Synthesis of (S)-γ- lactones with a combination of lipase-catalyzed resolution and mitsunobu reaction

Article abstract of DOI:10.1080/00397910802546177

Six kinds of (S) - lactones [e.g., (S) - decalactone, (S) - undecalactone, and (S) - jasmolactone] were synthesized with 71-88% yields and 97% optical purities by combining lipase-catalyzed resolution with the Mitsunobu reaction. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802546177

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Synthesis of (S)-γ-Lactones
with a Combination of Lipase-
Catalyzed Resolution and
Mitsunobu Reaction
Yasutaka Shimotori a & Tetsuo Miyakoshi a
a Department of Applied Chemistry, School of
Science and Technology , Meiji University ,
Kawasaki, Japan
Published online: 02 Apr 2009.
To cite this article: Yasutaka Shimotori & Tetsuo Miyakoshi (2009) Synthesis of (S)-γ-
Lactones with a Combination of Lipase-Catalyzed Resolution and Mitsunobu Reaction,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:9, 1570-1582, DOI: 10.1080/00397910802546177
To link to this article: http://dx.doi.org/10.1080/00397910802546177
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Synthetic Communications1, 39: 1570–1582, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802546177
Synthesis of (S)-c-Lactones with a
Combination of Lipase-Catalyzed Resolution
and Mitsunobu Reaction
Yasutaka Shimotori and Tetsuo Miyakoshi
Department of Applied Chemistry, School of Science and Technology,
Meiji University, Kawasaki, Japan
Abstract: Six kinds of (S)-c-lactones [e.g., (S)-c-decalactone, (S)-c-undecalactone,
and (S)-c-jasmolactone] were synthesized with 71–88% yields and >97% optical
purities by combining lipase-catalyzed resolution with the Mitsunobu reaction.
Keywords: Asymmetric synthesis, enzyme, kinetic resolution, Mitsunobu reaction
INTRODUCTION
Lactone functionality is present in a variety of natural products and bio-
logically active compounds.[1] Most of them are chiral, and their bioactiv-
ity often depends on chirality. Because of the primary importance of this
class of compounds, many methods to prepare chiral lactones, mostly
synthesis via asymmetric reactions, have been reported.[2–6] The prepara-
tion of chiral lactones has also been achieved by resolution of race-
mates.[7–11] The lipase-catalyzed kinetic resolution of racemic alcohols
has proved to be a good method to obtain enantiomerically enriched
materials. Recently, we reported that both enantiomers of c-lactones
were obtained by lipase-catalyzed resolution.[12,13] However, no more
than 50% of the desired enantiomer was obtained using this method.
One strategy for obtaining more than 50% of an enantiomer is to perform
Received August 3, 2008.
Address correspondence to Tetsuo Miyakoshi, Department of Applied
Chemistry, School of Science and Technology, Meiji University, 1-1-1 Higashi-
mita, Tama-ku, Kawasaki 214-8571, Japan. E-mail: miya@isc.meiji.ac.jp
1570

Synthesis of (S)-c-Lactones
1571
an enantioconvergent process, using a combination of biochemical and
chemical reactions.[14] Methods based on dynamic kinetic resolution pro-
cesses combine a lipase-catalyzed kinetic resolution and a transition-
metal-catalyzed racemization of a slowly reacting enantiomer.[15–23]
Another method is a combination of lipase-catalyzed kinetic resolution
and the Mitsunobu reaction.[24–28] The Mitsunobu reaction is one of
the most favored methods for the inversion of secondary alcohols. This
transformation was found to be very efficient for inverting the configura-
tion of chiral secondary alcohols because a clean SN2 process is generally
observed.[29] In our laboratory, the method of lipase-catalyzed resolution
is well established,[12,13] and therefore, we have applied this method to the
synthesis of (S)-c-lactones.
RESULTS AND DISCUSSION
Effect of Nucleophilic Agents in Mitsunobu Reaction
The racemic N-benzyl-4-hydroxydecanamide (rac-1c) was chosen as a
model substrate for evaluation of the effect of nucleophilic agents in the
Mitsunobu reaction on overall yield and optical purity of c-lactone
obtained (Scheme 1). The evaluation was performed with five benzoic acid
derivatives and two carboxylic acids as nucleophilic agents in the Mitsu-
nobu reaction. The major nucleophilic agent in the Mitsunobu reaction
was benzoic acid. However, a combination of lipase-catalyzed acetylation
of secondary alcohols and the Mitsunobu reaction was performed with
acetic acid as a nucleophilic agent, and the acetates were obtained with high
yields and optical purity.[27] Therefore, acetic acid and 2-ethylhexanoic acid
were also evaluated for comparable aliphatic carboxylic acids (Table 1,
entries 6 and 7). Benzoic acid, 4-nitrobenzoic acid, and 4-chlorobenzoic acid
(which have electron-receiving groups; Table 1, entries 1, 2, and 3, respec-
tively), and 3,5-dimethylbenzoic acid and 3,5-dimethoxybenzoic acid
(which have electron-donating groups; Table 1, entries 4 and 5) were the
Scheme 1. Novozym 435-catalyzed acetylation and Mitsunobu reaction.

1572
Y. Shimotori and T. Miyakoshi
Table 1. Effect of nucleophilic agents in the Mitsunobu reaction using rac-1c
Entry
Nucleophilic agent
Yield (%)a of (S)-4c
Ee (%)b of (S)-4c
1
2
3
4
5
6
7
Benzoic acid
79
73
70
79
98
97
98
88
99
—
—
4-Nitrobenzoic acid
4-Chlorobenzoic acid
3,5-Dimethylbenzoic acid
3,5-Dimethoxybenzoic acid
Acetic acid
80
No reaction
No reaction
2-Ethylhexanoic acid
aYield based on rac-1c.
bDetermined by GC using Chirasil-Dex CB column.
benzoic acid derivatives used as nucleophilic agents. Conditions of the
Novozym 435–catalyzed resolution were reported previously.[12] The
Mitsunobu reaction was performed using a mixture of unreacted (R)-N-
benzyl-4-hydroxydecanamide [(R)-1c] and reacted N-benzyl-4-acetoxy-
decanamide [(S)-2c] in Novozym 435–catalyzed acetylation with seven
nucleophilic agents, and the crude products obtained were lactonized
without purification. The purification by column chromatography was per-
formed only once after lactonization. The solvent in this evaluation was
tetrohydrofuran (THF), which is generally used in the Mitsunobu reaction.
The overall yield from racemic N-benzyl-4-hydroxydecanamide (rac-1c)
and the optical purity were calculated from (S)-4c. As a result, when ben-
zoic acid derivatives were used in the Mitsunobu reaction, the reaction pro-
gressed (Table 1, entries 1–5). However, when aliphatic carboxylic acids
were used, the reaction did not progress (Table 1, entries 6 and 7). There
was no drastic difference between benzoic acid derivatives in the yield of
(S)-4c (Table 1, entries 1–5). In contrast, some decrease in yield was
observed when 4-nitrobenzoic acid or 4-chlorobenzoic acid were used as
the electron-receiving group (Table 1, entries 2 and 3). There was no differ-
ence in the yield between 3,5-dimethylbenzoic acid and 3,5-dimethoxyben-
zoic acid, which have electron-donating groups. However, there was an
extreme decrease in optical purity when 3,5-dimethylbenzoic acid was
used (Table 1, entries 4 and 5). All benzoic acid derivatives except 3,5-
dimethylbeizoic acid produced an optical purity of more than 97% ee.
Effect of Solvents in Mitsunobu Reaction
Solvents were evaluated using benzoic acid, 4-nitrobenzoic acid, and 3,5-
dimethoxybenzoic acid as nucleophilic agents. It was reported that when

Synthesis of (S)-c-Lactones
1573
Table 2. Effect of solvent in the Mitsunobu reaction using rac-1c
Yield (%)a
of (S)-4c
Ee (%)b
of (S)-4c
Entry
Nucleophilic agent
Benzoic acid
Solvent
1
2
3
4
5
6
7
8
9
THF
79
69
69
73
86
78
80
83
74
98
93
80
97
97
96
99
97
98
Benzene
Toluene
THF
Benzene
Toluene
THF
4-Nitrobenzoic acid
3,5-Dimethoxybenzoic acid
Benzene
Toluene
aYield based on rac-1c.
bDetermined by GC using Chirasil-Dex CB column.
benzene and toluene were used as solvent, they showed results as good as
THF did.[30–32] The yields of the reaction products were decreased in ben-
zene and toluene as compared to that in THF when benzoic acid was used
as the nucleophilic agent, and the optical purities also were decreased
(Table 2, entries 1–3). There was no difference in the optical purity of
the products when 4-nitrobenzoic acid was used. However, the yields of
the products were higher when benzene and toluene were used than when
THF was used as solvent (Table 2, entries 4–6). The yield was highest
when benzene was used (Table 2, entry 5). There was no difference in
the optical purity of the products even when 3,5-dimethoxybenzoic acid
was used as nucleophilic agent (Table 2, entries 7–9). Consequently, when
4-nitrobenzoic acid was used as the nucleophilic agent and benzene as the
solvent, a satisfactory result was obtained in both the yield and optical
purity of the products (Table 2, entry 5). Therefore, these conditions were
assumed to be the optimum conditions of the reaction.
Application of Optimum Mitsunobu Conditions to Other Substrates
A combination of lipase-catalyzed resolution and Mitsunobu reaction
was performed using five other racemic N-benzyl-4-hydroxyalkylamides
(rac-1a, b, and d–f) as the substrates to synthesize other (S)-c-lactones
using the optimum conditions. When rac-1a and rac-1f were used as
the substrate, the yield of the product was about 70%, which was lower
than the other substrates (Table 3, entries 1 and 6). In contrast, when
rac-1b–e were used as the substrates, the yields exceeded 80%, which
was satisfactory (Table 3, entries 2–5). Moreover, the optical purity of

1574
Y. Shimotori and T. Miyakoshi
Table 3. Application of optimum Mitsunobu conditions to other substrates
Entry
Substrate
R
Yield (%)a of (S)-4
Ee (%)b of (S)-4
1
2
3
4
5
6
rac-1a
rac-1b
rac-1c
rac-1d
rac-1e
rac-1f
n-C4H9
76
81
83
86
88
71
97
97
97
97
98
99
n-C5H11
n-C6H13
n-C7H15
n-C8H17
cis-3-C6H11
aYield based on rac-1.
bDetermined by GC using Chirasil-Dex CB column.
the resulting products exceeded 97% in all cases, which was a satisfactory
result (Table 3, entries 1–6). Therefore, (S)-c-lactones were synthesized
with a high yield and high optical purity by combining lipase-catalyzed
resolution with the Mitsunobu reaction regardless of substrate rac-1a–f.
CONCLUSION
(S)-c-Lactones were synthesized with 71–88% yield and more than 97%
optical purity by performing Novozym 435–catalyzed resolution of rac-
1a–e prepared from corresponding rac-c-lactones and rac-1f prepared
from N-benzylsuccinimide, the Mitsunobu reaction on the resulting reac-
tion mixture, and lactonization. Moreover, when the Mitsunobu reaction
was performed using 4-nitrobenzoic acid as the nucleophilic agent and
benzene as the solvent, the best results were obtained.
EXPERIMENTAL
General
Thin-layer chromatography (TLC) was performed using silica-gel F-254
on aluminum purchased from Merck Ltd. (Darmstadt, Germany). Crude
products were purified by column chromatography on silica-gel FL60D
purchased from Fuji Silysia Chemical Ltd. (Aichi, Japan). Melting points
(mp) were determined using a MP-500D micro-melting-point apparatus
from Yanaco Technical Science Co., Ltd. (Kyoto, Japan) and were
uncorrected. Infrared (IR) spectra were recorded on a Fourier transform
(FT)=IR-460plus spectrometer from Jasco Corporation (Tokyo, Japan).
1H NMR and 13C NMR spectra were recorded in CDCl3 solution on a

Synthesis of (S)-c-Lactones
1575
500-MHz FT-NMR spectrometer (Jeol JNM-ECA 500 system). Chemi-
cal sifts were reported in parts per million (ppm) with respect to the inter-
nal tetramethylsilane (TMS). Coupling constants (J) were quoted in
Hertz. High-resolution mass spectral (HRMS) analyses were measured
on a Mariner Biospectrometry Workstation (PerSeptive Biosystems,
Framingham, MA, USA). The enantiomeric excesses were determined
using a Shimadzu GC-18A gas chromatograph equipped with the chiral
capillary column Chirasil-Dex CB (25 m ꢀ 0.25 mm i.d. ꢀ 0.25 mm film
thickness, Varian, Walnut Creek, CA, USA). The carrier gas was helium.
c-Octalactone, c-nonalactone, c-decalactone, c-undecalactone, c-dodeca-
lactone, 4-nitrobenzoic acid, 4-chlorobenzoic acid, 3,5-dimethoxybenzoic
acid, and 3,5-dimethoxybenzoic acid were purchased from Tokyo Chemi-
cal Industry Co., Ltd. (Tokyo, Japan). cis-3-Hexenol was purchased from
Soda Aromatic Co., Ltd (Tokyo, Japan). Succinic anhydride, benzoic
acid, and triphenylphosphine (TPP) were purchased from Nacalai Tesque
Inc. (Kyoto, Japan). Diisopropyl azodicarboxylate (95%, d 1.0127)
(DIAD) was purchased from Sigma-Aldrich Corp. (St. Louis, MO,
USA). Novozym 435 (immobilized lipase from Candida antarctica) was
ꢀ
a gift from Novozymes A=S (Parana, Brazil). All other materials were
commercially obtained. Diethyl ether, tetrahydrofuran (THF), benzene,
and toluene were dried before use.
Preparation of rac-N-Benzyl-4-hydroxyalkylamides (rac-1a–e)
Rac-c-lactones rac-4a–e (10.0 mmol) were added to benzylamine (2.14 g,
20.0 mmol) and stirred at room temperature for 2–5 days. H2O was added
to the reaction mixture, and it was neutralized with HCl aq. The organic
phases were extracted with EtOAc, and the combined organic layers were
dried over Na2SO4. The EtOAc was removed under reduced pressure,
and the residue was purified by column chromatography on silica gel
(eluent: EtOAc) (rac-1a) and crystallization from n-hexane (rac-1b–e) to
give the corresponding rac-N-benzyl-4-hydroxyalkylamides (rac-1a–e) as
colorless solids. N-Benzyl-4-hydroxyoctanamide (rac-1a) was soluble in
n-hexane and N-benzyl-4-hydroxynonan-, decan-, undecan-, and dodeca-
namide (rac-1b–e) were insoluble in n-hexane. The spectra data were
reported previously.[12]
Preparation of rac-N-Benzyl-4-hydroxy-cis-7-decenamide (rac-1f)
The Grignard reagent was freshly prepared from 1-chloro-cis-3-hexene
(1.96 g, 16.5 mmol) in dry diethyl ether (5 ml) with magnesium (0.37 g,

1576
Y. Shimotori and T. Miyakoshi
15.0 mmol). The resulting Grignard reagent was added dropwise to a
solution of N-benzylsuccinimide (3.78 g, 10.0 mmol) in dry diethyl ether
(10 ml) with stirring at 0ꢁC. The reaction mixture was stirred at the same
temperature for a further 30 min and then stirred at room temperature for
8 h. The mixture was poured into saturated aqueous NH4Cl solution and
extracted with EtOAc (3 ꢀ 50 ml). The collected EtOAc layers were com-
bined, washed with water and brine, dried over Na2SO4, and concen-
trated under reduced pressure. NaBH4 (0.76 g, 20.0 mmol) was added
to a solution of the reaction mixture in methanol (20 ml) at 0ꢁC and then
stirred at room temperature for 1 h. After evaporation, H2O was added to
the mixture and extracted with EtOAc (3 ꢀ 50 ml). The combined organic
phases were washed with water and brine, dried over Na2SO4, concen-
trated under reduced pressure, and purified through column chromato-
graphy (eluent: n-hexane–EtOAc, 70:30, v=v) to give rac-1f (1.21 g) at
44% (overall yield from N-benzylsuccinimide).
Colorless oil; Rf 0.14 (eluent: n-hexane–EtOAc, 3:2, v=v). IR (NaCl):
1
cmꢂ1 3290, 3086, 3065, 2962, 2930, 2872, 1654, 1646, 1550, 1454. H
NMR (500 MHz, CDCl3): d 0.96 (t, J ¼ 7.4 Hz, 3H, CH3), 1.52 (m, 2H,
CH2), 1.72, 1.88 (mꢃm, 2H, CH2), 2.12 (m, 4H, 2CH2), 2.40 (m,
2H, CH2), 2.76 (br, 1H, OH), 3.66 (m, 1H, CH), 4.44 (d, J ¼ 5.7 Hz,
2H, PhCH2), 5.37 (m, 2H, CH ¼ CH), 5.96 (br, 1H, NH), 7.31 (m, 5H,
Ph). 13C NMR (126 MHz, CDCl3): d 14.3, 20.5, 23.5, 32.5, 33.2, 37.6,
43.7, 71.2, 127.6, 127.8, 128.5, 128.7, 132.3, 138.1, 173.4. HRMS (ESI)
calcd. for C17H25NO2 (MþH)þ, 276.1964; found: (MþH)þ, 276.1973.
General Procedure for Synthesis of (S)-c-Lactones with a Combination
of Novozym 435–Catalyzed Acetylation and Mitsunobu Reaction
Novozym 435 (0.2 g) was added to a solution of the appropriate rac-1a–f
(1.0 mmol) and vinyl acetate (0.17 g, 2.0 mmol) in diethyl ether (20 ml),
while stirring at room temperature. After stirring, the mixture was fil-
tered, and the solvent was evaporated. The reaction time was reported
previously.[12] Enzymatic acetylation of rac-1f was continued for 8 h,
and both enantiomers of c-jasmolactone were obtained with >99% ee.
The resulted crude reaction mixture was subjected the Mitsunobu
reaction without purification.
TPP (0.26 g, 1.0 mmol), 4-nitrobenzoic acid (0.17 g, 1.0 mmol), and
DIAD (0.21 ml, 1.0 mmol) were added to a solution of a crude mixture
in benzene (5 ml) and stirred at room temperature for 48 h. The benzene
was removed under reduced pressure, H2O was added, and the mixture
was neutralized with Na2CO3. The aqueous phases were extracted with
EtOAc (3 ꢀ 30 ml). The combined organic phases were washed with brine

Synthesis of (S)-c-Lactones
1577
and dried over Na2SO4, then concentrated under reduced pressure. The
crude products were subjected to lactonization without purification.
NaOH (2.0 g) was added to a solution of the crude mixture in metha-
nol (20 ml), and the reaction mixture was refluxed for 2 h. The methanol
was removed under reduced pressure, 2 N HCl aq. was added until the
pH reached 3, and the mixture was stirred at room temperature for 1 h.
The aqueous phases were extracted with EtOAc (3 ꢀ 30 ml). The com-
bined organic phases were washed with saturated aqueous NaHCO3 solu-
tion, water, and brine; dried over Na2SO4; concentrated under reduced
pressure; and purified through column chromatography (eluent: n-hexane–
EtOAc, 85:15, v=v) to give the corresponding (S)-4a–f as a colorless oil.
The enantiomeric excess of obtained (S)-4a–f was calculated from the chiral
GC chromatograms. General GC conditions: injection 180ꢁC; detector
180ꢁC; pressure 150 kPa. The configurations of (R)-1a–f, (S)-2a–f, and
(S)-3a–f were based on the corresponding lactones. The spectra data of
(R)-1a–e, (S)-2a–e, and (S)-4a-f were reported previously.[12,13]
(S)-N-benzyl-4-acetoxy-cis-7-decenamide [(S)-2f]
Colorless oil; Rf 0.38 (eluent: n-hexane–EtOAc, 3:2, v=v). IR (NaCl): cmꢂ
1 3295, 3088, 3063, 2963, 2932, 2873, 1735, 1654, 1648, 1545, 1454, 1242.
1H NMR (500 MHz, CDCl3): d 0.95 (t, J ¼ 7.3 Hz, 3H, CH3), 1.59 (m,
2H, CH2), 1.95 (m, 6H, 3CH2), 2.02 (s, 3H, COCH3), 2.21 (m, 2H,
CH2), 4.42 (d, J ¼ 6.0 Hz, 2H, PhCH2), 4.89 (m, 1H, CH), 5.32 (m, 2H,
CH ¼ CH), 6.18 (br, 1H, NH), 7.38 (m, 5H, Ph). 13C NMR (126 MHz,
CDCl3): d 14.2, 20.4, 21.1, 22.9, 30.1, 32.5, 34.2, 43.5, 73.3, 127.4,
127.5, 127.7, 128.6, 132.4, 138.2, 171.1, 172.0. HRMS (ESI) calcd. for
C19H27NO3 (MþH)þ, 318.2069; found: (MþH)þ, 318.2081.
(S)-N-Benzyl-4-(4-nitrobenzoyl)oxyoctanamide [(S)-3a]
Colorless solid; mp 87–88ꢁC; Rf 0.45 (eluent: n-hexane–EtOAc, 3:2, v=v).
IR (KBr): cmꢂ1 3302, 3082, 3067, 2962, 2942, 2868, 2854, 1719, 1646,
1
1607, 1530, 1496, 1456, 1351, 1283, 872. H NMR (500MHz, CDCl3): d
0.89 (t, J ¼ 6.9 Hz, 3H, CH3), 1.34 (m, 4H, 2CH2), 1.72 (m, 2H, CH2),
2.10 (m, 2H, CH2), 2.29 (m, 2H, CH2), 4.38 (qd, J ¼ 14.3, 5.7 Hz, 2H,
PhCH2), 5.20 (m, 1H, CH), 5.91 (br, 1H, NH), 7.28 (m, 5H, Ph), 8.19
(m, 2H, COPh), 8.27 (m, 2H, COPh). 13C NMR (126MHz, CDCl3): d
13.9, 22.5, 27.4, 30.0, 32.6, 34.0, 43.7, 75.9, 123.5, 127.5, 127.8, 128.7,
130.7, 135.7, 138.1, 150.5, 164.6, 171.7. HRMS (ESI) calcd. for
C22H26N2O5 (MþH)þ, 399.1920; found: (MþH)þ, 399.1926.

1578
Y. Shimotori and T. Miyakoshi
(S)-N-Benzyl-4-(4-nitrobenzoyl)oxynonanamide [(S)-3b]
Colorless oil; Rf 0.45 (eluent: n-hexane–EtOAc, 3:2, v=v). IR (NaCl):
cmꢂ1 3297, 3080, 3066, 2955, 2932, 2870, 2859, 1721, 1645, 1607,
1527, 1496, 1455, 1349, 1275, 873. 1H NMR (500 MHz, CDCl3): d
0.87 (t, J ¼ 6.9 Hz, 3H, CH3), 1.32 (m, 6H, 3CH2), 1.71 (m, 2H,
CH2), 2.10 (m, 2H, CH2), 2.29 (m, 2H, CH2), 4.38 (qd, J ¼ 14.9,
5.7 Hz, 2H, PhCH2), 5.20 (m, 1H, CH), 5.95 (br, 1H, NH), 7.28 (m,
5H, Ph), 8.19 (m, 2H, COPh), 8.27 (m, 2H, COPh). 13C NMR
(126 MHz, CDCl3): d 13.9, 22.4, 24.9, 30.0, 31.5, 32.6, 34.3, 43.6,
75.9, 123.5, 127.5, 127.8, 128.7, 130.7, 135.7, 138.1, 150.5, 164.6,
171.7. HRMS (ESI) calcd. for C23H28N2O5 (MþH)þ, 413.2077; found:
(MþH)þ, 413.2076.
(S)-N-Benzyl-4-(4-nitrobenzoyl)oxydecanamide [(S)-3c]
Colorless oil; Rf 0.45 (eluent: n-hexane–EtOAc, 3:2, v=v). IR (NaCl):
cmꢂ1 3298, 3080, 3066, 2954, 2929, 2858, 1722, 1647, 1607, 1528,
1
1497, 1455, 1349, 1276, 874. H NMR (500 MHz, CDCl3): d 0.86 (t,
J ¼ 6.9 Hz, 3H, CH3), 1.31 (m, 8H, 4CH2), 1.72 (m, 2H, CH2), 2.10
(m, 2H, CH2), 2.29 (m, 2H, CH2), 4.38 (qd, J ¼ 14.9, 5.7 Hz, 2H,
PhCH2), 5.20 (m, 1H, CH), 5.93 (br, 1H, NH), 7.28 (m, 5H, Ph),
8.19 (m, 2H, COPh), 8.27 (m, 2H, COPh). 13C NMR (126 MHz,
CDCl3): d 14.0, 22.5, 25.2, 29.0, 30.0, 31.6, 32.6, 34.3, 43.6, 75.9,
123.5, 127.5, 127.8, 128.7, 130.7, 135.7, 138.1, 150.5, 164.6, 171.7.
HRMS (ESI) calcd. for C24H30N2O5 (MþH)þ, 427.2233; found:
(MþH)þ, 427.2236.
(S)-N-Benzyl-4-(4-nitrobenzoyl)oxyundecanamide [(S)-3d]
Colorless oil; Rf 0.51 (eluent: n-hexane–EtOAc, 3:2, v=v). IR (NaCl):
cmꢂ1 3298, 3080, 3066, 2954, 2928, 2857, 1721, 1651, 1607, 1530,
1
1496, 1455, 1349, 1276, 874. H NMR (500 MHz, CDCl3): d 0.86 (t,
J ¼ 6.9 Hz, 3H, CH3), 1.32 (m, 10H, 5CH2), 1.71 (m, 2H, CH2), 2.09
(m, 2H, CH2), 2.29 (m, 2H, CH2), 4.37 (qd, J ¼ 14.9, 5.7 Hz, 2H,
PhCH2), 5.20 (m, 1H, CH), 6.04 (br, 1H, NH), 7.27 (m, 5H, Ph),
8.18 (m, 2H, COPh), 8.25 (m, 2H, COPh). 13C NMR (126 MHz,
CDCl3): d 14.0, 22.5, 25.2, 29.0, 29.3, 29.9, 31.6, 32.5, 34.3, 43.6,
75.9, 123.5, 127.4, 127.7, 128.6, 130.6, 135.7, 138.1, 150.4, 164.5,
171.7. HRMS (ESI) calcd. for C25H32N2O5 (MþH)þ, 441.2390; found:
(MþH)þ, 441.2389.

Synthesis of (S)-c-Lactones
1579
(S)-N-Benzyl-4-(4-nitrobenzoyl)oxydodecanamide [(S)-3e]
Colorless oil; Rf 0.55 (eluent: n-hexane–EtOAc, 3:2, v=v). IR (NaCl):
cmꢂ1 3298, 3082, 3065, 2954, 2927, 2856, 1723, 1647, 1607, 1528, 1496,
1454, 1349, 1257, 873. 1H NMR (500 MHz, CDCl3): d 0.86 (t, J ¼ 6.9 Hz,
Hz, 3H, CH3), 1.32 (m, 12H, 6CH2), 1.71 (m, 2H, CH2), 2.10 (m, 2H,
CH2), 2.29 (m, 2H, CH2), 4.38 (qd, J ¼ 14.9, 5.7 Hz, 2H, PhCH2), 5.20
(m, 1H, CH), 5.93 (br, 1H, NH), 7.28 (m, 5H, Ph), 8.19 (m, 2H, COPh),
8.27 (m, 2H, COPh). 13C NMR (126 MHz, CDCl3): d 14.0, 22.6, 25.2,
29.1, 29.4, 30.0, 31.8, 32.6, 34.3, 43.6, 75.9, 123.5, 127.5, 127.8, 128.7,
130.7, 135.7, 138.1, 150.5, 164.6, 171.7. HRMS (ESI) calcd. for
C26H34N2O5 (MþH)þ, 455.2546; found: (MþH)þ, 455.2546.
(S)-N-Benzyl-4-(4-nitrobenzoyl)oxy-cis-7-decenamide [(S)-3f]
Colorless oil; Rf 0.45 (eluent: n-hexane–EtOAc, 3:2, v=v). IR (NaCl): cmꢂ1
3296, 3080, 3066, 2961, 2931, 2872, 1722, 1653, 1646, 1607, 1528, 1496,
1454, 1350, 1276, 873. 1H NMR (500 MHz, CDCl3): d 0.91 (t, J ¼ 7.4 Hz,
Hz, 3H, CH3), 1.72, 1.83 (mꢃm, 2H, CH2), 1.97 (m, 2H, CH2), 2.10 (m, 4H,
2CH2), 2.30 (m, 2H, CH2), 4.37 (qd, J ¼ 14.3, 5.7 Hz, 2H, PhCH2), 5.21 (m,
1H, CH), 5.33 (m, 2H, CH ¼ CH), 6.12 (br, 1H, NH), 7.27 (m, 5H, Ph),
8.18 (m, 2H, COPh), 8.25 (m, 2H, COPh). 13C NMR (126 MHz, CDCl3):
d 14.1, 20.4, 22.9, 29.9, 32.4, 34.2, 43.5, 75.4, 123.4, 127.2, 127.4, 127.7,
128.6, 130.6, 132.7, 135.6, 138.0, 150.4, 164.5, 171.7. HRMS (ESI) calcd.
for C24H28N2O5 (MþH)þ, 425.2076; found: (MþH)þ, 425.2079.
Evaluation of Nucleophilic Agents in the Mitsunobu Reaction
Nucleophilic agents (1.0 mmol) were added to a solution of the crude
products of (R)-N-benzyl-4-hydroxydecanamide [(R)-1c] and (S)-N-ben-
zyl-4-acetoxydecanamide [(S)-2c] in THF. The reaction mixture was
stirred at room temperature for 48 h. The solvents were removed under
reduced pressure. The crude products were hydrolyzed under alkaline
conditions, and intra-esterification was performed under acidic condi-
tions. The optimum nucleophilic agent were determined from the yield
and the optical purity of the product [(S)-4c].
Evaluation of Solvents in the Mitsunobu Reaction
Nucleophilic agents (benzoic acid, 4-nitrobenzoic acid, or 3,5-dimethoxy-
benzoic acid) (1.0 mmol) were added to a solution of the crude products

1580
Y. Shimotori and T. Miyakoshi
of (R)-N-benzyl-4-hydroxydecanamide [(R)-1c] and (S)-N-benzyl-4-acet-
oxydecanamide in solvents (THF, benzene, or toluene). The lactonization
was performed with the same conditions as the general procedure. The
optimum solvent was determined from the yield and the optical purity
of the product [(S)-4c].
ACKNOWLEDGMENT
We are grateful to Novozymes A=S for the generous gift of Novozym
435. Financial support from Meiji University (Grant-in-Aid for Young
Scientists) is gratefully acknowledged.
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