Spirocyclic Products Research Articles

Ferric Chloride Mediated Dearomative Spirocyclization of Biaryl Ynones: Synthesis of 3,3-Spiroindanones.

Ferric chloride mediated dearomative spirocyclization of biaryl ynones for the synthesis of new series of densely functionalized 3,3-spiroindanone derivatives has been reported. This study is the first to describe the regioselective synthesis of a five-membered ring from biaryl ynones. The scope of the reaction is broad and the spirocyclic products were obtained in moderate to good yields (up to 87%) and with high stereoselectivities.

Cyclization Modes in Anilides of N-Protected 3-Oxo-4-phenylaminobutyric Acid Under Knorr Conditions

Anilides of 3-oxo-4-phenylaminobutyric acid with Troc or COOEt protection at the phenylamino group undergo competing cyclization processes in neat polyphosphoric acid at 80 °C. Depending on the protecting group and the duration of the process, three main products in different ratios are formed. Along with the quinolin-2-ones, resulting from the classic Knorr cyclization, an indole derivative and a spirocyclic product have also been obtained from the COOEt-protected substrate. It has been demonstrated that the obtained indole derivative is capable of further dearomative spirocyclization under the studied conditions.

Synthesis of Cationic Azatriphenylene Derivatives by Anodic Pyridination and Their Optoelectronic Properties

Polycyclic aromatic hydrocarbons (PAHs) have attracted attentions due to their unique properties derived from their planar structure with wide π-conjugation. Heteroatom-doping of PAHs is a powerful method to control their optoelectronic properties and packing structures. Among heteroatom-doped PAHs, cationic nitrogen (N +)-doped PAHs have stable electrochemical properties, fluorescent properties, and peculiar aggregation behavior that can lead their application in organic photocatalysts, fluorescence molecules, and bioimaging[1]. However, the approaches to synthesizing N +-doped PAHs are still limited,[2] thus a facile synthesis is required to explore further molecular design.In this study, we demonstrate the facile synthesis of cationic azatriphenylene derivatives by electrochemical pyridination[3]. This protocol is a quite simple and efficient method without transition metal catalysts.First, the electrochemical oxidation of 1a was carried out under constant-current conditions in a H-type divided cell equipped with a carbon felt anode, and a Pt plate cathode under the reported standard conditions[4]. Under the optimized conditions, the 6-endo-trig cyclization successfully proceeded to yield product 2a in 60% isolated yield (Figure 1a). The structure of 2a was characterized by NMR, HR-MS, elemental analysis, and X-ray analysis. Furthermore, this cyclization was tolerant to various aryl substitutions such as dimethoxyphenyl, phenyl, and naphthyl groups, but 1f provided spirocyclic product 2f’ selectively via 5-exo-tet cyclization. These differences in reactivity and regioselectivity depending on the position of functional groups can be explained by DFT simulation.In UV-vis absorption and fluorescence measurements, it was observed that the obtained cationic azatriphenylene derivatives exhibited good emission properties attributed to the donor-acceptor structure (Figure 1b). The cyclic voltammograms of obtained products showed irreversible reduction peak at lower potential. This result indicates that the reduced species of 2a is unstable to undergo side reactions such as dimerization.In single crystal X-ray diffraction analysis, the cationic azatriphenylene derivatives formed relatively high planar structures and columnar packing patterns with cation species like charge-segregated assemblies (Figure 1c)[5]. Although counter-anions are expected to be important components to adjust layer distance between cationic π-surfaces, we could not observe remarkable differences among three anions (BF4 −, PF6 −, ClO4 −). This result is due to the rigid structures of the triphenylene unit, indicating that a more bulky counter anion is required to change the crystal structure.In conclusion, we successfully achieved the facile synthesis of cationic azatriphenylene derivatives for the first time by intramolecular anodic pyridination. This method is very useful for introducing a nitrogen cation into PAHs to perturb the π-electron system.-----Reference--------------------------------------------------------------------------------------------------------(1) D. Wu, R. Liu, W. Pisula, X. Feng, K. Müllen, Angew. Chem. Int. Ed. 2011, 50, 2791−2794.(2) A. Borissov, Y. K. Maurya, L. Moshniaha, W. S. Wong, M. Z. Karwowska, M. Stepien, Chem. Rev. 2022, 122, 565−788.(3) Y. Ohno, S. Ando, D. Furusho, R. Hifumi, Y. Nagata, I. Tomita, S. Inagi, Org. Lett. 2023, 25,3951−3955.(4) T. Morofuji, A. Shimizu, J. Yoshida, J. Am. Chem. Soc., 2013, 135, 5000−5003.(5) B. Dong, H. Maeda, Chem. Commun., 2013, 49, 4085−4099. Figure 1

Enantioselective Nickel-Catalyzed α-Spirocyclization of Lactones.

Herein we report a strategy for the enantioselective synthesis of spirocycles containing all-carbon quaternary centers via nickel-catalyzed intramolecular addition of lactone enolates to aryl nitriles. The established lactone α-spirocyclization efficiently and enantioselectively forges 5-, 6-, and 7-membered rings, performing best in the synthesis of 7-membered rings (up to 90% ee). This discovery represents an expansion of the synthetic toolkit for enantioselective spirocyclization, providing access to chiral, pharmaceutically relevant spirocyclic products.

Evolution of a Strategy for the Unified, Asymmetric Total Syntheses of DMOA-Derived Spiromeroterpenoids.

DMOA-derived spiromeroterpenoids are a group of natural products with complex structures and varied biological activities. Recently, we reported the first enantioselective total synthesis of five spiromeroterpenoids based on a fragment coupling strategy. This full account describes details of a strategy evolution that culminated in successful syntheses of the targeted natural products. Although our alkylative dearomatization methodology was unable to deliver the desired spirocyclic products in our first-generation approach, our second-generation approach based on oxidative [3 + 2] cycloaddition produced the asnovolin H core along with several complex dimers. Challenges with the dearomatization approach finally led us to develop a third generation, non-dearomatization approach based on a fragment coupling strategy to construct the conserved, sterically hindered bis-neopentyl linkage of the spiromeroterpenoids through 1,2-addition. To enable scalable access of the natural products, a refined, multigram-scale synthesis of the coupling partners was developed. A series of stereoselective transformations were developed through judicious choice of reagents and conditions. Finally, modular spirocycle construction logic was demonstrated through the synthesis of a small library of spiromeroterpenoid analogues.

Stereoselective Double Spirocyclization of 2-Benzyl-3-alkynyl Chromone with Nitrone via Gold-Catalyzed Cascade Reactions.

A novel, highly stereoselective gold-catalyzed spirocyclization of 2-benzyl-3-alkynyl chromone with nitrone is described. This cascade reaction involves gold-catalyzed cycloisomerization, nitrone-olefin [3 + 2]-annulation, alkene oxidation, and rearrangement for the formation of spirocyclic products. Interestingly, the isoxazolidine ring generated from [3 + 2]-annulation donates oxygen to alkene to generate a new pyran-3(4H)-one and azetidine ring for dispiro-benzofuran formation upon heating. This work demonstrates the one-pot, gold-catalyzed, multiple-step reaction, and the reaction temperature directly affects the formation of spirocyclic products.

Synthesis of Fluorinated Spiroindolenines by Transition Metal‐Catalyzed Indole Dearomatizations

AbstractA strategy to access fluorinated spiroindolenines has been developed, involving a selective functionalization of indoles with fluorinated moieties and subsequent catalytic dearomatization. Trifluomethylthio (SCF3), diethyl phosphono(difluoromethyl)thio (SCF2P(O)(OEt)2) and (phenylsulfonyl)difluoromethyl (CF2SO2Ph) groups were embedded at the C2 position of indole derivatives substituted with alkynes, allenes, and allyl carbonate moieties at the C3 position. A gold‐catalyzed cycloisomerization gave access to five spiroindolenines, and an enantioselective palladium catalyzed cyclization provided 10 fluorinated spirocyclic products with up to 77% ee.

Breaking the Rules: On the Relative Stability of Some Methylencyclopropane and Methylcyclopropene Derivatives.

The structure of the spirocyclic product obtained by reacting catechol with 1,1-dichloro-2-(chloromethyl)cyclopropane is shown by NMR and X-ray analysis to be that of a 2-methylcyclopropene (MeCP), instead of the previously reported 2-methylenecyclopropane (MCP) one. The study of the equilibration between the two isomeric forms by experimental and computational means (including both Density Functional Theory - DFT - and Coupled Cluster with single, double, and perturbative triple excitations - CCSD(T) - calculations) revealed that, at variance with most of the alkylidenecyclopropane/alkylcyclopropene systems described to date, for the compounds of the present study the MeCP derivative is more stable by≈ 2.5-3.0 Kcal mol-1 than the MCP one. The extension of the DFT and CCSD(T) study to other spiro-MCP/MeCP pairs suggests that the origin of the unexpected shift of the equilibrium position can be tracked back to a combination of electronic and ring-strain effects. These findings lead to re-think a long-standing, and substantially undisputed belief in the area of unsaturated cyclopropane derivatives.

BBr3-mediated dearomative spirocyclization of biaryl ynones: facile access to spiro[5.5]dienones.

This report covers boron tribromide (BBr3) mediated dearomative spirocyclization of biaryl ynones. The direct synthesis of spiro[5.5]dienones with a tri-substituted double bond is described for the first time in this paper. The scope of the reaction is broad and the spirocyclic products were obtained in moderate to good yields.

Catalytic Enantioselective [4+2] Cycloadditions of Salicylaldehyde Acetals with Enol Ethers

AbstractA readily accessible conjugate‐base‐stabilized carboxylic acid (CBSCA) catalyst facilitates highly enantioselective [4+2] cycloaddition reactions of salicylaldehyde‐derived acetals and cyclic enol ethers, resulting in the formation of polycyclic chromanes with oxygenation in the 2‐ and 4‐positions. Stereochemically more complex products can be obtained from racemic enol ethers. Spirocyclic products are also accessible.

Catalytic Enantioselective [4+2] Cycloadditions of Salicylaldehyde Acetals with Enol Ethers.

A readily accessible conjugate-base-stabilized carboxylic acid (CBSCA) catalyst facilitates highly enantioselective [4+2] cycloaddition reactions of salicylaldehyde-derived acetals and cyclic enol ethers, resulting in the formation of polycyclic chromanes with oxygenation in the 2- and 4-positions. Stereochemically more complex products can be obtained from racemic enol ethers. Spirocyclic products are also accessible.

Meroterpenoids with divers' rings systems from Phyllosticta capitalensis and their anti-inflammatory activity

Four undescribed sesquiterpene-shikimates (1–4), eight undescribed monoterpene-shikimates (5–12), together with two known ones were isolated and identified from the 95% ethanol extract of the plant endophytic fungus Phyllosticta capitalensis cultured in rice medium. Capitalensis A (1) was identified as the first sesquiterpene-shikimate-conjugated spirocyclic meroterpenoid degradation product, while capitalensis B (2) is a sesquiterpene-shikimate-conjugated spirocyclic meroterpenoid with a unique D-ring formed by a C-2–O–C-9′ connection. The structures of these previously undescribed compounds were elucidated by multiple techniques, including IR, HR-ESI-MS, and NMR analysis. Furthermore, their absolute configurations were established through the comprehensive approach that involved the calculations of ECD spectra, optical rotation values, and single-crystal X-ray analysis. Moreover, the anti-inflammatory activity of all isolated compounds was evaluated using a lipopolysaccharide (LPS)-induced inflammation model in BV2 microglial cells. Meanwhile, these compounds exhibited activity in inhibiting NO production. Four compounds, capitalensis C (3), capitalensis D (4), 15-hydroxyl tricycloalternarene 5b (13) and guignarenone A (14) showed strong inhibitory effects with IC50 values of 21.6 ± 1.33, 12.2 ± 1.08, 18.6 ± 1.27, and 15.8 ± 1.20 μM, respectively. In addition, the structure-activity relationship of the anti-inflammatory activity of the compounds was discussed.

Facile Stereoselective Synthesis and Structural Study of Camphor‐ and Fenchone‐Based Spirocyclic 1,3,4‐Oxadiazolines

AbstractFor the first time, an effective method for the synthesis of spirocyclic camphor‐ and fenchone‐based 1,3,4‐oxadiazolines has been developed. The influence of the molecular structure of the terpene substrate on the reaction stereoselectivity was studied. The structural features of the target products were studied using NMR spectroscopy and X‐ray diffraction analysis. The proposed method allows obtaining of spirocyclic products with a wide structural diversity, stereoselectively and in good yields.

Radical Dearomatising Spirocyclisation of Benzisoxazole‐Tethered Ynones

AbstractThe dearomative spirocyclisation of benzisoxazoles through a radical chain mechanism is described. Densely functionalised spirocycles were prepared in high yields by reacting benzisoxazole‐tethered ynones with aryl thiols in 1,2‐dichloroethane (DCE) at 60 °C. The identification of stabilising three‐electron interactions was key to the development of this new radical cascade reaction. The obtained spirocyclic products were converted into other spirocyclic scaffolds through a two‐step hydrogenolysis‐cyclisation sequence.

Expedient Access to Enantioenriched 1‐Azaspiro Cyclobutanones Enabled by Modified Heyns Rearrangement

AbstractLeveraging the unexplored regions of chemical space, the integration of spirocyclic cyclobutane in a molecular scaffold opens up a new vista in modern drug discovery. Despite recent advancements in achieving the synthesis of such motifs, strategies for their asymmetric construction have not been well‐recognized and remain a formidable challenge. Herein, for the first time, we have demonstrated a chiral Brønsted acid‐catalyzed enantioselective synthesis of 1‐azaspiro cyclobutanone enabled by an unusual reactivity of enamine that explore the potentiality of Heyns rearrangement upon electrophilic modification. This design strategy offers viable access to a wide range of cyclobutanone containing spiroindoline and spiropyrrolidine derivatives in good yields with excellent stereoselectivities (up to >99 % ee, >20 : 1 dr). Furthermore, the practicality of this methodology has been shown by a scale‐up synthesis of spirocyclic products and their facile post‐synthetic modifications.

Expedient Access to Enantioenriched 1-Azaspiro Cyclobutanones Enabled by Modified Heyns Rearrangement.

Leveraging the unexplored regions of chemical space, the integration of spirocyclic cyclobutane in a molecular scaffold opens up a new vista in modern drug discovery. Despite recent advancements in achieving the synthesis of such motifs, strategies for their asymmetric construction have not been well-recognized and remain a formidable challenge. Herein, for the first time, we have demonstrated a chiral Brønsted acid-catalyzed enantioselective synthesis of 1-azaspiro cyclobutanone enabled by an unusual reactivity of enamine that explore the potentiality of Heyns rearrangement upon electrophilic modification. This design strategy offers viable access to a wide range of cyclobutanone containing spiroindoline and spiropyrrolidine derivatives in good yields with excellent stereoselectivities (up to >99 % ee, >20 : 1 dr). Furthermore, the practicality of this methodology has been shown by a scale-up synthesis of spirocyclic products and their facile post-synthetic modifications.

Accessing Phase-Transfer Catalysts and a Phosphoramidite Ligand via the Asymmetric Intramolecular Hydroamination Reaction

Within the last few years, our group has developed the intramolecular, asymmetric hydroamination (HA) reaction to a point where essentially enantiopure products can be obtained. The question then arose as to whether we can apply the reaction in useful ways beyond the synthesis of natural/pharmaceutically relevant products. In the present paper, we incorporate a select few HA products for the production of new chiral phase-transfer catalysts. These species are synthesized in one or two synthetic steps from new spirocyclic HA products and are applied in a classical substitution reaction, showing negligible enantioselectivity. In a second application, we introduce a novel phosphoramidite ligand, obtained by combining BINOL (1,1′-bi-2-naphthol) and an optically pure HA product with phosphorous trichloride. The representative ligand shows high enantioselectivity and activity in the rhodium-catalyzed conjugate addition reaction (Hayashi–Miyaura reaction).

Fully Biocatalytic Rearrangement of Furans to Spirolactones.

A multienzymatic pathway enables the preparation of optically pure spirolactone building blocks. In a streamlined one-pot reaction cascade, the combination of chloroperoxidase, an oxidase, and an alcohol dehydrogenase renders an efficient reaction cascade for the conversion of hydroxy-functionalized furans to the spirocyclic products. The fully biocatalytic method is successfully employed in the total synthesis of the bioactive natural product (+)-crassalactone D, and as the key module in a chemoenzymatic route yielding lanceolactone A.

Stereospecific naphthoquinone photoredox reactions: Total syntheses of spirocyclic natural products

This account outlines our recent studies on the photoredox reaction of naphthoquinones. The mechanism consists of three consecutive events triggered by photo-irradiation, (1) hydrogen abstraction by the excited quinone to generate a biradical species, (2) internal single electron transfer (SET) to convert the biradical to the corresponding zwitterion, and (3) oxy-cyclization to give the product. The overall process allows replacement of a C–H bond by a C–O bond in a stereospecific, retentive manner. This photo-induced reaction has a broad scope, enabling otherwise-difficult stereocontrolled synthesis of natural products, as demonstrated by the syntheses of two classes of antibiotics, the spiroxins and the preussomerins. The former targets feature stereogenic spirocyclic ether structures, which were effectively constructed by a photoredox reaction involving 1,5-HAT, while the latter targets featuring stereogenic acetal structures were constructed by a photoredox reaction involving 1,6-HAT. Also described is the synthetic study of the rubromycins, centering attention to the stereospecific construction of the spiroacetal center.

Divergent Reaction of Indoline-derived Azadienes with α-Bromohydroxamates: Synthesis of Spiro-indolinepyrrolidinones and Indoline-fused Diazepinones.

A divergent reaction of indoline-derived azadienes with α-bromohydroxamates for the selective synthesis of spiro-indolinepyrrolidinones and indoline-fused diazepinones was disclosed. This reaction sequence involved an initial formation of five-membered spirocyclic products followed by an intramolecular ring-opening and ring expansion to produce seven-membered diazepinones. We demonstrated that controlling the reaction time could modulate the reaction pathway for formation of different molecular frameworks for the same set of substrates. Based on the experimental results, the reaction mechanism was also discussed and proposed to explain the phenomena observed in the process.