Synthesis Of Pyrrolidines Research Articles

Phosphonium ylides in the multicomponent synthesis of pyrrolidines

A multicomponent synthesis of pyrrolidines starting from phosphonium ylides, N-alkylglycines and carbonyl compounds was performed in 37–87% yields. This approach is based on a Wittig/Huisgen tandem reaction and simultaneous generation of the two reactive intermediates: alkene and azomethine ylide from the same carbonyl compound. Both stabilized and nonstabilized azomethine ylides were employed in this process allowing the construction of highly substituted dispiropyrrolidines as well as simple 3-substituted pyrrolidines.

Cobalt‐Catalyzed Selective Transformation of Levulinic Acid and Amines into Pyrrolidines and Pyrrolidinones using Hydrogen

AbstractCobalt‐catalyzed selective transformation of levulinic acid and primary amines into pyrrolidines and pyrrolidinones under H2has been developed. The catalyst system consisting of Co(NTf2)2, 1,1,1‐tris(di(4‐methoxyphenyl)phosphinomethyl) ethane ((p‐anisyl)triphos) and Me3SiOTf works well for the synthesis of pyrrolidines via reductive amination/cyclization/deoxygenative reduction of amide, and using Co(NTf2)2/1,1,1‐tris(diphenylphosphinomethyl) ethane (triphos) as the catalyst under reduced hydrogen pressure results in exclusive formation of pyrrolidinones. Both aryl and alkyl primary amines are suitable substrates, and a variety of functional groups are tolerated. Meanwhile, 4‐oxo‐4‐arylbutanoic acids, 5‐oxohexanoic acid, 6‐oxoheptanoic acid, 2‐formylbenzoic acid, 2‐acetylbenzoic acid and 2′‐acetyl‐[1,1′‐biphenyl]‐2‐carboxylic acid are also applicable, allowing for convenient access to cyclic amines and lactams with different ring size.magnified image

Mechanistic Studies on the Synthesis of Pyrrolidines and Piperidines via Copper-Catalyzed Intramolecular C-H Amination.

We have recently developed a method for the synthesis of pyrrolidines and piperidines via intramolecular C–H amination of N-fluoride amides using [TpxCuL] complexes as precatalysts [Tpx = tris(pyrazolyl)borate ligand and L = THF or CH3CN]. Herein, we report mechanistic studies on this transformation, which includes the isolation and structural characterization of a fluorinated copper(II) complex, [(TpiPr2OH)CuF] [TpiPr = hydrotris(3,5-diisopropylpyrazolyl)borate], pertinent to the mechanistic pathway. The effects of the nature of the Tpx ligand in the copper catalyst as well as of the halide in the N–X amides employed as reactants have been investigated both from experimental and computational perspectives.

Phosphine-Catalyzed Enantioselective (3+2) Annulation of Vinylcyclopropanes with Imines for the Synthesis of Chiral Pyrrolidines.

A phosphine-catalyzed highly enantioselective and diastereoselective (up to 98 % ee and >20 : 1 dr) (3+2) annulation between vinylcyclopropanes and N-tosylaldimines has been developed, which allows facile access to a range of highly functionalized chiral pyrrolidines. Notably, this method makes use of vinylcyclopropanes as a synthon for phosphine-mediated asymmetric annulation reaction, which will offer new opportunities for potential applications of cyclopropanes substrates in phosphine-catalyzed organic transformations.

Phosphine‐Catalyzed Enantioselective (3+2) Annulation of Vinylcyclopropanes with Imines for the Synthesis of Chiral Pyrrolidines

AbstractA phosphine‐catalyzed highly enantioselective and diastereoselective (up to 98 % ee and >20 : 1 dr) (3+2) annulation between vinylcyclopropanes and N‐tosylaldimines has been developed, which allows facile access to a range of highly functionalized chiral pyrrolidines. Notably, this method makes use of vinylcyclopropanes as a synthon for phosphine‐mediated asymmetric annulation reaction, which will offer new opportunities for potential applications of cyclopropanes substrates in phosphine‐catalyzed organic transformations.

Enantioselective Synthesis of Pyrrolidines by a Phosphine-Catalyzed γ-Umpolung/β-Umpolung Cascade.

Herein, we report an enantioselective catalytic annulation of electron-poor allenes with aminocrotonates. The reaction proceeds by the umpolung γ-amination of the allenoate and β-umpolung intramolecular conjugate addition. The reaction provides ready access to pyrrolidines using a homochiral phosphepine catalyst, which allows most products to form in good yields (55-85%) with ≥95:5 er and ≥4:1 dr. An assisted tandem-catalytic variant is also viable, and mechanistic studies supporting the proposed reaction pathway are reported.

Stereoselective synthesis of dispiroindano pyrrolidines by the [3 + 2] cycloaddition of thiazolo[3,2‐a]indole tethered dipolarophile with azomethine ylides

AbstractAzomethine ylides generated by the reaction of cyclic ketones, namely ninhydrin, acenaphthene quinone and 11H‐indeno[1,2‐b]‐quinoxalin‐11‐one, with (i) α‐amino acids (ii) primary/secondary amines, have been successfully utilized for one‐pot three‐component [3 + 2] cycloaddition reactions with a thiazolo[3,2‐a]indole containing dipolarophile (in‐turn generated by the reaction of thieno[2,3‐b]indole‐2,3‐dione and dimethyl acetylene dicarboxylate). Dispiro heterocycles were synthesized in excellent yields and with high stereo‐ and regioselectivity.

Asymmetric Synthesis of Pyrrolidines via Oxetane Desymmetrization.

Asymmetric synthesis of chiral pyrrolidines bearing an all-carbon quaternary stereocenter in the 3-position remains challenging. Herein we report two efficient protocols by means of oxetane desymmetrization, featuring the use of a readily available tert-butylsulfinamide chiral auxiliary and a catalytic system with chiral phosphoric acid as the source of chirality, respectively.

Chemoselective and diastereodivergent synthesis of new spirooxindolo-pyrrolizidines and pyrrolidines stemming from unsymmetrical 1,3-bis(arylidene)tetral-2-ones: a combined experimental and theoretical study

An experimental and theoretical study of an efficient one-pot three-components cycloaddition reaction leading to pentacyclic dispiropyrrolizidin/pyrrolidinoxindoles endowed by four contiguous stereogenic centres with moderate to good yields was reported.

Stable D-xylose ditriflate in divergent syntheses of dihydroxy prolines, pyrrolidines, tetrahydrofuran-2-carboxylic acids, and cyclic β-amino acids.

Double nucleophilic displacement of D-xylo-ditriflate by amines, water and alkyl cyanoacetates, respectively, gave a series of bicyclic divergent intermediates for the synthesis of a wide range of highly functionalized targets, including hydroxylated prolines, pyrrolidines, furanoic acids, and cyclopentanes.

Straightforward Synthesis of 3-Substituted Pyrrolidines from Active Methylene Compounds, Sarcosine and Formaldehyde

Straightforward Synthesis of 3-Substituted Pyrrolidines from Active Methylene Compounds, Sarcosine and Formaldehyde

Benzodioxole grafted spirooxindole pyrrolidinyl derivatives: synthesis, characterization, molecular docking and anti-diabetic activity.

A highly stereoselective, three-component method has been developed to synthesize pyrrolidine and pyrrolizidine containing spirooxindole derivatives. The interaction between the dipolarophile α,β-unsaturated carbonyl compounds and the dipole azomethine ylide formed in situ by the reaction of 1,2-dicarbonyl compounds and secondary amino acids is referred to as the 1,3-dipolar cycloaddition reaction. The reaction conditions were optimized to achieve excellent stereo- and regioselectivity. Shorter reaction time, simple work-up and excellent yields are the salient features of the present approach. Various spectroscopic methods and single crystal X-ray diffraction examinations of one example of compound 6i validated the stereochemistry of the expected products. The anti-diabetic activity of the newly synthesized spirooxindole derivatives was tested against the α-glucosidase and α-amylase enzymes. Compound 6i was found to exhibit potent inhibition activity against α-glucosidase and α-amylase enzymes which is further evidenced by molecular docking studies.

Mild and Efficient Synthesis of Pyrrolidines Catalyzed by Ceric Ammonium Nitrate

Mild and Efficient Synthesis of Pyrrolidines Catalyzed by Ceric Ammonium Nitrate

Catalytic asymmetric synthesis of enantioenriched α-deuterated pyrrolidine derivatives.

The recent promising applications of deuterium-labeled pharmaceutical compounds have led to an urgent need for the efficient synthetic methodologies that site-specifically incorporate a deuterium atom into bioactive molecules. Nevertheless, precisely building a deuterium-containing stereogenic center, which meets the requirement for optimizing the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of chiral drug candidates, remains a significant challenge in organic synthesis. Herein, a catalytic asymmetric strategy combining H/D exchange (H/D-Ex) and azomethine ylide-involved 1,3-dipolar cycloaddition (1,3-DC) was developed for the construction of biologically important enantioenriched α-deuterated pyrrolidine derivatives in good yields with excellent stereoselectivities and uniformly high levels of deuterium incorporation. Directly converting glycine-derived aldimine esters into the deuterated counterparts with D2O via Cu(i)-catalyzed H/D-Ex, and the subsequent thermodynamically/kinetically favored cleavage of the α-C–H bond rather than the α-C–D bond to generate the key N-metallated α-deuterated azomethine ylide species for the ensuing 1,3-DC are crucial to the success of α-deuterated chiral pyrrolidine synthesis. The current protocol exhibits remarkable features, such as readily available substrates, inexpensive and safe deuterium source, mild reaction conditions, and easy manipulation. Notably, the synthetic utility of a reversed 1,3-DC/[H/D-Ex] protocol has been demonstrated by catalytic asymmetric synthesis of deuterium-labelled MDM2 antagonist idasanutlin (RG7388) with high deuterium incorporation.

A Diastereoselective Catalytic Approach to Pentasubstituted Pyrrolidines by Tandem Anionic‐Radical Cross‐Over Reactions

AbstractPentasubstituted pyrrolidines are ubiquitous constituents of natural products and drugs, however the access options to them especially with respect to absolute and relative stereochemistry are not well developed. We report an asymmetric synthesis of N,2,3,4,5‐pentasubstituted pyrrolidines by oxidative single‐electron transfer‐catalyzed tandem aza‐Michael addition/radical 5‐exo cyclization/oxygenation reactions. The absolute stereochemistry is set by applying readily accessible chiral allylamines in asymmetric conjugate additions to various β‐substituted‐α,β‐unsaturated esters, which dependent on the substituent R2 sets the configuration of the two stereocenters next to the amine function, whereas two more are diastereoselectively generated by the radical 5‐exo cyclization step. This allows the diastereodivergent single‐step synthesis of pyrrolidines with four contiguous stereogenic centers. The stereoselectivity is rationalized by a predictive model.magnified image

Synthesis of Pyrrolidine- and γ-Lactam-Containing Natural Products and Related Compounds from Pyrrole Scaffolds.

Polycyclic alkaloid natural products featuring pyrrolidine and pyrrolidinone motifs remain enduring targets of total synthesis endeavors. Pyrrole and its derivatives have been exploited to access many such frameworks, including alkaloids belonging to the Aspidosperma, Stemona, and batzelladine families. In this article, a selection of exemplars that highlight the utility of pyrrole-based approaches to facilitate total syntheses of pyrrolidine- and pyrrolidinone-containing alkaloids and related molecules are showcased.

Nickel-Catalyzed Regiodivergent Asymmetric Cycloadditions of α,β-Unsaturated Carbonyl Compounds

Nickel-Catalyzed Regiodivergent Asymmetric Cycloadditions of α,β-Unsaturated Carbonyl Compounds

Aza-heterocycles via copper-catalyzed, remote C–H desaturation of amines

The majority of medicines contain a nitrogen atom within a five- or six- membered ring. To rapidly access both such aza-heterocycles, we sought to develop a remote C-H desaturation of amines. Inspired by the Hofmann-Löffler-Freytag synthesis of five-membered pyrrolidines, we tackled the century-old challenge of synthesizing six-membered piperidines by H-atom transfer. We present herein a double, vicinal C-H oxidation by dual catalysis, entailing Ir photocatalytic initiation of 1,5-HAT by an N-centered radical and Cu-catalyzed interception of the C-centered radical to facilitate desaturation. By this mechanism, two C-H bonds (δ and ε to N) are regioselectively removed from unbiased, remote positions of an alkyl chain. Over 50 examples illustrate efficiency, selectivity, functional group tolerance, and medicinal utility of this synthesis of both internal and terminal δ vinylic amines and aza-heterocycles. Mechanistic experiments probe the alkylcopper intermediate, as well as kinetics and regioselectivity of the HAT and elimination steps.

Solid phase synthesis of bicyclic pyrrolidines

Solid phase synthesis of bicyclic pyrrolidines

Asymmetric Synthesis of Enantiopure Pyrrolidines by C(sp3)−H Amination of Hydrocarbons

The asymmetric synthesis of enantiopure pyrrolidines is reported via a streamlined strategy relying on two sequential C-H functionalizations of simple hydrocarbons. The first step is a regio- and stereoselective catalytic nitrene C-H insertion. Then, a subsequent diastereoselective cyclization involving a 1,5-hydrogen atom transfer (HAT) from a N-centered radical leads to the formation of pyrrolidines that can then be converted to their free NH-derivatives.