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New Methodologies for Oligosaccharide Synthesis
Man-Kit LauDepartment of ChemistryMichigan 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
Outline
1. Introduction
2. Solid Phase Approach: Automated Oligosaccharide Synthesizer
3. Solution Phase Approach: OptiMer One-Pot Oligosaccharide Synthesis
4. Summary
What are Oligosaccharides?
Lehninger, A. L.; Nelson, D. L.; Cox, M. M. Principles of Biochemistry, Worth Publishers, Inc., 1993.
OHHHHOOHHOHH
CH2OH
HO
D-Glucose
OHO
OHO
OHO
Maltotriose
OH
HO
HOOH
OOH
OOH
HO
HO
OHO
OH
HO
HOOH
HOW?
Traditional View of Oligosaccharides
Starch Cellulose
Lehninger, A. L.; Nelson, D. L.; Cox, M. M. Principles of Biochemistry, Worth Publishers, Inc., 1993.
Plant Animal
Energy Storage Starch GlycogenStructural Scaffold Cellulose Chitin
Cell Surface Glycoproteins
Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357.Sears, P.; Wong, C.-H. Angew. Chem. Int. Ed. 1999, 38, 2300.
cell surface glycoproteins act asprotein ligands for cell-cell recognition
Synthetic Chemistry is Key to Studying Glycobiology
Koeller, K. M.; Wong, C.-H. Chem. Rev. 2000, 100, 4465.
Protein and DNA Synthesis: Template Driven
Glycoprotein Synthesis: Post-Translational Attachment
Biopolymer Primary Synthetic Methods
DNA 1. Automated nucleic acid synthesis2. Polymerase chain reaction (PCR)
Protein 1. Automated peptide synthesis2. Overexpression system3. Even unnatural proteins can be made now
Oligosaccharide 1. Isolation from natural sources2. Enzymatic synthesis3. Chemical synthesis
Glycoprotein Biosynthesis
Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357.
Structural homogeneity isdifficult to achieve.
Possible Routes to Homogeneous Oligosaccharides
Oligosaccharides
Natural Sources
Chemical Synthesis
Enzymatic Synthesis
Koeller, 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.
Ultimate Goal: General and Efficient Synthesis of Oligosaccharides
¥
Oligosaccharides Synthesis: A Big Challenge
Paulsen, H. Angew. Chem. Int. Ed. Engl. 1982, 21, 155.
“ There are no universal reaction conditions for oligosaccharides synthesis” - Hans Paulsen
Structural Complexity of DNA and Peptides
Monomeric Building Blocks Oligomeric Biomolecules
DNA (linear)O
OH
baseO(HO)2PONucleotide
R COOH
NH2
Amino Acid Polypeptide (linear)
Linhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, Wiley-VCH: Weinheim, 2003.
nucleotide
amino acid
Structural Complexity of Oligosaccharides
Monomeric Building Blocks Oligomeric Biomolecules
a
b
Linear and branched!
Linhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, Wiley-VCH: Weinheim, 2003.
OO OH
HOO
HO
HO
OHO
HO
O
OH
HO
OH
HO HO
OHO OH
HOOH
HOpyranoside
Oligomer Oligonucleotides Oligopeptides Oligosaccharides
Dimer 2 2 20Trimer 6 6 720Tetramer 24 24 34,560Pentamer 120 120 2,144,640
Possible Isomers Among Biopolymers
Linhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, Wiley-VCH: Weinheim, 2003.
2,144,640
Selective Protection and Deprotection Steps
OOH
HOHO
OHOH
OHHHHOOHHOHH
CH2OH
HOanomeric hydroxyl
3 x 2o hydroxyl
1o hydroxyl
OHO
OH
HO
H2NOH glucosamine
1o amine
aldehyde
Selective Protection and Deprotection Steps
Linhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, Wiley-VCH: Weinheim, 2003.
Ac =
O
BzO
BzO
OBzOCH3
1. ClCH2C(O)Cl DMF, -50oC, 55%2. BzCl, pyridine, 90%
O
BzO
BzO
OBzOCH3
thioureaCH2Cl2
OMCA
OH
OMCA = monochloroacetyl = Bz =
O OCl
O
HO
HO
OHOCH3
methyl-D-glucopyranoside
OH
Glycosidic Bond Formation
L = SRBr O O
NH
CCl3, , , etc.
R = etc.O O
O
O
O, , ,
OOR
RORO
ROL
OOR
RORO
ROOR'
OOR
RORO
RO
OOR
RORO
RO
activator (Lewis Acid)
R'O
H
glycosyl donor
glycosyl acceptor
oxonium ion
Classical Approaches Towards Oligosaccharide Synthesis
Linhorst, T. K. Essentials of Carbohydrate Chemistry and Biochemistry, Wiley-VCH: Weinheim, 2003.
1. Chemical Synthesis: eg. Glycosyl halide coupling.
OOAc
AcOAcO
AcO
ROH, Ag2CO3, CH2Cl2-AgBr
OOAc
AcOAcO
AcOORBr
OOAc
AcOAcO
OO
O
OO
OAc
RO
H
AcOAcO
anchimeric assistance-AgBr
Classical Approaches Towards Oligosaccharide Synthesis
Scigelova, 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.
2. Enzymatic Synthesis: eg. Synthesis of the core trisaccharide of N-linked glycoprotein.
OOH
HOHO
OH
OpNP
OOH
HOHO
OOH
OHONHAc
NHAcOH
+ OOH
OHO
OOH
OHONHAc
NHAcOH
OOH
HOHO
OHb-mannosidase fromHelix pomatia (edible snails)
pNP: para-nitrophenyl
20% yield
Outline
1. Introduction
2. Solid Phase Approach: Automated Oligosaccharide Synthesizer
3. Solution Phase Approach: OptiMer One-Pot Oligosaccharide Synthesis
4. Summary
Solid Phase: Automated Oligosaccharide Synthesizer
Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science, 2001, 291, 1523.
The first automated oligosaccharidesynthesizer based on Applied Biosystems Inc. Model 433APeptide synthesizer
Solid Phase Synthesis of Oligosaccharides
Fréchet, J. M. J.; Schuerch, C. J. Am. Chem. Soc. 1971, 93, 492.
...
P = protecting group
OO
P1OOP2
OP3
OO
P1OOP2
OH
OO
P1OOP2
OO
P9OOP10
OP11
OO
P5OOP6
OP7
OP4 OP4 OP4
OP8
OO
P1OOP2
OO
P5OOP6
OH
OP4
OP8
OO
P1OOP2
OO
P5OOP6
OP4
OP8
OP12
Deprotection Coupling
Deprotection
Coupling
1 1 1
2
1
2
1
2
3
HCH2C
n
=
First Solid Phase Synthesis of Disaccharide
Fréchet, J. M. J.; Schuerch, C. J. Am. Chem. Soc. 1971, 93, 492.
HCH2C
n
OH= R =
O
NO2
75% yieldOBnOBnO
O
OH
BnO
OBnOBnO
OR
BnO
O
OBnO
BnO
BnO
BrO
BnOBnO
OR
BnO O
Bn =R =
Solid Phase Synthesis of OligosaccharidesUsing Glycal Assembly
Randolph, J. T.; McClure, K. F.; Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117, 5712.
...
P = protecting group
O
P1OOP2
O
P1OOP2
O
P1OOP2
O
P3OOP4
OO
OH
O
P3OOP4
HO
[O]
O
P1OOP2
O
P3OOP4
O
OH
O
glycal
O
P1OOP2
O
P3OOP4
O
OH
O
P6OOH
P5OO
P6OO
P5O
OH
1,2-epoxyglycal
O OO O O
OO
= HCH2C
n
Si(iPr)2
Tetrasaccharide Synthesis Using Glycal Assembly
Randolph, J. T.; McClure, K. F.; Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117, 5712.
= HCH2C
n
Si(iPr)2
O
74% overall yield
OO
O
OO O
O
O
OO
OO
O
O
O
OO
O
OO
OHO
OO
O
O
OO
O
OO
HO
OO
O
OO
OHO
O
OO
O
OO
HO
OO
O
OO
HO
OO
O
OO
OHO
BnOBnO
OBnOBnO
OH
OO
O
OHO
repeat
O O
O O1.
2.
ZnCl2, THF
CH2Cl2 ZnCl2, THF
, CH2Cl2
Bn =
Choice of Glycosylating Agents
Plante, O. J.; Andrade, R. B.; Seeberger, P. H. Org. Lett. 1999, 1, 211.Schmidt, R. R. Angew. Chem. Int. Ed. Engl. 1986, 25, 212.
O
tBu O
O
O
N
N
OAc =
Lev =DMAP =
Bn =
Piv =
O
PivO
OLev
BnOBnO O
P(OBu)2
O
OOBn
BnOBnO O
NH
CCl3
AcO
OBnOBnO
OLev1. DMDO2. HOP(O)(OBu)23. PivCl, DMAP
OOBn
BnOBnO OH
K2CO3, Cl3CCNAcO
The Octenediol Linker
Andrade, R. B.; Plante, O. J.; Melean, L. G.; Seeberger, P. H. Org. Lett. 1999, 1, 1811.
Merrifield's resinHC
H2C
n
= ClNO O
Br
Cl
Merrifield's resin
HO
O
OPivO
OBnBnOBnO
O
O
O
PivO
OLev
BnOBnO O P(OBu)2
O
O
PivO
OLev
BnOBnO O
O
PivO
OLev
BnOBnO OR
1. NBS2. ROH
1. TMSOTf2.
RuCl
ClPCy3
PCy3
PhH2C CH2
NBS = O
O
OLev =
O
tBuPiv = Cy =
Automated Solid Phase Synthesis of Protectedb-Phytoalexin Elicitor (PE)
Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.
O
PivO
O
BnOBnO O
O
PivO
BnOO
O
BnO
OBn
BnOBnO
O
PivO
BnOBnO O
O
PivO
BnOO
O
BnO
BnOBnO
O
OBnOLev
Plant glucan oligosaccharide.
Induce plant to produce antibiotic phytoalexin.
O
O
OLev =
Piv =O
tBu
Bn =
Automated Solid Phase Synthesis of Protectedb-Phytoalexin Elicitor (PE)
Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.
Deprotection Coupling
HO
O
O
PivO
OLev
BnOBnO O
P(OBu)2
O
O
PivO
OH
BnOBnO O
O
O
PivO
OLev
BnOBnO O
O
TMSOTfH2NNH23 equiv.
O
O
OLev =
Piv =O
tBu
Bn =
O
PivO
OH
BnOBnO O
O
Automated Solid Phase Synthesis of Protectedb-Phytoalexin Elicitor (PE)
Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.
O
PivO
BnOO
O
BnO
OBn
BnOBnO
OLev
OP(OBu)2
O
O
PivO
BnOO
O
BnO
OBn
BnOBnO
OLev
O
PivO
O
BnOBnO O
O
O
PivO
BnOO
O
BnO
OBn
BnOBnO
OH
O
PivO
O
BnOBnO O
O
Deprotection CouplingTMSOTfH2NNH2
10 equiv.
O
O
OLev =
Piv =O
tBu
Bn =
O
PivO
BnOO
O
BnO
OBn
BnOBnO
OH
O
PivO
O
BnOBnO O
O
Automated Solid Phase Synthesis of Protectedb-Phytoalexin Elicitor (PE)
Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.
O
PivO
BnOO
O
BnO
OBn
BnOBnO
O
PivO
O
BnOBnO O
O
O
PivO
OH
BnOBnO O
O
PivO
BnOO
O
BnO
OBn
BnOBnO
O
PivO
O
BnOBnO O
O
O
PivO
OLev
BnOBnO O
Deprotection CouplingO
PivO
OLev
BnOBnO O
P(OBu)2
O
TMSOTfH2NNH210 equiv.
O
O
OLev =
Piv =O
tBu
Bn =
O
PivO
BnOO
O
BnO
OBn
BnOBnO
O
PivO
O
BnOBnO O
O
O
PivO
OH
BnOBnO O
Automated Solid Phase Synthesis of Protectedb-Phytoalexin Elicitor (PE)
Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.
O
PivO
BnOO
O
BnO
OBn
BnOBnO
OLev
OP(OBu)2
O
O
PivO
BnOO
O
BnO
OBn
BnOBnO
O
PivO
O
BnOBnO O
O
O
PivO
BnOBnO O
O
PivO
BnOO
O
BnO
OBn
BnOBnO
O
OLev
Deprotection Coupling
Cleavage
O
PivO
O
BnOBnO O
O
PivO
BnOO
O
BnO
OBn
BnOBnO
O
PivO
BnOBnO O
O
PivO
BnOO
O
BnO
BnOBnO
O
OBnOLev
TMSOTf10 equiv.
O
O
OLev =
Piv =O
tBu
Bn =
H2C CH2RuCl
ClPCy3
PCy3
Ph
Coupling Cycle For Phosphate Donors
Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.
Step Function Reagent Time/min
1 Couple 5 equiv. donor and 5 equiv. TMSOTf 302 Wash CH2Cl2 63 Couple 5 equiv. donor and 5 equiv. TMSOTf 304 Wash 1:9 (MeOH : CH2Cl2) 45 Wash THF 46 Wash 3:2 (pyridine : acetic acid) 37 Deprotection 2 x 20 equiv. H2NNH2 808 Wash 3:2 (pyridine : acetic acid) 39 Wash 1:9 (MeOH : CH2Cl2) 4
10 Wash 0.2 M acetic acid in THF 411 Wash THF 412 Wash CH2Cl2 6
Each cycle: 3 hours
O
BzO
O
BzOBzO O
NO2
O
O
BzO
BnOO
O
AcO
OAc
AcOAcO
O
BzO
BzOBzO O
O
BzO
BnOO
O
AcO
OAc
AcOAcO
O
AcO
OAc
AcOAcO O
O
Solid Phase Synthesis of Protectedb-Phytoalexin Elicitor
Nicolaou, K. C.; Winssinger, N.; Pastor, J.; DeRoose, F. J. Am. Chem. Soc. 1997, 119, 449.
O
BzO
OH
BzOBzO O
NO2
O
O
BzO
O
BzOBzO O
NO2
O
O
BzO
BnOO
O
AcO
OAc
AcOAcO
O
BzO
OH
BzOBzO O
c(a) , DMTST, then Et3NOOTBDPS
BnOFmocO
OBzSPh
OOAc
AcOAcO
OAcSPh(b) , DMTST, then HF/pyr.
OOTBDPS
BzOBzO
OBzSPh
(c) , DMTST, then HF/pyr.
O
BzO
O
BzOBzO O
NO2
O
O
BzO
OTBDPS
BnOHOa
O
BzO
O
BzOBzO O
NO2
O
O
BzO
OH
BnOO
O
AcO
OAc
AcOAcO
b
MeS
SMe
MeOTfDMTST =
TBDPS =
Fmoc = O
O
Si(Ph)2(tBu)
O
BzO
O
BzOBzO OAc
O
BzO
BnOO
O
AcO
OAc
AcOAcO
O
BzO
BzOBzO O
O
BzO
BnOO
O
AcO
OAc
AcOAcO
O
AcO
OAc
AcOAcO O
O hv
20% overall yield
Automated vs. Non-Automated Syntheses
automated (Seeberger) non-automated (Nicolaou)
automated labor intensive10 machine hours 122 reaction hours
80% yield 20% yield
Plante, 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.
O
BzO
O
BzOBzO OAc
O
BzO
BnOO
O
AcO
OAc
AcOAcO
O
BzO
BzOBzO O
O
BzO
BnOO
O
AcO
OAc
AcOAcO
O
AcO
OAc
AcOAcO O
O
O
PivO
O
BnOBnO O
O
PivO
BnOO
O
BnO
OBn
BnOBnO
O
PivO
BnOBnO O
O
PivO
BnOO
O
BnO
BnOBnO
O
OBnOLev
Other Protected Oligosaccharides Synthesized withAutomated Synthesizer Approach
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.
OOBn
BnOBnO
O
OOBn
OBnO
O
O
OOBn
BnOBnO
OAc
OOBn
BnOOPiv
BnOpolymannosideLeishmania tetrasaccharide
50% yield(84% average yield per unit)
OOBn
BnO OOBn
HOO
OOBn
PivO
OO
OBn
PivOO O
OBn
PivO
OOTCAHN BnO
OPiv
BnOBnO
HO
Lewisx pentasaccharide
12.6% yield (66% average yield per unit)
Piv =O
tBu
Bn =
OAc =
NH
O
CCl3TCAHN =
OOBn
BnOBnO
O
OOBn
BnOBnO
O
O
OOBn
BnOBnO
OAc
n
n = 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)
OO
OH
O OOH
HO ORHOO
OOH
O
HOO
AcNH
OOH
HOO
HO HO
OOH
HOHO
HO2C
OH
HO
HO
NHAcHO
How About More Complex Molecules?
Sialyl Lewisx tetrasaccharide4% overall yield in 8 steps(Denishefsky and Wong, 1992)
Fucosyl 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.
OOH
HO OOH
ORHOO
NHAcO
OHHO
HO
O
O
HO
OHOH
AcHNHO
HO2C
O
Outline
1. Introduction
2. Solid Phase Approach: Automated Oligosaccharide Synthesizer
3. Solution Phase Approach: OptiMer One-Pot Oligosaccharide Synthesis
4. Summary
Solution Phase: OptiMer Programmed One-PotOligosaccharide Synthesis
Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
The “Armed - Disarmed” Concept
Mootoo, 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.
OL
+HO
OL
HO
activator
O
OO
L
HO
Armed Disarmed
React Faster React Slower
O
OL
+HO
HO
Protecting Groups Control
Mootoo, 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.
OL
+HO
OL
HO
activator
EDG
EWG
O
OO
L
HO
EDG
EWG
EDG = electron donating groupEWG = electron withdrawing group
O
OL
+HO
HO
EDG
EWG
Disaccharide Synthesis Using Protecting Groups Control
Mootoo, D. R.; Date, V.; Fraser-Reid, B. J. Am. Chem. Soc. 1988, 110, 2662.
OBzO
O
OBzO
OBnO
BnO
OBn
BnO
BzO
OBzO
O
OBzO
OBzO
BzO
is NOT formedBzO
OH
BzO
armed
disarmed
Bn =
OBz =
62% yielda : b = 1 : 1
NO OBr
NBS =
NBS
OBzO O
BzO
OBnO O
+
BzO
OH
BnO
OBn
BnO
Disaccharide Synthesis Using Protecting Groups Control
Mootoo, D. R.; Date, V.; Fraser-Reid, B. J. Am. Chem. Soc. 1988, 110, 2662.
Bn =
OBz =
OOBn
BnOBnO
BnO
OOBn
BnOBnO
BnO
O
OBzOBzO
BzOO
OOBn
BnOBnO
BnOO
Br O
Br
HO
OBzO
O
OBzO
OBnO
BnO
OBn
BnO
BzO
NO O
Br
Anomeric Reactivity Control
Mootoo, 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.
L1 is better leaving group than L2
OL2
+HO
OL1
HO
activatorO
OO
L2
HOO
OL2
+HO
HO
One-Pot Synthesis of Protected Ciclamycin
Raghavan, S.; Kahne, D. J. Am. Chem. Soc. 1993, 115, 1580.
0.05 equiv. TfOH-78oC
O
O O
O
O
S
SO
OBn
OBn+
HO
O
O
O
O
O
O
S
OBn
OBn
Ciclamycin
-70oC
Ciclamycin25% overall yield S
OSO
OMe S> >>
most reactiveless reactive least reactive
O
O
O O
SSSO O
OMe
TMSOOBn
HOOBn
+ +
Bn =
Strategy for Sequential One-Pot Linear andBranched Oligosaccharides Synthesis
Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
OX
OXHO O
XHO OORHO
less reactivemost reactive
donor
least reactive reducing endO O O O
ORO O O
OX
OXHO O
ORHO
less reactivemost reactive
donor
reducing endO O OO O OR
OO O
O
OptiMer Database of Thioglycosyl Donors
Ritter, T. K.; Mong, K.-K. T.; Liu, H.; Nakatani, T.; Wong, C.-H. Angew. Chem. Int. Ed. 2003, 42, 4657.
Number in bracket represents the Relative Reactivity Value (RRV)
OptiMer Database of Thioglycosyl Donors
Zhang, 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 Donors
Ye, X.-S.; Wong, C.-H. J. Org. Chem. 2000, 65, 2410.
OptiMer Database of Thioglycosyl Donors
Ritter, T. K.; Mong, T. K.-K.; Liu, H.; Nakatani, T.; Wong, C.-H. Angew. Chem. Int. Ed. 2003, 42, 4657.
Relative Reactivity in Competitive Reactions
Zhang, Z.; Ollmann, I. R.; Ye, X. -S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
O
OMeOH (5eq.)
NIS
O
O
SR
SR
OMe
OMe
donor (D0)
reference (R0)
product (Dt)
referenceproduct (Rt)
HPLC analysis
O
STol
OAc
AcOAcO
AcO
reference compound =
NO O
I
NIS =
Relative Reactivity in Competitive Reaction
Larger the number, higher the reactivity
RRV = In([Dt]/[D0]) In([Rt]/[R0])
kD
kR=
Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
The result is normalized based on O
STol
OAc
AcOAcO
AcO
RRV = 1
Dt
D0
R0
Rt
t = 0ht = 2h
Sequential One-Pot Synthesis of Globo H
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.
O
O
O O
OHOH
HOO
O
OHOH OHOH
OO
OOH
HO OOH
HO OR
HOAcNH
HOHO
OOHHO
HO Globo H
Globo H1% overall yield in 19 steps(Denishefsky, 1995)
Human breast tumor associated antigen.
First total synthesis was reported by Danishefsky in 1995 using glycal assembly.
Sequential One-Pot Synthesis of Globo H
Burkhart, F.; Zhang, Z.; Wacowich-Sgarbi, S.; Wong, C.-H. Angew. Chem. Int. Ed. 2001, 40, 1274.
O
O
O O
OHOH
HOO
O
OHOH OHOH
OO
OOH
HO OOH
HO OR
HOAcNH
HOHO
OOHHO
HO Globo H
O STolOBn
OBnBnO
O O OOBn
BnO O
OBz ONBz
OTrocHN OClBn
BzOBnO NBzO
STolHO
OHO
OBn
BnO OOBn
BnO ORBnO
BnOO
RRV = 72,000
RRV = 6
OptiMer
Globo H
(67% yield)ClBn =
ClO
NO2
NBz =
TrocHN = NH
O
O CCl3
R =
Bn =
OMe
Sequential One-Pot Synthesis of Globo H
Burkhart, F.; Zhang, Z.; Wacowich-Sgarbi, S.; Wong, C.-H. Angew. Chem. Int. Ed. 2001, 40, 1274.
O STolOBn
OBnBnO
O O OOBn
BnO O
OBz ONBz
OTrocHN OClBn
BzOBnO NBzO
STolHO
RRV = 72,000
RRV = 6
NIS, TfOH, CH2Cl2
O
O
O O
OHOH
HOO
O
OHOH OHOH
OO
OOH
HO OOH
HO OR
HOAcNH
HOHO
OOHHO
HO Globo HGlobo H
1. Zn-AcOH2. Ac2O-pyridine3. NaOMe-MeOH4. H2-Pd/C
20% overall yield
NO O
I
NIS =
ClBn =Cl
O
NO2
NBz =
TrocHN = NH
O
O CCl3
R =
Bn =
OMe
OHO
OBn
BnO OOBn
BnO ORBnO
BnOO
O
O
O OOBn
BnOO
O
OBz ONBz
OO
OOBn
BnO OOBn
BnO OR
ClBnOTrocNH
BnOBnO
OOBnOBn
BnO Globo H
BzO BzO BzO
41% yield
Other Oligosaccharides Synthesized with OptiMer
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.
Sialyl Lewisx hexasaccharide8% overall yieldin 2 one-pot reactions(cf. 4% overall yield in 8 steps)
OO
OH
O OOH
HO ORHOO
OOH
O
HOO
AcNH
OOH
HOO
HO HO
OOH
HOHOHO2C
OH
HO
HO
NHAcHOFucosyl GM16% overall yield in 3 one-pot reaction(cf. 5% overall yield in 15 steps)
And more..
OOH
HO OOH
HOO
NHAcO
OHHO
HO
O
O
HO
OHOH
AcHNHO
HO2C
OO
OH
OHOH
O O
OHOR
OH
HOO
Comparison of the Two Approaches
Common Advantages:
They both reduce labor cost.They both allow for high throughput synthesis of oligosaccharides
Advantages 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 Challenge
Belongs 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.
OOSO3
OHO
OOHO
O3SHNO
OHOO
HOOSO3
OOSO3
O3SOO3SHN
OOSO3
OHO
O3SHN
CO2
O2CO
a
a
iduronic acid
Outline
1. Introduction
2. Solid Phase Approach: Automated Oligosaccharide Synthesizer
3. Solution Phase Approach: OptiMer One-Pot Oligosaccharide Synthesis
4. Summary
Summary
1. Novel strategies towards oligosaccharide synthesis were discussed:
- Solid Phase Automated Oligosaccharide Synthesizer
- Solution Phase OptiMer One-Pot Oligosaccharide Synthesis
2. From a chemical point of view, the reactivity based one-pot strategy makesthe design of oligosaccharide synthesis easier.
Acknowledgement
Prof. John FrostDr. Karen Frost
Prof. Chris ChangProf. Babak BorhanProf. Joan Broderick
Frost Group
The End
Example in Calculating RRV
O
O
STol
OAc
AcOAcO
AcO1:
O
OH
OBn
STolO
PMBO
LevO
BnO OBn
40:
Zhang, 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 RRV
Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
Experimental values are shown without parenthesesCalculated values are shown in parentheses
Relationship Between Relative Rates andSubstrate Comsumption
Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734.
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