Non-Covalent Interactions in Enantioselective Organocatalysis: Theoretical and Mechanistic Studies of Reactions Mediated by Dual H-Bond Donors, Bifunctional Squaramides, Thioureas and Related Catalysts

Abstract

Chiral bifunctional dual H-bond donor catalysts have become one of the pillars of organocatalysis. They include squaramide, thiosquaramide, thiourea, urea, and even selenourea-based catalysts combined with chiral amines, cinchona alkaloids, sulfides, phosphines and more. They can promote several types of reactions affording products in very high yields and excellent stereoselectivities in many cases: conjugate additions, cycloadditions, the aldol and Henry reactions, the Morita–Baylis–Hilman reaction, even cascade reactions, among others. The desire to understand mechanisms and the quest for the origins of stereoselectivity, in attempts to find guidelines for developing more efficient catalysts for new transformations, has promoted many mechanistic and theoretical studies. In this review, we survey the literature published in this area since 2015.

Enantioselective Povarov Reactions: An Update of a Powerful Catalytic Synthetic Methodology

“…[85] A wide variety of chiral (thio)urea organocatalysts are known in the literature for use in enantioselective organic syntheses, e. g. Michael addition, nitro-Mannich reaction, amination reaction, domino aza-Michael-Henry reaction, Mannich reaction, Diels-Alder reaction and others. [86][87][88] Furthermore, chiral bifunctional (thio)ureaÀ amine organocatalysts have been gaining prominence recently by activating both the electrophile and the nucleophile at the same time. The amine group of these organocatalysts activates the nucleophiles and the (thio)urea moiety activates the electrophiles by double hydrogen bonding.…”

“…Pioneer works of (thio)urea based catalysts include Jacobsen's catalyst 126 and derivatives (Figure 10). [85] A wide variety of chiral (thio)urea organocatalysts are known in the literature for use in enantioselective organic syntheses, e. g. Michael addition, nitro‐Mannich reaction, amination reaction, domino aza‐Michael‐Henry reaction, Mannich reaction, Diels‐Alder reaction and others [86–88] . Furthermore, chiral bifunctional (thio)urea−amine organocatalysts have been gaining prominence recently by activating both the electrophile and the nucleophile at the same time.…”

“…Therefore, this action mode increase the reaction rates and the enantioselectivity of the reaction. [32,86] Organocatalysis using (thio)urea in PRs is not very common. In particular the first report occurred in a conceptually different type of enantioselective Brønsted acid catalysis reported by H. Xu et al, [32] an intriguing combination of an achiral Brønsted acid and a chiral urea.…”

“…The amine group of these organocatalysts activates the nucleophiles and the (thio)urea moiety activates the electrophiles by double hydrogen bonding. Therefore, this action mode increase the reaction rates and the enantioselectivity of the reaction [32,86] …”

New bifunctional 1,3‐diamine organocatalysts derived from (+)‐camphoric acid for asymmetric Michael addition of 1,3‐dicarbonyl compounds to nitroolefins

“…[1][2][3][4][5][6][7] In particular, the conjugate addition of 1,3-dicarbonyl compounds to trans-β-nitrostyrenes has attracted particular interest due to the reactivity of the resulting enantiopure products which are key intermediates for the preparation of a large number of pharmaceutical compounds. The asymmetric control of this reaction has been achieved with organocatalysts such as diamines, [8][9][10][11][12][13][14] amine-thioureas, [15][16][17][18][19][20] and Cinchona derivatives. [21][22][23][24][25][26][27][28][29] Therefore, the development of chiral bifunctional hydrogen-bonding organocatalysts, which can activate nucleophiles and electrophiles at the same time, have emerged as powerful organocatalysts.…”