Synthesis of Aminoindolizidines through the Chemoselective and Diastereoselective Catalytic Hydrogenation of Indolizines

Abstract

Indolizidines are great-potential bioactive heterocyclic compounds normally prepared following multi-step routes. However, to the best of our knowledge, the synthesis of 1-amino indolizidines has never been reported. Herein, 1-dialkylamino-3-substituted indolizidines have been straightforwardly synthesized using an atom-economy protocol which involves a copper-catalyzed three-component synthesis of indolizines followed by heterogeneous catalytic hydrogenation. The latter was found to be chemoselective using platinum(IV) oxide as the catalyst at 3.7 atm, providing the amino indolizidines in modest-to-high yields (35-95%) and high diastereoselectivity (92:8 to > 99:1).It has been experimentally demonstrated that the hydrogenation occurs through the intermediate 5,6,7,8-tetrahydroindolizine, which contains a pyrrole moiety. Moreover, the diastereomerically pure 1-dibenzylamino-3-substituted indolizidines could be further transformed into the corresponding monobenzylated or fully debenzylated amino indolizidines by selective hydrogenolysis catalyzed by Pt/C or Pd/C, respectively, under ambient conditions.

Three-Step Catalytic Asymmetric Total Syntheses of 13-Methyltetrahydroprotoberberine Alkaloids

“…After the identification of ( S , R )- N -PINAP for the asymmetric redox-A 3 reaction, we then expanded the substrates ( 1a – d and 2a – d ) and successfully accomplished the asymmetric total synthesis of 12 natural 13-MeTHPBs ( 6a – l ) through Pd-catalyzed reductive carbocyclization and hydrogenation under PtO 2 (or Pd/C) catalysis (Scheme ) using our previously reported protocols . For the hydrogenation step, we compared the stereochemistry integrity of the PtO 2 and Pd/C catalysis and found that both catalysts reliably delivered the hydrogenation product ( 6a ) with comparable optical purity (PtO 2 , 94% ee; Pd/C, 92% ee) but with consistently higher yield by PtO 2 catalysis.…”

Substrate‐Controlled Divergent Synthesis of Enaminones and Pyrroles from Indolizines and Nitroso Compounds

“…By virtue of our current interest in the application of copper nanoparticles to multicomponent reactions, we published the solvent‐controlled three‐component synthesis of amino‐substituted indolizines and the synthesis of heterocyclic chalcones from pyridine‐2‐carbaldehyde derivatives, secondary amines and terminal alkynes catalyzed by copper nanoparticles on activated carbon (CuNPs/C) (Scheme ) . The reactivity of the aforementioned indolizines has been explored only recently: their heterogeneous catalytic hydrogenation led to indolizidines in a chemo‐ and diastereoselective manner, whereas an acid‐base treatment furnished a new family of solvatochromic dyes through a metal‐free C−H site‐selective alkenylation…”

P4O10/TfOH mediated domino condensation–cyclization of amines with diacids: a route to indolizidine alkaloids under catalyst- and solvent-free conditions

“…Moreover, practicing chemists usually require two or more steps to construct the indolizidine ring core from different substrates under various conditions. 13 Ramanathan et al elaborated a precise methodological syntheses of isoindoloisoquinolinones, pyrroloisoquinolinones, and benzo[ a ]quinolizinones using TfOH. They have also prepared numerous annulated tetrahydroisoquinolines.…”