benzo condensed pyridines: quinolines and isoquinolines alkaloid natural products largets class of...
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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
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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)
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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”
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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
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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
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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.
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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
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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
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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