Pyrrolidine Derivatives Research Articles

Synthesis and Application of New, Optically Active Compounds as Catalysts and Ligands in Enantioselective Reactions

New methods for efficient preparation of optically active compounds developed recently are reported. Combination of selective organometallic, organocatalytic, phase transfer catalytic and catalytic hydrogenation reactions provided numerousnew optically active members of the families of atropisomeric 1-phenylpyrrole derivatives, 4-aminobutan-1-ol and 3,4-disubstituted pyrrolidine derivatives and optically active α- and β-aminophosphonic acids. The products can be used as valuable new chiral ligands or organocatalysts and can serve as building blocks of practically important biologically active compounds.

Squaramide-catalysed asymmetric cascade aza-Michael/Michael addition reaction for the synthesis of chiral trisubstituted pyrrolidines.

A bifunctional squaramide catalysed aza-Michael/Michael cascade reaction between nitroalkenes and tosylaminomethyl enones or enoates has been developed. This organocatalytic cascade reaction provides easy access to highly functionalized chiral pyrrolidines with a broad substrate scope, giving the desired products in good yields (up to 99%) with good diastereoselectivities (up to 91 : 9 dr) and excellent enantioselectivities (up to >99% ee) under mild conditions. This protocol provides a straightforward entry to highly functionalized chiral trisubstituted pyrrolidine derivatives from simple starting materials.

Construction of an all-substituted pyrrolidine derivative with multiple stereogenic centers and Betti-base-derived γ-amino alcohols by [1,2]-Wittig rearrangement

The construction of Betti base-derived γ-amino alcohols and all-substituted pyrrolidine derivative with multiple stereogenic centers has been developed successfully through neighboring lithium-assisted [1,2]-Wittig rearrangement (NLAWR).

A strategic approach to the synthesis of functionalized spirooxindole pyrrolidine derivatives: in vitro antibacterial, antifungal, antimalarial and antitubercular studies

A series of spirooxindole pyrrolidine derivatives has been synthesized and evaluated for theirin vitrobiological activities. The observed regio- and stereoselectivity of the cycloaddition reaction has been rationalized using DFT calculations.

Synthesis of pyrrolidine derivatives by a platinum/brønsted acid relay catalytic cascade reaction.

A new catalytic reaction for the synthesis of pyrrolidine derivatives is presented. The method implies the coupling of N-Boc-protected alkynamine derivatives and appropriate alkenes or alkynes in a process catalysed by a platinum/triflic acid catalytic binary system. This reaction is believed to proceed through a cascade process implying an initial platinum-catalysed cycloisomerization of the alkynamine derivative followed by a triflic acid promoted nucleophilic addition of the alkene or alkyne and trapping of the cationic species formed by the Boc group. Not only simple alkenes and alkynes were used in this reaction but also allyltrimethylsilane and propargyltrimethylsilane. Particularly, when allyltrimethylsilane is used as the alkene counterpart interesting bicyclic compounds containing a trimethylsilane group are obtained. However, when propargyltrimethylsilane is used in the presence of water we observed the formation of a related bicyclic compound lacking the trimethylsilane group and containing an exocyclic carbon-carbon bond.

ChemInform Abstract: Cu(I)/TF—BiphamPhos‐Catalyzed Asymmetric 1,3‐Dipolar Cycloaddition of Azomethine Ylides with Dimethyl Itaconate and 2‐Methyleneglutarate.

Catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with dimethyl itaconate and 2-methyleneglutarate was realized with the Cu(I)/TF–BiphamPhos complex as the catalyst for the efficient construction of pyrrolidine derivatives bearing one unique all carbon-quaternary and two tertiary stereogenic centers. The current catalytic system exhibited excellent diastereoselectivity (> 20:1), good enantioselectivity (88–>99% ee) and broad substrate scope under mild conditions.

ChemInform Abstract: Chiral Phosphoric Acid Catalyzed 1,3‐Dipolar Cycloadditions of Aldehydes, Diethyl α‐Aminomalonate, and Nitroalkenes.

AbstractThe synthesis of optically active pyrrolidine derivatives is accomplished via BINOL derived phosphonic acid catalyzed reaction of in situ generated 1,3‐dipoles with nitroalkenes.

Design and synthesis of sulfonamide derivatives of pyrrolidine and piperidine as anti-diabetic agents.

Type 2 diabetes (T2D) is a lifestyle disease affecting millions of people worldwide. Various therapies are available for the management of T2D and dipeptidyl peptidase-IV (DPP-IV) inhibition has emerged as a promising therapy for the treatment of type 2 diabetes (T2D). Here we report design, synthesis and in vitro efficacy of sulfonamide derivatives of pyrrolidine and piperidine as anti-diabetic agents. Amongst all the compounds synthesized in this series, 9a, is the most potent (IC50 = 41.17 nM).

Sterically shielded spin labels for in-cell EPR spectroscopy: Analysis of stability in reducing environment

Electron paramagnetic resonance (EPR) spectroscopy is a powerful and widely used technique for studying structure and dynamics of biomolecules under bio-orthogonal conditions. In-cell EPR is an emerging area in this field; however, it is hampered by the reducing environment present in cells, which reduces most nitroxide spin labels to their corresponding diamagnetic N-hydroxyl derivatives. To determine which radicals are best suited for in-cell EPR studies, we systematically studied the effects of substitution on radical stability using five different classes of radicals, specifically piperidine-, imidazolidine-, pyrrolidine-, and isoindoline-based nitroxides as well as the Finland trityl radical. Thermodynamic parameters of nitroxide reduction were determined by cyclic voltammetry; the rate of reduction in the presence of ascorbate, cellular extracts, and after injection into oocytes was measured by continuous-wave EPR spectroscopy. Our study revealed that tetraethyl-substituted nitroxides are good candidates for in-cell EPR studies, in particular pyrrolidine derivatives, which are slightly more stable than the trityl radical.

ChemInform Abstract: Enantioselective Synthesis of α‐Heteroarylpyrrolidines by Copper‐Catalyzed 1,3‐Dipolar Cycloaddition of α‐Silylimines.

α-Heteroarylpyrrolidines have been efficiently prepared via 1,3-dipolar cycloaddition between silylimines and activated olefins. In the presence of Cu(CH3CN)4PF6/Walphos as catalytic system, high levels of enantioselectivity (up to ≥99% ee) and diastereoselectivity were achieved (major formation of C-2/C-4 trans-substituted pyrrolidines). The reaction is compatible with a broad variety of dipolarophiles including maleimides, maleates, fumarates, nitroalkenes, and vinylsulfones. The resulting cycloadducts can be transformed into bioactive pyrrolidine derivatives.

ChemInform Abstract: Organocatalysis in Synthesis of Pyrrolidine Derivatives via Cycloaddition Reactions of Azomethine Ylides

AbstractReview: 29 refs.

Sequential Biocatalytic Aldol Reactions in Multistep Asymmetric Synthesis: Pipecolic Acid, Piperidine and Pyrrolidine (Homo)Iminocyclitol Derivatives from Achiral Building Blocks

AbstractA multistep chemoenzymatic synthesis for stereodiverse polyhydroxypipecolic acid analogues, homoiminocyclitols and polyhydroxylated piperidine and pyrrolidine derivatives combining glycine‐dependent aldolases and both D‐fructose‐6‐phosphate aldolase (FSA) or dihydroxyacetone phosphate (DHAP)‐dependent aldolases is presented. The methodology allowed the preparation of known and innovative imine‐derived molecules with a great structural diversity from simple achiral substrates. The strategy consisted of two key aldol addition steps: a first aldol addition of glycine to dimethoxyacetaldehyde catalyzed by L‐ and D‐glycine aldolases and a second aldol addition of DHAP, dihydroxyacetone, hydroxyacetone or glycolaldehyde using FSA or DHAP‐dependent aldolases as catalysts to a conveniently transformed aldol adduct from the first aldol addition. Catalytic reductive amination on the aldol adducts rendered the polyhydroxypipecolic acid analogues, (homo)iminocyclitols and polyhydroxylated pyrrolidine iminocyclitols. The reported strategy is thus designed to create up to five new stereogenic centers in three steps, four of them being controlled in two enzymatic reactions. Moreover, it allowed the installation of diverse functionalities in the molecules. This was possible by taking the full advantage of using aldolases in a multistep approach by virtue of their stereocomplementarity, stereoselectivity and broad substrate tolerance.magnified image

Insertion of Imines into Vinylcyclopropanes Catalyzed by Nucleophilic Iron Complexes: A Formal [3+2]-Cycloaddition Strategy for the Synthesis of Substituted Pyrrolidine Derivatives

Pyrrols are substructures in various biological active molecules. A straightforward iron-catalyzed synthesis of pyrrols via insertion of an imine into a vinylcyclopropane is presented. The corresponding pyrrols are obtained in moderate to good yields. Scope and limitations will be discussed.

Hydrogenolysis of N- and O-protected hydroxyazetidines over palladium: Efficient and selective methods for ring opening and deprotecting reactions

Some N- and O-protected hydroxyazetidine derivatives were hydrogenated to the corresponding amines or aminoalcohols over a Pd/C catalyst, in different solvents (methanol, dichloromethane, tetrahydrofuran), at 30–60°C and 1–10bar. These amino compounds, formed during hydrogenolytic ring opening and/or deprotecting reactions, are potential starting materials for preparing optically active, practically important pyrrolidine derivatives.

Enantioselective Intramolecular Hydroamination of Unactivated Alkenes Catalyzed by Mono‐ and Bis(gold) Phosphine Complexes

AbstractA 1:2 mixture of (P1)(AuCl)2 [P1=(S)‐DTBM‐MeO‐BIPHEP] and silver tetrafluoroborate (AgBF4) in methanol catalyzes the intramolecular hydroamination of unactivated alkenes with carbamates and ureas to form pyrrolidine derivatives with up to 85% ee.magnified image

Bromolactamization: key step in the stereoselective synthesis of enantiomerically pure, cis-configured perhydropyrroloquinoxalines.

Compounds based on the pyrroloquinoxaline system can interact with serotonin 5-HT3 , cannabinoid CB1 , and μ-opioid receptors. Herein, a chiral pool synthesis of diastereomerically and enantiomerically pure bromolactam (S,R,R,R)-14A is presented. Introduction of the cyclohexenyl ring at the N-atom of (S)-proline derivatives 8 or methyl (S)-pyroglutamate (12) led to the N-cyclohexenyl substituted pyrrolidine derivatives 4 and 13, respectively. All attempts to cyclize the (S)-proline derivatives 4 with a basic pyrrolidine N-atom via [3 + 2] cycloaddition, aziridination, or bromolactamization failed. Fast aromatization occurred during treatment of cyclohexenamines under halolactamization conditions. In contrast, reaction of a 1:1 mixture of diastereomeric pyroglutamates (S,R)-13bA and (S,S)-13bB with LiO(t) Bu and NBS provided the tricyclic bromolactam (S,R,R,R)-14A with high diastereoselectivity from (S,R)-13bA, but did not transform the diastereomer (S,S)-13bB. The different behavior of the diastereomeric pyroglutamates (S,R)-13bA and (S,S)-13bB is explained by different energetically favored conformations.

The Lewis acid-catalyzed [3+1+1] cycloaddition of azomethine ylides with isocyanides

A Lewis acid-catalyzed [3+1+1] cycloaddition reaction between aliphatic isocyanides and azomethine ylides generated in situ from aziridines, leading to pyrrolidine derivatives, has been developed. This reaction proceeds smoothly under mild conditions and can also be modified by employing aromatic isocyanides to generate four-membered heterocycles, azetidines, through a [3+1] cycloaddition reaction.

Easily Accessible Polycyclic Amines that Inhibit the Wild-Type and Amantadine-Resistant Mutants of the M2 Channel of Influenza A Virus

Amantadine inhibits the M2 proton channel of influenza A virus, yet most of the currently circulating strains of the virus carry mutations in the M2 protein that render the virus amantadine-resistant. While most of the research on novel amantadine analogues has revolved around the synthesis of novel adamantane derivatives, we have recently found that other polycyclic scaffolds effectively block the M2 proton channel, including amantadine-resistant mutant channels. In this work, we have synthesized and characterized a series of pyrrolidine derivatives designed as analogues of amantadine. Inhibition of the wild-type M2 channel and the A/M2-S31N, A/M2-V27A, and A/M2-L26F mutant forms of the channel were measured in Xenopus oocytes using two-electrode voltage clamp assays. Most of the novel compounds inhibited the wild-type ion channel in the low micromolar range. Of note, two of the compounds inhibited the amantadine-resistant A/M2-V27A and A/M2-L26F mutant ion channels with submicromolar and low micromolar IC50, respectively. None of the compounds was found to inhibit the S31N mutant ion channel.

Organocatalysis in Synthesis of Pyrrolidine Derivatives via Cycloaddition Reactions of Azomethine Ylides

Organocatalysis in Synthesis of Pyrrolidine Derivatives via Cycloaddition Reactions of Azomethine Ylides

ChemInform Abstract: Broensted Acid‐Assisted N‐Alkylation of Sulfonamides Using Ethers as the Alkylation Reagents.

AbstractThe reaction of cyclic ethers affords pyrrolidine and piperidine derivatives, whereas the reaction of symmetrical and unsymmetrical ethers give the corresponding mono N‐alkylated products.