Spirocyclic Ring Research Articles

Desymmetrization of meso-bisphosphates using copper catalysis and alkylzirconocene nucleophiles

The desymmetrization of meso-compounds is a useful synthetic method, as illustrated by numerous applications of this strategy in natural product synthesis. Cu-catalyzed allylic desymmetrizations enable the enantioselective formation of carbon-carbon bonds, but these transformations are limited in substrate scope and by the use of highly reactive premade organometallic reagents at cryogenic temperatures. Here we show that diverse meso-bisphosphates in combination with alkylzirconium nucleophiles undergo highly regio-, diastereo- and enantio-selective Cu-catalyzed desymmetrization reactions. In addition, C2-symmetric chiral bisphosphates undergo stereospecific reactions and a racemic substrate undergoes a Cu-catalyzed kinetic resolution. The reaction tolerates functional groups incompatible with many common organometallic reagents and provides access to a broad range of functionalized carbo- and hetero-cyclic structures. The products bear up to three contiguous stereogenic centers, including quaternary centers and spirocyclic ring systems. We anticipate that the method will be a useful complement to existing catalytic enantioselective reactions.

Aqueous monitoring of toxic mercury through a rhodamine-based fluorescent sensor

Mercury is a toxic heavy element, which contaminates air, land, and water, thus posing environment and human health-related threats to the ecological system. Considering the adverse ecological effects, there is an urgent need to design and develop strategic tools to detect a broader spectrum of toxic elements in different environments. The development of point-of-care tools, e.g., sensor-based devices offers a noteworthy solution to detect and monitor real-time generation or release of environmentally-related toxic elements from different sectors, even with or without partial treatments. For a first-hand estimate, a qualitative method (colorimetric) for detection of mercury could suffice. Benefiting from the colorimetric recognition methodology, herein, we developed a new system (2-(5-bromothiazol-2-yl)-3',6'-bis(diethylamino)spiro[isoindoline-1,9' xanthen]-3-one) for the detection of mercury ions. The newly developed chemical sensor is composed of a fluorescent part (rhodamine b) and a binding site (2-amino-5-bromothiazole). A highly selective and sensitive response accompanied by visual color change (colorless to pink) towards Hg²⁺ was observed among miscellaneous metal cations. This colorimetric change confirmed that the coordination complex exists as spirocyclic ring opened derivative of rhodamine moiety. Furthermore, the binding affinity and detection limit was also calculated from the absorbance and emission data. The calculated values are in the order of 4.72 × 10⁴ M⁻¹ and 6.9 μM, respectively. In addition, the results reveal that the complex between the chemical sensor (S) and Hg²⁺ is reversible in the presence of ethylenediaminetetraacetate (EDTA²⁻). Finally, the newly developed sensor S was employed to detect Hg²⁺ in the wastewater. The fluorescence intensity was measured at 583 nm with S followed by spiking with Hg²⁺ at different concentrations and related linearly. In summary, taken together all the properties suggest that the newly developed sensor might display great potential in the field of environmental monitoring of toxic elements.

Ophiorrhines A and B, Two Immunosuppressive Monoterpenoid Indole Alkaloids from Ophiorrhiza japonica.

Two monoterpenoid indole alkaloids, ophiorrhines A (1) and B (2), were obtained from plant Ophiorrhiza japonica BI. Their structures were elucidated by extensive spectroscopic methods and single crystal X-ray diffraction. Compounds 1 and 2 possess a novel spirocyclic ring system. Its biosynthesis pathway is proposed. Compound 2 exhibits potent inhibitory activity against concanavalin A (Con A) induced T cell proliferation and lipopolysaccharide (LPS) induced B lymphocyte cell proliferation with IC50 values 13.3 and 7.5 μM, respectively. Compound 1 exhibits significant inhibition specifically against the LPS-induced proliferation of B lymphocyte cells with IC50 value 18.6 μM.

Rhodamine derivatives bearing thiourea groups serve as fluorescent probes for selective detection of ATP in mitochondria and lysosomes

ATP functions as an energy source in all living things and it also plays key roles in a variety of important biological processes. Moreover, low levels of ATP are indicators of cardiovascular disease, Parkinson’s disease and ischemia. As a result, the development of fluorescent probes that detect ATP selectively is a significant goal. In the current study, we synthesized two new rhodamine derivatives, 1 and 2, bearing thiourea groups, and assessed their abilities to serve as selective fluorescent and colorimetric probes for ATP. Thiourea groups were incorporated in 1 and 2 to act as hydrogen bonding donors to recognize tris-phosphate groups and induce photophysical property changing, spirocyclic ring opening. Indeed, we observed that solutions of these probes undergo a large fluorescent enhancement at 590 nm and a distinct colorimetric change from colorless to dark pink upon addition of ATP. Moreover, these probes can be used to image ATP in HeLa cells. Because it was found to locate mainly in mitochondria, 2 can be employed to image ATP in mitochondria. On the other hand, probe 1, bearing a lysosome directing morpholine group displays moderately selective localization in lysosomes and can be utilized to image ATP in lysosomes. Furthermore, both probes were shown to have extremely low cytotoxicities by using MTT assays.

Structurally Diverse Sesquiterpenoids from the Endangered Ornamental Plant Michelia shiluensis.

A preliminary phytochemical investigation on the MeOH extract of the leaves and twigs of the endangered ornamental plant Michelia shiluensis led to the isolation of 16 sesquiterpenoids. The isolated compounds comprised germacrane- (1-4, 13, 14), guaiane- (5-9, 15), amorphane- (10), and eudesmane-type (11, 12, 16) sesquiterpenoids. The new structures (1-12) were elucidated by spectroscopic and computational methods, and their absolute configurations (except for 9) were assigned by single-crystal X-ray diffraction crystallographic data and/or electronic circular dichroism spectra. Shiluolides (A-D, 1-4) are unprecedented C16 or C17 homogermacranolides, and their putative biosynthetic pathways are briefly discussed. Shiluone D (8) is a rare 1,10- seco-guaiane sesquiterpenoid featuring a new ether-containing spirocyclic ring, whereas shiluone E (9) represents the first example of a 1,5-4,5-di- seco-guaiane with a rare 5,11 -lactone moiety. Shiluone F (10) is the first amorphane-type sesquiterpenoid possessing an oxetane ring bridging C-1 and C-7. Bioassay evaluations indicated that lipiferolide (13) showed noteworthy cytotoxicities toward human cancer cell lines MCF-7 and A-549, with IC50 values of 1.5 and 7.3 μM, respectively. Shiluone D (8) exerted inhibition against protein tyrosine phosphatase 1B (IC50: 46.3 μM).

Isothiocyanate Strategy for the Synthesis of Quaternary α‐Amino Acids Bearing a Spirocyclic Ring System

AbstractThis study demonstrates that isothiocyanates derived from α‐substituted α‐amino acids are useful building blocks in the heteroannulation reactions with electron‐deficient olefins. The developed strategy proceeds in a cascade manner and involves Michael addition followed by a cyclization via nucleophilic addition. Target, spirocyclic heterocycles bearing either a quaternary α‐amino acid moiety or α‐aminophosphonate group have been efficiently synthesized in very high yield (up to 99%) and with excellent stereocontrol. The usefulness of heterocycles obtained has been demonstrated in selected transformations.magnified image

Building Rhodamine-BODIPY fluorescent platform using Click reaction: Naked-eye visible and multi-channel chemodosimeter for detection of Fe3+ and Hg2+

A novel ratiometric fluorescent probe RhB-BODIPY-OH based on Rhodamine and boron dipyrromethene (BODIPY) platform for sensing Fe3+ and Hg2+ ions was synthesized by Click reaction. RhB-BODIPY-OH dendron was a hybrid fluorescent probe with reaction-based as well as lock/key-based detection sites, which contains four recognition positions including Schiff base CN functionality, triazole–triazole linker and the spirocyclic ring of the Rhodamine unit. Naked eye detection was realized with the obvious color change. In addition, low detection limit was calculated from titration results with the value were 7.74 × 10−8 M for RhB-BODIPY-OH/Hg2+ as well as 3.91 × 10−7 M for RhB-BODIPY-OH/Fe3+, separately. The probe is highly sensitive, the detection time is less than 2s. On top of that, living cell imaging experiment was carried out, which demonstrated that RhB-BODIPY-OH is a good bioimaging agent in living cells. Eventually, amino-group-functionalized silica fluorescent nanoparticles (FNPs) encapsulating the RhB-BODIPY-OH dyes were prepared and characterized by transmission electron microscopy.

New Six-Membered pH-Insensitive Rhodamine Spirocycle in Selective Sensing of Cu2+ through C-C Bond Cleavage and Its Application in Cell Imaging.

A new rhodamine-based chemosensor 1 with a six-membered spirocyclic ring has been synthesized, which exhibits excellent pH stability and shows selective “turn-on” fluorescent detection of Cu2+ ions over a series of other metal ions including Cu+ ions. The expansion of spirocycle improves the stability and selectivity of the chemosensors in sensing of metal ions. Till today only few rhodamine structures R1–R5 with thiourea-, hydrazine amide-, or pyrrole-decorated six-membered spirocyclic rings are known that exhibit metal-ion sensing via C–N bond cleavage of the spiro ring. In this context, rhodamine compound that responds to the metal ion through C–C bond cleavage of the six-membered spiro ring is completely unknown. The present example is a first-time report that demonstrates selective sensing of Cu2+ ions through C–C bond cleavage over the conventional existing systems in the literature. The chemosensor 1 is cell permeable and can detect Cu2+ in live cells using confocal microscopy in the biologically relevant pH range with high photostability.

An intramolecular para-phenolic allylation free radical cyclization strategy for the synthesis of alkaloids and terpenes with spiro[4.5]decane architectures

A Tsuji-Trost variant of the Winstein-Masamune reaction has been investigated for the synthesis of the AC spirocyclic ring system 9 bearing a quaternary carbon found in the fawcettimine type Lycopodium alkaloids magellanine 1 and lycojaponicumin B 2 and cyclopiane diterpenes such as conidiogenone 3. Annulation of the B ring for the synthesis of tricyclic ABC cores was demonstrated utilizing a 5-exo-trig free radical cyclization of a primary carbon radical onto a cyclohexadienone generated with tri-n-butylgermanium hydride (9→11).

Total Syntheses of Lepadiformine Marine Alkaloids with Enantiodivergency, Utilizing Hg(OTf)2 -Catalyzed Cycloisomerization Reaction and their Cytotoxic Activities.

The enantioselective total syntheses of lepadiformine marine alkaloids, azatricyclic natural products isolated from marine tunicates, were completed. These alkaloids have a unique chemical structure characterized by the trans-1-azadecalin (AB ring system) fused with the spirocyclic ring (AC ring system). Here we found that a cycloisomerization reaction from functionalized linear substrates to a 1-azaspiro[4.5]decane framework corresponding to the AC ring in lepadiformines is promoted by a catalytic amount of mercury(II) triflate (Hg(OTf)2 ). The total syntheses of (-)-lepadiformines A and B were achieved in 28 % and 21 % overall yields, respectively, through the novel cycloisomerization reaction. The syntheses of (+)- and (-)-lepadiformine C hydrochloride salts also enabled us to determine the absolute configuration of natural lepadiformine C. It has been found that a phenomenon of enantiodivergence occurs in lepadiformine alkaloids from a single species of marine tunicate, Clavelina moluccensis. The cytotoxic activities of synthesized lepadiformine hydrochloride salts and their synthetic intermediates were evaluated.

Hypercoordinate Iodine Catalysts in Enantioselective Transformation: The Role of Catalyst Folding in Stereoselectivity

The need for metal-free environmentally benign catalysts has provided a strong impetus toward the emergence of hypercoordinate iodine reagents. At this stage of development, molecular insights on the mechanism and origin of stereoselectivity are quite timely. In this study, the origin of stereoinduction in a class of iodoresorcinol-based chiral hypercoordinate iodine-catalyzed synthesis of biologically important spirocyclic bisoxindoles from aryl dianilides has been established by using density functional computations. Formation of an interesting helical fold by the 2,6-chiral amide arms on the resorcinol framework is found to be facilitated by a network of noncovalent interactions. In the chiral environment provided by the helical fold, enantioselectivity is surprisingly controlled in a mechanistic event prior to the ring closure to the final spirocyclic product, unlike that commonly found in spirocyclic ring formation. A vital 1,3-migration of the chiral aryl iodonium (Ar*-I(CF3COO)) in an O-iodonium en...

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.

Competition Studies and the Use of Mechanistic Insight to Overcome Synthetic Barriers

Because intramolecular anodic olefin coupling reactions involve a reversal in polarity of a normally nucleophilic olefin, they can be used to develop entirely new pathways to a variety of molecules. The reactions are compatible with a wide variety of functional groups, the generation of fused, bridged, and spirocyclic ring skeletons, and the formation of quaternary carbons. However, not all anodic olefin coupling reactions work. The reactions are triggered by the formation of a highly reactive radical cation intermediate. If the desired reaction pathway is not fast enough, then the radical cation will initiate undesirable reaction pathways, often involving elimination, fragmentation, or solvent trapping. When this occurs, the question quickly becomes what can be done to solve the problem and channel the reaction down a more productive pathway? The best way to address this question has been to carefully probe the mechanism of the reactions, identify the nature of the undesirable reactions, and then manipulate the relative rates of the reactions available to the radical cation to favor the process that is wanted. Several steps in the reaction can be important, but two play an especially important role (Scheme 1). First, the rate of the cyclization is important. If the cyclization is too slow, then side reactions involving the reactive radical cation will begin to dominate. The rate of the second oxidation (k2) is also critical for the success of the reaction. Many radical cyclizations are reversible and in those cases the loss of the second electron helps to drive the product to completion. Understanding these principles is essential for the design of more complex reactions, and in the talk to be presented, a series of new anodic cyclization reactions (Scheme 2) will be used to highlight the important interplay between mechanistic considerations and synthetic design. Each of the reactions discussed will involve a transformation that was originally a failure but is now a cornerstone of ongoing synthetic efforts. Figure 1

A simple rhodamine hydrazide-based turn-on fluorescent probe for HOCl detection.

Hypochlorous acid (HOCl) plays a crucial role in daily life and mediates a variety of physiological processes, however, abnormal levels of HOCl have been associated with numerous human diseases. It is therefore of significant interest to establish a simple, selective, rapid and sensitive fluorogenic method for the detection of HOCl in environmental and biological samples. A hydrazide-containing fluorescent probe based on a rhodamine scaffold was facilely developed that could selectively detect HOCl over other biologically relevant reactive oxygen species, reactive nitrogen species and most common metal ions in vitro. Via an irreversible oxidation-hydrolysis mechanism, and upon HOCl-triggered opening of the intramolecular spirocyclic ring during detection, the rhodamine hydrazide-based probe exhibited large fluorescence enhancement in the emission spectra with a fast response, low detection limit and comparatively wide pH detection range in aqueous media. The probe was further successfully applied to monitoring trace HOCl in tap water and imaging both exogenous and endogenous HOCl within living cells. It is anticipated that this simple and useful probe might be an efficient tool with which to facilitate more HOCl-related chemical and biological research. Copyright © 2015 John Wiley & Sons, Ltd.

Total Synthesis of (-)-Lepadiformine A Utilizing Hg(OTf)2-Catalyzed Cycloisomerization Reaction.

A cytotoxic marine alkaloid (-)-lepadiformine A (1) possesses a unique structure characterized by the trans-1-azadecalin AB ring system fused with the AC spiro-cyclic ring. In this research, we found that a cycloisomerization reaction from amino ynone 2 to a 1-azaspiro[4.5]decane skeleton 3, corresponding to the AC ring system of 1, is promoted by Hg(OTf)(2). Thus, we have accomplished the efficient total synthesis of (-)-lepadiformine A in 28% overall yield by featuring the novel Hg(OTf)(2)-catalyzed cycloisomerization.

Discovery of a Novel, Potent Spirocyclic Series of γ-Secretase Inhibitors.

In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulting series is devoid of the CYP2C9 inhibition liability of MRK-560. A few representative analogs were assessed in a nontransgenic animal model of Alzheimer's disease (AD), demonstrating reduction of amyloid-β (Aβ) in the CNS after acute oral dosing. A spirocyclic phosphonate was identified as the optimal ring system for both potency and pharmacokinetics. Compared to GSIs studied in the clinic, representative spirocyclic phosphonate 18a(-) features improved selectivity for the inhibition of the PS-1 isoform of γ-secretase (33-fold vs PS-2), which may alleviate the adverse effect profile of the clinical GSIs.

Host–guest-recognition-based polymer brush-functionalized mesoporous silica nanoparticles loaded with conjugated polymers: A facile FRET-based ratiometric probe for Hg2+

This article reports a new strategy for constructing a fluorescence resonance energy transfer (FRET) based ratiometric sensor for Hg2+ detection with organic-inorganic hybrid mesoporous silica nanoparticles (MSNs) as the scaffolds. The fluorescent conjugated polymer of poly(p-phenylenevinylene) (PPV) as the donor is encapsulated into the MSNs and a spirolactam rhodamine-linked adamantane (AD-SRhB) as mercury ion-recognition element is introduced to cyclodextrin (CD) functionalized polymer brush on the shell of MSNs via the host–guest interaction. Upon the addition of Hg2+, the rhodamine spirocyclic ring opens, and the fluorescence (578 nm) of rhodamine is observed due to the FRET. This novel nanosensor can selectively detect Hg2+ ions with a detection limit of 4.2 μM. On the other hand, compared with pure AD-SRhB as probe, the novel ion probe fabricated by us can selectively detect Hg2+ from other correlative metal ions, especially Fe3+ and Al3+.

ChemInform Abstract: Rhodium(III)‐Catalyzed [3 + 2] Annulation of 5‐Aryl‐2,3‐dihydro‐1H‐pyrroles with Internal Alkynes Through C(sp2)—H/Alkene Functionalization.

Abstractleading to a variety of spirocyclic indene‐pyrrolidine derivatives

Importance of ligand exchanges in Pd(II)-Brønsted acid cooperative catalytic approach to spirocyclic rings.

Increasing number of reports in the most recent literature convey the use of palladium and Brønsted acids as cooperative catalytic partners. However, the mechanistic understanding of several such cooperative catalytic reactions and the origin of cooperativity continue to remain limited. In transition metal catalysis, it is typically assumed that the native ligands, such as the acetates in palladium acetate, are retained throughout the catalytic cycle. Herein, we convey the significance of invoking ligand exchanges in transition metal catalysis by using the mechanism of a representative cooperative dual-catalytic reaction. Density functional theory (M06 and B3LYP) computations have been employed to decipher the mechanism of Pd(II)-Brønsted acid catalyzed migratory ring expansion reaction of an indenyl cyclobutanol to a spirocyclic indene bearing a quaternary carbon. The molecular role of water, benzoquinone and phosphoric acid has been probed by computing the energetics using several combinations of all these as ligands on palladium. Of the two key mechanistic possibilities examined, a Wacker-type pathway (involving a semipinacol ring expansion of cyclobutanol followed by a reductive elimination) is found to be energetically more preferred over an allylic pathway wherein the ring expansion in a Pd-π-allyl intermediate occurs subsequent to the initial allylic C-H activation. The Gibbs free energies of the transition states with the native palladium acetate are much higher than a Pd-bis-phosphate species generated through ligand exchanges.

Rhodium(III)-catalyzed [3+2] annulation of 5-aryl-2,3-dihydro-1H-pyrroles with internal alkynes through C(sp²)-H/alkene functionalization.

This study describes a new rhodium(III)-catalyzed [3+2] annulation of 5-aryl-2,3-dihydro-1H-pyrroles with internal alkynes using a Cu(OAc)2 oxidant for building a spirocyclic ring system, which includes the functionalization of an aryl C(sp(2))-H bond and addition/protonolysis of an alkene C=C bond. This method is applicable to a wide range of 5-aryl-2,3-dihydro-1H-pyrroles and internal alkynes, and results in the assembly of the spiro[indene-1,2'-pyrrolidine] architectures in good yields with excellent regioselectivities.