Quinine, natural product

Woodward achieved his first signal success of a lifetime devoted to the preparation of increasingly complex natural products by total synthesis by the successful preparation of quinine. Despite its elegance, this synthesis did not provide a commercially viable alternative to isolation of the drug from chincona bark. A rather short synthesis for this drug from readily available starting materials has been only recently developed by the group at Hoffmann-LaRoche. (The economics of this synthesis are,... 

Quinidine, a natural product epimeric with quinine at Cg and C9, was accessed through the diastereoisomeric trans epoxide prepared from 86 by SAD, in this case by using AD-mix a [2b, 41]. 

Only a few other cobalt complexes of the type covered in this review (and therefore excluding, for example, the cobalt carbonyls) have been reported to act as catalysts for homogeneous hydrogenation. The complex Co(DMG)2 will catalyze the hydrogenation of benzil (PhCOCOPh) to benzoin (PhCHOHCOPh). When this reaction is carried out in the presence of quinine, the product shows optical activity. The degree of optical purity varies with the nature of the solvent and reaches a maximum of 61.5% in benzene. It was concluded that asymmetric synthesis occurred via the formation of an organocobalt complex in which quinine was coordinated in the trans position (133). Both Co(DMG)2 and cobalamin-cobalt(II) in methanol will catalyze the following reductive methylations ... 

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. 

In the first half of the 19th century, when the colonial expansion of the European nations was at its height, malaria became a serious problem in the newly colonised territories overseas and the price of natural quinine, whose production was at that time monopolised by the Dutch, became exorbitant. In an attempt to provide a cheap alternative to the natural material, the French Pharmaceutical Society offered, in 1850, a prize of 4.000 francs to any chemist who could prepare synthetic quinine in the laboratory. 

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 use of natural products as medicine has invoked the isolation of active compounds the first commercial pure natural product introduced for therapeutic use is generally considered to be the narcotic morphine (1), marketed by Merck in 1826, and the first semi-synthetic pure dmg aspirin (2), based on a natural product salicin (3) isolated from Salix alba, was introduced by Bayer in 1899. This success subsequently led to the isolation of early dmgs such as cocaine, codeine, digitoxin (4), quinine (5), and pilocarpine (6), of which some are still in use. ... 

Key Natural Products in Malaria Chemotherapy From Quinine to Artemisinin and Beyond... 

Some Key Natural Products in the Malaria Chemotherapy 2.1. Quinine and Derivatives... 

It is clear that no other compound or family of compounds have affected the chemotherapy of malaria as much as quinine and its derivatives, and artemisinin and its derivatives. Nevertheless, there are some classes of natural products that have made it to the market or at least at the advanced stage of clinical trials as antimalarial. Among them are quinones, chalcones and xanthones. 

Since the early times of stereochemistry, the phenomena related to chirality ( dis-symetrie moleculaire, as originally stated by Pasteur) have been treated or referred to as enantiomericaUy pure compounds. For a long time the measurement of specific rotations has been the only tool to evaluate the enantiomer distribution of an enantioimpure sample hence the expressions optical purity and optical antipodes. The usefulness of chiral assistance (natural products, circularly polarized light, etc.) for the preparation of optically active compounds, by either resolution or asymmetric synthesis, has been recognized by Pasteur, Le Bel, and van t Hoff. The first chiral auxiliaries selected for asymmetric synthesis were alkaloids such as quinine or some terpenes. Natural products with several asymmetric centers are usually enantiopure or close to 100% ee. With the necessity to devise new routes to enantiopure compounds, many simple or complex auxiliaries have been prepared from natural products or from resolved materials. Often the authors tried to get the highest enantiomeric excess values possible for the chiral auxiliaries before using them for asymmetric reactions. When a chiral reagent or catalyst could not be prepared enantiomericaUy pure, the enantiomeric excess (ee) of the product was assumed to be a minimum value or was corrected by the ee of the chiral auxiliary. The experimental data measured by polarimetry or spectroscopic methods are conveniently expressed by enantiomeric excess and enantiomeric... 

With the development of chemistry in the early 1800s came the understanding that natural products owe their medicinal properties to certain substances they contain. In 1806, for example, morphine was isolated from opium, and in 1820 quinine, a drug useful in fighting malaria, was isolated from the bark of the cinchona tree. Soon, compounds produced in the laboratory were also found to have medicinal properties. In the 1840s, for example, anesthetic activity was found in the synthetic chemicals chloroform, nitrous oxide, and ethyl ether, making painless surgery and dentistry possible. 

Natural products have served as a major source of drugs for centuries, and about half of the pharmaceuticals in use today are derived from natural products. Quinine, theophylline, penicillin G, morphine, paclitaxel, digoxin, vincristine, doxorubicin, cyclosporin, and vitamin A all share two important characteristics they are cornerstones of modem pharmaceutical care, and they are all natural products. The use of natural substances, particularly plants, to control diseases is a centuries-old practice that has led to the discovery of more than half of all modem pharmaceuticals. 

A variety of alkaloids bind to or intercalate with DNA or DNA/RNA processing enzymes and affect either transcription or replication (quinine, harmane alkaloids, melinone, berberine), act at the level of DNA and RNA polymerases (vinblastine, coralyne, avicine), inhibit protein synthesis (sparteine, tubulosine, vincrastine, lupanine), attack electron chains (pseudane, capsaicin, solenopsine), disrupt biomembranes and transport processes (berbamine, ellipticine, tetrandrine), and inhibit ion channels and pumps (nitidine, caffeine, saxitoxin). In addition, these natural products attack a variety of other systems that can result in serious biochemical destabilization... 

Stereoisomers can have different therapeutic effects. Quinine, a natural product isolated from the bark of the cinchona tree, was the first compound effective against malaria. Quinidine, a stereoisomer of quinine, is used to treat irregular heartbeat. 

Quinolines represent an important class of heterocycles, and the quinoline skeleton is present in various natural products, especially in alkaloids. Among them quinine is an active ingredient for the treatment of malaria [286]. Despite its relatively low efficacy and tolerability, quinine still plays an important role in the treatment of multiresistant malaria, one of the world s most devastating infectious diseases [287]. Therefore, the design of many drugs and affordable chemotherapies are based upon synthetic quinoline derivatives, such as chloroquine, mefloquine or quinacrine [288-292]. In addition, chimanine alkaloids, are also effective against parasitic diseases such as leishmaniasis and trypanosomiasis [293-295]. Besides,... 

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