A Model System For A Diazine-Benzofuran Cycloaddition/Fragmentation Approach To Thebaine

Alex HadduckMember 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