Cinchona natural

This group of natural alkaloids occurs in the various species of the two Rubiaceous genera. Cinchona and Bemijia, indigenous to the eastern slopes of the Andes between latitudes 10° N. and 20° S. 

It is over three centuries since cinchona bark came into use in European medicine, and no other natural drug has had so much written about it. There are the stories, sometimes legendary, of its discovery by Europeans, vigorous early discussions of its therapeutic value, the destruction of the S. American cinchona trees to meet the demand for bark, the labours of botanical explorers in collecting seed for the formation of plantations, the establishment and development of these plantations in Ceylon, India and Java, the competition between them, the gradual emergence of Java as the world s most important source of supply of cinchona bark, and the development of the manufacture of quinine sulphate in Europe, the United States and the Tropics. ... 

Stereoisomerism in the Cinchona Bases It was at first common practice to number the four asymmetric carbon atoms indicated in the general formula (I), 1, 2, 3 and 4, but this is now replaced by the more general system introduced by Rabe, who suggested the name ruban for (HI), which can be regarded as the parent substance of the natural cinchona alkaloids, and rubatoxan (IV) for that of the quinicines (quinatoxines). The formifiae, with notation, for ruban (III) and rubatoxan (IV) are shown below, and the general formula (I) for cinchona bases has been numbered in accordance with that scheme. 

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

Not so long ago, the general opinion was that high enantioselectivity can only be achieved with natural, structurally unique, complex modifiers as the cinchona alkaloids. Our results obtained with simple chiral aminoalcohols and amines demonstrate the contrary. With enantiomeric excesses exceeding 80%, commercially available naphthylethylamine is the most effective chiral modifier for low-pressure hydrogenation of ethyl pyruvate reported to... 

Catalytic asymmetric hydrogenation is a relatively developed process compared to other asymmetric processes practised today. Efforts in this direction have already been made. The first report in this respect is the use of Pd on natural silk for hydrogenating oximes and oxazolones with optical yields of about 36%. Izumi and Sachtler have shown that a Ni catalyst modified with (i ,.R)-tartaric acid can be used for the hydrogenation of methylacetoacetate to methyl-3-hydroxybutyrate. The group of Orito in Japan (1979) and Blaser and co-workers at Ciba-Geigy (1988) have reported the use of a cinchona alkaloid modified Pt/AlaO.i catalyst for the enantioselective hydrogenation of a-keto-esters such as methylpyruvate and ethylpyruvate to optically active (/f)-methylacetate and (7 )-ethylacetate. 

Both quinine and dihydroquinine favored the required (S)-enantiomer. A small ee difference of the product might be due to inconsistent purity of the naturally obtained cinchona alkaloids. It was noted that quinidine (the pseudo-enantiomer of quinine) gave the (R)-enantiomer with a similar 55% ee. Since quinine was... 

Another microwave-mediated intramolecular SN2 reaction forms one of the key steps in a recent catalytic asymmetric synthesis of the cinchona alkaloid quinine by Jacobsen and coworkers [209]. The strategy to construct the crucial quinudidine core of the natural product relies on an intramolecular SN2 reaction/epoxide ringopening (Scheme 6.103). After removal of the benzyl carbamate (Cbz) protecting group with diethylaluminum chloride/thioanisole, microwave heating of the acetonitrile solution at 200 °C for 2 min provided a 68% isolated yield of the natural product as the final transformation in a 16-step total synthesis. 

The first attempt to effect the asymmetric cw-dihydroxylation of olefins with osmium tetroxide was reported in 1980 by Hentges and Sharpless.54 Taking into consideration that the rate of osmium(VI) ester formation can be accelerated by nucleophilic ligands such as pyridine, Hentges and Sharpless used 1-2-(2-menthyl)-pyridine as a chiral ligand. However, the diols obtained in this way were of low enantiomeric excess (3-18% ee only). The low ee was attributed to the instability of the osmium tetroxide chiral pyridine complexes. As a result, the naturally occurring cinchona alkaloids quinine and quinidine were derived to dihydroquinine and dihydroquinidine acetate and were selected as chiral... 

Sometimes natural fine chemicals are by-products in bulk products refining. Examples are (a) lecithin and steroids in vegetable oil refining (b) betaine, pectin and raffinose in sugar manufacture (c) quinic acid in quinine extraction of the bark of Cinchona trees (d) chitin and the red pigment asthaxanthin in lobster and shrimp processing and (e) lanolin, lanosterol and cholesterol in sheep wool purification. 

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]. 

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). 

Since the reaction has been reviewed recently (12) only a few additional facts will be mentioned. Many optically active cyanohydrins can be prepared (33) with e.e. s of 84 to 100% by the use of the flavopnotein D-oxynitrilase adsorbed on special (34) cellulose ion-exchange resins. Although the enzyme is stable, permitting the use of a continuously operating column, naturally only one enantiomer, usually the R isomer, is produced in excess. This (reversible) enzyme-catalyzed reaction is very rapid (34). Nonenzymic catalysts, such as the cinchona alkaloids, permit either enantiomer to be prepared in excess. 

The catalyst is a combination of a chemo-catalyst and a natural product taken from the cinchona alkaloids giving amazing results. In phosphine catalysed asymmetric catalysis these types of structures are lacking, as nature does not produce phosphines ( ) and the phosphines used in the early years of development of asymmetric homogeneous catalysis lacked the complexity of... 

Asymmetric dihydroxylation can be achieved using osmium tetroxide in conjunction with a chiral nitrogen ligand. " The very successful Sharpless procedure uses the natural cinchona alkaloids dihydroquinine (DHQ) and its diastereomer dihy-droquinidine (DHQD), as exemplified in the epoxidation of imni-stilbene... 

It is also worthwhile to outline at this place the immobilization procedure that was used for the preparation of type I CSPs A bifunctional linker with a terminal isocyanate on one side and a triethoxysilyl group on the other end (3-isocyanatopropyl triethoxysilane) was reacted with the native cinchona alkaloids quinine and quinidine and subsequently the resultant carbamate derivative in a second step with silica [30], Remaining silanols have been capped with silane reagents, yet, are less detrimental for acidic solutes because of the repulsive nature of such electrostatic interactions. CSPs prepared in such a way lack the hydrophobic basic layer of the thiol-silica-based CSPs mentioned earlier, which may be advantageous for the separation of certain analytes. 

During the nineteenth century, chemists had a good deal of success in isolating and purifying natural products from plant sources. Morphine was isolated as a pure compound from crude opium in 1804. Quinine was isolated from the bark of the cinchona tree in 1820 and was initially employed as a fever reducer. However, its effectiveness against malaria was soon discovered and it found an alternative highly important medical use. Sodium salicylate was isolated from the bark of the willow tree in 1821 and was also shown to have analgesic, antipyretic, and antiinflammatory properties. It took an additional 76 years, until 1897, to synthesize the acetyl derivative, acetylsalicyclic acid, commonly known as aspirin. 

The Cinchona tree remains the only economically practical source of quinine. Although the development of synthetic quinine is considered a milestone in organic chemistry, it has never been produced industrially as a substitute for naturally occurring quinine. Nevertheless, the implications of the total synthesis of quinine in new strategies for the development of safer and more efficient antimalarial drugs, as we will show in the course of the next paragraphs, is priceless. But, let us discuss this total synthesis first. 

The notable mode of stereoselectivity of Cinchona alkaloids is presented by its psendoenantiomeric pairs which can be employed to generate either enantiomer of chiral prodnct. Key moieties that are central to Cinchona alkaloids are the quinuclidine nitrogen and the adjacent C(9)-OH (the N-C(8)-C(9)-OH moiety) (Fig. 2). In psendoentiomeric alkaloids in the natural open conformation, the torsion angle N-C(8)-C(9)-0 are opposite in sign Q and CD are (-), and thereby induce selectivity for one enantiomer, whereas QD and C are (-I-) and afford the other enantiomer [28, 29],... 

The efficiency with which modified Cinchona alkaloids catalyze conjugate additions of a-substituted a-cyanoacetates highlights the nitrile group s stereoselective role with the catalyst. Deng et al. [60] utilized this observation to develop a one-step construction of chiral acyclic adducts that have non-adjacent, 1,3-tertiary-quatemary stereocenters. Based on their mechanistic studies and proposed transition state model, the bifimctional nature of the quinoline C(6 )-OH Cinchona alkaloids could induce a tandem conjugate addition-protonation reaction to create the tertiary and quaternary stereocenters in an enantioselective and diastereoselective manner (Scheme 18). 

Following the reaction, simple extraction provided access to both the hemiester prodnct and the alkaloid withont chromatography and the recovered cinchona alkaloid conld be reused with no deterioration in the ee or yield. This method has found use in the synthesis of P-amino alcohols and in natural product synthesis [198-201] and has recently been reported as an Organic Syntheses method [202],... 

The development of predictive transition state models for the interpretation of selectivity data pertaining to the use of cinchona alkaloid derivatives in all the processes described above is challenging due to the complex conformational behaviour of these natural scaffolds (for example, it is well known that 0-acylated quinidines undergo major conformational changes upon protonation) [223]. Consequently, hypotheses regarding the details of chirality transfer in these systems are notably absent. 

C9-epi-122 98% conv. (99% ee) after 30h, respectively (Figure 6.40). This structure-efficiency relationship supported the results already published by the Soos group for quinine- and quinidine-derived thioureas (Figure 6.39) [278]. C9-epimeric catalysts were found to be remarkably more efficient in terms of rate acceleration and stereoinduction than the analogs of natural cinchona alkaloid stereochemistry. This trend was also observed for the corresponding (thio)ureas derived from DHQD as shown by the experimental results in Figure 6.40 [279]. 

C. Adenosine is a product of the metabolism of adenosine triphosphate. Phenytoin and lidocaine are totally synthetic, while digoxin occurs naturally in plants and quinine occurs in the cinchona tree. 

The availability of ctetq) advanced synthons that carry the required chirality is an advantage, particularly in projects aimed at industrial total synthesis. Natural products are often used as synthons, ideally fi om a renewable source, such as microbial fermentations. In a few cases, biotechnology has become an ahemative source. The total theses of the antitumor agent esperamicin A and the immunosuppressant FK-506 are exanq>les. In both cases, the synthon was quinic acid (Barco 1997), cheaply obtained by biotechnology (Chapter 14.1.e) rather than fi om the environmentally noxious extraction fi om the bark of Cinchona spp. Used to build up combinatorial libraries, quinic acid has gained further inq)ortance in organic thesis (Phoon 1999). 

Spanish botanist, physician, and ecclesiastic who devoted his life to studying the natural history of northern South America. He investigated the cinchona (or chm-chona) forests of Colombia (New Granada) and collaborated with Don Juan Jose de Elhuyar in developing its mines. He stated that the gold m the ores of Choco cannot be separated from the platinum except by amalgamation (87)... 

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