Pyrrolidines

Introduction

Pyrrolidine, also called as tetrahydropyrrole, is a class of hetero-aromatic organic compound with empirical formula C4H9N (Fig.1). The pyrrolidine ring is the common structure of the many amino acid proline and its derivatives. Chiral pyrrolidines play an important role both as chiral building blocks for auxiliaries as well as key structures relevant to biologically active substances. Derivatives of the methylpyrrolidinyl fragment are common structural motifs present in several inhibitors and antagonists, including a series of HIV-1 reverse transcriptase inhibitors and histamine H3 receptor and dopamine D4 antagonists. Sigma-Aldrich has a large selection of pyrrolidines as heterocyclic building blocks for organic synthesis and medicinal chemistry, the majority of which are available as racemates or in either enantiomeric form.

Pyrrolidines Fig. 1 The Full structural formula and 3d molecular spacefill of pyrrolidine (cited from Wikipedia)

Applications

Pharmaceutical Chemistry:

Functionalized pyrrolidines and pyrrolizines are the central skeleton of numerous alkaloids and constitute classes of compounds with significant biological properties, such as anticancer activity . Heterocycles containing piperidine sub-structures display important biological activities, such as anticancer activity as well as being useful as synthons in the construction of alkaloid natural Products. Inspired by the previously reported biological potency of spiro compounds and as a part of our ongoing research in the construction of novel hybrid heterocycles, Ali group reported the synthesis of three different classes of spiro-pyrrolidines and spiro-pyrrolizines derivatives by the [3+2]-cycloaddition of azomethine ylides with 3,5-bis[(E)-arylmethylidene]tetrahydro -4(1H)-pyridinones and evaluation of their anticancer activities.

Organic Synthesis:

McGrath group developed a modular synthetic strategy for preparing amine–imine ligands based on trans-2,5-disubstituted pyrrolidines. Since their initial report of this class of ligands, several examples of both trans-2,5-disubstituted pyrrolidine-containing and pyridine-amine and ligands have been reported, in addition to many tertiary diamines. This type of ligand is constructed by linking a pyridine ring to the pyrrolidine ring as chiral bidentate ligands for palladium-catalyzed allylic alkylation. Nitrogen atoms from both the pyridine and pyrrolidine moieties are different electronically and are assumed to provide different binding properties to transition metals.

Environmental concerns as-sociated with chemical processes have encouraged the devel-opment of environmentally more friendly methodologies for organic reactions. Recently,some recyclable organocatalysts, such as fluorous pyrrolidinesulfonamides, ionic liquid supported pyrrolidine-basedcatalysts, and polymer-supported thiourea catalysts ]for the asymmetric Michael addition of ketones and alde-hydes with nitroolefins have also been developed. Zhang group discovered the novel designed polymer-supportedpyrrolidine-based organocatalysts (Fig.2), which were easily prepared from (S)-Boc-proline, catalyzed the reactions of ketones and aldehydes with aryl-substituted nitroolefins smoothly at room temperature in high yields with excellent diastereo selectivities and enantioselectivities under solvent-free reaction conditions.

Pyrrolidines Fig.2 The catalyst applications in the Michael additions

References

  1. Facile, Regio- and Diastereoselective Synthesis of Spiro-Pyrrolidine and Pyrrolizine Derivatives and Evaluation of Their Antiproliferative Activities, Molecules 2014, 19, 10033-10055
  2. Chiral amine–imine ligands based on trans-2,5-disubstituted pyrrolidines and their application in the palladium-catalyzed allylic alkylation, Tetrahedron: Asymmetry 20, 1672-1682
  3. Polymer-Immobilized Pyrrolidine-Based Chiral Ionic Liquids as RecyclableOrganocatalysts for Asymmetric Michael Additions to Nitrostyrenes underSolvent-Free Reaction Conditions, Eur. J. Org. Chem. 2008, 1157-1160
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