Short-step anodic access to emissive RNA homonucleosides

Article abstract of DOI:10.1002/ejoc.201301604

Emissive RNA homonucleosides were added to the growing library of synthetic probes. The emissive nucleobases were constructed in one step from the methallyl C-glycoside of D-ribofuranose, which was prepared stereoselectively. The homonucleosides displayed various emission colors by using a single excitation wavelength that could be fine-tuned merely by changing the carbonyl substituent on the methoxyphenol. Emissive RNA homonucleosides are added to the growing library of synthetic probes. The emissive nucleobases are constructed in one step from the methallyl C-glycoside of D-ribofuranose, which is prepared stereoselectively. The homonucleosides display various emission colors by using a single excitation wavelength. Copyright

Full text of DOI:10.1002/ejoc.201301604

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301604
Short-Step Anodic Access to Emissive RNA Homonucleosides
[a]
[a]
[a]
[a]
Yohei Okada, Kouhei Shimada, Yoshikazu Kitano, and Kazuhiro Chiba*
Keywords: Allylation / Cycloaddition / Homonucleosides / Oxidation / RNA
Emissive RNA homonucleosides were added to the growing
library of synthetic probes. The emissive nucleobases were
constructed in one step from the methallyl C-glycoside of D-
homonucleosides displayed various emission colors by using
a single excitation wavelength that could be fine-tuned
merely by changing the carbonyl substituent on the meth-
oxyphenol.
ribofuranose, which was prepared stereoselectively. The
Introduction
The early finding that allylsilanes could react with acetals
[
4]
in the presence of Lewis acids led to the elaboration of
an efficient procedure for the synthesis of an anomerically
allylated C-glycoside of d-ribofuranose that could be a con-
Emissive nucleoside analogues have been widely used to
monitor fundamental biochemical transformations directly,
because natural nucleobases are not emissive.[ This charac-
teristic has led to the construction of useful libraries of syn-
thetic emissive nucleoside analogues. Typically, these syn-
thetic probes are prepared through glycosylation with pre-
formed emissive nucleobases under carefully selected condi-
tions to control both stereoselectivity at the anomeric posi-
tion and regioselectivity of the aglycon attack. Because
these selectivities are affected by the interaction of the pro-
tected groups of both the sugar and aglycon, glycosylation
usually requires a time-consuming trial-and-error pro-
cedure. These synthetic probes also should exhibit minimal
structural perturbation, provide visible emission, and likely
be resistant to nonspecific enzymatic degradation. In this
context, C-nucleosides and homonucleosides show greater
metabolic stabilities than natural nucleosides, and they have
been studied extensively.[2] Although there are various prac-
tical, well-established synthetic routes for generating emis-
1]
[5]
venient precursor for the preparation of homonucleosides.
We have been developing anodic methods by using an
LiClO /MeNO electrolyte solution that facilitates intermo-
4
2
[6]
lecular carbon–carbon bond-formation reactions. In par-
ticular, unactivated olefinic nucleophiles were shown to trap
anodically generated phenoxonium ions to yield emissive
[7]
[
3+2] cycloadducts in one step. In light of previous stud-
ies, we sought to realize a short-step synthesis of emissive
RNA homonucleosides assisted by anodic methods
Scheme 1). In this scenario, stereochemistry at the anom-
eric position could be addressed at an earlier stage, and the
regioselectivity could be fully controlled.
(
Results and Discussion
The present work began with the allylation of β-d-ribo-
sive C-nucleosides, the synthesis of homonucleoside vari- furanose 1,2,3,5-tetraacetate (1) with methallyltrimethyl-
ants remains challenging, as alkyl-C-glycosylation is re- silane (2). The tertiary olefinic carbon atom is required for
[
3]
quired instead of commonly studied aryl-C-glycosylation.
subsequent cycloadditions. Although the direct allylation of
Scheme 1. Anodic access to emissive RNA homonucleosides.
both 1 and β-d-deoxyribofuranose 1,3,5-triacetate with
simple allyltrimethylsilane has been accomplished in high
yield by using TMSOTf (Tf = trifluoromethylsulfonyl) as a
promoter in MeCN, allylation with methallyltrimethyl-
silane (2) under the same conditions was disappointing
[
a] Department of Applied Biological Science,
Tokyo University of Agriculture and Technology,
3
-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan
[
8]
E-mail: chiba@cc.tuat.ac.jp
http://www.tuat.ac.jp/~bio-org/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301604.
(Table 1, Entry 1). The corresponding methallyl C-glycoside
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Y. Okada, K. Shimada, Y. Kitano, K. Chiba
SHORT COMMUNICATION
of d-ribofuranose (3) was obtained only in low yield, to- ment of the protecting groups was required, as isopropylid-
gether with several byproducts that were not readily separa- ene protection was not suitable for subsequent acidic elec-
ble. Although the use of other Lewis acids in MeCN did trochemical conditions.
not efficiently afford the desired product 3 (Table 1, En-
tries 2–5), a remarkable solvent effect was observed with
THF (Table 1, Entry 8). Under these conditions, the α-me-
thallyl C-glycoside of d-ribofuranose (3α) was selectively
obtained in excellent yield. Although TMSOTf induced se-
vere gelation of THF, the reaction took place efficiently,
and the gel was readily removable upon completion of the
reaction. In contrast, dioxane and Et O provided only mod-
2
est solvent effects (Table 1, Entries 9 and 10), which sug-
gested that the solvent effect observed with THF was not
simply due to the coordinating nature of ethers. Moreover,
the addition of MeCN was found to significantly impact
the solvent effect of THF. For example, little α/β selectivity
was observed upon using a 9:1 (v/v) mixture of THF/
MeCN as the solvent (Supporting Information, Table S1).
The excellent α-selectivity observed can be rationalized in (aq.), 70 °C; (2) Ac O, pyridine, r.t., 81% over two steps.
Scheme 2. Preparation of the β-methallyl C-glycoside of d-ribofur-
anose (3β). Reagents and conditions: (a) ZnBr
2 2
, MeNO , r.t., 65%,
α/β = 1:13. (b) The α-anomer was removed. (c) (1) 70% AcOH
2
terms of the stereoelectronic effects of five-membered-ring
oxocarbenium ions.
[
9]
With both 3α and 3β in hand, we then focused on the
anodic construction of the emissive [3+2] cycloadducts. In
a preliminary experiment, we found that the addition of
Table 1. Allylation of β-d-ribofuranose 1,2,3,5-tetraacetate (1) with AcOH, which might stabilize the corresponding cationic in-
methallyltrimethylsilane (2).
termediates and/or function as a proton source for cathodic
[
11]
reduction, was effective for these reactions.
It was also
found that the olefinic nucleophilicities of both 3α and 3β
toward anodically generated phenoxonium ions were sim-
ilar, and no epimerization at the anomeric position was ob-
served under these electrochemical conditions. The anodic
oxidation of methoxyphenols 6–8 in the presence of 3α or
3β gave the [3+2] cycloadducts 9–11 (Table 2). Deprotection
under basic conditions afforded the desired homonucleo-
sides 12–14.
Table 2. Anodic construction of the emissive [3+2] cycloadducts by
using methoxyphenols 6–8.[
a]
The β-methallyl C-glycoside of d-ribofuranose (3β) was
prepared by using 2,3-O-isopropylidene diacetate (4), which
was obtained in two steps from d-ribose (Supporting Infor-
mation, Scheme S1). The allylation of 4 with 2 was per-
formed by using ZnBr as a promoter in MeNO to yield
2
2
the methallyl C-glycoside of d-ribofuranose (5) with high
β-selectivity (Scheme 2).[ After purification, acidic depro-
tection of the β-methallyl C-glycoside of d-ribofuranose
10]
[
a] Reagents and conditions: (1) LiClO
4 2
, MeNO , carbon felt an-
ode, platinum cathode, 1.1–1.3 V vs. Ag/AgCl, r.t.; (2) MeONa,
(5β) followed by acetylation gave the desired 3β. Replace- MeOH, r.t.
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Eur. J. Org. Chem. 2014, 1371–1375

Short-Step Anodic Access to Emissive RNA Homonucleosides
The photophysical properties of homonucleosides 12–14
are summarized in Table 3. As expected, the anomeric con-
figuration had little impact on the photophysics of the re-
spective [3+2] cycloadducts. Homonucleosides 12–14 dis-
played emission bands ranging from 408 to 493 nm in
EtOH or H O that could be fine-tuned merely by changing
2
the carbonyl substituent on methoxyphenols 6–8.
This simple change in structure yielded various emission
colors by using a single excitation wavelength (Figure 1).
These emission bands were blueshifted if homonucleosides
1
2–14 were dissolved in dioxane; however, the absorption Figure 1. Fluorescence (λex = 365 nm) of (a) homonucleosides 12–
bands were essentially unaffected by solvent polarity. This 14 in EtOH and (b) homonucleoside 13 in dioxane or H
2
O.
Table 3. Photophysical data of homonucleosides 12–14.
3
–1
[
a] Absolute quantum yield. [b] 10 cm .
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Y. Okada, K. Shimada, Y. Kitano, K. Chiba
SHORT COMMUNICATION
suggested that environmental polarity could be monitored Acknowledgments
in real time by using these compounds.
This work was partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology of Japan.
Conclusions
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[
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13
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Received: October 25, 2013
Published Online: January 28, 2014
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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