Highly Enantioselective Synthesis of Both Enantiomers of γ-Substituted Butenolides by Bakers' Yeast Reduction and Lipase-Catalyzed Hydrolysis. Total Synthesis of (3AS,6aS)-Ethisolide, Whisky Lactone, and (-)-Avenaciolide

Article abstract of DOI:10.1021/jo970045r

Reduction of 3-chloro-4-oxoalkanoates 5 with bakers' yeast gave (4S)-3-chloro-4-hydroxyalkanoates, which were hydrolyzed and dehydrochlorinated to give (γS)-alkylbutenolides with >96% ee. Reduction of 5 with NaBH₄ gave syn-3-chloro-4-hydroxyalkanoate 6. Asymmetric hydrolysis of syn-4-chloro-3-hydroxyalkanoate (±)-10 with lipase afforded (3R,4R)-6 and (3S,4S)-10 with high optical purities. Hydrolysis and dehydrochlorination of (3R,4R)-6 gave (γA)-alkylbutenolides with >85% ee. Total syntheses of (3aS,6aS)-ethisolide, whisky lactone, and (-)-avenaciolide from these butenolides are described.

Full text of DOI:10.1021/jo970045r

1102
J . Org. Chem. 1998, 63, 1102-1108
High ly En a n tioselective Syn th esis of Both En a n tiom er s of
γ-Su bstitu ted Bu ten olid es by Ba k er s’ Yea st Red u ction a n d
Lip a se-Ca ta lyzed Hyd r olysis. Tota l Syn th esis of
(3AS,6a S)-Eth isolid e, Wh isk y La cton e, a n d (-)-Aven a ciolid e
Sadao Tsuboi*
Department of Environmental Chemistry and Materials, Okayama University, Tsushima,
Okayama 700, J apan
J un-ichi Sakamoto,† Hiroshi Yamashita, Takashi Sakai, and Masanori Utaka
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushima,
Okayama 700, J apan
Received August 15, 1997
Reduction of 3-chloro-4-oxoalkanoates 5 with bakers’ yeast gave (4S)-3-chloro-4-hydroxyalkanoates,
which were hydrolyzed and dehydrochlorinated to give (γS)-alkylbutenolides with >96% ee.
Reduction of 5 with NaBH4 gave syn-3-chloro-4-hydroxyalkanoate 6. Asymmetric hydrolysis of
syn-4-chloro-3-hydroxyalkanoate (()-10 with lipase afforded (3R,4R)-6 and (3S,4S)-10 with high
optical purities. Hydrolysis and dehydrochlorination of (3R,4R)-6 gave (γR)-alkylbutenolides with
>85% ee. Total syntheses of (3aS,6aS)-ethisolide, whisky lactone, and (-)-avenaciolide from these
butenolides are described.
An optically active butenolide is an important and
and (-)-avenaciolide (4)10 have been established from
optically active butenolides obtained by the present
reactions.
versatile compound for the synthesis of naturally occur-
ring compounds containing a γ-butyrolactone ring. Many
papers on the syntheses of optically active butenolides
have been reported. For example, γ-methylbutenolide (â-
angelicalactone) has been synthesized via the reduction
of sulfur compounds with bakers’ yeast1,2 and also via
several steps from D-ribonolactone3,4 and (+)-L-tartaric
acid.5 Syntheses by the use of microbes and pig liver
esterase are also reported.6 In this paper, we wish to
report a convenient and highly enantioselective synthesis
of both enantiomers of optically active γ-substituted
butenolides by using bakers’ yeast reduction and lipase-
catalyzed hydrolysis.7 Furthermore, syntheses of some
natural products such as (3aS,6aS)-ethisolide (2) (a
diastereoisomer of ethisolide (1)),8 whisky lactone (3),9
† Present address: Sumitomo Seika Chemicals Co. LTD., 346-1
Miyanishi, Harima-cho, Kako-gun, Hyogo Pref. 675-01, J apan.
(1) Kozikowski, P. A.; Mugrage, B. B.; Li, C. S.; Felder, L. Tetrahe-
dron Lett. 1986, 27, 4817.
(2) Tanikaga, R.; Hosoya, K.; Kaji, A. Synthesis 1987, 389.
(3) Chen, S. Y.; J oullie, M. M. J . Org. Chem. 1984, 49, 2168.
(4) Camps, C.; Cardellach, J .; Corbera, J .; Font, J .; Ortuno, R. M.;
Ponsati, O. Tetrahedron 1983, 39, 395.
(5) Ortuno, R. M.; Alonso, D.; Font, J . Tetrahedron Lett. 1986, 27,
1079.
(6) (a) Karube, I.; Takahashi, O.; Suzuki, S.; Furuhashi, K.; Takaki,
M. Abstr. 48th Annual Meeting Chem. Soc. J pn. 1984, II, 1J 08. (b)
Bloch, R.; Gilbert, L. J . Org. Chem. 1987, 52, 4603.
(7) Preliminary communication: (a) Tsuboi, S.; Sakamoto, J .; Sakai,
T.; Utaka, M. Synlett 1991, 867. (b) Tsuboi, S.; Sakamoto, J .; Sakai,
T.; Utaka, M. Chem. Lett. 1989, 1427.
(8) (a) Aldridge, D. C.; Turner, W. B. J . Chem. Soc. C 1971, 2431.
(b) Anderson, R. C.; Fraser-Reid, B. Tetrahedron Lett. 1977, 18, 2865.
(c) Burke, S. D.; Pacofsky, G. J . Tetrahedron Lett. 1986, 27, 445. (d)
Takei, H.; Fukuda, Y.; Taguchi, T.; Kawara, T.; Mizutani, H.; Mukuta,
T. Chem. Lett. 1980, 1311.
(9) (a) Gunther, C.; Masandle, A. Liebigs Ann. Chem. 1986, 2112.
(b) Otsuka, K.; Zenibayashi, Y.; Ito, M.; Totsuka, A. Agric. Biol. Chem.
1974, 38, 485. (c) Tsukasa, H. Koryo 1988, 158, 98. (d) Obata, S. J .
Pharm. Soc. J pn. 1953, 73, 1298. (e) Tsukasa, H. Yukagaku 1987,
36, 51. (f) Miyakoshi, T.; Saito, S. Ibid. 1983, 22, 31. (g) Marino, J .
P.; Pradilla, R. F. Tetrahedron Lett. 1985, 26, 5381.
Although there are many methods for the preparation
of chiral building blocks, practical and convenient meth-
ods are quite restricted. Among them, the asymmetric
reduction with bakers’ yeast (Saccharomyces cerevisiae)
is quite practical and experimentally simple and often
provides chiral compounds with high optical purity.11 For
a decade, we have been studying the asymmetric reduc-
tion of ketones and olefins with bakers’ yeast.12 Recently,
(10) Brookes, D.; Tidd, B. K.; Turner, W. B. J . Chem. Soc. 1963,
5385.
(11) Reviews: (a) Mori, K.; Sugai, T. J . Synth. Org. Chem. 1983,
41, 1044. (b) Ohta, H.; Iriuchijima, S. Kagaku no Ryoiki 1979, 33, 209.
(c) J ones, J . B. Tetrahedron 1986, 42, 3351. (d) Utaka, M.; Sakai, T.;
Tsuboi, S. J . Synth. Org. Chem. 1991, 49, 647. (e) Csuk, R.; Gla¨nzer,
B. I. Chem. Rev. 1991, 91, 49.
(12) (a) Tsuboi, S.; Nishiyama, E.; Utaka, M.; Takeda, A. Tetrahe-
dron Lett. 1986, 27, 1915. (b) Tsuboi, S.; Nishiyama, E.; Furutani,
H.; Utaka, M.; Takeda, A. J . Org. Chem. 1987, 52, 1359. (c) Utaka,
M.; Konishi, S.; Okubo, T.; Tsuboi, S.; Takeda, A. Tetrahedron Lett.
1987, 28, 1447.
S0022-3263(97)00045-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/04/1998

Synthesis of Enantiomers of γ-Substituted Butenolides
J . Org. Chem., Vol. 63, No. 4, 1998 1103
Ta ble 2. Syn th esis of (γS)-Bu ten olid es 7
Ta ble 1. Red u ction of Ch lor o Keton e 5 w ith Ba k er s’
Yea st
OH
Cl
O
OH
19% HCl
R S
CO2R′
bakers' yeast
25 °C, 1 day
R
R
O
O
+
R
CO2R′
R
CO2R′
R
O
O
Cl
(4S)-6
O
Cl
Cl
(4S)-6
5
7
Et3N
S
O
25 °C, 2 days
5
(4S)-6
7
reaction
(S)-7
entry
R
R′
time (day) yield (%) [R]D (CHCl3) yield (%)
a
b
c
CH3
C2H5
C2H5
C2H5
CH3
C2H5
2
4
3
4
7
75
41
41
53
22
0
+10.1
+11.1
+10.4
+8.71
+5.78
0
10
0
0
4
(S-7
[R]D (CHCl3)
yield
entry
R
R′ (two steps, %)
eea (%)
d
e
n-C4H9 C2H5
n-C8H17 CH3
a
b
c
d
[e
Me
Et
Et
Et
Me
Et
Et
56
66
69
73
11
+110.6 (c 1.23)
+95.3 (c 3.61)
+103 (c 2.71)
+92.3 (c 3.39)
+40.7 (c 1.18)
99b
>96
15
11
>96
we reported asymmetric reduction of R-chlorinated ke-
tones with bakers’ yeast.7a,13 The present paper describes
the synthesis of optically active butenolides 7 starting
from the reduction of 3-chloro-4-oxoalkanoates 5 with
bakers’ yeast. Compound 5 was prepared via 3 steps
from tert-butyl 3-oxoalkanoate (8) as shown below. The
n-C4H9
n-C8H17 Me
>96
>59]c
a
1
Optical purity was determined by H NMR analysis of CCl4-
CDCl3 (3/1) solution in the presence of Eu(hfc)3, unless otherwise
noticed. Determined by GC fitted with chiral column. c These are
b
data of the sample obtained in Table 1.
in low yields accompanied with (γS)-alkylbutenolides,
which were simultaneously produced via hydrolysis,
lactonization, and dehydrochlorination reactions.
Hydrolysis of (4S)-6 with 19% hydrochloric acid at 25
°C for 24 h and the subsequent dehydrochlorination with
an excess amount of triethylamine gave optically pure
(γS)-alkylbutenolides (7) in good yields, as shown in Table
2.
Enantiomeric excess was determined by 1H NMR
analysis of CCl4-CDCl3 (3/1) solution in the presence of
Eu(hfc)3. Irradiation of the signal of the γ-proton of (S)-
7d showed a single doublet due to the R-proton in
contrast to the spectrum of (()-7d exhibiting a pair of
two doublets at the same irradiation level. The enan-
tiomeric purity of (γS)-octylbutenolide (7e) was unsatis-
factory.
reaction of 8 with iodoacetate in the presence of sodium
hydride gave diester 9 in 77-99% yields. Chlorination
of 9 with sulfuryl chloride and the subsequent decar-
boxylation by heating the chlorinated product at the
reflux temperature of benzene in the presence of p-
toluenesulfonic acid afforded 5 in 78-99% yields.
The low yields on the bakers’ yeast reduction of longer
alkyl chain molecules such as 5d and 5e were improved
by using lipase-catalyzed hydrolysis of acetates. The
racemic acetates of 3-chloro-4-hydroxyalkanoate (()-6,
which is easily obtainable by NaBH4 reduction of ketone
5, were prepared and treated with lipase “Amano P” in
1/10 M phosphorus buffer solution. The reaction mixture
was checked by TLC, and the reaction was stopped when
the spots of the starting material 10 and optically active
hydroxyl ester (3R,4R)-6 became almost equal in their
largeness. The products were purified with column
chromatography and analyzed by 1H NMR spectra.
These results are tabulated in Table 3. Most of the
optical purities were determined in the next step.
Optically active hydroxyester (3R,4R)-6 was converted
to butenolides (R)-7 by the same method as shown in the
preparation of (S)-7, and these results are shown in Table
4. Optical purities were determined by comparison of
[R]D with those of authentic samples. All of the buteno-
lides were obtained in more than 85% enantiomeric
excess.
Reduction of 5 with industrial bakers’ yeast was
carried out in tap water at 35 °C for 2-7 days, giving
(4S)-3-chloro-4-hydroxyalkanoates 6 in 22-75% yields.
These results are tabulated in Table 1.
Alkanoates substituted with small alkyl groups were
reduced to afford chiral alcohols in good yields. On the
other hand, alkanoates (5d and 5e) bearing longer chains
such as butyl and octyl groups gave the reduced products
Some of the optically active natural products possess-
ing a γ-lactone ring were prepared by the conjugate
addition to the butenolide. Bis-γ-lactone 2, the diaste-
reomer of ethisolide 1, was prepared via Michael addition
to R,â-unsaturated esters 7, as shown in Scheme 1.
Michael addition of tert-butyl R-substituted propionates
(13) (a) Tsuboi, S.; Sakamoto, J .; Kawano, T.; Utaka, M.; Takeda,
A. J . Org. Chem. 1991, 56, 7177. (b) Sakai, T.; Wada, K.; Murakami,
T.; Kohra, K.; Imajo, N.; Ooga, Y.; Tsuboi, S.; Takeda, A.; Utaka, M.
Bull. Chem. Soc. J pn. 1992, 65, 631.

1104 J . Org. Chem., Vol. 63, No. 4, 1998
Ta ble 3. Asym m etr ic Hyd r olysis of (()-10 w ith Lip a se
Tsuboi et al.
OAc
OH
OAc
lipase
+
R
CO2R′
R
CO2R′
R
CO2R′
Cl
(±)-10
Cl
(3R,4R)-6
Cl
(3S,4S)-10
reaction
(3R,4R)-6
(3S,4S)-10
entry
R
R′
T (°C)
time (h)
yield (%)
[R]D
yield (%)
[R]D
a
b
c
d
e
f
CH3
C2H5
C2H5
n-C4H9
n-C8H17
n-C8H17
C2H5
CH3
C2H5
C2H5
CH3
25
25
25
25
25
25
12
29
29
29
35
26
31
+11.9
+21.4
+22.1
+19.5
+10.6
+12.3
30
43
22
18
31
22
-33.6
-18.3
-23.9
+5.58
+15.7
+8.16
7.5
10.5
40
42
40
C2H5
Ta ble 4. Syn th esis of (γR)-Bu ten olid es 7
Sch em e 1
OH
(1) 19% HCl, 25 °C
R
R R
CO2R′
R
O
(2) Et3N, 25 °C
R
O
Cl
(R)-7
(3R,4R)-6
(R)-7
entry
R
R′
yield (%)
[R]D (CHCl3)
ee (%)
a
b
c
d
e
f
CH3
C2H5
CH3
C2H5
C2H5
45
34
39
74
31
58
-100 (c 0.13)
-106.5 (c 0.92)
-99.6 (c 1.35)
-99.0 (c 1.38)
-59.0 (c 0.80)a
-64.9 (c 2.46)a
>99b
96b
86b
98c
C2H5
C2H5
n-C4H9
n-C8H17 CH3
n-C8H17 C2H5
87c
94c
a
b
Measured in 1,4-dioxane. Determined by GC fitted with
chiral column. c Determined by comparison of the optical rotation.
[CH3CHXCO2Bu-t] (11a , X ) SCH3; 11b, X ) SC6H5; 11c,
X ) SeC6H5) to the butenolide 7c followed by the
subsequent addition of iodine proceeded smoothly to give
all trans-substituted γ-lactones 12 in good yields. Ther-
mal treatment of 12 in DMSO at 140-150 °C gave bis-
γ-lactone 13 in 47-91% yields. Oxidation of 13a and 13b
with m-chloroperbenzoic acid (m-CPBA) afforded the
corresponding sulfoxides in 45 and 91% yields, respec-
tively. Thermal desulfonylation of these sulfoxides,
however, resulted in the recovery of the starting materi-
als. On the other hand, oxidation of the phenylseleno
lactone 13c with peracetic acid led to spontaneous
deselenation, giving exo-methylene lactone 2 in 71% yield.
Michael addition of Me2CuLi to (R)-7d stereospecifi-
cally afforded the trans-addition product, whisky lactone
3, in 69% yield, of which physical data were identical with
those of the literature.14
groups.15,16
The synthetic method reported by
Schlessinger15b was modified and applied for the present
synthesis. Here, we describe the total synthesis of 4
starting from (R)-7e, as shown in Scheme 2. Michael
addition of lithiated 11c to (R)-7e followed by the addition
of iodine gave all-trans-substituted tetrahydro-2-furanone
12e in 89% yield exclusively. Treatment of 12e in DMSO
at 140-150 °C gave γ-bislactone 13e in 47% yield. Mild
oxidation of the selenide 13e with peracetic acid at 0-25
°C proceeded via the elimination of phenylselenol to give
(-)-avenaciolide 4 with 91% ee. This total synthesis
consists of completely stereocontrolled reactions that
afforded only the desired products without any stereoi-
somers.
Although the chirality of carbon-3 of 5 bearing the
chlorine atom is no consideration for the synthesis of
optically active butenolides, the chlorine atom activates
the carbonyl group for the reduction of ketone 5 with
bakers’ yeast because 4-oxoalkanoates bearing no chlo-
Furthermore, butenolide (γR)-7e, which has been
prepared via the lipase-catalyzed kinetic resolution as
shown in Tables 3 and 4, was used for the total synthesis
of (-)-avenaciolide.7b Avenaciolide (4) is an antifungal
agent first isolated from Aspergillus avenaceaus10 and
attracts the attention of organic chemists because of the
unique bis-γ-lactone structure. Total synthesis of opti-
cally active avenaciolide has been reported by many
(15) Syntheses of (()-avenaciolide: (a) Parker, W. L.; J ohnson, F..
J . Org. Chem. 1973, 38, 2489. (b) Herrmann, J . L.; Berger, M. H.;
Schlessinger, R. H. J . Am. Chem. Soc. 1979, 101, 1544. (c) See ref 8d.
(d) Sakai, T.; Horikawa, H.; Takeda, A. J . Org. Chem. 1980, 45, 2039.
(e) Kallmerten, J .; Gould, T. J . J . Org. Chem. 1985, 50, 1128.
(16) Syntheses of optically active avenaciolide: (a) Anderson, R. C.;
Fraser-Reid, B. J . Am. Chem. Soc. 1975, 97, 3870. (b) Ohrui, H.;
Emoto, S. Tetrahedron Lett. 1975, 3657. (c) Suzuki, K.; Miyazawa,
M.; Shimazaki, M.; Tsuchihashi, G. Tetrahedron Lett. 1986, 27, 6237.
(d) Suzuki, K.; Miyazawa, M.; Shimazaki, M.; Tsuchihashi, G. Tetra-
hedron 1988, 44, 4061.
(14) Masuda, M.; Nishimura, K. Chem. Lett. 1981, 1333.

Synthesis of Enantiomers of γ-Substituted Butenolides
J . Org. Chem., Vol. 63, No. 4, 1998 1105
cm-1; 1H NMR (CDCl3, 200 MHz) δ 1.26 (t, J ) 7.14 Hz, 3H),
2.40 (s, 3H), 2.79 (dd, J ) 6.22, 17.0 Hz, 1H), 3.12 (dd, J )
7.44, 17.0 Hz, 1H), 4.16 (q, J ) 7.16 Hz, 2H), 4.61 (dd, J )
7.54, 7.48 Hz, 1H). Anal. Calcd for C7H11ClO3: C, 47.07; H,
6.28. Found: C, 46.77; H, 6.46.
Sch em e 2
Meth yl 3-Ch lor o-4-oxoh exa n oa te (5b). To a mixture of
2.3 g (57.5 mmol) of 60% NaH in an oil and anhydrous benzene
(150 mL) was added tert-butyl 3-oxopentanoate (9.49 g, 55.2
mmol) and then trioctylmethylammonium chloride (0.5 g).
After 30 min, methyl iodoacetate (11.0 g, 55.2 mmol) was
added dropwise, and then the mixture was stirred for 19 h at
room temperature. It was poured into water and acidified with
10% HCl, and then the organic layer was extracted with ether.
The combined extract was washed with water and dried over
anhydrous MgSO4. Removal of the solvent gave an oil, which
was purified with column chromatography [silica gel (100 g),
hexane/ethyl acetate ) 40/1-3/1] to give 10.4 g (77%) of methyl
tert-butyl 2-propanoylsuccinate (5b′).
To a solution of 5b′ (1.12 g, 4.59 mmol) in CH2Cl2 (2 mL)
was added dropwise a solution of sulfuryl chloride (0.505 mL,
5.71 mmol) in CH2Cl2 (1 mL). The mixture was stirred for 2
h
at room temperature and then for 2 h at the reflux
temperature. After removal of volatile materials under re-
duced pressure, the residue obtained was dissolved in benzene
(5 mL), and p-toluensulfonic acid (0.2 g) was added. The
mixture was heated at the reflux temperature for 12 h, and
then usual workup gave the crude 5b, which was purified with
column chromatography [silica gel (20 g), hexane/ethyl acetate
) 10/1] to give 810 mg (99%) of 5b: IR (neat) 3000, 2950, 1740,
rine atom are scarcely reduced by bakers’ yeast. The
chlorine atom also plays an important role in the forma-
tion of the CdC bond. The present method is experi-
mentally simple, practical, and useful for the syntheses
of optically active butenolides and their derivatives.
1730 cm-1 1H NMR (CDCl3, 200 MHz) δ 1.10 (t, J ) 7 Hz,
;
3H), 2.8 (m, 4H), 3.62 (s, 3H), 4.48 (dd, J ) 7, 9 Hz, 1H), 4.47
(dd, J ) 7, 9 Hz, 1H). Anal. Calcd for C7H11O5Cl: C, 47.07;
H, 6.21. Found: C, 47.12; H, 6.00.
Eth yl 3-ch lor o-4-oxoh exa n oa te (5c) was prepared by the
decarboxylation of the corresponding succinate, which was
obtained in 99% yield from tert-butyl 3-oxopentanoate, as
described above: 98% yield; Rf 0.53 (hexane/ethyl acetate )
2/1).
Eth yl 3-ch lor o-4-oxoocta n oa te (5d ) was prepared by the
decarboxylation of the corresponding succinate, which was
obtained in 79% yield from tert-butyl 3-oxoheptanoate, as
described above: 86% yield; Rf 0.49 (hexane/ethyl acetate )
4/1).
Exp er im en ta l Section
IR spectra were measured as films for oils or by the KBr
method for solids. 1H NMR spectra were determined at 60,
100, 200, and 500 MHz and 13C NMR spectra at 50 MHz. 1H
NMR spectra were obtained at 60 MHz unless otherwise
described. Enantiomeric excess was determined with an
HPLC apparatus fitted with Daicel Chiralcel OB-H (4.6 mm
L × 250 mm) or with a GC apparatus fitted with a chiral
column (Chirasil-DEX CB, 0.25 mm × 25 m) or by comparison
of the optical rotation with that of an authentic sample. TLC
was performed on glass plates coated with silica gel (Merk
silica gel 60 plate, 0.25 mm in thickness).
Fermentation was carried out in boiled tap water in a
thermostated bath at 35 ( 2 °C by using industrial pressed
bakers’ yeast purchased from oriental Yeast Co., Ltd. All
glassware was sterilized with boiling water before use.
The synthesis of 3-chloro-4-oxoalkanoate 5 was carried out
via three steps from tert-butyl 3-oxoalkanoate 8. Some
representative examples are shown.
Meth yl 3-ch lor o-4-oxod od eca n oa te (5e) was prepared by
the decarboxylation of the corresponding succinate, which was
ohtained in 91% yield from tert-butyl 3-oxoundecanoate, as
described above: 88% yield; Rf 0.48 (hexane/ethyl acetate )
4/1).
Syn th esis of eth yl (4S)-3-ch lor o-4-h yd r oxyp en ta n oa te
(6a ) is reported in the previous paper.13a
Eth yl 3-Ch lor o-4-oxop en ta n oa te (5a ). To a mixture of
880 mg (22.0 mmol) of 60% NaH in oil and 60 mL of dry
benzene was added 3.48 mL (21.0 mmol) of tert-butyl 3-ox-
obutanoate, and then 0.2 g of trioctylmethylammonium chlo-
ride was added. After 20 min, 2.48 g (21.0 mmol) of ethyl
iodoacetate was added, and then the mixture was stirred for
36 h at room temperature. It was poured into water and
acidified with 10% HCl, and then the organic layer was
extracted with ether. The combined extract was washed with
water and dried over anhydrous MgSO4. Removal of the
solvent gave 7.47 g of an oil, which was purified with column
chromatography [silica gel (100 g), hexane/ethyl acetate ) 40/
1-3/1] to give 5.15 g (100%) of ethyl tert-butyl 2-acetylsucci-
nate (5a ′).
To a solution of 5a ′ (3.08 g, 12.6 mmol) in CH2Cl2 (2 mL)
was added dropwise a solution of sulfryl chloride (1.39 mL,
15.7 mmol) in CH2Cl2 (2 mL). The mixture was stirred for 3
h at room temperature and then for 40 min at reflux temper-
ature. After removal of the volatile materials under reduced
pressure, the residue obtained was dissolved in benzene (10
mL), and p-toluensulfonic acid (0.1 g) was added. The mixture
was heated at the reflux temperature, and then usual workup
gave 2.51 g of crude 5a , which was purified with column
chromatography [silica gel (20 g), hexane/ethyl acetate ) 10/
1] to give 1.75 g (78%) of 5a : IR (neat) 3000, 1740, 1730, 1380
Meth yl (4S)-3-Ch lor o-4-h yd r oxyh exa n oa te (6b). To a
mixture of KH2PO4 (0.4 g), NH4H2PO4 (0.4 g), MgSO4 (0.2 g),
CaCO3 (1.2 g), glucose (12 g), and boiling water (200 mL) was
added 12 g of bakers’ yeast at 35 °C. After bubbles formed
(ca. 30 min), 1.42 g (7.96 mmol) of 5b was added, and then
the mixture was stirred at 35 °C. After 4 and 12 h, respec-
tively, 12 g of glucose was added. After 50 h, 6 g of bakers’
yeast was added. After 4 days, the organic materials were
extracted with ether, washed with water, dried over MgSO4,
and concentrated. The residual oil (1.11 g) was chromato-
graphed on silica gel (40 g) [hexane/ethyl acetate (20/1-1/1)]
to give 591 mg (43%) of (4S)-6b: Rf 0.35 (hexane/ethyl acetate
) 2/1); [R]22D +11.1 (c 3.11, CHCl3); IR (neat) 3500, 3000, 1745
1
cm-1; H NMR (CCl4) δ 0.98 (t, J ) 7 Hz, 3H), 1.50 (m, 2H),
2.75 (m, 2H), 3.20 (broad s, 1H), 3.60 (m, 1H), 3.65 (s, 3H),
4.15 (m, 1H).
Anal. Calcd for C7H13ClO3: C, 46.55; H, 7.25. Found: C,
46.76; H, 7.31.
The second fraction gave 108 mg (10%) of (S)-7b.
Eth yl (4S)-3-Ch lor o-4-h yd r oxyh exa n oa te (6c). To a
mixture of KH2PO4 (2.4 g), NH4H2PO4 (2.4 g), MgSO4 (1.2 g),
CaCO3 (7.2 g), glucose (70 g), and boiling water (1.2 l) was
added 70 g of bakers’ yeast at 35 °C. After bubbles formed
(ca. 30 min), 7.94 g (41.2 mmol) of 5c was added, and then
the mixture was stirred at 35 °C. After 5, 12, and 68 h,

1106 J . Org. Chem., Vol. 63, No. 4, 1998
Tsuboi et al.
respectively, 70 g of glucose was added. After 34 h, 70 g of
bakers’ yeast was added. After 3 days, the organic materials
were extracted with ether, washed with water, dried over
MgSO4, and concentrated. The residual oil (6.16 g) was
chromatographed on silica gel [hexane/ethyl acetate (20/1-1/
1)] to give 0.856 g (11%) of the starting material 5c as a first
fraction: Rf 0.43 (hexane/ethyl acetate ) 4/1). Second fraction
gave 3.4 g (42%) of (4S)-6c: Rf 0.23 (hexane/ethyl acetate )
(()-syn -Eth yl 3-Ch lor o-4-h yd r oxyp en ta n oa te (6a ). To
a solution of 709 mg (3.97 mmol) of 5a in ethanol (7 mL) was
added NaBH4 (50 mg, 1.32 mmol) at 0 °C. The mixture was
stirred for 10 min and worked up as described above. The
crude product was purified with column chromatography on
silica gel (hexane/ethyl acetate ) 2/1), giving 597 mg (83%) of
6a : syn/anti ) 78/22 by GC analysis of the acetate 10a ; Rf
0.30 (hexane/ethyl acetate ) 2/1); IR (neat) 3470, 3000, 1740,
1380 cm-1; 1H NMR (CCl4) δ 1.23 (d, J ) 6 Hz, 3H), 1.25 (t, J
) 7 Hz, 3H), 2.25 (broad s, 1H), 2.70 (m, 2H), 3.6-4.2 (m, 2H),
4.08 (q, J ) 7 Hz, 2H).
(()-syn -Eth yl 3-Ch lor o-4-h yd r oxyh exa n oa te (6c). To a
solution of 340 mg (1.77 mmol) of 5c in ethanol (4 mL) was
added NaBH4 (22 mg, 0.59 mmol) at 0 °C. The mixture was
stirred for 10 min and then worked up as described above. The
crude product was purified with column chromatography on
silica gel (hexane/ether ) 5/1-3/1), giving 165 mg (48%) of
(()-syn-6c: Rf 0.40 (hexane/ethyl acetate ) 2/1).
(()-syn -Eth yl 3-Ch lor o-4-h yd r oxyocta n oa te (6d ). To a
solution of 2.00 g (9.07 mmol) of 5d in ethanol (20 mL) was
added NaBH4 (90 mg, 2.37 mmol) at 0 °C. The mixture was
stirred for 15 min and then worked up as described above.
Column chromatography (silica gel, hexane/ethyl acetate ) 20/
1-1/1) of the crude product gave 1.47 g (73%) of (()-syn-6d :
Rf 0.3 (hexane/ethyl acetate ) 4/1).
(()-syn -Meth yl 3-Ch lor o-4-h yd r oxyd od eca n oa te (6e).
To a solution of 4.30 g (16.4 mmol) of 5e in ethanol (50 mL)
was added NaBH4 (207 mg, 5.46 mmol) at 0 °C. The mixture
was stirred for 20 min and then worked up as described above.
Column chromatography (silica gel, hexane/ethyl acetate ) 4/1)
of the crude product gave 3.74 g (86%) of (()-syn-6e: syn/anti
) 98/2 by 13C NMR of the acetate 10e; Rf 0.25 (hexane/ethyl
acetate ) 4/1).
4/1); [R]22 +10.4 (c 3.22, CHCl3).
D
Eth yl (4S)-3-Ch lor o-4-h yd r oxyocta n oa te (6d ). Com-
pound 5d (1.90 g, 8.62 mmol) was treated with 27 g (total) of
bakers’ yeast and 63 g (total) of glucose for 7 days, as shown
in the preparation of (4S)-6c. The crude oil (1.94 g) was
chromatographed on silica gel [hexane/ethyl acetate (30/1-1/
1)] to give 421 mg (22%) of the starting material 5d : Rf 0.67
(hexane/ethyl acetate ) 2/1). The second fraction gave 417
mg (22%) of 6d : Rf 0.56 (hexane/ethyl acetate ) 2/1); [R]22
D
+5.78 (c 3.0, CHCl3). The third fraction gave 52 mg (4%) of
7d : Rf 0.31 (hexane/ethyl acetate ) 2/1).
(S)-5-Octyl-2(5H)-fu r a n on e (7e). Compound 5e (2.77 g,
8.45 mmol) was treated with 48 g (total) of bakers’ yeast and
96 g (total) of glucose at 30-31 °C for 8 days, as shown in the
preparation of (4S)-6c. The crude oil (2.97 g) was chromato-
graphed on silica gel [hexane/ethyl acetate (10/1-1/1)] to give
182 mg (11%) of (S)-7e: Rf 0.26 (hexane/ethyl acetate ) 4/1);
[R]23 +40.7 (c 1.18, dioxane) [lit.17 [R]25 +69.2 (c 2.10,
D
D
dioxane)]; 59% ee by 1H NMR (100 Mz, CCl4/CHCl3 (3/1)) in
the presence of Eu(hfc)3.
Syn th esis of (5S)-5-m eth yl-2(5H)-fu r a n on e (7a ) is re-
ported in the previous paper.13a
(S)-5-Eth yl-2(5H)-fu r a n on e (7c). A mixture of 3.40 g
(17.5 mmol) of 6c, concentrated HCl (15 mL), and water (15
mL) was stirred for 1 day at room temperature. The organic
materials were extracted with methylene chloride, washed
with water, dried over MgSO4, and concentrated. The residual
oil (2.35 g) was dissolved in dry ether (30 mL), and triethy-
lamine (6 mL) was added. The mixture was stirred for 2 days
at room temperature and then acidified. The organic materials
were extracted with ether, washed with water, and dried.
Concentration of the solvent gave the crude product (1.39 g),
which was chromatographed on silica gel (hexane/ethyl acetate
) 20/1-1/1) to give 1.35 g (69%) of (S)-7c: Rf 0.38 (hexane/
ethyl acetae ) 1/1); [R]22 +103 (c 2.71, CHCl3) (lit.17 [R]23
(()-syn -Eth yl 4-Acetoxy-3-ch lor od od eca n oa te (10f). A
mixture of (()-syn-6f (1.27 g, 4.56 mmol), acetic anhydride (1
mL), and pyridine (3 mL) was stirred for 24 h at room
temperature and then acidified with 10% HCl. The organic
materials were extracted with methylene chloride, washed
with water, dried over MgSO4, and concentrated. The residual
oil was chromatographed on silica gel (hexane/ethyl acetate
) 20/1-1/1) to give 1.49 g (100%) of (()-syn-10f: Rf 0.6
(hexane/ethyl acetate ) 4/1); IR (neat) 2950, 1740, 1370 cm-1
;
1H NMR (CCl4) δ 0.89 (broad t, J ) 6 Hz, 3H), 1.27 (t, J ) 7
Hz, 3H), 1.29 (broad s, 12H), 1.60 (m, 2H), 2.05 (s, 3H), 2.63
(d, J ) 7 Hz, 2H), 4.13 (q, J ) 7 Hz, 2H), 4.31 (m, 1H), 5.06
(m, 1H). Anal. Calcd for C16H29ClO4: C, 59.89; H, 9.11.
Found: C, 59.86; H, 9.48.
D
D
1
-95 (liquid)); >96% ee by H NMR (100 MHz, CCl4/CHCl3 (3/
1)) in the presence of Eu(hfc)3.
(S)-5-Bu tyl-2(5H)-fu r a n on e (7d ). A mixture of 400 mg
(1.80 mmol) of 6d , concd HCl (2 mL), and water (2 mL) was
stirred for 1 day at room temperature and then worked up as
described above. The product was dissolved in dry ether (5
mL), and triethylamine (1 mL) was added. The mixture was
stirred for 2 days at room temperature and then worked up
as described above. The crude product (227 mg) was chro-
matographed on silica gel (hexane/ethyl acetate ) 10/1-2/1)
to give 184 mg (73%) of (S)-7d : Rf 0.31 (hexane/ethyl acetate
Other acetates 10 were prepared as described in the
preparation of 10f.
(()-syn -Eth yl 4-Acetoxy-3-ch lor open tan oate (10a): 92%
yield; Rf 0.6 (hexane/ethyl acetate ) 2/1); syn/anti ) 78/22 by
GC analysis.
(()-syn -Meth yl 4-Acetoxy-3-ch lor oh exan oate (10b): 74%
yield; Rf 0.55 (hexane/ethyl acetate ) 2/1); syn/anti ) 77/23
) 2/1); [R]22 +92.3 (c 3.39, CHCl3) (lit.6b [R]D -101 (CHCl3));
1
by H NMR (200 MHz, CDCl3) analysis.
D
>96% ee by 1H NMR (100 MHz, CCl4/CHCl3 (3/1)) in the
(()-syn -Eth yl 4-Acetoxy-3-ch lor oh exa n oa te (10c): 89%
yield; Rf 0.4 (hexane/ethyl acetate ) 4/1).
presence of Eu(hfc)3.
(()-syn -Eth yl 3-Ch lor o-4-h yd r oxyd od eca n oa te (6f). To
a solution of 1.00 g (5.60 mmol) of 5f in ethanol (10 mL) was
added NaBH4 (71 mg, 1.87 mmol) at 0 °C. The mixture was
stirred for 10 min and then acidified with 10% HCl. The
organic materials were extracted with ether, washed with
water, and dried over MgSO4. Removal of the solvent gave
1.48 g of the crude product, which was chromatographed on
silica gel (hexane/ethyl acetate ) 10/1-1/1) to give 717 mg
(71%) of (()-syn-6f: Rf 0.35 (hexane/ethyl acetate ) 2/1); IR
(()-syn -Eth yl 4-Acetoxy-3-ch lor oocta n oa te (10d ): 100%
yield; Rf 0.6 (hexane/ethyl acetate ) 4/1).
(()-syn -Meth yl 4-Acetoxy-3-ch lor od od eca n oa te (10e):
76% yield; Rf 0.66 (hexane/ethyl acetate ) 2/1); syn/anti )
>98/2 by 13C NMR.
(3R,4R)-Eth yl 3-Ch lor o-4-h ydr oxydodecan oate (6f) an d
(3S,4S)-Eth yl 4-Acetoxy-3-ch lor od od eca n oa te (10f).
A
mixture of (()-10f (750 mg, 2.34 mmol), 1/10 M phosphoric
acid buffer solution (pH 7.2, 80 mL), and lipase P (400 mg)
was stirred for 40 h at 25 °C. The organic materials were
extracted with ether, and the combined extract was washed
with water, dried over MgSO4, and concentrated. The residual
oil was chromatographed on silica gel (hexane/ethyl acetate
) 30/1-4/1) to give 166 mg (22%) of (3S,4S)-10f as a first
(neat) 3500, 2970, 1745, 1380 cm-1 1H NMR (CCl4) δ 0.88
;
(broad t, J ) 6 Hz, 3H), 1.26 (t, J ) 7 Hz, 3H), 1.27 (broad s,
14H), 2.77 (m, 2H), 3.60 (broad s, 1H), 4.11 (t, J ) 7 Hz, 2H),
4.20 (m, 2H). Anal. Calcd for C14H27ClO3: C, 60.31; H, 9.76.
Found: C, 60.69; H, 10.08.
fraction: Rf 0.60 (hexane/ethyl acetate ) 4/1); [R]26 +8.16 (c
D
2.99, CHCl3). Anal. Calcd for C16H29ClO4: C, 59.89; H, 9.11.
Found: C, 59.86; H, 9.48.
(17) Vigneron, J . P.; Blanchard, J . M. Tetrahedron Lett. 1980, 21,
1739.

Synthesis of Enantiomers of γ-Substituted Butenolides
J . Org. Chem., Vol. 63, No. 4, 1998 1107
The second fraction gave 201 mg (31%) of (3R,4R)-6f: Rf
0.50 (hexane/ethyl acetate ) 4/1); [R]26D +12.3 (c 2.60, CHCl3).
Spectral data were identical with those of the racemate. Anal.
Calcd for C14H27ClO3: C, 60.31; H, 9.76. Found: C, 60.69; H,
10.08.
the combined extract was washed with water, dried over
MgSO4, and concentrated. A mixture of the residual oil (239
mg), triethylamine (1.5 mL, mmol), and dry ether (9 mL) was
stirred for 3 days at room temperature and poured into ice-
water. The organic materials were extracted with ethyl
acetate and dried over MgSO4. Concentration of the solvent
gave the crude product (107 mg), which was chromatographed
on silica gel (hexane/ethyl acetate ) 50/1-5/1) to afford 71 mg
(45.3%) of 7e: Rf 0.20 (hexane/ethyl acetate ) 2/1); [R]19D -96.4
(c 1.40, CHCl3) (lit.3 [R]D -107.0 (c 0.92, CHCl3)); >99% ee by
GC analysis fitted with chiral column. The spectral data were
identical with those of the authentic sample.13a
(3R,4R)-Eth yl 3-Ch lor o-4-h yd r oxyp en ta n oa te (6a ) a n d
(3S,4S)-4-Acetoxy-3-ch lor op en ta n oa te (10a ). A mixture of
(()-10a (1.80 g, 8.09 mmol), 0.1 M phosphate buffer solution
(pH 7.2, 100 mL), and lipase PS (0.90 g) was stirred for 12 h
at 25 °C. The organic materials were extracted with ethyl
acetate, and the combined extract was washed with water,
dried over MgSO4, and concentrated. The residual oil (1.55
g) was chromatographed on silica gel (hexane/ethyl acetate )
50/1-2/1) to give 435 mg (29.9%) of (3S,4S)-10a as a first
(R)-5-Eth yl-2(5H)-fu r a n on e (7b). Ester (3R,4R)-6b (108
mg, 0.598 mmol) was hydrolyzed with 19% HCl and then
treated with triethylamine, as described in the preparation of
(R)-7a . The crude product was chromatographed on silica gel
(hexane/ethyl acetate )50/1-10/1) to give 23 mg (34%) of 7b:
fraction: Rf 0.50 (hexane/ethyl acetate ) 2/1); [R]22 -33.6 (c
D
1.90, CHCl3). The second fraction gave 518 mg (28.8%) of
(3R,4R)-6a : Rf 0.28 (hexane/ethyl acetate ) 2/1); [R]22D +11.9
(c 1.04, CHCl3). The spectral data were identical with those
of the racemate.
Rf 0.29 (hexane/ethyl acetate); [R]22 -106.5 (c 0.92, CHCl3)
D
(lit.17 [R]D -95.0 (liquid)); 96% ee by GC analysis fitted with
chiral column. The spectral data were identical with those of
(S)-7b.
(3R,4R)-Meth yl 3-Ch lor o-4-h yd r oxyh exa n oa te (6b) a n d
(3S,4S)-4-Acetoxy-3-ch lor oh exa n oa te (10b). A mixture of
(()-10b (750 mg, 3.37 mmol), 0.1 M phosphate buffer solution
(pH 7.2, 80 mL), and lipase PS (400 mg) was stirred for 7.5 h
at 25 °C. The organic materials were extracted with ethyl
acetate, and the combined extract was washed with water,
dried over MgSO4, and concentrated. The residual oil (512
mg) was chromatographed on silica gel (hexane/ethyl acetate
) 30/1-2/1) to give 322 mg (42.9%) of (3S,4S)-10b as a first
(R)-5-Bu tyl-2(5H)-fu r a n on e (7d ). Ester (3R,4R)-6d (54
mg, 0.24 mmol) was hydrolyzed with 19% HCl and then
treated with triethylamine, as described in the preparation of
(R)-7a . The crude product was purified with column chroma-
tography (silica gel, hexane/ethyl acetate ) 10/1-3/1) to give
25 mg (74%) of 7d : Rf 0.35 (hexane/ethyl acetate ) 2/1); [R]22
D
-99.0 (c 1.38, CHCl3) (lit.9h [R]D -101 (CHCl3)); 98% ee by
comparison of the optical rotation. The spectral data were
identical with those of the authentic sample.9h
fraction [Rf 0.53 (hexane/ethyl acetate ) 2/1); [R]22 -18.3 (c
D
1.90, CHCl3)] and to give 91 mg (28.8%) of (3R,4R)-6b as a
second fraction: Rf 0.33 (hexane/ethyl acetate ) 2/1); [R]22
(R)-Octyl-2(5H)-fu r a n on e (7e). Ester (3R,4R)-6e (527 mg,
1.72 mmol) was hydrolyzed with 19% HCl and treated with
triethylamine, as described in the preparation of (R)-7a . The
crude product was chromatographed on silica gel (hexane/ethyl
acetate ) 20/1) to give 232 mg (69%) of (R)-7e: Rf 0.30 (hexane/
D
+21.4 (c 1.04, CHCl3). The spectral data were identical with
those of the racemate.
(3R,4R)-Eth yl 3-Ch lor o-4-h yd r oxyh exa n oa te (6c) a n d
(3S,4S)-4-Acetoxy-3-ch lor oh exa n oa te (10c). A mixture of
(()-10c (1.75 g, 7.40 mmol), 0.1 M phosphate buffer solution
(pH 7.2, 100 mL), and lipase PS (0.90 g) was stirred for 10.5
h at 25 °C. The organic materials were extracted with ethyl
acetate, and the combined extract was washed with water,
dried over MgSO4, and concentrated. The residual oil (1.47
g) was chromatographed on silica gel (hexane/ethyl acetate )
30/1-3/1) to give 389 mg (22.4%) of (3S,4S)-10c as a first
ethyl acetate ) 4/1); [R]22 -66.7 (c 2.37, CHCl3) (lit.17 [R]D
D
-69.2 (c 2.0, dioxane); 87% ee by comparison of the optical
rotation. Spectral data were identical with those of (S)-7e.
Syn th esis of (R)-7f fr om (3R,4R)-6f. Ester (3R,4R)-6f
(180 mg, 0.646 mmol) was hydrolyzed with 19% HCl and then
treated with triethylamine, as described in the preparation of
(R)-7a . The crude product was chromatographed on silica gel
(hexane/ethyl acetate ) 20/1) to give 92 mg (73%) of (R)-7f:
fraction: Rf 0.55 (hexane/ethyl acetate ) 2/1); [R]22 -23.9 (c
D
1.59, CHCl3). The second fraction gave 435 mg (29.4%) of
Rf 0.25 (hexane/ethyl acetae ) 4/1); [R]25 -64.9 (c 2.56,
D
(3R,4R)-6c: Rf 0.35 (hexane/ethyl acetate ) 2/1); [R]22 +22.1
dioxane) (lit.17 [R]D -69.2 (c 2.0, dioxane)); 94% ee by com-
parison of the optical rotation. Spectral data were identical
with those of (S)-7e.
D
(c 2.02, CHCl3). The spectral data were identical with those
of the racemate.
(3R,4R)-Eth yl 3-Ch lor o-4-h yd r oxyocta n oa te (6d ) a n d
(3S,4S)-4-Acetoxy-3-ch lor oocta n oa te (10d ). A mixture of
(()-10d (400 mg, 1.51 mmol), 0.1 M phosphate buffer solution
(20 mL), and lipase P (200 mg) was stirred for 40 h at 25 °C
and then worked up as described above. The crude product
(329 mg) was purified by column chromatography (silica gel,
hexane/ethyl acetate ) 10/1), giving 70 mg (18%) of (3S,4S)-
10d as a first fraction [Rf 0.55 (hexane/ethyl acetate ) 4/1);
(3R,4R,5S)-4-[1-(ter t-Bu toxyca r bon yl)-1-(p h en ylselen o-
)eth yl]-5-eth yl-3-iod otetr a h yd r o-2-fu r a n on e (12c). To a
solution of diisopropylamine (0.134 mL, 1.0 mmol) in dry THF
(1 mL) was added dropwise butyllithium (1.6 M, 0.63 mL, 1.0
mmol) at -20 °C. The mixture was stirred for 30 min, and
then a solution of tert-butyl 2-(phenylseleno)propanoate (230
mg, 0.80 mmol) in 1 mL of dry THF was added at -78 °C.
After 30 min, (R)-7c (111 mg, 1.0 mmol) was slowly added.
After 3 h, a solution of iodine (253 mg, 1.0 mmol) in dry THF
(0.5 mL) was added. The mixture was stirred for 30 min and
then quenched with 10% HCl. The organic materials were
extracted with ether, and the combined extract was washed
with aqueous sodium thiosulfate and water and dried over
MgSO4. Concentration of the solvent gave a crude product
(510 mg), which was chromatographed on silica gel (hexane/
ethyl acetate ) 2/1 to ethyl acetate) to give 384 mg (92%) of
12c: Rf 0.75 (hexane/ethyl acetate ) 1.1); IR (neat) 3000, 1780,
1720, 1570 cm-1; 1H NMR (CCl4) δ 1.22 (t, J ) 7 Hz, 3H), 1.44
(s, 9H), 1.47 (s, 3H), 1.70 (m, 2H), 2.93 (m, 1H), 4.0-4.5 (m,
[R]26 +5.58 (c 2.33, CHCl3)] and 117 mg (35%) of (3R,4R)-6d
D
as a second fraction: Rf 0.30 (hexane/ethyl acetate ) 4/1); [R]26
D
+19.5 (c 1.96, CHCl3). The spectral data were identical with
those of the racemate.
(3R,4R)-3-Ch lor o-4-h yd r oxyd od eca n oa te (6e) a n d (3S,-
4S)-4-Acetoxy-3-ch lor od od eca n oa te (10e). A mixture of
200 mg (0.653 mmol) of (()-10e, 0.1 M phosphate buffer
solution (pH 7.2, 10 mL), and lipase P (100 mg) was stirred at
25 °C for 42 h and then worked up as described above. The
crude product (234 mg) was purified by column chromatogra-
phy (silica gel, hexane/ethyl acetate ) 10/1), giving 62 mg
(31%) of (3S,4S)-10e as a first fraction: Rf 0.50 (hexane/ethyl
acetate ) 2/1); [R]27D +15.7 (c 2.72, CHCl3); 87% ee by 1H NMR
in the presence of Eu(hfc)3. The second fraction gave 45 mg
1H), 4.64 (m, 1H), 7.2-7.7 (m, 5H). Anal. Calcd for C19H25
-
IO4Se: C, 43.61; H, 4.82. Found: C, 43.35; H, 4.64.
Bisla cton iza tion of 12c to 13c. A solution of 12c (384
mg, 0.734 mmol) in DMSO (0.5 mL) was stirred for 20 min at
150 °C and then quenched with water. The organic materials
were extracted with methylene chloride, and the combined
extract was washed with water, dried over MgSO4, and
concentrated. The residue was chromatographed on silica gel
(hexane/ethyl acetate ) 3/1 to ethyl acetate) to give 98 mg
(26%) of (3R,4R)-6e: Rf 0.40 (hexane/ethyl acetate ) 2/1); [R]26
+10.6 (c 1.94, CHCl3).
D
(R)-5-Meth yl-2(5H)-fu r a n on e (7a ). A mixture of (3R,-
4R)-6 (280 mg, 1.60 mmol) and 19% HCl (3 mL) was stirred
for 2 days at room temperature and then for 1 day at 40 °C.
The organic materials were extracted with ethyl acetate, and

1108 J . Org. Chem., Vol. 63, No. 4, 1998
Tsuboi et al.
(40%) of 13c: 1H NMR (CDCl3) δ 1.05 (t, J ) 7 Hz, 3H), 1.2-
2.0 (m, 2H), 1.60 (s, 3H), 2.93 (t, J ) 7 Hz, 1H), 4.30 (m, 1H),
4.60 (d, J ) 7 Hz, 1H), 7.0-7.8 (m, 5H).
10% HCl. The organic materials were extracted with ether,
and the etherial solution was washed with an aqueous solution
of sodium thiosulfate and water and dried over MgSO4.
Concentration of the solvent gave 316 mg of the crude product,
which was chromatographed (hexane/ethyl acetate (50/1 ) 5/1)
on silica gel to give 206 mg (89%) of 12e: Rf 0.55 (hexane/
(3a S,6a S)-Eth isolid e (2). To a mixture of 13c (71 mg, 0.21
mmol), acetic acid (0.037 mL), and THF (1 mL) was added 35%
H2O2 (0.21 mL, 2.2 mmol) at 0 °C. The ice bath was removed,
and the mixture was stirred for 1 h. The organic materials
were extracted with ether, and the combined extract was
washed with water, dried over MgSO4, and concentrated. The
crude product (35 mg) was purified with preparative TLC
(hexane/ethyl acetate ) 1/2) to give 27 mg (71%) of 2: Rf 0.3-
0.5 (hexane/ethyl acetate ) 1/2); [R]24D +75 (c 0.34, EtOH); IR
ethyl acetate ) 4/1); [R]23 -15.2 (c 2.33, CHCl3); IR (neat)
D
1
2950, 1775, 1720, 1580 cm-1; H NMR (CDCl3) δ 0.89 (broad
t, J ) 6 Hz, 3H), 1.28 (broad s, 14H), 1.42 (s, 9H), 1.47 (s, 3H),
2.9-3.1 (m, 1H), 4.0-4.4 (m, 1H), 5.6-5.8 (dd, 1H), 7.2-7.7
(m, 5H).
Bisla cton iza tion of 12e to 13e. A solution of 12e (180
mg, 0.297 mmol) in dry DMSO (2 mL) was heated at 140-
150 °C for 15 min under an atmosphere of nitrogen and then
poured into water. The organic materials were extracted with
methylene chloride, washed with water, dried over MgSO4, and
concentrated. The crude product was chromatographed on
silica gel (hexane/ethyl acetate ) 10/1-1/1) to give 59 mg (47%)
of 13e: Rf 0.55 (hexane/ethyl acetate ) 2/1); IR (neat) 2950,
1
(neat) 2950, 1780, 1770, 1570 cm-1; H NMR (CDCl3) δ 1.07
(t, J ) 7 Hz, 3H), 1.85 (m, 2H), 3.55 (m, 1H), 4.38 (m, 1H),
5.03 (d, J ) 8.5 Hz, 1H), 5.86 (d, J ) 2.0 Hz, 1H), 6.47 (d, J )
2.0 Hz, 1H); 13C NMR (CDCl3) δ 9.09, 29.1, 43.7, 74.3, 86.2,
126.3, 134.6, 167.4, 169.7. These data were identical with
those of the literature data.8d
(5R,4S)-5-Bu tyl-4-m eth yltetr ah ydr o-2-fu r an on e (Wh isky
La cton e) (3). To a mixture of CuI (162 mg, 0.85 mmol) and
ether (1 mL) was added dropwise methyllithium (1.19 M, 1.4
mL (1.7 mmol)) at -25 °C. After 30 min, a solution of (R)-7d
(22 mg, 0.157 mmol) in ether (0.5 mL) was added dropwise,
and the mixture was stirred for 1 h at -25 °C and quenched
with saturated NH4Cl solution (1 mL). The organic materials
were extracted with ether, and the combined extact was
washed with water, dried over MgSO4, and concentrated. The
residual oil was chromatographed on silica gel (hexane/ether
) 3/1), giving 17 mg (69%) of 3: Rf 0.50 (hexane/ethyl acetate
1
1785, 1580 cm-1; H NMR (CCl4) δ 0.89 (broad t, J ) 6 Hz,
3H), 1.30 (broad s, 14H), 1.58 (s, 3H), 3.00 (m, 1H), 4.40 (m,
1H), 4.92 (d, J ) 9 Hz, 1H), 7.2-7.8 (m, 5H).
(-)-Aven a ciolid e 4. To a solution of 13e (31 mg, 0.073
mmol) and acetic acid (0.02 mL) in THF (0.4 mL) was added
35% H2O2 (0.76 mL, 0.78 mmol) at 0 °C. The ice bath was
removed, and the mixture was stirred for 1 h and quenched
with water. The organic materials were extracted with ether,
washed with water, and dried over MgSO4. Concentration of
the solvent gave the crude product (18 mg), which was
chromatographed on silica gel (hexane/ethyl acetate ) 5/1) to
give 6 mg (31%) of 4: Rf 0.45 (hexane/ethyl acetate ) 2/1);
[R]24 -38 (c 1.0, EtOH) (lit.16a [R]20 -41.1 (c 0.27, EtOH);
) 2/1); [R]24 +79.3 (c 1.08, MeOH) (lit.14 [R]D +79 (c 1.04,
D
MeOH)).
(3R,4R)-Eth yl 3-Ch lor o-4-h yd r oxyh exa n oa te (6c).
A
D
D
mixture of (()-10c (1.75 g, 7.40 mmol), 1/10 M phosphoric acid
buffer solution (pH 7.2, 100 mL), and lipase PS (0.90 g) was
stirred for 10.5 h at 25 °C. The organic materials were
extracted with ethyl acetate, and the combined extract was
washed with water, dried over MgSO4, and concentrated. The
residual oil (1.47 g) was chromatographed on silica gel (hexane/
ethyl acetate ) 30/1-3/1) to give 389 mg (22.4%) of (3S,4S)-
10c as a first fraction [Rf 0.55 (hexane/ethyl acetate ) 2/1);
91% ee; mp 49-51 °C (lit.16a mp 50-51 °C, lit.16b mp 54-56
°C); IR (neat) 2950, 2860, 1785, 1665 cm-1; 1H NMR (500 MHz,
CDCl3) δ 0.88 (broad t, J ) 7 Hz, 3H), 1.2-1.6 (m, 12H), 1.78
(m, 2H), 3.50 (m, 1H), 4.42 (dt, J ) 3.8 and 6.6 Hz, 1H), 5.03
(d, J ) 8.6 Hz, 1H), 5.87 (d, J ) 2.0 Hz, 1H), 6.48 (d, J ) 2.4
Hz, 1H).
Ack n ow led gm en t. This work was partially sup-
ported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science and Culture, J apan.
We are grateful to SC-NMR Laboratory of Okayama
University for the measurement of NMR spectra.
[R]22 -23.9 (c 1.59, CHCl3)] and 435 mg (29.4%) of (3R,4R)-
D
6c as a second fraction: Rf 0.35 (hexane/ethyl acetate ) 2/1);
[R]22D +22.1 (c 2.02, CHCl3). The spectral data were identical
with those of the racemate.
(3S,4S,5R)-4-[1-(ter t-Bu toxyca r bon yl)-1-(p h en ylselen o-
)eth yl]-3-iod o-5-octyltetr a h yd r o-2-fu r a n on e (12e). To a
10 mL two-necked flask were charged diisopropylamine (0.06
mL, 0.45 mmol) and dry THF (0.5 mL), and the solution was
cooled to -20 °C. Butyllithium (1.57 M, 0.29 mL, 0.45 mmol)
was added dropwise, and the mixture was stirred for 30 min
and cooled to -78 °C. A solution of tert-butyl 2-(phenylsele-
no)propionate (110 mg, 0.38 mmol) in dry THF (0.5 mL) was
added. After 1 h, a solution of 7e (75 mg, 0.38 mmol) in THF
(0.5 mL) was added, and the mixture was stirred for 3 h. A
mixture of iodine (100 mg, 0.40 mmol) and THF (0.5 mL) was
added, and the mixture was stirred for 1 h and quenched with
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
of compounds 5c-e, 6c,d , (S)-7c, (S)-7d , (S)-7e, (()-syn-6c,
(()-syn-6d , (()-syn-6e, (()-syn-10a , (()-syn-10b, (()-syn-10c,
(()-syn-10d , and (()-syn-10e and elemental analysis data of
some of them (3 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O970045R