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Asymmetric Synthesis of Adjacent Tri‐ and Tetrasubstituted Carbon Stereocenters: Organocatalytic Aldol Reaction of an Hydantoin Surrogate with Azaarene 2‐Carbaldehydes
Author(s) -
Izquierdo June,
Demurget Noémie,
Landa Aitor,
Brinck Tore,
Mercero Jose M.,
Dinér Peter,
Oiarbide Mikel,
Palomo Claudio
Publication year - 2019
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.201902817
Subject(s) - stereocenter , chemistry , aldol reaction , squaramide , enantiopure drug , hydantoin , moiety , organocatalysis , enantioselective synthesis , medicinal chemistry , bifunctional , catalysis , organic chemistry
A bifunctional amine/squaramide catalyst promoted direct aldol addition of an hydantoin surrogate to pyridine 2‐carbaldehyde N ‐oxides to afford adducts bearing two vicinal tertiary/quaternary carbons in high diastereo‐ and enantioselectivity (d.r. up to >20:1; ee up to 98 %) is reported. Acid hydrolysis of adducts followed by reduction of the N ‐oxide group yields enantiopure carbinol‐tethered quaternary hydantoin‐azaarene conjugates with densely functionalized skeletons. DFT studies of the potential energy surface (B3LYP/6–31+G(d)+CPCM (dichloromethane)) of the reaction correlate the activity of different catalysts and support an intramolecular hydrogen‐bond‐assisted activation of the squaramide moiety in the transition state of the catalytic reaction.