Recyclable helical poly(phenylacetylene)‐supported catalyst for asymmetric aldol reaction in aqueous media

A novel one‐handed helical poly(phenylacetylene) bearing L‐hydroxyproline pendants (poly(PA‐P)) was synthesized as an eco‐friendly polymer‐supported catalyst for asymmetric reactions. The helical poly(PA‐P) catalyzed the asymmetric aldol reactions of cyclohexanone with p‐nitrobenzaldehyde, and showed good recyclability and higher enantiomeric excess (ee) in aqueous medias than that in organic medias. The one‐handed helicity of poly(PA‐P) was clearly affected by the water content in the aqueous media. The helical poly(PA‐P) showed the higher enantioselectivity (ee = 99%) than its monomer PA‐P (ee = 54%) in THF/H₂O (H₂O vol % = 25.0 vol %). After the one‐handed helical structure of poly(PA‐P) was destroyed by grinding treatment, the ee of the reaction clearly decreased from 99 to 49%. These indicate that the one‐handed helical structure of poly(PA‐P) played an important role in the high enantioselectivity of the asymmetric aldol reactions in the aqueous media. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 1024–1031     

BINOL Phosphoric Acid‐Catalyzed Asymmetric Mannich Reaction of Cyclic N‐Acyl Ketimines with Cyclic Enones

A highly enantio‐ and diastereoselective Mannich reaction of cyclic N‐acyl ketimines generated in situ from 3‐hydroxyisoindolin‐1‐ones with cyclic enones has been accomplished using a chiral phosphoric acid catalyst to afford the chiral isoindalinone derivatives in high yields with excellent enantioselectivities (upto 97 % ee). This is the first report on the synthesis of chiral isoindolin‐1‐ones bearing adjacent quaternary and tertiary stereogenic centers.     

Optically Active Helical Poly[(S)‐3‐vinyl‐2,2′‐dihydroxy‐1,1′‐binaphthyl]: New Ligand for Asymmetric Addition of Diethylzinc to Aryl Aldehyde

Poly[(S)‐3‐vinyl‐2,2′‐dihydroxy‐1,1′‐binaphthyl] (L*) was obtained by taking off the protecting groups of poly[(S)‐3‐vinyl‐2,2′‐bis(methoxymethoxy)‐1,1′‐binaphthyl] (poly‐ 1 ). L* was proved to keep a stable helical conformation in solution. The application of helical L* in the asymmetric addition of diethylzinc to aldehydes has been studied. The catalytic system employing 10 mol% of L* and 150 mol% of Ti(OⁱPr)₄ was found to promote the addition of diethylzinc to a wide range of aromatic aldehydes, giving up to 99% enantiomeric excess (ee) and up to 93% yield of the corresponding secondary alcohol at 0°C. The chiral polymer can be easily recovered and reused without loss of catalytic activity as well as enantioselectivity.     

Nickel(II)‐Catalyzed Asymmetric Propargyl [2,3] Wittig Rearrangement of Oxindole Derivatives: A Chiral Amplification Effect

A highly enantioselective [2,3] Wittig rearrangement of oxindole derivatives was realized by using a chiral N,N′‐dioxide/Ni^II complex as the catalyst under mild reaction conditions. A strong chiral amplification effect was observed, and allowed access to chiral 3‐hydroxy 3‐substituted oxindoles bearing allenyl groups in high yields and enantioselectivities (up to 92 % ee) by using a ligand with only 15 % ee. A reasonable explanation was given based on the experimental investigations and X‐ray crystal structures of enantiomerically pure and racemic catalysts. Moreover, the first catalytic kinetic resolution of racemic oxindole derivatives by a [2,3] Wittig rearrangement was realized with high efficiency and stereoselectivity.     

Two modes of asymmetric polymerization of phenylacetylenes having an L‐amino alcohol residue and two hydroxy groups

Four novel chiral phenylacetylenes having an L ‐amino alcohol residue and two hydroxymethyl groups were synthesized and polymerized by an achiral catalyst ((nbd)Rh⁺[η⁶‐(C₆H₅)B^?(C₆H₅)₃]) or a chiral catalytic system ([Rh(nbd)Cl]₂/(S)‐ or (R)‐phenylethylamine ((S)‐ or (R)‐PEA)). The two resulting polymers having an L ‐valinol or L ‐phenylalaninol residue showed Cotton effects at wavelengths around 430 nm. This observation indicated that they had an excess of one‐handed helical backbones. Positive and negative Cotton effects were observed only for the polymers having an L ‐valinol residue produced by using (R)‐ and (S)‐PEA as a cocatalyst, respectively, although the monomer had the same chirality. Even when the achiral catalyst was used, the two resulting polymers having an L ‐valinol or L ‐phenylalaninol residue showed Cotton effects despite the long distance between the chiral groups and the main chain. We have found the first example of a new type of chiral monomer, that is, a chiral phenylacetylene monomer having an L ‐amino alcohol residue and two hydroxy groups that was suitable for both modes of asymmetric polymerization, that is, the helix‐sense‐selective polymerization ( HSSP ) with the chiral catalytic system and the asymmetric‐induced polymerization ( AIP ) with the achiral catalyst. The other two monomers having L ‐alaninol and L ‐tyrosinol were found to be unsuitable to neither HSSP nor AIP because of their polymers' low solubility. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Chiral N,N′‐Dioxide‐Organocatalyzed Regio‐, Diastereo‐ and Enantioselective Michael Addition–Alkylation Reaction

A highly regio‐, diastereo‐ and enantioselective Michael addition–alkylation reaction between α‐substituted cyano ketones and (Z)‐bromonitrostyrenes has been realized by using a chiral N,N′‐dioxide as organocatalyst. A variety of substrates performed well in this reaction, and the corresponding multifunctionalized chiral 2,3‐dihydrofurans were obtained in up to 95 % yield with 95:5 dr and 93 % ee.     

Highly Enantioselective Iron‐Catalyzed cis‐Dihydroxylation of Alkenes with Hydrogen Peroxide Oxidant via an FeIII‐OOH Reactive Intermediate

The development of environmentally benign catalysts for highly enantioselective asymmetric cis‐dihydroxylation (AD) of alkenes with broad substrate scope remains a challenge. By employing [Fe^II(L)(OTf)₂] (L=N,N′‐dimethyl‐N,N′‐bis(2‐methyl‐8‐quinolyl)‐cyclohexane‐1,2‐diamine) as a catalyst, cis‐diols in up to 99.8 % ee with 85 % isolated yield have been achieved in AD of alkenes with H₂O₂ as an oxidant and alkenes in a limiting amount. This “[Fe^II(L)(OTf)₂]+H₂O₂” method is applicable to both (E)‐alkenes and terminal alkenes (24 examples >80 % ee, up to 1 g scale). Mechanistic studies, including ¹⁸O‐labeling, UV/Vis, EPR, ESI‐MS analyses, and DFT calculations lend evidence for the involvement of chiral Fe^III‐OOH active species in enantioselective formation of the two C?O bonds.     

Copper‐Complex‐Catalyzed Asymmetric Aerobic Oxidative Cross‐Coupling of 2‐Naphthols: Enantioselective Synthesis of 3,3′‐Substituted C1‐Symmetric BINOLs

A novel chiral 1,5‐N,N‐bidentate ligand based on a spirocyclic pyrrolidine oxazoline backbone was designed and prepared, and it coordinates CuBr in situ to form an unprecedented catalyst that enables efficient oxidative cross‐coupling of 2‐naphthols. Air serves as an external oxidant and generates a series of C₁‐symmetric chiral BINOL derivatives with high enantioselectivity (up to 99 % ee) and good yield (up to 87 %). This approach is tolerant of a broader substrates scope, particularly substrates bearing various 3‐ and 3′‐substituents. A preliminary investigation using one of the obtained C₁‐symmetric BINOL products was used as an organocatalyst, exhibiting better enantioselectivity than the previously reported organocatalyst, for the asymmetric α‐alkylation of amino esters.     

Enantioselective Synthesis of Chiral Isotopomers of 1‐Alkanols by a ZACA–Cu‐Catalyzed Cross‐Coupling Protocol

Chiral compounds arising from the replacement of hydrogen atoms by deuterium are very important in organic chemistry and biochemistry. Some of these chiral compounds have a non‐measurable specific rotation, owing to very small differences between the isotopomeric groups, and exhibit cryptochirality. This particular class of compounds is difficult to synthesize and characterize. Herein, we present a catalytic and highly enantioselective conversion of terminal alkenes to various β and more remote chiral isotopomers of 1‐alkanols, with ≥99 % enantiomeric excess (ee), by the Zr‐catalyzed asymmetric carboalumination of alkenes (ZACA) and Cu‐catalyzed cross‐coupling reactions. ZACA‐in situ iodinolysis of allyl alcohol and ZACA‐in situ oxidation of TBS‐protected ω‐alkene‐1‐ols protocols were applied to the synthesis of both (R)‐ and (S)‐difunctional intermediates with 80–90 % ee. These intermediates were readily purified to provide enantiomerically pure (≥99 % ee) compounds by lipase‐catalyzed acetylation. These functionally rich intermediates serve as very useful synthons for the construction of various chiral isotopomers of 1‐alkanols in excellent enantiomeric purity (≥99 % ee) by introducing deuterium‐labeled groups by Cu‐catalyzed cross‐coupling reactions without epimerization.     

Design,Synthesis, and Application of Chiral C2‐Symmetric Spiroketal‐Containing Ligands in Transition‐Metal Catalysis

We present an expedient and economical route to a new spiroketal‐based C₂‐symmetric chiral scaffold, termed SPIROL. Based on this spirocyclic scaffold, several chiral ligands were generated. These ligands were successfully employed in an array of stereoselective transformations, including in iridium‐catalyzed hydroarylations (up to 95 % ee), palladium‐catalyzed allylic alkylations (up to 97 % ee), intermolecular palladium‐catalyzed Heck couplings (up to 94 % ee), and rhodium‐catalyzed dehydroalanine hydrogenation (up to 93 % ee).     

Efficient Synthesis of Differentiated syn‐1,2‐Diol Derivatives by Asymmetric Transfer Hydrogenation–Dynamic Kinetic Resolution of α‐Alkoxy‐Substituted β‐Ketoesters

Asymmetric transfer hydrogenation was applied to a wide range of racemic aryl α‐alkoxy‐β‐ketoesters in the presence of well‐defined, commercially available, chiral catalyst Ru^II–(N‐p‐toluenesulfonyl‐1,2‐diphenylethylenediamine) and a 5:2 mixture of formic acid and triethylamine as the hydrogen source. Under these conditions, dynamic kinetic resolution was efficiently promoted to provide the corresponding syn α‐alkoxy‐β‐hydroxyesters derived from substituted aromatic and heteroaromatic aldehydes with a high level of diastereoselectivity (diastereomeric ratio (d.r.)>99:1) and an almost perfect enantioselectivity (enantiomeric excess (ee)>99 %). Additionally, after extensive screening of the reaction conditions, the use of Ru^II‐ and Rh^III‐tethered precatalysts extended this process to more‐challenging substrates that bore alkenyl‐, alkynyl‐, and alkyl substituents to provide the corresponding syn α‐alkoxy‐β‐hydroxyesters with excellent enantiocontrol (up to 99 % ee) and good to perfect diastereocontrol (d.r.>99:1). Lastly, the synthetic utility of the present protocol was demonstrated by application to the asymmetric synthesis of chiral ester ethyl (2S)‐2‐ethoxy‐3‐(4‐hydroxyphenyl)‐propanoate, which is an important pharmacophore in a number of peroxisome proliferator‐activated receptor α/γ dual agonist advanced drug candidates used for the treatment of type‐II diabetes.     

Chiral 2‐endo‐Substituted 9‐Oxabispidines: Novel Ligands for Enantioselective Copper(II)‐Catalyzed Henry Reactions

A flexible approach, applicable on a gram scale, to chiral 2‐endo‐substituted 9‐oxabispidines was developed. The key intermediate, a cis‐configured 6‐aminomethylmorpholine‐2‐carbonitrile, was prepared from (R)‐3‐aminopropane‐1,2‐diol and 2‐chloroacrylonitrile. The 2‐endo substituent was introduced by Grignard addition, cyclization, and exo‐selective reduction, thus furnishing the enantiomerically pure bi‐ and tricyclic 9‐oxabispidines in 19–59 % yield. The CuCl₂ complex of the tricyclic 9‐oxabispidine, which carries an 2‐endo,N‐anellated piperidine ring, is an excellent catalyst for enantioselective Henry reactions giving the S‐configured β‐nitro alcohols in 91–98 % ee (13 examples). Surprisingly, the analogous copper complexes of the bicyclic 9‐oxabispidines delivered the enantiocomplementary R‐configured products in 33–57 % ee. The respective transition states were discussed.     

Highly Enantioselective Direct Synthesis of Endocyclic Vicinal Diamines through Chiral Ru(diamine)‐Catalyzed Hydrogenation of 2,2′‐Bisquinoline Derivatives

An asymmetric hydrogenation of 2,2′‐bisquinoline and bisquinoxaline derivatives, catalyzed by chiral cationic ruthenium diamine complexes, was developed. A broad range of chiral endocyclic vicinal diamines were obtained in high yields with excellent diastereo‐ and enantioselectivity (up to 93:7 dl/meso and >99 % ee). These chiral diamines could be easily transformed into a new class of chiral N‐heterocyclic carbenes (NHCs), which are important but difficult to access.     

Helix‐sense‐selective copolymerization of triphenylmethyl methacrylate with chiral 2‐isopropenyl‐4‐phenyl‐2‐oxazoline

The asymmetric induction leading to a one‐handed helix was investigated in the anionic and radical copolymerization of triphenylmethyl methacrylate (TrMA) and (S)‐2‐isopropenyl‐4‐phenyl‐2‐oxazoline ((S)‐IPO), and highly isotactic copolymers with a reasonable optical activity were obtained. In the anionic copolymerization, the optical activity of the obtained copolymers depended on the polarity of solvents, and a highly optically active copolymer was produced in the copolymerization in toluene. The chiral oxazoline monomer functioned not only as a comonomer but also as a chiral ligand to endow the polymer with large negative optical rotation in the copolymerization with TrMA. The copolymers with small positive optical rotation were obtained in THF, indicating that IPO unit may work only as the chiral monomer that dictates the helical sense via copolymerization with TrMA. The isotacticity of the obtained copolymers depended on the contents of TrMA units in the copolymers, but was almost independent of the solvent for copolymerization. In the radical copolymerization, the obtained copolymers exhibited small optical activities. It seemed that the chiral monomer cannot induce one‐handed helical structure of TrMA sequences even if the sequences probably have a high isotacticity. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 441–447     

Modulation of Multifunctional N,O,P Ligands for Enantioselective Copper‐Catalyzed Conjugate Addition of Diethylzinc and Trapping of the Zinc Enolate

In this work, we have successfully synthesized a new family of chiral Schiff base–phosphine ligands derived from chiral binaphthol (BINOL) and chiral primary amine. The controllable synthesis of a novel hexadentate and tetradentate N,O,P ligand that contains both axial and sp³‐central chirality from axial BINOL and sp³‐central primary amine led to the establishment of an efficient multifunctional N,O,P ligand for copper‐catalyzed conjugate addition of an organozinc reagent. In the asymmetric conjugate reaction of organozinc reagents to enones, the polymer‐like bimetallic multinuclear Cu? Zn complex constructed in situ was found to be substrate‐selective and a highly excellent catalyst for diethylzinc reagents in terms of enantioselectivity (up to >99 % ee). More importantly, the chirality matching between different chiral sources, C₂‐axial binaphthol and sp³‐central chiral phosphine, was crucial to the enantioselective induction in this reaction. The experimental results indicated that our chiral ligand (R,S,S)‐ L1 ‐ and (R,S)‐ L4 ‐based bimetallic complex catalyst system exhibited the highest catalytic performance to date in terms of enantioselectivity and conversion even in the presence of 0.005 mol % of catalyst (S/C=20 000, turnover number (TON)=17 600). We also studied the tandem silylation or acylation of enantiomerically enriched zinc enolates that formed in situ from copper‐ L4 ‐complex‐catalyzed conjugate addition, which resulted in the high‐yield synthesis of chiral silyl enol ethers and enoacetates, respectively. Furthermore, the specialized structure of the present multifunctional N,O,P ligand L1 or L4 , and the corresponding mechanistic study of the copper catalyst system were investigated by ³¹P NMR spectroscopy, circular dichroism (CD), and UV/Vis absorption.     

Trio Catalysis Merging Enamine,Brønsted Acid,and Metal Lewis Acid Catalysis: Asymmetric Three‐Component Aza‐Diels–Alder Reaction of Substituted Cinnamaldehydes,Cyclic Ketones,and Arylamines

A trio catalyst system, composed of arylamine, BINOL‐derived phosphoric acid, and Y(OTf)₃, enables the combination of enamine catalysis with both hard metal Lewis acid catalysis and Brønsted acid catalysis for the first time. Using this catalyst system, a three‐component aza‐Diels–Alder reaction of substituted cinnamaldehyde, cyclic ketone, and arylamine is carried out with high chemo‐ and enantioselectivity, affording a series of optically active 1,4‐dihydropyridine (DHP) derivatives are obtained in 91–99 % ee and 59–84 % yield. DHPs bearing a chiral quaternary carbon center are also obtained with good enantioselectivity and moderate yield (three examples). Preliminary mechanistic investigations have also been conducted.     

Atropselective Dibrominations of a 1,1′‐Disubstituted 2,2′‐Biindolyl with Diverging Point‐to‐Axial Asymmetric Inductions. Deriving 2,2′‐Biindolyl‐3,3′‐diphosphane Ligands for Asymmetric Catalysis

On the ¹H NMR timescale, 2,2′‐biindolyls with (R)‐configured (1‐alkoxyprop)‐2‐yl, (1‐hydroxyprop)‐2‐yl, or (1‐siloxyprop)‐2‐yl substituents at C‐1 and C‐1′ are atropisomerically stable at <0 °C and interconvert at >30 °C. A 2,2′‐biindolyl (R,R)‐ 17 a of that kind and achiral (!) brominating reagents gave the atropisomerically stable 3,3′‐dibromobiindolyls (M)‐ and/or (P)‐ 18 a at best atropselectively—because of point‐to‐axial asymmetric inductions—and atropdivergently, exhibiting up to 95 % (M)‐ and as much (P)‐atropselectivity. This route to atropisomerically pure biaryls is novel and should extend to other substrates and/or different functionalizations. The dibromobiindolyls (M)‐ and (P)‐ 18 a furnished the biindolyldiphosphanes (M)‐ and (P)‐ 14 without atropisomerization. These syntheses did not require the resolution of a racemic mixture, which distinguishes them from virtually all biaryldiphosphane syntheses known to date. (M)‐ and (P)‐ 14 acted as ligands in catalytic asymmetric allylations and hydrogenations. Remarkably, the β‐ketoester rac‐ 25 c was hydrogenated trans‐selectively with 98 % ee; this included a dynamic kinetic resolution.     

Catalytic Michael/Ring‐Closure Reaction of α,β‐Unsaturated Pyrazoleamides with Amidomalonates: Asymmetric Synthesis of (−)‐Paroxetine

A highly enantioselective tandem Michael/ring‐closure reaction of α,β‐unsaturated pyrazoleamides and amidomalonates has been accomplished in the presence of a chiral N,N′‐dioxide–Yb(OTf)₃ complex (Tf: trifluoromethanesulfonyl) to give various substituted chiral glutarimides with high yields and diastereo‐ and enantioselectivities. Moreover, this methodology could be used for gram‐scale manipulation and was successfully applied to the synthesis of (?)‐paroxetine. Further nonlinear and HRMS studies revealed that the real catalytically active species was a monomeric L ‐PMe₂ –Yb³⁺ complex. A plausible transition state was proposed to explain the origin of the asymmetric induction.     

Cationic Ir/Me‐BIPAM‐Catalyzed Asymmetric Intramolecular Direct Hydroarylation of α‐Ketoamides

Asymmetric intramolecular direct hydroarylation of α‐ketoamides gives various types of optically active 3‐substituted 3‐hydroxy‐2‐oxindoles in high yields with complete regioselectivity and high enantioselectivities (84–98 % ee). This is realized by the use of the cationic iridium complex [Ir(cod)₂](BAr^F₄) and the chiral O‐linked bidentate phosphoramidite (R,R)‐Me‐BIPAM.     

The More Gold—The More Enantioselective: Cyclohydroaminations of γ‐Allenyl Sulfonamides with Mono‐, Bis‐, and Trisphospholane Gold(I) Catalysts

A series of chiral mono‐, di‐, and trinuclear gold(I) complexes have been prepared and used as precatalysts in the asymmetric cyclohydroamination of N‐protected γ‐allenyl sulfonamides. The stereodirecting ligands were mono‐, di‐, and tridentate 2,5‐diphenylphospholanes, which possessed C₁, C₂, and C₃ symmetry, respectively, thereby rendering the catalytic sites in the di‐ and trinuclear complexes symmetry equivalent. The C₃‐symmetric trinuclear complex displayed the highest activity and enantioselectivity (up to 95 % ee), whilst its mono‐ and dinuclear counterparts exhibited considerably lower enantioselectivities and activities. A similar trend was observed in a series of mono‐, di‐, and trinuclear 2,5‐dimethylphospholane gold(I) complexes. Aurophilic interactions were established from the solid‐state structures of the trinuclear gold(I) complexes, thereby raising the question as to whether these secondary forces were responsible for the different catalytic behavior observed.