1. Michael Caputo Dr. Paul Blakemore Department of Chemistry
Synthesis of Thebaine Model System Using an Intramolecular [4+2] Cycloaddition Method
Michael Caputo
Dr. Paul Blakemore
Department of Chemistry

2. 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

3. 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

4. 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

5. Facts About Opiates Used for/as: Chronic pain relief Cough suppressant
Analgesic
Epidural anesthesia
Anti-diarrhea
Respiratory suppression

6. 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

7. The Ring System

8. The Starting Materials
isovanillin
3,6-dichloropyridazine
3-hydroxy-4-methoxybenzaldehyde
Cost: $1.84 g-1
Cost: $1.02 g-1

9. Research Strategy
The use of dichloropyridazine and isovanillin as the starting materials for the synthesis will lead to the desired thebaine product

10. Helpful Information 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

11. Helpful Information
Reaction Arrows:

12. The Procedure
The proposed procedure involves the creation of two sub-products
6-iodo-3-methoxypyridazine
3-(acetaldehyde diethyl acetal)-4-methoxybenzaldehyde

13. The Procedure
Synthesis of sub-product 1:
(pyridazine)
(*Hadduck)

14. The Procedure
Synthesis of sub-product 2:
(isovanillin)

15. The Procedure
Tandem Linge-Pin Wittig Coupling:

16. The Procedure
Hydrogenation of Alkene:

17. The Procedure
Cylclization of Benzofuran:

18. Proposed Cycloaddition

19. The Model System Thebaine model Thebaine
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

20. Thanks Dr. Paul Blakemore Chris Emerson Heath Giesbrecht J Gunderson
Dr. Kevin Ahern
Howard Hughes Medical Institute

21. The Procedure
Synthesis of Phosphonium Salt 1 2