Novel 1′-homo-: N -2′-deoxy-α-nucleosides: Synthesis, characterization and biological activity

Article abstract of DOI:10.1039/d0ra03254a

For the first time, a series of novel 1′-homo-N-2′-deoxy-α-nucleosides containing natural nucleobases as well as 5-fluoro and 5-iodopyrimidine analogs have been synthesized in an efficient manner. Additionally, a high yield protocol for the assembly of a dimeric scaffold containing two sugar moieties linked to the N-1 and N-3 positions of a single pyrimidine base has been accomplished. The structures of the novel homonucleosides were established by a single crystal X-ray structure of 1′-homo-N-2′-deoxy-α-adenosine and NMR studies. The biological activity of these 1′-homo-N-2′-deoxy-α-nucleosides as antiviral (HIV-1 and HBV) and cytotoxic studies was measured in multiple cell systems. The unique structure and easy accessibility of these compounds may allow their use in the design of new nucleoside analogs with potential biological activity and as a scaffold for combinatorial chemistry.

Full text of DOI:10.1039/d0ra03254a

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0
0
Novel 1 -homo-N-2 -deoxy-a-nucleosides:
synthesis, characterization and biological activity†
Cite this: RSC Adv., 2020, 10, 15815
a
a
b
c
Alejandro Carnero, Virginia Martın-Nieves, Yogesh S. Sanghvi, Olivia O. Russel,
´
Leda Bassit, Raymond F. Schinazi, Susana Fernandez * and Miguel Ferrero *a
c
c
a
´
0
0
For the first time, a series of novel 1 -homo-N-2 -deoxy-a-nucleosides containing natural nucleobases as
well as 5-fluoro and 5-iodopyrimidine analogs have been synthesized in an efficient manner. Additionally,
a high yield protocol for the assembly of a dimeric scaffold containing two sugar moieties linked to the N-1
and N-3 positions of a single pyrimidine base has been accomplished. The structures of the novel
0
0
homonucleosides were established by a single crystal X-ray structure of 1 -homo-N-2 -deoxy-a-
Received 13th February 2020
Accepted 14th April 2020
0
0
adenosine and NMR studies. The biological activity of these 1 -homo-N-2 -deoxy-a-nucleosides as
antiviral (HIV-1 and HBV) and cytotoxic studies was measured in multiple cell systems. The unique
structure and easy accessibility of these compounds may allow their use in the design of new nucleoside
analogs with potential biological activity and as a scaffold for combinatorial chemistry.
DOI: 10.1039/d0ra03254a
rsc.li/rsc-advances
analogs, we embarked on the synthesis of less common modi-
1
. Introduction
0
0

cation 1 -homo-N-2 -deoxy-a-nucleosides where two features
Nucleosides are building-blocks of nucleic acids, where these are incorporated in a single molecule. To the best of our
0
molecules play a key role in the genetic process of all living knowledge, this is the rst report on the synthesis of 1 -homo-N-
0
organisms. Natural nucleosides offer a unique framework for 2 -deoxy-a-nucleosides containing all four natural bases in an
the design of novel therapeutic drugs due to their central efficient manner. Additionally, herein we describe the synthesis
function in biological processes. As a result, over thirty chemi- of a bifunctional scaffold where two sugar units were linked to
cally modied nucleosides and their analogs are on the market a single pyrimidine base.
1
for the treatment of cancer and viral infections. Undoubtedly
Considering the importance of nucleoside analogs as
nucleoside scaffolds have been an excellent starting point for bioactive motif, we reasoned that new methods for the synthesis
0
0
introducing chemical modications leading to the discovery of of 1 -homo-N-2 -deoxy-a-nucleosides are warranted. Hitherto,
0
biologically functional molecules. In nature, nucleosides two major methods were used to prepare 1 -homo-N-nucleo-
appear mainly as b-anomers and rarely as the a-anomers. More sides: (i) introduction of the nucleobase by nucleophilic
0
recently the syntheses of a-anomeric nucleosides have attracted displacement of a leaving group at C-1 exocyclic methyl group
wide attention due to their unique properties and potential of the pentofuranose ring; and (ii) de novo construction of the
2
applications. Additionally, the position of the glycosidic bond nucleobase by condensation reactions from methylamino
0
0
4
could be altered by inserting another carbon atom to create 1 - derivatives at C-1 .
homo-N-nucleoside structures. This structural motif imparts
Following these routes, 1 -homo-N-bicyclic carbonucleosides
several unique features such as the absence of an anomeric 1 (Fig. 1), 1 -homo-N-bicyclico-[2.2.1]heptane nucleosides 2,
0
5
0
6
0
7
0
effect, enzymatic and chemical stability of the glycosidic bond, emissive 1 -homo-N-nucleosides 3, and 1 -homo-N-locked
8
conformational exibility, extra lipophilicity and increased nucleoside 4 were synthesized. Also, a-nucleosides analogs
distance between the 5 -hydroxyl group and the base. In our on- such as arabinonucleosides 5 or 2 -deoxy-a-nucleosides 6 are
going quest for the design and synthesis of novel nucleoside easily formed due to reduced steric hindrance compared with b-
0
3
0
2,9
ribonucleosides.
Additionally, a-nucleosides are used to
prepare a-oligonucleotides which leads to more stable
duplexes.
a
Departamento de Qu ´ı mica Org a´ nica
3006-Oviedo, Asturias, Spain. E-mail: mferrero@uniovi.es; fernandezgsusana@
e
Inorg a´ nica, Universidad de Oviedo,
10
3
Related with the research described in this manuscript, b-
uniovi.es
b
1
1
12
0
ribo and a-ribo 1 -homo-N-nucleosides (7 and 8, respectively)
have been prepared with variable success due to the use of
multistep process and undesired side reactions. Whereas, fewer
Rasayan Inc., 2802 Crystal Ridge Road, Encinitas, CA 92024-6615, USA
c
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of
Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
0
0
†
Electronic supplementary information (ESI) available: Copies of 1D and 2D examples are available related to the synthesis of 1 -homo-N-2 -
spectra. CCDC 1980305. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/d0ra03254a
deoxynucleosides. For example, b-deoxy derivatives (9) were
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0
0
Fig.
2
Structures of a/b-ribo and a/b-2 -deoxy 1 -homo-N-
nucleosides.
demonstrates a highly efficient protocol compared to the liter-
16b
ature report for the corresponding b-anomer.
Protection of the hydroxyl groups with tert-butyldimethylsilyl
chloride (TBSCl) in the presence of imidazole gave silyl ether
derivative 14. The reduction of ester 14 with lithium aluminum
ꢁ
hydride in THF at ꢀ45 C afforded aer 30 min alcohol 15 in
0
Fig. 1 Structures of 1 -homo-N-nucleosides and/or a-nucleosides.
9
0% yield. It is noteworthy that higher reaction temperatures
during reduction leads to deprotection of the silyl groups and
low temperature is critical to the successful outcome. Trans-
formation of the alcohol into the mesylate 16 was achieved in
excellent yield with methanesulfonyl chloride and catalytic
DMAP in pyridine.
1
3a
13b,c
described by Saladino and Crucianelli, Doboszewski,
and
13d
Herdewijn. In relation to the closest work described here, that
is, the synthesis of a-deoxy 1 -homo-N-2 -nucleosides only
Beaucage and co-workers have reported the synthesis with one
nucleobase, thymine (10c).
Our pursuit for the design of novel nucleosides and the
development of their synthesis protocols,
report the synthesis of 1 -homo-N-2 -deoxy-a-nucleosides 10
with both purine and pyrimidine nucleobases. Installation of
bioactive 5-uoro and 5-iodo uracil derivatives is also demon-
strated to access new structures and test their biological activ-
ities. Eight modied nucleosides reported herein were tested for
their biological activity as antiviral against HIV-1 and HBV.
Their cytotoxicity assay is also included in this study.
0
0
14
With mesylate 16 in hand, the stage was set for rapid
synthesis of a-homonucleosides 10. Next, we opted for the base
mediated displacement reaction using K
2 3
CO and 18-crown-6 in
8,15
here we wish to
DMF. To our delight, the coupling of unprotected adenine base
0
0
ꢁ
0
with mesylate 16 under these conditions at 90 C furnished 1 -
0
homo-N-2 -deoxy-a-adenosine (17a) in 84% yield aer column
chromatography purication. With the guanine base, the reac-
tion of mesylate 16 under similar conditions furnished
a complex mixture of products.
Under identical reaction conditions, uracil, a pyrimidine
base when coupled with mesylate 16 furnished a mixture of two
0
0
products. The expected 1 -homo-N-2 -deoxy-a-uridine (17b) was
isolated in 45% yield. The second product was characterized as
a dimer 18b, in which the uracil is linked with two deoxyribose
moieties at the N-1 and N-3 positions of the base. The structure
2
. Results and discussion
Synthesis of 1 -homo-N-2 -deoxy-a-nucleosides
0
0
0
Beaucage and coworkers reported on the synthesis of 1 -homo- of dimer 18b was supported by spectral data.
a-thymidine where pyrimidine ring was constructed via an
Interestingly, the coupling of thymine base with mesylate 16
acyclic analog. This approach is not practical for the synthesis furnished two products where desired homonucleoside 17c was
of multiple analogs containing both natural and unnatural isolated in 12% yield and dimer 18c in 55% yield (Scheme 1).
nucleobases. Therefore, we wish to develop a new synthetic Similarly, the coupling of 5-uorouracil base with mesylate 16
14
0
route which permits the synthesis of any 1 -homo-a-nucleoside resulted in the formation of dimer 18d in 73% yield as a major
analog from a single precursor such as sugar derivative 11. To
0
0
prepare the 1 -homo-N-2 -deoxy-a-nucleoside derivatives 10, we
envisioned a synthetic approach wherein the nucleobase was
introduced by nucleophilic displacement of a leaving group in
sugar precursor 11, readily obtained from the a-cyano sugar
16
derivative 12 (Fig. 2 and 3).
Therefore, nitrile 12 was converted into the corresponding
methyl ester by treatment with potassium hydroxide in MeOH/
H O. Under these conditions, removal of the toluoyl protecting
2
groups is also observed, affording compound 13 in 75% isolated
yield aer chromatography (Scheme 1). One-pot deprotection of
0 0
1 -homo-N-2 -deoxy-a-
Fig.
3
Retrosynthetic
analysis
to
toluoyl groups, hydrolysis of nitrile and in situ esterication nucleosides.
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Scheme 1 Reaction conditions: (a) KOH, MeOH/H
2
O, rt, 3 h (75%); (b)
ꢁ
, THF, ꢀ45 ꢁC,
TBSCl, imidazole, CH
2
Cl
2
, 50 C, 5 h (85%); (c) LiAlH
4
ꢁ
3
0 min (90%); (d) MsCl, DMAP, Py, 0 C to rt, 24 h (95%).
product along with 17d in 14% yield. This observation is
unprecedented where a dimer is obtained as a major product
and offers a new synthetic pathway to the assembly of unique
nucleoside scaffolds.
The synthesis of 1 -homo-N-2 -deoxy-a-cytidine was also
complicated due to the formation of two products. Reaction of
Fig. 4 HMBC spectra enlargements of: (a) 17e and (b) its N-3 analog.
0
0
Since alternative coupling protocol failed to improve the
outcome of the reaction and the formation of desired product,
we revisited the rst protocol offering a viable option. This time,
we replaced the mesylate with tosylate hoping that we might
observe better coupling efficiency and overall yield.
1
6 with cytosine gave a mixture of N-1 (compound 17e) and N-3
see Fig. 4b) coupled nucleosides. The structure of these prod-
ucts was established by homonuclear (COSY) and heteronuclear
(
1
3
1
(
HSQC, HMBC) correlations. In the C– H HMBC experiment
The synthesis of tosylate 20 (Scheme 3) was straightforward
by the reaction of alcohol 15 with p-toluensulfonyl chloride
for 17e, a correlation cross-peak was observed between the H6
0
proton of the base and the methylene carbon at 6 -position.
(TsCl) and catalytic DMAP in pyridine. Next, we performed the
However, in the N-3 derivative this cross-peak does not exist.
In an attempt to improve the yield of the desired pyrimidine
coupled products, other strategies were tested. Glycosylation
coupling reaction of 20 with the corresponding nucleobase in
17
under Vorbr u¨ ggen's conditions required acetate 19 (Scheme
), which was easily prepared from 15 by treatment with acetic
anhydride, Et N, and DMAP in CH Cl . Reaction of 19 with
2
3
2
2
silylated bases such as uracil or 5-uorouracil or 5-iodouracil in
the presence of trimethylsilyl triate failed to provide the
coupled product, while deprotection of the TBS groups was
observed.
The Mitsunobu reaction is an important technique in
nucleoside synthesis for the direct coupling of alcohols with
bases under mild conditions. Thus, treatment of 15 with uracil,
0
0
Ph P and DIAD generated 1 -homo-N-2 -deoxy-a-uridine (17b),
3
but with only 15% yield. The low yield is due, in part, to the
difficulty of isolating the product during chromatography, since
several byproducts are obtained post Mitsunobu reaction.
Scheme 2 Reaction conditions: (a) Ac
2
O, Et
3
N, DMAP, CH
2
Cl
2
, rt, 2 h
ꢁ
(
90%); (b) (i) Base (U, 5-FU, 5-IU), BSA, MeCN, 80 C, 1 h, (ii) TMSOTf,
ꢁ
ꢁ
ꢁ
ꢁ
0 C to 80 C; (c) Ph P, DIAD, uracil, THF, ꢀ10 C to 25 C, 24 h (15%).
3
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products were observed when 20 was coupled with the guanine
base.
Finally, the treatment of compounds 17a–f with tetrabuty-
0
0
lammonium uoride (TBAF) in THF afforded the 1 -homo-N-2 -
deoxy-a-nucleosides 10a–f in 90–95% yield. The structure of all
derivatives was established by NMR homonuclear (COSY) and
heteronuclear (HSQC, HMBC) correlations. Unambiguous
conrmation of the structure of the synthesized compounds
was obtained by a single crystal X-ray analysis of 10a (Fig. 5).
Single crystal X-ray data for compound 10a is given in Table
0
1
. Homo-N-2 -deoxynucleoside analog 10a crystallized as col-
19
ourless small crystals. Fig. 5 is a Chimera drawing, which
corresponds to asymmetric unit X-ray diffraction studies of
20
compound 10a. Note that the sugar conformation is North
0
0
type with the 2 -exo and 3 -endo congurations. The structure
shows three molecules per asymmetric unit linked by H-bonds,
that is, six molecules per crystal.
The formation of various dimers 18 is synthetically impor-
tant because it offers an access to the assembly of bifunctional
0
2
-deoxynucleoside analogs. Literature search for reports on
similar structures has been limited to two examples. First report
21
1
3
by Prystas and Sorm describing the formation of N ,N -diri-
ꢁ
Scheme 3 Reaction conditions: (a) TsCl, DMAP, Py, 0 C to rt, 9 h
Bz
ꢁ
bofuranosyl derivative as a byproduct during ribosylation of 6-
(
90%); (b) B ¼ A, U, T , 5-FU, C, 5-IU, K
2 3
CO , 18-crown-6, DMF, 90 C,
ꢁ
methyl-4-methoxy-2(1H)-pyrimidinone with
a ribofuranosyl
7
–8 h; (c) TBAF, THF, 25 C, 2 h (90–95%).
chloride derivative. In the second example, Zhang and co-
22
workers reported the isolation of a similar derivative in the
synthesis of isonucleosides. In order to further investigate the
importance of this bifunctional nucleoside, we have evaluated
the biological activity of dimeric compounds 21 (Scheme 4). For
that, desilylation of 18d and 18f with TBAF in THF furnished the
desired derivatives 21d and 21f in 80% and 75% yield,
respectively.
the presence of K CO and 18-crown-6. The reaction of 20 with
2
3
adenine proceeds with excellent yield, giving rise to a-homo-
nucleoside 17a with a 91% isolated yield, slightly higher than
when the reaction was carried out with mesylated 16. Signicant
improvement was observed when 20 reacted with uracil or
0
0
0
cytosine, isolating 1 -homo-N-2 -deoxy-a-uridine (17b) and 1 -
0
homo-N-2 -deoxy-a-cytidine (17e) with 65% and 69% yield,
respectively, versus 45% and 20% yield obtained from the
mesylate derivative. However, the coupling of the tosylated
derivative 20 with thymine led exclusively to the dimer 18c. To
Biological evaluation
23
Antiviral assays against HIV-1. A set of eight compounds
the best of our knowledge, this is rst report of dimer 18c 10a–f and 21d,f were tested against HIV-1 (strain LAI) and
0
0
synthesis in high yield. Next, in order to control the regiose- compared to 3 -azido-3 -deoxythymidine (AZT, zidovudine) as
lectivity of the coupling with thymine, the N-3-position of the a control in an assay with human peripheral blood mono-
base was protected. The reaction was carried out according to nuclear (PBM) cells. Positive control AZT exhibited expected
18
the procedure described by Ludek and Meier. For that, anti-HIV-1 activity, with EC50 of 0.006 mM. There was no anti-
thymine was allowed to react with benzoyl chloride in HIV activity observed from the six homonucleosides 10a–f and
3
acetonitrile-pyridine to give N -benzoylthymine. Reaction of 20 the two dimeric compounds 21d,f tested, all with an EC50 > 10
3
and N -benzoylthymine under the reaction conditions indicated mM.
0
0
23c,24
above afforded 1 -homo-N-2 -deoxy-a-thymidine (17c) in 30%
Antiviral assays against HBV.
As expected, the control
yield, although the major product of the reaction was still the Lamivudine demonstrates desired antiviral response, with an
dimer 18c, probably due to the in situ deprotection of the base
during the coupling. Nevertheless, the formation of the desired
3
product 17c has been considerably improved when N protected
thymine was utilized.
The coupling of 20 and 5-uorouracil or 5-iodouracil was
performed next. The major product was the dimer derivative but
the N-1 coupled analog was also formed in 15% and 13% yield,
respectively. In both cases, the N-3 protection of the base did
not improve the yield of the N-1 substituted product. Multiple
0
0
Fig. 5 X-ray structure of 1 -homo-N-2 -deoxy-a-adenosine (10a).
The structure shows three molecules per asymmetric unit.
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Table 1 Crystal data for homo-N-nucleoside analog 10a
3.50 (m, 1H, H
0
), 3.59 (dd, 1H, H
0
, J ¼ 11.8, 3.9 Hz), 3.85 (q, 1H,
5
5
H4
H6
0
, J ¼ 4.5 Hz), 4.25 (dt, 1H, H
0
, J ¼ 6.6, 5.2 Hz), 4.38 (m, 2H,
3
Formula
C
11
H
15
N
5
O
3
13
0
), 4.45 (m, 1H, H
0
), 8.16 (s, 1H, H ) 8.20 (s, 1H, H ) ppm;
C
1
2
8
Molecular weight
Crystal system
Space group
265.28
Monoclinic
P2
15.8711 (6)
8.04111 (18)
16.4342 (5)
6
NMR (75.5 MHz, MeOH-d ): d 38.5 (C
0
), 48.8 (C6
0
), 63.3 (C5
0
),
),
4
2
73.2 (C
3
0
), 77.8 (C
), 157.2 (C
[M + H] : 266.1248, found: 266.1251.
-Homo-N-2 -deoxy-a-uridine (10b). 95% yield. R
1 4 4 2 5
), 87.6 (C ), 119.7 (C ), 143.6 (C ), 150.8 (C
0 0
1
˚
+
a, A
153.6 (C
) ppm; HRMS (ESI , m/z): calcd for
8
6
˚
+
b, A
C
11
H
1
16
N
5
O
3
˚
c, A
0
0
f
: 0.13 (10%
): d 1.70 (ddd,
), 3.53 (m, 2H, H5 ),
, J ¼ 14.1, 3.4 Hz), 4.25
Z
1
MeOH/CH
1H, H2
, J ¼ 13.1, 5.9, 4.9 Hz), 2.33 (m, 1H, H
.87 (m, 2H, H
2 2 4
Cl ); H NMR (300.13 MHz, MeOH-d
Final R
Reections
0.035
4865
0
0
0
2
3
0
+ H
0
), 3.96 (dd, 1H, H
0
4
6
6
(
dt, 1H, H3
7.9 Hz), 7.60 (d, 1H, H
MeOH-d ): d 38.4 (C ), 53.2 (C
7.6 (C ), 101.6 (C ), 148.5 (C
0
, J ¼ 6.6, 4.6 Hz), 4.34 (m, 1H, H
0
), 5.63 (d, 1H, H , J
1 5
1
3
¼
6
, J ¼ 7.9 Hz) ppm; C NMR (75.5 MHz,
), 63.3 (C ), 73.3 (C ), 77.7 (C ),
), 153.0 (C ), 166.9 (C ) ppm;
NaO [M + Na] : 265.0795,
0
0
0
0
0
1
4
2
6
5
3
8
4
0
5
6
2
4
+
+
HRMS (ESI , m/z): calcd for C10
H
14
N
2
5
found: 265.0797.
0
14
1
-Homo-N-a-thymidine (10c). 95% yield. R : 0.40 (15%
f
1
MeOH/CH Cl ); H NMR (300.13 MHz, MeOH-d ): d 1.69 (m, 1H,
2
2
4
H2
0
), 1.87 (d, 3H, Me–H , J ¼ 1.1 Hz), 2.33 (dt, 1H, H , J ¼ 13.9,
5
2
0
ꢁ
Scheme 4 Reaction conditions: (a) TBAF, THF, 25 C, 2 h.
7
2
1
.1 Hz), 3.55 (qd, 2H, H
), 4.24 (dt, 1H, H
, J ¼ 6.6, 4.7 Hz), 4.34 (m, 1H, H
H, H
, J ¼ 1.2 Hz) ppm; C NMR (75.5 MHz, MeOH-d
), 38.5 (C ), 53.1 (C ), 63.4 (C ), 73.3 (C ), 77.7 (C
), 110.4 (C ), 144.3 (C ), 153.1 (C ), 167.0 (C ) ppm; HRMS
ESI , m/z): calcd for C H N O [M + H] : 257.1132, found:
5
0
, J ¼ 11.8, 4.6 Hz), 3.87 (m, 3H, H
), 7.44 (s,
): d 12.2
), 87.6
4
0
+
H
6
0
3
0
0
1
1
3
6
4
EC50 value < 10 mM (97% HBV DNA inhibition at 10 mM). Among
eight derivatives, none displayed anti-HBV activity, with EC50
values > 10 mM.
(
CH
3
2
0
6
0
5
0
3
0
0
1
(C
4
0
5
6
2
4
+
+
(
2
1
1
17 2 5
23c,25
Cytotoxicity prole.
These assays were performed in
57.1134.
human PBM, T lymphoblast CEM-CCRF (CEM), African green
monkey kidney (Vero) or human liver (HepG2) cells. Results
represent means from triplicate wells. Positive control cyclo-
heximide exhibited expected toxicity in the PBM, CEM, Vero,
and HepG2 cells, with an IC50 (mM) of 0.6, 0.08, 0.5, and 0.8,
respectively (data not shown). None of the eight compounds
exhibited apparent cytotoxicity (IC50 values > 100 mM) in four
cell types tested.
0
0
1
-Homo-N-2 -deoxy-a-5-uorouridine (10d). 90% yield. R :
f
1
0
.29 (15% MeOH/CH
2
Cl
2
); H NMR (300.13 MHz, MeOH-d
4
):
, J ¼
0
), 4.24 (m,
6
d 1.70 (ddd, 1H, H
2
0
, J ¼ 13.2, 5.9, 4.8 Hz), 2.34 (dt, 1H, H
2.0, 6.0 Hz), 3.55 (m, 2H, H ), 3.88 (m, 3H, H + 2H
H, H ), 4.35 (m, 1H, H ), 7.81 (d, 1H, H
, J ¼ 6.4 Hz) ppm;
): d 38.4 (C ), 53.2 (C ), 63.3 (C
), 87.6 (C4
), 132.4 (d, C , J ¼ 33.5 Hz), 141.3 (d,
C , J ¼ 231.1 Hz), 151.7 (C ), 159.9 (d, C , J ¼ 25.7 Hz) ppm;
2
0
1
1
5
0
4
0
13
0
0
C
3
1
6
NMR (75.5 MHz, MeOH-d
3.3 (C3 ), 77.7 (C1
4
2
0
6
0
5
0
),
7
0
0
0
6
5
2
4
+
+
HRMS (ESI , m/z): calcd for C H FN O [M + H] : 261.0881,
found: 261.0874 and calcd for C H FN NaO [M + Na] :
10 13 2 5
83.0701, found: 283.0695.
1
0
14
2 5
+
3. Experimental
2
General
0
0
1
-Homo-N-2 -deoxy-a-cytidine (10e). 95% yield. R
f
: 0.07 (15%
): d 1.68 (ddd,
, J ¼ 13.8, 7.0 Hz),
, J ¼ 11.8, 4.0 Hz), 3.80 (m,
TLC plates were visualized with 2.5% p-anisaldehyde, 3.5%
sulfuric acid, and 1% acetic acid in ethanol. Pure a-cyano-sugar
2 is commercially available and T was prepared as previ-
ously reported. Unless otherwise specied column chroma-
tography was performed over silica 60 A (230–400 mesh).
1
MeOH/CH
2
Cl
, J ¼ 13.1, 6.0, 5.2 Hz), 2.33 (dt, 1H, H
.50 (m, 1H, H ), 3.58 (dd, 1H, H
2 4
); H NMR (300.13 MHz, MeOH-d
1
3
1
4
H, H
2
0
2
0
16a
Bz
1
0
0
5
5
18
H, H6
.24 (dt, 1H, H3
, J ¼ 7.2 Hz), 7.58 (d, 1H, H
MHz, MeOH-d ): d 38.6 (C ), 54.7 (C
), 87.4 (C ), 95.2 (C ), 148.6 (C ), 159.1 (C
[M + H] : 242.1135,
0
), 3.84 (m, 1H, H4
0
), 4.04 (dd, 1H, H
0
, J ¼ 13.8, 3.1 Hz),
6
˚
0
, J ¼ 6.6, 4.9 Hz), 4.36 (m, 1H, H
0
), 5.82 (d, 1H,
1
1
3
H
5
6
, J ¼ 7.3 Hz) ppm; C NMR (75.5
), 63.4 (C ), 73.3 (C ), 77.6
), 168.0 (C ) ppm;
General procedure for desilylation of 17. Synthesis of 10
0
0
0
0
3
4
2
6
5
TBAF (6 eq., 1.0 M in THF) was added dropwise to a stirred (C
1
0
4
0
5
6
2
4
ꢁ
+
+
solution of 17 (1 eq.) in anhydrous THF (0.1 M) at 0 C. Aer HRMS (ESI , m/z): calcd for C10
H
16
N
3
O
4
5
min, the ice bath was removed, and the reaction mixture was found: 242.1138.
0
0
stirred at room temperature for 2 h. Next, solvents were evap-
1 -Homo-N-2 -deoxy-a-5-iodouridine (10f). 92% yield. R
f
: 0.47
): d 1.69
, J ¼ 13.9, 7.3 Hz),
), 4.25 (m, 1H, H ), 4.33
) ppm; HRMS (ESI , m/z): calcd for
5
O [M + H] : 368.9942, found: 368.9943 and calcd for
1
orated, and the residue was puried by column chromatog- (15% MeOH/CH
raphy (gradient eluent 15–20% MeOH/CH Cl
for 10a–c, 10e; (dt, 1H, H
, J ¼ 13.1, 5.6 Hz), 2.33 (dt, 1H, H
gradient eluent 5–20% MeOH/CH Cl
for 10d and 10f) to afford 3.54 (m, 2H, H ), 3.89 (m, 3H, H + 2H
0a–f in 90–95% yield. (m, 1H, H ), 8.05 (s, 1H, H
Cl ); H NMR (300.13 MHz, MeOH-d
2
2
4
0
0
2
2
2
2
0
0
0
0
3
2
2
5
4
6
+
1
1
0
6
0
0
+
1
-Homo-N-2 -deoxy-a-adenosine (10a). 95% yield. R : 0.18
C
C
10
10
H
H
14IN
13IN
2
2
f
1
+
(
(
20% MeOH/CH
dt, 1H, H
2
Cl
2
); H NMR (300.13 MHz, MeOH-d
4
): d 1.69
5
NaO [M + Na] : 390.9761, found: 390.9764.
0
, J ¼ 13.1, 5.8 Hz), 2.38 (dt, 1H, H
0
, J ¼ 13.3, 6.7 Hz),
2
2
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,2-Dideoxy-1a-(methoxycarbonyl)-D-ribofuranose (13)
Paper
1
3
1
3.9 Hz) ppm; C NMR (75.5 MHz, MeOH-d
4
): d ꢀ5.3 (Si–CH
3
),
ꢀ
5.2 (Si–CH ), ꢀ4.6 (Si–CH ), ꢀ4.5 (Si–CH ), 18.8 (SiCMe ), 19.2
3
3
3
3
To a solution of 12 (500 mg, 1.3 mmol) in MeOH (15 mL) at
room temperature were added 3.1 mL of a 2.5 M KOH solution
t
t
(
SiCMe ), 26.3 (3CH – Bu), 26.4 (3CH – Bu), 37.9 (C ), 64.4 (C ),
3 3 3 2 5
+
6
6.0 (C ), 74.4 (C ), 80.9 (C ), 87.9 (C ) ppm; HRMS (ESI , m/z):
6
3
1
4
(
25% MeOH : H
by TLC (10% MeOH/CH
apparent (3 h). Next, the mixture was neutralized with DOWEX
0WX8 hydrogen form (50–100 mesh). Aer removal of the resin
by ltration, the solution was evaporated, and the residue was
puried by column chromatography (5% MeOH/CH Cl ) to To a solution of 15 (135 mg, 0.36 mmol) in anhydrous pyridine
2
O). The progress of the reaction was monitored
+
calcd for C18
H
4 2
40NaO Si [M + Na] : 399.2357, found: 399.2358.
2
Cl ) until no further reaction was
2
3
(
,5-Bis-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1a-
((methylsulfonyl)oxy)methyl)-D-ribofuranose (16)
5
2
2
ꢁ
afford 13 as a yellowish oil in 75% yield. R : 0.22 (5% MeOH/ (0.65 mL) at 0 C were added MsCl (62 mL, 0.8 mmol) and
f
1
CH
2
Cl
2
); H NMR (300.13 MHz, MeOH-d
4
): d 2.11 (dt, 1H, H
, J ¼ 13.2, 8.8, 6.2 Hz), 3.59 (m, temperature for 24 h. Then, the solvent was removed in
), 3.73 (s, 3H, Me), 3.99 (q, 1H, H
, J ¼ 4.2 Hz), 4.23 (dt, a vacuum, and the residue was dissolved in water and extracted
, J ¼ 6.3, 3.6 Hz), 4.60 (dd, 1H, H , J ¼ 8.8, 4.2 Hz) ppm; with Et O. The organic layers were dried (Na SO ) and evapo-
C NMR (75.5 MHz, MeOH-d ): d 39.7 (C
2.7 (C ), 77.3 (C ), 88.6 (C ), 175.6 (C]O) ppm; HRMS (ESI , m/ matography (20% EtOAc/hexane) to yield 16 as a viscous liquid
2
, J ¼ catalytic DMAP (5 mg). The solution was stirred at room
1
2
1
3.2, 3.9 Hz), 2.47 (ddd, 1H, H
H, H
H, H
2
5
4
3
1
2
2
4
1
3
4
2 5
), 52.5 (Me), 63.1 (C ), rated in a vacuum. The residue was puried by column chro-
+
7
3
1
4
+
1
z): calcd for C H NaO [M + Na] : 199.0577, found: 199.0578.
in 95% yield. R : 0.42 (20% EtOAc/hexane); H NMR (300.13
f
7
12
5
MHz, MeOH-d
(
4
): d 0.08 (s, 6H, Si–Me), 0.11 (s, 6H, Si–Me), 0.92
s, 18H, Si– Bu), 1.75 (dt, 1H, H
, J ¼ 13.0, 3.9 Hz), 2.32 (m, 1H,
), 3.09 (s, 3H, Ms–Me), 3.61 (dq, 2H, H
, J ¼ 11.0, 4.6 Hz), 3.89
, J ¼ 4.3 Hz), 4.20 (m, 1H, H ), 4.39 (m, 3H, H + H
) ppm; C NMR (75.5 MHz, MeOH-d ), ꢀ5.2
): d ꢀ5.3 (Si–CH
Si–CH ), ꢀ4.62 (Si–CH ), ꢀ4.57 (Si–CH ), 18.8 (SiCMe ), 19.2
t
2
3
(
,5-Bis-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1a-
methoxycarbonyl)-D-ribofuranose (14)
TBSCl (904.3 mg, 6 mmol) was added to a solution of 13
210 mg, 1.2 mmol) and imidazole (408.5 mg, 6 mmol) in
H
2
5
(
H
q, 1H, H
4
6
1
3
+
13
6
4
3
(
(
(
(
3
3
3
3
anhydrous CH
2
Cl
2
(4 mL) at room temperature. The reaction
t
t
SiCMe ), 26.3 (3CH – Bu), 26.4 (3CH – Bu), 37.5 (Ms–Me), 37.6
3
3
3
ꢁ
mixture was stirred at 50 C for 5 h, then diluted with water/ice,
C ), 64.4 (C ), 73.4 (C ), 74.4 (C ), 78.0 (C ), 88.6 (C ) ppm;
2
5
6
3
1
4
and extracted with CH
2
Cl
2
. The organic layers were dried
+
+
HRMS (ESI , m/z): calcd for C19
H
6 2
42NaO SSi [M + Na] : 477.2133,
(
Na SO ) and evaporated in a vacuum. The residue was puried
2
4
found: 477.2134.
by column chromatography (10% EtOAc/hexane) to yield 14 as
a viscous liquid in 85% yield. R : 0.65 (20% EtOAc/hexane); H
NMR (300.13 MHz, MeOH-d
3
Si– Bu), 0.92 (s, 9H, Si– Bu), 2.16 (dt, 1H, H
2
1
1
f
General procedure for coupling of 20 with nucleobases.
Synthesis of 17 and 18
4
): d 0.088 (s, 3H, Si–Me), 0.095 (s,
H, Si–Me), 0.098 (s, 3H, Si–Me), 0.102 (s, 3H, Si–Me), 0.87 (s, 9H,
t
t
2 3
To a solution of 20 in anhydrous DMF (0.1 M) was added K CO
2
, J ¼ 13.0, 2.4 Hz),
, J ¼ 13.0, 8.9, 5.2 Hz), 3.53 (dd, 1H, H , J ¼
1.0, 5.8 Hz), 3.67 (dd, 1H, H
, J ¼ 11.0, 3.8 Hz), 3.71 (s, 3H, O–
Bz
(1.5 eq. for A, C, 5-FU, and 5-IU; 1.2 eq. for U; 2.1 eq. for T ), 18-
.39 (ddd, 1H, H
2
5
crown-6 (1.5 eq.), and the nucleobase (1.2 eq. for A, U, C, and
5
Bz
ꢁ
T ; 1.5 eq. for 5-FU and 5-IU). The mixture was stirred at 90 C
2
and the reaction progress followed by TLC (5% MeOH/CH Cl )
Me), 4.01 (ddd, 1H, H , J ¼ 5.7, 3.7, 2.0 Hz), 4.36 (dt, 1H, H , J ¼
4
3
1
3
5
.2, 2.1 Hz), 4.59 (dd, 1H, H , J ¼ 8.9, 2.7 Hz) ppm; C NMR
2
1
until no further reaction was apparent (7–8 h). Solvents were
evaporated and the residue was puried by column chroma-
tography (5% MeOH/CH Cl ) to yield 17 (or 18). Yields are
(
75.5 MHz, MeOH-d ): d ꢀ5.3 (Si–CH ), ꢀ5.2 (Si–CH ), ꢀ4.7 (Si–
4
3
3
CH
3
), ꢀ4.6 (Si–CH
3
), 18.7 (SiCMe
3
), 19.2 (SiCMe
3
), 26.2
), 74.2
t
t
(
(
3CH
C
3
– Bu), 26.4 (3CH
), 89.5 (C
40NaO Si
3
– Bu), 39.9 (C
2
), 52.5 (Me), 64.3 (C
5
2
2
+
indicated in Scheme 3.
3
), 77.7 (C
1
4
), 175.4 (C]O) ppm; HRMS (ESI , m/z):
+
0
0
3,5-Bis-O-(tert-butyldimethylsilyl)-1 -homo-N-2 -deoxy-a-
calcd for C19
H
5
2
[M + Na] : 427.2306, found: 427.2302.
ꢁ
adenosine (17a). White solid. mp 137–138 C; R
f
: 0.32 (5%
): d ꢀ0.02 (s,
H, Si–Me), 0.01 (s, 3H, Si–Me), 0.06 (s, 3H, Si–Me), 0.08 (s, 3H,
1
2 2 4
MeOH/CH Cl ); H NMR (300.13 MHz, MeOH-d
3
3
(
,5-Bis-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1a-
hydroxymethyl)-D-ribofuranose (15)
t
t
2
Si–Me), 0.86 (s, 9H, Si– Bu), 0.87 (s, 9H, Si– Bu), 1.72 (dt, 1H, H ,
0
LiAlH4 (44 mg, 1.16 mmol) was added to a solution of 14 J ¼ 13.1, 5.0 Hz), 2.38 (dt, 1H, H
0
, J ¼ 13.4, 6.6 Hz), 3.60 (m, 2H,
2
ꢁ
(
360 mg, 0.89 mmol) in anhydrous THF (6 mL) at ꢀ45 C, and
H
0
), 3.87 (q, 1H, H
0
, J ¼ 4.0 Hz), 4.40 (m, 4H, H
0
+ H
0
+ 2H ),
6
0
5
4
1
3
1
3
the reaction was stirred for 30 min at the same temperature. 8.09 (s, 1H, H
Next, the mixture was diluted with THF and MeOH, the residue MeOH-d
): d ꢀ5.3 (2Si–CH
was ltered on Celite and concentrated to afford 15 as a viscous (SiCMe ), 26.29 (3CH
), 64.4 (C ), 74.6 (C
), 150.8 (C ), 153.6 (C
2
), 8.20 (s, 1H, H
8
) ppm; C NMR (75.5 MHz,
), 18.9 (SiCMe ), 19.1
), 48.9
), 143.5
4
3
), ꢀ4.6 (2Si–CH
3
3
t
t
3
3
– Bu), 26.34 (3CH
), 78.3 (C ), 88.3 (C
), 157.2 (C ) ppm; HRMS (ESI , m/z):
3
– Bu), 39.1 (C
0
2
liquid (90% yield), which was sufficiently pure for the next step. (C
6
0
5
0
3
0
1
0
4
0
), 119.7 (C
4
1
+
R
f
: 0.34 (20% EtOAc/hexane); H NMR (300.13 MHz, MeOH-d
4
): (C
2
5
8
6
+
d 0.082 (s, 3H, Si–Me), 0.084 (s, 3H, Si–Me), 0.10 (s, 6H, Si–Me), calcd for C H N O Si [M + H] : 494.2977, found: 494.2984.
2
3
44
5
3
2
t
t
0
0
0
1
.91 (s, 9H, Si– Bu), 0.92 (s, 9H, Si– Bu), 1.73 (ddd, 1H, H , J ¼
3,5-Bis-O-(tert-butyldimethylsilyl)-1 -homo-N-2 -deoxy-a-
2
ꢁ
2.8, 5.9, 4.8 Hz), 2.24 (ddd, 1H, H , J ¼ 12.9, 7.5, 6.5 Hz), 3.54 uridine (17b). White solid. mp 102–103 C; R : 0.49 (5% MeOH/
2
f
1
(dd, 1H, H
6
, J ¼ 11.4, 4.6 Hz), 3.62 (m, 3H, 2H
5
+ H
6
), 3.81 (q, 1H, CH
2
Cl
2
); H NMR (300.13 MHz, MeOH-d
4
): d 0.05 (s, 3H, Si–Me),
t
H
4
, J ¼ 4.1 Hz), 4.13 (m, 1H, H
1
), 4.40 (ddd, 1H, H
3
, J ¼ 6.4, 4.7, 0.06 (s, 3H, Si–Me), 0.11 (s, 6H, Si–Me), 0.90 (s, 9H, Si– Bu), 0.92
15820 | RSC Adv., 2020, 10, 15815–15824
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Paper
RSC Advances
t
(
H2
3
1
s, 9H, Si– Bu), 1.70 (dt, 1H, H
0
2
0
, J ¼ 13.0, 4.9 Hz), 2.32 (dt, 1H, 1H, H
2
0
, J ¼ 13.0, 5.9, 4.4 Hz), 2.33 (ddd, 1H, H
2
0
, J ¼ 13.5, 7.6, 6.4
, J ¼ 13.5, 6.9 Hz), 3.62 (m, 2H, H ), 3.87 (m, 2H, H + H ), Hz), 3.62 (dd, 2H, H
0
0
0
0
, J ¼ 4.4, 1.6 Hz), 3.90 (m, 3H, H
0
+ 2H
0
6
),
5
4
6
5
4
1
3
.96 (dd, 1H, H
0
, J ¼ 14.1, 3.0 Hz), 4.32 (m, 1H, H
0
), 4.43 (m, 4.30 (m, 1H, H1
0
), 4.42 (m, 1H, H
0
), 7.98 (s, 1H, H ) ppm;
C
6
1
3
6
H, H3
0
), 5.62 (d, 1H, H , J ¼ 7.8 Hz), 7.53 (d, 1H, H , J ¼ 7.9 NMR (75.5 MHz, MeOH-d ): d ꢀ5.2 (2Si–CH ), ꢀ4.56 (Si–CH ),
5
6
4
3
3
1
3
t
Hz) ppm; C NMR (75.5 MHz, MeOH-d
4
): d ꢀ5.3 (Si–CH
3
), ꢀ5.2 ꢀ4.52 (Si–CH
3
), 18.9 (SiCMe
3
), 19.2 (SiCMe
3
), 26.37 (3CH
3
– Bu),
), 74.7
) ppm;
2
[M + H] : 597.1671,
t
(
(
Si–CH
SiCMe
3
), ꢀ4.6 (Si–CH
3
), ꢀ4.5 (Si–CH
3
), 18.9 (SiCMe
3
), 19.2 26.42 (3CH
3
– Bu), 38.9 (C
), 78.0 (C ), 88.3 (C ), 152.6 (C
), HRMS (ESI , m/z): calcd for C22
found: 597.1684 and calcd for C22
619.1491, found: 619.1504.
2
0
), 53.2 (C
), 152.7 (C
Si
6
0
), 64.4 (C
5 5
0
), 67.2 (C
t
t
), 26.3 (3CH
), 74.6 (C ), 78.1 (C
), 166.8 (C ) ppm; HRMS (ESI , m/z): calcd for C22
3
– Bu), 26.4 (3CH
3
– Bu), 38.9 (C
2
0
), 53.4 (C
6
0
), (C
3
0
1
0
4
0
6
2
), 163.4 (C
4
3
+
+
6
1
4.4 (C
52.9 (C
5
0
3
0
1
0
), 88.2 (C
4
0
+
), 101.6 (C
5
), 148.4 (C
6
H
42IN
2
O
5
+
2
4
+
H
42
-
2 5 2
H41IN NaO Si [M + Na] :
N NaO Si [M + Na] : 493.2524, found: 493.2529.
2
5
2
0
1
3
3
,5-Bis-O-(tert-butyldimethylsilyl)-1 -homo-N-a-thymidine
17c). R : 0.16 (50% Et O/hexane); H NMR (300.13 MHz, MeOH- ribofuranosylmethyl]uracil (18b). Colourless oil. R : 0.40 (20%
): d 0.05 (s, 3H, Si–Me), 0.06 (s, 3H, Si–Me), 0.11 (s, 6H, Si–Me), EtOAc/hexane); H NMR (300.13 MHz, MeOH-d
N ,N -Bis-[3,5-bis-O-(tert-butyldimethylsilyl)-1,2-dideoxy-a-
1
(
f
2
f
1
d
0
1
H
3
4
4
): d 0.04 (s, 6H,
t
t
.90 (s, 9H, Si– Bu), 0.92 (s, 9H, Si– Bu), 1.70 (ddd, 1H, H
2.9, 5.9, 4.5 Hz), 1.86 (d, 3H, Me–C
, J ¼ 1.1 Hz), 2.32 (dt, 1H, Me), 0.89 (s, 9H, Si– Bu), 0.90 (s, 9H, Si– Bu), 0.92 (s, 9H, Si– Bu),
, J ¼ 13.6, 6.6 Hz), 3.62 (dd, 2H, H
H, H + 2H ), 4.31 (m, 1H, H ), 4.41 (m, 1H, H
H ) ppm; C NMR (75.5 MHz, MeOH-d ): d ꢀ5.30 (Si–CH ), 2H6
2
0
, J ¼ Si–Me), 0.05 (s, 3H, Si–Me), 0.06 (s, 3H, Si–Me), 0.11 (s, 12H, Si–
t t t
5
t
0
0
, J ¼ 4.4, 1.9 Hz), 3.88 (m, 0.93 (s, 9H, Si– Bu), 1.74 (m, 2H, H
), 7.37 (s, 1H, 4H, H ), 3.78 (dd, 1H, H
, J ¼ 12.9, 3.9 Hz), 3.92 (m, 4H, 2H
), 4.38 (m, 4H, 2H1 + 2H ), 4.56 (dd, 1H, H
, J ¼ 12.9, 8.8
2 2
), 2.27 (m, 2H, H ), 3.60 (m,
0 0
2
5
0
0
0
0
0
0
0
+
4
6
1
3
5
7
4
1
3
0
0
0
0
7
6
4
3
3
ꢀ
5.26 (Si–CH ), ꢀ4.6 (Si–CH ), ꢀ4.5 (Si–CH ), 12.3 (CH –C ) Hz), 5.69 (d, 1H, H , J ¼ 7.9 Hz), 7.51 (d, 1H, H , J ¼ 7.9 Hz) ppm;
3
3
3
3
t
5
5
6
t
13
1
3
1
8.9 (SiCMe ), 19.2 (SiCMe ), 26.3 (3CH – Bu), 26.4 (3CH – Bu),
C NMR (75.5 MHz, MeOH-d ): d ꢀ5.3 (2Si–CH ), ꢀ5.2 (2Si–
3
3
3
3
4
3
9.0 (C
10.4 (C
2
0
), 53.1 (C
), 144.2 (C
z): calcd for C23
,5-Bis-O-(tert-butyldimethylsilyl)-1 -homo-N-2 -deoxy-a-5-
uorouridine (17d). White solid. mp 134–136 C; R
6
0
), 64.4 (C
5
0
), 74.6 (C
), 167.0 (C
3
0
), 78.2 (C
1
0
), 88.2 (C
4
0
), CH
3
), ꢀ4.6 (2Si–CH
3
), ꢀ4.5 (2Si–CH
3
), 18.8 (SiCMe
– Bu), 26.42 (3CH
3
), 18.9
+
t
t
5
6
), 152.9 (C
Si
2
4
) ppm; HRMS (ESI , m/ (SiCMe
3
), 19.2 (2SiCMe
3
), 26.36 (6CH
3
3
– Bu),
+
t
H
45
N
2
O
5
2
[M + H] : 485.2862, found: 485.2851. 26.44 (3CH
3
– Bu), 39.0 (C
), 74.6 (C ), 74.7 (C
), 101.0 (C ), 146.4 (C
2
0
), 39.8 (C
), 77.4 (C
), 153.2 (C
2
0
), 46.2 (C
), 78.1 (C
4
), 165.7 (C ) ppm; HRMS
7
0
), 54.5 (C ), 64.4
0
), 88.0 (C ), 88.2
4
6
0
0
0
3
(2C
5
0
3
0
3
0
1
0
1
0
ꢁ

f
: 0.57 (5% (C
4
0
5
6
2
1
+
+
MeOH/CH Cl ); H NMR (300.13 MHz, MeOH-d ): d 0.05 (s, 3H, (ESI , m/z): calcd for C H N O Si [M + H] : 829.5065, found:
2
2
4
40 81
2
8
4
Si–Me), 0.07 (s, 3H, Si–Me), 0.10 (s, 3H, Si–Me), 0.11 (s, 3H, Si– 829.5065.
t
t
1
3
Me), 0.90 (s, 9H, Si– Bu), 0.91 (s, 9H, Si– Bu), 1.70 (ddd, 1H, H
0
, J
N ,N -Bis-[3,5-bis-O-(tert-butyldimethylsilyl)-1,2-dideoxy-a-
, J ¼ 13.7, 7.0 Hz), 3.62 (dd, ribofuranosylmethyl]thymine (18c). Colourless oil. R : 0.50
): d 0.04 (s,
, J ¼ 6.3 Hz) ppm; C NMR 6H, Si–Me), 0.049 (s, 3H, Si–Me), 0.054 (s, 3H, Si–Me), 0.108 (s,
2
¼
13.0, 5.7, 4.4 Hz), 2.34 (dt, 1H, H
H, H
, J ¼ 4.3, 1.7 Hz), 3.88 (m, 3H, H
), 4.42 (m, 1H, H ), 7.74 (d, 1H, H
): d ꢀ5.31 (Si–CH
), 18.9 (SiCMe
2
0
f
1
2
5
0
4 6 4
+ 2H ), 4.33 (m, 1H, (20% EtOAc/hexane); H NMR (300.13 MHz, MeOH-d
0 0
1
3
H
1
0
3
0
6
t
(
(
(
(
75.5 MHz, MeOH-d
4
3
), ꢀ5.26 (Si–CH
3
), ꢀ4.6 6H, Si–Me), 0.114 (s, 6H, Si–Me), 0.891 (s, 9H, Si– Bu), 0.893 (s,
t
t
t
Si–CH
3
), ꢀ4.55 (Si–CH
3
t
3
), 19.2 (SiCMe
3
), 26.3 9H, Si– Bu), 0.92 (s, 9H, Si– Bu), 0.93 (s, 9H, Si– Bu), 1.74 (m, 2H,
t
3CH – Bu), 26.4 (3CH – Bu), 38.9 (C
0
), 53.2 (C6
0
), 64.4 (C5
0
), 74.6 H2
0
), 1.89 (d, 3H, H , J ¼ 0.8 Hz), 2.27 (m, 2H, H
0
), 3.60 (m, 4H,
2
3
3
2
7
C3
0
), 78.2 (C1
0
), 88.2 (C4
0
), 132.3 (d, C , J ¼ 33.5 Hz), 141.2 (d, C , H5
0
), 3.79 (dd, 1H, H
0
, J ¼ 13.0, 3.9 Hz), 3.90 (m, 4H, 2H
0
+
4
6
5
7
J ¼ 131.5 Hz), 151.6 (C ), 159.9 (d, C , J ¼ 25.3 Hz) ppm; HRMS 2H6
0
), 4.36 (m, 4H, 2H1
[M + H] : 489.2611, found: Hz), 7.37 (d, 1H, H
, J ¼ 1.0 Hz) ppm; C NMR (75.5 MHz,
): d ꢀ5.3 (2Si–CH ), ꢀ5.2 (2Si–CH ), ꢀ4.6 (2Si–CH ),
ꢀ4.5 (2Si–CH ), 13.1 (C ), 18.8 (SiCMe ), 18.9 (SiCMe ), 19.2
,5-Bis-O-(tert-butyldimethylsilyl)-1 -homo-N-2 -deoxy-a-cyti- (2SiCMe ), 26.36 (6CH
), 46.5 (C ), 54.2 (C
), 77.5 (C1 ), 78.2 (C1
0
+ 2H
0
), 4.58 (dd, 1H, H
0
, J ¼ 13.0, 8.8
2
4
3
7
+
+
13
(
4
ESI , m/z): calcd for C22
89.2635 and calcd for C22
found: 511.2456.
H
42FN
2
O
5
Si
NaO
2
6
+
H
41FN
2
5
Si
2
[M + Na] : 511.2430, MeOH-d
4
3
3
3
3
7
3
3
0
0
t
t
3
3
3
– Bu), 26.42 (6CH
), 64.4 (C ), 64.5 (C
), 88.0 (C4 ), 88.1 (C4
3
– Bu), 39.0 (C ), 39.9
0
), 74.6 (C ), 74.7
3
2
0
1
dine (17e). R
f
: 0.22 (5% MeOH/CH
2
Cl
2
); H NMR (300.13 MHz, (C
2
0
0
7
0
6
0
5
0
5
0
MeOH-d ): d 0.04 (s, 3H, Si–Me), 0.05 (s, 3H, Si–Me), 0.11 (s, 6H, (C3
0
0
0
0
), 109.6 (C ), 142.4
4
5
t
t
+
Si–Me), 0.89 (s, 9H, Si– Bu), 0.92 (s, 9H, Si– Bu), 1.68 (dt, 1H, H
0
,
(C ), 153.2 (C ), 166.0 (C ) ppm; HRMS (ESI , m/z): calcd for
2
6
2
4
+
J ¼ 12.8, 5.2 Hz), 2.32 (dt, 1H, H , J ¼ 13.3, 6.8 Hz), 3.61 (m, 2H, C H N O Si [M + H] : 843.5221, found: 843.5218.
0
2
41 83
2
8
4
1 3
H
5
0
), 3.77 (dd, 1H, H
Hz), 4.05 (dd, 1H, H
dt, 1H, H
, J ¼ 5.9, 4.2 Hz), 5.82 (d, 1H, H
H, H
, J ¼ 7.2 Hz) ppm; C NMR (75.5 MHz, MeOH-d
Si–CH
6
0
, J ¼ 13.7, 8.5 Hz), 3.85 (q, 1H, H
, J ¼ 13.8, 2.7 Hz), 4.32 (m, 1H, H
, J ¼ 7.2 Hz), 7.50 (d, 0.50 (20% EtOAc/hexane); H NMR (300.13 MHz, MeOH-d
): d ꢀ5.3 d 0.039 (s, 3H, Si–Me), 0.041 (s, 3H, Si–Me), 0.05 (s, 3H, Si–Me),
), 18.9 0.06 (s, 3H, Si–Me), 0.10 (s, 6H, Si–Me), 0.113 (s, 3H, Si–Me),
4
0
, J ¼ 4.1
N ,N -Bis-[3,5-bis-O-(tert-butyldimethylsilyl)-1,2-dideoxy-a-
0
0
), 4.41 ribofuranosylmethyl]-5-uorouracil (18d). Colourless oil. R
f
:
4
):
6
1
1
(
1
3
0
5
1
3
6
4
(
(
(
(
3
), ꢀ5.2 (Si–CH
3
), ꢀ4.6 (Si–CH
3
), ꢀ4.5 (Si–CH
3
t
t
t
t
SiCMe ), 19.2 (SiCMe ), 26.3 (3CH – Bu), 26.4 (3CH – Bu), 39.0 0.115 (s, 3H, Si–Me), 0.890 (s, 9H, Si– Bu), 0.892 (s, 9H, Si– Bu),
3
3
3
3
t
t
C2
0
), 54.9 (C6
0
), 64.4 (C5
0
), 74.5 (C3
0
), 78.0 (C1
0
), 88.0 (C4
0
), 95.2 0.91 (s, 9H, Si– Bu), 0.93 (s, 9H, Si– Bu), 1.75 (m, 2H, H ), 2.28
2
0
+
C ), 148.5 (C ), 159.0 (C ), 168.0 (C ) ppm; HRMS (ESI , m/z): (m, 2H, H2
0
), 3.58 (m, 4H, H5
Hz), 3.92 (m, 4H, 2H + 2H ), 4.38 (m, 4H, 2H
1H, H , J ¼ 5.9 Hz) ppm;
, J ¼ 12.9, 9.1 Hz), 7.75 (d, 1H, H
); H NMR (300.13 NMR (75.5 MHz, MeOH-d ), ꢀ5.17 (Si–CH
): d ꢀ5.24 (2Si–CH
): d 0.05 (s, 3H, Si–Me), 0.07 (s, 3H, Si–Me), 0.11 ꢀ5.1 (Si–CH ), ꢀ4.54 (2Si–CH ), ꢀ4.48 (2Si–CH ), 18.8 (SiCMe
s, 6H, Si–Me), 0.90 (s, 9H, Si– Bu), 0.92 (s, 9H, Si– Bu), 1.70 (ddd, 18.9 (SiCMe ), 19.2 (2SiCMe ), 26.38 (6CH
0
), 3.77 (dd, 1H, H7
0
, J ¼ 13.1, 3.7
5
6
2
4
+
calcd for C22
H
44
N
3
O
4
Si
2
[M + H] : 470.2865, found: 470.2868.
4
0
6
0
1
0
+ 2H
0
3
), 4.62 (dd,
0
0
13
3
,5-Bis-O-(tert-butyldimethylsilyl)-1 -homo-N-2 -deoxy-a-5-
7
0
6
C
1
iodouridine (17f). R
MHz, MeOH-d
f
: 0.63 (5% MeOH/CH
2
Cl
2
4
3
3
),
),
4
3
3
3
3
t
t
t
(
3
3
3
– Bu), 26.43
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RSC Adv., 2020, 10, 15815–15824 | 15821

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Paper
t
t
(
(
(
3CH
3
– Bu), 26.5 (3CH
3
– Bu), 39.0 (C
), 64.5 (C5 ), 74.6 (C3 ), 74.8 (C3
), 88.1 (2C4
2
0
), 39.7 (C
2
0
), 46.9 (C
), 77.3 (C1
7
0
), 54.3 13.3, 3.4 Hz), 2.21 (ddd, 1H, H
2
, J ¼ 13.7, 8.1, 5.8 Hz), 2.45 (s, 3H,
C6
C1
0
), 64.4 (C5
0
0
0
0
0
), 78.1 Ts–Me), 3.46 (dd, 1H, H , J ¼ 10.9, 5.6 Hz), 3.57 (dd, 1H, H , J ¼
5
5
0
0
), 130.6 (d, C , J ¼ 33.3 Hz), 140.8 (d, C , J ¼ 229.4 10.9, 3.8 Hz), 3.69 (m, 1H, H ), 3.98 (dd, 1H, H , J ¼ 10.0, 4.0 Hz),
6
5
4
6
+
Hz), 151.7 (C ), 159.5 (d, C , J ¼ 25.2 Hz) ppm; HRMS (ESI , m/z): 4.12 (dd, 1H, H , J ¼ 10.0, 7.6 Hz), 4.27 (m, 1H, H ), 4.33 (m, 1H,
2
4
6
1
+
calcd for C40
H
79FN
2
NaO
8
Si
4
[M + Na] : 869.4790, found:
H
3
), 7.43 (d, 2H, Harom, J ¼ 8.5 Hz), 7.79 (d, 2H, Harom, J ¼ 8.4
1
3
8
69.4762.
Hz) ppm; C NMR (75.5 MHz, MeOH-d
(Si–CH ), 18.7 (SiCMe
), ꢀ4.6 (2Si–CH
: 0.56 (CH –Ts), 26.3 (3CH
): d 0.04 (s, 73.6 (C ), 74.5 (C ), 77.9 (C
H, Si–Me), 0.050 (s, 3H, Si–Me), 0.052 (s, 3H, Si–Me), 0.07 (s, 3H, (2Carom), 134.4 (Cipso), 146.3 (C ) ppm; HRMS (ESI , m/z):
4
): d ꢀ5.3 (Si–CH
), 19.2 (SiCMe
– Bu), 26.4 (3 Bu–CH ), 37.6 (C
), 88.7 (C ), 129.1 (2Carom), 131.0
3
), ꢀ5.2
1
3
N ,N -Bis-[3,5-bis-O-(tert-butyldimethylsilyl)-1,2-dideoxy-a-
ribofuranosylmethyl]-5-iodouracil (18f). Colourless oil. R
3
3
3
3
), 21.6
t
t
f
3
3
3
2 5
), 64.4 (C ),
1
(
3
20% EtOAc/hexane); H NMR (300.13 MHz, MeOH-d
4
6
3
1
4
+
ipso
+
Si–Me), 0.108 (s, 6H, Si–Me), 0.114 (s, 6H, Si–Me), 0.89 (s, 9H, calcd for C H O SSi [M + H] : 531.2626, found: 531.2632.
Si– Bu), 0.90 (s, 9H, Si– Bu), 0.92 (s, 9H, Si– Bu), 0.93 (s, 9H,
2
5
47
6
2
t
t
t
t
Si– Bu), 1.73 (m, 2H, H
2
0
), 2.28 (m, 2H, H
, J ¼ 13.1, 3.7 Hz), 3.89 (m, 2H, 2H
), 4.38 (m, 4H, 2H + 2H ), 4.63 (dd, 1H, H
.0 Hz), 7.99 (s, 1H, H ) ppm; C NMR (75.5 MHz, MeOH-d
), ꢀ5.19 (Si–CH
2
0
), 3.62 (m, 4H, H
), 3.96 (m,
, J ¼ 13.0,
):
5
0
),
General procedure for desilylation of 18d and 18f. Synthesis of
1d and 21f
3
2
9
.82 (dd, 1H, H
7
0
0
4
2
H, 2H
6
0
1
0
3
0
0
7
A procedure analogous to that described for the synthesis of 10
1
3
6
4
was used.
d ꢀ5.24 (Si–CH
3
3
), ꢀ5.1 (2Si–CH
3
), ꢀ4.5 (4Si–
1
3
N ,N -Bis-(1,2-dideoxy-a-ribofuranosylmethyl)-5-uorouracil
CH ), 18.8 (SiCMe ), 18.9 (SiCMe ), 19.2 (2SiCMe ), 26.4
3
3
3
3
1
(
(
3
H
21d). Colourless oil. R
300.13 MHz, MeOH-d ): d 1.74 (m, 2H, H
.54 (m, 4H, H ), 3.90 (m, 5H, 2H + 2H
), 4.39 (m, 2H, H ), 4.50 (dd, 1H, H
d, 1H, H
, J ¼ 6.0 Hz) ppm; C NMR (75.5 MHz, MeOH-d
d 38.4 (C2 ), 39.3 (C ), 46.6 (C ), 54.2 (C6 ), 63.2 (C5 ), 63.4 (C5
), 87.1 (C4 ), 87.7 (C4
f
: 0.15 (15% MeOH/CH
), 2.33 (m, 2H, H
+ H ), 4.22 (m, 2H,
2
Cl
2
); H NMR
t
t
(
(
(
6CH – Bu), 26.5 (6CH – Bu), 38.9 (C
0
), 39.8 (C2
0
), 47.8 (C7
0
), 54.4
), 78.0
) ppm;
4
[M + H] : 955.4031,
3
3
2
0
0
2
),
4
2
C6
C
0
), 64.4 (2C5
), 88.0 (C
HRMS (ESI , m/z): calcd for C40
found: 955.4033 and calcd for C40
0
), 66.5 (C ), 74.6 (C
0
), 74.7 (C3
0
), 77.4 (C1
), 162.4 (C
4
0
5
3
0
0
0
0
7
5
4
6
0
0
), 88.3 (C
0
), 150.9 (C
), 152.9 (C
Si
1
4
4
6
2
0
0
0
, J ¼ 12.6, 8.8 Hz), 7.84
+
+
3
1
7
H
80IN
2
O
8
1
3
(
6
4
):
),
),
+
H
2 8 4
79IN NaO Si [M + Na] :
0
0
0
7
0
0
0
2
9
77.3850, found: 977.3851.
7
1
1
C
C
3.3 (C3
0
), 73.4 (C3
0
), 76.7 (C1
0
), 77.7 (C1
0
0
0
30.9 (d, C , J ¼ 33.5 Hz), 140.8 (d, C , J ¼ 229.0 Hz), 151.9 (C ),
6
5
2
3
,5-Bis-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1a-((acetoxy)
methyl)-D-ribofuranose (19)
+
59.6 (d, C
4
, J ¼ 25.0 Hz) ppm; HRMS (ESI , m/z): calcd for
+
16
16
H
24FN
23FN
2
2
8
O [M + H] : 391.1511, found: 391.1526 and calcd for
NaO [M + Na] : 413.1331, found: 413.1345.
8
+
To a solution of 15 (44 mg, 0.12 mmol) in anhydrous CH
2
Cl
2
(1.2
H
1
3
mL) at room temperature was added Et
Ac O (170 mL, 1.8 mmol) and catalytic DMAP (2 mg). The solu- (21f). Colourless oil. R
tion was stirred for 2 h. Solvents were evaporated, and the (300.13 MHz, MeOH-d ): d 1.73 (m, 2H, H
residue puried by column chromatography (10% EtOAc/ 3.53 (m, 4H, H5
hexane) to afford 19 in 90% yield as a viscous liquid. R : 0.65 (m, 2H, H3
3
N (50 mL, 0.36 mmol),
N ,N -Bis-(1,2-dideoxy-a-ribofuranosylmethyl)-5-iodouracil
1
2
f
: 0.24 (15% MeOH/CH
2
Cl
2
); H NMR
),
), 4.23
, J ¼ 12.9, 8.7
) ppm; C NMR (75.5 MHz, MeOH-d ): d 38.4
), 66.4
), 151.2
0
2
), 2.32 (m, 2H, H2
0
4
0
), 3.89 (m, 3H, 2H4
0
+ H7
0
), 3.96 (m, 2H, H6
0
0
), 4.39 (m, 2H, H ), 4.52 (dd, 1H, H7
0
1
0
f
1
13
(
(
9
20% EtOAc/hexane); H NMR (300.13 MHz, MeOH-d
4
): d 0.081 Hz), 8.08 (s, 1H, H
6
4
s, 3H, Si–Me), 0.085 (s, 3H, Si–Me), 0.10 (s, 6H, Si–Me), 0.91 (s, (C
2
5
6
0
), 39.3 (C
), 73.4 (2C
), 153.1 (C
2
0
), 47.6 (C
), 76.7 (C
), 162.5 (C
7
0
), 54.4 (C
6
0
), 63.2 (C
), 87.0 (C
5
0
), 63.3 (C
), 87.8 (C
5
0
t
t
H, Si– Bu), 0.92 (s, 9H, Si– Bu), 1.71 (dt, 1H, H
, J ¼ 13.6, 6.9 Hz), 3.63 (C
, J ¼ 11.0, 4.5 Hz), 3.85 (q, 1H, H , J ¼ 3.9 Hz), 4.05
2
, J ¼ 13.1, 4.5 (C
3
0
1
0
), 77.6 (C
1
0
4
0
0
4
+
Hz), 2.05 (s, 3H, Ac–Me), 2.28 (dt, 1H, H
2
2
4
) ppm; HRMS (ESI , m/z): calcd for
+
(
(
4
qd, 2H, H
5
4
C
16
H
24IN
2
O
8
[M + H] : 499.0572, found: 499.0577 and calcd for
+
dd, 1H, H , J ¼ 10.9, 3.7 Hz), 4.24 (m, 1H, H ), 4.27 (m, 1H, H ), C H IN NaO [M + Na] : 521.0391, found: 521.0397.
6
6
1
16 23
2
8
1
3
.40 (dt, 1H, H , J ¼ 6.2, 3.9 Hz) ppm; C NMR (75.5 MHz,
3
MeOH-d ): d ꢀ5.3 (Si–CH ), ꢀ5.2 (Si–CH ), ꢀ4.6 (Si–CH ), ꢀ4.5
4
3
3
3
Antiviral assays
(
(
(
Si–CH
3CH
C
3
t
), 18.8 (SiCMe
3
), 19.2 (SiCMe
3
), 20.8 (Ac–CH
3
), 26.3
), 74.4
HIV assay. The assay was performed as described pre-
t
3
– Bu), 26.4 (3CH
), 88.4 (C
3
– Bu), 38.1 (C
2
), 64.4 (C
5
), 68.1 (C
6
23a,b
23c
viously,
with some modications described elsewhere.
3
), 78.1 (C
1
4
), 172.6 (C]O) ppm.
Briey, human PBM cells were stimulated with PHA/IL-2 prior
to infection with HIV-1 LAI (MOI 0.1) for 6 days in the presence
of various concentrations of test compounds (10a–f, 21d, and
3
,5-Bis-O-(tert-butyldimethylsilyl)-1,2-dideoxy-1a-((tosyloxy)
methyl)-D-ribofuranose (20)
21f) or AZT (control). Supernatants were harvested, and HIV-1
To a solution of 15 (100 mg, 0.26 mmol) in anhydrous pyridine RT was quantied. Median effective concentrations (EC50
)
ꢁ
0.5 mL) at 0 C were added TsCl (111.3 mg, 0.58 mmol) and were determined using described method.
23d
(
24
catalytic DMAP (5 mg). The solution was stirred at room
HBV assay. HepAD38 cells were seeded at 50 000 cells per
temperature for 9 h. Solvents were evaporated, and the residue well in collagen-coated 96-well plates. Test compounds or 3TC
was puried by column chromatography (15% EtOAc/hexane) to (control) were added to HepAD38 cells to a nal concentration
yield 20 as a colourless viscous liquid in 90% yield. R : 0.60 (20% of 10 mM. Real-time PCR for HBV DNA lasted 7 days. On day 7,
f
1
EtOAc/hexane); H NMR (300.13 MHz, MeOH-d ): d 0.040 (s, 3H, total DNA was puried from supernatant using commercially
4
Si–Me), 0.042 (s, 3H, Si–Me), 0.05 (s, 3H, Si–Me), 0.06 (s, 3H, Si– available kit (DNeasy 96 Blood & Tissue kit, Qiagen). The HBV
t
t
Me), 0.84 (s, 9H, Si– Bu), 0.90 (s, 9H, Si– Bu), 1.64 (dt, 1H, H
2
, J ¼ DNA was amplied in a real-time PCR assay using LightCycler
15822 | RSC Adv., 2020, 10, 15815–15824
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Paper
80 (Roche) as described elsewhere. All samples were tested
RSC Advances
23c
4
References
in triplicate. Analysis: the concentration of compound that
inhibited HBV DNA replication by 50% (EC ) was determined
5
0
1 (a) E. De Clercq, Curr. Opin. Microbiol., 2005, 8, 552–560; (b)
S. Rachakonda and L. Cartee, Curr. Med. Chem., 2004, 11,
775–793; (c) Recent Advances in Nucleosides: Chemistry and
Chemotherapy, ed. C. K. Chu, Elsevier Science, New York,
2002; (d) Nucleoside Analogs in Cancer Therapy, ed. B. D.
Chenson, M. J. Keating and W. Plunkett, Marcel Dekker,
New York, 1997; (e) Nucleosides and Nucleotides as
Antitumor and Antiviral Agents, ed. C. K. Chu and D. C.
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by linear regression.
Cytotoxicity assays. These were performed in primary blood
mononuclear (PBM), T lymphoblast CEM-CCRF (CEM), African
green monkey kidney (Vero) or human liver (HepG2) cells via
®
MTT assay using the CellTiter 96 . Non-Radioactive Cell
23c
Proliferation (Promega) kit as previously described. Cytotox-
icity was expressed as the concentration of test compounds that
inhibited cell proliferation by 50% (IC ) and calculated using
5
0
25
the Chou and Talalay method.
2
See a recent review on a-nucleosides: G. Ni, Y. Du, F. Tang,
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4
. Conclusions
3
0
0
We have synthesized a series of novel 1 -homo-N-2 -deoxy-a-
nucleoside analogs of A, U, T, 5-FU, C, and 5-IU via coupling of
a nucleobase and a tosylated intermediate sugar precursor
readily obtained from a cyano derivative, which is easily acces-
sible on large-scale. Displacement reactions took place in the
4
5
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6
spectroscopy and conrmation was obtained by a single crystal
0
0
X-ray analysis of 1 -homo-N-2 -deoxy-a-adenosine. It is worthy of
mention that only the thymine derivative has been previously
described synthesized via a more complex route. In addition to
the desired compounds we have obtained the corresponding
dimer derivatives resulting from the coupling of the sugar
moiety at the N-1 and N-3 positions of the base. The occurrence
of these dimers is very interesting since few derivatives of this
type have been reported in the literature, primarily as byprod-
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antiviral activity against HIV-1 and HBV. Also, none of them
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Although the results obtained from the preliminary biological
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