Synthesis of C-6-substituted uridine phosphonates through aerobic ligand-free Suzuki-Miyaura cross-coupling

Article abstract of DOI:10.1039/c0ob00061b

An efficient protocol for the construction of C-6-(hetero)aryl-substituted uridine phosphonate analogues utilizing an aerobic, ligand-free Suzuki-Miyaura cross-coupling reaction of a 6-iodo-precursor in aqueous media has been established. The method presents a modular approach toward the target compounds as demonstrated by the synthesis of a small library comprising 14 novel nucleoside phosphonates.

Full text of DOI:10.1039/c0ob00061b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of C-6-substituted uridine phosphonates through aerobic ligand-free
Suzuki–Miyaura cross-coupling†‡
Radim Nencka,a,b Davy Sinnaeve,c Izet Karalic,a Jose´ C. Martinsc and Serge Van Calenbergh*a
Received 29th April 2010, Accepted 17th August 2010
DOI: 10.1039/c0ob00061b
An efficient protocol for the construction of C-6-(hetero)aryl-substituted uridine phosphonate
analogues utilizing an aerobic, ligand-free Suzuki–Miyaura cross-coupling reaction of a
6-iodo-precursor in aqueous media has been established. The method presents a modular approach
toward the target compounds as demonstrated by the synthesis of a small library comprising 14 novel
nucleoside phosphonates.
Introduction
Nucleoside phosphonates (NPs) have received considerable atten-
tion due to their interesting pharmacological properties and the
synthesis of novel nucleotides containing a phosphonate moiety
as bioisostere of a phosphate group has been extensively attracting
the focus of medicinal chemists during last years.1 Acyclic NPs,
such as cidofovir 1, tenofovir 2 and adefovir 3, represent efficient
agents that are clinically used against various viral diseases.2
Several cyclic NPs also express promising activity profiles. GS-
9148 (4), for example, combines favorable activity against multiple
NRTI-resistant HIV-1 strains with a low potential for mito-
chondrial toxicity and minimal nephrotoxicity.3 Besides antiviral
activity, NPs may exert a broad spectrum of other activities in-
cluding antiparasitic, cytostatic and immunomodulatory activity.4
Recently, we have identified uridine 5¢-methylenephosphonate 5
as an agonist of the P2Y2 receptor, which contrasted with lack of
such activity displayed by the analogous uridine monophosphate.5
Since 5 probably activates the P2Y2 receptor through binding to a
yet unknown allosteric site, further derivatization may strengthen
the binding affinity of 5 (Fig. 1).
Although extensive synthetic efforts have been devoted towards
modifications of all nucleobases and several methodologies based
on palladium catalyzed cross-couplings6 or C–H activations7
have been invented, the 6-position of uridine has been largely
overlooked and only a few 6-aryl derivatives of uridine have been
aLaboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences
(FFW), Ghent University, Harelbekestraat 72, B-9000, Ghent, Belgium.
E-mail: serge.vancalenbergh@ugent.be; Fax: +32 9 2648146; Tel: +32 9
2648124
Fig. 1 Biologically active nucleoside phosphonates.
bCentre for New Antivirals and Antineoplastics, Institute of Organic
Chemistry and Biochemistry Academy of Sciences of the Czech Republic,
v.v.i.(IOCB), Gilead & IOCB Research Center, 166 10, Prague 6, Czech
Republic. E-mail: nencka@uochb.cas.cz; Fax: +420 220183560; Tel: +420
220183323
reported so far. The Stille cross coupling8 and photochemical
synthesis9 have been recently presented as possible synthetic
routes towards these derivatives. However, both methods suffer
from known drawbacks such as the toxicity of the organotin
reagents used in the Stille coupling and the limited control of
regioselectivity in the case of photochemical derivatization.
We decided to explore the Suzuki–Miyaura cross-coupling for
the introduction of aryl groups at position 6 of 5. Although the
Suzuki reaction is one of the most efficient methods for carbon–
carbon bond formation10 and has been adopted in the chemistry of
nucleic acid components,11 most examples used for the synthesis
of nucleoside and nucleotide analogues have been performed in
the presence of (often complicated and/or sensitive) phosphine
cNMR and Structure Analysis Unit, Department of Organic Chemistry,
Ghent University, Krijgslaan 281 S4, B-9000, Ghent, Belgium. E-mail:
jose.martins@ugent.be; Fax: +32 9 2644972
† Electronic supplementary information (ESI) available: Tables depicting
cross-coupling optimization and spectral data of compounds 8a–e, 9a–
d, 11, 12, 16, copies of 1H NMR spectra (700 MHz) of 5, 22a and 9b,
measured scalar couplings [Hz] for compounds 5, 22a and 9b, and oberved
nOe contacts for compounds 5, 22a and 9b. See DOI: 10.1039/c0ob00061b
‡ Abbreviations: NPs nucleoside phosphonates; IBX 2-iodoxybenzoic
acid; dppf 1,1¢-bis(diphenylphosphino)ferrocene; TPPTS tris(3-
sulfonatophenyl)phosphine trisodium salt; TFA triflouroacetic acid.
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Table 1 Suzuki–Miyaura cross coupling of protected 6-iodouridine
Entry
1.
ArB(OH)2
Product
Ar
Time/min
120
T/◦C
Solvent
Yield (%)a
83
10a
8a
100
Toluene : H2O
2.
3.
10b
10c
8b
8c
120
45
100
100
Toluene : H2O
Toluene : H2O
81
82
4.
5.
6.
7.
10d
10d
10e
10e
8d
8d
8e
8e
360
60
100
140
100
140
Toluene : H2O
o-Xylene : H2O
Toluene : H2O
o-Xylene : H2O
17
66
0
45
60
10
a Isolated yield.
Scheme 1 Synthesis of C-6 substituted uridines via “classical” Suzuki–Miyaura cross coupling procedure.
ligands. Recently, a great deal of effort was invested into the
research of the Suzuki–Miyaura cross-coupling under ligand-free
conditions, usually in aqueous media, thereby better complying
with economical and green chemistry concepts.12
employing Pd(dppf)Cl2·CH2Cl2 as the catalyst and mixture of
toluene and water as solvent. Under these conditions, we were able
to obtain a number of the desired coupling products (Scheme 1,
Table 1).
Recent papers also describe protocols to perform this coupling
reaction under aerobic conditions.12d However, most reports on the
ligandless Suzuki–Miyaura coupling, only involve simple aromatic
or heteroaromatic systems.
The main goal of the current study was to investigate possible
routes towards analogues of 5, with aryl substituents at position 6
of the uracil moiety.
However, heterocyclic boronic acids such as 10d and 10l
(Table 2) afforded only poor yields or failed to react. This
inconvenience could be partially overcome by using o-xylene
instead of toluene, which allowed to rise the temperature up to
140 ◦C. Furthermore, we found that the resulting C-6 substituted
nucleosides can be readily deprotected by simple treatment with
trifluoroacetic acid (TFA) in water to afford the appropriate uri-
dine derivatives. However, the synthesis of such uridine derivatives
was not our main interest and only a limited number of such
derivatives was prepared for illustrative purposes (Table 3).
Intermediate 8a could be converted to phosphonate 13a by
subsequent desilylation, IBX-mediated oxidation,14 and Horner–
Wadsworth–Emmons reaction of the resulting aldehyde 12 with
the sodium salt of bisphosphonate 14 (Scheme 2, Fig. 2).15
However, we felt that incorporation of the phosphonate moiety
after C-6 derivatization is rather impractical due to the number
of subsequent reaction steps. Therefore, we decided to investigate
the use of intermediate 18 towards a more divergent synthesis of
the target NP. Selective deprotection of the 5¢-position of 7 with
ammonium fluoride afforded 16. However, the introduction of
Results and discussion
In order to synthesize the desired C-6 substituted derivatives,
we explored two distinct pathways. Both routes started from
derivative 7, which was easily accessible in 3 steps from uridine by
a known procedure13 that was modified to meet the requirements
of a large-scale synthesis, i.e. most of the chromatographic steps
were replaced by crystallizations. Next, we turned our attention
to the Suzuki–Miyaura cross coupling of protected 6-iodouridine
7. Unfortunately, the substrate appeared to be quite unstable and
degradation was observed under most experimental conditions
tested (ESI Table S1†). The only satisfactory results were obtained
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Table 2 Derivatives and boronic acids used in the study
Entry
1.
Derivative
ArB(OH)2
Ar
a
10a
2.
3.
b
c
10b
10c
4.
5.
6.
7.
8.
d
e
f
10d
10e
10f
10g
10h
g
h
9.
i
j
10i
10j
Scheme
2
Introduction of the phosphonate moiety through
Horner–Wadsworth–Emmons reaction.
10.
11.
12.
k
l
10k
10l
13.
14.
m
n
10m
—
Table 3 Deprotection of C-6 substituted uridines
Entry
Substrate
Product
Yield (%)a
1.
2.
3.
4.
8a
8b
8c
8d
9a
9b
9c
9d
93
61
91
98
a Isolated yield.
Scheme 3 Synthesis of strategic intermediate 18.
the phosphonate moiety presented a serious synthetic challenge
(Scheme 3).
were faced during the olefination step (Table 4), but optimization
of the reaction conditions allowed to obtain 18 in 43% yield (over
the oxidation and olefination step).
Having the protected 6-iodouridine phosphonate precursor in
hand, the Suzuki–Miyaura cross coupling with diverse boronic
acids was investigated. Remarkably, the conditions optimized for
the cross coupling of the protected 6-iodouridine 7 failed when
applied to 18. Many other conditions and catalysts were tested
and mostly found unsatisfactory (ESI Table S2†).
First, intermediate 17, prepared by the oxidation of alcohol
16 by IBX, usualy contained some impurities that were hardly
separable from the desired compound due to its inherent insta-
bility. Extractions or column chromatography were found to be
highly inefficient. The best way to remove most of the impurities
was to cool down the acetonitrile solution in an ice bath and
to remove the insoluble material by filtration. Further difficulties
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Table 4 Oxidation-olefination sequence
Table 6 Synthesis of C-6 substituted nucleoside phosphonates via
Suzuki–Miyaura cross-couplinga
Entry
Reagent
Ratio
Time/h
Temp.
Yield (%)a
Entry
1.
ArB(OH)2
Product
Ar
Yield (%)b
45
1.
2.
3.
4.
15
14
14
14
14
14
14
3eq.
1eq.
3eq.
3eq.
5eq.
2.4eq.
3eq.
16
16
1.5
2.75
4
2.5
2.5
r.t.
r.t.
r.t.
0
8
21
31
32
29
43
10a
13a
0 ◦
0 ◦
0 ◦
0 ◦
C
C
C
C
2.
3.
10b
10c
13b
13c
64
5.
6.b
7.b
trace
a Isolated yield based on 16 (two steps). b Large scale.
4.
5.
6.
7.
10d
10f
10g
10h
13d
13f
13g
13h
24
53
63
51
Fig. 2 Reagents for olefination reactions.
In search for suitable reaction conditions, we experienced that
the phosphine ligands presented no actual advantage for the reac-
tion. In addition, the use of inert atmosphere could be omitted and
reactions could be performed open to air. Further optimization of
the Pd(OAc)2-catalyzed reaction led to proper conditions for this
ligandless coupling reaction (Scheme 4, Table 5).
8.
9.
10i
10j
13i
13j
45
trace
10.
11.
10k
10l
13k
13l
52
64
12.
10m
13m
80
a Reaction conditions: compound 18 (1 mmol), 5% Pd(AcO)2, K3PO4,
PrOH/H2O (1 : 1), 50 ◦C, 30 min. b Isolated yield.
Scheme 4 Cross-coupling reaction of nucleoside phosphonates.
the reaction performed using K3PO4 as a base in the 1 : 1 mixture
of n-propanol and water. These conditions were applied with a
reduced amount of catalyst (5%) for the synthesis of various 6-aryl
substituted nucleoside phosphonates 13 (Table 6). As a notable
benefit, the conversion could be conveniently monitored by 31P-
NMR.
All test reactions were carried out in presence of 10 mol%
Pd(AcO)2 at 50 ◦C for 30 min. The best results were obtained for
Table 5 Optimization of the aerobic ligand-free Suzuki cross couplinga
Entry ArB(OH)2 Product
Solvent
Base
Yield(%)
The reaction is remarkably fast and in most cases the conversion
was quantitative within 30 min. Although the moderate yields of
this cross-coupling reaction can be ascribed partly to the reductive
dehalogention, our preliminary experiments also showed that the
cleavage of the N-glycosidic bond could be one of important side
reactions.
Seven C-6 substituted products (i.e., 13a,b,f,g,h,k and m) were
used for subsequent transformations. For the synthesis of the
unsaturated NPs, compounds 13 were first treated with TMSBr
in dichloromethane. In the case of compound 13a, it was possible
to isolate the product of the partial deprotection 19a (1H-NMR
and HR-MS), which, however, underwent spontaneous decom-
position during the 13C-NMR measurement in D2O overnight.
The isopropylidene group of 19a could be removed by treatment
with aqueous trifluoroacetic acid (TFA) to give the desired
1.
2.
3.
4.
5.
6.
7.
8.
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
10b
13b
13b
13b
13b
13b
13b
13b
13b
13b
13b
13b
13b
13b
13b
13b
CH3CN–H2O
H2O
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsF
K3PO4
NaHCO3 41
NaOH
KOAc
Et3N
43
2
EtOH–H2O
MeOH–H2O
iPrOH/H2O
tBuOH/H2O
Dioxane/H2O
PrOH/H2O
PrOH/H2O
PrOH/H2O
PrOH/H2O
PrOH/H2O
PrOH/H2O
PrOH/H2O
PrOH/H2O
52
61
58
50
43
63
57
72
9.
10.
11.
12.
13.
14.
15.
0
30
55
54
K2CO3
a Yield determined by quantitative 31P NMR.
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Table 7 The yields of saturated compounds 21 and final NPs 20 and 22
phosphonate 20a. For the other examples, the isolation of the
intermediate 19 was omitted and the reaction with TMSBr was
directly followed by hydrolysis of the acetonide with TFA.
The saturated analogues were obtained by catalytic hydrogena-
tion of the coupling products 13 on Pd(OH)2/C. This step afforded
excellent yields of intermediates 21 that were subsequently depro-
tected by identical procedure as used above. Both double bonds
of the compounds 13m were hydrogenated to give product 21n,
which was further converted to the free phosphonate 22n. The
purity of the final products 20 and 22 was determined by LC-
MS. Compounds that did not meet 95% purity were purified by
reversed-phase HPLC. The yields of compounds 20, 21 and 22 (see
Scheme 5) are summarized in Table 7.
Yields of compounds (%)a
Derivative
20
21
22
a
b
f
g
h
k
m
n
40%
91%
87%
96%
77%
46%
95%
—
90%
88%
88%
97%
82%
95%
—
21%
81%
30%
94%
49%
71%
—
99%
93%
a Isolated yield.
Table 8 1H-NMR derived mole fraction of the N-type conformer of 5,
22a and 9b at different temperatures
% N
T/◦C
5
22a
9b
20
27
35
42
50
60
55.5
54.8
54.4
54.1
54.0
—
74.7
74.2
73.6
73.0
73.0
—
—
64.3
65.3
60.5
58.5
58.7
To assess the impact of the presence of a substituent at the C-6
position of the uracil base on the relative proportions of Northern
and Southern conformers, these scalar couplings were measured at
five different temperatures for the 6-naphthyl substituted uridine
(9b) and the 6-phenyl substituted uridine phosphonate (22a),
while the same was done for the non-C-6 substituted uridine
phosphonate (5). The fraction of the N-type conformer was
obtained by minimizing the sum of square difference between
the experimental couplings and those calculated from the above
equations. The results are shown in Table 8.
For 5, the Northern and Southern conformers are nearly equally
present, with a small preference for the Northern. For both C-
6 substituted nucleotides, this preference increases significantly,
while an increase in temperature makes it decrease.
A second aspect of the conformation is the orientation of the
base relative to the ring structure, which is here assumed to be
either syn (with the substituent pointing away from the ring) or
anti (with the substituent pointing towards the ring). For all three
nucleotides, 2D NOESY spectra were recorded to study the nOe
contacts between the base protons and the ribofuranse protons.
In the case of 5, the H6 proton can only come close enough to
the H3¢ and the H5¢ protons to provide a nOe contact when the
anti rotamer is adopted. The NOESY spectrum indeed shows
clear cross-peaks from the H6 proton to the H3¢ and both H5¢
protons, indeed confirming that the anti rotamer can be adopted.
The NOESY spectrum indeed shows clear cross¢peaks with the H3¢
and both H5¢ protons, indeed confirming that the anti rotamer can
be adopted. In the case of 22a, the anti rotamer is expected to lead
to strong nOe contacts with protons of the phenyl group, while in
the syn rotamer the fenyl group will be oriented too far away from
the H3¢ and certainly the H5¢ protons. Only nOe contacts from
the ortho and meta protons to H1¢ and from the ortho protons to
H2¢ are observed in the NOESY, demonstrating that in this case
Scheme 5 Deprotection and hydrogenation-deprotection steps.
For nucleotides, it is known that the five membered ring
structure can be in equilibrium between two favored puckering
conformations, labeled the North (N) and South (S) state.16 Davies
et al.17 have derived a simple set of equations that relate the fraction
of the Northern conformer XN with the values of the three vicinal
scalar couplings that can be measured between the protons of the
ring:
JH1¢,H2¢ = 9.3(1 - XN )
JH2¢,H3¢ = 4.6XN + 5.3 (1 - XN )
JH3¢,H4¢ = 9.3XN
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only the syn rotamer is available. This demonstrates that bulky
substituents at the C-6 position of the base strongly limit the
rotational freedom of the C1¢–N1 bond. Similar results are found
for 9b, where only nOe contacts are detected between H1¢ and
both the H2¢¢ and H10¢¢ protons of the naphthyl group, and a weak
contact between H2¢ and H2¢¢. ESI Fig. S4† gives an overview of
all observed nOe contacts.
0.068 mmol) were suspended in toluene or o-xylene (4 cm3) and
added to a bath preheated to 100 ◦C or 140 ◦C (see Table 1). After
2 min., degassed water (0.9 cm3) was added and the mixture was
heated for an additional 45 min. Then, the reaction mixture was
poured onto saturated aqueous NH4Cl (7 cm3) and extracted with
EtOAc (3 ¥ 15 cm3). The organic layers were combined and dried
over MgSO4. Evaporation afforded the crude product that was
purified on a silica gel column (EtOAc : Hexanes, 1 : 1).
Conclusions
Synthesis of unprotected nucleosides 9a–d: General procedure
Two synthetic procedures are described for the preparation of
C-6 substituted NPs as derivatives of lead compound 5. In a
first approach a Suzuki–Miyaura cross coupling of protected
nucleoside analogue 7 was performed under classical conditions
using Pd(dppf)Cl2·CH2Cl2 as the catalyst and a mixture of toluene
or o-xylene with water as solvent. This method mostly afforded
good yields of the C-6 arylated products 8, which could be
further converted to the desired NPs as demonstrated for 8a,
or deprotected to the free C-6 substituted nucleosides 9. This
approach offers one of the rare alternatives to Stille coupling
for the synthesis of C-6 substituted derivatives of uridine and
its phosphonate analogues. Since it was desirable to realize the
C-6 derivatisation in the later stage of the synthesis, however,
a more divergent synthetic route was developed for the NPs 20
and 22. Towards this end, we first optimized the preparation of
the key intermediate 18, which was then used in the subsequent
Suzuki–Miyaura coupling. Intriguingly, carrying out this reaction
under aerobic and ligand-free conditions proved to be the most
convenient in this case. Seven C-6 substituted products were
further converted to the desired unsaturated and saturated NPs
20 and 22, respectively. This way, 14 new analogues of lead
compound 5 were obtained. As far as we know, this is the first
example of an aerobic, ligand-free Suzuki–Miyaura cross coupling
reaction applied for the preparation of molecules with this level of
complexity.
The protected nucleoside 8 (0.3 mmol) was suspended in a mixture
of water (1 cm3) and TFA (1.5 cm3) at 0 ◦C and the resulting
mixture was stirred at rt in the dark for 3 h. The solvents were
evaporated and co-distilled with water (2 ¥ 5 cm3) and EtOH (2 ¥
5 cm3). Column chromatography (EtOAc : Acetone : EtOH : water,
20 : 3 : 1 : 1) of the crude product afforded the desired nucleoside 9.
Synthesis of partially unprotected nucleosides 11 and 16: General
procedure
The silylated compound 7 or 8a (4 mmol) was dissolved in
methanol (25 cm3) and treated with NH4F (1.48 g, 40 mmol) for
48 h. The solvent was evaporated and the residue was partioned
between EtOAc (100 cm3) and water (60 cm3). The water phase
was extracted with EtOAc (4 ¥ 100 cm3). The organic phases were
combined, dried over Mg2SO4 and evaporated. The residue was
chromatographed on a silica gel column (EtOAc : Toluene, 10 : 1)
to give the desired alcohols 11 (form 8a, white solid, 1.05 g, 73%)
and 16 (from 7, white foam, 1.16 g, 71%).
1-((3aR,4R,6R,6aR)-6-(Hydroxymethyl)-2,2-dimethyltetra-
hydrofuro[3,4-d][1,3]dioxol-4-yl)-6-phenylpyrimidine-2,4
(1H,3H)-dione 12
IBX (2.15 g, 7.7 mmol) was added to the stirred solution of the 6-
phenyluridine derivative 11 (920 mg, 2.6 mmol) in CH3CN (22 cm3)
and the resulting slurry was heated at 80 ◦C for 4 h. The reaction
mixture was cooled to 0 ◦C for 30 min, solids were filtered off and
the filtrate cake was washed several times with cold CH3CN. Then,
the collected filtrates were evaporated and the residue was purified
by column chromatography (EtOAc : Toluene, 10 : 1) to afford
aldehyde 12 (0.9 g, 98%) as slightly opalescent colorless oil.
Experimental
Chemical Synthesis
Chemicals were obtained from commercial sources (Acros Or-
ganics, Sigma-Aldrich and Alfa Aesar) or prepared according to
published procedures. NMR spectra were recorded at room tem-
perature on a Varian Mercury 300 spectrometer. Chemical shifts
are quoted in ppm relative to residual solvent peaks as appropriate.
Exact mass measurements were performed on a Waters LCT
Premier XETM Time of flight (TOF) mass spectrometer equipped
with a standard electrospray ionization and modular LockSpray
TM interface. Samples were infused in a CH3CN–water (1 : 1)
mixture at 10 mL min-1. The purity of the final phosphonic acids
was assessed by HPLC and PDA detection (190–400 nm) using
a reverse phase column (Phenomenex Luna 2.5 mm C18(2)-HST,
100 ¥ 2.00 mm) with a linear gradient of 10–100% B over 9 min,
where A is 0.1% formic acid in H2O and B is 0.1% formic acid in
CH3CN at a flow rate of 0.4 mL min-1).
Diethyl (E)-2-((3aR,4R,6R,6aR)-6-(2,4-dioxo-6-phenyl-3,4-
dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)vinylphosphonate 13a
A solution of aldehyde 12 (0.9 g, 2.5 mmol) in THF (10 cm3)
was added to the stirred solution of freshly prepared sodium salt
of bisphosphonate 14 (prepared by addition of bisphosphonate
14 (1.35 cm3, 5.5 mmol) to the stirred suspension of NaH (60%
dispersion in mineral oil, 211 mg, 5.3 mmol) and stirring of the
resulting suspension for 30 min) under argon atmosphere. The
mixture was stirred overnight and subsequently evaporated to half
its volume, diluted with EtOH (3 cm3) and adsorbed onto silica
gel. Column chromatography (EtOAc : Acetone : EtOH : water,
42 : 6 : 1 : 1) afforded the desired phosphonate 13a (765 mg, 61%)
as colorless oil.
Synthesis of compounds 8a–e: General procedure
Compound 4 (100 mg, 0.19 mmol), boronic acid (0.30 mmol),
K2CO3 (38.5 mg, 0.28 mmol) and Pd(dppf)Cl2·CH2Cl2 (5.6 mg,
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Diethyl (E)-2-((3aR,4R,6R,6aR)-6-(6-iodo-2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)vinylphosphonate 18
7.55–7.58 (3 H, m, Ar), 11.62 (1 H, s, NH); dC(75 MHz; DMSO-d6;
DMSO) 16.18, 16.25, 24.99, 26.79, 61.31 (d, J 5.4), 61.36 (d, J 5.4),
84.33, 84.51, 88.64 (d, J 24.3), 92.52, 103.63, 112.75, 118.87 (d,
J 182.4), 128.16, 129.04 (2C, s), 130.37, 132.69, 149.02 (d, J 5.5),
150.78, 155.04, 162.26; dP(121 MHz; DMSO-d6; H3PO4) 17.59;
m/z 493.1740 (ESI) (M+H+. C23H30N2O8P+ requires 493.1734).
IBX (2.94 g, 10.5 mmol) was added to a solution of 16 (1.43 g,
3.5 mmol) in CH3CN and the resulting suspension was stirred at
85 ◦C for 4 h. After cooling in an ice bath (15 min), the solid was
removed by filtration and washed with cold CH3CN (2 ¥ 15 cm3).
The solvent was evaporated and the residue was co-distilled with
toluene (2 ¥ 30 cm3). The obtained crude aldehyde was dissolved
in dry THF (25 cm3) under argon. The salt of bisphosphonate 14
was freshly prepared by addition of the latter (2.6 cm3, 10.5 mmol)
to a suspension NaH (417 mg, 10.5 mmol) in THF (25 cm3) and
stirring for 30 min. The solution of the aldehyde was added to the
Diethyl (E)-2-((3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-(naphtha-len-
2-yl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetra-
hydrofuro[3,4-d][1,3]dioxol-4-yl)vinylphosphonate 13b
Phosphonate 13b was obtained as a colorless oil (64 mg,
64%) dH(300 MHz; DMSO-d6; Me4Si) 1.20–1.30 (12 H, m,
2¥OCH2CH3+ 2¥CH3), 3.99 (4 H, m, 2 ¥ CH2), 4.51 (1 H, m,
4¢-H), 4.85 (1 H, dd, J3¢,2¢ 6.2, J3¢,4¢ 4.0, 3¢-H), 5.32 (1 H, br d,
J2¢,3¢ 5.5, 2¢-H), 5.38 (1 H, s, 1¢-H), 5.68 (1 H, d, J5,NH 2.1, 5-H),
6.03 (1 H, ddd, J6¢,4¢ < 1, J6¢,5¢ 17.4, J6¢,P 19.3, 6¢-H), 6.74 (1 H,
ddd, J5¢,4¢ 6.4, J5¢,6¢ 17.2, JH5¢,P 23.3, 5¢-H), 7.57–7.69 (3 H, m, Ar),
8.02–8.12 (4 H, m, Ar), 11.67 (1 H, d, J2¢,3¢ 2.0,NH); dC(75 MHz;
DMSO-d6; DMSO) 16.18, 16.25, 24.95, 26.73, 61.32 (d, J 5.5),
61.37 (d, J 5.5), 84.40, 84.50, 88.68 (d, J 24.9), 92.64, 103.99,
112.77, 118.87 (d, J 183.0), 127.27, 127.80, 128.09, 128.48, 128.52,
130.07, 132.38, 133.18, 149.01 (d, J 5.5), 150.77, 155.05, 162.23;
dP(121 MHz; DMSO-d6; H3PO4) 17.60 (s); m/z 543.1892 (ESI)
(M+H+. C27H32N2O8P+ requires 543.1891).
◦
resulting mixture at 0 C and stirring was continued for another
2.5 h at the 0 ◦C. Then, a solution of NH4Cl (100 cm3) was added
and the mixture was extracted with EtOAc (3 ¥ 200 cm3). The
combined organic layers were washed with saturated solution of
NaHCO3 (100 cm3), dried over MgSO4 and evaporated to dryness.
Chromatography on a silica gel column (EtOAc : Hexanes, 20 : 1)
afforded the desired phosphonate 18 (818 mg, 43%). dH(300 MHz;
DMSO-d6; Me4Si) 1.22 (6 H, t, J 7.0, 2¥OCH2CH3), 1.30 (3 H, s,
CH3), 1.51 (3 H, s, CH3), 3.92 (4 H, m, 2 ¥ CH2), 4.64 (1 H, m,
4¢-H), 4.84 (1 H, dd, J3¢,2¢ 6.2, J3¢,4¢ 3.8, 3¢-H), 5.28 (1 H, d, J2¢,3¢
6.7, 2¢-H), 5.96 (1 H, ddd, J6¢,4¢ 1.2, J6¢,5¢ 17.0, J6¢,P 19.9, 6¢-H), 6.05
(1 H, s, 1¢-H), 6.37 (1 H, d, J 2.1, 5-H), 6.66 (1 H, ddd, J5¢,4¢ 6.5,
J
5¢,6¢ 17.0, JH5¢,P 21.7, 5¢-H), 11.66 (1 H, d, J 1.8, NH); dC(75 MHz;
Diethyl (E)-2-((3aR,4R,6R,6aR)-6-(6-(furan-2-yl)-2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro
[3,4-d][1,3]dioxol-4-yl)vinylphosphonate 13d
DMSO-d6; DMSO) 16.15 (s), 16.23 (s), 25.08 (s), 26.92 (s), 61.34
(d, J 4.5), 61.35 (d, J 4.5), 84.45 (2C, s), 88.84 (d, J 24.1), 100.72
(s), 112.96 (s), 115.45 (s), 116.51(s), 118.82 (d, J 183.0), 147.76
(s), 148.82 (d, J 5.3), 161.50 (s); dP(121 MHz; DMSO-d6; H3PO4)
17.47 (s); m/z 543.0399 (ESI) (M+H+. C17H25IN2O8P+ requires
543.0388).
Phosphonate 13d was obtained as a colorless oil (21 mg, 24%)
dH(300 MHz; DMSO-d6; Me4Si) 1.22 (6 H, t, J 7.0, 2¥OCH2CH3),
1.28 (3 H, s, CH3), 1.43 (3 H, s, CH3), 3.96 (4 H, m, 2 ¥ CH2), 4.63
(1 H, m, 4¢-H), 4.88 (1 H, dd, J3¢,2¢ 6.2, J3¢,4¢ 3.8, 3¢-H), 5.30 (1 H, d,
J
2¢,3¢ 6.6, 2¢-H), 5.65 (1 H, s, 1¢-H), 5.84 (1 H, d, J2¢,3¢ 2.2, 5-H), 5.99
Synthesis of nucleoside phosphonates 13 by ligandless Suzuki
cross-coupling: General procedure
(1 H, ddd, J6¢,4¢ 1.3, J6¢,5¢ 17.1, J6¢,P 20.1, 6¢-H), 6.72 (1 H, ddd, J5¢,4¢
6.5, J5¢,6¢ 17.1, JH5¢,P 21.7, 5¢-H), 6.76 (1 H, dd, J 3.5, J 1.8, Ar), 7.09
(1H, dd, J 3.5, J 0.7, Ar), 8.03 (1H, dd, J 1.8, J 0.7,Ar), 11.64 (1 H,
d, J 1.8, NH); dC(75 MHz; DMSO-d6; DMSO) 16.14, 16.23, 25.04,
26.85, 61.30 (d, J 5.8), 61.35 (d, J 5.7), 84.55, 88.90 (d, J 24.2),
93.09, 102.59, 112.40, 112.73, 114.94, 118.72 (d, J 183.3), 144.05,
144.16, 149.09 (d, J 5.5), 150.64, 162.23; dP(121 MHz; DMSO-
d6; H3PO4) 17.48; m/z 483.1516 (ESI) (M+H+. C21H28N2O9P+
requires 483.1526).
In a test tube opened to air, a mixture of iodophosphonate 18
(100 mg, 0.18 mmol), K3PO4 (78 mg, 0.36 mmol), boronic acid
(0.27 mmol) and Pd(AcO)2 (2 mg, 9 mmol) in n-PrOH (1 cm3)
and H2O (1 cm3) was stirred at 50 ◦C for 30 min. Brine was added
(5 cm3) and the mixture was extracted with EtOAc (3 ¥ 15 cm3). The
organic layers were combined, dried over MgSO4 and evaporated.
The crude product was purified by column chromatography
(EtOAc : Acetone : EtOH : H2O, 42 : 6 : 1 : 1), dissolved in MeOH
(5 cm3), treated with activated charcoal (10 mg) overnight, and
filtered through a silica gel pad yielding the cross coupling
products 13.
Diethyl (E)-2-((3aR,4R,6R,6aR)-6-(2,4-dioxo-6-m-tolyl-3,4-
dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)vinylphosphonate 13f
Phosphonate 13f was obtained as a colorless oil (49.5 mg,
53%) dH(300 MHz; DMSO-d6; Me4Si) 1.21 (6 H, t, J 7.1,
2¥OCH2CH3), 1.22 (3 H, s, CH3), 1.32 (3 H, s, CH3), 3.97
(4 H, m, 2¥CH2), 4.51 (1 H, m, 4¢-H), 4.83 (1H, dd, J3¢,2¢ 6.2,
J3¢,4¢ 3.8, 3¢-H), 5.28 (1H, d, J2¢,3¢ 6.2, 2¢-H), 5.36 (1H, s, 1¢-
H), 5.53 (1H, s, 5-H), 6.00 (1H, ddd, J6¢,4¢ 1.2, J6¢,5¢ 17.0, J6¢,P
20.1, 6¢-H), 6.72 (1H, ddd, J5¢,4¢ 6.6, J5¢,6¢ 17.0, J5¢,P 22.0, 5¢-
H), 7.33–7.45 (4H, m, Ar), 11.61 (1H, s, NH); dC(75 MHz;
DMSO-d6; DMSO) 16.16, 16.24, 24.96, 26.76, 61.31 (d, J 5.3),
61.38 (d, J 5.4), 84.33, 84.50, 88.58 (d, J 14.3), 90.51,103.46,
112.76, 118.86 (d, J 183.0), 125.17, 128.82, 130.98, 132.58,
Diethyl (E)-2-((3aR,4R,6R,6aR)-6-(2,4-dioxo-6-phenyl-3,4-
dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)vinylphosphonate 13a
The title compound was obtained as a colorless oil (41 mg, 45%)
dH(300 MHz; DMSO-d6; Me4Si) 1.24 (6 H, t, J 6.9, 2¥OCH2CH3),
1.24 (3 H, s, CH3), 1.32 (3 H, s, CH3), 3.97 (4 H, m, 2 ¥ CH2),
4.51 (1 H, m, 4¢-H), 4.83 (1 H, dd, J3¢,2¢ 6.1, J3¢,4¢ 4.0, 3¢-H), 5.28
(1 H, d, J2¢,3¢ 6.4, 2¢-H), 5.32 (1 H, s, 1¢-H), 5.54 (1 H, s, 5-H),
6.01 (1 H, ddd, J6¢,4¢ 1.3, J6¢,5¢ 17.3, J6¢,P 20.3, 6¢-H), 6.72 (1 H,
ddd, J5¢,4¢ 6.7, J5¢,6¢ 17.0, JH5¢,P 21.6, 5¢-H), 7.48–7.51 (2 H, m, Ar),
5240 | Org. Biomol. Chem., 2010, 8, 5234–5246
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138.55, 148.99 (d, J 5.0), 150.73, 155.18, 162.19; dP(121 MHz;
DMSO-d6; H3PO4) 17.58; m/z (ESI) 507.1901 (M+H+.
C24H32N2O8P+ requires 507.1891).
DMSO-d6; H3PO4) 17.54 (s); m/z 517.1747 (negESI) (M - H+.
C25H30N2O8P+ requires 517.1745).
Diethyl (E)-2-((3aR,4R,6R,6aR)-6-(2,4-dioxo-6-p-tolyl-3,4-
dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)vinylphosphonate 13k
Diethyl (E)-2-((3aR,4R,6R,6aR)-6-(6-(3-methoxyphenyl)-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetra-
hydrofuro[3,4-d][1,3]dioxol-4-yl)vinylphosphonate 13g
Phosphonate 13k was obtained as a colorless oil (48.5 mg, 52%)
dH(300 MHz; DMSO-d6; Me4Si) 1.22 (6H, t, J 7.1, 2¥OCH2CH3),
1.26 (3H, s, CH3), 1.31 (3 H, s, CH3), 3.97 (4H, m, 2¥CH2), 4.49
(1 H, m, H4¢), 4.81 (1H, dd, J3¢,2¢ 6.2, J3¢,4¢ 4.1 Hz, 3¢-H), 5.25 (1H,
d, J2¢,3¢ 6.2, 2¢-H), 5.35 (1H, s, 1¢-H), 5.50 (1H, d, J5,NH 2.0, 5-H),
6.01 (1H, ddd, J6¢,4¢ 1.2, J6¢,5¢ 17.2, J6¢,P 20.2 Hz, 6¢-H), 6.72 (1H,
ddd, J5¢,4¢ 6.5, J5¢,6¢ 17.2, J5¢,P 21.7, 5¢-H), 7.37 (4H, br d, J 1.3, Ar),
11.57 (1H, d, JNH,5 1.3, NH); dC(75 MHz; DMSO-d6; DMSO)
16.16, 16.24, 20.89, 24.94, 26.80, 61.30 (d, J 3.9), 61.38 (d, J 3.9),
84.40, 84.51, 88.66 (d, J 23.8), 92.40, 103.44, 112.76, 118.84 (d, J
182.4), 128.05, 129.56, 129.78, 140.24, 149.03 (d, J 5.5), 150.79,
155.20, 162.21; dP(121 MHz; DMSO-d6; H3PO4) 17.60; m/z (ESI)
507.1887 (M+H+. C24H32N2O8P+ requires 507.1891).
Phosphonate 13g was obtained as a colorless oil (61 mg, 63%)
dH(300 MHz; DMSO-d6; Me4Si) 1.23 (6 H, t, J 7.1, 2¥OCH2CH3),
1.25 (3 H, s, CH3), 1.34 (3 H, s, CH3), 3.81 (3 H, s, OCH3), 3.94
(4 H, m, 2¥CH2), 4.52 (1 H, m, 4¢-H), 4.83 (1H, dd, J3¢,2¢ 6.2,
J
3¢,4¢ 3.8, 3¢-H), 5.29 (1H, d, J2¢,3¢ 6.6, 2¢-H), 5.36 (1H, s, 1¢-H), 5.58
(1H, s, 5-H), 6.00 (1H, ddd, J6¢,4¢ 1.2, J6¢,5¢ 17.2, J6¢,P 20.2, 6¢-H), 6.72
(1H, ddd, J5¢,4¢ 6.5, J5¢,6¢ 17.0, J5¢,P 21.7, 5¢-H), 7.02–7.16 (3H, m,
Ar), 7.47 (1H, dd, J 8.2, J 7.9, Ar), 11.61 (1H, s, NH); dC(75 MHz;
DMSO-d6; DMSO) 16.16, 16.24, 24.99, 26.79, 55.30, 61.30 (d, J
6.1), 61.36 (d, J 5.8), 84.34, 84.44, 88.54 (d, J 24.6), 92.51, 103.46,
112.79, 113.67, 118.86 (d, J 183.2), 120.06, 130.27, 133.83, 148.97
(d, J 5.3), 150.71, 154.82, 159.24, 162.22; dP(121 MHz; DMSO-
d6; H3PO4) 17.52; m/z (ESI) 523.1845 (M+H+. C24H32N2O9P+
requires 523.1840).
Diethyl (E)-2-((3aR,4R,6R,6aR)-6-(6-(1H-indol-5-yl)-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetra-hydrofuro[3,4-
d][1,3]dioxol-4-yl)vinylphosphonate 13l
Diethyl (E)-2-((3aR,4R,6R,6aR)-6-(6-(4-fluorophenyl)-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetra-hydrofuro[3,4-
d][1,3]dioxol-4-yl)vinylphosphonate 13h
Phosphonate 13l was obtained as a colorless oil (63 mg,
64%) dH(300 MHz; DMSO-d6; Me4Si) 1.21–1.27 (9 H, m,
2¥OCH2CH3+CH3), 1.28 (3 H, s, CH3), 3.98 (4 H, m, 2 ¥ CH2),
4.49 (1 H, m, 4¢-H), 4.83 (1 H, dd, J3¢,2¢ 5.9, J3¢,4¢ 4.1, 3¢-H), 5.27
(1 H, d, J2¢,3¢ 6.1, 2¢-H), 5.35 (1 H, s, 1¢-H), 5.52 (1 H, d, J5,NH 2.3 Hz,
5-H), 6.02 (1 H, ddd, J6¢,4¢ < 1, J6¢,5¢ 17.6, J6¢,P 19.4, 6¢-H), 6.56 (1 H,
br s, Ar), 6.74 (1 H, ddd, J5¢,4¢ 6.7, J5¢,6¢ 17.3, J5¢,P 22.0, 5¢-H), 7.17
(1 H, br d, J 8.2, Ar), 7.50 (1 H, t, J 2.6, Ar), 7.50 (1 H, t, J 2.6, Ar),
7.55 (1 H, d, J 8.5, Ar), 7.69 (1 H, s, Ar), 11.45 (1 H, s, NH), 11.55
(1 H, s, NH); dC(75 MHz; DMSO-d6; DMSO) 16.20 (d, J 6.1),
24.93, 26.77, 61.31 (d, J 5.1), 61.36 (d, J 5.2), 84.50, 84.59, 88.63
(d, J 23.2), 92.37, 101.89, 103.39, 104.30, 111.91, 112.72, 118.83
(d, J 182.4), 123.25, 127.22, 127.39, 149.20 (d, J 5.4), 150.95,
156.87, 162.26; dP(121 MHz; DMSO-d6; H3PO4) 17.62 (s); m/z
(ESI) 532.1837 (M+H+. C25H31N3O8P+ requires 532.1843).
Phosphonate 13h was obtained as a colorless oil (48 mg, 51%)
dH(300 MHz; DMSO-d6; Me4Si) 1.24 (6 H, t, J 7.0, 2¥OCH2CH3),
1.25 (3 H, s, CH3), 1.33 (3 H, s, CH3), 3.98 (4 H, m, 2 ¥ CH2), 4.53
(1 H, m, 4¢-H), 4.84 (1 H, dd, J3¢,2¢ 6.2, J3¢,4¢ 4.1, 3¢-H), 5.28 (1 H, d,
J
2¢,3¢ 6.2, 2¢-H), 5.29 (1 H, s, 1¢-H), 5.57 (1 H, d, J5,NH 2.1 Hz, 5-H),
6.02 (1 H, ddd, J6¢,4¢ 1.2, J6¢,5¢ 17.0, J6¢,P 20.2, 6¢-H), 6.73 (1 H, ddd,
J5¢,4¢ 6.4, J5¢,6¢ 17.0, JH5¢,P 23.4, 5¢-H), 7.42 (2 H, t, J 9.0, Ar), 7.58
(2 H, m, Ar), 11.61 (1 H, d, J 1.5, NH); dC(75 MHz; DMSO-d6;
DMSO) 16.16, 16.24, 24.94, 26.78, 61.31 (d, J 5.3), 61.36 (d, J
5.2), 84.30, 84.50, 88.68 (d, J 24.3), 92.56, 103.92, 112.75, 116.14
(2C, d, J 22.1), 118.81 (d, J 182.4), 129.07 (d, J 3.3), 130.76 (d, J
8.8), 149.00 (d, J 5.5), 150.71, 154.09, 162.15, 163.01 (d, J 248.2);
dP(121 MHz; DMSO-d6; H3PO4) 17.56; dF(282 MHz; DMSO-
d6; CCl3F) 90.18 (s); m/z (ESI) 511.1644 (M+H+. C25H32N2O8P+
requires 511.1640).
Diethyl (E)-2-((3aR,4R,6R,6aR)-6-(2,4-dioxo-6-styryl-3,4-
dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)vinylphosphonate 13m
Diethyl (E)-2-((3aR,4R,6R,6aR)-6-(2,4-dioxo-6-(1-phenyl-vinyl)-
3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetra-hydrofuro[3,4-
d][1,3]dioxol-4-yl)vinylphosphonate 13i
Phosphonate 13m was obtained as a colorless oil (76.5 mg, 80%)
dH(300 MHz; DMSO-d6; Me4Si) 1.22 (6 H, t, J 7.0, 2¥OCH2CH3),
1.28 (3 H, s, CH3), 1.46 (3 H, s, CH3), 3.96 (4 H, m, 2 ¥ CH2),
4.63 (1 H, m, 4¢-H), 4.86 (1 H, dd, J3¢,2¢ 6.2, J3¢,4¢ 4.1, 3¢-H), 5.29
(1 H, d, J2¢,3¢ 6.4, 2¢-H), 5.79 (1 H, s, 1¢-H), 5.85 (1 H, d, J5,NH
2.3 Hz, 5-H), 5.99 (1 H, ddd, J6¢,4¢ 1.5, J6¢,5¢ 17.3, J6¢,P 19.7, 6¢-
H), 6.71 (1 H, ddd, J5¢,4¢ 6.2, J5¢,6¢ 17.0, JH5¢,P 23.1, 5¢-H), 7.09
(1 H, d, J 15.8, CH CH–Ph), 7.30 (1 H, d, J 16.1, CH CH–
Ph), 7.39–7.47 (3 H, m, Ar), 7.68 (2 H, m, Ar), 11.49 (1 H, s,
NH); dC(75 MHz; DMSO-d6; DMSO) 16.15, 16.23, 25.01, 26.90,
61.30 (d, J 5.3), 61.36 (d, J 5.2), 84.24, 84.35, 88.31 (d, J 24.3),
91.81, 100.67, 112.94, 118.56 (d, J 183.6), 118.88, 127.81, 128.88,
129.59, 134.99, 138.42, 148.89 (d, J 5.0), 150.62, 153.00, 162.56;
dP(121 MHz; DMSO-d6; H3PO4) 17.53 (s); m/z 519.1889 (ESI)
(M+H+. C25H32N2O8P+ requires 519.1891).
Phosphonate 13i was obtained as a colorless oil (43 mg, 45%)
dH(300 MHz; DMSO-d6; Me4Si) 1.17 (3 H, s, CH3), 1.22 (6 H, t,
J 7.0, 2¥OCH2CH3), 1.28 (3 H, s, CH3), 3.95 (4 H, m, 2 ¥ CH2),
4.40 (1 H, m, 4¢-H), 4.77 (1 H, dd, J3¢,2¢ 6.2, J3¢,4¢ 4.0, 3¢-H), 5.12
(1 H, d, J2¢,3¢ 6.2, 2¢-H), 5.41 (1 H, s, 1¢-H), 5.60 (2 H, m, 5-H+
C
CHa), 5.92 (1 H, ddd, J6¢,4¢ 1.0, J6¢,5¢ 17.2, J6¢,P 20.1, 6¢-H), 6,15
(1 H, s, C CHb), 6.66 (1 H, ddd, J5¢,4¢ 6.6, J5¢,6¢ 17.2, JH5¢,P 21.7,
5¢-H), 7.37–7.45 (3 H, m, Ar), 7.49 –7.56 (2H, m, Ar), 11.64 (1 H,
d, J 1.8, NH); dC(75 MHz; DMSO-d6; DMSO) 16.15 (s), 16.23
(s), 25.04 (s), 26.75 (s), 61.28 (d, J 3.7), 61.35 (d, J 3.7), 84.35
(2C, s), 88.49 (d, J 24.4), 92.76 (s), 103.55 (s), 112.63 (s), 118.80
(d, J 182.9), 125.92(2C, s), 129.01 (2C, s), 135.24 (s), 140.49 (s),
149.03 (d, J 5.4), 150.55 (s), 154.45 (s), 162.56 (s); dP(121 MHz;
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Preparation of saturated nucleoside phosphonates 21: General
procedure
150.53, 155.31, 162.19; dP(121 MHz; DMSO-d6; H3PO4) 31.80;
m/z 509.2052 (ESI) (M+H+. C24H34N2O8P+ requires 509.2047).
The vinyl phosphonates 13 (0.2 mmol) were dissolved in MeOH
(5 cm3) and Pd(OH)2/C (12 mg) was added. The resulting suspen-
sion was stirred under hydrogen atmosphere for 48 h. The catalyst
was filtered off, and the filtrate was evaporated to dryness and pu-
rified by column chromatography (EtOAc : Acetone : EtOH : H2O,
42 : 6 : 1 : 1) to give the desired products 21.
Diethyl 2-((3aR,4R,6R,6aR)-6-(6-(3-methoxyphenyl)-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetra-hydrofuro[3,4-
d][1,3]dioxol-4-yl)ethylphosphonate 21g
The title compound was obtained from 13g (98 mg, 0.19 mmol) as
a colorless oil (96 mg, 97%) dH(300 MHz; DMSO-d6; Me4Si) 1.22
(6 H, t, J 7.2, 2¥OCH2CH3), 1.24 (3 H, s, CH3), 1.30 (3 H, s,
CH3), 1.71–1.87 (4 H, m, 5¢-H+6¢-H), 3.81 (4 H, m, 4¢-H +
OCH3), 3.97 (4 H, m, 2 ¥ CH2), 4.64 (1 H, dd, J3¢,2¢ 1.2, J3¢,4¢
6.4, 3¢-H), 5.25 (1 H, d, J2¢,3¢ 1.2, 2¢-H), 5.27 (1 H, s, 1¢-H),
5.53 (1 H, s, 5-H), 7.04–7.46 (5 H, m, Ar), 7.49 (5 H, t, J 8.2,
Ar), 11.57 (1 H, br s, NH); dC(75 MHz; DMSO-d6; DMSO)
16.22, 16.31, 20.87(d, J 140.8), 25.19, 25.74(d, J 4.9), 27.01,
55.27, 60.88 (d, J 2.9), 60.96 (d, J 2.9), 83.30, 83.87, 87.07 (d, J
17.4), 91.65, 103.36, 112.78, 113.48, 116.20, 120.18, 130.25, 133.92,
150.53, 154.96, 159.19, 162.23; dP(121 MHz; DMSO-d6; H3PO4)
31.80; m/z 525.2001 (ESI) (M+H+. C24H34N2O9P+ requires
525.1996).
Diethyl 2-((3aR,4R,6R,6aR)-6-(2,4-dioxo-6-phenyl-3,4-dihy-
dropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-d]
[1,3]dioxol-4-yl)ethylphosphonate 21a
The title compound was obtained from 13a (423 mg, 0.86 mmol)
as a colorless oil (383 mg, 90%) dH(300 MHz; DMSO-d6; Me4Si)
1.22 (6 H, t, J 7.1, 2¥OCH2CH3), 1.23 (3 H, s, CH3), 1.28 (3 H, s,
CH3), 1.80 (4H, m, 5¢-H+6¢-H), 3.88 (1 H, m, 4¢-H), 3.95 (4 H,
m, 2 ¥ CH2), 4.65 (1 H, dd, J3¢,2¢ 1.0, J3¢,4¢ 5.5, 3¢-H), 5.22 (1 H,
d, J2¢,3¢ 1.0, 2¢-H), 5.24 (1 H, s, 1¢-H), 5.53 (1 H, s, 5-H), 7.47–
7.57 (5 H, m, Ar), 11.58 (1 H, br s, NH); dC(75 MHz; DMSO-d6;
DMSO) 16.23, 16.31, 20.87(d, J 140.4), 25.18, 25.80(d, J 4.4),
27.00, 60.89 (d, J 2.7), 60.97 (d, J 2.7), 83.34, 83.84, 87.18 (d,
J 18.0), 93.09, 102.59, 112.73, 128.09, 128.99, 130.34, 132.74,
150.54, 155.18, 162.18; dP(121 MHz; DMSO-d6; H3PO4) 31.81;
m/z 495.1891 (ESI) (M+H+. C23H30N2O8P+ requires 495.1891).
Diethyl 2-((3aR,4R,6R,6aR)-6-(6-(4-fluorophenyl)-2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydro-furo[3,4-
d][1,3]dioxol-4-yl)ethylphosphonate 13h
The title compound was obtained from 21h (55 mg, 0.11 mmol)
as a colorless oil (45 mg, 82%) dH(300 MHz; DMSO-d6; Me4Si)
1.22 (6 H, t, J 7.0, 2¥OCH2CH3), 1.23 (3 H, s, CH3), 1.29 (3 H, s,
CH3), 1.72–1.88 (4 H, m, 5¢-H+6¢-H), 3.84 (1 H,dd, J 6.8, J 11.4,
4¢-H), 3.97 (4 H, m, 2 ¥ CH2), 4.65 (1 H, dd, J3¢,2¢ 6.2 Hz, J3¢,4¢ 4.7,
3¢-H), 5.19 (1 H, d, J1¢,2¢ 1.2, 1¢-H), 5.24 (1 H, dd, J2¢,1¢ 1.2, J2¢,3¢ 6.4,
2¢-H), 5.54 (1 H, s, 5-H), 7.36–7.45 (2 H, m, Ar), 7.53–7.58 (2 H,
m, Ar), 11.59 (1 H, s, NH); dC(75 MHz; DMSO-d6; DMSO) 16.23,
16.30, 20.88 (d, J 140.4), 25.18, 25.83 (d, J 4.5), 27.00, 60.88 (d, J
2.5), 60.96 (d, J 2.5), 83.35, 83.80, 87.25 (d, J 18.3), 91.70, 103.83,
112. 67, 116.10 (2C, d, J 21.8), 129.16 (2C, d, J 3.3), 130.76 (d, J
7.7), 150.53, 154.17, 162.17, 162.98 (2C, d, J 248.2); dP(121 MHz;
DMSO-d6; H3PO4) 31.82; dP(282 MHz; DMSO-d6; CCl3F)
90.13; m/z 513.1797 (ESI) (M+H+. C23H31FN2O8P+ requires
513.1797).
Diethyl 2-((3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-(naphthalen-2-yl)-
2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydro-furo[3,4-
d][1,3]dioxol-4-yl)ethylphosphonate 21b
The title compound was obtained from 13b (126 mg, 0.23 mmol) as
a colorless oil (111 mg, 88%) dH(300 MHz; DMSO-d6; Me4Si) 1.22
(12 H, m, 2¥OCH2CH3 + 2¥CH3), 1.75–1.90 (4H, m, 5¢-H+6¢-H),
3.82 (1 H, m, 4¢-H), 3.98 (4 H, m, 2 ¥ CH2), 4.66 (1 H, dd, J3¢,2¢
4.7, J3¢,4¢ 5.8, 3¢-H), 5.23 (2 H, br s, 2¢-H+1¢-H), 5.66 (1 H, s, 5-H),
7.55–7.69 (3 H, m, Ar), 8.01–8.11 (4 H, m, Ar), 11.62 (1 H, br s,
NH); dC(75 MHz; DMSO-d6; DMSO) 16.23, 16.31, 20.86(d, J
140.4), 25.15, 25.77, 26.95, 60.88 (d, J 2.5), 60.97 (d, J 2.4), 83.34,
83.91, 87.17 (d, J 17.1), 91.76 (s), 103.88 (s), 112.69 (s), 127.24 (s),
127.78 (2C, s), 128.44 (2C, s), 128.44 (2C, s), 130.15 (s), 132.35 (s),
133.16 (s), 150.58 (s), 155.16 (s), 162.22 (s); dP(121 MHz; DMSO-
d6; H3PO4) 31.75 (s); m/z 545.2045 (ESI) (M+H+. C27H34N2O8P+
requires 545.2047).
Diethyl 2-((3aR,4R,6R,6aR)-6-(2,4-dioxo-6-p-tolyl-3,4-dihy-
dropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-d]
[1,3]dioxol-4-yl)ethylphosphonate 21k
Diethyl 2-((3aR,4R,6R,6aR)-6-(2,4-dioxo-6-m-tolyl-3,4-
dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)ethylphosphonate 21f
The title compound was obtained from 13k (98 mg, 0.19 mmol)
as a colorless oil (93 mg, 95%) dH(300 MHz; DMSO-d6; Me4Si)
1.22 (6 H, t, J 7.0, 2¥OCH2CH3), 1.23 (3 H, s, CH3), 1.30 (3 H, s,
CH3), 1.72–1.85 (4 H, m, 5¢-H+6¢-H), 2.38 (3 H, s, CH3), 3.56
(1 H,dd, J4¢,3¢5.9, J4¢,3¢ 10.5, 4¢-H), 3.97 (4 H, m, 2 ¥ CH2), 4.65
(1 H, dd, J3¢,2¢ 6.4 Hz, J3¢,4¢ 5.9, 3¢-H), 5.22 (1 H, d, J2¢,3¢ 6.4, 2¢-
H), 5.28 (1 H, s, 1¢-H), 5.49 (1 H, d, J5,NH 2.3, 5-H), 7.36 (4 H,
m, Ar), 11.55 (1 H, d, JNH, H5 2.3, NH); dC(75 MHz; DMSO-d6;
DMSO) 16.22, 16.30, 20.86 (d, J 140.4), 20.87, 25.15, 25.76 (d, J
4.5), 27.02, 60.88 (d, J 2.6), 60.96 (d, J 2.6), 83.94, 84.32, 87.20
(d, J 18.3), 91.51, 103.33, 112.67, 127.99, 129.51, 129.86, 140.20,
150.59, 155.31, 162.19; dP(121 MHz; DMSO-d6; H3PO4) 31.74;
m/z 509.2053 (ESI) (M+H+. C24H34N2O8P+ requires 509.2047).
The title compound was obtained from 13f (71 mg, 0.14 mmol)
as a colorless oil (63 mg, 88%) dH(300 MHz; DMSO-d6; Me4Si)
1.22 (6 H, t, J 7.0, 2¥OCH2CH3), 1.24 (3 H, s, CH3), 1.29 (3 H, s,
CH3), 1.67–1.90 (4 H, m, 5¢-H+6¢-H), 2.37 (3 H, s, CH3), 3.83
(1 H,dd, J4¢,3¢5.9, J4¢,3¢ 10.5, 4¢-H), 3.97 (4 H, m, 2 ¥ CH2), 4.64
(1 H, dd, J3¢,2¢ 6.2 Hz, J3¢,4¢ 4.8, 3¢-H), 5.24 (1 H, d, J2¢,3¢ 6.2, 2¢-H),
5.27 (1 H, s, 1¢-H), 5.51 (1 H, d, J5,NH 2.1, 5-H), 7.35–7.50 (4 H,
m, Ar), 11.56 (1 H, d, JNH, H5 1.2, NH); dC(75 MHz; DMSO-d6;
DMSO) 16.23, 16.30, 20.85(d, J 140.4), 20.88, 25.18, 25.76 (d, J
4.4), 26.98, 60.88 (d, J 2.9), 60.96 (d, J 2.9), 83.30, 83.80, 87.03
(d, J 18.2), 91.63, 103.35, 112.70, 128.78, 130.94, 132.66, 138.48,
5242 | Org. Biomol. Chem., 2010, 8, 5234–5246
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Diethyl 2-((3aR,4R,6R,6aR)-6-(2,4-dioxo-6-phenethyl-3,4-
dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl)ethylphosphonate 21n
Deprotection of final nucleoside phosphonates 20 and 22: General
procedure
The phosphonic diester (0.2 mmol) was dissolved in CH2Cl2
(4 cm3) under argon. TMSBr (0.528 cm3, 4 mmol) was added
and the resulting solution was stirred for 18 h. The solvents
were evaporated and the residue was co-distilled with toluene
(2 ¥ 10 cm3). Then, water (2 cm3) was added followed by TFA
(50%, 4 cm3) and the mixture was stirred for 2 h. The solvent was
evaporated, the residue was co-distilled with water (5 ¥ 10 cm3)
and subsequently partioned between EtOAc–Et2O (1 : 1, 10 cm3)
and water (25 cm3). The organic phase was washed with water
(15 cm3) and the water layers were combined and evaporated to
afford the final product. The purity of all final compounds (>95%)
was confirmed by LC-MS, the substances that did not meet this
standard were further purified by C18 (Phenomenex Luna 250 ¥
21.20 mm 5 mm) RP-HPLC with an elution gradient of 10–100%
B over 18 min, where A is 0.1% formic acid in H2O and B is 0.1%
formic acid in CH3CN.
The title compound 21n was obtained from 13m (124 mg, 0.24
mmol) as a colorless oil (124 mg, 99%) dH(300 MHz; DMSO-d6;
Me4Si) 1.21 (6 H, t, J 7.0, 2¥OCH2CH3), 1.23 (3 H, s, CH3), 1.30
(3 H, s, CH3), 1.70–1.90 (4 H, m, 5¢-H+6¢-H), 2.88 (4 H, s, 2¥CH2),
3.96 (4 H, m, 2 ¥ CH2), 4.01 (1 H, m, 4¢-H), 4.70 (1 H, dd, J3¢,2¢
4.7, J3¢,4¢ 6.3, 3¢-H), 5.25 (1 H, dd, J2¢,1¢ 0.8, J2¢,3¢ 6.5, 2¢-H), 5.45
(1 H, s, 1¢-H), 5.70 (1 H, s, 5-H), 7.19–7.33 (5 H, m, Ar), 11.35
(1 H, br s, NH); dC(75 MHz; DMSO-d6; DMSO) 16.22 (s), 16.30
(s), 20.87(d, J 141.0), 25.30 (s), 25.81(d, J 4.4), 27.17 (s), 32.92
(s), 33.60 (s), 60.90 (d, J 3.3), 60.94 (d, J 3.3), 83.39 (s), 84.14 (s),
87.47 (d, J 17.6), 90.29 (s), 101.98 (s), 113.06 (s), 126.38 (s), 128.35
(2C, s), 128.43 (2C, s), 139.61 (s), 150.66 (s), 154.93 (s), 162.41 (s);
dP(121 MHz; DMSO-d6; H3PO4) 31.74 (s); m/z 523.2204 (ESI)
(M+H+. C23H30N2O8P+ requires 523.2201).
(E)-2-((3aR,4R,6R,6aR)-6-(2,4-dioxo-6-phenyl-3,4-dihydro-
pyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]
dioxol-4-yl)vinylphosphonic acid 19a
2-((2R,3S,4R,5R)-5-(2,4-dioxo-6-phenyl-3,4-dihydropyri-midin-
1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)ethyl-phosphonic
acid 22a
TMSBr (0.86 cm3, 6.5 mmol) was added to a solution of 13a
(320 mg, 0.65 mmol) in CH2Cl2 (15 cm3) under argon and the
resulting mixture was stirred for 24 h at rt. After evaporation of the
solvents and co-distillation with toluene (3 ¥ 25 cm3), the residue
was dissolved in water (35 cm3) and washed with Et2O (2 ¥ 25 cm3).
The water phase was immediately frozen and lyophilized to afford
the compound 19a (276 cm3, 97%) as a white hygroscopic powder.
dH(300 MHz; D2O; dioxane) 1.34 (3 H, s, CH3), 1.39 (3 H, s,
CH3), 4.57 (1 H, dddd, J4¢,5¢ 5.8, J4¢,3¢ 4.4, J4¢,P 2.9, J4¢,6¢ 1.5, 4¢-H),
4.98 (1 H, dd, J3¢,2¢ 6.3, J3¢,4¢ 4.4, 3¢-H), 5.43 (1 H, dd, J2¢,1¢ 1.1,
J2¢,3¢ 6.3, 2¢-H), 5.58 (1 H, d, J1¢,2¢ 1.2, 1¢-H), 5.78 (1 H, s, 5-H),
6.07 (1 H, ddd, J6¢,4¢ 1.5, J6¢,5¢ 17.2, JH6¢,P 18.8, 6¢-H), 6.63 (1 H,
ddd, J5¢,4¢ 5.8, J5¢,6¢ 17.2, JH5¢,P 21.4, 5¢-H), 7.46–7.63 (5 H, s, Ar);
dP(121 MHz; D2O; H3PO4) 13.78; m/z 435.0969 (negESI) (M -
H+. C19H22N2O8P+requires 435.0963).
Phosphonic acid 22a was obtained from 21a (335 mg, 0.68
mmol) as a white foam (58 mg, 21%) after HPLC purification.
dH(300 MHz; DMSO-d6; Me4Si) 1.37–1.94 (4H, m, 5¢-H+6¢-H),
3.42 (1 H, dd, J4¢,3¢ 6.9, J4¢,5¢ 12.1, 4¢-H), 4.01 (1 H, dd, J3¢,2¢ 6.8,
J3¢,4¢ 7.1, 3¢-H), 4.46 (1 H, dd, J2¢,1¢ 2.5, J2¢,3¢ 6.3, 2¢-H), 5.00 (1 H,
d, J1¢,2¢ 2.5, 1¢-H), 5.50 (1 H, s, 5-H), 7.44–7.59 (5 H, m, Ar),
11.45 (1 H, s, NH); dC(75 MHz; D2O, EtOH) 23.52 (d, J 135.6),
26.17 (d, J 3.7), 58.05, 72.33, 72.74, 83.03 (d, J 17.8), 93.93,
104.39; 128.71, 129.64, 131.42, 132.62, 152.09, 158.62, 165.84;
dP(121 MHz; D2O; H3PO4) 28.30; m/z 399.0948 (ESI) (M+H+.
C16H20N2O8P+ requires 399.0952).
(E)-2-((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-(naphthalen-2-yl)-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-
yl)vinylphosphonic acid 20b
(E)-2-((2R,3S,4R,5R)-5-(2,4-dioxo-6-phenyl-3,4-dihydropyri-
midin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)vinyl-
phosphonic acid 20a
The unsaturated phosphonic acid 20b was obtained from 13b
(60 mg,0.11 mmol) as a white foam (45 mg, 91%) dH(300 MHz;
D2O, dioxane) 4.51 (1 H, ddd app t, J 7.0, 4¢-H), 4.28 (1 H, dd, J3¢,2¢
6.5, J3¢,4¢ 7.9, 3¢-H), 4.71 (1 H, dd, J2¢,1¢ 2.6, J2¢,3¢ 6.5, 2¢-H), 5.32 (1 H,
d, J1¢,2¢ 2.6, 1¢-H), 5.65 (1 H, s, 5-H), 6.12 (1 H, ddd app t, J 18.5,
6¢-H), 6.55 (1 H, ddd, J5¢,4¢ 6.2, J5¢,6¢ 17.3, JH5¢,P 21.7, 5¢-H), 7.44–
7.47 (1 H, m, Ar), 7.62–7.68 (2 H, m, Ar), 7.93–8.00 (4 H, m, Ar);
dC(75 MHz; DMSO-d6; DMSO) 71.98, 73.34, 82.91 (d, J 22.7),
94.31, 103.92, 123.95 (d, J 179.6), 127.45, 127.72, 128.30, 128.47,
130.47, 132.35, 133.18, 143.42 (d, J 5.0), 150.43, 155.83, 162.22;
dP(121 MHz; D2O; H3PO4) 13.71; m/z 543.1892 (ESI) (M+H+.
C27H32N2O8P+ requires 543.1891).
To an ice-cooled solution of phosphonic acid 19a (246 mg, 0.56
mmol) in water (6 cm3), TFA (50%, 6 cm3) was added. After
removal of the ice bath, the mixture was stirred under exclusion
of light for 2 h at rt. Evaporation of the solvent and multiple co-
distillation with water (5 ¥ 15 cm3) afforded the crude product,
which was crystallized from an EtOH–Et2O mixture to give
extremely hygroscopic crystals (95 mg, 40%), which according to
1H NMR contain EtOH (3.9%) and Et2O (1.9%). dH(300 MHz;
DMSO-d6; Me4Si) 4.12–4.19 (1 H, m, 4¢-H), 4.31 (1 H, dd, J3¢,2¢
6.4, J3¢,4¢ 7.9, 3¢-H), 4.73 (1 H, dd, J2¢,1¢ 2.7, J2¢,3¢ 6.3, 2¢-H), 5.33
(1 H, d, J1¢,2¢ 2.7, 1¢-H), 5.75 (1 H, s, 5-H), 6.15 (1 H, ddd, J6¢,4¢ 1.2,
2-((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-(naphthalen-2-yl)-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-
yl)ethylphosphonic acid 22b
J
6¢,5¢ 17.2, JH6¢,P 19.4, 6¢-H), 6.61 (1 H, ddd, J5¢,4¢ 6.0, J5¢,6¢ 17.2, JH5¢,P
21.7, 5¢-H), 7.46–7.63 (5 H, s, Ar); dC(75 MHz; D2O; EtOH) 72.47,
73.60, 83.24 (d, J 23.2), 94.40, 104.44, 123.72 (d, J 179.1), 128.66,
129.67, 131.48, 132.54, 144.17 (d, J 5.2), 152.08, 158.45, 165.70;
dP(121 MHz; D2O; H3PO4) 14.19; m/z 397.0799 (ESI) (M+H+.
C16H18N2O8P+ requires 397,0795).
Phosphonic acid 22b was obtained from 21b (99 mg, 0.18 mmol) as
a pale beige foam (66 mg, 81%) dH(300 MHz; DMSO-d6; Me4Si)
1.55–1.91(4H, m, 5¢-H+6¢-H), 3.42 (1 H, dd, J4¢,3¢ 6.1, J4¢,5¢ 11.39,
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4¢-H), 4.02 (1 H, dd, J3¢,2¢ = J3¢,4¢ 7.1, 3¢-H), 4.50 (1 H, dd, J2¢,1¢ 2.1,
J2¢,3¢ 5.9, 2¢-H), 5.05 (1 H, d, J 2.1, 1¢-H), 5.64(1 H, d, J 2.1, 5-H),
7.57–7.69 (3 H, m, Ar), 7.99–8.13 (4 H, m, Ar), 11.51 (1 H, d, J 1.9,
NH); dC(75 MHz; DMSO-d6; DMSO) 23.61(d, J 137.7), 25.95 (d,
J 3.3), 71.95, 72.09, 82.36 (d, J 18.0), 93.98, 103.84, 127.13, 127.66,
128.24, 128.47, 130.54, 132.33, 133.18, 150.38, 155.91, 162.23;
dP(121 MHz; DMSO-d6; H3PO4) 27.03; m/z 447.0970 (negESI)
(M - H+. C20H20N2O8P+ requires 447.0963).
2-((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-(3-methoxyphenyl)-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-
yl)ethylphosphonic acid 22g
Phosphonic acid 22g was obtained from 21g (66 mg, 0.13 mmol)
as a white foam (51 mg, 94%) dH(300 MHz; DMSO-d6; Me4Si)
1.47–1.93 (4H, m, 5¢-H+6¢-H), 3.81 (3H, s, CH3), 3.43 (1 H, dt,
J4¢,3¢ 7.6, J4¢,5¢ 15.7, 4¢-H), 4.02 (1 H, dd, J3¢,2¢ 6.6, J3¢,4¢ 7.2, 3¢-H),
4.47 (1 H, dd, J2¢,1¢ 2.5, J2¢,3¢ 6.2, 2¢-H), 5.02 (1 H, d, J1¢,2¢ 2.5, 1¢-H),
5.48 (1 H, d, J5,NH 2.2, 5-H), 7.03–7.14 (2 H, m, Ar), 7.39–7.50
(2 H, m, Ar), 11.45 (1 H, d, JNH,5 2.0, NH); dC(75 MHz; D2O,
EtOH) 23.27 (d, J 134.9), 26.61 (br s), 56.17, 72.31, 72.75, 82.90
(d, J 18.0), 93.98, 104.26, 117.34, 131.09, 133.88, 152.05, 158.17,
159.64, 165.84; dP(121 MHz; D2O; H3PO4) 26.77; m/z 429.1057
(ESI) (M+H+. C17H22N2O9P+ requires 429.1059).
(E)-2-((2R,3S,4R,5R)-5-(2,4-dioxo-6-m-tolyl-3,4-dihydropyri-
midin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)vinyl-
phosphonic acid 20f
The unsaturated phosphonic acid 20f was obtained from 13f
(71 mg, 0.14 mmol) as a pale beige foam (50 mg, 87%) dH(300 MHz;
DMSO-d6; Me4Si) 2.37 (3H, s, CH3), 3.97 (1 H, ddd, J 1.8, J 6.2,
J 7.6, 4¢-H), 4.12 (1 H, dd, J3¢,2¢ 6.4, J3¢,4¢ 7.3, 3¢-H), 4.49 (1 H, dd,
J2¢,1¢ 2.3, J2¢,3¢ 5.9, 2¢-H), 5.01 (1 H, d, J1¢,2¢ 2.3, 1¢-H), 5.50 (1 H, d,
J5,NH 2.1, 5-H), 5.92 (1 H, ddd, J 1.2, J 17.3, J 18.7, 6¢-H), 6.43
(1 H, ddd, J5¢,4¢ 6.2, J5¢,6¢ 17.3, JH5¢,P 21.4, 5¢-H), 7.27–7.43 (4 H, m,
Ar), 11.48 (1H, d, JNH, 5 2.1, NH); dC(75 MHz; DMSO-d6; DMSO)
20.93, 72.04, 73.33, 82.52 (d, J 22.7), 94.14, 103.41, 123.91 (d, J
179.7), 128.67, 130.84, 132.96, 138.33, 143.48 (d, J 5.0), 150.43,
154.94, 162.19; dP(121 MHz; D2O; H3PO4) 12.36; m/z 411.0952
(ESI) (M+H+. C17H20N2O8P+ requires 411.0952).
(E)-2-((2R,3S,4R,5R)-5-(6-(4-fluorophenyl)-2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-
yl)vinylphosphonic acid 20h
The unsaturated phosphonic acid 20h was obtained from 13h
(40 mg, 0.078 mmol) as a white foam (25 mg, 77%) after HPLC
purification. dH(300 MHz; DMSO-d6; Me4Si) 3.99 (1 H, ddd app
t, J 7.0, 4¢-H), 4.14 (1 H, dd, J3¢,2¢ 6.4, J3¢,4¢ 7.3, 3¢-H), 4.49 (1 H,
dd, J2¢,1¢ 2.6, J2¢,3¢ 6.2, 2¢-H), 5.02 (1 H, d, J1¢,2¢ 2.6, 1¢-H), 5.54 (1 H,
d, J5,NH 2.1, 5-H), 5.93 (1 H, ddd, J 0.9, J 18.5, J 18.6, 6¢-H),
6.43 (1 H, ddd, J5¢,4¢ 6.2, J5¢,6¢ 17.3, JH5¢,P 21.4, 5¢-H), 7.35–7.41
(2 H, m, Ar), 7.54–7.59 (2 H, m, Ar), 11.51 (1H, d, JNH, 5 2.1,
NH); dC(75 MHz; DMSO-d6; DMSO) 71.91, 73.33, 82.82 (d, J
22.7), 94.11, 103.87, 115.93 (2 C, d, J 22.1), 123.94 (d, J 179.7),
129.41 (2C, d, J 3.3), 130.55 (d, J 9.9), 143.34 (d, J 4.7), 150.37,
154.77, 162.11, 162.97 (d, J 248.0); dP(121 MHz; D2O; H3PO4)
12.33; dP(282 MHz; DMSO-d6; CCl3F) 89.87; m/z 415.0701 (ESI)
(M+H+. C16H17FN2O8P+ requires 415.0701).
2-((2R,3S,4R,5R)-5-(2,4-dioxo-6-m-tolyl-3,4-dihydropyri-midin-
1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)ethyl-phosphonic
acid 22f
Phosphonic acid 22f was obtained from 21f (59 mg, 0.12 mmol) as
a white foam (15 mg, 30%) after HPLC purification. dH(300 MHz;
DMSO-d6; Me4Si) 1.45–1.90 (4H, m, 5¢-H+6¢-H), 1.83 (3H, s,
CH3), 2.36(3H, s, CH3), 3.42(1H, dd, J4¢,3¢ 7.0, J4¢,5¢ 12.0, 4¢-H), 3.99
(1 H, dd, J3¢,2¢ 6.7, J3¢,4¢ 7.0, 3¢-H), 4.44 (1 H, dd, J2¢,1¢ 2.6, J2¢,3¢ 6.4, 2¢-
H), 5.01 (1 H, d, J1¢,2¢ 2.6, 1¢-H), 5.48 (1 H, s, 5-H), 7.27–7.54 (2 H,
m, Ar), 7.54–7.58 (2 H, m, Ar), 11.43 (1 H, s, NH); dC(75 MHz;
D2O, dioxane) 21.06, 24.08 (d, J 134.9), 26.61 (d, J 3.8), 72.36,
72.75, 83.26 (d, J 17.7), 93.91, 104.16; 129.52, 132.01, 132.58,
140.04, 152.07, 158.76, 165.83; dP(121 MHz; D2O; H3PO4) 26.15;
m/z 413.1110 (ESI) (M+H+. C20H20N2O8P+ requires 413.1108).
2-((2R,3S,4R,5R)-5-(6-(4-fluorophenyl)-2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)-
ethylphosphonic acid 22h
Phosphonic acid 22h was obtained from 21h (40 mg, 0.078
mmol) as a white foam (16 mg, 49%) after HPLC purification.
dH(300 MHz; DMSO-d6; Me4Si) 1.45–1.91 (4H, m, 5¢-H+6¢-H),
3.45 (1 H, dd, J4¢,3¢ 6.9, J4¢,5¢ 9.8, 4¢-H), 4.00 (1 H, dd, J3¢,2¢ = J3¢,4¢ 7.1,
3¢-H), 4.46 (1 H, dd, J2¢,1¢ 2.6, J2¢,3¢ 6.3, 2¢-H), 4.95 (1 H, d, J1¢,2¢ 2.6,
1¢-H), 5.52 (1 H, d, J 2.1, 5-H), 7.35–7.54 (2 H, m, Ar), 7.54–7.58
(2 H, m, Ar), 11.47 (1 H, d, J 1.8, NH); dC(75 MHz; DMSO-d6;
DMSO) 23.59 (d, J 137.9), 25.98 (d, J 3.9), 71.88, 72.13, 82.37
(d, J 17.4), 93.77, 103.77, 115.89 (2 C, d, J 22.1), 129.49 (2C, d,
J 3.3), 130.58 (br s), 150.32, 154.85, 162.12, 162.96 (d, J 248.2);
dP(121 MHz; D2O; H3PO4) 26.86; dP(282 MHz; DMSO-d6; CCl3F)
89.89; m/z 447.0970 (negESI) (M - H+. C20H20N2O8P+ requires
447.0963).
(E)-2-((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-(3-methoxyphenyl)-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-
yl)vinylphosphonic acid 20g
The unsaturated phosphonic acid 20g was obtained from 13g
(51 mg, 0.10 mmol) as a white foam (40 mg, 96%) dH(300 MHz;
DMSO-d6; Me4Si) 3.81 (3H, s, CH3), 3.98 (1 H, app t, J 6.5, 4¢-H),
4.16 (1 H, dd, J3¢,2¢ 6.4, J3¢,4¢ 7.2, 3¢-H), 4.51 (1 H, dd, J2–,1– 2.5,
J2–,3– 6.1, 2—H), 5.09 (1 H, d, J1¢,2¢ 2.5, 1¢-H), 5.55 (1 H, d, J5,NH
2.2, 5-H), 5.92 (1 H, ddd, J6¢,4¢ 1.2, J6¢,5¢ 17.4, JH6¢,P 18.8, 6¢-H), 6.43
(1 H, ddd, J5¢,4¢ 6.1, J5¢,6¢ 17.1, JH5¢,P 21.2, 5¢-H), 7.01–7.13 (3 H,
m, Ar), 7.43 (1H, dd, J 8.8 and 4.1 Hz), 11.49 (1H, d, JNH, 5 2.0,
NH); dC(75 MHz; D2O; EtOH) 56.17, 72.42, 73.63, 83.46 (d, J
22.7), 94.39, 104.32, 117.32, 125.16 (d, J 177.2), 131.12, 133.82,
143.00 (d, J 5.2), 152.08, 158.07, 159.69, 165.83; dP(121 MHz;
D2O; H3PO4) 13.11; m/z 427.0901 (ESI) (M+H+. C17H20N2O9P+
requires 427.0901).
(E)-2-((2R,3S,4R,5R)-5-(2,4-dioxo-6-p-tolyl-3,4-dihydropyri-
midin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)vinyl-
phosphonic acid 20k
The unsaturated phosphonic acid 20k was obtained from 13k
(48 mg, 0.094 mmol) as a white foam (18 mg, 46%) after HPLC
purification. dH(300 MHz; D2O; HCOOH) 2.40 (3H, s, CH3), 4.16
5244 | Org. Biomol. Chem., 2010, 8, 5234–5246
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(1 H, ddd app t, J 6.2, J 7.0, 4¢-H), 4.31 (1 H, dd, J3¢,2¢ 6.5, J3¢,4¢
7.6, 3¢-H), 4.73 (1 H, dd, J2¢,1¢ 2.6, J2¢,3¢ 6.5, 2¢-H), 5.37 (1 H, d, J1¢,2¢
2.6, 1¢-H), 5.70 (1 H, s, 5-H), 6.15 (1 H, ddd, J 18.7, J 19.6, 6¢-H),
6.60 (1 H, ddd, J5¢,4¢ 5.9, J5¢,6¢ 17.3, JH5¢,P 21.7, 5¢-H), 7.37 (4 H, s,
Ar); dC(75 MHz; D2O; HCOOH) 21.14, 72.48, 73.63, 83.23 (d, J
22.9), 94.40, 104.21, 124.07 (d, J 179.9), 128.63, 129.59, 130.19,
142.38, 143.88 (d, J 5.0), 152.16, 158.65, 165.73; dP(121 MHz;
D2O; H3PO4) 13.92; m/z 411.0953 (ESI) (M+H+. C17H20N2O8P+
requires 411.0952).
Conformational analysis
Approximately 5.0 mg of 5 and 22a were dissolved in 600 ml
D2O. Due to solubility issues, we were forced to dissolve 9b
in DMSO-d6 (3.0 mg in 600 ml). The 1D 1H spectra of each
compound are shown in the ESI.†
All NMR spectra were measured on an Avance II Bruker
Spectrometer operating at a 1H frequency of 700 MHz and
equipped with a 1H/13C/15N TXI-z probe. The JH1¢H2¢
,
3JH2¢H3¢
,
3
3JH3¢H4¢ scalar couplings were measured for each compound at five
different temperatures, i.e. 20 ◦C, 27 ◦C, 35 ◦C, 42 ◦C and 50 ◦C
for 5 and 22a, and 27 ◦C, 35 ◦C, 42 ◦C, 50 ◦C and 60 ◦C for 9b. The
3JH1¢H2¢ scalar couplings could be measured directly from the H1¢
doublet in a Gaussian resolution enhanced 1D 1H spectrum. When
the resonance line width was too broad, the multiplets overlapped
with other multiplets or showed too complex patterns, the scalar
coupling constants were determined by selectively irradiating both
involved resonances during a SERF experiment.18 This was the
case for 5 and 9b.
2-((2R,3S,4R,5R)-5-(2,4-Dioxo-6-p-tolyl-3,4-dihydropyri-midin-
1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)ethyl-phosphonic
acid 22k
Phosphonic acid 22k was obtained from 21k (88 mg, 0.17 mmol) as
a white foam (22 mg, 30%) after HPLC purification. dH(300 MHz;
D2O, dioxane) 1.76–2.08 (4H, m, 5¢-H+6¢-H), 2.40 (3H, s, CH3),
3.66 (1 H, dd, J4¢,3¢ 7.1, J4¢,5¢ 11.7, 4¢-H), 4.19 (1 H, dd, J3¢,2¢ 6.4,
J3¢,4¢ 7.1, 3¢-H), 5.22 (1 H, dd, J2¢,1¢ 3.2, J2¢,3¢ 6.4, 2¢-H), 5.28 (1 H,
d, J1¢,2¢ 3.2, 1¢-H), 5.74 (1 H, s, 5-H), 7.38 (4 H, s, Ar); dC(75 MHz;
DMSO-d6, DMSO) 21.13, 23.22 (d, J 136.0), 25.98 (d, J 3.6),
72.35, 72.76, 82.84 (d, J 18.0), 93.95, 104.20; 128.67, 129.70,
130.17, 142.32, 152.16, 158.82, 165.85; dP(121 MHz; D2O; H3PO4)
29.77; m/z 411.0963 (negESI) (M - H+. C17H20N2O8P-requires
411.0963).
The 2D NOESY spectra were measured at 20 ◦C (27 ◦C in the
case of 9b), with 2048 time domain points in the direct dimension
and 256 time domain points in the indirect dimension (except
for 9b, where 450 indirect time domain points were sampled).
The mixing time was 600 ms for each compound. Before Fourier
transform, both dimensions were multiplied with a squared cosine
bell window function and zero filled until a 1024 ¥ 1024 real data
matrix was obtained. The spectra were baseline corrected using a
fifth order polynomial.
(E)-2-((2R,3S,4R,5R)-5-(2,4-dioxo-6-styryl-3,4-dihydropyri-
midin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)vinyl-
phosphonic acid 20m
Acknowledgements
The unsaturated phosphonic acid 20m was obtained from 13m
(48 mg, 0.092 mmol) as a yellow foam (37 mg, 95%). dH(300 MHz;
D2O, dioxane) 4.18 (1 H, dd, J3¢,2¢ 6.3, J3¢,4¢ 7.9, 3¢-H), 4.42 (1 H,
ddd app t, J 6.8, 4¢-H), 4.44 (1 H, dd, J2¢,1¢ 2.4, J2¢,3¢ 6.2, 2¢-
H), 5.54 (1 H, d, J1¢,2¢ 2.3, 1¢-H), 5.69 (1 H, s, 5-H), 6.07 (1 H,
ddd, J6¢,4¢ 0.6, J6¢,5¢ 17.1, JH6¢,P 18.1, 6¢-H), 6.54 (1 H, ddd, J5¢,4¢
5.6, J5¢,6¢ 17.3, JH5¢,P 22.0, 5¢-H), 6.68 (1H, d, J 15.8, CH CH),
7.02 (1H, d, J 15.8, CH CH), 7.21–7.26 (3 H, m, Ar), 7.30–7.37
(2 H, m, Ar); dC(75 MHz; D2O, dioxane) 72.59, 73.85, 83.01 (d,
J 23.6), 93.46, 100.81, 118.09, 123.27 (d, J 180.2), 128.17, 129.57,
130.89, 135.02, 140.60, 144.83 (d, J 5.1), 151.48, 155.73, 165.83;
dP(121 MHz; D2O; H3PO4) 14.54; m/z 421.0803 (negESI) (M+H+.
C18H20N2O8P+ requires 421.0806).
The work performed at IOCB was part of research project #Z4
055 0506.
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