Solvent-free asymmetric vinylogous aldol reaction of Chan's diene with aromatic aldehydes catalyzed by hydrogen bonding

Article abstract of DOI:10.1016/j.tet.2009.01.112

Chan's diene proved to react with aromatic aldehydes under organocatalytic conditions in presence of a chiral naphthyl-TADDOL derivative to give vinylogous aldols (up to 65% ee) with complete γ-selectivity. A further process of hetero-Diels-Alder cycloadd

Full text of DOI:10.1016/j.tet.2009.01.112

Tetrahedron 65 (2009) 5571–5576
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Solvent-free asymmetric vinylogous aldol reaction of Chan’s diene with aromatic
aldehydes catalyzed by hydrogen bonding
,
b
b
b
b,
*
Rosaria Villano a , Maria Rosaria Acocella , Antonio Massa , Laura Palombi , Arrigo Scettri
*
a Istituto di Chimica BiomolecolaredCNR, Trav. La Crucca 3, Reg. Baldinca, 07040 Li Punti (Sassari), Italy
b
`
Dipartimento di Chimica, Universita di Salerno, via Ponte don Melillo, 84084 Fisciano (Salerno), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 October 2008
Received in revised form 27 January 2009
Accepted 28 January 2009
Available online 14 April 2009
Chan’s diene proved to react with aromatic aldehydes under organocatalytic conditions in presence of
a chiral naphthyl-TADDOL derivative to give vinylogous aldols (up to 65% ee) with complete -selectivity.
A further process of hetero-Diels–Alder cycloaddition, leading to chiral pyran-4-one derivatives (up to
60% ee), was favoured by electron-withdrawing substituents on the aromatic ring.
Ó 2009 Elsevier Ltd. All rights reserved.
g
Keywords:
Asymmetric synthesis
Chan’s diene
Organocatalysis
Hydrogen bonding
Vinylogous aldol reaction
Hetero-Diels–Alder reaction
1. Introduction
As clearly reported in Table 1, a high level of enantioselectivity
can be observed with variously substituted aldehydes, indicating
In the last years Chan’s diene 1, a highly oxygenated masked
form of an acetoacetate ester, has proven to be a valuable starting
material for the synthesis of a notable variety of classes of com-
pounds.1 Particularly, Chan’s diene has been conveniently used in
highly enantioselective vinylogous aldol reactions,2 to afford
a negligible occurrence of a background reaction leading to racemic
aldols 3.
However, a set of experiments performed under solvent-free
conditions on benzaldehyde (chosen as the representative sub-
strate) pointed out the relevant nucleophilic properties of Chan’s
diene 1 (Scheme 2): in fact, in the absence of any added catalyst, the
vinylogous aldol reaction leading to the corresponding aldol 3a was
found to take place in significant yield (entries 1–3, Table 2).
d
-hydroxy-b-ketoesters, key-intermediates in the preparation of
many bio-active compounds. In fact, in the presence of catalytic
amounts (2–8 mol %) of chiral Ti(OiPr)4/BINOL complex, the ex-
clusive formation of products 3 was found to take place in high
yields and enantiomeric excesses (Scheme 1, Table 1).2b,3
Table 1
Ti(OiPr)4/R-BINOL catalyzed vinylogous aldol reaction of 1
Entry
2
R
Conditions
Yielda (%)
eeb (%)
1) Ti(IV)/R-BINOL,
2 h/ꢀ78 ꢁC; 16 h/rt
2 h/ꢀ78 ꢁC; 16 h/rt
2 h/ꢀ78 ꢁC; 16 h/rt
2 h/ꢀ78 ꢁC; 16 h/rt
4 h/rt
94
68
86
77
d
d
d
>99
91
90
93
d
Me3SiO
OSiMe3
OMe
OH O
1
2a
2b
2c
2d
2a
2a
2a
Ph
MS, THF
+
2
4-MeOC6H4
4-NO2C6H4
4-CF3C6H4
Ph
Ph
Ph
COOMe
RCHO
2) H+
R
3b
4
1
2
3
5c
6d
7d
Scheme 1.
4 h/rt
16 h/rt
d
d
a
Yields refer to isolated chromatographically pure compounds 3, whose struc-
tures were confirmed by spectroscopic data (1H NMR, 13C NMR, MS, IR).
b
* Corresponding authors. Tel.: þ39 0792841204; fax: þ39 0793961036 (R.V.); tel.:
þ39 089969583; fax: þ39 089969603 (A.S.).
ees were determined by HPLC analysis.
c
In this entry the reaction was carried out in the absence of Ti(OiPr)4/R-BINOL and
MS.
E-mail addresses: rosaria.villano@icb.cnr.it (R. Villano), scettri@unisa.it
(A. Scettri).
d
In this entry the reaction was carried out in the absence of Ti(OiPr)4/R-BINOL.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.112

5572
R. Villano et al. / Tetrahedron 65 (2009) 5571–5576
O
Me3SiO
OSiMe3
OMe
OH O
no catalyst
+
+
COOMe
RCHO
R
no solvent, rt
R
O
4
OMe
1
2
3
Scheme 2.
by hydrogen bonding has been exploited only in a few procedures
both for the vinylogous aldol condensations9 and HDA reactions7 of
masked acetoacetates.
Table 2
Solvent-free reaction of Chan’s diene 1 with aldehydes 2
Entry
2
R
Reaction time (h)
3 Yielda (%)
4 Yielda (%)
1
2
3
4
5
6
7
2a
2a
2a
2b
2c
2e
2e
Ph
Ph
Ph
4
24
72
4
4
4.5
24
36
46
25
9
44
39
50
d
d
d
d
12
21
37
2. Results and discussion
4-MeOC6H4
4-NO2C6H4
2-NO2C6H4
2-NO2C6H4
Therefore the reactivity of Chan’s diene was examined under
solvent-free conditions in the presence of a set of commercially
available hydrogen bond donors.
Benzaldehyde 2a and 2-NO2-benzaldehyde 2e were chosen,
respectively, as non-activated and activated representative
substrates.
a
Yields refer to isolated chromatographically pure compounds 3 and 4, whose
structures were confirmed by spectroscopic data (1H NMR, 13C NMR, MS, IR).
As reported in Scheme 5 and Table 3, benzaldehyde was sub-
mitted to reaction with Chan’s diene 1 in the presence of some
commercially available hydrogen bond donors.
Furthermore, while electron-rich aldehydes, such as 4-MeO-
benzaldehyde, exhibited a very poor reactivity (entry 4, Table 2),
a quite different result was obtained by using electron-poor alde-
hydes (entries 5–7), which were converted, under the reported
conditions, in rather good overall yield into a mixture of aldols 3
and pyran-4-one derivatives 4.
The formation of products 4 can be reasonably explained
through a hetero-Diels–Alder (HDA) reaction involving the forma-
tion of the intermediates A and B (Scheme 3).
It is noteworthy that the dihydro-pyran-4-one moiety of prod-
ucts 4 represents the main structural feature of a family of patho-
toxins isolated from Alternaria Citri,4 a fungus responsible of the
damage of rough lemon plants.
The reaction was carried out at ꢀ20 ꢁC under solvent-free con-
ditions in order (a) to limit the occurrence of the non-asymmetric
background reaction (entry 1, Table 3) and (b) to enhance the level
of activation of the aldehydic functionality by hydrogen bonding.
However, most of the used organocatalysts gave rather disap-
pointing results (entries 2–5), while, conversely, naphthyl-TADDOL
derivative (S,S)-7a (commercially available, Fig. 1) proved to be
a more promising organocatalyst. In fact, although the reaction had
to be performed at room temperature in order to have an accept-
able stirring of the very dense mixture, the formation of the
expected aldol 3a took place in modest yield and, interestingly,
in 61% ee in spite of the competing non-asymmetric pathway
(entry 6).
Rather interestingly, Brassard’s diene 5,5 strictly related to
Chan’s diene from a structural point of view, is characterized by
a quite different reactivity exhibiting a very strong tendency to
afford the isomeric pyran-2-one derivatives 6 through a [4þ2]
concerted mechanism (Scheme 4) under a variety of metal-6 or
organocatalyzed7 processes.
No significant improvement was observed after more prolonged
reaction times (entry 7), while slight increase of ee was obtained at
0 ꢁC at the expense of the efficiency of the process (compare entries
6 and 8).
Now, in these last years an even increasing interest has been
devoted to the organocatalysis8 and, particularly, carbonyl activation
1) organocatalyst, -20 °C
OH
O
no solvent
1
+ 2a
COOMe
2) H+
Ph
OSiMe3
3a
OSiMe3
H
Scheme 5.
+
MeO
OSiMe3
OMe
R
O
R
O
OSiMe3
1
2
A
Table 3
Asymmetric vinylogous aldol reaction of Chan’s diene 1 on PhCHO 2a promoted by
organocatalysts
O
O
Entry
Catalyst
Reaction time (h)
3a Yielda (%)
3a eeb (%)
OSiMe3
R
O
1
2
3
4
d
72
72
72
72
72
24
72
24
25
33
d
d
R
O
4
OMe
OMe
(2R,3R)-Butanediol
0
d
B
D
-Mandelic acid
Scheme 3.
(R)-BINOL
(R,R)-7b
(S,S)-7a
(S,S)-7a
(S,S)-7a
25
43
42
42
32
8 (S)
11 (S)
61 (R)
58 (R)
65 (R)
5
6c
7c
8d
OMe
a
OMe
In all entries 1:1.3:0.1 aldehyde/1/catalyst ratios were used under solvent-free
conditions. All the yields refer to isolated chromatographically pure compounds,
whose structures were confirmed by spectroscopic data (1H NMR, 13C NMR, MS, IR).
H
cat.
+
MeO
R
O
b
R
O
O
Determined by chiral-phase HPLC analysis (CHIRALPAK AD, Hexane/EtOH
OSiMe3
5
95:5þ0.1% TFA, 1 ml/min, ¼254 nm).
l
2
6
c
The experiment was performed at room temperature.
The experiment was performed at 0 ꢁC.
d
Scheme 4.

R. Villano et al. / Tetrahedron 65 (2009) 5571–5576
5573
Ar
OH
OH
Ar
Ar
O
7a: Ar= 1-naphthyl
7b: Ar= 1-phenyl
Ph
Ph
OH
OH
Ph
Ph
OH
OH
O
Ar
Figure 1.
O
8: (R)-VANOL
9: (R)-VAPOL
OH
O
1) organocatalyst, rt
no solvent
2) H+
COOMe
1 + 2e
+
Figure 2.
O
OMe
4e
3e
NO2
NO2
OH
O
1) (S,S)-7a, rt
2) H+
Scheme 6.
1 + 2
COOMe
R
3
In the case of 2-NO2-benzaldehyde 2e (Scheme 6) not only the
competing background process seemed to be a serious problem to
circumvent (entry 1, Table 4) but the steric bulk of the ortho sub-
stituent and the Lewis basicity of the nitro group could represent
further disadvantages for an asymmetric pathway.
In fact, in the presence of some commercially available hydrogen
bonding donors (entries 2–4, Fig. 2) the usual mixture of products
3e and 4e was obtained in rather high overall yields but in almost
racemic forms. Compound (S,S)-7a again gave an interesting result
leading to 3e and 4e as enantioenriched compounds (respectively
21% and 53% ees) (entry 5).
Notably, a 30:64 3e/4e ratio was observed, reversed with respect
to the control experiment (entry 1). This different outcome can be
explained through a strong intermolecular hydrogen bond through
the organocatalyst –OH and the aldehydic carbonyl resulting in the
decrease of the LUMO energy, which favours the hetero-Diels–Al-
der pathway.9,10
In order to assess the scope of the procedure a set of non-elec-
tron-poor aldehydes was reacted with Chan’s diene 1 in the pres-
ence of (S,S)-7a (Scheme 7, Table 5) and in all entries 1–5 the
vinylogous aldols of type 3 were isolated as exclusive products.
Furthermore, aliphatic aldehydes proved to be unreactive, so
that they could be recovered completely unchanged after more
prolonged reaction times (entry 6). The results obtained in entries 4
and 5 pointed out a strong dependence both of efficiency and
enantioselectivity on the substitution pattern of the aromatic
nucleus.
Scheme 7.
All the tested aldehydes 2 showed an enhanced reactivity with
respect to non-activated aldehydes and were converted in good to
high yields in the usual mixture of enantioenriched vinylogous al-
dols 3 and pyran-4-one derivatives 4.
The choice of the experimental conditions represented a critical
factor for the preparative and stereochemical outcome: in fact,
when the experiment of entry 2 was carried out at ꢀ20 ꢁC for 72 h
in the presence of toluene (0.1 ml), 3e and 4e were isolated in
comparable yields (respectively, 32% and 30%) and a significant
increase of ees could be observed (respectively, 46% and 60%)
(entry 3).
As regards the mechanistic aspects, it has to be reminded that
a general model has been proposed for other related TADDOL-
catalyzed processes, such as the asymmetric hetero-Diels–Alder
reactions of Rawal’s10,13 and Brassard’s7 dienes, as well as the
vinylogous Mukaiyama reaction of dienol silylethers derived from
2,2,6-trimethyl-4H-1,3-dioxin-4-one.9 The main structural feature
of the TADDOL derivatives is represented by an intramolecular
hydrogen bond between the two –OH groups, while the formation
of an intermolecular hydrogen bond between the free –OH and the
aldehyde oxygen is responsible for the carbonyl activation through
the lowering of its LUMO energy. Furthermore, the sense of the
asymmetric induction has been explained in terms of a
teraction between a naphthyl nucleus and the electron-poor alde-
hydic carbonyl.
In agreement with this general model, one only TADDOL de-
rivative molecule is involved in the corresponding transition state,
consequently no evidence of nonlinear effects should have been
detected by performing a set of experiments in the presence of
variously enantioenriched organocatalysts. However, taking in
mind that the above model was proposed for reactions taking place
p–p in-
*
It is noteworthy that o-anisaldehyde and p-anisaldehyde
exhibited a similar difference of reactivity in the Mukaiyama aldol
reaction of O-silyl-N,O-ketene acetals promoted by the cyclo-
hexylidene TADDOL derivative of type 7.11
The behaviour of electron-poor aromatic and hetero-aromatic
aldehydes was successively examined under the usual conditions
(Scheme 8, Table 6).
Table 4
Table 5
Vinylogous aldol reaction of Chan’s diene 1 on 2-nitrobenzaldehyde 2e promoted by
Asymmetric vinylogous aldol reaction of Chan’s diene 1 to non-activated aldehydes
RCHO 2 promoted by 7a
organocatalysts
Entry
Catalyst
(mol %)
Reaction
time (h)
3e Yielda
(%)
3e eeb
(%)
4e Yielda
(%)
4e eeb
(%)
Entry
R
Product
3 Yielda (%)
3 eeb (%)
1
2
3
4
5
6
Ph
p-Tol
2-Furyl
p-MeOC6H4
o-MeOC6H4
n-C9H19
3a
3f
3g
3b
3h
3i
42
39
40
18
57
d
61
57
37
11
40
d
1
2
3
4
5
6
7c
d
24
24
24
24
4.5
24
72
50
53
47
42
37
30
32
d
2
4
37
35
3
26
32
64
30
d
3
0
(R)-BINOL (10%)
(R)-VANOL (5%)
(R)-VAPOL (5%)
(S,S)-7a
(S,S)-7a
(S,S)-7a
4
1
19
21
46
57
53
60
a
In all entries 1:1.3:0.1 aldehyde/1/7a ratios were used under solvent-free con-
ditions. All the yields refer to isolated chromatographically pure compounds, whose
structures were confirmed by spectroscopic data (1H NMR, 13C NMR, MS, IR).
a
In all entries 1:1.3:0.1 aldehyde/1/catalyst ratios were used under solvent-free
conditions. All the yields refer to isolated chromatographically pure compounds,
whose structures were confirmed by spectroscopic data (1H NMR, 13C NMR, MS, IR).
b
ees were determined by HPLC with a CHIRALPAK AD column. Absolute config-
uration of compounds 3a,3a 3f,12 3g12 and 3b3a was assigned as (R) by comparison of
the sign of the optical rotation with the one reported in the literature.
b
Determined by chiral-phase HPLC analysis (CHIRALPAK AD and CHIRALCEL OD).
The experiment was performed at ꢀ20 ꢁC in toluene (0.1 ml).
c

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R. Villano et al. / Tetrahedron 65 (2009) 5571–5576
O
70
60
50
40
30
20
10
0
1) (S,S)-7a,
OH
O
24h/rt
+
1 + 2
COOMe
2) H+
Ar
Ar
O
4
OMe
3
Scheme 8.
Table 6
Asymmetric vinylogous aldol reaction of Chan’s diene 1 with electron-poor aromatic
aldehydes RCHO 2 promoted by 7a
Entry Ar
Product 3 Yielda (%) eeb (%) Product 4 Yielda (%) eeb (%)
1
2
3c
4
5
6
7
p-NO2C6H4
3c
3e
3e
3d
3j
39
30
32
52
46
35
38
54
21
46
31
56
29
ND
4c
4e
4e
4d
4j
32
64
30
38
39
26
30
57
53
60
51
59
49
28
o-NO2C6H4
o-NO2C6H4
p-CF3C6H4
o-CNC6H4
p-CNC6H4
3k
4k
4l
5-NO2-2-Furyl 3l
a
In all entries 1:1.3:0.1 aldehyde/1/7a ratios were used under solvent-free con-
ditions. All the yields refer to isolated chromatographically pure compounds, whose
structures were confirmed by spectroscopic data (1H NMR, 13C NMR, MS and IR).
b
0
20
40
60
80
100
Determined by chiral-phase HPLC analysis.
Reaction conditions: 72 h/ꢀ20 ꢁC and 0.1 ml of toluene.
c
ee (S,S)-7a (%)
Figure 4.
in toluene solution, the possibility of different catalytic systems,
active under solvent-free conditions, was examined. Therefore,
2-nitro-benzaldehyde was chosen as representative substrate and
submitted to the usual treatment with Chan’s diene in the pres-
ence of enantioenriched (S,S)-7a. The results are reported in
Figures 3 and 4 and both for the vinylogous aldol condensation
and hetero-Diels–Alder reaction deviations from linearity have
been observed, allowing, therefore, to exclude the involvement of
the Rawal’s model. In our opinion, solvent-free conditions should
have favoured the formation of aggregate catalytic species and,
consequently, led to the attainment of complex curves from the
experiments performed in the presence of enantioenriched
organocatalysts. It has to be noted that three-shaped curves, as
the ones reported in Figures 3 and 4, have been rationalized on
the ground of a ML4 model.14,15
3. Conclusions
In conclusion, Chan’s diene has confirmed its synthetic versatility,
being employable in vinylogous aldol reactions proceeding with
complete g-selectivity. In spite of a strongly competing background
reaction, acceptable levels of enantioselectivity have been observed
by using a chiral naphthyl-TADDOL derivative (up to 65% ee). Fur-
thermore, in the case of electron-poor aldehydes, Chan’s diene
exhibited an additional unprecedented reactivity affording chiral
pyran-4-ones (ees up to 60%) through a hetero-Diels–Alder cyclo-
addition. Finally, the detection of nonlinear effects suggested the
involvement in the transition states of both the processes of naph-
thyl-TADDOL aggregates, as effective catalytic species.
4. Experimental
4.1. General
25
20
15
10
5
All reactions were performed in oven-dried (140 ꢁC) vials. Thin-
layer chromatography was performed on Merck Kiesegel 60 F254
plates eluting with the solvents indicated, visualized by a 254 nm
UV lamp and aqueous ceric sulfate solution. Column chromato-
graphic purification of products was carried out using silica gel 60
(70–230 mesh, Merck). All reagents (Aldrich, Fluka and Strem) were
used without further purification. Infrared spectra were recorded
on a Bruker 22 series FT-IR spectrometer. NMR spectra were
recorded on
100.03 MHz for 13C) spectrometer. Chemical shifts are given in parts
per million ( ) scale and they were referenced to residual chloro-
form (
7.26 1H, 77.0 13C). Coupling constants (J) are reported in
hertz. HPLC analysis was performed with Waters Associates
equipment (Waters 2487 Dual absorbance Detector) using
a
Bruker DRX 400 (400.135 MHz for 1H and
d
d
d
l
a CHIRALPAK AD or a CHIRALCEL OD column with mixtures and
flow rates as indicated. Mass spectrometry analysis was carried out
using an electrospray spectrometer Waters 4 micro quadrupole.
0
4.2. General procedure (Table 6)
0
20
40
60
80
100
ee (S,S)-7a (%)
In a dry vial (S,S)-7a (0.05 mmol), aldehyde (0.5 mmol) and di-
ene 1 (0.65 mmol) were added. The resulting mixture was stirred
Figure 3.

R. Villano et al. / Tetrahedron 65 (2009) 5571–5576
5575
for 24 h at room temperature, and then dry THF (2 ml) was added.
This solution was cooled at ꢀ78 ꢁC and TFA (0.2 ml) was added
dropwise, then it was permitted to warm to room temperature and
after completion of the desilylation reaction, it was neutralized by
addition of saturated aq NaHCO3. The reaction mixture was
extracted with AcOEt and the combined organic phase was dried
(MgSO4) and concentrated. The residue was purified by non-flash
chromatography (petroleum ether/AcOEt from 8:2 to 1:1) to give
the products 3 and 4.
The same procedure was used for the other chiral hydrogen
bonding donors (Tables 3 and 4) and for non-asymmetric vinylogous
reactions by omitting the employment of the chiral donor (Table 2).
The spectroscopic (IR, 1H NMR and 13C NMR) data of aldols 3a,3a
3b,3a 3c,12 3d,17 3f,12 3g,12 3h16 and 3k17 matched the ones reported
in the literature.
major enantiomer tR¼28.0; (3j): yellow oil, m/z: 248 [MþH]þ, 270
[MþNa]þ; IR (KBr, neat) 3465, 2955, 2226, 1745, 1716, 1325–1065;
1H NMR (CDCl3, 400 MHz):
d 7.65 (3H, m), 7.38 (1H, m), 5.52 (1H,
dd, J¼9.5, 2.4 Hz), 3.74 (3H, s), 3.54 (2H, s), 3.08 (1H, dd, J¼17.7,
2.4 Hz), 2.94 (1H, dd, J¼17.7, 9.5 Hz); 13C NMR (CDCl3, 400 MHz):
d
202.2, 167.0, 145.8, 133.2,132.8, 128.0, 126.6, 117.1, 109.6, 67.6, 52.5,
50.2, 49.3; enantiomeric excess was determined by HPLC (Chir-
alpak AD), hexane/iPrOH 80:20, 0.8 ml/min, major enantiomer
tR¼11.6, minor enantiomer tR¼14.3; (4j): yellow oil, m/z: 230
[MþH]þ, 252 [MþNa]þ; IR (KBr, neat) 2923, 2853, 2226, 1658, 1586,
1449, 1254; 1H NMR (CDCl3, 400 MHz):
d 7.69 (3H, m), 7.51 (1H, m),
5.83 (1H, dd, J¼13.6, 3.6 Hz), 5.00 (1H, s), 3.85 (3H, s), 2.84 (1H, dd,
J¼16.7, 13.6 Hz), 2.70 (1H, dd, J¼16.7, 3.6 Hz); 13C NMR (CDCl3,
400 MHz): d 190.5,173.6,140.4, 133.4,129.5,126.9,116.5,110.9, 83.0,
78.8, 56.1, 41.1; enantiomeric excess was determined by HPLC
(Chiralcel OD), hexane/iPrOH 95:5, 0.8 ml/min, minor enantiomer
tR¼97.0, major enantiomer tR¼101.5; (3k):17 enantiomeric excess
was determined by HPLC (Chiralpak AD), hexane/EtOH 95:5þ0.1%
TFA, 0.5 ml/min, major enantiomer tR¼132.3, minor enantiomer
tR¼140.6; (4k): yellow oil, m/z: 230 [MþH]þ; IR (KBr, neat) 2923,
2229, 1653, 1586, 1450, 1273–1181; 1H NMR (CDCl3, 400 MHz):
4.3. Spectral data of new compounds
All new compounds were fully characterized on the basis of IR,
1H NMR, 13C NMR and mass spectroscopic data. Spectral data of
selected compounds: (3f):12 enantiomeric excess was determined
by HPLC (Chiralpak AD), hexane/EtOH 95:5þ0.1% TFA, 1 ml/min
major enantiomer (R) tR¼23.3, minor enantiomer (S) tR¼30.3;
(3g):12 enantiomeric excess was determined by HPLC (Chiralpak
AD), hexane/EtOH 95:5þ0.1% TFA, 1 ml/min, major enantiomer (R)
tR¼29.4, minor enantiomer (S) tR¼42.3; (3h):16 enantiomeric excess
was determined by HPLC (Chiralpak AD), hexane/EtOH 95:5þ0.1%
TFA, 1 ml/min minor enantiomer tR¼21.2, major enantiomer
tR¼23.5; (3c):12 enantiomeric excess was determined by HPLC
(Chiralcel OD), hexane/iPrOH 90:10, 0.8 ml/min, minor enantiomer
(S) tR¼48.0, major enantiomer (R) tR¼53.0; (4c): yellow oil, m/z: 250
[MþH]þ, 272 [MþNa]þ; IR (KBr, neat) 2922, 1656, 1583, 1521, 1450,
d
7.73 (2H, d, J¼8.2 Hz), 7.53 (2H, d, J¼8.2 Hz), 5.56 (1H, dd, J¼13.0,
3.9 Hz), 4.97 (1H, s), 3.85 (3H, s), 2.76 (1H, dd, J¼16.7, 13.0 Hz), 2.66
(1H, dd, J¼16.7, 3.9 Hz); 13C NMR (CDCl3, 400 MHz):
d 190.7, 173.7,
142.3, 132.7, 126.5, 118.1, 112.8, 82.8, 79.9, 56.1, 41.9; enantiomeric
excess was determined by HPLC (Chiralcel OD), hexane/iPrOH
90:10, 0.8 ml/min, minor enantiomer tR¼73.8, major enantiomer
tR¼83.0; (3l): yellow oil, m/z: 280 [MþNa]þ; IR (KBr, neat) 3467,
2956, 2923, 1744, 1716, 1529, 1499, 1357, 1240–1021; 1H NMR
(CDCl3, 300 MHz):
d
7.28 (1H, d, J¼3.7 Hz), 6.58 (1H, d, J¼3.7 Hz),
5.25 (1H, m), 3.75 (3H, s), 3.55 (2H, s), 3.18 (2H, m); 13C NMR (CDCl3,
300 MHz):
d 202.2, 167.6, 157.2, 113.1, 110.4, 64.4, 53.3, 49.9, 47.9;
1394, 1231; 1H NMR (CDCl3, 400 MHz):
d
8.28 (2H, d, J¼8.6 Hz), 7.59
(4l): yellow oil, m/z: 240 [MþH]þ; IR (KBr, neat) 2924, 2853, 1656,
(2H, d, J¼8.6 Hz), 5.61 (1H, dd, J¼12.9, 3.9 Hz), 4.98 (1H, s), 3.86 (3H,
1586, 1505, 1449, 1393, 1234; 1H NMR (CDCl3, 300 MHz):
d 7.30 (1H,
s), 2.77 (1H, dd, J¼16.8, 12.9 Hz), 2.68 (1H, dd, J¼16.8, 3.9 Hz); 13C
d, J¼3.6 Hz), 6.70 (1H, d, J¼3.6 Hz), 5.61 (1H, dd, J¼11.5, 4.2 Hz),
NMR (CDCl3, 400 MHz):
d 190.6, 173.7, 148.0, 144.1, 126.6, 124.1,
4.95 (1H, s), 3.83 (3H, s), 2.99 (1H, dd, J¼16.8, 11.5 Hz), 2.78 (1H, dd,
82.8, 79.7, 56.2, 42.0; enantiomeric excess was determined by HPLC
(Chiralcel OD), hexane/iPrOH 90:10, 0.8 ml/min, minor enantiomer
tR¼84.9, major enantiomer tR¼113.6; (3e): yellow oil, m/z: 290
[MþNa]þ; IR (KBr, neat) 3507, 2957, 1745,1716,1526,1345–1077; 1H
J¼16.8, 4.2 Hz); 13C NMR (CDCl3, 300 MHz):
d 190.1, 173.5, 152.6,
113.0, 112.2, 83.7, 73.5, 57.0, 38.4; enantiomeric excess was de-
termined by HPLC (Chiralcel OD), hexane/iPrOH 90:10, 0.8 ml/min,
minor enantiomer tR¼89.5, major enantiomer tR¼99.1.
NMR (CDCl3, 400 MHz):
d
7.96 (1H, d, J¼8.2 Hz), 7.89 (1H, d,
J¼7.8 Hz), 7.67 (1H, m), 7.44 (1H, m), 5.70 (1H, dd, J¼9.2, 1.9 Hz),
3.75 (3H, s), 3.55 (2H, s), 3.22 (1H, dd, J¼17.7, 1.9 Hz), 2.87 (1H, dd,
Acknowledgements
J¼17.7, 9.2 Hz); 13C NMR (CDCl3, 400 MHz):
d 202.4, 167.1, 147.0,
`
We are grateful to Universita di Salerno for financial support.
138.0, 133.8, 128.4, 128.1, 124.4, 65.4, 52.5, 50.7, 49.2; enantiomeric
excess was determined by HPLC (Chiralcel OD), hexane/iPrOH
90:10, 0.8 ml/min, minor enantiomer tR¼28.0, major enantiomer
tR¼31.4; (4e): yellow oil, m/z: 250 [MþH]þ; IR (KBr, neat) 2923,
2853, 1659, 1590, 1527, 1449, 1395–1054; 1H NMR (CDCl3,
References and notes
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400 MHz):
d
8.05 (1H, d, J¼8.2 Hz), 7.84 (1H, d, J¼7.6 Hz), 7.74 (1H,
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m), 7.56 (1H, m), 6.15 (1H, dd, J¼13.4, 3.3 Hz), 4.99 (1H, s), 3.83 (3H,
s), 2.94 (1H, dd, J¼16.8, 3.3 Hz), 2.71 (1H, dd, J¼16.8, 13.4 Hz); 13C
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d 190.9, 173.7, 147.3, 134.7, 134.0, 129.6,
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127.9, 124.9, 83.0, 65.4, 56.1, 41.7; enantiomeric excess was de-
termined by HPLC (Chiralcel OD), hexane/iPrOH 90:10, 0.8 ml/min,
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antiomeric excess was determined by HPLC (Chiralpak AD), hex-
ane/EtOH 95:5þ0.1% TFA, 1 ml/min, major enantiomer tR¼15.9,
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(CDCl3, 400 MHz):
d
7.69 (2H, d, J¼8.0 Hz), 7.53 (2H, d, J¼8.0 Hz),
5.56 (1H, dd, J¼13.4, 3.5 Hz), 4.97 (1H, s), 3.84 (3H, s), 2.79 (1H, dd,
J¼16.7, 13.4 Hz), 2.65 (1H, dd, J¼16.7, 3.5 Hz); 13C NMR (CDCl3,
400 MHz):
d 191.1, 173.8, 145.0, 141.1, 126.2, 125.8, 108.2, 82.8, 80.3,
56.0, 42.0; enantiomeric excess was determined by HPLC (Chiralcel
OD), hexane/iPrOH 90:10, 0.8 ml/min, minor enantiomer tR¼22.8,

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