A convergent total synthesis of epolactaene: An application of the bridgehead oxiranyl anion strategy

Article abstract of DOI:10.1016/j.tet.2003.09.021

The generation and reaction of a lactone-derived oxiranyl anion is described. The aldol-type reaction of the epoxylactone and aldehydes was accomplished by a two-step procedure via the trimethylsilyl epoxylactone. The application of this methodology to th

Full text of DOI:10.1016/j.tet.2003.09.021

Tetrahedron 59 (2003) 9743–9758
A convergent total synthesis of epolactaene:
an application of the bridgehead oxiranyl anion strategy
a
Kouji Kuramochi, Seigo Nagata, Hideyoshi Itaya, Yasuaki Matsubara, Takashi Sunoki,
b
b
b
b
b
b,†
Hiromi Uchiro, Ken-ichi Takao and Susumu Kobayashi
a,b,
*
a
Frontier Research Center for Genomic Drug Discovery, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan
b
Received 2 July 2003; revised 11 August 2003; accepted 5 September 2003
Abstract—The generation and reaction of a lactone-derived oxiranyl anion is described. The aldol-type reaction of the epoxylactone and
aldehydes was accomplished by a two-step procedure via the trimethylsilyl epoxylactone. The application of this methodology to the total
synthesis of (þ)-epolactaene and its analogs is described.
q 2003 Elsevier Ltd. All rights reserved.
5
1. Introduction
rule, an oxiranyl anion derived from epoxylactone should
be localized at the bridgehead. Therefore the reactivity of
this anion as well as the method of generation is of immense
interest. This paper describes the generation and reaction of
the oxiranyl anion to the synthesis of epolactaene and its
anologs.
Epolactaene (1), which was isolated from fungal strain
Penicillium sp. BM1689-P by Osada et al., possesses a
potent neurite outgrowth activity in a human neuroblastoma
6
1
cell line SH-SY5Y. The characteristic features of epolac-
taene include the highly functionalized a,b-epoxy-g-lactam
and the conjugated triene moiety in the side chain. The
significant biological activity as well as the structural
complexity of epolactaene has stimulated intensive syn-
thetic interests, culminating in the total syntheses and
determination of its absolute stereochemistry by two
2. Results and discussion
2.1. The generation and reaction of the oxiranyl anion
derived from a,b-epoxy-g-butyrolactone
2
groups.
We first attempted the direct condensation of propionalde-
hyde with the oxiranyl anion generated from the racemic
b-angelica lactone epoxide ((^)-2) (Table 1). After (^)-2
was treated with LDA in THF at 2788C, propionaldehyde
was added to the reaction mixture. We isolated the dimer 3
in 16% yield but did not obtain the desired product 4 (entry
During the course of our investigation towards the synthesis
of epolactaene, we became interested in the strategy
involving the reaction of the oxiranyl anion derived from
7
a
3
epoxylactone with aldehydes (Scheme 1). Although the
oxiranyl anion stabilized by an ethoxycarbonyl group is
4
known, the oxiranyl anion derived from a,b-epoxy-g-
butyrolactone has not been reported. According to Bredt’s
1). Use of a different solvent, such as ether (0.02 M) at
8
21108C or the Trapp mixture (THF/Et O/hexane¼3:1:1)
2
Scheme 1.
Keywords: epolactaene; epoxylactone; TBAF; aldol reaction.
*
Corresponding author. Address: Frontier Research Center for Genomic Drug Discovery, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-
8
510, Japan. Tel.: þ81-4-7121-3671; fax: þ81-4-7126-6550; e-mail: kobayash@rs.noda.tus.ac.jp
†
Present address: Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.021

9744
K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
Table 1. Direct condensation of propionaldehyde with b-angelica lactone epoxide
Entry
Solvent
Concentration (M)
Temperature (8C)
Yield (%)
1
2
3
THF
Et
Trapp mixture
0.1
0.02
0.02
280
2110
2110
16
43
65
2
O
at 21108C were also unsuccessful, resulting in the
undesirable formation of dimer 3 in moderate yield (entries
mixture at 21108C, the desired silylated product (^)-5 was
isolated in 70% yield (entry 3).
2
and 3). Although the desired aldol-type product was not
obtained, these results clearly indicated that the oxiranyl
anion can be generated and that the anion is so reactive that
it attacks another epoxylactone during the lithiation step
even at 21108C.
When ether was used as a solvent instead of Trapp mixture,
dimer 3 was the main product and the yield of (2)-5 was
only 5% (entry 4). The reaction did not proceed when
MHMDS (M¼Li, Na and K) was used as a base, and the
epoxylactone (2)-2 was recovered (entry 5).
We then examined an alternative stepwise approach via the
a-trimethylsilyl epoxylactone. We reasoned that the
reactive oxiranyl anion could be trapped as the trimethyl-
silyl derivative 5 when the deprotonation was carried out in
the presence of excess trimethylsilyl chloride (TMSCl). We
also expected that the desired aldol-type reaction might
occur when a mixture of trimethylsilyl derivative 5 and an
aldehyde was treated with a catalytic amount of a fluoride
anion. By this method, the generation of the reactive
oxiranyl anion becomes possible in the presence of an
aldehyde, and the formation of dimer 3 might be prevented.
We next carried out the silylation of the chiral anti-
epoxylactone (þ)-2 and syn-epoxylactone (2)-7 in order to
obtain the enantiomerically pure materials and to investigate
the structure–reactivity relationships of the bridgehead
oxiranyl anion. According to the method reported by
Ogawa, (þ)-2 and (2)-7 were prepared from D-xylose
in a stereoselective manner. Contrary to the anti-isomer
(þ)-2, syn-isomer (2)-7 afforded the corresponding silyl-
ated product (2)-8 in only 8% yield under the same reaction
conditions. The low yield was due to the formation of
undesirable oligomers (Scheme 2). The results might be
rationalized by considering the difference in the steric
environment around the lactone carbonyl. Both faces of the
lactone carbonyl are blocked by either an epoxide oxygen or
methyl group in the anti-isomer 2, whereas a nucleophile
can readily approach from the re-face (upper face) of the
lactone carbonyl in the case of the syn-isomer 7.
7
b
4
Following Eisch’s method, a solution of LDA was added to
a mixture of the epoxylactone (^)-2 and TMSCl at 21108C.
But the silylated product (^)-5 was not produced and the
dimers 3 and 6 were isolated (Table 2; entries 1 and 2).
However, when a solution of epoxylactone in Trapp mixture
was added to a solution of LDA and TMSCl in Trapp
Table 2. Trimethylsilylation of b-angelica lactone epoxide
a
Entry
Base (equiv.)
TMSCl (equiv.)
Solvent
Concentration (M)
Yield (%)
Dimers
5
1
2
LDA (1.2)
LDA (1.2)
5
5
Ether
Trapp mixture
0.1
0.1
-
-
3 65
3 13
b
6
3 6
58
3
4
LDA (3.0)
LDA (3.0)
11
10
Trapp mixture
Ether
0.02
0.02
70
5
3 55
6
3
5
MHMDS (3.0)
10
Trapp mixture
0.02
No reaction
a
Unless otherwise noted, reactions were carried out as follows: a solution of epoxylactone was added to a mixture of a base and TMSCI in a solvent indicated.
A solution of LDA was added to a mixture of epoxylactone and TMSCl in a solvent indicated.
b

K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
9745
Scheme 2.
Having prepared the silylated epoxylactone 5, the coupling
of 5 with an aldehyde was attempted. As expected, the
aldol-type reaction of 5 and propionaldehyde took place in
effective. We found that the condensation proceeded
moderately in THF/hexane¼1:1 (entry 5 vs. entry 6).
Condensationof5witharomaticaldehydeswasalsoexamined
to obtain the corresponding condensation products. In this
case, an interesting diastereoselectivity was observed (entries
7 and 8).
9
the presence of 0.1 equiv. of tetrabutylammonium fluoride
0
1
(
after the desilylation (aq. HF in CH CN) of the initially
TBAF) and MS4A in THF to obtain 11a in 61% yield
3
formed TMS ether 10a (Table 3; entry 1). Prolonged
reaction time was necessary for long chain aliphatic
aldehyde and a-methylated-a,b-unsaturated aldehydes.
For example, 11e was obtained in 23% yield by the
2.2. Synthetic plan for epolactaene
Scheme 3 outlines a strategy for epolactaene based on the
oxiranyl anion approach. Epolactaene might be synthesized
from the key intermediate 12, which can be obtained from
the condensation of epoxylactone (2)-5 and aldehyde 13.
The chiral epoxylactone (2)-5 is derived from L-xylose or
1
1
treatment of 5 and 9e with TBAF for three times. The use
of an equimolar amount of TBAF resulted in the formation
of a complex mixture of products. A catalytic amount of
the fluoride anion source appeared to be essential for the
reaction. Other fluoride anion sources or the presence of a
from (S)-ethyl lactate according to the reported procedure
7,13
1
2
co-additive such as trimethylsilyl fluoride were not
with some modification.
The side-chain aldehyde 13 can
Table 3. TBAF-catalyzed aldol reaction
a
Yield (11) % (ds )
Entry
RCHO (9)
CHO (9a)
Solvent
Temperature (8C)
Time (h)
1
2
3
4
CH
CH
CH
3
3
3
CH
(CH
(CH
2
THF
THF
0–rt
rt
rt
6
61 (ca. 1:1)
50 (ca. 1:1)
48 (ca. 1:1)
57 (ca. 1:1)
2
)
4
CHO (9b)
10CHO (9c)
11
24
24
2
)
THF/hexane¼1:1
THF
rt
(
9d)
b
5
6
THF
rt
rt
24 h£3
23 (ca. 1:1)
57 (ca. 1:1)
(
9e)
9e)
THF/hexane¼1: 1
24
(
7
8
THF/hexane¼1:1
THF/hexane¼1:1
rt
rt
25
25
44 (ca. 1:1)
(9f)
62 (single isomer)
(
9g)
a
1
Diastereoselectivity was determined by H NMR.
Reaction was carried out three times.
b

9746
K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
Scheme 3.
Scheme 4.
be prepared from the dienyl iodide 14 and the vinylstannane
1
the employment of expensive L-xylose as a starting material
is unsuitable for large-scale synthesis. This led us to
improve the method for the preparation of the enantiomeri-
cally pure epoxylactone (Scheme 4).
5 using Stille coupling as a key reaction.
2
.3. Synthesis of the enantiomerically pure
2)-b-angelica lactone epoxide (2)-2 and its
(
a-trimethylsilyl derivative
The Z-selective Horner–Emmons reaction of ethyl diphenyl-
1
4
phosphonoacetate with (S)-2-(t-butyldimethylsilyloxy)-
13b
3
b
In the preceding paper, we prepared the enantiomerically
pure (2)-b-angelica lactone epoxide (2)-2 from L-xylose
propanal (16) afforded a 20:1 mixture of Z- and E- a,b-
unsaturated esters 17. The treatment of 17 with aqueous
HF in acetonitrile led to desilylation and cyclization to form
7
b
according to the procedure reported by Ogawa. However,
Scheme 5.

K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
9747
Scheme 6.
b-angelica lactone 18. Epoxidation of 18 according to the
7
solution of the epoxyester 19 in THF was added to a solution
of LDA (1.4 equiv.) and TMSCl (1.3 equiv.) in THF,
affording a 5.5:1 mixture of the silylated epoxyesters 20
in 80% yield. Selective desilylation with aqueous HF in
a
modified Font’s procedure gave the enantiomerically pure
b-angelica lactone epoxide (2)-2 in 60% yield and 98% ee
(
by HPLC).
CH CN and recyclization with a catalytic amount of CSA
3
In order to obtain the silylated epoxylactone 5 in large
quantities, we also had to improve the trimethylsilylation of
the epoxylactone because severe conditions (a high dilution
condition, a very low temperature and excess amount of
reagents) are necessary to reduce the dimerization of
epoxylactone. Although various additives (MgBr ·Et O,
in refluxing benzene gave the desired silyllactone (2)-5 in
75% yield with 13% of the alcohol 21 derived from the
isomerized silyl ester. Despite the requirement for five steps
to obtain the silyllactone (2)-5 from epoxylactone (2)-2
and the loss in yield due to isomerization during the
silylation step, this route can give enantiomerically pure
silylated epoxylactone (2)-5 in large quantities.
2
2
ZnCl , CeCl , Sn(OTf) etc.) at the silylation step were
3
2
2
investigated, no significant improvements were achieved.
We reasoned that the dimerization was caused by nucleo-
philic attack at the carbonyl carbon of the epoxylactone, in
addition to the high reactivity of the localized oxiranyl
anion. We therefore transformed the lactone into the
corresponding acyclic ester (Scheme 5).
2.4. Synthesis of the side-chain moiety of epolactaene
The preparation of the dienyl iodide 14 and the vinyl-
15
stannane 15 is shown in Scheme 6. Wittig reaction of 22,
4
prepared from 1,4-butanediol by 2 steps, with the known
6
1
phosphonium salt 23, gave a ca. 5.7:1 mixture of E
and Z-enyne 24. Without separation of isomers, the enyne
After the treatment of (2)-2 with K CO in MeOH, the
2
3
1
7
resulting alcohol was protected as the TBS ether 19. A
24 was converted into 25 with K CO in MeOH. 25 was
2 3
Scheme 7.

9748
K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
Table 4. TBAF-catalyzed reaction of (2)-5 and 13
Entry
(2)-5
13
equiv.)
TBAF
(equiv.)
Solvent
Time
Yield
(%)
(
a
b
b
b
1
2
3
2.0
2.0
1.5
1.0
1.0
1.0
0.2
0.3
0.1
THF
THF/hexane¼1:1
1 day£7
3 days£2
1 day
53 (71)
35 (63)
39 (78)
c
THF/hexane¼1:1
a
Not treated with aq. HF in CH
3
CN.
Yield based on the recovered 13.
M solution of TBAF in THF was treated with MS4A for 3 h before use.
b
c
1
1
8
23
subjected to a stereoselective carbometallation with
Cp TiCl –Me Al followed by treatment with iodine,
affording the dienyl iodide 14. The vinylstannane 15 was
oxidation, the resulting aldehyde 30 was subjected to
2
4
the Wittig reaction to obtain the side-chain aldehyde
13 (Scheme 7). The separation of stereoisomers was
conveniently performed at this stage to yield stereochemi-
cally pure 13.
2
2
3
1
9
prepared from the known stannyl alcohol 26. A two step
2
0
oxidation [(i) MnO , 95%; (ii) NaClO –H O , 71%] of
2
2
2 2
the alcohol 26 gave the carboxylic acid 27. 27 was
transformed to the ester 15 in 88% yield by treatment with
CH I and t-BuOK.
2.5. Coupling of two segments and the completion of the
synthesis of epolactaene
3
Construction of the conjugated triene moiety was achieved
by Stille coupling. The treatment of 14 and 15 with a
catalytic amount of PdCl (CH CN) in the presence of CuI
in DMF gave 28 in 91% yield. The PMB group in 28 was
cleanly cleaved by heating at 608C in 4N aq. HCl/dioxane
The TBAF-catalyzed reaction of (2)-5 and 13 was
examined (Table 4). When the reaction was conducted in
THF, only a catalytic amount of the desired aldol-type
product 31 (not its TMS ether) was obtained and a con-
2
3
2
2
1
3
b
siderable amount of (2)-5 and 13 was recovered (entry 1).
(
1:4) affording 29 in 81% yield. The conventional method
2
(2)-5 and 13 were recovered and treated with TBAF and
MS4A in THF for 1 day (six times) to obtain 31 in a total
yield of 53% (71% yield based on recovered 13). Based on
2
using DDQ or CAN was unsuccessful, resulting in the
formation of a complex mixture of products. After Swern
Scheme 8.

K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
9749
Scheme 9.
model studies of this aldol-type reaction, the coupling was
conducted in THF/hexane (1:1) (entry 2). However, the
yield as well as the catalytic cycle was not improved. We
thought that the water contained in the commercially
available 1 M solution of TBAF in THF might influence
the catalytic cycle. Thus when the reaction was performed
using a solution of TBAF in THF, which was treated with
activated MS4A (1 g/1 mmol) for 3 h, 31 was obtained in
(2)-5 with aldehydes 9b, 9c, 9e and 9h. Biological studies
on the a, b-epoxy-g-lactam derivatives 35 as well as the
synthetic intermediates containing 11, 33, 34 and 36 were
investigated. As a result, we observed that the synthetic (þ)-
epolactaene and 35c inhibited the activities of mammalian
2
5
27
DNA polymerase a, b and human DNA topoisomerase II.
We found that the synthetic (þ) and (2)-epolactaene, 35b,
2
8
35c, 35e and 35h induced apotosis in BALL-1 cells.
39% (78% yield based on the recovered 13) in a one-time
reaction (entry 3).
Interestingly, there is no difference on the apotosis-inducing
activity between epolactaene and its enantiomer. We
also found that the a, b-epoxy-g-lactam, the straight alkyl
side-chain, and the carbonyl group at 3-position are required
for these activities.
Having obtained the desired aldol-type product 31, we were
in a position to complete the total synthesis of epolactaene
2
3
(
Scheme 8). Swern oxidation of 31 with trifluoroacetic
anhydride (TFAA) and DMSO produced the corresponding
ketone 12. After ammonolysis of 12, the resulting hydroxy-
2
26
amide 32 was oxidized with Dess–Martin periodinane
to give (þ)-epolactaene which was isolated as a 5.4:1
3. Conclusion
diastereomixture at C-15. Synthetic epolactaene had a
2
In summary, we have successfully performed an aldol-type
condensation of the epoxylactone with a series of
aldehydes by a two-step procedure via the trimethylsilyl
epoxylactone. Although the catalytic efficiency of the
reaction is not fully optimized, the present approach
provides the first example of the generation and reaction
of the highly reactive bridgehead oxiranyl anion derived
from the epoxylactone. Its synthetic utility was demon-
strated by the total synthesis of epolactaene. The most
significant feature of the present approach is that the
silylated epoxylactone serves as a key intermediate for the
synthesis of various substituted epolactaene analogs.
Several analogs were synthesized and are currently under-
going biological studies. Our synthetic probes will be
candidate compounds for detailed studies into the mechan-
ism of action of epolactaene.
6
specific rotation [a] of þ34 (c 0.2, MeOH) [lit.:
D
2
1
[
(
a] ¼þ32 (c 0.1, MeOH)] and exhibited spectral data
D
1
13
H and C NMR and HRMS) identical with those reported
1
for the natural product.
2.6. Synthesis of epolactaene analogs and their biological
activities
The most significant feature of the present approach is that
the trimethylsilylated epoxylactone 5 serves as a potential
intermediate for the synthesis of various substituted
epolactaene analogs (Scheme 9). The enantiomer of the
natural epolactaene was synthesized by the same route using
the silylated product (þ)-5. Several analogs were also
prepared by the coupling of the silylated epoxylactone

9750
K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
4. Experimental
Then the mixture was cooled at 21108C. After the addition
of trimethylsilyl chloride (2.4 mL, 18.96 mmol), a solution
of b-angelica lactone epoxide (2)-7 (106.9 mg, 0.937 mmol)
in Trapp mixture (30 mL) in portions for 30 min. The
4
.1. General
1
13
H and C NMR were recorded on a JEOL JNM-EX2,
JNM-300, JNM-400, JNM-500, or on BRUKER DRX600.
Chemical shifts were reported in d, parts per million (ppm),
relative to TMS as an internal standard. IR spectra were
recorded on Horiba FT-210 or Hitachi 215 infrared
spectrometer. Mass spectra were obtained on Hitachi
M-80 spectrometer or API QSTAR Pulsar i spectrometer.
Optical rotations were measured on a JASCO DIP-360
digital polarimeter. Column chromatography was carried
out on Fujisilisiachem K.K.BW-127ZH. Analytical thin-
layer chromatography (TLC) was performed on precoated
Merck silica gel HF254 plates, and compounds were
visualized by UV illumination (254 nm) or heating 1508C
after spraying phosphomolylbdic acid in ethanol. Ether and
THF were distilled from sodium/benzophenone. CH Cl
mixture was quenched by the addition of H O and extracted
2
with EtOAc (£3). The combined extract was washed with
brine, dried and concentrated. The residue was purified by
chromatography (4:1 hexane/EtOAc) to afford (2)-8
2
1
(13.2 mg, 8%) as a pale yellow oil. [a] ¼262.5 (c 0.80,
D
CHCl ); IR (neat) 2962, 2902, 1774, 1452, 1381, 1346,
3
1254, 1220, 1101, 989, 908, 847, 781 cm2 ; H NMR
1
1
(270 MHz, CDCl ) d: 0.21 (9H, s, SiMe ), 1.47 (3H, d,
3
3
J¼6.6 Hz, 5-Me), 3.83 (1H, d, J¼1.7 Hz, H-5), 4.54 (1H,
1
3
dq, J¼1.7, 6.6 Hz, H-4); C NMR (75 MHz, CDCl ) d:
3
23.8, 15.5, 53.6, 62.1, 74.8, 173.5; HRMS, calcd for
C H O Si (M ) 186.0713, found 186.0713.
þ
8
14 3
4.2. General method for the preparation of 11
2
2
were distilled from P O . Benzene, (CH Cl) , diisopropyl-
2
To a solution of (^)-5 (55.1 mg, 0.296 mmol), propion-
aldehyde (40 mL, 0.554 mmol) and MS4A (0.21 g) in THF
(5 mL) was added TBAF (30 mL of a 1 M solution in THF,
30 mmol) at 08C. The mixture was stirred at rt for 6 h and
then filtrated through Celite and washed with EtOAc. The
2
5
2
amine, DMF, DMSO, hexane, toluene and trimethylsilyl
chloride were distilled from CaH . Hexanal, oxaly chloride,
2
trans-2-methyl-2-butenal, 2-methyl-2-pentenal, propion-
aldehyde were distilled before use. All other solvent and
reagents were obtained from commercial sources and used
without further purification. Organic extracts were dried
organic layer was washed with H O, brine, dried and
2
concentrated. A solution of the residue in CH CN (2 mL)
3
over MgSO , filtered, concentrated using a rotary evapor-
4
was added a solution of 5% aqueous HF in CH CN (1 mL)
3
ator. Nonvolatile oils and solids were vacuum dried.
at rt for 30 min. The mixture was quenched by the addition
of H O and extracted with EtOAc (£3). The combined
2
p
p
p
.1.1. (1R ,4S ,5S )-4-Methyl-1-trimethylsilyl-3,6-
4
extract was washed with brine, dried and concentrated. The
residue was purified by chromatography (4:1 hexane/
EtOAc) to afford 11a (31.2 mg, 61%) as a colorless oil.
dioxa-bicyclo[3.1.0]hexan-2-one 5. To a solution of diiso-
propylamine (0.37 mL, 2.62 mmol) in Trapp mixture (THF/
hexane/ether¼3:1:l, 23 mL) was added n-BuLi (1.7 mL of a
p
0
p
p
1
.53 M solution in hexane, 2.60 mmol) at 08C for 20 min.
4.2.1. (1S ,1 RS,4S ,5S )-1-(1-Hydroxypropyl)-4-
methyl-3,6-dioxabicyclo-[3.1.0]hexan-2-one 11a. IR (neat)
3493, 2976, 2937, 2881, 1774, 1460, 1382, 1340, 1230,
Then the mixture was cooled at 21108C. After the addition
of trimethylsilyl chloride (1.2 mL, 9.48 mmol), a solution of
b-angelica lactone epoxide (100.8 mg, 0.883 mmol) in
Trapp mixture (20 mL) in portions for 30 min and the
mixture was stirred at 21108C for 10 min. The mixture was
1111, 1074, 1003, 922, 881, 850, 783, 696 cm2 ; H NMR
1 1
0
(270 MHz, CDCl ) d: 1.06 (3H, t, J¼7.3 Hz, H-3 ), 1.07*
3
0
(3H, t, J¼7.6 Hz, H-3 ), 1.38 (3H, d, J¼6.6 Hz, 4-Me),
0
1.67–1.88* (2H, m, H-2 ), 2.10 (1H, brs, OH), 2.10* (1H,
quenched by the addition of H O and extracted with EtOAc
2
1.38* (3H, d, J¼6.6 Hz, 4-Me), 1.67–1.88 (2H, m, H-2 ),
0
brs, OH), 3.97 (1H, s, H-5), 3.97* (1H, s, H-5), 4.18 (1H, m,
(
£3). The combined extract was washed with brine, dried
and concentrated. The residue was purified by chromato-
graphy (4:1 hexane/EtOAc) to afford 5 (116.9 mg, 70%) as a
colorless oil. IR (neat) 2962, 2904, 1767, 1450, 1383, 1333,
0
0
H-1 ), 4.18* (1H, m, H-1 ), 4.67 (1H, q, J¼6.6 Hz, H-4),
1
3
4.67* (1H, q, J¼6.6 Hz, H-4); C NMR (75 MHz, CDCl )
3
2
1
1
1
(
254, 1211, 1072, 976, 914, 847, 785 cm ; H NMR
270 MHz, CDCl ) d: 0.22 (9H, s, SiMe ), 1.35 (3H, d,
d: 9.6, 9.8, 17.7, 25.5, 61.6, 61.7, 62.1, 65.9, 67.7, 75.4,
170.5, 170.9 (diasteromeric mixture); HRMS, calcd for
3
3
þ
J¼6.6 Hz, 4-Me), 3.72 (1H, s, H-5), 4.69 (1H, q, J¼6.6 Hz,
C H O (M 2H) 171.0657, found 171.0640.
8 11 4
1
3
H-4); C NMR (75 MHz, CDCl ) d: 23.9, 18.0, 51.7, 63.4,
3
þ
p
0
p
p
75.1, 173.4; HRMS, calcd for C H O Si (M ) 186.0713,
8
found 186.0713.
4.2.2. (1S ,1 RS,4S ,5S )-1-(1-Hydroxyhexyl)-4-methyl-
3,6-dioxabicyclo-[3.1.0]hexan-2-one 11b. The title com-
pound was prepared by the coupling of (^)-5 with 9b in
50% yield as a colorless oil. IR (neat) 3504, 2956, 2933,
2862, 1774, 1458, 1381, 1340, 1221, 1115, 1012, 923, 854,
14 3
4
.1.2. (1R,4S,5S)-4-Methyl-1-trimethylsilyl-3,6-dioxabi-
cyclo[3.1.0]hexan-2-one (2)-5. [a] ¼250.6 (c 1.01, CHCl ).
2
1
D
3
2
1 1
7
85 cm ; H NMR (500 MHz, CDCl ) d: 0.89–0.91 (3H,
3
0 0
m, H-6 ), 0.89–0.91* (3H, m, H-6 ), 1.25–1.39 (6H, m, H-
3 , H-4 , H-5 ), 1.25–1.39* (6H, m, H-3 , H-4 , H-5 ), 1.41
4
.1.3. (1S,4R,5R)-4-Methyl-1-trimethylsilyl-3,6-dioxabi-
1
2
D
0
0
0
0
0
0
cyclo[3.1.0]hexan-2-one (1)-5. [a] ¼þ51.1 (c 0.88,
CHCl ).
3
(3H, d, J¼6.7 Hz, 4-Me), 1.41* (3H, d, J¼6.7 Hz, 4-Me),
0 0
.43–1.80 (2H, m, H-2 ), 1.43–1.80* (2H, m, H-2 ), 2.05
(1H, brs, OH), 2.12* (1H, brs, OH), 3.97 (1H, s, H-5), 3.97*
1
4
.1.4. (1R,4R,5S)-4-Methyl-1-trimethylsilyl-3,6-dioxabi-
0
cyclo[3.1.0]hexan-2-one (2)-8. To a solution of diisopro-
pylamine (0.40 mL, 2.83 mmol) in Trapp mixture (THF/
hexane/ether¼3:1:1, 23 mL) was added n-BuLi (1.8 mL of
a 1.53 M solution in hexane, 2.75 mmol) at rt for 20 min.
(1H, s, H-5), 4.13–4.15 (1H, m, H-1 ), 4.23–4.25* (1H, m,
0
H-4); C NMR (125 MHz, CDCl ) d: 13.9, 13.9, 17.7, 22.4,
22.4, 24.8, 25.0, 31.4, 32.1, 32.3, 49.8, 61.7, 61.7, 62.0,
H-1 ), 4.65 (1H, q, J¼6.7 Hz, H-4), 4.66* (1H, q, J¼6.7 Hz,
1
3
3

K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
9751
p
0
p
p
6
HRMS, calcd for C H O (M ) 214.1204, found
4.7, 66.3, 75.4, 75.4, 170.6, 171.0 (diasteromeric mixture);
þ
4.2.6. (1S ,1 RS,4S ,5S )-1-(1-Hydroxy-1-phenyl-
methyl)-4-methyl-3,6-dioxabicyclo-[3.1.0]hexan-2-one
11f. The title compound was prepared by the coupling of
1
1
18 4
2
14.1210.
(
IR (neat) 3583, 3020, 2980, 2935, 1778, 1456, 1338, 1216,
^)-5 with 9f in THF/hexane (1:1) in 44% as a colorless oil.
p
0
p
p
4
.2.3. (1S 1 RS,4S ,5S )-1-(1-Hydroxydodecyl)-4-
1
1
methyl-3,6-dioxabicyclo-[3.1.0]hexan-2-one 11c. The title
compound was prepared by the coupling of (^)-5 with 9c
in THF/hexane (1:1) in 48% yield as a white solid.
1066, 756, 700, 677 cm2 (diastereomeric mixture); H
NMR (300 MHz, CDCl ) d: 1.21 (3H, d, J¼6.8 Hz, 4-Me),
3
2.73 (1H, s, OH), 3.96 (1H, s, H-5), 4.62 (1H, q, J¼6.8 Hz, H-
13
0
isomer); C NMR (75 MHz CDCl ) d: 17.8, 61.6, 62.3, 66.8,
Mp¼47–498C. IR (CHCl ) 3689, 3026, 2927, 2856, 1778,
4), 5.42 (1H, s, H-1 ), 7.34–7.53 (5H, m, Ar) (the major
3
601, 1458, 1383, 1340, 1228, 1072, 1009, 852, 716 cm2
1
;
1
1
3
H NMR (500 MHz, CDCl ) d: 0.88 (3H, t, J¼6.7 Hz, H-
75.4, 127.1, 127.9, 128.7, 137.0, 170.0 (the major isomer);
þ
3
0
H-3 , H-4 , H-5 , H-6 , H-7 , H-9 , H 10 , H-11 ), 1.26* (20H,
0
0
1
2 ), 0.88* (3H, t, J¼6.7 Hz, H-12 ), 1.26 (20H, m, H-2 ,
HRMS, calcd for C H O (M ) 220.0735, found 220.0748.
12 12 4
0
0
0
0
0
0
0
0
m, H-2 , H-3 , H-4 , H-5 , H-6 , H-7 , H-9 , H-10 , H-11 ),
0
0
0
0
0
0
0
0
0
p
0
p
p
4.2.7. (1S ,1 RS,4S ,5S )-1-[1-Hydroxy-1-(4-metoxyl-
phenyl)methyl]-4-methyl-3,6-dioxabicyclo-[3.1.0]hexan-
2-one 11g. The title compound was prepared by the
coupling of (^)-5 with 9g in THF/hexane (1:1) in 62% as
a colorless oil. IR (neat) 3583, 3020, 2979, 2940, 1778,
1614, 1513, 1463, 1338, 1251, 1215, 1174, 1072, 1036, 758,
1.41 (3H, d, J¼6.7 Hz, 4-Me), 1.41* (3H, d, J¼6.7 Hz, 4-
Me), 2.17 (1H, brs, OH), 2.27–2.29* (1H, m, OH), 3.97
0
(
4
1H, s, H-5), 3.97* (1H, s, H-5), 4.10–4.18 (1H, m, H-1 ),
0
.22–4.24* (1H, m, H-1 ), 4.65 (lH, q, J¼6.7 Hz, H-4),
1
3
4
d: 14.1, 17.8, 17.8, 22.6, 25.2, 25.4, 29.3, 29.3, 29.4, 29.5,
.66* (1H, q, J¼6.7 Hz, H-4); C NMR (125 MHz, CDCl )
3
699 cm2 ; H NMR (400 MHz, CDCl ) d: 1.21 (3H, d,
1
1
3
2
7
9.6, 31.9, 32.2, 32.3, 61.6, 61.7, 61.7, 62.1, 64.8, 66.4,
5.4, 75.4, 170.5, 170.9 (diasteromeric mixture); HRMS,
J¼6.6 Hz, 4-Me), 3.03 (1H, brs, OH), 3.78 (3H, s, OMe),
4.00 (1H, s, H-5), 4.59 (1H, q, J¼6.6 Hz, H-4), 5.32 (1H, s,
þ
0
Ar); C NMR (100 MHz, CDCl ) d: 17.7, 55.1, 61.4, 62.2,
calcd for C H O (M ) 298.2143, found 298.2149.
7 30 4
H-1 ), 6.88 (2H, d, J¼8.5 Hz, Ar), 7.35 (2H, d, J¼8.5 Hz,
1
1
3
3
p
0
p
p
4
.2.4. (1S ,1 RS,4S ,5S )-1-(1-Hydroxy-2-methylbut-2-
66.2, 75.3, 113.9, 128.4, 129.2, 159.8, 170.0; HRMS, calcd
þ
enyl)-4-methyl-3,6-dioxabicyclo-[3.1.0]hexan-2-one 11d.
The title compound was prepared by the coupling of (^)-5
with 9d in 57% yield as a colorless oil. IR (neat) 3481, 2983,
2
8
1
4
for C H O (M ) 250.0840, found 250.0850.
13 14 5
0
4.2.8. (1S,1 RS,4S,5S)-1-(1-Hydroxyoctadecyl)-4-methyl-
3,6-dioxabicyclo-[3.1.0]hexan-2-one 11h. The title com-
pound was prepared by the coupling of (2)-5 with 9h in
THF/hexane (1:1) in 52% as a white solid. Mp¼62–658C.
924, 2862, 1778, 1448, 1383, 1340, 1225, 1072, 1030, 921,
58, 802, 733, 694 cm ; H NMR (270 MHz, CDCl ) d:
21 1
3
.41 (3H, d, J¼6.9 Hz, 4-Me), 1.41* (3H, d, J¼6.9 Hz,
0
-Me), 1.67 (3H, d, J¼1.3 Hz, 2 -Me), 1.67* (3H, d,
IR (CHCl ) 3583, 3019, 2927, 2854, 1776, 1465, 1381,
3
0
0
21 1
J¼7.6 Hz, H-4 ), 1.68 (3H, d, J¼7.6 Hz, H-4 ), 1.69* (3H,
1340, 1220, 1071, 1009, 726 cm ; H NMR (400 MHz,
0
0
d, J¼1.3 Hz, 2 -Me), 2.23* (1H, brs, OH), 2.58 (1H, d,
CDCl ) d: 0.88 (3H, t, J¼6.8 Hz, H-18 ), 0.88* (3H, t,
3
0
0
0
J¼6.3 Hz, OH), 3.89 (1H, s, H-5), 4.04* (1H, s, H-5), 4.56
J¼6.8 Hz, H-18 ), 1.25 (32H, m, H-2 –H-17 ), 1.25* (32H,
0
0
0
(
(
1H, d, J¼6.3 Hz, H-1 ), 4.66* (1H, q, J¼6.7 Hz, H-4), 4.67
m, H-2 –H-17 ), 1.41 (3H, d, J¼6.7 Hz, 4-Me), 1.41* (3H,
0
H-3 ), 5.78* (1H, m, H-3); C NMR (75 MHz, CDCl )
0
(2H, m, H-2 ), 2.13 (1H, brs, OH), 2.17* (1H, brs, OH), 3.98
1H, q, J¼6.7 Hz, H-4), 4.76* (1H, s, H-1 ), 5.70 (1H, m,
d, J¼6.7 Hz, 4-Me), 1.44–1.78 (2H, m, H-2 ), 1.44–1.78*
0
d:12.1, 13.1, 13.2, 13.3, 17.7, 17.8, 60.7, 60.9, 61.8, 61.9,
13
0
(1H, s, H-5), 3.98* (1H, s, H-5), 4.14–4.16 (1H, m, H-1 ),
3
0
0
7
1.1, 75.2, 123.6, 126.6, 131.4, 132.5, 169.7, 170.8
þ
4.24* (1H, dd, J¼2.9, 8.8 Hz, H-1 ), 4.65 (1H, q, J¼6.7 Hz,
13
(
diasteromeric mixture); HRMS, calcd for C H O (M )
1
H-4), 4.66* (1H, q, J¼6.7 Hz, H-4); C NMR (100 MHz,
0 14 4
1
98.0893, found 198.0883.
CDCl ) d: 14.1, 17.9, 17.9, 22.7, 25.3, 25.4, 29.3, 29.4, 29.4,
3
29.5, 29.6, 29.6, 29.7, 29.7,29.7, 31.9, 32.2, 32.3, 32.4, 61.6,
61.8, 61.8, 62.2, 62.2, 64.8, 66.5, 75.4, 75.4, 170.5, 170.9
p
0
p
p
4
2
1
.2.5. (1S ,1 RS,4S ,5S )-1-(1-Hydroxy-2-methylpent-
-enyl)-4-methyl-3,6-dioxabicyclo-[3.1.0]hexan-2-one
1e. The title compound was prepared by the coupling of
þ
(diasteromeric mixture); HRMS, calcd for C H O (M )
2
3 42 4
382.3083, found 382.3091.
(^)-5 with 9e in THF/hexane (1:1) in 57% yield as a
colorless oil. IR (neat) 3466, 3020, 2968, 2935, 2875, 1778,
4.2.9. Ethyl (4S)-4-(t-butylsimethylsilyloxy)-(2Z)-pent-2-
enoate 17. To a solution of ethyl (diphenylphosphono)ace-
tate (151 g, 0.47 mol) in THF (500 mL) was added Triton B
(199 g of a 40% solution in MeOH, 0.48 mol) at 2788C and
the mixture was stirred at 2788C for 30 min. A solution of
16 (77 g, 0.41 mol) in THF (200 mL) was added to the
mixture at 2788C in portions for 10 min. The mixture was
warmed up to 08C and stirred for 08C for 2 h. Then the
1
7
643, 1454, 1383, 1340, 1217, 1072, 1036, 943, 920, 858,
1
58, 667 cm2 ; H NMR (500 MHz, CDCl ) d: 0.98 (3H, t,
1
3
0
0
J¼7.6 Hz, H-5 ), 0.99* (3H, t, J¼7.6 Hz, H-5 ), 1.41 (3H, d,
J¼6.9 Hz, 4-Me), 1.41* (3H, d, J¼6.9 Hz, 4-Me), 1.69*
0
.03–2.14 (2H, m, H-4 ), 2.03–2.14* (2H, m, H-4 ), 2.20
0
(
2
3H, d, J¼1.0 Hz, 2 -Me), 1.70 (3H, d, J¼1.3 Hz, 2 -Me),
0
0
(
(
1H, d, J¼0.7 Hz, OH), 2.57 (1H, d, J¼1.6 Hz, OH), 3.88*
0
.70 (1H, m, H-4), 4.59–4.70* (1H, m, H-4), 4.75 (1H, s,
1H, s, H-5), 4.04 (1H, s, H-5), 4.56* (1H, brs, H-1 ), 4.59–
mixture was quenched by the addition of H O and extracted
2
4
with EtOAc. The extract was washed with brine, dried and
concentrated. The residue was purified by chromatography
(20:1 hexane/EtOAc) to afford a ca. 20:1 mixture of 17
(88 g, 83%) as a colorless oil. IR (neat) 3039, 2929, 2858,
1720, 1649, 1464, 1410, 1363, 1306, 1254, 1192, 1117,
0
H-1 ), 5.58* (1H, dt, J¼1.0, 7.3 Hz, H-3), 5.67 (1H, dt,
0
13
J¼1.3, 7.3 Hz, H-3 ); C NMR (100 MHz, CDCl ) d: 12.2,
3
1
6
1
3.2, 13.5, 13.6, 17.6, 17.6, 20.7, 20.8, 49.7, 58.7, 60.6,
0.9, 61.6, 61.8, 69.3, 70.7, 75.1, 75.2, 130.1, 130.7, 131.0,
33.5, 169.8, 170.8 (diasteromeric mixture); HRMS, calcd
1078, 1003, 939, 835, 777, 665 cm2 ; H NMR (500 MHz,
1 1
þ
for C H O (M 2H O) 194.0943, found 194.0939.
4
CDCl ) d: 0.02 (3H, s, SiMe), 0.04 (3H, s, SiMe), 0.86 (9H,
3
11
16
2

9752
K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
s, Sit-Bu), 1.24 (3H, d, J¼6.4 Hz, 4-Me), 1.27 (3H, t,
J¼7.2 Hz, OCH CH ), 4.15 (2H, q, J¼7.2 Hz, OCH CH ),
and extracted with EtOAc. The extract was washed with
brine, dried and concentrated. The residue was purified by
chromatography (40:1 hexane/EtOAc) to afford 19 (17.5 g,
70%) as a colorless oil and the recovered (2)-2 (1.44 g,
2
3
2
3
5
.43 (1H, ddq, J¼1.5, 6.4, 7,9 Hz, H-4), 5.63 (1H, dd,
J¼1.5, 11.6 Hz, H-2), 6.19 (1H, dd, J¼7.9, 11.6 Hz, H-3);
1
3
21
C NMR (125 MHz, CDCl ) d: 24.9, 24.8, 14.2, 18.1,
3
13%). [a] ¼þ35.6 (c 1.6, CHCl ); IR (neat) 2956, 2931,
D
3
2
calcd for C H O Si (M ) 258.1649, found 258.1641.
3.5, 25.7, 25.8, 60.0, 65.5, 116.8, 154.6, 165.8; HRMS,
þ
2889, 2858, 1802, 1756, 1463, 1443, 1385, 1254, 1210,
1171, 1111, 1000, 934, 836, 778 cm ; H NMR (600 MHz,
CDCl ) d: 20.03 (3H, s, SiCH ), 0.01 (3H, s, SiCH ), 0.86
21 1
1
3 26 3
3
3
3
4
2
.2.10. (5S)-5-Methyl-5H-furan-2-one 18. A solution of a
0:1 mixture of the ester 17 (88 g, 0.34 mmol) in CH CN
(9H, s, t-Bu), 1.34 (3H, d, J¼6.1 Hz, H-5), 3.07 (1H, dd,
J¼4.3 Hz, 7.9 Hz, H-3), 3.55 (1H, d, J¼4.3 Hz, H-2), 3.78
3
1
3
(
(
50 mL) was added a solution of 5% aqueous HF in CH CN
3
560 mL) at rt for 45 min. The mixture was quenched by
(1H, m, H-4), 3.79 (3H, s, CO CH ); C NMR (150 MHz,
2 3
CDCl ) d: 25.0, 24.5, 17.9, 22.0, 25.6, 52.2, 52.9, 61.2,
3
þ
the addition of saturated aqueous NaHCO solution and
3
64.9, 168.4; HRMS, calcd for C H O Si (MþH )
12 25 4
extracted with EtOAc (£2). The combined extract was
washed with brine, dried and concentrated. The residue was
purified by chromatography (4:1 hexane /EtOAc) to afford
1
1
1
261.1504, found 261.1516.
4.2.13. (2R,3S,4S)-Methyl 2,3-epoxy-4-(t-butyldimethyl-
silyloxy)-2-trimethylsilyl-pentanoate 20. To a solution of
diisopropylamine (13.5 mL, 96.3 mmol) in THF (120 mL)
was added n-BuLi (60 mL of a 1.56 M solution in hexane,
93.6 mmol) at 08C for 10 min. Then the mixture was cooled
at 21108C. After the addition of trimethylsilyl chloride
(11 mL, 86.7 mmol), a solution of 19 (17.5 g, 67.2 mmol) in
THF (30 mL) was added to the mixture at 2788C and the
mixture was stirred at 2788C for 10 min. The mixture was
8 (29 g, 87%) as a colorless oil. IR (neat) 3091, 2985, 2937,
846, 1761, 1635, 1603, 1452, 1377, 1323, 1167, 1076,
2
1 1
028, 960, 891, 762, 712, 671 cm ; H NMR (500 MHz,
CDCl ) d: 1.47 (3H, d, J¼7.0 Hz, 5-Me), 5.16 (1H, ddq,
3
J¼1.5, 1.8, 7.0 Hz, H-5), 6.10 (1H, dd, J¼1.8, 5.8 Hz, H-3),
1
3
7
CDCl ) d: 18.6, 79.5, 120.9, 157.5, 173.0; HRMS, calcd for
.51 (1H, dd, J¼1.5, 5.8 Hz, H-4); C NMR (125 MHz,
3
þ
C H O (M ) 98.0304, found 98.0307.
5 6 2
quenched by the addition of H O and extracted with EtOAc.
2
4.2.11. (1R,4S,5S)-4-Methyl-3,6-dioxabicyclo[3.1.0]-
hexan-2-one (2)-2. To a solution of 18 (1.07 g, 10.9 mmol)
The extract was washed with brine, dried and concentrated.
The residue was purified by chromatography (40:1 hexane/
EtOAc) to afford a 5.5:1 mixture of 20 (17.8 g, 80%) as a
colorless oil. IR (neat) 2956, 2931, 2898, 2858, 1803, 1748,
1720, 1472, 1463, 1436, 1370, 1293, 1252, 1214, 1157,
in THF (100 mL) was added H O (3.18 mL of a 40%
2
2
solution in H O, 32.7 mmol) and Triton B (4.30 mL of a
2
4
2
0% solution in H O, 10.9 mmol) at 2158C in portions for
2
0 min, and the mixture was stirred at 2158C for 4 h. The
1105, 994, 914, 839, 777 cm2
1
;
CDCl ) d: 20.06 (3H, s, SiCH ) 20.05 (3H, s, SiCH ),
1
H NMR (600 MHz,
mixture was quenched by the addition of H O and extracted
2
3
3
3
with EtOAc. The aqueous layer was acidified to pH 1 by the
addition of aqueous conc. HCl solution and the mixture was
stirred at rt for 2 h. Then aqueous layer was extracted with
EtOAc (£6). The combined extract was dried and con-
centrated. A solution of the residue in benzene (10 mL) was
refluxed for 2 h and then concentrated. The residue was
purified by chromatography (3:1 hexane/EtOAc) to afford
0.05* (3H, s, SiCH ), 0.06* (3H, s, SiCH ), 0.11 (9H, s,
3 3
TMS), 0.18* (9H, s, TMS), 0.85 (9H, s, t-Bu), 0.86* (9H, s,
t-Bu), 1.25* (3H, d, J¼6.3 Hz, H-5), 1.29 (3H, d, J¼6.2 Hz,
H-5), 2.84 (1H, d, J¼7.3 Hz, H-3), 2.95* (1H, d, J¼7.9 Hz,
H-3), 3.58 (1H, m, H-4), 3.68* (1H, m, H-4), 3.70* (3H, s,
1
3
CO CH ), 3.71 (3H, s, CO CH ); C NMR (150 MHz,
2
3
2
3
CDCl ) d: 25.1, 24.4, 24.1*, 23.6, 23,5*, 21.7*, 17.8,
3
2
1
(
CHCl ); IR (neat) 3089, 2987, 2939, 2879, 1878, 1776,
2)-2 (740 mg, 60%) as a colorless oil. [a] ¼234.6 (c 2.0,
17.9*, 21.5*, 22.0, 25.6, 25.7*, 51.6, 51.9*, 56.8*, 57.4,
63.7, 66.2, 66.7, 67.4, 168.4, 172.8; HRMS, calcd for
D
3
þ
1
7
452, 1385, 1340, 1284, 1190, 1063, 989, 943, 891, 847,
2
C H O NaSi (MþNa ) 355.1700, found 355.1731.
1
5
32
4
2
1 1
70, 696, 636 cm ; H NMR (500 MHz, CDCl ) d: 1.43
3
(
3H, d, J¼6.7 Hz, 4-Me), 3.81 (1H, d, J¼2.4 Hz, H-5), 3.99
4.2.14. (1R,4S,5S)-4-Methyl-1-trimethylsilyl-3,6-dioxabi-
cyclo[3.1.0]hexan-2-one (2)-5. To a solution of 20 (17.8 g,
53.5 mmol) in CH CN (50 mL) was added a solution of 5%
1
3
( C
NMR (125 MHz, CDCl ) d: 17.6, 49.8, 58.8, 76.3, 170.3;
1H, d, J¼2.4 Hz, H-1), 4.71 (1H, q, J¼6.7 Hz, H-4);
3
3
þ
HRMS, calcd for C H O (M ) 114.0317, found 114.0320.
3
aqueous HF in CH CN (50 mL) at rt. The mixture was
3
5
6
The enantiomeric purity of (2)-2 was determined to be
8% ee by analytical HPLC analysis [Daicel Chiralcel OC,
stirred for 4 h and the mixture was quenched by the addition
of a solution of saturated aqueous NaHCO and extracted
9
3
i-PrOH/hexane¼1:10, Flow rate¼1 mL/min, t ¼18.17 min
with EtOAc. The extract was dried and concentrated. A
solution of the residue and camphorsulfonic acid (253 mg,
1.1 mmol) in benzene (150 mL) was refluxed for 1 h and the
mixture was quenched by the addition of a solution of
R
(
with the racemic and authentic sample.
(1R,4S,5S)-isomer), t ¼21.22 min ((1S,4R,5R)-isomer)]
R
4.2.12. (2S,3S,4S)-Methyl 2,3-epoxy-4-(t-butyldimethyl-
silyloxy)pentanoate 19. A solution of (2)-2 (11 g, 96 mmol)
saturated aqueous NaHCO and extracted with EtOAc (£2).
3
The extract was washed with brine, dried and concentrated.
The residue was purified by chromatography (4:1 hexane/
EtOAc) to afford (2)-5 (7.5 g, 75%) and 21 (1.5 g, 13%) as
a colorless oil.
and K CO (1.3 g, 9.3 mmol) in MeOH (60 mL) was stirred
2
3
at rt for 35 min. The mixture was quenched by the addition
of H O and extracted with EtOAc (£3). The combined
2
extract was washed with brine, dried and concentrated. To a
solution of the residue in DMF (60 mL) was added
imidazole (14 g, 206 mmol), TBSCl (16 g, 106 mmol) and
DMAP (1 g, 8.2 mmol) at rt and the mixture was stirred at rt
2
2
(2)-5: [a] ¼247.7 (c 1.7, CHCl ).
D
3
4.2.15. (2S,3S,4S)-Methyl 2,3-epoxy-4-hydroxy-2-tri-
2
1
D
for 1 h. The mixture was quenched by the addition of H O
2
methylsilylpentanate 21. [a] ¼þ11.2 (c 1.2, MeOH); IR

K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
9753
1 1
1099, 1038, 820 cm2 ; H NMR (270 MHz, CDCl ) d: 1.70
(
1
neat) 3496, 2956, 2903, 1727, 1437, 1371, 1251, 1146,
1
3
076, 1014, 949, 900, 847, 766 cm2 ; H NMR (600 MHz,
1
(2H, tt, J¼6.3, 7.6 Hz, H-6), 1.92 (3H, d, J¼1.0 Hz, 2-Me),
2.15 (2H, dt, J¼6.9, 7.6 Hz, H-5), 3.44 (2H, t, J¼6.3 Hz,
H-7), 3.81 (3H, s, OCH ), 4.42 (2H, s, CH Ar), 5,74 (1H, td,
CDCl ) d: 0.20 (9H, s, TMS), 1.34 (3H, d, J¼6.2 Hz, H-5),
3
1
m, H-4), 3.70 (3H, s, CO CH ); C NMR (150 MHz,
.91 (1H, brs, OH), 2.93 (1H, d, J¼7.7 Hz, H-3), 3.61 (1H,
2 3
3
2
1
3
J¼6.9, 15.5 Hz, H-4), 6.13 (1H, d, J¼15.5 Hz, H-3), 6.17
CDCl ) d: 21.7, 21.1, 51.9, 65.7, 66.6, 172.8; HRMS, calcd
3
for C H O NaSi (MþNa ) 241.0866, found 241.0866.
(1H, S. H-1), 6.88 (2H, d, J¼8.6 Hz, Ar), 7.26 (2H, d,
þ
þ
J¼8.6 Hz, Ar); HRMS, calcd for C H O I (M )
16 21 2
9
18
4
372.0586, found 372.0585.
4
.2.16. (3E)-7-(4-Metoxybenzyloxy)-1-trimethylsilyl-3-
hepten-1-yne 24. To a solution of 23 (11 g, 24 mmol) in
THF/toluene (1:1, 80 mL) was added n-BuLi (12 mL of a
4.2.19. (Z)-2-Tributyltin-2-butenoic acid 27. A solution of
26 (1.12 g, 3.1 mmol) and MnO (5.0 g, 58 mmol) in THF
2
1
.65 M solution in hexane, 20 mmol) at 2608C and the
mixture was stirred at 2608C for 30 min. Then a solution of
2 (4.0 g, 20 mmol) in THF/toluene (1:1, 10 mL) was added
(28 mL) was stirred at rt for 24 h. Then the mixture was
filtered through Celite and washed with EtOAc. After
removing solvent, the residue was purified by chromato-
graphy (9:1 hexane/EtOAc) to afford the aldehyde (1.06 g,
95%) as a colorless oil. IR (neat) 2956, 2924, 2854, 1674,
2
at 2608C and the mixture was stirred at 2608C for 2 h. The
mixture was quenched by the addition of H O and extracted
with hexane (£3). The combined extract was washed with
brine, dried, concentrated. The residue was purified by
chromatography (9:1 hexane/EtOAc) to afford 24 (5.1 g,
2
1605, 1169, 1066 cm2 ; H NMR (270 MHz, CDCl ) d:
1 1
3
0.88 (9H, t, J¼7.3 Hz), 1.04 (6H, t, J¼7.3 Hz), 1.27–1.35
(6H, m), 1.42–1.50 (6H, m), 2.07 (3H, d, J¼6.6 Hz, H-4),
7.43 (1H, q, J¼6.6 Hz, H-3), 9.59 (1H, s, CHO).
8
6%, E/Z¼5.7:1) as a yellow oil. E-isomer: IR (neat) 2956,
2
1 1
2854, 1614, 1514, 1250, 1086, 1038, 845 cm ; H NMR
270 MHz, CDCl ) d: 0.19 (9H, s, TMS), 1.69 (2H, m, H-6),
(
To a solution of the aldehyde (1.06 g, 3.0 mmol), H O
2 2
3
2
H-7), 3.81 (3H, s, OCH ), 4.42 (2H, S, CH Ar), 5.51 (1H, td,
.20 (2H, dq, J¼1.7, 7.3 Hz, H-5), 3.44 (2H, t, J¼6.6 Hz,
(0.3 mL of a 35% aqueous solution, 3.0 mmol) and
NaH PO (127 mg, 0.81 mmol) in CH CN/H O (20:1,
5 mL) was added NaClO (0.49 g, 79%, 4.3 mmol) at 08C
3
2
2
4
3
2
J¼1.7, 16.2 Hz, H-3), 6.21 (1H, td, J¼7.3, 16.2 Hz, H-4),
2
6
HRMS, calcd for C H O Si (M ) 302.1702, found
.88 (2H, d, J¼8.6 Hz, Ar), 7.26 (2H, d, J¼8.6 Hz, Ar);
in portions for 30 min. After stirring at rt for 8 h, the mixture
was quenched by the addition of H O and extracted with
þ
1
8
26
2
2
3
02.1702.
CH Cl (£5). The combined extract was washed with brine,
2
2
dried, concentrated. The residue was purified by chromato-
graphy (19:1 hexane/EtOAc) to afford 27 (0.86 g, 78%) as a
colorless oil. IR (neat) 2956, 2924, 2854, 2629, 1666, 1605,
4.2.17. (3E)-7-(4-Metoxybenzyloxy)-3-hepten-1-yne 25.
A solution of 24 (2.2 g, 7.2 mmol) and K CO (1.1 g,
7
Then the mixture was quenched by the addition of H O and
extracted with hexane (£3). The combined extract was
washed with brine, dried, concentrated. The residue was
purified by chromatography (9:1 hexane/EtOAc) to afford
2
3
1458, 1402, 1273 cm2 ; H NMR (270 MHz, CDCl ) d:
1 1
.2 mmol) in MeOH (70 mL) was stirred at rt for 30 min.
3
0.88 (9H, t, J¼7.3 Hz), 1.00–1.06 (6H, m), 1.23–1.38 (6H,
m), 1.43–1.56 (6H, m), 1.92 (3H, d, J¼6.9 Hz, H-4), 7.58
(IH, q, J¼6.9 Hz, H-3).
2
2
5 (1.5 g, 95%, E/Z¼5.7:1) as a yellow oil. E-isomer: IR
4.2.20. Methyl (Z)-2-tributyltin-2-butenoate 15. To a
solution of 27 (0.86 g, 2.29 mmol) in DMF (4 mL) was
added t-BuOK (386 mg, 3.40 mmol) at 08C. After stirring at
(
neat) 3286, 2933, 2856, 1612, 1464, 1314, 1248, 1099,
036 cm2 ; H NMR (270 MHz, CDCl ) d: 1.67–1.72 (2H,
1 1
1
3
m, H-6), 2.20 (2H, ddt, J¼1.3, 6.9, 7.3 Hz, H-5), 2.78 (1H,
d, J¼2.6 Hz), 3.44 (2H, t, J¼6.3 Hz, H-7), 3.80 (3H, s,
OCH ), 4.42 (2H, s, CH Ar), 5.46 (1H, m, H-3), 6.24 (1H,
08C for 10 min, CH I (210 mL, 3.37 mmol) was added and
3
the mixture was stirred at rt for 30 min. Then the mixture
was quenched by the addition of H O and extracted with
3
2
2
td, J¼6.9, 15.8 Hz, H-4), 6.88 (2H, d, J¼8.6 Hz, Ar), 7.24
hexane (£3). The combined extract was washed with brine,
dried, concentrated. The residue was purified by chromato-
graphy (19:1 hexane/EtOAc) to afford 15 (0.79 g, 88%) as
a colorless oil. IR (neat) 2956, 2924, 2854, 1713,
1
3
(
2H, d, J¼8.6 Hz, Ar); C NMR (100 MHz, CDCl ): 28.6,
3
2
9.6, 55.2, 68.9, 72.5, 75.8, 82.4, 108.9, 113.7, 129.1, 130.5,
þ
1
found 230.1299.
46.0, 159.1; HRMS, calcd for C H O (M ) 230.1302,
1
5 18 2
1610, 1458, 1433, 1244, 1211 cm2 ; H NMR (270 MHz,
1 1
CDCl ) d: 0.89 (9H, t, J¼7.3 Hz), 1.01 (6H, t, J¼7.3 Hz),
3
4
1
3
.2.18. (1E,3E)-1-Iodo-7-(4-metoxybenzyloxy)-2-methyl-
,3-heptentadiene 14. To a solution of Cp TiCl (0.78 g,
.1 mmol) in 1,2-dichloroethane (20 mL) was added Me Al
3
1.27–1.35 (6H, m), 1.45–1.49 (6H, m), 1.89 (3H, d,
J¼6.9 Hz, H-4), 3.69 (3H, s, CO CH ), 7.45 (IH, q,
2
2
2
3
J¼6.9 Hz, H- 3).
(
29 mL of 1.08 M solution in hexane, 31 mmol) and the
mixture was stirred at rt for 30 min. Then a solution of 25 in
,2-dichloroethane (7 mL) was added to the mixture and the
4.2.21. Methyl (2E,3E,5E)-2-ethylidene-9-(4-methoxy-
benzyloxy)-4-methylnona-3,5-dienoate 28. To a solution
of PdCl (CH CN) (34 mg, 0.13 mmol) and CuI (254 mg,
1
mixture was stirred at rt for 90 min. The mixture was cooled
to 2408C, a solution of I (3.2 g, 13 mmol) was added via
2
3
2
1.34 mmol) in degassed DMF (20 mL) was added a solution
of 14 (500 mg, 1.34 mmol) in DMF (3 mL) at rt. After
stirring at rt for 10 min, a solution of 15 (781 mg,
2.01 mmol) was added to the mixture. Then the mixture
was warmed up to 508C and stirred at 508C for 24 h. Then
the mixture was quenched by the addition of 30% aqueous
NH solution and extracted with Et O (£3). The combined
2
canula. After stirring at 2408C for 1 h, the mixture was
quenched by the addition of a solution of saturated aqueous
K CO and extracted with hexane (£3). The combined
2
3
extract was washed with brine, dried, concentrated. The
residue was purified by chromatography (19:1 hexane/
EtOAc) to afford 14 (2.6 g, 78%, E/Z¼5.7:1) as a yellow oil.
E-isomer: IR (neat) 2933, 2852. 1612, 1512, 1464, 1248,
3
2
extract was washed with brine, dried, concentrated.

9754
K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
The residue was purified by chromatography (9:1 hexane/
EtOAc) to afford a 5.7:1 mixture of 28 (421 mg, 91%) as a
yellow oil. E-isomer: IR (neat) 2949, 2852, 1716, 1612,
4.2.24. Methyl (2E,3E,5E)-2-ethyl-4,10-methyl-11-
oxoundeca-3,5,9-trienoate 13. A solution of 30 (270 mg,
1.21 mmol) and 2-(triphenylphosphoranylidene)propion-
aldehyde (1.75 g, 5.50 mmol) in toluene (40 mL) was
refluxed for 17 h. The solvent was removed under a reduced
pressure. The residue was purified by chromatography (4:1
hexane/EtOAc) to afford a 5.7:1 mixture of 13 and its
6Z-isomer (272 mg, 85%). Further purification by flash
chromatography (8:1 hexane/EtOAc) gave 13 as a yellow
oil. IR (neat) 2983, 2849, 2850, 1716, 1687, 1641, 1435,
1379, 1360, 1252, 1211, 1133, 1024, 966, 860, 833, 764,
2
1 1
1
514, 1250, 1099, 1036, 822 cm ; H NMR (270 MHz,
CDCl ) d: 1.64 (3H, d, J¼13 Hz, 4-Me), 1.65–1.70 (2H, m,
3
H-8), 1.72 (3H, dd, J¼1.3, 7.3 Hz, CH–Me), 2.17–2.27
(
CO Me), 3.80 (3H, s, ArOMe), 4.40 (2H, s, ArCH ), 5.71
2H, m, H-7), 3.47 (2H, t, J¼6.6 Hz, H-9), 3.73 (3H, s,
2 2
(
1H, m, H-6), 5.92 (1H, brs, H-3), 6.21 (1H, d, J¼15.5 Hz,
H-5), 6.88 (2H, d, J¼8.6 Hz, Ar), 7.26 (IH, dq, J¼1.0,
1
3
7
.3 Hz, CH–Me), 7.27 (2H, d, J¼8.6 Hz, Ar); C NMR
731 cm2 ; H NMR (270 MHz, CDCl ) d: 1.63 (3H, d,
1
1
(
75 MHz, CDCl ) d:14.3, 15.8, 29.4, 51.8, 55.2, 69.4, 72.5,
3
3
1
1
3
13.7, 122.1, 129.1, 129.2, 129.8, 130.6, 130.7, 134.3,
þ
J¼1.0 Hz, 4-Me), 1.73 (3H, dd, J¼1.0, 7.3 Hz, CH–Me),
39.4, 159.1, 167.9; HRMS, calcd for C H O (M )
1 28 4
1.76 (3H, d, J¼l.3 Hz, 10-Me), 2.36 (2H, m, H-7), 2.50 (2H,
2
44.1988, found 344.1987.
m, H-8), 3.74 (3H, s, CO Me), 5.72 (1H, m, H-6), 5.97 (IH,
2
brs, H-3), 6.27 (1H, d, J¼15.7 Hz, H-5), 6.51 (IH, dt, J¼1.3,
4.2.22. Methyl (2E,3E,5E)-2-ethylidene-9-hydroxy-4-
methylnona-3,5-dienoate 29. A solution of 28 (31.5 mg,
7.3 Hz, H-9), 6.95 (IH, dq, J¼1.0, 7.3 Hz, CH–Me), 9.42
1
3
(1H, s, CHO); C NMR (75 MHz, CDCl ) d: 9.3, 14.4,
3
9
6
1.5 mmol) in dioxane/4N aq. HCl (4:1, 5 mL) was stirred at
08C for 5 h. Then the mixture was quenched by the
addition of 30% aqueous NH solution and extracted with
15.8, 28.8, 31.5, 51.8, 123.0, 128.2, 130.5, 135.2, 137.6,
139.7, 153.5, 167.8, 195.2; HRMS, calcd for C H O
6 22 3
1
þ
(M ) 262.1572, found 262.1568.
3
Et O (£3). The combined extract was washed with H O,
2
2
brine, dried, concentrated. The residue was purified by
preparative TLC (5:1 hexane/EtOAc) to afford 29 (11.5 mg,
4.2.25. (1R,4S,5R)-4-Methyl-1-[(2E,6E,8E,10E)]-2,8-
dimethyl-1-hydroxy-10-methoxycarbonydodeca-2,6,10-
trienyl]-3,6-dioxa-bicyclo[3.1.0]hexan-2-one 31. To a
solution of (2)-5 (87.8 mg, 0.47 mmol), 13 (82.4 mg,
0.31 mmol) and MS4A (0.30 g) in THF/hexane (1:1,
2 mL) at rt was added TBAF (60 mL of a 0.5 M solution
in THF, 30 mmol), which had been treated with MS4A for
3 h before use. The mixture was stirred at rt for 24 h and
then filtered through Celite and diluted with EtOAc. The
56%) and the recovered 28 (9.6 mg, 31%). The recovered 28
was treated with HCl in the same way, affording 29 (5.0 mg,
5
9%) and the recovered 28 (1.4 mg, 11%). 29 (16.5 mg,
1%) and the recovered 28 (1.4 mg, 4%) are obtained in
8
total. 29: a yellow oil; IR (neat) 3358, 2949, 2858, 1716,
1
1
1
(
633, 1434, 1263, 1059, 1026, 731 cm2
270 MHz, CDCl ) d: 1.58 (1H, s, OH), 1.64 (3H, d,
;
H NMR
3
J¼1.0 Hz, 4-Me), 1.65–1.68 (2H, m, H-8), 1.72 (3H, dd,
organic layer was washed with H O, brine, dried and
2
concentrated. A solution of the residue in CH CN (2 mL)
3
was added a solution of 5% aqueous HF in CH CN (2 mL)
3
J¼1.3, 7.3 Hz, CH–Me), 2.24 (2H, q, J¼7.2 Hz, H-7), 3.68
(
2H, t, J¼6.6 Hz, H-9), 3.73 (3H, s, CO Me), 5.74 (1H, m,
2
H-6), 5.94 (1H, brs, H-3), 6.24 (1H, d, J¼15.8 Hz, H-5),
at rt for 30 min. The mixture was quenched by the addition
of saturated aqueous NaHCO solution and extracted with
1
3
6
CDCl ) d: 14.3, 15.7, 29.1, 32.3, 51.8, 62.3, 122.2, 129.6,
.94 (1H, dq, J¼1.0, 7.3 Hz, CH–Me); C NMR (75 MHz,
3
EtOAc (£3). The combined extract was washed with
brine, dried and concentrated. The residue was purified by
chromatography (4:1 hexane/EtOAc) to afford 31 (46.6 mg,
3
1
C H O (M ) 224.1411, found 224.1398.
30.5, 134.4, 137.9, 139.6, 167.9; HRMS, calcd for
þ
1
3 20 3
39%) and the recovered 13 (41.0 mg, 50%). 31: a pale
4.2.23. Methyl (2E,3E,5E)-2-ethylidene-4-methyl-9-oxo-
nona-3,5-dienoate 30. To a solution of (COCl) (0.40 mL,
yellow oil; IR (neat) 3467, 2981, 2922, 2854, 1782, 1716,
1635, 1437, 1381, 1338, 1263, 1213, 1134, 1024, 968, 858,
2
758, 733, 692 cm2 ; H NMR (270 MHz, CDCI ) d: 1.39
1 1
4
7
2
.7 mmol) in CH Cl (7.5 mL) was added DMSO (0.50 mL,
2 2
3
0
.0 mmol) at 2788C. After 10 min at 2788C, a solution of
9 (286 mg, 1.28 mmol) in CH Cl (12.5 mL) was added to
(3H, d, J¼6.6 Hz, 4-Me), 1.62 (3H, d, J¼l.3 Hz, 8 -Me),
0
2.20–2.23 (4H, m, H-4 and H-5 ), 3.72 (3H, s, CO Me),
0
1.71 (3H, s, 2 -Me), 1.71 (3H, dd, J¼1.3, 7.3 Hz, H-12 ),
2
2
0
0
the mixture and the mixture was stirred at 2788C for
0 min. Then Et N (1.8 mL, 12.9 mmol) was added and the
2
9
4.02 (1H, s, H-5), 4.65 (1H, q, J¼6.6 Hz, H-4), 4.77 (1H, s,
0 0 0
H-1 ), 5.68–5.72 (2H, m, H-3 and H-6 ), 5.94 (1H, brs,
3
mixture was stirred at rt for 10 min. The mixture was
quenched by the addition of H O and extracted with CH Cl
2
0
0
H-9 ), 6.22 (1H, d, J¼15.5 Hz, H-7 ), 6.94 (1H, dq, J¼1.0,
2
2
0
13
(
£3). The combined extract was washed with brine, dried,
concentrated. The residue was purified by chromatography
4:1 hexane/EtOAc) to afford a 5.7:1 mixture of 30 (270 mg,
7.3 Hz, H-11 ); C NMR (75 MHz, CDCl ) d: 12.6, 14.4,
3
15.8, 17.8, 27.7, 32.3, 51.8, 61.0, 61.9, 69.7, 75.2, 122.4,
129.5, 130.5, 131.2, 131.3, 134.6, 138.0, 139.6, 167.9,
(
þ
9
1
5%) as a yellow oil. IR (neat) 2951, 2852, 2723, 1716,
1
169.8; HRMS, calcd for C H O (M ) 376.1886, found
2
1 28 6
679, 1633, 1435, 1257, 1134, 1026, 966, 733 cm2 ; H
1
376.1868.
NMR (270 MHz, CDCl ) d: 1.61 (3H, d, J¼1.0 Hz, 4-Me),
3
1
.70 (3H, dd, J¼1.0, 7.3 Hz, CH–Me), 2.47 (2H, q,
4.2.26. (1R,4S,5R)-4-Methyl-1-[(2E,6E,8E,10E)-2,8-
dimethyl-10-methoxycarbony-1-oxododeca-2,6,10-tri-
enyl]-3,6-dioxa-bicyclo[3.1.0]hexan-2-one 12. To a solu-
tion of DMSO (71 mL, 0.46 mmol) in CH Cl (1 mL) was
J¼6.6 Hz, H-7), 2.56 (2H, dt, J¼1.3, 6.6 Hz, H-8), 3.72
(
(
3H, s, CO Me), 5.71 (1H, m, H-6), 5.95 (1H, brs, H-3), 6.24
2
1H, d, J¼15.8 Hz, H-5), 6.94 (1H, dq, J¼1.0, 7.3 Hz,
2
2
1
3
CH–Me), 9.80 (IH, t, J¼1.3 Hz, CHO); C NMR (75 MHz,
added TFAA (65 mL, 0.92 mmol) at 2788C. After 10 mm at
2788C, a solution of 31 (57.3 mg, 0.15 mmol) in CH Cl
2
CDCl ) d: 14.3, 15.8, 25.3, 43.4, 51.8, 123.1, 127.7, 130.5,
3
2
1
C H O (M ) 222.1255, found 222.1262.
35.2, 137.6, 139.7, 167.8, 201.9; HRMS, calcd for
þ
(1.5 mL) was added to the mixture and the mixture was
stirred at 2788C for 30 min. Then Et N (215 mL,
1
3
18
3
3

K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
9755
1
3
1
1
.54 mmol) was added and the mixture was stirred at rt for
0 min. The mixture was quenched by the addition of H O
7.02 (1H, dt, J¼1.3, 6.6 Hz, H-l0); C NMR (75 MHz,
CD OD) d: 11.9, 15.4, 16.7, 23.0, 31.0, 33.3, 53.2, 64.7,
3
2
and extracted with CH Cl (£2). The combined extract was
66.9, 85.5, 124.4, 130.7, 132.7, 137.2, 137.4, 138.0, 140.4,
141.6, 150.8, 170.4, 173.0, 192.9; HRMS, calcd for
2
2
washed with brine, dried, concentrated. The residue was
purified by chromatography (2:1 hexane/EtOAc) to afford
þ
C H NO (M ) 389.1839, found 389.1843.
2
1
27
6
2
1
1
CHCl ). IR (neat) 2981, 2925, 2852, 1782, 1713, 1680,
2 (50.8 mg, 89%) as a pale yellow oil. [a] ¼22.2 (c 0.90,
D
2
1
4.2.29. ent-Epolactaene (2)-1. [a] ¼234.2 (c 0.05, MeOH).
3
D
1
7
637, 1435, 1381, 1335, 1250, 1132, 1072, 1024, 970, 871,
2
1 1
79 cm ; H NMR (270 MHz, CDC1 ) d: 1.50 (3H, d,
3
4.3. The general method for the preparation of 33
0
J¼6.9 Hz, 4-Me), 1.63 (3H, d, J¼1.0 Hz, 8 -Me), 1.72 (3H,
0
0
H- 5 ), 2.48 (2H, m, H-4 ), 3.73 (3H, s, CO Me), 4.07 (1H, s,
dd, J¼1.3, 7.3 Hz, H-12 ), 1.86 (3H, s, 2 -Me), 2.35 (2H, m,
To a solution of 11b (36.0 mg, 0.168 mmol), which was
prepared by the coupling of (2)-5 with 1-hexanal, in
CH Cl (2 mL) was added Dess-Martin periodinane
0
0
2
0
H-5), 4.71 (1H, q, J¼6.9 Hz, H-4), 5.71 (2H, m, H-6 ), 5.96
2
2
0
0
(
1H, brs, H-9 ), 6.26 (1H, d, J¼15.5 Hz, 11-7 ), 6.89 (1H, qt,
(143 mg, 0.336 mmol) at rt and the mixture was stirred for
1 h. Then the mixture was diluted with EtOAc and washed
with saturated aqueous Na S O and saturated aqueous
0
C NMR (75 MHz, CDC1 ) d: 11.2, 14.3, 15.8, 17.8, 29.3,
0
J¼1.3, 7.3 Hz, H-3 ), 6.95 (1H, dq, J¼1.0, 7.3 Hz, H-11 );
1
3
3
2 2 3
3
1
1.6, 51,8, 63.9, 64.0, 75.5, 123.1, 128.0, 130.4, 135.5,
36.0, 137.6, 139.6, 139.7, 149.5, 167.8, 188.3; HRMS,
NaHCO , H O and brine. The organic layer was dried and
3 2
concentrated. The residue was purified by chromatography
(4:1 hexane/EtOAc) to afford 33b (26.5 mg, 74%) as a
colorless oil.
þ
calcd for C H O (M ) 374.1729, found 374.1733.
21 28 6
4
1
.2.27. Methyl (3E,5E,9E,12R,13R,14S)-12-carbamoyl-
2,13-epoxy-2-[(E)-ethylidene]-4,10-dimethyl-14-
4.3.1. (1S,4S,5S)-1-Hexanoyl-4-methyl-3,6-dioxabicylo-
2
1
D
hydroxy-11-oxopentadeca-3,5,9-trienoate 32. A solution
of 12 (50.8 mg, 0.14 mmol) and NH (,1 mL) in MeOH
[3.1.0] hexan-2-one 33b. [a] ¼296.0 (c 2.5, CHCl ); IR
3
(neat) 3061, 2958, 2933, 2864, 1786, 1716, 1460, 1404,
1335, 1255, 1130, 1072, 1016, 958, 910, 854, 775, 750, 696,
3
(
2 mL) was stirred at 08C in a sealed tube for 1 h. The
646 cm2 ; H NMR (400 MHz, CDCl ) d: 0.90 (3H, t,
1
1
solvent was removed under a reduced pressure. The residue
was purified by chromatography (1:1–1:2 hexane/EtOAc)
3
0
0
0
J¼6.8 Hz, H-6 ), 1.26–1.35 (4H, m, H-4 , H-5 ), 1.45 (3H,
2
1
0
to afford 32 (42.3 mg, 80%) as a colorless oil. [a] ¼254.5
d, J¼6.8 Hz, 4-Me), 1.59–1.66 (2H, m, H-3 ), 2.56–2.67
D
0
H-4); C NMR (100 MHz, CDCl ) d: 13.7, 17.7, 22.2, 22.2,
(
c 0.55, MeOH); IR (neat) 3460, 3344, 2978, 2951, 2929,
(2H, m, H-2 ), 4.21 (1H, s, H-5), 4.70 (1H, q, J¼6.8 Hz,
1
3
2
1
854, 1689, 1635, 1599, 1435, 1392, 1265, 1213, 1061,
1 1
024, 966, 870, 837, 758, 731 cm ; H NMR (270 MHz,
3
2
30.9, 39.6, 59.0, 65.3, 74.8, 166.7, 198.7; HRMS, calcd for
þ
CD OD) d: 1.33 (3H, d, J¼6.9 Hz, H-15), 1.62 (3H, d,
C H O (M-H ) 211.0970, found 211.0978.
11 16 4
3
J¼1.0 Hz, 4-Me), 1.71 (3H, dd, J¼1.3, 7.3 Hz, CH–Me),
1
.79 (3H, d, J¼1.0 Hz, 10-Me), 2.38 (2H, m, H-8), 2.46
4.3.2. (1S,4S,5S)-1-Dodecanoyl-4-methyl-3,6-dioxabi-
cylo-[3.1.0]hexan-2-one 33c. The title compound was pre-
(
2H, m, H-7), 3.17 (1H, d, J¼8.3 Hz, H-13), 3.61–3.68 (1H,
2
1
m, H-14), 3.71 (3H, s, CO Me), 5.78 (2H, td, J¼6.9,
pared in 90% yield as a white solid. Mp¼328C. [a] ¼þ63.0
2
D
1
5.5 Hz, H-6), 5.94 (1H, brs, H-3), 6.27 (1H, d, J¼15.5 Hz,
(c 1.86, CHCl ); IR (CHCl ); 3034, 2929, 2856, 1788, 1720,
3
3
H-5), 6.93 (1H, tq, J¼1.0, 7.3 Hz, H-9), 7.09 (1H, dt, J¼1.0,
1462, 1402, 1335, 1238, 1128, 1076, 1016, 962, 914, 856,
21 1
1
3
7
1
1
1
.3 Hz, CH–Me); C NMR (75 MHz, CD OD) d: 12.1,
3
696 cm ; H NMR (300 MHz, CDCl ), d: 0.86–0.88(3H, m,
3
0
4-Me), 2.62 (2H, m, H-2 ), 4.19 (1H, s, H-5), 4.69 (1H, q,
0
0
5.4, 16.7, 21.8, 31.0, 33.4, 53.1, 63.1, 66.1, 67.4, 67.7,
24.5, 130.7, 132.7, 137.2, 137.2, 136.0, 137.6, 141.6,
50.8, 170.2, 171.0, 195.5; HRMS, calcd for C H NO
H-12 ), 1.00 (18H, m, H-3 –H 11 ), 1.45 (3H, d, J¼6.8 Hz,
0
1
3
J¼6.8 Hz, H-4); C NMR (75 MHz, CDCl ) d: 14.1, 17.7,
2
1
29
6
3
þ
(
M ) 391.1995, found 391.1999.
22.6, 28.9, 29.2, 29.2, 29.3, 29.5, 29.5, 31.8, 39.7, 59.7,
65.4, 74.8, 166.7, 198.7; HRMS, calcd for C H O
(M2H ) 295.1907, found 295.1913.
17 28 4
þ
4.2.28. Epolactaene (1)-1. To a solution of Dess-Martin
periodinane (8.6 mg, 20 mmol) in CH Cl (1 mL) was added
2
2
a solution of 31 (3.3 mg, 8.4 mmol) in CH Cl (1 mL) at rt.
2
4.3.3. (1S,4S,5S)-4-Methyl-1-(2-methylpent-2-enol)-3,6-
dioxabicylo-[3.1.0]hexan-2-one 33e. The title compound
2
After stirring for 3 h, the mixture was quenched by the
addition of saturated aqueous NaHCO3 (1 mL) and
saturated aqueous NaHSO3 (1 mL) and extracted with
CHCl (£3). The combined extract was washed with H O
2
0
was prepared in 83% yield as a colorless oil. [a] ¼212.0
D
(c 0.31, CHCl ); IR (neat) 3550, 3026, 2974, 2937, 2877,
3
1782, 1678, 1635, 1456, 1385, 1335, 1244, 1215, 1134,
3
2
1072, 1016, 982, 924, 845, 756, 696, 640 cm2 ; H NMR
1 1
brine, dried and concentrated. The residue was purified by
chromatography (2:3 hexane/EtOAc) to afford (þ)- epo-
lactaene (2.3 mg, 70%) as a ca. 5.4:1 tautomeric mixture as
0
(400 MHz, CDCl ) d: 1.12 (3H, t, J¼7.6 Hz, H-5 ), 1.51
3
0
(3H, d, J¼6.8 Hz, 4-Me), 1.84 (3H, d, J¼1.2 Hz, 2 -Me),
2
1
0
a colorless foam. [a] ¼þ34.0 (c 0.25, MeOH); IR (CHCl )
2.35 (2H, dq, J¼7.0, 7.6 Hz, H-4 ), 4.12 (1H, s, H-5), 4.73
13
D
3
0
C NMR (100 MHz, CDCl ) d: 10.8, 12.5, 17.7, 22.7, 60.2,
3
1
1
425, 3026, 2927, 2854, 1728, 1691, 1631, 1439, 1381,
179, 1140, 964 cm2 ; H NMR (270 MHz, CD OD) d:
(1H, q, J¼6.8 Hz, H-4), 6.87 (1H, dq, J¼1.2, 7.0 Hz, H-3 );
1
1
3
3
.52 (3H, s, H-16), 1.62 (311, d, J¼1.0 Hz, H-21), 1.72 (3H,
63.9, 75.5, 135.1, 151.9, 168.3, 188.3; HRMS, calcd for
þ
dd, J¼1.3, 7.3 Hz, H-1), 1.79 (3H, d, J¼1.0 Hz, H-21), 1.83
C H O (M ) 210.0891, found 210.0900.
11 14 4
(
3H, d, J¼l.3 Hz, H-22), 2.35 (2H, m, H-8), 2.47 (2H, m,
H-9), 3.71 (3H, s, H-20), 3.98 (1H, s, H-14), 5.78 (2H, td,
J¼6.9, 15.5 Hz, H-7), 5.94 (1H, brs, H-4), 6.28 (1H, dd,
J¼0.7, 15.5 Hz, H-6), 6.93 (1H, dq, J¼1.0, 7.3 Hz, H-2),
4.3.4. (1S,4S,5S)-1-Dodecanoyl-4-methyl-3,6-dioxabi-
cylo-[3.1.0]hexan-2-one 33h. The title compound was
prepared in 88% yield as a white solid. Mp¼50–548C.

9756
K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
2
1
[
1
(
(
1
4
a] ¼257.1 (c 0.45, CHCl ); IR (CHCl ); 2927, 2855,
4.4.4. (2S,3S)-3-[(S)-1-Hydroxyethyl]-2-octadecanoylox-
irane-2-carboxamide 34h. The title compound was pre-
D
3
3
2
1 1
787, 1717, 1465, 1383, 1335, 1111, 1075 cm ; H NMR
0
22
400 MHz, CDCl ) d: 0.88 (3H, t, J¼6.8 Hz, H-18 ), 1.25
pared in 91% yield. Mp¼98–1018C. [a] ¼þ10.0 (c 0.30,
3
D
0
.65 (2H, m, H-3 ), 2.62 (2H, m, H-2 ), 4.17 (1H, s, H-5),
0
30H, m, H-4 –H-17 ), 1.45 (3H, d, J¼6.8 Hz, 4-Me), 1.49–
MeOH); IR (CHCl ) 3710, 3650, 3574, 3154, 2988, 2926,
3
0
0
2852, 1715, 1666, 1560, 1466, 1382, 1296, 1210, 1146,
21 1
1
3
.69 (1H, q, J¼6.8 Hz, H-4); C NMR (100 MHz, CDCl3)
1097, 902, 737 cm ; H NMR (400 MHz, CDCl ) d: 0.88
3
0
0
0
d: 14.1, 17.8, 22.7, 28.9, 29.2, 29.3, 29.4, 29.5, 29.6, 29.6,
2
(3H, t, J¼6.8 Hz, H-18 ), 1.25 (30H, m, H-4 –H-17 ), 1.41
00 0
9.6, 29.6, 29.6, 29.6, 31.9, 39.8, 59.1, 60.3, 65.4, 74.8,
þ
(3H, d, J¼6.3 Hz, H-2 ), 1.45–1.65 (3H, m, H-3 , OH),
0 0
2,46–2.55 (1H, m, H-2 ), 2.65–2.73 (IH, m, H-2 ), 3.17
1
found 380.2915.
66.7, 198.7; HRMS, calcd for C H O (M ) 380.2927,
2
3 40 4
0
0
(1H, d, J¼7.8 Hz, H-3), 3.66 (1H, m, H-1 ), 5.85 (1H, s,
1
3
NH), 6.75 (1H, s, NH); C NMR (100 MHz, CDCl ) d:
3
4
.4. The general method for the preparation of 34
14.1, 20.3, 22.7, 23.0, 29.0, 29.3, 29.4, 29.4, 29.6, 29.7,
29.7, 29.7, 29.7, 31.9, 38.0, 65.5, 65.6, 65.7, 166.8, 203.8;
HRMS, calcd for C H NO (M ) 397.3192, found
397.3188.
þ
A solution of 33b (15.7 mg, 0.074 mmol) and NH3
,0.1 mL) in MeOH (0.5 mL) was stirred at 08C in a
23
43
4
(
sealed tube for 3 h. The solvent was removed under a
reduced pressure. The residue was purified by chromato-
graphy (1:1 hexane/EtOAc) to afford 34b (14.6 mg, 86%) as
a white solid.
4.5. The general method for the preparation of 35
To a solution of 34b (31.1 mg, 0.136 mmol) in CH Cl
2
2
(
5 mL) was added Dess-Martin periodinane (115 mg,
4
.4.1. (2S,3S)-3-[(S)-1-Hydroxyethyl]-2-hexanoyloxir-
2
0.272 mmol) at rt and the mixture was stirred for 1 h.
Then the mixture was diluted with EtOAc and washed with
saturated aqueous Na S O and saturated aqueous NaHCO ,
2
D
ane-2-carboxanilde 34b. Mp¼63–658C. [a] ¼þ19.0 (c
0
1
1
.56, MeOH); IR (neat) 3476, 3020, 2960, 2933, 2864,
713, 1684, 1593, 1458, 1400, 1377, 1288, 1215, 1146,
2
2
3
3
H O and brine. The organic layer was dried and concen-
2
099, 1063, 970, 905, 756, 669 cm2 ; H NMR (500 MHz,
1
1
trated. The residue was purified by chromatography (4:1
hexane/EtOAc) to afford 35b (27.1 mg, 88%) as a ca. 1.7:1
tautomeric mixture, as a colorless foam.
0
CDCl ) d: 0.89 (3H, t, J¼7.0 Hz, H-6 ), 1.23–1.33 (4H, m,
3
0
m, H-3 ), 2.46–2.52 (1H, m, H-2 ), 2.62–2.69 (IH, m, H-2 ),
0
00
H-4 , H-5 ), 1.38 (3H, d, J¼6.1 Hz, H-2 ), 1.53–1.60 (2H,
0
0
0
0
1H, s, NH), 7.00 (1H, s, NH); C NMR (125 MHz, CDCl )
3
.17 (1H, d, J¼7.9 Hz, H-3), 3.64–3.70 (1H, m, H-1 ), 6.76
4.5.1. ((1R,5R)-1-Hexanoyl-4-hydroxy-4-methyl-6-oxa-3-
22
1
3
(
d: 13.8, 20.2, 22.3, 22.6, 31.0, 37.8, 65.1, 65.5, 65.6, 167.2,
azabicyclo-[3.1.0]hexan-2-one 35b. [a] ¼2130.5 (c
3
D
0.20, MeOH); IR (CHCl ) 3340, 3020, 2960, 2933, 2864,
3
þ
2
found 230.1392.
03.8; HRMS, calcd for C H NO (MþH ) 230.1391,
1736, 1697, 1593, 1466, 1400, 1365, 1217, 1155, 1119, 943,
1 1
1
1
19
4
2
889, 760, 667 cm ; H NMR (400 MHz, CDCl ) d: 0.84–
3
0 0
.95 (3H, m, H-6 ), 0.84–0.95* (3H, m, H-6 ), 1.21–1.35
(6H, m, H-3 –H-5 ), 1.21–1.35* (6H, m, H-3 –H-5 ), 1.58
(3H, s, 4-Me), 1.61* (3H, s, 4-Me), 2.24–2.81 (2H, m,
0
0
0
0
0
4.4.2. (2S,3S)-3-[(S)-1-Hydroxyethyl]-2-dodecanoyloxir-
ane-2-carboxamide 34c. The title compound was prepared
2
2
0
0
in 92% yield as a white solid. Mp¼94–958C. [a] ¼þ13.3
H-2 ), 2.24–2.81* (2H, m, H-2 ), 3.96* (IH, d, J¼2.4 Hz,
H-5), 4.21 (1H, d, J¼2.4 Hz, H-5), 5.25 (1H, brs, OH), 6.22
13
D
(
c 0.56, MeOH); IR (CHCl ) 3512, 3477, 3359, 3018, 2927,
3
2
1
0
1
856, 1708, 1695, 1578, 1458, 1396, 1284,1232,1146,1097,
2
(1H, brs OH), 6.98 (1H, d, J¼9.0 Hz, NH), 7.97 (1H, d,
1
1
051,960,912, 656 cm ; H NMR (300 MHz, CDCl ) d:
3
J¼9.0 Hz, NH); C NMR (100 MHz, CDCl ) d: 13.8, 21.3,
3
0
0
0
.8 (3H, t, J¼6.6 Hz, H-12 ), 1.25 (16H, m, H-4 –H-11 ),
22.2, 22.3, 22.7, 24.2, 27.9, 31.0, 31.0, 31.1, 38.2, 38.6,
39.8, 61.2, 62.2, 62.8, 63.9, 65.8, 82.8, 83.5, 165.0, 166.9,
169.2, 199.8, 199.9, 201.8, 202.1 (diastereomeric mixture);
00
0
.39 (3H, d, J¼6.2 Hz, H-2 ), 1.56 (2H, m, H-3 ), 2.49 (1H,
0
td, J¼7.3, 18.2 Hz, H-2 ), 2.66 (IH, td, J¼7.3, 18.2 Hz,
0
0
þ
H-2 ), 3.17 (lH, d, J¼7.7 Hz, H-3), 3.62–3.71 (1H, m,
HRMS, calcd for C H NO (MþH ) 228.1234, found
1
1
17
4
0
CDCl ) d: 14.1, 20.3, 22.7, 23.0, 29.0, 29.3, 29.3, 29.3, 29.4,
13
H-1 ), 6.35(1H, s, NH), 6.86(1H, s, NH); C NMR (75 MHz,
228.1234.
3
2
for C H NO (M ) 313.2252, found 313.2269.
9.6, 31.9, 38.0, 65.4, 65.5, 65.6, 167.0, 203.7; HRMS, calcd
þ
4.5.2. (1R,5R)-1-Dodecanoyl-4-hydroxy-4-methyl-6-oxa-
3-azabicyclo-[3.1.0]hexan-2-one 35c. The title compound
was prepared in 88% yield as a ca. 3.7:1 tautomeric mixture,
1
7
31
4
2
2
4.4.3. (2S,3S)-3-[(S)-1-Hydroxyethyl]-2(2-methylpent-2-
enoyl)oxirane-2-carboxamide 34e. The title compound
as a colorless foam. [a] ¼275.9 (c 0.12, MeOH); IR
D
(CHCl ) 3455, 3020, 2927, 2856, 1743, 1693, 1408, 1215,
3
2
2
21 1
was prepared in 97% yield as a colorless oil. [a] ¼275.9
1161, 1117, 1086, 949, 758, 667 cm ; H NMR (400 MHz,
0
D
(
c 0.34, MeOH); IR (neat) 3467, 3329, 3018, 2976, 2877,
CDCl ) d: 0.88 (3H, d, J¼6.6 Hz, H-12 ), 0.88* (3H, t,
3
0
1.50* (6H, m, H-3 –H-11 ), 1.58 (3H, s, 4-Me), 1.62* (3H,
0
0
1
7
686, 1593, 1458, 1398, 1217, 1149, 1070, 968, 899, 843,
1 1
J¼6.6 Hz, H-12 ), 1.25–150 (18H, m, H-3 –H-11 ), 1.25–
58, 667 cm2 H NMR (270 MHz, CDCl ) d: 1.10 (3H, t,
0
s, 4-Me), 2.19–2.30 (1H, m, H-2 ), 2.l9–2.30* (1H, m,
0
3
0
0
0
H-2 ), 2.42–2.61 (1H, m, H-2 ), 2.42–2.61* (1H, m, H-2 ),
J¼7.6 Hz, H-5 ), 1.38 (3H, t, J¼6.3 Hz, H-2 ), 1.79 (3H, d,
0
0
0
0
0
J¼1.3 Hz, 2 -Me), 2.26–2.37 (2H, m, H-4 ), 3.17 (1H, d,
J¼7.9 Hz, H-3), 3.60 (1H, brs, OH), 3.69–3.79 (1H, m,
3.18* (1H, brs, OH), 3.96* (1H, d, J¼1.8 Hz, H-5), 4.24
13
0
0
H-1 ), 6.51 (1H, s, NH), 6.74 (1H, s, NH), 7.09 (1H, dt,
(1H, d, J¼1.8 Hz, H-5), 5.25 (1H, brs, OH), 6.79 (1H, brs,
1
3
J¼1.3, 7.3 Hz); C NMR (75 MHz, CDCl ) d: 13.7, 17,7,
NH), 8.13 (1H, brs, NH); C NMR (100 MHz, CDCl )
3
3
22.2, 22.2, 30.9, 39.6, 59.0, 65.3, 74.8, 166.7, 198.7;
HRMS, calcd for C H NO (M ) 227.1157, found
d: 14.1, 21.3, 22.5, 22.6, 22.7, 24.1, 29.0, 29.3, 29.3,
29.4, 29.4, 29.4, 29.6, 29.6, 29.6, 31.9, 38.1, 39.9, 61.2,
62.8, 63.9, 65,9, 82.8, 83.7, 166.8, 169.4, 199.7, 202.3
þ
1
1
17
4
2
27.1159.

K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
9757
(
(
diastereomeric mixture); HRMS, calcd for C H NO
4
M ) 311.2096, found 311.2108.
32.8, 32.8, 33.2, 33.9, 64.3, 64.3, 65.5, 65.6, 65.9, 67.2,
69.0, 70.3, 173.1, 173.5 (diastereomeric mixture); HRMS,
1
7
29
þ
þ
calcd for C H NO (MþH ) 232.1547, found 232.1555.
1
1
21
4
4
.5.3. (1R,5R)-4-Hydroxy-4-methyl-1-(methylpent-2-
enoyl)-6-oxa-3-azabicyclo-[3.1.0]hexan-2-one 35e. The
title compound was prepared in 82% yield as a ca. 2.6:1
tautomeric mixture, as a white solid. Mp¼86–888C;
4.6.2. (2S,3S)-3-[(S)-1-Hrdroxyethyl]-2-[(1RS)-1-hydro-
xydodecanoyl]oxirane-2-carboxamide 36c. The title com-
pound was prepared in 91% yield as a ca. 1:1 diastereomeric
2
1
[
a] ¼þ12.6 (c 0.18, MeOH); IR (CHCl ) 3338, 2954,
mixture, as a colorless solid. Mp¼89–918C; IR (CHCl )
D
3
3
2
8
1
1
2
927, 2854, 1740, 1637, 1460, 1377, 1309, 1161, 1074, 960,
91, 843, 768, 721 cm ; H NMR (270 MHz, CDCl ) d:
3513, 3467, 3398, 3018, 2927, 2856, 1680, 1574, 1468,
1402, 1379, 1294, 1221, 1088, 966, 889, 669 cm ; H
2
1
1
21
1
3
0
.50 (3H, s, 4-Me), 1.59* (3H, s,4-Me), 1.81 (3H, s, 2 -Me),
0
0
0.88–0.91* (3H, m, H-12 ), 1.29–1.40 (21H, m, H-3 –H-
.08 (3H, t, J¼7.6 Hz, H-5 ), 1.09* (3H, t, J¼7.6 Hz, H-5 ),
NMR (500 MHz, CD OD) d: 0.88–0.91 (3H, m, H-l2 ),
3
0
.00* (3H, s, 2 -Me), 2.27–2.38 (2H, m, H-4 ), 2.27–2.38*
0
0
11 , H-2 ), 1.29–1.40* (21H, m, H-3 –H-11 , H-2 ), 1.45–
0
0
0 00 0 0 00
0
0
0
(
(
2H, m, H-4 ), 3.99 (1H, s, H-5), 4.07* (1H, s, H-5), 6.76*
0
1.61 (2H, m, H-2 ), 1.45–1.61* (2H, m, H-2 ), 2.93 (1H, d,
1H, dt, J¼1.2, 7.3 Hz, H-3 ), 6.98 (1H, dt, J¼1.2, 7.3 Hz,
J¼8.2 Hz, H-3), 3.13* (1H, d, J¼8.2 Hz, H-3), 3.50–3.56
0
2.2, 23.5, 23.6, 25.4, 63.9, 64.4, 65.9, 84.0, 84.7, 136.4,
13
00 00
(1H, m, H-1 ), 3.50–3.56* (1H, m, H-1 ), 3.67 (1H, dd,
H-3 ); C NMR (75 MHz, CDCl ) d: 10.9, 10.9, 12.9, 13.0,
3
2
1
0
0
J¼3.8, 9.0 Hz, H-1 ), 4.04* (1H, dd, J¼4.0, 8.5 Hz, H-1 );
C NMR (125 MHz, CD OD) d: 14.5, 20.9, 23.7, 26.6,
3
1
3
36.5, 151.7, 152.2, 172.4, 192.2 (diastereomeric mixture);
þ
25.1000.
HRMS, calcd for C H NO (M ) 225.1000, found
4
27.0, 30.5, 30.5, 30.6, 30.7, 30.8, 30.8, 33.1, 33.2, 34.0,
64.3, 65.5, 65.6, 65.8, 67,2, 69.0, 70.3, 73.0, 173.2, 173.5
1
1
15
2
(
diastereomeric mixture); HRMS, calcd for C H NO
17 33 4
þ
4.5.4. (IR,5R)-4-Hydroxy-4-methyl-1-octadecanoyl-6-
oxa-3-azabicyclo-[3.1.0]hexan-2-one 35h. The title com-
(MþH ) 316.2488, found 316.2471.
pound was prepared in 91% yield as a ca. 8.7:1 tautomeric
1
4.6.3. (2S,3S)-3-[(S)-1-Hydroxyethyl]-2-[(1RS)-1-hydro-
xymethyl-2-methylpent-2-enyl]oxirane-2-carboxamide
36e. The title compound was prepared in 93% yield as a ca.
1.6:1 diastereomeric mixture, as a colorless oil. IR (neat)
3473, 3400, 3344, 3018, 2970, 2933, 2873, 1676, 1593,
1443, 1414, 1375, 1304, 1215, 1151, 1095, 1059, 957, 758,
2
D
mixture, as a white solid. Mp¼928C; [a] ¼281.9 (c 0.4,
MeOH); IR (CHCl ) 3714, 3638, 3534, 3421, 3154, 2990,
3
2
1
927, 2854, 1741, 1642, 1561, 1465, 1381, 1293, 1158,
2
1
1
096, 1016, 909, 837, 713 cm
;
H NMR (600 MHz,
0
CDCl ) d: 0.88 (3H, d, J¼6.6 Hz, H-12 ), 0.88* (3H, t,
3
0
.50* (6H, m, H-3 –H-17 ), 1.59 (3H, s, 4-Me), 1.63* (3H,
0
0
21
1
J¼6.6 Hz, H-12 ), 1.25–1.50 (18H, m, H-3 –H-17 ), 1.25–
669 cm ; H NMR (500 MHz, CDCl ) d: 0.96 (3H, t,
3
0
s, 4-Me), 2.44–2.62 (1H, m, H-2 ), 2.44–2.62* (1H, m,
0
0
0
1
J¼7.6 Hz, H-5 ), 0.96* (3H, t, J¼7.6 Hz, H-5 ), 1.33 (3H, d,
0
H-2 ), 2.73–2.81 (1H, m, H-2 ), 2.73–2.81* (1H, m, H-2 ),
0
0
0
0
J¼6.3 Hz, H-2 ), 1,35* (3H, d, J¼5.9 Hz, H-2 ), 1.64 (3H,
0
0
0
0
0
0
0
s, 2 -Me), 1.64 (3H, s, 2 -Me), 1.98–2.11 (3H, m, H-4 ),
3
.96* (1H, d, J¼2.4 Hz, H-5), 4.21 (1H, d, J¼2.4 Hz, H-5),
l.98–2.11* (2H, m, 11-4 ), 2.96 (1H, d, J¼8.2 Hz, H-3),
0
0
5
NH), 7.81 (1H, brs, NH); C NMR (150 MHz, CDCl ) d:
.86 (1H, brs, OH), 6.26* (1H, brs, OH), 6.88* (1H, brs,
3.23* (1H, d, J¼8.2 Hz, H-3), 3.53–3.65 (1H, m, H-1 ),
00 0
3.53–3.65* (1H, m, H-1 ), 4.24 (1H, s, H-1 ), 4.57* (1H, s,
1
3
3
0 0 0
H-1 ), 5.47–5.56* (1H, m, H-3 ), 5.47–5.56* (1H, m, H-3 ),
1
2
8
4.1, 21.4, 22,6, 28.9, 29.4, 29.5, 29.5, 29.6, 29.6, 29.6,
9.6, 29.7, 29.7, 29.7, 29.7, 29.7, 31.9, 38.3, 61.2, 63.7,
3.6, 169.2, 202.0 (the major isomer); HRMS, calcd for
1
3
6.62 (2H, s, NH ), 6.39–6.46 (2H, m, NH ); C NMR
2
2
(125 MHz, CDCl ) d:12.6, 12.7, 13.8, 14.2, 20.3, 20.3, 20.8,
3
þ
C H NO (M ) 395.3036, found 395.3038.
2
60.4, 62.4, 65.1, 65.1, 65.2, 65.7, 67.0, 73.7, 130.8, 131.0,
131.1, 131.6, 171.5, 171.9 (diastereomeric mixture);
HRMS, calcd for C H NO (M ) 229.1314, found
3
41
4
þ
4
.6. The general method for the preparation of 36
1
1
19
4
229.1323.
A solution of 11b (9.8 mg, 0.047 mmol) and NH3
(
,0.1 mL) in MeOH (0.5 mL) was stirred at 08C in a
4.6.4. [(S)-1-Hyrdoxyethyl]-2-[(1RS)-1-hydroxyocta-
decanoyl]oxirane-2-carboxamide 36h. The title compound
was prepared in 91% yield as a ca. 1:1 diastereomeric mixture,
sealed tube for 30 min. The solvent was removed under a
reduced pressure. The residue was purified by chromato-
graphy (1:2 hexane/EtOAc) to afford 36b (7.8 mg, 74%) as
as a colorless solid. Mp¼94–978C; IR (CHCl ) 3671, 3579,
3
0
a ca. 1:1 diastereomeric mixture at C-1 , as a white solid.
3156, 3091, 3037, 2927, 2858, 1680, 1479, 1382, 1237,
1
187, 1097, 1036, 966, 812, 680 cm2 ; H NMR (500 MHz,
1 1
0
4
.6.1. (2S,3S)-3-[(S)-1-Hydroxyethyl]-2-[1RS]-1-hydro-
CDCl ) d: 0.88 (3H, t, J¼6.8 Hz, H-18 ), 0.88* (3H, t,
3
0
0
0
xyhexyl]oxirane-2-carboxamide 36b. Mp¼79–818C; IR
J¼6.8 Hz, H-18 ), 1.25 (32H, m, H-3 –H-17 ), 1.25* (32H,
0
0
0
0
(
1
(
0
1
1
1
3
3
CHCl ) 3471, 3359, 3020, 2958, 2933, 2858, 1676, 1414,
3
m, H-3 –H-17 ), 1.37 (2H, d, J¼6.3 Hz, H-2 ), 1.37* (2H, d,
215, 1082, 1045, 964, 935, 756, 669 cm2 ; H NMR
1
1
J¼6.3 Hz, H-2 ), 1.43–1.85 (2H, m, H-2 ), 1.43–1.85 (2H,
0 0
00 0
m, H-2 ), 2.05 (1H, brs, 1 -OH), 2.18 (1H, brs, OH), 3.08
0
.83* (3H, m, H-6 ), 1.14–1.30 (6H, m, H-3 –H-5 ), l.14–
500 MHz, CD OD) d: 0.80–0.83 (3H, m, H-6 ), 0.80–
3
0
0
0
(1H, d, J¼8.0 Hz, H-3), 3.17* (1H, d, J¼8.0 Hz, H-3), 3.47
0
0
00
00
3.63* (1H, m, H-1 ), 4.12 (1H, m, H-1 ), 4.12* (IH, m,
.30* (6H, m, H-3 –H-5 ), 1.23 (3H, d, J¼6.4 Hz, H-2 ),
(1H, brs, OH), 3.47* (1H, brs, OH), 3.63 (1H, m, H-1 ),
00
0
00
H-1 ), 5.80 (1H, brs, NH), 5.80* (1H, brs, NH), 6.37 (1H,
0
.23* (3H, d, J¼6.4 Hz, H-2 ), 1.36–1.49 (2H, m, H-2 ),
0
0
brs, NH), 6.37* (1H, brs, NH); C NMR (125 MHz,
.36–1.49* (2H, m, H-2 ), 2.84 (1H, d, J¼7.9 Hz, H-3),
0
0
13
.04* (1H, d, J¼8.2 Hz, H-3), 3.41–3.47 (1H, m, H-1 ),
0
0
.41–3.47* (1H, m, H-1 ), 3.57 (1H, dd, J¼3.2, 9.0 Hz,
CDCl ) d:14.1, 14.1, 14.2, 20.3, 20.4, 22.7, 23.0, 23.7, 25.5,
3
25.8, 28.9, 29.3, 29.3, 29.4, 29.5, 29.5, 29.5, 29.6, 29.6,
29.7, 29.7, 29.8, 29.9, 30.0, 30.3, 30.4, 32.9, 33.0, 39.8,
0
0
13
H-1 ), 3.94* (1H, dd, J¼3.8, 8.4 Hz, H-1 ); C NMR
125 MHz, CD OD) d: 14.4, 20.9, 23.6, 23.6, 26.3, 26.6,
(
3

9758
K. Kuramochi et al. / Tetrahedron 59 (2003) 9743–9758
˚
3
6
9.9, 40.1, 40.3, 40.4, 60.4, 63.8, 65.2, 65.2, 65.7, 65.9,
7.3, 68.1, 71.2, 73.5, 170.8, 171.2 (diastereomeric mixture);
aldehyde, and 10) was retreated with TBAF and MS4 A, and
this operation was repeated.
þ
HRMS, calcd for C H NO (MþH ) 399.3349, found
12. Noyori, R.; Nishida, I.; Sakata, J. J. Am. Chem. Soc. 1981, 103,
2106.
2
3
45
4
3
99.3339.
1
3. (a) Beckmann, M.; Hildebrandt, H.; Winterfeldt, E.
Tetrahedron: Asymmetry 1990, 1, 335. (b) Ito, Y.; Kobayashi,
Y.; Kawabata, T.; Takase, M.; Terashima, S. Tetrahedron
1989, 45, 5767. (c) Takadoi, M.; Katoh, T.; Ishiwata, A.;
Terashima, S. Tetrahedron Lett. 1999, 40, 3399. (d) Takadoi,
M.; Katoh, T.; Ishiwata, A.; Terashima, S. Tetrahedron 2002,
58, 9903.
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˚
0. Molecular sieves 4 A was added to remove H
1
2
O present in
commercial THF solution of TBAF. We found that the
˚
˚
addition of molecular sieves 3 A instead of 4 A was not
effective affording the desilylated epoxylactone 2.
1. Without purification and separation, the crude mixture (5,
28. Nakai, J.; Kawada, K.; Nagata, S.; Kuramochi, K.; Uchiro, H.;
Kobayashi, S.; Ikekita, M. Biochim. Biophys. Acta 2002,
1581, 1.
1