Enantioselective synthesis of cyclic β-amino [beta amino] alcohols via tandem hydroalumination cyclization reduction of ethoxycarbonyl vinyl sulfoximines and application to the synthesis of potential aggrecanase inhibitors [Elektronische Ressource] / vorgelegt von Serdar Açıkalın

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• Publié par: rheinisch-westfalischen_technischen_hochschule_-rwth-_aachen
• Publié le: 01 janvier 2009
• Nombre de lectures: 20
• Poids de l'ouvrage: 1 Mo

Extrait

EnantioselectiveSynthesisofCyclic β-Amino
AlcoholsviaTandem
Hydroalumination-Cyclization-Reductionof
EthoxycarbonylVinylSulfoximinesand
ApplicationtoTheSynthesisofPotential
AggrecanaseInhibitors
VonderFakulta¨tfur¨ Mathematik,InformatikundNaturwissenschaftender
Rheinisch-Westfa¨lischenTechnischenHochschuleAachenzurErlangungdes
akademischenGradeseinesDoktorsderNaturwissenschaftengenehmigte
Dissertation
vorgelegtvon
MasterofScience
SerdarAc¸ıkalın
ausSarayko¨y(Denizli/Tur¨ kei)
Berichter: Universita¨tsprofessorDr. H.-J.Gais
Universita¨tsprofessorDr. D.Enders
Tagdermun¨ dlichenPruf¨ ung: 10. Juli2009
DieseDissertationistaufdenInternetseitenderHochschulbibliothekonlineverfu¨gbar.DeinLebenseieinhundertfa¨ltigerVersuch:
deinMißlingenundGelingenseineinBeweis:
undsorgedafu¨r,daßmanwisse,
wasduversuchtundbewiesenhast.
NietzscheThe work presented in this thesis was carried out at the Institute of Organic Chemisry of the
RWTH-AachenUniversityundersupervisionofProf. Dr. Hans-JoachimGaisbetweenDecem-
ber2003andApril2008.
IwouldliketothankProf. Dr. H.-J.Gaisforgivingmetheopportunitytoworkonanexciting
researchtopic,excellentconditionsandsupport.
IwouldliketothankProf. Dr. Endersforhiskindassumptionoftheco-reference.Contents
1 Introduction 1
1.1 Synthesisofcyclic β-aminoalcohols . . . . . . . . . . . . . . . . . . . . . 3
1.1.1 β-AminoalcoholsviaC–Cbondformation . . . . . . . . . . . . . 3
1.1.2 β-Aminoalcoholsynthesiswithoutchangingcarbonskeleton . . 4
1.2 AggrecanaseInhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
1.3 Sulfoximinesinbiologicallyactivecompounds . . . . . . . . . . . . . . . 10
2 Carbometalation-Cyclization 13
3 Aimofthestudy 19
4 ResultsandDiscussion 21
4.1 Synthesisof β-AminoAlcohols . . . . . . . . . . . . . . . . . . . . . . . . 23
4.1.1 DIBAL-HReductionReaction . . . . . . . . . . . . . . . . . . . . . 24
4.1.2 InfluenceofDoubleBondConfiguration . . . . . . . . . . . . . . 36
Mechanismoffuranformation . . . . . . . . . . . . . . . . . . . . 38
4.2 FurtherTransformationsofCyclic β-AminoAlcohol100. . . . . . . . . . 40
4.2.1 Chlorine-Substitution . . . . . . . . . . . . . . . . . . . . . . . . . 40
4.2.2 IodineSubstitution . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
4.2.3 OxidationofSulfoximine . . . . . . . . . . . . . . . . . . . . . . . 43
4.2.4 Mitsunobuconditions . . . . . . . . . . . . . . . . . . . . . . . . . 44
4.2.5 Removalofsulfoximinegroup . . . . . . . . . . . . . . . . . . . . 46
Aluminiumamalgam . . . . . . . . . . . . . . . . . . . . . . . . . 46
Raney-Nickel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
4.2.6 DeprotectionofN-tert-butysulfonylgroup . . . . . . . . . . . . . 47
4.3 SynthesisofSulfoximine-SubstitutedPotentialAggrecanaseInhibitor72 48
4.3.1 RacemicApproach . . . . . . . . . . . . . . . . . . . . . . . . . . . 49SynthesisofMethyl3-(3-(benzyloxy)phenyl)propanoate(162) . . 49
Synthesisoftert-Butyl3-(3-(benzyloxy)phenyl)propanoate(163) . 50
Alkylationattemptstoobtainbenzyltert-butylsuccinate165 . . . 51
4.3.2 AsymmetricApproach . . . . . . . . . . . . . . . . . . . . . . . . . 54
5 SummaryandOutlook 67
6 Experimental 71
6.1 Generalmethodsandchemicals . . . . . . . . . . . . . . . . . . . . . . . . 71
6.1.1 Inertatmosphereconditionsandsolvents . . . . . . . . . . . . . . 71
6.1.2 Determinationofthephysicaldata . . . . . . . . . . . . . . . . . . 72
6.1.3 Chromatography . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
6.1.4 Attempted deprotection of the O,O-dibenzyl protected hydroxy
hydroxamicacid177 . . . . . . . . . . . . . . . . . . . . . . . . . . 119
6.2 XRAYstructureanalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
6.2.1 XraystructureofN-((1S,2R,3R,3aS,6aR)-2-hydroxy-3-((S)-N-methyl-
phenylsulfonimidoyl)octahydropentalen-1-yl)-2-methylpropane-
2-sulfonamide(108) . . . . . . . . . . . . . . . . . . . . . . . . . . 123
6.2.2 XraystructureofN-((1S,2R,3R,3aS,7aR)-2-hydroxy-3-((S)-N-methyl-
phenylsulfonimidoyl)octahydro-1H-inden-1-yl)-2-methylpropane-
2-sulfonamide(100) . . . . . . . . . . . . . . . . . . . . . . . . . . 134
7 Bibliography 147ListofFigures
1.1 Naturalproductshaving β-aminoalcoholmoiety. . . . . . . . . . . . . . 2
1.2 Vicinalaminoalcoholsaschiralauxiliariesandligands. . . . . . . . . . . 2
1.3 HIVproteaseinhibitorshaving β-aminoalcoholfunctionality. . . . . . . 3
1.4 Potentinhibitorsagainstcartilagedegradation. . . . . . . . . . . . . . . . 10
1.5 Methionine-andbuthioninesulfoximine(34,35). . . . . . . . . . . . . . . 11
1.6 CarboxypeptidaseAinhibitors. . . . . . . . . . . . . . . . . . . . . . . . . 11
1.7 SulfoximineanalogueofthenaturalhormoneCalcitriol(38). . . . . . . . 12
1.8 HIVproteaseinhibitorincorporatingsulfoximinefunctionality. . . . . . 12
2.1 Stabilizationofnegativechargedensitybysulfonemoiety. . . . . . . . . 15
2.2 Cyclizationofhex-1-en-5-yneviahydroalumintaion. . . . . . . . . . . . . 17
3.1 Plannedbicyclic1,2-aminoalcohol71synthesis. . . . . . . . . . . . . . . 20
1 43.2 Retrosyntheticanalysisofsulfoximine-substitutedN -hydroxy-N -(2-hydroxy-
octahydro-1H-inden-1-yl)succinamide(72). . . . . . . . . . . . . . . . . . 20
4.1 Addition-Elimination-IsomerizationRouteforthesynthesisofallylicsul-
foximines76–80. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
4.2 γ-Aminoalkylationofallylicsulfoximines76–80. . . . . . . . . . . . . . . 22
4.3 Planningsynthesisofcyclic1,2-aminoalcohols.. . . . . . . . . . . . . . . 23
4.4 Structureofent-E-82inthecrystal. . . . . . . . . . . . . . . . . . . . . . . 25
4.5 Plausbilemechanismofthesaturatedsulfoximine93formation. . . . . . 27
4.6 Structureof100inthecrystal. . . . . . . . . . . . . . . . . . . . . . . . . . 28
4.7 NOE’softhecyclic β-aminoalcohol101. . . . . . . . . . . . . . . . . . . . 29
4.8 Proposed mechanism for the formation of cyclic β-amino alcohols 100
and101.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
4.9 Structureof108inthecrystal. . . . . . . . . . . . . . . . . . . . . . . . . . 31
4.10 Possiblereactionpathwaysofthesulfoximine-substitutedhydroaluminated
intermediate113. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344.11 NOE’softhecyclictetrahydrofuranderivatives121and122. . . . . . . . 37
4.12 TetrahydrofuransynthesisbyGaisandReggelin. . . . . . . . . . . . . . . 38
4.13 ComparisonofchairconformationsofZ-82. . . . . . . . . . . . . . . . . . 38
4.14 ConformationalhinderanceofdoublebondhydroaluminationofZ-82. . 39
4.15 Mechanismoffuranformation. . . . . . . . . . . . . . . . . . . . . . . . . 40
4.16 Mechanismofformationofchloride138andketone139. . . . . . . . . . 42
4.17 Sulfoxoniumsalt145. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
4.18 Putativemechanismofdehydrationof100. . . . . . . . . . . . . . . . . . 45
4.19 Alternativemechanismoftheallylamine151formation. . . . . . . . . . 46
1 44.20 Retrosyntheticanalysisofsulfoximine-substitutedN -hydroxy-N -(2-hydroxy-
octahydro-1H-inden-1-yl)succinamide(72). . . . . . . . . . . . . . . . . . 49
14.21 Alternativeretrosyntheticanalysisofsulfoximine-substitutedN -hydroxy-
4N -(2-hydroxyoctahydro-1H-inden-1-yl)succinamide(72). . . . . . . . . 54
1 ◦ ◦4.22 HNMRspectrumof177recordedatA:at55 CandB:at25 C. . . . . 58
13 ◦ ◦4.23 CNMRspectrumof177recordedatA:at55 CandB:at25 C. . . . . 58
4.24 HPLCchromatograms: A.CDCl sample,B.177inCDCl . . . . . . . . . 653 3ListofSchemes
1.1 Radicalcyclizationaffordingcyclic1,2-aminoalcohols. . . . . . . . . . . 4
1.2 Cyclic1,2-aminoalcoholsviaintramolecularHenryreaction. . . . . . . . 4
1.3 Diastereoselectivereductionofα-aminoketone9. . . . . . . . . . . . . . 5
1.4 Enantiooselectivesynthesisofthe β-aminoalcohol13. . . . . . . . . . . . 6
1.5 Asymmetricringopeningofthemeso-epoxide15catalyzedby(salen)Cr(III)N3
complex14. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.6 Enantioselectivealkylativedoubleringopeningofazabicycloalkene-derived
epoxides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.7 Epoxideopeningwithnitrogennucleophile. . . . . . . . . . . . . . . . . 7
1.8 Aminohydroxylationreactionofcyclohexene(23). . . . . . . . . . . . . . 8
1.9 Enantioselectivesynthesisofcis-1-amino-2-indanol(22)byKo. . . . . . . 8
2.1 Synthesis of the heterocyclic β-amino acid 47 by tandem aza-Michael
addition/intramolecularcyclization. . . . . . . . . . . . . . . . . . . . . . 14
2.2 Copper-catalyzedconjugateaddition-cyclizationon48. . . . . . . . . . . 14
2.3 Rh-catalyzedenantioselectivecarbometallativealdolcycloreductionof51. 15
2.4 Stereoselctiveconjugateadditionofvinylsulfone55. . . . . . . . . . . . 16
2.5 Intramolecularconjugateaddition/intramolecularalkylationreactionof
thevinylsulfone58.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.6 Employingvinylsulfoxide60asaMichaeldonor. . . . . . . . . . . . . . 17
2.7 Reductivecyclizationof62withLiAlH . . . . . . . . . . . . . . . . . . . . 174
2.8 Reductivecyclizationofsulfone65withDIBAL-H–i-BuLi. . . . . . . . . 18
3.1 Aminoalkylationofcyclicallysulfoximines67. . . . . . . . . . . . . . . . 19
4.1 Reactionofsulfoximine91withDIBAL-H. . . . . . . . . . . . . . . . . . 24
4.2 DIBAL-Hreductionofα,β-unsaturatedsulf