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FREE-RADICAL HYDROTHIOLATION OF GLYCALS:
A THIOL-ENE-BASED SYNTHESIS OF S- DISACCHARIDES
UNIVERSITÀ DEGLI STUDI DI FERRARA
Dottorato in Scienze Chimiche XXVI Ciclo
Curriculum in Sintesi e Reattività Organica
PhD Student:Samuele Staderini
Tutor:Prof. Alberto Marra
OLIGOSACCHARIDES: BIOLOGICAL IMPORTANCE
Virus infectionBacterial infectionCancer metastasis
Inflammation
Immunological response
O-OLIGOSACCHARIDES: THE NATURAL ONES
O O O
OH OH
OH(OH)3(HO)3
• Not easy to isolate in pure form• Unstable towards chemical and
enzymatic degradation
Isosteres synthesis
O S O
OH OH
OH(OH)3(HO)3
O CH2O
OH OH
OH(OH)3(HO)3
• Probes for study of enzymes mechanisms
• Inhibitors of enzymes (pharmaceutical lead)
• More stable towards chemical and enzymatic degradation
• S-oligosaccharides are the smallest step from natural ones
S-DISACCHARIDES: A FLASHBACK
O SO
OH OH
OH(OH)3(HO)3
Several chemical syntheses established for these molecules
Our group has developed a Thiol-Ene Coupling (TEC) method between alkenyl sugars and sugar thiols
Fiore M.; Marra, A.; Dondoni, A. J. Org. Chem. 2009, 74, 4422-4425
1. Sugar thiolate anion + carbohydrate-LG2. Glycosylation of thiosugar acceptor with
activated glycosyl donor3. Michael additions of sugar thiolates to ,a b-
unsaturated systems
SHO
AcOOAc
OAc
AcO
Ph
MeO OMe
O
Ph
h (365 nm)CH2Cl2; 15 min
DPAP
OCH3
OAcO
AcO
AcO+
OCH3
OAcO
AcO
AcO
SO
AcOAcO
OAc
AcO
THIOL-ENE COUPLING (TEC): A BRIEF INTRODUCTION
• Catalyzed by light• Economic• High efficient and selective
RSR'
R'
RSR'
R S
R SH
R SH + Photoin itiatorh
S-DISACCHARIDES: A NEW IDEA
Igarashi, K., Honma, T. J. Org. Chem. 1970, 35, 606-610
SHO
AcOOAc
OAc
AcO h
OCH3
OAcO
AcO
AcO+
OCH3
OAcO
AcO
AcO
SO
AcOAcO
OAc
AcO
OAcO
AcS
OAc
AcOO
OAc
AcO
AcO
H3C SH
O
• Thiol – Ene Coupling know-how• Endo-cyclo enol-ethers sugars (glycals) importance• Only one example of thermal TEC in literature concerning D- glucal
Exploration of reactions between glycals and thiol-sugars
GLUCOSE THIOL SYNTHESIS
OAcO
OAc
OAcAcOO
HOOH
OHHO OH OAc
Pyr / Ac2O1:1
2 hr RT>90%
MeONa 0.2 MMeOH
-40°C1 hr
>90%
OAcO
AcO
OAcAcO
Br
OAcO
OAc
OAcAcO SAc
OAcO
OAc
OAcAcO SH
H3C SK
O
CH3CNOvernight RT
80%
HBr / CH3COOH
Overnight RT>90%
THIOL-ENE COUPLING (TEC): MODEL REACTION
OOAc
SHO
AcOAcO
OAc
AcOS
OAcO
SO
AcO+Ph
MeO OMe
O
Ph
h (365 nm)
DPAP
+
OAcO OAcAcO
OAc
OAcO O
Ac
AcO
OAc
AcOAcO AcOAcO
AcOAcO
Parameters to be established:• Irradiation time• Thiol sugar equivalents• Solvent
1 hour
6 equivalents
EtOH
RADICAL INTERMEDIATES
OAcO
OAcO
(AcO)2 (AcO)2SAc SAc
GLYCALS SYNTHESIS
OOAc
AcOAcO
OOAc
AcO
SPhO
OAc
AcO
OAc
PhSH ; BF3 Et2O0°C ; 15 min
CH2Cl246%
1) DMDO ; CH2Cl2 ; -78°C ; 1h2)Et2O / Et2NH ; RT ; Overnight
3) Ac2O / Pyr 1:137%
OHO
OH
OHOH
OHO
AcOOAc
OAcAcO
OAcO
AcOAcO
OAcAcO
Br
OOAcAcO
AcO
Ac2O / Pyr HBr / CH3COOH
Zn° / CuSO4NaOAcAcOHH2O
OvernightRT
25%
OvernightRT
>90%
OvernightRT
>90%
OOAcAcO
AcOO
OAcAcO
OAc
D- galactal
D- allal
D- gulal
THIOL-ENE COUPLING (TEC): GLYCALS
O
OAc
O
OAc
AcOAcO
(AcO)2 SHO
AcOAcO
OAc
AcOS
OAcO
SO
AcO
(AcO)2
(AcO)2+Ph
MeO OMe
O
Ph
h (365 nm)
DPAP
+
Glycal Conversion (%) Product(s) Y ield (%) ax:eq ratio
O
OAc
AcO
AcO
O
OAc
AcO
AcO
O
OAcAcO
AcO
100
100
40
35
80
59
38
20
57:43
37:63
100:0
100:0
OAc
O OAcAcO
OAc
OAc
O OAcAcO
OAc
S
OAcO
SO
AcO
OAc
O OAcAcO
OAc
OAc
O OAcAcO
OAcAcO
AcO
AcOAcO
S
OOAc
SO
AcOOAc
O OAcAcO
OAc
OAc
O OAcAcO
OAcAcO
AcO
AcO
AcO
SO
AcO
OAc
O OAcAcO
OAcAcO
AcO
SO
AcOOAc
O OAcAcO
OAc
AcO
AcO
GLUCOSAMINE THIOL SYNTHESIS
SHO
AcOAcHN
OAc
AcOSO
AcOAcHN
OAc
AcO
OHO
AcHN
OH
HOOH
NH
NH3Cl
OAcO
AcHN
OAc
AcOOAc
AcCl
RTOvernight
H2N NH2
S
Acetonereflux30 min
Na2S2O5H2O / CH2Cl2
50°C2h
>90%
55%
THIOL-ENE COUPLING (TEC): THIOLS
O
OAc
AcOAcO SH
O
AcOAcO
OAcAcO
Glycal Conversion (%)Products Yie ld (%) ax:eq ratio
O
OAc
AcOAcO
100
100
100
100
100
82
100
100
54:46
74:26
38:62
50:50
Thiol
O
OAcAcO
AcO
O
OAc
AcO
AcO
SHO
AcOAcHN
OAc
AcO
SHO
AcOAcHN
OAc
AcO
SHO
AcOAcO
OAcAcO
S
OAcO
SO
AcO
AcO
O
OAcAcO
OAc
AcO
O
OAcAcO
OAcAcO
AcO
AcOAcO
S
OAcO
SO
AcO
OAc
O OAcAcHN
OAc
OAc
O OAcAcHN
OAcAcO
AcO
AcOAcO
S
OOAc
SO
AcOAcO
O
OAcAcO
OAc
AcO
O
OAcAcO
OAcAcO
AcO
AcO
AcO
S
OOAc
SO
AcOOAc
O OAcAcHN
OAc
OAc
O OAcAcHN
OAcAcO
AcO
AcO
AcO
Moving on to two different thiols: D-galactose and D-glucosammine
CONCLUSIONS
1. Glycals can undergo a photoinduced addition of glycosylthiyl radicals
2. Total regioselectivity
3. Glucose-, galactose- and glucosamine- thiol additions to D-glucal and D-galactal give:
• Good to excellent yield• Products in pairs of diastereoisomers in comparable amounts
4. Glucose- and galactose- thiol additions to D-allal and D-gulal give:• Single product (axial) in low yield• Total stereoselectivity
Staderini, S. Chambery, A., Marra, A., Dondoni, A. Tetrahedron Lett. 2011 In press
Thank you for your kind attention
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