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molecules Review

Peroxides with Anthelmintic, Antiprotozoal, Fungicidal and Antiviral Bioactivity: Properties, Synthesis and Reactions 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

*

ID

N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prospekt, 119991 Moscow, 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, 125047 Moscow, Russia All-Russian Research Institute for Phytopathology, B. Vyazyomy, 143050 Moscow, Russia Correspondence: [email protected]; Tel.: +7-916-385-4080

Received: 9 October 2017; Accepted: 30 October 2017; Published: 2 November 2017

Abstract: The biological activity of organic peroxides is usually associated with the antimalarial properties of artemisinin and its derivatives. However, the analysis of published data indicates that organic peroxides exhibit a variety of biological activity, which is still being given insufficient attention. In the present review, we deal with natural, semi-synthetic and synthetic peroxides exhibiting anthelmintic, antiprotozoal, fungicidal, antiviral and other activities that have not been described in detail earlier. The review is mainly concerned with the development of methods for the synthesis of biologically active natural peroxides, as well as its isolation from natural sources and the modification of natural peroxides. In addition, much attention is paid to the substantially cheaper biologically active synthetic peroxides. The present review summarizes 217 publications mainly from 2000 onwards. Keywords: peroxides; anthelmintic; antiprotozoal; fungicidal; antiviral

1. Introduction Peroxides are widely used in various areas of life [1–3]. Traditional and the most developed field is the application of peroxides as radical initiators in industrial processes in the manufacture of polymers from unsaturated monomers: styrenes, butadienes, chlorovinyls, ethylenes, acrylates, as well as in crosslinking of silicone rubbers, acrylonitrile-butadiene rubbers, fluororubbers, polyethylene, ethylene-propylene copolymer, etc. [4–9]. Hydrogen peroxide and peracids are active components of antiseptics and disinfectants [10–14]. Synthesis and mechanism of antiseptic action of hydrogen peroxide and the most common peracids (performic, peracetic, etc.) are elucidated in a few studies [15–17] and are not considered in this review. Antimalarial properties of peroxides are currently intensively studied. Artemisinin (Qinghaosu) (1), a natural peroxide possessing high antimalarial activity, was isolated in 1971 from leaves of annual wormwood (Artemisia annua) in the context of the scientific program “Project 523”, initiated by Chinese government in 1967 [18–20]. The Nobel Prize in Physiology or Medicine 2015 was awarded to Chinese pharmaceutical chemist Tu Youyou “for her discoveries concerning a novel therapy against Malaria” [21–23]. Considering the development of antibiotic resistance of Plasmodium to some traditional drugs, such as quinine, chloroquine, and mefloquine, and other anti-parasitic ones, pharmaceuticals based on artemisinin and its semi-synthetic derivatives—dihydroartemisinin (2), artemether (3) and artesunate (4) (Figure 1)—are currently the most effective drugs against malaria [24–30]. Molecules 2017, 22, 1881; doi:10.3390/molecules22111881

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H O H O OO HO O O HO O

H H

O (1) artemisinin artemisinin (1)

H

H

O H O OO HO O O

O H O OO HO O O

H

H O OH H

HO O

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H

H

O H O OO HO O O

H

HO O

H H

O O O OH dihydroartemisinin (2) artemether (3) artesunate (4) O dihydroartemisinin (3)derivatives. artesunate (4) Figure Artemisinin(2) and its artemether semi-synthetic Figure 1.1.Artemisinin and semi-synthetic derivatives.

O O OH OH

1. Artemisinin and itsofsemi-synthetic The modern trend Figure in medicinal chemistry peroxides isderivatives. the search of effective anticancer

The modern trend in medicinal chemistry of peroxides is the search of effective anticancer drugs. The natural and synthetic peroxides exhibiting a cytotoxic effect on cancer cells already drugs. The Themodern natural trend and synthetic peroxides exhibiting a cytotoxic effect of oneffective cancer cells already in medicinal chemistry of peroxides is the search anticancer include hundreds of compounds [31–34]. Peroxides possessing antimalarial and cytotoxic activity drugs.hundreds The natural and synthetic peroxides exhibiting a cytotoxic effect on cancer cells activity alreadyare include of compounds [31–34]. Peroxides possessing antimalarial and cytotoxic are the subject of numerous studies [35–42], and are not considered in this review. hundreds of compounds [31–34]. Peroxides possessing in antimalarial and cytotoxic activity theinclude subject of numerous studies and are not considered this review. In the present review, we [35–42], deal with natural, semi-synthetic and synthetic peroxides exhibiting areInthe of numerous [35–42], and are not considered in this review. thesubject present review, westudies deal with natural, semi-synthetic and synthetic exhibiting anthelmintic, antiprotozoal, fungicidal, antiviral and other activities that have notperoxides been described in In the present review, we deal withantiviral natural, semi-synthetic and synthetic peroxides exhibiting anthelmintic, antiprotozoal, fungicidal, and other activities that have not been described detail earlier. The review is mainly concerned with the synthesis of such peroxides, as well as its anthelmintic, antiprotozoal, antiviral and other activities that haveperoxides, not been described in its in detail earlier. review isfungicidal, mainly concerned with the synthesis of1912 such as well as isolation from The natural sources and covers literature published between and 2017. detail earlier. The review is mainly concerned with the synthesis of such peroxides, as well as its isolationThere from are natural sources and articles, covers literature published 2017. activity of several review where the various between kinds of1912 the and biological isolation from natural sources and covers literature published between 1912 and 2017. There are[43–45] severaland review articles, where variousof kinds of the biological activity artemisinin artemether [46,47]; thethe problems trematode infection therapy with of There are several review articles, where the various kinds of the biological activity of artemisinin, its derivatives and several synthetic [48]; antiviral activity of therapy artemisinin artemisinin [43–45] and artemether [46,47]; theozonides problems ofand trematode infection with artemisinin [43–45] and artemether [46,47]; the problems of trematode infection therapy with and artesunate [49] are and discussed. in the development of anti-parasitic areand artemisinin, its derivatives severalAdvances synthetic ozonides [48]; and antiviral activity ofperoxides artemisinin artemisinin, its derivatives and several synthetic ozonides [48]; and antiviral activity of artemisinin described in are thediscussed. review of Advances Muraleedharan A numberofofanti-parasitic reviews are devoted to are promising artesunate [49] in the[50]. development peroxides described and artesunate [49] are discussed. Advances in the development of anti-parasitic peroxides are anthelmintic peroxides [51]. Some natural antiviral peroxides are mentioned in the review [52]. in the review of Muraleedharan [50]. A number of reviews are devoted to promising anthelmintic described in the review of Muraleedharan [50]. A number of reviews are devoted to promising However, none of these articles pay sufficient attention to the methods of peroxide synthesis. peroxides [51]. Some natural peroxides are mentioned review [52]. However, anthelmintic peroxides [51].antiviral Some natural antiviral peroxides in arethe mentioned in the review none [52]. of Since peroxides with a related structure have different types of activity, the systematization of these articlesnone pay sufficient attention the methods of peroxide synthesis. However, of these articles pay to sufficient attention to the methods of peroxide synthesis. this review is based on the structure of the peroxide fragment (Figure 2). The first sections consider Since peroxides differenttypes typesofofactivity, activity,the the systematization Since peroxideswith witha arelated relatedstructure structure have different systematization of of the preparation of cyclic peroxides in order of increasing cycle and the number of oxygen atoms in it, thisthis review is based ononthe fragment(Figure (Figure2). 2).The The first sections consider review is based thestructure structureof ofthe the peroxide peroxide fragment first sections consider while the last section deals with peroxides of acyclic structure. The following abbreviations are used preparationofofcyclic cyclic peroxides peroxides ininorder ofof increasing cycle and and the number of oxygen atoms inatoms it, thethe preparation order increasing cycle the number of oxygen in describing the biological activity of peroxides: minimum inhibitory concentration (MIC), while the the last last section dealsdeals with peroxides of acyclic structure. The following abbreviations are used in it, while section with peroxides of acyclic structure. The following abbreviations minimum lethal concentration (MLC), half maximal inhibitory concentration (IC50), concentration of describing the biological activity of peroxides: minimum inhibitory concentration (MIC), arein used in describing the biological activity of peroxides: minimum inhibitory concentration (MIC), inhibiting 90% of activity (IC90), half maximal effective concentration (ЕС50), and median effective minimum lethal concentration (MLC), half maximal inhibitory concentration (IC 50 ), concentration of of minimum lethal concentration (MLC), half maximal inhibitory concentration (IC ), concentration 50 dose (ED50) [53,54]. inhibiting 90% activity(IC (IC90),),half halfmaximal maximal effective effective concentration 50), and median effective inhibiting 90% of of activity concentration(ЕС (EC 90 50 ), and median effective dose (ED 50) [53,54]. dose (ED50 ) [53,54].

Figure 2. Reviewed cyclic and acyclic peroxides.

2. 1,2-Dioxolanes

Figure andacyclic acyclicperoxides. peroxides. Figure2.2.Reviewed Reviewed cyclic cyclic and

A number of cyclic peroxides, many of which exhibit antibacterial, antifungal and anti-cancer 2. 1,2-Dioxolanes 2. 1,2-Dioxolanes

activity, were isolated from the marine organisms, in particular from the sponges Plakinidae [55]. A number of cyclic peroxides, many of which exhibit antibacterial, antifungal and anti-cancer A number peroxides, many ofthe which exhibit antibacterial, antifungal and anti-cancer activity, Plakinic acidofАcyclic (5) effectively inhibits growth of fungi Saccharomyces cerevisiae and Penicillium activity, were isolated from the marine organisms, in particular from the sponges Plakinidae [55]. were isolated from the marine organisms, in particular from the sponges Plakinidae [55]. Plakinic acid Plakinic acid А (5) effectively inhibits the growth of fungi Saccharomyces cerevisiae and Penicillium

A (5) effectively inhibits the growth of fungi Saccharomyces cerevisiae and Penicillium atrounenetum [56];

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atrounenetum plakinic acid Facid (7) and acid Fantifungal (8) exhibit moderate antifungal activity plakinic acid F[56]; (7) and epi-plakinic F (8) epi-plakinic exhibit moderate activity against Candida albicans against Candida fumigatus albicans and Aspergillus fumigatus [57]; 1,2-dioxolane 9 and 10 inhibit the growth of and Aspergillus [57]; 1,2-dioxolane acids 9 and 10 inhibit acids the growth of Candida albicans [58]; Candida albicans E [58]; plakortide Е (11) show good activity against brucei (Scheme 1) [59]. and plakortide (11)and show good activity against Trypanosoma bruceiTrypanosoma (Scheme 1) [59].

Scheme 1. Antifungal and anti-parasitic activity of 1,2-dioxolanes, isolated from the sponges Plakinidae.

The first first synthesis synthesis of of diastereomeric diastereomeric saturated saturated analogs analogs of of plakinic plakinic acids C and and D D 17 17 was was The acids A, A, C reported in 1996 by Bloodworth and colleagues [60]. Peroxides 17 were prepared in four steps from reported in 1996 by Bloodworth and colleagues [60]. Peroxides 17 were prepared in four steps from ketones 12. 12.InInthethe ketone 12condensed was condensed with ethyl 3-methylbut-2-enoate with ketones firstfirst step,step, ketone 12 was with ethyl 3-methylbut-2-enoate with formation formation cyclic 13 hydrolysis, acids 14. Peroxymercuration of esters by 15 cyclic lactones 13 lactones hydrolysis, which led towhich acids led 14. to Peroxymercuration of esters 15 followed followed by reduction with sodium borohydride afforded 1,2-dioxolanes 16 saponification, which reduction with sodium borohydride afforded 1,2-dioxolanes 16 saponification, which resulted in resulted in 1,2-dioxolanes 17 withgroup carboxylic group 1,2-dioxolanes 17 with carboxylic (Scheme 2). (Scheme 2). Thesynthesis synthesis of diastereomeric 1,2-dioxolanes 22 from alkynes [61]. was Carboalumination described [61]. The of diastereomeric 1,2-dioxolanes 22 from alkynes was described Carboalumination of alkyne 18, followed by treatment of the intermediate alkenylaluminum with of alkyne 18, followed by treatment of the intermediate alkenylaluminum with acetaldehyde, resulted in acetaldehyde, resulted in an allylic alcohol that was oxidized to enone 19. Conjugate addition of an allylic alcohol that was oxidized to enone 19. Conjugate addition of H2 O2 to 19 in the presence of LiOH H 2O2 to 19 in the presence of LiOH followed by acid-catalyzed esterification of diastereomeric followed by acid-catalyzed esterification of diastereomeric dioxinole by 2-methoxyethanol provided dioxinole by 2-methoxyethanol alkoxydioxolane Substitution of the methoxyethoxy alkoxydioxolane 20. Substitution provided of the methoxyethoxy group20. in 20 by the action of silyl keteneacetal group in 20 by the action of silyl keteneacetal ethyl thioacetal in the presence of TiCl 4 led to thioether ethyl thioacetal in the presence of TiCl4 led to thioether 21 as a 1:1 mixture of two diastereomers. 21 as a 1:1 mixturecisof and twotrans-diastereomeric diastereomers. The hardly-separable cis- and The hardly-separable peroxides 22 were obtained as atrans-diastereomeric result of hydrolysis peroxides 22 were obtained as a result of hydrolysis with high yield (Scheme 3). with high yield (Scheme 3).

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Scheme 2. The first synthesis of saturated analogs of plakinic plakinic acids 17. 17. Scheme 2. 2. The The first first synthesis synthesis of of saturated saturated analogs analogs of of Scheme plakinic acids acids 17.

Scheme 3. 3. The The synthesis synthesis of of diastereomeric diastereomeric analogs analogs of of plakinic Scheme plakinic acids acids 22. 22. Scheme 3. The synthesis of diastereomeric analogs of plakinic acids 22.

synthesis of of plakinic acids waswas reported [62]. [62]. The key sideofchain In 2006, 2006, the thefirst firstasymmetric asymmetric synthesis plakinic acids reported Thestep key of step side In 2006, the first asymmetric synthesis of plakinic acids was reported [62]. The key step of side chain construction was synthesis of diastereomeric allylic alcohols 25 from bromobenzene. This construction was synthesis of diastereomeric allylic alcohols 25 from bromobenzene. This transformation chain construction was synthesis of diastereomeric allylic alcohols 25 from bromobenzene. This transformation included subsequent addition Mg-organic compound to formation crotonaldehyde with included subsequent addition Mg-organic compound to crotonaldehyde with of alcohol 23, transformation included subsequent addition Mg-organic compound to crotonaldehyde with formation of alcohol 23, Claiseninhomologation resulted of in an ester 24, and reaction of anwith intermediate Claisen homologation resulted ester 24, and reaction intermediate aldehyde propenyl formation of alcohol 23, Claisen homologation resulted in ester 24, and reaction of an intermediate aldehyde with propenyl lithium (Scheme 4). lithium (Scheme 4). aldehyde with propenyl lithium (Scheme 4). As a result of following transformation epoxy alcohol 29a was prepared, which was oxidized As a result of following transformation epoxy alcohol 29a was prepared, which was oxidized into aldehyde; subsequent addition of methylmagnesium methylmagnesium bromide bromide resulted in isomeric secondary into aldehyde; subsequent addition of methylmagnesium bromide resulted in isomeric secondary epoxy alcohols 30а 30a and 30b (Scheme 5). After transformation transformation of of minor minor 30b into 30a, the latter was epoxy alcohols 30а and 30b (Scheme 5). After transformation of minor 30b into 30a, the latter was reduced to diol 31. The The treatment treatment of of diol diol 31 31 with with stoichiometric stoichiometric quantity quantity of of TsCl TsCl and excess of reduced to diol 31. The treatment of diol 31 with stoichiometric quantity of TsCl and excess of t-BuOK led to oxetane 32. The ring opening with TMSOTf provided easily separable 3-hydroxy The ring opening t-BuOK led to oxetane 32. The ring opening with TMSOTf provided easily separable 3-hydroxy hydroperoxides 33 and epi-33; 33 was converted into peroxy ketone 34 by subsequent silylation and hydroperoxides 33 and epi-33; 33 was converted into peroxy ketone 34 by subsequent silylation and oxidation. The The ketone ketone 34 34 was was transformed transformed into into alkoxydioxolane alkoxydioxolane 35, 35, and and after after that that into into thioester thioester 36. 36. oxidation. The ketone 34 was transformed into alkoxydioxolane 35, and after that into thioester 36. The desirable plakinic acids 38 were prepared by hydrolysis of methyl esters 37. A similar strategy The desirable plakinic acids 38 were prepared by hydrolysis of methyl esters 37. A similar strategy stereomeric acids 39 39 from 3-hydroxy 3-hydroxy hydroperoxideepi-33. epi-33. was used for the synthesis of stereomeric was used for the synthesis of stereomeric acids acids 39 from from 3-hydroxy hydroperoxide hydroperoxide epi-33. A total synthesis of plakortide E (11) based on radical radical oxygenation oxygenation of vinylcyclopropanes was A total synthesis of plakortide E (11) based on radical oxygenation of vinylcyclopropanes was reported [63,64]. The key intermediate 2-ethyl-1,1,2-cyclopropanetricarboxylate (42) prepared from [63,64]. The The key key intermediate intermediate 2-ethyl-1,1,2-cyclopropanetricarboxylate 2-ethyl-1,1,2-cyclopropanetricarboxylate (42) reported [63,64]. prepared from methylene malonate(40) (40)and andα-chloro α-chloro ester 41 was transformed into lactone 43. treatment The treatment of the methylene malonate ester 41 was transformed into lactone 43. The of theof latter methylene malonate (40) and α-chloro ester 41 was transformed into lactone 43. The treatment the latter with oxygen, Ph 2 Se 2 and AIBN furnished spiro 1,2-dioxolane 44, followed by lactone ring with Ph2 Se2 Ph and AIBN furnished spiro 1,2-dioxolane 44, followed by lactone ring opening of latteroxygen, with oxygen, 2Se2 and AIBN furnished spiro 1,2-dioxolane 44, followed by lactone ring opening ofdiol 44 to form diol 45. The precursor of the plakortide E 49 was synthesized from the 44 to form 45. The precursor of the plakortide E 49plakortide was synthesized from the iodo-derivative opening of 44 to form diol 45. The precursor of the E 49 was synthesized from the iodo-derivative of471,2-dioxolane 47 and the halogen derivative 48 by Negishi reaction.ofDesilylation of 1,2-dioxolane and the halogen derivative 48 by Negishi reaction. Desilylation alcohol 49, iodo-derivative of 1,2-dioxolane 47 and the halogen derivative 48 by Negishi reaction. Desilylation of alcohol 49, subsequent oxidation and Horner–Wadsworth–Emmons olefination provided ester 51 subsequent andoxidation Horner-Wadsworth-Emmons olefination provided ester 51 which of alcohol 49,oxidation subsequent and Horner–Wadsworth–Emmons olefination provided esterwas 51 which was hydrolyzed withofformation of Eplakortide E (11) (Scheme 6) [63]. hydrolyzed with formation plakortide (11) (Scheme 6) [63]. which was hydrolyzed with formation of plakortide E (11) (Scheme 6) [63].

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Molecules 2017, 22, 1881 PhBr PhBr

5 of 39 Mg, CH3CH=CHCHO

OH

OH Mg, CH93% 3CH=CHCHO Ph 93% Ph 23

CH3CH Ph (EtO) 2COOH 3CCH 3 o C 140 CH3CH Ph 2COOH o 85% C 140

23

85% R OH 2 OH R2

1) LiAlH4 2)1)DMSO, LiAlH4 (COCl)2, Et3N 3)2) DMSO,Br(COCl) 2, Et 3N t-BuLi, THF 3) Br t-BuLi, THF 79% 79% (EtO)3CCH3 25a (EtO)3CCH3 CH 3CH2COOH 25a o COOH CH140 3CH2C 140oC (EtO)3CCH3 25d (EtO)3CCH3 25d CH3CH2COOH CH140 COOH 3CHo2C 140oC Ph Ph

Ti(OiPr) 4, (-)-DET Ti(OiPr) 4, (-)-DET t-BuOOH t-BuOOH 93% 93%

27 27

O

(EtO)3CCH3

Ph Ph

26 26

OH O OH O 29a 29a >80% ee >80% ee

OEt OEt

24

Ph R1 Ph 25b R = CH R = R H1 1 3, 2 25dRR H,3,RR22 == CH 25b = =CH H 3 11 25d R1 = H, R2 = CH3

1) LiAlH4 1)2)LiAlH DMSO, (COCl)2, Et3N 4 (COCl) , Et N OEt 2)3)DMSO, Zn, CBr4, PPh23 3 OEt 3)4)Zn, CBr4, PPh3 n-BuLi 4) n-BuLi 76% 76%

1) Me Al, Cp ZrCl 1) Me33Al, Cp22ZrCl22 2) n-BuLi, (CH O)n 2) n-BuLi, (CH22O)n 77% 77%

Ph Ph

24

OH R2 OH R2

Ph R1 Ph25a R = CH R = HR1 1 3, 2 25c H, 3, R2R=2 =CH 25a R11 == CH H3 25c R1 = H, R2 = CH3 O O

O

OH OH Ph Ph

28 28 OHOH OO

Ph Ph 29b 29b

Scheme 4.4.Construction Construction of asymmetric asymmetricplakinic plakinicacids acidsside sidechain. chain. Scheme4. Construction of asymmetric Scheme plakinic acids side chain.

Scheme of plakinic plakinicacids acids38 38and and39. 39. Scheme5.5.Asymmetric Asymmetric synthesis synthesis of

Scheme 5. Asymmetric synthesis of plakinic acids 38 and 39.

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Scheme 6. 6. Synthesis Synthesis of of plakortide plakortide EE (11) (11) by by radical radical oxygenation oxygenation of of cyclopropanes. cyclopropanes. Scheme

A similar strategy based on the radical oxygenation of vinyl cyclopropanes was used for the A similar strategy based on the radical oxygenation of vinyl cyclopropanes was used for the synthesis of synthesis of epiplakinic acid F (8) [65]. The vinyl cyclopropane 53 obtained from epiplakinic acid F (8) [65]. The vinyl cyclopropane 53 obtained from trans-1,2-cyclopropanedicarboxylate 52, trans-1,2-cyclopropanedicarboxylate 52, was then converted to 1,2-dioxolane 55 (Scheme 7). After was then converted to 1,2-dioxolane 55 (Scheme 7). After separation of the diastereomeric mixture isomer 55b separation of the diastereomeric mixture isomer 55b was used for further transformations. was used for further transformations. Enantiomerically pure 55b was reduced by LiBH4 to alcohol 56, which was transformed to Enantiomerically pure 55b was reduced by LiBH to alcohol 56, which was transformed to vinylether 57 by subsequent PCC oxidation and Wittig4olefination. Oxidation of 57 to methyl ester vinylether 57 by subsequent PCC oxidation and Wittig olefination. Oxidation of 57 to methyl ester 58, 58, reductive ozonolysis of 58, and Wittig olefination gave predominantly the Z-isomer of vinyl reductive ozonolysis of 58, and Wittig olefination gave predominantly the Z-isomer of vinyl iodide 59. iodide 59. The Negishi coupling of 59 with the halogen derivative led to the desired product 60. The Negishi coupling of 59 with the halogen derivative led to the desired product 60. Desilylation of 60 Desilylation of 60 followed by reduction of 61 resulted in saturated alcohol 62. The oxidation of 62 followed by reduction of 61 resulted in saturated alcohol 62. The oxidation of 62 led to an aldehyde, led to an aldehyde, the Wittig olefination of which provided the precursor 63 as a mixture of the Wittig olefination of which provided the precursor 63 as a mixture of isomers. The product of isomers. The product of photoinduced isomerization of this mixture was the trans-isomer 64. The photoinduced isomerization of this mixture was the trans-isomer 64. The target epiplakinic acid F (8) target epiplakinic acid F (8) was obtained by alkaline hydrolysis of ester 64 (Scheme 8). was obtained by alkaline hydrolysis of ester 64 (Scheme 8).

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Scheme Construction of 1,2-dioxolane Scheme fragment forepiplakinic epiplakinicacid acidFFF(8). (8). Scheme7.7. 7.Construction Constructionof of1,2-dioxolane 1,2-dioxolanefragment fragmentfor for epiplakinic acid (8).

Scheme Scheme8. 8.Asymmetric Asymmetricsynthesis synthesisof ofepiplakinic epiplakinicacid acidFF(8). (8). Scheme 8. Asymmetric synthesis of epiplakinic acid F (8).

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The method of the preparation of andavadoic acid (76), a natural compound isolated from the The of method of the of andavadoic acid (76), a natural reaction compound from sponges Plaxortis aff preparation simplex, based on the Isayama−Mukaiyama andisolated subsequent the sponges of known Plaxortis aff The simplex, based on thewas Isayama-Mukaiyama reaction andconverted subsequent cyclization was [66]. starting substrate epichlorohydrin (65), which was to cyclization wasa known [66]. the Theorganomagnesium starting substrate was epichlorohydrin (65),cyclization which waswith converted to epoxide 66 by subsequent compound addition and the help epoxide 66 by a subsequent the organomagnesium compound andthe cyclization theethyl help of alkaline. The regioselective opening of the epoxide cycleaddition of 66 by lithium with salt of of alkaline. in The of theinepoxide cycle of alcohol 66 by the salt quantitative of ethyl propiolate propiolate theregioselective presence of opening BF3 resulted the secondary 67lithium in almost yield. in the presence BF3 resulted the secondary alcohol 67 in almost quantitative Alcohol 67 Alcohol 67 wasofconverted intoinlactone 68 by reaction with Me2CuLi, followed yield. by acidification. was converted into lactone by reaction with Me2 CuLi, followed by acidification. Oxidation of Oxidation of lactone 68 to 69,68 subsequent ring opening, oxidation of hydroxyl to the carbonyl group, lactone 68 to 69, subsequent opening, oxidation of hydroxyl the converted carbonyl group, and methylation and methylation resulted ring in epoxy ketone 70, which was to then to epoxy alkene 71. resulted in epoxy ketone 70, which was converted to epoxy alkene 71. Isayama-Mukaiyama Isayama–Mukaiyama peroxidation, the then base-catalyzed cyclization of peroxide 72, leading to a peroxidation, the base-catalyzed cyclization of peroxide 72,separation leading to and a mixture of diastereomeric mixture of diastereomeric 1,2-dioxolanes 73/73a followed by thioacylation resulted in 1,2-dioxolanes 73/73a followed byconverted separationinto andandavadoic thioacylationacid resulted in asubsequent peroxy thioester 74 which a peroxy thioester 74 which was (76) by reduction and was converted into andavadoic acid (76) by subsequent reduction and hydrolysis of ester 75 (Scheme 9). hydrolysis of ester 75 (Scheme 9).

Scheme Scheme 9. 9. Synthesis Synthesis of of andavadoic andavadoic acid acid (76). (76).

The symbiont of beetle of the southern pine (Dendroctonus frontalis), actinomycetous bacterium The symbiont of beetle of the southern pine (Dendroctonus frontalis), actinomycetous bacterium produces mycangimycin peroxide (77) with pronounced fungicidal activity (Scheme 10) [67]. produces mycangimycin peroxide (77) with pronounced fungicidal activity (Scheme 10) [67]. Mycangimycin Mycangimycin effectively inhibits growth of Candida albicans wild type, C. albicans ATCC10231, effectively inhibits growth of Candida albicans wild type, C. albicans ATCC10231, amphotericin-resistant amphotericin-resistant strain C. albicans ATCC 200955, Saccharomyces cerevisiae and Ophiostoma minus [68]. strain C. albicans ATCC 200955, Saccharomyces cerevisiae and Ophiostoma minus [68].

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Scheme 10. Natural peroxide mycangimycin and its fungicidal activity. Scheme 10. Natural peroxide mycangimycin and its fungicidal activity. Scheme activity. Scheme 10. 10. Natural Natural peroxide peroxide mycangimycin mycangimycin and and its its fungicidal fungicidal activity.

Two saturated analogs of mycangimycin were synthesized from alkene 78 and ester 79 (Scheme Two saturated analogs mycangimycin were from alkene ester 79 Two The saturated analogs of of mycangimycin were79synthesized synthesized from alkene 78 78 and and ester 79 (Scheme (Scheme 11) [69]. Kulinkovich reaction of 78 with resulted in cyclopropane 80,78 which formed Two saturated analogs of mycangimycin were synthesized from alkene and ester 79 11) [69]. The Kulinkovich reaction of 78 with 79 resulted in cyclopropane 80, which formed 11) [69]. The Kulinkovich reaction of 78 with 79 resulted in cyclopropane 80, which formed 1,2-dioxolane 81 by a cobalt-catalyzed cleavage in the presence of oxygen. TfOH-catalyzed reduction (Scheme 11) [69]. The Kulinkovich reaction of 78 with 79 resulted in cyclopropane 80, which formed 1,2-dioxolane 81 by a cobalt-catalyzed cleavage presence TfOH-catalyzed reduction 1,2-dioxolane 81 by cobalt-catalyzed cleavage in in the the presence of of oxygen. oxygen. reduction of the alcohol81 81by byaasilane led to 3,5-disubstituted 1,2-dioxolane 82. The TfOH-catalyzed result of desilylation and 1,2-dioxolane cobalt-catalyzed cleavage in the presence of oxygen. TfOH-catalyzed reduction of the alcohol 81 by silane led to 3,5-disubstituted 1,2-dioxolane 82. The result of desilylation and of the alcohol 81 by silane led to 3,5-disubstituted 1,2-dioxolane 82. The result of desilylation and oxidation of the81obtained alcohol is the first saturated analog of mycangimycin, acid 84, which and can of the alcohol by silane led to83 3,5-disubstituted 1,2-dioxolane 82. The result of desilylation oxidation of the obtained alcohol 83 is the first saturated analog of mycangimycin, acid 84, which can oxidation of the obtained alcohol 83 is the first saturated analog of mycangimycin, acid 84, which can be converted into ester 85. oxidation of the obtained alcohol 83 is the first saturated analog of mycangimycin, acid 84, which can be converted into ester 85. be converted into ester 85. be converted into ester 85.

O O O

OR OR OR 78 78 78 Et3SiH, TfOH Et TfOH Et33SiH, SiH, TfOH CH2Cl 2 CH Cl 22Cl22 CH 66% 66% 66%

79 79 79

O O O

84 84 84

14 14 14

O O O O O O OR 82 OR 82 OR 82

O O O O O O HO HO HO

TiCl(OiPr) 3 TiCl(OiPr) TiCl(OiPr) C 5H9MgCl33 C C55H H99MgCl MgCl THF THF THF 91% 91% 91%

O O O

14 14 14

14 14 14

OH OH OH OR OR OR

MeO MeO MeO

80 80 80

O O O O O O

TBAF, AcOH TBAF, AcOH TBAF, AcOH THF THF THF 81% 81% 81%

TMSCHN2 TMSCHN TMSCHN22 MeOH MeOH MeOH 81% 81% 81%

14 14 14

Co(acac)2 Co(acac) Co(acac) O2 22 O O22 EtOH EtOH EtOH 90% 90% 90%

OH OH OH O O O O O O O O O

85 85 85

83 83 83

14 14 14

O O O O O O OH OH OH OR 81 OR 81 OR 81

14 14 14

H5IO6 H H553IO IOH662O RuCl RuCl 33 H RuCl H22O O3CN CCl4/H2O/CH CCl 22O/CH CCl44/H /H88% O/CH33CN CN 88% 88% R = TBDPS R R= = TBDPS TBDPS

14 14 14

Scheme 11. The The synthesis synthesis of of saturated saturated analogs of mycangimycin 84 and 85. Scheme Scheme 11. 11. The The synthesis synthesis of of saturated saturated analogs analogs of of mycangimycin mycangimycin 84 84 and and 85. 85.

The diterpenoid peroxide 86, which has a weak fungicidal activity against C. albicans, was The diterpenoid peroxide 86,86, which hashas a weak fungicidal activity againstagainst C. albicans, was isolated The diterpenoid peroxide which aa weak fungicidal activity C. was Thefrom diterpenoid peroxide 86, which has weak fungicidal against C. albicans, albicans, was isolated the liverwort Jungermannia atrobrunnea (Scheme 12)activity [70]. Dinardokanshone B (87), from the liverwort Jungermannia atrobrunnea (Scheme 12) [70]. Dinardokanshone B (87), sesquiterpene isolated from the liverwort Jungermannia atrobrunnea (Scheme 12) [70]. Dinardokanshone B (87), isolated from the liverwort Jungermannia atrobrunnea (Scheme 12) [70]. Dinardokanshone B (87), sesquiterpene peroxide, isolated from the roots and rhizomes of Nardostachys chinensis Batal. peroxide, isolated from theisolated roots and rhizomes of Nardostachys chinensis (Valerianaceae) sesquiterpene peroxide, from the and rhizomes of Nardostachys chinensisshowed Batal. sesquiterpene peroxide, isolated from the roots roots and on rhizomes of Batal. Nardostachys Batal. (Valerianaceae) showed significant enhancement effects SERT activity (Scheme 12)chinensis [71]. significant enhancement effects on SERT activity (Scheme 12) [71]. (Valerianaceae) showed significant enhancement effects on SERT activity (Scheme 12) [71]. (Valerianaceae) showed significant enhancement effects on SERT activity (Scheme 12) [71].

Scheme 12. 12. Terpene Terpene peroxides peroxides 86 86 and and 87. 87. Scheme Scheme Scheme 12. 12. Terpene Terpene peroxides peroxides 86 86 and and 87. 87.

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vitro activity activity against against helminths helminths Schistosoma Schistosoma mansoni Synthetic 1,2-dioxolanes 88 showed high in vitro Synthetic 1,2-dioxolanes 88 showed high in vitro activity against helminths Schistosoma mansoni (Scheme 13) [72]. (Scheme 13) [72]. R3 R3 OR R1 R1 O O OR O O 88 88 R1, R2 = Me, Bu, -(CH2)5R1,RR2==Me, Me,CH Bu,CH -(CH 2)53 2 2Ph Me, CH CH2Ph, CH2Bn Ph RR3 == CH 2 2 R = CH2CH2Ph, Bn NTS S. mansoni IC50 < 20 M NTS S. mansoni IC50 < 20 M R2 R2

Scheme 13. 1,2-Dioxolanes high activity activity against against schistosomiasis. schistosomiasis. Scheme 13. 1,2-Dioxolanes 88 88 exhibiting exhibiting high Scheme 13. 1,2-Dioxolanes 88 exhibiting high activity against schistosomiasis.

5,5-Dimethyl 1,2-dioxolanes 88a were prepared by peroxidation of mesityl oxide (89) in the 5,5-Dimethyl prepared by by peroxidation of mesityl oxideoxide (89) in theinbasic 5,5-Dimethyl 1,2-dioxolanes 1,2-dioxolanes88a 88awere were prepared peroxidation of mesityl (89) the basic medium, followed by alkylation of the free hydroxyl group of 3-hydroxy-1,2-dioxolanes 90 medium, followed by alkylation of the free of hydroxyl group of 3-hydroxy-1,2-dioxolanes 90 (Scheme 14) [73]. basic medium, followed by alkylation the free hydroxyl group of 3-hydroxy-1,2-dioxolanes 90 (Scheme 14) [73]. Synthesis of cyclohexyl derivatives 88b started from oxidation of alcohol 92 to an Synthesis of cyclohexyl derivatives 88b started from oxidation of alcohol to an unsaturated (Scheme 14) [73]. Synthesis of cyclohexyl derivatives 88b started from92 oxidation of alcoholketone 92 to 93, an unsaturated ketone 93, followed by Isayama–Mukaiyama peroxidation with formation of followed by Isayama-Mukaiyama peroxidation with formation of 1,2-dioxolane Further protection unsaturated ketone 93, followed by Isayama–Mukaiyama peroxidation 94. with formation of 1,2-dioxolane 94. Further protection of hydroxyl group resulted in derivatives 88b (Scheme 14) [73]. of hydroxyl group resulted in derivatives 88b (Scheme [73]. in derivatives 88b (Scheme 14) [73]. 1,2-dioxolane 94. Further protection of hydroxyl group14) resulted

Scheme 14. Synthesis of anthelmintic 1,2-dioxolanes 88. Scheme 14. Synthesis of anthelmintic 1,2-dioxolanes 88.

The series of tricyclic monoperoxides 97 with 1,2-dioxolane moiety showed a high The series series of tricyclic monoperoxides 97 with 1,2-dioxolane moiety showed a high The of tricyclic with 1,2-dioxolane moiety showed a high anti-schistosomal activity.monoperoxides The maximum97activity was observed for compound 97a,anti-schistosomal which revealed anti-schistosomal activity. The maximum activitycompound was observed for compound 97a, which revealed activity. Theburden maximum activity was82.8% observed which revealed burden high worm reductions by in S. for mansoni mouse97a, model (Scheme 15)high [74].worm Peroxides 97 high worm burden reductions by 82.8% in S. mansoni mouse model (Scheme 15) [74]. Peroxides 97 reductions by 82.8% in β, S. δ-triketones mansoni mouse (Schemeperoxide 15) [74]. Peroxides 97 either can besulfuric obtained from β, can be obtained from 96 model and hydrogen with use of acid [75], can be obtained from β, δ-triketones 96 and hydrogen peroxide with use of either sulfuric acid [75], δ-triketones 96 and hydrogen peroxide with use of either sulfuric acid [75], or boron trifluoride [76] as or boron trifluoride [76] as catalyst and co-solvent (Scheme 15). or boronand trifluoride [76](Scheme as catalyst catalyst co-solvent 15).and co-solvent (Scheme 15).

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Scheme 15.Synthesis Synthesis oftricyclic tricyclic monoperoxides 97 with high anti-schistosomal Scheme anti-schistosomalactivity. activity. Scheme15. 15. Synthesisof of tricyclicmonoperoxides monoperoxides 97 with high anti-schistosomal activity.

3. 1,2,4-Trioxolanes (Ozonides) 3. 3. 1,2,4-Trioxolanes 1,2,4-Trioxolanes(Ozonides) (Ozonides) Various tetrasubstituted 1,2,4-trioxolanes (ozonides) have become the breakthrough in the field Various tetrasubstituted1,2,4-trioxolanes 1,2,4-trioxolanes(ozonides) (ozonides) have have become the Various tetrasubstituted the breakthrough breakthroughin inthe thefield field of biologically active synthetic peroxides. Nowadays ozonides are considered as the most promising biologicallyactive activesynthetic syntheticperoxides. peroxides.Nowadays Nowadays ozonides ozonides are considered ofof biologically considered as asthe themost mostpromising promising candidates in the treatment of helminth diseases (Scheme 16). The 100% worm burden reductions candidatesininthe thetreatment treatmentofofhelminth helminthdiseases diseases (Scheme (Scheme 16). 16). The 100% candidates 100% worm worm burden burdenreductions reductions were observed with a single oral dose of 1000 mg/kg OZ78 (98) in Echinostoma caproni-infected mice. were observedwith witha asingle singleoral oraldose doseofof1000 1000mg/kg mg/kg OZ78 (98) were observed (98) in in Echinostoma Echinostomacaproni-infected caproni-infectedmice. mice. A single dose of 100 mg/kg OZ78 (98) resulted in 100% worm burden reductions against juvenile and A single dose of 100 mg/kg OZ78 (98) resulted in 100% worm burden reductions against juvenile and A adult singleFasciola dose of 100 mg/kg OZ78 in 100% burdenOZ78 reductions againstagainst juvenile hepatica-mouse model(98) [77].resulted Single oral doses worm of 100 mg/kg (98) is efficient adult Fasciola hepatica-mouse model [77]. [77]. SingleSingle oral doses of 100 of mg/kg mg/kg OZ78 (98) is efficient against and adult Fasciola hepatica-mouse oral[78]. doses (98) is efficient adult triclabendazole-resistant F.model hepatica-infected rats Later,100 the efficacyOZ78 of 1,2,4-trioxolane adult triclabendazole-resistant F. hepatica-infected rats [78]. Later, the efficacy of 1,2,4-trioxolane against triclabendazole-resistant F. hepatica-infected rats [78]. Later, the was efficacy of 1,2,4-trioxolane OZ78 adult (98) against an experimental infection with Fasciola hepatica in sheep confirmed [79,80]. It OZ78(98) (98)against againstan anexperimental experimental infection with Fasciola hepatica inin sheep was confirmed [79,80]. It OZ78 infection with Fasciola hepatica sheep was confirmed was found that the spiroadamantane fragment and the carboxyl group in the OZ78 (98)[79,80]. are was found that the spiroadamantane fragment and the carboxyl group in the OZ78 (98) are It was foundfor that the spiroadamantane fragment necessary activity against F. hepatica [81]. and the carboxyl group in the OZ78 (98) are necessary for activity against[81]. F. hepatica [81]. fornecessary activity against F. hepatica

Scheme 16. Tetrasubstituted synthetic ozonides with the highest anthelmintic activity. Scheme anthelminticactivity. activity. Scheme16. 16.Tetrasubstituted Tetrasubstitutedsynthetic syntheticozonides ozonides with with the highest anthelmintic

The ozonides OZ78 (98) and OZ288 (99) showed low toxicity and high efficiency against The ozonides OZ78 and OZ288 (99) showed low toxicity high against The ozonides OZ78 (98)(98) andmansoni OZ288 (99) low toxicity and high efficiency against helminth helminth cultures Schistosoma and showed S. japonicum harboured in and mice and efficiency hamsters with a helminth cultures Schistosoma mansoni and S. japonicum harboured in mice and hamsters with cultures Schistosoma mansoni and S. japonicum harboured in mice and hamsters with a single oral dose single oral dose of 200 mg/kg [82,83]. Antichistosomal activity of OZ78 (98) against S. japonicum wasa single oral dose of 200Antichistosomal mg/kg [82,83]. Antichistosomal activity of OZ78 againstwas S. japonicum wasin of 200 mg/kg [82,83]. activity of OZ78 (98) against S.(98) japonicum confirmed

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experiments mice and rabbits the promising ozonide OZ418 (100) OZ418 with high activity confirmed ininexperiments in mice[84]. andLater, rabbits [84]. Later, the promising ozonide (100) with against both helminths of S. mansoni and S. haematobium was discovered [85]. high activity against both helminths of S. mansoni and S. haematobium was discovered [85]. Synthesis tetrasubstituted unsymmetrical ozonides was discovered by Griesbaum and colleagues Synthesisofof tetrasubstituted unsymmetrical ozonides was discovered by Griesbaum and incolleagues 1995 (Scheme 17,(Scheme top) [86,87]. Later this Later method usedwas for the synthesis in 1995 17, top) [86,87]. thiswas method useddiastereoselective for the diastereoselective ofsynthesis tetrasubstituted ozonides 103.ozonides Peroxides were prepared by ozonolysis of tetrasubstituted 103.103Peroxides 103 were prepared of by2-adamantanone ozonolysis of O-methyl oxime (101) in the oxime presence of substituted cyclohexanones 102 (Scheme 17, bottom) [88,89]. 2-adamantanone O-methyl (101) in the presence of substituted cyclohexanones 102 (Scheme 1,2,4-Trioxolane ring1,2,4-Trioxolane in compoundsring 103iniscompounds resistant to action oftoathe wide range of reagents, 17, bottom) [88,89]. 103the is resistant action of a wide range which allowswhich to proceed a to variety of modifications of the cyclohexane substituent [88]. of reagents, allows proceed a variety of modifications of the cyclohexane substituent [88]. Griesbaum co-ozonolysis R1

OCH3 N

O

R2

R4

O3

R1 O O R3 R2 O R4

R3

OCH3 O N

Synthesis of tetrasubstituted unsymmetrical ozonides OCH3 N 101

O

R 102

O3

O O

CH2Cl2 78oC

O

reactions in which the peroxide ring remains intact R

103

Scheme 17. 17. Synthesis Synthesis of tetrasubstituted tetrasubstituted unsymmetrical Scheme unsymmetricalozonides. ozonides.

1,2-Dioxanes 4.4.1,2-Dioxanes numberofof compounds containing 1,2-dioxane fragment isolated from the Plakinidae sponges AAnumber compounds containing 1,2-dioxane fragment isolated from the Plakinidae sponges showed showed high fungicidal and anti-trypanosomal activity. Plakinic acid B (104) exhibited good high fungicidal and anti-trypanosomal activity. Plakinic acid B (104) exhibited good fungicidal activity fungicidal activity against Saccharomyces cerevisiae and Penicillium atrovenetum (Scheme [56]. The against Saccharomyces cerevisiae and Penicillium atrovenetum (Scheme 18) [56]. The acid 105 in18) vitro inhibits acid 105 in vitro inhibits the growth of fungi Aspergillus fumigatus with IC 90 = 5.6 µg/mL [58]. the growth of fungi Aspergillus fumigatus with IC90 = 5.6 µg/mL [58]. Compounds 106 and 107 were Compounds 106 and 107 were weakly active against Staphylococcus aureus [90]. weakly active against Staphylococcus aureus [90]. 11,12-Didehydro-13-oxo-plakortide Q (108) was 11,12-Didehydro-13-oxo-plakortide Q (108) was more active against Trypanosoma brucei [91]. more active against Trypanosoma brucei [91]. Plakortide F acid (PFA) (109) showed high activity Plakortide F acid (PFA) (109) showed high activity against Candida albicans, Cryptococcus neoformans against Candida albicans, Cryptococcus neoformans and A. fumigatus [21]. Plakortides 110 and 111 also and A. fumigatus [21]. Plakortides 110 and 111 also demonstrated high activity against a number of demonstrated high activity against a number of fungi [92]. Significant fungicidal activity of mixture of fungi [92]. Significant fungicidal activity of mixture of peroxyketal acids isolated from sea sponges peroxyketal acids isolated from sea sponges was also reported [93]. was also reported [93]. A series of peroxyterpenes was isolated from the sponges Diacarnus bismarckensis, the most A series of peroxyterpenes was isolated from the sponges Diacarnus bismarckensis, the most active of which, (+)-muqubilone B (112) and sigmosceptrellin B (113) showed high activity active of which, (+)-muqubilone B (112) and sigmosceptrellin B (113) showed high activity against against Trypanosoma brucei [94]. (+)-Muqubilone B (112) and muqubilin (114) (isolated from Trypanosoma brucei [94]. (+)-Muqubilone B (112) and muqubilin (114) (isolated from the sponges the sponges Prianos [95]) were in vitro effective against herpes virus (HSV-1), muqubilin (114) and Prianos [95]) were in vitro effective against herpes virus (HSV-1), muqubilin (114) and (−)-sigmosceptrellin B (113) exhibited in vitro activity against Toxoplasma gondii (Scheme 19) [96]. (−)-sigmosceptrellin B (113) exhibited in vitro activity against Toxoplasma gondii (Scheme 19) [96]. Muqubilin (114) possesses herbicidal activity against tobacco Nicotiana tabacum [97], as well as Muqubilin (114) possesses herbicidal activity against tobacco Nicotiana tabacum [97], as well as epimuqubilin Mycaperoxide ВB(116) (116)displays displayshigh highantiviral antiviral epimuqubilin(115) (115)showed showedNO NO inhibitory inhibitory activity activity [98]. [98]. Mycaperoxide activity against vesicular stomatitis virus and herpes simplex virus type-1 (HCV-1) [99]. activity against vesicular stomatitis virus and herpes simplex virus type-1 (HCV-1) [99]. Several approachestotoplakinic plakinic acids their derivatives containing 1,2-dioxane Several synthetic synthetic approaches acids andand their derivatives containing 1,2-dioxane ring ring were described. Natural 6-epiplakortolide E (127) was firstly synthesized from available were described. Natural 6-epiplakortolide E (127) was firstly synthesized from available 1-bromo-10-phenyldecane (117) in in 10 10steps stepsbybyDiels–Alder Diels-Alder reaction with singlet oxygen followed 1-bromo-10-phenyldecane (117) reaction with singlet oxygen followed by by iodolactonization (Scheme 20) [100]. thestage, first the stage, the addition of the organomagnesium iodolactonization (Scheme 20) [100]. In theInfirst addition of the organomagnesium reagent reagent to the unsaturated resulted in enone which converted a tertiary alcohol119. 119. to the unsaturated ketoneketone resulted in enone 118, 118, which waswas converted to ato tertiary alcohol Hydroboration of 119 led to diol 120, protection of hydroxyl group of which provide silyl ether 121. Hydroboration of 119 led to diol 120, protection of hydroxyl group of which provide silyl ether 121. Diels-Alder of 121 121 with with singlet singlet oxygen oxygenresulted resultedinin Diels–Alderreaction reactionof ofdiene diene 122 122 prepared prepared by by dehydration dehydration of diastereomeric 1,2-dioxanes 123a and 123b. Deprotected diastereomer 124 was oxidized to acid125, 125, diastereomeric 1,2-dioxanes 123а and 123b. Deprotected diastereomer 124 was oxidized to acid subsequent iodolactonization of this acid gave bicycle 126. Desirable 6-epiplakortolide E (127) was subsequent iodolactonization 126. Desirable 6-epiplakortolide E (127) was formed was noted notedthat thatrelated related formed as as result result of of radical radical reduction reduction of of iodine-containing iodine-containing bicycle 126. ItIt was plakortolide G (128) is active against the protozoa Toxoplasma gondii [101]. plakortolide G (128) is active against the protozoa Toxoplasma gondii

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Scheme 18. 18. 1,2-Dioxanes theirantifungal, antifungal,antibacterial antibacterial and Scheme 1,2-Dioxanesisolated isolatedfrom from the the sponges sponges Plakinidae; Plakinidae; their and anti-trypanosomal activity is isalso anti-trypanosomal activity alsoshown. shown. H O O

O

HO22C O muqubilone B (112) T. brucei IC50 50 = 2 g/mL herpes simplex type 1 (HSV-1) ED50 50 =30 g/mL O O H CO22H muqubilin (114) herpes simplex type 1 (HSV-1) ED50 50 =7.5 g/mL Toxoplasma gondii >90% inhibition 0.1 M гербицидный эффект 66% Nicotiana tabacum 6.4 M H

HO

H

O O H CO22H

sigmosceptrellin B (113) T. brucei IC50 50 = 0.2 g/mL Toxoplasma gondii >90% inhibition 0.1 M O O H CO22H epimuqubilin A (115) NO inhibitory activity IC50 50 = 7.4 M

O O H CO22H

mycaperoxide B (116) herpes simplex type 1 (HSV-1) IC50 50 =0.25-1.0 g/mL vesicular stomatitis virus IC50 50 =0.25-1.0 g/mL

Scheme19. 19.Muqubilin Muqubilin(114) (114) and related Scheme related natural naturalperoxides. peroxides.

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Scheme (127). Scheme20. 20. Synthesis Synthesis of of 6-epiplakortolide 6-epiplakortolide ЕE (127).

Asymmetric synthesis synthesis of 136136 related to plakortolides was realized in 8 stepsin Asymmetric ofalkoxy-1,2-dioxane alkoxy-1,2-dioxane related to plakortolides was realized from carbonyl compounds 129 and 130 (Scheme 21) [102]. Enantioselective aldol reaction in step 8 steps from carbonyl compounds 129 and 130 (Scheme 21) [102]. Enantioselective aldolfirst reaction in aldol 131 in which intoconverted protected diol in threediol steps. inresulted first step resulted aldolwas 131converted which was into 132 protected 132Diastereomeric in three steps. 1,2-dioxanes 133a and 133b were formed by selective ozonolysis of double bond of bond 132. Diastereomeric 1,2-dioxanes 133a and 133b were formed by selective ozonolysis of double Hydrozirconation of 133а with following treatment by iodine led to the formation of vinyl iodide of 132. Hydrozirconation of 133a with following treatment by iodine led to the formation of vinyl 134, followed cross-coupling of one resulted in 1,2-dioxane 135. Deprotection of of135 iodide 134, followed cross-coupling of one resulted in 1,2-dioxane 135. Deprotection 135provided provided desirable peroxide 136. desirable peroxide 136. Natural endoperoxide 9,10-dihydroplakortin (148) and diastereomer 149 were synthesized Natural endoperoxide 9,10-dihydroplakortin (148) and diastereomer 149 were synthesized through Evans’ chiral auxiliary chemistry (Scheme 22) [103]. Alkylation of oxazolidinone 137 and through Evans’ chiral auxiliary chemistry (Scheme 22) [103]. Alkylation of oxazolidinone 137 subsequent reduction of 138 led to alcohol 139, which was transformed into acrylic ester 140 and subsequent reduction of 138 led to alcohol 139, which was transformed into acrylic ester 140 (predominantly in E-configuration) by oxidation and Horner–Wadsworth–Emmons olefination. The (predominantly in E-configuration) by oxidation and Horner-Wadsworth-Emmons olefination. ester 140 was reduced into corresponding alcohol, which was converted into iodide 141, alkylation The ester 140 was reduced into corresponding alcohol, which was converted into iodide 141, alkylation of oxazolidinone by which resulted in derivative 142. The cleavage and olefination of 142 provided of oxazolidinone by which resulted in derivative 142. The cleavage and olefination of 142 provided the ester 143. The reduction of 143 furnished alcohol 144 followed by Sharpless epoxidation and the ester 143. The reduction of 143 furnished alcohol 144 followed by Sharpless epoxidation and protection of primary hydroxy-group with formation of epoxide 145. Isayama–Mukaiyama protection of primary hydroxy-group withmixture formation epoxide 145. Isayama-Mukaiyama peroxidation of epoxide 145 afforded of of diastereomeric 1,2-dioxanes 146 andperoxidation 147 which ofwere epoxide 145 afforded mixture of diastereomeric 1,2-dioxanes 146 and which were independently independently transformed into 9,10-dihydroplakortin (148) and 147 6-epi-dihydroplakortin (149). transformed into 9,10-dihydroplakortin (148) and 6-epi-dihydroplakortin (149).

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Scheme of 1,2-dioxane 1,2-dioxane136. 136. Scheme21. 21.Asymmetric Asymmetric synthesis synthesis of

Scheme 22. Synthesis of natural endoperoxide 9,10-dihydroplakortin (148) and its diastereomer 149. Scheme 22. Synthesis of natural endoperoxide 9,10-dihydroplakortin (148) and its diastereomer 149. Scheme 22. Synthesis of natural endoperoxide 9,10-dihydroplakortin (148) and its diastereomer 149.

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16 of 39 of 160 and and161, 161,the thekey keysteps stepsare areconstruction construction In the synthesisofofdiastereomeric diastereomeric plakortolides plakortolides 160 of protected diol 155 and vinyl vinylbromide bromide152, 152,diastereoselective diastereoselective protected diol 155from fromprotected protected2-methyl 2-methyl glycidol glycidol 154 and In the synthesis of diastereomeric plakortolides 160 and 161, the key steps are construction of Mukaiyama addition of of aldehyde 156 with formation ofof ester 157 and hydroperoxidation Mukaiyama addition aldehyde 156 with formation ester 157 and hydroperoxidationofofalkene alkene158 protected diol 155 from protected 2-methyl glycidol 154 and vinyl bromide 152, diastereoselective with cyclization of 159of(Scheme 23) [104]. 158subsequent with subsequent cyclization 159 (Scheme 23) [104]. Mukaiyama addition of aldehyde 156 with formation of ester 157 and hydroperoxidation of alkene 158 with subsequent cyclization of 159 (Scheme 23) [104].

Scheme23. 23.Synthesis Synthesisof of diastereomeric diastereomeric plakortolides Scheme plakortolides160 160and and161. 161. Scheme 23. Synthesis of diastereomeric plakortolides 160 and 161.

Synthesis of analogs of plakinic acids, 1,2-dioxanes 166 with a pronounced anti-trypanosomal Synthesis of of analogs of plakinic 1,2-dioxanes 166with withaapronounced pronounced anti-trypanosomal Synthesis analogs plakinicacids, acids, 1,2-dioxanes 166 activity was proposed fromofE-hexen-4-ol (162) (Scheme 24) [105]. Swern oxidationanti-trypanosomal of alcohol 162 and activity was proposed from E-hexen-4-ol (162) (Scheme 24) [105]. Swern oxidation of alcohol activity wasWittig-olefination proposed from E-hexen-4-ol 24) [105]. Swern oxidation of alcohol 162 and 162 subsequent led to ester(162) 163. (Scheme The reaction of unsaturated scaffold 163 with singlet and subsequent Wittig-olefination led to ester 163.reaction The reaction of unsaturated scaffold 163165. with subsequent led to ester 163.1,2-dioxane The of unsaturated 163 with singlet oxygen and Wittig-olefination following cyclization provided 164, which was scaffold hydrolyzed to acid singlet oxygen and following cyclization provided 1,2-dioxane 164, which was hydrolyzed to acid 165. oxygen and following cyclization provided 1,2-dioxane 164, which was hydrolyzed to acid 165. Derivatives 166 were prepared from ester 164 by consistent ozonolysis, reductive cleavage and Derivatives 166 were prepared from ester 164 by consistent ozonolysis, reductive cleavage and Wittig Derivatives 166Compounds were prepared from esterhigh 164activity by consistent reductive Wittig reaction. 166 exhibited against ozonolysis, T. brucei brucei BF427. cleavage and WittigCompounds reaction. Compounds 166 exhibited high activity T. brucei BF427. reaction. 166 exhibited high activity againstagainst T. brucei brucei brucei BF427.

Scheme 24. Synthesis of 1,2-dioxanes 166 with high anti-trypanosomal activity. Scheme 24.24. Synthesis 166 with withhigh highanti-trypanosomal anti-trypanosomal activity. Scheme Synthesisofof1,2-dioxanes 1,2-dioxanes 166 activity.

Diastereomeric cyclic peroxides 171, one of which is the methyl ester of the mycaperoxide B Diastereomeric cyclic peroxides 171, one of which is the methyl ester of the mycaperoxide B Diastereomeric cyclic peroxides one of which 167 is the methyl25)ester of In thethe mycaperoxide (116), were prepared from protected171, hydroxyperoxide (Scheme [106]. first step, (116), were prepared from protected hydroxyperoxide 167 (Scheme 25) [106]. In the first step, B (116), were prepared from protected hydroxyperoxide 167 (Scheme 25) [106]. In the first step,

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peroxide 167167 was oxidized to aldehyde 168,168, which waswas converted intointo unsaturated esterester 169 by peroxide was oxidized to aldehyde which converted unsaturated 169Wittig by peroxide 167 wasHydroperoxide oxidized to aldehyde which by wasof converted into ester 169 byand Wittig reaction. 170 synthesized deprotection of unsaturated 169 cyclized into reaction. Hydroperoxide 170 synthesized by168, deprotection 169 was cyclized intowas 1,2-dioxane 171 Wittig172 reaction. Hydroperoxide synthesized by deprotection of 169 was cyclized into 1,2-dioxane oxolane 172 by 170 the action of triethylamine. oxolane by171 theand action of triethylamine. 1,2-dioxane 171 and oxolane 172 by the action of triethylamine.

Scheme25. 25.Synthesis Synthesis of diastereomeric Scheme diastereomericperoxides peroxides171. 171. Scheme 25. Synthesis of diastereomeric peroxides 171.

5. 1,2-Dioxenes 5. 1,2-Dioxenes 5. 1,2-Dioxenes The plant Chenopodium ambrosioides is used for the production of essential chenopodium oil, The plant Chenopodium the production productionofofessential essentialchenopodium chenopodium The plant Chenopodiumambrosioides ambrosioides is is used used for for the oil,oil, which has been used as an anthelmintic agent for a long time [107,108]. The first isolation of the most which hashas been used asas anan anthelmintic time [107,108]. [107,108].The Thefirst firstisolation isolation most which been used anthelminticagent agentfor for aa long time of of thethe most active component-ascaridole (174), from the Chenopodium ambrosioides and the determination of its active component-ascaridole ambrosioidesand andthe thedetermination determination of its active component-ascaridole(174), (174),from from the the Chenopodium Chenopodium ambrosioides of its structure was dated to the beginning of the last century [109–112]. In the 1950s, the ascaridole (174) structure was dated thebeginning beginningof ofthe the last last century century [109–112]. the ascaridole (174) structure was dated toto the [109–112].InInthe the1950s, 1950s, the ascaridole (174) was completely characterized (Scheme 26) [113,114]. completely characterized(Scheme (Scheme26) 26)[113,114]. [113,114]. waswas completely characterized The first laboratory synthesis of ascaridole (174) was performed via photo-induced addition of The first laboratory synthesisofofascaridole ascaridole (174) (174) was was performed via addition of of The first laboratory synthesis performed viaphoto-induced photo-induced singlet oxygen to terpene 173 by Schenck in 1944 (Scheme 26) [115]. Later, this reaction wasaddition realized singlet oxygen to terpene173 173by bySchenck Schenckin in 1944 1944 (Scheme (Scheme 26) [115]. Later, this reaction was realized singlet oxygen to terpene 26) [115]. Later, this reaction realized in an industrial scale, because ascaridole was of great importance as an anthelmintic agentwas [116]. The in an industrial scale, because ascaridole was of great importance as an anthelmintic agent [116]. The in method an industrial scale, because ascaridole was of great importance as an anthelmintic agent [116]. for the preparation of ascaridole using singlet oxygen generated in situ from sodium method for the preparation ofofascaridole using singlet oxygen generated in in situ from sodium The method for the preparation ascaridole using singlet oxygen generated situ from sodium molybdate and hydrogen peroxide is known [117]. molybdate and hydrogen peroxide is known [117]. molybdate and hydrogen peroxide is known [117].

Scheme26. 26. Ascaridole synthesis Scheme synthesis(174). (174). Scheme 26.Ascaridole Ascaridole synthesis (174).

ItItwas shown that ascaridole (174) at concentration almost completely inhibits the the growth growth was shown that ascaridole(174) (174)at atconcentration concentration 444 mM mM inhibits It was shown that ascaridole mMalmost almostcompletely completely inhibits the growth of fungi Sclerotium rolfsii [118]. Presently, the side effects of ascaridole on the gastrointestinal tract of fungi Sclerotium rolfsii [118]. Presently, the side effects of ascaridole on the gastrointestinal tract of fungi Sclerotium rolfsii [118]. Presently, the side effects of ascaridole on the gastrointestinal tract have have been and is not used have beendescribed, described, and ascaridole ascaridole is currently currently not [119]. used [119]. [119]. been described, and ascaridole is currently not used In 1990, Gunasekera colleagues isolated 1,2-dioxenes 175 176 from from sea sea sponge sponge Plakortis Plakortis 1990,Gunasekera Gunasekerawith with isolated 1,2-dioxenes 175 and and 176 In In 1990, withcolleagues colleagues isolated 1,2-dioxenes 175 and 176 from sea sponge angulospiculatus (Scheme 27) [120]. It was shown that these natural peroxides exhibit antifungal angulospiculatus (Scheme 27) [120]. It was shown that these natural peroxides exhibit antifungal Plakortis angulospiculatus (Scheme 27) [120]. It was shown that these natural peroxides exhibit antifungal activity activityagainst againstCandida Candida albicans albicans (MIC (MIC == 1.6 1.6 µg/mL). µg/mL). activity against Candida albicans (MIC = 1.6 µg/mL).

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O O O O

175 175

O O O O

COOH COOH

Candida albicans MIC = 1.6 µg/mL Candida albicans MIC = 1.6 µg/mL

COOH COOH

176 176

Scheme27. 27.Antifungal Antifungal natural natural 1,2-dioxenes 1,2-dioxenes 175, 175, 176. Scheme 1,2-dioxenes 175,176. 176. Scheme 27. Antifungal

The total total synthesis synthesis of of stereoisomeric stereoisomeric 1,2-dioxenes 1,2-dioxenes 185 was was performed performed in in 18 18 steps steps with with aa total total The The total synthesis of stereoisomeric 1,2-dioxenes 185185 was performed in 18 steps with a total yield yield of 2.8% (Scheme 28) [121]. The treatment of hydroxy ester 177 with tert-butyldiphenylsilyl of 2.8% (Scheme 28)The [121]. The treatment of hydroxy ester 177 with tert-butyldiphenylsilyl ofyield 2.8% (Scheme 28) [121]. treatment of hydroxy ester 177 with tert-butyldiphenylsilyl chloride chloride followed followed by by DIBAL DIBAL reduction reduction and and replacement replacement of of hydroxyl hydroxyl by by iodine iodine provided provided iodide iodide 178, 178, chloride followed by DIBAL reduction and replacement of hydroxyl by iodine providedreduction iodide 178, which was which was converted into aldehyde 179 by subsequent asymmetric alkylation, of prepared which was converted into aldehyde 179 by subsequent asymmetric alkylation, reduction of prepared converted intoalcohol aldehyde by subsequent asymmetric alkylation, reduction prepared amide into amide into into and179 Swern oxidation. Alkene Alkene 180 was was synthesized fromof sulfone derivative of amide alcohol and Swern oxidation. 180 synthesized from sulfone derivative of alcohol and Swern oxidation. Alkene 180 was synthesized from sulfone derivative of aldehyde 179 aldehyde 179 to obtain mainly trans-isomer. Deprotection of 180, nucleophilic substitution of aldehyde 179 to obtain mainly trans-isomer. Deprotection of 180, nucleophilic substitution of tohydroxyl obtain mainly trans-isomer. Deprotection of 180, nucleophilic substitution of hydroxyl by iodine, by iodine, subsequent substitution of iodine by cyano-group and reduction of cyano-group hydroxyl by iodine, subsequent substitution of iodine by cyano-group and reduction of cyano-group subsequent substitution of iodine by cyano-group ofby cyano-group led to aldehyde 181 led to to aldehyde aldehyde 181 which which was then then transformedand intoreduction alkyne 182 182 PPh33/CBr /CBr44 treatment treatment and HBr HBr led 181 was transformed into alkyne by PPh and which was then transformed into alkyne 182 by PPh /CBr treatment and HBr elimination. The synthesis 3 4 by addition of ethylcuprate followed by elimination. The The synthesis synthesis of of enone enone 183 183 was was performed performed elimination. by addition of ethylcuprate followed by ofpropionyl enone 183chloride was performed by182. addition of ethylcuprate followed by propionyl in chloride to alkyne 182. to alkyne The diene 184 was prepared predominantly trans-conformation propionyl chloride to alkyne 182. The diene 184 was prepared predominantly in trans-conformation The diene 184 was prepared predominantly in trans-conformation byphosphonate condensation with of enone 183 with by condensation of enone 183 with lithium salt of propargyl subsequent by condensation of enone 183 with lithium salt of propargyl phosphonate with subsequent lithium salt of propargyl phosphonate with subsequent hydroboration. Ene reaction of diene 184 with hydroboration. Ene Ene reaction reaction of of diene diene 184 184 with with singlet singlet oxygen oxygen and and methylation methylation by by diazomethane diazomethane hydroboration. singlet oxygen and methylation by 185b. diazomethane resulted in 1,2-dioxenes 185a and 185b. resulted in 1,2-dioxenes 1,2-dioxenes 185а and and 185b. resulted in 185а

Scheme28. 28.Synthesis Synthesisof of stereoisomeric stereoisomeric 1,2-dioxenes 1,2-dioxenes 185. 185. Scheme 1,2-dioxenes 185. Scheme 28. Synthesis stereoisomeric

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The cyclic peroxide shuangkangsu (186) isolated from the buds of Lonicera japonica showed high The cyclic peroxide shuangkangsu (186) isolated from the buds of Lonicera japonica showed high antiviral activity activityagainst againstrespiratory respiratory syncytial virus on cell the lines cell and linesinfluenza and influenza in the syncytial virus on the virus invirus the chicken antiviral activity against respiratory syncytial virus on the cell lines and influenza virus in the chicken embryosembryos (Scheme(Scheme 29) [122].29) [122]. chicken embryos (Scheme 29) [122].

Scheme japonica. Scheme 29. 29. Peroxide Peroxide shuangkangsu shuangkangsu (186) (186) isolated isolated from from Lonicera Lonicera japonica. Scheme 29. Peroxide shuangkangsu (186) isolated from Lonicera japonica.

Ergosterol peroxide (187) isolated from different natural sources including the fungi Pycnoporus Ergosterol peroxide(187) (187) isolated different the fungi Ergosterol peroxide isolated fromfrom different naturalnatural sources sources includingincluding the fungi Pycnoporus cinnabarinus demonstrated moderate antiviral activity against Herpes simplex и Polio virus [123], and Pycnoporus cinnabarinus demonstrated moderate antiviral activity against Herpes simplex and Polio virus cinnabarinus demonstrated moderate antiviral activity against Herpes simplex и Polio virus [123],[123], and also antifungal activity against pathogenic fungi Microsporum canis, Trichophyton rubrum and and also antifungal activity againstpathogenic pathogenicfungi fungi Microsporum Microsporum canis, canis, Trichophyton Trichophyton rubrum and also antifungal activity against and Epidermophyton floccosum (Scheme 30) [124]. Ergosterol peroxide acetate 189 was synthesized with Epidermophyton floccosum (Scheme 30) [124]. peroxide acetate 189 was synthesized with Epidermophyton synthesized with quantitative yield by photo-oxidation of Ergosterol ergosterol acetate 188 in thewas presence of trityl quantitative by photo-oxidation of ergosterol acetate 188 in the presence trityl tetrafluoroborate quantitativeyield yield by photo-oxidation of ergosterol acetate 188 in of the presence of trityl tetrafluoroborate (Scheme 30) [125]. (Scheme 30) [125].(Scheme 30) [125]. tetrafluoroborate

Scheme 30. Ergosterol peroxide (187), exhibited antiviral and antifungal activities and synthesis of its Scheme 30. Ergosterol activities and synthesis of its Scheme Ergosterol peroxide peroxide(187), (187),exhibited exhibitedantiviral antiviraland andantifungal antifungal activities and synthesis of derivatives. derivatives. its derivatives.

Analogs of ergosterol peroxide without multiple bonds in the side chain 194 were obtained by Analogs of ergosterol peroxide without multiple bonds inhydrolysis the side chain 194 were obtained by eosinAnalogs Y catalyzed photooxidation ofwithout steroidsmultiple 191 followed and194 oxidation. Peroxides of ergosterol peroxide bondsby in the side chain were obtained by eosin Y catalyzed photooxidation of steroids 191 followed by hydrolysis and oxidation. Peroxides 194 showed significant ability to inhibit the grown of hepatitis B virus (Scheme 31) [126]. eosin Y catalyzed photooxidation of steroids 191 followed by hydrolysis and oxidation. Peroxides 194 194 showed significant ability to inhibit the grown of hepatitis B virus (Scheme 31) [126]. showed significant ability to inhibit the grown of hepatitis B virus (Scheme 31) [126].

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Scheme31. 31.Synthesis Synthesisof of 194, 194, antiviral antiviral analogs Scheme analogsof ofergosterol ergosterolperoxide. peroxide.

A number of 1,2-dioxenes 196 with simpler structure were synthesized from 1,3-butadienes 195. A number of 1,2-dioxenes 196 with simpler structure were synthesized from 1,3-butadienes 195. Epoxidation of 196 resulted in 1,2-dioxanes 197 and 198. These peroxides exhibit moderate Epoxidation of 196 resulted in 1,2-dioxanes 197 and 198. These peroxides exhibit moderate antifungal antifungal activity against Candida family (Scheme 32) [127]. Later, a wide range of derivatives 196, activity against Candida family (Scheme 32) [127]. Later, a wide range of derivatives 197 and 197 and 198 that inhibits Candida albicans was synthesized [128]. 1,2-Dioxene 196а196, showed high198 that inhibits Candida albicans was synthesized [128]. 1,2-Dioxene 196a showed high antifungal activity antifungal activity against C. tropicalis and C. krusei [129]. against C. tropicalis and C. krusei [129].

Scheme 196 and and their theirfurther furthermodification. modification. Scheme32. 32.Synthesis Synthesisof of1,2-dioxenes 1,2-dioxenes 196

6. 1,2,4-Trioxanes 6. 1,2,4-Trioxanes Among theclass classof of1,2,4-trioxane, 1,2,4-trioxane, various ofof thethe biological activity of artemisinin and its Among the variousaspects aspects biological activity of artemisinin and extensively. Synthetic strategies for peroxide ring ring construction in its derivatives derivativesare arestudied studiedmost most extensively. Synthetic strategies for peroxide construction thethesynthesis of of in artemisinin artemisinin were were discussed discussedinin detail detail [130]. [130]. Compared Comparedwith withother othermethods methods synthesis artemisinin (1) based on dihydroartemisinic acid seems most preferable [131], as it can satisfy the artemisinin (1) based on dihydroartemisinic acid seems most preferable [131], as it can satisfy cheaper production of sufficient quantities of artemisinin. The key of the of thedemand demandforfor cheaper production of sufficient quantities of artemisinin. Thestages key stages transformation of dihydroartemisinic acid into artemisinin (1) are described in the fundamental the transformation of dihydroartemisinic acid into artemisinin (1) are described in the fundamental studies of Richard K. Haynes [132]. studies of Richard K. Haynes [132].

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InInaddition artemisinin (1) (1) has has activity activityagainst against addition toto antimalarial antimalarial and and cytotoxic cytotoxic activity, artemisinin In additionLeishmania to antimalarial and cytotoxic activity, artemisinin (1) hasbrucei activity againstand trypanosomatides major [133], Leishmania donovani [134], Trypanosoma rhodesiense trypanosomatides Leishmania major [133], Leishmania donovani [134], Trypanosoma brucei rhodesiense trypanosomatides Leishmania major [133], Leishmania donovani [134], (Scheme Trypanosoma brucei Artemisinin rhodesiense and Trypanosoma cruzi [135], as parasite Toxoplasma gondii 33)Artemisinin [136]. Trypanosoma cruzi [135], as wellas as well parasite Toxoplasma gondii (Scheme 33) [136]. showed and Trypanosoma cruzi [135], as well as parasite Toxoplasma gondii (Scheme 33) [136]. Artemisinin showed a synergistic additive effect in combination with against itraconazole fungi Aspergillus a synergistic or additive or effect in combination with itraconazole fungi against Aspergillus fumigatus [137], showed a[137], synergistic effect in combination with Antiviral itraconazole against fungi Aspergillus as activity wellorasadditive moderate activity against Fusarium oxysporum [138]. Antiviral activity of as fumigatus well as moderate against Fusarium oxysporum [138]. activity of artemisinin (1) was fumigatus [137], as well as moderate activity against Fusarium oxysporum [138]. Antiviral activity of artemisinin (1) was reported in few studies; inhibition of the human immunodeficiency virus (HIV-1) reported in few studies; inhibition of the human immunodeficiency virus (HIV-1) at 60% in peripheral (1) was reported in few studies; inhibition of hepatitis the human virusliver (HIV-1) atartemisinin 60% in peripheral blood mononuclear cells [139],(HCV) the C immunodeficiency virus in human cells blood mononuclear cells [139], the hepatitis C virus in human liver(HCV) cells [140], the bovine viral at 60% in peripheral blood mononuclear cells [139], the hepatitis C virus (HCV) in human liver cells [140], the bovine viral diarrhea virus (BVDV) [141], as well as hepatitis B virus [142] was shown. diarrhea virus (BVDV) [141], as well as hepatitis B virus [142] was shown. [140], the bovine viral diarrhea virus (BVDV) [141], as well as hepatitis B virus [142] was shown. H O H O O O O H O HO H HO O O artemisinin (1) artemisinin (1)

L. major in vitro T. gondii complete elimination promastigotes L. major in vitroED50 = 0.75 M T. complete for 14elimination days at gondii 1.3 g/mL promastigotes = 0.75 M M amastigotes EDED at 1.3 g/mL for 14 days 5030 50 = amastigotes ED50 = 30 M A. fumigatus MIC50 = 125 g/mL g/mL A. MIC L. donovani in vitro F. fumigatus oxysporum inhibition at 50 = 12572% L. donovani in vitro F. oxysporum promastigotes IC50 = 160 M g/mL inhibition 72% at 200 = 160 promastigotes IC= 200 g/mL M M amastigotes IC50 5022 amastigotes IC50 = 22 M HIV-1 60% inhibition 10 M T. cruzi IC50 = 13.4 M HIV-1 60% = 78 M 10 M HCV EC 50 inhibition T. brucei cruzi ICrhodesiense T. 50 = 13.4 MIC50 = 20.4 M HCV EC = 78 M BVDV 60% 50 inhibition 100 M T. brucei rhodesiense IC50 = 20.4 M BVDV 60% inhibition 100 M

Scheme various types typesof ofits itsbioactivity. bioactivity. Scheme33. 33.Artemisinin Artemisinin and various Scheme 33. Artemisinin and various types of its bioactivity.

Artemisinin derivative, artemether (3), is actively used to treat schistosomiasis, a parasitic Artemisinin derivative, artemether (3),(3), is actively usedused to treat schistosomiasis, a parasitic disease Artemisinin derivative, artemether is actively to treat schistosomiasis, a parasitic disease caused by flat worms of the genus Schistosomiasis [46,47]. A double-blind field trial in the caused by flat worms of the genus Schistosomiasis [46,47]. A double-blind field trial in the Poyang Lake disease caused by flat worms of the genus Schistosomiasis [46,47]. A double-blind field trial in the Poyang Lake region (southern China) confirmed that artemether (3) significantly reduces the region (southern China) confirmed that artemether (3) significantly reduces the frequency and intensity Poyang Lake region (southern China) confirmed that artemether (3) significantly reduces the and intensity of S. japonicum infection and does not cause side effects [143]. Despite the of frequency S. japonicum infection does not cause side effects [143]. theeffects proven[143]. pathogenic frequency and intensityand of S. japonicum infection and does notDespite cause side Despite effects the proven pathogenic effects on the reproductive system of Fasciola hepatica [144,145], artemether (3) pathogenicsystem effects on the reproductive system ofartemether Fasciola hepatica [144,145], artemether (3) in on proven the reproductive of Fasciola hepatica [144,145], (3) had practically no effect had practically no effect in the treatment of fascioliasis in humans [146]. Artemether activity against practically no effect in the of fascioliasis in humans [146]. Artemether activitymajor against thehad treatment of fascioliasis in treatment humans [146]. Artemether activity against Leishmania [133], Leishmania major [133], and Toxoplasma gondii [136,147] was detected; it was shown also that Leishmania major [133], and Toxoplasma gondii [136,147] was detected; it was shown also that and Toxoplasma gondii [136,147] was detected; it was shown also that artemether is effective in artemether isis effective treatment experimental rheumatoid rheumatoid arthritis arthritis[148,149]. [148,149].Artemether Artemether effective in in the the treatment of of experimental theartemether treatment of experimental rheumatoid arthritis [148,149]. Artemether (3) is obtained by reduction of (3) isis obtained by reduction of artemisinin (1) to to dihydroartemisinin dihydroartemisinin (2) (2) followed followedby bymethylation methylation (3) obtained by reduction of artemisinin (1) artemisinin (1) to dihydroartemisinin (2) followed by methylation (Scheme 34) [150,151]. This synthesis (Scheme 34) This synthesis can performed in in flow flow reactor reactor[152,153]. [152,153]. 34)[150,151]. [150,151]. synthesis can be be performed can(Scheme be performed in flowThis reactor [152,153].

Scheme artemether (3)and andits itsbioactivity. bioactivity. Scheme34. Scheme 34.Synthesis Synthesis of of artemether artemether (3) (3) and its bioactivity.

Artesunate (4), artemisininderivative containing showed high efficiency Artesunate (4), artemisinin derivative containing containing free free carboxylic group showed high efficiency Artesunate (4), artemisinin freecarboxylic carboxylicgroup group showed high efficiency against S. japonicum [154,155], and also in the therapy of fascioliasis caused by Fasciola hepatica oror againstS.S.japonicum japonicum [154,155], [154,155], and also in thetherapy fascioliasis caused by Fasciola hepatica against therapyofof fascioliasis caused by Fasciola hepatica Fasciola gigantica (Scheme 35) [156]. It was determined that artesunate (4) causes changes in the 35)35) [156]. It was determined that that artesunate (4) causes changes in thein orFasciola Fasciolagigantica gigantica(Scheme (Scheme [156]. It was determined artesunate (4) causes changes reproductivesystem system of of Fasciola Fasciola hepatica hepatica [144]. [144]. Antiviral reproductive Antiviral activity activity of ofartesunate artesunateisisdisplayed displayedagainst againstthe the

the reproductive system of Fasciola hepatica [144]. Antiviral activity of artesunate is displayed

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hepatitisthe В virus [157]B and hepatitis C hepatitis virus [158], the herpes (HHV)virus type(HHV) 4 and type type 46 against hepatitis virusthe [157] and the C virus [158], virus the herpes [159,160], human cytomegalovirus (HCMV) [161–163], including therapy-resistant mutants of and type 6 [159,160], human cytomegalovirus (HCMV) [161–163], including therapy-resistant mutants human cytomegalovirus [164]. Artesunate of human cytomegalovirus [164]. Artesunate(4)(4)isisprepared preparedby byreaction reactionof ofdihydroartemisinin dihydroartemisinin (2) (2) with with succinic anhydride in basic conditions (Scheme 35) [152]. succinic anhydride in basic conditions (Scheme 35) [152].

Scheme Scheme 35. 35. Synthesis Synthesis of of artesunate artesunate (4) (4) and and its its bioactivity. bioactivity.

The library library of of 10-deoxo-derivativies 10-deoxo-derivativies of artemisinin 205 205 showed showed high high activity activity against against parasites parasites The of artemisinin Leishmania donovani artemisitene 199 by radical radical Leishmania donovani (Scheme (Scheme 36). 36). Synthesis Synthesis of of 205 205 was was performed performed from from artemisitene 199 by addition of of compound compound 200 200 followed followed by by reduction reduction of of carbonyl carbonyl group group in in 202. 202. Dehydration Dehydration and and addition deprotection resulted in phenol 204, which formed a series of compounds 205 by reaction with deprotection resulted in phenol 204, which formed a series of compounds 205 by reaction with derivatives of of carboxylic carboxylic and and sulfonic sulfonic acids acids [165]. [165]. derivatives H H

H H O O O O O O H HO O

OTIPS OTIPS H H

Br Br

O 199 199 O

[(CH [(CH33))33Si] Si]33 SiH SiH AIBN, AIBN, C C66H H66 63% 63%

O O O O O O H HO O O O

200 200 H H

DBU DBU THF THF 50% 50%

201 201

H H

O O O O O O H HO O

OTIPS OTIPS DIBAL-H DIBAL-H THF THF 85% 85%

H H O O

O O O O O O H HO O

H H O O O O O O H HO O

OH OH H H 204 204

H H OR OR11 H H

OTIPS OTIPS H H OH OH

202 202

1) 1) Et Et33SiH, SiH, BF BF33 OEt OEt22 CH CH22Cl Cl22 2) 2) pyridine pyridine 3) 3) TBAF, TBAF, THF THF 72% 72%

O O O O O O H HO O

OTIPS OTIPS H H

203 203

RCOCl/RSO RCOCl/RSO22Cl/RNCO Cl/RNCO or or thiophosgene thiophosgene Et Et33N N CH CH22Cl Cl22 60 60 98% 98% R R11 == RCO-, RCO-, RSO RSO22-,-, RNHCORNHCOR R == Alk, Alk, Ar Ar

L. L. donovani donovani IC IC50 = 0.26 0.26 -- 3.18 3.18 M M 50 =

205 205

Scheme 36. 36. Antileishmaniasis Antileishmaniasis derivatives derivatives of of artemisinin artemisinin 205. 205. Scheme

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Attempts to to synthesize Attempts synthesize the the antitoxoplasma antitoxoplasma derivatives derivatives of of artemisinin artemisinin have have been been made made [147,166], [147,166], however their their in in vitro vitro activity activity did did not not exceed exceed the the activity activity of of artemether artemether (3). (3). however Among artemisinin artemisininderivatives derivativestested testedforfor fungicidal activity, anhydrodihydroartemisinin Among fungicidal activity, anhydrodihydroartemisinin (206)(206) and and arteether (207) were most active against Cryptoccocus neoformans [167], their activity surpassed arteether (207) were most active against Cryptoccocus neoformans [167], their activity surpassed the one theamphotericin one of amphotericin B. Both derivatives were obtained [168,169] in one step from of B. Both derivatives were obtained [168,169] in one step from dihydroartemisinin (2) dihydroartemisinin (2) (Scheme 37). Later it was found that arteether (207) [170] exhibits moderate (Scheme 37). Later it was found that arteether (207) [170] exhibits moderate antiviral activity against antiviralimmunodeficiency activity against human immunodeficiency virus and anhydrodihydroartemisinin (206) human virus and anhydrodihydroartemisinin (206) [171] is high active against [171] is high active against hepatitis B virus. hepatitis B virus. H BF3 OEt2 Et 2O

H O O O HO

85%

2

H

HBV IC50 = 0.1 M

anhydrodihydroartemisinin (206) H

H OH

C. neoformans IC50 = 0.045 g/mL

O O O HO

EtOH BF3 OEt2 PhCH3 72%

O O O HO

H

C. neoformans IC50 = 0.085 g/mL HIV-1 IC50 = 30.9 M

O arteether (207)

Scheme Antifungal and and antiviral antiviral artemisinin artemisinin derivatives— derivatives— anhydrodihydroartemisinin anhydrodihydroartemisinin (206) Scheme 37. 37. Antifungal (206) and and arteether (207). arteether (207).

High antiviral antiviral activity activity against against human human immunodeficiency immunodeficiency virus was demonstrated demonstrated by by High virus [170] [170] was butyl-derivative of artemisinin 209, prepared via photo-oxidation of alcohol 208 with 12% yield butyl-derivative of artemisinin 209, prepared via photo-oxidation of alcohol 208 with 12% yield (Scheme 38) 38) [172]. [172]. (Scheme

Scheme Antiviral artemisinin Scheme 38. 38. Antiviral artemisinin derivative derivative 209. 209.

Combination of dihydroartemisinin (2) with antiviral drug azidothymidine (210) resulted in exhibited both both antimalarial antimalarial as as antiviral antiviral activity activity (Scheme (Scheme 39) 39) [173]. [173]. compound 211 exhibited derivatives is is the synthesis synthesis of of dimers dimers and A new trend in the medical chemistry of artemisinin derivatives trimers. Among Amongaaseries seriesofofartemisinin artemisinin dimers obtained by condensation of dihydroartemisinin (2) trimers. dimers obtained by condensation of dihydroartemisinin (2) with with binucleophile, compounds 213 showed theactivity highestagainst activity against fungi Cryptococcus binucleophile, compounds 212 and212 213and showed the highest fungi Cryptococcus neoformans neoformans and parasitesdonovani, Leishmania donovani, (Scheme respectively (Scheme 40) [174]. and parasites Leishmania respectively 40) [174].

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Scheme Synthesis hybrid 211based based on dihydroartemisinin dihydroartemisinin 22and 210. Scheme 39. of 211 on 22azidothymidine and azidothymidine 210. Scheme 39.39. Synthesis ofofhybrid 211 on and azidothymidine 210. Scheme 39.Synthesis Synthesis ofhybrid hybrid 211based based ondihydroartemisinin dihydroartemisinin and azidothymidine 210. Scheme 39. Synthesis of hybrid 211 based on dihydroartemisinin 2 and azidothymidine 210.

Scheme 40. Synthesis of artemisinin dimers 212 and 213 with antifungal and anti-parasitic activity.

Scheme 40. of dimers 213 antifungal and anti-parasitic activity. Scheme Synthesis artemisinin dimers 212 212 and 213 antifungal and activity. Scheme 40.Synthesis Synthesis ofartemisinin artemisinin dimers 212and andwith 213with with antifungal and anti-parasitic activity. Scheme 40.40. Synthesis ofofartemisinin dimers 212 and 213 with antifungal andanti-parasitic anti-parasitic activity.

Dimers and trimers of artemisinin showed antiviral activity were summarized in Table 1. Dimers and trimers of artemisinin showed antiviral activity werewere summarized in Table 1. 1.1. Dimers and trimers of showed antiviral activity summarized in Dimers and trimers ofartemisinin artemisinin showed antiviral activity were summarized inTable Table

Dimers and trimers of1.artemisinin showed antiviral activity summarized in Table 1. Table Dimers and trimers of artemisinin showed were antiviral activity. No. No. No. No. No.

Table 1. Dimers andand trimers of artemisinin showed antiviral activity. Table 1.1.Dimers trimers of showed antiviral activity. Table Dimers and trimers ofartemisinin artemisinin showed antiviral activity. Dimer/Trimer Table 1. Dimers and trimers of artemisinin showed antiviral activity.

Dimer/Trimer Dimer/Trimer Structure Dimer/Trimer Structure Structure Dimer/Trimer Structure Structure

1 11 1 1 214 214214 214 214 2 22

22 215 215215 215 215

Synthesis Synthesis Synthesis Synthesis Synthesis

Bioactivity Bioactivity Bioactivity Bioactivity Bioactivity

from artemisinin (1) 3 HCMV EC50 = 0.15 µM from artemisinin (1) 3(1) 3 HCMV EC50 EC = 0.15 µM steps, 67% [175] [176,177] from artemisinin HCMV 5050== 0.15 from artemisinin (1) (1) 3 HCMV EC50 = 0.15 µM from artemisinin HCMV EC 0.15µM µM steps, 67% [175] [176,177] 3 steps, steps, 67% [175] [176,177] [176,177] steps,67% 67%[175] [175] [176,177]

from 214 3 steps, 42% HCMV EC50 = 0.06 µM from 214[178] 3 steps, 42% 50 = 0.06 µM HCMV EC [176] from214 214 333steps, from steps, EC from 214 steps,42% 42% HCMVHCMV 50==0.06 0.06µM µM HCMV EC50µM EC50 = 0.06 [176] [176] [178] 42% [178] [176] [178] [176] [178]

Molecules 2017, 22, 1881

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Table 1. Cont. Molecules2017, 2017,22, 22,1881 1881 Molecules Molecules Molecules 2017, 2017, 22, 22, 1881 1881 No. Dimer/Trimer Structure

ART ART ART ART ART ART ART ART

3

3333

4

4444

O O O O P P P OP O O O O O O OO O O O Ph Ph Ph Ph Ph Ph Ph Ph 216 216 216 216 216

25of of39 39 25 25 25 of of 39 39 Synthesis

Bioactivity

HCMV EC 50 = 0.04 µM µM HCMV EC 50 0.04 µM HCMV 50 0.04 from 214 1step, step, 96% EC50EC = 0.04 HCMV EC 50 = ==µM 0.04 µM from 214 step, 96% [179] [179] HCMV from 214 [179] from 214 1111[179] step, 96% from 214 step, 96% [179] 96% [180–182] [180–182] [180–182] [180–182] [180–182]

HCMV EC EC50 50 = 44 44 nM nM 50 from 214 1 step, HCMV EC 50 = =[183] 44 nM from 214 1111 step, step, 25% 25% [183] [183]HCMVHCMV from 214 step, 25% [183] EC50 = 44 nM from 214 from 214 step, 25% [183] 25% [183] [183] [183] [183] [183] 217 217 217 217 217

5

fromthreo-214 threo-214 and from threo-214 and from threo-214 from and and from threo-214 and artesunate (4), 1 step, artesunate (4), 1 step, artesunate (4), 1 step, artesunate artesunate (4), (4), 11 step, step, quantitative yield [184] quantitative yield yield [184] [184] quantitative yield [184] quantitative quantitative yield [184]

5555

HCMV EC 50 = 0.04 µM µM HCMV EC 50 0.04 µM HCMV EC50EC = 0.04 HCMV 50 0.04 HCMV EC 50 = ==µM 0.04 µM [184,185] [184,185] [184,185] [184,185] [184,185]

218 218 218 218 218

6

from threo-214 step, 67% 67% HCMV 50 = 0.11 µM µM HCMV EC EC50 from threo-214 111step, step, 67% 50 === 0.11 0.11 HCMV EC from threo-214 11 from threo-214 step, from threo-214 step, 67% 50 0.11 µM HCMV EC HCMV EC50 = 0.11 µM [186] µM 67% [186] [186] [186] [186] [186] [186] [186] [186] [186]

6666

219 219 219 219 219

7

not reported not reported not reported

7777

not not reported reported

3.2 µM µM HCV EC EC5050 == 3.2 HCV [187] [187] [187] [187]

50 3.2 HCV EC HCV EC 50 = =[187] 3.2 µM µM HCV ECµM 50 = 3.2

220 220 220 220 220

Synthetic 1,2,4-trioxanes 223 obtained obtained by condensation condensation of hydroxy-hydroperoxide hydroxy-hydroperoxide 221 with Synthetic 1,2,4-trioxanes 223 obtained by condensation of hydroxy-hydroperoxide 221 with Synthetic 1,2,4-trioxanes 223 223 obtained by condensation of hydroxy-hydroperoxide 221 with Synthetic 1,2,4-trioxanes by of 221 with Synthetic 1,2,4-trioxanes 223 obtained by condensation of hydroxy-hydroperoxide 221 with adamantane followed by hydrolysis of ester 222 showed high in vivo activity against helminths adamantane followed by hydrolysis of ester 222 showed high in vivo activity against helminths adamantane followed by hydrolysis of ester 222222 showed high in vivo activity against helminths adamantane followed by hydrolysis of ester showed high in vivo activity against helminths Fasciola hepatica in(Scheme rats (Scheme (Scheme 41) [188]. [188]. Fasciola hepatica in rats (Scheme 41) [188]. Fasciola hepatica in rats 41) Fasciola hepatica in rats 41) [188]. Fasciola hepatica in rats (Scheme 41) [188].

Molecules 2017, 22, 1881 Molecules 22, 1881 1881 Molecules 2017, 2017, 22, Molecules 2017, 22, 1881

26 of 39 26 26 of of 39 39 26 of 39

Scheme 41. Anthelminthic activity of synthetic 1,2,4-trioxanes 223. Scheme Anthelminthic 223. Scheme 41. 41. Anthelminthic activity activity of of synthetic synthetic 1,2,4-trioxanes 1,2,4-trioxanes Scheme 41. Anthelminthic activity of synthetic 1,2,4-trioxanes 223. 223.

7. 1,2,4,5-Tetraoxanes 1,2,4,5-Tetraoxanes 7. 7. 1,2,4,5-Tetraoxanes 7. 1,2,4,5-Tetraoxanes Synthetic 1,2,4,5-tetraoxane 1,2,4,5-tetraoxane 226 226 [189], [189], prepared prepared by by condensation condensation of of bis-hydroperoxide bis-hydroperoxide 224 224 with with Synthetic Synthetic 1,2,4,5-tetraoxane 226 [189], [189], prepared by of bis-hydroperoxide 224 with Synthetic 1,2,4,5-tetraoxane 226 prepared by condensation condensation of bis-hydroperoxide 224 with adamantanone followed by hydrolysis ester 225, showed high in vivo activity against helminths adamantanone followed by hydrolysis ester 225, showed high in vivo activity against helminths adamantanone followed by hydrolysis hydrolysis ester 225, 225, showed showed high high in in vivo adamantanone by vivo activity activity against against helminths helminths Fasciola hepatica hepatica followed in rats rats (Scheme (Scheme 42) [188]. [188].ester Fasciola in 42) Fasciola hepatica in rats (Scheme 42) [188]. Fasciola hepatica in rats (Scheme 42) [188]. O O O

HOO HOO HOO

OOH OOH OOH

224 224 224

KOH KOH CH OH KOH CH33OH CH 3OH 87% 87% 87%

HBF HBF44 EtOAc HBF EtOAc 4 50% EtOAc 50% CO Et 50% CO22Et CO2Et O O O O O O O O O O 226O O 226 226

O O O O O O O O O O O225 O 225 225

CO Et CO22Et CO2Et

100% worm burden reduction 100% worm burden reduction F. hepatica rats atreduction 50 mg/kg CO2H 100% worm in burden CO2H F. hepatica in rats at 50 mg/kg F. hepatica in rats at 50 mg/kg CO2H

Scheme 42. Synthesis of 1,2,4,5-tetraoxane 226 with high anthelmintic activity. activity. Scheme 42. Synthesis of 1,2,4,5-tetraoxane 226 with high anthelmintic activity. Scheme 42. Synthesis of 1,2,4,5-tetraoxane 226 with high anthelmintic activity.

Based on on related related 1,2,4,5-tetraoxanes 1,2,4,5-tetraoxanes 227, 227, hybrids hybrids 229 229 with with aa fragment fragment of of an an anthelmintic anthelmintic drug drug Based 1,2,4,5-tetraoxanes Based on related 1,2,4,5-tetraoxanes 227, hybrids 229 with a fragment of an anthelmintic drug praziquantel 228 228 were were obtained obtained (Scheme (Scheme 43) 43) [190]. [190]. Synthesized Synthesized hybrids 229 exhibit high high activity activity praziquantel Synthesized hybrids hybrids 229 229 exhibit [190]. praziquantel 228 were obtained (Scheme 43) [190]. Synthesized hybrids 229 exhibit high activity against Schistosoma japonicum and Schistosoma mansoni [191]. against Schistosoma japonicum and Schistosoma mansoni [191]. against Schistosoma japonicum and Schistosoma mansoni [191].

R R R

O O O O O O

R R R

O O O O O O

O O O O O O 227 227 227 O O O O O O

NH NH22 NH2

O O O OH OH OH

N N N N N N 228 O 228 O 228 O

O O O NH NH NH

229 229 229

N N N

N N N

O O O

O O O

EDCl EDCl pyridine EDCl pyridine pyridine

worm burden reduction worm burden reduction adult and burden juvenilereduction S.japonicum worm adult and juvenile S.japonicum adult juvenile up S.japonicum 229a R =and adamantyl to 42% 229a R = adamantyl up to 42% 229b R = cyclopentyl up to 35% 229a R = adamantyl 229b cyclopentylup uptoto42% 35% 229c R dimethyl up up to 25% 229b R= = dimethyl cyclopentyl to 35% 229c up to 25% 229c R = dimethyl up to 25%

O O O Scheme 43. Synthesis of hybrids 229 as anti-schistosomal agents. Scheme 43. Synthesis of hybrids 229 as anti-schistosomal agents. Scheme 43. Synthesis of hybrids 229 as anti-schistosomal agents.

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Molecules 2017, 22, 1881 Molecules 2017, 22,1,2,4,5-tetraoxanes 1881 Bridged

27 of 39

27 of 39 231 demonstrated high in vitro and in vivo activity against trematodes Schistosoma mansoni [74,192]. The best result was shown for adamantane-substituted Bridged 1,2,4,5-tetraoxanes 1,2,4,5-tetraoxanes 231 demonstrated inand vitro and activity in vivo activity against Bridged demonstrated high high in vitro in vivo against trematodes tetraoxane 231a which caused231 75% worm burden reductions in S. mansoni harbored in mice trematodes mansoni Schistosoma mansoni [74,192]. best result was shown for adamantane-substituted Schistosoma [74,192]. The resultThe was shown fordose adamantane-substituted tetraoxane 231a following the administration of best peroxide at single oral of 400 mg/kg. Peroxides 231 were tetraoxane 231a which caused 75% worm burden reductions in S. mansoni harbored in mice which causedfrom 75% β-diketones worm burden230 reductions S. mansoni harbored following the administration synthesized and H2Oin 2 with good yields by in themice action of various acids: sulfuric following the administration of peroxide at Peroxides single oral dose ofsynthesized 400 mg/kg.from Peroxides 231 were of peroxide at single oral dose of 400 mg/kg. 231 were β-diketones 230 [193], phosphomolybdic and phosphotungstic acids [194] (Scheme 44). synthesized fromgood β-diketones 230the and H2O2of with good acids: yields sulfuric by the action various acids: sulfuric and H2 O2 with yields by action various [193],ofphosphomolybdic and [193], phosphomolybdic and(Scheme phosphotungstic acids [194] (Scheme 44). phosphotungstic acids [194] 44). O O O O O O O O O O O O H2O2 O O O O H2H SOO4 or 231a O O 2 2 R PMA or PWA in vitro OR O H41 231aIC50 = 0.3 M adult S. mansoni 2SO 4 or 230 231 83% R PMA or PWA R in vitro NTS S. mansoni IC50 = 0.1 M adult in vivoS. mansoni IC50 = 0.3 M 230 231 41 83% NTS worm S. mansoni ICreduction 75% burden 50 = 0.1 M in vivo 75% worm burden reduction Scheme 44. Synthesis of bridged 1,2,4,5-tetraoxanes 231.

8. Acyclic Peroxides

Scheme Scheme 44. 44. Synthesis Synthesis of of bridged bridged 1,2,4,5-tetraoxanes 1,2,4,5-tetraoxanes 231. 231.

ManyPeroxides acyclic peroxides are applied as oxidants in organic synthesis [195,196]. Benzoyl peroxide 8. Acyclic (234) is actively used in the food industry as a flour bleach [197–199], and in pharmaceuticals. The Many applied as as oxidants in organic synthesis [195,196]. Benzoyl peroxide (234) Many acyclic acyclicperoxides peroxidesare are applied oxidants in organic synthesis [195,196]. Benzoyl peroxide first mention about the medical using of benzoyl peroxide dates back to 1929, where Lyon and is actively used in theinfood as a flour bleachbleach [197–199], and inand pharmaceuticals. The first (234) is actively used the industry food industry as a flour [197–199], in pharmaceuticals. The Reynolds reported effective treatment of burns, wounds and varicose veins by benzoyl peroxide mention aboutabout the medical using of benzoyl peroxide dates back to 1929, Lyon and Lyon Reynolds first mention the medical using of benzoyl peroxide dates back where to 1929, where and [200]. Subsequently it was found that it has antibacterial [201,202], anti-inflammatory [203], reported of burns,ofwounds and varicose veins by benzoyl peroxide [200]. Reynolds effective reported treatment effective treatment burns, wounds and varicose veins by benzoyl peroxide cheratolic [204], and wound-healing [205,206] effects. Presently, benzoyl peroxide is widely used Subsequently it was found thatfound it has antibacterial anti-inflammatory [203], cheratolic [203], [204], [200]. Subsequently it was that it has [201,202], antibacterial [201,202], anti-inflammatory agent for acne treatment because of its efficacy and good tolerability in patients [207,208]. Benzoyl and wound-healing [205,206] effects. Presently, benzoyl peroxide is widely used agent for acne cheratolic [204], and wound-healing [205,206] effects. Presently, benzoyl peroxide is widely used peroxide is a good alternative to monotherapy with antibiotics for the treatment of Acne vulgaris treatment of its efficacy andofgood tolerability patients [207,208]. Benzoyl [207,208]. peroxide isBenzoyl a good agent for because acne treatment because its efficacy and in good tolerability in patients caused antibiotic-resistant strains, for example Propionibacterium acnes [209,210]. alternative with to antibiotics for the with treatment of Acnefor vulgaris caused antibiotic-resistant peroxide istoamonotherapy good alternative monotherapy antibiotics the treatment of Acne vulgaris Benzoyl peroxide is commercially produced by the reaction of benzoyl chloride (232), sodium strains, for example Propionibacterium [209,210]. caused antibiotic-resistant strains, for acnes example Propionibacterium acnes [209,210]. hydroxide and hydrogen peroxide (Scheme 45, top) [211,212]. Benzoyl peroxide can also be prepared Benzoyl is commercially produced by theby reaction of benzoyl chloride (232), sodium hydroxide Benzoylperoxide peroxide is commercially produced the reaction of benzoyl chloride (232), sodium from benzoic anhydride (233) by the action of an alkali metal perborate in an aqueous solution and hydrogen (Scheme 45, (Scheme top) [211,212]. Benzoyl peroxide can peroxide also be prepared benzoic hydroxide andperoxide hydrogen peroxide 45, top) [211,212]. Benzoyl can alsofrom be prepared (Scheme 45, bottom) [213]. anhydride (233) by the action of an alkali metal perborate in an aqueous solution (Scheme 45, bottom) [213]. from benzoic anhydride (233) by the action of an alkali metal perborate in an aqueous solution (Scheme 45, bottom) [213].

Scheme 45. Benzoyl peroxide (234) production. Scheme 45. Benzoyl peroxide (234) production.

Schemefrom 45. Benzoyl peroxide (234) production. Oxanthromicin (235) isolated bacteria Actinomadura sp. [214] showed high antifungal activity against Trichophyton mentagrophytes, Micosporum canis, M. gypseum, Epidermophyton floccosum, Oxanthromicin (235) isolated from bacteria[215]. Actinomadura sp. [214] showed high antifungal Candida albicans, and Aspergillus Aspergillus niger niger (Scheme (Scheme 46) 46) [215]. activity against Trichophyton mentagrophytes, Micosporum canis, M. gypseum, Epidermophyton floccosum, Candida albicans, and Aspergillus niger (Scheme 46) [215].

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OH O OH O

COOH COOH OH OH

O O O O

OH OH COOH COOH

Trichophyton mentagrophytes Trichophyton mentagrophytes Micosporum canis Micosporum canis M. gypseum M. gypseum Epidermophyton floccosum Epidermophyton Candida albicansfloccosum Candida albicans Aspergillus niger Aspergillus niger

MIC ( g/mL) MIC4( g/mL) 44 4 2 2 8 88 88 8

OH O OH O Oxantromicin (235) Oxantromicin (235)

Scheme 46. 46. Antifungal natural acyclic acyclic peroxide, peroxide, oxanthromicin oxanthromicin (235). (235). Scheme Antifungal natural Scheme 46. Antifungal natural acyclic peroxide, oxanthromicin (235).

Hydroperoxide 236 obtained by biotransformation of Artemisia cina metabolites exhibits high in 236 obtained obtainedby bybiotransformation biotransformationofofArtemisia Artemisiacina cina metabolites exhibits high Hydroperoxide 236 metabolites exhibits high in vitro activity against protozoa Trypanosoma brucei (Scheme 47) [216]. in vitro activity against protozoa Trypanosoma brucei (Scheme 47) [216]. vitro activity against protozoa Trypanosoma brucei (Scheme 47) [216].

H H

O H O O H O O O O OH O OH 236 236 Tripanosoma brucei EC50 ( g/mL) 0.40 Tripanosoma brucei EC50 50 ( g/mL) 0.40 Scheme 47. Anti-trypanosomal hydroperoxide 236. Scheme 47. Anti-trypanosomal Anti-trypanosomal hydroperoxide hydroperoxide 236.

Four monoterpene hydroperoxides 237a–d were isolated from aerial parts of Chenopodium Four monoterpene hydroperoxides 237a–d isolated fromparts aerial partsTrypanosoma of Chenopodium ambrosioides. Minimumhydroperoxides lethal concentration (MLC) in vitro of itsaerial peroxides against cruzi Four monoterpene 237a–d were were isolated from of Chenopodium ambrosioides. ambrosioides. Minimum lethal concentration (MLC) in vitro of its peroxides against Trypanosoma cruzi was 1.2, 1.6, 3.1, and 0.8 µM, respectively (Scheme [107]. against Trypanosoma cruzi was 1.2, 1.6, Minimum lethal concentration (MLC) in vitro of its48) peroxides was 1.2, 0.8 1.6,µM, 3.1,respectively and 0.8 µM,(Scheme respectively (Scheme 48) [107]. 3.1, and 48) [107]. HOO HOO

237a 237a 1.2 1.2

HOO HOO

OOH HOO OOH HOO

237b 237c 237b 237c Tripanosoma cruzi MLC ( Tripanosoma cruzi3.1 MLC ( 1.6 1.6 3.1

237d 237d M) M)0.8 0.8

Scheme 48. Hydroperoxides 237a–d isolated from Chenopodium ambrosioides. Scheme 48. 48. Hydroperoxides Hydroperoxides 237a–d 237a–d isolated isolated from from Chenopodium Chenopodium ambrosioides. Scheme ambrosioides.

A geminal bis-hydroperoxides 239 synthesized from cyclic ketones 238 show pronounced in A geminal geminalbis-hydroperoxides bis-hydroperoxides239 239synthesized synthesized from cyclic ketones pronounced in from cyclic ketones 238 238 showshow pronounced in vitro vitro antimicrobial and antifungal activity against B. cereus, E. coli, P. aeruginosa, S. aureus, C. albicans, vitro antimicrobial and antifungal activity against B. cereus, coli,and, aeruginosa, aureus, C. albicans, antimicrobial and antifungal activity against B. cereus, E. E. coli, P.P.aeruginosa, S.S.aureus, albicans, and A. niger comparable with the effect of some antiseptics to a lesser extent, antibiotics and A. niger comparable with the effect of some antiseptics and, to a lesser lesser extent, extent, antibiotics (Scheme 49) [217]. (Scheme 49) [217].

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Scheme 49. 49. Antimicrobial Antimicrobial and and antifungal antifungal geminal geminal bis-hydroperoxides Scheme bis-hydroperoxides 239. 239.

9. Conclusions 9. Conclusions The biological of organic peroxides is usually associated with the with antimalarial properties biologicalactivity activity of organic peroxides is usually associated the antimalarial of artemisinin and its derivatives. However,However, the analysis published data indicates that organic properties of artemisinin and its derivatives. the of analysis of published data indicates that peroxides exhibit a variety of biological activity—anthelmintic, antifungal, antiviral, etc.—which is organic peroxides exhibit a variety of biological activity—anthelmintic, antifungal, antiviral, still being given insufficient attention. etc.—which is still being given insufficient attention. Efforts chemists areare currently directed at theat development of methods for the synthesis Efforts ofofsynthetic synthetic chemists currently directed the development of methods for the of biologically active natural peroxides, the modification of natural peroxides and the search of synthesis of biologically active natural peroxides, the modification of natural peroxides and the synthetic peroxides, which are not are inferior to theirtonatural and semisynthetic analogs, but but are search of synthetic peroxides, which not inferior their natural and semisynthetic analogs, substantially cheaper. It seems thatthat progress in the synthesis of biologically active peroxides willwill be are substantially cheaper. It seems progress in the synthesis of biologically active peroxides mainly related to the last two directions. be mainly related to the last two directions. In view of very dynamic development development of of these these areas areas of of medical medical chemistry, chemistry, in the near future, future, one should expect a breakthrough in the synthesis of biologically active peroxides and in understanding should expect a breakthrough in the synthesis of biologically active peroxides and in of its action with to awith wide range to of abio-targets. understanding ofrespect its action respect wide range of bio-targets. The authors authorsare aregrateful gratefultotothe theRussian Russian Science Foundation (Grant 17-73-10364) for Acknowledgments: Acknowledgments: The Science Foundation (Grant 17-73-10364) for the the financial support. financial support. Author Contributions: All authors have contributed substantially: V.A.V., I.A.Y., I.A.I. and A.O.T. wrote Author Contributions: Alland authors contributed substantially: V.A.V., I.A.I. and A.O.T. wrote the the manuscript; and V.A.V. I.A.Y.have researched the literature and wrote the I.A.Y., manuscript. manuscript; and V.A.V. and I.A.Y. researched the literature and wrote the manuscript. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest.

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