Spiro Systems Research Articles

Construction of Spiro Systems from Tetrathiafulvalene Derivatives by a Pinacol‐like Rearrangement

An efficient and generalized pinacol‐like rearrangement of tetrathiafulvalene (TTF) derivatives has been achieved using 2, 2, 6, 6‐tetramethylpiperidine oxide (TEMPO) as a key reagent, in place of a traditional metal catalyst. Examination of numerous TTF derivatives demonstrates the reaction's exceptional tolerance to a variety of substituents, achieving an overall yield of up to 97%. The optimization of reaction conditions and evaluation of reaction applicability were achieved by varying factors such as the redox potential (E11/2) of the substrate molecule, substituent type, substituent position, number of substituents, and structural symmetry. Additionally, the reaction mechanism was explored using isotopic labeling, real‐time monitoring UV‐Vis absorption spectroscopy, and X‐ray diffraction (XRD) analysis. Specifically, TTF is oxidized to TTF+• by p‐toluenesulfonic acid (TsOH·H2O). TTF+• subsequently reacts with TEMPO and H2O to form a pinacol‐like intermediate, which undergoes a rearrangement to release a 2, 2, 6, 6‐tetramethylpiperidin‐1‐ol (TEMPOH) molecule, forming the rearranged product as a hydrogenated cation, this intermediate undergoes deprotonation, leading to the formation of the final spiro product. This investigation led to the identification of a class of reactions for the efficient conversion of TTF derivatives into their spiro products via pinacol‐like rearrangement reaction.

Comparative Study on Two Kinds of Spiro Systems for Constructing Through-Space Charge-Transfer Emitters

Comparative Study on Two Kinds of Spiro Systems for Constructing Through-Space Charge-Transfer Emitters

Cathodic Radical Cyclisation of Aryl Halides Using a Strongly-Reducing Catalytic Mediator in Flow.

Electro‐reductive radical cyclisation of aryl halides affords the corresponding hetero‐ and carbo‐cycles in an undivided flow reactor equipped with steel and carbon electrodes using an organic mediator. A dissolving metal anode is not needed, and the mediator can be employed in a sub‐stoichiometric amount (0.05 equiv), increasing the practical utility of cathodic radical cyclisation. The methodology is applied to O‐, N‐, and C‐tethers, yielding tricyclic fused and spiro systems. In the absence of mediator, the major pathway is hydrogenolysis of the C−X bond, a 2 e− process occurring at the cathode. Predominance of the radical pathway in presence of a strongly reducing mediator (M) is consistent with homogeneous electron‐transfer in a reaction layer detached from the cathode surface, where the flux of M .− leaving the electrode is such that little aryl halide reaches the cathode.

Cathodic Radical Cyclisation of Aryl Halides Using a Strongly‐Reducing Catalytic Mediator in Flow

AbstractElectro‐reductive radical cyclisation of aryl halides affords the corresponding hetero‐ and carbo‐cycles in an undivided flow reactor equipped with steel and carbon electrodes using an organic mediator. A dissolving metal anode is not needed, and the mediator can be employed in a sub‐stoichiometric amount (0.05 equiv), increasing the practical utility of cathodic radical cyclisation. The methodology is applied to O‐, N‐, and C‐tethers, yielding tricyclic fused and spiro systems. In the absence of mediator, the major pathway is hydrogenolysis of the C−X bond, a 2 e− process occurring at the cathode. Predominance of the radical pathway in presence of a strongly reducing mediator (M) is consistent with homogeneous electron‐transfer in a reaction layer detached from the cathode surface, where the flux of M.− leaving the electrode is such that little aryl halide reaches the cathode.

Copper acetate catalysed C-C bond formation en route to the synthesis of spiro indanedione cyclopropylpyrazolones.

This article reports the synthesis of spiro compounds based on an indanedione-cyclopropane-pyrazolone framework. The reaction relied upon the Michael-initiated ring closure strategy and was carried out under Cu(OAc)2 catalysis, assisted by an oxygen atmosphere and the base Et3N. The final compounds were obtained as an inseparable mixture in most cases with modest to good yields using diverse substrates. Among the two plausible routes, computational studies indicated the feasibility of a route which involves a four-membered Cu containing intermediate. Given the generic nature of the developed method, it may be utilised to synthesise other analogous spiro systems.

Diversity‐Oriented Synthesis of Spirocyclohexene Indane‐1,3‐diones and Coumarin‐Fused Cyclopentanes via an Organobase‐Controlled Cascade Reaction

AbstractAn organobase‐controlled, divergent cascade reaction to construct spirocyclohexene indane‐1,3‐diones and coumarin‐fused cyclopentanes is reported. The cascade reaction is triggered by the 1,6‐addition of 3‐homoacylcoumarins to the indanedione‐derived acceptors and further regio/chemoselective reaction that preferentially resulted in spiro systems and fused cyclopentanes in a diversity‐oriented manner. The 1,6‐addition/aldol and 1,6‐addition/vinylogous Michael addition cascade processes were controlled by different base/solvent systems to the predominant formation of one of the two carbocyclic compounds.magnified image

Enantioselective Heck‐Matsuda Reactions of Spirocyclopentenyl Hydantoins Directed by Non‐Covalent Interactions: Total Synthesis of the (S,S)‐VPC01091

AbstractA highly efficient Heck‐Matsuda desymmetrization of unsaturated spirohydantoins directed by non‐covalent interactions, which allows the construction of two simultaneous stereogenic centers, including a trisubstituted quaternary one, is described. This Heck arylation permitted a novel enantioselective total synthesis of the S1PR1 agonist (also an S1PR3 antagonist) compound VPC01091, a potential drug for the treatment of multiple sclerosis. The broad scope of these enantioselective Heck‐Matsuda protocol provided several arylated spiro systems in yields ranging from 76% to 99%, with enantiomeric ratios (er) up to 97:3, and diastereoselectivities (dr) of >20:1 in all cases studied. The method uses only 2% of Pd(TFA)2 and 3 mol% of the chiral N,N‐ligand Pyrabox in short reaction times of 1–2 h. These enantioselective Heck arylations can also be carried out at the gram scale in high yields with no erosion of their diastereoselectivity or enantioselectivity. The key spiro Heck products (R,R)‐21 and (R,R)‐27 bearing an aryl iodide moiety or an aryl n‐octyl moiety were employed as starting materials for the total enantioselective syntheses of the (S,S)‐VPC01091, in overall yields of 20% and 22% respectively after 10 or 9 steps from the starting spirohydantoin, with an er>95:5. Computational analysis of the enantioselective Heck‐Matsuda desymmetrization supports the rationale involving a key non‐covalent interaction between the imide carbonyl of the spirohydantoin and the cationic palladium bounded to the chiral N,N‐ligand.magnified image

Salivary adenoid cystic carcinoma: A clinicohistologic study in a nigerian tertiary institution

Background: Adenoid cystic carcinoma (ADCC) is a slow-growing salivary gland tumor with high recurrence and mortality rates. Histologic variants present variable aggression. This has not been investigated in Nigeria. This study aimed to investigate association of histologic variants with clinical aggression in Nigerian cases. Patients and Methods: Fifty-nine ADCC from 363 salivary gland tumors were selected from the departmental oral biopsy archives. Clinical data were retrieved, and hematoxylin and eosin sections were reviewed for confirmation and categorization into solid, cribriform, and tubular (modified Perzin, Spiro and van Weert systems). Estimated mean tumor growth rates (EMTGRs) were computed and matched with histologic variants. Statistical analysis was Chi-square, Kruskal–Wallis, and Mann–Whitney's test. P value was ≤0.05. Statistical package was SPSS. Results: Age ranged between 7 and 83 years (mean 49.2 ± 16.8 years). About 75.1% occurred in the 4th–6th decade (P = 0.02). Most common histologic variant was predominantly cribriform no solid (PCNS) pattern (40.7%). In major salivary glands, there was association between histologic variant and EMTGR (P = 0.025). PCNS had the highest EMTGR (0.840) followed by predominantly solid (PS) (EMTGR, 0.744). These were significantly higher than predominantly tubular no solid (PTNS) (EMTGR, 0.442) and predominantly tubular 30% solid (EMTGR, 0.115). In minor glands, there was also association between histologic variants and EMTGR (P = 0.017). However, the highest EMTGR (0.509) occurred in PTNS followed by PCNS (0.428). These were significantly higher than PS (0.259) with the least EMTGR. Conclusion: Trend of clinical aggression of histological variants based on EMTGR of ADCC varies depending on the type of salivary gland (major vs. minor).

A novel derivatives of thiazol-4(5H)-one and their activity in the inhibition of 11β-hydroxysteroid dehydrogenase type 1

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme that catalyzes the conversion of inactive cortisone into physiologically active cortisol. Inhibiting the activity of this enzyme plays a key role in the treatment of Cushing's syndrome, metabolic syndrome and type 2 diabetes. Therefore, new compounds that are selective inhibitors of this enzyme are constantly being looked for.In this work we present the synthesis of 2-(allylamino)thiazol-4(5H)-one derivatives by the reaction of N-allylthiourea with appropriate α-bromoesters. In the case of using of aliphatic α-bromoesters and α-bromo-β-phenylesters, the reactions were carried out in a basic medium (sodium ethoxide) and the products were isolated with a yield of up to 68%. Derivatives containing spiro systems in which carbon C-5 of the thiazole ring is the linker atom were obtained in the presence of N,N-diisopropylethylamine.Some of the obtained compounds, at a concentration of 10 μM have activity in the inhibition of 11β-HSD1 up to 71%. IC50 value for the most active compound: 2-(allylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one is 2.5 µM. With a high degree of 11β-HSD1 inhibition and a relatively large difference in the inhibition of 11β-HSD1 and 11β-HSD2 activity, this compound appears to be promising and should be subjected to further testing.

Synthesis and bioactivity of fused- and spiro-β-lactone-lactam systems.

An investigation of the formation of fused- and spiro-β-lactone annulate to γ-lactams has shown that the fused systems are formed preferentially, under standard conditions, but that spiro systems are accessible only when the formation of the fused system is blocked and require careful optimisation of reaction conditions. These systems display both weak antibacterial activity and proteasome inhibition.

Charting Biologically Relevant Spirocyclic Compound Space.

Spirocycles frequently occur in natural products and experience increasing interest in drug discovery, given their richness in sp3 centers and distinct three-dimensionality. We have systematically explored chemical space populated with currently available bioactive spirocycles. Compounds containing spiro systems were classified and their scaffolds and spirocyclic ring combinations analyzed. Nearly 47 000 compounds were identified that contained spirocycles in different structural contexts and were active against roughly 200 targets, among which several pharmaceutically relevant members of the G protein-coupled receptor (GPCR) family were identified. Spirocycles and corresponding compounds displayed notable scaffold diversity but contained only limited numbers of combinations of differently sized rings. These observations indicate that there should be significant potential to further expand spirocyclic chemical space for drug discovery, exploiting the privileged substructure concept. Inspired by those findings, we embarked on the design and chemical synthesis of three distinct novel spirocyclic scaffolds that qualify for downstream library synthesis, thus exploring principally new chemical space with high potential for pharmaceutical research.

The study on two kinds of spiro systems for improving the performance of host materials in blue phosphorescent organic light-emitting diodes

The introduction of spiro-acridine-fluorene (SAF) can affect the electronic structure of the whole molecule, which made SAF-based materials exhibit totally different photophysical properties from conventional spirobifluorene-based materials.

ChemInform Abstract: Intramolecular Transannulation of Alkynyl Triazoles via Alkyne—Carbene Metathesis Step: Access to Fused Pyrroles.

An intramolecular Rh-catalyzed transannulation reaction of alkynyl triazoles has been developed. This method allows efficient construction of various 5,5-fused pyrroles, including tetrahydropyrrolo and spiro systems. The method demonstrates excellent functional group compatibility. A rhodium carbene–alkyne metathesis mechanism is proposed for this transformation.

From Homoconjugated Push–Pull Chromophores to Donor–Acceptor‐Substituted Spiro Systems by Thermal Rearrangement

Series of homoconjugated push-pull chromophores and donor-acceptor (D-A)-functionalized spiro compounds were synthesized, in which the electron-donating strength of the anilino donor groups was systematically varied. The structural and optoelectronic properties of the compounds were investigated by X-ray analysis, UV/Vis spectroscopy, electrochemistry, and computational analysis. The homoconjugated push-pull chromophores with a central bicyclo[4.2.0]octane scaffold were obtained in high yield by [2+2] cycloaddition of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) to N,N-dialkylanilino- or N,N-diarylanilino-substituted activated alkynes. The spirocyclic compounds were formed by thermal rearrangement of the homoconjugated adducts. They also can be prepared in a one-pot reaction starting from DDQ and anilino-substituted alkynes. Spiro products with N,N-diphenylanilino and N,N-diisopropylanilino groups were isolated in high yields whereas compounds with pyrrolidino, didodecylamino, and dimethylamino substituents gave poor yields, with formation of insoluble side products. It was shown by in situ trapping experiments with TCNE that cycloreversion is possible during the thermal rearrangement, thereby liberating DDQ. In the low-yielding transformations, DDQ oxidizes the anilino species present, presumably via an intermediate iminium ion pathway. Such a pathway is not available for the N,N-diphenylanilino derivative and, in the case of the N,N-diisopropylanilino derivative, would generate a strained iminium ion (A1,3 strain). The mechanism of the thermal rearrangement was investigated by EPR spectroscopy, which provides good evidence for a proposed biradical pathway starting with the homolytic cleavage of the most strained (CN)C-C(CN) bond between the fused four- and six-membered rings in the homoconjugated adducts.

Intramolecular Transannulation of Alkynyl Triazoles via Alkyne–Carbene Metathesis Step: Access to Fused Pyrroles

An intramolecular Rh-catalyzed transannulation reaction of alkynyl triazoles has been developed. This method allows efficient construction of various 5,5-fused pyrroles, including tetrahydropyrrolo and spiro systems. The method demonstrates excellent functional group compatibility. A rhodium carbene-alkyne metathesis mechanism is proposed for this transformation.

ChemInform Abstract: Synthesis of the Functionalized Spiro[indoline‐3,5′‐pyrroline]‐2,2′‐diones via Three‐Component Reactions of Arylamines, Acetylenedicarboxylates, and Isatins.

AbstractDepending on the molar ratios of the reactants, 3′‐hydroxy or 3′‐arylamino derivatives of the biologically important spiro systems are available.

ドナー性アセチレン誘導体とTCNE, TCNQ, DDQの[2 + 2]環化付加反応：新規テトラシアノブタジエン誘導体とホモ共役型Push-Pull及びスピロ化合物の生成

ドナー性アセチレン誘導体とTCNE, TCNQ, DDQの[2 + 2]環化付加反応：新規テトラシアノブタジエン誘導体とホモ共役型Push-Pull及びスピロ化合物の生成

Homoconjugated Push–Pull and Spiro Systems: Intramolecular Charge‐Transfer Interactions and Third‐Order Optical Nonlinearities

Homoconjugated push–pull chromophores are obtained by [2+2] cycloaddition of 2,3-dichloro-5,6-dicyano-p-benzoquinone to anilino or ferrocene donor-substituted alkynes, and in one case a spiro compound (see picture: examples with corresponding electron adsorption spectra; C gray, Cl green, N blue, O red). Significant third-order optical nonlinearities could be measured for the first time for homoconjugated push–pull systems.

A New Synthesis of Highly Functionalized 2H‐Pyran Derivatives.

Abstract Ethyl oxo-(2-oxo-cycloalkyl)-ethanoates undergo a smooth reaction with triphenylphosphine and dialkyl acetylenedicarboxylates via intramolecular Wittig reaction to produce spiro-cyclobutene derivatives. These spiro systems undergo electrocyclic ring opening reaction to produce electron-deficient 1,3-dienes, which spontaneously cyclize to 2H-pyran derivatives.

A new synthesis of highly functionalized 2 H-pyran derivatives

Ethyl oxo-(2-oxo-cycloalkyl)-ethanoates undergo a smooth reaction with triphenylphosphine and dialkyl acetylenedicarboxylates via intramolecular Wittig reaction to produce spiro-cyclobutene derivatives. These spiro systems undergo electrocyclic ring opening reaction to produce electron-deficient 1,3-dienes, which spontaneously cyclize to 2 H-pyran derivatives.