BENZO CONDENSED PYRIDINES:

QUINOLINES AND ISOQUINOLINES

N

QuinolineBenzo[b]pyridine(1-azanaphtalene)

abc

1

2

34

4a

56

78

8a

N

IsoquinolineBenzo[c]pyridine(2-azanaphtalene)

abc

12

34

4a

56

78

8a

Alkaloid Natural Products

•Largets class of secondary metabolites, >6500 compds known•Contains N, most compds basic (alkaline), often heterocyclic•Often highly toxic•Found in certain higher plants (seldom in bacteria)•Little is known regarding why alkaloids are produced•Biosynthesis from amino acids

Quinoline alkaloidsCinchona pubescens (Kinatre) from South America

N

R

HO NH

R=OMe: Quinine (Cinchonidine epimer at C-9)

R=H: Quinidine (Cinchonine epimer at C-9)

Quinidine: AntiarytmicQuinine: Antimalaria

N CF3CF3

HONH

Mefloquine

N Cl

HNN

Chloroquine

Dihydroquini(di)ne and der.Chiral ligandsAsym. dihydroxylation (Sharpless)

Isoquinoline alkaloids

Curare - Pilgift - Søramerikanske indianereBland. Av flere alkaloider med muskeslammende effektFlere plantekilder bl.a. Chondodendron tomentosum

MeON

Me

MeO

MeONH

Me

MeO

MeO

MeO

MeO

MeO

MeO

OMe

O

OO

O

MeO

O

HO

OOH

OMe

NR

Me

NMe

Me

R=H: TubocurarinR=Me: Wrong struct.

N N

Ex. Mivacurium kloridMuscle relax, anesthesia

Cl

NO

ON

O

O

Cl

Esterase

Cl

NOH

HON

O

O

Cl

HOOH

Succinsyrekolin

Suksametonium, Curacit® “Nesset”

Isoquinoline alkaloids

Morfinanalogs, binds to opiopeptide (endorfin / enkefalin) reseptors

O OHO

NCH3

O OHHO

NCH3

H3CO OO

NCH3

H3C CH3

Thebaine Morfin

NH

OHHO OH

OH

Norlaudanosoline

NH

OH

OH

HO

HON

O

O

O

O

O O O

N

O

O

O

O

Papaverine(against spasms)

NH2

HO

CO2H

Tyr

Noskapin(not analgetic,not adiction)

OOHHO

N

Morfin

O

OHN

OH

H2N

OH

HN

HN

OO

O

NH

HO

NH

O

O

S

Met-enkefalin

Tyr N-terminalin opiopeptides

N NN

pKa 5.2 pKa 4.9 pKa 5.5

Protonation Electrophilic Ar. Subst.

N

E

N

N

E

N

Major isomers shownE

E

Halogenation in the Pyridine Ring

N

HClBr2

NH

Br

N

H BrH

Br Br

N

H Br

H BrH

- H

N

Br

HH Br

- HBr

N

Br

N

HClBr2

N

Br

Nucleophilic Addition - Nucleophilic Ar. Subst.

N

Nu

N Nu

N

Nu

N

Nu

N

Nu

N

Nu

N

XN X N

X

X=halogen

Reactivity towards Nu as N NX

X

Nu-radicals (Minisci react.)attacks in the same pos.

ANRORC (Add. Of Nu., Ring Opening and Ring Closure)

NH

NH

N

NH2

N

Br NaNH2N

Br

H NH2

N

Br

HNH2

NNH2

H

NuN N

Nu

X N NuX+ X

a) X=Hb) X=Good leaving group

Oxy- and Aminoderivatives - Tautomeri

-All - isomers amino (not imino)

-“One”-Isomers:

NH

O NH

O

NH

O

Tautomeric Mixt.:

N

OH

NH

OQuinoid struct.: NegativeAmide: Possitive

Synthesis - Quinolines

NH2

O

O

H

-2 H2O NNH2

OH

- H2O [ox]

NH

Synthesis - Isoquinolines

NH2

O

O

HH

N-2 H2O

O NH2

OEtEtO

H

- H2O- 2 EtOH

N

NH2

O

X R

X: -Cl, H

- H2O [ox]

N