Pyrrolidine Derivatives Research Articles

Synthesis of Fluoropyrrolidines and (Fluoroalkyl)pyrrolidines

Pyrrolidines and their derivatives are of great interest in medicinal chemistry and organic synthesis. Fluoropyrrolidines and (fluoroalkyl)pyrrolidines have been utilized in the preparation of medicinal drugs and also as organocatalysts. The synthesis of such compounds is achieved through the fluorination of pyrrolidine derivatives or by multistep synthesis from already containing fluoroalkyl precursors.1 Introduction1.1 General Interest of Fluorine-Containing Pyrrolidines1.2 Fluoroalkylpyrrolidines and the Gauche Effect2 Fluoropyrrolidines2.1 3-Fluoropyrrolidines2.2 3,3- and 3,4-Difluoropyrrolidines2.3 3,3,4-Trifluoropyrrolidines2.4 3,3,4,4-Tetrafluoropyrrolidines3 (Difluoromethyl)- and (Trifluoromethyl)pyrrolidines3.1 2-(Trifluoromethyl)pyrrolidines3.2 3- and 4-(Trifluoromethyl)pyrrolidines3.3 2-(Difluoromethyl)pyrrolidines3.4 3- and 4-(Difluoromethyl)pyrrolidines4 (Monofluoroalkyl)pyrrolidines4.1 2-(Monofluoromethyl)pyrrolidines4.2 2-(Monofluoroalkyl)pyrrolidines4.3 2-(Monofluoroalkenyl)pyrrolidines5 Conclusion

Ni(I)-Catalyzed Reductive Cyclization of 1,6-Dienes: Mechanism-Controlled trans Selectivity

Summary A Ni-catalyzed reductive cyclization of 1,6-dienes affords 3,4-disubstituted cyclopentane and pyrrolidine derivatives with high trans diastereoselectivity. This cyclization reaction enables the efficient synthesis of trans- 3,4-dimethyl gababutin, a pharmaceutical lead for treating neuropathic pain, and trans- 3,4-dimethylpyrrolidine, a precursor to drug candidates and pesticides. The trans selectivity distinguishes this reaction from relevant precedents that proceed via hydrogen-atom transfer and lead to cis products. Mechanistic investigation, including kinetic, spectroscopic, and radical clock studies, attributes the trans diastereoselectivity to a classic, organometallic catalytic cycle mediated by Ni(I) and Ni(III) intermediates. The electron-rich Ni(I) intermediate, stabilized by a redox-active α-diimine ligand, is responsible for the chemoselectivity toward reductive cyclization as opposed to the redox-neutral cycloisomerization observed with previous Ni(II) catalysts.

Does the Novel Class of (2R, 4S)-N-(2, 5-Difluorophenyl)-4-Hydroxy-1-(2, 2, 2-Trifluoroacetyl) Pyrrolidine-2-Carboxamide’s Have Any Effect on Cell Viability and Apoptosis of Human Hepatocellular Carcinoma Cells?

Background: The hepatocellular carcinoma is believed to be the third cause of death due to cancer, worldwide. A new derivative of the (2R,4S)-N-(2,5-difluorophenyl)-4-hydroxy-1-(2,2,2-trifluoroacetyl) pyrrolidine-2-carboxamide compound were synthesized, employing a facile one-pot reaction of trans-4-hydroxy proline and N-(2,5-difluorophenyl)-2,2,2-trifluoroacetimidoyl chloride in the presence of TiO2 as catalysts and sodium hydrogen carbonate. Objectives: Therefore, in the present study we aimed to explore whether if the above new derivative pyrrolidine-2-carboxamide can affect cellular viability and apoptosis in cancerous HepG2 cell line. Methods: HepG2 cells were cultured in RPMI 1640 medium containing fetal bovine serum. Cultured cells were then treated with 7.8 µM to 125 µM of pyrrolidine-2-carboxamide. The toxicity of the compound was assayed by MTT method and detection of annexin V signal, using a flowcytometry system. Results: We found the pyrrolidine-2-carboxamide derived inhibition of HepG2 cells following a dose and time dependent fashion. The highest numbers of dead cells were observed in 125 µM dose, after 48 hours of treatment. Flow cytometric analysis also revealed that massive numbers of apoptotic cells were detectable in response to treatment with this pyrrolidine derivative. Conclusions: Overall, according to the data presented here, the pyrrolidine-2-carboxamide could possibly control cellular viability/apoptosis. Thus it can potentially be concerned as a useful therapeutic tool for hepatocellular carcinoma treatment.

Synthesis of 2-carboxylated aza-ring derivatives through α-monohalogenation/ring-contraction of N-sulfonyl lactams

2-Carboxylated aza-rings have been synthesized in two steps through a highly selective monohalogenation of N-sulfonylated lactams of various ring sizes (from 5- to 8-membered rings) followed by a ring contraction reaction. The selective monohalogenation of N-sulfonyl lactams has been achieved in modest to excellent yields (9 examples, 39–96%) using N-halogenosuccinimides via the in situ generation of trimethylsilyl ketene aminal derivatives. The so-obtained α-halogeno N-sulfonyl lactams were engaged in a ring opening/ring closing reaction in the presence of various alcohols or anilines under basic conditions affording 2-carboxylated aza-rings, such as azetidine, pyrrolidine or piperidine derivatives in high yields (24 examples, 61–99%).

Selective Ring-Opening of N-Alkyl Pyrrolidines with Chloroformates to 4-Chlorobutyl Carbamates.

Our study shows that among aza-heterocycles of various ring sizes, including aziridines, azetidines, pyrrolidines, and piperidines, only N-alkyl pyrrolidines undergo competitive reaction pathways with chloroformates to yield N-dealkylated pyrrolidines and 4-chlorobutyl carbamates. The pathway taken depends on the substituent on the nitrogen, i.e., ring-opening with methyl and ethyl substituents and dealkylation with a benzyl substituent. Computational calculations support the substituent-dependent product formation by showing the energy difference between the transition states of both reaction pathways. Selective ring-opening reactions of N-methyl and N-ethyl pyrrolidine derivatives with chloroformates were utilized to prepare various 4-chlorobutyl carbamate derivatives as valuable 1,4-bifunctional compounds.

Asymmetric [3 + 2] Cycloaddition of 2,2′-Diester Aziridines To Synthesize Pyrrolidine Derivatives

A highly diastereo- and enantioselective [3 + 2] cycloaddition of 2,2′-diester aziridines with 3,4-dihydropyran derivatives and acyclic enol ethers has been established. Various optically active octahydropyrano[2,3-c]pyrrole and 3-methoxypyrrolidine derivatives were generated in moderate to high yields (up to 94%) and good stereoselectivities (>19:1 dr, up to 95.5:4.5 er). The methodology was also applied in the highly diastereoselective synthesis of d-galactal derivatives. The absolute configuration of the octahydropyrano[2,3-c]pyrroles showed that the reactions using 3,4-dihydropyran and 6-alkyl-substituted ones as substrates gave reversed diastereoselection in the final cyclization step.

Niobium-Catalyzed Intramolecular Addition of O-H and N-H Bonds to Alkenes: A Tool for Hydrofunctionalization.

A convenient, versatile, and easy to handle intramolecular hydrofunctionalization of alkenes (C-O and C-N bonds formation) is reported using a novel niobium-based catalytic system. This atom economic and eco-friendly methodology provides an additional synthetic tool for the straightforward formation of valuable building blocks enabling molecular complexity. Various pyran, furan, pyrrolidine, piperidine, lactone, and lactam derivatives as well as spirocyclic compounds are produced in high yields and selectivities.

Brønsted Acid/Silane Catalytic System for Intramolecular Hydroalkoxylation and Hydroamination of Unactivated Alkynes

The Bronsted acid-catalyzed intramolecular hydroalkoxylation and hydroamination of unactivated alkynes are described. We found that unactivated alkynes are electrophilically activated by a catalytic amount of bis(trifluoromethanesulfonyl)imide to undergo intramolecular hydroalkoxylation and hydroamination. In the presence of silane, the formed reactive exo-cyclic enol ether and exo-cyclic enamine intermediates are effectively reduced to the corresponding saturated cyclic ethers and N-protected cyclic amines. The 2,4-cis and 2,5-cis pyrrolidine derivatives are produced with high diastereoselectivity. Taking advantage of this selectivity, the 2,5-cis-disubstituted prolinol was also synthesized from glutamic acid in the optically active form.

Chemical structures of constituents from the leaves of Polyscias balfouriana.

A new pyrrolidine derivative, (5S)-hydroxyethyl 2-oxopyrrolidine-5-carboxylate (1), a new flavonol glycoside, tamaraxetin 3,7-di-O-α-L-rhamnopyranoside (2), and a new triterpene saponin, polyscioside A methyl ester (3), along with six known compounds (4-9) were isolated from the leaves of Polyscias balfouriana. Their chemical structures were elucidated on the basis of extensive spectroscopic analysis.

Palladium-catalyzed asymmetric allylic alkylation of acyclic ketones for synthesis of 2,2-disubsituted pyrrolidine derivatives

Palladium-catalyzed asymmetric allylic alkylation of acyclic ketones represents a significant challenge in organic synthesis. We report herein that the synthesis of chiral 2,2-disubsituted pyrrolidines from acyclic ketones has been accomplished by using catalytic asymmetric method in the presence of Pd(dba)2 and (R)-binap ligand. Theses reactions occur between allyl methyl carbonate and unstabilized acyclic lithium enolates to provide the products in moderate to good enantioselectivity (up to 81% ee).

Cytosolic Phospholipase A2 Alpha is Required for Human Smooth Muscle Cell Proliferation and Not Migration to Platelet Derived Growth Factor BB

Platelet derived growth factor BB (PDGF BB) has an important influence on smooth muscle cell migration and proliferation in restenosis and atherosclerosis. Our understanding of different signal transduction pathways involved in the response of smooth muscle cells to PDGF BB is potentially significant for understanding and manipulating these processes. Prior studies have demonstrated a crucial activation of cytosolic phospholipase A2 (cPLA2) in smooth muscle cells to PDGF BB with the production of arachidonic acid and prostaglandin E2. In this study, we first investigated the role of cPLA2α on human aortic smooth muscle cell (HASMC) migration using modified Boyden chamber assay and under agarose migration studies. AACOCF3 (cPLA2 and iPLA2 inhibitor), 1,2,4-trisubstituted pyrrolidine derivative (cPLA2 inhibitor), and Bromoenol lactone (iPLA2 inhibitor) had no effect on HASMC chemotaxis to PDGF-BB in a modified Boyden chamber. These results were confirmed with specific inhibition of cPLA2α using small interfering RNA (siRNA) showing that HASMC migration was not inhibited in modified Boyden chamber or under agarose migration studies. Using the same siRNA to cPLA2 alpha had very significant inhibition to PDGF-BB dependent HASMC proliferation. These data demonstrate there is a distinct role especially for cPLA2α on human aortic HASMC proliferation and not migration to PDGF-BB.

Selective synthesis of tetrahydroimidazo[1,2-a]pyridine and pyrrolidine derivatives via a one-pot two-step reaction.

In the presence of triethylamine, the addition reaction of substituted α-amino acid alkyl esters including ethyl hyperphenylalaninate, phenylalaninate, isoleucinate, and alaninate with dialkyl but-2-ynedioate afforded active β-enamino esters, which in turn reacted with aromatic aldehydes and malononitrile to give tetrahydroimidazo[1,2-a]pyridine derivatives in moderate yields. Under similar reaction conditions, the reaction of ethyl glycinate with dialkyl but-2-ynedioate resulted in a 1,3-dipolar azomethine ylide, which reacted further with in situ-generated arylidene malononitrile, alkyl cyanoacetate, and cyanoacetamide to give polysubstituted pyrrolidine derivatives in good yields.

Copper(i)-catalyzed 5-exo-trig radical cyclization/borylation of alkyl halides: access to functionalized pyrrolidine derivatives

This work reports the copper(i)-catalyzed 5-exo-trig radical cyclization/borylation of alkyl halides bearing an alkene moiety, during which a C-C bond and a C-B bond were formed in one step. Various functionalized pyrrolidine derivatives bearing a quaternary carbon center were obtained, and they showed good functional group tolerance and high chemoselectivity. This transformation was highly efficient and could be finished in 20 minutes. A radical mechanism has been proposed.

Copper-catalyzed remote (δ) C(sp3)-H bond amination: a practical strategy to construct pyrrolidine derivatives.

We report a copper-catalyzed remote C(sp3)-H bond amination reaction that converts acyclic amines to pyrrolidines. This reaction occurs selectively at the carbon δ to the amine functionality. Primary, secondary and tertiary C-H bonds are all suitable for the amination reactions in the presence of an inexpensive and commercially available copper catalyst.

ChemInform Abstract: Caveat in the Stereochemical Outcome of the Organocatalytic Diels—Alder Reaction in PEG‐400.

AbstractDiels—Alder reaction between cinnamaldehydes (I) and cyclopentadiene (II) in the presence of (S)‐pyrrolidine derivative as catalyst and perchloric acid as additive yields cycloaddition products favouring the endo formation (IV).

Fatty Acids from a Glass Sponge Aulosaccus sp. Occurrence of New Cyclopropane-Containing and Methyl-Branched Acids.

In order to identify new structures, the free fatty acids from an extract of a glass sponge Aulosaccus sp. (from the north-west Pacific) belonging to one of the least chemically investigated classes (Hexactinellida), were fractionated by RP-HPLC and analyzed by NMR spectroscopy and GC-MS of their pyrrolidine derivatives, methyl(ethyl) esters and their dimethyl disulfide adducts. One hundred and twenty-three C12-C31 acids (including nine new compounds) were detected, one hundred and ten of these compounds have not been found previously in glass sponges. The levels of common methylene-interrupted polyenes, monoenes of the (n-7) family and less common branched-chain components proved to be high. New acids were shown to be 5,13-dimethyl-tetradec-4-enoic, cis-10,11-methylene-heptadecanoic, 10,12-dimethyl-octadecanoic, cis-12,13-methylene-nonadecanoic, (14E)-13-methyl-eicos-14-enoic, 19-methyl-eicos-13-enoic, cis-20,21-methylene-heptacosanoic, 27-methyl-octacos-21-enoic and (22Z)-nonacos-22-enoic. Some important mass spectrometric characteristics of pyrrolidides of homologous cyclopropane fatty acids are reported and discussed.

NITROGEN-CONTAINING ACETALS AND KETALS IN THE SYNTHESIS OF PYRROLIDINE DERIVATIVES

This review offers analysis and generalization of data regarding the synthesis of substituted pyrrolidines by using nitrogen-containing acetals and ketals as starting compounds published from year 2000 to 2016. Particular attention has been focused on the synthesis of pyrrolidines that are substituted at position 2. Biological activity data for several pyrrolidine derivatives are reported. Authors: Andrey V. Smolobochkin, Almir S. Gazizov*, Alexander R. Burilov, Michael A. Pudovik

ChemInform Abstract: Palladium‐Initiated Radical Cascade Stereoselective Iodofluoroalkylation/Cycloisomerization of Ene‐vinylidenecyclopropanes.

AbstractThe mild, highly atom economic transformation offers a stereoselective access to diverse difluoromethylated or perfluoromethylated pyrrolidine derivatives endowed with an alkyl iodide tether.

Effect of Brønsted acids on the thiophenol-mediated radical addition–translocation–cyclization process for the preparation of pyrrolidine derivatives

A thiophenol-mediated method for the conversion of propargylamines to pyrrolidines under acidic conditions is described. This cascade reaction involves addition of a thiyl radical to the terminal alkyne followed by a 1,5-hydrogen transfer (radical translocation) and a rapid cyclization affording the pyrrolidine ring. Our studies reveal that complete protonation of the tertiary amine with 10 equivalents of trifluoroacetic acid avoids undesired hydrogen atom abstractions by the thiyl radicals.

Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate.

A mild aerobic intramolecular aminoacetoxylation method for the synthesis of pyrrolidine and indoline derivatives was achieved using molecular oxygen as the oxidant. A catalytic NOx species acts as an electron transfer mediator to access a high-valent palladium intermediate as the presumed active oxidant.