- Isolation and identification of dihydroartemisinic acid from Artemisia annua and its possible role in the biosynthesis of artemisinin
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Dihydroartemisinic acid (2) was isolated as a natural product from Artemisia annua in a 66% yield, and its structure was confirmed by 1H and 13C NMR spectroscopy. Compound 2 could be chemically converted to artemisinin (4) under conditions that may also be present in the living plant. The results suggest that the conversion of 2 into 4 in the living plant might be a nonenzymatic conversion.
- Wallaart, T. Eelco,Van Uden, Wim,Lubberink, Heidi G. M.,Woerdenbag, Herman J.,Pras, Niesko,Quax, Wim J.
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- A concise synthesis of (+)-artemisinin
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Malaria represents one of the most medically and economically debilitating diseases present in the world today. Fortunately, there exists a highly effective treatment based on the natural product artemisinin. Despite the development of several synthetic approaches to the natural product, a streamlined synthesis that utilizes low-cost chemical inputs has yet to materialize. Here we report an efficient, cost-effective approach to artemisinin. Key to the success of the strategy was the development of mild, complexity-building reaction cascades that allowed the use of readily available, affordable cyclohexenone as the key starting material.
- Zhu, Chunyin,Cook, Silas P.
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- A 2D MOF-based artificial light-harvesting system with chloroplast bionic structure for photochemical catalysis
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Developing an efficient artificial light-harvesting system (ALHS) with high solar spectrum overlap, energy transfer efficiency and photocatalytic performance remains a key challenge to realize sustainable energy utilization. Inspired by nature, herein, a 2D ALHS, namely, 2D MB/Yb-TCPP-SO4nanosheets with chloroplast bionic structure were successfully constructed by coupling a kind of porphyrin-based 2D lanthanide metal-organic framework (namely, Yb-TCPP MOF) and methylene blue (MB). The newly assembled 2D ALHS showed 100% spectrum efficiency in the visible light region and high-efficiency energy transfer (up to 78.6%) between 2D Yb-TCPP nanosheets and MB. Significantly, this 2D ALHS possessed high activity towards the photocatalytic semi-synthesis of artemisinin after installing Br?nsted acid sites, giving a record yield as high as 85%. This demonstrated that the as-constructed 2D ALHS is an ideal artificial solar converter, which showed a promising application for photochemical catalysis.
- Jiang, Zhong Wei,Zhao, Ting Ting,Zhen, Shu Jun,Li, Chun Mei,Li, Yuan Fang,Huang, Cheng Zhi
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- Selective Photooxygenation of Dihydroartemisinic Acid in a Reusable Microreactor with Physically Immobilized Photocatalysts
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Photocatalytic production of organic materials including Artemisinin has been hampered in the pharmaceutical industry because of low reusability and selectivity of photocatalysts. In this work, reusable photocatalysts were synthesized through novel physical and electrostatic immobilizations. After four reaction cycles of dihydroartemisinic acid (DHAA) photooxygenation using physically supported photosensitizers, the conversion was slightly reduced from 81 to 78%, indicating their high reusability. This occurred while maintaining the selectivity of the desired product above 85%, which was higher than that of the homogeneous photosensitizers. Then, a continuous-flow microreactor functionalized with these reusable polystyrene-supported photocatalysts was applied toward the photooxygenation of DHAA at ambient temperature and pressure to produce Artemisinin with a high yield confirmed by the 1H-NMR analysis. Moreover, theoretical evaluations using finite element method simulation showed a 2-μm high local singlet oxygen (1O2) concentration around the reusable photocatalysts which agreed very satisfyingly with the data available in the literature.
- Kazemeini, Mohammad,Roxas, Alexander Perez,Tamtaji, Mohsen,Tyagi, Abhishek
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- Continuous-flow synthesis of the anti-malaria drug artemisinin
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Malaria is a serious global health issue. Artemisinin combination treatments are the first-line drugs, but supplies are limited because artemisinin is obtained solely by extraction from Artemisia annua. A continuous-flow process that converts dihydroartemisinic acid into artemisinin (see scheme) was shown to be an inexpensive and scalable process that can ensure a steady, affordable supply of artemisinin. Copyright
- Levesque, Francois,Seeberger, Peter H.
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- Transition-metal-catalyzed group transfer reactions for selective C-H bond functionalization of artemisinin
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Three types of novel artemisinin derivatives have been synthesized through transition-metal-catalyzed intramolecular carbenoid and nitrenoid C-H bond insertion reactions. With rhodium complexes as catalysts, lactone 11 was synthesized via carbene insertion reaction at the C16 position in 90% yield; oxazolidinone 13 was synthesized via nitrene insertion reaction at the C10 position in 87% yield based on 77% conversion; and sulfamidate 14 was synthesized via nitrene insertion reaction at the C8 position in 87% yield.
- Liu, Yungen,Xiao, Wenbo,Wong, Man-Kin,Che, Chi-Ming
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- Enzymatic synthesis of artemisinin from natural and synthetic precursors
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To investigate the biosynthetic pathway of artemisinin, an assay system for the determination of activity of the enzymes involved in its synthesis has been developed. Results from these experiments have shown that HEPES provides a better buffer system than Tris-HCl. The enzyme(s) requires Mg2+ and/or Mn2+, and the addition of ATP and NADPH+H+ significantly enhances the enzyme activity. A new substrate, dihydroarteannuin B, has been synthesized that can easily be radiolabeled with high specific activity. It is utilized by the enzyme system and is converted to artemisinin with the same efficiency as the natural substrates. This can be conveniently used as a precursor for elucidation of the pathway for artemisinin biosynthesis.
- Bharel,Gulati,Abdin,Srivastava,Vishwakarma,Jain
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- Synthesis of [3,3-2H2]-Dihydroartemisinic Acid to Measure the Rate of Nonenzymatic Conversion of Dihydroartemisinic Acid to Artemisinin
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Dihydroartemisinic acid is the biosynthetic precursor to artemisinin, the endoperoxide-containing natural product used to treat malaria. The conversion of dihydroartemisinic acid to artemisinin is a cascade reaction that involves C-C bond cleavage, hydroperoxide incorporation, and polycyclization to form the endoperoxide. Whether or not this reaction is enzymatically controlled has been controversial. A method was developed to quantify the nonenzymatic conversion of dihydroartemisinic acid to artemisinin using LC-MS. A seven-step synthesis of 3,3-dideuterodihydroartemisinic acid (23) was accomplished beginning with dihydroartemisinic acid (1). The nonenzymatic rates of formation of 3,3-dideuteroartemisinin (24) from 3,3-dideuterodihydroartemisinic acid (23) were 1400 ng/day with light and 32 ng/day without light. Moreover, an unexpected formation of nondeuterated artemisinin (3) from 3,3-dideuterodihydroartemisinic acid (23) was detected in both the presence and absence of light. This formation of nondeuterated artemisinin (3) from its dideuterated precursor (23) suggests an alternative mechanistic pathway that operates independent of light to form artemisinin, involving the loss of the two C-3 deuterium atoms. copy; 2019 American Chemical Society and American Society of Pharmacognosy.
- Varela, Kaitlyn,Arman, Hadi D.,Yoshimoto, Francis K.
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- A facile and scalable synthesis of qinghaosu (artemisinin)
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A very simple and efficient approach for the conversion of dihydro-artemisinic acid into artemisinin is developed, featuring use of a molybdate induced disproportionation of hydrogen peroxide to generate singlet oxygen. The whole synthesis was completed by stirring at ambient temperature without need for any special equipments.
- Chen, Hui-Jun,Han, Wei-Bo,Hao, Hong-Dong,Wu, Yikang
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- Applying green chemistry to the photochemical route to artemisinin
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Artemisinin is an important antimalarial drug, but, at present, the environmental and economic costs of its semi-synthetic production are relatively high. Most of these costs lie in the final chemical steps, which follow a complex acid- and photo-catalysed route with oxygenation by both singlet and triplet oxygen. We demonstrate that applying the principles of green chemistry can lead to innovative strategies that avoid many of the problems in current photochemical processes. The first strategy combines the use of liquid CO 2 as solvent and a dual-function solid acid/photocatalyst. The second strategy is an ambient-temperature reaction in aqueous mixtures of organic solvents, where the only inputs are dihydroartemisinic acid, O 2 and light, and the output is pure, crystalline artemisinin. Everything else - solvents, photocatalyst and aqueous acid - can be recycled. Some aspects developed here through green chemistry are likely to have wider application in photochemistry and other reactions.
- Amara, Zacharias,Bellamy, Jessica F. B.,Horvath, Raphael,Miller, Samuel J.,Beeby, Andrew,Burgard, Andreas,Rossen, Kai,Poliakoff, Martyn,George, Michael W.
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- Synthesis of [15,15,15-2H3]-Dihydroartemisinic Acid and Isotope Studies Support a Mixed Mechanism in the Endoperoxide Formation to Artemisinin
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Artemisinin is the plant natural product used to treat malaria. The endoperoxide bridge of artemisinin confers its antiparasitic properties. Dihydroartemisinic acid is the biosynthetic precursor of artemisinin that was previously shown to nonenzymatically undergo endoperoxide formation to yield artemisinin. This report discloses the synthesis of [15,15,15-2H3]-dihydroartemisinic acid and its use to determine the mechanism of endoperoxide formation. Several new observations were made: (i) Ultraviolet-C (UV-C) radiation initially accelerates artemisinin formation and subsequently promotes homolytic cleavage of the O-O bond and rearrangement of artemisinin to a different product, and (ii) dideuterated and trideuterated dihydroartemisinic acid isotopologues at C3 and C15 converted to artemisinin at a slower rate compared to nondeuterated dihydroartemisinic acid, revealing a kinetic isotope effect in the initial ene reaction toward endoperoxide formation (kH/kD～ 2-3). (iii) The rate of conversion from dihydroartemisinic acid to artemisinin increased with the amount of dihydroartemisinic acid, suggesting an intermolecular interaction to promote endoperoxide formation, and (iv)18O2-labeling showed incorporation of three and four oxygen atoms from molecular oxygen into the endoperoxide bridge of artemisinin. These results reveal new insights toward understanding the mechanism of endoperoxide formation in artemisinin biosynthesis.
- Arman, Hadi D.,Varela, Kaitlyn,Yoshimoto, Francis K.
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supporting information
p. 1967 - 1984
(2021/07/19)
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- Precisely embedding active sites into a mesoporous Zr-framework through linker installation for high-efficiency photocatalysis
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The pore engineering of microporous metal-organic frameworks (MOFs) has been extensively investigated in the past two decades, and an expansive library of functional groups has been introduced into various frameworks. However, the reliable procurement of MOFs possessing both a targeted pore size and preferred functionality together is less common. This is especially important since the applicability of many elaborately designed materials is often restricted by the small pore sizes of microporous frameworks. Herein, we designed and synthesized a mesoporous MOF based on Zr6 clusters and tetratopic carboxylate ligands, termed PCN-808. The accessible coordinatively unsaturated metal sites as well as the intrinsic flexibility of the framework make PCN-808 a prime scaffold for postsynthetic modification via linker installation. A linear ruthenium-based metalloligand was successfully and precisely installed into the walls of open channels in PCN-808 while maintaining the mesoporosity of the framework. The photocatalytic activity of the obtained material, PCN-808-BDBR, was examined in the aza-Henry reaction and demonstrated high conversion yields after six catalytic cycles. Furthermore, thanks to the mesoporous nature of the framework, PCN-808-BDBR also exhibits exceptional yields for the photocatalytic oxidation of dihydroartemisinic acid to artemisinin.
- Pang, Jiandong,Di, Zhengyi,Qin, Jun-Sheng,Yuan, Shuai,Lollar, Christina T.,Li, Jialuo,Zhang, Peng,Wu, Mingyan,Yuan, Daqiang,Hong, Maochun,Zhou, Hong-Cai
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supporting information
p. 15020 - 15026
(2020/10/13)
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- Chemical semi-synthesis method of artemisinin
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The invention provides a chemical semi-synthesis method of artemisinin represented by a formula (VI) shown in the specification. The chemical semi-synthesis method comprises the following specific steps: (1) reacting dihydroartemisinic acid represented by a formula (I) shown in the specification with oxalyl chloride represented by a formula (II) shown in the specification to generate dihydroartemisinyl chloride represented by a formula (III) shown in the specification; (2) carrying out an acylation reaction on the dihydroartemisinyl chloride represented by the formula (III) and dihydroarteannuic acid represented by a formula (I) shown in the specification to generate dihydroarteannuic anhydride represented by a formula (IV) shown in the specification; and (3) carrying out a photooxidationreaction on the dihydroarteannuic anhydride represented by the formula (IV) by using a micro-channel reactor, and carrying out an oxidation rearrangement reaction to prepare the target product artemisinin represented by the formula (VI). Compared with the prior art, the method provided by the invention has the advantages of a high product yield, good purity of the product, a stable process, mild reaction conditions, easiness in industrial production and the like.
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Paragraph 0076; 0078-0080; 0082-0084; 0086-0087
(2020/01/03)
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- “Dark” Singlet Oxygen Made Easy
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An operationally simple continuous flow generator of “dark” singlet oxygen has been developed. The singlet oxygen was efficiently reacted with several chemical traps to give the corresponding oxygenated products in high yields. The developed “dark” singlet oxygen generator has been successfully applied in the synthesis of the antimalarial drug artemisinin.
- Elsherbini, Mohamed,Allemann, Rudolf K.,Wirth, Thomas
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supporting information
p. 12486 - 12490
(2019/08/26)
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- Concise synthesis of artemisinin from a farnesyl diphosphate analogue
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Artemisinin is one of the most potent anti-malaria drugs and many often-lengthy routes have been developed for its synthesis. Amorphadiene synthase, a key enzyme in the biosynthetic pathway of artemisinin, is able to convert an oxygenated farnesyl diphosphate analogue directly to dihydroartemisinic aldehyde, which can be converted to artemisinin in only four chemical steps, resulting in an efficient synthetic route to the anti-malaria drug.
- Tang, Xiaoping,Demiray, Melodi,Wirth, Thomas,Allemann, Rudolf K.
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p. 1314 - 1319
(2017/09/30)
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- Preparation method of artemisinin
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The invention discloses a preparation method of artemisinin, wherein the preparation method comprise the steps: with artemisinic acid as a starting material, obtaining dihydroartemisinic acid under the hydrogen/metal catalyst action, then oxidizing dihydroartemisinic acid into arteannuic acid dihydrogen peroxide by hydrogen peroxide in the presence of sodium molybdate, and finally acting with oxygen under the catalysis of copper trifluoromethanesulfonate, to obtain the target product artemisinin with high yield. Compared with the prior art, the preparation method has the following advantages:the used reagents are cheap and easy to get, the synthetic route is short, the reaction selectivity is high, the preparation process is environmentally friendly, the operation and post-processing aresimple, the total yield is high, and the preparation method is suitable for industrialized production.
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- Continuous Photo-Oxidation in a Vortex Reactor: Efficient Operations Using Air Drawn from the Laboratory
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We report the construction and use of a vortex reactor which uses a rapidly rotating cylinder to generate Taylor vortices for continuous flow thermal and photochemical reactions. The reactor is designed to operate under conditions required for vortex generation. The flow pattern of the vortices has been represented using computational fluid dynamics, and the presence of the vortices can be easily visualized by observing streams of bubbles within the reactor. This approach presents certain advantages for reactions with added gases. For reactions with oxygen, the reactor offers an alternative to traditional setups as it efficiently draws in air from the lab without the need specifically to pressurize with oxygen. The rapid mixing generated by the vortices enables rapid mass transfer between the gas and the liquid phases allowing for a high efficiency dissolution of gases. The reactor has been applied to several photochemical reactions involving singlet oxygen (1O2) including the photo-oxidations of α-terpinene and furfuryl alcohol and the photodeborylation of phenyl boronic acid. The rotation speed of the cylinder proved to be key for reaction efficiency, and in the operation we found that the uptake of air was highest at 4000 rpm. The reactor has also been successfully applied to the synthesis of artemisinin, a potent antimalarial compound; and this three-step synthesis involving a Schenk-ene reaction with 1O2, Hock cleavage with H+, and an oxidative cyclization cascade with triplet oxygen (3O2), from dihydroartemisinic acid was carried out as a single process in the vortex reactor.
- Lee, Darren S.,Amara, Zacharias,Clark, Charlotte A.,Xu, Zeyuan,Kakimpa, Bruce,Morvan, Herve P.,Pickering, Stephen J.,Poliakoff, Martyn,George, Michael W.
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supporting information
p. 1042 - 1050
(2017/07/26)
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- A to Dihydroartemisinic acid as the raw material for preparing arteannuin method and apparatus
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The invention relates to a method and equipment for preparing artemisinin by adopting dihydroarteannuic acid as a raw material. The method comprises: dissolving dihydroarteannuic acid in an organic solvent, adding a photosensitizer and an acid catalyst, adopting a light source to make the dihydroarteannuic acid be subjected to light oxidation so as to obtain peroxy alcohol of the dihydroarteannuic acid, carrying out acid catalysis so as to carry out Hock cut-off, and carrying out oxidation ring closing to produce the artemisinin, wherein the whole reaction or only the light oxidation reaction is performed in the photoreactor. The present invention further comprises the photoreactor for performing the method. According to the present invention, the method has characteristics of low reaction temperature, high artemisinin yield and high light source utilization rate, and the equipment has characteristics of simple structure, low manufacturing cost, and high single-batch productivity.
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Paragraph 0040; 0041; 0042
(2017/02/09)
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- Arteannuin residue using Artemisinic extracting arteannuin method of preparation
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The invention relates to a method and equipment for preparing artemisinin by using residue obtained through extraction of artemisinin from sweet wormwood herb. The method comprises: 1) adopting an organic solvent to extract arteannuic acid and dihydroarteannuic acid from residue obtained through extraction of artemisinin from sweet wormwood herb; 2) adopting hydrazine hydrate to reduce the arteannuic acid obtained in the step 1) into a dihydroarteannuic acid crude product; 3) dissolving the dihydroarteannuic acid crude product obtained in the step 2) in an organic solvent, adding a photosensitizer and an acid catalyst, and adopting a light source to carry out a light oxidation reaction of the dihydroarteannuic acid so as to synthesize a artemisinin crude product; and 4) carrying out column chromatography and recrystallization purification on the artemisinin crude product obtained in the step 3). The invention further provides the equipment light oxidation reactor for performing the method. According to the present invention, the residue obtained through extraction of artemisinin from sweet wormwood herb is recycled so as to provide advantages of low environment pollution and resource saving; and the effective component in the residue obtained through extraction of artemisinin from sweet wormwood herb is completely utilized so as to increase the conversion rate of preparation of artemisinin from sweet wormwood herb.
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Paragraph 0051; 0055; 0056
(2017/04/21)
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- Arteannuin method for the synthesis of
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The invention discloses a synthesis method of artemisinin. At present, artemisinin is mainly separated and extracted from plant artemisia apiacea, and the price of artemisinin is very high because the content of artemisinin contained in the artemisia apiacea is extremely low and the planting of the artemisia apiacea is influenced by the factors of natural disasters, geographical conditions, planting technologies and the like. Existing artemisinin total synthesis methods all have the defects of long synthetic route, high raw material cost, severe reaction condition, difficulty in mass production and the like. The new artemisinin total synthesis method provided by the invention has the advantages of short synthetic route, low raw material cost, moderate reaction condition and is suitable for mass production.
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- A scale preparation arteannuin method and apparatus
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The invention relates to a method and equipment for scale production of artemisinin. The method comprises: dissolving dihydroarteannuic acid in an organic solvent, adding a photosensitizer and an acid catalyst, adopting a light source to make the dihydroarteannuic acid be subjected to light oxidation so as to obtain peroxy alcohol of the dihydroarteannuic acid, carrying out acid catalysis so as to carry out Hock cut-off, and carrying out oxidation ring closing to produce the artemisinin, wherein the whole reaction or only the light oxidation reaction is performed in photosensitive oxidation reaction equipment. The present invention further comprises the photosensitive oxidation reaction equipment for performing the method. According to the present invention, the method has characteristics of low reaction temperature and high light source utilization rate, and the equipment has characteristics of high light source utilization rate, simple structure, low manufacturing cost, and high single-batch productivity.
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Paragraph 0043-0045
(2017/01/26)
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- METHOD AND APPARATUS FOR THE SYNTHESIS OF DIHYDROARTEMISININ AND ARTEMISININ DERIVATIVES
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The present invention is directed to a method for continuous production of dihydroartemisinin and also artemisinin derivatives derived from dihydroartemisinin by using artemisinin or dihydroartemisinic acid (DHAA) as starting material as well as to a continuous flow reactor for producing dihydroartemisinin as well as the artemisinin derivatives. It was found that the reduction of artemisinin to dihydroartemisinin in a continuous process requires a special kind of reactor and a special combination of reagents comprising a hydride reducing agent, at least one activator such as an inorganic activator, at least one solid base, at least one aprotic solvent and at least one C1-C5 alcohol.
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Page/Page column 59; 60
(2015/02/02)
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- Method and apparatus for the synthesis of dihydroartemisinin and artemisinin derivatives
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The present invention is directed to a method for continuous production of dihydroartemisinin and also artemisinin derivatives derived from dihydroartemisinin by using artemisinin or dihydroartemisinic acid (DHAA) as starting material as well as to a continuous flow reactor for producing dihydroartemisinin as well as the artemisinin derivatives. It was found that the reduction of artemisinin to dihydroartemisinin in a continuous process requires a special kind of reactor and a special combination of reagents comprising a hydride reducing agent, at least one activator such as an inorganic activator, at least one solid base, at least one aprotic solvent and at least one C1-C5 alcohol.
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Paragraph 0177-0183
(2015/02/02)
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- ARTEMISININ DERIVATIVES, METHODS FOR THEIR PREPARATION AND THEIR USE AS ANTIMALARIAL AGENTS
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Derivatives of the antimalarial agent artemisinin, compositions comprising the derivatives, methods for preparing the derivatives, and their uses in pharmaceutical compositions intended for the treatment of parasitic infections are provided. Methods are provided for the production of artemisinin derivatives via functionalization of positions C7 and C6a, and optionally, in conjunction with modifications at positions C10 and C9, via chemoenzymatic methods. Recombinant cytochrome P450 polypeptides are also provided for use in the methods. The artemisinin derivatives can be used for the treatment of malaria and other parasitic infections, alone or in combination with other antiparasitic drugs.
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Paragraph 0262; 0263
(2015/11/23)
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- Semisynthetic artemisinin, the chemical path to industrial production
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A new commercial-scale alternative manufacturing process to produce a complementary source of artemisinin to supplement the plant-derived supply is described by of biosynthetic artemisinic acid into semisynthetic artemisinin using diastereoselective hydrogenation and photooxidation as pivotal steps. This process was accepted by Prequalification of Medicines Programme (PQP) in 2013 as a first source of nonplant-derived-artemisinin in industrial scale from Sanofi production facility in Garessio, Italy.l scale from Sanofi production facility in Garessio, Italy.
- Turconi, Jo?l,Griolet, Frédéric,Guevel, Ronan,Oddon, Gilles,Villa, Roberto,Geatti, Andrea,Hvala, Massimo,Rossen, Kai,G?ller, Rudolf,Burgard, Andreas
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p. 417 - 422
(2014/04/17)
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- METHOD AND DEVICE FOR THE SYNTHESIS OF ARTEMISININ
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The present invention is directed to a method for producing artemisinin having the formula from dihydroartemisinic acid in a continuous flow reactor using singlet oxygen as well as to the continuous flow reactor for producing artemisinin.
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Paragraph 0532
(2015/01/06)
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- METHOD AND DEVICE FOR THE SYNTHESIS OF ARTEMISININ
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The present invention is directed to a method for producing artemisinin having the formula (6) from dihydroartennisinic acid in a continuous flow reactor using singlet oxygen as well as to the continuous flow reactor for producing artemisinin.
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Page/Page column 71; 72
(2013/03/28)
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- Method and device for the synthesis of artemisinin
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The present invention is directed to a method for producing artemisinin having the formula from dihydroartemisinic acid in a continuous flow reactor using singlet oxygen.
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Paragraph 0075; 0076
(2013/03/26)
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- High-level semi-synthetic production of the potent antimalarial artemisinin
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In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.
- Paddon,Westfall,Pitera,Benjamin,Fisher,McPhee,Leavell,Tai,Main,Eng,Polichuk,Teoh,Reed,Treynor,Lenihan,Jiang,Fleck,Bajad,Dang,Dengrove,Diola,Dorin,Ellens,Fickes,Galazzo,Gaucher,Geistlinger,Henry,Hepp,Horning,Iqbal,Kizer,Lieu,Melis,Moss,Regentin,Secrest,Tsuruta,Vazquez,Westblade,Xu,Yu,Zhang,Zhao,Lievense,Covello,Keasling,Reiling,Renninger,Newman
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p. 528 - 532
(2013/08/25)
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- Potent antimalarial 1,2,4-trioxanes through perhydrolysis of epoxides
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Perhydrolysis of a sterically congested multifunctional epoxide was achieved in ethereal H2O2 with the aid of a recently developed Mo catalyst. The resulting hydroperoxide cyclized to give a 1,2,4-trioxane, which could be readily elaborated into qinghaosu and a range of novel analogues. Some of the compounds with two such trioxane moieties showed in vitro antimalarial activity comparable to or even better than that of artesunate or chloroquine. Molybdenum magic: Facile perhydrolysis of a highly hindered epoxide was achieved with the aid of a molybdenum catalyst. The resulting hydroperoxide was readily converted into a 1,2,4-trioxane, from which natural qinghaosu (QHS, or artemisinin; see scheme) and a range of analogues were constructed. Some of the newly accessed trioxanes showed in vitro antimalarial activity comparable to or even better than that of chloroquine and artesunate. Copyright
- Hao, Hong-Dong,Wittlin, Sergio,Wu, Yikang
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p. 7605 - 7619
(2013/07/04)
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- A continuous-flow process for the synthesis of artemisinin
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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. Copyright
- Kopetzki, Daniel,Levesque, Francois,Seeberger, Peter H.
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p. 5450 - 5456
(2013/05/22)
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- TOTAL SYNTHESIS OF ARTEMISININ
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The present invention provides a method for manufacturing artemisinin and its congeners from cyclohexenone as a starting material.
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Page/Page column 18-19
(2012/12/13)
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- Photochemical process for producing artemisinin
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Provided is a new photochemical process for preparing artemisinin. Also provided are certain dihydroartemisinic acid derivatives useful for preparing artemisinin.
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- A hydrogen peroxide based access to qinghaosu (artemisinin)
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Attachment of H2O2 onto the highly hindered quaternary C-12a in an advanced qinghaosu (artemisinin) precursor has been achieved through a facile perhydrolysis of a spiro epoxy ring with the aid of a previously unknown molybdenum species without involving any special equipment or complicated operations. The resultant β-hydroxyhydroperoxide can be further elaborated into qinghaosu, illustrating an entry fundamentally different from the existing ones to this outstanding natural product of great importance in malaria chemotherapy.
- Hao, Hong-Dong,Li, Yun,Han, Wei-Bo,Wu, Yikang
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supporting information; experimental part
p. 4212 - 4215
(2011/10/18)
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- PHOTOCHEMICAL PROCESS FOR PRODUCING ARTEMISININ
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Provided is a new photochemical process for preparing artemisinin. Also provided are certain dihydroartemisinic acid derivatives useful for preparing artemisinin.
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Page/Page column 22-23; 25
(2011/04/14)
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- A concise stereoselective total synthesis of (+)-artemisinin
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A protective group free, concise, and stereoselective total synthesis of (+)-artemisinin, starting from readily available (R)-(+)-citronellal, is described. Asymmetric 1, 4-addition, Aldol condensation, Ene reaction, regioselective hydroboration are the key steps involved in the total synthesis of the target molecule.
- Yadav,Thirupathaiah,Srihari
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experimental part
p. 2005 - 2009
(2010/04/29)
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- PROCESSES FOR THE PREPARATION OF ARTEMISININ AN ITS PRECURSORS
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The present invention provides processes for the preparation of artemisinin and its precursors including amorphadiene, amorphadiene epoxide, dihydroartemisinic alcohol and dihydroartemisinic acid. Specifically, artemisinin is prepared by multi-step synthetic processes from amorphadiene, amorphadiene epoxide, dihydroartemisinic alcohol or dihydroartemisinic acid. Processes for the preparation of amorphadiene, amorphadiene epoxide, dihydroartemisinic alcohol and dihydroartemisinic acid are also disclosed.
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Page/Page column 53-54
(2009/09/04)
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- CONVERSION OF AMORPHA-4,11-DIENE TO ARTEMISININ AND ARTEMISININ PRECURSORS
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The present invention relates to methods for the conversion of amorpha-4,11-diene to artemisinin and various artemisinin precursors.
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Page/Page column 20
(2008/06/13)
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- Stereoselective total synthesis of (+)-artemisinin
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The total synthesis of the novel antimalarial drug, a sesquiterpene endoperoxide, (+)-artemisinin is described. The approach is flexible and stereoselective. The use of an intermolecular radical reaction on an intermediate iodolactone and a Wittig reaction on a ketone were employed for the synthesis.
- Yadav,Satheesh Babu,Sabitha
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p. 387 - 389
(2007/10/03)
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- Process for isolating artemisinin from artemisia annua
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The present invention relates to a process for the isolation of artemisinin, an antimalarial agent from the herb of the Artemisia annua plant, comprising of extracting the herb with ethanol, partitioning of the extract between water and hexane, followed by evaporative crystallization of artemisinin from hexane phase to produce substantially pure artemisinin.
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- The mechanism of the spontaneous autoxidation of dihydroartemisinic acid
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Dihydroartemisinic acid undergoes slow spontaneous autoxidation to artemisinin and other natural products, which have been reported from the medicinal plant Artemisia annua. The mechanism of this complex transformation is shown to involve four steps: (i) initial reaction of the Δ4.5-double bond of dihydroartemisinic acid with molecular oxygen, (ii) Hock cleavage of the resulting tertiary allylic hydroperoxide; (iii) oxygenation of the enol product from Hock cleavage; and (iv) cyclization of the resulting vicinal hydroperoxyl-aldehyde to the 1,2,4-trioxane system of artemisinin.
- Sy, Lai-King,Brown, Geoffrey D
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p. 897 - 908
(2007/10/03)
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- The role of the 12-carboxylic acid group in the spontaneous autoxidation of dihydroartemisinic acid
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Three of the four steps in the slow spontaneous autoxidation of dihydroartemisinic acid to artemisinin ('ene-type' reaction of molecular oxygen with the Δ4,5 double bond, Hock cleavage of the resulting tertiary allylic hydroperoxide, oxygenation of the enol product from Hock cleavage and cyclization of the resulting vicinal hydroperoxyl-aldehyde to the 1,2,4-trioxane system of artemisinin) are shown to be assisted by the proximity of the 12-carboxylic acid functional group in dihydroartemisinic acid to the functional groups participating in these reactions.
- Sy, Lai-King,Brown, Geoffrey D
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p. 909 - 923
(2007/10/03)
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- C-10 carbon-substituted artemisinin-like trioxane compounds having antimalarial, antiproliferative and antitumor activities
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The present invention provides a two-step procedure for the replacement of the pyranose anomeric 10-OH group in dihydroartemisinin by a variety of carbon nucleophiles, resulting in the novel C-10 carbon-substituted trioxanes of structure: wherein, when n is 1, R is selected from a group of unsubstituted or substituted aryls, heteroaryls, polyethylene glycol, acetylenics, or benzoylmethylenes, or alkanoylmethylenes; or when n is 2, R is selected from a group of unsubstituted or substituted aryls, heteroaryls, polyethylene glycol, alkenyls, alkyls, diketones or bis-acetylenes.
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- Microbial metabolism of artemisitene
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Studies on the microbial transformation of the sesquiterpene endoperoxide artemisitene have revealed that artemisitene was metabolized by Aspergillus niger (NRRL 599) to yield 11-epi-artemisinin, 9β-hydroxydeoxy- 11-epi-artemisinin and 9β-hydroxy-11-epi-artemisinnin. These metabolites were characterized on the basis of their spectral data.
- Orabi, Khaled Y.,Galal, Ahmed M.,Ibrahim, Abdel-Rahim S.,El-Feraly, Farouk S.,Khalifa, Sherief I.,El-Sohly, Hala N.
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p. 257 - 261
(2007/10/03)
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- Process for the simultaneous production of artemisnin and essential oil from the plant artemisia annua
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This invention relates to a novel process for the dual production of essential oil and artemisinin from the plant Artemisia annua, said process comprising extracting the plant with hexane, partitioning the hexane extract between hexane and acetonitrile, hydrodistillation of hexane residue and Marc to yield essential oil, further fractionation of acetonitrile solvent between hexane-benzene mixture to remove artemisinic acid, chromatographing of the acetonitrile phase to produce substantially pure artemisinin, the artemisinic acid is reduced to obtain dihydro artemisinic acid which is then oxidised in a single step to form artemisinin.
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- A process for the simultaneous production of artemisinin and essential oil from the plant artemisia annua
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The present invention relates to a novel process for the simultaneous production of essential oil and artemisinic acid optionally converted into artemisinin, from the plant Artemisia annua, comprising the following steps: a) extracting said plant with a non polar organic solvent, thereby obtaining a non polar organic extract; b) partitioning the non polar organic extract between an organic phase and an aqueous phase; c) evaporating the organic phase substantially to dryness thereby obtaining an organic phase residue, and performing a hydro-distillation of the residue preferably admixed with the plant marc yielding said essential oil d) purifying the aqueous phase to yield artemisinic acid; and e) optionally converting artemisinic acid into artemisinin. The present invention also relates both to the use of artemisinin obtained from said process as an anti-malarial drug, as well as the use of the essential oil produced from the process in perfumery, cosmetics, and aromatherapy.
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- Synthesis of (+)-Artemisinin and (+)-Deoxoartemisinin from arteannuin B and arteannuic acid
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(+)-Artemisinin and (+)-Deoxoartemisinin were prepared for the first time from arteannuin B. The synthetic route is short and efficient, making use of the prior art for the final photo-oxygenation/cyclization reaction. A convergent route to each of the above-named products from arteannuic acid is also described. A novel oxidative lactonization reaction was developed for this sequence.
- Nowak, Deanne M.,Lansbury, Peter T.
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p. 319 - 336
(2007/10/03)
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- A Total Synthesis of the Antimalarial Natural Product (+)-Qinghaosu
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Starting from (-)-β-pinene, an efficient total synthesis of the title antimalarial agent has been accomplished using an intermolecular Diels-Alder approach.
- Liu, Hsing-Jang,Yeh, Wen-Lung,Chew, Sew Yeu
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p. 4435 - 4438
(2007/10/02)
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- Antimalarial analogs of artemisinin
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Polyoxoheterocyclic tetracycles related to the Chinese antimalarial natural product qinghaosu (artemisinin) are disclosed. These materials have a STR1 core structure with an oxygen (carbonyl or alkyl ether) at position 12 and in some cases one or two alkyl or aralkyl substituents at position 11. These materials have antimalarial properties.
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