Enyne Cycloisomerization Route to an Anti-depressant Drug Candidate, GSK1360707

Significance

Reported is the improved synthesis of the antidepressive drug candidate GSK1360707 via an enyne cycloisomerization approach. The described route is initiated by coupling of iodide 4 with propargyl amine 3 to afford the desired enyne cycloisomerization precursor 5. In toluene, the reaction of 5 to 10 proceeds smoothly, giving access to the cyclic product in high yield and stereoselectivity. Employing methanol in mixed solvent systems proved detrimental, however, due to trapping of the intermediate cation 7 by the nucleophilic component of the solvent.