Synthesis of (purin-6-yl)methylphosphonate bases and nucleosides

Article abstract of DOI:10.1016/j.tetlet.2010.02.167

Three approaches to the synthesis of the title (purin-6-yl)methylphosphonates were investigated and compared. While, the Arbuzov reaction of 6-(iodomethyl)purines with triethyl phosphite did not work, Michaelis-Becker alkylation of the sodium salt of diet

Full text of DOI:10.1016/j.tetlet.2010.02.167

Tetrahedron Letters 51 (2010) 2464–2466
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Tetrahedron Letters
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Synthesis of (purin-6-yl)methylphosphonate bases and nucleosides
*
ˇ
Zbynek Hasník, Radek Pohl, Michal Hocek
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Flemingovo nam. 2,
CZ-16610 Prague 6, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Three approaches to the synthesis of the title (purin-6-yl)methylphosphonates were investigated and
compared. While, the Arbuzov reaction of 6-(iodomethyl)purines with triethyl phosphite did not work,
Michaelis–Becker alkylation of the sodium salt of diethyl phosphonate with 6-(mesyloxymethyl)purines
gave the desired products in good yields. The best method was based on Rh- or Pd-catalyzed cross-cou-
pling reactions of 6-iodopurines with (diisopropoxyphosphorylmethyl)zinc bromide. In this way a small
series of 6-(diisopropoxyphosphorylmethyl)purine bases and nucleosides was prepared in high yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 10 December 2009
Revised 13 February 2010
Accepted 26 February 2010
Available online 3 March 2010
Keywords:
Purines
Nucleosides
Phosphonates
Cross-coupling reactions
Purine is an important and extensively investigated heterocycle.
However, purines bearing functionalized C-substituents at position
6 have only recently been systematically studied. We have devel-
oped syntheses of many subtypes of these compounds, mostly
based on the cross-coupling reactions of halopurines with func-
tionalized organometallics followed by further functional group
transformations1,2 or by additions and cycloadditions to 6-vinyl-
and 6-ethynylpurines.3 Ribonucleosides derived from 6-hydroxy-
methyl-,1 6-(di/tri)fluoromethyl-, 6-(aminomethyl)-,2 6-(2-amino-
vinyl)-, and 6-(2-aminoethyl)purines3 were shown to possess
interesting cytostatic and anti-HCV activities. Purin-6-yl acetates
were recently prepared4 by the Pd-catalyzed cross-couplings of
halopurines with the Reformatsky reagent and were further con-
verted into carboxamides and 6-(2-hydroxyethyl)purines. Herein,
we report on the synthesis of hitherto unknown 6-(phosphonom-
ethyl)purine bases and nucleosides which are phosphorous ana-
logues of the acetates. Acyclic nucleoside phosphonates of
purines are clinical antivirals of paramount importance,5 however
the methylphosphonate moiety was never directly connected to
the purine. The only known related examples were phosphonopu-
rines (with a direct P–C linkage to purine).6
The methods were tested on model 9-benzylpurines. The
Michaelis–Arbuzov reaction is the most common method for the
preparation of diverse alkylphosphonates,7 and was the first ap-
proach tried in the synthesis of the title compounds (Scheme 1,
Path A). 9-Benzyl-6-(mesyloxymethyl)purine (1a) was converted
into the more reactive 6-(iodomethyl)purine (2a) which was sub-
jected to reaction with triethyl phosphite under standard condi-
tions. However, heating 2a in the presence of excess triethyl
phosphite resulted only in decomposition of the starting material
and no traces of the desired product. Therefore, we focused on
the alternative Michaelis–Becker approach (Scheme 1, Path B).
The mesylate 1a was reacted with the in situ-generated sodium
salt of diethyl phosphonate under various conditions (Table 1). Per-
forming this reaction at À20 °C gave the desired diethyl 6-(phos-
phonomethyl)purine 3a in a mixture with 4a (not isolated in
pure form; it was identified by NMR from the mixture with 3a)
as a side-product of its alkylation with a second equivalent of 1a
(entry 1). The selectivity of the substitution was significantly in-
creased by lowering the reaction temperature to À78 °C to give
the phosphonate 3a in a good yield of 79% (entry 2). When the
amount of sodium diethyl phosphonate was increased to 4 equiv,
the yield of the desired 6-(phosphonomethyl)purine 3a increased
to 84% (entry 3).
Three approaches for the synthesis of the title (purin-6-yl)meth-
ylphosphonates have been investigated: (i) Michaelis–Arbuzov
reaction7 of 6-(iodomethyl)purines with trialkyl phosphites, (ii)
Michaelis–Becker8 alkylation of sodium diethyl phosphonate, and
(iii) cross-coupling of (diisopropoxylphosphonylmethyl)zinc io-
dide9 with 6-halopurines.
Since the Michaelis–Becker approach required very efficient
cooling to prevent side reactions, we decided to investigate a direct
introduction of the phosphonomethyl group by cross-coupling
with an appropriate phoshonomethylzinc reagent. The only known
example9 of such coupling was the Rh-catalyzed reaction of aryl
halides with (diethoxyphosphonylmethyl)zinc iodide. Related
cross-couplings of (phosphonodifluoromethyl)zinc were de-
* Corresponding author. Tel.: +420 220183324; fax: +420 220183559.
E-mail address: hocek@uochb.cas.cz (M. Hocek).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.167

Z. Hasník et al. / Tetrahedron Letters 51 (2010) 2464–2466
2465
I
O
OMs
N
Path C
X
N
P(OiPr)2
N
N
N
N
IZnCH2P(O)(OiPr)2
NaI
N
N
N
N
(8)
N
N
acetone
N
N
Bn
N
Bn
Bn
N
Bn
X=Cl
6a X=I
catalyst, conditions
2a
1a
5a
7a
Path A
(Michaelis-Arbuzov)
P(OEt)3
Path B
(Michaelis-Becker)
Scheme 2. Cross-coupling of 6-halopurines with organozinc 8 (Path C).
HP(O)(OEt)2
NaH
Bn
N
N
Table 2
Optimization of the cross-coupling of 6a with 8
O
N
N
N
O
P(OEt)2
Entry
Catalyst (mol %)
8 (equiv)
T (°C)
Yield of 7a (%)
P(OEt)2
1
2
3
4
5
6
7
8
Rh(COD)Cl2/dppf (10)
Rh(COD)Cl2/dppf (10)
Pd(PPh3)4 (10)
4
4
4
4
2
2
2
2
rt
60
rt
60
60
50
50
60
34
94
0
95
94
91
85
94
N
N
N
N
N
N
Bn
N
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (5)
Bn
3a
4a
not isolated
Pd(PPh3)4 (5)
Scheme 1. Michaelis–Arbuzov (Path A) and Michaelis–Becker (Path B) approaches
to the title 6-phosphonomethylpurines.
O
P(OiPr)2
I
Table 1
Michaelis–Becker synthesis of 3a
N
N
N
IZnCH2P(O)(OiPr)2
N
N
Entry
Conditions
T (°C)
Yield of 3a (%)
Pd(PPh3)4, THF, 60 °C
N
R
7a,b,c,d
N
N
1
2
3
HP(O)(OEt)2 (2 equiv)/NaH
HP(O)(OEt)2 (2 equiv)/NaH
HP(O)(OEt)2 (4 equiv)/NaH
À20
À78
À78
59a
79
84
R
6a,b,c,d
a
6,7
R in
=
Unseparable mixture containing 29% of 4a (2:1).
TBSO
TBSO
O
O
Bn
THP
b
scribed10 earlier using Cu-catalysis. We have prepared a new
organozinc reagent, (diisopropoxyphosphonylmethyl)zinc iodide
(8) to avoid possible problems with alkyl transfer from diethyl
phosphonates. The organozinc 8 was prepared by the reaction of
diisopropyl iodomethylphosphonate with zinc dust preactivated
using TMSCl and 1,2-dibromoethane in analogy with our previous
procedure used for the generation of the Reformatsky reagent.4 The
organozinc 8 was tested in reactions with 9-benzyl-6-chloro-(5a)
and -6-iodopurine (6a) with Rh or Pd-catalysis under different con-
ditions (Scheme 2). 6-Chloropurine 5a was found to be completely
unreactive with all the tested catalytic systems even at high tem-
peratures. Therefore, only 6-iodopurine 6a was used for the opti-
mization (Table 2). The Rh-catalyzed9 (10 mol % Rh(COD)Cl2 with
dppf) reaction of 6a with 4 equiv of 8 at rt gave only low conver-
sion, while heating at 60 °C gave the desired 6-(phosphonometh-
yl)purine 7a in an excellent yield of 94% (entries 1 and 2). When
using cheaper Pd(PPh3)4 as the catalyst (10 mol %), the reaction
at rt did not proceed. However, at 60 °C the reaction proceeded
smoothly to give 7a in nearly quantitative yield (entry 4). Further
experiments (entries 5–8) were performed to decrease the excess
of the organozinc 8 and the loading of the catalyst. Thus, the opti-
mized conditions required 2 equiv of 8 and 5 mol % of Pd(PPh3)4 to
give an almost quantitative conversion to 7a (entry 8).
a
TBSO OTBS
TBSO
d
c
Dowex (H+)
Et3N.3HF
O
Et3N.3HF
HO
HO
O
H
HO
HO OH
7e
7g
7f
Scheme 3. Synthesis of 6-(diisopropoxyphosphorylmethyl)purine bases and
nucleosides.
Table 3
Synthesis of 6-(diisopropoxyphosphorylmethyl)purine bases and nucleosides
Entry
Substrate
Cross-coupling
product (yield)
Deprotection
product (yield)
1
2
3
4
6a
6b
6c
6d
7a (94%)
7b (93%)
7c (97%)
7d (93%)
—
7e (55%)
7f (63%)
7g (62%)
nucleosides 7c and 7d in almost quantitative yields (entries 3 and
4). The protecting groups were removed by standard procedures
giving the free purine base and nucleosides. The THP-protecting
group in 7b was cleaved using Dowex 50 (H+ form)11 in ethanol
at 70 °C yielding 55% of the free purine base 7e. Deprotection of
the TBS groups in nucleosides 7c,d was performed using a small
excess of Et3NÁ3HF in THF12 overnight to give the desired free
nucleosides 7f,g in good yields.
These optimized conditions were applied to the preparation of
other purine derivatives with protecting groups at position 9 of
the purine moiety (Scheme 3, Table 3). All the starting compounds
6b–d reacted readily and gave full conversion to the corresponding
phosphonates 7. THP-protected purine 6b showed good stability
toward this cross-coupling reaction and gave the desired phospho-
nomethylpurine 7b in 93% yield (entry 2). Both silyl-protected
iodopurine nucleosides 6c and 6d were also excellent substrates
for this cross-coupling reaction and gave the desired phosphonate
In conclusion, a novel and efficient approach to (purin-6-
yl)methylphosphonates was developed based on cross-coupling

2466
Z. Hasník et al. / Tetrahedron Letters 51 (2010) 2464–2466
reactions of 6-iodopurines with (diisopropoxyphosphonylmeth-
yl)zinc iodide. For the first time, these reactions were successfully
performed under Pd-catalysis. The resulting purine-phosphonates
can potentially be used for other synthetic transformations (alkyla-
tions, Horner–Emmons reactions, etc.).
Synthesis of 3a by Michaelis–Becker reaction: To a suspension of
NaH (20 mg, 0.5 mmol) in 2 ml of THF was added dropwise diethyl
phosphonate (79 mg, 64 ll, 0.5 mmol) at 0 °C and the mixture was
JC,P = 3.6, (CH3)2CH); 32.86 (d, JC,P = 135.8, CH2P); 47.23 (CH2N);
71.13 (d, JC,P = 6.7, CH(CH3)2); 127.75 (CH-o-Ph); 128.52 (CH-p-
Ph); 129.04 (CH-m-Ph); 132.97 (d, JC,P = 5.8, C-5); 134.90 (C-i-Ph);
144.17 (CH-8); 151.03 (d, JC,P = 1.2, C-4); 152.31 (d, JC,P = 2.7, CH-
2); 153.57 (d, JC,P = 9.4, C-6). 31P NMR (202.3 MHz, CDCl3): 21.16.
IR (CCl4): 3436, 2980, 1595, 1333, 1243, 994. Anal. Calcd for
C19H25N4O3PÁ3/4H2O (401.9): C, 56.78; H, 6.65; N, 13.94. Found:
C, 56.57; H, 6.94; N, 13.42.
allowed to warm to room temperature. After 2 h the solution was
cooled to À78 °C and transferred to a mixture of mesylate 1a
(80 mg, 0.25 mmol) in 2 ml of THF at À78 °C. The mixture was al-
lowed to warm to room temperature overnight, then quenched
with H2O, and extracted with CHCl3 (3 Â 15 ml). The combined or-
ganic layers were dried over anhydrous MgSO4, filtered, and the
solvent was evaporated. The residue was chromatographed on sil-
ica gel (hexane/EtOAc 10:1–1:1) to give pure 3a as a yellowish oil
in 84% yield. MS (ESI): 383 (100, M+Na), 361 (25, M+H). HRMS
(ESI): calcd for C17H21N4O3PNa: 383.1243, found: 383.1244. 1H
NMR (600.1 MHz, CDCl3): 1.28 (td, 6H, Jvic = 7.1, JH,P = 0.4, CH3CH2);
3.85 (d, 2H, JH,P = 22.7, CH2P); 4.17 (m, 4H, CH2CH3); 5.44 (s, 2H,
CH2N); 7.32 (m, 2H, H-o-Ph); 7.35 (m, 1H, H-p-Ph); 7.36 (m, 2H,
H-o-Ph); 8.04 (d, 1H, JH,P = 1.0, H-8); 8.96 (d, 1H, JH,P = 0.6, H-2).
13C NMR (150.9 MHz, CDCl3): 16.29 (d, JC,P = 6.3, CH3CH2); 31.74
(d, JC,P = 134.1, CH2P); 47.36 (CH2N); 62.55 (d, JC,P = 6.3, CH2CH3);
127.92 (CH-o-Ph); 128.66 (CH-p-Ph); 129.16 (CH-m-Ph); 133.05
(d, JC,P = 5.6, C-5); 134.90 (C-i-Ph); 144.23 (CH-8); 151.16 (d,
JC,P = 1.1, C-4); 152.53 (d, JC,P = 2.6, CH-2); 153.38 (d, JC,P = 9.4, C-
6). 31P{1H} NMR (202.3 MHz, CDCl3): 23.35. IR (CCl4): 3439, 2983,
1595, 1333, 1245, 1030.
Acknowledgments
This work is part of the research project Z4 055 0506 of the
Academy of Sciences of the Czech Republic. It was supported by
the Ministry of Education, Youth and Sports (1M0508), and by Gi-
lead Sciences, Inc. (Foster City, CA, USA).
Supplementary data
Supplementary data (complete experimental details and char-
acterization data of all compounds) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2010.02.167.
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(125.7 MHz, CDCl3): 23.66 (d, JC,P = 5.3, (CH3)2CH); 23.95 (d,
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ˇ