Contemporary Strategies for the Synthesis of Tetrahydropyran Derivatives: Application to Total

40 Pages·2016·6.22 MB·English

by  Haruhiko Fuwa

marine drugs
Review
Contemporary Strategies for the Synthesis of
Tetrahydropyran Derivatives: Application to Total
Synthesis of Neopeltolide, a Marine Macrolide
Natural Product
HaruhikoFuwa
GraduateSchoolofLifeSciences,TohokuUniversity,2-1-1Katahira,Aoba-ku,Sendai980-8577,Japan;
[email protected];Tel.:[phone]
AcademicEditor:OrazioTaglialatela-Scafati
Received:25January2016;Accepted:17March2016;Published:25March2016
Abstract:Tetrahydropyransarestructuralmotifsthatareabundantlypresentinarangeofbiologically
importantmarinenaturalproducts. Assuch,significanteffortshavebeenpaidtothedevelopment
ofefficientandversatilemethodsforthesynthesisoftetrahydropyranderivatives. Neopeltolide,
apotentantiproliferativemarinenaturalproduct,hasbeenanattractivetargetcompoundforsynthetic
chemistsbecauseofitscomplexstructurecomprisedofa14-memberedmacrolactoneembedded
withatetrahydropyranring, andtwentytotalandformalsynthesesofthisnaturalproducthave
beenreportedsofar. Thisreviewsummarizesthetotalandformalsynthesesofneopeltolideandits
analogues,highlightingthesyntheticstrategiesexploitedforconstructingthetetrahydropyranring.
Keywords: synthetic methods; tetrahydropyrans; oxocarbenium ions; hetero-Diels-Alder
cycloadditions;oxa-Michaelreactions;palladium-catalyzedalkoxycarbonylations;oxymercurations;
radicalcyclizations;ring-closingmetathesis
1. Introduction
Marinenaturalproducts,mainlythesecondarymetabolitesofmarinemicroorganisms,havebeen
arichsourceofstructurallydiverseandbiologicallyintriguingcompoundsthatarepotentiallyuseful
fordissectingcomplexcellularbiologicaleventsatthemolecularlevel[1–6]. Moreover,severalmarine
naturalproductshaverecentlybeendevelopedintoclinicallyapproveddrugs,includingtrabectedin
anderibulinmesylate,andmorearecurrentlyunderclinicaltrials[7–9]. Itismorethanlikelythat
marine natural products will continuously have significant impact on chemical biology and drug
discoveryintheforthcomingdecades. However,mostmarinenaturalproductsarenotabundantly
availablefromnaturalsourcesandmarinemicroorganismsareinmanycasesdifficulttocultivateon
alargescale. Thescarcityofmarinenaturalproductsoftentimesprecludestheirin-depthbiological
investigationsand,currently,totalsynthesisappearstobetheonlypracticalmeanstoovercomethe
materialsupplyproblematthebasicresearchlevel. Anadditionalbonusoftotalsynthesisisthatit
enablesmanipulationofthebiologicalfunctionsofnaturalproductsthroughstructuralalterations.
Structure-function analyses are important for understanding the mode-of-interactions of natural
productswithbiomoleculartargets,giventhatmanynaturalproductsareactuallymultifacetedligands
interactingwithmultiplebiomolecules[10]. Sincestructurallycomplexmarinenaturalproductsare
intractabletoselectivefunctionalizations,totalsynthesislaysstrongfoundationfordrugdiscovery
researchwhichinmanycasesrequiresstructuraloptimizationstudies. Thesebeneficialaspectsoftotal
synthesisjustifyitssignificanceinmarinenaturalproductschemistryandchemicalbiology.
Tetrahydropyransarestructuralmotifsthatareabundantlypresentinaplethoraofbiologically
activemarinenaturalproducts. SeveralrepresentativeexamplesareshowninFigure1. Gambierol(1)
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Tetrahydropyrans are structural motifs that are abundantly present in a plethora of biologically 
active marine natural products. Several representative examples are shown in Figure 1. Gambierol (1) 
wwaass  iissoollaatteedd  bbyy SSaattaakkee eett aall..  frforomm  ccuultluturreedd  cceelllsls  ooff  tthhee  cciigguuaatteerraa  ccaauussaattiivvee  ddiinnooffllaaggeellllaattee 
GGaammbbiieerrddiissccuuss ttooxxicicuussa nadnds trsutrcutucrtualrlayllcyh acrhaacrtearcitzeerdizbedy ebxyte nexsitveensNivMe RNaMnaRly saensaalynsdeas manodd ifia emdModoisfiheedr 
Manoaslhyseirs a[n1a1l,1y2s]is. T[1h1i,s12c]o. mThpiosu cnodmipnohuinbidt sinvhoilbtaitgs ev-oglattaegde‐pgoattaesds ipuomtasisoinumch iaonnn cehlsan(Knevlsc h(Kanv ncehlasn)ninelas) 
isnu baty psue-bsteylepcet‐isveelemctainvnee rmaatnnnanero maot lanracnoonmceonltarra ticoonnsc[e1n3t–ra1t6i]oannsd  [s1h3o–w16s]p oatnedn tsahcuotwesn epuorotetonxt icaictyutine 
nmeiucreo.tRoexciecinttyl yi,nt hmeicBeo.t Raneacegnrtolyu,p threep Boortteadnat hgartotuhpe rKevpocrhtaendn tehlaitn thhibe iKtovr ychaactninvietly inohfigbaimtobryie arocltirveistiyd oesf 
ginamthbeierirgohl tr-ehsaildfeosf itnh ethme orliegchutl‐ehaalnfd otfh tahteg mamolbeiceurolel aanndd itthsattr ugnacmatbeideraonl aalnodgu ietss trreudnuccaetdedth aenlaelvoegluseosf 
reexdtruac-eadn tdhein ltervaceelsl loufl aerxatrma‐y laonidd βintarnadcehllyuplaerr pahmoysplohidor βy laantedd htayupeinrpahnosinphviotrryolmatoedd etlaouf iAn laznh eiinm veitrr’os 
mdiosedaesle o[f1 A7,l1z8h]e.imer’s disease [17,18]. 

Figure 1. Structures of gambierol (1), irciniastatin A (2), bryostatin 1 (3), and neopeltolide (4). 
Figure1.Structuresofgambierol(1),irciniastatinA(2),bryostatin1(3),andneopeltolide(4).
Irciniastatin A (2) was isolated by Pettit and co‐workers from the marine sponge Ircinia ramosa 
IrciniastatinA(2)wasisolatedbyPettitandco-workersfromthemarinespongeIrciniaramosa[19].
[19]. Almost simultaneously, Crews et al. reported the isolation of psymberin from the marine 
Almost simultaneously, Crews et al. reported the isolation of psymberin from the marine sponge
sponge Psammocinia sp. [20]. Although the original stereochemical assignments made independently 
Psammocinia sp. [20]. Although the original stereochemical assignments made independently by
by Pettit and Crews were conflicting, irciniastatin A and psymberin were ultimately shown to be 
Pettit and Crews were conflicting, irciniastatin A and psymberin were ultimately shown to be
identical through total synthesis by De Brabander and co‐workers [21]. Irciniastatin A inhibits 
identicalthroughtotalsynthesisbyDeBrabanderandco-workers[21]. IrciniastatinAinhibitsprotein
protein synthesis and shows a highly potent and selective growth inhibitory effect in human solid 
synthesisandshowsahighlypotentandselectivegrowthinhibitoryeffectinhumansolidtumorcells.
tumor cells. A forward genetic screen in Caenorhabditis elegans has shown that iriciniastatin A 
AforwardgeneticscreeninCaenorhabditiseleganshasshownthatiriciniastatinAprimarilytargetsthe
primarily targets the ribosome [22]. A recent report has shown that irciniastatin A induces a potent 
ribosome[22]. ArecentreporthasshownthatirciniastatinAinducesapotentandsustainedactivation
and  sustained  activation  of  the  extracellular  signal‐regulated  kinase  (ERK)  to  promote  the 
of the extracellular signal-regulated kinase (ERK) to promote the ectodomain shedding of tumor
ectodomain shedding of tumor necrosis factor (TNF) receptor in the A549 human non‐small cell lung 
necrosisfactor(TNF)receptorintheA549humannon-smallcelllungadenocarcinomacellline[23].
adenocarcinoma cell line [23]. 
Bryostatin1(3),arepresentativemarinemacrolidenaturalproductthatcontainstetrahydropyran
Bryostatin 1 (3), a representative marine macrolide natural product that contains tetrahydropyran 
ringsassubstructures,wasisolatedbythePettitgroupfromthemarinebryozoanBugulaneritinaand
rings as substructures, was isolated by the Pettit group from the marine bryozoan Bugula neritina 
structurally identified by an X-ray crystallographic analysis [24]. More than 20 natural congeners
and  structurally  identified  by  an  X‐ray  crystallographic  analysis  [24].  More  than  20  natural 
have been identified to date [25]. Bryostatin 1 is a potent and isoform-selective protein kinase
congeners have been identified to date [25]. Bryostatin 1 is a potent and isoform‐selective protein 
C activator and shows anti-cancer, anti-Alzheimer’s disease, and anti-HIV activities. Because of
kinase C activator and shows anti‐cancer, anti‐Alzheimer’s disease, and anti‐HIV activities. Because 
thesesignificantbiologicalactivitiesandsyntheticallychallengingcomplexmoleculararchitecture,
of these significant biological activities and synthetically challenging complex molecular architecture, 
anumberofrenownedsyntheticchemistsdevotedtheireffortstothedevelopmentofconcisesynthesis
a number of renowned synthetic chemists devoted their efforts to the development of concise 
of bryostatin 1 and its congeners [26]. Furthermore, Wender et al. reported function-oriented
synthesis of bryostatin 1 and its congeners [26]. Furthermore, Wender et al. reported function‐oriented 
synthesis[27]ofstructurallysimplifiedbryostatinanalogues(bryologs)andtheirstructure-function
synthesis [27] of structurally simplified bryostatin analogues (bryologs) and their structure‐function 
relationships[28–30].
relationships [28–30].
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Neopeltolide(4),anewmemberofmarinemacrolidenaturalproducts,wasidentifiedbyWright
andco-workersfromadeep-waterspongeofthefamilyNeopeltidae, collectedoffthenorthcoast
ofJamaica[31]. Thegrossstructureincludingtherelativeconfigurationwasproposedonthebasis
ofextensive2D-NMRanalyses. Later,totalsynthesesbyPaneketal.[32]. andScheidtetal.[33,34]
partiallyreassignedtherelativeconfigurationandestablishedtheabsoluteconfiguration.Thestructure
ofneopeltolideresembleswiththatofleucascandrolideA,anothermarinemacrolidenaturalproduct
isolatedfromacalcareousspongecollectedalongtheeastcoastofNewCaledonia[35].Wrightreported
thatneopeltolideshowedpotentantiproliferativeactivityagainstseveralhumancancercelllinesat
nanomolarconcentrations. TheKozmingrouphasreportedthatneopeltolidespecificallyinhibitsthe
complexIIIofthemitochondrialelectrontransportchain[36]. Fuwaetal. haverecentlydescribedthe
apoptosis-inducingactivityofasyntheticanalogueofneopeltolideinHL-60humanpromyelocytic
leukemiacells[37].However,themode-of-actionofthisnaturalproducthavenotbeenfullyelucidated.
Theintriguingstructureandpotentbiologicalactivitiesofneopeltolidehaveattractedconsiderable
attentionfromthesyntheticcommunity,andtwentytotalandformalsynthesesofthisnaturalproduct
havebeenreportedsofar[38–58]. Furthermore,severalgroupshavereportedthestructure-activity
relationshipsofneopeltolidebyevaluatingtheantiproliferativeactivityofsyntheticanaloguesagainst
cancercells[34,43,47,56,59,60]. Theseeffortshaveculminatedintheelucidationofthepharmacophoric
structuralelementsforpotentantiproliferativeactivity[56].
Totalsynthesisofthesecomplexmarinenaturalproductsrequiresefficientandstereoselective
constructionoftetrahydropyranrings. Assuch,thesyntheticcommunityputsignificanteffortsto
thedevelopmentofmethodsforthestereoselectivesynthesisoftetrahydropyranderivatives[61,62].
In the past years, neopeltolide has served as an ideal target compound for synthetic chemists to
showcasetheircreativityinhowtoconstructthetetrahydropyranringinanefficientandstereoselective
manner. Thisreviewsummarizesthetotal/formalsynthesesofneopeltolide,highlightingthesynthetic
strategiesexploitedforconstructingthetetrahydropyranring[63,64].
2. SynthesisofTetrahydropyransviaOxocarbeniumIons
AsexemplifiedbythePrinsreactionanditsvariants,reactionsthatinvolveanintramolecular
addition of an alkene to an oxocarbenium ion intermediate have recently evolved to be powerful
andversatilemeanstoconstructtetrahydropyranringsincomplexsettings. Actually,severalgroups
haveexploitedPrins-typereaction,eitherintramolecularlyorintermolecularly,forthesynthesisofthe
tetrahydropyranringofneopeltolide.
2.1. TotalSynthesisbythePanekGroup
Panek and co-workers have developed a versatile method for the synthesis of 2,6-cis- and
2,6-trans-substituted dihydropyran derivatives by means of a formal diastereoselective
[4+2]-annulation of chiral allyl or crotyl silanes and aldehydes [65]. As shown in Figure 2,
thereactionbeginswithcouplingofthesyn-crotylsilanesyn-5withthealdehyde6undertheinfluence
of a Lewis acid to generate the oxocarbenium ion intermediate 7. Intramolecular addition of the
crotylsilanemoietytotheoxocarbeniumionwithconcomitantlossofthesilylgrouptakesplaceviaa
boat-likeconformerwithmaximalσ-porbitaloverlap,providingthe2,6-cis-substituteddihydropyran
derivative 2,6-cis-8. When the anti-crotylsilane anti-5 is used instead, the reaction proceeds via
theoxocarbeniumionintermediate71 todeliverthe2,6-trans-substituteddihydropyranderivative
2,6-trans-8. Thus, the stereochemical outcome of the [4+2]-annulation reaction depends on the
configurationofthecrotylsilaneused. Theversatilityofthissyntheticmethodhasbeendemonstrated
in total syntheses of apicularen A [66], bistramide A [67], callipeltoside A [68], kendomycin [69],
andleucascandrolideA[70].
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FFiigguurree 22.. SSteterreeoosseelelecctitvivees ysnytnhtehseissios fodfi hdyidhryodpryorpaynradne rdiveartiivvaetsivveias avifao ram afolr[m4+a2l] -[a4n+n2u]‐laantinounlaotfiochni roafl 
cchroirtayll scirlaontyelssialnandeasl danehdy adldese.hydes. 
The Panek group was the first to show that the original assignment of the relative configuration 
ThePanekgroupwasthefirsttoshowthattheoriginalassignmentoftherelativeconfigurationof
of neopeltolide was incorrect [32]. Inspection of the available spectroscopic data led them to 
neopeltolidewasincorrect[32]. Inspectionoftheavailablespectroscopicdataledthemtosynthesizea
synthesize a selected set of diastereomers to identify the correct structure. Consequently, Panek et al. 
selectedsetofdiastereomerstoidentifythecorrectstructure. Consequently,Paneketal. reassignedthe
reassigned the configuration of the C11 and C13 stereogenic centers and at the same time established 
configurationoftheC11andC13stereogeniccentersandatthesametimeestablishedtheabsolute
the absolute configuration as represented by the structure 4. 
configurationasrepresentedbythestructure4.
The Panek synthesis of neopeltolide started with reduction of methyl (R)‐(+)‐3‐methylglutarate 
ThePaneksynthesisofneopeltolidestartedwithreductionofmethyl(R)-(+)-3-methylglutarate
((99)) wwiitthh BBHH3∙¨SSMMee2 toto ggivivee aann aalclcoohhool,l ,wwhhicichh wwaass ssiliylylalatetedd toto ddeelilviveerr tthhee TTBBDDPPSS eetthheerr 1100 ((FFiigguurree 33)).. 
3 2
Half reduction of the ester moiety and dithioacetalization led to the dithiane 11, which was coupled 
Halfreductionoftheestermoietyanddithioacetalizationledtothedithiane11,whichwascoupled
with the epoxide 12 to afford, after removal of the dithioacetal, β‐hydroxy ketone 13. Modified 
with the epoxide 12 to afford, after removal of the dithioacetal, β-hydroxy ketone 13. Modified
Evans‐Tishchenko reduction [71], O‐methylation, desilylation, and oxidation [72] provided the 
Evans-Tishchenko reduction [71], O-methylation, desilylation, and oxidation [72] provided the
aldehyde 14. The tetrahydropyran ring was forged via a diastereoselective formal [4+2]‐annulation 
aldehyde14. Thetetrahydropyranringwasforgedviaadiastereoselectiveformal[4+2]-annulation
of the aldehyde 14 and the allylsilane 15, providing the dihydropyran derivative 16 in 75% yield 
of the aldehyde 14 and the allylsilane 15, providing the dihydropyran derivative 16 in 75% yield
with 10:1 diastereoselectivity. The requisite C5 hydroxy group was introduced after the construction 
with10:1diastereoselectivity. TherequisiteC5hydroxygroupwasintroducedaftertheconstruction
of the macrocyclic skeleton. Displacement of the sulfonyl group with NaCN, reductive removal of 
ofthemacrocyclicskeleton. DisplacementofthesulfonylgroupwithNaCN,reductiveremovalof
the acyl group, reduction of the nitrile group, and oxidation [73] of the resultant aldehyde afforded 
theacylgroup,reductionofthenitrilegroup,andoxidation[73]oftheresultantaldehydeafforded
the seco‐acid 17. Yamaguchi macrolactonization [74] of 17 delivered the 14‐membered macrolactone 
theseco-acid17. Yamaguchimacrolactonization[74]of17deliveredthe14-memberedmacrolactone
1188 iinn aa mmooddeerraattee yyiieeldld. .OOxyxmymerecrucurartaitoino nofo 1f81 8wwithit hHgH(Og(COOCCOFC3)F2 r)esruelsteudlt eind ainn aaxniaalx diaellidveelriyv eorfy thoef 
3 2
rtheaegreenatg eanntda, nadft,earf treerdruecdtuivcet ivweowrkourpk uwpitwhi tNhaNBaHB4H, th,eth aelcaolchoohl o1l91 9wwasa sisiosolaltaetded inin 6633%% yyiieelldd wwiitthh 
4
greater than 20:1 diastereoselectivity. Acylation of 19 with bis(2,2,2‐trifluoromethyl)phosphonoacetic 
greaterthan20:1diastereoselectivity. Acylationof19withbis(2,2,2-trifluoromethyl)phosphonoacetic
acid and subsequent Still‐Gennari‐modified Horner‐Wadsworth‐Emmons reaction [75] with the 
acid and subsequent Still-Gennari-modified Horner-Wadsworth-Emmons reaction [75] with the
aldehyde 20 [76] completed the first total synthesis of neopeltolide (4) (19 linear steps from methyl 
aldehyde20[76]completedthefirsttotalsynthesisofneopeltolide(4)(19linearstepsfrommethyl
(R)‐(+)‐3‐methylglutarate). 
(R)-(+)-3-methylglutarate).
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Figure 3. Panek synthesis of neopeltolide. 
Figure3.Paneksynthesisofneopeltolide.  
Figure 3. Panek synthesis of neopeltolide. 
2.2. Total Synthesis by the Scheidt Group 
2.2. TotalSynthesisbytheScheidtGroup
2.2. TSoctahle Sidynt tahnesdis  cboy‐ wthoe rSkcehresi dht aGvreo usph own that coupling of the β‐hydroxy dioxinone 21 with the 
Scheidt and co-workers have shown that coupling of the β-hydroxy dioxinone 21 with the
aldehyde 22 in the presence of Sc(OTf)3 gives the oxocarbenium ion intermediate 23, which 
Scheidt and co‐workers have shown that coupling of the β‐hydroxy dioxinone 21 with the 
aldeshuybdseequ2e2ntilny uthnedeprgroeesse nincteraomfolSecc(uOlaTr fP)3ringsi vcyecslizthateioonx tooc aafrfboredn ituhem biicoynclicin dtieorxmineodniea t2e4 (2F3i,guwreh ich
subsa4el)dq. euThehyned tsleyt e2rue2no dsienel regtchotieev siptiyrn eotsrfea tnmhceeo  Pleorcfi nuSsl acc(ryOPcTlrifiz)na3 stigociynvc eilssi  zaatshtciero ibnoaxtboolceaa tfrofbo earn dcihutahmier ‐bliioikcney  ctirnlaitcnersdmiitoieoxdniin asottean tee2.32 N,4 ow(tFahibgicluyhr,  e4).
subsequently undergoes intramolecular Prins cyclization to afford the bicyclic dioxinone 24 (Figure 
The2s4te irse oresaedleiclyti vcoitnyvoerfttihblee Ptori nthsec y2,c6l‐iczias‐tsiounbsitsitaustecdri bteatbralehytodraocphyarairn-‐l4ik‐oenter adnesriitvioatnivsetsa t2e5. Nsimotpalbyl yb,y2 4is
4). The stereoselectivity of the Prins cyclization is ascribable to a chair‐like transition state. Notably, 
read2hi4ley aistci onrenga vidnei rlDyti MbcloSenOtvo einrtt htihbelee2 p ,t6ro-e cstiehsn-esc u2e, b6os‐fct Hiistu‐2sOtue b[d7s7tti]et.u trtaehdy tdetrroaphyyrdarnop-4y-roanne‐4d‐oenreiv daetirviveasti2v5ess i2m5p sliymbpylyh beya ting
inDMSOinthepresenceofH O[77].
heating in DMSO in the pres2ence of H2O [77]. 

Figure 4. Stereoselective synthesis of 2,6‐cis‐substituted tetrahydropyran‐4‐one derivatives from 

β‐hydroxy dioxinones. 
Figure 4. Stereoselective synthesis of 2,6‐cis‐substituted tetrahydropyran‐4‐one derivatives from 
Figure 4. Stereoselective synthesis of 2,6-cis-substituted tetrahydropyran-4-one derivatives from
β‐hydroxy dioxinones. 
β-hydroxydioxinones.
Mar.Drugs2016,14,65 6of40
Mar. Drugs 2016, 14, 65  6 of 41 
InInth tehSe cShcehieditdts ysnytnhtheseissiso offn neeooppeellttoolliiddee,, aa PPrriinnss‐-ttyyppee mmaaccrrooccyyclcilziaztaiotino n[7[87]8 w] wasa ssuscucecscsefsuslfluy lly
imipmlepmlemenetnetdedto tos ismimuultlatanneeoouussllyy ccoonnssttrruucctt tthhee tteetrtarahhyyddrorpoypryarna nrinrgin agnadn tdhet hmeamcraoccryocclcy scklcelsektoenle itno na in
a ssiinnggllee sstteepp [[3333,,3344]].. TThhee ssyynnththeesissi ssstatartretded wwitihth NNoyooyroir iasaysmymmmetreitcr ichyhdyrdogroegneantioatni o[n79[]7 9o]f oeftheythl yl
3-o3x‐ooxhoehxeaxnaonaotaet(e2 (62)6t)o tod deleilviveerrt htheec coorrrreessppoonnddiinngg ββ‐-hhyyddrrooxxyy eessteter r(F(Figiguurer e5)5. )W. Weienirnerbe abmaimdaidtiaotnio [n80[]8 0]
and protection of the hydroxy group as its MPM ether gave the amide 27. This was reacted with a 
and protection of the hydroxy group as its MPM ether gave the amide 27. This was reacted with
lithiation product of the iodide 28 to afford the ketone 29 [81]. Cleavage of the MPM ether, 
a lithiation product of the iodide 28 to afford the ketone 29 [81]. Cleavage of the MPM ether,
Evans‐Tishchenko reduction [82], O‐methylation, and methanolysis led to the alcohol 30. The 
Evans-Tishchenkoreduction[82],O-methylation,andmethanolysisledtothealcohol30.Thedioxinone
dioxinone 31, prepared in four steps from 3‐(t‐butyldimethylsilyloxy)propanal via an asymmetric 
31,preparedinfourstepsfrom3-(t-butyldimethylsilyloxy)propanalviaanasymmetricvinylogous
vinylogous Mukaiyama aldol reaction [83], was coupled with the alcohol 30 under Yamaguchi 
Mukaiyamaaldolreaction[83],wascoupledwiththealcohol30underYamaguchiconditionstogive
conditions to give the ester 32. Cleavage of the silyl protecting groups and selective oxidation [84] of 
theester32.Cleavageofthesilylprotectinggroupsandselectiveoxidation[84]oftheliberatedprimary
the liberated primary alcohol delivered the cyclization precursor 33. Treatment of 33 with Sc(OTf)3 
alcoholdeliveredthecyclizationprecursor33. Treatmentof33withSc(OTf) affordedthecyclization
afforded the cyclization product 35 in 40% yield, via the oxocarbenium ion 334. Thermolysis of 35 in 
product 35 in 40% yield, via the oxocarbenium ion 34. Thermolysis of 35 in the presence of H O
the presence of H2O provided the ketone 36, which was reduced with NaBH4 to give neopeltolide2 
providedtheketone36,whichwasreducedwithNaBH togiveneopeltolidemacrolactone37. Finally,
macrolactone  37.  Finally,  Mitsunobu  reaction  [85,864]  of  37  with  the  acid  38  [87]  furnished 
Mitsunobureaction[85,86]of37withtheacid38[87]furnishedneopeltolide(4). Thesignificanceof
neopeltolide (4). The significance of this work lies in the demonstration of an intramolecular Prins 
thimsawcororckylcileizsaitniotnh, ewdheimcho nefsftercattiivoenlyo rfeaanliziendtr aam 1o6l‐elicnuelaarr sPterpin ssymntahcertoicc ypcalitzha ttioo nn,ewopheilctohliedfefe. cTtihvee ly
reaSlcizheedidat 1g6r-oliunpe afrusrttehpers yanptphleietidc pthaethir toPrnienos pmelatoclriodcey.cTlihzaetiSocnh esitdrtatgergoyu ptof utrhthe etroataplp lsiyendththeesiisr Porfi ns
maecxriogcuyocllidizea [t8io8n]. strategytothetotalsynthesisofexiguolide[88].

Figure 5. Scheidt synthesis of neopeltolide. 
Figure5.Scheidtsynthesisofneopeltolide.
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Mar. Drugs 2016, 14, 65  7 of 41 
2.32..T3o. tTaoltSaly Snythnetshiessibsy btyh tehLe eLeeeG Groruoupp 
ShSohrotlrytlya fatfetrert thhee aappppeeaarraannccee oof fthteh SechSecihdet isdytnsthyenstihs eosfi sneoofpenletoolpideelt, oalnidoteh,ear nmoathcreorcymclaicc rPorciynsc lic
Pricnyscliczyactliiozna taipopnroaapcph rtooawcahrdt onweoaprdeltonleidoep ewltaosl irdepeowrteads brye pthoer tLeede gbryouthpe, aLs esheogwrno uinp F,iagsurseh 6o [w38n]. in
The Lee synthesis began with asymmetric crotyl transfer reaction [89] of 1‐butanal (39) with chiral 
Figure 6 [38]. The Lee synthesis began with asymmetric crotyl transfer reaction [89] of 1-butanal
alcohol 40. The resultant homoallylic alcohol was benzylated and then subjected to ozonolysis to 
(39)withchiralalcohol40. Theresultanthomoallylicalcoholwasbenzylatedandthensubjectedto
give  the  aldehyde  41.  Chelate‐controlled  methallylation  [90]  followed  by  esterification  with 
ozonolysistogivethealdehyde41. Chelate-controlledmethallylation[90]followedbyesterification
2‐diphenylphospinobenzoic  acid  delivered  the  ester  42,  whose  hydroformylation  using 
with 2-diphenylphospinobenzoic acid delivered the ester 42, whose hydroformylation using
Rh(CO)2(acac)/P(OPh)3 catalyst [91] led to the aldehyde 43 in 65% yield with 5:1 diastereoselectivity. 
Rh(CO) (acac)/P(OPh) catalyst[91]ledtothealdehyde43in65%yieldwith5:1diastereoselectivity.
2 3
After masking the aldehyde moiety, the superfluous 2‐diphenylphosphinobenzoyl group was 
Aftermaskingthealdehydemoiety,thesuperfluous2-diphenylphosphinobenzoylgroupwasremoved
removed to liberate the hydroxy group, which was O‐methylated to give the methyl ether 44. 
toliberatethehydroxygroup,whichwasO-methylatedtogivethemethylether44. Hydrogenolysis
Hydrogenolysis of the benzyl ether followed by esterification with the carboxylic acid 45, and 
ofthebenzyletherfollowedbyesterificationwiththecarboxylicacid45,andsubsequentexposureto
subsequent exposure to DDQ provided the aldehydic homoallylic alcohol 46. Treatment of 46 with 
DDQprovidedthealdehydichomoallylicalcohol46. Treatmentof46withTESOTf/TMSOAcinAcOH
TESOTf/TMSOAc in AcOH at room temperature generated an oxocarbenium ion species 47 that 
atroomtemperaturegeneratedanoxocarbeniumionspecies47thatunderwentPrinscyclizationto
underwent Prins cyclization to afford, after methanolysis of 48, neopeltolide macrolactone 37 in 68% 
affyoiredld,a. fMteirtsmuentohbaun orleyascitsioonf 4o8f ,3n7e owpiethlt otlhide ecamrbaocrxoyllaicc taocnied 3378i nfu6r8n%ishyeidel dn.eoMpietlstuonliodbe u(4r)e.a Tcthioe nLoefe 37
witshynththeecsaisr boof xnyeloicpaecltiodli3d8ef wuransi schomedpnleetoepde ilnto 1l5id lein(e4a)r. TstheepsL,e heasrynnesthsiensgis tohfe nseteopp‐eelctoonliodmeiwcaals acsopmecpt loeft ed
in1th5el iPnreinasr msteapcrso,chyacrlnizeastsioinng sttrhaetesgteyp. -economicalaspectofthePrinsmacrocyclizationstrategy.

Figure 6. Lee synthesis of neopeltolide. 
Figure6.Leesynthesisofneopeltolide.
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2.4. Formal Synthesis by the Maier Group 
2.4. FormalSynthesisbytheMaierGroup
Maier  and  co‐workers  reported  the  total  synthesis  of  neopeltolide,  by  exploiting  an 
Maierandco-workersreportedthetotalsynthesisofneopeltolide,byexploitinganintermolecular
intermolecular Prins cyclization for the synthesis of the tetrahydropyran ring (Figure 7) [40,43]. The 
Prins cyclization for the synthesis of the tetrahydropyran ring (Figure 7) [40,43]. The synthesis
synthesis commenced with Noyori asymmetric hydrogenation of methyl 3‐oxobutanoate (49) to give 
commencedwithNoyoriasymmetrichydrogenationofmethyl3-oxobutanoate(49)togivetheoptically
the optically active alcohol 50 with excellent enantioselectivity (98% ee), which was silylated and 
activealcohol50withexcellentenantioselectivity(98%ee), whichwassilylatedandthenreduced
then reduced to provide the aldehyde 51. Leighton asymmetric allylation [92] of 51 using (R,R)‐52 
toprovidethealdehyde51. Leightonasymmetricallylation[92]of51using(R,R)-52deliveredthe
delivered the homoallylic alcohol 53. After O‐methylation, the terminal olefin was oxidatively 
homoallylic alcohol 53. After O-methylation, the terminal olefin was oxidatively cleaved to give
cleaved  to  give  the  aldehyde  54,  which  was  treated  with  Ph3P=CHCOSEt  to  afford  the 
thαe,βa‐ludnehsaytduera5t4ed,w thhiiocehswtera s5t5r.e DatieadstewreitohsePlhec3tPiv=eC HcoCnjOuSgEattet oadadffiotirodnt hoef Mα,eβM-ugnBsra tiunr athteed ptrheisoeensctee ro5f 5.
DCiausBterr∙SeMosee2l eacntidv e(cSo,Rn)j‐uJgosaitpehaodsd  liitgioanndo f[M93e]M  legdB rtoin  tthhee pthreioseesntceer o5f6C, uwBhri¨cShM  we2asa nrded(Su,cRe)d- Jousnipdhero s
ligFaunkduy[a9m3]al ecdontdoittihoensth [9io4e] sttoe prr5o6v,iwdeh tihche awldaeshryeddeu 5c7e.d Tuhnisd werasF ruekauctyeadm waitcho nthdei thioomnso[a9ll4y]litco aplcroohvoidl e
th5e8 ainld tehhey pdrees5e7n.cTe hoifs TwFaAs troe adcetleivdewr tihthe ttehterahhoymdrooaplylyrlainc a59lc ionh 7o2l%58 yiineldth weipthre 8s:e1n dcieasotfeTreFoAsetloecdtievliitvye. r
thAe ttherterae‐hsytedpr opproytreacntin5g9 ginro7u2p% myaineilpdulwatiitohns8 :l1edd tioa sttheer eaolcsoehleoclt 6iv0i,t wy.hiAcht whraese o-sxtiedpizpedro [t9e5c]t ianngd gthroenu p
mdaensiiplyulalatetido ntsol epdrotoduthcee atlhceo hsoelc6o0‐a,cwidh ic6h1. wYaasmoaxgiduiczheid  m[9a5c]roalnadctothneiznadtioesni lyolfa te6d1 taoffporroddedu cethteh e
semcoa-carcoildac6to1n.eY 6a2m. aCglueacvhaigme aocfr othlaec tMonOizMa tgiornouopf l6e1da tfofo nrdeoepdetlhtoelimdea cmroalcarcotloantoen6e 23.7C, cleoamvpagleetinogf tah e
MfOorMmagl rsoyunpthleesdist oofn neeooppeellttoolliiddee m(4)a.c Trohlias tfoonrme3a7l ,syconmthpesleist ipnrgocaefeodremd ailns 1y9n ltihneesairs sotefpnse ofrpoemlt omliedthey(l4 ).
Th3‐isoxfoorhmexaalnsoyantteh (e4s9i)s. proceededin19linearstepsfrommethyl3-oxohexanoate(49).

FFiigguurree 77.. MMaaiieerr ssyynntthheessiiss ooff nneeooppeellttoolliiddee. .
2.5. Total Synthesis by the Kozmin Group 
2.5. TotalSynthesisbytheKozminGroup
Kozmin and co‐workers completed the total synthesis of neopeltolide in a racemic form, 
Kozmin and co-workers completed the total synthesis of neopeltolide in a racemic form,
highlighting a desymmetrizing Prins cyclization for constructing the tetrahydropyran ring [36]. 
highlighting a desymmetrizing Prins cyclization for constructing the tetrahydropyran ring [36].
TrTeraetamtmenetnot fotfh tehev ivninyylologgoouusse essteterr6 633w witithhT TFFAAi innC CHH2CCll2 aatt 00 °˝CC rreessuultlteedd inin PPrirnins scycyclcilziaztaitoino nvivai athteh e
2 2
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oxocarbeniumion64togive,afterinsitucleavageofthetrifluoroacetylgroupof65,thetetrahydropyran
oxocarbenium  ion  64  to  give,  after  in  situ  cleavage  of  the  trifluoroacetyl  group  of  65,  the 
derivative66in84%yield(Figure8). BenzylationofthehydroxygroupfollowedbyWackeroxidation
tetrahydropyran derivative 66 in 84% yield (Figure 8). Benzylation of the hydroxy group followed 
oftheolefinprovidedthemethylketone67. Treatmentof67withCy BCl/Et Ngeneratedaboron
by Wacker oxidation of the olefin provided the methyl ketone 67. Treat2ment of 367 with Cy2BCl/Et3N 
enolate,whichwasreactedwiththealdehyde68todeliverthealcohol69in81%yieldwithexcellent
generated a boron enolate, which was reacted with the aldehyde 68 to deliver the alcohol 69 in 81% 
stereocontrol (dr > 98:2) [96]. Wittig methylenation of 69 and acidic workup gave the ketone 70,
yield with excellent stereocontrol (dr > 98:2) [96]. Wittig methylenation of 69 and acidic workup gave 
which was stereoselectively reduced with Et BOMe/NaBH [97] to afford the 1,3-diol 71. After
the ketone 70, which was stereoselectively red2uced with Et2BO4Me/NaBH4 [97] to afford the 1,3‐diol 
hydrolysisofthemethylestermoiety[98],Yamaguchimacrolactonizationoftheresultantseco-acid
71. After hydrolysis of the methyl ester moiety [98], Yamaguchi macrolactonization of the resultant 
ledtothemacrolactone72. Hydrogenationoftheexo-methyleneof72gavethealcohol73. Mitsunobu
seco‐acid led to the macrolactone 72. Hydrogenation of the exo‐methylene of 72 gave the alcohol 73. 
inversionof73(p-NO C H CO H,Ph P,DEAD)andmethanolysisoftheresultantp-nitrobenzoate
Mitsunobu inversion2 of6 743 (p‐2NO2C63H4CO2H, Ph3P, DEAD) and methanolysis of the resultant 
deliveredthealcohol74. O-Methylationof74wasfollowedbyhydrogenolysisofthebenzylether
p‐nitrobenzoate delivered the alcohol 74. O‐Methylation of 74 was followed by hydrogenolysis of the 
to afford the neopeltolide macrolactone 37. Mitsunobu coupling of 37 with the carboxylic acid 38
benzyl  ether  to  afford  the  neopeltolide  macrolactone  37.  Mitsunobu  coupling  of 37  with  the 
pcraorvbiodxeydlinc eaocpidel t3o8l ipdreo(v4i)d.eAd cnoenocpiseeltosylindteh e(4s)i.s Aof cnoenocpiseelt osylindteheinsias roafc neemoipceflotormlidwe ains tah ruascaemchiice vfoerdmin 
1w5alisn tehaurss taecphsiefvroemd ian c1o5m limneearrc isatellpysa fvroamila ba lceommamteerricaila.lly available material. 

Figure 8. Kozmin synthesis of neopeltolide. 
Figure8.Kozminsynthesisofneopeltolide.
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22..66.. FFoorrmmaall SSyynntthheessiiss bbyy tthhee FFlloorreeaanncciigg GGrroouupp 
FFlloorreeaanncciigg eett aall.. hhaavvee ddeevviisseedd aa DDDDQQ-‐mmeeddiiaatteedd ooxxooccaarrbbeenniiuumm ioionng geenneeraratitoionn//iinnttrraammoolleeccuullaarr 
PPrriinnss ccyycclliizzaattiioonn ffoorr ccoonncciissee ssyynntthheessiiss ooff 22,,66-‐cciiss-‐ssuubbssttiittuutteedd tteettrraahhyyddrrooppyyrraann-‐44-‐oonnee ddeerriivvaattiivveess 
((FFiigguurree 99)) [[9999]].. TThhee ssyynntthheettiicc ssttrraatteeggyy rreeqquuiirreess aapppprroopprriiaattee eellaabboorraattiioonn ooff ccyycclliizzaattiioonn pprreeccuurrssoorrss;; 
uuppoonn ooxxididataitoinono foafn aalnly laiclloyrlibc enozry lbicenetzhyelricm  eotiheetyr omf7o5iewtyit hoDf D7Q5 ,wthiethc orDreDsQpo, ntdhien gcooxrorecasprboenndiuinmg 
iooxnoc7a6ribsegneiunmer aiotend 7,6t oisw ghenicehraatnede,n tool wacheitcaht eanm eonieotly acaetttaatcek smionitertaym aottlaecckusl airnltyrawmitohlelcouslsaorlfyt hweitahc elotyssl 
gorf otuhpe toacpertoyvl idgerotuhpe 2t,o6 -cpisr-osvuibdset ittuhtee d2,t6e‐tcriash‐syudbrsotpityurtaend- 4t-eotnreahdyedrirvoaptiyvrean7‐74.‐Tohnee sdteerreiovsaetlievcet iv77it.y Tcahne 
bsteerreeoassoelneecdtivbiytyc ocnansi dbeer rineagsaonchedai rb-yli kceontrsaidnesirtiinogn as tcahtea,ira‐sliskheo twrann.sTithioenp srteasteen, tassy snhtohwetnic. sTthraet epgryesheanst 
bsyenenthaeptipcl sietrdatteogtyh ehatost baleesynn atphpesliiesdo ftoc ltahveo tsootlaidl seyAnt[h1e0s0i]s. of clavosolide A [100]. 

FFiigguurree 99.. DDDDQQ‐-mmeeddiiaatteedd iinnttrraammoolleeccuullaarr PPrriinnss ccyycclliizzaattiioonn.. 
The  Floreancig  group  has  successfully  applied  their  DDQ‐mediated  intramolecular  Prins 
The Floreancig group has successfully applied their DDQ-mediated intramolecular Prins
cyclization  strategy  to  neopeltolide  synthesis  (Figure  10)  [44].  The  synthesis  began  with 
cyclizationstrategytoneopeltolidesynthesis(Figure10)[44]. Thesynthesisbeganwithetherification
etherification of optically active alcohol 78, prepared in one step from a commercially available 
ofopticallyactivealcohol78,preparedinonestepfromacommerciallyavailablematerial,withthe
material, with the trichloroacetimidate derivative 79 under the influence of TfOH to give the vinyl 
trichloroacetimidatederivative79undertheinfluenceofTfOHtogivethevinyliodide80,whichwas
iodide 80, which was coupled with the alkyne 81 under Sonogashira conditions [101,102] to provide 
coupled with the alkyne 81 under Sonogashira conditions [101,102] to provide the endiyne 82.
the endiyne 82. Intramolecular hydrosilylation of 82 catalyzed by Pt(DVDS) followed by oxidation of 
Intramolecularhydrosilylationof82catalyzedbyPt(DVDS)followedbyoxidationofthederivedvinyl
the derived vinyl silane afforded the hydroxy ketone 83 in 57% yield in a regioselective manner [103]. 
silaneaffordedthehydroxyketone83in57%yieldinaregioselectivemanner[103]. Evnas-Tishchenko
Evnas‐Tishchenko reduction and O‐methylation led to the methyl ether 84. Hydrolysis of the ester 
reductionandO-methylationledtothemethylether84. Hydrolysisoftheestermoietiesof84gavea
moieties of 84 gave a seco‐acid, which underwent Yamaguchi macrolactonization to deliver the 
seco-acid,whichunderwentYamaguchimacrolactonizationtodeliverthemacrolactone85. Addition
macrolactone 85. Addition of AcOH to the terminal alkyne was catalyzed by [Ru(p‐cymene)Cl2]2 to 
ofAcOHtotheterminalalkynewascatalyzedby[Ru(p-cymene)Cl ] toaffordtheenolacetate86
2 2
afford the enol acetate 86 (82% yield, 5:1 regioselectivity) [104]. Exposure of 86 to DDQ in the 
(82%yield,5:1regioselectivity)[104]. Exposureof86toDDQinthepresenceof2,6-dichloropyridine
presence  of  2,6‐dichloropyridine  and  LiClO4  in  1,2‐dichloroethane  induced  the  expected 
andLiClO in1,2-dichloroethaneinducedtheexpectedoxocarbeniumiongeneration/intramolecular
4
oxocarbenium ion generation/intramolecular Prins cyclization sequence to provide the ketone 87 in 
Prinscyclizationsequencetoprovidetheketone87in58%yield. Stereoselectivehydrogenationof87
58% yield. Stereoselective hydrogenation of 87 furnished known compound 36, which intercepts the 
furnishedknowncompound36,whichinterceptstheScheidtsynthesisofneopeltolide. TheFloreancig
Scheidt synthesis of neopeltolide. The Floreancig formal synthesis was completed in 13 linear steps 
formalsynthesiswascompletedin13linearstepsfrom2-butyn-1-ol.
from 2‐butyn‐1‐ol. 
2.7. Formal Synthesis by the Yadav Group 
Yadav and Kumar described a formal synthesis of neoleptolide based on Lee’s intramolecular 
Prins macrocyclization strategy (Figure 11) [48]. The Yadav synthesis started with conversion of 
(S)‐citronellol (88) into the aldehyde 89, whose intermolecular Prins cyclization with the homoallylic 
alcohol 90 gave the tetrahydropyran derivative 91 (56% yield), where the C11 and C13 stereogenic 
centers were established. A three‐step functional group manipulation led to the iodide 92. The 
terahydropyran ring of 92 was cleaved by treatment with zinc to deliver the alcohol 93, which was 
elaborated to the alcohol 94 in four steps. The remainder of the synthesis was achieved in the same 
way as that reported by Lee et al. [38].