Hydrogen Bonding and Internal or External Lewis or Brønsted Acid Assisted (Thio)urea Catalysts

Abstract

The obtainment of more active organocatalysts has promoted the search for new modes of activation and new organocatalytic systems. Inspired on the mode of activation of enzymes, organocatalysis has recently focused on the challenge to create an enzyme‐like “active site” giving access to hydrogen‐bond donors (HBDs) with enhanced activity. Therefore, the assembly of catalytic species, connected through multiple weak inter‐ or intramolecular interactions, is a young and emerging topic of research which could become in the future a powerful tool for asymmetric catalysis. In the area of (thio)ureas, different alternatives such as internal hydrogen bonds or the use of an internal or an external Lewis or Brønsted acid assisted catalysts have been developed. The pivotal publications recently reported covering this family of organocatalysts are proof of this importance. This review treats to illustrate these important and scarce examples and to show a plausible mode of activation for each one.

Bifunctional Hydrogen Bond Donor‐Catalyzed Diels–Alder Reactions: Origin of Stereoselectivity and Rate Enhancement

“…In this regard, aw ide variety of chiral amines,h eterocyclicc arbenes,g uanidines, ureas, amidinium ions, diols, squaramides, and other Lewis acids have successfully been used to afford the corresponding cycloadduct with high enantiomeric excess. [3,4] In particular, bifunctional hydrogen bond donor organocatalysts, i.e.,m olecules able to act as Lewisa cid via two hydrogen bonds, have attracted considerable attention in this line of research. [4] For instance, the seminal works by Rawal and coworkers [5] and Schreiner and co-workers [6] on the use of TADDOL and thioureas, respectively,a so rganocatalysts for Diels-Alder reactions should be especially highlighted (Scheme 1).…”

“…[3,4] In particular, bifunctional hydrogen bond donor organocatalysts, i.e.,m olecules able to act as Lewisa cid via two hydrogen bonds, have attracted considerable attention in this line of research. [4] For instance, the seminal works by Rawal and coworkers [5] and Schreiner and co-workers [6] on the use of TADDOL and thioureas, respectively,a so rganocatalysts for Diels-Alder reactions should be especially highlighted (Scheme 1). The catalytic activity of these species is generally ascribed to the bidentate nature of the organocatalyst-substrate binding,w hich favorably preorganizes and activates the substrate.…”

Homochiral bifunctional L‐prolinamide‐ and L‐bis‐prolinamide‐catalyzed asymmetric aldol reactions performed in wet solvent‐free conditions

“…These structural features such as electron‐withdrawing groups and additional chiral centers might influence the stereoselectivity of the reaction. Thiourea group also may contribute to the catalysis of the aldolic reaction, through the formation of hydrogen bonds 29 . Second, tertiary amino ‐L ‐prolinamide 5 has a bulky substituent, which might favor hydrophobic‐hydrophobic interactions.…”

“…Thiourea group also may contribute to the catalysis of the aldolic reaction, through the formation of hydrogen bonds. 29 Second, tertiary amino-L-prolinamide 5 has a bulky substituent, which might favor hydrophobic-hydrophobic interactions. Finally, bis-L-prolinamide 6 has a C 2 -symmetry axis, which might have beneficial effects in the stereoselectivity of the reaction 30,31 (Figure 2).…”

Enantioselective “organocatalysis in disguise” by the ligand sphere of chiral metal-templated complexes

“…66,67 Although, recently highly efficient asymmetric organocatalysts have been developed (with requirement of o1 mol% (ppm levels) of catalyst loadings) [67][68][69][70] there is still need to develop more active and alternative catalysts and related catalytic reactions. The underlying reasons for this observation can be attributed to the relatively weak noncovalent interactions of the substrate and catalyst (e.g., hydrogen bonding, [71][72][73][74][75][76] ion-pairing, [77][78][79] etc.). [80][81][82][83] On the other hand, non-covalent interactions play a key role in catalysis by lowering the kinetic barriers to reactions through transition state stabilization.…”