Alkaloid | EPFL Graph Search

Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar structure may also be termed alkaloids. In addition to carbon, hydrogen and nitrogen, alkaloids may also contain oxygen or sulfur. More rarely still, they may contain elements such as phosphorus, chlorine, and bromine. Alkaloids are produced by a large variety of organisms including bacteria, fungi, plants, and animals. They can be purified from crude extracts of these organisms by acid-base extraction, or solvent extractions followed by silica-gel column chromatography. Alkaloids have a wide range of pharmacological activities including antimalarial (e.g. quinine), antiasthma (e.g. ephedrine), anticancer (e.g. homoharringtonine), cholinomimetic (e.g. galantamine), vasodilatory (e.g. vincamine), antiarrhythmic (e.g. quinidine), analgesic (e.g.

Directed Biosynthesis of Phytotoxic Alkaloids in the Cyanobacterium Nostoc 78-12A

Karl Gademann, Theresa Myers, Cyril Portmann, Cora Prestinari

Nostocarboline, a chlorinated and N-methylated carbolinium alkaloid, displays potent and selective inhibition of photoautotrophic organisms as well as the malaria parasite Plasmodium falciparum, while showing very low toxicity to bacterial and fungal pathogens, rat myoblasts and crustaceans. New derivatives of nostocarboline incorporating Br, F or methyl substituents have been obtained through precursor-directed biosynthesis in Nostoc 78-12A (identical to Nostoc sp. ATCC 43238) by feeding this cyanobacterium with differently substituted tryptophan derivatives or 6-Br-norharmane (eudistomin N). These experiments substantiate the biosynthetic hypothesis and validate the inherent flexibility of the corresponding enzymes for metabolic engineering. The new derivatives inhibit the growth of the toxic-bloom-forming cyanobacterium Microcystis aeruginosa PCC 7806 above 1 μM. The mode of action of nostocarboline was investigated by using chlorophyll-a fluorescence imaging, and it was demonstrated that a decrease in photosynthesis precedes cell death, thus establishing the phytotoxic properties of this alkaloid.

2009

Asymmetric Total Synthesis of Indole Alkaloids (+)-Condyfoline, (-)-Tubifoline, (+)-Dasycarpidone and (+)-Uleine

Bastien Delayre

The development of a titanium(III)-mediated cascade electrocyclisation/rearrangement for theenantioselective total synthesis of indole alkaloids (+)-condyfoline and (-)-tubifoline serve as the basisof the first chapter of this thesis. An introduction will focus on the use of domino sequencesincorporating a 1,2-shift in the context of complex natural product synthesis. The design of such adomino process is then presented, along with preliminary results originating from our research groupconcerning the titanium(III)-mediated Cadogan cyclisation. This novel domino sequence enabled thefirst enantioselective total synthesis of (+)-condyfoline. These results provided insights into themechanistic nature of the formal 1,2-shift, indicating that the formal 1,2-migration most likelyproceeds via 1,5-sigmatropic rearrangement rather than retro-Mannich/Mannich sequence. Theisolation of (+)-condyfoline enabled a re-investigation of its isomerisation process to Strychnos isomer(-)-tubifoline. The chapter concludes with synthetic studies towards (+)-tronoharine and (+)-tubotaiwine.The second chapter of this thesis deals with the development of an integratedOxidation/Reduction/Cyclisation (iORC) sequence for the enantioselective total synthesis of the Uleinefamily of monoterpene indole alkaloids. A brief introduction will review our group's previous effortsto implement iORC sequences for the total synthesis of alkaloids. The step-by-step development of theiORC sequence is described, along with the endgame strategy for the synthesis of (+)-nordasycarpidone, (+)-dasycarpidone, (-)-dasycarpidol and (+)-uleine. The chapter ends with theattempted titanium(III)-mediated cyclisation/rearrangement sequence towards (+)-uleine, andattempted iORC sequence towards (+)-condyfoline.The third chapter of this thesis reports a novel synthesis of benzofuro[3,2-b]indolines from onitrostylbene precursors using a titanium(III)-mediated interrupted Cadogan reaction. A rapidinvestigation of the substrate scope is presented. The remaining of the chapter reports our efforts toapply this newly developed transformation for the total synthesis of bis-indole alkaloid phalarine.The last chapter is dedicated to our synthetic studies towards (+)-pestalustaine A, a recently isolatedsesquiterpene possessing a unique 5/6/7-fused tricyclic system. A designed formal [3+2] reaction wasenvisioned to provide access to this novel sesquiterpene, but resulted in the isolation of a Wilson-Clokerearrangement product.

EPFL2022

Total Synthesis of Alstilobanine C, Undulifoline and Alstilobanine B

Nicolas David Gaeng

The total synthesis of pentacyclic monoterpene indole alkaloids is the focus of this thesis. Total syntheses of (±)-alstilobanine C, (±)-undulifoline and (±)-alstilobanine B, three natural products from the Ulean family of alkaloids, were accomplished. The characteristic features of our synthesis included: a) a domino sequence involving a highly diastereoselective Michael addition followed by chemoselective C-acylation of the resulting enolate by Mander¿s ester; b) an unprecedented Lewis acid mediated intramolecular addition of enolate to oxonium, generated in situ from MOM protective group; c) a sequence of chemoselective reduction/indolization/intramolecular aza-Michael addition. This domino process afforded directly the (±)-alstilobanine C, a pentacyclic monoterpene indole alkaloid in 87% yield. Reductive N-methylation of (±)-alstilobanine C provided (±)-undulifoline which, upon N-oxidation, was further converted to (±)-alstilobanine B. Enantioselective total synthesis of the same natural products through a different synthetic route is presented. After exploring different unsuccessful strategies, an enzymatic desymmetrization of a meso compound was adopted for the synthesis of enantioenriched cyclopentenone intermediate. Applying the two domino sequence developed previously, namely, Michael addition/C-acylation and oxepane formation, an efficient synthesis of the oxobicyclo[4.2.1]nonane was realized. A palladium-catalyzed decarboxylative cross-coupling, a methodology developed in our group, afforded an advanced bicyclic intermediate with all the carbon and functional groups needed to accomplish the total synthesis. However, conversion of the vinyl group to alkylazide or its synthetic equivalent proved to be difficult in spite of the efforts dedicated to this seemingly trivial transformation.

EPFL2018

Asymmetric Total Synthesis of Indole Alkaloids (+)-Condyfoline, (-)-Tubifoline, (+)-Dasycarpidone and (+)-Uleine

Bastien Delayre

EPFL2022