Enantioselective synthesis of δ-lactones with lipase-catalyzed resolution and mitsunobu reaction

Article abstract of DOI:10.1080/00397911.2010.529230

Both enantiomers of a series of δ-lactones (e.g., δ-decalactone, δ-dodelactone, and d-hexadecalactone) were synthesized stereoselectively by Novozym 435-catalyzed resolution. Furthermore, only (S)-enantiomers of d-lactones were synthesized with a combination of Novozym 435-catalyzed resolution and Mitsunobu reaction. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.529230

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Enantioselective Synthesis of δ-Lactones
with Lipase-Catalyzed Resolution and
Mitsunobu Reaction
Yasutaka Shimotori a , Masakazu Aoyama a & Tetsuo Miyakoshi b
a Department of Applied and Environmental Chemistry , Kitami
Institute of Technology , Kitami , Hokkaido , Japan
b Department of Applied Chemistry, School of Science and
Technology , Meiji University , Tama-ku , Kawasaki , Japan
Accepted author version posted online: 17 Aug 2011.Published
online: 01 Nov 2011.
To cite this article: Yasutaka Shimotori , Masakazu Aoyama & Tetsuo Miyakoshi (2012)
Enantioselective Synthesis of δ-Lactones with Lipase-Catalyzed Resolution and Mitsunobu Reaction,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:5, 694-704, DOI: 10.1080/00397911.2010.529230
To link to this article: http://dx.doi.org/10.1080/00397911.2010.529230
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Synthetic Communications1, 42: 694–704, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.529230
ENANTIOSELECTIVE SYNTHESIS OF d-LACTONES
WITH LIPASE-CATALYZED RESOLUTION AND
MITSUNOBU REACTION
Yasutaka Shimotori,1 Masakazu Aoyama,1 and
Tetsuo Miyakoshi2
1Department of Applied and Environmental Chemistry, Kitami Institute of
Technology, Kitami, Hokkaido, Japan
2Department of Applied Chemistry, School of Science and Technology,
Meiji University, Tama-ku, Kawasaki, Japan
GRAPHICAL ABSTRACT
Abstract Both enantiomers of a series of d-lactones (e.g., d-decalactone, d-dodelactone, and
d-hexadecalactone) were synthesized stereoselectively by Novozym 435–catalyzed resol-
ution. Furthermore, only (S)-enantiomers of d-lactones were synthesized with a combi-
nation of Novozym 435–catalyzed resolution and Mitsunobu reaction.
Keywords Enzymatic acetylation; d-lactone; lipase; Mitsunobu reaction; optical
resolution
INTRODUCTION
Chiral lactones are components commonly present in a number of natural
products that function as pheromones or medicinal compounds.[1–9] They often serve
as intermediates for the synthesis of other natural products.[10] Because of their bio-
logical activities, lactones possessing alkyl side chains have attracted much attention
from synthetic and medicinal chemists.[11,12] The short-chain alkyl lactones are
volatile and important aroma compounds in food and beverages. d-Lactones (e.g.,
d-decalactone, d-undecalactone, and d-dodecalactone) are well-known, naturally
occurring chiral flavor compounds, and they are important aroma components of
many fruits. Specific and characteristic enantiomeric ratios have been reported for
Received September 16, 2010.
Address correspondence to Yasutaka Shimotori, Department of Applied and Environmental
Chemistry, Kitami Institute of Technology, 165 Koen-cho, Kitami, Hokkaido 090-8507, Japan. E-mail:
yasu@mail.kitami-it.ac.jp
694

ENANTIOSELECTIVE SYNTHESIS OF d-LACTONES
695
lactones in apricots, peaches, raspberries, plums, mangoes, and passion fruit.[13]
They can also be detected in dairy products and other fermented food.[14,15] Mosandl
et al. have demonstrated the sensory differences in the enantiomers of d-lactones by
preparing optically pure (R)- and (S)-d-octa-, deca-, and dodecalactone. They
reported that the aroma from the (R)-configuration of d-decalactone was a milky
note, whereas that from the (S)-configuration was creamy peach note more intense
than the (R)-configuration.[16] In contrast, d-hexadecalactone, possessing the long
alkyl chain, is known as the sex pheromone of the queen of the Oriental hornet, Vsepa
olientalis.[17] Furthermore, antitumor and anti-invasive effects of d-lactones have been
reported.[18] Based on these facts, an efficient method to synthesize chiral d-lactones
was considered necessary. Furthermore, we attempted to synthesize chiral c- and
d-lactones by lipase-catalyzed resolution. Recently, we reported synthesis of (S)-
and (R)-c-lactones with a combination of lipase-catalyzed resolution and Mitsunobu
reaction.[19,20] In this article, we attempted to synthesize both enantiomers of
d-lactones by lipase-catalyzed resolution. Furthermore, we attempted to synthesize
d-lactones by a combination of lipase-catalyzed resolution and Mitsunobu reaction.
RESULTS AND DISCUSSION
Optimization of Novozym 435–Catalyzed Acylation
We attempted to synthesize optically active d-lactones by optical resolution
with Novozym 435–catalyzed enantioselective acylation.[21] The optical purities of
(R)- and (S)-lactones were about 80%, respectively. The aim was to increase optical
purities by using various acyl donors in Novozym 435–catalyzed acylation (Table 1).
The synthesis of optically active d-declactone (1a) was demonstrated as a model case
(Scheme 1). Racemic N-methyl-5-hydroxydecanamide (rac-2a) was used as a substrate
prepared by aminolysis of racemic d-decalactone (rac-1a) using methyl amine. Vinyl
acetate has been used commonly as an acyl donor. Vinyl benzoate (entry 2),
succinic anhydride (entry 3), acetic anhydride (entry 4), and vinyl chloroacetate
(entries 5–7) were used instead of vinyl acetate (entry 1). An amount of 2.0 w=w of
Table 1. Acyl donor screeninga
Yield (%)=enantiomeric excess (% e.e.)b=config.
Entry
Acyl donor
Solvent
Et2O
Time
2a
3a
1a
1
2
3
4
5
6
7
Vinyl acetate
24 h
7 d
44=93=(R)
81=9=(R)
75=2=(R)
75=14=(R)
42=79=(R)
54=59=(R)
76=15=(R)
54=81=(S)
1=—d=—d
Not detectedc
17=45=(S)
52=71=(S)
45=61=(S)
17=70=(S)
Not detectedc
18=5=(R)
Vinyl benzoate
Succinic anhydride
Acetic anhydride
7 d
7 d
26=racemic
Not detectedc
Not detectedc
Not detectedc
Not detectedc
Et2O
Vinyl chloroacetate tBuOMe 50 min
iPr2O
arac-2a: 1.0 mmol, acyl donor: 2.0 mmol, Novozym 435: 0.4 g, solvent: 20 ml, rt.
bDetermined by GC using InertCap CHIRAMIX column.
cDetermined by TLC.
dNot determined.

696
Y. SHIMOTORI, M. AOYAMA AND T. MIYAKOSHI
Scheme 1. Novozym 435–catalyzed resolution of rac-2.
lipase to the substrate was used, and the reaction temperature was 30 ꢀC. The amount
of lipase was increased to 0.4 g from 2.0 w=w, and the reaction temperature was
decreased to room temperature from 30 ꢀC. The reaction time until 50% conversion
increased from 12 h to 24 h. However, the optical purity of the (R)-enantiomer was
increased considerably (entry 1). Using vinyl benzoate, succinic anhydride, and acetic
anhydride, the progression of acylation was very slow, requiring up to 7 days (entries
2–4). The production of 1a was observed by thin-layer chromatography (TLC) using
vinyl benzoate and succinic anhydride. However, the enantioselectivity was not
observed by gas chromatography (GC) measurement (entries 2 and 3). Using vinyl
chloroacetate, the reaction time until 50% conversion was remarkably short compared
with that using vinyl acetate (entry 5). The optical purities of both enantiomers were
about 10% lower. tert-Buthylmethyl ether (tBuOMe) and diisopropyl ether (iPr2O)
were used as solvent instead of diethyl ether (entries 6 and 7). As a result, the pro-
i
gression of acylation was very slow (50 min) in Pr2O compared with diethyl ether
t
(Et2O) and BuOMe (entry 7). Additionally, there was not much difference between
tBuOMe and Et2O in conversion rate, while the optical purities of (R)-enantiomer
and (S)-enantiomer were 10% and 20%, respectively (entry 6). Based on these results,
vinyl acetate was the best acyl donor to show high enantioselectively (entry 1), and the
optimum enantioselective acylation conditions were determined entry 1.
Application of Optimum Conditions to Other Substrates
Novozym 435–catalyzed acetylation was performed with various substrates to
synthesize other d-lactones using the optimum conditions (Table 2). The substrates,
N-methyl-5-hydroxyalkylamides (rac-2b–f), were prepared from the corresponding
racemic d-lactones by aminolysis with methylamine. The reaction was stopped at
50% conversion of each substrate. As a result, the substrates possessing long alkyl
chains tended to require long reaction times compared with the substrates possessing
short alkyl chains. Although (R)-d-hexadecalactone [(R)-1f] had a somewhat low
optical purity (88%) (entry 6), the other optical purities of (R)-d-lactones exceeded
90% (entries 1–5). In contrast, (S)-1f had the greatest optical purity at 90% among
the other (S)-d-lactones (entry 6). All other (S)-d-lactones had optical purities of
about 80% (entries 1–5). These results demonstrated that the substrate affinity of
Novozym 435 to the short-chain substrates was greater than that to the long-chain
substrates. Because there was not much difference between the optical purity of each

ENANTIOSELECTIVE SYNTHESIS OF d-LACTONES
Table 2. Novozym 435–catalyzed acetylation of rac-2a
697
Yield (%)=enantiomeric
excess (% e.e.)b
Yield (%)
Entry
R
Substrate
Time (h)
(R)-2
(S)-3
(R)-1
(S)-1
1
2
3
4
5
6
n-C5H11
n-C6H13
n-C7H15
n-C8H17
n-C9H19
n-C11H23
rac-2a
rac-2b
rac-2c
rac-2d
rac-2e
rac-2f
24
27
44
44
42
41
43
45
54
55
57
56
53
46
92=93
88=96
83=81
89=84
90=84
89=82
96=88
80=90
30
42
89=>99
90=96
60
288
94=>99
75=88
arac-2: 1.0 mmol, vinyl acetate: 2.0 mmol, Novozym 435: 0.4 g, Et2O: 20 ml, rt.
bDetermined by GC using InertCap CHIRAMIX column.
(R)-d-lactone and its respective (S)-d-lactone, it was demonstrated that the substrate
selectivity of Novozym 435 to the all substrates was similar. Additionally, because
the optical purities of all (R)- and (S)-d-lactones were about 90% and more than
80%, respectively, it was demonstrated that the substrate specificity of Novozym
435 to all substrates was high.
Combination of Novozym 435–Catalyzed Acetylation and Mitsunobu
Reaction
Synthesis of (S)-d-lactones was performed by three steps (Scheme 2). The first
step was Novozym 435–catalyzed enantioselective acetylation of racemic N-methyl-
5-hydroxyalkylamides (rac-2). The second step was the stereo inversion of (R)-N-
methyl-5-hydroxyalkylamides [(R)-2] in the reaction mixture by Mitsunobu reaction
to afford (S)-N-methyl-5-(4-nitrobenzoyl)oxyalkylamides [(S)-4]. The third step was
the lactonization of the mixture [(S)-3 and (S)-4] to afford (S)-1. The results are
shown in Table 3. The optimum Mitsunobu reaction condition was reported pre-
viously.[19] The use of 4-nitrobenzoic acid as a nucleophilic agent and benzene as a
solvent produced excellent yield and stereo inversion. The Mitsunobu reagents
[4-nitrobenzoic acid, triphenylphosphine (TPP) and diisobutyl azodicarboxylate
(DIAD)] have been used in proportions of 1.0 mmol to 1.0 mmol substrate (rac-2)
Scheme 2. Combination of Novozym 435–catalyzed resolution and Mitsunobu reaction.

698
Y. SHIMOTORI, M. AOYAMA AND T. MIYAKOSHI
Table 3. Synthesis of (S)-1
Time (h) of
Mitsunobu reaction
Yield (%)a
of (S)-1
Enantiomeric excess
(% e.e.)b of (S)-1
Entry
R
Substrate
1
2
3
4
5
6
n-C5H11
n-C6H13
n-C7H15
n-C8H17
n-C9H19
n-C11H23
rac-2a
rac-2b
rac-2c
rac-2d
rac-2e
rac-2f
3
4
4
4
6
7
78
79
78
83
82
76
89
86
90
90
92
85
aTotal yield calculated from rac-2.
bDetermined by GC using InertCap CHIRAMIX column.
previously.[19,20] The reaction time required 24 h or 48 h. In this case, the proportion
of Mitsunobu reagent to the substrate was increased to 1.25 mmol, which shortened
the reaction time considerably. All (S)-d-lactones were synthesized with about 80%
total yield from the corresponding substrates (rac-2). Because d-lactones of both
enantiomers were synthesized with a range of about 80–90% yields from the corre-
sponding (R)-N-methyl-5-hydroxyalkylamides [(R)-2] and (S)-N-methyl-5-acetoxy-
alkylamides [(S)-3], it was thought that Mitsunobu reaction progressed with more
than 90% yield. Because (S)-d-lactones were synthesized with about 90% optical
purities, it was thought that Mitsunobu reaction progressed with a high stereo
inversion ratio. Moreover, the optical purities of all (S)-d-lactones except (S)-1f
(entry 6) synthesized by a combination of Novozym 435–catalyzed acetylation and
Mitsunobu reaction were greater than those of (S)-d-lactones synthesized by only
Novozym 435–catalyzed acetylation. As a result, it was demonstrated that the com-
bination of Novozym 435–catalyzed enantioselective acetylation and Mitsunobu
reaction is useful to synthesize (S)-d-lactones.
CONCLUSION
The syntheses of (R)- and (S)-enantiomers of six d-lactones were achieved with
about 90% and more than 80% optical purities, respectively. The enantioselective
acetylation of rac-2 was performed efficiently with vinyl acetate and Novozym 435
in Et2O under room temperature. Novozym 435 showed high substrate specificity
to all substrates. Moreover, six (S)-d-lactones were synthesized with about 80% total
yield from rac-2 and about 90% optical purities by using a combination of Novozym
435-catalyzed enantioselective acetylation and Mitsunobu reaction.
EXPERIMENTAL
Thin-layer chromatography (TLC) was performed using silica gel F-254 on
aluminum purchased from Merck Ltd. (Damstadt, Germany). Crude products were
purified by column chromatography on silica gel FL60D purchased from Fuji Silysia
Chemical Ltd. (Aichi, Japan). The melting points (mp) were recorded on a MP-500D
micro-melting-point apparatus from Yanaco Technical Science Co., Ltd. (Kyoto,
Japan) and are uncorrected. Infrared (IR) spectra were recorded on a Fourier

ENANTIOSELECTIVE SYNTHESIS OF d-LACTONES
699
transform (FT) IR-460-plus spectrometer from Jasco Corporation (Tokyo, Japan)
1
and are reported in wave numbers (cmꢁ1). H and 13C NMR spectra were recorded
in CDCl3 solution on a 500-MHz FT-NMR spectrometer (Jeol JNM-ECA 500
system). Chemical sifts are reported in parts per million with respect to the internal
tetramethylsilane (TMS). Coupling constants (J) are reported in hertz (Hz). High-
resolution mass spectral (HRMS) were analyzed on a Mariner Biospectrometry
Workstation (PerPestive Biosystems, Framingham, MA, USA). The enantiomeric
excesses were determined using a Perkin-Elmer Autosystem XL gas chromatgraph
equipped with the chiral capillary column InertCap CHIRAMIX (30 m ꢂ 0.25 mm
i.d. 0.25 mm film thickness, GC Science Co., Ltd. Tokyo, Japan). The carrier gas
was helium. d-Decalactone, d-undecalactone, d-dodecalactone, d-tridecalactone,
d-tetradecalactone, and 4-nitrobenzoic acid were purchased from Tokyo Chemical
Industry Co., Ltd. (Tokyo, Japan). d-Hexadecalactone was a gift from Soda
Aromatic Co., Ltd. (Tokyo, Japan). Diisopropyl azodicarboxylate (95%, d 1.0127)
(DIAD) was purchased from Sigma-Aldrich Corp. (St. Louis, MO, USA). Triphe-
nylphosphine (TPP) was purchased from Nacalai Tesque Inc. (Kyoto, Japan).
Novozym 435 (immobilized lipase from Candida antarctica) was a gift from
´
Novozymes A=S (Parana, Brazil). All other materials were commercially obtained.
Diethyl ether (Et2O), tert-butylmethyl ether (tBuOMe), diisopropyl ether (iPr2O),
and benzene were dried before use.
Preparation of Racemic N-Methyl-5-hydroxyhexadecanamide (rac-2f)
Racemic N-methyl-5-hydroxyhexadecanamide (rac-2f) was prepared by adding
methylamine hydrochloride (1.0 g, 15.0 mmol) and potassium acetate (1.5 g,
15.0 mmol) to a stirred solution of racemic d-hexadecalactone (2.5 g, 10.0 mmol) in
THF (30 ml). The mixture was stirred at room temperature for 5 days. After evap-
oration of the solvent, the aqueous phase was extracted with three portions of
CHCl3. The combined organic phase was dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by flash chromatography on silica (eluent:
AcOEt) to afford racemic N-methyl-5-hydroxyhexadecanamide (rac-2f) as a color-
less solid (2.8 g, 96%). Mp 87–88 ꢀC; Rf 0.14 (eluent: AcOEt). IR (KBr): cmꢁ1
=
3290 (N-H), 2956 (CH3), 2918 (CH2), 2873 (CH3), 2849 (CH2), 1639 (NHC O).
1H NMR (500 MHz, CDCl3): d 0.88 (t, J ¼ 6.9 Hz, 3H, CH2CH3), 1.26–1.32 (m,
18H, CH2 ꢂ 9), 1.38–1.54 (m, 4H, CH2 ꢂ 2), 1.70–1.81 (m, 2H, CH2), 2.09 (br, 1H,
=
OH), 2.22 (t, J ¼ 7.3 Hz, 2H, NHC OCH2), 2.80 (d, J ¼ 5.0 Hz, 3H, NHCH3),
3.58 (m, 1H, CH2CHCH2), 5.70 (br, 1H, NH). 13C NMR (126 MHz, CDCl3): d
14.1 (CH2CH3), 21.6 (CH2), 22.7 (CH2), 25.7 (CH2), 26.3 (CH2), 29.3 (CH2), 29.6
=
(CH2), 29.7 (CH2), 31.9 (CH2), 36.2 (NHC OCH2), 36.7 (CH2), 37.5 (CH2), 71.3
=
(CH2CHCH2), 173.8 (NHC O). HRMS (ESI) calcd. for C17H36NO2 (M þ H)þ,
286.2746; found: (M þ H)þ, 286.2742.
General Procedure for Novozym 435–Catalyzed Acetylation and
Lactonization
Novozym 435 (0.4 g) was added to a solution of racemic N-methyl-5-hydroxy-
alkylamides (rac-2a–f) (1.0 mmol) and vinyl acetate (0.2 g, 2.0 mmol) in Et2O (20 ml)

700
Y. SHIMOTORI, M. AOYAMA AND T. MIYAKOSHI
at room temperature. After stirring, the mixture was filtered and the solvent was
evaporated. The crude product was purified by flash chromatography on silica
(eluent: AcOEt) to afford the corresponding (R)-N-methyl-5-hydroxyalkylamides
[(R)-2a–f] as a colorless solid and (S)-N-methyl-5-acetoxyalkylamides [(S)-3a–f] as
a pale yellow oil.
NaOH (3.0 g) was added to a solution of (R)-2a–f and (S)-3a–f in MeOH
(20 ml), and the mixture was refluxed for 3 h. After cooling, MeOH was evaporated
under reduced pressure. H2SO4 (10%) in MeOH was added with stirring at 0 ꢀC until
the pH reached 3, and the mixture was stirred for 1 h at room temperature. MeOH
was evaporated under reduced pressure, and H2O was added. The aqueous phase
was extracted with three portions of AcOEt. The combined organic phase was
washed with brine, dried over Na2SO4, and concentrated under reduced pressure.
˚
p-TsOH (10 wt%) to the corresponding (R)-2a–f and (S)-3a–f, and 1 g 4-A molecular
sieves were added to a solution of (R)-2a–f and (S)-3a–f in toluene (10 ml). The mix-
ture was stirred at 80 ꢀC for 24 h. H2O was added, and the aqueous phase was
extracted with three portions of AcOEt. The combined organic phase was washed
with aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by flash chromatography on silica (eluent:
n-hexane–AcOEt, 4:1, v=v) to afford the corresponding d-lactones [(R)-1a–f and
(S)-1a–f] as a colorless oil [(R)-1a–e and (S)-1a–e] and as a colorless solid [(R)-1f
and (S)-1f]. The enantiomeric excess was calculated from the chiral GC chromato-
grams. General GC conditions were injection 250 ꢀC, detector 250 ꢀC, and pressure
150 kPa. The spectra data of 1a–e, 2a–e, and 3a–e were omitted.[22] The absolute con-
figurations of (R)-2 and (S)-3 were determined by optical rotation of corresponding
(R)- and (S)-1.[23,24]
Data for (S)-N-Methyl-5-acetoxyhexadecanamide [(S)-3f]
Colorless solid; mp 59–60 ꢀC; Rf 0.45 (eluent: AcOEt). IR (KBr): cmꢁ1 3277
=
(N-H), 2954 (CH3), 2919 (CH2), 2870 (CH3), 2850 (CH2), 1732 (OC O), 1640
1
=
=
(NHC O), 1241 (OC O). H NMR (500 MHz, CDCl3): d 0.88 (t, J ¼ 6.9 Hz, 3H,
CH2CH3), 1.25–1.32 (m, 18H, CH2 ꢂ 9), 1.51–1.58 (m, 4H, CH2CHCH2),
=
=
1.60–1.75 (m, 2H, CH2), 2.04 (OC OCH3), 2.11–2.24 (m, 2H, NHC OCH2), 2.80
(d, J ¼ 5.0 Hz, 3H, NHCH3), 4.86 (q, J ¼ 6.0, 6.4 Hz, 1H, CH2CHCH2), 5.52 (br,
1H, NH). 13C NMR (126 MHz, CDCl3): d 14.1 (CH2CH3), 21.3 (CH2), 21.5
(CH2), 22.7 (CH2), 25.3 (CH2), 26.2 (CH2), 29.3 (CH2), 29.5 (CH2), 29.6 (CH2),
=
31.9 (CH2), 33.6 (CH2), 34.0 (CH2), 36.1 (NHC OCH2), 73.7 (CH2CHCH2),
þ
=
=
171.0 (OC O), 173.2 (NHC O). HRMS (ESI) calcd. for C19H38NO3 (M þ H) ,
328.2852; found: (M þ H)þ, 328.2850.
Data for (S)-d-Hexadecalactone [(S)-1f]
Colorless solid; mp 33–34 ꢀC; Rf 0.30 (eluent: n-hexane–AcOEt, 4:1, v=v). IR
(KBr): cmꢁ1 2927 (CH3), 2915, 2848 (CH2), 1727, 1242 (OC O). 1H NMR
=
(500 MHz, CDCl3): d 0.88 (t, J ¼ 6.9 Hz, 3H, CH2CH3), 1.26–1.40 (m, 18H,
CH2 ꢂ 9), 1.44–1.62 (m, 2H, CH2CHCH2CH2), 1.64–1.75, 1.78–1.97 (m ꢃ m, 4H,
=
=
O CCH2CH2CH2CH), 2.39–2.49, 2.54–2.63 (m ꢃ m, 2H, O CCH2CH2), 4.24–4.31

ENANTIOSELECTIVE SYNTHESIS OF d-LACTONES
701
(m, 1H, CH2CHCH2). 13C NMR (126 MHz, CDCl3): d 14.1 (CH2CH3), 18.5 (CH2),
22.6 (CH2), 24.9 (CH2), 27.8 (CH2), 29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2),
=
31.9 (CH2), 35.8 (CH2CHCH2CH2), 80.6 (CH2CHCH2), 171.9 (OC O). HRMS
(ESI) calcd. for C11H31O2 (M þ H)þ, 255.2324; found: (M þ H)þ, 255.2320. GC
conditions: The column temperature was held at 160 ꢀC for 80 min and then pro-
grammed from 160 ꢀC to 180 ꢀC at 0.5 ꢀC=min. The carrier gas was helium at
25
2.5 mL=min. The retention time was 112.7 min. ½aꢄD ¼ ꢁ36:3 (90% e.e., THF,
c ¼ 0.2), lit. [a]D ¼ ꢁ40.2.[24]
Data for (R)-d-Hexadecalactone [(R)-1f]
The Rf value, the IR spectroscopic data, the NMR, and HRMS data are the
same as those for (S)-1f. The GC conditions was the same as for (S)-1f. The retention
25
time was 113.9 min. ½aꢄD ¼ þ35:9 (88% e.e., THF, c ¼ 0.2), lit. [a]D ¼ þ40.2.[24]
Acyl Donor Screening for Novozym 435–Catalyzed Acylation
Acyl donor screening was performed using racemic N-methyl-5-hydroxy-
decanamide (rac-2a) (0.2 g, 1.0 mmol), Novozym 435 (0.4 g), acyl donor (2.0 mmol),
and solvent (20 ml) at room temperature. To produce d-decalactone (1a), 1a was
purified by flash chromatography on silica (eluent: n-hexane–AcOEt, 4:1, v=v), and
2a and 3a were continuously purified (eluent: n-hexane–AcOEt, 4:1. v=v).
General Procedure for Synthesis of (S)-d-Lactones with a
Combination Novozym 435–Catalyzed Acetylation and Mitsunobu
Reaction
4-Nitrobenzoic acid (0.2 g, 1.25 mmol), TPP (0.3 g, 1.25 mmol), and DIAD
(0.3 ml, 1.25 mmol) were added to a solution of a crude mixture of (R)-2a–f and
(S)-3a–f, which had been obtained by Novozym 435–catalyzed acetylation, in
benzene (5 ml) and stirred at room temperature. The benzene was removed under
vacuum, H2O was added, and the mixture was neutralized with Na2CO3. The aque-
ous phase was extracted with AcOEt. The combined organic phase was washed with
brine, dried over Na2SO4, and concentrated under reduced pressure. The crude
products were subjected to lactonization without purification.
Data for (S)-N-methyl-5-(4-nitrobenzoyl)oxydecanamide [(S)-4a]. Colorless
solid; mp 88–89 ꢀC; Rf 0.54 (eluent: AcOEt). IR (KBr): cmꢁ1 3315 (N-H), 3110, 3091
=
(Ar, C-H), 2952 (-CH3), 2929 (-CH2-), 2869 (-CH3), 2851 (-CH2-), 1722 (O-C O),
=
1626 (H-N-C O), 1608 (H-N-C O), 1530 (N O), 1490, 1458 (Ar, C C), 1348
=
=
=
1
(O-C O), 1281 (N O), 873 (C-N), 718 (Ar, C C). H NMR (500 MHz, CDCl3):
=
=
=
d 0.87 (t, J ¼ 6.9 Hz, 3H, CH2CH3), 1.28–1.40 (m, 6H, CH2 ꢂ 3), 1.62–1.80 (m,
=
6H, CH2 ꢂ 3), 2.15–2.27 (m, 2H, NHC OCH2), 2.80 (d, J ¼ 5.0 Hz, 3H, NHCH3),
5.14–5.20 (m, 1H, CH2CHCH2), 5.53 (br, 1H, NH), 8.19–8.22 (m, 2H, Ar),
8.27–8.31 (m, 2H, Ar). 13C NMR (126 MHz, CDCl3): d 13.9 (CH2CH3), 21.4
(CH2), 22.4 (CH2), 25.0 (CH2), 26.2 (CH2), 31.6 (CH2), 33.6 (CH2), 33.9 (CH2),
=
=
36.0 (NHC OCH2), 75.8 (CH2CHCH2), 123.5 (Ar), 130.6 (C OAr), 136.0

702
Y. SHIMOTORI, M. AOYAMA AND T. MIYAKOSHI
=
=
=
(C OAr), 150.4 (ArNO2), 164.5 (OC O), 172.9 (NHC O). HRMS (ESI) calcd. for
C18H27N2O5 (M þ H)þ, 351.1920; found: (M þ H)þ, 351.1924.
Data for (S)-N-methyl-5-(4-nitrobenzoyl)oxyundecanamide [ꢁ(S1 )-4b].
Colorless solid; mp 97–98 ꢀC; Rf 0.51 (eluent: AcOEt). IR (KBr): cm
(N-H), 3110, 3091 (Ar, C-H), 2956 (-CH3), 2929 (-CH2-), 2873 (-CH3), 2858 (-CH2-),
3315
=
=
=
=
1722 (O-C O), 1637 (H-N-C O), 1608 (H-N-C O), 1529 (N O), 1490, 1458 (Ar,
=
C C), 1349 (O-C O), 1279 (N O), 873 (C-N), 717 (Ar, C C). 1H NMR
=
=
=
(500 MHz, CDCl3): d 0.86 (t, J ¼ 6.9 Hz, 3H, CH2CH3), 1.26–1.39 (m, 8H, CH2 ꢂ 4),
=
1.62–1.80 (m, 6H, CH2 ꢂ 3), 2.15–2.27 (m, 2H, NHC OCH2), 2.80 (d, J ¼ 4.6 Hz, 3H,
NHCH3), 5.14–5.20 (m, 1H, CH2CHCH2), 5.51 (br, 1H, NH), 8.19–8.22 (m, 2H, Ar),
8.27–8.31 (m, 2H, Ar). 13C NMR (126 MHz, CDCl3): d 14.0 (CH2CH3), 21.4 (CH2),
22.5 (CH2), 25.3 (CH2), 26.3 (CH2), 29.1 (CH2), 31.6 (CH2), 33.6 (CH2), 34.0 (CH2),
=
36.0 (NHC OCH2), 75.8 (CH2CHCH2), 123.5 (Ar), 130.6 (C OAr), 136.0 (Ar),
=
=
=
150.4 (ArNO2), 164.5 (OC O), 172.9 (NHC O). HRMS (ESI) calcd. for
C19H29N2O5 (M þ H)þ, 365.2076; found: (M þ H)þ, 365.2074.
Data for (S)-N-methyl-5-(4-nitrobenzoyl)oxydodecanamide [(S)-4c].
Colorless solid; mp 96–97 ꢀC; Rf 0.58 (eluent: AcOEt). IR (KBr): cmꢁ1 3315
(N-H), 3110, 3092 (Ar, C-H), 2947 (-CH3), 2929 (-CH2-), 2868 (-CH3), 2858
=
=
=
=
(-CH2-), 1722 (O-C O), 1637 (H-N-C O), 1608 (H-N-C O), 1529 (N O), 1491,
=
1458 (Ar, C C), 1349 (O-C O), 1282 (N O), 873 (C-N), 718 (Ar, C C). 1H
=
=
=
NMR (500 MHz, CDCl3): d 0.86 (t, J ¼ 6.9 Hz, 3H, CH2CH3), 1.25–1.40 (m, 10H,
=
CH2 ꢂ 5), 1.62–1.80 (m, 6H, CH2 ꢂ 3), 2.15–2.27 (m, 2H, NHC OCH2), 2.80 (d,
J ¼ 4.6 Hz, 3H, NHCH3), 5.14–5.20 (m, 1H, CH2CHCH2), 5.50 (br, 1H, NH),
8.19–8.22 (m, 2H, Ar), 8.27–8.31 (m, 2H, Ar). 13C NMR (126 MHz, CDCl3): d
14.0 (CH2CH3), 21.4 (CH2), 22.6 (CH2), 25.3 (CH2), 26.3 (CH2), 29.1 (CH2), 29.4
=
(CH2), 31.7 (CH2), 33.6 (CH2), 34.0 (CH2), 36.0 (NHC OCH2), 75.8 (CH2CHCH2),
=
=
123.5 (Ar), 130.7 (C OAr), 136.0 (Ar), 150.5 (ArNO2), 164.5 (OC O), 172.9
=
(M þ H)þ, 379.2235.
(NHC O). HRMS (ESI) calcd. for C20H31N2O5 (M þ H)þ, 379.2233; found:
Data for (S)-N-methyl-5-(4-nitrobenzoyl)oxytridecanamide [ꢁ(S1 )-4d].
Colorless solid; mp 85–86 ꢀC; Rf 0.60 (eluent: AcOEt). IR (KBr): cm
(N-H), 3109, 3091 (Ar, C-H), 2952 (-CH3), 2928 (-CH2-), 2871 (-CH3), 2855
3317
=
=
=
=
(-CH2-), 1723 (O-C O), 1638 (H-N-C O), 1608 (H-N-C O), 1530 (N O), 1491,
=
=
=
=
1458 (Ar, C C), 1349 (O-C O), 1281 (N O), 868 (C-N), 718 (Ar, C C).
1H NMR (500 MHz, CDCl3): d 0.86 (t, J ¼ 6.9 Hz, 3H, CH2CH3), 1.24–1.39 (m,
=
12H, CH2 ꢂ 6), 1.62–1.80 (m, 6H, CH2 ꢂ 3), 2.15–2.27 (m, 2H, NHC OCH2),
2.80 (d, J ¼ 4.6 Hz, 3H, NHCH3), 5.14–5.20 (m, 1H, CH2CHCH2), 5.50 (br, 1H,
NH), 8.19–8.22 (m, 2H, Ar), 8.27–8.31 (m, 2H, Ar). 13C NMR (126 MHz, CDCl3):
d 14.1 (CH2CH3), 21.4 (CH2), 22.6 (CH2), 25.3 (CH2), 26.3 (CH2), 27.1 (CH2), 29.2
=
(CH2), 29.4 (CH2), 31.8 (CH2), 33.6 (CH2), 34.0 (CH2), 36.0 (NHC OCH2), 75.8
=
(CH2CHCH2), 123.5 (Ar), 130.7 (C OAr), 136.0 (Ar), 150.5 (ArNO2), 164.5
=
(OC O), 172.9 (NHC O). HRMS (ESI) calcd. for C21H33N2O5 (M þ H)þ,
=
393.2389; found: (M þ H)þ, 393.2391.
Data for (S)-N-methyl-5-(4-nitrobenzoyl)oxytetradecanamide [ꢁ(S1 )-4e].
Colorless solid; mp 89–90 ꢀC; Rf 0.61 (eluent: AcOEt). IR (KBr): cm
3315

ENANTIOSELECTIVE SYNTHESIS OF d-LACTONES
703
(N-H), 3111, 3093 (Ar, C-H), 2949 (-CH3), 2927 (-CH2-), 2867 (-CH3), 2853 (-CH2-),
=
=
=
=
1723 (O-C O), 1637 (H-N-C O), 1608 (H-N-C O), 1530 (N O), 1490, 1457 (Ar,
=
C C), 1348 (O-C O), 1280 (N O), 873 (C-N), 717 (Ar, C C). 1H NMR
=
=
=
(500 MHz, CDCl3): d 0.87 (t, J ¼ 6.9 Hz, 3H, CH2CH3), 1.24–1.39 (m, 14H,
=
CH2 ꢂ 7), 1.63–1.80 (m, 6H, CH2 ꢂ 3), 2.15–2.27 (m, 2H, NHC OCH2), 2.80 (d,
J ¼ 5.0 Hz, 3H, NHCH3), 5.14–5.20 (m, 1H, CH2CHCH2), 5.49 (br, 1H, NH),
8.19–8.22 (m, 2H, Ar), 8.27–8.31 (m, 2H, Ar). 13C NMR (126 MHz, CDCl3): d
14.1 (CH2CH3), 21.4 (CH2), 22.6 (CH2), 25.3 (CH2), 26.3 (CH2), 29.2 (CH2), 29.4
=
(CH2), 29.5 (CH2), 31.8 (CH2), 33.6 (CH2), 34.0 (CH2), 36.0 (NHC OCH2), 75.8
=
(CH2CHCH2), 123.5 (Ar), 130.7 (C OAr), 136.0 (Ar), 150.5 (ArNO2), 164.5
=
(OC O), 172.9 (NHC O). HRMS (ESI) calcd. for C22H35N2O5 (M þ H)þ,
=
407.2546; found: (M þ H)þ, 407.2541.
Data for (S)-N-methyl-5-(4-nitrobenzoyl)oxyhexadecanamide [(S)-4f].
Colorless solid; mp 88–89 ꢀC; Rf 0.60 (eluent: AcOEt). IR (KBr): cmꢁ1 3314
(N-H), 3110, 3092 (Ar, C-H), 2950 (-CH3), 2923 (-CH2-), 2869 (-CH3), 2851
=
=
=
=
(-CH2-), 1723 (O-C O), 1637 (H-N-C O), 1608 (H-N-C O), 1530 (N O), 1490,
=
1467 (Ar, C C), 1348 (O-C O), 1280 (N O), 873 (C-N), 718 (Ar, C C). 1H
=
=
=
NMR (500 MHz, CDCl3): d 0.87 (t, J ¼ 6.9 Hz, 3H, CH2CH3), 1.24–1.37 (m, 18H,
=
CH2 ꢂ 9), 1.66–1.80 (m, 6H, CH2 ꢂ 3), 2.14–2.27 (m, 2H, NHC OCH2), 2.80 (d,
J ¼ 4.6 Hz, 3H, NHCH3), 5.14–5.20 (m, 1H, CH2CHCH2), 5.43 (br, 1H, NH),
8.19–8.22 (m, 2H, Ar), 8.27–8.31 (m, 2H, Ar). 13C NMR (126 MHz, CDCl3): d
14.1 (CH2CH3), 21.4 (CH2), 22.7 (CH2), 25.3 (CH2), 26.3 (NHCH3), 29.3 (CH2),
29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 31.9 (CH2), 33.6 (CH2), 34.0 (CH2), 36.0
=
=
(NHC OCH2), 75.9 (CH2CHCH2), 123.5 (Ar), 130.7 (C OAr), 136.0 (Ar), 150.5
=
=
(ArNO2), 164.5 (OC O), 172.9 (NHC O). HRMS (ESI) calcd. for C24H39N2O5
(M þ H)þ, 435.2859; found: (M þ H)þ, 435.2863.
ACKNOWLEDGMENTS
We are grateful to Novozymes A=S for the generous gift of Novozym 435.
A generous gift of d-hexadecalactone from Soda Aromatic Co., Ltd., is also
acknowledged.
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