2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent...

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Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 1 11.11.2016 | 2. Reactions at Non-Anomeric Hydroxyl Groups u Alkyl and aryl ethers are relatively stable to acids and bases due to the high C–O bond energy (358 KJ/mol) u most useful ether-type protections utilize resonance stabilization (by delocalization) of the benzylic-type cation or radical to facilitate the cleavage u The most common ethers used as protecting groups are: • Methyl Ethers • Benzyl (Bn) Ethers • Substituted Benzyl Ethers • Allyl and Related Ethers • Trityl (Tr) Ethers • 2-Naphthylmethyl (NAP) Ethers • Propargyl Ethers • o-Xylylene Ethers 2.1 Ether-Type Protecting Groups O BnO BnO BnO OBn OR O MeO MeO MeO OMe OR O PMBO PMBO PMBO OPMB OR O NapO MOMO TrtO OBn OR

Transcript of 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent...

Page 1: 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent to a hydroxyl group in carbohydrate substrates BotoA, et al. (2004) Org Lett 6:3785

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

Page 2: 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent to a hydroxyl group in carbohydrate substrates BotoA, et al. (2004) Org Lett 6:3785

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

Page 3: 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent to a hydroxyl group in carbohydrate substrates BotoA, et al. (2004) Org Lett 6:3785

Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 311.11.2016 |

Benzyl (Bn) Ethers

Benzylation ofmethylα-D-glucopyranoside

• Selectivebenzylation ofcarbohydratehydroxylfunctionsbydirectone-stepprotectionisdifficulttoachieve

• Severaltechniquesfortheselectiveprotectionhavebeendeveloped

• Generally,oneofthetwoC–Obondsinbenzylideneacetalscanbeselectivelycleaved

• thedirectionofthecleavageisdependentonstericandelectronicfactorsaswellas,onthenatureofthecleavagereagent

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Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 411.11.2016 |

Reductive Opening of Benzylidene Acetals

OORO

OMe

O

RO

Ph OHORO

OMe

BnO

RO

OBnORO

OMe

HO

RO+

Page 5: 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent to a hydroxyl group in carbohydrate substrates BotoA, et al. (2004) Org Lett 6:3785

Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 511.11.2016 |

Selective Opening of Benzylidene Acetals

Generalmechanism

Page 6: 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent to a hydroxyl group in carbohydrate substrates BotoA, et al. (2004) Org Lett 6:3785

Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 611.11.2016 |

Selective Opening of Benzylidene Acetals

Page 7: 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent to a hydroxyl group in carbohydrate substrates BotoA, et al. (2004) Org Lett 6:3785

Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 711.11.2016 |

Regioselective benzylation by opening of benzylidene acetals

• SubstratecanbetreatedwiththetinreagentformingoneortwoSn–Obonds,enhancingthenucleophilicity oftheoxygenatomsinthestannyl etherorstannyleneacetal.

• TheeffectisdifferentforthetwooxygenatomsforminganSn-acetal andcanbeusedforhigherregioselectivity.

“Benzylideneacetalscanalsobeopenedunderoxidativeconditions,typicallyusingNBSinCCl4“

Page 8: 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent to a hydroxyl group in carbohydrate substrates BotoA, et al. (2004) Org Lett 6:3785

Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 811.11.2016 |

Examples of stannyl-mediated regioselective benzylation

Page 9: 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent to a hydroxyl group in carbohydrate substrates BotoA, et al. (2004) Org Lett 6:3785

Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 911.11.2016 |

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

Page 10: 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent to a hydroxyl group in carbohydrate substrates BotoA, et al. (2004) Org Lett 6:3785

Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 1011.11.2016 |

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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Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 1111.11.2016 |

Removal of p-Methoxybenzyl Ethers with DDQ

Page 12: 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent to a hydroxyl group in carbohydrate substrates BotoA, et al. (2004) Org Lett 6:3785

Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 1211.11.2016 |

Removal of PMB with Acids

Examplesofdeprotectionofp-methoxybenzyl etherswithaLewisacid(SnCl4)

Two-stepdeprotectionofp-acetoxybenzyl protectinggroup

Page 13: 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent to a hydroxyl group in carbohydrate substrates BotoA, et al. (2004) Org Lett 6:3785

Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 1311.11.2016 |

Examples of p-substituted benzyl-type protecting groups

Page 14: 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent to a hydroxyl group in carbohydrate substrates BotoA, et al. (2004) Org Lett 6:3785

Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 1411.11.2016 |

Examples of p-substituted benzyl-type protecting groups

Page 15: 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent to a hydroxyl group in carbohydrate substrates BotoA, et al. (2004) Org Lett 6:3785

Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 1511.11.2016 |

Allyl and Related Ethers

Allyl-ethers

Exampleofregioselective allylationfromcoppercomplexes

• Theprotectionwithallylandrelated(prenyl,methylallyl,cinnamyl,homoallyl)groupsisofgreatimportanceduetotheirstabilityundertheconditionsrequiredforglycosideformation.

• Theyaremoderatelystabletoacidsandbases,andofferthepotentialforselectivedealkylation

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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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Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 1711.11.2016 |

Trityl-Ethers

Tritylation ofmethylα-D-glucopyranoside

Substitutedtrityl protectinggroups

Trityl-ethers• Itsutilityisattributedtotheeasypreparationandremovalaswellastothehigh

selectivityforprimarypositionsobservedinpolyols

Page 18: 2. Reactions at Non-Anomeric Hydroxyl Groups · groups The selective removal of an ether adjacent to a hydroxyl group in carbohydrate substrates BotoA, et al. (2004) Org Lett 6:3785

Max Planck Institute of Colloids and Interfaces | Daniel Varón Silva | Carbohydrate Chemistry and Biology | 1811.11.2016 |

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)


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