ATROPINE

1
1
2
3
4
Atropa belladonna
1
ATROPINE
(deadly nightshade)
Donald Pavia Chem 425a
Mandragora officinarum
2
(mandrake root)
Hyoscyamus niger
3
(henbane, Christmas rose)
..
Datura strammonium
Richard Willstatter 1895-1903
Gabor Fodor 1955-1960
4
(Jimson weed)
BIOSYNTHESIS - TROPIC ACID
STRUCTURE PROOF - TROPINE
STRUCTURE PROOF - TROPIC ACID
not chiral
racemic
levorotatory in plant
racemic
not chiral
pyridoxyl-5- phosphate
racemic
H
vigorous

CrO3
(/-)-Atropine
Tropine
(/-)-Tropic Acid
(-)-Hyoscyamine
H2SO4
Tropic Acid
Atropic Acid
hydrolysis
- H2O
or KMnO4
C9H10O3
C17H23NO3
C8H15NO
C17H23NO3
racemized during workup
C9H10O3
C9H8O2
COOH
COOH
phenylalanine
carboxybiotin
Pt
1 H2
Ac2O
(via enol ?)
CC
CH-C-OH
C9H10O2
C9H10O3
Tropidine
The reactions to the left require this part
structure.
thiamine -CO2
FEATURES
FEATURES
monoacetate derivative
POSSIBLE STRUCTURES
POSSIBLE STRUCTURES
NADPH
atrolactic acid (known) was eliminated
cinnamic acid (known) was eliminated
TROPIC ACID
ATROPINE
TROPINE
Tropine
Tropine
Tropinone
Derivative
ATROPIC ACID
TROPIC ACID

CHEMICAL SYNTHESIS
Tropic acid was shown to have (S) configuration
by relating it to R-(-)-alanine.
Methiodide
P
Zn
Br2
ether
HELL-VOLHARD-ZELINSKY REACTION
Two Hofmann
H2SO4
Reacted with Pd / 3 H2 to form cycloheptane, a
known compound.
REFORMATSKY REACTION
Tropine
Tropidine
ACTUAL STRUCTURE Confirmed by X-ray Crystallograp
hy
1) CH3I / NaOH 2) Ag2O 3) heat
- H2O
1) Ac2O
ATROPINE
CrO3
2) SOCl2
RETROANALYSIS
careful hydrolysis
TROPIC ACID
O-Acetyltropyl chloride
1) CH3MgBr
BIOSYNTHESIS - TROPINE
Known compound
2) CO2
Tropine is achiral requiring OH in the position
shown. Endo or exo to be determined.
The results above establish the bicyclic ring
structure.
3) EtOH / H
KOH / EtOH
ornithine
exo alcohol is more stable
H2 / Pd
epimerization
CrO3
strong base
1) H3O / heat (loss of CH3OH CO2)
H
acetyl CoA
1) FAD
H
H
?
H
2) H2O
-H2O
2) H2 / Pd
TROPINE
TROPINONE
approach from least hindered side gives endo
PSEUDOTROPINE
TROPINE
H
endo
exo
bottom approach hindered
malonyl CoA
TROPINE
H
-CO2
Ar p -nitrophenyl
PSEUDO- TROPINE
FAD
aldol condensation
A MORE MODERN METHOD OF SYNTHESIS OF TROPINE
Pseudotropine will form these cyclic derivatives
which shows that the OH group and the nitrogen
of the bridge are on the same side of the
molecule in pseudotropine.
-CO2
in the plant erythroxylon coca
aldol condensation
TROPINE
CH3-NH2
H2
KOH
TROPINE
Tropine will not react to form these cyclic
derivatives.
EtOH
Pd
SAdM
NADPH
This proves that the OH in pseudotropine is exo,
while that in tropine is endo.
hydrolysis
Tropine O-Acetyltropyl chloride
Atropine
COCAINE
of O-acetyl