Use of chiral-pool approach into epi-thieno analogues of the scarce bioactive phenanthroquinolizidine alkaloids

Abstract

The stereoselective synthesis of epi-thieno analogues of the phenanthroquinolizidine bioactive alkaloids (-)-Cryptopleurine and (-)-(15R)-Hydroxycryptopleurine was achieved in five steps starting from easily available enantiopure (S)-2-aminoadipic acid used as chiral pool and nitrogen atom source. During these investigations, both π-cationic cyclization of chiral N-thienylmethyl-6-oxopipecolinic acids into pure (S)-keto-lactams and theirs regioselective and diastereoselective reduction, considered as key steps of this sequence, were studied. Of particular interest, the Friedel-Crafts cyclization using (CF₃CO)₂O/BF₃·Et₂O show that near the expected keto-lactams, enamides and enamidones containing trifluoromethyl residue were isolated. A mechanism leading to the latter products with high synthetic potential was discussed.

Keywords: 6-Oxopipecolinic acid; Diastereoselective reduction; Phenanthroquinolizidine alkaloids; Thienoquinolizidine; π-Cationic cyclization.