Electrochemical synthesis of azanucleoside derivatives using a lithium perchlorate-nitromethane system

Article abstract of DOI:10.1039/c3cc43273d

We have developed a highly efficient synthetic method for azanucleosides using a lithium perchlorate-nitromethane reaction medium, allowing direct and exclusive installation of various nucleophiles, including protected nucleobases into prolinol derivatives at the preferred 5-position.

Full text of DOI:10.1039/c3cc43273d

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Electrochemical synthesis of azanucleoside derivatives
using a lithium perchlorate–nitromethane system†
Cite this: DOI: 10.1039/c3cc43273d
Shokaku Kim, Takao Shoji, Yoshikazu Kitano and Kazuhiro Chiba*
Received 3rd May 2013,
Accepted 26th May 2013
DOI: 10.1039/c3cc43273d
www.rsc.org/chemcomm
We have developed a highly efficient synthetic method for azanucleo-
sides using a lithium perchlorate–nitromethane reaction medium,
allowing direct and exclusive installation of various nucleophiles,
including protected nucleobases into prolinol derivatives at the
preferred 5-position.
Fig. 1 Schematic view of an electrochemically direct transformation reaction of
Nucleoside analogues have played a crucial role in the treatment of
viral infections and cancer.1 A variety of nucleoside analogues have
been developed with the aim of improving their therapeutic effects
non-activated prolinol derivatives for the synthesis of azanucleosides.
and reducing toxicity. Exploration of new active analogues has Indeed, this process often removes the opportunity of providing
primarily been focused on modification of the sugar moiety.2 diverse azanucleosides based on further modification of the
Specifically, the design of furanose rings through the introduction nitrogen atom. Therefore, a remaining challenge in the synthesis
of various heteroatoms has been one of the most useful approaches of azanucleosides is the reliance on the preparation of precursors
in the search for new nucleoside analogues with beneficial bearing leaving groups.
biological activity. Azanucleosides, in which the furanose oxygen
To address this challenge, we reasoned that direct selective
atom is replaced by a nitrogen atom, have attracted considerable attachment of a nucleobase to a prolinol moiety at the N-a position
attention due to the possibility of their further modification would preclude the need for activation through the introduction of
through the nitrogen atom and structural similarity to the furanose leaving groups and its related redundant synthetic efforts. We
ring system.2a,b,e Romeo and co-workers recently reported the proposed that an electro-organic method might provide such an
biological evaluation of the 30-deoxy-40-azaribonucleosides as approach to overcome the challenge of direct introduction of a
novel nucleoside templates.3 The synthesized compounds were nucleobase into an unactivated pyrrolidine moiety (Fig. 1).4 An
shown to be HCV inhibitors in a cell-based replicon assay in electrochemical method provides a clean, versatile and powerful
nanomolar order with no or low toxicity.
synthetic tool for organic synthesis, such as direct C–H activation.4g–j
Given their attractive features, many efforts have been made Specifically, we took advantage of the LiClO4–CH3NO2 reaction
to develop efficient methods for the synthesis of azanucleoside system, which provides a mild and efficient method for accessing
derivatives.2a A commonly used synthetic strategy relies on key intermediates by electrochemical oxidation.5 This reaction system
N-glycosyl bond formation through an iminium ion intermediate. can accumulate desired intermediates, anodically derived from
This process involves the incorporation of leaving groups, such as N-protected pyrrolidine derivatives such as N-acetyl- or methoxy-
alkoxy, acetoxy or halogen groups, into pyrrolidinyl precursors, in carbonyl proline methyl ester, by means of the media effect of the
order to generate key reactive intermediates. However, access highly concentrated LiClO4–CH3NO2 solution, enabling coupling
to such precursors requires a multi-step synthetic sequence, with a variety of nucleophiles in one-pot reactions.
cumbersome operations and harsh reaction conditions associated
In this communication, we report a mild, operationally simple
with protection–deprotection and oxidation–reduction steps. and straightforward strategy for coupling an unactivated prolinol
derivative with a nucleobase through anodic oxidation using a
LiClO4–CH3NO2 solution system, and demonstrate the utility of this
transformation by addition of various nucleophiles to readily avail-
able prolinol derivatives in a regioselective manner.
Laboratory of Bio-organic Chemistry, Tokyo University of Agriculture and
Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
E-mail: chiba@cc.tuat.ac.jp; Fax: +81 42 360 7167; Tel: +81 42 367 5667
Substituents on the pyrrolidine ring moiety, particularly a
hydroxymethyl group at the 2-position, can serve important
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc43273d
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functions in biological activity or in the incorporation of a nucleo- the potential over-oxidation reaction would be suppressed. Initially,
side analogue into a DNA/RNA sequence through chemical ligation we prepared several N-protected prolinol derivatives. All reactions
(for example, the phosphoramidite method6). Moreover, it has been were carried out in 1 M LiClO4–CH3NO2 in the presence of 50 mM
shown that substituents around the pyrrolidine ring, including AcOH using an undivided cell, a glassy carbon anode and a
N-protective groups, have a major effect on the regioselectivity of platinum cathode. The results are summarized in Table 1. Electro-
methoxylation by anodic oxidation. For example, when N-Boc-trans- lysis conducted under a constant current (0.5 mA cmꢀ2, 2.5 F molꢀ1
)
4-hydroxy-proline methyl ester was used, regioselectivity was at 0 1C followed by addition of allyltrimethylsilane (3 equiv.) as
low and significant amounts of the over-oxidized compounds a nucleophile successfully gave the coupled products in high
were produced.4d,e The use of RuO2–xH2O/NaIO4 as an oxida- yields. Furthermore, compounds 1a–e were exclusively allylated
tion reagent often results in the same difficulty as the electro- at the 5-position (the 10-position in the nucleoside analogue).
chemical method.2c It was unclear whether the LiClO4–CH3NO2 The accumulation system contributed significantly to this regio-
system could generate and accumulate the desired intermediate, selectivity. Although the anodic methoxylation reaction can pre-
derived from the prolinol moiety, to react with various nucleo- ferentially provide the 5-methoxylated product, further anodic
philes at the favoured 5-position, although it was expected that oxidation reaction results in a loss of the regioselectivity due to
the existence of nearly equal oxidation potential between the
starting substrate and the product. This system suppresses
further oxidation of the products because the intermediates
possess higher oxidation potentials than the substrate. This also
implies that no significant racemization took place during
each step (electrolysis, accumulation and coupling), as no dia-
stereomers, other than the a,b-anomeric isomers, were observed.
When thiophenol and 1,3,5-trimethoxy-benzene were used
as nucleophiles, the desired reactions took place smoothly to
provide the corresponding products 7 and 8 in a yield of 71%
and 84%, respectively. Cleavage of the acid-labile C–S bond did
not occur under this electrolytic condition. In this reaction, the
Table 1 Anodic coupling reaction of prolinol derivatives with nucleophiles in
LPC–NM solutiona
Substrate
Entry (Eox vs. Ag/AgCl)b
Nucleophile
Product yieldc (a : b)
1
Table 2 Anodic coupling reaction of compound 1f with nucleobasesa
2
3
Entry Nucleobase
Product
Yieldb
1
52% (a : b = 1 : 1)
4
5
6
2
3
44% (a : b = 3 : 2)
54% (a : b = 1 : 1)
4
NDc,d
7
a
b
All reactions were performed using an undivided cell. Isolated yield.
a
b
c
d
All reactions were performed using an undivided cell. The oxidation
Not detected. Electrochemical reaction was also tested in the
c
d
potential was determined using cyclic voltammetry. Isolated yield. The absence of T(TMS)2 to afford the hydroxylated product 13 in almost
reaction completes upon passing 10 F molꢀ1 of electricity.
the same yield (refer to Scheme 1).
c
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corresponding iminium cation intermediates, which were
stabilized and efficiently trapped by various nucleophiles. The
applicability and limitations of this system are currently under
investigation.
Scheme 1 Introduction of thymine into hydroxylated compound 13.
Notes and references
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undivided cell plays an important role in the suppression of the
unfavourable C–S bond cleavage.
Encouraged by these results, we then examined the coupling
reaction of prolinol 1f with four protected nucleobases, N-benzoyl
adenine (Abz), N-benzoyl guanine (Gbz), N-acetyl cytosine (Cac) and
2,4-bis(trimethylsilyl)thymine (TTMS2), under similar conditions.
The result is summarized in Table 2. The relative configurational
1
assignments for 9–11 were determined using H NMR and NOE
experiments (see ESI†). The reaction of 1f with Abz, Gbz, Cac afforded
the desired products in good yields. In such reactions, if proline
activated at the 5-position is used, reduction of the ester group
(2-position) to an alcohol group is required in the later synthetic
steps for the synthesis of azanucleosides. These processes often lead
to some difficulties associated with isolation or decomposition of
¨
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The resulting product 13 was acetylated using anhydrous acetic acid,
triethylamine (TEA) and 2,2-dimethylaminopyridine (DMAP) in
CH2Cl2 to provide the compound 13, which was then treated with
TMSOTf to afford thymine-type azanucleosides.
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nucleophiles, including protected nucleobases, into prolinol deriva-
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system anodically converted prolinol derivatives into the
22, 1859; (b) S. L. Beaucage and R. P. Iyer, Tetrahedron, 1992, 48, 2223.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.