Transcript Synthesis of Thebaine Model System Using an Intramolecular [4+2] Cycloaddition Method NMe MeO O H OMe Michael Caputo Dr. Paul Blakemore Department of Chemistry.

Synthesis of Thebaine Model
System Using an
Intramolecular [4+2]
Cycloaddition Method
NMe
MeO
O
H
OMe
Michael Caputo
Dr. Paul Blakemore
Department of Chemistry
What is Thebaine?
 Found naturally
occurring in the opium
poppy, Papaver
somniferum, as a
minor component
 It only makes up 0.1%
to 2.0% of all of the
alkaloidal extracts
from the poppy
What Makes Thebaine so
Special?
 A biogenetic precursor of morphine, codeine, etorphine,
heroine, naltrexone, naloxone, etc.
 It can be used to synthesize a wide array of medicinally
relevant compounds
 No practical synthesis of thebaine has been reported
codeine
thebaine
NMe
NMe
HO
MeO
H
OMe
heroin
AcO
O
O
H
OMe
NMe
NMe
HO
O
O
morphine
H
H
OH
OAc
Background of Opiates
 Use of Opiates date back to 3000 B.C.
 Legal Production
 Regulated by the United Nations
 India, Turkey, and Tasmania
(Australia)
 Main Consumer: USA
 Legal use exceeds 80,000 kg/year
in US
 Illicit Production
 More than $760 Billion USD
annually
 Afghanistan
Facts About Opiates
 Used for/as:
 Chronic pain relief
 Cough suppressant
 Analgesic
 Epidural anesthesia
 Anti-diarrhea
 Respiratory suppression
The Objective
 Create an efficient multi-step synthesis of
thebaine
 Do it in the least number of steps
 Do it with the highest yields
 Join the A and B rings via a [4+2]
intramolecular cycloaddition reaction
The Ring System
D
NMe
C
E
MeO
B
A
O
H
OMe
The Starting Materials
O
Cl
N
N
OH
Cl
3,6-dichloropyridazine
Cost: $1.02 g-1
OMe
isovanillin
3-hydroxy-4-methoxybenzaldehyde
Cost: $1.84 g-1
Research Strategy
 The use of dichloropyridazine and
isovanillin as the starting materials for
the synthesis will lead to the desired
thebaine product
Helpful Information
 Me : Methyl group (CH3)
O
 Et : Ethyl group (CH2CH3)
 Ac : Acetyl Group
 Ph : Phenyl Group
 -ane : Refers to a single bond
 -ene : Refers to a double
bond
 -yne : Refers to a triple bond
R
Helpful Information
 Reaction Arrows:
Reagents
Starting
Materials
Products
Solvents
The Procedure
 The proposed procedure involves the creation of two sub-
products
O
OMe
EtO
OEt
N
N
O
I
6-iodo-3-methoxypyridazine
OMe
3-(acetaldehyde diethyl acetal)-4methoxybenzaldehyde
The Procedure
 Synthesis of sub-product 1:
Cl
I
N
N
Cl
(pyridazine)
NaI
cat. HI
Acetone
 (56 °C)
46%
OMe
N
N
N
NaOMe
MeOH
N
54%*
I
I
(*Hadduck)
The Procedure
 Synthesis of sub-product 2:
EtO
O
OEt
O
EtO
Br
KOH
OH
OMe
(isovanillin)
DMSO
 (80 °C)
90%
O
OMe
OEt
The Procedure
 Tandem Linge-Pin Wittig Coupling:
Ylide 1
Ph
Ph
CH3
Ph
n-Buli
Ph
THF
(-20 oC)
-LiI
P
N
MeO
Ph
I
P
N
I
CH2
(rt)
Ph
Ylide2
MeO
MeO
N
N
N
N
PPh3
PPh3
I
H
H
H
MeO
O
N
N
EtO
OEt
OEt
O
EtO
OMe
O
(rt)
4%
OMe
The Procedure
 Hydrogenation of Alkene:
MeO
MeO
N
N
N
N
OEt
EtO
H2
Pd(C)
EtOH
(rt)
OEt
EtO
O
OMe
O
OMe
The Procedure
 Cylclization of Benzofuran:
MeO
MeO
N
N
N
N
OEt
EtO
PPA
Toluene
(80 oC)
O
O
OMe
OMe
Proposed Cycloaddition
H
N
N
N
Diels-Alder
N
OMe
[4+2]
O
O
H
±
OMe
OMe
Retro
Diels-Alder
H
OMe
O
H
±
OMe
(5 steps from isovanillin)
-N2
The Model System
 It represents the basic structure of the desired molecule
without specific substituents
 It acts as a major checkpoint for the completion of a
synthesis
D
NMe
C
D
MeO
B
C
A
O
E
MeO
B
A
O
H
H
OMe
Thebaine model
OMe
Thebaine
Thanks
 Dr. Paul Blakemore
 Chris Emerson
 Heath Giesbrecht
 J Gunderson
 Dr. Kevin Ahern
 Howard Hughes Medical Institute