《糖生物学》课程教学课件（讲稿）06 reactions of the anomeric centre-2

RxN of the anomeric center Il

RXN$of$the$anomeric$center$II$

Brief review of mutarotation andfuranose/pyranose inter-conversionOHH+BaseO.O-HHCHOOHOHHO'OHHOOHHObondHOHO'OH43HO"4'OHrotationOHHOOHOHOHOHOOHHO'OHOHHOOH

Brief$review$of$mutarota5on$and$ furanose/pyranose$inter;conversion$ OH O OH HO OH 5 1 4 3 2 HO 6 bond rotation O HO OH OH HO HO 1 2 3 4 5 6 O O OH HO OH HO ! H Base H+ O OH OH HO OH HO ! O OH HO OH OH HO ! O OH HO OH OH HO !

1. Nucleophilic substitution at anomericcentreGlycosylationGlycosidicDonerAcceptorBonda(RO)n(RO)n(RO)nto0ELNU-HLgSubstitutionActivationLg:Nu632

Doner Acceptor$ Glycosidic Bond$ Glycosyla(on 1.!Nucleophilic!subs/tu/on!at!anomeric centre

Good leaving groupb(RO)nO(RO)n(RO)n(RO)nO(O)P-OROHF/C/Br/O5746ORHNCCl3Mn+,R2S+-X,MesSi-OTfMn+MegSi-OTf,R3P+-X,ArylSO2-X(halophilic)BF3-OEt2(RO)n(RO)nO(RO)n(RO)nO/S_alkylSEarylH2C)3S/OR/ORI(0)OMeSR/NR2910118H*, Mn+RSt, Br+, I+,Ht, Cu2+Brt, I+Hg2+, R2S+-X,Tf20(oxo-,thio-,azaphilic)Nature2007,446,1000

Nature$2007,$446,$1000$ Good$leaving$group$

Stereochemistryconsideration/S1orS~2ORORRORORORCORORRingoxygenfacilitatesS1typepathwaysAidthedepartureofleavinggroupandstabilisethecarboniumionintermediate0ndonationAnomericeffect

Stereochemistry!considera/on/!SN1!or!SN2! O OR RO RO OR L O OR RO RO OR Ring!oxygen!facilitates!SN1!type!pathways! O n !" n !" donation Aid!the!departure!of!leaving!group!and!! stabilise!the!carbonium!ion!intermediate! Anomeric!effect!

S~1 PathwayORORORONu'RRCORTHORORORNuRONURatedeterminingfirststepofS1pathwaysThere are manyfactors,suchasthe nature of the solvent, orofthe protecting group R on neighbouring C-2 hydroxyl, that canplayan important roleindeterminingthe relativeamountofthesetwo pdts

O OR RO RO OR L O OR RO RO OR O OR RO RO OR H Nu￾Nu￾O OR RO RO OR Nu O OR RO RO OR Nu SN1!Pathway! Rate!determining!first!step!of!SN1!pathways! There!are!many!factors,!such!as!the!nature!of!the!solvent,!or!of! the!protec/ng!group!R!on!neighbouring!CG2!hydroxyl,!that!can! play!an!important!role!in!determining!the!rela/ve!amount!of! these!two!pdts.!

Anextracomplication,S2typeprocessescanoccurCompetitivelywithcleaninversionof theconfigurationatanomericcenterS2 PathwayORORNu'Direct Sn2ROROVUROROwith inversionORORIn the hypothetical example, clean Sn2 displacementof the α-anomeric leavinggroup would leadexclusivelyto theβ pdt

SN2!Pathway! O OR RO RO OR L Nu￾Direct SN2 with inversion O OR RO RO OR Nu An!extra!complica/on,!SN2!type!processes!can!occur!! Compe//vely!with!clean!inversion!of!the!configura/on!! at!anomeric!center! In$the$hypothe5cal$example,$clean$SN2$displacement$ of$the$α;anomeric$leaving$group$would$lead$ exclusively$to$the$β pdt.$$

NeighboringgroupparticipationOne ofthe strategies forcontrolling the sterochemicaloutcomeofnucleophilicsubstitutiontxnAcetate or benzoate on the 2-hydroxyl groupOAcOAcOACNu'OAcAcoAcOAcOAOAdOACParticipation of the carbonyl oxygen of the acetate at 2 positionmaystabilisetheintermediateglycosylcationThe formed cyclic oxonium ion can then be opened in an Sn2fashionbytheexternaladdednucleophile

O OAc AcO AcO OAc L O OAc AcO AcO O O O OAc AcO AcO O O Nu￾O OAc AcO AcO OAc Nu Neighboring!group!par/cipa/on! One$of$the$strategies$for$controlling$the$sterochemical outcome$of$nucleophilic$subs5tu5on$txn$$ Acetate$or$benzoate$on$the$2;hydroxyl$group$ Par5cipa5on$of$the$carbonyl$oxygen$of$the$acetate$at$2$posi5on$ may$stabilise$the$intermediate$glycosyl ca5on The$formed$cyclic$oxonium$ion$can$then$be$opened$in$an$SN2$ fashion$by$the$external$added$nucleophile.$

AcOOAcACOAcAcoACAcoAcCANuNu'Which type glycosidic bond is easy to form?

O AcO AcO AcO OAc L O AcO AcO AcO O O O AcO AcO AcO O O Nu￾O AcO AcO AcO Nu OAc Which$type$glycosidic$bond$is$easy$to$form?$

2.ANOMERIC ACETATESSugars canbeeasilyacetylatedleadingto α-orβ-anomericacetated depending on the rxn conditions.Anomericacetates are useful precursors for the introductionofother substituentsattheanomericposition,since acetates canact as a leaving group under acidic conditions.OHOAcOAcAc20HBr9AcoAcOOAcAcoAcoNaOAcOHOHOAO100°COAcBrBromidesformedexclusivelyastheα-anomerswhicharethermodynamicallyfavouredbytheanomericeffect.Although neighbouring group participation might lead to the lessstable β-pdts

2.!ANOMERIC!ACETATES! O OH HO HO OH OH Ac2O NaOAc 100oC O OAc AcO AcO OAc OAc HBr O OAc AcO AcO OAc Br Sugars$can$be$easily$acetylated$leading$to$α;$or$β-anomeric acetated$depending$on$the$rxn$condi5ons.$ Anomeric$acetates$are$useful$precursors$for$the$introduc5on$of$ other$subs5tuents$at$the$anomeric$posi5on,$since$acetates$can$ act$as$a$leaving$group$under$acidic$condi5ons.$ Bromides$formed$exclusively$as$the$α;$anomers$which$are$ thermodynamically$favoured$by$the$anomeric$effect.$ Although$neighbouring$group$par5cipa5on$might$lead$to$the$less$ stable$β;pdts.$