Development of Chiral Thiourea Catalysts and Its Application to Asymmetric Catalytic Reactions

Abstract

We have developed several multifunctional thiourea catalysts bearing a tertiary amine or an 1,2-amino alcohol in expectation of their synchronous activation of a nucleophile and an electrophile through both acid-base and hydrogen-bonding interactions. From these studies, it was revealed that the weak acidity of thioureas compared with metallic Lewis acids could be overcome by this modification. The bifunctional aminothiourea could be used efficiently for a wide range of diastereoselective and enantioselective nucleophilic reactions such as Michael addition of 1,3-dicarbonyl compounds to nitroolefines, aza-Henry reaction of nitroalkanes to N-Boc imines, and hydrazination of cyclic b b-keto esters. We also discovered that multifunctional thiourea catalyst, bearing an 1,2-amino alcohol moiety, significantly accelerated the Petasis-type reaction of alkenylboronic acids to Nphenoxycarbonyl quinolinium salts, prepared from quinolines and phenyl chloroformate, to afford 1,2-addition products with high enantioselectivity (up to 97% ee). Furthermore, to expand the synthetic applicability of the thiourea-catalyzed asymmetric reactions, tandem organocatalyzed reactions were explored to establish the concise one-pot synthesis of chiral densely functionalized three-, five-, and six-membered compounds.

Synthesis of Three New Bifunctional Glucose-Thiourea Organocatalysts and Their Application in Asymmetric <i>Michael</i> Addition

“…Numerous asymmetric reactions, such as aldol, Mannich, Michael, Henry, amination, Biginelli, cyanosilylation and aza-Morita-BaylisHillman reactions, have been accomplished by these catalysts [3]. Recently, bifunctional thiourea derivatives have been recognized as effective organocatalysts for asymmetric Michael addition reactions [4][5][6]. Therefore, the development of simple and efficient bifunctional thiourea catalysts has great interest.…”

Stereoselective synthesis towards unnatural proline based amino acids

“…[20][21][22] Specifically, the use of urea-and thiourea-based organic molecules as hydrogen-bond-donor organocatalysts has been reported to be compatible with various substrates and reaction conditions. [23][24][25] Jacobsen and co-workers developed a collection of thiourea catalysts that promote a diverse range of reactions with excellent enantioselectivity, along with the chiral versions as efficient hydrogen-bond-donor organocatalysts. 26 Other groups such as; Jørgensen and Ricci and later Dixon, Takemoto, and Deng have all reported highly enantioselective Mannich reactions of β-ketoesters, catalysed by bifunctional cinchona alkaloid-derived organocatalysts.…”

“…1,27 These catalysts are regarded as bifunctional chiral catalysts, bearing a tertiary amino group and hydrogen bond donors, which are expected to possess dual activation of both the electrophilic and nucleophilic components. 25,28,29 In this study, we explore the ability of a urea-type cinchonine and quinine alkaloid derivatives to catalyse the Mannich reaction between the scarcely used N-Boc protected 3-ketoproline substrate with various N-Boc-imines in an effort to create a new route to unnatural proline based amino acids.…”

Asymmetric Conjugate Additions of Carbonyl Compounds to Nitroalkenes under Solvent-Free Conditions Using Fluorous Diaminomethylenemalononitrile Organocatalyst

“…Thiourea organocatalysts, which are represented by Takemoto catalysts, are excellent catalysts and are applied to remarkably important asymmetric reactions. [18][19][20][21][22][23][24][25][26] Good organocatalytic activity is seen when a thiourea motif functions as a double hydrogen-bond donor for a nucleophilic substrate. In addition, a squaramide motif as a further double hydrogen-bond donor was reported by Rawal and colleagues, and the squaramide organocatalyst effectively promotes the asymmetric conjugate additions of 1,3-diketones to nitroalkenes.…”