Pyrrolidine Nitrogen Atom Research Articles

Facile entry into the 1H-pyrrolo[3,4-b]indolizine-1,3(2H)-dione scaffold via intramolecular Rh(II) carbene trapping

An unusual reactivity of Rh(II) carbenes generated from (E)-3-(2-pyridylmethylene)-4-diazopyrrolidine-2,5-diones was discovered which led to a novel type of fluorescent annelated indolizines (X-ray confirmed structure). The reaction was found to be insensitive to substitution pattern at pyrrolidine nitrogen atom and delivered a series of nine novel indolizines in 74–94% yields. Photophysical properties of obtained indolizines were investigated, which proved them to be blue or green luminophores with absolute quantum yields up to 13.8%. The latter strongly depended on substitution pattern at pyrrolidine nitrogen atom.

Synthesis of pyrrolidine-based hamamelitannin analogues as quorum sensing inhibitors in Staphylococcus aureus.

Interfering with bacterial cell-to-cell communication is a promising strategy to combat antimicrobial resistance. The natural product hamamelitannin and several of its analogues have been identified as quorum sensing inhibitors. In this paper the synthesis of pyrrolidine-based analogues of a more lead-like hamamelitannin analogue is reported. A convergent synthetic route based on a key ring-closing metathesis reaction was developed and delivered the pyrrolidine analogue in 17 steps in high yield. Chemoselective derivatization of the pyrrolidine nitrogen atom resulted in 6 more compounds. The synthesized compounds were evaluated in a biofilm model, but were all inactive.

Flexible and Modular Syntheses of Enantiopure 5-cis-Substituted Prolinamines from l-Pyroglutamic Acid

A wide range (25 examples) of 5-cis-substituted prolinamines is prepared in five to ten steps starting from cheap l -pyroglutamic acid. Three routes, differing mainly in the order of introduction of the substituents at the 5-cis position, the pyrrolidine nitrogen atom, and the exocyclic amino function, are successfully developed.

Pyrrolidine nucleotide analogs with a tunable conformation.

Conformational preferences of the pyrrolidine ring in nucleotide analogs 7–14 were investigated by means of NMR and molecular modeling. The effect of the relative configuration of hydroxy and nucleobase substituents as well as the effect of the alkylation or acylation of the pyrrolidine nitrogen atom on the conformation of the pyrrolidine ring were studied. The results of a conformational analysis show that the alkylation/acylation can be effectively used for tuning the pyrrolidine conformation over the whole pseudorotation cycle.

Conformational behaviour of peptides containing a 2-pyrrolidinemethanesulfonic acid (2PyMS) residue

The conformational behaviour of model peptides containing a 2-pyrrolidinemethanesulfonic acid (2PyMS) residue was studied in both the crystalline state and in solution using X-ray, NMR and IR experiments. It was found that in crystals dipeptide PhC(O)-2PyMS-Phe-NHiPr adopted β-turn conformation, which was not stabilized by an intramolecular hydrogen bond and could be classified as a type IV β-turn. In the crystalline state tripeptide PhC(O)-Ala-2PyMS-Phe-NHiPr existed as an α-turn with uncommon cis-conformation of the amide bond formed by the pyrrolidine nitrogen atom of the 2PyMS residue, for which no close analogue can be envisaged among the tight turns identified so far. Although the tendency to adopt folded conformations was only partially retained in solution, 2-PyMS could be considered as a promising structural unit for the design of foldamers and peptidomimetics with unusual conformational properties.

Highly efficient asymmetric anti-Mannich reactions of carbonyl compounds with N-carbamoyl imines catalyzed by amino-thiourea organocatalysts

A series of pyrrolidine-based organocatalysts which bear three synergistic features, i.e. secondary amino group, various H-bond donor groups at the 4-position and a stereocontrol silyl ether group at the α-position of the pyrrolidine nitrogen atom, were developed. They were screened in anti-Mannich reactions of carbonyl compounds with preformed or in situ generated N-protected α-imino ethylglyoxylate and aldehydes with preformed or in situ generated N-carbamoyl imines. The influence of H-bond donor ability at the 4-position was also investigated. Among all the catalysts, 2a was identified as a general efficient organocatalyst suitable for various types of anti-Mannich reactions and broad substrate scope. Excellent results (up to 98% yield, >99% ee and >99 : 1 dr) were achieved with 5 mol% catalyst load. Sulfones with ortho substituents or very strong withdrawing groups on the aromatic ring, which have been regarded as challenging substrates in the direct anti-Mannich reactions of aldehydes with in situ generated N-carbamoyl imines, also worked well. The optimization of our catalytic system also offered alternative and easily operational protocols to access anti-Mannich products with orthogonal N-Boc or N-Cbz protecting groups.

Hydrogen‐bonded complexes of nicotine with simple alcohols

AbstractAb initio and density functional theory studies have been performed on the hydrogen‐bonded complexes of neutral and protonated nicotine with ethanol, methanol, and trifluromethanol to explore their relative stability in a systematic way. Among all the hydrogen‐bonded nicotine complexes considered here, protonated forms in nicotine–ethanol and nicotine–methanol, and neutral form in nicotine–trifluromethanol complexes have been found to be the most stable. In the former two complexes, the proton attached to the pyrrolidine nitrogen acts as a strong hydrogen bond donor, whereas the pyrrolidine nitrogen atom acts as a hydrogen bond acceptor in the latter case. Neutral complex of nicotine with trifluromethanol has been found to possess a very short hydrogen bond (1.57 Å) and basis set superposition error corrected hydrogen bond energy value of 19 kcal/mol. The nature of the various hydrogen bonds formed has been investigated through topological aspects using Bader's atoms in molecules theory. From the calculated topological results, excellent linear correlation is shown to exist among the hydrogen bond length, electron density, and its Laplacian at the bond critical points for all the complexes considered. The natural bond orbital analysis has been carried out to investigate the charge transfer in the nicotine alcohol complexes. In contrast to the blue shifting behavior that is generally exhibited by other CH···O hydrogen bonds involving sp3 carbon atom, the CH···O hydrogen bond in the protonated nicotine–ethanol and methanol complexes has been found to be proper with red shifting in nature. © 2011 Wiley Periodicals, Inc.

3-Aminopyrrolidine-4-carboxylic acid as versatile handle for internal labeling of pyrrolidinyl PNA

Conformationally restricted pyrrolidinyl PNAs with an α/β-dipeptide backbone consisting of a nucleobase-modified proline and a cyclic five-membered amino acid spacer such as (1S,2S)-2-aminocyclopentanecarboxylic acid (ACPC) (acpcPNA) can form very stable hybrids with DNA with high Watson-Crick base pairing specificity. This work aims to explore the effect of incorporating 3-aminopyrrolidine-4-carboxylic acid (APC), which is isosteric to the ACPC spacer, into the acpcPNA. It is expected that the modification should not negatively affect the DNA binding properties, and that the additional nitrogen atom in the APC should provide a handle for internal modification. Orthogonally-protected (N(3)-Fmoc/N(1)-Boc and N(3)-Fmoc/N(1)-Tfa) APC monomers have been successfully synthesized and incorporated into the acpcPNA by Fmoc-solid-phase peptide synthesis. T(m), UV and CD spectroscopy confirmed that the (3R,4S)-APC could substitute the (1S,2S)-ACPC spacer in the acpcPNA with only slightly decreasing the stability of the hybrids formed between the modified acpc/apcPNA and DNA. In contrast, the (3S,4R) enantiomer of APC caused substantial destabilization of the hybrids. Furthermore, a successful on-solid-support internal labeling of the acpc/apcPNA via amide bond formation between pyrene-1-carboxylic acid or 4-(pyrene-1-yl) butyric acid and the pyrrolidine nitrogen atom of the APC spacer has been demonstrated. Fluorescence properties of the pyrene-labeled acpc/apcPNAs are sensitive to their hybridization states and can readily distinguish between complementary and single-mismatched DNA targets.

Two Solutions for the Same Problem: Multiple Binding Modes of Pyrrolidine-Based HIV-1 Protease Inhibitors

Structure-based drug design is an integral part of industrial and academic drug discovery projects. Initial lead structures are, in general, optimized in terms of affinity using iterative cycles comprising synthesis, biological evaluation, computational methods, and structural analysis. X-ray crystallography commonly suggests the existence of a single well-defined state, termed binding mode, which is generally assumed to be consistent in a series of similar ligands and therefore used for the following optimization process. During the further development of symmetrically disubstituted 3,4-amino-pyrrolidines as human immunodeficiency virus type 1 protease inhibitors, we discovered that, by modification of the P1/P1′ moieties of our lead structure, the activity of the inhibitors towards the active-site mutation Ile84Val was altered, however, not being explainable with the initial underlying structure–activity relationship. The cocrystallization of the most potent derivative in complex with the human immunodeficiency virus type 1 protease surprisingly led to two different crystal forms ( P2 12 12 1 and P6 122). Structural analysis revealed two completely different binding modes; the interaction of the pyrrolidine nitrogen atom with the catalytic aspartates remains as the only similarity. The study presented clearly demonstrates that structural biology has to escort the entire lead optimization process not to fail by an initially observed binding orientation.

Photoinduced charge transfer and electrochemical properties of triphenylamine I(h)-Sc3N@C80 donor-acceptor conjugates.

Two isomeric [5,6]-pyrrolidine-I(h)-Sc(3)N@C(80) electron donor-acceptor conjugates containing triphenylamine (TPA) as the donor system were synthesized. Electrochemical and photophysical studies of the novel conjugates were made and compared with those of their C(60) analogues, in order to determine (i) the effect of the linkage position (N-substituted versus 2-substituted pyrrolidine) of the donor system in the formation of photoinduced charge separated states, (ii) the thermal stability toward the retro-cycloaddition reaction, and (iii) the effect of changing C(60) for I(h)-Sc(3)N@C(80) as the electron acceptor. It was found that when the donor is connected to the pyrrolidine nitrogen atom, the resulting dyad produces a significantly longer lived radical pair than the corresponding 2-substituted isomer for both the C(60) and I(h)-Sc(3)N@C(80) dyads. In addition to that, the N-substituted TPA-I(h)-Sc(3)N@C(80) dyad has much better thermal stability than the 2-substituted one. Finally, the I(h)-Sc(3)N@C(80) dyads have considerably longer lived charge separated states than their C(60) analogues, thus approving the advantage of using I(h)-Sc(3)N@C(80) instead of C(60) as the acceptor for the construction of fullerene based donor-acceptor conjugates. These findings are important for the design and future application of I(h)-Sc(3)N@C(80) dyads as materials for the construction of plastic organic solar cells.

Stereospecific N-oxide-mediated monoprotection of trans-3,4-dihydroxypyrrolidine derivatives

We found that the syntheses of O-monosubstituted 1- N-alkyl- trans-3,4-dihydroxypyrrolidines, normally faces serious obstacles due to poorly reactive hydroxy groups as a consequence of the presence of a highly basic pyrrolidine nitrogen atom, but that they can be obtained easily in high yields by conversion of 1- N-alkyl- trans-3,4-dihydroxypyrrolidines into the corresponding N-oxides. N-Oxidation leads to the loss of the pyrrolidine nitrogen atom basicity and discrimination in the reactivity of the originally equivalent hydroxy groups by at least one order of magnitude. The reaction of N-oxide derivatives with DMTrCl or TBDPSCl then proceeds in an almost quantitative yield, rapidly, and stereospecifically on the hydroxy group which is in a cis-position to the N-oxide oxygen atom. In contrast to the TBDPS derivative, the DMTr derivative could be easily deoxygenated with triphenylphosphine in high yield. The structures of the products obtained were confirmed by 2D NMR experiments, and quantum-chemical calculations were performed to explain the reaction mechanism of the stereospecific course of the reaction.

Theoretical Study of Fulleropyrrolidines by Density Functional and Time-Dependent Density Functional Theory

Density functional theory (DFT) calculations have been employed in a study of various fulleropyrrolidines in order to determine their electronic structure and in particular the effect on the chemical properties of the pyrrolidine nitrogen atom of fullerene as well as of additional substituents. It is found that fullerene causes a large chemical shift in the calculated N 1s binding energy, while further substitution at N has smaller effect independent of the type of substituent. Time-dependent DFT calculations have been employed for the calculation of the energy of the lower-lying electronic states of fulleropyrrolidines, as well as on higher-lying states, in view of the intense interest related to photoinduced charge-transfer processes in these systems. The TDDFT calculations on the lower-lying states converge on the same lowest excitation energy for most of the substituted fulleropyrrolidines, favoring excitations from occupied orbitals localized on C60 even when the highest occupied molecular orbital (HOMO) is localized on the substituent groups. Good agreement is found with the experimental lowest excitation energy in fullerene and in the fulleropyrrolidine−porphyrin system. Finally, an excitation to a higher-lying state, related to the charge-transfer process, has been determined by TDDFT calculations on a porphyrin−fulleropyrrolidine system, where it is found that the absorption characteristics of the individual substituent are transferable to the combined system.

Spectroscopic study of the reaction of cis-1,3-di(2-pyridyl)[60]fullereno[1,2-c]pyrrolidine and 2-(2-pyridylmethyl)-1,3-di(2-pyridyl)[60]fullereno[1,2-c]pyrrolidine with zinc meso-tetraphenylporphyrinate

Axial coordination of the pyrrolidine nitrogen atom in cis-1,3-di(2-pyridyl)[60]fullereno[1,2-c]pyrrolidine to zinc meso-tetraphenylporphyrinate in cyclohexane gives rise to a donor-acceptor complex. The formation constant of the 1: 1 porphyrin—fullerenopyrrolidine complex was determined by spectrophotometric and fluorescence titration. The values of the constant estimated by spectrophotometric and fluorescence methods are 1.2·104 and 9.7·103 L mol−1, respectively.

Supplementing pharmaceutical analysis techniques using radiotracers

Radiolabeled compounds can be used for alleviating the degradation pathways and mass balance of drug products in the solid formulation, because it provides a very sensitive and specific method of locating and measuring particular compounds. The present study utilizes this methodology on levormeloxifene—a partial oestrogen receptor agonist—in the solid dosage form. It demonstrates how radiotracers can be used as a supplement to conventional analytical methods to investigate the degradation pathways and mass balance of drug substances as well as how they can be useful to cross validate the traditional analytical methods developed for the determination of uniformity of content, assay, and purity. To decrease the study time, pilot studies—in which the product was stored at high pressures of molecular oxygen and elevated temperatures—were performed. Conditions mimicking the degradation processes taking place under standard storage conditions of the drug substance were found, and these super-enhanced stress conditions were applied. The study time was thereby dramatically decreased. The produced degradation products were studied by liquid chromatography with mass spectrometric detection. The most important degradation pathway was ascribed to the oxidation of the pyrrolidine nitrogen atom in levormeloxifene to an N-oxide derivative of the drug substance. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1142–1153, 2004

Synthesis of water soluble fulleropyrrolidines bearing biologically active arylpiperazines

New water soluble fulleropyrrolidines endowed with biologically active arylpiperazines have been synthesized by 1,3-dipolar cycloaddition of in situ generated azomethyne ylides to C 60. The substitution pattern on the pyrrolidine and piperazine rings ensures their solubility in a H 2O/DMSO (9:1) solvents mixture. The mass spectrometry study reveals a different fragmentation pathway for the fulleropyrrolidines depending upon the substituent on the pyrrolidine nitrogen atom, affording in all cases to differently substituted methanofullerenes. Preliminary biological tests reveal a moderate activity in vitro experiments.

Optically active methacrylic polymers bearing side-chain conjugated azoaromatic chromophores

Novel optically active homopolymeric polymethacrylates have been synthesized by radical polymerization of the corresponding monomers (S)-3-methacryloyloxy-1-(4-azobenzene)pyrrolidine and (S)-3-methacryloyloxy-1-(4′-nitro-4-azobenzene)pyrrolidine. The polymers are characterized by the presence in the side chain of an optically active chiral moiety linked to the trans-azoaromatic system through the pyrrolidine nitrogen atom, which allows the establishment of a donor–acceptor conjugated system. The thermal properties of the polymeric derivatives indicate an appreciable thermal stability and increased glass transition temperature values with respect to similar polymeric derivatives bearing in the side chain the conjugated trans-azoaromatic chromophore. UV and circular dichroism spectra in solution suggest that dipolar interactions between the chromophores are present in the polymeric derivatives and that the macromolecules assume for chain sections dissymmetric conformations with a prevailing screw sense, induced by the presence of the conformationally rigid optically active cyclic moiety. This gives rise to much higher optical activity of the macromolecular systems with respect to that afforded by the structurally related low molecular weight compounds synthesized as models of the polymer repeating units, despite the low stereoregularity degree of the polymeric main chain.

Enantioselective Catalysis, XV Preparative and Structural Chemistry of Diastereomeric Derivatives of 3‐Phosphanylpyrrolidine and Their Palladium(II) Complexes ‐ Asymmetric Grignard Cross‐Coupling Reaction

AbstractThe preparation of both diastereomeric derivatives of 3‐(diphenylphosphanyl) pyrrolidine with chiral (tetrahydrofuran‐2‐yl)methyl and [(N‐neopentyl)pyrrolidin‐2‐yl]methyl groups as substituents on the pyrrolidine nitrogen atom and of (2S,4S)‐1‐benzyl‐4‐(diphenylphosphanyl)‐2‐(methoxymethyl) pyrrolidine is reported. [3S,P(RS)]‐3‐(phenylphosphanyl) pyrrolidine, bearing an additional chiral center on phosphorus, is the starting material for the preparation of phosphanes, in which one phenyl group of the PPh2 moiety is substituted by an 2‐methoxyphenyl (=An) or 2,4,6‐trimethoxyphenyl (=TMP) group. PdI2 complexes of these ligands were separated into diastereomers by chromatography on silica gel columns. The structural chemistry of these novel phosphane diastereomers and their PdI2 complexes is investigated by X‐ray crystallography and NMR. At the P,N‐coordinated palladium center displacement of an iodide anion is found for P,N,N′ ligands only. In the nickel complex catalysed cross‐coupling reaction, yielding 3‐phenyl‐1‐butene, we obtain the highest enantioselectivities in the case of simple 1‐alkyl‐3‐(diphenylphosphanyl)pyrrolidine ligands. The enantioselectivity obtained with diastereomeric derivatives, bearing additional ether or amine ligating sites is mainly determined by the chiral center in 3‐position of the 3‐(phosphanyl) pyrrolidine part of these ligands. Optimisation of enantioselectivity with these ligands can be carried out by a variation of the ligand to nickel ratio and by the choice of the vinyl halide used as starting compound. The catalytic cycle must contain at least one catalytically active species, bearing more than one β aminoalkylphosphane ligand.

Aromatic and Amine Substituent Effects on the Apparent Lipophiiicities of N-[(2-Pyrrolidinyl)methyl]-Substituted Benzamides

Lipophilic properties of 92 dopamine D-2 receptor antagonists belonging to the substituted benzamide class of compounds (orthopramides and methoxysalicylamides) were determined by oc- tadecylsilane reversed-phase HPLC. The apparent lipophilicity at pH 7.5 (log few) was obtained from the chromatographic capacity factors in 0.02M 3-(morpholino)propanesulfonic acid (MOPS) buffer at various concentrations of methanol. The experimental log Arw values were validated by comparison with the apparent octanol-water partitioning (log Papp) of 15 compounds of low to medium lipophilicity. The global lipophilicity of the neutral molecule (log few°) was obtained by correcting for ionization of the amine and the phenol, using known relationships for the effects on the pKa (where Ka is the dissociation constantS) of aromatic and aliphatic substituents. Multiple regression analysis showed that log few° can be expressed as the sum of π contributions and a cross correlation term (Σγσ) for interactions between the aromatic substituents. Comparison between the methoxysalicylamide (raclo- pride) series and the orthopramide (sulpiride) series demonstrated that an aromatic 6-hydroxy group increased log kw by 0.4 in the 5-halogen series and by 0.8 in the 5-alkyl series, and that a 6-methoxy group decreased log kw by 0.5. These paradoxical effects can be explained by the masking of the polarity of the amide caused by the 6-hydroxy group forming an intramolecular hydrogen bond with the amide carbonyl group. Introduction of an additional ortho-methoxy substituent had the opposite effect because the resulting steric hindrance prevents the amide moiety from adopting a coplanar conformation with the benzene ring. The presence of a substituent in the aromatic 3-position lowered log kw by 0.3 via a combination of steric and electronic influences on the adjacent 2-methoxy group, causing a weakening of the hydrogen bond between the amide and the oxygen atom of the 2- methoxy group. As a result, halogen and alkyl substituents in the 3- position increase the apparent lipophilicity only half that of similar substituents in the 5-position. Substitution with ω-fluoroalkoxyl groups in the aromatic 2- and 3-positions and with co-fluoroalkyl groups in the 5- position reduced lipophiiicities by 0.5 as compared with the corresponding desfluoro derivatives, thereby making them equivalent to an alkyl derivative with one less carbon atom in the chain. In contrast, substitution on the pyrrolidine nitrogen atom with a 2-fluoroethyl or a 3-fluoropropyl group produced compounds with apparent lipophiiicities ˜1.5 and ˜0.5 higher, respectively, than those of the corresponding W-ethyl derivatives. These effects result from a fluorine- induced decrease of the basicity of the amine. With these relationships, the apparent lipophiiicities at pH 7.4 were predicted for a series of recently developed benzamide radioligands to evaluate their utility as single photon emission computed topography and positron emission topography imaging agents of the dopamine D-2 receptor in the human brain.

Adsorption mechanisms of nicotine on humic acid and clay humic acid complex

AbstractThe adsorption isotherm of nicotine on humic acid ‐ surface was found to be multiphase according to the applied concentrations of nicotine. Each phase was characterized by its own change in free energy and represented a mechanism of interaction. At low concentrations, the isotherm showed a H‐curve of high affinity between both reactants as a result of protonation of the pyrrolidine nitrogen atom of nicotine, the second phase was that of flat adsorption in which the nitrogen atoms of nicotine acted as electron donor. The third phase was that of the rearrangement of the nicotine from flat to side adsorption on the humic surface, after which the phase of multilayer formation followed. The adsorption on the surface of the humic acid‐clay complex showed no distinct phases but an isotherm looks like the L‐type, although it could not verify Langmuir's equation. Probably the isotherm was the resultant of two mechanisms one due to the adsorption of the humic acid part and the other due to the clay part in the complex. Comparison of the constants of Freundlich's equation showed that the capacity of the adsorption humic surface was greater than that of the complex.

Conformation and crystal structure of L-prolyl-L-glutamic acid dihydrate.

The crystal structure of the dipeptide L-prolyl-L-glutamic acid dihydrate, L-Pro-L-Glu . 2H2O, C10H20O7N2, has been determined from three-dimensional X-ray diffractometer data. The dipeptide crystallizes in the space group P21 of the monoclinic system with two formula units in a cell of dimensions a = 5.629(2), b = 11.832(5), c = 10.485(4)A, and beta = 103.06(3) degrees. The structure was solved by direct methods and refined by least squares techniques to a final value of the conventional R-factor (on F) of 0.039 based on 1798 independent intensities with I greater than or equal to 3 sigma(I). The dipeptide occurs as a zwitterion in the crystal with the pyrrolidine nitrogen atom protonated and the main chain carboxyl group deprotonated. The conformation of the peptide linkage is trans, the omega torsional angle being 173.7 degrees. The pyrrolidine ring adopts the Cs-C beta endo conformation and the conformation of the glutamyl side chain is fully extended. There is considerable intermolecular hydrogen bonding in the crystals.