Pyrrolidine Fragments Research Articles

Enantioselective Synthesis of the Chiral Pyrrolidine Fragment of Upadacitinib via Chiral Auxiliary Directed Diastereoselective 1,3-Dipolar Cycloaddition

Enantioselective Synthesis of the Chiral Pyrrolidine Fragment of Upadacitinib <i>via</i> Chiral Auxiliary Directed Diastereoselective 1,3-Dipolar Cycloaddition

Active Base Hybrid Organosilica Materials based on Pyrrolidine Builder Units for Fine Chemicals Production

AbstractThe catalytic activity of “pyrrolidine type” fragments included or anchored in the mesoporous silica supports or polymeric frameworks have been fully reported for enantioselective transformation. Nevertheless, low attention was focused on their catalytic abilities to perform base‐catalyzed reaction. Accordingly, hybrid materials including pyrrolidine fragments in the mesoporous silica supports were prepared following different synthesis methods, such as micellar and fluoride sol‐gel routes in absence of structural directing agents. Their great catalytic performance was explored for various base‐catalyzed reactions to the formation of C−C bond through Knoevenagel, Claisen‐Schmidt and Henry condensations under microwave irradiation. The benefits of microwave irradiation combined with suitable catalytic properties of pyrrolidine hybrid materials with strong base sites and high accessibility to active centers, allowed carrying out successfully base‐catalyzed condensation reactions for the production of fine chemicals. Moreover, the hybrid catalyst exhibited high selectivity and good stability over different catalytic cycles contributing to environmental sustainability.

Study of Antioxidant Activity of New Compounds with 1,3-Thiazin-2,6-Dione and Pyrrolidine Fragments

Study of Antioxidant Activity of New Compounds with 1,3-Thiazin-2,6-Dione and Pyrrolidine Fragments

Combination of Pseudo-Natural Product Design and Formal Natural Product Ring Distortion Yields Stereochemically and Biologically Diverse Pseudo-Sesquiterpenoid Alkaloids.

We describe the synthesis and biological evaluation of a new natural product‐inspired compound class obtained by combining the conceptually complementary pseudo‐natural product (pseudo‐NP) design strategy and a formal adaptation of the complexity‐to‐diversity ring distortion approach. Fragment‐sized α‐methylene‐sesquiterpene lactones, whose scaffolds can formally be viewed as related to each other or are obtained by ring distortion, were combined with alkaloid‐derived pyrrolidine fragments by means of highly selective stereocomplementary 1,3‐dipolar cycloaddition reactions. The resulting pseudo‐sesquiterpenoid alkaloids were found to be both chemically and biologically diverse, and their biological performance distinctly depends on both the structure of the sesquiterpene lactone‐derived scaffolds and the stereochemistry of the pyrrolidine fragment. Biological investigation of the compound collection led to the discovery of a novel chemotype inhibiting Hedgehog‐dependent osteoblast differentiation

Combination of Pseudo‐Natural Product Design and Formal Natural Product Ring Distortion Yields Stereochemically and Biologically Diverse Pseudo‐Sesquiterpenoid Alkaloids

AbstractWe describe the synthesis and biological evaluation of a new natural product‐inspired compound class obtained by combining the conceptually complementary pseudo‐natural product (pseudo‐NP) design strategy and a formal adaptation of the complexity‐to‐diversity ring distortion approach. Fragment‐sized α‐methylene‐sesquiterpene lactones, whose scaffolds can formally be viewed as related to each other or are obtained by ring distortion, were combined with alkaloid‐derived pyrrolidine fragments by means of highly selective stereocomplementary 1,3‐dipolar cycloaddition reactions. The resulting pseudo‐sesquiterpenoid alkaloids were found to be both chemically and biologically diverse, and their biological performance distinctly depends on both the structure of the sesquiterpene lactone‐derived scaffolds and the stereochemistry of the pyrrolidine fragment. Biological investigation of the compound collection led to the discovery of a novel chemotype inhibiting Hedgehog‐dependent osteoblast differentiation

Атомная дипольная поляризация в прогнозах химических сдвигов амидных и пирролидиновых протонов

A quantitative relationship has been established between the localization indices of electrons in atomic basins and chemical shifts of protons in amide and pyrrolidine fragments when they are present together in organic molecules. The fragments under consideration are important as key functional groups in the molecules of chiral inducers involved in stereoselective syntheses, in order to obtain drugs based on pyrimidinone heterocyclic systems. Integral properties of electron density, such as the magnitude of intra-atomic dipole polarization and charges of hydrogen atoms, calculated by integration of the electron density over the volumes of atomic basins, correlate with chemical shifts significantly better than the point atomic charges. Our proposed parametric model for the rapid prediction of chemical shifts is based on an equation that includes the electron localization index in the hydrogen atom basin as a factor. The developed approach offers a theoretical model for a rapid quantitative assessment of chemical shifts and makes it possible to formulate the main structural factors that provide correlation between the calculated and experimental chemical shifts of hydrogen atoms involved in intramolecular hydrogen bonds. It has been revealed that intramolecular hydrogen bonds are the main structural features that ensure the correlation of atomic integral characteristics with chemical shifts in the considered molecules. The results obtained in the course of theoretical modeling have been verified by comparison with the experimental 1H NMR data for 4-hydroxyproline-2-carboxanilide podands with different oxyethylene chain lengths, which are chiral inductors of stereoselective syntheses of drugs based on pyrimidinone heterocyclic systems.

Escaping from Flatland: Substituted Bridged Pyrrolidine Fragments with Inherent Three-Dimensional Character.

The pressure to deliver new medicines to the patient continues to grow along with increases in compound failure rate, thus putting the current R&D model at risk. Analysis has shown that increasing the three-dimensionality of potential drug candidates decreases the risk of failure and improves binding selectivity and frequency. For this reason many workers have taken a new look at the power of photochemistry as a means to generate novel sp3 rich scaffolds for use in drug discovery programs. Here we report the design, synthesis, and computational structural analysis of a series of 2,4-methanoprolines having inherent 3D character (PMI and PBF scores) significantly higher than that of the broader AbbVie Rule of 3 (Ro3) collection.

Dearomative (3+2) cycloaddition of 2-substituted 3,5-dinitropyridines and N-methyl azomethine ylide

1,3-Dipolar cycloaddition of various 2-substituted 3,5-dinitropyridines and unstabilized N-methyl azomethine ylide has been studied. It was found that, depending on the nature of the substituent, the reaction results in addition of one or two equivalents of 1,3-dipole to the pyridine ring. Eventually, a convenient method for the synthesis of differently substituted heterocyclic systems containing one or two pyrrolidine fragments fused with a pyridine ring has been demonstrated.

Reaction of Aldonitrones with N-Phenyl-9,10-dihydro-9,10-ethenoanthracene-11,12-dicarboximide

Thermal addition of aldonitrones (C,N-diaryl- and N-aryl-C-arylcarbamoylnitrones) to the double bond of N-phenyl-9,10-dihydro-9,10-ethenoanthracene-11,12-dicarboximide yields heteropropellanes containing isoxazolidine and pyrrolidine fragments. The cycloaddition of C,N-diarylnitrones is stereoselective, and only one diastereoisomer is formed.

In vitro and in vivo antiproliferative activity of organo-nickel SCS-pincer complexes on estrogen responsive MCF7 and MC4L2 breast cancer cells. Effects of amine fragment substitutions on BSA binding and cytotoxicity.

A family of organonickel complexes has been prepared, fully characterized, and tested for their antiproliferative activity against estrogen-responsive human breast cancer cells (MCF7). The three SCS-type pincer ligands HL1, HL2, and HL3 and their corresponding Ni(ii) complexes NiL1, NiL2, and NiL3 have been synthesized and fully characterized, including by single crystal diffraction studies for the complexes. The complexes possess square planar geometry with two symmetrical 5-membered nickellacycles. Fluorescence spectroscopy, circular dichroism measurements, molecular modeling, colorimetric based assay and tumor transplantation studies were used to evaluate the protein binding and antiproliferative activities of these organometallic complexes both in vitro and in vivo. Fluorescence quenching was used to investigate bovine serum albumin (BSA) interaction at different temperatures (293, 303 and 313 K), and the results were analyzed using the classical Stern-Volmer equation, allowing us to propose a dynamic quenching mechanism. Studies in vitro on the antiproliferative activity of the three organonickel complexes against estrogen-responsive human breast cancer cells (MCF7) showed promising antitumor activity for NiL1 containing pyrrolidine fragments. In vivo administration of this compound significantly inhibits tumor growth in estrogen-dependent MC4L2 cancer cells in female BALB/c mice.

Determination of Enantioselectivities by Means of Chiral Stationary Phase HPLC in Order to Identify Effective Proline-Derived Organocatalysts

The pyrrolidine fragment is a privileged scaffold within chiral ligands employed in coordination complexes exhibiting catalytic activity in asymmetric reactions and, more recently, as enantioselective organocatalysts per se. Likewise, the employment of (S)-proline as starting material constitutes the most direct form to synthesize those chiral derivatives. Afterwards, a preliminary evaluation of the catalytic performance of proline-derived compounds consists of screening many prochiral substrates in well standardized model reactions such as Michael additions and Mannich reactions, with the aim of identifying “broad spectrum” catalysts for more complex synthetic applications. Therefore, a central part of this process involves the fast and direct measurement of enantioselectivities of optically active adducts. The growing development of chiral stationary phases and thus, the wide commercial availability of chiral columns have consolidated high performance liquid chromatography (HPLC) as the preferred technique to identify the most effective catalysts.

ChemInform Abstract: Syntheses of a Pyrrolidine Analogue of a Tetrahydrofuran Containing Acetogenin, cis‐Solamin.

AbstractThe synthesis of aza‐cis‐solamin (III) is achieved using a palladium‐catalyzed diastereoselective cyclization of compound (I) as the key step to obtain the pyrrolidine fragment (II).

Synthesis and Characterization of β‐Trifluoromethyl‐Substituted Pyrrolidines

AbstractA practical synthetic approach to the construction of a library of three isomeric/homologous β‐trifluoromethyl‐substituted pyrrolidines is disclosed. All products were prepared in multigram quantities from a common precursor. The key synthetic step was a [3+2] cycloaddition reaction. The influence of the trifluoromethyl group on the physicochemical characteristics of the pyrrolidine fragment was studied.

Reaction of 4-oxocarboxylic acids and 5-substituted 3H-furan-2-ones with 1,2-binucleophiles of aromatic and alicyclic series

Based on reactions of 5-substituted 3H-furan-2-ones or 4-oxocarboxylic acids with 1,2-binucleophiles of aromatic and aliphatic series methods were developed for the synthesis of tricyclic structures containing a pyrrolidine fragment fused with imidazolidine or oxazolidine ring. The pathways of the reactions are considered. It was demonstrated that the nature of the substrate did not affect the reaction direction, but changed the scheme of the interaction. The structures of compounds obtained for the first time were proved using IR and 1H NMR spectra.

Tris{N-[bis(pyrrolidin-1-yl)phosphoryl]-2,2,2-trichloroacetamide}trichloridoerbium(III)

The asymmetric unit of the title compound, [ErCl3(C10H17Cl3N3O2P)3], contains two independent mol­ecules. In each mol­ecule, the ErIII ion is six-coordinated in a slightly distorted octa­hedral ErO3Cl3 geometry with a fac-arrangement of the donor atoms. Intra­molecular N—H⋯Cl hydrogen bonds influence the mol­ecular conformations. Some of the pyrrolidine fragments in the N-[bis(pyrrolidin-1-yl)phosphoryl]-2,2,2-trichloroacetamide ligands are disordered over two conformations of equal occupancy. The unusually porous crystal packing exhibits voids of 162, 158 and 13 Å3 and short inter­molecular Cl⋯O contacts of 2.876 (3) and 3.022 (4) Å.

Bis{N-[bis(pyrrolidin-1-yl)phosphoryl]-2,2,2-trichloroacetamide}dinitratodioxidouranium(VI)

The crystal structure of the title compound, [U(NO3)2O2(C10H17Cl3N3O2P)2], is composed of centrosymmetric [UO2(L)2(NO3)2] mol­ecules {L is N-[bis­(pyrrolidin-1-yl)phosphor­yl]-2,2,2-trichloro­acetamide, C10H17Cl3N3O2P}. The UVI ion, located on an inversion center, is eight-coordinated with axial oxido ligands and six equatorial oxygen atoms of the phosphoryl and nitrate groups in a slightly distorted hexa­gonal-bipyramidal geometry. One of the pyrrolidine fragments in the ligand is disordered over two conformation (occupancy ratio 0.58:0.42). Intra­molecular N—H⋯O hydrogen bonds between the amine and nitrate groups are found.

Antioxidant capacity of novel amine derivatives of buckminsterfullerene: Determination of inhibition rate constants in a model oxidation system

The radical scavenging efficiency of fullerenes can be significantly activated by means of a connection with hydrogen donating groups of antioxidants such as phenolic, amine and sulfhydryl. The developed system of conjugated σ–π bonds arranged in the fullerene molecule in a closed shape can promote a strong resonance effect on the grafted units and increase the hydrogen atom abstraction efficiency. In this case the known ability of fullerene to trap alkyl radicals might be combined with the strong chain breaking functionality to afford a new class of antioxidants with bimodal action. Explorations in the field of fullerene derivatives on their antioxidant performance provide novel information on the potential stabilization properties of this type of molecular structure. A series of amine derivatives of buckminsterfullerene (C 60) with tethered aliphatic chain, cycloaliphatic and aromatic fragments were synthesized and their antioxidant activity was determined. The antioxidant activity of the investigated derivatives was studied by measuring the inhibition rate constants for their reaction with alkyl and peroxy radicals in a model cumene initiated (2,2′-azobisisobutyronitrile, AIBN) oxidation experiments and compared to that recorded under identical experiments for buckminsterfullerene itself and commercial primary aromatic amine stabilizers. The results indicate that linking the amine moieties groups directly to the fullerene core gives rise to a new chain breaking antioxidant mode for the buckminsterfullerene while cyclic fragments containing the same but distant amine group do not reveal this ability. The inhibition rate constants for trapping of peroxy radicals by the amine derivatives were found to be higher than that of known aromatic amine antioxidants Neozone-D and Naugard 445. In addition the C 60 part of these molecules acts synergistically by trapping alkyl radicals with inhibition rate constants which exceed that of underivatised fullerene. The amine derivative containing sterically hindered piperidine and pyrrolidine fragments also heighten the inherent rate constant of buckminsterfullerene for scavenging alkyl radicals due to the additional antioxidant contribution promoted by the radical-quenching ability of the formed nitroxyl intermediates. These novel C 60–amine conjugates may be considered as promising molecules for broad-spectrum radical scavenging antioxidants.

(E)-3-(4-Hydr-oxy-3-methoxy-benzyl-idene)-4-(4-hydroxy-phen-yl)pyrrolidin-2-one.

The title compound, C18H17NO4, was isolated from an ethanol extract of Ophiopogon japonicus. The dihedral angle between the 4-hydroxy-3-methoxyphenyl ring and the pyrrolidine ring is 17.4 (1)°. The 4-hydroxyphenyl ring makes a dihedral angle of 69.74 (6)° with the least-squares plane through the 4-hydroxy-3-methoxyphenyl ring and the pyrrolidine ring. The conformation of the pyrrolidine fragment is similar to a T-form. The crystal structure is stabilized by inter­molecular N—H⋯O and O—H⋯O hydrogen bonds.

Reaction of ketones with lithium hexamethyldisilazide: competitive enolizations and 1,2-additions.

Reaction of 2-methylcyclohexanone with lithium hexamethyldisilazide (LiHMDS, TMS(2)NLi) displays highly solvent-dependent chemoselectivity. LiHMDS in THF/toluene effect enolization. Rate studies using in situ IR spectroscopy are consistent with a THF concentration-dependent monomer-based pathway. LiHMDS in pyrrolidine/toluene affords exclusively 1,2-addition of the pyrrolidine fragment to form an alpha-amino alkoxide-LiHMDS mixed dimer shown to be a pair of conformers by using (6)Li, (15)N, and (13)C NMR spectroscopies. Rate studies are consistent with a monomer-based transition structure [(TMS(2)NLi)(ketone)(pyrrolidine)(3)](). The partitioning between enolization and 1,2-addition is kinetically controlled.

Electrochemical reduction and oxidation of fullerenopyrrolidines* and the ESR spectra of paramagnetic intermediates

Electroreduction and electrooxidation of monosubstituted N-methyl[60]fullerenopyrrolidines were studied by cyclic voltammetry and potentiostatic microelectrolysis in the cavity of an ESR spectrometer. Stepwise reversible transfer of three electrons to the fullerenopyrrolidine molecule results in the formation of stable radical anions (according to ESR, g = 2.0000, ΔH = 0.8 G), dianions, and radical trianions (according to ESR, g = 2.0015, ΔH = 1.5 G). The reduction potentials vary over narrow limits depending on the nature of the substituents in the pyrrolidine fragment of the compounds. Electrooxidation is irreversible and occurs in either one or two steps. For compounds containing the aniline, indole, or phenol fragment, the first step is associated with oxidation of these fragments and only after that, is the fullerenopyrrolidine core oxidized. Oxidation of the pyrrolidine fragment is substantially more difficult than that of tertiary amines.