New Methodologies For Oligosaccharide Synthesis - Chemistry
New Methodologies for Oligosaccharide SynthesisMan-Kit LauDepartment of ChemistryMichigan State UniversityMarch 10, 2004
Outline1.Introduction2.Solid Phase Approach: Automated Oligosaccharide Synthesizer3.Solution Phase Approach: OptiMer One-Pot Oligosaccharide Synthesis4.Summary
Outline1.Introduction2.Solid Phase Approach: Automated Oligosaccharide Synthesizer3.Solution Phase Approach: OptiMer One-Pot Oligosaccharide Synthesis4.Summary
What are hninger, A. L.; Nelson, D. L.; Cox, M. M. Principles of Biochemistry, Worth Publishers, Inc., 1993.
Traditional View of OligosaccharidesEnergy StorageStructural itinCelluloseLehninger, A. L.; Nelson, D. L.; Cox, M. M. Principles of Biochemistry, Worth Publishers, Inc., 1993.
Cell Surface Glycoproteinscell surface glycoproteins act asprotein ligands for cell-cell recognitionBertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357.Sears, P.; Wong, C.-H. Angew. Chem. Int. Ed. 1999, 38, 2300.
Synthetic Chemistry is Key to Studying GlycobiologyBiopolymerPrimary Synthetic MethodsDNA1. Automated nucleic acid synthesis2. Polymerase chain reaction (PCR)Protein1. Automated peptide synthesis2. Overexpression system3. Even unnatural proteins can be made nowOligosaccharide1. Isolation from natural sources2. Enzymatic synthesis3. Chemical synthesisProtein and DNA Synthesis: Template DrivenGlycoprotein Synthesis: Post-Translational AttachmentKoeller, K. M.; Wong, C.-H. Chem. Rev. 2000, 100, 4465.
Glycoprotein BiosynthesisStructural homogeneity isdifficult to achieve.Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357.
Possible Routes to Homogeneous OligosaccharidesOligosaccharides Enzymatic SynthesisNatural SourcesChemical SynthesisUltimate Goal: General and Efficient Synthesis of OligosaccharidesKoeller, K. M.; Wong, C.-H. Chem. Rev. 2000, 100, 4465.Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.Sears, P.; Wong, C.-H. Science 2001, 291, 2344.
Oligosaccharides Synthesis: A Big Challenge“ There are no universal reaction conditionsfor oligosaccharides synthesis” - Hans PaulsenPaulsen, H. Angew. Chem. Int. Ed. Engl. 1982, 21, 155.
Structural Complexity of DNA and PeptidesMonomeric Building Blocks(HO)2P ONucleotidenucleotideOOligomeric BiomoleculesbaseDNA (linear)OOHAmino Acidamino acidRCOOHNH2Polypeptide (linear)Linhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, Wiley-VCH: Weinheim, 2003.
Structural Complexity of OligosaccharidesMonomeric Building BlockspyranosideOHHOHOHOOligomeric BiomoleculesOHHOHOHOOHHOOOHHOHOOaOO HOHOOOOHbLinear and branched!Linhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, Wiley-VCH: Weinheim, 2003.
Possible Isomers Among 60Pentamer1201202,144,6402,144,640Linhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, Wiley-VCH: Weinheim, 2003.
Selective Protection and Deprotection Steps1o hydroxylanomeric hydroxylOOHHOHOHHOHHOOHOHHOHHOH aldehydeOHCH2OH3 x 2o hydroxylOHHOHOOOHH2N1o amineglucosamine
Selective Protection and Deprotection StepsOHHO1. ClCH2C(O)ClDMF, -50oC, 55%2. BzCl, pyridine, 3OBzOHBzOthioureaCH2Cl2OBzOOCH3OBzOOAc Bz OMCA monochloroacetyl ClLinhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, Wiley-VCH: Weinheim, 2003.
Glycosidic Bond FormationORROROactivator(Lewis Acid)OLORROROOROOROROROROROoxonium ionglycosyl donorglycosyl acceptorR'OHOROROROOR'RONHL R Br ,OSR ,O,OCCl3O,etc.O,,etc.OO
Classical Approaches Towards Oligosaccharide Synthesis1.Chemical Synthesis:eg. Glycosyl halide coupling.OAcOAcROH, Ag2CO3, CH2Cl2OAcOAcOBr-AgBrAcOOAcOAcOORAcO-AgBranchimeric assistanceOAcAcOAcOOAcOAcOAcOOOOOROHOLinhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, Wiley-VCH: Weinheim, 2003.
Classical Approaches Towards Oligosaccharide Synthesis2.Enzymatic Synthesis:eg. Synthesis of the core trisaccharide of N-linked glycoprotein.OHHOHOOHOOpNPb-mannosidase fromHelix pomatia (edible snails) OHHOHOOONHAc HOOHOHHOHOOHOHOOHOOHOONHAc HOOOHNHAcOOHNHAc20% yieldpNP: para-nitrophenylScigelova, M.; Singh, S.; Crout, D. H. G. J. Chem. Soc., Perkin Trans. 1 1999, 7, 777.Koeller, K. M.; Wong, C.-H. Chem. Rev. 2000, 100, 4465.
Outline1.Introduction2.Solid Phase Approach: Automated Oligosaccharide Synthesizer3.Solution Phase Approach: OptiMer One-Pot Oligosaccharide Synthesis4.Summary
Solid Phase: Automated Oligosaccharide SynthesizerThe first automated oligosaccharidesynthesizer based onApplied Biosystems Inc. Model 433APeptide synthesizerPlante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science, 2001, 291, 1523.
Solid Phase Synthesis of gP1OO1OOP2P5OOP11OP10 H2CHCnP protecting groupFréchet, J. M. J.; Schuerch, C. J. Am. Chem. Soc. 1971, 93, 492.OP8O2OHOP6
First Solid Phase Synthesis of DisaccharideORBnOBnOOHOBnOBnO BnOOROBrBnOOnBnO75% yieldOOBnOOOR HCOBnOBnOOHH2CBnOBnOBn NO2Fréchet, J. M. J.; Schuerch, C. J. Am. Chem. Soc. 1971, 93, 492.
Solid Phase Synthesis of OligosaccharidesUsing Glycal AssemblyHOOOOO calOOP2OOP4[O]OP5O.OOP3OOHP1OOP2 HCnP protecting groupRandolph, J. T.; McClure, K. F.; Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117, 5712.
Tetrasaccharide Synthesis Using Glycal AssemblyOOO OO OO OOOCH2Cl2OOHOOOOOOOZnCl2, THFOOOOOHO OOOOOOOOOO1.OHOOOHOOBn OHOO H2CSi(iPr)2HCn2. BnOBnOOOOO, CH2Cl2OrepeatOOO OOOOHOOOOOOOHO OOOOZnCl2, THFOHOBnOBnOO74% overall yieldRandolph, J. T.; McClure, K. F.; Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117, 5712.
Choice of Glycosylating AgentsOLevOLev1. DMDO2. HOP(O)(OBu)23. PivCl, DMAPOBnOBnOBnOBnOOOPivOP(OBu)2OOBnAcOBnOBnOK2CO3, Cl3CCNOOHBnOBnOOBnAcOOOCCl3NHOAc NBn Piv DMAP OOtBuLev NOOPlante, O. J.; Andrade, R. B.; Seeberger, P. H. Org. Lett. 1999, 1, 211.Schmidt, R. R. Angew. Chem. Int. Ed. Engl. 1986, 25, 212.
The Octenediol Linker1. OOMerrifield's resinOH2C CH2 ClClMerrifield's resin 1. NBSOORBnOBnO2. ROHPivOH2CClHCRuPCy3OLevOLevBnOBnOPCy3 PhNBS OBrNOOPivOOOLev OPiv OOtBuCy nAndrade, R. B.; Plante, O. J.; Melean, L. G.; Seeberger, P. H. Org. Lett. 1999, 1, 1811.
Automated Solid Phase Synthesis of Protectedb-Phytoalexin Elicitor (PE)OLevOBnBnOBnOOLev BnOOOPivOBnOBnOOBnOOOPiv O BnOOtBuBnOBnOOOPivOO BnOOBnOOOPivOBnOBnOOOPivOBn Plant glucan oligosaccharide.Induce plant to produce antibiotic phytoalexin.Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.
Automated Solid Phase Synthesis of Protectedb-Phytoalexin Elicitor NNH2OLev3 equiv.OBnOBnOOPivOP(OBu)2OOLev OLevBnOBnOOOPivOOOOOPiv Bn Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.tBu
Automated Solid Phase Synthesis of Protectedb-Phytoalexin Elicitor (PE)OHOHOBnBnOBnOBnOOBnOOBnOBnOOOOOPivOPivOBnO OBnOOOPivOOCouplingTMSOTfDeprotectionH2NNH210 equiv.BnOBnOO BnOOBnOOOPivOO BnOOBnOP(OBu)2OOOLevOBnBnOBnOOLevOBnLev OPivOBnOBnOOOOOOPivOOPiv OBn Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.tBu
Automated Solid Phase Synthesis of Protectedb-Phytoalexin Elicitor (PE)OHOBnOOBnBnOBnOOBn OPivOBnOOO vOPivOOOOOCouplingTMSOTfDeprotectionH2NNH2OLev10 equiv.OBnOBnOOPivOP(OBu)2OOLevBnOBnOOBnBnOBnOOOLev OPivOO BnOOBnOOOOPivOBnOBnOOPiv OOOPivOOBn Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.tBu
Automated Solid Phase Synthesis of Protectedb-Phytoalexin Elicitor (PE)OHOLevOBnBnOBnOOOBnOO BnOOOBnOOPivOOBnPivOOBnOOBnOO OOBnOPivOBnOBnOBnOOOPivOCleavageClPCy3 PhRuH2CDeprotectionClCouplingTMSOTfCH2PCy3BnOBnOO BnOOBnOOLevOBnBnOBnOOLevOBn10 equiv.O BnOOBnOOOPivOP(OBu)2OOPivOBnOBnOOBnBnOBnOOOOLev OPivOO BnOOBnOOOOPivOBnOBnOOPiv OOOPivOOBn Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.tBu
Coupling Cycle For Phosphate DonorsStep hDeprotectionWashWashWashWashWashReagentTime/min5 equiv. donor and 5 equiv. TMSOTfCH2Cl25 equiv. donor and 5 equiv. TMSOTf1:9 (MeOH : CH2Cl2)THF3:2 (pyridine : acetic acid)2 x 20 equiv. H2NNH23:2 (pyridine : acetic acid)1:9 (MeOH : CH2Cl2)0.2 M acetic acid in THFTHFCH2Cl2306304438034446Each cycle: 3 hoursPlante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.
Solid Phase Synthesis of Protectedb-Phytoalexin SPhOAcOAcOOAcAcOOBzO, DMTST, then Et3NBzOBzOSPhOOBzOBzOBzOOAc, DMTST, then HF/pyr.AcOAcOOBzOOO BnOOOBzOBzOBzOAcOSPhOAc, DMTST, then HF/pyr.Si(Ph)2(tBu)OFmoc AcOAcOOMeOTfDMTST MeSSMeOAcOAcOOAcAcOAcOOAcOO BnOOAcOOBzOBzOBzOOAcAcOAcOOAcOOO BnOOOBzOBzOBzOOAcAcOOAcOAcOOBzOO BnOOAcOOOOBzOO OAcTBDPS OBzOcOHOTBDPS(c)NO2OOOAc(b)OBzOBzOBzOOOOBzOO BnOOAcOAcONO2OTBDPSBnO(a) FmocOOHOAcNO2OOBzOOOOAcBzO20% overall yieldNicolaou, K. C.; Winssinger, N.; Pastor, J.; DeRoose, F. J. Am. Chem. Soc. 1997, 119, 449.
Automated vs. Non-Automated SynthesesOAcOLevOBnBnOBnOO BnOOBnOOOPivOBnOBnOOBnBnOBnOAcOAcOOOPivOO BnOOBnOOAcOAcOOAcOOPivOBnOBnOOOPivOOAcOO BnOOAcOOOBzOBzOBzOOAcAcOAcOOOBzOO BnOOAcOOOBzOBzOBzOOOAcBzOautomated (Seeberger)non-automated (Nicolaou)automatedlabor intensive10 machine hours122 reaction hours80% yield20% yieldPlante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.Nicolaou, K. C.; Winssinger, N.; Pastor, J.; DeRoose, F. J. Am. Chem. Soc. 1997, 119, 449.
Other Protected Oligosaccharides Synthesized withAutomated Synthesizer ApproachBnOBnOOBnOAcOn 3, 74% yield (90% average yield per unit)n 5, 42% yield (84% average yield per unit)n 8, 34% yield (87% average yield per unit)OBnOBnOBnOBnOBnOOOBnOBnOBnOnOOBnOOO50% yield(84% average yield per unit)OBnOBnOBnO OBn BnOpolymannosideOOBnOAcOOOPiv BnOBnOLeishmania tetrasaccharideOOOTCAHN NHOCCl3BnO OBnBnOAc HOOOPiv OOTCAHNOBntBuPivOOPivOBnOOO12.6% yield (66% average yield per unit)BnO OBnOBnOPivOOBnOO HOOPivOLewisx pentasaccharideBn Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.Hewitt, M. C.; Seeberger, P. H. Org. Lett. 2001, 3, 3699.Love, K. R.; Seeberger, P. H. Angew. Chem. Int. Ed. 2004, 43, 602.
How About More Complex OHOSialyl Lewisx tetrasaccharide4% overall yield in 8 steps(Denishefsky and Wong, 1992)HO OHHO OHOOHOOOOAcNHOOHHOHOOHOHOOHOHO2COHOOORHOOHOHOOHHO NHAcFucosyl GM15% overall yield in 15 steps(Denishefsky, 1999)Danishefsky, S. J.; Gervay, J.; Peterson, J. M.; McDonald, F. E.; Koseki, K.; Oriyama, T.; Griffith, D. A.;Wong, C.-H.; Dumas, D. P. J. Am. Chem. Soc. 1992, 114, 8329.Allen, J. R.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 10875.
Outline1.Introduction2.Solid Phase Approach: Automated Oligosaccharide Synthesizer3.Solution Phase Approach: OptiMer One-Pot Oligosaccharide Synthesis4.Summary
Solution Phase: OptiMer Programmed One-PotOligosaccharide SynthesisZhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
The “Armed - Disarmed” ConceptArmedDisarmedReact FasterReact SlowerHOHOOOHOLOactivator HOHOO OOOLLLMootoo, D. R.; Date, V.; Fraser-Reid, B. J. Am. Chem. Soc. 1988, 110, 2662.Linhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, Wiley-VCH: Weinheim, 2003.
Protecting Groups ControlHOHOOOLEDGactivator HOHOOEWGHOEDGOEDG OOOLEWGLEWGEDG electron donating groupEWG electron withdrawing groupMootoo, D. R.; Date, V.; Fraser-Reid, B. J. Am. Chem. Soc. 1988, 110, 2662.Linhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, Wiley-VCH: Weinheim, 2003.L
Disaccharide Synthesis Using Protecting Groups ControlOBnarmedOBnOBnOBnOOBnONBSBnOBnOOBnOBzOBzO OHdisarmed62% yielda:b 1:1OOOBzOOBzOBzOOBzOOHBrNNBS OOBz OBzOBzOOis NOT formedOBzOBzOBzOOOBzOBn Mootoo, D. R.; Date, V.; Fraser-Reid, B. J. Am. Chem. Soc. 1988, 110, 2662.
Disaccharide Synthesis Using Protecting Groups nOBnOBnOHOBzOBzOOBnBnOBnOOBz OOOBzOOBnOBzOBzOOOBzOBn Mootoo, D. R.; Date, V.; Fraser-Reid, B. J. Am. Chem. Soc. 1988, 110, 2662.
Anomeric Reactivity ControlHOHOOOHOL1Oactivator HOHOO OOOL2L2L2L1 is better leaving group than L2Mootoo, D. R.; Date, V.; Fraser-Reid, B. J. Am. Chem. Soc. 1988, 110, 2662.Linhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, Wiley-VCH: Weinheim, 2003.
One-Pot Synthesis of Protected CiclamycinOSOS OOless reactive OTMSOSOMeOBnOHOmost reactive0.05 equiv. TfOH-78oCOBnleast reactiveSOSO OO OBnOOHOOBnSBn O-70oCO OBnOO OBnOCiclamycinCiclamycin25% overall yieldOOSOMe SORaghavan, S.; Kahne, D. J. Am. Chem. Soc. 1993, 115, 1580. S
Strategy for Sequential One-Pot Linear andBranched Oligosaccharides SynthesisOXOXHOOXHOless reactiveOORHOleast reactivereducing endOOOOmost reactivedonorOOOOROOOXmost reactivedonorHOless reactiveOOXHOreducing endOOROOOOOOORZhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
OptiMer Database of Thioglycosyl DonorsNumber in bracket represents the Relative Reactivity Value (RRV)Ritter, T. K.; Mong, K.-K. T.; Liu, H.; Nakatani, T.; Wong, C.-H. Angew. Chem. Int. Ed. 2003, 42, 4657.
OptiMer Database of Thioglycosyl DonorsZhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
OptiMer Database of Thioglycosyl DonorsYe, X.-S.; Wong, C.-H. J. Org. Chem. 2000, 65, 2410.
OptiMer Database of Thioglycosyl DonorsRitter, T. K.; Mong, T. K.-K.; Liu, H.; Nakatani, T.; Wong, C.-H. Angew. Chem. Int. Ed. 2003, 42, 4657.
Relative Reactivity in Competitive ReactionsOSRdonor (D0)Oproduct (Dt)OMeNISHPLC analysisMeOH (5eq.)OSRreference (R0)OreferenceOMe product (Rt)OAcAcOreference compound AcOAcOOSTolNIS OINOZhang, Z.; Ollmann, I. R.; Ye, X. -S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
Relative Reactivity in Competitive ReactionRRV kDkR In([Dt]/[D0])In([Rt]/[R0])OAcR0AcOThe result is normalized based onD0OSTolRRV 1RtDtAcOAcOt 0ht 2hLarger the number,higher the reactivityZhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
Sequential One-Pot Synthesis of Globo HOHOHOHOHOHOOOHOHOOOOAcNHHO O OHOOHHOHOOHOHOGlobo HGlobo H1% overall yield in 19 steps(Denishefsky, 1995)HOOHOOORHOHuman breast tumor associated antigen.First total synthesis was reported by Danishefsky in 1995 using glycal assembly.Bilodeau, M. T.; Park, T. K.; Hu, S.; Randolph, J. T.; Danishefsky, S. J.; Livingston, P. O.; Zhang, S.J. Am. Chem. Soc. 1995, 117, 7840.
Sequential One-Pot Synthesis of Globo HOHOHOHOHOHOOHOHOOOOOAcNHOptiMerHO O OHOOOHHOOHHOGlobo HGloboHHOOOHOHOORHOBnO OBnBn BzO OBzOBnOClBn ClNO2R OTrocHNSTolOClBn(67% yield)OHOBnOONHORRV 6NBz TrocHN OOHOONBzO ONBzOCCl3OMeBnOSTolOBnOBnRRV 72,000OBnOBnOBnOOBnOOORBnOBurkhart, F.; Zhang, Z.; Wacowich-Sgarbi, S.; Wong, C.-H. Angew. Chem. Int. Ed. 2001, 40, 1274.
Sequential One-Pot Synthesis of Globo HOOBnONBzO ONBzOOBnORRV 6BnOR BnONBz TrocHN NHClOHOHOHOHOOHOHOOOOBnOOOBnTrocNHClBnO O OBnOBnOOOBnOORBnO1. Zn-AcOH2. Ac2O-pyridine3. NaOMe-MeOH4. H2-Pd/COHO O OHOHOGlobo HGlobo H20% overall yieldBnOGlobo HOAcNHOBnOCCl3OHOHO41% yieldOOBnNO2OOHOBzO ONBzOOClBn BzO OBzOOMeOBn ORBnOBzO OBnOOOBnOSTolOClBnTrocHNINOBnOOOHOOHOHOBnNIS, TfOH, CH2Cl2BzO OBzNIS ORRV 72,000OBnBnOBnO OBnSTolOBnHOHOOHOOORHOBurkhart, F.; Zhang, Z.; Wacowich-Sgarbi, S.; Wong, C.-H. Angew. Chem. Int. Ed. 2001, 40, 1274.
Other Oligosaccharides Synthesized with OHOHOOOHOROHHOOOOO OHOAcNHOOHHOHOSialyl Lewisx hexasaccharide8% overall yieldin 2 one-pot reactions(cf. 4% overall yield in 8 steps)HO OHHO OHHOHOOHOOHOHO2COHOOORHOOHOHOAnd more.OHHO NHAcFucosyl GM16% overall yieldin 3 one-pot reaction(cf. 5% overall yield in 15 steps)Zhang, Z.; Kikura, K.; Huang, X.-F.; Wong, C.-H. Can. J. Chem. 2002, 80, 1051.Mong, T. K.-K.; Lee, H.-K.; Duron, S. G.; Wong, C.-H. Proc. Natl. Acad. Sci. USA 2003, 100, 797.
Comparison of the Two ApproachesCommon Advantages:They both reduce labor cost.They both allow for high throughput synthesis of oligosaccharidesAdvantages for the one-pot approach over the automated synthesizer:It fundamentally helps planning of oligosaccharide synthesisIt involves no intermediate deprotectionScale-up is possible
Heparin-Like Oligosaccharides: A Synthetic ChallengeaOSO3OHOOO3SHN OHOCO2OOOH O3SOaOSO3OO3SHN OHOOO2COOSO3 HOOSO3OOO3SHNiduronic acidBelongs to the family of glycosaminoglycans (GAG).Heparin is widely used as an anticoagulant.Jacquinet, J.-C.; Petitou, M.; Duchaussoy, P.; Lederman, I.; Choay, J.; Torri, G.; Sinay, P.Carbohydr. Res. 1984, 130, 221.Yu, H. N.; Furukawa, J.-I; Ikeda, T.; Wong, C.-H. Org. Lett. 2004, 6, 723.Orgueira, H. A.; Bartolozzi, A.; Schell, P.; Litjens, R. E. J. N.; Palmacci, E. R.;Seeberger, P. H. Chem. Eur. J. 2003, 9, 140.
Outline1.Introduction2.Solid Phase Approach: Automated Oligosaccharide Synthesizer3.Solution Phase Approach: OptiMer One-Pot Oligosaccharide Synthesis4.Summary
Summary1.Novel strategies towards oligosaccharide synthesis were discussed:- Solid Phase Automated Oligosaccharide Synthesizer- Solution Phase OptiMer One-Pot Oligosaccharide Synthesis2.From a chemical point of view, the reactivity based one-pot strategy makesthe design of oligosaccharide synthesis easier.
AcknowledgementProf. John FrostDr. Karen FrostProf. Chris ChangProf. Babak BorhanProf. Joan BroderickFrost Group
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Example in Calculating RRVOAcAcO1:AcOAcOOSTolLevO OHOSTolPMBOO40:OBnOOBnOBnZhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
Accuracy Measurement of Calculated RRVExperimental values are shown without parenthesesCalculated values are shown in parenthesesZhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
Relationship Between Relative Rates andSubstrate ComsumptionZhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
Department of Chemistry Michigan State University March 10, 2004. Outline 1. Introduction 2. Solid Phase Approach: Automated Oligosaccharide Synthesizer 3. Solution Phase Approach: OptiMer One-Pot Oligosaccharide Synthesis 4. Summary . Isolation from natural sources 2. Enzymatic synthesis 3. Chemical synthesis.
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advances in the strategy and art of oligosaccharide assembly and oligosaccharide congener synthesis would find ready application. In our opinion and that of others, synthetic organic chemistry is destined to play a major role in understanding the relationship of the function and topology of carbohydrate domains to their biological role.
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Planned Methodologies vs. Agile Methodologies 27 Fig. 8. The complexity of design for future. Fig. 9. The complexity of design for today. If a difficult design problem is encountered, agile methodologies recommend the immediate creation of an operational prototype of that portion of the d
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