Synthesis Of Ergot Alkaloids Research Articles

Solving a Mystery with Classical and Dual Photoredox Catalysis: Application of Nickel in the Synthesis of Ergot Alkaloids.

A short synthesis of the ergot alkaloid lysergene and a formal total synthesis of lysergic acid diethylamide (LSD) under the avoidance of palladium and including two nickel-catalyzed steps instead have been developed. A key intermediate of this approach has already been reported by Hendrickson et al. in 2004 (Hendrickson, J.B. et al. Org. Lett. 2004, 6, 3-5), yet the spectral data do not match, adding to doubts about the course of their route. While the final steps of the Hendrickson synthesis could not be reproduced, we were able to leverage the elusive intermediate.

A Short Synthesis of (−)‐6,7‐Secoagroclavine via Metal‐Free Reductive Coupling

AbstractA concise, convergent, and enantioselective synthesis of (−)‐6,7‐secoagroclavine, a pivotal intermediate in the synthesis of both clavine and ergot alkaloids, was accomplished from a derivative of the renowned Uhle's ketone. The synthesis is centered on metal‐free reductive coupling of the tosylhydrazone derivative of protected 4‐amino Uhle's ketone and commercially available 2,2‐dimethylethenylboronic acid, which is used as a four‐carbon building block. This novel approach directly sets the stereochemistry on the difficult‐to‐access aryl vinyl methane carbon stereogenic center of (−)‐6,7‐secoagroclavine.

Biosynthesis, total synthesis, and biological profiles of Ergot alkaloids.

While the use of ergot alkaloids in folk medicine has been practiced for millennia, systematic investigations on their therapeutic potential began about 100 years ago. Subsequently, Albert Hofmann's discovery of lysergic acid diethylamide (LSD) and its intense psychedelic properties garnered worldwide attention and prompted further studies of this compound class. As a result, several natural ergot alkaloids were discovered and unnatural analogs were synthesized, and some were used to treat an array of maladies, including Alzheimer's and Parkinson's disease. While LSD was never commercially approved, recent clinical studies have found it can be an innovative and effective treatment option for several psychiatric disorders. Ongoing biosynthetic and total synthetic investigations aim to understand the natural origins of ergot alkaloids, help develop facile means to produce these natural products and enable their continued use as medicinal chemistry lead structures. This review recounts major developments over the past 20 years in biosynthetic, total synthetic, and pharmaceutical studies. Many ergot alkaloid biosynthetic pathways have been elucidated, with some of them subsequently applied toward "green" syntheses. New chemical methodologies have fostered a fast and efficient access to the ergoline scaffold, prompting some groups to investigate biological properties of natural product-like ergot alkaloids. Limited pharmaceutical applications have yet to completely bypass the undesirable side effects of ergotism, suggesting further studies of this drug class are likely needed and will potentially harness major therapeutic significance.

Quantitative and qualitative transcriptome analysis of four industrial strains of Claviceps purpurea with respect to ergot alkaloid production

The fungus Claviceps purpurea is a biotrophic phytopathogen widely used in the pharmaceutical industry for its ability to produce ergot alkaloids (EAs). The fungus attacks unfertilized ovaries of grasses and forms sclerotia, which represent the only type of tissue where the synthesis of EAs occurs. The biosynthetic pathway of EAs has been extensively studied; however, little is known concerning its regulation. Here, we present the quantitative transcriptome analysis of the sclerotial and mycelial tissues providing a comprehensive view of transcriptional differences between the tissues that produce EAs and those that do not produce EAs and the pathogenic and non-pathogenic lifestyle. The results indicate metabolic changes coupled with sclerotial differentiation, which are likely needed as initiation factors for EA biosynthesis. One of the promising factors seems to be oxidative stress. Here, we focus on the identification of putative transcription factors and regulators involved in sclerotial differentiation, which might be involved in EA biosynthesis. To shed more light on the regulation of EA composition, whole transcriptome analysis of four industrial strains differing in their alkaloid spectra was performed. The results support the hypothesis proposing the composition of the amino acid pool in sclerotia to be an important factor regulating the final structure of the ergopeptines produced by Claviceps purpurea.

Horizontal acquisition of toxic alkaloid synthesis in a clade of plant associated fungi

Clavicipitaceae is a fungal group that comprises species that closely interact with plants as pathogens, parasites or symbionts. A key factor in these interactions is the ability of these fungi to synthesize toxic alkaloid compounds that contribute to the protection of the plant host against herbivores. Some of these compounds such as ergot alkaloids are toxic to humans and have caused important epidemics throughout history. The gene clusters encoding the proteins responsible for the synthesis of ergot alkaloids and lolines in Clavicipitaceae have been elucidated. Notably, homologs to these gene clusters can be found in distantly related species such as Aspergillus fumigatus and Penicillium expansum, which diverged from Clavicipitaceae more than 400million years ago. We here use a phylogenetic approach to analyze the evolution of these gene clusters. We found that the gene clusters conferring the ability to synthesize ergot alkaloids and loline emerged first in Eurotiomycetes and were then likely transferred horizontally to Clavicipitaceae. Horizontal gene transfer is known to play a role in shaping the distribution of secondary metabolism clusters across distantly related fungal species. We propose that HGT events have played an important role in the capability of Clavicipitaceae to produce two key secondary metabolites that have enhanced the ability of these species to protect their plant hosts, therefore favoring their interactions.

Synthetic Philosophy: A Study Directed toward Creation of an Ideal Synthetic Method and Its Application for Preventing Global Warming by Combating Desertification

This review reports how the author has been realizing his synthetic philosophy and five dreams as his life work. The philosophy consists of such three elements as originality rate, intellectual property factor, and application potential factor. On the basis of these elements, an ideal and an efficient synthesis are defined. In the study for the total synthesis of ergot alkaloids, the first concrete example of an approximately ideal synthesis was demonstrated. Further examples are shown relying on the chemistry of 1-hydroxyindoles. A lot of intellectual properties created by the author are successfully condensed to provide promising lead compounds meeting for the respective dreams of developing five drugs 1) for making desert green and food increase in production, 2) for cardiovascular system disease, 3) for dementia, 4) for lifestyle-related disease (osteoporosis, etc.), and 5) for cancer and virus. With potent promoters of plant's root growth in hand, the first dream is going now successfully. Preliminary experiments combating desertification at Gobi desert in Inner Mongolia are reported in detail, aiming for preventing global warming.

The effect of some amino acids on the growth and biosynthesis of ergot alkaloids and quinocitrinins in the fungus Penicillium citrinum Thom 1910

The effect of some amino acids, added to the medium either during inoculation or in the stationary growth phase, on the growth and biosynthesis of ergot alkaloids and quinocitrinins in the fungus Penicillium citrinum VKM FW-800 has been studied. Exogenously added amino acids were mostly utilized in primary metabolism. When added during inoculation, tryptophan and leucine virtually did not influence fungal growth and synthesis of the alkaloids, whereas the addition of isoleucine enhanced the biomass accumulation. When added in the stationary growth phase, tryptophan stimulated the synthesis of both ergot alkaloids and quinocitrinins. Leucine added in the stationary growth phase did not influence the synthesis of ergot alkaloids but inhibited the synthesis of quinocitrinins. Isoleucine inhibited the synthesis of both ergot alkaloids and quinocitrinins irrespective of the time of its addition to the medium.

An Improved Synthesis of Optically Pure (R)-4-Bromo-N-methyl-1-tosyltryptophan Derivative, a Key Intermediate in the Synthesis of Ergot Alkaloids

Optically pure (R)-N-Boc- or (R)-Cbz-4-bromo-N-methyl-1-tosyltryptophan methyl ester (11a or b) was synthesized in 2 steps from (R)-N-acetyl-4-bromo-l-tosyltryptophan methyl ester (7) by simultaneous N-methylation and deacetylation using methyl trifluoromethanesulfonate (TfOMe) in the presence of 2,6-di-tert-butyl-4-methylpyridine (DTBMP).

2-Substituted-3,7-dinitro-11-oxatricycloundec-9-ene: an approach towards the synthesis of Ergot alkaloids

A simple and versatile method for the preparation of various ergoline or secoergoline skeleton, using 2-substituted-3,7-dinitro-11-oxatricycloundec-9-ene as key intermediates, is described. The key step involves an IMDAF reaction with an excellent stereocontrol. This novel synthetic route provides new cycloadducts as useful scaffolds for Ergot alkaloids synthesis.

2-Substituted-3,7-dinitro-11-oxatricycloundec-9-ene: an approach towards the synthesis of Ergot alkaloids

A simple and versatile method for the preparation of various ergoline or secoergoline skeleton, using 2-substituted-3,7-dinitro-11-oxatricycloundec-9-ene as key intermediates, is described. The key step involves an IMDAF reaction with an excellent stereocontrol. This novel synthetic route provides new cycloadducts as useful scaffolds for Ergot alkaloids synthesis.

Development of a Tryptophan Auxotrophic Mutant of Claviceps purpurea 1029 N5 and its Preliminary Application in the Synthesis of New Ergot Alkaloids

Four tryptophan dependent mutants of Claviceps purpurea 1029 N5 were derived by treatment with N-methyl-N'-nitro-N-nitroguanidine (NTG) and protoplasting of the treated fungus. The poor alkaloid production of these mutants required a systematic optimisation of the production media. Malic acid was essential for good alkaloid production. A preliminary attempt to modify the tryptophan moiety of the ergot alkaloid molecule by feeding one selected Trp - mutant with tryptophan derivatives (synthons) and preliminary analysis of the extracellular spent medium by HPLC are described. The utilisation of the synthon, 5-methoxytryptophan, from the medium by the Trp- mutant was 99%. The analysis of the spent medium extract of the flask fed with this synthon by HPLC showed the formation of a new peak in the ergot alkaloid region. This peak increased in intensity relative to the time of incubation. Its detailed analysis and further characterisation will be the focus of future studies.

Application of Palladium(0)-Catalyzed Processes to the Synthesis of Oxazole-Containing Partial Ergot Alkaloids

Syntheses of the potent 5-HT1A agonists 2 and 3 were accomplished in several steps from the 6-iodo partial ergoline alkaloid 8. Disparate tactics available for construction of differentially substituted oxazoles led to the development of new and general methodology critical to the efficient preparations of 2 and 3. A novel palladium(0)- and copper(I)-cocatalyzed cyanation reaction provided efficient access to the nitrile 10, a key intermediate in the synthesis of 2. A palladium(0)-catalyzed cross-coupling reaction of 16 with oxazol-2-ylzinc chloride formed the potent 5-HT1A agonist 3.

Synthesis of α-mannosylated ergot alkaloids employing α-mannosidase

The ergot alkaloids elymoclavine, ergometrine and chanoclavine were α-mannosylated with α-mannosidase as catalyst. The kinetic reaction with p-nitrophenyl α-mannoside as glycosyl donor gave ca 28 % yield of chanoclavine α-mannoside, whereas the equilibrium reaction with mannose as the glycosyl donor gave ca 11 % yield. However, in the case of elymoclavine and ergometrine, higher yields of α-mannosides were obtained with the equilibrium approach (18 and 13 %).

ChemInform Abstract: Photocyclization of Enamides. Part 29. Dehydrogenation with Benzeneseleninic Anhydride in the Total Synthesis of Ergot Alkaloids.

AbstractThe efficiency of the dehydrogenation of indolines such as (I) by treatment with the title reagent is markedly improved on addition of indole as a scavenger for trapping an intermediate Se(II) species (yield of (IIa) in the absence of indole: 57%).

ChemInform Abstract: Synthesis of Ergot Alkaloids

ChemInformVolume 21, Issue 19 Reviews ChemInform Abstract: Synthesis of Ergot Alkaloids T. BRUMBY, T. BRUMBY Schering AG, D-1000 BerlinSearch for more papers by this author T. BRUMBY, T. BRUMBY Schering AG, D-1000 BerlinSearch for more papers by this author First published: May 8, 1990 https://doi.org/10.1002/chin.199019355Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume21, Issue19May 8, 1990 RelatedInformation

Dehydrogenation with benzeneseleninic anhydride in the total synthesis of ergot alkaloids

Dehydrogenation with benzeneseleninic anhydride in the total synthesis of ergot alkaloids

ChemInform Abstract: Dehydrogenation with Phenylseleninic Anyhdride in the Total Synthesis of Ergot Alkaloids.

AbstractNach einem Verfahren der Dehydrierung von Indolinen zu Indolen durch die Selenverbindung (II) werden aus den Dihydroverbindungen (I) bzw. (III) Isofumigaclavin AB (IIa) bzw. Lysergol (IVa) hergestellt und modifi‐ ziert.

A Chemically Defined Medium for the Growth and Synthesis of Ergot Alkaloids by Species of Balansia

A chemically defined medium was developed for the growth of and ergot alkaloid synthesis by five species of Balansia (Clavicipitaceae). It was determined that the nitrogen required for growth was not strict, but NH4Cl (2.4 g/l) produced good growth and favored total ergot alkaloid synthesis. The fungi required thiamine, nicotinic acid, and pyridoxine for growth. Incorporating DL-tryptophan into the medium did not increase growth, but did cause a 2–4-fold increase in the yield of total alkaloid produced by the species tested.

A Chemically Defined Medium for the Growth and Synthesis of Ergot Alkaloids by Species ofBalansia

A chemically defined medium was developed for the growth of and ergot alkaloid synthesis by five species of Balansia (Clavicipitaceae). It was determined that the nitrogen required for growth was not strict, but NH4Cl (2.4 g/l) produced good growth and favored total ergot alkaloid synthesis. The fungi required thiamine, nicotinic acid, and pyridoxine for growth. Incorporating DL-tryptophan into the medium did not increase growth, but did cause a 2–4-fold increase in the yield of total alkaloid produced by the species tested.

Dehydrogenation with phenylseleninic anhydride in the total synthesis of ergot alkaloids

The standardised procedure for dehydrogenation of indolines into indoles with phenylseleninic anhydride 1 was successfully applied to the final steps in the total synthesis of ergot alkaloids.