Synthesis of 2,3,4,7-tetrahydro-1H-azepines as privileged ligand scaffolds for the design of aspartic protease inhibitors via a ring-closing metathesis approach

We have developed a short and highly efficient synthetic strategy towards the hitherto hardly known 3,5- and 3,6-disubstituted 2,3,4,7-tetrahydro-1H-azepine scaffold via a ring-closing metathesis approach utilizing inexpensive and readily available starting material such as methyl acrylate and allylamine. Both seven-membered azacycle scaffolds bearing suitable functional groups, which can easily be modified by means of standard synthetic chemistry, serve as non-peptidic heterocyclic core structures for the further design and synthesis of aspartic protease inhibitors. Through specific decoration with appropriate side chains, individual inhibitors can be tailored with respect to selectivity towards particular family members. A first generation of this class of non-peptidic inhibitors have been tested against the aspartic proteases Plasmepsin II and HIV-I protease, respectively, showing promising activity as well as selectivity with IC₅₀ values in the micromolar range.