First total synthesis of a naturally occurring nucleoside disulfide: 9-(5′-Deoxy-5′-thio-β-d-xylofuranosyl)adenine disulfide

Article abstract of DOI:10.1016/j.cclet.2012.06.011

A naturally occurring nucleoside disulfide, 9-(5′-deoxy-5′- thio-β-d-xylofuranosyl)adenine disulfide, was first synthesized from d-xylose over 7 steps in 20% overall yield. The key step involved Vorbru?ggen glycosylation of silylated N⁶-benzoyladenine with xylose diacetate moiety.

Full text of DOI:10.1016/j.cclet.2012.06.011

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Chinese Chemical Letters 23 (2012) 996–998
www.elsevier.com/locate/cclet
First total synthesis of a naturally occurring nucleoside disulfide:
9-(50-Deoxy-50-thio-b-D-xylofuranosyl)adenine disulfide
*
Hai Xin Ding, Ling Cui Da, Ru Chun Yang, Ban Peng Cao, Qi Sun, Qiang Xiao
Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science & Technology Normal University, Nanchang 330013, China
Received 27 April 2012
Available online 18 July 2012
Abstract
A naturally occurring nucleoside disulfide, 9-(50-deoxy-50-thio-b-D-xylofuranosyl)adenine disulfide, was first synthesized from
D-xylose over 7 steps in 20% overall yield. The key step involved Vorbru¨ggen glycosylation of silylated N6-benzoyladenine with
xylose diacetate moiety.
# 2012 Qiang Xiao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Naturally occurring nucleoside; Total synthesis; Vorbru¨ggen glycosylation; Marine sponge; Nucleoside disulfide
9-(50-Deoxy-50-thio-b-D-xylofuranosyl)adenine disulfide 1 was first isolated from an Australian marine sponge,
Trachycladus laevispirulifer, by Capon and coworkers in 2010 [1]. This compound is also the third natural xylo-
nucleoside identified, while the other two are 9-(50-deoxy-50-thiomethyl-b-D-xylofuranosyl)adenine 2 [2] and 4-
amino-7-(50-deoxy-b-D-xylofuranosyl)-5-iodopyrrolo[2,3-d]pyrimidine 3 [3]. Though nucleoside disulfide 1 exhibits
little cytotoxic effects against human breast and cervical cancer cell lines in biological assays, its chemical ecology
role in enhancing survival of the producing organism remains undetermined [4]. Due to its unique chemical structure
and our consistent interest in marine nucleosides [5], the first total synthesis of nucleoside disulfide 1 is reported in the
present paper, Fig. 1.
From a synthetic point of view, the target molecule 1 could be synthesized from either adenosine or D-xylose. In our
approach, D-xylose was employed as starting material, which is ideal for diversity-oriented synthesis of nucleoside
disulfides containing different nucleobases for biological studies, Scheme 1.
To this end, crystalline 1,2-O-isopropylidene-a-D-xylofuranose 2 was prepared in 73% yield by acid-catalyzed
acetylation of D-xylose, followed by partial hydrolysis with aqueous sodium carbonate in one pot with a
modification of the reported method [6]. Then 5-OH was selectively converted into tosylate with triethylamine as
base to afford 3 in 92% yield [7]. Protection of 3-OH as benzoate gave 4 in 91% yield. Substitution of the tosylate
with thioacetate in anhydrous DMF at 80 8C afforded 5 in 97% yield [8]. The 1,2-O-isopropylidene group was
removed in acetic acid/acetic anhydride with catalytic amount of sulfuric acid to give nucleoside acceptor 6 in
88% yield [9].
* Corresponding author.
E-mail address: xiaoqiang@tsinghua.org.cn (Q. Xiao).
1001-8417/$ – see front matter # 2012 Qiang Xiao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.06.011

H.X. Ding et al. / Chinese Chemical Letters 23 (2012) 996–998
997
NH2
NH2
N
NH2
I
OH
N
N
N
N
N
HO
O
N
N
N
N
N
S
S
H3C
O
OH
H3CS
O
OH
N
O
OH
N
N
N
OH
OH
OH
H2N
3
1
2
Fig. 1. Naturally occurring xylo-nucleosides.
In the key step of our synthetic route, Vorbru¨ggen glycosylation [10] was ultilized to attach adenine to xylose moiety.
When CH3CN/BSA/TMSOTf were used as solvent/silylating reagent/catalyst respectively, N3-, N7-, and N9-
glycosylatedproductswereobtainedina2:2:3ratio(determinedbyHPLC). Duetothefactthat1,2-dichloroethanefavors
the formation of d-complex of the persilyated purine 7 with TMSOTf [11], when it was used as the solvent instead of
CH3CN, desired nucleoside 8 was obtained in 87% yield [12]. Removal of all protecting groups with ammonia and in situ
oxidation with air afforded the target nucleoside disulfide 1 in 88% yield. All spectra data are in accordance with those of
the reported [13].
In conclusion, we developed the first efficient route for the synthesis of 9-(50-deoxy-50-thio-b-D-xylofuranosy-
l)adenine disulfide 1 from D-xylose. The D-xylose diacetates 6 were proved to be a valuable building block for
preparation of related nucleoside disulfides. Our progress in synthesis of other nucleoside disulfides and investigation
of their biological reactivity will be reported in due course.
HO
TsO
TsO
HO
O
O
O
O
c
a
OH
b
OH
OH
OBz
OH
O
O
O
O
O
O
OH
D-Xylose
3
4
2
O
O
S
S
O
OBz
e
f
O
OBz
OAc
d
O
OAc
O
6
5
NH2
OH
N
N
NHBz
N
N
N
HO
O
O
N
S
S
S
O
OH
N
N
g
N
N
O
OBz
N
N
OH
H2N
OAc
1
8
Scheme 1. Reagents and conditions: (a) Acetone, H2SO4, Na2CO3, r.t., 3 h, 73.1%; (b) TsCl, Py, r.t., 4 h, 92.1%; (c) BzCl, Py, r.t., 5 h, 97%; (d)
potassium thioacetate, DMF, 80 8C, 3 h, 97.5%; (e) AcOH, Ac2O, H2SO4, 24 h, 88%; (f) N6-benzoyladenine (7), BSA, TMSOTf, dichloroethane,
0 8C to 80 8C, 2 h, 87%; (g) aqueous ammonium hydroxide, methanolic ammonia, air, overnight, 88%.

998
H.X. Ding et al. / Chinese Chemical Letters 23 (2012) 996–998
Acknowledgments
We thank NSFC (Nos. 20962009 and 21062006), NCET (No. 11-1000), the Training Project of Jiangxi Youth
Scientists, Education Department of Jiangxi Province (No. GJJ 11223), and Bureau of Science & Technology of
Nanchang City for financial support.
References
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[3] P. Margiastuti, T. Ogi, T. Teruya, et al. Chem. Lett. 37 (2008) 448.
[4] A. Pani, M.E. Marongiu, P. Obino, et al. Experientia 47 (1991) 1228.
[5] J.Y. Sun, Y.H. Dou, H.X. Ding, et al. Mar. Drugs 10 (2012) 881.
[6] J. Moravcova, J. Capkova, J. Stanek, Carbohydr. Res. 263 (1994) 61.
[7] B. Hildebrandt, Y. Nakamura, S. Ogawa, Carbohydr. Res. 214 (1991) 87.
[8] P.H. Shang, C.M. Cheng, H. Wang, Chin. Chem. Lett. 21 (2010) 131.
[9] C. Mathe, J.L. Imbach, G. Gosselin, Carbohydr. Res. 323 (2000) 226.
[10] H. Vorbru¨ggen, C. Ruh-Pohlenz, Handbook of Nucleoside Synthesis, John Wiley & Sons, New York, 2001.
[11] H. Vorbru¨ggen, Acta Biochim. Polym. 43 (1996) 25.
[12] Spectra data of 8: Rf = 0.49 (EtOAc); 1H NMR (400 MHz, CDCl3): d 9.54 (s, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 7.93 (d, 2H, J = 8.0 Hz), 7.88 (d,
2H, J = 8.0 Hz), 7.54–7.46 (m, 2H), 7.38 (q, 4H, J = 8.0 Hz), 6.19 (s, 1H), 5.78 (s, 1H), 5.61 (d, 1H, J = 4 Hz), 4.56–4.52 (m, 1H), 3.3–3.29 (m,
2H), 2.27 (s, 3H). 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3): d 194.5, 169.1, 165.0, 164.9, 152.7, 151.6, 149.8, 141.2, 134.1, 133.5, 132.7,
129.7, 128.9, 128.7, 128.3, 128.0, 123.4, 88.1, 80.5, 80.0, 75.6, 30.5, 27.3, 20.7; ESI-MS: m/z 576.2 [M+H]+.
25
1
[13] Spectra data of 9-(50-deoxy-50-thio-b-D-xylofuranosyl)adenine disulfide 1: Rf = 0.20 (DCM:MeOH, 5:1); [a]D ꢀ16 (c 0.4, CH3OH); H
NMR (400 MHz, CDCl3): d 8.24 (s, 1H), 8.14 (s, 1H), 7.38 (br s, 2H), 6.16 (d, 1H, J = 5.4 Hz), 6.02 (d, 1H, J = 3.9 Hz), 5.88 (s, 1H), 4.43–4.39
(m, 1H), 4.34 (d, 1H, J = 2.5 Hz), 4.04 (br d, 1H, J = 2.7 Hz), 3.16–3.04 (m, 2H); 13C NMR (100 MHz, CDCl3): d 156.6, 152.9, 149.1, 140.3,
119.3, 90.2, 81.6, 81.3, 75.9, 37.6; ESI-MS: 587.1 [M+Na]+; HRMS (ESI) m/z calcd. for C20H25N10O6S2 [M+H]+: 565.13945, found:
565.13826.