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

  • Bioorg Med Chem Lett. 2010 Feb 1;20(3):1027-30. doi: 10.1016/j.bmcl.2009.12.043.
Lawrence R Marcin  1 ,  Ronald J Mattson ,  Qi Gao ,  Dedong Wu ,  Thaddeus F Molski ,  Gail K Mattson ,  Nicholas J Lodge
Affiliations
  • 1. Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
PMID: 20034793 DOI: 10.1016/j.bmcl.2009.12.043
Abstract

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.