CM3101 Alkaloids I - UCC Alkaloids I.pdf · 1963 – Definition based on chemotaxonomy. Alkaloids should be divided into 3 subgroups • Proper alkaloids • Proto alkaloids • Pseudo

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

β-CARBOLINE

NH

N

β-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