cm3101 alkaloids i - ucc alkaloids i.pdf · 1963 – definition based on chemotaxonomy. 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
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