Organocatalyzed Asymmetric Aldol Reactions of Ketones and β,γ-Unsaturated α-Ketoesters and Phenylglyoxal Hydrates

Abstract

Enantioselective aldol reactions of acetophenone with β,γ-unsaturated α-ketoesters and cyclic ketones with phenylglyoxal hydrates were realized with cinchona alkaloid-derived thiourea catalysts. The corresponding aldol products were obtained in high yields and good to excellent diastereoselectivities and enantioselectivities (up to 95% ee).

Further developments of β,γ-unsaturated α-ketoesters as versatile synthons in asymmetric catalysis

“…Recently, great progress has been made in asymmetric aldol reactions of ketones with β,γ -unsaturated α -ketoesters. In 2015, Zhao and coworkers developed an enantioselective aldol addition of acetophenones 29 to β , γ -unsaturated α -ketoesters 1c ( Scheme 4 A) ( Konda et al., 2015 ). The desired aldol products 30 were obtained in high yields (70–99%) with moderate to excellent ee values (50–91% ee), under the catalysis of a quinidine-derived thiourea.…”

Chiral Thioureas—Preparation and Significance in Asymmetric Synthesis and Medicinal Chemistry

“…Such derivatives, introduced by the groups of Connon and Soós (Figure 15), were first applied in enantioselective addition of malonates to nitroalkenes [216] and nitroalkanes to chalcones [217]. Later on, these bifunctional organocatalysts were found efficient in a variety of asymmetric transformations, including Michael and combined Michael-Henry reaction , sulfa-Michael and retro-sulfa-Michael reaction [239,240], aldol reaction [241], Mannich reaction [242], Strecker reaction [243,244], hydrophosphonylation [245,246], decarboxylative protonation [247], fluorination of ketoesters [248], arylation of cyclic ketoamides with quinone monoamine [249] and others.…”

“…Such derivatives, introduced by the groups of Connon and Soós (Figure 15), were first applied in enantioselective addition of malonates to nitroalkenes [216] and nitroalkanes to chalcones [217]. Later on, these bifunctional organocatalysts were found efficient in a variety of asymmetric transformations, including Michael and combined Michael-Henry reaction , sulfa-Michael and retro-sulfa-Michael reaction [239,240], aldol reaction [241], Mannich reaction [242], Strecker reaction [243,244], hydrophosphonylation [245,246], decarboxylative protonation [247], fluorination of ketoesters [248], arylation of cyclic ketoamides with quinone monoamine [249] Thiourea was also introduced in place of methoxy group of quinine by Hiemstra and co-workers (Figure 16), and the resulting catalysts used in enantioselective Henry reaction [250], though they were less efficient in other asymmetric transformations [221,[243][244][245]. Bis-alkaloid thioureas were prepared by Song and co-workers and were shown to exhibit high enantioselectivity in a dynamic kinetic resolution of racemic azlactone derived from valine (Figure 16) [251].…”

Organocatalytic Asymmetric Aldol Reaction of Arylglyoxals and Hydroxyacetone: Enantioselective Synthesis of 2,3-Dihydroxy-1,4-diones

“…The enantioselective aldol reaction is among the most important synthetic tools for C-C bond formation in organic synthesis [1][2][3]. Arylglyoxals are endogenous α-oxoaldehydes that have been extensively used as electrophiles in related enantioselective aldol processes to afford synthetically important chiral 2-hydroxy-1,4-dicarbonyl compounds [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. For example, in 2009, Feng and coworkers developed an asymmetric aldol-type reaction between arylglyoxal derivatives and 2-oxindoles catalyzed by an N,N -dioxide-Sc(III) complex [4].…”

“…Subsequently, Hayashi and coworkers reported a chiral diarylprolinol-catalyzed direct aldol reaction of glyoxal derivatives with aldehydes, affording chiral 2-hydroxy-1,4-dicarbonyl compounds with good experimental outcomes [6]. Zhao and coworkers also reported an aldol reaction between cyclic ketones and arylglyoxals using a cinchona alkaloid-derived thiourea catalyst [10]. Most recently, Wang and coworkers disclosed an aldol reaction of 2-hydroxyacetophenone with ethyl glyoxylate catalyzed by a dinuclear zinc-azaphenol complex [11].…”