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Enantioselective Synthesis of Complex Fused Heterocycles through Chiral Phosphoric Acid Catalyzed Intramolecular Inverse‐Electron‐Demand Aza‐Diels–Alder Reactions
Author(s) -
Jarrige Lucie,
Gandon Vincent,
Masson Géraldine
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201904902
Subject(s) - enantioselective synthesis , phosphoric acid , intramolecular force , chemistry , diastereomer , bifunctional , catalysis , diels–alder reaction , mannich reaction , yield (engineering) , combinatorial chemistry , organic chemistry , medicinal chemistry , materials science , metallurgy
A stable asymmetric intramolecular Povarov reaction has been established to provide an efficient method to access structurally diverse trans , trans ‐trisubstituted tetrahydrochromeno[4,3‐ b ]quinolines in high stereoselectivities of up to >99:1 diastereomeric ratio and 99 % enantiomeric excess, without any purification step. Additionally, to facilitate large‐scale application of this method, a low catalyst loading protocol was employed, 0.2 mol % chiral phosphoric acid, which provided the cycloadducts without any loss in yield and enantioselectivity. Theoretical studies revealed that the reaction occurred through a sequential Mannich reaction and an intramolecular Friedel–Crafts reaction, wherein the phosphoric acid acted as a bifunctional catalyst to activate the para ‐phenolic dienophile and N ‐2‐hydroxy‐2‐azadiene simultaneously.