Natural product synthesis Quinine

Quinine (2) is the major active principle of cinchona, which was isolated by Pelletier and Caventou in 1820 [16] however, its structure could only be established after 100 years [17]. The total synthesis of quinine was accomplished by Woodward and Doering [18] and others [19] but none of the synthetic methods are economical and, therefore, can not compete with the natural production of quinine the bark of the cinchona tree is still the only source of the drug. In addition to quinine (2), three more antimalarial components, quinidine (3), cinchonidine (4) and cinchonine (5) are present in the bark. 

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,... 

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. 

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... 

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... 

The final proof of the structure of a natural product after the latter has also been synthesized in the chemist s lab was, for a long time, common procedure [156], In a few cases, disagreement raised a few eyebrows. This was the case for patchouli alcohol and for a molecule called hexacyclinol [157]. Quinine is an example of the difficulties associated with the notion of a total synthesis. Shouts [35, 37,158] and murmurs [lib,159] have been expressed to comment on the wealth of total syntheses of natural products performed in the second half of the twentieth century. 

Woodward began his career as instructor at Harvard in autumn 1937 and remained there until he died. He is renowned for brilliant syntheses of natural products. With his first student, William von Eggers Doering, Woodward published in 1944 what was considered at the time the first total synthesis of quinine. He was an early advocate of instrumentation, developing useful rules for ultraviolet spectroscopy. The 28-year-old Woodward employed combustion calorimetry to successfully argue against Sir Robert Robinson s... 

The chemistry of natural products encompasses their isolation, structure elucidation, partial and total synthesis, elucidation of their biogenesis, and the biomi-metic synthesis of N. p. Major breakthroughs in analysis were, e.g., the structural clarifications of morphine, lignin, insulin, estrones, and cholesterol as well as the elucidation of the biosyntheses of terpenoids, morphine, penicillin, chlorophyll, and vitamin B 2. Major advances in synthetic chemistry were, e.g., the total syntheses of camphor, hemin, quinine, saccharose, tropine, stryehnine, chlorophyll, vitamin B 2, erythromycin, taxol and palytoxin. Numerous N. p. of the so-ealled ehiral pool are used as starting materials for the synthesis of optically active compounds or serve (in the form of their derivatives) as catalysts for enantioselective syntheses. 

There are quinoline-containing drugs from both nature and synthesis. Natural product drugs may be exemplified by quinine, an anti-malarial drug used for three centuries. Syndetic quinoline-containing drugs are... 

After identifying and classifying many biological compounds, chemists began to pursue the next obvious step, which was to attempt to synthesize the more important natural products. Syntheses that were pursued most vigorously were those of compounds with medicinal activity, and it may be recalled that Perkin was looking for quinine when he found mauve dye. Though the synthesis of quinine eluded chemists for another half-century, another folk remedy known to be a powerful fever reducer succumbed to the chemist s efforts more readily aspirin. 

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 ... 

---