110715-68-9

Usage

Uses

Used in Pharmaceutical Industry:
(S)-dihydroartemisinic acid is used as an antimalarial compound for its effectiveness against the malaria parasite. It plays a crucial role in the development of new and improved treatments for malaria due to its potent activity and potential for synthesis into artemisinin and its derivatives.
Used in Chemical Synthesis:
(S)-dihydroartemisinic acid is used as a precursor in the synthesis of artemisinin and its derivatives, which are vital for creating new antimalarial drugs and treatments. Its potential in this application is a result of its effectiveness and the ongoing research into its properties and uses.

Upstream product

• 80286-58-4 artemisinic acid 
• 917-54-4 methyllithium 
• 103740-02-9 2-(4-methyl-7-oxo-(1α-H),2,3,(4β-H),(4aα-H),5,6,7,8,(8aα-H)-decahydronaphthalen-1-yl)propionic acid 
• 93913-62-3 3(R)-methyl-6(S)-<1(R)-methyl-2-(phenylmethoxy)ethyl>-2(S)-(3-oxobutyl)cyclohexanone 
• 93913-63-4 1α-Δ⁵-10α-methyl-7β-<2'β-(1'-benzyloxy)-propyl>-decalone-4 
• 63968-64-9 C₁₂H₁₃O₂(CH₃)3(O)(OO) 
• 855425-51-3 dihydroartemisinic aldehyde 
• 92692-39-2 (1R,4R,4aS,8aR)-4,7-dimethyl-1-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,8a-octahydronaphthalene 
• 125184-93-2 (R)-2-[(1R,4R,4aS,8aS)-4,7-Dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalen-1-yl]propanal 
• 160454-01-3 <4a(S),8a(S)>-octahydro-5(R)-methyl-8(R)-<1(R)-methyl-2-hydroxyethyl>-2(1H)-naphthalenone 
• 84051-31-0 <1R>-5(R)-methyl-2(S)-<1(R)-methyl-2-(phenylmethoxy)ethyl>cyclohexanol 
• 84051-32-1 (2S,5R)-2-((R)-1-(benzyloxy)propan-2-yl)-5-methylcyclohexanone 
• 7786-67-6 isopulegol 
• 13834-07-6 (1R,3R,4S,8R)-9-hydroxy-p-menthol 

Downstream Products

• 105250-95-1 (R)-2-[(1R,2S,3S,4R)-2-Formyl-4-methyl-3-(3-oxo-butyl)-cyclohexyl]-propionic acid 
• 63968-64-9 C₁₂H₁₃O₂(CH₃)3(O)(OO) 
• 104196-16-9 (3R,3a,6R,6aS,10aS)-3a,4,5,6,6a,7,8,8a-octahydro-3,6,9-trimethylnaphtho[8a,1-b]furan-2(3H)-one 
• 207446-83-1 arteanniun H 
• 85031-60-3 4α-hydroperoxy-amorph-5-en-12-oic acid 
• 71816-53-0 (R)-3,6,9-Trimethyl-decahydro-benzo[de]chromen-2-one 
• 141377-47-1 (3R,6R,10aS)-3,6-Dimethyl-9-methylene-decahydro-1,10-dioxa-cyclohepta[de]naphthalen-2-one 
• 78092-22-5 (6R,10aR)-6,9-Dimethyl-3-methylene-3,3a,4,5,6,6a,7,8-octahydro-1-oxa-cyclopenta[d]naphthalen-2-one 
• 82462-58-6 Dihydro-epi-deoxyarteannuin B 
• 63968-64-9 artemisinic acid 
• 422565-48-8 (R)-2-[(1S,3S,4R)-2-Formyl-2-[(2R,4aS,5R,8S)-8-((R)-1-methoxycarbonyl-ethyl)-2,5-dimethyl-2,3,4,4a,5,6,7,8-octahydro-naphthalen-2-ylperoxy]-4-methyl-3-(3-oxo-butyl)-cyclohexyl]-propionic acid methyl ester 
• 256643-66-0 (1R,2S,3R,6S)-6-Isopropyl-3-methyl-2-(3-oxo-butyl)-cyclohexanecarbaldehyde 
• 103775-34-4 (R)-2-[(1R,2S,3S,4R)-2-Formyl-4-methyl-3-(3-oxo-butyl)-cyclohexyl]-propionic acid methyl ester 
• 380487-65-0 α-epoxy-dihydroartemisinic acid 

Relevant academic research and scientific papers

High-level semi-synthetic production of the potent antimalarial artemisinin

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.

Synthesis of labelled dihydroartemisinic acid

[15-13C2H3]-Dihydroartemisinic acid (2a), [15-C2H3]-dihydroartemisinic acid (2b) and [15- 13CH3]-dihydroartemisinic acid (2c) have been obtained in good yield and high isotopic enrichment by a reconstructive synthesis from artemisinin. These labelled compounds were designed to be used in biosynthetic experiments to determine the origins of artemisinin and other sesquiterpene natural products from Artemisia annua.

Online Stereochemical Process Monitoring by Molecular Rotational Resonance Spectroscopy

A molecular rotational resonance (MRR) spectrometer designed to monitor the product composition of an asymmetric continuous flow reaction online is presented. The MRR technique is highly sensitive to small changes in molecular structure and, as such, is capable of rapidly quantifying isomers as well as other impurities in a complex mixture, without chromatographic separation or chemometrics. The spectrometer in this study operates by automatically drawing a portion of the reaction solution into a reservoir, volatizing it by heating, and measuring the highly resolved MRR spectra of each of the components of interest in order to determine their relative quantity in the mixture. The reaction under study was the hydrogenation of artemisinic acid, an intermediate step in the semisynthesis of the antimalarial drug artemisinin. Four analytes were characterized in each measurement: the starting material, the product, a diastereomer of the product, and an overreduction byproduct that was not directly quantifiable by either HPLC or NMR methods. The MRR instrument has a measurement cycle time of approximately 17 min for this analysis and can run for several hours without any user interaction.

An Efficient Chemoenzymatic Synthesis of Dihydroartemisinic Aldehyde

Artemisinin from the plant Artemisia annua is the most potent pharmaceutical for the treatment of malaria. In the plant, the sesquiterpene cyclase amorphadiene synthase, a cytochrome-dependent CYP450, and an aldehyde reductase convert farnesyl diphosphate (FDP) into dihydroartemisinic aldehyde (DHAAl), which is a key intermediate in the biosynthesis of artemisinin and a semisynthetic precursor for its chemical synthesis. Here, we report a chemoenzymatic process that is able to deliver DHAAl using only the sesquiterpene synthase from a carefully designed hydroxylated FDP derivative. This process, which reverses the natural order of cyclization of FDP and oxidation of the sesquiterpene hydrocarbon, provides a significant improvement in the synthesis of DHAAl and demonstrates the potential of substrate engineering in the terpene synthase mediated synthesis of high-value natural products.

Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin

Malaria, caused by Plasmodium sp, results in almost one million deaths and over 200 million new infections annually. The World Health Organization has recommended that artemisinin-based combination therapies be used for treatment of malaria. Artemisinin is a sesquiterpene lactone isolated from the plant Artemisia annua. However, the supply and price of artemisinin fluctuate greatly, and an alternative production method would be valuable to increase availability. We describe progress toward the goal of developing a supply of semisynthetic artemisinin based on production of the artemisinin precursor amorpha-4,11-diene by fermentation from engineered Saccharomyces cerevisiae, and its chemical conversion to dihydroartemisinic acid, which can be subsequently converted to artemisinin. Previous efforts to produce artemisinin precursors used S. cerevisiae S288C overexpressing selected genes of the mevalonate pathway [Ro et al. (2006) Nature 440:940-943]. We have now overexpressed every enzyme of the mevalonate pathway to ERG20 in S. cerevisiae CEN.PK2, and compared production to CEN.PK2 engineered identically to the previously engineered S288C strain. Overexpressing every enzyme of the mevalonate pathway doubled artemisinic acid production, however, amorpha-4,11-diene production was 10-fold higher than artemisinic acid. We therefore focused on amorpha-4,11-diene production. Development of fermentation processes for the reengineered CEN.PK2 amorpha-4,11-diene strain led to production of >40 g/L product. A chemical process was developed to convert amorpha- 4,11-diene to dihydroartemisinic acid, which could subsequently be converted to artemisinin. The strains and procedures described represent a complete process for production of semisynthetic artemisinin.

Semisynthetic artemisinin, the chemical path to industrial production

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.

Preparation method for key intermediate for synthesis of artemisinin compounds

The invention relates to the technical field of organic chemical engineering, in particular to an asymmetric preparation method for synthesizing an artemisinin compound synthesis key intermediate dihydroartemisinic acid. When the intermediate is applied to synthesis of artemisinin compounds, the operation is simple and convenient, the yield and the product purity are improved, and industrial application is easy.

Chemical semi-synthesis method of artemisinin

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.

Preparation method of artemisinin

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.

Concise synthesis of artemisinin from a farnesyl diphosphate analogue

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.