Enantioselective Synthesis of Cyclic β-Amino Alcohols via Tandem Hydroalumination-Cyclization ...

168 Pages·2009·1.08 MB·English

Enantioselective Synthesis of Cyclic β-Amino
Alcohols via Tandem
Hydroalumination-Cyclization-Reduction of
Ethoxycarbonyl Vinyl Sulfoximines and
Application to The Synthesis of Potential
Aggrecanase Inhibitors
VonderFakulta¨tfu¨rMathematik,InformatikundNaturwissenschaftender
Rheinisch-Westfa¨lischenTechnischenHochschuleAachenzurErlangungdes
akademischenGradeseinesDoktorsderNaturwissenschaftengenehmigte
Dissertation
vorgelegtvon
MasterofScience
SerdarAc¸ıkalın
ausSarayko¨y(Denizli/Tu¨rkei)
Berichter: Universita¨tsprofessorDr. H.-J.Gais
Universita¨tsprofessor Dr. D.Enders
Tagdermu¨ndlichenPru¨fung: 10. Juli2009
DieseDissertationistaufdenInternetseitenderHochschulbibliothekonlineverfu¨gbar.
Dein Leben sei ein hundertfa¨ltiger Versuch:
dein Mißlingen und Gelingen sein ein Beweis:
und sorge dafu¨r, daß man wisse,
was du versucht und bewiesen hast.
Nietzsche
The 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 FurtherTransformations ofCyclic 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 Removal ofsulfoximinegroup . . . . . . . . . . . . . . . . . . . . 46
Aluminiumamalgam . . . . . . . . . . . . . . . . . . . . . . . . . 46
Raney-Nickel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
4.2.6 DeprotectionofN-tert-butysulfonylgroup . . . . . . . . . . . . . 47
4.3 SynthesisofSulfoximine-SubstitutedPotential AggrecanaseInhibitor72 48
4.3.1 RacemicApproach . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
SynthesisofMethyl3-(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 147
List of Figures
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-yne viahydroalumintaion. . . . . . . . . . . . . 17
3.1 Plannedbicyclic1,2-aminoalcohol71synthesis. . . . . . . . . . . . . . . 20
3.2 Retrosyntheticanalysisofsulfoximine-substitutedN1-hydroxy-N4-(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 Plausbilemechanismofthesaturated sulfoximine93formation. . . . . . 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
4.11 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
4.20 Retrosyntheticanalysisofsulfoximine-substitutedN1-hydroxy-N4-(2-hydroxy-
octahydro-1H-inden-1-yl)succinamide(72). . . . . . . . . . . . . . . . . . 49
4.21 Alternativeretrosyntheticanalysisofsulfoximine-substitutedN1-hydroxy-
N4-(2-hydroxyoctahydro-1H-inden-1-yl)succinamide(72). . . . . . . . . 54
4.22 1HNMRspectrumof177recordedatA:at55 ◦CandB:at25 ◦C. . . . . 58
4.23 13CNMRspectrumof177recordedatA:at55 ◦CandB:at25 ◦C. . . . . 58
4.24 HPLCchromatograms: A.CDCl sample,B.177inCDCl . . . . . . . . . 65
3 3
List of Schemes
1.1 Radicalcyclizationaffordingcyclic1,2-aminoalcohols. . . . . . . . . . . 4
1.2 Cyclic1,2-aminoalcoholsviaintramolecularHenryreaction. . . . . . . . 4
1.3 Diastereoselectivereductionof α-aminoketone9. . . . . . . . . . . . . . 5
1.4 Enantiooselectivesynthesisofthe β-aminoalcohol13. . . . . . . . . . . . 6
1.5 Asymmetricringopeningofthemeso-epoxide15catalyzedby(salen)Cr(III)N
3
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 . . . . . . . . . . . . . . . . . . . . 17
4
2.8 Reductivecyclizationofsulfone65withDIBAL-H–i-BuLi. . . . . . . . . 18
3.1 Aminoalkylationofcyclicallysulfoximines67. . . . . . . . . . . . . . . . 19
4.1 Reactionofsulfoximine91withDIBAL-H. . . . . . . . . . . . . . . . . . 24
4.2 DIBAL-Hreductionof α,β-unsaturatedsulfoximineE-82. . . . . . . . . . 24
4.3 Synthesisofsulfoximine-substitutedcyclic β-aminoalcohols100and101. 28
4.4 Synthesisofsulfoximine-substitutedcyclic β-aminoalcohols108and109. 31
4.5 ReactionofDIBAL-HwithvinylicsulfoximineE-83. . . . . . . . . . . . . 32
4.6 ReactionofDIBAL-HwithvinylicsulfoximineE-85. . . . . . . . . . . . . 35
4.7 Synthesisofketal-functionalizedbicyclic β-aminoalcohols119and120. 36
4.8 ReactionsofDIBAL-HwithZ-82andZ-83. . . . . . . . . . . . . . . . . . 37
4.9 Substitutionofsulfoximinebychloride. . . . . . . . . . . . . . . . . . . . 41
4.10 Substitutionofsulfoximinebyiodide. . . . . . . . . . . . . . . . . . . . . 42
4.11 Synthesisofsulfone147. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
4.12 AnexampleofMitsunoburingclosuremethod. . . . . . . . . . . . . . . 44
4.13 Synthesisofthe γ-aminovinylicsulfoximine151. . . . . . . . . . . . . . 45
4.14 Removalofsulfoximinesbyaluminiumamalgammethod. . . . . . . . . 46
4.15 Aluminiumamalgamreductionofsulfoximine100. . . . . . . . . . . . . 47
4.16 RemovalofsulfoximinebyRaney-Nickel. . . . . . . . . . . . . . . . . . . 47
4.17 Synthesisoftheβ-aminoalcohol161·1/2(CF SO H)viaacidicdeprotec-
3 3
tionof100. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.18 Synthesisofmethyl3-(3-(benzyloxy)phenyl)propanoate (162). . . . . . . 50
4.19 Attempted alkylation of tert-butyl acetate with 1-(benzyloxy)-3-(chloro-
methyl)benzene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
4.20 Synthesisoftert-butyl3-(3-(benzyloxy)phenyl)propanoate (163). . . . . . 51
4.21 Attempted alkylation of tert-butyl 3-(3-(benzyloxy)phenyl)propanoate
(163)withbenzyl2-bromoacetate. . . . . . . . . . . . . . . . . . . . . . . 52
4.22 Enolateformationverification. . . . . . . . . . . . . . . . . . . . . . . . . 52
4.23 Degreeofdeuterationofenolate. . . . . . . . . . . . . . . . . . . . . . . . 53
4.24 TestingLDAalkylationwithbenzyl2-iodoacetateaselectrophile. . . . . 53
4.25 Synthesisof4-tert-butoxy-4-oxobutanoicacid169startingfromtert-butyl
propanoate 163. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
4.26 AliteratureexampleofEvans’chiralenolatemethodology. . . . . . . . . 56
4.27 Couplingofacid169withsulfoximine-substituted β-aminoalcohol161. 56
4.28 SynthesisofO,O-dibenzylprotected hydroxyhydroxamicacid177. . . . 57
4.29 Attempteddeprotectionof177usinganautoclaveandPd/BaSO catalyst. 59
4
4.30 Hydroxamicacid33synthesisviahydrogenolysis. . . . . . . . . . . . . . 60
4.31 Testingtheshakerapparatusandcatalystquality. . . . . . . . . . . . . . 60
4.32 Attempted deprotection of 177 using shaker apparatus and Pd/BaSO
4
catalyst. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
4.33 Attempted deprotection of 177 employing Pd/C (wet support, Degussa
typeE101NO/W)catalyst. . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4.34 Attempted deprotectionsofbenzylgroupsviatransferhydrogenolysis. . 63
4.35 Testingthecatalystpoisoningpotentialofsulfoximinefunctionality. . . 63
4.36 Protonationpriortodeprotectionofbenzylgroupsviahydrogenolysis. . 64
5.1 HydroaluminationofE-andZ-configuredα,β-unsaturatedsulfoximine-
substituted α-aminoesters. . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
5.2 Planned synthesis of sulfoximine-substituted potential aggrecanase in-
hibitor72. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
5.3 Possiblebicyclicβ-aminoalcoholsynthesisviahydroaluminationofsulfoximine-
substituted α-hydroxyesters180. . . . . . . . . . . . . . . . . . . . . . . . 69