Moderate Ee Research Articles

Chiral Ion‐Pair Organocatalyst‐Promoted Efficient Enantio‐selective Reduction of α‐Hydroxy Ketones

AbstractThe enantioselective reduction of α‐hydroxy ketones with catecholborane has been developed employing 5 mol% of an 1,1′‐bi‐2‐naphthol (BINOL)‐derived ion‐pair organocatalyst. This methodology provides a straightforward access to the corresponding aromatic 1,2‐diols in high yields (up to 90%) with excellent enantioselectivities (up to 97%). Furthermore, the α‐amino ketones also could be reduced with moderate ee values under mild reaction condition.magnified image

The First Asymmetric Pilot-Scale Synthesis of TV-45070

TV-45070 is a small-molecule lactam containing a chiral spiro-ether that has been reported as a potential topical therapy for pain associated with the Nav1.7 sodium ion channel encoded by the gene SCN9A. A pilot-scale synthesis is presented that is highlighted by an asymmetric aldol coupling at ambient temperature, used to create a quaternary chiral center. Although only a moderate ee is obtained, the removal of the undesired isomer is achieved through preferential precipitation of a near racemic mixture from the reaction, leaving the enantiopure isomer in solution. Cyclization to form the final API uses an uncommon diphenylphosphine-based leaving group which proved successful on the neopentyl system when other traditional leaving groups failed.

PPh3-Catalyzed [3 + 2] Spiroannulation of 1C,3N-Bisnucleophiles Derived from Secondary β-Ketoamides with δ-Acetoxy Allenoate: A Route to Functionalized Spiro N-Heterocyclic Derivatives.

A [3 + 2] annulation of α-substituted secondary β-ketoamides with δ-acetoxy-modified allenoate has been developed in the presence of phosphine catalyst. In this spiroannulation reaction, β-ketoamides were used as the bis-nucleophilic partner while the γ,δ-carbon of 5-acetoxypenta-2,3-dienoate participated as a C2 synthon, affording the desired functionalized five-membered N-heterocyclic derivatives in moderate to excellent yields and diastereoselectivities under mild conditions. Preliminary attempts on the asymmetric variant of this reaction have been also examined, giving the corresponding products with moderate ee values.

Optically active, magnetic microspheres: Constructed by helical substituted polyacetylene with pendent prolineamide groups and applied as catalyst for Aldol reaction

This article reports on the preparation of a novel category of optically active magnetic microspheres (OAMMPs) consisting of Fe3O4 nanoparticles and helical substituted polyacetylene bearing pendent prolineamide groups and the use of them for asymmetric direct Aldol reactions. The microspheres (200–300μm in diameter) were prepared by using chiral acetylenic monomer and alkynyl-Fe3O4 nanoparticles via suspension polymerization approach. They were obtained in high yield (>99%) with regular spheric morphology and exhibited noticeable optical activity, according to circular dichroism spectra and specific optical rotation measurements. The microspheres further served as chiral catalyst for performing direct Aldol reactions between acetone and p-nitrobenzaldehyde, providing the product in moderate yield (68%) and ee (75%). The magnetic microspheres can be easily recycled and reused. Mechanism for the asymmetric catalysis of Aldol reaction was further proposed.

Asymmetric synthesis of multi-substituted triptycenes via enantioselective alkynylation of 1,5-dibromoanthracene-9,10-dione

Enantioselective alkynylation of 1,5-dibromoanthracene-9,10-dione by alkynyllithium reagents prepared from alkynes, n-BuLi, and sparteine gave chiral cis-diols possessing two alkyne moieties with moderate ee. Subsequent Ru-catalyzed [2+2+2] cycloaddition of the diol with alkynes afforded chiral 1,5-dibromotriptycenes.

Enzymatic desymmetrization of 3-(4-fluorophenyl)glutaric anhydride through enantioselective alcoholysis in organic solvents

The enzymatic desymmetrization of 3-(4-fluorophenyl)glutaric anhydride (3-FGA) was investigated through lipase-catalyzed enantioselective alcoholysis in organic solvents. An immobilized Lipase B from Candida Antarctica (Novozym 435) was found to be an efficient biocatalyst for the enantioselective alcoholysis of 3-FGA. Methyl tert-butyl ether (MTBE) and methanol were chosen as the suitable reaction medium and acyl acceptor, respectively. The optimum reaction temperature, molar ratio of methanol to 3-FGA and 3-FGA concentration were 25°C, 2:1 and 100 mM, respectively. Under these conditions, complete conversion was achieved and methyl (S)-3-(4-fluorophenyl)glutarate ((S)-MFG) was obtained in a moderate ee value of 80%. Furthermore, the reaction was performed on a gram scale and the ee value of (S)-MFG was enriched to 96% after treatment with a toluene/hexane (2/1, v/v) mixture.

An Unexpected Inversion of Enantioselectivity in a Copper-Catalyzed Intramolecular­ Desymmetric Aryl C–N Coupling Reaction

Enantioselective formation of indolines was achieved through desymmetrization of α,α-bis(2-iodobenzyl)glycines under the catalysis of copper(I) iodide and (2<i>S</i>,3a<i>S</i>,7a<i>S</i>)-octahydro-1<i>H</i>-­indole-2-carboxylic acid. An unexpected inversion of enantioselectivity was observed when achiral additives such as 4-(<i>N</i>,<i>N</i>-dimethylamino)pyridine were added which work together with the ligand. The configuration-reversed products were obtained in moderate yields as well as moderate ee values.

Enantioselective Synthesis of Triarylmethanes by Chiral Imidodiphosphoric Acids Catalyzed Friedel–Crafts Reactions

The first enantioselective synthesis of pyrrolyl-substituted triarylmethanes has been accomplished using a novel imidodiphosphoric acid catalyst, which is derived from two (R)-BINOL frameworks with different 3,3'-substituents. This strategy was also expanded to the synthesis of bis(indolyl)-substituted triarylmethanes with high enantioselectivities, which could only be obtained with moderate ee values in previous reports. These two efficient Friedel-Crafts alkylation processes feature low catalyst loading, broad functional group compatibilities, and the potential to provide practical pathways for the synthesis of enantioenriched bioactive triarylmethanes.

Rh-catalyzed asymmetric hydrogenation using a furanoside monophosphite second-generation ligand library: scope and limitations

The ligand design of one of the most successful monophosphite ligand classes in Rh-catalyzed hydrogenation was expanded upon by introducing several substituents at the C-3 position of the furanoside backbone. A small but structurally important library of monophosphite ligands was developed by changing the substituents at the C-3 position of the furanoside backbone and the substituents/configurations at the biaryl phosphite group. These new furanoside monophosphite ligands were evaluated in the Rh-catalyzed asymmetric hydrogenation of α,β-unsaturated carboxylic acid derivatives and enamides. The results show that the effect of introducing a substituent at the C-3 position of the furanoside backbone on the enantioselectivity depends not only on the configuration at the C-3 position of the furanoside backbone and the binaphthyl group but also on the substrate. Thus, the new ligands afforded high to excellent enantioselectivities in the reduction of carboxylic acid derivatives (ee’s up to >99.9%) and moderate ee’s (up to 67%) in the hydrogenation of enamides.

Enantioselective hydrogenation of methyl benzoylformate on an Ag electrode electrosorbed with cinchonine

Cinchonine was demonstrated to be adsorbed on electrodeposited Ag for enantioselective hydrogenation with moderate ee and excellent selectivity.

CO2 as a C1-organic building block: Enantioselective electrocarboxylation of aromatic ketones with CO2catalyzed by cinchona alkaloids under mild conditions

The enantioselective electrocarboxylation of pro-chiral aromatic ketones (2-acetonaphthone, 1-(6-methoxy-2-naphthyl)ethanone, 1-(4-methoxy-1-naphthyl)ethanone) with atmospheric pressure of CO2 catalyzed by cinchona alkaloids in the presence of phenol was investigated in an undivided cell for the first time to give optically active 2-hydroxy-2-arylpropionic acid. For the model compound 2-acetonaphthone, the influence of various reaction conditions, such as cathode material, current density, catalyst type, ratio of proton to catalyst and catalyst quantity, on the enantiomeric excesses (ee) and yield has been investigated. Under the optimized conditions of 2-acetonaphthone, all the aromatic ketones examined are converted into corresponding optically active 2-hydroxy-2-arylpropionic acids in moderate yield (32.2% - 41.3%) and ee (48.1% - 48.6%). In addition, the electrochemical behavior of 2-acetonaphthone has been studied by cyclic voltammetry (CV) in the absence and presence of CO2. Moreover, the probable reaction pathway was proposed accordingly.

Tropanes as Scaffolds for Phosphorus–Olefin Ligands and Their Application in Asymmetric Catalysis

AbstractTropane‐derived phosphorus–olefin hybrid ligands bearing various combinations of P‐units (chiral BINOL‐derived units/achiral PPh2‐units) with a tropene skeleton (chiral/achiral) have been synthesized and used in Cu‐catalysed conjugate 1,4‐additions of diethylzinc to cyclic enones and in Rh‐catalysed 1,4‐additions of phenylboronic acid (Hayashi–Miyaura reaction) with cyclic and acyclic enones. Whereas in Cu‐catalysed reactions only moderate yields and ee values (up to 49 % ee) were obtained, up to 97 % ee was observed in the Hayashi–Miyaura reaction with various substrates. The most promising results in both reactions were achieved with ligands 11 and 15, which contain a chiral alkene/achiral P‐unit or an achiral alkene/chiral P moiety, respectively, and where the metal is complexed on the exo side of the tropene skeleton. In contrast, ligands with an endo coordination mode showed only low (13) or no activity (12) in all of the 1,4‐additions. NMR and ESI‐MS experiments revealed the presence of two cationic [RhI(15)2]+ species in solution.

Synthesis, structure, and catalytic activity of a new chiral NHC–iridium(III) complex

The new chiral NHC–iridium complex 3 has been prepared in CH 3 CN from the reaction between [Ir(COD)Cl] 2 , NaOAc, KI, and dibenzimidazolium salt 2 which is derived from ( S )-2,2′-diamino-6,6′-dimethyl-1,1′-biphenyl. Complex 3 has been characterized by various spectroscopic techniques, elemental analyses, and X-ray diffraction analysis. It has a distorted-octahedral IrC 2 N 2 IH core structure, and shows good catalytic activity for the asymmetric hydrosilylation of arylmethyl ketones, leading to 1-arylethanol with moderate ee values. A new NHC–iridium complex has been prepared and structurally characterized. It shows good catalytic activity for the asymmetric hydrosilylation of arylmethyl ketones. ► A new chiral NHC–iridium complex has been prepared and structurally characterized. ► It has a distorted-octahedral IrC 2 N 2 IH core structure. ► It is an active catalyst for the asymmetric hydrosilylation of arylmethyl ketones.

Molecular and Merrifield supported chiral diamines for enantioselective addition of ZnR2 (R = Me, Et) to ketones

Chiral 1,2-ethylenediamines have been previously reported as active catalysts in the enantioselective addition reactions of ZnR2 to either methyl- or trifluoromethyl-ketones. Subtle changes in the molecular structure of different catalysts are described herein and lead to a dramatic effect in their catalytic activity. From these findings, we demonstrate the selective reactivity of the ligands used in the addition of ZnR2 (R = Me, Et) to methyl- and trifluoromethyl-ketones offering an enantioselective access either to chiral non-fluorinated alcohols or to chiral fluorinated tertiary alcohols. Considering the importance of the chiral trifluoromethyl carbinol fragment in several biologically active compounds, we have extended the scope of the addition reaction of ZnEt2 to several trifluoromethylketones catalyzed by (R,R)-1,2-diphenylethylenediamine derivatives. This work explores a homogeneous approach that provides excellent yields and very high ee and the use of a heterogenized tail-tied ligand affording moderate ee, high yields and allowing an easier handling and recycling.

Axially chiral N-heterocyclic carbene gold(I) complex catalyzed asymmetric Friedel–Crafts/cyclization reaction of nitrogen-tethered 1,6-enynes with indole derivatives

A class of axially chiral NHC–Au(I) complexes has been applied to the asymmetric Friedel–Crafts/cyclization reaction of nitrogen-tethered 1,6-enynes 14 with indole derivatives 15, affording the corresponding Friedel–Crafts and intramolecular cyclization products 16 in good yields and with moderate ee values under mild conditions.

Synthesis, structure, and catalytic activity of rhodium complexes with new chiral binaphthyl-based NHC-ligands

Three new chiral NHC–rhodium complexes have been prepared from the reactions between [Rh(COD)Cl] 2, NaOAc, KI, and dibenzimidazolium salts 3, 4 or 5, which are derived from ( S)-2,2′-diamino-1,1′-binaphthyl. The steric and electronic effects of the ligand play an important role in the complex formation. For example, treatment of pyridine substituted dibenzimidazolium salts 3 or 4 with 0.5 equiv of [Rh(COD)Cl] 2 in the presence of NaOAc and KI in CH 3CN at 85 °C gives the chiral Rh(III) complexes 6 and 7, respectively. However, under similar reaction conditions, pyridine-N-oxide substituted dibenzimidazolium salt 5 affords a binuclear Rh(I) complex 8. All compounds have been characterized by various spectroscopic techniques, and elemental analyses. The solid-state structures of compounds 4– 8 have been further confirmed by X-ray diffraction analyses. Rhodium complexes 6– 8 show good catalytic activity for the asymmetric hydrosilylation of acetophenone with moderate ee values.

Synthesis of chiral mono(N-heterocyclic carbene) palladium and gold complexes with a 1,1'-biphenyl scaffold and their applications in catalysis.

Axially chiral mono(NHC)–Pd(II) and mono(NHC)–Au(I) complexes with one side shaped 1,1'-biphenyl backbone have been prepared from chiral 6,6'-dimethoxybiphenyl-2,2'-diamine. The complexes were characterized by X-ray crystal structure diffraction. The Pd(II) complex showed good catalytic activities in the Suzuki–Miyaura and Heck–Mizoroki coupling reactions, and the (S)-Au(I) complexes also showed good catalytic activities in the asymmetric intramolecular hydroamination reaction to give the corresponding product in moderate ee.

ChemInform Abstract: Chiral Sodium Phosphate Catalyzed Enantioselective 1,4‐Addition of TMSCN to Aromatic Enones.

AbstractThe process offers generally moderate ee′s only.

4 + 3] Cycloaddition of Aromatic α,β-Unsaturated Aldehydes and Ketones with Epoxides: One-Step Approach to Synthesize Seven-Membered Oxacycles Catalyzed by Lewis Acid

A novel intermolecular [4 + 3] cycloaddition method to construct 1,4-dioxide seven-membered oxacycles was developed. This one-step method was carried out in the presence of catalytic amount of (C(2)H(5))(2)OBF(3) under mild conditions. Seven-membered oxacycles and some natural compounds could be easily synthesized via this protocol. Control experiments were carried out and possible mechanism for the reaction was proposed. Asymmetric reactions were proceeded and 3e was obtained with moderate ee value.

ChemInform Abstract: PPL-Catalyzed Resolution of 1,2- and 1,3-Diols in Methyl Propionate as Solvent. An Application of the Tandem Use of Enzymes.

Abstract The Porcine Pancreatic Lipase (PPL)-catalyzed transesterification of 1-phenyl-1,2-ethanediol 1, 2-phenyl-1,2-propanediol 2 1,2-decanediol 3 1,2-pentanediol 4 1,2-butanediol 5 1,2-propanediol 6 and 1,3-butanediol 7 in methyl propionate as solvent was evaluated. In alt substrates the primary hydroxy group is esterified exclusively. The enantioselectivity displayed in this PPL-catalyzed reaction is moderate. The enantiomeric excess of diol (-)-1 is enhanced by subjecting propionate (-)-8 with a moderate ee (obtained by a PPL-catalyzed esterification of racemic 1 in methylpropionate) to an enzyme-catalyzed hydrolysis (tandem principle).