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Christopher L Schardl - One of the best experts on this subject based on the ideXlab platform.
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Installation of the Ether Bridge of Lolines by the Iron- and 2-Oxoglutarate-Dependent Oxygenase, LolO: Regio- and Stereochemistry of Sequential Hydroxylation and Oxacyclization Reactions.
Biochemistry, 2018Co-Authors: Juan Pan, Minakshi Bhardwaj, Robert B Grossman, Christopher L Schardl, Bo Zhang, Wei-chen Chang, Carsten Krebs, J. Martin BollingerAbstract:The core of the Loline family of insecticidal alkaloids is the bicyclic pyrrolizidine unit with an additional strained ether bridge between carbons 2 and 7. Previously reported genetic and in vivo biochemical analyses showed that the presumptive iron- and 2-oxoglutarate-dependent (Fe/2OG) oxygenase, LolO, is required for installation of the ether bridge upon the pathway intermediate, 1-exo-acetamidopyrrolizidine (AcAP). Here we show that LolO is, in fact, solely responsible for this biosynthetic four-electron oxidation. In sequential 2OG- and O2-consuming steps, LolO removes hydrogens from C2 and C7 of AcAP to form both carbon–oxygen bonds in N-acetylnorLoline (NANL), the precursor to all other Lolines. When supplied with substoichiometric 2OG, LolO only hydroxylates AcAP. At higher 2OG:AcAP ratios, the enzyme further processes the alcohol to the tricyclic NANL. Characterization of the alcohol intermediate by mass spectrometry and nuclear magnetic resonance spectroscopy shows that it is 2-endo-hydroxy-1-e...
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Installation of the Ether Bridge of Lolines by the Iron- and 2‑Oxoglutarate-Dependent Oxygenase, LolO: Regio- and Stereochemistry of Sequential Hydroxylation and Oxacyclization Reactions
2018Co-Authors: Juan Pan, Minakshi Bhardwaj, Robert B Grossman, Christopher L Schardl, Bo Zhang, Wei-chen Chang, Carsten Krebs, Martin J. BollingerAbstract:The core of the Loline family of insecticidal alkaloids is the bicyclic pyrrolizidine unit with an additional strained ether bridge between carbons 2 and 7. Previously reported genetic and in vivo biochemical analyses showed that the presumptive iron- and 2-oxoglutarate-dependent (Fe/2OG) oxygenase, LolO, is required for installation of the ether bridge upon the pathway intermediate, 1-exo-acetamidopyrrolizidine (AcAP). Here we show that LolO is, in fact, solely responsible for this biosynthetic four-electron oxidation. In sequential 2OG- and O2-consuming steps, LolO removes hydrogens from C2 and C7 of AcAP to form both carbon–oxygen bonds in N-acetylnorLoline (NANL), the precursor to all other Lolines. When supplied with substoichiometric 2OG, LolO only hydroxylates AcAP. At higher 2OG:AcAP ratios, the enzyme further processes the alcohol to the tricyclic NANL. Characterization of the alcohol intermediate by mass spectrometry and nuclear magnetic resonance spectroscopy shows that it is 2-endo-hydroxy-1-exo-acetamidopyrrolizidine (2-endo-OH-AcAP). Kinetic and spectroscopic analyses of reactions with site-specifically deuteriated AcAP substrates confirm that the C2–H bond is cleaved first and that the responsible intermediate is, as expected, an FeIV–oxo (ferryl) complex. Analyses of the Loline products from cultures fed with stereospecifically deuteriated AcAP precursors, proline and aspartic acid, establish that LolO removes the endo hydrogens from C2 and C7 and forms both new C–O bonds with retention of configuration. These findings delineate the pathway to an important class of natural insecticides and lay the foundation for mechanistic dissection of the chemically challenging oxacyclization reaction
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RESEARCH ARTICLE Enzymes from Fungal and Plant Origin Required for Chemical Diversification of Insecticidal Loline Alkaloids in Grass-
2016Co-Authors: Epichloe ̈ Symbiota, Minakshi Bhardwaj, Padmaja Nagabhyru, Robert B Grossman, Juan Pan, Christopher L SchardlAbstract:The Lolines are a class of bioprotective alkaloids that are produced by Epichloë species, fungal endophytes of grasses. These alkaloids are saturated 1-aminopyrrolizidines with a C2 to C7 ether bridge, and are structurally differentiated by the various modifications of the 1-amino group:-NH2 (norLoline),-NHCH3 (Loline),-N(CH3)2 (N-methylLoline),-N(CH3)Ac (N-acetylLoline),-NHAc (N-acetylnorLoline), and-N(CH3)CHO (N-formylLoline). Other than the LolP cytochrome P450, which is required for conversion of N-methylLoline to N-formylLoline, the enzymatic steps for Loline diversification have not yet been established. Through isotopic labeling, we determined that N-acetylnorLoline is the first fully cyclized Loline alkaloid, implying that deacetylation, methylation, and acetylation steps are all involved in Loline alkaloid diversification. Two genes of the Loline alkaloid biosynthesis (LOL) gene cluster, lolN and lolM, were predicted to encode an N-acetamidase (deacetylase) and a methyltransferase, respectively. A knockout strain lacking both lolN and lolM stopped the biosynthesis at N-acetylnorLoline, and complementation with the two wild-type genes restored production of N-formylLoline and N-acetylLoline. Thes
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enzymes from fungal and plant origin required for chemical diversification of insecticidal Loline alkaloids in grass epichloe symbiota
PLOS ONE, 2014Co-Authors: Minakshi Bhardwaj, Padmaja Nagabhyru, Robert B Grossman, Christopher L SchardlAbstract:The Lolines are a class of bioprotective alkaloids that are produced by Epichloe species, fungal endophytes of grasses. These alkaloids are saturated 1-aminopyrrolizidines with a C2 to C7 ether bridge, and are structurally differentiated by the various modifications of the 1-amino group: -NH2 (norLoline), -NHCH3 (Loline), -N(CH3)2 (N-methylLoline), -N(CH3)Ac (N-acetylLoline), -NHAc (N-acetylnorLoline), and -N(CH3)CHO (N-formylLoline). Other than the LolP cytochrome P450, which is required for conversion of N-methylLoline to N-formylLoline, the enzymatic steps for Loline diversification have not yet been established. Through isotopic labeling, we determined that N-acetylnorLoline is the first fully cyclized Loline alkaloid, implying that deacetylation, methylation, and acetylation steps are all involved in Loline alkaloid diversification. Two genes of the Loline alkaloid biosynthesis (LOL) gene cluster, lolN and lolM, were predicted to encode an N-acetamidase (deacetylase) and a methyltransferase, respectively. A knockout strain lacking both lolN and lolM stopped the biosynthesis at N-acetylnorLoline, and complementation with the two wild-type genes restored production of N-formylLoline and N-acetylLoline. These results indicated that lolN and lolM are required in the steps from N-acetylnorLoline to other Lolines. The function of LolM as an N-methyltransferase was confirmed by its heterologous expression in yeast resulting in conversion of norLoline to Loline, and of Loline to N-methylLoline. One of the more abundant Lolines, N-acetylLoline, was observed in some but not all plants with symbiotic Epichloe siegelii, and when provided with exogenous Loline, asymbiotic meadow fescue (Lolium pratense) plants produced N-acetylLoline, suggesting that a plant acetyltransferase catalyzes N-acetylLoline formation. We conclude that although most Loline alkaloid biosynthesis reactions are catalyzed by fungal enzymes, both fungal and plant enzymes are responsible for the chemical diversification steps in symbio.
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Enzymes from Fungal and Plant Origin Required for Chemical Diversification of Insecticidal Loline Alkaloids in Grass-Epichloë Symbiota
2014Co-Authors: Juan Pan, Minakshi Bhardwaj, Padmaja Nagabhyru, Robert B Grossman, Christopher L SchardlAbstract:The Lolines are a class of bioprotective alkaloids that are produced by Epichloë species, fungal endophytes of grasses. These alkaloids are saturated 1-aminopyrrolizidines with a C2 to C7 ether bridge, and are structurally differentiated by the various modifications of the 1-amino group: -NH2 (norLoline), -NHCH3 (Loline), -N(CH3)2 (N-methylLoline), -N(CH3)Ac (N-acetylLoline), -NHAc (N-acetylnorLoline), and -N(CH3)CHO (N-formylLoline). Other than the LolP cytochrome P450, which is required for conversion of N-methylLoline to N-formylLoline, the enzymatic steps for Loline diversification have not yet been established. Through isotopic labeling, we determined that N-acetylnorLoline is the first fully cyclized Loline alkaloid, implying that deacetylation, methylation, and acetylation steps are all involved in Loline alkaloid diversification. Two genes of the Loline alkaloid biosynthesis (LOL) gene cluster, lolN and lolM, were predicted to encode an N-acetamidase (deacetylase) and a methyltransferase, respectively. A knockout strain lacking both lolN and lolM stopped the biosynthesis at N-acetylnorLoline, and complementation with the two wild-type genes restored production of N-formylLoline and N-acetylLoline. These results indicated that lolN and lolM are required in the steps from N-acetylnorLoline to other Lolines. The function of LolM as an N-methyltransferase was confirmed by its heterologous expression in yeast resulting in conversion of norLoline to Loline, and of Loline to N-methylLoline. One of the more abundant Lolines, N-acetylLoline, was observed in some but not all plants with symbiotic Epichloë siegelii, and when provided with exogenous Loline, asymbiotic meadow fescue (Lolium pratense) plants produced N-acetylLoline, suggesting that a plant acetyltransferase catalyzes N-acetylLoline formation. We conclude that although most Loline alkaloid biosynthesis reactions are catalyzed by fungal enzymes, both fungal and plant enzymes are responsible for the chemical diversification steps in symbio.
Lowell P. Bush - One of the best experts on this subject based on the ideXlab platform.
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Occurrence of Alkaloids in Grass Seeds Symbiotic With Vertically-Transmitted Epichloë Fungal Endophytes and Its Relationship With Antioxidants
Frontiers Media S.A., 2018Co-Authors: Pedro E. Gundel, Lowell P. Bush, Beatriz R. Vázquez-de-aldana, Charlotte E. Seal, Fernando Biganzoli, Marco A. Molina-montenegro, Iñigo Zabalgogeazcoa, María A. Martínez-ghersa, Claudio M. GhersaAbstract:Host organisms can acquire new functional traits through symbiosis. Seed-transmitted Epichloë fungal endophytes are known to protect host plants against herbivores and increase tolerance to abiotic stresses by alkaloids and antioxidants, respectively (currencies of mutualism). Whereas, alkaloids are fungal products with demonstrated effects at plant vegetative stage, few studies have focused on alkaloids in seeds. We assessed the occurrence of fungal alkaloids and determined their concentrations in seeds of two host grasses, Festuca rubra and Lolium multiflorum. Then, we sought for a relationship with the antioxidants tocochromanols and glutathione, which are involved in the control of oxidative stress. Different alkaloids were detected depending on the species and plant genotype. Most notably, Loline alkaloids were not detected in F. rubra seeds, whereas ergovaline and peramine were absent in L. multiflorum. In F. rubra, ergovaline concentration was dependent on the maternal line in interaction with the production year, diminishing in seeds after 1 year of storage. The exposure of L. multiflorum plants to ozone had no effect on the seed concentration of Lolines. There was a significant positive relationship between the concentrations of ergovaline and tocochromanols in both species, and between ergovaline concentration and EGSSG/2GSH (glutathione half-cell reduction potential) in RAB maternal line of F. rubra. These results suggest that alkaloid and antioxidants have a close association in seeds of host grasses, and that the alkaloid bioactivity could be related with the antioxidant capacity to control stress. This has important implications for the ecology of partner species, thus supporting its consideration for further research
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Microsite conditions influence nutritive value characteristics of a tall fescue cultivar devoid of, or infected with a native, or a novel non-ergogenic endophyte
Environmental and Experimental Botany, 2009Co-Authors: David P. Belesky, Joyce M. Ruckle, Lowell P. BushAbstract:Abstract Tall fescue [ Lolium arundinaceum , Schreb., S.J. Darbysh.] productivity and persistence often benefits from association with Neotyphodium coenophialum [Morgan-Jones and Gams], Glenn, Bacon, and Hanlin) endophyte. The influence of novel, non-ergogenic endophytes on nutritive value is unclear, especially when simultaneous stresses ( e.g. , defoliation and shading) are imposed on the association. We conducted a field experiment using Jesup tall fescue that had either a native or novel non-ergogenic fungal endophyte (AR542; referred to as MaxQ™), or that was endophyte free. Dry matter production and nutritive value including crude protein (CP), non-structural carbohydrates (TNC), ergo- and Loline alkaloids, and phenolics were determined for plants stockpiled or clipped repeatedly in sites differing in the amount of light. Productivity varied less among sites when plants were infected with a native endophyte compared to novel or no endophyte. The trend suggests that native endophyte contributed to resilience of the host in this experiment. Leaf dry matter content was affected by host–endophyte association interacting with light availability suggesting differences in leaf composition could occur. Herbage CP increased, whereas TNC decreased with increasing shade. The concentration of Loline alkaloids, irrespective of host–endophyte association, tended to increase in leaves with decreasing light availability and could be related to the relatively greater N concentrations in shade-grown leaves. Phenolics decreased in leaves, but increased in stembases as light availability decreased. The combination of increased Loline alkaloids in leaves and phenolics in stembases, suggests that shade-grown tall fescue might have some competitive advantage based on the known anti-herbivory attributes of Loline alkaloids and phenolic compounds.
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Production of Loline alkaloids by the grass endophyte, Neotyphodium uncinatum, in defined media.
Phytochemistry, 2001Co-Authors: Jimmy D. Blankenship, Martin J. Spiering, Heather H. Wilkinson, Franklin F. Fannin, Lowell P. Bush, Christopher L SchardlAbstract:Lolines (saturated 1-aminopyrrolizidines with an oxygen bridge) are insecticidal alkaloids produced in symbioses of certain Epichloe (anamorph-Neotyphodium) species (fungal endophytes) with grasses, particularly of the genera Lolium and Festuca. Prior to the present study, it was unknown whether Lolines were of plant or fungal origin. Neotyphodium uncinatum, the common endophyte of meadow fescue (Lolium pratense=Festuca pratensis) produced Loline, N-acetylnorLoline, and N-formylLoline when grown in the defined minimal media at pH 5.0-7.5, with both organic and inorganic nitrogen sources and sugars as carbon sources. In contrast, Lolines were not detected in complex medium cultures. GC-MS and 13C NMR spectroscopic analyses confirmed the identity of the alkaloids isolated from the defined medium cultures. Lolines accumulated to ca. 700 mg/l (4 mM) in cultures with 16.7 mM sucrose and 15-30 mM asparagine, ornithine or urea. Kinetics of Loline production and fungal growth were assessed in defined medium with 16.7 mM sucrose and 30 mM ornithine. The alkaloid production rate peaked after the onset of stationary phase, as is common for secondary metabolism in other microbes.
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Effect of a fungal endophyte on the growth and survival of two Euplectrus parasitoids
Oikos, 1997Co-Authors: Thomas L. Bultman, Kristin L. Borowicz, Robert M. Schneble, Thomas A. Coudron, Lowell P. BushAbstract:Presence of the endophytic fungus, Acremonium coenophialum, within tall fescue (Festuca arundinacea) deters many vertebrate and invertebrate herbivores, apparently because of alkaloids produced by the grass-fungus symbiotum. In one set of experiments we tested if A. coenophialum alters the growth and survival of two parasitoids of an insect herbivore feeding on tall fescue. We fed fall armyworm [Spodoptera fruigiperda (Lepidoptera: Noctuidae)] larvae tall fescue either infected or lacking its endophytic fungus and then allowed the parasitoids, Euplectrus comstockii and Euplectrus plathypenae (Hymenoptera: Eulophidae), to parasitize larvae. We found the presence of endophyte-infected plants in the diet of fall armyworm had a negative impact on the pupal mass of parasitoids. In contrast, developmental rate of the parasitoids was generally not affected by the fungal endophyte. Survival of neither parasitoid to the adult stage was reduced by the presence of endophyte-infected grass in the diet of fall armyworm. We also tested if effects of the fungus on E. comstockii were due to the specific alkaloids, N-acetyl and N-formyl Loline, that are produced by the grass-fungus symbiotum. When added to artificial diets of fall armyworm, both Lolines resulted in reduced survival of parasitoids. Overall, we found the fungus had a moderate negative impact on two natural enemies that mirrors some of the effects the fungus has on insect herbivores and that may be mediated, at least in part, by alkaloids associated with the fungus. We discuss implications of our work for the hypothesis that endophytes defend their host grasses from herbivores.
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Chemistry, occurrence and biological effects of saturated pyrrolizidine alkaloids associated with endophyte-grass interactions
Agriculture Ecosystems & Environment, 1993Co-Authors: Lowell P. Bush, F.f. Fannin, Malcolm R. Siegel, D. L. Dahlman, H. R. BurtonAbstract:Abstract Saturated amino pyrrolizidine alkaloids with an oxygen bridge between C-2 and C-7 have been isolated from grasses and the chemistry and biology of these substances are reviewed in this paper. These substances are commonly referred to as Loline alkaloids as they are derivatives of Loline and originally were isolated from Lolium spp. The saturated amino pyrrolizidine alkaloids are not hepatotoxic and must be distinguished from the 1,2-unsaturated pyrrolizidine alkaloids which are very significant animal and human toxins and carcinogens of plant origin. Chemical synthesis of Loline has been achieved based on starting materials of a nitrone and methyl 4-hydroxycrotonate. N-formylLoline is made by addition of ethyl formate to Loline and removal of excess ethyl formate and ethanol formed. N-acetylLoline is synthesized by addition of acetyl chloride to Loline in chlorofirm. N-acetylLoline is partitioned into a dilute acid, then from a dilute base with CHCl3, and the CHCl3 removed to yield N-acetylLoline. N-methylLoline, norLoline, N-formynorLoline, N-acetylLoline, and N-propionylnorLoline are also readily formed from Loline. Little is known about the biosynthesis of the Loline alkaloids but from biosynthesis of other pyrrolizidine alkaloids a proposed biosynthesis is ornithine → putrescine → spermidine → → dialdehyde → → norLoline → → Loline. Loline was first isolated from Lolium temulentum L. (Lolium cuneatum Nevski) and later several derivatives were identified in tall fescue (Festuca arundinacea Schreb.). Chromatographic methodologies have been used to separate the pyrrolizidine alkaloids but 50-m capillary columns (0.32 mm i.d.) or 10-m wide-bore columns (0.53 mm i.d.) provide the greatest resolution of the many Loline derivatives. Loline alkaloids have been found primarily in plants known to be infected witn Acremonium coenophialum Morgan-Jones and Gams. Lolines have been found in Lolium perenne L., F. arundinacea, and Poa autumnalus Muhl. ex Ell. infected with A. coenophialum and in Festuca gigantea (L.) Vill. infected with an unidentified Acremonium spp. Loline alkaloids were present in infected tall fescue in greatest amounts in seed, followed in decreasing amounts in the rachis, stem, leaf sheath, and leaf blade. Site of synthesis, plant and/or endophyte, is not known nor is the translocation tissue known. During the main part of the growing season there is little change in the accumulation of the Loline alkaloids in leaf blade. Alkaloid levels increased with plant age and increased in regrowth tissue. The concentration of endophyte mycelium in leaf sheaths is positively associated with Loline alkaloid accumulation. N-formylLoline is toxic to several different insects from ingestion, topical and injected applications. Larger animal bioassay have not been conducted with pure compounds but the observations suggest some pharmacological activity in these systems.
Dirk Trauner - One of the best experts on this subject based on the ideXlab platform.
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An efficient synthesis of Loline alkaloids
Nature Chemistry, 2011Co-Authors: Mesut Cakmak, Peter Mayer, Dirk TraunerAbstract:Loline ( 1 ) is a small alkaloid that, in spite of its simple-looking structure, has posed surprising challenges to synthetic chemists. It has been known for more than a century and has been the subject of extensive biological investigations, but only two total syntheses have been achieved to date. Here, we report an asymmetric total synthesis of Loline that, with less then ten steps, is remarkably short. Our synthesis incorporates a Sharpless epoxidation, a Grubbs olefin metathesis and an unprecedented transannular aminobromination, which converts an eight-membered cyclic carbamate into a bromopyrrolizidine. The synthesis is marked by a high degree of chemo- and stereoselectivity and gives access to several members of the Loline alkaloid family. It delivers sufficient material to support a programme aimed at studying the complex interactions between plants, fungi, insects and bacteria brokered by Loline alkaloids. Loline is a small alkaloid with a deceptively simple-looking structure. Here, a remarkably short synthesis is reported, the key step of which is a transannular aminobromination. The synthesis provides access to Loline and to several other members of the Loline family in sufficient yield to support a programme investigating the complex biological interactions of these compounds.
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An efficient synthesis of Loline alkaloids
Nature chemistry, 2011Co-Authors: Mesut Cakmak, Peter Mayer, Dirk TraunerAbstract:Loline is a small alkaloid with a deceptively simple-looking structure. Here, a remarkably short synthesis is reported, the key step of which is a transannular aminobromination. The synthesis provides access to Loline and to several other members of the Loline family in sufficient yield to support a programme investigating the complex biological interactions of these compounds.
Stuart D. Card - One of the best experts on this subject based on the ideXlab platform.
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A Tale of Two Grass Species: Temperature Affects the Symbiosis of a Mutualistic Epichloë Endophyte in Both Tall Fescue and Perennial Ryegrass
Frontiers in plant science, 2020Co-Authors: Priscila P. Freitas, John G. Hampton, M. Phil Rolston, Travis R. Glare, Poppy P. Miller, Stuart D. CardAbstract:Many cool-season grasses form permanent, mutualistic symbioses with asexual Epichloe endophytes. These fungal symbionts often perform a protective role within the association as many strains produce secondary metabolites that deter certain mammalian and invertebrate herbivores. Although initially a serious issue for agriculture, due to mammalian toxins that manifested in major animal health issues, selected strains that provide abiotic stress protection to plants with minimal ill effects to livestock are now commercialized and routinely used to enhance pasture performance in many farming systems. These fungal endophytes and their grass hosts have coevolved over millions of years, and it is now generally accepted that most taxonomic groupings of Epichloe are confined to forming compatible associations (i.e. symptomless associations) with related grass genera within a tribe. The most desired compounds associated with Epichloe festucae var. lolii, an endophyte species associated with perennial ryegrass are peramine and epoxy-janthitrems. No other major secondary metabolites with invertebrate bioactivity have been identified within this association. However, other agriculturally beneficial compounds, such as Lolines, have been discovered in related endophyte species that form associations with fescue grasses. A rationale therefore existed to develop novel grass-endophyte associations between Loline-producing endophytes originally isolated from tall fescue with elite cultivars of perennial ryegrass to achieve a wider spectrum of insect bioactivity. A suitable Loline-producing endophyte strain was selected and inoculated into perennial ryegrass. We hypothesed that endophyte transmission frequency, endophyte mycelial concentration and endophyte-derived alkaloid production would not differ between the original tall fescue host and the artificial association. This hypothesis was disproved, and our data strongly suggests that plant species significantly affects the plant-endophyte association. This effect became more apparent for transmission frequency and endophyte concentration as the plants matured. Overall, the viable endophyte infection frequency was greater in the tall fescue host than in perennial ryegrass, at all sampling dates. Additionally, temperature was found to be a significant factor affecting endophyte transmission frequency, endophyte mycelial concentration and alkaloid production. Implications for the development of novel grass-endophyte associations are discussed.
Mesut Cakmak - One of the best experts on this subject based on the ideXlab platform.
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Total synthesis of Loline alkaloids and studies toward naphthomycin K
2012Co-Authors: Mesut CakmakAbstract:Loline is the eponymous member of an alkaloid family, originally isolated in 1892 from tall fescue grasses, but later found in many other plant families. They are produced by endophytic fungi and are as toxic to insects as nicotine, thereby protecting the host plant from herbivores, but many aspects of their chemical ecology are not yet understood. Despite its long history and intriguing biological activity, there has been only one successful asymmetric synthesis of Loline to date, which required 20 steps. This may be due to its strained, heterotricyclic molecular skeleton, that incorporates polar functionalities in close proximity, thus rendering the Loline alkaloids more challenging targets than they may appear at first sight. This dissertation deals with different approaches for the synthesis of Loline alkaloids and reports interesting outcomes. The synthesis, which finally led to success is efficient and asymmetric and requires only 10 steps. The synthesis is scalable, diversifiable, gives access to all Loline alkaloids and has served to provide several research groups sufficient material to investigate the interesting chemical ecology of these alkaloids. The naphthomycins are a class of ansamycin antibiotics that contain a macrocycle of polyketide origin with an amide linkage to a naphthalenic moiety. To date, 11 different naphthomycins (naphthomycin A–K) have been isolated and structurally elucidated. In spite of their unique structure and broad spectrum of biological activities, none of the naphthomycins have been synthesized to date. This dissertation includes the syntheses of two building blocks from inexpensive commercially available starting materials in 9 steps each and their coupling in a Horner-Wadsworth-Emmons reaction (HWE) and further transformation to give the C6-C23 fragment of all naphthomycins. In addition, a naphthoquinone precursor has been synthesized starting from a literature known quinone and a novel Danishefsky-type diene. The synthesis of the novel Danishefsky-type diene and its reactivity in Diels-Alder reactions is reported.
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An efficient synthesis of Loline alkaloids
Nature Chemistry, 2011Co-Authors: Mesut Cakmak, Peter Mayer, Dirk TraunerAbstract:Loline ( 1 ) is a small alkaloid that, in spite of its simple-looking structure, has posed surprising challenges to synthetic chemists. It has been known for more than a century and has been the subject of extensive biological investigations, but only two total syntheses have been achieved to date. Here, we report an asymmetric total synthesis of Loline that, with less then ten steps, is remarkably short. Our synthesis incorporates a Sharpless epoxidation, a Grubbs olefin metathesis and an unprecedented transannular aminobromination, which converts an eight-membered cyclic carbamate into a bromopyrrolizidine. The synthesis is marked by a high degree of chemo- and stereoselectivity and gives access to several members of the Loline alkaloid family. It delivers sufficient material to support a programme aimed at studying the complex interactions between plants, fungi, insects and bacteria brokered by Loline alkaloids. Loline is a small alkaloid with a deceptively simple-looking structure. Here, a remarkably short synthesis is reported, the key step of which is a transannular aminobromination. The synthesis provides access to Loline and to several other members of the Loline family in sufficient yield to support a programme investigating the complex biological interactions of these compounds.
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An efficient synthesis of Loline alkaloids
Nature chemistry, 2011Co-Authors: Mesut Cakmak, Peter Mayer, Dirk TraunerAbstract:Loline is a small alkaloid with a deceptively simple-looking structure. Here, a remarkably short synthesis is reported, the key step of which is a transannular aminobromination. The synthesis provides access to Loline and to several other members of the Loline family in sufficient yield to support a programme investigating the complex biological interactions of these compounds.
