Chiral Adducts Research Articles

Desymmetric homologating annulation to access chiral pentafulvenes and their application in bioimaging

The architectural design of polycyclic/multisubstituted pentafulvenes has demonstrated great potential for the development of electrochromic materials and biologically active motifs. Unfortunately, the enantioselective construction of such distinctive cores with all carbon quaternary chiral centers has remained untouched to date. Herein, we disclose an enantioselective homologating annulation of cyclopent-4-ene-dione with 3-cyano-4-methylcoumarins through L-tert-leucine derived thiourea catalysis, affording a wide range of enantioenriched polycyclic multisubstituted embedded aminopentafulvenes with excellent stereocontrol (up to 99:1 er) and chemical yields up to 87%. A detailed photophysical and cytotoxicity analysis of racemic and chiral homologated adducts unveils the exceptional behavior of chiral adducts over their racemic analogs, highlighting the importance of stereoselectivity of the developed scaffolds. A cellular uptake experiment in a mammalian fibroblast cell line confirmed the potential of developed polycyclic aminopentafulvene cores as a highly promising labeling dye that can be utilized for bioimaging without any adverse effects.

Palladium-Catalyzed Asymmetric 1,4-Addition of Diarylphosphines to α,β-Unsaturated Sulfonyl Fluorides

AbstractA Pd-catalyzed asymmetric phosphination of α,β-unsaturated sulfonyl fluorides was developed, and a series of tertiary phosphorus compounds were obtained in excellent yields and enantioselectivities (up to 99% ee). The chiral adduct can be further converted into chiral phosphine sulfonic acid as the ligand for the arene Ru metal complex.

Iridium-catalyzed asymmetric addition of imides to alkenes.

Enantioselective addition of an imide N-H bond to alkenes was realized by use of a cationic iridium catalyst. Bulky diphosphine ligands such as DTBM-segphos, DTBM-MeO-biphep, and DTBM-binap were indispensable for the reaction. A variety of styrene derivatives, allylsilanes, and norbornene were good substrates to give the corresponding chiral adducts with high enantioselectivity.

Multiple Responsive CPL Switches in an Enantiomeric Pair of Perovskite Confined in Lanthanide MOFs.

Circularly polarized luminescence (CPL) switches have attracted widespread attention due to their potential applications in advanced information technologies. However, the design and fabrication of solid-state multiple-responsive CPL switches remain challenging. Here, through self-assembly of chiral metal-organic frameworks (MOFs) and perovskite nanocrystals (NCs), a pair of crystalline enantiomeric (P)-(+)/(M)-(-)-EuMOF⊃MAPbX3 (MA = CH3 NH3 + , X = Cl- , Br- , I- ) adducts is prepared, where the achiral MAPbBr3 perovskite NCs embedded into chiral MOFs inherit the chirality of host MOFs by host-guest EuBr and PbO coordination bonds, which is demonstrated by synchrotron-radiation-based X-ray absorption spectroscopy. The chiral adducts show enhanced photoluminescence quantum yield (PLQY), good thermal stability of CPL in air, and photoswitchable CPL properties upon altering different UV irradiation. Based on two chiral emission centers and their different characteristics, reversible CPL switches are realized upon a diversity of external stimuli, for example, chemicals (water /CH3 NH3 Br solution) or temperatures (room temperature/high temperature). Benefiting from the extraordinary stimuli-responsive and highly reversible switchable CPL, multiple information encryptions and decryptions integrated with CPL, together with a chiroptical logic gate are successfully designed. This work opens a new avenue to generally fabricate solid-state CPL composite materials and develops new applications based on switchable CPL.

Efficacy of Selenourea Organocatalysts in Asymmetric Michael Reactions under Standard and Solvent-Free Conditions.

By varying the steric and electronic surroundings of the hydrogen-bonding motif, the novel chiral Cinchona-alkaloid based selenoureas were developed. Acting as bifunctional catalysts, they were applied in the Michael reactions of dithiomalonate and nitrostyrene providing chiral adducts with up to 96% ee. The asymmetric Michael–-hemiacetalization reaction of benzylidene pyruvate and dimedone, performed with the assistance of 5 mol% of selenoureas, furnished the product with up to 93% ee and excellent yields. The effectiveness of the new hydrogen-bond donors was also proved in solvent-free reactions under ball mill conditions, supporting the sustainability of the devised catalytic protocol.

Conformational Landscape, Chirality Recognition and Chiral Analyses: Rotational Spectroscopy of Tetrahydro-2-Furoic Acid⋅⋅⋅Propylene Oxide Conformers.

A chiral adduct formed between a chiral carboxylic acid, tetrahydro-2-furoic acid (THFA), and a chiral ester, propylene oxide (PO), was investigated using rotational spectroscopy and DFT calculations. Isolated THFA exists dominantly as three different conformers: I, II, and III in a jet, with I and II taking on the trans-COOH configuration and III having the cis-COOH configuration. We utilized CREST, a conformational ensemble space exploration tool, to identify the possible conformations of the binary adduct, THFA⋅⋅⋅PO. Subsequent DFT geometry optimizations predicted about two hundred homochiral and heterochiral binary structures with 28 low energy structures within an energy window of 15 kJ mol-1 . A rich broadband rotational spectrum was obtained with a mixture of trace amounts of THFA+PO in neon in a supersonic jet expansion. Six THFA⋅⋅⋅PO conformers were identified experimentally. Kinetically favored binary products which contain trans-COOH I dominate among the observed conformers, while thermodynamically more stable adducts were also detected. Detailed analyses of the structures of the observed conformers show interesting chirality-controlled structural preferences. Such non-covalently bound chiral contact pairs are the foundation of chiral-tag rotational spectroscopy, an exciting new analytical application of rotational spectroscopy for determination of enantiomeric excess. Enantiomeric excess analyses were performed and the results are discussed.

From Antiaromatic Norcorrolatonickel(II) to Aromatic and Nonaromatic Zwitterions: Innocent Ligands with Unbalanced Charge of the Core.

A three-component reaction of antiaromatic meso-mesityl-3-nitronorcorrolatonickel(II) 1-NO2 with dialkyl acetylenedicarboxylate and PBu3 yields aromatic zwitterionic corrole nickel(II) complexes 3-R with one of the meso-substituents comprising a positively charged tributyl phosphonium group and negatively charged coordination core. Reaction of 1-NO2 with PBu3 alone resulted in a nonaromatic chiral adduct 5 of a zwitterionic phlorine character with a −PBu3+ group at a pyrrole β-position.

Chitosan-supported cinchona urea: Sustainable organocatalyst for asymmetric Michael reaction

A novel chitosan-supported cinchona urea heterogeneous catalyst was developed for asymmetric reaction. The catalytic activity of the chitosan-supported organocatalyst was examined in the asymmetric Michael addition reaction to give chiral adducts in good yields with excellent enantioselectivities (up to 99% ee). The insolubility of the chitosan-supported cinchona urea catalyst facilitated catalyst recovery. The catalyst was easily separated and reused without any loss in catalytic activity.

Cinchona Squaramide‐Catalyzed Intermolecular Desymmetrization of 1,3‐Diketones Leading to Chiral 1,4‐Dihydropyridines

AbstractAddition of prochiral cyclic 1,3‐diketones to Michael acceptors applying bifunctional Cinchona‐derived squaramides resulted in chiral adducts with stereoselectivities of up to 99% ee and allowed for desymmetrization of the nucleophile. These labile hemiacetal intermediates were transformed to new 1,4‐dihydropyridines with high diastereoselectivities and no erosion of optical purity. Their further oxidation to pyridine followed by Fisher indolization provided chiral pyridine‐indoles.magnified image

ADMET Polymerization of Dimeric Cinchona Squaramides for the Preparation of a Highly Enantioselective Polymeric Organocatalyst

Under the acyclic diene metathesis (ADMET) reaction condition, the C3-vinyl groups of cinchona alkaloids readily react with each other to form a C-C bond. A novel type of cinchona alkaloid polymers was synthesized from dimeric cinchona squaramides using the Hoveyda-Grubbs’ second-generation catalysts (HG2) by means of ADMET reaction. The chiral polymers, containing cinchona squaramide moieties in their main chains, were subsequently employed as catalysts for the enantioselective Michael reaction to give the corresponding chiral adducts in high yields with excellent enantioselectivity and diastereoselectivity. Both enantiomers from the asymmetric Michael reaction were distinctively prepared while using the polymeric catalysts, possessing pseudoenantiomeric structures. The catalysts were readily recovered from the reaction mixture and recycled several times due to the insolubility of the cinchona-based squaramide polymers.

Asymmetric Michael Reaction of Aldehydes and α‐Cyano α,β‐Unsaturated Esters Catalyzed by Diphenylprolinol Silyl Ether; a Facile Asymmetric Route to 3,4,5‐Trisubstituted Piperidines

AbstractA highly enantioselective diphenylprolinol silyl ether‐mediated asymmetric Michael reaction of a variety of aldehydes and β‐substituted α‐cyano α,β‐unsaturated esters was developed. The organocatalytic conjugate addition provided synthetically useful chiral adducts possessing three consecutive stereocenters and suitably oriented functional handles that were readily transformed via a sequence of reductive‐cyclization and subsequent epimerization to furnish single isomers of 3,4,5‐trisubstituted piperidines with high levels of yield and excellent enantiopurity.

Double Thiol-Chiral Brønsted Base Catalysis: Asymmetric Cross Rauhut-Currier Reaction and Sequential [4 + 2] Annulation for Assembly of Different Activated Olefins.

A double catalytic system combining 2-mercaptobenzoic acid and a chiral phase transfer substance was disclosed for the intermolecular cross Rauhut-Currier reaction of 2-cyclopentenone and isatin-based alkylidene malononitriles. The resulting chiral adducts were sequentially assembled with diverse electron-deficient olefins to furnish highly enantioenriched cyclohexane derivatives (up to 96:4 er, >19:1 dr). A similar catalytic system of 2-mercaptobenzoic acid and quinine was further developed for the reaction of 2-cyclopentenone and α-cyano chalcones (up to 96.5:3.5 er).

Polymer‐Shell‐Encapsulated Magnetite Nanoparticles Bearing Hexamethylenetetramine for Catalysing Aza‐Michael Addition Reactions

Polymer‐encapsulated magnetite nanoparticles bearing Hexamethylenetetramine (Fe3O4@HMTA) have been developed for catalysing the aza‐Michael addition to form β‐amino compounds. The effects of solvent, amount and reuse on catalytic activity of the Fe3O4@HMTA have been studied. The catalytic activity of the Fe3O4@HMTA has not deteriorated during successive recycling. Eight different substrates have been subjected to aza‐Michael additions, and yields of the products in the range of 50–90 % have been observed in the presence of catalyst depending upon the substituent groups in the reactants. The formation of a single chiral adduct by reacting a acrylamide derivative of l‐proline benzyl ester with morpholine seems to suggest that the reaction conditions preclude the racemization of products.

Photo‐Organocatalytic Enantioselective Radical Cascade Reactions of Unactivated Olefins

Radical cascade processes are invaluable for their ability to rapidly construct complex chiral molecules from simple substrates. However, implementing catalytic asymmetric variants is difficult. Reported herein is a visible‐light‐mediated organocatalytic strategy that exploits the excited‐state reactivity of chiral iminium ions to trigger radical cascade reactions with high enantioselectivity. By combining two sequential radical‐based bond‐forming events, the method converts unactivated olefins and α,β‐unsaturated aldehydes into chiral adducts in a single step. The implementation of an asymmetric three‐component radical cascade further demonstrates the complexity‐generating power of this photochemical strategy.

Photo‐Organocatalytic Enantioselective Radical Cascade Reactions of Unactivated Olefins

AbstractRadical cascade processes are invaluable for their ability to rapidly construct complex chiral molecules from simple substrates. However, implementing catalytic asymmetric variants is difficult. Reported herein is a visible‐light‐mediated organocatalytic strategy that exploits the excited‐state reactivity of chiral iminium ions to trigger radical cascade reactions with high enantioselectivity. By combining two sequential radical‐based bond‐forming events, the method converts unactivated olefins and α,β‐unsaturated aldehydes into chiral adducts in a single step. The implementation of an asymmetric three‐component radical cascade further demonstrates the complexity‐generating power of this photochemical strategy.

Asymmetric organocatalytic direct Mannich reaction of acetylacetone and isatin derived ketimines: Low catalyst loading in chiral cinchona-squaramides

A highly enantioselective synthesis of 3-amino-2-oxindoles by direct Mannich reaction between acetylacetone and N-carbamoyl isatin ketimine has been described herein. Corresponding chiral adducts were obtained in high yields (up to 98%) and with excellent enantioselectivities (up to >99% ee) by very low (1 mol%) catalyst loading of 2-adamantyl substituted bifunctional cinchona-squaramide.

Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors.

Enzymes of the ALDH1A subfamily of aldehyde dehydrogenases are crucial in regulating retinoic acid (RA) signaling and have received attention as potential drug targets. ALDH1A2 is the primary RA-synthesizing enzyme in mammalian spermatogenesis and is therefore considered a viable drug target for male contraceptive development. However, only a small number of ALDH1A2 inhibitors have been reported, and information on the structure of ALDH1A2 was limited to the NAD-liganded enzyme void of substrate or inhibitors. Herein, we describe the mechanism of action of structurally unrelated reversible and irreversible inhibitors of human ALDH1A2 using direct binding studies and X-ray crystallography. All inhibitors bind to the active sites of tetrameric ALDH1A2. Compound WIN18,446 covalently reacts with the side chain of the catalytic residue Cys320, resulting in a chiral adduct in ( R) configuration. The covalent adduct directly affects the neighboring NAD molecule, which assumes a contracted conformation suboptimal for the dehydrogenase reaction. The reversible inhibitors interact predominantly through direct hydrogen bonding interactions with residues in the vicinity of Cys320 without affecting NAD. Upon interaction with inhibitors, a large flexible loop assumes regular structure, thereby shielding the active site from solvent. The precise knowledge of the binding modes provides a new framework for the rational design of novel inhibitors of ALDH1A2 with improved potency and selectivity profiles.

Dual-reagent organophosphine catalyzed asymmetric Mannich reactions of isocyanoacetates with N-Boc-aldimines

A combination of an amino-acid derived chiral phosphine catalyst and methyl acrylate has been employed to catalyze the direct Mannich reaction of α-aryl isocyanoacetate and N-Boc-aldimines efficiently. The loading of the catalyst could be as low as 0.5 mol% without compromise on the yield and enantioselectivity and the corresponding chiral adducts were obtained in excellent yields (up to 98%) and good enantioselectivities (up to 95%).

Organocatalytic Enantioselective Decarboxylative Michael Addition of β‐Keto Acids to Dicyanoolefins and Disulfonylolefins

AbstractA convenient organocatalytic enantioselective decarboxylative Michael addition of β‐keto acids to dicyanoolefins and disulfonylolefins is realized. In the presence of saccharide‐derived chiral amino thioureas, the reaction proceeded smoothly to afford a wide range of the Michael adducts in 62–99% yield with 70–94% ee. Moreover, one of the chiral adducts obtained could be readily converted into the monofluorinated product in a total 68% yield over four steps with 85% ee.magnified image

ChemInform Abstract: Enantioselective Copper(II)‐Catalyzed Conjugate Addition of Diethylzinc to β‐Substituted Enones Utilizing BINOL‐Based Phosphoramidite Ligands.

Abstract A family of new chiral phosphoramidite ligands based on 3,3′-disubstituted ( S )-BINOL have been successfully synthesized. The chiral phosphoramidite ligands were subsequently applied to the copper(II)-catalyzed enantioselective addition of diethylzinc to β-substituted enones, giving the desired chiral adducts with enantioselectivities of up to 93% ee and high yields (up to 88%).