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

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Synthesis of Thebaine Model System Using an
Intramolecular 42 Cycloaddition Method

• Michael Caputo
• Dr. Paul Blakemore
• Department of Chemistry

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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

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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

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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

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Facts About Opiates

• Used for/as
• Chronic pain relief
• Cough suppressant
• Analgesic
• Epidural anesthesia
• Anti-diarrhea
• Respiratory suppression

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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 42 intramolecular
  cycloaddition reaction

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The Ring System
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The Starting Materials
isovanillin
3,6-dichloropyridazine
3-hydroxy-4-methoxybenzaldehyde
Cost 1.84 g-1
Cost 1.02 g-1
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Research Strategy

• The use of dichloropyridazine and isovanillin as
  the starting materials for the synthesis will
  lead to the desired thebaine product

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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

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Helpful Information

• Reaction Arrows

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The Procedure

• The proposed procedure involves the creation of
  two sub-products

6-iodo-3-methoxypyridazine
3-(acetaldehyde diethyl acetal)-4-methoxybenzaldeh
yde
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The Procedure

• Synthesis of sub-product 1

(pyridazine)
(Hadduck)
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The Procedure

• Synthesis of sub-product 2

(isovanillin)
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The Procedure

• Tandem Linge-Pin Wittig Coupling

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The Procedure

• Hydrogenation of Alkene

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The Procedure

• Cylclization of Benzofuran

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Proposed Cycloaddition
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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
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Thanks

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

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The Procedure

• Synthesis of Phosphonium Salt

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