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Methodsforα-Sialyla2on CarolineBraun TownsendGroupMee2ng May11,2016 SialicAcids • Familyof2-keto-3-deoxy-nononicacids – Neuraminicacid:C-5aminoderiva2ve OH HO O N O H OH CO2H OH HO OH HO O H αNeu5Ac O N HO HO αNeu5Gc OH HO CO2H OH O HO HO αKDN OH CO2H OH OH BiosynthesisofNeu5Ac HO HO OH OH NHAc O HO OH OH OH Neu5Ac aldolase OH AcHN O CO2 OH O AcHN OH HO O ManNAc HO Me CO2 Neu5Ac Kiefel,M.J.;vonItzstein,M.Chem.Rev.2002,102,471-490. SialosidesinNature • Equatorialglycosides:α-anomer • Terminalsugarsofglycoproteins – N-orO-linked – Linkagetogalactosides:α(2!3)orα(2!6) • Disialosylstructuresascons2tuentsofglycoproteins andlipids – Neu5Acα(2!8)Neu5Ac – Neu5Acα(2!9)Neu5Ac Boon,G-J.;Demchenko,A.V.Chem.Rev.2000,100,4539-4565. Kiefel,M.J.;vonItzstein,M.2002,102,471-490. Enzyma2cSynthesisofO-Sialosides ManNAc Neu5Ac aldolase pyruvic acid CMP-Neu5Ac synthase Neu5Ac CTP OH sialyltransferase HO-acceptor HO CO2 OH O AcHN CMP-Neu5Ac O acceptor HO sialoside Kiefel,M.J.;vonItzstein,M.Chem.Rev.2002,102,471-490. Synthe2cGlycosidicBondForma2on O O activator HO RO OR' X donor acceptor O O RO O OR' • Stereochemicalcontrol – Neighboringgrouppar2cipa2on(C-2) – Reac2oncondi2ons(i.e.solvent,temperature,and promoter) – Structureofdonorandacceptor Boon,G-J.;Demchenko,A.V.Chem.Rev.2000,100,4539-4565. Neu5AcDonors&StereochemicalControl • Issuestoaddress: – NoneighboringC-3func2onality – Proneto2,3-elimina2on – Stericallyhinderedanomericcenter OH HO CO2H OH O AcHN OH HO • Sialyldonorspossess“unusual”anomericleaving groups. Boon,G-J.;Demchenko,A.V.Chem.Rev.2000,100,4539-4565. Kiefel,M.J.;vonItzstein,M.2002,102,471-490. SialylGlycosyla2onMethods Direct–“forma2onofO- sialosidesinonesynthe2c step” • 2-halogenoderiva2ves – Cl,Br,F • 2-thioderiva2ves – alkyl,aryl,xanthates • 2-phosphites Indirect–“affordO-sialosides in2ormoresynthe2csteps, oneofwhichmaybea glycosyla2on” • AuxiliariesatC-3 – 3-O,3-Br,3-S,3-Se Boon,G-J.;Demchenko,A.V.Chem.Rev.2000,100,4539-4565. 2-HalogenoDeriva2ves • 2-Chloro:synthesisofsimpleglycosidesofNeu5Ac, orglycosyla2onswithprimaryalcohols OAc AcO OAc O AcHN TMS HO Ag2CO 3, AgClO4 Cl CO2Me AcO CH2Cl2 89% OAc AcO CO2Me OAc O AcHN O TMS AcO J. Carbohydr. Chem. 1989, 8, 125-133. • 2-Bromo:highreac2vityandlowstability • 2-Fluoro:consistentβ-selec2vity Boon,G-J.;Demchenko,A.V.Chem.Rev.2000,100,4539-4565. 2-ThioDeriva2ves • Widelyappliedforthesynthesisofsialicacidcontainingoligosaccharides • Goodchemicalstability • Canbetransformedinto otherglycosyldonors Boon,G-J.;Demchenko,A.V.Chem.Rev.2000,100,4539-4565. 2-PhosphiteDeriva2ves • WidelyappliedforO-sialyla2on • Requirecataly2camount ofac2vator Boon,G-J.;Demchenko,A.V.Chem.Rev.2000,100,4539-4565. Evalua2onofDirectMethods • 2-Clprovidesthebestselec2vityforglycosyla2ons withsimplealcoholsand1°carbohydratealcohols • Alterna2ves(2-SR,2-SAr,2-xanthate,2-phosphites) arebejerforhinderedcarbohydrates – Bejerselec2vitywhenacceptorshavefreediolortriol Boon,G-J.;Demchenko,A.V.Chem.Rev.2000,100,4539-4565. C-3Auxiliaries • U2lizingneighboringgrouppar2cipa2ontoform 2,3-trans-glycosides Boon,G-J.;Demchenko,A.V.Chem.Rev.2000,100,4539-4565. IndirectMethods Drawbacks: – Addi2onalsteps – Stereoselec2ve installa2onoftheC-3 auxiliary Boon,G-J.;Demchenko,A.V.Chem.Rev.2000,100,4539-4565. N-acetyl-5-N,4-O-CarbonylProtected ThiosialosideDonors • Oxazolidinonetrans-fusedringsialyldonors – Takahashi,DeMeo,andCrich DeMeo,C.,etal.Org.Le1.2012,14,1126-1129. Crich,D.;Li,W.J.Org.Chem.2007,72,2387-2391. N-acetyl-5-N,4-O-CarbonylProtected ThiosialosideDonors Crich,D.;Li,W.J.Org.Chem.2007,72,2387-2391. N-acetyl-5-N,4-O-CarbonylProtected ThiosialosideDonors Crich,D.;Li,W.J.Org.Chem.2007,72,2387-2391. N-acetyl-5-N,4-O-CarbonylProtected ThiosialosideDonors Crich,D.;Li,W.J.Org.Chem.2007,72,2387-2391. ProbingtheNitrileEffect Crich,D.;Li,W.J.Org.Chem.2007,72,7794-7797. ProbingtheNitrileEffect Crich,D.;Li,W.J.Org.Chem.2007,72,7794-7797. ProbingtheNitrileEffect Crich,D.;Li,W.J.Org.Chem.2007,72,7794-7797. RoleofOxazolidinone Crich,D.,etal.Angew.Chem.Int.Ed.2012,51,11105-11109. RoleofOxazolidinone Forderiva2ves4and5“the dipolemomentofthe heterocyclicsystemisaligned paralleltothepyranoseC4-O4 andC5-N5bonds,thereby enhancingtheirinherent electron-withdrawingability.” Crich,D.,etal.Angew.Chem.Int.Ed.2012,51,11105-11109. RoleofOxazolidinone Crich,D.,etal.Angew.Chem.Int.Ed.2012,51,11105-11109. RoleofOxazolidinone Kancharla,P.K.;Kato,T.;Crich,D.J.Am.Chem.Soc.2014,136,5472-5480. IsothiocyanatoMoiety Crich,D.,etal.Angew.Chem.Int.Ed.2015,54,1275-1278. IsothiocyanatoMoiety Crich,D.,etal.Angew.Chem.Int.Ed.2015,54,1275-1278. IsothiocyanatoMoiety Crich,D.,etal.Angew.Chem.Int.Ed.2015,54,1275-1278. 5-Ureido-ModifiedSialylDonor Kiso,M.,etal.Org.Le1.2016,18,1454-1457 α(2!8)-linkedDimers • LownucleophilicityofC-8hydroxylofNeu5Ac – Stericeffects – Interac2onswiththeacetamidogroupatC-5 – Internalhydrogenbonding • Earlyreportsu2lizedpar2cipa2ngauxiliariesatC-3 Boon,G-J.;Demchenko,A.V.Chem.Rev.2000,100,4539-4565. Demchenko,A.V.;Boons,G-J.Chem.Eur.J.1999,5,1278-1283. α(2!8)-linkedDimers Boon,G-J.;Demchenko,A.V.Chem.Rev.2000,100,4539-4565. α(2!8)-linkedDimers Demchenko,A.V.;Boons,G-J.Chem.Eur.J.1999,5,1278-1283. α(2!8)-linkedDimers DeMeo,C.;Demchenko,A.V.;Boons,G-J.J.Org.Chem.2001,66,5490-5497. α(2!8)-linkedDimers • Cleavecolominicacid – HomopolymerofNeu5Acα(2!8)Neu5Ac Boon,G-J.;Demchenko,A.V.Chem.Rev.2000,100,4539-4565. α(2!9)-linkedDimers • Highreac2vityofC-9hydroxylgroup Boon,G-J.;Demchenko,A.V.Chem.Rev.2000,100,4539-4565. α(2!9)-linkedDimers Demchenko,A.V.;Boons,G-J.Chem.Eur.J.1999,5,1278-1283.
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