A straightforward preparation of primary alkyl triflates and their utility in the synthesis of derivatives of ethidium

Article abstract of DOI:10.1039/a908389h

The reaction of primary alcohols with trifluoromethanesulfonic anhydride in the presence of poly(4-vinylpyridine) [or poly(2,6-di-tert-butyl-4-vinylpyridine)] allows the isolation of the corresponding alkyl triflates in good yields. The quaternisation of

Full text of DOI:10.1039/a908389h

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A straightforward preparation of primary alkyl triflates and their
utility in the synthesis of derivatives of ethidium
Steven A. Ross, Marguerite Pitié and Bernard Meunier*
1
Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne,
31077 Toulouse Cedex 4, France
Received (in Cambridge, UK) 29th October 1999, Accepted 2nd December 1999
The reaction of primary alcohols with trifluoromethanesulfonic anhydride in the presence of poly(4-vinylpyridine)
[or poly(2,6-di-tert-butyl-4-vinylpyridine)] allows the isolation of the corresponding alkyl triflates in good yields.
The quaternisation of 3,8-bis(ethoxycarbonylamino)-6-phenylphenanthridine (1) using these alkyl triflates was found
to proceed smoothly at room temperature in nitrobenzene or chlorobenzene. Deprotection of these quaternary
compounds using concentrated hydrobromic acid was found to be a more useful procedure than the previously
reported use of concentrated sulfuric acid. The synthesis of the novel ethidium derivative 3,8-diamino-5-(5-
aminopentyl)-6-phenylphenanthridinium bromide (12) is reported.
carbonylamino) (BOC) derivative of 3,8-diamino-6-phenyl-
phenanthridine. However, the synthesis of this material from
Introduction
The binding of polyaromatic heterocyclic compounds to
the parent aromatic diamine and di-tert-butyl dicarbonate was
nucleic acids by insertion between adjacent base pairs (or
very low yielding after chromatographic separation. Several
“intercalation”) was first proposed by Lerman in 1961.1 This
authors have reported synthetic difficulties in the preparation
phenomenon is exhibited by a wide range of synthetic and
of BOC derivatives of aromatic amines due to side reactions,
naturally occurring derivatives, including acridines,2 some
such as bis-carbamoylation, urea formation and decomposition
antibiotics3 and certain DNA groove-binding proteins.4 3,8-
to isocyanates.11 We therefore reverted to the previously
Diamino-5-ethyl-6-phenylphenanthridinium (or “ethidium”)
reported high-yielding synthesis of 3,8-bis(ethoxycarbonyl-
bromide was one of the first intercalators to be studied.5
amino)-6-phenylphenathridine (1).6 Quaternisation of this
This compound exhibits anti-trypanosomal activity and is also
compound has been reported using tosylate esters in nitro-
widely used as a nucleic acid staining agent, due to the sig-
nificant fluorescence enhancement which it exhibits upon
intercalation.
benzene at 155 ЊC. We wished to pursue the alkylation of this
compound under less harsh conditions and so we investigated
the reaction of trifluoromethanesulfonic acid esters under
ambient conditions.
Trifluoromethanesulfonic acid esters are usually prepared via
the reaction of the corresponding alcohol with triflic anhydride
at low temperature in the presence of a non-nucleophilic base.
The extreme electrophilicity of alkyl triflates can preclude the
Since the first early reports on the synthesis of ethidium
bromide,6 there has been a general lack of data on the prepar-
ation of its derivatives. This perhaps reflects some of the syn-
thetic difficulties involved with this class of compound.
Hertzberg and Dervan7 have reported the synthesis of an
Fe()–EDTA derivative of ethidium (MPE) where functionaliz-
ation was achieved through a carboxylate group at the para
position of the 6-phenyl ring. MPE is used as a footprinting
use of pyridine as the base in their preparation, due to alkyl-
ation of pyridine.12 This has necessitated the use of hindered
bases (such as 2,6-di-tert-butyl-4-methylpyridine) in some
agent, through its ability to generate hydroxyl radicals in the
instances. During the reaction of ethyl 6-hydroxyhexanoate
close vicinity of DNA via a Fenton-type reaction.8 Several
with triflic anhydride in the presence of 2,6-di-tert-butyl-4-
other derivatives have been reported where the exocyclic amino
methylpyridine, we found that our product was contaminated
groups of ethidium have been targeted as the starting points for
with the hindered base. Since alkyl triflates are not particularly
stable, we prepared the esters prior to use and purified them by
column chromatagraphy each time. Poly(2,6-di-tert-butyl-4-
vinylpyridine) thus appeared a logical choice of base to use in
this reaction, due to its ease of removal as the triflate salt by
filtration. Indeed, reaction of ethyl 6-hydroxyhexanoate with 1
equivalent of triflic anhydride in the presence of 2 equivalents
of hindered polymer base in dichloromethane at room temper-
ature afforded the alkyl triflate in 91% yield after filtration,
washing with bicarbonate solution and evaporation of solvent.
The same reaction can be carried out using poly(vinylpyrid-
ine) as the polymer-bound base, which also affords the alkyl
triflates in yields of around 90%. The much lower cost of poly-
(vinylpyridine) makes this a more interesting synthetic tool.
further functionalization.9 It should be stressed, however, that
the attachment of a novel group to an ethidium derivative will
have an effect upon the DNA binding orientation and, in par-
ticular, the orientation of the attached group with respect to
DNA. Such considerations will be very important if the
attached group is expected to have preferred reactivity in the
major or minor grooves.
We were interested in developing a strategy for preparing
derivatives where the point of attachment was via the quater-
nary nitrogen atom, partly since there has only been one deriv-
ative of this type previously reported,10 and we were interested
in the synthetic opportunities which would be made available by
such an approach.
Alkylation of vinylpyridine using primary alkyl triflates has
been reported previously to be extremely rapid at room
temperature.13 However, it would appear that alkylation of
poly(vinylpyridine) is sufficiently slow to be a negligible side-
reaction under our conditions.
Results and discussion
Preparation of alkyl triflates
Our initial approach was to prepare the bis(tert-butoxy-
DOI: 10.1039/a908389h
J. Chem. Soc., Perkin Trans. 1, 2000, 571–574
This journal is © The Royal Society of Chemistry 2000
571

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Alkyl triflates of eight different primary alcohols were
prepared to test the general utility of this reaction. These
comprised N-tert-butoxycarbonyl-6-aminohexanol, N-tert-but-
oxycarbonyl-4-aminobutanol, N-ethoxycarbonyl-6-aminohex-
anol, butanol (alkyl triflate 2), ethyl 6-hydroxyhexanoate (ester
3), N-(5-hydroxypentyl)phthalimide (ester 4), 5-(trifluoroacet-
amido)pentanol (ester 5) and 3-(tert-butyldimethylsilyloxy)-
propanol (ester 6). Five of these eight alcohols 2–6 gave clean
Deprotection was observed with concentrated hydrobromic
acid at reflux overnight. This has the advantage that the acid is
easily removed under reduced pressure, unlike conc. sulfuric
acid. Reaction of butyl quaternary derivative 7 with conc. HBr,
followed by removal of solvent and purification by chromato-
graphy afforded ethidium analogue 11 in 90% yield, which was
confirmed by comparison of the 1H NMR sample with a
commercial sample of ethidium bromide.
1
However, on several occasions an unusual impurity was
observed in large excess, which exhibited a triplet with a coup-
conversion to the alkyl triflates (as monitored by H NMR)
without any need to purify the product. The only exceptions
were the carbamate derivatives, which showed up to 30% of
impurities by NMR. These impurities are probably due to acid
catalysed hydrolysis of the carbamate groups. Alternatively, the
carbamate N atom may be sufficiently nucleophilic to undergo
an intramolecular reaction with the alkyl triflate. For example,
Nicolaou and co-workers14 have reported the nucleophilic dis-
placement of primary alkyl triflates by the nitrogen atom of the
trifluoroacetamido group.
1
ling constant of 51 Hz in the H NMR spectrum. This was
attributed to the decomposition of the triflate anion to give
difluoromethanesulfonate, which is consistent with the 19F–1H
geminal coupling constant observed. Repeated chromato-
graphy could not remove this product. This problem was
overcome by exchanging the counter-ion to bromide prior to
reaction with concentrated HBr.
Our interests lay in the preparation of an ethidium derivative
where further functionalisation could be readily achieved via
the presence of an appropriate group on the alkyl chain
attached to the quaternary nitrogen. A primary amine was
chosen, since this would be a much better nucleophile than the
aromatic amines at the 3 and 8 positions, which are known to
be very poor nucleophiles (reaction of ethidium bromide with
glutaric anhydride gives incomplete substitution after 48 h at
70 ЊC in DMF).9 Reaction of the bromide salt of 10 with conc.
HBr at reflux for 12 hours, followed by removal of solvent and
purification by chromatography gave the expected product 12 as
Alkylation reactions
Initial attempts to react alkyl triflates 2–5 with 1 at elevated
temperatures gave a complex mixture of products. However, the
reactions were found to proceed smoothly with yields of around
60% at room temperature in nitrobenzene or chlorobenzene, to
give the quaternary triflate salts 7–10. These mild conditions
a hygroscopic solid, which represents a useful starting material
for the synthesis of ethidium derivatives.
contrast with the previously reported reaction of alkyl tosylates
at 155 ЊC.6 Protonated 1Hϩ CF3SO3Ϫ was found to be the other
component in the reaction mixture, presumably formed by elim-
ination of triflic acid from the esters. No other products were
observed.
Experimental
1H NMR spectra were recorded on a Bruker AC 250 instrument
running at 250.134 MHz. Methylene groups adjacent to the
quaternary phenanthridinium centre are labelled as NquatCH2
for assignment.
Deprotection studies
The aromatic ethyl carbamate protecting groups in this class of
compounds are normally removed by heating in conc. sulfuric
acid at 120 ЊC for 2 hours, followed by neutralisation and pre-
cipitation.6 However, we found that isolation of our products
from conc. sulfuric acid was problematic and thus we tried a
range of acids as alternatives. No deprotection was observed
with trifluoroacetic acid, either at room temperature or at
reflux, nor with concentrated hydrochloric acid at reflux.
All chemicals were used as supplied unless stated. Trifluoro-
methanesulfonic anhydride was freshly prepared prior to use by
distillation of a 1:1 w/w mixture of trifluoromethanesulfonic
acid and phosphorus pentoxide.15 N-tert-Butoxycarbonyl-
6-aminohexanol,16 N-tert-butoxycarbonyl-4-aminobutanol,16
5-(trifluoroacetamido)pentanol,17 N-(5-hydroxypentyl)phthal-
imide18 and 3-(tert-butyldimethylsilyloxy)propanol19 were pre-
pared according to literature methods. CAUTION: ethidium
572
J. Chem. Soc., Perkin Trans. 1, 2000, 571–574

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and its derivatives are believed to be carcinogenic; appropriate
care should be taken when dealing with these products.
NMR (CD2Cl2): 0.81 (3H, t, J = 7 Hz, CH3), 1.24 (3H, t, J = 7
Hz, CH3), 1.35 (3H, t, J = 7 Hz, CH3), 1.37 (2H, m, CH2), 1.94
(2H, br m, CH2), 4.13 (2H, q, J = 7 Hz, CH2OCO), 4.27 (2H, q,
J = 7 Hz, CH2OCO), 4.72 (2H, br t, J = 8 Hz, NquatCH2), 7.48
(1H, d, J = 2 Hz, ArH), 7.51 (1H, d, J = 2 Hz, ArH), 7.77–7.88
(5H, m, ArH), 8.19 (1H, dd, J = 9, 2 Hz, ArH), 8.25 (1H, dd,
J = 9, 2 Hz, ArH), 8.58 (1H, d, J = 9 Hz, ArH), 8.65 (1H, d,
J = 9 Hz), 8.74 (1H, s, NH) and 8.92 ppm (1H, s, NH); FAB-MS
486 (Mϩ cation, 100%) (Found: C, 51.9; H, 4.7; N, 5.7.
C30H32F3N3O7SؒCH2Cl2 requires: C, 51.7; H, 4.7; N, 5.8%).
3,8-Bis(ethoxycarbonylamino)-6-phenylphenanthridine (1)
This was prepared according to the method described by
Watkins.6 The 1H NMR data is included here for completeness,
since this has not been previously reported. 1H NMR (DMSO-
d6): 1.33 (3H, t, J = 7 Hz, CH3), 1.40 (3H, t, J = 7 Hz, CH3), 4.23
(2H, q, J = 7 Hz, CH2), 4.30 (2H, q, J = 7 Hz, CH2), 7.68 (3H,
m, ArH), 7.80 (2H, m, ArH), 7.95 (1H, dd, J = 9, 1 Hz, ArH),
8.09 (1H, dd, J = 9, 1 Hz, ArH), 8.32 (1H, d, J = 1 Hz, ArH),
8.43 (1H, d, J = 1 Hz, ArH), 8.75 (1H, d, J = 9 Hz, ArH), 8.84
(1H, d, J = 9 Hz, ArH), 10.12 (1H, s, NH) and 10.15 ppm (1H,
s, NH); FAB-MS: 429 (Mϩ, 100%).
3,8-Bis(ethoxycarbonylamino)-5-(5-ethoxycarbonylpentyl)-6-
phenylphenanthridinium trifluoromethanesulfonate (8). Yield 454
1
mg, 63%; H NMR (DMSO-d6): 1.31 (3H, t, J = 7 Hz, CH3),
1.35 (3H, t, J = 7 Hz, CH3), 1.42 (3H, t, J = 7 Hz, CH3), 1.3–1.5
(4H, m, CH2CH2), 2.08 (2H, br m, CH2), 2.32 (2H, t, J = 6 Hz,
CH2COOEt), 4.14 (2H, q, J = 7 Hz, CH2OCO), 4.19 (2H, q,
J = 7 Hz, CH2OCO), 4.34 (2H, q, J = 7 Hz, CH2OCO), 4.64
(2H, br t, J = 8 Hz, NquatCH2), 7.8–8.0 (6H, m, ArH), 8.22 (1H,
dd, J = 9, 2 Hz, ArH), 8.34 (1H, dd, J = 9, 2 Hz, ArH), 8.78
(1H, s, ArH), 9.12 (1H, d, J = 9 Hz, ArH), 9.19 (1H, d, J = 9 Hz,
ArH), 10.39 (1H, s, NH) and 10.67 ppm (1H, s, NH); FAB-MS
572 (Mϩ cation, 100%) (Found: C, 47.1; H, 4.1; N, 4.8. C34H38-
F3N3O9Sؒ³CH2Cl2 requires: C, 47.1; H, 4.7; N, 4.7%).
Preparation of alkyl triflates
The following general procedure was employed. Poly(vinylpyrid-
ine) (220 mg, 2 mmol) was added to dichloromethane (5 mL),
followed by trifluoromethanesulfonic anhydride (282 mg, 1
mmol). The primary alcohol (0.95 mmol) was then added (as
a solution in dichloromethane) in a dropwise fashion over
1 minute at room temperature. The reaction mixture was stirred
for 5 minutes, then filtered under gravity. The poly(vinylpyridin-
ium triflate) precipitate was washed with 2 mL of dichloro-
methane. The combined organics were washed once with
saturated NaHCO3 solution, dried (MgSO4) and concentrated
under vacuum to give the products as colourless oils, which
gave a pinkish hue upon standing. Dichloromethane solutions
of the products became black over time. The methylene group
adjacent to the alkyl triflate gives a characteristic triplet at
approximately 4.5 ppm in the 1H NMR spectrum, compared to
the starting alcohols, where the corresponding methylene group
is observed at approximately 3.5 ppm.
¯
²
3,8-Bis(ethoxycarbonylamino)-6-phenyl-5-(5-phthalimido-
pentyl)phenanthridinium trifluoromethanesulfonate (9). Yield
1
452 mg, 57%; H NMR (DMSO-d6): 1.31 (3H, t, J = 7 Hz,
CH3), 1.35 (3H, t, J = 7 Hz, CH3), 1.4 (2H, m, CH2), 1.56 (2H,
br m, CH2), 2.09 (2H, br m, CH2), 3.61 (2H, t, J = 6 Hz, CH2N-
[phthalimide]), 4.18 (2H, q, J = 7 Hz, CH2OCO), 4.27 (2H, q,
J = 7 Hz, CH2OCO), 4.64 (2H, br t, J = 8 Hz, NquatCH2), 7.87
(5H, s, ArH), 7.91 (1H, d, J = 2 Hz, ArH), 7.89 (4H, s, ArH-
[phthalimide]), 8.24 (1H, dd, J = 9, 2 Hz, ArH), 8.36 (1H, dd,
J = 9, 2 Hz, ArH), 8.76 (1H, s, ArH), 9.13 (1H, d, J = 9 Hz,
ArH), 9.19 (1H, d, J = 9 Hz, ArH), 10.39 (1H, s, NH) and 10.62
ppm (1H, s, NH); FAB-MS 645 (Mϩ cation, 100%) (Found: C,
58.8; H, 4.6; N, 6.7. C39H37F3N4O9S requires: C, 58.9; H, 4.6; N,
7.0%).
Butyl triflate (2). Yield 189 mg, 92%; 1H NMR (CD2Cl2): 0.78
(3H, t, J = 7 Hz), 1.34 (2H, m), 1.88 (2H, m) and 4.49 ppm (2H,
t, J = 6 Hz).
Ethyl 6-(trifluoromethylsulfonyloxy)hexanoate (3). Yield 265
mg, 91%; 1H NMR (CD2Cl2): 1.23 (3H, t, J = 7 Hz), 1.45 (2H,
m), 1.66 (2H, m), 1.82 (2H, m), 2.32 (2H, t, J = 7 Hz), 4.10 (2H,
q, J = 7 Hz) and 4.56 ppm (2H, t, J = 6 Hz).
3,8-Bis(ethoxycarbonylamino)-6-phenyl-5-(5-trifluoroacet-
amidopentyl)phenanthridinium trifluoromethanesulfonate (10).
1
Yield 372 mg, 49%; H NMR (DMSO-d6): 1.31 (3H, t, J = 7
Hz, CH3), 1.42 (3H, t, J = 7 Hz, CH3), 1.3–1.5 (4H, m, CH2-
CH2), 2.09 (2H, br m, CH2), 3.23 (2H, m, CH2NHCOCF3), 4.19
(2H, q, J = 7 Hz, CH2OCO), 4.36 (2H, q, J = 7 Hz, CH2OCO),
4.65 (2H, br t, J = 8 Hz, NquatCH2), 7.8–8.0 (6H, m, ArH), 8.22
(1H, dd, J = 9, 2 Hz, ArH), 8.37 (1H, dd, J = 9, 2 Hz, ArH),
8.79 (1H, s, ArH), 9.13 (1H, d, J = 9 Hz, ArH), 9.18 (1H,
d, J = 9 Hz, ArH), 9.48 (1H, br t, J = 6 Hz, NHCOCF3),
10.39 (1H, s, NHCOOEt) and 10.69 ppm (1H, s, NHCOOEt);
FAB-MS 611 (Mϩ cation, 100%) (Found: C, 49.6; H, 3.9; N, 7.0.
C33H34F6N4O8Sؒ¹CH2Cl2 requires: C, 50.1; H, 4.3; N, 7.0%).
5-Phthalimidopentyl triflate (4). Yield 317 mg, 87%; 1H NMR
(CD2Cl2): 1.46 (2H, m), 1.70 (2H, m), 1.89 (2H, m), 3.68 (2H, t,
J = 7 Hz), 4.56 (2H, t, J = 6 Hz) and 7.76 ppm (4H, m).
5-(Trifluoroacetamido)pentyl triflate (5). Yield 256 mg, 81%;
1H NMR (CDCl3): 1.38 (2H, m), 1.55 (2H, m), 1.77 (2H, m),
3.23 (2H, q, J = 7 Hz), 4.46 (2H, t, J = 6 Hz) and 8.01 ppm (1H,
br s).
3-(tert-Butyldimethylsilyloxy)propyl triflate (6). Yield 294 mg,
¯
²
1
84%; H NMR (CD2Cl2): 0.07 (6H, s), 0.89 (9H, s), 1.92 (2H,
Deprotection reactions
m), 3.74 (2H, t, J = 6 Hz) and 4.53 ppm (2H, t, J = 6 Hz).
The following procedure was employed to prepare products 11
and 12. The alkylated triflate salt 7 (or 10) (1 mmol) was dis-
solved in dichloromethane (50 mL), then washed with dilute
hydrobromic acid (1 M, 4 × 100 mL). The organic layer was
separated and concentrated under vacuum (addition of MgSO4
as drying agent should be avoided, as this precipitates the brom-
ide salt from dichloromethane). Hydrobromic acid (10 mL,
48%) was then added and the solution was heated at reflux for
18 hours. The acid was removed under vacuum and the crude
residue was purified by column chromatography (dichloro-
methane–methanol, 4:1) to give the products as intensely col-
oured red solids. The aromatic amine groups were found to be
unprotonated after this work-up procedure, being clearly
Alkylation of 3,8-bis(ethoxycarbonylamino)-6-phenylphenan-
thridine
The following general procedure was employed. The appropri-
ate alkyl triflate (1 mmol) was added to a solution of 1 (1 mmol)
in nitrobenzene (5 mL) and stirred at room temperature for 18
hours. The nitrobenzene was then removed by column chrom-
atography using 100% dichloromethane. The product was then
eluted from the column using a dichloromethane–methanol
mixture (9:1). Evaporation of solvent afforded the pure
product as a bright yellow fluorescent solid.
5-Butyl-3,8-bis(ethoxycarbonylamino)-6-phenylphenanthrid-
1
inium trifluoromethanesulfonate (7). Yield 387 mg, 61%; 1H
observed in the H NMR spectra at approx. 6.1 and 6.6 ppm
J. Chem. Soc., Perkin Trans. 1, 2000, 571–574
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Basis of Specificity in Nucleic Acid-Drug Interactions, eds. B.
with the correct integration, and in agreement with the
spectrum of commercially available ethidium bromide.
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3,8-Diamino-5-butyl-6-phenylphenanthridinium bromide (11).
1
Yield 395 mg, 91%; H NMR (DMSO-d6): 0.78 (3H, t, J = 7
Hz, CH3), 1.32 (2H, br m, CH2), 1.93 (2H, br m, CH2), 4.46
(2H, br m, NquatCH2), 6.08 (2H, br s, ArNH2), 6.37 (1H, s,
ArH), 6.57 (2H, br s, ArNH2), 7.44 (1H, d, J = 9Hz, ArH), 7.47
(1H, s, ArH), 7.64 (1H, d, J = 9Hz, ArH), 7.81 (5H, m, ArH),
8.71 (2H, d, J = 9Hz, ArH) and 8.76 ppm (2H, d, J = 9 Hz,
ArH); ES-MS 342 (Mϩ cation, 100%) (Found: C, 60.1; H, 6.3;
N, 8.8. C23H24BrN3ؒ2H2O requires: C, 60.3; H, 6.1; N, 9.2%).
6 L. P. Walls, J. Chem. Soc., 1947, 67; T. I. Watkins, J. Chem. Soc.,
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10 Previously reported N-alkylated ethidium derivative.
11 T. A. Kelly and D. W. McNeil, Tetrahedron Lett., 1994, 35, 9003;
T. J. Thornton and M. Jarman, Synthesis, 1990, 295; M. C. Venuti,
R. A. Stephenson, R. Alvarez, J. J. Bruno and A. M. Strosberg,
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14 R. Hirschmann, K. C. Nicolaou, S. Pietranico, E. M. Leahy,
J. Salvino, B. Arison, M. A. Cichy, P. G. Spoors, W. C. Shakespeare,
P. A. Sprengeler, P. Hamley, A. B. Smith III, T. Reisine, K. Raynor,
L. Maechler, C. Donaldson, W. Vale, R. M. Freidinger, M. R.
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Chem., 1992, 3, 414.
3,8-Diamino-5-(5-aminopentyl)-6-phenylphenanthridinium
bromide (hydrobromide salt) (12). Yield 374 mg, 83%; 1H NMR
(DMSO-d6): 1.35 (2H, m, CH2), 1.54 (2H, m, CH2), 1.96 (2H,
br m, CH2), 2.80 (2H, t, J = 10 Hz, CH2NH3ϩ), 4.42 (2H, br m,
NquatCH2), 6.09 (2H, s, ArNH2), 6.35 (1H, d, J = 2 Hz, ArH),
6.66 (2H, s, ArNH2), 7.47 (1H, d, J = 9 Hz, ArH), 7.64 (1H, s,
ArH), 7.68 (1H, d, J = 2 Hz, ArH), 7.89 (5H, m, ArH), 7.97 (3H,
br s, CH2NH3ϩ), 8.73 (1H, d, J = 9 Hz) and 8.77 ppm (1H, d,
J = 9 Hz); ES-MS 371 (Mϩ cation, 100%).
Acknowledgements
We thank the European Commission for a Marie Curie
Fellowship (Training and Mobility of Researchers; Grant No.
ERBFMBICT972447) to S. A. R.
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