molecules Review
Synthetic Strategies for Peroxide Ring Construction in Artemisinin Vera A. Vil’ 1,2,3 , Ivan A. Yaremenko 1,2,3 , Alexey I. Ilovaisky 1 and Alexander O. Terent’ev 1,2,3, * 1 2 3
*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prospekt, Moscow 119991, Russia;
[email protected] (V.A.V.);
[email protected] (I.A.Y.);
[email protected] (A.I.I.) Faculty of Chemical and Pharmaceutical Technology and Biomedical Products, D. I. Mendeleev University of Chemical Technology of Russia, 9 Miusskaya Square, Moscow 125047, Russia All-Russian Research Institute for Phytopathology, 143050 B. Vyazyomy, Moscow Region, Russia Correspondence:
[email protected]; Tel.: +7-916-385-4080
Academic Editor: Svetlana B. Tsogoeva Received: 25 December 2016; Accepted: 9 January 2017; Published: 11 January 2017
Abstract: The present review summarizes publications on the artemisinin peroxide fragment synthesis from 1983 to 2016. The data are classified according to the structures of a precursor used in the key peroxidation step of artemisinin peroxide cycle synthesis. The first part of the review comprises the construction of artemisinin peroxide fragment in total syntheses, in which peroxide artemisinin ring resulted from reactions of unsaturated keto derivatives with singlet oxygen or ozone. In the second part, the methods of artemisinin synthesis based on transformations of dihydroartemisinic acid are highlighted. Keywords: artemisinin; artemisinic acid; organic peroxide; peroxidation; cycles
1. Introduction In accordance with World Health Organization reports, malaria is one of the most widespread diseases, with 149–303 million of new malaria cases and 438,000 malaria deaths registered in 2015 all over the world. The largest number of new infection cases occur in the African Region (88%), the second one in Southeast Asia (10%), and the third in the Eastern Mediterranean (2%) [1]. Malaria is an infection caused by unicellular organisms of the Plasmodium type parasites. The growth and development of the parasites in red blood cells determine the pathology of malaria. In most cases, the disease is initiated by Plasmodium falciparum infection, although P. vivax, P. ovale, P. malariae, and P. knowlesi infection also cause malaria [2,3]. Traditionally, some drugs, such as quinine, chloroquine, mefloquine, doxycycline, and other antiparasitic ones, have been used for malaria treatment. However, the development of antibiotic resistance of Plasmodium significantly reduced the efficacy of therapy [4,5]. Much effort has been directed toward the treatment and prevention of malaria; as a result, the incidence of malaria (new cases of infection) reduced by 37% worldwide and by 42% in the African Region from 2000 to 2015. Over the same period, the rate of malaria deaths decreased by 60% worldwide and by 66% in the African Region [1]. Such impressive results have been achieved due to a complex of measures: insecticide-treated mosquito nets (ITNs), indoor residual spraying (IRS), rapid diagnostic testing (RDTs), and mainly artemisinin-based combination therapy (ACT) [6,7]. Artemisinin-based combination therapy (ACT) is highly efficient against malaria caused by P. falciparum, which is the most abundant and pathogenic type of Plasmodium for humans [8]. Artemisinin (Qinghaosu) (1) is a natural peroxide with high antimalarial activity [9,10]. It has been playing a key role in malaria treatment over the past several decades. Artemisinin was isolated from Artemisia annua for the first time in 1971 in the context of the scientific program “Project 523”, Molecules 2017, 22, 117; doi:10.3390/molecules22010117
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initiated by the Chinese government in 1967 [11–13]. The Nobel Prize in Physiology or Medicine pharmaceutical chemist chemist Tu Tu Youyou “for her discoveries concerning a 2015 was awarded to Chinese pharmaceutical novel therapy against Malaria” [14–16]. drugs is largely limited by their [17,18]. isolation The availability availabilityofofartemisinin-based artemisinin-based drugs is largely limited byhigh theircost high cost Its [17,18]. Its from Artemisia annua is still the main way for artemisinin production [19–21]. Full cycle time is isolation from Artemisia annua is still the main way for artemisinin production [19–21]. Full cycle 12–18 while overall yield ofyield isolated artemisinin is usually less than 1 wt % [22,23]. time ismonths, 12–18 months, while overall of isolated artemisinin is usually less than 1 wt % [22,23]. As a result, the production of a sufficient amount of artemisinin with the use of only an isolation The problem of the sustainable manufacturing of method remains an extremely challenging task. The canbe besolved solvedthrough througha nontransgenic a nontransgenic method (selection, variation of nutrients artemisinin can method [24][24] (selection, variation of nutrients and and ambient conditions, of test-tube cultures [25]), theuse useofoftransgenic transgenicA. A. annua annua [26], [26], ambient conditions, and and the the use use of test-tube cultures [25]), the heterologous transgenic transgenic systems systems [27,28] [27,28] (introduction (introduction of of genes genes encoding encoding the artemisinin biosynthesis heterologous into others cultures), semi-synthetic approaches based on available relative structures [29] and total synthesis [30] (Figure 1). heterologous transgenic systems (modified E. coli, S. cerevisiae et al.)
H isolation from nontransgenic or transgenic Artemisia Annua
O O O H O
H
semi-synthesis from others metabolites A.annua
O artemisinin (1)
total synthesis Figure 1. Main strategies for artemisinin production. Figure 1. Main strategies for artemisinin production.
Synthetic strategies for artemisinin production have been reported in several reviews [31–35]. Synthetic strategies for artemisinin productionofhave been reported in several reviews [31–35]. The interdisciplinary approaches to the preparation artemisinin were demonstrated by Abdin et al. The interdisciplinary approaches to the preparation of artemisinin were demonstrated by Abdin et al. [36] [36] and Corsello et al. [37]. Semi-synthetic methods for artemisinin (1) production from artemisinic (3) and Corsello et al. [37]. Semi-synthetic methods for artemisinin (1) production from artemisinic (3) and and dihydroartemisinic (4) acids, more available metabolites of Artemisia annua, were shown in two dihydroartemisinic (4) acids, more available metabolites of Artemisia annua, were shown in two other other reviews [38,39]. reviews [38,39]. 1,2,4-Trioxolane cycle spiro-conjugated with lactone is the key pharmacophore fragment in 1,2,4-Trioxolane cycle spiro-conjugated lactone is the keyboth pharmacophore fragment in artemisinin. The construction of this fragment iswith the most difficult stage in synthetic and biological artemisinin. The construction of this fragment is the most difficult stage both in synthetic and biological approaches to artemisinin production. The construction of peroxide fragment of artemisinin is carried approaches to final artemisinin production. of peroxide fragment of artemisinin is carried out mainly in synthetic steps withThe theconstruction use of one-pot peroxidation/cyclization reactions. out mainly in final synthetic steps with the use of one-pot peroxidation/cyclization reactions. The present review is devoted to the strategies for construction of artemisinin peroxide fragment in The present review is devoted to the strategies of the artemisinin peroxide fragment in synthetic and semi-synthetic approaches (Schemefor 1).construction According to published data, unsaturated synthetic and semi-synthetic approaches (Scheme 1). According published data, unsaturated keto keto derivatives 2 (route A) or dihydroartemisinic acid (4) (routetoB)the serve as the precursor substance on derivatives 2 (route A) or dihydroartemisinic acid (4) (route B) serve as the precursor substance on final final peroxidation/cyclization step in artemisinin synthesis. Synthetic methods where dihydroartemisinic peroxidation/cyclization step in artemisinin Synthetic methods where(1) dihydroartemisinic acid (4) obtained from artemisinic acid (3) issynthesis. directly oxidized into artemisinin (route B) deserve acid (4) obtained from artemisinic acid (3) is directly oxidized into artemisinin (1) (route B) deserve special attention, due to the fact that these approaches form the basis of modern methods of artemisinin special attention, due to the fact that these approaches form the basis of modern methods of artemisinin production [40]. In 2013, the Sanofi company launched the semi-synthetic artemisinin manufacturing production [40]. In 2013, the Sanofi company launched semi-synthetic artemisinin manufacturing based on photooxidation of dihydroartemisinic acid (4)the [41]. based on photooxidation of dihydroartemisinic acid (4) [41].
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Scheme 1. Peroxidation steps based on the formation of hydroperoxides in synthetic approaches to Scheme 1. Peroxidation steps based on the formation of hydroperoxides in synthetic approaches to artemisinin (1). artemisinin (1).
In the peroxidation step, the unsaturated keto derivative 2 initially forms the hydroperoxyaldehyde In the peroxidation step, the unsaturated ketoofderivative 2 initially forms the hydroperoxyaldehyde 6, cyclizing into artemisinin (1) under the action acids. Peroxidation of dihydroartemisinic acid (4) 6, cyclizing under the action of was acids. Peroxidation of dihydroartemisinic acid (4) starts frominto theartemisinin formation of(1) intermediate 5, which converted into artemisinin (1) via compound starts from the formation intermediate 5, which wasprimarily converted into artemisinin 6. Consequently, in the of present review, the data are classified according(1) to via the compound structures 6. of final precursors and 4 and secondly according to the peroxidation methods. Consequently, in the 2present review, the data are primarily classified according to the structures of final precursors 2 and 4 and secondly according to the peroxidation methods. 2. Construction of Artemisinin Peroxide Fragment in Total Synthesis 2. Construction of Artemisinin Peroxide Fragment in Total Synthesis 2.1. Using Singlet Oxygen 2.1. Using Singlet Oxygen In 1983, Schmid and Hofheinz presented the first example of artemisinin (1) total synthesis In 1983, Schmid Hofheinz presented the first example of used artemisinin (1) total synthesis (Scheme 2) [30]. The and available terpene alcohol, (−)-isopulegol (7), was as a starting compound. The ketone 8 was from (−)-isopulegol (7) in five steps with a 58% Later, it was (Scheme 2) [30]. Thesynthesized available terpene alcohol, (−)-isopulegol (7), was used as ayield. starting compound. alkylated Stork–Jung vinylsilane with the formation silylated with a Later, 62% yield. The ketone by 8 was synthesized from iodide (−)-isopulegol (7) in fiveofsteps withketone a 58%9 yield. it was The key intermediate 12 was synthesized from silylated ketone 9 in four steps. After the treatment of alkylated by Stork–Jung vinylsilane iodide with the formation of silylated ketone 9 with a 62% yield. ketone 9 by excess of TMSCH(OMe)Li, the major diastereomer 10 was isolated with an 89% yield (ratio The key intermediate 12 was synthesized from silylated ketone 9 in four steps. After the treatment diastereomers 8:1).ofThe lactone 11 prepared successive debenzylation oxidation alcohol 10 of of ketone 9 by excess TMSCH(OMe)Li, the by major diastereomer 10 wasand isolated withofan 89% yield was transformed into enol ether 12 by TBAF (tetra-n-butylammonium fluoride). Ene reaction of enol (ratio of diastereomers 8:1). The lactone 11 prepared by successive debenzylation and oxidation of 1О2 and subsequent acid-catalyzed cyclization of obtained hydroperoxide led to desired ether 10 12 was withtransformed alcohol into enol ether 12 by TBAF (tetra-n-butylammonium fluoride). Ene reaction artemisinin (1) with1a 30% yield. The total yield was 5% in 14 steps. of enol ether 12 with O2 and subsequent acid-catalyzed cyclization of obtained hydroperoxide led to desired artemisinin (1) with a 30% yield. The total yield was 5% in 14 steps.
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Scheme 2. Total synthesis of artemisinin by Schmid and Hofheinz. Scheme 2. Total synthesis of artemisinin by Schmid and Hofheinz.
Zhou et al. demonstrated the second example of artemisinin total synthesis in 1986 (Scheme 3) et al. demonstrated the second examplematerial, of artemisinin total synthesis in 1986into (Scheme 3) [42]. [42].Zhou R-(+)-Citronellal (13), chosen as a starting was initially transformed dihydroxy R-(+)-Citronellal (13),benzylation chosen as aand starting material, was initially into dihydroxy compound compound 14. The subsequent oxidation of 14transformed resulted in ketone 8 with a 51% yield. 14. The benzylation and subsequent oxidation of 14 resulted in ketone 8 with a 51% yield. The reaction The reaction of deprotonated ketone 8 with silylated vinyl ketone afforded 1,5-diketone 15, which ofwas deprotonated ketone 8 with silylated vinyl 1,5-diketone 15, which was transformed transformed into unsaturated ketone 16ketone with a afforded 62% yield. The reduction of unsaturated ketone into unsaturated ketone 16bywith a 62% yield. The 16 followed by 16 followed by oxidation chromium trioxide ledreduction to ketoneof17unsaturated with a 47% ketone yield. The addition of oxidation by chromium trioxide led to ketone 17 with a 47% yield. The addition of MeMgI to ketone MeMgI to ketone 17 followed by dehydration afforded the mixture of isomers from which the 17unsaturated followed byproduct dehydration afforded mixture of yield. isomers which the unsaturated product 18 18 was isolatedthe with a 46% It from was transformed into methyl ester of was isolated with a 46% wassteps transformed into methyl ester of of dihydroartemisinic acid (19) dihydroartemisinic acid yield. (19) in It three with a 72% yield. Ozonolysis 19 afforded ketoaldehyde in20. three a 72% Ozonolysis of 19 afforded ketoaldehyde 20. The ketone group of21, 20 The steps ketonewith group of 20yield. was protected by 1,3-propanedithiol with the formation of intermediate was protected by 1,3-propanedithiol with22the formation oftrimethyl intermediate 21, whichThe wasdeprotection converted into which was converted into the enol ether with the use of orthoformate. of 22 afforded enol of enol ether 23 in the presence ofof oxygen and Rose Bengal the enol ether 22 ether with 23. theThe usephotooxidation of trimethyl orthoformate. The deprotection 22 afforded enol ether following by the treatment of 70% HClO 4 resulted in artemisinin with a yield of 0.2% in 21 steps. 23. The photooxidation of enol ether 23 in the presence of oxygen(1)and Rose Bengal following by the treatment of 70% HClO4 resulted in artemisinin (1) with a yield of 0.2% in 21 steps.
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Scheme 3. Total synthesis of artemisinin by Zhou and co-workers. Scheme 3. Total synthesis of artemisinin by Zhou and co-workers.
A few years later, Ravindranathan et al. reported the approach to aldehyde 20, which reduced few years later, Ravindranathan et al. reported the approach aldehyde which reduced the A synthetic pathway from 15 to 8 steps [43]. The synthesis of key to precursor 2020, was based on an the synthetic pathway from 15 to 8 steps [43]. 25 The synthesis of key precursor 20 in was based on intramolecular Diels–Alder reaction of triene prepared from (+)-3-carene (24) three steps an(Scheme intramolecular Diels–Alder reaction of triene 25 prepared from (+)-3-carene (24) in three steps 4). The triene 25 was cyclized into unsaturated ether 26 under high temperature conditions. (Scheme 4). The triene was cyclized into unsaturated 26 alcohol under high temperature conditions. The epoxidation of 2625followed by reduction by LiAlHether 4 led to 27, which was transformed intoepoxidation key precursor 20followed in five steps. The of 26 by reduction by LiAlH4 led to alcohol 27, which was transformed into Yadav and colleagues key precursor 20 in five steps.used (+)-isolimonene (28) obtained by (+)-2-carene heating as a starting reagent forand the colleagues synthesis ofused artemisinin. Hydroboration with subsequent oxidation of (+)-isolimonene Yadav (+)-isolimonene (28) obtained by (+)-2-carene heating as a starting (28) resulted acid 29 (Scheme 5) [44].Hydroboration Iodolactonization acid 29 ledoxidation to the separable mixture of reagent for thein synthesis of artemisinin. withofsubsequent of (+)-isolimonene iodolactones 30 and 31. The intermolecular radical reaction of iodolactone 30 with methyl vinyl (28) resulted in acid 29 (Scheme 5) [44]. Iodolactonization of acid 29 led to the separable mixture (MVK) resulted in The the formation of diastereomers 32/33of mixture, which30can be separable by ofketone iodolactones 30 and 31. intermolecular radical reaction iodolactone with methyl vinyl the introduction of thioacetal fragment.ofMethyl ester 3432/33 was mixture, prepared which by saponification and ketone (MVK) resulted in the formation diastereomers can be separable consequent methylation of thioacetal-derivative. The ester oxidation of hydroxyl-group, the introduction by the introduction of thioacetal fragment. Methyl 34 was prepared by saponification and of methoxymethyl fragment, and the removal ofThe the oxidation thioacetal of group led to the mixture of enol ether consequent methylation of thioacetal-derivative. hydroxyl-group, the introduction of 23 isomers with a 32% yield. The construction of bicyclic peroxide fragment of artemisinin is a
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Molecules 2017, 22, 117 methoxymethyl fragment, Molecules 2017, 22, 117
6 of23 20 and the removal of the thioacetal group led to the mixture of enol ether 6 of 20 isomers with a 32% yield. The construction of bicyclic peroxide fragment of artemisinin is a two-step 1O2, and 1 O , andby two-stepThe process. Theisfirst step is photooxidation of the mixture of 23 enol ether 23 isomers process. first step photooxidation of the mixture ofmixture enol ether isomers 1O2,second 2 two-step process. The first step is photooxidation of the of enol ether 23byisomers by the and the second one is acid-catalyzed Theof total yield of artemisinin (1) was 0.3% in 12 steps. onethe is second acid-catalyzed cyclization.cyclization. The total yield artemisinin (1) was 0.3% 120.3% steps. one is acid-catalyzed cyclization. The total yield of artemisinin (1) in was in 12 steps.
Scheme 4. The synthesis of ketoaldehyde 20 through the Diels–Alder approach. Scheme 4. 4. The The synthesis synthesis of of ketoaldehyde ketoaldehyde 20 20 through through the the Diels–Alder Diels–Alder approach. Scheme approach.
Scheme 5. Total synthesis of artemisinin by Yadav and co-workers (2003).
The synthesis of artemisinin (1) based on artemisinic acid (3) a total yield of 37% via cyclic Scheme 5. of by andwith co-workers (2003). Scheme 5. Total Total synthesis synthesis of artemisinin artemisinin by Yadav Yadav and co-workers (2003). enol ether 35 was reported (Scheme 6) [45]. Photooxidation of 35 using 1O2 followed by the treatment with TMSOTf (trimethylsilyl trifluoromethanesulfonate), resulted deoxoartemisinin (36). Oxidation The synthesis of artemisinin (1) based on artemisinic acid (3)inwith a total yield of 37% via cyclic of ether 36 by 35 thewas RuC1 3–NaIO4(Scheme system afforded 1 with a 96% yield. enol reported 6) [45]. Photooxidation of 35 using 1O2 followed by the treatment
with TMSOTf (trimethylsilyl trifluoromethanesulfonate), resulted in deoxoartemisinin (36). Oxidation of 36 by the RuC13–NaIO4 system afforded 1 with a 96% yield.
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The synthesis of artemisinin (1) based on artemisinic acid (3) with a total yield of 37% via cyclic enol ether 35 was reported (Scheme 6) [45]. Photooxidation of 35 using 1 O2 followed by the treatment with TMSOTf (trimethylsilyl trifluoromethanesulfonate), resulted in deoxoartemisinin (36). Oxidation of 36 Molecules by the 2017, RuC1 –NaIO4 system afforded 1 with a 96% yield. 22,3117 7 of 20 Molecules 2017, 22, 117
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Scheme 6. Synthesis of artemisinin from artemisinic acid (3) via enol ether 35.
Scheme 6. Synthesis of artemisinin from artemisinic acid (3) via enol ether 35.
An efficient partial synthesis of artemisinin (1) starting from artemisinic acid or arteannuin B Scheme 6. Synthesis of artemisinin from artemisinic acid (3) via enol ether 35.
An synthesis of artemisinin (1) starting from artemisinic acid Artemisinic or arteannuin (38)efficient through partial enol ether 40 was reported by Lansbury and Nowak (Scheme 7) [46]. acidB (38) or arteannuin B were converted to lactone 37. Reduction of double bond of arteannuin (38) followed through enol ether 40 was reported byartemisinin Lansbury and Nowak (Scheme 7) [46]. acid An efficient partial synthesis of (1) starting from artemisinic acid Artemisinic orB arteannuin B or by deoxygenation of formed saturated epoxide resulted in lactone (37) with a 44% yield. Ozonolysis arteannuin B were converted to lactone 37. Reduction of double bond of arteannuin B (38) followed (38) through enol ether 40 was reported by Lansbury and Nowak (Scheme 7) [46]. Artemisinic acid by of 37 and protection obtainedtocarbonyl group ledintolactone aldehyde 39with that transformed into enol of 37 or arteannuin B were of converted lactone 37. Reduction of double bond of was B (38) followed deoxygenation of formed saturated epoxide resulted (37) aarteannuin 44% yield. Ozonolysis ether 40 by the cleavage of lactone ring with subsequent methylation. The construction of artemisinin by deoxygenation of formed saturated epoxide in lactone a 44% yield. Ozonolysis and protection of obtained carbonyl group led toresulted aldehyde 39 that(37) waswith transformed into enol ether 40 1O2 followed by camphorsulfonic acid peroxide wasobtained realized carbonyl by photooxidation 37 and fragment protection group led towith aldehyde that was transformed into enol by theofcleavage of lactoneofring with subsequent methylation. The 39 construction of artemisinin peroxide (CSA)-catalyzed cyclization. The total yieldsubsequent of artemisinin (1) from The arteannuin B (38)ofwas 10% in ether 40 by the cleavage of lactone ring with methylation. construction artemisinin 1 fragment was realized byauthors photooxidation with O2 followed by camphorsulfonic acid (CSA)-catalyzed eight steps. Later, thewas proposed an alternative route arteannuin (38) to artemisininacid (1) 1O2 followed peroxide fragment realized by photooxidation with from byBcamphorsulfonic cyclization. The total yield of artemisinin (1) from arteannuin B (38) was 10% in eight steps. Later, in six steps with a 5% yield [47]. (CSA)-catalyzed cyclization. The total yield of artemisinin (1) from arteannuin B (38) was 10% in the authors proposed an alternative route from arteannuin B (38) to artemisinin (1) in six steps with a eight steps. Later, the authors proposed an alternative route from arteannuin B (38) to artemisinin (1) 5% yield in six[47]. steps with a 5% yield [47].
Scheme 7. The synthesis of artemisinin by Lansbury and Nowak.
A cost-effective total synthesis of artemisinin with a total yield of 9% in nine steps was reported Scheme 7. The synthesis of artemisinin by Lansbury and Nowak. Scheme 7. The synthesisaofgram artemisinin by Lansbury and Nowak. (41)—a widely by Cook and colleagues. They conducted scale synthesis from cyclohexenone available starting material (Scheme [48]. Thewith synthesis α,β-unsaturated aldehyde 43 was A cost-effective total synthesis of 8) artemisinin a total of yield of 9% in nine steps was reported performed by successive Michael-type methylation, allylation with the formation of ketone and by Cook and colleagues. They conducted a gram scale synthesis from cyclohexenone (41)—a 42, widely Shapiro-process. The unusual [4 + 2] reaction between α,β-unsaturated aldehyde 43 and a silyl available starting material (Scheme 8) [48]. The synthesis of α,β-unsaturated aldehyde 43 was performed by successive Michael-type methylation, allylation with the formation of ketone 42, and Shapiro-process. The unusual [4 + 2] reaction between α,β-unsaturated aldehyde 43 and a silyl
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A cost-effective total synthesis of artemisinin with a total yield of 9% in nine steps was reported by Cook and colleagues. They conducted a gram scale synthesis from cyclohexenone (41)—a widely available starting material (Scheme 8) [48]. The synthesis of α,β-unsaturated aldehyde 43 was performed by successive Michael-type methylation, allylation with the formation of ketone 42, Molecules 2017, 22, 117 8 of 20 and Shapiro-process. The unusual [4 + 2] reaction between α,β-unsaturated aldehyde 43 and a silyl ketene acetal provided ortho ester of proposed proposedtotal total synthesis of artemisinin lies in ketene acetal provided ortho ester44. 44.The Thefeature feature of synthesis of artemisinin lies in usingusing of selective oxidation reactions in two final steps. The mild Wacker-type oxidation of internal of selective oxidation reactions in two final steps. The mild Wacker-type oxidation of internal olefinolefin of 44ofafforded enol olefin 45.45.The rearrangement latter by singlet oxygen 44 afforded enol olefin Thefinal finaloxidative oxidative rearrangement of of thethe latter by singlet oxygen from from the decomposition of H O22Oby ammonium molybdateresulted resulted artemisinin the decomposition of2H 2 by ammonium molybdate in in artemisinin (1). (1). 1) (CH3)2Zn, Cu(OTf)2, L* 2)
1) TsNHNH2 2) n-BuLi, TMEDA 3) DMF
Br
61%–71%
O
72%–77%
O 42
41 TIPSO
OCH3 PdCl2, H2O2
3:1 E:Z CH3 Et2AlCl >95%
O 43 O
H
O
H3CO OTIPS 44
1) 50% H2O2, (NH4)2MoO4 O O 2) p-TsOH O 29% (1.26 g) H H O
O
Ph L* =
Et P N
O
Et Ph
H
H
O 1, 9% on 9 steps
45 H3CO OTIPS
O
61%
TsNHNH2 = p-CH3C6H4SO2NHNH2 TMEDA =
N
N
TIPS = triisopropylsilyl
Scheme 8. The gram scale total synthesis of artemisinin by Cook and co-workers.
Scheme 8. The gram scale total synthesis of artemisinin by Cook and co-workers.
2.2. Other Methods
2.2. Other Methods
Avery and colleagues developed quite a different precursor for the construction of bicyclic
Avery and colleagues developed quite for synthesis the construction of the bicyclic peroxide artemisinin fragment—vinyl silane a51different (Scheme precursor 9) [49,50]. The started from peroxide artemisinin fragment—vinyl 51 (Scheme 9)a[49,50]. The synthesis from the transformation of (R)-(+)-pulegone (46)silane into sulfoxide 47 with 70% yield. The alkylationstarted of sulfoxide 47 with LDA and 1,3-dioxane-derivative followed desulfurization an aluminum transformation of (R)-(+)-pulegone (46) into bromide sulfoxide 47 withby a 70% yield. The with alkylation of sulfoxide amalgam afforded the ketone 48 with a 50% yield. followed The two-step reaction converted 47 with LDA and 1,3-dioxane-derivative bromide by Shapiro desulfurization with an ketone aluminum 48 into homologous aldehyde 49. The silylation and acylation of aldehyde 49 produced silane 50, amalgam afforded the ketone 48 with a 50% yield. The two-step Shapiro reaction converted ketone which was transformed into vinyl silane 51 via Ireland–Claisen rearrangement. The reaction of vinyl 48 into homologous aldehyde 49. The silylation and acylation of aldehyde 49 produced silane 50, silane 51 (the step of removing of acetal protecting group was in the first version of synthesis [49]) which was transformed into vinyl silane 51 via Ireland–Claisen rearrangement. The reaction of vinyl with ozone followed by the rearrangement of unstable peroxide intermediate provided artemisinin silane(1)51with (thea step of removing acetal group was in the first version of synthesis [49]) 35% yield (the total of yield was protecting 3.5% in 14 steps). with ozone followed by the rearrangement of unstable peroxide intermediate provided artemisinin (1) with a 35% yield (the total yield was 3.5% in 14 steps).
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Scheme 9. The total synthesis of artemisinin by Avery and co-workers (1992). Scheme 9. The total synthesis of artemisinin by Avery and co-workers (1992).
Wu and colleagues hydrogen peroxide-based access artemisinin (1) with an overall Scheme 9.reported The totalthe synthesis of artemisinin by Avery and to co-workers (1992). Wu and colleagues the hydrogen peroxide-based access to epoxide artemisinin (1) with overall yield of 14.5% in sevenreported steps starting from aldehyde 39 converted into spiro 52 (Scheme 10)an [51]. Wu and colleagues the hydrogen peroxide-based artemisinin (1) 52 with an overall yieldAddition of 14.5% in H seven starting from aldehyde 39 C-12a converted intotospiro epoxide (Scheme 10) of 2O2 tosteps thereported highly hindered quaternary in access precursor 52 was achieved through a [51]. yield of 14.5% in seven steps starting from aldehyde 39 converted into spiro epoxide 52 (Scheme 10) [51]. facile perhydrolysis of a spiro epoxy ring with the help of molybdenum species (prepared from Addition of H2 O2 to the highly hindered quaternary C-12a in precursor 52 was achieved through Addition H2glycine). O2 toofthe highly hindered quaternary in 52cyclized wasspecies achieved through Na 2perhydrolysis MoO4 of and β-hydroxyhydroperoxide was further by p-TsOH witha from a facile aResulting spiro epoxy ring with theC-12a help 53 ofprecursor molybdenum (prepared facile perhydrolysis of a spiro epoxy ring with the help of molybdenum species (prepared from the formation of peroxide 54, followed by oxidation, which resulted in ketal 36. The artemisinin (1) Na2 MoO 4 and glycine). Resulting β-hydroxyhydroperoxide 53 was further cyclized by p-TsOH with Na2MoO 4 and by glycine). Resulting β-hydroxyhydroperoxide 53 was further cyclized by p-TsOH with was prepared the oxidation of 36 by the RuCl3/NaIO4 system. the formation of peroxide 54, followed by oxidation, which resulted in ketal 36. The artemisinin (1) the formation of peroxide 54, followed by oxidation, which resulted in ketal 36. The artemisinin (1) was prepared by the oxidation of of 3636bybythe 4 system. was prepared by the oxidation theRuCl RuCl33/NaIO /NaIO4 system.
Scheme 10. The hydrogen peroxide-based access to artemisinin. Scheme 10. The hydrogen peroxide-based access to artemisinin.
Scheme 10. The hydrogen peroxide-based access to artemisinin.
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3. Artemisinin on Dihydroartemisinic Dihydroartemisinic Acid Acid 3. Artemisinin Synthesis Synthesis Based Based on 3.1. Preparation of Dihydroartemisinic Acid
Currently, semi-synthetic methods of artemisinin (1) synthesis from available available biosynthetic precursorssuch suchas as artemisinic (3) attracted have attracted an increasing attention as precursors artemisinic acid acid (3) have an increasing amount of amount attention of as cost-effective, cost-effective, environmentally friendly, approaches and high-quality approaches to the production of environmentally friendly, and high-quality to the production of artemisinin from reliable artemisinin sources [40].from reliable sources [40]. Artemisinic acid, arteannuic acid (3),(3), is 8–10-fold more abundant in A. in annua than 1than [39] Artemisinic acid,also alsocalled called arteannuic acid is 8–10-fold more abundant A. annua and can be isolated without chromatography [52]. The developed biosynthetic methods allow for the 1 [39] and can be isolated without chromatography [52]. The developed biosynthetic methods allow production of artemisinic acid on a large other organisms [53–55]. In 2006, the for the production of artemisinic acid on a scale large with scale the withuse theofuse of other organisms [53–55]. In 2006, fermentation process with engineered yeast toto produce the fermentation process with engineered yeast producehigh hightiters titersofofartemisinic artemisinicacid acidwas was developed in Amyris Inc. Inc. and the University of California California [56]. [56]. In 2013, Paddon, Newman, and co-workers co-workers reported the themethod method biological production of artemisinic acidthe with help of genetically reported forfor biological production of artemisinic acid with helpthe of genetically modified modified strains of Saccharomyces cerevisiae (baker’s This development avoids in the increase in strains of Saccharomyces cerevisiae (baker’s yeast). This yeast). development avoids the increase fermentation fermentation titersartemisinic of produced artemisinic titers of produced acid to 25 g/Lacid [57].to 25 g/L [57]. One of the most critical steps during the production of artemisinin is the regio- and diastereoselective reduction (3)(3) to diastereomeric dihydroartemisinic acidacid (4). The reductionofofartemisinic artemisinicacid acid to diastereomeric dihydroartemisinic (4). mostmost perspective method in the of industry is the reduction by hydrogen (22–46 atm)atm) on The perspective method in context the context of industry is the reduction by hydrogen (22–46 Rh-based catalysts—(Ph 3P)RhCl 2 [57], RuCl 2 [(R)-DTBM-Segphos](DMF) 2 (the full name of ligand on Rh-based catalysts—(Ph P)RhCl [57], RuCl [(R)-DTBM-Segphos](DMF) (the full name of 3 2 2 2 0 0 (R)-DTBM-Segphos is (R)-(−)-5,5′-Bis[di(3,5-di-tert-butyl-4-methoxyphenyl) phosphino]-4,4′-biligand (R)-DTBM-Segphos is (R)-(−)-5,5 -Bis[di(3,5-di-tert-butyl-4-methoxyphenyl) phosphino]-4,4 -bi> 98% andand 99%, respectively. In 1,3-benzodioxole) [58], [58], the the yield yieldofofdihydroartemisinic dihydroartemisinicacid acid(4)(4)was was > 98% 99%, respectively. addition, NaBH 4/NiCl 2 [59] (98% yield) and LiBH 4 /NiCl 2 [60] (quantitative yield) were used for the In addition, NaBH /NiCl [59] (98% yield) and LiBH /NiCl [60] (quantitative yield) were used for 4 2 4 2 reduction of artemisinic acid. An An attractive method toward the the diastereoselective synthesis of the reduction of artemisinic acid. attractive method toward diastereoselective synthesis dihydroartemisinic acidacid (4) from artemisinic acid (3) was with use of diimide a reducing of dihydroartemisinic (4) from artemisinic acid (3)realized was realized with use of as diimide as a agent (generated by the reaction hydrazine monohydrate and oxygen) the pilot plant scale-up reducing agent (generated by theof reaction of hydrazine monohydrate and in oxygen) in the pilot plant with a yield >90% [61–63]. Moreover, dihydroartemisinic acidacid (4) (4) or or itsitsmethyl scale-up with aofyield of >90% [61–63]. Moreover, dihydroartemisinic methylester ester were in 17 17 steps steps from from((−)-β-pinene prepared in −)-β-pinene [64], [64], in 9 steps from ((−)-isopulegol −)-isopulegol [65], [65], and and in in 8 steps from (R)-(+)-citronellal [66]. 3.2. Transformation Transformation of of Dihydroartemisinic Dihydroartemisinic Acid Acid into into Artemisinin Artemisinin via via Hydroperoxidation Hydroperoxidationand andRearrangements Rearrangements The first first example exampleofoftwo-step two-stepconversion conversion dihydroartemisinic (4) into artemisinin (1) of of dihydroartemisinic acidacid (4) into artemisinin (1) was was reported by Roth Acton 1989[29]. [29].Dihydroartemisinic Dihydroartemisinicacid acid(4) (4) was was photooxidized photooxidized into reported by Roth andand Acton in in 1989 hydroperoxide 5, which in situ rearranged into artemisinin (1) by action action of of trifluoroacetic trifluoroacetic acid acid (TFA) (TFA) (Scheme 11).
Scheme acid (4) (4) into into artemisinin artemisinin (1). (1). Scheme 11. 11. The The transformation transformation of of dihydroartemisinic dihydroartemisinic acid
Photooxygenation of dihydroartemisinic acid (4) with subsequent CH2N2 treatment provided Photooxygenation dihydroartemisinic (4) with subsequent provided 2 Na 2 treatment corresponding ester 55 of which was converted acid into peroxides 56 and 57 CH with catalytic amount of corresponding ester 55 which was converted into peroxides 56 and 57 with a catalytic amount of Cu(OTf)2 (Scheme 12) [67]. The artemisinin (1) was prepared by p-TsOH-catalyzed cyclization of the Cu(OTf) 12) [67]. The artemisinin (1) was methylation prepared by step p-TsOH-catalyzed cyclization of the 2 (Scheme crude mixture of peroxides 56 and 57. Additional did not significantly affect the crude mixture of peroxides 56 and 57. Additional methylation step did not significantly affect the yield yield of artemisinin. The total artemisinin (1) yield was 20% in four steps. of artemisinin. The total artemisinin (1) yield was 20% in four steps.
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Scheme 12. The transformation of dihydroartemisinic acid (4) into artemisinin (1) via hydroperoxyester 55.
Scheme 12. 12. TheThe transformation ofof dihydroartemisinic into artemisinin artemisinin(1) (1)via via hydroperoxyester Scheme transformation dihydroartemisinicacid acid (4) into hydroperoxyester 55. 55. Later, many attempts have been made to in situ transformation of dihydroartemisinic acid (4) to (1) (Tablehave 1); however, the yield (1) did not exceed 30%. Later, many attempts been to in situ of acid Later,artemisinin many attempts have been made made to of inartemisinin situ transformation transformation of dihydroartemisinic dihydroartemisinic acid (4) (4) to to artemisinin (1) (Table 1); however, the yield of artemisinin (1) did not exceed 30%. artemisinin (1) (Table 1); however, the yield of artemisinin (1) did not exceed 30%. Table 1. In situ transformation of dihydroartemisinic acid (4) or its ester 19 into artemisinin (1).
Table Table 1. In situ transformation of dihydroartemisinic acid (4) or its ester 19 into artemisinin (1). Scheme 12. The transformation of dihydroartemisinic acid (4) into artemisinin (1) via hydroperoxyester 55.
Later, many attempts have been made to in situ transformation of dihydroartemisinic acid (4) to of of artemisinin (1) Condition artemisinin (1) (Table 1); however,Condition the yield did notofexceed 30%.Yield Reference No. Substrate Peroxidation Step
1
Rearrangement/Cyclization Step
of 1, %
O2/hv, Methylene Blue, TFA (cat.), petroleum ether, Table 1. In4situ transformation of dihydroartemisinic acid (4) or its ester 19 into artemisinin (1).[59] 30
acetone, 0 °C, 30 min air, r.t., 4 days crude mixture of 19 and Condition of Blue, Condition ofair, Yield O2/hv, Methylene TFA (cat.), petroleum ether, 2 Substrate isomer with double Condition of 30 [64] No. Reference Condition of 90 min 20 °C, 4 days CH2Cl2, 20 °C, No. Substrate Yield of 1, Reference Peroxidation Step Rearrangement/Cyclization Step 1, % % bond C6-C7 position Peroxidation Step Rearrangement/Cyclization Step O2/hv, Methylene Blue, TFA (cat.), petroleum ether, crude mixture of 4 and /hv, Methylene Blue, TFA (cat.), petroleum ether, air, 4isomer with doubleO2 /hv,O2Methylene 1 30 [59] 3 26 [65] acetone, 0 °C, minTFA (cat.), petroleum air, air, r.t., ◦30 acetone, 20 °C,r.t., 24ether, h 4 days 1 4 bond C6-C7 position Blue, acetone, 00 °C, C,30 min 30 [59] 4 days crude mixture of 19 and 30Methylene min (1) O2, Cu(OTf) 2/hv, Rose bengal, 2, CH3CN, −20ether, °C; O TFA (cat.), petroleum air, 2/hv, O Blue, 19 25 [66] 4 with double 2 isomer 30 [64] 3CN, −30 °C, 6h , 20 °C, 4 h CH (2) p-TsOH Condition (cat.), Condition Yield crude No. mixture of 19 and OCH 2ClMethylene 2, 20 °C, 90 of min 20 CH °C,2Cl 4of2days 2 /hv, Substrate Reference TFARearrangement/Cyclization (cat.), petroleum ether, air, bond C6-C7 position ◦ Peroxidation Step Step of 1, % 2 isomer with double Blue, CH2 Cl2 , 20 C, 30 [64] ◦ C, 4 days 20(cat.), crude mixture of 4 and of transformation O2/hv, TFA petroleum ether, The mechanism of Blue, dihydroartemisinic acid (4) into artemisinin (1) was bond 1C6-C7 position 90 minMethylene 4 30 [59] O2/hv, Methylene Blue, TFA (cat.), petroleum ether, air, 0 °C, 30 min 4 days 3 isomer with studied double [68–73]. Theacetone, 26 that [65] thoroughly first step is peroxidation of 4air, to r.t., form 5. Initially, it was suggested crude mixture ofmixture 4 and of 19 O acetone, 0 °C, 30 min TFA (cat.), petroleum 20 °C,ether, 24 h air, 2 /hv, Methylene crude and bond C6-C7 position ◦ O TFA (cat.), petroleum ether, air, 2/hv, Methylene Blue, conversion of hydroperoxide 5 into artemisinin (1) mainly proceeds through [2 + 2] cycloaddition 3 isomer double Blue, acetone, 0 C, 26 [64] of [65] 2 withisomer with double 30 ◦ C, 24 h 20 20 2Cl2, 20 °C, 90 min °C, 4 days CHRose (1) O58 O2/hv, bengal, 2, Cu(OTf) 2, by CHoxidation 3CN, −20 °C; singlet oxygen to 5,position with the formation of intermediate followed to intermediate 6 bond C6-C7 position 30 min bond C6-C7 19 25 [66] 4 2Cl2,◦20 °C, 4 h p-TsOH, (cat.), CH− mixture of 4 andCH3CN, −30 °C, 6 h (Schemecrude 13) [74]. (1) O2(2) , TFA Cu(OTf) CH3 CN, 20air,C; O2 /hv, ORose bengal, Blue, 2/hv, Methylene (cat.),2petroleum ether, [66] 25 [65] 3 19 isomer with double 26 4 ◦ (2) p-TsOH (cat.),20CH Cl2h, 20 ◦ C, 4 h CH3 CN,acetone, −30 C, 6 h30 min 0 °C, °C,224 bond C6-C7 position The mechanism of transformation ofbengal, dihydroartemisinic acid (1) O2, Cu(OTf)2, CH3CN, O2/hv, Rose −20 (4) °C; into artemisinin (1) was 19 25 [66] 4 CH3CN, −30 °C, 6 h (2) p-TsOH (cat.), CH2Cl2, 20 °C, 4 h
thoroughly studied [68–73]. The first step isofperoxidation of 4 to form 5. Initially, was suggested that The mechanism of transformation dihydroartemisinic acid (4) into itartemisinin (1) was conversion hydroperoxide 5 transformation into artemisinin (1) mainly proceeds [2 + 2]itcycloaddition of thoroughlyof studied [68–73].ofThe first step isof peroxidation of 4acid to form 5. artemisinin Initially, The mechanism dihydroartemisinic (4)through into (1)was wassuggested singlet oxygen to 5, with the formation of intermediate 58 followed by oxidation to intermediate 6 thoroughly studied [68–73]. The first step is peroxidation of 4 to form 5. Initially, it was suggested that that conversion of hydroperoxide 5 into artemisinin (1) mainly proceeds through [2 + 2] cycloaddition conversion of hydroperoxide 5 into artemisinin (1) mainly proceeds through [2 + 2] cycloaddition of (Scheme 13) [74]. of singlet oxygen to 5, with the formation of intermediate 58 followed by oxidation to intermediate singlet oxygen to 5, with the formation of intermediate 58 followed by oxidation to intermediate 6
6 (Scheme(Scheme 13) [74]. Scheme 13. The mechanistic possibilities for the conversion of artemisinic acid into artemisinin. 13) [74].
Scheme 13. The mechanistic possibilities for the conversion of artemisinic acid into artemisinin.
Scheme Scheme 13. 13. The The mechanistic mechanistic possibilities possibilities for for the the conversion conversion of of artemisinic artemisinic acid acid into into artemisinin. artemisinin.
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Later, it was shown that the key steps involve terminal protonation of hydroperoxide 5, Hock cleavage via intermediate 59, and reaction of enol 60 with triplet oxygen to form hydroperoxide 6, Molecules 22, 117 to artemisinin (1) (Scheme 14) [75]. The formation of possible by-products, such 12 of as 20 which is2017, cyclized five-membered lactone dihydro-epi-deoxyarteannuin B (37) and enol ester 61, was minimized by TFA Later, catalysis. Molecules 2017, 22, 117 12 of 20 it was shown that the key steps involve terminal protonation of hydroperoxide 5, Hock cleavageLater, via intermediate 59,the and of enol 60 with tripletofoxygen to form5, hydroperoxide it was shown that keyreaction steps involve terminal protonation hydroperoxide Hock H viato intermediate 59, (1) and(Scheme reaction of14) enol 60 with oxygenof to possible form hydroperoxide 6, Hartemisinin 6, which iscleavage cyclized [75]. Thetriplet formation by-products, such as H which islactone cyclized to artemisinin (1) of possible by-products, such as + (Scheme 14) [75]. TheBformation five-membered dihydro-epi-deoxyarteannuin (37) and enol ester 61, was minimized by H - Hester five-membered lactone dihydro-epi-deoxyarteannuin B (37) and enol 2O2 61, was minimized by TFA catalysis. TFA catalysis.
HOO
H H
HO2C 5
H+
HOO
H
H+
HO2C 5
OOH H HO2HC
H - H2O2
OOH H HO2C
O
H
HO2OC
HO
H
6
HO2C
H
6
O
O
H
HO
O
O
H
HO C HO2C 2 59
59
37
H
60
O
O O O H O
H
O HO2C
O HO2C
H
O O O H O
H
O2
1
O2
H O
HO2C
O
1
H
H
H
H H
H
O
O
H H
H HC HO 2
O H
H
HO HO
60
H
H
HOO
H H2O
O
H
O HOO
H2O
37
H
H H+
O
O H
H
H
O 61
H
O O
61
Scheme 14. Acid-catalyzed reaction steps in the formation of artemisinin and side products.
O
Scheme 14. Acid-catalyzed reaction steps in the formation of artemisinin and side products. Scheme 14. Acid-catalyzed reaction steps in the formation of artemisinin and side products.
A continuous-flow process for the synthesis of artemisinin (1) from dihydroartemisinic acid (4), which does not require isolation and purification of intermediates, was proposed (Scheme 15) [76]. A process for synthesis of artemisinin artemisinin (1) (1) from from dihydroartemisinic dihydroartemisinic acid (4), A continuous-flow continuous-flow for the the synthesis of The key step is a process photochemical transformation involving a singlet-oxygen induced ene reaction, acid (4), which does not require isolation and purification of intermediates, was proposed (Scheme 15) [76]. [76]. which does notcleavage, requireand isolation andofpurification intermediates, was proposed (Scheme Hock the addition triplet oxygen, of followed by cyclization with the formation of an 15) The is transformation involving aa singlet-oxygen induced ene reaction, endoperoxide group. Tetraphenylporphyrin (TPP) was used as photosensitizer. Isolated yieldene of reaction, The key key step step is aa photochemical photochemical transformation involving singlet-oxygen induced artemisinin wasaddition 39% (1.36 g). Hock cleavage, and(1)the of triplet oxygen, followed by cyclization with the formation of
Hock cleavage, and the addition of triplet oxygen, followed by cyclization with the formation of an an endoperoxide group. Tetraphenylporphyrin (TPP) wasused usedasasphotosensitizer. photosensitizer. Isolated Isolated yield yield of endoperoxide group. Tetraphenylporphyrin (TPP) was of artemisinin (1) was 39% (1.36 g). artemisinin (1) was 39% (1.36 g).
Scheme 15. Reaction conditions for continuous flow synthesis of artemisinin.
Scheme 15. 15. Reaction for continuous continuous flow flow synthesis synthesis of of artemisinin. artemisinin. Scheme Reaction conditions conditions for
Later, the authors succeeded in optimizing this one-pot photochemical continuous-flow method for the synthesis of artemisinin from dihydroartemisinic acid (4). The optimization of reaction
Later, the authors succeeded in optimizing this one-pot photochemical continuous-flow method for the synthesis of artemisinin from dihydroartemisinic acid (4). The optimization of reaction conditions was conducted (LED lamp emitting at 420 nm, temperature, solvent, TFA concentration); as a result, yield of artemisinin (1) increased to 57% [75]. Molecules 2017,the 22, isolated 117 13 of 20 The continuous synthesis of derivatives of artemisinin: dihydroartemisinin 62, artemether 63, Molecules 2017, 22, 117 13 of 20 arteether 64, and artesunate 65 was also realized (Scheme 16) [77]. The system consists of three linkage Later, the authors succeeded optimizingat this one-pot continuous-flow conditions conducted (LED lampinemitting 420 nm, photochemical temperature, solvent, concentration); modules forwas photooxidation/cyclization (9,10-dicyanoanthracene (DCA) was chosenTFA as method photosensitizer), for the synthesisyield of artemisinin from dihydroartemisinic acid (4). The optimization of reaction as a result, the isolated of artemisinin (1) increased to 57% [75]. reduction,conditions and derivatization steps. The purification of crude products was carried out by column was conducted (LED lamp emitting at 420 nm, temperature, solvent, TFA concentration); The continuous synthesis of derivatives of artemisinin: dihydroartemisinin 62, artemether 63, chromatography in fourth module. as a result, the isolated yield of artemisinin (1) increased to 57% [75]. arteether 64, and artesunate 65 was realizedof(Scheme 16)dihydroartemisinin [77]. The system62, consists of three linkage The continuous synthesis also of derivatives artemisinin: artemether 63, arteether 64, and artesunate 65 was also realized (Scheme 16) [77]. The systemwas consists of three linkage modules for photooxidation/cyclization (9,10-dicyanoanthracene (DCA) chosen as photosensitizer), H H H for photooxidation/cyclization (DCA) was chosen as photosensitizer), reduction,modules and derivatization steps. The (9,10-dicyanoanthracene purification of crude products was carried out by column O O O column reduction, and derivatization steps. The purification of crude products was carried out by O DCA NaBH4, LiCl 1)fourth O2/hv,module. chromatography in chromatography in fourth module. O O Li2CO3, Celite, H H H H H H 2) TFA, O2 H O H O EtOH H HO O 4
O O O O H 1 O
1) O2/hv, DCA HO
H
H
2) TFA, O2
O O OH O H H dihydroartemisinin O
NaBH4, LiCl H
Li2CO3, Celite, EtOH
O
O 4
dihydroartemisinin 62
1
O
O
O O
O
O
CH(OEt)3, HCl
Et3N/CH2Cl2 O
H Et3N/CH2Cl2
O O H O O O O H H H OH O
O
O O HO HO artesunate artesunate O O 65 65 146 mg 146 mg
62
OH
CH(OEt)3, H HCl
O HO O O O OH H O O O
CH(OMe)3, HCl CH(OMe)3, HCl H
O O O O O O HH O H O H
H
O
arteether arteether 64 64 70 mg
70 mg
H
H O
O
artemether artemether 63 63 61 mg
61 mg
Scheme 16. Flow-synthesis of artemisinin derivatives—dihydroartemisinin (62), artemether (63), 16. Flow-synthesis of artemisinin derivatives—dihydroartemisinin (62), artemether arteether (64), and artesunate (65). 16. Flow-synthesis of artemisinin derivatives—dihydroartemisinin (62), artemether
Scheme Scheme arteether (64), and artesunate (65). arteether (64), and artesunate (65).
(63), (63),
The Paddon group showed that chemical conversion of dihydroartemisinic acid (4) into artemisinin (1) can be performed without specific photochemical equipment (Scheme 17) [57]. The The Paddon showed conversion of which dihydroartemisinic acid (4) (4) into into The Paddon group showed that thatacidchemical chemical conversion of dihydroartemisinic acid methylationgroup of dihydroartemisinic (4) afforded methyl ester 19, was oxidized by singlet artemisinin (1) can can performed without specific photochemical equipment 17) [57]. oxygen, generated through the disproportionation of concentratedequipment H 2O 2 under (Scheme the (Scheme action17) of [57]. artemisinin (1) bebeperformed without specific photochemical The molybdate The methylation ofcatalyst. dihydroartemisinic acid (4) afforded methyl ester 19, which was oxidized by
methylation of dihydroartemisinic acid (4) afforded methyl ester 19, which was oxidized by singlet singlet oxygen, generated through the disproportionation of concentrated theaction action of of 2 under oxygen, generated through the disproportionation of concentrated H2H O22 Ounder the molybdate catalyst. molybdate catalyst.
Scheme 17. Conversion of dihydroartemisinic acid to artemisinin using a chemical source of singlet oxygen.
Scheme 17. Conversion of dihydroartemisinic acid to artemisinin using a chemical source of Scheme 17. Conversion of dihydroartemisinic acid to artemisinin using a chemical source of singlet oxygen. singlet oxygen.
Using the same Na2 MoO4 /H2 O2 protocol, Yikang Wu also realized the gram-scale synthesis of artemisinin (1) without any special equipment (Scheme 18) [78]. Ene reaction of dihydroartemisinic acid (4) with singlet oxygen afforded intermediate 5, which was rearranged into artemisinin (1) by action of TFA and oxygen.
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Using the same Na2MoO4/H2O2 protocol, Yikang Wu also realized the gram-scale synthesis of Using the Naany 2MoO 4/H2O2equipment protocol, Yikang the gram-scale synthesis of artemisinin (1) same without special (SchemeWu 18)also [78].realized Ene reaction of dihydroartemisinic artemisinin (1) without any special equipment (Scheme 18) [78]. Ene reaction of dihydroartemisinic acid (4) 2017, with22,singlet oxygen afforded intermediate 5, which was rearranged into artemisinin 14 (1)ofby Molecules 117 20 acid (4)ofwith oxygen afforded intermediate 5, which was rearranged into artemisinin (1) by action TFAsinglet and oxygen. action of TFA and oxygen.
Scheme 18. The gram-scale synthesis of artemisinin by Wu. Scheme 18. The gram-scale synthesis of artemisinin by Wu. Scheme 18. The gram-scale synthesis of artemisinin by Wu.
Sanofi company developed the large-scale process of artemisinin (1) production from artemisinic Sanofi company developed the the large-scale large-scale process process of artemisinin artemisinin(Scheme (1) production production from company developed of (1) from artemisinic acid Sanofi (3) using diastereoselective hydrogenation and photooxidation 19, Figure 2)artemisinic [58]. At 22 acid (3) using diastereoselective hydrogenation and photooxidation (Scheme 19, Figure 2) [58]. At 22 acid (3) using diastereoselective hydrogenation and photooxidation (Scheme 19, Figure 2) [58]. Atbar 22 bar of H2, a mixture of enantiomers 4 and 4′ was obtained with the help of RuCl2[(R)-DTBM0 was obtained with the help of RuCl [(R)-DTBM-Segphos](DMF) of H , a mixture of enantiomers 4 and 4 2 2 bar of H2, a mixture of The enantiomers 4 and664′and was with the were help obtained of RuClfrom 2[(R)-DTBMSegphos](DMF) 2 catalyst. activated esters 66′ obtained (mixed anhydride) 4 and 4′2 0 (mixed anhydride) were obtained from 4 and 40 with the use of catalyst. The activated esters 66 and 66 Segphos](DMF) catalyst. The activated esters 66carbonate. and 66′ (mixed anhydride) were 4 and 4′ with the use of 2ethyl chloroformate/potassium They were expected to obtained facilitate from the final ring ethyl chloroformate/potassium carbonate. They were expected to facilitate the final ring closure. Mixed with the Mixed use of ethyl chloroformate/potassium Theyene were expected to facilitate the final ring closure. anhydrides were introduced tocarbonate. the Schenck reaction using tetraphenylporphyrin anhydrides were introducedwere to theintroduced Schenck using tetraphenylporphyrin (TPP) in additional CH2 Cl2 as closure. anhydrides the Schenck ene reaction using tetraphenylporphyrin (TPP) inMixed CH 2Cl 2 as a sensitizer. Cascadeeneto ofreaction several chemical steps (Hock cleavage, aoxygenation, sensitizer. of several chemical cleavage, additional oxygenation, closure) (TPP) in CHCascade 2Cl 2 as a sensitizer. Cascade of (Hock several chemical steps (Hock cleavage, additional ring closure) initiated by steps TFA resulted in a high overall yield (55%)ring of isolated initiated by TFA resulted in a high overall yield (55%) of isolated artemisinin (1) (370 kg) from artemisinic oxygenation, by acid TFA(3)resulted high overall (55%) of isolated artemisinin (1)ring (370closure) kg) frominitiated artemisinic used as in theastarting materialyield (Scheme 19). acid (3) used(1) as (370 the starting material (Scheme artemisinin kg) from artemisinic acid19). (3) used as the starting material (Scheme 19).
Figure 2. Photooxidation process in semi-synthetic artemisinin (1) production by Sanofi (Reprinted Figure 2. Photooxidation in semi-synthetic (1) production by Sanofi (Reprinted with permission from [58]process Copyright 2016 Americanartemisinin Chemical Society). Figure 2. Photooxidation process in semi-synthetic artemisinin (1) production by Sanofi (Reprinted with with permission from [58] Copyright 2016 American Chemical Society). permission from [58] Copyright 2016 American Chemical Society).
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Scheme 19. The production of semi-synthetic artemisinin (1) by Sanofi. Scheme 19. The production of semi-synthetic artemisinin (1) by Sanofi. Scheme 19. The production of semi-synthetic artemisinin (1) by Sanofi.
Rossen, Poliakoff, and George with colleagues reported two green chemistry approaches to Rossen, and George colleagues reported two green chemistry approaches artemisinin (1) from dihydroartemisinic acid (4) [79]. The first strategy in the use of liquid CO2 as a to Rossen, Poliakoff, Poliakoff, George with with colleagues reported two lies green chemistry approaches to artemisinin (1)photocatalyst from dihydroartemisinic [79].porphyrins—TPP The first firststrategy strategy liesTPFPP) inthe theuse use liquidCO CO asa solvent and (commercially available and immobilized onto artemisinin acid (4) [79]. The lies in ofofliquid 2 2as the sulfonated ion-exchange resin Amberlyst-15; 460porphyrins—TPP mg of artemisinin and (1) was isolated (Scheme 20). asolvent solvent andphotocatalyst photocatalyst (commercially available porphyrins—TPP and immobilized onto and (commercially available TPFPP) onto the sulfonated ion-exchange resin Amberlyst-15; 460 mg of artemisinin (1) was isolated (Scheme the sulfonated ion-exchange resin Amberlyst-15; 460 mg of artemisinin (1) was isolated (Scheme20). 20). O2 + CO2
O2 + CO2
H
H
H HO
HO
H
H O 4 O 4
H
toluene
TPP / Amberlyst 15 Fixed-bed photoreactor TPP / Amberlyst 15 5 oC, 18 MPa, 10 min
O O H O O O H H OO
H O O 1, 39% (460 mg) O 1, 39% (460 mg) Scheme 20. Synthesis artemisinin (1) with use of dual solid catalyst. H
toluene
Fixed-bed photoreactor 5 oC, 18 MPa, 10 min
H
Scheme 20.isSynthesis Synthesis artemisinin (1) with with use of of dual dual solid solid catalyst. The second strategy [79] based onartemisinin an application of alcohol/water mixtures. The major advance of Scheme 20. (1) use catalyst. this method is the possibility of recycling of solvents, photocatalyst (tris(bipyridine)ruthenium(II) The second strategy acid [79] is based on an application of alcohol/water mixtures. The major advance of chloride), and aqueous (Scheme 21). The second strategy [79] is based on an application of alcohol/water mixtures. The major advance this method is theyield possibility of recycling of solvents, (tris(bipyridine)ruthenium(II) The isolated of artemisinin (1) after three cycles is photocatalyst 37% (2.094 g). The authors [79] attempted to of this method is the possibility of recycling of solvents, photocatalyst (tris(bipyridine)ruthenium(II) explain the yield of(Scheme artemisinin chloride), andmodest aqueous acid 21).(1). In slightly changed reaction conditions (Scheme 21, the chloride), and aqueous acid (Scheme 21). lower artemisinin (1) (50%(1) NMR theisstable minorg). hydroperoxide 68 (10% NMR to Theequation), isolated yield of artemisinin afteryield) three and cycles 37% (2.094 The authors [79] attempted The isolated yield of artemisinin (1) after three cycles is 37% (2.094 g). The authors [79] attempted yield) were detected and isolated. Hydroperoxide 68 is likely formed as a by-product in the ene reaction explain the modest yield of artemisinin (1). In slightly changed reaction conditions (Scheme 21, the to of explain the modest yield artemisinin (1). In slightly changed reaction conditions (Scheme 21, acid of (4) with singlet oxygen. column chromatography of the reaction lowerdihydroartemisinic equation), artemisinin (1) (50% NMR yield) andAfter the stable minor hydroperoxide 68 (10% NMR themixture lower equation), artemisinin (1) (50% NMR yield) and the stable minor hydroperoxide 68 (10% NMR with high polar solvents (EtOAc 68 andisEtOH) the oily as yellow oligomersinwere isolated. yield) wereresidue detected and isolated. Hydroperoxide likely formed a by-product the ene reaction yield) were detected and isolated. Hydroperoxide 68 is likely formed asbetween a by-product instabilizing the ene reaction The moderate yields of artemisinin are the result of a balance factors the of dihydroartemisinic acid (4) with singlet oxygen. After column chromatography of the reaction of artemisinin dihydroartemisinic acidthe (4)ease with singlet oxygen. After column chromatography of the reaction structure and of side reactions. On the one hand, it was shown [80] that the strong mixture residue with high polar solvents (EtOAc and EtOH) the oily yellow oligomers were isolated. mixture residue high polarstabilizes solventsartemisinin. (EtOAc and EtOH) the hand, oily yellow oligomers were isolated. anomeric nO →with σ*CO interaction On the other in the peroxidation/cyclization The moderate yields of artemisinin are the result of a balance between factors stabilizing the The moderate yields of artemisinin are the result of a balance between step, highly reactive compounds can be easily oxidized, polymerized, and rearranged.factors stabilizing artemisinin structure and the ease of side reactions. On the one hand, it was shown [80] that the strong the artemisinin structure and the ease of side reactions. On the one hand, it was shown [80] anomeric nO → σ*CO interaction stabilizes artemisinin. On the other hand, in the peroxidation/cyclization that the strong anomeric nO → σ*CO interaction stabilizes artemisinin. On the other hand, in the step, highly reactive compounds can be easily oxidized, polymerized, and rearranged. peroxidation/cyclization step, highly reactive compounds can be easily oxidized, polymerized, and rearranged.
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16 of 20
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H
H
HO
H
O2, [Ru(bpy)3]Cl2, LED lamps H2SO4 (0.5 eq.)
EtOH/H2O (60/40)
O O O H O
H
O 1, 37% (2.094 g)
o o H 0 C, 9 h then 20 C, O2 dark for 12-24 h
H
O 4 EtOH/H2O (80/20)
O O O H O
H oligomers
H
O 1, 50% (NMR)
HO
O
H
H CO2H
68, 10% (NMR)
Scheme21. 21.The Thesynthesis synthesisof ofartemisinin artemisinin (1) Scheme (1) in in an an aqueous aqueouscondition. condition.
4. Conclusions 4. Conclusions Analysis of the published data shows that synthetic approaches to the construction of peroxide Analysis of the published data shows that synthetic approaches to the construction of peroxide ring in artemisinin has attracted increasing interest in recent times (Scheme 22). In total syntheses, ring in artemisinin has attracted increasing recent times (Scheme 22).forInthe total syntheses, various unsaturated keto derivatives 12, 23, 40,interest 45, or 51inwere used as key precursors construction various unsaturated keto derivatives 12, 23, 40, 45, or 51 were used as key precursors for the of artemisinin via hydroperoxyaldehyde 6. The less common strategy lies in the construction of peroxide construction of artemisinin hydroperoxyaldehyde 6. The formation less common lies in the fragment based on precursorsvia 35 or 52 followed by the subsequent of the strategy artemisinin lactone construction of peroxide fragment based on precursors 35 or 52 followed by the subsequent formation cycle. In the past two decades, significant progress has been made in semi-synthetic methods. of Compared the artemisinin lactone cycle. In the past decades, significant progress has been made with other routes to artemisinin, itstwo semi-synthesis is still less studied, despite the fact that in semi-synthetic methods. Compared other routes toofartemisinin, its semi-synthesis is still less it could satisfy the demand for thewith cheap production sufficient amounts of artemisinin. The studied, despite of theartemisinin fact that based it could satisfy theacid demand forbethe cheap production of sufficient semi-synthesis on artemisinic seems to more efficient and environmentally friendly reliable sources are used in production and chemical amounts of because artemisinin. The semi-synthesis of artemisinin based on high-quality artemisinic acid seems methods to be more (catalytic and photooxidation) are applied. in efficient and hydrogenation environmentally friendly because reliable sourcesNowadays, are used inartemisinin productionconstruction and high-quality semi-synthetic is performed through 4, 19, orare 66.applied. Nowadays, artemisinin chemical methodsmethods (catalytic hydrogenation andprecursors photooxidation) The drawback of the majority of isthe available through methodsprecursors for the synthetic to the construction in semi-synthetic methods performed 4, 19, orapproaches 66. artemisinin, which limits their application, is the low to moderate yield in the final to The drawback of the majority of the available methods for the synthetic approaches step. Intheir all published studies, theperoxidation/cyclization artemisinin, which limits application, is the theyield low oftoartemisinin moderatenever yieldexceeds in the57%. final Moreover, the synthesis often requires UV-irradiation equipment. peroxidation/cyclization step. In all published studies, the yield of artemisinin never exceeds 57%. The main goals in the development of the synthetic strategies for the construction of a peroxide Moreover, the synthesis often requires UV-irradiation equipment. ring of artemisinin are as follows: (1) a development of methods for artemisinin precursor synthesis The main goals in the development of the synthetic strategies for the construction of a (artemisinic and dihydroartemisinic acids); (2) an investigation of the mechanisms of the peroxide ring of artemisinin are as follows: (1) a development of methods for artemisinin precursor peroxidation/cyclization step in order to predict optimal conditions for efficient synthesis; (3) the synthesis (artemisinic and dihydroartemisinic acids); (2) an investigation of the mechanisms of the search for selective one-pot methods of peroxidation/cyclization; (4) applying green chemistry peroxidation/cyclization stepproduction. in order to predict optimal conditions for efficient synthesis; (3) the search approaches to artemisinin for selective one-pot methods of peroxidation/cyclization; (4) applying green chemistry approaches to artemisinin production.
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Scheme 22. Summary of key-precursors in different approaches.
Scheme 22. Summary of key-precursors in different approaches. Acknowledgments: The authors are grateful to the Russian Foundation for Basic Research (Grant 16-29-10678) for financial support.
Acknowledgments: The authors are grateful to the Russian Foundation for Basic Research (Grant 16-29-10678) Author Contributions: All authors have contributed substantially: A.O.T., V.A.V., and A.I.I. wrote the for financial support. manuscript, I.A.Y. conducted the research. Conflicts All of Interest: The authors declare no conflict of interest. Author Contributions: authors have contributed substantially: A.O.T., V.A.V., and A.I.I. wrote the manuscript, I.A.Y. conducted the research.
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