Asymmetric Ring Opening of meso‐Epoxides with Aromatic Amines Catalyzed by a New Proline‐Based N,N′‐Dioxide‐Indium Tris(triflate) Complex

The catalytic asymmetric ring opening of meso‐epoxides with aromatic amines was achieved using a new proline‐based N,N′‐dioxide‐indium tris(triflate) complex in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee) under mild conditions. The coordination ability of N,N′‐dioxide 1c was investigated by X‐ray and NMR analysis. A plausible seven‐coordinate transition state model was proposed. The chiral N,N′‐dioxides surveyed were synthesized from proline through only three conventional steps. The procedure could be run on a gram‐scale without any loss of enantioselectivity. This protocol provides a highly practical and useful tool for the bulky preparation of optically pure β‐amino alcohols.     

Cyclometalated N‐Heterocyclic Carbene‐Platinum Catalysts for the Enantioselective Cycloisomerization of Nitrogen‐Tethered 1,6‐Enynes

Platinum(II) complexes which combine six‐membered N‐heterocyclic carbene‐containing metallacyclic units and monodentate chiral phosphines have been prepared. The key step of their synthesis is the intramolecular oxidative addition of N‐2‐iodobenzylimidazolylidene‐platinum(0)‐diene complexes in the presence of the chiral phosphorus ligands. The platinum(II) metallacycles have been used as well‐defined pre‐catalysts for the enantioselective cycloisomerization of nitrogen‐tethered 1,6‐enynes into 3‐azabicyclo[4.1.0]hept‐4‐enes. High enantiomeric excesses have been obtained with either Monophos or phenyl‐Binepine based catalysts (ees=82–96%), although phenyl‐Binepine outperforms Monophos in these reactions. The absolute configuration of the final 3‐azabicyclo[4.1.0.]heptenes has been established by X‐ray diffraction studies. The method has been extended then to the cycloisomerization of dienynes with enantiotopic vinyl groups. An (S)‐phenyl‐Binepine‐platinum(II) complex allows total diastereoselectivity and high enantioselectivity levels to be attained in these reactions (ees up to 95%) which represent the first enantioselective desymetrizations achieved via enyne cycloisomerizations.     

Highly Enantioselective Hydrogenation of Quinoline and Pyridine Derivatives with Iridium‐(P‐Phos) Catalyst

The use of a chiral iridium catalyst generated in situ from the (cyclooctadiene)iridium chloride dimer, [Ir(COD)Cl]₂, the P‐Phos ligand [4,4′‐bis(diphenylphosphino)‐2,2′,6,6′‐tetramethoxy‐3,3′‐bipyridine] and iodine (I₂) for the asymmetric hydrogenation of 2,6‐substituted quinolines and trisubstituted pyridines [2‐substituted 7,8‐dihydroquinolin‐5(6H)‐one derivatives] is reported. The catalyst worked efficiently to hydrogenate a series of quinoline derivatives to provide chiral 1,2,3,4‐tetrahydroquinolines in high yields and up to 96% ee. The hydrogenation was carried out at high S/C (substrate to catalyst) ratios of 2000–50000, reaching up to 4000 h⁻¹ TOF (turnover frequency) and up to 43000 TON (turnover number). The catalytic activity is found to be additive‐controlled. At low catalyst loadings, decreasing the amount of additive I₂ was necessary to maintain the good conversion. The same catalyst system could also enantioselectively hydrogenate trisubstituted pyridines, affording the chiral hexahydroquinolinone derivatives in nearly quantitative yields and up to 99% ee. Interestingly, increasing the amount of I₂ favored high reactivity and enantioselectivity in this case. The high efficacy and enantioselectivity enable the present catalyst system of high practical potential.     

Direct Enantioselective Three‐Component Kabachnik–Fields Reaction Catalyzed by Chiral Bis(imidazoline)‐Zinc(II) Catalysts

A direct three‐component reaction of aldehydes, amines and diaryl phosphites was catalyzed by a zinc(II) complex of 1,3‐bis(imidazolin‐2‐ly)pyridine (pybim) giving the corresponding α‐aminophosphonates in good yield with good enantioselectivity. The reaction was applied to a wide variety of aromatic aldehydes to give products with excellent yields (up to 99%) and enantiomeric excesses (up to 93% ee).     

Iron‐Catalyzed Highly Enantioselective Reduction of Aromatic Ketones with Chiral P2N4‐Type Macrocycles

Novel P₂N₄‐donors containing chiral 22‐membered macrocyclic ligands have been synthesized and the structures have been determined by an X‐ray diffraction study. The catalytic systems in situ generated from triiron dodecarbonyl, Fe₃(CO)₁₂, and the chiral macrocyclic ligand exhibited high activity (TOF up to 1940 h⁻¹) and excellent enantioselectivity with up to 99% ee in the asymmetric transfer hydrogenation of various aromatic ketones.     

Storable and Air‐Stable Zirconium Complex‐Catalyzed Highly Enantioselective Darzens Reaction of Diazoacetamide with Aldehydes

An asymmetric Darzens reaction of aldehydes with diazo‐N,N‐dimethylacetamide ( 3 ) catalyzd by an air‐stable and storable chiral zirconium Lewis acid catalyst, which is formed from 3,3′‐diiodobinaphthol and tetrabutoxyzirconium, gives solely the cis‐glycidic amides in high yields with excellent enantioselectivity (up to 97% yield, >99% ee).     

Enantioselective Synthesis of Chiral Tetrahydroisoquinolines by Iridium‐Catalyzed Asymmetric Hydrogenation of Enamines

Chiral iridium complexes based on spiro phosphoramidite ligands are demonstrated to be highly efficient catalysts for the asymmetric hydrogenation of unfunctionalized enamines with an exocyclic double bond. In combination with excess iodine or potassium iodide and under hydrogen pressure, the complex Ir/(S_a,R,R)‐ 3a provides chiral N‐alkyltetrahydroisoquinolines in high yields with up to 98% ee. The L/Ir ratio of 2:1 is crucial for obtaining a high reaction rate and enantioselectivity. A deuterium labeling experiment showed that an inverse isotope effect exists in this reaction. A possible catalytic cycle including an iridium(III) species bearing two monophosphoramidite ligands is also proposed.     

A Protection Strategy Substantially Enhances Rate and Enantioselectivity in ω‐Transaminase‐Catalyzed Kinetic Resolutions

The kinetic resolution of 3‐aminopyrrolidine (3AP) and 3‐aminopiperidine (3APi) with ω‐transaminases was facilitated by the application of a protecting group concept. 1‐N‐Cbz‐protected 3‐aminopyrrolidine could be resolved with >99% ee at 50% conversion, the resolution of 1‐N‐Boc‐3‐aminopiperidine yielded 96% ee at 55% conversion. The reaction rate was up to 50‐fold higher by using protected substrates. Most importantly, enantioselectivity increased remarkably after carbamate protection compared to the unprotected substrates (86 vs. 99% ee). Surprisingly, benzyl protection of 3AP had no influence on enantioselectivity. A possible explanation for this observation could be the different flexibility of the benzyl‐ or carbamate‐protected 3AP as confirmed by NMR spectroscopy.     

Efficient Catalytic Asymmetric Synthesis of trans‐5‐Aryl‐2‐substituted Cyclohexanones by Rhodium‐Catalyzed Conjugate Arylation of Racemic 6‐Substituted Cyclohexenones

Catalytic asymmetric conjugate arylation of racemic 6‐substituted cyclohexenones with arylboronic acids was catalyzed by 3 mol % of chiral amidophosphane‐[RhCl(C₂H₄)]₂ in a 10:1 mixture of 1,4‐dioxane and water at 70 °C to afford a nearly 1:1 mixture of trans‐ and cis‐5‐aryl‐2‐substituted cyclohexanones in high enantioselectivity, which was subsequently epimerized with sodium ethoxide in ethanol to give thermodynamically stable trans‐5‐aryl‐2‐substituted cyclohexanones with 99–97 % ee in high two‐step yields.     

Chiral Bioinspired Non‐Heme Iron Complexes for Enantioselective Epoxidation of α,β‐Unsaturated Ketones

Chiral bioinspired iron complexes of N₄ ligands based on the ethylenediamine backbone display remarkable levels of enantioselectivity for the first time in the asymmetric epoxidation of α,β‐unsaturated ketones using hydrogen peroxide (up to 87% ee) or peracetic acid as oxidant, respectively. Notablely, isotopic labeling with H₂¹⁸O strongly demonstrated that there is a reversible water binding step prior to generation of the significant intermediate. Besides, the complex [L₂Fe(III)₂(μ‐O)(μ‐CH₃CO₂)]³⁺ usually derived from the decay of the LFe(IV)O species or thermodynamic sinks for a number of iron complexes was identified by HR‐MS. In addition, the possible mechanisms were proposed and LFe(V)O species may be the main active intermediate in the catalytic system.     

Reusable Chiral Dicationic Chromium(III) Salen Catalysts for Aminolytic Kinetic Resolution of trans‐Epoxides

A series of new recyclable chiral dicationic chromium(III) salen complexes 1 – 10 bearing different substituents, viz., hydrogen, methyl, tert‐butyl, triphenylphosphinomethyl, triethylaminomethyl, methylimidazolium, methylpyridinium, methyl‐N,N‐dimethylpyridinium at the 3,3′‐ and 5,5′‐ positions of the salen unit with (1S,2S)‐(+)‐1,2‐diaminocyclohexane, (1S,2S)‐(−)‐1,2‐diphenyl‐1,2‐diaminoethane, and (S)‐(−)‐1,1′‐binaphthyl‐2,2′‐diamine collars have been synthesized and characterized by various physico‐chemical methods. These complexes were used as catalysts for the highly enantioselective aminolytic kinetic resolution of racemic trans‐epoxides with different anilines as nucleophiles at room temperature. With the use of catalyst 3 , anti‐β‐amino alcohols were obtained in excellent yields (>99% with respect to the nucleophile) and enantioselectivities (ee>99%) with the concomitant recovery of corresponding epoxides in high optical purity (ee up to >99%) and quantitative yields in 12 h. The catalyst 3 is recyclable in the aminolytic kinetic resolution process and worked well up to six cycles with retention of enantioselectivity.     

Ferrocenyl‐Aryl Based trans‐Chelating Diphosphine Ligands: Synthesis,Molecular Structure and Application in Enantioselective Hydrogenation

Potentially trans‐chelating diphosphine ligands based on a ferrocenyl‐aryl backbone were synthesised in a four‐step sequence and the molecular structures in the solid state of two representatives were determined by X‐ray diffraction. High throughput screening of these ligands in rhodium‐, ruthenium‐ and iridium‐mediated hydrogenations of a variety of alkenes and ketones revealed that these ligands can deliver high enantioselectivity for alkenes (up to 98% ee) but are less selective when ketones are used as the substrates. The coordination behaviour of one ligand in its square planar palladium and platinum dichloride complexes was studied by ³¹P NMR and only trans‐chelated complexes, together with oligomeric by‐products, were observed. Reaction with the (p‐cymene)ruthenium dichloride dimer, [RuCl₂(p‐cymene)]₂, resulted in a mixture of diastereomeric complexes.     

MOP‐Type Binaphthyl Phosphite and Diamidophosphite Ligands and Their Application in Catalytic Asymmetric Transformations

Monodentate phosphite and diamidophosphite ligands have been developed based on O‐methyl‐BINOL. These chiral ligands are easy to prepare from readily accessible phosphorylating reagents – (S_a or R_a)‐2‐chlorodinaphtho[2,1‐d:1′,2′‐f][1,3,2]dioxaphosphepine and (2R,5S)‐2‐chloro‐3‐phenyl‐1,3‐diaza‐2‐phosphabicyclo[3.3.0]octane. The new ligands have demonstrated excellent enantioselectivity in the palladium‐catalysed allylic substitution reactions of (E)‐1,3‐diphenylallyl acetate with sodium p‐toluenesulfinate (up to 99 % ee), pyrrolidine (up to 97 % ee), dipropylamine (up to 95 % ee) and dimethyl malonate (up to 99 % ee). In the palladium‐catalysed deracemization of ethyl (E)‐1,3‐diphenylallyl carbonate, up to 96 % enantioselectivity has been achieved. The diamidophosphite ligands have exhibited very good enantioselectivity in the Rh‐catalysed asymmetric hydrogenation of dimethyl itaconate (up to 90 % ee).     

N,N′‐Dioxide‐Magnesium Ditriflate Complex‐Catalyzed Asymmetric α‐Hydroxylation of β‐Keto Esters and β‐Keto Amides

The highly catalytic asymmetric α‐hydroxylation of 1‐tetralone‐derived β‐keto esters and β‐keto amides using tert‐butyl hydroperoxide (TBHP) as the oxidant was realized by a chiral N,N′‐dioxide‐magnesium ditriflate [Mg(OTf)₂] complex. A series of corresponding chiral α‐hydroxy dicarbonyl compounds was obtained in excellent yields (up to 99%) with excellent enantioselectivities (up to 98% ee). The products were easily transformed into useful building blocks and the precursor of daunomycin was achieved in an asymmetric catalytic way for the first time.     

Enantioselective Cyanosilylation of Ketones with Amino Acid/BINAP/Ruthenium(II)‐Lithium Phenoxide Catalyst Systems

Enantioselective reactions of simple ketones, α,α‐ and β,β‐dialkoxy ketones, and α‐alkoxy ketones with trimethylsilyl cyanide catalyzed by the bimetallic systems of amino acid/BINAP/ruthenium(II) complexes and lithium phenoxide have been studied [BINAP=2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl]. The Ru(PhGly)₂(BINAP)‐lithium phenoxide system showed high enantioselectivity for the reaction of acetophenone derivatives to afford the cyanated products in up to 90% ee [PhGly=phenylglycinate]. For the cyanosilylation of dialkoxy ketones and α‐alkoxy ketones, the Ru(t‐Leu)₂(BINAP)‐lithium phenoxide system exhibited the best catalyst performance to produce the cyanohydrin derivatives in up to 99% ee and 98% ee, respectively [t‐Leu=tert‐leucinate]. The excellent catalytic activity resulted in complete conversion in the reaction with a substrate‐to‐catalyst molar ratio (S/C) of 10,000 in the best cases.     

Synthesis, structural characterization and microbial activities of mixed ligand copper(II) complexes of 2,2′-bipyridine and acetylacetonate

Two new mixed ligand complexes of copper(II) with acetylacetonate (acac) and 2,2′-bipyridine (bpy) belonging to the class of cytotoxic and antineoplastic compounds known as CASIOPEINAS® have been synthesized and characterized on the basis of analytical and spectroscopic data. Molecular structures of the complexes, [Cu(acac)(bpy)Cl][Cu(acac)(bpy)(H₂O]Cl.H₂O and [Cu(acac)(bpy)Br]H₂O, were established by single crystal X-ray study. The Cu(II) ion in both the complexes exhibited square pyramidal geometry with acac and bpy in the equatorial plane and halide/water in the axial position. Interestingly, for the complex with chloride anion, two types of complexes with chloride and water at the axial positions were derived from the same reaction and co-crystallized in the asymmetric unit with strong intermolecular interactions. Microbial property of these two complexes as antibacterial and antifungal agents has been investigated and some of the results are comparable to that of the standard drugs such as E. coli, P. aeruginosa, S. aureus, S. pyogenes, A. niger and C. albicans, used in this study.     

Highly Enantioselective Phase‐Transfer Catalytic α‐Alkylation of α‐tert‐Butoxycarbonyllactams: Construction of β‐Quaternary Chiral Pyrrolidine and Piperidine Systems

A new enantioselective α‐alkylation of α‐tert‐butoxycarbonyllactams for the construction of β‐quaternary chiral pyrrolidine and piperidine core systems is reported. α‐Alkylations of N‐methyl‐α‐tert‐butoxycarbonylbutyrolactam and N‐diphenylmethyl‐α‐tert‐butoxycarbonylvalerolactam under phase‐transfer catalytic conditions (solid potassium hydroxide, toluene, −40 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐3,3′,5,5′‐tetrahydro‐2,6‐bis(3,4,5‐trifluorophenyl)‐4,4′‐spirobi[4H‐dinaphth[2,1‐c:1′,2′‐e]azepinium] bromide [(S,S)‐NAS Br] (5 mol%) afforded the corresponding α‐alkyl‐α‐tert‐butoxycarbonyllactams in very high chemical (up to 99%) and optical yields (up to 98% ee). Our new catalytic systems provide attractive synthetic methods for pyrrolidine‐ and piperidine‐based alkaloids and chiral intermediates with β‐quaternary carbon centers.     

Palladium(II) Complexes of C2‐Bridged Chiral Diphosphines: Application to Enantioselective Carbonyl‐Ene Reactions

(11bR,11′bR)‐4,4′‐(1,2‐Phenylene)bis[4,5‐dihydro‐3H‐dinaphtho[2,1‐c:1′,2′‐e]phosphepin] [abbreviated as (R)‐BINAPHANE], (3R,3′R,4S,4′S,11bS,11′bS)‐4,4′‐bis(1,1‐dimethylethyl)‐4,4′,5,5′‐tetrahydro‐3,3′‐bi‐3H‐dinaphtho[2,1‐c:1′,2′‐e]phosphepin [(S)‐BINAPINE], (1S,1′S,2R,2′R)‐1,1′‐bis(1,1‐dimethylethyl)‐2,2′‐biphospholane [(S,S,R,R)‐TANGPHOS] and (2R,2′R,5R,5′R)‐1,1′‐(1,2‐phenylene)bis[2,5‐bis(1‐methylethyl)phospholane] [(R,R)‐i‐Pr‐DUPHOS] are C₂‐bridged chiral diphosphines that form stable complexes with palladium(II) and platinum(II) containing a five‐membered chelate ring. The Pd(II)‐BINAPHANE catalyst displayed good to excellent enantioselectivities with ee values as high as 99.0% albeit in low yields for the carbonyl‐ene reaction between phenylglyoxal and alkenes. Its Pt(II) counterpart afforded improved yields while retaining satisfactory enantioselectivity. For the carbonyl‐ene reaction between ethyl trifluoropyruvate and alkenes, the Pd(II)‐BINAPHANE catalyst afforded both good yields and extremely high enantioselectivities with ees as high as 99.6%. A comparative study on the Pd(II) catalysts of the four C₂‐bridged chiral diphosphines revealed that Pd(II)‐BINAPHANE afforded the best enantioselectivity. The ee values derived from Pd(II)‐BINAPHANE are much higher than those derived from the other three Pd(II) catalysts. A comparison of the catalyst structures shows that the Pd(II)‐BINAPHANE catalyst is the only one that has two bulky (R)‐binaphthyl groups close to the reaction site. Hence it creates a deep chiral space that can efficiently control the reaction behavior in the carbonyl‐ene reactions resulting in excellent enantioselectivity.     

Enantioselective Addition of Malonates and β‐Keto Esters to Nitroalkenes over an Organonickel‐Functionalized Periodic Mesoporous Organosilica

A periodic mesoporous organosilica (PMO) with chiral cyclohexyldiamine‐based nickel(II) complexes incorporated within the silica framework was prepared through a co‐condensation of (1R,2R)‐cyclohexyldiamine‐derived silane and Ph‐bridged silane followed by complexation of nickel(II) bromide in the presence of (1R,2R)‐N,N′‐dibenzylcyclohexyldiamine. Structural analyses by X‐ray powder diffraction, nitrogen sorption and transmission electron microscopy disclosed its orderly mesostructure while characterization by solid‐state NMR and X‐ray photoelectron spectroscopy demonstrated the well‐defined single‐site chiral bis(cyclohexyldiamine)‐based nickel(II) active centers incorporated within the PMO material. In particular, as a heterogeneous chiral catalyst, this periodic mesoporous organosilica showed high catalytic activity and excellent enantioselectivity in asymmetric Michael addition of 1,3‐dicarbonyl compounds to nitroalkenes (more than 92% conversions and up to 99% ee values). More importantly, this heterogeneous catalyst could be recovered easily and reused repeatedly nine times without obviously affecting its ee value, showing good potential for industrial applications.     

A Simple Approach to Unsymmetric Atropoisomeric Bipyridine N,N′‐Dioxides and Their Application in Enantioselective Allylation of Aldehydes

The [2+2+2] cyclotrimerization of 1‐isoquinolinyl‐1,7‐octadiyne with benzonitrile catalyzed by CpCo(CO)₂ opened a new pathway for a synthesis of unsymmetrical axially chiral bipyridine N,N′‐dioxides. The N,N′‐dioxide 3a was found to be highly catalytically active and enantioselective for the asymmetric allylation of aldehydes with allyltrichlorosilane. The allylation took place with even 1 % of the catalyst with an enantioselectivity up to 87 % ee.