Asymmetric Synthesis of Adjacent Tri‐ and Tetrasubstituted Carbon Stereocenters: Organocatalytic Aldol Reaction of an Hydantoin Surrogate with Azaarene 2‐Carbaldehydes

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 hyd...

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Veröffentlicht in:Chemistry : a European journal 2019-09, Vol.25 (53), p.12431-12438
Hauptverfasser: Izquierdo, June, Demurget, Noémie, Landa, Aitor, Brinck, Tore, Mercero, Jose M., Dinér, Peter, Oiarbide, Mikel, Palomo, Claudio
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Sprache:eng
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Zusammenfassung: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. Assembled by aldol: A highly diastereo‐ and enantioselective direct aldol reaction between an hydantoin surrogate and azaarene 2‐carbaldehyde N‐oxides is enabled by a multifunctional amine‐squaramide‐amide catalyst. The process serves to assemble carbinol‐tethered hydantoin‐azaarene conjugates featuring vicinal tertiary/quaternary carbon stereocenters (see scheme).
ISSN:0947-6539
1521-3765
1521-3765
DOI:10.1002/chem.201902817