A straightforward and versatile FeCl3 catalyzed Friedel-Crafts C-glycosylation process. Application to the synthesis of new functionalized C-nucleosides

Article abstract of DOI:10.1039/c8nj06300a

A new, straightforward and eco-compatible route to C-(hetero)aryl nucleosides is reported. This ribosylation process consists of a one-step FeCl₃ catalyzed Friedel-Crafts β-C-glycosydation reaction. This reaction occurs through an oxonium intermediate from readily available protected sugars leading to functionalized C-nucleosides with high stereocontrol. The expected new C-nucleosides were obtained in good yields within a short reaction time (10 min). Moreover, this approach is compatible with the use of a range of bulky (poly)aromatics such as naphthalene, anthracene and pyrene, which are not easily accessible via classical routes. These new C-aryl-nucleosides exhibit interesting photophysical properties, underling their potential use for further nucleic acid labelling.

Full text of DOI:10.1039/c8nj06300a

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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A straightforward and versatile FeCl3 catalyzed Friedel-Crafts C-glycosylation process. Application to the synthesis
of new functionalized C-nucleosides
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Hamza Tachallait#,1,2 Mauro Safir Filho#,2,4 Hamid Marzag#,1,2 Khalid Bougrin*,2 Luc Demange,1,3 Anthony R. Martin,1 Rachid
Benhida*1,5
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1 Université Côte d’Azur, CNRS, Institut de Chimie de Nice UMR 7272 - 06108 Nice, France.
2 Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, URAC23, Faculté des Sciences, Université Mohammed V, B.P.
1014 Rabat, Maroc.
3 Département de Chimie, Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Pharmaceutiques, 4 avenue de l’Observatoire & UFR
Biomédicale des Saints Pères, 45 rue des Saints Pères, Paris Fr-75006, France.
4 CAPES Foundation, Ministry of Education of Brazil, Brasília DF 70040-020, Brazil
5 Mohamed VI Polytechnic University, UM6P, 43150 Ben Guerir, Morocco.
View Article Online
DOI: 10.1039/C8NJ06300A
ABSTRACT
A new, straightforward and eco-compatible route to C-(hetero)aryl nucleosides is reported. This ribosylation process consists of a one-step FeCl3
catalyzed Friedel-Crafts -C-glycosydation reaction. This reaction occurs trough an oxonium intermediate from readily available protected sugars
leading to functionalized C-nucleosides with high stereocontrol. The expected new C-nucleosides were obtained in good yields within a short
reaction time (10 min). Moreover, this approach is compatible with the use of a range of bulky (poly)aromatics such as naphthalene, anthracene
and pyrene, which are not easily accessible via classical routes. These new C-aryl-nucleosides exhibit interesting photophysical properties,
underling their potential use for further nucleic acids labelling.

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Synthetic nucleosides are extensively used in medicinal chemistry and drug discovery programs due to their ability to mimic their natural
counterparts. However, C-nucleosides may be considered as better pharmacophores than N-nucleosides, since their carbon-carbon glycosidic bond
confers to these molecules greater stability and resistance towards chemical and enzymatic hydrolysis.1 Thereby, in the last decades, several C-
nucleosides have emerged as therapeutic agents, including antiviral (e.g. BCX-4430),2 antibiotic (e.g. pyrazomicin, showdomycin),3 anti-protozoan
(e.g. formycin)4 and anticancer drugs (e.g. tiazofurin).5 In addition, their use as building blocks for the synthesis of DNA- and RNA-containing
artificial nucleobases allowed the emergence of new therapeutic solutions through the regulation of genes expression.6
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Moreover, artificial C-nucleosides have also been used in the design of biochemical and biophysical probes for RNA and DNA labelling.7,8 Such
tools have recently been used as nucleases chemosensors,9 as well as probes for monitoring DNA repair10 and DNA/RNA-Protein interactions.11
Among them, one can discriminate between the fluorescent expanded natural base analogs, whose scaffolds include one or more (hetero)aromatic
ring fused to the natural base, and the non-polar analogs, whose scaffold does not retain part of the natural base scaffold.7b
Therefore, several synthetic routes to C-aryl-nucleosides have been disclosed in the literature. Among these different approaches, which have been
recently reviewed by Yang and Yu,12 Bokor and coll.,13 Hocek,14 Adamo and Pergoli,15 the following may be highlighted due to their versatility:
(i) the addition of nucleophilic aryl groups (usually a lithiated derivative) to an electrophilic/carbocationic carbohydrate, but this strategy leads
only to a decreased stereocontrol; (ii) the intramolecular rearrangements (e.g. Claisen or Wittig reactions), which requires the prior synthesis of
elaborated intermediates; (iii) the coupling of halobenzene derivatives mediated by palladium catalysts is also a convenient strategy, but its use is
restricted to the 2’-deoxy series only; and (iv) the stereoselective Heck reaction for the syntheses of 2’-deoxy-C-nucleosides and 2’,3’-dideoxy-C-
View Article Online
DOI: 10.1039/C8NJ06300A
nucleosides (Scheme 1).
Scheme 1. Examples of strategies to access C-nucleosides.12-15
In summary, despite the numerous synthetic option towards C-nucleosides, there is only limited examples using a direct strategy, i.e., a
stereoselective one-step preparation of C-aryl--D-ribosides. In this context, we formerly reported a pioneer work using a Friedel-Crafts
ribosylation reaction, mediated by a stoichiometric amount of SnCl4 as Lewis acid (1.1 eq., Table 1, Line 1).16 This process paved the way to short
syntheses of C-nucleosides, bearing a (hetero)aryl aglycone, selectively functionalized on their -face. This methodology was subsequently
extended to the preparation bioactive O- and N-nucleosides, that are structurally related to the anti-cancer agent AICAR (acadesine).17 However,
despite its advantages, this ribosylation process requires the use of a very toxic Lewis acid (SnCl4), and thereby is not compatible with the
development of modern eco-compatible organic reactions. Therefore, in continuation of our efforts in the development of greener processes,18 we
report herein an optimization of this Friedel-Crafts reaction, and its use for the synthesis of non-polar fluorescent probes.
Table 1. Optimization of the ribosylation catalyzed by metal salts.

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MeO
O
O
AcO
AcO
AcO
AcO
Lewis acid (cat.)
MeO
OAc
+
R
R
OAc
R = I,
OAc
3a
R = I,
R = OMe, 2b
2a
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R = OMe, 3b
Entry
1
R
Catalyst, (mol %) Solvent
Conditions (T°, Time)
0°C, 16h.
Yield a
72%b
55%
I
SnCl4, (110)
SnCl4, (50)
SnBr4, (50)
FeCl3, (50)
CuCl2, (50)
AlCl3, (50)
ZnCl2, (50)
InCl3, (50)
FeCl3, (20)
FeCl3, (10)
FeCl3, (10)
FeCl3, (5)
CH2Cl2
CH2Cl2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3NO2
CH3NO2
Xylene
2
OMe
r.t., 30 min.
3
I
Reflux, 12h.
50%
4
I
Reflux, 10 min.
Reflux, 12h.
68%
c
5
I
-
c
6
I
Reflux, 12h.
-
7
I
Reflux, 12h.
45%
40%
73%
65%
8
I
Reflux, 12h.
9
I
Reflux, 10 min.
Reflux, 10 min.
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DOI: 10.1039/C8NJ06300A
Reflux, 10 min.
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19
I
OMe
62%
27%
26%
OMe
Reflux, 10 min.
r.t., 24 h.
OMe
FeCl3, (10)
Fe2O3, (50)
FeSO4, (50)
FeCl3, (20)
FeCl3, (20)
FeCl3, (20)
FeCl3, (20)
c
I
I
I
I
I
I
Reflux, 12h.
Reflux, 12h.
Reflux, 12h.
Reflux, 12h.
Reflux, 12h.
Reflux, 12h.
-
c
-
c
-
CH3C6H5
ClC6H5
DMF
20%
c
-
c
-
a Yield of isolated product; b See reference 16; c no reaction observed via TLC monitoring.
In line with our previous work, we selected as the benchmark reactions the Friedel-Crafts condensation between 1’--ribofuranose-1’,2’,3’,5’-
tetraacetate (1, 1.0 eq.) and 1-iodo-4-methoxybenzene or 1,4-dimethoxybenzene (2a-b, 2.0 eq.), a better nucleophile due to the presence of the
second methoxy group. In both cases, we observed conversion rates to the corresponding products (3a-b) in the 50% range, when reduced amounts
of SnCl4 and SnBr4 were employed (0.5 eq., Table 1, entries 2 & 3). Based on these initial results, we next evaluated a series of metal salts as Lewis
acids for comparison studies. We selected CuCl2,19 AlCl3,20 InCl321 and ZnCl2,22 which all are known to efficiently promote Friedel-Crafts reactions
(Table 1, entries 4-8). However, in our hands, the ribosylation preformed in presence of CuCl2 and AlCl3 completely failed, and when performed
under InCl3 and ZnCl2 catalysis, it only led to moderate conversion rates (40-45%).
Then, we focused our attention on iron salts, since we already reported the use of a catalytic amounts of FeCl3 to efficiently promote the anomeric
azidation of 1 (78% yield).17a,c Moreover, it is noteworthy that FeCl3 is a costless, poorly toxic and easy to handle Lewis acid; hence it is perfectly
relevant in the context of the development of eco-compatible chemistry processes. Interestingly, using FeCl3, at 20 mol% loading, 1 and 2a could
be efficiently coupled in good yields (Table 1, entry 9, 73%). Lowering the catalyst charge to 10 mol% still promoted the Friedel-Crafts
ribosylations of both 2a and 2b in good yields (65% and 62% respectively, Table 1, entries 10 & 11) and short reaction times (10 min.). Importantly,
these reactions occurred at moderate temperature. We next assayed other Fe(II) and Fe(III) iron salts (Fe2O3 and FeSO4), known to catalyze Friedel-
Crafts reactions.23 However, even when using larger catalytic charges (50 mol%), increased reaction times (up to 12 h.) and higher temperature
(refluxing nitromethane), we did not observe any conversion (Table 1, entries 14-15). Finally, we tried to perform the ribosylation catalyzed by
FeCl3 in other solvents than dichloromethane (Table 1, entries 16-19). However, even in refluxing xylene or DMF, no reaction occurred. These
latter results may be due to solvation problems.
From the mechanistic point of view, it is to note that the ribosylation occurs with a marked stereoselectivity. Indeed, the / molar ratio of purified
product have been estimated as 2/8 for 3a and 4/6 for 3b by 1H NMR spectroscopy. This interesting result may be related to the mechanism of this

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reaction. It likely proceeds through the formation of an oxonium intermediate, that may be partially stabilized by anchimeric assistance (neighboring
group effect), before its trapping by the nucleophile (aryl).17a,c
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Table 2. Scope of the C-Glycosylation: a survey of nucleophiles.a
9
X
X
10
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12
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O
AcO
AcO
O
FeCl3, 10 mol%
CH2Cl2, reflux
AcO
AcO
R
R
OAc
+
OAc
4a-k; 5a-e
OAc
(hetero)(poly)aromatic
nucleophile
1
Ratio
Reaction
time (min)
Entry
Nucleophile
Isolated C-Glycoside
Yield
/
MeO
O
AcO
AcO
MeO
1
10
62%
6/4
OMe
OAc
OMe
4a
MeO
O
MeO
AcO
AcO
2
3
10
10
65%
45%
8/2
View Article Online
DOI: 10.1039/C8NJ06300A
I
OAc
4b
I
MeO
AcO
O
MeO
6/4
9/1
7/3
AcO
OAc
4c
MeO
AcO
O
MeO
4
5
30
10
40%
49%
Br
Br
AcO
OAc
Br
4d
AcO
O
Br
S
AcO
S
OAc
4e
6
7
10
10
30%
47%
8/2
9/1
Br
S
4f
AcO
O
Br
S
AcO
Br
S
OAc
4g
8
9
10
10
33%
48%
9/1
7/3
I
S
4h
S
O
CO2Et
AcO
S
CO2Et
AcO
OAc
4i

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AcO
O
5
6
7
8
O
10
11
10
10
32%
61%
9/1
AcO
O
OAc
4j
9
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CO2Et
AcO
CO2Et
O
10/0
O
AcO
O
OAc
4k
AcO
O
12
10
35%
10/0
AcO
OMe
OAc
OMe
5a
AcO
O
13
20
45%
95/5
View Article Online
DOI: 10.1039/C8NJ06300A
AcO
OAc
5b
AcO
O
AcO
14
30
58%
9/1
OAc
5c
AcO
O
15
30
53%
10/0
AcO
HN
O
OAc
HN
5d
AcO
AcO
O
O
16
25
72%
10/0
OAc
5e
a Reaction conditions: -D-ribose tetraacetate 1 (1 mmol), nucleophile (2 mmol), FeCl3 (10 mol%), CH2Cl2 (8 mL), 40°C.
Next, we explored the scope of this ribosylation process on a set of six-membered and five-membered (hetero)aromatic compounds (Table 2,
compounds 4a-k). In all cases, the expected products were obtained, in moderate-to-good yields (30-60%), after 10 – 30 min. reaction in refluxing
CH2Cl2. These compounds were isolated as a mixture of anomers, in / ratio ranging from 4/6 to 0/10. The scope of the (hetero)arene glycosyl
acceptor encompasses activated (electron-rich) and non-activated benzene derivatives (Table 2, entries 1-4). These may feature bromo- and iodo-
moieties that are suited for further transformations (e.g. [Pd] catalyzed cross-couplings). In addition, 5-membered heteroaryl ribosyl acceptor were
successfully employed. Indeed, these 5-membered heteroaryl rings include a variety of thiophene and furane moieties bearing methyl, halide or
ester functions (Table 2, entries 5-11).24 Of note, compounds 4i and 4k can be converted, in one step, into thiophenfurine and furanfurine which
are known anticancer analogues of tiazofurin.25
Interestingly, Yokoyama and coll. have previously reported a multi-step synthesis of 4j.26 Their synthetic path to 4j was based on the addition of
the 2-lithiated furan to the 2,3,5-tri-O-benzyl--D-ribose, leading to an open ribitol chain, whose subsequent treatment with p-toluenesulfonic acid
affords the 2-ribofuranosylfurane. Lastly, the interconversion of the protecting groups (benzyl to acetyl) gives compound 4j. However, by
comparison with our Friedel-Crafts single step synthesis, this methodology appears time-consuming, and suffers from low yields (7-30%) and poor
stereoselectivity (/ ratio of 1/3).27

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We next tested our conditions on the ribosylation of bulky polyaromatic molecules such as 2-methoxynaphthalene, benzofuran, anthracene and
pyrene (Table 2, compounds 5a-e). Satisfactorily, compounds 5a-5e could be prepared in moderate to good yields (35-72%) and short reaction
times (10-30 min.). It is worth noting that 5a-5e were obtained with a high stereoselectivity; the anomeric / ratio ranged from 1/9 to 0/10.
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These results are well complementing the glycosylation reaction arsenal as it was already reported, that using a highly reactive 1-chlorosugar, the
glycosylation of anthracene (and fluorene) proved difficult.28 In fact, the use of mildly Lewis acid conditions could not promote the reaction,
whereas stronger Lewis acid, i.e. SnCl4, induces the decomposition of the glycosyl donor. In sharp contrast, under our specific conditions, i.e. 10
mol% of FeCl3 in refluxing dichloromethane, the glycosylation of anthracene provides the desired anthracenyl-C-nuleoside 5b in 45% yield, as a
95/5 mixture of / anomers.
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Importantly, anthracene29 and pyrene30 have been extensively used as non-polar nucleobase analogues for DNA-labelling. Indeed, even if the pyrene
has a larger size than the natural nucleobases, recent structural analyses revealed that, in DNA duplexes, this polyaromatic scaffold can be used as
a Watson-Crick base pair surrogate when facing an abasic site on the complementary strand.31 In addition, pyrene exhibits very strong chemical
stability and its fluorescence parameters are highly related to the chemical properties of its local environment. Thereby, tetra-pyrene
deoxynucleotide sensors, also called oligodeoxyfluoroside, have been synthesized by Kool and co-workers, and used to monitor catalytic activity
of polymerases, deoxynucleotidyl transferases and esterases.31 However, to the best of our knowledge, we report herein the first single-step, eco-
friendly and stereoselective synthesis of 2,3,5-tri-O-acetyl--D-riboses functionalized on their anomeric position, and on the -face, by these two
motifs (anthracene and pyrene). Moreover, to date such tools have been used as RNA fluorescent probes.
View Article Online
DOI: 10.1039/C8NJ06300A
In this context, to get insights about the photophysical properties of the compounds 5b and 5c, UV-vis absorption and steady state fluorescence
emission spectra in solution were acquired in solvents with distinct polarity (Figure 1). The main spectroscopic data are given in Table 3. The
UV−vis spectra of the pyrene and anthracene derivatives present similar spectral shape compared with the parent unsubstituted molecules.32 As
already reported in the literature,33 it seems that the inductive effect along the glycosidic bond controls the red shift absorption band. Apart from
that, emission spectra revealing the characteristics mirror image of the parent absorption spectra were observed for both fluorophores. Additionally,
concerning the pyrene glycoside, no strong evidence indicating a putative excimer emission in solution was observed regardless of the broad range
of concentrations evaluated in extremely non-polar environment (ca. cyclohexane, Figure S1). Nevertheless, these observations do not rule out the
possibilities of a fluorescent ratiometric monomer-excimer emitting probe that could be obtained using 5c under different conditions. As reported
by Chiba and co-workers,28d even without evidences of the excited state dimer emission in a pure monomer-containing solution, the excimer and
heteroexcimer emissions could be observed when alkynyl pyrene, anthracene and perylene nucleosides were incorporated in oligonucleotide
sequences. Finally, any noticeable solvent dependency was observed on the main photophysical parameters (λabs, λem and ϕf) and both probes were
less emissive when compared with their non-substituted analogues.
In conclusion, we report herein a straightforward and eco-compatible route to C-(poly)aromaic nucleosides. This single-step synthetic pathway
proceeding through a Friedel-Crafts reaction, occurs stereoselectively on the -face of the carbohydrate, and the expected products have been
isolated in good yields. Interestingly, this versatile methodology allows the unprecedented introduction on the ribose scaffold of bulky poly-
aromatic derivatives, such as the anthracene and pyrene ones. Such highly functionalized C-nuleosides present interesting photophysical properties,
including fluorescence. Their use for RNA labeling to afford new biological probes and sensors, is currently investigated by our team, and will be
reported in due course.
Figure 1. Normalized UV-vis absorption (dashed line) and fluorescence emission spectra (full line) for compounds 5c (a) and 5b (b) in organic
solvents.
Table 3. Spectroscopic properties of compounds 5b and 5c in solution.

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Compound
Solvent
λabs (nm)
λem (nm)
ε (x 103)a ϕfb
5
6
7
8
Anthracene Cyclohexane
275, 329, 345, 367, 386
6.1
5.8
0.25
0.39
0.30
0.28
0.05
0.14
0.05
0.05
5b
1,4-Dioxane
MeCN
275, 330, 347, 368, 388
274, 329, 347, 367, 387
274, 330, 347, 366, 386
392, 414, 438, 466
390, 413, 437, 463
392, 411, 435, 465
9
5.5
10
11
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13
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MeOH
5.6
Pyrene
5c
Cyclohexane 242, 264, 275, 312, 326, 342 375, 286, 393, 415
1,4-Dioxane 242, 265, 276, 313, 327, 343 373, 385, 395, 416
47.0
45.0
44.0
47.0
MeCN
MeOH
240, 263, 274, 311, 325, 341 373, 385, 395, 415
239, 262, 273, 310, 324, 340 373, 385, 393, 415
Molar extinction coefficients (L.mol-1.cm-1) are related to the highlighted absorption maxima; fluorescence quantum yield values were
a
b
determined by using quinine sulfate in 0.1 M H2SO4 solution (ϕf = 0.54)34 as standard; The highlighted absorption maxima were used as the
excitation wavelengths.
AKNOWLEDGEMENTS
View Article Online
This work is supported by CNRS and UCA, Canceropôle PACA, PHC Toubkal, CAPES (fellowship to MSF, process number 00000.001495/2015-
DOI: 10.1039/C8NJ06300A
01), CNRST, Institut National du Cancer. This article is based upon work form COST Action CA15135, supported by COST.
# Equal contribution of the authors
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DOI: 10.1039/C8NJ06300A
Rapid and straightforward access to C-nucleosides using the inexpensive FeCl3 catalyst.
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