An efficient method for the synthesis of selenium modified nucleosides: its application in the synthesis of Se-adenosyl-l-selenomethionine (SeAM)

Article abstract of DOI:10.1039/c5ob01316j

In this paper, we report that a versatile method for the synthesis of 5′-selenium modified nucleosides has been explored on the basis of a 2-(trimethylsilyl)ethyl (TSE) selenyl group as a selenating donor. We demonstrate the broad utility of this method through direct introduction of various functional groups into 5′-TSE-selenonucleosides. This original method offers additional advantages for the preparation of these compounds, such as high functional group tolerance, ready availability of various electrophilic reagents, mild conditions, simple operation, and good yields. The utility of this approach is further demonstrated by the synthesis of Se-adenosyl-l-selenomethionine (SeAM) as a chemical reporter for methyltransferases.

Full text of DOI:10.1039/c5ob01316j

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ARTICLE
An Efficient Method for the Synthesis of Selenium Modified
Nucleosides: Its application to the synthesis of Se-adenosyl-L-
selenomethionine (SeAM)
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Masakazu Kogami, Mamoru Koketsu*
www.rsc.org/
In this paper, we report that a versatile method for the synthesis of 5′-selenium modified nucleosides has been explored
on the basis of 2-(trimethylsilyl)ethyl (TSE) seleno group as a selenating donor. We demonstrate the broad utility of this
method through direct introduction of various functional groups into a 5′-TSE-selenonucleosides. This original method
offers additional advantages for the preparation of these compounds, such as highly functional group tolerance, ready
availability of various electrophilic reagents, mild conditions, simple operation, and good yields. The utility of this approach
is further demonstrated by the synthesis of Se-adenosyl-L-selenomethionine (SeAM) as chemical reporter for
methyltransferases.
preparations. Based on our knowledge, 5′-selenonucleosides
or these diselenides have been synthesized by Sivapriya′s
Introduction
8
a
8b
group , Braga′s group, Belostotskii′s group and Huang′s
8c
In recent years, modified nucleosides have proved to be useful
in biochemistry, molecular biology, gene therapy, and drug
1
discovery. The modification of the nucleobase or ribose
4
group. Sivapriya′s method is based on the use of
tetraethylammonium tetraselenotungstate as a selenium
transfer reagent. Braga′s method exploited in situ selenolate
anion generated by the reduction of the symmetrical
diorganodiselenide with sodiumborohydride in ethanol.
Belostotskii et al. synthesized 5′-selenocyanate by nucleophilic
substitution of tosylated nucleoside with tetrabutylammonium
selenocyanate. Huang et al. exploited in situ 2-cyanoethyl
selenide generated by the reduction of symmetrical 2-
oxygen moiety in nucleoside with other elements such as
carbon, nitrogen, sulfur, selenium is a promising alternative to
2
conventional cancer chemotherapy and viral infections.
Moreover, the selenium modification of ribose moiety has
been extensively studied for structural determination of
nucleic acids. For example, the substitution of the 2′ and 5′-
oxygen atom in nucleotides by selenium is successfully used in
the 3-D structural study of DNA and RNA for multi-wavelength
9
cyanoethyl diselenide. The active form of 2-cyanoethyl
3
diselenide is 2-cyanoethyl ethaneselenolate, which is
anomalous dispersion (MAD) in X-ray crystallography and
4
labeled nucleic acid . Therefore, the functional group
2 3
generated by treatment with 0.05M K CO in MeOH. In
particular, Huang′s method is efficient for the synthesis of
organoselenium compounds. However, only several examples
transformation at the exocyclic C-5′ position of nucleosides by
the replacement of the 5′-oxygen is attractive due to the
5
biological importance of these molecules. For example, 5′-
of simple electrophile as benzylhalides and α-haloamide were
demonstrated and the reaction required high dilution
condition that may reduce volume efficiency. Therefore,
utilizing the previous methods for introduction of a selenium
atom into a nucleic acid molecule, requires the preparation of
diselenide having a necessary functional group. While these
methods have proved adequate for the synthesis of simple
functional groups, they are associated with the lack of
functional group compatibility due to inherent problems. To
address this challenge, we report a new, versatile method for
the synthesis of 5′-selenium modified nucleosides by the use
of 2-(trimethylsilyl)ethyl (TSE) seleno group.
thiouridine derivatives is useful for selective inhibitors against
6
-1,3-galactosyl transferases. Moreover, the selective DOT1L
α
7
methyltransferase inhibitor, which was designed on the basis
of the cofactor S-adenosyl-L-methionine (SAM) is attractive
due to the potential therapeutic target for the drug discovery
of the anti-cancer drug known as the epigenetic drugs.
In this context, the synthesis of selenium-modified
nucleosides has attracted attention. However, few reports are
available in the literature for the synthesis of 5′-
selenonucleosides due to difficulties involved in their
In our strategy outlined in Scheme 1, the TSE seleno group
serves as a convenient protecting group for the selenol
functional group because this protecting group was easily
converted into a corresponding selenolate anion via treatment
with tetrabutyl ammonium fluoride (TBAF). The driving force
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behind this reaction is the extreme Si-F single bond strength of electrophiles were added to the solution of
7
or 15 in DMF at
1
82 kJ/mol by the high affinity of Si to F.
0
5
room temperature and the mixture was stirred at room
temperature to bring the reactions to completion. In this
reaction, the 2-(trimethylsilyl)ethyl (TSE) group was removed
with TBAF, followed by nucleophilic attack of the generated
selenolate anion to an existing electrophile. We first examined
alkylation with alkyl halide which led to the corresponding
alkylated selenide 8a-8i and 9a-9f in good yield (61-93%,
entries 1-9 and 46-75%, entries 19-24). The reaction with
isobutylene oxide yielded the corresponding alcohol 8j via
Results and discussion
1
1
2-(Trimethylsilyl)ethyl (TSE) diselenide
1
(Fig.1) prepared
from 2-(bromoethyl)trimethyl silane with selenolate anion was
generated in situ by reduction of elemental selenium with
diisobutyl aluminium hydride (DIBAL) or sodium borohydride.
Another selenating reagent
1
of potassium p-methylseleno benzoate with (2-bromoethyl)
2 was synthesized by the reaction
2
N
ring-opening reaction (70%, entry 10). S Ar reaction with 2-
fluoronitrobenzene and 4-fluoronitrobenzene afforded a good
yield of aryl selenide 8k and 8l (60% and 63%, entries 11, 12).
Furthermore, we succeeded in the introduction of active
functionalized groups such as ketone (8m: 60% and 8n: 80%,
entries 13, 14), ester (8o: 90% and 8p: 77%, entries 15, 16),
nitrile (8q: 67%, entry 17) with good to excellent yields.
Reduction-labile functional groups, including nitro, epoxide,
ketone, ester, and nitrile, remain intact under the reaction
conditions. Consequently, this result indicated an extensive
precedent for introduction of selenium functionality. We
demonstrated the construction of selenomethionine
structures (8r: 73% and 9g: 72%, entries 18, 25). In this
trimethylsilane. Previously, we reported the stereoselective
1
3
synthesis of
methylseleno benzoate. Furthermore, appealing the
usefulness of , we explored a general synthetic approach to
the variety of selenium-containing
reagent The active form of
ethaneselenolate, which is generated by treatment with amine
in the presence of Cs CO . This anion reacted smoothly with
α- and β-selenoglycosides using potassium p-
2
1
4
β
-lactam using selenating
is 2-(trimethylsilyl)
2
.
2
2
3
the electrophilic part of target reactants, following the
introduction of the 2-(trimethylsilyl) ethylseleno moiety;
therefore, we applied it to the synthesis of 5′-TSE-
selenonucleosides using these selenating reagents (1 and 2).
reaction, epimerization of the
α-carbon did not occur during
Our synthetic route for 5′-TSE-selenouridine is shown in
Scheme 2. According to the previously reported procedure, the
the course of the reaction. As a result, TSE approaches enabled
a relatively straightforward access to a large variety of 5′-
selenium modified nucleosides and synthetic methodologies
for the construction of complex organic molecules.
1
5
2
′,3′-O-isopropylidene uridine
commercially available and inexpensive uridine
smoothly converted to the key intermediate 2′,3′-O-
4
was synthesized from
3, which was
1
6
With the successful results in hand, we next turned our
attention to the synthesis of Se-uridyl-L-selenohomocysteine,
Se-adenosyl-L-selenohomocysteine (SeAH) and Se-adenosyl-L-
selenomethionine (SeAM). S-adenosyl-L-methionine (SAM) is
an important molecule with the most diverse methyl donor for
enzymatic methylations by SAM-dependent methyl
isopropylidene-2,5′-anhydrouridine (cyclouridine)
5
through
provided a yield of
4%. It is noteworthy to mention that compound was stable
in the freezer at -20°C for half a year. Next, the ring-opening
reaction of cyclouridine with in the presence of N-
methylhydrazine and Cs CO in DMF provided the 2-
trimethylsilyl)ethane seleno group substituted uridine in a
1
7
Mitsunobu reaction using DIAD and PPh
3
9
5
5
2
2
3
2
1
transferases. Recently, SeAM has been reported to have a
significantly better methylation activity than SAM, thus making
(
6
yield of 97% via ring-opening reaction (Method A). Since there
was no reaction, no product was formed in the absence of
2
1
it a useful probe. In addition, SeAH is important as the
synthetic precursor of SeAM-analogues. Few strategies have
been exploited for the synthesis of SeAH and SeAM. However,
Cs
2 3 2 3
CO . Therefore, Cs CO accelerated selenium nucleophilicity
for this ring-opening reaction. Furthermore, an excellent
1
regioselectivity was observed for reaction with cyclouridine
8
these methods commonly required highly flammable Na/NH
reduction for the generation of a selenolate anion from L-
2
selenomethionine or Se-benzyl-selenohomocysteine. Very
3
5
at the ribose C-5′ position by nucleophilic substitution of an
activated selenolate anion. Additionally, the chemical shifts of
2
7
7
recently, as an improved method, Luo et al. reported a large-
C-5′ selenium of compound
81.9 ppm, indicating the presence of selenide function. In
the case of the reaction between and TSE selenolate anion,
which was generated by reductive cleavage of selenating
reagent with sodium borohydride in ethanolic DMF afforded
the 5′-TSE-selenouridine a yield of 95% (Method B) was
observed. The structure of was further confirmed by single-
crystal X-ray crystallography (See Supporting Information).
Finally, 5′-TSE-selenouridine was treated with BzCl in the
to provide the N-Benzoylated 5′-TSE-
in a yield of 94%.
As indicated in Table 1, we prepared various derivatives of
6 in Se NMR was observed at
2
3
1
9
scale protection-free synthesis of SeAH and SeAM, wherein
they successfully avoided the use of air-reactive metal.
Therefore, this method provides several advantages over the
precedents, involving practicality and safety. However, this
route requires much purification by using expensive resin and
lacks the functional group compatibility as mentioned
previously. Furthermore, the use and low yield preparation of
1
5
1
6
6
2
4
unstable 5′-iodo-5′-deoxyadenosine as a precursor of SeAH
seem to need improvement. Therefore, the present method is
applied to the synthesis of Se-uridyl-L-selenohomocysteine,
SeAH and SeAM.
6
2
0
presence of Et
3
N
selenouridine
7
7
As depicted in Scheme 3, we investigated the deprotection
of selenomethionine functionalized uridine. The methyl ester
and N-Bz group of 8r were hydrolyzed to provide the Boc-
and 15. For the scope of this methodology, uridine and
adenosine were selected as representative compounds of
pyrimidine and purine nucleosides, respectively. All
2
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protected Se-uridyl-L-selenohomocysteine 10 in a yield of 90%. methyltransferase inhibitors and the development of
Lastly, the deprotection of Boc-group and isopropylidene epigenetic cancer therapies.
conducted in acidic conditions provided fully deprotected Se-
uridyl-L-selenohomocysteine 11 in a yield of 93%.
Experimental
As another example of
a synthetic application, we
investigated the synthesis of SeAH 18 and SeAM 19 (Scheme
General methods
4
). Our synthesis of SeAH 18 commenced with the synthesis of
Commercially available reagents were used without further
1
1
14
15
16
25
1 , 2 , 4 , 5 , 13 , 14 16 were
25,
26
5′-TSE-selenoadenosine 15 starting from commercially
purification. Compound
2
5
available and inexpensive adenosine 12. First, 5′-chloro-5′-
synthesized according to the previously reported procedure.
2
5
deoxyadenosine 13 was prepared from 12 via Appel reaction.
Subsequently, 2′- and 3′-hydroxyl groups of 13 was protected
with isopropylidene group, yielding 2′,3′-O-isopropylidene-5′-
All reactions were performed in a dry solvent under an argon
atmosphere. Transfer of air- and moisture-sensitive reagents
were performed via cannula under a positive pressure of argon
atmosphere. DMF was degassed by argon bubbling prior to
use. Analytical thin- layer chromatography (TLC) analysis was
performed on Merck TLC (silica gel 60F254 on glass plate). The
developed chromatography was analyzed by UV lamp (254
2
5
chloro-5′-deoxyadenosine 14, following a reported method.
Next, the reaction between 14 and TSE selenolate anion, which
was generated by reductive cleavage of selenating reagent
with sodium borohydride in ethanolic DMF afforded the 15 in
a yield of 65% (Method B). In the use of selenating reagent
as a nucleophilic substitution reaction, a little lower yield
46%) was observed, due to difficulty in separating from the
byproduct derived from the selenating reagent (Method A).
1
2
2 4
nm) or by spraying 10 % H SO solution in EtOH, 20 %
phosphomolybdic acid solution in EtOH, or ninhydrin reagent,
followed by heating. Silica gel 60N (spherical, neutral)
manufactured by Kanto Chemical Co. Inc. was used for flash
column chromatography. NMR spectra were recorded on JEOL
(
2
Next, the 2-(trimethylsilyl)ethyl group was removed with TBAF,
followed by nucleophilic attack to Boc-protected
1
13
77
JNM-ECS400 ( H NMR: 400 MHz, C NMR: 100 MHz, Se
13
2
6
1
NMR: 75 MHz), JEOL JNM-ECA500 ( H NMR: 500 MHz,
iodohomoserine 16
2%. The methyl ester of 9g was hydrolyzed to give the Boc-
protected Se-Adenosyl-L-selenohomocysteine 17 in a yield of
1%. The deprotection of Boc-group and isopropylidene
, giving selenomethionine 9g in a yield of
C
7
NMR: 125 MHz, Se NMR: 94 MHz) and JEOL JNM-ECA600 ( H
7
1
7
1
3
77
NMR: 600 MHz, C NMR: 150 MHz, Se NMR: 113 MHz)
1
spectrometers. Chemical shifts of H NMR are reported in δ
9
conducted in acidic conditions provided fully deprotected
SeAH 18 in a yield of 97%.
values referred to CHCl
O ( 4.79 ppm) as an internal standard and the following
abbreviation were used as follows: s: singlet, d: doublet, t:
3 3
(δ 7.26 ppm), CH OH (δ 3.31 ppm), or
D
2
δ
Finally, we demonstrated the Se-alkylation of SeAH 18 with
methyl iodide in the presence of silver (I) perchlorate, followed
by salt formation with 10% TFA aq., which gave the
corresponding SeAM 19 in 73% yield. The structure of 19 was
1
3
triplet, m: multiplet. Chemical shifts of C NMR are reported
in δ values referred to CHCl 77.1 ppm), CH OH ( 49.0 ppm)
as an internal standard. The Se NMR chemical shifts are
reported in ppm ( ) relative to the external standard. High-
3
(
δ
3
δ
7
7
1
13
confirmed by H and C NMR spectra compared to previous
2
δ
1b, 23
report. The appearance of a newly formed methylseleno
group of 19 was observed at 2.81 ppm and 2.77 ppm,
resolution mass spectra (HRMS) was measured with a Waters
UPLC system (Aquity UPLC XevoQTof). Melting points were
measured by a Yanagimoto micromelting point apparatus. IR
spectra were measured on JASCO FT/IR-410 Fourier Transform
7
7
respectively (47 : 53, Se-epimers). Furthermore, the Se NMR
of the selenonium 19 shifted downfield ( = 325.5 ppm, 325.0
δ
ppm : Se-epimers) compared to the selenide 18 (δ = 130.0
ppm).
3
Infrared Spectrometer in CHCl or MeOH. Optical rotations
were measured with a JASCO P-2300.
Typical procedure for the direct functionalization of 2-
Conclusions
(
trimethylsilyl)ethyl (TSE) seleno groups
(27.6 mg, 0.05 mmol) and methyl
L, 0.25 mmol) in DMF (0.5 mL) was added 1M
the idea of direct functionalization of 2-(trimethylsilyl)ethyl solution of tetrabutyl ammonium fluoride in THF (150 L, 0.15
TSE) seleno groups. This method allows for rapid and easy mmol) at rt. The mixture was stirred for 1 h at rt (TLC
In summary, an efficient method for the synthesis of 5′- To a stirred solution of
selenium modified nucleosides has been explored based on iodide (16
7
ꢀ
ꢀ
(
access to a variety of 5′-selenium modified nucleosides that monitoring; EtOAc:n-hexane = 1:1), then the reaction mixture
would be more difficult to access with traditional methods; was diluted with EtOAc, and the solution was washed with
2 4
thereby the 2-(trimethylsilyl)ethyl group appears very water and brine, dried over Na SO , and then concentrated.
attractive for introduction of the selenium functionality in the The residue was purified by column chromatography on silica
synthesis of 5′-selenium modified nucleosides. Furthermore, gel (EtOAc:n-hexane = 1:2) to afford 8a (18.5 mg, 80%) as a
this method was successfully applied to the synthesis of highly white foam.
functionalized biological important nucleosides such as SeAH
N-Benzoyl-5′-deoxy-5′-methylseleno-2′,3′-O-isopropyridene
and SeAM. As a result, we expect this simple protocol to be of uridine (8a): white foam (18.5 mg, 80% yield)
1
broad utility for the synthesis and development of new
3
H NMR (400 MHz, CDCl ): δ 7.94-7.92 (m, 2H, Ph), 7.69-7.65
selenium-modified nucleosides. We believe that this method (m, 1H, Ph), 7.53-7.49 (m, 2H, Ph), 7.43 (d, 1H, J = 8.2 Hz, H-6),
would be very useful for the future drug discovery of 5.86 (d, 1H, J = 8.2 Hz, H-5), 5.65 (d, 1H, J = 1.8 Hz, H-1′), 5.05
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(dd, 1H, J = 6.4, 1.8 Hz, H-2′), 4.74 (dd, 1H, J = 6.4, 4.1 Hz, H-3′), Hz, H-2′), 4.60 (dd, 1H, J = 6.9, 4.1 Hz, H-3′), 4.22 (ddd, 1H, J =
4
.31 (ddd, 1H, J = 6.9, 6.9, 4.1 Hz, H-4′), 2.79 (d, 2H, J = 6.8 Hz, 6.4, 6.4, 4.6 Hz, H-4′), 3.82-3.78 (m, 2H, -SeCH Ph), 2.81-2.70
2
1
3
H-5′), 2.06-2.02 (m, 3H, -SeCH
3
), 1.55 (s, 3H, CH
); C NMR (100 MHz, CDCl ): 168.4 (COPh), 162.0 (C-4), MHz, CDCl
49.2 (C-2), 142.3 (C-6), 135.4, 131.4, 130.7, 129.4 (Ph), 114.8 6), 138.8 (Ph), 135.4, 131.4, 130.7, 129.4, 129.0, 128.8, 127.2
-C(CH ), 102.8 (C-5), 95.3 (C-1′), 87.4 (C-4′), 84.6 (C-2′), 83.9 (Ph), 114.8 (-C(CH ), 102.8 (C-5), 94.9 (C-1′), 87.1 (C-4′), 84.5
C-3′), 27.5 (C-5′), 27.2 (-C(CH ), 25.4 (-C(CH ), 5.5 (-SeCH ); (C-2′), 83.8 (C-3′), 28.2 (-SeCH Ph), 27.2 (-C(CH ), 25.8 (C-5′),
49.9; IR (film): 1748, 1709, 1673; 25.4 (-C(CH ); Se NMR (75 MHz, CDCl ): 221.4; IR (film):
+3.1 (c 0.55, CHCl ); HRMS (ESI): calcd for 1749, 1709, 1673; [ ); HRMS (ESI): calcd
SeNa [M+Na] : 489.0541, found: 489.0539. SeNa [M+Na] : 565.0854, found: 565.0856.
3
), 1.34 (s, 3H, (m, 2H, H-5′), 1.53 (s, 3H, CH
3 3
), 1.31 (s, 3H, CH ); C NMR (100
1
3
CH
3
3
δ
3
): 168.4 (COPh), 162.0 (C-4), 149.1 (C-2), 142.2 (C-
δ
1
(
(
3
)
2
3 2
)
3
)
2
3
)
2
3
2
3 2
)
7
7
77
Se NMR (75 MHz, CDCl
3
):
δ
3
)
2
3
δ
2
0
20
[α
]
D
3
D 3
α] +1.2 (c 0.67, CHCl
+
+
C
20
H
22
N
2
O
6
26 2 6
for C26H N O
N-Benzoyl-5′-deoxy-5′-ethylseleno-2′,3′-O-isopropyridene
uridine (8b): white foam (17.7 mg, 74% yield)
The reaction was conducted with
iodide (20 L, 0.25 mmol) and 1M solution of tetrabutyl methylbenzyl bromide (44.4 mg, 0.24 mmol) and 1M solution
ammonium fluoride in THF (150 L, 0.15 mmol). of tetrabutyl ammonium fluoride in THF (240 L, 0.24 mmol).
7.94-7.92 (m, 2H, Ph), 7.68-7.65 7.93-7.92 (m, 2H, Ph), 7.67-7.64
m, 1H, Ph), 7.53-7.49 (m, 2H, Ph), 7.44 (d, 1H, J = 8.6 Hz, H-6), (m, 1H, Ph), 7.50-7.48 (m, 2H, Ph), 7.42 (d, 1H, J = 8.3 Hz, H-6),
.85 (d, 1H, J = 8.2 Hz, H-5), 5.67 (d, 1H, J = 2.3 Hz, H-1′), 5.03 7.15-7.14 (m, 2H, Ph), 7.09-7.08 (m, 2H, Ph), 5.84 (d, 1H, J = 7.6
dd, 1H, J = 6.9, 1.8 Hz, H-2′), 4.74 (dd, 1H, J = 6.8, 4.2 Hz, H-3′), Hz, H-5), 5.65 (d, 1H, J = 2.0 Hz, H-1′), 4.96-4.95 (m, 1H, H-2′),
.31 (ddd, 1H, J = 6.4, 6.4, 4.1 Hz, H-4′), 2.82 (d, 2H, J = 6.4 Hz, 4.58 (dd, 1H, J = 6.2, 4.1 Hz, H-3′), 4.23 (ddd, 1H, J = 6.2, 6.2,
H-5′), 2.61 (q, 2H, J = 7.8 Hz, -SeCH CH ), 1.55 (s, 3H, CH ), 1.37 4.1 Hz, H-4′), 3.77 (s, 2H, -SeCH Ph), 2.78 (dd, 1H, J = 13.1, 6.9
t, 3H, J = 7.8 Hz, -SeCH CH ), 1.34 (s, 3H, CH ); C NMR (100 Hz, H-5′a), 2.71 (dd, 1H, J = 13.1, 6.2 Hz, H-5′b), 2.31 (s, 3H,
MHz, CDCl ): 168.4 (COPh), 162.0 (C-4), 149.2 (C-2), 142.2 (C- PhCH
), 135.4, 131.4, 130.7, 129.4 (Ph), 114.8 (-C(CH ), 102.8 (C- CDCl
), 95.0 (C-1′), 87.4 (C-4′), 84.6 (C-2′), 83.8 (C-3′), 27.2 (- 136.8, 135.7, 135.4, 131.3, 130.6, 129.4
), 25.5 (C-5′), 25.4 (-C(CH ), 18.7 (-SeCH CH ), 15.8 (- 114.8 (-C(CH ), 102.7 (C-5), 94.7 (C-1′), 86.9 (C-4′), 84.5 (C-2′),
); Se NMR (113 MHz, CDCl ): 161.5; IR (film): 83.7 (C-3′), 27.9 (-SeCH Ph), 27.2 (-C(CH ), 25.7 (C-5′), 25.3 (-
+1.6 (c 0.58, CHCl ); Se NMR (94 MHz, CDCl ): 220.6; IR
+4.6 (c 0.72, CHCl ); HRMS
SeNa [M+Na] : 579.1010, found:
N-Benzoyl-5′-deoxy-5′-(4-methylbenyl)seleno-2′,3′-O-
isopropyridene uridine (8e): white foam (41.4 mg, 93% yield)
7
(27.6 mg, 0.05 mmol), ethyl The reaction was conducted with 7 (44.1 mg, 0.08 mmol), 4-
ꢀ
ꢀ
ꢀ
1
1
H NMR (400 MHz, CDCl
3
):
δ
3
H NMR (600 MHz, CDCl ): δ
(
5
(
4
2
3
3
2
1
3
(
2
3
3
1
3
3
δ
3
), 1.52 (s, 3H, CH
): 168.4 (COPh), 162.0 (C-4), 149.1 (C-2), 142.1 (C-6),
, 129.3 , 128.9 (Ph),
3 3
), 1.30 (s, 3H, CH ); C NMR (150 MHz,
6
5
3
)
2
3
δ
4
6
C(CH
SeCH
748, 1709, 1670; [
SeNa [M+Na] : 503.0697, found: 503.0697.
3
)
2
3
)
2
2
3
3 2
)
7
7
2
CH
3
3
δ
2
77
3 2
)
2
]
0
1
α
D
3
); HRMS (ESI): calcd C(CH
3
)
2
), 21.2 (PhCH
3
3
δ
+
20
for C21
H
24
N
2
O
6
(film): 1749, 1709, 1674; [
α
]
D
3
+
N-Benzoyl-5′-deoxy-5′-isopropylseleno-2′,3′-O-
(ESI): calcd for C27
579.1012.
28 2 6
H N O
isopropyridene uridine (8c): white foam (15.8 mg, 64% yield)
The reaction was conducted with
isopropyl iodide (20 L, 0.25 mmol) and 1M solution of isopropyridene uridine (8f): pale yellow foam (28.6 mg, 61%
tetrabutyl ammonium fluoride in THF (150 L, 0.15 mmol). yield)
7.94-7.92 (m, 2H, Ph), 7.68-7.64 The reaction was conducted with
m, 1H, Ph), 7.53-7.49 (m, 2H, Ph), 7.45 (d, 1H, J = 8.2 Hz, H-6), nitrobenzyl bromide (51.8 mg, 0.24 mmol) and 1M solution of
.86 (d, 1H, J = 8.2 Hz, H-5), 5.67 (d, 1H, J = 2.3 Hz, H-1′), 5.02 tetrabutyl ammonium fluoride in THF (240 L, 0.24 mmol).
8.11-8.09 (m, 2H, Ph), 7.94-7.92
.32 (ddd, 1H, J = 6.4, 6.4, 4.1 Hz, H-4′), 3.18-3.11 (m, 1H, - (m, 2H, Ph), 7.69-7.65 (m, 2H, Ph), 7.52-7.48 (m, 2H, Ph), 7.40-
), 2.89-2.80 (m, 2H, H-5′), 1.54 (s, 3H, CH ), 1.41-1.36 7.33 (m, 3H, H-6, Ph), 5.86 (d, 1H, J = 8.3 Hz, H-5), 5.54 (d, 1H, J
); C NMR (100 MHz, = 1.8 Hz, H-1′), 5.09-5.08 (m, 1H, H-2′), 4.68 (dd, 1H, J = 6.9, 4.1
168.4 (COPh), 162.1 (C-4), 149.2 (C-2), 142.2 (C-6), Hz, H-3′), 4.19 (ddd, 1H, J = 6.9, 6.9, 4.1 Hz, H-4′), 3.85-3.82 (m,
35.4, 131.4, 130.7, 129.4 (Ph), 114.9 (-C(CH ), 102.8 (C-5), 2H, -SeCH Ph), 2.80-2.71 (m, 2H, H-5′), 1.52 (s, 3H, CH ), 1.32
4.8 (C-1′), 87.4 (C-4′), 84.7 (C-2′), 83.8 (C-3′), 30.4 (-CH(CH ), (s, 3H, CH 168.3 (COPh), 162.0
7.2 (-C(CH ), 25.4 (-C(CH ), 24.9 (C-5′), 24.6 (-CH(CH ); (C-4), 149.1 (C-2), 147.0, 147.0 (Ph, overlap), 143.0 (C-6),
Se NMR (75 MHz, CDCl ): 254.9; IR (film): 1749, 1709, 1671; 135.6, 131.2, 130.7, 129.8, 129.4, 124.0 (Ph), 114.8 (-C(CH ),
+3.2 (c 0.65, CHCl ); HRMS (ESI): calcd for 102.9 (C-5), 96.4 (C-1′), 88.0 (C-4′), 84.5 (C-2′), 83.9 (C-3′), 27.2
7
(27.6 mg, 0.05 mmol),
N-Benzoyl-5′-deoxy-5′-(4-nitrobenyl)seleno-2′,3′-O-
ꢀ
ꢀ
1
H NMR (400 MHz, CDCl
3
):
δ
7 (44.1 mg, 0.08 mmol), 4-
(
5
ꢀ
1
(dd, 1H, J = 6.9, 2.3 Hz, H-2′), 4.74 (dd, 1H, J = 6.8, 4.1 Hz, H-3′),
3
H NMR (400 MHz, CDCl ): δ
4
CH(CH
m, 6H, -CH(CH
CDCl ):
3
)
2
3
1
3
(
3 2 3
) ), 1.34 (s, 3H, CH
3
δ
1
9
2
3
)
2
2
3
1
3
3
)
2
3 3
); C NMR (100 MHz, CDCl ): δ
3
)
2
3
)
2
3 2
)
7
7
3
δ
3 2
)
2
0
[α
]
D
3
+
77
C
22
H
26
N
2
O
6
SeNa [M+Na] : 517.0854, found: 517.0855.
(-C(CH
3
)
2
), 27.0 (-SeCH
):
+16.5 (c 0.20, CHCl
3
2
Ph), 25.9 (C-5′), 25.3 (-C(CH
243.3; IR (film): 1749, 1709, 1671;
); HRMS (ESI): calcd for
SeNa [M+Na] : 610.0705, found: 610.0703.
3 2
) ); Se
N-Benzoyl-5′-deoxy-5′-benzylseleno-2′,3′-O-isopropyridene NMR (94 MHz, CDCl
3
δ
2
]
0
uridine (8d): white foam (21.9 mg, 81% yield)
[α
D
+
The reaction was conducted with
benzyl bromide (12 L, 0.1 mmol) and 1M solution of
tetrabutyl ammonium fluoride in THF (150 L, 0.15 mmol).
7.93-7.91 (m, 2H, Ph), 7.67-7.63 The reaction was conducted with
m, 1H, Ph), 7.51-7.47 (m, 2H, Ph), 7.40 (d, 1H, J = 8.2 Hz, H-6), bromide (13 L, 0.15 mmol) and 1M solution of tetrabutyl
.30-7.19 (m, 5H, Ph, overlap with CDCl ), 5.84 (d, 1H, J = 8.2 ammonium fluoride in THF (150 L, 0.15 mmol).
Hz, H-5), 5.64 (d, 1H, J = 2.3 Hz, H-1′), 4.97 (dd, 1H, J = 6.9, 2.3
7
(27.6 mg, 0.05 mmol),
C
26
H
25
N
3
O
8
ꢀ
N-Benzoyl-5′-deoxy-5′-allylseleno-2′,3′-O-isopropyridene
uridine (8g): white foam (20.8 mg, 85% yield)
(27.6 mg, 0.05 mmol), allyl
ꢀ
1
H NMR (400 MHz, CDCl
3
):
δ
7
(
ꢀ
7
3
ꢀ
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 5 of 12
Orga Pn l iec a s&e Bd oi o nmo to al ed cj uu sl ta mr Ca rhg ei nms istry
View Article Online
DOI: 10.1039/C5OB01316J
Journal Name
ARTICLE
1
H NMR (400 MHz, CDCl
3
):
δ
7.94-7.92 (m, 2H, Ph), 7.69-7.65 The reaction was conducted with
7
(55.2 mg, 0.1 mmol),
(
m, 1H, Ph), 7.53-7.49 (m, 2H, Ph), 7.42 (d, 1H, J = 8.2 Hz, H-6), isobutylene oxide (88.8
ꢀ
L, 1 mmol) and 1M solution of
), 5.65 (d, 1H, J = 2.3 Hz, H- tetrabutyl ammonium fluoride in THF (300 L, 0.3 mmol).
7.96-7.93 (m, 2H, Ph), 7.70-7.66
.1 Hz, H-3′), 4.28 (ddd, 1H, J = 6.9, 6.9, 4.1 Hz, H-4′), 3.21-3.19 (m, 1H, Ph), 7.54-7.50 (m, 2H, Ph), 7.40 (d, 1H, J = 8.2 Hz, H-6),
CHCH ), 2.81-2.71 (m, 2H, H-5′), 1.55 (s, 3H, 5.86 (d, 1H, J = 8.2 Hz, H-5), 5.61 (s, 1H, H-1′), 5.09-5.07 (m, 1H,
), 1.34 (s, 3H, CH
5
1
4
.89-5.78 (m, 2H, H-5, -SeCH
2
CHCH
CHCH
2
ꢀ
1
′), 5.04-4.97 (m, 3H, H-2′, -SeCH
2
2
), 4.73 (dd, 1H, J = 6.9,
3
H NMR (400 MHz, CDCl ): δ
(m, 2H, -SeCH
2
2
1
3
CH
3
3
); C NMR (100 MHz, CDCl
3
):
δ
168.4 H-2′), 4.77-4.74 (m, 1H, H-3′), 4.33-4.30 (m, 1H, H-4′), 2.88-
C(CH OH), 2.34 (br s, 1H, -
OH), 1.55 (s, 3H, CH ), 1.34 (s, 3H, CH ), 1.28-1.27
OH); C NMR (100 MHz, CDCl ): 168.4
3 2
) ), 25.0 (Allyl); Se NMR (75 (COPh), 162.1 (C-4), 149.2 (C-2), 142.7 (C-6), 135.5, 131.3,
(
COPh), 162.0 (C-4), 149.1 (C-2), 142.3 (C-6), 135.4 (Ph), 134.4 2.73 (m, 4H, H-5′, -SeCH
Allyl), 131.2, 130.6, 129.3 (Ph), 117.1 (Allyl), 114.7 (-C(CH ), SeCH C(CH
02.6 (C-5), 94.9 (C-1′), 87.1 (C-4′), 84.5 (C-2′), 83.7 (C-3′), 27.2 (m, 6H, -SeCH
2
3 2
)
(
3
)
2
2
3
)
2
3
3
1
3
1
2
C(CH
3
)
2
3
δ
7
7
(
-C(CH
3
)
2
), 26.9 (C-5′), 25.3 (-C(CH
): 157.2; IR (film): 1749, 1710, 1670; [
); HRMS (ESI): calcd for C22 SeNa [M+Na] : (C-4′), 84.6 (C-2′), 83.8 (C-3′), 70.2 (-SeCH
15.0697, found: 515.0700. SeCH C(CH OH), 29.0 (-SeCH C(CH OH), 28.0 (C-5′), 27.2 (-
N-Benzoyl-5′-deoxy-5′-propargylseleno-2′,3′-O- C(CH ), 25.4 (-C(CH ); Se NMR (94 MHz, CDCl ): 68.4; IR
isopropyridene uridine (8h): white foam (25.3 mg, 86% yield) (film): 3491 (OH), 1748, 1709, 1672; [
The reaction was conducted with (33.1 mg, 0.06 mmol), CHCl ); HRMS (ESI): calcd for C23
propargyl bromide (13.6 L, 0.18 mmol) and 1M solution of 547.0959, found: 547.0953.
tetrabutyl ammonium fluoride in THF (180 L, 0.18 mmol). N-Benzoyl-5′-deoxy-5′-(2-nitrophenyl)seleno-2′,3′-O-
7.94-7.92 (m, 2H, Ph), 7.69-7.65 isopropyridene uridine (8k): yellow foam (17.2 mg, 60% yield)
m, 1H, Ph), 7.53-7.49 (m, 2H, Ph), 7.40 (d, 1H, J = 8.3 Hz, H-6), The reaction was conducted with (27.6 mg, 0.05 mmol), 2-
L, 0.1 mmol) and 1M solution of
.05 (m, 1H, H-2′), 4.78 (dd, 1H, J = 6.9, 4.1 Hz, H-3′), 4.39-4.35 tetrabutyl ammonium fluoride in THF (150 L, 0.15 mmol).
8.28-8.27 (m, 1H, Ph), 7.93-7.92
), 1.33 (s, 3H, (m, 2H, Ph), 7.62-7.60 (m, 1H, Ph), 7.47-7.45 (m, 4H, Ph), 7.33-
168.4 (COPh), 162.0 (C-4), 7.30 (m, 2H, H-6, Ph), 5.82 (d, 1H, J = 8.2 Hz, H-5), 5.56 (d, 1H, J
49.1 (C-2), 142.4 (C-6), 135.5, 131.3, 130.7, 129.4 (Ph), 114.9 = 1.4 Hz, H-1′), 5.15 (d, 1H, J = 6.2 Hz, H-2′), 4.83 (dd, 1H, J =
-C(CH ), 102.8 (C-5), 95.3 (C-1′), 87.5 (C-4′), 84.6 (C-2′), 83.9 6.9, 4.1 Hz, H-3′), 4.41-4.38 (m, 1H, H-4′), 3.25-3.18 (m, 2H, H-
C-3′), 80.4 (-SeCH
6.3 (C-5′), 25.4 (-C(CH
2
0
MHz, CDCl
3
δ
α
]
D
+6.6 (c 130.7, 129.4 (Ph), 114.8 (-C(CH
3
)
2
), 102.8 (C-5), 95.7 (C-1′), 87.7
C(CH OH), 41.7 (-
+
0
.55, CHCl
3
H
24
N
2
O
6
2
3 2
)
5
2
3
)
2
2
3 2
)
7
7
3
)
2
3
)
2
3
δ
2
0
α
]
D
+12.8 (c 0.57,
+
7
3
H
28
N
2
O
7
SeNa [M+Na] :
ꢀ
ꢀ
1
3
H NMR (400 MHz, CDCl ): δ
(
7
5
.86 (d, 1H, J = 8.3 Hz, H-5), 5.64 (d, 1H, J = 2.3 Hz, H-1′), 5.07- fluoronitrobenzene (10.5 ꢀ
5
ꢀ
1
(m, 1H, H-4′), 3.24-3.22 (m, 2H, -SeCH
2
CCH), 3.04-3.02 (m, 2H,
CCH), 1.54 (s, 3H, CH
):
3
H NMR (600 MHz, CDCl ): δ
H-5′), 2.26 (s, 1H, -SeCH
2
3
1
3
CH
3
); C NMR (100 MHz, CDCl
3
δ
1
(
(
3 2
)
1
3
2
CCH), 72.1 (-SeCH
), 8.0 (-SeCH
220.2; IR (film): 3288 (alkyne), 1748, 1709, 143.0 (C-6), 135.5, 133.9, 132.3, 131.2, 130.6, 129.4, 129.2,
+13.6 (c 0.48, CHCl ); HRMS (ESI): calcd for 126.6, 126.0 (Ph), 114.8 (-C(CH ), 102.8 (C-5), 96.7 (C-1′), 86.9
(C-4′), 84.6 (C-2′), 84.4 (C-3′), 28.5 (C-5′), 27.1 (-C(CH ), 25.3 (-
329.2; IR (film): 1749,
); HRMS (ESI): calcd for
SeNa [M+Na] :596.0548, found: 596.0548.
N-Benzoyl-5′-deoxy-5′-(4-nitrophenyl)seleno-2′,3′-O-
isopropyridene uridine (8l): yellow foam (18.0 mg, 63% yield)
7.93-7.92 (m, 2H, Ph), 7.68-7.65 The reaction was conducted with (27.6 mg, 0.05 mmol), 4-
m, 1H, Ph), 7.52-7.49 (m, 2H, Ph), 7.43 (d, 1H, J = 8.2 Hz, H-6), fluoronitrobenzene (10.6 L, 0.1 mmol) and 1M solution of
.85 (d, 1H, J = 8.2 Hz, H-5), 5.66 (s, 1H, H-1′), 5.02 (d, 1H, J = tetrabutyl ammonium fluoride in THF (150 L, 0.15 mmol).
8.06-8.04 (m, 2H, Ph), 7.95-7.93
), (m, 2H, Ph), 7.68-7.64 (m, 1H, Ph), 7.52-7.47 (m, 4H, Ph), 7.29
), 2.87 (d, 2H, J = 6.2 Hz, H-5′), 2.77- (d, 1H, J = 8.3 Hz, H-6), 5.84 (d, 1H, J = 8.3 Hz, H-5), 5.51 (d, 1H,
OCH ), 1.54 (s, 3H, CH ), 1.33 (s, 3H, J = 1.4 Hz, H-1′), 5.16-5.14 (m, 1H, H-2′), 4.80 (dd, 1H, J = 6.4,
); C NMR (150 MHz, CDCl ): 168.4 (COPh), 162.0 (C-4), 4.1 Hz, H-3′), 4.33 (ddd, 1H, J = 6.9, 6.9, 4.1 Hz, H-4′), 3.33-3.22
2
CCH), 27.2 (-C(CH
3
)
2
), 5′), 1.51 (s, 3H, CH
3 3
), 1.32 (s, 3H, CH ); C NMR (150 MHz,
7
7
2
3
)
2
2
CCH); Se NMR (94 CDCl ): 168.3 (COPh), 162.0 (C-4), 149.3 (C-2), 147.0 (Ph),
3
δ
MHz, CDCl
3
0
):
δ
2
1
671; [
α
O
]
D
3
3 2
)
+
C
22
H
22
N
2
6
SeNa [M+Na] : 513.0541, found: 513.0546.
N-Benzoyl-5′-deoxy-5′-(2-methoxyethyl)seleno-2′,3′-O-
isopropyridene uridine (8i): white foam (75.6 mg, 74% yield)
The reaction was conducted with (113.1 mg, 0.2 mmol), 2-
bromoethyl methyl ether (57 L, 0.6 mmol) and 1M solution of
tetrabutyl ammonium fluoride in THF (600 L, 0.6 mmol).
3 2
)
7
7
C(CH
3
)
2
); Se NMR (94 MHz, CDCl
3
):
δ
2
0
1709, 1672; [
α
]
D
+81.0 (c 0.54, CHCl
3
+
7
25 23 3 8
C H N O
ꢀ
ꢀ
1
H NMR (600 MHz, CDCl
3
):
δ
7
(
ꢀ
5
ꢀ
1
5
.5 Hz, H-2′), 4.74 (dd, 1H, J = 6.8, 4.1 Hz, H-3′), 4.32 (ddd, 1H, J
6.2, 6.2, 4.1 Hz, H-4′), 3.61-3.59 (m, 2H, -SeCH CH OCH
.34 (s, 3H, -SeCH CH OCH
.75 (m, 2H, -SeCH CH
3
H NMR (400 MHz, CDCl ): δ
=
2
2
3
3
2
2
3
2
2
2
3
3
1
3
CH
3
3
δ
1
3
1
49.1 (C-2), 142.3 (C-6), 135.4, 131.3, 130.6, 129.4 (Ph), 114.8 (m, 2H, H-5′), 1.51 (s, 3H, CH
-C(CH ), 102.8 (C-5), 94.9 (C-1′), 87.4 (C-4′), 84.6 (C-2′), 83.7 MHz, CDCl ): 168.3 (COPh), 161.9 (C-4), 149.2 (C-2), 146.5
C-3′), 72.7 (-SeCH CH OCH ), 58.7 (-SeCH CH OCH ), 27.2 (- (Ph), 143.2 (C-6), 140.6, 135.6, 131.2, 130.7, 130.6, 129.4,
), 26.3 (C-5′), 25.4 (-C(CH ), 24.2 (-SeCH CH OCH ); 124.0 (Ph), 114.7 (-C(CH ), 102.9 (C-5), 97.1 (C-1′), 87.6 (C-4′),
Se NMR (75 MHz, CDCl ):  116.2; IR (film): 1749, 1709, 1673; 84.7 (C-2′), 84.1 (C-3′), 29.1 (C-5′), 27.1 (-C(CH ), 25.3 (-
283.9; IR (film): 1749,
); HRMS (ESI): calcd for
SeNa [M+Na] :596.0548, found: 596.0555.
N-Benzoyl-5′-deoxy-5′-(2-oxopropyl)seleno-2′,3′-O-
3 3
), 1.32 (s, 3H, CH ); C NMR (100
(
(
3
)
2
3
δ
2
2
3
2
2
3
C(CH
7
3
)
2
3
)
2
2
2
3
3 2
)
7
3
3 2
)
2
0
77
[α
]
D
+12.4 (c 0.12, CHCl
3
); HRMS (ESI): calcd for C(CH
3
)
2
); Se NMR (75 MHz, CDCl
3
):
δ
+
20
C
22
H
26
N
2
O
7
SeNa [M+Na] : 533.0803, found: 533.0803. 1709, 1672; [
α
]
D
+42.3 (c 0.40, CHCl
3
+
N-Benzoyl-5′-deoxy-5′-(2,2-dimethylethane-2-ol)seleno-
′,3′-O-isopropyridene uridine (8j): white foam (36.5 mg, 70%
25 23 3 8
C H N O
2
yield)
isopropyridene uridine (8m): white foam (15.2 mg, 60% yield)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 12
View Article Online
DOI: 10.1039/C5OB01316J
ARTICLE
Journal Name
The reaction was conducted with
7
(27.6 mg, 0.05 mmol), The reaction was conducted with
7
(55.2 mg, 0.1 mmol), tert-
bromoacetone (41.9
ꢀ
L, 0.5 mmol) and 1M solution of butyl bromoacetate (73.8
L, 0.15 mmol). tetrabutyl ammonium fluoride in THF (300
7.97-7.95 (m, 2H, Ph), 7.69-7.65
m, 1H, Ph), 7.53-7.49 (m, 2H, Ph), 7.38 (d, 1H, J = 8.2 Hz, H-6), (m, 1H, Ph), 7.53-7.49 (m, 2H, Ph), 7.42 (d, 1H, J = 8.7 Hz, H-6),
ꢀ
L, 0.5 mmol) and 1M solution of
L, 0.3 mmol).
3
H NMR (400 MHz, CDCl ): δ 7.95-7.93 (m, 2H, Ph), 7.69-7.65
tetrabutyl ammonium fluoride in THF (150
ꢀ
ꢀ
1
1
H NMR (400 MHz, CDCl
3
):
δ
(
5.86 (d, 1H, J = 8.2 Hz, H-5), 5.60 (d, 1H, J = 1.8 Hz, H-1′), 5.07- 5.85 (d, 1H, J = 8.2 Hz, H-5), 5.66 (d, 1H, J = 1.8 Hz, H-1′), 5.04-
5.05 (m, 1H, H-2′), 4.72 (dd, 1H, J = 6.4, 4.1 Hz, H-3′), 4.30 (ddd, 5.03 (m, 1H, H-2′), 4.75 (dd, 1H, J = 6.4, 4.2 Hz, H-3′), 4.38-4.34
1
H, J = 6.9, 6.9, 4.6 Hz, H-4′), 3.30-3.22 (m, 2H, -SeCH
.86-2.84 (m, 2H, H-5′), 2.31 (s, 3H, -SeCH COCH ), 1.55 (s, 3H, (m, 2H, H-5′), 1.54 (s, 3H, CH
); C NMR (100 MHz, CDCl
), 168.5 (COPh), 162.1 (C-4), 149.2 (C-2), 142.6 (C- SeCH
), 135.5, 131.3, 130.7, 129.4 (Ph), 114.8 (-C(CH ), 102.8 (C- 142.3 (C-6), 135.4, 131.3, 130.6, 129.4 (Ph), 114.8 (-C(CH
), 95.6 (C-1′), 87.5 (C-4′), 84.6 (C-2′), 83.9 (C-3′), 32.3 (- 102.8 (C-5), 95.1 (C-1′), 87.1 (C-4′), 84.6 (C-2′), 83.8 (C-3′), 81.7
COCH ), 27.7 (-SeCH COCH ), 27.2 (-C(CH ), 26.4 (C-5′), (-SeCH CO C(CH ), 28.0 (-SeCH CO C(CH ), 27.2 (-C(CH ),
5.4 (-C(CH ); Se NMR (94 MHz, CDCl ): 166.9; IR (film): 26.7 (C-5′), 25.3 (-C(CH ), 24.6 (-SeCH CO ); Se NMR
748, 1708, 1668; [ ); HRMS (ESI): calcd (94 MHz, CDCl ): 179.3; IR (film): 1749, 1709, 1673; [
SeNa [M+Na] : 531.0646, found: 531.0643. +0.82 (c 0.55, CHCl ); HRMS (ESI): calcd for C25 SeNa
N-Benzoyl-5′-deoxy-5′-(2-oxo-2-phenylethyl)seleno-2′,3′-O- [M+Na] : 589.1065, found: 589.1064.
isopropyridene uridine (8n): white foam (36.4 mg, 80% yield) N-Benzoyl-5′-deoxy-5′-cyanomethylseleno-2′,3′-O-
The reaction was conducted with (44.1 mg, 0.08 mmol), 2- isopropyridene uridine (8q): white foam (19.8 mg, 67% yield)
bromoacetophenone (47.8 mg, 0.24 mmol) and 1M solution of The reaction was conducted with (33.1 mg, 0.06 mmol),
tetrabutyl ammonium fluoride in THF (240 L, 0.24 mmol). bromoacetonitrile (12.5 L, 0.18 mmol) and 1M solution of
7.95-7.92 (m, 4H, Ph), 7.65-7.56 tetrabutyl ammonium fluoride in THF (180 L, 0.18 mmol).
7.97-7.95 (m, 2H, Ph), 7.70-7.67
.81 (d, 1H, J = 8.2 Hz, H-5), 5.64 (m, 1H, H-1′), 5.02-5.00 (m, (m, 1H, Ph), 7.55-7.51 (m, 2H, Ph), 7.33 (d, 1H, J = 8.2 Hz, H-6),
H, H-2′), 4.70 (dd, 1H, J = 6.8, 4.1 Hz, H-3′), 4.34 (m, 1H, H-4′), 5.87 (d, 1H, J = 8.2 Hz, H-5), 5.56 (d, 1H, J = 1.8 Hz, H-1′), 5.14-
.89-3.82 (m, 2H, -SeCH COPh), 2.94-2.92 (m, 2H, H-5′), 1.53 5.12 (m, 1H, H-2′), 4.78 (dd, 1H, J = 6.9, 4.1 Hz, H-3′), 4.37 (ddd,
2
COCH
3
), (m, 1H, H-4′), 3.15-3.08 (m, 2H, -SeCH
2 2 3 3
CO C(CH ) ), 3.01-3.00
2
2
3
3
), 1.45 (s, 9H, -SeCH
2
CO
2
3 3
C(CH ) ),
1
3
13
CH
3
), 1.33 (s, 3H, CH
COCH
3
3
):
δ
203.7 (- 1.33 (s, 3H, CH
CO C(CH
3
); C NMR (100 MHz, CDCl
3
):
δ
170.4 (-
SeCH
2
3
2
2
3
)
3
), 168.4 (COPh), 162.0 (C-4), 149.1 (C-2),
),
6
5
3
)
2
3 2
)
SeCH
2
3
2
3
3
)
2
2
2
3
)
3
2
2
3
)
3
3 2
)
7
7
77
2
1
3
)
2
3
δ
3
)
2
2
2 3 3
C(CH )
2
0
20
α]
D
α
]
D
+5.6 (c 0.43, CHCl
3
3
δ
+
for C22
H
24
N
2
O
7
3
30 2 8
H N O
+
7
7
ꢀ
ꢀ
1
H NMR (400 MHz, CDCl
3
):
δ
ꢀ
1
(m, 2H, Ph), 7.50-7.45 (m, 4H, Ph), 7.39 (d, 1H, J = 8.2 Hz, H-6),
3
H NMR (400 MHz, CDCl ): δ
5
1
3
2
1
3
(
s, 3H, CH
3
), 1.31 (s, 3H, CH
3
); C NMR (100 MHz, CDCl
COPh), 168.4 (COPh), 162.0 (C-4), 149.1 (C-2), 1.55 (s, 3H, CH
168.4 (COPh), 162.0 (C-4), 149.2 (C-2), 143.0 (C-6), 135.6,
), 102.8 (C-5), 95.0 (C-1′), 87.2 (C-4′), 131.2, 130.7, 129.4 (Ph), 117.4 (-SeCH CN), 115.0 (-C(CH ),
4.6 (C-2′), 83.8 (C-3′), 27.3 (-SeCH COPh), 27.2 (-C(CH ), 26.9 103.0 (C-5), 96.4 (C-1′), 88.3 (C-4′), 84.5 (C-2′), 84.0 (C-3′), 27.6
); Se NMR (94 MHz, CDCl ): 179.2; IR (-C(CH
+0.09 (c 0.45, CHCl ); HRMS NMR (94 MHz, CDCl
3
):
δ
1H, J = 7.8, 7.8, 2.3 Hz, H-4′), 3.25-3.02 (m, 4H, H-5′, -SeCH
2
CN),
1
3
1
1
1
8
94.8 (-SeCH
2
3
), 1.34 (s, 3H, CH
3
); C NMR (100 MHz, CDCl ):
3
42.3 (C-6), 135.4, 135.1, 133.6, 131.3, 130.7, 129.3, 128.9,
28.8 (Ph), 114.8 (-C(CH
δ
3
)
2
2
3 2
)
2
3 2
)
7
7
77
(
(
(
C-5′), 25.4 (-C(CH
film): 1748, 1708, 1670; [
ESI): calcd for C27
93.0804.
N-Benzoyl-5′-deoxy-5′-(methyl-2-acetate)seleno-2′,3′-O-
isopropyridene uridine (8o): white foam (23.6 mg, 90% yield)
The reaction was conducted with (27.6 mg, 0.05 mmol), isopropyridene uridine (8r): white foam (97.2 mg, 73% yield)
methyl bromoacetate (18.6 L, 0.2 mmol) and 1M solution of The reaction was conducted with (113.1 mg, 0.2 mmol), (S)-
tetrabutyl ammonium fluoride in THF (150 L, 0.15 mmol). methyl 2-(tert-butoxycarbonylamino)-4-iodobutanoate 16
7.95-7.93 (m, 2H, Ph), 7.69-7.65 (137.3 mg, 0.4 mmol) and 1M solution of tetrabutyl
m, 1H, Ph), 7.53-7.49 (m, 2H, Ph), 7.38 (d, 1H, J = 8.2 Hz, H-6), ammonium fluoride in THF (600 L, 0.6 mmol).
7.94-7.92 (m, 2H, Ph), 7.69-7.65
.05 (m, 1H, H-2′), 4.74 (dd, 1H, J = 6.9, 4.1 Hz, H-3′), 4.34 (ddd, (m, 1H, Ph), 7.53-7.49 (m, 2H, Ph), 7.43 (d, 1H, J = 8.3 Hz, H-6),
H, J = 6.9, 6.9, 4.1 Hz, H-4′), 3.70 (s, 3H, -SeCH CO CH ), 3.25- 5.86 (d, 1H, J = 8.3 Hz, H-5), 5.65 (s, 1H, H-1′), 5.10-5.02 (m,
.17 (m, 2H, -SeCH CO CH ), 3.05-2.97 (m, 2H, H-5′), 1.55 (s, 2H, H-2′, NH), 4.74-4.71 (m, 1H, H-3′), 4.39-4.38 (m, 1H, H- ),
H, CH ), 1.33 (s, 3H, CH ), 2.83-2.81 (m, 2H,
CO CH ), 168.4 (COPh), 162.0 (C-4), 149.1 (C-2), 142.5 H-5′), 2.61 (t, 2H, J = 7.8 Hz, H- ), 2.17-2.13 (m, 1H, H- a), 2.01-
C-6), 135.4, 131.2, 130.6, 129.3 (Ph), 114.7 (-C(CH ), 102.7 1.93 (m, 1H, H- b), 1.55 (s, 3H, CH ), 1.44 (s, 9H, CO
C-5), 95.2 (C-1′), 87.3 (C-4′), 84.5 (C-2′), 83.7 (C-3′), 52.5 (- 1.33 (s, 3H, CH
3
)
2
3
δ
3
)
2
), 27.2 (C-5′), 25.4 (-C(CH
): 234.3; IR (film): 2241 (CN), 1747,
+6.4 (c 0.47, CHCl ); HRMS (ESI): calcd for
SeNa [M+Na] : 514.0493, found: 514.0502.
N-Benzoyl-5′-deoxy-5′-(2-(tert-
butoxycarbonylamino)butanoate)seleno-2′,3′-O-
3 2 2
) ), 3.4 (-SeCH CN); Se
2
]
0
α
D
3
3
δ
+
20
]
H
26
N
2
O
7
SeNa [M+Na] : 593.0803, found: 1709, 1668; [
α
D
3
+
5
21 21 3 6
C H N O
7
ꢀ
7
2
6
ꢀ
1
3
H NMR (400 MHz, CDCl ): δ
(
ꢀ
1
5
5
1
3
3
.86 (d, 1H, J = 8.2 Hz, H-5), 5.63 (d, 1H, J = 2.3 Hz, H-1′), 5.06-
3
H NMR (400 MHz, CDCl ): δ
2
2
3
2
2
3
α
1
3
3
3 3 2 3
); C NMR (100 MHz, CDCl ): δ 171.6 4.30-4.26 (m, 1H, H-4′), 3.73 (s, 3H, CO CH
(
(
(
-SeCH
2
2
3
γ
β
3
)
2
β
3
2
C(CH
3
)
3
),
),
1
3
3
); C NMR (100 MHz, CDCl
), 22.7 168.4 (COPh), 162.0 (C-4), 155.5 (CO C(CH
186.9; IR (film): 142.3 (C-6), 135.5, 131.3, 130.7, 129.4 (Ph), 114.9 (-C(CH
3
):
δ
2
172.7 (CO CH
3
SeCH
2
CO
2
CH
3
), 27.1 (-C(CH
3
)
2
), 27.0 (C-5′), 25.3 (-C(CH
3
)
2
2
3 3
) ), 149.2 (C-2),
7
); Se NMR (75 MHz, CDCl ):
7
(-SeCH CO
2
2
CH
3
3
δ
3
)
2
),
2
0
1748, 1708, 1668; [
D 3
α] +1.8 (c 0.96, CHCl ); HRMS (ESI): calcd 102.9 (C-5), 95.1 (C-1′), 87.2 (C-4′), 84.6 (C-2′), 83.8 (C-3′), 80.3
+
SeNa [M+Na] : 547.0596, found: 547.0596.
for C22
H
24
N
2
O
8
(CO
2
C(CH
3
)
3
), 53.6 (C-
α
), 52.6 (CO
), 26.1 (C-5′), 25.4 (-C(CH
): 139.0; IR (film): 1748, 1709,
2
CH
3
), 33.8 (C-
γ
), 28.4
N-Benzoyl-5′-deoxy-5′-(tert-butylacetate)seleno-2′,3′-O-
isopropyridene uridine (8p): white foam (43.6 mg, 77% yield)
(CO
2
C(CH
7
3
)
3
), 27.2 (-C(CH
3
)
2
) ), 20.3
3 2
7
(C-β
); Se NMR (75 MHz, CDCl
3
δ
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 7 of 12
Journal Name
Orga Pn l iec a s&e Bd oi o nmo to al ed cj uu sl ta mr Ca rhg ei nms istry
View Article Online
DOI: 10.1039/C5OB01316J
ARTICLE
2
0
1
672; [
α
]
D
+17.8 (c 0.30, CHCl
3
); HRMS (ESI): calcd for The reaction was conducted with 15 (47.1 mg, 0.1 mmol),
10SeNa [M+Na] : 690.1542, found: 690.1541. benzyl bromide (23.7 L, 0.2 mmol) and 1M solution of
′-deoxy-5′-methylseleno-2′,3′-O-isopropyridene adenosine tetrabutyl ammonium fluoride in THF (300 L, 0.3 mmol).
8.33 (s, 1H, H-2), 7.91 (s, 1H, H-8),
The reaction was conducted with 15 (47.1 mg, 0.1 mmol), 7.24-7.23 (m, 2H, Ph), 7.20-7.17 (m, 3H, Ph), 6.06 (d, 1H, J = 2.8
methyl iodide (32 L, 0.5 mmol) and 1M solution of tetrabutyl Hz, H-1′), 5.59 (br s, 2H, NH ), 5.44 (dd, 1H, J = 6.2, 2.7 Hz, H-
ammonium fluoride in THF (300 L, 0.3 mmol). 2′), 4.91 (dd, 1H, J = 6.2, 3.4 Hz, H-3′), 4.37 (ddd, 1H, J = 6.2,
8.35 (s, 1H, H-2), 7.94 (s, 1H, H-8), 6.2, 3.4 Hz, H-4′), 3.78-3.75 (m, 2H, -SeCH Ph), 2.80 (dd, 1H, J =
.09 (d, 1H, J = 2.1 Hz, H-1′), 5.78 (br s, 2H, NH ), 5.52 (dd, 1H, J 12.4, 7.6 Hz, H-5′a), 2.70 (dd, 1H, J = 13.0, 6.2 Hz, H-5′b), 1.60
6.2, 2.1 Hz, H-2′), 5.05 (dd, 1H, J = 6.2, 3.4 Hz, H-3′), 4.46-4.43 (s, 3H, CH
), 1.62 155.6 (C-6), 153.4 (C-2), 149.5 (C-4), 140.1 (C-8), 138.9, 129.0,
); C NMR (150 MHz, CDCl ): 128.7, 127.1, 120.5 (C-5), 114.7 (-C(CH ), 90.8 (C-1′), 87.2 (C-
55.7 (C-6), 153.3 (C-2), 149.5 (C-4), 140.2 (C-8), 120.5 (C-5), 4′), 84.4 (C-2′), 84.3 (C-3′), 27.9 (-SeCH
+
C
29
H
37
N
3
O
ꢀ
5
ꢀ
1
(
9a): white foam (8.8 mg, 46% yield)
3
H NMR (600 MHz, CDCl ): δ
ꢀ
2
ꢀ
1
H NMR (600 MHz, CDCl
3
):
δ
2
6
=
2
1
3
3
3 3
), 1.37 (s, 3H, CH ); C NMR (150 MHz, CDCl ): δ
(
m, 1H, H-4′), 2.85-2.75 (m, 2H, H-5′), 1.99 (s, 3H, -SeCH
3
1
3
(s, 3H, CH
3
), 1.40 (s, 3H, CH
3
3
δ
3 2
)
1
1
2
2
Ph), 27.3 (-C(CH
3
)
2
),
7
7
14.6 (-C(CH
3
)
2
), 90.9 (C-1′), 87.3 (C-4′), 84.4 (C-3′), 84.3 (C-2′), 25.7 (C-5′), 25.5 (-C(CH
3
)
2
); Se NMR (113 MHz, CDCl ):
3
δ
7
7
20
7.4 (C-5′), 27.2 (-C(CH
3
)
2
), 25.5 (-C(CH
53.2; IR (film): 3335, 1647, 1599, CHCl
); HRMS (ESI): calcd for 484.0864, found: 484.0862.
SeNa [M+Na] : 408.0551, found: 408.0568. 5′-deoxy-5′-allylseleno-2′,3′-O-isopropyridene
3
)
2
), 5.2 (-SeCH
3
); Se 227.1; IR (film): 3332, 1647, 1599, 1085; [
D
α] -51.5 (c 0.18,
+
NMR (113 MHz, CDCl
3
):
δ
3
); HRMS (ESI): calcd for C20
23 5 3
H N O SeNa [M+Na] :
2
]
0
1085; [
α
D
-41.6 (c 0.20, CHCl
3
+
C
14
H
19
N
5
O
3
adenosine
5′-deoxy-5′-ethylseleno-2′,3′-O-isopropyridene adenosine (9e): white foam (12.6 mg, 61% yield)
(9b): white foam (28.1 mg, 71% yield)
The reaction was conducted with 15 (23.5 mg, 0.05 mmol),
The reaction was conducted with 15 (47.1 mg, 0.1 mmol), ethyl allyl bromide (12.7
iodide (24 L, 0.3 mmol) and 1M solution of tetrabutyl tetrabutyl ammonium fluoride in THF (150
ammonium fluoride in THF (300
ꢀ
L, 0.15 mmol) and 1M solution of
L, 0.15 mmol).
8.34 (s, 1H, H-2), 7.93 (s, 1H, H-8),
8.36 (s, 1H, H-2), 7.99 (s, 1H, H-8), 6.08 (d, 1H, J = 2.8 Hz, H-1′), 5.94 (br s, 2H, NH ), 5.84-5.77 (m,
), 6.11 (d, 1H, J = 2.3 Hz, H-1′), 5.51 (dd, 1H, J 1H, -SeCH CHCH ), 5.50 (dd, 1H, J = 6.9, 2.8 Hz, H-2′), 5.03 (dd,
6.4, 2.3 Hz, H-2′), 5.05 (dd, 1H, J = 6.4, 3.2 Hz, H-3′), 4.48-4.44 1H, J = 6.9, 2.7 Hz, H-3′), 4.96-4.92 (m, 2H, -SeCH CHCH ), 4.42-
CHCH ), 2.82 (dd,
), 1.35 (t, 3H, J = 1H, J = 12.4, 7.6 Hz, H-5′a), 2.72 (dd, 1H, J = 12.4, 6.2 Hz, H-
ꢀ
ꢀ
1
ꢀ
L, 0.3 mmol).
3
H NMR (600 MHz, CDCl ): δ
1
H NMR (400 MHz, CDCl
3
):
δ
2
6
.27 (br s, 2H, NH
2
2
2
=
2
2
(m, 1H, H-4′), 2.90-2.78 (m, 2H, H-5′), 2.58 (q, 2H, J = 7.8 Hz, - 4.39 (m, 1H, H-4′), 3.19-3.16 (m, 2H, -SeCH
2
2
SeCH
2
CH
3
), 1.62 (s, 3H, CH
3
), 1.41 (s, 3H, CH
); C NMR (100 MHz, CDCl
52.5 (C-2), 149.3 (C-4), 140.3 (C-8), 120.3 (C-5), 114.7 (- CDCl
3
1
3
13
7.8 Hz, -SeCH
2
CH
3
3
):
δ
155.4 (C-6), 5′b), 1.61 (s, 3H, CH
): 155.8 (C-6), 153.3 (C-2), 149.4 (C-4), 140.1 (C-8),
), 134.6 (Allyl), 120.4 (C-5), 117.0 (Allyl), 114.7 (-C(CH ), 90.9 (C-
); 1′), 87.1 (C-4′), 84.4 (C-2′), 84.3 (C-3′), 27.3 (-C(CH ), 26.8 (C-
Allyl); Se NMR (113 MHz,
3 3
), 1.39 (s, 3H, CH ); C NMR (150 MHz,
1
3
δ
C(CH
3
)
2
), 91.0 (C-1′), 87.4 (C-4′), 84.3, 84.3, 27.2 (-C(CH
5.5 (-C(CH ), 25.4 (C-5′), 18.4 (-SeCH CH ), 15.8 (-SeCH CH
):
-60.7 (c 0.13, CHCl
3
)
2
3 2
)
2
3
)
2
2
3
2
3
3 2
)
7
7
77
Se NMR (94 MHz, CDCl
3
δ
165.0; IR (film): 3335, 1643, 1599, 5′), 25.5 (-C(CH
); HRMS (ESI): calcd for CDCl ): 161.8; IR (film): 3335, 1643, 1599, 1086; [
SeNa [M+Na] : 422.0707, found: 422.0708. (c 0.48, CHCl ); HRMS (ESI): calcd for C16 SeNa [M+Na] :
434.0707, found: 434.0714.
5′-deoxy-5′-propargylseleno-2′,3′-O-isopropyridene
The reaction was conducted with 15 (23.5 mg, 0.05 mmol), adenosine (9f): pale yellow foam (15.3 mg, 75% yield)
isopropyl iodide (14.9 L, 0.15 mmol) and 1M solution of The reaction was conducted with 15 (23.5 mg, 0.05 mmol),
tetrabutyl ammonium fluoride in THF (150 L, 0.15 mmol). propargyl bromide (11.3 L, 0.15 mmol) and 1M solution of
8.35 (s, 1H, H-2), 7.94 (s, 1H, H-8), tetrabutyl ammonium fluoride in THF (150 L, 0.15 mmol).
8.35 (s, 1H, H-2), 7.92 (s, 1H, H-8),
6.3, 2.3 Hz, H-2′), 5.04 (dd, 1H, J = 6.3, 3.5 Hz, H-3′), 4.45 6.09 (d, 1H, J = 2.0 Hz, H-1′), 5.79 (br s, 2H, NH ), 5.51 (dd, 1H, J
3 2 2
) ), 25.2 (-SeCH
2
0
20
1085; [
α
]
D
3
3
δ
D
α] -19.2
+
+
C
15
H
21
N
5
O
3
3
21 5 3
H N O
5′-deoxy-5′-isopropylseleno-2′,3′-O-isopropyridene
adenosine (9c): white foam (10.5 mg, 51% yield)
ꢀ
ꢀ
ꢀ
1
H NMR (500 MHz, CDCl
3
):
δ
ꢀ
1
6.09 (d, 1H, J = 2.3 Hz, H-1′), 5.78 (br s, 2H, NH
=
2
), 5.51 (dd, 1H, J
3
H NMR (600 MHz, CDCl ): δ
2
(ddd, 1H, J = 6.3, 6.3, 1.8 Hz, H-4′), 3.16-3.09 (m, 1H, - = 6.2, 2.1 Hz, H-2′), 5.10 (dd, 1H, J = 6.2, 3.4 Hz, H-3′), 4.51
SeCH(CH
3
)
2
), 2.91-2.85 (m, 1H, H-5′a), 2.81-2.78 (m, 1H, H-5′b), (ddd, 1H, J = 6.9, 6.9, 2.8 Hz, H-4′), 3.21-3.15 (m, 2H, -
1
.61 (s, 3H, CH
3
), 1.40 (s, 3H, CH
3
), 1.38-1.32 (m, 6H, - SeCH
): 155.7 (C-6), 153.3 SeCH
2
CCH), 3.10-3.04 (m, 2H, H-5′), 2.19-2.18 (m, 1H, -
1
3
13
SeCH(CH
3
)
2
); C NMR (125 MHz, CDCl
3
δ
2
CCH), 1.61 (s, 3H, CH
): 155.7 (C-6), 153.4 (C-2), 149.4 (C-4), 140.2 (C-8),
1.0 (C-1′), 87.5 (C-4′), 84.5 (C-2′), 84.3 (C-3′), 30.1 (C-5′), 27.2 120.5 (C-5), 114.7 (-C(CH ), 90.8 (C-1′), 87.3 (C-4′), 84.4 (C-
-C(CH ), 25.5 (-C(CH ), 24.9 (-SeCH(CH ), 24.5 (- 2′), 84.3 (C-3′), 80.5 (-SeCH CCH), 71.7 (-SeCH CCH), 27.3 (-
SeCH(CH ); Se NMR (75 MHz, CDCl ): 259.1; IR (film): C(CH ), 26.4 (C-5′), 25.5 (-C(CH ), 7.8 (-SeCH
332, 1647, 1599, 1087; [ -26.1 (c 0.60, CHCl ); HRMS NMR (113 MHz, CDCl ): 225.6; IR (film): 3366, 1643, 1598,
ESI): calcd for C16 -39.0 (c 0.36, CHCl ); HRMS (ESI): calcd for
36.0854. SeNa [M+Na] : 432.0551, found: 432.0555.
′-deoxy-5′-benzylseleno-2′,3′-O-isopropyridene adenosine 5′-deoxy-5′-(2-(tert-
9d): white foam (32.0 mg, 70% yield) butoxycarbonylamino)butanoate)seleno-2′,3′-O-
3 3
), 1.40 (s, 3H, CH ); C NMR (150
(C-2), 149.4 (C-4), 140.2 (C-8), 120.5 (C-5), 114.6 (-C(CH
3
)
2
), MHz, CDCl
3
δ
9
3
)
2
4
(
3
)
2
3
)
2
3
)
2
8
2
2
7
7
77
3
)
2
3
δ
3
)
2
3
)
2
2
CCH); Se
2
]
0
3
α
D
3
3
δ
+
20
(
H
23
N
5
O
3
SeNa [M+Na] : 436.0864, found: 1085; [
α
]
D
3
+
4
16 19 5 3
C H N O
5
(
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
Page 8 of 12
View Article Online
DOI: 10.1039/C5OB01316J
ARTICLE
Journal Name
isopropyridene adenosine (9g): white foam (154.3 mg, 72% then the reaction mixture was quenched with H
yield) extracted with CHCl , and the organic layer was washed with
The reaction was conducted with 15 (173.1 mg, 0.368 mmol), saturated aqueous NaHCO , dried over Na SO , and then
concentrated. The residue was purified by column
252.5 mg, 0.736 mmol) and 1M solution of tetrabutyl chromatography on silica gel (EtOAc:n-hexane = 1:10 to 1:5) to
afford (517.8 mg, 94%) as a white foam.
H NMR (400 MHz, CDCl ): 7.93-7.91 (m, 2H, Ph), 7.67-7.63
), 5.50 (d, 1H, J (m, 1H, Ph), 7.52-7.48 (m, 2H, Ph), 7.44 (d, 1H, J = 8.2 Hz, H-6),
6.2 Hz, H-2′), 5.25-5.24 (m, 1H, NH), 5.02 (dd, 1H, J = 6.2, 2.8 5.84 (d, 1H, J = 8.2 Hz, H-5), 5.68 (d, 1H, J = 2.3 Hz, H-1′), 5.00
), 3.70 (s, 3H, CO CH ), (dd, 1H, J = 6.4, 2.3 Hz, H-2′), 4.73 (dd, 1H, J = 6.9, 4.1 Hz, H-3′),
.84 (dd, 1H, J = 12.4, 7.6 Hz, H-5′a), 2.76 (dd, 1H, J = 12.4, 6.2 4.31 (ddd, 1H, J = 6.4, 6.4, 4.2 Hz, H-4′), 2.82 (d, 2H, J = 6.4 Hz,
2
O and
3
3
2
4
2
6
(S)-methyl 2-(tert-butoxycarbonylamino)-4-iodobutanoate 16
(
ammonium fluoride in THF (1.1 mL, 1.1 mmol).
7
1
1
H NMR (600 MHz, CDCl
3
):
δ
8.32 (s, 1H, H-2), 7.92 (s, 1H, H-8),
3
δ
6
=
.07 (d, 1H, J = 2.0 Hz, H-1′), 6.02 (br s, 2H, NH
2
Hz, H-3′), 4.41-4.35 (m, 2H, H-4′, H-
α
2
3
2
Hz, H-5′b), 2.54 (t, 2H, J = 7.6 Hz, H-
γ
), 2.09-2.08 (m, 1H, H-
β
a), H-5′), 2.67-2.62 (m, 2H, -SeCH
2
CH
2
TMS), 1.54 (s, 3H, CH
3
), 1.33
TMS), -0.0046 (s, 9H, -
δ 168.4 (COPh), 162.0 (C-
1
.90-1.87 (m, 1H, H-
CO C(CH ), 1.38 (s, 3H, CH
72.8 (CO CH ), 155.9 (C-6), 155.5 (CO
49.3 (C-4), 140.2 (C-8), 120.4 (C-5), 114.6 (-C(CH
′), 87.4 (C-4′), 84.4, 84.3, 80.2 (CO C(CH ), 53.6 (C-
CH ), 33.7 (C- ), 28.4 (CO C(CH ), 27.2 (-C(CH ), 26.0 (C- SeCH
′), 25.5 (-C(CH ), 20.0 (C- ); Se NMR (113 MHz, CDCl
43.8; IR (film): 3338, 1740, 1706, 1644, 1599, 1088; [
2.0 (c 1.00, CHCl ); HRMS (ESI): calcd for C23
β
b), 1.59 (s, 3H, CH
3
), 1.40 (s, 9H, (s, 3H, CH
3
), 0.95-0.90 (m, 2H, -SeCH
2
CH
2
1
3
13
); C NMR (100 MHz, CDCl
2
3
)
3
3
); C NMR (150 MHz, CDCl
C(CH
3
):
δ
Si(CH
3
)
3
3
):
1
1
1
2
3
2
3
)
3
), 153.3 (C-2), 4), 149.2 (C-2), 142.1 (C-6), 135.4, 131.4, 130.7, 129.4 (Ph),
), 90.9 (C- 114.8 (-C(CH ), 102.8 (C-5), 94.7 (C-1′), 87.3 (C-4′), 84.6 (C-2′),
), 52.6 83.8 (C-3′), 27.2 (-C(CH ), 25.7 (C-5′), 25.4 (-C(CH ), 20.3 (-
CH TMS), 18.6 (-SeCH CH TMS), -1.8 (-Si(CH
):0δ NMR (75 MHz, CDCl ): 181.6; IR (film): 1750, 1710, 1675;
+7.4 (c 0.70, CHCl ); HRMS (ESI): calcd for
SeSiNa [M+Na] : 575.1093, found: 575.1094.
3
)
2
3 2
)
2
3
)
3
α
3
)
2
3 2
)
7
7
(CO
2
3
γ
2
3
)
3
3
)
2
2
2
2
2
3 3
) ); Se
7
7
5
1
+
3
)
2
β
3
3
δ
2
]
20
α
SeNa
D
[
α
]
D
3
+
3
H
34
N
6
O
7
C
24
H
32
N
2
O
6
+
[M+Na] : 609.1552, found: 690.1551.
5′-deoxy-5′-(2-(tert-butoxycarbonylamino)butanoic
acid)seleno-2′,3′-O-isopropyridene uridine (10): To a stirred
solution of 8r (24 mg, 0.036 mmol) in MeOH was added 1N
Product derivatization
′-deoxy-5′-(2-(trimethylsilyl)ethyl)seleno-2′,3′-O-
isopropyridene uridine (6): To a stirred solution of 2- for 1 h at 40 °C (TLC monitoring; CHCl
5
NaOH aq. (108
ꢀ
L, 0.108 mmol) at rt. The mixture was stirred
:MeOH = 10:1), then the
trimethylsilyl)ethyl 4-methylselenobenzoate (1.98 g, 6.6 reaction mixture was diluted with CHCl , and the solution was
Cl, followed by the
3
(
3
1
2
4
mmol)
2 3 4
and Cs CO (2.15 g, 6.6 mmol) in degassed DMF acidified with saturated aqueous NH
(
4 mL) was added N-methylhydrazine (0.35 mL, 6.6 mmol) separation of the organic layer. The aqueous layer was
under an argon atmosphere, and successively a solution of extracted with CHCl three times; combined organic layers
SO , and concentrated. The residue was
mmol) in degassed DMF (4 mL) was added via cannula at rt. purified by column chromatography on silica gel
The mixture was stirred for 1 h at rt (TLC monitoring; EtOAc:n- (CHCl :MeOH = 20:1 to 10:1) to afford 10 (17.8 mg, 90%) as a
hexane = 1:1). The reaction mixture was diluted with EtOAc, white solid. Mp: 148-150 °C (Recrystallized from CHCl
and the solution was washed with water and brine, dried over NMR (600 MHz, CD OD): 7.67 (d, 1H, J = 7.6 Hz, H-6), 5.79 (s,
Na SO , and co-evaporated with toluene in vacuo. The residue 1H, H-1′), 5.71 (d, 1H, J = 7.6 Hz, H-5), 5.00-4.99 (m, 1H, H-2′),
was purified by column chromatography on silica gel (EtOAc:n- 4.78-4.76 (m, 1H, H-3′), 4.27-4.24 (m, 1H, H-4′), 4.02-3.97 (m,
hexane = 1:5 to 1:2) to afford 6 (2.38 g, 97%) as a white foam. 1H, H- ), 2.91-2.86 (m, 2H, H-5′), 2.65-2.62 (m, 2H, H- ), 2.16-
Mp: 115-117 °C (Recrystallized from EtOAc); H NMR (600 MHz, 2.15 (m, 1H, H- a), 2.01-1.95 (m, 1H, H- b), 1.54 (s, 3H, CH ),
CDCl ): 9.45 (br s, 1H, NH), 7.35 (d, 1H, J = 8.3 Hz, H-6), 5.74 1.44 (s, 9H, CO C(CH ), 1.34 (s, 3H, CH ); C NMR (150 MHz,
d, 1H, J = 7.6 Hz, H-5), 5.70 (d, 1H, J = 2.0 Hz, H-1′), 4.95 (dd, CD OD): 178.7 (CO H), 167.1 (C-4), 157.6 (CO C(CH ), 152.6
H, J = 6.2, 2.0 Hz, H-2′), 4.77 (dd, 1H, J = 6.2, 4.8 Hz, H-3′), (C-2), 144.0 (C-6), 115.4 (-C(CH ), 103.0 (C-5), 94.3 (C-1′), 87.9
.30 (dd, 1H, J = 10.3, 5.5 Hz, H-4′), 2.92-2.84 (m, 2H, H-5′), (C-4′), 85.7, 85.1, 80.1 (CO C(CH ), 57.5 (C- ), 36.0 (C- ), 28.8
.71-2.62 (m, 2H, -SeCH CH TMS), 1.56 (s, 3H, CH ), 1.35 (s, 3H, (CO C(CH ), 27.5 (-C(CH ), 26.4 (C-5′), 25.5 (-C(CH ), 21.4
), 0.95-0.92 (m, 2H, -SeCH CH TMS), -0.0098 (s, 9H, - (C- ); Se NMR (113 MHz, CD OD): 137.4; IR (film): 1690,
); C NMR (150 MHz, CDCl ): 163.5 (C-4), 150.0 (C-2), 1587; [ OH); HRMS (ESI): calcd for
42.3 (C-6), 114.9 (-C(CH ), 102.8 (C-5), 93.8 (C-1′), 87.0 (C-4′), SeNa [M+Na] : 572.1123, found: 572.1113.
4.6 (C-2′), 83.8 (C-3′), 27.3 (-C(CH ), 25.7 (C-5′), 25.4 (- Se-uridyl-L-selenohomocysteine TFA salt (11)
), 20.4 (-SeCH CH TMS), 18.7 (-SeCH CH TMS), -1.8 (- compound 10 (12.6 mg, 0.023 mmol) was dissolved in 80%
): 181.9; IR (film): 1692, trifluoroacetic acid in distilled water (0.5 mL). The reaction
); HRMS (ESI): calcd for mixture was stirred for 30 min at rt, then concentrated in
SeSiNa [M+Na] : 471.0830, found: 471.0833. vacuo. The residue was triturated with Et O, the precipitate
was collected by filtration and rinsed with Et O, then the solid
(447 was dried by high vacuum line to afford 11 (10.8 mg, 93%) as a
3
1
6
2′,3′-O-isopropylidene-2,5′-anhydrouridine
5
(1.46 g, 5.5 were dried over Na
2
4
3
1
3
); H
3
δ
2
4
α
γ
1
β
β
3
1
3
3
δ
2
3
)
3
3
(
3
δ
2
2
3 3
)
1
4
2
3 2
)
2
3
)
3
α
γ
)
3 2
2
2
3
2
3
)
3
3
)
2
7
7
CH
Si(CH
3
2
2
β
3
δ
1
3
20
3
)
3
3
δ
D 3
α] -24.7 (c 0.10, CH
+
1
8
3
)
2
21 31 3 9
C H N O
3
)
2
:
The
C(CH
Si(CH
631; [
3
)
2
2
2
2
2
7
7
3
)
3
); Se NMR (113 MHz, CDCl
3
δ
2
]
0
1
α
D
+28.2 (c 1.05, CHCl
3
+
C
17
H
28
N
2
O
5
2
N-Benzoyl-5′-deoxy-5′-(2-(trimethylsilyl)ethyl)seleno-2′,3′-
O-isopropyridene uridine (7): To a stirred solution of
mg, 1 mmol) and Et N (348 L, 2.5 mmol) in CH Cl (9 mL) was white solid. H NMR (600 MHz, D
added benzoyl chloride (230 L, 2 mmol) at rt. The mixture H-6), 5.88 (d, 1H, J = 8.2 Hz, H-5), 5.85 (d, 1H, J = 4.1 Hz, H-1′),
was stirred for 3 h at rt (TLC monitoring; EtOAc:n-hexane = 1:1), 4.40-4.39 (m, 1H, H-2′), 4.22-4.19 (m, 1H, H- ), 4.16-4.14 (m,
2
6
1
3
ꢀ
2
2
2
O): δ 7.71 (d, 1H, J = 7.6 Hz,
ꢀ
α
8
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 12
Journal Name
Orga Pn l iec a s&e Bd oi o nmo to al ed cj uu sl ta mr Ca rhg ei nms istry
View Article Online
DOI: 10.1039/C5OB01316J
ARTICLE
1
H, H-3′), 3.99-3.97 (m, 1H, H-4′), 3.04 (dd, 1H, J = 13.7, 4.9 Hz, 91.6 (C-1′), 88.4 (C-4′), 85.5 (C-3′), 85.3 (C-2′), 80.5
H-5′a), 2.95 (dd, 1H, J = 13.7, 6.9 Hz, H-5′b), 2.74 (t, 2H, J = 7.6 (CO C(CH ), 54.7 (C- ), 33.8 (C- ), 28.7 (CO C(CH ), 27.4 (-
Hz, H- ), 2.30 (ddd, 1H, J = 14.4, 14.4, 7.6 Hz, H- a), 2.21 (ddd, C(CH ), 26.4 (C-5′), 25.5 (-C(CH ), 21.2 (C- ); Se NMR (113
H, J = 14.4, 14.4, 7.6 Hz, H- b); C NMR (150 MHz, D O): MHz, CD OD): 138.3; IR (film): 3349, 1691, 1597; [
66.2 (C-4), 151.6 (C-2), 142.2 (C-6), 102.5 (C-5), 90.0 (C-1′), (c 0.50, CH OH); HRMS (ESI): calcd for C22
), 25.2 (C-5′), 19.1 [M+Na] : 595.1395, found: 595.1392.
130.2; IR (film): 1682, 1643; SeAH TFA salt (18): The compound 17 (22.4 mg, 0.0392
O); HRMS (ESI): calcd for mmol) was dissolved into a mixture of 80% trifluoroacetic acid
2
3
)
3
α
γ
2
3 3
)
7
7
γ
β
3
)
2
3
)
2
β
1
3
20
]
1
β
2
δ
3
δ
α
D
-16.9
1
8
3
H N O SeNa
32 6 7
+
3.1 (C-4′), 73.2, 72.6, 53.9 (C-α), 31.2 (C-γ
7
7
(C-
β
]
); Se NMR (113 MHz, D
2
O):
δ
2
0
[α
D
+43.7 (c 0.10,
H
2
+
C
13
H
19
N
3
O
7
SeNa [M+Na] : 432.0286, found: 432.0295.
in distilled water (0.5 mL). The reaction mixture was stirred for
30 min at rt, then concentrated in vacuo. The residue was
5′-deoxy-5′-(2-(trimethylsilyl)ethyl)seleno-2′,3′-O-
isopropyridene adenosine (15): To a stirred solution of bis[2- triturated with Et
2
O, the precipitate was collected by filtration
2
O, then the solid was dried by high vacuum
1
1
(
trimethylsilyl)ethyl] diselenide
1
(204 mg, 0.566 mmol) and and linsed with Et
L, 1.416 mmol) in DMF (1.5 mL), sodium line to afford 18 (21.6 mg, 97%) as a white solid. H NMR (600
O): 8.49 (s, 1H, H-2), 8.41 (s, 1H, H-8), 6.11 (d, 1H, J =
4.8 Hz, H-1′), 4.86 (dd, 1H, J = 5.5, 4.8 Hz, H-2′), 4.40 (dd, 1H, J
153.8 mg, 0.472 mmol) was added to the solution at 0 °C. The = 5.5, 4.8 Hz, H-3′), 4.35 (dt, 1H, J = 6.8, 4.8 Hz, H-4′), 3.90 (t,
mixture was warmed to 60 °C, and stirred for 2 h at 60 °C (TLC 1H, J = 6.2 Hz, H- ), 3.08-3.00 (m, 2H, H-5′), 2.68 (t, 2H, J = 7.9
monitoring; EtOAc:n-hexane = 2:1), then the reaction mixture Hz, H- ), 2.26-2.12 (m, 2H, H-
was quenched by saturated aqueous NH Cl at rt. The solution 173.0 (CO H), 150.3 (C-6), 148.4 (C-2), 145.0 (C-4), 142.9 (C-8),
was extracted with EtOAc, washed with water and brine, dried 119.0 (C-5), 88.4 (C-1′), 84.2 (C-4′), 73.7 (C-2′), 73.0 (C-3′), 53.9
1
EtOH (82.6
ꢀ
borohydride (21.4 mg, 0.566 mmol) was slowly added at 0 °C. MHz, D
2
δ
2
5
The mixture was stirred for 30 min at 0 °C, after which 14
(
α
1
3
γ
2
β); C NMR (150 MHz, D O): δ
4
2
7
7
over Na
2
SO
4
, and concentrated. The residue was purified by (C-
α
), 31.2 (C-
O): 130.0; IR (film): 3434, 1686, 1639; [
O); HRMS (ESI): calcd for C14 SeNa [M+Na] : 455.0558,
γ), 25.5 (C-5′), 19.0 (C-β); Se NMR (113 MHz,
2
0
column chromatography on silica gel (EtOAc:n-hexane = 1:2 to
D
H
2
δ
D
α] +14.3 (c 0.50,
1
+
2
:1) to afford 15 (144.4 mg, 65%) as a white foam. H NMR
500 MHz, CDCl ):
), 6.08 (d, 1H, J = 2.3 Hz, H-1′), 5.50 (dd, 1H, J = 6.3,
2
20 6 5
H N O
(
3
δ
8.30 (s, 1H, H-2), 7.92 (s, 1H, H-8), 6.47 (br found: 455.0556.
SeAM TFA salt (19): SeAH 18 (81.2 mg, 0.143 mmol) was
s, 2H, NH
2
2
.3 Hz, H-2′), 5.01 (dd, 1H, J = 6.3, 2.9 Hz, H-3′), 4.43-4.40 (m, dissolved into a mixture of 1:1 formic acid and acetic acid (0.5
H, H-4′), 2.86-2.75 (m, 2H, H-5′), 2.62-2.50 (m, 2H, - mL). Methyl iodide (445 L, 7.15 mmol) and silver (I)
CH TMS), 1.58 (s, 3H, CH ), 1.37 (s, 3H, CH ), 0.87-0.83 perchlorate (29.6 mg, 0.143 mmol) was added to the reaction
m, 2H, -SeCH CH TMS), -0.09 (s, 9H, -Si(CH
MHz, CDCl ): 156.0 (C-6), 153.1 (C-2), 149.2 (C-4), 139.9 (C-8), with 10% trifluoroacetic acid in distilled water (1.0 mL), then
20.3 (C-5), 114.5 (-C(CH ), 90.8 (C-1′), 87.5 (C-4′), 84.4, 84.2, the aqueous layer was washed with CHCl three times. The
7.2 (-C(CH ), 25.6 (C-5′), 25.4 (-C(CH ), 19.9 (- insoluble materials (AgI) were filtered off, and the aqueous
CH TMS), 18.5 (-SeCH CH TMS), -1.9 (-Si(CH
NMR (94 MHz, CDCl ): 188.2; IR (film): 3322, 1650, 1599; 73%) as a pale yellow waxy solid (47 : 53 mixture of Se-epimers
-13.9 (c 1.00, CHCl
1
ꢀ
SeCH
2
2
3
3
3
1
(
2
2
3 3
) ); C NMR (125 mixture, and stirred for 5 h at rt. The solution was acidified
3
δ
1
2
3
)
2
3
3
)
2
3 2
)
7
7
SeCH
2
2
2
2
3 3
) ); Se layer was concentrated in vacuo to afford SeAM 19 (56.8 mg,
3
δ
2
]
0
1
[α
D
3
); HRMS (ESI): calcd for as determined by
H NMR). As previously reported,
+
C
18
H
29
N
5
O
3
SeSiNa [M+Na] : 494.1103, found: 494.1114. degradation of the SeAM was observed when stored at room
2
1b, 23
5
′-deoxy-5′-(2-(tert-butoxycarbonylamino)butanoic
acid)seleno-2′,3′-O-isopropyridene adenosine (17)
stirred solution of 9g (85 mg, 0.145 mmol) in MeOH (0.85 mL) J = 4.1 Hz, H-1′), 4.85-4.81 (m, 1H, H-2′), 4.60-4.58 (m, 1H, H-3′),
was added 1N NaOH aq. (436 L, 0.436 mmol) at rt. The 4.53-4.51 (m, 1H, H-4′), 4.05-3.98 (m, 1H, H- ), 3.90-3.82 (m,
mixture was stirred for 1 h at 40 °C (TLC monitoring; 2H, H-5′), 3.63-3.36 (m, 2H, H- ), 2.81/2.77 (s, 3H, 47 : 53, Se-
CHCl :MeOH = 10:1), then the reaction mixture was diluted epimers, -SeCH ), 2.50-2.31 (m, 2H, H-
with CHCl , and the solution was acidified with saturated O): 170.8 (CO H), 150.2 (C-6), 148.2 (C-2), 145.0 (C-4),
aqueous NH Cl, then the organic layer was separated. The 144.1 (C-8), 119.5 (C-5), 90.3 /90.3 (C-1′), 79.4 (C-4′), 73.6,
aqueous layer was extracted with CHCl three times, the 73.5, 73.3, 73.2 (C-2′, C-3′), 52.3 (C- ), 42.1/41.7 (C-5′),
combined organic layers were dried over Na SO , and 35.8/35.5 (C- ), 25.8/25.7 (C- ), 19.8/19.7 (SeCH
concentrated. The residue was purified by column (113 MHz, D O): 325.5/325.0; [
chromatography on silica gel (CHCl :MeOH = 50:1 to 10:1) to HRMS (ESI): calcd for C15 Se [M] : 447.0895, found:
temperature due to this instability.
1
:
To
a
2
H NMR (600 MHz, D O): δ 8.44 (s, 2H, H-2, H-8), 6.12 (d, 1H,
ꢀ
α
γ
1
3
3
3
β); C NMR (150 MHz,
3
D
2
δ
2
4
5
0
3
α
7
7
2
4
γ
β
3
); Se NMR
+13.5 (c 0.50, H O);
2
]
0
2
δ
α
D
2
+
3
23 6 5
H N O
afford 17 (75.1 mg, 91%) as a white solid.
447.0892.
1
3
Mp: 182-184 °C (Recrystallized from CHCl ); H NMR (600 MHz,
CD
3
OD):
.50-5.49 (m, 1H, H-2′), 5.03 (m, 1H, H-3′), 4.39 (m, 1H, H-4′),
.04-3.98 (m, 1H, H- ), 2.86-2.79 (m, 2H, H-5′), 2.59 (m, 2H, H-
a), 1.94 (m, 1H, H- b), 1.58 (s, 3H, CH ),
C(CH ), 1.38 (s, 3H, CH ); C NMR (100 MHz,
175.9 (CO H), 158.1 (C-6), 157.2 (CO C(CH ), 153.7
C-2), 150.2 (C-4), 141.9 (C-8), 120.5 (C-5), 115.5 (-C(CH ),
δ 8.30 (s, 1H, H-8), 8.23 (s, 1H, H-2), 6.17 (s, 1H, H-1′),
Acknowledgements
5
4
α
The authors wish to thank Prof. Masahiro Ebihara for X-ray
crystallographic analysis and Mr. Shota Fukuno and Mr.
Masayuki Ninomiya for providing technical assistance on
instrumental analysis. This work was supported by a Grant-in-
Aid for Scientific Research from the Ministry of Education,
γ
), 2.10 (m, 1H, H-
.41 (s, 9H, CO
CD OD):
β
β
3
1
3
1
2
3
)
3
3
3
δ
2
2
3 3
)
(
3 2
)
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0 | J. Name., 2012, 00, 1-3
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ARTICLE
Table 1 Synthesis of 5′-selenium modified nucleosides having various functional group
Electrophile
a
Entry
Base
Time (h)
R
Yield (%)
R-X
Equiv.
5.0
5.0
3.0
2.0
3.0
3.0
3.0
3.0
3.0
1
2
3
4
5
6
7
8
9
MeI
EtI
1
2
3
2
2
3
2
1
2
Me
Et
80 (8a)
74 (8b)
64 (8c)
81 (8d)
93 (8e)
61 (8f)
85 (8g)
86 (8h)
74 (8i)
i-PrI
PhCH
i-Pr
PhCH
2
Br
2
4-Me-C H -CH Br
4-Me-C H -CH
6 4 2
6
4
2
4-NO
allyl Br
propargyl Br
MeO(CH Br
2
-C
6
H
4
-CH
2
Br
4-NO
allyl
2 6 4 2
-C H -CH
propargyl
2 2
MeO(CH )
2
)
2
10
10
3
70 (8j)
11
12
13
14
1-F-2-NO
2
-C
6
H
4
2.0
2.0
10
0.5
0.5
5
2-NO
2
-C
6
H
4
4
60 (8k)
63 (8l)
1-F-4-NO -C H
4-NO -C H
2
6
4
2
6
MeC(=O)CH
2
Br
MeC(=O)CH
2
60 (8m)
80 (8n)
PhC(=O)CH Br
3.0
3
PhC(=O)CH2
2
15
16
17
MeOC(=O)CH Br
4.0
5.0
3.0
5
10
3
MeOC(=O)CH2
90 (8o)
77 (8p)
67 (8q)
2
t-BuOC(=O)CH
2
Br
t-BuO(C=O)CH
2
NCCH Br
NCCH2
2
18
2.0
6
73 (8r)
19
20
21
22
23
24
MeI
EtI
5.0
3.0
3.0
2.0
3.0
3.0
5
4
Me
46 (9a)
71 (9b)
51 (9c)
70 (9d)
61 (9e)
75 (9f)
Et
i-PrI
10
4
i-Pr
PhCH Br
PhCH2
allyl
2
allyl Br
3
propargyl Br
4
propargyl
25
2.0
10
72 (9g)
a
Isolated yield
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O
N
Bz
O
2
MeO C
1
N NaOH aq.
3.0 eq)
N
(
BocHN
Se
O
MeOH, 40 °C
0%
O
O
9
8
r
O
N
NH
HO
2
C
O
BocHN
Se
8
0% TFA aq.
rt
O
O
O
Scheme 1 Synthetic strategy of 5′-selenium modified nucleosides.
9
3%
1
0
O
N
NH
HO
2
C
O
TFA·H
2
N
Se
O
HO OH
1
1
Scheme 3 Synthesis of Se-uridyl-L-selenohomocysteine (11).
<Method A>
2
(1.2 eq)
Cs CO (1.2 eq)
NH
2
NH2
N
2
MeNHNH
3
N
N
N
N
2
DMF, rt to 60 °C
(1.2 eq)
N
N
1 h, 46%
N
Cl
Se
Si
O
O
<
Method B>
O
O
1 (1.2 eq)
O
O
4
NaBH (1.2 eq)
EtOH (3.0 eq)
1
4
DMF, 0 °C to 60 °C
30 min, 65%
15
I
NH
2
(
2.0 eq)
N
N
RO C
2
BocHN CO
2
Me
N
N
1
6
BocHN Se
80% TFA aq.
TBAF (3.0 eq)
O
DMF, rt
rt
O
O
72%
97%
Scheme 2 Synthesis of key intermediate
reagent and
7
using selenating
1M NaOH aq.
MeOH, 40 °C
9
1
g R = Me
7 R = H
1
2.
9
1%
NH2
N
NH2
N
N
N
N
N
HO C
2
HO C
2
N
N
MeI (50 eq) TFA·H
N
2
Se
TFA·H N Se
2
O
O
AgClO4 (1.0 eq)
Me
HCO
then 10% TFA aq.
2
H-AcOH, rt
HO OH
9: SeAM
HO OH
8: SeAH
1
1
73%
Scheme 4 Synthesis of SeAH (18) and SeAM (19).
1
2 | J. Name., 2012, 00, 1-3
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