Naming Alkaloids

Most compounds end in ……ine. Majority of alkaloids known by a trivial name.

• Colchicine Named after the common name of the organism.

NH

N

HN

O

NO

O

OH

HHO

ergotamine(Claviceps purpurea)

also known as the fungus, ergot

Species of organism

cocaine(Erythroxylum coca)

NCOOMe

OCOPh

Genus of organism

N

O

O

CH2OH

Ph

atropine(Atropa belladonna)Deadly nightshade

Physiological effect

N

MeN

MeO

MeO

OMe

OMe

H

H

H

emetine(Cephaelis ipecacuanha)

Ipecacuanhaemesis inducer

Mythology

O

HO

HO

N

morphine(Papaver somniferum)

Opium poppyname derived from Greek God morpheus

Researcher

N

NH

nicotine(Nicotiana tabacum)

named after the researcher Jaen Nicot

Animal Alkaloids

NCH2OH

O

H

(−)-castoramine(Castor fiberi)

Canadian beaver

N

(R)-(+)-muscopyridine(Moschus moschiferus)

Musk deer

NH OH

histrinocotoxin(Dendrobates histrionicus)

South American poison dart frogspiro piperidine

HN

OHH

H

O HH

samandarine(Salamandra maculosa)

European fire salamander

HN

N

Cl

epabitidine(Epipedobates tricolor)Ecuadorian poison frog

Insect Alkaloids

2,6-dialkylpiperidinesn = 10, 12, 14

Solenopsis invicta)Southern fire ant

precoccinelline

NH

(CH2)nCH3

N

H

H H

ON

H

H H

coccinelline

(Coccinella septempunctata)European 7-spotted ladybird beetle

N

N OMe

pyrazine

N

N

O

glomerineEuropean millipede

(Glomeris marginata)quinazolone

N

O

danaidone(Danaus chrysippus)

African Monarch butterflyphermone

epilachnene(Epilachna varivestis)Mexican bean beetle

azamacrolide

ONH

O

NH

O

O

NHO

O

(Subcoccinella 24-punctata)24-spotted ladybird

Marine Alkaloids

S SS

SSOMe

MeO

H2N

varacin(Polycitors sp.)

ascadian (sea squirt)

BrOMe

Br

BrN

O

convolutamine D(Amathia convoluta)

bryozoan (moss animal)

NH

NSO

BrNH2

Eudistomin L(Eudistoma gilboverde)

N NH

N

N

O

OH

H

OH

H

Manzamine F(Pellina sp.)

Okinawan sponge)

HN

OO

H2N

OH

CH2OHHO

OH

O

HHO

tetrodotoxin(Tetraodon sp.)

Japanese puffer fish(liver and ovaries)

Fungal Alkaloids

fusaric acid(Fusarium heterosporium)

mycotoxin

rugulovasine A(Penicillium concavo-rugulosum)

viridicatin(Penicillium viridactum)

2-quinolonechief mold on stored corn

N COOH

HN

OH

O

HN

NHCH3

O

O

sporidesmin A(Pithomyces chartarum.)

animal toxincauses pithomycotoxicosis

N

NNCl

MeOOMe

O

O

HOHO

H

SS

teleocidin B4(Streptomyces blastmyceticum)indole alkaloid tumor promotor

NH

NH

N

O

HOH

HN O

OO OH

HOH

H

cytochalasin b(Helminthosporia sp.)

NH O

OH

H

Me

Me

OHOH

H HMe

Me Me

(−)-penitrem D(Penicillium crustosum)tremogenic mycotoxin

roquefortine(Penicillium roquefortii)

blue cheese

NH

NNH

O

OHN

N

ergotamine

D-(+)-lysergic acid

NH

NMeH

HOOC

H

NH

NMeHH

HN

O

NO

NH

HO O

O

(Claviceps purpurea)sclerotium of fungus develops on the

ovary of rye, Secale cerale

Bacterial Alkaloids Very rare in nature.

procyanine(Pseudomonas aeroginosa)

deep blue colour

N

O

Alkaloid Extraction and Isolation General aspects Small amounts of alkaloid to isolate. Alkaloids must be free from impurities and artefacts. Crude material must be defatted (hexane, petroleum ether). Extract crude alkaloid from raw material into suitable solvent. Purify alkaloid by repeated conversion from base to salt and partitioning between organic and aqueous phases. Alkalis

• NH3/NH4OH • Ca(OH)2

Acids

• HCl, H2SO4, tartaric acid Solvents

• Benzene • Toluene • Chlorinated solvents (chloroform, dichloromethane) • Diethylether • Ethylacetate

Groups of Impurities to be Removed H2O/Ethanol soluble impurities

• proteins, saponins, gums, starches Organic solvent soluble impurities

• Lipids, fats, waxes, resins, pigments Organic Acids

• NH4OH Organic bases other than alkaloids

• Selective solubilities • Ion exchange resins • Preparative HPLC • Thick layer (preparative) TLC • Flash column chromatography

Extraction Methods Kian-Douglas method

• NH3/NH4OH Stats-Otto method

• HCl, H2SO4, tartaric acid Steam distilaltion

• nicotine pH gradient separation

• Vincristine, vinblastine (Catharanthus roseus)

Structural Elucidation Mass spectrometry

• FAB (Fast Atom Bombardment) • EI (Electron Impact) • MALDI-TOF (Matrix Assisted Laser Desorption/Ionisation –

Time of Flight) NMR (Nuclear Magnetic Resonance)

• 1-D: 1H, 13C, 15N • 2-D: HMQC, HMBC, TOCSY, NOE

Derivitisation Degradation studies IR, UV, elemental analysis X-ray crystallography Total synthesis Total synthesis – ultimate proof of structure

O

NH

ClO

HNO

N

O

N ClHN

OH2N

(−)-diazonamide A (proposed initial structure, 1991)

O NH

NH

ClO

HNO

N

O

N ClHN

OHO

(−)-diazonamide A (revised structure, 2001)

OH

HO

Harran P.G. et al, Angew. Chem. Int. Ed., 2001, 40, 4765-4773 Fenical W. et al, J. Am. Chem. Soc., 1991, 113, 2303-2304

(–)-Diazonamide A (toxin extracted from the marine invertebrate Diazona angulata). Total synthesis – ultimate proof of absolute configuration (–)-Quadrigemine C (representative of a higher order N-methyltryptamine derived plant alkaloid).

HN

MeN

H

HN

MeN

NMe

NH

H

H

NMe

NH H

absolute stereochemistry established as R (1999)

total synthesis (2002) ultimatelydetermined absolute stereochemistry of the vicinal quaternary carbons.Optical rotation, 1H, 13C-NMR, HRMS,HPLC properties identical to natural product.

Quadrigemine CPsychotria colorata

Amazonian plant used for treating paintetrapyrrolindoline alkaloid

Overman L.E. et al, J. Am. Chem. Soc., 2002, 124, 9008-9009