An effective method for the synthesis of carboxylic esters and lactones using substituted benzoic anhydrides with Lewis acid catalysts

Article abstract of DOI:10.1016/j.tet.2003.12.013

An efficient mixed-anhydride method for the synthesis of carboxylic esters and lactones using benzoic anhydride having electron withdrawing substituent(s) is developed by the promotion of Lewis acid catalysts. In the presence of a catalytic amount of TiCl₂(ClO₄)₂, various carboxylic esters are prepared in high yields through the formation of the corresponding mixed-anhydrides from 3,5-bis(trifluoromethyl)benzoic anhydride and carboxylic acids. The combined catalyst consisting of TiCl ₂(ClO₄)₂ together with chlorotrimethylsilane functions as an effective catalyst for the synthesis of carboxylic esters from free carboxylic acids and alcohols with 4-(trifluoromethyl)benzoic anhydride. Various macrolactones are prepared from the free ω-hydroxycarboxylic acids by the combined use of 4-(trifluoromethyl)benzoic anhydride and titanium(IV) catalysts together with chlorotrimethylsilane under mild reaction conditions. The lactonization of trimethylsilyl ω-(trimethylsiloxy) carboxylates using 4-(trifluoromethyl)benzoic anhydride is also promoted at room temperature in the presence of a catalytic amount of TiCl ₂(ClO₄)₂. An 8-membered ring lactone, a synthetic intermediate of cephalosporolide D, is successfully synthesized according to this mixed-anhydride method using 4-(trifluoromethyl)benzoic anhydride by the promotion of a catalytic amount of Hf(OTf)₄.

Full text of DOI:10.1016/j.tet.2003.12.013

Tetrahedron 60 (2004) 1587–1599
An effective method for the synthesis of carboxylic esters
and lactones using substituted benzoic anhydrides
with Lewis acid catalysts
*
Isamu Shiina
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 31 October 2003; accepted 1 December 2003
Abstract—An efficient mixed-anhydride method for the synthesis of carboxylic esters and lactones using benzoic anhydride having electron
withdrawing substituent(s) is developed by the promotion of Lewis acid catalysts. In the presence of a catalytic amount of TiCl2(ClO4)2,
various carboxylic esters are prepared in high yields through the formation of the corresponding mixed-anhydrides from 3,5-bis(trifluoro-
methyl)benzoic anhydride and carboxylic acids. The combined catalyst consisting of TiCl2(ClO4)2 together with chlorotrimethylsilane
functions as an effective catalyst for the synthesis of carboxylic esters from free carboxylic acids and alcohols with 4-(tri-
fluoromethyl)benzoic anhydride. Various macrolactones are prepared from the free v-hydroxycarboxylic acids by the combined use of
4-(trifluoromethyl)benzoic anhydride and titanium(IV) catalysts together with chlorotrimethylsilane under mild reaction conditions. The
lactonization of trimethylsilyl v-(trimethylsiloxy)carboxylates using 4-(trifluoromethyl)benzoic anhydride is also promoted at room
temperature in the presence of a catalytic amount of TiCl2(ClO4)2. An 8-membered ring lactone, a synthetic intermediate of cephalosporolide
D, is successfully synthesized according to this mixed-anhydride method using 4-(trifluoromethyl)benzoic anhydride by the promotion of a
catalytic amount of Hf(OTf)4.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
anhydrides prepared in situ from silyl carboxylates with
4-(trifluoromethyl)benzoic anhydride (TFBA) using a
catalytic amount of a Lewis acid such as Sn(OTf)2,
TiCl2(ClO4)2, TiCl2(OTf)2, ZrCl2(OTf)2, HfCl2(OTf)2,
AlCl(OTf)2, InCl(OTf)2, etc.5 In 1994, we extended this
method to the reaction between nearly equimolar amounts
free carboxylic acids and alcohols by varying the combi-
nation of Lewis acids.6 The corresponding carboxylic esters
or lactones are obtained in high yields by treating nearly
equimolar amounts of free carboxylic acids and alcohols
or v-hydroxycarboxylic acids with substituted benzoic
anhydrides possessing electron withdrawing group(s) in
the presence of catalytic amounts of TiCl2(ClO4)2 or
TiCl2(OTf)2 together with chlorotrimethylsilane. Yamamoto
et al. also found that Sc(OTf)3 or Sc(NTf2)3 is an effective
Lewis acid for the promotion of this reaction in 1995 and the
desired carboxylic esters including medium-sized lactones
were produced in high yields.2e–g
While numerous esterifications using Brønsted and Lewis
acid catalysts have been reported, a few methods have
actually been utilized for the effective preparation of
carboxylic esters from equimolar amounts of carboxylic
acids and alcohols under mild conditions.1 On the other
hand, some acylation reactions of alkyl silyl ethers, alcohols
or thiols with an excess amount of acetic or benzoic
anhydrides were presented since acid anhydrides could be
efficiently activated by acidic species.2 Furthermore, it is
also well known that a mixed-anhydride method using
trifluoroacetic anhydride is sometimes very convenient for
the generation of bulky carboxylic esters.3
During the course of our studies on the exploration of new
catalytic synthetic reactions using Lewis acids,4 a unique
method for the preparation of carboxylic esters was
developed in 1992 starting from silyl carboxylates and
alkyl silyl ethers via the active intermediary mixed-
In this paper, we describe in detail the results of our
investigations on the effective method for the preparation
of carboxylic esters from nearly equimolar amounts of
carboxylic acids and alcohols using an active Lewis acid
catalyst initially reported in a previous communication,6a
and also further developments of the above reactions
applied to the preparations of lactones including synthetic
intermediates of natural compounds.5c,6b,7
Keywords: Carboxylic esters; Macrolactones; Medium-sized lactones;
Cephalosporolide D; 4-(Trifluoromethyl)benzoic anhydride; 3,5-Bis-
(trifluoromethyl)benzoic anhydride; Mixed-anhydrides; Lewis acid
catalysts.
*
Tel.: þ81-3-3260-4271; fax: þ81-3-3260-5609;
e-mail address: shiina@ch.kagu.sut.ac.jp
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.12.013

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I. Shiina / Tetrahedron 60 (2004) 1587–1599
Scheme 1. Synthesis of carboxylic esters from silyl carboxylates with alkyl silyl ethers using benzoic anhydrides.
2. Results and discussion
of Lewis acid, and (2) the alcoholysis of the mixed-
anhydrides by alkyl silyl ethers with the assistance of a
Lewis acid.
2.1. Esterification reaction via mixed-anhydrides using
benzoic anhydrides
The mixed-anhydride consisting of aromatic and aliphatic
acyl parts is generated in the first cycle and it will be
successively consumed in the second cycle to afford the
desired carboxylic ester (Scheme 2). Therefore, the mixed-
anhydride formed in situ is assumed to be the most
important intermediate in the catalytic process.
Recently, an effective method for the synthesis of
carboxylic esters from nearly equimolar amounts of silyl
carboxylates and alkyl silyl ethers via mixed-anhydrides
was developed by employing a substituted benzoic
anhydride and a Lewis acid catalyst (Scheme 1).5a,b In the
report, it was indicated that the following successive
reactions would lead to the formation of carboxylic esters;
that is, (1) the initial formation of the mixed-anhydride from
benzoic anhydride and silyl carboxylates by the promotion
It was also found in previous research that the use of silyl
derivatives of carboxylic acids and of alcohols was essential
for the completion of the esterification reaction at room
Scheme 2. Catalytic cycle for the production of carboxylic esters using benzoic anhydrides as coupling reagents.

I. Shiina / Tetrahedron 60 (2004) 1587–1599
1589
Table 1. Effect of substituted benzoic anhydrides
perfect (entries 2–7). Although the formation of a small
amount of 1-methyl-3-phenylpropyl (3-trifluoromethyl)-
benzoate, a by-product, was observed when using (3-tri-
fluoromethyl)benzoic anhydride as the condensation
reagent, the product selectivity is nearly equal to that of
the reaction using TFBA (see entries 6 and 7). It was finally
determined that the desired ester was exclusively obtained
when 3,5-bis(trifluoromethyl)benzoic anhydride (BTFBA)
was employed as shown in entry 8.
Some examples for the synthesis of carboxylic esters from
the corresponding carboxylic acids and alcohols using
BTFBA and TiCl2(ClO4)2 are shown in Table 2. In every
case, the reactions smoothly proceed at room temperature in
dichloromethane to give the corresponding carboxylic esters
in good to high yields from nearly equimolar amounts of
carboxylic acids and alcohols. It is noteworthy that pivalic
acid esters, derived from a bulky carboxylic acid, were
also obtained in high yields by the present reaction (entries
5 and 6).
Entry
Xn
Yielda (%)
1/2b
17/1
70/1
60/1
40/1
80/1
180/1
180/1
.200/1
1
2
3
4
5
6
7
8
H
2-F
50
82
72
57
88
87
88
89
3-NO2
4-NO2
2-CF3
3-CF3
4-CF3
3,5-(CF3)2
Although the yields of the esterification using BTFBA were
relatively higher compared to those obtained by TFBA, the
reaction did not completely proceed under these conditions
probably due to the deactivation of the catalyst. Next,
several combinations of reactants were examined using the
present mixed-anhydride method for the preparation of
carboxylic esters in higher yields (Table 3). When
trimethylsilyl 3-phenylpropanoate and 4-phenyl-2-butanol
were employed in the presence of 20 mol% of TiCl2(ClO4)2
with BTFBA, nearly the same yield of the desired ester was
obtained as that for the reaction between silyl carboxylate
and alkyl silyl ether (see entries 1 and 2). However, the yield
slightly decreased when using 3-phenylpropanoic acid and
1-methyl-3-phenylpropyl trimethylsilyl ether as the sub-
strates under the identical reaction conditions (entry 3).
Therefore, it was assumed that the free carboxylic acid
particularly deactivated the Lewis acid catalyst by ligand
exchange on the catalyst. The esterification yield of the free
carboxylic acid with the free alcohol was apparently lower
compared to those of the other combinations (entry 4).
a
Isolated yield of 1.
Determined by 1H NMR using a crude mixture.
b
temperature. Therefore, the development of further useful
and convenient methods for the preparation of carboxylic
esters from free carboxylic acids and alcohols was next
required. However, when the condensation of 3-phenyl-
propanoic acid and 4-phenyl-2-butanol was carried out in
the presence of TFBA and 20 mol% of TiCl2(ClO4)2, the
alcohol was not completely consumed and the desired ester
was obtained in 88% yield along with a small amount of
an undesirable ester, 1-methyl-3-phenylpropyl (4-trifluoro-
methyl)benzoate (product selectivity¼180:1). Several sub-
stituted benzoic anhydrides were then examined for the
reaction of free carboxylic acids and alcohols to improve the
yield and chemoselectivity (Table 1). The reaction smoothly
took place to afford the desired carboxylic ester in good
yields using mono-substituted benzoic anhydrides having
an electron withdrawing group such as fluoride, nitro and
trifluoromethyl, however, the chemoselectivity was not
Table 3. Synthesis of carboxylic esters using silylated or free substrates
Table 2. Synthesis of several carboxylic esters using BTFBA
Entry
R1
R2
R1COOR2
Yielda (%)
Entry
X
Y
Yielda (%)
1
2
3
4
5
6
Ph(CH2)2
Ph(CH2)2
c-C6H11
c-C6H11
tBu
Ph(CH2)3
Ph(CH2)2CHCH3
Ph(CH2)3
Ph(CH2)2CHCH3
Ph(CH2)3
Ph(CH2)2CHCH3
3
1
4
5
6
7
91
89
88
86
91
88
1
2
3
4
SiMe3
SiMe3
H
SiMe3
H
SiMe3
H
98
96
93
89
tBu
H
a
a
Isolated yield.
Isolated yield.

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I. Shiina / Tetrahedron 60 (2004) 1587–1599
Scheme 3. Yield of 1 using pre-treated titanium(IV) catalysts.
˚
First, molecular sieves (MS 5 A) were added to the reaction
Furthermore, the order of addition of the free carboxylic
acids and alcohols was examined to clarify the deactivation
process (Scheme 3). When 4-phenyl-2-butanol was mixed
with 20 mol% of TiCl2(ClO4)2 in dichloromethane for 1 h
prior to the addition of 3-phenylpropanoic acid and BTFBA,
the desired ester was obtained in relatively good yield
(85%). However, the titanium(IV) catalyst, which was
treated with 3-phenylpropanoic acid before the esterifica-
tion, gave the desired ester in 70% yield. The activity of the
TiCl2(ClO4)2 was considerably decreased in the latter
case. Therefore, we next tried to employ a suitable additive
which functions as a co-reagent to maintain the activity of
the titanium(IV) catalyst under the influence of the free
carboxylic acids.
mixture consisting of 3-phenylpropanoic acid and 4-phenyl-
2-butanol in the presence of (3-trifluoromethyl)benzoic
˚
anhydride, TFBA or BTFBA since MS 5 A are known to
have a weak acidity. However, the reactions did not go to
completion and the formation of sufficient quantities of the
by-products was observed in each case (Table 4, entries 2, 4
or 8). Further screening was carried out using several
ingredients such as other molecular sieves and hexamethyl-
disiloxane for the model reaction with BTFBA; it was found
that chlorotrimethylsilane was a very effective co-reagent
for keeping the activity of the titanium(IV) catalyst. In the
presence of 2 mol of chlorotrimethylsilane and 1.1 mol of
BTFBA, 10 mol% of TiCl2(ClO4)2 was not deactivated
during the reaction, and the desired ester was exclusively
obtained in 94% yield (entry 9).
Table 4. Effect of additives
Table 5. Effect of catalysts and reaction conditions
Entry
Xn
Additive
˚
Yielda (%)
1/2b
1
2
3
4
5
6
7
8
9
10
3-CF3
3-CF3
4-CF3
4-CF3
3,5-(CF3)2
3,5-(CF3)2
3,5-(CF3)2
3,5-(CF3)2
3,5-(CF3)2
3,5-(CF3)2
—
MS 5 A
—
87
89
88
90
89
90
78
85
94
88
180/1
90/1
180/1
70/1
.200/1
.200/1
.200/1
120/1
.200/1
.200/1
Entry
Catalyst (amount/mol%)
Xn
Y
Yielda (%)
˚
MS 5 A
1
2
3
4
5
6
7
TiCl2(ClO4)2 (10)
TiCl2(ClO4)2 (10)
TiCl2(ClO4)2 (10)
TiCl2(ClO4)2 (10)
TiCl2(ClO4)2 (10)
TiCl2(OTf)2 (10)
Sn(OTf)2 (20)
3,5-(CF3)2
4-CF3
4-CF3
4-CF3
4-CF3
2
2
1
0.5
0.2
0.2
0.2
94
95
96
97
—
MS 3 A
˚
˚
MS 4 A
˚
MS 5 A
94
78
Me3SiCl (2 equiv.)
(Me3Si)2O (2 equiv.)
4-CF3
4-CF3
78 (5)b
a
a
Isolated yield of 1.
Determined by 1H NMR using a crude mixture.
Isolated yield of 1.
Yield of 1-methyl-3-phenylpropyl 4-(trifluoromethyl)benzoate.
b
b

I. Shiina / Tetrahedron 60 (2004) 1587–1599
1591
The reaction conditions were optimized using several
catalysts (see Table 5). The existence of chlorotrimethyl-
silane was so effective that the corresponding ester was
obtained in high yield without the accompanying undesired
ester even though TFBA was used as the condensation
reagent instead of BTFBA (entries 2–6). For example, the
desired ester was exclusively produced in nearly quantita-
tive yield when the reaction was carried out in the presence
of TFBA, 10 mol% of TiCl2(ClO4)2 and 0.5 mol of
chlorotrimethylsilane (entry 4).
BTFBA as the condensation reagent as shown in entries 12
and 13.
It is noted that the procedure for this synthesis is quite
simple and almost pure carboxylic esters are obtained just
by washing the reaction mixture with saturated aqueous
NaHCO3.
The esterification reaction of crotonic acid or 3-methyl-2-
butenoic acid is a base sensitive reaction leading to the
rearrangement of a double bond to form an a,b-unsatu-
rated ester 18 or 19 even under weakly basic conditions
(Scheme 4).5b,8 For example, the esterification reaction of
crotonic acid with 3-phenylpropanol using 1-ethyl-2-
fluoropyridinium tetrafluoroborate and triethylamine pro-
duced a mixture of the desired ester and rearrangement
product (76%, 15/18¼4:1). A similar result was also
observed in the case of 3-methyl-2-butenoic acid (50%,
17/19¼1:2). Therefore, the esterification reaction between
equimolar amounts of crotonic acid and alcohol has been
generally carried out using DCC or thionyl chloride. It is
also noted that the present method was successfully applied
to the synthesis of alkyl crotonate and alkyl 3-methyl-2-
butenoate from nearly equimolar amounts of carboxylic
acids and alcohols under mild conditions. When 10 mol% of
TiCl2(ClO4)2 was used in the present experiment, no
Various examples of the present condensation reaction are
listed in Table 6. In every case, the reaction smoothly
proceeded at room temperature in dichloromethane to give
the corresponding esters in excellent yields from nearly
equimolar amounts of free carboxylic acids and alcohols.
It was also revealed that the use of 1 mol% of the catalyst
was enough to produce 1-methyl-3-phenylpropyl 3-phenyl-
propanoate in 99% yield from the corresponding carboxylic
acid and alcohol (entry 4). When using branched alcohols
such as menthol and chorestanol or a hindered carboxylic
acid such as pivalic acid, the corresponding carboxylic
esters were also produced in high yields at room
temperature (entries 6, 7, 10 or 11). The reaction of benzoic
acid with primary and secondary alcohols afforded the
desired alkyl benzoates with good chemoselectivities using
Table 6. Synthesis of various carboxylic esters using TFBA or BTFBA
Entry
R1
R2
R1COOR2
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
c-C6H11
c-C6H11
tBu
tBu
Ph
Bn
CH2vCHCH2
Ph(CH2)3
Ph(CH2)2CHCH3
c-C6H11
Menthyl
5a-Chorestan-3b-yl
Ph(CH2)3
Ph(CH2)2CHCH3
Ph(CH2)3
Ph(CH2)2CHCH3
Ph(CH2)3
Ph(CH2)2CHCH3
Ph(CH2)3
Ph(CH2)2CHCH3
Ph(CH2)3
8
9
3
12
0.5
0.5
13
12
13
17
0.5
3
0.5
16
12
12
12
12
12
93
92
96
97 (99)b
93
93
90
96
95
95
95
90 (1.1)d
93 (1.5)e
93
1
10
11
12
4
5
6
9
10
11
12c
13c
14
15
16
7
13
14
15
16
17
Ph
(E)-CH3CHvCH
(E)-CH3CHvCH
(CH3)2CHvCH
93
95
a
Isolated yield. 10 mol% of catalyst was used.
1 mol% of catalyst was used.
BTFBA was used instead of TFBA.
Yield of 3-phenylpropyl 3,5-bis(trifluoromethyl)benzoate.
Yield of 1-methyl-3-phenylpropyl 3,5-bis(trifluoromethyl)benzoate.
b
c
d
e

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I. Shiina / Tetrahedron 60 (2004) 1587–1599
Scheme 4. Base-induced rearrangement in the synthesis of alkyl crotonate and 3-methyl-2-butenoate.
Table 7. Synthesis of lactones from silyl v-siloxycarboxylates using TFBA
Entry
n
Yielda (%) (ring number)
Monomer
Dimer
1
2
10
13
75 (13)
89 (16)
4 (26)
2 (32)
a
Isolated yield.
rearranged product was isolated at all and the desired esters
were obtained in high yields (Table 6, entries 14–16). These
examples show the mildness of the conditions in the present
esterification reaction.
addition of the substrates to the reaction mixture, silyl
derivatives of seco-acids were employed as precursors for
the present cyclization instead of using free v-hydroxy-
carboxylic acids. On the other hand, the equimolar
condensation reaction between free carboxylic acids and
2.2. Lactonization via mixed-anhydrides using benzoic
anhydrides
Several macrolide antibiotics have become important
therapeutic agents in clinical medicine. As a result,
numerous derivatives of various macrolactones have been
synthesized and the discovery of new macrolide antibiotics
has attracted our attention over the past two decades.9 The
chemical synthesis of macrolactones has made great
progress due to the development of efficient methods for
the ring closure from v-hydroxycarboxylic acids (seco-
acids) or their activated derivatives. Though a variety of
methods have been reported for the synthesis of macro-
lactones,1a there are a few reactions which efficiently
proceed under acidic conditions.10 Recently, we developed
an effective method for the preparation of macrolactones
starting from the silyl derivatives of seco-acids via
formation of the corresponding mixed-anhydrides.5c
Namely, in the presence of TFBA and 10 mol% of
TiCl2(ClO4)2, the cyclization of trimethylsilyl v-(trimethyl-
siloxy)carboxylates smoothly takes place at room tempera-
ture to afford the corresponding lactones in good to high
yields as shown in Table 7.
Scheme 5. Synthesis of macroactones starting from silyl v-siloxycarboxyl-
ates or v-hydroxycarboxylic acids using benzoic anhydrides as the
condensation reagents.
To avoid deactivation of the titanium(IV) catalyst during the

I. Shiina / Tetrahedron 60 (2004) 1587–1599
1593
Table 8. Effect of catalysts and reaction temperature
Table 10. Synthesis of lactones from v-hydroxycarboxylic acids using
TFBA
Entry
Catalyst
Temp.a (8C)
Yieldb (%)
Monomer
Entry
R
n
Yieldb (%) (ring number)
Dimer
Monomer
Dimer
1
2
3
4
5
6
TiCl2(ClO4)2
TiCl2(OTf)2
TiCl2(OTf)2
TiCl2(OTf)2
TiCl(OTf)3
TiCl2(OTf)2
rt
rt
40
50
50
60
68
29
81
83
77
55
2
1
4
5
3
8
1
H
C6H13
C6H13
H
H
H
H
H
10
10
10
11
12
13
13
14
83 (13)
91 (13)
83 (13)
80 (14)
89 (15)
88 (16)
63 (16)
88 (17)
5 (26)
3 (26)
8 (26)
3 (28)
2 (30)
5 (32)
5 (32)
1 (34)
2
3c
4
5
6
7c
8
a
Bath temperature.
Isolated yield.
b
a
Bath temperature.
Isolated yield. 5 mol% of catalyst was used.
1 mol% of catalyst was used.
b
c
alcohols had been established in the former section by
the combined use of TFBA and a catalytic amount of
TiCl2(ClO4)2 together with chlorotrimethylsilane, therefore,
it was then anticipated that the direct lactonization of free
v-hydroxycarboxylic acids would function more efficiently
by the promotion of Lewis acids under the influence of a
co-catalyst (Scheme 5). In this section, a useful method for
the preparation of macrolactones directly from v-hydroxy-
carboxylic acids will be described by the combined use
of TFBA and a catalytic amount of TiCl2(ClO4)2 or
TiCl2(OTf)2 together with chlorotrimethylsilane.
When the mixture of 12-hydroxydodecanoic acids and
TFBA in dichloromethane was added over a 5 h period to
the suspension of 5 mol% of TiCl2(ClO4)2 and 3 mol of
chlorotrimethylsilane in dichloromethane at room tempera-
ture, the desired macrolactone was obtained in 68% yield.
In order to improve the yield of the monomeric lactone,
several catalysts and reaction temperatures were examined
(Table 8). As shown in entry 4, the best result was attained
when using TiCl2(OTf)2 as the catalyst in gently refluxing
dichloromethane.
Table 9. Effect of benzoic anhydrides and amounts of chlorotrimethylsilane
Next, the effect of the amount of chlorotrimethylsilane
and the kind of substituent(s) in benzoic anhydrides
was screened under the optimized reaction conditions. It
was found that the existence of chlorotrimethylsilane was
essential to this reaction in order to maintain the activity
of the titanium(IV) catalyst, and the use of 3 mol of
chlorotrimethylsilane was enough to provide a good result
for the production of the monomeric 13-membered ring
lactone (see Table 9, entry 3).
Several examples of the present cyclization reaction are
listed in Table 10. In entries 4–6 and 8, macrolactones
including over 13-membered rings were obtained in higher
yields compared with those of the previously reported
methods. A 13-membered ring lactone derived from a
branched seco-acid was also isolated in 91% yield (entry 2),
and the reaction was effectively accelerated using only
1 mol% of TiCl2(OTf)2 together with chlorotrimethylsilane
as shown in entry 3.
Entry
X
Y
Yieldb (%)
Monomer
Dimer
1
2
3
4
5
6
4-CF3
4-CF3
4-CF3
4-CF3
3,5-(CF3)2
4-F
0
2
3
10
3
3
31
60
83
80
51
44
3
4
5
6
7
7
Even for the labile seco-acids, the reactions smoothly
proceeded to afford the corresponding lactones in high
yields. (þ)-(E)-9-Octadecen-12-olide ((R)-ricinelaidic acid
lactone)11 and (þ)-(Z)-9-octadecen-12-olide ((R)-ricinoleic
a Bath temperature.
b
Isolated yield.

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I. Shiina / Tetrahedron 60 (2004) 1587–1599
Table 13. Synthesis of an 8-membered ring lactone using TFBA
Table 11. Synthesis of (R)-ricinelaidic acid lactone using TFBA
Entry
Catalyst
X
Yielda (%)
Recovery (%)
1
2
3
4
TiCl2(OTf)2
Sc(OTf)3
Zr(OTf)4
Hf(OTf)4
3
0
0
0
2
0
Entry
X
Catalyst (amount/mol%)
Y
Temp.a (8C) Yieldb (%)
44
20
67
31
48
17
1
2
3
H
H
TiCl2(OTf) (5)
TiCl2(ClO4)2 (5)
3
3
0
50
rt
89
92
73
a
Isolated yield.
Me3Si TiCl2(ClO4)2 (10)
rt
a
in 1985 from Cephalosporium aphidicola together with
related compounds by Hanson et al.13 The structure
contained two chiral centers and an unusual saturated
8-membered ring lactone moiety. A similar characteristic
structure possessing a medium-sized lactone moiety was
also found in octalactin A which exhibited a potent
cytotoxic activity against some tumor cell lines.14
Bath temperature.
Isolated yield.
b
acid lactone)11b,12 were respectively obtained in high yields
employing 5 mol% of TiCl2(OTf)2 without any accompany-
ing isomerization of the double bond and also racemization
(Tables 11 and 12, entry 1). TiCl2(ClO4)2 is an equally
effective catalyst in these cases to produce the desired
macrolactones in high yields at room temperature (entry 2).
Furthermore, these unsaturated macrolides were also
produced from the corresponding trimethylsilyl v-(tri-
methylsiloxy)carboxylates in the presence of TFBA and a
catalytic amount of TiCl2(ClO4)2 at room temperature
without using chlorotrimethylsilane as an additive (entry 3).
Next, lactonization of a seco-acid 20, a synthetic inter-
mediate of cephalosporolide D, was tried using the present
mixed-anhydride method with a catalytic amount of a Lewis
acid in the presence of TFBA.7 First, the reaction was
carried out by the promotion of a catalytic amount of
TiCl2(OTf)2 together with chlorotrimethylsilane, however,
several unidentifiable products were obtained and the
8-membered ring lactone 21 was obtained in only 2%
yield. Since Yamamoto et al. reported that Sc(OTf)3
effectively functions with this mixed-anhydride method
producing medium sized lactones,2f we then utilized
Sc(OTf)3 as a catalyst combined with TFBA. The cycliza-
tion reaction of 20 was actually catalyzed to afford the
desired lactone 21 in 44% yield, and 31% of 20 was
recovered. To improve the yield of the desired 8-membered
ring lactone, we re-investigated other Lewis acids consisting
of metals in group IV as shown in Table 13. Although the
reaction was not facilitated using Zr(OTf)4, it was found
that Hf(OTf)4 is very effective for the promotion of the
cyclization to produce the desired 8-membered ring lactone
21 in 67% yield.15 Since 17% of the starting seco-acid 20
was recovered after the reaction, conversion yield of 21
reached 81% based on the consumed 20. It is noted that this
cyclization exclusively gave the monomeric lactone and the
corresponding diolide was not formed at all.16 Thus, an
efficient method for the preparation of the synthetic
precursor of cephalosporolide D was established via the
effective construction of the 8-membered ring lactone
moiety.
2.3. Synthesis of the 8-membered ring lactone moiety of
cephalospoloride D
Cephalosporolide D (22), a fungus metabolite, was isolated
Table 12. Synthesis of (R)-ricinoleic acid lactone using TFBA
Entry
X
Catalyst (amount/mol%)
Y
Temp.a (8C) Yieldb (%)
1
2
3
H
H
TiCl2(OTf)2 (5)
TiCl2(ClO4)2 (5)
3
3
0
50
rt
rt
83
83
72
Me3Si TiCl2(ClO4)2 (10)
3. Conclusion
a
Bath temperature.
Isolated yield.
b
In summary, it is determined that the mixed-anhydride

I. Shiina / Tetrahedron 60 (2004) 1587–1599
1595
method using a substituted benzoic anhydride provided an
efficient method for the preparation of various derivatives
of carboxylic acids.17 As an example of this synthetic
methodology, we demonstrated the combined use of
BTFBA or TFBA and a catalytic amount of TiCl2(ClO4)2
together with chlorotrimethylsilane for the preparation of
carboxylic esters from free carboxylic acids and alcohols.
An efficient and convenient method for the preparation of
lactones from v-hydroxycarboxylic acids or trimethylsilyl
v-(trimethylsiloxy)carboxylates was also established using
the substituted benzoic anhydride and a catalytic amount of
a Lewis acid such as TiCl2(ClO4)2, TiCl2(OTf)2 or Hf(OTf)4
under mild conditions.
was washed with water and brine, dried over sodium sulfate.
After filtration of the mixture and evaporation of the solvent,
the crude product was purified by recrystallization from
dichloromethane to afford 23.2 g (89%) of TFBA as a white
solid: mp 132–133 8C; IR (KBr) 1732, 1795 cm21 1H
;
NMR (CDCl3) d 7.79 (4H, d, J¼8.1 Hz), 8.26 (4H, d, J¼
8.1 Hz); 13C NMR (CDCl3) d 123.2 (q, J¼272.2 Hz), 125.9
(q, J¼3.9 Hz), 130.8, 131.5, 135.9 (q, J¼33.0 Hz), 160.6.
4.2.2. 3,5-Bis(trifluoromethyl)benzoic anhydride
(BTFBA). A mixture of 3,5-bis(trifluoromethyl)benzoic
acid (5.2 g, 20 mmol) and thionyl chloride (9.5 g, 80 mmol)
was stirred for 4 h at 80 8C. The solvent and thionyl chloride
were distillated under reduced pressure at 50 8C and then
dichloromethane (80 mL), 3,5-bis(trifluoromethyl)benzoic
acid (5.2 g, 20.0 mmol) and a solution of pyridine (1.7 mL,
21 mmol) in dichloromethane (40 mL) were successively
added at 0 8C. After the reaction mixture had been stirred for
21 h at room temperature, cooled water (100 mL) was added
at 0 8C. The mixture was extracted with dichloromethane,
and the organic layer was washed with water and brine,
dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified by
recrystallization from dichloromethane to afford 7.0 g
(70%) of BTFBA as a white solid: mp 104.5–105 8C; IR
4. Experimental
4.1. General methods
All melting points were measured on a Yanaco MP-S3
micro melting point apparatus. Optical rotations were
recorded on a Jasco DIP-360 or a Jasco P-1020 digital
polarimeter. IR spectra were recorded on a Horiba FT-300
infrared spectrometer. 1H and 13C NMR spectra were
recorded on a JEOL JNM-EX270L, a JEOL JNM-AL300 or
a JEOL JNM-LA500 spectrometer with tetramethylsilane
(TMS), chloroform (in chloroform-d) or benzene (in
benzene-d6) as internal standard. HPLC was carried out
using a Hitachi LC-Organizer, L-4000 UV Detector, L-6200
Intelligent Pump, and D-2500 Chromato-Integrator. High-
resolution mass spectra were recorded on a JEOL JMS-
SX102A instrument using 4-nitrobenzyl alcohol as a matrix.
Column chromatography was performed on Silica gel 60
(Merck) or Wakogel B5F. Thin layer chromatography was
performed on Wakogel B5F.
1
(KBr) 1712, 1805 cm21; H NMR (CDCl3) d 8.23 (2H, s),
8.58 (4H, s); 13C NMR (CDCl3) d 122.4 (q, J¼272.8 Hz),
127.2 (q, J¼3.9 Hz), 130.4 (q, J¼4.5 Hz), 131.2, 133.1 (q,
J¼34.4 Hz), 158.2.
4.3. Typical experimental procedure for the synthesis of
carboxylic esters using TFBA
A typical experimental procedure is described for the
reaction of 3-phenylpropanoic acid with 4-phenyl-2-buta-
nol; to a suspension of AgClO4 (7.7 mg, 0.037 mmol) in
dichloromethane (10.0 mL) were added a solution of TiCl4
in toluene (0.50 M, 0.037 mL, 0.019 mmol) and chloro-
trimethylsilane (0.118 mL, 0.930 mmol). After the reaction
mixture had been stirred for 30 min, a solution of TFBA
(740 mg, 2.04 mmol) and 3-phenylpropanoic acid (307 mg,
2.04 mmol) in dichloromethane (7.5 mL) and a solution of
4-phenyl-2-butanol (278 mg, 1.85 mmol) in dichloro-
methane (2.5 mL) were successively added. The reaction
mixture was stirred for 3 h at room temperature and then
saturated aqueous sodium hydrogencarbonate was added.
The mixture was extracted with dichloromethane, and the
organic layer was washed with water and brine, dried over
sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was purified
by thin layer chromatography to afford 518 mg (99%) of
1-methyl-3-phenylpropyl 3-phenylpropanoate with an
excellent chemoselectivity (.200:1).
All reactions were carried out under argon atmosphere in
dried glassware, unless otherwise noted. Dichloromethane
was distilled from diphosphorus pentoxide, then calcium
˚
hydride, and dried over MS 4 A, benzene and toluene were
distilled from diphosphorus pentoxide, and dried over MS
˚
4 A, and THF and diethyl ether were distilled from
sodium/benzophenone immediately prior to use.
4.2. Starting materials
All reagents were purchased from Tokyo Kasei Kogyo Co.,
Ltd., Kanto Chemical Co., Inc. or Aldrich Chemical Co.,
Inc., and used without further purification unless otherwise
noted. Titanium dichlorobis(trifluoromethanesulfonate) was
prepared by the literature method.18
4.2.1. 4-(Trifluoromethyl)benzoic anhydride (TFBA).
4-(Trifluoromethyl)benzoic anhydride was purchased from
Tokyo Kasei Kogyo Co., Ltd. (TCI) or synthesized from
4-(trifluoromethyl)benzoic acid and 4-(trifluoromethyl)ben-
zoyl chloride. To a mixture of 4-(trifluoromethyl)benzoic
acid (13.7 g, 72.0 mmol) and 4-(trifluoromethyl)benzoyl
chloride (15.0 g, 72.0 mmol) in dichloromethane (144 mL)
at 0 8C was added pyridine (6.11 mL, 75.6 mmol). The
reaction mixture was stirred for 21 h at room temperature
and then cold water (50 mL) was added at 0 8C. The mixture
was extracted with dichloromethane, and the organic layer
4.3.1. 1-Methyl-3-phenylpropyl 3-phenylpropanoate5b
1
(1). IR (neat) 1730 cm21; H NMR (CDCl3) d 1.21 (3H,
d, J¼6.3 Hz), 1.72–1.96 (2H, m), 2.51–2.69 (4H, m), 2.95
(2H, t, J¼7.6 Hz), 4.94 (1H, m), 7.11–7.31 (10H, m).
Found: C, 80.74; H, 7.99%. Calcd for C19H22O2: C, 80.82;
H, 7.85%.
4.3.2. 3-Phenylpropyl 3-phenylpropanoate19 (3). IR
1
(neat) 1735 cm21; H NMR (CDCl3) d 1.91 (2H, m), 2.62

1596
I. Shiina / Tetrahedron 60 (2004) 1587–1599
(4H, m), 2.95 (2H, t, J¼7.8 Hz), 4.08 (2H, t, J¼6.6 Hz),
7.13–7.31 (10H, m). Found: C, 80.35; H, 7.77%. Calcd for
C18H20O2: C, 80.56: H,7.51%.
172.42; HR MS: calcd for C36H57O2 (MþHþ) 521.4358,
found 521.4360.
4.3.12. 3-Phenylpropyl benzoate5b (13). IR (neat)
4.3.3. 3-Phenylpropyl cyclohexanecarboxylate5b (4). IR
1718 cm21; H NMR (CCl4) d 2.23 (2H, m), 2.77 (2H, t,
1
1
(neat) 1732 cm21; H NMR (CCl4) d 1.05–2.40 (13H, m),
J¼8 Hz), 4.27 (2H, t, J¼6 Hz), 7.05–7.54 (8H, m), 7.85–
8.10 (2H, m). Found: C, 79.69; H, 6.97%. Calcd for
C16H16O2: C, 79.97; H, 6.71%.
2.65 (2H, t, J¼8.0 Hz), 4.00 (2H, t, J¼6.0 Hz), 7.15 (5H, s).
Found: C, 77.89; H, 8.90%. Calcd for C16H22O2: C, 78.01;
H, 9.00%.
4.3.13. 1-Methyl-3-phenylpropyl benzoate5b (14). IR
;
(neat) 1716 cm21 1H NMR (CCl4) d 1.44 (3H, d,
J¼6 Hz), 1.74–2.23 (2H, m), 2.55–2.90 (2H, m), 5.15
(1H, m), 7.05–7.54 (8H, m), 7.98 (2H, dd, J¼8, 2 Hz).
Found: C, 80.47; H, 7.22%. Calcd for C17H18O2: C, 80.28;
H, 7.13%.
4.3.4. 1-Methyl-3-phenylpropyl cyclohexanecarboxyl-
1
ate5b (5). IR (neat) 1728 cm21; H NMR (CCl4) d 1.15
(3H, d, J¼6.0 Hz), 1.25–2.25 (13H, m), 2.25–2.80 (2H, m),
4.85 (1H, m), 7.15 (5H, s). Found: C, 78.18; H, 9.07%.
Calcd for C17H24O2: C, 78.42; H, 9.29%.
4.3.5. 3-Phenylpropyl 2,2-dimethylpropanoate5b (6). IR
(neat) 1728 cm21; 1H NMR (CDCl3) d 1.26 (9H, s), 1.97–
2.03 (2H, m), 2.74 (2H, t, J¼7.6 Hz), 4.12 (2H, t, J¼
6.3 Hz), 7.21–7.34 (5H, m). Found: C, 76.06; H, 9.21%.
Calcd for C14H20O2: C, 76.33; H, 9.15%.
4.4. Typical experimental procedure for the synthesis of
a,b-unsaturated esters
The same procedure as typical experimental procedure for
the catalytic esterification reaction except for using
phosphate buffer (pH¼7) as a reagent for quenching.
4.3.6. 1-Methyl-3-phenylpropyl 2,2-dimethylpropano-
ate5b (7). IR (neat) 1726 cm21; H NMR (CDCl3) d 1.22
1
4.4.1. 3-Phenylpropyl (E)-crotonate5b (15). IR (neat)
(9H, s), 1.25 (3H, d, J¼6.3 Hz), 1.73–2.00 (2H, m), 2.54–
2.74 (2H, m), 4.91 (1H, m), 7.15–7.31 (5H, m). Found: C,
76.70; H, 9.52%. Calcd for C15H22O2: C, 76.88; H, 9.46%.
1722 cm21
;
1H NMR (CDCl3) d 1.87 (3H, dd, J¼6.9,
1.7 Hz), 1.99 (2H, tt, J¼7.6, 6.6 Hz), 2.70 (2H, t, J¼7.6 Hz),
4.14 (2H, t, J¼6.6 Hz), 5.85 (1H, dq, J¼15.0, 1.7 Hz),
6.96 (1H, dq, J¼15.0, 6.9 Hz), 7.15–7.31 (5H, m). Found:
C, 76.21; H, 8.00%. Calcd for C13H16O2: C, 76.44; H,
7.90%.
4.3.7. Benzyl 3-phenylpropanoate20 (8). IR (neat)
1
1736 cm21; H NMR (CDCl3) d 2.67 (2H, t, J¼7.8 Hz),
2.96 (2H, t, J¼7.8 Hz), 5.10 (2H, s), 7.12–7.40 (10H, m).
4.4.2. 1-Methyl-3-phenylpropyl (E)-crotonate (16). IR
4.3.8. Allyl 3-phenylpropanoate (9). IR (neat) 1736 cm21
;
(neat) 1730 cm21; H NMR (CDCl3) d 1.27 (3H, d, J¼
1
1H NMR (CDCl3) d 2.66 (2H, t, J¼7.8 Hz), 2.97 (2H, t,
J¼7.8 Hz), 4.57 (2H, td, J¼1.3, 5.6 Hz), 5.21 (1H, tdd,
J¼1.3, 1.7, 10.6 Hz), 5.28 (1H, tdd, J¼1.3, 1.7, 17.2 Hz),
5.89 (1H, tdd, J¼5.6, 10.6, 17.2 Hz), 7.10–7.35 (5H, m);
HR MS: calcd for C12H15O2 (MþHþ) 191.1072, found
191.1073.
6.3 Hz), 1.70–2.06 (2H, m), 1.87 (3H, dd, J¼1.8, 6.9 Hz),
2.50–2.76 (2H, m), 4.99 (1H, tq, J¼6.3, 6.3 Hz), 5.84 (1H,
qd, J¼1.8, 15.4 Hz), 6.96 (1H, qd, J¼6.9, 15.4 Hz), 7.10–
7.34 (5H, m); HR MS: calcd for C14H19O2 (MþHþ)
219.1385, found 219.1387.
4.4.3. 3-Phenylpropyl 3-methyl-2-butenoate5b (17). IR
4.3.9. Cyclohexyl 3-phenylpropanoate21 (10). IR (neat)
(neat) 1716 cm21; H NMR (CDCl3) d 1.88 (3H, d, J¼
1
1
1730 cm21; H NMR (CDCl3) d 1.10–1.19 (8H, m), 1.80
1.0 Hz), 1.95 (2H, tt, J¼7.9, 6.6 Hz), 2.17 (3H, d, J¼
1.0 Hz), 2.69 (2H, t, J¼7.9 Hz), 4.10 (2H, t, J¼6.6 Hz), 5.69
(1H, q, J¼1.3 Hz), 7.14–7.30 (5H, m). Found: C, 76.86; H,
8.37%. Calcd for C14H18O2: C, 77.03; H, 8.31%.
(2H, td, J¼5.4, 9.1 Hz), 2.60 (2H, t, J¼7.8 Hz), 2.95 (2H,
t, J¼7.8 Hz), 4.75 (1H, tt, J¼4.4, 9.1 Hz), 7.09–7.38
(5H, m).
4.3.10. (2)-Mentyl 3-phenylpropanoate (11). [a]2D8¼
4.5. Typical experimental procedure for the synthesis of
lactones from trimethylsilyl v-(trimethylsiloxy)-
carboxylates
1
258.08 (c 1.67, CHCl3); IR (neat) 1730 cm21; H NMR
(CDCl3) d 0.62 (3H, d, J¼6.9 Hz), 0.68–1.75 (14H, m),
1.78–1.93 (1H, m), 2.53 (2H, t, J¼7.8 Hz), 2.87 (2H, t, J¼
7.8 Hz), 4.59 (1H, dt, J¼4.6, 10.9 Hz), 7.05–7.26 (5H, m);
HR MS: calcd for C19H29O2 (MþHþ) 289.2167, found
289.2177.
A typical experimental procedure is described for the
synthesis of pentadecan-15-olide; to a suspension of
AgClO4 (16.6 mg, 0.080 mmol) in dichloromethane
(90 mL) was added a solution of TiCl4 in toluene (0.5 M,
0.080 mL, 0.040 mmol). After the reaction mixture had been
stired for 30 min, a solution of trimethylsilyl 15-(trimethyl-
siloxy)pentadecanoate (161 mg, 0.400 mmol) and TFBA
(145 mg, 0.400 mmol) in dichloromethane (10 mL) was
slowly added to the suspension including TiCl2(ClO4)2 with
a mechanically driven syringe over a 31 h period at room
temperature. The reaction mixture was additionally stirred
for 3 h at room temperature and then saturated aqueous
sodium hydrogencarbonate was added at 0 8C. The mixture
4.3.11. (1)-5a-Cholestan-3b-yl 3-phenylpropanoate
(12). Mp. 96–98 8C; [a]2D8¼þ13.28 (c 1.00, CHCl3); IR
(KBr) 1730 cm21; 1H NMR (CDCl3) d 0.52–2.02 (46H, m),
2.58 (2H, t, J¼7.8 Hz), 2.93 (2H, t, J¼7.8 Hz), 4.69 (1H, tt,
J¼5.6, 11.2 Hz), 7.07–7.36 (5H, m); 13C NMR (CDCl3) d
12.06, 12.20, 18.65, 21.19, 22.55, 22.81, 23.83, 24.19,
27.44, 28.00, 28.23, 28.59, 31.05, 31.97, 33.98, 35.44,
35.78, 36.16, 36.26, 36.73, 39.50, 39.97, 42.57, 44.62,
54.20, 56.25, 56.39, 73.77, 126.15, 128.30, 128.41, 140.61,

I. Shiina / Tetrahedron 60 (2004) 1587–1599
1597
was extracted with dichloromethane, and the organic layer
was washed with water and brine, dried over sodium sulfate.
After filtration of the mixture and evaporation of the solvent,
the crude product was purified by thin layer chromatography
to afford 85.6 mg (89%) of pentadecan-15-olide and 3.8 mg
(2%) of diolide.
(2H, t, J¼5.6 Hz); EI MS: calcd for C16H30O2 (Mþ) 254,
found 254.
4.6.7. (1)-(E)-9-Octadecen-12-olide11 ((R)-ricinelaidic
acid lactone). [a]2D6¼þ41.38 (c 1.85, CHCl3); IR (neat)
1
1732 cm21; H NMR (CDCl3) d 0.88 (3H, t, J¼6.6 Hz),
1.19–1.71 (20H, m), 2.06–2.55 (6H, m), 4.92–5.00 (1H,
m), 5.33–5.53 (2H, m); 13C NMR (CDCl3) d 14.0, 22.5,
23.4, 24.5, 25.6, 25.7, 26.1, 27.3, 29.1, 29.5, 31.7, 31.8,
33.8, 35.2, 73.8, 124.8, 132.4, 174.4; EI MS: calcd for
C18H32O2 (Mþ) 280, found 280.
4.6. Typical experimental procedure for the synthesis of
lactones from v-hydroxycarboxylic acids
A typical experimental procedure is described for the
synthesis of octadecan-12-olide; to a suspension of
TiCl2(OTf)2 (10.8 mg, 0.026 mmol) and chlorotrimethyl-
silane (0.2 mL, 1.57 mmol) in gently refluxing dichloro-
methane (220 mL) was added a solution of 12-hydroxy-
octadecanoic acid (157.6 mg, 0.524 mmol) and TFBA
(209.5 mg, 0.578 mmol) in dichloromethane (40 mL) with
a mechanically driven syringe over a 5 h period. After
addition of the solution, the reaction mixture was concen-
trated to ca. 20 mL by evaporation of the solvent under
reduced pressure and then saturated aqueous sodium
hydrogencarbonate was added at 0 8C. The mixture was
extracted with dichloromethane, and the organic layer was
washed with water and brine, dried over sodium sulfate.
After filtration of the mixture and evaporation of the solvent,
the crude product was purified by thin layer chromatography
to afford 135.1 mg (91%) of octadecan-12-olide and 9.4 mg
(3%) of diolide.
4.6.8. (1)-(Z)-9-Octadecen-12-olide11b,12 ((R)-ricinoleic
acid lactone). [a]2D8¼þ32.08 (c 1.77, CHCl3); IR (neat)
1
1732 cm21; H NMR (CDCl3) d 0.80 (3H, t, J¼7.0 Hz),
1.10–1.70 (20H, m), 2.06–2.55 (6H, m), 4.92–5.00 (1H,
m), 5.13–5.33 (2H, m); 13C NMR (CDCl3) d 14.0, 22.5,
23.7, 25.3, 26.9, 27.1, 27.5, 29.1, 29.7, 31.7, 32.2, 34.1,
35.0, 37.7, 73.0, 126.3, 134.2, 173.7; EI MS: calcd for
C18H32O2 (Mþ) 280, found 280.
4.7. Experimental procedure for the synthesis of an
8-membered ring lactone moiety of cephalosporolide D
To a solution of Hf(OTf)4 (28.6 mg, 0.037 mmol) and
TFBA (133.8 mg, 0.369 mmol) in acetonitrile (78 mL) at
reflux temperature was added a solution of 3-benzyloxy-7-
hydroxyoctanoic acid (20) (49.2 mg, 0.184 mmol) in THF
(4.6 mL) with a mechanically driven syringe over a 15 h
period. After the reaction mixture had been stirred for 5 h at
reflux temperature, saturated aqueous sodium hydrogen-
carbonate (1.9 mL) was added at room temperature. The
mixture was concentrated by evaporation of the solvent and
then it was extracted with diethyl ether, and the organic
layer was washed with brine, and dried over sodium sulfate.
After filtration of the mixture and evaporation of the solvent,
the crude product was purified by preparative thin layer
chromatography to afford 30.5 mg (67%) of 3-benzyl-
oxyoctan-7-olide (21) and 8.4 mg (17%) of recovered 20
as colorless oils.
4.6.1. Dodecan-12-olide2f (13-membered ring lactone).
IR (neat) 1734 cm21; 1H NMR (CDCl3) d 1.23–1.48 (14H,
m), 1.60–1.73 (4H, m), 2.33–2.38 (2H, m), 4.15 (2H, dd,
J¼4.0, 5.1 Hz); EI MS: calcd for C12H22O2 (Mþ) 198,
found 198.
4.6.2. Octadecan-12-olide12c (12-hydroxystearic acid
1
lactone). IR (neat) 1730 cm21; H NMR (CDCl3) d 0.87
(3H, t, J¼6.7 Hz), 1.17–1.80 (28H, m), 2.24 (1H, ddd,
J¼3.9, 9.0, 12.3 Hz), 2.43 (1H, ddd, J¼3.6, 8.1, 12.3 Hz),
4.92 (1H, dddd, J¼2.2, 4.3, 6.5, 8.9 Hz); EI MS: calcd for
C18H34O2 (Mþ) 282, found 282.
4.7.1. 3-Benzyloxyoctan-7-olide (21). IR (neat):
1
4.6.3. Tridecan-13-olide2f (14-membered ring lactone).
IR (neat) 1736 cm21; 1H NMR (CDCl3) d 1.19–1.50 (16H,
m), 1.58–1.72 (4H, m), 2.35–2.39 (2H, m), 4.14 (2H, dd,
J¼4.5, 5.3 Hz); EI MS: calcd for C13H24O2 (Mþ) 212,
found 212.
1720 cm21; H NMR (CDCl3): d 1.26 (3H, d, J¼6.3 Hz,
8-H), 1.02–1.33 (1H, m, 5-H), 1.46–1.96 (5H, m, 4-H, 5-H,
6-H), 2.67 (1H, dd, J¼6.6, 11.9 Hz, 2-H), 2.71 (1H, dd,
J¼4.3, 11.9 Hz, 2-H), 3.62–3.77 (1H, m, 3-H), 4.44 (1H, d,
J¼11.9 Hz, Bn-H), 4.61 (1H, d, J¼11.9 Hz, Bn-H), 4.69
(1H, dqd, J¼5.3, 6.3, 10.5 Hz, 7-H), 7.14–7.39 (5H, m, Ph);
13C NMR(CDCl3): d 18.9 (5), 21.3 (8), 32.9 (4), 37.7 (2),
38.3 (6), 70.1 (Bn), 75.3 (7), 77.3 (3), 127.5 (Ph), 127.6
(Ph), 128.3 (Ph), 138.1 (Ph), 172.3 (1). Anal. calcd for
C15H20O3: C, 72.55; H, 8.12. Found: C, 72.15; H, 8.03; HR
MS: calcd for C15H21O3Na (MþNaþ) 249.1491, found
249.1539.
4.6.4. Tetradecan-14-olide2f (15-membered ring lac-
1
tone). IR (neat) 1728 cm21; H NMR (CDCl3) d 1.19–
1.48 (18H, m), 1.56–1.73 (4H, m), 2.32–2.37 (2H, m), 4.13
(2H, t, J¼4.1, 5.3 Hz); EI MS: calcd for C14H26O2 (Mþ)
226, found 226.
4.6.5. Pentadecan-15-olide2f (16-membered ring lac-
1
tone). IR (neat) 1740 cm21; H NMR (CDCl3) d 1.24–
1.49 (20H, m), 1.56–1.72 (4H, m), 2.33 (2H, dd, J¼6.6,
7.1 Hz), 4.13 (2H, dd, J¼5.4, 5.6 Hz); EI MS: calcd for
C15H28O2 (Mþ) 240, found 240.
Acknowledgements
The author would like to express his hearty thanks to
Professor Teruaki Mukaiyama (the Kitasato Institute) for his
helpful discussion and useful suggestions. The author is also
grateful to Drs Mitsutomo Miyashita, Yoshio Fukuda,
and Hidehiko Fujisawa and Mr So Miyoshi for their
4.6.6. Hexadecan-16-olide2f (17-membered ring lactone).
IR (neat) 1736 cm21; 1H NMR (CDCl3) d 1.22–1.45 (22H,
m), 1.55–1.71 (4H, m), 2.32 (2H, dd, J¼6.6, 6.9 Hz), 4.12

1598
I. Shiina / Tetrahedron 60 (2004) 1587–1599
Saravanan, P.; Singh, V. K. Tetrahedron Lett. 1999, 40,
2611–2614. (s) Cu(OTf)2: Chandra, K. L.; Saravanan, P.;
Singh, R. K.; Singh, V. K. Tetrahedron 2002, 58, 1369–1374.
(t) Nafion-H: Kumareswaran, R.; Pachamuthu, K.; Vankar,
Y. D. Synlett 2000, 1652–1654. (u) Bi(OTf)3: Orita, A.;
Tanahashi, C.; Kakuda, A.; Otera, J. Angew. Chem., Int. Ed.
Engl. 2000, 39, 2877–2879. (v) Bi(OTf)3: Orita, A.;
Tanahashi, C.; Kakuda, A.; Otera, J. J. Org. Chem. 2001,
66, 8926–8934. (w) Bi(OTf)3: Carrigan, M. D.; Freiberg,
D. A.; Smith, R. C.; Zerth, H. M.; Mohan, R. S. Synthesis
2001, 2091–2094. (x) BiCl3, Bi(TFA)3, Bi(OTf)3:
Mohammadpoor-Baltork, I.; Aliyan, H.; Khosropour, A. R.
Tetrahedron 2001, 57, 5851–5854. (y) Yttria–zirconia:
Kumar, P.; Pandey, R. K.; Bodas, M. S.; Dongare, M. K.
Synlett 2001, 206–209. (z) LiClO4: Nakae, Y.; Kusaki, I.;
Sato, T. Synlett 2001, 1584–1586. (aa) Sc(OTf)3/
(nBu2ClSnOSnnBu2Cl)2: Nagano, Y.; Orita, A.; Otera, J.
Tetrahedron 2002, 58, 8211–8217. (bb) HBF4: Chakraborti,
A. K.; Gulhane, R. Tetrahedron Lett. 2003, 44, 3521–3525.
(cc) Mg(ClO4)2: Chakraborti, A. K.; Sharma, L.; Gulhane, R.;
Shivani, Tetrahedron 2003, 59, 7661–7668.
considerable cooperation. This study was partially sup-
ported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science, Sports and Culture,
Japan.
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