Preparation of nucleoside 5′-deoxy-5′-methylenephosphonates as building blocks for the synthesis of methylenephosphonate analogues

Article abstract of DOI:10.1039/a906066i

Efficient synthesis of suitably protected 2′-deoxycytidine, 2′-deoxyadenosine, and 2′-deoxyguanosine derivatives bearing the 5′-methylenephosphonate moiety with the 4-methoxy-1-oxido-2-picoIyl function as an intramolecular nucleophile catalytic group is d

Full text of DOI:10.1039/a906066i

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Preparation of nucleoside 5Ј-deoxy-5Ј-methylenephosphonates
as building blocks for the synthesis of methylenephosphonate
analogues
Annika Kers, Tomas Szabó and Jacek Stawinski*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
S-106 91 Stockholm, Sweden
Received (in Lund) 17th May 1999, Accepted and transferred from Acta Chem. Scand.
28th July 1999
Efficient synthesis of suitably protected 2Ј-deoxycytidine, 2Ј-deoxyadenosine, and 2Ј-deoxyguanosine derivatives
bearing the 5Ј-methylenephosphonate moiety with the 4-methoxy-1-oxido-2-picolyl function as an intramolecular
nucleophile catalytic group is described.
method in solid-phase synthesis of oligonucleotide analogues
Introduction
was demonstrated by preparing several 5Ј-deoxy-5Ј-methyl-
phosphonate-linked thymidine oligonucleotides with a chain
length of up to 20 nucleotidic units.9 As expected, the produced
oligonucleotide analogues in which the 5Ј-oxygen atom was
replaced by a methylene group bound to the phosphorus
were resistant to bovine spleen phosphodiesterase (BSPDE)
digestion.9
In this paper we report on the preparation of protected 4-
methoxy-1-oxido-2-picolyl 5Ј-deoxy-5Ј-methylenephosphonate
derivatives of deoxycytidine, deoxyadenosine, and deoxyguano-
sine, suitable for incorporation into oligonucleotides or other
biologically active phosphorus-containing natural products, e.g.
phosphorylated sugars, phospholipids.
Although naturally occurring oligonucleotides with 3Ј,5Ј-
internucleoside phosphodiester bonds can modulate gene
expression1,2 via formation of stable complexes with DNA or
RNA targets, they do not meet the criteria for potential anti-
sense or antigene agents; in the first place, due to their high
susceptibility to nuclease degradation in vivo. To overcome
this and other problems connected with antisense therapy a
plethora of oligonucleotide analogues have been designed,3 but
a modification (or combinations of modifications) that can
provide satisfactory chemical, enzymic and pharmaco-dynamic
properties to a potential oligonucleotide drug has yet to be
found.4
Since the presence of a P–C bond confers nuclease resistance
to biologically active phosphates, the most well studied class
of DNA analogues are oligonucleoside methylphosphonates.
However, due to chirality of the phosphorus centre in these
compounds, their chemical synthesis usually leads to a pool of
diastereomeric products with different physicochemical proper-
ties; e.g., varying ability to form stable complexes with a target
DNA or RNA. In this respect, oligonucleoside methylene-
phosphonate analogues, bearing the P–C bond in a bridging
position of the internucleosidic linkage (the 3Ј or 5Ј position),
may offer some advantages. Due to the presence of a P–C bond,
they retain resistance to nucleases similar to that of methyl-
Results and discussion
We considered that the most convenient combination of
protecting groups in nucleoside 5Ј-deoxy-5Ј-methylene-
phosphonate building blocks would consist of the acid-labile
dimethoxytrityl group for protection of the 3Ј-OH function,
base-labile acyl groups for protection of amino functions in the
heterocyclic bases, and the 4-methoxy-1-oxido-2-picolyl group,
as a phosphonate-protecting group. The last group should also
simultaneously act as an intramolecular nucleophile catalytic
group to facilitate coupling of the 5Ј-methylenephosphonate
building blocks to a suitable acceptor molecule, e.g. protected
oligonucleotide, carbohydrates, lipids, etc.
The general synthetic scheme for the preparation of building
blocks 7 (Scheme 1) followed that developed by us previously
for the thymidine unit,9 and used as starting materials easily
accessible N-protected nucleosides 1 bearing a 3Ј-O-tert-
butyldiphenylsilyl (TBDPS) group. This rather stable 3Ј-OH
protection group can at the end of synthesis be replaced by the
4,4Ј-dimethoxytrityl (DMT) group, which is more suitable for
further applications.
phosphonate analogues, but the achiral P(᎐O)OϪ functional-
᎐
ity (a high resemblance to natural oligonucleotides) alleviates
problems of diastereomeric inhomogeneity of the produced
oligonucleotide analogues.
1
Apart from these, H NMR studies revealed that in nucleo-
sides with a 5Ј-deoxy-5Ј-C-(phosphonomethyl) moiety, the
most populated rotamers around the C4Ј–C5Ј bond are γt and
γϪ.5 In the light of the observed correlation between biological
activity and the rotamers’ distribution around the C4Ј–C5Ј
bond in some nucleoside analogues,6,7 it is possible that the
structural motif present in the 5Ј-methylenephosphonate
analogues, namely the P–C–C function, can be of biological
importance for modulation of their interactions with DNA-
synthesizing enzymes.
Recently, we have reported on a new method for the form-
ation of phosphonate esters that makes use of intramolecular
nucleophiliccatalysisexertedbya4-methoxy-1-oxido-2-picolyl†
group attached to the phosphonate centre.8 The efficacy of this
The 5Ј-phosphonomethyl group was introduced into nucleo-
sides 1 using a modification of the procedure previously
developed by Jones and Moffatt.10 This commenced with a one-
pot oxidation of the 5Ј-hydroxy function of 1 using DCC–
DMSO, followed by reaction of the produced aldehyde with
a mixed phosphorane–phosphonate Wittig reagent11 to give
the appropriate vinylphosphonate 2 [almost exclusively in the
1
(E)-form, H NMR]. For the deoxyguanosine 1b and deoxy-
adenosine 1c derivatives, the introduction of the phosphonate
function was effected by diphenyl triphenylphosphoranyl-
† 2-Picolyl = pyridin-2-ylmethyl.
J. Chem. Soc., Perkin Trans. 1, 1999, 2585–2590
This journal is © The Royal Society of Chemistry 1999
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Scheme 1 Reagents and conditions: (i) DCC, pyridine, TFA, DMSO; (ii) Ph3P᎐CHP(O)(OPh)2 or Ph3P᎐CHP(O)(OC6H4Cl-o)2; (iii) PADA, AcOH,
᎐
᎐
pyridine; (iv) pyridine-2-aldoxime, TMG, dioxane–H2O (3:1 v/v); (v) 4-methoxy-1-oxidopyridine-2-methanol, 4-methoxypyridine 1-oxide, 2-chloro-
5,5-dimethyl-2-oxo-2λ5-1,3,2-dioxaphosphinane, pyridine; (vi) Bu4NF, THF; (vii) TAF, THF; (viii) DMT-Cl, DMAP, pyridine, 70 ЊC; (ix) DMT-Cl,
AgNO3, THF–DMF (1:1 v/v). 1a–7a, B = N4-isobutyrylcytosin-1-yl; Ar = o-chlorophenyl. 1b–7b, B = N2-isobutyrylguanin-9-yl; Ar = phenyl. 1c–7c,
B = N6-benzoyladenin-9-yl; Ar = phenyl. Abbreviations: DMT—4,4Ј-dimethoxytrityl; DCC—1,3-dicyclohexylcarbodiimide; DMAP—4-dimethyl-
aminopyridine; DMSO—dimethyl sulfoxide; PADA—potassium azodicarboxylate; TAF—triethylamine trishydrofluoride; TBDPS—tert-butyldi-
phenylsilyl; TFA—trifluoroacetic acid; TMG—1,1,3,3-tetramethylguanidine.
idenemethylphosphonate,11 while for the deoxycytidine 1a the
di-(o-chlorophenyl) derivative was used instead. In this
instance, the more labile o-chlorophenyl phosphonate protect-
ing group was required to achieve a better compatibility in
some of the later reaction steps (vide infra).
of 6b, some depurination during the removal of the silyl group
was observed, which may explain the rather moderate yield of
the isolated 7b (41%). For deoxyadenosine derivative 6c, which
was expected to be even more prone to depurination, these reac-
tion conditions failed to produce 7c. However, using triethyl-
amine trishydrofluoride as desilylating reagent, followed by
precipitation of the crude product before the dimethoxytrityl-
ation, produced the desired product 7c in good yield. In this
instance, changes in the tritylation conditions (RT, DMF,
AgNO3)14 had a beneficial effect on the total yield of the
conversion 6c to 7c.
In conclusion, we have developed a reliable protocol for the
preparation of protected nucleoside 5Ј-deoxy-5Ј-methylene-
phosphonates that can serve as building blocks for incorpor-
ation of the methylenephosphonate function into various
biomolecules. By introducing appropriate changes into the
presented method, 5Ј-methylenephosphonate building blocks
with other combinations of protecting groups can also be
prepared.
Catalytic hydrogenation that worked well for the vinyl-
phosphonate derived from thymidine9 was found to be ineffi-
cient for vinylphosphonates 3a–c. Very sluggish catalytic
hydrogenation of an adenosine vinylphosphonate was also
reported by Jones and Moffatt,10 who proposed using diimide
as reducing agent in this instance. We found that potassium
azodicarboxylate (PADA) in the presence of acetic acid and
pyridine12 efficiently reduced vinylphosphonates 2b and 2c to
produce the appropriate phosphonates 3. For the deoxycytidine
derivative 2a, a partial loss of the base protection was observed
during this reduction. It was, however, possible to restore the
N-protection through a reaction with isobutyric anhydride
before the purification and thus achieve a satisfactory yield of
the phosphonate 3a.
The selective removal of one aryl group from 3 to produce
phosphonate monoesters 4 was effected by treatment with
pyridine-2-aldoximate.13 To secure stability of the N4-isobutyryl
group in the deoxycytidine derivatives under the reaction condi-
tions, it was necessary to use an o-chlorophenyl instead of a
phenyl group for protection of the phosphonate function in 3a.
This allowed a significant shortening of the deprotection time
of 3a with pyridinealdoximate (from several hours to 30 min)
and thus eliminated the occasionally observed losses of the N4-
isobutyryl group.
Experimental
Materials and methods
1H, 13C, and 31P NMR spectra were recorded on a JEOL GSX-
270 FT or a Varian 300 MHz spectrometer. Chemical shifts are
given in ppm relative to tetramethylsilane (1H and 13C NMR,
CDCl3, 25 ЊC) or 2% H3PO4 in D2O (31P NMR, CH3CN, 25 ЊC).
The assignment of proton and carbon resonances was done on
the basis of known or expected chemical shifts in conjunction
with 1H–1H and 1H–13C correlated NMR spectroscopy. Reson-
The intramolecular catalytic group, 4-methoxy-1-oxido-2-
picolyl, was introduced analogously as for the thymidine deriv-
ative,9 i.e., via condensation of the phosphonate monoesters 4
with 4-methoxy-1-oxidopyridine-2-methanol in the presence
#
ances marked with a superscript refer to nuclei of the picolyl
moiety in the corresponding compounds. The multiple
number of some C and H resonances is due to the presence of
diastereomers (compounds of type 5) or to the diastereotopic
character of certain substituents. High-resolution FAB mass
spectra were recorded on a JEOL SX-102 instrument.
Pyridine was dried by refluxing with CaH2 overnight fol-
lowed by distillation, re-distillation from toluene-p-sulfonyl
chloride and storage over molecular sieves (4 Å). 1,4-Dioxane
was dried by distillation from LiAlH4 and stored over Na-wire.
Tetrahydrofuran was dried by distillation from LiAlH4 directly
of
2-chloro-5,5-dimethyl-2-oxo-2λ5-1,3,2-dioxaphosphinane
(NEP-Cl) and 4-methoxypyridine N-oxide as a nucleophilic
catalyst. From the produced phosphonate diesters 5, the aryl
protecting groups were removed via the oximate treatment (vide
supra) to produce the phosphonate monoesters 6.
The conversion of 6a and 6b into the final products 7 was
achieved via removal of the 3Ј-O-TBDPS groups with tetra-
butylammonium fluoride followed by dimethoxytritylation
with DMTCl in pyridine in the presence of DMAP. In the case
2586
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before use. Chloroform was passed through basic Al2O3 prior
to use. DMF and DMSO were made anhydrous by distillation
from CaH2 at reduced pressure (≈10 mmHg) and stored over
molecular sieves (4 Å).
purified via silica gel column chromatography using a stepwise
gradient of methanol (0–1%) in chloroform (2.81 g, 75%).
1
Some diagnostic spectral data: 31P NMR, δ 26.7; H NMR,
δ 1.72–2.27 (5H, m, H-2Ј, H2-5Ј, and H2-6Ј), 6.28 (1H, t, J 6.4
NEP-Cl,15 4-methoxy-1-oxidopyridine-2-methanol16–18 and
Hz, H-1Ј); 13C NMR, δ 23.2 (C-6Ј, d, JPC 143.0 Hz), 87.0 (C-1Ј).
diphenyl
(triphenylphosphoranylidenemethyl)phosphonate,9
were prepared by the published procedures. 3Ј-O-tert-Butyl-
diphenylsilylated nucleosides 1a–c were synthesized analo-
gously as described for thymidine5 and di-(o-chlorophenyl)
(triphenylphosphoranylidenemethyl)phosphonate, analogously
to its diphenyl ester.9 PADA was synthesised starting from
azodicarboxamide in a one-step reaction according to Thiele’s
procedure.19 Pyridine-2-aldoxime, tetrabutylammonium fluor-
ide trihydrate, and triethylamine trishydrofluoride were com-
mercial grades (Aldrich). 4-Methoxypyridine 1-oxide hydrate
(Aldrich) was dried over P2O5 overnight at 70 ЊC at 0.2 mmHg,
and 1,3-dicyclohexylcarbodiimide (Aldrich) and 1,1,3,3-tetra-
methylguanidine (Aldrich) were vacuum distilled. 1 M Triethyl-
ammonium bicarbonate buffer (pH ≈ 7) (TEAB) was prepared
by passing carbon dioxide through an aqueous solution con-
taining the appropriate amount of triethylamine. For column
chromatography, silica gel (35–70 µm) from Amicon Europe
was used, and the columns were run in the flash mode. All
evaporations were carried out under reduced pressure using a
rotary evaporator, unless stated otherwise.
o-Chlorophenyl [1-(3Ј-O-tert-butyldiphenylsilyl-2Ј,5Ј,6Ј-
trideoxy-ꢀ-D-erythro-hexofuranosyl)-4-N-isobutyrylcytosin-6Ј-
yl]phosphonate, triethylammonium salt 4a
Phosphonate diester 3a (0.77 g, 0.92 mmol) was dissolved in
1,4-dioxane–water (3:1 v/v; 10 mL) and pyridine-2-aldoxime
(0.17 g, 1.4 mmol) and 1,1,3,3-tetramethylguanidine (0.17 mL,
1.4 mmol) were added. The reaction mixture was stirred for
5 min and then partitioned between 1 M aq. TEAB (40 mL)
and chloroform (2 × 40 mL). The combined organic phase
was evaporated and the residue was purified by silica gel
column chromatography using a stepwise gradient of methanol
(0–10%) in chloroform containing triethylamine (0.5%) (0.62 g,
82%).
1
Some diagnostic spectral data: 31P NMR, δ 21.2; H NMR,
δ 3.00 (6H, q, J 7.3 Hz, 3 × CH2TEAH), 6.30 (1H, t, J 6.4 Hz,
H-1Ј); 13C NMR, δ 45.2 (3 × CH2TEAH), 87.6 (C-1Ј).
4-Methoxy-1-oxido-2-picolyl o-chlorophenyl [1-(3Ј-O-tert-butyl-
diphenylsilyl-2Ј,5Ј,6Ј-trideoxy-ꢀ-D-erythro-hexofuranosyl)-4-N-
isobutyrylcytidin-6Ј-yl]phosphonate 5a
Bis(o-chlorophenyl)[1-(3Ј-O-tert-butyldiphenylsilyl-2Ј,5Ј,6Ј-
trideoxy-ꢀ-D-erythro-hex-5Ј-enofuranosyl)-4-N-isobutyryl-
cytosin-6Ј-yl]phosphonate 2a
Phosphonate monoester 4a (2.06 g, 2.5 mmol), 4-methoxy-1-
oxidopyridine-2-methanol (0.43 g, 2.8 mmol) and 4-methoxy-
pyridine 1-oxide (1.07 g, 7.5 mmol) were rendered anhydrous by
evaporation of added pyridine and then dissolved in pyridine
(25 mL). 2-Chloro-5,5-dimethyl-2-oxo-2λ5-1,3,2-dioxaphos-
phinane (1.38 g, 7.5 mmol) was added and the reaction mixture
was stirred for 1 h. The reaction mixture was concentrated,
partitioned between 0.5 M aq. NaHCO3 (75 mL) and chloro-
form (2 × 75 mL), and the combined organic layer was dried
over Na2SO4. After evaporation under vacuum, the residue was
subjected to column chromatography using a stepwise gradient
of methanol (0–6%) in chloroform (1.65 g, 77%).
To a solution of 3Ј-O-tert-butyldiphenylsilyl-2Ј-deoxycytidine
1a (3.54 g, 6.6 mmol) and 1,3-dicyclohexylcarbodiimide (4.09 g,
19.8 mmol) in dimethyl sulfoxide (25 mL) containing pyridine
(0.53 mL, 6.6 mmol) was added trifluoroacetic acid (0.25 mL,
3.3 mmol) and the mixture was stirred for 20 h. After that time,
bis(o-chlorophenyl) (triphenylphosphoranylidenemethyl)phos-
phonate (5.72 g, 9.9 mmol) was added. After 6 h the reaction
was quenched by the careful addition of a solution of oxalic
acid dihydrate (1.66 g, 13.2 mmol) in methanol (5 mL). The
urea formed was removed via filtration and washed with tolu-
ene (150 mL). The combined filtrate and washings were washed
with water (4 × 75 mL), dried over Na2SO4 and evaporated.
The residue was purified using silica gel column chromatog-
raphy with toluene–ethyl acetate (2:1) to afford the title com-
pound as a white foam (3.87 g, 70%).
Some diagnostic spectral data: 31P NMR, δ 31.4 and 31.3; 1H
#
NMR, δ 5.37 (2H, m, CH2 ), 6.30 (1H, m, H-1Ј); 13C NMR,
#
δ 62.4 (CH2 ), 86.7 and 87.0 (C-1Ј).
4-Methoxy-1-oxido-2-picolyl [1-(3Ј-O-tert-butyldiphenylsilyl-
2Ј,5Ј,6Ј-trideoxy-ꢀ-D-erythro-hexofuranosyl)-4-N-isobutyryl-
cytosin-6Ј-yl]phosphonate, triethylammonium salt 6a
1
Some diagnostic spectral data: 31P NMR, δ 12.2; H NMR,
δ 5.89 (1H, ddd, J 1.8, 17.2 and 22.0 Hz, H-6Ј), 6.41 (1H, t, J 6.6
Hz, H-1Ј), 6.62 (1H, ddd, J 4.8, 17.2 and 24.2 Hz, H-5Ј); 13C
NMR, δ 26.8 (3 × CH3t-Bu), 87.4 (C-1Ј).
Phosphonate diester 5a (1.55 g, 1.8 mmol) was dissolved in 1,4-
dioxane–water (3:1 v/v; 20 mL) and then pyridine-2-aldoxime
(0.33 g, 2.7 mmol) and 1,1,3,3-tetramethylguanidine (0.34 mL,
2.7 mmol) were added. After 1 h the reaction mixture was
partitioned between 1 M aq. TEAB (75 mL) and chloroform
(2 × 100 mL), and the combined organic phase was evaporated.
The residue was purified by silica gel column chromatography
using a stepwise gradient of methanol (0–20%) in chloroform
containing triethylamine (0.5%) (1.11 g, 72%).
Bis(o-chlorophenyl)[1-(3Ј-O-tert-butyldiphenylsilyl-2Ј,5Ј,6Ј-
trideoxy-ꢀ-D-erythro-hexofuranosyl)-4-N-isobutyrylcytosin-6Ј-
yl]phosphonate 3a
To vinylphosphonate 2a (3.75 g, 4.5 mmol), coevaporated with
and dissolved in pyridine (45 mL), was added potassium azodi-
carboxylate (3.50 g, 18.0 mmol), followed by a slow addition
(90 min) of a mixture of acetic acid (5.15 mL, 90.0 mmol) in
pyridine (5.2 mL). After stirring of the mixture overnight,
another portion of acetic acid (2.57 mL, 45.0 mmol) in pyridine
(2.6 mL) was added during 90 min. When the reaction was
complete (TLC analysis) the formed precipitate was removed,
the filtrate concentrated, and the residue partitioned between
0.5 M aq. NaHCO3 (150 mL) and chloroform (2 × 150 mL).
The combined organic phase was dried over Na2SO4, and evap-
orated with added toluene. The residue was coevaporated with
pyridine, dissolved in N,N-dimethylformamide (25 mL) and,
after addition of isobutyric anhydride (0.83 mL, 4.95 mmol),
stirred for 3 h. The reaction mixture was taken up in toluene
(250 mL) and washed with water (3 × 100 mL). The organic
phase was dried over Na2SO4, evaporated and the residue was
1
Some diagnostic spectral data: 31P NMR, δ 23.4; H NMR,
#
δ 5.08 (2H, d, JPH 7.3 Hz, CH2 ), 6.31 (1H, t, J 6.4 Hz, H-1Ј);
#
13C NMR, δ 60.6 (CH2 ), 87.5 (C-1Ј).
4-Methoxy-1-oxido-2-picolyl {1-[2Ј,5Ј,6Ј-trideoxy-3Ј-O-(4,4Ј-
dimethoxytrityl)-ꢀ-D-erythro-hexofuranosyl]-4-N-isobutyryl-
cytosin-6Ј-yl}phosphonate, triethylammonium salt 7a
Phosphonate 6a (1.02 g, 1.2 mmol) was dissolved in freshly
distilled tetrahydrofuran (12 mL) and tetrabutylammonium
fluoride trihydrate (1.51 g, 4.8 mmol) was added. After 2.5 h
water (2 mL) was added, the reaction mixture was concen-
trated, and the residue partitioned between diethyl ether (40
mL) and water (40 mL). The aqueous layer was concentrated,
the residue dissolved in water (20 mL) and the tetrabutyl-
J. Chem. Soc., Perkin Trans. 1, 1999, 2585–2590
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ammonium ions were removed by passing the solution through
an ion-exchange column (Dowex 50W, pyridinium form). The
fractions containing the product were combined and lyophil-
ized to afford the crude desilylated product. This material was
made anhydrous by evaporation of added pyridine and dis-
solved in the same solvent (12 mL). 4-(Dimethylamino)pyridine
(15 mg, 0.12 mmol) and 4,4Ј-dimethoxytrityl chloride (0.45 g,
1.3 mmol) were added and the reaction mixture was stirred at
70 ЊC for 6 h. After cooling of the product to room temper-
ature, methanol (2 mL) was added and the reaction mixture was
concentrated to near dryness. The residue was partitioned
between 1 M aq. TEAB (50 mL) and chloroform (2 × 50 mL)
and the combined organic phase was evaporated. The residue
was purified using silica gel column chromatography with a
stepwise gradient of methanol (0–25%) in chloroform contain-
ing triethylamine (0.5%) (0.58 g, 53%).
form (2 × 100 mL), and the combined organic phase was dried
over Na2SO4 and evaporated. The residue was coevaporated
with added toluene and then subjected to purification by silica
gel column chromatography using a stepwise gradient of
methanol (0–2%) in chloroform (1.44 g, 71%).
1
Some diagnostic spectral data: 31P NMR, δ 29.2; H NMR,
δ 1.55–2.36 (5H, m, H-2Ј, H2-5Ј and H2-6Ј), 6.27 (1H, dd, J 5.1
and 9.9 Hz, H-1Ј); 13C NMR, δ 21.4 (C-6Ј, d, J 141.2 Hz), 87.6
(C-1Ј).
Phenyl [9-(3Ј-O-tert-butyldiphenylsilyl-2Ј,5Ј,6Ј-trideoxy-ꢀ-
D-erythro-hexofuranosyl)-2-N-isobutyrylguanin-6Ј-yl]-
phosphonate, triethylammonium salt 4b
Phosphonate diester 3b (1.37 g, 1.7 mmol) was dissolved in the
1,4-dioxane–water (3:1 v/v; 15 mL), and pyridine-2-aldoxime
(0.62 g, 5.1 mmol) and 1,1,3,3-tetramethylguanidine (0.64 mL,
5.1 mmol) were added. The reaction mixture was stirred over-
night and then partitioned between 1 M aq. TEAB (75 mL)
and chloroform (2 × 75 mL). The combined organic phase
was evaporated and the residue was subjected to purification by
silica gel column chromatography using a stepwise gradient of
methanol (0–10%) in chloroform containing triethylamine
(0.5%) (1.11 g, 78%).
31P NMR, δ 24.4; 1H NMR, δ 1.17 (6H, d, J 6.4 Hz,
2 × CH3ibu), 1.27 (9H, t, J 7.3 Hz, 3 × CH3TEAH), 1.48–1.77 (5H,
m, H-2Ј, H2-5Ј and H2-6Ј), 2.20 (1H, m, H-2Љ), 2.58 (1H, septet,
J 6.4 Hz, CHibu), 3.03 (6H, q, J 7.3 Hz, 3 × CH2TEAH), 3.75–3.81
(10H, m, 3 × CH3O and H-4Ј), 4.00 (1H, m, H-3Ј), 5.10 (2H, d,
#
J 7.0 Hz, CH2 ), 6.28 (1H, dd, J 5.9 and 8.2 Hz, H-1Ј), 6.73 (1H,
dd, J 2.9 and 7.0 Hz, H-5#), 6.78–6.81 (4H, m, 4 × ArH), 7.15–
7.43 (11H, m, H-3#, H-5 and 9 × ArH), 7.85 (1H, d, J 7.6 Hz,
H-6), 8.14 (1H, d, J 7.6 Hz, H-6#), 8.61 (1H, br, NH), 12.88
(1H, br, TEAH); 13C NMR, δ 8.7 (3 × CH3TEAH), 19.4 and 19.3
(2 × CH3ibu), 24.2 (C-6Ј, d, JPC 138.1 Hz), 28.9 (C-5Ј), 36.2
(CHibu), 39.8 (C-2Ј), 45.5 (3 × CH2TEAH), 55.4 (2 × CH3O), 56.4
1
Some diagnostic spectral data: 31P NMR, δ 21.8; H NMR,
δ 2.88 (6H, q, J 7.3 Hz, 3 × CH2TEAH), 6.23 (1H, dd, J 5.1 and
9.9 Hz, H-1Ј); 13C NMR, δ 45.4 (3 × CH2TEAH), 87.6 (C-1Ј).
4-Methoxy-1-oxido-2-picolyl phenyl [9-(3Ј-O-tert-butyldiphenyl-
silyl-2Ј,5Ј,6Ј-trideoxy-ꢀ-D-erythro-hexofuranosyl)-2-N-iso-
butyrylguanin-6Ј-yl]phosphonate 5b
#
(CH3O), 60.8 (CH2 ), 77.2 (C-3Ј), 87.1 (C-4Ј, d, JPC 21.3 Hz),
87.3 (CDMT), 87.6 (C-1Ј), 97.0 (C-5), 108.9 (C-3#), 110.5 (C-5#),
140.2 (C-6#), 143.8 (C-6), 151.1 (C-2#, d, J 7.5 Hz), 155.4 (C-2),
159.1 (C-4#), 162.9 (C-4), 178.2 (C᎐Oibu), 113.4, 127.2, 128.0,
Phosphonate monoester 4b (1.08 g, 1.3 mmol), 4-methoxy-1-
oxidopyridine-2-methanol (0.22 g, 1.4 mmol) and 4-methoxy-
pyridine 1-oxide (0.56 g, 3.9 mmol) were rendered anhydrous by
evaporation of added pyridine and then dissolved in the same
solvent (15 mL). 2-Chloro-5,5-dimethyl-2-oxo-2λ5-1,3,2-dioxa-
phosphinane (0.72 g, 3.9 mmol) was added and the reaction
mixture was stirred for 1 h. Concentration, partitioning
between 0.5 M aq. NaHCO3 (75 mL) and chloroform (2 × 75
mL), and evaporation to dryness afforded a residue, which was
purified using silica gel column chromatography with a stepwise
gradient of methanol (0–6%) in chloroform (1.07 g, 95%).
᎐
128.4, 130.3, 130.4 (methine Cs of DMT), 136.3, 136.4, 145.2,
158.7, 158.8 (tertiary Cs of DMT); HRMS [M ϩ Na]ϩ, Found:
837.2922. C42H47N4NaO11P requires m/z, 837.2877.
Diphenyl [9-(3Ј-O-tert-butyldiphenylsilyl-2Ј,5Ј,6Ј-trideoxy-ꢀ-
D-erythro-hex-5Ј-enofuranosyl)-2-N-isobutyrylguanin-6Ј-yl]-
phosphonate 2b
3Ј-Silylated nucleoside 1b (2.02 g, 3.5 mmol) was rendered
anhydrous by evaporation of added pyridine and dissolved in
dimethyl sulfoxide (15 mL). To this were added pyridine (0.28
mL, 3.5 mmol), trifluoroacetic acid (0.14 mL, 1.8 mmol) and
1,3-dicyclohexylcarbodiimide (2.17 g, 10.5 mmol) and the reac-
tion mixture was stirred overnight. Diphenyl (triphenylphos-
phoranylidenemethyl)phosphonate (2.67 g, 5.3 mmol) was
added and the stirring was continued for 7 h. The reaction was
quenched by the careful addition of oxalic acid (0.88 g, 7.0
mmol) in methanol (5 mL). The urea formed was removed by
filtration and washed with toluene (150 mL). The combined
filtrate and washings were washed with water (4 × 100 mL),
dried over Na2SO4 and evaporated. The residue was purified by
silica gel column chromatography using toluene–ethyl acetate
(2:1 v/v) as eluent (2.10 g, 75%).
Some diagnostic spectral data: 31P NMR, δ 32.8 and 33.2; 1H
#
NMR, δ 5.14–5.45 (2H, m, CH2 ), 6.19–6.26 (1H, m, H-1Ј); 13
C
#
NMR, δ 62.0 and 62.3 (CH2 , d, JPC 5.5 Hz and d, JPC 5.5 Hz),
87.1 and 87.2 (C-1Ј).
4-Methoxy-1-oxido-2-picolyl [9-(3Ј-O-tert-butyldiphenylsilyl-
2Ј,5Ј,6Ј-trideoxy-ꢀ-D-erythro-hexofuranosyl)-2-N-isobutyryl-
guanin-6Ј-yl]phosphonate, triethylammonium salt 6b
Phosphonate diester 5b (1.04 g, 1.2 mmol) was dissolved in 1,4-
dioxane–water (3:1 v/v; 12 mL) and pyridine-2-aldoxime (0.44
g, 3.6 mmol) and 1,1,3,3-tetramethylguanidine (0.45 mL, 3.6
mmol) were added. The reaction mixture was stirred for 6 h and
then partitioned between 1 M aq. TEAB (75 mL) and chloro-
form (2 × 75 mL). The combined organic phase was evaporated
and the residue was purified by silica gel column chrom-
atography using a stepwise gradient of methanol (0–25%) in
chloroform containing triethylamine (0.5%) (0.82 g, 76%).
1
Some diagnostic spectral data: 31P NMR, δ 14.0; H NMR,
δ 5.34 (1H, dd, J 17.6 and 23.1 Hz, H-6Ј), 6.35 (1H, dd, J 5.5
and 9.9 Hz, H-1Ј), 7.99 (1H, m, H-5Ј); 13C NMR, δ 26.9
(CH3t-Bu), 88.1 (C-1Ј).
1
Diphenyl [9-(3Ј-O-tert-butyldiphenylsilyl-2Ј,5Ј,6Ј-trideoxy-
ꢀ-D-erythro-hexofuranosyl)-2-N-isobutyrylguanin-6Ј-yl]-
phosphonate 3b
Some diagnostic spectral data: 31P NMR, δ 25.1; H NMR,
#
δ 5.04 (2H, J 7.0 Hz, CH2 ), 6.21 (1H, dd, J 3.7 and 7.1 Hz,
#
H-1Ј); 13C NMR, δ 60.5 (CH2 ), 87.5 (C-1Ј).
Vinylphosphonate 2b (2.01 g, 2.5 mmol) was made anhydrous
by evaporation of added pyridine and dissolved in the same
solvent (25 mL). To this was added potassium azodicarboxylate
(1.94 g, 10.0 mmol) followed by a slow addition (80 min) of a
mixture of acetic acid (2.86 mL, 50.0 mmol) in pyridine (2.86
mL). The mixture was stirred overnight and then filtered. The
filtrate was partitioned between 0.5 M aq. NaHCO3 and chloro-
4-Methoxy-1-oxido-2-picolyl {9-[2Ј,5Ј,6Ј-trideoxy-3Ј-O-(4,4Ј-
dimethoxytrityl)-ꢀ-D-erythro-hexafuranosyl]-2-N-isobutyryl-
guanin-6Ј-yl}phosphonate, triethylammonium salt 7b
Phosphonate 6b (0.80 g, 0.90 mmol) was dissolved in freshly
distilled tetrahydrofuran (10 mL) containing tetrabutylam-
monium fluoride trihydrate (1.14 g, 3.6 mmol) and the reaction
2588
J. Chem. Soc., Perkin Trans. 1, 1999, 2585–2590

View Article Online
mixture was stirred for 5.5 h. The reaction was quenched by the
addition of water (1 mL) and the mixture was concentrated.
The residue was taken up into water (30 mL) and washed with
diethyl ether (30 mL). The removal of tetrabutylammonium
ions from the reaction mixture was carried out as described
above for 7a. The obtained crude product was coevaporated
with pyridine and then dissolved in pyridine (10 mL). 4,4Ј-
Dimethoxytrityl chloride (0.34 g, 0.99 mmol) and 4-(dimeth-
ylamino)pyridine (11 mg, 0.090 mmol) were added and the
reaction mixture was stirred at 70 ЊC overnight, allowed to
attain room temperature, and then methanol (1 mL) was added.
The reaction mixture was concentrated and partitioned between
1 M aq. TEAB (50 mL) and chloroform (2 × 50 mL). Product
7b was obtained by silica gel column chromatography using a
stepwise gradient of methanol (0–25%) in chloroform (0.35 g,
41%).
tion mixture was filtered, concentrated and partitioned between
saturated aq. NaHCO3 (150 mL) and chloroform (2 × 150 mL).
The combined organic phase was dried over Na2SO4 and con-
centrated. The residue was coevaporated with toluene and then
purified by silica gel column chromatography using a stepwise
gradient of methanol (0–2%) in chloroform (2.74 g, 88%).
1
Some diagnostic spectral data: 31P NMR, δ 26.5; H NMR,
δ 1.82–2.05 (4H, m, H2-5Ј and H2-6Ј), 6.44 (1H, t, J 6.8 Hz,
H-1Ј); 13C NMR, δ 22.4 (C-6Ј, d, JPC 144.8 Hz), 84.9 (C-1Ј).
Phenyl [9-(3Ј-O-tert-butyldiphenylsilyl-2Ј,5Ј,6Ј-trideoxy-ꢀ-D-
erythro-hexafuranosyl)-6-N-benzoyladenin-6Ј-yl]phosphonate,
triethylammonium salt 4c
To phosphonate diester 3c (2.72 g, 3.3 mmol) dissolved in 1,4-
dioxane–water (3:1 v/v; 30 mL) were added pyridine-2-
aldoxime (1.21 g, 9.9 mmol) and 1,1,3,3-tetramethylguanidine
(1.24 mL, 9.9 mmol) were added. The mixture was stirred for 7
h, partitioned between 1 M aq. TEAB (100 mL) and chloroform
(2 × 100 mL), and the combined organic phase was evaporated.
The residue was subjected to silica gel column chromatography
using a stepwise gradient of methanol (0–14%) in chloroform
(2.28 g, 81%).
31P NMR, δ 22.7; 1H NMR, δ 1.14 (1H, d, J 7.0 Hz, CH3ibu),
1.09 (3H, d, J 6.3 Hz, CH3ibu), 1.27 (9H, t, J 7.4 Hz,
3 × CH3TEAH), 1.34–2.27 (5H, m, H-2Ј, H2-5Ј and H2-6Ј), 2.48
(1H, m, H-2Љ), 2.97 (6H, q, J 7.4 Hz, 3 × CH2TEAH), 3.07 (1H,
m, CHibu), 3.77 (6H, s, 2 × CH3O), 3.78 (3H, s, CH3O), 3.96
#
(1H, m, H-4Ј), 4.13 (1H, m, H-3Ј), 5.07 (2H, d, J 4.7 Hz, CH2 ),
6.11 (1H, dd, J 5.2 and 8.6 Hz, H-1Ј), 6.74 (1H, m, H-5#), 6.81
(4H, m, 4 × ArH), 7.11 (1H, m, H-3#), 7.19–7.53 (9H, m,
9 × ArH), 7.58 (1H, s, H-8), 8.08 (1H, d, J 7.4 Hz, H-6#), 12.42
1
Some diagnostic spectral data: 31P NMR, δ 19.9; H NMR,
δ 2.95 (6H, q, J 7.3 Hz, 3 × CH2TEAH), 6.52 (1H, t, J 7.0 Hz,
H-1Ј); 13C NMR, δ 45.8 (3 × CH2TEAH), 85.2 (C-1Ј).
(1H, br, NH), 12.61 (1H, br, NH), 12.89 (1H, br, NHTEAH); 13
C
NMR, δ 8.8 (3 × CH3TEAH), 18.9 and 20.0 (2 × CH3ibu), 23.4
(C-6Ј, d, J 136.3 Hz), 29.2 (C-5Ј), 35.1 (CHibu), 37.2 (C-2Ј), 45.8
4-Methoxy-1-oxido-2-picolyl phenyl [9-(3Ј-O-tert-butyldiphenyl-
silyl-2Ј,5Ј,6Ј-trideoxy-ꢀ-D-erythro-hexafuranosyl)-6-N-benzoyl-
adenin-6Ј-yl]phosphonate 5c
#
(3 × CH2TEAH), 55.5 (2 × CH3O), 56.3 (CH3O), 60.8 (CH2 ),
78.4 (C-3Ј), 87.9 (C-4Ј, d, J 17.4 Hz), 87.5 (CDMT), 87.7 (C-1Ј),
108.3 (C-3#), 110.4 (C-5#), 123.1 (C-5), 139.0 (C-8), 139.8
(C-6#), 148.4 (C-2 and C-4), 151.3 (C-2#), 156.2 (C-6), 158.5
Phosphonate monoester 4c (2.21 g, 2.6 mmol), 4-methoxy-1-
oxidopyridine-2-methanol (0.44 g, 2.9 mmol) and 4-methoxy-
pyridine 1-oxide (1.12 g, 7.8 mmol) were rendered anhydrous by
evaporation of added pyridine and then dissolved in the same
solvent (25 mL). 2-Chloro-5,5-dimethyl-2-oxo-2λ5-1,3,2-dioxa-
phosphinane (1.44 g, 7.8 mmol) was added, and the reaction
mixture was stirred for 3 h, and then partitioned between 0.5 M
aq. NaHCO3 (150 mL) and chloroform (2 × 100 mL). The
organic layer was dried over Na2SO4, evaporated, and the
residue was subjected to silica gel column chromatography
using a stepwise gradient of methanol (0–5%) in chloroform
(2.26 g, 98%).
(C-4#), 181.6 (C᎐Oibu), 113.4, 113.5, 127.3, 128.2, 128.5, 130.2,
᎐
130.4 (methine Cs of DMT), 136.4, 136.6, 145.3, 158.9, 159.0
(tertiary Cs of DMT); HRMS [M ϩ Na]ϩ, Found: 877.3007.
C43H47N4NaO11P requires m/z, 877.2938.
Diphenyl [9-(3Ј-O-tert-butyldiphenylsilyl-2Ј,5Ј,6Ј-trideoxy-ꢀ-
D-erythro-hex-5-enofuranosyl)-6-N-benzoyladenin-6Ј-yl]phos-
phonate 2c
3Ј-Silylated nucleoside 1c (5.64 g, 9.5 mmol) was rendered
anhydrous by evaporated of added pyridine and dissolved in
dimethyl sulfoxide (40 mL). To this were added 1,3-dicyclo-
hexylcarbodiimide (5.88 g, 28.5 mmol), pyridine (0.77 mL,
9.5 mmol) and trifluoroacetic acid (0.37 mL, 4.8 mmol) and
the reaction mixture was stirred for 7 h. Diphenyl (triphenyl-
phosphoranylidenemethyl)phosphonate was added and the
stirring was continued overnight. Oxalic acid (2.40 g, 19.0
mmol) as a solution in methanol (10 mL) was added carefully.
The urea formed was removed via filtration, washed with tolu-
ene (200 mL) and the combined organic phases were washed
with water (4 × 100 mL), dried over Na2SO4 and evaporated.
The residue was purified using silica gel column chromato-
graphy with toluene–ethyl acetate (2:1, v/v) as eluent (6.07 g,
78%).
Some diagnostic spectral data: 31P NMR, δ 30.8 and 30.9;
#
1H NMR, δ 5.22–5.28 (2H, m, CH2 ), 6.42–6.49 (1H, m, H-1Ј);
#
13C NMR, δ 62.2 (CH2 ), 84.8 and 84.9 (C-1Ј).
4- Methoxy-1-oxido-2-picolyl [9-(3Ј-O-tert-butyldiphenylsilyl-
2Ј,5Ј,6Ј-trideoxy-ꢀ-D-erythro-hexafuranosyl)-6-N-benzoyl-
adenin-6Ј-yl]phosphonate, triethylammonium salt 6c
To phosphonate diester 5c (2.21 g, 2.5 mmol), dissolved in 1,4-
dioxane–water (3:1 v/v; 20 mL), were added pyridine-2-
aldoxime (0.92 g, 7.5 mmol) and 1,1,3,3-tetramethylguanidine
(0.94 mL, 7.5 mmol). The reaction mixture was stirred for 6.5 h,
concentrated, and the residue was partitioned between 1 M aq.
TEAB (100 mL) and chloroform (2 × 100 mL). The combined
organic phase was evaporated and the residue was purified by
silica gel column chromatography using a stepwise gradient of
methanol (0–25%) in chloroform (1.87 g, 82%).
1
Some diagnostic spectral data: 31P NMR, δ 11.6; H NMR,
δ 5.95 (1H, ddd, J 1.8, 16.9 and 21.6, H-6Ј), 6.55–6.77 (2H, m,
H-1Ј and -5Ј); 13C NMR, δ 26.9 (3 × CH3t-Bu), 85.3 (C-1Ј).
1
Some diagnostic spectral data: 31P NMR, δ 25.8; H NMR,
#
Diphenyl [9-(3Ј-O-tert-butyldiphenylsilyl-2Ј,5Ј,6Ј-trideoxy-ꢀ-D-
erythro-hexafuranosyl)-6-N-benzoyladenin-6Ј-yl]phosphonate 3c
δ 5.05 (2H, d, J 7.0 Hz, CH2 ), 6.54 (1H, t, J 6.8 Hz, H-1Ј);
#
13C NMR, δ 60.7 (CH2 , d, JPC 3.7 Hz), 84.5 (C-1Ј).
To vinylphosphonate 2c (3.12 g, 3.8 mmol), coevaporated with
added pyridine and dissolved in the same solvent (40 mL), was
added potassium azodicarboxylate (2.95 g, 15.2 mmol), fol-
lowed by a slow addition (135 min) of a mixture of acetic acid
(4.35 mL, 76.0 mmol) in pyridine (4.35 mL). The reaction mix-
ture was left for 3 h and then an additional portion of acetic
acid (4.35 mL, 15.2 mmol) in pyridine (4.35 mL) was added
dropwise during 30 min. After an additional 30 min, the reac-
4-Methoxy-1-oxido-2-picolyl {9-[2Ј,5Ј,6Ј-trideoxy-3Ј-O-(4,4Ј-
dimethoxytrityl)-ꢀ-D-erythro-hexafuranosyl]-6-N-benzoyladenin-
6Ј-yl}phosphonate, triethylammonium salt 7c
To phosphonate 6c (0.51g, 0.56 mmol), coevaporated twice
with added acetonitrile (20 mL) and then dissolved in freshly
distilled tetrahydrofuran (3 mL), was added triethylamine
trishydrofluoride (0.36 mL, 2.2 mmol), and the reaction mixture
J. Chem. Soc., Perkin Trans. 1, 1999, 2585–2590
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was stirred for 48 h. After addition to diethyl ether–acetonitrile
(3:1 v/v; 200 mL) at Ϫ70 ЊC, the formed precipitate was col-
lected, evaporated twice with added acetonitrile, and dissolved
in a mixture of tetrahydrofuran–dimethylformamide (1:1 v/v;
10 mL). To this were added AgNO3 (0.23 g, 1.3 mmol) and 4,4Ј-
dimethoxytrityl chloride (0.45 g, 1.3 mmol) and the reaction
mixture was kept in the dark overnight. Methanol (0.5 mL) was
added, the reaction mixture was stripped of low boiling con-
tents, and the residue was filtered through a pad of Celite
and washed with methylene dichloride (100 mL). The organic
phase was washed with 1 M aq. TEAB (100 mL) and then the
aqueous layer was extracted once with methylene dichloride
(100 mL). The organic layers were combined and evaporated,
and the residue was purified using silica gel column chrom-
atography with a stepwise gradient of methanol (0–20%) in
methylene dichloride containing triethylamine (0.5%) (0.36 g,
67%).
Acknowledgements
We are indebted to Professor Per J. Garegg for his interest in
this work. Financial support from the Swedish Natural Science
Research Council and the Swedish Foundation for Strategic
Research is gratefully acknowledged.
References
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31P NMR, δ 26.3; 1H NMR, δ 1.25 (9H, t, J 7.6 Hz,
3 × CH3TEAH), 1.43–1.91 (5H, m, H-2Ј, H2-5Ј and H2-6Ј), 2.20–
2.29 (1H, m, H-2Љ), 3.00 (6H, q, J 7.6 Hz, 3 × CH2TEAH), 3.76–
#
3.79 (9H, m, 3 × CH3O), 5.08 (2H, d, J 7.0 Hz, CH2 ), 6.45 (1H,
dd, J 8.2 and 5.9 Hz, H-1Ј), 6.69 (1H, dd, J 2.9 and 7.0 Hz,
H-5#), 6.82–6.85 (1H, m, 4 × ArH), 7.18–7.59 (13H, m, H-3#
and 12 × ArH), 8.02–8.08 (3H, m, 2 × ArH and H-6#), 8.12 and
8.72 (2H, 2s, H-8 and H-2), 9.47 (1H, br, NH), 12.8 (1H, br,
TEAH); 13C NMR, δ 8.7 (3 × CH3TEAH), 23.8 (C-6Ј, d, JPC
137.0 Hz), 28.8 (C-5Ј), 38.6 (C-2Ј), 45.5 (3 × CH2TEAH), 55.4
#
(2 × CH3O), 56.4 (CH3O), 60.8 (CH2 ), 77.4 (C-3Ј), 84.7
(C-1Ј), 87.0 (C-4Ј, d, JPC 17.3 Hz), 87.4 (CDMT), 108.7 (C-3#),
110.5 (C-5#), 124.1 (C-5), 139.9 (C-6#), 141.7 (C-8), 150.0
(C-4), 151.3 (C-2#, d, J 7.5 Hz), 151.9 (C-6), 152.4 (C-2), 159.1
(C-4#), 165.7 (C᎐Obz), 113.4, 113.5, 127.2, 128.1, 128.3, 128.4,
18 Y. Mizuno and T. Endo, J. Org. Chem., 1978, 43, 684.
19 J. Thiele, Justus Liebigs Ann. Chem., 1892, 271, 127.
᎐
128.7, 130.3, 130.4, 132.6 (methine Cs of Ar), 133.9, 136.2,
136.4, 145.2, 158.8, 158.9 (tertiary Cs of Ar); HRMS
[M ϩ Na]ϩ, Found: 895.2899. C46H45N6NaO10P requires m/z,
895.2833.
Paper 9/06066I
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J. Chem. Soc., Perkin Trans. 1, 1999, 2585–2590