Tricyclic Lactone Research Articles

Insights into stereoselective ring formation in canonical strigolactone: Identification of a dirigent domain-containing enzyme catalyzing orobanchol synthesis

Strigolactones (SLs) are plant apocarotenoids with diverse roles and structures. Canonical SLs, widespread and characterized by structural variations in their tricyclic lactone (ABC-ring), are classified into two types based on C-ring configurations. The steric C-ring configuration emerges during the BC-ring closure, downstream of the biosynthetic intermediate, carlactonoic acid (CLA). Most plants produce either type of canonical SLs stereoselectively, e.g., tomato (Solanum lycopersicum) yields orobanchol with an α-oriented C-ring. The mechanisms driving SL structural diversification are partially understood, with limited insight into functional implications. Furthermore, the exact molecular mechanism for the stereoselective BC-ring closure reaction is yet to be known. We identified an enzyme, the stereoselective BC-ring-forming factor (SRF), from the dirigent protein (DIR) family, specifically the DIR-f subfamily, whose biochemical function had not been characterized, making it a key enzyme in stereoselective canonical SL biosynthesis with the α-oriented C-ring. We first confirm the precise catalytic function of the tomato cytochrome P450 SlCYP722C, previously shown to be involved in orobanchol biosynthesis [T. Wakabayashi et al., Sci. Adv. 5, eaax9067 (2019)], to convert CLA to 18-oxocarlactonoic acid. We then show that SRF catalyzes the stereoselective BC-ring closure reaction of 18-oxocarlactonoic acid, forming orobanchol. Our methodology combines experimental and computational techniques, including SRF structure prediction and conducting molecular dynamics simulations, suggesting a catalytic mechanism based on the conrotatory 4π-electrocyclic reaction for the stereoselective BC-ring formation in orobanchol. This study sheds light on the molecular basis of how plants produce SLs with specific stereochemistry in a controlled manner.

Construction of stereogenic center beta to the N-Pyrrolidinyl moiety via diastereoselective reactions of tricyclic lactones and the synthesis of (−)-Indolizidine 195G

The Enolates of hexahydro-3,4-dioxa-8a-aza-as-indacen-2-ones can react with electrophiles in a substrate-controlled fashion to create a new stereogenic center positioned beta to the N-pyrrolidinyl moiety. Preferential diastereoselective reactions predominantly proceeded from the convex face of the enolates, yielding stereospecific alkylated or halo-substituted products with high yields and exceptional diastereoselectivities. Di-substituted compounds were obtained by the alkylation or halogenation of the enolates of the corresponding mono-substituted compounds. Total synthesis of (−)-indolizidine 195G was also accomplished. © 2024 Elsevier Science. All rights reserved.

Identification of novel Nrf2-activating neuroprotective agents: Elucidation of structural congeners of (-)-galiellalactone and congener-based novel Nrf2 activators

Herein, (-)-galiellalactone 1 congeners responsible for the nuclear factor erythroid 2-related factor 2 (Nrf2)-activating neuroprotective effects were elucidated. Additionally, novel congener-based Nrf2 activators were identified using a drug repositioning strategy. (-)-Galiellalactone, which comprises a tricyclic lactone skeleton, significantly activates antioxidant response element (ARE)-mediated transcription in neuroblastoma SH-SY5Y cells. Interestingly, two cyclohexene-truncated [3.3] bicyclic lactone analogs, which possess an exocyclic α-methylene-γ-butyrolactone moiety, exhibited higher Nrf2/ARE transcriptional activities than the parent (-)-galiellalactone. We confirmed that the cyclohexene moiety embedding the [3.3] bicyclic lactone congener does not play the essential role of (-)-galiellalactone for Nrf2/ARE activation. Nrf2/ARE activation by novel analogs resulted in the upregulation of downstream antioxidative and phase II detoxifying enzymes, heme oxygenase-1, and NAD(P)H quinone oxidoreductase 1, which are closely related to the cytoprotective effects on neurodegenerative diseases. (-)-Galiellalactone and its [3.3] bicyclic variants 3l and 3p increased the expression of antioxidant genes and exhibited neuroprotective effects against 6-hydroxydopamine-mediated neurotoxicity in the neuroblastoma SH-SY5Y cell line.

Stereoselective synthesis of an advanced trans-decalin intermediate towards the total synthesis of anthracimycin.

Progress towards the total synthesis of the macrolide natural product anthracimycin is described. This new approach utilises an intermolecular Diels-Alder strategy followed by epimeirsation to form the key trans-decalin framework. The route culminates in the stereoselective synthesis of an advanced tricyclic lactone intermediate, containing five contiguous sterogenic centres with the correct relative and absolute stereochemistry required for the anthracimycin core motif.

Photochemistry of β-γ-Unsaturated Spirolactones

β-γ-unsaturated spirolactones are easily available by Birch reduction. We describe their photochemistry in the presence of or without carbonyl compounds. The spirolactones show a distinct absorption band at 230 nm, which is not present in other cyclohexadienes. We explain this behavior by an interaction of the double bonds with the carbonyl group through space, further proven by TDDFT calculations. This allows their direct excitation with UV-C light. Interestingly, we obtain only products of an oxa-di-π-methane rearrangement, hitherto unknown for lactones. This speaks for a reaction pathway starting from singlet states, confirmed by calculated relative energies of biradical intermediates. Although polymerization is the main side reaction, we were able to isolate tricyclic lactones in moderate yields in a pure form. In the presence of benzaldehyde or benzophenone, excitation with UV-B light was possible, leading to H-atom abstraction in the allylic position and formation of alcohols. With an electron-rich double bond, the Paternó–Büchi products were isolated as well. The different diastereomers were separated by column chromatography or HPLC. Their relative configurations were determined using NOESY measurements or X-ray structure analysis. Overall, β-γ-unsaturated spirolactones show a remarkably different photochemistry compared to other cyclohexadienes, affording new products in only a few steps.

Synthesis of (±)-zeapyranolactone, a noncanonical strigolactone isolated from maize, and determination of its overall relative configuration

Strigolactones are a class of apocarotenoids known as rhizosphere semiochemicals and plant hormones. They are classified as either canonical, with a tricyclic lactone (ABC ring) and a butenolide (D ring) comprising their basic skeleton, or noncanonical, deviating from the basic skeleton. Here, zeapyranolactone, a noncanonical strigolactone isolated from maize, was synthesized for the first time as a racemic and diastereomeric mixture, and its relative stereochemistry was determined by three-dimensional electron diffraction crystallography as 4S*,4aS*,2′R*. The synthetic route developed is straightforward and does not rely on the use of typical protective groups.

Research progress in strigolactones and application prospect in medicinal plants

Strigolactones(SLs) are a class of sesquiterpenoids derived from the carotenoid biosynthesis pathway with the core carbon skeleton consisting of tricyclic lactone(ABC tricyclic ring) and α,β-unsaturated furan ring(D ring). SLs are widely distributed in higher plants and are symbiotic signals between plants and Arbuscular mycorrhiza(AM), which play key roles in the evolution of plant colonizing terrestrial habitats. As a new type of plant hormone, SLs possess such important biological functions as inhibiting shoot branching(tillers), regulating root architecture, promoting secondary growth, and improving plant stress resistance. Therefore, SLs have attracted wide attention. The biological functions of SLs are not only closely related to the formation of "excellent shape and quality" of Chinese medicinal materials but also have important practical significance for the production of high-quality medicinal materials. However, SLs have been currently widely studied in model plants and crops such as Oryza sativa and Arabidopsis thaliana, and few related studies have been reported on SLs in medicinal plants, which need to be strengthened. This review focused on the latest research progress in the isolation and identification, biological and artificial synthesis pathways, biosynthesis sites and transport modes, signal transduction pathways and mechanisms, and biological functions of SLs, and prospected the research on the regulation mechanism of SLs in the growth and development of medicinal plants and their related application on targeted regulation of Chinese herbal medicine production, which is expected to provide some references for the in-depth research on SLs in the field of Chinese medicinal resources.

An Asymmetric Total Synthesis of Picrotoxinin through a Mizoroki–Heck Reaction

AbstractAn asymmetric total synthesis of picrotoxinin was performed by using a Mizoroki–Heck reaction of an enantioenriched tricyclic lactone with isopropenyl bromide as a key transformation, permitting the highly diastereoselective introduction of the requisite C4-isopropenyl group. After functional-group manipulations, including carbonylation, bromoetherification, epoxidation, and dihydroxylation, picrotoxinin was obtained in a moderate to good yield.

Identification of novel canonical strigolactones produced by tomato.

Canonical strigolactones (SLs), such as orobanchol, consist of a tricyclic lactone ring (ABC-ring) connected to a methylbutenolide (D-ring). Tomato plants have been reported to produce not only orobanchol but also various canonical SLs related to the orobanchol structure, including orobanchyl acetate, 7-hydroxyorobanchol isomers, 7-oxoorobanchol, and solanacol. In addition to these, structurally unidentified SL-like compounds known as didehydroorobanchol isomers (DDHs), whose molecular mass is 2 Da smaller than that of orobanchol, have been found. Although the SL biosynthetic pathway in tomato is partially characterized, structural elucidation of DDHs is required for a better understanding of the entire biosynthetic pathway. In this study, three novel canonical SLs with the same molecular mass as DDHs were identified in tomato root exudates. The first was 6,7-didehydroorobanchol, while the other two were not in the DDH category. These two SLs were designated phelipanchol and epiphelipanchol because they induced the germination of Phelipanche ramosa, a noxious root parasitic weed of tomato. We also proposed a putative biosynthetic pathway incorporating these novel SLs from orobanchol to solanacol.

Access to Highly Strained Tricyclic Ketals Derived from Coumarins.

Synthesis of highly strained fused substituted dihydrobenzopyran cyclopropyl lactones derived from coumarin carboxylates are reported. The substrate scope tolerates a variety of 6- and 8-substituents on the coumarin ring. Substitution at the 5- or 7-position is resistant to tricyclic lactone formation except with 7-methyl substitution. Benzamide-containing coumarins afford the tricyclic ketal. A plausible mechanism is proposed for the formation of the fused lactone: intramolecular rearrangement of trans cyclopropyl methyl ketones with phenolic acetate via the formation of a hemiacetal.

Magnetoliposomes Based on Magnetic/Plasmonic Nanoparticles Loaded with Tricyclic Lactones for Combined Cancer Therapy.

Liposome-like nanoarchitectures containing manganese ferrite nanoparticles covered or decorated with gold were developed for application in dual cancer therapy, combining chemotherapy and photothermia. The magnetic/plasmonic nanoparticles were characterized using XRD, UV/Visible absorption, HR-TEM, and SQUID, exhibiting superparamagnetic behavior at room temperature. The average size of the gold-decorated nanoparticles was 26.7 nm for MnFe2O4 with 5–7 nm gold nanospheres. The average size of the core/shell nanoparticles was 28.8 nm for the magnetic core and around 4 nm for the gold shell. Two new potential antitumor fluorescent drugs, tricyclic lactones derivatives of thienopyridine, were loaded in these nanosystems with very high encapsulation efficiencies (higher than 98%). Assays in human tumor cell lines demonstrate that the nanocarriers do not release the antitumor compounds in the absence of irradiation. Moreover, the nanosystems do not cause any effect on the growth of primary (non-tumor) cells (with or without irradiation). The drug-loaded systems containing the core/shell magnetic/plasmonic nanoparticles efficiently inhibit the growth of tumor cells when irradiated with red light, making them suitable for a triggered release promoted by irradiation.

Synthesis of racemic orobanchols via acid-mediated cascade cyclization: Insight into the process of BC-ring formation in strigolactone biosynthesis

Strigolactones, a class of apocarotenoids, are known to function as rhizosphere semiochemicals and plant hormones. Canonical strigolactones consist of a tricyclic lactone (ABC-rings) and a butenolide moiety (D-ring), and their biosynthesis has been extensively studied. However, the process of BC-ring formation is yet to be clarified. The conversion of an 18-oxocarlactonoate derivative into racemic orobanchols was performed in the same way as in our previous study, which demonstrated that the BC-ring formation is possible “in flask” via acid-mediated cascade cyclization. The results strongly suggested that the mechanism of acid-mediated BC-ring formation may be based on the conrotatory electrocyclic reaction, and may provide significant insights into the process of BC-ring formation in strigolactone biosynthesis.

Enantioselective Construction of 5‐6‐5 Tricyclic Lactone Framework Bearing a Quaternary Bridgehead Carbon via Rh‐Catalyzed Asymmetric [2+2+2] Cycloaddition of Enediynes

AbstractHerein, we report a Rh‐catalyzed asymmetric [2+2+2] cycloaddition of ene‐yne‐yne enediynes to generate enantio‐enriched tricyclic cyclohexadienes bearing a quaternary bridgehead carbon. We found that the Rh‐Phanephos complex is an appropriate catalyst for the cycloaddition of enediynes bearing an unsubstituted propiolate terminus, whereas Rh‐biaryl bisphosphine catalysts, which have been widely used for asymmetric cycloadditions of alkynes and alkenes, are not applicable for the reaction of such enediynes. Several control experiments suggest that the reaction using the Rh‐Phanephos complex exclusively proceeds via a rhodacyclopentadiene intermediate, unlike when using a Rh‐biaryl bisphosphine complex that can form a rhodacyclopentadiene intermediate as well as a rhodacyclopentene intermediate in a substrate‐dependent manner.magnified image

Total synthesis of the proposed structure of Anti-TMV active tabasesquiterpene A

The proposed structure of Tabasesquiterpene A, an illudalane type of sesquiterpene has been synthesized in twelve steps from 2-methoxy-4-methylbenzaldehyde in 40% overall yield. Triflic acid mediated intramolecular Freidel-Crafts acylation allows to develop the critical indanone moiety, a key intermediate of this synthesis. A careful ortho-selective formylation and subsequent Knoevenagel condensation to incorporate three carbon side chain, followed by reduction, formation of tricyclic lactone and DIBAL-H supported reduction of lactone to target were other key transformation involved. The NMR spectroscopic data of the synthetic sample differ from those of natural tabasesquiterpene A.

Studies on strigolactone BC-ring formation: Chemical conversion of an 18-hydroxycarlactonoate derivative into racemic 4-deoxyorobanchol/5-deoxystrigol via the acid-mediated cascade cyclization

Strigolactones are a group of apocarotenoids known as rhizosphere semiochemicals and phytohormones. Canonical strigolactone consists of a tricyclic lactone (ABC-rings) and a butenolide moiety (D-ring). Although strigolactone biosynthesis has been extensively studied, the process of BC-ring formation has not been elucidated to date. In this study, the chemical conversion of an 18-hydroxycarlactonoate derivative into racemic 4-deoxyorobanchol/5-deoxystrigol was achieved by the acid-mediated cascade cyclization. The acid-mediated BC-ring formation may offer inspiring suggestion for the currently unclear BC-ring formation in strigolactone biosynthesis.

Enantioselective Organocatalytic Synthesis of δ‐Lactone‐Fused 4‐Chromanones

AbstractAn organocatalytic enantioselective synthesis of δ‐lactone‐fused 4‐chromanones was demonstrated using 1‐(2‐hydroxyaryl)‐1,3‐butanedione and α,β‐unsaturated aldehydes in the presence of the Jørgensen‐Hayashi catalyst. The reaction proceeded through a Michael addition/cycloketalization/hemiacetalization sequence, and the resulting hemiacetals were oxidized into the corresponding lactone derivatives in a one‐pot manner. The desired fused O,O‐ketal tricyclic lactone motifs containing three contiguous chiral centers were obtained in excellent chemical yields (up to 97%) and with high stereoselectivities (up to >20:1 dr and up to 95% ee).magnified image

CYP722C from Gossypium arboreum catalyzes the conversion of carlactonoic acid to 5-deoxystrigol.

CYP722C from cotton, a homolog of the enzyme involved in orobanchol synthesis in cowpea and tomato, catalyzes the conversion of carlactonoic acid to 5-deoxystrigol. Strigolactones (SLs) are important phytohormones with roles in the regulation of plant growth and development. These compounds also function as signaling molecules in the rhizosphere by interacting with beneficial arbuscular mycorrhizal fungi and harmful root parasitic plants. Canonical SLs, such as 5-deoxystrigol (5DS), consist of a tricyclic lactone ring (ABC-ring) connected to a methylbutenolide (D-ring). Although it is known that 5DS biosynthesis begins with carlactonoic acid (CLA) derived from β-carotene, the enzyme that catalyzes the conversion of CLA remains elusive. Recently, we identified cytochrome P450 (CYP) CYP722C as the enzyme that catalyzes direct conversion of CLA to orobanchol in cowpea and tomato (Wakabayashi et al., Sci Adv 5:eaax9067, 2019). Orobanchol has a different C-ring configuration from that of 5DS. The present study aimed to characterize the homologous gene, designated GaCYP722C, from cotton (Gossypium arboreum) to examine whether this gene is involved in 5DS biosynthesis. Expression of GaCYP722C was upregulated under phosphate starvation, which is an SL-producing condition. Recombinant GaCYP722C was expressed in a baculovirus-insect cell expression system and was found to catalyze the conversion of CLA to 5DS but not to 4-deoxyorobanchol. These results strongly suggest that GaCYP722C from cotton is a 5DS synthase and that CYP722C is the crucial CYP subfamily involved in the generation of canonical SLs, irrespective of the different C-ring configurations.

Aromatic substituent effects in palladium-catalyzed intramolecular olefin oxyarylation reactions

The effect of electron-donating groups on the palladium-catalyzed intramolecular oxyarylation reaction was studied. In the case of activation at the ortho-position, the reaction favors the formation of a tricyclic lactone via CH insertion. However, when the ipso-position is activated, the major product is instead a novel α,β-unsaturated lactone formed by way of a stabilized phenonium intermediate followed by elimination.

Toward the Synthesis of SB-203207: Construction of Four Contiguous Nitrogen-Containing Stereogenic Centers.

SB-203207 is an altemicidin-type alkaloid that potently inhibits isoleucyl tRNA synthetase activity. Its main structural feature is a hexahydro-6-azaindene framework containing a unique β-hydroxy α,α-disubstituted α-amino acid moiety on the cyclopentane portion. Herein we have established a method for constructing the four contiguous nitrogen-containing stereogenic centers of SB-203207 by using as key steps the stereoselective alkylation of bowl-shaped tricyclic lactone to construct a quaternary carbon at C1, the stereoselective hydroboration-oxidation reaction to install the C2 hydroxy group, and the Curtius rearrangement to introduce a nitrogen atom onto the C1 quaternary carbon.

AMIDES OF SUBSTITUTED 3-(PTERIDIN-6-YL)PROPANOIC ACIDS: SYNTHESIS, SPECTRAL CHARACTERISTICS, AND CYTOTOXIC ACTIVITY

A heterocyclization reaction of 5,6-diamino-1-methyluracil and 2-oxopentanedioic acid was used in this study to synthesize 3-(1-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropteridin-6-yl)propanoic acid, intramolecular cyclization of which led to the formation of a tricyclic lactone, namely, 1-methyl-6,7-dihydro-2H-pyrano[3,2-g]pteridine-2,4,8-(1H,3H)-trione. Reactions of the latter with N-nucleophiles gave a series of amides – structural analogs of antifolates. The structure and identity of the synthesized compounds were confirmed by IR spectroscopy, 1 H and 13 C NMR spectroscopy, LC-MS analysis, and mass spectrometry. It was established that the synthesized compounds showed cytotoxic effects against human hepatocellular carcinoma (HepG2) cells and may be of interest for further studies of their antitumor activity against other cell lines.