Catalyhtic asymmetric Henry reactions--a simple approach to optically active beta-nitro alpha-hydroxy esters

The development and potential of a catalytic enantioselective Henry reaction of nitromethane with various alpha-keto esters catalyzed by chiral bisoxazoline-copper(II) complexes are presented.     

Enantioselective addition of nitromethane to alpha-keto esters catalyzed by copper(II)-iminopyridine complexes

The copper complex of a chiral iminopyridine easily prepared from (R)-(-)-fenchone and picolylamine catalyzes the enantioselective Henry (nitroaldol) reaction between nitromethane and alpha-keto esters. Good yields and modest to good enantioselectivities are obtained for a wide range of alpha-keto esters, bearing aromatic, alkyl or alkenyl groups attached to the ketone carbonyl group.     

A new class of urea-substituted cinchona alkaloids promote highly enantioselective nitroaldol reactions of trifluoromethylketones

The first class of bifunctional cinchona-alkaloid catalysts incorporating a urea moiety at C-5' has been developed. These materials catalyze the efficient and highly enantioselective 1,2-addition of nitromethane to trifluoromethylketones to form synthetically pliable products incorporating a quaternary stereocenter. Excellent product yields and levels of enantiomeric excess are possible, and the optimum catalyst structure is capable of promoting the Henry reaction involving alkyl trifluoromethylketones with unprecedented enantioselectivity.     

Calcium-catalyzed diastereo- and enantioselective 1,4-addition of glycine derivatives to alpha,beta-unsaturated esters

The first highly diastereo- and enantioselective catalytic asymmetric 1,4-addition reactions of a glycine Schiff base to beta-substituted alpha,beta-unsaturated esters have been developed. The reaction pathway was successfully controlled, and the desired 1,4-addition products were exclusively obtained with high enantioselectivities. The product obtained was converted to a 3-substituted glutamic acid derivative by acid hydrolysis.     

Mimicking enzymatic transaminations: attempts to understand and develop a catalytic asymmetric approach to chiral alpha-amino acids

Attempts are made to build a bridge between asymmetric catalysis and enzymatic reactions by mechanistic investigations and the development of a catalytic and enantioselective approach to amination of alpha-keto esters by primary amines catalyzed by chiral Lewis acids as a model for transamination enzymes. Different Lewis acids can catalyze the half-transamination of alpha-keto esters using primary amine nitrogen sources such as pyridoxamine and 4-picolylamine. The mechanistic studies of the Lewis-acid catalyzed half-transamination using deuterium-labelled compounds show the incorporation of deuterium atoms in several positions of the alpha-amino acid derivative, indicating that the enol of the alpha-keto ester plays an important role along the reaction path. The catalytic enantioselective reactions are dependent on the pKa-value of the solvent since enantioselectivities were only obtained in solvents with high pKa-values relative to methanol. However, stronger acidic conditions generally gave better yields, but poor enantioselectivities. A series of chiral Lewis acids were screened as catalysts for the enantioselective half-transamination reactions and moderate yields and enantioselectivities of up to 46% ee were obtained.     

Copper(I) catalyzed asymmetric 1,2-addition of Grignard reagents to α-methyl substituted α,β-unsaturated ketones

The first catalytic enantioselective 1,2-addition of Grignard reagents to ketones is presented. This additive-free copper(I) catalyzed 1,2-addition provides chiral allylic tertiary alcohols with an er of up to 98:2 and excellent yields due to the complete shift of overwhelming 1,4-selectivity of copper(I)-catalysts towards 1,2-selectivity in the addition reaction to enones.     

Asymmetric Henry reaction catalyzed by C2-symmetric tridentate bis(oxazoline) and bis(thiazoline) complexes: metal-controlled reversal of enantioselectivity

[reaction: see text] C(2)-symmetric tridentate bis(oxazoline) and bis(thiazoline) ligands with a diphenylamine backbone have been investigated in the catalytic asymmetric Henry reaction of alpha-keto esters with different Lewis acids. Their Cu(OTf)(2) complexes furnished S enantiomers, while Et(2)Zn complexes afforded R enantiomers, both of them with higher enantioselectivities (up to 85% ee). Reversal of enantioselectivity in asymmetric Henry reactions was achieved with the same chiral ligand by changing the Lewis acid center from Cu(II) to Zn(II). The results show that the NH group in C(2)-symmetric tridentate chiral ligands plays a very important role in controlling both the yields and enantiofacial selectivity of the Henry products.     

Catalytic asymmetric direct alpha-amination reactions of 2-keto esters: a simple synthetic approach to optically active syn-beta-amino-alpha-hydroxy esters

The catalytic enantioselective direct alpha-amination reaction of 2-keto esters with easily available azo dicarboxylates as the nitrogen source and chiral bisoxazoline-copper(II) complexes as the catalyst is presented. The reactions proceed with excellent enantioselectivities and high yields. The scope of the reaction is demonstrated by the direct amination of a series of 2-keto esters having different substituent patterns. The reaction provides an easy catalytic route to optically active syn-beta-amino-alpha-hydroxy esters, as demonstrated for the synthesis of masked syn-beta-amino-alpha-hydroxy esters (as oxazolidinones) and N-Boc-syn-beta-amino-alpha-hydroxy esters. On the basis of the absolute configuration of the products a tentative model for the transition state is suggested.     

Formal Umpolung Addition of Phosphites to 2-Azaaryl Ketones under Chiral Brønsted Base Catalysis: Enantioselective Protonation Utilizing [1,2]-Phospha-Brook Rearrangement

The formal enantioselective umpolung addition of dialkyl phosphites to 2-azaaryl ketones was developed under Brønsted base catalysis. The reaction involves the enantioselective protonation of the transient α-oxygenated (2-azaaryl)methyl anion generated through the 1,2-addition of the anion of dialkyl phosphite to the 2-azaaryl ketone and the subsequent [1,2]-phospha-Brook rearrangement. A chiral bis(guanidino)iminophosphorane organosuperbase efficiently catalyzed the reaction to provide enantio-enriched phosphates in high yields with good to high enantioselectivities. This is a rare example of the catalytic enantioselective protonation of transient carbanions other than enolates, constructing a trisubstituted stereogenic center α to 2-azaarenes.     

单环手性胍催化的对映选择性Henry反应

从取代乙二胺方便地合成了4个手性单环胍．它们催化苯甲醛或异丁基醛同硝 基甲烷的Henry反应．能以较好的产率得到产物，但产物的对映体纯度不高．苯甲 醛Henry反应产物ee值最高为31％，异丁基醛获得的ee值最高为34％．这一反应速 度快，条件温和，是合成手性硝基醇的有效方法．     

Rhodium-catalyzed addition of arylboronic acids to isatins: an entry to diversity in 3-aryl-3-hydroxyoxindoles

[reaction: see text] A general method for the catalytic 1,2-addition of aryl and alkenyl boronic acids to isatins is described using a rhodium(I)/triphenylphosphite catalyst. The application of this transformation allows the synthesis of a variety of 3-aryl-3-hydroxyoxindole building blocks in high yields. An enantioselective version of this reaction using a rhodium(I)/phosphoramidite system is also presented.     

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.     

Direct, catalytic enantioselective nitroaldol (Henry) reaction of trifluoromethyl ketones: an asymmetric entry to alpha-trifluoromethyl-substituted quaternary carbons

Herein we describe the first direct, catalytic enantioselective nitroaldol (Henry) reaction of simple alpha-trifluoromethyl ketones with nitromethane using a chiral monometallic lanthanum(III) triflate salt complex, namely [(Delta,S,S,S)-Binolam]3.La(OTf)3, as enantioselective catalyst. The resulting alpha-trifluoromethyl tertiary nitroaldols were obtained in moderate to high yields (up to 93%) and enantioselectivities (up to 98% ee). These adducts are versatile chiral building blocks and may be reduced (NiCl2/NaBH4) to their beta-amino-alpha-trifluoromethyl tertiary alcohols without loss of enantiomeric purity.     

Chiral Lewis acid-catalyzed enantioselective intramolecular carbonyl ene reactions of unsaturated alpha-keto esters

[reaction: see text] Chiral Lewis acid-promoted highly enantioselective intramolecular carbonyl ene reactions of unsaturated alpha-keto esters have been investigated. In the presence of chiral Lewis acids such as [Sc((R,R)-Ph-pybox)](OTf)(3) and [Cu((S,S)-Ph-box)](OTf)(2), several unsaturated alpha-keto esters underwent carbonyl ene reactions in CH(2)Cl(2) at room temperature to give monocyclic products in good yield and excellent enantioselectivity.     

Organocatalytic asymmetric 1,6-additions of beta-ketoesters and glycine imine

The first organocatalytic enantioselective 1,6-addition of beta-ketoesters and benzophenone imine to electron-poor delta-unsubstituted dienes using cinchona alkaloids under phase-transfer conditions is demonstrated. The scope of the reaction for the beta-ketoesters is outlined for reactions with different delta-unsubstituted dienes having ketones, esters, and sulfones as electron-withdrawing substituents giving the corresponding optically active products in good yields and enantioselectivities in the range of 90-99% ee. The 1,6-addition also proceeds with a number of cyclic beta-ketoesters having different ring sizes, ring systems and substituents in high yields and enantioselectivities. The potential of this new organocatalytic 1,6-addition for beta-ketoesters is demonstrated by a two-step synthesis of the bicyclo[3.2.1]octan-8-one structure, a bicyclic bridged skeleton occurring in a variety of natural compounds. Benzophenone imines also undergo the organocatalytic asymmetric 1,6-addition to the activated dienes in high yields and with enantioselectivities from 92% to 98% ee, except in one case. The synthetic utility of this asymmetric reaction is demonstrated by the two-step transformation of the allylated alpha-amino acid derivative to highly attractive optically active pyrrolidines.     

Catalytic asymmetric Henry reactions of silyl nitronates with aldehydes

A catalytic enantioselective Henry reaction of silyl nitronates with aldehydes has been developed. Different chiral Lewis acids have been tested for the reaction and it has been found that a variety of chiral copper-ligand complexes can catalyze the Henry reaction. The best yield, diastereo- and enantioselectivity of the nitroalcohols formed are obtained by the application of a copper(II)-diphenyl-bisoxazoline complex as the catalyst in the presence of tetrabutylammonium triphenylsilyldifluorosilicate (TBAT). In order to minimize the epimerization of the nitroaldol products they were converted into the corresponding Mosher esters. The reaction proceeds well for different aromatic aldehydes reacting with alkyl nitronates.     

Reduction of activated carbonyl groups by alkyl phosphines: formation of alpha-hydroxy esters and ketones

Reduction of activated carbonyl groups such as alpha-keto esters, benzils, 1,2-cyclohexanedione, and alpha-ketophosphonates by alkyl phosphines afforded the corresponding alpha-hydroxy esters or ketones in good to excellent yields in THF at room temperature. The mechanism of the proton transfer and intramolecular hydrolysis has been studied on the basis of deuterium and 18O labeling experiments.     

One‐Pot Organocatalytic Asymmetric Synthesis of 3‐Nitro‐1,2‐dihydroquinolines by a Dual‐Activation Protocol

Generally, amine‐catalyzed enantioselective transformations rely on chiral enamine or unsaturated iminium intermediates. Herein, we report a protocol involving dual activation by an aromatic iminium and hydrogen‐bonding. An enantioselective aza‐Michael–Henry domino reaction of 2‐aminobenzaldehydes with nitroolefins has been developed through this protocol using primary amine thiourea catalysts to provide a variety of 3‐nitro‐1,2‐dihydroquinolines in moderate yields and with up to 90 % ee. The mechanism for the catalytic enantioselective reaction was confirmed by ESI mass spectrometric detection of the reaction intermediates. The products formed are substructures found in skeletons of important biological and pharmaceutical molecules.     

Asymmetric aza-Henry reaction under phase transfer catalysis: an experimental and theoretical study

An efficient catalytic asymmetric aza-Henry reaction under phase transfer conditions is presented. The method is based on the reaction of the respective nitroalkane with alpha-amido sulfones effected by CsOH x H2O base in toluene as solvent and in the presence of cinchone-derived ammonium catalysts. This direct aza-Henry reaction presents as interesting features its validity for both nonenolizable and enolizable aldehyde-derived azomethines and the tolerance of nitroalkanes, other than nitromethane, for the production of beta-nitroamines. The synthetic value of the methodology described is demonstrated by providing (a) a direct route for the asymmetric synthesis of differently substituted 1,2-diamines and (b) a new asymmetric synthesis of gamma-amino alpha,beta-unsaturated esters through a catalytic, highly enantioselective formal addition of functionalized alkenyl groups to azomethines. Finally, a preferred TS that nicely fits the observed enantioselectivity has been identified. Most remarkable, an unusual hydrogen bond pattern for the catalyst-nitrocompound-imine complex is predicted, where the catalyst OH group interacts with the NO2 group of the nitrocompound.     

Catalytic enantioselective fluorination of beta-keto esters by phase-transfer catalysis using chiral quaternary ammonium salts

[reaction: see text] The catalytic enantioselective electrophilic fluorination promoted by quaternary ammonium salt from cinchonine as a phase-transfer catalyst is described. Treatment of beta-keto esters with N-fluorobenzenesulfonimide as the fluorine source under mild reaction conditions afforded the corresponding alpha-fluoro beta-keto esters in exellent yields with good to moderate enantiomeric excesses