Synthesis of (±)-aureol by bioinspired rearrangements

Article abstract of DOI:10.1021/jo502841u

A bioinspired and sustainable procedure for the straightforward synthesis of (±)-aureol has been achieved in eight steps (14% overall yield) from epoxyfarnesol. The key steps are the titanocene(III)-catalyzed radical cascade cyclization of an epoxyfarneso

Full text of DOI:10.1021/jo502841u

Article
pubs.acs.org/joc
Synthesis of ( )-Aureol by Bioinspired Rearrangements
Antonio Rosales,*,‡ Juan Munoz-Bascon,† Esther Roldan-Molina,† Nazaret Rivas-Bascon,†
́
́
̃
Natalia M. Padial,† Roman Rodríguez-Maecker,⊥ Ignacio Rodríguez-García,§ and J. Enrique Oltra*,†
†Department of Organic Chemistry, Faculty of Sciences, University of Granada, 18071 Granada, Spain
‡Department of Chemical and Environmental Engineering, Escuela Politec
́
nica Superior, University of Sevilla, 41011 Sevilla, Spain
§Química Organ
́
ica, CeiA3, Universidad de Almería, 04120 Almería, Spain
⊥Petrochemical Engineering, Universidad de las Fuerzas Armadas-ESPE, 050150 Latacunga, Ecuador
S
* Supporting Information
ABSTRACT: A bioinspired and sustainable procedure for the straightfor-
ward synthesis of ( )-aureol has been achieved in eight steps (14% overall
yield) from epoxyfarnesol. The key steps are the titanocene(III)-catalyzed
radical cascade cyclization of an epoxyfarnesol derivative and a biosyntheti-
cally inspired sequence of 1,2-hydride and methyl shifts.
approaches have too many steps or start from natural synthons
INTRODUCTION
■
which are not widely accessible.8−14
Many biologically active compounds, some of them having a
marine origin, are composed of a sesquiterpene unit linked to a
phenolic moiety.1 Prominent examples include (+)-aureol
(1),2,3 (+)-stachyflin (2),4 and (+)-strongylin A (3)5 (Figure
1). (+)-Aureol was originally isolated in 1980 by Faulker et al.2
In recent years, titanocene(III)-catalyzed radical cyclization
has become a powerful tool in organic synthesis.15−18 In fact,
this reaction has paved the way to the straightforward synthesis
of several terpenes.19
RESULTS AND DISCUSSION
■
As part of our ongoing efforts in the synthesis of biologically
active terpenoids of marine origin,20−23 we were interested in
the development of a new concise synthesis of aureol (1). It
was our intention to use the already proposed biosynthesis of
aureol (Scheme 1) as a guideline for our retrosynthetic analysis
(Scheme 2).
The biosynthesis of aureol (1) presumably involves the
stereoselective cyclization of polyene 4 to generate the tertiary
carbocation 5 (Scheme 1). This carbocation could then
undergo a sequence of stereospecific 1,2-hydride and methyl
shifts to produce another tertiary carbocation 6, which could be
stabilized by cyclization with the adjacent hydroquinone to give
aureol.
Inspired by this biosynthesis, we deemed that the synthesis of
aureol (1) could be efficiently achieved through a key
titanocene(III)-catalyzed cascade cyclization of the epoxyfarne-
sol derivate 7 and a new biogenetic-type rearrangement as the
pivotal step (Scheme 2).
Figure 1. Representative members of the aureol family of
sesquiterpenoid natural products.
from the caribbean sponge Smeonspongia aurea, and sub-
sequently in 2000 by Fattorusso and his co-workers3 from
another species of caribbean sponge, Verongula gigantea. The
aureol structure contains a compact tetracyclic ring system, with
four contiguous stereocenters and a cis-relationship between
the two cyclohexane rings of the decalin fragment. This marine
natural product has been shown to exhibit selective cytotoxicity
against A549 human nonsmall cell lung cancer cells (IC = 4.3
μg/mL)6 and anti-influenza-A virus activity (IC = 4.3 μg/mL).7
Beside the unique structural features and interesting variety
of biological activities of this group of compounds, there is still
a need for efficient synthetic methods, as the already described
In this way, our synthesis of aureol (1) (Scheme 3) started
with the epoxidation of farnesyl acetate following a previously
described procedure24 to form the epoxyfarnesol 7. One-pot
Received: December 16, 2014
Published: January 15, 2015
© 2015 American Chemical Society
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Scheme 1. Proposed Biosynthesis of Aureol
Scheme 2. Biosynthetically Inspired Retrosynthesis of Aureol
a
Scheme 3. Synthesis of Aureol (1) from Epoxyfarnesol (7)
a
Reagents and conditions: (a) (i) MsCl (1.3 equiv), Et3N (2.0 equiv), THF, 1 h; (ii) LiBr (5 equiv), 30 min, quantitative; (b) Li2CuCl4 (0.1 equiv),
C8H9O2MgBr (1.2 equiv), THF, 3 h at 0 °C, over night at rt, 97%; (c) Cp2TiCl (0.2 equiv), THF, 3 h, 48%; (d) DMAP (3.0 equiv), C6F5OC(S)Cl
(2.0 equiv), CH2Cl2, 5 h 30 min, quantitative; (e) AIBN (0.2 equiv), n-Bu3SnH (3.0 equiv), benzene, 4 h, 86%; (f) BF3·Et2O (5.0 equiv), CH2Cl2, 5
h, 63%; (g) (i) AgO (2.0 equiv), 6 N HNO3 (3.0 equiv), 1,4-dioxane, rt, 15 min; (ii) Pd/C (0.05 equiv), H2 (1 atm), CHCl3, 25 min, 82%; (h) BF3·
Et2O (4.5 equiv), CH2Cl2, 3 h, 62%.
mesylation of compound 7 with MsCl in Et3N at −40 °C and
subsequent addition to the reaction medium of LiBr at 0 °C
afforded a quantitative yield of the bromide 8. Condensation of
8 with 2,5-dimethoxyphenylmagnesium bromide using sub-
stoichiometric amounts of Li2CuCl4 gave a 97% yield of the
epoxyfarnesol derivate 9, previously described as the starting
material in our synthesis of zonarol.21
radical reaction gave the trans-fused decalin 10 bearing a crucial
exocyclic double bond on C-8, although in a moderate 48%
yield. The cyclization proceeds with high regio- and stereo-
selectivity, and the yield can be regarded as satisfactory, if it is
considered that the new compound has four stereocenters with
a defined relative configuration. Previous theoretical and
experimental evidence suggested that this radical cyclization
proceeds through a nonconcerted fashion via discrete carbon-
centered radicals.17 Assuming the nonconcerted nature or this
The first key step was, as proposed, the titanocene(III)-
catalyzed cascade cyclization of epoxyfarnesol derivate 9. This
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Scheme 4. Proposed Reaction Mechanism for the BF3·Et2O-Mediated Rearrangement of 12 to 13 and 15
radical cyclization, the stereoselectivity observed can be
explained in terms of Beckwith−Houk rules described else-
where.25 Deoxygenation of alcohol 10 was achieved by means
of the reduction of its thiocarbonate derivate.26 Thus, treatment
of alcohol 10 with DMAP and C6F5OC(S)Cl in CH2Cl2
yielded quantitatively the thiocarbonate 11. Subsequent
reduction with n-Bu3SnH and AIBN in benzene gave the
deoxygenated derivate 12 in 86% yield.
late deprotection of 13 was also unfruitful, as only the
monodeprotected product was formed. A significant improve-
ment was made through a two-step oxidative (AgO, HNO3)/
reductive (Pd/C, H2) sequence, following the procedure
reported by Wright et al.28 in the synthesis of (+)-frondosin
A. Under these reaction conditions, the dihydroquinone 14 was
1
obtained in 82% yield. The H NMR data of this synthetic
compound 14 was identical to those reported by Faulkner et
al.2 Finally, the phenolic compound 14 was treated with BF3·
Et2O using the same reaction conditions as described by
George et al. for the synthesis of (+)-aureol.14 In our hands,
this cyclization afforded aureol (1) in a gratifying 62% yield.
Spectroscopic data for synthetic aureol (1) were identical to
those of the natural compound.2
The remarkable stereocontrolled BF3·Et2O rearrangement of
12 to give 13 can be rationalized by the mechanistic route
shown in Scheme 4. The process is, to the best of our
knowledge, the first example of an acid-mediated rearrange-
ment of a labdane derivate bearing an exo-olefin at C-8. The
reaction process would involve four possible carbocationic
intermediates such as I, II, III, and IV. Thus, the first
coordination−activation between the Lewis acid and the C-8
exo-olefin moiety in 12 would lead to the formation of the
intermediate I, which would suffer a 1,2-hydride shift from the
C-9 position to the C-8 carbocation to provide the intermediate
II. This carbocationic species II would lead to the intermediate
III via migration of the C-9 methyl group to the C-8
carbocation center. Stabilization of the intermediate III by
proton loss gives the tetrasubstituted alkene 14. On the other
The second key step in our synthesis of aureol (1) was the
BF3·Et2O-mediated rearrangement of 12 to the tetrasubstituted
olefin 13 which proceeded via stereospecific 1,2-hydride and
methyl shifts. The reaction afforded the desired compound 13
in 63% yield, together with a minor compound 15 in 30% yield.
Formation of 13 was confirmed by the presence of three
singlets at 1.02, 0.99, and 0.93 ppm characteristic of methyl
groups and one doublet at 0.79 due to the methyl group on C-8
1
in the H NMR spectrum. The 13C NMR of this compound
showed two quaternary signals at 132.6 and 129.6 ppm
characteristic of the Δ5,10 internal carbon−carbon double bond.
The 1H and 13C NMR spectra of the synthetic 15 were
identical to those reported.27 The exocyclic double bond on C-
8 of the compound 10 again has been of paramount importance
to complete the synthesis of aureol (1). A similar exocyclic
olefin was functionalized with formation of a C−O bond in the
synthesis of puupehedione and its epimer, as reported by
Gansauer et al.20
̈
Attempts to deprotect the methoxy groups in 13 with CAN/
Na2SO4 proved to be ineffective, as only a disappointing 25%
product could be recovered. The reported sodium ethanethio-
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(CH3), 16.0 (CH3); HRMS (ESI): calculated for C23H35O3 [M + H]+:
359.2586; found: 359.2593.
hand, this intermediate III could suffer a 1,2-hydride shift from
the C-1 position to the C-10 carbocation to provide the
intermediate IV, which can react with the aromatic ring to form
the tetracyclic compound 15.
Cp2TiCl-Catalyzed Cyclization of Epoxyfarnesol Derivate 9.
THF (15 mL) was added to a mixture of [TiCp2Cl2] (50 mg, 0.2
mmol) and Mn dust (440 mg, 8.0 mmol) under Ar, and the
suspension was stirred at room temperature until it turned green
(about 15 min). Then a solution of 2,4,6-collidine (0.9 mL, 7.0 mmol)
and Me3SiCl (0.5 mL, 4.0 mmol) in THF (5 mL) was added, the
mixture was stirred for 5 min, a solution of 9 (358.3 mg, 1 mmol) in
THF (5 mL) was added, and the mixture was stirred at room
temperature for 3 h. Then 2 N HCl was added, and the mixture was
extracted with Et2O. The combined organic layers were dried with
Na2SO4 anhydrous, and the solvent was removed. The residue was
dissolved in THF, and a 1 M solution of n-Bu4NF in THF (1.2 mmol)
was added. The new mixture was stirred for 30 min, diluted with Et2O,
and washed with brine. The organic layer was dried with Na2SO4
anhydrous and the solvent removed. The residue was purified by flash
chromatography (hexane/AcOEt 9:1) to yield 172.1 mg of the
cyclization compound 10 (48%). IR, NMR, and HRMS of compound
10 were consistent with that of the original isolation literature.21
Synthesis of Xanthate 11. O-Pentafluorophenyl chlorothiofor-
mate (523.2 mg, 2.0 mmol) was added to a stirred solution of 10
(358.5 mg, 1.0 mmol) and DMAP (362.8 mg, 3.0 mmol) in CH2Cl2
(7.0 mL) at 0 °C, and the solution was stirred at room temperature for
5 h 30 min. Then AcOEt was added, the mixture was washed with
water, the organic layer was dried with anhydrous Na2SO4, and the
solvent was removed. The residue was purified by flash chromatog-
raphy (hexane/AcOEt 98:2) to yield 578.8 mg of the xanthate 11
(99%) as a colorless oil. IR, NMR, and HRMS of compound 11 were
consistent with that of the original isolation literature.21
CONCLUSIONS
■
In summary, we have described a novel procedure for the
straightforward synthesis of bioactive aureol (1). The key steps
are the titanocene(III)-catalyzed radical cascade cyclization of
epoxyfarnesol (7) and a new biomimetic sequence of 1,2-
hydride and methyl shifts. Further applications of the
cyclization/rearrangement strategy to the synthesis of bio-
logically important natural products possessing monocyclic,
bicyclic, tricyclic, and tetracyclic skeletons and the nonracemic
synthesis or aureol (1) using a chiral epoxyfarnesol 7 are
currently under investigation and will be reported in due
course.
EXPERIMENTAL SECTION
■
General Methods. All chemicals used were purchased from
commercial suppliers and used as received. All organic extracts were
dried over anhydrous sodium sulfate. Products were purified by flash
chromatography on Merck silica gel 50.Visualization was aided by
viewing under a UV lamp and staining with CAM stain followed by
heating. Infrared spectra were recorded using a FT-IR system
spectrometer as the neat compounds. 1H and 13C NMR spectra
were recorded on 600, 500, and 300 MHz spectrometers. The NMR
solvent used was CDCl3 unless otherwise specified. 1H chemical shifts
are reported in ppm on the δ-scale relative to chloroform (δ 7.26), and
13C NMR are reported in ppm relative to chloroform (δ 77.0).
Multiplicities are reported as (br) broad, (s) singlet, (d) doublet, (t)
triplet, (q) quartet, (qnt) quintet, (sxt) sextet, and (m) multiplet. All J
values were rounded to the nearest 0.5 Hz. Mass spectra were
recorded by LC-QTof-MS by electrospray ionization.
Synthesis of Compound 12. The xanthate 11 (585 mg, 1.0
mmol) was dissolved in benzene (10 mL), AIBN (33 mg, 0.2 mmol)
and n-Bu3SnH (0.8 mL, 3.0 mmol) were added, and the mixture was
stirred at reflux for 4 h. Then the solvent was removed. The residue
was purified by flash chromatography (hexane/AcOEt, 99:1) to yield
294.6 mg of the product 12 (86%) as a colorless oil. IR, NMR, and
HRMS of compound 12 were consistent with that of the original
isolation literature.21
Preparation of Bromide 8. Et3N (0.29 mL, 2.0 mmol) and MsCl
(0.1 mL, 1.3 mmol) were added to a cooled solution of 7 (238.4 mg,
1.0 mmol) in dry THF (6.5 mL) in a nitrogen atmosphere at −40 °C.
The reaction mixture was stirred a −40 °C for 1 h. To the resulting
mesylate solution was added LiBr (400 mg, 5.0 mmol) in dry THF
(2.5 mL) at −40 °C. The reaction mixture was stirred at 0 °C for 30
min. After adding aq NH4Cl and EtOAc, the reaction mixture was
extracted with EtOAc (40 mL). The combined organic extract was
washed with saturated brine, dried over anhydrous Na2SO4, and
concentrated in vacuum to afford 298.3 mg of the crude product 8
(99%), isolated as a colorless oil. IR, NMR, and HRMS of compound
8 were consistent with that of the original isolation literature.29
Synthesis of Epoxyfarnesol Derivate 9. A 0.1 M solution of
Li2CuCl4 in THF (0.4 mL, 0.04 mmol) was added dropwise to a
solution of the compound 8 (300.1 mg, 1.0 mmol) in THF (9 mL) at
0 °C. Then a solution of 2,5-dimethoxyphenylmagnesium bromide
(2.4 mL, 1.2 mmol) was added dropwise over 20 min. The mixture
was stirred at 0 °C for 3 h and then at room temperature overnight.
Saturated aq NH4Cl was added, the mixture was extracted with EtOAc,
the extract was dried over anhydrous Na2SO4, and the solvent was
removed. The residue was purified by flash chromatography (hexane/
AcOEt 9:1) to yield 347.5 mg of the coupling product 9 (97%),
isolated as a colorless oil.
BF3·Et2O-Mediated Rearrangement of 12. Compound 12
(342.5 mg, 1.0 mmol) was dissolved in CH2Cl2 (100 mL). The
solution was cooled to −50 °C, and BF3·Et2O (0.7 mL, 5.0 mmol) was
added. Then the solution was gradually warmed up to −5 °C. After 5
h, the stirring was stopped and the solvent removed. The crude
product was dissolved in Et2O and washed with brine. The organic
layer was dried, and the solvent was removed in vacuum. The residue
was purified by flash chromatography (cyclohexane) to yield 215.8 mg
of the product 13 (63%) together with byproduct 15 (98.6 mg, 30%).
IR, NMR, and HRMS of compound 15 were consistent with that of
the original isolation literature.26
Data for compound 13: mp 58−61 °C; IR (film) νmax 1592, 1490,
1239, 1461 cm−1; 1H NMR (500 MHz, CDCl3): δ 6.87 (d, J = 3.1 Hz,
1H), 6.75 (d, J = 8.8 Hz, 1H), 6.68 (dd, J = 8.8, 3.1 Hz, 1H), 3.76 (s,
3H), 3.73 (s, 3H), 2.93 (d, J = 15.2 Hz, 1H), 2.62 (d, J = 15.2 Hz, 1H),
2.09−2.01 (m, 4H), 1.96−1.90 (m, 1H), 1.69−1.58 (m, 4H), 1.39−
1.32 (m, 2H), 1.01 (s, 3H), 1.00 (s, 3H), 0.92 (s, 3H), 0.79 (d, J = 6.8
Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 152.9 (C), 152.2 (C),
135.6 (C), 132.6 (C), 129.6 (C), 116.4 (CH), 110.8 (CH), 110.7
(CH), 55.7 (CH3), 55.5 (CH3), 41.4 (C), 39.7 (CH2), 34.5 (CH2),
34.2 (C), 33.3 (CH), 28.2 (CH3), 28.0 (CH3), 26.6 (CH2), 26.2
(CH2), 23.4 (CH2), 21.9 (CH3), 19.8 (CH2), 15.9 (CH3); HRMS
(ESI): calculated for C23H35O2 [M + H]+: 343.2637; found: 343.2645.
Deprotection of the Methyl Ether Groups in 13. To a flame-
dried flask was added alkene 13 (328.2 mg, 1.0 mmol) in dioxane (26
mL). The solution was sequentially treated with AgO (250 mg, 2.0
mmol) and 6 N HNO3 (0.47 mL, 3.0 mmol). The reaction was stirred
for 15 min at room temperature before being quenched by the
addition of saturated aq NaHCO3 and diluted with Et2O. The aqueous
layer was extracted with Et2O (2 × 10 mL), and the combined organic
layers were washed with H2O (3 × 20 mL) and brine (2 × 20 mL),
dried, over Na2SO4, concentrated, and used without further
1
Data for compound 9: IR (film) νmax 1588, 1253, 1240 cm−1 ; H
NMR (500 MHz, CDCl3): δ 6.79−6.67 (m, 3H), 5.30 (t, J = 7.1 Hz,
1H), 5.17 (t, J = 7.1 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.31 (d, J =
7.3 Hz, 2H), 2.69 (t, J = 6.3 Hz, 1H), 2.16−2.02 (m, 8H), 1.70 (s,
3H), 1.61 (s, 3H), 1.29 (s, 3H), 1.25 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 153.6 (C), 151.6 (C), 136.3 (C), 134.1 (C), 131.4 (C),
124.8 (CH), 122.2 (CH), 116.0 (CH), 111.1 (CH), 110.4 (CH), 64.2
(CH), 58.3 (C), 56.0 (CH3), 55.6 (CH3), 39.7 (CH2), 36.3 (CH2),
28.2 (CH2), 27.4 (CH2), 26.6 (CH2), 24.9 (CH3), 18.7 (CH3), 16.1
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purification. The crude quinone obtained above was dissolved in
CHCl3 (30 mL). To the solution was added 10% Pd/C (110 mg, 0.05
mmol), and the flask was evacuated and backfilled with H2 (three
cycles). The reaction mixture was stirred under an atmosphere of H2
(balloon) for 15 min before being filtered through a pad of SiO2
eluting with Et2O (3.0 mL). The solvent was removed under vacuum,
and the residue was purified by flash chromatography (hexane/AcOEt,
95:5) to give 258 mg of product 14 (82%) as a white foam. IR, NMR,
and HRMS of compound 14 were consistent with that of the original
isolation literature.2
(12) Watanabe, K.; Sakurai, J.; Abe, H.; Katoh, T. Chem. Commun.
2010, 46, 4055.
(13) Ngoc, D. T.; Albicker, M.; Schneider, L.; Cramer, N. Org.
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Lett. 2012, 14, 4710.
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Chem. 2002, 67, 2566.
(16) Barrero, A. F.; Rosales, A.; Cuerva, J. M.; Oltra, J. E. Org. Lett.
2003, 5, 1935.
Synthesis of Aureol (1). To a solution of hydroquinone 14 (314.2
mg, 1.0 mmol) in anhydrous CH2Cl2 (100 mL) at −60 °C was added
BF3·Et2O (0.56 mL, 4.5 mmol). The reaction mixture was stirred for 3
h at −60 °C, warmed to −20 °C, and then quenched with saturated
NH4Cl solution. The mixture was then extracted with CH2Cl2 (3 × 20
mL). The organic phases were combined, dried over Na2SO4, filtered,
and concentrated in vacuum. The crude material was purified by flash
column chromatography (hexane/AcOEt 9:1) to give aureol (1) as a
white solid (195 mg, 62%). IR, NMR, and HRMS of aureol (1) were
consistent with that of the original isolation literature.2
(17) Justicia, J.; Rosales, A.; Bunuel, E.; Oller-Lop
́
ez, J. L.; Valdivia,
̃
M.; Haïdour, A.; Oltra, J. E.; Barrero, A. F.; Car
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denas, D. J.; Cuerva, J.
M. Chem.Eur. J. 2004, 10, 1778.
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(18) Justicia, J.; Alvarez de Cienfuegos, L.; Estev
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M.; Lasanta, A. M.; Oller, J. L.; Rosales, A.; Cuerva, J. M.; Oltra, J. E.
Tetrahedron 2008, 64, 11938.
́
(19) Justicia, J.; Alvarez de Cienfuegos, L.; Campana, A. G.; Miguel,
̃
D.; Jakoby, V.; Gansauer, A.; Cuerva, J. M. Chem. Soc. Rev. 2011, 40,
̈
3525.
(20) Gansauer, A.; Rosales, A.; Justicia, J. Synlett 2006, 6, 927.
̈
(21) Gansauer, A.; Justicia, J.; Rosales, A.; Worgull, D.; Rinker, B.;
̈
ASSOCIATED CONTENT
Cuerva, J. M.; Oltra, J. E. Eur. J. Org. Chem. 2006, 4115.
■
́
́ ́
ez-Sanchez, C.; Alvarez-Corral, M.; Munoz-
̃
(22) Rosales, A.; Lop
Dorado, M.; Rodríguez-García, I. Lett. Org. Chem. 2007, 4, 553.
(23) Rosales, A.; Munoz-Bascon, J.; Morales-Alcazar, V. M.; Castilla,
J. A.; Oltra, J. E. RSC Adv. 2012, 2, 12922.
S
* Supporting Information
1
Copies of H NMR spectra for compounds 1 and 8−15 and
́
́
̃
13C NMR spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(24) Snyder, S. A.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 740.
(25) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; VCH: Weinheim, 1995.
(26) Zard, S. Z. In Radical in Organic Synthesis; Renaud, P.; Mukund,
P. S.; Renaud, P.; Mukund, P. S., Eds.; Wiley-VCH: Weinheim, 2001;
Vol. 1, p 90.
(27) Urban, S.; Capon, R. J. Aust. J. Chem. 1994, 47, 1023.
(28) Oblak, E. Z.; VanHyst, M. D.; Li, J.; Wiemer, A. J.; Wright, D. L.
J. Am. Chem. Soc. 2014, 136, 4309.
(29) Colombo, L.; Gennari, C.; Potenza, D.; Scolastico, C.;
Aragozzini, F.; Gualandris, R. J. Chem. Soc., Perkin Trans. 1 1982, 2,
365.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: arosales@us.es.
■
*Fax: (+34) 958248437. E-mail: joltra@ugr.es.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Spanish MICINN (Projects CTQ2008-06790, CTQ2010-
17115 and CTQ2011-24443) and the Regional Government of
Andalucia (Projects P07-FQM-3213 and P10-FQM-6050) are
acknowledged for financial support. A. Rosales acknowledges
University of the Sevilla for his position as professor.
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