Additive and Emergent Catalytic Properties of Dimeric Unnatural Amino Acid Derivatives: Aldol and Conjugate Additions

• Published in: Chemistry : a European journal 2021-11, Vol.27 (63), p.15671-15687
• Main Authors: Gracia Retamosa, María, Ruiz‐Olalla, Andrea, Agirre, Maddalen, Cózar, Abel, Bello, Tamara, Cossío, Fernando P.
• Format: Article
• Language: English
• Subjects: 1,3-dipolar reactions; Aldehydes; aldol reaction; Amino Acids; asymmetric catalysis; Catalysis; conjugate additions; DFT calculations; Ketones; Stereoisomerism
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202102394

Different densely substituted L‐ and D‐proline esters were prepared by asymmetric (3+2) cycloaddition reactions catalyzed by conveniently selected EhuPhos chiral ligands. The γ‐nitro‐2‐alkoxycarbonyl pyrrolidines thus obtained in either their endo or exo forms were functionalized and coupled to yield the corresponding γ‐dipeptides. The catalytic properties of these latter dimers were examined using aldol and conjugate additions as case studies. When aldol reactions were analyzed, an additive behavior in terms of stereocontrol was observed on going from the monomers to the dimers. In contrast, in the case of the conjugate additions between ketones and nitroalkenes, the monomers did not catalyze this reaction, whereas the different γ‐dipeptides promoted the formation of the corresponding Michael adducts. Therefore, in this latter case emergent catalytic properties were observed for these novel γ‐dipeptides based on unnatural proline derivatives. Under certain conditions stoichiometric amounts of ketone, acid and nitroalkene), formation of N‐acyloxy‐2‐oxooctahydro‐1H‐indoles was observed. Monomeric and dimeric organocatalysts behave differently: Aldol and Michael reactions catalysed by γ‐dipeptides derived from densely substituted unnatural proline derivatives show different behaviours. In aldol reactions an additive scheme is observed, whereas in conjugate reactions the catalytic activity of these dipeptides constitutes an emergent property. Experimental, kinetic and computational studies are reported to understand these phenomena.