Peroxides with Anthelmintic, Antiprotozoal, Fungicidal and Antiviral Bioactivity

39 Pages·2017·11.85 MB·English

molecules
Review
Peroxides with Anthelmintic, Antiprotozoal,
Fungicidal and Antiviral Bioactivity:
Properties, Synthesis and Reactions
VeraA.Vil’1,2,3,IvanA.Yaremenko1,2,3,AlexeyI.Ilovaisky1andAlexanderO.Terent’ev1,2,3,* ID
1 N.D.ZelinskyInstituteofOrganicChemistry,RussianAcademyofSciences,47LeninskyProspekt,
119991Moscow,Russia;[email protected](V.A.V.);[email protected](I.A.Y.);[email protected](A.I.I.)
2 FacultyofChemicalandPharmaceuticalTechnologyandBiomedicalProducts,D.I.MendeleevUniversity
ofChemicalTechnologyofRussia,9MiusskayaSquare,125047Moscow,Russia
3 All-RussianResearchInstituteforPhytopathology,B.Vyazyomy,143050Moscow,Russia
* Correspondence:[email protected];Tel.:[phone]
Received:9October2017;Accepted:30October2017;Published:2November2017
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
thatorganicperoxidesexhibitavarietyofbiologicalactivity,whichisstillbeinggiveninsufficient
attention. In the present review, we deal with natural, semi-synthetic and synthetic peroxides
exhibitinganthelmintic,antiprotozoal,fungicidal,antiviralandotheractivitiesthathavenotbeen
describedindetailearlier. Thereviewismainlyconcernedwiththedevelopmentofmethodsfor
thesynthesisofbiologicallyactivenaturalperoxides,aswellasitsisolationfromnaturalsourcesand
themodificationofnaturalperoxides. Inaddition,muchattentionispaidtothesubstantiallycheaper
biologicallyactivesyntheticperoxides. Thepresentreviewsummarizes217publicationsmainlyfrom
2000onwards.
Keywords: peroxides;anthelmintic;antiprotozoal;fungicidal;antiviral
1. Introduction
Peroxides are widely used in various areas of life [1–3]. Traditional and the most developed
fieldistheapplicationofperoxidesasradicalinitiatorsinindustrialprocessesinthemanufactureof
polymersfromunsaturatedmonomers:styrenes,butadienes,chlorovinyls,ethylenes,acrylates,aswellas
in crosslinking of silicone rubbers, acrylonitrile-butadiene rubbers, fluororubbers, polyethylene,
ethylene-propylenecopolymer,etc.[4–9].
Hydrogenperoxideandperacidsareactivecomponentsofantisepticsanddisinfectants[10–14].
Synthesisandmechanismofantisepticactionofhydrogenperoxideandthemostcommonperacids
(performic,peracetic,etc.) areelucidatedinafewstudies[15–17]andarenotconsideredinthisreview.
Antimalarialpropertiesofperoxidesarecurrentlyintensivelystudied.Artemisinin(Qinghaosu)(1),
anaturalperoxidepossessinghighantimalarialactivity, wasisolated in 1971 from leaves of annual
wormwood (Artemisia annua) in the context of the scientific program “Project 523”, initiated by
Chinesegovernmentin1967[18–20]. TheNobelPrizeinPhysiologyorMedicine2015wasawarded
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
sometraditionaldrugs,suchasquinine,chloroquine,andmefloquine,andotheranti-parasiticones,
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].
Molecules2017,22,1881;doi:10.3390/molecules22111881 www.mdpi.com/journal/molecules
Molecules2017,22,1881 2of39
Molecules 2017, 22, 1881 2 of 39
Molecules 2017, 22, 1881 2 of 39
H
H H H
O
H
OO H OO H OO H OOO
OOHHOOOOO HH OOHHOOOOOH HH OOHHOOOOO HH OHHOOOO HH OO OH
O O
artemisiOnin(1) dihydroartOemHisinin(2) artemeOther (3) artesunate(4) OH

O
artemisinin(1) dihydroartemisinin(2) artemether (3) artesunate(4)
FiFgiugruere1 .1A. Artretemmisisininiinn aanndd iittss sseemmii--ssyynntthheetticic ddeerirvivataitvievse.s .
Figure 1. Artemisinin and its semi-synthetic derivatives.
The modern trend in medicinal chemistry of peroxides is 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. TThhee mnoadtuerrna ltraenndd siynn mtheedtiiccinpael rochxeidmeisstreyx hoifb piteinrogxiadecsy tios ttohxei cseeafrfechct oofn efcfaecntciveer caenltliscaanlcreera dy
include hundreds of compounds [31–34]. Peroxides possessing antimalarial and cytotoxic activity
incdlurduegsh. uTnhder endastuorfacl oamndp osuynndthse[t3ic1 –p3e4r]o.xPideeros xeixdheisbpitoinsgse ass icnygtoatonxtiimc eaflfaercita loann dcacnycteort ocxelilcs aacltrievaitdyy are
are the subject of numerous studies [35–42], and are not considered in this review.
theinsuclbujdecet houfnndurmedesr oouf scostmupdoieusn[d3s5 –[3412–]3,4a]n. dPearroexnidoetsc opnosssidesesriendg ianntthimisarleavriiaelw a.nd cytotoxic activity
In the present review, we deal with natural, semi-synthetic and synthetic peroxides exhibiting
arIen ththe esupbrjeescet notf nreuvmieewro,uws estduedaielsw [3it5h–4n2a],t uanradl ,asree mnoi-ts cyonntshideetirceda nind tshyisn rtheveiteicwp. eroxidesexhibiting
anthelmintic, antiprotozoal, fungicidal, antiviral and other activities that have not been described in
anthelmInin tthice, parnetsiepnrto rteovzioeawl,, wfuen dgeicaild walit,ha nnatitvuirraall, saenmdi-ostyhnetrheatcicti avnitdie ssytnhthatethica vpeernoxoitdbese eenxhdibeistcinrigb ed
detail earlier. The review is mainly concerned with the synthesis of such peroxides, as well as its
anthelmintic, antiprotozoal, fungicidal, antiviral and other activities that have not been described in
indiseotalaitlioeanr flrioemr. Tnhateurreavl iseowurcisesm aanidn lcyovceornsc leitrenraetdurwe ipthubthlisehseydn bthetewsieseonf 1s9u1c2h anpde r2o0x1i7d. es,aswellasits
detail earlier. The review is mainly concerned with the synthesis of such peroxides, as well as its
isolationThfreorme anraet usreavlesroaul rrceevsieawnd acrotvicelerss, liwtehraetrue rethpeu bvlairsihoeuds bkeitnwdes enof1 9th1e2 abniodlo2g0i1c7a.l activity of
isolation from natural sources and covers literature published between 1912 and 2017.
arTtehmeirseinainr e[4s3e–v4e5r]a lanrde vaiertwemaerthtiecrl e[s4,6,w47h];e rtehet hperovblaermiosu sof ktirnedmsatoofdet hienfebcitoiolong itchaelraapcyt ivwiittyh of
There are several review articles, where the various kinds of the biological activity of
arteamrteisminisiinnin[4, 3it–s4 d5]eraivnadtivaerst eamnde tsheevrera[4l 6s,y4n7t]h;ettihce ozpornoibdleesm [4s8]o; fantrde manatitvoidrael ainctfievcittiyo nof tahrteermapisyiniwn ith
artemisinin [43–45] and artemether [46,47]; the problems of trematode infection therapy with
arteamndis ianritne,siutnsadteer i[v4a9t]i vaeres adnidscsuesvseedra. lAsydnvtahnecteics oinz otnhied edse[v4e8l]o;pamndenatn otifv iarnatli-apcatirvaistiytico fpaerrtoexmidiseisn ianrea nd
artemisinin, its derivatives and several synthetic ozonides [48]; and antiviral activity of artemisinin
artedseusncraitbee[d4 9in] atrhee driesvciueswse odf. AMduvraalneceedshainratnh e[5d0e].v eAlo npummebnetro offa nretvi-ipewarsa sairteic dpeevrootxeidd etso aprerodmeisscinrigb ed
and artesunate [49] are discussed. Advances in the development of anti-parasitic peroxides are
intahnethreelvmieiwntioc fpMeruoxraidleees d[h51a]r.a Sno[m50e] .nAatunrualm abnetirvoirfarl epveierowxsidaerse adree vmoteendtiotonepdr oinm itshien greavnietwhe l[m52i]n. tic
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]. Somenaturalantiviralperoxidesarementionedinthereview[52]. However,noneof
anthelmintic peroxides [51]. Some natural antiviral peroxides are mentioned in the review [52].
Since peroxides with a related structure have different types of activity, the systematization of
theHseoawretivceler,s npoanye souf ftfihceiseen atratitctleenst pioany tsouftfhiceiemnet tahttoednstioonf ptoe rtohxei mdeetshyondtsh eosf ips.eroxide synthesis.
this review is based on the structure of the peroxide fragment (Figure 2). The first sections consider
SinSciencpee proerxoidxiedsews withitha ar erlealatetedds sttrruuccttuurree hhaavvee ddiiffffeerreenntt tytyppees soof facatcivtiivtyit,y t,hteh seyssytesmteamtiaztaitzioanti oonf of
the preparation of cyclic peroxides in order of increasing cycle and the number of oxygen atoms in it,
thisthriesv rieevwiewis bisa bsaesdedo nonth tehes tsrtuructcuturereo offt hthee ppeerrooxxiiddee ffrraaggmmeenntt ((FFigiguurer e2)2. )T.hTeh feirfistr sstescteicotnios ncsoncsoindseird er
while the last section deals with peroxides of acyclic structure. The following abbreviations are used
thethper eppreapraartiaotinono fofc cyycclliicc ppeerrooxxiiddeess inin orodredre orf oinfcirnecarseinagsi ncygclcey acnled athned ntuhmebneur mof boexrygoefno axtyogmesn ina tito, ms
in describing the biological activity of peroxides: minimum inhibitory concentration (MIC),
in iwt,hwileh itlhee tlhaset lsaescttisoenc dtieoanlsd weiatlhs pweritohxipdeesro oxf iadceyscloicf satcruycctluicres.t rTuhcet uforlelo.wTihneg faoblblorewviiantgioanbs barreev uisaetdio ns
minimum lethal concentration (MLC), half maximal inhibitory concentration (IC50), concentration of
areinu seddesicnridbeinsgcr itbhien gbtihoelobgiiocalol gaiccatilvaitcyt ivoift ypoefropxeirdoexsi:d emsi:nmiminuimm uimnhiibnihtoibryit ocroynccoennctreantitorant io(MnI(CM),I C),
inhibiting 90% of activity (IC90), half maximal effective concentration (ЕС50), and median effective
minmdiominseuim m(EuDmle5t 0l)he [at5hl3ac,l5o 4cno]c.n ecnetnrtartaiotinon( M(MLLCC),),h haalflfm maaxxiimmaall iinnhhiibbiittoorryy ccoonncceenntrtaratitoino n(I(CIC50)5,0 c)o,ncocenncternattiroanti oonf of
inhiinbhitibinitgin9g0 %90%of oafc aticvtiivtyity(I C(IC9)0,),h haalflfm maaxxiimmaall eeffffeeccttiivvee ccoonncceennttrraatitoionn (Е(EСC50), )a,nadn dmemdeiadni aenffeecffteivceti ve
90 50
dosdeo(sEe D(ED)50[)5 [35,53,45]4.].
50

Figure 2. Reviewed cyclic and acyclic peroxides.
FiFgiguurere2 2..R Reevviieewweedd ccyycclliicc aanndd aaccyycclilcic ppeeroroxixdidese.s .
2. 1,2-Dioxolanes
2. 12,.2 1-D,2A-iDo xnioouxlmaonlbaeensre osf cyclic peroxides, many of which exhibit antibacterial, antifungal and anti-cancer
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
PlAakninuimc baceirdo fАc y(5cl)i cefpfeecrotixviedleys ,inmhaibniytso tfhwe hgircohwexthh iobfi tfaunntgibi aScatcecrhiaalr,oamnytcifeus ncgeraelvaisniade aanntid-c Panenciecrilalicutmiv ity,
activity, were isolated from the marine organisms, in particular from the sponges Plakinidae [55].
wereisolatedfromthemarineorganisms,inparticularfromthespongesPlakinidae[55]. Plakinicacid
P lakinic acid А (5) effectively inhibits the growth of fungi Saccharomyces cerevisiae and Penicillium
A(5)effectivelyinhibitsthegrowthoffungiSaccharomycescerevisiaeandPenicilliumatrounenetum[56];
Molecules2017,22,1881 3of39
Molecules 2017, 22, 1881 3 of 39
patlraokuinneicneatcuimd F[5(76)];a pnldakepini-ipc laakciidn icFa (c7id) aFn(d8) eepxih-piblaitkminoicd earcaidte Fa n(t8if) uenxghailbaitc tmivoitdyearagtaei nasnttCifaunndgidaal aalcbtiicvaintys
aangdainAsstp Ceragnidlliudsa faulbmiciagnast uasn[d5 7A]s;p1e,r2g-idlliuosx foulmanigeaatucsi d[5s79];a 1n,2d-d1i0oixnohlaibniet athciedgs r9o wantdh 1o0f Cinahnidbiidt athaelb gicraonwst[h5 8o]f;
aCnadndpidlaa kaolbritciadnes E[5(81];1 a)nsdho pwlakgoorotdidae cЕti (v1i1ty) sahgoawin gstoTordy apcatnivositoym aagbariuncset iT(rSycphaenmoseom1)a [b5r9u]c.ei (Scheme 1) [59].

SScchheemmee 11.. AAnnttiiffuunnggaall aanndd aannttii--ppaarraassiittiicc aaccttiivviittyy ooff 11,,22--ddiiooxxoollaanneess,, iissoollaatteedd ffrroomm tthhee ssppoonnggeess PPllaakkiinniiddaaee..
The first synthesis of diastereomeric saturated analogs of plakinic acids A, C and D 17 was
The first synthesis of diastereomeric saturated analogs of plakinic acids A, C and D 17 was
reported in 1996 by Bloodworth and colleagues [60]. Peroxides 17 were prepared in four steps from
reportedin1996byBloodworthandcolleagues[60]. Peroxides17werepreparedinfourstepsfrom
ketones 12. In the first step, ketone 12 was condensed with ethyl 3-methylbut-2-enoate with
ketones12. Inthefirststep,ketone12wascondensedwithethyl3-methylbut-2-enoatewithformation
formation cyclic lactones 13 hydrolysis, which led to acids 14. Peroxymercuration of esters 15
cyclic lactones 13 hydrolysis, which led to acids 14. Peroxymercuration of esters 15 followed by
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 with carboxylic group (Scheme 2).
1,2-dioxolanes17withcarboxylicgroup(Scheme2).
The synthesis of diastereomeric 1,2-dioxolanes 22 from alkynes was described [61].
Thesynthesisofdiastereomeric1,2-dioxolanes22fromalkyneswasdescribed[61].Carboalumination
Carboalumination of alkyne 18, followed by treatment of the intermediate alkenylaluminum with
ofalkyne18,followedbytreatmentoftheintermediatealkenylaluminumwithacetaldehyde,resultedin
acetaldehyde, resulted in an allylic alcohol that was oxidized to enone 19. Conjugate addition of
anallylicalcoholthatwasoxidizedtoenone19.ConjugateadditionofH O to19inthepresenceofLiOH
2 2
fHol2lOo2w teod 1b9y ainc idth-cea tparleyszeendcee sotefr iLfiicOaHtio nfoollfodwiaesdt ebreyo maceidri-ccadtiaolxyizneodle ebsyte2r-ifmiceatthioonx yoeft hdainaostleprreoovmideeridc
dioxinole by 2-methoxyethanol provided alkoxydioxolane 20. Substitution of the methoxyethoxy
alkoxydioxolane20. Substitutionofthemethoxyethoxygroupin20bytheactionofsilylketeneacetal
egtrhoyulpt hinio 2a0c ebtya lthine athcteiopnr eosfe snilcyel koeftTeinCelaceletdal teothtyhli otheitohaecre2ta1l ains tah1e: 1prmesiexntucere ofo fTitCwlo4 ldedia tsote trheioometehresr.
4
21 as a 1:1 mixture of two diastereomers. The hardly-separable cis- and trans-diastereomeric
Thehardly-separablecis-andtrans-diastereomericperoxides22wereobtainedasaresultofhydrolysis
peroxides 22 were obtained as a result of hydrolysis with high yield (Scheme 3).
withhighyield(Scheme3).
MMoolleeccuulleess 22001177,, 2222,, 11888811 44 ooff 3399
Molecules 2017, 22, 1881 4 of 39

SSSccchhheeemmmeee 222... TTThhheee fffiiirrrsssttt sssyyynnnttthhheeesssiiisss ooofff sssaaatttuuurrraaattteeeddd aaannnaaalllooogggsss ooofff ppplllaaakkkiiinnniiiccc aaaccciiidddsss 111777...

Scheme3.Thesynthesisofdiastereomericanalogsofplakinicacids22.
Scheme 3. The synthesis of diastereomeric analogs of plakinic acids 22.
Scheme 3. The synthesis of diastereomeric analogs of plakinic acids 22.
IInn 22000066,, tthheef ifrisrtsta saysmymmmeterticriscy snytnhtehsiessoisf opfl apkliankicinaicci dasciwdas swreaps orretpedor[t6e2d] .[T62h]e. kTehyes kteepy osftespid eofc hsiadine
In 2006, the first asymmetric synthesis of plakinic acids was reported [62]. The key step of side
ccohnasintr uccotniosntrwucatsiosnyn wthaess issyonftdhieasstise reoof mdeiarisctearlleyolmicearlcico haolllsyl2i5c farolcmohborlosm 2o5b efrnozmen eb.rTohmisotbreannzsfeonrem. aTtihoins
chain construction was synthesis of diastereomeric allylic alcohols 25 from bromobenzene. This
tinracnlusdfoerdmsautbiosneq uinecnltuaddeddi tisounbMsegq-uoerngta naicddcoitmiopno uMndg-toorgcraontiocn aclodmehpyoduenwd ittho focrrmotaotnioanldoefhayldcoeh owli2t3h,
transformation included subsequent addition Mg-organic compound to crotonaldehyde with
fColramisaetniohno omf oallocgoahtoiol n23r,e Csulaltiesdeni nhoesmteorlo2g4a,tainond rreeasuctlitoedn oinf aensteinr t2e4rm, aenddia rteeaacltdioenh yodf eanw iinthteprmroepdeinaytel
formation of alcohol 23, Claisen homologation resulted in ester 24, and reaction of an intermediate
aliltdheiuhmyd(eS wchiethm per4o)p.enyl lithium (Scheme 4).
aldehyde with propenyl lithium (Scheme 4).
AAss aa rreessuulltt ooff ffoolllloowwiinngg ttrraannssffoorrmmaattiioonn eeppooxxyy aallccoohhooll 2299aa wwaass pprreeppaarreedd,, wwhhiicchh wwaass ooxxiiddiizzeedd
As a result of following transformation epoxy alcohol 29a was prepared, which was oxidized
iinnttoo aallddeehhyyddee;; ssuubbsseeqquueenntt aaddddiittiioonn ooff mmeetthhyyllmmaaggnneessiiuumm bbrroommiiddee rreessuulltteedd iinn iissoommeerriicc sseeccoonnddaarryy
into aldehyde; subsequent addition of methylmagnesium bromide resulted in isomeric secondary
eeppooxxyy aallccoohhoollss 3300аa aanndd 3300bb ((SScchheemmee 55)).. AAfftteerr ttrraannssffoorrmmaattiioonn ooff mmiinnoorr 3300bb iinnttoo 3300aa,, tthhee llaatttteerr wwaass
epoxy alcohols 30а and 30b (Scheme 5). After transformation of minor 30b into 30a, the latter was
rreedduucceedd ttoo ddiiooll 3311.. TThhee ttrreeaattmmeenntt ooff ddiiooll 3311 wwiitthh ssttooiicchhiioommeettrriicc qquuaannttiittyy ooff TTssCCll aanndd eexxcceessss ooff
reduced to diol 31. The treatment of diol 31 with stoichiometric quantity of TsCl and excess of
tt--BBuuOOKK lleedd ttoo ooxxeettaannee 3322.. TThhee rriinngg ooppeenniinngg wwiitthh TTMMSSOOTTff pprroovviiddeedd eeaassiillyy sseeppaarraabbllee 33--hhyyddrrooxxyy
t-BuOK led to oxetane 32. The ring opening with TMSOTf provided easily separable 3-hydroxy
hhyyddrrooppeerrooxxiiddeess 3333 aanndd eeppii--3333;; 3333 wwaass ccoonnvveerrtteedd iinnttoo ppeerrooxxyy kkeettoonnee 3344 bbyy ssuubbsseeqquueenntt ssiillyyllaattiioonn aanndd
hydroperoxides 33 and epi-33; 33 was converted into peroxy ketone 34 by subsequent silylation and
ooxxiiddaattiioonn.. TThhee kkeettoonnee 3344 wwaass ttrraannssffoorrmmeedd iinnttoo aallkkooxxyyddiiooxxoollaannee 3355,, aanndd aafftteerr tthhaatt iinnttoo tthhiiooeesstteerr 3366..
oxidation. The ketone 34 was transformed into alkoxydioxolane 35, and after that into thioester 36.
TThhee ddeessiirraabbllee ppllaakkiinniicc aacciiddss 3388 wweerree pprreeppaarreedd bbyy hhyyddrroollyyssiiss ooff mmeetthhyyll eesstteerrss 3377.. AA ssiimmiillaarr ssttrraatteeggyy
The desirable plakinic acids 38 were prepared by hydrolysis of methyl esters 37. A similar strategy
wwaass uusseedd ffoorr tthhee ssyynntthheessiiss ooff sstteerreeoommeerriicc aacciiddss 3399 ffrroomm 33--hhyyddrrooxxyy hhyyddrrooppeerrooxxiiddee eeppii--3333..
was used for the synthesis of stereomeric acids 39 from 3-hydroxy hydroperoxide epi-33.
AA ttoottaall ssyynntthheessiiss ooff ppllaakkoorrttiiddee EE ((1111)) bbaasseedd oonn rraaddiiccaall ooxxyyggeennaattiioonn ooff vviinnyyllccyycclloopprrooppaanneess wwaass
A total synthesis of plakortide E (11) based on radical oxygenation of vinylcyclopropanes was
rreeppoorrtteedd [[6633,,6644]].. TThhee kkeeyy inintteerrmmeeddiiaattee 22--eetthhyyll--11,,11,,22--ccyycclloopprrooppaanneettrriiccaarrbbooxxyyllaattee ((4422)) pprreeppaarreedd ffrroomm
reported [63,64]. The key intermediate 2-ethyl-1,1,2-cyclopropanetricarboxylate (42) prepared from
mmeetthhyylleenneem maalolonnaatete( 4(04)0a) nadndα -αc-hclholrooreos teesrte4r1 4w1a wstarsa ntrsafonrsmfoerdmiendto inlatcot olancet4o3n.eT 4h3e. tTrheaet mtreeanttmofetnhte olfa tttheer
methylene malonate (40) and α-chloro ester 41 was transformed into lactone 43. The treatment of the
wllaattitttheerro wwxyiigtthhe noo,xxPyyhgg2eeSnne,,2 PPahnh2d2SSeeA22 IBaannNddf uAArIInBBisNNh effduurrsnnpiiissrhhoee1dd,2 s-sdppiiiorroox o11la,,22n--eddii4oo4xx,oofollaallnnoeew 44e44d,, bffoyolllllaoocwwtoeendde bbryyin gllaaocctptooennneei n rrgiinnoggf
o44petonifnogr mofd 4io4l t4o5 .foTrhme pdrieoclu 4r5so. rTohfe thperepcularksoorrt iodfe tEhe4 9plwakaosrstyidnet hEe s4iz9e dwfarso msynththeeisoidzeod-d ferroivma ttihvee
opening of 44 to form diol 45. The precursor of the plakortide E 49 was synthesized from the
ioofd1o,2-d-derioivxaotliavnee o4f 71,a2n-ddiothxoelhanaelo 4g7e nandde rtihvea thivaleog48enb ydeNrievgaitsivhei r4e8a cbtyio Nn.egDisehsii lryelaactitoionno. fDaelsciolyhloaltio49n,
iodo-derivative of 1,2-dioxolane 47 and the halogen derivative 48 by Negishi reaction. Desilylation
osuf baslceoqhuoeln 4t9o, xsuidbasteiqouneannt doxHidoartnioenr- Wanadd Hswoornrtehr-–EWmamdsownosrothle–fiEnmamtioonnsp orolevfiidneadtioens tperro5v1idwedh iecshtewr 5a1s
of alcohol 49, subsequent oxidation and Horner–Wadsworth–Emmons olefination provided ester 51
whyhdicrohl ywzaesd hwyditrhofloyrzmeda twiointho ffoprmlakatoirotnid oef Epl(a1k1o)r(Sticdhee Em (e161)) [(6S3c]h.eme 6) [63].
which was hydrolyzed with formation of plakortide E (11) (Scheme 6) [63].
Molecules2017,22,1881 5of39
Molecules 2017, 22, 1881 5 of 39
Molecules 2017, 22, 1881 5 of 39
OH O
PhBr Mg, CH3CH=CHCHO (EtO)3CCH3
PhBr Mg, CH933C%H=CHCHO Ph OH (CEHtO3C)3HC2CCHO3OH Ph O OEt
93% Ph 23 CH3C1H420CoCOOH Ph 24 OEt
23 14805o%C 24
85%
1) LiAlH4 OH R2 OH R2
32))312 D))) DLMiMASlSOHO4, B,( BCr(7CrO9tO%-CtB-CBlu)lu2)L2,L i,,E i ,ET tT3tH3NHNFF PPhh222555caa RRR111=== CCHHH, 3R3O,,2RHR=22 =C=R HH H23RR11 PPh2h225b55bd R RR111= ==C HCH3H,O ,R3RH,22R==2 R CH=2H RH31R1
79% 25c R1= H, R2= CH3 25d R1= H, R2= CH3
(EtO)3CCH3
225522ad55ad C(CEC(CH(HEEtHOH33tt1OC13OC3)C413C4H)H)C034H30H2C2Co0oCC2C2CCoCCCCHCOOHHOO3OO33OOHHHH PPhh 2266 OOOOEEtt12431243)))) ))))ZDLn ZDLn-inMAB-in,MABl SuH,Cl SuLHOC4BiLO4,Bri 74(,r, C674(P,%C6OPP%OChPCl3)h2l3), 2E, tE3Nt3N
140oC
OH
OH
PPhh 2277 1122)))) MMnn--eeBB33uAuAL7Ll7l,i,7i ,7 ,C C% (%(CpCp2H2HZZ2r2OrCOC)l2)nl2n PPhh 2828
OH OH
TiT(Oi(OitP-itBPr-)Bur4)uO,4O(,O-(O)-H-)DH-DEETT PPhh OOOH PPhh OOOH
9933%% 2299aa 292b9b
>>8800%% eeee
SSScchchheeemmmeee 44 4.. .C CCooonnnssstttrrruuuccctttiiiooonnn ooofff aaasssyyymmmmmmeeetttrrriiiccc p ppllalaakkkiininniicicc a aaccicdiiddss ss sisdiiddee ec hcchahiaaniin.n ..

SSchcheemmee5 5..A Assyymmmmeettrriicc ssyynntthheessiiss ooff ppllaakkiinniicc aaccididss 3388 aanndd 393.9 .
Scheme 5. Asymmetric synthesis of plakinic acids 38 and 39.
Molecules2017,22,1881 6of39
Molecules 2017, 22, 1881 6 of 39

SScchheemmee 66.. SSyynntthheessiiss ooff ppllaakkoorrttiiddee EE ((1111)) bbyy rraaddiiccaall ooxxyyggeennaattiioonn ooff ccyycclloopprrooppaanneess..
A similar strategy based on the radical oxygenation of vinyl cyclopropanes was used for the
Asimilarstrategybasedontheradicaloxygenationofvinylcyclopropaneswasusedforthesynthesisof
synthesis of epiplakinic acid F (8) [65]. The vinyl cyclopropane 53 obtained from
epiplakinicacidF(8)[65].Thevinylcyclopropane53obtainedfromtrans-1,2-cyclopropanedicarboxylate52,
trans-1,2-cyclopropanedicarboxylate 52, was then converted to 1,2-dioxolane 55 (Scheme 7). After
wasthenconvertedto1,2-dioxolane55(Scheme7).Afterseparationofthediastereomericmixtureisomer55b
separation of the diastereomeric mixture isomer 55b was used for further transformations.
wasusedforfurthertransformations.
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
4
vinylether 57 by subsequent PCC oxidation and Wittig olefination. Oxidation of 57 to methyl ester
vinylether57bysubsequentPCCoxidationandWittigolefination. Oxidationof57tomethylester58,
58, reductive ozonolysis of 58, and Wittig olefination gave predominantly the Z-isomer of vinyl
reductiveozonolysisof58,andWittigolefinationgavepredominantlytheZ-isomerofvinyliodide59.
iodide 59. The Negishi coupling of 59 with the halogen derivative led to the desired product 60.
TheNegishicouplingof59withthehalogenderivativeledtothedesiredproduct60. Desilylationof60
Desilylation of 60 followed by reduction of 61 resulted in saturated alcohol 62. The oxidation of 62
followedbyreductionof61resultedinsaturatedalcohol62. Theoxidationof62ledtoanaldehyde,
led to an aldehyde, the Wittig olefination of which provided the precursor 63 as a mixture of
theWittigolefinationofwhichprovidedtheprecursor63asamixtureofisomers. Theproductof
isomers. The product of photoinduced isomerization of this mixture was the trans-isomer 64. The
photoinducedisomerizationofthismixturewasthetrans-isomer64. ThetargetepiplakinicacidF(8)
target epiplakinic acid F (8) was obtained by alkaline hydrolysis of ester 64 (Scheme 8).
wasobtainedbyalkalinehydrolysisofester64(Scheme8).
Molecules2017,22,1881 7of39
Molecules 2017, 22, 1881 7 of 39
Molecules 2017, 22, 1881 7 of 39

SScShcchehmeemmeee7 7.7.C. CCoononnsststrtruruucctctitioioonnn o oofff 1 11,,2,22---dddiiioooxxxooolllaaannneee fffrrraaagggmmmeeennnttt fffooorrr eeepppiipippllalaakkkiininniicic c aacaciciddid FF F ((88()8).. ) .

Scheme 8. Asymmetric synthesis of epiplakinic acid F (8).
Scheme 8. Asymmetric synthesis of epiplakinic acid F (8).
Scheme8.AsymmetricsynthesisofepiplakinicacidF(8).
Molecules 2017, 22, 1881 8 of 39
Molecules2017,22,1881 8of39
The method of the preparation of andavadoic acid (76), a natural compound isolated from the
spongTehse omf etPhloaxdorotfist haeff psriemppalrexa,t iobnasoefd anodna vthaed oIiscaaycaimda(−7M6)u, kaaniyaatmuraa lrceoamctpioonu nadndis osluabtesdeqfuroenmt
cthyecliszpaotinogne wsaosf kPnloaxwonrt i[s66a]f.f Tshime pstleaxr,tinbga sseudbsotnratteh ewaIssa eypaimchal-oMrouhkyadiyrianm (6a5)r,e wachtiiochn wanasd csounbvseerqteude ntot
ecypcolxizidatei o6n6 bwya as ksunboswenqu[6e6n]t. tThhe eosrgtaarntionmgasgunbesstriuatme wcoamseppoiucnhdlo arodhdyitdiorinn a(6n5d) ,cwychliizcahtiwoans wcoitnhv tehret ehdeltpo
oepf oaxlikdaeli6n6e.b yThaes urbegseioqsueelnectttihvee oorpgeannionmg aogfn etshieu mepcooxmidpeo ucnydclea dodfi t6io6n bayn dthcey clliitzhaituiomn wsailtth othf eehtheylpl
pofroaplkioalliantee. iTnh tehree pgiroesseelnecceti voef oBpFe3 nriensgulotfedth eine pthoex isdeecocnycdlaeroyf a6l6cobhyotlh 6e7l iitnh iaulmmosasltt qoufaenthtiytaltpivroep yioielaldte.
Ainlctohheoplr e6s7e nwcaeso fcoBnFv3erretesudl tiendtoi nlathcteosneec o6n8d bayry raelaccothioonl 6w7iitnh aMlmeo2CstuqLui,a fnotliltoawtiveed ybieyl da.ciAdlicfiochaotilo6n7.
wOxaisdcaotinovne ortfe ldacitnotnoe l6a8c ttoon 6e9,6 s8ubbyserqeuaectnito rninwgi othpeMniengC,u oLxii,dfaotliloonw oefd hybdyraocxiydli fitoc athtieo nca.rbOoxnidyla gtiroonupof,
2
alancdto nmee6t8hytola6t9io,nsu bresesuqulteendt riinn gepopoexnyi nkge,tooxnied a7t0io, nwohfhicyhd rwoxays lttohethne ccoanrbvoenrtyeldg rtoou pe,paonxdym aeltkheynlea ti7o1n.
Irseasyualtmeda–iMnuepkoaixyyamkeat opneero70x,idwathiiocnh, wthaes tbhaesne-ccoantavlyerzteedd tcoycelpizoaxtiyonal koefn epe7r1o.xIidsaey a7m2, al-eMaduiknagi ytaom aa
mpeirxotuxirdea otfi odnia,sthteereboamsee-rciact 1a,l2y-zdeidoxcoylcalnizeas t7io3n/73oaf pfoelrloowxidede b7y2, sleepaadriantgiotno aanmd tixhtiuoarecyolfatdioians treerseuoltmeder iinc
1a, 2p-edriooxxyo ltahnioeses7t3e/r 7734a wfohlliochw ewdabsy csoenpvaerratteidon inatnod atnhdioaavcaydlaotiico nacrieds u(7lt6e)d biny asupbesreoqxuyetnhito reesdteurc7ti4own haincdh
whyadsrcoolnyvsiesr toefd eisntetor a7n5 d(Sacvhaedmoiec 9ac).i d(76)bysubsequentreductionandhydrolysisofester75(Scheme9).

SScchheemmee 99.. SSyynntthheessiiss ooff aannddaavvaaddooiicc aacciidd ((7766))..
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].
producesmycangimycinperoxide(77)withpronouncedfungicidalactivity(Scheme10)[67].Mycangimycin
Mycangimycin effectively inhibits growth of Candida albicans wild type, C. albicans ATCC10231,
effectivelyinhibitsgrowthofCandidaalbicanswildtype,C.albicansATCC10231,amphotericin-resistant
amphotericin-resistant strain C. albicans ATCC 200955, Saccharomyces cerevisiae and Ophiostoma minus [68].
strainC.albicansATCC200955,SaccharomycescerevisiaeandOphiostomaminus[68].
MMoolleeccuulleess 22001177,, 2222,, 11888811 99 ooff 3399
MMoolleeccuulleess 22001177,, 2222,, 11888811 99 ooff 3399

Scheme 10. Natural peroxide mycangimycin and its fungicidal activity.
SSSccchhheeemmmeee 111000... NNNaaatttuuurrraaalll pppeeerrroooxxxiiidddeee mmmyyycccaaannngggiiimmmyyyccciiinnn aaannnddd iiitttsss fffuuunnngggiiiccciiidddaaalll aaaccctttiiivvviiitttyyy...
Two saturated analogs of mycangimycin were synthesized from alkene 78 and ester 79 (Scheme
TTwwoo ssaattuurraatteedd aannaallooggss ooff mmyyccaannggiimmyycciinn wweerree ssyynntthheessiizzeedd ffrroomm aallkkeennee 7788 aanndd eesstteerr 7799 ((SScchheemmee
11) [69]. The Kulinkovich reaction of 78 with 79 resulted in cyclopropane 80, which formed
Two saturated analogs of mycangimycin were synthesized from alkene 78 and ester 79
1111)) [[6699]].. TThhee KKuulliinnkkoovviicchh rreeaaccttiioonn ooff 7788 wwiitthh 7799 rreessuulltteedd iinn ccyycclloopprrooppaannee 8800,, wwhhiicchh ffoorrmmeedd
1,2-dioxolane 81 by a cobalt-catalyzed cleavage in the presence of oxygen. TfOH-catalyzed reduction
(Scheme11)[69]. TheKulinkovichreactionof78with79resultedincyclopropane80,whichformed
o11,f,22 t--hddeiioo axxlooclloaahnnoeel 888111 bb byyy aa s ccioolabbnaaellt t--lcecaadtt aatlolyy zz3ee,5dd- dccillseeuaavbvasatggieteu iitnne dtthh 1ee , p2p-rrdeeissoeexnnoccleea oonffe oo8xx2yy. ggTeehnne.. TTrfefOOsuHHlt-- ccoaaftt aadllyeyszzieelyddl arreetiddouuncc tatiinoodnn
1,2-dioxolane81byacobalt-catalyzedcleavageinthepresenceofoxygen. TfOH-catalyzedreduction
ooff tthhee aallccoohhooll 8811 bbyy ssiillaannee lleedd ttoo 33,,55--ddiissuubbssttiittuutteedd 11,,22--ddiiooxxoollaannee 8822.. TThhee rreessuulltt ooff ddeessiillyyllaattiioonn aanndd
oxidation of the obtained alcohol 83 is the first saturated analog of mycangimycin, acid 84, which can
ofthealcohol81bysilaneledto3,5-disubstituted1,2-dioxolane82. Theresultofdesilylationand
ooxxiiddaattiioonn ooff tthhee oobbttaaiinneedd aallccoohhooll 8833 iiss tthhee ffiirrsstt ssaattuurraatteedd aannaalloogg ooff mmyyccaannggiimmyycciinn,, aacciidd 8844,, wwhhiicchh ccaann
be converted into ester 85.
oxidationoftheobtainedalcohol83isthefirstsaturatedanalogofmycangimycin,acid84,whichcan
bbee ccoonnvveerrtteedd iinnttoo eesstteerr 8855..
beconvertedintoester85.
O OOO TCTCTCiii55C5CCHHHTlll(((999HOOOMMMFiiiPgPgPgCCrCrr)))ll3l33 OOOHHH14 CCCoooE(((aOaOaOtOccc222aaaHccc)))222 OOO OOO OOO1HHH4
OOORRR 777888 OO 777999 111444 9T9T9111HH%%%FF OOORRR 8880001144 EE999tt000OO%%%HH OOORRR 888111 1144
O O O O H IO
5 6
EEEttt333SSSCCCiiiH6H6HH6HH666,,,222 %%%CCTCTTfflfll2O2O2OHHH OOORRROO 8O8O8222 111444 TTTBBBAAAT8T8T8FFF11H,1H,H, %%%AFAFAFcccOOOHHH OOOHHHOO OO888333 111444 CCCCCCllRlRR444///uuuHHHHHCCC28282855OlOlOl88833I3IOO%%/%//HHHCCC66222HHHOOO333CCCNNN
O O O O R = TBDPS
OO OO TMSCHN OO OO RR == TTBBDDPPSS
2
14 TTMMMSSeCCOHHHNN22 14
HHHOOO OOO 888444 1144 MM888ee111OO%%%HH MMMeeeOOO OOO 888555 1144
SScchheemmee 1111.. TThhee ssyynntthheessiiss ooff ssaattuurraatteedd aannaallooggss ooff mmyyccaannggiimmyycciinn 8844 aanndd 8855..
SScchheemmee 1111.. TThhee ssyynntthheessiiss ooff ssaattuurraatteedd aannaallooggss ooff mmyyccaannggiimmyycciinn 8844 aanndd 8855..
The diterpenoid peroxide 86, which has a weak fungicidal activity against C. albicans, was
TTThhheee dddiititteeerrrpppeeennnoooidiiddp pepreeorrxooixxdiiedde8e 6 88,66w,, hwwichhhiicchhha shhaaawss eaaa kwwfeeuaankkg iffcuuidnnaggliiccaiicddtiaavll i taaycctatiigvvaiittiyny s ataggCaa.iiannlbssittc aCCn..s ,aawllbbiaiccsaaninssso,, lawwteaadss
isolated from the liverwort Jungermannia atrobrunnea (Scheme 12) [70]. Dinardokanshone B (87),
ifissrooomllaattteehdde fflrirvooemmrw ttohhreet Jlluiivvneegrrewwrmoorarttn nJJuuiannaggteerrrommbraaunnnnnniiaae a aa(ttSrrcoohbbrreuumnnennee1aa2 )((S[S7cc0hh]ee.mmDeein 1a12r2d)) o[[k77a00n]]..s hDDoiinnneaarrBddoo(8kk7aa)nn,ssshehsooqnnueei tBeBr p((88e77n))e,,
sesquiterpene peroxide, isolated from the roots and rhizomes of Nardostachys chinensis Batal.
psseeessrqqouuxiiidtteeerr,ppieseonnleea teppdeerrfooroxxmiiddeet,h, eiissrooolloaatttseeddan dffrroorhmmiz ottmhheee srrooofooNttssa raadnnoddst acrrhhhyiizzsoocmmhineesse n sooiffs BNNaaatarrldd.oo(ssVttaaacclhehryyissa nccahhciinneaeenne)ssiisssh oBBwaatteaadll..
(Valerianaceae) showed significant enhancement effects on SERT activity (Scheme 12) [71].
(s(VVigaanlleiefirriciaaannnaatcceeenaaheea)) nsshhceoomwweeenddt sseiifggfnenciifftiisccaoannnttS eeEnnRhhTaannaccceetimmvieetnnytt( eeSffcffheeecctmtss eoonn12 SS)EE[R7R1TT] .aaccttiivviittyy ((SScchheemmee 1122)) [[7711]]..

SScchheemmee 1122.. TTeerrppeennee ppeerrooxxiiddeess 8866 aanndd 8877..
SScchheemmee 1122.. TTeerrppeennee ppeerrooxxiiddeess 8866 aanndd 8877..
Molecules2017,22,1881 10of39
Molecules 2017, 22, 1881 10 of 39
Molecules 2017, 22, 1881 10 of 39
SSyynntthheettiicc 11,,22--ddiiooxxoollaanneess 8888 sshhoowweedd hhiigghh iinn vviittrroo aaccttiivviittyy aaggaaiinnsstt hheellmmiinntthhss SScchhiissttoossoommaa mmaannssoonnii
Synthetic 1,2-dioxolanes 88 showed high in vitro activity against helminths Schistosoma mansoni
((SScchheemmee 1133)) [[7722]]..
(Scheme 13) [72].
R R
2 3
R R
2 3
R OR
R1 O O OR
1 O O
88
88
R R = Me, Bu, -(CH ) -
1, 2 2 5
R R = Me, Bu, -(CH ) -
1R, 2= Me, CH CH Ph2 5
3 2 2
R = Me, CH CH Ph
R3 = CH CH2Ph, 2Bn
2 2
R = CH CH Ph, Bn
2 2
NTS S. mansoni IC < 20 M
NTS S. mansoni IC50< 20 M
50
SScchheemmee 1133.. 11,,22--DDiiooxxoollaanneess 8888 eexxhhiibbiittiinngg hhiigghh aaccttiivviittyy aaggaaiinnsstt sscchhiissttoossoommiiaassiiss..
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
55,,55--DDiimmeetthhyyll 11,2,2-d-dioioxxoolalanneess8 88a8aw wereerpe rpepreapreadrebdy bpye rpoexridoaxtiidoantioofnm oef smityelsoitxyild eox(8id9e) i(n89th) einb atshiec
basic medium, followed by alkylation of the free hydroxyl group of 3-hydroxy-1,2-dioxolanes 90
mbaesdiciu mme,fdoilulomw, efdobllyowalekdyl abtyio nalokfytlhaetiforene ohfy dthroex fyrleger ohuypdorofx3y-hl ygdrroouxyp- 1o,2f -3d-ihoxyodlraonxeys-910,2(S-dchioexmoela1n4e)s[ 7930].
(Scheme 14) [73]. Synthesis of cyclohexyl derivatives 88b started from oxidation of alcohol 92 to an
S(Sycnhtehmeseis 1o4f)c [y7c3l]o.h Seyxnytlhdeesriisv oatfi vcyescl8o8hbexstyalr tdeedrifvroamtivoexsi d88abti osntaorfteadlc ofrhooml9 o2xtiodaantiuonn soaft uarlactoehdokl e9t2o ntoe 9a3n,
unsaturated ketone 93, followed by Isayama–Mukaiyama peroxidation with formation of
fuonllsoawtuerdatbeyd Iskayetaomnae- M9u3k, aifyoallmowaepde robxyid aItsioaynawmiath–Mfourmkaaityioanmoaf 1p,2e-rdoixoixdoaltainoen 94w.iFtuhr thfoerrmparotitoenct ioonf
1,2-dioxolane 94. Further protection of hydroxyl group resulted in derivatives 88b (Scheme 14) [73].
o1,f2h-dyidorxooxlyalnger 9o4u.p Furerstuheltre dpriontedcetrioivna toifv hesyd88robx(ySlc ghreomuep1 r4e)su[7l3te].d in derivatives 88b (Scheme 14) [73].

Scheme 14. Synthesis of anthelmintic 1,2-dioxolanes 88.
SScchheemmee 1144.. SSyynntthheessiiss ooff aanntthheellmmiinnttiicc 11,,22--ddiiooxxoollaanneess 8888..
The series of tricyclic monoperoxides 97 with 1,2-dioxolane moiety showed a high
anti-sTTchhheeis steosresieorismeosaf lt oraifcc tyictvrliiitccyym.c Tloihnc eo pmmeroaoxnxioimdpeuesrmo9x 7aiwdcteiitvsh it1y9,7 2w -dawiso ixotohbl saen1re,v2me-ddoi oifeoxtroy lcsaohnmoew peomduonaideht iy9g7 has,ah nwotiwh-sieccdhh isretaov seohamilgeadhl
ahacnigttiihv- siwtcyh.oirTsmthoe sbomumradaxlei mnac urteimvdiutaycc.tt iiTovhnitesy mbwyaa x8si2om.8bu%sme riv nae cSdt.i vfmoitraync oswomnasip mooubonsuedsrev9 e7mda,o fwdoerh lic c(oShmcrhpeevomeuaenl de1d 59)h7 [ai7g, 4hw].wh Piocerhrmo rxebivdueerasdl ee9nd7
rcheaidgnuh bc weti ooonbrsmtab iybnue8dr2d .8fer%no mirne dβS,u. δmc-tatiorninskosen tbioymn e8os2u .9s86e% ma niondd Seh.l ym(dSarcnohsgeomennie pm1e5or)uo[x7se4id ]m.eP owedrioethlx i(udSsecehs eo9mf7 eceia t1hn5eb)r e [s7ou4bl]f.tu aPrineicre odaxcfiirddoe m[s7 59β]7,,
δoca-rt nrbi okbreeot oonnb tetrasiifn9lu6eodar nifdrdoehm [y7 d6β]r, oaδgs-te crniaktpaeetlyroosnxte iasdn e9d6w caionth-dsou hlsvyeedonrfto e(giSetchnhe eprmesrueol fx1ui5dr)i.ec waciitdh [u7s5e], oofr ebiothroern sturilflfuuroirci daeci[d7 6[7]5a]s,
coart baloyrsotna tnrdiflcuoo-sriodlve e[n76t]( Sacsh ceamtaely1s5t) .and co-solvent (Scheme 15).