Multicomponent synthesis of dihydropyrano[2,3-c]pyrazoles catalyzed by lipase from Aspergillus niger
Graphical abstract
Introduction
Although hydrolases are known to be highly substrate specific for hydrolysis or transesterification of esters and amides, recent surge in biocatalytic method employing hydrolases have opened up a new avenue in organic synthesis namely, enzymatic promiscuity [1], [2], [3], [4], [5], [6]. This property of enzymes facilitates carbon–carbon and carbon–heteroatom coupling under most environmentally benign reaction conditions. Interestingly, barring a handful of biocatalytic multicomponent reactions (MCRs) [7], [8], [9], [10], [11], [12], most of such reactions are restricted to two component reactions. Given the potential of multicomponent synthesis in industrial and medicinal chemistry applications, there can be no better choice of reaction design than enzyme catalyzed synthesis.
Lipases isolated from filamentous fungi Aspergillus niger (ANL) are among the most widely used enzymes, and they are recognized as GRAS (generally regarded as safe) enzymes by the FDA [13]. ANL is known to catalyze the kinetic resolution of secondary alcohols, carboxylic acids, and epoxides by enantioselective acylation and hydrolysis [14], [15], [16], [17], [18], [19]. It is known to catalyze many other important reactions such as conversion of glycerol to glycerol carbonate [20], oxidation of amino group in Nα-Benzyloxycarbonyl-l-lysine (Nα-Z-l-lysine) and Nα-Z-d-lysine to corresponding aldehydes [21], reduction of hydroperoxides [22] and 5-Acyl-isoxazolines [23], nitrile biotransformations [24], and regiospecific hydroxylation of acyclic monoterpene alcohols [25].
Dihydropyrano[2,3-c]pyrazole is an important building block with rich bioactivity profile that include anticancer [26], anti-inflammatory [27], antimicrobial [28], analgesic properties [29], and Chk1 kinase inhibitory activity [30]. It is ideally synthesized by multicomponent reaction of ethylacetoacetate, hydrazine hydrate, aldehyde and malononitrile in the presence of base catalysts [31], [32], [33], [34], [35]. Recently, some environment-compatible catalysts such as l-proline [36], γ-alumina [37], and per-6-amino-β-cyclodextrin [38] were also used to achieve this transformation, but mostly at elevated temperature. Zhao and co-workers [39], [40] reported the first organocatalytic methods for asymmeteric synthesis of dihydropyrano[2,3-c]pyrazole. Recently, we have reported a catalyst-free protocol for the said synthesis employing mechanochemistry to achieve excellent yield [41]. Xu et al. also reported an interesting biocatalytic route for the synthesis of tetrahydrochromene derivatives from the reaction of aldehyde, malononitrile and 1,3-dicarbonyl compound by a lipase (PPL) catalyzed three-component reaction [42]. To our surprise, we could not find any literature report on biocatalytic four-component reaction. Here, we report an environmentally benign and effective protocol for four-component synthesis of dihydropyrano[2,3-c]pyrazoles in ethanol in the presence of a catalytic amount of ANL at room temperature (Scheme 1). To the best of our knowledge, no enzymatic synthesis of this important building block is reported in the literature.
Section snippets
General
IR spectra were recorded on a Perkin-Elmer Spectrum One FTIR spectrometer. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were obtained on a Bruker AC-400 using CDCl3 and/or DMSO-d6 as solvent and TMS as internal standard, unless otherwise stated. Mass spectra were obtained from Waters ZQ 4000 mass spectrometer by the ESI method, while the elemental analyses of the complexes were performed on a Perkin-Elmer-2400 CHN/S analyzer. Reactions were monitored by thin layer chromatography (TLC). TLC
Screening of lipases for the synthesis of dihydropyrano[2,3-c]pyrazole
Given the fact that the synthesis of dihydropyrano[2,3-c]pyrazoles are generally achieved by employing environmentally incompatible bases as catalyst, we reasoned that lipase may catalyze such transformations with ease due to the presence of basic histidyl residue. To test our assumption, we chose the reaction of an equimolar (1 mmol each) mixture of hydrazine hydrate, ethyl acetoacetate, m-nitrobenzaldehyde, and malononitrile as our pilot reaction. When the pilot reaction was carried out in
Conclusion
For the first time, we have reported a biocatalytic four-component reaction in organic synthesis. It is also reported that lipase from A. niger (ANL) can effectively catalyze the synthesis of dihydropyrano[2,3-c]pyrazole at room temperature from a mixture of ethyl acetoacetate, hydrazine hydrate, aldehyde/ketone and malononitrile in ethanol. The lipase showed a wide range of promiscuous activity toward both aldehyde and ketone. Being a reaction at ambient temperature, the synthesis of
Acknowledgements
Thanks are due to CSIR, New Delhi [Grant No. 01(1992)/05/EMR-II] for providing financial support. The analytical services provided by SAIF, NEHU, Shillong, India are highly appreciated.
References (61)
- et al.
Curr. Opin. Chem. Biol.
(2006) - et al.
Chem. Biol.
(1999) Curr. Opin. Chem. Biol.
(2003)- et al.
Tetrahedron
(2008) - et al.
Tetrahedron Lett.
(2007) - et al.
Bioresour. Technol.
(2009) - et al.
Tetrahedron
(1995) - et al.
Tetrahedron Assym.
(1997) - et al.
J. Mol. Catal. B: Enzym.
(2004) - et al.
J. Mol. Catal. B: Enzym.
(2004)
Tetrahedron Lett.
Bioorg. Med. Chem.
Tetrahedron Lett.
Tetrahedron Lett.
Tetrahedron Lett.
Tetrahedron Lett.
Tetrahedron Lett.
Tetrahedron
J. Mol. Catal. B: Enzym.
J. Mol. Catal. B: Enzym.
J. Mol. Catal. B: Enzym.
Tetrahedron
Nat. Chem. Biol.
Angew. Chem. Int. Ed.
Chem. Rev.
Chem. Commun.
Angew. Chem. Int. Ed.
Chem. Commun.
Org. Lett.
J. Org. Chem.
Cited by (77)
Radical synthesis of dihydropyrano[2,3-c]pyrazoles using acridine yellow G as a photo-induced electron transfer photocatalyst
2023, Journal of Heterocyclic ChemistrySynthesis of dihydropyrano[2,3-c]pyrazole scaffolds by methylene blue (MB<sup>+</sup>) as a photo-redox catalyst via a single-electron transfer (SET)/energy transfer (EnT) pathway
2023, Current Research in Green and Sustainable ChemistryMicrowave-assisted synthesis of pyrano[2,3-c]-pyrazole derivatives and their anti-microbial, anti-malarial, anti-tubercular, and anti-cancer activities
2022, Journal of Molecular StructureCitation Excerpt :Particularly, dihydropyrano [2,3-c]pyrazole is a crucial scaffold with high biological activity, including anti-inflammatory [21], anti-cancer [22], anti-microbial [23], Chk1 kinase inhibitory activity [24], and analgesic properties [25]. Given these diverse biological activities of dihydropyrano [2,3-c]pyrazole, several methods [26–28] were developed and reported which includes utilization of various catalysts for the synthesis of pyrano-pyrazole derivatives under varied conditions namely: maltose [29], tungstate sulfuric acid (TSA) [30], saccharose [31], meglumine [32], urea [33], DBU [34], lipase [35], acetic acid [36], Fe3O4 nanoparticles [37], DABCO [38], nano-TiO2 [39], piperidine and pyridine [40], citric acid [41], nano-ZnO [42], sodium benzoate [43], nickel nanoparticles [44], nano-titania sulfuric acid (TSA) [45], pyrrolidine [46], CuO-CeO2 nanocomposite [47], nano-CuFe2O4 [48], amberlyst A21 [49], CeCl3 [50], borax [51], cerium ammonium nitrate (CAN) [52], I2 [53], glycerol [54] and CMCSO3H [55]. Upon closer inspection of the literature, we realized that comparatively very few methodologies utilized zinc triflate-zinc salt of trifluoromethane sulphonic acid.
A new role for photoexcited Na<inf>2</inf> eosin Y as direct hydrogen atom transfer (HAT) photocatalyst in photochemical synthesis of dihydropyrano[2,3-c]pyrazole scaffolds promoted by visible light irradiation under air atmosphere
2021, Journal of Photochemistry and Photobiology A: ChemistryCitation Excerpt :We report dihydropyrano[2,3-c]pyrazole scaffolds with various pharmacological features as (Fig. 1) potential inhibitor of the human Chk1 kinase [10], anticancer [11], analgesic [11], molluscicidal [12] and antimicrobial [13]. Many approaches are accessible such as choline chloride/Urea deep [14], isonicotinic [15], molecular sieves [16], meglumine [17], CAPB [18], L-proline/KF-alumina [19], CTACl [20], lipase [21], bovine serum albumin [22], β-cyclodextrin [23], morpholine triflate [24], TPSPPTNM [25], [Dabco-H][AcO] [26], Fe3O4@SiO2 nanoparticle-supported IL [27], sodium ascorbate [28], theophylline [29], nano-SiO2/DABCO [30], NaF [31] and nano-SiO2 [32]. These procedures resulted in numerous cases.