Aqueous trichloroacetic acid: Another useful reagent for highly selective 5′-desilylation of multisilylated nucleosides

Article abstract of DOI:10.1081/SCC-120021027

Highly selective 5′-desilylation of multisilylated nucleosides can be achieved in excellent yield by treatment with 4.2 M aqueous trichloroacetic acid:THF (1:4) at 0°C.

Full text of DOI:10.1081/SCC-120021027

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Aqueous Trichloroacetic Acid: Another Useful Reagent
for Highly Selective 5′-Desilylation of Multisilylated
Nucleosides
Xue-Feng Zhu a , Howard J. Williams a & A. Ian Scott a
a Center for Biological NMR , Department of Chemistry , Texas A&M University , College
Station, Texas, USA
Published online: 17 Aug 2006.
To cite this article: Xue-Feng Zhu , Howard J. Williams & A. Ian Scott (2003) Aqueous Trichloroacetic Acid: Another Useful
Reagent for Highly Selective 5′-Desilylation of Multisilylated Nucleosides, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 33:12, 2011-2016, DOI: 10.1081/SCC-120021027
To link to this article: http://dx.doi.org/10.1081/SCC-120021027
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 12, pp. 2011–2016, 2003
Aqueous Trichloroacetic Acid: Another Useful
Reagent for Highly Selective 50-Desilylation of
Multisilylated Nucleosides
*
Xue-Feng Zhu, Howard J. Williams, and A. Ian Scott
Center for Biological NMR, Department of Chemistry,
Texas A&M University, College Station, Texas, USA
ABSTRACT
Highly selective 50-desilylation of multisilylated nucleosides can be
achieved in excellent yield by treatment with 4.2 M aqueous trichloro-
acetic acid:THF (1:4) at 0ꢀC.
Key Words: Nucleoside; Deprotection; Selective desilylation.
The protection and deprotection of free hydroxyl groups has become
commonplace in chemical synthesis.[1] This is particularly true in syn-
thetic nucleoside chemistry, where most of nucleosides possess two or
three hydroxyl groups. Among numerous different types of protective
*Correspondence: A. Ian Scott, Center for Biological NMR, Department of
Chemistry, Texas A&M University, P.O. Box 30012, College Station, TX
77842-3012, USA; E-mail: scott@mail.chem.tamu.edu.
2011
DOI: 10.1081/SCC-120021027
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2012
Zhu, Williams, and Scott
groups the silyl ethers are frequently used in nucleoside chemistry, the
tert-butyldimethylsilyl (TBDMS) group being the most popular, mainly
because TBDMS ethers are stable towards a variety of reaction condi-
tions during nucleotide synthesis.[2]
Selective 50-desilylation of multisilylated nucleosides is a very useful
transformation, by which some important nucleosides such as 20,30-di-O-
TBDMS, 20- and 30-mono-O-TBDMS protected nucleosides can be pre-
pared simply from the corresponding 20,30,50-trisilylated, 20,50- and 30,50-
disilylated derivatives, respectively. Although some neutral reagents and
conditions such as catalytic hydrogenation,[3] NH4F/MeOH,[4] neutral
alumina[5] and Lewis acids[6] have been reported for this transformation,
the selective removal of the 50-TBDMS group of mutisilylated nucleosides
is normally achieved under acidic conditions. For example, acidic hydro-
lysis of 50-TBDMS ethers has been carried out with aqueous or alcoholic
mineral acids,[7] aqueous acetic acid,[8] aqueous trifloroacetic acid[9] and
camphorsulfonic acids.[10] However, these methods often suffer from
unsatisfactory yields because of concomitant side reactions such as
acidic cleavage of glycosidic bonds and didesilylation. In a preceding
communication, we modified Robins0 method[9] by adding THF as a
co-solvent and found that highly selective 50-desilylation of 20,30,50-
tri-O-TBDMS nucleosides can be achieved upon treatment with trifluoro-
acetic acid (TFA)–H2O–THF (1:1:4) at 0ꢀC.[11] The addition of THF as
a co-solvent not only improves the selectivity of 50-desilylation but avoids
the unwanted depyrimidination and depurination side reactions seen in
other procedures. We now report that another efficient 50-desilylation
reagent, 4.2 M aqueous trichloroacetic acid (TCA):THF (1:4), can be
used as an economical alternative (Sch. 1). To the best of our knowledge,
this is the first example of the use of aqueous TCA as a selective desilyla-
tion reagent. The results of 50-desilylation are summarized in Table 1.
Under these novel conditions, 20,30,50-tri-O-TBDMS nucleosides
(Entries 1–2) and arabinonucleoside (Entry 3) are smoothly transformed
into the expected 20,30-disilylated derivatives and excellent yields of pure
products are obtained. More importantly, this milder reagent is superior
Scheme 1.

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Aqueous Trichloroacetic Acid
2013
Table 1. Selective 50-desilylation of multisilylated nucleosides by aqueous TCA.
Entry
Basea
R1
R2
Time (h)
Yieldb (%)
1
2
ABz
CBz
U
ABz
ABz
U
OTBDMS
OTBDMS
ara-OTBDMS
OH
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OH
3
99
93
95
94
98
93
98
90
95
85
97
8
3
6
4
3
5
OTBDMS
OH
3
6
OTBDMS
OH
4.5
4
7
U
OTBDMS
OH
8
GBz
GBz
CBz
CBz
OTBDMS
OH
2.5
2.5
6
9
OTBDMS
OH
OTBDMS
10
11
OTBDMS
OH
5.5
aABz ¼ 6-N-benzoyladenine, CBz ¼ 4-N-benzoylcytosine, U¼uracil, GBz¼2-N-
benzoylguanine.
1
bIsolated yield characterized by H NMR, 13C NMR, and MS.
to our previously reported TFA reagent in terms of the selectivity of 50-
desilylation of 20,50- or 30,50-disilylated nucleosides. Under our current
conditions, 20- or 30-monosilyl nucleosides were obtained in good to
excellent yields (Entries 4–11) in comparison with the relatively low
yields generated by the TFA reagent. The monosilylated nucleosides
were isolated as single products with no observed isomerization of
TBDMS ether between two vicinal hydroxyl groups. Since 20,50- and
30,50-di-O-TBDMS nucleoside substrates can easily be prepared by
a well-established selective disilylation procedure developed by Ogilvie
et al,[9b,12,13] an improved 50-desilylation method has become highly desir-
able in nucleoside chemistry. The ready availability of 20(30)-monosilyl
nucleosides may afford an attractive alternative to prepare silyl phos-
phoramidite nucleosides 3 and 4, two commonly used RNA building
blocks[14] which now might simply be made from 20 (30)-monosilylated
nucleosides via 50-tritylation and 30(20)-phosphitylation. However, the
currently available literature approach to 3 and 4 starts from 50-DMTr
nucleosides, and monosilylation of 50-trityl nucleoside only gives a mix-
ture of 50-DMTr-20-O-TBDMS protected nucleoside and its 50-isomer
even under conditions similar to those used by Ogilvie utilized for
selective disilylation of nucleosides (Fig. 1).[12,15]
We also applied this novel method to the 50-end partial cleavage of
30,50-TIPDS protected nucleosides, the expected products 6 and 8 being
obtained in nearly quantitative yield (Sch. 2). In the case of 20-deoxy
nucleoside 9, the steric differences between 30-end and 50-end silyl ethers

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Zhu, Williams, and Scott
Figure 1.
Scheme 2.
are reduced because it lacks any functional group at the 20-position,
leading to a mixture of 50-end and 30-end partial cleavage products
with the ratio of about 4:1. Once again, a variety of protecting groups
such as the benzoyl group for the nucleobase and 20-hydroxyl, and
TBDMS ether for the 20-hydroxyl group were found to be compatible
with these mild reaction conditions.[16]
In conclusion, we have discovered another highly efficient and regio-
selective reagent (4.2 M aqueous TCA:THF ¼ 1:4) for the 50-desilylation
of 20,30,50-tri-O-TBDMS and 30,50-TIPDS protected nucleosides.
Compared with the TFA reagent (TFA–H2O–THF ¼ 1:1:4), this novel
reagent is particularly useful for the highly selective deprotection of
20,50- and 30,50-di-O-TBDMS protected nucleosides at the 50-position.
This mild deprotection method should find wide application in the

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Aqueous Trichloroacetic Acid
2015
synthesis of nucleosides as well as carbohydrates and other complex
molecules.
EXPERIMENTAL
Typical procedure for 50-desilylation of 20,50-di-O-TBDMS nucleo-
sides (Entry 5 of Table 1): To a stirred solution of 20,50-di-O-TBDMS-N6-
benzoyladenosine 1e (200 mg) in THF (4 mL) was added aqueous TCA
(2.12 g in 1 mL H2O) at 0ꢀC. After stirring for 3 h at 0ꢀC, the reaction
mixture was neutralized with aqueous NaHCO3 (1.1 g in 15 mL H2O) and
diluted with dichloromethane (50 mL). After separation, the aqueous
phase was further extracted with dichloromethane (3 ꢁ 25 mL). The
combined extracts were dried over anhydrous Na2SO4 and evaporated
at reduced pressure. The residue was subjected to flash chromatography
(CH2Cl2:MeOH ¼ 100:0.5 to 100:2) to provide 159 mg (98%) of 20-
monosilylated product 2e as a white solid.
ACKNOWLEDGMENTS
This work was supported by grants from the Texas Advanced
Technology Research Program and the Robert A. Welch Foundation.
X. F. Z. thanks members of the Scott group, especially Dr. Clotilde
Pichon-Santander, for offering him invaluable help during his post-
doctoral appointment at Texas A&M University.
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Received in the USA September 16, 2002