Access to a new family of medium ring aromatic lactones

Article abstract of DOI:10.1016/j.tet.2006.06.071

We report a new method for preparation of hydroxyacids as precursors of benzolactones using a simple and an efficient electrochemical step. This gives in only four steps six- to eleven-membered lactones with high isolated yields from conveniently substituted aryl bromides. The lactonisation was performed according to the Yamamoto's process.

Full text of DOI:10.1016/j.tet.2006.06.071

Tetrahedron 62 (2006) 8515–8524
Access to a new family of medium ring aromatic lactones
*
Estelle Metay, Eric Leonel, Sylvie Condon and Jean-Yves Nedelec
ꢀ
ꢀ
ꢀ ꢀ
Institut des Sciences Chimiques Seine-Amont, IFR 1780, Laboratoire d’Electrochimie, Catalyse et Syntheꢁse Organique, UMR 7582,
´
CNRS—Universite Paris XII, 2 Rue Henri Dunant, B.P. 28, F-94320 Thiais, France
Received 19 May 2006; accepted 21 June 2006
Available online 20 July 2006
Abstract—We report a new method for preparation of hydroxyacids as precursors of benzolactones using a simple and an efficient electro-
chemical step. This gives in only four steps six- to eleven-membered lactones with high isolated yields from conveniently substituted aryl
bromides. The lactonisation was performed according to the Yamamoto’s process.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
including the protection–deprotection of the alcohol (respec-
tively, steps a and c in Scheme 1).
The development of new methods for the construction of
hetero- and carbo-cyclic medium ring systems has been
a long standing goal to organic chemists. Among the tar-
geted structures, medium ring lactones are of interest as
backbones of many bioactive compounds like antibiotics.1
Their access is staying difficult despite number of cyclisa-
tion methods.2 Our current investigations have focused on
the preparation of medium ring benzolactones, which are
core structures of compounds like Salicylihalamide A, a po-
tential anticancer drug.3 As a general feature, these benzo-
lactones have a non-conjugated carbonyl, and therefore,
are not obtainable through conventional methods. We have
already reported a method for preparation of the precursor
hydroxyacid, using an efficient electrochemical C–C bond
forming step (Scheme 1).4
To improve the efficiency of the synthesis, we thought of
avoiding the alcohol protection step. This can be done by
having a carbonyl group as an alcohol precursor. Based on
this, the carbonyl group should be first introduced, that re-
quires it being compatible with the electrochemical step,
or, alternatively, introduced through the electrochemical
step conducted on a starting compound bearing a carb-
oxylic group. These two pathways have been explored and
compared in this study. The first run involved 2-bromo-
phenylacetone as the starting material in the electrochemical
coupling with ethyl acrylate. As shown in Scheme 2,
the unexpected bicyclic compound 1 was only formed as
a result of a tandem reaction involving the favoured
nucleophilic addition to the carbonyl (Scheme 2). Such a
ring forming tandem reaction has already been observed,5
and cannot be avoided whatever the reaction parameters are.
2. Results and discussion
In view of this result, we chose to reverse the order of inser-
tion of the functional groups, i.e., first the carboxylic group
by a chemical step if the starting compound is not commer-
cially available, then the carbonyl in the electrochemical
coupling. We checked this route with the ester 2 and methyl-
vinylketone (MVK) (Scheme 3). We obtained the formation
of the products 3 and 4. However, the reduction product 4 is
In this approach, the starting material bears the alcohol func-
tion, while the carboxylic group is introduced through the
electrochemical step. This method was used to prepare
seven- to ten-membered benzolactones in good yields. How-
ever, this strategy requires five steps from the alcohol, which
may also be eventually commercially unavailable, and
O
c. cleavage of
b. electrochemical
coupling
Br
the protective group
Br
a. alcohol protection
OEt
Pg
O
d. saponification
e. lactonisation
O
n
O
n
quantitative
yields
OH
O
OEt
PMB
n
n
overall isolated yields
31-58%
O
yields: 40-80%
n = 1 to 4
yields: 45-80%
Scheme 1.
* Corresponding author. Tel.: +33 149781127; fax: +33 149781148; e-mail: eric.leonel@glvt-cnrs.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.071

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E. Meꢀtay et al. / Tetrahedron 62 (2006) 8515–8524
e-, NiBr2. xH2O (10%)
0.2 A, T=100°C
O
(64/36) iron/nickel rod, can quite favourably improve the
yield and the selectivity. The effect of these parameters
can be understood on the basis of the mechanism given in
Scheme 5.
Br
O
OEt
OEt
OH
+
DMF, Pyridine
O
1
O
The formation of 7 along with 6 indicates that, as shown in
Scheme 5, the key intermediate (I) can reversibly evolve into
intermediate (II) by addition to the C–C double bond. In ad-
dition, (II) can be assumed to be at least as stable as (I). This
would account for the formation of 7 in significant amount,
and for the need for some more nickel catalysts than usually
required in order to improve the yield of 6. Similar effects
have already been mentioned.6 So, having a large excess
of MVK as both reagent and ligand to shift the equilibrium
back to (I) enabled to obtain 6 in 63% isolated yield, and
without even traces of compound 7.
BrNi
OEt
O
Scheme 2.
the major isolated compound (43%). Interestingly, no cycli-
sation has occurred.
According to this procedure, we could develop a new ap-
proach to the aimed benzolactones in a shorter sequence
than the one in the previous method.4 This is summarised
in Scheme 6.
Compound 5, which was prepared by a Wittig reaction, was
next involved in the electrochemical coupling with MVK.
The purpose for this study was to check whether the conju-
gated double bond would react or not in the reaction condi-
tions, for the reason that, it could be necessary to keep it as
such to have it in the final compound, or simply not to have it
reduced in the early stage, but later along with the ketone
group (see below). Actually, this reaction ended with the
formation of a 1/1 mixture (GC) of 6 and 7 (not isolated),
as reported in Scheme 4.
We first prepared a series of commercially unavailable ortho-
bromoesters (ethyl ortho-bromophenylalkenoates) from ei-
ther ortho-bromo-2-phenylacetic acid (for n¼1 and n0¼0)
or ortho-bromobenzaldehyde (for n¼0, 1 and n0¼0–2).
Thus, compound 2 was prepared by esterification of the cor-
responding acid.7 Compounds corresponding to n¼0, 1 and
n0¼0–2 were prepared by Wittig or Wadsworth–Emmons
methods as described by Gibson8 (5 and 10), Jordis9 (9)
and Touchard10 (8). Also, to examine the possibility of
having medium ring lactones with double C–C bonds, we
have prepared the (E)-(5) and (Z)-(8) isomers of ethyl 3-(2-
bromophenyl)prop-2-enoate.
To obtain 6 selectively, and without 7, we tuned several
reaction parameters (solvent DMF–ACN instead of DMF–
Pyridine, temperature, etc.) and notably found that the use
of a large amount of MVK (ca. 10 equiv instead of 2.5 vs
ArX) as well as of a higher amount of nickel catalyst by gen-
erating nickel salts from the anode, either stainless steel or
e-, NiBr2.xH2O (10%)
Br
O
+
0.2 A, T=100°C
+
CO2Et
CO2Et
CO2Et
DMF, Pyridine
O
2
4
3
10 mmol
25 mmol
43%
38%
Scheme 3.
e-, NiBr2. xH2O (10%)
0.2 A, T=100°C
Br
O
O
+
+
CO2Et
DMF, Pyridine
O
CO2Et
5
6
7
EtO2C
50/50
Scheme 4.
O
2x
+
NiX
O
O
in or ex situ
protonation
O
O
+
O
O
O
O
NiX
O
+
NiX
EtO2C
(II)
OEt
OEt
OEt
6
(I)
Scheme 5.

E. Meꢀtay et al. / Tetrahedron 62 (2006) 8515–8524
8517
a. Electrochemical
coupling
b. Reduction of carbonyl
and / or double bond
Br
c. Saponification
d. Lactonisation
O
OH
CO2Et
n'
O
CO2Et
n'
CO2Et
n'
O
n
n
n
n
n'
n = 0, 1; n' = 0, 1, 2
Scheme 6.
The next step was the electrochemical coupling with MVK
(Scheme 7) using reaction conditions described above.
Yields are given in Table 1.
its diethyl acetal can be used instead.11 This gives the ex-
pected aldehyde 14, after hydrolysis of the adduct, with
a yield in agreement with our previous investigations11
(Scheme 8).
Br
e-, NiBr2. xH2O (10%)
O
Hydroxyesters were obtained by reduction of the carbonyl.
The keto-esters containing a C–C double bond can also be
reduced selectively either at the carbonyl of the ketone (re-
duction by NaBH4)12 or at both the carbonyl and the C–C
double bond by reaction of NiCl2/NaBH4 in MeOH, at
0 ꢀC to room temperature, as described by Narisada.13
Results are shown in Table 2.
+
CO2Et
n'
CO2Et
n'
DMF/ACN, T= 80°C
O
n
n
n = 0, 1; n' = 0, 1, 2
Scheme 7.
Isolated yields are good and show that the steric ortho ef-
fect has only a slight influence on the results in agreement
with our previous results.5 No internal tandem addition
was observed whatever the starting ester was. Of the
two stereoisomers 5 and 8 (see Table 1, entries 2 and 3)
the Z-isomer gives a lower yield along with the formation
of more of the reduced product of the C-halogen bond
(ArH). Access to primary alcohols would require acrolein
as substrate. However, previous investigations have shown
that reactions involving acrolein are unsuccessful, and that
The two final steps were conducted (Scheme 9) as in our pre-
vious paper.4 Hydroxyesters were converted to the corre-
sponding hydroxyacids by saponification in KOH–dioxane
at reflux (quantitative yields).14 Lactones were obtained
from hydroxyacids by the efficient Yamamoto’s process15
using Sc(OTf)3 (10%) and p-(NO2C6H4CO)2O (2 equiv) in
acetonitrile.
Yields for the lactonisation step are given in Table 3.
Table 1. Nickel-catalysed arylation of methylvinylketone with ortho-bromoarylester
Entry
ortho-Bromoarylester
Compound number
Product
Compound number
Isolated yield (%)
65
Br
1
2
3
O
CO2Et
CO2Et
Br
O
2
3
5
8
6
63
50
CO2Et
Br
CO2Et
O
11
EtO2C
EtO2C
Br
4
5
9
12
13
84
63
O
CO2Et
CO2Et
Br
10
O
CO2Et
CO2Et
OEt
OEt
H
Br
OEt
O
HCl, 6M
23%
e-, NiBr2, 0.1 A, T=80°C
DMF, Pyridine
CO2Et
CO2Et
CO2Et
14
5
not isolated
Scheme 8.

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E. Meꢀtay et al. / Tetrahedron 62 (2006) 8515–8524
Table 2. Reductions of keto-esters by NaBH4 or NaBH4/NiCl2
Entry
Hydroxyester obtained by NaBH4 reduction in methanol at 0 ꢀC
Hydroxyester obtained by NiCl2/NaBH4 reduction in methanol at 0 ꢀC
Compound
Isolated yield (%)
Compound
Isolated yield (%)
OH
OH
CO2Et
1
2
15
16
70
20
21
75
CO2Et
OH
OH
95
Quantitative
CO2Et
CO2Et
OH
3
17
Quantitative
—
—
EtO2C
OH
CO2Et
OH
CO2Et
4
5
18
19
Quantitative
93
22
23
Quantitative
90
OH
OH
CO2Et
CO2Et
R
O
R
R
Sc(OTf)3, 10%
KOH
Dioxane reflux
OH
OH
CO2Et
CO2H
(p-NO2C6H4CO)2O (2 equiv)
( )
( )
O
n'
n
n'
n
( )
n
n'
CH3CN
quantitative yields
for all compounds
24 to 29
15, 17, 21, 22, 23 (R = CH3),
20 (R = H)
30 to 35
Scheme 9.
Table 3. Lactonisation of hydroxyacids
Entry
Hydroxyacid
Compound number
Benzolactone
Compound number
Isolated yield (%)
8
OH
CO2H
O
1
24
30
53
O
OH
2
25
31
66
9
O
O
HO2C
OH
9
O
3
4
26
27
32
33
66
74
CO2H
O
OH
O
9
CO2H
O
O
O
5
6
28
29
34
35
65
60
OH
10
CO2H
O
O
OH
CO2H
11

E. Meꢀtay et al. / Tetrahedron 62 (2006) 8515–8524
8519
Thus, we prepared six benzolactones with ring size from 8 to
11. Regarding the possible presence of a C–C double bond in
the medium-size lactone ring, it comes out that the cyclisa-
tion was only observed from the Z-isomer (25) leading to
a nine-membered lactone, whereas no cyclisation has
occurred from the corresponding E-isomer. These benzo-
lactones, which have methyl group on lactone ring, are
racemic. No attempt to perform enantioselective reduction
was made so far. The obtained yields range from 53 to
74%, and no trend can be found to explain the observed dif-
ferences in yields, though the lowest yield is obtained in the
formation of a eight-membered lactone, as mentioned in our
previous study.4 Most of the prepared compounds, either
precursors or lactones are new compounds.
7.19–7.09 (m, 1H, ArH), 6.82 (dd, J¼11.1 Hz and
J¼15.4 Hz, 1H), 6.05 (d, J¼15.4 Hz, 1H), 4.27 (q,
J¼7.1 Hz, 2H), 1.35 (t, J¼7.1 Hz, 3H). 13C NMR (CDCl3,
75 MHz, d ppm): 166.7, 144.1, 138.5, 135.7, 133.3, 130.1,
128.7, 127.6, 127.0, 124.6, 122.5, 60.5, 14.4. EIMS m/z (%
relative abundance): 282 (19), 280 (21), 209 (23), 208 (17),
207 (26), 206 (16), 156 (20), 129 (31), 128 (100), 127 (13).
IR nmax in CHCl3 solution (cmꢂ1): 3065, 2979, 1707, 1627.
HRMS (ESI) m/z Calcd for C13H14BrO2 (M+H): 281.0177;
Found: 281.0192.
3.1.4. Ethyl (Z)-3-(2-bromophenyl)prop-2-enoate (8). In
a 500-mL flask were added under argon K2CO3 (4 g,
29 mmol), 18-crown-6 (18C6) (0.76 g, 1.44 mmol) and
300 mL of chlorobenzene. The mixture was stirred at room
temperature for 3 h before being cooled to 0 ꢀC. The phos-
phonate (5.06 g, 15.24 mmol) and the aldehyde (3.4 mL,
14.5 mmol) were then added. The mixture was maintained
at 0 ꢀC until the work-up. The reaction mixture was
quenched with 50 mL saturated NH4Cl and the organic
phase washed by saturated NH4Cl and water until neutrality.
It was then dried over Na2SO4 and the solvent removed un-
der vacuum. The Z/E-mixture was purified by gel chromato-
graphy (pentane–Et2O, 95/5). Colorless oil, 3.27 g, 98%;
RN: [99134-35-7]. 1H NMR (Acetone-d6, 300 MHz,
d ppm): 7.63–7.19 (m, 4H, ArH), 7.13 (d, J¼12.2 Hz, 1H),
6.05 (d, J¼12.2 Hz, 1H), 4.15 (q, J¼7.1 Hz, 2H), 1.21 (t,
J¼7.1 Hz, 3H). 13C NMR (Acetone-d6, 75 MHz, d ppm):
165.5, 142.5, 135.9, 132.2, 130.8, 129.9, 126.6, 123.1,
121.8, 60.3, 14.0. EIMS m/z (% relative abundance): 257
(<10), 255 (<10), 175 (57), 147 (100), 103 (34), 102 (24).
IR nmax in CHCl3 solution (cmꢂ1): 3029, 3021, 2925,
2940, 1719, 1637.
3. Experimental
3.1. General
All reagents and supporting electrolytes were used as ob-
tained commercially. All reactions were performed under
an inert atmosphere (argon) unless otherwise indicated. An
iron rod was used as the anode. The cathode was made of
nickel foam.
1H and 13C NMR spectra were recorded on a Bruker AC-200
(200 MHz) or AVANCE 300 (300 MHz) spectrometer at
room temperature, except for 33 and 34 at 70 ꢀC. Regarding
the 13C data, some of aromatic signal are missing. This might
be a consequence of the overlapping of certain signal. Infra-
red spectra were recorded on a Perkin Elmer Spectrum BX II
spectrometer. Mass spectra (electron impact) were obtained
on a Thermoquest GCQ spectrometer coupled to a Finnigan-
GCQ chromatograph with a CPSIL5CB/MS capillary col-
umn. High-resolution mass spectra and elemental analyses
were performed by ‘Service Central d’Analyses du CNRS,
Lyon’.
3.2. General procedure for the arylation of electron-
deficient olefins
Under argon, in an undivided cell equipped with a nickel
grid (area 40 cm2) as the cathode and a Fe/Ni (64/36) rod
as the anode, tetrabutylammonium bromide (0.34 mmol)
and tetrabutylammonium iodide (0.21 mmol) as supporting
electrolytes were dissolved in a mixture of DMF (25 mL)
and ACN (25 mL). 1,2-Dibromoethane (0.1 mmol) was in-
troduced. After a short electrolysis run at constant current
density (0.2 A) and at room temperature over 15 min, the ac-
tivated olefin (100 mmol), NiBr2$3H2O (1 mmol) was added
and the reaction mixture was heated at 80 ꢀC. The electro-
synthesis was run at current density (0.2 A) 10 min after,
the aryl bromide (10 mmol) was added. The reaction was
monitored by GC and stopped after the aryl bromide was
consumed. The mixture was then hydrolysed with hydro-
chloric acid (1 N, 30 mL) and diluted with diethyl ether
(2ꢁ50 mL) and the combined organic layers were washed
with water and saturated NaCl solution, then dried over
MgSO4. The oil thus obtained was purified by column chro-
matography (silica gel, pentane–ether, 90/10 eluent) to give
the desired compound.
3.1.1. Ethyl 2-(2-bromophenyl)ethanoate (2). RN: [2178-
24-7].16
3.1.2. Ethyl (E)-3-(2-bromophenyl)prop-2-enoate (5) and
ethyl (E)-4-(2-bromophenyl)but-2-enoate (9). See in
Ref. 4, respectively, for compounds 11 and 12.
3.1.3. Ethyl (E,E)-5-(2-bromophenyl)penta-2,4-dienoate
(10). Triethyl phosphonocrotonate (9.31 mL, 42 mmol)
was added to a stirred suspension of sodium hydride
(1.5 g, 39 mmol) in THF (50 mL) at 0 ꢀC to give a white
foam. The mixturewas allowed to warm to room temperature
for 30 min then recooled in an ice bath and 2-bromobenz-
aldehyde (5.55 mL, 30 mmol) was added as a solution in
THF (70 mL). After 20 min the reaction mixturewas allowed
to warm to room temperature and stirred for 1 h. Saturated
aqueous ammonium chloride (50 mL) was then added to
the mixture. Diethyl ether was added and the combined
layers were washed with water (3ꢁ25 mL), dried (MgSO4)
and the solvent removed under vacuum to give 10. Colorless
oil, 5.71 g, 68%, purification by column chromatography
(silica gel, pentane–Et2O, 90/10). 1H NMR (CDCl3,
300 MHz, d ppm): 7.63–7.57 (m, 2H, ArH), 7.51 (dd,
J¼11.1 and J¼15.3 Hz, 1H), 7.35–7.26 (m, 2H, ArH),
3.2.1. Ethyl 2-[2-(3-oxobutyl)phenyl]ethanoate (3). Color-
less oil, 1.52 g, 65%. H NMR (CDCl3, 300 MHz, d ppm):
1
7.27–7.17 (m, 4H, ArH), 4.18 (q, J¼7.2 Hz, 2H), 3.70 (s,
2H), 2.97–2.92 (m, 2H), 2.81–2.76 (m, 2H), 2.18 (s, 3H),
1.29 (t, J¼7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz,

8520
E. Meꢀtay et al. / Tetrahedron 62 (2006) 8515–8524
d ppm): 207.8, 171.7, 139.7, 132.5, 130.7, 129.2, 127.6,
126.5, 60.9, 44.5, 38.6, 30.0, 26.6, 14.2. EIMS m/z (% rela-
tive abundance): 234 (2), 216 (21), 189 (12), 188 (78), 170
(25), 161 (15), 146 (17), 145 (100), 144 (36), 143 (50),
142 (26), 131 (11), 129 (11), 128 (10), 117 (63), 116 (12),
115 (32), 91 (17). IR nmax in CHCl3 solution (cmꢂ1):
3036, 2941, 1719, 1604, 1493. HRMS (ESI) m/z Calcd for
C14H19O3 (M+H): 235.1334; Found: 235.1329.
abundance): 272 (15), 229 (16), 214 (39), 198 (23), 186
(10), 185 (23), 183 (25), 181 (33), 180 (24), 169 (23), 168
(47), 165 (16), 155 (40), 153 (16), 142 (17), 141 (100),
129 (20), 128 (18), 115 (28). IR nmax in CHCl3 solution
(cmꢂ1): 3032, 2984, 2875, 1708, 1610. HRMS (ESI) m/z
Calcd for C17H20O3Na (M+Na): 295.1310; Found:
295.1299.
3.2.6. Ethyl (E)-3-[2-(3-oxopropyl)phenyl]prop-2-enoate
(14). Under argon, in an undivided cell equipped with
a nickel grid (area 40 cm2) as the cathode and a Fe/Ni (64/
36) rod as the anode, tetrabutylammonium bromide
(0.34 mmol) and tetrabutylammonium iodide (0.21 mmol)
as supporting electrolytes were dissolved in a mixture of
DMF (50 mL) and pyridine (5 mL). 1,2-Dibromoethane
(0.1 mmol) was introduced after a short electrolysis run at
constant current density (0.2 A) and at room temperature
over 15 min, the olefin (30 mmol), NiBr2$3H2O
(0.75 mmol) and the aryl bromide (10 mmol) were added,
and the reaction mixture heated at 80 ꢀC. The electrosynthe-
sis was run at current density (0.1 A). The reaction was
monitored by GC and stopped after the aryl bromide was
consumed. The mixture was then hydrolysed with hydro-
chloric acid (6 N, 30 mL) and diluted with diethyl ether
(2ꢁ50 mL) and the combined organic layers were washed
with water and saturated NaCl solution, then dried over
MgSO4. The oil thus obtained was purified by column chro-
matography (silica gel, pentane–ether, 70/30 eluent) to give
14. Colorless oil, 0.54 g, 23%. 1H NMR (CDCl3, 300 MHz,
d ppm): 9.77 (s, 1H), 7.98 (d, J¼15.8 Hz, 1H), 7.56–7.20 (m,
4H, ArH), 6.37 (d, J¼15.8 Hz, 1H), 4.25 (q, J¼7.1 Hz, 2H),
3.10–3.04 (m, 2H), 2.75–2.69 (m, 2H), 1.32 (t, J¼7.1 Hz,
3H). 13C NMR (CDCl3, 75 MHz, d ppm): 200.8, 166.8,
141.4, 139.9, 133.0, 130.2, 129.9, 127.0, 126.8, 120.2,
60.4, 44.9, 25.4, 14.3. EIMS m/z (% relative abundance):
231 (27), 204 (19), 203 (100), 202 (34), 178 (17). IR nmax
in CHCl3 solution (cmꢂ1): 3068, 2979, 2828, 1711. HRMS
(ESI) m/z Calcd for C14H17O3 (M+H): 233.1178; Found:
233.1175.
3.2.2. Ethyl (E)-3-[2-(3-oxobutyl)phenyl]prop-2-enoate
(6). Colorless oil, 1.55 g, 63%. 1H NMR (CDCl3,
300 MHz, d ppm): 8.00 (d, J¼15.8 Hz, 1H), 7.71–7.24 (m,
4H, ArH), 6.45 (d, J¼15.8 Hz, 1H), 4.23 (q, J¼7.0 Hz,
2H), 3.03–2.98 (m, 2H), 2.80–2.74 (m, 2H), 2.12 (s, 3H),
1.30 (t, J¼7.0 Hz, 3H). 13C NMR (CDCl3, 75 MHz,
d ppm): 206.8, 166.1, 141.4, 141.0, 132.9, 130.1, 129.8,
126.7, 126.6, 119.8, 59.9, 44.1, 28.9, 26.6, 13.7. EIMS m/z
(% relative abundance): 246 (3), 201 (17), 200 (18), 172
(30), 158 (16), 157 (100), 131 (11), 130 (17), 129 (60),
128 (15), 115 (17). IR nmax in CHCl3 solution (cmꢂ1):
3068, 2985, 2940, 2905, 2876, 1704, 1634, 1601, 1368.
HRMS (ESI) m/z Calcd for C15H19O3 (M+H): 247.1334;
Found: 247.1335.
3.2.3. Ethyl (Z)-3-[2-(3-oxobutyl)phenyl]prop-2-enoate
(11). Colorless oil, 1.23 g, 50%. 1H NMR (CDCl3,
300 MHz, d ppm): 7.57–7.19 (m, 5H, ArH), 6.09 (d,
J¼12.0 Hz, 1H), 4.11 (q, J¼7.1 Hz, 2H), 2.93–2.88 (m,
2H), 2.77–2.71 (m, 2H), 2.16 (s, 3H), 1.17 (t, J¼7.1 Hz,
3H). 13C NMR (CDCl3, 75 MHz, d ppm): 207.9, 165.9,
142.8, 138.5, 129.2, 128.6, 126.7, 125.8, 122.0, 60.2, 44.2,
30.1, 27.5, 14.0. EIMS m/z (% relative abundance): 201
(16), 200 (20), 172 (17), 158 (17), 157 (100), 131 (10),
130 (12), 129 (62), 128 (19), 115 (20). IR nmax in CHCl3
solution (cmꢂ1): 3032, 2987, 2962, 1713, 1634. HRMS
(ESI) m/z Calcd for C15H19O3 (M+H): 247.1334; Found:
247.1347.
3.2.4. Ethyl (E)-4-[2-(3-oxobutyl)phenyl]but-2-enoate
(12). Colorless oil, 2.19 g, 84% mixture of E/Z (80/20). H
1
NMR (CDCl3, 300 MHz, d ppm): 7.25–7.17 (m, 4H, ArH),
7.09 (dt, Jtrans¼15.6 Hz, J¼6.4 Hz, 1H), 5.75 (dt,
Jtrans¼15.6 Hz, J¼1.7 Hz, 1H), 4.13 (q, J¼7.1 Hz, 2H),
3.62 (dd, J¼6.4 Hz, J¼1.7 Hz, 2H), 2.92–2.75 (m, 4H),
2.11 (s, 3H), 1.24 (t, J¼7.1 Hz, 3H). 13C NMR (CDCl3,
75 MHz, d ppm): 206.3, 165.6, 147.5, 139.7, 135.8, 129.9,
129.3, 127.0, 126.4, 121.9, 59.7, 43.8, 35.0, 29.0, 26.1,
13.7. EIMS m/z (% relative abundance): 260, 215 (14),
214 (88), 196 (10), 181 (14), 173 (11), 171 (17), 169 (14),
157 (49), 156 (100), 145 (11), 144 (13), 143 (22), 129
(83), 128 (83), 127 (10), 115 (24). IR nmax in CHCl3 solution
(cmꢂ1): 3072, 2983, 1715, 1603, 1491. HRMS (ESI) m/z
Calcd for C16H20O3Na (M+Na) 283.1310; Found: 283.1311.
3.3. Reduction of carbonyl function only
To a solution of product (1 equiv, 7 mmol, 1.64 g) in meth-
anol (30 mL) was added NaBH4 (1 equiv, 0.27 g) portion
by portion at 0 ꢀC. The reaction mixture was stirred for 3 h
at room temperature and then quenched with aqueous satu-
rated sodium hydrogen carbonate (10 mL). The mixture
was extracted with ethyl acetate (3ꢁ20 mL). The organic
layers were dried over MgSO4 and evaporated. Purification
was done by column chromatography on silica gel (eluent:
pentane–ethyl acetate system) to give the desired hydroxy-
esters.
3.3.1. Ethyl 2-[2-(3-hydroxybutyl)phenyl]ethanoate (15).
Colorless oil, 1.14 g, 70%, purification by column chromato-
graphy (silica gel, pentane–ethyl acetate, 70/30). H NMR
3.2.5. Ethyl (E,E)-5-[2-(3-oxobutyl)phenyl]penta-2,4-di-
enoate (13). Colorless oil, 1.72 g, 63%. H NMR (Ace-
1
1
tone-d6, 200 MHz, d ppm): 7.62–7.14 (m, 6H, ArH), 6.95
(dd, J¼15.4 and 10.9 Hz, 1H), 6.00 (d, Jtrans¼15.3 Hz,
1H), 4.12 (q, J¼7.2 Hz, 2H), 2.97–2.89 (m, 2H), 2.79–
2.69 (m, 2H), 2.04 (s, 3H), 1.21 (t, J¼7.2 Hz, 3H). 13C
NMR (Acetone-d6, 50 MHz, d ppm): 207.1, 167.6, 145.8,
141.2, 138.5, 135.6, 130.9, 129.9, 128.7, 127.6, 126.9,
122.2, 60.7, 45.2, 29.9, 27.8, 14.7. EIMS m/z (% relative
(CDCl3, 300 MHz, d ppm): 7.28–7.17 (m, 4H, ArH), 4.18
(q, J¼7.1 Hz, 2H), 3.87–3.83 (m, 1H), 3.72 (s, 2H), 2.84–
2.68 (m, 3H), 1.79–1.72 (m, 2H), 1.29 (t, J¼7.1 Hz, 3H),
1.26 (d, J¼6.7 Hz, 3H). 13C NMR (CDCl3, 75 MHz,
d ppm): 172.1, 140.8, 132.4, 130.6, 129.4, 127.5, 126.2,
67.2, 61.0, 40.1, 38.7, 28.9, 23.5, 14.2. EIMS m/z (% relative
abundance): 237 (<10), 218 (29), 192 (16), 190 (23), 175

E. Meꢀtay et al. / Tetrahedron 62 (2006) 8515–8524
8521
(12), 172 (22), 149 (10), 147 (14), 146 (28), 145 (100), 144
(93), 143 (50), 131 (27), 130 (24), 129 (82), 128 (12), 119
(21), 118 (29), 117 (49), 116 (13), 115 (20), 105 (31), 104
(14), 103 (10), 91 (26). IR nmax in CHCl3 solution (cmꢂ1):
3474, 3037, 2970, 2875, 1727, 1603, 1493. HRMS (ESI)
m/z Calcd for C14H21O3 (M+H): 237.1491; Found:
237.1496.
3.3.5. Ethyl (E,E)-5-[2-(3-hydroxybutyl)phenyl]penta-
2,4-dienoate (19). Colorless oil, 0.79 g, 93%, purification
by column chromatography (silica gel, pentane–ether, 70/
1
30). H NMR (Acetone-d6, 300 MHz, d ppm): 7.51 (dd,
J¼15.3 Hz, J¼11.1 Hz, 1H), 7.45 (d, Jtrans¼15.3 Hz, 1H),
7.69–7.22 (m, 4H), 7.03 (dd, J¼15.3 Hz, J¼11.1 Hz, 1H),
6.00 (d, Jtrans¼15.3 Hz, 1H), 4.19 (q, J¼7.2 Hz, 2H),
3.84–3.76 (m, 1H), 3.02–2.76 (m, 3H), 1.71–1.63 (m, 2H),
1.27 (t, J¼7.2 Hz, 3H), 1.18 (d, J¼6.1 Hz, 3H). 13C NMR
(Acetone-d6, 75 MHz, d ppm): 167.2, 145.9, 142.4, 138.7,
135.2, 130.8, 129.7, 128.2, 127.1, 126.5, 121.8, 67.1, 60.6,
41.9, 29.9, 24.2, 14.6. EIMS m/z (% relative abundance):
274 (10), 228 (20), 200 (14), 185 (14), 183 (26), 182 (22),
181 (21), 170 (40), 169 (27), 168 (25), 167 (46), 157 (18),
156 (16), 155 (25), 153 (28), 144 (16), 143 (58), 142 (66),
141 (100), 132 (13), 129 (43), 128 (43), 117 (12), 116
(12), 115 (44). IR nmax in CHCl3 solution (cmꢂ1): 3510,
2971, 2875, 1707, 1600. HRMS (ESI) m/z Calcd for
C17H23O3 (M+H): 275.1647; Found: 275,1641.
3.3.2. Ethyl (E)-3-[2-(3-hydroxybutyl)phenyl]prop-2-
enoate (16). Colorless oil, 0.94 g, 95%, purification by col-
umn chromatography (silica gel, pentane–ethyl acetate,
1
70/30). H NMR (Acetone-d6, 200 MHz, d ppm): 8.15 (d,
J¼15.8 Hz, 1H), 7.84–7.34 (m, 4H), 6.57 (d, J¼15.8 Hz,
1H), 4.35 (q, J¼7.1 Hz, 2H), 3.94–3.83 (m, 1H), 3.11–
2.90 (m, 2H), 2.1 (br s, 1H, HOH), 1.84–1.73 (m, 2H), 1.42
(t, J¼7.1 Hz, 3H), 1.31 (d, J¼5.9 Hz, 3H). 13C NMR (Ace-
tone-d6, 50 MHz, d ppm): 167.0, 143.2, 142.6, 142.4, 133.6,
130.8, 127.4, 127.2, 120.1, 67.0, 60.7, 42.0, 24.0, 23.8, 14.5.
EIMS m/z (% relative abundance): 248 (<5), 230 (8), 203
(12), 185 (14), 169 (12), 160 (14), 159 (31), 158 (19), 157
(52), 156 (52), 155 (15), 147 (12), 145 (15), 144 (26), 143
(34), 142 (88), 141 (21), 132 (11), 131 (40), 130 (47), 129
(100), 128 (23), 117 (33), 116 (33), 115 (37). IR nmax in
CHCl3 solution (cmꢂ1): 3462, 3036, 2932, 2876, 1694,
1600, 1484. HRMS (ESI) m/z Calcd for C15H20O3Na
(M+Na): 271.1310; Found: 271.1303.
3.4. Typical procedure for reduction
To a solution of product (1 equiv, 5.7 mmol) and NiCl2
(5.7 mmol) in methanol (50 mL) was added NaBH4
(7 equiv, 39.9 mmol) portionwise at 0 ꢀC. The reaction mix-
ture was stirred for 3 h at room temperature and then
quenched with aqueous saturated sodium hydrogen carbon-
ate (20 mL). The mixture was extracted with ethyl acetate
(3ꢁ20 mL). The organic layers were dried over MgSO4
and evaporated. Purification was done by column chromato-
graphy on silica gel (pentane–ethyl acetate system, eluent) to
give the desired hydroxyl-esters.
3.3.3. Ethyl (Z)-3-[2-(3-hydroxybutyl)phenyl]prop-2-
enoate (17). Colorless oil, 1.08 g, quantitative yield, purifi-
cation by column chromatography (silica gel, pentane–ethyl
acetate, 70/30). 1H NMR (CDCl3, 300 MHz, d ppm): 7.59–
7.17 (m, 5H, ArH and olefinic H), 6.06 (d, J¼12.0 Hz, 1H),
4.09 (q, J¼7.1 Hz, 2H), 3.83–3.76 (m, 1H), 2.77–2.65 (m,
2H), 2.56 (br s, 1H, HOH), 1.75–1.68 (m, 2H), 1.21 (d,
J¼6.2 Hz, 3H), 1.15 (t, J¼7.1 Hz, 3H). 13C NMR (CDCl3,
75 MHz, d ppm): 166.2, 143.1, 139.8, 134.9, 129.2, 128.8,
128.6, 125.4, 121.1, 67.1, 60.2, 39.8, 29.8, 23.6, 13.9.
EIMS m/z (% relative abundance): 185 (25), 169 (12), 159
(13), 158 (20), 157 (45), 156 (43), 155 (12), 147 (14), 144
(22), 143 (13), 142 (34), 141 (21), 131 (26), 130 (21), 129
(100), 128 (27), 117 (17), 116 (20), 115 (40). IR nmax in
CHCl3 solution (cmꢂ1): 3474, 2970, 2931, 1713, 1633.
HRMS (ESI) m/z Calcd for C15H21O3 (M+H): 249.1491;
Found: 249.1492.
3.4.1. Ethyl 3-[2-(3-hydroxypropyl)phenyl]propanoate
(20). See Ref. 4 (compound 6c), 0.97 g, 75%. RN:
[136416-11-0].4
3.4.2. Ethyl 3-[2-(3-hydroxybutyl)phenyl]propanoate
(21). Colorless oil, 1.42 g, quantitative yield, purification
by column chromatography (silica gel, pentane–ethyl
1
acetate, 50/50). H NMR (Acetone-d6, 200 MHz, d ppm):
7.31–7.20 (m, 4H, ArH), 4.20 (q, J¼7.0 Hz, 2H), 3.94–
3.86 (m, 1H), 3.75 (br s, 1H, HOH), 3.12–2.66 (m, 6H),
1.85–1.74 (m, 2H), 1.35–1.28 (m, 6H). 13C NMR
(Acetone-d6, 50 MHz, d ppm): 173.0, 141.3, 139.2, 130.0,
129.6, 127.1, 126.6, 67.1, 60.6, 41.7, 35.8, 28.2, 24.1,
23.9, 14.4. EIMS m/z (% relative abundance): 250 (3),
232 (55), 187 (24), 186 (78), 185 (10), 179 (11), 171
(23), 160 (12), 159 (18), 158 (63), 157 (15), 156 (11),
146 (14), 145 (40), 144 (56), 143 (75), 142 (21), 133
(24), 131 (37), 130 (27), 129 (100), 128 (53), 118 (20),
117 (79), 116 (31), 115 (52), 105 (21), 104 (10), 91 (28).
IR nmax in CHCl3 solution (cmꢂ1): 3473, 3034, 2980,
2875, 1724, 1603, 1491. Anal. Calcd for C15H22O3: C,
71.97; H, 8.86; O, 19.17. Found: C, 71.77; H, 8.84; O,
19.30.
3.3.4. Ethyl (E)-4-[2-(3-hydroxybutyl)phenyl]but-2-
enoate (18). Colorless oil, 1.04 g, quantitative yield, E/Z
(80/20) purification by column chromatography (silica gel,
pentane–ethyl acetate, 70/30). 1H NMR (CDCl3, 300 MHz,
d ppm): 7.50–7.11 (m, 5H), 5.77 (dt, Jtrans¼15.6 Hz,
J¼1.7 Hz, 1H), 4.21 (q, J¼7.1 Hz, 2H), 3.93–3.80 (m,
1H), 3.60 (dd, J¼6.4 Hz, J¼1.7 Hz, 2H), 2.92–2.61 (m,
2H), 2.03 (br s, 1H, HOH), 1.83–1.70 (m, 2H), 1.33–1.25
(m, 6H). 13C NMR (CDCl3, 75 MHz, d ppm): 166.7,
147.6, 140.4, 135.5, 130.0, 129.5, 127.1, 126.3, 122.2,
67.6, 60.3, 40.4, 35.5, 28.9, 23.6, 14.2. EIMS m/z (% relative
abundance): 262, 216 (18), 215 (12), 198 (11), 183 (18), 173
(11), 171 (16), 170 (39), 169 (38), 157 (26), 156 (29), 155
(16), 145 (15), 144 (11), 143 (18), 141 (29), 131 (13), 130
(23), 129 (100), 128 (61), 127 (12), 117 (19), 115 (27), 91
(11). IR nmax in CHCl3 solution (cmꢂ1): 3608, 3504, 3020,
2970, 2874, 1712, 1602, 1490. HRMS (ESI) m/z Calcd for
C16H22O3Na (M+Na): 285.1467; Found: 285.1470.
3.4.3. Ethyl 4-[2-(3-hydroxybutyl)phenyl]butanoate (22).
Colorless oil, 0.575 g, quantitative yield, purification by
column chromatography (silica gel, pentane–ethyl acetate,
50/50). 1H NMR (CDCl3, 300 MHz, d ppm): 7.31–7.16
(m, 4H, ArH), 4.19 (q, J¼7.1 Hz, 2H), 3.97–3.86 (m, 1H),
2.92–2.61 (m, 4H), 2.43 (t, J¼7.1 Hz, 2H), 2.01–1.90

8522
E. Meꢀtay et al. / Tetrahedron 62 (2006) 8515–8524
(m, 3H, HOH), 1.81–1.71 (m, 2H), 1.33–1.28 (m, 6H).
13C NMR (CDCl3, 75 MHz, d ppm): 173.8, 140.1, 139.3,
129.4, 129.3, 126.6, 126.0, 67.7, 60.5, 40.9, 33.9, 32.0,
28.7, 26.4, 23.7, 14.3. EIMS m/z (% relative abundance):
264, 246 (49), 201 (42), 200 (72), 199 (14), 185 (17), 182
(17), 177 (12), 172 (16), 160 (21), 159 (47), 158 (65), 157
(27), 156 (12), 147 (22), 146 (26), 145 (60), 144 (19), 143
(54), 142 (15), 132 (14), 131 (90), 130 (54), 129 (100),
128 (17), 118 (20), 117 (82), 116 (17), 115 (37), 105 (22),
91 (36). IR nmax in CHCl3 solution (cmꢂ1): 3055, 2968,
1727, 1603, 1491. HRMS (ESI) m/z Calcd for C16H25O3
(M+H): 265.1804; Found: 265.1802.
3.5.3. 3-[2-(3-Hydroxypropyl)phenyl]propanoic acid
(26). See Ref. 4 (compound 7c).
3.5.4. 3-[2-(3-Hydroxybutyl)phenyl]propanoic acid (27).
Colorless oil, 0.475 g, 97%. 1H NMR (Acetone-d6,
200 MHz, d ppm): 7.06–6.92 (m, 4H, ArH), 3.73–3.64
(m, 1H), 2.85–2.40 (m, 6H), 1.61–1.49 (m, 2H), 1.06 (d,
J¼6.2 Hz, 3H). 13C NMR (Acetone-d6, 50 MHz, d ppm):
174.7, 141.2, 139.4, 130.0, 129.6, 127.1, 126.7, 67.4,
41.5, 35.6, 28.2, 23.9, 23.8. IR pellet of KBr (n cmꢂ1):
3387, 3040, 2968, 2875, 1711, 1604, 1491. HRMS (ESI)
m/z Calcd for C13H18O3Na (M+Na): 245.1154; Found:
245.1141.
3.4.4. Ethyl 5-[2-(3-hydroxybutyl)phenyl]pentanoate
(23). Colorless oil, 1.61 g, 90%, purification by column
chromatography (silica gel, pentane–ethyl acetate, 50/50).
1H NMR (CDCl3, 300 MHz, d ppm): 7.31–7.15 (m, 4H,
ArH), 4.17 (q, J¼7.1 Hz, 2H), 3.96–3.86 (m, 1H), 2.89–
2.64 (m, 4H), 2.43–2.38 (m, 2H), 2.16 (br s, 1H, HOH),
1.83–1.62 (m, 6H), 1.30 (d, J¼6.2 Hz, 3H), 1.30 (t,
J¼7.1 Hz, 3H). 13C NMR (CDCl3, 75 MHz, d ppm):
173.9, 140.0, 139.9, 129.3, 129.2, 126.1, 126.0, 67.7, 60.4,
40.8, 34.2, 32.3, 30.7, 28.8, 25.0, 23.7, 14.3. EIMS m/z (%
relative abundance): 278, 260 (47), 215 (17), 214 (28), 186
(19), 185 (11), 173 (14), 171 (18), 158 (11), 146 (15), 145
(100), 144 (34), 143 (26), 131 (54), 130 (20), 129 (59),
128 (20), 117 (48), 115 (21), 105 (22), 91 (22). IR nmax in
CHCl3 solution (cmꢂ1): 3517, 3017, 2937, 2869, 1728,
1602, 1490. HRMS (ESI) m/z Calcd for C17H26O3Na
(M+Na): 301.1780; Found: 301.1780.
3.5.5. 4-[2-(3-Hydroxybutyl)phenyl]butanoic acid (28).
Colorless oil, 0.45 g, quantitative yield. 1H NMR (Ace-
tone-d6, 300 MHz, d ppm): 7.99–6.96 (m, 4H, ArH), 3.82–
3.76 (m, 1H), 2.99–2.62 (m, 4H), 2.39 (t, J¼7.3 Hz, 2H),
1.92–1.82 (m, 2H), 1.71–1.63 (m, 2H), 1.19 (d, J¼6.2 Hz,
3H). 13C NMR (Acetone-d6, 300 MHz, d ppm): 173.9,
140.5, 139.5, 129.2, 126.0, 125.8, 66.5, 41.1, 33.0, 31.6,
28.6, 26.5, 23.1. IR pellet of KBr (n cmꢂ1): 3200–2800,
3018, 2967, 1710, 1604, 1491. HRMS (ESI) m/z Calcd for
C14H21O3 (M+H): 237.1491; Found: 237.1496.
3.5.6. 5-[2-(3-Hydroxybutyl)phenyl]pentanoic acid (29).
Colorless oil, 1.61 g, 90%. 1H NMR (Acetone-d6,
300 MHz, d ppm): 7.19–7.08 (m, 4H, ArH), 3.89–3.83 (m,
1H), 2.89–2.67 (m, 4H), 2.38–2.33 (m, 2H), 1.75–1.63 (m,
6H), 1.23 (d, J¼6.0 Hz, 3H). 13C NMR (Acetone-d6,
75 MHz, d ppm): 174.6, 140.3, 140.0, 129.2, 129.17,
125.9, 125.8, 66.8, 40.9, 33.3, 32.1, 30.7, 28.6, 24.8, 23.1.
IR pellet of KBr (n cmꢂ1): 3200–2800, 3018, 2937, 2870,
1705, 1604, 1490. HRMS (ESI) m/z Calcd for
C15H22O3Na (M+Na): 273.1467; Found: 273.1458.
3.5. Typical procedure for saponification
To a solution of product (7 mmol) in dioxane–water
(1:1, v:v, 70 mL) was added a 20% solution of potassium
hydroxide in water (24 mmol). The reaction mixture was
refluxed for 16 h and cooled to room temperature, then
H2SO4 was added until pH¼1 was reached. The mixture
was extracted with ether (3ꢁ25 mL). The combined organic
layers were dried (MgSO4) and evaporated to leave a crude
product.
3.6. Preparation of p-nitrobenzoic anhydride
To a mixture of p-nitrobenzoic acid (3.34 g, 20 mmol) and
p-nitrobenzoic chloride (3.71 g, 20 mmol) in dichloro-
methane (50 mL) was added pyridine (2.02 mL, 25 mmol)
dropwise at 0 ꢀC. The reaction mixture was stirred for 15 h
at room temperature and then quenched with cold water
(20 mL). The mixture was extracted with dichloromethane
several times. The organic layers were dried over MgSO4
and evaporated. The crude product was purified by recrystal-
lisation from dichloromethane–hexane to afford p-nitro-
benzoic anhydride (5.4 g, 85% yield).
3.5.1. 2-[2-(3-Hydroxybutyl)phenyl]ethanoic acid (24).
Colorless oil, 0.73 g, quantitative yield. 1H NMR (Ace-
tone-d6, 300 MHz, d ppm): 7.26–7.13 (m, 4H, ArH), 3.83–
3.71 (m, 1H), 3.71 (s, 2H), 2.86–2.65 (m, 2H), 1.73–1.66
(m, 2H), 1.19 (d, J¼6.2 Hz, 3H). 13C NMR (Acetone-d6,
75 MHz, d ppm): 172.4, 141.3, 133.1, 130.6, 129.2, 127.1,
125.7, 66.4, 40.4, 37.7, 28.9, 23.1. IR nmax in CHCl3 solution
(cmꢂ1): 3406, 3200–2800, 2968, 2646, 1712, 1603, 1493.
HRMS (ESI) m/z Calcd for C12H17O3 (M+H): 209.1178;
Found: 209.1190.
3.7. Typical procedure for lactonisation
p-Nitrobenzoic anhydride (506 mg, 1.6 mmol) was
dissolved in dry acetonitrile (340 mL), and a cloudy solu-
tion of scandium triflate (1.6 mL, 0.16 mmol, 0.1 M)
in acetonitrile was added to the solution at room temper-
ature under argon. A solution of hydroxycarboxylic acid
(20 mL, 0.8 mmol, 0.08 M) in THF was slowly added
with a syringe pump over 15 h to the mixed solution at
reflux under argon, and the reaction mixture was stirred
for an additional 5 h at reflux. After being cooled to
room temperature, the solution was quenched with
aqueous saturated sodium hydrogen carbonate (8 mL).
The resulting mixture was concentrated under reduced
3.5.2. (Z)-3-[2-(3-Hydroxybutyl)phenyl]prop-2-enoic
acid (25). Colorless oil, 0.884 g, 91%. H NMR (Acetone-
1
d6, 300 MHz, d ppm): 7.35–7.10 (m, 5H, ArH), 6.07 (d,
J¼12.2 Hz, 1H), 3.80–3.70 (m, 1H), 2.98–2.62 (m, 2H),
1.70–1.62 (m, 2H), 1.15 (d, J¼6.2 Hz, 3H). 13C NMR
(Acetone-d6, 75 MHz, d ppm): 166.4, 142.2, 140.5, 134.9,
129.2, 128.7, 128.2, 125.1, 121.3, 66.2, 40.2, 29.7, 23.1.
IR pellet of KBr (n cmꢂ1): 3200–2800, 1703, 1364. HRMS
(ESI) m/z Calcd for C13H17O3 (M+H): 221.1178; Found:
221.1174.

E. Meꢀtay et al. / Tetrahedron 62 (2006) 8515–8524
8523
pressure and extracted with diethyl ether twice. The organic
layers were dried over magnesium sulfate, filtered and
concentrated under vacuum. Purification was done by flash
column chromatography on silica gel to give the desired
lactone.
column chromatography (silica gel, pentane–Et2O, 90/
1
10). H NMR (DMF-d7 70 ꢀC, 300 MHz, d ppm): 7.25–
7.11 (m, 4H, ArH), 4.68–4.52 (m, 1H), 2.98–2.65 (m,
4H), 2.32–2.02 (m, 5H), 1.94–1.82 (m, 1H), 1.18 (d,
13
J¼6.2 Hz, 3H). C NMR (DMF-d7, 70 ꢀC, 75 MHz,
d ppm): 172.8, 140.7, 139.2, 129.4, 128.8, 125.7, 125.6,
70.8, 36.8, 33.5, 28.3, 27.5, 26.7, 20.3. EIMS m/z (% rel-
ative abundance): 218 (21), 201 (17), 200 (100), 185 (16),
160 (11), 159 (10), 158 (50), 157 (21), 146 (17), 145 (68),
144 (18), 143 (79), 132 (11), 131 (88), 130 (62), 129 (59),
128 (16), 118 (27), 117 (81), 116 (16), 115 (45), 105 (12),
104 (10), 91 (33), 78 (15). IR nmax in CH2Cl2 solution
(cmꢂ1): 3017, 2977, 2932, 2867, 1725, 1492. HRMS
(ESI) m/z Calcd for C14H19O2 (M+H): 219.1385; Found:
219.1393.
3.7.1. 2-[2-(3-Hydroxybutyl)phenyl]ethanoic acid, z lac-
tone (30). Colorless oil, 0.08 g, 53%, purification by flash
column chromatography (silica gel, pentane–Et2O, 90/10).
1H NMR (CDCl3, 300 MHz, d ppm): 7.30–7.14 (m, 4H,
ArH), 4.84–4.79 (m, 1H), 4.12 (d, AB system Dn/
J¼7.2 Hz, J¼14.4 Hz, 1H), 3.78 (d, AB system Dn/
J¼7.2 Hz, J¼14.4 Hz, 1H), 2.97–2.90 (m, 2H), 2.05–1.86
(m, 2H), 1.40 (d, J¼6.2 Hz, 3H). 13C NMR (CDCl3,
75 MHz, d ppm): 173.1, 139.3, 133.3, 130.3, 129.8, 127.9,
127.2, 77.1, 39.7, 38.6, 33.0, 22.4. EIMS m/z (% relative
abundance): 190 (<10), 148 (17), 146 (31), 131 (79), 118
(11), 117 (41), 115 (30), 105 (14), 104 (100), 103 (17), 91
(25), 78 (37). IR nmax in CHCl3 solution (cmꢂ1): 3024,
2971, 2931, 1728, 1603, 1493. HRMS (ESI) m/z Calcd for
C12H15O2 (M+H): 191.1072; Found: 191.1064.
3.7.6. 5-[2-(3-Hydroxybutyl)phenyl]pentanoic acid, i lac-
tone (35). Colorless oil, 0.11 g, 60%, purification by flash
column chromatography (silica gel, pentane–Et2O, 90/10).
1H NMR (Acetone-d6, 300 MHz, d ppm): 7.18–7.07 (m,
4H, ArH), 5.11–5.02 (m, 1H), 3.03–2.96 (m, 2H), 2.62–
2.47 (m, 3H), 2.33–2.25 (m, 1H), 1.92–1.75 (m, 5H),
1.53–1.35 (m, 1H), 1.27 (d, J¼6.5 Hz, 3H). 13C NMR (Ace-
tone-d6, 75 MHz, d ppm): 172.8, 140.6, 139.9, 129.8, 129.3,
125.9, 125.8, 69.5, 36.4, 33.1, 29.9, 29.2, 25.5, 23.7, 18.1.
EIMS m/z (% relative abundance): 232 (37), 214 (17), 185
(10), 157 (12), 156 (14), 146 (14), 145 (100), 144 (16),
143 (30), 132 (10), 131 (78), 130 (32), 129 (48), 128 (18),
117 (51), 116 (12), 115 (33), 105 (13), 91 (31). IR nmax in
CH2Cl2 solution (cmꢂ1): 3061, 2871, 1723, 1603, 1492.
HRMS (ESI) m/z Calcd for C15H21O2 (M+H): 233.1542;
Found: 233.1554.
3.7.2. (Z)-3-[2-(3-Hydroxybutyl)phenyl]prop-2-enoic
acid, h lactone (31). Colorless oil, 0.097 g, 0.66%, purifica-
tion by flash column chromatography (silica gel, pentane–
Et2O, 90/10). 1H NMR (DMF-d7, 300 MHz, d ppm):
7.38–7.20 (m, 5H, ArH), 6.15 (d, J¼12.2 Hz, 1H), 5.24–
5.13 (m, 1H), 2.79–2.72 (m, 1H), 2.47–2.35 (m, 2H),
1.90–1.78 (m, 1H), 1.10 (d, J¼6.5 Hz, 3H). 13C NMR
(DMF-d7, 75 MHz, d ppm): 168.1, 142.8, 142.3, 134.6,
131.0, 130.6, 128.9, 125.5, 121.7, 71.0, 34.7, 29.75, 21.8.
EIMS m/z (% relative abundance): 202 (31), 174 (24), 161
(11), 160 (37), 159 (40), 158 (16), 157 (31), 156 (100),
147 (15), 146 (25), 145 (12), 143 (13), 142 (62), 141 (18),
133 (12), 132 (46), 131 (52), 130 (27), 129 (58), 128 (41),
127 (13), 118 (34), 117 (16), 116 (24), 115 (60), 104 (10),
103 (13), 91 (12), 89 (12). IR nmax in CH2Cl2 solution
(cmꢂ1): 3058, 2984, 2935, 1705. HRMS (ESI) m/z Calcd
for C13H15O2 (M+H): 203.1072; Found: 203.1068.
References and notes
1. Bartra, M.; Urpi, F.; Vilarrasa, J. Recent Progress in the
Chemical Synthesis of Antibiotics and Related Microbial
Products; Lukas, G., Ed.; Springer: Berlin, Heidelberg, New
York, NY, London, Paris, Tokyo, Hong Kong, Barcelona,
Budapest, 1993; Vol. 2, pp 1–65.
3.7.3. 3-[2-(3-Hydroxypropyl)phenyl]propanoic acid,
h lactone (32). See Ref. 4 (compound 8c).
2. Rousseau, G. Tetrahedron 1995, 51, 2777–2849.
3. (a) Schen, R.; Lin, C. T.; Bowman, E. J.; Bowman, B. J.; Porco,
J. A. J. Am. Chem. Soc. 2003, 125, 7889–7901; (b) Lebreton, S.;
Xie, X.-S.; Ferguson, D.; Brabander, J. K. Tetrahedron 2004,
60, 9635–9647.
3.7.4. 3-[2-(3-Hydroxybutyl)phenyl]propanoic acid, h
lactone (33). Colorless oil, 0.121 g, 74%, purification by
flash column chromatography (silica gel, pentane–Et2O,
90/10). 1H NMR (DMF-d7 70 ꢀC, 300 MHz, d ppm): 7.39–
7.20 (m, 4H, ArH), 4.93–4.85 (m, 1H), 3.41–3.32 (m, 1H),
2.99–3.12 (m, 2H), 2.66–2.78 (m, 2H), 2.54–2.63 (m, 1H),
2.34–2.42 (m, 1H), 2.07–2.14 (m, 1H), 1.38 (d, J¼6.4 Hz,
ꢀ
ꢀ
ꢀ ꢀ
4. Metay, E.; Leonel, E.; Sulpice-Gaillet, C.; Nedelec, J.-Y.
Synthesis 2005, 1682–1688.
ꢀ
Org. Chem. 2002, 105–111.
ꢀ ꢀ
5. Condon, S.; Dupre, D.; Falgayrac, G.; Nedelec, J.-Y. Eur. J.
13
3H). C NMR (DMF-d7, 70 ꢀC, 75 MHz, d ppm): 173.9,
ꢀ
ꢀ ꢀ
6. Condon, S.; Dupre, D.; Lachaise, I.; Nedelec, J.-Y. Synthesis
142.5, 138.7, 130.8, 130.6, 126.9, 126.2, 70.9, 38.9, 37.3,
30.6, 27.1, 20.7. EIMS m/z (% relative abundance): 205
(13), 204 (10), 187 (12), 186 (66), 171 (13), 158 (11), 157
(15), 146 (13), 145 (29), 144 (100), 143 (29), 142 (12),
133 (15), 131 (44), 130 (13), 129 (55), 128 (33), 118 (42),
117 (99), 116 (22), 115 (73), 104 (15), 91 (34), 77 (11). IR
nmax in CH2Cl2 solution (cmꢂ1): 3058, 2929, 2856, 1728,
1604, 1492. HRMS (ESI) m/z Calcd for C13H17O2 (M+H):
205.1229; Found: 205.1233.
2002, 1752–1758.
7. Barry, J.; Bram, G.; Decodts, G.; Loupy, A.; Orange, C.; Petit,
A.; Sansoulet, J. Synthesis 1985, 40–45.
8. Gibson, S. E.; Guillo, N.; Middleton, R. J.; Thuilliez, A.; Tozer,
M. J. Chem. Soc., Perkin Trans. 1 1997, 447–455.
9. Poschalko, A.; Welzig, S.; Treu, M.; Nerdinger, S.; Mereiter,
K.; Jordis, U. Tetrahedron 2002, 58, 1513–1518.
10. Touchard, F. P. Tetrahedron Lett. 2004, 45, 5519–5523.
ꢀ
11. Condon, S.; Dupre, D.; Nedelec, J.-Y. Org. Lett. 2003, 5, 4701–
ꢀ ꢀ
3.7.5. 4-[2-(3-Hydroxybutyl)phenyl]butanoic acid, q lac-
tone (34). Colorless oil, 0.113 g, 65%, purification by flash
4703.
12. Ward, D. E.; Rhee, C. K. Can. J. Chem. 1989, 67, 1206–1211.

8524
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13. Narisada, M.; Horibe, I.; Watanabe, F.; Takeda, K. J. Org.
Chem. 1889, 54, 5308–5313.
15. Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org.
Chem. 1996, 61, 4560–4567.
14. Miller, M.; Bajwa, J.; Mattingly, P.; Peterson, K. J. Org. Chem.
1982, 47, 4928–4933.
16. Ogura, K.; Ito, Y.; Tsughihashi, G.-I. Bull. Chem. Soc. Jpn.
1979, 52, 2013–2022.