Progress in (Thio)urea‐ and Squaramide‐Based Brønsted Base Catalysts with Multiple H‐Bond Donors

Abstract

Thiourea‐ and squaramide‐based bifunctional base catalysts represent nowadays a powerful tool in the field of asymmetric catalysis and have demonstrated very efficient for promoting a wide variety of transformations enantioselectively. New versions that incorporate one or various additional H‐bond donor site(s) in the catalyst structure have been developed recently which led to more active (reduced catalyst loadings) and selective catalysts. This review highlights the pioneering ideas and the most recent contributions to the area with the material organized according to the nature of the additional H‐bond donor functionality. The advantages, current limitations and perspectives of these new multifunctional catalysts are discussed.

Enantio- and Diastereoselective Variations on α-Iminonitriles: Harnessing Chiral Cyclopropenimine-Thiourea Organocatalysts

“…9 However, the corresponding asymmetric variants remain underdeveloped, likely due to the difficulty in the control of stereoselectivity by a chiral catalyst, arising from the linear nature of the nitrile group and thereby the demanding spatial orientation between chiral catalysts and nitrile substrates for stereodifferentiation. 7,10 For example, Lambert demonstrated the enantioselective conjugate additions of α-iminoesters to α,β-unsaturated esters catalyzed by a chiral cyclopropenimine 11 superbase tethered to an alcohol moiety as a bifunctional Brønsted base 12,13 (Scheme 1B); 14 while highly enantioselective for the addition of αiminoesters (97% ee), such addition of α-iminonitriles exhibited significantly lower enantiocontrol (10% ee). 14b Thus, innovative strategies, potentially involving catalyst design, are necessary to address challenges in the stereoselective variations on α-aminonitrile-containing pronucleophiles.…”

Prolinamides containing 2-(2-aminocyclohexyl)phenols as highly enantioselective organocatalysts for aldol reactions

“…In particular, some (thio)ureas and squaramides incorporating prim -, sec - or tert -amine group have been proven to be highly active and enantioselective bifunctional catalysts in a variety of reactions. 45 Remarkably, however, higher efficiencies and enantioselectivities have been often observed with squaramide-based catalysts than with their thiourea-based analogues. 46–48 Those higher catalyst reactivities and enantioselectivities displayed by squaramides have been attributed mainly to the larger NH⋯NH distance of squaramide core (2.72 Å, the calculated value using the 6-31G* basis set) 46 than that of thiourea (2.13 Å, the calculated value using the 6-31G* basis set) 46 as well as the greater H-bond spacing of squaramides, which in turn provides a geometrically more proper arrangement for H-bonding activation of the electrophile component, although the activation power (H-bond strength) of a dual H-bond donor catalyst depends on several factors, such as H-bond spacing, distance between H-atoms, H-bond angle, rigidity, and p K a .…”

Dehydroabietane-type bifunctional organocatalysts in asymmetric synthesis: recent progress

“…Chiral thioureas and squaramides are representative organocatalysts in asymmetric synthesis that have been developed for enantioselective reactions. 11–34 Owing to their specific strong hydrogen-bonding capabilities combined with the notable features of the dehydroabietane scaffold, a series of effective bifunctional organocatalysts based on the dehydroabietane structure have been employed in various catalytic asymmetric reactions so far. 11–26…”