Zinc Acetate Catalyzed Enantioselective Reductive Aldol Reaction of Ketones

Abstract

A highly enantioselective method for the synthesis of β‐hydroxy esters via reductive aldol reaction of acrylates with aryl and heteroaromatic ketones is described. In situ generated catalyst composed of zinc acetate and chiral diamine afforded enantioenriched tertiary alcohols in high yields and with excellent enantioselectivity (up to 91% ee). This is also the first successful application of the zinc hydride reagent in stereoselective reductive aldol reactions of ketones.

Recent developments in enantioselective zinc-catalyzed transformations

“…Scheme 105. Three-component domino reductive Michael/aldol reaction of acrylates, aromatic ketones and (EtO) 3 SiH in the presence of a diamine ligand [143]. Scheme 106.…”

“…In 2020, Mlynarski et al described the first enantioselective three-component domino reductive Michael/aldol reaction of acrylates 14, (hetero)aromatic ketones 88 and (EtO) 3 SiH using Zn (OAc) 2 as cheap precatalyst [143]. Optimal diamine ligand 227 was employed at 15 mol% of catalyst loading in m-xylene as solvent to promote the reaction at À30 °C.…”

Asymmetric Zinc Catalysis in Green One-pot Processes

“…ZnMe 2 (20 mol%) + 108 107 In 2020, a novel asymmetric synthesis of β-hydroxy esters was disclosed by Mlynarski et al through the first enantioselective three-component domino reductive Michael/aldol reaction of acrylates 108, (hetero)aromatic ketones 115 and triethoxysilane ((EtO) 3 SiH) using zinc acetate as cheap precatalyst [68]. Among chiral ligands based on (R,R)-diphenylethylenediamine, diamine 116 was selected as optimal ligand to promote this reaction at 15 mol% of catalyst loading in m-xylene as a solvent.…”

Catalytic Reductive Aldol and Mannich Reactions of Enone, Acrylate, and Vinyl Heteroaromatic Pronucleophiles

“…In this review, catalytic reductive couplings of enone, acrylate, and vinyl heteroaromatic pronucleophiles to carbonyl and imine partners are exhaustively catalogued on the basis of the metal catalyst or organocatalyst. − Catalytic reductive Michael reactions are described elsewhere. ,,,− Stepwise processes involving conjugate reduction to form discrete (me...…”

“…132−146 As described in the review literature, this abundance of prior art laid the foundation for catalytic reductive couplings of α,β-unsaturated carbonyl compounds with carbonyl electrophiles, termed "reductive aldol reactions". 147−162 Discovered over 30 years ago by Revis (1987), 163 catalysts for reductive aldol coupling based on rhodium, 163−189 cobalt, 190−195 iridium, 175,196 ruthenium, 197−199 palladium, 200 nickel, 201−203 platinum, 204 copper, 205−220 zinc, 221 and indium 222−225 have been described. More recently, Lewis basecatalyzed reductive aldol additions have been reported.…”