Amino Acids, Peptides and Proteins in Organic Chemistry: Volume 4 - Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis (Amino Acids, Peptides and Proteins in Organic Chemistry (VCH))

538 Pages·2011·5.84 MB·English

by  Andrew B. Hughes

Edited by
Andrew B. Hughes
Amino Acids, Peptides
and Proteins in
Organic Chemistry
Further Reading
Pignataro, B.(ed.) Drauz, K.,Gröger,H., May,O. (eds.)
Ideas in Chemistry and Enzyme Catalysis in Organic
Molecular Sciences Synthesis
AdvancesinSyntheticChemistry Third,completelyrevised
andenlargededition
2010
ISBN:978-3-527-32539-9 3Volumes
2011
Theophil Eicher,Siegfried Hauptmann
ISBN:978-3-527-32547-4
andAndreas Speicher
The Chemistry of Heterocycles Fessner,W.-D.,Anthonsen, T.
Structure,Reactions,Synthesis,and Modern Biocatalysis
Applications StereoselectiveandEnvironmentally
2011 FriendlyReactions
ISBN:978-3-527-32868-0(Hardcover) 2009
ISBN:978-3-527-32747-8(Softcover) ISBN:978-3-527-32071-4
Royer,J. (ed.) Lutz, S., Bornscheuer,U. T. (eds.)
Asymmetric Synthesis of Protein Engineering Handbook
Nitrogen Heterocycles 2VolumeSet
2009 2009
ISBN:978-3-527-32036-3 ISBN:978-3-527-31850-6
Reek, J.N.H.,Otto,S. Sewald, N., Jakubke,H.-D.
Dynamic Combinatorial Peptides: Chemistry and
Chemistry Biology
2010 2009
ISBN:978-3-527-32122-3 ISBN:978-3-527-31867-4
Rutjes,F., Fokin, V.V. (eds.) Jakubke, H.-D., Sewald, N.
Click Chemistry Peptides from A to Z
inChemistry,Biologyand AConciseEncyclopedia
MacromolecularScience
2008
2011 ISBN:978-3-527-31722-6
ISBN:978-3-527-32085-1
Nicolaou,K.C., Chen,J. S.
Classics in Total Synthesis III
NewTargets,Strategies,Methods
2011
ISBN:978-3-527-32958-8(Hardcover)
ISBN:978-3-527-32957-1(Softcover)
Edited by
Andrew B. Hughes
Amino Acids, Peptides and Proteins
in Organic Chemistry
Volume 4 - Protection Reactions, Medicinal Chemistry,
Combinatorial Synthesis
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ISBN:978-3-527-32103-2
V
Contents
List of Contributors XVII
1 ProtectionReactions 1
VomminaV.SureshbabuandNarasimhamurthyNarendra
1.1 GeneralConsiderations 1
1.2 a-AminoProtection(NaProtection) 4
1.2.1 Non-Urethanes 4
1.2.1.1 AcylType 4
1.2.1.1.1 MonoacylGroups 5
1.2.1.1.2 GroupsCleavableviaLactamFormation 6
1.2.1.1.3 DiacylGroups 7
1.2.1.2 Phosphine-TypeGroups 10
1.2.1.3 Sulfonyl-TypeGroups 10
1.2.1.4 Alkyl-TypeGroups 11
1.2.1.4.1 Triphenylmethyl(TritylorTrt)Group 11
1.2.1.4.2 BenzhydrylGroups 12
1.2.1.4.3 N,N-Bis-BenzylProtection 12
1.2.1.4.4 VinylGroups 12
1.2.1.5 Sulfanyl-TypeGroups 13
1.2.2 Urethanes(CarbamatesorAlkyloxycarbonylGroups) 14
1.2.2.1 FormationoftheUrethaneBond 16
1.2.2.2 UrethanesDerivedfromPrimaryAlcohols 16
1.2.2.2.1 Benzyloxycarbonyl(CbzorZ)Group 16
1.2.2.2.2 UrethanesCleavedbyb-Elimination 19
1.2.2.2.3 UrethanesCleavedviaMichael-TypeAddition 24
1.2.2.2.4 Allyloxycarbonyl(Aloc)Group 25
1.2.2.3 UrethaneGroupsDerivedfromSecondaryAlcohols 25
1.2.2.4 UrethanesDerivedfromTertiaryAlcohols 25
1.2.2.4.1 tert-Butoxycarbonyl(Boc)Group 25
1.2.2.4.2 BocAnalogs 28
1.2.2.5 OtherAspectsofUrethaneProtectors 29
AminoAcids,PeptidesandProteinsinOrganicChemistry.
Vol.4–ProtectionReactions,MedicinalChemistry,CombinatorialSynthesis.EditedbyAndrewB.Hughes
Copyright(cid:1)2011WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:978-3-527-32103-2
VI Contents
1.2.2.5.1 FormationofDipeptideImpuritiesduringtheIntroduction
ofUrethanesandProtocolstoOvercomeIt 29
1.2.2.5.2 IntroductionofUrethanesviaTransprotection 30
1.2.2.5.3 ProtectionoftheNitrogenofa-AminoAcid
N-CarboxyAnhydrides(NCAs) 31
1.2.2.5.4 Na,Na-bis-ProtectedAminoAcids 32
a
1.2.3 OtherN -ProtectingGroups 32
1.2.3.1 a-AzidoAcidsasa-AminoAcidPrecursors 33
a a
1.2.3.2 One-PotN ProtectionandC Activation 33
a
1.2.3.3 EffectofN -ProtectingGroupsintheSynthesisofNMAs 33
1.3 CarboxyProtection 34
1.3.1 MethylandEthylEsters 35
1.3.1.1 SubstitutedMethylandEthylEsters 36
1.3.2 BenzylEster 36
1.3.2.1 Cleavage 36
1.3.3 SubstitutedBenzylEsters 38
1.3.4 tert-ButylEster 38
1.3.5 OtherAcid-LabileEsters 39
1.3.6 Temporarya-CarboxyProtection 39
1.3.7 a-CarboxyProtectorsasPrecursorstoUsefulAmino
AcidDerivatives:FormationofAcidHydrazides 41
1.4 Side-ChainProtection 41
1.4.1 o-AminoGroupofDiaminoAcids 41
1.4.2 GuanidinoGroupofArg 43
1.4.2.1 ProtectionThroughProtonation 43
1.4.2.2 Nitration 44
1.4.2.3 ArgPrecursors 45
1.4.3 ImidazoleGroupofHis 45
1.4.4 IndoleGroupofTrp 48
1.4.5 o-AmidoGroupofAsnandGln 49
1.4.6 b-ThiolGroupofCys 50
1.4.6.1 CommonSide-ReactionswithS-ProtectedCysDerivatives 51
1.4.6.1.1 Racemization 51
1.4.6.1.2 b-Elimination 51
1.4.6.1.3 Oxidation 51
1.4.6.2 SynthesisofPeptidesUsingCystineas‘‘Self-Protected’’Cys 51
1.4.7 ThioetherGroupofMet 53
1.4.8 HydroxyGroupofSer,Thr,andthePhenolicGroupofTyr 54
1.4.9 o-CarboxyGroupofAspandGlu 55
1.4.9.1 AspartimideFormation 55
1.5 PhotocleavableProtections 57
1.6 Conclusions 58
1.7 ExperimentalProcedures 59
1.7.1 ProtectionReactions 59
1.7.1.1 GeneralProcedureforthePreparationofTfa-Arg-OH 59
Contents VII
a
1.7.1.2 GeneralProcedureforthePreparationofN -PhthaloylAmino
AcidsusingN-(Ethoxycarbonyl)phthalimide 59
a
1.7.1.3 GeneralProcedureforthePreparationofN -Trt-AminoAcids 59
a
1.7.1.4 GeneralProcedureforthePreparationofN -Ns-AminoAcids 60
a
1.7.1.5 GeneralProcedureforthePreparationofN -Z-AminoAcids 61
1.7.1.5.1 MethodA:UsingZ-Cl 61
1.7.1.5.2 MethodB:UsingZ-OSu 62
a
1.7.1.6 GeneralProceduresforthePreparationofN -Fmoc-AminoAcids 62
1.7.1.6.1 MethodA:UsingFmoc-OSu 62
1.7.1.6.2 MethodB:UsingFmoc-ClandN,O-bis-TMS-AminoAcids 62
1.7.1.6.3 MethodC:UsingFmoc-ClinthePresenceofZincDust 63
1.7.1.6.4 MethodD:UsingFmoc-N 63
3
a
1.7.1.7 GeneralProcedureforthePreparationofN -Nsc-AminoAcids 64
1.7.1.8 GeneralProcedureforthePreparationof
a
N -Bsmoc-AminoAcids 64
1.7.1.9 GeneralProcedureforthePreparationof
a
N -Aloc-AminoAcids 65
1.7.1.10 GeneralProceduresforthePreparation
a
ofN -Boc-AminoAcids 65
1.7.1.10.1 MethodA:Using(Boc) O 65
2
1.7.1.10.2 MethodB:UsingBoc-ON 65
1.7.1.10.3 MethodC:UsingBoc-N 66
3
1.7.1.11 GeneralProcedureforthePreparation
ofN,N0-di-Boc-AminoAcids 66
1.7.1.12 GeneralProcedureforthePreparationof
a
N -Bpoc-AminoAcids 67
1.7.1.13 GeneralProceduresforthePreparationofAmino
AcidMethylEsters 68
1.7.1.13.1 PreparationofAminoAcidMethylEsterHydrochlorideSalts 68
1.7.1.13.2 IsolationofAminoAcidMethylEsters:Deprotonation
oftheHydrochlorideSaltUsingZincDust 69
1.7.1.13.3 GlutamicAcida-Methyl,c-tert-ButylDiester
UsingDiazomethane 69
1.7.1.13.4 Z-Glu-OMeviaMethanolysisofCyclicAnhydride 69
1.7.1.14 GeneralProcedureforthePreparationofAmino
AcidEthylEsters 69
1.7.1.15 GeneralProcedureforthePreparationofAmino
AcidBenzylEsterp-ToluenesulfonateSalts 70
1.7.1.15.1 PreparationofAminoAcidBenzylEsterp-ToluenesulfonateSalts
UnderMicrowaveIrradiation 70
1.7.1.16 GeneralProcedureforthePreparationoftert-ButylEsters
a
ofN -UnprotectedAminoAcidsUsingIsobutene 71
1.7.1.16.1 PreparationofZ-Phe-OtBubytheSilverSaltMethod 71
1.7.1.17 GeneralProcedureforConcomitantProtectionandActivation
ofAminoAcidsUsingPentafluorophenylCarbonate 80
VIII Contents
1.7.2 DeprotectionReactions 81
1.7.2.1 RemovalofthePhthGroupbyHydrazinolysis 81
1.7.2.2 RemovaloftheNpsGroup 81
1.7.2.3 RemovaltheZ-group 82
1.7.2.3.1 ProtocolA:EmployingCH 82
1.7.2.3.2 ProtocolB:EmployingSilylhydride 82
1.7.2.3.3 ProtocolC:ThroughCTHusing1,4-Cyclohexadieneas
HydrogenDonor 83
1.7.2.4 CleavageoftheFmocGroup 83
1.7.2.4.1 MethodA:UsingTAEA[67] 83
1.7.2.4.2 MethodB:UsingDEA:SimultaneousRemovaloftheFmocGroup
and9-FluorenylmethylEster 83
1.7.2.5 CleavageoftheBocGroup 84
1.7.2.5.1 ProtocolA:RemovaloftheBocgroupwithTFA
inthePresenceofScavengers 84
1.7.2.5.2 ProtocolB:CleavageofBocGroupwith
TMS/Phenol 84
a
1.7.2.6 TransprotectionofN -ProtectingGroups:
Fmoc-Met-OHtoBoc-Met-OH 84
1.7.2.7 SelectiveMethylEsterHydrolysisinthePresence
a
oftheN -FmocGroup 84
1.7.2.8 Cleavageoftert-ButylEsterUsingBF (cid:1)Et O 84
3 2
1.7.2.9 SelectiveCleavageofPhenacylEsterinthe
a
PresenceoftheN -NosylGroup 85
1.7.2.10 RemovaloftheTrtGroup(Iodolysis) 85
1.7.2.11 DeprotectionofthePbfGroupfromZ-Arg(Pbf)-OH 85
1.7.2.12 RemovalofthePhenocGroupthroughPhotolysis 85
a
1.7.2.13 ConversionoftheDCHASaltofN -ProtectedAminoAcids
intoFreeAcids 85
References 86
PartOne AminoAcid-BasedPeptidomimetics 99
2 HuisgenCycloadditioninPeptidomimeticChemistry 101
DanielSejerPedersenandAndrewDavidAbell
2.1 Introduction 101
2.2 Huisgen[2þ3]CycloadditionBetweenAzidesand
Acetylenes 102
2.3 MechanisticConsiderationfortheCu-Huisgen
andRu-HuisgenCycloadditions 103
2.4 BuildingBlocksfortheSynthesisofTriazole-Modified
Peptidomimetics 106
2.5 CyclicTriazolePeptidomimetics 109
2.6 AcyclicTriazolePeptidomimetics 113
2.7 UsefulExperimentalProcedures 121
Contents IX
2.7.1 MonitoringHuisgenCycloadditionsandCharacterizing
Triazoles 121
2.7.2 GeneralProcedurefortheSynthesisof1,4-Triazoles
UsingCu-HuisgenCycloaddition 122
2.7.3 GeneralProcedurefortheSynthesisof1,5-Triazoles
UsingRu-HuisgenCycloaddition 123
References 124
3 RecentAdvancesinb-StrandMimetics 129
WendyA.LoughlinandDavidP.Fairlie
3.1 Introduction 129
3.1.1 b-Strands 129
3.1.2 b-Sheets 130
3.1.3 DifferencesinStrand/Sheet/Turn/HelixRecognition 130
3.1.4 Towardsb-StrandMimetics 131
3.2 MacrocyclicPeptidomimetics 133
3.3 AcyclicCompounds 135
3.4 AliphaticandAromaticCarbocycles 136
3.5 LigandsContainingOneRingwithOneHeteroatom(N) 137
3.6 LigandsContainingOneorMultipleRingswith
OneHeteroatom(O,S) 138
3.7 LigandsContainingOneRingwithTwoHeteroatoms(N,N) 139
3.8 LigandsContainingOneRingwithTwoHeteroatoms(N,S)
orThreeHeteroatoms(N,N,SorN,N,N) 140
3.9 LigandsContainingTwoRingswithOneHeteroatom(NorO) 140
3.10 LigandsContainingTwoRingswithTwoorThree
Heteroatoms(N,NorN,SorN,N,N) 141
3.11 Conclusions 142
References 143
PartTwo MedicinalChemistryofAminoAcids 149
4 MedicinalChemistryofa-AminoAcids 151
LennartBunchandPovlKrogsgaard-Larsen
4.1 Introduction 151
4.2 GlutamicAcid 151
4.3 ConformationalRestriction 153
4.3.1 Synthesis–GeneralConsiderations 154
4.3.2 CaseStudy:SynthesisofDCAN 155
4.3.3 CaseStudy:SynthesisofLY354740 157
4.3.4 CaseStudy:SynthesisofABHD-VandABHD-VI 158
4.4 Bioisosterism 159
4.4.1 CaseStudy:DesignandSynthesisofAMPA 160
4.4.2 CaseStudy:DesignandSynthesisofThioibotenicAcid 161
4.5 Structure–ActivityStudies 162