A Model System For A Diazine Benzofuran Cycloaddition/Fragmentation Approach To Thebaine Alex Hadduck Member of the Paul Blakemore Research Group 2006

Why Thebaine?

 Not medicinally used, but the precursor to many opiates including morphine, codeine, heroin, and dozens of other tranquilizers (such as the elephant tranquilizer Etorphine).

 Current opiate synthesis requires dozens of steps with low yields, nowhere near the efficiency of harvesting raw poppy  Political instability in Asia Minor, the primary source of natural poppy, makes natural poppy production unreliable

Thebaine

Codeine

 *Analgesic, antitussive, antidiarrheal

Morphine

 Severe pain relief – trauma, surgery, cancer.

Diamorphine (aka heroin)

 Still used in hospitals – acute pain

Ethics

  “All opiod analgesics cause dependence and tolerance, but that is no deterrent in the control of pain in terminal illness.” -British National Formulary Federal regulations and laboratory integrity

Goals and reasoning

    Create 14 carbon morphinan skeleton Coax the skeleton into a cycloaddition, creating a thebaine analogue Using a model system allows to test the basic theories involved in the envisioned synthesis without extra hindrance. No controlled substances!

Target synthesis = trial and error

Overall Scheme

Reactions thus far

Reactions thus far cont.

The rest of the summer and beyond    Joining of the benzofuran and pyridazine Closure of the morphinan skelton Future work

Thanks

     Howard Hughes Medical Institute Paul Blakemore Selena Milicevic Mark Sephton Kevin Ahern and Indira Rajagopal