Octahydrocyclopenta[c]pyridine Scaffold – Enantioselective Synthesis and Indole Annulation

Abstract

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.

Silver-Catalyzed Radical Umpolung Cross-Coupling of Silyl Enol Ethers with Activated Methylene Compounds: Access to Diverse Tricarbonyl Derivatives

“…However, these approaches rely on the utilization of superstoichiometric amounts of chemical oxidants, such as manganese­(III) acetate, and highly elaborate starting materials to form the intended products. In 2016, Christoffers and co-workers utilized a novel umpolung approach for the oxidative cross-coupling reaction of β-dicarbonyl compounds with enol acetates by employing catalytic amounts of cerium trichloride hydrate as a one-electron oxidant . In this strategy, although the issues of employing stoichiometric metal-based oxidants were circumvented, a large excess of one of the coupling partners is required, thus significantly reducing the atom economy of the developed protocol.…”

“…In 2016, Christoffers and co-workers utilized a novel umpolung approach for the oxidative cross-coupling reaction of β-dicarbonyl compounds with enol acetates by employing catalytic amounts of cerium trichloride hydrate as a one-electron oxidant. 7 In this strategy, although the issues of employing stoichiometric metal-based oxidants were circumvented, a large excess of one of the coupling partners is required, thus significantly reducing the atom economy of the developed protocol. In 2019, Hilt and co-workers demonstrated the electrochemical synthesis of C–C bonds between β-dicarbonyl compounds and an excess of the silyl enol ether coupling partner (5.0 equiv) in the presence of catalytic amounts of manganese salts.…”