Phosphoramidite building blocks for efficient incorporation of 2′-O-aminoethoxy(and propoxy)methyl nucleosides into oligonucleotides

Article abstract of DOI:10.1016/j.tet.2008.04.110

A simple and efficient method for the preparation of eight phosphoramidite building blocks for incorporation of 2′-O-(2-aminoethoxymethyl)ribonucleosides and 2′-O-(3-aminopropoxymethyl)ribonucleosides into synthetic oligonucleotides has been developed. The synthetic routes are maximally convergent and provide sufficient amounts of phosphoramidites for several solid-phase synthesis coupling reactions. Using acyclic derivatives 17a,b the overall yields of phosphoramidites 2 and 3 were increased up to 50% for pyrimidine nucleosides and up to 30% for purine derivatives with substantial decrease of total reaction steps. The 2′-O-substituent was found to be stable during oligonucleotide synthesis. The resulting oligonucleotides are of particular interest for post-synthetic functionalization and conjugation.

Full text of DOI:10.1016/j.tet.2008.04.110

Tetrahedron 64 (2008) 6238–6251
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Phosphoramidite building blocks for efficient incorporation of 20-O-
aminoethoxy(and propoxy)methyl nucleosides into oligonucleotides
,
,
b
,
,
z
Georgii V. Bobkova y, Sergey N. Mikhailova , Arthur Van Aerschot z, Piet Herdewijn b
*
a Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, Moscow 119991, Russia
b Rega Institute, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Asimpleandefficientmethodforthepreparationofeightphosphoramiditebuildingblocks forincorporation
of 20-O-(2-aminoethoxymethyl)ribonucleosides and 20-O-(3-aminopropoxymethyl)ribonucleosides into
synthetic oligonucleotides has been developed. The synthetic routes are maximally convergent and provide
sufficient amounts of phosphoramidites for several solid-phase synthesis coupling reactions. Using acyclic
derivatives 17a,b the overall yields of phosphoramidites 2 and 3 were increased up to 50% for pyrimidine
nucleosides and up to 30% for purine derivatives with substantial decrease of total reaction steps. The 20-O-
substituent was found to be stable during oligonucleotide synthesis. The resulting oligonucleotides are of
particular interest for post-synthetic functionalization and conjugation.
Received 30 March 2008
Received in revised form 26 April 2008
Accepted 28 April 2008
Available online 30 April 2008
Keywords:
20-O-Modified nucleosides
20-O-(
u-Aminoalkoxymethyl)-
Ó 2008 Elsevier Ltd. All rights reserved.
ribonucleosides
Oligonucleotides
1. Introduction
groups are used,9,10 which in most cases are not compatible with
standard automated ON synthesis.
Modified oligonucleotides (ONs) are used widely in various
fields, such as molecular biology, biochemistry, and medicine.1–3
ONs carrying reactive groups are needed in order to synthesize
conjugates with reporter compounds, markers, peptides, proteins,
and other biomolecules.4,5 Research in this field increased in impact
by the discovery of RNA interference.6
Numerous attempts have been made to improve the properties
of natural ONs. It is believed that the 20-carbohydrate modifications
are the most universal and promising7–9 since this generally leads
to minimal distortions in ON structure. The ribose 20-position is
particularly useful for chemical modification because of its location
in the minor groove of A-form duplex nucleic acid, where it points
outward into solution. This position is also readily modified syn-
thetically, as described in this work. A typical strategy for the
preparation of such ONs is the synthesis of modified nucleoside
followed by conversion to the corresponding phosphoramidite
suitable for automated ON synthesis. Most of 20-O-modifications
were achieved via alkylation reactions of partially blocked ribo-
nucleosides. The heterocyclic bases should be protected in order to
avoid their alkylation. For each nucleoside the specific blocking
A large number of oligonucleotides containing a different ami-
noalkyl modification at the sugar moiety have been reported, the
amino group normally being protonated at physiological pH.
Oligonucleotides having such a positively charged modification
exhibit high binding properties toward RNA and DNA and maintain
nuclease resistance. Among the 20-O-substituents developed,
recently high affinity was found for the aminoethyl9 (phosphor-
amidites 1, Fig. 1) and aminopropyl7,11 derivatives, which may form
specific contact with a proximal phosphate group in the nucleic
acids duplex. Modified oligonucleotides bearing 20-reporting and
reactive groups or 20-conjugated molecules have found wide ap-
plication as structural tools in molecular biology.12
Very recently for the preparation of 20-O-modified nucleosides
we have developed another type of chemistry based on O-glycosyl-
ation reactions, which have several important advantages, such
as increased yields and simplification.13–16 A simple and effective
method for the preparation of 20-O-
starting from readily available 30,50-O-blocked N-acylribonucleo-
b-D-ribofuranosylnucleosides,
sides and 1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranose in the
presence of tin tetrachloride in 1,2-dichloroethane at 0 ꢀC, has been
recently developed.17–19 Holding this line an efficient synthesis of
pyrimidine 20-O-(
u-hydroxyalkoxymethyl)ribonucleosides has been
* Corresponding author. Tel.: þ7 499 1359733; fax: þ7 499 1351405.
E-mail addresses: smikh@eimb.ru (S.N. Mikhailov), piet.herdewijn@rega.
kuleuven.ac.be (P. Herdewijn).
achieved and the 20-O-substituent was found to be stable during
oligoribonucleotide synthesis.20,21 This synthetic scheme is nearly
the same as for the preparation of disaccharide nucleosides and their
incorporation into ONs.22
y
Tel.: þ7 499 1359733; fax: þ7 499 1351405.
z
Tel.: þ32 16 337387; fax: þ32 16 337340.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.110

G.V. Bobkov et al. / Tetrahedron 64 (2008) 6238–6251
6239
DMTrO
N
B
MMTrO
B
MMTrO
B
O
O
O
O
O
O
O
O
O
NHCOCF3
O
O
P
P
N
P
N
NHCOCF3
NHCOCF3
O
O
O
CN
CN
CN
1
3
2
Figure 1. Structure of phosphoramidites 1,9 2, and 3. For 1: (a) B¼Ura, (b) B¼4-(1,2,4-triazol-1-yl)pyrimidin-2-one, (c) B¼GuaiBu, (d) B¼AdeiBu. For 2 and 3: (a) B¼Ura, (b) B¼CytBz
,
(c) B¼GuaiBu, (d) B¼AdeBz
.
2. Results and discussion
Here we present our recent results on the preparation of 20-O-(
aminoalkoxymethyl)ribonucleoside synthons (phosphoramidites
2 and 3, Fig. 1) suitable for automatic oligonucleotide synthesis.
The synthesis of aminoalkyl nucleosides is usually performed via
azido derivatives followed by reduction. Preparation of 20-O-(
u-
Different methods have been used for the conversion of an azido
group to an amino group, for example, hydrogenolysis, reduction
with metal hydrides, sulphide ions, or tin derivatives, reaction with
phosphines, and others. The most suitable method for obtaining
amino nucleosides appeared to be the reduction of an azido group
with H2 over Pd–C. To avoid the formation of undesirable N-acyl
by-products simultaneous N-(trifluoroacetylation) was carried out.
One-step reduction of 10a,b and 11a,b in the presence of an excess
of ethyl trifluoroacetate afforded 15a,b and 16a,b in 55–60% yields
after silica gel chromatography.
u
-
azidoalkoxymethyl)ribonucleosides 10 and 11 was realized in two
different ways (Scheme 1). In the first approach 20-O-(
u-acetoxy-
alkoxymethyl)uridines 6a and 7a,20 which were easily prepared
starting from 5a,b and uridine derivative 4a, were chosen as starting
compounds. The acetyl group was selectively removed with MeONa
In order to shorten and simplify the preparation of 20-O-(
u-
aminoalkoxymethyl)nucleosides we decided to prepare the acyclic
derivatives 17a,b. These compounds were easily synthesized
starting from aminoethanol and aminopropanol in three steps:
trifluoroacetylation, chloromethylation, and nucleophilic displace-
ment with acetate ion. The overall yields of acetals 17a,b were
around 65%.
Condensation of 17a,b with 30,50-O-blocked ribonucleosides
4a,b in the presence of tin tetrachloride in 1,2-dichloroethane at
ꢁ12 ꢀC for 20 min gave products 15a,b and 16a,b in the yields of
75–85% (Scheme 2). Guanosine derivative 15c was obtained in 48%
yield. In the case of preparation of 16c we could not separate the
product from the starting 4c in several solvent systems and the
formed mixture was used in the next step. During reaction with 4d
a complex mixture was formed evidently due to the instability of
N-glycoside bond during reaction in the presence of Lewis acid.23,24
So we decided to use N-unprotected adenosine 4e. The following
in methanol to yield 20-O-(
u-hydroxyalkoxymethyl)uridines 8a and
9a. Introduction of the azide functionality consisted in reaction
of the primary hydroxyl group with tosylchloride followed by
replacement with azide ion, without chromatographic separation of
the intermediate tosylate. The overall yield of azido nucleosides 10a
and 11a starting from 30,50-O-blocked uridines 4awas about 50–55%.
The preparation of azido nucleosides 10 and 11 was further
improved using AcOCH2O(CH2)nBr (n¼2, 3) (12a,b), which were
easily prepared starting from bromoethanol and bromopropanol via
their chloromethyl esters. Condensation of protected uridine and
cytidine derivatives 4a,b with 12a,b gave 20-O-(
methyl)ribonucleosides 13a,b and 14a,b in high yields (87–90%).
Treatment of the 20-O-(
-bromoalkoxymethyl)ribonucleosides
u-bromoalkoxy-
u
13a,b and 14a,b with NaN3 in DMF afforded azides 10a,b and 11a,b
in 88–92% yield.
OAc
Br
NHCOCF3
AcO
O
5a
AcO
O
AcO
AcO
O
12a
17a
AcO
O
OAc
AcO
O
Br
O
NHCOCF3
12b
17b
5b
B
O
O
O
Si
O
Si
Ura
Ura
O
O
Si
(ii)
(iii, iv)
O
O
O
Si
O
OCH2O(CH2)nCH2N3
Si
O
OCH2O(CH2)nCH2OH
Si
O
OCH2O(CH2)nCH2OAc
10 n=1
11 n=2
6 n=1
7 n=2
8 n=1
9 n=2
(v)
(iv)
a
+5
O
Si
B
B
O
Si
O
Si
B
O
O
O
(i)
+
12
O
O
O
Si
O
OCH2O(CH2)nCH2Br
Si
O
OCH2O(CH2)nCH2NHCOCF3
Si
O
OH
15 n=1
16 n=2
13 n=1
14 n=2
4
Scheme 1. (a) B¼Ura, (b) B¼CytBz. (i) SnCl4–1,2-dichloroethane, ꢁ12 ꢀC, 20 min; (ii) MeONa–methanol, 20 ꢀC, 30 min; (iii) TosCl–pyridine, 20 ꢀC, 16 h; (iv) NaN3–DMF, 80 ꢀC, 2 h; (v)
H2, Pd–C(10%)–dioxane, F3CO2Et–DBU, 20 ꢀC, 5 h.

6240
G.V. Bobkov et al. / Tetrahedron 64 (2008) 6238–6251
O
Si
O
Si
B
B
HO
B
O
O
O
(i)
(iii)
+
17
O
O
Si
O
OH
Si
O
OCH2O(CH2)nCH2NHCOCF3
HO
OCH2O(CH2)nCH2NHCOCF3
18 n=1
15 n=1,16 n=2
4
19 n=2
(iv)
15e, 16e
(ii)
15d, 16d
MMTrO
N
B
MMTrO
B
O
O
(v)
(vi)
O
O
OCH2O(CH2)nCH2NHCOCF3
ONs
HO
OCH2O(CH2)nCH2NHCOCF3
P
2 n=1
20 n=1
21 n=2
3 n=2
CN
Scheme 2. (a) B¼Ura, (b) B¼CytBz, (c) B¼GuaiBu, (d) B¼AdeBz, (e) B¼Ade. (i) SnCl4–dichloroethane, ꢁ12 ꢀC, 20 min (B¼Ura, CytBz), 40 min (B¼Ado, GuaiBu); (ii) BzCl–pyridine, 20 ꢀC,
2 h, 4% NH4OH, 20 ꢀC, 1 h; (iii) Bu4NF–THF, 20 ꢀC, 15 min; (iv) MMTrCl–Py, 20 ꢀC, 24 h; (e) iPr2NPCl(OCH2CH2CN), iPr2NEt–dichloromethane, 20 ꢀC, 4 h; (v) automatic oligonu-
cleotide synthesis.
Table 2
benzoylation of the formed nucleosides 15e and 16e gave desired
N-protected 15d and 16d in good yields (70–75%). The structure of
compounds 15 and 16 was established by NMR and mass spec-
troscopies. The 1H NMR spectra of nucleoside clearly indicate the
presence of the CF3CONHCH2– group, with the NH moiety
appearing as a broadened triplet. The signals at 157–158 ppm
(JC]O,F¼36–38 Hz) and 115–117 ppm (JC,F¼287–289 Hz) in the 13C
NMR spectrum confirm the presence of the CF3CO group in 15 and
16. It should be mentioned that some of the 1H NMR spectra of the
obtained compounds are rather complicated due to the overlap of
signals of the ribofuranose residue and the diastereotopic protons
of CH2OCH2CH2O and CH2OCH2CH2CH2O groups. The acetal group
appeared as two doublets around 5 ppm. In spite of this most of the
chemical shifts and coupling constants may be calculated directly
from NMR spectra. In some cases comparison with the published
Molecular mass measurements of oligoribonucleotides containing 20-O-
aminoalkoxymethylribonucleosides
Starting
synthon
Oligoribonucleotide
MS (Mþ
Calcd
)
Yield
OD260
Found
2a
50-GACGUAAACGGCCACAAGUU-dT-30
50-GACGUAAACGGCCACAAGUU-dT-30
50-ACUUGUGGCCGUUUACGUCG-dT-30
50-ACUUGUGGCCGUUUACGUCG-dT-30
50-ACUUGUGGCCGUUUACGUCG-dT-30
50-GACGUAAACGGCCACAAGUU-dT-30
50-GACGUAAACGGCCACAAGUU-dT-30
50-ACUUGUGGCCGUUUACGUCG-dT-30
50-ACUUGUGGCCGUUUACGUCG-dT-30
50-ACUUGUGGCCGUUUACGUCG-dT-30
6859.1
7078.2
6782.9
6856.0
6929.0
6887.1
7148.3
6811.0
6898.0
6985.1
6860.0
7079.0
6784.2
6857.3
6930.1
6888.0
7149.7
6812.3
6899.5
6986.6
65.3
73.8
61.4
55.7
70.4
53.7
69.1
33.3
33.7
28.7
2a, 2b
2a, 2b
2a, 2b
2a, 2b
3a
3a, 3b
3a, 3b
3a, 3b
3a, 3b
U: residue of 20-O-aminoalkoxymethyluridine; C: residue of 20-O-aminoalkoxy-
methylcytidine.
spectra of disaccharide nucleosides and double resonance, 1H–13
correlation and COSY spectra were used for the assignment.
C
monomethoxytrityl group was dictated by handling convenience
during the chemical manipulations but required an increase
in acidic deprotection time during oligonucleotide assembly (180 s
TCA vs 60 for DMTr groups) without further consequences.
The silyl group was deblocked with TBAF to yield the partially
protected nucleosides 18 and 19, which were converted using
standard procedures to the corresponding monomethoxytrityl
derivatives 20 and 21. The phosphitylation was carried out in
dichloromethane using freshly distilled diisopropylethylamine and
2-cyanoethyl N,N-diisopropylchlorophosphoramidite under argon
to afford 2 and 3 in high overall yields (Table 1). The choice for the
With these phosphoramidites (2 and 3), several oligo-
ribonucleotides with one or more modifications were assembled,
using commercial fast deprotecting tBDMSi amidites for the natural
nucleosides. Trityl yields were excellent, even with multiple in-
corporations of the modified building blocks. For deprotection of
the modified RNAs a 1:1 ammonia–methylamine cocktail in water
was used, followed by a 1 M TBAF treatment. All oligos were pu-
rified by ion exchange chromatography, desalted by gel filtration,
and analyzed by mass spectrometry (Table 2). Only the main part of
the product-containing peak was collected, affording in general at
Table 1
Overall yields of phosphoramidites 1,9 2, and 3
Starting
compounds
Product
Overall
yield (%)
Number
of steps
Urd
Urd
2-Amino-Ado
Ado
4aþ5a
1a
1f
16.6
8.3
5.7
12
13
12
11
8
8
6
6
6
6
4
4
4
4
4
4
5
least 25 up to 70 OD260 starting from a 1 mmol loaded support (see
1c
1e
2a
3a
2a
3a
2b
3b
2a
3a
2b
3b
2c
3c
2d
3d
Table 2 for isolated yields). A figure with the crude profile for both
sequences containing five modifications is shown as an example for
the straightforward incorporation of the new congeners, with the
peak for the full length sequence being strongly predominant (see
Supplementary data). Incorporation of the purine phosphor-
amidites 2 and 3 proved straightforward as well and these results
will be published elsewhere.
12.1
15.6
18.9
26.1
28.1
26.3
26.7
46.3
49.7
45.1
48.5
29.7
28.0
22.2
24.3
4aþ5b
4aþ12a
4aþ12b
4bþ12a
4bþ12b
4aþ17a
4aþ17b
4bþ17a
4bþ17b
4cþ17a
4cþ17b
4eþ17a
4eþ17b
3. Conclusion
The general method for the preparation of 20-O-
furanosylnucleosides and 20-O-(
-hydroxyalkoxymethyl)ribo-
nucleosides was found to be applicable to the synthesis of
b-D-ribo-
u
5

G.V. Bobkov et al. / Tetrahedron 64 (2008) 6238–6251
6241
20-O-(
u
-aminoalkoxymethyl)ribonucleosides. The 20-O-substituent
96.52 (C-5), 91.99 (C-10), 82.25 (C-40), 75.36 (C-20), 68.89 (C-30),
was found to be stable during oligonucleotide synthesis. We have
described efficient experimental procedures for synthesizing all
four standard RNA nucleoside phosphoramidites, having amino-
linkers at 20-position. The synthetic routes are maximallyconvergent
and provide sufficient amounts of phosphoramidites for several
solid-phase synthesis coupling reactions. Using acyclic derivatives
17a,b the overall yields of 2 and 3 were increased up to 50% for
pyrimidine nucleosides and up to 30% for purine derivatives with
substantial decrease of total reaction steps (Table 1). The resulting
oligonucleotides are of particular interest for post-synthetic func-
tionalization and conjugation. In addition, although not evaluated
here, in general introduction of amine moieties at the 20-O-position
further increases the stability of duplexes with both DNA and RNA
complementary sequences, as recently shown again by Engels
et al.25
60.32 (C-50), 17.57, 17.52, 17.42, 17.14, 16.97, 13.54, 13.09, 12.69 (iPr).
4.4. 9-[3,5-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)-
b-D-
ribofuranosyl]-N2-isobutyrylguanine (4c)
Rf 0.29 (A). 1H NMR (CDCl3): 12.13 (br s, 1H, NH Guo), 9.41 (br s,
0
0
0
1H, NHiBu), 7.92 (s, 1H, H-8), 5.84 (d, 1H, J1 ,2 ¼1.20, H-1 ), 4.52 (dd,
0
0
0
0
0
1H, J3 ,2 ¼5.2, J3 ,4 ¼7.6, H-3 ), 4.31 (dd, 1H, H-2 ), 4.14 (dd, 1H,
J5 a,4 ¼2.8, J5 a,5 b¼ꢁ12.4, H-50a), 4.10 (ddd, 1H, J4 ,5 b¼2.5, H-40), 4.05
(dd, 1H, H-50b), 3.55 (br s, 1H, OH), 2.76 (sept, 1H, J¼6.9, iBu), 1.25
(m, 6H, iBu), 1.08–0.98 (m, 28H, iPr). 13C NMR (CDCl3): 179.06
(C]O), 155.76 (C6), 147.97 (C2), 147.74 (C4), 136.82 (C8), 121.72 (C5),
88.97 (C10), 81.99 (C40), 75.40 (C20), 70.06 (C30), 61.07 (C50), 36.54
(iBu), 19.15, 19.08 (iBu) 17.55, 17.39, 17.20, 17.08, 16.97, 13.49, 13.11,
13.04, 12.69 (iPr).
0
0
0
0
0
0
4. Experimental
4.1. General
4.5. 9-[3,5-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)-
b-D-
ribofuranosyl]-N6-benzoyladenine (4d)
Rf 0.34 (A). 1H NMR (CDCl3): 9.07 (br s, 1H, NHBz), 8.15 (s, 1H,
0
0
Column chromatography (CC) was performed on silica gel
Kieselgel 60 (0.063–0.200 mm, Merck). (0.040–0.063 mm), TLC was
carried out on Kieselgel 260 F (Merck) with detection by UV and the
following solvent systems (compositions expressed as v/v): methy-
lene chloride–ethanol 95:5 (A); methylene chloride–ethanol 9:1
(B); hexane–acetone–triethylamine 49:49:2 (C), detection by
UV light and iodine vapors. NMR spectra: Bruker AMX 400 NMR
spectrometers and Bruker Avance 300 NMR spectrometers; at
H-8), 8.74 (s, 1H, H-2), 8.03–7.51 (m, 5H, Bz), 6.03 (d, 1H, J1 ,2 ¼1.02,
H-10), 5.10 (dd, 1H, J3 ,2 ¼5.5, J3 ,4 ¼7.7, H-3 ), 4.63 (dd, 1H, H-2 ),
4.14–4.05 (m, 3H, H-40, H-50a, H-50b), 1.13–1.07 (m, 28H, iPr). 13C
NMR (CDCl3): 163.86 (C]O), 152.69 (C2), 151.18 (C6), 149.81 (C4),
142.12 (C8), 133.83, 132.91, 128.99, 128.04 (Ph), 123.85 (C5), 90.00
(C10), 82.47 (C40), 75.23 (C20), 71.05 (C30), 61.89 (C50), 17.55, 17.49,
17.40, 17.24, 17.13, 13.43, 13.19, 12.93, 12.80 (iPr).
0
0
0
0
0
300 K. Chemical shifts
d
in parts per million were measured relative
4.6. 9-[3,5-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)-b-D-
to the solvent signals (1H and 13C) and relative external refer-
ence¼H3PO4 capil. (31P). The coupling constants (J) are given in
hertz. The signals were assigned using double resonance tech-
niques, COSY and HSQC experiments. Mass spectrometry and exact
mass measurements of the nucleoside intermediates were per-
formed on a quadrupole/orthogonal-acceleration time-of-flight
tandem mass spectrometer (Q-Tof-2, Micromass, Manchester, UK)
equipped with a standard electrospray ionization (ESI) interface.
ESI spectra for the modified ONs were obtained by coupling the
Q-Tof-2 to a capillary HPLC (CapLC, Waters, Milford, MA). Masses
were obtained by deconvolution of the spectra using the MaxEnt
1 algorithm (MassLynx 3.4, Micromass, Manchester, UK).
ribofuranosyl]adenine (4e)
Rf 0.21 (A). 1H NMR (DMSO-d6): 8.21 (s, 1H, H-2), 8.08 (s, 1H, H-
8), 7.33 (s, 2H, NH2), 5.87 (s, 1H, H-10), 5.62 (d, 1H, J2 OH¼4.6, OH-20),
0
0
0
0
0
0
0
4.80 (dd, 1H, J3 ,2 ¼4.9, J3 ,4 ¼8.5, H-3 ), 4.52 (dd, 1H, H-2 ), 4.06 (dd,
1H, J5 a,4 ¼3.1, J5 a,5 b¼ꢁ12.3, H-50a), 3.99 (ddd, 1H, J4 ,5 b¼2.1, H-40),
3.93 (dd, 1H, H-50b), 1.12–0.92 (m, 28H, iPr). 13C NMR (DMSO-d6):
156.09 (C6), 152.48 (C8), 148.62 (C4), 139.20 (C2), 119.25 (C5), 89.33
(C10), 80.75 (C40), 73.64 (C20), 69.81 (C30), 60.80 (C50), 17.36, 17.16,
17.00, 16.91, 16.82, 12.73, 12.44, 12.23, 12.06 (iPr).
0
0
0
0
0
0
4.7. Diacetate of 2-oxa-1,4-butanediol (5a)27
30,50-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)nucleosides (4)
were prepared according to literature.26
1H NMR (CDCl3): 5.25 (s, 2H, OCH2O), 4.18 (t, 2H, J¼4.8, OCH2
-
CH2OAc), 3.80 (t, 2H, OCH2CH2OAc), 2.06 (s, 3H, Ac), 2.04 (s, 3H, Ac).
13C NMR (CDCl3): 170.87, 170.46 (C]O), 89.16 (OCH2O), 68.24
(OCH2CH2OAc), 63.25 (OCH2CH2OAc), 21.00, 20.86 (Me).
4.2. 1-[3,5-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)-b-D-
ribofuranosyl]uracil (4a)
Rf 0.33 (A). 1H NMR (CDCl3): 8.52 (br s, 1H, NH), 7.66 (d, 1H,
J6,5¼8.1, H-6), 5.72 (s, 1H, H-10), 5.67 (dd, 1H, J5,NH¼1.8, H-5), 4.38
4.8. Diacetate of 2-oxa-1,5-pentanediol (5b)27
(dd, 1H, J3 ,2 ¼4.7, J3 ,4 ¼8.7, H-30), 4.19 (dd, 1H, J5 a,4 ¼2.2,
1H NMR (CDCl3): 5.17 (s, 2H, OCH2O), 4.07 (t, 2H, J¼6.4,
OCH2CH2CH2OAc), 3.63 (t, 2H, J¼6.4, OCH2CH2CH2OAc), 2.01 (s, 3H,
Ac), 1.97 (s, 3H, Ac),1.83 (p, 2H, OCH2CH2CH2OAc). 13C NMR (CDCl3):
170.98, 170.56 (C]O), 89.26 (OCH2O), 66.99 (OCH2CH2CH2OAc),
61.28 (OCH2CH2CH2OAc), 28.97 (OCH2CH2CH2OAc), 21.01, 20.91
(Me).
0
0
0
0
0
0
J5 a,5 b¼ꢁ13.1, H-50a), 4.17 (d, 1H, H-20), 4.09 (ddd, 1H, J4 ,5 b¼2.8, H-
40), 4.01 (dd, 1H, H-50b), 1.09–1.02 (m, 28H, iPr). 13C NMR (CDCl3):
163.43 (C-4), 150.21 (C-2), 140.15 (C-6), 102.13 (C-5), 91.24 (C-10),
82.14 (C-40), 75.32 (C-20), 69.26 (C-30), 60.58 (C-50), 17.58, 17.47,
17.40, 17.24, 17.15, 16.97, 13.54, 13.11, 12.72 (iPr).
0
0
0
0
4.3. 1-[3,5-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)-
b-D
-
4.9. 1-{2-O-[(2-Hydroxyethoxy)methyl]-3,5-O-(1,1,3,3-
ribofuranosyl]-N4-benzoylcytosine (4b)
tetraisopropyldisiloxane-1,3-diyl)-b-D-ribofuranosyl}-
uracil (8a)
Rf 0.34 (A). 1H NMR (CDCl3): 8.85 (br s, 1H, NH), 8.22 (d, 1H,
J6,5¼7.5, H-6), 7.92–7.50 (m, 6H, Bz, H-5), 5.84 (s, 1H, H-10), 4.35 (dd,
To a solution of nucleoside 6a (275 mg, 0.46 mmol) in dry
methanol (5 ml) 0.3 M sodium methylate (3 ml) was added and the
solution was kept for 30 min at room temperature and then 1 M
acetic acid in methanol was added to pH 7.0. The reaction mixture
was concentrated in vacuo to near dryness and the residue was
0
0
0
0
0
0
0
0
0
1H, J3 ,2 ¼4.6, J3 ,4 ¼8.9, H-3 ), 4.28 (dd, 1H, J5 a,4 ¼1.8, J5 a,5 b¼ꢁ13.4,
H-50a), 4.26 (d, 1H, H-20), 4.21 (dd, 1H, J4 ,5 b¼2.8, H-40), 4.01 (dd, 1H,
H-50b), 1.11–1.00 (m, 28H, iPr). 13C NMR (CDCl3): 165.78 (C]O),
162.63 (C-4), 154.33 (C-2), 144.78 (C-6), 133.29, 129.13, 127.82 (Ph),
0
0

6242
G.V. Bobkov et al. / Tetrahedron 64 (2008) 6238–6251
0
0
0
0
partitioned between ethyl acetate (100 ml) and water (40 ml),
the organic layer was washed with water (2ꢂ20 ml), dried over
anhydrous sodium sulfate, evaporated to dryness, and purified by
column chromatography on silica gel (30 g, dry application). The
column was washed with methylene chloride (150 ml), methylene
chloride–ethanol 99:1 (100 ml) and then eluted with methylene
chloride–ethanol 98:2 to give 8a as a powder. Yield 183 mg (71%).
Rf 0.30 (A). 1H NMR (DMSO-d6): 11.41 (br s, 1H, NH), 7.66 (d, 1H,
J6,5¼8.1, H-6), 5.59 (s, 1H, H-10), 5.52 (d, 1H, H-5), 4.91 (d, 1H,
J¼ꢁ6.5, OCHHO), 4.83 (d, 1H, OCHHO), 4.61 (t, 1H, JOH0 ,H¼5.4, OH),
OCHHO), 4.25 (d, 1H, J5 a,5 b¼ꢁ13.7, H-50a), 4.23 (dd, 1H, J3 ,2 ¼4.4,
J3 ,4 ¼9.2, H-3 ), 4.21 (d, 1H, H-2 ), 4.13 (dd, 1H, J4 ,5 b¼2.2, H-40),
3.99 (dd, 1H, H-50b), 3.93–3.88 (m, 1H, OCHHCH2N3), 3.81–3.76
(m, 1H, OCHHCH2N3), 3.51–3.39 (m, 2H, OCH2CH2N3), 1.11–1.02 (m,
28H, iPr). 13C NMR (CDCl3): 163.37 (C4), 150.12 (C2), 139.34 (C6),
101.85 (C5), 94.73 (OCH2O), 89.48 (C10), 81.96 (C40), 78.12
(C20), 68.44 (C30), 66.98 (OCH2CH2N3), 59.54 (C50), 50.91
(OCH2CH2N3), 17.62, 17.52, 17.45, 17.32, 17.23, 17.10, 16.96, 13.60,
13.25, 13.05, 12.80 (iPr). LSI-MS (C24H43N5O8Si2þHþ): 586.2719.
Calcd 586.2728.
0
0
0
0
0
0
0
0
0
0
0
4.31 (d, 1H, J2 ,3 ¼4.9, H-2 ), 4.25 (dd, 1H, J3 ,4 ¼9.3, H-3 ), 4.15 (d, 1H,
J5 a,5 b¼ꢁ13.7, H-50a), 3.98 (dd, 1H, J4 ,5 b¼2.0, H-40), 3.91 (dd, 1H, H-
4.11.2. Method B
0
0
0
0
50b), 3.63–3.55 (m, 2H, OCH2CH2OH), 3.53–3.46 (m, 2H, OCH2
To a solution of nucleoside 13a (715 mg, 1.15 mmol) in dimethyl
formamide (20 ml) sodium azide (112 mg, 1.73 mmol) was added.
The reaction mixture was heated under stirring at 80 ꢀC for 2 h and,
after cooling to room temperature, diluted with diethyl ether
(50 ml) and washed with 10% aqueous solution of sodium hydrogen
carbonate (20 ml) and water (2ꢂ20 ml). The organic layer was
dried over anhydrous sodium sulfate, evaporated in vacuo, and
purified by column chromatography on silica gel (30 g). The column
was washed with methylene chloride (200 ml) and then eluted
with methylene chloride–ethanol 99:1 to give 10a as a foam. Yield
640 mg (96%).
-
CH2OH), 1.05–0.99 (m, 28H, iPr). 13C NMR (DMSO-d6): 163.35 (C4),
150.09 (C2), 139.49 (C6), 101.06 (C5), 93.80 (OCH2O), 89.22 (C10),
81.08 (C40), 77.19 (C20), 69.37 (OCH2CH2OH), 68.11 (C30), 60.07
(OCH2CH2OH), 59.71 (C50), 17.38, 17.28, 17.23, 17.15, 17.03, 16.91,
16.86, 12.70, 12.37, 12.02 (iPr). LSI-MS (C24H44N2O9Si2þHþ):
561.2655. Calcd 561.2664.
4.10. 1-{2-O-[(3-Hydroxypropoxy)methyl]-3,5-O-(1,1,3,3-
tetraisopropyldisiloxane-1,3-diyl)-
uracil (9a)
b-D-ribofuranosyl}-
Analogous deacylation of 7a (1.02 g, 1.66 mmol) yielded 9a as
a powder (720 mg, 76%). Rf 0.30 (A). 1H NMR (CDCl3): 9.92 (br s,
1H, NH), 7.89 (d, 1H, J6,5¼8.1, H-6), 5.75 (s, 1H, H-10), 5.68 (d, 1H,
H-5), 5.01 (d, 1H, J¼ꢁ6.7, OCHHO), 4.90 (d, 1H, OCHHO), 4.25 (d,
4.12. 1-{2-O-[(2-Azidoethoxy)methyl]-3,5-O-(1,1,3,3-
tetraisopropyldisiloxane-1,3-diyl)-
benzoylcytosine (10b)
b-D
-ribofuranosyl}-N4-
1H, J5 a,5 b¼ꢁ13.4, H-50a), 4.21 (m, 2H, H-20, H-30), 4.13 (dd, 1H,
Analogous conversion of 13b (625 mg, 0.86 mmol) yielded 10b
as a foam (560 mg, 94%). Rf 0.39 (A). 1H NMR (CDCl3): 8.75 (br s, 1H,
NH), 8.33 (d, 1H, J6,5¼7.5, H-6), 7.92–7.48 (m, 6H, Bz, H-5), 5.83 (s,
1H, H-10), 5.07 (d,1H, J¼ꢁ6.7, OCHHO), 5.04 (d,1H, OCHHO), 4.29 (d,
0
0
J4 ,3 ¼9.0, J4 ,5 b¼2.0, H-40), 4.01 (m, 1H, OCHHCH2CH2OH), 3.97 (dd,
1H, H-50b), 3.80–3.59 (m, 3H, OCHHCH2CH2OH), 1.90–1.82 (m, 2H,
OCH2CH2CH2OH), 1.10–0.95 (m, 28H, iPr). 13C NMR (CDCl3): 163.55
(C4), 150.47 (C2), 139.28 (C6), 102.04 (C5), 94.89 (OCH2O), 89.56
(C10), 81.97 (C40), 77.72 (C20), 68.52 (C30), 65.98 (OCH2CH2CH2OH),
60.13 (OCH2CH2CH2OH), 59.50 (C50), 32.56 (OCH2CH2CH2OAc),
17.58, 17.50, 17.41, 17.32, 17.22, 17.06, 16.93, 13.54, 13.22, 12.99,
12.71 (iPr). LSI-MS (C25H46N2O9Si2þHþ): 575.2811. Calcd
575.2820.
0
0
0
0
0
1H, J5 a,5 b¼ꢁ13.7, H-50a), 4.27 (d, 1H, J2 ,3 ¼3.4, H-2 ), 4.22 (dd, 1H,
0
0
0
0
J3 ,4 ¼9.6, H-3 ), 4.21 (dd, 1H, J4 ,5 b¼1.6, H-40), 4.03–3.97 (m, 2H, H-
50b, OCHHCH2N3), 3.83–3.77 (m, 1H, OCHHCH2N3), 3.56–3.50 (m,
1H, OCH2CHHN3), 3.45–3.39 (m, 1H, OCH2CHHN3), 1.12–0.99 (m,
28H, iPr). 13C NMR (CDCl3): 167.09 (C]O), 162.46 (C4), 154.52 (C2),
144.45 (C6), 133.33, 129.18, 127.74 (Ph), 96.21 (C5), 94.81 (OCH2O),
90.53 (C10), 82.09 (C40), 77.75 (C20), 68.24 (C30), 66.93 (OCH2CH2N3),
59.55 (C50), 51.00 (OCH2CH2N3),17.61,17.55,17.42,17.21,17.08,16.98,
13.59, 13.25, 13.06, 12.82 (iPr). LSI-MS (C31H48N6O8Si2þHþ):
689.3136. Calcd 689.3150.
0
0
0
0
0
4.11. 1-{2-O-[(2-Azidoethoxy)methyl]-3,5-O-(1,1,3,3-
tetraisopropyldisiloxane-1,3-diyl)-
uracil (10a)
b-D-ribofuranosyl}-
4.11.1. Method A
4.13. 1-{2-O-[(3-Azidopropoxy)methyl]-3,5-O-(1,1,3,3-
To a solution of nucleoside 8a (650 mg, 1.16 mmol) in 1,2-
dichloroethane (15 ml) tosylchloride (550 mg, 2.90 mmol) and
pyridine (5 ml) were added. The reaction mixture was maintained
at room temperature for 16 h and methanol (1 ml) was added. The
reaction mixture was stirred at room temperature for 30 min and
concentrated in vacuo to near dryness. The residue was dissolved
in methylene chloride (50 ml) and washed with 10% aqueous so-
lution of sodium hydrogen carbonate (20 ml) and water (2ꢂ20 ml).
The organic layer was dried over anhydrous sodium sulfate,
evaporated in vacuo, and evaporated with toluene (2ꢂ10 ml). The
residue was dissolved in dimethyl formamide (20 ml) and sodium
azide (110 mg, 1.75 mmol) was added. The reaction mixture was
heated under stirring at 80 ꢀC for 2 h and, after cooling to room
temperature, diluted with diethyl ether (50 ml) and washed with
10% aqueous solution of sodium bicarbonate (20 ml) and water
(2ꢂ20 ml). The organic layer was dried over sodium sulfate,
evaporated in vacuo, and purified by column chromatography on
silica gel (30 g). The column was washed with methylene chloride
(200 ml) and then eluted with methylene chloride–ethanol 99:1 to
give 10a as a foam. Yield 560 mg (82%). Rf 0.38 (A). 1H NMR
(CDCl3): 9.07 (br s, 1H, NH), 7.87 (d, 1H, J6,5¼8.1, H-6), 5.75 (s, 1H,
H-10), 5.68 (d, 1H, H-5), 5.01 (d, 1H, J¼ꢁ6.8, OCHHO), 4.99 (d, 1H,
tetraisopropyldisiloxane-1,3-diyl)-
uracil (11a)
b-D-ribofuranosyl}-
4.13.1. Method A
Analogous conversion of 9a (693 mg, 1.21 mmol) yielded 11a as
a foam (730 mg, 85%).
Rf 0.38 (A). 1H NMR (CDCl3): 8.96 (br s, 1H, NH), 7.88 (d, 1H,
J6,5¼8.1, H-6), 5.75 (s, 1H, H-10), 5.67 (d, 1H, H-5), 4.98 (d, 1H,
0
0
J¼ꢁ6.7, OCHHO), 4.94 (d, 1H, OCHHO), 4.26 (d, 1H, J5 a,5 b¼ꢁ13.6, H-
50a), 4.22 (dd, 1H, J3 ,2 ¼4.4, J3 ,4 ¼9.4, H-3 ), 4.17 (d, 1H, H-2 ), 4.13
0
0
0
0
0
0
(dd, 1H, J4 ,5 b¼2.2, H-40), 3.98 (dd, 1H, H-50b), 3.80–3.68 (m, 2H,
OCH2CH2CH2N3), 3.40 (t, 2H, J¼6.6, OCH2CH2CH2N3), 1.88 (m, 2H,
OCH2CH2CH2N3), 1.11–1.02 (m, 28H, iPr). 13C NMR (CDCl3): 163.39
(C4), 150.03 (C2), 139.45 (C6), 101.76 (C5), 94.74 (OCH2O), 89.48
(C10), 82.01 (C40), 78.26 (C20), 68.33 (C30), 65.22 (OCH2CH2CH2N3),
59.57 (C50), 48.71 (OCH2CH2CH2N3), 29.12 (OCH2CH2CH2N3), 17.62,
17.53, 17.45, 17.36, 17.24, 17.10, 16.96, 13.50, 13.27, 13.05, 12.80 (iPr).
LSI-MS (C25H45N5O8Si2þHþ): 600.2880. Calcd 600.2885.
0
0
4.13.2. Method B
Analogous conversion of 14a (892 mg, 1.40 mmol) yielded 11a as
a foam (812 mg, 97%).

G.V. Bobkov et al. / Tetrahedron 64 (2008) 6238–6251
6243
4.14. 1-{2-O-[(3-Azidopropoxy)methyl]-3,5-O-(1,1,3,3-
OCH2CH2CH2Br), 2.08 (tt, 2H, OCH2CH2CH2Br), 2.06 (s, 3H, Ac). 13
C
NMR (CDCl3): 170.48 (C]O), 89.13 (OCH2O), 67.65 (OCH2CH2CH2Br),
32.64 (Me), 29.99 (OCH2CH2CH2Br), 21.02 (OCH2CH2CH2Br).
tetraisopropyldisiloxane-1,3-diyl)-
benzoylcytosine (11b)
b-D
-ribofuranosyl}-N4-
Analogous conversion of 14b (1.04 g, 1.41 mmol) yielded 11b as
a foam (920 mg, 93%). Rf 0.39 (A). 1H NMR (CDCl3): 8.75 (br s, 1H,
NH), 8.35 (d, 1H, J6,5¼7.5, H-6), 7.91–7.45 (m, 6H, Bz, H-5), 5.85 (s,
1H, H-10), 5.08 (d, 1H, J¼ꢁ6.5, OCHHO), 4.99 (d, 1H, OCHHO), 4.31
4.17. 1-{2-O-[(2-Bromoethoxy)methyl]-3,5-O-(1,1,3,3-
tetraisopropyldisiloxane-1,3-diyl)-b-D-ribofuranosyl}-
uracil (13a)
(d, 1H, J5 a,5 b¼ꢁ13.4, H-50a), 4.28–4.20 (m, 3H, H-20, H-30, H-40),
4.02 (d, 1H, H-50b), 3.87–3.81 (m, 1H, OCHHCH2CH2N3), 3.77–3.71
(m, 1H, OCHHCH2CH2N3), 3.42 (t, 2H, J¼6.7, OCH2CH2CH2N3), 1.90
(m, 2H, OCH2CH2CH2N3), 1.13–0.99 (m, 28H, iPr). 13C NMR (CDCl3):
167.25 (C]O), 162.94 (C4), 154.27 (C2), 144.69 (C6), 133.31, 128.98,
128.09 (Ph), 96.41 (C5), 94.67 (OCH2O), 90.35 (C10), 82.08 (C40),
77.80 (C20), 67.82 (C30), 65.10 (OCH2CH2CH2N3), 59.46 (C50), 48.68
(OCH2CH2CH2N3), 29.08 (OCH2CH2CH2N3), 17.61, 17.55, 17.42, 17.21,
17.09, 13.51, 13.20, 12.97, 12.65 (iPr). LSI-MS (C32H50N6O8Si2þHþ):
703.3295. Calcd 703.3307.
To a cool solution (ꢁ15 ꢀC) under nitrogen of nucleoside 4a
(973 mg, 2.0 mmol) and (2-bromoethoxy)methyl acetate (12a)
(788 mg, 4.0 mmol) in 1,2-dichloroethane (20 ml) tin tetrachloride
(0.36 ml, 3.0 mmol) was added and the solution was kept at ꢁ12 ꢀC
for 20 min. A 10% aqueous solution of sodium hydrogen carbonate
(10 ml) and methylene chloride (20 ml) were added and the sus-
pension was stirred at 0 ꢀC for 20 min. The suspension was filtered
through Hyflo Super Cel, organic layer was separated, washed with
water (20 ml), dried over anhydrous sodium sulfate, and evapo-
rated to dryness. The residue was purified by column chromatog-
raphy on silica gel (30 g). The column was washed with methylene
chloride (200 ml) and methylene chloride–ethanol 99:1 (200 ml),
and then eluted with methylene chloride–ethanol 98:2 to give 13a
as a foam. Yield 1.10 g (87%). Rf 0.36 (A). 1H NMR (CDCl3): 9.05 (br s,
1H, NH), 7.86 (d, 1H, J6,5¼8.3, H-6), 5.73 (s, 1H, H-10), 5.66 (dd, 1H,
J5,NH¼1.1, H-5), 5.02 (d, 1H, J¼ꢁ6.8, OCHHO), 4.97 (d, 1H, OCHHO),
0
0
4.15. (2-Bromoethoxy)methyl acetate (12a)
The mixture of 2-bromoethanol (150 g, 1.20 mol) and para-
formaldehyde (43 g, 1.43 mol) in methylene chloride (200 ml) was
cooled in an ice bath under stirring. Anhydrous hydrogen chloride
was bubbled through the mixture for 3 h. The reaction mixture was
allowed up to room temperature and two clear homogeneous
layers were separated. The organic layer was dried over anhydrous
calcium chloride and concentrated on a rotary evaporator to liquid.
The residue was distilled under diminished pressure (10–
11 mmHg). The fraction with boiling temperature 82–87 ꢀC was
collected to give 1-bromo-2-(chloromethoxy)ethane. Yield 170 g
(82%). 1H NMR (CDCl3): 5.51 (s, 2H, OCH2Cl), 4.00 (t, 2H, J¼6.1,
OCH2CH2Br), 3.51 (t, 2H, OCH2CH2Br). 13C NMR (CDCl3): 82.38
(OCH2Cl), 70.18 (OCH2CH2Br), 29.12 (OCH2CH2Br). The obtained 1-
bromo-2-(chloromethoxy)ethane was dissolved in benzene
(200 ml) and potassium acetate (180 g, 1.8 mol) was added. The
mixture was stirred at 50 ꢀC for 4 h. The precipitate was filtered off;
the filtrate was concentrated on a rotary evaporator to liquid. The
residue was dissolved in ethyl acetate (100 ml) and washed with
10% aqueous solution of sodium hydrogen carbonate (50 ml) and
water (2ꢂ50 ml). The organic layer was dried over anhydrous so-
dium sulfate and concentrated on a rotary evaporator to liquid. The
residue was distilled under diminished pressure (10–11 mmHg).
The fraction with boiling temperature 112–117 ꢀC was collected to
give (2-bromoethoxy)methyl acetate (12a). Literature data:28 80–
82 ꢀC (5 mmHg). Yield 163 g (84% to 1-bromo-2-(chloro-
methoxy)ethane). Yield for two steps 69%. 1H NMR (CDCl3): 5.30 (s,
2H, OCH2O), 3.95 (t, 2H, J¼6.2, OCH2CH2Br), 3.47 (t, 2H,
OCH2CH2Br), 2.10 (s, 3H, Ac). 13C NMR (CDCl3): 170.55 (C]O), 89.06
(OCH2O), 70.47 (OCH2CH2Br), 30.02 (Me), 21.14 (OCH2CH2Br).
4.24 (d, 1H, J5 a,5 b¼ꢁ13.5, H-50a), 4.21 (dd, 1H, J3 ,2 ¼4.4, J3 ,4 ¼9.2,
0
0
0
0
0
0
H-30), 4.19 (d, 1H, H-20), 4.12 (dd, 1H, J4 ,5 b¼1.7, H-40), 4.05–3.99 (m,
1H, OCHHCH2Br), 3.97 (dd, 1H, H-50b), 3.96–3.90 (m, 1H,
OCHHCH2Br), 3.52 (t, 2H, J¼6.2, OCH2CH2Br), 1.15–0.87 (m, 28H,
iPr). 13C NMR (CDCl3): 163.57 (C4), 150.15 (C2), 139.35 (C6), 101.83
(C5), 94.63 (OCH2O), 89.35 (C10), 81.95 (C40), 78.34 (C20), 68.34 (C30),
68.19 (OCH2CH2Br), 59.47 (C50), 30.59 (OCH2CH2Br), 17.61, 17.51,
17.44, 17.33, 17.24, 17.07, 16.97, 13.53, 13.25, 13.02, 12.77 (iPr). LSI-MS
(C24H43BrN2O8Si2þHþ): 623.1801. Calcd 623.1820.
0
0
4.18. 1-{2-O-[(2-Bromoethoxy)methyl]-3,5-O-(1,1,3,3-
tetraisopropyldisiloxane-1,3-diyl)-
benzoylcytosine (13b)
b-D
-ribofuranosyl}-N4-
Analogous (see preparation of 13a) condensation of (2-bro-
moethoxy)methyl acetate (12a) (788 mg, 4.0 mmol) in the presence
of tin tetrachloride (0.36 ml, 3.0 mmol) with nucleoside 4b (1.18 g,
2.0 mmol) in 1,2-dichloroethane (20 ml) at ꢁ12 ꢀC for 20 min gave
13b as a foam. Yield 1.28 g (88%). Rf 0.36 (A). 1H NMR (CDCl3): 8.84
(br s, 1H, NH), 8.34 (d, 1H, J6,5¼7.5, H-6), 7.91–7.47 (m, 6H, Bz, H-5),
5.82 (s, 1H, H-10), 5.12 (d, 1H, J¼ꢁ6.8, OCHHO), 5.01 (d, 1H, OCHHO),
4.29 (d, 1H, J5 a,5 b¼ꢁ13.5, H-50a), 4.27 (d, 1H, J2 ,3 ¼2.8, H-2 ), 4.20
0
0
0
0
0
(m, 2H, H-30, H-40), 4.12–4.06 (m, 1H, OCHHCH2Br), 4.01 (dd, 1H,
0
0
0
J5 b,4 ¼1.8, H-5 b), 3.98–3.92 (m, 1H, OCHHCH2Br), 3.55 (t, 2H, J¼6.4,
OCH2CH2Br), 1.11–0.98 (m, 28H, iPr). 13C NMR (CDCl3): 166.89
(C]O), 162.49 (C4), 154.50 (C2), 144.43 (C6), 133.34, 129.18, 127.73
(Ph), 96.24 (C5), 94.74 (OCH2O), 90.42 (C10), 82.09 (C40), 78.07 (C20),
68.35 (C30), 67.98 (OCH2CH2Br), 59.52 (C50), 30.73 (OCH2CH2Br),
17.61, 17.43, 17.15, 17.00, 13.54, 13.04, 12.80 (iPr). LSI-MS
(C31H48BrN3O8Si2þHþ): 726.2235. Calcd 726.2242.
4.16. (3-Bromopropoxy)methyl acetate (12b)
Analogous conversion of 3-bromopropanol (52 g, 0.37 mol) yiel-
ded (3-bromopropoxy)methyl acetate (12b) as a liquid (59 g, 76%).
4.19. 1-{2-O-[(3-Bromopropoxy)methyl]-3,5-O-(1,1,3,3-
4.16.1. 1-Bromo-3-(chloromethoxy)propane
tetraisopropyldisiloxane-1,3-diyl)-b-D-ribofuranosyl}-
Bp 85–89 ꢀC (10–11 mmHg). 1H NMR (CDCl3): 5.48 (s, 2H,
OCH2Cl), 3.82 (t, 2H, J¼5.9, OCH2CH2CH2Br), 3.47 (t, 2H, J¼6.5,
OCH2CH2CH2Br), 2.15 (tt, 2H, OCH2CH2CH2Br). 13C NMR (CDCl3):
83.01 (OCH2Cl), 68.08 (OCH2CH2CH2Br), 32.19 (OCH2CH2CH2Br),
29.76 (OCH2CH2CH2Br).
uracil (14a)
Analogous (see preparation of 13a) condensation of (3-bromo-
propoxy)methyl acetate (12b) (844 mg, 4.0 mmol) in the presence
of tin tetrachloride (0.36 ml, 3.0 mmol) with nucleoside 4a
(973 mg, 2.0 mmol) in 1,2-dichloroethane (20 ml) at ꢁ12 ꢀC for
20 min gave 14a as a foam. Yield 1.08 g (85%). Rf 0.36 (A). 1H NMR
(CDCl3): 8.99 (br s, 1H, NH), 7.88 (d, 1H, J6,5¼8.1, H-6), 5.75 (s, 1H, H-
10), 5.67 (d, 1H, H-5), 4.98 (d, 1H, J¼ꢁ6.7, OCHHO), 4.94 (d, 1H,
4.16.2. (3-Bromopropoxy)methyl acetate (12b)
Bp 118–122 ꢀC (10–11 mmHg). 1H NMR (CDCl3): 5.23 (s, 2H,
OCH2O), 3.73 (t, 2H, J¼5.8, OCH2CH2CH2Br), 3.46 (t, 2H, J¼6.4,

6244
G.V. Bobkov et al. / Tetrahedron 64 (2008) 6238–6251
OCHHO), 4.25 (d, 1H, J5 a,5 b¼ꢁ13.3, H-50a), 4.22 (dd, 1H, J3 ,2 ¼4.2,
4.21.2. Method B
0
0
0
0
J3 ,4 ¼9.4, H-3 ), 4.17 (d, 1H, H-2 ), 4.14 (dd, 1H, J4 ,5 b¼2.2, H-40), 3.98
(dd, 1H, H-50b), 3.83–3.67 (m, 2H, OCH2CH2CH2Br), 3.51 (t, 2H,
J¼6.5, OCH2CH2CH2Br), 2.13 (p, 2H, OCH2CH2CH2Br), 1.11–1.02 (m,
28H, iPr). 13C NMR (CDCl3): 163.36 (C4), 150.25 (C2), 139.48 (C6),
101.78 (C5), 94.84 (OCH2O), 89.54 (C10), 82.01 (C40), 78.37 (C20),
68.35 (C30), 66.13 (OCH2CH2CH2Br), 59.61 (C50), 32.90
(OCH2CH2CH2Br), 30.56 (OCH2CH2CH2Br), 17.63, 17.55, 17.45, 17.37,
17.27, 17.13, 16.99, 13.63, 13.35, 13.07, 12.84 (iPr). LSI-MS
(C25H45BrN2O8Si2þHþ): 637.1963. Calcd 637.1976.
Analogous (see preparation of 13a) condensation of (2-(2,2,2-
trifluoroacetamido)ethoxy)methyl acetate(17a) (920 mg, 4.0 mmol)
in the presence of tin tetrachloride (0.36 ml, 3 mmol) with nucleo-
side 4a (973 mg, 2.0 mmol) in 1,2-dichloroethane (20 ml) at ꢁ12 ꢀC
for 20 min gave 15a as a foam. Yield 1.09 g (83%).
0
0
0
0
0
0
4.22. 1-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-
3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-
b-D-
ribofuranosyl}-N4-benzoylcytosine (15b)
4.22.1. Method A
4.20. 1-{2-O-[(3-Bromopropoxy)methyl]-3,5-O-(1,1,3,3-
tetraisopropyldisiloxane-1,3-diyl)-
benzoylcytosine (14b)
Analogous (see preparation of 15a) reduction of 10b (827 mg,
1.2 mmol) yielded 15b as a foam (550 mg, 60%). Rf 0.35 (A). 1H NMR
(CDCl3): 8.84 (br s, 1H, NH), 8.38 (d, 1H, J6,5¼7.5, H-6), 8.07 (br s, 1H,
NHCOCF3), 7.92–7.50 (m, 6H, Bz, H-5), 5.78 (s, 1H, H-10), 5.05 (d, 1H,
b-D
-ribofuranosyl}-N4-
0
0
0
Analogous (see preparation of 13a) condensation of (3-bromo-
propoxy)methyl acetate (12b) (844 mg, 4.0 mmol) in the presence
of tin tetrachloride (0.36 ml, 3.0 mmol) with nucleoside 4b (1.18 g,
2.0 mmol) in 1,2-dichloroethane (20 ml) at ꢁ12 ꢀC for 20 min gave
14b as a foam. Yield 1.28 g (86%). Rf 0.36 (A). 1H NMR (CDCl3): 8.73
(br s, 1H, NH), 8.34 (d, 1H, J6,5¼7.5, H-6), 7.91–7.41 (m, 6H, Bz, H-5),
5.84 (s, 1H, H-10), 5.08 (d, 1H, J¼ꢁ6.5, OCHHO), 4.98 (d,1H, OCHHO),
J¼ꢁ6.7, OCHHO), 4.94 (d, 1H, OCHHO), 4.32 (d, 1H, J2 ,3 ¼2.8, H-2 ),
0
4.30 (d, 1H, J5 a,5 b¼ꢁ13.4, H-50a), 4.22 (dd, 1H, J3 ,4 ¼9.7, H-3 ), 4.20
0
0
0
0
(dd, 1H, J4 ,5 b¼1.6, H-40), 4.13–4.07 (m, 1H, OCHHCH2NHCOCF3),
4.02 (dd, 1H, H-50b), 3.82–3.73 (m, 1H, OCHHCH2NHCOCF3), 3.72–
3.67 (m, 1H, OCH2CHHNHCOCF3), 3.55–3.50 (m, 1H, OCH2CHHNH-
COCF3), 1.12–0.98 (m, 28H, iPr). 13C NMR (CDCl3): 168.45 (C]O),
162.72 (C4), 158.00 (q, J¼36.5, COCF3), 151.92 (C2), 144.50 (C6),
133.44,133.13,127.77 (Ph),116.82 (q, J¼287.6, CF3), 96.69 (C5), 95.22
(OCH2O), 90.71 (C10), 82.16 (C40), 77.39 (C20), 68.40 (C30), 66.41
(OCH2CH2NHCOCF3), 59.50 (C50), 40.37 (OCH2CH2NHCOCF3), 17.61,
17.56, 17.43, 17.18, 17.05, 16.94, 13.56, 13.26, 13.07, 12.79 (iPr). LSI-MS
(C33H49F3N4O9Si2þHþ): 759.3025. Calcd 759.3068.
0
0
4.31 (d,1H, J5 a,5 b¼ꢁ13.4, H-50a), 4.27–4.19 (m, 3H, H-20, H-30, H-40),
4.02 (d, 1H, H-50b), 3.89–3.86 (m, 2H, OCH2CH2CH2Br), 3.52 (t, 2H,
J¼6.5, OCH2CH2CH2Br), 2.16 (m, 2H, OCH2CH2CH2Br), 1.13–0.99 (m,
28H, iPr). 13C NMR (CDCl3): 166.97 (C]O), 162.53 (C4), 155.25 (C2),
144.44 (C6), 133.28, 129.18, 127.72 (Ph), 96.27 (C5), 94.93 (OCH2O),
90.52 (C10), 82.12 (C40), 78.05 (C20), 68.09 (C30), 66.11
(OCH2CH2CH2Br), 59.62 (C50), 32.97 (OCH2CH2CH2Br), 30.78
(OCH2CH2CH2Br), 17.63, 17.44, 17.15, 17.00, 13.60, 13.29, 13.08 (iPr).
LSI-MS (C32H50BrN3O8Si2þHþ): 740.2391. Calcd 740.2398.
0
0
4.22.2. Method B
Analogous (see preparation of 13a) condensation of (2-
(2,2,2-trifluoroacetamido)ethoxy)methyl acetate (17a) (920 mg,
4.0 mmol) in the presence of tin tetrachloride (0.36 ml, 3.0 mmol)
with nucleoside 4b (1.18 g, 2.0 mmol) in 1,2-dichloroethane (20 ml)
at ꢁ12 ꢀC for 20 min gave 15b as a foam. Yield 1.29 g (85%).
4.21. 1-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-
3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-b-D-
ribofuranosyl}uracil (15a)
4.23. 9-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-
3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-
b-D-
4.21.1. Method A
ribofuranosyl}-N2-isobutyrylguanine (15c)
To a solution of nucleoside 10a (585 mg, 1.0 mmol) in dioxane
(40 ml) Pd–C (10%,100 mg, 0.1 mmol), ethyl trifluoroacetate (1.2 ml,
10.0 mmol), and DBU (0.31 ml, 2.0 mmol) were added. The mixture
was stirred in hydrogen current at atmospheric pressure for 5 h. The
suspension was filtered through Hyflo Super Cel and the filtrate was
concentrated in vacuo to near dryness. The residue was dissolved in
methylene chloride (50 ml) and washed with 10% aqueous solution
of sodium hydrogen carbonate (20 ml) and water (2ꢂ20 ml). The
organic layer was dried over anhydrous sodium sulfate, evaporated
in vacuo, and purified by column chromatography on silica gel
(50 g). The column was washed with methylene chloride (200 ml)
and methylene chloride–ethanol 99:1 (200 ml), and then eluted
with methylene chloride–ethanol 98:2 to give 15a as a foam. Yield
370 mg (56%). Rf 0.34 (A). 1H NMR (CDCl3): 9.47 (br s, 1H, NH), 7.94
(d, 1H, J6,5¼8.1, H-6), 7.73 (br s, 1H, NHCOCF3), 5.71 (dd, 1H,
J5,NH¼1.5, H-5), 5.69 (s, 1H, H-10), 4.98 (d, 1H, J¼ꢁ7.2, OCHHO), 4.94
To a cool solution (ꢁ15 ꢀC) under nitrogen of nucleoside 4c
(596 mg,1.0 mmol)and(2-(2,2,2-trifluoroacetamido)ethoxy)methyl
acetate (17a) (460 mg, 2.0 mmol) in 1,2-dichloroethane (20 ml) tin
tetrachloride (0.24 ml, 2.0 mmol) was added and the solution was
kept at ꢁ12 ꢀC for 40 min. A 10% aqueous solution of sodium hy-
drogen carbonate (10 ml) and methylene chloride (20 ml) were
added and the suspension was stirred at 0 ꢀC for 20 min. The sus-
pension was filtered through Hyflo Super Cel, organic layer was
separated, washed with water (20 ml), dried over anhydrous sodium
sulfate, and evaporated to dryness. The residue was purified by col-
umn chromatography on silica gel (30 g). The column was washed
with methylene chloride (200 ml) and methylene chloride–ethanol
99:1 (200 ml), and then eluted with methylene chloride–ethanol
98:2 to give 15c as a foam. Yield 367 mg (48%). Rf 0.30 (A). 1H NMR
(CDCl3): 12.09 (brs,1H, NH Guo),10.11 (br s,1H, NHiBu), 8.32 (br t,1H,
NHCOCF3), 8.07 (s, 1H, H-8), 5.91 (s, 1H, H-10), 5.00 (d, 1H, J¼ꢁ7.02,
(d, 1H, OCHHO), 4.27 (d, 1H, J5 a,5 b¼ꢁ13.7, H-50a), 4.20 (m, 2H, H-20,
0
0
H-30), 4.13 (dd, 1H, J4 ,3 ¼9.0, J4 ,5 b¼2.2, H-40), 4.03–3.98 (m, 1H,
OCHHCH2NHCOCF3), 3.97 (dd, 1H, H-50b), 3.73–3.66 (m, 2H,
OCHHCHHNHCOCF3), 3.57–3.52 (m, 1H, OCH2CHHNHCOCF3), 1.10–
0.92 (m, 28H, iPr). 13C NMR (CDCl3): 163.20 (C4), 157.23 (q, J¼36.6,
COCF3), 150.64 (C2), 139.23 (C6), 116.72 (q, J¼287.3, CF3), 102.17
(C5), 95.33 (OCH2O), 89.60 (C10), 82.02 (C40), 78.47 (C20), 68.37
(C30), 66.55 (OCH2CH2NHCOCF3), 59.45 (C50), 40.28 (OCH2CH2NH-
COCF3), 17.61, 17.52, 17.43, 17.34, 17.22, 17.08, 16.92, 13.59, 13.27,
13.04, 12.78 (iPr). LSI-MS (C26H44F3N3O9Si2þHþ): 656.2637. Calcd
656.2646.
OCHHO), 4.91 (d,1H, OCHHO), 4.53 (dd,1H, J3 ,2 ¼4.1, J3 ,4 ¼9.6, H-3 ),
0
0
0
0
0
0
0
0
4.26 (d, 1H, J5 a,5 b¼ꢁ13.7, H-50a), 4.17 (d, 1H, H-20), 4.13 (dd, 1H,
0
0
J4 ,5 b¼2.3, H-40), 4.02 (dd, 1H, H-50b), 3.94 (m, 1H, OCHHCH2NH-
COCF3), 3.81–3.64 (m, 3H, OCHHCH2NHCOCF3), 2.81 (sept,1H, J¼6.9,
iBu), 1.25 (m, 6H, iBu), 1.10–0.95 (m, 28H, iPr). 13C NMR (CDCl3):
180.21 (C]O), 157.51 (q, J¼36.8, COCF3), 156.00 (C6), 148.54 (C2),
147.71 (C4), 136.46 (C8), 121.65 (C5), 116.02 (q, J¼285.7, CF3), 95.96
(OCH2O), 87.92 (C10), 81.52 (C40), 80.44 (C20), 69.03 (C30), 66.87
(OCH2CH2NHCOCF3), 59.77 (C50), 40.21 (OCH2CH2NHCOCF3), 36.04
(iBu), 19.15, 19.00 (iBu) 17.61, 17.43, 17.32, 17.13, 17.10, 13.54, 13.04,
0
0

G.V. Bobkov et al. / Tetrahedron 64 (2008) 6238–6251
6245
12.77 (iPr). LSI-MS (C31H51F3N6O9Si2þHþ): 765.3249. Calcd
1H, J¼ꢁ7.0, OCHHO), 4.84 (d, 1H, OCHHO), 4.32 (d, 1H, J2 ,3 ¼2.2, H-
0
0
0
0
0
0
0
765.3281.
20), 4.31 (d, 1H, J5 a,5 b¼ꢁ13.2, H-50a), 4.22 (dd, 1H, J3 ,4 ¼10.1, H-3 ),
4.20 (d, 1H, H-40), 4.14–4.09 (m, 1H, OCHHCH2CH2NHCOCF3), 4.02
(d, 1H, H-50b), 3.63–3.55 (m, 1H, OCHHCH2CH2NHCOCF3), 3.51–3.39
4.24. 9-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-
3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-
ribofuranosyl}adenine (15e)
b
-
D
-
(m, 2H, OCH2CH2CH2NHCOCF3), 1.98–1.93 (m, 2H, OCH2CH2CH2
-
COCF3), 1.12–0.98 (m, 28H, iPr). 13C NMR (CDCl3): 168.93 (C]O),
162.89 (C4), 157.52 (q, J¼36.4, COCF3), 150.03 (C2), 144.49 (C6),
133.41,129.22,127.70 (Ph),116.48 (q, J¼287.3, CF3), 96.70 (C5), 95.37
(OCH2O), 90.71 (C10), 82.12 (C40), 77.36 (C20), 68.66 (C30), 66.11
(OCH2CH2CH2NHCOCF3), 59.55 (C50), 37.63 (OCH2CH2CH2NH-
COCF3), 28.49 (OCH2CH2CH2NHCOCF3), 17.61, 17.42, 17.22, 17.09,
16.98,13.62,13.26,13.07,12.84 (iPr). LSI-MS (C34H51F3N4O9Si2þHþ):
773.3186. Calcd 773.3225.
Analogous (see preparation of 15c) condensation of (2-(2,2,2-
trifluoroacetamido)ethoxy)methylacetate(17a)(460 mg, 2.0 mmol)
in the presence of tin tetrachloride (0.22 ml, 1.8 mmol) with nucle-
oside 4e (510 mg, 1.0 mmol) in 1,2-dichloroethane (15 ml) at ꢁ12 ꢀC
for 40 min gave 15e as a foam. Yield 380 mg (56%). Rf 0.23 (A). 1H
NMR (CDCl3): 8.28 (s, 1H, H-8), 8.20 (s, 1H, H-2), 8.10 (br t, 1H,
NHCOCF3), 6.07 (s, 1H, H-10), 5.86 (s, 2H, NH2), 5.02 (d, 1H, J¼ꢁ7.1,
0
0
0
0
0
OCHHO), 4.98 (d,1H, OCHHO), 4.59 (dd,1H, J3 ,2 ¼4.4, J3 ,4 ¼9.5, H-3 ),
4.26.2. Method B
4.38 (d, 1H, H-20), 4.29 (d, 1H, J5 a,5 b¼ꢁ13.5, H-50a), 4.16 (dd,
Analogous (see preparation of 13a) condensation of (3-(2,2,2-
trifluoroacetamido)propoxy)methyl acetate (17b) (1.46 g, 6.0 mmol)
in the presence of tin tetrachloride (0.54 ml, 4.5 mmol) with nucle-
oside 4b (1.77 g, 3.0 mmol) in 1,2-dichloroethane (30 ml) at ꢁ12 ꢀC
for 20 min gave 16b as a foam. Yield 2.01 g (86%).
0
0
1H, J4 ,5 b¼1.9, H-40), 4.02 (dd, 1H, H-50b), 3.96–3.89 (m, 1H,
OCHHCH2NHCOCF3), 3.85–3.78 (m, 1H, OCHHCH2NHCOCF3), 3.74–
3.65 (m, 1H, OCH2CHHNHCOCF3), 3.62–3.56 (m, 1H, OCH2CHHNH-
COCF3), 1.11–0.95 (m, 28H, iPr). 13C NMR (CDCl3): 157.65 (q, J¼36.8,
COCF3),155.70 (C6),153.02(C8),148.82 (C4),138.38 (C2),120.42 (C5),
116.04 (q, J¼286.5, CF3), 95.94 (OCH2O), 88.75 (C10), 81.82 (C40), 79.57
(C20), 68.69 (C30), 68.06 (OCH2CH2NHCOCF3), 59.69 (C50), 40.30
(OCH2CH2NHCOCF3),17.57,17.52,17.41,17.25,17.11,17.08,13.52,13.05,
12.72 (iPr). LSI-MS (C27H45F3N6O7Si2þHþ): 679.2906. Calcd
679.2913.
0
0
4.27. 9-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-
b-D-
ribofuranosyl}-N2-isobutyrylguanine (16c)
Analogous (see preparation of 15c) condensation of (3-(2,2,2-tri-
fluoroacetamido)propoxy)methyl acetate (17b) (490 mg, 2.0 mmol)
in the presence of tin tetrachloride (0.24 ml, 2.0 mmol) with
nucleoside 4c (596 mg, 1.0 mmol) in 1,2-dichloroethane (15 ml) at
ꢁ12 ꢀC for 40 min gave unseparatable mixture of 16c and starting 4c
as a foam in a ratio of 9:1. Yield 375 mg. Rf 0.29 (A). 1H NMR (CDCl3):
12.20 (br s,1H, NH Guo), 9.37 (br s,1H, NHiBu), 8.01 (s, 1H, H-8), 7.43
(br t, 1H, NHCOCF3), 5.89 (s, 1H, H-10), 4.99 (d, 1H, J¼ꢁ6.9, OCHHO),
4.25. 1-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-b-D-
ribofuranosyl}uracil (16a)
4.25.1. Method A
Analogous (see preparation of 15a) reduction of 11a (675 mg,
1.13 mmol) yielded 16a as a foam (430 mg, 57%). Rf 0.34 (A). 1H NMR
(CDCl3): 9.29 (br s, 1H, NH), 7.91 (d, 1H, J6,5¼8.1, H-6), 7.71 (br s, 1H,
NHCOCF3), 5.72 (s, 1H, H-10), 5.68 (d, 1H, H-5), 4.99 (d, 1H, J¼ꢁ6.9,
0
0
0
0
0
4.89 (d, 1H, OCHHO), 4.53 (dd, 1H, J3 ,2 ¼4.4, J3 ,4 ¼9.3, H-3 ), 4.23 (d,
1H, J5 a,5 b¼ꢁ13.5, H-50a), 4.17 (d,1H, H-20), 4.10 (dd,1H, J4 ,5 b¼2.5, H-
40), 4.01 (dd,1H, H-50b), 3.73 (m, 2H, OCH2CH2CH2NHCOCF3), 3.56 (m,
2H, OCH2CH2CH2NHCOCF3), 2.73 (sept, 1H, J¼6.7, iBu), 1.91 (m, 2H,
0
0
0
0
OCHHO), 4.87 (d, 1H, OCHHO), 4.250 (d, 1H, J5 a,5 b¼ꢁ13.5, H-50a),
0
0
4.22 (dd, 1H, J3 ,2 ¼4.1, J3 ,4 ¼9.5, H-3 ), 4.17 (d, 1H, H-2 ), 4.14 (dd,
OCH2CH2CH2NHCOCF3), 1.24 (m, 6H, iBu), 1.11–0.98 (m, 28H, iPr). 13
C
0
0
0
0
0
1H, J4 ,5 b¼2.0, H-40), 3.98 (dd, 1H, H-50b), 3.97–3.92 (m, 1H,
OCHHCH2CH2NHCOCF3), 3.62–3.57 (m, 1H, OCHHCH2CH2NH-
COCF3), 3.57–3.50 (m, 1H, OCH2CH2CHHNHCOCF3), 3.46–3.39 (m,
1H, OCH2CH2CHHNHCOCF3), 1.94–1.87 (m, 2H, OCH2CH2CH2NH-
COCF3),1.10–1.00 (m, 28H, iPr). 13C NMR (CDCl3): 163.39 (C4),157.43
(q, J¼36.7, COCF3), 150.55 (C2), 139.22 (C6), 116.24 (q, J¼287.5, CF3),
102.07 (C5), 95.19 (OCH2O), 89.59 (C10), 82.01 (C40), 78.21 (C20),
68.64 (C30), 66.59 (OCH2CH2CH2NHCOCF3), 59.49 (C50), 38.01
(OCH2CH2CH2NHCOCF3), 28.49 (OCH2CH2CH2NHCOCF3), 17.61,
17.52, 17.43, 17.34, 17.22, 17.08, 16.92, 13.59, 13.27, 13.04, 12.78 (iPr).
LSI-MS (C27H46F3N3O9Si2þHþ): 670.2792. Calcd 670.2803.
NMR (CDCl3): 179.84 (C]O), 158.06 (q, J¼36.7, COCF3), 155.92 (C6),
148.34 (C2), 147.63 (C4), 136.49 (C8), 121.61 (C5), 116.11 (q, J¼286.1,
CF3), 95.30 (OCH2O), 87.78 (C10), 81.56 (C40), 80.14 (C20), 69.00 (C30),
66.69 (OCH2CH2CH2NHCOCF3), 59.77 (C50), 38.12 (OCH2CH2CH2NH-
COCF3), 36.18(iBu), 29.83(CH2CH2CH2),19.05,19.08(iBu),17.60,17.45,
17.31, 17.11, 17.08, 13.53, 13.13, 13.04, 12.72 (iPr). LSI-MS
(C32H53F3N6O9Si2þHþ): 779.3426. Calcd 779.3437.
0
0
4.28. 9-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-b-D-
ribofuranosyl}adenine (16e)
4.25.2. Method B
Analogous (see preparation of 15c) condensation of (3-(2,2,2-tri-
fluoroacetamido)propoxy)methyl acetate (17b) (490 mg, 2.0 mmol)
in the presence of tin tetrachloride (0.22 ml, 1.8 mmol) with nucle-
oside 4e (510 mg, 1.0 mmol) in 1,2-dichloroethane (15 ml) at ꢁ12 ꢀC
for 40 min gave 16e as a foam. Yield 374 mg (54%). Rf 0.23 (A).1H NMR
(CDCl3): 8.24 (s, 1H, H-8), 8.20 (s, 1H, H-2), 7.77 (br t, 1H, NHCOCF3),
6.04 (s,1H, H-10), 5.92 (s, 2H, NH2), 5.02 (d,1H, J¼ꢁ7.0, OCHHO), 4.93
Analogous (see preparation of 13a) condensation of (3-(2,2,2-tri-
fluoroacetamido)propoxy)methyl acetate (17b) (980 mg, 4.0 mmol)
in the presence of tin tetrachloride (0.36 ml, 3.0 mmol) with
nucleoside 4a (973 mg, 2.0 mmol) in 1,2-dichloroethane (20 ml) at
ꢁ12 ꢀC for 20 min gave 16a as a foam. Yield 1.12 g (83%).
0
0
0
0
0
4.26. 1-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
(d,1H, OCHHO), 4.61 (dd,1H, J3 ,2 ¼4.4, J3 ,4 ¼9.0, H-3 ), 4.41 (d,1H, H-
20), 4.28 (d, 1H, J5 a,5 b¼ꢁ13.4, H-50a), 4.16 (dd, 1H, J4 ,5 b¼2.5, H-40),
4.02 (dd, 1H, H-50b), 3.95 (m, 1H, OCHHCH2CH2NHCOCF3), 3.65 (m,
1H, OCHHCH2CH2NHCOCF3), 3.60–3.43 (m, 2H, OCH2CH2CH2NH-
COCF3), 2.08–1.82 (m, 2H, OCH2CH2CH2NHCOCF3),1.15–0.86 (m, 28H,
iPr). 13C NMR (CDCl3): 157.51 (q, J¼36.9, COCF3), 155.79 (C6), 152.96
(C8), 148.97 (C4), 138.59 (C2), 120.54 (C5), 115.86 (q, J¼286.1, CF3),
95.36 (OCH2O), 88.78 (C10), 81.68 (C40), 78.93 (C20), 69.28 (C30), 66.67
(OCH2CH2CH2NHCOCF3), 59.97 (C50), 38.33 (OCH2CH2CH2NHCOCF3),
0
0
0
0
3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-
b-D-
ribofuranosyl}-N4-benzoylcytosine (16b)
4.26.1. Method A
Analogous (see preparation of 15a) reduction of 11b (1.34 g,
1.9 mmol) yielded 16b as a foam (830 mg, 58%). Rf 0.35 (A). 1H NMR
(CDCl3): 8.78 (br s, 1H, NH), 8.62 (br s, 1H, NHCOCF3), 8.38 (d, 1H,
J6,5¼7.5, H-6), 7.91–7.49 (m, 6H, Bz, H-5), 5.80 (s, 1H, H-10), 5.07 (d,

6246
G.V. Bobkov et al. / Tetrahedron 64 (2008) 6238–6251
28.02 (OCH2CH2CH2NHCOCF3), 17.59, 17.49, 17.43, 17.34, 17.24, 17.08,
16.92, 13.59, 13.27, 13.08, 12.88 (iPr). LSI-MS (C28H47F3N6O7Si2þHþ):
693.3089. Calcd 693.3069.
mixture was warmed to room temperature, stirred for 2 h, and
evaporated in vacuo to oil, which crystallized on standing. Yield
21.0 g (100%), mp: 32–33 ꢀC (lit. mp: 32–35 ꢀC). 1H NMR (CDCl3):
7.01 (br s, 1H, NH), 3.78 (t, 2H, J¼5.1, HOCH2CH2NHCOCF3), 3.52 (dt,
2H, JCHNH¼5.6, OCH2CH2NHCOCF3), 2.33 (br s, 1H, OH). 13C NMR
(CDCl3): 158.08 (q, J¼36.9, COCF3), 116.03 (q, J¼287.2, CF3), 60.73
(OCH2CH2NHCOCF3), 42.25 (OCH2CH2NHCOCF3).
4.29. 9-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-
3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-
b-D-
ribofuranosyl}-N6-benzoyladenine (15d)
The obtained N-(2-hydroxyethyl)-2,2,2-trifluoroacetamide
(21.0 g, 0.14 mol) and paraformaldehyde (4.8 g, 0.16 mol) in meth-
ylene chloride (50 ml) were cooled in an ice bath under stirring.
Anhydrous hydrogen chloride was bubbled through the mixture for
3 h. The reaction mixture was allowed up to room temperature and
two clear homogeneous layers were separated. The organic layer
was degassed, dried over anhydrous calcium chloride, and con-
centrated on a rotary evaporator to give N-[2-(chloromethox-
y)ethyl]-2,2,2-trifluoroacetamide as oil. Yield 23.4 g (85%). 1H NMR
(CDCl3): 6.74 (br s, 1H, NH), 5.46 (s, 2H, OCH2Cl), 3.82 (t, 2H, J¼5.1,
OCH2CH2NHCOCF3), 3.60 (q, 2H, OCH2CH2NHCOCF3). 13C NMR
(CDCl3): 157.59 (q, J¼36.9, COCF3), 115.98 (q, J¼287.5, CF3), 82.32
(OCH2Cl), 68.05 (OCH2CH2NHCOCF3), 39.30 (OCH2CH2NHCOCF3).
TheobtainedN-[2-(chloromethoxy)ethyl]-2,2,2-trifluoroacetamide
was dissolved in benzene (50 ml) and potassium acetate (17 g,
0.17 mol) was added. The mixture was stirred at 50 ꢀC for 4 h. The
precipitate was filtered off; the filtrate was concentrated on a rotary
evaporator to oil. The residue was dissolved in ethyl acetate (50 ml) and
washed with 10% aqueous solution of sodium hydrogen carbonate
(20 ml) and water (2ꢂ20 ml). The organic layer was dried over anhy-
drous sodium sulfate and concentrated on a rotary evaporator to
oil. The residue was purified by column chromatography on silica
gel (150 g). The column was washed with methylene chloride (400 ml)
and then eluted with methylene chloride to give [2-(2,2,2-tri-
fluoroacetamido)ethoxy]methyl acetate (17a) as oil. Yield 20.7 g (80%).
Yield for three steps 68%. Rf 0.30 (methylene chloride).1H NMR (CDCl3):
6.95 (br s, 1H, NH), 5.22 (s, 2H, OCH2O), 3.75 (t, 2H, J¼5.2,
OCH2CH2NHCOCF3), 3.52 (q, 2H, OCH2CH2NHCOCF3), 2.05 (s, 3H, Ac).
13C NMR (CDCl3): 170.57 (C]O), 157.43 (q, J¼37.8, COCF3), 115.82 (q,
J¼287.5, CF3), 88.94 (OCH2O), 67.91 (OCH2CH2NHCOCF3), 39.87
(OCH2CH2NHCOCF3), 20.80 (Me).
Nucleoside 15e (1.83 g, 2.70 mmol) was dried by evaporation of
pyridine (2ꢂ30 ml) and suspended in dry pyridine (50 ml). Benzoyl
chloride (1.4 ml, 12.0 mmol) was added and the reaction was
maintained at room temperature for 2 h. The mixture was then
cooled in an ice bath and water (3 ml) was added. After 5 min 25%
aqueous ammonia (10 ml) was added and the mixture was stirred
at room temperature for 1 h. The reaction mixture was concen-
trated in vacuo to near dryness. The residue was dissolved in
methylene chloride (50 ml), and washed with 10% aqueous solution
of sodium hydrogen carbonate (20 ml) and water (2ꢂ20 ml). The
organic layer was dried over anhydrous sodium sulfate, evaporated
in vacuo, evaporated with toluene (2ꢂ10 ml), and purified by col-
umn chromatography on silica gel (50 g). The column was washed
with methylene chloride (200 ml) and methylene chloride–ethanol
99:1 (200 ml), and then eluted with methylene chloride–ethanol
98:2 to give 15d as a foam. Yield 1.53 g (73%). Rf 0.34 (A). 1H NMR
(CDCl3): 9.06 (br s, 1H, NHBz), 8.77 (s, 1H, H-8), 8.38 (s, 1H, H-2),
8.04–7.51 (m, 6H, Bz, NHCOCF3), 6.14 (s, 1H, H-10), 5.08 (d, 1H,
0
0
J¼ꢁ7.1, OCHHO), 5.00 (d, 1H, 0 OCHHO), 4.64 (dd, 1H, J3 ,2 ¼4.4,
0
J3 ,4 ¼9.4, H-3 ), 4.46 (d, 1H, H-2 ), 4.30 (d, 1H, J5 a,5 b¼ꢁ13.5, H-50a),
0
0
0
0
4.19 (dd, 1H, J4 ,5 b¼1.5, H-40), 4.04 (dd, 1H, H-50b), 3.98–3.90 (m, 1H,
OCHHCH2NHCOCF3), 3.85–3.77 (m, 1H, OCHHCH2NHCOCF3), 3.65–
3.60 (m, 2H, OCH2CH2NHCOCF3), 1.12–0.99 (m, 28H, iPr). 13C NMR
(CDCl3): 164.74 (C]O),157.50 (q, J¼36.7, COCF3),152.79 (C8),150.85
(C6), 149.78 (C4), 140.95 (C2), 133.80, 132.98, 128.96, 127.85 (Ph),
123.95 (C5), 116.00 (q, J¼285.8, CF3), 95.83 (OCH2O), 88.90 (C10),
81.81 (C40), 79.48 (C20), 68.77 (C30), 67.79 (OCH2CH2NHCOCF3),
59.67 (C50), 40.18 (OCH2CH2NHCOCF3), 17.58, 17.52, 17.43, 17.28,
17.13, 17.08, 13.54, 13.05, 12.75 (iPr). LSI-MS (C34H49F3N6O8Si2þHþ):
783.3153. Calcd 783.3175.
0
0
4.30. 9-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
4.32. [3-(2,2,2-Trifluoroacetamido)propoxy]methyl
acetate (17b)
3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-
b-D-
ribofuranosyl}-N6-benzoyladenine (16d)
Analogous conversion of 3-amino-1-propanol (15.2 ml,
0.20 mol) yielded [3-(2,2,2-trifluoroacetamido)propoxy]methyl
acetate (17b) as an oil 31.6 g (65%). Rf 0.30 (methylene chloride).
Analogous benzoylation of 16e (1.12 g, 1.62 mmol) yielded 16d as
a foam (965 mg, 76%). Rf 0.34 (A). 1H NMR (CDCl3): 9.17 (br s, 1H,
NHBz), 8.74 (s, 1H, H-8), 8.40 (s, 1H, H-2), 8.04–7.51 (m, 5H, Bz), 7.40
(br t, 1H, NHCOCF3), 6.13 (s, 1H, H-10), 5.04 (d, 1H, J¼ꢁ6.9, OCHHO),
4.32.1. N-(3-Hydroxypropyl)-2,2,2-trifluoroacetamide
0
0
0
0
0
4.98 (d, 1H, OCHHO), 4.65 (dd, 1H, J3 ,2 ¼4.4, J3 ,4 ¼9.3, H-3 ), 4.46 (d,
1H NMR (CDCl3): 7.79 (br s, 1H, NH), 3.73 (t, 2H, J¼5.6,
HOCH2CH2CH2NHCOCF3), 3.47 (dt, 2H, J¼5.9, HOCH2CH2CH2NH-
1H, H-20), 4.29(d,1H, J5 a,5 b¼ꢁ13.4, H-50a), 4.20 (dd,1H, J4 ,5 b¼2.5, H-
40),4.05(dd,1H, H-50b), 3.97(m,1H,OCHHCH2CH2NHCOCF3),3.70(m,
1H, OCHHCH2CH2NHCOCF3), 3.59–3.41 (m, 2H, OCH2CH2CH2NH-
COCF3),1.95–1.89 (m, 2H, OCH2CH2CH2NHCOCF3),1.11–0.99 (m, 28H,
iPr).13C NMR (CDCl3): 164.65 (C]O),157.41 (q, J¼36.8, COCF3),152.67
(C8), 150.74 (C6), 149.63 (C4), 141.12 (C2), 133.80, 132.91, 128.97,
128.03(Ph),123.91(C5),115.92(q, J¼285.9,CF3),95.27(OCH2O),88.97
(C10), 81.87 (C40), 78.64 (C20), 69.27 (C30), 67.04 (OCH2CH2CH2NH-
COCF3), 59.91 (C50), 38.53 (OCH2CH2CH2NHCOCF3), 28.21
(OCH2CH2CH2NHCOCF3), 17.58, 17.49, 17.43, 17.34, 17.24, 17.08, 13.55,
13.27, 13.08, 12.85 (iPr). LSI-MS (C35H51F3N6O8Si2þHþ): 797.3375.
Calcd 797.3332.
0
0
0
0
COCF3), 3.12 (br s, 1H, OH), 1.78 (tt, 2H, OCH2CH2CH2NHCOCF3). 13
C
NMR (CDCl3): 157.91 (q, J¼36.9, COCF3), 116.04 (q, J¼287.2, CF3),
60.84 (HOCH2CH2CH2NHCOCF3), 38.27 (HOCH2CH2CH2NHCOCF3),
30.61 (HOCH2CH2CH2NHCOCF3).
4.32.2. N-[3-(Chloromethoxy)propyl]-2,2,2-trifluoroacetamide
1HNMR(CDCl3):7.04(brs,1H,NH),5.46(s, 2H, OCH2Cl), 3.78(t,2H,
J¼5.9, OCH2CH2CH2NHCOCF3), 3.46 (dt, 2H, J¼6.2, OCH2CH2CH2NH-
COCF3), 1.89 (tt, 2H, OCH2CH2CH2NHCOCF3). 13C NMR (CDCl3): 157.36
(q, J¼37.1, COCF3), 116.13 (q, J¼287.3, CF3), 82.82 (OCH2Cl), 68.49
(OCH2CH2CH2NHCOCF3), 37.92 (OCH2CH2CH2NHCOCF3), 27.93
(OCH2CH2CH2NHCOCF3).
4.31. [2-(2,2,2-Trifluoroacetamido)ethoxy]methyl
acetate (17a)
4.32.3. [3-(2,2,2-Trifluoroacetamido)propoxy]methyl acetate (17b)
1HNMR(CDCl3):7.18(brs,1H,NH), 5.21(s,2H,OCH2O),3.72 (t,2H,
J¼5.8, OCH2CH2CH2NHCOCF3), 3.43 (dt, 2H, J¼6.2, OCH2CH2CH2NH-
COCF3), 2.06 (s, 3H, Ac),1.84 (tt, 2H, OCH2CH2CH2NHCOCF3).13C NMR
2-Amino-1-ethanol (8.5 ml, 0.14 mol) was added to ethyl tri-
fluoroacetate (22.3 ml, 0.19 mol) at 0 ꢀC under stirring. The reaction

G.V. Bobkov et al. / Tetrahedron 64 (2008) 6238–6251
6247
(CDCl3): 170.74 (C]O), 156.92 (q, J¼37.6, COCF3), 116.42 (q, J¼287.1,
4.36. 9-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-
D
b-
CF3), 89.07 (OCH2O), 68.67 (OCH2CH2CH2NHCOCF3), 38.30
(OCH2CH2CH2NHCOCF3), 28.31 (OCH2CH2CH2NHCOCF3), 20.93 (Me).
-ribofuranosyl}-N6-benzoyladenine (18d)
Analogous desilylation of 15d (1.41 g, 1.80 mmol) yielded 18d as
4.33. 1-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-
b-
a foam (810 mg, 84%). Rf 0.19 (B). 1H NMR (CDCl3): 9.25 (br s, 1H,
D
-ribofuranosyl}uracil (18a)
NHBz), 8.76 (s, 1H, H-8), 8.14 (s, 1H, H-2), 8.04–7.53 (m, 6H, Bz,
0
0
0
0
0
0
NHCOCF3), 6.02 (d, 1H, J1 ,2 ¼7.3, H-1 ), 4.99 (dd, 1H, J2 ,3 ¼4.7, H-2 ),
Nucleoside 15a (940 mg, 1.40 mmol) was dissolved in 0.5 M
4.67 (d,1H, J¼ꢁ6.7, OCHHO), 4.62 (d,1H, OCHHO), 4.53 (d,1H, H-30),
4.36 (d, 1H, J4 ,5 a¼1.2, H-40), 3.98 (dd, 1H, J5 a,5 b¼ꢁ12.3, H-50a), 3.77
(d, 1H, H-50b), 3.59–3.51 (m, 1H, OCHHCH2NHCOCF3), 3.43–3.21 (m,
3H, OCHHCH2NHCOCF3). 13C NMR (CDCl3): 165.13 (C]O), 157.43 (q,
J¼37.7, COCF3), 152.32 (C8), 151.03 (C6), 150.41 (C4), 143.41 (C2),
133.33, 133.31, 129.28, 128.16 (Ph), 124.91 (C5), 115.93 (q, J¼285.8,
CF3), 96.32 (OCH2O), 89.35 (C10), 87.82 (C40), 80.62 (C20), 71.60 (C30),
66.67 (OCH2CH2NHCOCF3), 63.04 (C50), 39.45 (OCH2CH2NHCOCF3).
LSI-MS (C22H23F3N6O7þHþ): 541.1652. Calcd 541.1653.
0
0
0
0
tetrabutylammonium fluoride trihydrate in tetrahydrofuran (7 ml),
kept for 10 min at 20 ꢀC, evaporated to dryness, evaporated with
chloroform (10 ml), and applied on a column with silica gel (30 g).
The column was washed with methylene chloride (100 ml),
methylene chloride–ethanol 98:2 (200 ml), and methylene chlo-
ride–ethanol 96:4 (200 ml), and then eluted with methylene
chloride–ethanol 94:6 to give 18a as a powder. Yield 490 mg (83%).
Rf 0.20 (B). 1H NMR (DMSO-d6): 11.28 (br s, 1H, NH), 9.39 (br t, 1H,
0
0
0
NHCOCF3), 7.92 (d, 1H, J6,5¼8.1, H-6), 5.88 (d, 1H, J1 ,2 ¼4.7, H-1 ),
5.63 (dd, 1H, J5,NH¼2.2, H-5), 5.18 (br s, 2H, OH-30, OH-50), 4.74 (d,
4.37. 1-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
b-D-ribofuranosyl}uracil (19a)
0
0
1H, J¼ꢁ7.2, OCHHO), 4.72 (d, 1H, OCHHO), 4.14 (t, 1H, J2 ,3 ¼4.7, H-
20), 4.11 (dd, 1H, J3 ,4 ¼3.9, H-3 ), 3.87 (dd, 1H, J4 ,5 a¼2.3, H-40), 3.66
0
0
0
0
0
(dd, 1H, J5 a,5 b¼ꢁ12.8, H-50a), 3.63–3.53 (m, 3H, H-50b,
OCH2CH2NHCOCF3), 3.43–3.31 (m, 2H, OCH2CH2NHCOCF3). 13C
NMR (DMSO-d6): 163.02 (C4), 156.32 (q, J¼36.2, COCF3), 150.56
(C2), 140.24 (C6), 116.25 (q, J¼287.9, CF3), 101.75 (C5), 93.90
(OCH2O), 86.41 (C10), 85.02 (C40), 78.31 (C20), 68.47 (C30), 65.01
(OCH2CH2NHCOCF3), 60.35 (C50), 39.35 (OCH2CH2NHCOCF3). LSI-
MS (C14H18F3N3O8þHþ): 414.1116. Calcd 414.1124.
Analogous desilylation of 16a (670 mg, 1.0 mmol) yielded 19a as
0
0
a powder (340 mg, 80%). Rf 0.20 (B). 1H NMR (DMSO-d6): 11.29 (br s,
1H, NH), 9.34 (br t,1H, NHCOCF3), 7.93 (dd,1H, J6,5¼8.1, J6,NH¼1.6, H-
0
0
0
6), 5.89 (d,1H, J1 ,2 ¼5.0, H-1 ), 5.64 (dd,1H, J5,NH¼2.2, H-5), 5.16 (br s,
2H, OH-30, OH-50), 4.71 (d0,1H, J¼ꢁ7.5, OCHHO), 4.68 (d,01H, OCHHO),
0
0
0
0
4.13 (t, 1H, J2 ,3 ¼5.0, H-2 ), 4.10 (dd, 1H, J3 ,4 ¼3.2, H-3 ), 3.88 (ddd,
1H, J4 ,5 a¼2.6, J4 ,5 b¼2.2, H-40), 3.64 (dd, 1H, J5 a,5 b¼ꢁ12.0, H-50a),
3.57 (dd, 1H, H-50b), 3.51–3.41 (m, 2H, OCH2CH2CH2NHCOCF3),
3.26–3.17 (m, 2H, OCH2CH2CH2NHCOCF3), 1.71–1.64 (m, 2H,
OCH2CH2CH2NHCOCF3).13C NMR (DMSO-d6): 162.98 (C4),156.01 (q,
J¼36.3, COCF3), 150.57 (C2), 140.36 (C6), 115.93 (q, J¼287.4, CF3),
101.84 (C5), 94.00 (OCH2O), 86.20 (C10), 85.21 (C40), 78.03 (C20),
68.58 (C30), 64.85 (OCH2CH2CH2NHCOCF3), 60.56 (C50), 36.59
(OCH2CH2CH2NHCOCF3), 28.35 (OCH2CH2CH2NHCOCF3). LSI-MS
(C15H20F3N3O8þHþ): 428.1267. Calcd 428.1281.
0
0
0
0
0
0
4.34. 1-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-
-ribofuranosyl}-N4-benzoylcytosine (18b)
b-
D
Analogous desilylation of 15b (705 mg, 0.93 mmol) yielded 18b
as a powder (379 mg, 79%). Rf 0.21 (B). 1H NMR (DMSO-d6): 11.29
(br s,1H, NH), 9.39 (t,1H, JCH,NH¼5.2, NHCOCF3), 8.54 (d,1H, J6,5¼7.4,
0
0
H-6), 8.02–7.49 (m, 5H, Bz), 7.33 (d, 1H, H-5), 5.89 (d, 1H, J1 ,2 ¼1.9,
H-10), 5.15 (br s, 2H, OH-30, OH-50), 4.92 (d, 1H, J¼0 ꢁ6.5, OCHHO),
0
0
4.81 (d, 1H, OCHHO), 4.15 (dd, 1H, J2 ,3 ¼5.0, H-2 ), 4.12 (dd, 1H,
4.38. 1-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
J3 ,4 ¼6.5, H-3 ), 4.95 (ddd, 1H, J4 ,5 a¼1.9, J4 ,5 b¼3.1, H-40), 3.82 (dd,
b-D
-ribofuranosyl}-N4-benzoylcytosine (19b)
0
0
0
0
0
0
0
1H, J5 a,5 b¼ꢁ12.5, H-50a), 3.71–3.62 (m, 3H, H-50b, OCH2CH2NH-
COCF3), 3.39 (m, 2H, OCH2CH2NHCOCF3). 13C NMR (DMSO-d6):
167.49 (C]O), 162.99 (C4), 156.35 (q, J¼36.1, COCF3), 154.28 (C2),
144.79 (C6), 133.17, 132.69, 132.14, 128.34 (Ph), 115.55 (q, J¼288.3,
CF3), 96.09 (C5), 93.80 (OCH2O), 88.77 (C10), 84.21 (C40), 78.87 (C20),
67.52 (C30), 65.08 (OCH2CH2NHCOCF3), 59.39 (C50), 39.22
(OCH2CH2NHCOCF3). LSI-MS (C21H23F3N4O8þHþ): 517.1541. Calcd
517.1546.
0
0
Analogous desilylation of 16b (580 mg, 0.83 mmol) yielded 19b
as a powder (334 mg, 84%). Rf 0.21 (B). 1H NMR (DMSO-d6): 11.19 (br
s, 1H, NH), 9.31 (t, 1H, JCH,NH¼6.2, NHCOCF3), 8.52 (d, 1H, J6,5¼7.2, H-
0
0
0
6), 8.02–7.49 (m, 5H, Bz), 7.35 (d,1H, H-5), 5.91 (d,1H, J1 ,2 ¼1.9, H-1 ),
5.15 (br s, 2H, OH-30, OH-50), 4.87 (d,1H, J¼ꢁ6.5, OCHHO), 4.80 (d,1H,
OCHHO), 4.14 (m, 2H, H-20, H-30), 3.96 (ddd, 1H, J4 ,3 ¼5.6, J4 ,5 a¼1.9,
0
0
0
0
J4 ,5 b¼2.2, H-40), 3.81 (dd, 1H, J5 a,5 b¼ꢁ12.2, H-50a), 3.65 (dd, 1H, H-
50b), 3.56 (t, 2H, JCH,H¼6.2, OCH2CH2CH2NHCOCF3), 3.24 (m, 2H,
OCH2CH2CH2NHCOCF3), 1.72 (m, 2H, OCH2CH2CH2NHCOCF3). 13C
NMR (DMSO-d6): 167.75 (C]O), 163.02 (C4), 155.94 (q, J¼36.2,
COCF3), 153.82 (C2), 144.90 (C6), 132.57, 129.14, 128.30, 127.52 (Ph),
115.74 (q, J¼287.9, CF3), 96.12 (C5), 93.84 (OCH2O), 88.64 (C10), 84.35
(C40), 78.66 (C20), 67.68 (C30), 64.78 (OCH2CH2CH2NHCOCF3), 59.54
(C50), 36.61 (OCH2CH2CH2NHCOCF3), 28.31 (OCH2CH2CH2NH-
COCF3). LSI-MS (C22H25F3N4O8þHþ): 531.1699. Calcd 531.1703.
0
0
0
0
4.35. 9-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-
D
b-
-ribofuranosyl}-N2-isobutyrylguanine (18c)
Analogous desilylation of 15c (923 mg,1.22 mmol) yielded 18c as
a foam (574 mg, 91%). Rf 0.16 (B).1H NMR (DMSO-d6): 12.09 (br s,1H,
NH Guo),11.61 (br s,1H, NHiBu), 9.37 (br t,1H, NHCOCF3), 8.27 (s,1H,
H-8), 5.95 (d, 1H, J1 ,2 ¼6.2, H-1 ), 5.31 (d, 1H, J3 ,OH¼4.7, OH-30), 5.11
0
0
0
0
(t, 1H, J5 ,OH¼5.1, OH-50), 4.70 (d, 1H, J¼ꢁ6.9, OCHHO), 4.65 (d, 1H,
0
0
0
0
0
0
0
OCHHO), 4.56 (dd,1H, J3 ,2 ¼5.0, H-2 ), 4.28 (ddd,1H, J3 ,4 ¼2.1, H-3 ),
4.39. 9-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
3.96 (dt, 1H, J5 a,4¼J5 b,4¼2.8, H-40), 3.63 (ddd, 1H, J5 a,5 b¼ꢁ11.8, H-
50a), 3.57 (ddd,1H, H-50b), 3.47 (m,1H, OCHHCH2NHCOCF3), 3.35 (m,
1H, OCHHCH2NHCOCF3), 3.23–3.12 (m, 2H, OCH2CH2NHCOCF3), 2.76
(sept,1H, J¼6.9, iBu),1.12 (s, 3H, MeiBu),1.11 (s, 3H, MeiBu). 13C NMR
(DMSO-d6): 180.10 (C]O), 156.35 (q, J¼36.1, COCF3), 154.80 (C6),
148.82 (C2), 148.24 (C4), 137.46 (C8), 120.07 (C5), 115.82 (q, J¼288.3,
CF3), 94.19 (OCH2O), 86.16 (C10), 84.78 (C40), 79.04 (C20), 69.28 (C30),
65.07 (OCH2CH2NHCOCF3), 61.19 (C50), 38.93 (OCH2CH2NHCOCF3),
34.75 (CHiBu),18.77 (MeiBu). LSI-MS (C19H25F3N6O8þHþ): 523.1759.
Calcd 523.1759.
b-D
-ribofuranosyl}-N2-isobutyrylguanine (19c)
0
0
0
0
Analogous desilylation of a mixture of 16c and starting 4c (ratio of
9:1) (852 mg,1.10 mmol) yielded 19c as a foam (498 mg, 37% for two
steps). Rf 0.16 (B).1H NMR (DMSO-d6): 12.08 (br s,1H, NH Guo),11.60
(br s, 1H, NHiBu), 9.30 (br t, 1H, NHCOCF3), 8.26 (s, 1H, H-8), 5.95 (d,
0
1H, J1 ,2 ¼6.5, H-1 ), 5.26 (d, 1H, J3 ,OH¼4.4, OH-30), 5.08 (t, 1H,
0
0
0
J5 ,OH¼5.3, OH-50), 4.69 (d,1H, J¼ꢁ6.9, OCHHO), 4.62 (d,1H, OCHHO),
0
0
0
0
0
0
0
4.59 (dd, 1H, J3 ,2 ¼5.0, H-2 ), 4.28 (ddd, 1H, J3 ,4 ¼2.3, H-3 ), 3.96 (dt,
1H, J5 a,4¼J5 b,4¼2.5, H-40), 3.71–3.53 (m, 2H, OCH2CH2CH2NHCOCF3),
0
0

6248
G.V. Bobkov et al. / Tetrahedron 64 (2008) 6238–6251
3.25–3.02 (m, 4H, H-50a, H-50b, OCH2CH2CH2NHCOCF3), 2.77 (sept,
1H, J¼6.9, iBu),1.55–1.49 (m, 2H, OCH2CH2CH2NHCOCF3),1.11 (m, 6H,
MeiBu).13C NMR (DMSO-d6): 180.10 (C]O),156.13 (q, J¼36.1, COCF3),
154.83 (C6), 148.87 (C2), 148.27 (C4), 137.59 (C8), 120.07 (C5), 115.91
(q, J¼288.3, CF3), 94.20 (OCH2O), 86.30 (C10), 84.79 (C40), 78.68 (C20),
69.25 (C30), 64.95 (OCH2CH2CH2NHCOCF3), 61.28 (C50), 36.49
(OCH2CH2CH2NHCOCF3), 34.81(iBu), 28.96(OCH2CH2CH2NHCOCF3),
18.84 (MeiBu). LSI-MS (C20H27F3N6O8þHþ): 537.1916. Calcd 537.1915.
d6): 11.21 (br s, 1H, NH), 9.39 (t, 1H, JCH,NH¼5.0, NHCOCF3), 8.33 (d,
1H, J6,5¼7.2, H-6), 8.02–7.28 (m, 17H, Bz, Tr), 7.18 (br s,1H, H-5), 6.93
(d, 2H, J¼9.0, mPhOMe), 5.87 (s, 1H, H-10), 5.30 (d, 1H, JOH,3 ¼6.2,
0
OH-30), 4.98 (d, 1H, J¼ꢁ6.5, O0CHHO), 4.85 (d, 1H, OCHHO), 4.35 (dd,
0
0
0
0
0
1H, J3 ,2 ¼5.0, J3 ,4 ¼8.4, H-3 ), 4.20 (d, 1H, H-2 ), 4.09 (dd, 1H,
J4 ,5 b¼1.2, H-40), 3.76 (s, 3H, OMe), 3.74–3.66 (m, 2H,
0
0
OCH2CH2NHCOCF3), 3.43–3.39 (m, 3H, H-50a, OCH2CH2NHCOCF3),
3.35 (dd, 1H, J5 a,5 b¼ꢁ10.9, H-50b). 13C NMR (DMSO-d6): 166.95
(C]O), 163.04 (C4), 158.25 (pPhOMe), 155.92 (q, J¼36.2, COCF3),
154.14 (C2), 144.19 (C6), 143.92, 143.65, 134.82, 135.97, 129.88,
127.77, 126.95 (Tr), 116.28 (q, J¼287.9, CF3), 113.27 (mPhOMe), 96.11
(C5), 93.78 (OCH2O), 89.44 (C10), 86.25 (Ph3C), 81.88 (C40), 78.48
(C20), 67.77 (C30), 65.06 (OCH2CH2NHCOCF3), 61.73 (C50), 54.95
(OMe), 39.23 (OCH2CH2NHCOCF3). LSI-MS (C41H38F3N4O9ꢁHþ):
787.2596. Calcd 787.2591.
0
0
4.40. 9-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
b-D
-ribofuranosyl}-N6-benzoyladenine (19d)
Analogous desilylation of 16d (965 mg,1.19 mmol) yielded 19d as
a foam (575 mg, 86%). Rf 0.19 (B). 1H NMR (CDCl3): 9.40 (br s, 1H,
NHBz), 8.70 (s, 1H, H-8), 8.17 (s, 1H, H-2), 8.02–7.48 (m, 6H, Bz,
0
0
0
0
0
0
NHCOCF3), 6.02 (d, 1H, J1 ,2 ¼7.4, H-1 ), 5.00 (dd, 1H, J2 ,3 ¼4.5, H-2 ),
4.64 (d,1H, J¼ꢁ6.9, OCHHO), 4.56 (d,1H, OCHHO), 4.53 (d,1H, H-30),
4.43. 9-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-5-
4.32 (d, 1H, J4 ,5 a¼1.2, H-40), 3.95 (dd, 1H, J5 a,5 b¼ꢁ12.8, H-50a), 3.76
(d, 1H, H-50b), 3.50–3.29 (m, 2H, OCH2CH2CH2NHCOCF3), 3.25–3.18
(m, 2H, OCH2CH2CH2NHCOCF3), 1.59–1.24 (m, 2H, OCH2CH2CH2NH-
COCF3). 13C NMR (CDCl3): 165.30 (C]O), 157.59 (q, J¼36.1, COCF3),
152.22 (C8), 151.43 (C6), 150.51 (C4), 143.43 (C2), 133.51, 133.14,
129.04, 128.16 (Ph), 125.20 (C5), 116.85 (q, J¼288.3, CF3), 96.01
(OCH2O), 89.42 (C10), 87.79 (C40), 80.12 (C20), 71.55 (C30), 66.78
(OCH2CH2CH2NHCOCF3), 63.09 (C50), 37.51 (OCH2CH2CH2NHCOCF3),
28.73 (OCH2CH2CH2NHCOCF3). LSI-MS (C23H25F3N6O7ꢁHþ):
553.1652. Calcd 553.1664.
O-(4-methoxytrityl)-
b-D
-ribofuranosyl}-N2-isobutyryl-
0
0
0
0
guanine (20c)
Analogous tritylation of nucleoside 18c (450 mg, 0.86 mmol)
yielded 20c as a foam (569 mg, 83%). Rf 0.25 (A). 1H NMR (CDCl3):
12.18 (br s, 1H, NH Guo), 8.95 (br s, 1H, NHiBu), 7.80–7.20 (m, 14H,
H-8, NHCOCF3, Tr), 6.79 (d, 2H, J¼9.0, mPhOMe), 5.98 (d, 1H,
0
0
0
0
0
0
J1 ,2 ¼4.7, H-1 ), 4.87 (dd, 1H, J2 ,3 ¼5.3, H-2 ), 4.81 (d, 1H, J¼ꢁ7.2,
0
0
0
OCHHO), 4.77 (d, 1H, OCHHO), 4.56 (dd, 1H, J3 ,4 ¼4.4, H-3 ), 4.21
(ddd, 1H, J4 ,5 a¼2.2, J4 ,5 b¼4.0, H-40), 3.75 (s, 3H, OMe), 3.71–3.60
0
0
0
0
(m, 2H, OCH2CH2NHCOCF3), 3.54–3.45 (m, 3H, OCH2CH2NHCOCF3,
H-50a), 3.28 (dd,1H, J5a ,5 b¼ꢁ10.5, H-50b), 2.20 (sept,1H, J¼6.9, iBu),
1.04 (d, 3H, MeiBu), 0.92 (d, 3H, MeiBu). 13C NMR (CDCl3): 179.46
(C]O), 159.01 (pPhOMe), 157.03 (q, J¼36.2, COCF3), 155.81 (C6),
148.56 (C2), 147.98 (C4), 136.17 (C8), 144.49, 135.41, 130.48, 128.53,
128.10, 127.36 (Ph), 121.85 (C5), 116.48 (q, J¼288.1, CF3), 113.45
(mPhOMe), 96.19 (OCH2O), 87.01 (Ph3C), 86.96 (C10), 84.05 (C40),
80.22 (C20), 70.40 (C30), 66.85 (OCH2CH2NHCOCF3), 63.72 (C50),
55.38 (OMe), 39.88 (OCH2CH2NHCOCF3), 36.16 (iBu), 18.84, 18.76,
(MeiBu). LSI-MS (C39H41F3N6O9ꢁHþ): 793.2777. Calcd 793.2814.
0
0
4.41. 1-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-5-
O-(4-methoxytrityl)-b-D-ribofuranosyl}uracil (20a)
Nucleoside 18a (650 mg, 1.62 mmol) was dried by evaporation
with pyridine (2ꢂ20 ml). The residue was dissolved in dry pyridine
(30 ml), monomethoxytrityl chloride (970 mg, 3.1 mmol) was
added, and the resulted solution was kept in the dark for 16 h at
20 ꢀC. MeOH (1 ml) was added and after 30 min the mixture was
concentrated in vacuo to near dryness. The residue was dissolved in
methylene chloride (50 ml), and washed with 10% aqueous solution
of sodium bicarbonate (20 ml) and water (2ꢂ20 ml). The organic
layer was dried over anhydrous sodium sulfate, evaporated in
vacuo, evaporated with toluene (2ꢂ10 ml), and purified by column
chromatography on silica gel (30 g). The column was washed with
methylene chloride (200 ml) and methylene chloride–ethanol 99:1
(200 ml), and then eluted with methylene chloride–ethanol 98:2 to
give 20a as a foam. Yield 904 mg (80%). Rf 0.31 (A). 1H NMR (DMSO-
d6): 11.32 (br s, 1H, NH), 9.39 (t, 1H, JCH,NH¼6.8, NHCOCF3), 7.71 (d,
1H, J6,5¼8.1, H-6), 7.42–7.22 (m, 12H, Ph), 6.92 (d, 2H, J¼9.0,
4.44. 9-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-5-
O-(4-methoxytrityl)-b-D
-ribofuranosyl}-N6-benzoyl-
adenine (20d)
Analogous tritylation of nucleoside 18d (777 mg, 1.44 mmol)
yielded 20d as a foam (956 mg, 82%). Rf 0.30 (A). 1H NMR (CDCl3):
9.05 (br s,1H, NHBz), 8.71 (s,1H, H-8), 8.25 (s,1H, H-2), 8.02–7.21 (m,
18H, Bz, Tr, NHCOCF3), 6.83 (d, 2H, J¼8.9, mPhOMe), 6.28 (d, 1H,
0
0
0
0
0
0
J1 ,2 ¼4.9, H-1 ), 4.88 (dd, 1H, J2 ,3 ¼5.2, H-2 ), 4.85 (d, 1H, J¼ꢁ7.0,
0
0
0
0
0
0
mPhOMe), 5.85 (d, 1H, J1 ,2 ¼3.4, H-1 ), 5.31 (d, 1H, H-5), 4.82 (d, 1H,
OCHHO), 4.82 (d,1H, OCHHO), 4.52 (ddd,1H, J3 ,4 ¼4.2, J3 ,OH¼4.8, H-
30), 4.27 (ddd,1H, J4 ,5 a¼2.1, J4 ,5 b¼1.5, H-40), 3.78 (s, 3H, OMe), 3.65–
3.31 (m, 6H, H-50a, H-50b, OCH2CH2NHCOCF3), 2.95 (d,1H, OH-30).13C
NMR (CDCl3): 165.06 (C]O), 158.88 (pPhOMe), 157.72 (q, J¼36.8,
COCF3), 152.81 (C8), 151.89 (C6), 149.72 (C4), 144.04 (C2), 143.96,
135.10, 133.11, 129.05, 128.51, 128.12, 127.34 (Ph), 123.80 (C5), 115.96
(q, J¼288.5, CF3), 113.41 (mPhOMe), 96.10 (OCH2O), 87.23
(Ph3C), 86.86 (C10), 84.07 (C40), 80.65 (C20), 70.46 (C30), 66.98
(OCH2CH2NHCOCF3), 63.21 (C50), 55.37 (OMe), 39.66 (OCH2CH2NH-
COCF3). LSI-MS (C42H39F3N6O8þHþ): 813.2845. Calcd 813.2854.
0
0
0
0
0
0
J¼ꢁ6.9, OCHHO), 4.79 (d, 1H, OCHHO), 4.27 (t, 1H, J3 ,2 ¼5.0,
J3 ,4 ¼5.0, H-3 ), 4.24 (dd, 1H, H-2 ), 4.01 (dd, 1H, J4 ,5 b¼1.9, H-40),
0
0
0
0
0
0
3.75 (s, 3H, OMe), 3.66–3.62 (m, 2H, OCH2CH2NHCOCF3), 3.42–3.33
(m, 3H, H-50a, OCH2CH2NHCOCF3), 3.28 (dd, 1H, J5 b,5 a¼ꢁ10.6, H-
50b). 13C NMR (DMSO-d6): 162.80 (C4), 158.23 (pPhOMe), 156.23 (q,
J¼36.1, COCF3), 150.24 (C2), 144.03, 143.75 (Tr), 140.05 (C6), 134.56,
129.99, 127.92, 127.81, 126.86 (Tr), 116.32 (q, J¼288.2, CF3), 113.22
(mPhOMe), 101.46 (C5), 93.93 (OCH2O), 87.48 (C10), 86.15 (Ph3C),
82.51 (C40), 77.87 (C20), 68.49 (C30), 65.01 (OCH2CH2NHCOCF3),
62.66 (C50), 54.97 (OMe), 39.06 (OCH2CH2NHCOCF3). LSI-MS
(C34H33F3N3O9ꢁHþ): 684.2172. Calcd 684.2169.
0
0
4.45. 1-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
5-O-(4-methoxytrityl)-b-D-ribofuranosyl}uracil (21a)
4.42. 1-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-5-
O-(4-methoxytrityl)-
cytosine (20b)
b
-
D
-ribofuranosyl}-N4-benzoyl-
Analogous tritylation of nucleoside 19a (642 mg, 1.50 mmol)
yielded 21a as a foam (937 mg, 88%). Rf 0.31 (A). 1H NMR (CDCl3):
9.45 (br s, 1H, NH), 8.59 (d, 1H, J6,5¼8.2, H-6), 7.53 (br s, 1H,
NHCOCF3), 7.45–7.20 (m, 012H, Ph), 6.85 (d, 2H, J¼9.0, mPhOMe),
Analogous tritylation of nucleoside 18b (350 mg, 0.67 mmol)
yielded 20b as a foam (431 mg, 81%). Rf 0.32 (A). 1H NMR (DMSO-
0
0
5.96 (d, 1H, J1 ,2 ¼1.6, H-1 ), 5.29 (d, 1H, H-5), 5.00 (d, 1H, J¼ꢁ6.7,

G.V. Bobkov et al. / Tetrahedron 64 (2008) 6238–6251
6249
0
0
0
0
0
0
OCHHO), 4.87 (d, 1H, OCHHO), 4.49 (dd, 1H, J3 ,2 ¼5.0, J3 ,4 ¼7.8, H-
Bz, Tr, NHCOCF3), 6.81 (d, 2H, J¼9.0, mPhOMe), 6.24 (d, 1H, J1 ,2 ¼5.0,
30), 4.22 (dd, 1H, H-20), 4.05 (ddd, 1H, J4 ,5 b¼2.2, J4 ,5 b¼2.5, H-40),
H-10), 4.98 (dd,1H, J2 ,3 ¼5.3, H-2 ), 4.81 (m, 2H, OCH2O), 4.52 (dd,1H,
0
0
0
0
0
0
0
0
J3 ,4 ¼3.7, H-3 ), 4.28 (ddd,1H, J4 ,5 a¼3.4, J4 ,5 b¼4.4, H-40), 3.78 (s, 3H,
0
0
0
0
0
0
3.79 (s, 3H, OMe), 3.75–3.65 (m, 2H, OCH2CH2CH2NHCOCF3), 3.61
(dd, 1H, J5 a,5 b¼11.2, H-50a), 3.55 (dd, 1H, H-50b), 3.47–3.43 (m, 2H,
OCH2CH2CH2NHCOCF3), 3.04 (br s, 1H, OH-30), 1.90–1.83 (m, 2H,
OCH2CH2CH2NHCOCF3). 13C NMR (CDCl3): 163.05 (C4), 159.04
(pPhOMe), 156.01 (q, J¼36.5, COCF3), 149.84 (C2), 144.04, 143.78
(Tr), 139.99 (C6), 136.18, 134.80, 130.61, 128.99, 127.92, 127.81,
126.86 (Tr), 117.02 (q, J¼288.2, CF3), 113.53 (mPhOMe), 102.49 (C5),
95.73 (OCH2O), 88.48 (C10), 87.04 (Ph3C), 83.23 (C40), 80.56 (C20),
68.93 (C30), 66.73 (OCH2CH2CH2NHCOCF3), 61.48 (C50), 55.39
(OMe), 37.68 (OCH2CH2CH2NHCOCF3), 28.64 (OCH2CH2CH2NH-
COCF3). LSI-MS (C35H35F3N3O9ꢁHþ): 698.2332. Calcd 698.2325.
OMe), 3.55 (dd, 1H, J5 a,5 b¼ꢁ10.6, H-50a), 3.48–3.42 (m, 3H, H-50b,
OCH2CH2CH2NHCOCF3), 3.28–3.24 (m, 2H, OCH2CH2CH2NHCOCF3),
2.98 (br s, 1H, OH-30), 1.65–1.60 (m, 2H, OCH2CH2CH2NHCOCF3). 13C
NMR (CDCl3): 165.14 (C]O), 158.94 (pPhOMe), 157.65 (q, J¼36.3,
COCF3), 152.79 (C8), 152.13 (C6), 149.91 (C4), 144.08 (C2), 143.93,
141.98,135.82,133.04,129.05,128.57,128.07,127.30 (Ph),123.87 (C5),
116.43 (q, J¼287.2, CF3), 113.45 (mPhOMe), 95.90 (OCH2O), 87.24
(Ph3C), 87.07 (C10), 84.34 (C40), 80.03 (C20), 70.67 (C30), 66.81
(OCH2CH2CH2NHCOCF3), 63.42 (C50), 55.38 (OMe), 37.64
(OCH2CH2CH2NHCOCF3), 28.64 (OCH2CH2CH2NHCOCF3). LSI-MS
(C43H41F3N6O8ꢁHþ): 825.2824. Calcd 825.2865.
0
0
0
0
4.46. 1-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
5-O-(4-methoxytrityl)-
b-D
-ribofuranosyl}-N4-benzoyl-
4.49. 1-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-3-
O-[(2-cyanoethyl)(diisopropylamino)phosphanyl]-5-O-(4-
cytosine (21b)
methoxytrityl)-b-D-ribofuranosyl}uracil (2a)
Analogous tritylation of nucleoside 19b (371 mg, 0.70 mmol)
yielded 21b as a foam (480 mg, 86%). Rf 0.32 (A). 1H NMR (CDCl3):
8.75 (br s, 1H, NH), 8.55 (d, 1H, J6,5¼7.5, H-6), 8.13 (br s, 1H,
NHCOCF3), 7.87–7.32 (m, 18H, Bz, Tr, H-5), 6.88 (d, 2H, J¼8.7,
mPhOMe), 5.98 (s, 1H, H-10), 5.08 (d, 1H, J¼ꢁ6.5, OCHHO), 4.95 (d,
The methoxytritylated derivative 20a (535 mg, 0.78 mmol) was
dissolved in 6 ml dichloromethane under argon and ethyl-
(diisopropyl)amine (407
mL, 2.34 mmol) and 2-cyanoethyl diiso-
propylphosphoramidochloridite (261
mL, 1.17 mmol) were added
0
0
0
0
0
1H, OCHHO), 4.49 (dd, 1H, J3 ,2 ¼5.0, J3 ,4 ¼9.0, H-3 ), 4.27 (d, 1H,
H-20), 4.12 (d, 1H, H-40), 3.82–3.79 (m, 4H, H-50a, OMe), 3.64–3.59
(m, 3H, OCH2CH2CH2NHCOCF3, H-50b), 3.53–3.35 (m, 2H,
OCH2CH2CH2NHCOCF3), 3.11 (br s, 1H, OH-30), 1.91–1.86 (m, 2H,
OCH2CH2CH2NHCOCF3). 13C NMR (CDCl3): 167.01 (C]O), 162.72
(C4), 159.05 (pPhOMe), 155.15 (q, J¼36.2, COCF3), 149.88 (C2),
144.90 (C6),143.97,143.73,136.13,135.97,129.88,127.77,127.51 (Tr),
116.38 (q, J¼287.3, CF3), 113.58 (mPhOMe), 97.04 (C5), 95.75
(OCH2O), 90.22 (C10), 87.66 (Ph3C), 82.95 (C40), 80.16 (C20), 68.36
(C30), 66.18 (OCH2CH2CH2NHCOCF3), 61.07 (C50), 55.37 (OMe), 37.42
(OCH2CH2CH2NHCOCF3), 28.57 (OCH2CH2CH2NHCOCF3). LSI-MS
(C42H40F3N4O9ꢁHþ): 801.2754. Calcd 801.2747.
and, after stirring the solution for 3 h, TLC indicated complete re-
action. A 10% aqueous solution of sodium hydrogen carbonate
(2 ml) was added, the solution was stirred for 10 min, and parti-
tioned between methylene chloride (50 ml) and aqueous sodium
carbonate (30 ml). The organic phase was washed with aqueous
sodium chloride (2ꢂ30 ml) and the aqueous phases were back
extracted with methylene chloride (20 ml). Evaporation of the or-
ganics left an oil, which was flash purified on 50 g of silica gel
(hexane–acetone–triethylamine, 124:75:1) to afford the product as
a foam after coevaporation with dichloromethane. The foam was
dissolved in 2 ml of dichloromethane and precipitated in 150 ml
cold (ꢁ70 ꢀC) hexane–diisopropyl ether (9:1) to afford 551 mg
(0.62 mmol, 80%) of the title product as a white powder. Rf 0.37
(hexane–acetone–triethylamine, 49:49:2dsolvent C). 31P NMR
(CDCl3): 151.44, 149.13. LSI-MS (C43H51N5O10F3P1þHþ): 886.3398.
Calcd 886.3404.
4.47. 9-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
5-O-(4-methoxytrityl)-
isobutyrylguanine (21c)
b-D
-ribofuranosyl}-N2-
Analogous to the previous procedure the following amidites
were prepared.
Analogous tritylation of nucleoside 19c (473 mg, 0.88 mmol)
yielded 21c as a foam (620 mg, 87%). Rf 0.25 (A). 1H NMR (CDCl3):
12.18 (br s,1H, NH Guo), 8.89 (br s,1H, NHiBu), 7.83–7.21 (m,14H, H-
4.50. 1-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-3-
O-[(2-cyanoethyl)(diisopropylamino)phosphanyl]-5-O-(4-
0
0
8, NHCOCF3, Tr), 6.79 (d, 2H, J¼8.7, mPhOMe), 5.96 (d, 1H, J1 ,2 ¼5.6,
H-10), 5.00 (dd,1H, J2 ,3 ¼5.0, H-2 ), 4.75 (d,1H, J¼ꢁ6.9, OCHHO), 4.72
methoxytrityl)-b-D
-ribofuranosyl}-N4-benzoylcytosine (2b)
0
0
0
0
0
0
0
0
(d,1H, OCHHO), 4.55 (dd,1H, J3 ,4 ¼3.4, H-3 ), 4.22 (dd,1H, J4 ,5 b¼2.7,
H-40), 3.75 (s, 3H, OMe), 3.54–3.49 (m, 2H, OCH2CH2CH2NHCOCF3),
3.41–3.34 (m, 3H, OCH2CH2NHCOCF3, H-50a), 3.24 (dd, 1H,
Starting with compound 20b (736 mg, 0.93 mmol), 764 mg of the
required amidite was obtained (0.77 mmol, 83%). Rf 0.42 (solvent C).
31P NMR (CDCl3): 151.75, 149.32. LSI-MS (C50H56N6O10F3P1þHþ):
989.3818. Calcd 989.3826.
J5a ,5 b¼ꢁ10.6, H-50b), 2.07 (sept, 1H, J¼7.0, iBu), 1.70 (m, 2H,
0
0
OCH2CH2CH2NHCOCF3), 0.99 (d, 3H, MeiBu), 0.86 (d, 3H, MeiBu). 13
C
NMR (CDCl3): 179.40 (C]O), 158.97 (pPhOMe), 157.71 (q, J¼36.1,
COCF3), 155.81 (C6), 149.77 (C2), 147.89 (C4), 135.40 (C8), 144.24,
138.81, 130.48, 128.11, 127.36 (Ph), 121.90 (C5), 116.07 (q, J¼288.2,
CF3), 113.44 (mPhOMe), 95.79 (OCH2O), 86.95 (Ph3C), 86.85 (C10),
84.39 (C40), 79.35 (C20), 70.33 (C30), 66.45 (OCH2CH2CH2NHCOCF3),
63.80 (C50), 55.35 (OMe), 37.48 (OCH2CH2CH2NHCOCF3), 36.10 (iBu),
4.51. 9-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-3-
O-[(2-cyanoethyl)(diisopropylamino)phosphanyl]-5-O-(4-
methoxytrityl)-b-D
-ribofuranosyl}-N2-isobutyrylguanine (2c)
Starting with compound 20c (240 mg, 0.31 mmol), 248 mg of the
required amidite was obtained (0.24 mmol, 82%). Rf 0.33 (solvent C).
31P NMR (CD3CN): 149.76, 149.47. LSI-MS (C48H58F3N8O10P1þHþ):
995.3986. Calcd 995.4044.
28.74
(OCH2CH2CH2NHCOCF3),
18.73
(MeiBu).
LSI-MS
(C40H43F3N6O9þHþ): 809.3087. Calcd 809.3116.
4.48. 9-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
5-O-(4-methoxytrityl)-
benzoyladenine (21d)
b-D
-ribofuranosyl}-N6-
4.52. 9-{2-O-[(2-(2,2,2-Trifluoroacetamido)ethoxy)methyl]-3-
O-[(2-cyanoethyl)(diisopropylamino)phosphanyl]-5-O-(4-
methoxytrityl)-b-D
-ribofuranosyl}-N6-benzoyladenine (2d)
Analogous tritylation of nucleoside 19d (492 mg, 0.89 mmol)
yielded21d asafoam(625 mg, 85%). Rf 0.30(A).1HNMR(CDCl3):9.04
(br s,1H, NHBz), 8.69 (s,1H, H-8), 8.22 (s,1H, H-2), 8.03–7.22 (m,18H,
Starting with compound 20d (674 mg, 0.83 mmol), 669 mg
of the required amidite was obtained (0.66 mmol, 79%). Rf 0.40

6250
G.V. Bobkov et al. / Tetrahedron 64 (2008) 6238–6251
(solvent C). 31P NMR (CD3CN): 149,95, 149.49. LSI-MS
Oligonucleotides were characterized and their purity was
checked by HPLC/MS on a capillary chromatograph (CapLC, Waters,
Milford, MA). Columns of 150ꢂ0.3 mm length (LCPackings, San
Francisco, CA) were used. Oligonucleotides were eluted with an
acetonitrile gradient in 50 mM triethylammonium adjusted to pH
(C51H56F3N8O9P1þHþ): 1013.3868. Calcd 1013.3938.
4.53. 1-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
3-O-[(2-cyanoethyl)(diisopropylamino)phosphanyl]-5-O-(4-
methoxytrityl)-
b-
D-ribofuranosyl}uracil (3a)
8.0 with 1,1,1,3,3,3-hexafluoropropan-2-ol. The flow rate was 5 mL/
min. Electrospray spectra were acquired on an orthogonal accel-
eration/time-of-flight mass spectrometer (Q-Tof-2, Micromass,
Manchester, UK) in the negative ion mode. The scan time used was
2 s. The combined spectra from a chromatographic peak were
deconvoluted using the MaxEnt algorithm of the software (Mas-
slynx 3.4, Micromass, Manchester, UK). Theoretical oligonucleotide
molecular weights were calculated using the monoisotopic atomic
weights.
Starting from compound 21a (0.60 mmol, 421 mg), 462 mg of
the required amidite was obtained (0.51 mmol, 85%). Rf 0.37 (solvent
C). 31P NMR (CDCl3): 151.20,149.26. LSI-MS (C44H53N5O10F3P1þHþ):
900.3558. Calcd 900.3560.
4.54. 1-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
3-O-[(2-cyanoethyl)(diisopropylamino)phosphanyl]-5-O-(4-
methoxytrityl)-b-D
-ribofuranosyl}-N4-benzoylcytosine (3b)
Acknowledgements
Starting with compound 21b (700 mg, 0.87 mmol), 676 mg of the
required amidite was obtained (0.67 mmol, 78%). Rf 0.43 (solvent C).
31P NMR (CDCl3): 151.38, 149.20. LSI-MS (C51H58N6O10F3P1þHþ):
1003.3975. Calcd 1003.3982.
Authors thank Valentin V. Novikov for NMR measurements and
Guy Schepers for technical assistance in the synthesis of oligo-
ribonucleotides. This work was supported by Russian Foundation
for Basic Research, INTAS, and KUL Research Council.
4.55. 9-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
3-O-[(2-cyanoethyl)(diisopropylamino)phosphanyl]-5-O-(4-
methoxytrityl)-b-D
-ribofuranosyl}-N2-isobutyrylguanine (3c)
Supplementary data
Starting with compound 21c (280 mg, 0.34 mmol), 301 mg of the
required amidite was obtained (0.29 mmol, 86%). Rf 0.34 (solvent D).
31P NMR (CD3CN): 149.68, 149.49. LSI-MS (C49H60N8O10F3P1þHþ):
1009.4139. Calcd 1009.4200.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.04.110.
References and notes
4.56. 9-{2-O-[(3-(2,2,2-Trifluoroacetamido)propoxy)methyl]-
3-O-[(2-cyanoethyl)(diisopropylamino)phosphanyl]-5-O-(4-
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