Synthesis and Antiviral Evaluation of 3'-C-Hydroxymethyl-3'-O-Phosphonomethyl-β-D-5'-deoxyxylose Nucleosides

Article abstract of DOI:10.1002/ejoc.202000831

L-2'-deoxythreose nucleoside phosphonates PMDTA and PMDTT possess potent anti-HIV activity. Herein, a novel class of 3'-C-branched-l-threose nucleoside phosphonate analogs, 5'-deoxy-3'-C-hydroxymethyl-3'-O-phosphonomethyl-d-xylose nucleosides, were synthesized and biologically evaluated. The key sugar intermediate 3-C-benzyloxymethyl-3-O-diethylphosphonomethyl-1,2-O-isopropylidene-α-d-5-deoxyxylose (8) was firstly synthesized, which may be an interesting scaffold for access to diverse 3'-C-branched l-threosyl nucleoside phosphonate derivatives. And the key synthesis involved Wittig olefination of 1,2-O-isopropylidene-3-oxo-α-d-5-deoxyxylose, stereoselective dihydroxylation of alkenes by aqueous KMnO₄, selective benzylation of hydroxymethyl group under activation of dibutyltin oxide, and introduction of phosphonate group by nucleophilic substitution. Eventually, glycosylation under Vorbrüggen conditions provided 3'-C-hydroxymethyl-3'-O-phosphonomethyl-β-d-5'-deoxyxylose nucleoside analogs in satisfying yield.

Full text of DOI:10.1002/ejoc.202000831

Full Paper
doi.org/10.1002/ejoc.202000831
EurJOC
European Journal of Organic Chemistry
Nucleoside Phosphonates
Synthesis and Antiviral Evaluation of 3′-C-Hydroxymethyl-3′-O-
Phosphonomethyl-ꢀ-D-5′-deoxyxylose Nucleosides
Shujie Ji,[a][‡] Song Wang,[a][‡] Haixia Wang,[a] Yingying Gao,[a] Wenke Xu,[a] Xiangyu Huo,[a]
Piet Herdewijn,[b] and Feng-Wu Liu*[a]
Abstract: L-2′-deoxythreose nucleoside phosphonates PMDTA side phosphonate derivatives. And the key synthesis involved
and PMDTT possess potent anti-HIV activity. Herein, a novel Wittig olefination of 1,2-O-isopropylidene-3-oxo-α-
class of 3′-C-branched- -threose nucleoside phosphonate ana- xylose, stereoselective dihydroxylation of alkenes by aqueous
logs, 5′-deoxy-3′-C-hydroxymethyl-3′-O-phosphonomethyl- KMnO4, selective benzylation of hydroxymethyl group under
D-5-deoxy-
L
D
-
xylose nucleosides, were synthesized and biologically evalu- activation of dibutyltin oxide, and introduction of phosphonate
ated. The key sugar intermediate 3-C-benzyloxymethyl-3-O-di- group by nucleophilic substitution. Eventually, glycosylation un-
ethylphosphonomethyl-1,2-O-isopropylidene-α-
xylose (8) was firstly synthesized, which may be an interesting phosphonomethyl-ꢀ-
D
-5-deoxy- der Vorbrüggen conditions provided 3′-C-hydroxymethyl-3′-O-
-5′-deoxyxylose nucleoside analogs in
D
scaffold for access to diverse 3′-C-branched L-threosyl nucleo- satisfying yield.
Introduction
Viral infections are a leading cause of death worldwide and
significantly affect global health. Despite the rapid progress in
the development of various vaccines and antiviral drugs, there
are often no effective vaccines or antiviral therapies available
to control fatal outbreaks due to the generation of viral mu-
tants, the emergence of new strains and developing resistance
towards drugs. Therefore the search for new antiviral com-
pounds that are more potent and effective against viruses with
low cytotoxicity is always necessary and significant. Evidence
has shown that effective drug treatment can not only control
the development of viral disease but also reduce its transmis-
sion.[1] Nucleoside analogs are a key class of agents for the
treatment of viral diseases.[2] To date, many nucleoside drugs
have been widely used in clinical practice,[3] such as Clevudi,
telbivudine, chidovudine, and cidofovir (Figure 1). In addition,
Remdesivir, a small-molecule broad-spectrum antiviral drug de-
veloped by Gilead Sciences, is also a nucleoside analog that is
expected to be used to treat COVID-19 and Ebola viruses.[4] The
nucleoside drugs that are currently also used in antitumor and
antifungal therapy,[5] which makes nucleoside analogs more at-
tractive[6] in the pharmaceutical field.
Figure 1. Structures for PMDTA and PMDTT (a), their 2′-hydroxyl analogs (b)
and target compounds 15.
Effective structural modification of sugar rings or bases is an
important method to obtain new nucleoside analogs.[7] In our
research,
L-threose was selected as the basic motif for sugar
modifications, and a series of modified
L-threose nucleoside
phosphonate analogs were synthesized and evaluated for their
antiviral activities. It is well known that most nucleoside analogs
undergo three consecutive phosphorylation reactions to pro-
duce biologically active triphosphate analogs, which exhibits
antiviral effects as a substrate for viral RNA or DNA polymerase.
In this process, the first phosphorylation reaction is generally
inefficient and is a rate-limiting step.[8] Meanwhile, nucleoside
monophosphate molecules are extremely unstable in human
blood or cells due to the effect of phosphatase. In order to
address the above problems, a phosphonate, the isosteric ana-
log of a nucleoside monophosphate, was first selected as a
good alternative for mononucleotide by Clercq and Holy.[9]
Herdewijn and co-workers[10] were the first to report that 1-
[a] S. Ji, S. Wang, H. Wang, Y. Gao, W. Xu, X. Huo, Prof. Dr. F.-W. Liu
Key Laboratory of Technology of Drug Preparation, Ministry of Education
of China; School of Pharmaceutical Sciences, Zhengzhou University,
Zhengzhou 450001, PR China
(Adenin-9-yl)-3′-O-phosphonomethyl-
(PMDTA, EC50 = 2.5 μ ) and 1-(Thymin-1-yl)-3′-O-phosphono-
methyl- -2′-deoxythreose (PMDTT, EC50 = 6.59 μ ) selectively
L
-2′-deoxythreose
[b] Prof. Dr. P. Herdewijn
Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven,
Herestraat 49, 3000, Leuven, Belgium
E-mail: fwliu@zzu.edu.cn (F.-W. Liu)
M
L
M
inhibit HIV without affecting normal cell proliferation (Fig-
[‡] Both authors contribute equally to this work.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202000831.
ure 1a). Meanwhile, the 2′-hydroxyl counterpart (3′-O-phos-
phonomethyl-
-threose nucleosides)[10] and 3′-S-phosphono-
L
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methyl-
cant antiviral and antitumor activity. Being interested in the nu- nished sugar ketone 4 in 77 % yield. 3-Methene furanose 5 was
cleoside phosphonate with modification of the -threose skele- obtained through a Wittig reaction of 4 with the ylide gener-
ton, we designed and synthesized a series of novel -threose ated from a phosphonium salt. Oxidation of compound 5 with
nucleoside analogs: 3′-C-hydroxymethyl-3′-O-phosphono- dilute neutral potassium permanganate gave oily vicinal diol 6
methyl- -5′-deoxyxylose nucleosides (Figure 1, 15). Herein we with a yield of 58 %.
L
-threose nucleosides[11] (Figure 1b) showed no signifi- in 94 % yield. Oxidation of 3-hydroxyl group of 3 with PDC fur-
L
L
D
report the synthesis and the result for the biological evaluation
of the target compounds.
Attempts to determine of the absolute configuration of C-3
in compound 6 was unsuccessful by NOESY analysis, thus the
X-ray single-crystal diffraction method was used to confirm the
configuration further. Conversion of the oily compound 6 into
a crystallizable solid was achieved by selective tosylation of 3-
C-hydroxymethyl group to produce tosylate of 6. Single crystal
of the tosylated 6 was obtained by vapor-phase diffusion
method using n-hexane and ethyl acetate co-solvent system.
The absolute configuration of C-3 was well established as the
desired 3S-configuration by X-ray crystallographic analysis of
the suitable single crystal of tosylated 6 (as shown in Figure 2,
CCDC No. 2012122). This result indicated that the permanga-
nate attacked C=C bond from the less-hindered face (opposite
to isopropylidene group) of furanose ring to form two vicinal C–
O bonds, resulting in the stereoselective formation of 3S-carbon
stereogenic center.
Results and Discussion
The retro-synthetic analysis for the target compounds 15 start-
ing from
D-xylose is shown in Scheme 1. Target nucleoside
phosphonates 15 can be obtained by glycosylation of the sugar
phosphonate 11 and subsequent deprotection. Compound 11
is prepared by acetolysis of 1,2-O-isopropylidenylfuranose inter-
mediate 8 and the following benzoylation. Compound 8 is de-
rivatived from 6 by selective introduction of phosphonate func-
tion to 3-hydroxy group. Compound 6 is synthesized from sugar
ketone 4. Compound 4 is obtained by a consecutive four-step
modification of D-xylose.
Scheme 1. Retrosynthesis route of target compound 15.
Figure 2. The absolute configuration of tosylated 6.
As shown in Scheme 2, intermediate 6 was synthesized via
key sugar ketone 4 starting from commercially available
D-
Deposition Number 2012122 (for 6) contains the supplementary
crystallographic data for this paper. These data are provided free of
charge by the joint Cambridge Crystallographic Data Centre and
Fachinformationszentrum Karlsruhe Access Structures service
www.ccdc.cam.ac.uk/structures.
xylose. The 1,2-dihydroxyl groups of -xylose were selectively
D
protected with isopropylidene group by using acetone accord-
ing to the ref.[12] with some modifications, to generate 1,2-O-
isopropylidene-
D
-xylose (1) in 79 % yield. Tosylation of the free
primary hydroxyl group at C-5 of 1 by tosyl chloride in pyridine
Phosphonate furanose 11 was obtained by selective intro-
gave compound 2. Reductive removal of tosylate group using duction of phosphonate group to 3-hydroxyl of 6 and further
LAH (lithium aluminum hydride) afforded 4-methylfuranose 3 conversion of 1,2-O-isopropylidene into 1,2-O-diacyl groups as
Scheme 2. Synthesis of 3-C-hydroxymethyl-1,2-O-isopropylidene-D-5-deoxyxylose. (a) H2SO4, acetone, r.t., 9 h, 79 %; (b) TsCl, Pyr, 0 °C to r.t., 10 h, 84 %; (c)
LiAlH4, THF, 0 °C to r.t., 6 h, 94 %; (d) PDC, Ac2O, DCM, reflux, 6 h, 77 %; (e) Ph3P+CH3Br–, NaH, tert-amyl alcohol, THF, 0 °C to r.t., 7 h, 76 %; (f) KMnO4, acetone,
0 °C, 4 h, 58 %.
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Scheme 3. Synthesis of 1-O-acetyl-2-O-benzoyl-3-C-hydroxymethyl-3-O-phosphonomethyl-D-5-deoxyxylose (11). (a) (1) Bu2SnO, toluene, 140 °C, 2 h; (2) TBAB,
BnBr, 100 °C, 8 h, 90 %. (b) NaH, (EtO)2P(=O)CH2OTs, THF, 45 °C, 72 h, 52 %; (c) H2SO4, MeOH, 50 °C, 17 h, 68 %; (d) BzCl, Pyr, 0 °C to r.t., 6.5 h, 96 %; (e) Ac2O,
AcOH, H2SO4, r.t., 8 h, 89 %.
shown in Scheme 3. In order to selectively functionalize 3-
hydroxyl group of compound 6, the primary hydroxyl group of
6 was selectively protected with benzyl group via dibutyltin
oxide activation according to the procedure described in ref.[13]
to afford compound 7 in 90 % yield. Alkylation of 3-hydroxyl
group of 7 with tosylate of diethylphosphonomethanol in the
presence of NaH gave compound 8 with a yield of 52 %. Alco-
holysis of 8 by methanol under the catalysis of sulfuric acid
allowed to provide methyl glycoside 9 as an α/ꢀ anomeric mix-
ture in 68 % yield. It was known that the presence of the 2-
O-acyl group in sugar precursor would allowed stereoselective
introduction of the base moiety on C1-position of sugar during
Vorbrüggen glycosylation for nucleoside synthesis, and espe-
cially 2-O-benzoyl sugar will be more advantageous than 2-O-
acetoxy counterpart. Therefore compound 9 was benzoylated
with benzoyl chloride in pyridine to provide 10 in 96 % yield,
and then acetoxy exchange of 1-methoxy afforded more reac-
tive sugar precursor 11 as an α/ꢀ anomeric mixture in 89 %
yield.
Target nucleoside phosphonates 15a–15e were obtained by
Scheme 4. Synthesis of target nucleoside phosphonates 15a–15e. (a) BSA,
TMSOTf, uracil for 12a, thymine for 12b, N4-benzoylcytosine for 12c, 5-chloro-
uracil for 12d, 6-chloroadenine for 12e, CH3CN; (b) Pd/C, H2, MeOH, r.t.;
(c) BzCl, Pyr, r.t.; (d) NH3/CH3OH, r.t.; (e) TMSBr, 2,6-lutidine, CH3CN, r.t.
Vorbrüggen glycosylation of sugar precursor 11 or its altenative
16 with various base moieties and followed by deprotection
reactions as shown in Scheme 4.
Vorbrüggen glycosylation of sugar precursor 11 with uracil
and thymine using N,O-bis(trimehtylsilyl)acetamide (BSA) as a
silylating agent and trimethylsilyl trifluoromethanesulfonate
(TMSOTf) as Lewis acid gave corresponding protected nucleo-
side 12a and 12b, in 78 % and 89 % yields, respectively. Like-
wise, glycosylation of 4-Benzoylcytosine, 5-Cl-uracil and 6-Cl-
purine also afforded corresponding protected nucleosides suc-
cessfully, however, further deprotection of benzyl group by cat-
alytic hydrogenation didn't succeed, and the undesired reduc-
on phosphonate compounds 14a–14b and 13c–13e were hy-
drolyzed with TMSBr/2,6-lutidine at room temperature. After
purification by C18-silica gel chromatography, nucleoside phos-
phonic acids 15a–15e were obtained as white foamy solids.
Conclusion
tion of the chlorine from 5-chlorouracil and 6-chloroadenine An effective synthetic methodology to obtain 3′-C-branched-3′-
was observed. Therefore, the deprotection of the benzyl group O-phosphonomethyl-
-threosyl nucleoside phosphonates was
in 11 by catalytical hydrogenation, followed by protection with developed starting from
-xylose. A series of novel 3′-C-
benzoyl group to provide precursor 16. Replacement of 11 with branched
-threosyl nucleoside phosphonate analogs (15a–
L
D
L
precursor 16 in the Vorbrüggen glycosylation gave 12c, 12d, 15e) bearing a 3′-C-hydroxylmethyl group and diverse base
and 12e smoothly. Deprotection of benzoyl groups of 12a–12e moieties have been synthesized. The absolute configuration of
by saturated ammonia in methanol produced 13a–13e. Reduc- the newly generated stereocenter at C-3′ was confirmed by X-
tive removal of benzyl group of 13a and 13b by Pd/C catalytic ray single-crystal diffraction method. Unfortunately, no signifi-
hydrogenation afforded 14a and 14b. The diethyl ester groups cant in vitro biological activities were observed against HBV,
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p-toluenesulfonyl chloride (22 g, 116 mmol) was added in portions
at 0 °C under nitrogen. After the mixture was stirred at room tem-
perature for 10 h, 10 mL of water was added to quench the reaction.
The resulted mixture was concentrated under reduced pressure, the
residue was partitioned between 100 mL of saturated sodium chlor-
ide solution and 50 mL of dichloromethane (DCM). The water layer
was extracted with 50 mL of DCM three times. The combined or-
ganic layer was dried with Na2SO4, concentrated to dryness. The
residue was recrystallized with PE and EA (3:1) to provide most of
the target compound. The filtrate was concentrated and purified by
silica gel column chromatography (petroleum ether/ethyl acetate =
5:1–1:1) to allow the second part of 2. Compound 2 (30.5 g in total,
88 mmol) was obtained as a white solid with a yield of 84 %.
HSV, and RSV as well as against tumor cells MCF-7 and PC-3.
The possible reason for lack of biological activity may be due
to the poor cellular permeability of these negative charged
phosphonic acid groups at physiological pH. Further bioactive
evaluation of the target compounds is undergoing in our labo-
ratory. Moreover, the key intermediate 1,2-O-isopropylidene-3-
O-phosphonomethyl-3-C-hydroxymethyl-
provide a useful platform for access to diverse 3′-C-branched
-threosyl nucleoside phosphonate derivatives bearing interest-
D-5-deoxyxylose will
L
ing 3′-C modifications such as a vinyl, ethynyl or alkyl group.
1
Experimental Section
2: H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.3 Hz, 2H, Ar-H), 7.36
(d, J = 8.0 Hz, 2H, Ar-H), 5.88 (d, J = 3.6 Hz, 1H, H-1), 4.51 (d, J =
3.6 Hz, 1H, H-2), 4.40–4.26 (m, 3H, H-5a, H-3, H-4), 4.14 (dd, J = 14.0,
8.9 Hz, 1H, H-5b), 2.46 (s, 3H, Ar-CH3), 2.40 (d, J = 5.1 Hz, 1H, OH),
1.46 (s, 3H, CH3), 1.30 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3):
δ = 145.3, 132.4, 130.0, 128.0 (Ar-C), 112.1 (CMe2), 105.0 (C-1), 85.0
(C-2), 77.6 (C-4), 74.3 (C-3), 66.2 (C-5), 26.8 (CH3), 26.2 (CH3), 21.7
(Ar-CH3).
General Information: Except in special cases, all reactants and rea-
gents were obtained commercially and were not reprocessed. The
required anhydrous reagents are all treated by standard methods.
Dichloromethane, acetonitrile, and pyridine are treated with cal-
cium hydride, THF is treated with sodium particles, and benzophen-
one is used as an indicator. Moisture-sensitive reactions are carried
in dried glassware and are protected with nitrogen. Thin-layer chro-
matography (TLC) was performed on a glass plate precoated with
silica gel GF 254 (5–40 μm) and detected by placing it under an
ultraviolet lamp or by spraying the chromatogram with 5 % ethanol
phosphomolybdic acid and charring them using a heat gun. 1H, 13C,
and 31P NMR spectra were recorded on Bruker AVANCE III 400 MHz
5-Deoxy-1,2-O-isopropylidene-α-D-xylose (3): LiAlH4 (6.61 g,
174 mmol) was added to the cold anhydrous tetrahydrofuran
(350 mL) in portions under nitrogen. After the mixture was stirred
in an ice-water bath for 30 min, compound 2 (40 g, 116 mmol) was
added. The mixture was stirred in an ice-water bath for another
spectrometer with tetramethylsilane as the internal standard. 300– 30 min, then continued to stir at room temperature for 5 h. The
400 mesh silica gel was used as the stationary phase of the chroma-
tography column.
reaction was quenched by dropwise addition of water (20 mL) un-
der ice-water cooling. Then 20 mL of 15 % aqueous NaOH was
added and stirred for 40 minutes. The resulted slurry was filtered
through Celite, the cake was dispersed in 100 mL of ethyl acetate
and filtered. The dispersion and filtration were repeated twice. The
combined filtrate was dried with anhydrous sodium sulfate and
concentrated. The residue was purified by silica gel column chroma-
tography (PE/EA= 5:1–2:1) to give off-white crystalline solid 3
(18.9 g, 108.5 mmol) in 94 % yield.
X-ray Diffraction Experiment: X-ray diffraction analysis was carried
out on a Rigaku Oxford Xcalibur Gemini, Eos CCD diffractometer
with graphite-monochromated Cu-Kα (λ = 1.54184Å) radiation. A
monoclinic crystal was selected and mounted on a glass fiber. The
crystal was kept at 293(2) K during data collection. The structure
was solved with the ShelXS structure solution program[14] using
direct methods and refined with the ShelXL refinement package[15]
using Least Squares minimization. The non-hydrogen atoms were
refined with anisotropic thermal parameters. Hydroxyl hydrogen
1
3: H NMR (400 MHz, CDCl3): δ = 5.89 (d, J = 3.8 Hz, 1H, H-1), 4.53
(d, J = 3.8 Hz, 1H, H-2), 4.32 (qd, J = 6.5, 2.5 Hz, 1H, H-4), 3.99 (s,
atoms were refined with isotropic thermal parameters. Other hydro- 1H, H-3), 1.50 (s, 3H, CCH3), 1.31 (s, 3H, CCH3), 1.30 (d, J = 6.5 Hz,
gen atoms were included but not refined. All calculations were per- 3H, H-5). 13C NMR (101 MHz, CDCl3) δ = 111.4 (CMe2), 104.4 (C-1),
formed using the CrysAlisPro crystallographic software system.[16]
85.5 (C-2), 76.4 (C-4), 75.9 (C-3), 26.6 (CH3), 26.1 (CH3), 12.7 (C-5).
1,2-O-Isopropylidene-α-D-xylose (1):
was suspended in 500 mL of acetone in an ice-water bath, then
concentrated sulfuric acid (40 mL, 747 mmol) was added dropwise
D
-xylose (50 g, 333 mmol)
5-Deoxy-1,2-O-isopropylidene-3-oxo-α-D-xylose (4): To a solu-
tion of 3 (3.5 g, 20.1 mmol) in 80 mL of anhydrous dichloromethane
was added Pyridinium dichromate (9.07 g, 24.1 mmol) and acetic
in 30 min. The reaction mixture was stirred at room temperature anhydride (2.83 mL, 30 mmol) at 0 °C under nitrogen. After stirring
for 6 h. 140 mL of a 30 % aqueous sodium hydroxide was added
dropwise in an ice-water bath to adjust the pH of the mixture to
1–2. The reaction was stirred at room temperature for 2 h and then
at the same temperature for 20 min, the mixture was heated to
reflux and maintained for 6 h. Most of the solvent was evaporated
under reduced pressure. 100 mL of ethyl acetate was added to the
3 g solid NaOH was added to adjust the pH to 7–8. The precipitate residue and stirred for 30 min, the resulting slurry was filtered. Chro-
was filtered out, and the cake was washed with acetone. The com-
bined filtrate was concentrated, the residue was purified by silica
gel column chromatography (PE/EA = 3:1–1:1) to give compound 1
(50 g, 263 mmol) in 79 % yield as a yellowish oil.
mium salt cake was washed with ethyl acetate twice. The combined
filtrate was dried with Na2SO4, concentrated and purified by silica
gel column chromatography (PE/EA= 5:1–1:1) to obtain compound
4 (2.68 g, 15.6 mmol) in 77 % yield as pale yellow oil.
1
1
1: H NMR (400 MHz, [d6]DMSO): δ = 5.80 (d, J = 3.7 Hz, 1H, H-1),
4: H NMR (400 MHz, CDCl3): δ = 6.05 (d, J = 4.5 Hz, 1H, H-1), 4.44
5.14 (d, J = 4.8 Hz, 1H, OH), 4.62 (t, J = 5.7 Hz, 1H, H-3), 4.37 (d, J =
3.7 Hz, 1H, H-2), 4.02–3.93 (m, 2H, H-4, OH), 3.60 (m, 1H, H-5a), 3.51
(m, 1H, H-5b), 1.38 (s, 3H, CH3), 1.23 (s, 3H, CH3). 13C NMR (101 MHz,
[d6]DMSO): δ = 110.2 (CMe2), 104.2 (C-1), 85.0 (C-2), 81.3 (C-4), 73.4
(C-3), 58.8 (C-5), 26.6 (CH3), 26.1 (CH3).
(q, J = 6.8 Hz, 1H, H-4), 4.35 (d, J = 4.4 Hz, 1H, H-2), 1.51 (s, 3H, CH3),
1.40 (s, 3H, CH3), 1.32 (d, J = 6.8 Hz, 3H, H-5). 13C NMR (101 MHz,
CDCl3): δ = 208.6 (C-3), 112.8 (CMe2), 101.2 (C-1), 74.6 (C-2), 72.6 (C-
4), 26.1 (CH3), 25.9 (CH3), 14.4 (C-5).
5-Deoxy-1,2-O-isopropylidene-3-methene-α-D-xylose (5): Meth-
yltriphenylphosphine bromide (4.98 g, 13.94 mmol) and tert-amyl
alcohol (1.65 mL, 15.10 mmol) were sequentially added to 60 mL of
1,2-O-Isopropylidene-5-O-tosyl-α-D-xylose (2): Compound
1
(20 g, 105 mmol) was dissolved in 200 mL of anhydrous pyridine,
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anhydrous THF under nitrogen. To the solution, NaH (60 % in min- in the ice-water bath for 30 min and then heated to 45 °C for 72 h.
eral oil, 0.93 g, 23.23 mmol) was added with cooling in an ice bath.
The mixture was stirred at 0 °C for 30 min and at room temperature
The reaction mixture was quenched by adding 50 mL of saturated
aqueous NaCl, then THF was evaporated under reduced pressure.
for 3 h. A solution of compound 4 (2 g, 11.62 mmol) in anhydrous The resulting solution was extracted with ethyl acetate (4 × 30 mL).
THF (20 mL) was added dropwise to the above solution in an ice- The combined organic layer was dried with anhydrous sodium sulf-
water bath. The mixture was stirred at room temperature for 4 h. ate, concentrated, and purified by silica gel column chromatogra-
30 mL of saturated ammonium chloride solution was added to
quench the reaction. After rotary evaporation of THF, the residue
was extracted with EA (20 mL × 4). The combined organic layer was
dried with anhydrous sodium sulfate, concentrated, and purified by
silica gel column chromatography (PE/EA = 20:1–10:1) to obtain a
colorless oil 5 (1.5 g, 8.8 mmol) in 76 % yield.
phy (PE/EA= 5:1–1:1) to give compound 8 (2.5 g, 5.62 mmol) as a
pale yellow oil in 52 % yield.
8: 1H NMR (400 MHz, CDCl3): δ = 7.36–7.27 (m, 5H, Ar-H), 5.85 (d,
J = 3.8 Hz, 1H, H-1), 4.59 (d, J = 4.0 Hz, 1H, H-2), 4.57 (d, J = 12.1 Hz,
1H, ArCH2O), 4.52 (d, J = 12.1 Hz, 1H, ArCH2O), 4.20 –4.08 (m, 5H,
H-4, PCH2O, OCH2CH3), 4.07–4.00. (m, 2H, OCH2CH3), 3.81 (d, J =
11.0 Hz, 1H, CCH2O), 3.62 (d, J = 11.0 Hz, 1H, CCH2O), 1.47 (s, 3H,
CCH3), 1.33–1.25 (m, 12H, H-5, OCH2CH3, CCH3). 13C NMR (101 MHz,
CDCl3): δ = 137.7, 128.4, 127.7, 127.6 (Ar-C), 111.9 (CMe2), 104.4 (C-
1), 86.5 (d, JC,P = 11.0 Hz, C-3), 81.7 (C-2), 79.2 (ArCH2), 73.7 (CH2O),
68.5 (C-4), 62.7 (d, JC,P = 6.4 Hz, CH2), 62.5 (d, JC,P = 6.4 Hz, CH2),
1
5: H NMR (400 MHz, CDCl3): δ = 5.80 (d, J = 4.1 Hz, 1H, H-1), 5.32
(d, J = 1.6 Hz, 1H, =CH2), 5.08 (dd, J = 2.0, 0.8 Hz, 1H, =CH2), 4.85
(d, J = 4.0 Hz, 1H, H-2), 4.75 (q, J = 6.2 Hz, 1H, H-4), 1.51 (s, 3H, CH3),
1.35 (s, 3H, CH3), 1.32 (d, J = 6.2 Hz, 3H, H-5). 13C NMR (101 MHz,
CDCl3): δ = 150.2 (C-3), 111.8 (CMe2), 110.6 (C-1), 103.6 (=CH2), 81.7
(C-2), 74.5 (C-4), 27.0 (CH3), 26.7 (CH3), 17.8 (C-5).
59.3 (d, JC,P = 169 Hz, PCH2), 26.9 (CH3), 26.4 (CH3), 16.5 (d, JC,P
=
6.4 Hz, CH3), 16.4 (d, JC,P = 6.4 Hz, CH3), 13.4 (C-5). 31P NMR
(162 MHz, CDCl3) δ = 20.8.
5-Deoxy-3-C-hydroxymethyl-1,2-O-isopropylidene-α-D-xylose
(6): To a solution of 5 (5 g, 29.4 mmol) in 67 mL of acetone in
an ice–water bath was added dropwise a solution of potassium
permanganate (5.43 g, 34.37 mmol) in 287.5 mL of water. After
stirring for 4 h in an ice-water bath, the reaction was quenched by
adding 2.0 g of sodium bisulfite. The resulting mixture was filtered,
and the cake was washed with 20 mL of acetone. The filtrate was
combined, concentrated under reduced pressure, co-evaporated
with toluene, and purified by silica gel column chromatography (PE/
EA = 3:1–1:3) to allow 6 (3.5 g, 17.1 mmol, 58 %) as a colorless oil.
3-C-Benzyloxymethyl-5-deoxy-3-O-diethylphosphonomethyl-1-
O-methyl-D-xylose (9): Concentrated sulfuric acid (0.45 mL,
8.44 mmol) was added to a solution of compound 8 (2.5 g,
5.62 mmol) in 60 mL of anhydrous methanol at 0 °C under nitrogen
atmosphere. The mixture was stirred at this temperature for 30 min,
then heated to 50 °C and maintained for 17 h. After the reaction
mixture was cooled to room temperature, solid NaHCO3 (2.0 g) was
added to quench the reaction. Inorganic salt was filtered off, the
filtrate was dried with Na2SO4, concentrated by rotary evaporation,
and purified by silica gel column chromatography (petroleum
ether/ethyl acetate = 1: 2–1: 5) to obtain 9 (1.6 g, 3.82 mmol, 68 %)
as an oily anomeric mixture.
1
6: H NMR (400 MHz, CDCl3): δ = 5.88 (d, J = 3.9 Hz, 1H, H-1), 4.40
(d, J = 3.9 Hz, 1H, H-2), 4.04 (q, J = 6.4 Hz, 1H, H-4), 3.84 (d, J =
11.4 Hz, 1H, CH2OH), 3.52 (d, J = 11.4 Hz, 1H, CH2OH), 3.18 (s, 1H,
OH), 2.96 (s, 1H, OH), 1.48 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.20 (d, J =
6.4 Hz, 3H, H-5). 13C NMR (101 MHz, CDCl3): δ = 111.2 (CMe2), 103.0
(C-1), 84.2 (C-2), 80.7 (C-4), 75.4 (C-3), 61.2 (CH2OH), 25.7 (CH3), 25.3
(CH3), 11.6 (C-5).
1
9: α-Anomer: H NMR (400 MHz, CDCl3): δ = 7.38–7.26 (m, 5H, Ar-
H), 4.69 (d, J = 3.3 Hz, 1H, H-1), 4.58 (d, J = 11.8 Hz, 1H, ArCH2O),
4.52 (d, J = 11.8 Hz, 1H, ArCH2O), 4.28 (s, 1H, OH), 4.25 (q, J = 6.6 Hz,
1H, H-4), 4.21–4.05 (m, 5H, OCH2CH3, H-2), 4.05–3.93 (m, 2H, PCH2),
3.84 (d, J = 11.0 Hz, 1H, CCH2O), 3.68 (d, J = 11.0 Hz, 1H, CCH2O),
3.41 (s, 3H, OCH3), 1.33 (t, J = 7.1 Hz, 3H, CH3), 1.29(t, J = 7.1 Hz,
3H, CH3), 1.26 (d, J = 6.6 Hz, 3H, H-5). 13C NMR (101 MHz, CDCl3): δ =
137.4, 128.5, 128.0, 127.8 (Ar-C), 109.2 (C-1), 85.3 (d, JC,P = 10.1 Hz,
3-C-Benzyloxymethyl-5-deoxy-1,2-O-isopropylidene-α-D-xylose
(7): To a solution of compound 6 (1 g, 4.90 mmol) in anhydrous
toluene (36 mL) was added dibutyltin oxide (2.01 g, 8.08 mmol)
under nitrogen atmosphere. After the mixture was stirred at 140 °C
for 2 hours, the reaction temperature was decreased to 100 °C. Then
tetrabutylammonium bromide (0.79 g, 2.45 mmol) and benzyl
bromide (0.90 mL, 7.59 mmol) were added. The mixture was stirred
at 100 °C for 8 hours and then cooled to room temperature. Con-
centration under reduced pressure, purification by silica gel column
chromatography (petroleum ether/ethyl acetate = 10:1–6:1) pro-
vided 7 (1.3 g, 4.42 mmol) as a light yellow oil in 90 % yield.
7: 1H NMR (400 MHz, CDCl3): δ = 7.40–7.27 (m, 5H, Ar-H), 5.89 (d,
J = 3.8 Hz, 1H, H-1), 4.62 (d, J = 12.0 Hz, 1H, ArCH2O), 4.58 (d, J =
12.0 Hz, 1H, ArCH2O), 4.40 (d, J = 3.8 Hz, 1H, H-2), 4.05 (q, J = 6.3 Hz,
1H, H-4), 3.77 (d, J = 9.4 Hz, 1H, CCH2O), 3.43 (d, J = 9.4 Hz, 1H,
CCH2O), 2.71 (s, 1H, OH), 1.48 (s, 3H, CH3), 1.32 (s, 3H, CH3), 1.24 (d,
J = 6.4 Hz, 3H, H-5). 13C NMR (101 MHz, CDCl3): δ = 137.7, 128.5,
127.9, 127.7 (Ar-C), 112.0 (CMe2), 104.3 (C-1), 85.4 (C-2), 80.6 (C-4),
77.1 (ArCH2), 73.7 (C-3), 69.5 (CH2O), 26.9 (CH3), 26.4 (CH3), 12.9
(C-5).
C-3), 80.2 (ArCH2), 78.9 (C-2), 73.8 (CH2O), 69.1 (C-4), 62.9 (d, JC,P
=
6.4 Hz, CH2), 62.7 (d, JC,P = 6.4 Hz, CH2), 59.0 (d, JC,P = 167 Hz, PCH2),
1
56.0 (OCH3), 16.44 (CH3), 16.38 (CH3), 16.0 (C-5). ꢀ-Anomer: H NMR
(400 MHz, CDCl3): δ = 7.37–7.26 (m, 5H, Ar-H), 4.93 (d, J = 4.8 Hz,
1H, H-1), 4.54 (s, 2H, ArCH2O), 4.32–4.21 (m, 2H, H-2, H-4), 4.17 (q,
J = 7.2 Hz, 2H, CH2), 4.12 (q, J = 7.2 Hz, 2H, CH2), 3.94–3.87 (m, 2H,
PCH2), 3.85 (d, J = 11.0 Hz, 1H, CCH2O), 3.52 (d, J = 11.0 Hz, 1H,
CCH2O), 3.43 (s, 3H, OCH3), 2.97 (d, J = 7.6 Hz, 1H, OH), 1.35–1.25
(m, 9H, H-5, CH3). 13C NMR (101 MHz, CDCl3): δ = 137.9, 128.4, 127.7,
127.5 (Ar-C), 101.2 (C-1), 84.7 (d, JC,P = 12 Hz, C-3), 79.2 (ArCH2), 77.9
(C-2), 73.6 (CH2O), 69.0 (C-4), 62.7 (d, JC,P = 6.2 Hz, CH2), 62.5 (d,
JC,P = 6.2 Hz, CH2), 58.3 (d, JC,P = 169 Hz, PCH2), 55.3 (OCH3), 16.5
(d, JC,P = 5.8 Hz, CH3), 16.4 (d, JC,P = 5.8 Hz, CH3), 14.9 (C-5).
2-O-Benzoyl-3-C-benzyloxymethyl-5-deoxy-3-O-diethylphos-
phonomethyl-1-O-methyl-D-xylose (10): Compound 9 (0.92 g,
2.20 mmol) was dissolved in 6 mL of anhydrous pyridine, benzoyl
chloride (0.52 mL, 4.40 mmol) was added at 0 °C under N2. The
mixture was stirred at 0 °C for 30 min and then at room temperature
for 6 h. The reaction was quenched by adding 1 mL of water, con-
3-C-Benzyloxymethyl-5-deoxy-3-O-diethylphosphonomethyl-
1,2-O-isopropylidene-α-D-xylose (8): To a solution of compound
7 (3.2 g, 10.9 mmol) in 100 mL of anhydrous THF was added NaH
(60 % in mineral oil, 1.30 g, 32.62 mmol) and tosylate of diethyl- centrated under reduced pressure to dryness. The residue was puri-
phosphonomethanol (4.2 g, 13.1 mmol) upon cooling in an ice-
water bath under a nitrogen atmosphere. The mixture was stirred
fied by silica gel column chromatography (PE/EA = 5:1–1:1) to ob-
tain 10 (1.1 g, 2.11 mmol, 96 %) as an oily anomeric mixture.
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1
10: α-Anomer: H NMR (400 MHz, CDCl3) δ 7.93–7.85 (m, 2H, Ar-H), H-5), 5.55 (d, J = 2.5 Hz, 1H, H-2′), 4.39 (d, J = 11.7 Hz, 1H, ArCH2O),
7.55–7.48 (m, 1H, Ar-H), 7.37 (t, J = 7.7 Hz, 2H, Ar-H), 7.29–7.18 (m, 4.34 (d, J = 11.7 Hz, 1H, ArCH2O), 4.30 (q, J = 6.3 Hz, 1H, H-4′), 4.20–
5H, Ar-H), 5.17 (d, J = 4.6 Hz, 1H, H-1), 5.12 (d, J = 4.6 Hz, 1H, H-2),
4.52 (d, J = 11.8 Hz, 1H, ArCH2O), 4.48 (d, J = 11.8 Hz, 1H, ArCH2O),
4.33 (q, J = 6.4 Hz, 1H, H-4), 4.13–4.02 (m, 4H, OCH2CH3), 3.94 (d,
J = 11.0 Hz, 1H, CCH2O), 3.85 (dd, J = 13.1, 9.9 Hz, 1H, PCH2), 3.73
(t, J = 12.4 Hz, 1H, PCH2), 3.69 (d, J = 11.0 Hz, 1H, CCH2O), 3.24 (s,
3H, OCH3), 1.28 (d, J = 6.4 Hz, 3H, H-5), 1.24 (t, J = 7.1 Hz, 3H, CH3),
1.21(t, J = 7.1 Hz, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ = 164.2
(C=O), 136.8, 132.4, 128.7, 128.3, 127.5, 127.4, 126.7, 126.5 (Ar-C),
99.3 (C-1), 83.3 (d, JC,P = 13.4 Hz, C-3), 78.1 (C-2), 77.8 (ArCH2), 72.7
4.10 (m, 4H, OCH2CH3), 4.06 (dd, J = 13.2 10.7 Hz, 1H, PCH2), 3.97
(dd, J = 13.2 11.4 Hz, 1H, PCH2), 3.77 (d, J = 10.9 Hz, 1H, CCH2O),
3.67 (d, J = 10.9 Hz, 1H, CCH2O), 1.44 (d, J = 6.3 Hz, 3H, H-5′), 1.32
(t, J = 7.0 Hz, 6H, OCH2CH3). 13C NMR (101 MHz, CDCl3): δ = 164.8
(ArCO), 163.0 (C-4), 150.2 (C-2), 140.9 (C-6), 136.8, 133.8, 129.9, 128.7,
128.6, 128.4, 128.0, 127.7 (Ar-C), 103.0 (C-5), 88.3 (C-1′), 85.1 (d, JC,P
=
12.2 Hz, C-3′), 81.6 (C-2′), 79.0 (ArCH2), 73.9 (OCH2C), 67.7 (C-4′), 62.7
(d, JC,P = 6.4 Hz, CH2CH3), 62.4 (d, JC,P = 6.4 Hz, CH2CH3), 58.7 (d,
JC,P = 170.5 Hz, PCH2), 16.6 (d, JC,P = 5.4 Hz, CH3), 16.5 (d, JC,P
=
(CH2O), 68.0 (C-4), 61.7 (d, JC,P = 6.2 Hz, OCH2CH3), 61.6 (d, JC,P
=
6.0 Hz, CH3), 13.5 (C-5′). 31P NMR (162 MHz, CDCl3): δ = 20.9.
HRMS(ESI-TOF): calcd. for C29H36N2O10P+ [M + H]+ 603.2102, found
603.2110.
6.2 Hz, OCH2CH3), 57.2 (d, JC,P = 169 Hz, PCH2), 54.3 (OCH3), 15.43
(d, JC,P = 6.2 Hz, OCH2CH3), 15.37 (d, JC,P = 6.2 Hz, OCH2CH3), 14.1
(C-5). HRMS(ESI-TOF): calcd. for C26H36O9P [M + H]+ 523.2097, found
523.2104.
3-C-Benzyloxymethyl-5-deoxy-3-O-diethylphosphonomethyl-
1-(uracil-1-yl)-ꢀ-D-xylose (13a): Compound 12a (205 mg,
0.34 mmol) was dissolved in a saturated methanolic ammonia solu-
tion (5 mL) and stirred at room temperature for 6 h. The mixture
was concentrated under reduced pressure and purified by silica gel
column chromatography (DCM/MeOH = 50:1–30:1) to obtain 13a
(145 mg, 0.29 mmol) as a colorless syrup with a yield of 86 %.
1-O-Acetyl-2-O-benzoyl-3-C-benzyloxymethyl-5-deoxy-3-O-di-
ethylphosphonomethyl-D-xylose (11): Compound 10 (1 g,
1.91 mmol) was dissolved in a solution of glacial acetic acid
(6.35 mL, 111 mmol) and acetic anhydride (0.81 mL, 8.61 mmol).
Concentrated sulfuric acid (0.051 mL, 0.96 mmol) were added at
0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for
10 minutes and then at room temperature for 8 h. Saturated aque-
ous NaHCO3 was added to quench the reaction. The resulting mix-
ture was filtered and extracted with ethyl acetate(5 × 20 mL). The
combined organic layer was dried with anhydrous sodium sulfate,
concentrated to dryness in vacuo, and purified by silica gel column
chromatography (PE/EA = 5:1–1:1) to give 11 (0.93 g, 1.69 mmol) in
88 % yield as an oily anomeric mixture.
1
13a: H NMR (400 MHz, [d6]DMSO): δ = 11.35 (d, J = 1.6 Hz, 1H, N-
H), 7.64 (d, J = 8.1 Hz, 1H, H-6), 7.41–7.26 (m, 5H, Ar-H), 5.97 (d, J =
5.9 Hz, 1H, H-1′), 5.69 (d, J = 3.1 Hz, 1H, OH), 5.58 (dd, J = 8.1, 2.1 Hz,
1H, H-5), 4.53 (s, 2H, ArCH2O), 4.20 (q, J = 6.4 Hz, 1H, H-4′), 4.13 (dd,
J = 5.8, 3.2 Hz, 1H, H-2′), 4.08–3.96 (m, 4H, OCH2CH3), 3.87(d, J =
11.4 Hz, 1H, CCH2O), 3.85 (m, 2H, PCH2), 3.61 (d, J = 11.4 Hz, 1H,
CCH2O), 1.29 (d, J = 6.4 Hz, 3H, H-5′), 1.21 (t, J = 7.2 Hz, 3H, CH2CH3),
1.19 (t, J = 7.2 Hz, 3H, CH2CH3). 13C NMR (101 MHz, [d6]DMSO): δ =
163.1 (C-4), 150.6 (C-2), 140.9 (C-6), 138.1, 128.2, 127.5, 127.4 (Ar-C),
101.8 (C-5), 89.6 (C-1′), 84.8 (d, J = 13.2 Hz, C-3′), 80.7 (C-2′), 77.6
(ArCH2), 72.6 (OCH2), 67.2 (C-4′), 61.9 (d, JC,P = 6.1 Hz, OCH2CH3),
61.7 (d, J = 6.1 Hz, OCH2CH3), 57.0 (d, JC,P = 167 Hz, PCH2), 16.3 (d,
1
11: α-Anomer: H NMR (400 MHz, CDCl3) δ 7.97–7.93 (m, 2H, Ar-H),
7.62 (t, J = 7.4 Hz, 1H, Ar-H), 7.46 (t, J = 7.8 Hz, 2H, Ar-H), 7.2–7.23
(m, 5H, Ar-H), 6.53 (d, J = 4.8 Hz, 1H, H-1), 5.57 (d, J = 4.8 Hz, 1H,
H-2), 4.53 (s, 2H, ArCH2O), 4.50 (q, J = 6.4 Hz, 1H, H-4), 4.22–4.12 (m,
4H, OCH2CH3), 3.99 (dd, J = 13.2, 9.9 Hz, 1H, PCH2), 3.93 (dd, J =
13.2, 11.8 Hz, 1H, PCH2), 3.91 (d, J = 10.9 Hz, 1H, CCH2O), 3.72 (d,
J = 10.9 Hz, 1H, CCH2O), 1.91 (s, 3H, COCH3), 1.36 (d, J = 6.4 Hz, 3H,
H-5), 1.34 (t, J = 7.1 Hz, 3H, CH3), 1.31 (t, J = 7.1 Hz, 3H, CH3). ꢀ-
J
C,P = 5.8 Hz, OCH2CH3), 16.2 (d, JC,P = 5.8 Hz, OCH2CH3), 14.2 (C-5′
). 31P NMR (162 MHz, [d6]DMSO): δ = 21.6. HRMS(ESI-TOF): calcd. for
22H32N2O9P+ [M + H]+ 499.1840, found 499.1835.
C
1
5-Deoxy-3-O-phosphonomethyl-3-C-hydroxymethyl-1-(uracil-1-
yl)-ꢀ-D-xylose (15a): Compound 13a (140 mg, 0.28 mmol) was dis-
solved in 5 mL of methanol, 50 mg of Pd-C (10 %) was added.
The oscillating mixture was hydrogenated under 50 psi at room
temperature for 10 h. The resulting mixture was filtered and con-
centrated under reduced pressure to dryness. The residue (14a) was
directly used to next step without further purification.
Anomer: H NMR (400 MHz, CDCl3) δ 7.96–7.92 (m, 2H, Ar-H), 7.60
(t, J = 7.4 Hz, 1H, Ar-H), 7.44 (t, J = 7.8 Hz, 2H, Ar-H), 7.25–7.12 (m,
5H, Ar-H), 6.10 (s, 1H, H-1), 5.75 (s, 1H, H-2), 4.46 (q, J = 6.5 Hz, 1H,
H-4), 4.47 (d, J = 11.7 Hz, 1H, ArCH2O), 4.38 (d, J = 11.7 Hz, 1H,
ArCH2O), 4.26–4.13 (m, 5H, OCH2CH3, PCH2), 4.03 (dd, J = 12.9,
10.7 Hz, 1H, PCH2), 3.81 (d, J = 10.6 Hz, 1H, CCH2O), 3.69 (d, J =
10.6 Hz, 1H, CCH2O), 2.13 (s, 3H, Ac CH3), 1.38 (d, J = 6.5 Hz, 3H, H-
5), 1.34 (t, J = 7.3 Hz, 3H, CH3), 1.32 (t, J = 7.3 Hz, 3H, CH3). HRMS(ESI-
TOF): calcd. for C27H36O10P [M + H]+ 551.2046, found 551.2059.
The above residue 14a was dissolved in 5 mL of anhydrous aceto-
nitrile, 2,6-lutidine (0.18 mL, 1.57 mmol) and TMSBr (0.41 mL,
3.13 mmol) were added at 0 °C under nitrogen atmosphere. The
mixture was stired at 0 °C for 30 min and then at room temperature
for 5 h. After the disappearance of 14a by TLC monitorring, the
reaction was quenched by addition of a little water. The resulting
solution was concentrated under reduced pressure and the residue
was purified by C18-silica gel column chromatography (water/meth-
anol = 10:1–5: 1) to obtain 15a (50 mg, 0.14 mmol) as a white foam
with a yield of 50 % (two steps).
2-O-Benzoyl-3-C-benzyloxymethyl-5-deoxy-3-O-diethylphos-
phonomethyl-1-(uracil-1-yl)-ꢀ-D-xylose (12a): To a solution of
compound 11 (240 mg, 0.44 mmol) in 5 mL of anhydrous aceto-
nitrile, uracil (73 mg, 0.65 mmol) and BSA (0.32 mL, 1.31 mmol)
were added at room temperature under nitrogen atmosphere. The
mixture was stirred at 65 °C for 10 min and then cooled to room
temperature. TMSOTf (0.24 mL, 1.31 mmol) was added and stirred
at room temperature for 6 h. After being quenched by the addition
of 1 mL of water, the mixture was concentrated in vacuo and puri-
fied by silica gel column chromatography (petroleum ether/ethyl
acetate = 2:1–1:4) to provide 12a (205 mg, 0.34 mmol) in 78 % yield
as a colorless syrup.
1
15a: H NMR (400 MHz, D2O): δ = 7.83 (d, J = 8.1 Hz, 1H, H-6), 5.79
(d, J = 8.1 Hz, 1H, H-5), 5.71 (d, J = 2.0 Hz, 1H, H-1′), 4.36 (q, J =
6.4 Hz, 1H, H-4′), 4.30 (d, J = 2.0 Hz, 1H, H-2′), 3.99 (d, J = 13.4 Hz,
1H, CCH2O), 3.69 (d, J = 13.4 Hz, 1H, CCH2O), 3.58 (dd, J = 12.8,
11.4 Hz, 1H, PCH2O), 3.32 (dd, J = 12.8, 9.3 Hz, 1H, PCH2O), 1.36 (d,
J = 6.4 Hz, 3H, H-5′). 13C NMR (101 MHz, D2O): δ = 166.4 (C-4), 151.6
1
12a: H NMR (400 MHz, CDCl3): δ = 8.81 (s, 1H, N-H), 7.99–7.94 (m,
2H, Ar-H), 7.84 (d, J = 8.2 Hz, 1H, H-6), 7.61 (t, J = 7.5 Hz, 1H, Ar-H),
7.44 (t, J = 7.8 Hz, 2H, Ar-H), 7.26–7.20 (m, 3H, Ar-H), 7.15–7.10 (m, (C-2), 142.3 (C-6), 101.7 (C-5), 90.7 (C-1′), 84.9 (d, JC,P = 9.1 Hz, C-3′),
2H, Ar-H), 6.12 (d, J = 2.5 Hz, 1H, H-1′), 5.80 (dd, J = 8.2, 1.9 Hz, 1H,
82.8 (C-2′), 77.6 (C-4′), 58.5 (CH2OH), 13.6 (C-5′). 31P NMR (162 MHz,
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D2O): δ = 15.7. HRMS(ESI-TOF): calcd. for C11H16N2O9P– [M – H]–
the method as described for 15a using 14b as starting material in
351.0599, found 351.0595.
61 % yield.
15b: 1H NMR (400 MHz, D2O): δ = 7.59 (d, J = 0.96 Hz, 1H, H-6),
5.74 (d, J = 2.9 Hz, 1H, H-1′), 4.37 (q, J = 6.4 Hz, 1H, H-4′), 4.32 (d,
J = 2.9 Hz, 1H, H-2′), 4.02 (d, J = 13.3 Hz, 1H, CCH2O), 3.73 (d, J =
13.3 Hz, 1H, CCH2O), 3.64 (dd, J = 12.6, 10.9 Hz, 1H, PCH2), 3.39 (dd,
J = 12.6, 9.8 Hz, 1H, PCH2), 1.85 (d, J = 0.96 Hz, 3H, T-CH3), 1.39 (d,
J = 6.4 Hz, 3H, H-5′). 13C NMR (101 MHz, D2O): δ = 166.5 (C-4), 151.7
(C-2), 137.5 (C-6), 111.1 (C-5), 89.9 (C-1′), 84.8 (d, JC,P = 9.4 Hz, C-3′),
82.3 (C-2′), 77.7 (C-4′), 59.1 (d, JC,P = 162 Hz, PCH2), 58.7 (CH2OH),
13.7 (C-5′), 11.6 (T-CH3). 31P NMR (162 MHz, D2O): δ = 16.2. HRMS
(ESI-TOF): calcd. for C12H18N2O9P– [M – H]– 365.0755, found
365.0754.
2-O-Benzoyl-3-C-benzyloxymethyl-5-deoxy-3-O-diethylphos-
phonomethyl-1-(thymin-1-yl)-ꢀ-D-xylose (12b): The preparation
method of 12b is as described for 12a using thymine as starting
nucleobase. 12b was obtained (300 mg, 0.49 mmol) with a yield of
89 %.
1
12b: H NMR (400 MHz, CDCl3): δ = 9.17 (s, 1H, N-H), 7.93 (dd, J =
8.4, 1.2 Hz, 2H, Ar-H), 7.58 (t, J = 7.8 Hz, 1H, Ar-H), 7.55 (d, J = 0.9 Hz,
1H, H-6), 7.41 (t, J = 7.7 Hz, 2H, Ar-H), 7.25–7.18 (m, 3H, Ar-H), 7.14–
7.10 (m, 2H, Ar-H), 6.05 (d, J = 2.7 Hz, 1H, H-1′), 5.60 (d, J = 2.7 Hz,
1H, H-2′), 4.39 (d, J = 11.8 Hz, 1H, ArCH2O), 4.35 (d, J = 11.8 Hz, 1H,
ArCH2O), 4.30 (q, J = 6.3 Hz, 1H, H-4′), 4.20–4.07 (m, 5H, PCH2,
OCH2CH3), 4.03 (dd, J = 13.3, 11.4 Hz, 1H, PCH2), 3.78 (d, J = 10.9 Hz,
1H, CCH2O), 3.67 (d, J = 10.9 Hz, 1H, CCH2O), 1.97 (d, J = 0.7 Hz, 3H,
T-CH3), 1.45 (d, J = 6.3 Hz, 3H, H-5′), 1.29 (t, J = 7.1 Hz, 6H, OCH2CH3).
13C NMR (101 MHz, CDCl3): δ = 165.1(Ar-CO), 164.2 (C-4), 150.5 (C-
2), 136.9 (Ar-C), 136.5 (C-6), 133.8, 129.9, 128.60, 128.58, 128.4, 127.9,
127.7 (Ar-C), 111.5 (C-5), 88.4 (C-1′), 85.2 (d, JC,P = 12.3 Hz, C-3′),
1-O-Acetyl-2-O-benzoyl-3-C-benzoyloxymethyl-5-deoxy-3-O-di-
ethylphosphonomethyl-D-xylose (16): Compound 11 (430 mg,
0.78 mmol) was dissolved in 10 mL of methanol, 180 mg of Pd-C
(10 %) was added. The oscillating mixture was hydrogenated under
50 psi at room temperature for 5 h. The resulting mixture was fil-
tered and concentrated under reduced pressure to dryness. The
residue was evaporated with pyridine twice, then dissolved in 5 mL
of anhydrous pyridine. Benzoyl chloride (0.36 mL, 3.12 mmol) was
added at 0 °C under nitrogen atmosphere. After stirring at 0 °C for
10 min and at room temperature for 4 h, the reaction mixture was
quenched by the addition of 0.5 mL of water. Concentration by
rotary evaporation and purification by silica gel column chromatog-
raphy (PE/EA = 5:1–1:1) allowed compound 16 (420 mg, 0.74 mmol)
in ca. 95 % yield as an inseparable oily anomeric mixture.
81.6, (C-2′), 79.1 (ArCH2), 73.8 (OCH2C), 67.6 (C-4′), 63.1 (d, JC,P
6.3 Hz, OCH2CH3), 62.8 (d, JC,P = 6.1 Hz, OCH2CH3), 58.4 (d, JC,P
=
=
170 Hz, PCH2), 16.4 (d, JC,P = 6.1 Hz, OCH2CH3), 16.3 (d, JC,P = 6.1 Hz,
OCH2CH3), 13.6 (C-5′), 12.3 (T-CH3). 31P NMR (162 MHz, CDCl3): δ =
21.0. HRMS(ESI-TOF): calcd. for C30H38N2O10P+ [M + H]+ 617.2259,
found 617.2255.
3-C-Benzyloxymethyl-5-deoxy-3-O-diethylphosphonomethyl-1-
(thymin-1-yl)-ꢀ-D-xylose (13b): Compound 13b was synthesized
using 12b as starting material following the method as described
for 13a. 13b was obtained (204 mg, 0.40 mmol) with a yield of
82 %.
16: HRMS(ESI-TOF): calcd. for C27H34O11P+ [M + H]+ 565.1833, found
565.1838.
1-(Cytosin-1-yl)-5-deoxy-3-O-phosphonomethyl-3-C-hydroxy-
methyl-ꢀ-D-xylose (15c): To a solution of compound 16 (430 mg,
0.76 mmol) in 10 mL of anhydrous acetonitrile, N4-Benzoylcytosine
(246 mg, 1.14 mmol) and BSA (0.74 mL, 3.05 mmol) were added at
room temperature under nitrogen atmosphere. The mixture was
stirred at 65 °C for 10 min and then cooled to room temperature.
TMSOTf (0.41 mL, 2.29 mmol) was added and stirred at room tem-
perature for 10 h. After being quenched by the addition of 1 mL of
water, the mixture was concentrated in vacuo and purified by silica
gel column chromatography (petroleum ether/ethyl acetate = 3:1–
1:3) to provide 12c with a small amount of impurity as a colorless
syrup.
1
13b: H NMR (400 MHz, [d6]DMSO): δ = 11.34 (s, 1H, N-H), 7.44 (d,
J = 1.0 Hz, 1H, H-6), 7.40–7.28 (m, 5H, Ar-H), 5.90 (d, J = 5.9 Hz, 1H,
H-1′), 5.71 (d, J = 3.9 Hz, 1H, OH), 4.53 (s, 2H, ArCH2O), 4.15 (q, J =
6.3 Hz, 1H, H-4′), 4.11 (dd, J = 5.8, 4.0 Hz, 1H, H-2′), 4.08–3.98 (m,
4H, OCH2CH3), 3.86 (d, J = 11.5 Hz, 1H, CCH2O), 3.84 (d, J = 10.8 Hz,
2H, PCH2), 3.60 (d, J = 11.5 Hz, 1H, CCH2O), 1.83 (d, J = 0.72 Hz, 3H,
T CH3), 1.30 (d, J = 6.3 Hz, 3H, H-5′), 1.213 (t, J = 7.1 Hz, 3H, CH3),
1.210 (t, J = 7.1 Hz, 3H, CH3). 13C NMR (101 MHz, [d6]DMSO): δ =
163.7 (C-4), 150.6 (C-2), 138.2 (Ar-C), 136.2 (C-6), 128.2, 127.5, 127.4
(Ar-C), 109.8 (C-5), 89.0 (C-1′), 84.8 (d, JC,P = 12.8 Hz, C-3′), 80.3
(C-2′), 77.7 (ArCH2), 72.6(OCH2C), 67.3 (C-4′), 62.1 (d, JC,P = 6.0 Hz,
OCH2CH3), 61.6 (d, JC,P = 6.2 Hz, OCH2CH3), 57.1 (d, JC,P = 167 Hz,
PCH2), 16.24 (d, JC,P = 5.3 Hz, OCH2CH3), 16.21 (d, JC,P = 5.6 Hz,
OCH2CH3), 14.2 (C-5′), 12.0 (T-CH3). 31P NMR (162 MHz, [d6]DMSO):
δ = 21.6. HRMS(ESI-TOF): calcd. for C23H34N2O9P+ [M + H]+ 513.1996,
found 513.1993.
Impure 12c was dissolved in a saturated methanolic ammonia solu-
tion (5 mL) and stirred at room temperature for 6 h. The mixture
was concentrated under reduced pressure to produce 13c, which
was used directly in the next step without further purification.
Compound 13c was hydrolyzed by using TMSBr and 2,6-lutidine
following the procedure for preparation of 15a from 14a to yield
15c as a white foam.
5-Deoxy-3-O-diethylphosphonomethyl-3-C-hydroxymethyl-1-
(thymin-1-yl)-ꢀ-D-xylose (14b): Compound 14b was obtained fol-
lowing the method as described for 14a using 13b as starting ma-
terial and purification by column chromatography in 73 % yield.
1
15c: H NMR (400 MHz, D2O): δ = 7.78 (d, J = 7.6 Hz, 1H, H-6), 5.99
(d, J = 7.6 Hz, 1H, H-5), 5.81 (s, 1H, H-1′), 4.64 (s, 1H, H-2′), 4.43 (dd,
J = 16.1, 12.5 Hz, 1H, PCH2), 4.28 (q, J = 6.4 Hz, 1H, H-4′), 4.23 (dd,
J = 12.5, 4.7 Hz, 1H, PCH2), 3.70 (dd, J = 14.5, 10.0 Hz, 1H, CCH2O),
3.61 (dd, J = 14.5, 2.1 Hz, 1H, CCH2O), 1.40 (d, J = 6.4 Hz, 3H, H-5′).
13C NMR (101 MHz, D2O) δ = 166.3 (C-4), 157.5 (C-2), 141.8 (C-6),
95.0 (C-1′), 92.2 (C-5), 81.2 (d, J = 4.1 Hz, C-3′), 79.5 (C-2′), 73.8
(C-4′), 65.9 (d, J = 6.2 Hz, OCH2), 59.3 (d, J = 142 Hz, PCH2), 12.0
(C-5′). 31P NMR (162 MHz, D2O): δ = 10.0. HRMS (ESI-TOF): calcd. for
C11H17N3O8P– [M – H]– 350.0759, found 350.0751.
1
14b: H NMR (400 MHz, CDCl3): δ = 10.56 (s, 1H, N-H), 7.54 (d, J =
0.9 Hz, 1H, H-6), 5.69 (s, 1H, H-1′), 5.49 (s, 1H, OH), 4.54 (q, J = 6.4 Hz,
1H, H-4′), 4.33 (s, 1H, OH), 4.29–4.09 (m, 5H, OCH2CH3, H-2′), 4.05
(d, J = 12.2 Hz, 1H, CCH2O), 3.96 (dd, J = 14.1, 10.9 Hz, 1H, PCH2),
3.89 (dd, J = 13.4, 9.0 Hz, 1H, CCH2O), 3.48 (dd, J = 14.1, 7.5 Hz, 1H,
PCH2), 1.93 (s, 3H, T-CH3), 1.47 (d, J = 6.4 Hz, 3H, H-5′), 1.36 (t, J =
7.1 Hz, 3H, OCH2CH3), 1.33 (t, J = 7.1 Hz, 3H, OCH2CH3). HRMS(ESI-
TOF): calcd. for C16H28N2O9P+ [M + H]+ 423.1527, found 423.1521.
5-Deoxy-3-O-phosphonomethyl-3-C-hydroxymethyl-1-(thymin-
1-yl)-ꢀ-D-xylose (15b): Compound 15b was obtained following
1-(5-Chlorouracil-1-yl)-5-deoxy-3-O-phosphonomethyl-3-C-
hydroxymethyl-ꢀ-D-xylose (15d): Substitution of N4-Benzoyl-
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cytosine with 5-chlorouracil in Vorbrüggen glycosylation by follow-
ing the procedure for preparation of 12c gave 12d with a small
amount of impurity as a colorless syrup. Impure 12d was depro-
tected with saturated methanolic ammonia and followed by hydrol-
ysis with TMSBr/2,6-lutidine according to the method for prepara-
tion of 15c from 12c to allow 15d as a white foam in 25 % yield
(three steps).
15d: 1H NMR (400 MHz, D2O): δ = 7.96 (s, 1H, H-6), 5.67 (d, J =
2.0 Hz, 1H, H-1′), 4.41 (q, J = 6.4 Hz, 1H, H-4′), 4.33 (d, J = 2.0 Hz,
1H, H-2′), 4.01 (d, J = 13.4 Hz, 1H, CCH2O), 3.72 (d, J = 13.4 Hz, 1H,
CCH2O), 3.61 (dd, J = 12.8, 11 Hz, 1H, PCH2), 3.34 (dd, J = 12.8,
9.4 Hz, 1H, PCH2), 1.40 (d, J = 6.4 Hz, 3H, H-5′). 13C NMR (101 MHz,
D2O): δ = 164.5 (C-4), 153.2 (C-2), 141.1 (C-6), 111.0 (C-5), 93.6
(C-1′), 87.4 (d, JC,P = 8.9 Hz, C-3′), 85.6 (C-2′), 80.1 (C-4′), 61.8 (d,
JC,P = 160 Hz, PCH2), 61.0 (OCH2), 16.2 (C-5′). 31P NMR (162 MHz,
D2O): δ = 18.5. HRMS (ESI-TOF): calcd. for C11H15ClN2O9P– [M – H]–
385.0209, found 385.0211.
(C-5′). 31P NMR (162 MHz, D2O): δ = 10.2. HRMS (ESI-TOF): calcd. for
C12H15ClN4O7P– [M – H]– 393.0372, found 393.0376.
Acknowledgments
This work was supported by National Natural Science Founda-
tion of China (NO. 21372207) and Natural Science Foundation
of Henan Province (NO. 162300410281).
Keywords: Carbohydrates · Nucleosides · Phosphonates ·
Synthetic methods
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12e: H NMR (400 MHz, CDCl3): δ = 8.79 (s, 1H, H-2), 8.72 (s, 1H, H-
8), 7.98–7.90 (m, 4H, Ar-H), 7.62–7.55 (m, 2H, Ar-H), 7.42 (t, J =
7.8 Hz, 4H, Ar-H), 6.40 (d, J = 2.5 Hz, 1H, H-1′), 6.03 (d, J = 2.5 Hz,
1H, H-2′), 4.79 (d, J = 13.0 Hz, 1H, CCH2O), 4.68 (d, J = 13.0 Hz, 1H,
CCH2O), 4.60 (q, J = 6.4 Hz, 1H, H-4′), 4.25–4.14 (m, 4H, OCH2CH3),
4.12–3.99 (m, 2H, PCH2), 1.58 (d, J = 6.4 Hz, 3H, H-5′), 1.35 (t, J =
7.1 Hz, 3H, OCH2CH3), 1.32 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR
(101 MHz, CDCl3): δ = 165.6 (C=O), 164.8 (C=O), 152.2 (C-2), 151.5
(C-4), 151.1 (C-6), 144.4 (C-8), 134.2 (C-5), 133.7, 131.8, 129.9, 129.6,
128.8, 128.7, 128.6, 127.9 (Ar-C), 87.6 (C-1′), 84.9 (d, JC,P = 12.2 Hz,
C-3′), 82.1 (C-2′), 79.4 (C-4′), 62.85 (d, JC,P = 20 Hz, OCH2CH3), 62.79
(d, JC,P = 20 Hz, OCH2CH3), 61.7 (OCH2), 59.1 (d, JC,P = 171 Hz, PCH2),
16.53 (d, J = 5.3 Hz, OCH2CH3), 16.51 (d, JC,P = 5.9 Hz, OCH2CH3),
13.7 (C-5′). 31P NMR (162 MHz, CDCl3): δ = 19.9. HRMS (ESI-TOF):
calcd. for C30H33ClN4O9P+ [M + H]+ 659.1668, found 659.1661.
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Compound 12e was deprotected with saturated methanolic ammo-
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the method for preparation of 15c from 12c to allow 15e as a white
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1
15e: H NMR (400 MHz, D2O): δ = 8.67 (s, 1H, H-2), 8.54 (s, 1H, H-
8), 6.15 (s, 1H, H-1′), 4.84 (s, 1H, H-2′), 4.41 (dd, J = 16.1, 12.6 Hz,
1H, PCH2), 4.28 (q, J = 6.4 Hz, 1H, H-4′), 4.21 (dd, J = 12.6, 5.0 Hz,
1H, PCH2), 3.62 (dd, J = 14.5, 10.1 Hz, 1H, CCH2O), 3.40 (dd, J = 14.5,
2.3 Hz, 1H, CCH2O), 1.39 (d, J = 6.4 Hz, 3H, H-5′). 13C NMR (101 MHz,
D2O) δ = 151.8 (C-2), 150.5 (C-4), 149.9 (C-6), 145.6 (C-8), 131.1 (C-
5), 90.6 (C-1′), 81.6 (d, JC,P = 4 Hz, C-3′), 79.8 (C-2′), 74.3 (C-4′), 65.7
(d, JC,P = 6.2 Hz, CH2OH), 59.5 (d, JC,P = 142 Hz, PCH2), 12.3
Received: June 12, 2020
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Nucleoside Phosphonates
S. Ji, S. Wang, H. Wang, Y. Gao,
W. Xu, X. Huo, P. Herdewijn,
F.-W. Liu* .............................................. 1–9
A novel class of
phosphonates, 3′-C-hydroxymethyl-3′-
O-Phosphonomethyl- -5′-deoxyxylose
L
-threose nucleoside 15 or 16-step reactions starting from
-xylose. However, none of the target
nucleoside phosphonates showed po-
Synthesis and Antiviral Evaluation
of 3′-C-Hydroxymethyl-3′-O-Phos-
phonomethyl-ꢀ-D-5′-deoxyxylose
Nucleosides
D
D
nucleosides, were synthesized through tent antiviral activity and cytotoxicity.
doi.org/10.1002/ejoc.202000831
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© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim