Synthesis of Bioactive Fluoropyrrolidines via Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides

Abstract Chiral pyrrolidinyl units are important building blocks in biologically active natural products and drugs, thereupon, searching approaches for the synthesis of diverse structured pyrrolidine derivatives is of great importance. Meanwhile, owing to the special physicochemical properties of fluorine atoms, the introduction of fluorine containing groups into small molecules often change their activities to a great extent. Herein, we reported an efficient route to chiral 3,3-difluoro- and 3,3,4-trifluoropyrrodinyl derivatives by Cu(I)-catalyzed enantioselective 1,3-dipolar cycloaddition of azomethine ylides with less active 1,1-difluoro- and 1,1,2-trifluoroalkenes. A series of new fluorinated pyrrolidines have been prepared in high yields (up to 96%) and excellent stereoselectivities (up to > 20:1 dr and 97% ee), and these unique structural blocks could be readily introduced into some natural compounds and pharmaceuticals. Additionally, antifungal activity investigation against four common plant funguses showed that some products possess general and high biological activities (up to 93% inhibition rate), the comparison with the antifungal activities of corresponding non-fluorinated compounds (low to 13% inhibition rate) revealed that the fluorine atoms at pyrrolidinyl rings play a crucial role in the antifungal activity, which prove the special properties of fluorine atoms in organic molecules.

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Synthesis of Bioactive Fluoropyrrolidines via Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides

Chemical Science ◽

10.1039/d1sc04595d ◽

2021 ◽

Author(s):

Xiao Xu ◽

Longzhu Bao ◽

Lu Ran ◽

Zhenyan Yang ◽

Dingce Yan ◽

...

Keyword(s):

Natural Products ◽

Building Blocks ◽

Biologically Active ◽

Azomethine Ylides ◽

Dipolar Cycloaddition ◽

Active Natural

Chiral pyrrolidinyl units are important building blocks in biologically active natural products and drugs, and the develpment of efficient methods for the synthesis of diverse structured pyrrolidine derivatives is of...

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Synthetic Routes for 1,4-disubstituted 1,2,3-triazoles: A Review

Current Organic Chemistry ◽

10.2174/1385272823666190514074146 ◽

2019 ◽

Vol 23 (8) ◽

pp. 860-900 ◽

Cited By ~ 8

Author(s):

Chander P. Kaushik ◽

Jyoti Sangwan ◽

Raj Luxmi ◽

Krishan Kumar ◽

Ashima Pahwa

Keyword(s):

Solid Phase ◽

Click Reaction ◽

Biological Activities ◽

Triazole Ring ◽

Copper Catalysts ◽

Biologically Active ◽

Pharmaceutical Chemistry ◽

Biological Targets ◽

Synthetic Routes ◽

High Yields

N-Heterocyclic compounds like 1,2,3-triazoles serve as a key scaffolds among organic compounds having diverse applications in the field of drug discovery, bioconjugation, material science, liquid crystals, pharmaceutical chemistry and solid phase organic synthesis. Various drugs containing 1,2,3-triazole ring which are commonly available in market includes Rufinamide, Cefatrizine, Tazobactam etc., Stability to acidic/basic hydrolysis along with significant dipole moment support triazole moiety for appreciable participation in hydrogen bonding and dipole-dipole interactions with biological targets. Huisgen 1,3-dipolar azide-alkyne cycloaddition culminate into a mixture of 1,4 and 1,5- disubstituted 1,2,3-triazoles. In 2001, Sharpless and Meldal came across with a copper(I) catalyzed regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles by cycloaddition between azides and terminal alkynes. This azide-alkyne cycloaddition has been labelled as a one of the important key click reaction. Click synthesis describes chemical reactions that are simple to perform, gives high selectivity, wide in scope, fast reaction rate and high yields. Click reactions are not single specific reaction, but serve as a pathway for construction of simple to complex molecules from a variety of starting materials. In the last few decades, 1,2,3-triazoles attracted attention of researchers all over the world because of their broad spectrum of biological activities. Keeping in view the biological importance of 1,2,3-triazole, in this review we focus on the various synthetic routes for the syntheisis of 1,4-disubstituted 1,2,3-triazoles. This review involves various synthetic protocols which involves copper and non-copper catalysts, different solvents as well as substrates. It will boost synthetic chemists to explore new pathway for the development of newer biologically active 1,2,3-triazoles.

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The Molecular Diversity Scope of Urazole in the Synthesis of Organic Compounds

Current Organic Synthesis ◽

10.2174/1570179416666190925162215 ◽

2019 ◽

Vol 16 (7) ◽

pp. 953-967 ◽

Cited By ~ 1

Author(s):

Ghodsi M. Ziarani ◽

Fatemeh Mohajer ◽

Razieh Moradi ◽

Parisa Mofatehnia

Keyword(s):

Biological Activities ◽

Biological Properties ◽

Biologically Active ◽

Microtubule Assembly ◽

Heterocyclic Molecules ◽

Biological Perspective ◽

Highly Active ◽

Anti Inflammatory ◽

High Yields ◽

Short Time

Background: As a matter of fact, nitrogen as a hetero atom among other atoms has had an important role in active biological compounds. Since heterocyclic molecules with nitrogen are highly demanded due to biological properties, 4-phenylurazole as a compound containing nitrogen might be important in the multicomponent reaction used in agrochemicals, and pharmaceuticals. Considering the case of fused derivatives “pyrazolourazoles” which are highly applicable because of their application for analgesic, antibacterial, anti-inflammatory and antidiabetic activities as HSP-72 induction inhibitors (I and III) and novel microtubule assembly inhibitors. It should be mentioned that spiro-pyrazole also has biological activities like cytotoxic, antimicrobial, anticonvulsant, antifungal, anticancer, anti-inflammatory, and cardiotonic activities. Objective: Urazole has been used in many heterocyclic compounds which are valuable in organic syntheses. This review disclosed the advances in the use of urazole as the starting material in the synthesis of various biologically active molecules from 2006 to 2019. Conclusion: Compounds of urazole (1,2,4-triazolidine-3,5-dione) are the most important molecules which are highly active from the biological perspective in the pharmaceuticals as well as polymers. In summary, many protocols for preparations of the urazole derivatives from various substrates in multi-component reactions have been reported from different aromatic and aliphatic groups which have had carbonyl groups in their structures. It is noted that several catalysts have been synthesized to afford applicable molecules with urazole scaffolds. In some papers, being environmentally friendly, short time reactions and high yields are highlighted in the protocols. There is a room to synthesize new catalysts and perform new reactions by manipulating urazole to produce biologically active compounds, even producing chiral urazole component as many groups of chiral urazole compounds are important from biological perspective.

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Cu(ii)/DM-Segphos catalyzed asymmetric 1,3-dipolar cycloaddition of benzoisothiazole-2,2-dioxide-3-ylidenes and azomethine ylides

RSC Advances ◽

10.1039/c6ra26543j ◽

2017 ◽

Vol 7 (18) ◽

pp. 10816-10820 ◽

Cited By ~ 5

Author(s):

Feifei Li ◽

Guorui Cao ◽

Yanfeng Gao ◽

Dawei Teng

Keyword(s):

Azomethine Ylides ◽

Dipolar Cycloaddition ◽

High Yields

Cu(OTf)2/DM-Segphos catalyzed asymmetric 1,3-dipolar cycloaddition of benzoisothiazole-2,2-dioxide-3-ylidenes and azomethine ylides was studied. The spiropyrrolidinyl-benzoisothiazolines were obtained in high yields with up to >99 : 1 dr and 99% ee.

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Decarboxylative-Mediated Regioselective 1,3-Dipolar Cycloaddition for Diversity-Oriented Synthesis of Structurally exo′-Selective Spiro[oxindole-pyrrolidine-dihydrocoumarin] Hybrids

Synthesis ◽

10.1055/s-0040-1707895 ◽

2020 ◽

Author(s):

Ying Zhou ◽

Xiong-Wei Liu ◽

Shun-Qin Chang ◽

Qi-Lin Wang ◽

Shuang Chen ◽

...

Keyword(s):

Carboxylic Acid ◽

Transition State ◽

Azomethine Ylides ◽

Dipolar Cycloaddition ◽

Diversity Oriented Synthesis ◽

Biologically Relevant ◽

Good Substrate ◽

Quaternary Center ◽

Substrate Tolerance ◽

High Yields

A general and practical three-component regioselective 1,3-dipolar cycloaddition of 3-amino-oxindole-based azomethine ylides and coumarins has been developed. This reaction displayed good substrate tolerance and gave a diverse array of biologically relevant spiro[ox-indole-pyrrolidine-dihydrocoumarin] derivatives bearing four contiguous stereocenters including one spiro quaternary center in moderate to high yields (up to 90%) with high diastereoselectivities (up to 15:1 dr). It is based on the application of carboxylic acid activated coumarins as dienophiles followed by a decarboxylation process. The possible mechanism of the 1,3-dipolar cycloaddition is proposed via an exo′-transition state. Furthermore, this is the first example of decarboxylative-mediated regioselective 1,3-dipolar cycloaddition of 3-amino-oxindole-based azomethine ylides and coumarins.

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Concise Synthesis of Tryptanthrin Spiro Analogues with In Vitro Antitumor Activity Based on One-Pot, Three-Component 1,3-Dipolar Cycloaddition of Azomethine Ylides to Сyclopropenes

Synthesis ◽

10.1055/s-0037-1611059 ◽

2018 ◽

Vol 51 (03) ◽

pp. 713-729 ◽

Cited By ~ 6

Author(s):

Vitali Boitsov ◽

Alexander Stepakov ◽

Alexander Filatov ◽

Nickolay Knyazev ◽

Stanislav Shmakov ◽

...

Keyword(s):

Antitumor Activity ◽

Azomethine Ylides ◽

Azomethine Ylide ◽

Dipolar Cycloaddition ◽

One Pot ◽

Economic Method ◽

Reaction Proceeds ◽

High Yields

A simple, efficient and atom-economic method has been developed for the synthesis of complex alkaloid-like compounds with spiro-fused indolo[2,1-b]quinazoline and cyclopropa[a]pyrrolizine or 3-azabicyclo[3.1.0]hexane moieties. We have found that one-pot, three-component 1,3-dipolar cycloaddition reactions allow the desired products to be obtained from various cyclopropene derivatives with tryptanthrin-derived azomethine ylides generated in situ, in good to high yields and excellent diastereoselectivity. The possibility of ylide generation was exemplified by using α-amino acids (l-proline, l-4-thiazolidincarboxylic acid) and simplest peptides (dipeptide Gly-Gly, tripeptide Gly-Gly-Gly). Quantum chemical investigations indicate that the reaction proceeds through the S-shaped azomethine ylide, the interaction of which with cyclopropenes proceeds via a less sterically hindered endo-transition state. The antitumor activity of some of spiro-tryptanthrin derivatives against erythroleukemia (K562), cervical carcinoma (HeLa) and colon carcinoma (CT26) cell lines was evaluated in vitro by MTS-assay.

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A New Method for the Synthesis of 2-Substituted Benzoxazoles from 2-Nitrophenol Derivatives and Aldehydes

JST: Engineering and Technology for Sustainable Development ◽

10.51316/jst.151.etsd.2021.31.3.8 ◽

2021 ◽

Vol 31 (3) ◽

pp. 43-46

Keyword(s):

Biological Activities ◽

Catalyst System ◽

Biologically Active ◽

New Method ◽

Redox Catalyst ◽

High Pressure High Temperature ◽

One Step ◽

High Yields ◽

Strong Acids ◽

Single Reaction

Benzoxazole derivatives are one of the compounds with many interesting biological activities. Conventional methods are often performed under complex conditions using strong acids, expensive metal catalysts, requiring high pressure, high temperature, and under microwave irradiation. In this study, we reported a new method of benzoxazole synthesis with redox catalyst using FeCl3.6H2O and sulfur. This is a suitable, efficient, readily available and environmentally friendly catalyst system for redox and condensation reactions in one step at 100 oC. Applying this new method, we have synthesized eight 2-arylbenzoxazole derivatives with high yields (calculated according to 2-nitrophenol). This research is an important step forward in the synthesis of biologically active compounds containing the benzoxazole framework from readily available starting materials in a single reaction.

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Activated Carbon/MoO3: Efficient Catalyst for Green Synthesis of Chromeno[d]pyrimidinediones and Xanthenones

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323666200924111602 ◽

2020 ◽

Vol 23 ◽

Author(s):

Niloofar Sabet Mehr ◽

Shahrzad Abdolmohammadi ◽

Maryam Afsharpour

Keyword(s):

Activated Carbon ◽

Room Temperature ◽

Bulk Material ◽

Biological Activities ◽

Reaction Times ◽

Aromatic Aldehydes ◽

Biologically Active ◽

Efficient Catalyst ◽

Calcium Blockers ◽

High Yields

Background: Nanoscale metal oxide catalysts have been extensively employed in organic reactions because they have been found to influence the chemical and physical properties of the bulk material. The chromene (benzopyran) nucleus constitutes the core structure in a major class of many biologically active compounds, and interest in their chemistry consequently continues because of their numerous biological activities. The xanthene (dibenzopyran) derivatives are classified as highly significant compounds which display a number of various bioactive properties. Pyrimidinones have also gained interest due to their remarkable biological utilization such as antiviral, antibacterial, antihypertensive, antitumor and calcium blockers effects. Objective: Our aim in the work presented herein was to prepare activated carbon/MoO3 nanocomposite and explore its role as a green and recyclable catalyst for the synthesis of chromeno[d]pyrimidinediones and xanthenones under ethanol-drop grinding at room temperature. Methods: The activated carbon/MoO3 nanocomposite was prepared successfully via a simple route in which carbonization of gums as new natural precursors was used for the synthesis of activated carbon. This nanocomposite was then effectively used in a reaction of 3,4- methylenedioxyphenol, aromatic aldehydes and active methylene compounds including 1,3-dimethylbarbituric acid and dimedone to synthesize a series of chromeno[d]pyrimidinediones and xanthenones in high yields. The synthesized catalyst was characterized by Fourier transform infrared spectroscopy (FT-IR), Powder x-ray diffractometry (XRD), Scanning electron microscope (SEM), Raman spectroscopy, and also by TGA analysis. Confirmation of the structures of compounds 5(a-g) and 6(a-g) were also established with IR, 1 H NMR and 13C NMR spectroscopic data and also by elemental analyses. Results: A number of 6,8-dimethyl-10-phenyl-6,10-dihydro-7H-[1,3]dioxolo[4΄,5΄:6,7]chromeno[2,3-d]pyrimidine-7,9(8H)-diones and 7,7- dimethyl-10-(4-methylphenyl)-6,7,8,10-tetrahydro-9H-[1,3]dioxolo[4,5-b]xanthen-9-ones were effectively synthesized using activated carbon/MoO3 nanocomposite (0.05 gr) as catalyst under ethanol-drop grinding at room temperature. The desired products were obtained in high yields (93-97%) within short reaction times (15-20 min). Conclusion: This paper investigates the catalytic potential of the synthesized activated carbon/MoO3 nanocomposite for the prepataion of chromeno[d]pyrimidinediones and xanthenones under ethanol-drop grinding procedure. The mildness of the reaction conditions, high yields of products, short reaction times, experimental simplicity, and avoid the use of harmful solvents or reagents makes this procedure preferable for the synthesis of these compounds.

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Solution phase synthesis of short oligoribonucleotides on a precipitative tetrapodal support

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.10.237 ◽

2014 ◽

Vol 10 ◽

pp. 2279-2285 ◽

Cited By ~ 7

Author(s):

Alejandro Gimenez Molina ◽

Amit M Jabgunde ◽

Pasi Virta ◽

Harri Lönnberg

Keyword(s):

Building Block ◽

Rna Synthesis ◽

Building Blocks ◽

Solution Phase ◽

Dipolar Cycloaddition ◽

Proof Of Concept ◽

Phase Synthesis ◽

Solution Phase Synthesis ◽

High Yields

An effective method for the synthesis of short oligoribonucleotides in solution has been elaborated. Novel 2'-O-(2-cyanoethyl)-5'-O-(1-methoxy-1-methylethyl) protected ribonucleoside 3'-phosphoramidites have been prepared and their usefulness as building blocks in RNA synthesis on a soluble support has been demonstrated. As a proof of concept, a pentameric oligoribonucleotide, 3'-UUGCA-5', has been prepared on a precipitative tetrapodal tetrakis(4-azidomethylphenyl)pentaerythritol support. The 3'-terminal nucleoside was coupled to the support as a 3'-O-(4-pentynoyl) derivative by Cu(I) promoted 1,3-dipolar cycloaddition. Couplings were carried out with 1.5 equiv of the building block. In each coupling cycle, the small molecular reagents and byproducts were removed by two quantitative precipitations from MeOH, one after oxidation and the second after the 5'-deprotection. After completion of the chain assembly, treatment with triethylamine, ammonia and TBAF released the pentamer in high yields.

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