Thiourea-Catalyzed Enantioselective Cyanosilylation of Ketones

Abstract

The new chiral amino thiourea catalyst 3d promotes the highly enantioselective cyanosilylation of a wide variety of ketones. The hindered tertiary amine substituent plays a crucial role both with regard to stereoinduction and reactivity, suggesting a cooperative mechanism involving electrophile activation by thiourea and nucleophile activation by the amine. Lewis acid catalysis stands as the traditional and proven strategy for activation of carbonyl compounds toward enantioselective reactions. 1 Only recently, general acid catalysis with small molecule hydrogen-bond donors has emerged as promising alternative for electrophile activation in asymmetric synthesis. 2 Catalysts that function as H-bond donors exploit a mode of activation common in enzymatic pathways, 3 and may hold complementary reactivity and scope relative to metal-based systems. Our own efforts in general acid asymmetric catalysis have focused on chiral urea and thiourea derivatives (e.g. 1) for activation of alkyl-or acyl-substituted imines in Strecker, 4 Mannich, 5 hydrophophonylation, 6 nitro-Mannich, 7 and acyl Pictet-Spengler 8 reactions. 9 Application of achiral urea and thiourea derivatives to carbonyl activation reactions was demonstrated in seminal work by Curran 10 and subsequent studies by Schreiner, 11 but only very recently have thiourea derivatives been applied with varying success to the asymmetric catalytic activation of carbonyl compounds. 12 We describe here a significant new example of thiourea catalysis in carbonyl 1,2-addition chemistry, in the highly enantioselective cyanosilylation of ketones and aldehydes with a new bifunctional thiourea-amine derivative. The catalytic asymmetric cyanation of carbonyl compounds ranks among the most important and well-studied reaction classes in asymmetric catalysis, due in large part to the utility of the product cyanohydrins as precursors to α-hydroxy acids, β-amino alcohols, and other valuable chiral building blocks. 13 Wheareas several outstanding catalyst systems have been identified for cyanation of aldehydes, 14 ketones present a greater challenge as a substrate class, and only recently have effective methods using chiral metal complexes, 15 cinchona alkaloids, 16 and chiral oxazaborolidinium ions 17 been devised. The known Schiff base derivative 1 displayed no measurable catalytic activity in the model cyanosilylation of acetophenone with TMSCN (Table 1). However, primary amine 2, the immediate synthetic precursor to 1, proved highly active and led to product formation in 25% ee. The modular nature of the thiourea derivatives allowed straightforward and systematic optimization of the catalyst structure. 18 While tert-leucine proved to be the optimal amino acid component, less sterically demanding amide derivatives led to improved enantioselectivities, with secondary methyl amides (catalysts 3a-d) affording best results. Replacement of the primary amine in 3a with the corresponding N,N-dimethyl tertiary amine (3b) resulted in complete suppression of reactivity. However, introduction of...

Recent Progress in Chiral Brønsted Acid Catalysis

“…[23] Wang et al developed the bifunctional thiourea 5, bearing a binaphthyl backbone and an amine moiety, which catalyzed the Morita-Baylis-Hillman reaction of cyclohexenone with a wide range of aldehydes (Scheme 12). [24] The same catalyst promoted the asymmetric Michael addition of acetylacetone to nitroolefins (Scheme 13).…”

Michael Addition Initiated Substrate- or Catalyst-Controlled Chemodivergent Three-Component Construction of Fused and Bridged Polycyclic Heterocycles

“…Assuming that a reason for this lack of reactivity was the high steric hindrance of methacrolein (8a), we turned our attention towards primary amines. Even though cinchona-alkaloid derived catalyst II 15 was inefficient (entry 2), bifunctional thiourea-primary amine III 16 enabled the chemoselective formation of the fused bicyclic product (entry 3). After reduction, perhydrocyclopenta [b]pyridine 5b was isolated in 65% yield with an encouraging 45% enantiomeric excess.…”

Synthesis and Characterization of Complexes of Some Transition Metals with Two Bifunctional Thiourea Derivatives

“…In fact, they are employed as inhibitors for metals corrosion in aqueous aggressive environments 1 . They play also an important role in the field of asymmetric organocatalysis 2 , such as the cyanosilylation of ketones 3 , Michael additions 4 , Baylis-Hillman reactions 5 and hydrophosphonylation of imines 6 . In addition, they show a broad spectrum of biological activities such as antibacterial, antiviral, anticancer and anticonvulsion [7][8][9] .…”