Chiral Bifunctional Catalysts Research Articles

Highly Enantioselective Construction of Chiral Eight-Membered Cyclic Ethers through Tandem Cyclization of Ynones and Dicarbonyl Compounds.

The enantioselective synthesis of eight-membered cyclic ether has always been a challenge in organic synthesis. Herein, we reported a highly enantioselective tandem cyclization reaction of alkyne ketone and dioxypyridines mediated by chiral bifunctional catalysts. This reaction generates two adjacent stereocenters using an atomeconomic manner, providing a simple and effective method for the one-step synthesis of highly enantioselective eight-membered cyclic ethers.

Asymmetric Photoinduced Excited-State Nazarov Reaction.

We report herein the first asymmetric photoinduced excited-state Nazarov reaction of non-aromatic dicyclic divinyl ketones by using hydrogen-bonding catalysis. The enantioselectivity of photoinduced electrocyclization is highly dependent on the structural features of the substrate and its interaction with chiral catalysts. For the simple dicyclic divinyl ketone substrates, there is no discernible selectivity of the hydrogen bond coordination between the thiourea and carbonyl groups of the substrates in the ground state. However, we found that the direction of the electrocyclization was well controlled in each coordination model and the N,N'-dimethylamine motif acts as a base in the regioselective deprotonation process, which leads to the formation of two stereoisomers with high enantioselectivity. Photolysis of dicyclic divinyl ketones bearing a 1,3-dioxolane motif in the presence of bifunctional hybrid peptide-thiourea chiral catalysts gave the tricyclic cis-hydrofluorenones with good enantioselectivity. Mechanistic and DFT studies suggested that the amide and thiourea groups in the bifunctional chiral catalysts play a key role as H-bond donors, which coordinate with both the carbonyl group and the 1,3-dioxolane motif to provide a more favorable chiral species, and control the direction of the electrocyclization. Due to the presence of the rigid 1,3-dioxolane ring, the deprotonation/protonation process occurs regiospecifically with high driving force. This photo-electrocyclization is mild (room temperature and neutral solution), which results a broad reaction scope and functional group tolerance and demonstrates its synthetic potential in organic synthesis.

Cross-assembly confined bifunctional catalysis via non-covalent interactions for asymmetric halogenation

•Assembling bifunctional catalysts via non-covalent interactions •Enantioselectivity is largely optimized by changing the achiral catalytic species •Asymmetric halogenation to give various valuable building blocks •Access to the advanced intermediates of drugs and natural products Bifunctional catalysis plays a key role in the synthesis of useful compounds. By offering a sterically confined environment, chiral bifunctional catalysts can achieve highly enantioselective reactions. However, introducing suitable substituents to create a confined microenvironment for asymmetric catalysis on many occasions involves tedious procedures, leading to inefficient reaction optimization. Herein, we report a proof-of-concept study on formulating confined bifunctional catalysts by linking catalytic species via non-covalent interactions (NCIs). Chiral phosphate and achiral cyclopropenium cations cross-assembled to give a confined bifunctional system for asymmetric bromo-semipinacol rearrangement. By changing the achiral catalyst to aminopyridine, the system can be applied to asymmetric bromocycloetherification. These reactions are largely optimized by simply changing the achiral catalyst. A computational study revealed that the strength of the NCI donor is crucial in creating tighter catalytic pockets to amplify the effect of enantiofacial discrimination of substrates. Bifunctional catalysis plays a key role in the synthesis of useful compounds. By offering a sterically confined environment, chiral bifunctional catalysts can achieve highly enantioselective reactions. However, introducing suitable substituents to create a confined microenvironment for asymmetric catalysis on many occasions involves tedious procedures, leading to inefficient reaction optimization. Herein, we report a proof-of-concept study on formulating confined bifunctional catalysts by linking catalytic species via non-covalent interactions (NCIs). Chiral phosphate and achiral cyclopropenium cations cross-assembled to give a confined bifunctional system for asymmetric bromo-semipinacol rearrangement. By changing the achiral catalyst to aminopyridine, the system can be applied to asymmetric bromocycloetherification. These reactions are largely optimized by simply changing the achiral catalyst. A computational study revealed that the strength of the NCI donor is crucial in creating tighter catalytic pockets to amplify the effect of enantiofacial discrimination of substrates.

Synthesis and a Catalytic Study of Diastereomeric Cationic Chiral-at-Cobalt Complexes Based on (R,R)-1,2-Diphenylethylenediamine.

Here we report the first synthesis of two diastereomeric cationic octahedral Co(III) complexes based on commercially available (R,R)-1,2-diphenylethylenediamine and salicylaldehyde. Both diastereoisomers with opposite chiralities at the metal center (Λ and Δ configurations) were prepared. The new Co(III) complexes possessed both acidic hydrogen-bond donating (HBD) NH moieties and nucleophilic counteranions and operate as bifunctional chiral catalysts for the challenging kinetic resolution of terminal and disubstituted epoxides by the reaction with CO2 under mild conditions. The highest selectivity factor (s) of 2.8 for the trans-chalcone epoxide was achieved at low catalyst loading (2 mol %) in chlorobenzene, which is the best achieved result currently for this type of substrate.

Access to Chiral Polycyclic 1,4-Dihydropyridines via Organocatalytic Formal [3 + 3] Annulation of 2-(1-Alkynyl)-2-alken-1-ones with 3-Aminobenzofurans.

A rational designed tandem reaction of 2-(1-alkynyl)-2-alken-1-ones with 3-aminobenzofurans enabled by a chiral bifunctional catalyst is described, affording biologically significant polycyclic 1,4-dihydropyridines in moderate to good yields (43-82%) with good to excellent enantioselectivities (83-99%). This formal [3 + 3] annulation reaction reveals good practicality when conducted on a gram scale, and the cycloadduct has the capability for further elaborations.

Expanding the Family of Octahedral Chiral-at-Metal Cobalt(III) Catalysts by Introducing Tertiary Amine Moiety into the Ligand

Chiral metal-templated complexes are attractive catalysts for organic synthetic transformations. Herein, we introduce a novel chiral cobalt(III)-templated complex based on chiral trans-3,4-diamino-1-benzylpyrrolidine and 3,5-di-tert-butyl-salicylaldehyde which features both hydrogen bond donor and Brønsted base functionalities. The obtained complexes were fully characterized by 1H, 13C NMR, IR-, UV-vis, CD-spectroscopy and by a single X-ray diffraction analysis. It was shown that chlorine anion is connected with amino groups of the complex via a hydrogen bonding. DFT calculations of charges and molecular electrostatic potential of the cobalt(III) complex showed that the basicity of the complex is certainly diminished as compared with the routine tertiary amines but the acidity of the conjugated acid of the complex should be increased. Thus, the catalytic potential of the complex may be much greater as a chiral acid than a chiral base. We believe that this work opens a new way in chiral bifunctional catalyst design.

Chiral Proline-Decorated Bifunctional Pd@NH2-UiO-66 Catalysts for Efficient Sequential Suzuki Coupling/Asymmetric Aldol Reactions

The design and development of site-isolating and multifunctional catalysts for multistep sequential reactions at the molecular level is a significant challenge. Herein, we first report bifunctional metal NPs@chiral MOFs catalysts for asymmetric sequential reactions. Pd nanoparticles and chiral proline were successfully added to NH2-UiO-66 to construct two chiral bifunctional catalysts, in which active Pd nanoparticles were encapsulated into the frameworks via the "bottle-around-ship" method, and chiral proline was introduced into NH2-UiO-66 by coordination to zirconium nodes and postsynthetic modification (PSM) of the organic linkers. The chiral proline-decorated bifunctional Pd@NH2-UiO-66 catalysts were applied to sequential Suzuki coupling/asymmetric aldol reactions with excellent coupling performance (yields up to 99.9%) and good enantioselectivities (eeanti values up to 97%). The heterogeneous catalyst by coordination of proline can be reused, and the reaction activity was not significantly reduced after four cycles.

Chiral Bifunctional Phase-Transfer Catalysts for Asymmetric Aminations

Key words phase-transfer catalysis - asymmetric catalysis - amination - chiral bifunctional catalyst

Dynamics and Bifunctional Substrate Activation by an Arginine Drive Catalysis in Plant Chalcone Isomerases

In organic synthesis, bifunctional chiral catalysts are an increasingly popular tool to position and stabilize a nucleophile and activate an electrophile for asymmetric addition reactions. It turns out that organic chemists were not first to employ this synthetic strategy, plants have been using an similar method for quite some time (~500 million years). By using techniques in structural biology, enzymology and NMR, we characterize a novel mechanism by which the enzyme chalcone isomerase (CHI) catalyzes oxa‐Michael cyclizations of 2′‐hydroxychalcones into flavanones; a key early step in the synthesis of flavonoid compounds in plants. The enzyme enhances these reaction rates by utilizing the guanidine of a conserved arginine in a bifunctional capacity to position the nucleophilic phenoxide and activate the electrophilic enone of the chalcone substrate. In addition, we reveal the structural and biochemical basis of an evolutionary neofunctionalization event, in which a divergent clade of CHIs unique to Legumes expanded it's substrate repertoire to include 6′‐deoxychalcone substrates. Together these results reveal the details of key evolutionary mechanistic innovations unique to this class of plant enzymes.Support or Funding InformationHHMIThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Synthesis of Cinchona Alkaloid Sulfonamide Polymers as Enantioselective Catalysts for the Michael Addition Reaction of β-Ketoester and Nitrostyrene

Mizoroki–Heck (MH) polymerization of cinchonidine-based sulfonamide dimers produces polymers containing a chiral sulfonamide moiety in each repeat unit. Quinidine sulfonamides are known to have excellent catalytic activity in the asymmetric Michael addition reaction of β-ketoester and nitrostyrene. We found that cinchonidine sulfonamides used as bifunctional chiral catalysts showed even higher stereoselectivity in the same reaction. The polymers synthesized by MH polymerization also showed high levels of diastereo- and enantioselectivity (up to 99% enantiomeric excess) in the reaction. Owing to the insolubility of the polymeric catalysts, they were separated easily from the reaction mixture and reused several times without any loss of catalytic activity.

ChemInform Abstract: Enantio‐ and Diastereoselective Synthesis of exo‐Peroxyacetals: An Organocatalyzed Peroxyhemiacetalization/Oxa‐Michael Addition Cascade.

AbstractAn unprecedented peroxyhemiacetalization/oxa‐Michael addition cascade of ortho‐formyl homochalcones is conducted using cinchona‐alkaloid‐based chiral bifunctional catalysts to provide cis‐configured exo‐peroxyacetals, a new class of organic peroxide.

From meso-Lactide to Isotactic Polylactide: Epimerization by B/N Lewis Pairs and Kinetic Resolution by Organic Catalysts.

B/N Lewis pairs have been discovered to catalyze rapid epimerization of meso-lactide (LA) or LA diastereomers quantitatively into rac-LA. The obtained rac-LA is kinetically polymerized into poly(L-lactide) and optically resolved D-LA, with a high stereoselectivity k(L)/k(D) of 53 and an ee of 91% at 50.6% monomer conversion, by newly designed bifunctional chiral catalyst 4 that incorporates three key elements (β-isocupreidine core, thiourea functionality, and chiral BINAM) into a single organic molecule. The epimerization and enantioselective polymerization can be coupled into a one-pot process for transforming meso-LA directly into poly(L-lactide) and D-LA.

ChemInform Abstract: Stereoselective Reaction of 2‐Carboxythioesters‐1,3‐dithiane with Nitroalkenes: An Organocatalytic Strategy for the Asymmetric Addition of a Glyoxylate Anion Equivalent.

AbstractThe enantioselective organocatalyzed conjugate addition of a newly activated thioester acting as an acyl anion mimic is presented using a chiral bifunctional catalyst to control the stereochemistry.

Asymmetric Base‐Free Michael Addition at Room Temperature with Nickel‐Based Bifunctional Amido‐Functionalized N‐Heterocyclic Carbene Catalysts

AbstractA series of nickel‐based chiral bifunctional catalysts (1d–3d) with N‐heterocyclic carbene (NHC) ligands derived from (1R)‐(–)‐menthol, (1S)‐(–)pinene, and (1R)‐(+)‐camphor have been successfully designed for asymmetric Michael addition reactions under base‐free conditions. The NHC complexes, namely, [1‐R‐3‐{N‐(phenylacetamido)}imidazol‐2‐ylidene]2Ni [R = (1S)‐menthyl (1d), (1S)‐pinane (2d), and (1R)‐isobornyl (3d)], bearing chiral ancillaries on the amido‐functionalized side arms of the NHC ligands, performed the bifunctional catalysis of the asymmetric base‐free Michael addition reaction of the α‐methyl cyano ester substrates ethyl 2‐cyanopropanoate (4), isopropyl 2‐cyanopropanoate (5), and tert‐butyl 2‐cyanopropanoate (6) with the activated olefinic substrates methyl vinyl ketone (7) and acrylonitrile (8) in 63–98 % yields with enantiomeric excess (ee) values of 2–75 % at room temperature in 8 h. More interestingly, only the longest of the three catalysts, the menthol derivative 1d, showed significant chiral induction of up to 75 % ee; this has been attributed to the reduction of the steric influence owing to the relatively distant dispositions of the chiral ancillaries from the catalytically active metal center that arise as a consequence of the cis geometries of 1d–3d.

Continuous-Flow Stereoselective Synthesis in Microreactors: Nucleophilic Additions to Nitrostyrenes Organocatalyzed by a Chiral Bifunctional Catalyst

Metal-free stereoselective additions of activated nucleophiles to β-nitrostyrenes were investigated under continuous-flow conditions in microreactors, in the presence of a chiral bifunctional catalyst. Optimization of the experimental setup gave excellent enantioselectivities (up to 85% e.e.) and higher productivities if compared to the flask syntheses. The potential of this flow chemistry approach was demonstrated by the successful synthesis of an advanced intermediate for the preparation of the GABAB receptor agonist Baclofen.

ChemInform Abstract: A Heterogeneous Layered Bifunctional Catalyst for the Integration of Aerobic Oxidation and Asymmetric C—C Bond Formation.

AbstractA novel layered heterogeneous bifunctional chiral catalyst consisting of bimetallic alloy nanoparticles and a chiral polymer‐supported Jorgensen—Hayashi‐type organocatalyst (POC) is designed, synthesized and successfully applied to the sequential aerobic oxidation—asymmetric Michael reaction of primary allylic alcohols and dibenzyl malonate.

Mechanism and Selectivity of Bioinspired Cinchona Alkaloid Derivatives Catalyzed Asymmetric Olefin Isomerization: A Computational Study

Asymmetric olefin isomerization of β,γ- to α,β-unsaturated butenolides catalyzed by novel cinchona alkaloid derivatives was investigated in-depth using density functional theory (M05-2x and B2PLYP-D). Three possible mechanistic scenarios, differing in the binding modes of the substrate to the catalyst, have been evaluated. Computations revealed that both the protonated quinuclidine and the 6'-OH of catalysts may act as the proton donor in the stereocontrolling step. Variation of the catalytic activity and enantioselectivity by tuning the electronic effect of catalyst was well reproduced computationally. It suggested that, for certain acid-base bifunctional chiral catalysts, the acid-base active sites of catalysts may interconvert and give new catalyst varieties of higher activity and selectivity. In addition, the noncovalent interactions in the stereocontrolling transition-state structures were identified, and their strength was quantitatively estimated. The weak nonconventional C-H···O hydrogen-bonding interactions were found to be crucial to inducing the enantioselectivity of the cinchona alkaloid derivatives catalyzed asymmetric olefin isomerization. The computational results provided further theoretical evidence that the rate-limiting step of this bioinspired organocatalytic olefin isomerization is inconsistent with that of the enzyme catalyzed olefin isomerization.

A family of novel bifunctional organocatalysts: Highly enantioselective alcoholysis of meso cyclic anhydrides and its application for synthesis of the key intermediate of P2X7 receptor antagonists

Abstract A family of novel squaramides/sulfamides based on 1,2-alkamine was developed as chiral bifunctional catalysts to promote the asymmetric alcoholysis of meso cyclic anhydrides. The hemiesters were obtained in high yield with up to 93% ee. The usefulness of this methodology was demonstrated in the asymmetric synthesis of the key intermediate of P2X7 receptor antagonists.

A heterogeneous layered bifunctional catalyst for the integration of aerobic oxidation and asymmetric C–C bond formation

The design and synthesis of a heterogeneous bifunctional chiral catalyst for the sequential aerobic oxidation-asymmetric Michael reactions between primary allylic alcohols and dibenzyl malonate are described. Interestingly, we found that layering bimetallic nanoparticles over the organocatalyst, within the chiral composite material, is crucial for catalytic activity.

In Situ Preparation of Chiral Bifunctional Catalysts and Their Application to Asymmetric Michael Addition Reactions

Combine and conquer! The asymmetric conjugate addition of α-chloro aldehydes to vinyl sulfones catalyzed by chiral bifunctional catalysts is described. Two acid additives were mixed with a trans-diamine-based organocatalyst precursor to create a highly efficient bifunctional catalyst in situ. Each additive either activates the Michael acceptor or modifies the chiral environment, which gives high yields and enantioselectivity. Tf=trifluoromethansulfonate.