Synthesis and hSERT activity of homotryptamine analogs. Part 6: [3+2] dipolar cycloaddition of 3-vinylindoles

Substituted 1-tosyl-3-vinylindoles undergo [3+2] dipolar cycloaddition with cyclic nitrones to afford substituted isoxazoles in good yield and high diastereoselectivity. The cycloadducts were readily converted in 4 steps into ring constrained homotryptamine analogs. These analogs exhibited excellent binding affinity for the human serotonin transporter (hSERT). Indoles bearing a 5-cyano group and a pendent ethyl(tetrahydroisoquinoline) moiety at the 3-position displayed the best potency for hSERT and high selectivity versus hDAT and hNET.

Graphical abstractA series of ring constrained homotryptamine analogs was prepared in 5 steps from 1-tosyl-3-vinylindoles via [3+2] dipolar cycloaddition with cyclic nitrones. The final products, including (−)-21a, demonstrated potent and selective binding affinity for the human serotonin transporter (hSERT).Figure optionsDownload full-size imageDownload as PowerPoint slide