Cooperative Trifunctional Organocatalysts for Proficient Proton Transfer Reactions

Abstract

Cooperativity is essential to proficient catalysis, and designing biomimetic, cooperative catalysis is a major avenue to finding new and efficient chemical reactions with practical applications. One challenge in designed cooperative catalysis is to access high catalytic proficiency (large enhancement in both rate and enantioselectivity) as seen in biocatalysis. Here described is an approach of developing and investigating trifunctional organocatalysts with three distinct catalytic functionalities, in order to understand how cooperativity could be organized for enantioselective activation that confers the observed proficiency in a tandem Michael-aldol-proton transfer elimination model reaction. This in future may assist in finding not just cooperative but also regulated catalysis to expand the level of catalytic complexity and efficiency in biomimetic systems.

Horizons in Asymmetric Organocatalysis: En Route to the Sustainability and New Applications

“…In this sense, the bifunctionality has served as the inspiration for many synthetic catalytic systems, such as chiral thioureas/ureas, cinchona alkaloids, chiral phosphoric acids, or chiral proline derivatives, which retain the simultaneous activation of nucleophile and electrophile. Interestingly, and more recently, the term trifunctional has acquired more importance [106,107]. Generally, this family of molecules is expected to activate the process by their three different functionalities, achieving optimal cooperativity and increasing the activity of the catalytic species.…”

Morita–Baylis–Hillman reaction: how do optimal enzyme active sites compare with organocatalysts

“…Nucleophilic Lewis base-Brønsted acid pairs have been extensively explored as bifunctional organocatalysts, and more recently a trifunctional framework containing also a Brønsted base motif selectively catalyzed the aza-MBH and MBH reactions in the presence of an acid additive. 4 Such multifunctional chiral organocatalysts are highly flexible however, and a higher structural control in pre-organizing individual motifs in catalytic constellations is required to achieve the advantages of multifunctional cooperativity. 5 Recent advances in the use of enzymes in organic synthesis 6 have led to the exploration of promiscuous biocatalytic routes to MBH adducts.…”

“…In the Novozyme 435 catalyzed reaction, site-directed mutagenesis experiments (H224A) provided evidence for the nucleophilic role of the active site histidine, and the amide co-catalyst was hypothesized to take part in the activation of the aldehyde and stabilization of the oxyanion intermediates. 13 Pepsin in combination with an amine-based organocatalyst (1,4-diazabicyclo[2.2.2]octane (DABCO)) gave the MBH adducts. 14 While DABCO was confirmed to promote the MBH reaction, a significant decrease in the activity upon irreversible inhibition of active site aspartate residues (Asp32 and Asp215) suggested the possibility of the reaction taking place in the active site.…”

“…To develop intelligent multifunctional Catalysis Science & Technology Paper catalytic strategies, it is crucial to understand the contribution of various catalytic elements to catalysis and the synergy between them. However, despite great efforts for elucidating the catalytic mechanism of the MBH reaction, 4,18,20,24,[27][28][29][30][31][32][33][34][35][36] there are no reports on how catalytic components can cooperate to enhance the reaction rate.…”

Multifunctional chiral aminophosphines for enantiodivergent catalysis in a palladium‐catalyzed allylic alkylation reaction

“…[38][39][40] In this work, a new type of metal-ligand-substrate donor-type ligands is investigated ( Figure 1C). These ligands are multifunctional chiral phosphines, studied as trifunctional organocatalysts in our previous works [41][42][43][44][45][46][47][48] that have demonstrated proficient catalysis in Morita-Baylis-Hillman model reactions. Our trifunctional system, which combines catalytic motifs such as phosphine Lewis base, amine Brønsted base, and phenol or sulfonamide Brønsted acid, can now be tested for its ability to provide potential metal-coordination sites and H-bonding interactions concurrently for dual activation in a model Pd-catalyzed allylic alkylation.…”