The Upside of Downsizing: Asymmetric Trifunctional Organocatalysts as Small Enzyme Mimics for Cooperative Enhancement of Both Rate and Enantioselectivity With Regulation

Abstract

Small molecule organic catalysts (organocatalysts) are widely used in asymmetric catalysis and synthesis. Compared to their enzymatic and transition-metal counterparts, organocatalysts have advantages in catalytic scope and efficiency but are more limited in proficiency. Chiral trifunctional organocatalysts, in which multiple catalytic motifs act cooperatively on a chiral scaffold, are an emerging class of organocatalysts with improved proficiency. Cooperativity design that enables both enantioselectivity and rate enhancement is essential to developing future generations of organocatalysts in biomimetic asymmetric catalysis. Chirality 25:675-683, 2013.

Trifunctional Squaramide Catalyst for Efficient Enantioselective Henry Reaction Activation

“…Multifunctional scaffolds have received special attention in the last decade, with the increasing interest for the synthesis of more complex catalytic systems with a high organization grade and a multidentate activation, to offer a cooperative effect resembling the role of enzymes 1,2. These structures could facilitate the formation of cooperative non‐covalent interactions in a synergic way and thereby significantly improve their catalytic activity.…”

C2‐symmetric sulfonamides as homogeneous and heterogeneous organocatalysts that mimic enzymes in enantioselective Michael additions

“…This was supported by density functional calculations, which showed the O···Cl bond interaction in the transition state with an energy comparable to that of hydrogen bonding. Thus, the organocatalyst in this case is proposed to be multifunctional in the transition state of the reaction as shown in Figure B, mimicking an enzyme with multiple non‐covalent interactions stabilizing the transition state …”

“…Thus, the organocatalyst in this case is proposed to be multifunctional in the transition state of the reaction as shown in Figure 1B, mimicking an enzyme with multiple noncovalent interactions stabilizing the transition state. 29 Continuing on the same line, to make the transition state more stable and enzyme-like, we recently reported the synthesis of C 2 -symmetric bis-sulfonamide organocatalysts (1a, 1b, 2a, and 2b, Scheme 2) 30 and tested them in the conjugate carbonylic 1,4-Michael addition to β-nitrostyrene. We hypothesized that the C 2 -symmetric organocatalysts could accommodate the β-nitrostyrene and the enamine within the groove and increase the hydrogen bonding with the substrate, mimicking an enzyme.…”

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.…”