CBr4-photoirradiation protocol for chemoselective deprotection of acid labile primary hydroxyl protecting groups

Article abstract of DOI:10.1016/j.tetlet.2003.10.205

CBr₄-photoirradiation protocol was found to be a mild, highly efficient and selective method for deprotection of isopropylidene, benzylidene, triphenylmethyl and tert-butyldimethylsilyl protecting groups on sugar molecules. The conditions of this reaction can also be used to cleave peptides off from acid-labile resin linkers in solid-phase peptide synthesis.

Full text of DOI:10.1016/j.tetlet.2003.10.205

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 635–639
CBr4-photoirradiation protocol for chemoselective deprotection
of acid labile primary hydroxyl protecting groups
Ming-Yi Chen,a,* Laxmikant N. Patkar,b Mi-Dan Jan,b Adam Shih-Yuan Leec
and Chun-Cheng Linb,*
aDepartment of General Education, Taipei Nursing College, Taipei 112, Taiwan
bInstitute of Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan
cDepartment of Chemistry, Tamkang University, Tamsui 251, Taiwan
Received 6 August 2003; revised 5 September 2003; accepted 15 October 2003
Abstract—CBr4-photoirradiation protocol was found to be a mild, highly efficient and selective method for deprotection of iso-
propylidene, benzylidene, triphenylmethyl and tert-butyldimethylsilyl protecting groups on sugar molecules. The conditions of this
reaction can also be used to cleave peptides off from acid-labile resin linkers in solid-phase peptide synthesis.
Ó 2003 Elsevier Ltd. All rights reserved.
The success of the multi-step synthesis of complex nat-
ural products depends on efficient protection–deprotec-
tion of the several functional groups involved.1
Although many methods have been reported for the
selective deprotection of protected hydroxyl groups, a
great need remains to explore simple, effective and
selective ones for carbohydrate chemistry. Of the vari-
ous protecting groups used for hydroxyl groups in car-
bohydrate chemistry, isopropylidene, benzylidene,
triphenylmethyl (trityl) and tert-butyldimethylsilyl
groups are those most frequently used for protecting
primary hydroxyl due to their availability for selective
protection and orthogonal deprotection.1
in methanol under photochemical reaction conditions.10
Our longstanding interest in carbohydrate chemistry
prompted us to investigate further the application of this
methodology to the deprotection of other acid-labile
protecting groups. Here we report the extension of this
methodology to the deprotection of isopropylidene,
benzelidene, trityl and TBDMS groups on sugar mole-
cules. Moreover, this method is applicable to cleaving
some types of acid-labile linkers in solid-phase peptide
synthesis.11
Although many reagents have been reported to be
effective in the cleavage of isopropylidene groups,1;8;9
lack of selectivity was encountered with most of the
methods. Recently, a few of selective isopropylidene
deprotection methods were reported.12 Here, we first
examined the selective deprotection of isopropylidene of
furanose derivatives with various hydroxyl protecting
groups at position C-3 using CBr4-photoirradiation
method10 (Table 1, entries 1–4). The selective removal of
the isopropylidene group attached to the primary
hydroxyl group was observed in the presence of acetyl,
PMB, p-toluenesulfonyl and TBDMS, all of which
remained intact during the reactions. Although the time
required varied widely (24–48 h), uniformly high yields
(81–89%) were obtained, indicating the efficiency of the
method. Remarkably, the acetyl group migration
reported under CBr4/MeOH reflux conditions2 was not
observed when the present protocol was applied (entry
1). Also, the PMB group, reported to be cleaved easily
A catalytic amount of carbon tetrabromide (CBr4) in
methanol, at a reflux temperature, was demonstrated to
successfully deprotect trityl,2 p-methoxybenzyl (PMB),3
b-(trimethylsilyl)ethoxymethyl,4 methoxyethoxymethyl,5
tetrahydropyranyl6 and trialkylsilyl7 ethers and gem-
diacetates,8 ketals9 and acetals.9 However, this method
did not exhibit any chemoselectivity for deprotection of
the most acid-labile protecting groups from other acid-
sensitive groups. Recently, we reported a mild, highly
efficient and selective deprotection of primary tert-
butyldimethylsilyl (TBDMS) ethers in the presence of
secondary silyl ethers using a catalytic amount of CBr4
* Corresponding author. E-mail: cclin@chem.sinica.edu.tw
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.205

636
M.-Y. Chen et al. / Tetrahedron Letters 45 (2004) 635–639
Table 1. Selective deprotection of isopropylidene and benzylidene with 5 mol % CBr4/MeOH
Entry
1
Acetonide
Product
Time (h)a
Yield (%)b
O
HO
OAc
OAc
O
HO
24
89
O
O
O
O
O
O
9
1
O
O
HO
HO
OPMB
O
OPMB
O
2
3
4
35
48
45
83
88
81
O
O
O
O
O
O
O
O
O
O
2
10
O
O
HO
HO
OTs
O
OTs
O
11
3
O
O
HO
HO
OTBDMS
O
OTBDMS
O
O
O
4
12
OTBDPS
O
OTBDPS
O
O
HO
5
6
7
22
43
5
89
72
93
OPMB
OPMB
O
HO
OTBDMS
5
OTBDMS
13
OH C7H15
OH C7H15
O
HO
O
O
O
O
O
OH
14
6
HO
HO
HO
O
O
SPh
O
O
NH
SPh
HO
O
Cl3C
NH
O
O
Cl3C
1
5
O
7
Ph
O
HO
HO
TBDMSO
O
O
O
SPh
SPh
TBDMSO
8
32
86
TBDMSO
TBDMSO
16
8
a Irradiated for 0.5 h then stirred at room temperature.
b Isolated yield.
under CBr4/MeOH reflux conditions,3 survived under
the present photoirradiation conditions (entry 2).
Accordingly, the present protocol is superior to those
reported earlier, overcoming some of the disadvantages
described above. Moreover, the isopropylidene or ben-
zylidene protecting groups of pyranoses 5, 7 and 8 were
selectively deprotected with high yields (Table 1).
Notably, the terminal isopropylidene on the di-isopro-
pylidene-protected compound 6 was selectively depro-
tected under CBr4/MeOH photoirradiation conditions.
deprotecting the trityl group1;2 have several drawbacks,
including the cleavage of glycosidic bond, the migration
of acyl groups, tedious work-up procedures and low
yields.13 Monosaccharides 15–19 with a trityl group at
the primary hydroxyl group position, were prepared14
and subjected to the CBr4/MeOH photoirradiation
conditions. As expected, selective deprotection of trityl
group was observed giving high yields of the products.
The reaction conditions were tolerated by Ac and PMB
groups (entries 1 and 2, Table 2). Notably, the trityl
group on compound 17 was selectively cleaved in the
presence of isopropylidene groups (cf. entry 5 in Table
1). Furthermore, the present methodology was very
effective in the deprotection of trityl groups attached to
Next, the deprotection of trityl ether, a widely used
protecting group in carbohydrate and nucleoside
chemistry, was explored. The known methods for

M.-Y. Chen et al. / Tetrahedron Letters 45 (2004) 635–639
Table 2. Selective deprotection of trityl protecting group with 5 mol % CBr4/MeOH
637
Entry
Trityl ethera
Product
Time (h)b
Yield (%)c
OTr
OH
O
O
AcO
AcO
AcO
AcO
1
6
86
AcO
AcO
OMe
OMe
20
15
OH
OTr
O
O
2
3
4
38
91
90
97
HO
HO
PMBO
PMBO
HO
HO
OMe
OMe
16
21
OTr
OH
O
O
O
O
O
O
9
O
O
O
O
17
22
O
N
O
N
HN
HN
13
HO
TrO
O
O
O
O
OH
23
OH
18
O
N
O
N
HN
HN
5
12
94
TrO
HO
O
O
O
O
OH OH
OH OH
24
19
a Tr ¼ Trityl group.
b Irradiated for 0.5 h then stirred at room temperature.
c Isolated yield.
the primary hydroxyl groups of nucleosides 18 and 19
(Table 2).
Finally, this method was also found effective in cleaving
amino acids from acid-labile resin linkers (Table 4).
Fmoc amino acid-preloaded trityl, HMPB-BHA and
Wang resins were subjected to photoirradiation condi-
tions and subsequent stirring for 3 days to yield the
corresponding methyl ester amino acid residues in high
yields (92–96%). Thus, this method can be applied to
cleave peptides off from the resins in solid-phase peptide
synthesis.
The photoirradition conditions were also applied to the
selective deprotection of the primary TBDMS ethers10 of
full TBDMS protected nucleosides (Table 3). The pri-
mary TBDMS ethers of deoxythymine 25 and uridine 26
were successfully deprotected in high yields (85% and
92%). In the presence of the amino group of adenosine 27
and guanosine 28, only moderate yields were obtained
after reacting for 3 days (62% and 54%, respectively) even
when the amount of CBr4 was increased to 50% equiva-
lent. Carbon tetrabromide in the presence of protic sol-
vent is generally believed to release a hydrobromic acid
molecule,3 which is responsible for cleaving the trialkyl
silyl ethers, and the other protecting groups mentioned
above. In the presence of a basic amine on the nucleoside
base, the acidic hydrobromide would be trapped, making
it unavailable for deprotection. Contrary to the expec-
tation, the deprotection of primary TBDMS in nucleo-
sides proceeded smoothly. However, the details of the
mechanism of the CBr4/MeOH photoirradiation depro-
tection would require further investigation.
In summary, a highly selective protocol is developed for
deprotection of a wide range of acid-labile protecting
groups on primary alcohols. This method was applied in
carbohydrate, nucleoside and solid-phase peptide syn-
thesis.
Experiment: A typical procedure for the selective
cleavage of a protecting group using CBr4 is as follows:
A solution of saccharide (1.0 equiv), CBr4 (0.05 equiv)
and anhydrous MeOH (10 mL) in a Pyrex round bottom
was irradiated by a TLC-lamp (Uvltec Limited, 245 nm,
8 W) for 0.5 h, followed by stirring without irradiation at
room temperature. After the reaction was completed (by

638
M.-Y. Chen et al. / Tetrahedron Letters 45 (2004) 635–639
Table 3. Selective deprotection of TBDMS ether with 20 mol % CBr4/MeOH
Entry
TBDMS-nucleotides
Product
Time (h)a
Yield (%)
O
O
N
HN
HN
O
N
O
1
68
85
TBDMSO
HO
O
O
TBDMSO
25
TBDMSO
29
O
N
O
N
HN
HN
2
68
92
O
O
HO
TBDMSO
O
O
TBDMSO
TBDMSO
OTBDMS
OTBDMS
30
26
NH2
NH2
N
N
N
N
N
N
3
72
62(33)b
N
O
N
O
TBDMSO
HO
TBDMSO
TBDMSO
OTBDMS
OTBDMS
31
27
O
O
N
N
N
N
HN
HN
H2N
H2N
N
N
54(43)b
TBDMSO
4
72
HO
O
O
TBDMSO
TBDMSO
OTBDMS
OTBDMS
32
28
a Irradiated for 0.5 h then stirred at room temperature.
b The number in parenthesis indicates the yield of recovery of the starting material.
Table 4. Transesterification by 20 mol % CBr4/MeOH
Entry
Substrate
Product
Time (days)a
Yield (%)b
O
Fmoc
N
OMe
N
H
PEG
H
O
Fmoc
N
O
1
2.5
96
92
36
H
O
Ph
Ph
33
Fmoc
N
OMe
O
H
2
3
MeO
O
O
O
N
H
36
Fmoc
N
PEG
34
H
O
Fmoc-Val-HMPB-BHA resin
PEG
OMe
Fmoc
N
O
H
3
3
95
O
O
Fmoc
N
37
H
35
O
Fmoc-β-Ala-Wang
a Irradiated for 0.5 h then stirred at room temperature.
b Isolated yield.

M.-Y. Chen et al. / Tetrahedron Letters 45 (2004) 635–639
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