Trichlorosilyl triflate-mediated enantioselective directed cross-aldol reaction between ketones using a chiral phosphine oxide as an organocatalyst

Trichlorosilyl triflate-promoted directed cross-aldol reaction between ketones in the presence of a chiral phosphine oxide as an organocatalyst is described. This is the first enantioselective cross-aldol reaction between simple ketones with good enantioselectivity.     

Efficient organocatalytic cross-aldol reaction between aliphatic aldehydes through their functional differentiation

A chemo- and stereoselective asymmetric direct cross-aldol reaction between aliphatic aldehydes and α-chloroaldehydes has been developed as a method for the formation of the sole cross-aldol adduct with both enantio- and diastereocontrol, and either anti- or syn-aldol adducts were obtained in good to excellent stereoselectivities by use of proline or a novel axially chiral amino sulfonamide as catalyst.     

Direct catalytic asymmetric aldol reactions of pyruvates: scope and mechanism

The direct aldol reaction of 2-ketoesters catalyzed by chiral bisoxazoline copper(II) complexes has been investigated. First the direct homo-aldol reaction of ethyl pyruvate is reported which proceeds to give diethyl 2-hydroxy-2-methyl-4-oxoglutarate. This was isolated as the more stable optically active isotetronic acid in good yield and enantiomeric excess in the absence of bases such as amines. Detailed investigations of the use of different chiral Lewis acids as the catalyst, amines, ratios of chiral bisoxazoline copper(II) salts:amine, and solvents gave up to 96% ee of the isotetronic acid. Then the reaction was extended to a cross-aldol reaction of various 2-ketoesters with activated carbonyl compounds to give the cross-aldol adduct with excellent enantiomeric excess. Furthermore, the synthesis of the isotetronic acids was investigated from these cross-aldol adducts giving important information about the formation of the stereogenic centers during the aldol reaction. Based on the absolute configuration of the homo-aldol adduct the mechanism for the aldol reaction is discussed.     

手性伯胺催化剂用于顺式选择性的不对称Cross-Aldol反应

基于酸碱作用,将手性伯胺与质子酸原位结合制得有机小分子催化剂,并用于醛与醛的不对称Cross-aldol反应.与一般手性仲胺催化剂不同,该类伯胺催化剂得到的是顺式选择性构型的Cross-aldol产物,其产率达90%,顺反比和ee值分别为9:1和90%.相比而言,采用简单易得的(1S,2S)-(+)-环己二胺即可得到较高选择性的顺式产物.     

TiCl4-Et3N-mediated one-step synthesis of γ-alkylidenebutenolides from ketones: Application to natural product synthesis

TiCl₄-Et₃N-mediated condensation of ketones with methyl pyruvate afforded γ-alkylidene butenolides via a tandem cross-aldol addition/dehydroxylation/intramolecular lactonization process in one-pot. The application of the methodology to the straightforward synthesis of elem-1,3,7,8-tetraen-8,12-olide, chloranthalactone A, and dehydromenthofurolactone, is demonstrated.     

N-(heteroarenesulfonyl)prolinamides-catalyzed aldol reaction between acetone and aryl trihalomethyl ketones

Enantiomerically enriched trihalomethyl-substituted alcohols having a quaternary chiral carbon center can be prepared by the catalytic enantioselective cross-aldol reaction of acetone with trihalomethyl ketones by using N-(8-quinolinesulfonyl)prolinamide as an organocatalyst. The MO calculations elucidate that the hydrogen bonding between the sulfonimide proton and the 8-quinolyl nitrogen atom plays an important role in exerting the enantioselectivity of the reaction.     

Diarylprolinol as an Effective Organocatalyst in Asymmetric Cross-Aldol Reactions of Two Different Aldehydes

The aldol reaction is one of the most important carbon-carbon bond-forming reactions in organic chemistry. Asymmetric direct cross-aldol reaction of two different aldehydes has been regarded as a difficult reaction because of the side reactions such as self-aldol reaction and over reaction. We found that trifluoromethyl-substituted diarylprolinol, α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol ( 1 ), is an effective organocatalyst that promotes several cross-aldol reactions of aldehydes with excellent diastereo- and enantioselectivities. Acetaldehyde can be employed as a suitable nucleophilic aldehyde. Successful electrophilic aldehydes are ethyl glyoxylate, chloroacetaldehyde, dichloroacetaldehyde, chloral, α-alkyl-α-oxo aldehyde, trifluoroacetaldehyde, glyoxal, alkenyl aldehyde, alkynyl aldehyde, and formaldehyde. Some of the aldehydes are commercially available as a polymer solution, an aqueous solution, or in the hydrated form. They can be used directly in the asymmetric aldol reaction as a commercially available form, which is a synthetic advantage. Given that the obtained aldol products possess several functional groups along with a formyl moiety, they are synthetically useful chiral building blocks.     

Organocatalytic asymmetric cross-aldol reaction of 2-chloroethoxy acetaldehyde: diversity-oriented synthesis of chiral substituted 1,4-dioxanes and morpholines

Herein we report a facile organocatalytic asymmetric direct cross-aldol reaction of 2-chloroethoxy acetaldehyde with aromatic aldehydes using (S)-(?)-α,α-diphenyl-2-pyrrolidinemethanol as an organocatalyst to afford anti-2-(2-chloroethoxy)-1-arylpropane-1,3-diols with excellent enantioselectivities (95–98%) and moderate diastereoselectivities (3.5–7:1). The 1,3-diols, obtained after the aldehyde reduction, represent highly functional intermediates that allow for further diversification into both chiral 1,4-dioxanes and morpholines, compounds that frequently display interesting biological activities.     

γ-Hydroxy-α,β-acetylenic esters: asymmetric syntheses and applications

γ-Hydroxy-α,β-acetylenic esters are versatile synthetic precursors to many organic compounds. This paper reviews the synthesis of chiral γ-hydroxy-α,β-acetylenic esters by asymmetric reduction of γ-oxo-α,β-acetylenic esters, enantioselective addition to aldehydes in the presence of chiral catalysts, and diastereoselective addition to chiral aldehydes. The preparation of racemic γ-hydroxy-α,β-acetylenic esters is also included. Examples are provided for the application of γ-hydroxy-α,β-acetylenic esters in organic synthesis.     

Side-arm-promoted highly enantioselective ring-opening reactions and kinetic resolution of donor-acceptor cyclopropanes with amines

A Ni-catalyzed asymmetric ring-opening reaction of 2-substituted cyclopropane-1,1-dicarboxylates with aliphatic amines has been accomplished using the chiral indane-trisoxazoline (In-TOX) ligand. This highly enantioselective reaction provides an efficient approach to a variety of chiral γ-substituted γ-amino acid derivatives, which are readily transformed into multifunctionalized piperidines and γ-lactams. The single-crystal X-ray structure of the TOX-Ni complex is provided, and the role of the side arm in the chiral ligand is discussed.     

Diastereoselective Alkene Hydroesterification Enabling the Synthesis of Chiral Fused Bicyclic Lactones

Palladium-catalysed diastereoselective hydroesterification of alkenes assisted by the coordinative hydroxyl group in the substrate afforded a variety of chiral γ-butyrolactones bearing two stereocenters. Employing the carbonylation-lactonization products as the key intermediates, the route from the alkenes with single chiral center to chiral THF-fused bicyclic γ-lactones containing three stereocenters was developed.     

Stereoselective kinetic protonation of chiral γ-lactone enolates

When lithium enolates generated from five chiral α, γ-disubstituted γ-lactones are treated with proton sources, formation of the α, γ-syn epimers always predominates over the a,y-anti epimers in ratios of 10.2–2.9:1. Higher syn/anti ratios are obtained via silyl enolates in some cases. Chirality discrimination by chiral proton source is also observed in particular cases.     

Asymmetric cross-aldol reaction of isatin and ketones catalyzed by crude earthworm extract as efficient biocatalyst

ABSTRACT

The asymmetric cross-aldol reaction of simple ketones (acetone, cyclohexanone) with isatin derivatives in the presence of crude extract from earthworms as green and effective biocatalyst proceeds easily in MeCN/H₂O (1:1) as solvent to afford 3-hydroxy-2-oxindoles derivatives. Ten compounds were synthesized in high yields (62–88%) and moderate ee (29–42%). Structure of the synthesized compounds has been characterized on the basis of NMR spectra and CHN analysis. The ee of the obtained compounds was determined by chiral phase HPLC analysis.     

γ-Chiral β-ketosulfones in asymmetric synthesis: a unified synthetic strategy for enantiopure γ-amino and γ-hydroxy vinyl sulfones

Enantiopure γ-hydroxy and γ-amino vinyl sulfones have been prepared in a short synthetic sequence from the chiral pool derived γ-acetoxy/amino β-ketosulfones.     

Diastereoselective and enantioselective capture of chiral zinc enolate using nitroolefins: a rapid access to chiral γ-nitro carbonyl compounds

Highly diastereoselective and enantioselective catalytic capture of chiral zinc enolates using nitroolefins as electrophiles is described. The tandem products γ-nitro ketones were obtained in good yields with high diastereoselectivities and enantioselectivities. The γ-nitro ketones were readily hydrogenated to the optically enriched and diastereomerically pure chiral pyrrolidines with four contiguous stereocentres under mild conditions.     

Asymmetric synthesis of highly functionalized γ-lactams through an organocatalytic aza-Michael–Michael reaction cascade using fumaric acid amide esters as multi-reactive substrates

We developed a novel method for the asymmetric synthesis of highly functionalized γ-lactams through an organocatalytic aza-Michael–Michael reaction cascade using fumaric acid amide esters as multi-reactive substrates. Using chiral primary or secondary amine organocatalysts, we obtained two types of γ-lactams with three contiguous chiral centers in moderate to good yield with excellent enantioselectivity and diastereoselectivity.     

Stereoselective synthesis of γ-amino acids

γ-Amino acids have attracted considerable attention as biologically active compounds in the central nervous system (CNS) of mammals. Over the last few years, significant interest in the stereoselective synthesis and practical application of linear and cyclic chiral γ-amino acids in the synthesis and design of α,β- and β,γ-hybrid peptides with definite secondary structures and design of nanotubes has been reported, thus demonstrating the theoretical interest and the practical importance of γ-amino acids. An overview of synthetic approaches to linear and cyclic chiral γ-amino acids and derivatives is presented. Data on the practical applications of γ-amino acids are also discussed.     

Direct catalytic asymmetric cross-aldol reactions in ionic liquid media

Enantioselective proline-catalyzed direct asymmetric cross-aldol reactions with aldehydes were performed in ionic liquid 1-n-butyl-3-methylimidazolium hexafluorophosphate media, which simplified product isolation and catalyst recycling, affording 3-hydroxy aldehydes in high yield with excellent stereoselectivity. In addition, the enhanced reactivity of the asymmetric cross-aldol reactions in ionic liquid allowed the catalyst loading to be lowered significantly.     

Enantio- and Diastereoselective Synthesis of Chiral Tetrasubstituted α-Amino Allenoates Bearing a Vicinal All-Carbon Quaternary Stereocenter with Dual-Copper-Catalysis

The skeletons of chiral tetrasubstituted allenes bearing a vicinal all-carbon quaternary stereocenter are of importance but still challenging to synthesize. Herein, we report enantio- and diastereoselective γ-additions of 1-alkynyl ketimines with dual-copper-catalysis under mild conditions, affording chiral tetrasubstituted α-amino allenoates bearing a vicinal all-carbon quaternary stereocenter in high yields (up to 99 % yield) with excellent enantioselectivities (up to 99 % ee) and diastereoselectivities (up to >20 : 1 dr). Importantly, the stereodivergent synthesis of the products was realized by the asymmetric γ-addition reaction and the Grignard reagent promoted epimerization. Moreover, the dual-copper-catalyzed γ-addition reactions were smoothly applied to a gram-scale reaction and adopted to introduce chiral tetrasubstituted allenyl moieties into bioactive molecules. Mechanistic experiments and density functional theory (DFT) calculations demonstrated that the asymmetric γ-addition reactions were catalyzed by double chiral copper catalysts.     

Enantiomeric separation of dansylamino acids by capillary zone electrophoresis with selectively methylated γ-cyclodextrin derivatives

The chiral separation ability of octakis2-, 3- and 6-mono-O-methyl, 2,3-, 2,6- and 3,6-di-O-methyl, and 2,3,6-tri-O-methyl)-γ-cyclodextrins as chiral selectors in capillary zone electrophoresis was investigated using twelve dansylamino acids. Unmodified and 6-monomethylated -γ-cyclodextrins (γ-CDs) exhibited similar high enantioselectivities. γ-CD still exhibited a chiral separation ability after 2-monomethylation or 2,6-dimethylation. 3-Monomethylated -γ-CD could only separate the enantiomers of two dansylamino acids, but further methylation of the hydroxyl groups at the 6-positions of 3-monomethylated γ-CD resulted in the highest chiral separation ability. γ-CD completely lost its high enantioselectivity after methylation of both the 2- and 3-positions, regardless of 6-methylation.