Cyclopropane Ring Research Articles

4‐(Dimethylamino)Pyridinium Azide in Protic Ionic Liquid Media as a Stable Equivalent of Hydrazoic Acid

AbstractWe report a procedure for the multigram synthesis of 4‐(dimethylamino)pyridinium azide, a stable, non‐explosive, low‐hygroscopic source of azide ion soluble in both protic and aprotic organic solvents. In protic ionic liquid media this reagent was shown to serve as a safer equivalent of toxic and unstable hydrazoic acid. The synthetic utility of this system was demonstrated using donor‐acceptor cyclopropane ring opening as a model process. General procedures furnishing a variety of dialkyl (2‐azido‐2‐arylethyl)malonates or 4‐azido‐4‐arylbutyrates, depending on the protic ionic liquid applied, were elaborated. The conversion times for studied donor‐acceptor cyclopropanes were established providing the relative reactivity sequence. The application of 4‐(dimethylamino)pyridinium azide for a conventional nucleophilic substitution, oxirane ring opening, (3+2)‐cycloaddition to (thio)cyano group as well as their combinations realized as telescopic synthesis was also demonstrated.magnified image

Metal Free Approach towards the Synthesis of Structurally Diverse 1, 2‐Dihydronaphthalene Scaffolds and Theoretical Investigation

AbstractBiologically potent and synthetically significant 1,2‐dihydronaphthalene derivatives have gained considerable attention due to their wide applications in industrial as well as in medicinal fields also. A mild and efficient metal‐free protocol via the rearrangement of cyclopropylcarbinols has been reported to construct these 1,2‐dihydronaphthalene skeletons utilizing cyclopropane ring as the scaffold. We obtained conjugated dienes and, in some cases, homoallylic chlorides as major products in good to excellent yields. They have no literature precedence till date. The fate of this rearrangement depends on the substituent patterns of the cyclopropane bearing aryl moiety. Besides the synthetic studies, to get deep insight into the electronic transitions, time dependent DFT studies have also been performed.

Advances in the Structural Biology, Mechanism, and Physiology of Cyclopropane Fatty Acid Modifications of Bacterial Membranes.

Cyclopropane fatty acid (CFA) synthase catalyzes a remarkable reaction. The cis double bonds of unsaturated fatty acyl chains of phospholipid bilayers are converted to cyclopropane rings by transfer of a methylene moiety from S-adenosyl-L-methionine (SAM). The substrates of this modification are functioning membrane bilayer phospholipids. Indeed, in Escherichia coli the great bulk of phospholipid synthesis occurs during exponential growth phase, but most cyclopropyl synthesis occurs in early stationary phase. In vitro the only active methylene group acceptor substrate is phospholipid bilayers containing unsaturated fatty acyl chains.

Diversity-Oriented Synthesis Catalyzed by Diethylaminosulfur-Trifluoride-Preparation of New Antitumor Ecdysteroid Derivatives.

Fluorine represents a privileged building block in pharmaceutical chemistry. Diethylaminosulfur-trifluoride (DAST) is a reagent commonly used for replacement of alcoholic hydroxyl groups with fluorine and is also known to catalyze water elimination and cyclic Beckmann-rearrangement type reactions. In this work we aimed to use DAST for diversity-oriented semisynthetic transformation of natural products bearing multiple hydroxyl groups to prepare new bioactive compounds. Four ecdysteroids, including a new constituent of Cyanotis arachnoidea, were selected as starting materials for DAST-catalyzed transformations. The newly prepared compounds represented combinations of various structural changes DAST was known to catalyze, and a unique cyclopropane ring closure that was found for the first time. Several compounds demonstrated in vitro antitumor properties. A new 17-N-acetylecdysteroid (13) exerted potent antiproliferative activity and no cytotoxicity on drug susceptible and multi-drug resistant mouse T-cell lymphoma cells. Further, compound 13 acted in significant synergism with doxorubicin without detectable direct ABCB1 inhibition. Our results demonstrate that DAST is a versatile tool for diversity-oriented synthesis to expand chemical space towards new bioactive compounds.

Localization of Intrachain Modifications in Bacterial Lipids Via Radical-Directed Dissociation.

Intrachain modifications of membrane glycerophospholipids (GPLs) due to formation of the carbon-carbon double bond (C═C), cyclopropane ring, and methyl branching are crucial for bacterial membrane homeostasis. Conventional collision-induced dissociation (CID) of even-electron ions of GPL favors charge-directed fragmentation channels, and thus little structurally informative fragments can be detected for locating intrachain modifications. In this study, we report a radical-directed dissociation (RDD) approach for characterization of the intrachain modifications within phosphoethanolamines (PEs), a major lipid component in bacterial membrane. In this method, a radical precursor that can produce benzyl or pyridine methyl radical upon low-energy CID at high efficiency is conjugated onto the amine group of PEs. The carbon-centered radical ions subsequently initiate RDD along the fatty acyl chain, producing fragment patterns key to the assignment and localization of intrachain modifications including C═C, cyclopropane rings, and methyl branching. Besides intrachain fragmentation, RDD on the glycerol backbone produces fatty acyl loss as radicals, allowing one to identify the fatty acyl chain composition of PE. Moreover, RDD of lyso-PEs produces radical losses for distinguishing the sn-isomers. The above RDD approach has been incorporated onto a liquid chromatography-mass spectrometry workflow and applied for the analysis of lipid extracts from Escherichia coli and Bacillus subtilis.

Stereocontrolled Synthesis of 1,3‐Substituted 2‐Oxabicyclo[3.1.0]hexanes as Ring‐Constrained Tetrahydrofuranosyl C‐Glycosides

AbstractHerein, we describe the stereocontrolled synthesis of 2,3‐α‐methano 2‐substituted‐5‐(S)‐hydroxymethyl tetrahydrofurans, (formally 1,3‐disubstituted 2‐oxabicyclo[3.1.0]hexanes), using a TFA‐mediated destannylative cyclopropanation reaction, starting from commercially available 4‐(S)‐hydroxymethyl‐butyrolactone. A variety of chiral aryl, alkynyl and heterocyclic anomeric substituents were prepared in good to excellent yields. Facile derivatizations of these versatile compounds provide a series of anomerically functionalized chiral non‐racemic 2,3‐α‐methano tetrahydrofurans as potential substrates for heteroatom mediated ring opening reactions of potential interest in medicinal chemistry. Acid‐promoted methanolysis of a phenyl C‐glycoside analogue resulted in cleavage of the cyclopropane ring and formation of (1S,4S,6R)‐6‐methyl‐1‐phenyl‐2,7‐dioxabicyclo[2.2.1]heptane, a novel dioxabicyclo ketal and its oxocarbenium ion mediated oligomers.

Fluorocyclopropane-Containing Proline Analogue: Synthesis and Conformation of an Item in the Peptide Chemist's Toolbox.

Over the years, numerous modifications to the structure of proline have been made in order to tune its effects on bioactive compounds. Notably, the introduction of a cyclopropane ring or a fluorine atom has produced interesting results. Herein, we describe the synthesis of a proline containing fluorocyclopropane. This modified amino acid was inserted into a tripeptide, whose conformation was studied by nuclear magnetic resonance and density functional theory calculations.

Experimental analysis of Sterculia foetida biodiesel and butanol blends as a renewable and eco-friendly fuel

The current research intended to investigate the performance, emission and combustion characteristics of Sterculia foetida biodiesel blending with n-butanol at two different proportions (5% and 10%). The non-edible nature of the Sterculia foetida kernel oil favored choosing as feedstock. It comprises more than 70% of sterculic acid, a cyclopropane ring in its chemical structure. The base-catalyzed transesterification process converted Sterculia foetida kernel oil into biodiesel. The n-butanol additive was added in 5% & 10% volume as an oxygenated fuel to S. foetida / diesel blends for reducing emissions and improving thermal efficiency. Investigations revealed that brake thermal efficiency was improved by adding n-butanol in the blends compared with 20% S. foetida biodiesel + 80% Diesel. The emissions such as carbon monoxide, smoke opacity and hydrocarbons have significantly reduced vis-à-vis standard diesel. The oxides of nitrogen (NOX) and carbon dioxide (CO2) decreased relative to 20% S. foetida biodiesel + 80% Diesel. The analysis in combustion registered an improvement for butanol/diesel/biodiesel blends relative to S. foetida biodiesel owing to the innate content of oxygen in Heat Release Rate and In-Cylinder Pressure. Hence the addition of butanol with S. foetida biodiesel appears as a good substitute for straight diesel.

Organoelectrocatalysis Enables Direct Cyclopropanation of Methylene Compounds.

Cyclopropane is a prevalent structural unit in natural products and bioactive compounds. While the transition metal-catalyzed alkene cyclopropanation of functionalized compounds such as α-diazocarbonyl derivatives has been well established and provides straightforward access to cyclopropanes, cyclopropanation directly from the more stable and simpler methylene compounds has remained an unsolved challenge despite the highly desirable benefits of minimal prefunctionalization and increased operational safety. Herein we report an electrocatalytic strategy for the cyclopropanation of active methylene compounds, employing an organic catalyst. The method shows a broad substrate scope and excellent scalability, requires no metal catalyst or external chemical oxidant, and provides convenient access to several types of cyclopropane-fused heterocyclic and carbocyclic compounds. Mechanistic investigations suggest that the reactions proceed through a radical-polar crossover process to form the two new carbon-carbon bonds in the nascent cyclopropane ring.

Reductive Ring Opening of Arylcyclopropanecarboxamides Accompanied by Borylation and Enolate Formation.

Treatment of arylcyclopropanecarboxamides with a sodium dispersion in the presence of methoxypinacolborane as a reduction-resistant electrophile leads to reductive cleavage of the cyclopropane ring followed by instant trapping with the boron electrophile to yield the enolates of γ-aryl-γ-borylalkanamides. The enolates react further with a different electrophile to yield the corresponding α-substituted amides with anti selectivity.

A Green Chemistry Approach toward the Stereospecific Synthesis of Densely Functionalized Cyclopropanes via the Solid-State Photodenitrogenation of Crystalline 1-Pyrazolines.

The cyclopropane ring features prominently in active pharmaceuticals, and this has spurred the development of synthetic methodologies that effectively incorporate this highly strained motif into such molecules. As such, elegant solutions to prepare densely functionalized cyclopropanes, particularly ones embedded within the core of complex structures, have become increasingly sought-after. Here we report the stereospecific synthesis of a set of cyclopropanes with vicinal quaternary stereocenters via the solvent-free solid-state photodenitrogenation of crystalline 1-pyrazolines. Density functional theory calculations at the M062X/6-31+G(d,p) level of theory were used to determine the origin of regioselectivity for the synthesis of the 1-pyrazolines; favorable in-phase frontier molecular orbital interactions are responsible for the observation of a single pyrazoline regioisomer. It was also shown that the loss of N2 may take place via a highly selective solid-state thermal reaction. Scalability of the solid-state photoreaction is enabled through aqueous nanocrystalline suspensions, making this method a "greener" alternative to effectively facilitate the construction of cyclopropane-containing molecular scaffolds.

Tuning the Cyclopropane Ring-Opening Reaction over Electronic Bias by Fusion to a Pre-Aromatic Ring: TfOH-Promoted Aromatization of Dibenzonorcaradienes to Dibenzo[f,h]isocoumarins.

Fusion of the cyclopropane ring bearing two vicinal acceptors to the pre-aromatic dihydrophenanthrene ring, which is constructed by the Pd-catalyzed cross-coupling between the vicinal aromatic rings, is found to effectively direct the cleavage of the electronically unfavored cyclopropane bond between the vicinal acceptors. Consequently, a modular method for the rapid synthesis of dibenzo[f,h]isocoumarins from methyl ketones, aryl aldehydes, and α-keto esters via a reaction cascade of aldol condensation, Kukhtin-Ramirez cyclopropanation, Pd-catalyzed direct arylation, and acid-promoted aromatization has been realized.

1,3-Oxyalkynylation of Aryl Cyclopropanes with Ethylnylbenziodoxolones Using Photoredox Catalysis.

Alkynes and cyclopropanes are vital motifs in chemistry. Herein, a photoredox catalyzed 1,3-oxyalkynylation of aryl cyclopropanes with ethylnylbenziodoxolones (EBXs) in an atom-economic fashion is described. This cascade comprises single-electron oxidation of the aryl cyclopropane and nucleophilic ring opening followed by radical alkynylation at the benzylic position. The EBX compounds act as bifunctional reagents providing the nucleophilic acid as well as the alkynyl entity. The introduced method features mild conditions and wide substrate scope.

Identification of Cyclopropane Formation in the Biosyntheses of Hormaomycins and Belactosins: Sequential Nitration and Cyclopropanation by Metalloenzymes.

Hormaomycins and belactosins are peptide natural products that contain unusual cyclopropane moieties. Bioinformatics analysis of the corresponding biosynthetic gene clusters showed that two conserved genes, hrmI/belK and hrmJ/belL, were potential candidates for catalyzing cyclopropanation. Using in vivo and in vitro assays, the functions of HrmI/BelK and HrmJ/BelL were established. HrmI and BelK, which are heme oxygenase-like dinuclear iron enzymes, catalyze oxidation of the ϵ-amino group of l-lysine to afford l-6-nitronorleucine. Subsequently, HrmJ and BelL, which are iron- and α-ketoglutarate-dependent oxygenases, effectively convert l-6-nitronorleucine into 3-(trans-2-nitrocyclopropyl)-alanine through C4-C6 bond installation. These observations disclose a novel pathway of cyclopropane ring construction and exemplify the new chemistry involving metalloenzymes in natural product biosynthesis.

Identification of Cyclopropane Formation in the Biosyntheses of Hormaomycins and Belactosins: Sequential Nitration and Cyclopropanation by Metalloenzymes

AbstractHormaomycins and belactosins are peptide natural products that contain unusual cyclopropane moieties. Bioinformatics analysis of the corresponding biosynthetic gene clusters showed that two conserved genes, hrmI/belK and hrmJ/belL, were potential candidates for catalyzing cyclopropanation. Using in vivo and in vitro assays, the functions of HrmI/BelK and HrmJ/BelL were established. HrmI and BelK, which are heme oxygenase‐like dinuclear iron enzymes, catalyze oxidation of the ϵ‐amino group of l‐lysine to afford l‐6‐nitronorleucine. Subsequently, HrmJ and BelL, which are iron‐ and α‐ketoglutarate‐dependent oxygenases, effectively convert l‐6‐nitronorleucine into 3‐(trans‐2‐nitrocyclopropyl)‐alanine through C4−C6 bond installation. These observations disclose a novel pathway of cyclopropane ring construction and exemplify the new chemistry involving metalloenzymes in natural product biosynthesis.

Stereoselective construction of cycloheptene-fused indoline frameworks through photosensitised formal [5+2] cycloaddition

Irradiation of 1-acylindole derivatives that possess a vinylcyclopropane moiety at the end of the acyl side chain by a high-pressure mercury lamp through Pyrex glass under sensitization of an aromatic ketone gave the corresponding cyclised products stereoselectively in high yields. The distribution of the products was highly dependent on the substituents on the cyclopropane ring. In the case of a simple cyclopropane, the product was a mixture of ring-expanded cycloheptene-fused indoline and all-cis-fused cyclopropylcyclobutane-fused indoline through [2 + 2] cycloaddition, while cycloheptene-fused indolines were predominantly produced via formal [5 + 2] cyclisation in the case of substituted cyclopropanes. In particular, the product selectivity was substantially high in the case of silylcyclopropane.

Sesquiterpenoids from the Stem Bark of <i>Aglaia simplicifolia</i> and Their Cytotoxic Activity against B16-F10 Melanoma Skin Cancer Cell

Four sesquiterpenoid derivatives, i.e., 4β,10α-dihydroxyaromadendrane (1), caryophyllenol-II (2), senecrassidiol (3), and clovane-2β,9α-diol (4) have been isolated from the stem bark of Aglaia simplicifolia. The chemical structures of compounds 1-4 were determined based on spectroscopic data, including one and two-dimensional NMR and mass spectroscopy. In addition, these sesquiterpenoids 1-4, were also tested for their cytotoxic activity against B16-F10 melanoma skin cancer cell lines through in vitro assay. Among the isolated compounds 1-4, compound 1 showed the highest activity with an IC50 value of 44.8 μg/mL, suggesting the presence of a cyclopropane ring that plays an essential role in cytotoxic activity against B16-F10 melanoma skin cancer cell lines.

A Modular Access to 1,2- and 1,3-Disubstituted Cyclobutylboronic Esters by Consecutive Radical Additions.

A modular approach to substituted cyclobutylboronic esters is described. It proceeds by successive intermolecular radical additions of xanthates to pinacolato 1-cyclobutenylboronate and to pinacolato bicyclo[1.1.0]but-1-ylboronate. Success hinges on tuning the stability of the α-boryl radical by exploiting the stabilizing influence of the trivalent boronic ester and the slightly destabilizing cyclobutane, which increases the σ-character of the radical. Reductive removal of the xanthate group finally provides a range of 1,2- and 1,3-disubstituted cyclobutylboronic esters. The contrast with cyclopropylboronic esters is striking, since the strong destabilization by the highly strained cyclopropane ring allows the first radical addition to take place but not the second. Furthermore, the first adducts are geminal xanthyl boronic esters that can be converted into cyclobutanones. This chemistry furnishes cyclobutylboronic esters that would be quite difficult to obtain otherwise and thus complements existing methods.

A Modular Access to 1,2‐ and 1,3‐Disubstituted Cyclobutylboronic Esters by Consecutive Radical Additions

AbstractA modular approach to substituted cyclobutylboronic esters is described. It proceeds by successive intermolecular radical additions of xanthates to pinacolato 1‐cyclobutenylboronate and to pinacolato bicyclo[1.1.0]but‐1‐ylboronate. Success hinges on tuning the stability of the α‐boryl radical by exploiting the stabilizing influence of the trivalent boronic ester and the slightly destabilizing cyclobutane, which increases the σ‐character of the radical. Reductive removal of the xanthate group finally provides a range of 1,2‐ and 1,3‐disubstituted cyclobutylboronic esters. The contrast with cyclopropylboronic esters is striking, since the strong destabilization by the highly strained cyclopropane ring allows the first radical addition to take place but not the second. Furthermore, the first adducts are geminal xanthyl boronic esters that can be converted into cyclobutanones. This chemistry furnishes cyclobutylboronic esters that would be quite difficult to obtain otherwise and thus complements existing methods.

Structures of ganorbifates C–I, seven previously undescribed lanostanoids from the mushroom Ganoderma orbiforme, and insights of computed biosynthesis with DFT

Ganorbifates C–I, seven undescribed biosynthetically related polyoxygenated 3,4-seco-27-norlanostanoid congeners, were isolated from the edible mushroom, Ganoderma orbiforme. Ganorbifate C features a unique cyclobutene ring constructed at C19/C11, and both D and E incorporate an unusual cyclopropane ring formed by C-19/C-9 linkage. Their structures, including the absolute configurations, were determined by spectroscopic methods and ECD calculations. The proposed Norrish-Yang cyclization-based key biosynthetic pathway for ganorbifates C-E is revealed by density functional theory (DFT) calculations. The computational studies uncover the formation of both cyclobutene and cyclopropane rings in the isolates and the stereoselectivity centers of these steps are consistent with those in the natural products. All compounds exhibited NO generation inhibition in LPS-induced BV-2 microglial cells, among them ganorbifate C was the most promising one with the IC50 values of 4.37 μM.