2 ( 3 H ) Pyrrolone – A Biologically Active Scaffold ( A Review )

Pyrrolones are potent medicinal scaffolds and exhibit a broad spectrum of biological activities. This review throws light on the detailed synthetic approaches which have been used for the synthesis of pyrrolones. This has been followed by an in depth analysis of the pyrrolones with respect to their medicinal significance. This review may help the medicinal chemists to develop new leads possessing pyrrolone nucleus with higher efficacy.

These are also known as pyrrolin-2ones.The g-lactone ring present in butenolide (3)  derivatives possess significant reactivity and has been utilized in the synthesis of pyrrolone derivatives with potent biological acitivity 3,4 .Pyrrolone and N-benzyl pyrrolone derivatives were reported to have good antifungal, antibacterial and anti-inflammatory activities 5 .Pyrrolones have been proved important as chiral synthons used in the preparation of a variety of bioactive compounds 6 .The frequent use of these compounds as chiral intermediates provides a fast universal method for the determination of absolute configuration. 7The chemistry of these versatile building blocks has been explored by a number of groups.Because of their multifunctional nature, these heterocycles can take part in several stereo selective transformations like conjugate additions 8,9 , cycloadditions 10,11 , acyliminium ion chemistry 12 and allylic substitution 13 .

Synthesis of an enantioselective enzymatic transesterification
N-Methyl derivatives of D 3 -pyrrolinones have been synthesized from pyrroles using an enantioselective enzymatic transesterification 33 .
N-Methyl pyrrolinone (28) have been synthesized by photo-oxidation of N-methylpyrrole ( 27) followed by esterification.Subsequent enzymatic resolution by Candida antarctica mediated transesterification has been reported.
The addition of lithium propiolate (33) to nitrone (32) takes place with complete syn selectivity and in quantitative yield to afford the prop-2-ynyl hydroxylamine. 34,35

Synthesis of unsaturated hydroxy-butyrolactones under phase transfer conditions
Unsaturated hydroxy-butyrolactones or 2-alkylidene-3-ketocarbocyclic acids ( 17) can be synthesized by carbonylation of a-ketoalkynes in the presence of Ni(CN) 2 under phase-transfer conditions 24 .By changing the reaction conditions it is possible to obtain hydroxyl-butyrolactams (18) in good yields 25 .

C
However the formation of hydroxylactams by hydrocyanation of a-ketoalkynes in water under mild conditions, it is possible to obtain hydroxyl butyrolactams (19) and ( 20) 26

Synthesis of D 3 and D 4 -pyrrolinones by oxidation of pyrrole Using sulfoxide electrophillic sulfenylation:
D 3 Pyrrolinones with very small amounts of D 4 isomer can be obtained by the oxidation of pyrrole 25 during sulfoxide electrophilic sulfenylation (SES).Sulfoxide electrophilic sulfenylation (SES) is a useful technique for the synthesis of heterocycles.Pyrrole-containing sulfoxides have been exploited for intramolecular sulfenylation to form a wide variety of N,S-heterocycles.][29] Upon treatment with trifluro acetic acid (TFAA) (DMF, room temperature) compound (21) produced the expected SES product only as minor product (23) and the major product was the pyrrolinones (22).Similarly compound (24) produced a mixture of pyrrolinones (25) and ( 26) SES cyclization product [30][31][32] .The selective hydrogenation of the triple bond was achieved in 1 hr at ambient temperature and 1 atm pressure using the lindlar catalyst.The corresponding allylhydroxylamine was obtained in quantitative yields 36 .Further deoxygenation of hydroxylamine was accomplished with Zn-Cu catalyst in acetic acid as a solvent.Under these conditions, resulting allylamine could not be isolated since it cyclized spontaneously to the pyrrolin-2-one (34)  which was obtained in 84% yield after purification by column chromatography 37 .This is a straight forward method of preparing enantiomerically pure ´3-pyrrolin-2-ones which can serve as templates for the construction of a number of highly functionalized 2-pyrrolidones and pyrrolidines.The latter has attracted much attention due to their ability to act as selective glycosidase inhibitors with a variety of therapeutic effects [38][39][40][41][42] .

Spectral Properties Circular dichroism (CD) spectra
In case of the simple 3-pyrrolin-2-ones bearing no substituents on the olefinic bond, the maximum of the p-p* cotton effect is observed at l max 200 nm.The maximum of the p-p * cotton effect is seen at longer wavelength, around 230 nm, where the UV spectrum displays a broad shoulder.The 3-pyrrolin-2-ones with an oxygen substituent at C (5) generally display much stronger cotton effects than those containing alkyl group.A methoxy substituent at C(3) shifts the positions of the p-p * band to l max 230 nm, as does tosyl substitution at N 1 .3-Pyrrolin-2-ones with an imide-type group (R 2 = acyl) display an additional cotton effect at 280 nm, presumably due to a second p-p * transition.Such double p-p * cotton effects are observed at 250 nm in a saturated imides 43 and result from the transitions involving combinations of the carbonyl n orbitals of opposite symmetry.This cotton effect however is much smaller than the n-p* cotton effects caused primarily by the a,b-unsaturated lactam chromophore [49][50][51][52] .

Candida albicans
(2 MIC, μg ml −1 ) 5 Candida albicans (2 MIC, μg ml −1 ) 5 1 H NMR: In structure A, the chemical shift (d) value at 6.44-6.95ppm confirmed the presence of proton at C-4 of pyrrolone ring.Also, the chemical shift ranging between 7.39-7.68showed the presence of olefinic proton at C-3 position.Both these peaks appeared as singlet which further evidenced that these are not aromatic protons.The proton attached to N of pyrrolone ring generally appeared at d = 7.92-8.10.The formation of benzyl pyrrolones (structure B) could be confirmed by disappearance of -NH proton and appearance of a sharp singlet at d = 4.74-4.88.(methylene proton).IR: The IR spectra of structure A showed the absorption bands at 1680-1710 cm -1 due to the stretching vibrations of the lactam carbonyl groups 21 .MS: Generally, the mass spectra 3(H)-pyyrolin-2-ones showed peaks at M + and M + -Ar with high intensities 26 .

43
Nootropic / Antiamnesic activity The compounds 3-hydroxy-5-nitro phenyl-4-pivaroyl-2,5-dihydro-2-pyrrolones (44) 19 and 4-Acetyl-5-(3,4-dimethoxy-phenyl)-3-hydroxy-1-1(2-piperidin-1-ylethyl)-2,5-dihydro-2-pyrrolones (45) 63 were found to have antiamnesic activity.The drugs were characterized by the ability to eliminate amnesia, increase the latent period and change the number of animals in the test group visiting a dark compartment of the experimental box.The time of stay in the light and dark compartments was determined three minutes after drug injection 19 .All synthesized compounds favored recovery of the memory trace in the test rats, as evidence by a drop in the number of animals visiting the dark compartment and the time of stay there 66 .

CONCLUSION
It may be concluded that pyrrolones and N benzyl pyrrolones exhibit a broad spectrum of biological activities like anti-inflammatory, anticancer, antibacterial, antifungal, antiviral, analalegic and anti-HIV activities.Thus the pyrrolone scaffold still remains as therapeutic target for the development of new leads in the modern medicinal chemistry.The physical, chemical and the pharmacokinetic properties of pyrrolones still maintains the importance of this moiety inspite of the rising levels of drug resistance in today's era.