CM3101 Alkaloids I - Alkaloids I.pdf1963 – Definition based on chemotaxonomy. Alkaloids should be divided into 3 subgroups • Proper alkaloids • Proto alkaloids •

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  • Alkaloids Found in ~20% of vascular plants. Compounds usually basic (alkaline). ~40,000 compounds currently described. Structurally the most diverse class of secondary metabolites.

    NH

    H

    (+)-coniine(Conium maculatum)

    poison hemlock

    HOH

    HO

    O

    HO

    O

    NH

    N

    batrachotoxin(Phyllobates aurotaenia)

    Columbian arrow frogLD50 (mice) = 2mcg/kg sc

  • Many natural product alkaloids are of biological interest Morphine (painkiller) Vincristine (anticancer agent) Cocaine (anaesthetic, drug of abuse) Nicotine (tobacco, poison) Caffeine (stimulant)

    Relatively straightforward to isolate. Of intense interest to organic chemists for the challenge of structural elucidation and total synthesis.

    Devise new synthetic methodologies

    Alkaloids - Definitions First definition (1817)

    Basic compounds Contain N (nitrogen) in molecule Can form salts with acids Occur in plants Pharmacologically active

    1963 Definition based on chemotaxonomy. Alkaloids should be divided into 3 subgroups

    Proper alkaloids Proto alkaloids Pseudo alkaloids

  • Proper Alkaloids Also known as true alkaloids. Basic. Nitrogen part of a heterocyclic ring system. Chemically complex. Derived biosynthetically from amino acids, especially the cyclic amino acids:

    Phe, Tyr, Try, His Many physiologically active. Have limited distributions in the plant kingdom.

    N

    N

    O

    O

    H H

    HH

    H

    NH

    COOH

    NH2

    L-tryptophan()-strychnine

    (Strychnos nux vomica)

    ()-strychnine from the dried seeds of Strychnos vux vomica. Small tree found from India to Northern Australia. Fruit is a large berry with a hard coat and pulpy interior containing 3-5 fleshy grey seeds contain ~1.2% strychnine. 60mg can kill an adult.

  • Proto Alkaloids Physiologically active. Nitrogen atom is outside the ring system.

    COOH

    NH2

    L-Phenylalanine

    OH

    NHCH3

    ()-ephedrinesympathomimetic amine

    (Ephedra sp.)

    O

    OMe

    H

    NH

    O

    colchicine(Colchicum autumnale)used in the tx of gout

    cycloheptatrienonering

  • Pseudoalkaloids Nitrogen containing (physiologically active) compounds not derived from amino acids. The purine ring is gradually elaborated by piecing together small components from primary metabolism.

    HN

    N N

    N

    O

    O

    OHHO

    PO

    inosine monophosphate(IMP)

    N

    N N

    HN

    O

    O

    theophylline

    HN

    N N

    N

    O

    O

    theobromine

    N

    N N

    N

    O

    O

    caffeine

    N

    N NH

    Nformate

    formate

    L-GlnL-Gln

    L-asp

    CO2 Gly

    purine alkaloids from Coffea species (C. arabica, C. canephora, C. liberica, etc)

  • Alkaloid Nomenclature

    N

    O

    ()-hygrine(Erythroxylum coca)

    PYRROLIDINE

    N

    O

    O

    OH

    ( )-hyoscyamine (atropine)(Atropa belladonna)Deadly nightshade

    TROPANE

    NORTROPANE

    HN

    epibatidine(Epipedobates tricolor)Ecuadorian poison frog

    200-500x potent then morphine

    N

    Cl

    N

    O

    PIPERIDINE

    N-methylpelletierine

    N

    O

    pseudopelletierine

    (Punica granatum)pomegranate bark

    possesses activity against intestinal tapeworms

  • N

    OHO

    lobeline(Lobelia inflata)antiasthmatic

    PIPERIDINE

    PYRROLIZIDINE

    N

    pyrrolizidineN

    HHO OH

    retronecine

    N

    OO

    OHO OH

    O H

    riddelliine

    retronecine

    riddellic acid

    Senecio sp(S. vulgaris) groundsel(S. jacobaea) ragwort

    PYRROLIZIDINE

  • ()-lupinine(Lupinus luteus)

    yellow lupin

    QUINOLIZIDINE

    N

    quinolizidine

    N

    HOH

    N

    N

    H

    H

    ()-sparteine(Cytisus scoparius)

    Scotch broom

    PYRIDINE

    nicotine

    (Nicotiana tabacum)tobacco

    N

    NH

    anabasine

    NH

    NH

    INDOLIZIDINE

    indolizidinecastanospermine

    (Castanospermum australe)Moreton Bay chestnut

    N N

    OHHOH

    HO

    HO

  • PYRROLOINDOLE

    physostigmine(Physostigma venenosum)

    Calabar beans (Nigeria)Cholinesterase inhibitor

    NH

    NH

    pyrroloindole

    N

    NO

    O

    MeHN

    H

    PHENETHYLAMINE

    O

    NH2

    ()-cathinone(Catha edulis)

    khatCNS stimulant

    QUINOLINE PURINE

    purinequinoline

    N

    N

    MeO

    N

    H

    H

    HOH

    ()-quinine(Cinchona sp)

    antimalarial

    N

    N NH

    N

    caffeine

    N

    N N

    N

    O

    O

  • IMIDAZOLE

    N

    N OO

    pilocarpine(Pilocarpus jaborandi)

    cholinergic for glaucoma

    -CARBOLINE

    NH

    N

    -carboline

    NH

    N

    harmine(Peganum harmala)

    Syrian rue

    MeO

    SIMPLE INDOLE

    NH

    NMe2

    OP

    psilocybin(Psilocybe mexicana)

    magic mushrooms

    ACRIDINE

    rutacridone(Ruta graveolens)

    Garden rue

    N

    acridineN O

    O OH

  • QUINAZOLINE

    quinazolineN

    N

    peganine(Peganum harmala)

    Syrian rue

    N

    N

    OH

    PYRROLOQUINOLINE

    pyrroloquinoline camptothecin(Camptotheca acuminata)

    Chinese treetopoisomerase I inhibitor

    NN

    NN

    O

    O

    OOH

    STEROIDAL ALKALOIDS

    HO

    H

    HH

    cholestrol

    O

    HN

    H

    H

    HH

    H

    H

    HO

    tomatidine(Lycopersicon esculente)

    tomato

    squalamine(Squalus acanthias)

    dogfish sharkantimicrobial

    H

    NH H

    OHH H

    OSO3H

    NH

    H2N

  • BENZYLTETRAHYDROISOQUINOLINE

    benzyltetrahydroisoquinoline (R)-reticuline

    NH N

    MeO

    HOHO

    MeO

    H

    TETRAHYDROISOQUINOLINE

    tetrahydroisoquinoline

    anhalamine(Lophophora williamsii)

    Peyote

    NH NH

    OHMeO

    MeO

    O

    MeO

    MeOH

    N

    thebaine

    O

    RO

    HOH

    N

    R = H morphineR = Me codeine

    H

    (Papaver somniferum)Opium poppy

    analgesic, antitussive

    MODIFIED BENZYLTETRAHYDROISOQUINOLINE

    NH

    morphinan

  • BISBENZYLTETRAHYDROISOQUINOLINE

    NO

    N

    O

    OHOMe

    OHMeO

    HH

    (+)-tubocurarine(Chondrodendron tomentosum)

    arrow poison curare