Synthesis of 8-alkoxy-6-alkylamino-2-alkylthiopurine nucleosides with a straightforward multiple-functionalization strategy

Article abstract of DOI:10.1016/j.tetlet.2016.05.057

A straight forward strategy to synthesize purine nucleosides with multiple functionalization on 2-, 6-, and 8-positions has been developed successfully, which provides a series of 8-alkoxy-6-alkylamino-2-alkylthiopurine nucleosides in moderate to good yields for further biological and medical activity screening.

Full text of DOI:10.1016/j.tetlet.2016.05.057

Accepted Manuscript
Synthesis of 8-alkoxy-6-alkylamino-2-alkylthiopurine Nucleosides with a
Straightforward Multiple-functionalization Strategy
Hongguang Du, Xiaoyang Sun, Mingwu Yu, Miao Tian, Shunlai Li, Zhiqian
Wang
PII:
S0040-4039(16)30580-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.057
TETL 47676
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 March 2016
12 May 2016
16 May 2016
Please cite this article as: Du, H., Sun, X., Yu, M., Tian, M., Li, S., Wang, Z., Synthesis of 8-alkoxy-6-alkylamino-2-
alkylthiopurine Nucleosides with a Straightforward Multiple-functionalization Strategy, Tetrahedron Letters
(2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.05.057
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Synthesis of 8-alkoxy-6-alkylamino-2-alkylthiopurine Nucleosides with
a Straightforward Multiple-functionalization Strategy
Hongguang Du, Xiaoyang Sun, Mingwu Yu, Miao Tian, Shunlai Li, Zhiqian Wang*
State Key Laboratory of Chemical Resource Engineering, College of Science, Beijing University of
Chemical Technology, Beijing, China 100029
*Corresponding authors’ e-mail: wangzhq@mail.buct.edu.cn
Abstract: A straight forward strategy to synthesize purine nucleosides with multiple
functionalization on 2-, 6-, and 8-positions has been developed successfully, which
provides a series of 8-alkoxy-6-alkylamino-2-alkylthiopurine nucleosides in moderate to
good yields for further biological and medical activities screening.
Key words: purine nucleosides, multiple functionalization, alkylthiolation,
alkoxylation, amination
Purine bases, as the basic structural units in RNA and DNA, play paramount roles in
numerous biological processes. Purine nucleosides decorated at N9 position with sugar
ring draw extensive attention since they exhibit broad bioactivities1-3 in biochemistry and
medicinal chemistry. Recently, purine nucleosides are found to have anti-cancer,
anti-viral and anti-bacterial activities4-8, especially outstanding anti-platelet aggregation
activities represented by N6-phenethyl-2-ethylthiopurien nucleosides 49 (Fig.1). Thus, the
chemical synthesis and structural modification of purines10-13 have being attracted
people’s attention for many years.

Fig. 1 Selected purine nucleosides with biological and pharmaceutical activities
Usually, the 2-, 6-, 8-positions with similarity in reactivity can all be functionalized
by nucleophilic substitution after the halogenation or diazotization9, 14-18. In other words,
the similarity in reactivity makes the selective functionalization more challenging in the
synthesis of multiple-functionalized purines on 2-, 6-, and 8-positions. Despite the
approaches for respective modification19-24 on purinyl 2-, 6-, and 8-positions have been
well developed, the methods for multiple functionalization of all three positions (2-, 6-,
and 8-position) are still less mentioned. Previously our group has ever successfully
developed a method to synthesize 2, 6, 8-trisubstituted purines14, but it is not satisfying
for limitations on narrow substrate scope and complicated operation. Herein, we will
develop
a
straight
forward
strategy
(Scheme
1)
to
synthesize
8-alkoxy-6-alkylamino-2-alkylthiopurine nucleosides for their potential biological
activities6-9, 14, 25-27, during which several routes were tried to seek the most appropriate
sequence of functionalization.

Scheme 1 Modification on guanosine with three substitutions
The synthetic route in sequence of amination, alkoxylation, and alkylthiolation
(scheme 2) was chosen for our initial study. The strategy was found to be successful till
affording intermediate 8 in an overall yield of 24% with five steps including protection,
chlorination, amination, bromination and alkoxylation. But, when intermediate 8 was
treated with isoamyl nitrite and diethyl disulfide, no desired product 9 could be detected
and the reaction system was messy. This is probably because the alkylthiolation reaction
was severely impeded by high electron density on the purine ring. To gain a more
efficiency strategy, the alkylthiolation would be switch with amination and alkoxylation
in order to provide a lower-electron-density substrate.

Scheme 2 The first exploration to synthesize 8-alkoxy-6-alkylamino-2-alkylthiopurine
nucleosides
Consequently, we adjusted the sequence of functionalization to make the
alkylthiolation reaction prior to the others in the synthesis (scheme 3). As we proposed,
the alkylthiolation went well on electron deficient substrate 6 affording product 10 in a
good yield (66%). The adjusted strategy was efficient in realizing functionalization before
the bromination of 11. The bromination of 11 with bromine was failed to afford the
desired product 12 for the sulfur atom cannot survive from the oxidation conditions of
various bromide reagent including Br2, NBS et al. This result indicated the bromine atom
had better be introduced before the alkylthiolation to avoid the unexpected oxidation.

Scheme 3 The second exploration to synthesize 8-alkoxy-6-alkylamino-2-alkylthiopurine
nucleosides
Based on results above, the synthetic route was adjusted to a new sequence:
alkylthiolation, alkoxylation and amination (scheme 4). Bromination and acetyl
protection of guanosine afforded 13 in a yield of 66%. After chlorination and
alkylthiolation, the intermediate 16a was isolated successfully in 49% overall yield.
Notably, ultrasound technology was used to the process of alkylthiolation, which avoided
the use of N2 gas and resulted in much shorter reaction time and simpler operation. It is
well known that Br atom is more able to be substituted by the nucleophilic substrate than
Cl atom, therefore, sodium methoxide was used to react with 16a. To our delight,
C8-substituted purine nucleoside 17aa was obtained in 65% yield. Then, the final product
tri-functionalized 18aaa was synthesized by amination of 17aa with 2-phenethylamine by
employing Et3N in ethanol under reflux condition. Therefore, the appropriate
modification order was confirmed and the approach to
8-alkoxy-6-alkylamino-2-alkylthiopurine nucleosides was established.
synthesize

Scheme 4 The third exploration to synthesize 8-alkoxy-6-alkylamino-2-alkylthiopurine
nucleosides
In order to demonstrate the generality of the current method, we utilized the
optimized route to synthesize 8-alkoxy-6-alkylamino-2-alkylthiopurine nucleosides
(Table 1). This straight forward approach could tolerate various primary and secondary
amines and most products (18aaa-18bbg) were obtained in moderate isolated yields. We
observed that the reaction of 6 with phenethylamine derivatives, bearing
electron-donating groups on aryl ring such as methyl and electron-withdrawing groups
such as fluorine and chlorine afforded the corresponding targets. Notably, the yields of
p-fluorophenethylamine (18aaf, 18baf) and p-chlorophenethylamine (18aab) were
slightly lower than those of p-methylphenethylamine (18aac, 18bac) possibly due to the
lower electron density of alkylamino groups caused by the electron-withdrawing effect of
fluorine or chlorine at aromatic ring. Meanwhile, the brief screening disclosed that the
steric hindrance of substituents at C-2 position in the purine ring merely had limited

impact on the yields.
Table 1 The final step for synthesis of 8-alkoxy-6-alkylamino-2-alkylthiopurine
nucleosides

We have developed a straight forward strategy for the synthesis of purine
nucleosides with multiple functionalization on 2-, 6-, and 8-positions. In the optimal
sequence
of
alkylthiolation,
alkoxylation
and
amination,
the
8-alkoxy-6-alkylamino-2-alkylthiopurine nucleosides could be afforded successfully in
moderate to good yields with broad generality bearing various primary and secondary

amines. This synthetic strategy provided a series of 2-, 6-, and 8-functionalized purine
nucleosides for biological and pharmaceutical activities screening, but also a successful
example for selective functionalization among reactivity-similar positions in a
complicated purine nucleoside system.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at….
Acknowledgments
We thank the National Natural Science Foundation of China (NSFC 21272022, 21302010)
and the Fundamental Research Funds for the Central Universities (YS1406, buctrc
201321) for their generous support. We acknowledge support from the “Public Hatching
Platform for Recruited Talents of Beijing University of Chemical Technology”.
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Graphical abstract

Highlights
 Synthesis of a series of 8-alkoxy-6-alkylamino-2-alkylthiopurine nucleosides
 Differentiate the 2-, 6-, and 8-positions of similar reactivity in nucleophilic
substitution
 The sequence of alkylthiolation, alkoxylation and amination facilitated the synthesis