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