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

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

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

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

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

Helpful Information Reaction Arrows:

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

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

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

The Procedure Tandem Linge-Pin Wittig Coupling:

The Procedure Hydrogenation of Alkene:

The Procedure Cylclization of Benzofuran:

Proposed Cycloaddition

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

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

The Procedure Synthesis of Phosphonium Salt 1 2