Dihydro cinchona alkaloids

A) Natural dihydro-cinchona alkaloids and their epimerides, CH, CH, — CH,. CH,. 

As found in commerce, the cinchona alkaloids are not necessarily pure quinidine, for example, may contain up to 30 per cent, of dihydroquinidine. Working with carefully pmdfied specimens of the four chief cinchona alkaloids and their dihydro-derivatives, Buttle, Henry and Trevan found the results recorded in the table (p. 471) in tests with malaria in canaries. The figures in brackets represent the dose of quinine necessary to produce the same degree of protection as unit dose of the alkaloid named. To the results are also added the data found later by the same authors, with Solomon and Gibbs, for some of the transformation products (p. 449) of quinine and quinidine. The Roman numeral at the head of each column refers to the type formula on p. 470. 

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. 

The essential components of the catalyst for the asymmetric dihydroxylation process are osmium tetroxide (OSO4) and an ester of one or the other of the pseudoenantiomeiic cinchona alkaloids dihydro-quinidine (DH( D) and dihydroquinine (DHQ). An amine oxide, generally N-methylmorpholine N-oxide, serves as the oxidant for foe reaction. When an alkenic substrate is added very slowly to a... 

The photochemical behavior of the W-oxides of the Cinchona alkaloids has been examined 49). Photolysis (> 300 nm) of the aromatic mono-iV-oxides 183 of the dihydro derivatives of quinine, quinidine, cincho-nidine, and cinchonine in alcoholic solvents gave the expected carbo-styrils 186 in yields of 70-85%. The same results were obtained with the corresponding AjiV-dioxides 184. An interesting rearrangement was observed in the case of the iV,A -dioxides of dihydrocinchonine and dihydrocinchonidine. Photolysis in benzene solution afforded, in addition to the carbostyrils, the iV -formylindole methanols 188 in 30% yield. The hydrolysis-sensitive benz[d]-l,3-oxazepines 185 were proposed as the probable intermediates. 

Cinchona alkaloids have been used since the sixteenth century to treat malaria. It is well established that quinine, quinidine, cinchonidine, cinchonine, and their dihydro derivatives exhibit similar antimalarial activity (50, 51). Quinine owes its favored position in malaria therapy to its earlier isolation. Its use is becoming increasingly important in treating infections caused by strains of Plasmodium falciparum which are resistant to all other antimalarial drugs (52). However, some of the... 

The simplest cinchona alkaloids, cinchonidine and its 10,11-dihydro-derivative, have been shown by D-tracer studies and by NEXAFS and ATR-IR spectroscopy to adsorb by interaction of the quinoline moiety with the platinum surface. Mechanistic studies have established that a site exists adjacent to the open-3 conformation of adsorbed cinchonidine at which pyruvate ester can undergo selective enantioface adsorption. Hydrogenation of the preferred enantioface results in preferential formation of one enantiomer of the product, methyl lactate, MeC H(OH)COOMe. Pt modified by cinchonidine provides R-lactate preferentially, whereas the near enantiomer cinchonine provides 5-lactate in excess. Values of the enantiomeric excess of 75% can be obtained without optimisation, and of 98% under special conditions. In solution, conditions that achieve enantioselectivity normally promote the reaction rate by a factor of 2 to 100 depending on conditions. ... 

The synthesis of dihydromeroquinene derivatives from secologanin (268) affords a new and convenient stereoconservative synthesis of the Cinchona alkaloids. Two routes were developed (Scheme 44) both resulted in the conservation of the easily epimerised centre at C-2 in the secologanin derivatives. The first route resulted in the formation of dihydromeroquinene (cincholoipon) hydrochloride (269), which was identified by conversion into methyl N-benzoyldihydromeroquinenate (270) the other afforded methyl dihydro-meroquinenate (271), which has previously been converted into quinine. 

A number of nitrogen ligands are of natural origin. Owing to the pioneering research of Sharpless and co-workers, the cinchona alkaloids and their derivatives (67) play a fundamental role in the osmium-catalyzed dihydro lation reaction. This is a typical ligand accelerated reaction in which the chiral ligands enhance the reaction rates by a factor of 25 over the uncatalyzed reaction. 

Early in 2003, Choudary et al. studied the catalytic activity of a unique tri-functional heterogeneous catalyst system consisting of palladium, osmium, and tungsten species for tandem Heck olefination followed by asymmetric dihydro>ylation reaction induced by cinchona alkaloid (DHQD)2PHAL in the presence of a tertiary amine such as N-methylmorpholine (NMM) in one pot. The trimetal catalyst system of Pd-Os-W was embedded into hexagonal layered double-hydroxides (LDHs). As shown in Scheme 7.57, the corresponding almost enantiopure diol was achieved in high yield. This remarkable result was not clearly understood by the authors. 

Figure 6.1 Structures of the natural cinchona alkaloids and of cupreine and cupreidine. The analogs of quinine, quinidine, cinchonidine, and cinchonine with an ethyl at C3 (the dihydro species) are also isolated from natural sources.

In the cinchona series 8 the method is particularly easy of application and has been used for the production of the dihydro alkaloids, whose biological prbp-erties were first extensively studied by Morgenroth and his collaborators.9... 

Four cinchophylline-type alkaloids, including three previously known ones, were isolated from Cinchona ledgeriana, viz., isocinchophylline (3a,17a-einchophyl-line) (255), cinchophylline (3a,17 S-cinchophylline) (256), 3/l,17a-cinchophylline (257), and cinchophyllamine (3 S,17 S-cinchophylline) (258). The stereochemistry of these compounds was assigned based on IR, NMR, and CD spectra (156). The structure of isocinchophylline was previously established by X-ray diffraction analysis (757). Three additional new cinchophylline alkaloids, 17,4, 5, 6 -tetradehydro-3a-cinchophylline (259), 17,4 -dehydro-3a-cinchophylline (260) and 18,19-dihydro-3 S,17 S-cinchophylline (261) were also obtained from the same plant (755). 

SxJSZKO-PuRZYCKA and Tbzebny [233, 233 b] have used silica gel G layers in order to separate the four principal alkaloids of the cinchona tree from theic dihydro-derivatives. They found that the dihydrobases migrate more slowly than the original vinyl-bases. 

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