Synthesis of novel 2-cyano-7-deaza-8-azapurine- and 2-cyano-8-azapurine- derived nucleosides

Article abstract of DOI:10.1055/s-0030-1260943

A novel systematic approach to the synthesis of 2-cyano-7-deaza-8-azapurine derived nucleosides is described. It is shown how this chemistry was developed with the labile 2-substituted nitrile position in mind, and also how the same approach is applicable to 2-cyano-8-azapurine derived nucleosides.

Full text of DOI:10.1055/s-0030-1260943

1900
LETTER
Synthesis of Novel 2-Cyano-7-deaza-8-azapurine- and 2-Cyano-8-azapurine-
Derived Nucleosides
Synthesis of
N
h
ovel 2-Cyan
i
o-7-dea
l
za-8-a
i
z
apurin
p
e
-
and2-Cyano-8-a
W
zapurine-DerivedNucle
a
osides inwright,*a Adrian Maddaford,a Michael Simms,a Neil Forrest,a Rebecca Glen,a James Hart,a
Xiurong Zhang,a David C. Pryde,b Peter T. Stephenson,b Donald S. Middleton,b Thierry Guyot,b Scott C. Suttonc
a
Peakdale Molecular Ltd., Peakdale Science Park, Sheffield Road, Chapel-en-le-frith, High Peak, SK23 0PG, UK
Fax +44(1298)816701; E-mail: phil.wainwright@peakdale.co.uk
Discovery Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, CT13 9NJ, UK
Pfizer Global Research and Development, 10770 Science Centre Drive, San Diego, CA 92121, USA
b
c
Received 30 March 2011
R
Abstract: A novel systematic approach to the synthesis of 2-cyano-
7-deaza-8-azapurine derived nucleosides is described. It is shown
how this chemistry was developed with the labile 2-substituted ni-
trile position in mind, and also how the same approach is applicable
to 2-cyano-8-azapurine derived nucleosides.
HN
N
N
N
N
CN
sugar
Key words: nucleosides, nitriles, protecting groups, heterocycles,
glycosylation
Figure 1
Synthesis of such a target could have relied on a previous
literature8 approach in which coupling of the base and
sugar took place prior to the introduction of the nitrile
group (Scheme 1).
Nucleosides and their analogues continue to be investigat-
ed to treat a range of diseases including cancer and viral
infections.1 In addition, nucleosides and nucleotides form
the primary building blocks for the construction of natural
and modified genetic material. For example, oligomeric
nucleoside constructs form the basis of antisense/RNA in-
terference applications.2 Finally, nucleosides are intimate-
ly involved in key processes such as metabolic regulation
and energy storage.3
Cl
Cl
O
N
DCBO
N
I
O
ii
N
i
DCBO
N
N
N
N
DCBO
OH
2
NH2
DCBO
OH
1
A large body of synthetic methodology to access modified
bases and riboses has accumulated over the last several
decades,4 spurred along by several highly successful
drugs in this class.5 Research in this area is complicated by
a requirement that the nucleoside must be converted into
its triphosphate in cellular assays followed by effective in-
hibition of the target in the designated pathway. Lack of
biological activity due to poor or no recognition by the
cellular kinases required to activate the parent nucleoside
is often a high hurdle to overcome. The effect of structural
modifications on the conformational preference of nucle-
oside analogues has been proposed as a significant driver
of subsequent recognition by biological systems.6 Two
strong drivers in nucleoside design include a desire to stay
close in structure to the natural bases and riboses, while
designing novelty into target compounds.
NH2
N
NH2
O
N
DCBO
O
N
DCBO
iii
N
I
N
CN
DCBO
OH
DCBO
OH
4
3
Scheme 1 Reagents and conditions: (i) CuI, I2, CH2I2, isoamyl ni-
trite, 51%; (ii) NH3, MeOH, 75%; (iii) CuCN, DMF, 100 °C, 44%.
However, this was a linear approach requiring the often
precious sugar–base adduct to be exposed to functional-
group transformations to access the target nucleoside. An
approach whereby the nitrile group was introduced prior
to the sugar coupling step (Figure 2) was sought.
Cl
Cl
Cl
With these considerations in mind, we became interested
in 2-cyano-8-aza-7-deazapurines (Figure 1) as a potential
adenine mimic by virtue of a replacement of the C2-hy-
drogen of adenine with CN and an isomeric movement of
N7 to C8.7
N
N
N
N
N
N
N
N
N
N
CN
N
I
N
NH2
H
PG
PG
5
6
7
Figure 2 Proposed retrosynthetic route
The retrosynthetic plan was to convert 7 into iodo 6 via di-
azotization chemistry, followed by CuCN cyanation. It
was anticipated that protection of the N9 position would
be required for these transformations in addition to help-
ing improve the poor solubility and of the azapurine base.
SYNLETT 2011, No. 13, pp 1900–1904
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260943; Art ID: D09811ST
© Georg Thieme Verlag Stuttgart · New York
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x
.x
x
.2
0
1
1

LETTER
Synthesis of Novel 2-Cyano-7-deaza-8-azapurine- and 2-Cyano-8-azapurine-Derived Nucleosides
1901
O
O
Cl
Cl
Cl
N
Cl
N
i
NH
N
N
N
ii
N
N
i
N
N
N
N
HO
N
NH2
Cl
N
NH2
N
NH2
CN
H
N
H
CN
8
9
7
7
Scheme 2 Reagents and conditions: (i) POCl3, DMF, 84%; (ii) hy-
drazine, 93%.
OMe
12
Cl
N
R2
N
Cl
O
Cl
iii
ii
N
N
N
N
N
N
N
N
N
CN
CN
i
N
N
NH2
R1
R1
Cl
N
9
NH2
13
14
Scheme 4 Reagents and conditions: (i) CAN, MeCN, 81%; (ii)
BF3·OEt2, MeCN, sugar R1 (see Table 1), 11–61%; (iii) amine (see
Table 2), 6–59%.
OMe
N
10
Cl
N
Cl
Table 1 Synthesis of Compounds 13
N
N
N
Compound
R1
Yield (%)
59
b/a
ii
iii
N
N
I
N
CN
O
O
O
AcO
BzO
BzO
13a
1:0
OMe
AcO
OAc
OMe
11
12
13b
25
6:9
Scheme 3 Reagents and conditions: (i) p-methoxybenzylhydrazine,
Et3N, THF, 82%; (ii) isoamyl nitrite, CH2I2, CuI, I2, 62%; (iii) CuCN,
DMF, 100 °C, 55%.
BzO
13c
13d
13e
61
57
46
1:0
4:7
1:0
2-Amino-6-chloro-8-aza-7-deazapurine (7) was prepared
using a published procedure9 (Scheme 2) allowing us to
investigate protecting the N9 position. Several protecting
groups were investigated. Incorporation of the THP group
was attempted (3,4-dihydro-2H-pyran, PTSA, EtOAc,
DMF) but resulted in degradation of the starting material
with no evidence of the THP incorporation. Our attention
next turned to the use of the Boc group [(Boc)2O, NaH, or
K2CO3]. However, this only led to degraded material. Re-
action of unprotected 7 directly with isoamyl nitrite, cop-
per(I) iodide, iodine, and diiodomethane also failed,
giving only decomposition products. Backing up to an
earlier step on the way to 7, it was decided to attempt in-
troduction of a p-methoxybenzyl (PMB) group at N9 via
p-methoxybenzylhydrazine leading to 10 (Scheme 3).
OAc
O
O
AcO
BzO
BzO
BzO
OBz
F
O
BzO
13fa
11
–
a b/a could not determined from the crude data, only the b-isomer was
isolated.
that published for analogous 8-aza-7-deazapurines.11 The
C6 chloride of 13 was displaced with ammonia in metha-
nol, which also cleaved the acetyl groups giving 14a. As
expected the nitrile survived all these transformations in-
tact.
Reaction of 9 with p-methoxybenzylhydrazine gave 10 in
82% yield. The Sandmeyer reaction using isoamyl nitrite
afforded a 62% yield of 11 and CuCN-promoted cyana-
tion proceeded at 100 °C in DMF to afford 12 in 55%
yield. We next turned our attention to the removal of the
protecting group and introduction of the sugar
(Scheme 4).
With the synthesis of parent compounds 13 and 14 in
place, the chemistry was repeated with five additional
sugars (13b–f, Table 1). All sugars were purchased with
an O-acetyl at the anomeric position, or in the case of en-
try 13d, prepared as described in the literature with an
anomeric O-methoxy group.12 The exception to this were
entries 13e and 13f which were purchased with O-benzoyl
substituents at the anomeric position. It was found that no
glycosylation occurred on treatment of these under our
The PMB group was removed cleanly with CAN in 81%
yield. Using conditions provided by Tripathi10 we tested
the reaction of 7 with b-D-ribofuranose 1,2,3,5-tetraace-
tate and BF3·OEt2. This reaction went in 54% yield giving
the desired b anomer selectively. The point of glycosyla-
tion was determined by comparison of the 13C NMR with
Synlett 2011, No. 13, 1900–1904 © Thieme Stuttgart · New York

1902
P. Wainwright et al.
LETTER
Table 2 Synthesis of Compounds 14 (continued)
standard BF3·OEt2 conditions. Consequently, the anomer-
ic benzoyl group was converted into acetyl (AcOH, Ac2O,
H2SO4, CH2Cl2) in 81% yield. The glycosylation reactions
then proceeded smoothly. Nucleosides derived from sug-
ars 13b,13 13d,14 and 13f15 by virtue of lacking a protected
3¢-hydroxyl gave a mixture of anomers as anticipated. The
a/b anomers were separated by chromatography and the
Compound
R1
R2
Yield (%)
35
HN
36
8
H2N
1
O
stereochemistry determined by comparison of the H
14d
NH2
HO
NMR’s to analogus purine nucleosides for the same sug-
ars. A further complication with sugars 13b,c,e,f (Table 2)
was significantly slower benzoyl deprotection compared
with the acetyl counterparts under the methanolic ammo-
nia conditions. The consequence of this slow reaction was
degradation of the C2 nitrile on the nucleobase. In these
cases, the C6 chloro displacement with amines was con-
ducted first and the sugar-protected intermediates isolat-
ed. Attempted deprotection of the benzoyl groups with
sodium methoxide in methanol led to the imidate at the C2
position. So, we turned to lithium hydroxide in water–
THF (1:1) which led to varying degrees of successful
deprotection. Sugar 13e was particularly problematic, and
it was found that only stoichiometric quantities of sodium
methoxide in THF worked but only in 14–27% yields.
NHMe
NMe2
19
22
17
19
HN
H2N
O
HO
14e
NH2
22
HO
OH
NHMe
NMe2
14
17
Our desire to extend the scope of this approach to 2-cy-
ano-8-azapurines (Figure 3) led to a similar approach as
outlined above.
26
27
HN
H2N
Table 2 Synthesis of Compounds 14
O
HO
14f
NH2
23
Compound
R1
R2
Yield (%)
59
F
HO
O
NHMe
NMe2
35
39
HO
14a
NH2
HO
OH
NHMe
NMe2
52
34
11
H2N
Our attention was therefore focused on the synthesis of in-
termediate 21 (Scheme 5).
42
64
HN
The transformation of 15 to 19 was carried out in a proce-
dure previously published for the N-benzyl analogue16 in
20% overall yield. Conversion of the ester 19 into the
amide 20 was achieved with aqueous concentrated ammo-
nia in a sealed vessel in 93%. The nitrile and chloride were
then introduced via the use of phosphorous oxychloride in
64%.
H2N
O
HO
14b
14c
NH2
6
HO
NHMe
19
21
H2N
R
HN
O
HO
NH2
13
N
N
N
N
OH
N
CN
NHMe
NMe2
12
18
sugar
Figure 3
Synlett 2011, No. 13, 1900–1904 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel 2-Cyano-7-deaza-8-azapurine- and 2-Cyano-8-azapurine-Derived Nucleosides
1903
O
Cl
N
N
N
N
N
N
N
N
N
NH2
NH2
N
N
N
N
N
N
OH
N3
N
N
ii
ii
i
i
N
N
CN
CN
MeO
MeO
N
H
CN
15
16
23
OMe
OEt
OMe
OMe
17
21
AcO
22
O
O
N
N
HO
HO
N
N
N
NH2
O
NH
N
N
O
O
iii
iv
CN
N
N
iii
iv
N
N
N
N
N
N
N
AcO
H
OEt
N
N
N
N
CN
O
O
OAc
OH
24
25
OMe
OMe
19
Scheme 6 Reagents and conditions: (i) 2 M Me2NH in THF,
MeCN, 98%; (ii) TFA, 45 °C, 42%; (iii) BF3·OEt2, MeCN, 78%; (iv)
2 M NaOH, 11%.
18
O–NH4
+
Cl
N
N
N
quence could be extended to a range of amino or sugar
motifs, and could also be used to access the 2-substituted
acid and amide analogous. Furthermore, it has been dem-
onstrated that this approach also has potential for the anal-
ogous 2-cyano-8-azapurine nucleosides.
N
N
N
N
N
NH2
v
vi
N
N
CN
O
OMe
OMe
20
21
Supporting Information for this article is available online at
Scheme 5 Reagents and conditions: (i) SOCl2, DMF, NaN3, 100%;
(ii) cyanoacetamide, Na, EtOH, 71%; (iii) ethyl oxalyl chloride, pyri-
dine, 37%; (iv) HMDS, xylenes, 150 °C,78%; (v) concd NH3, 80 °C,
93%; (vi) POCl3, PCl5, 64%.
http://www.thieme-connect.com/ejournals/toc/synlett.
References and Notes
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Haas, J.; Andree, C.; Barman, J.; Wenska, M.; Srivastava, P.;
Zhou, C.; Honcharenko, D.; Hess, S.; Müller, E.; Bobkov, G.
V.; Mikhailov, S. N.; Fava, E.; Meyer, T. F.;
Chattopadhyaya, J.; Zerial, M.; Engels, J. W.; Herdewijn, P.;
Wengel, J.; Kjems, J. Nucleic Acids Res. 2009, 37, 2867.
(3) Chemistry of Nucleosides and Nucleotides, Vol. 3;
Townsend, L. B., Ed.; Plenum Press: New York, 1994.
(4) (a) de Clercq, E.; Holy, A.; Rosenberg, I.; Sakuma, T.;
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Initial attempts to deprotect the p-methoxybenzyl group
with CAN to provide des-PMB 21 led to decomposition of
the starting material. We were concerned that the liberated
triazine anion could self-react, considering the reactivity
of the chloride. It was decided to change the order of the
steps to avoid this complication. Compound 21 was treat-
ed with dimethyl amine to afford the SNAr product in 98%
yield, and the CAN deprotection was attempted again.
Unfortunately, decomposition was observed again, how-
ever, the use of trifluoroacetic acid at 45 °C was found to
remove the PMB group cleanly to afford 23 in 42% yield.
This was then coupled with b-D-Ribofuranose 1,2,3,5-tet-
raacetate and BF3·OEt2 to give the single b anomer in
78%. The acetyl protecting groups were then hydrolyzed
with 2 M sodium hydroxide, and after purification by pre-
parative HPLC the nucleoside 25 was isolated in 11%
yield (Scheme 6). As with the 7-deaza analogue, the loss
of yield was due to the formation of the acid and amide.
The point of glycosylation at N8 was determined by
1
HSQC (13C vs. H), HMBC, and by 13C NMR chemical
shift with respect to the 13C chemical shifts reported from
analogus N8 and N9 nucleosides in the literature.17
(7) We have chosen the historical purine numbering system in
this communication.
(8) Nair, V.; Buenger, G. S. J. Am. Chem. Soc. 1989, 111, 8502.
(9) Seela, F.; Steker, H. Heterocycles 1985, 23, 2521.
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(11) Montgomery, J. A.; Shortnacy, A. T.; Secrist, J. A. J. Med.
Chem. 1983, 26, 1483.
In conclusion, we have developed a systematic approach
to access a wide variety of 2-cyano-7-deaza-8-azapurine
derived nucleosides. The chemistry has been developed to
accommodate the labile 2-substituted nitrile functional
group, with conditions provided for the coupling and
deprotection of a variety of sugars. In principal, this se-
Synlett 2011, No. 13, 1900–1904 © Thieme Stuttgart · New York

1904
P. Wainwright et al.
LETTER
(12) Jung, M. E.; Castro, C.; Gardiner, J. M. Tetrahedron. Lett.
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(16) Barili, P. L.; Biagi, G.; Livi, O.; Scartoni, V. J. Heterocycl.
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(17) He, J.; Seela, F. Org. Biomol. Chem. 2003, 11, 187.
Synlett 2011, No. 13, 1900–1904 © Thieme Stuttgart · New York