INTRODUCTION:

Pyrrolines and their analogs can be considered as simple five membered heterocycles possessing one nitrogen atom as a part of the ring. These exist in different forms; the fully unsaturated ring is described by the terminal ending –ole (pyrrole 1a), the fully saturated ring is described by the terminal ending –olidine (pyrrolidine 1b) and partially reduced rings are called by the ending oline (pyrroline 1c-e). The position of the double bonds in partially reduced rings is designated as D¹- (1-pyrroline 1c) or D²- (2-pyrroline 1d) or D³- (3-pyrroline 1e).

The five-member heterocyclic compounds; particularly nitrogen heterocycles such as pyrroline derivatives have been successfully tested against several diseases and therefore received special attention in bioorganic chemistry. They have demonstrated a broad spectrum of biological properties in both pharmaceutical and agrochemical fields; and continuously draw interest for development of newer drug moiety.

The most recent review article reported by Fabio Bellina et al¹ describes the methods used for the synthesis of vicinal diaryl-substituted pyrrole, pyrroline and pyrrolidine derivatives and bioactivity data of some of these compounds. The paucity of reviews on pyrroline and their derivatives facilitated us to undertake this project. This review article comprises of up to date information about the strategies adopted for the synthesis and studies on their biological activity specifically enzymatic activity.

Synthesis of pyrrolines:

2-Acetyl-1-pyrroline, the principal rice flavor component with a cracker-like flavor was synthesized by a reaction sequence involving the conversion of pyrrolidine into tripyrroline, subsequent hydrocyanation of the latter into 2-cyanopyrrolidine, oxidation into 2-cyano-1-pyrroline, and Grignord addition of methyl magnesium iodide².

An efficient alkene aza-Cope-Mannich cyclization between 2-hydroxy homoallyl tosylamine and aldehydes in the presence of iron(III) salts gives 3-alkyl-1-tosyl pyrrolidines in good yields. The process is based on the consecutive generation of a γ-unsaturated iminium ion, 2-azonia-[3,3]-sigmatropic rearrangement, and further intramolecular Mannich reaction. The cyclization of 2-hydroxy homopropargyl tosylamines gives dihydro-1H-pyrroles (Scheme-1)³. Iron(III) salts are also shown to be excellent catalysts for the new aza-Cope-Mannich cyclisation using 2-hydroxy homopropargyl tosylamine.

Liang Y et al⁴ developed a facile and efficient one-pot synthesis of substituted D¹-pyrrolines in aqueous media. The method involves the treatment with aqueous sodium hydroxide in N,N-dimethylformamide, a range of chalcones underwent room temperature Michael addition reactions with nitroalkanes. The resulting adducts were directly reduced in situ with Zn/HCl (aq) and subsequently underwent an intramolecular cyclization, affording the corresponding substituted D¹-pyrrolines in high yields (Scheme-2)⁴.

Potassium carbonate mediated cyclisation reactions of dienes and/or enynes leads to the formation of pyrroline and its derivatives effectively. For instance; 3-Pyrroline has been prepared from (Z)-1,4-dichloro-2-butene in three steps in an overall yield of 74%. The Delepine Reaction permitted the monoamination of the substrate in practically quantitative yields (Scheme-3)⁵. The subsequent ring-closing reaction was less efficient.

Treatment of α-amino allenes bearing a protected amino group with potassium carbonate in DMF under reflux in the absence of any transition-metal catalysts gave the corresponding 3-pyrrolines in good to excellent yields, by 5-endo-trig mode cycloisomerization. The reaction of internal allenes with an axial chirality afforded the corresponding 3-pyrrolines in a stereoselective manner (Scheme-4)⁶.

Literature reveals that the ruthenium supported catalysts (2, 3, 4) were considered as an effective catalysts in the synthesis of pyrroline analogs.

A wide screening of substrates in ring-closing metathesis reactions reveals the great efficiency of phosphabicyclononane (phoban)-containing ruthenium-based pre-catalysts. Comparison of the catalytic activities with Grubbs' first-generation pre-catalyst illustrates the key role of the Phoban ligand⁷. A novel sequential Pd-catalysed termolecular allenylation cascade/Ru catalysed RCM process affords a diverse range of Δ³-aryl/heteroaryl substituted five-seven membered nitrogen and oxygen heterocycles. Further elaboration, via 1,3-dipolar cycloaddition, in selected cases, afforded fused heterocyclic ring systems (Scheme-5)⁸.

A series of pyrrolidine derivatives were prepared directly in very good yields, from substrates containing a basic or nucleophilic N-atom via ring-closing enyne metathesis reaction under mild reaction conditions. Moreover, the reaction occurs smoothly without the presence of ethylene gas (Scheme-6)⁹.

Allenylidene-ruthenium complexes on protonation with HOTf at -40˚C are completely transformed into alkenylcarbyne complexes. At -20˚C the latter undergo intramolecular rearrangement of the allenylidene ligand, with the release of HOTf, into indenylidene-ruthenium complexes. The in situ prepared indenylidene-ruthenium complexes (4) are efficient catalyst precursors for ring-opening metathesis polymerization of cyclooctene and cyclopentene. Isolation of these derivatives improves catalytic activity of the ring closing metathesis of a variety of dienes and enynes (Scheme-7)¹⁰.

Grubbs second generation ruthenium catalyst (2), which catalyzes various ring closing metathesis and hydrosilylation reactions in aqueous medium. Reactions proceeded in pure water without any additives or co-solvents, in a short period of time. The in homogeneity of the reaction mixture does not prevent high conversion of the products in both reactions (Scheme-7)¹¹.

[RuCl₂(CO)₃]₂/dppp is found to be a highly effective catalyst system for the intramolecular oxidative amination of various aminoalkenes in presence of K₂CO₃ and allyl acetate in N-methylpiperidine to give the corresponding cyclic imines and indoles in excellent yields. For instance, the reaction of 2,2-diphenyl-4-pentenyl-1-amine performed in the presence of [RuCl₂(CO)₃]₂/dppp, K₂CO₃ and allyl acetate in N-methylpiperidine at 140˚C produced 4,4-diphenyl-2-methyl-1-pyrroline in excellent yield (Scheme-8)¹².

A phosphine-catalyzed annulation of modified allylic ylides with various aromatic imines gives 3-pyrrolines in moderate to very good yield. The presence of a substituent (R) in the allylic compound is crucial for this reaction. Without the substituent, (E)-dienylimines will be produced via the dimerization of the allylic compounds (Scheme-9)¹³.

A reaction between dialkyl acetylenedicarboxylates and β-aminoketones promoted by triphenylphosphine allows an efficient one-pot synthesis of polysubstituted 2,5-dihydropyrrole derivatives. The prepared 2,5-dihydropyrroles can be easily oxidized to the corresponding pyrrole derivatives with chromium trioxide (Scheme-10¹⁴.

The reaction of alkynyl ketones with N-tosylimines catalyzed by Bu₃P at room temperature in toluene in a nitrogen atmosphere gives highly functionalized 3-pyrrolines in very good yields (Scheme-11)¹⁵. However when DMAP in CH₂Cl₂ medium was used in place of Bu₃P as catalyst to facilitate the cycloaddition, completely substituted azetidines in moderate yields.

The reduction of various heterocyclic aromatic compounds under ammonia free conditions uses lithium Di-tert-butylbiphenyl (LiDBB) as a source of electrons, bis(methoxyethyl)amine (BMEA) as a protonating agent, and THF as a solvent. In contrast to Birch type conditions, the described ammonia free conditions allow the use of reactive electrophiles (Scheme-12)¹⁶.

Diversity-oriented synthesis (DOS) of highly functionalized Δ³-pyrrolines has been accomplished by AgNO₃ as catalyst. For example, various highly functionalized Δ³-pyrrolines have been synthesized by AgNO₃-catalyzed cyclization reaction of allenic amino acids that proceeds with transfer of chiral information (Scheme-13)¹⁷. It was observed that a new mode of cyclization of allenic benzoyl-protected amines in the Ag(I)-catalyzed reaction leading to oxazines.

Ajay kumar and co-workers¹⁸ reported the use of silver nitrate and chloramine-T as a effective catalyst and reagent respectively for the transformation of alkene to aziridine derivative. They successfully employed the new method for the generation of nitrene intermediates by the reaction of chloramine-T with silver nitrate as catalyst and trapped the in situ generated nitrene with olefins to produce aziridines. In a typical reaction, an equimolar mixture of an acrylo nitrile (5), chloramine-T trihydrate and a catalytic amount of silver nitrate in ethyl alcohol was stirred thoroughly at room temperature for 3 hours, which afforded the 2-substituted aziridine (6) in 28% yield. They observed that, the same reaction yielded higher percentage of product when carried out in benzene, dichloromethane or tetrahydrofuran. Their observation draws the conclusion that, the aziridination in aprotic solvents affords better yields than in protic solvents. Then they carried out a ring expansion reaction of aziridines with acrylo nitrile and/or ethyl acrylate in the presence of solid sodium hydroxide as the base in tetrahydrofuran as the solvent under reflux conditions in a sealed tube and obtained 1-pyrrolines (7) in 40-58% yield (Scheme-14).

Enantioenriched propargyl mesylates or perfluorobenzoates react with α-(N-carbamoyl)alkylcuprates to afford scalemic α-(N-carbamoyl) allenes. Subsequent N-Boc deprotection and AgNO₃-promoted cyclization afford enantioenriched N-alkyl-3-pyrrolines in good yield (Scheme-15)¹⁹.

An efficient, scalable and mild cyclocarboamination reaction of nonactivated alkynes with aziridines, catalyzed by low loadings of Lewis or Bronsted acids, to form a wide range of polysubstituted 2,3-dihydropyrroles in a highly regioselective manner through a formal [3+2] cycloaddition (Scheme-16)²⁰.

An intramolecular chloroamination of allenes with N-chlorosuccinimide proceeds under mild conditions in the presence of a 1,10-phenanthroline-ligated cationic silver complex (8) and 2,6-lutidine as a base. The reaction tolerates various functional groups. The chloroamination products are useful synthetic intermediates and can be easily transformed into functionalized 3-pyrroline and pyrrole derivatives (Scheme-17)²¹.

Rhee et al²² reported the first use of cationic silver (AgSbF₄) as a catalyst for intra- and intermolecular alkyne-carbonyl coupling to form conjugated enones (Scheme-18). Accordingly, intermolecular coupling proceeds stereoselectively to afford the corresponding trisubstituted enones as single geometrical isomers. The method is found to be economical to the use of stabilized Wittig reagents in carbonyl olefination and is considered as a formal alkyne-carbonyl metathesis.

A class of 1,3,4-triaryl-2,5-dihydropyrroles were synthesized using the McMurry coupling reaction as key step involving the use of TiCl₄/Zn catalyst. A facile and reliable non-catalytic photoconversion of 1,3,4-triaryl-2,5-dihydropyrroles furnished 1,3,4-triarylpyrroles in good yields (Scheme-19)²³. It was observed that the solvent play an in important role in the percentage of yield formation in a reaction.

SIGNIFICANCES OF PYRROLINES:

2-Acetyl-1-pyrroline is an impact compound in the crust of a baguette-type wheat bread. Its formation during baking was quantified in model experiments and in breads prepared by different dough formulas using a stable isotope dilution assay. The treatment of a ground yeast/sucrose mixture is an important source of the 2-acetyl-1-pyrroline formed during the baking process. The results of the study suggested that the reaction between 1-pyrroline, the Strecker degradation product of proline, and pyru-valdehyde is responsible for the formation of 2-acetyl-1-pyrroline during bread crust formation. The influence of baker's yeast on the composition of other crust flavor compounds was followed by an aroma extract dilution analysis.

Pyrroline-5-carboxylate synthase (P5CS) is a bifunctional enzyme that exhibits glutamate kinase (GK) and gamma-glutamyl phosphate reductase (GPR) activities. The enzyme is highly relevant in humans because it belongs to a combined route for the interconversion of glutamate, ornithine and proline. The deficiency of P5CS activity in humans is associated with a rare, inherited metabolic disease. It is well established that some bacteria and plants accumulate proline in response to osmotic stress. The alignment of P5CSs from different species and analysis of the solved structures of GK and GPR reveal high sequence and structural conservation²⁴.

5-(Diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide (DEPMPO) synthesized via two step synthetic route has been evaluated for in vitro spin trapping for hydroxyl and superoxide radicals. The rates of spin trapping of hydroxyl and superoxide radicals with DEPMPO were found to be close to that of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). However, the DEPMPO-superoxide adducts were found to be significantly more persistent (15 times greater at pH 7) than the DMPO-superoxide adduct. Using DEPMPO as spin trap, the production of superoxide has been clearly characterized during the refurfusion of ischemic isolated rat hearts²⁵.

High pressure catalytic hydrogenation of 4-methyl-4-nitro-3-phenyl-1-(3-pyridyl)-1-pentanone yields primarily 5,5-dimethyl-4-phenyl-2-(3-pyridyl)-D¹-pyrroline together with a small quantity of hydrogenated secondary amines²⁶. The isolation and characterization is reported of a cDNA for delta 1-pyrroline-5-carboxylate (P5C) synthetase (cAtP5CS), an enzyme involved in the biosynthesis of proline. Southern blot analysis suggested that only one copy of the corresponding gene (AtP5CS) is present in A. thaliana. The deduced amino acid sequence of the P5CS protein (AtP5CS) from A. thaliana exhibited 74% homology to that of the P5CS from Vigna aconitifolia. Northern blot analysis revealed that the gene for P5CS was induced by dehydration, high salt and treatment with ABA, while it was not induced by heat or cold treatment²⁷.

Type II hyperprolinemia is an inherited abnormality in amino acid metabolism characterized by elevated plasma proline concentrations, iminoglycinuria, and the urinary excretion of D¹-pyrroline compounds. For instance, The proline degradative enzyme D¹-pyrroline-5-carboxylic acid dehydrogenase activity in the cultured fibroblasts from three patients with type II hyperprolinemia experiment confirmed above. It was also found significantly decreased levels of D¹-pyrroline-5-carboxylic acid dehydrogenase activity in the leukocyte extracts from five obligate heterozygotes for type II hyperprolinemia²⁸.

Proline (Pro) accumulation has been correlated with tolerance to drought and salinity stresses in plants. Overproduction of Pro in plants leads to increased tolerance against these abiotic stresses. This was overexpressed in tobacco the mothbean [delta]-pyrroline-5-carboxylate synthetase, a bifunctional enzyme able to catalyze the conversion of glutamate to [delta]-pyrroline-5-carboxylate, which is then reduced to Pro. The results of the study suggested that activity of the first enzyme of the pathway is the rate-limiting factor in Pro synthesis. The experimental data demonstrated that Pro acts as an osmoprotectant and that overproduction of Pro results in the increased tolerance to osmotic stress in plants²⁹.

D¹-Pyrroline-5-carboxylic acid, an intermediate in both the biosynthesis and degradation of l-proline, was synthesized by the periodate oxidation of hydroxylysine and isolated as a pure compound, as indicated by enzymatic assay with pyrroline-5-carboxylate reductase from Escherichia coli. The studies on the instability in solution of D¹-pyrroline-5-carboxylic acid have led to the conclusion that the rate of decomposition is sensitive to concentration of the compound. Colorimetric assay with o-aminobenzaldehyde was found to be an inadequate measure of the pyrroline compound in partially decomposed solutions³⁰.

The 45-days-old seedlings of drought resistant and susceptible rice (Oryza sativa L.) genotypes (Panidhan, Pusa-169) were subjected to osmotic stress in PEG-6000 solution of -10 and -16 bar and the relative water content (RWC), proline content, and pyrroline-5-carboxylate synthetase (P5CS) activity and its P5CS expression. The results revealed that there was a gradual decrease in RWC in tolerant genotypes, whereas the decrease was drastic in susceptible ones. Proline content and P5CS activity increased both in susceptible and tolerant genotypes; the increase was higher in tolerant genotypes. Higher proline levels in tolerant genotypes were due to increased P5CS activity³¹.

In vitro studies of a child with hyperprolinaemia type II; that pyridoxal phosphate forms a novel adduct with a proline metabolite, pyrroline-5-carboxylic acid, through Claisen condensation. Studies indicated that previously unsuspected generic reaction of aldehydes and some ketones have subsequently found the acetoacetic acid adduct in both plasma and urine from the affected child. Pyrroline-5-carboxylic acid forms adduct with acetoacetic acid, which was present in urine of a sick child with hyperprolinaemia type II³².

SUMMARY:

Though the synthetic strategies presented in the article looks the use of somewhat expensive catalysts, and not easy accessible procedures, it may give the researchers an insight of developing new methodologies for the synthesis of pyrroline derivatives, device new molecules of greater biological potency; and to study their structure-activity relationship.

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Received on 14.12.2012 Modified on 30.12.2012

Research J. Pharm. and Tech. 6(2): Feb. 2013; Page 137-142