Facile and highly selective 5′-desilylation of multisilylated nucleosides

Article abstract of DOI:10.1039/b003562i

The facile and highly selective 5′-desilylation of multisilylated nucleosides was discussed. The selective 5′-desilylation using aqueous acetic acid can be improved if THF is added as a co-solvent. It was found that the use of THF increases the solubility

Full text of DOI:10.1039/b003562i

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Facile and highly selective 5Ј-desilylation of multisilylated
nucleosides
Xue-Feng Zhu, Howard J. Williams and A. Ian Scott*
1
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
Received (in Cambridge, UK) 4th May 2000, Accepted 22nd May 2000
Published on the Web 16th June 2000
Table 1 Selective 5Ј-desilylation of multisilylated nucleosides by TFA–
Efficient methods for selective 5Ј-desilylation of multi-
silylated nucleosides are described.
H2O–THF (1:1:4)
Entry
Basea
R1
R2
Time/h
Yield (%)b
Since its introduction by Stork and Hudrlik,1 and Corey and
Venkateswarlu,2 the tert-butyldimethylsilyl (TBDMS) group
has become the most popular and useful hydroxy protecting
group in chemical synthesis.3,4 One of the greatest challenges in
this field is the selective deprotection of primary TBDMS
groups in the presence of their secondary counterparts, a pro-
cedure which has considerable utility for synthetic chemists.5
During a recent oligonucleotide study, we needed to syn-
thesize 2Ј,3Ј-di-O-TBDMS protected nucleosides, which can be
prepared via the selective 5Ј-desilylation of the corresponding
2Ј,3Ј,5Ј-trisilylated derivatives. Because of the strong affinity of
fluoride ions for silicon and lack of primary/secondary silyl
preference, fluoride ion based reagents such as tetrabutyl-
ammonium fluoride (TBAF) were not useful. Selective cleavage
of primary TBDMS ethers using Lewis acids such as zinc
bromide and lithium bromide/18-crown-6 suffers from longer
reaction times, higher temperature, low yields and complicated
procedures.6–9
1
2
3
4
5
6
7
8
9
10
11
12
13
ABz
A
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OH
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OH
2
3
3
3
6
6
6
2
2
2
2
2
2
93
93
95
96
90
99
96
92
86
87
81
73
85
GBz
G
CBz
C
U
ABz
ABz
U
OTBDMS
OH
OTBDMS
OTBDMS
OTBDMS
OTBDMS
OH
H
U
ABz
C
H
a ABz = N6-Benzoyladenine, A = adenine, GBz = N2-benzoylguanine,
G = guanine, CBz = N4-benzoylcytosine, C = cytosine, U = uracil.
b Isolated yield characterized by 1H NMR, 13C NMR and MS.
It is well known that primary silyloxy groups are cleaved
under acidic conditions more easily than secondary ones.5
Ogilvie and co-workers demonstrated that selective 5Ј-desilyl-
ation can be accomplished using 80% aqueous acetic acid with
yields up to 75%.10,11 However, our attempts to partially depro-
tect N6-benzoyl-2Ј,3Ј,5Ј-tri-O-TBDMS adenosine 1a with 80%
acetic acid resulted in either no reaction (rt, 10 h) or complete
deprotection (100 ЊC, 3 h). When 1a was treated with acetic
acid–H2O–THF (13:7:3) at rt for 30 h, 2Ј,5Ј- and 3Ј,5Ј-
didesilylation as well as the cleavage of the glycosidic linkage
were observed. The poor selectivity of this procedure indicates
that aqueous acetic acid is not an ideal reagent for selective 5Ј-
desilylation. Robins et al. reported that selective deprotection
of the 5Ј-OH of 2Ј,5Ј-di-O-TBDMS-3Ј-keto adenosine was
achieved by reaction with aqueous trifluoroacetic acid (TFA).12
During our preliminary study using aqueous acetic acid we
observed that the addition of THF improves the selectivity
toward primary silyl ethers. We therefore attempted to modify
Robins’ method by adding THF as a co-solvent. After extensive
investigation of the various combinations of TFA, H2O and
THF, we finally discovered that TFA–H2O–THF (1:1:4) gives
the most satisfactory results at 0 ЊC. Under these optimized
conditions, 2Ј,3Ј,5Ј-tri-O-TBDMS nucleosides are quanti-
tatively transformed into the expected 2Ј,3Ј-disilylated deriv-
atives and excellent yields of pure products are obtained
(Scheme 1, Table 1). The use of THF as co-solvent affords
the following benefits: (i) increase of solubility of nucleoside
substrates and hence acceleration of the reaction rate; (ii)
significantly improved selectivity of 5Ј-desilylation even
when the reaction is carried out at rt; (iii) complete absence of
depyrimidination and depurination, which are common side-
reactions of the acidic hydrolysis of nucleosides.
Greene and Wuts attributed the rationale for Robins’ selec-
tive desilylation to the reduced basicity of 2Ј-O-TBDMS due to
the presence of a 3Ј-carbonyl group.4 In our case, since there is
no such electron-withdrawing group in the substrates, we
reasoned that steric rather than electronic effects may dominate
the selectivity of desilylation. The explanation is further sup-
ported by simple modeling in which Geistiger–Hückel charges
are calculated indicating that 2Ј-, 3Ј- and 5Ј-O-TBDMS groups
have almost the same charge on their oxygen atoms. On the
other hand, the steric environments of these TBDMS groups
are quite different. For example, 5Ј-O-TBDMS groups of tri-
silylated nucleosides (1a–g) are obviously much less hindered
than the 2Ј- and 3Ј-O-TBDMS groups, leading to excellent
selectivity in favor of the removal of the 5Ј-O-TBDMS group
(entries 1–7). These steric effects are somewhat reduced for
disilylated ribonucleosides and deoxynucleosides in which 2Ј- or
3Ј-positions have smaller OH (entry 1 vs. entries 8–9, entry 7 vs.
entries 10–11) or H (entries 12–13) moieties, leading to slightly
poorer desilylation selectivity and yield.
We also assumed that the 2Ј-O-TBDMS group of 2Ј,3Ј,5Ј-
trisilylated or 2Ј,3Ј-disilylated nucleosides should be more
resistant to acidic hydrolysis than the 3Ј-O-TBDMS group due
to the adjacent base of the nucleoside. This assumption was
confirmed by treatment of 1a (Scheme 2) with TFA–H2O
(5.5:4.5) at rt for 2 h which effected removal of the 5Ј-O-
TBDMS and 3Ј-O-TBDMS groups to give N6-benzoyl-2Ј-O-
TBDMS adenosine (2h) as the major product. Under these
conditions, a similar result is obtained starting from 2a. Extend-
ing the reaction time increases the ratio of the desired products
(determined by HPLC), but the overall yield is decreased
because of didesilylation and depurination.
Scheme 1
DOI: 10.1039/b003562i
J. Chem. Soc., Perkin Trans. 1, 2000, 2305–2306
This journal is © The Royal Society of Chemistry 2000
2305

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Scheme 3
an efficient way to synthesize the 2Ј,3Ј-disilyl, 2Ј-monosilyl and
3Ј-monosilyl nucleosides, which are important building blocks
for oligonucleotide synthesis. This method can also be applied
to the 5Ј-end partial cleavage of a TIPDS protected nucleoside
and to the best of our knowledge, this is the first example of
partial cleavage of the TIPDS group by aqueous TFA. Given
the very mild conditions, high regioselectivity and quantitative
yield, this procedure provides a practical solution for the syn-
thesis of various protected nucleosides. Further investigations
of this methodology in our laboratory are currently underway.
Experimental
Typical procedure for the 5Ј-desilylation of 2Ј,3Ј,5Ј-tri-O-
TBDMS nucleosides (entry 7 of Table 1): to a stirred solution
of 2Ј,3Ј,5Ј-tri-O-TBDMS uridine (200 mg) in THF (4 ml) was
added aqueous TFA (2 ml, TFA–H2O = 1:1) at 0 ЊC. After stir-
ring for 6 h at 0 ЊC, the reaction mixture was neutralized with
saturated aqueous NaHCO3 and diluted with ethyl acetate (80
ml). After separation, the organic phase was washed with H2O
(10 ml) and brine (10 ml), dried over anhydrous Na2SO4 and
evaporated at reduced pressure. The residue was subjected to
flash chromatography (hexane–Et2O = 2:1 then Et2O) to pro-
vide 155 mg (96%) of 2Ј,3Ј-disilylated product as a white solid.
Acknowledgements
This contribution is dedicated (by A. I. S.) to the memory of
Leslie Crombie, a lifelong friend, a gifted organic chemist and,
above all, a true gentleman. This work was supported by grants
from the Texas Advanced Technology Research Program and
the Robert A. Welch Foundation. We thank Dr Clotilde
Pichon-Santander for helpful discussion.
Scheme 2
Since Markiewicz developed the 1,1,3,3-tetraisopropyl-
disiloxane-1,3-diyl (TIPDS) group for the simultaneous
protection of the 3Ј- and 5Ј-hydroxy groups of nucleosides,13
this method has found widespread applications, particularly in
carbohydrate and nucleotide chemistry.3,4 One useful feature of
the TIPDS protecting group is that it can be partially cleaved at
the 5Ј-position of 3Ј,5Ј-TIPDS protected ribofuranoses using
0.2 M HCl in dioxane–H2O (4:1)13 or 1 M HCl in dioxane.14
However, the cleavage of the 3Ј-end as well as full deprotection
are often unavoidable under these conditions, so that the
yields of expected 3Ј-silylation products are only moderate.15–17
Markiewicz also mentions that the selectivity of this cleavage
can be enhanced when electron-withdrawing groups are present
in the 2Ј-position of nucleosides.18
In view of our successful 5Ј-desilylation of multisilylated
nucleosides described above and in order to extend the scope of
this procedure, the partial cleavage of TIPDS protected nucleo-
side 3 was tested using TFA–H2O–THF (1:1:4) which was
optimal for the O-TBDMS analogs. After stirring at 0 ЊC for
2 h, the expected product 4 was obtained in excellent yield
(98%) (Scheme 3). Once again, selectivity is more likely to be
the result of steric differences associated with 3Ј- and 5Ј-ethers
rather than electronic effects. According to our calculations, the
charges of the 3Ј- and 5Ј-oxygen atoms are almost equal, and
replacing the benzoyl ester group at the 2Ј-position with other
groups such as hydroxy and phosphate does not change the
electron density.
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In conclusion, we have demonstrated here a highly selective
5Ј-desilylation of multisilylated nucleosides using TFA–H2O–
THF (1:1:4) as a mild deprotection agent. Since the syntheses
of 2Ј,3Ј,5Ј-tri-O-TBDMS nucleosides and 2Ј,5Ј- and 3Ј,5Ј-di-O-
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