Asymmetric Ring-opening Reaction Research Articles

Catalytic Asymmetric Ring Opening Reactions of Vinylcyclopropanes

AbstractVinylcyclopropanes (VCPs) are important building blocks with multifaceted reactivity. Catalytic asymmetric ring opening of vinylcyclopropanes is a highly efficient process to access valuable chiral molecules with diverse functionalities that can be further functionalized for a series of synthetic purposes. VCPs are very well‐known substrates for cycloaddition reactions and this chemistry has been widely explored. On the contrary, despite of enormous synthetic potential, development of new innovative strategies for the catalytic, asymmetric ring opening of VCPs is somewhat underdeveloped. Recently, several significant examples have emerged in the literature for various asymmetric ring opening of both activated and unactivated vinylcyclopropanes that involve transition metal catalysis. These developments are relevant additions to the vinylcyclopropane chemistry. In this review, we aim to summarize all the catalytic asymmetric ring opening transformations reported till date and provide a comprehensive analysis of these research outcomes.

Substrate Directed Regio‐ and Enantioselective Ring‐Opening of Epoxides and Aziridines

AbstractThe oxirane and aziridine rings are valuable building blocks in modern synthetic chemistry and catalytic asymmetric ring opening reactions of these three membered ring systems have emerged as a powerful chemical tool for the synthesis of natural products and biologically active compounds. In this context, the regioselective ring‐opening of structurally or electronically unbiased epoxides and aziridines is challenging. Recently, metal‐catalyzed substrate directed strategies have successfully applied in the regio‐ and enantioselective ring opening of functionalized epoxy alcohols by the Yamamoto group. Subsequently, our group realized the ring opening reactions of functionalized 2,3‐aziridinyl alcohols with the dinuclear zinc complex. These enantioselective nucleophilic ring opening reactions of functionalized epoxy alcohols and aziridinyl alcohols allow for the facile synthesis of amino alcohol derivatives and the introduction of new concepts in catalysis.

Catalytic asymmetric ring-opening of aminocyclopropanes with oxygen nucleophiles: access to chiral γ-amino acid derivatives

Donor–acceptor aminocyclopropanes bearing both amino and carboxyl groups underwent catalytic asymmetric ring-opening reactions with diverse oxygen nucleophiles to afford chiral γ-oxygen-substituted γ-aminobutyric acid derivatives with good results.

Magnesium catalyzed asymmetric ring-opening reactions of high-strained three membered cyclic systems

Magnesium catalyzed asymmetric ring-opening reactions of high-strained three membered cyclic systems

Catalytic Asymmetric Ring-Opening Reactions of Unstrained Heterocycles Using Cobalt Vinylidenes.

Cobalt catalysts promote highly enantioselective ring-opening reactions of 2,5-dihydrofurans using vinylidenes. The products are acyclic organozinc compounds that can be functionalized with an electrophile. The proposed mechanism involves the generation of a cobalt vinylidene species that adds to the alkene by a [2+2]-cycloaddition pathway. Ring-opening then occurs via outer-sphere β-O elimination assisted by coordination of a ZnX2 Lewis acid to the alkoxide leaving group. DFT models reveal that competing inner-sphere syn β-H and β-O elimination pathways are suppressed by the geometric constraints of the metallacycle intermediate. These models rationalize the observed stereochemical outcome of the reaction.

Asymmetric ring-opening reactions of donor-acceptor cyclopropanes with 1,3-cyclodiones.

Asymmetric ring-opening reactions of donor-acceptor cyclopropanes with 1,3-cyclodiones have been established for the synthesis of enantioenriched γ-hydroxybutyric acid derivatives in the presence of Cu(ii)/trisoxazoline catalyst. These reactions offered the desired products in 70% to 93% yields with 79% to 99% enantiomeric excesses.

Understanding the Reaction Mechanism of Nickel-Catalyzed Enantioselective Arylative Activation of the Aromatic C–O Bond

Mild synthetic methods to transform aromatic carbon–oxygen (C–O) bonds into useful molecules have great potential in renewable biomass conversion. Recently, a Ni–NHC (N-heterocyclic carbene) complex catalyzing an asymmetric ring-opening reaction of dinaphthofuran with PhMgCl at room temperature was reported. In this work, we carried out density functional theory (DFT) calculations to investigate the detailed mechanism. The DFT results reveal a novel mechanism that involves Mg(II)–O coordination followed by migration of the phenyl nucleophile to the Ni(0) metal center prior to oxidative addition of a C–O bond to Ni(0). Insights into how the chiral NHC ligand helps induce the enantioselectivity have been obtained.

Di- and Tetranuclear Dysprosium Single-Molecule Magnets Bridged by Unprecedentedly Disassembled Nitrogen-Enriched Tetrazine Derivatives

A series of di- and tetranuclear lanthanide complexes with the formulas [Dy2bmzch(tmhd)5 (CH3OH)]·CH3OH (1), [Dy2bmzch(dbm)4 (CH3O)(CH3OH)]·0.5CH3OH·0.5H2O (2), and Dy4bmzch(btfa)10 (3), where tmhd = 2,2,6,6-tetramethyl-3,5-heptanedionate, dbm = dibenzoylmethane, btfa = benzoyltrifluoroacetone, and bmzch = (Z)-N-[(E)-pyrimidin-2-ylmethylene]pyrimidine-2-carbohydrazonate, were structurally and magnetically characterized. More strikingly, although the nitrogen-enriched bridged ligand 3,6-di(pyrimidin-2-yl)-1,2,4,5-tetrazine (bmtz) was initially adopted, the structures of the complexes obtained indicated that bmtz underwent unprecedented asymmetric ring opening and generated a new ligand bmzch. Combined with different β-diketonates, di- and tetranuclear dysprosium complexes were constructed in which the structural patterns are very sensitive to the selected β-diketonates. In view of this, the bilateral and unilateral dinuclear Dy2 complexes 1 and 2 and tetranuclear Dy4 complex 3 were obtained by choosing different β-diketonates. Magnetic test results reveal that both complexes 1 and 3 showcase typical slow magnetic relaxation behavior without an external direct-current field and the effective energy barrier of the latter is almost twice that of the former, while complex 2 only displays in-field single-molecule-magnetic behavior. Also of note is that these are the first tetrazine-type dysprosium-based single-molecule-magnets undergoing in situ asymmetric ring-opening reaction of this ligand that are formed.

G-type Halohydrin Dehalogenases Catalyze Ring Opening Reactions of Cyclic Epoxides with Diverse Anionic Nucleophiles.

Halohydrin dehalogenases are promiscuous biocatalysts, which enable asymmetric ring opening reactions of epoxides with various anionic nucleophiles. However, despite the increasing interest in such asymmetric transformations, the substrate scope of G-type halohydrin dehalogenases toward cyclic epoxides has remained largely unexplored, even though this subfamily is the only one known to display activity with these sterically demanding substrates. Herein, we report on the exploration of the substrate scope of the two G-type halohydrin dehalogenases HheG and HheG2 and a newly identified, more thermostable member of the family, HheG3, with a variety of sterically demanding cyclic epoxides and anionic nucleophiles. This work shows that, in addition to azide and cyanide, these enzymes facilitate ring-opening reactions with cyanate, thiocyanate, formate, and nitrite, significantly expanding the known repertoire of accessible transformations.

Transition Metal-Catalyzed Biaryl Atropisomer Synthesis via a Torsional Strain Promoted Ring-Opening Reaction.

Arising from the restricted rotation of a single bond caused by steric or electronic effects, atropisomerism is one of the few fundamental categories for molecules to manifest their three-dimensional characters into which axially chiral biaryl compounds fall. Despite the widespread occurrence of axially chiral skeletons in natural products, bioactive molecules, and chiral ligands/organocatalysts, catalytic asymmetric methods for the synthesis of these structures still lag behind demand. Major challenges for the preparation of these chiral biaryls include accessing highly sterically hindered variants while controlling the stereoselectivity. A couple of useful strategies have emerged for the direct asymmetric synthesis of these molecules in the last two decades.Recently, we have engaged in catalytic asymmetric synthesis of biaryl atropisomers via transition metal catalysis, including asymmetric ring-openings of dibenzo cyclic compounds. During these studies, we serendipitously discovered that the two substituents adjacent to the axis cause these dibenzo cyclic molecules to be distorted to minimize steric repulsion. The distorted compounds display higher reactivity in the ring-opening reactions than the non-distorted molecules. In other words, torsional strain can promote a ring-opening reaction. On the basis of this concept, we have successfully realized the catalytic asymmetric ring-opening reaction of cyclic diaryliodoniums, dibenzo silanes, and 9H-fluoren-9-ols, which delivered several differently substituted ortho tetra-substituted biaryl atropisomers in high enantioselectivity. The torsional strain not only activates the substrates toward ring-opening under mild conditions but also changes the chemoselectivity of bond-breaking events. In the palladium-catalyzed carboxylation of S-aryl dibenzothiophenium, the torsional strain inversed the bond selectivity from exocyclic C-S bond cleavage to the ring-opening reaction.In this Account, we summarize our studies on copper-, rhodium-, or palladium-catalyzed asymmetric ring-opening reactions of dibenzo cyclic compounds as a useful collection of methods for the straightforward preparation of ortho tetra-substituted biaryl atropisomers with high enantiopurity on the basis of the above-mentioned torsional strain-promoted ring-opening coupling strategy. In the last part, the torsional strain energies are also discussed with the aid of density functional theory (DFT) calculations.

Copper-Catalyzed Asymmetric Ring-Opening Reaction of Cyclic Diaryliodonium Salts with Imides.

An efficient copper-catalyzed asymmetric ring-opening reaction of diaryliodonium salts with imides has been developed, affording a wide range of axially chiral 2-imidobiaryl compounds with excellent enantioselectivities and better convertibility. The potential utility of the current method has been supported by the synthesis of two known chiral ligands with better efficiency, which would be of great significance to the development of other catalytic asymmetric reactions.

Chiral Bicyclic NHC/Rh Complexes and Their Application to Catalytic Asymmetric Ring-Opening Reaction of Oxabenzonorbornadienes with Amines.

A rhodium complex bearing a chiral bicyclic NHC ligand, [RhCl(3az)(cod)] 4az, was synthesized and fully characterized by X-ray diffraction analysis, high-resolution mass spectrometry, and multinuclear NMR spectroscopy. The electronic and steric properties of NHC ligand 3az were evaluated by IR measurement and X-ray diffraction analysis of dicarbonyl complex [RhCl(3az)(CO)2] 5az, which was prepared by replacing the COD ligand of 4az with CO. The potential of novel complex 4az as a chiral catalyst was investigated in the Rh-catalyzed asymmetric ring-opening reaction of oxabenzonorbornadienes with amines, and the corresponding products were afforded in good yields with good enantioselectivities (up to 81% ee).

Progress in Transition Metal-Catalyzed Asymmetric Ring-Opening Reactions of Epoxides and Aziridines

Progress in Transition Metal-Catalyzed Asymmetric Ring-Opening Reactions of Epoxides and Aziridines

Enantioselective Thiolysis and Aminolysis of Cyclic Anhydrides Using a Chiral Diamine-Derived Thiourea Catalyst.

Catalytic desymmetrization of cyclic anhydrides has been widely investigated in the field of organocatalysis. Using this approach, many stereocenters can be established in a single, symmetry-breaking transformation. Herein, a thiourea organocatalyst was prepared in a single step from a chiral diamine, (R,R)-1,2-diphenylethylenediamine, and used for the desymmetrization of various cyclic anhydrides through double hydrogen-bonding activation. The asymmetric ring-opening reaction of the cyclic anhydride proceeded via the enantioselective addition reaction catalyzed by diamine thiourea. Thiolysis afforded the desired products in the yields of 86–98% and enantioselectivities of 60–94%, while aminolysis afforded the yields of 90–94% and enantioselectivities of 90–95%.

The Mechanism and Origin of Enantioselectivity in the Rhodium-Catalyzed Asymmetric Ring-Opening Reactions of Oxabicyclic Alkenes with Organoboronic Acids: A DFT Investigation

The mechanism and origins of enantio- and stereoselectivity in the asymmetric ring-opening (ARO) reactions of oxabicyclic alkenes with organoboronic acids catalyzed by rhodium/Josiphos has been examined at the B3LYP/defTZVP level of theory. The mechanism consists of four steps including transmetalation, carborhodation, β-oxygen elimination, and hydrolysis. Energetic discrimination in the chirality-imparting step arises from attractive C–H−π interactions between the transmetalated aryl group and the Josiphos ligand, as well as steric clashes between the Josiphos ligand and the oxabicyclic alkene. Computational results indicate that the rate-determining step is involved in the hydrolysis of the rhodium(I) alkoxide from the ring-opened intermediate. In the overall catalytic cycle, the greatest free energy barrier is 23.4 kcal/mol, which supports that the Rh-catalyzed ARO reactions take place at mild reaction conditions, which is consistent with experimental observations.

Catalytic Asymmetric Synthesis of Atropisomeric Nitrones: Versatile Intermediate for Axially Chiral Biaryls.

A Cu-catalyzed asymmetric ring-opening reaction of five-membered diaryliodonium salts and oximes is introduced. The reactions undergo selective N-arylation of oximes and provide an efficient protocol for the synthesis of atropisomeric nitrones. The optically active nitrones, serving as versatile intermediates, were converted to diversely functionalized axially chiral aniline derivatives and N-heterocycles.

Catalytic asymmetric C\u2013Si bond activation via torsional strain-promoted Rh-catalyzed aryl-Narasaka acylation

Atropisomers are important organic frameworks in bioactive natural products, drugs as well as chiral catalysts. Meanwhile, silanols display unique properties compared to their alcohol analogs, however, the catalytic synthesis of atropisomers bearing silanol groups is challenging. Here, we show a rhodium-catalyzed torsional strain-promoted asymmetric ring-opening reaction for the synthesis of α-silyl biaryl atropisomers. The reaction features a dynamic kinetic resolution of C(Ar)-Si bond cleavage, whose stereochemistry was controlled by a phosphoramidite ligand derived from (S)-3-methyl-1-((2,4,6-triisopropylphenyl)sulfonyl)piperazine. This work is a demonstration of an aryl-Narasaka acylation, where the C(Ar)-Si bond cleavage is promoted by the torsional strain of α, α’-disubstituted silafluorene.

Front Cover: The Binomial Copper‐Catalysis and Asymmetric Ring Opening of Strained Heterocycles: Past and Future Challenges (Eur. J. Org. Chem. 18/2020)

The Front Cover shows how chiral copper catalysts promote in a unique way the asymmetric ring-opening reactions of strained heterocycles. The coordination of the copper catalyst with the unsaturation adjacent to the heteroatom serving as leaving group triggers a variety of ring openings by changing the nucleophile bound to copper. A variety of chiral non-racemic building blocks can be efficiently obtained with regio- and stereoselectivities that are complimentary to the selectivities attainable by other metal catalysts. More information can be found in the Minireview by M. Pineschi.

Feedback Inhibition in Chemical Catalysis Leads the Dynamic Kinetic to Kinetic Resolution in C3-Indolylation of Spiro-epoxyoxindoles.

The first feedback inhibition, similar to enzyme catalysis, in the Co(III)salen-catalyzed asymmetric ring-opening reaction of N-free spiro-epoxyoxyindole has been discovered, which leads dynamic kinetic to kinetic resolution. This is the first report of the enantioselective construction of all carbon quaternary center from any epoxide employing metal-salen catalyst until date. This protocol provides an easy access of 3-(3- indolyl)oxindole methanols, a privileged building block for the synthesis of a large variety of 3,3'-bisindole alkaloids.

Significant improvement of the enantioselectivity of a halohydrin dehalogenase for asymmetric epoxide ring opening reactions by protein engineering.

Halohydrin dehalogenases (HHDHs) have attracted much attention due to their ability to synthesize enantiomerically enriched epoxides and β-haloalcohols. However, most of the HHDHs exhibit low enantioselectivity. Here, a HHDH from the alphaproteobacteria isolate 46_93_T64 (AbHHDH), which shows only poor enantioselectivity in the catalytic resolution of rac-PGE (E = 9.9), has been subjected to protein engineering to enhance its enantioselectivity. Eight mutants (R89K, R89Y, V137I, P178A, N179Q, N179L, F187L, F187A) showed better enantioselectivity than the wild type. The best single mutant N179L (E = 93.0) showed a remarkable 9.4-fold increase in the enantioselectivity. Then, the single mutations were combined to produce the double, triple, quadruple, and quintuple mutants. Among the combinational mutants, the best variant (R89Y/N179L) showed an increased E value of up to 48. The E values of the variants N179L and R89Y/N179L for other epoxides 2-7 were 12.2 to > 200, which showed great improvement compared to 1.2 to 10.5 for the wild type. Using the variant N179L, enantiopure (R)-PGE with > 99% ee could be readily prepared, affording a high yield and a high concentration.