ATROPINE

1
PART FOUR
Stereochemistry
ATROPINE
MODERN METHODS
2
GABOR FODOR
Most of this work was done by Gabor Fodor.
Gabor Fodor b. 1916 Budapest, Hungary
Szeged University
Fled Hungary during the Hungarian Revolution in
the mid 1950s.
The work on atropine was done in Hungary and at
Universite Laval in Quebec, Canada in the 1950s.
Later Fodor moved to West Virginia University.
3
STEREOCHEMISTRY OF TROPINE
4
AN OXIDATION - REDUCTION CYCLE EXPERIMENT
CrO3
H2 Pd
tropine
tropine
tropinone
assumed endo
Oxidation to tropinone erases the OH stereocenter.
It was assumed that catalytic reduction would
occur at the least-hindered face. That would mean
the OH group should end up endo.
.
.
catalyst surface
The end product of this sequence was identical in
all properties to the starting compound,
suggesting that tropine is endo.
not a conclusive proof ...
5
BASIC EPIMERIZATION
assumed exo
Na amyloxide
D / amyl alcohol
..
tropine
pseudotropine

O-C5H11
..
-
(different from tropine)
endo
E N E R G Y
exo
exo
It is assumed that the exo ion would have lower
energy and predominate in the equilibrium.

-
..
-
HO-C5H11
endo
.. better proof is still required
6
von Braun Reaction
USED TO REMOVE AN N-METHYL GROUP
SN2
nucleophilic addition
elimination of bromide
cyanogen bromide
hydrolysis of the cyano group to a carboxylic acid
7
CONVERSION OF
PSEUDOTROPINE TO NORPSEUDOTROPINE
The prefix nor means that one carbon atom,
usually a methyl group, has been lost.
pseudotropine
(assumed exo)
acetic anhydride
norpseudotropine
1) von Braun Br-CN 2) NaOH, H2O
acetate protecting group
8
A STRATEGY FOR DETERMINING STEREOCHEMISTRY
H
..
cis
..

OH
O
NH
N
..
NH
no reaction
Bridging can occur only if the two groups are on
the same side of the ring ( i.e., cis ).
trans

OH
..
9
NORPSEUDOTROPINE DOES THE TRICK
C14H16N2O3
norpseudotropine
forms a cyclic adduct that can be isolated
nortropine
will not form the cyclic adduct
.. this implies that pseudotropine has the exo
hydroxyl group
10
INTRAMOLECULAR TRANSFER OF ACETYL
ADDITIONAL EVIDENCE
Cl-
amide salt is formed first
norpseudotropine


INFRARED

• still shows OH
• 3300-3400 cm-1
• NH shifts to
• lower frequency

acetyl chloride
160oC
..
-

..
thermally rearranges to the ester


INFRARED
must be cis

• now shows NH
• and the
• ester group at
• 1735 cm-1

Infrared spectroscopy was available in the 1950s.
11
NORTROPINE AND NORPSEUDOTROPINE
norpseudotropine

?
exo
OR

nortropine
?
Although the stereochemistry of the hydroxyl
group is determined, that of the N-methyl group
is still in question.
endo
.. we will show how this was proved next
12
PROVING THE POSITION OF THE N-METHYL GROUP
SN2
-
ethyl iodoacetate
I


pseudotropine
Tropine would not form the lactone.
lactone
Why did tropine not behave in the same way?
13
CORRECT STRUCTURE FOR TROPINE

not chiral
endo
14
STEREOCHEMISTRY OF TROPIC ACID
15
USES OF THE CHEMICAL LITERATURE
Fodor was able to show the absolute
stereochemistry of tropic acid without doing any
laboratory work.
He simply combined information he obtained
from doing a couple of library searches.
NEVER AVOID DOING YOUR LITERATURE SEARCH
WHEN STARTING A PROJECT - YOU COULD END UP SAVING
TIME AND AVOID COSTLY MISTAKES!
First we will look at a couple of chemical
reactions that are germane to his conclusions.
16
CURTIUS REACTION
Converts an acid to an amine
SOCl2
NaN3



..

-2
..
-
..


acid azide


..

sodium azide
Ag
..
..
heat


-
-

nitrogen
rearranges

H2O




..
WOLFF REARR.
..
an isocyanate
a nitrene
- CO2
electron deficient
no charge, incomplete octet on N


If the alkyl group R is chiral, it retains its
configuration throughout all steps.
17
OZONOLYSIS
Everyone knows that a double bond can be
cleaved by ozonolysis.
H3O
O3
0oC
CH2Cl2
However, not emphasized in organic lecture
A benzene ring can be destroyed by ozonolysis if
you react for a longer time and a higher temp.
all CC bonds are destroyed
O3
a carboxylic acid is formed in place of the ring
harsh conditions long time
18
KNOWN WORK - PART ONE
none of this changes the stereocenter
S-()-a-methylphenylacetic acid
Curtius
O3



(-)-a-phenylethylamine
L-()-alanine
The structure of L-()-alanine was known
WORKING BACKWARDS
19
KNOWN WORK - PART TWO
R-(-)-a-methylphenylacetic acid
H2 / Pt
H3O
The opposite stereoisomer to the one on
the previous slide!
(-)-tropic acid
(-)-isomer
WORKING BACKWARDS
HENCE switch the H and CH3 groups
20
ABSOLUTE CONFIGURATION OF TROPIC ACID
3
(S)
Ph
H
HOOC
CH2OH
1
2
S-(-)-TROPIC ACID
21
(-)-HYOSCYAMINE

If this stereocenter is racemized, you have
atropine.
22
CONFIRMATION BY X-RAY CRYSTALLOGRAPHY
Soon after Fodors work was done, the structure
was confirmed by a single-crystal x-ray crystal
structure analysis.
23
X-RAY DIFFRACTION
SCATTERING PATTERN - EXPOSED FILM
Structures can be determined by mathematical
analysis of the scattering pattern.
calculation
single crystal of substance
beam of x-rays
structure
Method developed by Max von Laue (1912)
24
OTHER TROPANE ALKALOIDS
These were easy to figure out once atropine was
proven.
25
epoxide
hyoscyamine and atropine
scopolamine
Scopolia atropoides
Datura metel
cocaine
Erythroxylon coca
exo
26
BIOSYNTHESIS
27
BIOSYNTHETIC PATH TO TROPINE
amine oxidase
ornithine
acetyl CoA
Mannich-1
(from glycolysis)
x2
H2O
-CO2

-CoASH
malonyl CoA
Mannich-2
NADH
SAM
tropine
28
BIOSYNTHETIC PATH TO (-)-TROPIC ACID
PLP
B6
phenylalanine
Biotin-COOH
TPP
-CO2
NADH
(-)-hyoscyamine
(-)-tropic acid
tropine
29
MORE COENZYMES
30
THE COENZYME BIOTIN
A carrier of carboxyl groups
This mixed anhydride transfers CO2 to
biotin making carboxybiotin.
H2O CO2 ATP

biotin
Nu
The carboxyl group can be transferred to
suitable nucleophilic acceptors to synthesize
carboxylic acids.
carboxybiotin
31
COENZYME A
A fancy carrier or transport agent for acyl
groups.
..
..
CoA-S
..
Nu
Nu

32
THIAMINE PYROPHOSPHATE
Vitamin B1 (TPP)
-

works with lipoic acid and CoASH
an ylide


H2O
H3O
..
-
Sulfur also helps to stabilize the (-) charge
with d-orbitals.
too fast to follow at pH 7
thiazolium ring
33
LIPOIC ACID
Oxidizing agent and acyl carrier
LIP(S)2
NADPH
2e- 2H
NADP
LIP(SH)2
regenerated by NADP
34
HOW THIAMINE, LIPOIC ACID AND CoA WORK TOGETHER
DECARBOXYLATION AND OXIDATION OF AN a-KETOACID
..


- CO2
TPP
-
..
Enz-BH
Lip(S)2
Enz-B
HB-Enz
acetylCoA


-
..
CoASH
..