On the intermediates in chiral bis(oxazoline)copper(II)-catalyzed enantioselective reactions--experimental and theoretical investigations

The intermediates in the chiral bis(oxazoline)copper(II)-catalyzed reactions have been investigated by means of experimental and theoretical investigations. It is shown that the absolute configuration of the hetero-Diels-Alder adduct obtained from the reaction of ethyl glyoxylate with 1,3-cyclohexadiene in the presence of the chiral bis(phenyloxazoline)copper(II) is dependent on the solvent. In this case, a linear relationship between the enantiomeric excess (ee) and the dielectric constant of the solvent was observed. However, the enantiomeric excess for the adduct obtained with the chiral bis(tert-butyloxazoline)copper(II) complex is independent of the solvent. The addition of different coordinating solvents to the chiral catalysts was investigated and no effect on the enantioselectivity of the reaction was observed. A series of chiral bis(tert-butyloxazoline)-, bis(phenyloxazoline)-, and bis(indaneoxazoline)copper(II) complexes has been prepared and characterized by X-ray analysis, and the similarity between the structures is discussed. For comparison, two related chiral bis(tert-butyloxazoline)- and bis(phenyloxazoline)zinc(II) complexes were also prepared and characterized. A series of chiral bis(oxazoline)copper(II)-substrate (the substrate being glyoxal or methyl glyoxylate) complexes was investigated by means of ab initio calculations. Calculation of the total energy of the optimized structure of 17-, 19-, and 21-electron bis(oxazoline)copper(II)-substrate complexes give the 17-electron complex as the most stable and the most reactive complex, while the 21-electron complex is less stable and also much less reactive. The optimized structures of both the 17-electron bis(tert-butyloxazoline)- and bis(phenyloxazoline)copper(II)-substrate complexes show that the plane of the substrate molecule is twisted by approximately 40-45 degrees out of the bis(oxazoline)copper(II) plane, in agreement with the X-ray structures. On the basis of the experimental results, X-ray structures, and ab initio calculations, the structure of the intermediate(s) and reactivity of the chiral bis(oxazoline)copper(II)-substrate complexes are discussed.     

Reductive cross-aldol reaction using bromoaldehyde and an aldehyde mediated by germanium(II): one-pot, large-scale protocol

[reaction: see text] The reaction of alpha-bromoaldehyde with aldehyde in the presence of GeCl(2)-dioxane gave the syn-selective cross-aldol equivalent. A catalytic amount of Bu(4)NBr improved the yield and selectivity. The initially formed aldol adduct (beta-germoxyaldehyde) did not suffer from over-reaction. This system enabled an intramolecular aldol reaction to give cyclic compounds effectively. One-pot synthetic methodology including bromination of aldehyde followed by cross-aldol reaction with the second aldehyde was successful on a large-scale.     

Enantiopure azetidine-2-carboxamides as organocatalysts for direct asymmetric aldol reactions in aqueous and organic media

A family of enantiopure azetidine-2-caboxamides was asymmetrically synthesized, and was examined as organocatalyst in direct aldol reactions. A well chosen chiral azetidine-2-caboxamide was found to smoothly catalyze the direct aldol reaction of various benzaldehydes with acetone in brine, and β-hydroxy ketones were produced with enantiomeric excess up to 96%. The reaction of benzaldehydes with cyclic ketones also led to the formation of anti-products in diastereomeric ratio up to 99:1 and enantiomeric excess up to 99%.     

Catalytic, highly enantioselective Friedel-Crafts reactions of aromatic and heteroaromatic compounds to trifluoropyruvate. A simple approach for the formation of optically active aromatic and heteroaromatic hydroxy trifluoromethyl esters.

A new catalytic enantioselective synthetic method for the formation of optically active aromatic and heteroaromatic hydroxy-trifluoromethyl ethyl esters is presented. This catalytic enantioselective Friedel-Crafts reaction of trifluoromethyl pyruvate with aromatic and heteroaromatic compounds is catalyzed by a chiral bisoxazoline copper(II) complex and proceeds in good yield and with high enantiomeric excess. For a series of substituted indoles, the corresponding 3-substituted hydroxy-trifluoromethyl ethyl esters are formed in up to 93% yield and 94% ee. Pyrrole and 2-substituted pyrroles also react with trifluoromethyl pyruvate in a highly enantioselective aromatic electrophilic reaction and up to 93% ee and good yields are obtained. Furanes and thiophenes give the corresponding 2-hydroxy-trifluoromethyl ethyl esters in high enantiomeric excess; however, the yields of the products are only moderate. Various types of aromatic compounds react in this catalytic reaction with trifluoromethyl pyruvate to give the aromatic electrophilic addition product in good yield. To obtain high enantiomeric excess (> 80% ee) it is necessary that aromatic amines are protected with sterically demanding protecting groups such as benzyl or allyl. This prevents coordination of the amine nitrogen atom to the catalyst, as aromatic amines having a N,N-dimethyl group probably coordinate to the catalyst, leading to a significant reduction of the enantioselective properties of the catalyst. On the basis of the experimental results and the absolute configuration of the formed chiral center, the mechanism for the catalytic enantioselective Friedel-Crafts reaction is discussed.     

Stereoselective Copper-Catalyzed Direct Aldol Reaction of β, γ-Unsaturated α-Ketoesters with Coumaran-3-Ones

An efficient direct aldol reaction between coumaran-3-ones and β, γ-unsaturated α-ketoesters by virtue of a chiral copper complex is developed. A series of coumaran-3-one derivatives containing chiral tertiary alcohol structures are obtained in excellent yields and stereoselectivities.     

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.     

Asymmetric synthesis of chiral β-hydroxy-α-amino acid derivatives by organocatalytic aldol reactions of isocyanoesters with β,γ-unsaturated α-ketoesters

The first organocatalytic asymmetric aldol reaction of isocyanoesters with various β,γ-unsaturated α-ketoesters has been described. Using cinchona alkaloid-derived bifunctional thiourea as the catalyst, chiral β-hydroxy-α-amino acid derivatives can be obtained in excellent yields and enantioselectivities (up to 95% yield and 92% ee) after acidic hydrolysis. This protocol provides a straightforward method to access multiple substituted β-hydroxy-α-amino acid derivatives with high enantiomeric purity.     

Asymmetric syn-selective Henry reaction catalyzed by the sulfonyldiamine-CuCl-pyridine system

A catalytic asymmetric Henry reaction has been developed with use of a sulfonyldiamine-CuCl complex as a catalyst. A series of new binaphthyl-containing sulfonyldiamine ligands (2a-h) were readily synthesized in two steps starting from commercially available chiral 1,2-diamines. The (R,R)-diamine-(R)-binaphthyl ligand (2d)-CuCl complex smoothly catalyzed the enantioselective Henry reaction with the assistance of pyridine to give the corresponding adduct with high enantiomeric excess (up to 93%). Moreover, the 2d-CuCl-pyridine system promotes the diastereoselective Henry reaction in syn-selective manner to give the adduct in up to 99% yield with 92:8 syn/ anti selectivity. The enantiomeric excess of the syn-adduct was 84% ee.     

Bis(oxazoline) Lewis acid catalyzed aldol reactions of pyridine N-oxide aldehydes--synthesis of optically active 2-(1-hydroxyalkyl)pyridine derivatives: development, scope, and total synthesis of an indolizine alkaloid

A new, short, and simplified procedure for the synthesis of optically active pyridine derivatives from pro-chiral pyridine-N-oxides is presented. The catalytic and asymmetric Mukaiyama aldol reaction between ketene silyl acetals and 1-oxypyridine-2-carbaldehyde derivatives catalyzed by chiral copper(II)-bis(oxazoline) complexes gave optically active 2-(hydroxyalkyl)- and 2-(anti-1,2-dihydroxyalkyl)pyridine derivatives in good yields and diastereoselectivities, and in excellent enantioselectivities-up to 99 % enantiomeric excess. As a synthetic application of the developed method, a full account for the asymmetric total synthesis of a nonnatural indolizine alkaloid is provided.     

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.     

Organocatalytic direct asymmetric aldol reactions in water

We have developed direct asymmetric cross-aldol reactions that can be performed in water without addition of organic solvents. A bifunctional catalyst with a long hydrophobic alkyl chain efficiently catalyzed the reactions and afforded the desired aldol products in excellent yield with high enantiomeric excess, even when only an equal molar ratio of the donor and acceptor was used. These results reveal an effective design strategy for the development of aqueous organocatalytic systems.     

Enantioselective Friedel-Crafts alkylation reactions catalyzed by a chiral nonracemic C2-symmetric 2,2'-bipyridyl copper(II) complex

Enantioselective Friedel-Crafts alkylation reactions of a series of substituted indoles with methyl trifluoropyruvate, catalyzed by a chiral nonracemic C(2)-symmetric 2,2'-bipyridyl copper(II) triflate complex, are described. The corresponding 3,3,3-trifluoro-2-hydroxy-2-indole-3-yl-propionic acid methyl esters were formed in good yield and in high enantiomeric excess (up to 90%). This is the first report of the use of a chiral nonracemic 2,2'-bipyridyl ligand in catalytic and enantioselective Friedel-Crafts alkylation reactions. The structural characterization of a copper(II) chloride complex of the chiral 2,2'-bipyridyl ligand by X-ray crystallography is also presented. [reaction: see text]     

Stereoselective pinacol coupling of chiral formylferrocene using divalent samarium triflate: preparation of a new chiral bisferrocenyl oxazoline ligand and its application to asymmetric Diels-Alder reactions

[reaction: see text] The pinacol coupling reaction of planar chiral ortho-oxazoline-substituted formylferrocene was smoothly mediated by SmI2 or Sm(OTf)3 to give the (R,R) isomer selectivity (up to 76% diastereomeric excess). The combination of Yb(OTf)3 and the (R,R)-ferrocenyl diol was revealed to be a good catalyst for the asymmetric Diels-Alder reaction of 3-acyloxazolidinone with cyclopentadiene, and the endo adduct was produced in up to 80% enantiomeric excess.     

5R-Methyl-1-chloromethyl-2-pyrrolidinone: Determining Enantiomeric Excess in Chiral Nonracemic Amines1

5R-Methyl-1-chloromethyl-2-pyrrolidinone reacts with chiral, racemic amines to form a diastereomeric adduct. Analysis of the N-CH₂-O signals in the proton NMR spectra allows determination of the enantiomeric excess of the original amine.     

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.     

Direct regiospecific and highly enantioselective intermolecular α-allylic alkylation of aldehydes by a combination of transition-metal and chiral amine catalysts

The first direct intermolecular regiospecific and highly enantioselective α-allylic alkylation of linear aldehydes by a combination of achiral bench-stable Pd(0) complexes and simple chiral amines as co-catalysts is disclosed. The co-catalytic asymmetric chemoselective and regiospecific α-allylic alkylation reaction is linked in tandem with in situ reduction to give the corresponding 2-alkyl alcohols with high enantiomeric ratios (up to 98:2 e.r.; e.r.=enantiomeric ratio). It is also an expeditious entry to valuable 2-alkyl substituted hemiacetals, 2-alkyl-butane-1,4-diols, and amines. The concise co-catalytic asymmetric total syntheses of biologically active natural products (e.g., Arundic acid) are disclosed.     

Enantiomeric impurities in chiral synthons,catalysts, and auxiliaries: Part 3

The enantiomeric excess of chiral reagents used in asymmetric syntheses directly affects the reaction selectivity and product purity. In this work, 84 of the more recently available chiral compounds were evaluated to determine their actual enantiomeric composition. These compounds are widely used in asymmetric syntheses as chiral synthons, catalysts, and auxiliaries. These include chiral alcohols, amines, amino alcohols, amides, carboxylic acids, epoxides, esters, ketones, and oxolanes among other classes of compounds. All enantiomeric test results were categorized within five impurity levels (i.e., <0.01%, 0.01–0.1%, 0.1–1%, 1–10%, and >10%). The majority of the reagents tested were determined to have enantiomeric impurities over 0.01%, and two of them were found to contain enantiomeric impurities exceeding the 10% level. The most effective enantioselective analysis method was a GC approach using a Chiraldex GTA chiral stationary phase (CSP). This method worked exceedingly well with chiral amines and alcohols.     

A Closer Look at Spontaneous Mirror Symmetry Breaking in Aldol Reactions

The aldol reaction between acetone and 4‐nitrobenzaldehyde run in the nominal absence of any enantioselective catalyst was monitored by chiral HPLC with the aid of an internal standard. The collected data show the presence of a detectable initial enantiomeric excess of the aldol product in the early stages of the reaction in about 50 % of the experiments. Only a small fraction of the reaction contained the non‐racemic aldol product after 24 h. This temporary emergence of natural optical activity could be the signature of a coupled reaction network that leads to a spontaneous mirror‐symmetry‐breaking process, which originates at very low conversions (i.e., strongly depends on events taking place at the very first stages of the process). The reaction is not autocatalytic in the aldol product, which rules out a simple Frank‐type reaction network as the source of the observed symmetry breaking. On the other hand, the isolation and characterisation of a double‐aldol adduct suggested a reaction network that involved both indirect autocatalysis and indirect mutual inhibition between the enantiomers of the reaction product.     

Diels-alder reactions with cyclic sulfones: VIII. Organic catalysis in the synthesis of spiro[1-benzothiophene-4,5′-pyrimidine]-2′,4′,6′-trione 1,1-dioxides and 2′-thioxospiro[1-benzothiophene-4,5′-pyrimidine]-4′,6′-dione 1,1-dioxides

5-Isopropenyl-2,3-dihydrothiophene 1,1-dioxide reacted with 5-methylidenepyrimidine-2,4,6-triones and 5-methylidene-2-thioxopyrimidine-4,6-diones in the presence of chiral amines or amino acids with high regio- and stereoselectivity to give optically active derivatives of barbituric and thiobarbituric acids spirofused at the 5-position to 1-benzothiophene 1,1-dioxide fragment. The reaction of 5-isopropenyl-2,3-dihydrothiophene 1,1-dioxide with 5-(2-methoxybenzylidene)-2-thioxopyrimidine-4,6-dione (generated in situ from 2-methoxybenzaldehyde and thiobarbituric acid) in the presence of (?)-ephedrine or L-4-(tert-butyldimethylsiloxy) proline gave the corresponding 2-thioxospiro[1-benzothiophene-4,5′-pyrimidine]-4′,6′-dione 1,1-dioxide with an enantiomeric excess of 80%.     

Direct Regiospecific and Highly Enantioselective Intermolecular α‐Allylic Alkylation of Aldehydes by a Combination of Transition‐Metal and Chiral Amine Catalysts

The first direct intermolecular regiospecific and highly enantioselective α‐allylic alkylation of linear aldehydes by a combination of achiral bench‐stable Pd⁰ complexes and simple chiral amines as co‐catalysts is disclosed. The co‐catalytic asymmetric chemoselective and regiospecific α‐allylic alkylation reaction is linked in tandem with in situ reduction to give the corresponding 2‐alkyl alcohols with high enantiomeric ratios (up to 98:2 e.r.; e.r.=enantiomeric ratio). It is also an expeditious entry to valuable 2‐alkyl substituted hemiacetals, 2‐alkyl‐butane‐1,4‐diols, and amines. The concise co‐catalytic asymmetric total syntheses of biologically active natural products (e.g., Arundic acid) are disclosed.