SYNAPS July 2011 -The Biological Roles of Carbohydrates - Glycosylation Methods: O-, C-, N- Glycosylation; 2-deoxy Glycosides - Synthesis of Carbohydrate-Containing Natural Compounds Cristina Nativi Department of Chemistry University of Florence - Italy Cristina Nativi Department of Chemistry University of Florence - Italy
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The ECM is a complex mixture of molecules with multiple functions:
1.Filling the space between cells, binding cells and tissue together2.Providing a lattice through cells can move3.Filtration4.Support and elasticity (see connective tissue)5.Influence on cell growth and differentiation (many cells interact with their ECM)
The ECM is composed of 3 types of macromolecules
1. Glycoproteins, glycoconjugates2. Glycosaminoglycans (GAGs): large unbrunched polymers of repeating disaccharides3. With the excetion of hyaluronic acid, all GAGs are covalently attached to core Proteins thereby forming a proteoglycan (PG)
SYNAPS July 2011
Biological Roles of Carbohydrates
Type andnumber of
monosaccharidicunits are essential
to distinguish betweennormal or abnormal
cells
Mucin Antigens
SYNAPS July 2011ACIE 2011, vol. 50 pag. 1770
SYNAPS July 2011
Biological Roles of Carbohydrates
Type andnumber of the
monosaccharidicunits
Type of linkage
Possible Mechanisms of Origin of TAAPossible Mechanisms of Origin of TAA1) New genetic information caused by a virus2) Alteration of ocogenes by carcinogenes, which can cause the induction of genes
normally unexpressed3) Uncovering of antigens normally hidden in the cell membrane4) Release, when neoplastic cells die, of antigens normally sequestered in the cell
TumorCell Tumor-Associated
Antigen (TAA, TSAs)
SYNAPS July 2011
TumorCell
B cell/T cell
Tumour Antigen
During the growth of tumors,mechanisms that allow tumor-presentedantigens to be seen as “self”by their immune system havebeen identified (escape mechanisms)
TAA No molecolar recognitionis observed!
SYNAPS July 2011
TAA and ImmunotherapyTAA and Immunotherapy(Biologic Therapy)(Biologic Therapy)
Induce therapeutic cellular immunity in the tumor-bearing host
Chromomycin A3Mithramycin,Olivomycin A
Biological Roles of Carbohydrates
Aureolic Acid Family Structurally related drugs synthesizedby different streptomycete species
2,6- dideoxy sugars
SYNAPS July 2011
SYNAPS July 2011
Carbohydrates as Starting Material(Chiral Pool – Chirons)
Jean Baptiste Regnault
Achilles educated by ChironLouvre Museum
Chirons: Enantiomerically PureSynthons
SYNAPS July 2011
OOH
HO
HOHO
OH
trans Vicinal
trans Vicinal
OOH
OHHO
HOOH
trans Vicinal
cis Vicinal
Types of Hydroxyl Groups Found in Sugars
OOH
HO
HOHO
OH
trans Vicinal
trans Vicinal
OOH
HO
HOHO
OH
Anomeric
Primary
Secondary
OOH
HO
HO
OH OH
trans Vicinal
cis Vicinal
SYNAPS July 2011
Carbohydrates as Starting Material
Synthesis of (+)-Spectinomycin
S. Hanessian -Total Synthesis of Natural Product: The Chiron Approach
O
O O Me
HO OH
H
HO
OH
MeHN
MeHN
HO OO
O
OHOHNHMe
HO
MeHN
OHHO
Me
OO
OOH
NHMe
OH
MeHN
Me
OH
HOOH
O
OO
MeO
HO OH
OHMeHN NHMe
OHHO OH
OHMeHN NHMe O
OO
HO Me
+
Actinamine Spectinose
Aminocyclitol AntibioticStreptomices Spectabilis
SYNAPS July 2011
OO
OOH
NHMe
OH
MeHN
Me
OH
HOOH
OO
OOH
NHMe
OH
MeHN
Me
OH OH
OHO
OOH
NHMe
OH
MeHN
Me
OH OH
OHHO OH
OHMeHN NHMeO
X
Me
OH OH+
OOH
HOHO
OH OH
D- Glucose Actinamine
Synthesis of (+)-Spectinomycin
SYNAPS July 2011
OOH
HOHO
OH OH
D- Glucose
OOH
HOHO
HO OMe
MeOHHCl SO2Cl2
pyO
ClCl
HOHO OMen-Bu3SnHAIBN (rdn)
OHO
HO OMe
4,6-dideoxyderivative
OOO
HO OMe
SOO
Cl
Cl -
Nu -
α- anomer !
OOO
HO
OMeS
OO
Cl
Cl -
Nu -
β- anomer !
Synthesis of (+)-Spectinomycin
SN2 reaction
SYNAPS July 2011
OHO
HO OMe
OHO
BzO OMe
O
HO HO OMe
O
AcOAcOCl
O
AcOAcOO
HO OH
CbzMeNOH
NMeCbz
O
AcO HO
O
TCCO OTCC
CbzMeNOTCC
NMeCbz
O
O O
O
TCCO OTCC
CbzMeNOTCC
NMeCbz
O
AcO O
O
TCCO OTCC
CbzMeNOTCC
NMeCbz
TCC = trichloroethoxycarbonylOMe
1) (Bu2Sn)2O MeOH reflux2) BzCl
1) PCC2) NaBH4
1) Ac2OBF3OEt2) HCl
Cbz-actinamineAgOTf, THF- 40 °C
MeONaMeOH
1) MeONa MeOH
2) MeC(OMe)3 TsOH, C6H6
3) ClCO2CH2CCl3 Py / DMAP
aq. Ac2O
Mild cond.
PCCbenzenereflux
Synthesis of (+)-Spectinomycin
SYNAPS July 2011
Synthesis of (+)-Spectinomycin
O
AcO O
O
TCCO OTCC
CbzMeNOTCC
NMeCbz
O
HO OH
OO OH
CbzMeNOH
NMeCbz
O
O O
OO OH
CbzMeNOH
NMeCbz
SnBu Bu
O
O OH
OO OH
CbzMeNOH
NMeCbz
O
O O Me
HO OH
H
HO
OH
MeHN
MeHN
HO
Zn, MeOH (Bu2Sn)2O
MeOHreflux
1) NBS, benzene2) H2 - Pd/C, 2-PrOH
SYNAPS July 2011
Types of Hydroxyl Groups Found in Sugars
OOH
HO
HOHO
OH
Anomeric
Primary
Secondary
SYNAPS July 2011
Glycosylation Methods:Synthesis of O-Glycosides
SYNAPS July 2011
OO
OX
+ HO
Glycosides and Glycosylation
ONH
OS
OCH2
Aglycon Donor Acceptor
O-glycoside
SYNAPS July 2011
O-Glycosidic Bond Formation
O YRO
RO
OX
OR
+a)
X = LGY = O-
O O ORO
ORRO
b) Y = LGX = OH
ORO
RO
O
OR
O Lewis Acid = Promoter
Regiochemical problems
SYNAPS July 2011
OO O
H
O
O
O
OLG
OH
R
α - face
O-Glycosidic Bond Formation
Path a)
O
LG
OH
Rβ - face
Path b)
Tricky equilibrium among donor, acceptor and promoter
SYNAPS July 2011
OOR
HOHO
HO
OHO
OR
OH
HOHO
HO
O
OR
OHHO
HOHO
O OR
OHHOHO
Stereochemical Aspects of Glycoside Bond Formation
SN1 vs SN2
OOR
OH
HOHO
OH
OOR
OHHO
HOOH
O
OR
HOHO
HO
OH
O
OR
OHHOHO
1,2–trans -O-glycosides
1,2–cis -O-glycosides
Glc Gal Man Rha
Glc Gal Man Rha
SYNAPS July 2011
Stereochemical Aspects of Glycoside Bond FormationNeighbouring Group Participation
OX
OR'
O
OR'
Promoter O
OR'
O
O O
R'
RO
H
RO
H
O
ORO
R'
OOR
OR'
1, 2 - cis glycoside
1, 2 - trans glycoside
SYNAPS July 2011
Stereochemical Aspects of Glycoside Bond FormationSolvent Participation
O
R'
Et2O
MeCN
OO
R'
Et
Et
O
NR'
C
Me
RO
H
RO
H
O
R' OR
O
R'OR
SYNAPS July 2011
OOH
HOHO
HOOH
H+ OOH2
HOHO
HOOH
OHO
HOHO
OH
MeOH O
OMe
HOHO
HOHO
OHO
HOHO
OH
+O
OMe
HOHO
HOHO
O
OMe
HOHO
HO
OH
α- Man
Fischer – Helferish Glycosylation
O
OMe
HOHO
HOHO
α- Glc
SYNAPS July 2011
OOH
HOHO
HOOH
O
Br
RORO
RORO
Prom. ORO
RORO
OR
ORO
RORO
OR
ONu
RORO
ROOR
NuR = Ac, Bz, Piv Bn
Koenigs - Knorr Glycosylation
ORO
RORO
OR Br
ORO
RORO
OR Br
R
O H O NuRO
RORO
OR
ORO
RORO
OR
ONu
RORO
ROOR
ORO
RORO
OR Br
ORO
RORO
OR Br
R
O H O NuRO
RORO
OR
ORO
RORO
OR
ONu
RORO
ROOR
SN2 vs SN1Promoter
δ
δ δ
δ
SYNAPS July 2011
Stereoselective Synthesis of Mannosyl cis-glycosides(β O-Man)
OOBn
Br
BnOBnO
BnOAg-silicate
OOBn
Br
BnOBnO
BnO
Ag
O
H
RO
OBn
ORBnO
BnOBnO
C-2 – non partecipant group (OBn)C-1 - SN2 reaction
SYNAPS July 2011
Stereoselective Synthesis of Mannosyl cis-glycosides(β O-Man)
Stereoselective Synthesis of Mannosyl cis-glycosides
A
SYNAPS July 2011
Stereoselective Synthesis of Mannosyl cis-glycosidesIAD (Intramolecular Aglycon Delivery)
OO
O
BnOBnO
BnO
LG
OO
O
BnOBnO
BnO
LG
OR O
O
OOH
BnOBnO
BnOO
R
O
R
H+
O-nucleophile
2-O-para methoxybenzyl mannoside
A variety of β O-mannosides can be obtained
DDQ
O
O+
Quinone-like species
SYNAPS July 2011
Stereoselective Synthesis of Mannosyl cis-glycosidesSynthesis of β-O-Octyl-2-O-mannopiranosyl-α (1,2)-mannopyranoside
O
OO
OHHO
HO
HO
HOHO
HOO
OBnOBnO
BnOOH
OOBnO
BnO
BnO OAc
O NH
CCl3
OBnOBnO
BnOO O
OCH3
+
OrthoesterCommon intermediate
Dr. Gabriele Gabrielli Marco Palchetti
University of Florence
SYNAPS July 2011
Stereoselective Synthesis of Mannosyl cis-glycosides
Synthesis of β-O-Octyl-2-O-mannopyranosyl-α (1,2)-mannopyranoside
OAcOAcO
AcO OAc
OAc
OAcOAcO
AcO
OAcOAcO
AcO O
Br
OO
OCH3BnBrNaH
DMF
2,6-Lutidine MeOH
HBr 33% inCH3COOH
CH2Cl2
K2CO3 cat.
MeOH
CHCl3
OHOHO
HO OH
OH
Ac2OPy
> 90%> 90%
73%
> 90%
OHOHO
HO OO
OCH3
85%
OBnOBnO
BnO OO
OCH3
O
β face!
SYNAPS July 2011
Stereoselective Synthesis of Mannosyl cis-glycosidesSynthesis of β-O-Octyl-2-O-mannopyranosyl-α (1,2)-mannopyranoside
OBnOBnO
BnOOAc
ONH
Cl3C
O
OO
OAcBnO
BnO
BnO
BnOBnO
BnOO
OBnOBnO
BnO OAc
OH
Cl3CCN
DBUCH2Cl2
89%
OBnOBnO
BnO OO
OCH3
H+ / H2O99%
OBnOBnO
BnO OAc
ONH
Cl3C
+OBnO
BnO
BnO OHO
TMSOTf (cat)CH2Cl2
67%
Deprotect.
O
OO
OHHO
HO
HO
HOHO
HOO
SYNAPS July 2011
How to Choose the Good Glycosyl Donor?
OOP
POPO
OYOH
OOBnO
OBnO
S(O)Ph
Ph
OPOPO
OYPO
OR
OPOPO
O
PO
OR
OPOPO
OPO
L
XOR
A B
C D
SYNAPS July 2011
O
OPX O
OPSP O
OPOR O
OPXR
Glycosyl halides Thio derivatives O- Derivates Other derivatives
BromidesChlorides
FluoridesIodides
Sulfides(Thioglycosides)
SulfoxidesSulfones
ImidatesEsters
PhosphitesPhosphatesCarbonates
Selenoglycosides
Promoters for Glycosyl Bromides and Chlorides:
AgOTf, SnCl4, BF3 OEt2, AgClO4, TfOH, Ag2O, Ag silicate,
Types of Glycosyl Donors
SYNAPS July 2011
Glycosyl Fluorides
• Too reactive to be activated under standard Koenigs-Knorr conditions• They were introduced late (1981)• More stable than chlorides and bromides• Can be activated under specific conditions consistent with several protecting groups• They are currently among the most frequently used donors
• Instable• Glycosylation proceed through in situ generation of glycosyl iodide intermediates by activating glycosyl bromide with tetralkylamonium iodide
O
I
MeO2CPivO
PivOPivO
+ O
PivO
NMeH
HHO
I2CH2Cl2
55%
OMeO2C
PivOPivO
PivO
O
PivO
NMeHH
O
3-O-Pivaloyl morphine
OHO2C
HOHO
HO
O
HO
NMeHH
O
Morphine-6-gluconoride
SYNAPS July 2011
Synthesis of Glycosides from Anomeric Thio Derivatives
• Readily prepared by nucleophilic substitution at the anomeric center• Remarkably stable• They tolerate diverse protecting group manipulations• They are inert under several glycosylation conditions (useful acceptors)• Despite their stability they can be activated with thiophilic reagents
(soft electrophilic reagents under mild conditions)
OX + RSH
OSR
X = OAc (1,2-trans), Cl, Br
Lewis Acid
SYNAPS July 2011
OSR' Electrophile O
S R'E
-R'SE O ROHO
OR
sulfonium ion
Promoter
Me SMe
S MeTfO-
DMTST dimethyl(methylthio)solfonium triflate
Me SMe
S Me
BF4-
DMTSF
SS
O OMe
MBPTS-(4-methoxyphenyl)benezenethiosulfinate
SN I
O
OO
NISacN-Iodosaccharine
Synthesis of Glycosides from Anomeric Thio Derivatives
R' (Aglycon)
N
N
O
N
S
SYNAPS July 2011
Synthesis of Glycosides from Anomeric Thio Derivatives
An unique feature of thioglycosides is that their reactivity can be turned not only by the protecting groups of the sugars but also by the choice of the aglycone.
OS
OAc
AcOAcO
OBn O
N+
OBzO OH
BzOBzO
SEt
OBzO O
BzOBzO
SEt
OOAc
AcOAcO
BnOAgOTfCH2Cl2
98%α only
SYNAPS July 2011
OOAc
AcOAcO
OAcOH O
OAc
AcOAcO
OAcO
NH
CCl3CCl3CN, K2CO3
CH2Cl2, RT54%
Glycosyl Trichloroacetimidates
• Glycosyl acetimidates were introduced by Sinaÿ(synthesis of the blood group B determinant)
• Glycosyl trichloroacetimidates were developed by Schmidt
OOBn
BnOBnO
BnOOH CCl3CN, NaH
CH2Cl2, RT96%
OOBn
BnOBnO
BnO O CCl3NH
• Relatively stable under neutral o basic conditions but extremely reactive under acidic conditions• Can be purified by column chromathography on silica gel
α
β
SYNAPS July 2011
50
%
Min20 40
NaH
α
β
OOBn
BnOBnO
BnOOH
OOBn
BnOBnO
BnO O CCl3NH
OOBn
BnOBnO
BnOO CCl3
NH
BaseCl3C CN
50
20 40
α
β
% K2CO3
h
The electron-deficient nitrile readly adds to the free hydroxyl group; under week-basic conditions the kinetic product is formed (b), with strong base the thermodinamic product is obtained (a).
Glycosyl Trichloroacetimidates
SYNAPS July 2011
OOBn
BnOBnO
BnOO CCl3
NH
O
OMe
HOBnO
BnOBnO
+TMSOTf
Et2ORT, 1h
OOBn
BnOBnO
BnOO
O
OMe
BnOBnO
BnO83%
α / β = 8:1
+O
OMe
HOBnO
BnOBnO
BF3Et2OCH2Cl2
- 20 °C2h
OOBn
BnOBnO
BnOO
O
OMe
BnOBnO
BnO90%
α / β > 1:19
OOBn
BnOBnO
BnO O CCl3NH
+ Cl3C
O
NH2
Glycosyl Trichloroacetimidates
Cl3C
O
NH2 - H2OCl3C CN
• Several promoter can be successfully used• Molecular sieves
Catalytic process?
SYNAPS July 2011
Glycosyl Trichloroacetimidates
The normal and inverse procedureThe normal and inverse procedure
O
O
Me
BnO OBnOBn
NH
CCl3O O
OHOAcO
AcOAcO
OAcOBn
N3
OTBS+ O OOO
AcO
AcOAcO
OAcOBn
N3
OTBS
OMe OBnOBnBnO
TMSOTfEt2O
RT
Normal procedure: 43%Inverse procedure: 78%
SYNAPS July 2011
Glycosyl Trifluoroacetimidates
• Recently introduced as glycosyl donor• The conversion of trifluoroacetimidates into glycosides are
promoted by the same reagents used for trichloroacetimidates
• 1,2-Anhydro sugars such as Brigl’s anhydride has been known for a long time• Lemieux used 1,2-anhydro sugars in the first synthesis of sucrose (1953)• Curci (1980) and Murray (1985) developed the DMDO reagent• Danishefsky developed an efficient synthesis of anhydro sugars with DMDO• Seeberger employed anhydro sugars as donors in automatic oligosaccaride synthesis
O
OTBDMSTBDMSO
TBDMSO
OOO
TBDMSO
O
OTBDMSTBDMSO
TBDMSOO
Ph OOO
TBDMSO
Ph O
OOO
TBDMSO
Ph
O
OO
TBDMSO
Ph
OGulo
Allo
Gal
Brigl’s anhydride
SYNAPS July 2011
OBnO
BnOBnO
DMDO99%
α:β / 20:1
OBnO
BnOBnO
O
OHO
BnOBnO
ZnCl2THF, - 78 °C- rt
56%
OBnO
BnOBnO
ROO
OBnOBnO
R = HR = Bn
DMDO
OBnO
BnOBnO
ROO
OBnOBnO
O
OHO
BnOBnO
ZnCl2THF, - 78 °C- rt32% for 2 steps
OBnO
BnOBnO
ROO
OBnOBnO
RO OO
BnOBnO
1,2-Anhydro Derivatives
SYNAPS July 2011
Solid-Phase Synthesis Using Glycal-Derived1,2-Anhydrosugars
O
OSiPh2O
O
ODMDO O
OSiPh2O
O
O
O
O
OHO
O
OO
OSiPh2O
O
O
HOO
O
O
O
DMDO
O
OSiPh2O
O
O
HOO
O
O
O
O
OO
O
OHO
O
O
OSiPh2O
O
O
HOO
O
O
OO
O
O
OHO
O
O
DMDO
O
OSiPh2O
O
O
HOO
O
O
O
O
OO
O
OHO
O
O
OHO
O
OO
OHO
OHO
OO
O
O
O
OO
O
OHO
O
OO
O
OHO
TFA, AcOH32 %
overall yield
O
O O
O
SYNAPS July 2011
N-Pentenyl Glycosides
• Introduced by Fraser-Reid• Highly stable glycosyl donors• Activate by halogenation of the double bond• A major difference in the reactivity of n-pentenyl glycosides possessing
benzyl protecting groups compared to acylated glycosides was observed
O
X
OHO
X
Oacid
X = OH, OAc, Br, OCOR
HO
acid = H+, SnCl4 , AgOTf, NIS(depending on X and protecting groups)
Glycosylation Methods:Synthesis of 2-Deoxy-O-Glycosides
SYNAPS July 2011
Special Problems in Glycosylation Reactions:2-Deoxy Sugars
O OHOHO OH
HO
HOHO OH
2-deoxy glucose 2-6-dideoxy glucose
2 2
6
Chromomycin A3
Deoxy Carbohydrates
Aureolic Acid Family Structurally related drugs synthesizedby different streptomycete species
2,6- dideoxy sugars
SYNAPS July 2011
SYNAPS July 2011
Special Problems in Glycosylation Reactions:2-Deoxy Sugars
O OHOHO OH
HO
HOHO OH
2-deoxy glucose 2-6-dideoxy glucose
2 2
6
• 2-Deoxy and 2,6-dideoxy glycosides are important structural units in many naturalproducts including antitumor drugs, antibiotics active against Gram-positive bacteria, cardiac glycosides, antiparasitic agents• The lack of a stereodirecting neighbouring group adjacent to the anomeric centermakes 2-deoxyglycoside synthesis a real challenge• The absence of electron-withdrawing substituent at C-2 makes the glycosidic bondMuch more acid-labile giving rise to easy hydrolysis or anomerization
SYNAPS July 2011
Special Problems in Glycosylation Reactions:2-Deoxy Sugars
ORO
RORO
ORO
RORO
Y
YX
ORO
RORO
X
Y
X
ORO
RORO
YX
ORO
RORO X
Yα-Manno β-Gluco
S S
ORO
RORO
Y
SX
ORO
RORO
XY
ORO
RORO
Y
SX
ORO
RORO
Y Xβ-Manno α-Gluco
Y = participating group, easily removable
Temporary Assistance
SYNAPS July 2011
Special Problems in Glycosylation Reactions:2-Deoxy Sugars
Addition of PhSCl to glycals was introduced by Schmidtand widely investigate by Roush
Addition of Sulfur-based Electrofiles to Glycals
O
X
ROTBDSO
O
X
RO
TBDSO
4H55H4
O
X
ROTBDSO
SPhO
XRO
TBDSOCl
SPh O
X
ROTBDSO
SPh
O
X
RO
TBDSO
SPh
OX
ROTBDSO
ClPhS
X = Br, Cl, OTs 5H4 is favouredProtecting group at C-4 influences the
up-, bottom-face attack (TBDS favoures the bottom-face attack)
Episulfoniumspecies
SYNAPS July 2011
Special Problems in Glycosylation Reactions:2-Deoxy Sugars
OX
AcOTBDSO
ClPhS
OX
AcOTBDSO
OPhS NH
CCl3
OX
AcOTBDSO OR
PhS
OX
AcOTBDSO
SPhO
X
OAc
TBDSO
PhS
OX
AcOTBDSO OR
PhS
OX
AcOTBDSO
ORPhSO
X
AcO
TBDSO
SPh
1) DBU, THF-H2O2) NaH, CCl3CN- 40 °C - - 20 °C
TMSOTf, ROHCH2Cl2 , - 78 °C
SN2 DisplacementTMSOTf, ROHCH2Cl2 , - 78 °C
ROH Felkin-Anh ControlO
X
AcOTBDSO
SPh
ROH
ROHROH
Stereoelectronic Control
SN2 Displ.
20-50% in glycosylationof hindered alcohols
SYNAPS July 2011
Special Problems in Glycosylation Reactions:2-Deoxy Sugars
Removal of Temporary Protecting Group
OX
AcOTBDSO OR
PhS
Raney- Nichel OX
AcOTBDSO OR
H
H
2-Deoxy-β-O-glycoside
SYNAPS July 2011
Special Problems in Glycosylation Reactions:2-Deoxy Sugars
Addition of Selenium-based Electrofiles to Glycals
OBnOBnO
BnO OAcPhSe
OBnOBnO
BnO
PhSeClAgOAc
toluene25 °C, 1h
+O
HOBnO
BnOOMeBnO
α / β = 1 / 981%
TMSOTfEt2O, 0 °C15 min
OBnOBnO
BnO OPhSe OBnO
BnOBnO OMe
α / β = 1 / 1698%
OBnOBnO
BnO OOBnO
BnOBnO OMe
Ph3SnHAIBN
H
H
SYNAPS July 2011
Special Problems in Glycosylation Reactions:2-Deoxy Sugars
OBnO
BnOBnO
O+ O
OBnBnO
HO ZnCl2
42%
OBnO
BnOBnO
OHO
O
OBnBnO
OBnO
BnOBnO
O
OO
OBnBnO
SO
F F
F
FF
OBnO
BnOBnO O
O
OBnBnOBu3SnH
AIBN90%
77%S
O
F F
F
FF
Cl
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-GlycosidesA new reagent ….
N
O
O
SCl
NK
O
O
N
O
ON
O
O
SSCH2Cl2, r.t.
= PhthNSClN
O
ON
O
O
SS
SO2Cl2
40 °C, 36h
> 90%
> 90%
S2Cl2
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-GlycosidesA new reagent ….
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-GlycosidesA new reagent …..
Y
O O
SNPhth
H
Y
O O
SY
O - O
S NPhth
Y = R, OR, SR,
- PhthN -
Y
O O
SNPhth
HY
O O
Y
O OSiMe3
PhthN-SCl
CHCl3, rt
Base
N
O
O
SCl = PhtN-SCl
Unstable
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-GlycosidesA new reagent …..
O O
SNPhth
H
- PhthN -
BaseO
S
O O
O
S
O
O
O
LUMO (eV)
HOMO (eV)
0.19
5.58
- 9.80- 9.01
[4+2]S
O
O
Ab initio 3-21G*
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-GlycosidesA new reagent …..
EDG EDG
OH
EDG
O
SSNPhth EDG
O-
SNPhth
OH
EDG = R, OR, OH, Cond. Ar. Ring
PhthN-SCl - PhthN -Base
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-GlycosidesA new reagent …..
OH O
SSNPhth
O
SO
O
S
O O
LUMO (eV)
HOMO (eV)
- 0.26
5.58
- 8.98- 9.01
Base
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
O O
SNPhth
H
- PhthN -
Base
O
S
O O
O[4+2]S
O
O
Cycloaddition on Solid Support
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
+ OBnO
BnOBnO
CHCl3r.t.
OBnO
BnOBnO
S OO
OBnO
BnOBnO
SO
O
95 : 5
O O
S
α-O-glicoside β-O-glicoside
+
OBnO
BnOBnO
SO
O
α-O-glicoside
OBnO
BnOBnO
OS
O
β-O-glicoside
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
SO
+ OBnO
BnOBnO
CHCl360 °C
OBnO
BnOBnO
S O OBnO
BnOBnO
SO
80 : 20β-O-glycosideα-O-glycoside
+
SOOH
PhthNSCl PyOH
SNPhth
CHCl3
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
OBnO
BnOBnO
OO
OHO
OOBnBnO
BnO
OBnO
BnO
BnO
OAcO
AcOAcO
OBnO
BnOBnO
S OO
OO
OHO
S OO
OOBnBnO
BnO
S OO
OBnO
BnO
BnO
SO
O
Dienophile Cycloadduct Yield % ΔE (HOMO-LUMO)eV
80
54
73
68
7.91
7.91
7.55
7.88
8.12No Reaction
α /β
95/5
only α
only α
only β
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
OBnOBnO
BnO
OHOHO
t BDMSO
OBnOBnO
t BDMSO
OBnO
BnO
OBn
O
BnO
BnO
O
BnO OBn
OBnOBnO
BnO
S O
OHOHO
t BDMSO
S O
OBnOBnO
t BDMSO
S O
OBnO
BnO
OBn
S O
O S
O
Dienophile Cycloadduct Yield (%)
80/20
95/5
92/8
only α
only β
α / β
85
69
80
68
73
BnO OBn
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
OBnO
BnOBnO
S O
OBnO
BnOBnO
OTHF
OBnO
BnOBnO
S O
O
O
OBnO
BnOBnO
OO
O
THF
OOBnBnO
BnOS O
O
O
OOBnBnO
BnOO
OO
THF
O
O
S
BnOOBnO
O
BnOOBnTHF
Raney-Ni
68%
Raney-Ni0-25 °C
45%
Raney-Ni0-25 °C
31%
Raney-Ni
60°C
57%
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
OH
COOMe
CbzHN
OH
COOMe
CbzHN
SNPhth
OBnO
BnOBnO
OH
COOMe
CbzHN
SNPhth OBnO
BnOBnO
S O
CbzHN COOMe
OBnO
BnOBnO
O
COOMeCbzHN
+ py60%
PhthNSCl60%
Raney-Ni
58%(82%)
(89%)
SYNAPS July 2011
ROOBn
O O NHBoc
ORO
OBnO O NHBoc
OSNPhth
PhthNSClRO
OBnO O NHBoc
OS
OOBn
BnOBnO
Base
O
S OO
RO
OBn
BnOBnO
NHBoc
OOBn
R = Me, tBu, Ph, Me3SiCH2CH2
HOOBn
O NHBoc
O
50-60%
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
Chiara VenturiUniversity of Florence
2−Deoxy−α-O-Glucoaminoacid
SYNAPS July 2011
OOR
RORO RO
OR'O O NHR''
OS
OOR
RORO
S OO
RONHR''
OOR'
+
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
Glycopeptide Mimetics with Native Sugar Peptide Linkage
X, Y, Z = functional groupsA, B, C = orthogonal protecting groupsa, b, c = orthogonal deprotection cond.
Orthogonal protecting groups are “a set of completely independent classes of protecting groupssuch that each class can be removed in any order and in the presence of all other classes”Baranay & Marrifield
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
O
S OO
Me3SiCH2CH2O
OBn
BnOBnO
NHBoc
OOBn
O
S OO
HO
OBn
BnOBnO
NHBoc
OOBn
TBAFTHFr.t.80%
O
S OO
NH
OBn
BnOBnO
NHBoc
OOBn
OtBu
OtBuO
HOBT, EDCI, DIPEADMF, rt, 86% tBuO
O
OtBu
H2N
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
O
S OO
MeO
OBn
BnOBnO
NHBoc
OOBn
O
S OO
MeO
OBn
BnOBnO
NH2
OOBn
Me3SiCl (4M)PhOH (4M)CH2Cl2
O
S OO
MeO
OBn
BnOBnO
NH
OOBn
N-Cbz-L-Phe ONHCbz
O
S OO
MeO
OBn
BnOBnO
NH
OOBn
N-Fmoc-(N-Boc)-TrpO
NHFmoc
NBoc
66% (2 steps)
62% (2 steps)
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
O
S OO
MeO
OAc
BnOBnO
NHAc
OOBn
O
S OO
MeO
OH
BnOBnO
NHAc
OOBn
Ac2OMe3SiOTf MeONa
rt86%- 40 °C
68%
O
S OO
MeO
OBn
BnOBnO
NHBoc
OOBn
O
S OO
MeO
O
BnOBnO
NHAc
OOBn
O
AcO
SPh
OAc
AcOAcO
NISTfOH
CH2Cl20 °C-rt
O
AcO
OAc
AcOAcO
64%β / α = 5/1
MeOH-CH2Cl2
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
O
S O
ROH O
SOH
OR O OR
β-attack
L. A.
Raney-Ni
O
S O
O
O
Raney-Ni
α-O-glycoside
β-O-glycoside
α-O-glycoside
SYNAPS July 2011
OBnO
BnOBnO S
OO
OHTMSOTf
CH3NO2
OBnO
BnOBnO S
O
OOH
+
α / β = 9/1 (74%)
23 h
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
OBnO
BnOBnO S
O
OOH
OHTMSOTf
CH3NO2
OBnO
BnOBnO S
O
OOH
OBnO
BnOBnO S
OO
+ +
7%
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
OBnO
BnOBnO S
OO
OBnO
BnOBnO S
OAcO
1) LiAlH42) Ac2O
OBnO
BnOBnO S
OO
OBnO
BnOBnO S
OTiCl4
O
Zn
Nysted
OBnO
BnOBnO S
OH
ORROHMeOTfMeNO2
OBnO
BnOBnO S
O
ORROHTfOHCH2Cl2
Nysted Reagent
60-70%
98%
ZnBrBrZn
Promoter
β- attach
The Remote Activation Concept
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
OBnO
BnOBnO S
OH
O
OBnO
BnOBnO S
OH
O
OBnO
BnOBnO S
OH
O
OBnO
BnOBnO S
OH
O
OH
OBnO
BnOBnO S
OH
O
OOO
OO
OH
OOMeBnO
BnOBnO
OOMeBnO
BnOBnO
HO
OBnO
BnOBnO S
OAcO
O-Glycoside Donor AcceptorReaction Time (min.) Yield (%)
r.t.
2 equiv.
3 equiv.α / β = 5/95
2 equiv.
2 equiv.
5r.t. 61
40r.t. 68
40
45
35
50
r.t.
r.t.
HO5225
HOO
OO
OO
2-Deoxy-β-O-glycosides
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-O-Glycosides
OBnO
BnOBnO S
OH
O
OBnO
BnOBnO S
OH
O
OBnO
BnOBnO S
OH
O
OBnO
BnOBnO S
OH
O
OOMeBnO
BnOBnO
OBnO
BnOBnO O
OBnO
BnOBnO O
OBnO
BnOBnO O
OOMeBnO
BnOBnO
Raney-Ni
Raney-Ni
Raney-Ni
Raney-Ni
OBnO
BnOBnO O
67%
69%
51%
56%
O
OO
O OO
OO
O O
SYNAPS July 2011
Glycosylation Methods:Synthesis of C-Glycosides
SYNAPS July 2011
Naturally Occurring C-GlycosidesAloin is an irritant laxative contained in the yellow sap of Aloe,which is a constituent of the
Anthraquinone complex.
Anthraquinone naturally occurs in some plants (eg. aloe, senna, rhubarb), fungi, lichens, and insects,where it serves as a basic
skeleton for their pigments. Natural anthraquinone derivatives tend to have laxative effects.
Metathesis is a bimolecular process involving the exchange of bondsbetween the two reacting chemical species, which results in the creation of products with similar or identical bonding affiliations
An important and influential reaction within organic chemistry, which involves the principle of metathesis is the olefin metathesis reaction developed by Yves Chauvin, Richard R. Schrock and Robert H. Grubbs, who shared a Nobel Prize in Chemistry in 2005.
Similar reactivity as Grubbs 1st gen.useful in the industrial productionof macrocycles via RCM
Initiates readely at low temperature,efficient for the methatesis ofelectron-deficient or sterically demandind substrates
N N
RuCl
Cl
PCy3Ph
MesMes
Grubbs 2nd generation catalyst
N N
RuCl
Cl
PPh3Ph
MesMes
SYNAPS July 2011
Metathesis Catalyst Technology
N N
RuCl
Cl
PCy3Ph
MesMes - PCy3
+ PCy3
N N
RuCl
ClPh
MesMesR R
RR
[Ru]Ph
[Ru]
R R
Ph
R
Ph[Ru]
R
Ph
R
Different initiation ratevarying the detachable
phosphine ligands
SYNAPS July 2011
OOH
ROHO
HOOH
(CH2)nCH3
O
(CH2)nCH3
O
NaHCO3+
OOH
ROHO
HO O
(CH2)nCH3
Solvent: H2O + cosolvent (THF, CH3CN, EtOH)
R = HR = α-D-Glc n = 0, 5, 8
β-Glycosidic Ketones in Aqueous Media
Marie-Christine ScherrmannUniversite’ de Paris XI
SYNAPS July 2011
OOH
HOHO
NHAcOH
O
O+
OOR
RORO
NHAc
ORO
RORO
NHAc
O O
R = H
R = Ac
Ac2OPy
100%
Ac2OPy
100%
R = H
R = Ac
NaHCO3
H2OTHF83%
+
4 : 6
OO
O
HOHO
HONHAc
NaO
O
O
HOHO
HO
NHAcNa
OO
O
HOHO
HO
NHAcNa
β-Glycosidic Ketones in Aqueous Media
OOHHO
HOR
OH
R = OH; GalR = NHAc; GalNAc
O
O+
NaHCO3 OOHHO
HOR
O
Ac2OPy O
OAcAcO
AcOR
OR = OAc; 100%R = NHAc; 50% (2 steps)
SYNAPS July 2011
Glycosylation Methods:Synthesis of N-Glycosides
SYNAPS July 2011
O
OH
HN
OO
NH
Asparagine
N-Glycosides
N-Glycosides Natural Glycoproteins (Saccaride units covalently linked to a peptide backbone)
The structural and biological diversity emerging from the combination of the aminoacid
and carbohydrates is immense
N-Acetylgalactosamine
N-Acetylglucosamine
D-Glucose
L-Rhamnose
β-N-glycoside
SYNAPS July 2011
N-Glycosides
OOH
[P]OO
NH2
[P]ONH4HCO3
H2O
OOAc
[P]OTMSN3
SnCl486%
ON3
[P]OPR3
H2O - THFO
NH2
[P]O
PR3
ON
[P]ON N PR3
phosphazide
- N2 ON
[P]O
PR3
OO
[P]O NBS, CH3CN O[P]O
NC
CH3
H2O O[P]O
NHAc
MW
Kochetkov amination(dimer formation)
α-anomer
SYNAPS July 2011
N-Glycosides
OO
[P]O NBS, CH3CN O[P]O
NC
CH3
H2O O[P]O
HN
O
N OO
[P]O NBS, Et3SiOTf
O
N OOO
[P]O CH3CN O
N OO
[P]O N C CH3
H2O
O
N OO
[P]O HN
O
O
α-glycoside
β-glycoside
HO
O
O
O PhNHR
O
N OO
[P]O N
O
O NHR
O
O Ph
SYNAPS July 2011
N-Glycosides
Glycosylasparagine Amino Acids
ON3
[P]O PPh3 , DCMor MeOH
[P]-Asp-O[P]
COOH
O HN
[P]O
O [P]-Asp-O[P]
OSO
[P]O PhTf2O, DCM
[P]-Asp-O[P]
CONHSiMe3
O HN
[P]O
O [P]-Asp-O[P]
SYNAPS July 2010
Glycosylation Methods:Synthesis of 2-Deoxy-N-Glycosides
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-N-Glycosides
Y
N O
SNPhthY
N OR
R
Y
N O
S
R
Y
O O
S
ORO
ROOR
N
SO
R
O
S N
ORRO
RO
OR
PhthN-SCl
?
α-imino-α’-oxothione
R = H, EDG
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-N-Glycosides
OEt
O O
OEt
N OSO2Ph
OEt
HN O
SNPhth
SO2Ph
EtO
N
SO
SO2Ph
OOBn
BnOBnO
O
S NO
EtO
SO2Ph
OBn
BnOBnO
O
S NO
EtO
SO2Ph
OBnBnO
BnO
OBnO
OBn
BnO NS
OEtO
SO2Ph
PhthN-SCl
85 %
Base
87 %
71 %
OOBn
BnO
OBnO
OBnBnO
BnO
EtO
N
SO
SO2Ph
SYNAPS July 2011
The Cycloaddition Approach to 2-Deoxy-N-Glycosides
EtOOBn
O O NHBoc
OEtO
OBnO NTs NHBoc
O
EtOOBn
O NTs NHBoc
OSNPhth
EtOOBn
O NTs NHBoc
OS
OOBnBnO
BnOO
S NTsO
EtO
OBnBnO
BnO
PhthNSCl
Base
NHBoc
OOBn
75 %
H H
92% - 2 steps 65% - 2 steps
HOOBn
O NHBoc
O
α-N-Galattohomoglutamate
SYNAPS July 2011
Synthesis of Carbohydrate-Containing Natural Compounds
SYNAPS July 2011
OHOOC
HO OHO
O
HO
NHAcO
GLYCOSAMINOGLYCANS
Glycosaminoglycans are unbranched polymers of alternating uronic acid and hexosamine residue
The extra cellular spaces, particularly those of connective tissues (cartilage,tendon, skin …) consist of collagen and elastin fibers embedded in a gel-like matrix known as ground substance.
Ground substances is composed largely of glycosaminoglycans also called mucopolysaccharides (solution of glycosaminoglycans are mucus-like)
O
O OOOC
OHO
HOHO
OSO3
O3SHN ORepeating unit ofHeparin
SYNAPS July 2011
HEPARIN
• Heparin is a variable sulfated glycosaminoglycan that consists predominantly of alternating a-(1,4)-linked residues of L-iduronic acid and N-, O-di-sulfated glucosamine.• Heparin is not a constituent of connective tissue but occurs almost exclusively• In the intracellular granules of the mast cells that line artherial walls.• It inhibits clotting of blood• It is widely used to inhibit blood clotting in postsurgical patients• Heparin’s anticoagulant effect has been attributed to its binding to antithombin III(factor of blood clotting cascade)
• A pentasaccharidic fragment has been identified as the minimal effective structuralelement in heparin binding to antithrombin