Correction to Semisynthetic Artemisinin, the Chemical Path to Industrial Production

Turconi, Joël; Griolet, Frédéric; Guével, Ronan Le; Oddon, G.; Villa, Roberto Edoardo; Geatti, Andrea; Hvala, Massimo; Rossen, Kai; Göller, Rudolf; Burgard, Andreas

doi:10.1021/op5001397

Cited by 6 publications

(3 citation statements)

References 2 publications

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“…To address this issue, a semisynthetic route for producing artemisinin has been implemented on a process scale by Sanofi. 83,84 This work has gathered much attention in recent years, not only for its innovation in combining biotechnology with a photochemical reaction, but also serving as an inspiring example of how academia (UC Berkeley), industry (Sanofi, Amyris), non-profit organizations (NRC, Canada, OneWorld Health), as well as funding agencies (WHO, Bill & Melinda Gates Foundation), can form a powerful alliance to deliver innovative solutions to global challenges. The major breakthrough in this remarkable story began with the genetic engineering of Baker's yeast to produce artemisinic acid, a precursor to the mixed anhydride 20.…”

Section: Reaction Chemistry and Engineering Reviewmentioning

confidence: 99%

Aerobic oxidations in flow: opportunities for the fine chemicals and pharmaceuticals industries

et al. 2016

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Molecular oxygen is without doubt the greenest oxidant for redox reactions, yet aerobic oxidation is one of the most challenging to perform with good chemoselectivity, particularly on an industrial scale. This collaborative review (between teams of chemists and chemical engineers) describes the current scientific and operational hurdles that prevent the utilisation of these reactions for the production of speciality chemicals and active pharmaceutical ingredients (APIs). The safety aspects of these reactions are discussed, followed by an overview of (continuous flow) reactors suitable for aerobic oxidation reactions that can be applied on scale. Some examples of how these reactions are currently performed in the industrial laboratory (in batch and in flow) are presented, with particular focus on the scale-up strategy. Last but not least, further challenges and future perspectives are presented in the concluding remarks

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Section: Reaction Chemistry and Engineering Reviewmentioning

confidence: 99%

Aerobic oxidations in flow: opportunities for the fine chemicals and pharmaceuticals industries

et al. 2016

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“…In particular, the use of photosensitizers allowing the energy transfer from the sensitizer to a substrate and/or a reagent is relevant for benzylic halogenation . If the scale-up of photochemical reactions in batch is limited to specific targets, , then flow chemistry exhibits great potential for large-scale processes …”

Section: Introductionmentioning

confidence: 99%

Selective Photochemical Continuous Flow Benzylic Monochlorination

Radjagobalou

Imbratta²,

Bergraser³

et al. 2022

Org. Process Res. Dev.

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A selective photochemical monochlorination of 2-fluorotoluene has been developed by a continuous flow process using two different flow reactors, one for the tuning of the conditions and the second one for the scale-up. The key reaction parameters were optimized using one-factor-at-a-time and design of experiment methods, with the goal of minimizing the formation of the dichlorinated by-product. This transformation has been performed on a multi decagram scale.

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“…Although the biosynthesis of DHAA has been demonstrated (Zhang et al, 2008), the productivity (about 15.7 mg/L) has not yet to be optimized in a heterologous host. Although hydrogenation conversion of AA to DHAA was efficient (conversion efficiency 99%), the production of unexpected isoform (R, S)-DHAA (about 6%) was not avoided (Paddon et al, 2013;Turconi et al, 2014;Pieber et al, 2015). Instead, biosynthesis of DHAA produced very little (R, S) isomer in yeast (Zhang et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Engineering of Saccharomyces cerevisiae for Enhanced Dihydroartemisinic Acid Production

Zeng

Yao

Wang

et al. 2020

Front. Bioeng. Biotechnol.

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Direct bioproduction of DHAA (dihydroartemisinic acid) rather than AA (artemisinic acid), as suggested by previous work would decrease the cost of semi-biosynthesis artemisinin by eliminating the step of initial hydrogenation of AA. The major challenge in microbial production of DHAA is how to efficiently manipulate consecutive key enzymes ADH1 (artemisinic alcohol dehydrogenase), DBR2 [artemisinic aldehyde 11(13) reductase] and ALDH1 (aldehyde dehydrogenase) to redirect metabolic flux and elevate the ratio of DHAA to AA (artemisinic acid). Herein, DHAA biosynthesis was achieved in Saccharomyces cerevisiae by introducing a series of heterologous enzymes: ADS (amorpha-4,11-diene synthase), CYP71AV1 (amorphadiene oxidase), ADH1, DBR2 and ALDH1, obtaining initial DHAA/AA ratio at 2.53. The flux toward DHAA was enhanced by pairing fusion proteins DBR2-ADH1 and DBR2-ALDH1, leading to 1.75-fold increase in DHAA/AA ratio (to 6.97). Moreover, to promote the substrate preference of ALDH1 to dihydroartemisinic aldehyde (the intermediate for DHAA synthesis) over artemisinic aldehyde (the intermediate for AA synthesis), two rational engineering strategies, including downsizing the active pocket and enhancing the stability of enzyme/cofactor complex, were proposed to engineer ALDH1. It was found that the mutant H194R, which showed better stability of the enzyme/NAD + complex, obtained the highest DHAA to AA ratio at 3.73 among all the mutations. Then the mutant H194R was incorporated into above rebuilt fusion proteins, resulting in the highest ratio of DHAA to AA (10.05). Subsequently, the highest DHAA reported titer of 1.70 g/L (DHAA/AA ratio of 9.84) was achieved through 5 L bioreactor fermentation. The study highlights the synergy of metabolic engineering and protein engineering in metabolic flux redirection to get the most efficient product to the chemical process, and simplified downstream conversion process.

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Correction to Semisynthetic Artemisinin, the Chemical Path to Industrial Production

Cited by 6 publications

References 2 publications

Aerobic oxidations in flow: opportunities for the fine chemicals and pharmaceuticals industries

Aerobic oxidations in flow: opportunities for the fine chemicals and pharmaceuticals industries

Selective Photochemical Continuous Flow Benzylic Monochlorination

Metabolic Engineering of Saccharomyces cerevisiae for Enhanced Dihydroartemisinic Acid Production

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