Black light induced radical cyclization approach to cyclonucleosides: An independent approach

Article abstract of DOI:10.2174/157017811795685108

The paper highlights an efficient methodology based on consecutive radical reaction for the preparation of cyclonucleoside derivatives. The reactions were performed in organic and aqueous media, using common and efficient free radical hydrogen donors in the range of innovative and conventional initiation conditions to afford good to excellent yields of corresponding cyclonucleosides. The mechanistic aspects of the transformations are also addressed.

Full text of DOI:10.2174/157017811795685108

Letters in Organic Chemistry, 2011, 8, 337-340
337
Black Light Induced Radical Cyclization Approach to Cyclonucleosides:
An Independent Approach
Victoria T. Perchyonok*
VTPCHEM PTY LTD, Melbourne, 3163, Australia
Received April 23, 2010: Revised March 12, 2011: Accepted March 15, 2011
Abstract: The paper highlights an efficient methodology based on consecutive radical reaction for the preparation of
cyclonucleoside derivatives. The reactions were performed in organic and aqueous media, using common and efficient
free radical hydrogen donors in the range of innovative and conventional initiation conditions to afford good to excellent
yields of corresponding cyclonucleosides. The mechanistic aspects of the transformations are also addressed.
Keywords: Cyclo-nucleosides, black light, aqueous media, free radical reactions.
Cyclopurine and cyclopyrimidine lesions are observed
among the decomposition products of DNA, when exposed
to ionizing radiation or to some antitumor agents [1].
Recently, several examples of independent formation of
these lesions and their incorporation on specific sites of DNA
are of considerable importance in order to investigate, in
detail, the biochemical and biophysical features of the double
helix damage [6, 9, 10].
5’,6-cyclo-5,6-dihydrothymidine
and
5’,8-cyclo-2’-
Several key contributions in the area have recently reported
synthetically usefull cascade methodologies for effective
generation of the cyclonucleosides in order obtain a general
procedure for the preparation of some of the diastereoisomers
of the cyclonucleosides as well as try to overcome the
limitations of the existing approaches, due to low yield
multiple-step synthesis, problematic chromatographic and
separation properties [6-10].
deoxyadenosine have been reported [2]. The unique
structural features of the cyclo-nucleosides incorporate an
additional base-sugar linkage between the C6 position of
pyrimidine or C8 position of purine and the C5’ position of
the 2’-deoxyribose [3]. Conformationally fixed nucleosides
analogues are a unique class of compounds that can be
used as a tool for investigating steric interactions between
nucleosides or nucleotides and the enzymes that utilize
them [4] (Fig. 1).
Photolysis is one of the most appropriate and widely used
methods of generating nucleosidyl radicals, with numerous
O
NH2
O
O
N
N
N
N
NH
NH
NH
R1
N
O
N
O
O
NH2
O
O
O
R2
HO
HO
OH
OH
HO
OH
HO
OH
where R1=H, R2=OH
R1=OH, R2=H
Fig. (1). Structure of C-Cyclonucleosides.
To date, various modified 2-deoxynucleosides
containing specific DNA lesions and their incorporation
into a defined sequence of oligonucleotides have been an
outstanding approach to investigate the biological
consequences. Synthetic oligonucleotides that contain the
modified nucleosides [5-7] as well as similar cyclopurine
[7] and cyclopyrimidine [8] moieties were also prepared.
Recent studies have shown that the chemical synthesis of
reports in the literature reported of sources and set-ups for the
generation, however most of the methods require specialized
experimental setups, glassware and rather expensive light
sources for the desired transformations.
In order to overcome these problems, we decided to
investigate the use of a black light, which has a maximum
peak wavelength at 352nm, and performs effectively in a
broad range of free radical transformations as reported by Ryu
et al. [10] and is applicable to generation of C5’ nucleosidyl
purine and pyrimidyl radicals in organic and aqueous media in
*Address correspondence to this author at the VTPCHEM PTY LTD,
Melbourne, 3163, Australia; Tel/Fax: +61414596304;
E-mail: tamaraperchyonok@gmail.com
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

338 Letters in Organic Chemistry, 2011, Vol. 8, No. 5
Victoria T. Perchyonok
Black Light
O
B
O
B
TMS3SiH
or
CBr4
PPh3
HO
Br
Cyclonucleoside
(Bu4N)H2PO2
Et3B/Air
CH2Cl2
HO
HO
OH
OH
benzene or H2O
Scheme 1. General synthetic approaches and methodology.
the presence of derivatives of hypophosphorous acids in
organic and aqueous media.
radical 6- exo-trig cascade reaction. However in the case of
Bu3SnH, the yield of product R (minor product) accounts for
30% in the final product mixture, which is consistent with the
difference in the hydrogen donor ability of Bu3SnH vs
TMS3SiH vs H3PO2/Bu4N+Cl-, highlighting the potential for
further development of the methodology. This observation is
consistent with the previous reports by Navacchia,
Chatgilialoglu and Cadet in there pioneering work on the
understanding of the mechanistic aspects of C5’ radicals.[11,
12]
In this paper we report an independent generation of
C5’ radical precursor of 5’-bromouridine as radical
precursors for C5’ radical generation under black light
initiation (Scheme 1).
RESULTS AND DISCUSSION
Commercially available nucleosides such as uridine,
adenosine and quanosine were reacted with freshly
prepared Appel bromide in CH2Cl2 in order to prepare
corresponding 5’-Bromonucleosides derivatives. The
compounds were prepared in moderate to good yields. The
5’- bromonucleoside derivatives were purified on the C18
HPLC chromatography column and identified through
comparison of spectral data reported in the literature.
The proposed mechanism for the transformation in
question is represented in Scheme 4. Initiator decomposes to
abstract a hydrogen atom from the radical mediator such as
((TMS)3SiH, H3PO2 or Bu3SnH), which generates
a
corresponding silyl, phosphorous centered or stannyl radical.
The latter abstracts the halogen atom to form a C5’ radical. In
the case of ((TMS)3SiH, H3PO2 or Bu3SnH) as hydrogen
donors, C5’radical undergoes a 6-exo-trig cyclization adding
to the double bond of the base. The resulting C5-radical
abstracts hydrogen from the hydrogen donor, yielding a cyclo-
compound, while completing the radical chain. The minor
product, which is the product of the direct reduction is also
formed due to much less but still competitive H-abstraction
reaction and is observed in all transformations in different
amounts as pointed out in Table 1.
O
O
B
B
CBr4
PPh3
HO
Br
CH2Cl2
HO
HO
OH
OH
where B=Ur 54%
=Ad 42%
=Gua 46%
Scheme 2. Preparation of 5’bromonucleosides.
Following our initial plan, we examined tandem radical
1,6-HAT-cyclization of 5’-bromouridine in the presence of
a. TMS3SiH, b. H3PO2/Bu4N+Cl- c. Bu3SnH and in benzene
and water under black light initiation, Et3B/air and
AIBN/80oC conditions and the results are summarized in
Scheme 3 and Table 1.
CONCLUSION
We have disclosed a short and efficient synthetic sequence,
based on consecutive radical reactions in aqueous media, for
the preparation of cyclonucleosides. The C5’ radicals,
generated by tandem homolytic bond cleavage followed by
carbon-carbon bond formation are the key intermediates in
these transformations. The chemical biology approach used for
studying purine 5’,8- cyclonucleoside lesions has brought
significant achievements so far [13]. The site-specific
generation of sugar radicals has been the key approach for a
better understanding of chemical molecular mechanisms
Major reaction products of all the transformations
summarized in the table are indicative of the intra-
molecular radical 6-exo-trig reaction being predominant,
suggesting that intermolecular hydrogen transfer reaction is
a much slower process in comparison to intra-molecular
O
N
O
N
Black Light
NH
NH
O
B
TMS3SiH
O
O
Br
O
O
C
or
(Bu4N)H2PO2
Et3B/Air
HO
OH
HO
HO
OH
OH
benzene or H2O
R
Scheme 3. Radical cyclization reaction of C5’-BromoUridine in benzene and water under various initiation conditions and in the presence of
free radical hydrogen donors.

Black Light Induced Radical Cyclization Approach
Letters in Organic Chemistry, 2011, Vol. 8, No. 5
339
Table 1. Radical Cyclization Reactions of C5’-BromoUridine under Black light, Et3B/air(rt) and AIBN/80oC Initiation Conditions
with Various free Radical Hydrogen Donors
Entry
H-Donor
Initiation
Solvent
% yield C:R
1
2
TMS3SiH
Black light
Et3B/air(rt)
AIBN/80oC
Black light
Et3B/air(rt)
AIBN/80oC
Black light
Et3B/air(rt)
AIBN/80oC
Black light
Et3B/air(rt)
AIBN/80oC
Black light
Et3B/air(rt)
AIBN/80oC
Black light
Et3B/air(rt)
AIBN/80oC
Benzene
Benzene
Benzene
H2O
78:5
72:5
3
78:4
4
72:6
5
H2O
70:4
6
H2O
79:4
7
H3PO2/Bu4N+Cl-
Benzene
Benzene
Benzene
H2O
73:5
8
70:6
9
67:3
10
11
12
13
14
15
16
17
18
72:4
H2O
70:6
H2O
71:5
Bu3SnH
Benzene
Benzene
Benzene
H2O
60:30
58:25
50:30
50:30
55:35
54:30
H2O
H2O
O
(TMS)3SiH
or H3PO2
NH
N
O
or Bu3SnH
O
C5'
HO
OH
R
(TMS)3Si
or H2PO2
or Bu3Sn
6-exo-trig vs H-transfer
C5
O
NH
(TMS)3SiH
N
O
O
C
or H3PO2
HO
OH
or Bu3SnH
Scheme 4. Proposed Radical Chain Mechanism for the formation of the cyclised product (major product) and product of direct reduction
(minor product).
occurring at the biological level. The chemistry of the C5’
radicals in the purine nucleosides is fairly well understood
and it is now clear that the fate of the C5’ radicals is
partitioned between uni-molecular processes (cyclizations)
and bimolecular processes (reactions with oxygen, thiols,
or oxidants) [13]. Therefore, the local concentration of
these components and pH are extremely important in
selecting the preferred pathway. Work is currently on the
way to gain further insight into these important
transformations at a molecular level under aerobic and
anaerobic conditions.
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