Stereoselective synthesis and absolute configuration of the C1′-C25′ fragment of symbiodinolide

Article abstract of DOI:10.1021/jo901162v

(Chemical Equation Presented) Stereoselective synthesis of the C1′-C25′ fragment of symbiodinolide, which was obtained as a degraded product from symbiodinolide by alkaline hydrolysis, has been accomplished. The synthetic route features Kotsuki coupling and Julia-Kocienski olefination in the introduction of the side chains. This enantioand stereoselective synthesis has established the absolute configuration of the C1′-C25′ fragment.

Full text of DOI:10.1021/jo901162v

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Stereoselective Synthesis and Absolute Configuration of the
C10-C250 Fragment of Symbiodinolide
Hiroyoshi Takamura,*,† Takeshi Murata,‡ Takahiro Asai,‡ Isao Kadota,*,† and
Daisuke Uemura§
†Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushimanaka,
Kita-ku, Okayama 700-8530, Japan, ‡Graduate School of Science, Nagoya University, Furo-cho,
Chikusa-ku, Nagoya 464-8602, Japan, and §Faculty of Science and Technology, Keio University,
3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
takamura@cc.okayama-u.ac.jp
Received June 4, 2009
Stereoselective synthesis of the C10-C250 fragment of symbiodinolide, which was obtained as a degraded
product from symbiodinolide by alkaline hydrolysis, has been accomplished. The synthetic route features
Kotsuki coupling and Julia-Kocienski olefination in the introduction of the side chains. This enantio-
and stereoselective synthesis has established the absolute configuration of the C10-C250 fragment.
Introduction
particular, polyol and polyether compounds with a large
molecular weight, such as palytoxins, brevetoxins, and
halichondrins, are some of the most attractive molecules
for natural product chemists, synthetic chemists, bioche-
mists, and pharmacological scientists.2 In our continuing
search for these types of compounds,3 we reported the
isolation of symbiodinolide (1) from the symbiotic marine
dinoflagellate Symbiodinium sp. in 2007 (Figure 1).4,5
Symbiodinolide (1), a novel polyol macrolide, exhibits a
voltage-dependent N-type Ca2þ channel-opening activity at
7 nM and COX-1 inhibitory effect at 2 μM. The planar
structure and partial stereochemistry of 1 were elucidated by
spectroscopic analysis4 and chemical synthesis.6 Previously,
we obtained the C10-C250 fragment 2 as a degraded product
of 1 by alkaline hydrolysis (Scheme 1).4 Herein, as a part of
our structural and synthetic studies of 1, we describe the
enantio- and stereocontrolled synthesis of the C10-C250
fragment, thereby establishing that the absolute configura-
tion of this fragment is that described in 2.
Various biologically and physiologically active secondary
metabolites have been isolated from marine origin.1 In
(1) (a) Uemura, D. Bioorganic Marine Chemistry; Scheuer, P. J., Ed.;
Springer: Berlin, Heidelberg, 1991; Vol. 4, pp 1-31. (b) Shimizu, Y. Chem.
Rev. 1993, 93, 1685. (c) Uemura, D. Chem. Rec. 2006, 6, 235.
(2) (a) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897. (b) Murata,
M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293 and references therein.
(3) For recent results, see: (a) Washida, K.; Koyama, T.; Yamada, K.;
Kita, M.; Uemura, D. Tetrahedron Lett. 2006, 47, 2521. (b) Kita, M.; Roy,
M. C.; Siwu, E. R. O.; Noma, I.; Takiguchi, T.; Itoh, M.; Yamada, K.;
Koyama, T.; Iwashita, T.; Uemura, D. Tetrahedron Lett. 2007, 48, 3423.
(c) Kita, M.; Roy, M. C.; Siwu, E. R. O.; Noma, I.; Takiguchi, T.; Yamada,
K.; Koyama, T.; Iwashita, T.; Wakamiya, A.; Uemura, D. Tetrahedron Lett.
2007, 48, 3429.
(4) Kita, M.; Ohishi, N.; Konishi, K.; Kondo, M.; Koyama, T.; Kitamura,
M.; Yamada, K.; Uemura, D. Tetrahedron 2007, 63, 6241.
(5) Symbiodinolide (1) is a structural congener of zooxanthellatoxins,
which are polyol macrolides isolated from the dinoflagellate Symbiodinium
sp. For the structural elucidation of zooxanthellatoxins, see: (a) Nakamura,
H.; Asari, T.; Murai, A.; Kondo, T.; Yoshida, K.; Ohizumi, Y. J. Org. Chem.
1993, 58, 313. (b) Asari, T.; Nakamura, H.; Murai, A.; Kan, Y. Tetrahedron
Lett. 1993, 34, 4059. (c) Nakamura, H.; Asari, T.; Murai, A.; Kan, Y.;
Kondo, T.; Yoshida, K.; Ohizumi, Y. J. Am. Chem. Soc. 1995, 117, 550.
(d) Nakamura, H.; Asari, T.; Fujimaki, K.; Maruyama, K.; Murai, A.;
Ohizumi, Y.; Kan, Y. Tetrahedron Lett. 1995, 36, 7255. (e) Nakamura, H.;
Fujimaki, K.; Murai, A. Tetrahedron Lett. 1996, 37, 3153. (f) Nakamura, H.;
Sato, K.; Murai, A. Tetrahedron Lett. 1996, 37, 7267. (g) Nakamura, H.;
Takahashi, M.; Murai, A. Tetrahedron: Asymmetry 1998, 9, 2571. (h)
Nakamura, H.; Maruyama, K.; Fujimaki, K.; Murai, A. Tetrahedron Lett.
2000, 41, 1927.
(6) (a) Takamura, H.; Ando, J.; Abe, T.; Murata, T.; Kadota, I.; Uemura,
D. Tetrahedron Lett. 2008, 49, 4626. (b) Takamura, H.; Kadonaga, Y.;
Yamano, Y.; Han, C.; Aoyama, Y.; Kadota, I.; Uemura, D. Tetrahedron
Lett. 2009, 50, 863. (c) Murata, T.; Sano, M.; Takamura, H.; Kadota, I.;
Uemura, D. J. Org. Chem. 2009, 74, 4797. (d) Takamura, H.; Kadonaga, Y.;
Yamano, Y.; Han, C.; Kadota, I.; Uemura, D. Tetrahedron 2009 DOI: 10.1016/
j.tet.2009.07.019.
6658 J. Org. Chem. 2009, 74, 6658–6666
Published on Web 08/05/2009
DOI: 10.1021/jo901162v
r
2009 American Chemical Society

Takamura et al.
JOCArticle
FIGURE 1. Structure of symbiodinolide (1).
SCHEME 1. Alkaline Hydrolysis of Symbiodinolide (1)
N,N-dimethylacetamide dimethyl acetal in refluxing xylene
formed Eschenmoser-Claisen rearrangement product 10 in
93% yield. Iodolactonization of 10 proceeded smoothly to
give iodolactone 11 as a single stereoisomer. The lactone 11
was converted to epoxy ester 12 under the methanolysis
conditions.9 The regio- and stereoselective opening of the
epoxide 12 promoted by TFA proceeded at 60 °C to afford
trihydroxy lactone 13.9,10 Continuous protection of the
primary hydroxy group with TBDPSCl/imidazole and the
vicinal diol as an acetonide gave silyl ether 14. The config-
1
urational determination of 14 was verified by H-1H cou-
pling constants and NOE correlations. The large magnitude
of J14 ,15 (9.7 Hz) indicated that H140 and H150 were in an
0 0
Retrosynthetic Analysis
0
0
axial-axial relationship. The moderate magnitude of J13 ,14
Scheme 2 outlines the retrosynthetic analysis of 2. We
planned to synthesize 2 by the construction of C80-C90
trisubstituted olefin moiety from left-hand side segment 3
and right-hand side segment 4. The left side chain of 3 would
be introduced via the coupling of alkynyllithium reagent
derived from alkyne 5 and triflate 6.7 The tetrahydropyran 6
with three contiguous oxygenated functional groups would
be provided by the functionalization of dihydropyran 7. On
the other hand, aldehyde 4, the coupling partner of 3, would
be synthesized via the stereoselective methylation of ester 8.
The ester 8 would be prepared from D-(þ)-xylose.
(5.5 Hz) suggested that H130 and H140 were oriented in
equatorial and axial conformations, respectively. The ob-
served NOEs H110/H120 and H110/H150 confirmed that they
were in syn relationships to each other. Reduction of 14 in
two-step sequence (DIBALH and NaBH4) followed by
protection of the primary hydroxy moiety as TBS ether
and the secondary hydroxy group as MOM ether provided
protected tetrahydropyran 15. The TBDPS ether 15 was
converted to triflate 16 by the selective deprotection of
TBDPS group and triflation.
Scheme 4 describes the introduction of the left side chain.
Coupling of the triflate 16 with n-C7H15CCLi under Kotsuki
conditions7 gave alkyne 17. The alkyne 17 was subjected to
the Birch reduction conditions to afford trans-alkene 18 as a
single stereoisomer. The Sharpless AD11 of 18 proceeded
Results and Discussion
Synthesis of the Left-Hand Side Segment. Stereoselective
construction of the tetrahydropyran ring moiety is described
in Scheme 3. Treatment of allylic alcohol 9, which can be
easily prepared from tri-O-acetyl-D-glucal in two steps,8 with
(9) Colombo, L.; Casiraghi, G.; Pittalis, A. J. Org. Chem. 1991, 56, 3897.
(10) For the reaction mechanism on lactonization of γ,δ-epoxy esters, see:
Wawrzenczyk, C.; Grabarczyk, M.; Bialonska, A.; Ciunik, Z. Tetrahedron
2003, 59, 6595.
(11) For a review of the Sharpless AD reaction, see: Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
(7) Kotsuki, H.; Kadota, I.; Ochi, M. Tetrahedron Lett. 1990, 31, 4609.
(8) Bartolozzi, A.; Pacciani, S.; Benvenuti, C.; Cacciarini, M.; Liguori, F.;
Menichetti, S.; Nativi, C. J. Org. Chem. 2003, 68, 8529.
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SCHEME 2. Retrosynthetic Analysis of 2
SCHEME 3. Synthesis of 16
smoothly to provide diol 19 quantitatively as the sole pro-
duct. The absolute stereochemistry of the resulting chiral
centers at C170 and C180 positions of 19 were elucidated by
modified Mosher method.12 Figure 2 depicts the ΔδS-R
values of bis-MTPA esters (S)-20 and (R)-20, which were
prepared from 19. The signs at the C170 and C180 positions
were negative (-0.05 and -0.12, respectively). Therefore,
the absolute configurations of the C170 and C180 positions
were elucidated to be 170R and 180R, respectively.
The next task was the functionalization of the right side
chain. Protection of the diol 19 as an acetonide, followed by
removal of the TBS protecting group with TBAF, gave alcohol
21 (Scheme 5). The alcohol 21 was converted to the coupling
precursor 22 by four-step sequence: (1) Parikh-Doering
oxidation,13 (2) methylation of the resulting aldehyde,
~ ꢀ
(12) Freire, F.; Seco, J. M.; Quinoa, E.; Riguera, R. J. Org. Chem. 2005,
70, 3778.
(13) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505.
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SCHEME 4. Synthesis of 19
SCHEME 5. Synthesis of 22
and oxazolidinone).16 Asymmetric methylation of 28 in ac-
cordance with Evans’ report17 proceeded at -78 to -40 °C to
give the desired methylated product 29 as a single stereoiso-
mer. The chiral auxiliary was removed by LiAlH4, and
Parikh-Doering oxidation13 ofthe resultingalcoholprovided
the right-hand side coupling precursor 30.
(3) Mitsunobu reaction of the resulting secondary alcohol
with 1-phenyl-1H-tetrazole-5-thiol, and (4) oxidation of
the resulting sulfide.
The aldehyde 30 was transformed to lactone 32 for the
confirmation of the absolute stereochemistry at the C70 chiral
center, which was introduced by the Evans asymmetric alky-
lation of 28 (Scheme 7). Pinnic oxidation of 30 gave carboxylic
acid 31. Benzyl protecting groups of 31 were removed,
followed by lactonization under the reflux conditions in
toluene to provide the lactone 32. The observed NOE H50/
H70 of 32 indicated that they were in syn relationships to each
other. Therefore, it was confirmed that the Evans asymmetric
methylation of 28 proceeded in a desired stereoselectivity.
Completion of the Synthesis. Julia-Kocienski coupling18
of the sulfone 22 and the aldehyde 30 was examined under
various conditions, and the results are summarized in
Table 1. When 22 was deprotonated with KHMDS or
NaHMDS as the base and treated with 30, only a trace
amount of the coupling products was observed (entry 1 and
2). Treatment of 22 with LiHMDS gave the desired E-alkene
33 along with the Z-alkene 34 at a 1:1 E/Z diastereomeric
ratio in 43% yield (entry 3). When LDA that was prepared
from (i-Pr)2NH and n-BuLi was used as the base, diastereo-
selectivity and chemical yield were improved to 1.5:1 diaster-
eomeric ratio and 61% yield (entry 4). The alkenes 33 and 34
could be easily separated by preparative TLC. Stereostruc-
ture of 33 was confirmed by ROESY correlation between
Ha and Hb as shown with an arrow. Similarly, the structural
determination of 34 was performed by NOE observation
FIGURE 2. Chemical shift differences (ΔδS-R) of (S)-20 and
(R)-20. R = MTPA. MTPA = R-methoxy-R-(trifluoromethyl)-
phenylacetyl.
Synthesis of the Right-Hand Side Segment. With the left-
hand side segment 22 in hand, we next examined the
preparation of the right-hand side segment (Scheme 6). One-
carbon elongation of the known alcohol 23,14 prepared from
D-(þ)-xylose in 4 steps, was carried out by Parikh-Doering
oxidation13 and subsequent Wittig methylenation to give
alkene 24 in 86% yield by 2 steps. Hydroboration of 24 with
BH3 SMe2 followed by oxidative workup and protection of
3
the resulting alcohol with TBSCl/imidazole provided silyl
ether 25. After hydrolysis of the dithioacetal moiety with
AgNO3, Ag2O, and H2O,15 the resulting aldehyde was treated
with Ph3PdCHCO2Me to give R,β-unsaturated ester 26.
Chemoselective hydrogenation of 26 was carried out with
H2 and Pd/C in EtOAc, and ester moiety was saponified with
LiOH H2O to afford carboxylic acid 27. The carboxylic acid
3
27was convertedtoimide28 possessinga chiral oxazolidinone
under the mild reaction conditions (PivCl and Et3N; then LiCl
(16) Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271.
(17) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
(14) Kireev, A. S.; Breithaupt, A. T.; Collins, W.; Nadein, O. N.;
Kornienko, A. J. Org. Chem. 2005, 70, 742.
(15) Corey, E. J.; Shibasaki, M.; Knolle, J.; Sugahara, T. Tetrahedron
Lett. 1977, 18, 785.
(18) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett
1998, 26.
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SCHEME 6. Synthesis of 30
SCHEME 7. Determination of Absolute Configuration at C70
Position of 30
TABLE 1. Julia-Kocienski Coupling of 22 and 30
entry
base
33:34
% yielda
between the allylic methyl moiety and Hc as described with
an arrow.
1
2
3
4
KHMDS
NaHMDS
LiHMDS
LDA
NDb
NDb
1:1
trace
trace
43
Remaining tasks were the removal of protecting groups
and functionalization at C10 position. Removal of the
TBS protecting group of 33 with TBAF and subsequent
stepwise Parikh-Doering oxidation13 and Pinnick oxida-
tion19 gave carboxylic acid 35 in 93% yield for 2 steps
(Scheme 8). Deprotection of the benzyl moieties under the
Birch reduction conditions provided triol 36. The aceto-
nide and methoxymethyl protecting groups of 36 were
removed with TFA to give the carboxylic acid 2 and
its corresponding lactone, whose structure was not char-
acterized. Finally, treatment of the mixture obtained
1.5:1
61
aIsolated yields. bNot determined.
above with KOH provided 2. The synthetic 2 was iden-
tical to the degraded C10-C250 fragment of symbio-
dinolide (1) in all aspects (1H NMR, HRMS, and optical
rotation20). Thus, the absolute configuration of the
C10-C250 fragment was confirmed to be that described
in 2.
(19) (a) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175. (b)
Bal, B. S.; Childers, W. E. Jr; Pinnick, H. W. Tetrahedron 1981, 37, 2091.
(20) The degraded C10-C250 fragment: [R]20D = þ10.6 (c 0.05, CH3OH).
The synthetic 2: [R]23D = þ10.6 (c 0.05, CH3OH).
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SCHEME 8. Completion of the Synthesis of 2
temperature, the reaction was quenched with saturated aqueous
NaHCO3. The resultant mixture was diluted with Et2O, washed
with saturated aqueous CuSO4, H2O, and brine, and dried over
MgSO4. Concentration and column chromatography (hexane/
EtOAc, 9:1) gave triflate 16 (915 mg) as a yellow oil, which was
used for the next reaction without further purification.
To a solution of 1-nonyne (0.42 mL, 2.56 mmol) in THF
(10 mL) was added n-BuLi (1.59 M in hexane, 1.6 mL, 2.54 mol)
at -78 °C. The mixture was stirred for 30 min at the same
temperature, allowed to warm to 0 °C, and stirred for 30 min
at the same temperature. The resultant mixture was cooled to
-30 °C, then to the mixture were added DMPU (4.0 mL) and
triflate 16 obtained above in THF (4.0 mL þ 3.0 mL þ 3.0 mL).
The mixture was stirred for 1 h at the same temperature. The
reaction was quenched with saturated aqueous NH4Cl. The
resultant mixture was diluted with Et2O, washed with H2O and
brine, and dried over MgSO4. Concentration and column
chromatography (hexane/EtOAc, 9:1) gave alkyne 17 (661 mg,
76% in two steps): yellow oil; Rf = 0.41 (hexane/EtOAc, 4:1);
1
[R]17 þ23.1 (c 1.29, CHCl3); IR (neat) 2930, 1471 cm-1; H
D
NMR (400 MHz, CDCl3) δ 4.79 (d, J = 7.1 Hz, 1 H), 4.65 (d,
J = 7.1 Hz, 1 H), 4.27 (dd, J = 5.0, 2.4 Hz, 1 H), 3.90 (dd, J =
9.2, 5.0 Hz, 1 H), 3.84-3.75 (m, 4 H), 3.40 (s, 3 H), 3.35 (td, J =
8.7, 3.4 Hz, 1 H), 2.54 (ddd, J = 16.8, 5.6, 2.4 Hz, 1 H), 2.36 (ddt,
J = 16.8, 8.3, 2.2 Hz, 1 H), 2.14-2.10 (m, 2 H), 1.99-1.91 (m,
1 H), 1.69-1.61 (m, 1 H), 1.45 (s, 3 H), 1.35 (s, 3 H), 1.29-1.20
(m, 10 H), 0.87 (s, 9 H), 0.85 (t, J = 7.1 Hz, 3 H), 0.05 (s, 3 H),
0.04 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 109.3, 96.6, 81.4,
77.2, 76.2, 74.4, 74.2, 74.1, 72.3, 59.5, 56.0, 34.2, 31.7, 29.0, 28.8,
28.2, 26.4, 25.9, 23.4, 22.6, 18.9, 18.3, 14.1, -5.3, -5.4; HRMS
(FAB) calcd for C28H52O6SiNa (M þ Na)þ 535.3431, found
535.3442.
Conclusion
We have synthesized the C10-C250 fragment of 1, which
was obtained as a degraded product from 1 by alkaline
hydrolysis, via Kotsuki coupling and Julia-Kocienski
olefination as key steps from the known alcohol 9 with
2.8% overall yield. On the basis of the spectroscopic data
of the synthetic and degraded samples, we concluded that the
absolute stereochemistry of this fragment was that depicted
in 2. Further structural and synthetic studies on 1 are under-
way in our laboratories.
Alkene 18. To a solution of alkyne 17 (123 mg, 0.240 mmol) in
liquid NH3 (12 mL), THF (6.0 mL), and t-BuOH (2.0 mL) was
added Na (100 mg, 4.34 mmol) at -78 °C, and the resultant
mixture was gradually warmed to -50 °C for 40 min. After the
mixture was stirred at the same temperature for 20 min, the
reaction was quenched with saturated aqueous NH4Cl. The
mixture was diluted with H2O and Et2O. The aqueous layer
was extracted with Et2O, and the combined organic layer
was washed with H2O and brine, and dried over Na2SO4.
Concentration and column chromatography (hexane/Et2O,
9:1) gave alkene 18 (116 mg, 94%): colorless oil; Rf = 0.62
Experimental Section
Alkyne 17. To a solution of TBDPS ether 15 (116 mg,
180 μmol) in THF (3.6 mL) was added TBAF-AcOH
(premixed solution, 1.0 M TBAF in THF 5.0 mL þ AcOH
0.30 mL, 0.20 mL, 0.188 mmol) at room temperature. The
mixture was stirred for 9 h at the same temperature. The mixture
was diluted with EtOAc, washed with H2O and brine, and then
dried over MgSO4. Concentration and column chromatography
(hexane/EtOAc, 50:1, 9:1, 1:1) gave the corresponding alcohol
(44.7 mg, 61%) and recovered TBDPS ether 15 (25.6 mg, 22%).
The corresponding alcohol: colorless oil; Rf = 0.32 (hexane/
(hexane/EtOAc, 4:1); [R]25 þ32.5 (c 0.76, CHCl3); IR (neat)
D
2927, 1470 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.52-5.45 (m,
2 H), 4.80 (d, J = 7.0 Hz, 1 H), 4.66 (d, J = 7.0 Hz, 1 H), 4.26
(dd, J = 5.2, 2.2 Hz, 1 H), 3.84 (dd, J = 9.2, 5.1 Hz, 1 H), 3.81-
3.74 (m, 4 H), 3.40 (s, 3 H), 3.22 (td, J = 9.2, 3.3 Hz, 1 H), 2.39-
2.33 (m, 1 H), 2.18-2.12 (m, 1 H), 1.98-1.89 (m, 3 H), 1.68-
1.63 (m, 1 H), 1.46 (s, 3 H), 1.36 (s, 3 H), 1.35-1.21 (m, 10 H),
0.89 (s, 9 H), 0.87 (t, J = 7.0 Hz, 3 H), 0.51 (s, 3 H), 0.47 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 132.8, 125.9, 109.2, 96.7, 78.6,
74.9, 74.4, 74.3, 72.1, 59.5, 56.1, 36.4, 34.2, 32.7, 31.9, 29.5, 29.2,
28.2, 26.5, 26.0, 22.6, 18.3, 14.1, -5.3, -5.4; HRMS (FAB) calcd
for C28H54O6SiNa (M þ Na)þ 537.3587, found 537.3583.
Diol 19. To a solution of alkene 18 (164 mg, 0.319 mmol) in
t-BuOH (1.5 mL) and H2O (2.0 mL) were added MeSO2NH2
(30.0 mg, 0.319 mmol) and AD-mix-β (446 mg) at 0 °C. After the
mixture was stirred at the same temperature for 23 h, the reac-
tion was quenched with Na2SO3 (500 mg). The mixture was
diluted with H2O and extracted with EtOAc. The organic layer
was washed with 2 M aqueous NaOH and brine and dried over
Na2SO4. Concentration and column chromatography (hexane/
EtOAc, 2:1) gave diol 19 (178 mg, quant.): colorless oil; Rf =
EtOAc, 1:1); [R]16 þ36.2 (c 0.74, CHCl3); IR (neat) 3502,
D
2930 cm-1 1H NMR (400 MHz, CDCl3) δ 4.79 (d, J =
;
6.8 Hz, 1 H), 4.66 (d, J = 6.8 Hz, 1 H), 4.30 (dd, J = 5.1, 2.4
Hz, 1 H), 4.00 (dd, J = 9.0, 5.1 Hz, 1 H), 3.89 (ddd, J = 9.2, 3.9,
1.5 Hz, 1 H), 3.81 (dd, J = 11.7, 2.9 Hz, 1 H), 3,78 (t, J = 1.7 Hz,
1 H), 3.76-3.73 (m, 2 H), 3.62 (dd, J = 11.7, 6.8 Hz, 1 H), 3.45-
3.41 (m, 1 H), 3.41 (s, 3 H), 2.92 (s, 1 H), 1.97-1.89 (m, 1 H),
1.75-1.67 (m, 1 H), 1.48 (s, 3 H), 1.36 (s, 3 H), 0.89 (s, 9 H), 0.05
(s, 3 H), 0.05 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 109.5,
96.8, 78.4, 74.1, 74.0, 71.9, 70.7, 63.5, 59.2, 56.1, 33.9, 28.1, 26.3,
25.9, 18.3, -5.3, -5.4; HRMS (FAB) calcd for C19H38O7SiNa
(M þ Na)þ 429.2284, found 429.2268.
To a solution of the alcohol obtained above (694 mg,
1.70 mmol) in CH2Cl2 (20 mL) were added 2,6-lutidine
(0.40 mL, 3.40 mmol) and Tf2O (0.34 mL, 2.04 mmol) at
-78 °C. After the mixture was stirred for 15 min at the same
0.31 (hexane/EtOAc, 1:1); [R]25 þ31.4 (c 0.63, CHCl3); IR
D
(neat) 3466, 2928 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.81 (d,
J = 6.8 Hz, 1 H), 4.67 (d, J = 6.8 Hz, 1 H), 4.30 (dd, J = 5.0,
2.4 Hz, 1 H), 3.95 (dd, J = 9.3, 5.1 Hz, 1 H), 3.90-3.85 (m, 1 H),
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Takamura et al.
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3.80-3.74 (m, 3 H), 3.67 (ddd, J = 9.0, 5.9, 3.2 Hz, 1 H), 3.53
(td, J = 8.4, 3.9 Hz, 1 H), 3.43-3.42 (m, 1 H), 3.42 (s, 3 H),
1.95-1.85 (m, 2 H), 1.76-1.64 (m, 2 H), 1.49 (s, 3 H), 1.49-1.47
(m, 2 H), 1.38 (s, 3 H), 1.34-1.20 (m, 10 H), 0.90 (s, 9 H), 0.87 (t,
J = 7.1 Hz, 3 H), 0.07 (s, 3 H), 0.06 (s, 3 H); 13C (100 MHz,
CDCl3) δ 109.5, 96.8, 75.9, 74.6, 74.4, 74.2, 74.0, 72.6, 71.4, 59.4,
56.1, 36.6, 33.6, 33.2, 31.8, 29.6, 29.2, 28.2, 26.4, 25.8, 25.6, 22.6,
18.3, 14.0, -5.3, -5.4; HRMS (FAB) calcd for C28H56O8SiNa
(M þ Na)þ 571.3642, found 571.3633.
1 H), 4.81 (d, J = 7.1 Hz, 1 H), 4.67 (d, J = 7.1 Hz, 1 H), 4.66
(d, J = 7.1 Hz, 1 H), 4.30-4.25 (m, 2 H), 4.12-4.03 (m, 2 H),
3.90-3.73 (m, 8 H), 3.65-3.56 (m, 4 H), 3.43 (s, 3 H), 3.42 (s,
3 H), 2.24-2.22 (m, 4 H), 2.04-1.93 (m, 2 H), 1.87-1.80 (m,
2 H), 1.69-1.60 (m, 2 H), 1.56-1.50 (m, 2 H), 1.50-1.21 (m,
50 H), 0.87 (t, J = 5.6 Hz, 3 H), 0.87 (t, J = 5.6 Hz, 3 H); HRMS
(FAB) calcd for C26H48O8Na (M þ Na)þ 511.3247, found
511.3246.
To a solution of the alcohol obtained above (216 mg, 0.441
mmol) in toluene (5.0 mL) and THF (1.0 mL) were added
1-phenyl-1H-tetrazole-5-thiol (94.0 mg, 0.530 mmol), PPh3
(139 mg, 0.530 mmol), and DEAD (2.2 M in toluene, 0.24 mL,
0.530 mmol) at 0 °C. The mixture was stirred at the same
temperature for 2 h and a further 2 h at room temperature. The
mixture was concentrated and purified by column chromatogra-
phy (hexane/EtOAc, 9:1, 5:1) to give the corresponding sulfide
(205 mg, 72%) as a 1:1 diastereomeric mixture: colorless oil; Rf =
0.44 (hexane/EtOAc, 2:1); 1H NMR (400 MHz, CDCl3) δ 7.59-
7.51(m, 10H), 4.81(d, J = 7.1 Hz, 1 H), 4.80 (d, J = 7.1Hz, 1 H),
4.68 (d, J = 7.1 Hz, 1 H), 4.66 (d, J = 7.1 Hz, 1 H), 4.29-4.28
(m, 2 H), 4.24-4.17 (m, 2 H), 3.92 (brd, J = 9.8 Hz, 1 H), 3.86-
3.78 (m, 7 H), 3.60-3.51 (m, 4 H), 3.41 (s, 3 H), 3.41 (s, 3 H),
2.40-2.33 (m, 1 H), 2.30-2.21 (m, 1 H), 2.07-1.97 (m, 2 H),
1.85-1.76 (m, 2 H), 1.63-1.19 (m, 56 H), 0.89-0.84 (m, 6 H);
HRMS (FAB) calcd for C33H52N4O7SNa (M þ Na)þ 671.3454,
found 671.3463.
Alcohol 21. To a solution of diol 19 (178 mg, 0.319 mmol) in
2,2-dimethoxypropane (3.0 mL) and acetone (1.0 mL) was
added PPTS (7.5 mg, 30.0 μmol) at 0 °C, then the resultant
solution was allowed to warm up to room temperature. After the
mixture was stirred at the same temperature for 2 h, the reaction
was quenched with Et3N. Concentration and column chroma-
tography (hexane/EtOAc, 9:1, 4:1) gave the corresponding
acetonide (172 mg, 92%): colorless oil; Rf = 0.58 (hexane/
EtOAc, 4:1); [R]26D þ50.2 (c 0.71, CHCl3); IR (neat) 2930 cm-1
;
1H NMR (400 MHz, CDCl3) δ 4.81 (d, J = 7.0 Hz, 1 H), 4.67 (d,
J = 7.0 Hz, 1 H), 4.27 (dd, J = 4.8, 2.4 Hz, 1 H), 3.86-3.73 (m,
6 H), 3.63-3.58 (m, 1 H), 3.53 (brt, J = 9.0 Hz, 1 H), 3.42 (s,
3 H), 1.98-1.89 (m, 1 H), 1.86-1.79 (m, 1 H), 1.73-1.55 (m,
4 H), 1.49 (s, 3 H), 1.37 (s, 3 H), 1.36 (s, 3 H), 1.34 (s, 3 H), 1.31-
1.22 (m, 10 H), 0.89 (s, 9 H), 0.87 (t, J = 6.8 Hz, 3 H), 0.06 (s,
3 H), 0.53 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 109.4, 108.0,
96.8, 81.4, 76.6, 75.1, 74.9, 74.4, 74.3, 72.7, 59.9, 56.2, 37.0, 34.3,
32.7, 31.8, 29.7, 29.2, 28.1, 27.5, 27.4, 26.5, 26.0, 26.0, 22.6, 18.3,
14.1, -5.3; HRMS (FAB) calcd for C31H60O8SiNa (M þ Na)þ
611.3955, found 611.3956.
To a solution of the sulfide obtained above (205 mg,
0.315 mmol) in EtOH (3.0 mL) were added aqueous H2O2
(30%, 0.32 mL, 3.14 mmol) and (NH4)6Mo7O24 4H2O (39.0 mg,
3
To a solution of the TBS ether obtained above (172 mg,
0.292 mmol) in THF (3.0 mL) was added TBAF (1.0 M in THF,
0.40 mL, 0.40 mmol) at 0 °C. The mixture was stirred at room
temperature for 3 h. The resultant mixture was poured into H2O
and extracted with EtOAc. The organic layer was washed with
brine and dried over Na2SO4. Concentration and column
chromatography (hexane/EtOAc, 4:1, 2:1) gave alcohol 21
31.5 μmol) at 0 °C. The mixture was stirred at room temperature
and extracted with EtOAc. The organic layer was washed with
H2O and brine and dried over MgSO4. Concentration and column
chromatography (hexane/EtOAc, 9:1, 5:1) gave sulfone 22 (176mg,
82%) as a 1:1 diastereomeric mixture: colorless oil; Rf = 0.20
1
(hexane/EtOAc, 1:1); H NMR (400 MHz, CDCl3) δ 7.68-7.55
(m, 10 H), 4.81 (d, J = 7.1 Hz, 1 H), 4.81 (d, J = 7.1 Hz, 1 H), 4.66
(d, J = 7.1 Hz, 1 H), 4.65 (d, J = 7.1 Hz, 1 H), 4.30-4.27 (m, 2 H),
4.10-4.05 (m, 2 H), 3.92 (brd, J = 9.0 Hz, 1 H), 3.87-3.77 (m,
7 H), 3.62-3.52 (m, 4 H), 3.40 (s, 3 H), 3.39 (s, 3 H), 2.76-2.69 (m,
1 H), 2.35-2.29 (m, 1 H), 2.17-2.08 (m, 1 H), 1.86-1.77 (m, 3 H),
1.61-1.21 (m, 56 H), 0.88-0.80 (m, 6 H); HRMS (FAB) calcd for
C33H52N4O9SNa (M þ Na)þ 703.3353, found 703.3368.
(112 mg, 81%): colorless oil; Rf = 0.20 (hexane/EtOAc, 2:1);
1
[R]27 þ61.9 (c 0.92, CHCl3); IR (neat) 3500, 2931 cm-1; H
D
NMR (400 MHz, CDCl3) δ 4.82 (d, J = 7.1 Hz, 1 H), 4.67 (d,
J = 7.1 Hz, 1 H), 4.28 (dd, J = 4.9, 2.2 Hz, 1 H), 3.91 (ddd, J =
10.3, 3.2, 1.5 Hz, 1 H), 3.87-3.77 (m, 5 H), 3.65-3.56 (m, 2 H),
3.42 (s, 3 H), 2.08-1.99 (m, 3 H), 1.87-1.81 (m, 1 H), 1.72-1.62
(m, 2 H), 1.50 (s, 3 H), 1.38 (s, 3 H), 1.38 (s, 3 H), 1.36 (s, 3 H),
1.31-1.26 (m, 10 H), 0.87 (t, J = 6.8 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ 109.5, 108.2, 96.8, 81.5, 76.7, 75.0, 74.9,
74.7, 74.3 74.0, 60.3, 56.2, 36.0, 32.9, 32.7, 31.8, 29.7, 29.1, 28.2,
27.3, 27.2, 26.4, 25.9, 22.6, 14.1; HRMS (FAB) calcd for
C25H46O8Na (M þ Na)þ 497.3090, found 497.3080.
(E)-Alkene 33. To a solution of sulfone 22 (49.8 mg,
73.1 μmol) in freshly distilled THF (1.0 mL) was added LDA
(0.5 M in THF, 175 μL, 88 μmol) at -78 °C. After the mixture
was stirred at the same temperature for 15 min, to the mixture
was added aldehyde 30 (35.9 mg, 61.0 μmol) in THF (0.30 mL þ
0.15 mL þ 0.15 mL). The mixture was gradually warmed up to
-40 °C for 30 min. After the mixture was stirred at the same
temperature, the reaction was quenched with saturated aqueous
NH4Cl. The mixture was extracted with EtOAc, and then the
organic layer was washed with H2O and brine and dried over
MgSO4. Concentration and purification by preparative TLC
(hexane/EtOAc, 6:1) to give (E)-alkene 33 (22.8 mg, 36%) and
(Z)-alkene 34 (16.0 mg, 25%). (E)-Alkene 33: colorless oil; Rf =
Sulfone 22. To a solution of alcohol 21 (112 mg, 0.235 mmol)
in DMSO (2.0 mL) and CH2Cl2 (2.0 mL) were added Et3N
(0.33 mL, 2.35 mmol) and SO3 pry (188 mg, 1.18 mmol) at 0 °C.
3
The mixture was stirred at the same temperature for 2 h. The
reaction was quenched with saturated aqueous NH4Cl, and the
mixture was extracted with EtOAc. The organic layer was
washed with H2O and brine, dried over MgSO4, and concen-
trated to give the corresponding aldehyde (107 mg) as a colorless
oil, which was used for the next reaction without further
purification.
0.52 (hexane/EtOAc, 4:1); [R]28 þ36.3 (c 0.61, CHCl3); IR
D
(neat) 2929 cm-1; 1H NMR (600 MHz, C6D6) δ 7.40-7.36 (m,
5 H), 7.22-7.09 (m, 10 H), 5.26 (d, J = 8.8 Hz, 1 H), 4.79 (d, J =
11.3 Hz, 1 H), 4.76 (d, J = 11.7 Hz, 1 H), 4.71 (d, J = 11.7 Hz,
1 H), 4.67-4.64 (m, 2 H), 4.57-4.52 (m, 2 H), 4.48-4.46 (m,
2 H), 4.18 (brt, J = 8.5 Hz, 1 H), 4.11-4.08 (m, 1 H), 4.00-3.97
(m, 2 H), 3.93-3.83 (m, 3 H), 3.80-3.77 (m, 1 H), 3.75-3.71 (m,
1 H), 3.64-3.61 (m, 2 H), 3.16 (s, 3 H), 2.74-2.70 (m, 2 H),
2.20-2.17 (m, 2 H), 2.07 (brt, J = 12.1 Hz, 1 H), 1.93-1.85 (m,
2 H), 1.79-1.76 (m, 1 H), 1.75 (s, 3 H), 1.63-1.58 (m, 3 H), 1.54
(s, 3 H), 1.51 (s, 3 H), 1.46 (s, 3 H), 1.35 (s, 3 H), 1.29-1.24 (m,
10 H), 1.06 (d, J = 6.6 Hz, 3 H), 0.98 (s, 9 H), 0.89 (t, J = 7.0 Hz,
3 H), 0.06 (s, 3 H), 0.06 (s, 3 H); 13C NMR (150 MHz, C6D6);
To a solution of aldehyde obtained above in Et2O (2.0 mL)
was added MeMgBr (3.0 M in Et2O, 0.13 mL, 0.352 mmol) at
0 °C. The mixture was stirred at the same temperature for 1 h.
The reaction was quenched with saturated aqueous NH4Cl, and
the mixture was extracted with EtOAc. The organic layer was
washed with H2O and brine and dried over MgSO4. Concentra-
tion and column chromatography (hexane/EtOAc, 4:1, 2:1, 1:1)
gave the corresponding alcohol (104 mg, 90% in two steps) as a
1:1 diastereomeric mixture: colorless oil; Rf = 0.30 (hexane/
EtOAc, 2:1); 1H NMR (400 MHz, CDCl3) δ 4.82 (d, J = 7.1 Hz,
6664 J. Org. Chem. Vol. 74, No. 17, 2009

Takamura et al.
JOCArticle
δ 139.8, 139.7, 139.5, 134.2, 130.7, 128.5, 128.5, 128.5, 128.3,
127.9, 127.7, 127.5, 127.5, 109.4, 108.1, 97.3, 82.9, 81.8, 77.7,
77.1, 76.9, 75.7, 75.4, 75.3, 75.0, 74.6, 74.5, 73.4, 72.4, 59.9, 55.7,
41.5, 38.8, 37.2, 34.9, 33.2, 32.2, 30.1, 29.6, 29.4, 28.6, 27.9, 27.8,
26.8, 26.7, 26.1, 23.0, 21.1, 18.4, 16.1, 14.3, -5.2, -5.2; HRMS
(ESI) calcd for C62H96O11SiNa (M þ Na)þ 1067.6620, found
1067.6621. (Z)-Alkene 34: colorless oil; Rf = 0.38 (hexane/
colorless oil; Rf = 0.28 (hexane/EtOAc, 2:1); [R]27 þ41.2
D
(c 0.56, CHCl3); IR (neat) 3030, 1733 cm-1 1H NMR
;
(400 MHz, CDCl3) δ 7.35-7.25 (m, 15 H), 4.90 (d, J =
9.5 Hz, 1 H), 4.86-4.82 (m, 2 H), 4.69-4.58 (m, 5 H), 4.38 (d,
J = 12.0 Hz, 1 H), 4.28 (dd, J = 4.7, 2.4 Hz, 1 H), 4.07 (dt, J =
7.3, 4.6 Hz, 1 H), 3.92 (brt, J = 8.8 Hz, 1 H), 3.81-3.78 (m, 2 H),
3.74 (dd, J = 7.6, 2.9 Hz, 1 H), 3.49-3.42 (m, 2 H), 3.49-3.44
(m, 2 H), 3.44 (s, 3 H), 2.51 (dd, J = 15.6, 5.6 Hz, 1 H), 2.40 (dd,
J = 14.2, 9.5 Hz, 1 H), 2.09-1.99 (m, 3 H), 1.85-1.72 (m, 2 H),
1.61-1.42 (m, 4 H), 1.58 (d, J = 1.0 Hz, 3 H), 1.46 (s, 3 H), 1.39
(s, 3 H), 1.37 (s, 3 H), 1.36 (s, 3 H) 1.29-1.23 (m, 10 H), 0.88 (t,
J = 6.8 Hz, 3 H), 0.73 (d, J = 6.6 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) δ 179.3, 138.8, 137.8, 137.7, 132.7, 130.0, 129.4, 128.4,
128.2, 128.2, 128.1, 127.9, 127.4, 127.2, 109.3, 107.7, 97.1, 81.4,
77.2, 76.1, 74.9, 74.8, 74.6, 74.4, 73.4, 71.9, 71.1, 71.0, 60.4, 56.1,
40.5, 39.2, 37.5, 36.1, 32.6, 31.8, 29.7, 29.1, 28.5, 28.2, 27.4, 27.4,
26.5, 26.1, 22.6, 21.4, 21.0, 15.0, 14.2, 14.1; HRMS (ESI) calcd
for C56H80O12Na (M þ Na)þ 967.5547, found 967.5560.
Carboxylic Acid 2. To a solution of tribenzyl ether 35
(15.2 mg, 16.1 μmol) in liquid NH3 (10 mL), THF (5.0 mL),
and t-BuOH (1.0 mL) was added Na (181 mg, 7.86 mmol) at
-78 °C. After the mixture was stirred at the same temperature
for 1 h, the reaction was quenched with saturated aqueous
NH4Cl, and the mixture was allowed to warm to room tem-
perature. The mixture was diluted with H2O and desalted by
passing through the polystyrene gel chromatography (TSK-
G3000S, H2O, aqueous 50% EtOH, EtOH). The aqueous
50% EtOH and EtOH fractions were concentrated to give triol
36 (11.0 mg) as a colorless oil, which was used for the next
reaction without further purification.
EtOAc, 4:1); [R]27D þ17.7 (c 0.96, CHCl3); IR (neat) 2929 cm-1
;
1H NMR (400 MHz, C6D6) δ 7.41-7.37 (m, 5 H), 7.28-7.08 (m,
10 H), 5.18 (d, J = 9.5 Hz, 1 H), 4.81-4.70 (m, 3 H), 4.64 (q, J =
5.8 Hz, 1 H), 4.56 (t, J = 6.8 Hz, 2 H), 4.51-4.46 (m, 2 H), 4.16
(brt, J = 8.6 Hz, 1 H), 4.10-4.05 (m, 1 H), 4.02-3.98 (m, 2 H),
3.93-3.89 (m, 2 H), 3.86-3.78 (m, 2 H), 3.74-3.69 (m, 1 H),
3.66-3.59 (m, 2 H), 3.18 (s, 3 H), 2.77-2.71 (m, 1 H), 2.64 (dd,
J = 14.0, 9.4 Hz, 1 H), 2.54 (dd, J = 14.0, 3.4 Hz, 1 H), 2.20-2.15
(m, 1 H), 2.07 (t, J = 12.2 Hz, 1 H), 1.95 (s, 3 H), 1.92-1.74 (m,
3 H), 1.67-1.49 (m, 3 H), 1.52 (s, 3 H), 1.47 (s, 3 H), 1.45 (s, 3 H),
1.34 (s, 3 H), 1.31-1.24 (m, 10 H), 0.98 (s, 9 H), 0.95 (d, J =
6.4 Hz, 3 H), 0.89 (t, J = 6.4 Hz, 3 H), 0.05 (s, 3 H), 0.05 (s, 3 H);
13C NMR (100 MHz, C6D6); δ 139.8, 139.6, 139.5, 133.8, 132.0,
128.5, 128.5, 128.5, 127.9, 127.7, 127.6, 127.5, 109.4, 108.1, 97.4,
83.4, 81.8, 77.6, 77.2, 77.2, 76.6, 75.7, 75.6, 75.5, 75.4, 74.7, 73.5,
72.6, 60.0, 55.9, 39.1, 37.0, 35.1, 33.8, 33.2, 32.3, 30.2, 29.8, 29.3,
28.6, 27.9, 27.9, 26.9, 26.9, 26.3, 25.0, 23.2, 21.2, 18.6, 14.4, -5.0,
-5.0; HRMS (ESI) calcd for C62H96O11SiNa (M þ Na)þ
1067.6620, found 1067.6621.
Carboxylic Acid 35. To a solution of TBS ether 33 (15.2 mg,
14.5 μmol) in THF (0.50 mL) was added TBAF (1.0 M in THF,
0.10 mL, 0.10 mmol) at room temperature. After the mixture
was stirred at the same temperature for 4 h, the mixture was
poured into Et2O, washed with H2O and brine, and dried over
MgSO4. Concentration and column chromatography (hexane/
EtOAc, 3:1) gave the corresponding alcohol (13.6 mg, quant.):
colorless oil; Rf = 0.39 (hexane/EtOAc, 2:1); [R]27D þ64.5 (c 0.36,
CHCl3); IR (neat) 3502, 2930 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.37-7.27 (m, 15 H), 4.94 (d, J = 9.5 Hz, 1 H), 4.86-4.75 (m,
2 H), 4.69-4.67 (m, 2 H), 4.59 (d, J = 3.9 Hz, 1 H), 4.56 (d, J =
4.4 Hz, 1 H), 4.43 (d, J = 11.7 Hz, 1 H), 4.29 (dd, J = 4.9, 2.9 Hz,
1 H), 3.87-3.77 (m, 4 H), 3.69 (dd, J = 10.3, 3.2 Hz, 1 H), 3.60-
3.36 (m, 7 H), 3.43 (s, 3 H), 2.42 (dd, J = 14.2, 9.5 Hz, 1 H), 2.13-
2.02 (m, 2 H), 1.81-1.74 (m, 1 H), 1.71-1.63 (m, 1 H), 1.59-1.43
(m, 6 H), 1.57 (s, 3 H), 1.52 (s, 3 H), 1.38 (s, 3 H), 1.37 (s, 3 H), 1.35
(s, 3 H), 1.29-1.22 (m, 10 H), 0.88 (t, J = 7.1 Hz, 3 H), 0.75 (d,
J = 6.6 Hz, 3 H); 13C NMR (150 MHz, CDCl3) δ 138.4, 138.4,
133.3, 130.8, 128.7, 128.4, 128.4, 128.4, 128.3, 128.1, 127.7, 127.7,
109.5, 108.0, 97.0, 81.4, 80.6, 78.8, 76.3, 75.9, 74.9, 74.7, 74.7, 74.6,
74.5, 74.5, 73.5, 71.3, 59.9, 56.2, 41.3, 36.7, 36.3, 33.9, 32.6, 31.8,
29.7, 29.1, 28.6, 28.1, 27.5, 27.3, 26.5, 26.0, 22.6, 21.2, 15.9, 14.1;
HRMS (ESI) calcd for C56H82O11Na (M þ Na)þ 953.5755,
found 953.5742.
A solution of triol 36 obtained above in H2O-TFA (3:1,
0.50 mL) was heated to 40 °C and stirred at the same temperature
for 24 h. The mixture was concentrated to give the mixture of
carboxylic acid 2 and its corresponding lactone (9.0 mg) as a
colorless oil, which was used for the next reaction without further
purification.
A solution of the mixture of carboxylic acid 2 and its
corresponding lactone obtained above in MeOH (0.60 mL)
and aqueous KOH (1.0 M, 0.30 mL) was heated to 30 °C and
stirred at the same temperature for 14 h. The resultant mixture
was diluted with H2O and desalted by passing through poly-
styrene gel column chromatography (TSK-G3000S, H2O, aqu-
eous 50% EtOH, EtOH), and the aqueous 50% EtOH and
EtOH fractions were concentrated. The residue was purified by
column chromatography (ODS, aqueous 30% to 50% MeOH)
to give carboxylic acid 2 (8.4 mg, 95% in three steps): colorless
oil; Rf = 0.32 (ODS, aqueous 70% MeOH); [R]23 þ10.6
D
1
(c 0.05, CH3OH); IR (neat) 3406, 2925, 1633, 1576 cm-1; H
NMR (800 MHz, CD3OD) δ 5.08 (d, J = 9.2 Hz, 1 H), 4.04 (dd,
J = 11.5, 6.0 Hz, 1 H), 3.90 (t, J = 3.7 Hz, 1 H), 3.89 (t, J =
6.9 Hz, 1 H), 3.74 (td, J = 10.0, 1.8 Hz, 1 H), 3.71 (ddd, J = 10.0,
3.6, 2.8 Hz, 1 H), 3.68 (td, J = 6.9, 3.7 Hz, 1 H), 3.56 (d, J =
3.7 Hz, 1 H), 3.52 (dd, J = 10.0, 2.8 Hz, 1 H), 3.39-3.37 (m,
1 H), 3.25 (dd, J = 4.8, 2.8 Hz, 1 H), 2.59-2.53 (m, 1 H), 2.41-
2.39 (m, 2 H), 2.26 (dd, J = 12.8, 7.4 Hz, 1 H), 2.22 (dd, J = 13.8,
6.5 Hz, 1 H), 1.96 (ddd, J = 14.4, 10.6, 1.8 Hz, 1 H), 1.68 (s, 3 H),
1.63 (dt, J = 13.8, 6.4 Hz, 1 H), 1.54-1.49 (m, 3 H), 1.46-1.41
(m, 2 H), 1.35-1.30 (m, 10 H), 0.96 (d, J = 6.4 Hz, 3 H), 0.90 (t,
J = 6.9 Hz, 3 H); 13C NMR (150 MHz, CD3OD) δ 180.2, 134.8,
131.5, 76.3, 75.9, 74.2, 73.8, 72.3, 71.9, 71.6, 71.6, 70.1, 42.3,
42.0, 41.7, 37.1, 34.0, 33.1, 30.8, 30.5, 30.1, 27.1, 23.7, 21.4, 16.8,
14.4; HRMS (ESI) calcd for C27H50O11Na (M þ Na)þ 573.3251,
found 573.3237.
To a solution of the alcohol obtained above (13.6 mg,
14.6 μmol) in CH2Cl2 (0.25 mL) and DMSO (0.25 mL) were
added Et3N (21 μL, 0.154 mmol) and SO3 pry (12.2 mg,
3
77 μmol) at room temperature. After the mixture was stirred
at the same temperature for 30 min, the mixture was poured into
Et2O, washed with H2O and brine, and dried over MgSO4.
Concentration gave the corresponding aldehyde (15.8 mg) as a
pale yellow oil, which was used for the next reaction without
further purification.
To a solution of aldehyde obtained above in t-BuOH
(0.40 mL) and H2O (0.10 mL) were added 2-methyl-2-butene
(32 μL, 0.308 mmol), NaH2PO4 (11.1 mg, 92.4 μmol), and
NaClO2 (10.4 mg, 92.4 μmol) at room temperature. After the
mixture was stirred at the same temperature for 30 min, the
mixture was diluted with H2O and extracted with EtOAc. The
organic layer was washed with brine and dried over MgSO4.
Concentration and column chromatography (CHCl3/MeOH,
49:1) gave carboxylic acid 35 (12.8 mg, 93% in two steps):
Acknowledgment. We thank Okayama Foundation for
Science and Technology, NOVARTIS Foundation (Japan)
for the Promotion of Science, The Mitsubishi Foundation,
J. Org. Chem. Vol. 74, No. 17, 2009 6665

Takamura et al.
JOCArticle
and WESCO Scientific Promotion Foundation for their
financial supports. This research was partially supported
by Grant-in-Aid for Scientific Research (19710184,
21710231 and 16GS0206) from the Japan Society for the
Promotion of Science.
Supporting Information Available: Additional experi-
mental procedures and spectral and analytical data for new
compounds and copies of 1H and 13C NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
6666 J. Org. Chem. Vol. 74, No. 17, 2009