Enantioselective copper-catalyzed allylic alkylation with dialkylzincs using phosphoramidite ligands

[reaction: see text]. In the presence of a catalytic amount of copper salts, cinnamyl halides undergo a regio- and enantioselective S(N)2' alkylation with dialkylzincs using chiral phosphoramidites as ligands. An S(N)2':S(N)2 ratio of 85:15 and enantiomeric excesses up to 77% for the chiral S(N)2' products are found. Variation of solvent and reaction temperature revealed that the highest regio- and enantioselectivities are found using coordinating solvents of -40 degrees C.     

Highly regioselective asymmetric copper-catalyzed allylic alkylation with dialkylzincs using monodentate chiral spiro phosphoramidite and phosphite ligands

The copper complexes of chiral spiro phosphoramidite and phosphite ligands were found to be effective catalysts in the asymmetric allylic alkylations of cinnamyl halides with dialkylzincs. The allylic alkylation products were obtained in high regioselectivities (S_N2′/S_N2 up to 98:2) and enantiomeric excesses of up to 74% for S_N2′ products.     

Z-Selective copper-catalyzed asymmetric allylic alkylation with Grignard reagents

Allylic gem-dichlorides undergo regio- and enanantioselective (er up to 99:1) copper-catalyzed allylic alkylation with Grignard reagents affording chiral Z-vinyl chlorides. This highly versatile class of synthons can be subjected to Suzuki cross coupling affording optically active Z-alkenes and 1,3-cis,trans dienes.     

Dendritic phosphoramidite ligands in Rh-catalysed asymmetric hydrogenations

The axially chiral BICOL backbone was functionalised with two third generation carbosilane dendritic wedges and further elaborated to a phosphoramidite ligand. High enantioselectivities were obtained when these monodentate ligands were applied in the rhodium-catalysed asymmetric hydrogenation of methyl 2-acetamidocinnamate.     

Biphenol-based phosphoramidite ligands for the enantioselective copper-catalyzed conjugate addition of diethylzinc

Phosphoramidite ligands, based on ortho-substituted biphenols and a chiral amine, induce high enantioselectivities (ee's up to 99%) in the copper-catalyzed conjugate addition of dialkylzinc reagents to a variety of Michael acceptors. Particularly, the best reported ee's were obtained for acyclic nitroolefins.     

The effects of solvent on switchable stereoselectivity: copper-catalyzed asymmetric conjugate additions using D2-symmetric biphenyl phosphoramidite ligands

A highly enantioselective copper-catalyzed conjugate addition of diethylzinc to acyclic aromatic enones was developed with phosphoramidite ligands bearing a D(2)-symmetric biphenyl backbone. This type of reaction demonstrated that toluene and THF solvents can completely reverse the absolute configuration of the products, thus simplifying the process of accessing either enantiomer (S: 92% ee, 94% yield; R: 99% ee, 96% yield).     

Highly enantioselective copper-catalyzed conjugate addition of diethylzinc to cyclic enones with spirocyclic phosphoramidite ligands

A series of spirocyclic phosphoramidite ligands 6-9 with different substituents on the amine moiety were synthesized from the chiral spirocyclic diol (R)-5. These monodentate ligands have been applied in copper-catalyzed conjugate addition of diethylzinc to cyclic enones. Excellent enantioselectivities (up to 99% ee) can be achieved by the use of ligand (R,S,S)-9 bearing stereochemically matched structure derived from the C₂-symmetric (S,S)-bis(α-methylbenzyl)amine.     

Catalytic asymmetric transformations with fine-tunable biphenol-based monodentate ligands

A library of new fine-tunable monodentate phosphite and phosphoramidite ligands based on chiral biphenol have been designed and developed. These monodentate phosphorus ligands have exhibited excellent enantioselectivity in the Pd-catalyzed asymmetric allylic alkylation and Rh-catalyzed asymmetric hydrogenation.     

Sulfoximines as ligands in copper-catalyzed asymmetric vinylogous Mukaiyama-type aldol reactions

[reaction: see text] gamma,delta-Unsaturated alpha-hydroxy diesters with quaternary centers have been obtained with up to 99% ee in high yields using catalysts prepared from copper(II) triflate and C(1)-symmetric aminosulfoximines.     

Rhodium-catalyzed asymmetric hydrogenation of functionalized olefins using monodentate spiro phosphoramidite ligands

Novel chiral monodentate phosphorus ligands, SIPHOS, were conveniently synthesized from 1,1'-spirobiindane-7,7'-diol. The Rh complexes of SIPHOS can catalyze the hydrogenation of alpha-dehydroamino esters in mild conditions, providing alpha-amino acid derivatives in up to 99% ee. Enamides and beta-dehydroamino esters can also be hydrogenated in good to excellent enantioselectivities (up to 99% and 94% ee, respectively). The SIPHOS ligand with smaller alkyl groups on the N-atom afforded higher enantioselectivity. The X-ray analysis of single crystal showed that the structure of Rh/SIPHOS catalyst is [Rh(COD)((S)-SIPHOS-Me)(2)](+), which clarified the configuration of the catalyst with the monodentate chiral phosphorus ligand in Rh-catalyzed asymmetric hydrogenation. A positive nonlinear effect in the relationship of the optical purities of ligand and product was observed in the hydrogenation of dehydroamino acid derivatives. The kinetic study of hydrogenation showed that the reaction is zero order in the concentration of substrate and first order in the concentration of Rh catalyst and the hydrogenation pressure. The rate of hydrogenation decreased when the Rh/L ratio changed from 1:1 to 1:4.     

Rhodium-catalyzed asymmetric conjugate additions of boronic acids using monodentate phosphoramidite ligands

Monodentate phosphoramidites have been used for the first time as chiral ligands in the Rh-catalyzed enantioselective conjugate addition of arylboronic acids to enones, unsaturated esters, lactones, and nitro alkenes. High reaction rates and ee's up to 89% have been obtained.     

Catalytic enantioselective addition of organometallic reagents to N-formylimines using monodentate phosphoramidite ligands

The asymmetric synthesis of protected amines via the copper/phosphoramidite-catalyzed addition of organozinc and organoaluminum reagents to N-acylimines, generated in situ from aromatic and aliphatic alpha-amidosulfones, is reported. High yields of optically active N-formyl-protected amines and enantioselectivities up to 99% were obtained. Under the reaction conditions, partial oxidation of the phosphoramidite ligand to the corresponding phosphoric amide was detected. A preliminary study on the origin and the effect on the catalytic addition reaction is presented.     

Tunable phosphinite, phosphite and phosphoramidite ligands for the asymmetric hydrovinylation reactions

Only a limited number of ligands have been successfully employed for the Ni-catalyzed asymmetric hydrovinylation reaction. Diarylphosphinites, carrying β-acylamino groups prepared from readily available carbohydrates, in conjunction with highly dissociated counteranions {[(3,5-(CF₃)₂C₆H₃]₄B⁻ or SbF₆⁻}, effect the hydrovinylation of vinylarenes under ambient pressure of ethylene with high enantioselectivity. Nitrogen substituents such as -COCF₃ and COPh groups lead to isomerization of the primary products (3-arylbutenes) to Z- and E-2-aryl-2-butenes. In a prototypical synthesis of a 2-arylproionic acid, (S)-3-(4-bromophenyl)-1-butene (89% ee) has be transformed into (R)-ibuprofen by Ni-catalyzed cross-coupling with i-BuMgBr, followed by oxidation of the double bond with NaIO₄ and KMnO₄. Asymmetric codimerization of norbonene and ethylene using binaphthol-derived phosphoramidites as ligands gives 1:1, 2:1 or polymeric adducts depending on the relative configurations and nature of the BINAP and amine moieties. With one of the phosphoramidite-Ni complexes, counteranions BAr₄⁻ [Ar=3,5-(CF₃)₂C₆H₃] and SbF₆⁻, which had been used interchangeably in other reactions, give either a 1:1 adduct or a 2:1 adduct, respectively.     

Axially dissymmetric binaphthyldiimine chiral salen-type ligands for copper-catalyzed asymmetric aziridination

Axially dissymmetric chiral salen-type ligands 1–4 and 7 were prepared from the reaction of (R)-(+)-1,1′-binaphthyl-2,2′-diamine with 2,6-dichlorobenzaldehyde, 2,3-dichlorobenzaldehyde, 3,4-dichlorobenzaldehyde or salicylaldehyde in high yields, respectively. The catalytic asymmetric aziridination of alkenes has been examined using these novel chiral ligands. Excellent enantioselectivity in the aziridination of cinnamates has been achieved using the C₂-symmetric chiral ligand 1.     

Copper catalyzed tandem asymmetric conjugate addition-cyclization reaction in the presence of chiral phosphoramidite ligands

Copper-catalyzed intramolecular conjugate addition-cyclization in the presence of chiral phosphoramidite ligands was described. Cyclic products with multiple chiral centers were obtained with up to 93:7 diastereomeric ratio and 94% ee.     

Copper-catalyzed asymmetric conjugate addition with Grignard reagents and SimplePhos ligands

Herein we report the copper-catalyzed asymmetric conjugate addition of Grignard reagents to cyclic and acyclic enones, with SimplePhos as chiral ligands. A variety of Grignard reagents can be added to a range of cyclic and acyclic enones, with moderate to good enantioselectivities (ee’s up to 86%).     

PipPhos and MorfPhos: privileged monodentate phosphoramidite ligands for rhodium-catalyzed asymmetric hydrogenation

A library of 20 monodentate phosphoramidite ligands has been prepared and applied in rhodium-catalyzed asymmetric hydrogenation. This resulted in the identification of two ligands, PipPhos and MorfPhos, that afford excellent and in several cases unprecedented enantioselectivities in the hydrogenation of N-acyldehydroamino acid esters, dimethyl itaconate, acyclic N-acylenamides, and cyclic N-acylenamides. In addition, a method for the parallel enantioselectivity determination of eight acylated amines is presented.     

Highly modular synthesis of C1-symmetric aminosulfoximines and their use as ligands in copper-catalyzed asymmetric Mukaiyama-aldol reactions

The development of C1-symmetric aminosulfoximines, their highly modular synthesis, and their application in enantioselective copper-catalyzed Mukaiyama-type aldol reactions between pyruvates and enolsilanes is described. In this context, the influence of the ligand architecture as well as the optimization of the reaction conditions are discussed. In detail, the dependence of the catalyst efficiency on the solvent, the metal source and the temperature are reported, and an interesting additive effect is highlighted. Furthermore, the substrate scope will be presented. With the optimized catalyst system, a number of aldol products with quaternary stereogenic centers have been obtained in high yields and with enantiomeric excesses up to 99 %.     

Novel thiolated amino-alcohols as chiral ligands for copper-catalyzed asymmetric nitro-aldol reactions

Thiolated amino-alcohols have been synthesized and evaluated as a potential new class of chiral ligands for copper-catalyzed nitro-aldol reactions. The model nitro-aldol reaction took place smoothly at ambient temperature in the presence of catalytic amounts (5-15 mol %) of the ligands and copper(II) acetate to afford the nitro-aldol product in good to excellent yield without accompanying dehydration. Amino-alcohol ligands bearing N-(2-alkylthio)benzyl substituents provided only modest enantioselectivities (22-46% ee) while those carrying N-2-thienylmethyl substituents provided better enantioselectivities (up to 75% ee). A range of aromatic aldehydes were acceptable for the nitro-aldol reaction with nitromethane, giving moderate to good enantioselectivities (69-88% ee).     

Unprecedented copper-catalyzed asymmetric conjugate addition of organometallic reagents to alpha,beta-unsaturated lactams

For the first time, an excellent enantioselectivity has been obtained in the conjugate addition of hard organometallic reagents to alpha,beta-unsaturated lactams bearing appropriate protecting-activating groups on the nitrogen.