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