Bicyclic Pyrrolidine Research Articles

Synthesis of Heterocycles by HNTf2-Catalyzed C–H Functionalization of Vinyldiazo Compounds with 3-Phenyl-3-hydroxyisoindolinone

AbstractA Brønsted acid catalyzed C–H functionalization of vinyldiazoacetates with 3-hydroxyisoindolinone is developed. This methodology provides a general access to E-substituted isoindolinone vinyldiazo compounds in good yields and excellent diastereoselectivities with broad substrate generality under mild conditions, and with 4-substituted 2-diazo-3-butenoates produces fused bicyclic pyrrolidines. The reaction generally involves addition of the N-acyl ketiminium electrophile, formed from the 3-hydroxyisoindolinone, to the vinylogous position of the vinyldiazo compound resulting in vinyldiazonium ion intermediates that undergo deprotonation to new vinyldiazo compounds or ring closure to fused bicyclic pyrrolidines.

Evaluation of the antioxidant and cryoprotective activity of bicyclic pyrrolidine derivatives with a 2,6-di-tert-butylphenol fragment

Evaluation of the antioxidant and cryoprotective activity of bicyclic pyrrolidine derivatives with a 2,6-di-tert-butylphenol fragment

Bicyclic Pyrrolidine Inhibitors of Toxoplasma gondii Phenylalanine t-RNA Synthetase with Antiparasitic Potency In Vitro and Brain Exposure.

Previous studies have shown that bicyclic azetidines are potent and selective inhibitors of apicomplexan phenylalanine tRNA synthetase (PheRS), leading to parasite growth inhibition in vitro and in vivo, including in models of Toxoplasma infection. Despite these useful properties, additional optimization is required for the development of efficacious treatments of toxoplasmosis from this inhibitor series, in particular, to achieve optimal exposure in the brain. Here, we describe a series of PheRS inhibitors built on a new bicyclic pyrrolidine core scaffold designed to retain the exit-vector geometry of the isomeric bicyclic azetidine core scaffold while offering avenues to sample diverse chemical space. Relative to the parent series, bicyclic pyrrolidines retain reasonable potency and target selectivity for parasite PheRS vs host. Further structure-activity relationship studies revealed that the introduction of aliphatic groups improved potency and ADME and PK properties, including brain exposure. The identification of this new scaffold provides potential opportunities to extend the analogue series to further improve selectivity and potency and ultimately deliver a novel, efficacious treatment of toxoplasmosis.

"Synthesis of Bicyclic Pyrrolidine Derivatives and their Photoluminescent Properties"

"Synthesis of Bicyclic Pyrrolidine Derivatives and their Photoluminescent Properties"

Solid phase synthesis of bicyclic pyrrolidines

Solid phase synthesis of bicyclic pyrrolidines

GSK2818713, a Novel Biphenylene Scaffold-Based Hepatitis C NS5A Replication Complex Inhibitor with Broad Genotype Coverage.

Pan-genotype NS5A inhibitors underpin hugely successful hepatitis C virus (HCV) therapy. The discovery of GSK2818713 (13), a nonstructural protein 5A (NS5A) HCV inhibitor characterized by a significantly improved genotype coverage relative to first-generation NS5A inhibitor daclatasvir (DCV), is detailed herein. The SAR analysis revealed cooperative potency effects of the biphenylene, bicyclic pyrrolidine (Aoc), and methyl-threonine structural motifs. Relative to DCV, 13 improved activity against genotype 1a (gt1a) and gt1b NS5A variants as well as HCV chimeric replicons containing NS5A fragments from genotypes 2-6. Long-term treatment of subgenomic replicons with 13 potently and durably decreased HCV RNA levels for gt1a, gt2a, and gt3a. These properties, suitable pharmacokinetics, and the lack of cross-resistance resulted in the selection of 13 as a preclinical candidate.

Catalytic (3+2) Palladium‐Aminoallyl Cycloaddition with Conjugated Dienes

AbstractWe describe the design and application of tailored aminoallyl precursors for catalytic (3+2) cycloaddition with conjugated dienes via a Pd‐aminoallyl intermediate. The new cycloaddition reactions override the conventional (4+3) selectivity of aminoallyl cation cycloaddition through a sequence of Pd‐allyl transfer and ring closure. A variety of highly substituted or fused pyrrolidine rings were synthesized using the cycloaddition, and can further undergo [1,3] N‐to‐C rearrangement to five‐membered carbocycles with a different palladium catalyst. The utility of the (3+2) cycloaddition is also demonstrated by the preparation of various derivatives from the bicyclic pyrrolidine products.

Catalytic (3+2) Palladium-Aminoallyl Cycloaddition with Conjugated Dienes.

We describe the design and application of tailored aminoallyl precursors for catalytic (3+2) cycloaddition with conjugated dienes via a Pd-aminoallyl intermediate. The new cycloaddition reactions override the conventional (4+3) selectivity of aminoallyl cation cycloaddition through a sequence of Pd-allyl transfer and ring closure. A variety of highly substituted or fused pyrrolidine rings were synthesized using the cycloaddition, and can further undergo [1,3] N-to-C rearrangement to five-membered carbocycles with a different palladium catalyst. The utility of the (3+2) cycloaddition is also demonstrated by the preparation of various derivatives from the bicyclic pyrrolidine products.

A new trifluoromethylated sulfonamide phosphine ligand for Ag(i)-catalyzed enantioselective [3 + 2] cycloaddition of azomethine ylides.

A newly developed Ming-Phos ligand with a 3,5-bis(trifluoromethyl)phenyl substituent was demonstrated to be highly efficient for Ag-catalyzed asymmetric [3 + 2] cycloaddition reactions of azomethine ylides with maleimides, cyclopentene-1,3-diones, and N-(2-t-butylphenyl)maleimide. Being easily prepared on the gram scale in one step, the ligand in combination with a Ag catalyst enables the synthesis of a variety of highly functionalized bicyclic pyrrolidine derivatives in good yields and excellent enantioselectivities under mild conditions.

Proline-Catalyzed Asymmetric α-Amination in the Synthesis of Bioactive Molecules

The direct α-amination of carbonyl compounds using organocatalysts represents a powerful and atom-economical tool for asymmetric C–N bond formation. We describe a complete account of α-functionalization of carbonyl compounds, through iterative sequential α-aminoxylation/amination using electrophilic O and N sources, as well as sequential α-amination/HWE reaction for enantio- and diastereoselective synthesis of both syn- and anti-1,3-aminoalcohols and 1,3-diamines. Additionally this protocol is further extended for the easy construction of alkaloids such as indolizidine, pyrrolizidine, and quinolizidine fused-ring systems just by tuning the chain length of the aldehyde used as a starting material. This methodology provides further scope to extrapolate it for a variety of naturally occurring hydroxylated monocyclic and fused bicyclic pyrrolidine and piperidine based alkaloids such as lentiginosine, epi-lentiginosine, dihydroxypyrrolizidine, (+)-deoxoprosophylline and (–)-deoxoprosopinine alkaloids. Furthermore, we have also uncovered proline-catalyzed anti-selectivity for the synthesis of 1,2-amino alcohols in α-amination of aldehyde and one-pot indium-mediated Barbier type allylation of α-hydrazino aldehydes to accomplish the total synthesis of clavaminols, sphinganine and spisulosine with reduced number of steps and with high overall yields.1 Introduction2 Application in the Total Synthesis of Alkaloids3 Conclusion

Silver-Catalyzed Asymmetric Desymmetrization of Cyclopentenediones via [3 + 2] Cycloaddition with α-Substituted Isocyanoacetates.

A highly selective and practical asymmetric Ag(I) catalyst system has been developed for the [3 + 2] cycloaddition reactions between isocyanoacetates and cyclopentenediones. The current Ag(I) catalyst system tolerates moisture and air and readily utilizes class III solvents such as EtOAc and acetone. The development of on demand generation of an active chiral catalyst in the presence of isocyanides paves a way to the efficient asymmetric preparation of bicyclic pyrrolidines with four stereogenic centers, including two quaternary centers in 80-97% ee.

ChemInform Abstract: Silver(I)—Ferrophox Catalyzed Enantioselective Desymmetrization of Cyclopentenedione: Synthesis of Highly Substituted Bicyclic Pyrrolidines.

AbstractA scalable, operationally simple [3 + 2]‐cycloaddition reaction of cyclopentenediones with azomethine ylides is described which provides 5,5‐fused bicyclopyrrolidine derivatives with five stereocenters in moderate to high yields and with very high enantiomeric excesses.

ChemInform Abstract: Chiral γ‐Lactams by Enantioselective Palladium(0)‐Catalyzed Cyclopropane Functionalizations.

AbstractEnantioselective Pd(0)‐catalyzed cyclization of N‐chloroacetyl substituted cyclopropylamines (I) and (III) offers a novel approach to cyclopropane fused chiral bicyclic pyrrolidines (II) and (IV) with moderate to good stereoselectivity.

Silver(I)-Catalyzed Enantioselective Desymmetrization of Cyclopentenediones: Access to Highly Functionalized Bicyclic Pyrrolidines.

A highly enantioselective desymmetrization of prochiral cyclopentenediones via Ag(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylide has been developed successfully. The methodology performs well over a broad scope of substrates, which provides facile access to a series of highly functionalized bicyclic pyrrolidine/cyclopentane derivatives in good to high yields with excellent stereoselectivities.

ChemInform Abstract: One‐Pot Stereocontrolled Synthesis of Bicyclic Pyrrolidine Derivatives by a Platinum—Broensted Acid Relay Cascade Reaction

AbstractReview: 16 refs.

Silver(I)-Ferrophox Catalyzed Enantioselective Desymmetrization of Cyclopentenedione: Synthesis of Highly Substituted Bicyclic Pyrrolidines.

A highly enantioselective desymmetrization of prochiral cyclopentene-1,3-dione via [3 + 2] cycloaddition of azomethine ylide using a silver(I)-ferrophox complex has been demonstrated. The method has been utilized in the synthesis of highly functionalized enantioenriched 5,5-fused bicyclic pyrrolidine derivatives under mild reaction conditions.

One‐Pot Stereocontrolled Synthesis of Bicyclic Pyrrolidine Derivatives by a Platinum–Brønsted Acid Relay Cascade Reaction

One‐Pot Stereocontrolled Synthesis of Bicyclic Pyrrolidine Derivatives by a Platinum–Brønsted Acid Relay Cascade Reaction

Ugi and Passerini reactions of biocatalytically derived chiral aldehydes: application to the synthesis of bicyclic pyrrolidines and of antiviral agent telaprevir.

Lipase mediated desymmetrization of a meso-diol (1,2-cyclopentanedimethanol) allows the synthesis of both enantiomers of some chiral aldehydes, whose behavior in Passerini and Ugi reactions has been explored. Exploiting these two complementary multicomponent reactions and coupling them with a subsequent cyclization process, we observed that 6 out of all 8 possible stereoisomers of peptidomimetic pyrrolidines can be obtained in good yields. The potential of these protocols has been proved by the development of a new efficient synthesis of antiviral drug telaprevir.

ChemInform Abstract: Catalyst‐Free Cascade Reaction of Heterocyclic Ketene Aminals with N‐Substituted Maleimide to Synthesise Bicyclic Pyrrolidinone Derivatives.

AbstractThe title reaction provides a facile access to a wide variety of bicyclic pyrrolidine derivatives.

Expeditious synthesis of bicyclic pyrrolidine/pyrrolizidine/thiazolidine grafted macrocycles through intramolecular 1,3-dipolar cycloaddition of azomethine ylides

Stereoselective synthesis of bicyclic pyrrolidine and pyrrolizidine grafted macrocycles has been accomplished through intramolecular 1,3-dipolar cycloaddition (1,3-DC) reaction. Alkenyl aldehydes 4a–b derived from salicylaldehyde have been reacted with secondary aminoacids to generate azomethine ylides which in turn were trapped intramolecularly by suitably placed dipolarophiles to give the corresponding macrocycle in moderate yield. The structures were assigned by 2D NMR spectra and the regio- and stereochemical outcome of the cycloadducts was established by a single crystal X-ray analysis of one of the products.