Alkaloids

Found in ~20% of vascular plants.

Compounds usually basic (alkaline).
~40,000 compounds currently described.
Structurally the most diverse class of secondary metabolites.

H
N
H

(+)-coniine
(Conium maculatum)
poison hemlock

O
O

NH

HO

HO

batrachotoxin
(Phyllobates aurotaenia) Columbian arrow frog
LD50 (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.

COOH
NH2
N
H

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

NHCH3

(
sympa
(E

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.
O

HN

N
PO
HO

OH

inosine monophosphate
(IMP)

caffeine

theobromine
O
H

N
O

L-asp
theophylline
formate
L-Gln
L-Gln

purine alkaloids from Coffea species

(C. arabica, C. canephora, C. liberica, etc)

Alkaloid Nomenclature
PYRROLIDINE

TROPANE
N

O
N

OH
O

()-hygrine
(Erythroxylum coca)

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

NORTROPANE
Cl
N
HN

epibatidine
(Epipedobates tricolor)
Ecuadorian poison frog
200-500x potent then morphine

PIPERIDINE
O
N

N
O

N-methylpelletierine

pseudopelletierine

(Punica granatum)
pomegranate bark
possesses activity against intestinal tapeworms

PIPERIDINE
O

OH
N

lobeline
(Lobelia inflata)
antiasthmatic

PYRROLIZIDINE
HO

OH

N
N

pyrrolizidine

PYRROLIZIDINE
HO

OH

riddellic acid

O
O

retronecine

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

retronecine

QUINOLIZIDINE

quinolizidine
OH
H

N
H

()-sparteine
(Cytisus scoparius)
Scotch broom

()-lupinine
(Lupinus luteus )
yellow lupin

PYRIDINE

nicotine

anabasine

(Nicotiana tabacum)
tobacco

INDOLIZIDINE
OH

H OH

HO

N HO

indolizidine
castanospermine (Castanospermum australe) Moreton Bay chestnut

PYRROLOINDOLE

MeHN
NH
N

physostigmine pyrroloindole
(Physostigma venenosum)
Calabar beans (Nigeria)
Cholinesterase inhibitor

PHENETHYLAMINE
O

NH2

()-cathinone
(Catha edulis)
khat
CNS stimulant

QUINOLINE

MeO
N

quinoline
purine

()-quinine caffeine (Cinchona sp)

antimalarial

IMIDAZOLE
N
O
N

pilocarpine
(Pilocarpus jaborandi)
cholinergic for glaucoma

-CARBOLINE
N
N
H

-carboline

SIMPLE INDOLE
OP
NMe2
N
H

psilocybin
(Psilocybe mexicana)
magic mushrooms

ACRIDINE
O

OH

N
N

acridine
rutacridone
(Ruta graveolens)
Garden rue

QUINAZOLINE
N

N
N

OH

quinazoline

peganine

(Peganum harmala)
Syrian rue

PYRROLOQUINOLINE
O
N
N

N
N

pyrroloquinoline

camptothecin

(Camptotheca acuminata)
Chinese tree
topoisomerase I inhibitor

HO
H

tomatidine
esculente)
tomato

H2N
N

cholestrol (Lycopersicon

BENZYLTETRAHYDROISOQUINOLINE

NH

benzyltetrahydroisoquinoline

TETRAHYDROISOQUINOLINE

NH

tetrahydroisoquinoline

OH
anhalamine
(Lophophora williamsii)
Peyote

MODIFIED BENZYLTETRAHYDROISOQUINOLINE
MeO
O
NH

H
MeO

morphinan
RO

O
HH

HO

R = H morphine
R = Me codeine

thebaine

(R)-reticuline

BISBENZYLTETRAHYDROISOQUINOLINE
O
OMe
N

OH
H

H
O
N

MeO

OH

(+)-tubocurarine (Chondrodendron tomentosum)

arrow poison curare