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Scalable Enantioselective Total Synthesis of Taxanes

Holton's technique, however, yieldssynthetic taxol equivalent to 40% of the starting material.

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Enantioselective Total Synthesis of (−)-Maoecrystal V

The taxanes are a large family of 350 or so natural products, of which the best known is taxol itself, a multibillion dollar anticancer drug with a rich and storied history, whose name and distinctive tetracyclic system are instantly recognisable to most organic chemists. Taxol itself has already been the subject of 7 epic total syntheses (see if you need a quick reminder), all using conventional functional group lead approaches to bond formation. Nature's (and Phil's) approach is a bit different, though, as we'll see.

T1 - Synthesis of biologically active taxol analogues with modified phenylisoserine side chains

The actual first synthesis of taxol, albeit it as the unnatural antipode. Counting the number of steps for this route was particularly difficult as the origin of the starting material isn't obvious from reading the original papers. Although it's described as 'readily available', as far as I can tell no procedure for its preparation is given. An previously reported literature preparation by Büchi took 16 steps, and if this route was used then Holton could be a strong contender for the longest synthesis on record. Additionally, natural inexpensive (£0.26/g) (+)-camphor actually gave the wrong enantiomer of the natural product. In principle, (-)-camphor could be used to give the correct enantiomer, although it is far more costly (£10/g). I love the Chan rearrangement, which is the closest thing we're likely to get to a retro-Baeyer-Villager for some time... would you include one in your synthetic plan?

Total Synthesis of Jiadifenolide

Total Synthesis of (+)-Crotogoudin

That's right, for the first time in three and a half years' blogging I find myself writing about that rarest of publications: the collaborative total synthesis. Also somewhat unusually, the two US-based groups involved in the collaboration are both headed up by professors who originally hail from outside the States.[1]

The ability to synthesize taxol is of great importance, as chemists will now be able to concoct modified versions of the drug. Natural taxol suffers from poor solubility, which makes it difficult to administer. Nicalaou says, "We might find one [modification] that is less toxic and more effective than [natural] taxol. There are a lot of advances to be made" (Science, 1994).

11-Step Total Synthesis of Araiosamines, J.

11-Step Total Synthesis of (-)-Maoecrystal V, J.

The paclitaxel drug development process took over 40 years. Theanti-tumor activity of a bark extract of the Pacific yew tree wasdiscovered in 1963 as a follow up of a government plant screening programalready in existence 20 years before that. The active substanceresponsible for the anti-tumor activity was discovered in 1969 andstructure elucidation was completed in 1971. Robert A Holton of succeeded in the total synthesis of paclitaxel in 1994, a projectthat he had started in 1982. In 1989 Holton had also developed asemisynthetic route to paclitaxel starting from . This compound is abiosynthetic precursor and is found in larger quantities thanpaclitaxel itself in (the European Yew). In1990 bought alicence to the patent for this process which in the years to followearned Florida State University and Holton (with a 40% take) over200 million .

The total synthesis of taxol is called one of the most hotlycontested of the 1990s witharound 30 competing research groups by 1992. The number of researchgroups actually having reported a total synthesis currently standsat 6 with the Holton group (article first accepted for publication)and the Nicolaou group (article first published) first and secondin what is called a photo finish.

11-Step Total Synthesis of Pallambins C and D, J.
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  • Total synthesis of (+)-16-epivinoxine and (−)-vinoxine

    As the production of Taxol is still far from being optimized, thereis still a lot of research going on in this field .

  • Scalable EnantioselectiveTotal Synthesis of Taxanes, Nature Chem.

    The precursor BaccatinIII can be isolated from the needles of the Atlantic Yew tree as a quicklyregrowable resource.

  • C–H Functionalization Logic in Total Synthesis, Chem.

    Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes, Angew.

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Total Synthesis of Palau'amine, Angew.

The commercial (by ) ofpaclitaxel starting from 10-deacetylbaccatin III (isolated from theEuropean yew) is based on tail addition of the so-called to itsfree hydroxyl group:

Total Synthesis of Vinigrol, J.

Our synthesis began with the preparation of 6 (>99% ) from 5 in 5 steps in 21.8% overall yield, as reported previously (). The diastereoselective reduction of the ketone group in 6, followed by the chemoselective methylation of the resulting alcohol, afforded 8 in 75% yield (1.0 g scale). The structure of 8 was unambiguously confirmed using X-ray crystallography. After extensive experimentation, we found that the regioselective Wacker oxidation of the substituted olefin using air as a co-oxidant gave ketone 9 in good yield. We reasoned that the methoxy group at C10 in 8 was critical for this regioselective outcome. Finally, the double elimination of the oxa-bridge in 9 proceeded smoothly using a slightly modified version of Cha’s procedure in the presence of TMSOTf and Me2EtN in DCM to complete our total synthesis of (−)-1 in 81% yield in >99% . The 1H and 13C NMR spectra of synthetic 1, as well as its optical rotation, were identical to those of the natural product.

Enantiospecific Total Syntheses of Kapakahines B and F, J.

Sources of Drugs: Biological, marine, mineral and plant tissue cultures as sources of drugs;
Classification of Drugs: Morphological, taxonomical, chemical and pharmacological classification of drugs; Study of medicinally important plants belonging to the families with special reference to: Apocynacae, Solanaceae, Rutacease, Umbelliferae, Leguminosae, Rubiaceae, Liliaceae, Graminae, Labiatae, Cruciferae, Papaveraceae; Cultivation, Collection, Processing and Storage of Crude Drugs: Factors influencing cultivation of medicinal plants, Types of soils and fertilizers of common use. Pest management and natural pest control agents, Plant hormones and their applications, Polyploidy, mutation and hybridization with reference to medicinal plants. Quality Control of Crude Drugs: Adulteration of crude drugs and their detection by organoleptic, microscopic, physical, chemical and biological methods and properties. Introduction to Active Constituents of Drugs: Their isolation, classification and properties.
Systematic pharmacognostic study of the followings:
CARBOHYDRATES and derived products: agar, guar gum acacia, Honey, Isabagol, pectin, Starch, sterculia and Tragacanth; Lipids: Bees wax, Castor oil, Cocoa butter, Codliver oil, Hydnocarpus oil, Kokum butter, Lard, Linseed oil, Rice, Bran oil, Shark liver oil and Wool fat; RESINS: Study of Drugs Containing Resins and Resin Combinations like Colophony, podophyllum, jalap, cannabis, capsicum, myrrh, asafoetida, balsam of Tolu, balsam of Peru, benzoin, turmeric, ginger;
TANNINS: Study of tannins and tannin containing drugs like Gambier, black catechu, gall and myrobalan;
VOLATILE OILS: General methods of obtaining volatile oils from plants, Study of volatile oils of Mentha, Coriander, Cinnamon, Cassia, Lemon peel, Orange peel, Lemon grass, Citronella, Caraway, Dill, Spearmint, Clove, Fennel, Nutmeg, Eucalyptus, Chenopodium, Cardamom, Valerian, Musk, Palmarosa, Gaultheria, Sandal wood; Phytochemical Screening: Preparation of extracts, Screening of alkaloids, saponins, cardenolides and bufadienolides, flavonoids and leucoanthocyanidins, tannins and polyphenols, anthraquinones, cynogenetic glycosides, amino acids in plant extracts; FIBERS: Study of fibers used in pharmacy such as cotton, silk, wool, nylon, glass-wool, polyester and asbestos.
Study of the biological sources, cultivation, collection, commercial varieties, chemical constituents, substitutes, adulterants, uses, diagnostic macroscopic and microscopic features and specific chemical tests of following groups of drugs:
GLYCOSIDE CONTAINING DRUGS: Saponins : Liquorice, ginseng, dioscorea, sarsaparilla, and senega. Cardioactive glycosides: Digitalis, squill, strophanthus and thevetia, Anthraquinone cathartics: Aloe, senna, rhubarb and cascara, Others: Psoralea, Ammi majus, Ammi visnaga, gentian, saffron, chirata, quassia.
ALKALOID CONTAINING DRUGS: Pyridine-piperidine: Tobacco, areca and lobelia. Tropane: Belladonna, hyoscyamus, datura, duboisia, coca and withania. Quinoline and Isoquinoline: Cinchona, ipecac, opium. Indole: Ergot, rauwolfia, catharanthus, nux-vomica and physostigma. Imidazole: Pilocarpus. Steroidal: Veratrum and kurchi. Alkaloidal Amine: Ephedra and colchicum. Glycoalkaloid: Solanum. Purines: Coffee, tea and cola. Biological sources, preparation, identification tests and uses of the following enzymes: Diastase, papain, pepsin, trypsin, pancreatin. Studies of Traditional Drugs: Common vernacular names, botanical sources, morphology, chemical nature of chief constituents, pharmacology, categories and common uses and marketed formulations of following indigenous drugs: Amla, Kantkari, Satavari, Tylophora, Bhilawa, Kalijiri, Bach, Rasna, Punamava, Chitrack, Apamarg, Gokhru, Shankhapushpi, Brahmi, Adusa, Atjuna, Ashoka, Methi, Lahsun, Palash, Guggal, Gymnema, Shilajit, Nagarmotha and Neem. The holistic concept of drug administration in traditional systems of medicine. Introduction to ayurvedic preparations like Arishtas, Asvas, Gutikas, Tailas, Chumas, Lehyas and Bhasmas.
General Techniques of Biosynthetic Studies and Basic Metabolic Pathways/Biogenesis: Brief introduction to biogenesis of secondary metabolites of pharmaceutical importance. Terpenes: monoterpenes, sesquiterpenes, diterpenes, and triterpenoids. Carotenoids: a-carotenoids, ß-carotenes, vitamin A, Xanthophylls of medicinal importance. Glycosides: Digitoxin, digoxin, hecogenin, sennosides, diosgenin and sarasapogenin. Alkaloids: Atropine and related compounds, Quinine, Reserpine, Morphine, Papaverine, Ephedrine, Ergot and Vinca alkaloids. Lignans, quassanoids and flavonoids. Role of plant-based drugs on National economy: A brief account of plant based industries and institutions involved in work on medicinal and aromatic plants in India. Utilization and production of phyto-constituents such as quinine, calcium sennosides, podophyllotoxin, diosgenin, solasodine, and tropane alkaloids. Utilization of aromatic plants and derived products with special reference to sandalwood oil, mentha oil, lemon grass oil, vetiver oil, geranium oil and eucalyptus oil. World-wide trade in medicinal plants and derived products with special reference to diosgenin (disocorea), taxol (Taxus sps) digitalis, tropane alkaloid containing plants, Papain, cinchona, Ipecac, Liquorice, Ginseng, Aloe, Valerian, Rauwolfia and plants containing laxatives. Plant bitters and sweeteners. Plant Tissue Culture: Historical development of plant tissue culture, types of cultures, nutritional requirements, growth and their maintenance. Applications of plant tissue culture in pharmacognosy. Marine pharmacognosy: Novel medicinal agents from marine sources. Natural allergens and photosensitizing agents and fungal toxins. Herbs as health foods. Herbal cosmetics. Standardization and quality control of herbal drugs, WHO guidelines for the standardization of herbal drugs.

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