Formation Of Pyrrolidines Research Articles

Tailoring C-H amination activity via modification of the triazole-derived carbene ligand.

Two new C,O-bidentate chelating triazolylidene-phenolate ligands were synthesized that feature a diisopropylphenyl (dipp) and an adamantyl (Ad) substituent respectively on the triazole scaffold. Subsequent metalation afforded iron(II) complexes [Fe(C^O)2] that are active catalysts for the intramolecular C-H amination of organic azides. When compared to the parent complex containing a triazolylidene with a mesityl substituent (Mes) the increased steric bulk led to slightly lower activity (TOFmax = 23 h-1vs. 30 h-1), however selectivity towards pyrrolidine formation increases from 92% up to >99%. Kinetic studies indicate that the mechanism is similar in all three complexes and includes a half-order dependence in [Fe(C^O)2], congruent with the involvement of a dimetallic catalyst resting state within this catalyst class. Structural analysis suggests that enhanced bulkiness disfavors N2 loss and nitrene formation, yet shields the nitrene from intermolecular processes and thus favors intramolecular nitrene insertion into the C-H bond. This model rationalizes the high selectivity and the lower reaction rate observed with dipp and with Ad substituents on the ligand.

From the bottle: simple iron salts for the efficient synthesis of pyrrolidines via catalytic C-H bond amination.

Commercially available iron salts FeX2 are remarkably active catalysts for pyrrolidine formation from organic azides via direct C-H bond amination. With FeI2, amination is fast and selective, (<30 min for 80% yield at 2 mol% loading), TONs up to 370 are reached with just 0.1 mol% catalyst, different functional groups are tolerated, and a variety of C-H bonds were activated.

Nickel‐Catalyzed Cascade Cyclization‐Negishi Coupling of Redox Active Esters for the Synthesis of Pyrrolidines

AbstractWe have developed a Ni‐catalyzed cascade cyclization/Negishi‐coupling reaction for the formation of pyrrolidines and pyrrolidinones starting from N‐protected allylamines and acrylamides which contain a redox active ester group. The reaction provides two C−C bonds in a single operation and takes place with both alkylzinc and arylzinc bromides as nucleophiles. Activation of RAE by low valent Ni complexes involving a radical pathway followed by a fast cyclization of intermediate carbon radicals is proposed.

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.

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

AbstractThe 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.

Iridium-Catalyzed Reductive Allylation of Esters.

The catalytic reductive transformation of carboxylic esters into α-branched ethers is described. The procedure pivots on the chemoselective iridium-catalyzed hydrosilylation of ester and lactone functionality to afford a silyl acetal intermediate. Upon treatment with a Lewis acid, these hemilabile intermediates dissociate to form reactive oxocarbenium ions, which can be intercepted by allyltributyltin nucleophiles, resulting in the formation of valuable α-branched alkyl-alkyl ether derivatives. This reductive allylation procedure was found to be amenable to a range of carboxylic ester starting materials, and good chemoselectivity for ethyl over tert-butyl esters was demonstrated. Furthermore, downstream synthetic manipulation of α-amino acid-derived products led to the efficient formation of pyrrolidine, piperidine, and azepane frameworks.

A Rh(III)-Catalyzed Formal [4+1] Approach to Pyrrolidines from Unactivated Terminal Alkenes and Nitrene Sources.

We have developed a formal [4+1] approach to pyrrolidines from readily available unactivated terminal alkenes as 4-carbon partners. The reaction provides a rapid construction of various pyrrolidine containing structures, especially for the diastereoselective synthesis of spiro-pyrrolidines. Mechanistic investigation suggests a Rh(III)-catalyzed intermolecular aziridination of the alkene and subsequent acid-promoted ring expansion for the pyrrolidine formation.

Chemoselective Kumada‐Type Iron Catalysis with Alkyl Grignard Reagents: Reductive Cyclization and Cyclomethylation

AbstractA chemoselective reductive cyclization and cyclomethylation reaction of 7‐iodohept‐2‐yne and 7‐iodohepta‐1,2‐diene derivatives has been carried out using an iron catalyst and various alkyl Grignard reagents, resulting in the formation of pyrrolidines, tetrahydrofurans, and carbocycles with an alkene functional group. The reaction is initiated by single‐electron transfer from reduced Fe species to alkyl iodides and the resulting Fe−H or Fe−Me compound differentiated the structures of the cyclized products, which exhibited diverse complexities and synthetic utilities.

Total Syntheses of (–)-7-epi-Alexine and (+)-Alexine Using Stereoselective Allylation

Total syntheses of (–)-7-epi-alexine and (+)-alexine were achieved by using stereoselective allylation via a functionalized pyrrolidine obtained from an extended chiral 1,3-oxazine. The synthetic strategies include pyrrolidine formation via oxazine cleavage and diastereoselective allylations of a pyrrolidine aldehyde. (–)-7-epi-Alexine and (+)-alexine were synthesized from anti,syn,anti-oxazine in 12 steps.

Co(TPP)]-Catalyzed Formation of Substituted Piperidines.

Radical cyclization via cobalt(III)‐carbene radical intermediates is a powerful method for the synthesis of (hetero)cyclic structures. Building on the recently reported synthesis of five‐membered N‐heterocyclic pyrrolidines catalyzed by CoII porphyrins, the [Co(TPP)]‐catalyzed formation of useful six‐membered N‐heterocyclic piperidines directly from linear aldehydes is presented herein. The piperidines were obtained in overall high yields, with linear alkenes being formed as side products in small amounts. A DFT study was performed to gain a deeper mechanistic understanding of the cobalt(II)‐porphyrin‐catalyzed formation of pyrrolidines, piperidines, and linear alkenes. The calculations showed that the alkenes are unlikely to be formed through an expected 1,2‐hydrogen‐atom transfer to the carbene carbon. Instead, the calculations were consistent with a pathway involving benzyl‐radical formation followed by radical‐rebound ring closure to form the piperidines. Competitive 1,5‐hydrogen‐atom transfer from the β‐position to the benzyl radical explained the formation of linear alkenes as side products.

Sustainable Manganese-Catalyzed Solvent-Free Synthesis of Pyrroles from 1,4-Diols and Primary Amines.

A general and selective metal-catalyzed conversion of biomass-derived primary diols and amines to the highly valuable 2,5-unsubstituted pyrroles has been developed. The reaction is catalyzed by a stable nonprecious manganese complex (1 mol %) in the absence of organic solvents whereby water and molecular hydrogen are the only side products. The manganese catalyst shows unprecedented selectivity, avoiding the formation of pyrrolidines, cyclic imides, and lactones.

Stereoselective Syntheses of (+)‐Broussonetine D and (+)‐Australine via a Functionalized Pyrrolidine from an Extended Chiral 1,3‐Oxazine

The asymmetric syntheses of (+)‐broussonetine D and (+)‐australine have been achieved via a functionalized pyrrolidine obtained from an extended chiral 1,3‐oxazine. The key steps include pyrrolidine formation by oxazine cleavage and diastereoselective allylation to a pyrrolidine aldehyde. (+)‐Broussonetine D and (+)‐australine were synthesized from anti,syn,syn‐oxazine, in six steps, with an overall yield of 22.2 %, and in seven steps, with an overall yield of 33.2 %.

Diastereoselective Carbamate Annulation for the Synthesis of 2,5‐Dideoxy‐2,5‐iminoglycitols

AbstractA combination of the Vasella‐reductive‐amination and carbamate annulation reactions was applied on a ketose starting material for the diastereoselective total synthesis of 2,5‐dideoxy‐2,5‐imino‐glycitols. The synthesis of 2,5‐dideoxy‐2,5‐imino‐l‐iditol (4) was particularly expedient (6 steps and 18% overall yield) as the route minimises the use of protecting groups, thereby reducing the number of synthetic steps and increasing the overall yield. The Vasella reductive amination methodology could be readily applied to the amination of ketones, albeit with moderate diastereoselectivity. However, the I2‐mediated carbamate annulation strongly favours the formation of pyrrolidines with the 2,5‐trans and 4,5‐cis relationships. The highly diastereoselective carbamate annulation thus provided a general means by which to synthesise 2,5‐dideoxy‐2,5‐imino‐glycitols of defined stereochemistry.

An Asymmetric Pathway to Dendrobine by a Transition‐Metal‐Catalyzed Cascade Process

AbstractAn asymmetric pathway to the caged tetracyclic pyrrolidine alkaloid, dendrobine, is reported. The successful synthetic strategy features a one‐pot, sequential palladium‐catalyzed enyne cycloisomerization and rhodium‐catalyzed diene‐assisted pyrrolidine formation by allylic CH activation. The developed transition‐metal‐catalyzed cascade process permits rapid access to the dendrobine core structure and circumvents the handling of labile intermediates. An intramolecular aldol condensation under carefully defined reaction conditions takes place with a concomitant detosylation, followed by reductive amine methylation, to afford a late‐stage intermediate (previously identified by several prior dendrobine syntheses) in only 10 synthetic steps overall.

An Asymmetric Pathway to Dendrobine by a Transition-Metal-Catalyzed Cascade Process.

An asymmetric pathway to the caged tetracyclic pyrrolidine alkaloid, dendrobine, is reported. The successful synthetic strategy features a one-pot, sequential palladium-catalyzed enyne cycloisomerization and rhodium-catalyzed diene-assisted pyrrolidine formation by allylic CH activation. The developed transition-metal-catalyzed cascade process permits rapid access to the dendrobine core structure and circumvents the handling of labile intermediates. An intramolecular aldol condensation under carefully defined reaction conditions takes place with a concomitant detosylation, followed by reductive amine methylation, to afford a late-stage intermediate (previously identified by several prior dendrobine syntheses) in only 10 synthetic steps overall.

Biosynthesis of the pyrrolidine protein synthesis inhibitor anisomycin involves novel gene ensemble and cryptic biosynthetic steps

The protein synthesis inhibitor anisomycin features a unique benzylpyrrolidine system and exhibits diverse biological and pharmacologic activities. Its biosynthetic origin has remained obscure for more than 60 y, however. Here we report the identification of the biosynthetic gene cluster (BGC) of anisomycin in Streptomyces hygrospinosus var. beijingensis by a bioactivity-guided high-throughput screening method. Using a combination of bioinformatic analysis, reverse genetics, chemical analysis, and in vitro biochemical assays, we have identified a core four-gene ensemble responsible for the synthesis of the pyrrolidine system in anisomycin: aniQ, encoding a aminotransferase that catalyzes an initial deamination and a later reamination steps; aniP, encoding a transketolase implicated to bring together an glycolysis intermediate with 4-hydroxyphenylpyruvic acid to form the anisomycin molecular backbone; aniO, encoding a glycosyltransferase that catalyzes a cryptic glycosylation crucial for downstream enzyme processing; and aniN, encoding a bifunctional dehydrogenase that mediates multistep pyrrolidine formation. The results reveal a BGC for pyrrolidine alkaloid biosynthesis that is distinct from known bacterial alkaloid pathways, and provide the signature sequences that will facilitate the discovery of BGCs encoding novel pyrrolidine alkaloids in bacterial genomes. The biosynthetic insights from this study further set the foundation for biosynthetic engineering of pyrrolidine antibiotics.

Total Synthesis of (–)-Lycoposerramine-S

Key words lycoposerramine-S - azomethine ylides - 1,3-dipolar cycloaddition

ChemInform Abstract: A Carbaboranylmercuric Salt Catalyzed Reaction: Highly Regioselective Cycloisomerization of 1,3‐Dienes.

AbstractThe title salt efficiently promotes the formation of pyrrolidine, piperidine, indole, quinoline, isoquinoline, and tetrahydronaphthalene derivatives.

Coupled cluster investigation of the axial and equatorial isomers of pyrrolidine

The CCSD(T) methodology coupled with Dunning's correlation-consistent basis sets was employed to study the relative energies of the axial and equatorial pyrrolidine. The enthalpies of formation of both isomers were computed including corrections for relativistic and core-valence effects as well as anharmonic effects. The accurate determination of the lowest energy isomer is a very complex task because of the very small energy gap. At the CCSD(T)/CBS level, equatorial pyrrolidine is 0.10 kcal/mol lower in energy than axial pyrrolidine. When core-valence, scalar relativistic and spin-orbit effects are included, the relative energy is similar, 0.11 kcal/mol. However, when zero-point energies are taken into account, some difficulties are observed. Anharmonic effects on ZPEs were not possible to be accurately estimated as problems were detected in the lowest vibrational modes. Thus, the question of which is the lowest energy isomer of pyrrolidine remains open until accurate ZPEs can be determined for both isomers. The enthalpy of formation of pyrrolidine is predicted to be −2.7 ± 1 kcal/mol at 298 K.

An Amine‐Catalyzed Enantioselective [3+2] Cycloaddition of Azomethine Ylides and α,β‐Unsaturated Aldehydes: Applications and Mechanistic Implications

The catalytic enantioselective [3+2] cycloaddition between azomethine ylides and α,β-unsaturated aldehydes catalyzed by α,α-diphenylprolinol has been studied in detail. In particular, the reaction has been extended to the use of 2-alkenylidene aminomalonates generated in situ as azomethine ylide precursors. These reactions lead to the formation of pyrrolidines containing a 5-alkenyl side chain with potential for chemical manipulation. Moreover, a detailed and concise computational study has been carried out to understand the exact nature of the mechanism of this reaction and especially the consequences derived from the incorporation of the chiral secondary amine catalyst on the reaction pathway.