38
1 Drug Discovery and Organic Chemistry Dr. Kendrew K. W. Mak Department of Chemistry The Chinese University of Hong Kong 2 Organic Chemistry in NSS Chemistry Curriculum Topic V Fossil Fuels and Carbon Compounds (b) Homologous series, structural formulae and naming of carbon compounds (c) Alkanes and alkenes (d) Addition polymers Topic XI Chemistry of Carbon Compounds (a) Introduction to selected homologous series (b) Isomerism (c) Typical reactions of various functional groups (d) Inter-conversions of carbon compounds (e) Important organic substances (drugs, detergents, polymers, biomolecules)

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  • 1

    Drug Discovery and Organic Chemistry

    Dr. Kendrew K. W. Mak

    Department of ChemistryThe Chinese University of Hong Kong

    2

    Organic Chemistry in NSS Chemistry Curriculum Topic V Fossil Fuels and Carbon Compounds

    (b) Homologous series, structural formulae and naming of carbon compounds

    (c) Alkanes and alkenes(d) Addition polymers

    Topic XI Chemistry of Carbon Compounds(a) Introduction to selected homologous series(b) Isomerism(c) Typical reactions of various functional groups(d) Inter-conversions of carbon compounds(e) Important organic substances (drugs, detergents, polymers,

    biomolecules)

  • 3

    STSE ConnectionsTopic XI (page 63)

    The search for new carbon compounds often requires the synthesis of hundreds of compounds which are variations of their basic structures. Some compounds which have been synthesized may have certain useful aspects, but also dangerous side-effects which prohibit their general use. It is often necessary to look for other compounds with similar structures but without the side-effects.

    Often more than one synthetic route may be available to prepare a particular carbon compound. However, some synthetic routes may have undesirable effects on our health and our environment. The bestsynthetic route may not be the one with the fewest steps or the lowest cost. It is, therefore, essential to apply our knowledge of organic chemistry so that useful organic products are developed and manufactured by safe, economic and environmentally acceptable routes.

    4

    Aims of This Lecture

    Introduce the role of organic chemistry in the drug discovery and development processes.

    Stimulate students interest in learning organic chemistry.

    STSE Connections

  • 5

    Contents

    Part 1 Drugs, Molecules, Structures and Drug Actions

    Part 2 The Drug Discovery Processes

    Part 3 Organic Synthesis The Essential Tool for Making Drugs

    6

    Drugs, Molecules, Structures and Drug Actions

    Part 1

  • O OH

    O CH3

    O

    Aspirin

    CH3COO

    O

    CH3COO

    HNCH3

    Heroin

    O

    O

    OO

    OH

    OO

    O

    HO

    NH

    OH

    OO

    O

    O

    Taxol

    Oseltamivir (Tamif luTM)

    OEt

    O

    NH O

    O

    H3C

    H2N

    19991999

    18991899

    18981898

    19931993

    8

    Lets Begin with Aspirin

    Analgesic (to relieve pain) Antipyretic (to lower fever) Anti-inflammatory agent (to reduce

    inflammation)

    Treatment of rheumatoid arthritis ()

    Preventing some types of strokes and heart attacks

    O OH

    O CH3

    O

  • 9

    Aspirin Had a Very Long History

    http://upload.wikimedia.org/wikipedia/commons/0/00/Salix_alba_Morton.jpg

    Ancient people found the willow bark had medical properties.

    Ancient Egyptian medical literature Ebers Papyrus(written in 1534 BC)

    The Papyrus copied some ancient documents 1000 years earlier they knew using willow since 2500 BC

    10

    Aspirin Had a Very Long History

    Ancient Egyptian use willow as a pain reliever and anti-inflammatory therapy.

    For treating cough, ear infection and arthritis.

    Willow was also described in ancient Sumerian medical text written in around 3000 BC

    http://upload.wikimedia.org/wikipedia/commons/8/8b/Ebers7766.jpg

    Jeffreys, D. Aspirin: The Remarkable Story of a Wonder Drug. Bloomsbury: London. 2004, pp. 8-11.

  • 11

    What is Present in the Willow Bark?

    O

    HO

    OHO

    OH

    HO

    OH

    Salicin ()

    HydrolysisGlucose +

    CH2OHOH

    Salicyl alcohol

    oxidation

    O OH

    OH

    Salicylic acid ()

    Isolated from willow bark in 1827

    Sour and irritating when taken orally!

    12

    Derivatives of Salicylic Acid being hydrolyzed

    to salicylic acid and phenol in the small intestine

    Sodium salicylate()

    Phenyl salicylate (Salol)()

    unpleasant toswallow

    irritating to the stomach

    COO-Na+

    OH

    COO

    OH

    introduced by Bayer in 1899

    Acetylsalicylic acid (Aspirin, )

    COOH

    OCCH3O

    Salicylic acid()

    18861875

    COOH

    OH

    Sneader, W. Drug Discovery: A History. John Wiley & Sons: West Sussex. 2005, pp. 357-359.

  • 13

    O OH

    OH +H3C O

    O

    CH3

    OO OH

    O CH3

    O

    +O

    OHH3C

    Salicylic acid()

    Acetic anhydride()

    Aspirin()

    Acetic acid()

    Synthesis of Aspirin

    14

    What Have We Learnt from The Story of Aspirin?

    It is a synthetic drug which cannot be found in nature, but has a plant origin.

    Compounds having similar structure are likely to have related medical properties.

    The drug properties of a compound can be improved by modifying its chemical structure.

  • 15

    Opioid Analgesics

    http://upload.wikimedia.org/wikipedia/commons/2/2a/Slaapbol_R0017601.JPG

    The unripe seed pods of the poppy Papaver somniferum

    Using the juice from the unripe seed pods for medical purposes:

    As a sedative for children (in Ebers Papyrus)

    In the Sumerian culture as early as 3500 BC.

    16

    HO

    O

    HO

    HNCH3

    Morphine

    Morphine

    First isolated in 1805

    The principal alkaloid (~10% w/w) of raw opium

    The most important narcotic analgesic in medicine - for relief severe pain

    But it is an addictive!

    It causes digestion problems

  • 17

    Opium

    Opium, the dried sap of the poppy, contains:

    HO

    O

    HO

    HNCH3

    H3CO

    O

    H3CO

    HNCH3

    H3CO

    O

    HO

    HNCH3

    N

    OCH3

    OCH3

    OCH3H3CO

    Morphine ThebaineCodeine Papaverine

    Alkaloids ()

    Opium contains approximately 20 alkaloids.

    18

    Synthesis of Heroin and Codeine

    HO

    HOH

    ON

    MeCH3O

    HOH

    ON

    Me

    Morphine Codeine

    CH3COO

    CH3COOH

    ON

    Me

    Heroin

    Ac2O, AcOHHeat KOH, CH3I

    Heroin was accidentally synthesized by Felix Hoffmann (a synthetic chemist in Bayer) while he was searching way to synthesize codeine from morphine.

    Heroin is a much more powerful narcotic and cough-suppressant than morphine.

  • 19

    How Aspirin Works?

    20

    How the Nervous System Works?

    A nerve impulse (reaching a synaptic cleft causes these vessels to release neurotransmitters.

    Neurotransmitters migrate across the cleft to the receptor sites to trigger a nerve impulse in the next neuron, or start a bodily response.

  • 21

    Endorphins () and Enkephalins

    Enkephalins (a kind of endorphins) are released in the body as the natural pain-killer.

    The opium alkaloids play the roles as endorphins.

    Enkephalins bind to the opiate receptors and block the release of neurotransmitters that would convey the pain message to the pain.

    22

    The Key and Lock Model of Drug Action

  • 23

    Drug-Receptor Interactions

    CH

    HH

    N ReceptorH

    Covalent bond

    H4N O Ionic bondCO

    Receptor

    H O Hydrogen bondO Receptor

    HC H C Receptor Hydrophobic Interactions(van der Waals forces)

    24

    The Drug Discovery Processes

    Part 2

  • 25

    COOH

    OH

    Salicylic acid

    Lead Compound

    COO-Na+

    OHSodium salicylate

    COO

    OH

    Phenyl salicylate(Salol)

    COOCH3

    OH

    Methyl salicylate(Major constituent of wintergreen oil)

    COOH

    OCOCH3

    Acetylsalicylic acid(Aspirin)

    Lead Compound and Synthetic Derivatives

    Lead Compound: A chemical compound that has drug activity. Used as a starting point for chemical modifications in order to improve drug

    performance.

    N OHH3C

    O

    OHMorphine

    N OCOCH3H3C

    O

    OCOCH3Heroin

    NH3C

    OCH3Dextromethorphan

    effective cough suppressant

    NOCH3H3C

    O

    OHEtorphine

    2000 times more potent than morphinefor tranquilizing large animals

    OHCH2CH2CH3

    NH3C OC2H5

    O

    Pethidinevery much less potent

    NH3C

    OHLevorphanol

    more potent but also highly additive

    NCH3H3C

    H3CCO

    CH3

    Methadoneequally potent but much less additive

    Lead compound

    Thomas, G. Medicinal Chemistry, 2nd Ed. John Wiley & Sons: West Sussex. 2007, pp. 79-80.Bruice, P. Y. Organic Chemistry, 5nd Ed. Pearson Prentice-Hall: Upper New Jersay. 2007, pp. 1299-1300.

  • Drug Discovery ProcessTarget

    identification

    Leadidentification

    Leadoptimization

    Preclinicaland clinical

    development

    Targetvalidation High throughput screening

    Natural product screening Virtual screening Combinatorial chemistry Compound library design Structure-based design

    Medicinal chemistry Design of focused compound libraries Molecular modeling

    (quantitative structure-activity relationships) Structure-based design

    Chemical developments in lead identification

    Chemical developments in lead optimization

    28

    Lead Identification

    From Traditional Medical Practices (Local folk remedies)

    Salicylic acid (from willow barks / salicin)

    Morphine (from opium)

    Random Screening

    Random screening of soil samples in search of new antibiotics in1940s and 1950s --> discovery of two important antibiotics: streptomycin and tetracyclines.

    Taxol

  • 29

    Taxol: A Famous Anti-Cancer Drug

    O

    O

    OO

    OH

    OO

    O

    HO

    NH

    OH

    OO

    O

    O

    Taxol

    In 1960, the National Cancer Institute (NCI) and the United State Department of Agriculture (USDA) started a very ambitious programme to collect and screen plant products as potential anti-cancer agents.

    114,000 plant extracts from 35,000 samples were screened.

    Barks of a Pacific yew tree (Taxusbrevifolia) was collected 1962, and it was found to be cytotoxic in 1964.

    Pure sample of the active ingredient, taxol, was isolated in 1966.

    Goodman, J. Walsh, V. The Story of Taxol: Nature and Politics in the Pursuit of an Anti-cancer Drug. Cambridge University Press: Cambridge. 2001, Chapter 1.

    30

    Compound collections, data bases and synthesis

    All large pharmaceutical companies maintain extensive compound libraries (10K to > 2M compounds).

    By high-throughput screening (HTS). A robot system can screen >100,000 compounds per day.

    Combinatorial chemistry () produce large numbers of compounds required for high-throughput screening. It synthesizes a large number of compounds simultaneously from some building blocks.

    Computational approaches (virtual screening, de novo drug design)

    Thomas, G. Medicinal Chemistry, 2nd Ed. John Wiley & Sons: West Sussex. 2007, Chapter 1.

    Lead Identification

  • 31

    Non-random screening

    Compounds which are weakly active are chosen as lead, and compounds which are structurally similar to them are screened selectively.

    Lead Identification

    Compound libraries are generated to mimic or blocking the effects of a natural mediator (developed Tamiflu)

    Compound libraries are generated from the chemical structure of a known, existing active drug. the me-too approach

    32

    Lead Identification

    Rational Approach to Drug Discovery

    Basic research into the disease process and its causes.

    Assessment of the biochemical and biological processes of the disease and/or this cause.

    To decide what intervention is most likely to bring about the desired result (identify a key ligand, protein, DNA, etc).

    Study the structural information of the possible target site (protein structure, DNA structure)

    Use molecular modeling technique to study whether a potential drug (ligand) can superimpose to the target site DOCKING.

  • 33

    How Tamiflu Prevents the Avian Flu and Swine Flu From Spreading?

    Neuraminidase (NA) is an essential enzyme for viral replication

    It catalyzes the cleavage of sialicacid residues from glycoproteins and liberates the budding virion.

    NA forms a complex with sialic acid

    Strategy:Design and make a compound that binds to NA to inhibit its function.

    34

    O

    O

    OH

    OH

    HOOH

    NH

    HNO

    H3C

    NH2HN

    OOH

    HOOH

    HOOH

    O OH

    NH

    H3C

    O

    Sialic acid Zanamivir (RelenzaTM)

    Corey, E.J.; Czak, B.; Krti, L. Molecules and Medicine; Wiley: New Jersey, 2007; p 150

    Developed in 1989 using structure-based design

    Limited clinical use because of its poor bioavailability (~ 2%)

    The First Neuraminidase Inhibiting Drug

  • 35

    OOH

    HOOH

    HOOH

    O OH

    NH

    H3C

    O

    Sialic acid Oseltamivir (TamifluTM)

    OEt

    O

    NH O

    O

    H3C

    H2N

    Corey, E.J.; Czak, B.; Krti, L. Molecules and Medicine; Wiley: New Jersey, 2007; p 150

    Developed by C. U. Kim at Gilead Sciences in early 1990sMarketed as Tamiflu by Roche

    The First Orally Active Neuraminidase Inhabiting Drug

    36

    Lead Optimization / Lead Modification

    Once a lead compound is identified, molecular modification of the lead compound will be carried out to:

    Optimize the potency of the lead compound (minimize cost and dosage). Chirality Minimize the side-effects of the lead compound. Ease of formulation (solubility, dissolution and stability)

    The classical example : From salicylic acid to aspirin

    COOH

    OH

    COOH

    OCOCH3

    Too corrosive to be taken orally.Causing digestive problems(e.g. stomach bleeding)

    Much less corrosiveEqually potent

  • 37

    Lead Optimization

    Functional Group Modification

    Solubility and drug design Stereochemistry and drug design Structure-activity relationships (SARs)

    Identification of the Active Part: The Pharmacophore Metabolism

    38

    Lead OptimizationSolubility and drug design

    A potent drug should have a good balance between: solubility in aqueous media solubility in lipid tissues

    to optimize the absorption and transportation to the site of action.

    A drug should be hydrophilic enough: to dissolve in the aqueous gastric fluid for absorption to be effectively transport via the systemic circulation to the site of action

    A drug should be lipophilic enough: to pass through the appropriate lipid membrane to reach the site of action

  • 39

    Lead OptimizationSolubility and drug design

    HO

    HOH

    ON

    MeCH3COO

    CH3COOH

    ON

    Me

    Morphine Heroin

    Acetic Anhydride

    Less lipophilic More lipophilicCan pass through the blood-brain barrier more effectively.

    Very polar, More hydrophilic

    Very polar, More hydrophilic

    Less polar, More lipophilic

    Less polar, More lipophilic

    40

    Stereochemistry and Drug Actions The Tragedy of Thalidomide

    NH

    O O

    HN

    NH

    OO

    HN

    (R)-ThalidomideSedative

    (S)-ThalidomideTeratogen

    Thalidomide - Sold in the form of racemate in 1958 - 1960

    For suppressing morning-sickness during early pregnancy

    Resulted in 12,000 of deformed births.

  • 41

    Structure-ActivityRelationship of TaxolStructure-ActivityRelationship of Taxol

    42

    Organic Synthesis The Essential Tool for Making Drugs

    Part 3

  • 43

    Chemical Techniques in Drug Discovery and Development

    Compound isolation and purificationIsolate the active compounds from natural sourcesIsolate the desired compound with good purity from a synthesis

    Structural identificationNuclear magnetic resonance spectroscopy (NMR)Infrared spectroscopy (IR)Mass spectrometry (MS)X-ray crystallography

    Organic synthesisBuilding up the compound library for screening (lead identification)Making derivatives for lead modificationSynthesize an approved drug with good efficiency

    Theoretical ChemistryMolecular modeling for rational drug design

    44

    Compound Isolation and Purification

    Salicin / Morphine

    Plant extracts for medical uses: ~ 2500 3000 BC

    Isolated as pure forms: salicin (1827); morphine (1805)

    Aspirin First synthesis: 1853

    No follow-up because could not purify and identify the structure of the product.

    Second synthesis: 1897

  • 45

    Activity for StudentsIsolation of caffeine from tea leaves

    N

    N N

    N

    O

    O

    H3C

    CH3

    CH3

    Caffeine

    Black Tea / English TeaBlack Tea / English Tea

    Green TeaGreen Tea

    Ground CoffeeGround Coffee

    Instant CoffeeInstant Coffee

    46

    Tea Leaves Solid-Liquid Extraction(water)

    Water InsolubleCellulose

    Water SolubleCaffeineOther water-soluble substances

    Liquid-Liquid Extraction(dichloromethane / water)

    Soluble in WaterProteinsAminoOther water-soluble substances

    Soluble in CH2Cl2CaffeinePigments(removed by recrystallization)

    Base(CaCO3)

    Isolation of Caffeine From Tea Leaves(A commonly used method)

  • 47

    Extraction of Limonene from Citrus Fruit Peels

    (R)-(+)-Limonened-Limonene

    Main component (~ 90%) of the essential oil of oranges.

    Orange peel zest (outer peel) contains about 0.5 1.0% of limonene.

    Method 1 : Isolation of Limonene by Extraction into a Solvent

    Method 2 : By Steam Distillation

    Method 1 : Isolation of Limonene by Extraction into a Solvent

    Method 2 : By Steam Distillation

    48

    Vitamin C Natural Sources

    O OH

    HOOH

    HO OH

    Vitamin C

    6 carbon atoms5-membered ringLactone (cyclic ester)4 hydroxyl groups2 chiral centers

    90Broccoli

    50Orange

    23Pork liver

    90Kiwifruit

    190Red pepper

    200Blackcurrant

    Amount (mg / 100 g)

    Plant source

    Vitamin C supplements and in drinks

    110,000 tonnes of Vitamin C is synthesized from D-glucose annually.

  • The Reichstein Process of Synthesizing Vitamin C

    O OH

    OH

    HOHO

    OH

    D-glucose

    123

    4 56

    + H2 (Ni)

    CH2OHCC

    OHHHHO

    C OHHC OHHCH2OH

    1

    2

    3

    4

    56

    D-sorbitol

    Microbial oxidation(fermentation)

    acetobacter

    CH2OHCC

    OHHO

    C OHHC OHHCH2OH

    1

    2

    3

    4

    56

    D-sorbose

    O

    H+ CH2OH

    H

    O H

    H OO

    O

    OKMnO4 / H+

    1

    23

    45

    6

    COOHCC

    OHO H

    CH OHC HHOCH2OH

    1

    4

    5

    6

    2

    3 esterification

    - H2O

    OO

    OHH

    H OHHO

    HO

    Vitamin C~ 60% yield

    (f rom D-glucose)

    1456

    23

    4 chemical synthetic steps + 1 fermentation

    Reported in 1933Reported in 1933

    50

    Restraints of Organic Synthesis

    Chemoselectivity To perform a required structural change.

    Regioselectivity To orient the reacting partners in a correct

    fashion.

    Diastereoselectivity To create the correct orientations of various parts of

    the molecule with respect to each other.

    Enantioselectivity To enable the formation of a molecule in one

    handedness or as one mirror image isomer.

  • 51

    Industrial Synthesis of Salicylic Acid

    OH CO2, NaOH

    ~ 120oC, 100 atm

    OH

    O-Na+

    O

    H+OH

    OH

    O

    Regioselective

    Chemoselectivity(to carry out a desired functional transformation)

    52

    The Reichstein Process of Synthesizing Vitamin C

    O OH

    OH

    HOHO

    OH

    D-glucose

    CCC

    OHHHHO

    C OHHC OHHCH2OH

    O H

    D-glucose(Fischer projection)

    1

    2

    3

    4

    56

    123

    4 56

    + H2 (Ni)

    CH2OHCC

    OHHHHO

    C OHHC OHHCH2OH

    1

    2

    3

    4

    56

    D-sorbitol

    Microbial oxidation(fermentation)

    acetobacter

    CH2OHCC

    OHHO

    C OHHC OHHCH2OH

    1

    2

    3

    4

    56

    D-sorbose

    Acetobacter is the bacteria for converting ethanol to acetic acid (vinegar production).

    The oxidation of D-sorbitol to D-sorbose is difficult due to the required regioselectivity.

  • CH2OHCC

    OHHO

    C OHHC OHHCH2OH

    1

    2

    3

    4

    56

    D-sorbose

    H

    HO

    HO

    H

    HOH2C

    H OH O

    CH2OH

    H

    HO

    HO

    H

    HOH2C

    H OH CH2OH

    O

    H+

    H+

    CH2OH

    OH

    HOH2C

    H

    OH H

    H HOO

    OH

    CH2OH

    HOH2C

    H

    OH H

    H HOO

    O

    H+

    O

    H+

    OH

    H

    O H

    H OO

    O

    O

    2 6-membered cyclic acetals(less stable)

    CH2OH

    H

    O H

    H OO

    O

    O

    1 5-membered cyclic acetal1 6-membered cyclic acetal

    (more stable)

    1

    2

    34

    5

    61

    2

    34

    5

    61

    2

    3456

    OOH

    H

    OH

    CH2OHOH

    HOH

    H

    H

    H

    1

    2

    34

    5

    6UnstableIncorrect stereochemistry forforming the cyclic acetal

    (a)

    (b)

    (route b)

    (route a)

    (route a)

    Formation of cyclic hemiacetal(diastereoselective)

    CH2OH

    H

    O H

    H OO

    O

    OKMnO4 / H+

    1. oxidation of the -CH2OH group2. deprotection3. open up the 5-membered hemiacetal

    COOH

    H

    O H

    H OO

    O

    OH+

    1

    23

    45

    61

    23456

    COOHCC

    OHO H

    CH OHC HHOCH2OH

    1

    23

    4

    5

    6

    esterification

    - H2O

    OO1

    2

    3

    4

    O

    OH

    H

    tautomerizationH

    H OHHO 5

    6

    OO

    OHH

    H OHHO

    HO

    Regioselective

    Vitamin C~ 60% yield

    from D-glucose

  • The Roches Process

    Rohloff, J. C. et. al. J. Org. Chem. 1998, 63, 4545-4550.

    CO2HHO

    HOOH

    shikimic acid(extracted from Chinese star anise)

    CO2Et

    OMs

    O

    O

    3 steps 2 stepsCO2EtO

    O

    CO2EtO

    HON3

    CO2EtO

    HN

    CO2EtO

    AcHNN3

    2 steps

    CO2EtO

    AcHNNH2.H3PO4

    10 Steps, ~ 21% yield

    The commercial synthesis of TamifluThe commercial synthesis of Tamiflu

    56

    Drawbacks of the Roches Process

    The limited availability of shikimic acid

    CO2HHO

    HOOH

    shikimic acid(extracted from Chinese star anise)

    CO2EtO

    AcHNNH2.H3PO4

    13 g of dried plant gives 1.3 g of shikimic acid(just enough for making ten 75 mg capsules)

    To meet the annual worldwide demand of 300 million doses, 840 tons of star anise is needed.

    90% of Chinese star anise is used for making Tamiflu

    Chinese Star AniseFrom www.wikipedia.org

  • CO2HHO

    HOOH

    shikimic acid(extracted from Chinese star anise)

    CO2Et

    OMs

    O

    O

    3 steps 2 stepsCO2EtO

    O

    CO2EtO

    HON3

    CO2EtO

    HN

    CO2EtO

    AcHNN3

    2 steps

    CO2EtO

    AcHNNH2.H3PO4

    10 Steps, ~ 21% yield

    The use of the potentially explosive azide-containing intermediates.

    Drawbacks of the Roches Process

    58

    An Azide-free RouteDeveloped by Roche

    Karpf, M.; Trussardi, R. J. Am. Chem. Soc. 2001, 66, 2044-2051.

    CO2HHO

    HOOH

    shikimic acid

    6 stepsCO2EtO

    O

    CO2EtO

    AcHNNH2.H3PO4

    11 Steps, ~ 21% yield

    CO2EtO

    HOHN

    CO2EtO

    HONH2

    CO2EtO

    H2NHN

    CO2EtO

    AcHNHN

    The route does not involve potentially explosive azide-containing intermediates.

  • +CO2CH2CF3

    NB O

    HPhPhH

    o-Tol

    NTf2

    CO2CH2CF3

    3 steps

    NOBoc

    I

    NOBoc

    NOBoc

    Br

    CO2EtBocHN

    CO2Et

    AcHNO

    BocHN

    CO2EtBocHN

    BrNHAc

    2 steps

    CO2Et

    AcHNO

    H3NH3PO4

    11 steps, 30% yield No shikimic acid No azide intermediates

    Corey, Yeung and Co-workers Approach

    Yeung, Y. -Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310-3611.

    EnantioselectiveDiels-Alder Reaction

    Regioselective and diastereoselectiveaddition reaction

    Efforts Made By Japanese ChemistsShibasakis Method 3rd Generation

    CO2EtO

    AcHNNH2.H3PO4

    12 steps, ~ 2.8% yield

    (2 steps)OTMS

    O

    ClCl

    ON3

    O

    O

    N3

    OHNH

    OO

    NHBoc

    OHNHAc

    NHBoc

    ONHAc

    NHBoc

    (2 steps)O

    NHAc

    NHBocNC

    OHNHAc

    NHBocNC

    (2 steps)O

    NHAc

    NHBocNCresolution bychiral HPLC

    (2 steps)

    Yamatsugu, K.; kamijo, S.; Suto, Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.2007, 48, 1403-1406.

    Poor overall yield Resolution by chiral HPLC

    impractical for large-scale synthesis

  • Chemists Are Still Working Out a Shorter Route

    Trost, B. M.; Zhang, T. Angew. Chem. Int. Ed. 2008, 47, 3759-3761.

    OO

    CO2EtPhthN CO2EtSPh

    PhthN CO2EtPhthN

    CO2EtPhthN

    SESN

    CO2EtPhthN

    SESHNO

    CO2EtPhthN

    SESNOAc

    CO2EtPhthN

    AcHNO

    CO2EtH2N

    AcHNO

    8 steps, 30% yield

    Good yield obtained from a short synthesis (concise and efficient)

    Palladium catalyzed asymmetric allylic alkylation

    62

    Is total synthesis always practical for making a drug?

  • 63

    Early Studies of the Medical Uses of Taxol

    May 1964: Found to be cytotoxic (toxic to cell)Sept 1966: Isolated in pure form

    1971: Its chemical structure published

    Apr 1984: Clinical trial began(60,000 lbs of barks required)

    May 1988: Shown to be effective for treating ovarian cancer(anticipated that 360,000 trees had to be destroyed to meet the US demand)

    Jan 1993: Taxol available on the market(29 years after its first discovery)

    64

    Difficulties in Developing Clinical Applications of Taxol

    The natural supply is very limited. Complicated extraction steps. Very low yield: 0.004% of bark. Three mature 100-year old trees

    to yield 1 g of taxol. (dosage: ~150 mg/week)

    Destructive harvesting.

    It is very insoluble in water.

    http://commons.wikimedia.org/wiki/File:Yew_bark_Taxol_PD.jpg

  • 65

    O

    O

    OO

    OH

    OO

    O

    HO

    NH

    OH

    OO

    O

    O

    Taxol An Extreme ChallengeFor Organic Synthesis

    4 fused ring structure

    8-membered ring

    4-membered ring

    11 chiral centers

    EtO

    O

    OB

    O

    Ph

    O

    O

    O

    EtO

    O O

    OBO

    Ph O

    OH

    O

    OH

    OTBS

    OTBDPS

    OH

    OBn

    OHOH

    OTBDPS

    O

    OBn

    OO

    HOAc

    OH

    O

    OH

    NHN

    SO2Ar

    +A C

    O

    OTBDPS

    O

    HOH O

    OTBS

    Ph

    A C

    Building the C ring

    Building the A ring

    Joining A ring and C ring

    Total Synthesis of Taxol(Part 1)

    O

    O

    OO

    OH

    OO

    O

    HO

    NH

    OH

    OO

    O

    O

    Developed by Prof. K. C. Nicolaou(1994)

  • O

    OTBDPS

    O

    HOH O

    OTBS

    Ph

    A C

    O

    O O

    OH O

    OPh

    A C

    O

    HH

    O

    O

    O

    H O

    Ph

    C

    O

    HO OH

    O

    O

    A B

    Building the B ring

    racemic

    O

    O

    Cl

    O

    O

    O

    H O

    Ph

    C

    O

    HO OH

    O

    O

    A B

    O

    O

    O

    O

    O

    H O

    Ph

    C

    O

    HO O

    O

    O

    A B

    O

    O

    H O

    Ph

    C

    O

    HO O

    O

    O

    A B

    O

    O

    O

    +

    Total Synthesis of Taxol(Part 2)

    Resolving the racemic mixture

    Total Synthesis of Taxol(Part 3)

    O

    O

    H O

    Ph

    C

    O

    HO OH

    O

    O

    A B

    O

    O

    H OHAc

    C

    O

    O O

    O

    O

    A B

    TESAc

    O Ms

    O

    O

    H

    Ac

    C

    O

    O O

    O

    O

    A B

    TESAc

    O

    O

    O

    H

    Ac

    C

    OH

    O O

    O

    A B

    TESAc

    O

    HO

    PhO

    N

    O

    O

    OTES

    O

    O

    H

    Ac

    C

    OH

    O O

    O

    A B

    TESAc

    O

    O

    PhO

    O

    PhOH

    NHO

    Ph

    Building the D ring

    Adding the Tail

    The total synthetic route involved > 40 stepsOverall yield < 2%

  • 69

    Semi Synthesis of Taxol

    O

    OH

    H

    AcOH

    HO O

    OO

    HO

    PhO

    10-Deacetylbacctain IIIhttp://commons.wikimedia.org/wiki/File:Taxus_baccata_tree.jpg

    Isolated from the leaves of the American and European yew

    Up to 0.2% yield of dry leaves. The leaves are re-grown rapidly after

    harvested, providing a steady source of starting material.

    http://commons.wikimedia.org/wiki/File:Yew_Berries.jpg

    4 steps

    80% yieldTaxol

    70

    Modern Biochemistry Technology Made Taxol Synthesis Easier

    By Plant Cell FermentationBy Plant Cell Fermentation

    Starting materials: Feedstock for cell growth consisting sugars, amino acids, vitamins and trace elements.

    Biosynthesis: Feeding the feedstock to a specific taxus cell line in aqueous medium in large fermentation tanks.

    Isolation: Extract from the fermentation mixture, purify by chromatography and crystallization.

  • 71

    O

    O

    OO

    OH

    OO

    O

    HO

    NH

    OH

    OO

    O

    O

    Lead OptimizationGetting a Better Derivative

    Taxolalmost insoluble in water

    difficult to administrate by IV infusion

    O

    O

    OHO

    OH

    OO

    O

    HO

    NH

    OH

    O

    O

    O

    O

    Taxoteremore soluble in water

    more potent

    72

    Scope of Organic Synthesis

    Organic SynthesisOrganic Synthesis

    Nicolaou, K.C.; Sorensen, E.J. Classics in Total Synthesis; VCHWiley: Weinheim, 1996; p 4

    Target Oriented(Total Synthesis)Target Oriented

    (Total Synthesis) Methods OrientedMethods Oriented

    Natural ProductsNatural Products

    DesignedMoleculesDesignedMolecules

    ReagentsReagents CatalystsCatalysts Synthetic Strategies

    Synthetic Strategies

    SyntheticTactics

    SyntheticTactics

    TheoreticallyInteresting Molecules

    TheoreticallyInteresting Molecules

    BiologicallyInteresting Molecules

    BiologicallyInteresting Molecules

    MedicallyInteresting Molecules

    MedicallyInteresting Molecules

    Materials ScienceInteresting Molecules

    Materials ScienceInteresting Molecules

  • 73

    Can We Participate the Drug Discovery Research?

    74

    Computer Aided Drug Design -Docking

    To superimpose the three-dimensional structure of a potential drug (ligand) on its possible target site.

    A small molecule docked to a protein

    http://en.wikipedia.org/wiki/File:Docking.jpg

  • 75

    Participating the Drug Discovery @Home

    Distributed Computing

    E.g. World Community Gridhttp://www.worldcommunitygrid.org/

    Projects

    Influenza Antiviral Drug SearchHelp Fight Childhood Cancer.