(R)-TTCA·K催化下环己酮与丙烯腈的加成反应

手性催化剂催化下的不对称合成反应是近年来不对称合成研究中受到重视的领域，如在手性催化剂如，在手性冠醚，手性镧配合物、手性硒、手性铑及手性脯氨酸铷盐等催化下，醛、酮与二烃基锌形成手性醇和不对称羟醛缩合反应等，催化下通过Michael加成反应合成手性化合物的方法近年来也有报道，     

手性β-氨基醇的合成及其催化二乙基锌与醛的不对称加成反应

以烯烃为原料通过Sharpless不对称双羟化等多步反应合成7种手性β-氨基醇, 并将该类化合物用于催化二乙基锌和醛的不对称加成反应. 分别考察了影响对映选择性的催化剂结构、催化剂用量、溶剂、反应温度等各种因素. 当催化剂用量为5%、甲苯溶剂、在－10 ℃下、以(1S,2R)-(＋)-2-氨基-1,2-二苯基乙醇(1b)作催化剂时, 所得仲醇的对映体过量最高为85% ee, 产率高达100%.     

Synthesis of Chiral Bis-Thiazolines and Asymmetric Diels–Alder Reactions

Abstract

New chiral ligands, bis-thiazoline derivatives (sulfur analogues of known oxazolines) were prepared from chiral bis-(N-acylamino alcohols) with Lawesson's reagent. Bis-thiazolines thus obtained proved to be useful chiral ligands for metal in asymmetric Diels–Alder reaction.     

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.     

Asymmetric zinc-Reformatsky reaction of Evans chiral imide with acetophenones and its application to the stereoselective synthesis of triazole antifungal agents

The Ni(acac)₂ catalytic ZnEt₂-mediated asymmetric Reformatsky-type reaction of Evans chiral imide with various acetophenones was studied. The chiral imido zinc enolate, which was formed through the metal–halogen exchange reaction of chiral α-bromopropionyl-2-oxazolidinones 2 with diethyl zinc under the catalysis of Ni(acac)₂, performed the asymmetric zinc-Reformatsky reaction with activated α-haloacetophenones 3 to give the chiral β-hydroxyamide 4 in good yields and high ratios of syn-(2R,3R)-isomers (up to >97%). This new asymmetric synthesis technology affords a practical method to synthesize the versatile chiral building block 5 for triazole antifungal agents, such as Voriconazole, Ravuconazole, TAK-187, and RO-0094815.     

Asymmetric Hydrosilylation of Aromatic Ketones Catalyzed by an Economical and Effective Copper-Diphosphine Catalytic System in Air

In the presence of the inexpensive and non‐toxic polymethylhydrosiloxane, the combination of copper(II) acetate and a chiral diphosphine displayed high catalytic efficiency in the asymmetric hydrosilylation of a series of aromatic ketones in air atmosphere and at room temperature. (R)‐1‐Arylethanols were obtained with up to 99% yield and 93% enantiomeric excess. Meanwhile, the electron effect and steric hindrance of substituents on the aromatic ring had an interesting influence on both the yields and enantioselectivities. Furthermore, a possible mechanism was presented to explain the influence of some key factors on the reaction.     

Study of the efficiency of new phenoxo-ether titanium (IV) complexes as catalysts in asymmetric epoxidation processes. Comparison of HPLC and CE chiral methodologies

The efficiency as catalysts in asymmetric epoxidation of cinnamyl alcohol, of a new family of phenoxo-ether titanium complexes synthesized by our research team has been studied. The influence of the metal environment and the presence of chiral moieties in the molecule on the efficiency of the studied catalysts has been investigated. The study of the catalytic activity of these compounds in the asymmetric epoxidation process has been carried out at − 20 °C with a catalyst/substrate/tert-butylhydroperoxide ratio of 1/2/4 and 1/20/40 using dichloromethane as solvent. For routine determination of the enantiomeric excess obtained in these processes, chiral HPLC and CE methodologies previously developed by our research team were applied. Results obtained for both methods were statistically compared in order to show that there were no significant differences between them.     

Podand Solvents for Organic Reactions

Three tris(oxaalkyl)phenylsilanes and two tris(oxaalkyl)phosphates were used as podand solvents in kinetic studies of proton transfer reactions between C-acids: dimethyl (4-nitrophenyl)malonate or phenyl-4-nitrophenylcyanomethane and the strong base: 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD). The acceptor numbers were measured for all new podand solvents. The kinetic parameters for studied reactions were obtained, discussed and compared with those of acetonitrile and OP(OEt) 3 as non-podand solvents. This study demonstrated that the second order rate constants strongly decreased and the energy barrier increased for the proton transfer reaction in podand solvents. Spectroscopic observations showed that ionic products were strongly stabilised and therefore their lifetime was relatively long. The podand solvents formed the ionic channels in which ionic products are strongly solvated.     

Guanidine chemistry

Guanidines are categorized as strong organobases; however, their catalytic utility in organic synthesis has not been discussed thoroughly. The author's group has extensively and systematically studied their potential ability focusing on: 1) modified guanidines as chiral auxiliaries; 2) guanidinium ylides for aziridine formation; 3) the affinity of bisguanidine for proton and metal salts; and 4) the potential chirality of bisguanidine. Under the first topic, a variety of chiral guanidines was designed by the introduction of chirality on the three guanidinyl nitrogens, and the modified guanidines prepared using our original methods were found to be effective not only in catalytic but also in stoichiometric asymmetric syntheses. Under the second topic, the reaction of guanidinium salts carrying a glycinate function with aromatic or unsaturated aldehydes under basic conditions unexpectedly afforded aziridine-2-carboxylates, which were available as useful building blocks in organic synthesis due to their convertibility to functionalized amino acid derivatives in the ring-opening reaction, together with urea compounds recyclable to the starting guanidinium salts. The introduction of a chiral template to the guanidinium salt allowed us to expand the cyclic aziridination reaction to an asymmetric version. Under the third topic, effective complexabilty of bisguanidines with either proton or metal ions in water was observed, suggesting their possible application to the removal of toxic substances from polluted water and recovery of rare elements as material sources. Under the final topic, monomethylation or monoethylation of bisguanidine afforded a chiral product via asymmetric crystallization, indicating that bisguanidines have a potential chiral character due to the plane asymmetry.     

Synthesis of Novel Chiral Ionic Liquid and Its Application in Reduction of Prochiral Ketones to the Corresponding Chiral Alcohols Using NaBH4

A novel chiral ionic liquid (CIL) based on nicotinium salt has been synthesized and used as an efficient asymmetric chiral catalyst for reduction of acetophenone derivatives with NaBH₄ in methanol at room temperature. The optically active alcohols were obtained in low to moderate enantiomeric excess in a short reaction time.     

Systematic Study of the Asymmetric Methoxycarbonylation of Styrene Catalyzed by Palladium Systems Containing Chiral Ferrocenyl Diphosphine Ligands

We present the first systematic study of the Pd‐catalyzed asymmetric methoxycarbonylation of styrene in the presence of chiral ferrocenyl phosphine ligands. The reaction conditions were optimized, and a screening of different catalyst precursors was performed. A number of 1,1′‐bis(phosphino)ferrocenes of the Mandyphos, Josiphos, Walphos, and Taniaphos types were tested in combination with [PdCl₂(NCPh)₂], in the presence of TsOH as the acid source. These systems afforded high enantioselectivities, although the regioselectivity of the reaction was found to be in favor of the (undesired) linear ester. The catalytic system made with the Josiphos ligand 1 gave rise to an enantiomeric excess (ee) of 86%.     

Enantioface differentiation by chiral polymers having (+)-5,6-exo-bornanediol moieties. II. Asymmetric reduction of prochiral ketones by chiral polymers containing (+)-5,6-exo-bornanediol derivatives

The asymmetric reduction of prochiral aromatic ketones with modified reagents prepared from sodium borohydride and carboxylic acids in the presence of both chiral polymers and relating low molecular weight compounds having (+)-5,6-exo-dihydroxybornyl derivatives was carried out. The enantioface differentiation took place effectively by raising the reaction temperature, and the highest enantiomeric excess was achieved at 10°C (24.3%) in the presence of the chiral polymers. A higher optical yield (87.8%) can be obtained in the asymmetric reduction by using the low molecular weight (+)-5,6-exo-diol compounds. The effect of the reaction temperature, solvents, and the advantages of the chiral polymer-bound reagents were also discussed.     

Asymmetric Henry reaction catalyzed by a chiral Cu(II) complex: a facile enantioselective synthesis of (S)-2-nitro-1-arylethanols

A catalytic asymmetric Henry reaction has been developed using a novel chiral Cu(II) complex derived from (R)-2-(diphenylmethanol)-l-(2-pyridylmethyl)pyrrolidine and copper(II) acetate in ethanol under mild conditions. The corresponding chiral 2-nitro-1-arylethanol derivatives were obtained in high yields with moderate to good enantiomeric excess (up to 86% ee). The results indicate that the coordination of a metal atom to the nitrogen of the pyridine ring is essential in determining the stereochemistry of the process.     

Recent progress in a chiral multinucleating system utilizing tartaric acid esters

In order to develop a practical method for the construction of chiral molecules, we have designed a novel chiral reaction system possessing multi‐metal centers utilizing tartaric acid ester as a chiral auxiliary. Based on this concept, we have developed an asymmetric 1,3‐dipolar cycloaddition reaction of azomethine imines, an asymmetric hetero Diels‐Alder reaction of nitroso compounds, an asymmetric Diels‐Alder reaction of o‐quinodimethanes. Furthermore, an asymmetric nucleophilic addition of alkynylzinc reagents, prepared in situ from dialkylzinc and 1‐alkynes, to nitrones was achieved with high level of stereocontrol. In the last case, the addition of methylzinc salt of a product‐like racemic hydroxylamine was found to be effective for unprecedented enhancement of enantioselectivity. © 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 10: 173–187; 2010: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.201000002     

A Facile Circular Dichroism Protocol for Rapid Determination of Enantiomeric Excess and Concentration of Chiral Primary Amines

A protocol for the rapid determination of the absolute configuration and enantiomeric excess (ee) of α‐chiral primary amines with potential applications in asymmetric reaction discovery has been developed. The protocol requires derivatization of α‐chiral primary amines through condensation with pyridine carboxaldehyde to quantitatively yield the corresponding imine. The Cu^I complex with 2,2′‐bis (diphenylphosphino)‐1,1′‐dinaphthyl (BINAP? Cu^I) with the imine yields a metal‐to‐ligand charge‐transfer (MLCT) band in the visible region of the circular dichroism (CD) spectrum upon binding. Diastereomeric host–guest complexes give CD signals of the same signs but different amplitudes, allowing for differentiation of enantiomers. Processing the primary optical data from the CD spectrum with linear discriminant analysis (LDA) allows for the determination of the absolute configuration and identification of the amines, and processing with a supervised multilayer perceptron artificial neural network (MLP‐ANN) allows for the simultaneous determination of the ee and concentration. The primary optical data necessary to determine the ee of unknown samples is obtained in two minutes per sample. To demonstrate the utility of the protocol in asymmetric reaction discovery, the ee values and concentrations for an asymmetric metal‐catalyzed reaction are determined. The potential of the application of this protocol in high‐throughput screening (HTS) of ee is discussed.     

Palladium-catalyzed asymmetric umpolung allylation of imines with allylic alcohols

A palladium-catalyzed asymmetric umpolung allylation reaction of imines with allylic alcohols has been developed. In the presence of chiral spiro phosphoramidite ligand 4, the allylation was accomplished with high yields and good enantioselectivities. The use of highly stable and easily available allylic alcohols instead of allylic metal reagents facilitated the preparation of chiral homoallylic amines.     

Synthesis of 4,4′-biquinazoline alcohols as chiral catalysts in enantioselective alkynylation of aldehydes with phenyl acetylene

Optically active propargylic alcohols are important chiral-building blocks in asymmetric synthesis, while the asymmetric addition of a terminal alkyne to an aldehyde is one of the most important procedures to prepare these chiral-building blocks. In this work, a family of chiral 4,4′-biquinazoline alcohols has been conveniently prepared from the easily accessible (S)-2-acetoxycarboxylic acid chlorides by reaction sequences beginning with condensation and followed by key synthetic steps including chlorination, nickel(0)-mediated homocoupling, and deprotection in addition to being examined as potential ligands in the enantioselective addition of phenylacetylene to aldehydes. These chiral ligands can be combined with Ti(OiPr)₄ and then used to catalyze the asymmetric addition of zinc acetylide, produced in situ by the reaction of phenylacetylene with diethylzinc, to aldehydes. The best enantiomeric excess obtained in this study was 75%.     

Development of Asymmetric Reactions Catalyzed by Chiral Organotin‐Alkoxide Reagents

Asymmetric catalysis under almost‐neutral reaction conditions is key for the efficient synthesis of optically active polar molecules. We have developed catalytic enantioselective reactions of acyclic or cyclic alkenyl esters by using an (S)‐BINOL‐derived chiral tin‐dibromide reagent that possesses a bulky aryl group at the 3 or 3′ position as the chiral pre‐catalyst in the presence of a sodium alkoxide and an alcohol, in which a chiral tin alkoxide bromide is generated in situ and recycled with the assistance of an alcohol. In this Personal Account, we describe three types of asymmetric transformation that proceed through a chiral tin enolate: 1) The asymmetric aldol reaction of alkenyl esters or unsaturated lactones with aldehydes or isatins; 2) the asymmetric three‐component Mannich‐type reaction of alkenyl esters and related cycloaddition reactions; and 3) the asymmetric N‐nitroso aldol reaction of unsaturated lactones with nitrosoarenes.     

Merger of Visible Light Induced Oxidation and Enantioselective Alkylation with a Chiral Iridium Catalyst

A single chiral octahedral iridium(III) complex is used for visible light activated asymmetric photoredox catalysis. In the presence of a conventional household lamp and under an atmosphere of air, the oxidative coupling of 2‐acyl‐1‐phenylimidazoles with N,N‐diaryl‐N‐(trimethylsilyl)methylamines provides aminoalkylated products in 61–93 % yields with high enantiomeric excess (90–98 % ee). Notably, the iridium center simultaneously serves three distinct functions: as the exclusive source of chirality, as the catalytically active Lewis acid, and as a central part of the photoredox sensitizer. This conceptionally simple reaction Scheme may provide new avenues for the green synthesis of non‐racemic chiral molecules.     

Synthesis of chiral water-soluble metalloporphyrins (Fe, Ru,): new catalysts for asymmetric carbene transfer in water

The reaction of optically active Halterman porphyrin with sulfuric acid (95%) provided the expected water-soluble para-tetrasulfonated porphyrin in 82% yield. The metalloporphyrin complexes were prepared by metal insertion (iron) or direct sulfonation of the chiral ruthenium porphyrin. The asymmetric addition of diazoacetate to styrene to give optically active trans cyclopropyl ester (ee up to 86%) was carried out in water by using chiral iron or ruthenium porphyrins with a possible reuse due to the high solubility and stability in aqueous solution.