François Lévesque

Continuous-Flow Synthesis of the Anti-Malaria Drug Artemisinin

Malaria remains a major global health problem, killing about one million people each year, with the protozoan parasite Plasmodium falciparum responsible for this most deadly illness. The sesquiterpene endoperoxide artemisinin is currently the most effective treatment against multi-drug resistant Plasmodium species, and artemisinin combination treatments (ACTs) are now first-line drugs, as recommended by the WHO. The compound is extracted from the plant Artemisia annua (sweet wormwood), now cultivated in many countries for this purpose. However, reliance on cultivated A. annua restricts the supply of the drug and elevates costs for the patients. The total synthesis of artemisinin is too laborious to be considered a viable alternative for supplying the highly costsensitive market. Artemisinic acid, a much-less complex molecular precursor, can be extracted from the same plant in higher yields, or produced in engineered yeast. Therefore, artemisinic acid is an ideal starting point for synthetically producing artemisinin. Still, the conversion of artemisinic acid to artemisinin has proven a formidable challenge for chemists, since a high-yielding, scalable, and low-cost process for constructing a highly complex molecule is needed. Herein we report a continuous-flow conversion of dihydroartemisinic acid, derived from artemisinic acid by hydrogenation or produced by fermentation in engineered yeast, into artemisinin. Central to the reaction is a continuous photochemical transformation involving a singlet-oxygeninduced ene reaction and the addition of triplet oxygen, which triggers the reaction cascade that incorporates the essential endoperoxide group. This technically simple, efficient, and inexpensive synthesis is readily scalable by virtue of the continuous-flow process, and does not require isolation and purification of intermediates. Combined with the production of artemisinic acid in engineered yeast, access to the muchneeded malaria drug is now possible by semi-synthesis rather than isolation from plants, ensuring a steady supply of artemisinin at greatly reduced cost. Artemisinic acid (1, Scheme 1), a bicyclic molecule, lacks the structural complexity that imparts anti-malarial activity to artemisinin (6, Scheme 1) a sesquiterpene endoperoxide with

Highly Efficient Continuous Flow Reactions Using Singlet Oxygen as a “Green” Reagent

Described is a new method for the efficient in situ production of singlet oxygen in a simple continuous flow photochemical reactor. The extremely large interfacial area generated by running the biphasic mixture in a narrow channel at a high flow rate ensures high throughput as well as fast and efficient oxidation of various alkenes, 1,3-dienes, and thioethers on a preparative scale.

A Continuous‐Flow Process for the Synthesis of Artemisinin

Isolation of the most effective antimalarial drug, artemisinin, from the plant sweet wormwood, does not yield sufficient quantities to provide the more than 300 million treatments needed each year. The high prices for the drug are a consequence of the unreliable and often insufficient supply of artemisinin. Large quantities of ineffective fake drugs find a market in Africa. Semisynthesis of artemisinin from inactive biological precursors, either dihydroartemisinic acid (DHAA) or artemisinic acid, offers a potentially attractive route to increase artemisinin production. Conversion of the plant waste product, DHAA, into artemisinin requires use of photochemically generated singlet oxygen at large scale. We met this challenge by developing a one-pot photochemical continuous-flow process for the semisynthesis of artemisinin from DHAA that yields 65 % product. Careful optimization resulted in a process characterized by short residence times. A method to extract DHAA from the mother liquor accumulated during commercial artemisinin extractions, a material that is currently discarded as waste, is also reported. The synthetic continuous-flow process described here is an effective means to supplement the limited availability of artemisinin and ensure increased supplies of the drug for those in need.

Continuous Synthesis and Purification by Direct Coupling of a Flow Reactor with Simulated Moving-Bed Chromatography

Continuous synthesis meets continuous purification to produce pure products from crude reaction mixtures. In the nucleophilic aromatic substitution of 2,4-difluoronitrobenzene with morpholine the desired monosubstituted product can be continuously separated from the byproducts in a purity of over 99 % by coupling a flow reactor to a simulated moving bed (SMB) chromatography module.

Continuous flow photolysis of aryl azides: Preparation of 3H-azepinones

Summary Photolysis of aryl azides to give nitrenes, and their subsequent rearrangement in the presence of water to give 3H-azepinones, is performed in continuous flow in a photoreactor constructed of fluorinated ethylene polymer (FEP) tubing. Fine tuning of the reaction conditions using the flow reactor allowed minimization of secondary photochemical reactions.

Synthesis of the tetracyclic core of daphnilactone B-type and yuzurimine-type alkaloids.

The core of daphnilactone B-type and yuzurimine-type alkaloids was synthesized in only 16 steps from a known β-allyl-γ-butyrolactone. The key sequence of Vilsmeier-Haack cyclization and intramolecular azomethine ylide cycloaddition allowed the construction of, in a single step, three of the five rings common to all alkaloids found in both of these classes with perfect chemocontrol.

Acridinium-Based Photocatalysts: A Sustainable Option in Photoredox Catalysis

The emergence of visible light photoredox catalysis has enabled the productive use of lower energy radiation, leading to highly selective reaction platforms. Polypyridyl complexes of iridium and ruthenium have served as popular photocatalysts in recent years due to their long excited state lifetimes and useful redox windows, leading to the development of diverse photoredox-catalyzed transformations. The low abundances of Ir and Ru in the earths crust and, hence, cost make these catalysts nonsustainable and have limited their application in industrial-scale manufacturing. Herein, we report a series of novel acridinium salts as alternatives to iridium photoredox catalysts and show their comparability to the ubiquitous [Ir(dF-CF3-ppy)2(dtbpy)](PF6).

Oxyfunctionalization of the Remote C−H Bonds of Aliphatic Amines by Decatungstate Photocatalysis

Aliphatic amines, oxygenated at remote positions within the molecule, represent an important class of synthetic building blocks to which there are currently no direct means of access. Reported herein is an efficient and scalable solution that relies upon decatungstate photocatalysis under acidic conditions using either H2 O2 or O2 as the terminal oxidant. By using these reaction conditions a series of simple and unbiased aliphatic amine starting materials can be oxidized to value-added ketone products. Lastly, NMR spectroscopy using in situ LED-irradiated samples was utilized to monitor the kinetics of the reaction, thus enabling direct translation of the reaction into flow.