Direct biocatalysed synthesis of first sulfur-, selenium- and tellurium- containing l-ascorbyl hybrid derivatives with radical trapping and GPx-like properties

Article abstract of DOI:10.1039/c9cc02427a

6-O-l-Ascorbyl selenoesters, thioesters and telluroesters can be efficiently and directly prepared from l-ascorbic acid and suitable functionalised chalcogenoesters through lipase-catalysed transesterification reactions. Novel synthesised l-ascorbyl deriv

Full text of DOI:10.1039/c9cc02427a

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DOI: 10.1039/C9CC02427A
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Direct biocatalysed synthesis of first sulfur-, selenium- and
tellurium containing L-ascorbyl hybrid derivatives with radical
trapping and GPx-like properties
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Damiano Tanini,* Beatrice Lupori, Gianni Malevolti, Moira Ambrosi, Pierandrea Lo Nostro,
Antonella Capperucci*
6
-O-L-ascorbyl selenoesters, thioesters and telluroesters can be never been described. The paucity of such results is reasonably
efficiently and directly prepared from L-ascorbic acid and suitable due to the instability of the L-ascorbic acid core, which easily
functionalised chalcogenoesters through lipase-catalised undergoes oxidation of the enediol moiety and ring opening of
transesterification reactions. Novel synthesised L-ascorbyl the lactone. Furthermore, several alcohol protecting group
derivatives exhibited remarkable chain breaking and glutathione strategies cannot be applied since the conditions of the
peroxidase-like activities.
endgame protecting group cleavage are often not compatible
with chalcogens or with the L-ascobic acid core. For example,
because the presence of chalcogens poisons the Pd-catalyst,
the most commonly employed benzyl protecting group cannot
be cleaved under mild Pd/C catalysed hydrogenation
conditions. Additionally, harsh bases- or acid-mediated
L-ascorbic acid (vitamin C) is a powerful water soluble
antioxidant essential for the correct functioning of the body,
being involved in a number of biological processes ranging,
amongst others, from the biosynthesis of collagen and
catecholamine to the modulation of neurotransmission.
11
1
2
deprotection
procedures
cause
severe
products
The enhanced concentration of harmful reactive oxygen
species (ROS) has long been related with the onset of several
human diseases such as cancer, immune disorders, cystic
decomposition.
We sought to approach this problem from a different
perspective and evaluated the possibility of applying lipase
biocatalysed transesterifications
3
fibrosis, and neurodegenerative deseases. Liposoluble vitamin
12
of chalcogen-containing
E and hydrosoluble vitamin C, together with phenolic
compounds, carotenoids, and trace elements such as zinc and
selenium are the main exogenous defences against oxidative
stress. In this context, the design and the development of
novel antioxidants have been attracting growing interest over
esters and L-ascorbic acid. This approach would ideally allow a
straightforward access to chalcogen-containing L-ascorbic acid
derivatives, without requiring tedious and detrimental
protection/deprotection
steps.
Lipase
B
catalysed
transesterification is indeed a versatile tool to synthesise L-
4
the last decades. Particularly, owing to their capability to
13
ascorbyl esters under green and mild conditions. However, to
mimic the glutathione peroxidase activity, the synthesis of
chalcogen-containing antioxidants has recently attracted
growing attention. Furthermore, organochalcogenides can
possess anticancer, antibacterial, and enzyme inhibitor
the best of our knowledge, its application to chalcogen-
containing acyl donors has never been described and its
feasibility and functional group tolerance were not obvious.
We commenced our studies by establishing the optimal
conditions required to promote the biocatalysed
transesterification reaction of -selenoester 2a, prepared
through seleno-Michael addition from benzeneselenol 1a and
methyl acrylate (see ESI), with L-ascorbic acid 3. According to a
literature survey, the optimal temperature for the enzyme
activity was established to be 45°C. Polar solvents, such as
acetone and tertiary alcohols are the media of choice for
5
activities. The functionalization of bioactive natural products
with chalcogens represents an effective strategy to modulate
or improve their biological properties. For example, the
introduction of chalcogen-containing moieties onto natural
6
,7
7
8
compounds such as tocopherols,
tocotrienols, retinol,
hydrxytyrosol, chrysin, quercetine,10a and resveratrol10c have
been extensively studied. However, whilst sulfur-, selenium-,
or tellurium-functionalised vitamin E and vitamin A derivatives
have been reported, to the best of our knowledge the
synthesis of chalcogen-containing vitamin C derivatives has
9
10
12,13
lipase-catalysed L-ascorbic acid esterifications.
In our
hands, acetone proved to be the most effective, plausibly
owing both to the high capability to dissolve both 2a and 3. In
addition non protic solvents as acetone do not promote the
dissociation of L-ascorbic acid to the more oxidisable L-
ascorbate. Evaluation of different solvents commonly used for
Lipase B catalysed reactions, such as tert-butanol and 2-
University of Florence, Department of Chemistry "Ugo Schiff", Via della Lastruccia
1
3, I-50019 Sesto Fiorentino, Italy.
damiano.tanini@unifi.it; antonella.capperucci@unifi.it.
Electronic supplementary information (ESI) available: Full experimental details
and products characterisation. See DOI: 10.1039/x0xx00000x
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COMMUNICATION
Journal Name
methyl-1-butanol gave lower yields. Thus, we investigated the electrophiles (Scheme S1, via A and via B). DisulfidVeiew6Aj,rtbicleeaOrnilninge
effect of the reaction stoichiometry and the amount of lipase. two ester functions and four sulfur atoDmOIs: ,10w.10a3s9/sCy9nCtCh0e2s4is2e7dA
We found that, whilst poor yields were achieved by using 500 from 1,9-nonanethiol through a two-step procedure involving
U/mmol of enzyme (Table 1, entries 1-3), a doubling of the a thio-Michael addition and a DCF (dicyanofumarate) mediated
1
6b
enzyme amount brought about
improvement (Table 1, entry 4).
a
significant yield oxidation sequence (see ESI for details). -Aryltelluroesters
8a,b were prepared from the corresponding ditellurides and
The optimal reaction time was found to be 48 h, as partial methyl 3-bromopropionate (Scheme 1 and S1).
decomposition of the reaction product was observed after 72 See ESI for reagents and conditions, and experimental details
Via A. Hetero-Michael addition
Via B. Nucleophilic substitution
h (Table 1, entry 5). On the other hand, shorter times resulted
in much lower yields (Table 1, entry 6). Pleasingly, we found
that by using an excess of -selenoester 2a the desired 6-O-L-
ascorbyl ester 4a was formed in rather good yield for this type
of biocatalysed transformations (45%, Table 1, entry 8).
O
O
Br
n
R1
n = 1,2,3
R/ArX
O
O
O
O
or ArTeTeAr
R/ArX
n
R1
R/ArXH
R/ArXH
Al2O3, PhMe
r.t., 6 h
- Conditions i
- Conditions ii
O
O
2
6
: X = Se
: X = S
1: X = Se
5: X = S
1: X = Se
5: X = S
7
2: X = Se
6: X = S
8
n = 1,2,3
: X = Te
Remarkably, a significant improvement in yield was achieved
upon performing the reaction in the presence of 4 A molecular
sieves (Table 1, entries 9 and 10). Particularly, by using an
excess of 2a under these conditions, the ascorbyl derivative 4a
was formed in 74% yield, which represents a very good result
for lipase-catalysed transesterification reactions. The striking
effect of zeolites can be reasonably ascribed to the trapping of
Scheme 1. Synthesis of selenoesters 2, thioesters 6, and
telluroesters 8.
Having in hands range of differently substituted and
functionalised chalcogen-containing esters, we then explored
the scope of the lipase-catalysed transesterification reaction
with L-ascorbic acid (Scheme 2). Under the optimised reaction
conditions, o-, m-, and p-methoxy phenylselenoesters 2b-d
2
both MeOH and H O. Indeed, the removal of methanol
produced by the transesterification displaces the equilibrium
of the reaction toward the formation of 4a. Furthermore, by
trapping water, molecular sieves hamper the competitive
lipase-catalysed hydrolysis of 4a.
gave
arylselenoalkanoates 4b-d in good yield. -Selenoester 2e,
bearing a p-F-C ring, also reacted efficiently with 3 to afford
selectively
the
corresponding
6-O-ascorbyl
6 4
H
compound 4e. The reaction was also successfully applied to
the synthesis of L-ascorbyl derivatives 4f,g bearing different
alkylseleno moieties, including the functionalised glycidol
derivative (4g). Furthermore, methyl and ethyl - and -
selenoesters 2h-j were efficiently transesterified with 3
yielding the corresponding 6-O-L-ascorbyl esters 4h-j in rather
good yields, therefore demonstrating the versatility of the
biocatalysed approach towards the synthesis of variously
functionalised homologous L-ascorbyl selenoesters. Next, we
turned our attention to evaluating the generality of such
reaction with respect to sulfur-containing esters. -
Arylthioesters 6a-d were smoothly converted into the
corresponding sulfurated 6-O-ascorbyl derivatives bearing a
Table 1. Optimization of the biocatalysed synthesis of
selenium-containing 6-O-ascorbyl ester 4a.
HO
HO
O
OH
O
OH
O
H
H
Lipase B (da C. antarctica)
PhSe
O
+
HO
PhSe
O
O
Acetone, 45°C, Time
O
O
2a
OH
4a
OH
3
(1.0 Equiv.)
Entry 2a (Eq.) Lipase B (U/mmol) Time (h) Yield (%)a
Entry
2a (Eq.) Lipase B (U/mmol) Time (h) Yield (%)a
1
2
3
1.0
0.5
0.3
500
500
500
48
48
48
12
6
7
8
9
0.3
1.0
3.0
3.0
1000
1000
1000
1000
24
48
48
48
<10
26
<10
<10
45
74c
4
5
0.3
0.3
1000
1000
48
72
22
14b
10
0.3
1000
48
32c
aIsolated yield is reported; bPartial decomposition of 4a was observed; c4 A phenyl ring (9a) or o- (9b), m- (9c), and p- (9d) bromo-
molecular sieves (300 mg) were added. See ESI for details. The use of molecular substituted benzenes bonded to the S atom. This methodology
sieves with lower enzyme loading (500 U/mmol) gave slight yield improvements.
could also be applied to more interesting highly functionalised
alkyl sulfides. The hydroxy-substituted S-alkyl -thioester 6e
Having identified optimal reaction conditions, we proceeded and the enantioenriched epichlorohydrin derivatives (S)-6f and
to investigate the scope of the transformation with respect to (R)-6f were successfully transferred onto the L-ascorbic acid
different chalcogen-containing esters. Thus, a large variety of core, affording the corresponding functionalised ester 9e and
differently substituted selenium-, sulfur-, and tellurium- the enantioenriched derivatives 9f and 9g, containing three
containing esters (Schemes 1 and S1, ESI) was synthesised as controlled stereogenic centers and the further functionalisable
reported in the Scheme 1. -Arylseleno- and -alkylseleno- chlorinated chain. Additionally, chiral enantioenriched N-Tosyl
esters 2a-g were smoothly achieved through a novel seleno- amino-substituted -thioester 6g, synthesised from L-
Michael addition14 involving suitable aryl- or alkyl-selenols
and methyl acrylate. The reaction occurred under very mild enantioenriched S,N-containing 6-O-L-ascorbyl ester 9h.
conditions in the presence of Al (Schemes 1 and S1, via A). Furthermore, also - and -thioesters 9i and 9j were
15
1
valine,
14,15a
could be efficiently employed to access the
2 3
O
Furthermore, -selenoesters 2h,i and -selenoester 2j were conveniently achieved treating 3 with 6h and 6j, respectively,
easily obtained by exploiting the reactivity of selenols 1 with under the above described conditions. Remarkably, the
methyl bromoacetate and ethyl 4-bromobutyrate, respectively disulfide 6j was successfully used in a double biocatalysed
(Schemes 1 and S1, via B). Similarly, variously substituted and transesterification to afford the potentially valuable bola type
functionalised -, -, and -thioesters 6a-i were prepared from bis-ascorbyl ester 9k, bearing two L-ascorbyl moieties and four
1
6a
the corresponding aryl or alkyl thiols
and suitable sulfur atoms. Indeed, owing to the unique physicochemical
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
COMMUNICATION
properties of bola type structures, novel bifunctional The stoichiometry of the reaction (n, numbeVriewoAfrticrleaOdniclinael
chalcogen-containing amphiphilic ascorbic acid derivatives trapped within 10 minutes) was found tDoObI:e10n.10=392/Cf9oCrCa0l2l4t2h7Ae
could find wide application both in polymers and material tested L-ascorbyl esters 4, 9, and 10, thus indicating that under
sciences and in medicinal chemistry for the drug delivery of the experimental conditions the oxidation products of these
lipophilic molecules.1
2a,17
compounds are not capable of reacting with DPPH.
Furthermore, the catalytic thiol peroxidase like activity of
selected L-ascorbyl derivatives was also pursued according to
HO
HO
O
OH
O
O
OH
H
Lipase B da C. antarctica
Molecular sieves (4A) R/Ar
Acetone, 45°C, 48 h
H
X
X
R/Ar
OR1
+
HO
O
n
O
n
O
O
OH
OH
19
2
6
8
: X = Se
: X = S
: X = Te
3
4: X = Se
9: X = S
literature reported methods using dithiothreitol (DTT) or
n = 1,2,3
(1.0 eq.)
10: X = Te
19
glutathione (GSH) as substrates (see Scheme S2 and Fig. S2,
(3.0 eq.)
HO
H
HO
S3). We were delighted to discover that all tested selenium-
and tellurium-contained vitamin C derivatives behave as
catalysts in promoting the reduction of hydrogen peroxide in
the presence of a thiol cofactor (Table 2). Intriguingly, when
the DTT oxidation assay is accomplished using 1.0 eq. of
hydrogen peroxide ca. 10-20% of DTT remained unreacted.
Control experiments suggested that reaction of the L-
O
OH
O
OH
R
H
Se
a, R = H, 77%
O
Se
O
O
O
O
O
4
4
4
4
4
OH
4f, 72%
OH
HO
b, R = o-MeO, 67%
c, R = m-MeO, 64%
d, R = p- MeO, 71%
e, R = p-F, 69%
O
OH
HO
H
O
OH
O
Se
H
O
R
O
O
O
Se
O
H
OH
O
OH
4g, 58%
OH
4h, R = H, 73%
i, R = o-Me, 56%
4
HO
R
HO
O
OH
OH
O
O
H
Se
O
O
S
O
2 2
ascorbate moiety with H O proceeds slowly in absence of
O
O
4
j, 53%
OH
O
9
a, R = H, 64%
OH
HO
9b, R = o-Br, 62%
9c, R = m-Br, 75%
9d, R = p-Br, 83%
catalysts. The observed results might be reasonably ascribed
to the formation of tricarbonyl derivatives, proceeding through
a redox reaction involving the enediol moiety and a selenoxide
O
OH
O
H
HO
O
S
O
OH
O
O
H
OH
9e, 61%
OH
Cl
S
O
O
HO
OH
9f, 54%
OH
HO
20
O
OH
or telluroxide intermediate. On the other hand, complete
H
Cl
S
O
O
OH
O
O
H
DTT oxidation was achieved upon using an excess (1.2 eq.) of
H O . As can be noticed (Table 2 and Figure 1), under these
2 2
O
OH
9g, 58%
OH
HO
S
O
O
HN
9
h, 62%
OH
Ts
Br
O
O
OH
O
HO
H
conditions all the tested compounds exhibited catalytic thiol-
peroxidase like properties, being able to promote the
oxidation of both DTT and GSH. Intriguingly, the -
alkylselenoester 4g showed higher catalytic activity with
respect to the arylseleno-substituted analogues 4a-c,e.
Furthermore, according to both assays, L-ascorbyl -
aryltelluroalkanoates 10a,b behaved as more effective
catalysts with respect to the similar selenium-containing
derivatives 4a-e.
S
O
OH
H
O
S
9
i, 76%
OH
O
O
9
j, 57%
O
OH
O
Br
HO
OH
H
OH
O
O
H
O
O
S
S
S
2
S
O
O
2
HO
O
9k, 64%
OH
OH
OMe
HO
HO
O
OH
O
MeO
MeO
OH
H
O
H
Te
O
O
Te
O
O
OH
10b, 67%
O
1
0a, 74%
OH
Scheme 2. Biocatalysed direct synthesis of selenium-, sulfur-,
and tellurium-containing 6-O-ascorbyl esters 4, 9, 10 from L- Table 2. Thiol-peroxidase like activity of selenium- and
ascorbic acid. Isolated yields are reported.
tellurium-containing 6-O-L-ascorbyl esters 4 and 10 according
to DTT and GSH/GR methods
Finally, in order to enlarge the scope of this methodology to
Entry
Compound
DTT (T50)a,b
GSH/GR (T50)a,c
organotellurium derivatives, we evaluated the reactivity of -
1
2
3
4
5
4a
4b
3405 (±268)
4270 (±325)
4046 (±314)
3862 (±362)
1346 (±151)
43 (±5)
48 (±7)
45 (±5)
53 (±4)
37 (±3)
aryltelluroesters
8a,b
with
3.
6-O-L-Ascorbyl
4c
4e
4g
aryltelluroalkanoates 10a,b were directly and selectively
formed in good yield, thus highlighting the remarkably broad
scope of the procedure and the possibility to use the lipase-
catalysed approach with all chalcogens.
Owing to the presence of both the vitamin C free enediol aT50 is the time required, in seconds, to halve the initial thiol concentration after
moiety and the selenium or tellurium atom, ascorbyl the addition of H
derivatives 4 and 10 can exhibit both chain breaking and oxidation was monitored by the mean of H NMR spectroscopy; 10 mol% of 4
catalytic antioxidant activities, therefore representing and 1 mol% of 10 were used. cNADPH consumption was monitored by UV
excellent antioxidant candidates. Therefore, having developed spectroscopy (340 nm).
6
7
8
4h
2846 (±116)
654 (±104)
386 (±93)
42 (±6)
18 (±3)
14 (±3)
10a
10b
O
2 2
; data in parenthesis are the experimental error. bDTT
1
a convenient procedure to access novel chalcogen-containing
L-ascorbic acid derivatives, we wished to investigate their Furthermore, particularly interesting are the results obtained
antioxidant properties. Pleasingly, according to the DPPH through the GSH/GR/NADPH coupled test, that better
assay, all the synthesised 6-O-ascorbyl esters exhibited reproduces the cellular environment (Figure 1). Indeed, under
1
8
remarkable chain breaking activity, leading to a rapid free these conditions the novel synthesised L-ascorbyl derivatives
radical quenching (complete decolouration of ethanolic DPP· exhibited GPx-like activity, thus demonstrating the effective
solution occurred within 3 seconds) and, thus, showing radical enhanced antioxidant properties of these novel amphiphilic
scavenger properties comparable to those of L-ascorbic acid, systems, thus offering new opportunities for their potentially
which represents the most powerful hydrophilic antioxidant. wide application in chemistry, biology, and materials science.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
Chem., Int. Ed., 2011, 50, 2125; (b) C. W. NoguVieewiraAr,ticGle.OZnelinnei
and J. B. T. Rocha, Chem. Rev., 2004, 104.
DOI: 10.1039/C9CC02427A
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(a) A. R. Patra, S. S. Roy, A. Basu, A. Bhuniya, A.
Bhattachariee, S. Hajra, U. H. Sk, R. Baral and S.
Bhattacharya, Sci. Rep., 2018, 8, 2194; (b) A. Angeli, D.
Tanini, A. Capperucci and C. T. Supuran, Bioorg. Chem., 2018,
7
6, 268; (c) A. Angeli, D. Tanini, A. Capperucci, G. Malevolti,
F. Turco, M. Ferraroni, C. T. Supuran, Bioorg. Chem., 2018,
8
1, 642; (d) A. Angeli, D. Tanini, A. Capperucci and C. T.
Supuran, ACS Med. Chem. Lett., 2017, 8, 1213.
6
7
(a) V. P. Singh, J. F. Poon and L. Engman, Org. Lett., 2013, 15,
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274.
Figure 1. NADPH-coupled GPx assay. Reaction conditions:
P. S. Vraka, C. Drouza, M. P. Rikkou, A. D. Odysseos and A. D.
Keramidas, Biorg. Med. Chem., 2006, 14, 2684.
[
0 0 2 2 0
NADPH] = 0.3 mM, [GSH] = 1.0 mM, [H O ] = 2.5 mM, [GR]
8
9
S. C. Welch and M. Gruber, J. Med. Chem., 1979, 22, 1532.
=
4 units per mL, [catalyst] = 0.1 mM in pH 7.4 phosphate
G.
Rodríguez‑Gutiérrez,
F.
Rubio‑Senent,
A.
buffer at ambient temperature. The mean ± SD values of three
separate experiments are reported.
Gómez‑Carretero, I. Maya,·J. Fernández‑Bolaños, G. G.
Duthie and B. de Roos, Eur. J. Nutr., 2018, doi:
1
0.1007/s00394-018-1733-y.
1
0 (a) S. F. Fonseca, D. B. Lima, D. Alves, R. G. Jacob, G. Perin, E.
Preliminary physicochemical characterisation of these
unreported amphiphilic antioxidants showed that most of
them behave as semicrystalline solids. The evolution of the
crystal and of the amorphous fraction depends on the thermal
history of the sample, a common behaviour of polymers. As an
example, the DSC curves obtained for 9c are reported in Fig. S1
J. Lenardão and L. Savegnago, New J. Chem., 2015, 39, 3043;
(b) I. L. Martins, C. Charneira, V. Gandin, J. L. Ferreira da
Silva, G. C. Justino, J. P. Telo, A. J. S. C. Vieira, C. Marzano and
A. M. M. Antunes, J. Med. Chem., 2015, 58, 4250; (c) D.
Tanini, L. Panzella, R. Amorati, A. Capperucci, E. Pizzo, A.
Napolitano, S. Menichetti and M. d’Ischia, Org. Biomol.
Chem., 2015, 13, 5757.
(see ESI). The crystalline fraction in 9c melted at about 75 °C
1
1 P. Albers, J. Pietsch and S. F. Parker, J. Mol. Catal. A: Chem.,
producing an endothermic peak with H = 21.6 J/g. When the
2
001, 173, 275.
melt was slowly cooled to -20 °C (at 5 °C/min), crystallisation 12 (a) C. Dolle, P. Magrone, S. Riva, M. Ambrosi, E. Fratini, N.
occurred producing an exothermic peak at about 35.5 °C with
Peruzzi and P. Lo Nostro, J. Phys. Chem. B, 2011, 115, 11638;
b) G. Carrea and S. Riva, Angew. Chem. Int. Ed., 2000, 39,
(
2

H = 28.2 J/g. The crystalline fraction was found to melt
22
between 40 °C and 100 °C upon heating. Instead, when the
sample was cooled quickly down to -20 °C (at 50 °C/min), no
crystallisation was shown, and a cold crystallisation exothermic
peak was detected in the following heating cycle followed by a
broad endothermic melting peak. Remarkably, while this
behaviour is typical for polymers, it is rather unusual for such
small molecules and may represent an opportunity for their
application in materials science.
In summary, we have found a convenient, green, mild, and
direct route to synthesise novel chalcogen-containing L-
ascorbyl derivatives, which would not have been accessible
through classic methodologies. Owing to their enhanced chain
breaking and catalytic antioxidant properties, these conjugate
1
3 (a) K. Nott, A. Brognaux, G. Richard, P. Laurent, A. Favrelle, C.
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Conflicts of interest
There are no conflicts to declare.
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Notes and references
0 A reasonable catalytic cycle is the following. Ring opening of
the oxidised lactone ring cannot be ruled out.
1
2
R. S. Pinnell, Yale J Biol Med., 1985, 58, 553.
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HO
O
2
015, 6, 397.
H2O2
H2
O
O
O
OH
O
O
H
H
L-Ascorbyl ester
6 or 8
X
X
3
(a) J. K. Andersen, Nat. Rev. Neurosci., 2004, 5, S18; (b) R. C.
S. Seet, C.-Y. J. Lee, E. C. H. Lima, J. J. H. Tan, A.M. L.Quek,
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and B. Halliwell, Free Radical Biol. Med., 2010, 48, 560.
R
O
R
O
n
O
O
n
O
O
OH
DTTox
+
H2O
OH
n = 1,2,3
X = Se, Te
H2O2
DTTred
O
H2O
4
(a) S. Yoshida, F. Kumakura, I. Komatsu, K. Arai, Y. Onuma, H.
Hojo, B. G. Singh, K. I. Priyadarsini and M. Iwaoka, Angew.
O
O
O
H
X
R
O
n
O
O
OH
4
| J. Name., 2012, 00, 1-3
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