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Organic & Biomolecular Chemistry
JournalꢀNameꢀ
ꢀARTICLEꢀ
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Acknowledgementsꢀ
DOI: 10.1039/C6OB02659A
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Ourꢀ researchꢀ isꢀ supportedꢀ byꢀ theꢀ EPSRC,ꢀ BBSRC,ꢀ MRC,ꢀ Wellcomeꢀ
TrustꢀandꢀERCꢀ(FP7/2007-2013;ꢀ279337/DOS).ꢀD.A.RꢀthanksꢀCancerꢀ
ResearchꢀUKꢀforꢀfunding.ꢀD.R.S.ꢀacknowledgesꢀsupportꢀfromꢀaꢀRoyalꢀ
SocietyꢀWolfsonꢀResearchꢀMeritꢀaward.ꢀDataꢀaccessibility:ꢀallꢀdataꢀ
supportingꢀ thisꢀ studyꢀ areꢀ providedꢀ asꢀ Supplementaryꢀ Informationꢀ
accompanyingꢀthisꢀpaper.ꢀ
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R2O
Cr
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OH
CrR2
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Referencesꢀ
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1
(a)ꢀ L.ꢀ Crombie,ꢀ inꢀ Progressꢀ inꢀ theꢀ Chemistryꢀ ofꢀ Organicꢀ
NaturalꢀProducts,ꢀSpringer,ꢀVienna,ꢀ1963,ꢀch.ꢀ6,ꢀ275-325;ꢀ(b)ꢀ
N.ꢀR.ꢀKrishnaswamyꢀandꢀC.ꢀN.ꢀSundaresan,ꢀResonance,ꢀ2015,ꢀ
18,ꢀ 428-439;ꢀ (c)ꢀ L.ꢀ Crombieꢀ andꢀ D.ꢀ A.ꢀ Whiting,ꢀ
Phytochemistry,ꢀ 1998,ꢀ 49,ꢀ 1479-1507.ꢀ (d)ꢀ L.ꢀ Crombie,ꢀ Nat.ꢀ
Prod.ꢀRep.,ꢀ1984,ꢀ1,ꢀ3-19;ꢀ(e)ꢀP.ꢀM.ꢀDewick,ꢀMedicinalꢀNaturalꢀ
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Cr(OH)R2
ꢀ
Products:ꢀ Aꢀ Biosyntheticꢀ Approach,ꢀ Wiley-Blackwell,ꢀ
Hoboken,ꢀ2001,ꢀ2 ꢀEd.,ꢀp.ꢀ155-157;ꢀꢀ
nd
ꢀ
Schemeꢀ 2:ꢀ Proposedꢀ mechanismꢀ forꢀ theꢀ diastereoselectiveꢀ
2
(a)ꢀ C.ꢀ Gerhauser,ꢀ W.ꢀ Mar,ꢀ S.ꢀ K.ꢀ Lee,ꢀ N.ꢀ Suh,ꢀ Y.ꢀ Luo,ꢀ J.ꢀ
Kosmeder,ꢀ L.ꢀ Luyengi,ꢀ H.ꢀ H.ꢀ Fong,ꢀ A.ꢀ D.ꢀ Kinghorn,ꢀ R.ꢀ M.ꢀ
Moriarty,ꢀR.ꢀG.ꢀMehta,ꢀA.ꢀConstantinou,ꢀR.ꢀC.ꢀMoonꢀandꢀJ.ꢀM.ꢀ
Pezzuto,ꢀNat.ꢀMed.,ꢀ1995,ꢀ1,ꢀ260-266;ꢀ(b)ꢀC.ꢀIto,ꢀM.ꢀItoigawa,ꢀ
N.ꢀKojima,ꢀH.ꢀT.ꢀW.ꢀTan,ꢀJ.ꢀTakayasu,ꢀH.ꢀTokuda,ꢀH.ꢀNishinoꢀ
andꢀ H.ꢀ Furukawa,ꢀ Plantaꢀ Med.,ꢀ 2004,ꢀ 70,ꢀ 585-588;ꢀ (c)ꢀ R.ꢀ
Palorini,ꢀ T.ꢀ Simonetto,ꢀ C.ꢀ Cirulliꢀ andꢀ F.ꢀ Chiaradonna,ꢀ Int.ꢀ J.ꢀ
CellꢀBiol.,ꢀ2013,ꢀ2013,ꢀ1-14.ꢀ(d)ꢀH.-Y.ꢀLee,ꢀBiochem.ꢀPharm.,ꢀ
ꢀ
(
stereocontrolled)ꢀ Etard-likeꢀ hydroxylationꢀ ofꢀ deguelinꢀ 1ꢀ toꢀ tephrosinꢀ 2,
involvingꢀ aꢀ faciallyꢀ selectiveꢀ eneꢀ reactionꢀ followedꢀ byꢀ aꢀ [2,3]-sigmatropic
ꢀ
rearrangementꢀandꢀchromateꢀesterꢀhydrolysis.ꢀ
ꢀ
Conclusionsꢀ
2
004,ꢀ68,ꢀ1119-1124;ꢀ(e)ꢀH.-Y.ꢀLee,ꢀY.-A.ꢀSuh,ꢀJ.ꢀW.ꢀKosmeder,ꢀ
Weꢀ haveꢀ developedꢀ stereocontrolledꢀ semi-synthesesꢀ ofꢀ bothꢀ
deguelinꢀ1ꢀandꢀtephrosinꢀ2ꢀstartingꢀfromꢀrotenoneꢀ3ꢀandꢀproceedingꢀ
viaꢀrot-2’-enonicꢀacidꢀ5.ꢀFirstly,ꢀaꢀnewꢀtransformationꢀofꢀrotenoneꢀ3ꢀ
intoꢀrot-2’-enonicꢀacidꢀ5ꢀisꢀdescribedꢀthatꢀinvolvesꢀaꢀzinc-mediatedꢀ
ringꢀ openingꢀ ofꢀ rotenoneꢀ hydrobromideꢀ 6.ꢀ Thisꢀ alternativeꢀ
preparationꢀofꢀrot-2’-enonicꢀacidꢀ5ꢀavoidsꢀtheꢀuseꢀofꢀtheꢀhighlyꢀtoxicꢀ
J.ꢀM.ꢀPezzuto,ꢀW.ꢀK.ꢀHongꢀandꢀJ.ꢀM.ꢀKurie,ꢀClin.ꢀCancerꢀRes.,ꢀ
2004,ꢀ10,ꢀ1074-1079;ꢀ(f)ꢀH.-Y.ꢀLee,ꢀS.-H.ꢀOh,ꢀJ.ꢀK.ꢀWoo,ꢀW.-Y.ꢀ
Kim,ꢀC.ꢀS.ꢀVanꢀPelt,ꢀR.ꢀE.ꢀPrice,ꢀD.ꢀCody,ꢀH.ꢀTran,ꢀJ.ꢀM.ꢀPezzuto,ꢀ
R.ꢀM.ꢀMoriartyꢀandꢀW.ꢀK.ꢀHong,ꢀJ.ꢀNatl.ꢀCancerꢀInst.,ꢀ2005,ꢀ97,ꢀ
1
695-ꢀ1699;ꢀ(g)ꢀQ.ꢀJin,ꢀL.ꢀFeng,ꢀC.ꢀBehrens,ꢀB.ꢀN.ꢀBekele,ꢀI.ꢀI.ꢀ
Wistuba,ꢀ W.-K.ꢀ Hongꢀ andꢀ H.-Y.ꢀ Lee,ꢀ Cancerꢀ Res.,ꢀ 2007,ꢀ 67,ꢀ
11630-11639;ꢀ (h)ꢀ J.ꢀ K.ꢀ Woo,ꢀ D.ꢀ S.ꢀ Choi,ꢀ H.ꢀ T.ꢀ Tran,ꢀ B.ꢀ E.ꢀ
Gilbert,ꢀW.ꢀK.ꢀHongꢀandꢀH.-Y.ꢀLee,ꢀCancerꢀPrev.ꢀRes.ꢀPhila.,ꢀ
9
reagentsꢀpreviouslyꢀrequiredꢀinꢀAnzeveno’sꢀsynthesis ꢀandꢀaffordsꢀaꢀ
2
009,ꢀ 2,ꢀ 361-369;ꢀ (i)ꢀ V.ꢀ Thamilselvan,ꢀ M.ꢀ Menonꢀ andꢀ S.ꢀ
higherꢀ yieldꢀ acrossꢀ twoꢀ stepsꢀ (approximatelyꢀ 70%ꢀ vsꢀ 35%).ꢀ Theꢀ
Thamilselvan,ꢀInt.ꢀJ.ꢀCancer,ꢀ2011,ꢀ129,ꢀ2916-ꢀ2927;ꢀ(j)ꢀS.ꢀR.ꢀ
Boreddyꢀ andꢀ S.ꢀ K.ꢀ Srivastava,ꢀ Oncogene,ꢀ 2013,ꢀ 32,ꢀ 3980-
3
conversionꢀ ofꢀ rot-2’-enonicꢀ acidꢀ 5ꢀ intoꢀ deguelinꢀ 1ꢀ wasꢀ achievedꢀ
9
991.ꢀ
followingꢀ Anzeveno’sꢀ method. ꢀ Finally,ꢀ theꢀ transformationꢀ ofꢀ
3
4
(a)ꢀM.ꢀHanriot,ꢀCompt.ꢀrend.ꢀAcad.ꢀSci.,ꢀ1907,ꢀ144,ꢀ150;ꢀ(b)ꢀ
M.ꢀHanriot,ꢀCompt.ꢀrend.ꢀSoc.ꢀBiol.,ꢀ1907,ꢀ62,ꢀ384.ꢀ
(a)ꢀE.ꢀP.ꢀClark,ꢀScience,ꢀ1930,ꢀ71,ꢀ1841;ꢀ(b)ꢀE.ꢀP.ꢀClark,ꢀJ.ꢀAm.ꢀ
Chem.ꢀSoc.,ꢀ1930,ꢀ52,ꢀ2461-2464;ꢀ(c)ꢀE.ꢀP.ꢀClark,ꢀJ.ꢀAm.ꢀChem.ꢀ
Soc.,ꢀ 1931,ꢀ 53,ꢀ 313-317;ꢀ (d)ꢀ E.ꢀ P.ꢀ Clark,ꢀ J.ꢀ Am.ꢀ Chem.ꢀ Soc.,ꢀ
deguelinꢀ 1ꢀ intoꢀ tephrosinꢀ 2ꢀ wasꢀ accomplishedꢀ usingꢀ aꢀ highlyꢀ
diastereoselectiveꢀchromium-mediatedꢀhydroxylation,ꢀforꢀwhichꢀanꢀ
12b
Étard-likeꢀ reactionꢀ mechanismꢀ isꢀ tentativelyꢀ proposed. ꢀ Ourꢀ
synthesesꢀprovideꢀdeguelinꢀ1ꢀandꢀtephrosinꢀ2ꢀinꢀ56%ꢀandꢀ42%ꢀyieldꢀ
respectively,ꢀ involveꢀ onlyꢀ twoꢀ chromatographicꢀ purificationsꢀ andꢀ
allowꢀ gramꢀ quantitiesꢀ ofꢀ valuableꢀ enantiopureꢀ materialsꢀ toꢀ beꢀ
preparedꢀ simplyꢀ andꢀ efficiently,ꢀ facilitatingꢀ biologicalꢀ studiesꢀ
thereof.ꢀ
1
5
3
931,ꢀ53,ꢀ729-732;ꢀ(e)ꢀE.ꢀP.ꢀClark,ꢀJ.ꢀAm.ꢀChem.ꢀSoc.,ꢀ1931,ꢀ
3,ꢀ3431-3436;ꢀE.ꢀP.ꢀClark,ꢀJ.ꢀAm.ꢀChem.ꢀSoc.,ꢀ1932,ꢀ54,ꢀ3000-
008.ꢀ
5
(a)ꢀG.ꢀBuchi,ꢀL.ꢀCrombie,ꢀP.ꢀJ.ꢀGodin,ꢀJ.ꢀS.ꢀKaltenbronn,ꢀK.ꢀS.ꢀ
SiddalingaiahꢀandꢀD.ꢀA.ꢀWhiting,ꢀJ.ꢀChem.ꢀSoc.,ꢀ1961,ꢀ2843-
2
2
860.ꢀ (b)ꢀ L.ꢀ Crombieꢀ andꢀ P.ꢀ J.ꢀ Godin,ꢀ J.ꢀ Chem.ꢀ Soc.,ꢀ 1961,ꢀ
861-2876;ꢀ(c)ꢀL.ꢀCrombie,ꢀP.ꢀJ.ꢀGodin,ꢀD.ꢀA.ꢀWhitingꢀandꢀK.ꢀS.ꢀ
Siddalingaiah,ꢀJ.ꢀChem.ꢀSoc.,ꢀ1961,ꢀ2876-2889.ꢀ
C.ꢀDjerassi,ꢀW.ꢀD.ꢀOllisꢀandꢀR.ꢀC.ꢀRussell,ꢀJ.ꢀChem.ꢀSoc.,ꢀ1961,ꢀ
Lastly,ꢀweꢀnoteꢀthatꢀalthoughꢀcommerciallyꢀavailableꢀatꢀtheꢀtimeꢀofꢀ
6
7
4
writing,ꢀdeguelinꢀ1ꢀandꢀtephrosinꢀ2ꢀcostꢀapproximatelyꢀ2x10 ꢀandꢀ
1
448-1453.ꢀ
5
2
x10 ꢀ timesꢀ moreꢀ thanꢀ rotenoneꢀ 3.ꢀ Weꢀ presentꢀ operationallyꢀ
(a)ꢀD.-J.ꢀChang,ꢀH.ꢀAn,ꢀK.-S.ꢀKim,ꢀH.ꢀH.ꢀKim,ꢀJ.ꢀJung,ꢀJ.ꢀM.ꢀLee,ꢀ
N.-J.ꢀKim,ꢀY.ꢀT.ꢀHan,ꢀH.ꢀYun,ꢀS.ꢀLee,ꢀG.ꢀLee,ꢀS.ꢀLee,ꢀJ.ꢀS.ꢀLee,ꢀJ.-
H.ꢀCha,ꢀJ.-H.ꢀPark,ꢀJ.ꢀW.ꢀPark,ꢀS.-C.ꢀLee,ꢀS.ꢀG.ꢀKim,ꢀJ.ꢀH.ꢀKim,ꢀH.-
Y.ꢀ Lee,ꢀ K.-W.ꢀ Kimꢀ andꢀ Y.-G.ꢀ Suh,ꢀ J.ꢀ Med.ꢀ Chem.,ꢀ 2012,ꢀ 55,ꢀ
simpleꢀsemi-synthesesꢀofꢀdeguelinꢀ1ꢀandꢀtephosinꢀ2ꢀstartingꢀfromꢀ
relativelyꢀinexpensiveꢀrotenoneꢀ3ꢀusingꢀsimilarlyꢀlow-costꢀreagents.ꢀ
10863-10884;ꢀ(b)ꢀS.-C.ꢀLee,ꢀH.-Y.ꢀMin,ꢀH.ꢀChoi,ꢀH.ꢀS.ꢀKim,ꢀK.-C.ꢀ
Kim,ꢀ S.-J.ꢀ Park,ꢀ M.ꢀ A.ꢀ Sung,ꢀ J.ꢀ H.ꢀ Seo,ꢀ H.-J.ꢀ Park,ꢀ Y.-G.ꢀ Y.-G.ꢀ
ꢀ
ꢀ
Suh,ꢀK.-W.ꢀKim,ꢀJ.ꢀLeeꢀandꢀH.-Y.ꢀLee,ꢀMol.ꢀPharmacol.,ꢀ2015,ꢀ
8
8,ꢀ245-255.ꢀ
(a)ꢀH.ꢀFukami,ꢀJ.ꢀOda,ꢀG.ꢀSakataꢀandꢀM.ꢀNakajima,ꢀAgric.ꢀBiol.ꢀ
Chem.,ꢀ 1961,ꢀ 25,ꢀ 252-256;ꢀ (b)ꢀ H.ꢀ Omokawaꢀ andꢀ K.ꢀ
8
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ3ꢀ
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