Download Vlsg-4-Protecting Groups I

2. Reactions at Non-Anomeric Hydroxyl Groups
2.1Ether-TypeProtectingGroups
u AlkylandarylethersarerelativelystabletoacidsandbasesduetothehighC–Obond
energy(358KJ/mol)
u mostusefulether-typeprotectionsutilizeresonancestabilization(bydelocalization)of
thebenzylic-typecation orradicaltofacilitatethecleavage
u Themostcommonethersusedasprotectinggroupsare:
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MethylEthers
Benzyl(Bn)Ethers
SubstitutedBenzylEthers
AllylandRelatedEthers
Trityl (Tr)Ethers
2-Naphthylmethyl(NAP)Ethers
Propargyl Ethers
o-Xylylene Ethers
Max Planck Institute of Colloids and Interfaces
BnO
BnO
BnO
O
OR
MeO
MeO
MeO
OBn
PMBO
PMBO
PMBO
O
OR
OPMB
O
OR
OMe
TrtO
NapO
MOMO
O
OR
OBn
| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Alkylation Reactions: Ether-Type
Protecting Groups
MethylEthers
• Methylethersarenotnormallyregardedasprotectinggroups
• Theremovalisdifficultrequiringconditionsnotcompatiblewithotherfunctional
groupsTheselectiveremovalofanetheradjacenttoahydroxylgroupincarbohydrate
substrates
Selectiveremovalofmethoxy protectinggroups
Boto A,etal.(2004)Org Lett6:3785
(Diacetoxyiodo)benzene(DIB)
Benzyl(Bn)Ethers
• Theclassicalpermanentprotectinggroupforcarbohydrates
• Itisverystableandcanbereadilyremovedunderessentiallyneutralconditions
• Benzyletherformationisusuallyachievedbythereactionofalcoholsandbenzylhalides
Max Planck Institute of Colloids and Interfaces
| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Benzyl (Bn) Ethers
Benzylation ofmethylα-D-glucopyranoside
• Selectivebenzylation ofcarbohydratehydroxylfunctionsbydirectone-stepprotectionis
difficulttoachieve
• Severaltechniquesfortheselectiveprotectionhavebeendeveloped
• Generally,oneofthetwoC–Obonds
inbenzylideneacetalscanbe
selectivelycleaved
• thedirectionofthecleavageis
dependentonstericandelectronic
factorsaswellas,onthenatureof
thecleavagereagent
Max Planck Institute of Colloids and Interfaces
| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Reductive Opening of Benzylidene Acetals
Ph
O
O
RO
BnO
HO
RO
O
RO
OMe
Max Planck Institute of Colloids and Interfaces
O
RO
+
OMe
HO
BnO
RO
O
RO
OMe
| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Selective Opening of Benzylidene Acetals
Generalmechanism
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| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Selective Opening of Benzylidene Acetals
Max Planck Institute of Colloids and Interfaces
| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Regioselective benzylation by opening of
benzylidene acetals
“Benzylideneacetalscanalsobeopenedunderoxidativeconditions,typically
usingNBSinCCl4“
• SubstratecanbetreatedwiththetinreagentformingoneortwoSn–Obonds,
enhancingthenucleophilicity oftheoxygenatomsinthestannyl etherorstannylene
acetal.
• TheeffectisdifferentforthetwooxygenatomsforminganSn-acetal andcanbeused
forhigherregioselectivity.
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| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Examples of stannyl-mediated
regioselective benzylation
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| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Examples of regioselective de-O-benzylation
Selectivede-O-benzylation ofeasilyavailablepolybenzylated precursors.
Thishasbeenachievedinlimitedcasesby:
• catalytichydrogenolysis
• Catalytichydrogen-transfercleavage
• Acetolysis
• hypoiodite fragmentation
• iodine-mediatedaddition-eliminationsequences
• Lewisacids
• Byisobutylalanes orthecombinationCrCl2/LiI
Max Planck Institute of Colloids and Interfaces
| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Substituted Benzyl Ethers
• Substitutedbenzyletherscanbeselectivelyremovedinthepresenceofunsubstituted
benzylethershavebeendeveloped.
MeO
O
BnO
BnO
O
OR
OBn
v p-methoxy benzyl(PMB)isanimportantincarbohydratechemistryduetoitseasy
introductionandremoval.
v PMBgroupremovalcanbemediatedbyoxidizingagentsorbyLewisacids
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ByoxidationwithDDQ
DDQ-FeCl3
DDQ-Mn(OAc)3
CAN(CeriumAmmoniumNitrate)
PMBetherscanbecleavedwithZrCl4,SnCl2/TMS-Cl/anisole,CF3CO2HinCH2Cl2,
CeCl3.7H2O/NaI,orI2/MeOH
Max Planck Institute of Colloids and Interfaces
| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Removal of p-Methoxybenzyl Ethers with
DDQ
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| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Removal of PMB with Acids
Examplesofdeprotectionofp-methoxybenzyl etherswithaLewisacid(SnCl4)
Two-stepdeprotectionofp-acetoxybenzyl protectinggroup
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| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Examples of p-substituted benzyl-type
protecting groups
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| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Examples of p-substituted benzyl-type
protecting groups
Max Planck Institute of Colloids and Interfaces
| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Allyl and Related Ethers
Allyl-ethers
• Theprotectionwithallylandrelated(prenyl,methylallyl,cinnamyl,homoallyl)groups
isofgreatimportanceduetotheirstabilityundertheconditionsrequiredfor
glycosideformation.
• Theyaremoderatelystabletoacidsandbases,andofferthepotentialforselective
dealkylation
Exampleofregioselective allylation
fromcoppercomplexes
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| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Removal of Allyl Ethers
• Commonallyldeprotectionmethodsaretwo-stageproceduresthatinclude
isomerizationto1-propenylgroupwithavarietyofagents
• Themostfrequentlyemployedconditionsare:
treatmentwitht-BuOK,Wilkinson catalyst,Pd/C,PdCl2,ruthenium(II),andiridium(I)
complexesfollowedbyacidhydrolysisoroxidation.
Selectivecleavageofbranchedallylethers
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| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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Trityl-Ethers
Trityl-ethers
• Itsutilityisattributedtotheeasypreparationandremovalaswellastothehigh
selectivityforprimarypositionsobservedinpolyols
Tritylation ofmethylα-D-glucopyranoside
Substitutedtrityl protectinggroups
Max Planck Institute of Colloids and Interfaces
| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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2- Naphtyl-methyl Ether (NAP)
The“NAP”protectinggroupwasintroducedbyEsko andSpencerandithashigher
stabilitytoacidicglycosylationconditionsthanPMB
NAPcanberemovedby:
• hydrogenolysis,
• acids
• oxidationconditions(similartoPMB)
• Sarkar AK,RostandKS,JainRK,Matta KL,Esko JD(1997)JBiol Chem 272:25608
• GauntMJ,YuJ,SpencerJB(1998)JOrgChem,63:4172
Max Planck Institute of Colloids and Interfaces
| Daniel Varón Silva | Carbohydrate Chemistry and Biology | 11.11.2016 |
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