Bases Cinchonine

It remained to establish the manner of linkage of the two portions of the molecule represented by the known cleavage products, von Miller and Rohde had rediscovered a reaction first observed by Pasteur (70), namely, that the bitertiary bases cinchonine and quinine were converted under acidic conditions into ketones, designated as toxines, which contained a secondary amine function, and in order to explain these observations, made the fruitful suggestion that the non-aromatic moiety of the alkaloid molecules contained a bicyclic system with nitrogen at the... 

The same conclusion is reached through consideration of the formation of the anhydro bases cinchonine and cinchonidine pve the same cinchene (Cni), while quinene is obtained from both quinine and quinidine (qf. Section II, 1, b). 

Schans and co-workers envisioned the apphcation of cinchona alkaloids 47a-d as chiral Brpnsted base catalysts in the asymmetric Mannich reaction of acetoacetates 45 with iV-acylimines 23a, 46a-c (Schane 5.25) [35]. Promising results were reported when the chiral base cinchonine (47a) was employed, while the cinchona alkaloid quinine (47b) gave considerably lower selectivities. Opposite selectivities were observed when the pseudo-ematiamers cinchoitidine (47c) and qniitidine (47d) were used. 

The resolution of mandelic acid by way of its diastereomeric salts with the natural chiral base cinchonine is illustrated in Figure 3.9. Racemic mandelic acid and optically pure (+)-cinchonine (Cin) are dissolved in boiling water, giving a solution of a pair of diastereomeric salts. Diastereomers have different solubilities, and when the solution cools, the less soluble diastereomeric salt crystallizes. This salt is collected and purified by further recrystallization. The filtrates, richer in the more soluble diastereomeric salt, are concentrated to give this salt, which is also purified by further recrystallization. The purified diastereomeric salts are treated with aqueous HCl to precipitate the nearly pure enantiomers of mandelic acid. Cinchonine remains in the aqueous solution as its water-soluble hydrochloride salt. 

This is an example of the Doebner synthesis of quinoline-4-carboxylic acids (cinchoninic acids) the reaction consists in the condensation of an aromatic amine with pyruvic acid and an aldehj de. The mechanism is probably similar to that given for the Doebner-Miller sj nthesis of quinaldiiie (Section V,2), involving the intermediate formation of a dihydroquinoline derivative, which is subsequently dehydrogenated by the Schiff s base derived from the aromatic amine and aldehyde. 

For the separate determination of the four principal components in the total alkaloids, the method in general use is based on the isolation of quinine and cinchonidine as d-tartrates, of cinchonine as the base in virtue of its sparing solubility in ether, and of quinidine as the hydriodide. Types of this method have been described by Chick, and special modifications designed for use in the analysis of totaquina are given in the British Pharmacopoeia 1932 and in a special report by the Malaria Commission of the League of Nations. Goodson and Henry have critically examined this process and shown that, with care, it gives satisfactory... 

The ethereal solution of crude quinidine and cinchonidine, obtained as described under cinchonine, is shaken with dilute hydrochloric acid, the excess acid neutralised with ammonia and sodium potassium tartrate added. The base is recovered from the precipitated tartrate by dissolving the latter in dilute acid and pouring the filtered solution in a thin stream, slowly and with constant stirring, into excess of ammonia solution. The crude alkaloid is converted into the neutral sulphate, and this recrystallised... 

The directions of rotation at C and C have been arrived at from the following considerations. The deoxy-bases (II p. 443 Q = quinoline residue) obtained from cinchonine and cinchonidine are structurally identical, i but optically different, and since they must be optically identical at C and C, and C is no longer asymmetric, the difference between them (see table, p. 446) must be due to difference in direction of rotation at C , which must therefore be dextrorotatory in cinchonine and laevorotatory in cinchonidine, and this must also be true of quinidine and quinine respectively and of the corresponding dihydro-bases. The keto-bases, cinchoninone and quininone, might be expected to exist each in two pairs, since carbon atom 8 is, according to the formula (p. 442), asymmetric, but it is better represented by the tautomeric grouping —... 

Of the other cinchona bases, the dextrorotatory forms cinchonine and quinidine have been used as anti-malarial drugs in cases of idiosyncrasy to quinine, a subject to which Dawson has given much attention. Quinidine is used to eontrol auricular fibrillation, and its value for this purpose in comparison with dihydroquinidine has been investigated by several workers. Dawes has recently devised a method of testing... 

Bohman and Allenmark resolved a series of sulphoxide derivatives of unsaturated malonic acids of the general structure 228. The classical method of resolution via formation of diastereoisomeric salts with cinchonine and quinine has also been used by Kapovits and coworkers " to resolve sulphoxides 229, 230, 231 and 232 which are precursors of chiral sulphuranes. Miko/ajczyk and his coworkers achieved optical resolution of sulphoxide 233 by utilizing the phosphonic acid moiety for salt formation with quinine. The racemic sulphinylacetic acid 234, which has a second centre of chirality on the a-carbon atom, was resolved into pure diastereoisomers by Holmberg. Racemic 2-hydroxy- and 4-hydroxyphenyl alkyl sulphoxides were separated via the diastereoisomeric 2- or 4-(tetra-0-acetyl-D-glucopyranosyloxy)phenyl alkyl sulphoxides 235. The optically active sulphoxides were recovered from the isolated diastereoisomers 235 by deacetylation with base and cleavage of the acetal. Racemic 1,3-dithian-l-oxide 236... 

Other chiral leaving groups have been used (see Table 4), for instance (—)-methyl-S-thioglycolate 42), or the conjugate base of cinchonine 92), which seems to give rather good results yielding for instance benzylmethylphenyl-t-butyltin with [a] 6 = —22.6. 

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... 

Although thiolacetic acid additions are free-radical reactions (60), it was found recently that the addition to electron-poor olefins can be base catalyzed (61) (eqs. [14], [15]). Thus the (S)-(-) adduct is obtained with an e.e. of 54% when cyclohexenone is treated with thiolacetic acid in benzene in the presence of catalytic amounts of cinchonine. The reaction appears to be quite general, although very high e.e. s (>80%) have not yet been achieved. 

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. 

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. 

Hippuric acid, or benzoylglycine, has been known for a long time, and by preparing the benzoyl derivatives of the other amino acids, Fischer found that their acidic character was greatly increased, and that they then combined with the optically active bases brucine, strychnine, cinchonine, morphine, forming stable salts. These salts were much less soluble and their power of crystallising much greater than the salts of the amino acids themselves, and consequently they were more easily isolated further, they were easily reconverted into the amino acids. 

It has recently been shown that when the tetrahedral intermediate of the reaction is cyclic, it is a better donor of nucleophilic CF3. These cyclic intermediates can be generated intramolecularly from trifluoroacetamides or trifluorosulfmamides derived from (9-silylated ephedrine. These reagents are able to trifluoromethylate aldehydes and ketones, even in the case of enolizable substrates, as a strong base is not required (Figure 2.34). However, while the source of CF3 is chiral, there is no chirality transfer to the addition product, and the replacement of ephedrine by other chiral amino alcohols did not show any improvement. " Similar to asymmetric trifluoromethylation with the Ruppert reagent, only the use of a fluoride salt of cinchonine can increase the enantioselectivity. " " ... 

A characteristic feature of this solid-phase amino acid synthesis is the use of the phosphazene bases 53 and 54 for the PTC alkylation reaction [64, 65]. Because these compounds, which are soluble in organic media, do not react with alkyl halides, both alkyl halide and phosphazene bases can be added together at the start of the reaction, which is useful practically [65], Cinchonine and cinchonidine-derived salts, e.g. 25, were found to be very efficient catalysts. Under optimum conditions the alkylation proceeds with enantioselectivity in the range 51-99% ee, depending on the alkyl halide component [65], Seventeen different alkyl halides were tested. After subsequent hydrolysis with trifluoroacetic acid the corresponding free amino acids were obtained in high yield (often >90%). 

Aldol reactions using a quaternary chinchona alkaloid-based ammonium salt as orga-nocatalyst Several quaternary ammonium salts derived from cinchona alkaloids have proven to be excellent organocatalysts for asymmetric nucleophilic substitutions, Michael reactions and other syntheses. As described in more detail in, e.g., Chapters 3 and 4, those salts act as chiral phase-transfer catalysts. It is, therefore, not surprising that catalysts of type 31 have been also applied in the asymmetric aldol reaction [65, 66], The aldol reactions were performed with the aromatic enolate 30a and benzaldehyde in the presence of ammonium fluoride salts derived from cinchonidine and cinchonine, respectively, as a phase-transfer catalyst (10 mol%). For example, in the presence of the cinchonine-derived catalyst 31 the desired product (S)-32a was formed in 65% yield (Scheme 6.16). The enantioselectivity, however, was low (39% ee) [65],... 

The first example of a catalytic asymmetric Horner-Wadsworth-Emmons reaction was recently reported by Arai et al. [78]. It is based on the use of a chiral quaternary ammonium salt as a phase-transfer catalyst, 78, derived from cinchonine. Catalytic amounts (20 mol%) of organocatalyst 78 were initially used in the Homer-Wadsworth-Emmons reaction of ketone 75a with a variety of phospho-nates as a model reaction. The condensation products of type 77 were obtained in widely varying yields (from 15 to 89%) and the enantioselectivity of the product was low to moderate (< 43%). Although yields were usually low for methyl and ethyl phosphonates the best enantioselectivity was observed for these substrates (43 and 38% ee, respectively). In contrast higher yields were obtained with phosphonates with sterically more demanding ester groups, e.g. tert-butyl, but ee values were much lower. An overview of this reaction and the effect of the ester functionality is given in Scheme 13.40. 

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