Synthesis of Thebaine Model System Using an Intramolecular [4+2] Cycloaddition Method Michael Caputo...
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Transcript of Synthesis of Thebaine Model System Using an Intramolecular [4+2] Cycloaddition Method Michael Caputo...
Synthesis of Thebaine Model System Using an Intramolecular [4+2] Cycloaddition Method
Michael CaputoDr. Paul Blakemore
Department of Chemistry
O
H
NMe
OMe
MeO
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
OH
NMe
OMe
MeO
OH
NMe
OH
HOO
H
NMe
OMe
HO
thebaine morphinecodeine
O
H
NMe
OAc
AcO
heroin
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 Starting Materials
N
N
Cl
Cl
3,6-dichloropyridazine 3-hydroxy-4-methoxybenzaldehyde
OMe
OH
O
isovanillin
Cost: $1.84 g-1Cost: $1.02 g-1
Research Strategy
The use of dichloropyridazine and isovanillin as the starting materials for the synthesis will lead to the desired thebaine product
Me : Methyl group (CH3)
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
Helpful Information
O
R
The Procedure The proposed procedure involves the creation of
two sub-products
N
N
OMe
I
6-iodo-3-methoxypyridazine 3-(acetaldehyde diethyl acetal)-4-methoxybenzaldehyde
OMe
O
O
EtO OEt
The Procedure Synthesis of sub-product 1:
(pyridazine)
N
N
Cl
Cl
N
N
I
I
N
N
OMe
I
NaIcat. HI
AcetoneΔ (56 °C)
NaOMe
MeOH
54% *46%
(*Hadduck)
The Procedure Synthesis of sub-product 2:
(isovanillin)
OMe
OH
O
OMe
O
O
EtO OEtBr
OEtEtO
KOH
DMSOΔ (80 °C)90%
The Procedure Tandem Linge-Pin Wittig Coupling:
P
Ph
Ph
Ph
CH3 THF
n-Buli
(rt)
I
(-20 oC)
NN
MeO I
-LiI
P
Ph
Ph
Ph
CH2
Ylide 1
N
N
MeO
PPh3
IH H
N
N
MeO
PPh3
H
Ylide2
OMe
O
O
EtO OEt
(rt)
OMe
O
EtO
OEt
N
N
MeO
4%
Proposed Cycloaddition
OMe
O
N
NOMe
Diels-Alder
[4+2]
OMe
O
NN
H
H±
RetroDiels-Alder
-N2O
OMe
OMe
H
H
±
(5 steps from isovanillin)
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
Thebaine model Thebaine
O
H
NMe
OMe
MeOAB
C
D
E
O
HOMe
MeOAB
C D