Stereoselective Arene‐Forming Aldol Condensation: Synthesis of Axially Chiral Aromatic Amides

Abstract

The increasing awareness of the importance of amide atropisomers prompts the development of novel strategies for their selective preparation. Described herein is a method for the enantioselective synthesis of atropisomeric aromatic amides by an amine-catalyzed arene-forming aldol condensation. The high reactivity of the glyoxylic amide substrates enables a remarkably efficient construction of a new aromatic ring, which proceeds within minutes at ambient temperature to afford products with excellent stereoselectivity. The high rotational barriers of the reduced products highlight the utility of this stable, spatially organized chiral scaffold.

Stereoselektive arenbildende Aldolkondensation: Synthese axial‐chiraler aromatischer Amide

“…Chemie und ortho-Gruppen. [15] [16] Im Festkçrper wurde eine minimale Abweichung des Ar-CO-Torsionswinkels von der Orthogonalität festgestellt (Abbildung 1). Die exocyclische Verzerrung der Bindungswinkel und vergrçßerte Abstände zwischen Amid und der peri-Seitenkette weisen auf eine für die Atropisomerie charakteristische sterische Wechselwirkung der parallel angeordneten Substituenten hin.…”

“…Thermische Ellipsoide für 50 %W ahrscheinlichkeit. [16] Angewandte Chemie Zuschriften wir die stereoselektive arenbildende Aldolkondensation als Plattform für Atropisomeriestudien und die diastereoselektive Synthese Ar-CO-, N-CO-und R-N-rotationsgehinderter aromatischer Amide. [8b,15] Danksagung…”

Stereoselective Arene‐Forming Aldol Condensation: Catalyst‐Controlled Synthesis of Axially Chiral Compounds

“…To corroborate the generality of the stereoselective areneforming aldol condensation as as ynthetic concept, the preparation of axially chiral aromatic amides was studied. [21] Furthermore, as aromatic amides are ac ommon motif in medicinal chemistry,a ni ncreasing awareness of atropisomerism has been established in drug discovery. [22] In accord with the generic substrate layout, at erminal amide group provides a highly reactive substrate, thus giving tertiaryf ormyl-naphthamides.A dditionally,t he intramolecular reactivity that affects the configurationals tability of the products is balanced by installing a peri-substituent (Scheme 8).…”

First Air Liquide Awards on Essential Small Molecules: K. Sivula, S.Kitagawa, R. Matsuda, J.‐M. Savéant, M. Robert, and C. Costentin / Wolf Prize in Chemistry: R. G. Bergman / Swiss Chemical Society Awards: K. Sivula, C. Sparr, and R. R. Knowles / Knighthood: S. Balasubramanian / Wheeler Bequest Award: J. I. Seeman

“…Sparr and his group are interested in the development of new synthetic methods and the creation of unique molecular structures. He has reported in Angewandte Chemie on a stereoselective arene‐forming aldol condensation reaction …”