Premium
Octahydrocyclopenta[ c ]pyridine Scaffold – Enantioselective Synthesis and Indole Annulation
Author(s) -
Wachtendorf Daniel,
Geibel Irina,
Schmidtmann Marc,
Christoffers Jens
Publication year - 2018
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201801102
Subject(s) - chemistry , stereocenter , enantioselective synthesis , pyridine , annulation , alkylation , moiety , structural isomer , stereochemistry , piperidine , indole test , aldol reaction , medicinal chemistry , intramolecular force , combinatorial chemistry , catalysis , organic chemistry
An optically active hexahydrocyclopenta[ c ]pyridine derivative with quaternary stereocenter was prepared as a new heterocyclic scaffold. Key reaction was the Pd‐catalyzed asymmetric allylic alkylation of a piperidine‐based β‐oxoester, which proceeded in very good yield with high level of enantioselectivity (90 %, 95 % ee ). The α‐allyl moiety was transformed into a 1,4‐diketone by Pd‐catalyzed Wacker oxidation with molecular oxygen (89 %). This intermediate was cyclized in an intramolecular aldol reaction furnishing the cyclopentenone motif (86 %). Hydrogenation of the C–C double bond gave the cis ‐annulated octahydrocyclopenta[ c ]pyridine (86 %), which was submitted to Fischer indolization (85 %). Although two regioisomers could be expected, only the angular constitution was observed. Relative and absolute configurations were established by X‐ray crystallography of a para ‐iodo benzamide derivative. The utility of the title compound as scaffold is further highlighted by a number of synthetically useful transformations, for instance formation of carboxamides, sulfonamides, ureas and reductive aminations with aldehydes.