Tandem Hock and Friedel–Crafts reactions allowing an expedient synthesis of a cyclolignan-type scaffold

• Viktoria A. Ikonnikova,
• Cristina Cheibas,
• Oscar Gayraud,
• Alexandra E. Bosnidou,
• Nicolas Casaretto,
• Gilles Frison and
• Bastien Nay

Beilstein J. Org. Chem. 2024, 20, 162–169, doi:10.3762/bjoc.20.15

• C–C bond adjacent to the hydroperoxide group (Scheme 1a). The best-known application of this reaction is the cumene process, which allows the production of millions of tons of phenol each year [2]. The reaction has also been used in an industrial synthesis of artemisinin [3]. Allylic hydroperoxides

Functional characterisation of twelve terpene synthases from actinobacteria

• Anuj K. Chhalodia,
• Houchao Xu,
• Georges B. Tabekoueng,
• Binbin Gu,
• Kizerbo A. Taizoumbe,
• Lukas Lauterbach and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 1386–1398, doi:10.3762/bjoc.19.100

• artemisinin [44]. From bacteria only the α-amorphene synthase from S. viridochromogenes is known [29][30], but no enzyme for the biosynthesis of 12 has been reported before. The enzymes described here were named Streptomyces lavendulae (−)-Amorpha-4,11-diene Synthase (SlADS) and Streptomyces subrutilus

• synthase is involved in the biosynthesis of artemisinin. The newly discovered bacterial enzyme may be useful for future heterologous pathway reconstitution towards this important drug [52][53][54]. Enzymes rather closely related to known epi-isozizaene [24] and 7-epi-α-eudesmol synthases [29][30], but

• for a pathway reconstruction towards artemisinin. The increased knowledge about terpene synthases together with the structures of their products will also be of interest for machine learning approaches to enable the prediction of terpene synthase functions from their amino acid sequences. Both aspects

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• successfully treated by artemisinin combination therapy (ACT). Artemisinin can be isolated from the Artemisia annua (sweet wormwood) plant. This sesquiterpene lactone bearing a peroxide is a prodrug of the biologically active dihydroartemisinin. In 2012, Zhu and Cook developed a gram-scale asymmetric total

• synthesis of (+)-artemisinin (Scheme 55) [102]. Using the commercially available and cheap cyclohexenone 1 as starting material, they have demonstrated an economic synthesis plan in only five steps. In the first step, the Cu-catalyzed conjugate addition of Me2Zn is followed by alkylation with 1-bromobut-2

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• stationary phases is simulated by periodically shifting the two inlet and outlet ports in the direction of the mobile phase flow after a certain time. This technique was also applied to isolate artemisinin from a continuously produced reaction mixture. However, an offline crystallization had to be added to

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• considered relevant. However, this changed after the identification [219][220] of the temperature-sensitive and endoperoxide-containing qinghaosu/artemisinin (43) as the active constituent of the herb Artemisia annua to treat fever and malaria in China. For this discovery, the chemist Tu Youyou was granted

• the 2015 Nobel price. This also triggered extensive research aiming at improving the rather poor pharmacological properties of artemisinin (43) and led to many hemisynthetic derivatives [221]. Moreover, artificial peroxide-containing compounds were also investigated at least partly to address the

• high-throughput screenings [287]. This strategy is certainly visible when considering compounds 34–36 or the switch from artemisinin (43) to the peroxides 41, 42 and 44 depicted above and it is also a source of chemical challenges for instance to achieve a scaffold hoping or a bioisosteric replacements

Structural basis for endoperoxide-forming oxygenases

• Takahiro Mori and
• Ikuro Abe

Beilstein J. Org. Chem. 2022, 18, 707–721, doi:10.3762/bjoc.18.71

• ]. Artemisinin, the antimalarial agent isolated from the plant Artemisia annua [8][13][14], and ergosterol peroxides with anticancer and antiviral activities, identified in many fungi, algae, lichens, and plants, also belong to this group [15][16][17]. Due to the significant biological activities of the

• endoperoxide-containing natural products, numerous synthetic analyses and biosynthesis of endoperoxide compounds have been reported [18][19][20][21]. In some cases; e.g., in the biosynthesis of artemisinin and ergosterol peroxides, a reactive oxygen species (ROS) such as singlet oxygen, which is generated by

Chemistry of polyhalogenated nitrobutadienes, 17: Efficient synthesis of persubstituted chloroquinolinyl-1H-pyrazoles and evaluation of their antimalarial, anti-SARS-CoV-2, antibacterial, and cytotoxic activities

• Viktor A. Zapol’skii,
• Isabell Berneburg,
• Ursula Bilitewski,
• Melissa Dillenberger,
• Katja Becker,
• Stefan Jungwirth,
• Aditya Shekhar,
• Bastian Krueger and
• Dieter E. Kaufmann

Beilstein J. Org. Chem. 2022, 18, 524–532, doi:10.3762/bjoc.18.54

• decades because of its efficacy, safety, and low cost. However, the widespread resistance of Plasmodium falciparum to chloroquine has hampered efforts to combat malaria [2] resulting in artemisinin-based combination therapies as currently recommended standard. Notably, the use of chloroquine

First total synthesis of hoshinoamide A

• Haipin Zhou,
• Zihan Rui,
• Yiming Yang,
• Shengtao Xu,
• Yutian Shao and
• Long Liu

Beilstein J. Org. Chem. 2021, 17, 2924–2931, doi:10.3762/bjoc.17.201

• artemisinin derivatives [7]. The emergence of drug resistance makes the efficacy of these drugs decline year by year, forcing scientists to constantly search for new antimalarial drugs [8][9][10]. In recent years, Iwasaki and co-workers have reported three novel linear lipopeptide natural products

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• the need for directing groups, presenting a broad scope and satisfactory yields. The late-stage modification of complex molecules like (+)-artemisinin (69) and a (+)-tetrahydrogibberellic acid analogue 70 could be rapidly achieved in moderate yields (Scheme 25C). In 2014, Brown and Rasik employed

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• bearing aromatic groups were also successfully azidated, predominantly at the benzylic position (see 11e and 11f). Notably, diazidation of 9e was observed as the major side reaction (18%). Interestingly, OBz-substituted artemisinin 9g was converted to OBz-substituted N3–artemisinin 11g via azidation at

Dawn of a new era in industrial photochemistry: the scale-up of micro- and mesostructured photoreactors

• Emine Kayahan,
• Mathias Jacobs,
• Leen Braeken,
• Leen C.J. Thomassen,
• Simon Kuhn,
• Tom van Gerven and
• M. Enis Leblebici

Beilstein J. Org. Chem. 2020, 16, 2484–2504, doi:10.3762/bjoc.16.202

• treatment installations [2]. In addition, artemisinin, which is a drug to treat malaria, was produced in an industrial-scale photoreactor in a Sanofi production facility in Italy [3]. Furthermore, the production of some fine chemicals, such as ε-caprolactam, rose oxide, and vitamin D on an industrial scale

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

• postsynthetic modifications in flow [63]. Poliakoff, George, and co-workers reported a porphyrin photosensitiser ionically immobilised to sulphonate-cross-linked ion exchange polystyrene resins (amberlyst-15) for the synthesis of artemisinin (49). This resulted in a bifunctional material, which acts as a HPCat

Recent applications of porphyrins as photocatalysts in organic synthesis: batch and continuous flow approaches

• Rodrigo Costa e Silva,
• Luely Oliveira da Silva,
• Aloisio de Andrade Bartolomeu,
• Timothy John Brocksom and
• Kleber Thiago de Oliveira

Beilstein J. Org. Chem. 2020, 16, 917–955, doi:10.3762/bjoc.16.83

• -flow with O2). One very relevant example of a photooxygenation protocol is the Seeberger group’s semi-synthesis of the antimalarial API artemisinin (Scheme 32) [79]. They have established a gram-scale continuous protocol with a photooxygenation promoted by TPP starting from dihydroartemisinic acid

• . This work is crucial for the success of the subsequent industrial process introduced by the pharmaceutical company Sanofi [80]. After this seminal publication, a consortium between Sanofi and UK/China universities also reported a green protocol for artemisinin synthesis using supercritical CO2 as a

• novelty (Scheme 33) [81]. They have also used TPP (immobilized acidic form) as photosensitizer and were able to produce up to 2.4 g of artemisinin per batch. The importance of artemisinin for Big Pharma has been confirmed during the last 20–30 years with many relevant publications. As mentioned before

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• metathesis as a key step, we herein survey representative examples where this reaction is effectively associated with traditional chemical transformations to produce bioactive synthetic targets. Review Artemisinin and nanolobatolide Due to its biological relevance, artemisinin, a tricyclic compound bearing a

• peroxide bridge, has been subject of extensive scientific investigations during the last decade [53][54][55][56][57][58][59][60][61][62][63]. In this context, Seeberger and co-workers successfully developed an ingenious continuous-flow process for the hemisynthesis of pure artemisinin from

• dihydroartemisinic acid (DHAA) [64][65]. Also, high efficient and recyclable catalytic systems based on metal-organic frameworks (MOFs) have also been reported for the tandem hemisynthesis of artemisinin [66]. In a remarkable work, this antimalarial drug was obtained by a new route involving enyne metathesis as the

Terpenes

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 2966–2967, doi:10.3762/bjoc.15.292

• taxol from Taxus brevifolia that is used to treat breast and other types of solid cancers, while artemisinin from Artemisia annua is used as a cure against malaria [4]. This thematic issue covers all different aspects of terpene chemistry and biochemistry, including compound isolation and structure

Bacterial terpene biosynthesis: challenges and opportunities for pathway engineering

• Eric J. N. Helfrich,
• Geng-Min Lin,
• Christopher A. Voigt and
• Jon Clardy

Beilstein J. Org. Chem. 2019, 15, 2889–2906, doi:10.3762/bjoc.15.283

• restricted members possess significant biological activities, like the anticancer agent taxol (1) [4] or the antimalarial agent artemisinin (2, Figure 1) [5][6]. The structural diversity and functional utility of this class of specialized metabolites have combined to encourage efforts to apply the tools of

Harnessing enzyme plasticity for the synthesis of oxygenated sesquiterpenoids

• Melodi Demiray,
• David J. Miller and
• Rudolf K. Allemann

Beilstein J. Org. Chem. 2019, 15, 2184–2190, doi:10.3762/bjoc.15.215

• synthesised in amorphadiene synthase-catalysed reactions from 8- and 12-methoxyfarnesyl diphosphates due to the highly plastic yet tightly controlled carbocationic chemistry of this sesquiterpene cyclase. Keywords: artemisinin; amorphadiene synthase; oxygenated terpenoids; sesquiterpenoids; substrate

• engineering; terpenes; Introduction Amorphadiene synthase (ADS) from Artemisia annua is a key enzyme involved in the biosynthesis of the antimalarial sesquiterpene drug artemisinin (1) [1][2][3][4]. ADS catalyses the Mg2+-dependent conversion of farnesyl diphosphate (FDP, 2) to amorpha-4,11-diene (3) with

• nevertheless allows the conversion of 12-hydroxy-FDP (9) to dihydroartemisinic aldehyde (10), a biosynthetic intermediate and valuable precursor in the synthesis of artemisinin [29]. Results and Discussion Here we report that ADS accepts the bulkier FDP analogues 8-methoxy-FDP (11) and 12-methoxy FDP (12) as

Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica

• Silvie Rimpelová,
• Michal Jurášek,
• Lucie Peterková,
• Jiří Bejček,
• Vojtěch Spiwok,
• Miloš Majdl,
• Michal Jirásko,
• Miloš Buděšínský,
• Juraj Harmatha,
• Eva Kmoníčková,
• Pavel Drašar and
• Tomáš Ruml

Beilstein J. Org. Chem. 2019, 15, 1933–1944, doi:10.3762/bjoc.15.189

• . Immunobiological properties of compound 1 SLs, natural compounds predominantly isolated from the species Asteraceae and Apiaceae represent a rich source of small molecules with potential pharmacological effects. Indeed, some of them have reached clinical applications as antimalarial (artemisinin; [24]) or

Synthesis and biological investigation of (+)-3-hydroxymethylartemisinin

• Toni Smeilus,
• Farnoush Mousavizadeh,
• Johannes Krieger,
• Xingzhao Tu,
• Marcel Kaiser and
• Athanassios Giannis

Beilstein J. Org. Chem. 2019, 15, 567–570, doi:10.3762/bjoc.15.51

• , Socinstrasse 57, 4051 Basel, Switzerland University of Basel, Petersplatz 1, 4003 Basel, Switzerland 10.3762/bjoc.15.51 Abstract Herein, we describe a biomimetic entry to (+)-3-hydroxymethylartemisinin (2) as well as to the artemisinin derivatives (+)-3-hydroxymethyl-9-desmethylartemisinin (16) and (+)-3

• -hydroxymethyl-9-epi-artemisinin (18), starting from the known and readily available chiral aldehyde 3 and alkyne 4. Subsequently, the synthesized compounds have been evaluated for their antimalarial activity against the drug-sensitive P. falciparum NF54 strain. All of them were inactive. In addition, they did

• not show any toxicity against L6 cells (a primary cell line derived from rat skeletal myoblasts). These results contribute to a better understanding of artemisinins mechanism of action. Keywords: artemisinin; biomimetic synthesis; Diels–Alder reaction; malaria; peroxides; Introduction The isolation

Opportunities and challenges for the sustainable production of structurally complex diterpenoids in recombinant microbial systems

• Katarina Kemper,
• Max Hirte,
• Markus Reinbold,
• Monika Fuchs and
• Thomas Brück

Beilstein J. Org. Chem. 2017, 13, 845–854, doi:10.3762/bjoc.13.85

• ), artemisinin [2] (antimalarial agent) and α-pinene [3] (antibiotic, anti-inflammatory). Apart from bioactive compounds with applications as drugs/pharmaceuticals [4] or in the nutrition or agricultural sector, isoprenoids of minor structural complexity are used as bulk chemicals or fuel additives [5][6]. To

• -pinene or limonene [78]. At present, 27.4 g/L of amorphadiene is the highest published titer for any reported terpenoid produced in E. coli. This result is of particular industrial relevance as amorphadiene constitutes the sesquiterpenoid scaffold of the antimalarial drug artemisinin [79]. In comparison

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• is compatible with sensitive functional groups such as silyl ether, halogenes, and benzyl groups. A very nice application of this approach was the highly selective reduction of artemisinic acid to dihydroartemisinic acid, which are of interest in the synthesis of the antimalarial drug artemisinin

A flow reactor setup for photochemistry of biphasic gas/liquid reactions

• Josef Schachtner,
• Patrick Bayer and
• Axel Jacobi von Wangelin

Beilstein J. Org. Chem. 2016, 12, 1798–1811, doi:10.3762/bjoc.12.170

• photooxidations of citronellol [35][40][41][42], indanes [43], monoterpenes [36], furans [42], furfurals [44], thiols [37] and amines [45] as well as the syntheses of ascaridol [46] and artemisinin [47]. Related microreactor setups were applied to biphasic gas/liquid mixtures in the photochlorination of

Rearrangements of organic peroxides and related processes

• Ivan A. Yaremenko,
• Vera A. Vil’,
• Dmitry V. Demchuk and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2016, 12, 1647–1748, doi:10.3762/bjoc.12.162

• processes of important natural and synthetic peroxides are discussed separately. Keywords: artemisinin; Baeyer−Villiger; Criegee; Hock; peroxide; rearrangement; Introduction The chemistry of organic peroxides has more than a hundred-year history. Currently, organic peroxides are widely used as oxidizing

• six-membered 1,2-dioxane [40][41][42], 1,2-dioxene [43], 1,2,4-trioxane [22][44][45] cycles. The naturally occuring peroxide artemisinin and its semisynthetic derivatives, artemether, arteether, and artesunate, are applied in large scale for malaria treatment [46][47]. Organic peroxides, their

• photochemical route developed for the synthesis of artemisinin the Hock rearrangement of hydroperoxide 223 selectively affords enol 224. This reactive intermediate 224 is then finally oxidized into artemisinin (Scheme 66) [334]. 1.4 Kornblum−DeLaMare rearrangement The Kornblum−DeLaMare rearrangement (KDLM) is a

Natural products in synthesis and biosynthesis II

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 413–414, doi:10.3762/bjoc.12.44

• Sciences) for the discovery of the terpenoid antimalaria drug artemisinin that is produced by the plant Artemisia annua [3], and to Satoshi Õmura and William C. Campbell for the discovery of avermectins isolated from the actinobacterium Streptomyces avermitilis at the famous Kitasato Institute and for the

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• products and are remarkably diverse in structure, bioactivity, and use. Prominent examples such as the antimalaria drug artemisinin (28) from Artemisia annua, ingenol (29) and its derivatives from Euphorbia ingens [56], or the anticancer drug paclitaxel (30) feature highly functionalized polycyclic carbon

• stereocenters deduced from labeling experiments. Structure of thiomarinol A (27). Bold bonds indicate carbon atoms derived from 4-hydroxybutyrate. Structures of artemisinin (28), ingenol (29) and paclitaxel (30). The revised (31) and the previously suggested (32) structure of hypodoratoxide and the structure of