A Practical Method for Regioselective 5′-O-tert-Butyldimethylsilyl Deprotection of Persilylated Nucleosides by Methanolic Phosphomolybdic Acid

Article abstract of DOI:10.1055/s-0037-1610300

In nucleoside/nucleotide chemistry, the regioselective cleavage of 5′-O-TBS groups of persilylated nucleosides is a desired approach for structural functionalization at the 5′-position. However, efficient and practical methods for this purpose are still limited. In our research, we found that homogeneous methanolic phosphomolybdic acid (PMA) efficiently catalyzes the regioselective deprotection of 5′- O -TBS groups of a diversity of persilylated nucleoside substrates and can be applied in practical synthesis at scales of up to 15 g. ³¹ P NMR results indicated that an anion cluster forms and the Lewis acidity of homogeneous PMA is organic-solvent dependent. The efficacy and pronounced regioselectivity of methanolic PMA occurs as a result of a lowering of the Lewis acid strength upon solvation of the molybdophosphate anions.

Full text of DOI:10.1055/s-0037-1610300

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–G
letter
A
en
H.-S. Huang et al.
Letter
Synlett
A Practical Method for Regioselective 5′-O-tert-Butyldimethylsilyl
Deprotection of Persilylated Nucleosides by Methanolic Phospho-
molybdic Acid
Hua-Shan Huang
Rui Kong
Xiu-An Zheng
Wei-Jie Chen
Shuai-Bo Han
De-Yun Zeng
Shan-Shan Gong*
Qi Sun*
0
0
0
0-
0
0
0
1-5
0
6
6-2
9
7
5
Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science
and Technology Normal University, 605 Fenglin Avenue, Nan-
chang, Jiangxi 330013, P. R. of China
gongshanshan@jxstnu.edu.cn
sunqi@jxstnu.edu.cn
Received: 08.08.2018
Accepted after revision: 12.09.2018
Published online: 12.10.2018
parison, an alternative shortcut approach would be to si-
lylate all the hydroxy groups and then to cleave the 5′-O-
TBS group regioselectively; however, the most commonly
used fluoride-based reagent, TBAF, has little discrimination
between primary and secondary hydroxy groups in nucleo-
sides.16
DOI: 10.1055/s-0037-1610300; Art ID: st-2018-w0504-l
Abstract In nucleoside/nucleotide chemistry, the regioselective cleav-
age of 5′-O-TBS groups of persilylated nucleosides is a desired approach
for structural functionalization at the 5′-position. However, efficient
and practical methods for this purpose are still limited. In our research,
we found that homogeneous methanolic phosphomolybdic acid (PMA)
efficiently catalyzes the regioselective deprotection of 5′-O-TBS groups
of a diversity of persilylated nucleoside substrates and can be applied in
practical synthesis at scales of up to 15 g. 31P NMR results indicated that
an anion cluster forms and the Lewis acidity of homogeneous PMA is
organic-solvent dependent. The efficacy and pronounced regioselectiv-
ity of methanolic PMA occurs as a result of a lowering of the Lewis acid
strength upon solvation of the molybdophosphate anions.
Early attempts at regioselective cleavage of 5′-O-TBS
groups of persilylated nucleosides were made by using Zn-
Br2,3,17 LiBr/18-crown-6,18 or Ce(NH4)2(NO3)6(CAN)·SiO2,19
but these methods suffered various problems such as mod-
erate yields, long reaction times, the need for excess re-
agent, or high reaction temperatures. More recently, HF–
pyridine,4 NH4F–DMF,5 PPTS–EtOH,6,7 CBr4–MeOH,20 and I2–
MeOH8 have been reported to permit selective 5′-O-TBS
deprotection of certain specific polysilylated nucleoside
substrates in moderate to good yields, but the lack of gener-
ality limits their application. In contrast, acid-based meth-
ods are effective for both pyrimidine and purine nucleo-
sides. Generally, methods based on acetic acid (AcOH) re-
quire heating and long reaction time.9,10 Desilylations with
more-acidic trifluoroacetic acid (TFA)11–13 or trichloroacetic
acid (TCA)14,15 are much faster (1–2 h) and are typically per-
formed at 0 °C to enhance selectivity toward 5′-O-TBS
groups. In a research paper on regioselective TBS-deprotec-
tion of polysilylated nucleosides, Scott and co-workers
found that the addition of THF as a cosolvent can improve
5′-O-TBS regioselectivity, accelerate the rate, and inhibit the
hydrolysis of nucleosides.21 In our synthesis of 5–HOMedCTP,
5–CHOdCTP, 5–COOHdCTP, and 5–COOHdUTP, efficient regioselec-
tive desilylation at the 5′-position of the nucleoside inter-
mediates was achieved in yields of 60–70% by this TFA-
based method.22,23 However, the yields of the 5′-monodesil-
Key words deprotection, nucleosides, regioselectivity, desilylation,
phosphomolybdic acid, butyldimethylsilyl group
Among silyl ethers, the tert-butyldimethylsilyl (TBS)
group is one of the most popular hydroxy-protecting
groups in organic synthesis.1,2 In nucleoside and nucleotide
chemistry, such as syntheses of oligonucleotides, nucleo-
side polyphosphates, or novel nucleoside analogues, the TBS
group has been widely used for the protection of 2′- and/or
3′-hydroxy groups of ribose and deoxyribose in many re-
searches on structural modifications or functionalizations
at the 5′-position.3–15 Typically, the 5′-OH group is initially
protected by a dimethoxytrityl (DMT) group; this is fol-
lowed by 2′,3′-OH or 3′-OH silylation with TBSCl. The DMT
group is then cleaved with TFA. This method not only re-
quires three steps, but can also result in cleavage of a small
proportion of the TBS groups during detritylation. In com-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

B
H.-S. Huang et al.
Letter
Synlett
Table 1 The Catalytic Activity of PMA-Based Catalysts in Regioselective Deprotection of the 5′-O-TBS Group of 1
O
O
O
O
N
NH
NH
NH
NH
TBSO
HO
TBSO
HO
N
O
N
O
N
O
O
O
O
O
O
1 mol% catalyst
20 °C
+
+
TBSO
TBSO
HO
HO
Entry
Catalyst
Solventa
Timeb (h)
Yieldsc of 1′/1′′/1′′′ (%)
1
2
3
4
5
6
7
PMA–SiO2
PMA
THF
12
68/4/23
66/4/25
11/0/0
n.r.
THF
3
TfOHd
MoO3
PMA
THF
12
THF
12
MeCN
MeOH
i-PrOH
0.25
0.75
18
18/19/58
77/2/16
78/2/15
PMA
PMA
a [1] = 0.3 M.
b The reaction was stopped when less than 5% of 1 remained.
c The yields of 1′/1′′/1′′′ were determined by integrating the distinctive H(6) signal for each compound (see Supplementary Information, Figure S1).
d 3% TfOH was used.
ylated products dropped to ~50% when the reactions were
scaled up to a multigram scale. The reaction temperature
and time for this TFA-based method must be very carefully
controlled, otherwise, polydesilylation will be exacerbated.
Here we report a practical and general method for the regi-
oselective 5′-O-TBS deprotection of persilylated nucleosides
by using a catalytic amount of methanolic phosphomolyb-
dic acid (PMA).
In our search for more-robust and more-practical meth-
ods for regioselective 5′-O-TBS deprotection, we noted that
Kumar and Baskaran found that phosphomolybdic acid sup-
ported on silica gel (PMA–SiO2) as a heterogeneous catalyst
in THF showed preference toward primary TBS groups over
secondary TBS groups.24 However, this method had never
been tested on polysilylated nucleoside substrates. We
therefore adopted the reported procedure to treat diTBS-dT
(1) with 1 mol% PMA–SiO2 (10% w/w) in THF ([1] = 0.3 M).
To our surprise, the reaction solution turned green immedi-
ately on adding the PMA–SiO2, showing that the supported
PMA leached into THF. We found that ~45% of the PMA dis-
solved in the reaction solution and functioned as a homoge-
neous catalyst. Further desorption experiment showed that
over 90% of the PMA on SiO2 (10% w/w) was washed off in
three cycles.
ed that PMA-mediated desilylation proceeds through ho-
mogeneous catalysis essentially. Because it had been pro-
posed that the Brønsted acid generated from PMA–SiO2 cat-
alyzed the desilylation, we added 3 mol% of triflic acid
(TfOH) to the reaction mixture, but this only had very slight
effect on desilylation over 12 hours. Furthermore, heteroge-
neous MoO3 alone did not result in any desilylation either
(entries 3 and 4). These results indicate that desilylation is
promoted through the interaction of the TBS ether with ho-
mogeneous Mo(VI) in the form of soluble phosphomolybdic
acid. The promising aspect of our preliminary experiment
was that, for both PMA-based reactions, the desired 3′-O-
TBS-dT (1′) was obtained in 66–68% yields, whereas only a
trace of 5′-O-TBS-dT (1′′) was observed, and dT (1′′′) was ob-
tained in 23–25% yields, which indicated that 5′-O-TBS was
more labile to homogeneous PMA than was 3′-O-TBS in THF.
The solvent effect was investigated in regular MeCN,
MeOH, and i-PrOH (AR grade) with 1 mol% PMA. The results
listed in Table 1 (entries 5–7) show that desilylation in
MeCN was so fast that no regioselectivity between the 5′-
and 3′-O-TBS groups was observed and that 1′ and 1′′ were
formed near the start of the reaction. At the stage when the
starting material 1 disappeared after 15 minutes, nearly
60% of the fully desilylated dT (1′′′) was formed. In contrast,
the reactions in MeOH and i-PrOH proceeded with better
5′-O-TBS selectivity. Whereas the reaction in MeOH fin-
ished within 45 minutes, the one in i-PrOH required 18
hours. It is obvious that PMA-mediated desilylation is much
more efficient in MeOH than in THF in terms of both the re-
gioselectivity and the reaction rate. However, before we
moved on to further optimization in MeOH, we tried gradu-
ally lowering the amount of PMA from 1 mol% to see
whether the reaction in MeCN might show any regioselec-
Comparison of PMA–SiO2 with a 1% solution of PMA in
THF (Table 1, entries 1 and 2) showed that the reaction rate
of homogeneous PMA was much faster (3 h) than that of
PMA–SiO2 (12 h) in THF. However, due to the leaching of
PMA, this result could not realistically be ascribed to a dif-
ference between homogeneous and heterogeneous cataly-
sis. The fact that the outcomes for 0.45 mol% homogeneous
PMA (the same amount that 1 mol% PMA–SiO2 leached into
THF) and 1 mol% PMA-SiO2 were exactly the same suggest-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

C
H.-S. Huang et al.
Letter
Synlett
Table 2 The Concentration Effect in PMA-Catalyzed Regioselective Deprotection of 5′-O-TBS of 1 in MeOH
O
O
O
O
N
NH
NH
NH
NH
TBSO
HO
TBSO
HO
N
O
N
O
N
O
O
O
O
O
O
PMA, MeOH
20 °C
+
+
TBSO
TBSO
HO
HO
1
1'
1''
1'''
Entry
[1] (M)
PMAa (mol%)
Timeb (h)
Yieldsc of 1′/1′′/1′′′ (%)
1
2
3
4
0.3
0.5
1
3.5
1.5
3
81/2/12
82/2/11
85/1/9
89/1/5
0.2
0.1
1
0.05
4
3
a The minimum amount of PMA needed.
b The reaction was stopped when less than 5% of 1 was left.
c The yields of 1′/1′′/1′′′ were determined by integrating the distinctive H(6) signal of each compound (see Supplementary Information, Figures S1 and S2 ).
tivity. Unfortunately, even at 0.2 mol%, the lowest PMA level
for complete consumption of 1, products 1′ and 1′′ were still
obtained simultaneously.
Having determined the optimal conditions, we applied
this method to the regioselective deprotection of 5′-O-TBS
groups of a diversity of persilylated nucleoside substrates
2–16. As shown in Table 3, 4 mol% PMA was effective for the
cleavage of the 5′-O-TBS of persilylated uridine, 5–MeOHdU, 5–
COOHdU, and 5–IdU. Acetate, 2-cyanoethyl ether, and benzyl
ester protecting groups on the nucleobases were stable un-
der the reaction conditions. In addition, two 3′-O-TBS-pro-
tected dT derivatives with an allylamine or a propagyl-
amine linker were also obtained in good yields. However, 4
mol% PMA was no longer sufficient for substrates contain-
ing N4-benzoyl cytosine, N6-benzoyl adenine, N2-isobutyryl
guanine, or hypoxanthine moieties (11–16); the amount of
PMA needed to be increased to 20 mol% to achieve selective
5′-O-TBS deprotection of these substrates. The reaction on
3′,5′-O-diTBS-dABz was the only one that was not success-
ful; product analysis indicated that most of the substrate
underwent depurination.
In our subsequent studies, we gradually lowered the re-
action concentration from an initial 0.3 M to 0.05 M, opti-
mized the amount of PMA required, and determined the
yields of all the desilylated products. The results listed in
Table 2 show that when the desilylation was performed at a
lower concentration, more PMA was needed to drive the re-
action to completion. For instance, only 0.5 mol% PMA was
needed at 0.3 M, whereas 4 mol% PMA was required at 0.05
M. However, it was quite noteworthy that the 5′-O-TBS se-
lectivity improved markedly when the reaction was per-
formed at a low concentration. The best regioselectivity of
5′-O-TBS was achieved at 0.05 M, and the desired 3′-O-TBS-
dT (1′) was isolated in 85% yield. In addition, it should be
noted that the reaction temperature is also a critical factor
for regioselectivity. Compared with the reaction at 20 °C,
that at 30 °C generated significantly more 1′′′.
Table 3 Regioselective 5′-O-TBS Desilylation of Persilylated Nucleosides 1–16 by Methanolic PMA
TBSO
HO
Base
Base
O
O
PMA, MeOH
20 °C
TBSO
1–16
TBSO
1'–16'
R
R
R = H or OTBS
Entry
1
Substrate
Product
PMA (mol%)
4
Time (h)
3
Yield (%)
85 (83)b
O
O
N
NH
NH
HO
TBSO
N
O
O
O
O
TBSO
TBSO
1'
1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

D
H.-S. Huang et al.
Letter
Synlett
Entry
Substrate
Product
PMA (mol%)
Time (h)
Yield (%)
O
N
O
NH
O
NH
HO
TBSO
N
O
2
3
4
5
6
7
8
4
3
84
80
81
85
82
80
71
O
O
TBSO
OTBS
O
TBSO
OTBS
O
2'
2
AcO
HO
NH
O
AcO
TBSO
NH
N
N
O
4
4
4
4
4
4
3
3
3
3
3
3
O
O
TBSO
TBSO
3'
3
O
O
NC
NC
O
NH
O
NH
HO
TBSO
N
O
N
O
O
O
TBSO
TBSO
4'
4
O
O
HO
NH
HO
NH
O
TBSO
HO
N
O
N
O
O
TBSO
TBSO
5
5'
O
N
O
N
I
I
NH
NH
O
TBSO
HO
O
O
O
TBSO
TBSO
6
6'
O
O
N
O
O
N
BnO
NH
BnO
TBSO
NH
O
HO
O
O
O
TBSO
TBSO
7'
7
O
O
N
O
O
N
HO
NH
O
HO
NH
TBSO
HO
O
O
O
TBSO
TBSO
8
8'
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

E
H.-S. Huang et al.
Letter
Synlett
Entry
Substrate
Product
PMA (mol%)
Time (h)
Yield (%)
O
O
O
O
N
F3C
N
NH
F3C
N
H
NH
H
TBSO
N
O
HO
O
9
4
3
82
O
O
TBSO
TBSO
9
9'
O
O
O
N
O
N
F3C
N
H
F3C
N
H
NH
O
NH
10
4
3
72
TBSO
HO
O
O
O
TBSO
TBSO
10
10'
NHBz
NHBz
N
N
N
TBSO
O
HO
N
O
11
12
13
14
15
20
20
20
20
20
6
6
8
8
8
77 (75)b
69 (65)b
81
O
O
TBSO
TBSO
11
11'
O
N
O
N
N
N
N
N
NH
NH
TBSO
HO
NHiBu
NHiBu
O
O
TBSO
TBSO
12
12'
NHBz
NHBz
N
N
N
N
HO
TBSO
O
O
O
O
TBSO
OTBS
TBSO
OTBS
13'
13
NHBz
NHBz
N
N
N
N
N
N
N
N
HO
TBSO
80
O
O
TBSO
TBSO
OTBS
OTBS
14'
14
O
O
N
N
N
N
NH
NH
N
TBSO
HO
N
NHiBu
NHiBu
82
O
O
TBSO
OTBS
TBSO
OTBS
15
15'
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

F
H.-S. Huang et al.
Letter
Synlett
Entry
Substrate
Product
PMA (mol%)
Time (h)
Yield (%)
O
O
N
N
N
N
NH
NH
TBSO
HO
N
N
16
20
3
90
O
O
TBSO
TBSO
OTBS
OTBS
16
16'
a Isolated yield of 100 to 300 mg scale reaction.
b Isolated yield of 10 to 15 g scale reaction.
In the case of 3′,5′-O-diTBS-dGiBu (12), depurination was
only a minor side reaction during desilylation, and the de-
sired product 12′ was obtained in 69% yield. For the ribonu-
cleoside substrates 13–16, especially 2′,3′,5′-O-triTBS-ABz,
no depyrimidination or depurination was observed at all. In
our preparations of dinucleotide phosphoramidites,25 the
current PMA-based method was used for the synthesis of
3′-O-TBS-dT (1′), 3′-O-TBS-dCBz (11′), and 3′-O-TBS-dGi-
Bu(12′) on a 10–15 g scale, and the desired nucleosides were
obtained in only slightly lowered yields.
The distinctive catalytic activities of PMA in different
organic solvents aroused our interest in mechanistic as-
pects of this PMA-mediated desilylation process. 31P NMR
spectroscopy was employed as a reliable method to identify
the molybdophosphate species in MeCN, THF, and MeOH.26–29
As shown in Figure 1A, PMA alone in MeCN appeared as a
major peak ( = –2.38 ppm, 84.2%) and a minor peak ( = –2.02
ppm, 15.8%) corresponding to Keggin [PMo12O40]3– and Wells–
Dawson [P2Mo18O62]6– anions. Similarly, PMA in THF also
existed in two forms: the Keggin ( = –2.77 ppm, 91.0%) and
Wells–Dawson ( = –2.33 ppm, 9.0%) anions (Figure 1B). In
MeOH, however, in addition to the Keggin ( = –2.35 ppm,
76.3%) and Wells–Dawson ( = –1.70 ppm, 6.9%) structures,
a third molybdophosphate species, an Anderson anion
[PMo6O25]9– ( = 2.15 ppm, 16.8%) was observed. The equi-
librium between the various PMA species in each solvent
was not substantially disturbed either by the addition of
diTBS-dT (1) or by the completion of the reaction. There-
fore, it is obvious that the solvation of PMA by various or-
ganic solvents has a significant impact on the equilibrium
of homogeneous molybdophosphate complexes. It was de-
termined that PMA exists primarily as a Keggin-type struc-
ture in all three organic solvents, and more-complex anion
forms are formed in MeOH, possibly due to its stronger in-
teraction with the PMA anions.
Figure 1 The 31P NMR spectra of PMA in MeCN (A), THF (B), and MeOH
(C), and polyhedral representations of the Anderson, Keggin, and
Wells–Dawson polyoxoanions (D).
solvation of PMA by various organic solvents dramatically
affects its Lewis acidity, and the Lewis acid strength of PMA
in MeCN is much stronger than those in THF or MeOH. This
result agreed well with the fact that desilylation of 1 in
MeCN was much faster but lacked regioselectivity.
On the basis of the these results, we propose a mecha-
nism for the regioselective and efficient desilylation of 5′-O-
TBS groups of persilylated nucleosides by methanolic PMA.
As shown in Figure 3, the lowered Lewis acidity of PMA due
to its solvation by MeOH exaggerates the steric hindrance
effect of the TBS group, which leads to pronounced 5′-O-TBS
In our subsequent research, we compared the Lewis acid
strength of PMA in various organic solvents by measuring
the changes in the 31P NMR chemical shift of Ph3PO (ΔPh3PO
)
upon addition of one equivalent of PMA; this is a simplified
form of the Gutmann–Beckett method.30 As shown in Fig-
ure 2, ΔPh3PO·CH3CN (14.87 ppm) >> ΔPh3PO·THF (2.73 ppm) >
ΔPh3PO·MeOH (0.65 ppm). The values of ΔPh3PO indicated that
Figure 2 The 31P NMR spectra of Ph3PO in the absence or presence of
equimolar amounts of PMA in MeCN (A), THF (B), and MeOH (C) for
comparison of the Lewis acidity
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G

G
H.-S. Huang et al.
Letter
Synlett
selectivity. Meanwhile, the interactions of MeOH with mo-
lybdophosphate at the surface of the anions also facilitates
an SN2-type substitution of TBS,29,31 giving TBSOMe as the
major silyl product, as determined by 13C NMR monitoring
of the reaction shown in Table 2, entry 4 (see Supplementa-
ry Information, Figure S3). Because a large excess of MeOH
can function as a nucleophile in desilylation, the reaction
rate in MeOH is markedly faster than that in THF, making
MeOH the ideal solvent for PMA-catalyzed regioselective 5′-
O-TBS deprotection.
References and Notes
(1) Greene, T. W.; Wus, P. G. M. Protective Groups in Organic Synthe-
sis, 3rd ed.; Wiley: New York, 1999.
(2) Kocieński, P. J. Protecting Groups, 3rd ed.; Thieme: Stuttgart,
2005.
(3) Kotch, F. W.; Sidorov, V.; Lam, Y.-F.; Kayser, K. J.; Li, H.; Kaucher,
M. S.; Davis, J. T. J. Am. Chem. Soc. 2003, 125, 15140.
(4) Toti, K. S.; Verbeke, F.; Risseeuw, M. D. P.; Frecer, V.; Munier-
Lehmann, H.; Van Calenbergh, S. Bioorg. Med. Chem. 2013, 21,
257.
(5) Ikeuchi, K.; Fujii, R.; Sugiyama, S.; Asakawa, T.; Inai, M.;
Hamashima, Y.; Choi, J.-H.; Suzuki, T.; Kawagishi, H.; Kan, T. Org.
Biomol. Chem. 2014, 12, 3813.
(6) Hong, S.-p.; Lindsay, H. A.; Yaramasu, T.; Zhang, X.; McIntosh, M.
C. J. Org. Chem. 2002, 67, 2042.
(7) Lin, G.; Chen, C.-H.; Pink, M.; Pu, J.; Li, L. Chem. Eur. J. 2011, 17,
9658.
(8) Madhuri, V.; Kumar, V. A. Nucleosides, Nucleotides Nucleic Acids
2012, 31, 97.
(9) Moharram, S.; Zhou, A.; Wiebe, L. I.; Knaus, E. E. J. Med. Chem.
2004, 47, 1840.
(10) Kim, S. E.; Kim, S. Y.; Kim, S.; Kang, T.; Lee, J. Bioorg. Med. Chem.
Lett. 2005, 15, 3389.
(11) Somu, R. V.; Wilson, D. J.; Bennett, E. M.; Boshoff, H. L.; Celia, L.;
Beck, B. J.; Barry, C. E.; Aldrich, C. C. J. Med. Chem. 2006, 49, 7623.
(12) Tallman, K. A.; Greenberg, M. M. J. Am. Chem. Soc. 2001, 123, 5181.
(13) Lin, G.; Li, L. Angew. Chem. Int. Ed. 2013, 52, 5594.
(14) Pradere, U.; Amblard, F.; Coats, S. J.; Schinazi, R. F. Org. Lett.
2012, 14, 4426.
(15) Seamon, K. L.; Hansen, E. C.; Kadina, A. P.; Kashemirov, B. A.;
McKenna, C. E.; Bumpus, N. N.; Stivers, J. T. J. Am. Chem. Soc.
2014, 136, 9822.
(16) Crouch, R. D. Tetrahedron 2013, 69, 2383; and references therein.
(17) Seela, F.; Ott, J.; Potter, B. V. L. J. Am. Chem. Soc. 1983, 105, 5879.
(18) Tandon, M.; Begley, T. P. Syn. Commun. 1997, 27, 2953.
(19) Hwu, J. R.; Jain, M. L.; Tsai, F.-Y.; Tsay, S.-C.; Balakumar, A.;
Hakimelahi, G. H. J. Org. Chem. 2000, 65, 5077.
(20) Chen, M.-Y.; Patkar, L. N.; Lu, K.-C.; Lee, A. S.-Y.; Lin, C.-C. Tetra-
hedron 2004, 60, 11465.
Figure 3 Proposed mechanism for methanolic PMA-catalyzed regio-
selective cleavage of 5′-O-TBS groups of persilylated nucleosides
In summary, our revisit of the PMA–SiO2/THF heteroge-
neous catalysis system as a potential tool for regioselective
5′-O-TBS deprotection of persilylated nucleosides showed
that significant amount of PMA leached from the solid sup-
port and that desilylation catalyzed by PMA essentially pro-
ceeded in a homogeneous manner. Our research indicated
that the nature of the organic solvent, the reaction concen-
tration, and the temperature significantly affect the reactiv-
ity and regioselectivity of homogeneous PMA. We conclud-
ed that 4–20 mol% of methanolic PMA at 0.05 M and 20 °C
provided the best outcome in terms of regioselective 5′-O-
TBS deprotection of a variety of persilylated nucleoside
(21) Zhu, X.-F.; Williams, H. J.; Scott, A. I. J. Chem. Soc., Perkin Trans. 1
2000, 2305.
(22) Sun, Q.; Sun, J.; Gong, S.-S.; Wang, C.-J.; Pu, S.-Z.; Feng, F.-D. RSC
Adv. 2014, 4, 36036.
substrates on scales of up to 15 g. With the assistance of 31
P
NMR, we found that both the anion cluster forms and the
Lewis acidity of PMA were quite solvent dependent. We
propose that the strong solvation of PMA in MeOH not only
lowers its Lewis acid strength for higher regioselectivity,
but also facilitates the substitution of TBS by MeOH.
(23) Gong, S.-S.; Sun, J.; You, Y.-H.; Chen, J.-Z.; Liu, G.-D.; Sun, Q.
Nucleosides, Nucleotides Nucleic Acids 2016, 6, 295.
(24) Kumar, G. D. K.; Baskaran, S. J. Org. Chem. 2005, 70, 4520.
(25) Janczyk, M.; Appel, B.; Springstubbe, D.; Fritz, H.-J.; Müller, S.
Org. Biomol. Chem. 2012, 10, 1510.
(26) van Veen, J. A. R.; Sudmeijer, O.; Emeis, C. A.; de Wit, H. J. Chem.
Soc., Dalton Trans. 1986, 1825.
(27) Larionov, O. V.; Stephens, D.; Mfuh, A. M.; Arman, H. D.;
Naumova, A. S.; Chaveza, G.; Skenderia, B. Org. Biomol. Chem.
2014, 12, 3026.
(28) Guo, H.; Yin, G. J. Phys. Chem. C 2011, 115, 17516.
(29) López, X.; Carbó, J. J.; Bo, C.; Poblet, J. M. Chem. Soc. Rev. 2012,
41, 7537.
Funding Information
This work was supported by National Natural Science Foundation of
China (21562021), Natural Science Foundation (20143ACB21014),
Fellowship for Young Scientists (2015BCB23009), and a Sci & Tech
Project from the Department of Education (GJJ160763) of Jiangxi
(30) Beckett, M. A.; Strickland, G. C.; Holland, J. R.; Varma, K. S.
Polymer 1996, 37, 4629.
Province.
N
ati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
5
6
2
0
2
1)NaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
(2
0
1
4
3
A
C
B
2
1
0
1
4)
(31) Song, Y.-F.; Tsunashima, R. Chem. Soc. Rev. 2012, 41, 7384.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610300.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–G