Quinine oxidant

There has been considerable work in recent years on the nature of the degradation products of the cinchona alkaloids. The work stemmed from the in vitro studies of Kelsey and Oldham (74) on the distribution of quinine oxidase in animal tissues, work which in turn rested upon the demonstration that various tissues could metabolize quinine in vitro (74a, 75-78). The work of Kelsey and Oldham showed that rabbit liver contained a high concentration of an enzyme which oxidized quinine, that the concentration in... 

The isomeride quiienidine, similarly produced by the oxidation of quinidine, crystallises in prisms, m.p. 246°, [a]f ° -(- 258° (A -H jS04), and, like quitenine, gives quininic and cincholoiponic acids by further oxidation. 

On autoxidation by aeration in tertiary butyl alcohol containing potassium tert-butyl oxide, quininone yields quininic acid (98 per cent.) and meroquinenine terf-butyl ester, CgHi N. CO. O. C4H9, b.b. 127°/20 mm., dj 0-9832, [a]o° -(- 50-0° (EtOH), identified by hydrolysis to meroquinenine (meroquinene) and eonversion of this to the better-known ethyl ester (p. 438). (Doering and Chanley.)... 

These results indicate that quinine and quinidine differ in structure from cinchonine and cinehonidine in containing a methoxyl group in position 6 in a quinoline nucleus. The identity of the other oxidation products, meroquinenine, cincboloiponic and loiponic acids, in all foiu" cases indicates that the second half of the molecule has the same structure in all four alkaloids. Further, this second half must be joined to the quinoline nucleus at position 4 by a group capable of conversion into carboxyl. 

In the ease of the dextrorotatory pair, einchonine and quinidine, these hydroxydihydro-bases may lose a molecule of water between the two. CHOH. groups at positions 9 and 10 with the formation of ether oxides, represented by formula (C) of which there should be a pair of stereoiso-merides for eaeh alkaloid. This type of compound has not been obtained from the laevorotatory bases, einchonidine and quinine. 

Mth quinine in cinchona bark), is now prc]5.a> cd fmin anilmc. The aniline, in pioccss of oxidation to quinone, -ippeais to jiass throug h the following intermediate stag es. 

It was found, during a study of synthetic routes leading to quinine analogues, that oxidation of a specific bicydic pyrazoline derivative with mercuric acetate gives an enamine-like pyrazole (87b). 

Important organic applications are to the determination of quinine and the vitamins riboflavin (vitamin B2) and thiamine (vitamin Bj). Riboflavin fluoresces in aqueous solution thiamine must first be oxidised with alkaline hexacyanoferrate(III) solution to thiochrome, which gives a blue fluorescence in butanol solution. Under standard conditions, the net fluorescence of the thiochrome produced by oxidation of the vitamin Bj is directly proportional to its concentration over a given range. The fluorescence can be measured either by reference to a standard quinine solution in a null-point instrument or directly in a spectrofluorimeter.27... 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

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... 

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

The next milestone in the development of organic synthesis was the preparation of the first synthetic dye, mauveine (aniline purple) by Perkin in 1856 Perkin, 1856, 1862). This is generally regarded as the first industrial organic synthesis. It is also a remarkable example of serendipity. Perkin s goal was the synthesis of the antimalarial drug quinine by oxidation of N-allyl toluidine (Fig. 2.4). 

Interestingly, Jacobsen et al. have also reported that addition of a /3-hydroxy ammonium salt to the reaction medium accelerates the isomerization in the presence of an /V-benzylated quinine salt epoxidation of cw-stilbene with (27) gives Zrarax-stilbene oxide with 90% ee as the major product (trans cis= >96 4).109 In 2000, Adam et al. reported that the isomerization ratio was related to the triplet-quintet energy gap of the radical intermediate which was affected by the... 

As dehydrogenases (DH) are widely distributed enzymes, a number of studies have been carried out with these biocatalysts. For example, Willner el al. [20] have used a PQQ-monolayer functionalized gold electrode for the catalytic oxidation of NADH in the presence of Ca2+. In this scheme, the pyrrolo-quinoline quinine co-factor, PQQ, was covalently linked, as before for the GOx system [15, 20, 21], to the Au electrode,... 

A complex naturally occurring amino acid 5-hydroxypiperazic acid (5HyPip) 100 was prepared by a multistep procedure that included Diels-Alder addition of 2,4-pentadienoic acid to phthalazinedione 83a as a first step (Scheme 24). Adduct 97 was esterified and oxidized with mercuric acetate to 98, which on hydrogenation over rhodium on alumina and subsequent hydrolysis provided a mixture of enantiomers from which the required enantiomer 99 was obtained by resolution with quinine. Its hydrazinolysis provided 100 [71JCS(C)514 77H119],... 

Methods for determination of thiol drugs (i.e., captopril [21-25], penicillamine [26-28], hydrochlorothiazide [24, 25, 29, 30], and tiopronin [31, 32]) have been developed. These methods are based on CL from a cerium (IV) oxidation system sensitized by adequate fluorophores such as quinine and rhodamine B. By using HPLC-coupled CL-flow-injection analysis method, tiopronin and its metabolite 2-mercaptopropionic acid in human urine were sensitively determined with the detection limits of 0.8 and 1 pM, respectively [32],... 

Volume 75 concludes with six procedures for the preparation of valuable building blocks. The first, 6,7-DIHYDROCYCLOPENTA-l,3-DIOXIN-5(4H)-ONE, serves as an effective /3-keto vinyl cation equivalent when subjected to reductive and alkylative 1,3-carbonyl transpositions. 3-CYCLOPENTENE-l-CARBOXYLIC ACID, the second procedure in this series, is prepared via the reaction of dimethyl malonate and cis-l,4-dichloro-2-butene, followed by hydrolysis and decarboxylation. The use of tetrahaloarenes as diaryne equivalents for the potential construction of molecular belts, collars, and strips is demonstrated with the preparation of anti- and syn-l,4,5,8-TETRAHYDROANTHRACENE 1,4 5,8-DIEPOXIDES. Also of potential interest to the organic materials community is 8,8-DICYANOHEPTAFULVENE, prepared by the condensation of cycloheptatrienylium tetrafluoroborate with bromomalononitrile. The preparation of 2-PHENYL-l-PYRROLINE, an important heterocycle for the synthesis of a variety of alkaloids and pyrroloisoquinoline antidepressants, illustrates the utility of the inexpensive N-vinylpyrrolidin-2-one as an effective 3-aminopropyl carbanion equivalent. The final preparation in Volume 75, cis-4a(S), 8a(R)-PERHYDRO-6(2H)-ISOQUINOLINONES, il lustrates the conversion of quinine via oxidative degradation to meroquinene esters that are subsequently cyclized to N-acylated cis-perhydroisoquinolones and as such represent attractive building blocks now readily available in the pool of chiral substrates. 

In this procedure, quinine is oxidatively degraded to meroquinene esters that are subsequently cyclized to N-acylated cis-decahydroisoquinolones in excellent overall yield, while maintaining the cis stereochemistry at the ring juncture. Furthermore, with the commercial availability of quinine, high overall yields, and ease of isolations, meroquinene and subsequent products are attractive members of a practical "chiral pool . 

Oxidation of the quinine C-9 hydroxy substituent to the ketone is best accomplished using the Woodward3 benzophenone/potassium t-butoxide method, now using toluene. The other oxidation methods investigated (Swern, Jones, ROCI variations) were less effective or limited because of the poor solubility of the substrate. Thermodynamic equilibration of these ketones has also been reported.3... 

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