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1
GRADUATE SEMINAR
Ande Chennaiah13107064
Supervisor: Prof. Y. D. VankarDepartment of Chemistry
IIT Kanpur
Naturally Occurring Sulfonium-Ion Glycosidase Inhibitors and Their
Derivatives
OUTLINE Introduction about glycosidase inhibitors
Synthesis of Salacinol and their analogues
Synthesis and structure elucidation of kotalanol
synthesis of Ponkoranol
Six and seven membered Salacinol analogues
3
Glycosidases
OHO
HOHO
OH
OR
glycosidic bondglycon
Aglycon
Aglycon may be Sugar or Non Sugar
OO
OO
O
O
OO
O
O
O
O
OH
Glycosidase
4
Mechanism of inverting glycosidases
Biol. Rev. Cambridge Philosophic. Soc. 1953, 28, 416-436
O OR(OH)n
Glycosidase O OR(OH)n
H2O
H
OO
OH
H
OO
O(OH)n
Transition state
+ ROH
O O
OHO
Enzyme
Enzyme
O HHOH
Enzyme
Enzyme
OO
Enzyme
OOH
Enzyme
5
Mechanism of retaining glycosidases
O OR(OH)n
Glycosidase O OR(OH)n
H
OO
OO
O O
OHO
Enzyme
Enzyme
Enzyme
Enzyme
O
(OH)nO O
Enzyme
OO
Enzyme
OR H
Enzyme
O(OH)n
O O
Enzyme
OO
O H
HO O
(OH)n
H
OO
OO
Enzyme
Enzyme
H
Enzyme
O(OH)n
OO
OR H
OH
6
O OR
OH
HO
HOOH
Effect of cationic character on anomeric carbon
Stereo-electronic requirements at this bond
Role of O-H in stabilization
The glycoside inhibitors are designed based on following consideration
Half chair Confirmation in transition state
7
Types of glycosidase inhibitors1. Carbasugars
2. Iminosugars
3.Thiosugars
4.Sulfonium ion Sugars
(-)-Swainsonine
S
OHO
HOHO
HO
O
OHOHOH
O
S
OHHO
HO
OHOSO3
OH
Salacinol
O
OO
HNNH2O
Oseltamivir Kojibioside
N
OH OH
OHH
(OH)n
HN
(OH)n
S
(OH)n
S
(OH)n
R
8
In 1984, Bernad Bellea et al proposed that S-methyl sulforphanol ( sulfonium ion analogue Of Morphine) has biological activity .
In 1992, H. Siriwardena et al synthesized pyrrolizidine analogue of sulfonium ion showing glycosidase inhibitory activity.
HO
S ClO4
H
S-methyl sulforphanol
SS
H
OHHO
Cl
Thioniaperhydropentalene Chloride
Can. J. Chem. 1985, 63, 1268-1274.
9J. Chem. Soc., Chem. Commun. 1992, 1531-1533
Synthesis of 1,2-Dihydroxy-7-thia-3a-thioniaperhydropentalene Chloride
OHOH
OHO
H
D-(-) ErythroseOH
OH
OHHS SH
HCl55%
S
SOH
OH
OTsS
STsCl, Py
-10o C, 2 days 40-70 %
SS
HOHHO
Cl
10
Similarity:-Cationic character of the trivalent sulfur atom resembles that of the anomeric carbon of the Transition state structure .
The permanent charge on sulfur would provide the necessary electrostatic stabilization to bind competitively to glycosidase enzyme.
Tetrahedron Lett. 1994, 35, 8243.
Sulfonium ion GlycosidasesTransition state of Glycosidases
O OR
OH
HO
HOOH
SHO
HOOH N
O2S CH3
Sulfimide derivative
Ki = 1.7 mM
SHO
HOOH OSO
O O
OHOH
11
Sulfonium-Ion Glycosidase Inhibitors Isolated from Salacia Species
S
OHHO
HO
OHOSO3
OH
S
OHHO
HOO
OHOH
OH
OH
OH
SO3S
OHHO
HOO
OH OH
SO3
OHOH S
OHHO
HOO
OH
SO3
Salacinol Kotalanol Ponkoranol Salaprinol
S
OHHO
HO
OHOH
OH
S
OHHO
HOOH
OHOH
OH
OH
OH
S
OHHO
HOOH
OH OH
OHOH S
OHHO
HOOH
OH
De-O-SulfonatedSalacinol De-O-Sulfonated
KotalanolDe-O-SulfonatedPonkoranol
De-O-SulfonatedSalaprinol
12
Salacinol
Isolated in 1997, from Salacia reticulata by Yoshikawa et al
Diabetics drank herbal extract, obtained by storing water overnight in a mug made from the root of this plant
Studies have shown that S. reticulata It is a potent -glycosidase inhibitor
Tetrahedron Lett. 1997, 48, 8367
S
OHHO
HO
OHOSO3
OH
Salacinol
13
J. Org. Chem.,2001, 66,2312.
Synthesis of salacinol
1D and 2D NMR experiments and a potassium rhodizonate test (a positive test that confirmed the presence of a sulfate moiety) suggested the presence of an unusual zwitterionic sulfonium-sulfate structure.
Retrosynthesis
S
OHHO
HO
OHOSO3
OH
Salacinol
S
OHHO
HO
O SOO
O OO
C6H5
2,4-O-benzylidene-L-1,3-cyclic sulfate
O OHHO
HOHO OH
L-Glucose
OHO
HO OH
OH
D-XyloseThioarabinitol
14
Synthesis of Thioarabinitol
Tetrahedron Lett, 1994, 35, 8243-8246.
OO
O O
Oacetone, H2SO40.1% HCl
TsCl, NaH BnCl, NaH
OHO
HO O
O
OTsO
HO O
OO
TsOBnO O
OO
BnSBnO O
O
HCl, MeOH
BnSNaEtOH
95%
80%90%
OHO
HO OH
OH
O OMeS
57%
NaBH3CN
90% AcOH71%
PPh3, I2Imidazole
OBnS
BnO OH
OMeS
OHBnOHO
Na/Liq.NH3
97%
S
OHHOHO
BnO
DMF DMF
EtOH
D-Xylose
15
OOHHO
OH
OHHO PhCHO, H O
OHHO OH
OOC6H5
NaHCO3, H2O CHOOHO
OC6H5
NaBH4
MeOHOHO
OC6H5OH
SOCl2Et3N O S
OOO
OC6H5
NaIO4, RuCl3,CH3CN, H2O,CCl4
O SOO
OO
C6H5
O2,4-O- Benzylidine-D-1,3 cyclic sulphate
D-Glucose
NaIO4
Synthesis of 2,4-O- Benzylidine D-1,3 cyclic sulphate from D- Glucose
16
Synthesis of 2,4-O- Benzylidine- L-1,3 cyclic sulphate from L-Glucose
O OHHO
HOHO OH
OOOC6H5
HOOH
OHPhCHO, H
OHOOC6H5
HO SOCl2 O SOO
O OC6H5
O SOO
O OO
C6H5
NaIO4, RuCl3
L-Glucose
2,4-O-benzylidene-L-1,3-cyclic sulfate
NaHCO3, H2O OHOOC6H5
CHO
MeOH CH3CN, H2O, CCl4Et3N
NaBH4
NaIO4
Carbohydr. Res. 1974, 35, 87-96
17
S
OBnBnO
BnO S
OBnBnO
BnO
OO
OSO3
Ph
Dry AcetoneK2CO3
O SOO
O OO
C6H5
2,4-O-benzylidene-L-1,3-cyclic sulfate
Per-O-Benzylated thioarabinitol 33% product
S
OHBnO
HO
Mono-Benzylated thioarabinitol
Dry AcetoneK2CO3
O SOO
O OO
C6H5
S
OHBnO
HO
OO
OSO3
Ph
32% product
S
OHHO
HO O SOO
O OO
C6H5
S
OHHO
HO
OO
OSO3
Ph
61% product
DMFK2CO3
1)
2)
3)
18
S
OHHO
HO
O SOO
O OO
C6H5
S
OHHO
HO
OO
OSO3
Ph
94% product
K2CO3
Hexafluoroisoprpopanol,
Hughes-Ingold solvent effect:-If the transition state for a reaction has a larger charge than the reactants, then the rate and yield of reaction will increase as the polarity of the solvent increases.
S
OHHO
HO
OHOSO3
OH
Salacinol
S
OHHO
HO
OO
OSO3
Ph
Pd(OH)2
80% aq. AcOH
Synlett , 9, 2003, 1259-1262.
19Bio.org. Med. Chem. Lett. , 2009, 19 , 2195–2198.
Synthesis of De-O-sulfonated Salacinol :-
O
OBn
OBn
S
OBnBnO
BnO
HBF4.(Me)2OCH2Cl2
S
OBnBnO
BnO
OBn
OH
OBnBF4
1.IRA-400J (Cl form) MeOH-H2O
S
OHHO
HO
OH
OH
OHCl
Dowex 1-X2(HCO2 form)
S
OHHO
HO
OH
OH
OHHCO2
De-O-sulfonated Salacinol
-60o C
H2, Pd/C,80% AcOH
H2O S
HO
OH
OH
OHHCO2
H
HH
nOe
20
S
OHHO
HO
OHOSO3
OH
IR : 1262 Cm-1
13C = 80.6 ppm
SHO
OH
OH
OHHCO2
OHHO No sulphate peak in IR
13C= 75.3 ppm
De-O-Sulfonated SalacinolSalacinol
Enzyme Inhibition:-It is noteworthy that desulfonated salacinol maintained almost equal activities to salacinol irrespective of species of the counteranion towa-rds - Glucosidase enzyme.
21
S
OHHO
HO
OHOH
OSO3 S
OHHO
HO
OHOH
OSO3 S
OHHO
HO
OHOH
OSO3
From D-Lyxitol From D-Ribitol
S
OHHO
HO
OHOH
OSO3 S
OPPO
PO OSO O
OO
O
Ph
Retro synthesis
+
From D-Arabitol
Carbohydr. Res. 2005, 340, 2612
Synthesis of D-lyxitol and D-ribitol analogues of the Salacinol
22
D-Lyxose
O
OBnBnO
BnOOH OH
OBnBnO
BnOOH
OH
OBnBnO
BnOOTBDMS
OBnBnO
OTBDMSp-O2NBzOOBn
OBnBnO
OTBDMSHOOBn
OBnBnO
OHHOOBn
NaBH4,
TBDMSCl
Imidazole, DMF.
p-NO2BzOH,
DIAD,
NaOMe, MeOH TBAF,THF
THFPPh3,
91%EtOH,
93%
O
OHHO
HOOH
Carbohydr. Res. 2005, 340, 2612–2619.
23
S
OBnBnO
BnO
S
OHHO
HO
OBnBnO
OMsMsOOBn
MsCl, PyNa2S.9H2O
Li/ NH3
DMF,
NaH/ DMF
PMBCl94%-78 oC
S
OPMBPMBO
PMBO
87%
86%
D-Ribose
S
OPMBPMBO
PMBO
90%
O
OHHO
HO Similar steps
24
O SOO
O OO
C6H5
S
OPMBPMBO
PMBO
S
OPMBPMBO
PMBO
HFIP,K2CO3
S
OPMBPMBO
PMBO
OO
OSO3
Ph
S
OPMBPMBO
PMBO
OO
OSO3
Ph
S
OHHO
HO
OHOH
OSO3
S
OHHO
HO
OHOH
OSO3
aq.TFA
aq.TFA
Activity:-
It is important to notice that the above D-Lyxitol and D- Ribitol analogues of salacinol are notShowing any inhibitory activity.
Thus the D- arabinitol configuration in heterocyclic ring of salacinol is critical for activity.
25
SubstrateSalacinol Acarbose
Maltase 0.31
0.12
Sucrase 0.32
0.37
Isomaltase 0.47
75
Ki(µM) values of salacinol and acarbose for rat small intestinal disaccharidase
Ki (mg/ml) Ki (mg/ml)
Tetrahedron Lett, 1997, 38, 8367-8370.
26
Kotalanol
S
OHHO
HO
OH OHOH
OSO3
OH
OH
S
OHHO
HO
OHO
HO OH
OH
D-XyloseThioarabinitolS
OHHO
HO
OH OHOH
OSO3
OH
OH
OO O
OPMBPMBO
O
OPMB
PhS
O O
OHOH OH
OHOH
OH
OH
D-persitol
27
OHOH OH
OHOH
OH
OH PhCHO, H
OO O
OHOH
O
OH
Ph Ph
PMBClNaH,DMF
2.pTSA,MeOH OOH O
OPMBPMBO
OH
OPMB
Ph
OH
O OH
OPMBPMBO
O
OPMB
Ph
1.SOCl2, Et3N, CH2Cl22.NaIO4, RuCl3 CCl4-CH3CN OO O
OPMBPMBO
O
OPMB
PhS
O O
S
OPMBPMBOPMBO
HFIP,K2CO3
S
OPMBPMBOPMBO
OO
PMBO
OSO3
OPMB OPMB
Ph
80% aq TFA S
OHHOHO
OHOH
OH
OSO3
OH OH
D-persitol
OOH O
OPMBPMBO
OH
OPMB
Ph
34% 41%
Synthesis of kotanalol from D-Persitol
Nat. Prod. Rep., 2010, 27, 481–488.
28
O
OH
O
Ph
1.CH2Br2,aq.NaOH
2.pTSA,MeOH(65%)
1.TBSCl, lmid2.BnBr,NaH3.TBAF,THF (62%)O O
OO
Ph
OHOH
OO
OH
Ph
O O
OO
Ph
OBnOH
1.Dess-Martin periodinane2.CH3Br,PPh3,n-BuLi (56%)
O O
OO
Ph
OBn
(84%)
O O
OO
Ph
OBn
OH
OH
1.BnBr,NaH
2.pTSA,MeOH (74%)
OH OH
OO
OBn
OBn
OBn1.SOCl2,Et3N,CH2Cl2
2.NaIO4,RuCl3 CCl4:CH3CN (61%)
OO
OBn
OBn
OBn
OS
OOO
AD-mix-
K2OsO2(OH)4
K2CO2, K3Fe(CN)6
Synthesis of De-O-Sulfonated Kotanalol from D-Mannitol
Di-O-benzylidene D-mannitol
Nat. Prod. Rep., 2010, 27, 481–488
29
OO
OBn
OBn
OBn
OS
OOOS
OPMBPMBO
PMBO
HFIP,K2CO3 61%
S
OPMBPMBO
PMBO
OO
OBn
OBn
OBn
OSO3
61%
S
OPMBPMBO
PMBO
OH OH
OHOH
OHOH
CH3OSO3
1.0 M BCl3then MeOH
30
Structure determination of Kotanalol
S
OHHO
HO
OH OH
OSO3
2' 3' 4' 5' 6'OH
OHOH
7'
1
23
45H
HH
1'
OO
OBn
OBn
OBn
OS
OOO
S
OPMBPMBO
PMBO
Through " SN2 " mechanism
1)
2) Through nOe analysis
Nat. Prod. Rep., 2010, 27, 481–488
31
S
OHHO
HO
OH OH
OSO3
1' 2' 3' 4' 5' 6'OH
OHOH
7'
1
23
4
5
S
From Salacinol
S
OHHO
HO
OH OH
OSO3 S
OHHO
HO
OH OH
OSO3
Ki = 0.65 m No Inhibition
1' 2' 3' 4' 5' 6'
OH
1' 2'3'
4'5'
OH6'
A B
OHOH
OHOH
7'7'
Experimental proof
32
S
OHHO
HO
OH OH
1' 2' 3' 4' 5' 6'
OH
OHOH
7'
OSO3
S
OHHO
HO
OH OH
1' 2' 3' 4' 5' 6'
OH
OHOH
7'
OSO3
Ki = 0.17 mM Ki = 0.25 mM
It can be fixed as “ S “
S R
Stereochemistry at C-4 and C-6
O
OH
O
Ph
OO
OH
Ph
O O
OO
Ph
OH
OH
OH TBSCl, imid
DMFO O
OO
Ph
OH
OH
OTBS
1. SOCl2, Et3N
2. NaIO4, RuCl3
OO
O
SO
O
OO
O HOTBS
PhH
H
H
H
33
O
O
O
SO
O
O
O
OH
OTBS
Ph
H1
3
2
4
5
6
7H
H
nOe
J= 10.6 HzDiaxial Relationship (Trans)
H
R Configuration at C-5' 13C- 80.5 ppm 13C- 81.8 ppm
S
OHHO
HO
OH OH
OSO3
1' 2' 3' 4' 5' 6'OH
OHOH
7'S
OHHO
HO
OH OH
OSO3
1' 2' 3' 4' 5' 6'OH
OHOH
7'
X Y
34
R Configuration at C-5' 13C- 80.5 ppm 13C- 81.8 ppm
S
OHHO
HO
OH OH
OSO3
1' 2' 3' 4' 5' 6'OH
OHOH
7'S
OHHO
HO
OH OH
OSO3
1' 2' 3' 4' 5' 6'OH
OHOH
7'
X Y
35
O
SO
S
HO
HO
HO
HO
O
O
OHR H
1'
2'3'4'
5'
12
3
45 OH
Nat. Prod. Rep., 2010, 27, 481–488
S
OHHO
HO
OH OH
OSO3
2' 3' 4' 5' 6'OH
OHOH
7'
1
23
45H
1'
13C( = 77.9 ppm
g-Gauche effect
Substrate Kotalanalol Acarbose
Maltase 0.23
0.12
Sucrase 0.18
0.37
Isomaltase 1.8
75
Ki(µM) values of kotalanol and acarbose for rat small intestinal disaccharidase
Tetrahedron Lett. 1997, 38, 8367-8370. 36
37
S
OHHO
HO
OH OHOH
OSO3
OH
OH
N
OHHO
HO
OH OHOH
OSO3
OH
OHH Se
OHHO
HO
OH OHOH
OSO3
OH
OH
Se
OHHO
HO
OH OHOH
OH
OH
OHClN
OHHO
HO
OH OHOH
OH
OH
OHHCl Kotalanol
Heteroanalogues of Kotalanol and De-O-Sulfonated Kotalanol
Org. Lett. 2010, 12,1088-1091.
X
OPPO
OSOO
OPO
RPO
PO
XR
OP OP
OSO3
OPPO
POX
R
OP OP
OSO3
OPPO
PO
Only product Not observed
1
23
4
If "X" is Sulfur
If "X" is Selenium Major Minor
The lesser steric congestion around the “ Se “ center as the Se–C bond was being formed, owing to the Se–C bond being longer than the S–C bond, observed the formation of both diastereomers for selenium.
39
Synthesis of PMB-protected D- selenoarabinitol
O
AcO OAc
OAcAcO
1,2,3,5-tetra-O-acetyl-L-xylofuranose
OH
BF3.Et2O, CH2Cl2
O
AcO OAc
OPentAcO MeONa
MeOH
O
HO OH
OPentHO
PMBClNaH, DMF
O
PMBO OPMB
OPentPMBO
NBS
90:10 CH3CN:H2O
O
PMBO OPMB
OHPMBO NaBH4
MeOH
OH
PMBO OPMB
OHPMBO MsCl,Pyridine
DMF
OMs
PMBO OPMB
OMsPMBO Se, NaBH4
EtOH
Se
PMBO OPMB
PMBO
PMB-protected D- Selenoarabinitol
J. Org. Chem., 2005, 70,753-755.
O
HO OH
OHHO
OMs
PMBO OPMB
OMsPMBO
L-xylose8 steps
N
PMBO OPMB
PMBONH2
DMF,100 oC
Synthesis of PMB-protected D-iminoarabinitol
HN
PMBO OPMB
PMBO
PMB-protectedD-iminoarabinitol
Rh(PPh3)3Cl
90% CH3CN
OHOH OH
OHOH
OH
OH PhCHO
OO O
OHOH
O
OH
Ph Ph
PMBClNaH,DMF
2.pTSA,MeOH OOH O
OPMBPMBO
OH
OPMB
Ph
OH
O OH
OPMBPMBO
O
OPMB
PhD-persitol
OOH O
OPMBPMBO
OH
OPMB
Ph
OO O
OPMBPMBO
O
OPMB
PhS
O O
1.SOCl2,Et3n,CH2Cl22.NaIO4, RuCl3 CCl4-CH3CN
H
J. Org. Chem, , 2006, Vol. 71, 3009.
41
OO O
OPMBPMBO
O
OPMB
PhS
O O
Se
PMBO OPMB
PMBO
HFIP, K2CO3
70 oC
Se
PMBO OPMBPMBO
OO
OPMBPMBO
OSO3
OPMB
Ph
40%
80% TFA,CHCl2, rt, 2h Se
HO OH
HOOHOH
OHOH
OSO3
OH
H
Se
PMBO OPMBPMBO
OO
OPMBPMBO
OSO3
OPMB
Ph
26%
80% TFA,CHCl2, rt, 2h
Se
HO OH
HOOHOH
OHOH
OSO3
OH
H
H
HH
H
OO O
OPMBPMBO
O
OPMB
PhS
O O
HN
PMBO OPMBPMBO
K2CO3, acetone, 60 oCN
PMBO OPMBPMBO
OO
OPMBPMBO
OSO3
OPMB
Ph
80% TFA,CHCl2, rt, 3hH HN
HO OH
HOOHOH
OHOH
OSO3
OH
42
Synthesis of De-O- sulfonated Compounds
X
HO OHHO
OHOH
OHOH
O
OH
1. 5% Methanolic HCl, rt, 3.5 h
2. Amberlyst A-26, MeOH, rt, 2.5 h
X
HO OHHO
OHOH
OHOH
OH
OH
X= NH, 96%X= Se, 98%
ClSO3
Enzyme Inhibition Study
S
HO OHHO
OHOH
OHOH
O
OH
SO3
KotalanolKi = 190 nM
S
HO OHHO
OHOH
OHOH
OH
OH
Cl
De-O-Sulfonated Kotalanol
Ki = 30 nM
43
N
HO OHHO
OHOH
OHOH
O
OH
SO3
H
Ki = 90 mM
N
HO OHHO
OHOH
OHOH
OH
OH
HCl
Ki = 61 nM
Se
HO OHHO
OHOH
OHOH
O
OH
SO3
Ki = 80 nM
ClSe
HO OHHO
OHOH
OHOH
OH
OH
Ki = 40 nM
44
Ponkoranol
S
OHHO
HO
OH OH
OSO3 OH
OH
S
OHHO
HOO OBn
OBnOBn
OS
OO
O
O OBn
OBnOBn
HO
HO
Retrosynthesis
S
OHHO
HO
OH OH
OSO3
2' 3' 4' 5'
OH
OH
1
23
45
1'6'
J. Org. Chem.2006, 71, 1111-1118.
45
D-Glucose penta-O-Acetate
O OAc
OAcOAcAcO
AcO
1) 30% HBr in AcOH, 0 oC, 2h2) BnOH, Ag2CO3, MS 4 Ao, CH2Cl2.
3) MeONa cat. MeOH rt, 6 h
O OBn
OHOHHO
HO 1) DMP, p-TsOH, DMF, rt, 3 h
2) NaH, 0 oC, 15 min. BnCl, rt, 15 h3) 60 % AcOH, 80 oC
O OBn
OBnOBnHO
HO
54%
O OBn
OBnOBnHO
HO
O OBn
OBnOBnHO
HO 1. SOCl2 / Et3N
2) RuCl3 / NaIO4
1. SOCl2 / Et3N
2) RuCl3 / NaIO4
O OBn
OBnOBn
OS
OO
O
O OBn
OBnOBn
OS
OO
O
O OAc
OAcOAc
AcO
AcO
O OBn
OBnOBnHO
HO
D-Galactose penta-O-Acetate
Synthesis of corresponding cyclic sulphates
46
S
OBnBnO
BnO HFIP, K2CO3
S
OBnBnO
BnO
OOBn
OBn
OBn
O3SOS
OBnBnO
BnO
OOBn
OBn
OBn
O3SOHFIP, K2CO3
AB
S
OHHO
HO
OOH
OH
OH
O3SO
S
OBnBnO
BnO
OH
OSO3
OH
OHOH
S
OBnBnO
BnO
OH
OSO3
OH
OHOH
S
OHHO
HO
OOH
OH
OH
O3SO
1) H2, Pd(C), MeOH
1) H2, Pd(C), MeOH 2) TFA/H2O2) TFA/H2O
NaBH4, H2O NaBH4, H2O
PonkoranaolKi = 0.25 mM Ki = 0.17 mM
47
De-O-Sulfonated ponkoranaol
S
OHHO
HO
OH
OH
OH
OH
OH1' 2'
3'4'
5'6'
Cl
S
OHHO
HO
OH OH
OH OH
OH
S
OHHO
HOO OBn
OHOH
TsO
HO
O OH
OHOH
HO
HO
Cl
D- Glucose
Retrosynthesis
Synthesis:-1st Method
O OMe
OHOHHO
HO PPh3, I2, imadazole,THF, reflux, 2h
O OMe
OHOHHO
I
S
OBnBnO
BnO
AgBF4, CH3CN, 65 oCNo Reaction
2nd Method
O OMe
OHOHHO
TsO
O OMe
OH
OHHO
S
OBnBnO
BnO
HFIP, 70 oC, 45%
S
OBnBnO
BnO 1) BCl3, -78 oC,CH2Cl22) 2 M HCl, 70 oC, 20h
O OMe
OH
OHHO
S
OHHO
HO2 M HCl No reactionAcOH
Org. Lett, 2010, 12, 1632-1635.
49
O
OHOHHO
HOO
OH
OHHO
S
OBnBnO
BnO
1.BnOH, p-TSOH,70 oC, 4 h, 36%
2.TsCl, Pyridine,-10 oC, 4 h, 60%
O
OHOHHO
TsO
S
OBnBnO
BnO
HFIP, 70 oC,52%
1.BCl3, CH2Cl2, -78 oC, 6 h2.Amberlyst, H2O, 3 h3. NaBH4, H2O, 3 h, 48%
OTs
S
OHHO
HO
OH
OH
OH
OH
OH
1' 2'3'
4'5'
6'Cl
OH OBnOBn
O
OHOHHO
HOO OBn
OH
OHHO
S
OBnBnO
BnO
1.BnOH, p-TSOH,70 oC, 4 h, 35%
2.TsCl, Pyridine,-10 oC, 4 h, 60%
O
OHOHHO
TsO
S
OBnBnO
BnO
HFIP, 70 oC, 45%
OTsOH OBn
D- Mannose
1.BCl3, CH2Cl2, -78 oC, 6 h
2.Amberlyst, H2O, 3 h
S
OHHO
HO
OH
OH
OH
OH
OH
3. NaBH4, H2O, 3 h
Cl1' 2'
3'4'
5'6'
Synthesis of 5’ stereoisomer of Ponkoranol
50
O OBn
OHOHHO
HOO OBn
OOHO
HO
O
OCH(OMe)3, CSA,CH2Cl2, reflux
OMe
MeO
O OBn
OOHO
HO
OMe
MeO
TsCl, Pyridine,75%
O OBn
OOHO
TsO
OMe
MeO
O OBn
OOHO
HO
OMe
MeO
Major (1.8%)
Minor (1%)
Major
MeI, NaOH
DMSO, 91%
O OBn
OOMeO
TsO
OMe
MeO
D- Glucopyranoside
Replacing the sulfate moiety by a methyl ether in Ponkoranol
S
OHHO
HO
OH
OH
OMe
OH
OH
1' 2'3'
4'5'
6'Cl
51
Enzyme inhibition study
Inhibitor Ki Value
3’-O-methyl Ponkoranol 0.50 ± 0.04m
De-O-sulfonated Ponkoranol 43 ± 3 nM
Ponkoranol 5’ stereoisomer 15 ± 1 nM
S
OBnBnO
BnO
HFIP, K2CO3 70 oC, 70%
S
OBnBnO
BnO
O
BnO
O
O
OMe
MeO
OMe
1' 2'
3'4'
5'6'
S
OHHO
HO
1.BCl3, CH2Cl2 -78 oC, 6h2. 80% TFA3.Amberlyst A-26,4.NaBH4, H2O, 3 h 51%
OH
OH
OMe
OH
OHOTs
1' 2'3'
4'5'
6'Cl
6 and 7 membered Salacinol analogues
S
OH
OHHO OH
HOOSO3
OH
S
OHHO
HO
OHOSO3
OH
Salacinol
S
OH
OHHO OH
OSO3
OH
S
HO
HO OHOH
OH
OSO3
OH
OHOHHO
HO OH
OHOHHO
Br Br
OH
O O
DMF, 2 hR.T OAc
OAcAcO
Br BrAc2O
NaOMeMeOH
D-Arabitol
NBS, PPh3
Pyridine
OHOHHO
SNa2S, 9 H2O
DMSOR.T
3,4,5-trihydroxy-tetrahydrothiopyran
OH OH
HOHO
OH
OH S
HO
HO OH
OH
3,4,5,6 Tetra hydroxy thiepanesD-Mannitol
OHOHHO
HO OH
OHOHHO
S
D-Ribitol3,4,5-trihydroxy-tetrahydrothiopyran
Tetrahedron: Asymmetry, 1996, 7, 3087-3090.
53
Carbohydr. Res.1971, 18, 342-344.
54
O
HO
HO
HO
OH
OHO
HO
O
O
O
OO
BzO
O
O
O
O
O
BzO
O
O
O
OO
BzO
HO
HO
O
O
O
H2SO4
BzCl,
K2CO3,THF
60% AcOH
H2O
O
BzO
Cl
Cl
O
OSOCl2Et2O
O
OBz
Cl
Cl
O
O
0o C
O
OBz
AcS
Cl
O
OO
OBz
AcS
SAc
O
O
A
S
O
KS
O
K
Dry AcetoneDry Acetone
BRT
Synthesis of acetylated Thioglucopyranose
J. Org. Chem., 1975, 58, 4.JACS., 2006, 128, 227-239.
S
OAcOAc
AcO
O3,CH2Cl2-78o C
1.
2. Ac2O -78o C
S
OAcOAc
AcO
AcO
O
BzO
AcS
Cl
O
O
A
Et3N
MeOH40o C
O
HO O
OS AcOH : Ac2O
3 : 1
O
O
K
O
AcO
AcO
AcS
O
O
S OAc
OAcOAc
AcO
OAcAc2O : AcOH : H2SO4
70 : 30 : 1Et2O, AcONa
56
OBnOBnBnO
S
3,4,5-tri-O-benzyltetrahydrothiopyran
SOO
O OC6H5
O2,4-O- Benzylidine-D-1,3 cyclic sulphate
OBnOBnBnO
S
O O
Ph
OSO3
OBnOBnBnO
S
O O
Ph
OSO3
MinorMajor
HFIP
O SOO
O OO
C6H5
2,4-O-benzylidene-L-1,3-cyclic sulfate
OBnOBnBnO
S
O O
Ph
OSO3
OBnOBnBnO
S
O O
Ph
OSO3
Major Minor
1,1,1,3,3,3-hexafluoro-2-propanol
HFIPOBn
OBnBnO
S
3,4,5-tri-O-benzyltetrahydrothiopyran
57
OBnOBnBnO
S
O O
Ph
OSO3
MajorOH
OHHO
S
OH OH
OSO3H2/Pd80% AcOH
Enzyme Inhibtion:- None of the above compounds shown considerable inhibition
OBnBnO
S
O O
Ph
OSO3
MajorOH
OHHO
S
OH OH
OSO3H2/Pd80% AcOH
OBn
58
OBnOBnBnO
S
Tetrahydrothiopyran
O SOO
O OO
C6H5
2,4-O-benzylidene-L-1,3-cyclic sulfate
OBnOBnBnO
S
O O
Ph
OSO3
OBnOBnBnO
S
O O
Ph
OSO3
Major
Minor
HFIP
OHOHHO
S
OH OH
OSO3
OHOHHO
S
OH OH
OSO3H2/Pd80% AcOH
H2/Pd80% AcOH
OBn
OBn
OBn OH
OH
59
OBnOBnBnO
S
Tetrahydrothiopyran
HFIP
H2/Pd80% AcOH
H2/Pd80% AcOH
OBnS
OOO
OC6H5
O2,4-O- Benzylidine-D-1,3 cyclic sulphate
OBnOBnBnO
S
O O
Ph
OSO3
OBnOBnBnO
S
O O
Ph
OSO3
Major
OHOHHO
S
OH OH
OSO3
OHOHHO
S
OH OH
OSO3OBn
OBn
OH
OH
Minor
S
OH
OHHO
HO
3,4,5,6 Tetra hydroxy thiepanes
OH OH
OSO3S
OH
OHHO
HO
OH OH
OSO3S
OH
OHHO
HO
OH OH
OSO3S
OH
OHHO
HO
OH OH
OSO3S
OH
OHHO
HO
61
Enzymes
α-Glucosidase(Rice)
1.41 1.32 NI
α-Glucosidase(Baker yeast)
NI NI NI
β-Galactosidase(A. oryze)
NI 0.85 NI
α-Manosidase(Jack beans)
0.46 1.34 1.83
S
HOOH
OH
OH
OSO3
OH
OHS
HOOH
OH
OH
OSO3
OH
OHS
HO
HO OHOH
OH
OSO3
OH
Evaluation of enzyme inhibition properties (Ki in mM)
Conclusion
62
In the last 20 years, the rate of discoveries in this field has increased enormously!
Some of these molecules have been considered as therapeutics for diabetes and are under clinical trials. Ex- Salacinol and De-O-sulfonated Kotalanol
The synthesis and study of sulfoinum ion glycosidase inhibitors is quite a Young discipline, has large scope for synthetic organic chemists to develop novel molecules as better and selective glycosidase inhibitors
SS
TsO
OHOH
SS
OTs
H
HOHO
SS
OHOH
SS
H
HOHO
H
Cl
Cl TsO
TsO
