2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent...
Transcript of 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent...
Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 111.11.2016 |
2. Reactions at Non-Anomeric Hydroxyl Groups
u AlkylandarylethersarerelativelystabletoacidsandbasesduetothehighC–Obondenergy(358KJ/mol)
u mostusefulether-typeprotectionsutilizeresonancestabilization(bydelocalization)ofthebenzylic-typecation orradicaltofacilitatethecleavage
u Themostcommonethersusedasprotectinggroupsare:
• MethylEthers• Benzyl(Bn)Ethers• SubstitutedBenzylEthers• AllylandRelatedEthers• Trityl (Tr)Ethers• 2-Naphthylmethyl(NAP)Ethers• Propargyl Ethers• o-Xylylene Ethers
2.1Ether-TypeProtectingGroups
OBnOBnO
BnO
OBnOR
OMeOMeO
MeO
OMeOR
OPMBOPMBO
PMBO
OPMBOR
ONapOMOMO
TrtO
OBnOR
Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 211.11.2016 |
Selectiveremovalofmethoxy protectinggroups
MethylEthers• Methylethersarenotnormallyregardedasprotectinggroups• Theremovalisdifficultrequiringconditionsnotcompatiblewithotherfunctional
groupsTheselectiveremovalofanetheradjacenttoahydroxylgroupincarbohydratesubstrates
Boto A,etal.(2004)Org Lett6:3785
(Diacetoxyiodo)benzene(DIB)
Benzyl(Bn)Ethers• Theclassicalpermanentprotectinggroupforcarbohydrates• Itisverystableandcanbereadilyremovedunderessentiallyneutralconditions• Benzyletherformationisusuallyachievedbythereactionofalcoholsandbenzylhalides
Alkylation Reactions: Ether-Type Protecting Groups
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Benzyl (Bn) Ethers
Benzylation ofmethylα-D-glucopyranoside
• Selectivebenzylation ofcarbohydratehydroxylfunctionsbydirectone-stepprotectionisdifficulttoachieve
• Severaltechniquesfortheselectiveprotectionhavebeendeveloped
• Generally,oneofthetwoC–Obondsinbenzylideneacetalscanbeselectivelycleaved
• thedirectionofthecleavageisdependentonstericandelectronicfactorsaswellas,onthenatureofthecleavagereagent
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Reductive Opening of Benzylidene Acetals
OORO
OMe
O
RO
Ph OHORO
OMe
BnO
RO
OBnORO
OMe
HO
RO+
Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 511.11.2016 |
Selective Opening of Benzylidene Acetals
Generalmechanism
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Selective Opening of Benzylidene Acetals
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Regioselective benzylation by opening of benzylidene acetals
• SubstratecanbetreatedwiththetinreagentformingoneortwoSn–Obonds,enhancingthenucleophilicity oftheoxygenatomsinthestannyl etherorstannyleneacetal.
• TheeffectisdifferentforthetwooxygenatomsforminganSn-acetal andcanbeusedforhigherregioselectivity.
“Benzylideneacetalscanalsobeopenedunderoxidativeconditions,typicallyusingNBSinCCl4“
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Examples of stannyl-mediated regioselective benzylation
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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
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Substituted Benzyl Ethers
• Substitutedbenzyletherscanbeselectivelyremovedinthepresenceofunsubstitutedbenzylethershavebeendeveloped.
v p-methoxy benzyl(PMB)isanimportantincarbohydratechemistryduetoitseasyintroductionandremoval.
v PMBgroupremovalcanbemediatedbyoxidizingagentsorbyLewisacids
• ByoxidationwithDDQ• DDQ-FeCl3• DDQ-Mn(OAc)3• CAN(CeriumAmmoniumNitrate)
PMBetherscanbecleavedwithZrCl4,SnCl2/TMS-Cl/anisole,CF3CO2HinCH2Cl2,CeCl3.7H2O/NaI,orI2/MeOH
OBnOBnO
O
OBnOR
MeO
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Removal of p-Methoxybenzyl Ethers with DDQ
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Removal of PMB with Acids
Examplesofdeprotectionofp-methoxybenzyl etherswithaLewisacid(SnCl4)
Two-stepdeprotectionofp-acetoxybenzyl protectinggroup
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Examples of p-substituted benzyl-type protecting groups
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Examples of p-substituted benzyl-type protecting groups
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Allyl and Related Ethers
Allyl-ethers
Exampleofregioselective allylationfromcoppercomplexes
• Theprotectionwithallylandrelated(prenyl,methylallyl,cinnamyl,homoallyl)groupsisofgreatimportanceduetotheirstabilityundertheconditionsrequiredforglycosideformation.
• Theyaremoderatelystabletoacidsandbases,andofferthepotentialforselectivedealkylation
Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 1611.11.2016 |
Removal of Allyl Ethers
Selectivecleavageofbranchedallylethers
• Commonallyldeprotectionmethodsaretwo-stageproceduresthatincludeisomerizationto1-propenylgroupwithavarietyofagents
• Themostfrequentlyemployedconditionsare:treatmentwitht-BuOK,Wilkinson catalyst,Pd/C,PdCl2,ruthenium(II),andiridium(I)complexesfollowedbyacidhydrolysisoroxidation.
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Trityl-Ethers
Tritylation ofmethylα-D-glucopyranoside
Substitutedtrityl protectinggroups
Trityl-ethers• Itsutilityisattributedtotheeasypreparationandremovalaswellastothehigh
selectivityforprimarypositionsobservedinpolyols
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2- Naphtyl-methyl Ether (NAP)
• Sarkar AK,RostandKS,JainRK,Matta KL,Esko JD(1997)JBiol Chem 272:25608• GauntMJ,YuJ,SpencerJB(1998)JOrgChem,63:4172
The“NAP”protectinggroupwasintroducedbyEsko andSpencerandithashigherstabilitytoacidicglycosylationconditionsthanPMBNAPcanberemovedby:• hydrogenolysis,• acids• oxidationconditions(similartoPMB)