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Current Bioactive Compounds

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ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

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Research Article

An Easy and Straight Forward Approach Towards the Synthesis of N-Benzyl-5(S)-Substituted Pyrrolidin-2-ones from N-Benzyl-5(S)-pyroglutaminol through Mitsunobu Reaction

Author(s): Sharad Kumar Panday* and Munish Kumar

Volume 19, Issue 6, 2023

Published on: 21 November, 2022

Article ID: e290822208125 Pages: 5

DOI: 10.2174/1573407218666220829104307

Price: $65

Abstract

Background: Pyroglutamic acid is one of the cheapest chiral synthon for the synthesis of a variety of bioactive molecules ranging from synthetic to natural origin. Derived from glutamic acid by internal cyclization pyroglutamic acid can serve easily as a precursor for prolines or pyroglutaminols by the selective reduction of lactam carbonyl or carboxylic group, respectively. Pyroglutamic acid has two differential carbonyls and a lactam NH group. All these can differentially be modified to get a variety of compounds. These applications coupled with the easy availability of pyroglutamic acid have made it a choice of interest for various research groups in recent years to get a range of bioactive compounds both of natural as well as synthetic origins. In our ongoing research programme, we were interested to develop an easy route for the synthesis of 5-substituted pyrrolidin-2-ones exploiting the chemistry of pyroglutamates, whose synthetic potential is well established.

Objective: To develop a simple and efficient methodology for the synthesis of 5-sustituted- pyrrolidin-2-ones as bioactive molecules/intermediate to bioactive molecules.

Methods: N-Benzyl-5(S)-pyroglutaminol 1, (0.96 g, 5.0 mmol) was taken in THF (15 mL) and diethylazodicarboxylate (DEAD) (1.21 g, 1.4 eq) and triphenylphosphine (Ph3P) (1.72 g, 1.4 eq), were added to it and the reaction mixture was stirred at RT for 30 min. After 30 min a solution of the substituted pyrazole/imidazole derivative (1.2 eq) in THF (10 mL) was added and the reaction mixture was stirred again at RT for 7 hr. The progress of the reaction was monitored by thin layer chromatography (TLC). At the completion of the reaction, the solvents were evaporated under a vacuum to give a liquid which was poured into water (15 mL) and extracted twice with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine solution (15 mL), dried over sodium sulfate, concentrated and purified by column chromatography on silica gel using 20% EtOAc-hexane as eluent to give pure compounds 2 a-d, 3 and 4, respectively in satisfactory yields.

Results: Herein, we wish to describe the synthesis of new 5(S)-substituted pyrrolidin-2- one derivatives through Mitsunobu reaction of N-benzyl-5(S)- pyroglutaminol with substituted pyrazole and imidazole derivatives.

Conclusion: An easy and straightforward approach towards the synthesis of enantiomerically pure N-benzyl- (S)-5-substituted pyrrolidin-2-ones from N-benzyl-5(S)- pyroglutaminol through Mitsunobu reaction has been developed. These N-benzyl-(S)-5-substituted pyrrolidin-2-ones could be useful for the synthesis of bioactive natural products requiring pyrazole/imidazole moiety attached at C-5 position of native pyrrolidin-2- one moiety.

Keywords: Optically pure, pyroglutaminol, piracetam, Doxapram, Mitsunobu reaction, 5-substituted pyrrolidin-2-ones

Graphical Abstract

[1]
Panday, S.K.; Prasad, J.; Dikshit, D.K. Pyroglutamic acid: A unique chiral. Synthon. Tetrahedron: Asymmetry, 2009, 20, 1581-1631.
[2]
Stefanucci, A.; Novellino, E.; Costante, R.; Mollica, A. Pyroglutamic acid derivatives: Building blocks for drug discovery. Heterocycles, 2014, 89(8), 1801-1825.
[http://dx.doi.org/10.3987/REV-14-800]
[3]
Panday, S.K. Pyroglutamic acid and its derivatives: The privileged precursors for the asymmetric synthesis of bioactive natural products. Mini Rev. Org. Chem., 2020, 17(6), 1-21.
[http://dx.doi.org/10.2174/1570193X16666190917142814]
[4]
Panday, S.K.; Dikshit, M.; Dikshit, D.K. Synthesis of N-3′-(acetylthio)alkanoyl and N-[3′-mercaptoalkanoyl]-4-α(s)-(phenylme-thyl) pyroglutamic acids and prolines as potent ACE inhibitors. Med. Chem. Res., 2009, 18(7), 566-578.
[http://dx.doi.org/10.1007/s00044-008-9150-z]
[5]
Dikshit, D.K.; Panday, S.K. Aldol reactions of pyroglutamates: Chiral synthesis of 4α(S)- and 4β(R)-(arylmethyl)pyroglutamates. J. Org. Chem., 1992, 57(6), 1920-1924.
[http://dx.doi.org/10.1021/jo00032a056]
[6]
Panday, S.K.; Brunet, D-G.; Langlois, N. A short and efficient synthesis of (S)-4-methylene proline benzyl ester from (S)-pyroglutamic acid. Tetrahedron Lett., 1994, 35(36), 6673-6376.
[http://dx.doi.org/10.1016/S0040-4039(00)73465-4]
[7]
Panday, S.K.; Langlois, N. An efficient straightforward synthesis of (-)-bulgecinine. Synth. Commun., 1997, 27(8), 1373-1384.
[http://dx.doi.org/10.1080/00397919708006067]
[8]
Ohfune, Y.; Tomita, M. Total synthesis of (-)-domoic acid. A revision of the original structure. J. Am. Chem. Soc., 1982, 104(12), 3511-3513.
[http://dx.doi.org/10.1021/ja00376a048]
[9]
a) Cossy, J.; Cases, M.; Pardo, D.G. Approaches to a synthesis of α- kainic acid. Tetrahedron, 1999, 55, 6153-6166.;
b) Hanessian, S.; Ninkovic, S. Stereoselective synthesis of (−)-α-kainic acid and (+)-α-allokainic acid via trimethylstannyl-mediated radical carbocyclization and oxidative destannylation. J. Org. Chem.,, 1996, 61, 5418-5424.;
c) Baldwin, J.E.; Moloney, M.G.; Parsous, A.F. Enantioselective kainoid synthesis by cobalt-mediated cyclisation of an amino acid derivative. Tetrahedron, 1990, 46, 7263-7282.
[10]
Peterson, J.S.; Fels, G.; Rapoport, H. Chirospecific syntheses of (+)- and (-)-anatoxin a. J. Am. Chem. Soc., 1984, 106(16), 4539-4547.
[http://dx.doi.org/10.1021/ja00328a040]
[11]
Panday, S.K.; Prasad, J.; Pathak, M.B. A straight forward and facile approach towards the N- derivatization of pyroglutamates through mitsunobu reaction: Synthesis of N-alkyl/N-acyl pyroglutamates. Synth. Commun., 2011, 41(24), 3654-3661.
[http://dx.doi.org/10.1080/00397911.2010.519844]
[12]
Wierzejska, J.; Motogoe, S.; Makino, Y.; Sengoku, T.; Takahashi, M.; Yoda, H. A new approach toward the total synthesis of (+)-batzellaside B. Beilstein J. Org. Chem., 2012, 8, 1831-1838.
[http://dx.doi.org/10.3762/bjoc.8.210] [PMID: 23209519]
[13]
Toyooka, N.; Zhou, D.; Nemoto, H.; Tezuka, Y.; Kadota, S.; Jones, T.H.; Garraffo, H.M.; Spande, T.F.; Daly, J.W. First enantioselective synthesis of a hydroxyindolizidine alkaloid from the ant myrmicaria melanogaster. Synlett, 2008, 12(12), 1894-1896.
[http://dx.doi.org/10.1055/s-2008-1078502]
[14]
a) Moutevelis-Minakakis, P.; Papavassilopoulou, E.; Mavromoustakos, T. Synthesis of new optically active 2-pyrrolidinones. Molecules, 2012, 18(1), 50-73.
[http://dx.doi.org/10.3390/molecules18010050] [PMID: 23344188];
b) Winblad, B. Piracetam: A review of pharmacological properties and clinical uses. CNS Drug Rev., 2005, 11(2), 169-182.
[http://dx.doi.org/10.1111/j.1527-3458.2005.tb00268.x] [PMID: 16007238]
[15]
Singh, P.; Dimitriou, V.; Mahajan, R.P.; Crossley, A.W. Double-blind comparison between doxapram and pethidine in the treatment of postanaesthetic shivering. Br. J. Anaesth., 1993, 71(5), 685-688.
[http://dx.doi.org/10.1093/bja/71.5.685] [PMID: 8251281]
[16]
Volkhard, A.; Eisert, W.; Himmelsbach, F.; Linz, G.; Mueller, T.; Pieper, H.; Weisenberger, J.U.S. Patent 5455348, 1995.
[17]
Siddiqui, N.; Ahsan, W.; Alam, M.S.; Ali, R.; Srivastava, K. Design, synthesis and evaluation of anticonvulsant activity of pyridinyl-pyrrolidones: A pharmacophore hybrid approach. Arch. Pharm. (Weinheim), 2012, 345(3), 185-194.
[http://dx.doi.org/10.1002/ardp.201100140] [PMID: 21997797]
[18]
Zhongli, G.; Ryan, H.; David, S. Substituted tetrahydropyran spiro pyrrolidinone and piperidinone, preparation and therapeutic use thereof. U.S. Patent 20120238757, 2012.
[19]
Hughes, D.L. The Mitsunobu reaction. Org. React., 1992, 42, 335-656.
[20]
But, T.Y.S.; Toy, P.H. Organocatalytic mitsunobu reactions, h. organocatalytic mitsunobu reactions. J. Am. Chem. Soc., 2006, 128(30), 9636-9637.
[http://dx.doi.org/10.1021/ja063141v] [PMID: 16866510]
[21]
Lepore, S.D.; He, Y. Use of sonication for the coupling of sterically hindered substrates in the phenolic Mitsunobu reaction. J. Org. Chem., 2003, 68(21), 8261-8263.
[http://dx.doi.org/10.1021/jo0345751] [PMID: 14535815]
[22]
Olofsson, B.; Wijtmans, R.; Somfai, P. Synthesis of N–H vinylaziridines: A comparative study. Tetrahedron, 2002, 58(30), 5979-5982.
[http://dx.doi.org/10.1016/S0040-4020(02)00610-5]
[23]
Swamy, K.C.; Kumar, N.N.; Balaraman, E.; Kumar, K.V. Mitsunobu and related reactions: Advances and applications. Chem. Rev., 2009, 109(6), 2551-2651.
[http://dx.doi.org/10.1021/cr800278z] [PMID: 19382806]
[24]
Panday, S.K.; Prasad, J.; Pathak, M.B. Straightforward and facile approach toward the N-derivatization of pyroglutamates through mitsunobu reaction: Synthesis of N-Alkyl/N-Acyl pyroglutamates. Synth. Commun., 2011, 41(24), 3654-3661.
[http://dx.doi.org/10.1080/00397911.2010.519844]
[25]
Panday, S.K. Advances in the mitsunobu reaction: An excellent organic protocol with versatile applications. Mini Rev. Org. Chem., 2019, 16(2), 1-14.
[http://dx.doi.org/10.2174/1570193X15666180612090313]
[26]
Prasad, J.; Pathak, M.B.; Panday, S.K. An efficient and straight forward synthesis of (5S)-1-benzyl-5-(1H-imidazol-1-ylmethyl)-2-pyrrolidinone (MM1): A novel antihypertensive agent. Med. Chem. Res., 2012, 21(3), 321-324.
[http://dx.doi.org/10.1007/s00044-010-9536-6]
[27]
Panday, S.K.; Pathak, M.B.; Prasad, J. An efficient and straight forward strategy for the synthesis of enantiomerically pure(S)-1- Benzyl-5-((Alkyl/Aryl amino-methyl)-Pyrrolidin-2-ones. Indian J. Chem.,, 2015, 54(B), 936-39.

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