Synthesis of a Threosyl-C-nucleoside Phosphonate

Article abstract of DOI:10.1002/ejoc.201901200

A general synthetic route for the preparation of the first analogue of a new series of sugar-modified C-nucleoside phosphonates is detailed. Such derivative contains a four-carbon l-threose sugar moiety substituted with a phosphonomethoxy group at the 3′-position and pyrrolo[2,1-f][1,2,4]triazin-4-amine as nucleobase. A C-nucleoside was initially prepared by coupling a benzyl protected l-threono-1,4-lactone intermediate with the corresponding aglycon moiety. The choice of a tert-butyldiphenylsilyl group was found to be crucial to achieve the regioselective protection of the hydroxyl group at the 3′-position. Moreover, it allowed to smoothly perform further synthetic manipulations, including the introduction of a benzyl protected phosphonate synthon under basic conditions, which eventually led to the desired compound after final deprotection.

Full text of DOI:10.1002/ejoc.201901200

DOI: 10.1002/ejoc.201901200
Full Paper
Threose C-Nucleosides
Synthesis of a Threosyl-C-nucleoside Phosphonate
Peng Nie,[a] Elisabetta Groaz,[a] and Piet Herdewijn*[a]
Abstract: A general synthetic route for the preparation of the of a tert-butyldiphenylsilyl group was found to be crucial to
first analogue of a new series of sugar-modified C-nucleoside
phosphonates is detailed. Such derivative contains a four-
carbon L-threose sugar moiety substituted with a phosphono-
methoxy group at the 3′-position and pyrrolo[2,1-f][1,2,4]tri-
azin-4-amine as nucleobase. A C-nucleoside was initially pre-
achieve the regioselective protection of the hydroxyl group at
the 3′-position. Moreover, it allowed to smoothly perform fur-
ther synthetic manipulations, including the introduction of a
benzyl protected phosphonate synthon under basic conditions,
which eventually led to the desired compound after final depro-
tection.
pared by coupling a benzyl protected L-threono-1,4-lactone in-
termediate with the corresponding aglycon moiety. The choice
Introduction
C-nucleosides bearing pyrrolo[2,1-f][1,2,4]triazin-4-amine as nu-
cleobase. While GS-6620 exhibits good activity against hepatitis
C virus (HCV) infections,[5] GS-5734 is a potential drug for the
treatment of the EBOV infection.[6]
C-Nucleosides are an important class of nucleoside analogues,
especially in the context of antiviral drug discovery.[1] Such
compounds are characterized by the presence of a C–C bond
in place of the natural C–N glycosidic linkage, which makes
them more resistant against hydrolytic and enzymatic degrada-
tion.[2] Some C-nucleosides isolated from natural sources have
shown interesting biological properties; for instance, showdo-
mycin and formycin A (Figure 1) can act as antibiotics.[3]
BCX4430 (Figure 1) is a synthetic C-nucleoside containing 9-
deazaadenine as nucleobase, which displays potent activity
against Ebola virus (EBOV) infections.[4] Furthermore, GS-6620
and GS-5734 (Figure 1) are representative examples of
Besides, α-L-threose nucleosides containing a four-carbon L-
threosyl sugar ring have been investigated for different pur-
poses.[7] In particular, they are the building blocks of threose
nucleic acid (TNA), which is an artificial genetic polymer able
to form thermally stable self-duplexes by Watson–Crick base
pairing as well as hybrids with complementary DNA and RNA
strands.[8] Its capacity to fold into functional tertiary structures
able to bind targets with high affinity and specificity has also
been demonstrated.[9] Furthermore, TNA has been investigated
for its potential role as early genetic material in a prebiotic set-
ting.[9] Recently, we reported 3′-2′ phosphonomethylthreosyl
nucleic acid (tPhoNA) as the first example of biorthogonal syn-
thetic genetic material with a dual modification at the sugar
and phosphate moiety.[10]
Nucleoside phosphonates are isosteric analogues of natural
nucleoside monophosphates, which have been developed as an-
tiviral drugs. Successful examples that received marketing ap-
proval for clinical use include tenofovir, adefovir, and cidofovir.[11]
Previous work in our group focused on the synthesis of a series
of threosyl nucleoside phosphonates, such as phosphonometh-
oxideoxythreosyl adenine (PMDTA, Figure 2),[12] as well as their
corresponding amidate prodrugs,[13] which were found to display
Figure 1. Structures of known biologically active C-nucleosides.
[a] Rega Institute for Medical Research, Medicinal Chemistry, KU Leuven,
Herestraat 49, 3000 Leuven, Belgium
E-mail: piet.herdewijn@kuleuven.be
http://medchem.rega.kuleuven.be/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901200.
Figure 2. Structures of PMDTA and target C-nucleoside phosphonate ana-
logue 1.
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potent anti-HIV activity. To date, no examples have been re- between 1′-H and 3′-H as well as 2′-H and 8-H, which confirmed
ported in the literature of α- -threosyl-C-nucleoside phosphon- the structure of the desired α-anomer.
L
ates. Therefore, based on the above rationale, we wished to de-
velop suitable synthetic methods for the preparation of such
analogues and further evaluate their potential antiviral activity.
In particular, we planned to prepare C-nucleoside phosphonate
analogue 1 (Figure 2) consisting of a L-threose sugar and
pyrrolo[2,1-f][1,2,4]triazin-4-amine base moiety as model com-
pound.
Results and Discussion
For the synthesis of C-nucleoside phosphonate 1, commercially
available -threono-1,4-lactone 2 was selected as starting mate-
L
rial (Scheme 1). Treatment of compound 2 with benzyl trichlo-
roacetimidate and triflic acid (TfOH) afforded benzyl protected
lactone 3 in good yield. 4-(Methylthio)pyrrolo[2,1-f][1,2,4]tria-
zine 4 was readily prepared according to a reported method.[14]
The coupling reaction between compounds 3 and 4 was ac-
complished by using lithium diisopropylamide (LDA) at –78 °C,
Figure 3. NOESY spectrum of threosyl-C-nucleoside 8α.
With C-nucleoside 8 in hand, we next attempted the intro-
which led to the formation of hemiacetal 5 as a mixture of two duction of a phosphonate moiety at the 3′-position. Although
anomers. Subsequently, compound 6 was obtained in good the selective benzoylation of
-threono-1,4-lactone 2 has been
L
yield (94 %) upon reduction of the 1′-hydroxyl group of 5 using previously reported,[17] the regioselective protection of the
Et3SiH as reducing agent and BF3·OEt2 as Lewis acid.[15] The hydroxyl groups of threosyl nucleosides remains an unsolved
thiomethyl group of compound 6 was substituted by an amino issue. Initial attempts to selectively protect either the 2′- or
group by heating in 7 N methanolic ammonia, thus providing 3′-hydroxyl group of 8 with a trityl group was unsuccessful,
benzyl protected C-nucleoside 7. The protecting groups were leading to a mixture of 2′-O- and 3′-O-tritylated derivatives
removed by palladium catalyzed debenzylation using cyclohex- along with the 2′,3′-bis-O-tritylated analogue. Similar results
ene as hydrogen donor,[16] thus affording threosyl-C-nucleoside were reported earlier by Eschemoser and co-workers.[18]
8 as a mixture of two isomers that were separated by silica gel
column chromatography. The α-anomer (8α) was obtained as
the major product in 49 % yield, while the ꢀ-anomer (8ꢀ) was
isolated in 23 % yield.
Previously, our group demonstrated that the benzoyl group
at the 2′-position of a classic threose N-nucleoside can be selec-
tively removed to give a 3′-O-benzoyl group protected product
under basic conditions (tBuOK, THF).[19] Thus, we decided to
The configuration of the two epimers of C-nucleoside 8 was prepare benzoylated compound 9 from C-nucleoside 8 under
determined by NOESY NMR spectroscopic analysis. As shown in mild conditions (BzCl, pyridine). As shown in Scheme 2, the
Figure 3 for compound 8α, NOE correlations were observed reaction proceeded in good yield. The resulting compound 9
Scheme 1. Synthesis of threosyl-C-nucleoside 8.
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Scheme 2. Regioselective debenzoylation of compound 9.
Scheme 3. Installation of the phosphonate moiety at the 3′-position.
was then subjected to regioselective debenzoylation reaction presence of the phosphonate moiety at the 3′-position. Accord-
conditions (tBuOK), however 3′-O-benzoylated compound 10 ing to the NOESY spectrum (Figure 4), H–H correlations be-
was obtained only in moderate yield (35 %).
tween 8-H and 2′-H as well as 8-H and the PCH2 group were
observed, supporting the configuration of compound 16 to be
as that shown in Scheme 3. A further evidence was observed
by the presence of a correlation between PCH2 and 2′-H. Next,
standard removal of the isopropyl protecting groups on the
phosphonate moiety by treating compound 16 with trimethyl-
silyl bromide in acetonitrile failed to give the desired com-
Pleasingly, a selective protection of the 3′-hydroxyl group
could be successfully performed by treating compound 8 with
tert-butyldiphenylsilyl chloride (TBDPSCl) in the presence of
AgNO3 (Scheme 3). For a good reaction selectivity, the concen-
tration of the starting material had to be approximately 0.02
M
in dry pyridine at 0 °C. Higher reaction concentrations in fact
led to the formation of the 2′,3′-O-bis-TBDPS protected product
instead of the desired compound 11. The remaining active pro-
tons of compound 11 were replaced by benzoyl groups to give
fully protected compound 12, which then underwent cleavage
of the silyl protecting group by using tetra-n-butylammonium
fluoride (TBAF) to afford key intermediate 13 (72 % yield over
3 steps from 8α). The triflate derivative of diisopropylphos-
phonylmethanol 14 and sodium hydride were used to intro-
duce the phosphonate unit at the 3′-position of compound 13,
leading to compound 15 in 72 % yield. Deprotection of the
benzoyl groups under basic conditions (7 N methanolic ammo-
nia) gave C-nucleoside phosphonate diester 16. The configura-
tion of compound 16 was confirmed by 2D NMR analyses
(HMBC and NOESY).
A strong correlation between the two protons of the phos-
phonomethoxy (PCH2) group and the 3′-carbon in the HMBC
spectrum of 16 (see Supporting Information) confirmed the
Figure 4. NOESY spectrum of compound 16.
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Scheme 4. Synthesis of threose C-nucleoside phosphonate 1.
Anhydrous THF was distilled from sodium/benzophenone. 1H, 31P,
and 13C NMR spectra were recorded on a Bruker 300, 500, or
600 MHz spectrometer. 2D NMR experiments (H,H-COSY, HSQC,
HMBC, and NOESY) were used for the characterization of the key
intermediates and final compound. High-resolution mass spectra
(HRMS) were obtained on a quadruple orthogonal acceleration
time-of-flight mass spectrometer (Synapt G2 HDMS, Waters, Milford,
MA). Samples were infused at 3 μL/min, and spectra were obtained
in positive (or negative) ionization mode with a resolution of 15000
(fwhm) using leucine enkephalin as lock mass. Precoated aluminum
sheets (254 nm) were used for TLC, and spots were examined under
UV light. Column chromatography was performed on silica gel 40–
60 μ, 60 Å. Preparative HPLC purification was performed using a
Shimadzu HPLC equipped with a LC-20AT pump, DGU-20A5 degas-
ser, SPD-20A UV detector, and Phenomenex Gemini 110A column
(C18, 10 μm, 21.2 mm × 250 mm).
pound. Therefore, it was necessary to replace the isopropyl
groups on the phosphonate synthon with benzyl functionali-
ties. Compound 17[20] was used for the installation of phos-
phonate moiety instead of compound 14 to provide compound
18 in 29 % yield. After removal of the benzoyl groups by
methanolic ammonia, the benzyl groups were cleaved upon
hydrogenolysis to furnish the desired threose C-nucleoside
phosphonate 1 in quantitative yield (Scheme 4).
Conclusions
In summary, a convenient synthetic route for the preparation
of the first analogue of a new series of C-nucleosides has been
established. The synthesized compound features a L-threose
sugar moiety modified with a phosphonomethoxy group at the
3′-position and pyrrolo[2,1-f][1,2,4]triazin-4-amine as nucleo-
base. The regioselective protection of 3′-hydroxyl group of the
α-isomer of an intermediate C-nucleoside was effectively ac-
complished by using TBDPS as protecting group. After subse-
quent protecting groups manipulation, a phosphonate moiety
was successfully introduced upon optimization of the reaction
conditions. Both the C-nucleoside intermediate and final
C-nucleoside phosphonate were evaluated against a panel of
RNA [respiratory syncytial virus (RSV), zika virus (ZIKV), and
dengue virus (DENV)] and DNA [herpes simplex virus (HSV),
varicella zoster virus (VZV), and cytomegalovirus (CMV)] viruses.
Unfortunately, no significant activity or cytotoxicity was ob-
served.
2,3-Di-O-benzyl-l-threono-1,4-lactone (3):[21] Benzyl trichloro-
acetimidate (16.0 mL, 87.2 mol) and trifluoromethanesulfonic acid
(0.77 mL, 8.72 mmol) were added at 0 °C to a solution of commer-
cially available l-threono-1,4-lactone 2 (5.15 g, 43.6 mol) in dry diox-
ane (150 mL) under a nitrogen atmosphere. The solution was stirred
for 3 h and then quenched with saturated aq. NaHCO3 and ex-
tracted with CH2Cl2. The organic layer was dried with Na2SO4, fil-
tered, and evaporated under reduced pressure to give a crude resi-
due, which was purified by flash column chromatography (petro-
leum ether/EtOAc = 10:1 to 5:1) to afford 3 as a colorless oil (9.45 g,
73 % yield). Rf 0.4 (petroleum ether/EtOAc = 4:1); 1H NMR (300 MHz,
CDCl3) δ = 7.41–7.18 (m, 10H, Ar-H), 5.02 (d, J = 11.6 Hz, 1H, Bn-
CH2), 4.76 (d, J = 11.6 Hz, 1H, Bn-CH2), 4.62 (d, J = 11.8 Hz, 1H, Bn-
CH2), 4.51 (d, J = 11.8 Hz, 1H, Bn-CH2), 4.43–4.27 (m, 2H, 4′-H, 3′-H),
4.22 (d, J = 5.7 Hz, 1H, 2′-H), 4.05 (dd, J = 9.0, 5.8 Hz, 1H, 4′-H); 13
C
NMR (75 MHz, CDCl3) δ = 172.5 (C=O), 137.3 (Ar-C), 137.0 (Ar-C),
137.0 (Ar-C), 129.2 (Ar-C), 129.0 (Ar-C), 128.9 (Ar-C), 128.9 (Ar-C),
128.7 (Ar-C), 128.6 (Ar-C), 128.6 (Ar-C), 128.2 (Ar-C), 78.7 (C-3′), 77.7
(C-2′), 72.8 (Bn-CH2), 72.6 (Bn-CH2), 69.4 (C-4′); ESI-HRMS calcd. for
Experimental Section
General Information: For all reactions, analytical grade solvents
were used. All moisture sensitive reactions were carried out in oven-
dried glassware (120 °C) under a nitrogen or argon atmosphere.
C
18H18N4Na [M + Na]+, 321.1097, found m/z 321.1094.
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(2′R,3′S)-2′,3′-Bis(benzyloxy)-1′-(4-(methylthio)pyrrolo[2,1-f]-
[1,2,4]triazin-7-yl)tetra-hydroofuran-1′-ol (5): To a solution of 4-
128.8 (Ar-C), 128.7 (Ar-C), 128.7 (Ar-C), 128.5 (Ar-C), 128.3 (Ar-C),
128.1 (Ar-C), 128.1 (Ar-C), 128.0 (Ar-C), 127.9 (Ar-C), 114.9 (C-5),
(methylthio)pyrrolo[2,1-f][1,2,4]triazine 4 (4.57 g, 27.6 mmol) in THF 114.3 (C-5), 111.7 (C-8), 110.8 (C-8), 100.7 (C-7), 100.5 (C-7), 86.6 (C-
(70 mL) was added lithium diisopropylamide (2 M in THF, 14.8 mL,
29.5 mmol) at –78 °C under an argon atmosphere. The resulting
mixture was stirred for 30 min at –78 °C. Then, a solution of com-
pound 3 (5.50 g, 18.4 mmol) in THF (15 mL) was added at –78 °C
and the resulting reaction mixture was stirred at this temperature
for 3 h. The reaction was quenched by adding saturated aq. NH4Cl
and further extracted with ethyl acetate. The organic layer was
washed with brine, dried with Na2SO4, and concentrated in vacuo.
The crude residue was purified by silica gel flash chromatography
(petroleum ether/EtOAc = 5:1 to 1:1) to give the title compound as
a brown syrup (6.0 g, 70 % yield). Rf 0.3 (petroleum ether/EtOAc =
2:1); 1H NMR (300 MHz, CDCl3) δ = 8.38–8.19 (m, 1H, 2-H), 7.37–7.04
(m, 10H, Ph-H), 6.86–6.73 (m, 2H, 7-H, 8-H), 5.41–5.12 (m, 1H, 2′-H),
4.71–4.45 (m, 4H, Ph-CH2), 4.36–4.28 (m, 1H, 3′-H), 4.02–3.75 (m, 2H,
4′-H), 2.66–2.69 (m, 3H, SMe); 13C NMR (75 MHz, CDCl3) δ = 166.5
(C-4), 165.4 (C-4), 146.8 (C-2), 145.2 (C-2), 145.1 (Ar-C), 138.0 (Ar-C),
137.6 (Ar-C), 137.4 (Ar-C), 128.9 (Ar-C), 128.7 (Ar-C), 128.7 (Ar-C),
128.6 (Ar-C), 128.5 (Ar-C), 128.5 (Ar-C), 128.4 (Ar-C), 128.3 (Ar-C),
128.3 (Ar-C), 128.1 (Ar-C), 127.9 (Ar-C), 127.9 (Ar-C), 126.4 (Ar-C),
125.5 (Ar-C), 122.9 (Ar-C), 122.4 (Ar-C), 120.6 (Ar-C), 113.5 (C-8),
112.6 (C-8), 104.5 (C-1′), 103.3 (C-7), 102.1 (C-7), 100.4 (C-1′), 84.8 (C-
2′), 84.2 (C-2′), 82.7 (C-3′), 82.2 (C-3′), 79.4 (Bn-C), 73.3 (Bn-C), 73.2
(Bn-C), 72.7 (Bn-C), 72.3 (Bn-C), 71.7 (Bn-C), 69.9 (C-4′), 62.2 (C-4′),
12.0 (SMe-C), 11.7 (SMe-C); ESI-HRMS calcd. for C25H25N3O4SNa
[M + Na]+, 486.1458, found m/z 486.1443.
2′), 84.1 (C-2′), 83.5 (C-3′), 82.0 (C-3′), 77.7 (C-1′), 76.1 (C-1′), 72.4
(C-4′), 72.3 (C-4′), 72.2 (Bn-C), 71.9 (Bn-C), 71.8 (Bn-C), 71.7 (Bn-C);
ESI-HRMS calcd. for C24H25N4O3 [M + H]+, 417.1921, found m/z
417.1920.
(2′R,3′S)-1′-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydro-
furan-2′,3′-diol (8): A mixture of compound 7 (835 mg, 2.00 mmol),
20 % Pd(OH)2/C (835 mg), and cyclohexene (6.0 mL, 60.1 mmol) in
EtOH (15 mL) was refluxed overnight. After filtration through Celite,
the filtrate was evaporated under reduced pressure to give a crude
residue, which was purified by silica gel column chromatography
(DCM/MeOH = 15:1 to 5:1) to afford compound 8 (ꢀ-isomer, 110 mg,
23 %; α-isomer, 230 mg, 49 %). Data for 8α: Rf 0.35 (DCM/MeOH =
7:1); 1H NMR (500 MHz, CD3OD) δ = 7.80 (s, 1H, 2-H), 6.85 (d, J =
4.5 Hz, 1H, 7-H), 6.75 (d, J = 4.5 Hz, 1H, 8-H), 5.13 (d, J = 4.2 Hz, 1H,
1′-H), 4.41 (ddd, J = 4.1, 2.1, 0.7 Hz, 1H, 2′-H), 4.21 (dt, J = 4.4, 2.3 Hz,
1H, 3′-H), 4.07 (dd, J = 9.6, 4.3 Hz, 1H, 4′-H), 3.95 (dd, J = 9.6, 2.3 Hz,
1H, 4′-H); 13C NMR (126 MHz, CD3OD) δ = 157.2 (C-4), 148.0 (C-2),
130.3 (C-9), 116.2 (C-5), 111.8 (C-8), 102.7 (C-7), 82.4 (C-2′), 81.2
(C-1′), 79.3 (C-3′), 74.6 (C-4′). Data for 8ꢀ: Rf 0.30 (DCM/MeOH = 7:1);
1H NMR (600 MHz, CD3OD) δ = 7.75 (s, 1H, 2-H), 6.86 (d, J = 4.5 Hz,
1H, 7-H), 6.76 (d, J = 4.9 Hz, 1H, 8-H), 5.60 (d, J = 3.3 Hz, 1H, 1′-H),
4.38 (dd, J = 3.3, 0.8 Hz, 1H, 2′-H), 4.34–4.29 (m, 2H, 3′-H, 4′-H), 3.80
(d, J = 8.5 Hz, 1H, 4′-H); 13C NMR (151 MHz, CD3OD) δ = 156.8
(C-4), 147.6 (C-2), 128.9 (C-9), 115.5 (C-5), 112.4 (C-8), 102.8 (C-7),
78.6 (C-3′), 78.0 (C-2′), 77.5 (C-1′), 74.3 (C-4′); ESI-HRMS calcd. for
C
10H13N4O3 [M + H]+, 237.0982, found m/z 237.0982.
7-((2′S,3′S)-2′,3′-Bis(benzyloxy)tetrahydrofuran-1′-yl)-4-(methyl-
thio)pyrrolo[2,1-f][1,2,4]-triazine (6): To a solution of compound
5 (3.18 g, 6.86 mmol) in dichloromethane (25 mL) was added tri-
ethylsilane (4.38 mL, 27.4 mmol) and trifluoroborane (1.7 mL,
13.7 mmol) at 0 °C under an argon atmosphere. The resulting solu-
tion was stirred for 40 min at 0 °C, quenched with saturated aq.
NaHCO3 and further extracted with ethyl acetate. The organic layer
was washed with water, brine, dried with Na2SO4, and concentrated
in vacuo. The crude residue was purified by flash chromatography
(petroleum ether/EtOAc = 10:1 to 4:1) to give compound 6 as a
yellow foam (2.90 g, 94 % yield). Rf 0.5 (petroleum ether/EtOAc =
5:1); 1H NMR (300 MHz, CDCl3) δ = 8.22–8.10 (m, 1H, 2-H), 7.37–7.14
(m, 9H, Ar-H), 6.99–6.75 (m, 3H, Ar-H), 5.64–5.54 (m, 1H, 1′-H), 4.67–
4.33 (m, 4H, Bn), 4.25–3.96 (m, 4H, 2′-H, 3′-H, 4′-H), 2.67–2.66 (m,
3H, SMe); 13C NMR (75 MHz, CDCl3) δ = 164.7 (C-4), 164.3 (C-4),
145.5 (C-2), 145.3 (C-2), 138.1 (Ar-C), 138.1 (Ar-C), 137.8 (Ar-C), 129.2
(Ar-C), 128.8 (Ar-C), 128.7 (Ar-C), 128.6 (Ar-C), 128.4 (Ar-C), 128.1 (Ar-
C), 128.1 (Ar-C), 128.1 (Ar-C), 128.0 (Ar-C), 127.9 (Ar-C), 127.9 (Ar-C),
127.8 (Ar-C), 122.4 (C-5), 121.9 (C-5), 113.3 (C-8), 112.4 (C-8), 102.4
(C-7), 102.3 (C-7), 86.4 (C-2′), 84.0 (C-2′), 83.4 (C-1′), 81.9 (C-1′), 77.7
(C-3′), 76.0 (C-3′), 72.4 (C-4′), 72.4 (C-4′), 72.3 (Bn-C), 71.9 (Bn-C), 71.8
(Bn-C), 71.7 (Bn-C), 11.7 (SMe-C); ESI-HRMS calcd. for C25H26N3O3S
[M + H]+, 448.1689, found m/z 448.1685.
(1′S,2′S,3′S)-1′-(4-(N-Benzoylbenzamido)pyrrolo[2,1-f][1,2,4]tri-
azin-7-yl)tetrahy-drofuran-2′,3′-diyl Dibenzoate (9): To a solution
of C-nucleoside 8 (168 mg, 0.7 mmol) in dry pyridine (10 mL) was
added BzCl (0.5 mL, 4.3 mmol) at 0 °C. The reaction was stirred at
room temperature overnight before quenching with saturated aq.
NaHCO3. The resulting mixture was extracted with DCM (twice) and
the organic layers were combined, dried with Na2SO4, and evapo-
rated in vacuo to give a crude residue, which was purified by flash
chromatography (petroleum ether/EtOAc = 6:1 to 1:1) to afford
compound 9 as a pale yellow foam (435 mg, 94 % yield). Rf 0.3
1
(petroleum ether/EtOAc = 3:1); H NMR (300 MHz, CDCl3) δ = 8.16
(s, 1H, 2-H), 8.10–8.07 (m, 2H, Bz), 7.96–7.93 (m, 2H, Bz), 7.87–7.84
(m, 4H, Bz), 7.63–7.36 (m, 12H, Bz), 7.15 (d, J = 4.7 Hz, 1H, 7-H), 6.76
(d, J = 4.7 Hz, 1H, 8-H), 6.06 (d, J = 2.9 Hz, 1H, 2′-H), 5.78 (d, J =
3.4 Hz, 1H, 3′-H), 5.70–5.68 (m, 1H, 1′-H), 4.51 (dd, J = 10.9, 4.5 Hz,
1H, 4′-H), 4.35 (d, J = 10.5 Hz, 1H, 4′-H); 13C NMR (75 MHz, CDCl3)
δ = 172.2 (Bz C=O), 165.9 (Bz C=O), 165.5 (Bz C=O), 154.7 (C-4),
146.4 (C-2), 134.0 (Ar-C), 133.9 (Ar-C), 133.8 (Ar-C), 133.7 (Ar-C),
130.4 (Ar-C), 130.2 (Ar-C), 130.1 (Ar-C), 129.5 (Ar-C), 129.3 (Ar-C),
128.8 (Ar-C), 128.7 (Ar-C), 119.7 (C-5), 114.4 (C-8), 103.9 (C-7), 80.4
(C-3′), 78.7 (C-2′), 77.6 (C-1′), 73.0 (C-4′); ESI-HRMS calcd. for
C38H29N4O7 [M + H]+, 653.2031, found m/z 653.2050.
7-((2′S,3′S)-2′,3′-Bis(benzyloxy)tetrahydrofuran-1′-yl)pyrrolo-
[2,1-f][1,2,4]triazin-4-amine (7): Compound 6 (2.90 g, 6.50 mmol)
was dissolved in 7 N methanolic ammonia (50 mL) and the resulting
solution was stirred for 12 h at 100 °C. The solvent was evaporated
in vacuo to give a crude product, which was purified by flash chro-
matography (petroleum ether/EtOAc = 2:1 to 1:4) to afford 2.50 g
of compound 7 as a white foam (92 % yield). Rf 0.3 (petroleum
ether/EtOAc = 1:3); 1H NMR (300 MHz, CDCl3) δ = 7.92–7.83 (m, 1H,
2-H), 7.35–7.17 (m, 9H, Ar-H), 6.94–6.54 (m, 3H, Ar-H), 6.11 (br, 2H,
(1′S,2′S,3′S)-1′-(4-Benzamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2′-
hydroxytetrahydro-furan-3′-yl Benzoate (10): A solution of tBuOK
(13.0 mg, 0.10 mmol) in 1 mL of dry THF was added to a solution
of compound 9 (30.0 mg, 0.05 mmol) in 5 mL of THF at –20 °C. The
reaction was stirred at 0 °C for 3 h and then quenched with satu-
rated aq. NH4Cl. The resulting mixture was extracted with ethyl
acetate (3 × 5 mL) and the combined organic layers were dried with
Na2SO4, filtered, and concentrated in vacuo. The crude product was
NH2), 5.66–7.53 (m, 1H, 1′-H), 4.70–4.31 (m, 4H, Bn), 4.24–3.94 (m, subjected to flash chromatography (petroleum ether/EtOAc = 2:1
4H, 2′-H, 3′-H, 4′-H); 13C NMR (75 MHz, CDCl3) δ = 155.8 (C-4), 155.6 to 1:2) to afford compound 10 (7 mg, 35 %). Rf 0.3 (petroleum ether/
(C-4), 147.4 (C-2), 147.2 (C-2), 138.1 (Ar-C), 138.0 (Ar-C), 129.2 (Ar-C),
EtOAc = 1:1); 1H NMR (600 MHz, CDCl3) δ = 8.13–8.05 (m, 2H, Ar-H),
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7.98–7.97 (m, 2H, Ar-H), 7.62–7.56 (m, 2H, Ar-H), 7.52–7.46 (m, 3H,
Ar-H), 7.45–7.41 (m, 3H, Ar-H), 6.94 (s, 1H, Ar-H), 5.43 (dt, J = 4.8,
2.1 Hz, 1H, 3′-H), 5.36 (d, J = 5.0 Hz, 1H, 1′-H), 4.66 (dd, J = 5.1,
1.8 Hz, 1H, 2′-H), 4.45 (dd, J = 10.8, 5.2 Hz, 1H, 4′-H), 4.34 (dd, J =
1H, 1′-H), 4.56–4.55 (m, 1H, 3′-H), 4.22–4.11 (m, 2H, 4′-H); 13C NMR
(75 MHz, CDCl3) δ = 172.3 (Bz C=O), 166.4 (Bz C=O), 151.5 (C-4),
146.3 (C-2), 133.9 (Ar-C), 133.8 (Ar-C), 133.3 (Ar-C), 133.2 (Ar-C),
130.2 (Ar-C), 130.2 (Ar-C), 130.1 (Ar-C), 129.5 (Ar-C), 129.3 (Ar-C),
10.8, 2.2 Hz, 1H, 4′-H); 13C NMR (126 MHz, CDCl3) δ = 166.6 (Bz C= 129.0 (Ar-C), 128.9 (Ar-C), 128.8 (Ar-C), 128.6 (Ar-C), 114.2 (C-5),
O), 150.9 (C-4), 133.6 (Ar-C), 133.5 (Ar-C), 132.9 (Ar-C), 130.0 (Ar-C),
129.7 (Ar-C), 129.2 (Ar-C), 128.7 (Ar-C), 128.5 (Ar-C), 111.4 (C-8),
109.0 (C-8), 104.2 (C-7), 84.2 (C-2′), 78.8 (C-3′), 77.0 (C-1′), 74.6 (C-4′
); ESI-HRMS calcd. for C24H21N4O5 [M + H]+, 445.1506, found m/z
108.8 (C-7), 81.7 (C-3′), 80.7 (C-2′), 80.2 (C-1′), 71.8 (C-4′); ESI-HRMS 445.1502.
calcd. for C24H21N4O5 [M + H]+, 445.1506, found m/z 445.1505.
(1′S,2′S,3′S)-1′-(4-Benzamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3′-
(1′S,2′S,3′S)-1′-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3′-
((tert-butyldiphenylsilyl)-oxy)tetrahydrofuran-2′-ol (11): To a so-
lution of C-nucleoside 8 (133 mg, 0.56 mmol) and TBDPSCl (0.6 mL,
((diisopropoxyphos-phoryl)methoxy)tetrahydrofuran-2′-yl
Benzoate (15): To a solution of 13 (50 mg, 0.1 mmol) and triflate
diisopropylphosphonomethanol (110 mg, 0.3 mmol) in anhydrous
2.30 mmol) in 25 mL of dry pyridine was added AgNO3 (430 mg, THF (50 mL) was added NaH (60 % in mineral oil, 13.5 mg,
2.50 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 min and
then quenched with brine. The resulting mixture was extracted with
DCM (twice) and the organic layers were combined, dried with
Na2SO4, filtered, and evaporated in vacuo to afford a crude product,
which was used directly in the next step without further purifica-
0.3 mmol) at 0 °C. The reaction mixture was stirred for 1 h. It was
then quenched with saturated aq. NH4Cl and extracted with EtOAc.
The organic layer was washed with brine, dried with Na2SO4, and
concentrated under reduced pressure to give a crude residue, which
was purified by column chromatography (petroleum ether/EtOAc =
tion. Rf 0.2 (petroleum ether/EtOAc = 1:3); 1H NMR (300 MHz, CDCl3) 3:1 to 1:3) to afford 15 (52 mg, 74 % yield) as a colorless foam. Rf
1
δ = 7.88 (s, 1H, 2-H), 7.65–7.57 (m, 4H, Ph-H), 7.44–7.30 (m, 6H, Ph-
H), 6.79 (d, J = 4.4 Hz, 1H, 7-H), 6.64 (d, J = 4.5 Hz, 1H, 8-H), 5.67
0.3 (petroleum ether/EtOAc = 1:2); H NMR (300 MHz, CD3OD) δ =
8.12–7.86 (m, 6H, Ar-H), 7.65–7.41 (m, 6H, Ar-H), 7.27–7.07 (d, J =
(br, 2H, NH2), 5.14 (d, J = 4.7 Hz, 1H, 1′-H), 4.45–4.39 (m, 2H, 2′-H, 4.7 Hz, 1H, Ar-H), 5.72 (s, 1H, 1′-H), 4.76–4.65 (m, 2H, iPr-CH), 4.43–
3′-H), 4.00–3.91 (m, 2H, 4′-H), 1.02 (s, 9H, TBDPS); 13C NMR (75 MHz,
CDCl3) δ = 155.5 (C-4), 147.5 (C-2), 136.0 (Ar-C), 130.1 (Ar-C), 130.1
(Ar-C), 128.0 (Ar-C), 128.0 (Ar-C), 114.5 (C-5), 109.6 (C-8), 100.5 (C-7),
83.0 (C-2′), 80.8 (C-3′), 79.8 (C-1′), 74.3 (C-4′), 27.1 (TBDPS), 19.4
(TBDPS); ESI-HRMS calcd. for C26H31N4O3Si [M + H]+, 475.2160,
found m/z 475.2159.
3.99 (m, 6H, 2′-H, 3′-H, 4′-H, PCH2), 1.38–1.26 (m, 12H, iPr-CH3); 13C
NMR (75 MHz, CD3OD) δ = 171.9 (Bz C=O), 165.3 (Bz C=O), 145.3
(C-2), 133.0 (Ar-C), 132.9 (Ar-C), 132.1 (Ar-C), 129.0 (Ar-C), 128.5 (Ar-
C), 128.4 (Ar-C), 128.1 (Ar-C), 128.0 (Ar-C), 127.9 (Ar-C), 122.2 (Ar-C),
114.1 (Ar-C), 111.7 (Ar-C), 103.3 (Ar-C), 99.7 (Ar-C), 85.9 (C-3′), 85.7
(C-3′), 80.5 (C-2′), 76.7 (C-1′), 71.6 (iPr-CH), 71.5 (iPr-CH), 71.4 (C-4′),
64.5 (PCH2), 62.3 (PCH2), 22.6 (iPr-CH3), 22.6 (iPr-CH3), 22.5 (iPr-CH3);
3 1 P NMR (121 MHz, CDCl3 ) δ = 19.0; ESI-HRMS calcd. for
C31H36N4O8P [M + H]+, 623.2265, found m/z 623.2268.
(1′S,2′S,3′S)-1′-(4-(N-Benzoylbenzamido)pyrrolo[2,1-f][1,2,4]tri-
azin-7-yl)-3′-((tert-butyldiphenylsilyl)oxy)-tetrahydrofuran-2′-yl
Benzoate (12): To a solution of compound 11 (451 mg, 0.59 mmol)
in 10 mL of dry pyridine was added BzCl (0.9 mL, 7.60 mmol) at
0 °C. The reaction was stirred at room temperature overnight, and
then quenched with saturated aq. NaHCO3. The resulting mixture
was extracted with DCM (twice) and the organic layers were com-
bined, dried with Na2SO4, filtered, and evaporated in vacuo. The
crude residue was purified by flash chromatography (petroleum
ether/EtOAc = 8:1 to 3:1) to afford compound 12 as a yellow foam.
Rf 0.4 (petroleum ether/EtOAc = 3:1); 1H NMR (300 MHz, CDCl3) δ =
8.15–8.10 (m, 2H, Ar-H), 7.96–7.86 (m, 6H, Ar-H), 7.66–7.61 (m, 3H,
Ar-H), 7.55–7.48 (m, 3H, Ar-H), 7.43–7.29 (m, 13H, Ar-H), 6.78 (d, J =
Diisopropyl((((1′S,2′S,3′S)-1′-(4-aminopyrrolo[2,1-f][1,2,4]tri-
azin-7-yl)-2′-hydroxytetra-hydrofuran-3′-yl)oxy)methyl)phos-
phonate (16): Compound 15 (50 mg, 0.08 mmol) was dissolved in
7 N methanolic ammonia (5 mL). The reaction was stirred at room
temperature overnight. The solvent was evaporated under reduced
pressure to give a crude product, which was purified by silica gel
column chromatography (DCM/MeOH = 50:1 to 10:1) to give com-
1
pound 16 (25 mg, 75 % yield). Rf 0.4 (DCM/MeOH = 20:1); H NMR
(600 MHz, CD3OD) δ = 7.78 (s, 1H, 2-H), 6.84 (d, J = 4.5 Hz, 1H, 7-
H), 6.73 (d, J = 4.5 Hz, 1H, 8-H), 5.24 (d, J = 4.3 Hz, 1H, 1′-H), 4.63–
4.7 Hz, 1H, 8-H), 5.86 (dd, J = 2.7, 1.8 Hz, 1H, 2′-H), 5.66 (d, J = 4.68 (m, 2H, iPr-CH), 4.54–4.53 (m, 1H, 2′-H), 4.12–4.08 (m, 3H, 3′-H,
2.6 Hz, 1H, 1′-H), 4.58–4.55 (m, 1H, 3′-H), 3.99 (d, J = 3.5 Hz, 2H,
4′-H), 1.05 (s, 9H, TBDPS); 13C NMR (75 MHz, CDCl3) δ = 172.3 (Bz
C=O), 165.5 (Bz C=O), 154.6 (C-4), 146.3 (C-2), 136.1 (Ar-C), 136.0
(Ar-C), 134.0 (Ar-C), 133.6 (Ar-C), 133.6 (Ar-C), 130.4 (Ar-C), 130.3 (Ar-
4′-H), 3.87 (d, J = 9.5 Hz, 2H, PCH2), 1.31–1.26 (m, 12H, iPr-CH3); 13
C
NMR (151 MHz, CD3OD) δ = 157.1 (C-4), 148.0 (C-2), 130.4 (C-9),
116.0 (C-5), 111.2 (C-8), 102.7 (C-7), 89.7 (C-3′), 89.6 (C-3′), 80.5 (C-2′
), 80.5 (C-1′), 73.3 (iPr-CH), 73.2 (iPr-CH), 72.2 (C-4′), 65.3 (PCH2), 64.2
C), 130.1 (Ar-C), 129.5 (Ar-C), 129.3 (Ar-C), 128.7 (Ar-C), 128.2 (Ar-C), (PCH2), 24.3 (iPr-CH3), 24.3 (iPr-CH3), 24.3 (iPr-CH3), 24.2 (iPr-CH3),
124.4 (Ar-C), 119.5 (Ar-C), 115.0 (C-8), 103.8 (C-7), 83.1 (C-2′), 78.0
24.2 (iPr-CH3); 31P NMR (121 MHz, CD3OD) δ = 19.4; ESI-HRMS calcd.
(C-3′), 77.2 (C-1′), 74.5 (C-4′), 27.2 (TBDPS), 19.4 (TBDPS); ESI-HRMS for C17H28N4O6P [M + H]+, 415.1741, found m/z 415.1741.
calcd. for C47H43N4O6Si [M + H]+, 787.2946, found m/z 787.2951.
(1′S,2′S,3′S)-1′-(4-Benzamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3′-
(1′S,2′R,3′S)-1′-(4-Benzamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3′-
hydroxytetrahydro-furan-2′-yl Benzoate (13): To a solution of
crude compound 12 (748 mg, 0.95 mmol) in dry pyridine was
added TBAF (1 M, 1.9 mL, 1.9 mmol). The reaction was stirred at
room temperature for 1 h. After complete consumption of the start-
((bis(benzyloxy)phospho-ryl)methoxy)tetrahydrofuran-2′-yl
Benzoate (18): To a solution of 16 (70 mg, 0.16 mmol) and triflate
dibenzylphosphonomethanol 17 (200 mg, 0.47 mmol) in anhydrous
THF (50 mL) was added NaH (60 % in mineral oil, 19.0 mg,
0.47 mmol) at 0 °C. The reaction mixture was stirred for 2 h. The
ing material, the volatiles were removed in vacuo to give a crude reaction was quenched with saturated aq. NH4Cl, and subsequently
residue, which was purified by flash chromatography (petroleum
ether/EtOAc = 4:1 to 1:2) to afford compound 13 as a yellow foam
(307 mg, 72 % over 3 steps). Rf 0.3 (petroleum ether/EtOAc = 1:1);
concentrated under reduced pressure. The remaining residue was
partitioned between water and EtOAc. The organic layer was
washed with brine, dried with Na2SO4, and concentrated under re-
1H NMR (300 MHz, CDCl3) δ = 8.14–8.09 (m, 2H, Ar-H), 8.07–8.04 (m, duced pressure. The residue was purified by column chromatogra-
3H, Ar-H), 7.63–7.58 (m, 2H, Ar-H), 7.54–7.39 (m, 5H, Ar-H), 6.97 (d,
phy (petroleum ether/EtOAc = 3:1 to 1:2) to afford 18 (33 mg, 29 %
J = 4.7 Hz, 1H, 8-H), 5.61 (d, J = 3.4 Hz, 1H, 2′-H), 5.37 (d, J = 3.6 Hz,
yield) as a colorless foam. Rf 0.25 (petroleum ether/EtOAc = 1:2);
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1H NMR (300 MHz, CDCl3) δ = 8.12–7.83 (m, 4H, Ar-H), 7.64–7.45 (m,
6H, Ar-H), 7.32–7.24 (m, 13H, Ar-H), 5.70 (s, 1H, 1′-H), 5.12–4.98 (m,
5H, Bn-CH2, 2′-H), 4.27–3.95 (m, 5H, 3′-H, 4′-H, PCH2); 13C NMR
(75 MHz, CDCl3) δ = 165.8 (Bz C=O), 161.6 (Bz C=O), 151.2 (C-4),
148.0 (C-2), 133.8 (Ar-C), 133.0 (Ar-C), 130.1 (Ar-C), 129.5 (Ar-C),
129.2 (Ar-C), 128.9 (Ar-C), 128.8 (Ar-C), 128.8 (Ar-C), 128.3 (Ar-C),
128.3 (Ar-C), 119.8 (Ar-C), 112.7 (Ar-C), 108.7 (Ar-C), 99.7 (Ar-C), 86.5
(C-3′), 86.4 (C-3′), 80.8 (C-2′), 80.7 (C-1′), 72.5 (C-4′), 68.4 (PCH2), 68.3
(PCH2), 68.2 (PCH2); 31P NMR (121 MHz, CDCl3) δ = 21.9; ESI-HRMS
calcd. for C39H36N4O8P [M + H]+, 719.2265, found m/z 719.2266.
Keywords: Nucleoside analogues · C-nucleosides ·
Phosphonates · Threose nucleosides · Nucleoside mimic
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Dibenzyl((((1′S,2′S,3′S)-1′-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-
yl)-2′-hydroxytetrahy-drofuran-3′-yl)oxy)methyl)phosphonate
(19): Compound 18 (33 mg, 0.05 mmol) was dissolved in 7 N meth-
anolic ammonia. The reaction was stirred at room temperature over-
night. The solvent was evaporated under reduced pressure to give
a crude product, which was purified by silica gel column chroma-
tography (DCM/MeOH = 50:1 to 15:1) to give 19 (18 mg, 78 %). Rf
0.4 (DCM/MeOH = 20:1); 1H NMR (600 MHz, CD3OD) δ = 7.77 (s, 1H,
2-H), 7.33–7.31 (m, 10H, Bn), 6.80 (d, J = 4.5 Hz, 1H, 7-H), 6.68 (d,
J = 4.5 Hz, 1H, 8-H), 5.23 (d, J = 4.2 Hz, 1H, 1′-H), 5.04–4.99 (m, 4H,
Bn-CH2), 4.48 (dd, J = 4.1, 1.6 Hz, 1H, 2′-H), 4.07–4.04 (m, 3H, 3′-H,
4′-H), 3.94 (d, J = 9.4 Hz, 2H, PCH2); 13C NMR (151 MHz, CD3OD) δ =
157.1 (C-4), 148.0 (C-2), 137.4 (Ar-C), 137.4 (Ar-C), 130.4 (Ar-C), 116.0
(C-5), 111.2 (C-8), 102.7 (C-7), 89.7 (C-3′), 89.6 (C-3′), 80.6 (C-1′), 80.3
(C-2′), 72.2 (C-4′), 69.6 (Bn-CH2), 69.5 (Bn-CH2), 64.8 (PCH2), 63.7
(PCH2); 31P NMR (121 MHz, CD3OD) δ = 22.1; ESI-HRMS calcd. for
C25H28N4O6P [M + H]+, 511.1741, found m/z 511.1742.
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((((1′S,2′S,3′S)-1′-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2′-
hydroxytetrahydrofuran –3′-yl)oxy)methyl)phosphonic Acid Tri-
ethylamine Salt (1): To a solution of compound 19 (25 mg,
0.05 mmol) in methanol was added 10 % Pd/C (25 mg). The reaction
mixture was stirred at room temperature under a hydrogen atmos-
phere (1 atm, balloon) for 12 h. The mixture was then filtered
through Celite to remove the residual catalyst. The filtrate was evap-
orated under reduced pressure to give a residue, which was then
purified by silica gel column chromatography (acetone:triethyl-
amine:water = 4:1:1) to afford 1. Further purification was performed
by reverse phase HPLC to afford the product (16 mg, 99 %). Rf 0.3
(acetone:triethylamine:water = 4:1:1); 1H NMR (600 MHz, D2O) δ =
7.78 (s, 1H, 2-H), 6.89 (d, J = 4.6 Hz, 1H, 7-H), 6.83 (d, J = 4.6 Hz, 1H,
8-H), 5.12 (d, J = 6.5 Hz, 1H, 1′-H), 4.72 (dd, J = 6.5, 2.8 Hz, 1H, 2′-
H), 4.28 (dt, J = 5.7, 2.9 Hz, 1H, 3′-H), 4.16 (dd, J = 10.4, 5.5 Hz, 1H,
4′-H), 4.04 (dd, J = 10.3, 2.9 Hz, 1H, 4′-H), 3.57 (d, J = 8.7 Hz, 2H,
PCH2); 13C NMR (151 MHz, D2O) δ = 155.4 (C-4), 147.1 (C-2), 127.2
(C-9), 115.0 (C-5), 110.7 (C-8), 102.2 (C-7), 86.7 (C-3′), 86.6 (C-3′),
78.3 (C-2′), 76.6 (C-1′), 71.1 (C-4′), 68.1 (PCH2), 67.1 (PCH2); 31P NMR
(121 MHz, D2O) δ = 14.4; ESI-HRMS calcd. for C11H14N4O6P [M – H]–,
329.0656, found m/z 329.0644.
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P. N. would like to thank the China Scholarship Council (CSC)
for funding (grant No. 201506200062). We are grateful to Prof.
Jef Rozenski (KU Leuven) for recording HRMS spectra, Luc Baud-
emprez for running the 2D NMR experiments. We are extremely
grateful to Prof. Graciela Andrei (KU Leuven) and Prof. Craig Day
(Utah State University) for the antiviral testing.
Received: August 14, 2019
Eur. J. Org. Chem. 2019, 6666–6672
www.eurjoc.org
6672
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim