DTIC ADA544464: Synthesis of (-)-callicarpenal, a Potent Arthropod Repellent

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Tetrahedron67(2011)3023e3029
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of ((cid:1))-callicarpenal, a potent arthropod repellent
Taotao Linga, Jing Xua, Ryan Smitha, Abbas Alib, Charles L. Cantrellc, Emmanuel A. Theodorakisa,*
aDepartmentofChemistryandBiochemistry,UniversityofCalifornia,SanDiego,9500GilmanDrive,LaJolla,CA92093-0358,USA
bNationalCenterforNaturalProductsResearch,TheUniversityofMississippi,University,MS38677,USA
cUnitedStatesDepartmentofAgriculture,AgriculturalResearchService,NaturalProductsUtilizationResearchUnit,University,MS38677,USA
a r t i c l e i n f o a b s t r a c t
Articlehistory: Callicarpenal (1), a natural terpenoid isolated from American beautyberry (Callicarpa americana), has
Received15December2010 shownsignificantrepellentactivitiesagainstmosquitoes,ticks,andimportedfireants.Herewereport
Receivedinrevisedform24February2011 ourefficientsyntheticapproachtothisnaturalproduct,andpreliminaryresultsofthemosquitobiting-
Accepted25February2011
Availableonline4March2011 deterrenteffectsofcallicarpenalaswellasitssyntheticprecursorsandrelatedC8-epimers.Thesynthetic
strategyallowsrapidaccesstovariousepimersandanaloguesofthenaturalproductthatcanbeusedto
exploreitsstructureeactivityrelationshipandoptimizeitsbiologicalproperties.
Keywords: (cid:1)2011ElsevierLtd.Allrightsreserved.
Arthropodrepellent
Arthropod-bornedisease
Naturalproducts
Callicarpenal
Asymmetricsynthesis
1. Introduction new arthropod repellents, led to the evaluation of plants of the
genus Beautyberry (Callicarpa).8 Interestingly, freshly crushed
Blood-feeding arthropods transmit many of the world’s most Americanbeautyberryleaveshavebeenusedinethnomedicineas
dangerousdiseases,suchasmalaria1,2aanddenguefever.2bAnes- atraditionalbiting-insectrepellentincertainsouthernstatesofthe
timated 243 million malaria cases led to approximately 863,000 UnitedStates.9Inspiredbythisinformation,Cantrelletal.studied
deathsin2008,2awhilenearlyonethirdoftheworld’spopulationis thechemicaloriginsofthebioactivitiesofthebeautyberryextracts
at risk of dengue fever.2b Very recently, an outbreak of infection against mosquitoes,9 ticks,10 and imported fire ants.11 These in-
casescausedbytickbitinghasbeenreportedresultinginafatality vestigationsledtotheisolationofthreepotentmosquito-repellent
rateashighas30%insomeareaofcentralChina.3Researchonthe
cause of this infection led to the isolation and identification of
anewtypeofBunyavirus.Asatick-bornevirus,thisnewspeciesof
Bunyavirusfamilyhasbeenconsideredasanewemergingdeadly
virus.3Consequently,asidefromtheurgentneedofstudyfornew
antiplasmodium/antivirusagents,thedevelopmentofnewsafeand
effective repellents against blood-feeding arthropods is in high
demand.4
Thebestknowninsectrepellent,duetoitspotencyandsimple
synthesis, is N,N-diethyl-3-methylbenzamide (DEET, 4), a com-
pounddevelopedbytheUSArmyin1946.1Althoughitisconsid-
ered as safe, extensive use of this compound can lead to skin
irritation.5 Picaridin (KBR3023, 5) is another synthetic repellent
thathasbeenreportedtobeaseffectiveasDEETbutnotastoxicin
humans.6 On the other hand, p-menthane-3,8-diol (PMD, 6), the
maincomponentincitrus/eucalyptussolutions,isthebestrepre-
sentativeofnaturalproduct-repellents.7Thegrowingdemandfor
* Correspondingauthor.Tel.:þ18588220456;fax:þ18588220386;e-mail
address:[email protected](E.A.Theodorakis). Fig.1. Structuresofvariousinsectrepellents.
0040-4020/$eseefrontmatter(cid:1)2011ElsevierLtd.Allrightsreserved.
doi:10.1016/j.tet.2011.02.078
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4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER
Synthesis of (-)-callicarpenal, a potent arthropod repellent
5b. GRANT NUMBER
5c. PROGRAM ELEMENT NUMBER
6. AUTHOR(S) 5d. PROJECT NUMBER
5e. TASK NUMBER
5f. WORK UNIT NUMBER
7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION
University of California, San Diego,Department of Chemistry and REPORT NUMBER
Biochemistry,9500 Gilman Drive,La Jolla,CA,92093-0358
9. SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S)
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13. SUPPLEMENTARY NOTES
14. ABSTRACT
Callicarpenal (1), a natural terpenoid isolated from American beautyberry (Callicarpa americana), has
shown significant repellent activities against mosquitoes, ticks, and imported fire ants. Here we report our
efficient synthetic approach to this natural product, and preliminary results of the mosquito
bitingdeterrent effects of callicarpenal as well as its synthetic precursors and related C8-epimers. The
synthetic strategy allows rapid access to various epimers and analogues of the natural product that can be
used to explore its structureeactivity relationship and optimize its biological properties.
15. SUBJECT TERMS
16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF 18. NUMBER 19a. NAME OF
ABSTRACT OF PAGES RESPONSIBLE PERSON
a. REPORT b. ABSTRACT c. THIS PAGE Same as 7
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3024 T.Lingetal./Tetrahedron67(2011)3023e3029
compounds: callicarpenal (1) and intermedeol (2), from the electrophilicC-4carbonylgroupof((cid:1))-7wasselectivelyprotected
American plant, and spathulenol (3), from the Japanese plant with 1.2 equiv of ethylene glycol to form the corresponding C-4
(Fig.1). ketal.14TheC-8enonewasthenreducedunderlithium/ammonia
The low isolation yield of callicarpenal (0.05e0.15% from dry conditionsandtheresultingenolatewasalkylatedinsituwithallyl
biomass)togetherwiththetediousbulkisolationandpurification bromidetoaffordketone8asasingleisomer(70%overtwosteps).
techniques,restrictsubstantiallytheavailabilityofthiscompound Conversion of 8 to silyl ether 10 was achieved in three steps: (a)
fromnaturalsources.Withthisinmind,wereporthereanefficient ozonolysis of the terminal alkene followed by reduction of both
stereoselectivesynthesisof((cid:1))-callicarpenal.Wealsoreportinitial carbonylgroups;(b)selectivesilylationoftheprimaryalcohol;and
mosquito deterrency studies of this natural product and various (c)oxidationoftheremainingC-8hydroxylgroup.Thelatterstep
syntheticderivatives.12 was performed using catalytic amount of TPAP (3.5mol %) and
NMOastheco-oxidant(88%forthreesteps).15Wealsoattempted
toreplacetheozonolysisreactionwithasequenceofalkenedihy-
2. Resultsanddiscussion droxylationfollowedbyoxidativecleavageoftheresulting1,2-diol.
However,treatmentof8withOsO4/NMOgaverisetohemiacetal9
Oursynthesisof((cid:1))-1departedfromthereadilyavailableen- complicatingsubsequentfunctionalizationstrategies.Thechemical
antiomericpurediketone((cid:1))-7(ee>95%)13(Scheme1).Themore structure of 9 was unambiguously confirmed via a single crystal
X-rayanalysis.16
We then turned our attention to the installation of the C-8
methylgroup. Tothis end, ketone 10 was converted toalkene 11
understandardWittigconditions(91%yield).Hydrogenationof11
under the standard Pd/C-catalyzed conditions proceeded pre-
dominantlyfromthestericallymoreaccessiblebottomfaceofthe
alkeneformingtheC8-epi-12asthemajorproduct(94%,dr¼10:1.)
ThestereochemistryofthenewlyformedC-8centerwasconfirmed
initially by comparing the NMR data of both epimers to those
reportedintheliterature17andultimatelybyasinglecrystalX-ray
analysis16of theundesiredfullydeprotectedepimerC8-epi-13.In
order to produce the desired C-8 epimer, alkene 11 was initially
desilylatedwithTBAFandsubsequentlyreducedunderPd/Ccon-
ditions. This sequence afforded the desired compound 13 as the
major product (97%, dr¼8:1). Importantly, treatment of 11 with
Crabtree’scatalyst18(3.5mol%)underH2atmosphere(70psi)gave
even higher diastereoselectivity (dr >99:1). Obviously, the better
interaction between the iridium compound and the free alcohol
exclusively delivered the hydrogen from the same face of the
molecule as the alcohol.19 The acetonide was subsequently re-
movedunderacidicconditionstoformketone13that,afterWittig
olefination,producedalkene14(92%fortwosteps).Isomerization
oftheexocyclicdoublebondof14wasachievedwithRuCl320under
refluxingethanolicconditionstoformthedesiredendo-alkene15
Scheme1. Reagentsandconditions:(a)(CH2OH)2(1.2equiv),p-TsOH,PhH,80(cid:3)C,24h
(90%);(b)Li/NH3,THF,(cid:1)78to(cid:1)30(cid:3)C,2h,thenCH2]CHCH2Br,2h(78%);(c)OsO4
(1mol%),NMO,acetone/H2O(3:1),rt,12h(95%);(d)O3,THF,(cid:1)78(cid:3)C,thenPPh3,2h,
then3.0equivNaBH4,0(cid:3)C,2h;(e)1.0equivTIPSOTf,2,6-lutidine,CH2Cl2,(cid:1)80(cid:3)C,1h;
(f)TPAP(3.5mol%),NMO,CH2Cl2,18h(88%forthreesteps);(g)CH3PPh3Br,NaHMDS,
THF,0(cid:3)Ctort,16h(91%);(h)Pd/C,H2,rt,12h(99%,dr¼10:1);(i)TBAF,THF,15h(94%);
(j)0.1NHCl,THF,8h(97%for13,93%forC8-epi-13);(k)H2,Crabtree’scatalyst([Ir
(COD)(PCy3)(Py)]PF6,3.5mol%),CH2Cl2,70psi,15h(94%,dr>99:1);(l)CH3PPh3Br, Scheme 2. Reagents and conditions: (a) 0.1N HCl, THF, 8h (93%); (b) CH3PPh3Br,
NaHMDS,THF,0(cid:3)Ctort,18h(95%);(m)RuCl3$H2O,EtOH,reflux,18h(97%);(n)TPAP NaHMDS,THF,0(cid:3)Ctort,18h(91%);(c)RuCl3$H2O,EtOH,reflux,18h(89%);(d)TPAP
(20mol%),NMO,CH2Cl2,15h(76%). (20mol%),NMO,CH2Cl2,15h(90%).
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T.Lingetal./Tetrahedron67(2011)3023e3029 3025
Table1 the bioactivity. These observations suggest that it is possible to
Mosquitobiting-deterrenteffectsof((cid:1))-callicarpenal(1)anditsanalogues13,14, furtheroptimizethestructureeactivityofthisnaturalproductand
and15against7e10daysoldadultfemalesofAe.aegypti
develop exclusively synthetic analogues of callicarpenal with
Treatment Amountapplied Meanproportion a simpler chemical motif, less lengthy synthesis, and optimized
(n¼100) (nmoles/cm2) notbiting(SE) mosquitobitingdeterrency.
DEET 25 0.91(0.029)a
((cid:1))-Callicarpenal(1) 25 0.72(0.045)b 3. Conclusions
13 25 0.61(0.049)c
14 25 0.61(0.049)c
15 25 0.64(0.048)c We have developed an efficient enantioselective synthesis of
Ethanol d 0.22(0.041)d ((cid:1))-callicarpenal, a promising arthropod repellent. Key to the
n¼Numberoffemalestestedagainsteachtreatment. synthesisisthestereoselectivereductionofC-8alkeneof11that
SE¼Standarderrorofthemean. dependingontheconditionscandelivereitherepimerinexcellent
Meanswithinacolumnnotfollowedbythesameletteraresignificantlydifferent yield and diastereoselectivity. The synthesis of ((cid:1))-callicarpenal
(P<0.05,DMRT). proceedsin12stepsand36%overallyieldfromdiketone((cid:1))-7.The
syntheticstrategyutilizesreadilyavailablematerialsandreagents
in97%yield.12e,21Oxidationof15wasachievedwithTPAPandNMO
makingtheoverallapproachamenabletoscale-up.Assuch,ital-
andproducedcallicarpenal((cid:1))-1in76%yield.Theanalyticaland
lows access to this natural product for further biological in-
spectroscopicdata(seetheExperimentalsection)ofoursynthetic
vestigationanddevelopment.Moreover,mosquitobiting-deterrent
((cid:1))-1perfectlymatchedthereporteddataofthenaturalproduct.22
studieswithcallicarpenalandselectedanaloguessuggestthatthe
To evaluate the effectof the C8 stereocenteron the insect-re-
chemicalstructureoftheparentmoleculecanbereadilymodified
pellent activities of callicarpenal, we synthesized C8-epi-((cid:1))-1. toimproveitsbioactivity.
Scheme2summarizesourapproach.
Thealdehydefunctionalityof((cid:1))-callicarpenal(1)couldgiverise
4. Experimentalsection
to long-term stability issues, thereby limiting its applications. To
overcomesuchpotentiallimitationswesoughttocompareitsbio-
4.1. Generalexperimentalprocedures
activitytothatofitssyntheticprecursors.Alongtheselines,ana-
logues 13, 14, and 15 were chosen due to their availability and
Unlessindicated,allcommercialreagentswereusedasreceived
structuralsimilaritywith1.Allthesecompoundswereevaluatedfor
withoutfurtherpurification.Allnon-aqueousreactionswerecarried
mosquito biting-deterrent effects against 7e10 days old adult fe-
out under argon atmosphere using dry glassware that had been
malesofAedesaegypti(Table1).Analoguesweretestedside-by-side
flame-driedunderastreamofargonunlessotherwisenoted.THF
againstDEETand1.Allofthecompoundstestedweremoreeffective
wasdriedoversodium/benzophenone,dichloromethaneandMeOH
tahnadnaeltlhoafniotlscaonnatlroogluate2s51n3m,1o4l,/camnd2.1D5E.ERTewduasctmioonreoefftfehcetiavledtehhaynd1e overCaH2.Et3Nwasdrydistilledfromflamedried4(cid:2)Apowdered
molecularsieves.Flashcolumnchromatographywasperformedon
functionalityof1tothecorrespondingalcoholdecreasedconsid-
silicagel(MerckKieselgel60,230e400mesh)usinghexane/ether
erablytheactivityofthenaturalproduct.Ontheotherhand,isom-
mixturesofincreasingpolarity.Theprogressofallthereactionswas
erization of the C4 double bond to the C-3,4 endocyclic position
monitored by thin-layer chromatography (TLC) using glass plates
appearstoimprovemarginallythecompoundpotency.Theseresults
areinagreementwithpreviousobservations.23 precoatedwithsilicagel-60F254toathicknessof0.5mm(Merck).
13CNMRand1HNMRspectrawererecordedoneithera400MHz
The C-8 epimers of callicarpenal and some callicarpenal ana-
lwogerueesa,lssoynetvhaelsuizaeteddafboorvmeforsoqmuitthoebtirtainngs--depetimererernotfecfofmecptsouangdain12st, wVaitrhianflainmsetrdurmieedntKo2rCaO53,0c0hMemHizcaJElOshLiifntsst(rdu)mareentq.uCoDtCedl3iwnapsatrrtesapteedr
million(ppm)referencedtotheappropriateresidualsolventpeak
e7pei1-103d,aCy8s-eoplid-1a4d,uClt8-feepmi-a1l5e,saonfdAeC.8a-eepgiy-p((cid:1)ti)(-T1abwleer2e).teAsnteadlogsiudees-bCy8-- b(CrHoaCdl3s),inwgilteht,thdeouabbblerte,vtiraiptiloent,sqsu,barrtse,td,,at,nqd,amnudlmtipdleetn,orteisnpgescitnivgelelyt.,
side against 1 and ethanol control. Again, all of the compounds
J¼coupling constants given in Hertz (Hz). High resolution Mass
tested were more effective than ethanol control at 25 nM/cm2.
spectra(HRMS)wererecordedonatrisectorWGAutoSpecQspec-
Callicarpenal(1)wasmoreeffectivethanC8-epi-13,C8-epi-14,and trometer. Optical rotation data were collected on a Jasco P-1010
C8-eEpvia-l1u5a;tiwonhioleftCh8e-edpait-a((cid:1)s)h-o1wwnaisnaTsaebflfeesc1tivaendas21s.uggeststhatthe polarimeterusingHPLCgradeCHCl3(driedovermolecularsieves).
relative stereochemistry at C8 does not play a significant role in
4.1.1. (R)-5,8a-Dimethyl-3,4,8,8a-tetrahydronaphthalene-1,6
determiningthebiologicalactivityofthedifferentepimers.More-
(2H,7H)-dione (((cid:1))-7). To a solution of 2-methyl-1,3-cyclo-
over,thefunctionalitiesattheC4centerdonotappeartoinfluence
hexadione(0.90g,7.17mmol)inethylacetate(50ml)wereadded
triethylamine(1.30ml,9.32mmol)andethylvinylketone(0.78ml,
TM1a3ob,sClqe8u-2eitpoi-b1i4t,inCg8--depeit-e1r5re,nantdefCfe8c-etspio-f((cid:1)((cid:1))-)1-caaglaliicnasrtp7eena1l0(d1a)yasnodlditasdaunlatlfoegmuaelseCs8o-feApei-. t7h.8e9nmcmooolel)d.Tthoe2re5a(cid:3)cCti.oTnhmeisxotulvreenwtawsahsearteemdoavte7d0u(cid:3)Cndfoerr1r0edhuacnedd
aegypti pressure and the resulting crude material was chromatographed
(silica,10%etherinhexanes)toyieldthecorrespondingtriketone
Treatment Amountapplied Meanproportion
(n¼100) (nmoles/cm2) notbiting(SE) (1.45g, 6.81mmol, 95%). A solution of the triketone (1.45g,
((cid:1))-Callicarpenal(1) 25 0.78(0.048)a 6.81mmol), L-phenylalanine (1.13g, 6.81mmol), and D-cam-
C8-epi-13 25 0.56(0.057)b phorsulfonicacid(0.79g,3.40mmol)inDMF(100ml)wasstirred
C8-epi-14 25 0.56(0.057)b at rt under argon atmosphere overnight. Then the mixture was
C8-epi-15 25 0.61(0.056)b heatedat30(cid:3)Cfor24h,andthetemperaturewasraisedin10(cid:3)C
ECt8h-eapnio-(l(cid:1))-1 2d5 00..7263((00..004499))ac intervalsevery24hduring4days.Afterthemixturewasstirredat
70(cid:3)Cfor24h,theoilbathwasremovedinordertoletthereaction
n¼Numberoffemalestestedagainsteachtreatment.
mixture cool down to rt. The resulting solutionwas thenpoured
SE¼Standarderrorofthemean.
Meanswithinacolumnnotfollowedbythesameletteraresignificantlydifferent into cold aqueous NaHCO3, extracted with ether (2(cid:4)50ml), then
(P<0.05,DMRT). dried over MgSO4. Evaporation of ether followed by column
Author's personal copy
3026 T.Lingetal./Tetrahedron67(2011)3023e3029
chromatography (silica, 0e20% ether in hexanes) of the residue added4-methylmorpholine-N-oxide(17.5g,0.149mol)followedby
affordedthecrudeenone7asaviscousoil,whichcrystallizedon tetrapropylammonium perruthenate (0.50g, 1.42mmol). The re-
standingat(cid:1)30(cid:3)C.Recrystallizationfromn-hexaneinanicebath action mixturewasstirredat25(cid:3)C for18h,thendirectlyconcen-
gave((cid:1))-7(1.05g,5.38mmol,79%)asacolorlesslongneedles;mp: tratedandsubjectedtoflashchromatography(silica,0e5%etherin
46e48 (cid:3)C; Rf¼0.46 (35% ether in hexanes); [a]D25 þ124.0 (c 1.0, hexanes)toaffordketone10(21.5g,0.049mol,98%)asacolorless
benzene);IR(film):n2952,1709,1665,1610,1352,1008;1HNMR liquid;Rf¼0.58(25%etherinhexanes);[a]D25(cid:1)62.3(c0.7,CH2Cl2);IR
(400MHz, CDCl3): d 2.92e2.81 (m, 1H), 2.73e2.64 (m, 1H), (film):n2939,2865,1703,1461,1098,884,682;1HNMR(500MHz,
2.55e2.37(m,4H),2.18e2.02(m,4H),1.81(d,J¼1.2Hz,3H),1.42(s, CDCl3):d3.96e3.92(m,2H),3.90e3.84(m,2H),3.64(m,1H),3.57(m,
3H); 13C NMR (100MHz, CDCl3): d 212.0,197.5,158.1,130.7, 50.6, 1H),2.48(m,1H),2.39(m,1H),2.16(dd,J¼12.0,3.0Hz,1H),2.07(m,
37.3,33.3,29.5,27.2,23.3,21.5,11.2;HRMS(ESI):calcdforC12H17O2 1H),1.99(m,1H),1.71e1.40(m,8H,overlappedwithwaterpeak),1.16
[MþH]þ193.1228,found193.1224. (s,3H),1.04(m,21H),1.02(s,3H);13CNMR(125MHz,CDCl3):d(C8
peakistooweaktoobserve)112.8,65.0,64.8,59.9,49.4,44.6,42.3,
4.1.2. (4a0R,50R,8a’R)-50-Allyl-50,8a0-dimethylhexahydro-20H-spiro 41.0,34.7,30.1,28.7,22.6,21.8,21.6,17.9(6C),16.3,11.8(3C);HRMS
[[1,3]dioxolane-2,10-naphthalen]-60(70H)-one(8). Asolutionofenone (ESI):calcdforC25H46O4SiNa[MþNa]þ461.3066,found461.3068.
((cid:1))-7 (1.05g, 5.38mmol) and p-toluenesulfonic acid (0.20g,
1.08mmol) in benzene (100ml) was treated with ethylene glycol 4.1.4. (2-((4a0R,50R,8a0R)-50,8a0-Dimethyl-60-methyleneoctahydro-
(0.36ml,6.46mmol),thenheatedat80(cid:3)Cfor24hunderanatmo- 20H-spiro[[1,3]dioxolane-2,10-naphthalen]-50-yl)ethoxy) triisopro-
sphereofargon.Aftercoolinginanicebath,theresultingsolutionwas pylsilane(11). Asolutionofmethyltriphenylphosphoniumbromide
pouredintoaqueousNaHCO3andthe mixturewasextractedwith (37.0g,0.068mol)inTHF(400ml)wastreateddropwisewithso-
ether (2(cid:4)50ml). The combined extracts were washed with water diumbis(trimethylsilyl)amide(90.0mlofa1.0MsolutioninTHF,
(20ml)andbrine(20ml)anddriedoverMgSO4.Evaporationofthe 0.09mol) at 0(cid:3)C and stirred at this temperature for 30min. The
solvent followed by flash column chromatography (silica, 0e10% resultingorangesolutionwastreateddropwisewithasolutionof
etherinhexanes)yieldedthecorrespondingketal(1.1g,4.84mmol, ketone10(30.0g,0.068mmol)inTHF(50ml)at0(cid:3)C.Afterstirring
90%)asacolorlessliquid.Toasolutionoflithium(0.15g,21.15mmol) at65(cid:3)Cfor15h,themixturewasquenchedwithsaturatedaqueous
inliquidammonia(100ml)at(cid:1)78(cid:3)Cwasaddeddropwiseasolution NaHCO3(500ml),dilutedwithether(500ml),washedwithbrine
oftheketalobtainedabove(0.98g,4.23mmol)inTHF(2ml).After (3(cid:4)300ml).The organic solutionwas driedover MgSO4,concen-
refluxfor1hat(cid:1)30(cid:3)C,water(76.2ml,4.23mmol)wasaddeddrop- trated,thensubjectedtoflashchromatography(silica,0e5%ether
wise.Thesolutionwasrefluxedforanotherhour,thenallylbromide inhexanes)toaffordalkene11(27.0g,0.062mol,91%)asacolor-
(1.83ml,21.15mmol)wasaddedasrapidlyaspossible,andthere- less liquid; Rf¼0.74 (25% ether in hexanes); [a]D25 þ75.1 (c 1.0,
actionmixturewasheatedatrefluxfor2h.Theammoniawasevap- CH2Cl2); IR (film): n 2939, 2865,1461,1085,1072, 884; 1H NMR
oratedandthereactionwasquenchedwithsaturatedNH4Clsolution (500MHz, CDCl3): d 4.74 (s,1H), 4.69 (s,1H), 3.92e3.88 (m, 3H),
(20ml). The resulting mixture was then extracted with ether 3.82(m,1H),3.72(m,1H),3.58(m,1H),2.33(m,1H),2.14(m,1H),
(3(cid:4)30ml) and the organic solutions were combined, dried over 1.83e1.71(m,2H),1.67e1.31(m,11H),1.24(s,1H),1.11(s,3H),1.04
MgSO4, concentrated, and subjected to column chromatography (m,18H), 0.96 (s, 3H); 13C NMR (125MHz, CDCl3): d 154.4,113.3,
(silica,0e10%etherinhexanes)toaffordketone8(0.91g,3.3mmol, 106.3, 65.1, 64.7, 59.5, 44.9, 43.3, 41.9, 41.5, 31.4, 30.2, 29.4, 23.7,
78%)asacolorlessliquid;Rf¼0.63(50%etherinhexanes);[a]D25(cid:1)64.4 22.8, 21.4, 18.0 (6C), 17.7, 11.9 (3C); HRMS (ESI): calcd for
(c1.0,CH2Cl2);IR(film):n2946,2872,1703,1441,1186,1045,910;1H C26H48O3SiCs[MþCs]þ569.2429,found569.2432.
NMR(500MHz,CDCl3):d5.66(m,1H),5.03e4.96(m,2H),3.96e3.83
(m,4H),2.57e2.50(m,2H),2.33(m,1H),2.13(m,1H),2.01e1.90(m, 4.1.5. 2-((4a0R,50S,60R,8a0R)-50,60,8a0-Trimethyloctahydro-20H-spiro
2H),1.70e1.31(m,7H),1.20(s,3H),1.03(s,3H);13CNMR(125MHz, [[1,3]dioxolane-2,10-naphthalen]-50-yl)ethanol (12). Olefin 11 (1.1g,
CDCl3):215.8,135.2,117.3,112.8,65.3,64.8,50.9,44.1,42.6,42.5,35.0, 2.52mmol)inTHF(20ml)andwastreatedwithTBAF(1.0MinTHF,
30.3, 28.8, 22.6, 21.7, 21.3,16.3; HRMS (ESI): calcd for C17H26O3Na 7.56ml, 7.56mmol) at 25(cid:3)C for 15h. Then the reaction was
[MþNa]þ301.3814,found301.3827. quenchedwithwater(50ml)andextractedwithether(3(cid:4)50ml).
The organic layers were dried over MgSO4, concentrated and
4.1.3. (4a0R,50R,8a0R)-50,8a0-Dimethyl-50-(2-((triisopropylsilyl) oxy) chromatographed (silica,10% ether in hexanes) to afford the cor-
ethyl)hexahydro-20H spiro[[1,3]dioxolane-2,10-naphthalen]-60(70H)- respondingalcohol(0.664g,2.37mmol,94%).Thisalcohol(0.30g,
one(10). Asolutionofketone8(12.0g,0.043mol)inTHF(50ml)was 1.07mmol) and the Crabtree’s catalyst ([Ir(COD)(PCy3)(Py)]PF6,
exposedtoozoneat(cid:1)78(cid:3)Cuntilthestartingmaterialwasconsumed. 30mg,0.037mmol)in30mlofCH2Cl2washydrogenatedinaParr
The resulting mixture was flushed with argon, treated with PPh3 apparatus(70psi)for15hat70psi.Thecatalystwasthenremoved
(22.5g,0.086mol)andallowedtowarmupto25(cid:3)C.Afterstirringfor by a short silica pad to afford the reduced product 12 (286mg,
2h,NaBH4(4.88g,0.129mol)wasaddedtotheabovereactionmix- 1.01mmol) as a single diastereomer at the C8 center (dr >99:1,
tureat0(cid:3)C,followedbyMeOH(5ml),thenthereactionmixturewas 94%);[a]D25þ52.1(c1.0,CH2Cl2);IR(film):n3382,2939,2872,1710,
allowedtoslowlywarmupto25(cid:3)Candstirredatthistemperaturefor 1448,1387,1139,1051;1HNMR(500MHz,CDCl3)d3.93e3.88(m,
2h,thenquenchedwithsaturatedbrine(100ml).Theorganiclayer 3H),3.83e3.79(m,1H),3.69e3.58(m,2H),1.68e1.29(m,15H),1.02
was extracted with ether (3(cid:4)100ml), combined and dried over (s, 3H), 0.83 (d, J¼6.5Hz, 3H), 0.70 (s, 3H); 13C NMR (125MHz,
MgSO4,concentrated,andsubjectedtoflashchromatography(silica, CDCl3)d113.4,65.1,64.6,58.1,44.4,43.4,40.5,38.4,37.1,30.2,30.0,
50% ether in hexanes) to afford the corresponding diol (11.2g, 26.7, 22.7, 20.4, 17.6, 16.9, 16.0; HRMS (ESI): calcd for C17H31O3
0.039mol,92%).AsolutionoftheabovediolinCH2Cl2(150ml)was [MþH]þ283.2275,found283.2273.
treated with 2,6-lutidine (6.81ml, 0.058mol) and triisopropylsilyl
trifluoromethanesulfonate(12.6ml,0.047mmol)at(cid:1)78(cid:3)C.There- 4.1.6. (4aR,5S,6R,8aR)-5-(2-Hydroxyethyl)-5,6,8a-trimethylocta hy-
actionmixturewasstirredfor1handthendilutedwithsaturated dronaphthalen-1(2H)-one (13). To a solution of ketal 12 (10.0g,
aqueousNaHCO3(100ml)andextractedwithether(3(cid:4)100ml).The 0.035mol)inTHF(100ml)wasaddedhydrochloricacid(10.0ml,
combinedorganicextractsweredriedoverMgSO4,concentrated,and 0.1N).Thereactionwasstirredatrtfor8h,thenneutralizedwith
subjectedtoflashchromatography(silica,0e20%etherinhexanes)to saturatedaqueousNaHCO3(150ml).Thetwolayerswereseparated
affordthecorrespondingsecondaryalcohol(16.9g,0.038mol,98%). and the aqueous layer was extracted with ether (3(cid:4)200ml). The
Asolutionofabovealcohol(22g,0.0499mol)inCH2Cl2(200ml)was organicsolutionswerecombined,driedoverMgSO4,concentrated,
Author's personal copy
T.Lingetal./Tetrahedron67(2011)3023e3029 3027
and subjected to flash chromatography (silica, 10e50% ether in treatedwithTBAF(1.0MinTHF,0.75ml,0.75mmol)at25(cid:3)Cfor
hexanes)toaffordhydroxyketone13(8.10g,0.034mmol,97%)as 12h. Then the reaction was quenched with water (5ml) and
awhitesolid;Rf¼0.25(50% etherin hexanes); [a]D25 þ14.5 (c1.0, extractedwithether(3(cid:4)10ml).Theorganiclayersweredriedover
benzene);IR(film):n3441,2938,1702,1455,1381,1257,1135,1027, MgSO4, concentrated, and chromatographed (silica, 10% ether in
952;1HNMR(500MHz,CDCl3):d3.40e3.70(m,2H),2.01e2.60(m, hexanes) to afford the corresponding alcohol (67mg, 0.24mmol,
3H),1.05e1.95(m,12H),1.12(s,3H),0.85(d,3H,J¼4.80Hz),0.81(s, 94%).Colorlessliquid;Rf¼0.33(silica,70%etherinhexanes);[a]D25
3H);13CNMR(125MHz,CDCl3):d215.8,57.9,49.3,48.9,40.6,39.6, þ16.8(c2.2,CH2Cl2);IR(film)n3355,2952,2878,1454,1381,1186,
37.4,37.1,32.9,26.5,26.0,20.8,19.1,18.1,16.1;HRMS(ESI):calcdfor 1031,937;1HNMR(500MHz,CDCl3)d3.94(m,3H),3.81(m,1H),
C15H27O2[MþH]þ239.2011,found239.2030. 3.68(m,2H),1.89e1.22(m,15H),1.07(s,3H),0.98(d,J¼7.0Hz,3H),
0.93 (s, 3H); 13C NMR (125MHz, CDCl3) d 113.8, 65.5, 65.0, 59.4,
4.1.7. 2-((1S,2R,4aR,8aR)-1,2,4a-Trimethyl-5-methylenedeca hydro- 43.9,43.1,42.7,37.5,36.1,30.5,25.0,23.7,23.2,21.3,20.1,17.7,15.0;
naphthalen-1-yl)ethanol (14). To a suspension of methyl- HRMS(ESI):calcdforC17H31O3[MþH]þ283.2275,found283.2271.
triphenylphosphonium bromide (16.60g, 46.6mmol) in THF
(300ml)wasaddeddropwisesodiumbis-trimethylsilylamide(1.0M 4.1.11. (4aR,5S,6S,8aR)-5-(2-Hydroxyethyl)-5,6,8a-trimethylocta hy-
inTHF,38.80ml,38.80mmol)andthesuspensionwasstirredat0(cid:3)C dronaphthalen-1(2H)-one (C8-epi-13). See Section 4.1.6; white
for30min.Hydroxyketone13(3.70g,15.50mmol)inTHF(50.0ml) solid,93%yield;mp:95e98(cid:3)C;Rf¼0.49(silica,80%ethyletherin
wasthenaddedtotheabovereactionandthemixtureandstirredat hexanes);[a]D25þ44.7(c1.0,benzene);IR(film):n3445,2935,1701,
25(cid:3)Cfor18h.Thereactionwasquenchedwithaqueoussaturated 1455, 1381, 1255, 1136, 1026, 950; 1H NMR (400MHz, CDCl3):
NaHCO3 (400ml) and the mixture was extracted with ethyl ether d 3.62e3.76 (m, 2H), 2.52e2.61 (m, 1H), 2.15e2.22 (m, 1H),
(3(cid:4)400ml). The organic layers were collected, dried over MgSO4, 2.02e2.10 (m,1H),1.84e1.89 (m, 2H),1.22e1.68 (m,10H),1.17 (s,
concentrated,andchromatographed(silica,10e20%etherinhexane) 3H),1.03(s,3H),0.93(d,3H,J¼6.8Hz);13CNMR(100MHz,CDCl3):
toaffordolefin14(3.50g,14.80mmol,95%)asawhitesolid;Rf¼0.30 d216.0,58.4,49.2,47.0,42.4,38.3,37.3,35.5,26.1,26.1,24.5,21.5,
(50%etherinhexane);[a]D25þ56.2(c1.0,benzene);IR(film):n3321, 20.2,19.6,14.6;HRMS(ESI):calcdforC15H27O2[MþH]þ239.2011,
2931,2859,1633,1447,1379,1026,889;1HNMR(500MHz,CDCl3): found239.2030.
d 4.49 (d, 2H, J¼1.60Hz), 3.40e3.70 (m, 2H), 1.84e2.40 (m, 3H),
1.05e1.80(m,13H),1.03(s,3H),0.86(d,3H,J¼6.40Hz),0.74(s,3H); 4.1.12. 2-((1S,2S,4aR,8aR)-1,2,4a-Trimethyl-5-methylenedeca hydro-
13CNMR(125MHz,CDCl3)d160.2,102.5,58.7,49.8,40.9,40.2,39.4, naphthalen-1-yl)ethanol(C8-epi-14). SeeSection4.1.7;whitesolid,
37.8,37.3,33.1,28.7,27.6,22.1,21.0,18.0,16.4;HRMS(ESI):calcdfor 91%yield; mp:53e57 (cid:3)C; Rf¼0.62(silica,80%ethyletherin hex-
C16H29O[MþH]þ237.2218,found237.2221. ane);[a]D25þ78.0(c0.33,benzene);IR(film):n3323,2932,2856,
1632,1445,1372,1026,890;1HNMR(400MHz,CDCl3):d4.53(brs,
4.1.8. 2-((1S,2R,4aR,8aR)-1,2,4a,5-Tetramethyl-1,2,3,4,4a,7,8,8a-octa- 1H),4.49(brs,1H),3.62e3.75(m,2H),1.02e2.36(m,15H),1.08(s,
hydronaphthalen-1-yl)ethanol(15). Toasolutionofolefin14(0.72g, 3H),0.99(s,3H),0.97(s,3H);13CNMR(100MHz,CDCl3):d160.4,
3.05mmol)inethanol(30ml)wasaddedRhodium(III)chloridehy- 102.1,59.5,47.9,42.8,40.3,38.1,36.2,33.0,30.1,28.8,25.8,21.7,21.6,
drate(0.14g,0.67mmol)andthemixturewasrefluxedfor18h.The 21.5,15.3;HRMS(ESI):calcdforC16H29O[MþH]þ237.2218,found
reactionmixturewascooledto25(cid:3)C,concentrated,andchromato- 237.2221.
graphed (10e20% ether in hexanes) to afford alcohol 15 (0.70g,
2.96mmol,97%)asaclearoil;Rf¼0.30(50%etherinhexanes);[a]D25 4.1.13. 2-((1S,2S,4aR,8aR)-1,2,4a,5-Tetramethyl-1,2,3,4,4a,7,8,8a-oc-
(cid:1)39.7(c1.0,benzene);IR(film):n3329,2939,1743,1266,1174,1134, tahydronaphthalen-1-yl)ethanol(C8-epi-15). SeeSection4.1.8;clear
1028; 1H NMR (500MHz, CDCl3): d 5.17 (s, 1H), 3.60 (m, 2H), oil, 92% yield; Rf¼0.60 (silica, 80% ethyl ether in hexane); [a]D25
1.85e2.20 (m, 2H), 1.02e1.90 (m, 14H), 0.99 (s, 3H), 0.86 (d, 3H, (cid:1)28.8(c0.50,benzene);IR(film):n3320,2942,1741,1269,1179,
J¼6.0Hz),0.73(s,3H);13CNMR(125MHz,CDCl3):d143.9,120.3,58.2, 1131,1028;1HNMR(400MHz,CDCl3):d5.17(brs,1H),3.68e3.79
47.4,40.8,38.7,38.2,37.3,36.7,27.5,26.8,19.9,18.6,18.1,17.9,16.2; (m,2H),1.25e2.09(m,16H),1.03(s,3H),0.97(d,3H,J¼6.8Hz),0.96
HRMS(ESI):calcdforC16H29O[MþH]þ237.2218,found237.2229. (s,3H);13CNMR(100MHz,CDCl3):d144.2,120.2,59.5,45.1,42.8,
38.4, 37.6, 36.2, 30.2, 27.1, 25.9, 21.4, 20.9,18.3,18.2,15.3; HRMS
4.1.9. ((cid:1))-Callicarpenal (((cid:1))-1). Asolutionofalcohol15(40.0mg, (ESI):calcdforC16H29O[MþH]þ237.2218,found237.2229.
0.169mmol)inCH2Cl2(5.0ml)wasadded4-methylmorpholine-N-
oxide (39.6mg, 0.338mmol) followed by tetrapropylammonium 4.1.14. C8-epi-((cid:1))-Callicarpenal (C8-epi-((cid:1))-1). See Section 4.1.9;
perruthenate (11.90mg, 0.034mmol). The reaction mixture was clear oil, 71% yield; Rf¼0.85 (silica, 25% ether in hexanes); [a]D25
stirredat25(cid:3)Cfor15h,thendirectlyconcentratedandsubjectedto (cid:1)36.4 (c 1.0, benzene); IR (film): n 2933,1710,1460,1381,1060,
flashchromatography(silica,0e5%etherinhexanes)toaffordal- 1000;1HNMR(400MHz,CDCl3):d9.91(d,1H,J¼3.6Hz),5.16(brs,
dehyde ((cid:1))-1 (((cid:1))-callicarpenal) (30.0mg, 0.128mmol, 76%) as 1H),2.18e2.40(m,2H),1.80e2.10(m,3H),1.20e1.58(m,10H),1.18
acolorlessliquid; Rf¼0.81(25%ether inhexanes); [a]D25 (cid:1)75.0(c (s, 3H), 1.03 (s, 3H), 1.01 (d, 3H, J¼6.8Hz); 13C NMR (100MHz,
0.50,benzene);IR(film):n2938,1710,1450,1385,1055,1010;1H CDCl3):d204.4,144.2,120.5,54.0,44.5,39.8,38.7,36.7,30.2,26.7,
NMR (400MHz, CDCl3): d 9.83 (d,1H, J¼3.6Hz), 5.17 (br s,1H), 26.0, 22.6, 20.6, 18.6, 18.1, 15.8; HRMS (ESI): calcd for C16H27O
2.30e2.48(m,2H),1.90e2.08(m,2H),1.15e1.76(m,11H),1.00(s, [MþH]þ235.2056,found235.2049.
3H),0.94(d,3H,J¼6.8Hz),0.81(s,3H);13CNMR(100MHz,CDCl3):
d203.8,143.6,120.5,51.7,49.4,41.7,39.0,38.4,36.4,27.3,26.6,19.9, 4.2. Biologicalexperimentalprocedures
18.9, 17.9, 17.2, 16.3; HRMS (ESI): calcd for C16H27O [MþH]þ
235.2056,found235.2059. 4.2.1. Insects. Ae.aegypti(L.)usedinthesestudieswerefromalabo-
ratorycolonymaintainedatMosquitoandFlyResearchUnitatCenter
4.1.10. 2-((4a0R,50S,60S,8a0R)-50,60,8a0-Trimethyloctahydro-20H-spiro for Medical, Agricultural and Veterinary Entomology, USDA-ARS,
[[1,3]dioxolane-2,10-naphthalen]-50-yl)ethanol (C8-epi-12). Olefin11 Gainesville,Florida.Thiscolonyhasbeenmaintainedsince1952using
(110mg, 0.25mmol) and 10% Pd/C (11mg) in MeOH was hydro- standardprocedures.24Wereceivedtheeggsandstoredtheseinour
genatedinaParrapparatus(70psi)for12h.Thecatalystwasthen laboratory to use as needed. Mosquitoes were reared to the adult
removedbyashortsilicapad,thecorrespondingreducedproduct stagebyfeedingthelarvaeonadietof2:1alfalfapellets(USNutrition
was then concentrated and re-dissolved in THF (2ml) and was Inc. Bohemia, NY) and hog chow (Ware Milling 150 ALF Drive,
Author's personal copy
3028 T.Lingetal./Tetrahedron67(2011)3023e3029
Houston,MS38851).Thedietcontentsweregroundinagrinderand instrumentation grants CHE-9709183 and CHE-0741968. We also
passedthroughsieveno.40,425mm(USAStandardSieve,Humboldt acknowledge the assistance of Dr. Anthony Mrse (UCSD NMR Fa-
MFG. Co. Norridge, IL 60706). Eggs were hatched under vacuum cility),Dr.YongxuanSu(UCSDMSFacility),Dr.ArnoldL.Rheingold,
(z1h)byplacingapieceofapapertowelwitheggsinacupfilled andDr.CurtisE.Moore(UCSDX-Rayfacility).WethankDr.JamesJ.
with50mlde-ionizedwatercontainingasmallquantityoflarvaldiet. Becnel,MosquitoandFlyResearchUnit,CenterforMedical,Agri-
Larvaewereremovedfromvacuumandheldovernightinthecup. cultural and Veterinary Entomology, USDA-ARS, Gainesville, for
Theselarvaewerethentransferredinto500mlcups(about50larvae supplying Ae. aegypti eggs. This study was supported, in part, by
percup)filledwithde-ionizedwater.Larvaldietwasaddedeveryday aDeployedWar-FighterProtectionResearchProgramGrantfunded
until pupation and the insects were kept in an environment con- bytheU.S.DepartmentofDefensethroughtheArmedForcesPest
trolledroom.Boththelarvaeandadultsweremaintainedatatem- ManagementBoard.
peratureof27(cid:3)C(cid:5)2(cid:3)Cand70(cid:5)5%RHinaphotoperiodregimenof
12:12(L:D)h.Theadultswerefedon10%sucrosesolution.Cotton Supplementarydata
padsmoistenedwiththesucrosesolutionwereplacedonthetopof
screensof4Lcages.5e9daysoldmatedfemaleswereusedinthese 1HNMRand13CNMRspectraforcompounds8,10,11e15,((cid:1))-1,
bioassays.Femalesweredeprivedofanyfoodfor24hpriortothetest. C8-epi-12,C8-epi-13,C8-epi-14,C8-epi-15,C8-epi-((cid:1))-1aswellasX-
Timingsofthesetestswerecenteredaround1200h. ray data of compounds 9 and C8-epi-13. Supplementary data as-
sociated with this article can be found in online version at
4.2.2. Chemicals. CPDA-125 was prepared by dissolving 3.33g so- doi:10.1016/j.tet.2011.02.078. These data include MOL files and
diumcitrate,0.376gcitricacid,4.02gdextrose,0.28gmonobasic InChIKeys of the most important compounds described in this
sodiumphosphate(FisherScientificChemicalCo.Fairlawn,NJ),and article.
0.346gofadenine(SigmaeAldrich,St.Louis,MO)in1026mlofde-
ionizedwater.ATPwasaddedtoCPDA-1toyield10(cid:1)3MATP.CPDA-
Referencesandnotes
1andATPpreparationswerefreshlymixedonthedayofthetest.
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feeding as blood.26 DEET (N,N-diethyl-m-toluamide 97%) was 2. (a) http://www.who.int/malaria/en/; (b) http://www.who.int/denguecontrol/
obtained from SigmaeAldrich (St. Louis, MO). Molecular biology en/index.html.
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(Fairlawn, NJ). ((cid:1))-Callicarpenal used as the positive control in Strickman,D.,Eds.;CRCPress:BocaRaton,FL,2007;ISBN978-0-8493-7196-7.
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usingasix-celledinvitroKlunandDebboun(KandD)modulebio- 8. Forsomeinvestigationsofbeautyberry’sotherbioactivitiessee:(a)Tellez,M.
assaysystemdevelopedbyKlunetal.26forquantitativeevaluationof R20.;0D0a,y4a8n,,3F0.0E8.;eS3c0h1r2a;de(br,)KK.oKb.a;isWy,edMg.e;,TDel.leEz.;,DMu.kRe.,;SD.aOy.anJ.,AFg.rEic.;.FDouokde,ChS.emO..
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bioassaymethoddeterminesspecificallymeasuredbiting(feeding) 9. (a)Cantrell,C.L.;Klun,J.A.;Bryson,C.T.;Kobaisy,M.;Duke,S.O.J.Agric.Food
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inInvertebrateandVertebrateRepellents;Paluch,G.,Coats,J.,Eds.;American
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Acknowledgements 21. Forsomeotherexamplesofexoeendoalkeneisomerisationinnaturalproduct
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T.Lingetal./Tetrahedron67(2011)3023e3029 3029
22. Thereisasmalldifferenceofopticalrotationsbetweenthesyntheticmaterial 25. AABB [American Association of Blood Banks] Technical Manual, 15th ed.;
([a]D25(cid:1)75.0,c0.5,benzene)andthenaturalproduct([a]D25(cid:1)45.3,c0.0053, AmericanAssociationofBloodBanks:Bethesda,MD,2005.
benzene),probablyduetothedifferencebetweenmeasuringconcentrations. 26. Klun,J.A.;Kramer,M.;Zhang,A.;Wang,S.;Debboun,M.J.Am.Mosq.Control
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24. (a)Gerberg,E.J.;Barnard,D.R.;Ward,R.A.Am.Mosq.ControlAssoc.Bull.No.5 28. Sincewearedealingwithanassayonawholeorganismweusestatisticsas
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