Lipase‐Catalyzed Dynamic Kinetic Resolution of C1‐ and C2‐Symmetric Racemic Axially Chiral 2,2′‐Dihydroxy‐1,1′‐biaryls

We have discovered that the racemization of configurationally stable, axially chiral 2,2′‐dihydroxy‐1,1′‐biaryls proceeds with a catalytic amount of a cyclopentadienylruthenium(II) complex at 35–50 °C. Combining this racemization procedure with lipase‐catalyzed kinetic resolution led to the first lipase/metal‐integrated dynamic kinetic resolution of racemic axially chiral biaryl compounds. The method was applied to the synthesis of various enantio‐enriched C₁‐ and C₂‐symmetric biaryl diols in yields of up to 98 % and enantiomeric excesses of up to 98 %, which paves the way for new developments in the field of asymmetric synthesis.     

Development of Ar‐BINMOL‐Derived Atropisomeric Ligands with Matched Axial and sp3 Central Chirality for Catalytic Asymmetric Transformations

Recently, academic chemists have renewed their interest in the development of 1,1′‐binaphthalene‐2,2′‐diol (BINOL)‐derived chiral ligands. Six years ago, a working hypothesis, that the chirality matching of hybrid chirality on a ligand could probably lead to high levels of stereoselective induction, prompted us to use the axial chirality of BINOL derivatives to generate new stereogenic centers within the same molecule with high stereoselectivity, obtaining as a result sterically favorable ligands for applications in asymmetric catalysis. This Personal Account describes our laboratory's efforts toward the development of a novel class of BINOL‐derived atropisomers bearing both axial and sp³ central chirality, the so‐called Ar‐BINMOLs, for asymmetric synthesis. Furthermore, on the basis of the successful application of Ar‐BINMOLs and their derivatives in asymmetric catalysis, the search for highly efficient and enantioselective processes also compelled us to give special attention to the BINOL‐derived multifunctional ligands with multiple stereogenic centers for use in catalytic asymmetric reactions.

     

New efficient ruthenium catalysts for racemization of alcohols at room temperature

(η⁵-Pentaphenylcyclopentadienyl)RuCl(CO)₂ was found to catalyze efficiently the racemization of chiral alcohols such as (S)-1-phenylethanol, (S)-1-phenylpropan-2-ol, (S)-4-phenylbutan-2-ol and (S)-4-methoxy-1-phenylethanol at room temperature in the presence of a base. The catalytic activity of three other Ru(II) complexes was also investigated. The effects of halide and solvent were studied as well.     

Highly enantioselective phenylacetylene additions to ketones catalyzed by (S)-BINOL-Ti complex

The readily available and inexpensive (S)-BINOL ligand in combination with Ti(O(i)Pr)(4) is an effective chiral catalyst for the catalytic asymmetric addition of alkynylzinc to unactivated simple ketones. Good to excellent enantioselectivities were achieved. No previous case has been reported successfully using BINOL to catalyze the addition of phenylacetylene to unactivated ketones, and thus the utility of BINOL in asymmetric catalysis is expanded.     

Chiral Macrocycle‐Enabled Counteranion Trapping for Boosting Highly Efficient and Enantioselective Catalysis

The tight binding enabled by tailor‐made macrocycles can be manipulated for tuning the catalysis process. In parallel to well‐developed crown ether‐based cation‐binding catalysis, a macrocycle‐enabled counteranion trapping strategy is presented for boosting highly efficient and enantioselective catalysis. A set of bis‐diarylthiourea macrocycles containing two BINOL moieties were designed and synthesized. They possess a well‐confined chiral cavity and strong binding affinities towards disulfonate anions. Caused by the tight binding, just 1 mol % macrocycle in combination with 1 mol % ethanedisulfonic acid can promote excellent conversion and up to 99 % ee in the Friedel–Crafts reaction of indoles with imines. The acid or the macrocycle alone do not afford any reactivity. The high catalytic efficiency and excellent stereocontrol was ascribed to large, complexation‐induced acidity enhancement and tight ion‐pairing facilitated by cave‐like macrocyclic cavity.     

Reversible Soft Mechanochemical Control of Biaryl Conformations through Crosslinking in a 3D Macromolecular Network

Tuning the dihedral angle (DA) of axially chiral compounds can impact biological activity, catalyst efficiency, molecular motor performance, or chiroptical properties. Herein, we report gradual, controlled, and reversible changes in molecular conformation of a covalently linked binaphthyl moiety within a 3D polymeric network by application of a macroscopic stretching force. We managed direct observation of DA changes by measuring the circular dichroism signal of an optically pure BINOL-crosslinked elastomer network. Stretching the elastomer resulted in a widening of the DA between naphthyl rings when the BINOL was doubly grafted to the elastomer network; no effect was observed when a single naphthyl ring of the BINOL was grafted to the elastomer network. We have determined that ca. 170 % extension of the elastomers led to the transfer of a mechanical force to the BINOL moiety of 2.5 kcal mol⁻¹ Å⁻¹ (ca. 175 pN) in magnitude and results in the opening of the DA of BINOL up to 130°.     

Enantioselective Synthesis of C−O Axially Chiral Diaryl Ethers by NHC-Catalyzed Atroposelective Desymmetrization**

Axially chiral diaryl ethers, a distinguished class of atropisomers possessing unique dual C−O axis, hold immense potential for diverse research domains. In contrast to the catalytic enantioselective synthesis of conventional single axis bearing atropisomers, the atroposelective synthesis of axially chiral ethers containing flexible C−O axis remains a significant challenge. Herein, we demonstrate the first N-heterocyclic carbene (NHC)-catalyzed synthesis of axially chiral diaryl ethers via atroposelective esterification of dialdehyde-containing diaryl ethers. Mechanistically, the reaction proceeds via NHC-catalyzed desymmetrization strategy to afford the corresponding axially chiral diaryl ether atropisomers in good yields and high enantioselectivities under mild conditions. The derivatization of the synthesized product expands the utility of present strategy via access to a library of C−O axially chiral compounds. The temperature dependency and preliminary investigations on the racemization barrier of C−O bonds are also presented.     

Are Two Metal Ions Better than One? Mono- and Binuclear α-Diimine-Re(CO)3 Complexes with Proton-Responsive Ligands in CO2 Reduction Catalysis

Here, the reduction chemistry of mono- and binuclear α-diimine-Re(CO)₃ complexes with proton responsive ligands and their application in the electrochemically-driven CO₂ reduction catalysis are presented. The work was aimed to investigate the impact of 1) two metal ions in close proximity and 2) an internal proton source on catalysis. Therefore, three different Re complexes, a binuclear one with a central phenol unit, 3 , and two mononuclear, one having a central phenol unit, 1 , and one with a methoxy unit, 2 , were utilised. All complexes are active in the CO₂-to-CO conversion and CO is always the major product. The catalytic rate constant k_cat for all three complexes is much higher and the overpotential is lower in DMF/water mixtures than in pure DMF (DMF=N,N-dimethylformamide). Cyclic voltammetry (CV) studies in the absence of substrate revealed that this is due to an accelerated chloride ion loss after initial reduction in DMF/water mixtures in comparison to pure DMF. Chloride ion loss is necessary for subsequent CO₂ binding and this step is around ten times faster in the presence of water [ 2 : k^Cl(DMF)≈1.7 s⁻¹; k^Cl(DMF/H₂O)≈20 s⁻¹]. The binuclear complex 3 with a proton responsive phenol unit is more active than the mononuclear complexes. In the presence of water, the observed rate constant k_obs for 3 is four times higher than of 2 , in the absence of water even ten times. Thus, the two metal centres are beneficial for catalysis. Lastly, the investigation showed that the phenol unit has no impact on the rate of the catalysis, it even slows down the CO₂-to-CO conversion. This is due to an unproductive, competitive side reaction: After initial reduction, 1 and 3 loose either Cl⁻ or undergo a reductive OH deprotonation forming a phenolate unit. The phenolate could bind to the metal centre blocking the sixth coordination site for CO₂ activation. In DMF, O−H bond breaking and Cl⁻ ion loss have similar rate constants [ 1 : k^Cl(DMF)≈2 s⁻¹, k^OH≈1.5 s⁻¹], in water/DMF Cl⁻ loss is much faster. Thus, the effect on the catalytic rate is more pronounced in DMF. However, the acidic protons lower the overpotential of the catalysis by about 150 mV.     

Cross-Coupling Reaction of Alkenyl Sulfoximines and Alkenyl Aminosulfoxonium Salts with Organozincs by Dual Nickel Catalysis and Lewis Acid Promotion

In this article, the cross-coupling reaction (CCR) of exocyclic, axially chiral, and acyclic alkenyl (N-methyl)sulfoximines with alkyl- and arylzincs is described_. The CCR generally requires dual Ni catalysis and MgBr₂ promotion, which is effective in diethyl ether but not in THF. NMR spectroscopy revealed a complexation of alkenyl sulfoximines by MgBr₂ in diethyl ether, which suggests an acceleration of the oxidative addition through nucleofugal activation. The CCR of alkenyl sulfoximines generally proceeds in the presence of Ni(dppp)Cl₂ as a precatalyst and MgBr₂ with alkyl- and arylzincs with a high degree of stereoretention at the C and the S atom. CCR of axially chiral alkenyl sulfoximines with Ni(PPh₃)₂Cl₂ as a precatalyst and ZnPh₂ does not require salt promotion and is stereoretentive. The reaction with Zn(CH₂SiMe₃)₂, however, demands salt promotion and is not stereoretentive. CCR of axially chiral α-methylated alkenyl sulfoximines afforded persubstituted axially chiral alkenes with high selectivity. Alkenyl (N-triflyl)sulfoximines engage in a stereoretentive CCR with Grignard reagents and Ni(PPh₃)₂Cl₂. Ni-Catalyzed and MgBr₂-promoted CCR of E-configured acyclic alkenyl sulfoximines and aminosulfoxonium salts with ZnPh₂ and Zn(CH₂SiMe₃)₂ is stereoretentive with Ni(dppp)Cl₂ and Ni(PPh₃)₂Cl₂. CCRs of acyclic alkenyl sulfoximines and alkenyl aminosulfoxonium salts, carrying a methyl group at the α position, take a different course and give alkenyl sulfinamides under stereoretention at the S and C atom. CCR of acyclic, exocyclic, and axially chiral alkenyl sulfoximines has been successfully applied to the stereoselective synthesis of homoallylic alcohols, exocyclic alkenes, and axially chiral alkenes, respectively.     

Highly efficient and stable blue‐light‐emitting binaphthol‐fluorene copolymers: A joint experimental and theoretical study of the main‐chain chirality

In a quest for the main‐chain chiral and highly stable blue‐light‐emitting π‐conjugated polymers, a novel series of soluble conjugated random and alternating copolymers (PF‐BN) derived from fluorene and axially chiral 1,1′‐binaphthol (BINOL) were successfully synthesized by Suzuki coupling polymerization. The polymer structures, optical properties, and their electrochemical properties were investigated by ¹H NMR, TGA/DSC, UV‐Vis absorption, photoluminescence, cyclic voltammetry, circular dichroism spectroscopy, and DFT calculations. The blue‐light‐emitting BINOL‐containing copolymers with proper content of BINOL show highly efficient photoluminescence and ultra highly stable light‐emission with almost unchanged fluorescent spectra after annealing at 200 °C in air for 10 h. The joint experimental and theoretical study of the main‐chain chirality reveals that (1) the chirality of BINOL can be transferred to the polymer backbone, (2) the effective conjugation length is about one BINOL and three fluorenes, (3) the main active chiral block in the copolymers is probably composed by one BINOL with the other two or three fluorenes, and (4) the dihedral angle in the PF‐BN copolymers should be larger than 105°. The incorporation of BINOL into the polyfluorene backbone is an effective way to produce highly efficient and stable blue‐light‐emitting main‐chain chiral conjugated polymer with interesting optoelectronic properties. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 3868–3879, 2010     

Catalytic hydrolysis of phosphate esters in microemulsions

We have continued our kinetics investigation of the iodosobenzoate (IBA) catalysis of the hydrolysis of p-nitrophenyl diphenyl phosphate (PNDP), in microemulsion media composed of hexadecane in water stabilized by cetyltrimethylammonium bromide and 1-butanol over a range of water mass fractions. We have examined two iodosobenzoic acid derivatives (5-nitro-2-iodosobenzoic acid and 5-octyloxy-2-iodosobenzoic acid) as catalysts. In addition, we have determined by³¹P FT-NMR techniques that the major product of the hydrolysis of PNDP, both in IBA catalyzed and in uncatalyzed media, is diphenylphosphate.     

Axially Chiral Aryl‐Alkene‐Indole Framework: A Nascent Member of the Atropisomeric Family and Its Catalytic Asymmetric Construction

A new class of axially chiral aryl‐alkene‐indole frameworks have been designed, and the first catalytic asymmetric construction of such scaffolds has been established by the strategy of organocatalytic (Z/E)‐selective and enantioselective (4+3) cyclization of 3‐alkynyl‐2‐indolylmethanols with 2‐naphthols or phenols (all >95 : 5 E/Z, up to 98% yield, 97% ee). This reaction also represents the first catalytic asymmetric construction of axially chiral alkene‐heteroaryl scaffolds, which will add a new member to the atropisomeric family. This approach has not only confronted the great challenges in constructing axially chiral alkene‐heteroaryl scaffolds but also provided a powerful strategy for the enantioselective construction of axially chiral aryl‐alkene‐indole frameworks.     

Rhodium-Catalyzed Enantioselective Synthesis,Structures, and Properties of Single and Double Azahelicene-Like Molecules

The enantioselective synthesis of aza[6] and [7]helicene-like molecules have been achieved by the cationic rhodium(I)/axially chiral biaryl bisphosphine complex-catalyzed intramolecular [2+2+2] cycloaddition of cyanodiynes. This protocol was successfully applied to the diastereo- and enantioselective synthesis of an S-shaped double aza[6]helicene-like molecule with a high ee value of 89 %. Although no epimerization and racemization were observed in the double carbo[6]helicene-like molecule at 80 °C, epimerization and racemization of the double aza[6]helicene-like molecule proceeded at 80 °C. This double aza[6]helicene-like molecule showed good fluorescent quantum yields and chiroptical responses under both neutral and acidic conditions.     

Enantioselective Synthesis of Chiral Oxime Ethers: Desymmetrization and Dynamic Kinetic Resolution of Substituted Cyclohexanones

Axially chiral cyclohexylidene oxime ethers exhibit unique chirality because of the restricted rotation of C=N. The first catalytic enantioselective synthesis of novel axially chiral cyclohexylidene oximes has been developed by catalytic desymmetrization of 4‐substituted cyclohexanones with O‐arylhydroxylamines and is catalyzed by a chiral BINOL‐derived strontium phosphate with excellent yields and good enantioselectivities. In addition, chiral BINOL‐derived phosphoric acid catalyzed dynamic kinetic resolution of α‐substituted cyclohexanones has been performed and yields versatile intermediates in high yields and enantioselectivities.     

Asymmetric hydrogenation of quinolines catalyzed by iridium complexes of BINOL-derived diphosphonites

A chiral diphosphonite, derived from BINOL and with an achiral diphenyl ether backbone, is an excellent ligand for the Ir-catalyzed asymmetric hydrogenation of quinolines; achiral P-ligands serving as possible additives (ee = 73-96%).     

聚合物负载的手性联二萘酚的合成及其在不对称催化中的应用进展

作为一种有机配体, 手性1,1'-联二萘酚(BINOL)被广泛应用于过渡金属催化的均相不对称有机反应. 为克服均相催化剂不易回收重复使用等缺陷, 人们深入研究了聚合物负载手性BINOL催化剂的方法. 总结了近年来聚合物负载手性BINOL催化剂的合成及其在不对称有机催化中的应用, 并对负载型BINOL催化剂进行了展望.     

Asymmetric Allylic Substitution-Isomerization for the Modular Synthesis of Axially Chiral N-Vinylquinazolinones

Axially chiral N-substituted quinazolinones are important bioactive molecules, which are presented in many synthetic drugs. However, most strategies toward their atroposelective synthesis are mainly limited to the axially chiral arylquinazolinone frameworks. The development of modular synthetic methods to access diverse quinazolinone-based atropisomers remains scarce and challenging. Herein, we report the regio- and atroposelective synthesis of axially chiral N-vinylquinazolinones via the strategy of asymmetric allylic substitution-isomerization. The catalysis system utilized both asymmetric transition-metal catalysis and organocatalysis to efficiently afford trisubstituted and tetrasubstituted N-vinylquinazolinone atropisomers, respectively. With the meticulous design of β-substituted allylic substrates, both Z- and E-tetrasubstituted axially chiral N-vinylquinazolinones were obtained in good yields and high enantioselectivities.     

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.     

Immobilization of BINOL by cross-linking copolymerization of styryl derivatives with styrene, and applications in enantioselective Ti and Al Lewis acid mediated additions of Et2Zn and Me3SiCN to aldehydes and of diphenyl nitrone to enol ethers

The chiral ligand 1,1'-bi-2-naphthol (BINOL) has been succesfully immobilized on polystyrene. Several dendritic and non-dendritic BINOL derivatives (3, and 13-17), bearing at least two polymerizable styryl groups, were prepared and fully characterized. Suspension copolymerization of the MOM- or TIPS-protected cross-linking BINOL ligands (MOM = methyloxymethyl, TIPS = triisopropylsilyl) with styrene, cleavage of the protecting-groups, and loading with a Lewis-acid afforded catalytically active polystyrene-supported BINOLates. The polymer-bound BINOLs p-3, and p-13-p-16 were tested in the Ti-BINOLate-mediated addition of Et2Zn to PhCHO. The enantioselectivities (up to 93%) and conversions obtained with the polymer-bound catalysts were in most cases identical (within experimental error) to those obtained with the unsubstituted 1,1'-bi-2-naphthol and with the non-polymerized BINOL cross-linkers under homogeneous conditions. Special focus was put on the reusability of the supported catalyst: the polymer-beads were used in up to 20 consecutive catalytic runs, with the best polymers showing no or only minor loss of selectivity. BINOL-polymers p-17, obtained by copolymerization of a 3,3'-distyryl-substituted BINOL 17a with styrene, were used in the BINOL. AlMe-mediated cycloaddition of diphenyl nitrone with alkyl vinyl ethers. In all cases the exo/endo selectivity (> or =92:8) and the enantioselectivities with which the exo-cycloadducts were formed (> or =95%) correspond to those observed in the homogeneous reactions. A dendritically cross-linked BINOL-polymer was also employed in the Ti-BINOLate-mediated cyanosilylation of pivalaldehyde. The enantiopurity of the cyanohydrine obtained in the first run was as high as in the homogeneous reaction (72%); surprisingly the catalytic performance of the supported catalyst increased steadily during the first catalytic cycles to reach 83%. Thus, cross-linking BINOLs can be succesfully incorporated into a polystyrene matrix (without racemization!) to give polymer-bound BINOL ligands that give excellent performance over many catalytic cycles with catalytic activities comparable with those of soluble analogues.     

Catalytic Asymmetric Ring‐Opening Reactions of Aziridines with 3‐Aryl‐Oxindoles

A highly enantioselective ring‐opening alkylation reaction between 3‐aryl‐oxindole and N‐(2‐picolinoyl) aziridine has been realized for the first time. The reaction is efficiently mediated by a simple in‐situ‐generated magnesium catalyst and 3,3′‐fluorinated‐BINOL (BINOL=1,1′‐binaphthalene‐2,2′‐diol) has been identified as a powerful chiral ligand. Notably, the fluorine atom on the chiral ligand plays a key role in providing the desired chiral 3‐alkyl‐3‐aryl oxindoles with excellent enantioselectivities.