Asymmetric Mukaiyama-Aldol Reaction in Aqueous Media Promoted by Zinc-Based Chiral Lewis Acids

Abstract

Asymmetric aldol reactions in aqueous media have been realized by using zinc-based chiral Lewis acids. The aldol products have been obtained with high yield, diastereocontrol and a good level of enantioselectivity. The reactivity of both acetophenone and propiophenone enol ether surrogates was tested with a range of aldehydes.

Study of the Lanthanide-Catalyzed, Aqueous, Asymmetric Mukaiyama Aldol Reaction

“…Compounds that contain optically active β-hydroxy carbonyl moieties have received great attention from chemists and biologists because these molecules are building blocks for pharmaceuticals and natural products, − and the Mukaiyama aldol reaction is commonly used to synthesize the carbon–carbon bonds in β-hydroxy carbonyls. − To be stereoselective, this reaction requires a catalyst to induce stereochemistry. Various Lewis-acid-catalyzed − and organocatalyst-catalyzed Mukaiyama aldol reactions have been reported for the enantioselective synthesis of β-hydroxy carbonyl compounds; however, the majority of these reactions require the use of aprotic anhydrous solvents because of the instability of precatalysts and reaction intermediates in the presence of water.…”

“…In recent years, efforts have focused on the asymmetric Mukaiyama aldol reaction in aqueous media because of the environmental and financial benefits associated with water-tolerant reactants . Examples of enantioselective catalysts that work in the presence of water include Cu(OTf) 2 , Pb(OTf) 2 , and Ln(OTf) 3 with chiral crown ethers; − Ga(OTf) 3 with Trost-type semicrowns; , and Zn(OTf) 2 and FeCl 2 with pybox-type ligands. − These systems produce a wide range of enantiometric ratios (er) that depend on the substrate identity.…”

Zn(pybox)-Complex-Catalyzed Asymmetric Aqueous Mukaiyama-Aldol Reactions

“…Our initial studies began with an evaluation of zinc complexes with ligands containing one, two, and three nitrogen atoms. The enantioselectivity of ligands was assessed in the catalytic aldol reaction of propiophenone silyl enol ether 4 and benzaldehyde as common substrates for the first stage optimization of the Mukaiyama process . Of the complexes surveyed, the Zn(OTf) 2 -pybox catalysts with ligands 1 − 3 provided superior levels of asymmetric inductions (Table ).…”

“…To address all of these deficiencies and develop new methodologies, we wish to report a novel chiral zinc catalyst with pybox-type ligand for asymmetric Mukaiyama-aldol reaction in aqueous media . Previously, synthetic Zn 2+ coordination complexes have been studied extensively as simplified models for various biological processes, e.g., aldol reactions catalyzed by type II aldolases, natural aldol reaction catalysts, containing Zn 2+ cofactor in the active site.…”

Development of Chiral Catalysts for Mukaiyama Aldol Reactions in Aqueous Media

“…The substrate scope was relatively wide and included thioketene silyl acetals, although the use of aliphatic aldehydes led to a significant loss of enantioselectivity . Chiral catalysts formed with Zn(OTf) 2 and i Pr‐pybox ligand L9 or FeCl 2 and hydroxymethyl‐pybox ligand L10 were also reported for asymmetric Mukaiyama aldol reactions in aqueous media. Although both aliphatic and aromatic aldehydes were applicable with moderate selectivity, aldehydes bearing heteroatoms and aqueous aldehydes were apt to be unsuccessful in the former catalytic system.…”