Stereoselective synthesis of chiral 2,3-disubstituted 2,3-dihydro-4(1H)- pyridones

Article abstract of DOI:10.1002/ejoc.200800697

The alkylation at C-3 of the easily accessible (R)-2-[(S)-1,2- bis(benzyloxy)ethyl]-1-[(S)-1-phenylethyl]-2,3-dihydro-4(1H)-pyridone with different electrophiles took place with total trans diastereoselectivity to afford the corresponding (2R,3S)-2,3-disubstituted 2,3-dihydro-4(1H)-pyridones in enantiomerically pure form. The configuration at C-3 can be inverted by deprotonation and subsequent reprotonation to yield the corresponding (2R,3R)-2,3-disubstituted 2,3-dihydro-4(1H)-pyridones in a highly diastereoselective manner. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800697

FULL PAPER
DOI: 10.1002/ejoc.200800697
Stereoselective Synthesis of Chiral 2,3-Disubstituted
2,3-Dihydro-4(1H)-pyridones
Pablo Etayo,[a] Ramón Badorrey,[a] María D. Díaz-de-Villegas,*[a] and José A. Gálvez*[a]
Keywords: Asymmetric synthesis / Enolate alkylation / Piperidines / Stereoselectivity / Synthetic methods
The alkylation at C-3 of the easily accessible (R)-2-[(S)-1,2-
verted by deprotonation and subsequent reprotonation to
bis(benzyloxy)ethyl]-1-[(S)-1-phenylethyl]-2,3-dihydro-4(1H)- yield the corresponding (2R,3R)-2,3-disubstituted 2,3-dihy-
pyridone with different electrophiles took place with total
trans diastereoselectivity to afford the corresponding (2R,3S)-
2,3-disubstituted 2,3-dihydro-4(1H)-pyridones in enantio-
merically pure form. The configuration at C-3 can be in-
dro-4(1H)-pyridones in a highly diastereoselective manner.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
In this paper, we detail the functionalisation of 2,3-dihy-
dro-4(1H)-pyridone 1 at C-3 with the diastereoselective al-
kylation of the corresponding enolate as a synthetic strat-
egy. In this context, the methylation at C-3 of the six-mem-
bered heterocyclic ring in chiral 2-substituted N-(alkoxycar-
bonyl)-2,3-dihydro-4(1H)-pyridones has been successfully
exploited by Comins an co-workers as an approach to the
asymmetric synthesis of dienomycin C,[12] indolizidine alka-
loids,[13] several benzomorphane derivatives[14] and other
piperidine-containing compounds.[15] Kunz et al. studied the
alkylation of chiral enolates derived from 2-substituted N-
arabinopyranosyl-2,3-dihydro-4(1H)-pyridones with methyl
and ethyl iodide,[16] and Ma and co-workers reported the
alkylation of a chiral 2-substituted 4-oxoquinoline with 2-
bromoethyl trifluoromethanesulfonate in a route to marti-
nellic acid[17]. The alkylation at C-3 of some racemic 2-sub-
stituted 2,3-dihydro-4(1H)-pyridones directed to the synthe-
sis of azadecalines has also been described.[18] Finally, dur-
ing the preparation of this manuscript, Wanner and Ege[19]
described the diastereoselective methylation and ben-
zylation of racemic 2-substituted N-acyl-2,3-dihydro-4(1H)-
pyridones as a key step in the synthesis of 2,3-disubstituted
β-amino acid derivatives.
Introduction
Numerous natural compounds and synthetic derivatives
with interesting biological activities[1] and useful chemo-
therapeutic profiles[2] feature piperidine subunits as an es-
sential pharmacophoric motif. Piperidines with various
substitution patterns exhibit different pharmacological
properties and, as a consequence, research into the develop-
ment of synthetic strategies for the preparation of polysub-
stituted piperidines in enantiomerically pure form has
grown dramatically in recent years.[3]
As a part of a programme aimed at the design and prepa-
ration of polyfunctionalised, chiral building blocks that are
useful for the asymmetric synthesis of biologically active
nitrogen-containing compounds, we have studied the behav-
iour of (R)-2-[(S)-1,2-bis(benzyloxy)ethyl]-1-[(S)-1-phenyl-
ethyl]-2,3-dihydro-4(1H)-pyridone (1) as a synthetic precur-
sor to obtain chiral 2,3-disubstituted 2,3-dihydro-4(1H)-pyr-
idones in enantiomerically pure form. This synthetic inter-
mediate is easily available on gram scale from inexpensive
-mannitol,[4] which comes from renewable sources. The
ease with which C-2 and/or C-4 can be functionalised is
well illustrated by the expedient asymmetric synthesis of
(R)-4-oxopipecolic acid,[5] (2S,4R)-1-(tert-butoxycarbonyl)-
N-tert-butyl-4-hydroxypipecolamide,[6] (R)- and (S)-2-sub-
stituted 4-alkylidenepiperidines,[7] (2R,4S)- and (2R,4R)-4-
phosphonomethylpiperidine-2-carboxylic acids,[8] cis- and
trans-1,2,4-trisubstituted piperidines,[9] (R)-quinuclidine-2-
carboxylic acid[10] and (2R,4R)-N-(tert-butoxycarbonyl)-4-
[2-(methoxycarbonylamino)ethyl]pipecolic acid.[11]
Results and Discussion
2,3-Dihydro-4(1H)-pyridone 1 was obtained by the reac-
tion of Danishefsky’s diene with (S)-2,3-di-O-benzyl-N-[(S)-
1-phenylethyl]glyceraldimine as described previously.[4] The
optimization of the reaction of 1 with methyl iodide was
first examined by exploring several bases (Table 1). Com-
pound 1 in THF was deprotonated with a slight excess of
base (1.1 equiv.) at –78 °C for 30 min. Methyl iodide was
then added in excess (4.8 equiv.), and after 3 h at –78 °C,
the reaction was quenched with aqueous ammonium chlo-
[a] Departamento de Química Orgánica, Instituto de Ciencia de
Materiales de Aragón, Instituto Universitario de Catálisis
Homogénea, Universidad de Zaragoza – CSIC,
50009 Zaragoza, Spain
Fax: +34-976-761202
E-mail: loladiaz@unizar.es
jagl@unizar.es
6008
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6008–6014

Stereoselective Synthesis of 2,3-Disubstituted 2,3-Dihydro-4(1H)-pyridones
ride. In all cases, the methylated product 2, with a trans trans diastereoselectivity but with a lower isolated yield. In
configuration, was obtained in diastereomerically pure an attempt to increase the yield, the amount of alkylating
1
form, as determined by H and 13C NMR analyses.
agent was doubled. It was gratifying to find that in contrast
to the results with methyl iodide, doubling the amount of
ethyl iodide provided ethylated trans-3 in improved yield.
Table 1. Diastereoselective methylation of 1.
Table 2. Diastereoselective alkylation of 1.
Entry
Base
2/1[a]
trans/cis[a]
Yield[b]
1
2
3
4
5
6
7
LDA
LiHMDS
NaHMDS
KHMDS
nBuLi
sBuLi
tBuLi
95:5
95:5
Ͼ98:2
77:23
Ͼ98:2
81:19
73:27
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
64%
66%
68%
52%
48%
39%
40%
Entry
RX (equiv.)
Product
dr[a]
Yield[b]
1
2
3
4
5
6
7
8
9
MeI (4.8)
EtI (4.8)
MeI (9.6)
EtI (9.6)
nPrI (9.6)
trans-2
trans-3
trans-2
trans-3
trans-4
trans-5
trans-6
trans-7
trans-8
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
Ͼ98:2
74%
55%
71%
66%
56%
58%
59%
53%
57%
nBuI (9.6)
1
[a] Determined by H NMR analysis of the crude reaction mixture.
[b] Isolated yield of the trans diastereomer.
CH2=CHCH2Br (9.6)
BnBr (9.6)
tBuO2CCH2Br (9.6)
1
[a] Determined by H NMR analysis of the crude reaction mixture.
As shown in Table 1, the best results were obtained with
NaHMDS. By using this base, the conversion was complete,
and 2 was isolated in 68% yield. When LDA or LiHMDS
were used, the isolated yield of 2 was similar, but some un-
[b] Isolated yield of the trans diastereomer.
The reaction of 1 with several other alkylating agents
reacted starting material was detected in the reaction mix- showed similar results. Alkyl, allyl and benzyl halides and
ture. The use of other bases such as KHMDS, nBuLi, sBuLi tert-butyl bromoacetate reacted to give satisfactory yields
or tBuLi did not have a positive influence, and a significant and total trans diastereoselectivities regardless of the size of
decrease in isolated yield was observed under the same reac- the electrophile.
tion conditions.
In order to study the synthesis of cis-2,3-disubstituted
In an effort to improve the reaction yield, a number of 2,3-dihydro-4(1H)-pyridones from trans-2,3-disubstituted
additional experiments with NaHMDS as the base were 2,3-dihydro-4(1H)-pyridones through a deprotonation/re-
performed. An increase in the temperature after the ad- protonation sequence, a new substrate was obtained accord-
dition of methyl iodide, even up to room temperature, did ing to Scheme 1. Treatment of 2,3-di-O-benzyl--glyceral-
not affect the yield or trans diastereoselectivity. When the dehyde with methylamine in the presence of anhydrous
amount of base was doubled, an increase in isolated yield MgSO4 afforded the corresponding N-methylimine. This
was observed at room temperature. The combination of the compound reacted with Danishefsky’s diene in the presence
base with some additives such as HMPA or a crown ether, of a ZnI2 catalyst at low temperature in anhydrous CH3CN
which in some cases have led to noticeable increases in reac- to give cyclic enaminone 9 as a diastereomeric mixture (dr
tion yields,[20] did not have a positive influence in this case. = 93:7), in which the (2R) diastereomer predominated. The
The isolated yield was similar when NaHMDS was used in methylation of 9 as described above cleanly led to a mixture
combination with HMPA, but a substantial decrease was of compounds with a trans configuration, from which trans-
observed when NaHMDS was used in combination with 10 was isolated in 77% yield.
15-crown-5.
Several bases and reaction conditions were explored for
The optimal isolated yield of trans-2 (74%) was obtained the epimerisation of C-3 in trans-10 (Table 3). Both the ex-
when the starting compound was treated with 2.2 equiv. of tent of the epimerisation and the isolated yield of the cis
NaHMDS at –78 °C for 30 min. After the addition of diastereomer depended on the base and the reaction condi-
4.8 equiv. of methyl iodide at –78 °C, the reaction mixture tions. The epimerisation only occurred to a considerable ex-
was warmed to room temperature, stirred for 18 h, and then tent when LDA was used in excess. Otherwise, unreacted
quenched with aqueous ammonium chloride.
trans-10 was recovered, or the cis diastereomer was the
Having optimised the reaction conditions, the scope and minor compound in the product mixture. At room tempera-
limitations of the alkylation of 1 with a range of electro- ture, the crude reaction mixture was contaminated with a
philes was investigated. The results are given in Table 2. The series of unidentified by-products, a situation that led to
reaction of the enolate derived from 1 with ethyl iodide un- poor isolated yields of cis-10. Lowering the temperature to
der the same conditions as described above was investigated –78 °C significantly improved the cis stereoselectivity and
first. This reaction provided the desired product 3 with total diminished the secondary reactions. The proton source
Eur. J. Org. Chem. 2008, 6008–6014
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6009

P. Etayo, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez
FULL PAPER
Scheme 2. Epimerisation of trans-2.
troscopy. We observed that the treatment of cis-2 at room
temperature with a large excess of LiOEt (5.0 equiv.), fol-
lowed after 22 d by neutralisation with aqueous ammonium
chloride, led to the exclusive formation of trans-2
(Scheme 3). This result clearly indicates that trans-2 is ther-
modynamically more stable than cis-2.
Scheme 1. Synthesis of trans-10.
proved to have a significant influence on the extent of epi-
merisation, and the best results were obtained with aqueous
ammonium chloride. The best results overall were obtained
by the treatment of trans-10 with an excess of LDA
(2.0 equiv.) at –78 °C for 14 h and subsequent neutralisation
with aqueous ammonium chloride. Under these conditions,
the major product, cis-10, was isolated in 61% yield.
Table 3. Diastereoselective epimerisation of trans-10.
Scheme 3. Thermodynamic epimerisation of cis-2.
The relative configurations of all the 2,3-disubstituted
2,3-dihydro-4(1H)-pyridones were unambiguously deter-
mined on the basis of their vicinal homonuclear 1H-1H
coupling constants (Table 4). Theoretical calculations of
Proton source T [°C] t [h] trans/cis[a] Yield[b]
3J2-H,3-H in 2,3-disubstituted N-(alkoxycarbonyl)-2,3-dihy-
Entry
Base (equiv.)
cis
dro-4(1H)-pyridones revealed[21] that
J
≈ 5 Hz Ͼ
1
2
3
4
5
6
7
LDA (1.1)
LDA (2.0)
LiHMDS (2.0)
aq. NH4Cl
aq. NH4Cl
aq. NH4Cl
r.t.
r.t.
r.t.
18
18
12
72
14
14
14
62:38
16:84
71:29
Ͼ98:2
9:91
18%
32%
13%
–
2-H,3-H
trans
J
≈ 1 Hz, which is consistent with other results
2-H,3-H
reported in the literature.[19,22] The pseudoaxial disposition
adopted by the C-2 substituent in 1,2,3-trisubstituted 2,3-
dihydro-4(1H)-pyridones to minimise 1,2-allylic strain[23]
NaHMDS (2.0) aq. NH4Cl
r.t.
LDA (2.0)
LDA (2.0)
LDA (2.0)
aq. NH4Cl
MeOH
iPrOH
–78
–78
–78
61%
38%
51%
28:72
24:76
3
[A(1,2)] accounts for the small value of J2-H,3-H observed in
[a] Determined by 1H NMR analysis of the crude reaction mixture.
the trans diastereoisomers.
[b] Isolated yield of the cis diastereomer.
3
Table 4. J2-H,3-H values.
The treatment of trans-2 with LDA as described above
led to an 84:16 cis/trans diastereomeric mixture, from which
the major compound, cis-2, was isolated in 57% yield. The
yield and diastereoselectivity were better with a large excess
of LDA (5.0 equiv.) and after 30 min neutralisation with
aqueous ammonium chloride at –78 °C. These new condi-
tions allowed for the isolation of cis-2 in 81% yield from the
94:6 cis/trans diastereomeric mixture obtained (Scheme 2).
We attempted to identify the thermodynamically most
stable diastereomer. Disubstituted 2,3-dihydro-4(1H)-pyri-
dones 2 of cis and trans configuration were treated with
several bases such as KOH, KOtBu and LiOEt. Whereas
trans-2 was recovered after several days, cis-2 slowly isomer-
ised to trans-2. The epimerisation of cis-2 with LiOEt, gen-
erated in situ by the addition of 5.0 equiv. of LiHMDS to
anhydrous ethanol, was monitored by 1H NMR spec-
Entry Compound
R1
R2
3J2-H,3-H
1
2
3
4
5
6
7
8
9
trans-2
cis-2
(S)-CH(Me)Ph
(S)-CH(Me)Ph
(S)-CH(Me)Ph
(S)-CH(Me)Ph
(S)-CH(Me)Ph
Me
Me
Et
nPr
nBu
1.3 Hz
6.3 Hz
1.3 Hz
1.4 Hz
1.3 Hz
trans-3
trans-4
trans-5
trans-6
trans-7
trans-8
trans-10
cis-10
(S)-CH(Me)Ph CH2CH=CH2 1.2 Hz
(S)-CH(Me)Ph
(S)-CH(Me)Ph
Me
Bn
CH2CO2tBu
Me
0 Hz
0 Hz
1.3 Hz
6.8 Hz
10
Me
Me
6010
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6008–6014

Stereoselective Synthesis of 2,3-Disubstituted 2,3-Dihydro-4(1H)-pyridones
with precoated silica gel polyester plates, and products were visual-
The total diastereoselectivity of the alkylation fully
agrees with other results previously reported in the litera-
ture and can be rationalised by taking into account the
structural properties of the enolate acting as the nucleo-
phile. As a consequence of the strong sp2-hybridised charac-
ter of the nitrogen atom in the enaminone system, the inter-
mediate endocyclic enolate must be almost planar, with the
nitrogen substituent placed in the heterocycle plane. This
forces the bulky substituent at C-2 into a pseudoaxial orien-
ised with UV light (254 nm) and exposed to ethanolic phosphomol-
ybdic acid solution, followed by heating. Column chromatography
was performed with silica gel (Kiesegel 60, 230–400 mesh). Melting
points were determined in open capillaries with a Gallenkamp cap-
illary melting point apparatus and are not corrected. IR spectra of
oils were recorded as thin films with NaCl plates with a Thermo
Nicolet Avatar 360 FT-IR spectrometer; ν values expressed in cm–1
˜
are given for the main absorption bands. NMR spectra were ac-
quired with Bruker AV spectrometers operating at 500 or 400 MHz
tation to minimise 1,2-allylic strain.[23] In this situation, the for H NMR and 125, 100 or 75 MHz for 13C NMR at room tem-
1
perature in CDCl3 with a 5 mm probe. Chemical shifts (δ) are re-
ported in parts per million (ppm) and were referenced to the resid-
ual solvent peak. Coupling constants (J) are quoted in Hz. The
following abbreviations are used: s, singlet; d, doublet; q, quartet;
m, multiplet; br. s, broad singlet; br. d, broad doublet; dd, doublet
of doublets; qd, quartet of doublets; ddd, doublet of doublet of
doublets; qdd, quartet of doublet of doublets; br. dd, broad doublet
of doublets; dddd, doublet of doublet of doublet of doublets. Op-
tical rotations were measured with a Jasco 1020 polarimeter at λ =
589 nm and 25 °C in a cell with 10 cm path length; [α]2D0 values are
given in 10–1 degcmg–1, and concentrations are given in g/100 mL.
High-resolution mass spectra were recorded with a Bruker Dalton-
ics MicroToF-Q electrospray instrument from methanolic solutions
with the positive electrospray ionization mode (ESI+). (R)-2,3-Di-
O-benzylglyceraldehyde[24] and (R)-2-[(S)-1,2-bis(benzyloxy)ethyl]-
1-[(S)-1-phenylethyl]-4-piperidone[4] (1) were prepared as described
previously in the literature.
attack of the electrophile opposite to the C-2 substituent
leading to trans compounds will be favoured on the basis
of both steric and stereoelectronic arguments (Figure 1).
The same rationale would explain the formation of cis com-
pounds in the protonation of enolates derived from trans-2
or trans-10.
General Procedure for the Diastereoselective Alkylation of (R)-2-
[(S)-1,2-Bis(benzyloxy)ethyl]-1-[(S)-1-phenylethyl]-2,3-dihydro-4(1H)-
pyridone (1): A solution of (R)-2-[(S)-1,2-bis(benzyloxy)ethyl]-1-[(S)-
1-phenylethyl]-2,3-dihydro-4(1H)-pyridone (1, 221 mg, 0.5 mmol) in
anhydrous THF (10 mL) was added to NaHDMS (1.0  in THF,
1.10 mL, 1.1 mmol), diluted in anhydrous THF (5 mL) at –78 °C un-
der argon, and the mixture was stirred at –78 °C for 30 min. The
appropriate alkylating agent (2.4 or 4.8 mmol) was then added at
–78 °C, and the reaction mixture was warmed to room temperature.
After stirring at room temperature for 18 h, saturated aqueous
Figure 1. Stereochemical course of enolate neutralisation.
Conclusions
(R)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-1-[(S)-1-phenylethyl]- NH4Cl (15 mL) was added carefully with stirring. The mixture was
extracted with Et2O (3ϫ20 mL), the combined organic layers were
dried with anhydrous MgSO4 and filtered, and the solvents were
evaporated in vacuo. Purification of the residue by filtration through
a silica gel path gave the corresponding (2R,3S)-2,3-disubstituted-2,3-
dihydro-4(1H)-pyridone.
2,3-dihydro-4(1H)-pyridone (1) is a versatile synthetic inter-
mediate for the asymmetric synthesis of 2,3-disubstituted
2,3-dihydro-4(1H)-pyridones by alkylation at C-3 as the key
step. Reaction of 1 with alkyl, allyl and benzyl halides and
tert-butyl bromoacetate allowed for the preparation of
trans-2,3-disubstituted 2,3-dihydro-4(1H)-pyridones with (2R,3S)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-2,3-dihydro-3-methyl-1-[(S)-1-
phenylethyl]-4(1H)-pyridone (trans-2): The residue was purified by fil-
tration through a silica gel path (eluent: AcOEt) to afford trans-2
the (2R,3S) configuration in enantiomerically pure form.
Once the trans diastereomer with a (2R,3S) configuration
was obtained, we converted it into the corresponding cis
diastereomer with a (2R,3R) configuration by deproton-
ation with an appropriate base and subsequent reproton-
ation. We note that this synthetic strategy allows the synthe-
sis of 2,3-disubstituted 2,3-dihydro-4(1H)-pyridones that
are structurally and stereochemically diverse at C-3 with a
simple methodology.
(168 mg, 74%). Oil. [α]2D5 = –20.1 (c = 1.29, CHCl ). IR (neat): ν =
˜
3
1634, 1576 cm–1. H NMR (400 MHz, CDCl3): δ = 1.21 (d, J =
1
7.3 Hz, 3 H), 1.59 (d, J = 6.9 Hz, 3 H), 2.36 (qdd, J = 7.3, 1.3,
1.2 Hz, 1 H), 3.56 (dd, J = 11.2, 3.9 Hz, 1 H), 3.75 (ddd, J = 8.2,
1.4, 1.3 Hz, 1 H), 3.78 (dd, J = 11.2, 2.4 Hz, 1 H), 4.03 (ddd, J =
8.2, 3.9, 2.4 Hz, 1 H), 4.51 (d, J = 11.7 Hz, 1 H), 4.54 (d, J = 12.1 Hz,
1 H), 4.57 (d, J = 12.1 Hz, 1 H), 4.70 (dd, J = 7.5, 1.2 Hz, 1 H), 4.71
(d, J = 11.7 Hz, 1 H), 4.74 (q, J = 6.9 Hz, 1 H), 6.67 (dd, J = 7.5,
1.4 Hz, 1 H), 7.22–7.41 (m, 15 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 18.3, 19.8, 40.3, 62.2, 62.7, 67.7, 72.2, 73.3, 76.9, 94.6,
127.6, 127.7, 127.7, 127.8, 128.2, 128.2, 128.3 (2 C), 128.7, 137.8,
138.0, 139.0, 148.6, 195.0 ppm. HRMS: calcd. for C30H34NO3 [M +
H]+ 456.2533; found 456.2527.
Experimental Section
General: All reagents were of analytical grade and were used as
obtained from commercial sources. Reactions were carried out with
anhydrous solvents. Whenever possible, the reactions were moni-
tored by thin layer chromatography (TLC). TLC was performed
(2R,3S)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-3-ethyl-2,3-dihydro-1-[(S)-1-
phenylethyl]-4(1H)-pyridone (trans-3): The residue was purified by fil-
Eur. J. Org. Chem. 2008, 6008–6014
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. Etayo, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez
FULL PAPER
tration through a silica gel path (eluent: AcOEt/hexanes, 3:1) to af- 7.29 (m, 2 H), 7.29–7.42 (m, 13 H) ppm. 13C NMR (125 MHz,
ford trans-3 (155 mg, 66%). Oil. [α]2D5 = –9.2 (c = 0.93, CHCl3). IR
CDCl3): δ = 20.3, 35.8, 45.4, 59.6, 62.3, 68.1, 72.2, 73.4, 77.1, 95.3,
1
(neat): ν = 1633, 1585 cm–1. H NMR (400 MHz, CDCl ): δ = 0.90 117.3, 127.7, 127.7, 127.7, 127.8, 128.1, 128.2, 128.3, 128.4, 128.8,
˜
3
(dd, J = 7.4, 7.4 Hz, 3 H), 1.29–1.44 (m, 1 H), 1.47 (d, J = 6.9 Hz,
3 H), 1.50–1.65 (m, 1 H), 2.00 (dddd, J = 8.0, 7.0, 1.3, 1.2 Hz, 1 H),
3.46 (dd, J = 11.2, 3.8 Hz, 1 H), 3.66 (dd, J = 11.2, 2.2 Hz, 1 H),
3.80 (ddd, J = 8.2, 1.3, 1.3 Hz, 1 H), 3.94 (ddd, J = 8.2, 3.8, 2.2 Hz,
1 H), 4.41 (d, J = 11.7 Hz, 1 H), 4.43 (d, J = 12.1 Hz, 1 H), 4.47 (d,
J = 12.1 Hz, 1 H), 4.60 (d, J = 11.7 Hz, 1 H), 4.60 (dd, J = 7.4,
1.2 Hz, 1 H), 4.64 (q, J = 6.9 Hz, 1 H), 6.58 (dd, J = 7.4, 1.3 Hz, 1
H), 7.11–7.31 (m, 15 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
11.7, 19.9, 25.0, 47.6, 60.2, 62.3, 67.6, 72.1, 73.4, 76.9, 95.0, 127.7 (2
C), 127.7, 127.8, 128.2, 128.2, 128.4 (2 C), 128.7, 137.8, 138.0, 139.2,
148.6, 194.3 ppm. HRMS: calcd. for C31H35NO3Na [M + Na]+
492.2635; found 492.2633.
135.6, 137.9, 138.0, 139.4, 149.0, 193.3 ppm. HRMS: calcd. for
C32H36NO3 [M + H]+ 482.2690; found 482.2683.
(2R,3S)-3-Benzyl-2-[(S)-1,2-bis(benzyloxy)ethyl]-2,3-dihydro-1-[(S)-1-
phenylethyl]-4(1H)-pyridone (trans-7): The residue was purified by fil-
tration through a silica gel path (eluent: AcOEt/hexanes, 2:1) to af-
ford trans-7 (141 mg, 53%). Oil. [α]2D5 = –65.8 (c = 1.26, CHCl3). IR
1
(neat): ν = 1636, 1588 cm–1. H NMR (500 MHz, CDCl ): δ = 1.40
˜
3
(d, J = 6.9 Hz, 3 H), 2.55 (dd, J = 14.3, 11.3 Hz, 1 H), 2.76 (dd, J =
11.3, 4.2 Hz, 1 H), 3.02 (dd, J = 14.3, 4.2 Hz, 1 H), 3.46 (dd, J =
11.0, 5.1 Hz, 1 H), 3.61 (dd, J = 11.0, 2.4 Hz, 1 H), 3.62 (br. d, J =
7.0 Hz, 1 H), 3.84 (ddd, J = 7.0, 5.1, 2.4 Hz, 1 H), 4.25 (d, J =
11.8 Hz, 1 H), 4.31 (d, J = 11.9 Hz, 1 H), 4.39 (q, J = 6.9 Hz, 1 H),
(2R,3S)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-2,3-dihydro-1-[(S)-1-phenyl- 4.42 (d, J = 11.9 Hz, 1 H), 4.43 (d, J = 11.8 Hz, 1 H), 4.74 (d, J =
ethyl]-3-n-propyl-4(1H)-pyridone (trans-4): The residue was purified 7.5 Hz, 1 H), 6.72 (dd, J = 7.5, 0.7 Hz, 1 H), 7.02–7.30 (m, 20 H)
by filtration through a silica gel path (eluent: AcOEt/hexanes, 2:1) to ppm. 13C NMR (125 MHz, CDCl3): δ = 20.6, 37.6, 46.2, 59.3, 62.2,
afford trans-4 (135 mg, 56%). Oil. [α]2D5 = –8.4 (c = 0.59, CHCl3). IR
68.7, 72.1, 73.4, 77.3, 95.7, 126.5, 127.6, 127.6, 127.6, 127.8, 127.8,
1
(neat): ν = 1631, 1582 cm–1. H NMR (400 MHz, CDCl ): δ = 0.84 128.3, 128.3, 128.3, 128.5, 128.9, 129.1, 137.9, 138.0, 138.2, 139.8,
˜
3
(dd, J = 7.0, 7.0 Hz, 3 H), 1.18–1.43 (m, 3 H), 1.42–151 (m, 1 H),
1.48 (d, J = 6.9 Hz, 3 H), 2.12 (br. dd, J = 6.9, 6.9 Hz, 1 H), 3.46
(dd, J = 11.2, 3.8 Hz, 1 H), 3.66 (dd, J = 11.2, 2.2 Hz, 1 H), 3.79
(ddd, J = 8.2, 1.4, 1.3 Hz, 1 H), 3.94 (ddd, J = 8.2, 3.8, 2.2 Hz, 1 H),
4.41 (d, J = 11.8 Hz, 1 H), 4.43 (d, J = 12.1 Hz, 1 H), 4.47 (d, J =
12.1 Hz, 1 H), 4.60 (d, J = 11.8 Hz, 1 H), 4.61 (dd, J = 7.4, 1.1 Hz,
1 H), 4.64 (q, J = 6.9 Hz, 1 H), 6.59 (dd, J = 7.4, 1.3 Hz, 1 H), 7.11–
7.35 (m, 15 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9, 19.9,
20.1, 33.9, 45.6, 60.3, 62.4, 67.7, 72.2, 73.5, 77.0, 95.1, 127.7, 127.7,
127.7, 127.8, 128.2, 128.3, 128.4, 128.4, 128.8, 137.9, 138.1, 139.2,
148.7, 194.5 ppm. HRMS: calcd. for C32H37NO3Na [M + Na]+
506.2666; found 506.2684.
149.3, 193.3 ppm. HRMS: calcd. for C36H38NO3 [M + H]+ 532.2846;
found 532. 2861.
(2R,3S)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-3-[(tert-butoxycarbonyl)-
methyl]-2,3-dihydro-1-[(S)-1-phenylethyl]-4(1H)-pyridone (trans-8):
The residue was purified by filtration through a silica gel path (eluent:
AcOEt/hexanes, 2:1) to afford trans-8 (158 mg, 57%). Oil. [α]2D5
=
+5.6 (c = 1.09, CHCl ). IR (neat): ν = 1727, 1638, 1580 cm–1. 1H
˜
3
NMR (400 MHz, CDCl3): δ = 1.38 (s, 9 H), 1.52 (d, J = 6.9 Hz, 3
H), 2.29 (dd, J = 15.5, 11.7 Hz, 1 H), 2.45 (dd, J = 15.5, 3.4 Hz, 1
H), 2.64 (dd, J = 11.7, 3.4 Hz, 1 H), 3.53 (dd, J = 11.0, 3.1 Hz, 1 H),
3.69 (dd, J = 11.0, 1.8 Hz, 1 H), 3.96–4.03 (m, 2 H), 4.42 (d, J =
11.4 Hz, 1 H), 4.44 (d, J = 12.1 Hz, 1 H), 4.54 (d, J = 12.1 Hz, 1 H),
(2R,3S)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-3-n-butyl-2,3-dihydro-1-[(S)-1- 4.62 (q, J = 6.9 Hz, 1 H), 4.62 (d, J = 11.4 Hz, 1 H), 4.64 (d, J =
phenylethyl]-4(1H)-pyridone (trans-5): The residue was purified by fil- 7.5 Hz, 1 H), 6.61 (d, J = 7.5 Hz, 1 H), 7.10–7.34 (m, 15 H) ppm.
tration through a silica gel path (eluent: AcOEt/hexanes, 2:1) to af- 13C NMR (100 MHz, CDCl3): δ = 20.0, 28.0, 36.3, 43.0, 59.4, 62.4,
ford trans-5 (144 mg, 58%). Oil. [α]2D5 = –13.8 (c = 0.57, CHCl3). IR
68.7, 72.4, 73.5, 76.2, 80.9, 95.6, 127.5, 127.7, 127.7, 128.0, 128.2,
1
(neat): ν = 1628, 1589 cm–1. H NMR (400 MHz, CDCl ): δ = 0.92 128.3, 128.3, 128.3, 128.8, 138.0, 138.0, 139.4, 149.5, 170.5,
˜
3
(dd, J = 7.0, 7.0 Hz, 3 H), 1.26–1.43 (m, 4 H), 1.38–1.49 (m, 1 H),
1.54–1.65 (m, 1 H), 1.58 (d, J = 6.9 Hz, 3 H), 2.19 (dddd, J = 7.4,
7.4, 1.3, 1.2 Hz, 1 H), 3.57 (dd, J = 11.2, 3.8 Hz, 1 H), 3.77 (dd, J =
11.2, 2.2 Hz, 1 H), 3.89 (ddd, J = 8.2, 1.3, 1.3 Hz, 1 H), 4.04 (ddd,
J = 8.2, 3.8, 2.2 Hz, 1 H), 4.52 (d, J = 11.7 Hz, 1 H), 4.53 (d, J =
12.1 Hz, 1 H), 4.57 (d, J = 12.1 Hz, 1 H), 4.70 (d, J = 11.7 Hz, 1 H),
4.70 (dd, J = 7.4, 1.2 Hz, 1 H), 4.74 (q, J = 6.9 Hz, 1 H), 6.70 (dd,
J = 7.4, 1.3 Hz, 1 H), 7.21–7.27 (m, 2 H), 7.26–7.40 (m, 13 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 14.0, 20.0, 22.6, 29.2, 31.5, 45.9,
60.3, 62.4, 67.8, 72.2, 73.5, 77.0, 95.2, 127.7, 127.7, 127.7, 127.8,
128.2, 128.2, 128.4, 128.4, 128.8, 137.9, 138.1, 139.3, 148.7,
194.5 ppm. HRMS: calcd. for C33H40NO3 [M + H]+ 498.3003; found
498.3009.
191.8 ppm. HRMS: calcd. for C35H41NO5Na [M + Na]+ 578.2877;
found 578.2891.
(2R,3R)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-2,3-dihydro-3-methyl-1-[(S)-1-
phenylethyl]-4(1H)-pyridone (cis-2): A solution of (2R,3R)-2-[(S)-1,2-
bis(benzyloxy)ethyl]-2,3-dihydro-3-methyl-1-[(S)-1-phenylethyl]-
4(1H)-pyridone (trans-2, 228 mg, 0.5 mmol) in anhydrous THF
(10 mL) was added to LDA (2.0  solution in n-heptane/THF/ethyl-
benzene, 1.25 mL, 2.5 mmol), diluted in anhydrous THF (5 mL) at
–78 °C under argon, and the mixture was stirred at –78 °C for 30 min.
The reaction mixture was then warmed to room temperature, and
saturated aqueous NH4Cl (15 mL) was added carefully with stirring.
The mixture was extracted with Et2O (3ϫ20 mL), the combined or-
ganic layers were dried with anhydrous MgSO4 and filtered, and the
solvents were evaporated in vacuo to yield 2 as a 94:6 mixture of
(2R,3S)-3-Allyl-2-[(S)-1,2-bis(benzyloxy)ethyl]-2,3-dihydro-1-[(S)-1-
phenylethyl]-4(1H)-pyridone (trans-6): The residue was purified by fil- cis/trans diastereoisomers. Purification of the residue by silica gel col-
tration through a silica gel path (eluent: AcOEt/hexanes, 2:1) to af- umn chromatography (eluent: AcOEt/hexanes, 2:1) gave cis-2
ford trans-6 (142 mg, 59%). Oil. [α]2D5 = –53.7 (c = 0.81, CHCl3). IR
(184 mg, 81%) as an oil. [α]2D5 = +27.4 (c = 0.95, CHCl3). IR (neat):
(neat): ν = 1640, 1631, 1589 cm–1. 1H NMR (500 MHz, CDCl ): δ =
ν = 1646, 1589 cm–1. 1H NMR (400 MHz, CDCl ): δ = 1.17 (d, J =
˜
˜
3
3
1.59 (d, J = 6.9 Hz, 3 H), 2.16–2.25 (m, 1 H), 2.37–2.44 (m, 1 H),
2.40–2.48 (m, 1 H), 3.58 (dd, J = 11.1, 4.3 Hz, 1 H), 3.76 (dd, J =
7.3 Hz, 3 H), 1.56 (d, J = 6.8 Hz, 3 H), 2.92 (qd, J = 7.3, 6.3 Hz, 1
H), 3.55 (dd, J = 10.4, 5.6 Hz, 1 H), 3.76 (dd, J = 10.4, 4.3 Hz, 1 H),
11.1, 2.4 Hz, 1 H), 3.93 (ddd, J = 7.7, 1.2, 1.2 Hz, 1 H), 4.04 (ddd, 3.82 (ddd, J = 6.3, 5.8, 1.0 Hz, 1 H), 3.92 (ddd, J = 5.8, 5.6, 4.3 Hz,
J = 7.7, 4.3, 2.4 Hz, 1 H), 4.52 (d, J = 12.0 Hz, 1 H), 4.52 (d, J =
11.7 Hz, 1 H), 4.57 (d, J = 12.0 Hz, 1 H), 4.69 (q, J = 6.9 Hz, 1 H),
4.70 (d, J = 11.7 Hz, 1 H), 4.75 (dd, J = 7.5, 0.9 Hz, 1 H), 5.12–5.18
(m, 2 H), 5.74–5.84 (m, 1 H), 6.74 (dd, J = 7.5, 1.2 Hz, 1 H), 7.22–
1 H), 4.50 (d, J = 12.0 Hz, 1 H), 4.51 (q, J = 6.8 Hz, 1 H), 4.51 (d,
J = 11.4 Hz, 1 H), 4.55 (d, J = 12.0 Hz, 1 H), 4.63 (d, J = 11.4 Hz,
1 H), 4.82 (d, J = 7.4 Hz, 1 H), 6.71 (dd, J = 7.4, 1.0 Hz, 1 H), 7.20–
7.38 (m, 15 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.1, 20.1,
6012
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 6008–6014

Stereoselective Synthesis of 2,3-Disubstituted 2,3-Dihydro-4(1H)-pyridones
41.7, 60.5, 61.7, 70.3, 73.2, 73.4, 76.5, 97.6, 127.6, 127.7, 127.7, 127.9,
128.0, 128.0, 128.3, 128.4, 128.7, 137.9, 138.1, 139.5, 150.0,
mg, 0.5 mmol) in anhydrous THF (10 mL) was added to LDA (2.0 
solution in n-heptane/THF/ethylbenzene, 0.50 mL, 1.0 mmol), di-
193.7 ppm. HRMS: calcd. for C30H34NO3 [M + H]+ 456.2533; found luted in anhydrous THF (5 mL) at –78 °C under argon, and the mix-
456. 2544.
ture was stirred at –78 °C for 14 h. The reaction mixture was then
warmed to room temperature, and saturated aqueous NH4Cl (15 mL)
was added carefully with stirring. The mixture was extracted with
Et2O (3ϫ20 mL), and the combined organic layers were dried with
anhydrous MgSO4 and filtered, and the solvents were evaporated in
vacuo to yield 10 as a 91:9 mixture of cis/trans diastereoisomers. Puri-
fication of the residue by silica gel column chromatography (1st elu-
(R)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-2,3-dihydro-1-methyl-4(1H)-pyr-
idone (9): To a solution of crude (R)-2,3-di-O-benzylglyceraldehyde
(456 mg, 1.69 mmol) in anhydrous Et2O (10 mL) were added success-
ively anhydrous MgSO4 (305 mg, 2.54 mmol) and methylamine (2.0 
in THF, 0.85 mL, 1.69 mmol). After stirring at room temperature for
6 h, the reaction mixture was filtered and concentrated in vacuo to
afford the crude imine, which was dissolved in anhydrous CH3CN
(5 mL), added to ZnI2 (98% suspension, 574 mg, 1.8 mmol) in anhy-
drous CH3CN (20 mL), and cooled under argon at –20 °C. The mix-
ture was stirred at –20 °C for 10 min, Danishefsky’s diene (0.47 mL,
2.5 mmol) was added, and stirring was continued at –20 °C for 16 h.
The mixture was treated with saturated aqueous NaHCO3 (10 mL)
and extracted with Et2O (3ϫ30 mL). The combined organic layers
were dried with anhydrous MgSO4 and filtered, and the solvents were
evaporated in vacuo. The residue obtained was purified by column
chromatography (1st eluent: Et2O/hexanes, 4:1; 2nd eluent: AcOEt)
to afford 356 mg (60%) of 2,3-dihydro-4(1H)-pyridone 9 as a 93:7
ent: Et2O; 2nd eluent: AcOEt) gave cis-10 (111 mg, 61%) as an oil.
1
[α]D25 = –97.5 (c = 0.83, CHCl ). IR (neat): ν = 1642, 1596 cm–1. H
˜
3
NMR (400 MHz, CDCl3): δ = 1.13 (d, J = 7.2 Hz, 3 H), 2.16 (qd, J
= 7.2, 6.8 Hz, 1 H), 3.07 (s, 3 H), 3.55 (dd, J = 10.3, 5.3 Hz, 1 H),
3.59 (dd, J = 6.8, 5.6 Hz, 1 H), 3.66 (dd, J = 10.3, 4.8 Hz, 1 H), 3.91
(ddd, J = 5.6, 5.3, 4.8 Hz, 1 H), 4.50 (d, J = 11.9 Hz, 1 H), 4.52 (d,
J = 11.4 Hz, 1 H), 4.54 (d, J = 11.9 Hz, 1 H), 4.60 (d, J = 11.4 Hz,
1 H), 4.85 (d, J = 7.2 Hz, 1 H), 6.86 (d, J = 7.2 Hz, 1 H), 7.23–7.39
(m, 10 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 10.8, 40.9, 43.3,
63.0, 70.1, 73.0, 73.4, 76.0, 96.7, 126.6, 126.7, 127.8, 127.8, 128.3,
128.4, 137.7, 138.0, 153.6, 193.6 ppm. HRMS: calcd. for C23H28NO3
[M + H]+ 366.2064; found 366.2061.
mixture of (2R)/(2S) diastereoisomers. Data for the (2R) dia-
stereomer: IR (neat): ν = 1635, 1592 cm–1. H NMR (400 MHz,
1
˜
CDCl3): δ = 2.27 (ddd, J = 16.9, 1.5, 1.2 Hz, 1 H), 2.83 (dd, J =
16.9, 7.2 Hz, 1 H), 3.18 (s, 3 H), 3.52 (dd, J = 11.1, 3.6 Hz, 1 H),
3.71 (dd, J = 11.1, 2.6 Hz, 1 H), 3.77 (dddd, J = 8.7, 7.2, 1.5, 1.1 Hz,
1 H), 4.11 (ddd, J = 8.7, 3.6, 2.6 Hz, 1 H), 4.46 (d, J = 11.7 Hz, 1
H), 4.55 (s, 2 H), 4.66 (d, J = 11.7 Hz, 1 H), 4.81 (dd, J = 7.3, 1.2 Hz,
Acknowledgments
The financial support of the Government of Aragón (project number:
GA E71) and the University of Zaragoza (project number: CIE-05) is
acknowledged. P. E. was supported by a fellowship from the Instituto
Universitario de Catálisis Homogénea.
1 H), 6.81 (dd, J = 7.3, 1.1 Hz, 1 H), 7.27–7.40 (m, 10 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 36.8, 44.3, 59.0, 68.0, 72.4, 73.5, 75.8,
96.3, 127.7, 127.8, 127.8, 128.1, 128.4, 128.4, 137.7, 137.7, 153.1,
189.7 ppm. HRMS: calcd. for C22H25NO3Na [M + Na]+ 374.1727;
found 374. 1742.
[1] For example, see: a) G. Lagler, Adv. Carbohydr. Chem. Biochem.
1990, 48, 319–384; b) B. Winchester, G. W. J. Fleet, Glycobiology
1992, 2, 199–210; c) M. J. Schneider in Alkaloids: Chemical and
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14, 637–651; e) J. W. Daly, T. F. Spande, H. M. Garraffo, J. Nat.
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(2R,3S)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-2,3-dihydro-1,3-dimethyl-
4(1H)-pyridone (trans-10): A solution of a 93:7 mixture of (R)-/(S)-2-
[(S)-1,2-bis(benzyloxy)ethyl]-2,3-dihydro-1-methyl-4(1H)-pyridone (9,
176 mg, 0.5 mmol) in anhydrous THF (10 mL) was added to
NaHDMS (1.0  solution in THF, 1.10 mL, 1.1 mmol), diluted in
anhydrous THF (5 mL) at –78 °C under argon, and the mixture was
stirred at –78 °C for 30 min. Methyl iodide (0.15 mL, 2.4 mmol) was
then added at –78 °C, and the reaction mixture was warmed to room
temperature. After the mixture had been stirred at room temperature
for 6 h, saturated aqueous NH4Cl (15 mL) was added carefully with
stirring. The mixture was extracted with Et2O (3ϫ20 mL), and the
combined organic layers were dried with anhydrous MgSO4 and fil-
tered, and the solvents were evaporated in vacuo. The residue ob-
tained was purified by filtration through a silica gel path (eluent:
AcOEt) to afford 141 mg (77%) of trans-10 as an oil. [α]2D5 = –172.3
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D. R. Stanski, Clin. Pharmacol. Ther. 1994, 56, 261–271; b) R. G.
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D. Zhang, Y. C. Xu, WO Patent 2004/094380, 2004; g) G. Alvaro,
(c = 0.64, CHCl ). IR (neat): ν = 1634, 1592 cm–1 1H NMR
.
˜
3
´
(400 MHz, CDCl3): δ = 1.17 (d, J = 7.3 Hz, 3 H), 2.16 (qdd, J = 7.2,
1.3, 0.9 Hz, 1 H), 3.18 (s, 3 H), 3.42 (ddd, J = 9.0, 1.3, 1.2 Hz, 1 H),
3.48 (dd, J = 11.1, 3.5 Hz, 1 H), 3.67 (dd, J = 11.1, 2.5 Hz, 1 H),
3.99 (ddd, J = 9.0, 3.5, 2.5 Hz, 1 H), 4.41 (d, J = 11.7 Hz, 1 H), 4.49
(d, J = 12.2 Hz, 1 H), 4.54 (d, J = 12.2 Hz, 1 H), 4.62 (d, J = 11.7 Hz,
1 H), 4.69 (dd, J = 7.2, 0.9 Hz, 1 H), 6.74 (dd; J = 7.2, 1.2 Hz, 1 H),
7.22–7.37 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.7,
40.6, 45.1, 65.0, 67.8, 72.4, 73.3, 75.8, 94.0, 127.6, 127.7, 127.8, 128.1,
128.3, 128.3, 137.7, 137.7, 151.8, 194.5 ppm. HRMS: calcd. for
C23H28NO3 [M + H]+ 366.2064; found 366. 2058.
F. Cardullo, L. DAdamo, E. Piga, C. Seri, WO Patent 2004/
005255, 2004; h) P. J. Coleman, C. D. Cox, R. M. Garbaccio,
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(2R,3R)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-2,3-dihydro-1,3-dimethyl-
4(1H)-pyridone (cis-10): A solution of (2R,3R)-2-[(S)-1,2-bis(benzyl-
oxy)ethyl]-2,3-dihydro-1,3-dimethyl-4(1H)-pyridone (trans-10, 183
Eur. J. Org. Chem. 2008, 6008–6014
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6013

P. Etayo, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez
FULL PAPER
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Published Online: October 31, 2008
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