Tandem cyclization-Michael reaction by combination of metal- and organocatalysis

Article abstract of DOI:10.1021/jo2013077

The use of a catalytic amount of platinum complexes (1 mol%) was found to be compatible with different organocatalysts (DABCO or the Jorgensen- Hayashi catalyst) that were used in the functionalization of various activated methylenes. By this method, a series of lactones with C-3 quaternary centers and substitution at C-5 were prepared.

Full text of DOI:10.1021/jo2013077

NOTE
pubs.acs.org/joc
Tandem CyclizationꢀMichael Reaction by Combination of Metal- and
Organocatalysis
Josꢀe Alemꢀan,*,† Virginia del Solar,‡ Cecilia Martín-Santos,‡ Leticia Cubo,‡ and Carmen Navarro Ranninger‡
†Departamento de Química Orgꢀanica (C-1) and ‡Departamento de Química Inorgꢀanica (C-7), Facultad de Ciencias,
Universidad Autꢀonoma de Madrid, Cantoblanco 28049-Madrid, Spain
S Supporting Information
b
ABSTRACT: The use of a catalytic amount of platinum complexes (1 mol %)
was found to be compatible with different organocatalysts (DABCO or the
JørgensenꢀHayashi catalyst) that were used in the functionalization of
various activated methylenes. By this method, a series of lactones with C-3
quaternary centers and substitution at C-5 were prepared.
actones are present in a large number of natural products.
Recently, a variety of lactones with quaternary centers at
L
C-3 and substitution at C-5 have been isolated.1 Examples of
complex structures which incorporate this moiety include spir-
ovibsanin (A),1a,b trans-dehydrocrotonin (B),1c and biologically
active tetranoditerpenoids (C)1d (Figure 1), along with teucrin A,1e
neoclerodane diterpenes,1f and sesquiterpenes of Collybia macu-
late (not shown).1g Less complex examples include some β3-
adrenergic receptor agonists (D)2a and serine protease inhib-
itors (E).2b Various methodologies have been developed for the
synthesis of furanones with this substitution pattern (F).2c,d
In the past decade, organocatalysis3 has opened a new window
for carrying out organic transformations. One of its primary
advantages is the avoidance of expensive metal reagents or catalysts.
However, more recent attention has been focused on the combina-
tion of metal4 and organocatalysis3 to provide a complementary
method for obtaining new complex structures or for enhancing the
reactivity of the metal.5 Dixon,6a Jørgensen,6b and Cꢀordova6c
have each reported catalytic systems involving initial activation
using a Lewis base followed by π-alkyne trapping with a metal
catalyst (eq 1, Scheme 1).
Figure 1. Lactones present in different natural products.
Subsequently, lactone 3, with its highly acidic R-proton, would be
a prime target for an organocatalytic addition to activated alkenes
(eq 2, Scheme 1) to afford compounds 4. In this work, we present
our efforts toward developing this tandem procedure for the
synthesis of γ-lactones with a C-3 quaternary center.
In this context, one of the most useful starting materials in
organocatalysis is a methylene activated by two electron-with-
drawing groups (EWG-CHR-EWG). However, a large difference
in reactivity is observed between acyclic and cyclic substrates,7
with better reactivities generally observed in the latter case due
to increased acidity (see the Bordwell pKa table).8 Given our
group's experience working with π-acid activated alkynes using
platinum catalysis9 and organocatalysis10 although in the oppo-
site mode as described above (i.e., first platinum catalysis, then the
Lewis base), we hypothesized that propargyl malonate derivatives
1 could be cyclized using platinum to afford intermediate 3.
We began by screening platinum catalysts (5aꢀf)9 in toluene
at room temperature while using 20 mol % of DABCO as the
organocatalyst to deprotonate the acidic position. As shown in
Table 1, the best catalyst was 5c,11 which gave compound 4a with
a conversion of 96% (entry 3, Table 1). Other similar catalysts,
Received: June 27, 2011
Published: July 25, 2011
r
2011 American Chemical Society
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NOTE
such as 5a, 5b, or the iodo derivative 5f (entries 1, 2, and 6), gave
only moderate conversion, and Pt(IV) complexes were even
less successful (entries 4 and 5). No reaction of any kind was
observed in the absence of platinum catalysts (entry 7), indicat-
ing that the cyclization was necessary to achieve deprotonation.
Next, we tested different solvents (entries 8ꢀ10) and found that
acetone, xylene, and toluene provided the best results.12 How-
ever, reaction times were slightly better in acetone than in the
nonpolar solvents. With these conditions in hand, we were
prepared to investigate the scope of the reaction (Table 2).
The ethyl-substituted malonate derivative 2b gave the corre-
sponding lactone (4b) in worse yield than 2a (see entries 1 and 2,
Table 2). Adding an extra methylene linker before the alkyne
Table 2. Scope of the Reaction with Different Alkenesa
entry
R1 (n)
EWG/R2/R3
R3
yieldb (%)
Scheme 1. Strategy for the Synthesis of Substituted Lactones
(LB = Lewis Base)
1
2
3c
Me (1), 2a
Et (1), 2b
Et (2), 2c
Me (1), 2a
Me (1), 2a
Me (1), 2a
Me (1), 2a
Me (1), 2a
Me (1), 2a
Me (1), 2a
Me (1), 2a
Me (1), 2a
SO2Ph/H/H, 6a
SO2Ph/H/H, 6a
SO2Ph/H/H, 6a
CN/H/H, 6b
H
H
69, 4a
46, 4b
22, 4c
70, 4d
71, 4e
66, 4f
nrd
H
4
H
5
COMe/H/H, 6c
CO2Et/H/H, 6d
CN/H/Me, 6e
H
6
H
7
Me
Ph
Me
Me
Et
8
CN/H/Ph, 6f
nrd
9
CO2Et/H/Me, 6g
CO2Et/CO2Et/Me, 6h
NO2/H/Et, 6i
nrd
53, 4g/4g0
30, 4h/4h0
10c
11c
12
e
e
e
NO2/H/Ph, 6j
Ph
72, 4i/4i0
a All reactions were performed with 0.30 mmol of 2aꢀc, 0.45 mmol of
6aꢀj, 1 mol % of catalyst 5c, 20 mol % of DABCO in 0.2 mL of
acetone, and 50 μL of H2O over 24 h. b Isolated yield after flash
chromatography. c This reaction was stopped after 48 h. d No reaction.
e A diastereomeric ratio of 3:1 was obtained.
Table 1. Screening Platinum Catalysts for the Tandem Reaction of 2-(Methoxycarbonyl)pent-4-ynoic Acid 2a in the Presence of
Catalytic DABCOa
entry
solvent
catalyst
conversionb (%)
1
2
Tol
5a
5b
5c
5d
5e
5f
41
57
96
0
Tol
3
Tol
4
Tol
5
Tol
22
29
nrc
96
73
>98
6
Tol
7
Tol
8
xylene
CH2Cl2
acetone
5c
5c
5c
9
10
a All reactions were performed on a 0.1 mmol scale in 0.1 mL of solvent and stopped after 24 h. b Conversion was determined by 1H NMR. c No reaction.
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NOTE
Scheme 2. Decarboxylation Process and Opening Lactone with Water Molecule
moiety was tolerated (e.g., 2c), but the yield was substantially
decreased (entry 3).
Scheme 3. Tandem Process Iminium-Metal-Catalyzed and
Enamine Reaction
Nitriles (6b), ketones (6c), and esters (6d) underwent the
reaction in this catalytic system with malonate 2b, providing
complete conversion and yields ranging from 66 to 71% (entries
4ꢀ6). Unfortunately, β-substituted double bonds 6eꢀg did not
react under these conditions, indicating that a greater electronic
activation was needed to overcome the added steric hindrance
(entries 7ꢀ9). Thus, we attempted the reaction with trisubsti-
tuted alkene 6h, which provided the final product 4g/4g0 as a 3:1
mixture of diastereomers (entry 10). Interestingly, a nitro group
was also reactive enough with the β-substituted double bonds 6i
and 6j to achieve the final compounds 4h and 4i in moderate to
good yields (entries 11 and 12).13
To know if we could increase the number of the steps in which
the catalyst is involved and to make the catalytic cycle more
complex, we increased the catalytic loading of the platinum
complex 5c to 5 mol % and lengthened the reaction time (eq a,
Scheme 2). Under these conditions, the reaction gave known
intermediate 4a (observed by TLC), which was then opened by
attack of a water molecule to the ester moiety catalyzed by 5c that
could act as a Lewis acid, enhancing this ring-opening process.14
Thus, intermediate ketone 7a was obtained and was subse-
quently decarboxylated by the basic conditions of the reaction
media (DABCO) to give the final sulfone 8a (eq a, Scheme 2).
Next, we performed an experiment to test the dependence
of the Michael addition on the existence of a cyclic lactone
intermediate (eq b, Scheme 2). We synthesized ketone 9a by
formation of lactone 3 followed by opening with a water molecule
catalyzed by platinum. Then, we tried to deprotonate it with
10 mol % of DABCO under the same reaction conditions, and
only starting material 9a was recovered, even after 5 days,
indicating that only the cyclic subtrates can react under these
reaction conditions.15
Given the known reactivity of enol lactones,16 and having
determined that the cyclic intermediate was required for the
Michael addition, we became interested in performing iminium
activation of R,β-unsaturated aldehydes using diarylprolinol
ethers.17 Following the reaction outlined in Scheme 3, lactone
3 would react under iminium catalysis to give the aldehyde 11,
followed by opening with a water molecule catalyzed by platinum
to give intermediate 12. Finally, aldehyde 12 would cyclize via
enamine chemistry with the prolinol ether catalyst, and dehydra-
tion of the obtained aldol would give the final compound 14.
With this premise in mind, we started the reaction with croto-
naldehyde 13a, lactone 3, the silylprolinol ether 15 (20 mol %)18
and 1 mol % of platinum catalyst 5c (eq 1, Scheme 4). Gratify-
ingly, the reaction gave the desired acid product as a mixture of
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Scheme 4. Reaction of Lactone 3 with Different R,β-Unsaturated Aldehydes 13
diastereoisomers (4:1) with a moderate enantiomeric ratio
(er = 85.15) and good yield. The relative configuration was
confirmed by NOESY experiments (see the Supporting In-
formation). This reaction allows the synthesis of these chiral
acids via an iminium ion/platinum/enamine ion catalysis
cascade.
To obtain the absolute configuration by chemical correlation, we
repeated the reaction but treated the crude mixture with N2CH2-
TMS (eq 2, Scheme 4). Thus, acid 14 was converted into diester
16a in a one-pot manner in good yield (eq 2, Scheme 4).
Aldehydes 13b (R = Ph) and 13c (R = 2-furyl) underwent the
same reaction to give diesters 16b and 16c with moderate yields
and moderate to good enantiomeric ratios. The absolute config-
uration of compounds 16b6c and 16c19 was obtained by correla-
tion with known compounds in the literature, obtaining similar
optical rotations and indicating R configuration for the chiral
center.
rotations were measured at room temperature (20ꢀ23 °C) using a
polarimeter (concentration in g/100 mL). Alkenes 6aꢀj, esters 1a,b,
catalyst 15, and aldehydes 13 were purchased from commercial available
sources. Platinum complexes were synthetized according to the proce-
dures described in the literature.8 The ee’s were determined by HPLC
employing chiral HPLC columns.
Diethyl 2-(But-3-ynyl)malonate (1c). Under an argon inert atmo-
sphere, NaH (5.5 mmol, 1.1 equiv) was added portionwise at 0 °C
to a solution of the corresponding malonate (5.0 mmol) in anhy-
drous THF (10 mL). The mixture was allowed to warm to room
temperature and the corresponding propargyl bromide was added
(5.5 mmol, 1.1 equiv). After the completion of the reaction (which is
followed by TLC), the reaction was quenched with water and extracted
with EtOAc (3 ꢁ 15 mL). The organic phase was dried with anhydrous
MgSO4 and concentrated under reduced pressure. The product was
directly obtained as colorless oil (40% yield) and purified using flash
column chromatography, elution with EtOAc/hexane (1:3): 1H NMR
(300 MHz, CDCl3) δ 4.19 (q, J = 7.5 Hz, 4H), 3.54 (t, J = 7.4 Hz, 1H),
2.28 (td, J = 7.1, 2.6 Hz, 2H), 2.10 (q, J = 7.1 Hz, 2H), 1.99 (t, J = 2.6 Hz,
1H.), 1.26 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 168.9 (C),
82.4 (C), 70.0 (CH), 61.4 (CH2), 50.5 (CH), 27.3 (CH2), 16.3 (CH2),
14.0 (CH3); (MS-ESI+) [M]+ calcd for C11H16O4 213.1126, found
213.1124.
Procedure for the Monohydrolysis of the Substituted
Malonates 2a and 2c. To a solution of substrate (2.2 mmol) in
methanol (2a) or ethanol (2c) (5 mL) was added NaOH (2.4 mmol,
1.1 equiv). The mixture was stirred at room temperature for 18 h.
Then, 10 mL of aqueous saturated sodium bicarbonate were added,
and the mixture was extracted with EtOAc (3 ꢁ 10 mL). The aqueous
phase was acidified to pH = 1 with concentrated HCl and extracted
with CH2Cl2. The organic phase was dried over Na2SO4, filtered,
and concentrated under reduced pressure, obtaining pure acid
compounds.
In conclusion, we have found that the use of catalytic amounts
of platinum complexes (1 mol %) is compatible with different
organocatalysts (DABCO or the JørgensenꢀHayashi catalyst),16
allowing the functionalization of various acylic malonates and
allowing the synthesis of lactones with a quaternary center at C-3
and substitution at C-5 in a facile manner.
’ EXPERIMENTAL SECTION
General Methods. NMR spectra were acquired on a 300 MHz
spectrometer, running at 300 and 75 MHz for 1H and 13C, respectively.
Chemical shifts (δ) are reported in ppm relative to residual solvent
1
signals (CDCl3, 7.26 ppm for H NMR, CDCl3, 77.0 ppm for 13C
NMR). 13C NMR spectra were acquired on a broad band decoupled
mode. Analytical thin-layer chromatography (TLC) was performed
using precoated aluminum-backed plates and visualized by ultraviolet
irradiation or KMnO4 dip. Purification of reaction products was carried
out by flash chromatography (FC) using silica gel. Melting points were
measured using an open capillary tubes and are uncorrected. The optical
2-(Methoxycarbonyl)pent-4-ynoic Acid (2a). The product was di-
rectly obtained following the standard procedure from commercial
available 1a as white solid (91% yield) without further purification:
mp = 94.9ꢀ95.3 °C; 1H NMR (300 MHz, CDCl3) δ7.82 (bs, 1H), 3.74
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(s, 3H), 3.59 (t, J = 7.5 Hz, 1H), 2.74 (dd, J = 7.4, 1.6 Hz, 2H), 1.99
(t, J = 2.5 Hz, 1H); 13C NMR (75 MHz, CDCl3)δ 172.8 (C), 168.2 (C),
79.5 (C), 70.8 (CH), 53.1 (CH3), 50.8 (CH), 18.4 (CH2); (electrospray+)
[M + Na]+ calcd for C7H8O4Na 179.0322, found 179.0314.
2-(Ethoxycarbonyl)hex-5-ynoic Acid (2c). The product was directly
obtained following the standardprocedure starting from1c ascolorlessoil
(87% yield) without further purification: 1H NMR (300 MHz, CDCl3)
δ 9.93 (bs, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.65 (t, J = 7.3 Hz, 1H),
2.34 (td, J = 6.8, 2.5 Hz, 2H), 2.15 (q, J = 7.1 Hz, 2H), 2.04 (t, J = 2.6 Hz,
1H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4 (C),
168.8 (C), 82.1 (C), 70.0 (CH), 61.9 (CH2), 50.3 (CH), 27.3 (CH2),
16.3 (CH2), 13.9 (CH3); (MS-ESI+) [M + Na]+ calcd for C9H12O4Na
207.0627, found 207.0627.
Procedure for the Synthesis of Acid 2b by Transesterifica-
tion. To a solution of compound 2a (2.2 mmol) in ethanol (5 mL) was
added NaOH (2.4 mmol, 1.1 equiv). The mixture was stirred at room
temperature for 18 h. Then, 10 mL of aqueous saturated sodium
bicarbonate were added, and the mixture was extracted with EtOAc
(3 ꢁ 10 mL). The aqueous phase was acidified to pH = 1 with
concentrated HCl and extracted with CH2Cl2. The organic phase was
dried over Na2SO4, filtered, and concentrated under reduced pressure,
obtaining pure the acid compound 2b.
2-(Ethoxycarbonyl)pent-4-ynoic Acid (2b). The product was directly
obtained following the procedure as a colorless oil (83% yield) without
further purification: 1H NMR (300 MHz, CDCl3) δ 11.26 (bs, 1H), 4.18
(q, J = 7.1 Hz, 2H), 3.56 (t, J = 7.6 Hz, 1H), 2.72 (ddd, J = 7.6, 2.5, 1.0 Hz,
2H), 1.99 (t, J = 2.6 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 173.1 (C), 167.8 (C), 79.6 (C), 70.7 (CH), 62.2
(CH2), 51.0 (CH), 18.3 (CH2), 13.9 (CH3); (MS-ESI+) [M + H]+ calcd
for C8H11O4 171.0657, found 171.0656.
Ethyl 6-Methylene-2-oxo-3-(2-(phenylsulfonyl)ethyl)tetrahydro-2H-
pyran-3-carboxylate (4c). The product was directly obtained following
the standard procedure as a colorless oil (22% yield): H NMR (300
1
MHz, CDCl3) δ 7.83 (d, J = 7.2 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.51 (t,
J = 7.5 Hz, 2H), 4.64 (s, 1H), 4.29 (s, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.43
(ddd, J = 13.7, 9.1, 7.1 Hz, 1H), 3.08 (ddd, J = 13.7, 10.9, 6.4 Hz, 1H),
2.56ꢀ2.46 (m, 2H), 2.30ꢀ2.16 (m, 2H), 1.69 (ddd, J = 13.6, 9.7, 7.3 Hz,
2H), 1.17 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.4 (C),
166.6 (C), 153.4 (C), 138.7 (C), 134.0 (CH), 129.4 (CH), 128.1 (CH),
96.0 (CH2), 62.8 (CH2), 53.1 (C), 52.0 (CH2), 28.7 (CH2), 28.1 (CH2),
24.0 (CH2), 14.0 (CH3); (MS-ESI+) [M + H]+ calcd for C17H21O6S
353.1053, found 353.1054.
Methyl 3-(2-Cyanoethyl)-5-methylene-2-oxotetrahydrofuran-3-
carboxylate (4d). The product was directly obtained following the
1
standard procedure as yellow oil (70% yield): H NMR (300 MHz,
CDCl3) δ 4.80 (s, 1H), 4.40 (s, 1H), 3.75 (s, 3H), 3.31 (d, J = 16.6 Hz,
1H), 2.86 (d, J = 16.6 Hz, 1H), 2.66ꢀ2.45 (m, 2H), 2.34ꢀ2.32 (m 2H);
13C NMR (75 MHz, CDCl3)δ171.3 (C), 168.5 (C), 151.6 (C), 118.4
(C), 90.8 (CH2), 53.8 (C), 53.7 (CH3), 36.3 (CH2), 29.8 (CH2), 13.1
(CH3); (MS-ESI+) [M + Na]+ calcd for C10H11NO4Na 232.0580,
found 232.0574.
Methyl 5-Methylene-2-oxo-3-(3-oxobutyl)tetrahydrofuran-3-
carboxylate (4e). The product was directly obtained following the
1
standard procedure as a yellow oil (71% yield): H NMR (300 MHz,
CDCl3) δ 4.75 (s, 1H), 4.33 (s, 1H), 3.72 (s, 3H), 3.26 (dt, J = 16.5,
1.5 Hz, 1H), 2.74 (dt, J = 16.5, 1.5 Hz, 1H), 2.70ꢀ2.43 (m, 2H), 2.16
(t, J = 7.6 Hz, 2H), 2.09 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 206.5
(C), 172.1 (C), 169.4 (C), 152.2 (C), 90.0 (CH2), 54.0 (C), 53.3
(CH3), 38.4 (CH2), 36.6 (CH2), 29.9 (CH3), 27.9 (CH2); (MS-ESI+)
[M + Na]+ calcd for C11H14O5Na 249.0733, found 249.0741.
Methyl 3-(3-Ethoxy-3-oxopropyl)-5-methylene-2-oxotetrahy-
drofuran-3-carboxylate (4f). The product was directly obtained follow-
ing the standard procedure as a colorless oil (66% yield): 1H NMR (300
MHz, CDCl3) δ 4.84 (s, 1H), 4.43 (s, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.82
(s, 3H), 3.38 (d, J = 16.5 Hz, 1H), 2.86 (d, J = 16.5 Hz, 1H), 2.61ꢀ2.50
(m, 1H), 2.46ꢀ2.24 (m, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 172.0 (C), 171.9 (C), 169.2 (C), 152.2 (C), 90.0
(CH2), 60.8 (CH2), 54.2 (C), 53.4 (CH3), 36.0 (CH2), 29.5 (CH2),
29.2 (CH2), 14.1 (CH3); (MS-ESI+) [M + Na]+ calcd for C12H16O6Na
279.0839; found 279.0837.
General Procedure for Addition Reaction (Tables 1 and 2,
Scheme 2). To a solution of the corresponding acid 2aꢀc (0.3 mmol)
in acetone (0.3 mL) were added the platinum complex 5c (0.003 mmol,
1 mol %), DABCO (0.06 mmol, 20 mol %), the corresponding Rβ-
unsaturated compound 6aꢀj (0.3 mmol, 1.5 equiv), and 50 μL of water.
After completion of the reaction (which is followed by TLC), the
mixture was concentrated to give a crude, which was purified using flash
column chromatography. Elution with EtOAc/hexane (1:3) afforded
the pure compounds.
Methyl 5-Methylene-2-oxo-3-(2-(phenylsulfonyl)ethyl)tetrahydro-
furan-3-carboxylate (4a). The product was directly obtained following
the standard procedure as a white solid (69% yield): mp = 105.2ꢀ
105.9 °C; 1H NMR (300 MHz, CDCl3) δ 7.93ꢀ7.89 (m, 2H), 7.71ꢀ
7.66 (m, 1H), 7.62ꢀ7.56 (m, 2H), 4.84 (dt, J = 2.9, 2.0 Hz, 1H), 4.42
(dt, J = 3.2, 1.6 Hz, 1H), 3.75 (s, 3H), 3.42 (ddd, J = 13.9, 10.3, 6.3 Hz,
1H), 3.30 (dt, J = 16.6, 1.8 Hz, 1H), 3.19 (ddd, J = 13.9, 10.4, 6.1 Hz,
1H), 2.82 (dt, J = 16.6, 2.0 Hz, 1H), 2.33 (ddd, J = 17.7, 14.0, 6.0 Hz,
2H); 13C NMR (75 MHz, CDCl3) δ 171.4 (C), 168.6 (C), 151.6 (C),
138.4 (C), 134.1 (CH), 129.5 (CH), 128.1 (CH), 90.8 (CH2), 53.7
(CH3), 53.4 (C), 51.6 (CH2), 36.6 (CH2), 27.1 (CH2); (MS-ESI+)
[M + Na]+ calcd for C15H16O6SNa 347.0565, found 347.0565.
Ethyl 5-Methylene-2-oxo-3-(2-(phenylsulfonyl)ethyl)tetrahydro-
furan-3-carboxylate (4b). The product was directly obtained following
the standard procedure as white solid (46% yield): mp = 101.4ꢀ
Diethyl 2-(1-(3-(Methoxycarbonyl)-5-methylene-2-oxotetrahydro-
furan-3-yl)ethyl)malonate (4g/4g0). The product was directly obtained
following the standard procedure as a colorless oil (53% yield). Major
isomer: 1H NMR (300 MHz, CDCl3) δ 4.80ꢀ4.77 (m, 1H), 4.40ꢀ4.38
(m, 1H), 4.25ꢀ4.12 (m, 4H), 3.78 (s, 3H), 3.57 (d, J = 5.7 Hz, 1H),
3.44ꢀ3.31 (m, 2H), 3.02 (dt, J = 17.0, 2.1 Hz, 1H), 1.30ꢀ1.23 (m, 6H),
1.10 (d, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.5 (C),
168.6 (C), 168.4 (C), 168.1 (C), 152.9 (C), 89.6 (CH2), 62.0 (CH2),
61.7 (CH2), 59.4 (C), 53.7 (CH3), 53.4 (CH), 36.3 (CH), 31.8 (CH2),
1
14.2 (CH3), 14.1 (CH3), 13.1 (CH3). Minor isomer: H NMR (300
MHz, CDCl3) δ 4.80ꢀ4.77 (m, 1H), 4.40ꢀ4.38 (m, 1H), 4.25ꢀ4.12
(m, 4H), 3.79 (s, 3H), 3.55 (d, J = 5.7 Hz, 1H), 3.44ꢀ3.31 (m, 2H), 3.00
(dt, J = 16.8, 2.3 Hz, 1H), 1.30ꢀ1.23 (m, 6H), 1.10 (d, J = 7.0 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 171.0 (C), 168.5 (C), 168.4 (C), 168.2
(C), 152.8 (C), 89.6 (CH2), 62.1 (CH2), 61.8 (CH2), 59.7 (C), 53.9
(CH3), 53.1 (CH), 36.1 (CH), 32.0 (CH2), 14.0 (CH3), 13.9 (CH3),
13.8 (CH3); (MS-ESI+) [M + Na]+ calcd for C16H22O8Na 343.1393,
found 343.1390.
Methyl 5-Methylene-3-(1-nitrobutan-2-yl)-2-oxo-tetrahydrofuran-
3-carboxylate (4h/4h0). The product was directly obtained following
the standard procedure as a white solid (30% yield), mp = 114.9ꢀ116.1 °C.
Major isomer: 1H NMR (300 MHz, CDCl3) δ 4.80ꢀ4.77 (m, 1H), 4.63
(dd, J = 14.0, 4.2 Hz, 1H), 4.43 (dd, J = 14.0, 6.4 Hz, 1H), 4.38ꢀ4.34 (m,
1H), 3.74 (s, 3H), 3.25 (dt, J = 17.0, 2.0 Hz, 1H), 3.00ꢀ2.90 (m, 1H),
1
102.2 °C; H NMR (300 MHz, CDCl3) δ 7.84 (d, J = 7.1 Hz, 2H),
7.62 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.4 Hz, 2H), 4.76 (dt, J = 2.9, 1.9 Hz,
1H), 4.35 (dt, J = 2.9, 1.5 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.37
(ddd, J = 13.9, 10.4, 6.2 Hz, 1H), 3.22 (dt, J = 16.5, 1.6 Hz, 1H), 3.13
(ddd, J = 13.9, 10.5, 6.1 Hz, 1H), 2.75 (dt, J = 16.5, 1.9 Hz, 1H), 2.25
(ddd, J = 17.4, 14.0, 6.0 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 171.4 (C), 168.1 (C), 151.6 (C), 138.6 (C), 134.1
(CH), 129.5 (CH), 128.1 (CH), 90.6 (CH2), 63.0 (CH2), 53.4 (C), 51.7
(CH2), 36.7 (CH2), 27.1 (CH2), 13.9 (CH3); (MS-ESI+) [M + H]+
calcd for C16H19O6S 339.0896; found 339.0902.
7291
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The Journal of Organic Chemistry
NOTE
2.90 (dt, J = 17.0, 2.0 Hz, 1H), 1.66 (ddq, J = 14.7, 7.4, 3.5 Hz, 1H),
1.46ꢀ1.27 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.9 (C), 168.9 (C), 151.6 (C), 90.4 (CH2), 76.0 (CH2),
57.7 (C), 53.7 (CH3), 41.9 (CH), 34.6 (CH2), 22.2 (CH2), 11.4 (CH3).
(ddt, J = 16.7, 10.4, 1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 169.7
(C), 167.4 (C), 153.2 (C), 89.8 (CH2), 53.4 (CH), 46.2 (CH3), 29.3
(CH2); (MS-TOF MS EI+) [M]+ calcd for C7H8O4 156.0423, found
156.0425.
1
Minor isomer: H NMR (300 MHz, CDCl3) δ 4.80ꢀ4.68 (m, 2H),
Procedure for the Synthesis of the Cyclic Acid 14
(Scheme 4). (1S,2R)-3-Formyl-1-(methoxycarbonyl)-2,4-dimethylcy-
clopent-3-enecarboxylic Acid (14). To a solution of lactone 3 (0.3 mmol)
in acetone (0.3 mL) were added DABCO (0.06 mmol, 20 mol %),
PtCl2(DMSO)2 (0.003 mmol, 1 mol %), 15 (0.06 mmol, 20 mol %), the
corresponding R,β-unsaturated aldehyde (0.45 mmol, 1.5 equiv), and 50 μL
of water. The reaction was stirred at room temperature for 24ꢀ72 h.
Then 3 mL of aqueous saturated sodium bicarbonate was added, and the
mixture was extracted with EtOAc (3 ꢁ 3 mL). The aqueous phase was
acidified to pH = 1 with concentrated HCl and then extracted with EtOAc
(3 ꢁ 3 mL). The organic solvent was dried over MgSO4, filtered, and
concentrated under reduced pressure, obtaining pure acid compounds
14aꢀc. The product 14a was directly obtained following the procedure as
yellow oil (yield 85%) without further purification. The relative config-
uration was confirmed by NOESY experiment (see SI-38, Supporting
Information). Major diastereoisomer: 1H NMR (300 MHz, CDCl3) δ9.87
(s, 1H), 8.06 (bs, 1H), 3.82 (q, J = 7.4 Hz, 1H), 3.75 (s, 3H), 3.55 (dquint,
J = 19.4, 1.4 Hz, 1H), 2.94 (d, J = 19.4 Hz, 1H), 2.12 (d, J = 1.4 Hz, 3H),
1.05 (d, J = 7,1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 187.4 (CH),
176.0 (C), 169.8 (C), 157.9 (C), 139.8 (C), 62.1 (C), 52.8 (CH3), 45.5
(CH2), 43.6 (CH), 14.6 (CH3), 14.0 (CH3) Minor diastereoisomer: 1H
NMR (300 MHz, CDCl3) δ 9.87 (s, 1H), 8.06 (bs, 1H), 3.89ꢀ3.42
(m, 1H), 3.74 (s, 3H), 3.51ꢀ3.42 (m, 1H), 2.90 (d, J = 19.4 Hz, 1H), 2,08
(s, 3H), 1.11 (d, J = 7,1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 187.4
(CH), 176.0 (C), 169.8 (C), 157.9 (C), 139.8 (C), 62.1 (C), 53.0 (CH3),
45.3 (CH2), 43.8 (CH), 14.6 (CH3), 14.0 (CH3); (MS-ESI+) [M + H]+
calcd for C11H15O5 227.0914, found 227.0920.
General Procedure for the Synthesis of Diesters 16aꢀc
(Scheme 4). To a solution of lactone 3 (0.3 mmol) in acetone (0.3 mL)
were added DABCO (0.06 mmol, 20 mol %), PtCl2(DMSO)2 (0.003
mmol, 1 mol %), 15 (0.06 mmol, 20 mol %), the corresponding Rβ-
unsaturated aldehyde (0.45 mmol, 1.5 equiv), and 50 μL of water. Then,
3 mL of aqueous saturated sodium bicarbonate was added, and the
mixture was extracted with EtOAc (3 ꢁ 3 mL). The aqueous phase was
acidified to pH = 1 with concentrated HCl and then extracted with
EtOAc (3 ꢁ 3 mL). The organic solvent was dried over MgSO4, filtered,
and concentrated under reduced pressure, obtaining pure acid com-
pounds14aꢀc. To a solution of these acid compounds 14aꢀc(0.2mmol)
in MeOH (0.2 mL) was added dropwise (diazomethyl)trimethylsilane
(0.6 mmol, 3 equiv), and the mixture was further stirred for 4 h in
darkness. After completion of the reaction (which is followed by TLC),
50 μL of glacial acetic was added, and stirring was continued for 30 min.
Then the reaction mixture was extracted with CH2Cl2 (3 ꢁ 3 mL), and
the organic layer was washed three times with 3 mL of aqueous saturated
sodium bicarbonate, dried over Na2SO4, filtered, and concentrated
under reduced pressure, obtaining the crude compounds which were
purified using flash column chromatography. Elution with EtOAc/
hexane (1:3) affords the pure compounds.
4.48ꢀ4.35 (m, 2H), 3.76 (s, 3H), 3.39 (dt, J = 16.8, 1.7 Hz, 1H),
3.00ꢀ2.87 (m, 1H), 2.79 (dt, J = 16.8, 1.8 Hz, 1H), 1.46ꢀ1.27 (m, 2H),
0.97 (t, J = 7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.9 (C), 168.9
(C), 151.9 (C), 90.2 (CH2), 75.3 (CH2), 58.2 (C), 53.7 (CH3), 42.4
(CH), 32.7 (CH2), 22.7 (CH2), 11.9 (CH3); (MS-ESI+) [M + H]+ calcd
for C11H16NO6 258.0972, found 258.0976.
Methyl 5-Methylene-3-(2-nitro-1-phenylethyl)-2-oxotetrahydrofur-
an-3-carboxylate (4i). The product was directly obtained following
the standard procedure as a white solid (72% yield). The minor diaster-
eoisomer could not be isolated: mp = 114.9ꢀ116.1 °C; 1H NMR
(300 MHz, CDCl3) δ 7.35ꢀ7.31 (m, 3H), 7.26ꢀ7.22 (m, 2H), 5.25
(dd, = 13.7, 10.9 Hz, 1H), 4.98 (dd, J = 13.7, 3.5 Hz, 1H), 4.58
(q, J = 2,4 Hz, 1H), 4.27 (dd, J = 10.8, 3.5 Hz, 1H), 4.10 (td, J = 3.2,
1.6 Hz, 1H), 3.85 (s, 3H), 3.09 (dt, J = 16.9, 1.6 Hz, 1H), 2.86
(dt, J = 16.9, 2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 171.5 (C),
169.2 (C), 151.5 (C), 133.8 (C), 129.5 (CH), 129.2 (CH), 129.0 (CH),
90.1 (CH2), 76.6 (CH2), 57.8 (C), 54.0 (CH3), 46.6 (CH), 35.6 (CH2);
(MS-ESI+) [M + Na]+ calcd for C15H15NO6Na 328.0797, found
328.0784.
Methyl 4-Oxo-2-(2-(phenylsulfonyl)ethyl)pentanoate (8a). To a
solution of acid 2a (0.3 mmol) in acetone (0.3 mL) were added platinum
complex 5c (0.003 mmol, 5 mol %), DABCO (0.06 mmol, 20 mol %),
the phenyl vinyl sulfone (0.3 mmol, 1.5 equiv), and 250 μL of water. The
reaction was stirred at room temperature during 72 h. Then the mixture
was concentrated and purified using flash column chromatography.
Elution with EtOAc/hexane (1:1) gave the pure compound 8a as a
yellow oil (57% yield): 1H NMR (300 MHz, CDCl3) δ 7.83 (dt, J = 7.1,
1.7 Hz, 2H), 7.60 (tt, J = 7.4, 1.7 Hz, 1H), 7.51 (tt, J = 7.4, 1.4 Hz, 2H),
3.81 (t, J = 7.0 Hz, 1H), 3.57 (s, 3H), 3.16ꢀ2.99 (m, 2H), 2.91ꢀ2.77
(m, 2H), 2.52ꢀ2.41 (m, 1H), 2.06 (s, 3H), 1.96ꢀ179 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ (C), 174.0 (C), 138.8 (C), 133.9 (CH),
129.4 (CH), 128.0 (CH), 53.9 (CH2), 52.1 (CH3), 44.7 (CH2), 38.5
(CH), 29.9 (CH3), 24.4 (CH2); (electrospray+) [M + Na]+ calcd for
C14H18O5SNa 321.0773, found 321.0755.
2-(Methoxycarbonyl)-4-oxopentanoic Acid (9a). To a solution of
acid 2a (0.3 mmol) in acetone (0.3 mL) were added platinum complex
5c (0.015 mmol, 5 mol %) and 250 μL of water. The mixture was stirred
at room temperature for 72 h. Then 3 mL of aqueous saturated sodium
bicarbonate was added, and the mixture was extracted with EtOAc
(3 ꢁ 3 mL). The aqueous phase was acidified to pH = 1 with
concentrated HCl and then extracted with EtOAc (3 ꢁ 3 mL). The
organic solvent was dried over MgSO4, filtered, and concentrated under
reduced pressure, obtaining pure acid compound 9a. The product was
directly obtained following the procedure as yellow oil (94% yield)
without further purification: 1H NMR (300 MHz, CDCl3) δ 7.31 (bs,
1H), 3.81 (t, J = 7.0 Hz, 1H), 3.69 (s, 3H), 3.03 (d, J = 7.0 Hz, 2H), 2.15
(s, 3H); 13C NMR (75 MHz, CDCl3) δ (C), 172.5 (C), 169.4 (C), 53.0
(CH3), 46.5 (CH), 41.9 (CH2), 29.6 (CH3); (MS-ESI+) [M + Na]+
calcd for C7H10O5Na 197.0420, found 197.0422.
Methyl 5-Methylene-2-oxotetrahydrofuran-3-carboxylate (3). To a
solution of acid 2a (0.3 mmol) in acetone (0.3 mL) were added platinum
complex 5c (0.003 mmol, 1 mol %) and 250 μL of water. The mixture
was stirred at room temperature during 6 h. Then the reaction mixture
was extracted with EtOAc (3 ꢁ 3 mL); the organic solvent was dried
over MgSO4, filtered and concentrated under reduced pressure, obtain-
ing pure compound 3. The product was directly obtained as a yellow oil
(yield 91%) without further purification: 1H NMR (300 MHz, CDCl3)
δ 4.75 (q, J = 2.3 Hz, 1H), 4.35 (dt, J = 2.7, 1.8 Hz, 1H), 3.76 (s, 3H),
3.71 (dd, J = 10.4, 7.6 Hz, 1H), 3.24 (ddt, J = 16.7, 7.6, 2.1 Hz, 1H), 3.02
(R)-Dimethyl 3-Formyl-2,4-dimethylcyclopent-3-ene-1,1-dicarbox-
ylate (16a). The product was directly obtained following the standard
procedure as yellow oil (yield 78%): [R]25D = ꢀ108.9 (c = 1.0, CH2Cl2);
1H NMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 3.83 (q, J = 7.1 Hz, 1H),
3.68 (s, 3H), 3.66 (s, 3H), 3.48 (d, J = 19.3 Hz, 1H), 2.81 (d, J = 19.3 Hz,
1H), 2.05 (s, 3H), 0.95 (d, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 187.0 (CH), 171.8 (C), 170.0 (C), 156.9 (C), 140.0 (C), 62.2 (C),
53.0 (CH3), 52.6 (CH3), 45.6 (CH2), 43.6 (CH), 14.7 (CH3), 14.0
(CH3); (MS-ESI+) [M + H]+ calcd for C12H17O5 241.1070, found
241.1072. The enantiomeric excess was determined by HPLC using a
Chiralcel IC column [hexane/i-PrOH (90:10)]; flow rate 1.0 mL/min;
τmajor = 39.2 min, τminor = 34.7 min (er = 85:15).
7292
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The Journal of Organic Chemistry
NOTE
(R)-Dimethyl 3-Formyl-4-methyl-2-phenylcyclopent-3-ene-1,1-di-
carboxylate (16b)6c. The product was directly obtained following the
Berkessel, A., Groger, H., Eds.; Wiley-VCH: Weinheim, 2005. (c) Hayashi, Y.
Synth. Org. Chem. Jpn. 2005, 63, 464.(d) Enantioselective Organocatalysis;
Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007. (e) Bertelsen, S.; Jørgensen,
K. A. Chem. Soc. Rev. 2009, 38, 2178.
(4) For selected reviews on metal catalysis, see: (a) Beller, M.; Bolm,
C. Transition Metals for Organic Synthesis: Building Blocks and Fine
Chemicals, 2nd ed.; Wiley-VCH: Weinheim, 2004; Vols. 1 and 2. (b)
Crabtree, R. H. The Organometallic Chemistry of the Transition Metals,
5th ed.; John Wiley & Sons: New York, 2009.
(5) For recent reviews in the combination of organo and metal
catalysis, see: (a) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745. (b)
Zhong, C.; Shi, X. Eur. J. Org. Chem. 2010, 2999. For dual catalysis, see:
(c) Klussmann, M. Angew. Chem., Int. Ed. 2009, 48, 7124. (d) de Armas,
P.; Tejedor, D.; García-Tellado, F. Angew. Chem., Int. Ed. 2010, 49, 1013.
(e) R€ueping, M.; K€onigs, R. M.; Atodiresei, I. Chem.—Eur. J. 2010,
16, 9350.
(6) (a) Yang, T.; Ferrali, A.; Campbell, L.; Dixon, D. J. Chem.
Commun. 2008, 2923. (b) Jensen, K. L.; Franke, P. T.; Arrꢀoniz, C.;
Kobbelgarrd; Jørgensen, K. A. Chem.—Eur. J. 2010, 16, 1750. (c) Zhao,
G.-L.; Ullah, F.; Deiana, L.; Lin, S.; Zhang, Q.; Sun, J.; Ibrahem, I.;
Dziedzic, P.; Cꢀordova, A. Chem.—Eur. J. 2010, 16, 1585.
(7) See, e.g.: (a) Poulsen, T. B.; Bernardi, L.; Alemꢀan, J.; Overgaard,
J.; Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 441. (b) Konishi, H.;
Lam, T. Y.; Malerich, J. P.; Rawal, V. H. Org. Lett. 2010, 12, 2028. (c)
Jiang, H.; Paixao, M. W.; Monge, D.; Jørgensen., K. A. J. Am. Chem. Soc.
2010, 132, 2775.
standard procedure as a yellow oil (40% yield): [R]25 = ꢀ157.4
D
(c = 1.0, CHCl3) (lit.6c [R]25D = ꢀ293.6 (c = 1.0, CHCl3)); 1H NMR
(300 MHz, CDCl3) δ 9.81 (s, 1H), 7.15ꢀ7.10 (m, 3H), 7.02ꢀ6.99 (m,
2H), 5.03 (s, 1H), 3.72 (d, J = 19.1 Hz, 1H), 3.70 (s, 3H), 3.08 (s, 3H),
2.88 (d, J = 19.6 Hz, 1H), 2.20 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
185.9 (CH), 171.0 (C), 168.4 (C), 157.2 (C), 137.5 (C), 137.3 (C),
127.8 (CH), 127.4 (CH), 126.7 (CH), 62.9 (C), 54.7 (CH), 52.5
(CH3), 51.5 (CH3), 45.9 (CH2), 13.5 (CH3). The enantiomeric excess
was determined by HPLC using a Chiralcel IC column [hexane/i-PrOH
(90:10)]; flow rate 1.0 mL/min; τmajor = 18.8 min, τminor = 34.2 min
(er = 92:8).
(R)-Dimethyl 3-Formyl-2-(furan-2-yl)-4-methylcyclopent-3-ene-1,1-
dicarboxylate (16c)16. The product was directly obtained following the
standard procedure as a yellow oil (35% yield): [R]25 = ꢀ207.6
D
(c = 1.0, CHCl3) (lit. enantiomer: ent-16c:16 [R]25 = +220.8
D
(c = 1.0, CHCl3)); 1H NMR (300 MHz, CDCl3) δ 9.88 (s, 1H), 7.16
(dd, J = 1.8, 0.8 Hz, 1 H), 6.18 (dd, J = 3.2, 1.9 Hz, 1H), 6.02 (dd, J = 3.2,
0.3 Hz, 1H), 5.10 (s, 1H), 3.74ꢀ3.70 (m, 1H), 3.69 (s, 3H), 3.38 (s, 3H),
2.92 (d, J = 19.4 Hz, 1H), 2.22 (q, J = 1.0 Hz, 3H). The enantiomeric
excess was determined by HPLC using a Chiralcel IC column [hexane/i-
PrOH (90:10)]; flow rate 1.0 mL/min; τmajor = 18.8 min, τminor = 34.2
min (er = 82:18).
(8) Bordwell, F. G. Acc. Chem. Res. 1988, 21 (456), 463 and references
cited inthere.
’ ASSOCIATED CONTENT
(9) (a) Alemꢀan, J.; del Solar, V.; Navarro-Ranninger, C. Chem.
Commun. 2010, 46, 454. (b) Alemꢀan, J.; del Solar, V.; Cubo, L.; Gꢀomez,
A.; Navarro-Ranninger, C. Dalton Trans. 2010, 39, 10601.
(10) For recent examples, see, e.g.: (a) García Manche~no, O.;
Tangen, P.; Rohlmann, R.; Fr€ohlich, R.; Alemꢀan, J. Chem.—Eur.
J. 2011, 17, 984. (b) Alemꢀan, J.; Nꢀu~nez, A.; Marzo, L.; Marcos, V.;
Alvarado, C.; García Ruano, J. L. Chem.—Eur. J. 2010, 16, 9453. (c)
Alemꢀan, J.; Marcos, V.; Marzo, L.; García Ruano, J. L. Eur. J. Org. Chem.
2010, 4482.
(11) The presence of water is completely necessary to obtain
reactivity toward the corresponding aqua complex (see ref 9).
(12) All these reactions were performed in the presence of 50 μL of
H2O. Dried solvents inhibit the cyclization reaction.
(13) Different trials with cinchona and thioureaꢀcinchona alkaloid
catalysts have been attempted, obtaining in all the cases moderate
enantioselectivies.
(14) Lower catalytic loading of complex 5c (1ꢀ2 mol%) did not
afford the final compound 8a, and only the intermediate lactone 4a was
observed. Lactone 3 exclusively in the presence of water did not react
after 48 h, indicating that the platinum complex is necessary to obtain the
opened products.
(15) DABCO and compound acid 9a gave the corresponding salt,
avoiding the deprotonation at the R-poisition to the acid moiety.
(16) For recent examples, see: (a) Muratore, M. E.; Holloway, C. A.;
Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon, D. J. J. Am. Chem. Soc.
2009, 131, 10796. (b) Singh, P. R.; Surpur, M. P.; Patil, S. B. Tetrahedron
Lett. 2008, 49, 3335. (c) Cam, K. R.; Woo, J. C. S.; Lee, S.; Tillyer, R. D.
Org. Lett. 2004, 6, 79.
(17) For a general review of the use of silyldiarylprolinol ethers as
catalysts see: (a) Mielgo, A.; Palomo, C. Chem. Asian J. 2008, 3, 922. (b)
Xu, L.-W.; Li, L.; Shi, Z.-H. Adv. Synth. Catal. 2010, 352, 243.
(18) We have tried lower catalyst loadings (5ꢀ10 mol%); however,
only lower yields were obtained.
Supporting Information. HPLC chromatograms and 1H
S
b
NMR and 13C NMR spectra for all of the compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: jose.aleman@uam.es.
’ ACKNOWLEDGMENT
We acknowledge a grant from the Spanish MEC (SAF2009-
09431). J.A. and V.S. thank the Spanish MICINN for a Ramꢀon y
Cajal contract and a predoctoral fellowship, respectively.
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