Cross-coupling reactions of unprotected halopurine bases, nucleosides, nucleotides and nucleoside triphosphates with 4-boronophenylalanine in water. Synthesis of (purin-8-yl)- and (purin-6-yl)phenylalanines

Article abstract of DOI:10.1039/b604010a

An expeditious and highly efficient single-step methodology for the introduction of a phenylalanine moiety into position 8 and 6 of the purine scaffold was developed based on aqueous-phase Pd-catalysed Suzuki-Miyaura cross-coupling reactions of unprotected 4-boronophenylalanine with 8-bromo- or 6-chloropurines. The scope of the methodology was demonstrated by syntheses of unprotected (adenin-8-yl)phenylalanine base, nucleosides, nucleotides and nucleoside triphosphates as well as (purin-6-yl)phenylalanine base and nucleosides. All these products were obtained in high yields and in optically pure form. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b604010a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Cross-coupling reactions of unprotected halopurine bases, nucleosides,
nucleotides and nucleoside triphosphates with 4-boronophenylalanine
in water. Synthesis of (purin-8-yl)- and (purin-6-yl)phenylalanines†
ˇ
Petr Capek, Radek Pohl and Michal Hocek*
Received 17th March 2006, Accepted 13th April 2006
First published as an Advance Article on the web 4th May 2006
DOI: 10.1039/b604010a
An expeditious and highly efficient single-step methodology for the introduction of a phenylalanine
moiety into position 8 and 6 of the purine scaffold was developed based on aqueous-phase Pd-catalysed
Suzuki–Miyaura cross-coupling reactions of unprotected 4-boronophenylalanine with 8-bromo- or
6
-chloropurines. The scope of the methodology was demonstrated by syntheses of unprotected
(
(
adenin-8-yl)phenylalanine base, nucleosides, nucleotides and nucleoside triphosphates as well as
purin-6-yl)phenylalanine base and nucleosides. All these products were obtained in high yields and in
optically pure form.
1
5
Introduction
recently we have reported in a preliminary communication on
the synthesis of 4-(adenosin-8-yl)phenylalanines by the Suzuki–
Miyaura cross-coupling of unprotected nucleosides in predom-
inantly aqueous solvent. Here we give the full account of this
methodology, which is further extended to the cross-coupling of
the corresponding free bases and mono- and triphosphates as
potential substrates for PCR, and to the cross-coupling of 9-
unprotected purines and unprotected 6-halopurine nucleosides.
Modified nucleic acids attract growing interest due to potential
applications ranging from therapeutics to catalysis or nanotech-
nology. To expand the scope of these applications, the introduction
of a variety of functional groups to DNA (especially to the nucle-
obase) is desirable. Apart from classical oligonucleotide synthesis
using functionalised nucleoside phosphoramidites, nucleobase-
functionalised DNA can be prepared by PCR using modified
1
2
nucleoside triphosphates (NTP). The latter approach using
functionalised NTPs is particularly interesting due to its potential
3
use in in vitro selection. Bioconjugates of oligonucleotides and
Results and discussion
4
peptides or proteins are another important class of compounds.
15
As we have already reported, we first tried to apply reactions
of protected 4-trimethylstannyl- and 4-boronophenylalanines in
organic solvents (DMF or dioxane), successfully used in reactions
Attachment of a peptide part to an oligonucleotide may facilitate
5
6
transport through membranes, increase stability to exonucleases,
7
and enhance the antisense effect. These conjugates are usually
12
8
of 6-halopurines, to the analogous reactions of protected 8-
bromoadenines. Surprisingly, though there are many examples
of such cross-coupling reactions of 8-bromopurines with diverse
constructed by postsynthetic ligation or by stepwise synthesis of
9
both parts on a solid support.
Recently, we have, within the framework of our project on
16
17
10
organostannanes or arylboronic acids, these reactions with
the protected phenylalanine-derived organometallics did not
bioactive purines bearing functionalised C-substituents, entered
the field of C–C-linked conjugates of purines and amino acids.
15
1
1
proceed.
A new methodology for the synthesis of (purin-6-yl)alanines
12
Aqueous-phase cross-coupling reactions using water-soluble
phosphine ligands have attracted great attention in recent years
and (purin-6-yl)phenylalanines was developed based on the
cross-coupling reactions of protected iodozinc alanines and 4-
borono- or 4-(trimethylstannyl)phenylalanines, respectively, with
18
19
and found a wide range of applications. Shaughnessy et al.
have recently applied them to the reactions of unprotected 8-
bromoadenosine with simple arylboronic acids. Therefore we
decided to apply these conditions for the synthesis of 4-(adenosin-
8-yl)phenylalanines. Fortunately, the reactions of unprotected (S)-
4-boronophenylalanine 2 with 8-bromoadenine nucleosides 1a
and 1b (Scheme 1) gave the desired 4-(adenin-8-yl)phenylalanine
6
-halopurines. Purine bases and nucleosides with the amino acid
attached to position 8 are particularly attractive, since such
conjugates should retain H-bonding ability to form duplexes (8-
substituted adenosines are known to favour the undesired syn-
conformation but there are several examples
containing these compounds) and thus are potential building
blocks for functionalised DNA or DNA–peptide conjugates. Very
13
2c,14
of stable duplexes
15
nucleosides 3a and 3b in a single step and in very good yields
(
Table 1, entries 1–2). The reactions were carried out in a water–
◦
acetonitrile (2 : 1) solvent mixture at 90 C in the presence of
Na CO as a base and a water-soluble catalytic system consisting
Centre for New Antivirals and Antineoplastics, Institute of Organic Chem-
istry and Biochemistry, Academy of Sciences of the Czech Republic,
Flemingovo nam. 2, CZ-16610, Prague 6, Czech Republic. E-mail: hocek@
uochb.cas.cz; Fax: +420 220183559; Tel: +420 220183324
2
3
of Pd(OAc)
2
/P(m-C
6
H
4
SO
3
Na) (L1, ratio 1 : 2.5). The products
3
were isolated from crude reaction mixtures by preparative reverse-
phase HPLC on a C18 phase (this separation technique was used
also for isolation of all other final products).
†
Electronic supplementary information (ESI) available: Preparation of
starting compounds, additional data on optimisation of reaction condi-
tions. See DOI: 10.1039/b604010a
2
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Table 1 Synthesis of (adenin-8-yl)phenylalanines
a
◦
b
Entry
Purine
Product
Catalyst
Base
Temperature/ C
Time
Yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
1a
1b
1a
1b
1a
1b
1c
1d
1d
1d
1e
1e
1f
3a
3b
3a
3b
3a
3b
3c
3d
3d
3d
3e
3e
3f
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
/L1 (1 : 2.5)
/L1 (1 : 2.5)
/L1 (1 : 2.5)
/L1 (1 : 2.5)
/L1 (1 : 5)
/L1 (1 : 5)
/L1 (1 : 5)
/L1 (1 : 5)
/L1 (1 : 5)
/L1 (1 : 5)
/L1 (1 : 5)
/L1 (1 : 5)
/L1 (1 : 5)
/L1 (1 : 5)
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
2
2
2
2
2
2
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
3
3
3
90
90
2 h
2 h
71
75
56
52
76
68
84
0
51
72
<1
71
0
150 (MW)
150 (MW)
150 (MW)
150 (MW)
150 (MW)
90
150 (MW)
125
150 (MW)
125
5 min
5 min
5 min
5 min
5 min
4 h
5 min
1.5 h
5 min
20 min
2 h
1
1
1
1
1
1
1
90
1f
3f
150 (MW)
125
125
5 min
30 min
20 min
<5
51
55
c
1f
1g
3f
3g
/L1 (1 : 5)
Cs
Cs
2
CO
CO
3
c
/L1 (1 : 5)
2
3
a
b
c
0
.05 eq. of Pd(OAc)
2
with respect to 8-halopurine reagent was used. (MW) means that the reaction was performed under microwave irradiation. 0.1
eq. of of Pd(OAc) with respect to 8-halopurine reagent was used.
2
L1 to Pd(OAc) to 5 : 1 (Table 1, entries 5–6). These yields were
2
already comparable to the classically heated reactions (entries 1
and 2). This ratio was further confirmed to be generally superior
in all other studied reactions.
The success with nucleosides encouraged us to try an application
of this method to the synthesis of purine base 3c. It is noteworthy
17a,20
that 9-unsubstituted halopurine bases are generally known
to
be unreactive under classical Suzuki–Miyaura reaction conditions,
and 9-(tetrahydropyran-2-yl)-protected halopurines are usually
used as their synthetic equivalents. Fortunately, the reaction of
free 8-bromoadenine (1c) with boronic acid 2 under the optimised
microwave-mediated conditions gave (adenin-8-yl)phenylalanine
3c in excellent yield of 84% (Table 1, entry 7). This is thus
the first example of a successful cross-coupling reaction of a 9-
unsubstituted 8-halopurine base. The extent of this reaction with
other boronic acids and other halopurines is currently under study
and will be published separately.
In order to extend the scope of this methodology to other
biologically relevant derivatives, we have decided to apply it to
the synthesis of important but rather labile purine nucleotides and
nucleoside triphosphates. However, the reaction of boronopheny-
lalanine 2 with 8-bromoAMP 1d under conventional heating at
◦
9
(
0
C did not give any conversion to the desired product 3d
◦
Table 1, entry 8). Application of microwave irradiation at 150 C
was more successful, giving the product 3d in 51% yield (entry 9).
◦
Finally, classical heating at the optimum temperature of 125 C
(
high enough to promote the reaction but without significant
decomposition), provided the nucleotide 3d in very good yield
of 72% (entry 10). In contrast to the reaction of ribonucleotide 1d,
complete decomposition of the nucleotides was observed in the
ꢀ
case of microwave-mediated reaction of 2 -deoxyribonucleotide 1e
(
entry 11). On the other hand, reaction of 1e under classical heating
Scheme 1 Synthesis of (adenin-8-yl)phenylalanines.
◦
at 125 C proceeded smoothly with an even higher reaction rate
than the reaction of ribonucleotide 1d, to give the desired product
in a high preparative yield of 71% (entry 12).
As an alternative, we also tried to carry out the reactions of
◦
1
a–b under microwave irradiation for 5 min at 150 C (Table 1,
entries 3 and 4). The preparative yields were somewhat lower but
the reaction time was substantially reduced. Additional studies of
microwave-mediated reactions of 1a and 1b showed that yields can
be further improved to ca. 70% by increasing the ratio of the ligand
The most challenging substrates were the nucleoside triphos-
phates 1f and 1g. Nucleoside triphosphates are rather labile
compounds, which are easily hydrolysed. Therefore, we tried to
employ the mildest possible conditions. At first, we employed
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◦
23
24
Na
2
CO
3
as base and heating at 90 C for the reaction of the
PdCl
used for Suzuki couplings in aqueous media. Results of all
these experiments showed that the originally used Pd(OAc) /L1
4
Na
2
/EDTA and Pd/C (entries 7 and 8), other systems
triphosphate 1f with boronic acid 2, but no desired product 3f
was formed (Table 1, entry 13). On the other hand, application
of microwave irradiation (150 C, 5 min) in this reaction resulted
in a complex mixture of by-products, including monophosphates
and diphosphates as the products of hydrolysis of 1f and 3f (by
HPLC), with only traces of target triphosphate 3f (<5%, entry
2
◦
catalytic system is probably the best one for our reaction. With
no space for improvement of the catalyst, we examined the use
of a stronger base Cs
efficiency of the reaction, giving the product 3a in 44% yield
(entry 9).
2
CO
3
instead of Na
2
CO . It increased the
3
1
4). We therefore further optimised the reaction conditions in two
ways: (i) by improving the catalytic system in order to increase the
cross-coupling reaction rate and (ii) by decreasing the triphosphate
hydrolysis rate.
Additionally, the stability of model adenosine triphosphate
(ATP) under heating (125 C) in diverse water–organic solvent
◦
mixtures (H O and acetonitrile, acetone, DMF, EtOH, THF, or
2
The optimisation of the cross-coupling was performed on
a stable, cheap and easily available 8-bromoadenosine, 1a. We
examined several Pd-based catalytic systems (Table 2, entries 1–
DMSO) with a variety of bases was studied by analytical HPLC
(for details, see ESI†). There were no significant differences in the
hydrolysis rates of ATP in diverse solvent mixtures. On the other
hand, the stability of ATP rose dramatically with the strength of
8
) in a water–acetonitrile (2 : 1) mixture, with Na
2
CO as base
3
◦
and with heating at 125 C for 6 min. Entries 1 and 2 show
the results of the originally used catalytic system, consisting of
the base used, in the order Li
As the use of Cs CO was superior in both tests, it was clearly the
base of choice. Stronger bases were not tested due to the risk of
2
CO
3
< Na
2
CO
3
∼ K
3
PO
4
< Cs
2
CO .
3
2
3
Pd(OAc)
2
/P(m-C
6
H
4
SO
3
Na)
3
(1 : 5). Pd(OAc) /L1 premixed in
2
12
reaction solvents and injected into the reaction mixture gave the
product 3a in 32% yield (entry 1), while a separate addition of solid
racemisation of the amino acid moiety.
Finally, the preparative reaction of triphosphate 1f was carried
out under the optimum conditions, employing Cs CO base,
, ligand L1 and
Pd(OAc)
2
and L1 into the reaction gave somewhat lower yield
prepared according
2
3
of 30% (entry 2). The direct use of Pd(L1)
4
1.5 eq. of boronic acid 2, 10% of Pd(OAc)
2
21
◦
to literature gave the lowest yield of 23% (entry 3). The second
catalytic system was based on a more sterically hindered phosphine
ligand L2 (Fig. 1), reported to be superior to L1 in reactions of 8-
heating at 125 C. Despite partial decomposition of the reaction
mixture (again, products of hydrolysis of both starting and
final compounds were observed) desired product 3f was isolated
from reaction after 30 min (the reaction was stopped before
full conversion of 1f) in good yield of 51% (Table 1, entry 15).
Attempts to reach full conversion of starting 1f by prolongation
of reaction time resulted in lower yields caused by further
ꢀ
19
bromo-2 -deoxyadenosine with several simple arylboronic acids.
In our case, it gave yields of ca. 11% only (entries 4 and 5). A
catalytic system based on a water-soluble Buchwald-type ligand
L3 (Fig. 1), recently reported to be excellent for Suzuki–Miyaura
22
ꢀ
couplings of low reactivity aryl chlorides and bromides, failed
completely in our model experiment, with only about 1% yield of
decomposition of the final triphosphate. Analogous reaction of 2 -
deoxyribonucleoside triphosphate 1g under the same conditions
gave 55% of product 3g after 20 min of heating (Table 1, entry
3f (entry 6). Similarly unsuccessful were experiments catalysed by
1
6). In this case, full conversion of starting material was achieved
after this time (again indicating a higher reaction rate). A small
amount of diphosphate analogue of 3g was observed as the only
by-product.
To the best of our knowledge, the syntheses of compounds
3d–g represent the first examples of cross-coupling reactions of
purine nucleoside monophosphates and triphosphates (though
2
5
one related example of the Suzuki reaction was recently described
ꢀ
for cyclic 8-bromoinosine 5 -diphosphate ribose). When applied
to reactions of 2 -deoxyribonucleoside triphosphate 3g with di-
Fig. 1 Structures of water-soluble phosphine ligands L1–L3.
ꢀ
verse boronic acids, this methodology should have great value
for facile and efficient single-step syntheses of a variety of 8-
C-modified-2 -deoxyATPs. Use of these as substrates of PCR
Table 2 Optimisation of reaction conditions of model cross-coupling
experiments of 8-bromoadenosine 1a with 2 to give product 3a
ꢀ
reactions would lead to enzymatic synthesis of modified nucleic
acids. This study is under way and will be published in due
course.
a
b
Entry
Catalyst
Base
Yield of 3a (%)
c
1
2
3
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
2
/L1 (1 : 5)
/L1 (1 : 5)
Na
Na
Na
Na
Na
Na
Na
Na
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
32
30
23
11
12
1
<1
0
44
d
The optical purity of products 3a–c prepared under both
standard heating and microwave irradiation was examined by
2
Pd(L1)
4
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
/L2 (1 : 5)
26
derivatisation with Marfey’s reagent. No racemisation of the
/L2 (1 : 2.5)
/L3 (1 : 2)
/EDTA (1 : 1)
amino acid moiety was observed in these reactions (all products
had optical purity >98% ee/de; optical purity of the commercial
starting boronic acid 2 was determined to be 99% ee). To prove
PdCl
4
Na
2
Pd/C
Pd(OAc)
2
/L1 (1 : 5)
Cs
2
CO
3
that no racemisation takes place when stronger Cs
2
CO was used
3
a
b
0
.05 eq. of Pd catalyst with respect to 8-halopurine reagent was used.
in reaction, the compound 3a was prepared under the conditions
Yields were determined by analytical HPLC after 6 min of heating at
25 C. A premixed solution of Pd(OAc)
◦
of entries 15 and 16 (using Cs
2
CO
3
base and heating at 125 C for
◦
c
1
2
/L1 was injected into the
d
30 min). This sample of 3a had optical purity 98% ee, indicating
that no racemisation took place even with Cs CO
reaction. Solid Pd(OAc)
2
and L1 were added separately.
2
3
.
2
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With this efficient and straightforward methodology in hand,
we decided to come back to (purin-6-yl)phenylalanines, originally
efficient for the synthesis of 8-substituted nucleosides and more
labile nucleotides andNTPs, while microwave irradiationwas more
efficient for purine bases and 6-substituted nucleosides. The wide
tolerance of this methodology towards a variety of functionalities
and applicability to extremely labile systems was demonstrated
particularly clearly by the very first examples of couplings of free
purine bases and nucleoside monophosphates and triphosphates.
In particular, the application of the methodology to the reaction of
12
prepared by a multistep sequence consisting of the protection
of nucleosides and amino acids, cross-coupling reactions and
deprotections. The aqueous methodology would be a much shorter
and more efficient alternative for their synthesis. Therefore, the
scope of the methodology was further examined on the cross-
coupling reactions of 6-chloropurine derivatives 4a–c with boronic
acid 2 (Scheme 2).
ꢀ
8-bromo-2 -deoxyATP is of great value for the synthesis of novel
8
-C-modified purine NTPs, which are potential substrates in PCR
reactions.
Experimental
General
NMR spectra were measured on Bruker AMX-3 400 (400 MHz
1
13
for H and 100.6 MHz for C nuclei) and Bruker DRX 500
1
13
(
500 MHz for H and 125.8 MHz for C) spectrometers in D
referenced to dioxane as internal standard, d
= 3.75 ppm,
= 67.19 ppm) or in DMSO-d (referenced to the residual
2
O
(
H
d
C
6
Scheme 2 Synthesis of (purin-6-yl)phenylalanines.
solvent signal). Chemical shifts (d) are given in ppm, and coupling
constants (J) in Hz. Complete assignment of all NMR signals
was performed using a combination of H,H-COSY, H,C-HSQC
and H,C-HMBC experiments. Mass spectra were measured on a
ZAB-EQ (VG Analytical) spectrometer using FAB (ionisation by
Xe, accelerating voltage 8 kV, glycerol + thioglycerol matrix) or
LCQ classic (Thermo-Finnigan) spectrometer using ES−. Optical
Reactions of 6-chloropurine nucleosides 4a–b with boronic
acid 2 were carried out using Pd(OAc)
conventional heating at 90 C. Complete conversion was observed
2
/L1 and Na
2
CO under
3
◦
after 1.5 h and products 5a and 5b were isolated in good yields of
6
5% and 63% (Table 3, entries 1 and 3). Reaction of 4a repeated
under microwave irradiation gave even better yield of 84% of 5a in
◦
rotations were measured at 25 C on a Autopol IV (Rudolph
20
less than 1 minute (entry 2). Free 6-halopurine bases are known
to be unreactive in Suzuki coupling reactions in organic solvents
with Pd(PPh catalyst. However, with our catalytic system and
20
D
−1
Research Analytical) polarimeter, and [a] values are given in 10
deg cm g . H
2
−1
2
O–acetonitrile was degassed in vacuo and stored
)
3 4
under argon. Preparative HPLC separations were performed on a
column packed with 10 lm C18 reversed phase (Phenomenex,
Luna C18(2)). Microwave-mediated reactions were performed
in an Initiator (Biotage, Inc.) microwave reactor, operated in a
temperature-priority mode (i.e. the microwave source performance
changes automatically to maintain the set temperature over the
course of the reaction). For the synthesis and availability of
starting materials, see ESI†.
aqueous solvent system, free purine base 4c underwent reaction
◦
with 2 under heating at 90 C, reaching full conversion within
9
h and giving the product 5c in 67% preparative yield (entry 4).
Furthermore, both reaction rate and product yield were enhanced
significantly by the use of microwave irradiation (yield 90% in
5
min, entry 5). The optical purity of all prepared (purin-6-
yl)phenylalanines (5a–c) was >98% ee/de, according to the assay
with Marfey’s reagent.
Synthesis of compounds 3a–e: General procedure
Conclusions
Water–acetonitrile (2 : 1, 1.2 ml) was added through a septum to
an argon-purged vial containing 8-bromoadenine 1 (0.1 mmol),
19
The Shaughnessy method for Suzuki–Miyaura cross-coupling
reactions in aqueous media was further optimised and applied to
the synthesis of novel purine–amino acid conjugates. An efficient
single-step synthesis of optically pure (adenin-8-yl)phenylalanines
and (purin-6-yl)phenylalanines was elaborated using both classical
heating and microwave irradiations. Classical heating was more
boronic acid 2 (26 mg, 0.125 mmol), Pd(OAc)
0.005 mmol), P(m-C SO Na) (14.2 mg, 0.025 mmol), and
Na CO (32 mg, 0.3 mmol). The mixture was stirred under heating
2
(1.12 mg,
6
H
4
3
3
2
3
or under microwave irradiation (for temperature and reaction
time see Table 1). Products were isolated from the crude reaction
Table 3 Synthesis of (purin-6-yl)phenylalanines
a
Entry
Purine
Product
Conditions
Yield (%)
◦
1
2
3
4
5
4a
4a
4b
4c
4c
5a
5a
5b
5c
5c
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
/L1, Na
/L1, Na
/L1, Na
/L1, Na
/L1, Na
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
, 90 C, 80 min
65
84
63
67
90
◦
, 150 C MW, 1 min
◦
, 90 C, 90 min
◦
, 90 C, 9 h
◦
, 150 C MW, 5 min
a
The ratio of Pd(OAc) /L1 was 1 : 2.5 in all cases and was not further optimised.
2
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mixture by HPLC on a C18 column: (i) compounds 3a–c with a
linear gradient of 0.3% AcOH in H O to 0.3% AcOH in MeOH
as eluent; (ii) compounds 3d–e with a linear gradient of 0.1 M
TEAB (triethylammonium bicarbonate) in H O to 0.1 M TEAB
in H O–MeOH (1 : 1) as eluent. Several co-distillations with water
to remove remaining TEAB or AcOH) followed by freeze-drying
from water gave the products as white solids.
m-phenylene); 8.08 (m, 2H, H-o-phenylene); 8.11 (s, 1H, H-2).
1
3
2
C NMR (125.8 MHz, D
2
O + NaOD, refdioxane = 69.3 ppm):
43.43 (CH ); 60.14 (CH); 124.47 (C-5); 129.36 (CH-o-phenylene);
2
2
132.53 (CH-m-phenylene); 134.79 (C-i-phenylene); 142.19 (C-p-
phenylene); 152.53 (CH-2); 156.30 (C-4); 163.57 (C-6); 164.39 (C-
8); 185.10 (CO). IR (KBr): 3322, 3187, 2870, 1637, 1620, 1599,
2
(
2
0
1490, 1406, 1331, 796, 628. [a]D = −10.2 (c = 2.76, DMSO).
(
S)-2-Amino-3-{4-[6-amino-9-(b-D-ribofuranosyl)purin-8-yl]-
phenyl}propanoic acid (3a). Prepared from 1a (35 mg, 0.1 mmol);
O. For reaction conditions and yields, see
(
S)-2-Amino-3-{4-[6-amino-9-(b-D-ribofuranosyl)purin-8-yl]-
ꢀ
phenyl}propanoic acid 5 -O-phosphate (3d). Prepared from
d·2H O (46 mg, 0.1 mmol); isolated as 3f·Et N·4H O. For
reaction conditions and yields, see Table 1. MS (FAB): 511 (78, M
1); 317 (100); 299 (80, M − PO(OH) Rf + 2). HRMS (FAB):
calculated 511.1342, found 511.1340. H NMR
(500 MHz, D O, ref
= 3.75 ppm): 1.26 (t, 9H, J = 7.4, CH -
isolated as 3a·2H
2
1
2
3
2
Table 1. MS (FAB): 432 (28, M + 1); 299 (100, M − Rf + 2). HRMS
1
(
FAB): for C19
H
23
N
6
O
6
calculated 431.1679, found 431.1701. H
+
2
NMR (400 MHz, D
2
O, refdioxane = 3.75 ppm): 3.20 (dd, 1H, Jgem
=
1
for C19
H
24
N
6
O
9
P
1
1
5
(
7
J
4.4, JbCH ,CH = 7.5, bCH
2
); 3.32 (dd, 1H, Jgem = 14.4, JaCH ,CH
=
2
2
2
dioxane
vic
3
ꢀ
.3, aCH
2
); 3.82 (dd, 1H, Jgem = 12.9, J5ꢀb,4ꢀ = 3.0, H-5 b); 3.88
Et
3
N); 3.17 (dd, 1H, Jgem = 14.5, Jvic = 7.5, bCH
2
); 3.19 (q, 6H,
ꢀ
dd, 1H, Jgem = 12.9, J5ꢀa,4ꢀ = 2.4, H-5 a); 4.04 (dd, 1H, JCH,bCH
=
2
Jvic = 7.4, CH -Et N); 3.28 (dd, 1H, J = 14.4, J = 5.3, aCH );
ꢀ
vic
2
3
gem
vic
2
.5, JCH,aCH = 5.3, CH); 4.20 (q, 1H, J4ꢀ,5ꢀb = 3.0, J4ꢀ,5ꢀa = 2.4,
2
4.04 (dd, 1H, J = 7.4, 5.3, CH); 4.13–4.23 (m, 3H, H-4 and H-
ꢀ
ꢀ
4ꢀ,3ꢀ = 2.3, H-4 ); 4.40 (dd, 1H, J3ꢀ,2ꢀ = 5.5, J3ꢀ,4ꢀ = 2.3, H-3 ); 5.07
ꢀ
ꢀ
5
6
); 4.47 (dd, 1H, J3ꢀ,2ꢀ = 6.1, J3ꢀ,4ꢀ = 4.4, H-3 ); 5.20 (t, 1H, J2ꢀ,3ꢀ
=
ꢀ
(
1
8
dd, 1H, J2ꢀ,1ꢀ = 7.2, J2ꢀ,3ꢀ = 5.5, H-2 ); 5.92 (d, 1H, J1ꢀ2ꢀ = 7.2, H-
ꢀ
ꢀ
.1, J2ꢀ,1ꢀ = 6.0, H-2 ); 5.85 (d, 1H, J1ꢀ2ꢀ = 6.0, H-1 ); 7.38 (m, 2H,
ꢀ
); 7.42 (m, 2H, H-m-phenylene); 7.63 (m, 2H, H-o-phenylene);
H-m-phenylene); 7.60 (m, 2H, H-o-phenylene); 8.20 (s, 1H, H-2).
1
3
.19 (s, 1H, H-2). C NMR (100.6 MHz, D
ppm): 36.87 (CH
2.71 (CH-2 ); 87.08 (CH-4 ); 89.88 (CH-1 ); 119.29 (C-5); 127.29
C-i-phenylene); 130.54 and 130.77 (CH-phenylene); 138.96 (C-
p-phenylene); 149.78 (C-4); 151.04 (CH-2); 153.46 (C-8); 154.83
C-6); 174.15 (CO). IR (KBr): 3335, 3191, 1641, 1484, 1397, 1336,
085, 1034, 799. [a] = −41.0 (c = 3.50, DMSO).
2
O, refdioxane = 67.19
13
C NMR (125.8 MHz, D
2
O, refdioxane = 69.3 ppm): 10.95, CH
3
-
=
ꢀ
ꢀ
2
); 56.38 (CH); 62.77 (CH -5 ); 71.56 (CH-3 );
2
Et
3
N); 38.89 (CH
2
); 49.38 CH
2
-Et
3
N); 58.36 (CH); 67.24 (d, JC,P
ꢀ
ꢀ
ꢀ
7
ꢀ
ꢀ
ꢀ
5
4
, CH
2
-5 ); 72.25 (CH-3 ); 73.00 (CH-2 ); 85.82 (d, JC,P = 8, CH-
(
ꢀ
ꢀ
); 91.63 (CH-1 ); 120.95 (C-5); 129.49 (C-i-phenylene); 132.49
and 132.65 (CH-o,m-phenylene); 140.78 (C-p-phenylene); 152.58
C-4); 154.52 (CH-2); 155.28 (C-8); 157.18 (C-6); 176.36 (CO).
P ( H dec.) NMR (162 MHz, D O, ref
IR (KBr): 3413, 3182, 2927, 2680, 1637, 1478, 1396, 1333, 1060,
045, 910, 519. [a]D = −28.5 (c = 2.68, H
for 3d·Et N·4H 13P (683.6): C 43.92%, H 6.78%, N
4.34%; found: C 43.57%, H 6.47%, N 14.06%.
(
1
(
2
D
0
31
1
2
H PO
3 4
= 0 ppm): 1.18.
(
S)-2-Amino-3-{4-[6-amino-9-(2-deoxy-b-D-erythropentofuranosyl)-
purin-8-yl]phenyl}propanoic acid (3b). Prepared from 1b (33 mg,
.1 mmol); isolated as 3b·2H O. For reaction conditions and
2
0
1
2
O). Anal. calculated
3
2
O, C25
H
46
7
N O
0
2
1
yields, see Table 1. MS (FAB): 415 (70, M + 1); 299 (100, M −
Rf + 2). HRMS (FAB): for C19
H
23
N
6
O calculated 415.1730,
5
ꢀ
1
(S)-2-Amino-3-{4-[6-amino-9-(2 -deoxy-b-D-erythropentofuranosyl)-
found 415.1716. H NMR (400 MHz, D
2
O, refdioxane = 3.75 ppm):
ꢀ
ꢀ
purin-8-yl]phenyl}propanoic acid 5 -O-phosphate (3e). Prepared
2
(
.29 (ddd, 1H, Jgem = 14.0, J2ꢀb,1ꢀ = 6.2, J2ꢀb,3ꢀ = 2.2, H-2 b); 3.01
ꢀ
from 1e·Et
O. For the reaction conditions and yields, see Table 1. MS
FAB): 596.6 (38, M + Et
3
N·2H
2
O (55 mg, 0.1 mmol); isolated as 3e·Et N·
3
ddd, 1H, Jgem = 14.0, J2ꢀa,1ꢀ = 8.9, J2ꢀa,3ꢀ = 6.2, H-2 b); 3.22 (dd,
2
(
H
2
1
1
3
H, Jgem = 14.4, JbCH ,CH = 7.5, bCH
2
); 3.32 (dd, 1H, Jgem
=
=
2
3
N + 1); 495 (76, M + 1); 299 (100, M −
24 6 8 1
4.4, JaCH ,CH = 5.4, aCH
2
); 3.81 (dd, 1H, Jgem = 12.6, J5ꢀb,4ꢀ
2
ꢀ
ꢀ
PO(OH)
2
dRf + 2). HRMS (FAB): for C19
H
N
O
P
calculated
.5, H-5 b); 3.87 (dd, 1H, Jgem = 12.6, J5ꢀa,4ꢀ = 2.7, H-5 a); 4.05
1
4
95.1393, found 495.1383. H NMR (400 MHz, D
2
O, refdioxane
N); 2.23 (ddd, 1H,
=
(
3
2
dd, 1H, JCH,bCH = 7.5, JCH,aCH = 5.4, CH); 4.10 (q, 1H, J4ꢀ,5ꢀ
=
=
2
2
ꢀ
3.75 ppm): 1.27 (t, 9H, Jvic = 7.3, CH
3
-Et
3
.5, 2.7, J4ꢀ,3ꢀ = 2.2, H-4 ); 4.63 (dt, 1H, J3ꢀ,2ꢀ = 6.2, 2.2, J3ꢀ,4ꢀ
ꢀ
ꢀ
ꢀ
J
7
gem = 14.0, J2ꢀb,1ꢀ = 7.2, J2ꢀb,3ꢀ = 3.8, H-2 b); 3.19 (q, 6H, Jvic
=
.2, H-3 ); 6.29 (dd, 1H, J1ꢀ2ꢀ = 8.9, 6.2, H-1 ); 7.44 (m, 2H,
.4, CH
2
-Et
3
N); 3.20 (dd, 1H, Jgem = 14.7, Jvic = 7.6, bCH
2
); 3.23
H-m-phenylene); 7.55 (m, 2H, H-o-phenylene); 8.17 (s, 1H, H-2).
ꢀ
1
3
(dt, 1H, Jgem = 14.0, J2ꢀa,1ꢀ = J2ꢀa,3ꢀ = 7.4, H-2 a); 3.32 (dd, 1H,
C NMR (100.6 MHz, D
8.82 (CH
CH-1 ); 88.53 (CH-4 ); 119.36 (C-5); 127.57 (C-i-phenylene);
30.48 and 130.58 (CH-phenylene); 138.95 (C-p-phenylene);
49.73 (C-4); 150.76 (CH-2); 152.91 (C-8); 154.79 (C-6); 174.17
CO). IR (KBr): 3354, 3205, 1642, 1526, 1483, 1406, 1337, 1091,
055, 1032, 798. [a] = −35.0 (c = 4.15, DMSO).
2
O, refdioxane = 67.19 ppm): 36.87 (CH
2
);
ꢀ
ꢀ
ꢀ
J
gem = 14.7, Jvic = 5.3, aCH
2
); 4.05 (dd, 1H, Jvic = 7.6, 5.3, CH);
3
(
2
-2 ); 56.37 (CH); 62.95 (CH
2
-5 ); 72.52 (CH-3 ); 87.13
ꢀ
ꢀ
ꢀ
ꢀ
4.07–4.17 (m, 3H, H-4 and H-5 ); 4.64 (dt, 1H, J3ꢀ,2ꢀ = 7.4, 3.8,
ꢀ
ꢀ
J
3ꢀ,4ꢀ = 3.8, H-3 ); 6.30 (t, 1H, J1ꢀ2ꢀ = 7.6, 7.4, H-1 ); 7.44 (m, 2H,
1
1
H-m-phenylene); 7.65 (m, 2H, H-o-phenylene); 8.23 (s, 1H, H-2).
1
3
C NMR (100.6 MHz, D
2
O, refdioxane = 69.3 ppm): 10.95 (CH
3
-
(
1
ꢀ
2
D
0
Et
3
N); 38.48 (CH
2
-2 ); 38.87 (CH
2
); 49.37 (CH
2
-Et N); 58.37
3
ꢀ
ꢀ
ꢀ
(
CH); 67.31 (d, JC,P = 5, CH
2
-5 ); 73.68 (CH-3 ); 87.42 (CH-1 );
ꢀ
(
S)-2-Amino-3-[4-(6-amino-9H -purin-8-yl)phenyl]propanoic
87.79 (d, JC,P = 8, CH-4 ); 121.17 (C-5); 130.05 (C-i-phenylene);
132.55 (CH-o,m-phenylene); 140.60 (C-p-phenylene); 152.56
(C-4); 154.59 (CH-2); 154.99 (C-8); 157.43 (C-6); 176.35 (CO).
acid (3c). Prepared from 1c (22 mg, 0.1 mmol) by microwave-
mediated reaction (150 C, 5 min), to give 25 mg (84%) of 3c.
MS (FAB): 299 (100, M + 1); 279 (16); 253 (22). HRMS (FAB):
for C14
◦
3
1
1
P ( H dec.) NMR (162 MHz, D
IR (KBr): 3421, 3179, 2683, 2488, 1637, 1577, 1478, 1397, 1334,
2
O, ref
H
PO = 0 ppm): 0.89.
3
4
1
H
15
N
6
O
2
calculated 299.1256, found 299.1265. H NMR
2
0
(
J
5
500 MHz, D
2
O + NaOD, refdioxane = 3.75 ppm): 2.89 (dd, 1H,
1179, 1052, 921, 618, 522. [a]D = −34.6 (c = 1.49, H
2
O). Anal.
gem = 13.5, Jvic = 7.5, bCH
2
); 3.05 (dd, 1H, Jgem = 13.5, Jvic
=
calculated for 3e·Et
3
N·2H
2
O, C25
H
42
N O
7
10P (631.6): C 47.54%, H
.6, aCH
2
); 3.55 (dd, 1H, Jvic = 7.5, 5.6, CH); 7.38 (m, 2H, H-
6.70%, N 15.52%; found: C 47.06%, H 6.57%, N 15.16%.
2
282 | Org. Biomol. Chem., 2006, 4, 2278–2284
This journal is © The Royal Society of Chemistry 2006

View Online
ꢀ
Synthesis of triphosphates 3f–g: General procedure
J
C,P = 8, CH-4 ); 121.25 (C-5); 130.46 (C-i-phenylene); 132.66
and 132.89 (CH-o,m-phenylene); 140.95 (C-p-phenylene); 152.95
C-4); 155.03 (CH-2); 155.34 (C-8); 157.77 (C-6); 176.46 (CO).
Water–acetonitrile (2 : 1, 0.8 ml) was added through a septum to
an argon-purged vial containing 8-bromoadenosine triphosphate
(
31
1
P ( H dec.) NMR (162 MHz, D
b, P
); −11.07 (d, J = 18.4, P
2
O, ref
); −9.60 (b, P
H
PO = 0 ppm): −22.46
3
4
1
(
(0.1 mmol), boronic acid 2 (31 mg, 0.15 mmol) and Cs
163 mg, 0.5 mmol). When the solid had dissolved, a solution of
Pd(OAc) (2.25 mg, 0.01 mmol) and P(m-C SO Na) (28.4 mg,
.05 mmol) in water–acetonitrile (2 : 1, 0.4 ml) was added, and the
2
CO
3
(
3
8
b
a
c
). IR (KBr): 3429,
189, 2679, 2490, 1638, 1478, 1398, 1333, 1235, 1056, 945, 897,
2
6
H
4
3
3
20
39, 618. [a]D = −16.5 (c = 2.23, H
2
O).
0
◦
mixture stirred with heating at 125 C.
Synthesis of compounds 5a–d: General procedure
(
S)-2-Amino-3-{4-[6-amino-9-(b-D-ribofuranosyl)purin-8-yl]-
Water–acetonitrile (2 : 1, 1.2 ml) was added through a septum
to an argon-purged vial containing 6-chloropurine 4 (0.1 mmol),
boronic acid 2 (26 mg, 0.125 mmol), Pd(OAc)2 (1.12 mg,
0.005 mmol), P(m-C H SO Na) (7.1 mg, 0.0125 mmol), and
ꢀ
phenyl}propanoic acid 5 -O-triphosphate (3f). Prepared from
1
1
f·3Et
3
N·2H
2
O (93 mg, 0.1 mmol). The reaction was heated at
◦
25 C for 30 min. The product was isolated from the crude
6
4
3
3
reaction mixture by HPLC on a C18 column with a linear gradient
of 0.1 M TEAB in H O to 0.1 M TEAB in H O–MeOH (1 : 1).
Several co-distillations with water followed by freeze-drying from
Na CO (32 mg, 0.3 mmol). The mixture was stirred under heating
2
3
2
2
or under microwave irradiation (for temperatures and reaction
time see Table 3). After neutralisation to pH 7 by aq. HCl, the
products were isolated from crude reaction mixture by HPLC
water gave the product, 3f·3Et
3
N·2H
2
O, in 51% yield as white
−
solid. MS (ES ): 669 (100, M − 1); 589 (60, M − PO(OH)
2
); 297
: calculated
on a C18 column with a linear gradient of 0.3% AcOH in H O
2
−
(
18, M − P
3
O
9
H
4
Rf). HRMS (ES ) for C19
H
24
N
6
O
15
P
3
to 0.3% AcOH in MeOH. Several co-distillations with water
1
6
3
7
69.0513, found 669.0489. H NMR (400 MHz, D
2
O, refdioxane
-Et N); 3.17 (q, 18H, Jvic
=
followed by freeze-drying from water gave the products as white
solids. For the yields, see Table 3. All analytical and spectral data
of compounds 5a–c were in accord with authentic samples and
.75 ppm): 1.26 (t, 27H, Jvic = 7.3, CH
3
3
=
.3, CH -Et
2
3
N); 3.21 (dd, 1H, Jgem = 14.3, Jvic = 7.7, bCH
2
); 3.37
12
(
dd, 1H, Jgem = 14.3, Jvic = 4.9, aCH
2
); 4.07 (dd, 1H, Jvic = 7.7,
previously published data.
ꢀ
ꢀ
4
6
1
.9, CH); 4.21–4.35 (m, 3H, H-4 and H-5 ); 4.49 (dd, 1H, J3ꢀ,2ꢀ
=
ꢀ
ꢀ
.2, J3ꢀ,4ꢀ = 4.1, H-3 ); 5.19 (t, 1H, J2ꢀ,1ꢀ = J2ꢀ,3ꢀ = 6.2, H-2 ); 5.93 (d,
Acknowledgements
ꢀ
H, J1ꢀ2ꢀ = 6.2, H-1 ); 7.49 (m, 2H, H-m-phenylene); 7.70 (m, 2H,
1
3
This work is a part of the research project Z4 055 0506. It was
supported by the “Centre of New Antivirals and Antineoplastics”
(1M0508), by the Programme of Targeted Projects of the Academy
of Sciences of the Czech Republic (1QS400550501) and by
Sumitomo Chemical, Inc. (Osaka, Japan).
H-o-phenylene); 8.31 (s, 1H, H-2). C NMR (100.6 MHz, D O,
2
refdioxane = 69.3 ppm): 10.95 (CH
3
-Et
3
N); 38.92 (CH
2
); 49.37 (CH -
2
ꢀ
ꢀ
Et
3
N); 58.38 (CH); 67.95 (d, JC,P = 5, CH
2
-5 ); 72.09 (CH-3 ); 73.12
ꢀ
ꢀ
ꢀ
(
CH-2 ); 85.81 (d, JC,P = 9, CH-4 ); 91.49 (CH-1 ); 121.09 (C-5);
129.76 (C-i-phenylene); 132.77 (CH-o,m-phenylene); 141.11 (C-
p-phenylene); 152.90 (C-4); 153.99 (CH-2); 155.77 (C-8); 156.90
3
1
1
References
(
0
C-6); 176.41 (CO). P ( H dec.) NMR (162 MHz, D
2
O, ref
H
PO
=
a
3
4
ppm): −23.15 (t, J = 19.6, 18.4, P
b
); −11.32 (d, J = 19.6, P
);
1
(a) H. Hashimoto, M. G. Nelson and C. Schwitzer, J. Am. Chem.
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Becker, E. Feiling and F. Seela, Bioconjugate Chem., 2002, 13, 1274–
−
10.77 (t, J = 18.4, P
c
). IR (KBr): 3428, 2679, 2492, 1637, 1478,
2
0
1
397, 1332, 1237, 1062, 1033, 946, 899, 618. [a] = −17.5 (c =
D
1
285; (c) J. A. Brazier, T. Shibata, J. Townsley, B. F. Taylor, E. Frary,
N. H. Williams and D. M. Williams, Nucleic Acids Res., 2005, 33,
362–1371.
2
.57, H O).
2
1
ꢀ
(
S)-2-Amino-3-{4-[6-amino-9-(2 -deoxy-b-D-erythropentofuranosyl)-
2
(a) O. Thum, S. J a¨ ger and M. Famulok, Angew. Chem., Int. Ed., 2001,
40, 3990–3993; (b) M. M. Masud, A. Ozaki-Nakamura, M. Kuwahara,
H. Ozaki and H. Sawai, ChemBioChem, 2003, 4, 584–588; (c) S. J a¨ ger,
G. Rasched, H. Kornreich-Leshem, M. Engeser, O. Thum and M.
Famulok, J. Am. Chem. Soc., 2005, 127, 15071–15082.
(a) T. M. Dewey, A. Mundt, G. J. Crouch, M. C. Zyzniewski and B. E.
Eaton, J. Am. Chem. Soc., 1995, 117, 8474–8475; (b) T. Schoetzau,
J. Langner, E. Moyroud, I. Roehl, S. Vonhoff and S. Klussmann,
Bioconjugate Chem., 2003, 14, 919–926.
(a) T. Da Ros, G. Spalluto, M. Prato, T. Saison-Behmoaras, A.
Boutorine and B. Cacciari, Curr. Med. Chem., 2005, 12, 71–88; (b) T. L.
Pierce, A. R. White, G. W. Treager and P. M. Sexton, Mini-Rev. Med.
Chem., 2005, 5, 41–55.
ꢀ
purin-8-yl]phenyl}propanoic
acid
5 -O-triphosphate
(3g).
Prepared from 1g·3Et
3
N·2H
2
O (91 mg, 0.1 mmol). The reaction
was heated at 125 C for 20 min. The product was isolated from
the crude reaction mixture by HPLC on a C18 column with 0.1 M
◦
3
4
TEAB in H O–MeOH (5 : 1) as eluent. Several co-distillations
2
with water followed by freeze-drying from water gave the product,
−
3
g·3Et
3
N·2H
2
O, in 55% yield as a white solid. MS (ES ): 653
(
100, M − 1); 573 (51, M − PO(OH)
2
); 297 (23, M − P
3
O
9
H
4
dRf).
−
HRMS (ES ) for C19
H
24
N
6
O
14
P
3
: calculated 653.0563, found
1
653.0544. H NMR (400 MHz, D
2
O, refdioxane = 3.75 ppm): 1.26
5
6
M. J. Gait, Cell. Mol. Life Sci., 2003, 60, 844–853.
J. Robles, M. Maseda, M. Beltran, M. Concernau, E. Pedroso and A.
Grandas, Bioconjugate Chem., 1997, 8, 785–788.
(
t, 27H, Jvic = 7.3, CH
3
ꢀ
-Et
3
N); 2.24 (ddd, 1H, Jgem = 13.9, J2ꢀb,1ꢀ
=
7
3
J
3
6
7
.2, J2ꢀb,3ꢀ = 4.3, H-2 b); 3.18 (q, 18H, Jvic = 7.3, CH
2
-Et N);
3
ꢀ
7 T. Kubo, Z. Zhelev, B. Rumiana, H. Ohba, K. Doi and M. Fujii, Org.
Biomol. Chem., 2005, 3, 3257–3259.
.20–3.27 (m, 2H, H-2 a and bCH
2
); 3.39 (dd, 1H, Jgem = 14.4,
vic = 5.0, aCH
2
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This journal is © The Royal Society of Chemistry 2006
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