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InvestigationoftheoriginandsyntheticapplicationofthepseudodilutioneffectforPd-catalyzedmacrocyclisationsinconcentratedsolutionswithimmobilizedcatalystsE.
Brehma,bandR.
Breinbauer*a,b,caMax-Planck-InstituteofMolecularPhysiology,Otto-Hahn-Str.
11,D-44227Dortmund,GermanybFachbereichChemie,TechnischeUniversittDortmund,Otto-Hahn-Str.
6,D-44227Dortmund,Germany.
cInstituteofOrganicChemistry,GrazUniversityofTechnology,Stremayrgasse9,A-8010Graz,Austria.
Fax:4331687332402;Tel:4331687332400;E-mail:breinbauer@tugraz.
atabs.
absolutealk.
alkyleq.
equivalentsar.
arylcalcd.
calculatedbrsbroadsingulettca.
circaCHcyclohexaneδchemicalshitt(inrelationtoTMS)ddublettTLCthinlayerchromatographyDCMdichlormethanedddublettofdublettddddublettofdublettofdublettdtdublettoftriplettDIADdiisopropylazodicarboxylateDIBALdiisobutylaluminiumhydrideDICdiisopropylcarbodiimideDMAPN,N-dimethylaminopyridineDMEdimethoxyethaneDMFN,N-dimethylformamideDMSOdimethylsulfoxideEAethylacetateEDC3,3-dimethylaminopropyl-ethyl-carbodiimidehydrochlorideEtethylEtOHethanolFABfastatombombardmentGC-MSgaschromatography–massspectrometrycouplingHOBT1-hydroxybenzotriazoleHPLChighperformanceliquidchromatographyHRMShighresolutionmassspectrometryJcouplingconstantconz.
concentratedmmultiplettMemethylMeOHmethanolmmolmillimolmol%molpercentmpmeltingpointMSmassspectrimm/zmass/chargeMWmicrowave3-NBA3-nitrobenzylalcoholNMMN-methyl-morpholineNMRnuclearmagneticresonanceolefin.
olefinicorg.
organicppmpartspermillionPPTSpyridinium-p-toluenesulfonateprep.
preparativePSpolystyreneqquadruplettquant.
quantitativeR,R'residueRTroomtemperaturessingulettstd.
saturatedttriplettTBDMSCltert-butyldimethylsilyl-chlorideTHFtetrahydrofuraneTMStetramethylsilaneresp.
trimethylsilyl-tRretentiontimeEquipmentandreagentsNMR-spectroscopyNMR-spectrawererecordedonthefollowinginstruments:BrukerAM400:400MHz1H-NMR,100.
6MHz13C-NMRVarianMercury400:400MHz1H-NMR,100.
6MHz13C-NMRChemicalshiftsarestatedinppm(referringtotetramethylsilane(TMS,δ=0ppm)asinternalstandard.
ThecouplingconstantsJarestatedinHertz(Hz).
Signalmultiplicitiesareabbreviatedasfollowing:s=singulett,d=doublett,dd=doublettofdoubletts,t=triplett,dt=doublettoftriplett,q=quartett,quint.
=quintett,m=multiplett,br=broadsignal.
Highresolutionmassspectrometry(HRMS)TheFAB-massspectrawererecordedonaJeolSX102Aspektrometer.
3-Nitrobenzylalcohol(3-NBA)servedasmatrix.
Thestatedvaluesarem/z.
MeltingpointsMeltingpointshavebeenmeasuredonaBüchiSchmelzpunktmessgert530andareuncorrected.
ChromatographyForanalyticalTLCSiO2-platesfromMerck(Silica60F254)wereused.
FordetectionwereusedUV-light(wavelength254nm)andthefollowingstains:ReagentA:12gmolybdatophosphoricacidin250mlethanolReagenzB:2.
5gmolybdatophosphoricacid,1gcerium(IV)-sulfate,6mlconc.
sulfuricacidand94mlH2OThecorrespondingeluentsandRf-valuesarestatedinthecharacterizationdataofthecompounds.
Purificationsviaflashchromatographywereperformedonsilica(particlesize:40-60m)fromBakerwithapressureof1.
3-1.
8bar.
HPLC-chromatographyPreparativeHPLCwasperformedwithaAgilent(1100Series)system.
CC125/21Nucleosil120-5C4,resp.
CC125/21Nucleodur120-5C18GravitycolumnsfromMacherey&Nagelwereused.
Theflowrateswere27ml/min.
AnalyticalHPLCwasperformedonaHP1100–modelfromHewlett-PackardwithCC125/4Nucleosil120-5C4resp.
CC125/4Nucleodur120-5C18GravitycolumnfromMacherey&Nagelwithflowratesof1ml/min.
Detectionoccurredatwavelengthsof210nmresp.
254nm.
AseluentsH2O+0.
1Vol.
-%TFA(A)andacetonitrile+0.
1Vol.
-%TFA(B)wereused.
Twostandardgradientswereused:GradientforC18column(C18):0.
5min10%B,thenwithin11minto100%B.
GradientforC4column(C4):1min10%B,thenwithin11.
7minto100%B.
Gas-ChromatographyGC-MS-measurementswereperformedonaGC6890coupledtoMS-detector5973fromHewlett-PackardwithcapillarycolumnHP-5TA(0.
33m,25mx0.
2mmID).
GC-MS(DB_100):1minat100°Candthenwithin5minto300°C.
GC-MS(RP70):2minat70°Candthenwithin6.
5minto300°C.
AllereagentswerepurchasedfromAcrosChimica,AdvancedChemtech,Aldrich,Fluka,Novabiochem,RiedeldeHaenandSigma.
Theusedsolventswereifnecessaryboughtabsolutelydryordriedaccordingtothefollowingprocedures.
DichlormethaneRefluxinganddistillationfirstoverP2O5andthenCaH2DiethyletherRefluxinganddistillationoversodiumMethanolRefluxinganddistillationovermagnesiumTriethylamineRefluxinganddistillationoverCaH2TetrahydrofuraneRefluxinganddistillationoversodium/potassiumTolueneRefluxinganddistillationoversodiumExperimentsrelatedtopreparationofPd-catalystbeadsGeneralprocedureforthesynthesisofsolidphaseboundligand1a-g/Pd(GP1)InaSchlenktubeunderinertconditionsaminomethyl-beadsareswolleninabs.
toluene.
Thesolventiscondensedoffunderoilpumpvacuumtoremovetheoxygenwithinthebeads.
AsecondinertSchlenktubeischargedwithparaformaldehyde(4eqinrespecttothebead-loading),abs.
methanol(10mlper1gparaformaldehyde)anddiphenylphosphine(4eqinrespecttothebead-loading).
Thereactionmixtureisheatedat60°Cuntilaclearsolutionforms(afterca.
48h).
Thesolventisremovedinoilpumpvacuumusingacoolingtrap.
Theoilyresidueisdissolvedinabs.
toluene(1.
5mlper1gparaformaldehyde).
ThissolutionisaddedtothefirstSchlenkwiththebeads,whichhavebeenswolleninabs.
toluene(10mlper1gbeads).
Thesuspensionisheatedfor2dat105°CuponwhichwaterdropsarecondensinginthecoldupperpartoftheSchlenktube.
AftercoolingtoRTthebeadsarecollectedbyfiltrationunderargon,washedwith4xabs.
toluene,2xabs.
DCM/THF(1/1)mixtureand3xabs.
DCM.
Thebeadsaredriedovernightinoilpumpvacuum.
ResinProducerArticleNumberMeshDVBin%Loadingoforiginalresin(NH2)inmmol\gCalculatedloadingofmodifiedresin(PPh2)inmmol\g1aNovabiochem01-64-0010200-40011.
130.
771bNovabiochem01-64-0143100-20010.
780.
591cNovabiochem01-64-019870-9011.
170.
791dFluka1730170-10011.
00.
721eAdvancedChemTechca12010.
330.
291fRappPolymereH50056002ca2010.
950.
681gArgonaut495638(Aldrich)ca100high"1.
390.
90Calculationofthetheoreticalresinloading(PPh2)inmmol/gafterthereaction:Determinationofactualloading1a(PPh2)byelementalanalysisTheoreticalValueforelementalanalyisof%Pand%N:Theoreticalloadingof1a(PPh2)xMpx2=0.
77x31x2=47.
7mg/g=4.
77%PTheoreticalloadingof1a(PPh2)xMN=0.
77x14=1.
08%NExperimentalValue(ElementalanalysisbyMikroanalytischesLaboratoriumH.
Kolbe,Mülheim/Ruhr)%P=4.
69%%N=1.
05%ExperimentalValue=%P/(31x2)=0.
76mmol/gControl:%N/14=0.
75mmol/gAstheresinmodificationhasbeenshowntoworkquantitative,thecalculatedvaluesweretakenforallotherresins.
GeneralprocedureforthesynthesisofsolidphaseboundPd-catalyst1a/Pd-1g/Pd(GP2)InadrySchlenktubethemodifiedligandbeads1a-gareinertizedby3vacuum/argoncyclesandthenswolleninabs.
toluenefor5min.
Pd[PPh3]4(1.
1eqinrespecttoligandloading)isadded.
TheSchlenkflaskisshakenfor30minandtheyellowsuspensionheatedfor24hto60°Cunderlightprotection.
AftercoolingtoRTthebeadsarecollectedbyfiltrationunderargon,washedwith2xabs.
diethylether(slighlyyellowwashsolutions),1xabs.
ethanol(slighlyyellowwashsolutions),5xabs.
THF(thefirst3washsolutionsareslightlyyellow,thelast2colorless)and2xabs.
diethylether(colorlesswashsolutions)anddriedovernightinoilpumpvacuum.
CatalystnameTheoreticalresinloading((CH2)PPh2)2)inmmol/g1a/Pd0.
521b/Pd0.
431c/Pd0.
531d/Pd0.
491e/Pd0.
241f/d0.
481g/Pd0.
57Calculationofthetheoreticalloadinginmmol/gafterreaction:ExperimentsrelatedtoTsuji-Trost-allylationGeneralprocedureforFischer-esterification(GP3)ThecarboxylicacidisdissolvedinMeOHandconc.
H2SO4isadded.
Thesolutionisheatedunderrefluxovernight.
Thenthevolatilesareremovedinvaccuousingarotovap.
Theresidueisdissolvedin200mlethylacetate,washedwith10%NaHCO3-solution(3x70ml)andbrine(1x70ml).
TheorganicphaseisdriedoverNa2SO4.
Afterconcentrationinvaccuothecrudeproductispurifiedviaflashchromatography.
Generalprocedureforthemono-silylationofadiol(GP4)Toasuspensionof1eqsodiumhydrideinabs.
THFisadded1eqdiol.
AfterstirringatRTfor2h1eqtert-butyldimethylsilylchlorideareaddedandthereactionmixturestirredatRTovernight.
Thereactionmixtureisdilutedwithdiethylether(100ml)andwashedwith10%NaHCO3solution(30ml)andbrine(30ml)anddriedoverNa2SO4.
Afterconcentrationinvaccuothecrudeproductispurifiedviaflashchromatography.
Generalprocedureforthemono-silylationofaglycol(GP5)Underaninertatmospheretoasolutionof6eqglycolinDCMareadded1eqabs.
triethylamine,0.
5eq.
DMAPand1eqtert-butyldimethylsilylchloride.
Thereactionmixtureisstirredfor2hatRT,thendilutedwith100mldiethylether.
Theorganicphaseiswashedwith10%NaHCO3(30ml)andbrine(30ml)anddriedoverNa2SO4.
Afterconcentrationinvaccuothecrudeproductispurifiedviaflashchromatography.
GeneralprocedureforSwern-oxidation(GP6)Inaninertatmosphereaflaskischargedwith1.
5eqoxalylchlorideinabs.
DCM,towhich3eqDMSOareslowlyaddedat–78°,uponwhichgasevolutionisobserved.
After10minasolutionof1eqalcoholinDCMisslowlyaddedandstirredfor1.
5h.
Then5eqabs.
triethylamineareaddedtothereactionmixture.
Thereactionmixtureislettowarmupovernight.
Afterdilutionwith200mldiethylether,theorganicphaseiswashedwith5%HCl(3x70ml),10%NaHCO3-solution(2x70ml)andH2O(70ml),andthendriedoverNa2SO4.
Afterconcentrationinvaccuothecrudeproductisusedwithoutfurtherpurification.
Generalprocedurefortheformationofavinylepoxide(GP7)InaSchlenkflask1.
5eqallylicbromidearedissolvedinMeOHandH2O.
3.
0eqtetrahydrothiopheneareaddedandthemixturestirredfor1h.
Withthehelpofacoolingtrapthevolatilesareremovedinvaccuo.
Thegel-likeresidueisthendissolvedinDCM.
Ina250-mlflaskasolutionof1eqaldehydeinDCMisprepared,aspatulatipofbenzyl-trimethylammoniumchlorideisaddedandthesolutioniscooledto-20°CinaMeOH/ice-bath.
Tothisaldehydesolutionisaddedthepreviouslypreparedsolutionofthesulfoniumsaltfollowedbyprecooled10MNaOH,whichisaddedinoneportion.
ThereactionmixtureisheavilystirredandinthethawingcoolingbathbroughttoRTovernight.
Thereactionmixtureisdilutedwith100mldiethyletherandwashedwithH2O(70ml).
Theaqueouslayerisextractedwithdiethylether(4x30ml).
ThecombinedorganiclayersaredriedoverNa2SO4.
Afterconcentrationinvaccuothecrudeproductispurifiedviaflashchromatography.
GeneralprocedureforthedeprotectionofTBDMS-group(GP8)Toasolutionof1eqTBDMS-protectedalcoholinMeOHareadded11.
5eqammoniumfluoride.
Thereactionmixtureisheatedunderrefluxfor2.
5h.
Thesolventisremovedinvaccuousingarotovap.
TheresidueistakenupinH2O(100ml)andextractedwithethylacetate(4x30ml).
ThecombinedorganiclayersaredriedoverNa2SO4.
Afterconcentrationinvaccuothecrudeproductispurifiedviaflashchromatography.
Generalprocedureforcarbodiimide-mediatedesterification(GP9)Toasolutionof1.
1eqacid,0.
5qDMAPand1.
0eqalcoholinDCMareadded0°C1.
1eqDICorEDC.
Afterstirringthereactionmixtureovernight,theorganicphaseiswashedwithH2O(3x10ml),10%NaHCO3-solution(3x10ml)andbrine(3x10ml).
ThecombinedorganiclayersaredriedoverNa2SO4.
Afterconcentrationinvaccuothecrudeproductispurifiedviaflashchromatography.
GeneralprocedureforTsuji-Trost-cyclisation(GP10)Inaninert5ml-flask0.
1eqPd-catalystbeadsareinertizedby3vacuum/argoncycles.
AfteradditionofTHFthereactionmixtureisheatedto75°Cunderargon.
After30min1eqsubstrateareaddedandthereactionmixtureheatedforanother15h.
AftercoolingtoRTthebeadsarefiltered,andwashedwithDCM(1x45ml,10min),DCM/MeOH(1/1)(2x20ml,2x10min)andDCM(1x20ml,10min).
Thecombinedorganicextractsareconcentratedinvaccuoandthecrudeproductispurifiedviaprep.
HPLC(EGC18).
SBrClO+1)MeOH:H2O(9:1)2)45,DCM,NaOH(10M)(1:1)-20°C->RT,1h7-8%+DCM:pyridine(4:1)RT,24h70%(COCl)2,DMSONEt3,DCM-78°C->RT,24h56%OHOHOOHOOOOOOO4524344466-Bromohexanoicacidmethylester(41)ThesynthesisproceededaccordingtoGP3with5.
00g(25.
63mmol)6-bromohexanoicacid(6),40mlmethanoland1mlconc.
sulfuricacid.
Thecrudeproductwaspurifiedviaflashchromatography(silica,column=5cm,length:20cm,cyclohexane:ethylacetate10:1).
Rf=0.
33Yield:3.
61g(17.
3mmol,66%)colorlessoil1H-NMR(400MHz,CDCl3):δ=3.
59(s,3H,-OCH3),3.
35(t,J=6.
8Hz,Br-CH2-R),2.
27(t,J=7.
3Hz,2H,R-CH2-COOMe),1.
81(quin,J=7.
2Hz,2H,Br-CH2-CH2-R),1.
60(quin,J=7.
5Hz,2H,R-CH2-CH2-COOMe),1.
42(quin,J=7.
7Hz,2H,Br-CH2-CH2-CH2-R)13C-NMR(100MHz,CDCl3):δ=173.
8(C=O),51.
8(-OCH3),34.
1(R-CH2-CH2-COOMe),33.
7(Br-CH2-R),32.
7(R-CH2-CH2-CH2-COOMe),28.
0(Br-CH2-CH2-R),24.
4(R-CH2-COOMe)Theanalyticaldataareinaccordancetotheliterature.
i7,7-Bis-(phenylsulfonyl)-heptanoicacidmethylester(42)ThreeSchlenk-flaskweredriedinvacuumandfilledwithargon.
InthefirstSchlenk-flaskasolutionof3.
61g(17.
3mmol,1.
0eq.
)6-bromohexanoicacidmethylester(41)in10mlabs.
N,N-dimethylformamidewasprepared,inthesecondSchlenk-flaskasolutionof5.
13g(PhSO2)2CH2(17.
3mmol,1.
0eq.
)in20mlabs.
N,N-dimethylformamide.
InthethirdSchlenk-flaskasuspensionof414mgNaH(17.
3mmol,1.
0eq.
)in10mlabs.
DMFwasprepared,cooledinanicebath,andthenthesolutionofbis(phenylsulfonyl)methanewasslowlydroppedtotheNaH-suspension,uponwhichgasevolutionwasobserved.
After90mintheformedyellowsolutionwasaddedtothe6-bromohexanoicacidsolutioninthefirstSchlenkflaskdropbydrop.
Thereactionmixturewasstirredat60°Covernight.
Thereactionmixturewastreatedwith250mlethylacetateand70ml5%HCl.
TheorganiclayerwaswashedwithH2O(70ml)andbrine(70ml).
ThecombinedorganiclayersweredriedoverNa2SO4.
Afterconcentrationinvaccuothecrudeproductwaspurifiedviaflashchromatography(silica,column=5cm,length:23cm,cyclohexane:ethylacetate3:2).
Rf=0.
51Yield:6.
33g(14.
9mmol,92%)colorlesssolid1H-NMR(400MHz,CDCl3):δ=7.
96-7.
93(m,4H,ar.
H),7.
71-7.
67(m,2H,ar.
H),7.
60-7.
54(m,4H,ar.
H),4.
38(t,J=5.
6Hz,1H,R-CH-(SO2Ph)2),3.
6(s,-OCH3),2.
25(t,J=7.
4Hz,2H,R-CH2-COOMe),2.
17-2.
12(m,2H,(PhSO2)2CH-CH2-R),1.
62-1.
51(m,4H,alk.
H),1.
30-1.
23(m,2H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
9(C=O)138.
0(ar.
C),134.
7(ar.
C),129.
8(ar.
C),129.
6(ar.
C),129.
3(ar.
C),129.
1(ar.
C),83.
9(PhSO2-CHR-SO2Ph),51.
9(-OCH3),28.
8((PhSO2)2CH-CH2-CH2-CH2-R),28.
1((PhSO2)2CH-CH2-CH2-CH2-CH2-R),27.
3((PhSO2)2CH-CH2-CH2-R),25.
9((PhSO2)2-CH-CH2-R),24.
6(R-CH2-COOMe)HRMS(FAB,3-NBA)forC20H25O6S2[M+H]+:calcd.
:425.
1093found:425.
10967,7-Bis-(phenylsulfonyl)-heptanoicacid(7)6.
33g(14.
9mmol,1.
0eq.
)7,7-bis-(phenylsulfonyl)-heptanoicacidmethylester(42)weredissolvedin20mlmethanol.
Then20mltetrahydrofurane,7mlH2Oand1.
87g(44.
56mmol,3.
0eq.
)LiOH.
H2Owereadded.
Thereactionmixturewasstirredat40°Cfor18h.
Thenthesolventswereremovedinvaccuousingarotovap.
Theresiduewastakenupin100mlethylacetateand40mlH2O.
Afterphaseseparationtheorganiclayerwasdiscarded.
TheaqueouslayerwasacidifiedtopH1andextractedwithethylacetate(3x150ml).
ThecombinedorganiclayersweredriedoverNa2SO4.
Afterconcentrationinvaccuothecrudeproductwaspurifiedviaflashchromatography(silica,column=5cm,length:23cm,ethylacetate:methanol40:1).
Rf=0.
58Yield:6.
65g(12.
86mmol,86%)colorlesscrystalsmp:81.
0°C1H-NMR(400MHz,MeOD):δ=7.
93-7.
90(m,4H,ar.
H),7.
76-7.
71(m,2H,ar.
H),7.
62-7.
58(m,4H,ar.
H),5.
05(t,J=5.
5Hz,1H,CH-(SO2Ph)2),4.
86(brs,COOH),2.
21(t,J=7.
3Hz,2H,CH2-COOMe),2.
16-2.
11(m,2H,(PhSO2)2CH-CH2),1.
54-1.
44(m,4H,alk.
H),1.
24(t,J=7.
2Hz,2H,alk.
H)13C-NMR(100MHz,CDCl3):δ=171.
3(C=O)138.
0(ar.
C),134.
7(ar.
C),129.
8(ar.
C),129.
3(aromC),83.
9(PhSO2-CHR-SO2Ph),28.
8((PhSO2)2CH-CH2-CH2-CH2-R),28.
1((PhSO2)2CH-CH2-CH2-CH2-CH2-R),25.
9((PhSO2)2-CH-CH2-R),24.
5(R-CH2-COOMe)HRMS(FAB,3-NBA)forC19H23O6S2[M+H]+:calcd.
:411.
0936found.
:411.
09206-(tert-Butyl-dimethyl-silanyloxy)-hexan-1-ol(51)ThesynthesisproceededaccordingtoGP4with4.
46g(186mmol)NaHin140mlabs.
THF,22.
0g(186mmol)1,6-hexandiol(2)and28.
0g(186mmol)tert-butyldimethylsilylchloride.
Thecrudeproductwaspurifiedviaflashchromatography(silica,column=7cm,length:23cm,pentane:ethylacetate7:1).
Rf=0.
39Yield:16.
3g(70.
2mmol,38%)colorlessoil.
1H-NMR(400MHz,CDCl3):δ=3.
68-3.
60(brm,4H,CH2OSiundCH2OH),1.
63(brs,1H,-OH),1.
60-1.
53(brm,4H,alk.
CH2),1.
39-1.
35(brm,4H,alk.
CH2),0.
90(s,9H,tert-Butyl),0.
06(s,6H,(CH3)2Si).
13C-NMR(100MHz,CDCl3):δ=63.
18(CH2OSi),62.
93(CH2OH),32.
86(alk.
CH2),26.
07(alk.
CH2),25.
71(alk.
CH2),25.
64(C(CH3)3),18.
49(C(CH3)3),-5.
09(Si(CH3)2)Theanalyticaldataareaccordingtoliterature.
ii10-(tert-Butyl-dimethyl-silanyloxy)-decan-1-ol(57)ThesynthesisproceededaccordingtoGP4with0.
64g(27.
0mmol)NaHin40mlabs.
THF,4.
7g(27.
0mmol)1,10-decandioland4.
10g(27.
0mmol)tert-butyldimethylsilylchloride.
Thecrudeproductwaspurifiedviaflashchromatography(silica,column=5cm,length:20cm,pentane:ethylacetate7:1).
Rf=0.
51Yield:2.
09g(7.
3mmol,27%)colorlessoil1H-NMR(400MHz,CDCl3):δ=3.
65-3.
57(brm,4H,CH2OSiundCH2OH),1.
63(brs,1H,-OH),1.
60-1.
45(brm,4H,alk.
CH2),1.
39-1.
20(brm,12H,alk.
CH2),0.
89(s,9H,tert-Butyl),0.
05(s,6H,(CH3)2Si).
13C-NMR(100MHz,CDCl3):δ=63.
34(CH2OSi),60.
41(CH2OH),32.
95(alk.
CH2),29.
64(alk.
CH2),29.
51(alk.
CH2),26.
08(alk.
CH2),25.
89(C(CH3)3),18.
49(C(CH3)3),-5.
08(Si(CH3)2)Theanalyticaldataareaccordingtoliterature.
ii6-(tert-Butyl-dimethyl-silanyloxy)-hexanal(3)ThesynthesisproceededaccordingtoGP6with2.
8ml(26.
1mmol)oxalylchloridein60mlDCM,3.
7ml(52.
2mmol)DMSO,asolutionofalcohol51in20mlDCMand12.
1ml(87.
0mmol)abs.
triethylamine.
Yield:4.
04g(17.
4mmol,99%)orangeoil.
1H-NMR(400MHz,CDCl3):δ=9.
73(s,1H,CHO),3.
58(t,J=6.
5Hz,2H,CH2OSi),2.
41(td,J=7.
4Hz,1.
8Hz,2H,CH2CHO),1.
62(quin,J=7.
5Hz,2H,alk.
CH2),1.
54-1.
49(m,2H,alk.
CH2),1.
41-1.
35(m,2H,alk.
CH2),0.
88(s,9H,tert-Butyl),0.
03(s,6H,(CH3)2Si).
HRMS(FAB,3-NBA)forC12H25O2Si[M-H]+:calcd:229.
1624found:229.
1609Theanalyticaldataareaccordingtoliterature.
iii10-(tert-Butyl-dimethyl-silanyloxy)-decanal(58)ThesynthesisproceededaccordingtoGP6with1.
2ml(10.
9mmol)oxalylchloridein30mlDCM,1.
5ml(21.
8mmol)DMSO,asolutionof2.
09g(7.
26mmol)10-(tert-butyl-dimethyl-silanyloxy)-decan-1-ol(57)in20mlDCMand5.
1ml(36.
3mmol)abs.
triethylamine.
Yield:2.
13g(7.
26mmol,99%)orangeoil.
1H-NMR(400MHz,CDCl3):δ=9.
73(s,1H,CHO),3.
58(t,J=6.
5Hz,2H,CH2OSi),2.
41(td,J=7.
4Hz,1.
8Hz,2H,CH2CHO),1.
60-1.
45(brm,4H,alk.
CH2),1.
39-1.
20(brm,12H,alk.
CH2),0.
88(s,9H,tert-Butyl),0.
05(s,6H,(CH3)2Si).
Theanalyticaldataareaccordingtoliterature.
ivtert-Butyl-dimethyl-[5-(3-vinyl-oxiranyl)-pentyloxy]-silane(52)ThesynthesisproceededaccordingtoGP7with2.
3ml(26.
3mmol)allylicbromidedissolvedin7.
8mlmethanoland0.
85mlH2O,4.
7ml(52.
6mmol)tetrahydrothiophene.
Thegel-likeresiduewastakenupin13.
5mlDCMandaddedtoasolutionof4.
04g(17.
4mmol)6-(tert-butyl-dimethyl-silanyloxy)-hexanal(3)in20mlDCM,immediatelyfollowedby33.
5mlprecooled10MNaOH.
Thecrudeproductwaspurifiedviaflashchromatography(silica,column=5cm,length:20cm,cyclohexane:ethylacetate20:1).
Rf=0.
32Ausbeute:3.
38g(12.
7mmol,73%)yellowishoil1H-NMR(400MHz,CDCl3):δ=5.
70-5.
52(m,1H,R-CH=CH2,2diastereomers),5.
48-5.
40(m,1H,R-CH=CH2cis,2diastereomers),5.
35-5.
22(m,1H,R-CH=CH2trans,2diastereomers),3.
59(t,J=6.
5Hz,2H,R-CH2-COOR'),3.
08(dd,J=2.
1Hz,7.
4Hz,1H,(R-CH2)CH(Oepoxid)CH-CH=CH2),2.
81(dt,J=2.
1Hz,5.
6Hz,1H,CHOepox),1.
60-1.
36(m,8H,alk.
H),0.
88(s,9H,tert-Butyl),0.
04(s,6H,(CH3)2Si)HRMS(FAB,3-NBA)forC12H25O2Si[M-H]+:calcd.
:269.
1936found.
:269.
1920tert-Butyl-dimethyl-[9-(3-vinyl-oxiranyl)-nonyloxy]-silane(59)ThesynthesisproceededaccordingtoGP7with0.
94ml(10.
9mmol)allylicbromidedissolvedin3.
2mlmethanoland0.
35mlH2O,and1.
9ml(21.
8mmol)tetrahydrothiophene.
Thegel-likeresiduewastakenupin7.
9mldichlormethaneandaddedtoasolutionof2.
13g(7.
3mmol)10-(tert-butyl-dimethyl-silanyloxy)-decanal(58)in6mlDCM,immediatelyfollowedby13.
9mlprecooled10MNaOH.
Thecrudeproductwaspurifiedviaflashchromatography(silica,column=4cm,Lnge:20cm,cyclohexane:ethylacetate50:1).
Rf=0.
28Yield:1.
58g(4.
8mmol,67%)yellowishoil1H-NMR(400MHz,CDCl3):δ=5.
76-5.
33(m,1H,-CH=CH2,),5.
38-5.
456(ddd,J=1.
6Hz,8.
7Hz,17.
2Hz,1H,-CH=CH2),5.
30(dd,J=0.
73Hz,10.
2Hz,1H,-CH=CH2),3.
60(t,J=6.
6Hz,2H,R-CH2-COOR'),3.
09(dd,J=2.
1Hz,7.
3Hz,1H,(R-CH2)CH(OEpoxid)CH-CH=CH2),2.
82(td,J=5.
6Hz,2.
2Hz,1H,CHOepox),1.
60-1.
55(m,2H,-CH2-epoxide),1.
52-1.
38(m,4H,alk.
H),1.
30-1.
25(m,10H,alk.
H),0.
90(s,9H,tert-Butyl),0.
05(s,6H,(CH3)2Si)13C-NMR(100MHz,CDCl3):δ=135.
8(-CH=CH2),118.
7(-CH=CH2),63.
34(-CH2OSi-),60.
52(CH2-O),58.
78(CH2-O),32.
97(alk.
C),32.
08(alk.
C),29.
53(alk.
C),27.
86(alk.
C),26.
10((CH3)3C),18.
52(C(CH3)3),-5.
05(CH3-Si).
5-(3-Vinyl-oxiranyl)-pentan-1-ol(5)ThesynthesisproceededaccordingtoGP8with1.
94g(7.
3mmol)tert-butyl-dimethyl-[5-(3-vinyl-oxiranyl)-pentyloxy]-silane(52)in150mlmethanoland3.
1g(83.
5mmol)ammoniumfluoride.
Thecrudeproductwaspurifiedviaflashchromatography(silica,column=5cm,length:20cm,cyclohexane:ethylacetate1:1).
Rf=0.
32Yield:0.
72g(4.
6mmol,63%)yellowishoil1H-NMR(400MHz,CDCl3):δ=5.
56-5.
18(m,3H,olefin.
H),3.
57(t,J=6.
5Hz,2H,CH2OH),3.
05(dd,J=7.
4Hz,2.
2Hz,1H,CHOepox),2.
78(td,J=5.
5Hz,2.
0Hz,,1H,CHOepox),1.
58-1.
34(m,8H,alk.
H).
HRMS(FAB,3-NBA)forC9H16O2Na[M+Na]+:calcd.
:179.
1048found:179.
10349-(3-Vinyl-oxiranyl)-nonan-1-ol(60)ThesynthesisproceededaccordingtoGP8with1.
57g(4.
8mmol)tert-butyl-dimethyl-[6-(3-vinyl-oxiranyl)-nonyloxy]-silane(59)in185mlmethanoland3.
2g(85.
4mmol)ammoniumfluoride.
Thecrudeproductwasusedwithoutfurtherpurfication.
Rf=0.
54(cyclohexane:ethylacetate1:1)Yield:0.
98g(4.
6mmol,96%)yellowishoil1H-NMR(400MHz,CDCl3):δ=5.
56-5.
18(m,3H,olefin.
H),3.
57(t,J=6.
5Hz,2H,CH2OH),3.
05(dd,J=7.
4Hz,2.
2Hz,1H,CHOepox),2.
78(td,J=5.
5Hz,2.
0Hz,,1H,CHOepox),1.
58-1.
34(m,8H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=135.
7(-CH=CH2),118.
7(-CH=CH2),63.
01(-CH2OSi-),60.
520(CH2-O),58.
77(CH2-O),32.
84(alk.
C),32.
03(alk.
C),29.
50(alk.
C),27.
81(alk.
C),26.
34(alk.
C),25.
81(alk.
C).
Tri(ethylenglycol)-mono-tert-butyldimethylsilylether(61)ThesynthesisproceededaccordingtoGP5with19.
0ml(142.
3mmol)triethylenglycol,3.
81g(25.
3mmol)tert-butyldimethylsilylchloride,0.
65g(6.
4mmol)DMAPand3.
5ml(25.
0mmol)abs.
triethylaminein50mlabs.
DCM.
Thecrudeproductwaspurifiedviaflashchromatography(silica,column=5cm,length:20cm,eluent:ethylacetate).
Rf=0.
64Yield:4.
81g(18.
2mmol,64%)yellowishoilGC-MS(DB_100):tR=3.
86min[M]+=2651H-NMR(400MHz,CDCl3):δ=3.
76(t,J=5.
38Hz,2H,Si-O-CH2-CH2-O),3.
72–3.
70(m,2H,O-CH2),3.
66(s,4H,O-CH2),3.
61–3.
59(m,2H,O-CH2),3.
56(t,2H,J=5.
38Hz,Si-O-CH2-CH2),0.
88(s,9H,Si-C-(CH3)3),0.
06(s,6H,Si-(CH3)2).
13C-NMR(100MHz,CDCl3):δ=72.
7(HO-CH2-),72.
4(CH2-O),70.
8(CH2-O),70.
5(CH2-O),62.
7(CH2-O),61.
8(CH2-O),26.
0((CH3)3C),18.
5(C(CH3)3),-5.
13(CH3-Si).
Theanalyticaldataareaccordingtoliterature.
vTetra(ethylenglycol)-mono-tert-butyldimethylsilylether(62)ThesynthesisproceededaccordingtoGP5with24.
3g(125.
0mmol)tetraethylenglycol,3.
77g(25.
0mmol)tert-butyldimethylsilylchloride,0.
61g(5.
0mmol)DMAPand3.
5ml(25.
0mmol)abs.
triethylaminein50mlabs.
DCM.
Thecrudeproductwaspurifiedviaflashchromatography(silica,column=5cm,length:20cm,ethylacetate).
Rf=0.
60Yield:5.
01g(16.
3mmol,65%)yellowishoilGC-MS(DB_100):tR=4.
67min[M]+=3091H-NMR(400MHz,CDCl3):δ=3.
53-3.
77(m,16H,alk.
H),0.
88(s,9H,Si-C-(CH3)3),0.
05(s,6H,Si-(CH3)2).
13C-NMR(100MHz,CDCl3):δ=73.
6,71.
4,71.
3,64.
0,62.
7(CH2-O),61.
8(CH2-O),26.
1((CH3)3C),18.
5(C(CH3)3),-5.
13(CH3-Si).
Theanalyticaldataareaccordingtoliterature.
vi2-(2-tert-Butyldimethylsilyloxy-ethoxy)-ethoxy-acetaldehyde(63)ThesynthesisproceededaccordingtoGP6with2.
9ml(27.
3mmol)oxalylchloridein60mlDCM,3.
9ml(54.
6mmol)DMSO,asolutionof4.
81g(18.
2mmol)alcohol61in20mlDCM,and12.
7ml(91.
0mmol)abs.
triethylamine.
Yield:4.
1g(15.
6mmol,86%)orange-redoilGC-MS(DB_100):tR=3.
69min[M]+=2631H-NMR(400MHz,CDCl3):δ=9.
68(s,1H,-CHO),4.
12(s,2H,CH2-CHO),3.
73(t,J=5.
28Hz,2H,CH2-O),3.
71–3.
67(m,4H,CH2-O),3.
52(t,J=5.
18Hz,2H,CH2-O),0.
85(s,9H,Si-C(CH3)3),0.
03(s,6H,Si(CH3)2).
13C-NMR(100MHz,CDCl3):δ=200.
5(-CHO),72.
7(CH2-O),71.
2(CH2-O),70.
8(CH2-O),62.
6(CH2-O),25.
9(C(CH3)3),18.
4(C(CH3)3),-5.
19(Si(CH3)2).
2-[2-(2-tert-Butyldimethylsilyloxy-ethoxy)-ethoxy]-ethoxy-acetaldehyde(64)ThesynthesisproceededaccordingtoGP6with2.
6ml(24.
0mmol)oxalylchloridein40mlDCM,3.
4ml(48.
0mmol)DMSO,asolutionof5.
01g(16.
3mmol)alcohol2in20mlDCM,and11.
2ml(80.
0mmol)abs.
triethylamine.
Yield:4.
45g(14.
8mmol,91%)yellowishoil1H-NMR(400MHz,CDCl3):δ=9.
72(s,1H,-CHO),4.
14(s,2H,CH2-CHO),3.
76-3.
53(m,13H,CH2-O),0.
90(s,9H,Si-C(CH3)3),0.
09(s,6H,Si(CH3)2).
13C-NMR(100MHz,CDCl3):δ=200.
7(-CHO),72.
7(CH2-O),71.
2(CH2-O),70.
8(CH2-O),62.
6(CH2-O),26.
1(C(CH3)3),18.
5(C(CH3)3),-5.
19(Si(CH3)2).
tert-Butyl-dimethyl-{2-[2-(3-vinyl-oxiranylmethoxy)-ethoxy]-ethoxy}-silane(65)ThesynthesisproceededaccordingtoGP7withasolutionof1.
98ml(22.
7mmol)allylicbromidein7.
8mlmethanoland0.
85mlH2O,and4.
0mltetrahydrothiophene.
Thegel-likeresiduewastakenupin13.
5mlDCMandaddedtoasolutionof3.
99g(15.
1mmol)aldehyd64in20mlDCM,immediatelyfollowedby33.
5ml10MNaOH.
Thecrudeproductwaspurifiedviaflashchromatography(silica,column=2cm,length:18cm,cyclohexane:ethylacetate3:1).
Rf=0.
44Yield:2.
45g(8.
1mmol,53%)yellow-orangeoilGC-MS(DB_100):tR=4.
42min[M]+=3031H-NMR(400MHz,CDCl3):δ=5.
57(m,1H,CH=CH2),5.
42(dd,J=17.
2Hz,2.
0Hz,1H,CH=CH2),5.
23(dd,J=9.
8Hz,0.
7Hz,1H,CH=CH2),3.
72(m,4H,CH2-O),3.
60(m,4H,CH2-O),3.
48(m,4H,CH2-O),3.
21(dd,J=7.
0Hz,2.
2Hz,1H,-CHOepox-CH),3.
01(ddt,J=3.
0Hz,3.
4Hz,2.
3Hz,1H,CH2-CHO-CHO),0.
83(s,9H,C(CH3)3),0.
00(s,6H,Si(CH3)2).
13C-NMR(100MHz,CDCl3):δ=134.
6(CH2=CH-),119.
5(CH2=),72.
51(CH2-O),70.
67(CH2-O),70.
53(CH2-O),62.
57(CH2-O),58.
52(CH-O),55.
89(CH-O),25.
86(C(CH3)3),18.
34(C(CH3)3),-5.
26(Si(CH3)2).
tert-Butyl-dimethyl-(2-{2-[2-(3-vinyl-oxiranylmethoxy)-ethoxy]-ethoxy}-ethoxy)-silane(66)ThesynthesisproceededaccordingtoGP7withasolutionof1.
88ml(21.
8mmol)allylicbromidein9.
0mlmethanoland1.
0mlH2O,and3.
8ml(43.
5mmol)tetrahydrothiophene.
Thegel-likeresiduewastakenupin13.
5mlDCMandaddedtoasolutionof4.
45g(14.
8mmol)aldehyde64in20mlDCM,immediatelyfollowedby33.
5ml10MNaOH.
Thecrudeproductwaspurifiedviaflashchromatography(silica,column=2cm,length:18cm,cyclohexane:ethylacetate20:1).
Rf=0.
92Yield:3.
20g(10.
2mmol,69%)colorlessoilGC-MS(DB_100):tR=5.
15min1H-NMR(400MHz,CDCl3):δ=5.
57(m,1H,CH=CH2),5.
42(dd,J=17.
2Hz,2.
0Hz,1H,CH=CH2),5.
23(dd,J=9.
8Hz,0.
7Hz,1H,CH=CH2),3.
72(m,4H,CH2-O),3.
60(m,4H,CH2-O),3.
48(m,4H,CH2-O),3.
21(dd,J=7.
0Hz,2.
2Hz,1H,-CHO-CHO-CH),3.
01(ddt,J=3.
0Hz,3.
4Hz,2.
3Hz,1H,CH2-CHO-CHO),0.
88(s,9H,C(CH3)3),0.
05(s,6H,Si(CH3)2).
13C-NMR(100MHz,CDCl3):δ=134.
8(CH2=CH-),119.
6(CH2=),72.
51(CH2-O),70.
67(CH2-O),70.
53(CH2-O),62.
57(CH2-O),58.
6(CH-O),56.
0(CH-O),26.
1(C(CH3)3),18.
5(C(CH3)3),-5.
10(Si(CH3)2).
2-[2-(3-Vinyl-oxiranylmethoxy)-ethoxy]-ethanol(67)ThesynthesisproceededaccordingtoGP8with2.
35g(7.
8mmol)vinylepoxide65in200mlmethanoland3.
51g(94.
9mmol)ammoniumfluoride.
Thecrudeproductwasusedwithoutfurtherpurification.
Yield:0.
88g(4.
7mmol,60%)yellowishoilGC-MS(DB_100):tR=3.
94min1H-NMR(400MHz,CDCl3):δ=5.
61(m,1H,CH=CH2),5.
46(dd,J=17.
2Hz,1.
8Hz,1H,CH=CH2),5.
25(d,1H,CH=CH2),3.
79(dd,J=11.
7Hz,2.
9Hz,2H,CH2-O),3.
64(m,6H,CH2-O),3.
48(dd,4H,J=11.
7Hz,5.
7Hz,CH2-O),3.
24(dd,J=7.
0Hz,2.
2Hz,1H,-CHO-CHO-CH),3.
06(ddt,J=5.
5Hz,3.
1Hz,2.
3Hz,1H,CH2-CHO-CHO).
13C-NMR(100MHz,CDCl3):δ=134.
6(CH2=CH-),119.
7(CH2=),72.
43(CH2-O),70.
95(CH2-O),70.
71(CH2-O),70.
29(CH2-O),61.
65(CH2-O),58.
55(CH-O),55.
89(CH-O).
2-{2-[2-(3-Vinyl-oxiranylmethoxy)-ethoxy]-ethoxy}-ethanol(68)ThesynthesisproceededaccordingtoGP8with3.
20g(10.
1mmol)vinylepoxide66in150mlmethanoland4.
28g(115.
7mmol)ammoniumfluoride.
Thecrudeproductwasusedwithoutfurtherpurification.
Rf=0.
34(cyclohexane:ethylacetate20:1)Yield:0.
88g(4.
7mmol,60%)yellowishoilGC-MS(DB_100):tR=4.
26min[M]+=2011H-NMR(400MHz,CDCl3):δ=5.
61(m,2H,CH=CH2),5.
46(dd,J=17.
2Hz,1.
8Hz,1H,CH=CH2),5.
25(d,1H,CH=CH2),3.
79(dd,J=11.
7Hz,2.
9Hz,2H,CH2-O),3.
64(m,6H,CH2-O),3.
48(dd,4H,J=11.
7Hz,5.
7Hz,CH2-O),3.
24(dd,J=7.
0Hz,2.
2Hz,1H,-CHOepox-CH),3.
06(ddt,J=5.
5Hz,3.
1Hz,2.
3Hz,1H,CH2-CHOepox).
13C-NMR(100MHz,CDCl3):δ=134.
6(CH2=CH-),119.
7(CH2=),72.
43(CH2-O),70.
95(CH2-O),70.
71(CH2-O),70.
29(CH2-O),61.
65(CH2-O),58.
55(CH-O),55.
89(CH-O).
7,7-Bis-(phenylsulfonyl)-heptanoicacid5-(3-vinyl-oxiranyl)-pentylester(8)ThesynthesisproceededaccordingtoGP9with0.
31g(2.
0mmol)alcohol5in10mlDCMand0.
90g(2.
2mmol)acid7in10mlDCM,0.
01g(0.
1mmol)DMAPand0.
42g(2.
2mmol)EDC.
Thecrudeproductwaspurifiedviaflashchromatography(silica,flashstation,cyclohexane:ethylacetate1:1).
Rf=0.
33Yield:0.
72g(4.
6mmol,63%)yellowishoil1H-NMR(400MHz,CDCl3):δ=7.
88-7.
85(m,4H,ar.
H),7.
62-7.
60(m,2H,ar.
H),7.
51-7.
48(m,4H,ar.
H),5.
40-5.
17(brm,3H,olefin.
H),4.
40(t,J=6Hz,1H,CH(SO2Ph)2),4.
04-3.
98(m,2H,CH2COO),3.
04-3.
03(m,1H,CHOepox),2.
76-2.
75(m,1H,CHOepox),2.
20-2.
16(m,2H,alk.
CH2),2.
11-2.
08(m,2H,alk.
CH2),1.
60-1.
17(m,14H,alk.
CH2).
13C-NMR(100MHz,CDCl3):δ=172.
9(COO),137.
5(ar.
C),135.
4(all.
C),134.
2(ar.
C),129.
1(ar.
C),128.
7(ar.
C),118.
6(all.
C),83.
05(CH(SO2Ph)2),63.
98(CH2COO),60.
11(CHOepox),60.
00(CHOepox),33.
75(alk.
C),31.
64(alk.
C),28.
39(alk.
C),28.
28(alk.
C),27.
46(alk.
C),25.
60(alk.
C),25.
41(alk.
C),25.
26(alk.
C),24.
07(alk.
C),20.
92(alk.
C),14.
12(CH2CH(SO2Ph)2)HRMS(FAB,3-NBA)forC28H37O7S2[M+H]+:calcd.
:549.
1981found:549.
2001HPLC(C18):tR=9.
96min7,7-Bis-(phenylsulfonyl)-heptanoicacid9-(3-vinyl-oxiranyl)-nonylester(10)ThesynthesisproceededaccordingtoGP9with0.
95g(4.
5mmol)9-(3-vinyl-oxiranyl)-nonan-1-ol(60)in20mlDCMand2.
0g(4.
9mmol)7,7-bis-(phenylsulfonyl)-heptanoicacid(7)in20mlDCM,0.
1g(0.
9mmol)DMAPand0.
94g(4.
9mmol)EDC.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate3:1).
Rf=0.
41(cyclohexane:ethylacetate3:1)Yield:0.
91g(1.
5mmol,33%)yellowishoil1H-NMR(400MHz,CDCl3):δ=7.
96-7.
94(m,4H,ar.
H),7.
72-7.
68(m,2H,ar.
H),7.
60-7.
55(m,4H,ar.
H),5.
75-5.
23(brm,3H,olefin.
H),4.
38(t,J=5.
7Hz,1H,CH(SO2Ph)2),4.
05(t,J=6.
7Hz,2H,CH2COO),3.
09(dd,J=2.
1Hz,7.
4Hz,1H,CHOepox),2.
82(dt,J=2.
3Hz,5.
5Hz,1H,CHOepox),2.
25(t,J=7.
5Hz,2H,alk.
CH2),2.
18-2.
13(m,2H,alk.
CH2),1.
63-1.
54(m,8H,alk.
CH2),1.
38-1.
27(m,12H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=173.
2(COO),137.
7(ar.
C),135.
7(all.
C),134.
4(ar.
C),129.
4(ar.
C),128.
9(ar.
C),118.
7(all.
C),83.
56(CH(SO2Ph)2),64.
52(CH2COO),60.
49(CHOepox),58.
75(CHOepox),34.
06(alk.
C),32.
05(alk.
C),29.
48(alk.
C),29.
31(alk.
C),28.
73(alk.
C),28.
57(alk.
C),27.
84(alk.
C),26.
00(alk.
C),25.
53(alk.
C),24.
35(alk.
C).
HPLC(C18):tR=11.
34min7,7-Bis-(phenylsulfonyl)-heptanoicacid2-[2-(3-vinyl-oxiranylmethoxy)-ethoxy]-ethylester(12)ThesynthesisproceededaccordingtoGP9with0.
82g(4.
4mmol)2-[2-(3-vinyl-oxiranylmethoxy)-ethoxy]-ethanol(67)in5mlDCMand2.
0g(4.
8mmol)7,7-bis-(phenylsulfonyl)-heptanoicacid(7)in5mlDCM,0.
1g(0.
9mmol)DMAPand0.
92g(4.
8mmol)EDC.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate3:2).
Rf=0.
32(cyclohexane:ethylacetate3:2)Yield:0.
93g(1.
6mmol,37%)yellowishoil1H-NMR(400MHz,CDCl3):δ=7.
96-7.
94(m,4H,ar.
H),7.
72-7.
68(m,2H,ar.
H),7.
60-7.
56(m,4H,ar.
H),5.
69-5.
28(brm,3H,olefin.
H),4.
38(t,J=5.
7Hz,1H,CH(SO2Ph)2),4.
24-4.
22(m,2H,CH2COO),3.
80(dd,J=11.
7Hz,3.
1Hz,1H,CH2-glycolchain),3.
71-3.
65(m,6H,-CH2-glycolchain),3.
51(dd,J=5.
5Hz,11.
7Hz,1H,CH2-glycolchain),3.
27(dd,J=7.
2Hz,2.
2Hz,1H,CHOepox),3.
08(ddd,J=2.
3Hz,5.
4Hz,3.
1Hz,1H,CHOepox),2.
28(t,J=7.
4Hz,2H,alk.
CH2),2.
18-2.
13(m,2H,alk.
CH2),1.
63-1.
54(m,4H,alk.
CH2),1.
32-1.
27(m,2H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=173.
1(COO),137.
7(ar.
C),134.
8(all.
C),134.
4(ar.
C),129.
4(ar.
C),129.
0(ar.
C),119.
7(all.
C),83.
53(CH(SO2Ph)2),71.
05(CH2-glycolchain),70.
77(CH2-glycolchain),70.
56(CH2-glycolchain),69.
20(CH2-glycolchain),63.
45(CH2COO),58.
66(CHOepox),55.
97(CHOepox),33.
88(alk.
C),28.
50(alk.
C),27.
81(alk.
C),25.
52(alk.
C),24.
25(alk.
C).
HRMS(FAB,3-NBA)forC28H37O9S2[M+H]+:calcd.
:581.
1879found:581.
1908HPLC(C18):tR=8.
85min7,7-Bis-(phenylsulfonyl)-heptanoicacid2-{2-[2-(3-vinyl-oxiranylmethoxy)-ethoxy]-ethoxy}-ethylester(14)ThesynthesisproceededaccordingtoGP9with0.
14g(0.
61mmol)2-{2-[2-(3-vinyl-oxiranylmethoxy)-ethoxy]-ethoxy}-ethanol(68)in2.
5mlDCMand0.
28g(0.
67mmol)7,7-bis-(phenylsulfonyl)-heptanoicacid(7)in2.
5mlDCM,0.
01g(0.
1mmol)DMAPand0.
13g(0.
67mmol)EDC.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate3:2).
Rf=0.
31(cyclohexane:ethylacetate3:2)Yield:0.
23g(0.
37mmol,60%)colorlessoil1H-NMR(400MHz,CDCl3):δ=7.
95-7.
93(m,4H,ar.
H),7.
71-7.
67(m,2H,ar.
H),7.
59-7.
55(m,4H,ar.
H),5.
73-5.
27(brm,3H,olefin.
H),4.
38(t,J=5.
7Hz,1H,CH(SO2Ph)2),4.
22(t,J=4.
9Hz,2H,CH2COO),3.
78(dd,J=11.
7Hz,3.
1Hz,1H,CH2-glycolchain),3.
71-3.
64(m,10H,-CH2-glycolchain),3.
50(dd,J=5.
5Hz,11.
7Hz,1H,CH2-glycolchain),3.
26(dd,J=7.
2Hz,2.
3Hz,1H,CHOepox),3.
07(ddd,J=2.
2Hz,5.
4Hz,3.
2Hz,1H,CHOepox),2.
27(t,J=7.
4Hz,2H,alk.
CH2),2.
15-2.
11(m,2H,alk.
CH2),1.
59-1.
53(m,4H,alk.
CH2),1.
28-1.
23(m,2H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=173.
1(COO),137.
6(ar.
C),134.
7(all.
C),134.
4(ar.
C),129.
4(ar.
C),128.
9(ar.
C),119.
7(all.
C),83.
47(CH(SO2Ph)2),70.
98(CH2-glycolchain),70.
75(CH2-glycolchain),70.
58(CH2-glycolchain),69.
13(CH2-glycolchain),63.
46(CH2COO),58.
63(CHOepox),55.
96(CHOepox),33.
84(alk.
C),28.
46(alk.
C),27.
77(alk.
C),25.
49(alk.
C),24.
21(alk.
C).
HRMS(FAB,3-NBA)forC30H40O10S2Na[M+Na]+:calcd.
:647.
1961found.
:647.
1968HPLC(C18):tR=8.
88min2-Hydroxy-benzoicacid5-(3-vinyl-oxiranyl)-pentylester(55)A25ml2-neckflaskequippedwitha10ml-droppingfunnelwasdriedinvacuumandfilledwithargon.
50mg(6,7-Epoxy)-8-nonen-1-ol(5)(0.
32mmol)and126mgtriphenylphosphine(1.
5eq,0.
48mmol)wereaddedtotheflaskanddissolvedin3mlabs.
THF.
Theasolutionof97mgDIAD(1.
5eq,0.
48mmol)in2mlabs.
THFwasaddeddropwisewithin1min.
After20minasolutionof44mgsalicylicacid(1eq,0.
32mmol)in2mlabs.
THFwasaddeddropwise,andthereactionmixturewasstirredatRTfor12h.
Thereactionmixturewastakenuponsilicaandputonasilicacolumntoperformpurificationviaflashchromatography(eluent:ethylacetate:cyclohexane1:1).
Rf≈0.
92(EA:CH1:1)Yield:67mg(0.
24mmol,75%),slightlyturbid,colorlessoil1H-NMR(400MHz,CDCl3):δ=10.
81(s,1H,-OH),δ=7.
83(dd,J=8.
0/1.
8Hz,1H,H-6),7.
44(m,1H,H-5),6.
97(dd,J=8.
4,1.
0Hz,1H,H-3),6.
96(m,1H,H-4),5.
76-5.
22(m,3H,R-CH=CH2),4.
34(t,J=6.
7Hz,2H,R-COO-CH2),3.
10(dd,J=7.
4,2.
2Hz,1H,epoxide-HαtoC=C),2.
83(m,1H,epoxide-Hαtoalkylchain),1.
80(td,J=13.
3,6.
7Hz,2H,R-COO-CH2CH2-R`),1.
52(m,6H,alkyl-H)13C-NMR(100MHz,CDCl3):δ=169.
9(-COOR),161.
4(Carom-OH),135.
6(R-CH=CH2),135.
4(C-4),132.
3(C-6),129.
7(C-5),120.
3(C-1),118.
9(C-3),117.
4(R-CH=CH2),65.
2(RCOOCH2R'),60.
2(epoxide-CαtoC=C),58.
6(epoxide-Cαtoalkylchain),31.
9(alkyl-C),28.
6(alkyl-C),25.
9(Alkyl-C),25.
8(alkyl-C)2-[7,7-Bis-(phenylsulfonyl)-heptanoyloxy])-benzoicacid5-(3-vinyl-oxiranyl)-pentylester(56)ThesynthesisproceededaccordingtoGP9with61.
0mg55(0.
22mmol)in2mlDCM,99.
0mg7,7-bis(phenylsulfonyl)-heptanoicacid(7)(0.
24mmol),6.
0mgDMAP(0.
05mmol)and37.
5lDIC(0.
24mmol).
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate1:1).
Rf≈0.
62(cyclohexane:ethylacetate1:1)Yield:47mg(0.
07mmol,32%),colorlessoilHPLC(C18):tR=10.
54min1H-NMR(400MHz,CDCl3):δ=8.
00(dd,J=7.
7Hz,1.
7Hz,1H,H-6),7.
96(dd,J=8.
5Hz,1.
3Hz,4H,Haromo-sulfonyl),7.
70(m,2H,Harp-sulfonyl),7.
57(m,5H,Harm-sulfonylu.
H-4),7.
31(td,J=7.
6Hz,1.
1Hz,1H,H-5),7.
09(dd,J=8.
0Hz,1.
2Hz,1H,H-3),5.
75-5.
22(m,3H,R-CH=CH2),4.
43(t,J=5.
7Hz,1H,R-CH(-SO2R')2),4.
25(t,J=6.
7Hz,2H,R-COO-CH2R'),3.
10(m,1H,epoxide-HαtoC=C),2.
83(m,1H,epoxid-Hαtoalkylchain),2.
59(t,J=7.
4Hz,2H,Rar-OOC-CH2R'),2.
19(m,2H,R-CH2CH(O2S-R')2),1.
57(m,14H,alkyl-H)13C-NMR(100MHz,CDCl3):δ=172.
1(Rar-OOCR'),164.
6(Rar-COOR'),150.
9(Car-OH),140.
6(R-CH=CH2u.
R2CSO2R'),136.
1(Car),134.
8(Car),134.
0(Car),132.
8(Car),131.
8(Car),129.
9(Car),126.
2(Car),124.
1(Car),123.
8(Car),120.
8(Car),119.
3(R-CH=CH2),83.
8(R-CH(SO2Ph)2),65.
4(RarCOOCH2R'),60.
7(epoxid-CαtoC=C),59.
1(epoxid-Cαtoalkylchain),34.
3(alkyl-C),32.
3(alkyl-C),29.
1(alkyl-C),28.
8(alkyl-C),28.
2(alkyl-C),26.
3(alkyl-C),26.
1(alkyl-C),25.
9(alkyl-C),24.
4(alkyl-C)HRMS(FAB,3-NBA)forC35H40O9S2Na[M+Na]+:calcd.
:691.
2011found:691.
2004(E)-8,8-Bis-(phenylsulfonyl)-12-hydroxy-1-oxacycloheptadec-10-en-2-one(9)ThesynthesiswasperformedaccordingtoGP10with17.
3mg(0.
009mmol)Pd-resin1a/Pdin1.
1mlabs.
THFand49.
8mg(0.
09mmol)substrate8in1.
1mlabs.
THF.
Thecrudeproductwastakenupinacetonitrileforthepurificationviaprep.
HPLC.
ThecorrespondingZ-Isomerwasnotobserved.
Yield:33.
5mg(0.
0603mmol,67%)colorlesscrystalls1H-NMR(400MHz,CDCl3):δ=8.
02-8.
00(m,4H,ar.
H),7.
70-7.
68(m,2H,ar.
H),7.
60-7.
57(m,4H,ar.
H),5.
87(dt,J=14.
3Hz,7.
4Hz,1H,olefin.
H),5.
63(dd,J=15.
3Hz,7.
1Hz1H,olefin.
H),4.
22-4.
17(m,1H,CHOH),4.
12-4.
00(m,2H,CH2COO),3.
09-2.
95(m,2H,CH2C(SO2Ph)2),2.
37-2.
22(m,2H,CH2C(SO2Ph)2),2.
20-2.
02(m,2H,alk.
H),1.
74-1.
19(m,14H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=173.
0(COO),139.
3(ar.
C),136.
6(ar.
C),134.
4(ar.
C),131.
0(alk.
C),130.
97(alk.
C),128.
5(ar.
C),123.
2(ar.
C),91.
12(C(SO2Ph)2),72.
37(CHOH),64.
14(CH2COO),37.
41(alk.
C),34.
72(alk.
C),32.
03(alk.
C),29.
59(alk.
C),29.
13(alk.
C),28.
73(alk.
C),26.
74(alk.
C),25.
21(alk.
C),24.
73(alk.
C),23.
20(alk.
C).
HRMS(FAB,3-NBA)forC28H36O7S2Na[M+Na]+:calcd.
:571.
1800found:571.
1776HPLC(C18):tR=8.
72min(E)-8,8-Bis-(phenylsulfonyl)-12-hydroxy-1-oxacycloheneicosan-10-en-2-one(11)ThesynthesisproceededaccordingtoGP10with16.
0mg(0.
008mmol)Pd-resin1a/Pdin1.
0mlabs.
THFand50.
0mg(0.
083mmol)substrate10in1.
0mlabs.
THF.
Thecrudeproductwastakenupinacetonitrileforthepurificationviaprep.
HPLC.
ThecorrespondingZ-Isomerwasnotobserved.
Yield:23.
1mg(0.
038mmol,46%)colorlesscrystalls1H-NMR(400MHz,CDCl3):δ=8.
05-8.
03(m,4H,ar.
H),7.
74-7.
70(m,2H,ar.
H),7.
62-7.
58(m,4H,ar.
H),6.
13-5.
32(m,2H,olefin.
H),4.
18-4.
12(m,2H,CH2COO),3.
52(m,1H,CHOH),3.
16-2.
96(m,2H,CH2C(SO2Ph)2),2.
32-2.
23(m,2H,CH2C(SO2Ph)2),2.
21-2.
01(m,2H,alk.
H),1.
86-1.
21(m,22H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=173.
4(COO),138.
8(ar.
C),136.
5(ar.
C),136.
3(ar.
C),134.
5(ar.
C),131.
7(all.
C),131.
1(all.
C),128.
5(ar.
C),123.
0(ar.
C),91.
05(C(SO2Ph)2),72.
69(CHOH),63.
99(CH2COO),36.
82(alk.
C),34.
74(alk.
C),33.
50(alk.
C),31.
81(alk.
C),31.
50(alk.
C),30.
01(alk.
C),29.
17(alk.
C),28.
85(alk.
C),28.
31(alk.
C),27.
87(alk.
C),25.
00(alk.
C),23.
40(alk.
C),22.
74(alk.
C).
HRMS(FAB,3-NBA)forC32H44O7S2[M]+:calcd.
:604.
2528found:604.
2581HPLC(C18):tR=10.
55min(E)-8,8-Bis-(phenylsulfonyl)-12-hydroxy-1,14,17-trioxacyclononadecan-10-en-2-one(13)ThesynthesisproceededaccordingtoGP10with16.
5mg(0.
009mmol)Pd-resin1a/Pdin1.
0mlabs.
THFand50.
0mg(0.
086mmol)substrate12in1.
0mlabs.
THF.
Thecrudeproductwastakenupinacetonitrileforthepurificationviaprep.
HPLC.
ThecorrespondingZ-Isomerwasnotobserved.
Yield:16.
3mg(0.
028mmol,33%)colorlesscrystalls1H-NMR(400MHz,CDCl3):δ=8.
03-8.
01(m,4H,ar.
H),7.
72-7.
68(m,2H,ar.
H),7.
60-7.
56(m,4H,ar.
H),6.
03(dt,J=15.
2Hz,6.
9Hz,1H,olefin.
H),5.
68(dd,J=15.
5Hz,6.
2Hz,1H,olefin.
H),4.
31-4.
27(m,1H,CHOH),4.
22(t,J=5.
7Hz,2.
7Hz,2H,CH2COO),3.
81-3.
76(m,1H,CH2-glycolchain),3.
72-3.
60(m,6H,CH2-glycolchain),3.
47(dd,J=7.
1Hz,10.
4Hz,1H,CH2-glycolchain),3.
07-3.
04(m,2H,CH2C(SO2Ph)2),2.
36-2.
29(m,2H,CH2C(SO2Ph)2),2.
17-2.
08(m,2H,alk.
H),1.
78-1.
70(m,2H,alk.
H),1.
69-1.
59(m,2H,alk.
H),1.
34-1.
27(m,2H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=173.
2(COO),136.
5(ar.
C),136.
3(ar.
C),135.
2(ar.
C),134.
4(ar.
C),131.
0(ar.
C),128.
4(all.
C),124.
2(ar.
C),91.
25(C(SO2Ph)2),75.
30(CHOH),71.
42(CH2-glycolchain),70.
91(CH2-glycolchain),69.
07(CH2-glycolchain),63.
48(CH2COO),33.
79(alk.
C),31.
60(alk.
C),28.
79(alk.
C),28.
27(alk.
C),23.
81(alk.
C),22.
16(alk.
C).
HRMS(FAB,3-NBA)forC28H36O9S2Na[M+Na]+:calcd.
:603.
1698found:603.
1728HPLC(C18):tR=7.
85min(E)-8,8-Bis-(phenylsulfonyl)-12-hydroxy-1,14,17,20-tetraoxacyclodocosan-10-en-2-one(15)ThesynthesisproceededaccordingtoGP10with15.
4mg(0.
008mmol)Pd-resin1a/Pdin1.
0mlabs.
THFand50.
0mg(0.
080mmol)substrate14in1.
0mlabs.
THF.
Thecrudeproductwastakenupinacetonitrileforthepurificationviaprep.
HPLC.
ThecorrespondingZ-Isomerwasnotobserved.
Yield:26.
6mg(0.
043mmol,53%)colorlessoil1H-NMR(400MHz,CDCl3):δ=8.
05-8.
00(m,4H,ar.
H),7.
73-7.
69(m,2H,ar.
H),7.
60-7.
56(m,4H,ar.
H),6.
00(dt,J=15.
4Hz,6.
9Hz,1H,olefin.
H),5.
74(dd,J=15.
4Hz,6.
2Hz,1H,olefin.
H),4.
31-4.
27(m,1H,CHOH),4.
24(t,J=4.
3Hz,2H,CH2COO),3.
72-3.
60(m,11H,CH2-glycolchain),3.
47(dd,J=6.
2Hz,10.
2Hz,1H,CH2-glycolchain),3.
07(ddd,J=7.
5Hz,16.
2Hz,26.
1Hz,2H,CH2C(SO2Ph)2),2.
36-2.
30(m,2H,CH2C(SO2Ph)2),2.
20-2.
12(m,2H,alk.
H),1.
77-1.
60(m,4H,alk.
H),1.
36-1.
25(m,2H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=173.
3(COO),136.
6(ar.
C),136.
5(ar.
C),135.
0(ar.
C),134.
4(ar.
C),131.
1(all.
C),128.
4(all.
C),124.
0(arom.
C),91.
43(C(SO2Ph)2),75.
02(CHOH),70.
95(CH2-glycolchain),70.
66(CH2-glycolchain),70.
54(CH2-glycolchain),70.
33(CH2-glycolchain),69.
16(CH2-glycolchain),63.
43(CH2COO),33.
56(alk.
C),31.
44(alk.
C),29.
05(alk.
C),28.
26(alk.
C),23.
85(alk.
C),22.
21(alk.
C).
HRMS(FAB,3-NBA)forC30H40O10S2Na[M+Na]+:calcd.
:647.
1961found:647.
1932HPLC(C18):tR=7.
94min(E)-Benzo-8,8-bis-(phenylsulfonyl)-12-hydroxy-1,18-dioxacycloheneicosan-10-en-2,19-dion(69)ThesynthesisproceededaccordingtoGP10with21.
0mg(0.
011mmol)Pd-resin1a/Pdin1.
38mlabs.
THFand70.
0mg(0.
11mmol)substrate56in1.
38mlabs.
THF.
After20hat50oCtheconversionwasdeterminedbyHPLCtobe69%.
Afteranother12hat50oCconversionreached78%.
Thecrudeproductwastakenupinacetonitrileforthepurificationviaprep.
HPLC.
ThecorrespondingZ-Isomerwasnotobserved.
Yield:53.
0mg(0.
08mmol,40%)colorlessoil1H-NMR(400MHz,CDCl3):δ=8.
05-8.
03(m,4H,Haro-sulfonyl),7.
98(dd,J=7.
8Hz,1.
8Hz,1H,ar.
H),7.
73-7.
69(m,2H,Harp-sulfonyl),7.
60(t,J=7.
9Hz,4H,Harm-sulfonyl),7.
54(ddd,J=8.
0Hz,7.
4Hz,1.
8Hz,1H,H-4),7.
31(td,J=7.
6Hz,1.
2Hz,1H,ar.
H),7.
06(dd,J=8.
0Hz,1.
0Hz,1H,ar.
H),5.
94(dt,J=14.
9Hz,6.
9Hz,1H,R-CHOH-CH=CH-R'),5.
67(dd,J=15.
4Hz,6.
9Hz1H,R-CHOH-CH=CH-R'),4.
30-4.
26(m,2H,R-COO-CH2R'),3.
03(m,2H,R-CHOHR'),2.
59(t,J=7.
5Hz,2H,Rar-OOC-CH2R'),2.
16(m,2H,R-CH2CR'(O2S-Ph)2),1.
90(m,2H,alkyl-H),1.
70(m,6H,alkyl-H),1.
56(m,2H,alkyl-H),1.
35(m,6H,alkyl-H),13C-NMR(100MHz,CDCl3):δ=171.
6(Rar-OOCR'),165.
5(Rar-COOR'),149.
8(RR'C-OH),139.
6(R-CH=CHR'u.
R2CSO2R'),136.
7(Car),134.
6(Car),133.
6(Car),131.
9(Car),131.
2(Car),128.
6(Car),126.
0(Car),124.
3(Car),123.
5(Car),123.
1(R-CH=CH2),100.
0(R-C(SO2Ph)2),72.
5(RCHOHR'),65.
4(RarCOOCH2R'),36.
9(alkyl-C),33.
9(alkyl-C),32.
3(alkyl-C),30.
0(alkyl-C),29.
2(alkyl-C),28.
7(alkyl-C),25.
7(alkyl-C),24.
9(alkyl-C),24.
0(alkyl-C),23.
4(alkyl-C)HPLC(C18):tR=9.
67minHRMS(FAB,3-NBA)forC35H41O9S2[M+H]+:calcd.
:369.
2192found:369.
2152forC35H40O9S2Na[M+Na]+:cacld.
:391.
2011found:391.
1985ExperimentsrealatedtoSonogashira-reactionsGeneralprocedureforestersaponification(GP11)Toasolutionof1eq.
esterinMeOHareaddedtetrahydrofurane,H2Oand7eq.
NaOH.
Thereactionmixtureisheatedunderrefluxovernight.
Thesolventsareremovedinvaccuousingarotovap.
Theresidueisextractedwith100mlethylacetateand40mldest.
H2O.
Afterphaseseparationtheorganiclayerisdiscarded,theaqueouslayerissettopH1byadditionof5%HCl,andthenextractedwith3x150mlethylacetate.
ThecombinedorganiclayersaredriedoverNa2SO4andthenconcentratedinvaccuousingarotovap.
Generalprocedureforthemethylationofanω-aminoacid(GP12)Aflaskischargedwithabs.
MeOHandcooledinanicebathto0°C.
Overaperiodof30min2.
2eqthionylchlorideareslowlyaddedandstirredforfurther20min.
Then1eqacidareadded,andthereactionmixturestirredfor10minat0°Cand3hatRT.
Thesolventsareremovedinvaccuousingarotovapandtheresiduerecrystallizedfromethylacetate:cyclohexane:methanol.
Generalprocedureforcarbodiimide-mediatedamideformation(GP13)Toasolutionof1.
0eqacid,1.
0eqtriethylamineand1.
0eqalcoholinCH2Cl2areadded1.
0eqDICand1.
1eqHOBtat0°C.
ThereactionmixtureisstirredovernightatRTandthenwashedwithH2O(3x10ml),NaHCO3-solution(3x10ml)andbrine(3x10ml).
Thecrudeproductispurifiedviaflashchromatography.
Generalprocedureforacidchloride-mediatedamideformation(GP14)Toasolutionof1eqamineand1eqacidchlorideinDCMcooledto0°Careaddeddropwise1.
05eqtriethylamine.
ThereactionmixtureisstirredovernightatRT.
Thesolventsareremovedinvaccuousingarotovapandthecrudeproductispurifiedviaflashchromatography.
Generalprocedureforsulfonamideformation(GP15)Toasolutionof1.
0eqamineinCHCl3:N-methylmorpholine(5:1)areadded1.
1eqsulfonylchlorideatRT.
ThereactionmixtureisstirredovernightatRTandthenwashedwithH2O(1x10ml)andbrine(1x10ml).
Thecrudeproductispurifiedviaflashchromatography.
Generalprocedurefortheesterificationofisatoicanhydride(GP16)Inanovendriedflask1.
0eqisatoicanhydride,2.
0eqalcohol,1eqDMAPinabs.
DMFareheatedto60°Cfor24h.
AftercoolingtoRTthereactionmixtureiswashedwithH2O.
Theaqueouslayerisextracted3xwithethylacetate.
ThecombinedorganiclayersaredriedoverNa2SO4,thesolventsareremovedinvaccuousingarotovapandthecrudeproductispurifiedviaflashchromatography.
GeneralprocedureforintramolecularSonogashira-reactions(GP17)AninertSchlenkflaskischargedwithPd-beadsorPd[PPh3]4(0.
1eqPd).
After3vacuum/argoncyclesthebeadsareswollenindegasseddioxane:piperidine(2:1).
0.
1eqCuIareaddedandthereactionmixtureisheatedto60°C.
Thesubstrate,dissolvedindioxane:piperidine(2:1),isadded.
Thereactionisheatedat60°Covernight.
ThereactionismonitoredbyHPLC.
Aftercompleteconversion(15h)thereactionmixtureiscooledtoRT.
InreactionswithPd-beadsthebeadsarefilteredoff,washedwithDCM(1x45ml,10min),withDCM:MeOH1:1(2x20ml,2x10min)andwithDCM(1x20ml,10min).
DiecollectedfiltratesinthereactionwithPd-resinorthereactionmixtureinthereactionswithPd[PPh3]4arewashedwithbrine(1x20ml).
TheaqueouslayerisextractedwithDCM(3x30ml).
ThecombinedorganiclayersaredriedoverNa2SO4,thesolventsareremovedinvaccuousingarotovapandthecrudeproductispurifiedviaflashchromatographyorviaprep.
HPLC(C4).
OH+HOOC(CH2)11OHOO(CH2)11OHIHOOCOO(CH2)11OOIEDC,DMAPDCM90%EDC,DMAP,DCM46%167071HNCOOMeOHNCOOHOIIICOOHH2NCOOMeHOHNOOOIH2NCOOH3MeOH,SOCl2,3hquant.
DIC,HOBt,overnight333NaOH,refluxMeOH:H2O1:1,30min,quant.
m=3resp.
8mDIC,DMAP,CH2Cl2,overnight3m63-67%63-87%7475resp.
7677resp.
7879:o-andm=380:o-andm=881:p-andm=382:p-andm=812-Hydroxydodecanoicacid(16)ThesynthesisproceededaccordingtoGP11with9.
32gdodecanelactone(47.
0mmol),3.
8gNaOH(94.
0mmol)and120mlMeOH:THF:H2O(2.
5:2.
5:1)Yield:10.
16g(47.
0mmol,quant.
)colorlesscrystalsmp:83.
5°C1H-NMR(400MHz,CDCl3):δ=3.
54(t,J=6.
7Hz,2H,-CH2OH),2.
27(t,J=7.
4Hz,2H,-CH2COOH),1.
62-1.
51(m,4H,alk.
H),1.
38-1.
31(m,14H,alk.
H)Theanalyticaldataareinaccordancetoliterature.
vii12-(tert-Butyl-dimethyl-silanyloxy)-dodecanoicacid(17)Inadriedflaskareaddedtoasolutionof500.
0mg(1eq,2.
31mmol)12-hydroxydodecanoicacid(16)and236.
2mg(2eq,3.
47mmol)imidazolein5mlabs.
DMF348.
2mg(1.
5eq,2.
31mmol)TBDMSCl.
ThereactionmixtureisstirredatRTfor24handthenwashedwith5mlH2O.
TheaqueouslayerisextractedwithEt2O(3x5ml).
Thecombinedorganiclayersarewashedwith10%NaHCO3solution,driedoverNa2SO4.
Thesolventsareremovedinvaccuousingarotovap.
Thecrudeproductispurifiedviaflashchromatography.
Rf=0.
32(CH:EA3:1)Yield:379.
1mg(1.
15mmol,50%)colorlessoilGC-MS(DB_100):tR=6.
05min1H-NMR(400MHz,CDCl3):δ=3.
59(t,J=6.
6Hz,2H,-CH2O-),2.
33(t,J=7.
5Hz,2H,-CH2COOH),1.
64-1.
60(m,2H,alk.
H),1.
51-1.
48(m,2H,alk.
H),1.
34-1.
25(m,14H,alk.
H),0.
89(s,12H,-C(CH3)3),0.
04(s,6H,-Si(CH3)2)Theanalyticaldataareinaccordancetoliterature.
12-(tert-Butyl-dimethyl-silanyloxy)-dodecanoicacidhex-5-inyl-ester(18)ThesynthesisproceededaccordingtoGP9with100.
0mg(0.
30mmol)12-(tert-butyl-dimethyl-silanyloxy)-dodecanoicacid(17),26.
5mg(0.
27mmol)1-hexinol,57.
4mg(0.
30mmol)EDC,6.
7mg(0.
055mmol)DMAPand5mlDCM.
Thecrudeproductispurifiedviaflashchromatography(silica,CH:EA20:1).
Rf=0.
42(CH:EA20:1)Yield:92.
0mg(0.
22mmol,83%)colorlessoilGC-MS(DB_100):tR=6.
31min1H-NMR(400MHz,CDCl3):δ=4.
08(t,J=6.
4Hz,2H,-CH2OOC-),3.
59(t,J=6.
5Hz,2H,-CH2O-Si-),2.
28(t,J=7.
5Hz,2H,-CH2COO),2.
23(dt,J=7.
0Hz,2.
7Hz,2H,-CH2CCH),1.
95(t,J=2.
6Hz,1H,-CCH),1.
77-1.
71(m,2H,alk.
H),1.
64-1.
57(m,4H,alk.
H),1.
51-1.
48(m,2H,alk.
H),1.
31-1.
26(m,16H,alk.
H),0.
89(s,12H,-C(CH3)3),0.
04(s,6H,-Si(CH3)2)13C-NMR(100MHz,CDCl3):δ=173.
6(-COO),83.
80(-CCH),68.
69(-CCH),63.
67(-CH2OOC),63.
33(-CH2OSi),34.
42(-CH2COO),32.
97(alk.
C),29.
69(alk.
C),29.
62(alk.
C),29.
53(alk.
C),29.
53(alk.
C),29.
35(alk.
C),29.
25(alk.
C),27.
80(alk.
C),26.
09(alk.
C),25.
90(alk.
C),25.
06(alk.
C),18.
50(alk.
C),18.
19(alk.
C),-5.
073(-Si(CH3)2)12-Hydroxy-dodecanoicacidhex-5-inyl-ester(72)ThesynthesisproceededaccordingtoGP8with100.
0mg(0.
24mmol)12-(tert-butyl-dimethyl-silanyloxy)-dodecanoicacidhex-5-inyl-ester(18),103.
8mg(2.
80mmol)NH4Fand6mlmethanol.
Yield:80.
6mg(0.
27mmol,quant.
)colorlessoilGC-MS(DB_100):tR=5.
70min1H-NMR(400MHz,CDCl3):δ=4.
08(t,J=6.
4Hz,2H,-CH2OOC-),3.
63(t,J=6.
6Hz,2H,-CH2O-Si-),2.
28(t,J=7.
5Hz,2H,-CH2COO),2.
23(dt,J=7.
0Hz,2.
6Hz,2H,-CH2CCH),1.
96(t,J=2.
6Hz,1H,-CCH),1.
77-7.
73(m,2H,alk.
H),1.
63-1.
54(m,6H,alk.
H),1.
33-1.
17(m,16H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
7(-COO),83.
83(-CCH),68.
68(-CCH),63.
69(-CH2OOC),63.
06(-CH2OSi),34.
42(-CH2COO),32.
86(alk.
C),29.
63(alk.
C),29.
56(alk.
C),29.
49(alk.
C),29.
31(alk.
C),29.
22(alk.
C),27.
79(alk.
C),25.
82(alk.
C),25.
06(alk.
C),18.
19(alk.
C)12-(2-Iodbenzoyl)-dodecanoicacidhex-5-inyl-ester(19)ThesynthesisproceededaccordingtoGP9with296.
2mg(1.
0mmol)12-hydroxy-dodecanoicacidhex-5-inyl-ester(72),272.
8mg(1.
1mmol)2-iodobenzoicacid,210.
3mg(1.
1mmol)EDC,24.
4mg(0.
2mmol)DMAPand10mlDCM.
Thecrudeproductwaspurifiedviaflashchromatography(silica,CH:EA3:1).
Rf=0.
69(CH:EA3:1)Yield:438.
9mg(0.
83mmol,83%)colorlessoilHPLC(C4):tR=7.
92min1H-NMR(400MHz,CDCl3):δ=7.
98(dd,J=8.
0Hz,1.
0Hz,1H,ar.
H),7.
77(dd,J=7.
8Hz.
1.
8Hz,1H,ar.
H),7.
39(dt,J=7.
6Hz,1,2Hz,1H,ar.
H),7.
14(dt,J=7.
6Hz,1.
8Hz,1H,ar.
H),4.
33(t,J=6.
7Hz,2H,-CH2OOC-Ar),4.
09(t,J=6.
5,2H,CH2OOC-),2.
29(t,J=7.
7Hz,2H,-CH2COO),2.
23(dt,J=7.
0Hz,2.
7Hz,2H,-CH2CCH),1.
96(t,J=2.
6Hz,1H,-CCH),1.
79-1.
72(m,4H,alk.
H),1.
63-1.
58(m,4H,alk.
H),1.
46-1.
42(m,2H,alk.
H),1.
33-1.
25(m,12H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
6(-COO),166.
5(Ar-COO),141.
1(ar.
C),132.
3(2ar.
C),130.
6(ar.
C),127.
7(ar.
C),93.
85(Carom-I),83.
87(-CCH),68.
67(-CCH),65.
86(-CH2OOC-Ar),63.
67(-CH2OOC),34.
43(-CH2COO),29.
53(alk.
C),28.
68(alk.
C),27.
80(alk.
C),26.
15(alk.
C),25.
07(alk.
C),18.
21(alk.
C)HRMS(FAB,3-NBA)forC24H33NO3[M+H]+:calcd.
:527.
1658found:527.
1691forC24H33NO3Na[M+Na]+:calcd.
:549.
1478found:549.
149612-(4-Iodbenzoyl)-dodecanoicacidhex-5-inyl-ester(73)ThesynthesisproceededaccordingtoGP9with296.
2mg(1.
0mmol)12-hydroxy-dodecanoicacidhex-5-inyl-ester(72),272.
8mg(1.
1mmol)4-iodobenzoicacid,210.
3mg(1.
1mmol)EDC,24.
4mg(0.
2mmol)DMAPand10mlDCM.
Thecrudeproductwaspurifiedviaflashchromatography(silica,CH:EA3:1).
Rf=0.
79(CH:EA3:1)Yield:454.
1mg(0.
86mmol,86%)colorlessoilHPLC(C4):tR=8.
18min1H-NMR(400MHz,CDCl3):δ=7.
81-7.
78(m,2H,ar.
H),7.
75-7.
72(m,2H,ar.
H),4.
30(t,J=6.
6Hz,2H,-CH2OOC-Ar),4.
09(t,J=6.
4,2H,CH2OOC-),2.
29(t,J=7.
5Hz,2H,-CH2COO),2.
23(dt,J=7.
0Hz,2.
5Hz,2H,-CH2CCH),1.
96(t,J=2.
6Hz,1H,-CCH),1.
79-1.
72(m,4H,alk.
H),1.
64-1.
56(m,4H,alk.
H),1.
45-1.
38(m,2H,alk.
H),1.
36-1.
28(m,12H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
6(-COO),165.
9(Ar-COO),137.
5(ar.
C),130.
8(2ar.
C),129.
8(2ar.
C),100.
4(Carom-I),83.
84(-CCH),68.
69(-CCH),65.
41(-CH2OOC-Ar),63.
70(-CH2OOC),34.
44(-CH2COO),29.
59(alk.
C),29.
58(alk.
C),29.
52(alk.
C),29.
35(alk.
C),29.
26(alk.
C),28.
77(alk.
C),27.
83(alk.
C),26.
11(alk.
C),25.
10(alk.
C),25.
08(alk.
C),18.
22(alk.
C)HRMS(FAB,3-NBA)forC24H33NO3[M+H]+:calcd.
:527.
1658found:527.
1686forC24H33NO3Na[M+Na]+:calcd.
:549.
1478found:549.
14956-Aminohexanoicacidmethylester(74)ThesynthesisproceededaccordingtoGP12with15mlmethanol,2.
4(33.
4mmol)thionylchlorideand2.
0g(15.
2mmol)6-aminocaproicacid.
Yield:2.
50g(15.
2mmol,quant.
)colorlesscrystalsmp.
:120-121°C1H-NMR(400MHz,CDCl3):δ=8.
26(brs,2H,-NH2),3.
66(s,3H,-OMe),3.
02(m,2H,-CH2NH2),2.
33(t,J=6.
8Hz,2H,-CH2COO-),1.
81(m,2H,alk.
H),1.
66(t,J=6.
5Hz,2H,alk.
H),1.
45-1.
41(m,2H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
9(-COO),51.
60(-OMe),43.
13(-CH2NH2),33.
61(-CH2COO-undalk.
C),27.
23(alk.
C),25.
89(alk.
C),24.
16(alk.
C)Theanalyticaldataareinaccordancetoliterature.
viii6-(4-Iodobenzamido)-hexanoicacidmethylester(76)ThesynthesisproceededaccordingtoGP13with1.
19g(4.
8mmol)4-iodobenzoicacid,0.
7g(4.
8mmol)6-aminohexanoicacidmethylester(74),0.
67ml(4.
8mmol)triethylamine,0.
75ml(4.
8mmol)DICand809.
0mg(5.
3mmol)HOBt.
Thecrudeproductwaspurifiedviaflashchromatography(silica,CH:EA3:1).
Rf=0.
43(CH:EA3:1)Yield:1.
14g(3.
03mmol,63%)colorlesscrytals1H-NMR(400MHz,CDCl3):δ=7.
78-7.
76(m,2H,ar.
H),7.
50-7.
48(m,2H,ar.
H),6.
25(brs,1H,-NH-),3.
66(s,3H,-OMe),3.
44(dt,J=5.
9Hz,7.
1Hz,2H,-CH2-NHCO-),2.
33(t,J=7.
3Hz,2H,-CH2COO-),1.
71-1.
59(m,4H,alk.
H),1.
44-1.
38(m,2H,alk.
H)13C-NMR(100MHz,CDCl3):δ=174.
3(-COO-),166.
9(-CONH-),138.
0(2ar.
C),134.
4(Carom-CONH-),128.
7(2ar.
C),98.
46(Carom-I),51.
79(-OMe),39.
99(CH2-NHCO-),34.
00(CH2-COO-),29.
36(alk.
C),26.
55(alk.
C),24.
53(alk.
C)6-(2-Iodobenzamido)-hexanoicacidmethylester(75)ThesynthesisproceededaccordingtoGP13with1.
19g(4.
8mmol)2-iodobenzoicacid,0.
7g(4.
8mmol)6-aminohexanoicacidmethylester(74),0.
67ml(4.
8mmol)triethylamine,0.
75ml(4.
8mmol)DICand809.
0mg(5.
3mmol)HOBt.
Thecrudeproductwaspurifiedviaflashchromatography(silica,CH:EA3:1).
Rf=0.
36(CH:EA3:1)Yield:1.
20g(3.
20mmol,67%)colorlesssolid1H-NMR(400MHz,CDCl3):δ=7.
82-7.
79(m,1H,ar.
H),7.
33-7.
32(m,2H,ar.
H),7.
05(ddd,J=7.
9Hz,3.
9Hz,5.
3Hz,1H,ar.
H),6.
02(brs,1H,-NH),3.
63(s,3H,-OMe),3.
39(dt,J=6.
5Hz,6.
6Hz,2H,-CH2NHCO-),2.
30(t,J=7.
3Hz,2H,-CH2COO-),1.
68-1.
58(m,4H,alk.
H),1.
45-1.
39(m,2H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
9(-COO),169.
3(-CONH-),142.
4(-CaromCONH-),139.
7(ar.
C),130.
9(ar.
C),128.
1(ar.
C),128.
0(ar.
C),92.
37(Carom-I),51.
45(-OMe),39.
71(-CH2-NHCO-),33.
78(-CH2-COO-),28.
96(alk.
C),26.
39(alk.
C),24.
40(alk.
C)6-(4-Iodbenzenesulfonyl)-hexanoicacidmethylester(83)ThesynthesisproceededaccordingtoGP15with0.
70g(4.
8mmol)6-aminohexanoicacidmethylester(74)and1.
68g(5.
3mmol)pipsylchloridein19mlNMM:CHCl3-solution.
Thecrudeproductispurifiedviaflashchromatography(silica,CH:EA3:1).
Rf=0.
46(CH:EA3:1)Yield:1.
06g(2.
59mmol,54%)colorlesssolid1H-NMR(400MHz,CDCl3):δ=7.
87(d,J=8.
4Hz,2H,ar.
H),7.
57(d,J=8.
4Hz,2H,ar.
H),4.
56(brs,1H,-NH-),3.
66(s,3H,-OMe),2.
96-2.
95(m,2H,-CH2NHCO-),2.
27(t,J=7.
3Hz,2H,-CH2COO-),1.
57(dt,J=15.
3Hz,7.
6Hz,2H,alk.
H),1.
49(dt,J=14.
8Hz,7.
4Hz,2H,alk.
H),1.
34-1.
26(m,2H,alk.
H)13C-NMR(100MHz,CDCl3):δ=174.
2(-COO-),139.
9(-Car-CONH-),138.
6(2ar.
C),128.
7(2ar.
C),98.
70(-Car-I),51.
83(-OMe),43.
18(-CH2NHCO),33.
91(-CH2COO-),29.
45(alk.
C),26.
11(alk.
C),24.
35(alk.
C)6-(4-Iodbenzamido)-hexanoicacid(78)ThesynthesisproceededaccordingtoGP11with187.
5mg(0.
5mmol)6-(4-iodobenzamido)-hexanoicacidmethylester(76),146.
0mg(3.
6mmol)NaOHand10mlMeOH:H2O(1:1).
Yield:169.
9mg(0.
47mmol,95%)colorlesssolid1H-NMR(400MHz,CDCl3):δ=7.
67-7.
65(m,2H,ar.
H),7.
42-7.
40(m,2H,ar.
H),6.
25(brs,1H,-NH-),3.
28(t,J=7.
1Hz,2H,-CH2-NHCO-),2.
21(t,J=7.
3Hz,2H,-CH2-COO-),1.
58-1.
48(m,4H,alk.
H),1.
34-1.
28(m,2H,alk.
H)13C-NMR(100MHz,CDCl3):δ=176.
2(-COO-),167.
4(-CONH-),137.
4(2ar.
C),133.
7(-Car-CONH-),128.
5(ar.
C),128.
4(ar.
C),98.
00(-Car-I),39.
52(-CH2NHCO-),33.
59(-CH2COO-),28.
66(alk.
C),26.
10(alk.
C),24.
16(alk.
C)6-(2-Iodobenzamido)-hexanoicacid(77)ThesynthesisproceededaccordingtoGP11with1.
2g(3.
2mmol)6-(2-iodobenzamido)-hexanoicacidmethylester(75),897.
0mg(22.
4mmol)NaOHand60mlMeOH:H2O(1:1).
Yield:1.
14g(3.
16mmol,99%)colorlesssolid1H-NMR(400MHz,CDCl3):δ=7.
89-7.
87(m,1H,ar.
H),7.
43(dt,J=1.
2Hz,7.
5Hz,1H,ar.
H),7.
32(dd,J=1.
7Hz,7.
7Hz,1H,ar.
H),7.
17-7.
13(m,1H,ar.
H),4.
92(brs,1H,-NH-),3.
37-3.
33(m,2H,-CH2-NHCO-),2.
32(t,J=7.
3Hz,2H,-CH2COO-),1.
70-1.
62(m,4H,alk.
H),1.
52-1.
46(m,2H,alk.
H)13C-NMR(100MHz,CDCl3):δ=177.
5(-COO),172.
5(-CONH),144.
2(-Car-CONH-),140.
7(ar.
H),131.
9(ar.
H),129.
2(ar.
H),128.
8(ar.
C),93.
25(-Car-I),40.
66(-CH2NHCO-),34.
81(-CH2COO-),29.
84(alk.
C),27.
59(alk.
C),25.
69(alk.
C)6-(4-Iodobenzenesulfonyl)-hexanoicacid(84)ThesynthesisproceededaccordingtoGP11with1.
02g(2.
49mmol)6-(4-iodobenzenesulfonyl)-hexanoicacidmethylester(83),698.
0mg(17.
4mmol)NaOHand50mlMeOH:H2O(1:1).
Yield:925.
9mg(2.
33mmol,94%)colorlesssolid1H-NMR(400MHz,CDCl3):δ=7.
95-7.
93(m,2H,ar.
H),7.
59-7.
57(m,2H,ar.
H),2.
85(t,J=6.
9Hz,2H,-CH2-NHCO-),2.
24(t,J=7.
3Hz,2H,-CH2-COO-),1.
54(tt,J=7.
5Hz,7.
6Hz,2H,alk.
H),1.
46(tt,J=7.
0Hz,7.
5Hz,2H,alk.
H),1.
34-1.
28(m,2H,alk.
H)13C-NMR(100MHz,CDCl3):δ=177.
5(-COO),141.
8(-Car-SO2-),139.
6(2ar.
C),129.
5(2ar.
C),100.
2(-Car-I),43.
84(-CH2NHSO2-),34.
72(-CH2COO-),30.
31(alk.
C),27.
11(alk.
C),25.
52(alk.
C)2-Aminobenzoicacidhex-5-inyl-ester(87)ThesynthesisproceededaccordingtoGP16with507.
0mg(2.
5mmol)isatoicanhydride,500.
0mg(5.
0mmol)1-hexinol,305.
0mg(2.
5mmol)DMAPand20mlDMF.
Thecrudeproductwaspurifiedviaflashchromatography(silica,CH:EA3:1).
Rf=0.
66(CH:EA3:1)Yield:426.
3mg(1.
96mmol,70%)yellowishoil1H-NMR(400MHz,CDCl3):δ=7.
86(ddd.
J=8.
1Hz,1.
5Hz,0.
3Hz,1H,ar.
H),7.
27(ddd,J=8.
4Hz,6.
9Hz,1.
6Hz,1H,ar.
H),6.
68-6.
63(m,2H,ar.
H),5.
73(brs,2H,-NH2),4.
30(t,J=6.
5Hz,2H,-CH2OOC-),2.
28(dt,J=7.
0Hz,2.
7Hz,2H,-CH2CCH),1.
98(t,J=2.
6Hz,1H,-CCH),1.
93-1.
86(m,2H,alk.
H),1.
74-1.
68(m,2H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=169.
1(-COO),150.
3(-CarNH2),134.
0(ar.
C),131.
1(ar.
C),116.
7(ar.
C),116.
3(ar.
C),111.
0(-Car-COO),83.
88(-CCH),68.
74(-CCH),63.
75(-CH2OOC),27.
77(alk.
C),25.
06(alk.
C),18.
10(alk.
C)2-Aminobenzoicaicdundec-10-inyl-ester(88)ThesynthesisproceededaccordingtoGP16with1.
0g(5.
5mmol)isatoicanhydride,1.
85g(11.
0mmol)1-undecinol,672.
0mg(5.
5mmol)DMAPand40mlDMF.
Thecrudeproductwaspurifiedviaflashchromatography(silica,CH:EA3:1).
Rf=0.
57(CH:EA3:1)Yield:481.
2mg(1.
70mmol,30%)colorlessoil1H-NMR(400MHz,CDCl3):δ=7.
87(dd.
J=8.
0Hz,1.
0Hz,1H,ar.
H),7.
28-7.
24(m,1H,arom.
H),6.
68-6.
63(m,2H,ar.
H),5.
71(brs,2H,-NH2),4.
26(t,J=6.
6Hz,2H,-CH2OOC-),2.
18(dt,J=7.
1Hz,2.
6Hz,2H,-CH2CCH),1.
94(t,J=2.
6Hz,1H,-CCH),1.
75(tt,J=7.
2Hz,7.
0Hz,2H,alk.
H),1.
52(tt,J=7.
4Hz,7.
3Hz,2H,alk.
H),1.
45-1.
36(m,5H,alk.
H),1.
35-1.
31(m,5H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=168.
2(-COO),150.
2(-CarNH2),133.
9(ar.
C),131.
2(ar.
C),116.
7(ar.
C),116.
3(ar.
C),111.
2(-Car-COO),84.
73(-CCH),68.
06(-CCH),64.
44(-CH2OOC),29.
33(alk.
C),29.
18(alk.
C),28.
98(alk.
C),28.
69(alk.
C),28.
67(alk.
C),28.
42(alk.
C),26.
03(alk.
C),18.
36(alk.
C)6-(4-Iodobenzamido)-hexanoicacidhex-5-inyl-ester(81)ThesynthesisproceededaccordingtoGP9with216.
6mg(0.
6mmol)6-(4-iodobenzamido)-hexanoicacid(78),58.
9mg(0.
6mmol)1-hexinol,36.
7mg(0.
3mmol)DMAP,83.
1mg(0.
66mmol)DICand5mlDCM.
Thecrudeproductwaspurifiedviaprep.
HPLC.
Yield:222.
4mg(0.
50mmol,84%)colorlesssolidHPLC(C4):tR=7.
92min1H-NMR(400MHz,CDCl3):δ=7.
78(d,J=8.
6Hz,2H,ar.
H),7.
48(d,J=8.
6Hz,2H,ar.
H),6.
41(brs,1H,-NH-),4.
09(t,J=6.
5Hz,2H,-CH2-OOC-),3.
46(dt,J=6.
3Hz,6.
8Hz,2H,-CH2-NHCO-),2.
33(t,J=7.
3Hz,2H,-CH2-COO-),2.
23(dt,J=2.
6Hz,7.
0Hz,2H,-CH2CCH),1.
96(t,J=2.
7Hz,1H,-CCH),1.
79-1.
71(m,2H,alk.
H),1.
70-1.
55(m,6H,alk.
H),1.
45-1.
37(m,2H,alk.
H)13C-NMR(100MHz,CDCl3):δ=174.
1(-COO),169.
1(-CONH),138.
1(2ar.
C),134.
3(Car-CONH),128.
8(2ar.
C),98.
94(-Car-I),84.
05(-CCH),69.
00(-CCH),64.
20(-CH2-OOC-),40.
23(-CH2NHCO),34.
18(-CH2COO),29.
12(alk.
C),27.
87(alk.
C),26.
46(alk.
C),25.
15(alk.
C),24.
42(alk.
C),18.
29(alk.
C)HRMS(FAB,3-NBA)forC19H25INO3[M+H]+:calcd.
:442.
0879found:442.
0867forC19H24INO3Na[M+Na]+:calcd.
:464.
0699found:464.
06956-(2-Iodobenzamido)-hexanoicacidhex-5-inyl-ester(79)ThesynthesisproceededaccordingtoGP9with216.
6mg(0.
6mmol)6-(2-iodebenzamido)-hexanoicacid(77),58.
9mg(0.
6mmol)1-hexinol,36.
7mg(0.
3mmol)DMAP,83.
1mg(0.
66mmol)DICand5mlDCM.
Thecrudeproductwaspurifiedviaprep.
HPLC.
Yield:172.
2mg(0.
39mmol,65%)colorlesssolidHPLC(C4):tR=7.
62min1H-NMR(400MHz,CDCl3):δ=7.
82(d,J=7.
82Hz,1H,ar.
H),7.
34(d,J=4.
1Hz,2H,arom.
H),7.
06(dt,J=7.
9Hz,4.
6Hz,1H,ar.
H),5.
95(brs,1H,-NH-),4.
06(t,J=6.
5Hz,2H,-CH2OOC-),3.
42(dt,J=7.
4Hz,6.
2Hz,2H,-CH2NHCO),2.
30(t,J=7.
3Hz,2H,-CH2COO),2.
21(dt,J=2.
7Hz,7.
0Hz,2H,-CH2-CCH),1.
94(t,J=2.
6Hz,1H,-CCH),1.
77-1.
71(m,2H,alk.
H),1.
70-1.
62(m,4H,alk.
H),1.
61-1.
53(m,2H,alk.
H),1.
47-1.
39(m,2H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
6(-COO),169.
4(-CONH),142.
4(-Car-CONH),139.
7(ar.
C),130.
9(ar.
C),128.
1(ar.
C),128.
0(ar.
C),92.
37(-Car-I),83.
80(-CCH),68.
70(-CCH),63.
76(-CH2OOC),39.
75(-CH2NHCO),34.
03(-CH2COO),29.
00(alk.
C),27.
60(alk.
C),26.
42(alk.
C),24.
87(alk.
C),24.
44(alk.
C),18.
00(alk.
C)HRMS(FAB,3-NBA)forC19H25INO3[M+H]+:calcd.
:442.
0879found:442.
0856forC19H24INO3Na[M+Na]+:calcd.
:464.
0699found:464.
07196-(4-Iodobenzenesulfonyl)-hexanoicacidhex-5-inyl-ester(85)ThesynthesisproceededaccordingtoGP9with198.
5mg(0.
5mmol)6-(4-iodobenzenesulfonyl)-hexanoicacid(84),49.
8mg(0.
5mmol)1-hexinol,12.
2mg(0.
1mmol)DMAP,69.
4mg(0.
55mmol)DICand5mlDCM.
Thecrudeproductwaspurifiedviaprep.
HPLC.
Yield:158.
5mg(0.
33mmol,66%)colorlesssolidHPLC(C4):tR=9.
02min1H-NMR(400MHz,CDCl3):δ=7.
88-7.
86(m,2H,ar.
H),7.
58-7.
56(m,2H,ar.
H),4.
62(t,J=6.
1Hz,1H,-NH-),4.
08(t,J=6.
5Hz,2H,-CH2OOC-),2.
95(dt,J=6.
6Hz,6.
5Hz,2H,-CH2NHCO-),2.
26(t,J=7.
2Hz,2H,-CH2COO),2.
23(dt,J=2.
7Hz,6.
9Hz,2H,-CH2CCH),1.
96(t,J=2.
6Hz,1H,-CCH),1.
78-1.
71(m,2H,alk.
H),1.
62-1.
55(m,4H,alk.
H),1.
49(tt,J=7.
6Hz,7.
3Hz,2H,alk.
H),1.
34-1.
28(m,2H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
5(-COO),139.
7(-Car-SO2),138.
3(2ar.
C),128.
4(2ar.
C),99.
88(-Car-I),83.
85(-CCH),68.
75(-CCH),63.
86(-CH2OOC),42.
93(-CH2NHSO2),33.
88(-CH2COO),29.
21(alk.
C),27.
64(alk.
C),25.
88(alk.
C),24.
91(alk.
C),24.
13(alk.
C),18.
05(alk.
C)2-Iodobenzoylamido-benzoicacidhex-5-inyl-ester(89)ThesynthesisproceededaccordingtoGP14with193.
2mg(0.
89mmol)2-aminobenzoicacidhex-5-inyl-ester(87),244.
4mg(0.
89mmol)2-iodobenzoylchloride,90.
0mg(0.
93mmol)triethylamineand1.
5mlDCM.
Thecrudeproductwaspurifiedviaflashchromatography(silica,CH:EA3:1).
Rf=0.
46(CH:EA3:1)Yield:354.
2mg(0.
79mmol,89%),yellowishoilHPLC(C4):tR=9.
41min1H-NMR(400MHz,CDCl3):δ=11.
40(brs,1H,-NH-),8.
89(d,J=8.
6Hz,1H,ar.
H),8.
08(dd,J=8.
0Hz,1.
4Hz,1H,ar.
H),7.
94(dd,J=7.
8Hz,1.
0Hz,1H,ar.
H),7.
62(ddd,J=8.
6Hz,7.
3Hz,1.
4Hz,1H,ar.
H),7.
56(dd,J=7.
6Hz,1.
6Hz,1H,ar.
H),7.
45(dt,J=7.
5Hz,1.
2Hz,1H,ar.
H),7.
15(dddd,J=7.
9,Hz,7.
5Hz,4.
2Hz,1.
3Hz,2H,ar.
H),4.
32(t,J=6.
5Hz,2H,-CH2OOC-),2.
27(dt,J=7.
0Hz,2.
6Hz,2H,-CH2CCH),1.
97(t,J=2.
6Hz,1H,-CCH),1.
90(tt,J=7.
7Hz,6.
6Hz,2H,alk.
H),1.
71-1.
66(m,4H,alk.
H)13C-NMR(100MHz,CDCl3):δ=168.
1(-COO),167.
6(-CONH),142.
0(-CaromCONH-),141.
2(-CarNHCO),140.
4(ar.
C),134.
7(ar.
C),131.
4(ar.
C),130.
8(ar.
C),128.
3(ar.
C),128.
0(ar.
C),123.
1(ar.
C),120.
6(ar.
C),115.
6(-CarCOO),92.
69(-Car-I),83.
62(-CCH),68.
92(-CCH),64.
94(-CH2OOC),27.
53(alk.
C),24.
92(alk.
C),18.
05(alk.
C)4-Iodobenzoylamido-benzoicacidhex-5-inyl-ester(91)ThesynthesisproceededaccordingtoGP14with325.
6mg(1.
50mmol)2-aminobenzoicacidhex-5-inyl-ester(87),407.
9mg(1.
50mmol)4-iodobenzoylchloride,159.
4mg(1.
57mmol)triethylamineand2.
5mlDCM.
Thecrudeproductwaspurifiedviaflashchromatography(silica,CH:EA3:1).
Rf=0.
42(CH:EA3:1)Yield:356.
2mg(0.
80mmol,53%),colorlesssolidHPLC(C4):tR=9.
21min1H-NMR(400MHz,CDCl3):δ=12.
09(brs,1H,-NH-),8.
89(d,J=8.
4Hz,1H,ar.
H),8.
09(d,J=8.
0Hz,1H,ar.
H),7.
87(d,J=8.
2Hz,1H,ar.
H),7.
79-7.
75(m,3H,ar.
H),7.
61(t,J=8.
1Hz,1H,ar.
H),7.
14(t,J=7.
9,Hz,1H,ar.
H),4.
39(t,J=6.
4Hz,2H,-CH2OOC-),2.
30(dt,J=6.
9Hz,2.
6Hz,2H,-CH2CCH),1.
99(t,J=2.
6Hz,1H,-CCH),1.
75-1.
68(m,4H,alk.
H)13C-NMR(100MHz,CDCl3):δ=168.
6(-COO),164.
9(-CONH),141.
7(-CaromNHCO),138.
0(ar.
C),137.
7(ar.
C),134.
8(ar.
C),134.
3(ar.
C),131.
0(ar.
C),130.
9(ar.
C),128.
9(ar.
C),122.
8(ar.
C),120.
4(ar.
C),115.
3(-CarCOO),99.
19(-Car-I),83.
64(-CCH),68.
95(-CCH),65.
06(-CH2OOC),27.
57(alk.
C),24.
95(alk.
C),18.
08(alk.
C)6-(4-Iodobenzamido)-hexanoicacidundec-10-inyl-ester(82)ThesynthesisproceededaccordingtoGP9with216.
6mg(0.
6mmol)6-(4-iodobenzamido)-hexanoicacid(78),100.
9mg(0.
6mmol)1-undecinol,36.
7mg(0.
3mmol)DMAP,83.
1mg(0.
66mmol)DICand5mlDCM.
Thecrudeproductwaspurifiedviaprep.
HPLC.
Yield:192.
2mg(0.
38mmol,63%)colorlesssolidHPLC(C4):tR=9.
17min1H-NMR(400MHz,CDCl3):δ=7.
76(d,J=8.
4Hz,2H,ar.
H),7.
49(d,J=8.
4Hz,2H,ar.
H),6.
27(brs,1H,-NH-),4.
04(t,J=6.
7Hz,2H,-CH2OOC-),3.
44(dt,J=4.
7Hz,11.
7Hz,2H,-CH2NHCO-),2.
31(t,J=7.
3Hz,2H,-CH2COO),2.
17(dt,J=2.
5Hz,6.
9Hz,2H,-CH2CCH),1.
93(t,J=2.
63,1H,-CCH),1.
70-1.
58(m,6H,alk.
H),1.
56-1.
48(m,2H,alk.
H),1.
44-1.
37(m,4H,alk.
H),1.
33-1.
25(m,8H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
7(-COO),166.
7(-CONH),137.
7(2ar.
C),134.
1(-CarCONH-),128.
5(2ar.
C),98.
20(-Car-I),84.
72(-CCH),68.
07(-CCH),64.
52–CH2OOC),39.
74(-CH2NHCO),34.
02(-CH2COO),29.
31(alk.
C),29.
14(alk.
C),29.
07(alk.
C),28.
97(alk.
C),28.
66(alk.
C),28.
58(alk.
C),28.
42(alk.
C),26.
29(alk.
C),25.
86(alk.
C),24.
29(alk.
C),18.
36(alk.
C)HRMS(FAB,3-NBA)forC24H35INO3[M+H]+:calcd.
:512.
1662found:512.
16906-(2-Iodobenzamido)-hexanoicacidundec-10-inyl-ester(80)ThesynthesisproceededaccordingtoGP9with216.
6mg(0.
6mmol)6-(2-iodobenzamido)-hexanoicacid(77),100.
9mg(0.
6mmol)1-undecinol,36.
7mg(0.
3mmol)DMAP,83.
1mg(0.
66mmol)DICand5mlDCM.
Thecrudeproductwaspurifiedviaprep.
HPLC.
Yield:268.
1mg(0.
52mmol,87%)colorlesssolidHPLC(C4):tR=8.
95min1H-NMR(400MHz,CDCl3):δ=7.
85(d,J=7.
8Hz,1H,ar.
H),7.
38-7.
36(m,2H,ar.
H),7.
10(ddd,J=8.
0Hz,3.
8Hz,5.
4Hz,1H,ar.
H),6.
00(brs,1H,-NH-),4.
04(t,J=6.
7Hz,2H,-CH2OOC-),3.
46(dt,J=6.
2Hz,6.
8Hz,2H,-CH2NHCO),2.
32(t,J=7.
3Hz,2H,-CH2COO-),2.
17(dt,J=2.
4Hz,7.
0Hz,2H,-CH2CCH),1.
93(t,J=2.
6,1H,-CCH),1.
72-1.
63(m,4H,alk.
H),1.
62-1.
57(m,2H,alk.
H),1.
55-1.
50(m,2H,alk.
H),1.
48-1.
40(m,2H,alk.
H),1.
39-1.
34(m,2H,alk.
H),1.
30-1.
27(m,8H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
8(-COO),170.
1(-CONH-),141.
8(ar.
H),139.
8(ar.
H),131.
2(ar.
H),128.
3(ar.
H),128.
2(ar.
H),92.
28(-Car-I),84.
72(-CCH),68.
07(-CCH),64.
60(-CH2OOC),40.
03(-CH2NHCO),34.
10(-CH2COO),29.
31(alk.
C),29.
13(alk.
C),28.
97(alk.
C),28.
89(alk.
C),28.
66(alk.
C),28.
57(alk.
C),28.
42(alk.
C),26.
42(alk.
C),25.
85(alk.
C),24.
44(alk.
C),18.
35(alk.
C)HRMS(FAB,3-NBA)forC24H35INO3[M+H]+:calcd.
:512.
1662found:512.
1647forC24H34INO3Na[M+Na]+:calcd.
:534.
1481found:534.
15086-(4-Iodobenzenesulfonyl)-hexanoicacidundec-10-inyl-ester(86)ThesynthesisproceededaccordingtoGP9with198.
5mg(0.
5mmol)6-(4-iodobenzenesulfonyl)-hexanoicacid(84),84.
1mg(0.
5mmol)1-undecinol,12.
2mg(0.
1mmol)DMAP,69.
4mg(0.
55mmol)DICand5mlDCM.
Thecrudeproductwaspurifiedviaprep.
HPLC.
Yield:144.
3mg(0.
26mmol,53%)colorlesssolidHPLC(C4):tR=10.
18min1H-NMR(400MHz,CDCl3):δ=7.
88-7.
86(m,2H,ar.
H),7.
58-7.
56(m,2H,ar.
H),4.
54(t,J=6.
2Hz,1H,-NH-),4.
04(t,J=6.
8Hz,2H,-CH2OOC),2.
95(dt,J=6.
7Hz,6.
6Hz,2H,-CH2NHCO),2.
26(t,J=7.
3Hz,2H,-CH2COO),2.
18(dt,J=2.
7Hz,7.
1Hz,2H,-CH2CCH),1.
94(t,J=2.
6Hz,1H,-CCH),1.
60-1.
47(m,8H,alk.
H),1.
42-1.
37(m,2H,alk.
H),1.
34-1.
29(m,10H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
6(-COO),139.
7(-Car-SO2),138.
3(2ar.
C),128.
5(2arom.
C),99.
89(-Car-I),84.
74(-CCH),68.
09(-CCH),64.
56(-CH2OOC),42.
94(-CH2NHSO2),33.
92(-CH2COO),29.
32(alk.
C),29.
22(alk.
C),29.
14(alk.
C),28.
97(alk.
C),28.
67(alk.
C),28.
58(alk.
C),28.
43(alk.
C),25.
89(alk.
C),25.
86(alk.
C),24.
14(alk.
C),18.
37(alk.
C)2-Iodobenzoylamido-benzoicacidundec-10-inyl-ester(90)ThesynthesisproceededaccordingtoGP14with225.
7mg(0.
79mmol)2-aminobenzoicacidundec-10-inyl-ester(88),215.
9mg(0.
79mmol)2-iodebenzoylchloride,83.
0mg(0.
82mmol)triethylamineand1.
5mlDCM.
Thecrudeproductwaspurifiedviaflashchromatography(silica,CH:EA3:1).
Rf=0.
44(CH:EA3:1)Yield:340.
2mg(0.
66mmol,84%)yellowishoilHPLC(C4):tR=10.
25min1H-NMR(400MHz,CDCl3):δ=11.
43(brs,1H,-NH-),8.
89(d,J=8.
0Hz,1H,ar.
H),8.
08(dd,J=8.
0Hz,1.
6Hz,1H,ar.
H),7.
94(dd,J=8.
0Hz,1.
0Hz,1H,ar.
H),7.
62(ddd,J=8.
6Hz,7.
3Hz,1.
4Hz,1H,ar.
H),7.
56(dd,J=7.
6Hz,1.
6Hz,1H,ar.
H),7.
44(dt,J=7.
5Hz,1.
1Hz,1H,ar.
H),7.
15(dddd,J=7.
8,Hz,7.
6Hz,5.
9Hz,1.
3Hz,2H,ar.
H),4.
28(t,J=6.
6Hz,2H,-CH2OOC-),2.
17(dt,J=7.
1Hz,2.
6Hz,2H,-CH2CCH),1.
93(t,J=2.
6Hz,1H,-CCH),1.
75(tt,J=7.
3Hz,6.
9Hz,2H,alk.
H),1.
51(tt,J=7.
6Hz,7.
0Hz,2H,alk.
H),1.
41-1.
37(m,4H,alk.
H),1.
35-1.
30(m,6H,alk.
H)13C-NMR(100MHz,CDCl3):δ=168.
2(-COO),167.
6(-CONH),142.
0(-CarCONH-),141.
2(-CaromNHCO),140.
4(ar.
C),134.
6(ar.
C),131.
4(ar.
C),130.
8(ar.
C),128.
3(ar.
C),128.
0(ar.
C),123.
0(ar.
C),120.
6(ar.
C),115.
7(-CarCOO),92.
69(-Car-I),84.
65(-CCH),68.
09(-CCH),65.
59(-CH2OOC),29.
10(alk.
C),28.
94(alk.
C),28.
63(alk.
C),28.
62(alk.
C),28.
45(alk.
C),28.
68(alk.
C),25.
92(alk.
C),18.
33(alk.
C)4-Iodobenzoylamido-benzoesure-undec-10-inyl-ester(92)ThesynthesisproceededaccordingtoGP14with200.
0mg(0.
70mmol)2-aminobenzoicacidundec-10-inyl-ester(88),189.
2mg(0.
70mmol)4-iodobenzoylchloride,73.
9mg(0.
73mmol)triethylamineand1.
2mlDCM.
Thecrudeproductwaspurifiedviaflashchromatography(silica,CH:EA3:1).
Rf=0.
42(CH:EA3:1)Yield:208.
2mg(0.
40mmol,58%)colorlessoilHPLC(C4):tR=10.
35min1H-NMR(400MHz,CDCl3):δ=12.
11(brs,1H,-NH-),8.
89(d,J=8.
6Hz,1H,ar.
H),8.
08(d,J=8.
0Hz,1H,ar.
H),7.
88-7.
86(m,2H,ar.
H),7.
77-7.
75(m,2H,ar.
H),7.
62-7.
58(m,1H,ar.
H),7.
16-7.
12(m,1H,ar.
H),4.
35(t,J=6.
6Hz,2H,-CH2OOC-),2.
20-2.
16(m,2H,-CH2CCH),1.
94(t,J=2.
6Hz,1H,-CCH),1.
81-1.
76(m,2H,alk.
H),1.
54-1.
49(m,2H,alk.
H),1.
45-1.
33(m,10H,alk.
H)13C-NMR(100MHz,CDCl3):δ=168.
7(-COO),164.
9(-CONH),141.
6(-CarNHCO),138.
0(2ar.
C),134.
7(ar.
C),134.
4(ar.
C),130.
9(2ar.
C),128.
9(ar.
C),122.
8(ar.
C),120.
4(ar.
C),115.
4(-CarCOO),99.
15(-Carom-I),84.
69(-CCH),68.
10(-CCH),65.
72(-CH2OOC),29.
32(alk.
C),29.
15(alk.
C),28.
98(alk.
C),28.
66(alk.
C),28.
52(alk.
C),28.
42(alk.
C),25.
97(alk.
C),18.
37(alk.
C)10-Oxa-3-aza-bicyclo[20.
2.
2]hexacosa-1(25),22(26),23-trien-20-in-2,9-dione(25)ThesynthesisproceededaccordingtoGP17with40.
0mg(0.
078mmol)6-(4-iodebenzamido)-hexanoicacidundec-10-inyl-ester(82),15.
0mg(0.
0078mmol)Pd-resin1a/Pdor9.
0mg(0.
0078mmol)Pd[PPh3]4,1.
5mg(0.
0078mmol)CuIin1.
95mldioxane:piperidine(2:1).
Thecrudeproductwaspurifiedviaflashchromatography(silica,CH:EA1:1).
Rf=0.
54(CH:EA1:1)Yield:3.
9mg(beads)(0.
0101mmol,13%)yellowishoil2.
6mg(homogenous)(0.
00678mmol,9%)yellowishoilHPLC(C4):tR=8.
68min1H-NMR(400MHz,CDCl3):δ=7.
82(d,J=8.
6Hz,2H,ar.
H),7.
41(d,J=8.
6Hz,2H,ar.
H),6.
99(brs,1H,-NH-),4.
00-3.
96(m,2H,-CH2OOC-),3.
60(dt,J=5.
9Hz,11.
7Hz,2H,-CH2NHCO-),2.
46-2.
43(m,2H,-CH2COO),2.
37-2.
32(m,2H,-CH2CCH),1.
67-1.
56(m,6H,alk.
H),1.
50-1.
45(m,2H,alk.
H),1.
43-1.
35(m,6H,alk.
H),1.
31-1.
25(m,6H,alk.
H)13C-NMR(100MHz,CDCl3):δ=174.
6(-COO),166.
9(-CONH),137.
7(ar.
C),133.
6(-CaromCONH-),131.
2(ar.
C),128.
5(ar.
C),127.
1(2ar.
C),93.
46(-CCH),81.
30(-CCH),65.
19(–CH2OOC),37.
24(-CH2NHCO),33.
10(-CH2COO),29.
18(alk.
C),28.
98(alk.
C),28.
64(alk.
C),27.
86(alk.
C),27.
24(alk.
C),27.
07(alk.
C),26.
81(alk.
C),25.
92(alk.
C),24.
63(alk.
C),21.
40(alk.
C),19.
10(alk.
C)HRMS(FAB,3-NBA)forC24H34NO3[M+H]+:calcd.
:384.
2539found:384.
2529forC24H33NO3Na[M+Na]+:calcd.
:406.
2358found:406.
2367Benzo-2-aza-9-oxacyclodocosan-19-in-1,8-dione(23)ThesynthesisproceededaccordingtoGP17with40.
0mg(0.
078mmol)6-(2-iodobenzamido)-hexanoicacidundec-10-inyl-ester(80),15.
0mg(0.
0078mmol)Pd-resin1a/Pdor9.
0mg(0.
0078mmol)Pd[PPh3]4,1.
5mg(0.
0078mmol)CuIin1.
95mldioxane:piperidine(2:1).
Thecrudeproductwaspurifiedviaflashchromatography(silica,CH:EA1:1).
Rf=0.
52(CH:EA1:1)Yield:8.
0mg(beads)(0.
0209mmol,27%)yellowishoil8.
7mg(homogeneous)(0.
0227mmol,29%)yellowishoilHPLC(C4):tR=8.
54min1H-NMR(400MHz,CDCl3):δ=8.
06-8.
04(m,ar.
H),7.
60(brs,1H,-NH-),7.
38-7.
36(m,2H,arom.
H),4.
14(t,J=5.
7Hz,2H,-CH2OOC-),3.
45(dt,J=9.
8Hz,5.
7Hz,2H,-CH2NHCO),2.
46(t,J=7.
6Hz,2H,-CH2COO-),2.
35(dt,J=2.
4Hz,7.
3Hz,2H,-CH2CCH),1.
73-1.
63(m,10H,alk.
H),1.
48-1.
25(m,10H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
4(-COO),166.
2(-CONH-),135.
2(ar.
H),133.
5(ar.
H),130.
3(ar.
H),130.
0(ar.
H),128.
2(ar.
H),120.
0(ar.
C),97.
26(-CC-Car),79.
46(-CC-Car),63.
77(-CH2OOC),40.
05(-CH2NHCO),34.
96(-CH2COO),29.
76(alk.
C),28.
84(alk.
C),28.
79(alk.
C),28.
50(alk.
C),28.
13(alk.
C),28.
07(alk.
C),27.
93(alk.
C),26.
75(alk.
C),25.
53(alk.
C),25.
10(alk.
C),19.
62(alk.
C)HRMS(FAB,3-NBA)forC24H34NO3[M+H]+:calcd.
:384.
2539found:384.
25742,2-Dioxo-10-oxa-2λ6-thia-3-aza-bicyclo[15.
2.
2]heneicosa-1(20),17(21),18-trien-15-in-9-one(26)ThesynthesisproceededaccordingtoGP17with30.
0mg(0.
063mmol)6-(4-iodobenzenesulfonyl)-hexanoicacidhex-5-inyl-ester(85),12.
1mg(0.
0063mmol)Pd-resin1a/Pdor7.
3mg(0.
0063mmol)Pd[PPh3]4,1.
2mg(0.
0063mmol)CuIin1.
57mldioxane:piperidine(2:1).
Thecrudeproductwaspurifiedviaflashchromatography(silica,CH:EA1:1).
Rf=0.
32Yield:2.
6mg(beads)(0.
0074mmol,12%)yellowishoil1.
4mg(homogeneous)(0.
0040mmol,6%)yellowishoilHPLC(C4):tR=6.
80min1H-NMR(400MHz,CDCl3):δ=7.
83-7.
81(m,2H,ar.
H),7.
51-7.
48(m,2H,ar.
H),4.
19(t,J=5.
4Hz,2H,-CH2OOC-),3.
08(dt,J=6.
0Hz,5.
7Hz,2H,-CH2NHCO-),2.
44(t,J=5.
4Hz,2H,-CH2COO),2.
23(dt,J=2.
7Hz,6.
9Hz,2H,-CH2CCH),1.
84-1.
79(m,10H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
3(-COO),138.
9(-Car-SO2),132.
0(2ar.
C),128.
7(2ar.
C),127.
2(ar.
C),95.
37(-CC-Car),80.
12(-CC-Car),63.
12(-CH2OOC),41.
89(-CH2NHSO2),33.
25(-CH2COO),28.
81(alk.
C),27.
89(alk.
C),26.
91(alk.
C),24.
76(alk.
C),23.
42(alk.
C),18.
97(alk.
C)HRMS(FAB,3-NBA)forC18H24NO4S[M+H]+:calcd.
:350.
1426found:350.
14258,9,10,11,12,13,14,15-Octahydro-7H,23H-6-oxa-23-aza-dibenzocyclononadecen-16-in-5,22-dione(29)ThesynthesisproceededaccordingtoGP17with40.
0mg(0.
077mmol)2-iodobenzoylamido-benzoicacidundec-10-inyl-ester(90),14.
8mg(0.
0077mmol)Pd-resin1a/Pdor8.
9mg(0.
0077mmol)Pd[PPh3]4,1.
7mg(0.
0077mmol)CuIin2.
20mldioxane:piperidine(2:1).
Thecrudeproductwaspurifiedviaprep.
HPLC.
Yield:9.
8mg(beads)(0.
0251mmol,33%)yellowishoil10.
5mg(homogeneous)(0.
0269mmol,35%)yellowishoilHPLC(C4):tR=9.
65min1H-NMR(400MHz,CDCl3):δ=11.
61(brs,1H,-NH-),8.
85(dd,J=8.
4Hz,1.
1Hz,1H,ar.
H),8.
11(dd,J=7.
9Hz,1.
7Hz,1H,ar.
H),7.
68(dd,J=7.
0Hz,2.
2Hz,1H,ar.
H),7.
61(ddd,J=8.
5Hz,7.
3Hz,1.
4Hz,1H,ar.
H),7.
50(dd,J=6.
8Hz,1.
7Hz,1H,ar.
H),7.
37(quind,J=7.
5Hz,1.
7Hz,2H,ar.
H),7.
14(ddd,J=8.
1,Hz,7.
3Hz,1.
1Hz,2H,ar.
H),4.
41(t,J=5.
7Hz,2H,-CH2OOC-),2.
28(t,J=7.
1Hz,2H,-CH2CCH),1.
81(tt,J=6.
2Hz,6.
0Hz,2H,alk.
H),1.
48(tt,J=7.
0Hz,6.
7Hz,2H,alk.
H),1.
40-1.
32(m,4H,alk.
H),1.
31-1.
24(m,6H,alk.
H)13C-NMR(100MHz,CDCl3):δ=167.
7(-COO),167.
3(-CONH),141.
4(-CarCONH-),139.
1(-CarNHCO),134.
5(ar.
C),133.
1(ar.
C),130.
8(ar.
C),130.
1(ar.
C),128.
6(ar.
C),127.
8(ar.
C),122.
8(ar.
C),121.
0(ar.
C),115.
7(-CarCOO),96.
26(-CC-Car),77.
95(-CC-Car),64.
51(-CH2OOC),28.
11(alk.
C),27.
95(alk.
C),27.
50(alk.
C),27.
36(alk.
C),26.
91(alk.
C),26.
56(alk.
C),23.
60(alk.
C),18.
33(alk.
C)HRMS(FAB,3-NBA)forC25H28NO3[M+H]+:calcd.
:390.
2069found:390.
208411-Oxa-3-aza-tricyclo[21.
2.
2.
04,9]heptacosa-1(26),4,6,8,23(27),24-hexaen-21-in-2,10-dione(30)ThesynthesisproceededaccordingtoGP17with30.
0mg(0.
058mmol)4-iodbenzoylamido-benzooicacidundec-10-inyl-ester(92),11.
2mg(0.
0058mmol)Pd-resin1a/Pdor6.
7mg(0.
0058mmol)Pd[PPh3]4,1.
1mg(0.
0058mmol)CuIin1.
45dioxane:piperidine(2:1).
Thecrudeproductwaspurifiedviaprep.
HPLC.
Yield:3.
2mg(beads)(0.
0082mmol,14%)yellowishoil3.
2mg(homogeneous)(0.
0082mmol,14%)yellowishoilHPLC(C4):tR=8.
87min1H-NMR(400MHz,CDCl3):δ=10.
15(brs,1H,-NH-),8.
60(dd,J=8.
4Hz,1.
0Hz,1H,ar.
H),8.
13(dd,J=8.
1Hz,1.
5Hz,1H,ar.
H),7.
72-7.
70(m,2H,ar.
H),7.
60(ddd,J=8.
4Hz,7.
1Hz,1.
5Hz,1H,ar.
H),7.
52-7.
50(m,2H,ar.
H),7.
19(ddd,J=8.
0Hz,7.
3Hz,0.
9Hz,1H,ar.
H),4.
25(t,J=8.
5Hz,2H,-CH2OOC-),2.
47(t,J=6.
2Hz,2H,-CH2CCH),1.
90-1.
85(m,2H,alk.
H),1.
62-1.
60(m,4H,alk.
H),1.
48-1.
35(m,8H,alk.
H)13C-NMR(100MHz,CDCl3):δ=167.
1(-COO),165.
7(-CONH),139.
0(-CarCONH-),135.
6(-CarNHCO),134.
6(ar.
C),134.
3(ar.
C),132.
8(ar.
C),131.
9(ar.
C),127.
9(ar.
C),127.
0(ar.
C),126.
9(ar.
C),123.
7(ar.
C),121.
0(ar.
C),117.
9(-CarCOO),95.
11(-CC-Car),77.
20(-CC-Car),66.
49(-CH2OOC),30.
08(alk.
C),29.
99(alk.
C),28.
25(alk.
C),27.
79(alk.
C),26.
91(alk.
C),26.
26(alk.
C),25.
78(alk.
C),18.
72(alk.
C)HRMS(FAB,3-NBA)forC25H27NO3[M]+:calcd.
:389.
1991found:389.
19943,16-Dioxa-bicyclo[21.
2.
2]heptacosa-1(26),23(27),24-trien-21-in-2,15-dione(21)ThesynthesisproceededaccordingtoGP17with50.
1mg(0.
095mmol)12-(4-iodobenzoyl)-dodecanoicacidhex-5-inyl-ester(73),18.
3mg(0.
0095mmol)Pd-resin1a/Pd,1.
8mg(0.
0095mmol)CuIin2.
40mldioxane:piperidine(2:1).
Thecrudeproductwaspurifiedviaprep.
HPLC.
Yield:9.
6mg(beads)(0.
024mmol,25%)yellowishoilHPLC(C4):tR=9.
16min1H-NMR(400MHz,CDCl3):δ=7.
90(d,8.
6Hz,2H,ar.
H),7.
37(d,8.
4Hz,2H,ar.
H),4.
30(t,J=5.
3Hz,2H,-CH2OOC-Ar),4.
13(t,J=6.
1Hz,2H,CH2OOC-),2.
44(t,J=6.
1Hz,2H,-CH2COO),2.
23(t,J=7.
5Hz,2H,CH2CC-Car),1.
87-1.
80(m,2H,alk.
H),1.
74-1.
62(m,4H,alk.
H),1.
57-1.
49(m,2H,alk.
H),1.
48-1.
47(m,2H,alk.
H),1.
36-1.
32(m,2H,alk.
H),1.
28-1.
22(m,4H,alk.
H),1.
19-1.
15(m,6H,alk.
H)13C-NMR(100MHz,CDCl3):δ=174.
1(-COO),166.
2(Ar-COO),131.
2(2ar.
C),129.
3(ar.
C),129.
2(2ar.
C),128.
6(ar.
C),93.
35(-CC-Car),81.
01(-CC-Car),65.
47(-CH2OOC-Ar),63.
73(-CH2OOC),34.
41(-CH2COO),30.
04(alk.
C),29.
15(alk.
C),29.
04(alk.
C),28.
46(alk.
C),27.
95(alk.
C),27.
56(alk.
C),27.
23(alk.
C),26.
78(alk.
C),25.
84(alk.
C),25.
34(alk.
C),24.
75(alk.
C),18.
92(alk.
C)HRMS(FAB,3-NBA)forC25H34O4[M]+:calcd.
:398.
2457found:398.
24528,9,10,11,12,13,14,15,16,17,20,21,22,23-Tetradecahydro-7H-6,19-dioxa-benzocyclotricosene-24-in-5,18-dione(20)ThesynthesisproceededaccordingtoGP17with50.
7mg(0.
095mmol)12-(2-iodobenzoyl)-dodecanoicacidhex-5-inyl-ester(19),18.
3mg(0.
0095mmol)Pd-resin1a/Pdor22.
0mg(0.
019mmol)Pd[PPh3]4,3.
6mg(0.
019mmol)CuIin2.
20mldioxane:piperidine(2:1).
Thecrudeproductwaspurifiedviaprep.
HPLC.
Yield:8.
3mg(beads)(0.
021mmol,22%)yellowishoil8.
3mg(homogeneous)(0.
021mmol,22%)yellowishoilHPLC(C4):8.
85min1H-NMR(400MHz,CDCl3):δ=7.
87(d,J=7.
8Hz,1H,ar.
H),7.
50(d,J=7.
8Hz,1H,ar.
H),7.
41(dt,J=7.
5Hz,1.
4Hz,1H,ar.
H),7.
32(dt,J=7.
6Hz,0.
9Hz,1H,ar.
H),4.
353(t,J=6.
5Hz,2H,-CH2OOC-Ar),4.
15(t,J=6.
1,2H,CH2OOC-),2.
51(t,J=6.
7Hz,2H,-CH2COO),2.
32(t,J=6.
9Hz,2H,-CH2CCH),1.
86-1.
70(m,6H,alk.
H),1.
69-1.
62(m,2H,alk.
H),1.
51-1.
43(m,2H,alk.
H),1.
35-1.
26(m,12H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
8(-COO),166.
9(Ar-COO),134.
0(ar.
C),132.
6(ar.
C),131.
1(ar.
C),130.
1(ar.
C),127.
2(ar.
C),123.
6(ar.
C),94.
44(-CC-Car),79.
80(-CC-Car),65.
40(-CH2OOC-Ar),63.
88(-CH2OOC),34.
47(-CH2COO),28.
85(alk.
C),28.
76(alk.
C),28.
60(alk.
C),28.
32(alk.
C),28.
29(alk.
C),28.
24(alk.
C),28.
23(alk.
C),27.
84(alk.
C),25.
88(alk.
C),25.
61(alk.
C),24.
76(alk.
C),19.
81(alk.
C)HRMS(FAB,3-NBA)forC25H35O4[M+H]+:calcd.
:399.
2535found:399.
2527forC25H34O4Na[M+Na]+:calcd.
:421.
2355found:421.
233210-Oxa-3-aza-bicyclo[15.
2.
2]heneicosa-1(20),17(21),18-trien-15-in-2,9-dione(22)ThesynthesisproceededaccordingtoGP17with40.
0mg(0.
091mmol)6-(4-iodobenzamido)-hexanoicacidhex-5-inyl-ester(79),17.
5mg(0.
0091mmol)Pd-resin1a/Pdor10.
5mg(0.
0091mmol)Pd[PPh3]4,1.
7mg(0.
0091mmol)CuIin2.
27mldioxane:piperidine(2:1).
Thecrudeproductwaspurifiedviaprep.
HPLC.
Yield:14.
2mg(beads)(0.
0453mmol,50%)yellowishoil11.
4mg(homogeneous)(0.
0364mmol,40%)yellowishoilHPLC(C4):tR=6.
52min1H-NMR(400MHz,CDCl3):δ=8.
09-8.
07(m,1H,ar.
H),7.
64(brs,1H,-NH-),7.
46-7.
44(m,1H,ar.
H),7.
38-7.
36(m,2Har.
H),4.
23(t,J=5.
6Hz,2H,-CH2OOC-),3.
50(t,J=6.
0Hz,2H,-CH2NHCO),2.
56(t,J=7.
1Hz,2H,-CH2COO),2.
40-2.
37(m,2H,-CH2-CCH),1.
84-1.
71(m,6H,alk.
H),1.
68-1.
61(m,2H,alk.
H),1.
52-1.
46(m,2H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
6(-COO),166.
1(-CONH),134.
8(ar.
C),133.
8(ar.
C),130.
3(ar.
C),130.
1(ar.
C),128.
2(ar.
C),119.
9(ar.
C),96.
59(-CC-Car),79.
93(-CC-Car),63.
11(-CH2OOC),40.
44(-CH2NHCO),34.
36(-CH2COO),28.
89(alk.
C),27.
90(alk.
C),27.
14(alk.
C),25.
55(alk.
C),24.
16(alk.
C),19.
30(alk.
C)HRMS(FAB,3-NBA)forC19H24NO3[M+H]+:calcd.
:314.
1756found:314.
17702,2-Dioxo-10-oxa-2λ6-thia-3-aza-bicyclo[20.
2.
2]hexacosa-1(25),22(26),23-trien-20-in-9-one(26)ThesynthesisproceededaccordingtoGP17with30.
0mg(0.
055mmol)6-(4-iodobenzenesulfonyl)-hexanoicacidundec-10-inyl-ester(85),10.
5mg(0.
0055mmol)Pd-resin1a/Pdor6.
3mg(0.
0055mmol)Pd[PPh3]4,1.
0mg(0.
0055mmol)CuIin1.
37mldioxane:piperidine(2:1).
Thecrudeproductwaspurifiedviaprep.
HPLC.
Yield:2.
6mg(beads)(0.
0074mmol,12%)yellowishoil1.
4mg(homogeneous)(0.
0040mmol,6%)yellowishoilHPLC(C4):tR=8.
49min1H-NMR(400MHz,CDCl3):δ=7.
80-7.
78(m,2H,ar.
H),7.
51-7.
49(m,2H,ar.
H),4.
39(t,J=6.
2Hz,1H,-NH-),4.
03(t,J=6.
9Hz,2H,-CH2OOC-),2.
98(dt,J=7.
0Hz,6.
2Hz,2H,-CH2NHCO-),2.
47(t,J=6.
3Hz,2H,-CH2COO),2.
17(t,J=7.
1Hz,2H,-CH2CCH),1.
59-1.
54(m,4H,alk.
H),1.
46-1.
40(m,4H,alk.
H),1.
38-1.
33(m,2H,alk.
H)13C-NMR(100MHz,CDCl3):δ=173.
4(-COO),138.
4(-Car-SO2),131.
9(2ar.
C),127.
1(2ar.
C),124.
8(ar.
C),94.
66(-CC-Car),80.
17(-CC-Car),64.
38(-CH2OOC),42.
87(-CH2NHSO2),33.
92(-CH2COO),28.
58(alk.
C),28.
50(alk.
C),28.
32(alk.
C),28.
05(alk.
C),27.
74(alk.
C),27.
32(alk.
C),27.
21(alk.
C),25.
68(alk.
C),25.
40(alk.
C),24.
07(alk.
C),19.
08(alk.
C)HRMS(FAB,3-NBA)f0rC18H24NO4S[M+H]+:calcd.
:350.
1426found:350.
1425ExperimentsrelatedtoSuzuki-reactionsGeneralprocedureforthesilylationof1,ω-alkinols(GP18)Inanovendriedflaskasolutionof1.
1eqTBDMSCl,1.
2eqtriethylamineand0.
05eqDMAPinabs.
DCMisprepared.
Thenasolutionof1eq1,ω-alkinolinDCMisaddedat0°C.
Thereactionmixtureisstirredfor2hat0°Cand24hatRT,andthenwashedwithsatd.
NH4Cl-solution.
TheaqueouslayerisextractedwithEt2O(3x).
Thecombinedorganiclayersarewashedwith1xNaHCO3-solutionand1xbrine,driedoverNa2SO4.
Thesolventsareremovedinvaccuousingarotovap.
Thecrudeproductispurifiedviaflashchromatography.
Generalprocedureforhydroborationof1-alkynes(GP19)Inanovendriedflask1eq1-alkyneand1.
5eqcatecholboranearedissolvedinabs.
THFandheatedto75°Cfor6h.
AftercoolingtoRT,waterisaddeddropwiseuntilnogasevolutionisobserved.
Afterstirringfor30min1eqformaldehydeinaqueoussolutionareadded.
Thereactionmixtureisstirredfor1h,then1.
1eq.
pinacolareaddedandthereactionmixtureheavilystirredovernight.
Thesolventsareremovedinvaccuousingarotovap.
Thecrudeproductispurifiedviaflashchromatography.
GeneralprocedureforintramolecularSuzuki-reactions(GP20)UnderinertconditionsaflaskischargedwithPd-beadsorPd[PPh3]4(0.
1eqPd).
After3vacuum/argoncylesthebeadsareswolleninadegassedsolutionofDME:H2O:DMF(1.
5:1.
5:1).
Afteradditionof2eqCs2CO3thereactionmixtureisheatedto80°C.
ThesubstrateisaddedassolutioninDME(2vinrespectto1vDMFofthecatalystsolution).
Thereactionmixtureisheatedto80°Covernight.
Aftercompleconversion(15h,monitoredbyHPLC)thereactionmixtureiscooledtoRT.
InreactionswithPd-beadsthebeadsarefilteredoff,washedwithDCM(1x45ml,10min),DCM:MeOH(1:1)(2x20ml,2x10min)andDCM(1x20ml,10min).
ThecombinedfiltratesorthereactionmixtureinthecaseofcatalysiswithPd[PPh3]4arewashedwithH2O(1x20ml).
TheaqueousphaseisextractedbackwithDCM(3x30ml).
ThecombinedorganiclayeraredriedoverNa2SO4.
Thesolventsareremovedinvaccuousingarotovap.
Thecrudeproductispurifiedviaflashchromatography.
HOTBDMSCl,Et3N,DMAP,DCM,overnightTBDMSOquant.
OOBH1)75°C,overnight2)H2O,30min3)CH2O,1h4)Pinacol,overnight1)75°C,6h2)H2O,30min3)CH2O,1h4)Pinacol,overnightHOBOO32%+TBDMSOBOO17%NH4F,MeOH,6hOOBHHOBOO25%61%overallyield49%313293131OHNCO2HI3OHNI3HOBOOmDIC,DMAP,DCMovernightm=3resp.
877resp.
7832resp.
99OOBOOm34:o-andm=394:o-andm=895:p-andm=396:p-andm=828-68%SOHNCO2H3SOHN3HOBOOmDIC,DMAP,DCMovernightm=3resp.
88432resp.
99OOBOOm27-36%I97resp.
98IOO1-tert-Butyldimethylsilanyloxyhex-5-ine(31)ThesynthesiswasperformedaccordingtoGP18with0.
15g(0.
99mmol)TBDMSCl,5.
5mg(0.
0045mmol)DMAP,0.
11g(1.
08mmol)triethylamineand0.
09g(0.
90mmol)1-hexinol.
Thecrudeproductwaspurifiedviaflashchromatography(silica,pentane).
Rf=0.
19(pentane)Yield:0.
19g(0.
90mmol,quant.
)colorlessoil1H-NMR(400MHz,CDCl3):δ=3.
63(t,J=6.
1Hz,2H,-CH2OSi-),2.
21(dt,J=6.
9Hz,2.
7Hz,2H,-CH2CCH),1.
93(t,J=2.
6Hz,1H,-CCH),1.
62-1.
59(m,4H,alk.
H),0.
89(s,9H,-C(CH3)3),0.
04(s,6H,-Si(CH3)2-).
Theanalyticaldataareinaccordancetoliterature.
ix1-tert-Butyldimethylsilanyloxyundec-10-ine(100)ThesynthesiswasperformedaccordingtoGP18with2.
7g(17.
8mmol)TBDMSCl,98.
9mg(0.
81mmol)DMAP,1.
94g(19.
4mmol)triethylamineand2.
72g(16.
2mmol)1-undecinol.
Thecrudeproductwaspurifiedviaflashchromatography(silica,pentane).
Rf=0.
15(pentane)Yield:3.
81g(13.
5mmol,83%)colorlessoil1H-NMR(400MHz,CDCl3):δ=3.
65(t,J=6.
1Hz,2H,-CH2OSi-),2.
22(dt,J=6.
8Hz,2.
7Hz,2H,-CH2CCH),1.
91(t,J=2.
6Hz,1H,-CCH),1.
62-1.
46(m,16H,alk.
H),0.
90(s,9H,-C(CH3)3),0.
05(s,6H,-Si(CH3)2-).
(E)-1-tert-Butyldimethylsilanyloxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hex-5-ene(93)ThesynthesiswasperformedaccordingtoGP19with0.
66g(3.
14mmol)1-tert-butyldimethylsilanyloxyhex-5-ine(31),4.
7ml(4.
7mmol)1M-catecholboranesolutioninabs.
THF,3mlH2O,2.
6ml(3.
14mmol)formaldehyde-solutionand0.
41g(3.
45mmol)pinacol.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate3:1).
Rf=0.
67(cyclohexane:ethylacetate3:1)Yield:0.
18g(0.
52mmol,17%)colorlessoil1H-NMR(400MHz,CDCl3):δ=6.
61(dt,J=18.
0Hz,6.
5Hz,1H,CH=CH),5.
45-4.
41(m,1H,CH=CH),3.
58(t,J=6.
1Hz,2H,-CH2OSi-),2.
15(m,2H,-CH2CH=CH),1.
53-1.
43(m,4H,alk.
H),1.
24(s,12H,-CH3),0.
87(s,9H,-C(CH3)3),0.
02(s,6H,-Si(CH3)2-).
13C-NMR(100MHz,CDCl3):δ=154.
5(-CH=CH-B),118.
4(-CH=CH-B),82.
98(-C(CH3)2),62.
98(-CH2O),35.
54(alk.
C),32.
22(alk.
C),25.
98(alk.
C),25.
97(-CH3),25.
96(-CH3),25.
95(-CH3),25.
94(-CH3),24.
76(-CH3),24.
57(-CH3),24.
47(-CH3),18.
35(C(CH3)3),-5.
29(-Si(CH3)2)(E)-1-tert-Butyldimethylsilanyloxy-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)undec-10-ene(101)ThesynthesiswasperformedaccordingtoGP19with2.
0g(7.
1mmol)1-tert-butyldimethylsilanyloxyundec-10-ine(100),10.
6ml(10.
6mmol)1M-catecholborane-solutioninabs.
THF,16mlH2O,5.
8ml(7.
1mmol)formaldehyde-solutionand0.
92g(7.
8mmol)pinacol.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate3:1).
Rf=0.
65(cyclohexane:ethylacetate3:1)Yield:1.
96g(4.
78mmol,67%)yellowishoil1H-NMR(400MHz,CDCl3):δ=6.
87-6.
76(m,1H,CH=CH),5.
70-5.
58(m,1H,CH=CH),3.
65-3.
61(m,2H,-CH2OSi-),2.
43-2.
39(m,2H,-CH2CH=CH),1.
53-1.
43(m,4H,alk.
H),1.
24(s,12H,-CH3),0.
88(s,9H,-C(CH3)3),0.
04(s,6H,-Si(CH3)2-).
13C-NMR(100MHz,CDCl3):δ=154.
8(-CH=CH-B),118.
5(-CH=CH-B),82.
97(-C(CH3)2),63.
32(-CH2O),35.
81(alk.
C),32.
87(alk.
C),29.
53(alk.
C),29.
42(alk.
C),29.
21(alk.
C),28.
21(alk.
C),25.
98(alk.
C),25.
78(-CH3),24.
76(-CH3),24.
56(-CH3),18.
37(C(CH3)3),-5.
26(-Si(CH3)2)(E)-6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)hex-5-en-1-ol(32)ThesynthesiswasperformedaccordingtoGP19with0.
66g(3.
14mmol)1-tert-butyldimethylsilanyloxyhex-5-ine(31),4.
7ml(4.
7mmol)1M-catecholborane-solutioninabs.
THF,3mlH2O,2.
6ml(3.
14mmol)formaldehyde-solutionand0.
41g(3.
45mmol)pinacol.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate3:1).
Rf=0.
30(cyclohexane:ethylacetate3:1)Ausbeute:0.
28g(1.
23mmol,39%)farbloseslThesynthesiswasperformedaccordingtoGP8mit37.
3mg(0.
11mmol)(E)-1-tert-butyldimethylsilanyloxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hex-5-ene(93),46.
8mg(1.
26mmol)NH4Fin2.
5mlMeOH.
Thecrudeproductwasusedwithourfurtherpurification.
Yield:15.
3mg(0.
68mmol,61%)yellowishoil1H-NMR(400MHz,CDCl3):δ=6.
62(dt,J=18.
0Hz,6.
5Hz,1H,CH=CH),5.
43(dt,J=18.
0Hz,1.
6Hz,1H,CH=CH),3.
63(t,J=6.
4Hz,2H,-CH2OSi-),2.
21-2.
15(m,2H,-CH2CH=CH),1.
60-1.
56(m,2H,alk.
H),1.
53-1.
43(m,4H,alk.
H),1.
26(s,12H,-CH3).
(E)-11-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)undec-10-en-1-ol(99)ThesynthesiswasperformedaccordingtoGP19with1.
56g(7.
4mmol)1-tert-butyldimethylsilanyloxyundec-10-ine(100),11.
1ml(11.
1mmol)1M-catecholborane-solutioninabs.
THF,16mldest.
Wasser,5.
9ml(7.
4mmol)formaldehyde-solutionand0.
96g(8.
1mmol)pinacol.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate3:1).
Rf=0.
26(cyclohexane:ethylacetate3:1)Yield:0.
16g(0.
54mmol,7%)colorlessoilThesynthesiswasperformedaccordingtoGP8with0.
75g(1.
83mmol)(E)-1-tert-butyldimethylsilanyloxy-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)undec-10-ene(101),0.
78mg(21.
0mmol)NH4Fin40mlMeOH.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate3:1).
Yield:0.
62g(2.
1mmol,33%)yellowishoil1H-NMR(400MHz,CDCl3):δ=6.
63(dt,J=18.
0Hz,6.
4Hz,1H,CH=CH),5.
42(dt,J=18.
0Hz,1.
6Hz,1H,CH=CH),3.
64(t,J=6.
6Hz,2H,-CH2OSi-),2.
17-2.
11(m,2H,-CH2CH=CH),1.
58-1.
52(m,4H,alk.
H),1.
42-1.
37(m,2H,alk.
H),1.
34-1.
27(m,8H,alk.
H),1.
26(s,12H,-CH3).
6-(4-Iodbenzamido)-hexansure-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-hex-5-enyl-ester(95)ThesynthesiswasperformedaccordingtoGP9with0.
11g(0.
5mmol)6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-hex-5-ene(32),0.
18g(0.
5mmol)6-(4-iodobenzamido)-hexanoicacid(78),30.
5mg(0.
25mmol)DMAP,69.
4mg(0.
55mmol)DICin5mlDCMand1mlDMF.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate3:1).
Rf=0.
33(cyclohexane:ethylacetate3:1)Yield:0.
13g(0.
23mmol,46%)colorlessoilHPLC(C18):tR=10.
94min1H-NMR(400MHz,CDCl3):δ=7.
78-7.
76(m,2H,ar.
H),7.
50-7.
48(m,2H,ar.
H),6.
60(dt,J=18.
0Hz,6.
5Hz,1H,CH=CH),6.
23(brs,1H,-NH-),5.
44(dt,J=18.
0Hz,1.
6Hz,1H,CH=CH),4.
05(t,J=6.
5Hz,2H,-CH2OOC-),3.
44(dt,J=6.
2Hz,6.
8Hz,2H,-CH2NH-),2.
31(t,J=7.
2Hz,2H,-CH2COO-),2.
21-2.
15(m,2H,-CH2CH=CH),1.
70-1.
59(m,6H,alk.
H),1.
51-1.
36(m,4H,alk.
H),1.
26(s,12H,-CH3).
13C-NMR(100MHz,CDCl3):δ=173.
7(-COO),166.
6(-CONH),153.
6(-CH=CH-B),137.
7(ar.
H),134.
1(ar.
C),128.
5(ar.
C),98.
16(-CarI),83.
06(-C(CH3)2),64.
22(-CH2OOC),39.
77(-CH2NHCO),35.
18(alk.
C),34.
01(-CH2-CC),29.
11(alk.
C),28.
11(alk.
C),26.
32(alk.
C),24.
84(alk.
C),24.
76(alk.
C),24.
52(alk.
C),24.
33(alk.
C)HRMS(FAB,3-NBA)forC25H37BINO5[M]+:calcd.
:569.
1809found:569.
1898fürC25H38BINO5[M+H]+:calcd.
:570.
1888found:570.
18806-(2-Iodobenzamido)-hexanoicacid6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-hex-5-enyl-ester(34)ThesynthesiswasperformedaccordingtoGP9with28.
7mg(0.
13mmol)6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-hex-5-ene(32),45.
8mg(0.
13mmol)6-(2-iodobenzamido)-hexanoicacid(77),9.
1mg(0.
07mmol)DMAP,20.
7mg(0.
16mmol)DICin1mlDCMand0.
01mlDMF.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate3:1).
Rf=0.
28(cyclohexane:ethylacetate3:1)Yield:50.
2mg(0.
088mmol,68%)colorlessoilHPLC(C18):tR=10.
55min1H-NMR(400MHz,CDCl3):δ=7.
83-7.
81(m,1H,ar.
H),7.
34-7.
33(m,2H,ar.
H),7.
08-7.
03(m,1H,ar.
H),6.
58(dt,J=17.
8Hz,6.
4Hz,1H,CH=CH),5.
96(brs,1H,-NH-),5.
44-5.
39(m,1H,CH=CH),4.
02(t,J=6.
5Hz,2H,-CH2OOC-),3.
42(dt,J=7.
0Hz,6.
5Hz,2H,-CH2NH-),2.
29(t,J=7.
3Hz,2H,-CH2COO-),2.
18-2.
13(m,2H,-CH2CH=CH),1.
63(tt,J=15.
1Hz,7.
5Hz,6H,alk.
H),1.
44(tt,J=14.
5Hz,7.
2Hz,4H,alk.
H),1.
24(s,12H,-CH3).
13C-NMR(100MHz,CDCl3):δ=173.
6(-COO),153.
7(-CH=CH-B),139.
8(ar.
H),131.
0(ar.
C),128.
2(ar.
C),118.
2(-CH=CH-B),92.
39(-CarI),83.
05(-C(CH3)2),64.
21(-CH2OOC),39.
82(-CH2NHCO),34.
11(-CH2-CC),29.
06(alk.
C),28.
12(alk.
C),26.
49(alk.
C),24.
75(alk.
C),24.
53(alk.
C),24.
51(alk.
C)HRMS(FAB,3-NBA)forC25H37BINO5[M]+:calcd.
:569.
1809found:569.
1779forC25H38BINO5[M+H]+:calcd.
:570.
1888found:570.
19126-(4-Iodbenzamido)-hexansure-11-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-undec-10-enyl-ester(96)ThesynthesiswasperformedaccordingtoGP9with0.
19g(0.
33mmol)11-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-undec-10-ene(99),0.
12g(0.
33mmol)6-(4-iodobenzamido)-hexanoicacid(78),20.
2mg(0.
16mmol)DMAP,45.
8mg(0.
36mmol)DICin3mlDCMand0.
6mlDMF.
Thecrudeproductwaspurifiedviaprep.
HPLC.
Yield:84.
5mg(0.
13mmol,40%)colorlesssolidHPLC(C18):tR=13.
58min1H-NMR(400MHz,CDCl3):δ=7.
75-7.
72(m,2H,ar.
H),7.
49-7.
46(m,2H,ar.
H),6.
61(dt,J=17.
9Hz,6.
3Hz,1H,CH=CH),6.
40(brs,1H,-NH-),5.
40(dt,J=17.
9Hz,1.
5Hz,1H,CH=CH),4.
02(t,J=6.
7Hz,2H,-CH2OOC-),3.
41(dt,J=6.
4Hz,6.
8Hz,2H,-CH2NH-),2.
29(t,J=7.
3Hz,2H,-CH2COO-),2.
15-2.
09(m,2H,-CH2CH=CH),1.
68-1.
56(m,6H,alk.
H),1.
42-1.
35(m,4H,alk.
H),1.
26-1.
23(brm,22H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=173.
7(-COO),166.
6(-CONH),154.
7(-CH=CH-B),137.
6(ar.
H),134.
1(ar.
C),128.
5(ar.
C),98.
12(-CarI),82.
92(-C(CH3)2),64.
48(-CH2OOC),39.
71(-CH2NHCO),35.
72(alk.
C),33.
99(-CH2-CC),29.
32(alk.
C),29.
30(alk.
C),29.
15(alk.
C),29.
10(alk.
C),29.
04(alk.
C),28.
55(alk.
C),28.
11(alk.
C),26.
27(alk.
C),25.
83(alk.
C),24.
71(alk.
C),24.
28(alk.
C).
HRMS(FAB,3-NBA)forC30H47BINO5[M]+:ber.
:639.
2592gef.
:639.
25976-(2-Iodobenzamido)-hexanoicacid11-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-undec-10-enyl-ester(94)ThesynthesiswasperformedaccordingtoGP9with44.
3mg(0.
15mmol)11-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-undec-10-ene(99),45.
9mg(0.
15mmol)6-(2-iodobenzamido)-hexanoicacid(77),9.
1mg(0.
07mmol)DMAP,20.
7mg(0.
16mmol)DICin1mlDCMand0.
01mlDMF.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate3:1).
Rf=0.
26(cyclohexane:ethylacetate)3:1Yield:26.
9mg(0.
042mmol,28%)colorlessoilHPLC(C18):tR=13.
04min1H-NMR(400MHz,CDCl3):δ=7.
86-7.
84(m,1H,ar.
H),7.
38-7.
36(m,2H,ar.
H),7.
11-7.
00(m,1H,ar.
H),6.
62(dt,J=18.
1Hz,6.
3Hz,1H,CH=CH),5.
81(brs,1H,-NH-),5.
44-5.
39(m,1H,CH=CH),4.
04(t,J=7.
0Hz,2H,-CH2OOC-),3.
48-3.
43(m,2H,-CH2NH-),2.
32(t,J=7.
3Hz,2H,-CH2COO-),2.
17-2.
10(m,2H,-CH2CH=CH),1.
72-1.
64(m,4H,alk.
H),1.
63-1.
55(m,4H,alk.
H),1.
50-1.
43(m,2H,alk.
H),1.
42-1.
36(m,2H,alk.
H),1.
34-1.
25(brs,20H,-CH3).
13C-NMR(100MHz,CDCl3):δ=173.
7(-COO),169.
3(-CONH),154.
7(-CH=CH-B),142.
5(ar.
C),139.
8(ar.
C),131.
0(ar.
C),128.
2(ar.
C),128.
1(ar.
C),92.
39(-CarI),82.
97(-C(CH3)2),64.
53(-CH2OOC),39.
83(-CH2NHCO),35.
78(alk.
C),34.
15(-alk.
C),29.
47(alk.
C),29.
39(alk.
C),29.
36(alk.
C),29.
21(alk.
C),29.
16(alk.
C),29.
08(alk.
C),28.
61(alk.
C),28.
17(alk.
C),26.
49(alk.
C),25.
91(alk.
C),25.
90(alk.
C),24.
76(alk.
C),24.
52(alk.
C),24.
23(alk.
C),22.
06(alk.
C).
HRMS(FAB,3-NBA)forC30H47BINO5[M]+:calcd.
:639.
2592found:639.
25706-(4-Iodobenzenesulfonyl)-hexanoicacid6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-hex-5-enyl-ester(97)ThesynthesiswasperformedaccordingtoGP9with0.
14g(0.
63mmol)6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-hex-5-ene(32),0.
25g(0.
63mmol)6-(4-iodobenzenesulfonyl)-hexanoicacid(84),37.
9mg(0.
31mmol)DMAP,87.
4mg(0.
69mmol)DICin5mlDCMand0.
5mlDMF.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate3:1).
Rf=0.
31(cyclohexane:ethylacetate3:1)Yield:0.
10g(0.
17mmol,27%)colorlessoilHPLC(C18):tR=11.
23min1H-NMR(400MHz,CDCl3):δ=7.
88-7.
85(m,2H,ar.
H),7.
57-7.
55(m,2H,ar.
H),6.
60(dt,J=17.
5Hz,5.
7Hz,1H,CH=CH),5.
44-5.
40(m,1H,CH=CH),4.
68(t,J=5.
7Hz,,1H,-NH-),4.
04(t,J=6.
3Hz,2H,-CH2OOC-),2.
97-2.
92(m,2H,-CH2NH-),2.
24(t,J=7.
2Hz,2H,-CH2COO-),2.
20-2.
14(m,2H,-CH2CH=CH),1.
70-1.
45(brm,10H,alk.
H),1.
31-1.
25(m,12H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=173.
5(-COO),153.
7(-CH=CH-B),139.
8(ar.
C),138.
3(ar.
C),128.
5(ar.
C),99.
83(-CarI),83.
09(-C(CH3)2),64.
25(-CH2OOC),42.
94(-CH2NHSO2),35.
15(alk.
C),33.
91(alk.
C),29.
23(alk.
C),28.
08(alk.
C),25.
90(alk.
C),24.
75(alk.
C),24.
50(alk.
C),24.
16(alk.
C).
HRMS(FAB,3-NBA)forC24H38BINO6S[M+H]+:calcd.
:606.
1558found:606.
1599forC24H37BINO6SNa[M+Na]+:calcd.
:628.
1377found:628.
14076-(4-Iodobenzenesulfonyl)-hexanoicacid11-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-undec-10-enyl-ester(98)ThesynthesiswasperformedaccordingtoGP9with0.
19g(0.
63mmol)11-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-undec-10-ene(95),0.
25g(0.
63mmol)6-(4-iodobenzenesulfonyl)-hexanoicacid(84),37.
9mg(0.
31mmol)DMAP,87.
4mg(0.
69mmol)DICin5mlDCMand0.
5mlDMF.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate3:1).
Rf=0.
34(cyclohexane:ethylacetate3:1)Yield:0.
15g(0.
23mmol,36%)colorlessoilHPLC(C18):tR=10.
55min1H-NMR(400MHz,CDCl3):δ=7.
85-7.
83(m,2H,ar.
H),7.
57-7.
55(m,2H,ar.
H),6.
62(dt,J=18.
0Hz,6.
4Hz,1H,CH=CH),5.
44-5.
39(m,1H,CH=CH),5.
21(t,J=6.
1Hz,1H,-NH-),3.
62(t,J=6.
6Hz,2H,-CH2OOC-),2.
97-2.
92(m,2H,-CH2NH-),2.
54(t,J=7.
3Hz,2H,-CH2COO-),2.
16-2.
10(m,2H,-CH2CH=CH),1.
73-1.
67(m,2H,alk.
H),1.
59-1.
51(m,6H,alk.
H),1.
49-1.
35(m,4H,alk.
H),1.
33-1.
24(m,20H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=170.
9(-COO),154.
8(-CH=CH-B),139.
6(ar.
H),138.
3(ar.
C),128.
4(ar.
C),99.
87(-CarI),82.
97(-C(CH3)2),63.
02(-CH2OOC),42.
84(-CH2NHSO2),36.
42(alk.
C),35.
75(alk.
C),33.
76(alk.
C),32.
76(alk.
C),32.
75(alk.
C),29.
58(alk.
C),29.
52(alk.
C),29.
44(alk.
C),29.
40(alk.
C),29.
36(alk.
C),29.
34(alk.
C),29.
32(alk.
C),29.
27(alk.
C),29.
11(alk.
C),28.
14(alk.
C),25.
84(alk.
C),25.
68(alk.
C),24.
74(alk.
C),24.
21(alk.
C).
HRMS(FAB,3-NBA)forC29H47BINO6S[M]+:calcd.
:675.
2262found:675.
2228forC29H48BINO6S[M+H]+:calcd.
:676.
2340found:676.
244210-Oxa-3-aza-bicyclo[20.
2.
2]hexacosa-1(25),20,22(26),23-tetraen-2,9-dione(38)ThesynthesiswasperformedaccordingtoGP20with7.
1mg(0.
0039mmolPd)Pd-beads1a/Pdor4.
5mg(0.
0039mmol)Pd[PPh3]4,25.
5mg(0.
078mmol)Cs2CO3in0.
64mlDME:H2O:DMF(1.
5:1.
5:1)and25.
0mg(0.
039mmol)6-(4-iodobenzamido)-hexanoicacid11-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-undec-10-enyl-ester(96)in0.
32mlDME.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate1:1).
Rf=0.
37(cyclohexane:ethylacetate1:1)Yield:7.
1mg(beads)(0.
018mmol,47%)colorlesssolid9.
2mg(homogeneous)(0.
024,61%)colorlesssolidSchmp:nichtbestimmt1H-NMR(400MHz,CDCl3):δ=7.
78(d,J=8.
2Hz,2H,ar.
H),7.
36(d,J=8.
2Hz,2H,ar.
H),6.
82(brs,1H,-NH-),6.
41(d,J=15.
8Hz,1H,CH=CH),6.
23(dt,J=15.
8Hz,7.
2Hz,1H,CH=CH),3.
86-3.
82(m,2H,-CH2OOC-),3.
60-3.
56(m,2H,-CH2NH-),2.
33-2.
26(m,4H,-CH2COO-und-CH2CH=CH),1.
67-1.
61(m,4H,alk.
H),1.
55-1.
52(m,2H,alk.
H),1.
48-1.
41(m,2H,alk.
H),1.
39-1.
35(m,2H,alk.
H),1.
32-1.
28(brm,10H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=174.
4(-COO),167.
4(-CONH),141.
1(ar.
C),133.
7(ar.
C),129.
7(-CH=CH-),127.
4(ar.
C),127.
2(ar.
C),125.
7(-CH=CH-),65.
00(-CH2OOC),37.
60(-CH2NHCO),33.
23(-CH2-COO),31.
97(alk.
C),28.
79(alk.
C),28.
51(alk.
C),28.
18(alk.
C),27.
32(alk.
C),27.
15(alk.
C),26.
91(alk.
C),26.
23(alk.
C),25.
55(alk.
C),24.
68(alk.
C),21.
91(alk.
C).
HRMS(FAB,3-NBA)forC24H35NO3[M]+:calcd.
:385.
2617found:385.
26196,7,8,9,10,11,15,16,17,18,19,20,21,22-Tetradecahydro-14H-13-oxa-6-aza-benzocyclodocosen-5,12-dione(36)ThesynthesiswasperformedaccordingtoGP20with4.
0mg(0.
0021mmolPd)Pd-beads1a/Pdor2.
4mg(0.
0021mmol)Pd[PPh3]4,13.
7mg(0.
042mmol)Cs2CO3in0.
33mlDME:H2O:DMF(1.
5:1.
5:1)and13.
4mg(0.
021mmol)6-(2-iodobenzamido)-hexanoicacid11-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-undec-10-enyl-ester(94)in0.
16mlDME.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate1:1).
Rf=0.
35(cyclohexane:ethylacetate1:1)Yield:4.
6mg(beads)(0.
012mmol,58%)yellowishoil4.
7mg(homogeneous)(0.
012mmol,57%)yellowishoilHPLC(C18):tR=11.
23min1H-NMR(400MHz,CDCl3):δ=7.
48(dd,J=7.
0Hz,1.
4Hz,1H,ar.
H),7.
44-7.
42(m,1H,ar.
H),7.
35(dt,J=7.
6Hz,1.
5Hz,1H,ar.
H),7.
24(dt,J=7.
4Hz,1.
4Hz,1H,ar.
H),6.
62(d,J=15.
8Hz,1H,CH=CH),6.
18(dt,J=15.
8Hz,6.
6Hz,1H,CH=CH),5.
78(brs,1H,-NH-),4.
14(t,J=5.
5Hz,2H,-CH2OOC-),3.
44(dt,J=6.
1Hz,7.
5Hz,2H,-CH2NH-),2.
34(t,J=7.
5Hz,2H,-CH2COO-),2.
23-2.
17(m,2H,-CH2CH=CH),1.
75-1.
67(m,2H,alk.
H),1.
66-1.
55(m,4H,alk.
H),1.
50-1.
45(m,2H,alk.
H),1.
42-1.
36(m,2H,alk.
H),1.
34-1.
25(m,10H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=173.
4(-COO),169.
4(-CONH),135.
5(ar.
C),135.
1(ar.
C),134.
5(ar.
C),130.
0(-CH=CH-),127.
8(ar.
C),127.
4(ar.
C),127.
0(-CH=CH-),126.
5(ar.
C),64.
00(-CH2OOC),39.
85(-CH2NHCO),34.
81(-alk.
C),32.
77(alk.
C),29.
78(alk.
C),28.
94(alk.
C),28.
80(alk.
C),28.
63(alk.
C),28.
32(alk.
C),28.
18(alk.
C),28.
11(alk.
C),26.
91(alk.
C),26.
61(alk.
C),25.
30(alk.
C).
HRMS(FAB,3-NBA)forC24H35NO3[M]+:cacld.
:385.
2617found:385.
2597forC24H36NO3[M+H]+:calcd.
:386.
2695found:386.
26716,7,8,9,10,11,14,15,16,17-Decahydro-13-oxa-6-aza-benzocycloheptadecen-5,12-dione(35)ThesynthesiswasperformedaccordingtoGP20with4.
0mg(0.
0021mmolPd)Pd-beads1a/Pdor2.
4mg(0.
0021mmol)Pd[PPh3]4,13.
7mg(0.
042mmol)Cs2CO3in0.
33mlDME:H2O:DMF(1.
5:1.
5:1)and11.
4mg(0.
021mmol)6-(2-iodobenzamido)-hexanoicacid6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-hex-5-enyl-ester(34)in0.
16mlDME.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate1:1).
Rf=0.
33(cyclohexane:ethylacetate1:1)Yield:2.
7mg(beads)(0.
00086mmol,41%)yellowishoil3.
8mg(homogeneous)(0.
013mmol,60%)yellowishoilHPLC(C18):tR=7.
22min1H-NMR(400MHz,CDCl3):δ=7.
50(dd,J=7.
5Hz,1.
5Hz,1H,ar.
H),7.
42-7.
40(m,1H,ar.
H),7.
35(dt,J=7.
8Hz,1.
5Hz,1H,ar.
H),7.
25(dt,J=7.
4Hz,1.
4Hz,1H,ar.
H),6.
68(d,J=16.
0Hz,1H,CH=CH),6.
19(dt,J=15.
8Hz,6.
5Hz,1H,CH=CH),5.
75(brs,1H,-NH-),4.
21(t,J=6.
2Hz,2H,-CH2OOC-),3.
51-3.
46(m,2H,-CH2NH-),2.
39-2.
36(m2H,-CH2COO-),2.
28-2.
22(m,2H,-CH2CH=CH),1.
76-1.
67(m,4H,alk.
H),1.
64-1.
52(m,4H,alk.
H),1.
50-1.
40(m,2H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=173.
7(-COO),169.
6(-CONH),135.
6(ar.
C),135.
0(ar.
C),133.
9(ar.
C),130.
1(-CH=CH-),128.
0(ar.
C),127.
9(ar.
C),127.
1(-CH=CH-),126.
7(ar.
C),63.
27(-CH2OOC),40.
39(-CH2NHCO),34.
42(alk.
C),31.
94(-alk.
C),29.
35(alk.
C),28.
30(alk.
C),27.
03(alk.
C),26.
91(alk.
C),24.
98(alk.
C).
HRMS(FAB,3-NBA)forC19H25NO3[M]+:calcd.
:315.
1834found:315.
1867forC19H26NO3[M+H]+:calcd.
:316.
1913found:316.
19442,2-Dioxo-10-oxa-2λ6-thia-3-aza-bicyclo[15.
2.
2]heneicosa-1(20),15,17(21),18-tetraen-9-one(36)ThesynthesiswasperformedaccordingtoGP20with4.
0mg(0.
0021mmolPd)Pd-beads1a/Pdor2.
4mg(0.
0021mmol)Pd[PPh3]4,13.
7mg(0.
042mmol)Cs2CO3in0.
33mlDME:H2O:DMF(1.
5:1.
5:1)and11.
4mg(0.
021mmol)6-(4-iodobenzenesulfonyl)-hexanoicacid6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-hex-5-enyl-ester(97)in0.
16mlDME.
Thecrudeproductwaspurifiedviaflashchromatography(silica,cyclohexane:ethylacetate1:1).
Rf=0.
35(cyclohexane:ethylacetate1:1)Yield:2.
1mg(beads)(0.
0063mmol,30%)yellowishoil1.
5mg(homogeneous)(0.
0046mmol,22%)yellowishoilHPLC(C18):tR=7.
88min1H-NMR(400MHz,CDCl3):δ=7.
82(d,J=8.
6Hz,2H,ar.
H),7.
46(d,J=8.
4Hz,2H,ar.
H),6.
42(d,J=15.
8Hz,1H,CH=CH),6.
31(dt,J=15.
8Hz,7.
2Hz,1H,CH=CH),4.
21(t,J=6.
1Hz,1H,-NH-),4.
00(t,J=5.
4Hz,2H,-CH2OOC-),3.
09-3.
05(m,2H,-CH2NH-),2.
28-2.
23(m,2H,-CH2COO-),1.
77-1.
72(m,2H,alk.
H),1.
70-1.
67(m,4H,alk.
H),1.
59-1.
52(m,6H,alk.
H).
13C-NMR(100MHz,CDCl3):δ=173.
2(-COO),138.
2(ar.
C),128.
9(-CH=CH-),127.
8(ar.
C),127.
5(-CH=CH-),126.
2(ar.
C),63.
69(-CH2OOC),41.
92(-CH2NHSO2),33.
36(alk.
C),32.
24(alk.
C),28.
52(alk.
C),26.
92(alk.
C),24.
77(alk.
C),24.
55(alk.
C),23.
39(alk.
C).
LRMS(FAB,3-NBA)forC18H25NO4S[M+H]+:calcd.
:352.
16found:352.
17iC.
A.
Dyke,T.
A.
Bryson,TetrahedronLett.
2001,42,3959-3962.
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McDougal,J.
G.
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D.
Condon,J.
Org.
Chem.
1986,51,3388-3390.
iiiT.
Sato,J.
Otera,H.
Nozaki,J.
Org.
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1993,58,4971-4978.
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E.
Sonnet,S.
F.
Osman,H.
C.
Gerard,R.
L.
Dudley,Chem.
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Lipids,1994,69,121-128.
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Ishizone,S.
Han,S.
Okuyama,S.
Nakahama,Macromolecules2003,36,42-49.
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MacMahon,R.
Fong,P.
S.
Baran,I.
Safonov,S.
R.
Wilson,D.
I.
Schuster,J.
Org.
Chem.
2001,66,5449-5455.
viiS.
K.
Bae,S.
-H.
Kim,J.
-D.
Kim,K.
I.
Koo,R.
K.
Tai,K.
Ryeom,X.
Fu,Y.
H.
Chang,TetrahedronLett.
2000,41,8495-8498.
viiiY.
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Lin,M.
J.
Miller,J.
Org.
Chem.
2001,66,8282-8286.
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Negishi,M.
Pour,F.
E.
Coderbaum,M.
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