MORPHINE

1
Part Three
Structure Proof
MORPHINE
2
NOW THAT WE KNOW THE STRUCTURE OF
METHYLMORPHENOL WE CAN BEGIN TO FORMULATE THE
STRUCTURE OF CODEINE
codeine
1 2 3
Hofmanns
these groups are in one of these two rings
1 2 3
.
.
loses nitrogen, oxygen and two carbons
-CH2-CH2-
N
CH3
methylmorphenol
OH
Codeine
H
3
MORPHINE
HERE IS THE CORRECT STRUCTURE
The location of the double bond was also
difficult to establish.
There was a great deal of difficulty in locating
the third oxygen.
4
A LITTLE BIT ABOUT THEBAINE
Thebaine was used in the studies to locate the
third oxygen.
Morphine C17H19NO3
Codeine C18H21NO3
Thebaine
Differs from codeine by having
C19H21NO3
a) one extra double bond b) the alcoholic -OH as
a methoxyl group
PtO2
2 H2
1) CH3I, NaOH
PhNMe3 OH-
Dihydromorphine dimethyl ether
2) PtO2, 1 H2
Codeine Morphine
These conversions imply that thebaine has the
same skeleton as morphine and codeine, and an
extra double bond.
Also implied are two methoxy groups, and no OH.
5
CONVERSION OF THEBAINE TO CODEINONE
KETONE
1N H2SO4
Thebaine
Codeinone
7 yield
C19H21NO3
C18H19NO3
This implies that there is an enol ether in
thebaine.
H
MeOH
H2O
H2O
hydrolysis of enol ether
enol
enol ether
keto
-



equilibrium
resonance
6
THEBAINE PART STRUCTURE
Thebaine has two double bonds, one an enol
(methyl) ether that hydrolyzes to a ketone.
CH2CH2-
We know from methylmorphenol work that morphine,
codeine and thebaine all have this skeleton.
7
ACETOLYSIS
The position of the third oxygen was proven by
doing acetolysis of all three compounds
(morphine, codeine, thebaine) and also codeinone.
NaOAc, HOAc
Ac2O D
Acetolysis involves heating the compounds with a
mixture of sodium acetate (NaOAc), a base, acetic
acid (HOAc), and acetic anhydride (Ac2O), an
acetylating compound.
All OH groups are acetylated and, if they are not
attached to an aromatic ring, an elimination
reaction forms a double bond (acetate is a good
leaving group) . After protonation, OH groups
may be eliminatated as water.
Ethers which have at least one aliphatic group
are cleaved.
Dehydrations, eliminations and enolizations cause
rings to become aromatic. Morphine, codeine and
tebaine all form aromatic rings with this
procedure.
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EXAMPLE ACETOLYSIS
OAC-
acetylate
..
..

-H2O
AcO-


open ether, lose bridge, aromatize, acetylate OH
9
ACETOLYSIS RESULTS
These were all synthesized by the Pschorr method.
CH3I NaOH
acetolysis
morphine
morphine methiodide
codeine
coedeine methiodide
codeinone
codeinone methiodide
thebaine
thebaine methiodide
These results establish the position of the third
oxygen atom.
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HYDROXYCODEINONE
K2Cr2O7
codeine
hydroxycodeine
dil H2SO4
-20oC
CH3I NaOH
A new OH group was introduced, position unknown.
acetolysis
I-
hydroxycodeine methiodide

Ac2O, HOAc
NaOAc D
1) Ag2O 2) D
H2SO4
CrO3
ltlt a ketone gtgt
this result means the nitrogen bridge must also
be a C9 or C10
loses one -OAc group - must be at C9 or C10
(see next slide)
ltlt an anthraquinone gtgt
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EXPLANATION OF THE KETONE RESULT
1) We know the new OH went into position C9 or
C10 in hydroxycodeine. 2) The nitrogen
bridge must also be at C9 or C10
KEEP IN MIND
C9-N
C9-N
C10-OH
C9-OH






BOTH ARE KETONES
The same two ketones would be obtained if N were
at C10.
12
ULTRAVIOLET SPECTROSCOPY COMES INTO PLAY


C10 CO
C9 CO
BOTH ARE KETONES
This ketone can be ruled out by the ultraviolet
spectrum.
The oxygen had to be at carbon 9.
lmax 245 (6500)
lmax 286 (1100)
vs.
lmax 278 (20)
conjugated ketone
unconjugated ketone
13
A RETURN TO THE a and b-CODEIMETHINES
codeine methiodide

codeine
double bond must be here (it cannot be in the
enolic position)
1) CH3I
x
2) Ag2O 3) D
All arguments lead to the same conclusion. Well
go through them all in detail.
styrene chromophore
extended chromophore
250o
lmax 275 (10000)
lmax 355 (10000)
lmax 310 (7000)
b-codeimethine
a-codeimethine
The other end of the chain containing N must
attach here otherwise a naphthalene ring would be
expected.
.
Second double bond moves into conjugation
BLOCKED
14
.
.
This would block rearrangement of a-codeimethine
to b-codeimethine.
These would not block the rearrangement to a
naphthalene system (which does not happen).
15


HO-
OH-
..
first Hofmann
a-codeimethine
codeine methiodide
second Hofmann
fragmentation
THE ABNORMAL HOFMANN DEGRADATION
..
OH-
aromatization
- H2O
methylmorphenol
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SOME DIFFICULTIES ALONG THE WAY
REARRANGEMENTS
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REARRANGEMENTS
Morphine, codeine and thebaine are star
performing acrobats !
One of the things that drew organic chemists to
natural products was the challenging and
interesting chemistry that they found.
EXAMPLE
concentrated HCl
Morphine
Apomorphine
- H2O
C17H19NO3
C17H17NO2
This looks like a simple dehydration of
morphine. Many hours of work were spent on
apomorphine on the assumption that it had the
same ring structure as morphine with only a loss
of water.
Eventually the structure of apomorphine was
proved to be the structure shown to the right.
All the work on apomorphine had no bearing on
the stucture of morphine and was, in fact,
misleading!
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REARRANGEMENTS
dilute HCl
boil 2 min.
thebaine
thebenine
dilute HCl
Another puzzler!
codeinone
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REARRANGEMENTS
PhMgBr
ether
thebaine
Bizarre, eh ?
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PHARMACOLOGY
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ENKEPHALINS
From larger peptide structures found in the
brain called endorphins. Bind to a pain-reducing
receptor in the brain.
Leu-enkephalin
Tyr-Gly-Gly-Phe-Leu
morphine
The enkephalins are rapidly degraded in the body
and are therefore not good for drug use.
Met-enkephalin
Tyr-Gly-Gly-Phe-Met
22
SYNTHETIC OPIUM ANALGESIC DRUGS
morphine
dextromethorphan (levomethorphan)
phenazocine
naloxone
pentazocine
oxycodone
naltrexone
(with cyclopropyl)
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SYNTHETIC OPIUM ANALGESIC DRUGS
meperidine (demerol) (pethidine)
morphine
fentanyl
methadone
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ASSIGNMENTS
Read
Hesse Alkaloids - Natures Cure or Curse,
Wiley-VCH (2000) 5.6 Morphines, pp 272-277
Discusses the effect of stereochemistry on
analgesic activity.