Cinchona alkaloids compounds

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. 

Work also prepared a series of carbinolamines and polyamines without a quinoline nucleus but, in other respects, conforming in type and range of molecular weight, with quinoline compounds known to possess plasmocidal activity. As none of these were active, it seems clear that the quinoline nucleus in the cinchona alkaloids and in certain synthetic anti-malarials is a potent factor in the production of plasmocidal action. Later the same author made (1942) a series of lepidylamine derivatives of the form R. Q. CHj. NH[CH2] . NEtj, which were found to be inactive, in spite of their similarity to the active examples of the type R. Q. NH[CH2] . NEt2 prepared by Magidson and Rubtzow. Rubtzow (1939) has also shown that an isomeride of dihydroquinine (II) with the quinuclidine nucleus attached via the carbinol group at C in the quinoline nucleus was inactive in an infection of Plasmodium prcecox in finches. 

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

Several examples exist of the application of chiral natural N-compounds in base-catalyzed reactions. Thus, L-proline and cinchona alkaloids have been applied [35] in enantioselective aldol condensations and Michael addition. Techniques are available to heterogenize natural N-bases, such as ephedrine, by covalent binding to mesoporous ordered silica materials [36]. 

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

The aim of this review is to summarize the difficulties likely to be encountered in the LC separation of basic solutes, which include the majority of pharmaceutical and also many biomedically important compounds. An answer to the problem of the separation of the cinchona alkaloids, fit for purpose, was obtained on the Hypersil column by adding the silanol blocking agent hexylamine to the mobile phase, which allowed the extra separation power of the smaller particle column to be exploited [3]. However, alternative solutions to the problem, which will be explored in this review, are more appropriate in particular circumstances there is no universal solution that is applicable in all cases. The present review will concentrate on the most recent developments in this subject for the past few years. Further background information can be found in earlier reviews by the present author [4,5] and by Snyder [6]. 

The use of diazodicarboxylates has been recently explored in Cinchona alkaloid catalyzed asymmetric reactions. Jprgensen [50] reported the synthesis of non-biaryl atropisomers via dihydroquinine (DHQ) catalyzed asymmetric Friedel-Crafts ami-nation. Atropisomers are compounds where the chirality is attributed to restricted rotation along a chiral axis rather than stereogenic centers. They are useful key moieties in chiral ligands but syntheses of these substrates are tedious. 

Uozumi has explored a series of (25, 4/ )-4-hydroxyproline-derived 2-aryl-6-hydroxy-hexahydro-lFf-pyrrolo[l,2-c]imidazolones as potential alternatives to cinchona alkaloid-based catalysts for the alcoholative ASD of meio-anhydrides (Fig. 16) [226]. Uozumi screened a small library of catalysts prepared by a four-step, two-pot reaction sequence from 4-hydroxyproline in combination with an aldehyde and an aniline. The most selective member, compound 67, mediated the methanolytic ASD of cw-hexahydrophthalic anhydride in 89% ee when employed at the 10 mol% level for 20 h at -25 °C in toluene [226]. 

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. 

A solid-phase sulfur oxidation catalyst has been described in which the chiral ligand is structurally related to Schiff-base type compounds (see also below). A 72% ee was found using Ti(OPr-i)4, aqueous H2O2 and solid-supported hgand 91 . More recently, a heterogeneous catalytic system based on WO3, 30% H2O2 and cinchona alkaloids has been reported for the asymmetric oxidation of sulfides to sulfoxides and kinetic resolution of racemic sulfoxides. In this latter case 90% ee was obtained in the presence of 92 as chiral mediator. ... 

To improve the position selectivity in the AD of oligoprenyl compounds bis-cinchona alkaloid ligand 8 was introduced by Corey 15,6]. Its design was based on the [3+2]-cycloaddition model for the AD mechanism, which will be discussed in Section 6E. 1.2. The two 4-heptyl ether substituents of the quinolines are supposed to assist fixation of the substrate in the binding cleft. Additionally, the jV-methylquinuclidinium unit and the linking naphthopyridazine were introduced to rigidify the osmium tetroxide complex of 8 [6],... 

Early work from the McIntosh group [1 lh,85] and extensive research from the Dehmlow group [24e-i,48b] concerning chiral catalyst design is noted. Recently, Lygo and co-workers have reported short enantio- and diastereoselective syntheses of the four stereoisomers of 2-(phenylhydroxymethyl)quinuclidine. The authors report that these compounds, which contain the basic core structure of the cinchona alkaloids, will be examined as possible chiral control elements in a variety of asymmetric transformations [86]. 

The effect of the nature of the cinchona alkaloid component was then investigated (Scheme 4.4). The cinchonine-derived PTC 9, which are in pseudoenantiomeric relationship to the cinchonidine-derived compound 7, produced the opposite... 

Esters 16b,c are used in reactions catalyzed by cinchona alkaloid-based phase-transfer catalysts, since the size of the ester is important for efficient asymmetric induction in these reactions [35], However, the syntheses of esters 16b,c adds considerable cost to any attempt to exploit this chemistry on a commercial basis. Fortunately, it was possible to develop reaction conditions which allowed the readily available and inexpensive substrate 16a to be alkylated with high enantios-electivity using catalyst 33 and sodium hydroxide, as shown in Scheme 8.18 [36]. The key feature of this modified process is the introduction of a re-esterification step following alkylation of the enolate of compound 16a. It appears that under... 

Both experimental and theoretical studies have been reported of fluoro-denitration and fluoro-dechlorination reactions using anhydrous tetrabutylammonium fluoride in DMSO. The absences of ion pairing and strong solvation are critical in contributing to the reactivity of the fluorinating agent24 Quaternary ammonium salts derived from cinchona alkaloids have been shown to be effective catalysts in an improved asymmetric substitution reaction of /1-dicarbonyl compounds with activated fluoroarenes. The products may be functionalized to yield spiro-oxindoles.25... 

Cinchona rubra, red cinchona, is the bark of C. Succirubra or of its hybrids, containing not less than 5% of cinchona alkaloids. From it is prepared the compound tincture of cinchona. 

Besides the glycinate ester derivatives described above, other types of enolate-forming compounds have proved to be useful substrates for enantioselective alkylation reactions in the presence of cinchona alkaloids as chiral PTC catalysts. The Corey group reported the alkylation of enolizable carboxylic acid esters of type 57 in the presence of 25 as organocatalyst [69]. The alkylations furnished the desired a-substituted carboxylate 58 in yields of up to 83% and enantioselectivity up to 98% ee (Scheme 3.23). It should be added that high enantioselectivity in the range 94-98% ee was obtained with a broad variety of alkyl halides as alkylation agents. The product 58c is a versatile intermediate in the synthesis of an optically active tetra-hydropyran. 

Obviously, the switch from neutral N-F compounds to N-F ammonium salts had not only a strong beneficial effect on reactivity but the commercial availability of both Selectjluor and cinchona alkaloids also ensures easy accessability of the chiral reagents. Still, from an economical point of view a catalytic version of the process would certainly be desirable and, based on recent catalytic variants by Lectka for bromination and chlorination [19], should be within reach. 

A different mechanism operates in the direct a-heteroatom functionalization of carbonyl compounds when chiral bases such as cinchona alkaloids are used as the catalysts. The mechanism is outlined in Scheme 2.26 for quinine as the chiral catalyst quinine can deprotonate the substrate when the substituents have strong electron-withdrawing groups. This reaction generates a nucleophile in a chiral pocket (see Fig. 2.6), and the electrophile can thus approach only one of the enantiotopic faces. 

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