Synthesis of non-symmetric bis(oxazoline)-containing ligands and their application in the catalytic enantioselective Nozaki-Hiyama-Kishi allylation of benzaldehyde

We report the good to high-yielding three-step synthesis of non-symmetrical bis(oxazoline)-containing ligands possessing an N-thienylaniline unit. The convergent synthesis employed a palladium-catalysed aryl amination of 2-(2'-bromothiophene)nitrile as the key step, with sixteen ligands prepared in total. These ligands were subsequently applied in the chromium-catalysed enantioselective Nozaki-Hiyama-Kishi allylation of benzaldehyde with an optimal enantioselectivity of 73%.     

Synthesis of highly modular bis(oxazoline) ligands by Suzuki cross-coupling and evaluation as catalytic ligands

New bis(oxazoline) ligands (BOXs) containing biaryl substitutents at the C-4 position and H or CH₂OR substituents at the C-5 position have been synthesized using Suzuki cross-coupling as the main tool for structural diversity. Copper, zinc, and palladium complexes of the prepared BOXs have been evaluated in the following catalytic asymmetric processes: Acylation with kinetic resolution of trans-1,2-cyclohexanediol (Cu), enantioselective Friedel-Crafts alkylation of indole (Zn), and enantioselective alkylation of 3-acetoxy-1,3-diphenylpropene (Pd).     

Mesopore immobilised copper bis(oxazoline) complexes for enantioselective catalysis

New supported heterogeneous catalysts have been synthesised through the tethering of copper bis(oxazoline) complexes to the surfaces of MCM-41 and MCM-48 mesoporous materials, and the prepared catalysts shown to be highly active in the enantioselective cyclopropanation of styrene with ethyl diazoacetate.     

Modular synthesis of chiral pentadentate bis(oxazoline) ligands

Highly modular N,Y,Z,Y,N-ligands (Y=N, O, S; Z=N, NO, OH, OMe) have been prepared using bis(oxazoline) building blocks either as nucleophiles or as electrophiles in coupling reactions with central aromatic units. This way, a great variety of pentadentate bis(oxazoline) ligands in diastereo- and enantiomerically pure form become readily available, which are useful for the construction of helical metal complexes with predetermined chirality.     

The synthesis of phosphine oxide-linked bis(oxazoline) ligands and their application in asymmetric allylic alkylation

The phosphine oxide-linked bis(oxazoline) ligands were designed and synthesized in two ways. One is the coupling of Grignard reagent derived from 2-(2-bromophenyl)oxazoline with phenylphosphonic dichloride, another route is the condensation of bis(2-formylphenyl)(phenyl)phosphine oxide with chiral amino alcohols followed by NBS oxidation. These new bis(oxazoline) ligands were applied in Pd-catalyzed asymmetric allylic alkylation reactions and good yields and enantioselectivities were obtained with diphenyl substituted ligand (up to 95% ee).     

Quantitative chirality analysis of molecular subunits of bis(oxazoline)copper(II) complexes in relation to their enantioselective catalytic activity

The analysis of the quantitative chirality of molecular subunits of spirocyclic bisoxazoline copper complexes was carried out in order to identify the molecular portions most responsible for the chirality of the whole molecule, and therefore also for its catalytic enantioselectivity. It is shown that the smallest fragment that carries the information on molecular chirality contains only a portion of the bidentate bisoxazoline ligands and most atoms of the two monodentate ligands. The structural parameters that are best correlated to the chirality measures of the studied systems are the bond angles at the bridgehead spiro-carbon atom. A prediction is made for an analogous catalyst with potentially high enatioselectivity.     

Dendritic oxazoline ligands in enantioselective palladium-catalyzed allylic alkylations

First to fourth generation dendritic substituents based on 2,2-bis(hydroxymethyl)propionic acid and (1R,2S,5R)-menthoxyacetic acid were attached to 2-(hydroxymethyl)pyridinooxazoline and bis[4-(hydroxymethyl)oxazoline] compounds. The new ligands obtained were assessed in palladium-catalyzed allylic alkylations. The first type of ligands exhibited enantioselectivity similar to that of a benzoyl ester derivative, whereas the latter type of ligands afforded products with higher selectivity than the analogous benzoyl ester. The activity of the dendritic catalysts decreased with increasing generation.     

The first synthesis of organic-inorganic hybrid materials with chiral bis(oxazoline) ligands

Condensation of tetraethoxysilane with silane-functionalized bis(oxazolines) in the presence of dodecylamine leads to hybrid materials whose textural and catalytic properties depend on both the ligand and the spacer structure.     

Oxaziridine-mediated enantioselective aminohydroxylation of styrenes catalyzed by copper(II) bis(oxazoline) complexes

We report an oxaziridine-mediated enantioselective aminohydroxylation of olefins catalyzed by a chiral copper(II) bis(oxazoline) complex. A variety of styrenic olefins undergo efficient aminohydroxylation with excellent regioselectivity and synthetically useful levels of enantioselectivity (up to 84% ee). The reaction can be conducted on multi-gram scale with as little as 2 mol % of the copper(II) catalyst. Hydrolysis of the resulting 1,3-oxazolines under acidic conditions produces N-sulfonyl amino alcohols that can be purified by recrystallization to afford very high levels of enantioselectivity.     

New chiral bis(diphenylphospholane) ligands: design, synthesis, and application to catalytic enantioselective aldol reaction to ketones

New chiral bidentate diphenylphospholanes were designed targeting a catalytic enantioselective aldol reaction to ketones. Ligands 5l and 5m having cis-2-butenyl and cyclopropyl groups at the linker part, respectively, were identified as effective chiral ligands for a CuF-catalyzed enantioselective aldol reaction to ketones. Catalysts prepared from CuF·3PPh₃·2EtOH and these ligands produced ketone aldol products with up to 66% ee, which is promising particularly for this extremely difficult and important catalytic enantioselective carbon-carbon bond forming reaction. The enantioselectivity was strongly dependent on the linker structure. Construction of a deep chiral pocket around the copper metal with stable bidentate chelation is the key to meaningful enantioinduction.     

Direct catalytic enantioselective alpha-aminomethylation of aldehydes

The direct catalytic asymmetric alpha-aminomethylation of aldehydes is presented. The chiral amine and amino acid catalyzed reactions between unmodified aldehydes and a formaldehyde-derived imine precursor were fast and proceeded with high chemo- and enantioselectivities. The corresponding dibenzyl-protected gamma-amino alcohols were isolated in high yields with up to 98% ee after in situ reduction. The reaction is a novel entry to valuable beta(2)-amino acid derivatives.     

Catalytic and highly enantioselective reactions of alpha-sulfonyl carbanions with chiral bis(oxazoline)s

The enantioselective reactions of lithiated benzyl trifluoromethyl sulfones with a substoichiometric amount of a bis(oxazoline) and various aldehydes is disclosed. The products were formed with excellent diastereo- and enantioselectivities. Fluorination of the sulfone with N-fluorobenzenesulfonimide and a stoichiometric amount of a bis(oxazoline) gave products with extremely high enantioselectivities (up to 99% ee; ee=enantiomeric excess). The enantioselective reaction was confirmed to proceed through a dynamic thermodynamic resolution pathway.     

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.     

3-Aminoquinazolinones as chiral ligands in catalytic enantioselective diethylzinc and phenylacetylene addition to aldehydes

A series of readily known enantiomerically pure 3-aminoquinazolinones 1a–d were synthesised from easily accessible chiral pool α-hydroxy acids and α-amino acids in only four steps without any requirement of chromatography. These quinazolinones were examined as chiral ligands for catalytic enantioselective diethylzinc and phenylacetylene additions to aldehydes. For enantioselective alkylations, the effects of temperature, solvent, diethylzinc and ligand criteria were analysed, and the desired chiral alcohols were obtained in up to 86% ee. 3-Aminoquinazolinones 1a–d were also shown to be very useful ligands in enantioselective alkynylations of aldehydes. Based upon the optimised conditions, the corresponding propargylic alcohols were obtained in up to 94% ee.     

Synthesis of novel chiral oxazoline ligands and application in the highly enantioselective diethylzinc addition to N-diphenylphosphinoylimines

Two sets of novel chiral oxazoline ligands were designed and conveniently prepared from readily available l-aspartic acid and evaluated in enantioselective diethylzinc addition to N-diphenylphosphinoyl imines. In the presence of stoichiometric amounts of these ligands, high enantioselectivities (up to 95% ee) and yields (up to 85%) were achieved for several aromatic imines in toluene at room temperature. Furthermore, the effect of the structure of the ligand on the reaction was studied.     

Highly enantioselective michael additions of indole to benzylidene malonate using simple bis(oxazoline) ligands: importance of metal/ligand ratio

[Structure: see text] Simple bis(oxazoline) ligands, especially azabis(oxazolines), can catalyze the copper-catalyzed addition of indoles to benzylidene malonates in up to >99% ee, provided that excess of chiral ligand is avoided. The paradigm followed in many asymmetric catalyses that an excess of chiral ligand with respect to the metal should improve enantioselectivity because a background reaction by free metal is suppressed, is not applicable here, which might call for revisiting some of the many copper(II)-bis(oxazoline)-catalyzed processes known.     

Ni(II) bis(oxazoline)-catalyzed enantioselective syn aldol reactions of N-propionylthiazolidinethiones in the presence of silyl triflates

An enantioselective aldol reaction of N-propionylthiazolidinethione and representative aldehydes is disclosed. The reaction is catalyzed by [Ni(S,S)-t-BuBox](Otf)2. Enolization is effected by 2,6-lutidine, and TMSOTf facilitates catalyst turnover. Syn diastereoselectivities range from 88:12 to 97:3, and enantioselectivities are 90% or greater. Both aromatic and enolizable aliphatic aldehydes are included within the scope of this aldol addition process.