Chapter 3: Protecting Groups
I. Protecting Groups of Hydroxyl Groups
Consider the stability and effect of anomeric group!
Consider the solubility of starting material (the choice of solvent)!
Consider the reactivity of different hydroxyl groups!
* DCM is common for pyranoses with 2-3 OH’s. For pyranose with more than 4 OH’s,
use DMF or pyridine.
* Nucleophilicity of OH groups on pyranoses (chair conformation) (Carbohydr. Res.
1987, 162, 159.)
1° OH > 2° OH
Equatorial OH > axial OH
Equatorial OH with vicinal axial OH (or OR) > Equatorial OH without vicinal
axial OH (or OR)
Examples:
6
OH
4
O
HO
HO
1
2
3
HO
OMe
Estimated order of nucleophilicity: 6-OH > 2-OH > 3-OH ~ 4-OH
HO
6
OH
O
4
OMe
HO
3
2
HO
1
Estimated order of nucleophilicity: 6-OH > 3-OH > 2-OH > 4-OH
1
(i) Alkyl ether type
Sug
OH
Sug
OR
Advantages:
* Relatively stable in harsh conditions (acidic, basic, reflux, etc.)
* Enhance the reactivity of glycosylation due to electron-donating effect
* More compatible to the conditions needed for deoxygenation or amino (azido)
substitution
* Selective protection is possible
Disadvantages:
* Relatively harder to remove (deprotect)
* Conditions for protection and deprotection may not be compatible to other types
of protecting groups
(a) R = methyl (CH3, Me)
* Not commonly used due to the difficulty of deprotection
* Methoxy group can be found in naturally occurring unusual sugars
Protection
Deprotection
Reagent/Condition
MeI, NaH in THF or DMF
Me3O+BF4MeOTf, DCM, py., 80°C
MeI, Ag2O
BBr3, EtOAc or DCM
SiCl4, NaH, DCM, CH3CN
AlCl3, AlBr3
Ac2O, FeCl3, 80°C
Reference
Tetrahedron Lett. 1989, 30, 641.
J. Org. Chem. 1972, 37, 912.
J. Am. Chem. Soc. 1980, 102, 7083.
J. Org. Chem. 1979, 44, 4863.
Synthesis 1982, 1048.
Chem. Lett. 1979, 97.
J. Org. Chem. 1974, 39, 3728
Examples:
OH
O
O
SPh
O
1) CH3I, NaH, THF
2) AcOH, TFA, H2O
O
SPh
HO
77%
OCH3
OH
2
(b) R = trityl, triphenylmethyl (Ph3C, Tr)
* Excellent for selective protection of primary OH
* Stable in basic but very labile in acidic conditions
* Easy to observe with TLC
* Deprotection can be tricky
Protection
Deprotection
Reagent/Condition
TrCl, 3° amines, DCM
TFA, t-BuOH
HCl, CHCl3, 0°C
TsOH, DCM, MeOH
BF3, Et2O
Examples:
3
Reference
Tetrahedron Lett. 1989, 30, 641.
Carbohydr. Res. 1978, 60, 206.
Carbohydr. Res. 1971, 17, 439.
Tetrahedron Lett. 1977, 18, 3473.
Can. J. Chem. 1978, 56, 2700
(c) R = methoxymethyl (CH3OCH2, MOM)
* Can be incorporated at relatively weak basic conditions (3° amine) but needs
relatively strong acid (TFA) to remove
* Stable in basic conditions
* The reagent, MOMCl, is considered carcinogenic
Protection
Deprotection
Reagent/Condition
MOMCl, NaH in THF or
DMF
MOMCl, DIPEA, 0°C or r.t. CH2(OMe)2, TsOH, LiBr, r.t.
Conc. HCl, MeOH
Me2BBr, DCM
TFA, DCM
LiBF4, CH3CN, 80°C
Examples:
4
Reference
J. Am. Chem. Soc. 1972, 94, 7827.
Synthesis 1975, 276.
Synthesis 1985, 74.
Chem. Commun. 1974, 298.
J. Am. Chem. Soc. 1981, 103, 3213.
J. Am. Chem. Soc. 1981, 103, 3210.
J. Org. Chem. 1986, 51, 635.
(d) R = benzyl (C6H5CH2, Bn)
* Can be traceless removed using hydrogenolysis
* Stable in basic conditions
* Relatively stable in acidic conditions
* Quenching excess reagent (BrBr) with MeOH can be tricky
Reagent/Condition
BnCl, Bu4N+-HSO4-, KOH
BnBr, NaH, THF or DMF,
TBAI
BnBr, Ag2O, DMF, r.t.
Protection
Reference
Tetrahedron Lett. 1975, 16, 3251.
Tetrahedron Lett. 1976, 17, 3535.
Bull. Korean Chem. Soc. 2003, 24, 163.
J. Org. Chem. 1985, 50, 3940.
J. Am. Chem. Soc. 1994, 116, 5647
BnBr, Bu2SnO or (Bu3Sn)2O,
toluene, reflux
BnOC(NH)CCl3, TfOH
J. Am. Chem. Soc. 1988, 110, 1624.
Synthesis 1987, 568.
H2, Pd/C or Pd(OH)2/C
TMSI, DCM
BF3-OEt2, NaI, CH3CN
Ac2O, cat.c. H2SO4, 0°C
FeCl3, DCM
Deprotection
J. Org. Chem. 1977, 42, 3761.
J. Chem. Res. Synop. 1985, 232.
J. Org. Chem. 2004, 69, 1513.
Tetrahedron: Asymmetry 1995, 857.
Examples:
Ph
O
O
HO
1) (n-Bu3Sn)2O
2) BnBr
O
HO
O
O
HO
Ph
Ph
O
+
BnO
OMe
O
O
BnO
O
HO
OMe
10
:
OMe
1
(Synthesis 1994, 1121)
Ph
O
O
HO
HO
n-Bu4N+-HSO4BnBr, NaOH, DCM
O
O
Ph
HO
Ph
O
O
BnO
OBn
O
O
O
HO
+
OMe
30%
Ph
O
O
HO
n-Bu4N+-HSO4BnBr, NaOH, DCM
O
HO
OMe
Ph
50%
O
O
HO
OMe
50%
O
BnO
(Org. Lett. 2004, 6, 1365)
5
OMe
OMe
(e) R = p-methoxybenzyl (CH3OC6H4CH2, PMB)
* More prone to oxidative cleavage than Bn but less prone to reductive cleavage
than Bn
* Stable in basic conditions
* Relatively stable in acidic conditions
Protection
Deprotection
Reagent/Condition
PMBCl, NaH, THF or DMF
PMBOC(NH)CCl3, TfOH
(NH3)2Ce(NO2)6, Ceric
ammonium nitrate (CAN),
CH3CN, H2O
DDQ, DCM
6
Reference
J. Org. Chem. 1984, 49, 51.
Tetrahedron Lett. 1988, 29, 4139.
Tetrahedron Lett. 1983, 24, 5364.
J. Am. Chem. Soc. 1985, 107, 4586.
(f) R = tetrahydropyranyl (THP)
* Stability similar to glycosidic bond
* Stable in basic conditions
Reagent/Condition
Dihydropyran, TsOH, DCM
Dihydropyran, PPTS, DCM
HOAc, THF, H2O
PPTS, EtOH, 55°C
TsOH, MeOH, r.t.
MgBr2, Et2O, r.t.
Protection
Deprotection
Reference
J. Org. Chem. 1979, 44, 1438.
J. Org. Chem. 1977, 42, 3772.
J. Org. Chem. 1979, 44, 1438.
J. Org. Chem. 1977, 42, 3772.
J. Am. Chem. Soc. 1978, 100, 1942.
Tetrahedron Lett. 1987, 28, 439.
Examples:
(ii) Silyl ether type
Sug
OH
+
R3Si
X
+
NR'3
Sug
OSiR3
+ H
NR'3 X
* Stability varies
General reagents for protection: R3SiX with 3° amines (DIPEA, TEA, immidazole,
lutidine, pyridine, etc)
Common reagents for deprotection: TBAF, BF3, KF, or pyridine-HF
Trimethylsilyl (TMS)
Triethylsilyl (TES)
Triisopropylsilyl (TIPS)
t-Butyldimethylsilyl (TBS)
t-Butyldiphenylsilyl (TBDPS)
Can be cleaved with K2CO3, MeOH or citric acid
Can be cleaved with HOAc
Possible for selective protection of 1° OH
Selective protection of 1° OH
Selective protection of 1° OH
Relatively stable in basic condition
7
(iii) Ester type
O
O
Sug
OH +
C
C
R
Sug
O
R
+
HX
X
(a) R = trifluoroacetyl (TFA)
General reagent for protection: trifluoroacetic anhydride with 3° amines (DIPEA, TEA,
immidazole, lutidine, pyridine etc), DMAP as catalyst
Common reagent for deprotection: weak acids or bases
(b) R = acetyl (Ac)
General reagents for protection: Ac2O with 3° amines (DIPEA, TEA, immidazole,
lutidine, pyridine etc) or Ac2O with cat. acids.
Common reagents for deprotection: K2CO3, MeOH, cat. NaOMe in MeOH, or LiOH,
THF, H2O (J. Org. Chem. 2004, 69, 1513)
* anomeric acetyl group can be selectively removed with H2NNH2-HOAc or
BnNH2
Examples:
8
(c) R = trimethylacetyl (Piv)
* Can be used for selective protection
General reagent for protection: pivaloyl chloride (PivCl) with 3° amines (DIPEA, TEA,
pyridine etc)
Reagent/Condition
Bu4N+OH-, r.t.
NaOH, EtOH, H2O
t-BuOK
DIBAL
Deprotection
Reference
Tetrahedron Lett. 1979, 20, 3561.
Tetrahedron Lett. 1973, 14, 317.
J. Org. Chem. 1977, 42, 918.
Examples:
OH
PivCl
(2 equiv.)
pyr.
O
HO
HO
HO
OH
HO
OPiv
O
HO
HO
PivO
OMe
PivCl
(2 equiv.)
pyr.
O
HO
HO
OPiv
HO
OMe
O
HO
PivO
OMe
OMe
HO
HO
OH
O
SPh
HO
PivCl
(2 equiv.)
pyr.
OPiv
O
SPh
PivO
HO
HO
(J. Org. Chem. 1998, 63, 6035)
9
(d) R = Benzoyl (Bz)
* Can be used for selective protection
General reagent for protection: benzoyl chloride (BzCl) with 3° amines (DIPEA, TEA,
pyridine etc)
* Less common method for protection: Benzoic acid, DEAD, PPh3
Deprotection
Reagent/Condition
Cat. NaOMe, MeOH
LiOH, THF/H2O (3/1)
K2CO3, MeOH
DIBAL
Examples:
10
Reference
J. Org. Chem. 2004, 69, 1513.
J. Org. Chem. 2004, 69, 1513.
II. Protecting Groups of 1,2- or 1,3-Dihydroxyl Groups
Consider the formation of acetal (ketal) from diol and aldehyde (ketone)!
Consider the solubility of ring or fused ring for selectivity!
Six-membered ring: thermodynamically favored
Five-membered ring: kinetically favored
General Mechanism
11
(i) For selection between 1,3-diol and trans-1,2-diol
O
HO
O
O
R
O
O
vs.
HO
O
R
(ii) For selection between 1,3-diol and cis-1,2-diol
R
HO
O
O
O
vs.
O
R
O
O
HO
R
HO
O
R
O
R
O
O
vs.
O
R
HO
O
(iii) For selection between trans-1,2-diol and cis-1,2-diol
OH
OH
OH
O
O
O
vs.
O
HO O
O
12
(iv) Acetonide (isopropylidene)
Common reagents for protection: acetone or Me2C(OMe)2 and acids (TsOH, PPTS,
ZnCl2 etc) with removal of water
Common reagents for deprotection: acids (TsOH, TFA, HCl etc) with addition of water
Examples:
13
(v) Benzylidene
Common reagents for protection: PhCHO or PhCH(OMe)2 and acids (TsOH, PPTS,
ZnCl2 etc) with removal of water
Common reagents for deprotection: acids (TsOH, TFA, HCl etc) with addition of water
* Can be selectively converted into Bn or Bz
Examples:
Ph
O
O
HO
HO
Ph
Br
BzO
HO
NBS, CCl4
BaCO3, reflux
O
O
HO
OMe
OMe
O
BzO
O
NBS, CCl4
BaCO3, reflux
O
HO
HO
Br
O
HO
HO
OMe
OMe
(J. Org. Chem. 1969, 34, 1035)
NaBH3CN
TFA, DMF
90%
MeO
O
O
BnO
PMBO
HO
BnO
O
OR
NPhth
O
OR
NPhth
NaBH3CN
TMSCl, MeCN
51%
(J. Org. Chem. 2000, 65, 2410)
14
HO
PMBO
BnO
O
OR
NPhth
(vi) Cyclohexane-1,2-diacetals (CDA)
OMe
OMe
MeOH, CH(OMe)3
cat. H2SO4, reflux
O
OMe
OMe
O
HO
HO
HO
HO
OMe
CDA, MeOH
CH(OMe)3, cat. CSA
reflux
O
OMe
HO
O
O
48%
HO
OMe
OMe
(Angew. Chem. Int. Ed. Engl. 1994, 33, 2290)
Similar reagent: CH3C(OMe)2C(OMe)2CH3, or 2,3-butanedione
(vii) Silyl-based protecting group
Triisopropyldisilyl (TIPDS)
iPr
HO
O
Z
iPr
O
Si
O
Z
O
HO
OH
Si
iPr
O
iPr
15
O
OH
(viii) Other examples
N3
HO
HO
N3
O
N3
Cyclohexone dimethyl
ketal, TsOH-H2O, CH3CN
N3
HO
HO
O
N3
O
HO
N3
N3
O
N3
O
OH
41%
(Org. Lett. 2004, 3, 1381)
16
O
III. Protecting Groups of Amino Groups
(i) Masking NH2 (amino) as N3 (azido)
* Organoazides can be explosive ([C+O]/N ≥ 3) ((a) P. A. S. Smith, Open-Chain
Nitrogen Compounds, vol. 2, Benjamin, New York, 1966, 211 – 256; (b) J. H. Boyer, R.
Moriarty, B. de Darwent, P. A. S. Smith, Chem. Eng. News 1964, 42, 6.)
Examples:
H2N
HO
HO
HO
HO
H2N
O O
O
HO
NH2
NH2
O
N3
O O
HO
N3
OH
O OH
O OH
O
O
H 2N
HO
HO
TfN3, Et3N, CuSO4,
MeOH/H2O/CH2Cl2
NH2
OH
O
N3
O
OH
N3
OH
(J. Am. Chem. Soc. 1999, 121, 6527-6541; Tetrahedron Lett. 1996, 37, 6029-6032)
NaN3
1) SO2Cl2, MeCN
2) imidazole
O
N3
S
N
N
O
(Org. Lett. 2007, 9, 3797–3800)
17
R
NH2
CuSO3, K2CO3
MeOH
R
N3
N3
N3
The azido group can be converted (reduced) to amino group using the following methods:
(1) H2, Pd/C; (2) PR3, THF, H2O; (3) LiAlH4; (4) thiols (HSCH2CH2SH, HSCH2CH2OH,
OH
HS
dithiothreitol
SH
OH
etc)
* Hydrogenation can be
* Mechanism of Staudinger reaction
18
* Staudinger reaction can be selective (J. Am. Chem. Soc. 2002, 124, 10773-10778; J.
Org. Chem. 2007, 72, 4055-4066)
N3
6'
O I
BnO
BnO
1'
2'
N3
proton  (ppm)
6'
H-1
3.18
H-3
3.38
H-2' 3.51
H-6' 3.49/3.35
N3
O
HO
3
II
O I
BnO
BnO
PMe3
1
N3
H2N
OBn
6'
1'
2'
N3
N3
O
BnO
1
II
3
1
N3
BnO
1'
2'
N3
N3
O
BnO
III
1"
H-1
3.6
H-3
3.4
H-2' 3.00
H-6' 3.27/3.10
H-3" 3.78
O I
PMe3 then
Cbz-Cl
O
1
BnO
3
N3
4
N3
II
1
O
5
O
1.0 M PMe3 in toluene
(1.1 eq.), Boc-ON (2.4 eq.),
toluene, -78oC to 10oC
N3
OAc
proton d (ppm)
III
45%
O OAc
OAc
AcO
N3
O
O OAc
OAc
N3
O
AcO
AcO
Z
N3
N3
O
AcO
28%
OAc
O
O
N3
O OAc
O
N3
OAc
(mixed with minor N-3 Boc adduct)
1) TFA/CH2Cl2
2) EDC, HOBt, Et3N, NMP, DMF
N
H
O
H
N
O
: approximate value
HO
O
N3
a
OH
N3
N3
O
OAc
H-1
3.43
H-3
3.53
H-2'
3.16
H-6'
3.3a
H-2'''
3.3a
H-6''' 3.59/3.28
O
6"'
HN Cbz
O
AcO
AcO
1"
IV
2"
N3
N3
2"'
OBn
OBn
O
Per-azido per-benzyl
tobramycin
N3
O
AcO
III
1"
O I
AcO
AcO
N3
O
N3
6'
II
3
OBn
OBn
O
2" 3"N
N3
N3
BnO
proton  (ppm)
OAc
II
3
OBn
O I
BnO
N3
O
HO
6,3',4'-tri-O-benzyltetraazidoneamine
N3
6'
1'
2'
N3
OAc
19
OH
H
N
OAc
O
N
H
Z
Boc
N3
6'
N3
O I
AcO
AcO
2'
N3
N3
O
II
3
1
O
AcO
O
1.0 M PMe3 in toluene
(1.1 eq.), Boc-ON (2.4 eq.),
toluene, -78oC to 10oC
N3
N3
N3
O
AcO
31%
OAc
1"
O
AcO
AcO
O
O
III
AcO OAc
AcO OAc
proton  (ppm)
H-1
H-3
H-2'
H-6'
Boc-ON:
3.4
3.5
3.25
3.3
CN
O
O
N
O
(ii) Phthalamide (intermediate involved in Gabriel amine synthesis)
Common reagents for protection: phthalic anhydride
Common reagents for deprotection: acids hydrazine, EtOH, reflux
Example:
20
H
N
OAc
Boc
(iii) Carbamate-type
Cl
R
NH2
O
R'
+
+
B
R
H
N
O
+
H
R'
O
O
* Solvent selection is important.
(a) 9-Fluorenylmethoxycarbonyl chloride (Fmoc-Cl)
* Stable in acidic and neutral conditions
* Easy to observe with strong UV absorption
Common reagents for deprotection: amines (piperidine)
Cl
O
O
(b) Di-tert-butyl dicarbonate , Boc anhydride (Boc2O)
O
* Stable in basic and neutral conditions
O
O
Common reagents for deprotection: acids (TFA)
21
B
Cl
(c) Benzyl chloroformate , Carbobenzoxy chloride (Cbz-Cl, Z-Cl)
Cl
* Stable in acidic, basic and neutral conditions
O
O
Common reagents for deprotection: hydrogenolysis (H2, Pd/C))
(d) Allyl chloroformate (Alloc-Cl)
Cl
* Stable in acidic, basic and neutral conditions
Common reagents for deprotection: Pd(0) reagents
22
O
O