Constrained TRPV1 agonists synthesized via silver-mediated intramolecular azo-methine ylide cycloaddition of α-iminoamides

摘要

As part of an effort to identify agonists of TRPV1, a peripheral sensory nerve ion channel, high throughput screening of the NIH Small Molecule Repository (SMR) collection identified MLS002174161, a pentacyclic benzodiazepine. A synthesis effort was initiated that ultimately afforded racemic seco analogs >12 of the SMR compound via a silver mediated intramolecular [3+2] cycloaddition of an azo-methine ylide generated from α-iminoamides >11. The cycloaddition set four contiguous stereocenters and, in some cases, also spontaneously afforded imides >13 from >12. The synthesis of compounds >12, the features that facilitated the conversion of >12–>13, and their partial agonist activity against TRPV1 are discussed.