Pyrrolidine Unit Research Articles

Multifaceted Applications of Luminescent Metalloporphyrin Derivatives: Fluorescence Turn-On Sensing of Nicotine and Antimicrobial Activity.

In this study, we designed and synthesized metalloporphyrin derivatives (with Ni and Zn) specifically intended for the fluorescence detection of nicotine in aqueous solutions. Our results showcased a notable selectivity for nicotine over other naturally occurring food toxins, exhibiting an exceptional sensitivity with a limit of detection as low as 7.2 nM. Through mechanistic investigations (1H NMR, FT-IR, etc.), we elucidated the binding mechanism, revealing the specific interaction between the pyridine ring of nicotine and the metal center, while the N atom pyrrolidine unit engaged in the hydrogen bonding with the side chain of the porphyrin ring. Notably, we observed that the nature of the metal center dictated the extent of interaction with nicotine; particularly, Zn-porphyrin demonstrated a superior response compared to Ni-porphyrin. Furthermore, we performed the quantitative estimation of nicotine in commercially available tobacco products. Additionally, we conducted the antibacterial (Staphylococcus aureus and Escherichia coli) and antifungal (Candida albicans) activities of the porphyrin derivatives.

Diastereoselective construction of carbazole‐based spiropyrrolidines and spiropyrrolizidines via cycloaddition reaction

AbstractA series of new spiro heterocyclic compounds having carbazole and pyrrolidine units were successfully synthesized through a one‐pot, three component, 1,3‐dipolar cycloaddition reaction in good yields with high diastereoselectivity. Simple reaction, easily accessible chemicals, high yield and diastereoselective formation of monospiropyrrolidine and monospiropyrrolizidine carbazole derivatives in one step are some advantages of this method. The structure of the obtained products was characterized by using spectroscopic techniques.

9-(Pyrrolidinium-1-yl)-9-boranuidabi-cyclo-[3.3.1]nona-ne.

The title compound, C12H24BN, is an adduct formed from 9-borabi-cyclo-[3.3.1]nonane (9-BBN) and pyrrolidine. It crystallizes in the triclinic space group P with three mol-ecules in the asymmetric unit, one of which has disorder of the pyrrolidine ring. The B-N bond lengths are between 1.631 (2) and 1.641 (2) Å. The boron and nitro-gen atoms are bound to one hydrogen atom each. These hydrogen atoms are in anti-periplanar orientation. Both six-membered rings of the 9-BBN unit are in a chair conformation in all three mol-ecules. Differences between the three crystallographic independent mol-ecules are found in the five-membered rings of the pyrrolidine unit. These adopt different twisted and envelope conformations.

Application of Proline-Derived (Thio)squaramide Organocatalysts in Asymmetric Diels–Alder and Conjugate Addition Reactions

AbstractThe synthesis of chiral proline-derived squaramide and thiosquaramide organocatalysts, which are capable of the dual activation in asymmetric reactions is reported. The (thio)squaramide moiety can form hydrogen bonds to activate the substrates and to stereocontrol the reaction, while the pyrrolidine unit can form enamines to activate carbonyl compounds via aminocatalysis. Comparing the performance of thiosquaramide to squaramide, the Diels–Alder reaction of (anthracen-9-yl)acetaldehyde and trans-β-nitrostyrene was examined, which has been investigated in the literature using quantum chemical calculations. Both squaramide and thiosquaramide gave excellent yields (up to 99%) and enantiomeric excess values (up to 98%). Moreover, their catalytic performance was compared in conjugate addition of lawsone to β,γ-unsaturated α-keto ester.

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

The synthesis of bifunctional N-sulfinylureas and thioureas with an appended pyrrolidine unit is presented. These organocatalysts were evaluated in Michael additions of aldehydes to nitroalkenes both under solvent-free conditions and in solution. The N-sulfinylurea catalyst was more efficient than the corresponding thiourea. For some substrates, enantioselectivities reached 98% ee. The stereogenic center on the sulfur did not have a considerable influence on the catalytic reactions. Under ball-milling conditions, the Michael adducts were obtained in good yields but with slightly lower enantiomeric purities than in solution. DFT calculations elucidated its mode of action and confirmed a dual activation mode, which combines enamine activation of aldehydes and hydrogen-bond activation of nitroalkenes.

Application of Polyamines and Amino Acid Derivatives Based on 2-Azabicycloalkane Backbone in Enantioselective Aldol Reaction.

Carbon–carbon bond forming reactions, such as aldol reaction and condensation, belong to extremely desired transformations as manifested by >25,000 entries in SciFinder. Their stereoselective variant requires the use of an appropriate catalyst with a strictly defined structure. Hence, chiral 2-azabicycloalkane-based catalysts were designed, synthesized and tested in a stereoselective aldol reaction between cyclic/acyclic ketone and p-nitrobenzaldehyde both in organic and aqueous media. Among catalysts containing a chiral bicyclic backbone, amide based on 2-azabicyclo[3.2.1]octane and pyrrolidine units showed the best catalytic activity and afforded aldol product in excellent chemical yields (up to 95%) and good diastereo- and enantioselectivity (dr 22:78, ee up to 63%).

A straightforward approach toward cytotoxic pyrrolidine alkaloids: Novel analogues of natural broussonetines

Straightforward access to a series of the cytotoxic sphingolipid-derived alkaloids possessing a pyrrolidine unit and a long hydrophobic side chain was accomplished. Two simple carbohydrate chirons, protected d- and l-erythrofuranose, were chosen as the starting material, and [3,3]-sigmatropic rearrangements, a late stage cross metathesis and an intramolecular nucleophilic substitution were involved as the key transformations. The final analogues of natural broussonetines were evaluated for their capacity to alter the proliferation of cancer cells.

Structural dynamism of chiral sodium peraza-macrocycle complexes derived from cyclic peptoids.

A variety of cyclen and hexacyclen derivatives decorated with (S)-1-phenylethyl side chains or (S)-pyrrolidine units have been prepared via a reductive approach from the corresponding cyclic peptoids containing N-(S)-(1-phenylethyl)glycine and l-proline residues. Spectroscopic and DFT studies on their Na+ complexes show that point chirality and ring size play a crucial role in controlling the structural dynamism of 1,2-diaminoethylene units and pendant arms. The detection of highly symmetric C4- and C3-symmetric metalated species demonstrates that a full understanding of the relationship between the structure and conformational properties of peraza-macrocyclic metal complexes is possible.

Interplay of Pyrrolidine Units with Homo/Hetero Chirality and CF3-Aryl Substituents on Secondary Structures of β-Proline Tripeptides in Solution.

All possible variants of β-proline functionalized tripeptides consisting of homo/hetero chiral monomeric all-cis 5-arylpyrrolidine-2,4-dicarboxylate units were synthesized for the first time by a nonpeptidic coupling method based on 1,3-dipolar cycloaddition chemistry of azomethine ylides. Secondary structures of β-proline tripeptides in solution were determined using the NMR spectroscopy data. o-(Trifluoromethyl)phenyl substituent contributes to stereoselectivity of 1,3-dipolar cycloaddition and structural features of β-proline tripeptides. A β-proline CF3-tripeptide with alternating absolute chirality between adjacent pyrrolidine units mimics natural PPII helix secondary structure.

Dynamic Control of Chiral Space Through Local Symmetry Breaking in a Rotaxane Organocatalyst.

We report on a switchable rotaxane molecular shuttle that features a pseudo-meso 2,5-disubstituted pyrrolidine catalytic unit on the axle whose local symmetry is broken according to the position of a threaded benzylic amide macrocycle. The macrocycle can be selectively switched (with light in one direction; with catalytic acid in the other) with high fidelity between binding sites located to either side of the pyrrolidine unit. The position of the macrocycle dictates the facial bias of the rotaxane-catalyzed conjugate addition of aldehydes to vinyl sulfones. The pseudo-meso non-interlocked thread does not afford significant selectivity as a catalyst (2-14 % ee), whereas the rotaxane affords selectivities of up to 40 % ee with switching of the position of the macrocycle changing the handedness of the product formed (up to 60 % Δee).

Dynamic Control of Chiral Space Through Local Symmetry Breaking in a Rotaxane Organocatalyst

AbstractWe report on a switchable rotaxane molecular shuttle that features a pseudo‐meso 2,5‐disubstituted pyrrolidine catalytic unit on the axle whose local symmetry is broken according to the position of a threaded benzylic amide macrocycle. The macrocycle can be selectively switched (with light in one direction; with catalytic acid in the other) with high fidelity between binding sites located to either side of the pyrrolidine unit. The position of the macrocycle dictates the facial bias of the rotaxane‐catalyzed conjugate addition of aldehydes to vinyl sulfones. The pseudo‐meso non‐interlocked thread does not afford significant selectivity as a catalyst (2–14 % ee), whereas the rotaxane affords selectivities of up to 40 % ee with switching of the position of the macrocycle changing the handedness of the product formed (up to 60 % Δee).

Bifunctional Thio/Squaramide Catalyzed Stereoselective Michael Additions of Aldehydes to Nitroalkenes towards Synthesis of Chiral Pyrrolidines

AbstractBifunctional squaramide and thiosquaramide organocatalysts were assessed in a stereoselective Michael addition of aldehydes to nitroalkenes. Organocatalysts feature pyrrolidine unit for enamine activation of aldehydes and hydrogen bond donating fragment for nitroalkene activation. The corresponding Michael adducts were obtained in good yields and good to high enantiomeric purities. Solvent‐free conditions were also tested but did not provide any significant improvement. Michael adducts were transformed into chiral pyrrolidines via reductive cyclization.

Influence of the Framework Topology on the Reactivity of Chiral Pyrrolidine Units Inserted in Different Porous Organosilicas

Three families of organosiliceous materials with different structuration level, order, and textural properties (non-ordered, M41S, and SBA-15 type materials) were prepared incorporating in their structural framework chiral pyrrolidine units with variable content. Likewise, non-ordered mesoporous hybrid solids were obtained through a sol-gel process in a fluoride medium, while M41S and SBA-15 type materials were obtained through micellar routes in the presence of long-chain neutral surfactants or block copolymers. Thanks to appropriate characterization studies and catalytic tests for the Michael addition between butyraldehyde and β-nitrostyrene, we showed how the void shapes and sizes present in the structure of hybrid materials control the diffusion of reactants and products, as well as confine transition states and reactive intermediates. The best catalytic results, considering activity and enantioselectivity, were achieved in the presence of a non-ordered material, NOH-Pyr-5%, which exhibited the highest Brunauer-Emmett-Teller (BET) area, with a 96% yield and a 82% ee for the Michael adduct.

Synthesis of heterocycle appended spiro(oxindole-3,2’-pyrrolidine) derivatives from heterocyclic ylidenes and azomethine ylide through 1,3-dipolar cycloaddition reactions

Spiro(oxindole-3,2’-pyrrolidine) is a privileged scaffold displaying a wide spectrum of biological activities. A series of these molecules containing heterocyclic rings attached to the pyrrolidine unit has been synthesized utilizing the classical 1,3-dipolar cycloaddition reaction of azomethine ylide with heterocyclic ylidenes. The method portrays a two-step functionalization of thiophene/furan with spiropyrrolidine oxindoles in the second/third positions. Biological activity evaluation for antibacterial, cell toxicity, and anticancer potential were done. Compounds exhibited no antibacterial activity. However, they were found to be non-cytotoxic upto 100 µg/ml and to exhibit potent anticancer activity by activating pro-apoptotic genes p53 and caspase 7.

Crystal structure of 4-[(1R,2S,5R)-2-isopropyl-5-methyl-cyclo-hex-yl] 2-methyl (2S,4S,5R)-1-[(2S,3R,5R)-5-meth-oxy-carbonyl-2-(2-methyl-phen-yl)pyrrolidine-3-carbon-yl]-5-(2-methyl-phen-yl)pyrrolidine-2,4-di-carboxyl-ate.

The title compound, C38H50N2O7, represents a chiral β-proline dipeptide. Corresponding stereogenic centres of constituting pyrrolidine units have opposite absolute configurations. The central amide fragment is planar within 0.1 Å and adopts a Z configuration along the N-CO bond. In the crystal, the hydrogen atoms of the methyl-ene groups form several short inter-molecular C-H⋯O contacts with the carbonyl oxygen atoms of an adjacent mol-ecule. The only active amino hydrogen atom is not involved in hydrogen bonding.

Asymmetric Synthesis of Vicinally Bis(trifluoromethyl)-Substituted 3,3′-Pyrrolidinyl Spirooxindoles via Organocatalytic 1,3-Dipolar Cycloaddition Reactions

Under bifunctional squaramide and thiourea organocatalysis, a series of vicinally bis(trifluoromethyl)-substituted 3,3′-pyrrolidinyl spirooxindoles were successfully synthesized via 1,3-dipolar cycloaddition reactions of 3-(trifluoroethylidene)oxindoles with diethyl 2-((2,2,2-trifluoroethyl)imino)malonate and N-(2,2,2-trifluoroethyl)isatin ketimines. The highlight of this protocol is the efficient construction of the vicinally bis(trifluoromethyl)-substituted pyrrolidine unit of spirooxindoles, including multiple contiguous stereogenic centres, in excellent yields and stereoselectivities.

Synthesis of pyrrolizidines and indolizidines by multicomponent 1,3-dipolar cycloaddition of azomethine ylides

AbstractDifferent multicomponent 1,3-dipolar cycloadditions (1,3-DC) of cyclic α-amino acid derivatives with aldehydes and dipolarophiles have been described as efficient and simple methodologies for the synthesis of the pyrrolidine unit of pyrrolizidines and indolizidines. When free cyclic α-amino acids are used, a thermal promoted decarboxylative process generatesin situthe corresponding non-stabilized azomethine ylides, which afforded the corresponding pyrrolizidines and indolizidines with a hydrogen in the bicyclic units. This methodology has been employed to the synthesis of complex systems including spiro derivatives when ketones are used as carbonyl component. In addition, working with cyclic α-amino acid derived esters, the three-component 1,3-DC takes place under milder reaction conditions giving the corresponding pyrrolizidines and indolizidines with an alkoxycarbonyl group in the bridge adjacent carbon to the nitrogen. This methodology can be carried out by a double consecutive or stepwise 1,3-DC to provide pyrrolizidines via the precursor prolinates. The conformation of the azomethine ylide controls the endo/exo diastereoselectivity of the 1,3-DC.

Exploration of Diverse Reactive Diad Geometries for Bifunctional Catalysis via Foldamer Backbone Variation.

What is the best spatial arrangement of a pair of reactive groups for bifunctional catalysis of a chemical transformation? The conformational versatility of proteins allows reactive group geometry to be explored and optimized via evolutionary selection, but it has been difficult for chemists to identify synthetic scaffolds that allow broad comparative evaluation among alternative reactive group geometries. Here we show that a family of helices, adopted predictably by oligomers composed partially or exclusively of β-amino acid residues, enables us to explore a range of orientations for a pair of pyrrolidine units that must work in tandem to catalyze a crossed aldol reaction. Thus, the crossed aldol reaction serves as an assay of reactive diad efficacy. We have chosen a test reaction free of stereochemical complexity in order to streamline our study of reactivity. The best geometry enhances the initial rate of product formation by two orders of magnitude. Our findings raise the possibility that rudimentary catalysts involving an isolated secondary structure might have facilitated the development of prebiotic reaction networks.

Theoretical and NMR Conformational Studies of β-Proline Oligopeptides With Alternating Chirality of Pyrrolidine Units.

Synthetic β-peptides are potential functional mimetics of native α-proteins. A recently developed, novel, synthetic approach provides an effective route to the broad group of β-proline oligomers with alternating patterns of stereogenic centers. Conformation of the pyrrolidine ring, Z/E isomerism of β-peptide bonds, and hindered rotation of the neighboring monomers determine the spatial structure of this group of β-proline oligopeptides. Preferences in their structural organization and corresponding thermodynamic properties are determined by NMR spectroscopy, restrained molecular dynamics and quantum mechanics. The studied β-proline oligopeptides exist in dimethyl sulfoxide solution in a limited number of conformers, with compatible energy of formation and different spatial organization. In the β-proline tetrapeptide with alternating chirality of composing pyrrolidine units, one of three peptide bonds may exist in an E configuration. For the alternating β-proline pentapeptide, the presence of an E configuration for at least of one β-peptide bond is mandatory. In this case, three peptide bonds synchronously change their configurations. Larger polypeptides may only exist in the presence of several E configurations of β-peptide bonds forming a wave-like extended structure.

Chiral hybrid materials based on pyrrolidine building units to perform asymmetric Michael additions with high stereocontrol.

A new chiral mesoporous hybrid material was synthesized based on pyrrolidine units included in a siliceous framework, HybPyr, and integrated into the organic-inorganic structure, from a specific bis-silylated precursor. A fluoride sol-gel methodology under soft synthesis conditions and in the absence of sophisticated structural directing agents allowed the generation of a mesoporous architecture with a homogeneous distribution of active chiral moieties along the network. The hybrid material was studied by means of different characterization techniques (TGA, NMR and IR spectroscopy, chemical and elemental analyses, TEM, and textural measurements), verifying the stability and integrity of the asymmetric active sites in the solid. The hybrid material, HybPyr, is an excellent asymmetric heterogeneous and recyclable catalyst for enantioselective Michael addition of linear aldehydes to β-nitrostyrene derivatives with high stereocontrol of the reaction products.