Combination of novozym 435-catalyzed hydrolysis and mitsunobu reaction for production of (r)γ-lactones

Article abstract of DOI:10.1080/00397910903134618

Chiral-lactones of both enantiomers were synthesized with more than 90% optical purities. The key step was Novozym 435-catalyzed hydrolysis of racemic N-benzyl-4-acetoxyalkylamides. Additionally, because (R)-γ-lactones are predominant in apricot, mango, peach, passion fruit, and strawberry, synthesis was attempted using only one enantiomer selectively. The (R)-enantimer was synthesized with more than 80% total yield and more than 90% optical purity by a combination of Novozym 435-catalyzed hydrolysis and the Mitsunobu reaction. Copyright

Full text of DOI:10.1080/00397910903134618

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Combination of Novozym 435–Catalyzed
Hydrolysis and Mitsunobu Reaction for
Production of (R)-γ-Lactones
Yasutaka Shimotori a & Tetsuo Miyakoshi a
a Department of Applied Chemistry, Meiji University, Tamaku,
Kawasakishi, Japan
Published online: 06 May 2010.
To cite this article: Yasutaka Shimotori & Tetsuo Miyakoshi (2010) Combination of Novozym
435–Catalyzed Hydrolysis and Mitsunobu Reaction for Production of (R)-γ-Lactones, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:11, 1607-1613, DOI: 10.1080/00397910903134618
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Synthetic Communications1, 40: 1607–1613, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903134618
COMBINATION OF NOVOZYM 435–CATALYZED
HYDROLYSIS AND MITSUNOBU REACTION FOR
PRODUCTION OF (R)-c-LACTONES
Yasutaka Shimotori and Tetsuo Miyakoshi
Department of Applied Chemistry, Meiji University, Tamaku,
Kawasakishi, Japan
Chiral c-lactones of both enantiomers were synthesized with more than 90% optical
purities. The key step was Novozym 435–catalyzed hydrolysis of racemic N-benzyl-4-
acetoxyalkylamides. Additionally, because (R)-c-lactones are predominant in apricot,
mango, peach, passion fruit, and strawberry, synthesis was attempted using only one
enantiomer selectively. The (R)-enantimer was synthesized with more than 80% total yield
and more than 90% optical purity by a combination of Novozym 435–catalyzed hydrolysis
and the Mitsunobu reaction.
Keywords: Enzymatic resolution; Mitsunobu reaction; optical purity; (R)-c-lactone
INTRODUCTION
Optically active c-lactones are important heterocyclic aliphatic compounds.[1]
They are versatile building blocks for the synthesis of bioactive molecules and are
also widespread in nature, especially as pheromones and aromatic components of
many fruits and other natural products.[2,3] Therefore, we attempted to synthesize
optically active c- and d-lactones using a lipase catalyst.[4–6] Recently, we reported
synthesis of (S)-c-lactones with a combination of lipase-catalyzed resolution and
the Mitsunobu reaction.[7] This system efficiently produces only one enantiomer of
c-lactones. However, Mosandl and Guenther reported that the (R)-enantiomer of
c-lactones has a stronger odor in most cases.[8] Additionally, the (R)-enantiomer is
often more plentiful than the (S)-enantiomer in natural products.[9] Previously, we
reported synthesis of optically active c-lactones with Novozym 435–catalyzed
hydrolysis of rac-N-methyl-4-acetoxyalkylamides.[5] It has been shown that
Novozym 435 selectively hydrolyzes the (S)-enantiomer. Therefore, we attempted
to synthesize the (R)-enantiomer by a combination of Novozym 435–catalyzed
hydrolysis and the Mitsunobu reaction.
Received April 9, 2009.
Address correspondence to Yasutaka Shimotori, Department of Applied Chemistry, Meiji
University, 1-1-1 Higashimita, Tamaku, Kawasakishi, Japan. E-mail: yasu@isc.meiji.ac.jp
1607

1608
Y. SHIMOTORI AND T. MIYAKOSHI
RESULTS AND DISCUSSION
Novozym 435–Catalyzed Hydrolysis
We recently reported a synthesis of (S)-c-lactones [(S)-1] with a combination of
Novozym 435–catalyzed resolution and the Mitsunobu reaction.[7] When the acety-
lation of racemic N-benzyl-4-hydroxyalkylamides (rac-3) were performed using
Novozym 435, predominantly (S)-enantiomers [(S)-3] were acetylated to afford
(R)-N-benzyl-4-acetoxyalkylamides [(R)-2].[4] (R)-N-Benzyl-4-hydroxyalkylamides
[(R)-3], which are secondary alcohols, were inverted to (S)-enantiomers [(S)-4] by
the Mitsunobu reaction, and the subsequent lactonization of the reaction mixture
afforded (S)-1. Therefore, we attempted to obtain a reaction mixture of (R)-2 and
(S)-3 to synthesize (R)-1 with a combination of a lipase-catalyzed resolution and
the Mitsunobu reaction. We previously performed Novozym 435–catalyzed hydro-
lysis of racemic N-methyl-4-acetoxyalkylamides in diethyl ether at 40 ꢀC.[5] (S)-
Enantiomers were predominantly hydrolyzed to afford (S)-N-methyl-4-hydroxy-
alkylamides. After separation of the reaction mixture of (R)-N-methyl-4-acetoxyalk-
ylamides and (S)-N-methyl-4-hydroxyalkylamides, lactonization afforded (R)-1 in
the range of 76–88% ee and (S)-1 with more than 97% ee. Therefore, Novozym
435–catalyzed hydrolysis of rac-2e was performed under the same conditions
(Scheme 1). As the result, predominantly (S)-2e was hydrolyzed, and the lactoniza-
tion of both enantiomers after separation afforded (S)-1e with 90% ee and (R)-1e
with >99% ee (Table 1, entry 5). This indicates that the substrate specificity of
Novozym 435 to rac-2e was greater than that to racemic N-methyl-4-acetoxydodeca-
namide. It is assumed that maximum Novozym 435 activity occurs at 60 ꢀC, and the
hydrolysis of rac-2e was performed at 60 ꢀC by changing diethyl ether to diisopropyl
ether to increase the optical purity. After separation of (R)-2e and (S)-3e and lacto-
nization, (R)-1e and (S)-1e were obtained with 95% ee and >99% ee, respectively
(Table 1, entry 6). The optical purity of (S)-1e was the same as before, but that of
(R)-1e was increased from 90% ee to 95% ee. Additionally, the reaction time required
to reach 50% conversion was shortened from 36 h (Table 1, entry 5) to 24 h (Table 1,
entry 6). The optimum conditions of Novozym 435–catalyzed hydrolysis of rac-2
were determined to be these conditions, which used diisopropyl ether as the solvent
at 60 ꢀC, and the conditions were applied to various substrates. In this article, six
kinds of c-lactones (c-octa-, nona-, deca-, undeca-, dodeca-, and jasmolactone) are
described. Novozym 435–catalzed hydrolysis and lactonization were performed on
Scheme 1. Optical resolution of rac-2 by Novozym 435–catalyzed hydrolysis.

PRODUCTION OF (R)-c-LACTONES
1609
Table 1. Novozym 435–catalyzed resolution of rac-2a
Yield (%)
Enantiomeric excess (% ee.)b
Entry Substrate
R
Solvent Time (h) (R)-2 (S)-3
(R)-1
(S)-1
Ec
1
2
3
4
5
6
7
rac-2a
rac-2b
rac-2c
rac-2d
rac-2e
n-C4H9
n-C5H11
n-C6H13
n-C7H15
n-C8H17
n-C8H17
iPr2O
iPr2O
iPr2O
iPr2O
Et2O
iPr2O
30
30
27
24
36
24
24
51
52
51
51
44
51
47
45
47
45
47
51
47
50
93
93
96
99
108
145
89
92
94
95
>99
>99
>99
>99
243
141
294
>500
90
95
rac-2f
cis-3-C6H11 iPr2O
>99
aSubstrate: 1.0 mmol, MeOH: 3.0 mmol, Novozym 435: 0.4 g, Pr2O: 20 ml, 60 ꢀC.
bDetermined by GC using Chirasil-Dex CB column.
cE ¼ln[1 ꢁ c (1 þ eep)]=ln[1 ꢁ c (1 ꢁ eep)], where c ¼ ees=(ees þ eep), ees ¼ enantiomeric excess of (R)-1,
eep ¼ enantiomeric excess of (S)-1.
all substrates (rac-2), and the results are shown in Table 1. (S)-1 and (R)-1 were
synthesized with >95% ee and >92% ee, respectively. The E-value exceeded 100 in
all substrates except rac-2c, but (R)-1c and (S)-1c had good optical purity, showing
that Novozym 435 had excellent substrate selectivity. The short side-chain substrates
required longer reaction time to reach 50% conversion than the long side-chain sub-
strates. Moreover, the enantiomeric excess of long side-chain c-lactones was greater
than that of short side-chain c-lactones. Therefore, the substrate specificity of
Novozym 435 to long side-chain substrate was greater than that to short side-chain
substrates. The subsequent Mitsunobu reaction was performed with a reaction
mixture that was obtained under these conditions.
Combination of Novozym 435–Catalyzed Hydrolysis and
Mitsunobu Reaction
The Mitsunobu reaction was performed with the mixture of (R)-N-benzyl-4-
acetoxyalkylamides [(R)-2] and (S)-N-benzyl-4-hydroxyalkylamides [(S)-3], which
was prepared from rac-N-benzyl-4-acetoxyalkylamides (rac-2) by Novozym 435–
catalyzed hydrolysis. The optimum Mitsunobu conditions for the mixture of 2 and
Scheme 2. Synthesis of (R)-1 with Novozym 435–catalyzed hydrolysis and Mitsunobu reaction.

1610
Y. SHIMOTORI AND T. MIYAKOSHI
Table 2. Synthesis of (R)-1 by Novozym 435–catalyzed hydrolysisa and Mitsunobu reactionb
Enantiomeric
Time Yield (%)c excess (% e.e.)c
Entry Substrate
R
Nucleophilic agent
4-Nitrobenzoic acid
3,5-dimethoxybenzoic acid THF
Solvent (h)
of (R)-1
of (R)-1
1
2
3
4
5
6
7
8
rac-2a
rac-2b
n-C4H9
Benzene 24
77
82
91
92
92
98
92
90
89
92
24
n-C5H11 4-Nitrobenzoic acid
Benzene 24
24
89
92
3,5-Dimethoxybenzoic acid THF
rac-2c
rac-2d
rac-2e
rac-2f
n-C6H13
92
92
n-C7H15 4-Nitrobenzoic acid
n-C8H17
cis-3-C6H11
Benzene 48
96
>99
i
aSubstrate: 1.0 mmol, MeOH: 3.0 mmol, Novozym 435: 0.4 g, Pr2O: 20 ml, 60 ꢀC.
bNucleophile: 1.0 mmol, PPh3: 1.0 mmol, DIAD: 1.0 mmol, solvent: 5 ml, rt.
cTotal yield based on rac-2.
dDetermined by GC using Chirasil-Dex CB column.
3 were evaluated previously, and the conditions were the use of 4-nitrobenzoic acid
as the nucleophilic agent and benzene as the solvent.[7] The conditions were also
applied to the synthesis of (R)-c-lactones [(R)-1] (Scheme 2). The results are shown
in Table 2. The yield of (R)-1 was calculated from rac-2. (R)-1a was synthesized with
a somewhat lesser yield of 77% (Table 2, entry 1), but all other (R)-1b–f were synthe-
sized with more than 90% yield (Table 2, entries 3 and 5–8). The optical purities of
(R)-1a and (R)-1b were 89% ee (Table 2, entries 1 and 3), but all other (R)-1c–f
optical purities were more than 99% ee (Table 2, entries 5–8). The optical purities
of all (R)-1 except (R)-1f produced via the Mitsunobu reaction were about 2% less
than that of the average of both enantiomers of (S)-1 and (R)-1 in Table 1. Accord-
ing to the results of thin-layer chromatography (TLC), (S)-3 was completely reactive.
It was thought that the optical purity was decreased because the estefirication of
(S)-3 and 4-nitrobenzoic acid, which acted as the carboxylic acid reagent and
acid catalyst, respectively, did not accompany the progression of steric inversion.
(R)-1a and (R)-1b may have low optical purities because this degree was somewhat
more than the other (R)-1. The Mitsunobu reaction was performed to improve the
optical purities of (R)-1a and (R)-1b under the Mitsunobu conditions that provided
the best optical purity using 3,5-dimethoxybenzoic acid as the nucleophilic agent and
tetrahydrofuran (THF) as the solvent, under conditions that were reported pre-
viously.[7] As a result, the optical purity was increased to 92% ee, which was 3% more
than the use of 4-nitrobenzoic acid and benzene, although there was no big difference
in yield (Table 2, entries 2 and 4). In conclusion, (R)-1 was synthesized with more
than 80% yield and 90% ee with a combination of Novozym 435–catalyzed hydroly-
sis and the Mitsunobu reaction.
CONCLUSION
Chiral c-lactones of both enantiomers were synthesized with Novozym 435–
catalyzed hydrolysis. (S)- and (R)-enantiomers were synthesized with more than
95% and 90% optically purities, respectively. Novozym 435–catalyzed hydrolysis

PRODUCTION OF (R)-c-LACTONES
1611
of racemic N-benzyl-4-acetoxyalkylamides was performed efficiently with diidopro-
pyl ether as the solvent at 60 ꢀC within 36 h. Additionally, (R)-c-lactones were
synthesized successfully in the range of 82 to 98% total yield and 92 to >99% optical
purities by a combination of Novozym 435–catalyzed hydrolysis and the Mitsunobu
reaction. The Mitsunobu reaction for synthesis of (R)-nona- and -decalactone was
performed efficiently by the use of 3,5-dimethoxybenzoic acid as the nucleophilic
agent and tetrahydrofuran (THF) as the solvent, and the Mitsunobu reaction for
the synthesis of (R)-undeca-, (R)-dodeca-, and (R)-jasmolactone was performed
efficiently with the use of 4-nitrobenzoic acid and benzene.
EXPERIMENTAL
General
TLC was performed using silica gel F-254 on aluminum purchased from Merck
Ltd. (Darmstadt, Germany). Crude products were purified by column chromato-
graphy 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)–
1
IR-460-plus spectrometer from Jasco Corporation (Tokyo, Japan). H NMR and
13C NMR spectra were recorded in CDCl3 solution on a 500-MHz FT-NMR spec-
trometer (Jeol JNM-ECA 500 system). Chemical sifts are reported in parts per mil-
lion with respect to the internal tetramethylsilane (TMS). Coupling constants (J) are
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 ꢂ 0.25 mm I.D. ꢂ 0.25 mm film thickness, Varian, Walnut Creek, CA, USA).
The carrier gas was helium. c-Octalactone, c-nonalactone, c-decalactone, c-undeca-
lactone, c-dodecalactone, 4-nitrobenzoic acid, and 3,5-dimethoxybenzoic acid were
purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Cis-3-hexanol
was purchased from Soda Aromatic Co., Ltd. (Tokyo, Japan). Succinic anhydride
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, THF, and benzene were dried
before used.
Preparation of rac-N-Benzyl-4-acetoxyalkylamides (rac-2a–f)
Rac-N-Benzyl-4-acetoxyalkylamides (rac-2a–f) were prepared by adding acetic
anhydride (0.82 g, 8.0 mmol) and 4-dimethylaminopyridine (0.10 g, 0.8 mmol) to a
stirred solution of rac-N-benzyl-4-hydroxyalkylamides (4.0 mmol) in CH2Cl2
(25 ml) and stirring the mixture for 24 h. CH2Cl2 was evaporated, and the mixture
was extracted with AcOEt. The combined extracts were washed with brine and dried

1612
Y. SHIMOTORI AND T. MIYAKOSHI
over Na2SO4. After filtration, AcOEt was evaporated to afford rac-N-benzyl-4-
acetoxyalkylamides (rac-2a–f). The yields of rac-N-benzyl-4-acetoxyalkylamides
except rac-2f were more than 99%, and the rac-2f yield was 95%. The spectra data
were reported previously.[4,7] The preparation of rac-N-benzyl-4-hydroxyalkylamides
was previously reported.[4]
General Procedure for Novozym 435–Catalyzed Hydrolysis
Novozym 435 (0.4 g) was added to a solution of the appropriate rac-2a–f
(1.0 mmol) and MeOH (0.10 g, 3.0 mmol) in diisopropyl ether (20 ml), while stirring
at 60 ꢀC in a water bath. After stirring, the mixture was filtered, and the solvent was
evaporated. The crude product was purified by flash chromatography on silica and
AcOEt to afford the corresponding (R)-N-benzyl-4-acetoxyalkylamides [(R)-2a–f]
and (S)-N-benzyl-4-hydroxyalkylamides [(S)-3a–f]. Lactonization of both amides
[(R)-2a–f and (S)-3a–f] was performed by hydrolysis under alkaline conditions and
subsequent intraesterification under acidic conditions. The spectra data of 3a–d
and 1a–f were reported previously.[4,5]
General Procedure for Synthesis of (R)-c-Lactones with a
Combination of Novozym 435–Catalyzed Hydrolysis and
Mitsunobu Reaction
Triphenylphosphine (TPP) (0.26 g, 1.0 mmol), a nucleophilic agent (1.0 mmol),
and DIAD (0.21 ml, 1.0 ml) 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 hydrolysis in
THF or benzene (5 ml) and stirred at room temperature. 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 ꢂ 30 ml). The combined
organic phases were washed with brine and dried over Na2SO4, then concentrated
under reduced pressure. The crude products were subjected to lactonization without
purification. The spectral data of 5a–f and (R)-1a–f were reported previously.[4,5]
Data for N-Benzyl-4-(3,5-dimethoxybenzoyl)oxyoctanamide [(R)-4a]
Colorless oil; Rf 0.34 (eluent: n-hexane–AcOEt, 3:2, v=v). IR (NaCl): cmꢁ1
3297 (ꢁNꢁH), 3087, 3066, 3003 (Ar, ꢁCꢁH), 2956 (ꢁCH3), 2934 (ꢁCH2ꢁ), 2871
(ꢁCH3), 2862 (ꢁCH2ꢁ), 1714 (ꢁC¼O), 1648 (ꢁC(¼ O)ꢁNꢁH), 1598, 1496, 1456
1
(Ar, ꢁC¼Cꢁ), 1235, 1050 (ꢁCꢁOꢁCꢁ). H NMR (500 MHz, CDCl3): d 0.88 (t,
J ¼ 6.9 Hz, 3H, CH3), 1.34 (m, 4H, CH2 ꢂ 2), 1.63 (m ꢃ m, 2H, CH2), 2.06 (m, 2H,
CH2), 2.27 (m, 2H, CH2), 3.83 (s, 6H, OCH3 ꢂ 2), 4.38 (qd, J ¼ 14.9, 5.7 Hz, 2H,
CH2), 5.15 (m, 1H, CH), 5.95 (br, 1H, NH), 6.65 (t, J ¼ 2.3 Hz, 1H, CH), 7.18 (d,
J ¼ 2.3 Hz, 2H, CH ꢂ 2), 7.25 (m, 3H, CH ꢂ 3), 7.32 (m, 2H, CH ꢂ 2). 13C NMR
(126 MHz, CDCl3): d 13.9 (CH3), 22.5 (CH2), 27.4 (CH2), 30.3 (CH2), 32.8 (CH2),
34.2 (CH2), 43.6 (Ar-CH2), 55.6 (OCH3 ꢂ 2), 74.7 (CH), 105.4 (Ar), 107.3 (Ar),
127.4 (Ar), 127.8 (Ar), 128.6 (Ar), 132.2 (Ar), 138.2 (Ar), 160.6 (Ar), 166.4
(C¼O), 172.0 (C¼O). HRMS (ESI) calcd. for C24H32NO5 (M þ H)þ, 414.2280;
found (M þ H)þ, 414.2287.

PRODUCTION OF (R)-c-LACTONES
1613
Data for N-Benzyl-4-(3,5-dimethoxybenzoyl)oxynonanamide [(R)-4b]
Colorless oil; Rf 0.39 (eluent: n-hexane–AcOEt, 3:2, v=v). IR (NaCl): cmꢁ1
3297 (N-H), 3087, 3065, 3003 (Ar, –C–H), 2955 (–CH3), 2932, 2859 (–CH2–), 1715
(–C¼O), 1648 (–C(¼O)–N–H), 1597, 1496, 1456 (Ar, –C¼C–), 1236, 1051 (–C–O–
1
C–). H NMR (500 MHz, CDCl3): d 0.87 (t, J ¼ 6.9 Hz, 3H, CH3), 1.34 (m, 6H,
CH2 ꢂ 3), 1.63 (m ꢃ m, 2H, CH2), 2.06 (m, 2H, CH2), 2.27 (m, 2H, CH2), 3.83 (s,
6H, OCH3 ꢂ 2), 4.38 (qd, J ¼ 14.9, 5.7 Hz, 2H, CH2), 5.15 (m, 1H, CH), 5.98 (br,
1H, NH), 6.64 (t, J ¼ 2.3 Hz, 1H, CH), 7.17 (d, J ¼ 2.3 Hz, 2H, CH ꢂ 2), 7.25 (m,
3H, CH ꢂ 2), 7.31 (m, 2H, CH ꢂ 2).13C NMR (126 MHz, CDCl3): d 14.0 (CH3),
22.5 (CH2), 24.9 (CH2), 30.3 (CH2), 31.6 (CH2), 32.7 (CH2), 34.5 (CH2), 43.6 (Ar-
CH2), 55.6 (OCH3 ꢂ 2), 74.7 (CH), 105.4 (Ar), 107.2 (Ar), 127.4 (Ar), 127.8 (Ar),
128.6 (Ar), 132.2 (Ar), 138.2 (Ar), 160.6 (Ar), 166.3 (C¼O), 172.0 (C¼O). HRMS
(ESI) calcd. for C25H34NO5 (M þ H)þ, 428.2437; found (M þ H)þ, 428.2447.
ACKNOWLEDGMENTS
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 of Meiji
University) is gratefully acknowledged.
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