A concise synthetic route to optically active cis-β,γ- disubstituted-γ-butyrolactones via tandem Michael-MPV reaction: New total synthesis of (-)-cis-whisky lactone and (-)-cis-cognac lactone

Article abstract of DOI:10.1016/j.tetasy.2005.03.017

Optically active cis-β,γ-disubstituted-γ-butyrolactones, for example, cis-whisky lactone and cis-cognac lactone, were readily synthesized by using tandem Michael-Meerwein-Ponndorf-Verley reactions that employed (-)-10-mercapto-isoborneol as a chiral template in the key step.

Full text of DOI:10.1016/j.tetasy.2005.03.017

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1663–1671
A concise synthetic route to optically active
cis-b,c-disubstituted-c-butyrolactones via tandem Michael–MPV
reaction: new total synthesis of (ꢀ)-cis-whisky lactone and
(ꢀ)-cis-cognac lactone
Minoru Ozeki, Daisuke Hashimoto, Kiyoharu Nishide,
Tetsuya Kajimoto and Manabu Node*
Department of Pharmaceutical Manufacturing Chemistry, 21st Century COE Program, Kyoto Pharmaceutical University,
Yamashina-ku, Kyoto 607-8414, Japan
Received 1 February 2005; accepted 14 March 2005
Available online 14 April 2005
Abstract—Optically active cis-b,c-disubstituted-c-butyrolactones, for example, cis-whisky lactone and cis-cognac lactone, were
readily synthesized by using tandem Michael–Meerwein–Ponndorf–Verley reactions that employed (ꢀ)-10-mercapto-isoborneol
as a chiral template in the key step.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
tiguous stereogenic centers of optically active cis-b,c-
disubstituted-c-butyrolactones I in one step.
c-Butyrolactones occur in nature as pheromones and
flavor components,1 and their enantiomeric purity and
absolute configuration often affect physiological activi-
ties.2 In addition, optically active c-butyrolactones are
useful as the chiral synthons for the synthesis of versatile
bioactive compounds.3 Thus, much attention has been
paid to asymmetric syntheses of c-butyrolactones. How-
ever, reports on the synthesis of cis-b,c-disubstituted-c-
butyrolactones I (Fig. 1) compared with that of the trans
form are limited.4 Moreover, construction of the two
stereogenic centers in b,c-disubstituted-c-butyrolactone
has required tedious, stepwise procedures.5 Herein we
report a facile synthetic route that can construct the con-
2. Result and discussion
We have recently developed a tandem Michael addition-
Meerwein–Ponndorf–Verley (MPV) reduction of a,b-
unsaturated ketones 2 with (ꢀ)-10-mercaptoisoborneol
1 to give the optically active alcohols 3 (Scheme 1).6a,b
Alcohols 3 having three contiguous stereogenic carbons
were obtained with high stereoselectivity and good yield
when the a,b-unsaturated ketones 2 (R1 5 H, R2 =
aryl group) were employed as substrates.6c An increase
in the stereoselectivity of the reaction was observed by
adding pentafluorobenzoic acid (PFBA) when substrate
2 (R1 5 H, R2 = alkyl group) was treated in the reac-
tion; almost no diastereoselectivity was observed with-
out the addition of PFBA (Table 1).6c
R1
Me
Me
R2
n-Bu
(-)-cis-whisky lactone 9
n-Pent
(-)-cis-cognac lactone 10
O
O
O
O
O
O
Based on these results, we planned to take advantage of
the tandem reaction for an asymmetric synthesis of cis-
b,c-disubstituted-c-butyrolactones I, as shown in the
retro-synthetic analysis (Scheme 2). c-Butyrolactones I
can be cyclized by acidic treatment of c-hydroxycarb-
oxylic acid II, which could in turn be obtained from 3-
arylpropanol derivative III by oxidative degradation of
I
Figure 1.
*
Corresponding author. Tel.: +81 75 595 4639; fax: +81 75 595
4775; e-mail: node@mb.kyoto-phu.ac.jp
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.03.017

1664
M. Ozeki et al. / Tetrahedron: Asymmetry 16 (2005) 1663–1671
O
OH
O
S
Me2AlCl (1.5 eq)
CH2Cl2, rt, 2d
Ar
R2
+
OH
R2
Ar
R1
SH
R1
~92% yield
~98% de
(-)-1 (1.5 eq)
2
3
Scheme 1. Tandem Michael–MPV reaction of 2 with (ꢀ)-1.
Table 1. Tandem Michael–MPV reaction of (ꢀ)-l with 2
O
O
(-)-1 (1.5 eq)
O
S
OH
S
OH
R2
PFBA
R2
Other
+
Ar
+
R2
Me2AlCl (1.5 eq)
CH2Cl2, rt, 2-3d
Ar
Ar
isomer
R1
R1
3A
R1
3B
2
Entry
Substrate
R1
PFBA [equiv]
Yielda (Ratio)b
Other isomer
Ar
R2
Ph
3A/3B
1
a
4-MeO-Ph
4-MeO-Ph
Et
Me
Ph
—
67 (94:6)
—
—
2b
3
—
4-ClPh
n-Bu
67 (94:6)
c
4-MeO-Ph
Ph
Me
Me
—
—
84 (97:3)
72(53:47)
62(71:29)
64 (51:49)
61 (73:27)
50 (98:2)
—
4
d
—
5
1.5
—
13
6
e
f
Ph
Ph
Me
Me
n-Pen
c-Hex
—
14
5
7
1.5
1.5
8
a Isolated yield.
b Ratio was determined by 1H NMR spectroscopy.
O
O P
R2
O P
R2
R1
S
O
P
R2
Ar
HO2C
R2
Ar
O
O
R1
R1
III
R1
3
II
I
(P: protecting group)
Scheme 2. Retro-synthetic strategy for asymmetric synthesis of cis-b,c-disubstituted-c-butyrolactones.
the aryl ring with RuCl3/NaIO4 (or H5IO6).7 Further-
more, introduction of a methoxy group on the phenyl
ring is known to be effective in the oxidation to carbox-
ylic acid.8 Alcohol III could be derived by the reductive
desulfurization of 3, the product of the tandem Mi-
chael–MPV reaction. Taking the above background into
consideration, we chose a,b-unsaturated ketones 2 hav-
ing a 4-methoxyphenyl group at the b-position as the
starting material for the tandem Michael–MPV reaction.
6 instead of the desired acetate 4a due to the hydrogeno-
lysis of the benzylic acetate.
In order to obtain the desired secondary acetate 4a, we
reversed the reaction sequence of the acetylation and
the reductive desulfurization of 3Aa. Namely, the de-
sired acetate 4a was obtained quantitatively by the treat-
ment of 3Aa with the milder Raney Ni (W2)–NaPH2O2
combination system10,11 to remove the chiral moiety,
followed by acetyl protection of the hydroxyl group
(Scheme 4). The resulting acetate 4a was oxidized to carb-
oxylic acid 7a with RuCl3xH2O/H5IO6.7,8 Successive
treatment of carboxylic acid 7a with 1 M NaOH and
10% HCl afforded the desired cis-b,c-disubstituted-c-
butyrolactone 8a12 in 57% yield from 4a.
We first attempted the conversion of 3Aa (Table 1)9 into
acetate 4a (Scheme 3). Unfortunately, acetyl protection
of the hydroxyl group of 3Aa, followed by the reductive
removal of the chiral moiety under the conventional
Raney Ni (W2) conditions afforded the undesired product

M. Ozeki et al. / Tetrahedron: Asymmetry 16 (2005) 1663–1671
1665
1) Ac2O (3 eq)
OAc
Ph
O
(-)-1 (1.5 eq)
DMAP (cat.)
O
Me2AlCl (1.5 eq)
OH
S
Ph
4-MeOPh
4-MeOPh
4-MeOPh
CH2Cl2, rt, 2d
Me
2a
Me
2) Raney Ni (W-2)
EtOH, rt
4-MeOPh
Ph
4a
Me
3Aa
67 % yield (88 %de)
Ph
Me
6 (68 %)
Scheme 3.
1) Raney Ni (W2)
NaPH2O2 (10 eq)
in pH 5.2
OAc
Ph
3) RuCl3.xH2O (20 mol%)
H5IO6 (20 eq)
4-MeOPh
3Aa
Me
CCl4 / MeCN / H2O, rt
2) Ac2O (3 eq)
DMAP (cat.)
4a
96 % (98 %ee)
Me
OAc
4) 1M NaOH aq, rt
5) 10 % HCl aq, rt
HOOC
Ph
O
Ph
57 % (from 4a)
O
Me
7a
8a
Scheme 4. Asymmetric synthesis of cis-b,c-disubstituted-b-butyrolactone.
Next, we tried to generalize the above method for the
synthesis of a broad range of cis-b,c-disubstituted-c-
butyrolactones 8 (Table 2). Compounds 3Ab-c, which
were obtained by using the tandem Michael–MPV reac-
tion with high diastereoselectivity and in good yield
(Table 1, entries 2and 3), were successfully converted into
the desired cis-b,c-disubstituted-c-butyrolactones 8b
and c (Table 2, entries 2and 3). Differing from these in-
stances, the preparation of 8f (R2 = alkyl group instead
of aryl group) gave a satisfactory result (Table 2, entry
4) by a sequence of acetylation of 3Af and the conven-
tional Raney Ni (W2) reduction since no undesired com-
pound, such as 6, was formed (Method B).
Finally, we focused our attention on the synthesis of
natural products as a practical application of the newly
developed methodology. Whisky and cognac lactones
were identified as essential flavor components of aged
alcoholic beverages such as whisky, cognac, brandy
and wine, and exist as cis- and trans-forms in nature
(Fig. 1).13 Although many enantioselective total synthe-
ses of trans-isomers have been reported,14 there are few
reports of enantioselective total syntheses of cis-isomers
9 and 10.5b,15
According to our retro-synthetic strategy (Scheme 2),
the key compound 3Ad, obtained by the tandem
Table 2. Asymmetric syntheses of cis-b,c-disubstituted-c-butyrolactones 8
1) RuCl3.xH2O (20 mol%)
R1
OAc
R2
R1
O
H5IO6 (20 eq)
S
OH
R2
CCl4/MeCN/H2O, rt
Method A
Method B
Ar
O
2) 1M NaOH aq, rt
3) 10 % HCl aq, rt
Ar
R2
O
R1
3A
4
8
Method A ; 1) Raney Ni (W-2), NaPH2O2 (10 eq). 2) Ac2O, DMAP.
Method B ; 1) Ac2O, DMAP. 2) Raney Ni (W-2).
Entry
3A
R1
Me
Ph
Method
4
8
Ar
R2
Ph
Yield (%)
Ee (%)
Yield (%)
1
a
4-MeO-Ph
4-MeO-Ph
Et
A
95
A
B
99
98a
a
57
56
60
67
2b
3
A
4-Cl-Ph
c-Hex
98
c
f
4-MeO-Ph
Ph
Me
Me
95
97
99a
99
4
a Ee value was determined for the corresponding free alcohol.

1666
M. Ozeki et al. / Tetrahedron: Asymmetry 16 (2005) 1663–1671
1) Ac2O (3 eq)
1) RuCl3.xH2O (20 mol%)
DMAP (cat.)
Me
O
H5IO6 (20 eq)
OAc
R
S
OH
py, rt
CCl4/MeCN/H2O, rt
Ph
O
Ph
2) Raney Ni (W2)
EtOH, rt
R
R
2) 1M NaOH aq, rt
3) 10 % HCl aq, rt
O
Me
Me
3Ad R = n-Bu
3Ae R = n-Pen
4d: 89 % (99 %ee)
4e: 90 % (99 %ee)
(-)-cis-whisky lactone 9
62 % (3 steps)
[α]D24 -76.9 (lit.15b; [α]D = -78.0)
(-)-cis-cognac lactone 10
70 % (3 steps)
[α]D23 -67.7 (lit.17; [α]D = -65.2)
Scheme 5. Asymmetric total syntheses of (ꢀ)-cis-whisky lactone and (ꢀ)-cis-cognac lactone.
Michael–MPV reaction (Table 1, entry 4) was acetylated
and followed by reductive removal of the chiral moiety
with Raney Ni (W2) to afford a secondary acetate 4d
in 89% yield (Scheme 5). After ruthenium-catalyzed oxi-
dative degradation of the phenyl group on 4d to carbox-
ylic acid, (ꢀ)-cis-whisky lactone 9 was obtained readily
by hydrolysis under basic conditions (1 M NaOH) and
lactonization under an acidic condition (10% HCl) in
Chromatograph series using a Daicel chiral column
(CHIRALCEL OD, OF). Their data were recorded on
Shimadzu C-R6A Chromatopac. Acetate buffer was ad-
justed by using a Horiba pH meter F-13. Wakogel C-200
(silica gel) (100–200 mesh, Wako) was used for open col-
umn chromatography. Flash column chromatography
was performed by using Silica Gel 60N (Kanto Chemi-
cal Co., Inc.) as a solid support of immobile phase. Kie-
selgel 60 F-254 plates (Merck) were used for thin layer
chromatography (TLC). Preparative TLC (PTLC) was
conducted with Kieselgel 60 F-254 plate (0.25 mm,
Merck) or Silica gel 60 F-254 plate (0.5 mm, Merck).
Unless purification with silica gel gave compound being
pure enough, the compounds were further treated with a
recycle HPLC (JAI LC-908) on GPC column (JAIGEL
1H and 2H). When possible, diastereomeric mixtures
were also separated by a recycle HPLC (JAI LC-908)
on silica gel column (Kusano Si-10) after the purifica-
tion mentioned above.
62% yield from 4d. The specific rotations
24
D
{½aŠ ¼ ꢀ76:9 (c 1.73, MeOH), lit.15b [a]D = ꢀ78.0
(MeOH)} and spectroscopic data of synthetic (ꢀ)-cis-
whisky lactone 9 were identical with those reported in
the literature.16 According to the same synthetic proce-
dure, we achieved asymmetric total synthesis of (ꢀ)-
cis-cognac lactone 10 (Scheme 5).15c,17
3. Conclusion
We have developed a highly enantio- and diastereoselec-
tive synthetic route to cis-b,c-disubstituted-c-butyrolac-
tones by using the tandem Michael–MPV reaction with
a chiral reagent (ꢀ)-1 as the key step to construct the
two required stereogenic centers in one step. As an
application of our lactone synthesis, we have succeeded
in the asymmetric total synthesis of (ꢀ)-cis-whisky lac-
tone 9 and (ꢀ)-cis-cognac lactone 10, which had hardly
been reported so far.
4.2. Materials
Most of the reagents were obtained from Wako Pure
Chemical Industries, Ltd., Nakalai Tesque, Inc., Aldrich
Chemical Inc. Raney Ni (W-2) (suspension in ethanol)
was prepared according to general procedure. (ꢀ)-10-
Mercaptoisoborneol (ꢀ)-1 was prepared by ElielÕs pro-
cedure.18,6a,b A typical procedure for the tandem
Michael–MPV reaction of (ꢀ)-1 with 2 should be referred
to the previous report.6c Mixtures of the diastereomers
of 3 were also separated to each diastereomer by the re-
cycle HPLC. The characterized data for 3a, 3b, and 3f
have been reported.6c
4. Experimental
4.1. General
Infrared (IR) spectra were recorded on a JASCO IR-810
or a Shimadzu FTIR-8300 diffraction grating infrared
spectrophotometer while 1H NMR spectra were ob-
tained on a JEOL JNM-AL300, a Varian XL-300, a
Varian Unity INOVA-400 spectrometer with tetrameth-
ylsilane as an internal standard. 13C NMR spectra were
obtained on a Varian Unity INOVA-400 spectrometer
with CDCl3 as an internal standard. Mass spectra
(MS) were determined on a JEOL JMS-SX 102A QQ
or a JEOL JMS-GC-mate mass spectrometer. Optical
rotations were recorded on a Horiba SEPA-200 auto-
matic digital polarimeter. Chiral HPLC analyses were
performed with a Shimadzu LC-9A and LC-10A Liquid
4.2.1. (1R,2R,3R)-1-(4-Chlorophenyl)-3-(4-methoxyphe-
nyl)-2-methyl-3-[(1S,4R)-2-oxobornane-10-sulfanyl]-1-pro-
23
D
panol 3Ac. Colorless oil; ½aŠ ¼ þ173:2 (c 1.12,
1
CHCl3); H NMR (400 MHz, CDCl3): d 7.34–7.28 (m,
4H), 7.24 (dt type, J = 8.8, 2.6 Hz, aromatic 2H), 6.84
(dt type, J = 8.8, 2.6 Hz, aromatic 2H), 5.53 (dd,
J = 4.2, 2.6 Hz, 1H), 3.92 (d, J = 10.6 Hz, 1H), 3.80 (s,
3H), 3.11 (d, J = 4.4 Hz, 1H), 2.56 (d, A part of AB,
JAB = 13.3 Hz, 1H), 2.34 (ddd,
A part of AB,
JAB = 18.4 Hz, J = 4.8, 3.2 Hz, 1H), 2.27 (d, B part of
AB, JAB = 13.3 Hz, 1H), 2.11–2.03 (m, 2H), 1.96–1.87
(m, 1H), 1.86 (d, B part of AB, JAB = 18.4 Hz, 1H),
1.79–1.71 (m, 1H), 1.65–1.58 (m, 1H), 1.38–1.31 (m,

M. Ozeki et al. / Tetrahedron: Asymmetry 16 (2005) 1663–1671
1667
1H), 0.89 (s, 3H), 0.79 (s, 3H), 0.50 (d, J = 7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d 218.7, 158.5, 142,1,
134.6, 132.1, 129.5 (2C), 128.1 (2C), 127.1 (2C), 113.7
(2C), 72.3, 61.0, 55.7, 55.2, 48.0, 45.8, 43.3, 43.2, 28.2,
27.0, 26.8, 19.9, 19.8, 10.9; IR (CHCl3): 3500, 3026,
3006, 2964, 2937, 1735, 1610, 1583, 1510, 1490, 1465,
1456, 1251 cmꢀ1; MS (20 eV) m/z: 472(M +, 0.3), 288
(29), 148 (100), 139 (37), 121 (65), 105 (8), 91 (6); HRMS
calcd for C27H33ClO2S (M+): 472.1839, found 472.1836.
3H), 0.73 (s, 3H), 0.69 (d, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 218.1, 143.0, 128.7 (2C), 128.2
(2C), 126.8, 71.4, 60.8, 56.1, 47.8, 43.3, 43.2, 43.1,
34.7, 32.0, 27.8, 26.8, 26.7, 26.2, 22.6, 19.8 (2C), 14.1,
11.1; IR (CHCl3): 3525, 2958, 2935, 2858, 1735, 1600,
1488, 1454, 1415, 1377 cmꢀ1; MS (70 eV) m/z: 402
(M+, 5), 273 (79), 218 (18), 151 (31), 118 (100), 91
(77), 64 (46), 55 (65); HRMS calcd for C25H38O2S
(M+): 402.2592, found 402.2594.
4.2.2. (1R,2R,3S)-2-Methyl-1-[(1S,4R)-2-oxobornane-10-
4.2.5. (1R,2S,3S)-2-Methyl-1-[(1S,4R)-2-oxobornane-10-
18
24
D
sulfanyl]-1-phenyl-3-heptanol 3Ad. Colorless oil; ½aŠ
¼
sulfanyl]-1-phenyl-3-octanol 3Be. Colorless oil; ½aŠ ¼
D
þ174:4 (c 0.82, CHCl3); 1H NMR (400 MHz, CDCl3): d
7.31–7.19 (m, 5H), 4.29–4.24 (br m, 1H), 3.82 (d,
J = 10.6 Hz, 1H), 2.57 (d, A part of AB, JAB = 13.3 Hz,
1H), 2.37 (d, J = 4.8 Hz, 1H), 2.30 (ddd, A part of AB,
JAB = 18.3 Hz, J = 4.6, 3.3 Hz, 1H), 2.14 (d, B part of
AB, JAB = 13.3 Hz, 1H), 2.02–1.99 (m, 1H), 1.94–1.84
(m, 2H), 1.83 (d, B part of AB, JAB = 18.3 Hz, 1H),
1.73–1.23 (m, 9H), 0.92 (t, J = 7.0 Hz, 3H), 0.85 (s,
3H), 0.73 (s, 3H), 0.70 (d, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 218.1, 143.0, 128.7 (2C), 128.3
(2C), 126.8, 71.4, 60.8, 56.1, 47.8, 43.3, 43.2, 43.1,
34.4, 28.7, 27.8, 26.8, 26.7, 22.8, 19.8 (2C), 14.1, 11.1;
IR (CHCl3): 3529, 3062, 3035, 2993, 2958, 2862, 1735,
1600, 1488, 1454, 1377, 1319, 1299 cmꢀ1; MS (70 eV)
m/z: 388 (M+, 6), 273 (85), 204 (35), 185 (46), 151 (43),
147 (37), 118 (89), 105 (17), 91 (100), 77 (23), 69 (55),
57 (55); HRMS calcd for C24H36O2S (M+): 388.2436,
found 388.2434.
þ128:3 (c 1.16, CHCl3); H NMR (400 MHz, CDCl3):
d 7.48–7.45 (m, 2H), 7.35–7.31 (m, 2H), 7.25–7.21 (m,
1H), 4.40 (d, J = 4.6 Hz, 1H), 3.63–3.57 (br m, 1H),
3.09 (d, J = 5.1 Hz, 1H), 2.44 (d, A part of AB,
1
JAB = 13.0 Hz, 1H), 2.32 (d,
JAB = 13.0 Hz, 1H), 2.31 (ddd,
B
A
part of AB,
part of AB,
JAB = 18.3 Hz, J = 5.1, 3.0 Hz, 1H), 2.04–2.02 (m, 1H),
1.99–1.82(m, 3H), 1.86 (d, B part of AB, JAB = 18.3 Hz,
1H), 1.67–1.48 (m, 3H), 1.42–1.20 (m, 7H), 0.92 (s, 3H),
0.88 (t, J = 7.0 Hz, 3H), 0.83 (d, J = 7.0 Hz, 3H), 0.75 (s,
3H); 13C NMR (100 MHz, CDCl3): d 218.1, 142.2, 128.8
(2C), 128.2 (2C), 126.7, 73.8, 60.7, 55.4, 47.9, 46.4, 43.2,
43.1, 33.9, 32.0, 28.6, 26.8, 26.6, 25.6, 22.7, 19.9, 19.8,
14.1, 11.8; IR (CHCl3): 3506, 3062, 2993, 2958, 2931,
2858, 1735, 1596, 1492, 1454, 1415, 1377 cmꢀ1; MS
(70 eV) m/z: 402(M +, 5), 273 (100), 233 (19), 218 (32),
185 (46), 151 (40), 147 (32), 118 (96), 91 (94), 64 (66),
55 (79); HRMS calcd for C25H38O2S (M+): 402.2592,
found 402.2599.
4.2.3. (1R,2S,3S)-2-Methyl-1-[(1S,4R)-2-oxobornane-10-
26
D
sulfanyl]-1-phenyl-3-heptanol 3Bd. Colorless oil; ½aŠ
¼
4.3. Asymmetric synthesis of c-butyrolactone 8
þ133:1 (c 1.06, CHCl3); 1H NMR (400 MHz, CDCl3): d
7.48–7.45 (m, 2H), 7.35–7.30 (m, 2H), 7.26–7.20 (m,
1H), 4.40 (d, J = 4.6 Hz, 1H), 3.63–3.57 (br m, 1H),
3.10 (d, J = 5.1 Hz, 1H), 2.44 (d, A part of AB,
The synthetic procedure of c-butyrolactone 8a is shown
below as a typical procedure. Compounds 8b and c were
synthesized in the same way as 8a.
JAB = 13.0 Hz, 1H), 2.32 (d,
JAB = 13.0 Hz, 1H), 2.31 (ddd,
B
A
part of AB,
part of AB,
4.3.1. (1R,2S)-1-Acetoxy-3-(4-methoxyphenyl)-2-methyl-
1-phenylpropane 4a. Freshly prepared Raney Ni (W-2)
(suspension in ethanol, 7 mL) was added to a solution of
3Aa (30 mg, 0.67 mmol) in a mixed medium (7 mL) of
an acetate buffer (pH 5.2) and ethanol (1:2), followed
by the immediate addition of aqueous solution (2mL)
of sodium hypophosphite monohydrate (710 mg,
6.70 mmol), and the reaction mixture stirred for another
0.5 h at room temperature. The reaction mixture was fil-
tered through Celite (washing with methanol), and the
filtrate evaporated. The residue was poured into water,
and then extracted with ethyl acetate three times. The
combined organic layer was washed with brine, and
dried over magnesium sulfate, filtered and concentrated
in vacuo. Purification of the residue by the prepara-
tive TLC (hexane/ethyl acetate = 5:1) gave (1R,2S)-3-
JAB = 18.3 Hz, J = 4.8, 2.9 Hz, 1H), 2.04–2.02 (m, 1H),
2.00–1.82 (m, 3H), 1.86 (d, B part of AB, JAB = 18.3 Hz,
1H), 1.68–1.24 (m, 8H), 0.92 (s, 3H), 0.90 (t, J = 7.3 Hz,
3H), 0.83 (d, J = 7.0 Hz, 3H), 0.75 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 218.1, 142.2, 128.8 (2C), 128.2
(2C), 126.7, 73.8, 60.7, 55.4, 47.9, 46.5, 43.2, 43.1,
33.7, 28.6, 28.2, 26.8, 26.6, 22.8, 19.9, 19.8, 14.1, 11.8;
IR (CHCl3): 3506, 3062, 3028, 2993, 2958, 2873, 1735,
1600, 1492, 1454, 1415, 1377, 1319, 1299 cmꢀ1; MS
(70 eV) m/z: 388 (M+, 6), 273 (100), 204 (48), 185 (57),
151 (51), 118 (95), 105 (11), 91 (91), 77 (13), 69 (55),
57 (43); HRMS calcd for C24H36O2S (M+): 388.2436,
found 388.2434.
4.2.4. (1R,2R,3S)-2-Methyl-1-[(1S,4R)-2-oxobornane-10-
23
D
sulfanyl]-1-phenyl-3-octanol 3Ae. Colorless oil; ½aŠ
¼
(4-methoxyphenyl)-2-methyl-1-phenyl-1-propanol (17.3
21
1
þ168:6 (c 0.89, CHCl3); H NMR (400 MHz, CDCl3):
d 7.32–7.19 (m, 5H), 4.27 (br m, 1H), 3.82 (d,
J = 10.6 Hz, 1H), 2.57 (d, A part of AB, JAB = 13.2Hz,
1H), 2.37 (d, J = 4.6 Hz, 1H), 2.30 (ddd, A part of AB,
JAB = 18.3 Hz, J = 4.6, 3.3 Hz, 1H), 2.14 (d, B part of
AB, JAB = 13.2Hz, 1H), 2.01–1.99 (m, 1H), 1.94–1.83
(m, 2H), 1.83 (d, B part of AB, JAB = 18.3 Hz, 1H),
1.73–1.26 (m, 11H), 0.90 (t, J = 6.9 Hz, 3H), 0.85 (s,
mg, 99%). Pale yellow oil; ½aŠ ¼ þ9:4 (c 0.64, CHCl3);
D
1H NMR (300 MHz, CDCl3): d 7.38–7.25 (m, 5H), 7.08–
7.06 (m, 2H), 6.84–6.81 (m, 2H), 4.60 (d, J = 4.9 Hz,
1H), 3.78 (s, 3H), 2.72 (dd, A part of AB, JAB = 13.4 Hz,
J = 5.9 Hz, 1H), 2.33 (dd, B part of AB, JAB = 13.4 Hz,
J = 9.0 Hz, 1H), 2.10–2.01 (m, 1H), 1.80 (br, 1H), 0.85
(d, J = 6.7 Hz, 3H); IR (CHCl3): 3607, 3032, 3010,
2934, 1610, 1512, 1454, 1300, 1250, 1178, 1035 cmꢀ1
;

1668
M. Ozeki et al. / Tetrahedron: Asymmetry 16 (2005) 1663–1671
MS (70 eV) m/z: 256 (M+, 27), 238 (76), 223 (23), 149
(56), 121 (92), 107 (100), 79 (19); HRMS calcd for
C17H20O2 (M+): 256.1463, found 256.1471. [98% ee, chi-
ral HPLC analysis; DAICEL CHIRALCEL OF
(25 · 0.46); eluent: hexane/isopropanol = 99/1; flow rate:
0.5 mL/min; Temp.: 25 ꢁC; detector: 254 nm, (ꢀ):
43.9 min, (+): 49.3 min].
989 cmꢀ1; MS (20 eV) m/z: 176 (M+, 35), 107 (100),
105 (41), 79 (11), 70 (16); HRMS calcd for C11H12O2
(M+): 176.0837, found 176.0840.
4.3.3. (1R,2S)-1-Acetoxy-2-ethyl-3-(4-methoxyphenyl)-1-
23
D
phenylpropane 4b. Colorless oil; ½aŠ ¼ þ29:2 (c 1.30,
1
CHCl3); H NMR (400 MHz, CDCl3): d 7.34–7.22 (m,
5H), 7.00 (dt type, J = 8.7, 2.5 Hz, aromatic 2H), 6.81
(dt type, J = 8.7, 2.5 Hz, aromatic 2H), 5.72 (d,
J = 5.9 Hz, 1H), 3.78 (s, 3H), 2.49 (dd, A part of AB,
JAB = 13.8 Hz, J = 6.6 Hz, 1H), 2.42 (dd, B part of
AB, JAB = 13.8 Hz, J = 7.9 Hz, 1H), 2.10 (s, 3H), 2.09–
2.01 (m, 1H), 1.44–1.30 (m, 2H), 0.89 (d, J = 7.5 Hz,
3H); 13C NMR (100 MHz, CDCl3): d 170.2, 157.8,
139.7, 132.5, 129.9 (2C), 128.2 (2C), 127.5, 126.7 (2C),
113.7 (2C), 76.7, 55.2, 47.1, 34.7, 21.2, 20.9, 11.0; IR
(CHCl3): 3026, 3010, 2964, 2935, 2877, 2837, 1732,
1612, 1512, 1496, 1463, 1456, 1245 cmꢀ1; MS (70 eV)
Next acetic anhydride (193 mg, 1.89 mmol) was added
solution of (1R,2S)-3-(4-methoxyphenyl)-2-
to
a
methyl-1-phenyl-1-propanol (161 mg, 0.63 mmol) and
4-dimethylaminopyridine (catalytic amount) in pyridine
(3 mL), and the reaction mixture stirred for 30 min at
room temperature. The reaction mixture was added into
methanol at 0 ꢁC, and concentrated in vacuo to give a
residue, which was purified by silica gel column chroma-
tography (hexane/ethyl acetate = 3:1) to give 4a
24
D
(188.0 mg, 100%). Colorless oil; ½aŠ ¼ þ17:7 (c 0.82,
1
+
CHCl3); H NMR (400 MHz, CDCl3): d 7.36–7.25 (m,
5H), 7.00 (dt type, J = 8.6, 2.5 Hz, aromatic 2H), 6.81
(dt type, J = 8.6, 2.5 Hz, aromatic 2H), 5.65 (d,
J = 5.7 Hz, 1H), 3.78 (s, 3H), 2.63 (dd, J = 12.8,
4.4 Hz, 1H), 2.26–2.10 (m, 2H), 2.12 (s, 3H), 0.86 (d,
J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
170.2, 157.9, 139.7, 132.3, 129.9 (2C), 128.2 (2C),
127.6, 126.7 (2C), 113.7 (2C), 78.8, 55.2, 41.1, 38.4,
21.2, 14.5; IR (CHCl3): 3035, 3026, 1732, 1612, 1512,
1465, 1456, 1371, 1244, 1178, 1020 cmꢀ1; MS (70 eV)
m/z: 298 (M+, 4), 238 (31), 223 (27), 121 (51), 107 (15),
105 (4), 91 (12), 83 (100), 77 (11); HRMS calcd for
C19H22O3 (M+): 298.1569, found 298.1567.
m/z: 312(M , 4), 252 (19), 223 (83), 121 (100), 105 (6),
77 (16); HRMS calcd for C20H24O3 (M+): 312.1725,
found 312.1727.
4.3.4. (3S,4R)-3-Ethyl-4-phenylbutan-4-olide 8b. Color-
21
D
1
less oil; ½aŠ ¼ þ42:6 (c 1.97, CHCl3); H NMR (400
MHz, CDCl3): d 7.41–7.03 (m, 3H), 7.23–7.20 (m,
2H), 5.62 (d, J = 6.6 Hz, 1H), 2.75 (ddd, A part of
AB, JAB = 16.7 Hz, J = 8.1, 0.4 Hz, 1H), 2.73–2.63 (m,
1H), 2.45 (dd,
B
part of AB, JAB = 16.7 Hz,
J = 5.7 Hz, 1H), 1.18–1.09 (m, 1H), 0.93–0.78 (m, 1H),
0.80 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 176.9, 136.3, 128.4 (2C), 128.1, 125.7 (2C), 84.2,
42.1, 33.9, 22.5, 11.9; IR (CHCl3): 3033, 2964, 2935,
1778, 1602, 1496, 1456, 1315, 1303, 1163 cmꢀ1; MS
(70 eV) m/z: 190 (M+, 34), 107 (100), 105 (59), 77 (32),
56 (70); HRMS calcd for C12H14O2 (M+): 190.0994,
found 190.0995.
4.3.2. (3S,4R)-3-Methyl-4-phenylbutan-4-olide 8a.12
Ruthenium(III) chloride hydrate (12mg, 0.06 mmol)
and orthoperiodic acid (1.3 g, 5.50 mmol) were added
to a biphasic solution of 4a (82mg, 0.28 mmol) in
CCl4/CH3CN/H2O = 5:5:8 (9 mL), and the reaction mix-
ture stirred for 2h at room temperature. The reaction
mixture was acidified with 1 M HCl aq to pH 1, and
the solution extracted with ethyl acetate three times.
The combined organic layer was successively washed
with a saturated aqueous solution of sodium thiosulfate
and brine, dried over magnesium sulfate, filtered and
concentrated in vacuo to give crude (3S,4R)-4-acetoxy-
3-methyl-4-phenylbutyric acid. Then, it was hydrolyzed
with 1 M NaOH (5 mL) at room temperature for 2h,
and the reaction mixture acidified with 10% HCl aq to
pH 1, and stirred for another 18 h. The reaction mixture
was neutralized with saturated aqueous solution of so-
dium bicarbonate, and extracted with ethyl acetate three
times. The combined organic layer was successively
washed with saturated aqueous solution of sodium thio-
sulfate and brine, dried over magnesium sulfate, filtered,
and concentrated in vacuo to give a residue. The residue
was purified with silica gel column chromatography
4.3.5. (1R,2S)-1-Acetoxy-1-(4-chlorophenyl)-3-(4-methoxy-
22
D
phenyl)-2-methylpropane 4c. Colorless oil; ½aŠ
¼
1
þ27:1 (c 1.57, CHCl3); H NMR (400 MHz, CDCl3): d
7.31(dt type, J = 8.6, 2.2 Hz, aromatic 2H), 7.22–7.19
(m, 2H), 6.98 (dt type, J = 8.6, 2.5 Hz, aromatic 2H),
6.80 (dt type, J = 8.6, 2.5 Hz, aromatic 2H), 5.59 (d,
J = 5.7 Hz, 1H), 3.78 (s, 3H), 2.61 (dd, A part of AB,
JAB = 13.4 Hz, J = 5.1 Hz, 1H), 2.33 (dd, B part of
AB, JAB = 13.4 Hz, J = 9.3 Hz, 1H), 2.17–2.07 (m,
1H), 2.12 (s, 3H), 0.85 (d, J = 6.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 189.5, 174.7, 151.0, 145.0, 143.4,
140.8 (2C), 139.1 (2C), 138.6 (2C), 121.3 (2C), 78.3,
50.7, 33.6, 30.4, 9.5, 1.5; IR (CHCl3): 3033, 3024,
3006, 2966, 2935, 2912, 1733, 1612, 1583, 1512, 1492,
1463, 1371, 1299, 1249, 1178, 1024, 1014 cmꢀ1; MS
(70 eV) m/z: 332(M +, 5), 334 (2), 274 (7), 272 (22),
257 (24), 121 (70), 83 (100), 77 (12); HRMS calcd for
C19H21ClO3 (M+): 332.1179, found 332.1178.
(hexane/ethyl acetate = 3:1) to give 8a (28 mg, 57% yield
25
from 4a). Colorless oil; ½aŠ ¼ þ56:7 (c 1.19, CHCl3);
4.3.6. (3S,4R)-4-(4-Chlorophenyl)-3-methylbutan-4-olide
8c. Colorless prism; mp 50–52 ꢁC (hexane/ethyl ace-
D
1H NMR (400 MHz, CDCl3): d 7.41–7.30 (m, 3H),
7.25–7.22 (m, 2H), 5.60 (d, J = 6.2Hz, 1H), 2.94–2.80
(m, 2H), 2.40–2.31 (m, 1H), 0.70 (d, J = 7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d 176.7, 136.1, 128.5
(2C), 128.0, 125.4 (2C), 84.0, 37.0, 34.9, 15.1; IR
(CHCl3): 3035, 1774, 1604, 1496, 1454, 1089, 1008,
22
D
tate); ½aŠ ¼ þ52:7 (c 1.46, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.37 (dt type, J = 6.6, 2.2 Hz, aro-
matic 2H), 7.21–7.17 (m, 2H), 5.57 (d, J = 5.9 Hz, 1H),
2.93–2.82 (m, 2H), 2.39–2.30 (m, 1H), 0.70 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 176.3,

M. Ozeki et al. / Tetrahedron: Asymmetry 16 (2005) 1663–1671
1669
134.6, 133.9, 128.7 (2C), 126.8 (2C), 83.3, 37.1 34.8, 15.1;
IR (CHCl3): 3020, 2970, 1782, 1600, 1494, 1456, 1305,
1161 cmꢀ1; MS (70 eV) m/z: 210 (M+, 35), 212 (9), 175
(10), 141 (85), 139 (91), 115 (15), 85 (68), 83 (100), 70
(48), 51 (19); HRMS calcd for C11H11ClO2 (M+):
210.0447, found 210.0452; Anal. Calcd for C11H11ClO2:
C, 62.72; H, 5.26. Found: C, 62.63; H, 5.41.
solution of 3Ad (253 mg, 0.65 mmol) and 4-dimethyl-
aminopyridine (catalytic amount) in pyridine (2mL),
and the reaction mixture stirred for 1 h at room temper-
ature. The reaction mixture was added into methanol at
0 ꢁC, and concentrated in vacuo to give a crude mate-
rial. This was subsequently added into a suspension of
freshly prepared Raney Ni (W-2) in ethanol (14 mL),
and the mixture stirred for 0.5 h at room temperature
and filtered through Celite (washing with methanol).
The filtrate was concentrated in vacuo to give a residue,
which was purified by silica gel column chromatography
4.3.7. (1R,2S)-1-Acetoxy-1-cyclohexyl-2-methyl-3-phen-
ylpropane 4f. Acetic anhydride (341 lL, 3.61 mmol)
was added to a solution of 3Af (300 mg, 0.72mmol)
and 4-dimethylaminopyridine (catalytic amount) in pyr-
idine (3 mL), and the reaction mixture stirred for 2h at
room temperature. The reaction mixture was added into
methanol at 0 ꢁC, and concentrated in vacuo to give a
crude material. It was subsequently added into a suspen-
sion of freshly prepared Raney Ni (W-2) in ethanol
(30 mL), and the mixture stirred for 0.5 h at room tem-
perature, and then the reaction mixture filtered through
Celite (washing with methanol). The filtrate was concen-
trated in vacuo to give a residue, which was purified with
silica gel column chromatography (hexane/ethyl ace-
tate = 50:1) to give 4f (192mg, 97% over two steps).
(hexane/ethyl acetate = 50:1) to give 4d (145 mg, 89%
23
D
over two steps). Colorless oil; ½aŠ ¼ ꢀ29:2 (c 1.72,
1
CHCl3); H NMR (400 MHz, CDCl3): d 7.30–7.12(m,
5H), 4.88 (ddd, J = 8.2, 4.8 and 4.0 Hz, 1H), 2.75 (dd,
A part of AB, JAB = 13.4 Hz, J = 5.1 Hz, 1H), 2.31
(dd, B part of AB, JAB = 13.4 Hz, J = 9.5 Hz, 1H),
2.07 (s, 3H), 2.00–1.91 (m, 1H), 1.66–1.48 (m, 2H),
1.35–1.19 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H), 0.85 (d,
J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
171.0, 140.7, 129.1 (2C), 128.2 (2C), 125.9, 77.0, 39.5,
38.5, 31.0, 27.9, 22.6, 21.2, 14.0, 13.9; IR (CHCl3):
3035, 3012, 2958, 2935, 2826, 1724, 1600, 1496, 1454,
1373, 1257, 1018 cmꢀ1; MS FAB(+) m/z: 249 (M++H,
57); HRMS calcd for C16H25O2 (M++H): 249.1855,
found 249.1850. [99% ee, chiral HPLC analysis; DAI-
CEL CHIRALCEL OD (25 · 0.46); eluent: hexane/iso-
propanol = 500:1; flow rate: 0.2mL/min; temp.: 27 ꢁC;
detector: 254 nm, (ꢀ): 37.8 min, (+): 40.1 min].
24
D
1
Colorless oil; ½aŠ ¼ ꢀ9:4 (c 1.49, CHCl3); H NMR
(400 MHz, CDCl3): d 7.30–7.24 (m, 2H), 7.20–7.11 (m,
3H), 4.78 (dd, J = 8.0, 3.7 Hz, 1H), 2.68 (dd, A part of
AB, JAB = 13.5 Hz, J = 4.9 Hz, 1H), 2.28 (dd, B part
of AB, JAB = 13.5 Hz, J = 9.4 Hz, 1H), 2.11 (s, 3H),
2.11–2.02 (m, 1H), 1.76–1.53 (m, 6H), 1.27–1.06 (m,
3H), 1.04–0.89 (m, 2H), 0.82 (d, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3): d 171.1, 140.7, 129.1 (2C),
128.2 (2C), 125.9, 80.4, 40.5, 39.2, 35.9, 29.4, 28.7,
26.3, 26.0, 25.9, 21.0, 13.0; IR (CHCl3): 3010, 2933,
2854, 1724, 1602, 1494, 1450, 1371, 1251, 1018,
970 cmꢀ1; MS FAB(+) m/z: 297 (M++Na, 100); HRMS
calcd for C18H26O2Na (M++Na): 297.1830, found
297.1834. [99% ee, chiral HPLC analysis; DAICEL
CHIRALCEL OD (25 · 0.46); eluent: hexane/isopropa-
nol = 500:1; flow rate: 1.0 mL/min; temp.: 27 ꢁC; detec-
tor: 254 nm, (ꢀ): 8.6 min, (+): 9.8 min].
4.4.2. (ꢀ)-cis-Whisky lactone 9.15b,16 Ruthenium(III)
chloride hydrate (21 mg, 0.10 mmol) and orthoperiodic
acid (2.30 g, 10.01 mmol) were added to a biphasic solu-
tion of 4d (125 mg, 0.50 mmol) in CCl4/CH3CN/
H2O = 5:5:8 (9 mL), and the reaction mixture stirred
for 20 h at room temperature. The reaction mixture
was acidified with 1 M HCl aq to pH 1, and extracted
with ethyl acetate three times. The combined organic
layer was successively washed with saturated aqueous
solution of sodium thiosulfate and brine, dried over
magnesium sulfate, filtered, and concentrated in vacuo
to give crude (3S,4S)-4-acetoxy-3-methyloctanoic acid.
Then, it was hydrolyzed with 1 M NaOH (5 mL) at
room temperature for 1.5 h, and the reaction mixture
acidified with 10% HCl aq to pH 1, and stirred for a fur-
ther 2.5 h. The reaction mixture was neutralized with
saturated aqueous solution of sodium bicarbonate, and
extracted with ethyl acetate three times. The combined
organic layer was successively washed with saturated
aqueous solution of sodium thiosulfate and brine, dried
over magnesium sulfate, filtered, and concentrated in va-
cuo to give a residue. The residue was purified by silica
gel column chromatography (hexane/ethyl acetate = 5:1)
4.3.8. (3S,4R)-4-Cyclohexyl-3-methylbutan-4-olide 8f.
24
D
Colorless prism; mp 74–75 ꢁC (hexane); ½aŠ ¼ ꢀ53:2
1
(c 0.97, CHCl3); H NMR (400 MHz, CDCl3): d 4.02
(dd, J = 9.8, 4.7 Hz, 1H), 2.72 (dd, A part of AB,
JAB = 16.8 Hz, J = 7.5 Hz, 1H), 2.59–2.50 (m, 1H),
2.19 (dd, B part of AB, JAB = 16.8 Hz, J = 1.2Hz,
1H), 2.09–2.02 (m, 1H), 1.79–1.56 (m, 5H), 1.34–1.13
(m, 3H), 1.10–0.88 (m, 2H), 1.00 (d, J = 7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d 177.0, 87.7, 38.7,
37.4, 32.0, 30.3, 28.0, 26.2, 25.4, 25.3, 13.5; IR (CHCl3):
3035, 2931, 2856, 1770, 1463, 1450, 1421, 1176, 983, 975,
935 cmꢀ1; MS (70 eV) m/z: 182(M +, 1), 154 (13), 111
(17), 99 (100), 83 (53), 71 (41), 55 (57); HRMS calcd
for C11H18O2 (M+): 182.1307, found 182.1305; Anal.
Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C,
72.44; H, 9.94.
to give (ꢀ)-cis-whisky lactone (63 mg, 62% yield from
24
4d). Colorless oil; ½aŠ ¼ ꢀ76:9 (c 1.73, MeOH); 1H
D
NMR (400 MHz, CDCl3): d 4.46–4.41 (m, 1H), 2.69
(dd, A part of AB, JAB = 16.9 Hz, J = 7.9 Hz, 1H),
2.63–2.53 (m, 1H), 2.20 (dd,
B
part of AB,
4.4. The asymmetric total synthesis of (ꢀ)-cis-whisky
JAB = 16.9 Hz, J = 4.0 Hz, 1H), 1.71–1.30 (m, 6H),
1.01 (d, J = 7.0 Hz, 3H), 0.92(t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3): d 176.9, 83.7, 37.5, 33.0,
29.5, 28.0, 22.5, 13.9, 13.8; IR (CHCl3): 3006, 2960,
2873, 2862, 1770, 1456 cmꢀ1; MS CI(+) m/z: 157
lactone 9
4.4.1. (2S,3S)-3-Acetoxy-2-methyl-1-phenylheptane 4d.
Acetic anhydride (184 lL, 1.95 mmol) was added to a

1670
M. Ozeki et al. / Tetrahedron: Asymmetry 16 (2005) 1663–1671
(M++H, 54); HRMS calcd for C9H17O2 (M++H):
157.1228, found 157.1237.
Otsuka, K.; Zenibayashi, Y.; Itoh, M.; Totsuka, A. Agric.
Biol. Chem. 1974, 38, 485; (d) Tumlinson, J. H.; Klein, M.
G.; Doolittle, R. E.; Ladd, T. L.; Proveaux, A. T. Science
1977, 197, 789; (e) Silverstein, R. M. In Semiochemistry,
Flavors and Pheromones. Proceedings ACS Symposium;
Acree, T. E., Ed.; W. de Gruyter and Co.: Berlin, 1985,
pp 121–140.
4.5. The asymmetric total synthesis of (ꢀ)-cis-cognac
lactone 10
(ꢀ)-cis-Cognac lactone 10 was synthesized in the same
way as (ꢀ)-cis-whisky lactone 9.
3. (a) Hanessian, S.; Murray, P. J.; Sahoo, S. P. Tetrahedron
Lett. 1985, 26, 5627; (b) Tomioka, K.; Cho, Y. S.; Sato, F.;
Koga, K. J. Org. Chem. 1988, 53, 4094; (c) Ariza, J.; Font,
J.; Ortun˜o, R. M. Tetrahedron 1990, 46, 1931.
4.5.1. (2S,3S)-3-Acetoxy-2-methyl-1-phenyloctane 4e.
Ninety percent yield from 3Ae. Colorless oil;
4. Reports for synthesis of cis-b,c-disubstituted-c-butyrolac-
tone: (a) Bystro¨m, S.; Ho¨gberg, H.-E.; Norin, T. Tetra-
25
D
½aŠ ¼ ꢀ26:6 (c 1.06, CHCl3); 1H NMR (400 MHz,
¨
hedron 1981, 37, 2249; (b) Nubbemeyer, U.; Ohrlein, R.;
CDCl3): d 7.30–7.11 (m, 5H), 4.88 (ddd, J = 8.4, 4.8
and 3.8 Hz, 1H), 2.75 (dd, A part of AB, JAB = 13.5 Hz,
J = 5.1 Hz, 1H), 2.31 (dd, B part of AB, JAB = 13.5 Hz,
J = 9.4 Hz, 1H), 2.07 (s, 3H), 2.00–1.91 (m, 1H), 1.63–
1.47 (m, 2H), 1.33–1.22 (m, 6H), 0.88 (t, J = 6.8 Hz,
3H), 0.85 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 170.9, 140.7, 129.1 (2C), 128.2 (2C), 125.9,
77.0, 39.5, 38.4, 31.7, 31.2, 25.3, 22.5, 21.2, 14.0, 13.9;
IR (CHCl3): 3062, 3035, 3012, 2954, 2931, 2858, 1724,
1600, 1496, 1458, 1373, 1253 cmꢀ1; MS FAB(+) m/z:
263 (M++H, 39); HRMS calcd for C17H27O2 (M++H):
263.2011, found 263.2016. [99% ee, chiral HPLC analy-
sis; DAICEL CHIRALCEL OD (25 · 0.46); eluent: hex-
ane/isopropanol = 500:1; flow rate: 0.2mL/min; temp.:
28 ꢁC; detector: 254 nm, (ꢀ): 44.4 min, (+): 46.9 min].
ˇ
Gonda, J.; Ernst, B.; Bellus, D. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1465; (c) Ferreira, J. T. B.; Marques, J. A.;
Marino, J. P. Tetrahedron: Asymmetry 1994, 5, 641; (d)
Brecht-Forster, A.; Fitremann, J.; Renaud, P. Helv. Chim.
Acta 2002, 85, 3965; (e) Wu, Y.; Shen, X.; Tang, C.-J.;
Chen, Z.-L.; Hu, Q.; Shi, W. J. Org. Chem. 2002, 67, 3802.
5. (a) Doyle, M. P.; Zhou, Q.-L.; Dyatkin, A. B.; Ruppar, D.
A. Tetrahedron Lett. 1995, 36, 7579; (b) Fukuzawa, S.;
Seki, K.; Tatsuzawa, M.; Mutoh, K. J. Am. Chem. Soc.
1997, 119, 1482; (c) Kerrigan, N. J.; Hutchison, P.;
Heightman, C. T. D.; Procter, D. J. Chem. Commun.
2003, 1402; (d) Ramachandran, P. V.; Padiya, K. J.;
Rauniyar, V.; Reddy, M. V. R.; Brown, H. C. Tetrahedron
Lett. 2004, 45, 1015.
6. (a) Nishide, K.; Shigeta, Y.; Obata, K.; Node, M. J. Am.
Chem. Soc. 1996, 118, 13103; (b) Node, M.; Nishide, K.;
Shigeta, Y.; Shiraki, H.; Obata, K. J. Am. Chem. Soc.
2000, 122, 1927; (c) Nishide, K.; Ozeki, M.; Kunishige, H.;
Shigeta, Y.; Patra, P. K.; Hagimoto, Y.; Node, M. Angew.
Chem., Int. Ed. 2003, 42, 4515.
7. (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless,
K. B. J. Org. Chem. 1981, 46, 3936; (b) Nun˜ez, M. T.;
Martin, V. S. J. Org. Chem. 1990, 55, 1928.
8. (a) Matsuura, F.; Hamada, Y.; Shioiri, T. Tetrahedron
1994, 50, 9457; (b) Boger, D. L.; Lee, R. J.; Bounaud, P.-
Y.; Meier, P. J. Org. Chem. 2000, 65, 6770.
9. 3Aa was used after purification by HPLC in order to
remove the minor diastereomer.
10. (a) Nishide, K.; Shigeta, Y.; Obata, K.; Inoue, T.; Node,
M. Tetrahedron Lett. 1996, 37, 2271; (b) Node, M.;
Nishide, K.; Shigeta, Y.; Obata, K.; Shiraki, H.; Kunish-
ige, H. Tetrahedron 1997, 53, 12883.
4.5.2. (ꢀ)-cis-Cognac lactone 10.15c,17 Seventy percent
23
yield from 4e. Colorless oil; ½aŠ ¼ ꢀ67:7 (c 1.78,
D
1
CHCl3); H NMR (400 MHz, CDCl3): d 4.46–4.41 (m,
1H), 2.69 (dd,
A
part of AB, JAB = 16.8 Hz,
J = 7.8 Hz, 1H), 2.63–2.53 (m, 1H), 2.20 (dd, B part of
AB, JAB = 16.8 Hz, J = 4.0 Hz, 1H), 1.69–1.25 (m,
8H), 1.01 (d, J = 7.1 Hz, 3H), 0.90 (t, J = 6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3): d 176.9, 83.7, 37.5,
33.0, 31.6, 29.8, 25.6, 22.5, 13.9, 13.8; IR (CHCl3):
3035, 2954, 2931, 2862, 1766, 1461 cmꢀ1; MS CI(+) m/z:
171 (M++H, 20); HRMS calcd for C10H19O2 (M++H):
171.1385, found 171.1393.
11. In reductive removal using Raney Ni (W-2)/NaPH2O2
combination system, partial epimerization was observed in
part (34:1). Resulting minor diastereomer was removed by
HPLC.
12. (a) Frenette, R.; Kakushima, M.; Zamboni, R.; Young, R.
N.; Verhoeven, T. R. J. Org. Chem. 1987, 52, 304; (b)
Forzato, C.; Gandolfi, R.; Molinari, F.; Nitti, P.; Pitacco,
G.; Valentin, E. Tetrahedron: Asymmetry 2001, 12,
1039.
13. (a) Masuda, M.; Nishimura, K. Chem. Lett. 1981, 1333;
(b) Tanaka, T.; Kouno, I. J. Nat. Prod. 1996, 59, 997.
14. For some asymmetric syntheses of trans-whisky and
cognac lactone see for instance: (a) Ebata, T.; Matsumoto,
K.; Yoshikoshi, H.; Koseki, K.; Kawakami, H.; Okano,
K.; Matsushita, H. Heterocycles 1993, 36, 1017; (b) Pai,
Y.-C.; Fang, J.-M.; Wu, S.-H. J. Org. Chem. 1994, 59,
6018; (c) Takahata, H.; Uchida, Y.; Momose, T. J. Org.
Chem. 1995, 60, 5628; (d) Nishikori, H.; Ito, K.; Katsuki,
T. Tetrahedron: Asymmetry 1998, 9, 1165; (e) Bertus, P.;
Acknowledgements
This research was financially supported in part by Fron-
tier Research Program and the 21st Century Center of
Excellence Program ÔDevelopment of Drug Discovery
Frontier Integrated from Tradition to ProteomeÕ of the
Ministry of Education, Culture, Sport and Technology,
Japan.
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