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Synthesis of Thebaine Model System Using an Intramolecular [4+2] Cycloaddition Method

Synthesis of Thebaine Model System Using an Intramolecular [4+2] Cycloaddition Method. Michael Caputo Dr. Paul Blakemore Department of Chemistry. What is Thebaine?. Found naturally occurring in the opium poppy, Papaver somniferum , as a minor component

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Synthesis of Thebaine Model System Using an Intramolecular [4+2] Cycloaddition Method

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  1. 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 • 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

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