1

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 OHs. For pyranose with more than 4 OHs,
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:

O
OH
HO
HO
HO
OMe
1
2
3
4
6

Estimated order of nucleophilicity: 6-OH > 2-OH > 3-OH ~ 4-OH


O
OH
HO
HO
HO
OMe
1
2
3
4
6


Estimated order of nucleophilicity: 6-OH > 3-OH > 2-OH > 4-OH










2
(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 (CH
3
, Me)

* Not commonly used due to the difficulty of deprotection
* Methoxy group can be found in naturally occurring unusual sugars

Reagent/Condition Reference
MeI, NaH in THF or DMF Tetrahedron Lett. 1989, 30, 641.
Me
3
O
+
BF
4
-
J. Org. Chem. 1972, 37, 912.
MeOTf, DCM, py., 80C
Protection
MeI, Ag
2
O J. Am. Chem. Soc. 1980, 102, 7083.
BBr
3
, EtOAc or DCM J. Org. Chem. 1979, 44, 4863.
SiCl
4
, NaH, DCM, CH
3
CN Synthesis 1982, 1048.
AlCl
3
, AlBr
3
Chem. Lett. 1979, 97.
Deprotection
Ac
2
O, FeCl
3
, 80C J. Org. Chem. 1974, 39, 3728

Examples:

O
O
O
OH
SPh
77%
O
OH
HO
OCH
3
SPh
1) CH
3
I, NaH, THF
2) AcOH, TFA, H
2
O









3
(b) R = trityl, triphenylmethyl (Ph
3
C, 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

Reagent/Condition Reference
Protection
TrCl, 3 amines, DCM Tetrahedron Lett. 1989, 30, 641.
TFA, t-BuOH Carbohydr. Res. 1978, 60, 206.
HCl, CHCl
3
, 0C Carbohydr. Res. 1971, 17, 439.
TsOH, DCM, MeOH Tetrahedron Lett. 1977, 18, 3473.
Deprotection
BF
3
, Et
2
O Can. J. Chem. 1978, 56, 2700

Examples:































4
(c) R = methoxymethyl (CH
3
OCH
2
, 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

Reagent/Condition Reference
MOMCl, NaH in THF or
DMF
J. Am. Chem. Soc. 1972, 94, 7827.
MOMCl, DIPEA, 0C or r.t.
-
Synthesis 1975, 276.
Protection
CH
2
(OMe)
2
, TsOH, LiBr, r.t. Synthesis 1985, 74.
Conc. HCl, MeOH Chem. Commun. 1974, 298.
Me
2
BBr, DCM J. Am. Chem. Soc. 1981, 103, 3213.
TFA, DCM J. Am. Chem. Soc. 1981, 103, 3210.
Deprotection
LiBF
4
, CH
3
CN, 80C J. Org. Chem. 1986, 51, 635.


Examples:



























5
(d) R = benzyl (C
6
H
5
CH
2
, 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 Reference
BnCl, Bu
4
N
+
-HSO
4
-
, KOH Tetrahedron Lett. 1975, 16, 3251.
BnBr, NaH, THF or DMF,
TBAI
Tetrahedron Lett. 1976, 17, 3535.
BnBr, Ag
2
O, DMF, r.t. Bull. Korean Chem. Soc. 2003, 24, 163.
J. Org. Chem. 1985, 50, 3940.
BnBr, Bu
2
SnO or (Bu
3
Sn)
2
O,
toluene, reflux
J. Am. Chem. Soc. 1994, 116, 5647
Protection
BnOC(NH)CCl
3
, TfOH J. Am. Chem. Soc. 1988, 110, 1624.
Synthesis 1987, 568.
H
2
, Pd/C or Pd(OH)
2
/C
TMSI, DCM J. Org. Chem. 1977, 42, 3761.
BF
3
-OEt
2
, NaI, CH
3
CN J. Chem. Res. Synop. 1985, 232.
Ac
2
O, cat.c. H
2
SO
4
, 0C J. Org. Chem. 2004, 69, 1513.
Deprotection
FeCl3, DCM Tetrahedron: Asymmetry 1995, 857.

Examples:

O
HO
OMe
HO
O
O
Ph
1) (n-Bu
3
Sn)
2
O
2) BnBr O
BnO
OMe
HO
O
O
Ph
+
O
HO
OMe
BnO
O
O
Ph
10 : 1

(Synthesis 1994, 1121)


O
HO
OMe
HO
O
O
Ph
n
-
Bu
4
N
+
-HSO
4
-
BnBr, NaOH, DCM
+
O
HO
OMe
BnO
O
O
Ph
O
OBn
OMe
HO
O
O
Ph
30%
50%



O
HO
OMe
HO
O
O
Ph
O
BnO
OMe
HO
O
O
Ph
n
-
Bu
4
N
+
-HSO
4
-
BnBr, NaOH, DCM
50%

(Org. Lett. 2004, 6, 1365)
6
(e) R = p-methoxybenzyl (CH
3
OC
6
H
4
CH
2
, 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

Reagent/Condition Reference
PMBCl, NaH, THF or DMF J. Org. Chem. 1984, 49, 51.
PMBOC(NH)CCl
3
, TfOH Tetrahedron Lett. 1988, 29, 4139.
Tetrahedron Lett. 1983, 24, 5364.
Protection

(NH
3
)
2
Ce(NO
2
)
6
, Ceric
ammonium nitrate (CAN),
CH
3
CN, H
2
O

DDQ, DCM J. Am. Chem. Soc. 1985, 107, 4586.
Deprotection






























7
(f) R = tetrahydropyranyl (THP)

* Stability similar to glycosidic bond
* Stable in basic conditions

Reagent/Condition Reference
Dihydropyran, TsOH, DCM J. Org. Chem. 1979, 44, 1438. Protection
Dihydropyran, PPTS, DCM J. Org. Chem. 1977, 42, 3772.
HOAc, THF, H
2
O J. Org. Chem. 1979, 44, 1438.
PPTS, EtOH, 55C J. Org. Chem. 1977, 42, 3772.
TsOH, MeOH, r.t. J. Am. Chem. Soc. 1978, 100, 1942.
Deprotection
MgBr
2
, Et
2
O, r.t. Tetrahedron Lett. 1987, 28, 439.

Examples:














(ii) Silyl ether type

Sug OH Sug OSiR
3 R
3
Si X + + NR'
3
NR'
3
H X +


* Stability varies

General reagents for protection: R
3
SiX with 3 amines (DIPEA, TEA, immidazole,
lutidine, pyridine, etc)
Common reagents for deprotection: TBAF, BF
3
, KF, or pyridine-HF

Trimethylsilyl (TMS) Can be cleaved with K
2
CO
3
, MeOH or citric acid
Triethylsilyl (TES) Can be cleaved with HOAc
Triisopropylsilyl (TIPS) Possible for selective protection of 1 OH
t-Butyldimethylsilyl (TBS) Selective protection of 1 OH
t-Butyldiphenylsilyl (TBDPS) Selective protection of 1 OH
Relatively stable in basic condition

8
(iii) Ester type

Sug OH
+ C
X
O
R
Sug O
C
R
O
+ HX


(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: Ac
2
O with 3 amines (DIPEA, TEA, immidazole,
lutidine, pyridine etc) or Ac
2
O with cat. acids.
Common reagents for deprotection: K
2
CO
3
, MeOH, cat. NaOMe in MeOH, or LiOH,
THF, H
2
O (J. Org. Chem. 2004, 69, 1513)

* anomeric acetyl group can be selectively removed with H
2
NNH
2
-HOAc or
BnNH
2


Examples:






















9
(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 Reference
Bu
4
N
+
OH
-
, r.t. Tetrahedron Lett. 1979, 20, 3561.
NaOH, EtOH, H
2
O Tetrahedron Lett. 1973, 14, 317.
t-BuOK J. Org. Chem. 1977, 42, 918.
Deprotection
DIBAL

Examples:

O
OH
HO
HO
HO
OMe
PivCl
(2 equiv.)
pyr.
O
OPiv
HO
HO
PivO
OMe
O
OH
HO
HO
HO
OMe
PivCl
(2 equiv.)
pyr.
O
OPiv
HO
PivO
HO
OMe
O
OH
HO
HO
HO
SPh
PivCl
(2 equiv.)
pyr.
O
OPiv
HO
PivO
HO
SPh

(J. Org. Chem. 1998, 63, 6035)













10
(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, PPh
3


Reagent/Condition Reference
Cat. NaOMe, MeOH J. Org. Chem. 2004, 69, 1513.
LiOH, THF/H
2
O (3/1) J. Org. Chem. 2004, 69, 1513.
K
2
CO
3
, MeOH
Deprotection
DIBAL

Examples:































11
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




































12

(i) For selection between 1,3-diol and trans-1,2-diol

O
O
vs.
O
HO
O
HO O
O
R
R




(ii) For selection between 1,3-diol and cis-1,2-diol
vs.
O
HO
O
O
O
O
O
HO
R
R



vs.
O
HO
O
O
O
O
O
HO
R
R
R
R




(iii) For selection between trans-1,2-diol and cis-1,2-diol

vs. O
OH
HO
O
O
OH
OH
O
O
O









13
(iv) Acetonide (isopropylidene)

Common reagents for protection: acetone or Me
2
C(OMe)
2
and acids (TsOH, PPTS,
ZnCl
2
etc) with removal of water
Common reagents for deprotection: acids (TsOH, TFA, HCl etc) with addition of water

Examples:







































14
(v) Benzylidene

Common reagents for protection: PhCHO or PhCH(OMe)
2
and acids (TsOH, PPTS,
ZnCl
2
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:

O
HO
OMe
HO
O
O
Ph NBS, CCl
4
BaCO
3
, reflux
O
HO
OMe
HO
Br
BzO
O
HO
OMe
HO
NBS, CCl
4
BaCO
3
, reflux
O
HO
OMe
HO
Br BzO
O
O
Ph

(J. Org. Chem. 1969, 34, 1035)

O
NPhth
OR
BnO
O
O
MeO
NaBH
3
CN
TFA, DMF
90%
NaBH
3
CN
TMSCl, MeCN
51%
O
NPhth
OR
BnO
PMBO
HO
O
NPhth
OR
BnO
HO
PMBO

(J. Org. Chem. 2000, 65, 2410)











15
(vi) Cyclohexane-1,2-diacetals (CDA)

O
O
MeOH, CH(OMe)
3
cat. H
2
SO
4
, reflux
OMe
OMe
OMe
OMe


O
HO
OMe
HO
HO
HO
CDA, MeOH
CH(OMe)
3
, cat. CSA
reflux
O
HO
OMe
HO
O
O
OMe
OMe
48%

(Angew. Chem. Int. Ed. Engl. 1994, 33, 2290)

Similar reagent: CH
3
C(OMe)
2
C(OMe)
2
CH
3
, or 2,3-butanedione













(vii) Silyl-based protecting group

Triisopropyldisilyl (TIPDS)

O
HO
OH
HO
Z
O
O
OH
O
Z
Si
O
Si
iPr
iPr
iPr
iPr







16

(viii) Other examples

O
N
3
HO
HO
N
3
N
3
HO
OH
N
3
O
Cyclohexone dimethyl
ketal, TsOH-H
2
O, CH
3
CN
O
N
3
HO
HO
N
3
N
3
O
O
N
3
O
41%

(Org. Lett. 2004, 3, 1381)


































17

III. Protecting Groups of Amino Groups

(i) Masking NH
2
(amino) as N
3
(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:
O
O
H
2
N
HO
HO
H
2
N
O
NH
2
NH
2
HO
O
HO
O OH
O
OH
NH
2
H
2
N
OH
TfN
3
, Et
3
N, CuSO
4
,
MeOH/H
2
O/CH
2
Cl
2
O
O
N
3
HO
HO
N
3
O
N
3
N
3
HO
O
HO
O OH
O
OH
N
3
N
3
OH

(J. Am. Chem. Soc. 1999, 121, 6527-6541; Tetrahedron Lett. 1996, 37, 6029-6032)


R NH
2
1) SO
2
Cl
2
, MeCN
2) imidazole
NaN
3 N
3
S
O
N
O
N
CuSO
3
, K
2
CO
3
MeOH
R N
3

(Org. Lett. 2007, 9, 37973800)




















18

The azido group can be converted (reduced) to amino group using the following methods:
(1) H
2
, Pd/C; (2) PR
3
, THF, H
2
O; (3) LiAlH
4
; (4) thiols (HSCH
2
CH
2
SH, HSCH
2
CH
2
OH,
dithiothreitol
HS
SH
OH
OH
etc)

* Hydrogenation can be

* Mechanism of Staudinger reaction




































19

* Staudinger reaction can be selective (J. Am. Chem. Soc. 2002, 124, 10773-10778; J.
Org. Chem. 2007, 72, 4055-4066)

O
N
3
BnO
BnO
N
3
N
3
HO
OBn
N
3
O
I
II
1
1'
2'
6,3',4'-tri-O-benzyl-
tetraazidoneamine
6'
O
N
3
BnO
BnO
H
2
N
N
3
HO
OBn
N
3
O
I
II
3
H-1 3.18
H-3 3.38
H-2' 3.51
H-6' 3.49/3.35
proton (ppm)
PMe
3
O
N
3
BnO
N
3
N
3
BnO
O
N
3
O
I
II
1
1'
2'
6'
3
O
BnO
N
3
III
1"
2"
OBn
OBn
3"
PMe
3
then
Cbz-Cl
O
N
3
BnO
N
3
N
3
BnO
O
N
3
O
I
II
1
1'
2'
6'
3
O
BnO
HN
III
1"
2"
OBn
OBn
Cbz
H-1 3.6
H-3 3.4
H-2' 3.00
H-6' 3.27/3.10
H-3" 3.78
proton (ppm)
Per-azido per-benzyl
tobramycin
1
3
1'
2'
6'



1.0 M PMe
3
in toluene
(1.1 eq.), Boc-ON (2.4 eq.),
toluene, -78
o
C to 10
o
C
45%
O
AcO
O OAc
O
OAc
N
3
N
3
OAc
O
N
3
AcO
AcO
N
3
N
3
O
OAc
N
3
O
I
II
1
4
5
III
IV
1"
6'
6"'
2"'
O
AcO
O OAc
O
OAc
N
3
N
3
OAc
O
N
3
AcO
AcO
N
3
N
3
O
OAc
H
N
O
Boc
28%
1) TFA/CH
2
Cl
2
2) EDC, HOBt, Et
3
N, NMP, DMF
O
AcO
O OAc
O
OAc
N
3
N
3
OAc
O
N
3
AcO
AcO
N
3
N
3
O
OAc
H
N
O
OH
O
N
H
(mixed with minor N-3 Boc adduct)
H-1 3.43
H-3 3.53
H-2' 3.16
H-6' 3.3
a
H-2''' 3.3
a
H-6''' 3.59/3.28
proton d (ppm)
a
: approximate value
Z
HO
OH
O
N
H
Z

20

1.0 M PMe
3
in toluene
(1.1 eq.), Boc-ON (2.4 eq.),
toluene, -78
o
C to 10
o
C
31%
O
AcO
AcO OAc
O
N
3
AcO
AcO
N
3
N
3
O
OAc
N
3
O
I
II
III
O
AcO
AcO OAc
O
N
3
AcO
AcO
N
3
N
3
O
OAc
H
N
O
Boc
H-1 3.4
H-3 3.5
H-2' 3.25
H-6' 3.3
proton (ppm)
1
3
6'
2'
1"


N
O
CN
O
O
Boc-ON:









(ii) Phthalamide (intermediate involved in Gabriel amine synthesis)

Common reagents for protection: phthalic anhydride
Common reagents for deprotection: acids hydrazine, EtOH, reflux

Example:













21

(iii) Carbamate-type

Cl
O
R'
O
R NH
2
+ + B
O
R'
O R
H
N + B H
Cl

* 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)












(b) Di-tert-butyl dicarbonate , Boc anhydride (Boc
2
O)


* Stable in basic and neutral conditions

Common reagents for deprotection: acids (TFA)












Cl
O
O
O
O
O
22


(c) Benzyl chloroformate , Carbobenzoxy chloride (Cbz-Cl, Z-Cl)


* Stable in acidic, basic and neutral conditions

Common reagents for deprotection: hydrogenolysis (H
2
, Pd/C))















(d) Allyl chloroformate (Alloc-Cl)


* Stable in acidic, basic and neutral conditions

Common reagents for deprotection: Pd(0) reagents





Cl
O
O
Cl
O
O