Stereoselective synthesis of selenium-containing glycoconjugates via the mitsunobu reaction

Article abstract of DOI:10.3390/molecules26092541

A simple and efficient route for the synthesis of new glycoconjugates has been developed. The approach acts as a model for a mini-library of compounds with a deoxy-selenosugar core joined to a polyphenolic moiety with well-known antioxidant properties. An unexpected stereocontrol detected in the Mitsunobu key reaction led to the most attractive product showing a natural Dconfiguration. Thus, we were able to obtain the target molecules from the commercially available D-ribose via a shorter and convenient sequence of reactions.

Full text of DOI:10.3390/molecules26092541

molecules
Communication
Stereoselective Synthesis of Selenium-Containing
Glycoconjugates via the Mitsunobu Reaction
Luigia Serpico 1, Mauro De Nisco 2,*, Flavio Cermola 1 , Michele Manfra 2 and Silvana Pedatella 1
1
Department of Chemical Sciences, University of Napoli Federico II, Via Cintia 4, I-80126 Napoli, Italy;
luigia.serpico@unina.it (L.S.); cermola@unina.it (F.C.); pedatell@unina.it (S.P.)
Department of Sciences, University of Basilicata, Via dell’Ateneo Lucano 10, I-85100 Potenza, Italy;
2
michele.manfra@unibas.it
*
Correspondence: mauro.denisco@unibas.it
Abstract: A simple and efficient route for the synthesis of new glycoconjugates has been developed.
The approach acts as a model for a mini-library of compounds with a deoxy-selenosugar core joined
to a polyphenolic moiety with well-known antioxidant properties. An unexpected stereocontrol
detected in the Mitsunobu key reaction led to the most attractive product showing a natural D-
configuration. Thus, we were able to obtain the target molecules from the commercially available
D-ribose via a shorter and convenient sequence of reactions.
Keywords: organoselenium compounds; selenosugar; mitsunobu reaction; antioxidants
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ꢀꢁꢂꢃꢄꢅꢆ
1. Introduction
Citation: Serpico, L.; De Nisco, M.;
Cermola, F.; Manfra, M.; Pedatella, S.
Stereoselective Synthesis of Selenium-
Containing Glycoconjugates via the
Mitsunobu Reaction. Molecules 2021,
26, 2541. https://doi.org/10.3390/
molecules26092541
In the last decade, a large amount of evidence has suggested a link to oxidative stress
(OS) and ageing-related neurodegenerative diseases (NDs) [1,2], which are characterized
by progressive damage in neural cells as well as by a selective loss of neuronal populations.
Since OS refers to an imbalance between the production and removal of reactive oxygen
species (ROS), antioxidant therapies have been proposed to prevent or attenuate their
induced damage [3,4].
Recently, the therapeutic effects of several small molecules, normally taken with the
diet, have been studied and their potential applications proposed. In more detail, several
selenium-containing compounds have been synthesized, and they turned out to be po-
tent neuroprotective agents with a modest effect on normal tissues and are clinically well
Academic Editors: Irina A. Balova
and Alexander S. Antonov
Received: 20 March 2021
Accepted: 23 April 2021
Published: 27 April 2021
tolerated [
lenium compound that acts as a glutathione peroxidase (GPx) mimetic. Likewise, several
polyphenolic molecules have shown a strong antioxidant activity [ ], including caffeic
5,6]. Among them, the best known is the Ebselen [7] (Figure 1), a small organose-
8,9
acid, which has the potential to modulate oxidation and inflammation, as demonstrated
in several studies [10]; curcumin, with proven anticancer and anti-inflammatory charac-
teristics [11,12]; and dopamine, whose loss is involved in the early phase of Alzheimer’s
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
Disease (AD) development [13].
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Figure 1. Ebselen.
Faced with setting up a library of new antioxidant glycoconjugates to address the
formulation of supplements focused on neurodegenerative disorders such as AD, we inves-
tigated the design and synthesis of new molecules combining the antioxidant properties of
Molecules 2021, 26, 2541. https://doi.org/10.3390/molecules26092541
https://www.mdpi.com/journal/molecules

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selenium with the chelating and antioxidant properties of a phenolic structure moiety, as
displayed in the Scheme 1.
Scheme 1. Retrosynthesis of target.
The introduction of selenium into organic structures has been performed via chemo-,
regio-, and stereoselective methods, such as nucleophile, electrophile, and radical tech-
niques only during the past three decades, challenging the well-known instability and
unusual behavior of early derivatives [14]. The results of Matsuda [15], Pinto [16], and
Jeong [17] represent the starting approach towards the chemistry of selenium-ribose com-
pounds.
Inspired by these studies and taking into account that, to the best of our knowledge,
no examples of 4-selenosugar-5-conjugates have been described in the literature to date;
we wish to report their first synthesis here.
2. Results and Discussion
As outlined in the retrosynthetic path (Scheme 1), we started from the commer-
cially available D-ribose. In fact, the latter was converted into the corresponding deoxy-
selenosugar derivative 1, modifying a procedure reported by Jeong et al. [18].
Firstly, we protected D-ribose with orthogonal groups, with a view of selectively
removing them during the synthetic strategy. In detail, isopropylidene was used to protect
hydroxyl groups in C-2 and C-3 through a protocol [19] already described, characterized by
smooth reaction conditions with a low environmental impact leading to compound
2 with
a 95% yield. The O-isopropilydene derivative, without any further time consuming work
up or purification procedures and after treatment with tert-butyl(chloro)diphenylsilane (TB-
DPSCl), triethylamine (TEA), and dimethylaminopyridine (DMAP) in anhydrous CH2Cl2,
afforded the silyl ether
under reductive conditions (sodium borohydride). The next step where the diol 4 was
converted to the corresponding dimesylate allowed us to enter good leaving groups on
with selenium in the presence of sodium
at a 95% yield.
18],
thus leading to the corresponding L-deoxy-selenosugar. Using dry conditions allowed the
optimization of the procedure [18], providing with a 99% yield (Scheme 2). Finally, the
3, which in turn provided the diol 4 with an excellent yield (>99%)
5
C-1 and C-4 so that the subsequent treatment of
borohydride in EtOH-THF at 60 C gave the deoxy-selenosugar derivative
5
◦
6
It is noteworthy that the reaction takes place with inversion of the configuration [16
–
6
removal of the TBDPS protecting group on C-5 exploiting the great affinity of fluoride to
silicon afforded the seleno building block 7 with a high yield (75% overall yield).
To perform the reaction giving the glycoconjugate, we attempted to convert
7 to
an iododerivative using a triphenylphosphine polymer-bound/iodine complex already
reported on different substrates [20], but the only product found was the dimer, probably
resulting from the quick formation of the corresponding iodide that was attacked by the
OH group of the remaining 7. It was not possible to evaluate the efficiency of mesyl or
tosyl derivatives, since both were prepared in very low yields. The failed results prompted
us to take a different approach based on the Mitsunobu reaction, which is well-known and

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carried out with an activated alcohol prepared in situ using triphenylphosphine (TPP) and
an azodicarboxylate as promoter.
Scheme 2. Synthesis of building block 7.
Therefore, our investigation began with the coupling of the seleno derivative
7 TPP-
complex with monoacetylated hydroquinone [21] chosen as a model compound. The
reaction in dry THF after three days gave a 43%-yield compound
pected product (Scheme 3).
8 as a major and unex-
Scheme 3. Mitsunobu reaction.
NMR was used to assign the configuration at C4 in the latter. It is well-known that
the stereostructure of the furanose moiety is often difficult to analyze due to the low
energy barriers between various puckering states [22]. It has already been reported in
the literature that the bulky selenium atom in the 40-selenoribonuclesosides led to a south
(C20-endo) pucker state [17]. However, since significant NOE effects were not detected for
the hydrogens at C2 and C4 and the coupling constants of 8 were not supportive for the

Molecules 2021, 26, 2541
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stereochemistry assignment with certainty, we decided to evaluate the outcome of the D-
deoxy-selenosugar derivative 11 coming from the commercially available D-ribonolactone
(Scheme 4). Thus, we employed the procedure reported by Batra et al. [23] to accomplish
a first inversion of the configuration leading to the intermediate 9, which, in turn, was
converted with a high yield into the corresponding D-target 11, using the same route
previously described for his isomer 7.
Scheme 4. Synthesis of the isomer of 7.
A comparative analysis of 1H NMR coupling constants in compounds
well as and 11 (Table 1) was therefore carried out to investigate the range of the vicinal
6 and 10 as
7
3
3
coupling constants. The J3,2 medium value was 5.6 Hz, the J2,1b was 4.8 Hz, and the
3J2,1a was 2.0 Hz. More interestingly, however, was that for
6
and
7
, the J3,4 medium
3
value was 4.3 Hz, while for 10 and 11, the same coupling value was 1.6 Hz. Taking this
into account, in glycoconjugates, the 3J3,4 medium value of 1.6 Hz is consistent with the
3,4-anti-configuration [15].
Table 1. Vicinal coupling constants. Comparative analysis.
Compound
3J2,1a
3J2,1b
3J3,2
3J3,4
6
7
10
11
1.5
2.0
2.3
2.1
4.7
4.1
5.1
5.2
5.3
6.1
5.3
5.5
4.5
4.2
1.8
1.4
The selectivity seen in the model reaction, whose mechanism is under investigation,
was also detected when the scope of our approach was explored. Indeed, all polyphenolic
substrates used gave the sole corresponding D-deoxy-seleno glycoconjugate (8, and 12–15,
Table 2). Moreover, when we performed the Mitsunobu reaction on the same polyphenols
using the isomer 11 as the starting seleno substrate, the spectral and analytical data clearly
indicated we had obtained the same product
8 and 12–15 with corresponding comparable
yields (Table 2). These results, presumably resulting from the already reported unusual
behavior of selenium [24], support the use in future of the “L-route” (seven steps up to
isomer
7, overall yield 75%) to obtain further products, thereby avoiding the alternative
time and products consuming “D-route” (eight steps up to isomer 11, overall yield 47%).

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Table 2. Scope with respect to polyphenolic substrates 1.
Polyphenol
Glycoconjugate
Yield 2
13 (14) 3
43 (44) 3
70 (72) 3
68 (67) 3
30 (28) 3
1
Reaction carried out on derivative
7 (1 eq), TPP (1.5 eq), diisopropyl azodicarboxyate (DIAD, 1.5 eq), and polyphenol (1.5 eq) in dry
2
THF under N2 atmosphere for three days. Percentage yield; isolated yield by column chromatography; double reaction products of the
polyphenol were never detected. Percentage yield; reaction starting from derivative 11 under same condition.
3
In the preliminary attempts performed on hydroquinone used as a model compound,
the presence of a hydroxyl group different from the one involved in the reaction appeared
to be a limit of reactivity for the methodology, thus affording a very low yield of the
desired conjugated. On the other hand, the reaction on the monoacetylated hydroquinone
proceeded with fair yields.
A different approach was reserved for curcumin, whose hydroxyl groups in C-4 have
not been intentionally protected due to known handling problems of the molecule. Nev-
ertheless, the yield was reasonable with the challenging purification procedure currently
under improvement.
Concerning the polyphenols having the COOH group in addition to the phenolic one
(caffeic and ferulic acids), as expected, due to the lower pka of the carboxyl group, they

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proved to be excellent substrates for the reaction (yields 67–72%), taking into account that
we used a protecting-free approach, which is very useful in multistep programs.
The removal of the isopropylidene group on C-2 and C-3 (Scheme 5) under acid
conditions provided, except for the curcumin, the corresponding derivatives 12a–14a (yield
68–80%) that will be investigated for their reducing and scavenging abilities consistent
with the mechanism generally accepted for antioxidant compounds.
Scheme 5. Removal of protecting group.
3. Materials and Methods
All the reagents were acquired (Aldrich, Fluka, Sigma) at the highest purity available
and used without further purification. Thin-layer chromatography was performed with
silicagel plates Merck 60 F254, and the display of the products on TLC was accomplished
with UV lamp lighting, molecular iodine, and in H2SO4–EtOH (95:5) with further heating
until the development of color. The column chromatographies were carried out using
70–230 mesh silica gel (Merck). The NMR spectra (Supplementary Materials) were recorded
on Bruker DRX (400MHz) and Varian Inova Marker (500MHz) spectrometers in CDCl3
solution unless otherwise specified. The chemical shifts are reported in ppm (δ
). The 1H
and 13C NMR full characterization of the products was obtained based on 2D NMR and
1D selective NOESY. The TopSpin 4.0.6 software package was used for the analysis.
Preparation of 2,3-O-isopropylidene-b-D-ribofuranose (2): To a magnetically stirred suspension
of anhydrous triphenylphosphine (0.525 g, ca. 2.0 mmol) in anhydrous acetone (6.0 mL) at
r.t., a solution of I2 (0.508 g, 2.0 mmol) in the same solvent (18.0 mL) was added dropwise
in the dark and under dry N2 atmosphere. After 15 min, solid D-ribose (0.150 g, 1.0 mmol)
was added in one portion to the suspension. TLC monitoring (CHCl3–MeOH, 9:1) showed
that the starting sugar was completely consumed within 30 min. The reaction mixture was
then filtered, washed with acetone, and dried (Na2SO4). The evaporation of the solvent
under reduced pressure gave a crude residue that was used directly in the next step without
1
further purification (0.181 g, 0.95 mmol, 95%). H NMR (500 MHz):
δ 1.33 (s, 3 H, CH3),
1.48 (s, 3 H, CH3), 3.70 (dd, J5a,5b = 11.6, J5a,4 = 1.5, 1H, H5a), 3.79 (dd, J5b,5a = 11.6, J5b,4 = 1.8,
1 H, H5b), 4.30 (m, 1 H, H4), 4.51 (d, J2,3 = 6.1 Hz, 1 H, H2), 4.84 (dd, J3,2 = 6.1, J3,4 = 1.0 Hz,
1 H, H3), 5.06 (bs, 1 H, H1β). 13C NMR (125 MHz):
δ 24.8, 26.4, 65.2, 81.9, 86.5, 87.7, 106.7,
111.9. Anal. Calcd for C8H14O5: C, 50.52; H, 7.42. Found: C, 50.60; H, 7.40. The NMR
spectral data were identical to values in the literature [19].
Preparation of 5-O-tert-butyldiphenylsilyl-2,3-O-isopropylidene-D-ribofuranose (
2.0 mmol), DMAP (0.024 g, 0.2 mmol), and TBDPSCl (0.26 mL, 1.5 mmol) at 0 C were
3
): TEA (0.28 mL,
◦
added to a magnetically stirred solution of
(5.0 mL). The mixture was stirred at room temperature for 4 h. As soon as the starting
compound was completely consumed (TLC monitoring), the organic layer was washed
2 (0.190 g, 1.0 mmol) in anhydrous CH2Cl2
2
with brine and dried (Na2SO4). The evaporation of the solvent under reduced pressure
gave a crude residue that was purified by silica gel column chromatography (hexane-ethyl
acetate 97:3 (v/v)) to give the oily product
3 as a yellowish syrup (0.386 g, 0.90 mmol, 90%).
The product was obtained as a mixture of both anomers, but the
β
anomer was the main
1
product (
α
:β, 1:1.9). H NMR (500 MHz):
δ
1.08 (s, 9Hα, CH3), 1.12 (s, 9Hβ,CH3), 1.34 (s,
3Hβ,CH3), 1.42 (s, 3Hα CH3), 1.50 (s, 3H, 3Hβ,CH3), 1.58 (s, 3Hα, CH3), 3.71–3.63 (m, 2H,
H5aα+β), 3.87–3.81 (m, 2H, H5bα+β), 3.96 (d, JOH,1α = 11.4 Hz, 1H, OHα), 4.18 (m, 1H,

Molecules 2021, 26, 2541
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H4α), 4.31 (m, 1H, H4 β),4.51 (d, JOH,1β = 10.6 Hz, 1H, OHβ), 4.63 (d, J2,3 = 5.9 Hz, 1H,
H2β), 4.68 (dd, J2,3 = 6.2 Hz, J2,1 = 4.0 Hz, 1H, H2α), 4.74 (d, J3,2 = 5.9 Hz, 1H, H3β), 4.80
(d, J3,2 = 6.2 Hz, 1H, H3α), 5.37 (d, J1,OH = 10.6 Hz, 1H, H1β), 5.64 (dd, J1,OH = 11.4 Hz,
J1,2 = 4.0 Hz, 1H, H1α), 7.53–7.64 (m, 20H, Arα+β); 13C NMR (125 MHz):
δ 19.1, 22.6, 25.0,
26.5, 27.0, 65.5, 66.1, 81.6, 87.1, 87.4, 98.0, 103.4, 127.7, 127.9, 128.0, 129.7, 130.2, 130.4, 134.8,
135.6, 135.7. Anal. Calcd for C24H32O5Si: C, 67.26; H, 5.53. Found: C, 67.31; H, 5.63.
Preparation of 5-O-tert-butyldiphenylsilyl-2,3-O-isopropylidene-D-ribitol (
4): To a magnetically
stirred solution of
3 (0.429 g, 1.0 mmol) in MeOH (10.0 mL), NaBH4 (0.113 g, 4.0 mmol)
◦
at 0 C was added. The mixture was stirred at room temperature for 2.5 h. As soon as
the starting compound
3 was completely consumed (TLC monitoring), the solvent was
evaporated under reduced pressure and replaced with AcOEt. The organic layer was
washed with brine and dried (Na2SO4). The evaporation of the solvent under reduced
1
pressure gave the pure product
(400 MHz):
OH), 3.77–3.93 (m, 4H, H1 and H5), 4.14 (m, 1H, H2), 4.38 (m, 1H, H3), 7.40–7.46 (m, 6H,
Ar), 7.67–7.70 (m, 4H, Ar); 13C NMR (125 MHz):
19.3, 25.2, 26.9, 27.7, 60.9, 65.3, 69.7, 76.5,
4
as a colorless syrup (0.430 g, 1.0 mmol, >99%). H NMR
δ
1.10 (s, 9H, CH3), 1.31 (s, 3H, CH3), 1.33 (s, 3H, CH3), 3.10 (m, 2H, H4 and
δ
77.6, 108.5, 127.8, 130.0, 132.8, 132.9, 135.6. Anal. Calcd for C24H34O5Si: C, 66.94; H, 7.96.
Found: C, 66.91; H, 7.93.
Preparation of 5-O-tert-butyldiphenylsilyl-2,3-O-isopropylidene-1,4-di-O-methanesulfonyl-D-ribitol
(
5
): DMAP (0.002 g, 0.02 mmol), TEA (1.1 mL, 8.0 mmol), and mesylchloride (0.309 mL,
4.0 mmol) at 0 ◦C were added to a magnetically stirred solution of
4
(0.430 g, 1.0 mmol)
in CH2Cl2 (14.0 mL), and the mixture was stirred at room temperature overnight. The
organic layer was washed with brine and dried (Na2SO4). The evaporation of the solvent
under reduced pressure gave a crude residue that was purified by silica gel column chro-
matography (hexane-ethyl acetate 6:4 (v/v)) to give the oily product
5 as a yellowish syrup
(0.575 g, 0.98 mmol, 98%). 1H NMR (500 MHz):
δ
1.11 (s, 9H, CH3), 1.38 (s, 3H, CH3),
1.43 (s, 3H, CH3), 3.06 (s, 6H, CH3), 4.00 (dd, J5a,5b = 12.2 Hz, J5a,4 = 3.8 Hz, 1H, H5a), 4.07
(dd, J5b,5a = 12.2 Hz, J5b,4 = 2.7 Hz, 1H, H5b), 4.34 (dd, J1a,1b = 10.4 Hz, J1a,2 = 6.4 Hz, 1H,
H1a), 4.46–4.54 (m, 3H, H1b, H2 and H3), 4.85 (m, 1H, H4), 7.40–7.49 (m, 6H, Ar), 7.73–7.67
(m, 4H, Ar); 13C NMR (125 MHz):
δ 19.3, 25.4, 26.8, 27.4, 37.5, 39.3, 63.1, 68.3, 73.8, 74.9,
79.2, 109.5, 127.9, 130.1, 132.4, 132.5, 135.6. Anal. Calcd for C26H38O9S2Si: C, 53.22; H, 6.53.
Found: C, 53.23; H, 6.43.
Preparation of 5-O-tert-butyldiphenylsilyl-1,4-deoxy-2,3-O-isopropylidene-4-seleno-L-lyxose (6):
NaBH4 was added to a magnetically stirred suspension of selenium powder (0.166 g,
2.1 mmol) in dry ethanol (13 mL) under N2 atmosphere, and the mixture was stirred at
room temperature until the color of the mixture changed from black to colorless. Then,
compound
5
◦(0.586 g, 1 mmol) in dry THF (8 mL) was added to the mixture, which was
heated at 60 C overnight. Then, the solvent was removed and replaced with AcOEt. Next,
the organic layer was washed with brine and dried (Na2SO4). The evaporation of the
solvent under reduced pressure gave the pure seleno derivative
6 as a pale-yellow oil
1
(0.470 g, 0.99 mmol, 99%). H NMR (500 MHz):
δ 1.08 (s, 9H, CH3), 1.30 (s, 3H, CH3), 1.48
(s, 3H, CH3), 2.97 (dd, J1a,1b = 12.2 Hz, J1a,2 = 1.5 Hz, 1H, H1a), 3.03 (dd, J1b,1a = 12.2 Hz,
J1b,2 = 4.7 Hz, 1H, H1b), 3.77 (m, 1H, H4), 3.93 (dd, J5a,5b = 10.2 Hz, J5a,4 = 7.9 Hz, 1H, H5a),
4.15 (dd, J5b,5a = 10.2 Hz, J5b,4 = 7.1 Hz, 1H, H5b), 4.77 (m, 1H, H2), 4.94 (dd, J3,2 = 5.3 Hz,
J3,4 = 4.5 Hz, 1H, H3), 7.37–7.47 (m, 6H, Ar), 7.72 (ddd, J = 11.0, 7.9, 1.4 Hz, 4H, Ar); 13
C
NMR (125 MHz):
δ 19.3, 24.7, 26.1, 26.8, 29.8, 50.5, 63.0, 83.3, 84.9, 110.3, 127.6, 127.7, 129.6,
129.7, 133.5, 133.6, 135.7, 135.7. Anal. Calcd for C24H32O3SeSi: C, 60.62; H, 6.78. Found: C,
60.59; H, 6.83.
Under the above conditions, 5-O-tert-butyldiphenylsilyl-1,4-deoxy-2,3-O-isopropylidene-4-seleno-
D-ribose (10) was obtained as a pale-yellow oil (96%) starting from the C4 isomer of compound
1
5
: H NMR (400 MHz):
δ
1.09 (s, 9H, CH3), 1.33 (s, 3H, CH3), 1.54 (s, 3H, CH3), 2.96 (dd,
J1a,1b = 11.8 Hz, J1a,2 = 2.3 Hz, 1, H, H1a), 3.20 (dd, J1b,1a = 11.8 Hz, J1b,2 = 5.1 Hz, 1, H,
H1b), 3.67 (ddt, J4,5a = 7.3 Hz, J4,5b = 5.3 Hz, J4,3 = 1.8 Hz, 1H, H4), 3.74 (dd, J5a,5b = 10.5 Hz,

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J5a,4 = 7.0 Hz, 1H, H5a), 3.88 (dd, J5b,5a = 10.5 Hz, J5b,4 = 5.4 Hz, 1H, H5b), 4.80 (dd,
J3,2 = 5.3 Hz, J3,4 = 1.8 Hz, 1H, H3), 4.86 (ddd, J2,1b = 5.5 Hz, J2,3 = 5.4 Hz, J2,1a = 2.3 Hz, 1H,
H2), 7.38–7.47 (m, 6H, Ar), 7.65–7.72 (m, 4H, Ar); 13C NMR (100 MHz):
δ 19.2, 24.7, 26.9,
29.6, 50.1, 64.5, 85.1, 87.3, 110.3, 127.7, 129.8, 133.1, 135.6. Anal. Calcd for C24H32O3SeSi: C,
60.62; H, 6.78. Found: C, 60.63; H, 6.79.
Preparation of 1,4-deoxy-2,3-O-isopropylidene-4-seleno-L-lyxose (7): A solution of tetrabutylam-
monium fluoride (1.7 mL of a 1.1 M solution in THF, 2.0 mmol) was added to a magnetically
stirred solution of seleno derivative 6 (0.475 g, 1.0 mmol) in anhydrous THF (7.0 mL) at 0
◦C under N2, and the mixture was stirred at room temperature for 1 h. The evaporation
of the solvent under reduced pressure gave a crude residue that was purified by silica
gel column chromatography (hexane-ethyl acetate 6:4 (v/v)) to give the pure product
7
1
as a crystalline white solid (0.216 g, 0.91 mmol, 91%). H NMR (500 MHz):
δ 1.33 (s, 3H,
CH3), 1.53 (s, 3H, CH3), 2.53 (brs, 1H, OH), 2.99–3.05 (m, 2H, H1), 3.66 (dt, J4,5b = 7.5 Hz,
J4,5a = 5.0 Hz, J4,3 = 4.2 Hz, 1H, H4), 3.91 (dd, J5a,5b = 11.5 Hz, J5a,4 = 5.0 Hz, 1H, H5a), 4.00
(dd, J5b,5a = 11.5 Hz, J5b,4 = 7.5 Hz, 1H, H5b), 4.87 (m, 1H, H3), 4.94 (ddd, J2,3 = 6.1 Hz,
J2,1b = 4.1 Hz, J2,1a = 2.0 Hz, 1H, H2); 13C NMR (125 MHz):
δ 24.5, 26.1, 29.0, 48.2, 62.2, 85.0,
85.1, 111.5. Anal. Calcd for C8H14O3Se: C, 40.52; H, 5.95. Found: C, 40.49; H, 5.96.
Under the above conditions, 1,4-deoxy-2,3-O-isopropylidene-4-seleno-D-ribose (11) was obtained as
1
an amorphous solid (90%) starting from the C4 isomer of compound 10. H NMR (500 MHz):
δ
1.33 (s, 3H, CH3), 1.54 (s, 3H, CH3), 3.02 (dd, J1a,1b = 12.0, J1a,2 = 2.1 Hz, 1H, H1a), 3.22 (dd,
1b,1a = 12.0 Hz, J1b,2 = 5.2, 1H, H1b), 3.62–3.75 (m, 3H, H4 and H5), 4.73 (dd, J3,2 = 5.5 Hz,
J3,4 = 1.4 Hz, 1H, H3), 4.99 (ddd, J2,3 = 5.5 Hz, J2,1b = 5.2 Hz, J2,1a = 2.1 Hz, 1H, H2); 13
NMR (125 MHz): 24.7, 26.8, 29.4, 52.2, 64.1, 85.1, 87.7, 111.6. Anal. Calcd for C8H14O3Se:
C, 40.52; H, 5.95. Found: C, 40.55; H, 5.93.
J
C
δ
Preparation of monoacetyl hydroquinone: DMAP (0.01 g, 0.091 mmol) was added to a magneti-
cally stirred solution of hydroquinone (0.100 g, 0.908 mmol) in acetic anhydride (1.09 mmol,
0.103 mL) and dry pyridine (0.90 mL) under N2. The reaction mixture was stirred overnight
at room temperature and then diluted in ethyl acetate (50 mL). The resulting solution
was washed with HCl (1 M, 50 mL
×
4), NH4Cl (50 mL), and brine and dried (Na2SO4).
The evaporation of the solvent under reduced pressure gave a crude residue that was
purified by silica gel column chromatography (CHCl3) to give the pure monoacetylated
hydroquinone as a crystalline white solid (0.125 g, 0.82 mmol, 70%). The NMR spectral
data were identical to the values in the literature [25].
Mitsunobu Reaction: Preparation of glycoconjugates. Typical Procedure: DIAD (0.303 mL,
1.5 mmol) was added to a magnetically stirred solution of TPP (0.393 g, 1.5 mmol) in
◦
anhydrous THF (2.3 mL) at 0 C under N2. After 15 min, a solution containing seleno
derivative
7 (0.200 g, 1.0 mmol) and monoacetylated hydroquinone (0.270 g, 1.5 mmol)
in anhydrous THF (3.0 mL) was added dropwise. The reaction mixture was stirred at
room temperature for three days. The solvent was evaporated under reduced pressure and
replaced with AcOEt. The organic layer was washed with brine and dried (Na2SO4). The
evaporation of the solvent under reduced pressure gave a crude residue that was purified
by silica gel column chromatography (hexane-diethyl ether 7:3 (v/v)) to give the pure
1
product
8
as a pale yellow-syrup (0.160 g, 0.43 mmol, 43%). H NMR (500 MHz):
δ
1.36
(s, 3H, CH3), 1.57 (s, 3H, CH3), 2.30 (s, 3H, CH3), 3.08 (dd, J1a,1b = 12.0 Hz, J1a,2 = 1.5 Hz,
1H, H1a), 3.34 (dd, J1b,1a = 12.0 Hz, J1b,2 = 5.0 Hz, 1H, H1b), 3.85 (m, 1H, H4), 4.03 (dd,
J5a,5b = 9.5 Hz, J5a,4 = 8.0 Hz, 1H, H5a), 4.21 (dd, J5b,5a = 9.5 Hz, J5b,4 = 5.5 Hz, 1H, H5b), 4.90
(dd, J3,2 = 5.5 Hz, J3,4 = 1.5 Hz, 1H, H3), 5.05 (dt, J2,3 = 5.5 Hz, J2,1b = 5.0 Hz, J2,1a = 2.0 Hz,
1H, H2), 6.90 (d, J = 9.0 Hz, 2H, Ar), 7.00 (d, J = 9.0 Hz, 2H, Ar); 13C NMR (125 MHz):
δ
21.0, 24.7, 26.7, 30.2, 47.0, 70.9, 85.2, 87.6, 110.6, 115.3, 122.4, 144.6, 156.0, 169.8. Anal. Calcd
for C16H20O5Se: C, 51.76; H, 5.43. Found: C, 51.66; H, 5.48.
Under the above conditions, 5-(4-hydroxyphenoxy)-1,4-deoxy-2,3-O-isopropylidene-4-seleno-D-
1
ribose (12) was obtained as oil (13%) starting from the compound
7
and hydroquinone: H NMR

Molecules 2021, 26, 2541
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(500 MHz):
δ
1.36 (s, 3H, CH3), 1.56 (s, 3H, CH3), 3.06 (dd, J1a,1b = 11.9 Hz, J1a,2 = 1.9 Hz,
1H, H1a), 3.33 (dd, J1b,1a = 11.9 Hz, J1b,2 = 5.1 Hz, 1H, H1b), 3.83 (m, 1H, H4), 3.99 (dd,
J5a,5b = 9.9 Hz, J5a,4 = 7.8 Hz, 1H, H5a), 4.16 (dd, J5b,5a = 9.9 Hz, J5b,4 = 5.2 Hz, 1H, H5b), 4.91
(dd, J3,2 = 5.6 Hz, J3,4 = 1.7 Hz, 1H, H3), 5.05 (dt, J2,3 = 5.6 Hz, J2,1b = 5.3 Hz, J2,1a = 1.9 Hz,
1H, H2), 6.77 (d, J = 9.2 Hz, 2H, Ar), 6.80 (d, J = 9.3 Hz, 2H, Ar); 13C NMR (125 MHz):
δ 24.7,
26.7, 30.2, 47.2, 71.3, 85.2, 87.7, 110.6, 115.9, 116.1, 150.0, 152.5. Anal. Calcd for C14H18O4Se:
C, 51.07; H, 5.51. Found: C, 51.10; H, 5.50.
Under the above conditions, (E)-5-((3-(3,4-dihydroxyphenyl)acryloyl)oxy)-1,4-deoxy-2,3-O-
isopropylidene-4-seleno-D-ribose (13) was obtained as oil (70%) starting from the compound
7
and caffeic acid: 1H NMR (500 MHz):
δ
1.34 (s, 3H, CH3), 1.54 (s, 3H, CH3), 3.06 (dd,
J1a,1b = 12.1 Hz, J1a,2 = 1.7 Hz, 1H, H1a), 3.26 (dd, J1b,1a = 12.1 Hz, J1b,2 = 4.9 Hz, 1H, H1b),
3.76 (m, 1H, H4), 4.26 (dd, J5a,5b = 11.6 Hz, J5a,4 = 8.9 Hz, 1H, H5a), 4.37 (dd, J5b,5a = 11.6 Hz,
J5b,4 = 5.8 Hz, 1H, H5b), 4.77 (dd, J3,2 = 5.5 Hz, J3,4 = 1.6 Hz, 1H, H3), 5.03 (ddd, J2,3 = 5.7 Hz,
J2,1b = 5.0 Hz, J2,1a = 2.0 Hz, 1H, H2), 6.00 (brs, 2H, OH), 6.24 (d, J = 15.9 Hz, 1H, H20),
6.87 (d, J = 8.2 Hz, 1H, H80), 7.00 (dd, J = 8.2 Hz, J = 1.5 Hz, 1H, H90), 7.07 (d, J = 1.5 Hz,
1H, H50), 7.58 (d, J = 15.9 Hz, 1H, H30); 13C NMR (125 MHz):
δ 24.7, 26.7, 29.7, 46.6, 65.7,
85.0, 87.3, 110.9, 114.5, 115.1, 115.6, 122.7, 127.6, 143.8, 145.5, 146.3, 167.0. Anal. Calcd for
C17H20O6Se: C, 51.14; H, 5.05. Found: C, 51.19; H, 5.03.
Under the above conditions, (E)-5-((3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)-1,4-deoxy-2,3-
O-isopropylidene-4-seleno-D-ribose (14) was obtained as oil (68%) starting from the compound
1
7
and ferulic acid: H NMR (500 MHz, acetone-d6):
δ
1.30 (s, 3H, CH3), 1.46 (s, 3H, CH3),
2.99 (dd, J1a,1b = 11.9 Hz, J1a,2 = 1.3 Hz, 1H, H1a), 3.37 (dd, J1b,1a = 11.9 Hz, J1b,2 = 4.9 Hz,
1H, H1b), 3.76 (ddd, J4,5a = 8.7 Hz, J4,5b = 7.4 Hz, J4,3 = 1.3 Hz, 1H, H4), 3.95 (s, 3H, CH3),
4.26 (dd, J5a,5b = 11.4 Hz, J5a,4 = 8.8 Hz, 1H, H5a), 4.36 (dd, J5b,5a = 11.4 Hz, J5b,4 = 6.8 Hz,
1H, H5b), 4.86 (dd, J3,2 = 5.8 Hz, J3,4 = 1.5 Hz, 1H0, H3), 5.11 (ddd, J2,3 = 6.1, J2,1b = 5.9 Hz,
0
J2,1a = 1.9 Hz, 1H, H2), 6.46 (d, J = 16.0 Hz, 1H, H2 ), 6.90 (dd, J = 8.0 Hz, 1H, H8 ), 7.18 (dd,
J = 8.5 Hz, J = 1.9 Hz, 1H, H90), 7.39 (d, J = 1.5 Hz, 1H, H50), 7.66 (d, J = 16.0 Hz, 1H, H30);
13C NMR (125 MHz):
δ 24.7, 26.7, 29.3, 46.7, 56.0, 65.6, 85.0, 87.3, 109.4, 110.8, 114.8, 114.8,
123.3, 126.8, 145.7, 146.8, 148.2, 166.9. Anal. Calcd for C18H22O6Se: C, 52.31; H, 5.37. Found:
C, 52.25; H, 5.43.
Under the above conditions, 5-(4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-
dien-1-yl)-2-methoxyphenoxy)-1,4-deoxy-2,3-O-isopropylidene-4-seleno-D-ribose (15) was obtained
as oil (30%) starting from the compound
7 δ 1.36 (s,
and curcumin: 1H NMR (400 MHz):
3H, CH3), 1.57 (s, 3H, CH3), 3.04 (dd, J1a,1b = 12.0 Hz, J1a,2 = 1.9 Hz, 1H, H1a), 3.55 (dd,
J1b,1a = 12.0 Hz, J1b,2 = 5.0 Hz, 1H, H1b), 3.93–3.86 (m, 4H, H4 and CH3), 3.96 (s, 3H, CH3),
4.16 (dd, J5a,5b = 9.7 Hz, J5a,4 = 8.0 Hz, 1H, H5a), 4.33 (dd, J5b,5a = 9.7 Hz, J5b,4 = 5.2 Hz, 1H,
H5b), 4.95 (dd, J3,2 = 5.6 Hz, J3,4 = 1.8 Hz, 1H, H3), 5.11 (ddd, J2,3 = 5.6 Hz, J2,1b = 5.0 Hz,
J2,1a = 1.9 Hz, 1H, H2), 5.82 (m, 2H, H100), 5.98 (bs, 1H, OH), 6.52–6.46 (m, 2H, H80 and
H1200), 6.84 (d, J = 8.3 Hz, 1H, H60), 6.94 (d, J = 8.3 Hz,01H, H180), 7.05 (d, J = 1.7 Hz, 1H,
0
0
0
H15 ), 7.07 (d, J = 1.9 Hz, 1H, H3 ), 7.14–7.09 (m, 2H, H5 and H19 ), 7.65–7.561 (m, 2H, H7
and H130); 13C NMR (125 MHz):
δ 24.6, 26.7, 31.1, 47.1, 56.0, 72.1, 85.6, 88.2, 101.2, 109.6,
110.4, 113.1, 114.8, 121.8, 122.3, 122.9, 129.0, 140.2, 140.6, 146.8, 147.9, 149.7, 182.9, 183.6.
Anal. Calcd for C29H32O8Se: C, 59.29; H, 5.49. Found: C, 59.19; H, 5.55.
Removal of the O-isopropylidene group. Typical Procedure: A solution (3.3 mL) of CH3COOH
/H2O (8:2, v/v) was added to compound 12 (0.329 g, 1.0 mmol). The mixture was stirred at
80 ◦C for 2 h. Then, the solvent was evaporated under reduced pressure; next, the organic
layer was washed with diethylether. The crude residue was purified to afford compound
1
12a as an amorphus solid (0.205 g, 0.8 mmol, 71%). H NMR (400 MHz, acetone-d6):
δ 2.82
(dd, J1a,1b = 10.0 Hz, J1a,2 = 5.1 Hz, 1H, H1a), 3.02 (dd, J1b,1a = 10.0 Hz, J1b,2 = 5.0 Hz, 1H,
H1b), 3.77 (m, 1H, H4), 3.99 (dd, J5a,5b = 9.7 Hz, J5a,4 = 8.3 Hz, 1H, H5a), 4.10 (m, 1H, H3),
4.35 (dd, J5b,5a = 9.7 Hz, J5b,4 = 5.9 Hz, 1H, H5b), 4.40 (m, 1H, H2), 6.75 (d, J = 9.2 Hz, 2H,
Ar), 6.79 (d, J = 9.2 Hz, 2H, Ar); 13C NMR (100 MHz, acetone-d6):
δ 23.9, 42.6, 72.4, 76.0,

Molecules 2021, 26, 2541
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78.4, 115.8, 151.6, 152.0. Anal. Calcd for C11H14O4Se: C, 45.69; H, 4.88. Found: C, 45.73;
H, 4.83.
Under the above conditions, (E)-5-((3-(3,4-dihydroxyphenyl)acryloyl)oxy)-1,4-deoxy-4-seleno-D-
ribose (13a) was obtained as an amorphous solid (68%) starting from the compound 13
NMR (500 MHz, acetone-d6): 2.84 (dd, J1a,1b = 9.9 Hz, J1a,2 = 5.3 Hz, 1H, H1a), 3.06 (dd,
1b,1a = 9.9 Hz, J1b,2 = 5.1 Hz, 1H, H1b), 3.74 (m, 1H, H4), 4.10 (dd, J3,4 = 5.9 Hz, J3,2 = 3.2 Hz,
:
1H
δ
J
1H, H3), 4.22 (dd, J5a,5b = 11.3 Hz, J5a,4 = 7.6 Hz, 1H, H5a), 4.43 (ddt, J2,1a = 5.3 Hz,
J2,1b = 5.1 Hz, J2,3 = 3.1 Hz, 1H, H2), 4.57 (dd, J5b,5a = 11.3 Hz, J5b,4 = 6.6 Hz, 1H, H5b),
6.32 (d, J = 15.9 Hz, 1H, H20), 6.90 (d, J = 8.2 Hz, 1H, H50), 7.09 (dd, J = 8.2 Hz, J = 2.0 Hz,
1H, H90), 7.19 (d, J = 2.0 Hz, 1H, H80), 7.58 (d, J = 15.6 Hz, 1H, H30); 13C NMR (125 MHz,
acetone-d6):
δ 24.1, 41.9, 66.5, 76.0, 78.4, 114.4, 115.5, 121.7, 126.7, 145.2, 145.4, 148.0, 166.2.
Anal. Calcd for C14H16O6Se: C, 46.81; H, 4.49. Found: C, 46.81; H, 4.45.
Under the above conditions, (E)-5-((3-(4-hydroxy-3-methoxyphenyl)acryloyl)oxy)-1,4-deoxy-4-
seleno-D-ribose (14a), an amorphous solid, was obtained (80%) starting from the compound 14
:
1H NMR (500 MHz, acetone-d6):
δ
2.85 (dd, J1a,1b = 10.0 Hz, J1a,2 = 5.3 Hz, 1H, H1a), 3.06
(dd, J1b,1a = 10.0 Hz, J1b,2 = 5.0 Hz, 1H, H1b), 3.74 (m, 1H, H4), 3.95 (s, 3H, CH3), 4.09
(m, 1H, H3), 4.22 (dd, J5a,5b = 11.3 Hz, J5a,4 = 7.8 Hz, 1H, H5a), 4.43 (m, 1H, H2), 4.58 (dd,
J
5b,5a = 11.3 Hz, J5b,4 = 6.5 Hz, 1H, H5b), 6.43 (d, J = 15.9 Hz, 1H, H20), 6.90 (d, J = 8.1 Hz,
1H, H80), 7.18 (dd, J = 8.2 Hz, J = 1.7 Hz, 1H, H90), 7.39 (bs, 1H, H50), 7.64 (d, J = 15.9 Hz,
1H, H30); 13C NMR (125 MHz, acetone-d6):
δ
24.1, 41.9, 55.5, 66.6, 76.0, 78.4, 110.4, 114.6,
115.2, 123.3, 126.5, 145.2, 145.3, 147.9, 149.3, 166.3. Anal. Calcd for C15H18O6Se: C, 48.27; H,
4.86. Found: C, 48.36; H, 4.82.
4. Conclusions
A new route for synthesizing unusual seleno-glyconjugates has been developed, ex-
ploiting a Mitsunobu reaction. Interestingly, the latter proceeded with high stereocontrol,
showing a preferential bias for the introduction of the acceptor moiety, leading to a com-
pound with the 3,4-anti-configuration not depending on the stereochemistry of the starting
seleno-donor.
1
Supplementary Materials: The following are available online. H, 13C NMR spectra of products.
Author Contributions: Conceptualization: M.D.N.; methodology: M.D.N., F.C., and S.P.; inves-
tigation spectroscopy: S.P., M.M., and L.S.; investigation and synthesis: M.D.N., F.C., and L.S.;
writing—original draft preparation: S.P., M.D.N., and L.S.; funding acquisition: S.P. All authors have
read and agreed to the published version of the manuscript.
Funding: The authors wish to thank the European Union (FSE, PON Ricerca e Innovazione 2014–
2020, Azione I.1 “Dottorati Innovativi con caratterizzazione Industriale”), for providing the funding
a Ph.D. grant to Luigia Serpico.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author.
Acknowledgments: This publication was in partial fulfilment of the requirements for the degree of
Ph.D. in Chemical Sciences−XXXIII Cycle, University of Naples Federico II.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Not available.
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