Application of Polyamines and Amino Acid Derivatives Based on 2-Azabicycloalkane Backbone in Enantioselective Aldol Reaction

Abstract

Carbon–carbon bond forming reactions, such as aldol reaction and condensation, belong to extremely desired transformations as manifested by >25,000 entries in SciFinder. Their stereoselective variant requires the use of an appropriate catalyst with a strictly defined structure. Hence, chiral 2-azabicycloalkane-based catalysts were designed, synthesized and tested in a stereoselective aldol reaction between cyclic/acyclic ketone and p-nitrobenzaldehyde both in organic and aqueous media. Among catalysts containing a chiral bicyclic backbone, amide based on 2-azabicyclo[3.2.1]octane and pyrrolidine units showed the best catalytic activity and afforded aldol product in excellent chemical yields (up to 95%) and good diastereo- and enantioselectivity (dr 22:78, ee up to 63%).

2-Azabicyclo[3.2.1]octane scaffold: synthesis and applications

“…Wojaczyńska and co-workers reported the synthesis of 2-azabicyclo[3.2.1]octane system via rearrangement of 2-azabicyclo[2.2.1]heptane derivatives under Mitsunobu conditions 18 g or sulfonyl chloride/base (Scheme 26). 29 The reaction mechanism proceeds through activation of the primary alcohol and intramolecular nitrogen nucleophilic attack forming an aziridinium intermediate, which was then regioselectively opened by nucleophilic attack at the more substituted carbon, releasing ring strain in the [2.2.1]heptane system (Scheme 26A).…”

“…The same authors installed a 1,10-phenanthroline moiety via imine formation ( 149 ), 30 and a proline via amide bond ( 150 ). 29 These molecules were evaluated as catalysts for asymmetric aldol reactions, as the chiral and rigid core of the 2-azabicyclo[3.2.1]octane system could induce stereoselectivity. While a pioneer study in the utilization of the 2-azabicyclo[3.2.1]octane system in asymmetric organocatalysis, the des and ees obtained were not outstanding, and no other studies were performed in this topic.…”