Total synthesis of a nonclassical bioactive acetogenin, (+)-muconin

Article abstract of DOI:10.1016/S0040-4020(00)00033-8

A convergent total synthesis of the tetrahydropyran-bearing acetogenin (+)-muconin 1 is described. All five chiral building blocks 7, 9, 17, 21, and 29 were prepared from D-glutamic acid, respectively. Four out of them were used to furnish the alkyne 16 and the iodoalkyne 33, respectively, and palladium(0)-mediated cross-coupling of alkynes 16 and 33, followed by hydrogenation, afforded 36. Simultaneous deprotection of the MOM and TBS groups in 36 with BF₃·Et₂O in the presence of Me₂S provided (+)-muconin 1. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00033-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1451–1461
Total Synthesis of a Nonclassical Bioactive Acetogenin,
(ϩ)-Muconin
*
Wen-Qian Yang and Takeshi Kitahara
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi,
Bunkyo-ku, Tokyo 113-8657, Japan
Received 3 December 1999; accepted 6 January 2000
Abstract—A convergent total synthesis of the tetrahydropyran-bearing acetogenin (ϩ)-muconin 1 is described. All five chiral building
blocks 7, 9, 17, 21, and 29 were prepared from d-glutamic acid, respectively. Four out of them were used to furnish the alkyne 16 and the
iodoalkyne 33, respectively, and palladium(0)-mediated cross-coupling of alkynes 16 and 33, followed by hydrogenation, afforded 36.
Simultaneous deprotection of the MOM and TBS groups in 36 with BF3·Et2O in the presence of Me2S provided (ϩ)-muconin 1. ᭧ 2000
Elsevier Science Ltd. All rights reserved.
Introduction
As illustrated in our retrosynthetic analysis (Scheme 1),
muconin 1 may be constructed from two key building
blocks, I and II. The aldehyde III and the bromide IV,
both of which would be synthesized from d-glutamic acid,
respectively, would furnish the segment I bearing both THP
and THF rings. Using the same amino acid, the iodides V
and VI might be derived and used for alkylation of the
lactone VII, which is obtainable via the known procedure
from d-glutamic acid. The corresponding alkylated products
should be convertible to the moiety II in a few steps.
Finally, palladium(0)-mediated coupling of the two blocks
I and II followed by hydrogenation and deprotection would
complete our total synthesis of muconin.
The annonaceous acetogenins are a class of natural products
that have excellent anticancer, antiinfective pesticidal, anti-
malarial, immunosuppressive, and antifeedant properties.1
Approximately 300 acetogenins have been isolated from
various annonaceae plants, and most of the reported aceto-
genins belong to several classic types with unsubstituted
tetrahydrofuran (THF) rings.1 Recently, several nonclassical
annonaceous acetogenin have been discovered and they
bear a hydroxylated or an unsubstituted tetrahydropyran
(THP) ring.2 Muconin 1,2b isolated from leaves of Rollinia
mucosa (Jacq.) Baill. (Annonaceae), is the second THP-
bearing acetogenin bearing an unsubstituted THP ring
along with an adjacent THF ring. Compared to adriamycin,
muconin showed to be more potent and selective in vitro
cytotoxicity against PACA-2 (pancreatic cancer) and MCF-
7 (breast cancer) in a panel of six human solid tumor cell
lines. The remarkable antitumor activity and the unique
structure of 1 have consequently stimulated synthetic efforts
toward 1.3 We show here an approach to 1 via an efficient
and convergent route4 using only d-glutamic acid as the
origin of all absolute stereochemistry (Fig. 1).
Results and Discussion
Synthesis of the building block I
We modified Koert’s procedure to provide the aldehyde 4 in
12% overall yield through eight steps from d-glutamic
acid.5 In our procedure, it is noteworthy that the
thermodynamically controlled conversion of the undesired
Figure 1.
Keywords: muconin; THP-bearing acetogenin; cytotoxicity; diyne coupling; d-glutamic acid.
* Corresponding author. Tel.: ϩ81-03-5841-5119; fax: ϩ81-03-5841-8019; e-mail: atkita@mail.ecc.u-tokyo.ac.jp
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00033-8

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W.-Q. Yang, T. Kitahara / Tetrahedron 56 (2000) 1451–1461
Scheme 1.
cis-nitrile 3 into the useful trans-nitrile 2 was developed: the
cis-nitrile 3 was treated with KOt-Bu in THF-t-BuOH at
room temperature to give isomers 2 and 3 in 83% yield in
a ratio of 5:1. Subsequent four-step transformation from 4
developed by our group in the synthesis of solamin6 was
adopted to elongate the side chain furnishing the aldehyde 7
in overall 62% yield. In order to improve the yield, again the
undesired erythro isomer 6 was inverted to threo isomer 5
by means of a Dess–Martin oxidation7/l -Selectride reduc-
tion sequence. Consequently, the overall yield of the
aldehyde 7 from the starting d-glutamic acid was much
more improved (Scheme 2).
isolable product nor the starting aldehyde. The stereo-
chemistry of 10 was assigned by the analysis of the H
NMR spectra: the chemical shift of the proton at C-17 of
the major isomer was 3.37 ppm, indicating that the ring was
flanked by the hydroxyl group in threo fashion according to
Born’s rule.9
1
Deprotection of the acetonide group of 10 with AcOH in
THF–H2O gave the triol 11 in 70% yield. Selective
sulfonylation of the primary hydroxyl group in 11 with
triisopropylbenzenesulfonyl chloride in the presence of
excess pyridine afforded the sulfonate 12 in 79% yield. It
is noteworthy that using toluenesulfonyl chloride or
mesitylsulfonyl chloride as the sulfonating agent led to
poor yield (Ͻ40%) with recovery of the triol (Ͼ30%).
The sulfonate 12 was treated with NaOMe in MeOH–
CH2Cl2 to provide the epoxide 13, which was cyclized
smoothly with CSA in CH2Cl2 at 0ЊC to give a separable
mixture of 14 (60%) and 15 (20%). The cis-THP ring of
14 was confirmed by the positive NOESY correlation at
H-13(d 3.44)/H-17(d 3.28).
Treatment of the alcohol 8, which was also synthesized from
d-glutamic acid according to the known procedure in 29%
yield,8 with Ph3P/CBr4/Et3N in methylene chloride gave
the bromide 9 in 78% yield. With the bromide 9 and the
aldehyde 7, we investigated the chelation-controlled addi-
tion reaction. The coupled product 10 was obtained as an
inseparable mixture with a 3:1 diastereoselection at C-17
favoring the desired a-epimer in 80% yield when
14 equiv. amount of the bromide 9 was used. To our
surprise, addition of CuBr·SMe2 to the solution of the
Grignard reagent prior to addition of 7 did not give any
Dess–Martin oxidation of 14 under basic conditions
furnished an aldehyde, which was allowed to react with
Scheme 2. Reagents and conditions: (a) KOt-Bu, t-BuOH, THF, rt, 83%, 2:3 ˆ 5:1; (b) (i) Dess–Martin periodinane, DCM, rt; (ii) l -Selectride, THF, Ϫ78ЊC,
74%, 5:6ˆ10:1.

W.-Q. Yang, T. Kitahara / Tetrahedron 56 (2000) 1451–1461
1453
Scheme 3. Reagents and conditions: (a) Ph3P, CBr4, Et3N, DCM, rt, 78%; (b) 9, Mg, Et2O, Ϫ78ЊCϳrt, 80%, threo:erythroˆ3:1; (c) AcOH, H2O, THF, rt, 70%;
(d) triisopropylbenzenesulfonyl chloride, Py, DCM, 0ЊCϳrt, 79%; (e) NaOMe, MeOH, DCM, rt, 90%; (f) CSA, DCM, 0ЊC, 80%, 14:15ˆ3:1; (g) (i) Dess–
Martin periodinane, NaHCO3, DCM, rt; (ii) HCxCMgBr, Tol, THF, ϳ78ЊCϳrt, 80%, a-isomer:b-isomerˆ1:1.4.
ethynylmagnesium bromide in toluene–THF10 to give 16 as
a 1:1.4 inseparable mixture of the desired a-isomer and its
epimer in 80% overall yield. The stereochemical assign-
ment of the two isomers in 16 was based on McLaughlin’s
analysis, extrapolating Born’s rule from the THF to a THP
system.2 In our case, if Born’s rule should also hold true
for a propargylated-hydroxyl flanked THP ring system,
we may predict the relatively smaller d value of H-12 at
4.22 ppm indicated a threo relationship at C-12/13. This
assignment was confirmed by converting 16 to the
corresponding reduced compounds 36 and 37 and both of
them would be transferred into muconin (vide infra). In
order to increase the stereoselectivity of the addition, we
selected to use a solution of TMSCxCMgBr in Et2O as
the Grignard agent since it was known that its addition to
sugar aldehydes occurred stereoselectively.11 To our dis-
appointment, the addition just led to a little higher stereo-
selectivity (threo:erythroˆ1.4:1) but in a lower yield (43%)
(Scheme 3).
Synthesis of the building block II
Initially, we selected iodide 21 as the alkylating agent since
it was protected by the same MOM group as that of 16.
Preparation of 21 is shown in Scheme 4. Protection of the
hydroxyl group in 8 with TBDPSCl/Et3N/DMAP, followed
by deprotection of the acetonide group of 18 with AcOH in
THF–H2O provided the diol 19 in good yield. Selective
protection of the secondary hydroxyl group was effected
by the method of Yamamoto using trimethyl orthoformate
and DIBAL.12 The resulting primary alcohol 20 was
transformed to the iodide 21 by treatment with Ph3P/I2/
imidazole. Unfortunately, alkylation of the lactone 17,
derived from d-glutamic acid in five steps13 with 21 using
NaHMDS as the base, gave the alkylated lactone 22 in poor
yield (23%). We considered that this result might be due
to the presence of the MOM group adjacent to the iodo
substituent. Since it was known that using TBS as a pro-
tective group in a similar alkylation reaction worked very
Scheme 4. Reagents and conditions: (a) TBDPSCI, Et3N, DMAP, DCM, 0ЊCϳrt, 90%; (b) AcOH, THF, H2O, rt, 74%; (c) (i) (MeO)3CH, CSA, DCM, rt; (ii)
DIBAL, Ϫ78ЊC, 70% (d) Ph3P, I2, imidazole, CH3CN, Et2O, Ϫ10ЊCϳrt, 78%; (e) 17, NaHMDS, THF, HMPA, Ϫ10ЊCϳrt, 23%.

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W.-Q. Yang, T. Kitahara / Tetrahedron 56 (2000) 1451–1461
Scheme 5. Reagents and conditions: (a) Ph3P, I2, imidazole, CH3CN, Et2O, Ϫ10ЊC, 63%; (b) TMSCxCH, n-BuLi, THF, HMPA, Ϫ78ϳ0ЊC, 95%; (c) AcOH,
H2O, 60ЊC, 88%; (d) triisopropylbenzenesulfonyl chloride, Py, DCM, 0ЊCϳrt, 77%; (e) NaH, THF, 0ЊC, 95%; (f) LiI, AcOH, H2O, THF, 0ЊC, 82%; (g) TBSCl,
DMF, imidazole, rt, 90%; (h) 17, NaHMDS, THF, HMPA, Ϫ10ЊCϳrt, 76%, 30:31ˆ6.6:1; (i) (i) K2CO3, MeOH, 0ЊCϳrt; (ii) I2, morpholine, C6H6, 45ЊC, 75%;
(j) (i) m-CPBA, DCM, ϳ78ЊC, (ii) Tol, reflux, 50%, 40% yield of 33 from 31.
well,3 we attempted our second route employing the iodide
with the TBS group.
to the methyl substituent were 1.50 ppm, at lower field
compared with that of 31 at 1.40 ppm. Selective removal
of the TMS group in 30 with K2CO3/MeOH liberated the
terminal alkyne, which was then iodinated with I2/morpho-
line14 to give 32 in overall 75% yield. Trial of one-pot
transformation of 30 into 32 with NBS catalyzed by silver
salts (AgNO3, AgOCOCF3)15 led to the decomposition of
the compound 30, probably due to the presence of the
methylthio group. Oxidation of the methyl sulfide with
m-CPBA followed by thermal elimination provided the
butenolide 33. Similarly, the lactone 33 was also obtained
from 31 via four steps in overall 40% yield (Scheme 5).
Iodination of the alcohol 8 with Ph3P/I2/imidazole in
CH3CN–Et2O at Ϫ10ЊC gave the iodide 23, which was
then alkylated with TMSCxCH in the presence of n-BuLi
to afford compound 24. Deprotection of the acetonide group
in 24 with AcOH in water at 60ЊC provided diol 25 in 88%
yield, but on using other condition (HCl/THF, AcOH/THF/
H2O, CSA/TsOH/MeOH, TFA/THF/H2O) at room tempera-
ture, all the reactions resulted in poor to modest yields
(25–60%) with recovery of 24. Sulfonylation of the primary
hydroxyl group with triisopropylbenzenesulfonyl chloride
in the presence of excess pyridine gave the sulfonate 26,
which was treated with NaH in THF at 0ЊC to afford the
epoxide 27. Treatment of 27 with LiI/AcOH/THF at 0ЊC,
followed by protection of the newly generated hydroxyl
group as TBS ether afforded the iodide 29. As expected,
alkylation of the enolate derived from 17 with iodoether
29 furnished a mixture of sulfides 30 and 31 in good
yield, which were separable on silical gel. Stereochemical
assignment of 30 and 31 was conclusively done by the
following 1H NMR data: chemical shifts of thiomethyl
protons in 30 whose methylthio group locates cis-position
Coupling and completion of the total synthesis
Palladium(0)-mediated coupling of the alkyne 16 with the
iodoalkyne 33 using Schreiber’s protocol [Pd2(dba)3, CuI,
i-Pr2NH, (2-furyl)3P]16 afforded a separable mixture of
diynes 34 (23%) and 35 (32%). Hydrogenation of 34 and
35 using Wilkinson’s catalyst gave the corresponding
reduced products 36 and 37, respectively (Scheme 6). At
this stage, we first tried to invert the b-alcohol under
Mitsunobu’s conditions (ClCH2COOH, Ph3P, DEAD)17
since we intended to completely convert the b-alcohol to
Scheme 6. Reagents and conditions: (a) Pd2(dba)3, CuI, i-Pr2NH, (2-furyl)3P, C6H6, rt, 55% 34:35ˆ1:1.4; (b) (Ph3P)3RhCl, H2, C6H6, MeOH, rt, 77% yield of
36, 75% yield of 37; (c) (i) Dess–Martin periodinane, DCM, rt; (ii) LiAl(Ot-Bu)3H, THF, Ϫ60ЊC, 80%, 36:37ˆ3:1; (d) BF3·Et2O, Me2S, Ϫ10ЊC, 82%.

W.-Q. Yang, T. Kitahara / Tetrahedron 56 (2000) 1451–1461
1455
the corresponding a-alcohol. It is surprising that the diyne
35 was converted to 34 in very poor yield with recovery of a
large amount of 35. There was no reaction observed by the
treatment of the compound 37 under the same conditions.
These results suggested to us to employ another possible
method: an oxidation–reduction sequence. By oxidation
of the diyne 35 with Dess–Martin reagent or MnO2, no
obvious reaction could be observed. Fortunately, oxidation
of the b-alcohol 37 with Dess–Martin periodinane,
followed by selective reduction of ketone with LiAl(Ot-
Bu)3H proceeded smoothly to give the a-alcohol 36 with
3:1 diastereoselectivity in 80% yield. Deprotection of the
MOM and TBS groups in 36 with AcCl/MeOH or TMSBr
caused the decomposition of the substrate, but treatment
with BF3·Et2O in the presence of Me2S at Ϫ10ЊC provided
(ϩ)-muconin 1 with spectral properties identical to those of
the natural product.
14%). trans-Nitrile 2; colorless oil; [a]2d4ˆϩ6.4Њ (c 0.50,
CHCl3); lit.5 [a]d20ˆϩ6.5Њ (c 1.00, CHCl3); 1H NMR
(300 MHz, CDCl3) d 7.77–7.69 and 7.46–7.42 (m, 10H),
4.78 (m, 1H), 4.33 (m, 1H), 3.78 (dd, Jˆ11.0, 4.0 Hz, 1H),
3.68 (dd, Jˆ11.0, 4.0 Hz, 1H), 2.40–2.03 (m, 4H), 1.11 (s,
9H). cis-Nitrile 3; white solid; mp 78–79ЊC; lit.5 mp 79ЊC;
[a]d24ˆϩ20.0Њ (c 0.72, CHCl3); lit.5 [a]2d0ˆϩ20.6Њ (c 1.00,
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.73–7.69 and
7.46–7.42 (m, 10H), 4.67 (m, 1H), 4.16 (m, 1H), 3.73 (d,
Jˆ2.8 Hz, 2H), 2.32–2.04 (m, 4H), 1.07 (s, 9H).
Conversion of the b-alcohol 6 to the a-alcohol 5
To a solution of 6 (1.24 g, 2.30 mmol) in dichloromethane
(18 mL) was added Dess–Martin periodinane (1.17 g,
2.76 mmol). After being stirred at room temperature for
1.5 h, saturated aqueous sodium bicarbonate (15 mL) and
sodium thiosulfate (4.5 g) were added. The resulting
mixture was stirred for 20 min and extracted with diethyl
ether. The organic phase was washed with brine and dried
over anhydrous sodium sulfate. The solvent was removed
under reduced pressure and the residue was dissolved in
tetrahydrofuran (18 mL) at Ϫ78ЊC. A solution of l -Selec-
tride (2.76 mL, 1.0 M, 2.76 mmol) in tetrahydrofuran was
added dropwise and the resulting mixture was stirred for 1 h
at the same temperature. After quenching the reaction by the
dropwise addition of methanol, the solvent was removed
under reduced pressure and the residue was chromato-
graphed on silica gel (n-hexane:diethyl etherˆ10:1–6:1)
to give 5 (831 mg, 67%, less polar) and 6 (83 mg, 7%) as
colorless oil. threo-Isomer 5; [a]2d4ˆϩ3.5Њ (c 0.50, CHCl3);
lit.6 [a]2d2ˆϩ3.4Њ(c 0.52, CHCl3); 1H NMR (300 MHz,
CDCl3) d 7.71–7.61 and 7.45–7.33 (m, 10H), 4.11 (m,
1H), 3.81 (m, 1H), 3.66 (d, Jˆ4.7 Hz, 2H), 3.37 (m, 1H)
2.17–1.61 (m, 4H), 1.48–1.16 (m, 22H), 1.05 (s, 9H), 0.88
(t, Jˆ6.7 Hz, 3H). erythro-Isomer 6; [a]2d4ˆϩ0.40Њ (c 1.10,
CHCl3); lit.6 [a]d25ˆϩ0.36Њ(c 1.60, CHCl3); 1H NMR
(300 MHz, CDCl3) d 7.71–7.66 and 7.42–7.35 (m, 10H),
4.14 (m, 1H), 3.87 (m, 1H), 3.77 (m, 1H), 3.65 (d, Jˆ4.7 Hz,
2H), 2.07–1.71 (m, 4H), 1.43–1.14 (m, 22H), 1.05 (s, 9H),
0.88 (t, Jˆ6.7 Hz, 3H).
In conclusion, we have succeeded in total synthesis of
muconin via a convergent route. Further studies on the
syntheses and biological activities of the related analogs
are in progress and will be reported in due course.
Experimental
All melting points (mp’s) were uncorrected. Infrared spectra
(IR) were measured on a Jasco FT/IR-230 spectrometer.
Proton magnetic resonance spectra (1H NMR) were
recorded on a JEOL JNM EX-90, a BRUKER AC300 or a
JEOL JNM a-500 spectrometer. Chemical shifts are
reported in parts per million (d) relative to internal chloro-
form (d 7.26). FABMS spectra were recorded on a JEOL
JMS-HX110 mass spectrometer. Optical rotations were
measured on a Jasco DIP 1000 polarimeter. Analytical
thin-layer chromatography (TLC) was carried out using
0.25-mm Merck silica gel 60 F254 precoated glass-backed
plates. Compounds were visualized by ultraviolet light
(254 nm), iodine vapor or phosphomolybdic acid spray
reagent. Preparative TLC was carried out using 0.5-mm
Merck silica gel 60 F254 precoated glass-backed plates.
Column chromatography was performed on Merck silica
gel 60. All solvents were of reagent grade. Tetrahydrofuran
and diethyl ether were freshly distilled from sodium–benzo-
phenone under argon. Dichloromethane, benzene and
hexamethylphosphoric triamide were distilled from calcium
(R)-5-Bromo-1,2-O-isopropylidenepentane-1,2-diol (9)
To a solution of 8 (1.60 g, 10.0 mmol), carbon tetrabromide
(4.65 g, 14.0 mmol) and triethylamine (1.53 mL, 11.0
mmol) in dichloromethane (10 mL) was added dropwise a
solution of triphenylphosphine (3.14 g, 12.0 mmol) in
dichloromethane (8 mL) over 2 h. After an additional 1 h
of stirring at room temperature, the mixture was diluted with
n-pentane (70 mL) and then poured into ice-cold half-
saturated sodium bicarbonate (10 mL). The organic
phase was washed with brine and dried over anhydrous
sodium sulfate. The solvent was removed under reduced
pressure and the residue was chromatographed on silica
gel (n-hexane:diethyl etherˆ5:1) to give 9 (1.74 g, 78%)
as a colorless oil. [a]d24ˆϪ7.2Њ (c 0.88, CHCl3); IR (film)
n 2990, 2940, 2880, 1460, 1370, 1220, 1160, 1060, 860; 1H
NMR (90 MHz, CDCl3) d 4.20–4.00 (m, 2H), 3.70–3.38
(m, 3H), 2.10–1.60 (m, 4H) 1.42 (s, 3H), 1.35 (s, 3H); Anal.
Calcd for C8H15BrO2: C 43.07, H 6.78; Found: C 43.55, H
6.73.
˚
hydride and stored over 4 A-molecular seives. Absolute
methanol was distilled from Mg(OMe)2 and stored over
˚
3 A-molecular sieves.
Conversion of the cis-nitrile 3 to the trans-nitrile 2
To a solution of 3 (7.31 g, 20.0 mmol) in tetrahydrofuran
(130 mL) and tert-butyl alcohol (10 mL) was added
potassium tert-butoxide (11.20 g, 100.0 mmol). After
being stirred at room temperature for 24 h, the resulting
mixture was acidified to pH 5 with 2 M hydrochloric acid
and extracted with diethyl ether. The organic phase was
washed with saturated aqueous sodium bicarbonate, brine
and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the residue was
chromatographed on silica gel (n-hexane:diethyl etherˆ
6:1) to give 2 (5.04 g, 69%, less polar) and 3 (1.01 g,

1456
W.-Q. Yang, T. Kitahara / Tetrahedron 56 (2000) 1451–1461
(100R, 20R, 50R, 2R, 6RS)-1,2-O-Isopropylidene-6-
(50-(100-(methoxymethoxy)tridecyl)tetrahydrofuran-20-
yl)hexane-1,2,6-triol (10)
extracted with diethyl ether. The organic phase was washed
with brine and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue
was chromatographed on silica gel (n-hexane:diethyl
etherˆ1:2) to give 12 (2.65 g, 79%) as an inseparable
mixture of two isomers, which was employed in the next
step without further purification. Colorless oil; IR (film) n
3440, 2920, 2860, 2830, 1600, 1460, 1350, 1180, 1040, 810;
1H NMR (500 MHz, CDCl3) d 7.33 (d, Jˆ0.5 Hz, 2H), 4.87
(d, Jˆ6.5 Hz, 0.25H), 4.86 (d, Jˆ7.0 Hz, 0.75H), 4.76 (d,
Jˆ6.5 Hz, 1H), 4.20 (sept., Jˆ6.5 Hz, 2H), 4.12 (m, 1H),
4.04–3.82 (m, 4.25H), 3.56–3.42 (m, 1.75H), 3.47 (s, 3H),
2.98 (sept., Jˆ7.0 Hz, 1H), 2.12–1.22 (m, 52H), 0.95 (t,
Jˆ7.0 Hz, 3H); Anal. Calcd for C40H72O8S: C 67.38, H
10.18; Found: C 66.94, H 9.84.
A solution of 9 (23.4 g, 105 mmol) in diethyl ether (80 mL)
was added dropwise to magnesium turnings (5.0 g,
210 mmol) covered with diethyl ether (20 mL) after
dibromoethane-initiation. The mixture was stirred at room
temperature for 2 h to complete the formation of the
Grignard reagent. The ethereal solution of the Grignard
reagent thus prepared was transferred with a syringe to a
stirred solution of 7 (2.57 g, 7.5 mmol) in diethyl ether
(15 mL) at Ϫ78ЊC, and the mixture was allowed to warm
to room temperature overnight. The reaction mixture was
treated with saturated aqueous ammonium chloride at 0ЊC
and extracted with diethyl ether. The organic phase was
washed with brine and dried over anhydrous sodium sulfate.
The solvent was removed under reduced pressure and the
residue was chromatographed on silica gel (n-hexane:
diethyl etherˆ1:2) to give 10 (2.93 g, 80%) as an insepar-
able mixture of two isomers, which was employed in the
next step without further purification. Colorless oil; IR
(film) n 3480, 2920, 2860, 1460, 1370, 1220, 1040, 920;
1H NMR (500 MHz, CDCl3) d 4.80 (d, Jˆ7.0 Hz, 0.25H),
4.79 (d, Jˆ7.0 Hz, 0.75H), 4.69 (d, Jˆ7.0 Hz, 0.75H), 4.69
(d, Jˆ7.0 Hz, 0.25H), 4.07 (m, 1H), 4.02 (m, 1H), 3.95 (m,
1H), 3.86 (m, 0.25H), 3.79 (m, 1H), 3.53–3.42 (m, 2H), 3.39
(s, 3H), 3.38 (m, 0.75H), 2.02–1.87 (m, 2H), 1.72–1.22 (m,
31H), 1.40 (s, 3H), 1.34 (s, 3H), 0.87 (t, Jˆ7.0 Hz, 3H);
Anal. Calcd for C28H54O6: C 69.09, H 11.18; Found: C
68.67, H 11.08.
(100R,20R,50R,1RS,5R)-5,6-Epoxy-1-(50-(100-(methoxy-
methoxy)tridecyl)tetrahydrofuran-20-yl)hexan-1-ol (13)
To a solution of 12 (2.64 g, 3.70 mmol) in dichloromethane
(80 mL) and methanol (100 mL) was added dropwise a
solution of sodium methoxide (7.4 mL, 1.0 M, 7.4 mmol)
at 0ЊC. After being stirred at the same temperature for 1 h,
the mixture was stirred at room temperature for 2 h. The
reaction mixture was then treated with saturated aqueous
ammonium chloride and extracted with diethyl ether.
The organic phase was washed with brine and dried over
anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was chromatographed on
silica gel (n-hexane:diethyl etherˆ1:2) to give 13 (1.43 g,
90%) as an inseparable mixture of two isomers, which was
employed in the next step without further purification.
Colorless oil; IR (film) n 3470, 3040, 2920, 2860, 1460,
(100R, 20R, 50R, 2R,6RS)-6-(50-(100-(Methoxymethoxy)tri-
1
decyl)tetrahydrofuran-20-yl)hexane-1,2,6-triol (11)
1150, 1100, 1040, 920; H NMR (500 MHz, CDCl3) d
4.81 (d, Jˆ6.5 Hz, 0.25H), 4.80 (d, Jˆ7.0 Hz, 0.75H),
4.70 (d, Jˆ7.0 Hz, 0.75H), 4.69 (d, Jˆ7.0 Hz, 0.25H),
4.02 (m, 0.25H), 3.96 (m, 0.75H), 3.87 (m, 0.25H), 3.80
(m, 1H), 3.47 (m, 1H), 3.41 (m, 0.75H), 3.40 (s, 3H), 2.91
(m, 1H), 2.75 (t, Jˆ4.0 Hz, 1H), 2.47 (m, 1H), 2.02–1.22
(m, 33H), 0.88 (t, Jˆ7.0 Hz, 3H); Anal. Calcd for C25H48O5:
C 70.05, H 11.29; Found: C 69.71, H 11.23.
To a solution of 10 (3.21 g, 6.6 mmol) in tetrahydrofuran
(15 mL) and water (7.5 mL) was added acetic acid
(18.8 mL). After being stirred at room temperature for
24 h, the solvent was removed by co-evaporation with
toluene and the residue was chromatographed on silica gel
(diethyl ether:methanolˆ40:1) to give 11 (2.07 g, 70%) as
an inseparable mixture of two isomers, which was employed
in the next step without further purification. Colorless oil; IR
(film) n 3400, 2920, 2860, 1460, 1100, 1040, 920; 1H NMR
(500 MHz, CDCl3) d 4.76 (d, Jˆ7.0 Hz, 0.25H), 4.75 (d,
Jˆ7.0 Hz, 0.75H), 4.65 (d, Jˆ7.0 Hz, 1H), 3.97 (m, 0.25H),
3.91 (m, 0.75H) 3.82 (m, 0.25H), 3.77 (m, 1H), 3.67 (m,
1H), 3.59 (m, 1H), 3.45-3.33 (m, 2.75H), 3.36 (s, 3H), 2.69
(br 1H, OH), 2.26 (br, 1H, OH), 1.98–1.20 (m, 33H), 0.83 (t,
Jˆ7.0 Hz, 3H); Anal. Calcd for C25H50O6: C 67.22, H
11.28; Found: C 67.27, H 11.18.
(100R,20R,50R,2S,6R)-6-(50-(100-(Methoxymethoxy)-
tridecyl)tetrahydrofuran-20-yl)tetrahydropyran-2-
methanol (14) and (100R,20R,50R,2S,6S)-6-(50-(100-
(Methoxymethoxy)tetrahydrofuran-20-yl)tetra-
hydropyran-2-methanol (15)
To a solution of 13 (1.59 g, 3.70 mmol) in dichloromethane
(100 mL) was added camphorsulfonic acid (72 mg,
0.31 mmol) at 0ЊC. After being stirred at the same tempera-
ture for 3 h, the mixture was treated with saturated aqueous
sodium bicarbonate and extracted with dichloromethane.
The organic phase was washed with brine and dried over
anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was chromatographed on
silica gel (n-hexane:diethyl etherˆ1:2) to give 14 (952 mg,
60%, more polar) and 15 (317 mg, 20%) as colorless oils.
Compound 14; [a]1d9ˆϩ28.2Њ (c 0.48, CHCl3); IR (film) n
3440, 2920, 2860, 1460, 1100, 1040, 920; 1H NMR
(500 MHz, CDCl3) d 4.78 (d, Jˆ6.5 Hz, 1H), 4.63 (d,
Jˆ7.0 Hz, 1H), 3.97 (m, 1H), 3.84 (m, 1H), 3.53 (m, 1H),
3.48–3.40 (m, 3H), 3.35 (s, 3H), 3.28 (m, 1H), 1.92–1.17
(100R,20R,50R,2R,6RS)-2,6-Dihydroxy-6-(50-(100-(methoxy
methoxy)tridecyl)tetrahydrofuran-20-yl)hexyl 2,4,6-tri-
isopropylbenzenesulfonate (12)
To a solution of 11 (2.10 g, 4.70 mmol) in dichloromethane
(25 mL) was added pyridine (15 mL) and triisopropyl-
benzenesulfonyl chloride (4.27 g, 14.1 mmol) successively
at 0ЊC. After being stirred at the same temperature for
15 min, the mixture was stirred at room temperature
overnight. The excess acid chloride was destroyed with
ice-water by stirring for 1 h and the resulting mixture was

W.-Q. Yang, T. Kitahara / Tetrahedron 56 (2000) 1451–1461
1457
(m, 33H), 0.83 (t, Jˆ7.0 Hz, 3H); Anal. Calcd for C25H48O5:
C 70.05, H 11.29; Found: C 69.63, H 10.92. Compound 15;
[a]1d9ˆϩ28.4Њ (c 1.65, CHCl3); IR (film) n 3440, 2920,
further purification. [a]1d9ˆϪ8.6Њ (c 1.07, CHCl3); IR (film)
n 3080, 3040, 2940, 2860, 1590, 1430, 1380, 1110, 1060,
1
700; H NMR (500 MHz, CDCl3) d 7.69–7.65 and 7.44–
1
2860, 1460, 1220, 1100, 1040, 760; H NMR (500 MHz,
7.36 (m, 10H), 4.08 (m, 1H), 4.01 (t, Jˆ6.5 Hz, 1H), 3.68 (t,
Jˆ5.5 Hz, 2H), 3.50 (t, Jˆ7.5 Hz, 1H), 1.76–1.53 (m, 4H),
1.40 (s, 3H), 1.35 (s, 3H), 1.05 (s, 9H).
CDCl3) d 4.77 (d, Jˆ6.5 Hz, 1H), 4.63 (d, Jˆ7.0 Hz, 1H),
4.06 (m, 1H), 3.91 (m, 1H), 3.75 (m, 1H), 3.66 (m, 1H), 3.49
(m, 1H), 3.44–3.36 (m, 2H), 3.35 (s, 3H), 2.07–1.12 (m,
33H), 0.83 (t, Jˆ7.0 Hz, 3H); Anal. Calcd for C25H48O5: C
70.05, H 11.29; Found: C 69.93, H 11.24.
(R)-5-tert-Butyldiphenylsilyoxypentane-1,2-diol (19)
To a solution of 18 (3.99 g, 10.0 mmol) in tetrahydrofuran
(20 mL) and water (10 mL) was added acetic acid (25 mL).
After being stirred at room temperature for 24 h, the solvent
was removed by co-evaporation with toluene and the
residue was chromatographed on silica gel (n-hexane:ethyl
acetateˆ1:1) to give 19 (2.65 g, 74%) as a colorless oil,
which was employed in the next step without further puri-
fication. [a]1d9ˆϩ1.0Њ (c 0.39, CHCl3); IR (film) n 3380,
3070, 3050, 2960, 2860, 1590, 1470, 1120, 1000, 820,
(1000R,200R,500R,20S,60R,1RS)-1-(60-(500-(1000-(Methoxy-
methoxy)tridecyl)tetrahydrofuran-200-yl)tetrahydro-
pyran-20-yl)prop-2-yn-1-ol (16)
To a solution of 14 (472 mg, 1.10 mmol) and sodium
bicarbonate (153 mg, 1.82 mmol) in dichloromethane
(15 mL) was added Dess–Martin periodinane (700 mg,
1.65 mmol). After being stirred at room temperature for
3 h, saturated aqueous sodium bicarbonate (14 mL) and
sodium thiosulfate (1.2 g) were added. The resulting
mixture was stirred for 20 min and extracted with diethyl
ether. The organic phase was washed with brine and dried
over anhydrous sodium sulfate. The solvent was removed
under reduced pressure and the residue was dissolved in
toluene (50 mL) at Ϫ78ЊC. A solution of ethynylmagnesium
bromide (15.4 mL, 0.50 M, 7.70 mmol) in tetrahydrofuran
was added dropwise and the mixture was allowed to warm
to room temperature overnight. The reaction mixture was
treated with saturated aqueous ammonium chloride at 0ЊC
and extracted with diethyl ether. The organic phase was
washed with brine and dried over anhydrous sodium sulfate.
The solvent was removed under reduced pressure and the
residue was chromatographed on silica gel (n-hexane:ethyl
acetateˆ3:1) to give 16 (399 mg, 80%) as an inseparable
mixture of two isomers, which was employed in the next
step without further purification. Colorless oil; IR (film) n
1
700; H NMR (500 MHz, CDCl3) d 7.68–7.65 and 7.45–
7.36 (m, 10H), 3.78–3.62 (m, 4H), 3.47 (m, 1H), 2.96 (br,
1H, OH), 2.02 (br, 1H, OH), 1.76–1.51 (m, 4H), 1.07 (s,
9H).
(R)-5-tert-Butyldiphenylsilyoxy-2-methoxymethoxy-
pentan-1-ol (20)
To a solution of 19 (1.706 g, 3.0 mmol) in dichloromethane
(6.0 mL) was added triethyl orthoformate (0.66 mL,
6.0 mmol)
and
camphorsulfonic
acid
(7.0 mg,
0.030 mmol). After being stirred at room temperature for
2 h, the mixture was cooled to Ϫ78ЊC. A solution of
diisobutylaluminum hydride (32.0 mL, 0.94 M, 30 mmol)
in hexane was added dropwise and the resulting mixture
was stirred at Ϫ78ЊC for 30 min and at 0ЊC for 10 min.
The reaction mixture was then treated with methanol and
saturated aqueous sodium bicarbonate. After extraction with
diethyl ether, the organic phase was washed with brine and
dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the residue was
chromatographed on silica gel (n-hexane:ethyl acetateˆ4:1)
to give 20 (824 mg, 70%) as a colorless oil, which was
employed in the next step without further purification. IR
(film) n 3400, 3070, 3050, 2960, 2860, 1590, 1470, 1430,
1110, 1040, 820, 700; 1H NMR (500 MHz, CDCl3) d
7.67–7.65 and 7.44–7.36 (m, 10H), 4.70 (dd, Jˆ7.0,
1.0 Hz, 1H), 4.64 (dd, Jˆ7.0, 1.0 Hz, 1H), 3.68 (t,
Jˆ6.0 Hz, 2H), 3.62–3.46 (m, 3H), 3.42 (s, 3H), 1.70–
1.54 (m, 4H), 1.05 (s, 9H).
1
3400, 3310, 3020, 2930, 2860, 1220, 1040, 760; H NMR
(500 MHz, CDCl3) d 4.83 (d, Jˆ6.5 Hz, 0.42H), 4.82 (d,
Jˆ7.0 Hz, 0.58H), 4.68 (d, Jˆ6.5 Hz, 0.58H), 4.67 (d,
Jˆ7.0 Hz, 0.42H), 4.41 (dd, Jˆ3.5, 2.5 Hz, 0.58H), 4.22
(dd, Jˆ7.5, 2.5 Hz, 0.42H), 4.01 (m, 1H), 3.91 (m, 1H),
3.54–3.45 (m, 2H), 3.40 (s, 1.74H), 3.39 (s, 1.26H), 3.35
(m, 1H), 2.43 (d, Jˆ2.5 Hz, 0.42H), 2.41 (d, Jˆ2.0 Hz,
0.58H), 1.98–1.20 (m, 33H), 0.88 (t, Jˆ7.0 Hz, 3H);
Anal. Calcd for C27H48O5: C 71.64, H 10.69; Found: C
71.38, H 10.67.
(R)-5-tert-Butyldiphenylsilyoxy-1,2-O-isopropylidene-
pentane-1,2-diol (18)
(R)-5-tert-Butyldiphenylsilyoxy-1-iodo-2-methoxy-
To a solution of 8 (4.80 g, 30.0 mmol) and triethyl amine
(7.0 mL, 50.4 mmol) in dichloromethane (30 mL) was
added to tert-butyldiphenylsilyl chloride (9.0 mL,
34.6 mmol) and 4-(dimethylamino)pyridine (50 mg,
0.41 mmol) at 0ЊC. After being stirred at the same tempera-
ture for 5 min, the mixture was stirred at room temperature
for 6 h. The reaction mixture was then treated with water
and extracted with diethyl ether. The organic phase was
washed with brine and dried over anhydrous sodium sulfate.
The solvent was removed under reduced pressure and the
residue was chromatographed on silica gel (n-hexane:
diethyl etherˆ15:1–10:1) to give 18 (10.86 g, 90%) as a
colorless oil, which was employed in the next step without
methoxypentane (21)
To a solution of 20 (785 mg, 2.0 mmol) in acetonitrile
(8 mL) and diethyl ether (12 mL) was added imidazole
(299 mg,
4.4 mmol),
triphenylphosphine
(1.05 g,
4.0 mmol) and iodine (1.22 g, 4.8 mmol) successively at
Ϫ10ЊC. After being stirred at the same temperature for
1 h, the mixture was stirred at room temperature for 5 h.
The reaction was quenched with 10% aqueous sodium
thiosulfate and saturated aqueous ammonium chloride, and
the resulting mixture was extracted with diethyl ether. The
organic phase was washed with brine and dried over
anhydrous sodium sulfate. The solvent was removed under

1458
W.-Q. Yang, T. Kitahara / Tetrahedron 56 (2000) 1451–1461
reduced pressure and the residue was chromatographed on
silica gel (n-hexane:diethyl etherˆ10:1–6:1) to give 21
(784 mg, 78%) as a colorless oil, which was employed in
the next step without further purification. IR (film) n 3070,
(R)-1,2-O-Isopropylidene-7-trimethylsilyl-6-heptyne-
1,2-diol (24)
To
a
solution of trimethylsilylacetylene (5.22 mL,
1
3050, 2920, 2860, 1590, 1430, 1110, 1040, 820, 700; H
37.0 mmol) in tetrahydrofuran (70 mL) was added dropwise
a solution of butyllithium (24.2 mL, 1.53 M, 37.0 mmol) in
hexane at Ϫ78ЊC. After being stirred at the same tempera-
ture for 40 min, a solution of 23 (5.00 g, 18.5 mmol) in
hexamethylphosphoric triamide (7.0 mL) and tetrahydro-
furan (6.0 mL) was added dropwise and the resulting
mixture was then allowed to warm to room temperature
overnight. After quenching with half-saturated aqueous
ammonium chloride, the mixture was extracted with diethyl
ether. The organic phase was washed with brine and dried
over anhydrous sodium sulfate. The solvent was removed
under reduced pressure and the residue was chromato-
graphed on silica gel (n-hexane:diethyl etherˆ15:1) to
give 24 (4.22 g, 95%) as a colorless oil [a]3d0ˆϪ9.9Њ (c
1.60, CHCl3); IR (film) n 2980, 2920, 2880, 2170, 1370,
NMR (500 MHz, CDCl3) d 7.68–7.65 and 7.44–7.36 (m,
10H), 4.63 (d, Jˆ7.0 Hz, 1H), 4.60 (d, Jˆ7.0 Hz, 1H), 3.63
(t, Jˆ6.5 Hz, 2H), 3.37 (m, 1H), 3.35 (s, 3H), 3.27 (m, 1H),
3.21 (m, 1H), 1.80–1.56 (m, 4H), 1.05 (s, 9H).
(20R, 3RS, 5S)-3-(50-tert-Butyldiphenylsilyoxy-20-
(methoxymethyoxy)pentyl)-5-methyl-3-(methyl-
sulfenyl)-tetrahydrofuran-2-one (22)
To a solution of 17 (73 mg, 0.50 mmol) in tetrahydrofuran
(1.5 mL) was added dropwise a solution of sodium bis(tri-
methylsilyl)amide (0.84 mL, 0.60 M, 0.50 mmol) in toluene
at Ϫ10ЊC. After being stirred at the same temperature for
30 min, a solution of 21 (252 mg, 0.50 mmol) in hexa-
methylphosphoric triamide (1.5 mL) was added dropwise.
The resulting mixture was then stirred at room temperature
for 2 h. After quenching with 0.5 M hydrochloric acid at
0ЊC, the mixture was extracted with diethyl ether. The
organic phase was washed with brine and dried over
anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was chromatographed on
silica gel (n-hexane:ethyl acetateˆ10:1–7:1) to give 22
(61 mg, 23%) as a colorless oil. [a]3d0ˆϪ39.3Њ (c 0.25,
CHCl3); IR (film) n 3070, 3050, 2930, 2860, 1760, 1430,
1
1250, 840, 760; H NMR (500 MHz, CDCl3) d 4.11 (m,
1H), 4.04 (dd, Jˆ6.0, 8.0 Hz, 1H), 3.53 (dd, Jˆ7.0,
7.5 Hz, 1H), 2.27 (t, Jˆ6.5 Hz, 2H), 1.82–1.50 (m, 4H),
1.41 (s, 3H), 1.35 (s, 3H), 0.15 (2, 9H); Anal. Calcd for
C13H24O2Si: C 64.95, H 10.06; Found: C 64.95, H 9.95.
(R)-7-Trimethylsilyl-6-heptyne-1,2-diol (25)
A solution of 24 (3.55 g, 14.8 mmol) in water (9 mL) and
acetic acid (36 mL) was stirred at 60ЊC for 5 h. The solvent
was then removed by co-evaporation with toluene and the
residue was chromatographed on silica gel (n-hexane:ethyl
acetateˆ2:1) to give 25 (2.60 g, 88%) as a colorless oil.
[a]3d1ˆϩ2.8Њ (c 1.69, CHCl3); IR (film) n 3360, 2960,
1
1180, 1110, 1040, 700; H NMR (500 MHz, CDCl3) d
7.67–7.64 and 7.44–7.36 (m, 10H), 4.69 (d, Jˆ6.5 Hz,
1H), 4.64 (d, Jˆ6.5 Hz, 1H), 4.61 (m, 1H), 4.00 (m, 1H),
3.66 (t, Jˆ6.0 Hz, 2H), 3.36 (s, 3H), 2.90 (dd, Jˆ14.5,
8.5 Hz, 1H), 2.12 (s, 3H), 2.05 (m, 1H), 1.87 (m, 1H),
1.82 (m, 1H), 1.74–1.66 (m, 2H), 1.65–1.47 (m, 2H), 1.51
(d, Jˆ6.5 Hz, 3H), 1.04 (s, 9H). Anal. Calcd for
C29H42O5SSi: C 65.62, H 7.98; Found: C 65.28, H 7.91.
1
2870, 2170, 1250, 1040, 840; H NMR (500 MHz, CDCl3)
d 3.74 (m, 1H), 3.64 (dd, Jˆ11.0, 3.0 Hz, 1H), 3.43 (dd,
Jˆ11.0, 7.0 Hz, 1H), 2.37 (br, 2H, OH), 2.25 (d, Jˆ7.0,
1.0 Hz, 2H), 1.73–1.47 (m, 4H), 0.15 (s, 9H); Anal. Calcd
for C10H20O2Si: C 59.95, H 10.06; Found: C 59.57, H 9.96.
(R)-5-Iodo-1,2-O-isopropylidenepentane-1,2-diol (23)
(R)-2-Hydroxy-7-trimethylsilyl-6-heptynyl 2,4,6-triiso-
propylbenzenesulfonate (26)
To a solution of 8 (4.80 g, 30 mmol) in acetonitrile
(120 mL) and diethyl ether (180 mL) was added imidazole
(4.49 g, 66 mmol), triphenylphosphine (15.72 g, 60 mmol)
and iodine (18.29 g, 72 mmol) successively at Ϫ10ЊC. After
being stirred at the same temperature for 1 h, the mixture
was then stirred at room temperature for 6 h. The reaction
was quenched with 10% aqueous sodium thiosulfate and
saturated aqueous ammonium chloride and the resulting
mixture was extracted with diethyl ether. The organic
phase was washed with brine and dried over anhydrous
sodium sulfate. The solvent was removed under reduced
pressure and the residue was chromatographed on silica
gel (n-hexane:diethyl etherˆ15:1–10:1) to give 23
(5.10 g, 63%) as a colorless oil. [a]2d9ˆϪ4.8Њ (c 0.84,
CHCl3); IR (film) n 2980, 2940, 2880, 1460, 1370, 1220,
To a solution of 25 (2.80 g, 14.0 mmol) in dichloromethane
(82 mL) was added pyridine (46 mL) and triisopropyl-
benzenesulfonyl chloride (12.73 g, 42.0 mmol) successively
at 0ЊC. After being stirred at the same temperature for
15 min, the mixture was stirred at room temperature
overnight. The excess acid chloride was destroyed with
ice-water by stirring for 1 h and the resulting mixture was
extracted with diethyl ether. The organic phase was washed
with brine and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue
was chromatographed on silica gel (n-hexane:diethyl
etherˆ10:1–5:1) to give 26 (5.03 g, 77%) as a white
solid. mp 68–69ЊC; [a]2d9ˆϪ1.7Њ (c 0.30, CHCl3); IR
(nujol) n 3420, 2920, 2170, 1710, 1600, 1460, 1380, 840,
760; 1H NMR (500 MHz, CDCl3) d 7.32 (d, Jˆ1.0 Hz, 2H)
4.18 (sept., Jˆ6.5 Hz, 2H), 4.13 (m, 1H), 4.03–3.97 (m,
2H), 2.98 (sept., Jˆ7.0 Hz, 1H), 2.35–2.28 (m, 2H),
1.80–1.60 (m, 4H), 1.33 (d, Jˆ7.0 Hz, 12H), 1.32 (d,
Jˆ6.5 Hz, 6H), 0.19 (s, 9H); Anal. Calcd for
C25H42O4SSi: C 64.33, H 9.07; Found: C 64.10, H 9.00.
1
1060, 860; H NMR (500 MHz, CDCl3) d 4.10 (m, 1H),
4.04 (dd, Jˆ6.0, 8.0 Hz, 1H), 3.53 (dd, Jˆ6.5, 8.0 Hz,
1H), 3.24–3.18 (m, 2H), 1.99 (m, 1H), 1.88 (m, 1H),
1.70–1.62 (m, 2H), 1.42 (s, 3H), 1.34 (s, 3H); Anal.
Calcd for C8H15IO2: C 35.57, H 5.60; Found: C 35.84, H
5.64.

W.-Q. Yang, T. Kitahara / Tetrahedron 56 (2000) 1451–1461
1459
(R)-7-Trimethylsilyl-6-heptyn-1,2-epoxide (27)
(20R, 3R, 5S)-3-(20-tert-Butyldimethylsilyoxy-70-tri-
methylsilyl-60-heptynyl)-5-methyl-3-(methylsulfenyl)-
tetrahydrofuran-2-one (30) and (20R,3S,5S)-3-(20-tert-
butyldimethylsilyoxy-70-trimethylsilyl-60-heptynyl)-5-
methyl-3-(methylsulfenyl)-tetrahydrofuran-2-one (31)
To a suspension of sodium hydride (1.76 g of 60% dis-
persion in mineral oil was washed repeatedly with n-hexane,
44.0 mmol) in tetrahydrofuran (200 mL) was added drop-
wise a solution of 26 (5.14 g, 11.0 mmol) in tetrahydrofuran
(60 mL) at 0ЊC. After being stirred at the same temperature
for 1 h, the mixture was stirred at room temperature over-
night. The resulting mixture was then treated with saturated
aqueous ammonium chloride and extracted with diethyl
ether. The organic phase was washed with brine and dried
over anhydrous sodium sulfate. The solvent was removed
under reduced pressure and the residue was chromato-
graphed on silica gel (n-pentane:diethyl etherˆ10:1) to
give 27 (1.90 g, 95%) as a colorless oil. [a]2d9ˆϩ34.0Њ (c
0.38, CHCl3); IR (film) n 3040, 2960, 2860, 2170, 1730,
To a solution of 17 (438 mg, 3.0 mmol) in tetrahydrofuran
(9 mL) was added dropwise a solution of sodium bis(tri-
methylsilyl)amide (5.0 mL, 0.60 M, 3.0 mmol) in toluene
at Ϫ10ЊC. After being stirred at the same temperature for
40 min, a solution of 29 (1.27 g, 3.0 mmol) in hexamethyl-
phosphoric triamide (9 mL) was added dropwise and the
resulting mixture was then stirred at room temperature for
2 h. After quenching with 0.5 M hydrochloric acid at 0ЊC,
the mixture was extracted with diethyl ether. The organic
phase was washed with brine and dried over anhydrous
sodium sulfate. The solvent was removed under reduced
pressure and the residue was chromatographed on silica
gel (n-hexane:diethyl etherˆ40:1–20:1) to give 30
(876 mg, 66%, more polar) and 31 (133 mg, 10%).
Compound 30; white solid; mp 44–46ЊC; [a]3d0ˆϪ45.9Њ
(c 0.45, CHCl3); IR (nujol) n 2960, 2930, 2860, 2170,
1
1250, 840, 760; H NMR (500 MHz, CDCl3) d 2.93 (m,
1H), 2.76 (dd, Jˆ5.0, 4.0 Hz, 1H), 2.49 (dd, Jˆ5.0,
3.5 Hz, 1H), 2.34–2.27 (m, 2H), 1.74–1.58 (m, 4H), 0.14
(s, 9H); Anal. Calcd for C10H18OSi: C 65.87, H 9.95; Found:
C 65.61, H 9.86.
1
1760, 1250, 1180, 1020, 840; H NMR (500 MHz, CDCl3)
(R)-1-Iodo-7-timethylsilyl-6-heptyn-2-ol (28)
d 4.61 (m, 1H), 4.20 (m, 1H), 2.93 (dd, Jˆ14.5, 8.5 Hz, 1H),
2.30–2.20 (m, 2H), 2.12 (s, 3H), 2.06 (dd, Jˆ15.0, 2.5 Hz,
1H), 1.82–1.75 (m, 2H), 1.70–1.40 (m, 4H), 1.50 (d,
Jˆ6.5 Hz, 3H), 0.89 (s, 9H), 0.14 (s, 9H), 0.13 (s, 3H),
0.11 (s, 3H); Anal. Calcd for C22H42O3SSi2: C 59.67, H
9.56; Found: C 59.19, H 9.49. Compound 31; colorless
oil; [a]3d0ˆϩ14.6Њ (c 0.50, CHCl3); IR (film) n 2960,
2930, 2860, 2170, 1760, 1250, 1190 840; 1H NMR
(500 MHz, CDCl3) d 4.75 (m, 1H), 3.96 (m, 1H), 2.29–
2.12 (m, 5H), 2.12 (s, 3H), 1.90 (dd, Jˆ15.0, 6.0 Hz, 1H),
1.70–1.50 (m, 4H), 1.40 (d, Jˆ6.5 Hz, 3H), 0.89 (s, 9H),
0.14 (s, 9H), 0.09 (s, 3H), 0.09 (s, 3H); Anal. Calcd for
C22H42O3SSi2: C 59.67, H 9.56; Found: C 59.33, H 9.58.
To a solution of 27 (546 mg, 3.0 mmol) in tetrahydrofuran
(9.0 mL) and water (1.8 mL) was added lithium iodide
(1.61 g, 12.0 mmol) and acetic acid (9.0 mL) at 0ЊC. After
being stirred at the same temperature for 5 h the mixture was
treated with saturated aqueous sodium bicarbonate and
extracted with diethyl ether. The organic phase was washed
with brine and dried over anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue
was chromatographed on silica gel (n-hexane:diethyl
etherˆ10:1–4:1) to give 28 (763 mg, 82%) as a colorless
oil. [a]3d0ˆϩ1.2Њ (c 1.05, CHCl3); IR (film) n 3400,
2960, 2170, 1250, 840, 760; 1H NMR (500 MHz,
CDCl3) d 3.57 (m, 1H), 3.38 (dd, Jˆ10.0, 4.0 Hz, 1H),
3.24 (dd, Jˆ10.5, 7.0 Hz, 1H), 2.24 (t, Jˆ6.0 Hz, 2H),
2.04 (br, 1H, OH), 1.75–1.55 (m, 4H), 0.14 (s, 9H); Anal.
Calcd for C10H19IOSi: C 38.71, H 6.17; Found: C 38.96,
H 6.16.
(20R, 3R,5S)-3-(20-tert-Butyldimethylsilyoxy-70-iodo-60-
heptynyl)-5-methyl-3-(methylsylfenyl)tetrahydrofuran-
2-one (32)
To a solution of 30 (2.66 g, 6.0 mmol) in methanol
(100 mL) was added potassium carbonate (1.08 g,
7.8 mmol) at 0ЊC. After being stirred at the same tempera-
ture for 10 min, the mixture was stirred at room temperature
for 4 h. After being diluted with diethyl ether, the resulting
mixture was filtered through a Celite pad. The filtrate was
washed with water, brine and dried over anhydrous sodium
sulfate. The solvent was removed under reduced pressure
and the residue was dissolved in benzene (96 mL). Morpho-
line (8.1 mL, 93 mmol) and iodine (7.62 mL, 30.0 mmol)
were added and the mixture was stirred at 45ЊC for 2 h.
The reaction mixture was then cooled to room temperature
and diluted with diethyl ether. After being filtered through a
Celite pad, the filtrate was concentrated in vacuo. The resi-
due was chromatographed on silica gel (n-hexane:diethyl
etherˆ10:1) to give 32 (2.23 g, 75%) as a colorless oil.
[a]2d9ˆϪ26.2Њ (c 0.54, CHCl3); IR (film) n 2960, 2930,
2860, 1760, 1250, 1180, 1020, 840, 780; 1H NMR
(500 MHz, CDCl3) d 4.61 (m, 1H), 4.21 (m, 1H), 2.92
(dd, Jˆ14.0, 8.5 Hz, 1H), 2.43–2.37 (m, 2H), 2.12 (s,
3H), 2.04 (dd, Jˆ15.0, 2.5 Hz, 1H), 1.82–1.77 (m, 2H,
1.70–1.40 (m, 4H), 1.50 (d, Jˆ6.5 Hz, 3H), 0.89 (s, 9H),
(R)-6-tert-Butyldimethylsilyloxy-7-iodo-1-trimethylsilyl-
heptyne (29)
To a solution of 28 (2.70 g, 8.7 mmol) in dimethylform-
amide (20 mL) was added imidazole (2.37 g, 34.8 mmol)
and tert-butyldimethylsilyl chloride (2.63 g, 17.4 mmol).
After being stirred at room temperature overnight, the
mixture was treated with water and extracted with diethyl
ether. The organic phase was washed with brine and dried
over anhydrous sodium sulfate. The solvent was removed
under reduced pressure and the residue was chromato-
graphed on silica gel (n-hexane:diethyl etherˆ40:1) to
give 29 (3.32 g, 90%) as a colorless oil. [a]3d0ˆϩ6.4Њ (c
0.65, CHCl3); IR (film) n 2960, 2860, 2170, 1470, 1250,
1
1080, 840, 780; H NMR (500 MHz, CDCl3) d 3.61 (m,
1H), 3.19 (d, Jˆ5.0, 2 Hz), 2.24 (t, Jˆ7.0 Hz, 2H), 1.75
(m, 1H), 1.67 (m, 1H), 1.59–1.49 (m, 2H), 0.90 (s, 9H),
0.15 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); Anal. Calcd for
C10H33IOSi2: C 45.27, H 7.84; Found: C 45.67, H 7.87.

1460
W.-Q. Yang, T. Kitahara / Tetrahedron 56 (2000) 1451–1461
0.13 (s, 3H), 0.11 (s, 3H); Anal. Calcd for C19H33IO3SSi:
45.96, H 6.70; Found: C 46.23, H 6.64.
[a]3d0ˆϩ11.0Њ (c 0.48, CHCl3); IR (film) n 3440, 2920,
1
2860, 1760, 1460, 1260, 1080, 1040, 840, 780; H NMR
(500 MHz, CDCl3) d 7.13 (d, Jˆ1.5 Hz, 1H), 5.02 (m,
1H), 4.81 (d, Jˆ7.0 Hz, 1H), 4.67 (d, Jˆ7.0 Hz, 1H), 4.45
(d, Jˆ3.0 Hz, 1H), 4.05–3.95 (m, 2H), 3.92 (m, 1H), 3.52–
3.45 (m, 2H), 3.40 (s, 3H), 3.34 (m, 1H), 2.48–2.38 (m, 2H),
2.30–2.26 (m, 2H), 1.95–1.20 (m, 37H), 1.42 (d, Jˆ6.5 Hz,
3H), 0.88 (t, Jˆ7.0 Hz, 3H), 0.87 (s, 9H), 0.06 (s, 3H),
0.04 (s, 3H); FABMS m=z: 756 [MHϪH2O]ϩ, 742
[MHϪCH3OH]ϩ, 712 [MHϪCH3OCH2OH]ϩ.
(20R,5S)-3-(20-tert-Butyldimethylsilyoxy-70-iodo-60-
heptynyl)-5-methyl-2,5-dihydrofuran-2-one (33)
To a solution of 32 (2.43 g, 4.9 mmol) in dichloromethane
(90 mL) was added dropwise a solution of m-chloroperoxy-
benzoic acid (1.06 g, 4.9 mmol) in dichloromethane
(45 mL) at Ϫ78ЊC. After being stirred at the same tempera-
ture for 1 h, the reaction was quenched with 10% aqueous
sodium thiosulfate. The resulting mixture was extracted
with diethyl ether and the organic phase was washed with
brine and dried over anhydrous sodium sulfate. After
removal of the solvent under reduced pressure, the residue
was dissolved in toluene (45 mL) and refluxed at 120ЊC for
5 h. After being cooled to room temperature, the solvent was
removed under reduced pressure and the residue was
chromatographed on silica gel (n-hexane:diethyl etherˆ
5:1) to give 33 (1.10 g, 50%) as a colorless oil.
[a]2d9ˆϩ15.6Њ (c 0.56, CHCl3); IR (film) n 2960, 2920,
(ϩ)-4-tert-Butyldimethylsilyloxy-22-methoxymethoxy-
muconin (36)
To a degassed solution of 34 (62 mg, 0.080 mmol) in
benzene (9 mL) and methanol (9 mL) was added tris(tri-
phenylphosphine)rhodium(I) chloride (74 mg, 0.080
mmol) under hydrogen atmosphere. After being stirred at
room temperature for 24 h, the solvent was removed under
reduced pressure and the residue was chromatographed on
silica gel (n-hexane:ethyl acetateˆ4:1) to give 36 (48 mg,
77%) as a colorless oil. [a]dˆϩ15.2Њ (c 0.30, CHCl3); IR
(film) n 3460, 2920, 2860, 1760, 1460, 1260, 1070, 1040,
840, 780; 1H NMR (500 MHz, CDCl3) d 7.12 (s, 1H), 5.00
(m, 1H), 4.84 (d, Jˆ6.5 Hz, 1H), 4.66 (d, Jˆ7.0 Hz, 1H),
4.01–3.80 (m, 3H), 3.47 (m, 1H), 3.40 (m, 1H), 3.39 (s, 3H),
3.30 (m, 1H), 3.14 (m, 1H), 2.41 (d, Jˆ5.5 Hz, 2H), 1.91–
1.20 (m, 47H), 1.41 (d, Jˆ6.5 Hz, 3H), 0.88 (t, Jˆ6.5 Hz,
3H), 0.87 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H); Anal. Calcd for
C45H84O8Si: C 69.18, H 10.84; Found: C 69.21, H 10.73.
1
2860, 1750, 1260, 1190, 840, 780; H NMR (500 MHz,
CDCl3) d 7.13 (d, Jˆ1.0 Hz, 1H), 5.02 (m, 1H), 3.99 (m,
1H), 2.47–2.36 (m, 3H), 1.60–1.53 (m, 5H), 1.42 (d,
Jˆ7.0 Hz, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H);
Anal. Calcd for C18H29IO3Si: C 48.21, H 6.52; Found: C
48.21, H 6.47.
Compound 33 was also obtained from 31 via four steps as
described above in overall 40% yield.
(ϩ)-4-tert-Butyldimethylsilyloxy-22-methoxymethoxy-
12-epi-muconin (37)
(ϩ)-4-tert-Butyldimethylsilyloxy-22-methoxymethoxy-
8,8,9,9,10,10,11,11-octadehydromuconin (34) and (ϩ)-4-
tert-Butyldimethylsilyloxy-22-methoxymethoxy-8,8,9,9,
10,10,11,11-octadehydro-12-epi-muconin (35)
Hydrogenation of 35 (39.0 mg, 0.050 mmol) and workup
were performed as described above to give 37 (29.3 mg,
75%) as a colorless oil. [a]2d8ˆϩ22.0Њ (c 0.47, CHCl3); IR
(film) n 3460, 2920, 2860, 1760, 1460, 1260, 1090, 1040,
840, 780; 1H NMR (500 MHz, CDCl3) d 7.12 (d, Jˆ1.5 Hz,
1H), 5.02 (m, 1H), 4.83 (d, Jˆ7.0 Hz, 1H), 4.67 (d,
Jˆ7.0 Hz, 1H), 4.02 (m, 1H), 3.93 (m, 1H), 3.87 (m, 1H),
3.67 (m, 1H), 3.48 (m, 1H), 3.40 (s, 3H), 3.36–3.28 (m, 2H),
2.42 (d, Jˆ5.5 Hz, 2H), 1.96–1.20 (m, 47H), 1.41 (d,
Jˆ7.0 Hz, 3H), 0.88 (t, Jˆ6.5 Hz, 3H), 0.87 (s, 9H), 0.05
(s, 3H), 0.02 (s, 3H); Anal. Calcd for C45H84O8Si: C 69.18,
H 10.84; Found: C 68.76, H 10.71.
To a degassed solution of tris(dibenzylideneacetone)dipal-
ladium (27.5 mg, 0.030 mmol), copper(I) iodine (11.4 mg,
0.060 mmol) and tri(2-furyl)phosphine (17.4 mg, 0.075
mmol) in benzene (3.0 mL) was added a solution of 16
(295 mg, 0.65 mmol) in benzene (6.8 mL) and a solution
of 33 (305 mg, 0.68 mmol) in benzene (6.8 mL) succes-
sively. The mixture was then degassed with argon in the
dark at room temperature for 20 min. Diisopropyl amine
(0.28 mL, 2.0 mmol) was added to this and the resulting
mixture was stirred in the dark for 18 h. After being diluted
with diethyl ether, the mixture was washed with saturated
aqueous ammonium chloride and the organic phase was
dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the residue was
chromatographed on silica gel (n-hexane:ethyl acetateˆ
4:1–2:1) to give 34 (116 mg, 23%, less polar) and 35
(161 mg, 32%) as colorless oils. Compound 34;
[a]3d0ˆϩ22.0Њ (c 0.40, CHCl3); IR (film) n 3440, 2920,
2850, 1760, 1460, 1100, 1040, 840, 790; 1H NMR
(500 MHz, CDCl3) d 7.13 (d, Jˆ1.5 Hz, 1H), 5.03 (m,
1H), 4.82 (d, Jˆ6.5 Hz, 1H), 4.66 (d, Jˆ6.5 Hz, 1H), 4.25
(d, Jˆ7.5 Hz, 1H), 4.01–3.95 (m, 2H), 3.88 (m, 1H), 3.46
(m, 1H), 3.40–3.31 (m, 2H), 3.39 (s, 3H), 2.48–2.38 (m,
2H), 2.30–2.26 (m, 2H), 1.96–1.18 (m, 37H), 1.42 (d,
Jˆ7.0 Hz, 3H), 0.87 (t, Jˆ6.5 Hz, 3H), 0.87 (s, 9H), 0.06
(s, 3H), 0.04 (s, 3H); Anal. Calcd for C45H76O8Si: C 69.91,
H 9.91; Found: C 69.87, H 9.75. Compound 35;
Conversion of the b-alcohol 37 to the a-alcohol 36
To a solution of 37 (15.6 mg, 0.020 mmol) in dichloro-
methane (1.0 mL) was added Dess–Martin periodinane
(12.7 mg, 0.030 mmol). After being stirred at room
temperature for 3 h, saturated aqueous sodium bicarbonate
(0.8 mL) and sodium thiosulfate (60 mg) were added. The
resulting mixture was stirred for 20 min and extracted with
diethyl ether. The organic phase was washed with brine and
dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the residue was
dissolved in tetrahydrofuran (0.6 mL) at Ϫ60ЊC. A solution
of lithium tri-tert-butoxyaluminohydride (60 mL, 1.0 M,
0.060 mmol) in tetrahydrofuran was added dropwise and
the resulting mixture was stirred for 1 h at the same
temperature. After quenching the reaction by dropwise

W.-Q. Yang, T. Kitahara / Tetrahedron 56 (2000) 1451–1461
1461
addition of 1 M hydrochloric acid, the mixture was
References
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solvent was removed under reduced pressure and the
residue was purified by preparative TLC (n-hexane:ethyl
acetateˆ2:1 to give 36 (9.4 mg, 60%, less polar) and 37
´
`
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W.-Q. Yang expresses his appreciation to the Japan Society
for the Promotion of Science (JSPS) for financial support.
We thank Ajinomoto Co., Ltd. for a generous gift of d-
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sity for providing spectral data of muconin. We also thank
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Shin-ya for measuring MS spectra. Financial support
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