Spirocyclic Research Articles

Formation of Carbon–Carbon Double Bond between Cp Ligand and Alkenyl Carbon of Titanacyclopentenes

AbstractReactions of bis(cyclopentadienyl)titanacyclopentenes with BiI3 gave coupling products of one Cp ligand and the alkenyl carbons in moderate yields. An NMR study of the tetracyanoethylene (TCNE) adduct of the product showed that the coupled Cp ring and the alkenyl carbons were connected by one carbon–carbon double bond. This is in sharp contrast to coupling reactions of one Cp ligand with the diene moiety in bis(cyclopentadienyl)titanacyclopentadienes, where two carbon–carbon single bonds were formed between those two components to give dihydroindenes or spiro compounds.

Cobalt-Catalyzed Divergence in C(sp3)-H Functionalization of 9H-Fluorene: A Streamlined Approach Utilizing Alcohols.

Sustainable chemical production demands the creation of innovative catalysts and catalytic technologies. While the development of coherent and robust catalytic systems using earth-abundant transition metals is essential, it remains a significant challenge. Herein, an expedient divergence strategy for tandem dehydrogenative C(sp3)-H alkylation and cyclization reactions of 9H-fluorene using a newly developed N,N-bidentate cobalt catalytic system is developed. This method capitalizes on the use of abundant and readily accessible alcohol. Demonstrating wide-ranging applicability, the catalytic protocol successfully integrated a diverse array of fluorenes and alcohols. This includes benzylic, heteroaromatic, and aliphatic primary and secondary alcohols, amassing a total of 75 distinct examples. When applied to sterically bulky alcohols, the reaction preferentially undergoes alkenylation, yielding a tetrasubstituted olefin as the main product. In the case of diols, the expected outcome is Dual-fluorescence at both terminal positions. This process leads to difluorination, followed by a cyclization step, culminating in the formation of a relatively unprecedented spiro compound. The scalability of this method has been validated through gram-scale synthesis. Control experiments have shed light on the reaction mechanism, indicating that it progresses through an unsaturated intermediate and adheres to the borrowing hydrogen pathway.

Recent Synthetic Applications of the Birch Reduction

The Birch reduction has found a renaissance during the last two decades. In this Synpacts article a short summary of selected recent synthetic applications will be provided. 1,4-Cyclohexadienes, which are formed by Birch reduction in one step, are suitable precursors for radical reactions and are used as surrogates for difficult to handle substances. Their rearomatization under acidic conditions offers easy access to selectively alkylated arenes. Additionally, the Birch reduction of benzoic acids and subsequent trapping affords spiro compounds in high yields. Very recently, it was shown that 1,3-cyclohexadienes are directly available by Birch reduction in a one-pot reaction as well.

Isomerization, Protonation, and Hydrolysis Properties of Naphthalimide-Containing Spiropyran in Aqueous Media.

Synthesis of spiropyrans exhibiting ring-opening/closing isomerization driven by external stimuli is a challenging subject for the development of molecular sensors. A napthalimide-containing spiropyran (1) promotes rapid isomerization between the spirocyclic (SP) form and ring-opened merocyanine (MC) form by the change in solvent polarity even under the dark condition at room temperature. In this work, the effect of water on the isomerization behavior of 1 was studied. The addition of water caused an MC-water H-bonding interaction and shifted the resonance MC structure to the zwitterionic form with a lower ground-state energy. The stabilized MC form promoted spontaneous SP → MC isomerization and increased the equilibrium MC concentration. The effect of pH on the behavior of 1 was also studied. In acidic-neutral media, protonation/deprotonation of the naphthalimide moiety led to rapid and reversible changes in the absorption spectra. In contrast, strongly basic media (pH > 12) promoted irreversible base-catalyzed hydrolysis of the alkene moiety.

Synthesis and Reactivity of Amino(Ylide)Stannylenes

AbstractThe synthesis of two stable monoylide‐substituted stannylenes of type YCNSnR [R=Cl (1) or N(SiMe3)2 (2), and YCN=Ph3P(CN)C] starting from the cyanido‐substituted α‐metallated ylide YCN–K and SnCl2 or (SiMe3)2NSnCl is reported. Coordination of the cyano group to the tin center results in the dimerization of both stannylenes 1 and 2 in the solid state as well as in solution, where syn‐ and anti‐isomers are present. X‐ray diffraction analyses in combination with DFT calculations revealed that the π‐electron density of the ylide ligand is predominantly shifted into the cyano moiety rather than towards the tin center. This results in a strong preference of the dimers over the monomers, which is further emphasized by the reaction with 2,5‐di‐tert‐butylhydroquinone, which undergoes a [1+4] addition to the tin center to yield a spiro compound while preserving the cyclic core of the dimer. In contrast, phenyl isocyanate and dicyclohexylcarbodiimide insert into the Sn−Cylide bond, ultimately leading to the cleavage of the dimer and the formation of monomeric stannylenes with an ylide‐substituted thioamidato and amidinato ligand, respectively.

Spirocyclic Hybrids of Nortropane and 1,3-Oxazinan-2-one Fragments

AbstractWe report facile and versatile procedures for the synthesis of exo- and endo-isomeric spirocyclic hybrids of pharmacophoric (1R,5S)-8-azabicyclo[3.2.1]octane (nortropane) and 1,3-oxazinan-2-one fragments. Our approach consists of the hydrocyanation of endo- and exo-isomeric N-Cbz-protected nortropane-3-spiroepoxides, the reduction of hydroxy nitriles into amino alcohols, the synthesis of N-alkylated amino alcohols via reductive amination, the spirocyclization of the amino alcohols, N-alkylation of the unsubstituted 1,3-oxazinan-2-one fragment in the spiro compounds, and removal of the Cbz protecting groups.

Identification and Quantitative Analysis of the Pharmacologically Active Components of Jianxin Granules by UHPLC-QTOF-MS/MS-Based Metabolomics

Jianxin Granules, a Traditional Chinese Medicine (TCM), consisting of eight flavors, including Huang Qi (astragalus), Hong Shen (red ginseng), Pu Huang (pollen typhae), Dan Shen (salvia miltiorrhiza), Zhu Ling (polyporus), Bai Zhu (atractylodes macrocephala), Gui Zhi (cassia twig), Ting Li Zi (semen lepidii). Jianxin granules has a multi-system, multi-target, and multi-directional comprehensive regulatory effect on inhibiting ventricular remodeling, which is an effective formulation for the prevention and treatment of heart failure, and has a good application prospect. However, many of the ingredients, including pharmacologically active ingredients, in the Jianxin granules remain unclear. Here, we attempted to develop a metabolomics method of component identification, quantitation, pattern recognition, and cross-comparison of Jianxin granules. Chemical analysis, component identification and quantification analyse of Jianxin granules were conducted with a combination of UHPLC-QTOF-MS/MS with bioinformatics. Assessment of the correlation between technical and bio-replicated pharmacological active ingredients was implemented by Principal Component Analysis (PCA), in addition to Partial Least Squares Discriminant Analysis (PLS-DA). UHPLC-QTOFMS/ MS, a metabolomics method, was developed and adapted to characterize Jianxin granules, which consisted of 178 to 216 molecular signatures. The quantitative analysis of 95 frequently occurring molecular signatures of Jianxin granules was carried out by a single exogenous reference internal standard. Of these, 47 have been identified using diverse databases, including 2 glycosylglycerol derivatives, 2 lipids, 2 spiro compounds, 2 cyclohexanecarboxylic acids, 2 glycosides, 5 terpenoids, 7 oligopeptides, 17 favonoids, and 8 various compounds, such as hydroxycoumarin, chalcone, benzofuran, benzodioxole, benzaldehyde, aromatic ketone, and alkyl cafeate ester. The established method demonstrates robust reliability and reproducibility, making it suitable for various applications including compositional identification, quantification, and quality assessment of the pharmacologically active constituents in Jianxin granules.

Modern electrosynthesis of spiro compounds

Modern electrosynthesis of spiro compounds

Reactivity of a Linear 2-Germapropadiene with Acids, Ketones, and Amines.

The reactivity of an isolable 2-germapropadiene with acids, ketones, and amines was investigated. The reactions of 2-germapropagiene 1 with hydrogen chloride and acetic acid afforded the corresponding dichlorogermane (2) and diacetoxygermane (3), respectively, indicating that the central germanium atom of 1 is electrophilic. The reaction of 1 with benzaldehyde proceeds via a formal [2+2] cycloaddition to afford the corresponding spiro compound (4). Moreover, 1 reacts smoothly with acetone to furnish germane 5, which contains a six-membered ring involving two acetone molecules. Furthermore, 1 undergoes N-H bond insertion with methylamine or aniline to afford diamino germanes 7 and 8, respectively. The reaction of 1 with urea selectively afforded the corresponding N-H-insertion product (8).

Chemo-/regio-selective ultrasound-assisted synthesis of new spirooxindole-pyrrolidines/spirooxindole-pyrrolizines: Synthesis, antimicrobial and antitubercular activities, SAR and in silico studies

In an exploration of novel spirooxindole-pyrrolidine/spirooxindole-pyrrolizine-based compounds as antimicrobial and antitubercular agents, we have prepared a new series of pharmacologically privileged substructures, i.e., chalcone-isatin based spirooxindole compounds 12a-j, 13a-e, 14a-d, and 15–16 which were derived by the reaction of various substituted amino acids 11a-d, respectively, substituted chalcone (Me, OMe, Cl) 10a-m and isatins 9a-bvia one-pot three-component [3 + 2] cycloaddition reaction. We also report the SAR, and in silico molecular docking studies of 12a-j, 13a-e, 14a-d, and 15. While compared to the standard drug ampicillin (MIC = 25 µg/mL), compounds 13c, 13e, 14a, and 15 (MIC = 12.5 µg/mL) have shown to be twice as potent against the Bacillus subtilis [BS] bacterial strain. Compounds 12a and 13c (MIC = 25 µg/mL) exhibited equipotent behavior towards ampicillin (MIC = 25 µg/mL), a bacterial strain of B. subtilis [BS]. Compounds 13b (MIC = 3.125 µg/Ml) and 15 (MIC = 1.56 µg/mL) demonstrated strong antitubercular activity in the antitubercular activity assay when compared to the conventional medications Rifampicin (MIC = 0.2 µg/mL) and INH (MIC = 0.1 µg/mL). We also report, for the first time, in vitro antimicrobial activity of some previously reported spiro compounds 12c, 12f and 12 g.

Synthesis and structural characterization of poly-thiolactones with varied ring sizes and endocyclic functional groups

The synthesis and isolation of new thiolactone species containing endocyclic ether, polyether, and lactone groups were designed using the reaction between diacyl chlorides with organometallic tin compounds as a template for controlled thioester bond formation. Thus, eight polythiolactones, including cyclo and spiro compounds with different ring sizes and functional groups were prepared, namely 1-oxa-4,9-dithiacycloundecane-5,8-dione (1a), 1-oxa-4,10-dithiacyclododecane-5,9-dione (1b), 1,4-dioxa-7,12-dithiacyclotetradecane-8,11-dione (2a), 1,4-dioxa-7,13-dithiacyclopentaecane-8,12-dione (2b), 2,15,19,32-tetraoxa-6,11,23,28-tetrathia-spiro[16.16]tritriacontane 3,7,10,14,20,24,27,31-octaone (3a), 2,16,20,34-tetraoxa-6,12,24,30-tetrathia-spiro[17.17]pentatriacontan-3,7,11,15,21,25,29,33-octaone (3b), 9,12,25,28-tetraoxa-6,15,22,31-tetratia-1(1,4),17(1,4)-diphenylcyclodotriacontane-5,16,21,32-tetraone (2c), and 2,17,21,36-tetraoxo-6,13,25,32-tetrathia-8(1,4)27(1,4)-diphenyl-spiro[18-18]heptatriacontane-3,7,12,16,22,26,31,35-octaone (3c). The structural characteristics of the eight closely related derivatives were determined by examining the impact of ring size and functional groups, through single-crystal X-ray diffraction techniques. The crystal packing of these polythiolactones was found to be mainly governed by weak C-H···O hydrogen bonding and van der Waals interactions, resulting in partially overlapping tubular arrangements. Hirshfeld analysis was performed to investigate the crystal packing and intermolecular interactions. The results of this study show the possibility of forming 3D tubular arrangements using polythiolactones with various endocyclic groups, including both flexible and rigid spacers.

Developments in Synthesis Strategies of Spiro-Barbiturate Compounds: A Classified Study

Abstract: Spiro compounds being multi-cyclic systems linked by a single atom, have distinct three dimensionalities, and prominently hold a position of interest in the fields of synthetic and medicinal chemistry, pharmacology, material sciences and physics. Spirobarbiturate compounds which incorporate barbituric ring derivatives into spirocyclic structures have emerged as attractive synthetic targets for drug discovery as they are known to exhibit far-ranging pharmacological applications. In this review, we aim to bring to light the extensive, contemporary research applied to the synthesis of different spirobarbiturates having varied ring sizes (3, 5, 6 and 7 membered) in a classified manner. It presents the reported methods of synthesis along with their mechanistic pathways as well as the pharmacological activities of some of these synthesized biologically significant motifs.

Three-Component Reaction for the Synthesis of Spiro-Heterocycles from Isatins, Substituted Ureas, and Cyclic Ketones.

We reported an efficient three-component reaction to access new spiro heterocycles through the annulation reactions of isatins, substituted ureas, and cyclic ketones under normal laboratory conditions, which is another example of isatins being used to build spiro compounds by the ring-opening and recyclization processes. The wide range of substrates, simple operation, normal experimental conditions, and high yields make the approach of high practical value.

Recent Advances in Cyclization Reactions of 1,6‐Enynes

AbstractElaborated molecular architectures, specifically those bearing one or more carbon stereocenters, stand as an important class of carbocyclic and heterocyclic frameworks because they are frequently occurring core structures in numerous natural products and biologically active pharmaceutical molecules. Over the past few decades, the development of versatile synthetic approaches via cascade cyclization reactions of 1,6‐enynes for the construction of a series of fused and spiro compounds has been the focus of a great deal of research initiatives. These synthesis strategies are peculiarly fascinating in the context of the assembly of a wide array of pharmaceutical molecules, natural products, agrochemicals, and functional materials. In this review, recent developments in the transformations of 1,6‐enynes with diverse coupling reagents are summarized since 2018, which could be divided into five categories: 1) Introduction; 2) Transition metal catalyzed cyclization of 1,6‐enynes; 3) Metal‐free cyclization of 1,6‐enynes; 4) Visible‐light‐induced cyclization of 1,6‐enynes; 5) Electrocatalytic cyclization of 1,6‐enynes.

Multicomponent synthesis, structural and molecular dynamics simulation studies of a novel spirooxindole derivative

The 4′-(4-chlorobenzoyl)-3,-(2,6-dichlorophenyl)-1′-methylspiro(indole-3,2′-pyrrolidin)-2(1H)-one (SOD1) compound has been synthesized and the single crystals are grown by the slow evaporation method using ethanol. Initially, FT-IR and NMR (1H and 13C NMR) spectroscopic studies were used to confirm the structure of the compound. Single crystal X-ray diffraction data were used to determine the solid state structure of the grown single crystals. The title compound SOD1 crystallizes in the orthorhombic space group Pbca. The crystal packing analysis of the compound shows that distinct hydrogen bonding intermolecular interactions construct the R22(12), R22(8), and R12(8), supramolecular synthons to stabilize the packing modes. The propensity of intermolecular interactions is quantified by the Hirshfeld surface analysis, 2-D fingerprint plots and enrichment ratio analysis. Further, the 3-D packing topology of the molecular fragments is visualized through energy frameworks, which reveal the predominance of dispersion energy over other interaction energies. The optimized structure's geometric parameters were computed using DFT calculations using B3LYP/6–311+G(d,p) basis set and compared with the crystal structure parameters obtained by the X-ray diffraction studies. To explore the anticancer activity of the spiro compound, molecular docking with the 6FS1 protein was performed and the binding score of -7.7 kcal/mol was observed. Further, the binding interaction was explored by the dynamics simulation studies.

Design, synthesis, pharmacological evaluation, and in silico studies of the activity of novel spiro pyrrolo[3,4-d]pyrimidine derivatives.

In the present study, spiro compounds are shown to have distinctive characteristics because of their interesting conformations and their structural impacts on biological systems. A new family of functionalized spiro pyrrolo[3,4-d]pyrimidines is prepared via the one-pot condensation reaction of amino cyclohexane derivatives with benzaldehyde to prepare fused azaspiroundecanedione and azaspirodecenone/thione derivatives. A series of synthesized spiro compounds were scanned against DPPH and evaluated for their ability to inhibit COX-1 and COX-2. All compounds exhibit significant antiinflammatory activity, and they inhibited both COX-1 and COX-2 enzymes with a selectivity index higher than celecoxib as a reference drug. The most powerful and selective COX-2 inhibitor compounds were 11 and 6, with selectivity indices of 175 and 129.21 in comparison to 31.52 of the standard celecoxib. However, candidate 14 showed a very promising antiinflammatory activity with an IC50 of 6.00, while celecoxib had an IC50 of 14.50. Our findings are promising in the area of medicinal chemistry for further optimization of the newly designed and synthesized compounds regarding the discussed structure-activity relationship study (SAR), in order to obtain a superior antioxidant lead compound in the near future. All chemical structures of the novel synthesized candidates were unequivocally elucidated and confirmed utilizing spectroscopic and elemental investigations.

Synthesis, computational docking and molecular dynamics studies of a new class of spiroquinoxalinopyrrolidine embedded chromanone hybrids as potent anti-cholinesterase agents.

Novel structurally intriguing heterocycles embedded with spiropyrrolidine, quinoxaline and chromanone units were synthesized in good yields using a [Bmim]Br accelerated multicomponent reaction strategy. The key step of the reaction is 1,3-dipolar cycloaddition involving highly functionalized dipolarophile, viz. 3-benzylidenechroman-4-one, to afford spiroquinoxalinopyrrolidine embedded chromanone hybrid heterocycles. The formation of spiro products occurs via two C-C, two N-C and one C-N bonds possessing four adjoining stereogenic centers, two of which are spiro carbons. The newly synthesized spiro compounds showed potent acetylcholinesterase and butyrylcholinesterase inhibitory activities. Moreover, compounds with fluorine displayed the highest AChE (3.20 ± 0.16 μM) and BChE (18.14 ± 0.06 μM) inhibitory activities. Further, docking studies, followed by all-atom molecular dynamics, showed results that are consistent with in vitro experimental findings. Although docking scores for the synthesized derivatives were higher than those of the standard drug, MD MMPBSA results showed better binding of synthesized derivatives (-93.5 ± 11.9 kcal mol-1) compared to the standard drug galantamine (-66.2 ± 12.3 kcal mol-1) for AChE but exhibited similar values (-98.1 ± 11.2 and -97.9 ± 11.5 kcal mol-1) for BChE. These differences observed in drug binding with AChE/BChE are consistent with RMSD, RMSF, LIG plots, and FEL structural analysis. Taken together, these derivatives could be potential candidates as inhibitors of AChE and BChE.

An Ultrasound-assisted Three Component Protocol for the Regio and Stereo-selective Synthesis of Some Novel Dispiroheterocycles and Their Biological Evaluation as Anti-inflammatory, Anti-obesity Agents

Background: The increasing utilization of spiro compounds in drug discovery, led us to design and synthesize regioselectively some novel dispiroheterocycles, by a standard 1,3-dipolar cycloaddition reaction between 6-hydroxyaurone and in situ generated azomethine ylides, using ultra-sonication as green energy source. These results are first of its kind in the literature reported so far for the similar conditions. After confirmation of the proposed structures spectroscopically, using 1H NMR, 13C NMR and FT-IR spectral data, all the compounds are screened for their potential biological activities. Methods: Three component protocol, that contain (Z)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one, sarcosine and unsubstituted isatin. In which azomethine ylides react with olefinic dipolarophiles through 1,3-dipolar cycloaddition, which is highly regio- and stero-selective way in situ. Structures of the proposed products have been confirmed using 1H NMR, 13C NMR and FT-IR spectral data. Results: In order to screen the potential biological activities of the synthesized compounds, their effect was observed on trypsin, amylase and lipase activities. Differential effect has been observed. Trypsin was substantially activated whereas an inhibitory effect was observed for amylase and lipase supported by insilico studies. Conclusion: Synthesis of six novel 6-hydroxy-1'-methyl-4'-phenyl-3H-dispiro[benzofuran-2,3'- pyrrolidine-2',3''-indoline]-2'',3-dione derivatives have been made using a multicomponent greener protocol. These synthesized compounds have exhibited differential effects toward trypsin, amylase and lipase well supported by in-silico studies. Thus, the present study highlights their potential use as antiinflammatory and anti-obesity agents.

Spiro-centre substitution effects in the intramolecular spin–spin interactions of spirobiacridine diradicals

Spirodiradicals with the Si and Ge spiro atoms exhibit a S = 1 state. The magnetic interaction in the Si derivative was found to be lower than that in the Ge derivative, implying a negative effect on σ*(Si–Cα)–π* hyperconjugation.

A Catalyst-Free One-Pot Multicomponent Green Strategy for the Synthesis of Spiroindene-1,3dione-Benzochromene/ Thio-Chromene Derivatives under Neat/Aqueous Conditions

An efficient, facile, and catalyst-free one-pot multicomponent green strategy under neat or aqueous conditions has been developed to synthesize a series of spiro compounds that contain two biologically active pharmacophores, benzochromenes/thio-chromenes and indan-1,3-dione, in a single molecular framework. The desired Spiroindene-1,3dione-benzochromene/thio-chromene derivatives were yielded through a one-pot, three-component reaction between ninhydrin, substituted 1,3-dicarbonyls, and 2-naphthol/2-naphthalene thiol via the Knoevenagel–Michael cascade. The advances of this strategy include high product yields (94–82%), the formation of a new asymmetric center, cost-effectiveness, atom economy, and a straightforward workup procedure that does not require any additional purification steps.