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

Peter Šafář; Štefan Marchalín; Nadežda Prónayová; Viktor Vrábel; Ata Martin Lawson; Mohamed Othman; Adam Daïch

doi:10.1016/j.tet.2016.04.047

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

Tetrahedron. 2016 Jun 9;72(23):3221-3231. doi: 10.1016/j.tet.2016.04.047. Epub 2016 Apr 21.

Authors

Peter Šafář¹, Štefan Marchalín¹, Nadežda Prónayová², Viktor Vrábel³, Ata Martin Lawson⁴, Mohamed Othman⁴, Adam Daïch⁴

Affiliations

¹ Department of Organic Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology, SK-81237 Bratislava, Slovak Republic.
² Central Laboratories, Faculty of Chemical and Food Technology, Slovak University of Technology, SK-81237 Bratislava, Slovak Republic.
³ Department of Analytical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology, SK-81237 Bratislava, Slovak Republic.
⁴ Normandie Univ, UNILEHAVRE, CNRS, URCOM, 76600 Le Havre, France.

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.