A highly efficient macrolactonization method via ethoxyvinyl ester

Article abstract of DOI:10.1002/chem.200801548

We present the highly efficient reaction procedure of the macrolactonization method via ethoxyvinyl esters (EVEs). The following procedure was performed: 1)The EVE was prepared from hydroxycarboxylic acid and ethoxyacetylene in the presence of the Ru catalyst [RuCl₂(p-cymene)] ₂ in acetone; 2) after filtration of the Ru catalyst through a short-neutral SiO₂ pad and evaporation of acetone, the EVE formed was diluted in 1,2-dichloroethane (DCE) and the solution was slowly added by a syringe pump to the highly diluted DCE solution of pTsOH (10mol%) at 80°C. Varioussized lactones could be produced by the method described here. It is note worthy that the method can give 9- to 14-membered macrolactones in good yields. This macrolactonization method via EVEs is useful for acid-/base-sensitive substrates. Furthermore, it was found that EVE formation was possible without loosing activity of the Ru catalyst even for the compounds with nucleophilic amine functions. The characteristic feature of the method was exemplified by the reaction of the compound 14 with many functional groups.

Full text of DOI:10.1002/chem.200801548

DOI: 10.1002/chem.200801548
A Highly Efficient Macrolactonization Method via Ethoxyvinyl Ester
Yusuke Ohba,[a] Mayuko Takatsuji,[a] Kenji Nakahara,[a] Hiromichi Fujioka,[a] and
Yasuyuki Kita*[a, b]
Abstract: We present the highly effi-
cient reaction procedure of the macro-
lactonization method via ethoxyvinyl
esters (EVEs). The following proce-
dure was performed: 1) The EVE was
prepared from hydroxycarboxylic acid
and ethoxyacetylene in the presence of
EVE formed was diluted in 1,2-di-
chloroethane (DCE) and the solution
was slowly added by a syringe pump to
the highly diluted DCE solution of
pTsOH (10 mol%) at 808C. Various-
sized lactones could be produced by
the method described here. It is note-
worthy that the method can give 9- to
14-membered macrolactones in good
yields. This macrolactonization method
via EVEs is useful for acid-/base-sensi-
tive substrates. Furthermore, it was
found that EVE formation was possi-
ble without loosing activity of the Ru
catalyst even for the compounds with
nucleophilic amine functions. The char-
acteristic feature of the method was ex-
emplified by the reaction of the com-
pound 14 with many functional groups.
the Ru catalyst [RuCl2ACHTUNRTGNEUNG(p-cymene)]2 in
acetone; 2) after filtration of the Ru
catalyst through a short-neutral SiO2
pad and evaporation of acetone, the
Keywords: cyclization · lactones ·
macrocycles · medium-sized rings
Introduction
Numerous macrolactones including natural products display
the interesting biological activities, such as the antibiotic
properties used clinically as macrolactone glycoside antibiot-
ics, and the cytotoxic and antiangiogenesis properties. Many
methods for constructing macrolactone skeletons have been
developed over the past years. They are widely divided in
two categories. One is the intramolecular lactonization of
hydroxycarboxylic acids.[1] The other is the intramolecular
ꢀ
C C bond formation of an ester using ring closing metathe-
sis (RCM) or the intramolecular Horner–Emmons reaction
Scheme 1. Representative methods for macrolactone formation.
leading to the macrolactone formation (Scheme 1).[2]
Although macrolactonization using RCM is rapidly devel-
oping,[2] traditional intramolecular lactonizations of hydroxy-
carboxylic acids are still widely used.[1] The intramolecular
lactonizations proceed in two ways: One through the acti-
vated carboxylic acid intermediates and the other through
the activated alcohol part. The representative intramolecular
macrolactonization of the latter one is the Mitsunobu reac-
tion (Scheme 2). However, this reaction has several disad-
vantages: 1) Only a few hydroxycarboxylic acids are avail-
able; 2) side reactions often occur, and 3) purification of the
products from the reagents is sometimes difficult, although
the reaction proceeds under neutral conditions. Therefore,
the use of this method has been slight in recent days.
[a] Y. Ohba, M. Takatsuji, K. Nakahara, Dr. H. Fujioka, Prof. Dr. Y. Kita
Graduate School of Pharmaceutical Sciences
Osaka University 1-6, Yamada-oka
Suita, Osaka, 565-0871 (Japan)
Fax : (+81)6-6879-8229
E-mail: kita@phs.osaka-u.ac.jp
On the other hand, macrolactonizations by activating the
carboxylic acid of hydroxycarboxylic acids are widely used.
In this method, active intermediates i must be formed with a
high selectivity and their successive macrolactonization must
smoothly proceed. The formation of the anhydrides ii by the
reaction of i and another hydroxycarboxylic acid decreases
[b] Prof. Dr. Y. Kita
Present address: College of Pharmaceutical Sciences
Ritsumeikan University, 1-1-1 Nojihigashi
Kusatsu, Shiga, 525-8577
3526
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FULL PAPER
Scheme 2. Mitsunobu macrolactone formation.
the yields of the macrolactones. Furthermore, the activity of
the anhydrous ii is low (Scheme 3).
Based on these points, various macrolactonizations of hy-
droxycarboxylic acids have already been developed. The Ya-
maguchi macrolactonization is most widely utilized. The
original Yamaguchi method uses 2,4,6-trichlorobenzoate for
Scheme 5. Mukaiyama–Corey–Nicolaou macrolactone formation.
esterification have been one of the hot topics in organic
chemistry.
In 1993, we reported that
the less toxic Bennett complex,
[RuCl2ACTHNUGTRNE(NUG p-cymene)]2, effectively
catalyzed the addition of a car-
boxy acid to ethoxyacetylene
producing the various func-
tionalized ethoxyvinyl esters
(EVEs) in high yields, and the
EVEs worked as good acylat-
ing reagents to produce the
corresponding acylated prod-
ucts by the reaction with
Scheme 3. Macrolactone formation via carboxylic acid-activated intermediate.
amines and alcohols under
nearly neutral conditions. The
reactions of the EVEs with
the selective formation of the mixed acid anhydride iii
(Scheme 4).[3] There have been many variations and modifi-
cations of the original one.[4] Shiina et al. reported improved
methods using more active mixed acid anhydrides.[4c,d] How-
ever, these methods need excess dimethylaminopyridine
(DMAP) to activate the mixed acid anhydride and a side re-
action often occurs because of its basicity.[5]
various nucleophiles produced only the low-boiling ethyl
acetate as a by-product. We also succeeded in using EVE
method for acid anhydride formation by intramolecular
attack of the carboxylic acid (Scheme 6).[8,9]
Although the Mukaiyama–Corey–Nicolaou macrolactoni-
zation using PySSPy and PPh3 and its modified methods[7]
[6]
proceed under neutral to slightly acidic conditions, the reac-
tivity of the intermediates iv, thioesters, is low and a large
amount of a Lewis acid, such as silver salts or cuprous salts,
is necessary to activate the intermediates (Scheme 5).
Scheme 6. EVE formation and the intermolecular reaction of EVE and
nucleophile.
Therefore, the investigations aimed at efficient and versa-
tile macrolactonization methods by an intramolecular
EVEs are stable against humidity, and column purification
is possible, whereas mixed acid anhydrides in Yamaguchiꢁs
and its corresponding methods need careful treatment under
no humidity conditions. Trost et al. showed that our EVE
method was useful for macrolactone formation.[10] The utili-
ty of his macrolactonization protocol via EVEs was proven
from the following natural macrolactones syntheses. Thus,
Tatsuta et al. synthesized cocheamycin A (10-membered lac-
tone). In this case, the EVE method only produced the de-
sired macrolide.[11a] Maier et al. emphasized the higher yield
of the macrolactonization of the 12-membered macrolactone
using the EVE method in the synthesis of apicularen A.[11b]
Scheme 4. Original Yamaguchi macrolactone formation.
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Y. Kita et al.
Lee et al. synthesized (ꢀ)-amphidinolide E (18-membered
ring), in which they mentioned that the EVE method gave
the best results.[11c] The reaction conditions used for these
studies[10,11] are the same as we developed for intermolecular
acylating reactions. As a result, the available substrates were
still limited, and the reaction of the hydroxycarboxylic acids
aimed at the medium-sized lactones gave poor results. The
protocol can be available only to the 14- or higher mem-
bered lactones. On the other hand, the method is not effec-
tive for the syntheses of the 12-membered or 13-membered
macrolactones.[10a]
It is widely known that the construction of the medium-
sized lactones is difficult not only by biosynthesis in nature,
but by artificial synthetic technology in the field of advanced
organic chemistry.[1] Trostꢁs results led to the same conclu-
sion even when using the EVE method.[10a] However, if the
EVE method could be improved for the formation of
medium-sized lactones, it would become the best method
which proceeds under nearly neutral conditions.
tone was over 95% (entry 4). We then decided to use the
ethoxyvinyl ester for further reactions without purification.
Efficient macrolactonization: Since acetone proved to be
the best solvent of choice for the EVE formation, we tried
the formation of the macrolactone 3a from the hydroxycar-
boxylic acid 1a via the EVE intermediate. Dichloromethane
and DCE were found to be the best solvents for the inter-
molecular esterification,[8,9] and the synthetic methods for
the medium-sized lactones are generally performed by the
slow addition of the activated hydroxycarboxylic acid to a
highly diluted solvent at high temperature to prevent any di-
merization. Since acetone was found to be the solvent of
choice for the EVEs formation, the following procedure was
performed: 1) The EVE was prepared from hydroxycarbox-
ylic acid and ethoxyacetylene in the presence of the Ru cat-
alyst in acetone; 2) after filtration of the Ru catalyst through
a short-neutral SiO2 pad and evaporation of the acetone, the
crude EVE was diluted in DCE and the solution was slowly
added by a syringe pump to the highly diluted DCE solution
of pTsOH (10 mol%) at 808C. Generally, the filtration of
the Ru catalyst is not crucial, but it is sometimes essential to
prevent any decomposition when this macrolactonization
method was applied to an unstable compound as will be de-
scribed later.
In this paper, we present the highly efficient reaction pro-
cedure of the macrolactonization method via EVEs, which
is available for the formation of medium-sized (9–10-mem-
bered) lactones.
Results and Discussion
To our delight, the 13-membered lactone 3a was obtained
in 64% yield (see Scheme 7). This was surprising, because
Trost et al. reported the formation of a poor amount of the
12-membered or 13-membered macrolactones by the EVE
method. In these cases, a fairly high amount of dimers were
obtained as by-products.[10a] The significant difference be-
tween our results and theirs must be the difference in the
solvent used for the intramolecular esterification, DCE vs.
toluene. We then studied the macrolactonization according
to our protocol in detail.
Efficient formation of EVE: In our previous study, toluene
was used as the solvent for the formation of the EVEs from
the carboxylic acids not having polar functions. However, in
the intramolecular version, the carboxylic acids have at least
one polar hydroxyl function in the same molecule. Although
Trost et al. used toluene for the formation of EVEs from hy-
droxycarboxylic acids, we first examined various solvents for
the synthesis of EVE 2 using the hydroxycarboxylic acid 1a
(Table 1). Ethoxyacetylene was added to the solution of 1a
and [RuCl2ACHTUNGTRENNUNG(p-cymene)]2 at 08C, and the mixture was stirred
at room temperature. Various ranges of solvents [toluene,
1,2-dichloroethane (DCE), acetone] were available. For the
all solvents, the EVE 2 could be obtained in moderate
yields (ca. 60–70% yield) by silica gel column chromatogra-
phy separation. However, this purification accompanied sig-
nificant hydrolysis of the ester (entries 1–3). A 1H NMR
analysis showed that the purity of the crude product in ace-
Table 1. Synthesis of EVE in various solvent.
Scheme 7. Formation of 13-membered lactone 3a by our EVE procedure.
Generality of macrolactonization: Table 2 shows the results
of the intramolecular acylation via EVEs forming the vari-
ous sized lactones. Expectedly, the 12-membered lactone 3e,
13-membered lactone 3 f and 14-membered lactone 3g were
obtained in good yields by our method. Although the 9–11-
membered lactones 3b–d were also obtained in moderate
Entry
Solvent
t [h]
Yield [%]
1
2
3
4
toluene
DCE
acetone
acetone
6
6
1
1
57
68
70
quant.[a]
1
[a] Crude yield (>95% purity based on H NMR analysis).
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A Highly Efficient Macrolactonization Method
Table 2. Stntheses of various ring sized lactones.
FULL PAPER
Table 3. Intermolecular acylation via EVE in the presence of acid-sensi-
tive group.
Entry
1
Hydroxyl acid (1)
1b (n=6)
Lactone (3)
Yield [%]
61[a]
Entry
R
Conditions
Yield [%]
1
2
3
4
TBS (4a)
MOM (4b)
THP (4c)
THP (4c)
DCE (0.13m), RT, 1 h
DCE (0.13m), RT, 1 h
DCE (0.13m), RT, 1 h
DCE (5 mm), 808C, 10 h
93
97
90
87
2
3
1c (n=7)
1d (n=8)
50[a]
typical macrolactonization, produced the ester in good yield
(entry 4).
68[a]
The results in Table 3 showed that the acylation condi-
tions through the EVEs were very mild and the macrolacto-
nization through the EVEs would become a very efficient
macrolactone formation even for hydroxycarboxylic acids
with acid-/base-sensitive functions. We then studied the ap-
plicability of the method for the construction of various
macrolactones.
Table 4 shows the results for producing macrolactones
with acid-/base-sensitive functions. The macrolactones with
acid-sensitive functions, such as TBS-ether (8a), MOM-
ether (8b), and THP-ether (8c), were obtained in good
yields (entries 1–3). The macrolactone 9a with an olefin was
produced in good yield without isomerization (entry 4). Fur-
thermore, quite acid-sensitive functions, such as an aceto-
nide and epoxide, did not cause any macrolactonization
problems (entries 5 and 6). Especially, it is noteworthy that
the classical Yamaguchi method yielded compound 9c with
an epoxide in only 20% yield, whereas the modified Yama-
guchi method by Shiina, a method using 2-methyl-6-nitro-
benzoic anhydride (MNBA), produced 9c in good yield. For
the structures of 6 and 7, see Experimental Section.
4
5
6
1e (n=9)
1 f (n=10)
1g (n=11)
62 (4)[10a]
69 (22)[10a]
89 (49)[10a]
[a] Macrolactonization via EVE was carried out 2.5 mm concentration.
yields, their chemical yields were remarkably improved
under higher diluted conditions (2.5 mm).
The method was next applied to acid-/base-sensitive sub-
strates. Before the macrolactonization of hydroxycarboxylic
acids with various functional
groups, we examined the avail-
Table 4. Macrolactonization via EVE in the pesence of acid-/base-sensitive group.
ability of the method against
acid-sensitive functions by in-
termolecular benzyl ester for-
mation from carboxylic acids
and benzyl alcohol through the
EVE intermediates (Table 3).
The acid-sensitive functions
such as the tert-butyldimethyl-
silyl (TBS) ether 4a (entry 1),
methoxymethyl (MOM) ether
4b (entry 2), and tetrahydro-
pyranyl (THP) ether 4c
(entry 3) did not cause any
trouble, and the desired esters
5a–c were obtained in good
yields for every entry. Further-
more, the conditions (highly
diluted concentration 5 mm, re-
action temperature at 808C, re-
action time of 10 h), used for
Entry
1
Product
Yield [%]
74[a]
Entry
4
Product
Yield [%]
72[b]
2
3
55[a]
5
6
52[b]
70[b] (20% by Yamaguchiꢁs method,
73% by MNBA)
67[a]
[a] Macrolactonization was carried out at 2.5 mm concentration. [b] Macrolactonization was carried out at
5 mm concentration.
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Y. Kita et al.
Table 6. Macrolactonization of hydroxycarboxylic acid (14) with many func-
tions.
The method could also be applied to the hydroxycarboxyl
acids with amine functions (Table 5). Amines are known as
a catalytic poison of the ruthenium catalyst. The formation
of the EVEs was then examined. We examined the macro-
lactonization of hydroxyacids 10 with various protected
amines. The hydroxycarboxylic acids 10a–c with amines pro-
tected with the electron-withdrawing groups such as tert-bu-
tyloxycarbonyl (Boc) or p-toluenesulfonyl (Ts) functions
gave the desired macrolactones 11a–c in good yields (en-
tries 1–3). However, for 10d having strong a nucleophilicity,
the seven-membered lactam 12 was obtained by intramolec-
ular attacking of the amino function instead of the hydroxyl
group (entry 4). For the formation of 12, simple dehydration
between the carboxylic acid and benzyl amine was ruled
out, and the route via the EVE intermediate was deter-
mined (Scheme 8) since the EVE intermediate 13 was ob-
Entry Method
Yield [%]
n.d.[a]
1
2
46[b]
3
4
decomp.
1
served by H NMR. These facts show that the EVE forma-
tion was possible without loosing activity of the Ru catalyst
even for compounds with nucleophilic amine functions.
[a] Macrolactone was not detected. [b] Compound 15 easily tend to give enone
16. Then, 15 was obtained as enone 16 by treatment of crude 15 with
mCPBA.[c] Macrolactone 15 was not detected, and the enone 16 was obtained
in 47% yield.
Table 5. Macrolactonization of hydroxycarboxylic acids with amine func-
tional group.
tions. When the reaction was performed using the conditions
reported by Trost,[11] a complex mixture was obtained and
no desired product 15 (entry 1). On the other hand, the
present method gave the desired product 15 in 46% yield
(entry 2). Results by previous representative macrolactoni-
zation methods are shown in entries 3 and 4. The Yamagu-
chi and its modified methods by Shiina caused decomposi-
tion that produced a complex mixture possibly due to the
strong basicity of DMAP (entry 3). The 10-membered lac-
tone 16 was obtained by the improved Mukaiyama–Corey–
Nicolaou method. However, b-elimination of PhSH also oc-
curred to form the enone unit by the excess AgOTf
(entry 4). Our macrolactonization method via EVE did not
cause b-elimination of PhSH and only intramolecular
esterification occurred to give 15 (entry 2).
Entry
NR1R2
Yield [%]
1
2
3
NHBoc (a)
NBnTs (b)
NHTs (c)
85
73
75
4
NHBn (d)
[a] Macrolactone was not detected, and the 7-membered lactam (12) was
obtained in 54% yield.
Reaction in the presence of a small amount of water: Our
method can also proceed by using the pTsOH monohydrate,
pTsOH·H2O, instead of anhydrous pTsOH (Table 7). Thus
the reactions worked well using pTsOH·H2O (entries 1 vs
2). Furthermore, the hydroxycarboxylic acid 6a with acid
labile TBS ether produced the desired macrolactone 8a in
good yield (entries 4, 5). Although the addition of H2O to
DCE decreased the yields of the products, the desired mac-
rolactones were still obtained (entries 3, 6). The acid anhy-
dride intermediates obtained by the Yamaguchi method are
quite unstable against humidity, and strict anhydrous condi-
tions are necessary. However, our method proceeds in the
presence of a small amount of water.
Scheme 8. Process of the formation of seven-membered lactam 12.
The mildness and usefulness of the method was also
proven from the following experiments (Table 6). In our
recent synthetic study for the total synthesis of (+)-Sch
642305 having a 10-membered lactone,[12] the macrolactoni-
zation of 14 was examined. Compound 14 has many func-
tional groups and is unstable under various reaction condi-
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A Highly Efficient Macrolactonization Method
FULL PAPER
Table 7. Macrolactonization by pTsOH or pTsOH·H2O as an acid.
d=14.2 (2C), 22.7, 24.6, 25.7, 25.7, 29.0, 29.2, 29.4 (2C), 29.5, 29.6, 29.7,
31.9, 33.9, 37.5 (2C), 64.8, 71.6, 72.0, 157.0, 170.9 ppm; IR (KBr): n˜ =
3287, 2922, 2853, 1771, 1672 cmꢀ1; LRMS (FAB): m/z: 393 [M+Na]+;
HRMS (FAB): m/z: calcd for C22H42O4Na: 393.2995; found: 393.2971.
General procedure of macrolactonization via EVE (Scheme 1, Table 2)
13-Hexyloxacyclotridecan-2-one (3a):[13] Under a nitrogen atmosphere,
ethoxyacetylene (21 mL, 0.30 mmol) was slowly added to the solution of
Entry
1
Acid (mol%)
Product
Yield [%]
64
[RuCl2ACHTNUTRGNEU(GN p-cymene)]2 (1.2 mg, 1.99 mmol) in acetone (0.5 mL) at 08C. The
resulting mixture was stirred at 08C for 5 min and 1a (30 mg,
0.098 mmol) in acetone (0.5 mL) was slowly added to the solution at 08C.
The resulting mixture was stirred at room temperature for 1 h. Ru was
filtered through short neutral SiO2 pad column elucidated by AcOEt.
The residue was concentrated in vacuo. The ethoxyvinyl ester (EVE)
(quant, >95% purity based on 1H NMR analysis) was used without fur-
ther purification.
pTsOH (10)
2
3
pTsOH·H2O (10)
pTsOH·H2O (10),
wet DCE[a]
60
25[b]
The crude EVE was diluted with DCE (10 mL) and slowly added by sy-
ringe pump to the high diluted pTsOH (0.05m in DCE/CH3CN 1:1,
0.2 mL, 0.01 mmol) solution in DCE (30 mL) over 10 h at 808C. The re-
action mixture was stirred at 808C for additional 1 h and cooled to room
temperature. Et3N (ca. 0.012 mmol) was added and the mixture was con-
centrated in vacuo. Purification of the residue by SiO2 column chroma-
tography (hexane/Et2O 20:1) gave 3a (18 mg, 64%) as a colorless oil.
1H NMR (270 MHz, CDCl3): d=0.85 (t, J=7.5 Hz, 3H), 1.24–1.65 (m,
28H), 2.18–2.27 (m, 1H), 2.37–2.45 (m, 1H), 4.89–4.91 ppm (m, 1H); IR
(KBr): n˜ =2930, 2858, 1732 cmꢀ1; LRMS (FAB): m/z: 283 [M+H]+;
HRMS (FAB): m/z: calcd for C18H35O2: 283.2697; found: 283.2614.
4
pTsOH (10)
74
5
6
pTsOH·H2O (10)
pTsOH·H2O (10),
wet DCE[a]
78
35[b]
[a] 1 v/v% H2O was contained. [b] 39% of S.M. 6a was recovered.
8-Octanolide (3b):[14] In the same procedure for 3a, 3b (33 mg, 61%)
was obtained from 1b (60 mg, 0.37 mmol). 1H NMR (270 MHz, CDCl3):
d=1.42–1.48 (m, 4H), 1.51–1.78 (m, 6H), 2.29 (t, J=6.7 Hz, 2H),
Conclusion
4.29 ppm (t, J=5.7 Hz, 2H); IR (KBr): n˜ =2928, 2855, 1738 cmꢀ1
.
In conclusion, various-sized lactones could be produced by
the method described here. It is noteworthy that the method
can give 9- to 14-membered macrolactones in good yields,
especially since medium-sized macrolactones are hard to be
formed by intramolecular esterification. This macrolactoni-
zation method via EVEs is useful for acid-/base-sensitive
substrates. Furthermore, it was found that EVE formation
was possible without loosing activity of the Ru catalyst even
for the compounds with nucleophilic amine functions. The
characteristic feature of the method was exemplified by the
reaction of 14 with many functional groups. Compound 15
was only obtained by our method. It would then be a useful
tool for the syntheses of biologically active macrolactones
including natural products.
9-Nonanolide (3c):[14] In the same procedure for 3a, 3c (27 mg, 50%)
was obtained from 1c (60 mg, 0.34 mmol). Colorless oil; 1H NMR
(270 MHz, CDCl3): d=1.17–1.25 (m, 2H), 1.41–1.54 (m, 6H), 1.73–1.82
(m, 4H), 2.30–2.35 (t, J=5.9 Hz, 2H), 4.26 ppm (t, J=5.3 Hz, 2H); IR
(KBr): n˜ =2926, 2853, 1732 cmꢀ1
.
10-Decanolide (3d):[14] In the same procedure for 3a, 3d (31 mg, 68%)
was obtained from 1d (50 mg, 0.26 mmol). Colorless oil; 1H NMR
(270 MHz, CDCl3): d=1.18–1.50 (m, 10H), 1.61–1.72 (m, 4H), 2.25–2.29
(m, 2H), 4.11 ppm (t, J=5.4 Hz, 2H); IR (KBr): n˜ =2930, 2853,
1732 cmꢀ1
.
11-Undecanolide (3e):[14] In the same procedure for 3a, 3e (17 mg, 62%)
was obtained from 1e (30 mg, 0.16 mmol). Colorless oil; 1H NMR
(270 MHz, CDCl3): d=1.20–1.43 (m, 10H), 1.46–1.55 (m, 2H), 1.60–1.71
(m, 4H), 2.32–2.37 (m, 2H), 4.17 ppm (t, J=5.1 Hz, 2H); IR (KBr): n˜ =
2930, 2864, 1732 cmꢀ1
.
12-Dodecanolide (3 f):[14] In the same procedure for 3a, 3 f (19 mg, 69%)
was obtained from 1 f (30 mg, 0.14 mmol). Colorless oil; 1H NMR
(270 MHz, CDCl3): d=1.23–1.43 (m, 14H), 1.60–1.68 (m, 4H), 2.31–2.36
(m, 2H), 4.14 ppm (t, J=5.1 Hz, 2H); IR (KBr): n˜ =2932, 2860,
1722 cmꢀ1; LRMS (FAB): m/z: 199 [M+H]+; HRMS (FAB): m/z: calcd
for C12H23O2: 199.1698; found: 199.1688.
13-Tridecanolide (3g):[14] In the same procedure for 3a, 3g (25 mg, 89%)
was obtained from 1g (30 mg, 0.13 mmol). Colorless oil; 1H NMR
(270 MHz, CDCl3): d=1.11–1.45 (m, 16H), 1.54–1.67 (m, 4H), 2.33–2.37
(m, 2H), 4.12 ppm (t, J=5.4 Hz, 2H); IR (KBr): n˜ =2930, 2860,
1732 cmꢀ1; LRMS (FAB): m/z: 213 [M+H]+; HRMS (FAB): m/z: calcd
for C13H25O2: 213.1840; found: 213.1859.
Experimental Section
General techniques: The 1H and 13C NMR spectra were measured at
300 MHz spectrometers with tetramethylsilane as the internal standard at
20–258C. IR spectra were recorded by a diffuse reflectance measurement
of samples dispersed in KBr powder. E. Merck silica gel 60 was used for
column chromatography.
Preparation of ethoxyvinyl ester (Table 1)
1-Ethoxyvinyl 12-hydroxyoctadecanoate (2): Under a nitrogen atmos-
phere, [RuCl2ACHTUNGTRENNUNG(p-cymene)]2 (1.2 mg, 2.0 mmol) and ethoxyacetylene
Preparation of benzyl ether (Table 3)
(48 mL, 0.20 mmol) was slowly added to the solution of 1a (30 mg,
0.098 mmol) in acetone (1.96 mL). The resulting mixture was stirred at
room temperature for 6 h and the resulting solution was concentrated in
vacuo. Purification of the residue by SiO2 column chromatography
(hexane/AcOEt 8:1) gave 2 (26 mg, 70%) as a colorless oil. 1H NMR
(270 MHz, CDCl3): d=0.86 (m, 3H), 1.25–1.66 (m, 28H), 2.38 (t, J=
7.3 Hz, 2H), 3.52–3.65 (m, 1H), 3.72 (d, J=4.0 Hz, 1H), 3.78 (d, J=
4.0 Hz, 1H), 3.85 ppm (q, J=6.9 Hz, 2H); 13C NMR (67.8 MHz, CDCl3):
10-tert-Butyldimethylsilyloxydecanoic acid (4a) has previously been de-
scribed.[15]
10-Methoxymethyloxydecanoic acid (4b; Scheme 9): Under a nitrogen at-
mosphere, MOMCl (0.38 mL, 5.0 mL) and 2,6-lutidine were added to the
solution of methyl 10-hydroxydecanoate (500 mg, 2.5 mmol) in CH2Cl2
(25 mL) at 08C. The resulting mixture was stirred at room temperature
for 10 h and poured into saturated aqueous NH4Cl. The mixture was ex-
Chem. Eur. J. 2009, 15, 3526 – 3537
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3531

Y. Kita et al.
column chromatography (hexane/AcOEt 20:1) gave 5a (99 mg, 93%
based on BnOH) as a colorless oil. 1H NMR (270 MHz, CDCl3): d=0.00
(s, 6H), 0.85 (s, 9H), 1.12–1.57 (m, 14H), 2.30 (t, J=7.7 Hz, 2H), 3.54 (t,
J=6.6 Hz, 2H), 5.06 (s, 2H), 7.30 ppm (s, 5H); 13C NMR (67.8 MHz,
CDCl3): d=ꢀ5.1 (2C), 18.5, 25.0, 25.8, 26.1 (3C), 29.2, 29.3, 29.4, 29.5,
32.9, 34.4, 63.3, 66.1, 128.1 (3C), 128.4 (3C), 173.5 ppm; IR (KBr): n˜ =
2930, 2856, 1738 cmꢀ1; LRMS (FAB): m/z: 393 [M+H]+; HRMS (FAB):
m/z: calcd for C23H41O3Si: 393.2809; found: 393.2836.
Scheme 9.
tracted with AcOEt. The organic layer was washed with brine, dried over
Na2SO4 and concentrated in vacuo.
Benzyl 10-methoxymethyloxydecanoate (5b): In the same procedure for
5a, 5b (110 mg, 97% based on BnOH) was obtained from 4b (100 mg,
0.43 mmol). Colorless oil; 1H NMR (270 MHz, CDCl3): d=1.17–1.23 (m,
10H), 1.47–1.60 (m, 4H), 2.28 (t, J=7.3 Hz, 2H), 3.29 (s, 3H), 3.45 (t,
J=6.7 Hz, 2H), 4.55 (s, 2H), 5.05 (s, 2H), 7.20–7.28 ppm (brs, 5H);
13C NMR (67.8 MHz, CDCl3): d=25.0, 26.2, 29.1, 29.2, 29.4, 29.4, 29.7,
34.3, 55.0, 66.0, 67.8, 92.3, 128.0 (2C), 128.0 (2C), 128.4, 136.0,
173.4 ppm; IR (KBr): n˜ =2930, 2855, 1738 cmꢀ1; LRMS (FAB): m/z: 323
[M+H]+; HRMS (FAB): m/z: calcd for C19H31O4: 323.2237; found:
323.2216.
Aqueous 2n NaOH (3.8 mL, 7.5 mmol) was added to the solution of the
residue in MeOH (5 mL) at 08C. The resulting mixture was stirred at
room temperature for 2 h and poured into aqueous 2n HCl at 08C. The
mixture was extracted with AcOEt. The organic layer was dried over
Na2SO4 and concentrated in vacuo. Purification of the residue by SiO2
column chromatography (hexane/AcOEt 4:1) gave 4b (500 mg, 87%) as
a colorless oil. 1H NMR (270 MHz, CDCl3): d=1.20–1.27 (m, 10H),
1.53–1.60 (m, 4H), 2.31 (t, J=7.4 Hz, 2H), 3.33 (s, 3H), 3.49 (t, J=
6.5 Hz, 2H), 4.60 ppm (s, 2H); 13C NMR (67.8 MHz, CDCl3): d=24.7,
26.2, 29.1 (2C), 29.2, 29.4, 29.7, 34.1, 55.1, 67.5, 96.2, 179.7 ppm; IR
(KBr): n˜ =2930, 2855, 1711 cmꢀ1; LRMS (FAB): m/z: 233 [M+H]+;
HRMS (FAB): m/z: calcd for C12H25O4: 233.1761; found: 233.1750.
Benzyl 10-(2-tetrahydropyranyloxy)decanoate (5c): In the same proce-
dure as for 5a, 5c (97 mg, 90% based on BnOH) was obtained from 4c
(100 mg, 0.36 mmol). Colorless oil; 1H NMR (270 MHz, CDCl3): d=
1.12–1.73 (m, 20H), 2.24 (t, J=7.4 Hz, 2H), 3.22–3.31 (m, 1H), 3.37–3.41
(m, 1H), 3.57–3.66 (m, 1H), 3.72–3.79 (m, 1H), 4.47 (s, 1H), 5.00 (s, 2H),
7.24 ppm (s, 5H); 13C NMR (67.8 MHz, CDCl3): d=19.8, 25.0, 25.6, 26.3,
29.2, 29.2, 29.4, 29.5, 29.8, 30.8, 34.4, 62.3, 66.0, 67.6, 98.8, 128.0 (3C),
128.4 (2C), 136.0, 173.5 ppm; IR (KBr): n˜ =2932, 2855, 1738 cmꢀ1; LRMS
(FAB): m/z: 385 [M+Na]+; HRMS (FAB): m/z: calcd for C22H34O4Na:
385.2331; found: 385.2370.
10-(2-Tetrahydropyranyloxy)decanoic acid (4c): Under a nitrogen atmos-
phere, 3,4-dihydro-2H-pyran (0.23 mL, 4.5 mmol) and PPTS (0.1 mmol)
were added to the solution of methyl 10-hydroxydecanoate (500 mg,
2.5 mmol) in CH2Cl2 (25 mL). The resulting mixture was stirred at room
temperature for 10 h and poured into saturated aqueous Na2CO3. The
mixture was extracted with AcOEt. The organic layer was dried over
Na2SO4 and concentrated in vacuo.
Preparation of hydroxycarboxylic acids 6 (Table 4), see Scheme 10
Methyl 12-benzyloxy-6-oxododecanoate (17):[16] Under a nitrogen atmos-
phere, oxalyl chloride (5.0 mL, 54.8 mmol) was added to the solution of
monomethyl adipate (2.2 g, 13.7 mmol) in CH2Cl2 (35 mL) at 08C. The
resulting mixture was stirred at room temperature for 4 h and concentrat-
ed in vacuo.
Aqueous 2n NaOH (3.8 mL, 7.5 mmol) was added to the solution of the
residue in MeOH (5 mL) at 08C. The resulting mixture was stirred at
room temperature for 2 h and poured into aqueous 2n HCl at 08C. The
resulting mixture was extracted with AcOEt. The organic layer was dried
over Na2SO4 and concentrated in vacuo. Purification of the residue by
SiO2 column chromatography (hexane/AcOEt 4:1) gave 4c (600 mg,
89%) as a colorless oil. 1H NMR (270 MHz, CDCl3): d=1.18–1.26 (m,
10H), 1.49–1.78 (m, 10H), 2.29 (t, J=7.6 Hz, 2H), 3.29–3.37 (m, 1H),
3.44–3.48 (m, 1H), 3.63–3.72 (m, 1H), 3.78–3.86 (m, 1H), 4.54 ppm (s,
1H); 13C NMR (67.8 MHz, CDCl3): d=19.6, 24.7, 25.5, 26.2, 29.0, 29.3,
29.4, 29.7, 30.7, 34.1, 62.2, 67.6, 98.7, 179.4 ppm; IR (KBr): n˜ =2932, 2855,
1709 cmꢀ1; LRMS (FAB): m/z: 273 [M+H]+; HRMS (FAB): m/z: calcd
for C15H29O4: 273.2062; found: 273.2068.
Under a nitrogen atmosphere, 6-benzyloxyhexylmagnesium bromide (1m
in THF, 18.0 mL, 18.0 mmol) was added to the solution of [FeIII
ACHTUNGTRENNUNG(acac)3]
(150 mg, 0.41 mmol) in THF (120 mL) at ꢀ788C. The resulting mixture
was stirred at ꢀ788C for 5 min. 5-Chlorocarbonylpentanoic acid methyl-
ester obtained above was added to the solution. The resulting mixture
was stirred at ꢀ788C for 15 min and poured into saturated aqueous
NH4Cl. The mixture was extracted with AcOEt. The organic layer was
washed with brine, dried over Na2SO4 and concentrated in vacuo. Purifi-
cation of the residue by SiO2 column chromatography (hexane/AcOEt
5:1) gave 17 (3.2 g, 70%) as a colorless oil. 1H NMR (270 MHz, CDCl3):
d=1.17–1.52 (m, 12H), 2.23–2.32 (m, 6H), 3.37 (t, J=6.5 Hz, 2H), 3.58
(s, 3H), 4.41 (s, 2H), 7.17–7.25 ppm (m, 5H); 13C NMR (67.8 MHz,
Intermolecular acylation (Table 3)
Benzyl 10-(tert-butyldimethylsilyloxy)decanoate (5a): Under a nitrogen
atmosphere, [RuCl2ACHTUNGTRENNUNG(p-cymene)]2 (4 mg, 6.60 mmol) and ethoxyacetylene
(78 mL, 0.99 mmol) were added to the solution of 4a (100 mg, 0.33 mmol)
in acetone (4.0 mL) at 08C. The re-
sulting mixture was stirred at room
temperature for 1 h and Ru was fil-
tered through short neutral SiO2 pad
column elucidated by hexane/AcOEt
2:1. The residue was concentrated in
vacuo. The ethoxyvinyl ester (EVE)
(quant, >95% purity based on
1H NMR analysis) was used without
further purification.
pTsOH (0.05m in DCE/CH3CN 1:1,
0.66 mL, 0.03 mmol) and BnOH
(28 mL, 0.27 mmol) were added to the
solution of the residue in DCE
(3.3 mL) under
a nitrogen atmos-
phere. The resulting mixture was
stirred at 808C for 1 h and poured
into saturated aqueous NaHCO3. The
mixture was extracted with AcOEt.
The organic layer was dried over
Na2SO4 and concentrated in vacuo.
Purification of the residue by SiO2
Scheme 10.
3532
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 3526 – 3537

A Highly Efficient Macrolactonization Method
FULL PAPER
CDCl3): d=23.1, 23.7, 24.4, 25.9, 28.9, 29.5, 33.7, 42.1, 42.6, 51.4, 70.1,
72.7, 127.2, 127.3 (2C), 128.0 (2C), 138.4, 173.5, 210.3 ppm; IR (KBr):
n˜ =3028, 2936, 2856, 1738, 1713 cmꢀ1; LRMS (FAB): m/z: 335 [M+H]+;
HRMS (FAB): m/z: calcd for C20H31O4: 335.2226; found: 336.2214.
layer was dried over Na2SO4 and concentrated in vacuo. Purification of
the residue by SiO2 column chromatography (hexane/AcOEt 2:1) gave
21b (230 mg, 100%) as a colorless oil. 1H NMR (270 MHz, CDCl3): d=
1.21–1.61 (m, 16H), 1.99 (s, 3H), 2.27 (t, J=7.6 Hz, 2H), 3.32 (s, 3H),
3.47 (t, J=5.7 Hz, 1H), 3.61 (s, 3H), 4.00 (t, J=6.8 Hz, 2H), 4.58 ppm (s,
2H); 13C NMR (67.8 MHz, CDCl3): d=21.0, 24.8, 25.1, 25.2, 25.9, 28.5,
29.4, 33.9, 34.0, 34.2, 51.4, 55.5, 64.5, 77.1, 95.3, 171.0, 173.8 ppm; IR
(KBr): n˜ =2936, 2860, 1738 cmꢀ1; LRMS (FAB): m/z: 339 [M+Na]+;
HRMS (FAB): m/z: calcd for C17H32O6Na: 355.2091; found: 355.2100.
Methyl 12-hydroxy-6-oxododecanate (18): Pd/C (0.5 g) was added to the
solution of 17 (1.0 g, 3.0 mmol) in MeOH (30 mL) at room temperature.
The resulting mixture was stirred at room temperature for 2 h under a
hydrogen atmosphere (4.0 atm). The mixture was passed through Celite
pad and concentrated in vacuo. Purification of the residue by SiO2
column chromatography (hexane/AcOEt 1:1) gave 18 (0.58 g, 80%) as
colorless crystals. M.p. 30.0–30.58C; 1H NMR (270 MHz, CDCl3): d=
1.32–1.58 (m, 12H), 2.30–2.40 (m, 6H), 3.62 (t, J=7.2 Hz, 2H), 3.64 ppm
(s, 3H); 13C NMR (67.8 MHz, CDCl3): d=23.1, 23.7, 24.4, 25.5, 28.9, 32.4,
33.7, 42.2, 42.6, 51.4, 62.5, 173.6, 210.6 ppm; IR (KBr): n˜ =3360, 2934,
2860, 1732, 1713 cmꢀ1; LRMS (FAB): m/z: 245 [M+H]+; HRMS (FAB):
m/z: calcd for C13H25O4: 245.1753; found: 245.1750.
Methyl 12-acetoxy-6-(2-tetrahydropyranyloxy)dodecanate (21c): Under a
nitrogen atmosphere, 3,4-dihydro-2H-pyran (0.086 mL, 0.95 mmol) and
PPTS (13 mg, 0.053 mmol) were added to the solution of 20 (150 mg,
0.53 mmol) in CH2Cl2 (2.7 mL) at 08C. The resulting mixture was stirred
at room temperature for 15 h and poured into saturated aqueous
NaHCO3. The mixture was extracted with AcOEt. The organic layer was
dried over Na2SO4 and concentrated in vacuo. Purification of the residue
by SiO2 column chromatography (hexane/AcOEt 5:1) gave 21c (150 mg,
77%) as a colorless oil. 1H NMR (270 MHz, CDCl3): d=1.21–1.79 (m,
22H), 1.79 (s, 3H), 2.30 (t, J=5.1 Hz, 2H), 3.46 (t, J=5.1 Hz, 1H), 3.58
(t, J=5.1 Hz, 1H), 3.64 (s, 3H), 3.87 (m, 1H), 4.03 (t, J=5.9 Hz, 2H),
4.60 ppm (s, 1H); 13C NMR (67.8 MHz, CDCl3): d=20.0, 20.9, 24.5, 24.8,
25.0*, 25.1, 25.4*, 25.4, 25.8, 28.5*, 28.5, 29.3*, 29.4, 31.1, 33.0*, 34.0*,
34.0, 34.5*, 34.8, 51.4*, 51.4, 62.8, 64.5*, 64.5, 76.4, 97.6, 171.1, 174.0 ppm
(*=minor diastereomer); IR (KBr): n˜ =2937, 2858, 1738 cmꢀ1; LRMS
(FAB): m/z: 373 [M+H]+; HRMS (FAB): m/z: calcd for C20H37O6:
373.2593; found: 373.2589.
Methyl 12-acetoxy-6-oxododecanate (19): Ac2O (2.0 mL) was added to a
solution of 18 (0.58 g, 2.4 mmol) in pyridine (4 mL) at 08C. The resulting
mixture was stirred at room temperature for 1 h and poured into saturat-
ed aqueous NH4Cl. The mixture was extracted with AcOEt. The organic
layer was washed with saturated aqueous NH4Cl, dried over Na2SO4 and
concentrated in vacuo. Purification of the residue by SiO2 column chro-
matography (hexane/AcOEt 4:1) gave 19 (0.72 g, 100%) as colorless
1
crystals. M.p. 27.0–27.58C; H NMR (270 MHz, CDCl3): d=1.30–1.60 (m,
12H), 2.02 (s, 3H), 2.28–2.42 (m, 6H), 3.64 (s, 3H), 4.04 ppm (t, J=
6.8 Hz, 2H); 13C NMR (67.8 MHz, CDCl3): d=20.9, 23.1, 23.6, 24.4, 25.7,
28.4, 28.8, 33.7, 42.2, 42.5, 51.4, 64.3, 170.9, 173.6, 210.3 ppm; IR (KBr):
6-(tert-Butyldimethylsilyloxy)-12-hydroxydodecanoic acid (6a): 2n
NaOH (1.1 mL, 2.2 mmol) was added to the solution of 21a (300 mg,
0.75 mmol) in MeOH (1.4 mL) at 08C. The resulting mixture was stirred
at room temperature for 12 h and poured into 2n HCl (0.8 mL,
1.6 mmol). The mixture was extracted with AcOEt. The organic layer
was dried over Na2SO4 and concentrated in vacuo. Purification of the res-
idue by SiO2 column chromatography (hexane/AcOEt 2:1) gave 6a
(260 mg, 100%) as a colorless oil. 1H NMR (270 MHz, CDCl3): d=0.01
(s, 6H), 0.86 (s, 9H), 1.27–1.66 (m, 16H), 2.33 (t, J=7.3 Hz, 2H), 3.60 (s,
1H), 3.63 ppm (t, J=6.5 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): d=
ꢀ4.4, ꢀ4.3, 18.2, 24.7, 25.0, 25.2, 25.7, 26.0 (3C), 29.6, 32.5, 34.1, 36.6,
36.8, 62.9, 71.9, 178.9 ppm; IR (KBr): n˜ =3690–3010, 2932, 2856, 2646,
1713 cmꢀ1; LRMS (FAB): m/z: 347 [M+H]+; HRMS (FAB): m/z: calcd
for C18H39O4Si: 347.2631; found: 347.2610.
n˜ =2939, 2862, 1738, 1713 cmꢀ1 LRMS (FAB): m/z: 287 [M+H]+;
;
HRMS (FAB): m/z: calcd for C15H27O5: 287.1807; found: 287.1880.
Methyl 12-acetoxy-6-hydroxydodecanate (20): Under a nitrogen atmos-
phere, NaBH4 (108 mg, 2.9 mmol) was added to a solution of 19 (720 mg,
2.4 mmol) in MeOH (24 mL) at 08C. The resulting mixture was stirred at
08C for 1 h and poured into H2O. The mixture was extracted with
AcOEt. The organic layer was dried over Na2SO4 and concentrated in
vacuo. Purification of the residue by SiO2 column chromatography
(hexane/AcOEt 3:1) gave 20 (580 mg, 80%) as a colorless oil. 1H NMR
(270 MHz, CDCl3): d=1.23–1.64 (m, 16H), 2.02 (s, 3H), 2.31 (t, J=
7.3 Hz, 2H), 3.57 (m, 1H), 3.65 (s, 3H), 4.03 ppm (t, J=6.8 Hz, 2H);
13C NMR (67.8 MHz, CDCl3): d=20.9, 24.8, 25.1, 25.5, 25.8, 28.5, 29.2,
33.9, 36.9, 37.3, 51.4, 64.4, 71.3, 171.0, 173.9 ppm; IR (KBr): n˜ =3028,
2934, 2858, 1738 cmꢀ1; LRMS (FAB): m/z: 289 [M+H]+; HRMS (FAB):
m/z: calcd for C15H29O5: 289.2004; found: 289.2020.
12-Hydroxy-6-methoxymethyloxydodecanoic acid (6b): In the same pro-
cedure for 6a, 6b (180 mg, 94%) was obtained from 21b (230 mg,
0.69 mmol). Colorless oil; 1H NMR (270 MHz, CDCl3): d=1.21–1.89 (m,
16H), 2.35 (t, J=7.3 Hz, 2H), 3.35 (s, 3H), 3.52 (t, J=5.7 Hz, 1H), 3.63
(t, J=6.2 Hz, 1H), 3.73 (t, J=6.5 Hz, 1H), 4.62 ppm (s, 2H); 13C NMR
(67.8 MHz, CDCl3): d=24.7, 24.9, 25.6, 29.4, 32.5, 33.8, 34.0, 53.4, 55.5,
62.8, 77.2, 95.2, 178.4 ppm; IR (KBr): n˜ =3650–3020, 2934, 2860,
1713 cmꢀ1; LRMS (FAB): m/z: 299 {M+Na]+; HRMS (FAB): m/z: calcd
for C14H28O5Na: 299.1824; found: 299.1839.
Methyl
12-acetoxy-6-(tert-butyldimethylsilyloxy)dodecanate
(21a):
Under a nitrogen atmosphere, TBSCl (0.92 mL, 4.0 mmol) and 2,6-luti-
dine (0.93 mL, 8.0 mmol) were added to the solution of 20 (580 mg,
2.0 mmol) in CH2Cl2 (20 mL) at 08C. The resulting mixture was stirred at
room temperature for 1.5 h and poured into saturated aqueous NH4Cl.
The mixture was extracted with AcOEt. The organic layer was dried over
Na2SO4 and concentrated in vacuo. Purification of the residue by SiO2
column chromatography (hexane/AcOEt 2:1) gave 21a (670 mg, 83%) as
12-Hydroxy-6-(2-tetrahydropyranyloxy)dodecanoic acid (6c): In the same
procedure for 6a, 6c (212 mg, 100%) was obtained from 21c (250 mg,
0.67 mmol). Colorless oil; 1H NMR (270 MHz, CDCl3): d=1.21–1.80 (m,
22H), 2.34 (t, J=6.2 Hz, 2H), 3.46 (t, J=5.5 Hz, 1H), 3.63 (t, J=6.6 Hz,
3H), 3.86–3.88 (m, 1H), 4.61 ppm (s, 1H); 13C NMR (67.8 MHz, CDCl3):
d=20.0, 24.4, 25.0, 25.4*, 25.5, 29.4*, 29.5, 31.2, 32.4, 33.0, 33.2, 34.0, 34.5,
34.7, 62.7, 62.8, 76.4, 97.5, 178.5 ppm (*=minor diastereomer); IR (KBr):
n˜ =3600–3115, 2936, 2860, 1713 cmꢀ1; LRMS (FAB): m/z: 317 [M+H]+;
HRMS (FAB): m/z: calcd for C17H33O5: 317.2346; found: 317.2319.
1
a colorless oil. H NMR (300 MHz, CDCl3): d=0.06 (s, 6H), 0.85 (s, 9H),
1.24–1.62 (m, 16H), 1.62 (s, 3H), 2.29 (t, J=6.8 Hz, 2H), 3.60–3.64 (m,
1H), 3.64 (s, 3H), 4.03 ppm (t, J=5.9 Hz, 2H); 13C NMR (75.5 MHz,
CDCl3): d=ꢀ4.5, ꢀ4.5, 18.1, 21.0, 24.8, 25.1, 25.1, 25.9 (2C), 25.9, 28.5,
29.4, 34.1, 36.6, 36.9, 51.4, 64.5, 71.9, 171.2, 174.1 ppm; IR (KBr): n˜ =
2934, 2856, 1742 cmꢀ1; LRMS (FAB): m/z: 403 [M+H]+; HRMS (FAB):
m/z: calcd for C21H43O5Si: 403.2889; found: 403.2873.
Methyl 12-acetoxy-6-methoxymethyl-
oxydodecanate (21b): Under a nitro-
gen atmosphere, MOMCl (200 mg,
0.69 mmol) and 2,6-lutidine (0.32 mL,
2.8 mmol) were added to the solution
of 20 (150 mg, 0.53 mmol) in CH2Cl2
(6.9 mL) at 08C. The resulting mix-
ture was stirred at room temperature
for 14.5 h and poured into saturated
aqueous NH4Cl. The mixture was ex-
tracted with AcOEt. The organic
Scheme 11.
Chem. Eur. J. 2009, 15, 3526 – 3537
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3533

Y. Kita et al.
Preparation of hydroxycarboxylic acids 7 (Table 4) (see Scheme 11)
11-Hydroxy-6-undecenoic acid (7a): Under nitrogen atmosphere,
21.5, 23.3, 24.3, 25.0, 25.9 (3C), 26.9, 27.4, 33.6, 34.5, 35.2, 64.8, 70.9,
174.0 ppm; IR (KBr): n˜ =2937, 2864, 1730 cmꢀ1; LRMS (FAB): m/z: 281
[M+Na]+; HRMS (FAB): m/z: calcd for C14H26O4Na: 281.1729; found:
281.1723; elemental analysis calcd (%) for C14H26O4: C 65.09, H 10.14;
found: C 65.20, H 9.94.
a
NHMDS (1m in THF, 0.3 mL, 0.95 mmol) was added to the solution of
(5-carboxypentyl)triphenylphosphonium bromide (85 mg, 0.48 mmol) in
THF (0.4 mL) at 08C. The resulting mixture was stirred at room temper-
ature for 30 min and 22[17] (20 mg, 0.19 mmol) in THF (0.3 mL) was
added to the resulting solution at 08C. The mixture was stirred at room
temperature for 6 h and poured into aqueous 10% HCl. The mixture was
extracted with AcOEt. The organic layer was washed with brine, dried
over Na2SO4 and concentrated in vacuo. Purification of the residue by
SiO2 column chromatography (hexane/AcOEt 2:1!1:1) gave 7a (25 mg,
64%) as a colorless oil. 1H NMR (270 MHz, CDCl3): d=1.37–1.69 (m,
8H), 2.00–2.08 (m, 4H), 2.34 (t, J=7.3 Hz, 2H), 3.64 (t, J=6.5 Hz, 2H),
5.35 ppm (t, J=5.7 Hz, 2H); 13C NMR (67.8 MHz, CDCl3): d=24.3, 25.8,
26.8, 26.9, 29.1, 32.2, 33.9, 62.8, 129.4, 129.9, 179.0 ppm; IR (KBr): n˜ =
3665–3040, 2936, 2860, 2853, 1712 cmꢀ1; LRMS (FAB): m/z: 201 [M+H]+;
HRMS (FAB): m/z: calcd for C11H21O3: 201.1522; found: 201.1483.
6-(2-Tetrahydropyranyloxy)oxacyclotridecan-2-one (8c): In the same pro-
cedure for 3a, 8c (25 mg, 67%) was obtained from 6c (43 mg,
0.14 mmol). Yellow oil; 1H NMR (270 MHz, CDCl3): d=1.16–2.02 (m,
22H), 2.61 (t, J=7.7 Hz, 2H), 3.31–3.41 (m, 1H), 3.47 (t, J=7.0 Hz, 1H),
3.66–3.74 (m, 1H), 3.80–3.87 (m, 1H), 4.19–4.20 (m, 1H), 4.53–4.55 ppm
(m, 1H); 13C NMR (67.8 MHz, CDCl3): d=21.6, 23.4, 24.1, 24.9, 26.8,
27.3, 30.7, 32.1, 34.5, 55.3, 64.6, 75.4, 94.6, 173.7 ppm; IR (KBr): n˜ =2937,
2862, 1768, 1738 cmꢀ1; LRMS (FAB): m/z: 265 [M+H]; HRMS (FAB):
m/z: calcd for C17H31O4: 299.2223; found: 299.2204; elemental analysis
calcd (%) for C17H30O4: C 68.42, H 10.13; found: C 68.03, H 10.15.
Oxacyclododec-7-en-2-one (9a): In the same procedure for 3a, 9a
(66 mg, 72%) was obtained from 7a (100 mg, 0.50 mmol). Colorless oil;
1H NMR (270 MHz, CDCl3): d=1.34–1.75 (m, 8H), 195 (m, 0.2H)*, 2.05
(dd, J=16.8, 8.4 Hz, 1.8H), 2.18 (dd, J=7.6, 7.6 Hz, 2H), 2.34 (dd, J=
7.5, 7.5 Hz, 2H), 4.05–4.06 (m, 0.2H)*, 4.18 (t, J=4.6 Hz, 1.8H), 5.26–
5.42 ppm (m, 2H); 13C NMR (67.8 MHz, CDCl3): d=23.0*, 23.5, 24.3,
25.6, 25.8, 26.0*, 26.9*, 27.2*, 28.2, 28.7, 30.4*, 31.2*, 33.4, 34.1*, 65.3,
129.9, 130.0, 131.1*, 131.2*, 173.9 ppm (*=minor diastereomer); IR
(KBr): n˜ =2930, 2858, 1732 cmꢀ1; LRMS (FAB): m/z: 205 [M+Na]+;
HRMS (FAB): m/z: calcd for C11H19O2: 183.1441; found: 183.1373.
5-[5-(4-Hydroxybutyl)-2,2-dimethyl
G
acid
(7b): Under an air, N-methylmorpholine-N-oxide (50% in water, 1.0 mL,
4.98 mmol) and OsO4 (1.0 mg, 0.1 equiv) were added to the solution of
7a (500 mg, 2.49 mmol) in tBuOH/H2O (v/v 1:1, 10 mL) at room temper-
ature. The resulting mixture was stirred at room temperature for 1 h and
Tiron (50 mg) was added. The resulting mixture was stirred at room tem-
perature for 15 min and poured into aqueous 10% HCl. The mixture was
extracted with AcOEt. The organic layer was dried over Na2SO4 and con-
centrated in vacuo.
2,2-Dimethyldecahydro-1,3,8-trioxacyclopentacyclododecen-9-one (9b):
In the same procedure for 3a, 9b (20 mg, 52%) was obtained from 7b
(40 mg, 0.15 mmol). Colorless oil; 1H NMR (270 MHz, CDCl3): d=1.23–
1.86 (m, 12H), 1.25 (s, 3H), 1.36 (s, 3H), 2.25–2.45 (m, 2H), 3.83–3.88
(m, 0.4H)*, 4.03–4.09 (m, 2.6H), 4.23–4.31 (m, 0.8H), 4.46 ppm (m,
0.2H)*; 13C NMR (67.8 MHz, CDCl3): d=22.3, 24.3, 25.0, 25.6, 26.2, 27.8,
28.2, 28.6, 34.1, 63.8, 76.5, 77.3 (2C), 107.0, 174.1 ppm (*=minor diaste-
reomer); IR (KBr): n˜ =2936, 2866, 1732 cmꢀ1; LRMS (FAB): m/z: 257
[M+H]+; HRMS (FAB): m/z: calcd for C14H25O4: 257.1748; found:
257.1754.
Acetone dimethylacetal (0.92 mL, 7.49 mmol) and camphor sulfonic acid
(CSA) (174 mg, 0.75 mmol) were added to the solution of the residue in
DMF (2.5 mL) under a nitrogen atmosphere. The resulting mixture was
stirred at room temperature for 24 h and poured into saturated aqueous
NH4Cl. The mixture was extracted with AcOEt. The organic layer was
dried over Na2SO4 and concentrated in vacuo. Purification of the residue
by SiO2 column chromatography (hexane/AcOEt 2:1!1:1) gave 7b
1
(40 mg, 6%) as a colorless oil. H NMR (270 MHz, CDCl3): d=1.26–1.75
(m, 12H), 1.26 (s, 3H), 1.36 (s, 3H), 2.29 (t, J=7.5 Hz, 2H), 3.59 (t, J=
6.3 Hz, 2H), 3.90–4.05 ppm (m, 2H); 13C NMR (67.8 MHz, CDCl3): d=
22.4, 24.6, 25.7, 25.9, 28.5, 29.3 (2C), 32.4, 33.8, 62.6, 77.7, 77.8, 107.4,
6,13-DioxabicycloACHTNUTGRNEUNG[10.1.0]tridecan-7-one (9c): In the same procedure for
3a, 9c (32 mg, 70%) was obtained from 7c (50 mg, 0.23 mmol). Colorless
178.6 ppm; IR (KBr): n˜ =3369, 2986, 2939, 3864, 1738 cmꢀ1
; LRMS
1
crystals; m.p. 58.0–58.58C; H NMR (270 MHz, CDCl3): d=1.33–1.66 (m,
(FAB): m/z: 275 [M+H]+; HRMS (FAB): m/z: calcd for C14H27O5:
8H), 1.84–2.06 (m, 4H), 2.51–2.68 (m, 2H), 3.37–3.47 (m, 2H), 3.97 (brd,
J=11.1 Hz, 1H), 4.16–4.21 ppm (m, 1H); 13C NMR (67.8 MHz, CDCl3):
d=23.0, 23.2, 25.7, 26.1, 28.3, 29.5, 34.8, 68.9, 78.7, 81.4, 175.0 ppm; IR
(KBr): n˜ =2936, 1732 cmꢀ1; elemental analysis calcd (%) for C11H19O3: C
66.64, H 9.15; found: C 66.62, H 9.00.
275.1887; found: 275.1848.
4-[3-(4-Hydroxybutyl)oxiranyl]butyric acid (7c): Under a nitrogen atmos-
phere, mCPBA (185 mg, 1.07 mmol) was added to a solution of 7a
(100 mg, 0.50 mmol) in CH2Cl2 (5.4 mL) at 08C. The resulting mixture
was stirred at room temperature for 5 h. Three drops of saturated aque-
ous Na2S2O3 were added to the resulting solution and the mixture was
concentrated in vacuo. Purification of the residue by SiO2 column chro-
matography (hexane/AcOEt 2:1!1:1) gave 7c (66 mg, 61%) as a color-
less oil. 1H NMR (270 MHz, C6D6): d=1.18–1.74 (m, 10H), 2.17 (t, J=
7.0 Hz, 2H), 2.99–3.04 (m, 1H), 3.12 (t, J=10.7 Hz, 1H), 3.48 (m, 1H),
3.89–3.93 ppm (m, 1H); 13C NMR (67.8 MHz, C6D6): d=23.5, 25.3, 25.5,
26.4, 27.9, 32.7, 34.3, 68.4, 74.2, 81.2, 179.0 ppm; IR (KBr): n˜ =3680–3040,
2939, 2858, 1713 cmꢀ1; LRMS (FAB): m/z: 217 [M+H]+; HRMS (FAB):
m/z: calcd for C11H21O4: 217.1480; found: 217.1429.
Preparation of hydroxycarboxylic acid (Table 5) (see Scheme 12)
Methyl 12-acetoxy-6-benzylaminododecanoate (23): Under a nitrogen at-
mosphere, benzylamine (85 mL, 0.77 mmol), AcOH (45 mL, 0.77 mmol)
and NaBHACHTUNRGTNE(UNG OAc)3 (330 mg, 1.54 mmol) were added to the solution of 19
(150 mg, 0.52 mmol) in DCE (5.2 mL) at 08C. The resulting mixture was
stirred at room temperature for 5 h and poured into aqueous sat.
Macrolactonization of functionalized substrates (Table 4)
6-(tert-Butyldimethylsilyloxy)oxacyclotridecan-2-one (8a): In the same
procedure for 3a, 8a (42 mg, 74%) was obtained from 6a (60 mg,
0.17 mmol). Colorless oil; 1H NMR (270 MHz, CDCl3): d=0.01 (s, 6H),
0.85 (s, 9H), 1.22–1.64 (m, 16H), 2.35 (m, 2H), 3.71 (m, 1H), 4.12–
4.13 ppm (m, 2H); 13C NMR (75.5 MHz, CDCl3): d=ꢀ4.5, ꢀ4.4, 18.2,
21.5, 23.3, 24.3, 25.0, 25.9 (3C), 26.9, 27.4, 33.6, 34.5, 35.2, 64.8, 70.9,
174.0 ppm; IR (KBr): n˜ =2932, 2856, 1732, 1713 cmꢀ1; LRMS (FAB):
m/z: 329 [M+H]+; HRMS (FAB): m/z: calcd for C18H37O3Si: 329.2491;
found: 329.2523.
6-Methoxymethyloxyoxacyclotridecan-2-one (8b): In the same procedure
for 3a, 8b (9.6 mg, 55%) was obtained from 6b (18.6 mg, 0.067 mmol).
Colorless oil; 1H NMR (300 MHz, CDCl3): d=1.19–1.75 (m, 16H), 2.29–
2.42 (m, 2H), 3.34 (s, 3H), 3.59–3.62 (m, 1H), 4.04–4.19 (m, 2H), 4.58–
4.63 ppm (m, 2H); 13C NMR (75.5 MHz, CDCl3): d=ꢀ4.5, ꢀ4.4, 18.2,
Scheme 12.
3534
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 3526 – 3537

A Highly Efficient Macrolactonization Method
FULL PAPER
NaHCO3 at 08C. The mixture was extracted with AcOEt. The organic
layer was dried over Na2SO4 and concentrated in vacuo. Purification of
the residue by SiO2 column chromatography (hexane/AcOEt 1:2) gave
23 (190 mg, 97%) as a yellow oil. 1H NMR (270 MHz, CDCl3): d=1.16–
1.60 (m, 16H), 1.96 (s, 3H), 2.24 (t, J=7.4 Hz, 2H), 2.50–2.55 (m, 1H),
2.85 (brs, 1H), 3.60 (s, 3H), 3.74 (s, 2H), 3.97 (t, J=6.6 Hz, 2H), 7.26–
7.32 ppm (m, 5H); 13C NMR (67.8 MHz, CDCl3): d=21.0, 25.1, 25.1,
25.5, 25.9, 28.5, 29.5, 33.3, 33.5, 34.0, 50.1, 51.4, 56.3, 64.5, 126.8, 128.0
(2C), 128.2 (2C), 140.1, 171.0, 173.8 ppm; IR (KBr): n˜ =3338, 2932,
28556, 1738 cmꢀ1; LRMS (FAB): m/z: 378 [M+H]+; HRMS (FAB): m/z:
calcd for C22H36O4N: 378.2660; found: 378.2635.
Methyl 12-acetoxy-6-azidododecanoate (25): Under a nitrogen atmos-
phere, Et3N (0.5 mL, 3.9 mmol) and MsCl (0.28 mL, 3.6 mmol) were
added to the solution of 20 (1.1 g, 3.0 mmol) in CH2Cl2 (6.0 mL) at 08C.
The resulting mixture was stirred at room temperature for 2.5 h. Precipi-
tated salt was filtered and the filtrate was concentrated in vacuo.
NaN3 (585 mg, 9.0 mmol) was added to the solution of the residue in
DMF (11 mL) under a nitrogen atmosphere. The resulting mixture was
stirred at 808C for 3 h and poured into water. The mixture was extracted
with AcOEt. The organic layer was washed with brine, dried over
Na2SO4 and concentrated in vacuo. Purification of the residue by SiO2
column chromatography (hexane/AOEt 8:1) gave 25 (930 mg, 78%) as a
1
Methyl 12-acetoxy-6-[benzyl(p-toluenesulfonyl)amino]dodecanoate (24):
Under a nitrogen atmosphere, NaH (32 mg, 0.79 mmol) was added to the
solution of 23 (250 mg, 0.66 mmol) in DMF (6.6 mL) at 08C. The result-
ing mixture was stirred at 08C for 30 min. TsCl (150 mg, 0.79 mmol) was
added to the solution at 08C and the resulting mixture was stirred at
room temperature for 3 h. Water was added and the mixture was extract-
ed with AcOEt. The organic layer was dried over Na2SO4 and concen-
trated in vacuo. Purification of the residue by SiO2 column chromatogra-
phy (hexane/AcOEt 2:1) gave 24 (100 mg, 28%) as a colorless oil.
1H NMR (270 MHz, CDCl3): d=1.02–1.48 (m, 16H), 1.99 (s, 3H), 2.04 (t,
J=7.3 Hz, 2H), 2.37 (s, 3H), 3.60 (s, 3H), 3.94 (t, J=6.8 Hz, 2H), 4.24 (s,
2H), 7.22–7.64 ppm (m, 9H); 13C NMR (67.8 MHz, CDCl3): d=21.1,
21.5, 25.0, 25.7, 26.3, 26.7, 28.4, 29.0, 33.0, 33.2, 33.7, 47.4, 51.4, 59.2, 64.4,
126.9 (2C), 127.4, 128.1 (2C), 128.3 (2C), 129.4 (2C), 129.4 (2C), 138.0,
colorless oil. H NMR (270 MHz, CDCl3): d=1.24–1.63 (m, 16H), 2.03 (s,
3H), 2.31 (t, J=7.3 Hz, 2H), 3.22 (brd, 1H), 3.66 (s, 3H), 4.03 (t, J=
6.9 Hz, 2H); 13C NMR (67.8 MHz, CDCl3): d=21.0, 24.7, 25.6, 25.8, 26.0,
28.5, 29.0, 33.8, 34.1, 34.3, 51.5, 62.7, 64.4, 170.9, 173.6 ppm; IR (KBr):
n˜ =2937, 2860, 2098, 1738 cmꢀ1 LRMS (FAB): m/z: 314 [M+H]+;
;
HRMS (FAB): m/z: calcd for C15H28O4N3: 314.2080; found: 314.2086.
Methyl 12-acetoxy-6-aminododecanoate (26): Under a nitrogen atmos-
phere, PPh3 (598 mg, 2.3 mmol) was added to the solution of 25 (357 mg,
1.1 mmol) in THF (5.0 mL). The resulting mixture was stirred at 408C
for 4.5 h. Water (0.1 mL, 5.7 mmol) was added to the solution. Resulting
mixture was stirred at room temperature for 8 hr and concentrated in
vacuo. Purification of the residue by SiO2 column chromatography
(CH2Cl2/MeOH 10:1) gave 26 (111 mg, 34%) as a colorless oil. 1H NMR
(270 MHz, CDCl3): d=1.18–1.55 (m, 16H), 1.97 (s, 3H), 2.25 (t, J=
7.4 Hz, 3H), 2.26 (brs, 1H), 3.59 (s, 3H), 3.98 ppm (t, J=6.6 Hz, 2H);
13C NMR (67.8 MHz, CDCl3): d=20.8, 24.8, 25.5, 25.7, 28.3, 29.2, 33.8,
37.5, 37.8, 50.7, 51.2, 64.3, 170.7, 173.7 ppm; IR (KBr): n˜ =2934, 2858,
138.2, 142.8, 171.0, 173.7 ppm; IR (KBr): n˜ =2939, 2860, 1738 cmꢀ1
;
LRMS (FAB): m/z: 532 [M+H]+; HRMS (FAB): m/z: calcd for
C29H42O6NS: 532.2731; found: 532.2735.
1736 cmꢀ1
.
6-[Benzyl(p-toluenesulfonyl)amino]-12-hydroxydodecanoic acid (10b): In
the same procedure for 6a, 10b (50 mg, 56%) was obtained from 24
(100 mg, 0.19 mmol). Colorless crystals; m.p. 119.58C; 1H NMR
(270 MHz, CDCl3): d=1.00–1.37 (m, 16H), 2.05 (t, J=7.0 Hz, 2H), 2.34
(s, 3H), 3.51 (t, J=6.5 Hz, 2H), 3.39–3.57 (m, 1H), 4.18 (d, J=15.5 Hz,
1H), 4.26 (d, J=15.5 Hz, 1H), 5.89 (brs, 1H), 7.19–7.33 (m, 7H), 7.58–
7.61 ppm (m, 2H); 13C NMR (67.8 MHz, CDCl3): d=21.5, 24.3, 25.4,
26.2, 26.6, 29.0, 31.0, 32.4, 32.9, 33.0, 47.4, 59.1, 62.8, 126.9 (2C), 127.4,
128.2 (2C), 128.3 (2C), 129.4 (2C), 138.1, 138.2, 142.9, 178.7 ppm; IR
(KBr): n˜ =2934, 2858, 1709 cmꢀ1; LRMS (FAB): m/z: 476 [M+H]+;
HRMS (FAB): m/z: calcd for C26H38O5NS: 476.2467; found: 476.2374.
Methyl 12-acetoxy-6-(p-toluenesulfonylamino)dodecanoate (27): Under a
nitrogen atmosphere, Et3N (0.2 mL) and TsCl (183 mg, 0.96 mmol) were
added to the solution of 26 (184 mg, 0.64 mmol) in DMF (6.4 mL). The
resulting mixture was stirred at room temperature for 2 h and poured
into aqueous sat. NH4Cl. The mixture was extracted with AcOEt. The or-
ganic layer was dried over Na2SO4 and concentrated in vacuo. Purifica-
tion of the residue by SiO2 column chromatography (hexane/AcOEt 2:1)
gave 27 (190 mg, 77%) as a colorless oil. 1H NMR (270 MHz, CDCl3):
d=1.15–1.57 (m, 16H), 2.03 (s, 3H), 2.17 (t, J=7.4 Hz, 2H), 2.40 (s, 3H),
3.19 (m, 1H), 3.64 (s, 3H), 3.99 (t, J=6.8 Hz, 2H), 7.25 (s, 1H), 7.28 (s,
1H), 7.70 (s, 1H), 7.73 ppm (s, 1H); 13C NMR (67.8 MHz, CDCl3): d=
21.0, 21.4, 24.5, 24.7, 25.1, 25.7, 28.4, 28.9, 33.7, 34.6, 34.9, 51.4, 53.7, 64.4,
126.8 (2C), 129.3 (2C), 138.3, 142.9, 171.0, 173.7 ppm; IR (KBr): n˜ =
3285, 2937, 2860, 1730, 1715 cmꢀ1; LRMS (FAB): m/z: 442 [M+H]+;
HRMS (FAB): m/z: calcd for C22H36O6NS: 442.2276; found: 442.2254.
6-Benzylamino-12-hydroxy-dodecanoic acid (10d): 2n NaOH (0.2 mL,
2.2 mmol) was added to the solution of 23 (150 mg, 0.40 mmol) in MeOH
(0.75 mL) at 08C. The resulting mixture was stirred at room temperature
for 3 h and poured into 2n HCl aq. (0.8 mL, 2.3 mmol). The mixture was
extracted with AcOEt. The organic layer was dried over Na2SO4 and con-
centrated in vacuo to give 10d (50 mg, 39%) as a colorless oil. 1H NMR
(270 MHz, CD3OD): d=1.33–1.70 (m, 16H), 2.23 (m, 2H), 3.11 (brs,
1H), 3.26 (m, 1H), 3.50 (t, J=7.0 Hz, 2H), 4.18 (s, 2H), 7.24–7.48 ppm
(m, 5H); 13C NMR (125.7 MHz, CD3OD): d=25.7, 26.0, 26.5, 26.6 (2C),
30.2 (2C), 30.8, 31.0, 33.4, 59.0, 62.8, 130.2 (3C), 130.4, 131.1 (2C),
12-Hydroxy-6-(p-toluenesulfonylamino)dodecanoic acid (10c): In the
same procedure as for 6a, 10c (150 mg, 91%) was obtained from 27
(190 mg, 0.43 mmol). Colorless oil; 1H NMR (270 MHz, CDCl3): d=
1.10–1.41 (m, 16H), 2.15 (t, J=7.2 Hz, 2H), 2.35 (s, 3H), 3.12 (m, 1H),
3.53 (t, J=6.5 Hz, 2H), 5.34 (d, J=8.4 Hz, 1H), 6.95 (brs, 2H), 7.23 (d,
J=5.4 Hz, 2H), 7.69 ppm (d, J=8.1 Hz, 2H); 13C NMR (67.8 MHz,
CDCl3): d=21.4, 24.4, 24.6, 24.9, 25.3, 28.9, 32.2, 33.7, 34.4, 34.6, 53.7,
62.5, 126.7 (2C), 129.3 (2C), 138.2, 142.9, 177.9 ppm; IR (KBr): n˜ =3479,
3271, 2936, 2858, 1769, 1713 cmꢀ1; LRMS (FAB): m/z: 386 [M+H]+;
HRMS (FAB): m/z: calcd for C19H32O5NS: 386.2007; found: 386.1997.
179.5 ppm; IR (KBr): n˜ =3288, 2934, 2858, 1740, 1558 cmꢀ1
.
Preparation of hydroxycarboxylic acid 10c (see Scheme 13)
Preparation of hydroxycarboxylic acid 10a (see Scheme 14)
Scheme 13.
Scheme 14.
Chem. Eur. J. 2009, 15, 3526 – 3537
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3535

Y. Kita et al.
Methyl 6-benzylamino-12-benzyloxydodecanoate (28): In the same proce-
dure for 23, 28 (240 mg, 90%) was obtained from 17 (210 mg,
0.63 mmol). Colorless crystals; m.p. 31.58C; H NMR (300 MHz, CDCl3):
(FAB): m/z: 368 [M+H]+; HRMS (FAB): m/z: calcd for C19H30O4NS:
368.1899; found: 368.1894.
1
7-Dibenzylamino oxacyclotridecan-2-one (11d): In the same procedure
for 3a, 11d (22 mg, 66%) was obtained from 10d (35 mg, 0.085 mmol).
Colorless oil; 1H NMR (300 MHz, CDCl3): d=1.08–1.52 (m, 16H), 2.11
(t, J=5.7 Hz, 2H), 2.30–2.36 (m, 2H), 3.24 (d, J=13.5 Hz, 2H), 3.58 (d,
J=13.5 Hz, 2H), 3.65–3.70 (m, 1H), 4.06–4.12 (m, 1H), 7.08–7.26 ppm
(m, 10H); 13C NMR (75.5 MHz, CDCl3): d=23.2, 23.7, 24.4, 25.4, 25.7,
27.0, 27.1, 27.6, 34.9, 53.6 (2C), 53.8, 63.9, 126.6 (2C), 128.0 (4C), 129.0
(4C), 140.9 (2C), 173.5 ppm; IR (KBr): n˜ =2932, 2855, 1730 cmꢀ1; LRMS
(FAB): m/z: 394 [M+H]+; HRMS (FAB): m/z: calcd for C26H36O2N:
394.2755; found: 394.2740.
d=1.14–1.55 (m, 16H), 1.96 (s, 3H), 2.22 (t, J=7.5 Hz, 2H), 2.42 (t, J=
5.4 Hz, 1H), 3.37 (t, J=6.6 Hz, 2H), 3.57 (s, 3H), 3.65 (s, 2H), 4.41 (s,
2H), 7.12–7.25 ppm (m, 10H); 13C NMR (75.5 MHz, CDCl3): d=25.1,
25.2, 25.5, 26.1, 29.7, 29.7, 3.5, 33.8, 34.0, 51.1, 51.4, 56.5, 70.4, 72.8, 126.7,
127.4, 127.5, 128.1 (2C), 128.3 (2C), 128.3 (2C), 128.3, 138.6, 140.9,
174.1 ppm; IR (KBr): n˜ =2932, 2856, 1738 cmꢀ1; LRMS (FAB): m/z: 426
[M+H]+; HRMS (FAB): m/z: calcd for C27H40O3N: 426.2998; found:
426.3015.
Methyl
6-(benzyl-tert-butoxycarbonylamino)-12-hydroxydodecanoate
(29): Pd(OH)2 (0.1 g) and di-tert-butyldicarbonate (0.16 mL, 0.71 mmol)
were added to the solution of 28 (200 mg, 0.47 mmol) in MeOH (4.7 mL)
at room temperature. The resulting mixture was stirred at room tempera-
ture for 12 h under a hydrogen atmosphere (4.0 atm). The mixture was
passed through celite pad and the filtrate was concentrated in vacuo. Pu-
rification of the residue by SiO2 column chromatography (hexane/AcOEt
2:1) gave 29 (130 mg, 64%) as a colorless oil. 1H NMR (270 MHz,
CDCl3): d=1.23–1.48 (m, 16H), 1.40 (s, 9H), 2.16–2.18 (m, 2H), 2.37 (s,
1H), 3.55 (t, J=6.5 Hz, 2H), 3.62 (s, 3H), 3.62 (m, 1H), 4.22 (s, 1H),
4.32 (s, 1H), 7.27 ppm (s, 5H); 13C NMR (67.8 MHz, CDCl3): d=24.5,
24.6, 25.5, 26.0, 26.3, 28.2, 28.4, 29.0, 32.5, 32.8*, 33.0, 33.2*, 33.5, 33.8,
46.4, 51.3, 55.8, 62.4, 79.3, 126.3*, 126.5, 126.8, 127.7, 127.8 (2C), 139.5*,
139.8, 155.9*, 156.5, 173.7 ppm (*=minor diastereomer); IR (KBr): n˜ =
3356, 2932, 2858, 1738, 1682 cmꢀ1 LRMS (FAB): m/z: 436 [M+H]+;
HRMS (FAB): m/z: calcd for C25H42O5N: 436.3059; found: 436.3066.
1-Benzyl-7-(6-hydroxyhexyl)azepan-2-one (12): Under a nitrogen atmos-
phere, ethoxyacetylene (59 mL, 0.42 mmol) was slowly added to the solu-
tion of [RuCl2ACHTUNRGTNEUNG(p-cymene)]2 (2.0 mg, 2.8 mmol) in acetone (2.0 mL) at
08C. The resulting mixture was stirred at 08C for 5 min and 10e (45 mg,
0.14 mmol) in acetone (1.2 mL) was slowly added at 08C. The resulting
mixture was stirred at room temperature for 1 h and Ru was filtered
through short neutral SiO2 pad column elucidated by AcOEt. The resi-
due was concentrated in vacuo. The ethoxyvinyl ester (quant, >95%
purity based on 1H NMR analysis) was used without further purification.
The crude EVE was diluted in DCE (10 mL) and slowly added by sy-
ringe pump to the high diluted pTsOH (0.05m in DCE/CH3CN 1:1,
0.32 mL, 0.014 mmol) solution in DCE (20 mL) over 10 h at 808C. Reac-
tion mixture was stirred at 808C for 1 h and cooled to room temperature.
Et3N (ca. 0.016 mmol) was added to the mixture, and the resulting solu-
tion was concentrated in vacuo. Purification of the residue by SiO2
column chromatography (hexane/Et2O 20:1) gave 12 (23 mg, 54%) as a
colorless oil. 1H NMR (270 MHz, CDCl3): d=1.21–1.74 (m, 16H), 2.49–
2.71 (m, 2H), 3.28–3.30 (m, 1H), 3.58 (t, J=6.5 Hz, 2H), 4.06 (d, J=
14.9 Hz, 1H), 5.04 (d, J=14.6 Hz, 1H), 7.22–7.29 ppm (m, 5H);
13C NMR (67.8 MHz, CDCl3): d=23.5, 24.0, 25.6, 27.1, 29.3, 31.6 (2C),
32.6 (2C), 37.8, 58.2, 62.8, 127.1, 128.2 (2C), 128.3 (2C), 138.2,
175.2 ppm; IR (KBr): n˜ =3319, 2930, 2856, 1614 cmꢀ1; LRMS (FAB):
m/z: 304 [M+H]+; HRMS (FAB): m/z: calcd for C19H30O2N: 304.2296;
found: 304.2232.
6-(Benzyl-tert-butoxycarbonylamino)-12-hydroxydodecanoic acid (10a):
In the same procedure for 6a, 10a (115 mg, 100%) was obtained from 29
(130 mg, 0.30 mmol).Colorless oil; 1H NMR (300 MHz, CDCl3): d=1.23–
1.49 (m, 16H), 1.49 (s, 9H), 2.22 (m, 2H), 3.59 (t, J=6.6 Hz, 2H), 4.11–
4.13 (m, 2H), 4.24 (s, 1H), 4.34 (s, 1H), 7.29 ppm (s, 5H); 13C NMR
(75.5 MHz, CDCl3): d=24.4, 25.4, 25.9, 26.2, 28.2, 28.4, 28.9, 32.2, 32.9,
33.2, 33.4, 33.8, 46.4, 53.3, 60.4*, 62.5, 79.6, 126.5, 126.7*, 126.9, 127.9,
128.0, 139.9, 156.2, 156.8*, 178.5 ppm (*=minor diastereomer); IR
(KBr): n˜ =2930, 2860, 1651 cmꢀ1
.
Macrolactonization (Table 5)
Macrolactonization in the total synthesis of (+)-Sch 642305[12] (Table 6)
7-[Benzyl(tert-butoxycarbonyl)amino]oxacyclotridecan-2-one (11a): In
the same procedure for 3a, 11a (575 mg, 85%) was obtained from 10a
(70 mg, 0.17 mmol). Colorless oil; 1H NMR (270 MHz, CDCl3): d=1.31–
1.72 (m, 16H), 1.49 (s, 9H), 2.20–2.38 (m, 1H), 2.38–2.46 (m, 1H), 3.81
(m, 1H)*, 3.95–4.00 (m, 1H), 4.08 (m, 1H), 4.27–4.39 (m, 3H), 7.18–
7.29 ppm (m, 5H); 13C NMR (67.8 MHz, CDCl3): d=23.9, 25.5, 25.9,
26.2, 27.2, 28.4, 28.6, 29.0, 29.7, 32.3, 33.2, 34.8, 47.3, 53.4*, 53.5, 64.2*,
64.5, 79.6, 126.5, 127.3, 128.0 (3C), 139.7*, 140.2, 155.6*, 156.3, 173.5 ppm
(*=minor diastereomer); IR (KBr): n˜ =2932, 2862, 1732, 1688 cmꢀ1; ele-
mental analysis calcd (%) for C24H37NO4: C 71.43, H 9.24, N 3.47; found:
C 71.04, H 9.21, N 3.41.
Since compound 15 is unstable and not easy to purify, crude 15 was oxi-
dized with mCPBA to give a stable 16. The yield of 15 in entry 2 of
Table 6 is the yield of the obtained 16.
O-[(1R)-1,2-Diphenyl-2-oxoethyl]-derivative Sch642305 (16): Under a ni-
trogen atmosphere, ethoxyacetylene (78 mL, 1.12 mmol) was added
slowly to the solution of 14 (20 mg, 0.035 mmol) in DCE (0.7 mL) in the
presence of catalytic amount of [RuCl2ACHTNUGTRENUNG(p-cymene)]2 at 08C. The resulting
mixture was stirred at 408C for 2 h and Ru was filtered by short pad SiO2
column elucidated by AcOEt. The residue was concentrated in vacuo.
The ethoxyvinyl ester (EVE) (quant, >95% purity based on 1H NMR
analysis) was used without further purification.
7-[Benzyl(p-toluenesulfonyl)amino]oxacyclotridecan-2-one (11b)
The crude EVE was diluted in DCE (10 mL) and slowly added by sy-
ringe pump to the high diluted DCE (25 mL) solution in the presence of
TsOH (0.05m in DCE/CH3CN 1:1, 0.08 mL, 0.004 mmol) over 10 h at
808C. The reaction mixture was stirred at 808C for 1 h; cooled to room
temperature, and poured into saturated NaHCO3. The mixture was ex-
tracted by AcOEt. The organic layer was washed with brine, dried over
Na2SO4 and concentrated in vacuo to give 15. 1H NMR (300 MHz,
CDCl3): d=0.78–1.15 (m, 3H), 1.19–2.03 (m, 8H), 2.28–2.40 (m, 2H),
2.56–2.66 (m, 2H), 2.88 (dd, J=15.6, 5.4 Hz, 1H), 3.13 (t, J=11.6 Hz,
1H), 3.71–3.76 (m, 2H), 4.99 (m, 1H), 5.67 (s, 1H), 7.17–7.46 (m, 12H),
7.44 (t, J=7.4 Hz, 1H), 7.77 ppm (d, J=7.2 Hz, 2H); LRMS (FAB): m/z:
557 [M+H]+; HRMS (FAB): m/z: calcd for C34H37O5S: 557.8369; found:
557.2380.
In the same procedure for 3a, 11b (35 mg, 73%) was obtained from 10b
(50 mg, 0.10 mmol). Yellow oil; 1H NMR (270 MHz, CDCl3): d=1.11–
1.71 (m, 16H), 2.05–2.15 (m, 1H), 2.34–2.42 (m, 1H), 2.37 (s, 3H), 3.67–
3.69 (m, 1H), 3.89–3.96 (m, 1H), 4.14–4.24 (m, 1H), 4.21 (d, J=15.9 Hz,
1H), 4.38 (d, J=15.9 Hzm 1H), 7.18–7.33 (m, 7H), 7.63–7.66 ppm (m,
2H); 13C NMR (67.8 MHz, CDCl3): d=21.2, 23.1, 23.4, 23.8, 25.0, 25.4,
26.6, 28.7, 31.6, 34.5, 47.2, 55.5, 64.2, 126.2 (2C), 126.8, 127.4 (2C), 127.8
(2C), 129.0 (2C), 137.7, 138.1, 142.5, 172.9 ppm; IR (KBr): n˜ =2932,
2860, 1728 cmꢀ1; LRMS (FAB): m/z: 458 [M+H]+; HRMS (FAB): m/z:
calcd for C26H36O4NS: 458.2359; found: 458.2370.
7-(p-Toluenesulfonylamino)oxacyclotridecan-2-one (11c): In the same
procedure for 3a, 11c (25 mg, 75%) was obtained from 10c (35 mg,
0.091 mmol). Yellow crystals; m.p. 92.0–92.58C; 1H NMR (300 MHz,
CDCl3): d=1.17–1.63 (m, 16H), 2.12–2.22 (m, 2H), 2.28–2.36 (m, 2H),
2.36 (s, 3H), 3.14–3.15 (m, 1H), 3.91–3.98 (m, 2H), 4.11–4.18 (m, 2H),
4.52 (d, J=8.1 Hz, 1H), 7.23 (d, J=7.3 Hz, 2H), 7.70 ppm (d, J=7.3 Hz,
2H); 13C NMR (75.5 MHz, CDCl3): d=21.5, 21.6, 23.8 (2C), 24.4, 26.1,
27.2, 31.3, 33.4, 34.5, 51.8, 64.5, 126.9 (2C), 129.5 (2C), 138.0, 143.0,
Under nitrogen atmosphere, mCPBA (12 mg, 0.07 mmol) was added to
the solution of the crude 15 in DCE (0.7 mL) at 08C. The resulting mix-
ture was stirred at room temperature for 30 min. Then Et3N (30 mL,
0.20 mmol) was added to the solution. The resulting mixture was stirred
at room temperature for 30 min and poured into saturated aqueous
Na2S2O3. The mixture was extracted by AcOEt. The organic layer was
173.5 ppm; IR (KBr): n˜ =3279, 2939, 2862, 1730, 1713 cmꢀ1
; LRMS
3536
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 3526 – 3537

A Highly Efficient Macrolactonization Method
FULL PAPER
washed with brine, dried over Na2SO4 and concentrated in vacuo. Purifi-
cation of the residue by SiO2 column chromatography (hexane/AcOEt
Angew. Chem. 2006, 118, 5964–5969; Angew. Chem. Int. Ed. 2006,
45, 5832–5837.
5:1) gave 16 (7 mg, 46%) as
a
colorless oil. [a]2D5:1 =65.9 (c=0.60,
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2.10 (m, 8H), 2.47 (d, J=16.8 Hz, 1H), 2.63–2.80 (m, 3H), 4.08 (d, J=
3.3 Hz, 1H), 4.90–5.05 (m, 1H), 5.64 (s, 1H), 6.02 (d, J=10.2 Hz, 1H),
6.95 (dd, J=10.2, 3.3 Hz, 1H), 7.19–7.36 (m, 7H), 7.46 (t, J=7.2 Hz,
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18.2, 20.8, 21.4, 22.7, 29.7, 36.8, 38.7, 47.1, 72.1, 73.1, 83.0, 126.7 (2C),
128.6 (2C), 128.9 (2C), 129.3 (2C), 132.6, 133.6, 134.5, 136.4, 144.1, 149.3,
171.4, 197.3, 199.8 ppm; IR (KBr): n˜ =1716, 1698, 1673 cmꢀ; LRMS
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Acknowledgements
This work was supported by Grant-in-Aid for Scientific Research (A)
and Grant-in-Aid for Scientific Research (B) from Japan Society for the
Promotion of Science and by Grant-in-Aid for Scientific Research on Pri-
ority Areas (17035047) from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
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Received: July 29, 2008
´
ner, C. Aꢄssa, C. Chevrier, F. Teply, C. Nevado, M. Tremblay,
Published online: February 19, 2009
Chem. Eur. J. 2009, 15, 3526 – 3537
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3537