functionalization of carbohydrates at c2-6
TRANSCRIPT
Functionalization of Carbohydrates
How to Selectively Derivatize Hydroxyl Groups on Carbohydrates??
O
H
HO
H
HO
H
OH
OHHH
OH
O
H
HO
H
HO
H
H
OHHO
OH OH
H
HO
H
HOH
H
OHHO
O
O
HO
OH
O
O
HO
OH
OH
OH
O
HO
OH
O
O
HO
OH
O-Cellulose
OH
OH
O
n: 10,000 -1500
C-6 Hydroxyl Derivatization
O
H
HO
H
HO
H
OCH3
OHHH
OH
Tr-Cl
Cl
Pyridine
Mechanism
O
H
HO
H
HO
H
OCH3
OHHH
O
O
H
HO
H
HO
H
OCH3
OHHH
OH N
Cl-
O
H
HO
H
HO
H
OCH3
OHHH
O
Ph
Ph
Ph
NaH
or NaNH2
CH3-I
PTSAorBF3/Et2OOrAcidic AmberlystorDry silicia gel
O
H
HO
H
HO
H
OCH3
OHHH
OH
Tr-Cl
Cl
Pyridine
R2
R1
R3
R1R2R3: H, H, OMe H, OMe, OMe OMe, OMe, OMe
CH3-Br/NaH
Acid hydrolysis
O
HO
HO
OH
O
O
HO
OH
O
O
O
HO
OH
O
O
HO
OH
OH
O
O
O
H3CO
OCH3OCH3
OCH3
OCH3
H3CO
Acid
O
H
-O
H
-O
H
OCH3
O-HH
O
Ph
Ph
Ph
CH3-IO
H
H3CO
H
H3CO
H
OCH3
OCH3H
H
O
Ph
Ph
Ph
O
H
H3CO
H
H3CO
H
OCH3
OCH3H
H
HO
O
H
H3CO
H
H3CO
H
OCH3
OCH3HH
OH
O
O
HO
OH
O
O
HO
OH
OH
OH
O
HO
OH
O
O
HO
OH
O-Cellulose
OH
OH
O
n: 10,000 -1500
Cl
R1
R1: O(CH2)xMe
Ac2O/Acid catalyst
Ifuku, Shinsuke; Kamitakahara, Hiroshi; Takano, Toshiyuki; Tanaka, Fumio; Nakatsubo, Fumiaki. Preparation of 6-O-(4-
alkoxytrityl)celluloses and their properties. Organic & Biomolecular Chemistry (2004), 2(3), 402-407.
O
O
HO
OH
O
O
HO
OH
OTr'
OTr'
O
HO
OH
O
O
HO
OH
O-Cellulose
OTr'
OTr'
O
n: 10,000 -1500
O
O
AcO
OAc
O
O
AcO
OAc
OTr'
OTr'
O
AcO
OAc
O
O
AcO
OAc
O-Cellulose
OTr'
OTr'
O
n: 10,000 -1500
O
H
HO
H
HO
H
OPh
OHHH
OH
CHO
PTSAorZnCl2orBF3
OCH3
OCH3
or
OH
OH
H
HO
H
OPh
OHHH
OH
EtBr
NaH
What happens with an acid?
Lewis AcidBronsted Acid
OO
H
HO
H
OPh
OHHH
O
O
O
H
HO
H
OPh
OHHH
O
O
O
H
EtO
H
OPh
OEtHH
O
OO
RO
OCH3
OR
O LAH...LiAlH3
LAH/AlCl3
R=Bn
R=Bn
What about Ac??
> 90% OBn
OO
RO
OCH3
OR
O
AlCl3-
H3Al-H
OHO
RO
OCH3
OR
O
H+
OO
RO
OCH3
OR
O
HCl..Et2ONaB(CN)H3
R=Bn
R=Bn
NaBH4
OO
RO
OCH3
OR
O
H
H-BH2(CN)
OO
RO
OCH3
OR
HOBn
OHO
R'O
OCH3
OR'
HO Si Cl
Et3N
Cl
O
EtN3
-50 -60oC
O
HO
HO OR
OH
OH
Ethyl AcetateAl2O3
O
HO
HOOR
OH
OO
N
N
2-OAc 3-OAc 4-OAc 6-OAc YieldAc2O, K2CO3 0.50 0.46 0.04 47%Ac2O, pyridine 0.57 0.23 0.20 60%AcCN, K2CO3 0.15 0.08 0.77 44%AcCN, pyridine 0.16 0.08 0.76 46%AcCl, K2CO3 0.06 0.17 0.03 0.74 44%AcCl, Pyridine 0.12 0.03 0.85 73%AcOCO2t-Bu,K2CO3 0.06 0.44 0.25 0.25 59%AcOCO2t-Bu, Pyridine 0.48 0.18 0.34 83%
Ac-X DMAPBase DCM See Kattnig, Egmont; Albert, Martin. Counterion-Directed Regioselective
Acetylation of Octyl -D-Glucopyranoside. Organic Letters (2004), 6(6), 945-948.
Ac2O
O
HO
HO
OX
OH
OH
O
O
Lipase
X 6-OAcGluco. Me 98 Gluco Ph 96Gluco CH2Ph 99Gluco Me 74Mann. CH2Ph 97
Ser
OHO
O
R
Ser
O
-O
OR
+ H+
Ser
O
O
+ ROH
R'OH
Ser
O
-O
OR'
+ H+
Regioselective acylation of polyhydroxylated natural compounds catalyzed by Candida antarctica lipase B (Novozym 435) in organic solvents. Danieli, Bruno; Luisetti, Monica; Sampognaro, Giannantonio; Carrea, Giacomo; Riva, Sergio. Dip. Chim. Org. Indust., Centro C.N.R. Studio Sost. Org. Nat., Milan, Italy. Journal of Molecular Catalysis B: Enzymatic (1997), 3(1-4), 193-201
OO
HO
OCH3
OH
O
H
NBS
OO
HO
OCH3
OH
O
H
Reflux
Br
OO
HO
OCH3
OH
O
Br
OO
HO
OCH3
OH
O
Br
OOHO
OCH3
OH
O Br-OO
HO
OCH3
OH
OBr
Bu3SnH
OO
HO
OCH3
OH
O
Ac-OkayBn- No
O
HO
HO
OCH3
OH
OH
N
O
O
X
X=Cl, Br
+ PPH3
N
O
O
PPh3 X-
O
HO
HO
OCH3
OH
O
PPh
Ph
Ph
LiX
X-O
HO
HO
OCH3
OH
X
OH3CO
HO
OMe
OH
H3CO
Na + H-
OH3CO
O
OMe
O
H3CO
Br
R
R: CH=CH2
Ph
OH3CO
O
OMe
O
H3CO
R
R
+ H2 or NH3
or Na NH2
Basic Conditions
No Reaction
Acidic Conditions
No Reaction
OH3CO
O
OMe
O
H3COO
H3CO
O
OMe
O
H3CO
H+
OH3CO
O
OMe
O
H3COO
H3CO
O
OMe
O
H3CO
HHH
H
O
H
OH3CO
O
OMe
O
H3CO
H
O
H
H
OH3COO
OMeO
H3CO
H
O
H
H+
OH3CHOO
OMeO
H3CO
H
O
H
H
OH3COHO
OMeO
H3CO
So on.....
Pd(PPh3)4
O
O
AllO
OAc
OCH3
O
isopropylidene
Wilkinson Catalyst
O
O
O
OAc
OCH3
O
H+
NO!!! why?
HgO/HgCl2
O
O
HO
OAc
OCH3
O
General Protection Strategies
O
AcO
HO
OH
OCH3
OAc
O
AcO
BnO
OBn
OCH3
OAc
NaH
Bn-Br No??Why??
OTf
+ N
or
N
N
HBF4
O
HN
CCl3
+ Triflic Acid
N
N
H
RO
H
R-O-Bn + N2 +
H+
O
NH2
CCl3R
O
H
R-O-Bn + H+ +NH2
O
CCl3
O
AcO
HO
OH
OCH3
OAc
OHO
OHOH
OCH3
OH
Allopyranoside
H+ + PhCH(OCH3)2
OO
OHOH
OCH3
OPh
OO
OO
OCH3
OPh
OCH3
OCH3
OCH3
Br
NaH
OO
OO
OCH3
HOPh
OCH3
OCH3
OO
OO
OCH3
AcOPh
OCH3
OCH3
Ac2O/Pyridine
If you want
2,3-OH
Can Not Use
Pd/C + H2
O
O
Cl
NC CN
Cl
OO
OHOH
OCH3
AcOPh
OHO
OH OHOCH3
AcO
Pd/C + H2
OHO
OHOH
OCH3
OH
Allopyranoside
OO
OHOH
OCH3
O
OO
OO
OCH3
O
Bn
Bn
Br
NaH
Ac2O/Pyridine
O
O
Cl
NC CN
Cl
OHO
OBnOBn
OCH3
AcO
OHO
OH OHOCH3
AcO
Pd/C + H2
H+
OCH3
H3CO OCH3
H3CO
H3CO
OO
OO
OCH3
HO
Bn
BnH3CO
LiAlH4
AlCl3
OO
OO
OCH3
AcO
BnBn
H3CO
Acetylation
O
OH
H
H
HO
OH
OEt
HHH
OH
Talopyranoside
O
O O
pyridine O
OH
H
H
HO
OH
OEt
HHH
OO
OO CH3
H
N
O
OH
H
H
HO
OH
OEt
HHH
OO
OO CH3
O
OH
H
H
HO
OH
OEt
HHH
O
O
CH3
O
OAc
H
H
AcO
OAc
OEt
HHH
O
O
CH3
O
OH
H
H
HO
OH
OEt
HHH
OH
Ph O Ph
O O
pyridine O
OH
H
H
HO
OH
OEt
HHH
OO
Ph
OO Ph
H
N
O
OH
H
H
HO
OH
OEt
HHH
OO
Ph
OO Ph
O
OH
H
H
HO
OH
OEt
HHH
O
O
Ph
O
OBz
H
H
BzO
BzO
OEt
HHH
O
O
Ph
R-O-Bz
Benzoyl group
Benzoylation
see
O
OH
H
H
HO
OH
OEt
HHH
OH
O
OAc
O
OAc
OEt
H
O
O
CH3
Na+ -OCH3
O
O
OAc
O
OAc
OEt
H
O
O
CH3
CH3
O
H3CO
O
OAc
O
OAc
OEt
H
O
O
CH3
CH3
O
H3COMeOH
O
OAc
HO
OAc
OEt
H
O
O
CH3
+ Me-OH
De-Acetylation
O
OH
H
H
HO
OH
OEt
HHH
OH
O
OAc
O
OAc
OEt
H
O
O
CH3
O
O
OAc
O
OAc
OEt
H
O
O
CH3
CH3
O
H2N
O
OAc
O
OAc
OEt
H
O
O
CH3
CH3
O
H3COMeOH
O
OAc
O
OAc
OEt
H
O
O
CH3
NH3
O
OAc
O
OAc
OEt
H
O
O
CH3
CH3
O
H2N
H
Me-OH
NH2
O+
Other agents that have been applied include: M+ CN-, M+ OH-
De-Benzoylation
O
O
H
H
BzO
H
H
OAcHOEt
O
NaOCH3/CH3OH
Mg(OCH3)2
O
O
H
H
HO
H
H
OHHOEt
O
O
O
H
H
BzO
H
H
OHHOEt
O
O
O
HO
O
O
H
OH
Bz
Bz
OCl
O O
Cl
Pyridine
O
O
O
O
O
H
O
Bz
Bz
Cl
O
Cl
O
R-O-C(O)-CH2-Cl is stable to deallylation and debenzylation
NaOCH3
O
HO
HO
O
OH
H
OH
R-O-C(O)-CH2-Cl is stable to deallylation and debenzylation
Hydrazinedithiocarbonate
2HN2HN
S
S
O
O
O
O
O
H
O
Bz
Bz
Cl
O
Cl
O
S
SNH2
NH2
O
O
O
O
O
H
O
Bz
Bz
O
Cl
O
S
SNH2
NH2
O
O
O
O
O
H
O
Bz
Bz
O
Cl
O
S
S
NH2
NH
O
O
HO
O
O
H
O
Bz
Bz
Cl
O
O
O
HO
O
O
H
OH
Bz
Bz
Can also use thiourea
One Last Group
O
OH
H
H
HO
H
OEt
OHHH
OHH3CO OCH3
PTSA
H3CO OCH3
H
OCH3
O
O
O
H
OEt
OH
H
OH
H3CO OCH3
PTSA
O
OH
H
H
HO
H
OEt
OHHH
OH
O
O
H
H
HO
H
OEt
OHHH
OH
O
O
O
H
H
HO
H
OEt
OHHH
OH
O
H
H+
O
O
H
HO
H
OEt
OHHH
OH
O
O
H
O
H
OEt
OHHH
OH
- H+
H
O
OH
H
H
HO
H
OEt
OHHH
OHH3CO OCH3
PTSA
O
O
HO
H
OEt
OH
H
O
Of course stable to base and hydrogenationNOT TO ACIDIC CONDITIONS
Tin Oxide Activation
2
HO
[Bu3Sn]2O
2
OSn
Bu
Bu
Bu
+ H2O
R-X
OR
HOO Sn
BuBu
+ H2O
R-X
OHBu2SnO O
RRRR(R)HO
OH(R)
SeeZhang, Zhiyuan; Wong, Chi-Huey. Regioselective benzoylation of sugars mediated by excessive Bu2SnO: observation of temperature promoted migration. Tetrahedron (2002), 58(32), 6513-6519
Whitfield, D. M.; Ogawa, T. Polymer-supported tin carbohydrate chemistry. Glycoconjugate Journal (1998), 15(1), 75-78
OO
HO
OMe
OH
H
OPh1. Bu2SnO/MeOH2. PhC(O)Cl
OO
HO
OMe
O
H
OPh
Bz85%
OHO
HO
OMe
OH
H
HO1. Bu2SnO/MeOH2. PhC(O)Cl
OHO
HO
OMe
O
H
HO
Bz85%
O
O
HOOBn
OH
H
O
Ph
1. Bu2SnO/MeOH2. Bu4NI allyl bromide
or benzyl bromideO
O
OOBnO
H
O
Ph
55% 10%