGURE 1.1 Chemistry and stereochemistry of the native cinchona alkaloids quinine, quinidine, cmchonidme, and cinchonine as well as their corresponding C9-epimeric compounds. 

A copolymerization approach of 0-9-[2-(methacryloyloxy)ethylcarbamoyl] cinchonine and cinchonidine with methacryl-modified aminopropylsilica particles was utilized by Lee et al. [71] for the immobilization of the cinchona alkaloid-derived selectors onto silica gel. The CSPs synthesized by this copolymerization procedure exhibited merely a moderate enantiomer separation capability and only toward a few racemates (probably because they were based on less stereodifferentiating cinchonine and cinchonidine). Moreover, the chromatographic efficiencies of these polymer-type CSPs were also disappointing. 

Rabe P. (1908) Contribution to our knowledge of the Cinchona alkaloids. Vll. Communication on a now oxidation product of Cinchonine. Ber Dtsh Chem Ges 40 3655-3658. 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

The Chen group early in 2005 constituted the novel class of thiourea-function-ahzed cinchona alkaloids with the first reported synthesis and application of thioureas 116 (8R, 9S) and 117 (8R, 9R) prepared from cinchonidine and cinchonine in over 60% yield, respectively (Scheme 6.112) [273]. In the Michael addition of thiophenol to an a,(5-unsaturated imide, the thioureas 116 and 117 displayed only poor stereoinduction (at rt 116 7% ee 117 17% ee), but high catalytic activity (99% yield/2h) (Scheme 6.112). 

Scheme 6.112 Michael addition of thiophenol to an a,p-unsaturated imide catalyzed by cinchonidine-derived thiourea 116 and cinchonine-derived thiourea 117, the first representatives of this class of bifunctional hydrogen-bonding cinchona alkaloid-thioureas.

Asymmetric ring opening of achiral monocyclic, bicyclic and tricyclic anhydrides under formation of the corresponding chiral monoesters can be accomplished in high yield with modest enantioselectivity with methanol in the presence of less than stoichiometric amounts of cinchona alkaloids in toluene or diethyl ether (Table 9)91 94. As expected the use of cinchonine A or quinidine C, and of cinchonidine B or quinine D gives opposite enantiomers. Recrystallization of the monoesters and lactones affords material of considerably higher enantiomeric purity (Table 9, entries 15, 16, 21, and 23). 

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