Total synthesis of marine oxylipin bacillariolides I-III

Article abstract of DOI:10.1016/S0040-4020(00)00730-4

Marine oxylipin bacillariolides I-III were synthesized from (R)-malic acid, using diastereoselective one-pot formation of the chiral cyclopentane derivative from the anion of allyl phenyl sulfone and chiral epoxymesylate as the key reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00730-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8083±8094
Total Synthesis of Marine Oxylipin Bacillariolides I±III
*
Hiroaki Miyaoka, Masahide Tamura and Yasuji Yamada
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 17 July 2000; accepted 21 August 2000
AbstractÐMarine oxylipin bacillariolides I±III were synthesized from (R)-malic acid, using diastereoselective one-pot formation of the
chiral cyclopentane derivative from the anion of allyl phenyl sulfone and chiral epoxymesylate as the key reaction. q 2000 Elsevier Science
Ltd. All rights reserved.
Marine carbocyclic oxylipins are of considerable interest for
their unique structural features, peculiar biosynthetic path-
ways and diverse biological activities.1 Bacillariolides I (1)
and II (2), isolated from the marine diatom, Pseudo-
nitzschia multiseries,2 a causative diatom of so-called
amnesic shell®sh poisoning (ASP),3 are cyclopentane-
containing structurally unique oxylipins.4 Bacillariolide III
(3), isolated from the culture broth of the same marine
diatom, is an extracellular metabolic oxylipin derived
from bacillariolide I.5 The relative con®gurations of
bacillariolides I±III were determined by spectroscopic
analysis and the absolute con®guration of bacillariolide I
was established by X-ray crystallography of its (2)-cam-
phanic acid derivative.6 The absolute con®gurations of
bacillariolides II and III were estimated based on an
apparent biosynthetic relationship of bacillariolides II and
III with bacillariolide I. Bacillariolide I possesses signi®cant
inhibitory activity toward phospholipase A2.7 The unique
structural features and biological activity of bacillariolides
prompted the authors to undertake their total synthesis. The
previous communication reported the total synthesis of
bacillariolide II using one-pot formation of the chiral cyclo-
pentane derivative as the key step.8 In this paper, the authors
wish to report the detail of synthesis of bacillariolide II
along with synthesis of bacillariolides I and III (Fig. 1).
The authors reported one-pot synthesis of cycloalkane
derivatives using allyl phenyl sulfone and epoxymesylate
(Fig. 2).9 The synthesis involves the following sequences:
(1) an anion of allyl phenyl sulfone reacts with epoxide i to
give epoxy sulfone ii; (2) a deprotonation of ii by an anion
of allyl phenyl sulfone in situ generates an anion iii; and
(3) cyclization of iii gives cycloalkane derivative iv.
Previously, the synthesis of cyclopropane-containing
marine oxylipin constanolactone E using the one-pot syn-
thesis of cyclopropane iv (nˆ0) was reported.10 This one-
pot reaction using chiral epoxide i (nˆ2) is applied to the
synthesis of cyclopentane-containing bacillariolides I±III.
The authors considered that the synthesis should be carried
out via a common synthetic intermediate for all of bacil-
lariolides I±III (Fig. 3). The one-pot synthesis of cyclo-
pentane is used for the synthesis of the C-1,8 segment
e.11 In this synthesis, an anion of allyl phenyl sulfone is
reacted with chiral epoxide a, prepared from (R)-malic
acid, to give epoxysulfone b, which is deprotonated in situ
by base to generate an anion c, then cyclized to give chiral
cyclopentane d. Cyclopentane d is converted to aldehyde e
possessing the chiral centers at C-2, C-5, C-6 and C-7 for
bacillariolide II by oxidative cleavage of vinyl group and
removal of phenylsulfonyl group. By the coupling reaction
Figure 1.
Keywords: marine metabolites; eicosanoids; sulfones; cyclopentanes.
* Corresponding author. Tel.: 1426-76-3046; fax: 1426-76-3069; e-mail: yamaday@ps.toyaku.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00730-4

8084
H. Miyaoka et al. / Tetrahedron 56 (2000) 8083±8094
Figure 2.
Figure 3.
of aldehyde e with Wittig reagent f, corresponding to
C-9,20 segment, bacillariolide II (2) is obtained. Epimeri-
zation of the C-7 position in aldehyde e gives aldehyde g
having requisite chiral centers at C-2, C-5, C-6 and C-7 for
bacillariolide I and III. The coupling reaction of aldehyde g
with Wittig reagent f or h leads to bacillariolide I (1) or III
(3), respectively.
Phosphonium bromide 9 corresponding to C-9,12 segment
h for bacillariolide III was prepared from 4-bromobutyric
acid (8) (Scheme 2). 4-Bromobutyric acid (8) was treated
with acetyl chloride in MeOH to provide methyl ester and
subsequent treatment with triphenylphosphine in CH3CN to
give phosphonium bromide 9.
Stereoselective synthesis of bacillariolide II using one-pot
formation of the chiral cyclopentane derivative as the key
step was carried out (Scheme 3). The primary hydroxyl
group of methyl (R)-3,4-dihydroxybutanoate (10),14
prepared from (R)-malic acid, was selectively protected as
triphenylmethyl (trityl) ether to give trityl ether 11.15 Trityl
ether 11 was converted to alcohol 12 in four steps: (1)
protection of the secondary hydroxyl group as MOM
Phosphonium iodide 7 corresponding to C-9,20 segment f
for bacillariolides I and II was prepared from 2,5-octadiyn-
1-ol (4) (Scheme 1). Bromination of 2,5-octadiyn-1-ol (4)12
was carried out by treating with carbon tetrabromide and
triphenylphosphine to give 1-bromo-2,5-octadiyne. The
coupling reaction of 1-bromo-2,5-octadiyne with 3-butyn-
1-ol in the presence of CuI, K2CO3 and NaI in DMF13 gave
3,6,9-dodecatriyn-1-ol (5). The stereoselective partial
hydrogenation of triynol 5 was ef®ciently carried out in
the presence of Pd±BaSO4 and quinoline to afford (Z,Z,Z)-
trienol 6. (Z,Z,Z)-Trienol 6 was converted to phosphonium
iodide 7 via iodide in three steps: (1) tosylation of hydroxyl
group; (2) treatment with NaI in acetone to give iodide; and
(3) treatment with triphenylphosphine in benzene.
Scheme 2. Reagents and conditions: A. (i) Ac-Cl, MeOH, rt, (ii) Ph3P,
CH3CN, re¯ux, 65% (2 steps).
Scheme 1. Reagents and conditions: A. (i) CBr4, Ph3P, CH2ClCH2Cl, 08C, (ii) 3-butyn-1-ol, K2CO3, CuI, NaI, DMF, rt, 80% (2 steps); B. H2, Pd±BaSO4,
quinoline, MeOH, rt, 76%; C. (i) Ts-Cl, Py, CHCl3, rt, quant., (ii) NaI, acetone, rt, 71%, (iii) Ph3P, benzene, re¯ux, 75%.

H. Miyaoka et al. / Tetrahedron 56 (2000) 8083±8094
8085
Scheme 3. Reagents and conditions: A. Tr-Cl, Et3N, DMAP, DMF, 658C, 87%; B. (i) MOM-Cl, iPr2NEt, CHCl3, 508C, (ii) LiAlH4, Et2O, 08C, (iii) TBDMS-
Cl, imidazole, DMF, rt, (iv) Na, liq. NH3±EtOH±THF, 2348C, 94% (4 steps); C. (i) DMSO, (COCl)2, Et3N, CH2Cl2, 2788C; (ii) (iPrO)2P(O)CH2CO2Et,
t
i
BuOK, THF, ±428C, (iii) DIBAL-H, toluene, 2788C, 89% (3 steps); D. (i) TBHP, d-(2)-DET, ( PrO)4Ti, 4AMS, CH2Cl2, 2208C, 89%, (ii) MPM2Br, NaH,
Ê
THF±DMF, 08C, 95%; E. (i) Bu4NF, THF, rt, (ii) Ms-Cl, DMAP, CH2Cl2, 08C,rt, quant. (2 steps); F. allyl phenyl sulfone, BuLi, THF, 2788C,rt, 99%; G. (i)
OsO4, NaIO4, 1,4-dioxane-H2O, rt, (ii) Jones ox., acetone, 08C, 82% (2 steps), (iii) Na±Hg, Na2HPO4, MeOH, rt, 91%; H. (i) CAN, CH3CN±H2O, rt, 88%, (ii)
DMSO, (COCl)2, Et3N, CH2Cl2, 2788C, quant.; I. (i) 7, BuLi, THF±HMPA, 2788C, 66%, (ii) AcOH±conc. HCl (50:1), 408C, 97%.
ether; (2) reduction of the ester with LiAlH4; (3) protection
of the primary hydroxyl group as TBDMS ether; and (4)
removal of the trityl group. The primary hydroxyl group of
12 was oxidized by Swern procedure followed by Horner±
Emmons reaction to give (E)-a,b-unsaturated ester as the
sole product, which was then reduced with DIBAL-H to
give allylic alcohol 13. The stereoselective epoxidation of
allylic alcohol 13 according to Sharpless procedure16 was
carried out followed by protection of hydroxyl group as
MPM ether to give 14. TBDMS ether 14 was converted to
epoxymesylate 15 by removal of the TBDMS group and
mesylation of the primary hydroxyl group. Reaction of the
lithio derivative of allyl phenyl sulfone (2.4 equiv.) with
epoxymesylate 15 (1.0 equiv.) in THF at 2788C to room
temperature over 12 h, gave cyclopentane 16 as the sole
product in 99% yield. Relative con®guration at C-2 position
in 16 was determined by NOESY correlations between H-1
(dH 6.42) and H-7 (dH 4.05) and H-6 (dH 3.15) and phenyl
protons (dH 7.81) (Fig. 4).
The terminal ole®n in 16 was oxidized by OsO4±NaIO4 to
give hemiacetal, then oxidized with Jones reagent to give
lactone and the phenylsulfonyl group was removed by
treatment with Na±Hg to give lactone 17 bearing the
requisite chiral centers at C-2, C-5, C-6 and C-7 correspond-
ing to C-1,8 segment e. Removal of MPM group in 17 by
treatment of CAN afforded an alcohol, then oxidized
according to Swern procedure to give aldehyde 18.
Coupling reaction of aldehyde 18 with Wittig reagent,
prepared from phosphonium iodide 7 and BuLi, in the
presence of HMPA afforded (8Z,11Z,14Z,17Z)-tetraene as
the sole product. Finally, removal of the MOM group
completed the synthesis of bacillariolide II (2), [a]Dˆ
258.58 (cˆ0.33, MeOH). The spectral data of 2 and natural
bacillariolide II, [a]Dˆ259.28 (cˆ0.33, MeOH),4 as well as
the sign of optical rotation were identical.
Stereoselective synthesis of bacillariolides I and III by
isomerization at C-7 position was carried out as shown in
Scheme 4. Aldehyde 18 was treated with K2CO3 in MeOH
to give aldehyde 180, which was isomerized at C-7 position,
at only 45% yield.
The lactone portion was protected as methyl acetal. Lactone
17 was reduced with DIBAL-H to give hemiacetal, which
was treated with PPTS in MeOH to afford methyl acetal 19
Figure 4.
Scheme 4.

8086
H. Miyaoka et al. / Tetrahedron 56 (2000) 8083±8094
MeOH). NMR spectrum and optical rotation of synthesized
bacillariolide III were not identical with reported spectral
data.5 Natural bacillariolide III, for which analytical data
were obtained, was ®nally puri®ed with ODS. Synthesized
bacillariolide III was also puri®ed with ODS. The NMR
spectral data of synthesized bacillariolide III, puri®ed with
ODS, was identical with those of natural bacillariolide III.
For further con®rmation, synthesized bacillariolide III was
converted to the bacillariolide III sodium salt by ®ltration
through Chelex 100 Na1 form. Spectral data of the sodium
salt of bacillariolide III was identical with those of the
sodium salt of natural bacillariolide III.17 The total synthesis
of bacillariolide III was thus considered to have been
achieved. Discrepancy in the value of optical rotation of
synthesized and natural bacillariolide III was shown to
arise from difference in purity (Scheme 5).
Figure 5.
as the sole product. Removal of the MPM group in 19 by
treatment with DDQ afforded an alcohol, subsequently
oxidized by the Swern procedure to give aldehyde 20.
Aldehyde 20 was treated with K2CO3 in MeOH at room
temperature and isomerization of C-7 proceeded to afford
aldehyde 21, possessing requisite chiral centers at C-2, C-5,
C-6 and C-7 corresponding to C-1,8 segment g. Relative
con®guration at C-7 position in 21 was con®rmed by
NOESY correlation between H-6 (dH 3.12) and aldehyde
proton H-8 (dH 9.70) (Fig. 5).
This paper presents the ®rst total synthesis of bacillariolides
I±III and absolute con®gurations of bacillariolides II and III
were con®rmed as 2 and 3, respectively.
Coupling reaction of aldehyde 21 with Wittig reagent,
prepared using phosphonium iodide 7 afforded all-Z-tetra-
ene 22 as the sole product. Hydrolysis of methyl acetal by
treatment with AcOH±H2O (4:1), oxidation of hemiacetal
with Jones reagent to give lactone and removal of MOM
group with AcOH±conc.HCl (50:1) afforded bacillariolide
I (1), [a]Dˆ223.68 (cˆ0.55, MeOH). The spectral data of
1 and natural bacillariolide I, [a]Dˆ225.98 (cˆ0.21,
MeOH),4 as well as the sign of optical rotation were iden-
tical. Coupling reaction of aldehyde 21 with Wittig reagent,
prepared from phosphonium bromide 9, corresponding to
C-9,12 segment h, and LiHMDS afforded Z-ole®n 23 as
the sole product. Hydrolysis of methyl acetal 23 with
AcOH2H2O (4:1) gave hemiacetal and oxidation of hemi-
acetal with Jones reagent produced lactone. Finally,
hydrolysis of methyl ester and MOM ether by treatment
with 1N HCl, followed by puri®cation with silica gel
afforded bacillariolide III (3), [a]Dˆ±54.28 (cˆ0.31,
Experimental
General experimental procedures
Melting points were measured on Yazawa BY-2 micro
melting point apparatus and uncorrected. Optical rotations
were measured with a JASCO DIP-360 automatic polari-
meter. IR spectra were recorded with a Perkin±Elmer
FT-IR 1710 spectrometer or JASCO FT-IR/620 spec-
trometer, UV spectra with a JASCO V-550 spectrophoto-
meter and H and 13C NMR spectra with a Varian Gemini-
1
300, a Bruker DPX-400 or a Bruker DRX-500. Chemical
shifts are given on a d (ppm) scale with tetramethylsilane
(TMS) or sodium 3-(trimethylsilyl)propionate (TSP) as the
internal standard (s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; br, broad). EIMS was obtained with a Thermo
Quest TSQ 700 spectrometer. FABMS spectra, high resolu-
tion EIMS (HREIMS) spectra and high resolution FABMS
Scheme 5. Reagents and conditions: A. (i) DIBAL-H, toluene, 2788C; (ii) PPTS, MeOH, rt, 99% (2 steps); B. (i) DDQ, CH2Cl2±H2O, rt, 92%, (ii) DMSO,
(COCl)2, Et3N, CH2Cl2, 2788C, 96%; C. K2CO3, MeOH, rt, 82%; D. 7, BuLi, THF±HMPA, 2788C, 99%; E. (i) AcOH±H2O (4:1), rt, 87%, (ii) Jones ox.,
acetone, 08C, 89%, (iii) AcOH±conc.HCl (50:1), rt, 90%; F.9, LiHMDS, THF±HMPA, 278,08C, 95%, G. (i) AcOH±H2O (4:1), rt, 67%, (ii) Jones ox.,
acetone, 08C, quant., (iii) 1N HCl, 608C, 70%.

H. Miyaoka et al. / Tetrahedron 56 (2000) 8083±8094
8087
(HRFABMS) spectra were obtained with a VG Auto Spec E
spectrometer. Column chromatography was carried out on
Merck silica gel 60 (70±230 mesh), Merck silica gel 60
(230±400 mesh) or ODS Wakogelw LP-40 C-18. Prepara-
tive TLC was conducted on a Merck silica gel 60 F254 plate.
mmol) and p-toluenesulfonyl chloride (2.84 g, 14.9 mmol)
and the mixture was stirred at rt for 3 h. The reaction
mixture was diluted with Et2O±CHCl3 (4:1), washed with
H2O and saturated aqueous NaCl, dried over anhydrous
MgSO4 and concentrated under reduced pressure. The resi-
due was puri®ed by silica gel column chromatography
(eluted with hexane±EtOAcˆ4:1) to give tosylate (3.63 g,
quantitative yield) as a colorless oil. IR (neat) 2964,
3,6,9-Dodecatriyn-1-ol (5). To a solution of 2,5-octandiyn-
1-ol (4) (11.5 g, 94.1 mmol) in 1,2-dichloroethane (280 mL)
were added a solution of tetrabromomethane (34.3 g,
104 mmol) and triphenylphosphine (32.1 g, 122 mmol) in
1,2-dichloroethane (34.0 mL). The mixture was stirred at
rt for 1 h, diluted with hexane and ®ltered through silica
gel. The ®ltrate was concentrated under reduced pressure
to give crude bromide for use in the reaction below without
puri®cation. A portion of a crude bromide was puri®ed for
spectral analysis by silica gel column chromatography
(eluted with hexane). Colorless oil; IR (neat) 2977, 2234,
612 cm21; 1H NMR (300 MHz, CDCl3) d ppm: 1.12 (3H, t,
Jˆ7.5 Hz), 2.17 (2H, ddt, Jˆ15.0, 7.5, 2.3 Hz), 3.21 (2H,
m), 3.92 (2H, t, Jˆ2.3 Hz); 13C NMR (75 MHz, CDCl3) d
ppm: 9.8, 12.1, 13.6, 14.7, 72.0, 75.1, 81.8, 82.3; EIMS
(m/z): 184 (M1, 40), 77 (100).
1
1599 cm21; H NMR (300 MHz, CDCl3) d ppm:0.97 (3H,
t, Jˆ7.5 Hz), 2.06 (2H, m), 2.42 (2H, td, Jˆ6.9, 1.5 Hz),
2.45 (3H, s), 2.76 (4H, br dd, Jˆ11.6, 6.3 Hz), 4.02 (2H, t,
Jˆ6.9 Hz), 5.21±5.52 (6H, m), 7.34 (2H, m), 7.79 (2H, m);
13C NMR (75 MHz, CDCl3) d ppm:14.2, 20.5, 21.5, 25.4,
25.5, 27.0, 69.5, 123.1, 126.7, 127.2, 127.8, 128.8, 129.7,
131.6, 132.0, 133.0, 144.6; EIMS (m/z):334 (M1, 0.5), 91
(100); HREIMS: Calcd for C19H26O3S (M1): 334.1602;
Found: 334.1584.
To a solution of the above tosylate (2.72 g, 8.13 mmol) in
acetone (16.0 mL) was added NaI (3.66 g, 24.4 mmol)
followed by stirring at rt for 24 h. The reaction mixture
was diluted with Et2O, washed with H2O, saturated aqueous
Na2S2O3 and saturated aqueous NaCl, dried over anhydrous
MgSO4 and concentrated under reduced pressure. The resi-
due was puri®ed by silica gel column chromatography
(eluted with hexane) to give iodide (1.67 g, 71%) as a color-
less oil. IR (neat) 2963 cm21; 1H NMR (300 MHz, CDCl3) d
ppm: 0.98 (3H, t, Jˆ7.5 Hz), 2.08 (2H, qdd, Jˆ7.5, 7.0,
0.8 Hz), 2.67 (2H, td, Jˆ7.3, 1.0 Hz), 2.81 (4H, br t, Jˆ
6.3 Hz), 3.15 (2H, t, Jˆ7.3 Hz), 5.26±5.45 (5H, m), 5.52
(1H, dtt, Jˆ10.7, 7.3, 1.4 Hz); 13C NMR (75 MHz, CDCl3)
d ppm: 5.1, 14.2, 20.4, 25.4, 25.6, 31.3, 126.7, 127.2, 128.0,
128.5, 130.2, 131.8; EIMS (m/z): 290 (M1, 5), 79 (100);
HREIMS: Calcd for C12H19I (M1): 290.0531; Found:
290.0564, Anal. Calcd for C12H19I: C, 49.67; H, 6.60.
Found: C, 49.58; H, 6.71.
To a suspension of K2CO3 (20.9 g, 151 mmol), NaI (22.7 g,
151 mmol) and CuI (14.4 g, 75.7 mmol) in DMF was added
a solution of 2-butyn-1-ol (6.40 mL, 83.3 mmol) and the
above crude bromide in DMF (16.4 mL) and stirred at rt
for 6 h. The reaction mixture was diluted with Et2O and
®ltered through celite. The ®ltrate was washed with satu-
rated aqueous NH4Cl, H2O and saturated aqueous NaCl,
dried over anhydrous MgSO4 and concentrated under
reduced pressure. The residue was puri®ed by silica gel
column chromatography (eluted with hexane±EtOAcˆ
3:1) to give 3,6,9-dodecatriyn-1-ol (5) (11.7 g, 80%, 2
steps) as a colorless oil. IR (neat) 3368, 2938, 2216 cm21
;
1H NMR (300 MHz, CDCl3) d ppm: 1.12 (3H, t, Jˆ7.5 Hz),
2.17 (2H, ddt, Jˆ15.0, 7.5, 2.3 Hz), 2.44 (2H, tt, Jˆ6.2,
2.3 Hz), 3.14 (4H, m), 3.70 (2H, t, Jˆ6.2 Hz); 13C NMR
(75 MHz, CDCl3) d ppm: 9.4, 9.5, 12.1, 13.6, 22.7, 60.8,
72.8, 74.2, 74.9, 75.6, 77.1, 81.9.
To a solution of the above iodide (1.48 g, 5.09 mmol) in
benzene (5.00 mL) was added Ph3P (1.47 g, 5.09 mmol)
and re¯uxed for 24 h. The reaction mixture was concen-
trated under reduced pressure to give phosphonium iodide
7 (2.11 g, 75%) as a pale yellow oil. IR (neat) 2962,
(3Z,6Z,9Z)-Dodecatrien-1-ol (6). A solution of 3,6,9-
dodecatriyn-1-ol (5) (4.01 g, 23.0 mmol) in MeOH
(13.0 mL) containing quinoline (0.4 mL) was hydrogenated
at rt over 5% Pd±BaSO4 (1.3 g). The mixture was stirred at
rt under a balloon pressure of hydrogen for 3 h. The catalyst
was ®ltered through celite and the ®ltrate was concentrated
under reduced pressure. The residue was puri®ed by silica
gel column chromatography (eluted with hexane±EtOAcˆ
2:1) to give (3Z,6Z,9Z)-dodecatrien-1-ol (6) (3.14 g, 76%)
1
1587 cm21; H NMR (300 MHz, CD3OD) d ppm: 0.94
(3H, t, Jˆ7.6 Hz), 2.01 (2H, qdd, Jˆ7.6, 7.0, 0.8 Hz),
2.46 (2H, m), 2.68 (4H, m), 3.49 (2H, m), 5.16±5.55 (6H,
m), 7.80±7.95 (15H, m); 13C NMR (75 MHz, CD3OD) d
ppm: 14.7, 21.3, 21.4, 21.4, 22.9 (d, JP±Cˆ49.2 Hz), 26.4 (d,
JP±Cˆ9.6 Hz), 119.6 (d, JP±Cˆ85.5 Hz), 127.6 (d, JP±C
ˆ
ˆ
16.0 Hz), 128.0 (d, JP±Cˆ19.3 Hz), 129.6 (d, JP±C
7.0 Hz), 129.8 (d, JP±Cˆ9.2 Hz), 131.5 (d, JP±Cˆ12.4 Hz),
1
as a colorless oil. IR (neat) 3339, 2964, 1653 cm21; H
132.9, 134.5, 134.8 (d, JP±Cˆ10.3 Hz), 136.2 (d, JP±Cˆ
NMR (300 MHz, CDCl3) d ppm: 0.98 (3H, t, Jˆ7.6 Hz),
2.08 (2H, qd, Jˆ7.6, 6.9 Hz), 2.37 (2H, dt, Jˆ7.2, 6.6 Hz),
2.83 (4H, m), 3.65 (2H, m), 5.26±5.45 (5H, m), 5.54 (1H,
dtt, Jˆ10.7, 7.2, 1.4 Hz); 13C NMR (75 MHz, CDCl3) d
ppm: 14.0, 20.3, 25.2, 25.4, 30.5, 61.7, 125.5, 126.7,
127.5, 128.3, 130.2, 131.7; EIMS (m/z): 180 (M1, 10), 79
(100); HREIMS: Calcd for C12H20O (M1) 180.1514; Found:
180.1507.
3.0 Hz); FABMS (m/z): 425 (M12I, 100); HRFABMS:
Calcd for C30H34P (M12I): 425.2398; Found: 425.2400.
3-Methoxycarbonylpropyltriphenylphosphonium bromide
(9). To a solution of 4-bromobutyric acid (1.15 g,
6.89 mmol) in MeOH (7.00 mL) was added acetyl chloride
(0.12 mL) at 08C and the mixture was stirred at rt for 24 h.
The reaction mixture was concentrated under reduced
pressure to give crude methyl ester for use in the reaction
below without puri®cation. Colorless oil; IR (neat) 2953,
(3Z,6Z,9Z)-1-Dodecatrienyltriphenylphosphonium iodide
(7). To a solution of alcohol 6 (1.92 g, 10.6 mmol) in
CHCl3 (11.0 mL) were added pyridine (3.42 mL, 42.4
;
1737 cm21 1H NMR (300 MHz, CDCl3) d ppm: 2.18
(2H, tt, Jˆ7.1, 6.4 Hz), 2.51 (2H, t, Jˆ7.1 Hz), 3.47 (2H,

8088
H. Miyaoka et al. / Tetrahedron 56 (2000) 8083±8094
t, Jˆ6.4 Hz), 3.69 (3H, s); 13C NMR (75 MHz, CDCl3) d
ppm: 27.5, 32.0, 32.6, 51.5, 172.7; EIMS (m/z): 180 (M1, 1),
149 (M12OMe, 11), 43 (100).
LiAlH4 (10.4 g, 273 mmol) at 08C, followed by stirring for
10 min. The reaction mixture was diluted with Et2O, satu-
rated aqueous NaCl was added and the mixture was stirred
at rt for 3 h. The organic layer was dried over anhydrous
MgSO4 and concentrated under reduced pressure to give
crude alcohol for use in the reaction below without puri®-
cation. A portion of a crude alcohol was puri®ed for spectral
analysis by silica gel column chromatography (eluted with
hexane±EtOAcˆ2:1). Colorless oil; [a]Dˆ141.08 (cˆ1.00,
To a solution of the above crude ester in acetonitrile
(7.00 mL) was added Ph3P (1.80 g, 6.89 mmol), followed
by re¯uxing for 24 h. The reaction mixture was concen-
trated under reduced pressure to give crude phosphonium
bromide and recrystallized from acetonitrile±Et2O to give
phosphonium bromide 9 as white crystals. mp 166±1688C;
1
CHCl3); IR (neat) 3444, 2932 cm21; H NMR (300 MHz,
1
IR (KBr) 2886, 1719, 1587 cm21; H NMR (300 MHz,
CDCl3) d ppm: 1.77 (2H, m), 3.13 (1H, dd, Jˆ9.9, 4.4 Hz),
3.22 (1H, dd, Jˆ9.9, 6.0 Hz), 3.39 (3H, s), 3.70 (1H, m),
3.75 (1H, m), 3.93 (1H, m), 4.69 (1H, d, Jˆ6.6 Hz), 4.85
(1H, d, Jˆ6.6 Hz), 7.21±7.46 (15H, m); 13C NMR
(75 MHz, CDCl3) d ppm: 34.6, 55.7, 59.3, 66.3, 75.1,
86.7, 96.6, 127.0, 127.8, 128.6, 143.8; EIMS (m/z): 392
(M1, 0.1), 243 (100).
CD3OD) d ppm: 1.93 (2H, m), 2.62 (2H, td, Jˆ6.7,
1.1 Hz), 3.46 (2H, m), 3.70 (3H, s), 7.73±7.94 (15H, m);
13C NMR (75 MHz, CD3OD) d ppm: 19.2, 22.1 (d, JP±C
52.4 Hz), 34.2 (d, JP±Cˆ18.8 Hz), 52.3, 119.7 (d, JP±C
86.0 Hz), 131.6 (d, JP±Cˆ12.5 Hz), 134.9 (d, JP±C
ˆ
ˆ
ˆ
9.8 Hz), 136.4 (d, JP±Cˆ3.2 Hz), 174.4; FABMS (m/z):
363 (M12Br, 100).
To a solution of the above alcohol in DMF (253 mL) were
added imidazole (26.8 g, 394 mmol) and tert-butyldi-
methylsilyl chloride (TBDMS-Cl) (50.2 g, 333 mmol).
After stirring at rt for 3 h, the reaction mixture was diluted
with Et2O, washed with H2O and saturated aqueous NaCl,
dried over anhydrous MgSO4 and concentrated under
reduced pressure to give crude silyl ether for use in the
reaction below without puri®cation. A portion of a crude
silyl ether was puri®ed for spectral analysis by silica gel
column chromatography (eluted with hexane±EtOAcˆ
20:1). Colorless oil; [a]Dˆ118.08 (cˆ1.00, CHCl3); IR
Methyl (R)-3-hydroxy-4-(triphenylmethyl)oxybutyrate
(11). To a solution of diol 10 (9.90 g, 73.8 mmol) in DMF
(74.0 mL) were added Et3N (20.6 mL, 148 mmol), DMAP
(904 mg, 7.40 mmol) and chlorotriphenylmethane (26.7 g,
95.9 mmol) followed by stirring at 658C for 4 h. The reac-
tion mixture was diluted with Et2O, washed with H2O and
saturated aqueous NaCl, dried over anhydrous MgSO4 and
concentrated under reduced pressure. The residue was
puri®ed by silica gel column chromatography (eluted with
hexane±EtOAcˆ5:1) to give alcohol 11 (24.2 g, 67%) as
colorless crystals. [a]Dˆ13.68 (cˆ1.00, CHCl3); mp 75.5±
1
(neat) 2928 cm21; H NMR (300 MHz, CDCl3) d ppm:
76.58C; IR (KBr) 3527, 2928, 1733 cm21
;
1H NMR
0.01 (6H, s), 0.86 (9H, s), 1.76 (1H, d, Jˆ6.4 Hz), 1.80
(1H, d, Jˆ6.4 Hz), 3.15 (2H, d, Jˆ4.9 Hz), 3.34 (3H, s),
3.65 (2H, m), 3.89 (1H, m), 4.68 (1H, d, Jˆ6.7 Hz), 4.76
(1H, d, Jˆ6.7 Hz), 7.20±7.47 (15H, m); 13C NMR
(75 MHz, CDCl3) d ppm: 25.4, 18.2, 25.9, 35.6, 55.4,
59.4, 66.1, 73.7, 86.5, 96.1, 126.9, 127.7, 128.7, 144.0;
EIMS (m/z): 360 (M12TBDMS±OMe, 0.01), 243 (Tr1,
30), 45 (100); Anal. Calcd for C31H42O4Si: C, 73.48; H,
8.35. Found: C, 73.54; H, 8.40.
(300 MHz, CDCl3) d ppm: 2.53 (1H, dd, Jˆ16.2, 7.7 Hz),
2.57 (1H, dd, Jˆ16.2, 4.8 Hz), 3.17 (2H, d, Jˆ5.4 Hz), 3.68
(3H, s), 4.23 (1H, ddd, Jˆ7.7, 5.4, 4.8 Hz), 7.22±7.45 (15H,
m); 13C NMR (75 MHz, CDCl3) d ppm: 38.3, 51.7, 66.5,
67.5, 86.7, 127.0, 127.8, 128.6, 143.6, 172.6; EIMS (m/z):
376 (M1, 4.0), 328 (M1±MeOH, 18), 243 (100); Anal. Calcd
for C24H24O4: C, 76.57; H, 6.43. Found: C, 76.76; H, 6.43.
(R)-4-(tert-Butyldimethylsilyl)oxy-2-(methoxymethyl)-
oxybutan-1-ol (12). To a solution of alcohol 11 (114 g,
303 mmol) in CHCl3 (303 mL) were added N,N-diisopropyl-
ethylamine (79.2 mL, 455 mmol) and chloromethyl methyl
ether (27.6 mL, 364 mmol). The mixture was stirred at 508C
for 24 h, diluted with Et2O, washed with H2O and saturated
aqueous NaCl, dried over anhydrous MgSO4 and concen-
trated under reduced pressure to give crude ether for use in
the reaction below without puri®cation. A portion of a crude
ether was puri®ed for spectral analysis by silica gel column
chromatography (eluted with hexane±EtOAcˆ5:1). Color-
less oil; [a]Dˆ120.98 (cˆ1.00, CHCl3); IR (neat) 2950,
To a cold solution of the above trityl ether in THF (640 mL)
and EtOH (80 mL) was introduced liquid NH3 and sodium
(ca. 8 g) was added at 2788C. The mixture was warmed to
2348C, stirred for 30 min, NH4Cl was added then and
removed with NH3. The reaction mixture was diluted with
Et2O, washed with H2O and saturated aqueous NaCl, dried
over anhydrous MgSO4 and concentrated under reduced
pressure. The residue was puri®ed by silica gel column
chromatography (eluted with hexane±EtOAcˆ4:1) to give
alcohol 12 (75.0 g, 94%, 4 steps) as a colorless oil. [a]Dˆ
1
221.48 (cˆ1.00, CHCl3); IR (neat) 3436, 2931 cm21; H
1740 cm21
;
1H NMR (300 MHz, CDCl3) d ppm: 2.61
NMR (300 MHz, CDCl3) d ppm: 0.05 (6H, s), 0.89 (9H,
s), 1.71 (2H, m), 3.32 (1H, dd, Jˆ8.6, 4.5 Hz), 3.42 (3H, s),
3.56 (1H, ddd, Jˆ11.9, 6.6, 4.5 Hz), 3.62 (1H, ddd, Jˆ11.9,
8.6, 3.3 Hz), 3.71 (2H, m), 3.77 (1H, m), 4.69 (1H, d,
Jˆ6.8 Hz), 4.72 (1H, d, Jˆ6.8 Hz); 13C NMR (75 MHz,
CDCl3) d ppm: 25.8, 17.8, 25.6, 34.5, 55.0, 58.8, 65.1,
77.8, 96.4; EIMS (m/z): 233 (M12MeOH, 0.6), 45 (100);
Anal. Calcd for C12H28O4Si: C, 54.51; H, 10.67. Found: C,
54.48; H, 10.56.
(1H, dd, Jˆ15.6, 7.6 Hz), 2.63 (1H, dd, Jˆ15.6, 5.2 Hz),
3.16 (1H, dd, Jˆ9.7, 5.3 Hz), 3.24 (1H, dd, Jˆ5.3, 4.4 Hz),
3.27 (3H, s), 3.66 (3H, s), 4.18 (1H, m), 4.65 (1H, d,
Jˆ6.9 Hz), 4.66 (1H, d, Jˆ6.9 Hz), 7.20±7.47 (15H, m);
13C NMR (75 MHz, CDCl3) d ppm: 37.9, 51.4, 55.4, 65.1,
73.4, 86.6, 96.1, 126.9, 127.7, 128.5, 143.7, 171.6; EIMS
(m/z): 420 (M1, 0.5), 388 (M12MeOH, 0.3), 243 (100);
Anal. Calcd for C26H28O5: C, 74.26; H, 6.71. Found: C,
74.24; H, 6.74.
(E)-(R)-6-(tert-Butyldimethylsilyl)oxy-4-(methoxymethyl)-
oxy-2-hexen-1-ol (13). To a cold (2788C) solution of
To a solution of the above ester in Et2O (1.52 L) was added

H. Miyaoka et al. / Tetrahedron 56 (2000) 8083±8094
8089
oxalyl chloride (17.7 mL, 197 mmol) in CH2Cl2 (400 mL)
was added DMSO (17.5 mL, 246 mmol) in CH2Cl2
(32.0 mL). The mixture was stirred at 2788C for 15 min,
treated with a solution of alcohol 12 (13.0 g, 49.2 mmol) in
CH2Cl2 (60.0 mL) and stirred for 15 min and then with Et3N
(41.1 mL, 295 mmol). The mixture was stirred for 15 min,
warmed to rt and stirred for 20 min. The reaction mixture
was diluted with Et2O±benzene (5:1), washed with H2O,
saturated aqueous NaHCO3 and saturated aqueous NaCl,
dried over anhydrous MgSO4 and concentrated under
reduced pressure to give crude aldehyde for use in the
reaction below without puri®cation. A portion of a crude
aldehyde was puri®ed for spectral analysis by silica gel
column chromatography (eluted with hexane±EtOAcˆ
3:1). Colorless oil; [a]Dˆ19.18 (cˆ1.20, CHCl3); IR
Jˆ6.2, 1.4 Hz), 4.23 (1H, dd, Jˆ13.6, 7.8 Hz), 4.54 (1H, d,
Jˆ6.6 Hz), 4.69 (1H, d, Jˆ6.6 Hz), 5.60 (1H, ddt, Jˆ15.6,
7.8, 1.4 Hz), 5.82 (1H, dtd, Jˆ15.6, 5.3, 0.8 Hz); 13C NMR
(75 MHz, CDCl3) d ppm: 25.5, 18.0, 25.7, 38.6, 55.1, 59.0,
62.1, 73.1, 93.5, 130.4, 132.3; EIMS (m/z): 245 (M12
MOM, 2), 89 (100).
(2R,3R,4R)-6-(tert-Butyldimethylsilyl)oxy-2,3-epoxy-4-
(methoxymethyl)oxy-1-{[40-methoxyphenyl)methyl]oxy}-
Ê
hexane (14). A mixture of powdered 4 A molecular sieves
(300 mg) and CH2Cl2 (7.80 mL) was cooled to 2208C and
then to which were added of Ti(OiPr)4 (0.117 mL,
0.40 mmol) and d-(2)-diethyl tartrate (DET) (103 mg,
0.50 mmol). After stirring for 30 min, tert-butyl hydro-
peroxide (TBHP) (1.20 mL, 3.60 mmol, 3.0 M in CH2Cl2)
was added, followed by stirring for 30 min and the addition
of allylic alcohol 13 (585 mg, 1.95 mmol) in CH2Cl2
(1.20 mL). Stirring was continued at 2208C for 5 h. The
reaction mixture was warmed to 08C, water (2.0 mL) was
added and the mixture was stirred for 1 h. Aqueous solution
of NaOH (30%) saturated with NaCl (0.50 mL) was added
and the mixture was stirred vigorously. After 1 h stirring,
the mixture was ®ltered through celite. The ®ltrate was
diluted with Et2O, washed with 1N NaOH, H2O and
saturated aqueous NaCl, dried over anhydrous MgSO4 and
concentrated under reduced pressure. The residue was
puri®ed by silica gel column chromatography (eluted with
hexane±EtOAcˆ2:1) to give epoxy alcohol (552 mg, 89%)
as a colorless oil. [a]Dˆ19.68 (cˆ1.00, CHCl3); IR (neat)
1
(neat) 2929, 1736 cm21; H NMR (300 MHz, CDCl3) d
ppm: 0.04 (6H, s), 0.89 (9H, s), 1.92 (2H, m), 3.42 (3H,
s), 3.74 (2H, m), 4.11 (1H, d, Jˆ6.8 Hz), 4.72 (1H, d, Jˆ
6.8 Hz), 4.73 (1H, d, Jˆ6.8 Hz), 9.67 (1H, d, Jˆ1.6 Hz);
13C NMR (75 MHz, CDCl3) d ppm: 25.6, 25.5, 18.1, 25.6,
33.7, 55.8, 57.9, 79.4, 79.4, 96.7, 202.5; EIMS (m/z): 233
(M12CHO, 3), 45 (100).
To a solution of ethyl diisopropylphosphonoacetate (37.2 g,
148 mmol) in THF (200 mL) was added BuOK (13.8 g,
t
123 mmol) at 08C. The mixture was warmed to rt, stirred
for 45 min, cooled to 2788C and to which a solution of the
above crude aldehyde in THF (46.0 mL) was added
followed by warming to 2428C and stirring for 30 min.
The reaction mixture was diluted with Et2O, washed with
saturated aqueous NH4Cl, H2O and saturated aqueous NaCl,
dried over anhydrous MgSO4 and concentrated under
reduced pressure to give crude ester for use in the reaction
below without puri®cation. A portion of a crude ester was
puri®ed for spectral analysis by silica gel column chroma-
tography (eluted with hexane±EtOAcˆ7:1). Colorless oil;
[a]Dˆ143.38 (cˆ1.00, CHCl3); UV (EtOH):lmax 208 nm
(e 10800); IR (neat) 2931, 1724 cm21; 1H NMR (300 MHz,
CDCl3) d ppm: 0.05 (6H, s), 0.89 (9H, s), 1.29 (3H, t,
Jˆ7.1 Hz), 1.78 (2H, m), 3.38 (3H, s), 3.70 (2H, m), 4.17
(1H, d, Jˆ7.2 Hz), 4.21 (1H, d, Jˆ7.2 Hz), 4.40 (1H, dd,
Jˆ12.7, 6.3 Hz), 4.61 (1H, d, Jˆ6.8 Hz), 4.63 (1H, d,
Jˆ6.8 Hz), 5.99 (1H, dd, Jˆ15.7, 1.3 Hz), 6.85 (1H, d,
Jˆ15.7, 6.3 Hz); 13C NMR (75 MHz, CDCl3) d ppm:
25.7, 13.9, 17.8, 25.5, 37.9, 55.1, 58.5, 59.9, 72.0, 94.5,
121.3, 147.7, 165.6; EIMS (m/z): 275 (M12tBu, 2), 45
(100); Anal. Calcd for C16H32O5Si: C, 57.80; H, 9.70.
Found: C, 57.70; H, 9.61.
1
3451, 2930, 1256 cm21; H NMR (300 MHz, CDCl3) d
ppm: 0.05 (6H, s), 0.88 (9H, s), 1.76 (1H, ddt, Jˆ14.0,
8.4, 5.3 Hz), 1.88 (1H, ddd, Jˆ14.0, 7.4, 4.2 Hz), 2.96
(1H, dd, Jˆ5.9, 2.2 Hz), 3.15 (1H, dt, Jˆ3.8, 2.2 Hz),
3.38 (3H, s), 3.58 (1H, ddd, Jˆ8.4, 5.9, 4.2 Hz), 3.71 (1H,
dt, Jˆ12.4, 3.8 Hz), 3.75 (2H, dt, Jˆ7.4, 5.3 Hz), 3.80 (1H,
ddd, Jˆ12.4, 4.7, 3.8 Hz), 4.66 (1H, d, Jˆ6.9 Hz), 4.69 (1H,
d, Jˆ6.9 Hz); 13C NMR (75 MHz, CDCl3) d ppm: 25.5,
25.5, 18.1, 25.9, 35.7, 55.4, 57.1, 57.2, 58.7, 61.5, 73.7,
96.4; EIMS (m/z): 249 (M1±tBu, 4), 157 (100); Anal.
Calcd for C14H30O5Si: C, 54.87; H, 9.87. Found: C, 54.90;
H, 9.74.
To a cold (08C) solution of the above epoxy alcohol (5.20 g,
17.0 mmol) in THF (68.0 mL) and DMF (17.0 mL) were
added 4-methoxybenzyl bromide (3.85 mL, 18.7 mmol)
and NaH (884 mg, 22.1 mmol, 60%). The mixture was
stirred at 08C for 1 h, diluted with Et2O, washed with
saturated aqueous NaHCO3, H2O and saturated aqueous
NaCl, dried over anhydrous MgSO4 and concentrated
under reduced pressure. The residue was puri®ed by silica
gel column chromatography (eluted with hexane±EtOAcˆ
10:1) to give MPM ether 14 (6.92 g, 95%) as a colorless oil.
To a cold (2788C) solution of the above crude ester in
toluene (246 mL) was added DIBAL-H (124 mL,
118 mmol, 0.95 M in hexane). The mixture was stirred for
30 min, treated with MeOH (20 mL), diluted with Et2O,
treated with saturated aqueous NaCl and stirred at rt for
5 h. The organic layer was dried over anhydrous MgSO4
and concentrated under reduced pressure. The residue was
puri®ed by silica gel column chromatography (eluted with
hexane±EtOAcˆ2:1) to give allylic alcohol 13 (12.7 g,
89%, 3 steps) as a colorless oil. [a]Dˆ158.38 (cˆ1.00,
[a]Dˆ122.88 (cˆ1.00, CHCl3); IR (neat) 2953, 1250 cm21
;
1H NMR (300 MHz, CDCl3) d ppm: 0.04 (6H, s), 0.88 (9H,
s), 1.75 (1H, ddt, Jˆ14.1, 8.5, 5.3 Hz), 1.85 (1H, m), 2.88
(1H, dd, Jˆ5.5, 2.2 Hz), 3.18 (1H, dt, Jˆ5.8, 2.2 Hz), 3.34
(3H, s), 3.42 (1H, dd, Jˆ11.5, 5.7 Hz), 3.61 (1H, m), 3.72
(1H, m), 3.76 (2H, dd, Jˆ7.2, 2.1 Hz), 3.80 (3H, s), 4.49
(1H, d, Jˆ11.5 Hz), 4.52 (1H, d, Jˆ11.5 Hz), 4.62 (1H, d,
Jˆ6.7 Hz), 4.68 (1H, d, Jˆ6.7 Hz), 6.88 (2H, m), 7.26 (2H,
m); 13C NMR (75 MHz, CDCl3) d ppm: 25.5, 25.5, 18.1,
25.8, 35.7, 55.0, 55.3, 55.7, 56.7, 58.7, 69.4, 72.7, 73.2,
96.3, 113.6, 129.2, 129.8, 159.1; EIMS (m/z): 395
1
CHCl3); IR (neat) 3422, 2930 cm21; H NMR (300 MHz,
CDCl3) d ppm: 0.04 (6H, s), 0.89 (9H, s), 1.71 (1H, m), 1.83
(1H, tt, Jˆ13.6, 6.0 Hz), 3.36 (3H, s), 3.67 (1H, td, Jˆ10.2,
6.0 Hz), 3.71 (1H, ddd, Jˆ10.2, 7.0, 6.0 Hz), 4.16 (2H, td,

8090
H. Miyaoka et al. / Tetrahedron 56 (2000) 8083±8094
(M12OMe, 5), 369 (M12tBu, 5), 121 (100); Anal. Calcd
for C22H38O6Si: C, 61.94; H, 8.98. Found: C, 61.84; H,
8.93.
puri®ed by silica gel column chromatography (eluted with
hexane±EtOAcˆ2:1) to give cyclopentane 16 (11.6 g, 99%)
as a colorless oil. [a]Dˆ274.48 (cˆ1.00, CHCl3); IR (neat)
1
2935, 1295, 1142 cm21; H NMR (300 MHz, CDCl3) d
(2R,3R,4R)-2,3-Epoxy-4-(methoxymethyl)oxy-1-{[(40-
methoxyphenyl)methyl]oxy}hexyl-6-methanesulfonate
(15). To a solution of TBDMS ether 14 (4.45 g, 9.96 mmol)
in THF (10.0 mL) was added tetrabutylammonium ¯uoride
(TBAF) (12.0 mL, 12.0 mmol, 1.0 M in THF). After stirring
at rt for 1 h, the reaction mixture was diluted with Et2O,
washed with H2O and saturated aqueous NaCl, dried over
anhydrous MgSO4 and concentrated under reduced pressure
to give crude alcohol for use in the reaction below without
puri®cation. A portion of a crude alcohol was puri®ed for
spectral analysis by silica gel column chromatography
(eluted with hexane±EtOAcˆ1:1). Colorless oil; IR (neat)
ppm: 1.84 (1H, m), 1.93 (1H, m), 2.25 (1H, ddd, Jˆ14.1,
11.8, 6.8 Hz), 2.36 (1H, ddd, Jˆ14.1, 7.4, 2.2 Hz), 3.15 (1H,
dd, Jˆ4.6, 3.6 Hz), 3.28 (3H, s), 3.60 (2H, d, Jˆ6.0 Hz),
3.81 (3H, s), 4.05 (1H, m), 4.47 (1H, d, Jˆ11.5 Hz), 4.50
(1H, d, Jˆ6.9 Hz), 4.56 (1H, d, Jˆ6.9 Hz), 4.57 (1H, d,
Jˆ11.5 Hz), 4.59 (1H, m), 5.11 (1H, d, Jˆ17.3 Hz), 5.37
(1H, d, Jˆ10.7 Hz), 6.42 (1H, dd, Jˆ17.3, 10.7 Hz), 6.90
(2H, m), 7.31 (2H, m), 7.45 (2H, m), 7.61 (1H, m), 7.81 (2H,
m); 13C NMR (75 MHz, CDCl3) d ppm: 30.0, 30.3, 48.5,
55.1, 56.0, 69.3, 72.6, 72.9, 74.9, 82.2, 95.1, 113.6, 119.9,
128.2, 129.4, 130.1, 130.7, 133.5, 134.4, 135.2, 159.0;
EIMS (m/z): 476 (M1, 3), 444 (M12OMe, 10), 121
(100); HREIMS: Calcd for C25H32O7S (M1) 476.1869:
Found: 476.1886.
1
3446, 2937, 1250 cm21; H NMR (300 MHz, CDCl3) d
ppm: 1.85 (1H, ddt, Jˆ14.4, 8.1, 5.5 Hz), 1.91 (1H, m),
2.90 (1H, dd, Jˆ5.5, 2.2 Hz), 3.21 (1H, m), 3.37 (3H, s),
3.47 (1H, dd, Jˆ11.5, 5.5 Hz), 3.68 (2H, dt, Jˆ8.1, 4.9 Hz),
3.73 (2H, dd, Jˆ11.5, 3.0 Hz), 3.80 (3H, s), 4.49 (1H, d,
Jˆ11.6 Hz), 4.50 (1H, d, Jˆ11.6 Hz), 4.50 (1H, d, Jˆ
6.8 Hz), 4.62 (1H, d, Jˆ6.8 Hz), 6.88 (2H, m), 7.26 (2H,
m); 13C NMR (75 MHz, CDCl3) d ppm: 35.0, 55.1, 55.5,
55.7, 56.4, 58.9, 69.2, 72.8, 74.3, 96.2, 113.6, 129.2, 129.7,
159.1.
(1S,4S,5S,6R)-6-(Methoxymethyl)oxy-4-{[(40-methoxy-
phenyl)methyl]oxy}methyl-3-oxabicyclo[3.3.0]octan-2-
one (17). To a solution of cyclopentane 16 (2.80 g,
5.58 mmol) in 1,4-dioxane (29 mL) and H2O (29 mL)
were added OsO4 (14 mg, 55.8 mmol) and NaIO4 (5.03 g,
23.6 mmol) over 2 h. After stirring for 24 h, the reaction
mixture was diluted with EtOAc, washed with H2O and
saturated aqueous NaCl, dried over anhydrous MgSO4 and
concentrated under reduced pressure to give a crude ano-
meric mixture of hemiacetals (about 10:1) for use in the
reaction below without puri®cation. A portion of a crude
hemiacetal was puri®ed for spectral analysis by silica gel
column chromatography (eluted with hexane±EtOAcˆ3:2).
Colorless oil; IR (neat) 3436, 2939, 1303, 1145 cm21; EIMS
To a cold (08C) solution of the above crude alcohol in
CH2Cl2 (50.0 mL) was added 4-N,N-dimethylaminopyri-
dine (DMAP) (1.90 g, 15.9 mmol). After stirring for
10 min, methanesulfonyl chloride (1.00 mL, 12.9 mmol)
was added and stirred for 15 min. The reaction mixture
was diluted with Et2O, washed with H2O and saturated
aqueous NaCl, dried over anhydrous MgSO4 and concen-
trated under reduced pressure. The residue was puri®ed by
silica gel column chromatography (eluted with hexane±
EtOAcˆ1:1) to give mesylate 15 (3.89 g, quantitative
yield) as a colorless oil. [a]Dˆ124.78 (cˆ1.00, CHCl3);
1
(m/z): 478 (M1, 2.5), 121 (100); major isomer: H NMR
(300 MHz, CDCl3) d ppm: 1.78 (1H, dtd, Jˆ13.2, 9.9,
3.3 Hz), 2.08 (1H, m), 2.89 (2H, m), 3.29 (1H, m), 3.31
(3H, s), 3.71 (1H, dd, Jˆ9.6, 6.0 Hz), 3.76 (1H, dd, Jˆ
9.6, 6.6 Hz), 3.80 (3H, s), 4.25 (1H, m), 4.26 (1H, m),
4.37 (1H, d, Jˆ6.4 Hz), 4.40 (1H, d, Jˆ6.8 Hz), 4.53 (1H,
d, Jˆ6.8 Hz), 4.57 (1H, d, Jˆ6.8 Hz), 5.61 (1H, d, Jˆ
11.6 Hz), 6.87 (2H, m), 7.23 (2H, m), 7.57 (2H, m), 7.68
(1H, m), 7.94 (2H, m); 13C NMR (75 MHz, CDCl3) d ppm:
25.5, 34.2, 52.7, 55.3, 56.5, 69.4, 72.9, 77.8, 81.1, 83.6,
96.1, 98.2, 113.8, 129.3, 129.4, 129.5, 129.9, 134.2, 136.5,
159.3.
1
IR (neat) 2937, 1248 cm21; H NMR (300 MHz, CDCl3)
d ppm: 2.00 (1H, ddt, Jˆ14.5, 8.5, 5.5 Hz), 2.11 (1H, m),
2.87 (1H, dd, Jˆ6.0, 2.2 Hz), 3.00 (3H, s), 3.17 (1H, m),
3.35 (3H, s), 3.45 (1H, dd, Jˆ11.5, 5.5 Hz), 3.54 (1H, ddd,
Jˆ8.5, 6.0, 4.1 Hz), 3.73 (1H, dd, Jˆ11.5, 2.8 Hz), 3.80
(3H, s), 4.38 (2H, m), 4.49 (1H, d, Jˆ11.8 Hz), 4.50 (1H,
d, Jˆ11.8 Hz), 4.61 (1H, d, Jˆ6.9 Hz), 4.79 (1H, d, Jˆ
6.9 Hz), 6.88 (2H, m), 7.26 (2H, m); 13C NMR (75 MHz,
CDCl3) d ppm: 32.1, 37.1, 55.1, 55.5, 56.0, 56.0, 65.9, 68.9,
72.7, 72.8, 96.2, 113.6, 129.2, 129.6, 159.1; EIMS (m/z):
390 (M1, 2), 121 (100); HREIMS: Calcd for C17H26O8S
(M1) 390.1348: Found: 390.1344.
To a cold (08C) solution of the above hemiacetal in acetone
(50.0 mL) was added Jones reagent (3.0 mL), followed by
stirring for 10 min and treatment with 2-propanol (3.0 mL).
After stirring for 15 min, the reaction mixture was diluted
with Et2O, washed with H2O, saturated aqueous NaHCO3
and saturated aqueous NaCl, dried over anhydrous MgSO4
and concentrated under reduced pressure. The residue was
puri®ed by silica gel column chromatography (eluted with
hexane±EtOAcˆ2:1) to give lactone (2.40 g, 82%, 2 steps)
as a colorless oil. [a]Dˆ215.68 (cˆ1.00, CHCl3); IR (neat)
2942, 1768, 1309, 1147 cm21; 1H NMR (300 MHz, CDCl3)
d ppm: 2.15 (1H, m), 2.30 (1H, m), 3.24 (3H, s), 3.59 (1H,
dd, Jˆ6.8, 4.3 Hz), 3.81 (3H, s), 3.86 (1H, dd, Jˆ10.6,
5.0 Hz), 4.00 (1H, dd, Jˆ10.6, 5.0 Hz), 4.35 (1H, m), 4.47
(1H, d, Jˆ7.0 Hz), 4.48 (1H, d, Jˆ11.8 Hz), 4.51 (1H, d,
Jˆ7.0 Hz), 4.57 (1H, d, Jˆ11.8 Hz), 5.07 (1H, dt, Jˆ6.8,
5.0 Hz), 6.90 (2H, m), 7.26 (2H, m), 7.59 (2H, m), 7.72 (1H,
(1S,10S,2S,3R)-2-{10-Hydroxy-20-[400-(methoxyphenyl)-
methyl]oxy}ethyl-3-(methoxymethyl)oxy-1-phenylsulfonyl-
1-vinylcyclopentane (16). To a cold (2788C) solution of
allyl phenyl sulfone (9.40 g, 61.5 mmol) in THF (206 mL)
was added BuLi (40.2 mL, 59.0 mmol, 1.47 M in hexane).
The mixture was stirred at 2788C for 30 min, treated with a
solution of epoxy mesylate 15 (9.60 g, 24.6 mmol) in THF
(20.0 mL), stirred for 30 min, warmed to rt over 3 h and then
stirred at rt for 3 h. The reaction mixture was diluted with
Et2O, washed with saturated aqueous NH4Cl, H2O and
saturated aqueous NaCl, dried over anhydrous MgSO4 and
concentrated under reduced pressure. The residue was

H. Miyaoka et al. / Tetrahedron 56 (2000) 8083±8094
8091
m), 7.92 (2H, m); 13C NMR (75 MHz, CDCl3) d ppm: 29.7,
32.3, 51.1, 54.8, 55.9, 67.9, 72.5, 77.7, 79.5, 79.9, 94.9,
113.4, 128.7, 129.1, 129.4, 129.9, 134.4, 134.9, 128.9,
171.4; EIMS (m/z): 476 (M1, 6), 431 (M12MOM, 70),
121 (100); Anal. Calcd for C24H28O8S: C, 60.49; H, 5.92.
Found: C, 60.34; H, 6.05.
silica gel column chromatography (eluted with hexane±
EtOAcˆ1:1) to give aldehyde 18 (79.0 mg, quantitative
yield) as a colorless oil. [a]Dˆ2118.38 (cˆ0.46, CHCl3);
IR (neat) 2948, 1768, 1730 cm21 1H NMR (300 MHz,
;
CDCl3) d ppm: 1.60 (1H, m), 2.05±2.27 (3H, m), 3.23
(1H, m), 3.31 (3H, s), 3.36 (1H, m), 4.12 (1H, td, Jˆ3.9,
0.9 Hz), 4.47 (1H, d, Jˆ7.0 Hz), 4.58 (1H, d, Jˆ7.0 Hz),
4.75 (1H, d, Jˆ7.3 Hz), 9.86 (1H, s); 13C NMR (75 MHz,
CDCl3) d ppm: 24.9, 31.2, 43.3, 50.7, 56.3, 77.9, 80.2, 95.2,
178.8, 200.3; EIMS (m/z): 185 (M12CHO, 8), 169
(M12MOM, 12), 45 (100); HREIMS: Calcd for C10H15O5
(M111) 215.0919: Found: 215.0911.
To a solution of the above lactone (2.50 g, 5.25 mmol) in
MeOH (105 mL) were added NaH2PO4 (5.00 g) and 5%
Na±Hg (6.90 g). After stirring at rt for 30±min, the reaction
mixture was diluted with EtOAc and ®ltered through silica
gel. The ®ltrate was concentrated under reduced pressure.
The residue was puri®ed by silica gel column chroma-
tography (eluted with hexane±EtOAcˆ1:1) to give lactone
17 (1.60 g, 91%) as a colorless oil. [a]Dˆ233.88 (cˆ1.00,
Bacillariolide II (2). To a cold (08C) suspension of
phosphonium iodide 7 (17.7 mg, 321 mmol) in THF
(0.80 mL) was added BuLi (146 mL, 214 mmol, 1.47 M in
hexane). The mixture was stirred at 08C for 20 min to give
Wittig reagent. To a cold (2788C) solution of aldehyde 18
(23.0 mg, 107 mmol) and HMPA (186 mL, 1.07 mmol) in
THF (4.60 mL) was added the above prepared Wittig
reagent and stirred at 2788C for 10 min. The reaction
mixture was diluted with Et2O, washed with H2O and
saturated aqueous NaCl, dried over anhydrous MgSO4 and
concentrated under reduced pressure. The residue was
puri®ed by preparative silica gel TLC (developed with
hexane±EtOAcˆ3:1, Rf 0.3) to give 5-O-methoxymethyl-
bacillariolide II (25.6 mg, 66%) as a colorless oil. [a]Dˆ
1
CHCl3); IR (neat) 2937, 1768 cm21; H NMR (300 MHz,
CDCl3) d ppm: 1.50 (1H, m), 2.09 (2H, m), 2.18 (1H, br t,
Jˆ4.1 Hz), 2.76 (1H, ddd, Jˆ9.8, 6.1, 3.9 Hz), 3.12 (1H,
m), 3.29 (3H, s), 3.80 (3H, s), 3.86 (1H, dd, Jˆ10.6, 4.5 Hz),
4.03 (1H, dd, Jˆ10.6, 6.7 Hz), 4.14 (1H, m), 4.47 (1H, d,
Jˆ11.5 Hz), 4.49 (1H, d, Jˆ6.9 Hz), 4.57 (1H, d, Jˆ
6.9 Hz), 4.58 (1H, d, Jˆ11.5 Hz), 4.76 (1H, td, Jˆ6.7,
4.5 Hz), 6.88 (2H, m), 7.27 (2H, m); 13C NMR (75 MHz,
CDCl3) d ppm: 29.7, 32.3, 51.1, 54.8, 55.9, 67.9, 72.5, 77.7,
79.5, 79.9, 94.9, 113.4, 128.7, 129.1, 129.4, 129.9, 134.4,
134.9, 128.9, 171.4; EIMS (m/z): 336 (M1, 2), 291 (M12
MOM, 90), 121 (100); Anal. Calcd for C18H24O6: C, 64.27;
H, 7.19. Found: C, 64.02; H, 7.18.
1
261.58 (cˆ0.33, CHCl3); IR (neat) 2957, 1767 cm21; H
NMR (400 MHz, CDCl3) d ppm: 0.98 (3H, t, Jˆ7.5 Hz),
1.51 (1H, m), 2.08 (2H, qdd, Jˆ7.5, 7.5, 0.7 Hz), 2.15 (3H,
m), 2.75±2.92 (7H, m), 3.13 (1H, m), 3.36 (3H, s), 4.10 (1H,
br t, Jˆ3.3 Hz), 4.58 (1H, d, Jˆ7.0 Hz), 4.65 (1H, d,
Jˆ7.0 Hz), 5.27±5.48 (7H, m), 5.62 (1H, dtd, Jˆ11.0,
7.5, 1.5 Hz), 5.91 (1H, ddt, Jˆ11.0, 7.7, 1.5 Hz); 13C
NMR (100 MHz, CDCl3) d ppm: 14.2, 20.6, 24.6, 25.5,
25.6, 26.2, 32.3, 44.2, 51.1, 56.3, 75.5, 78.9, 95.4, 126.6,
126.8, 127.0, 127.4, 128.8, 129.1, 131.5, 132.1, 179.8;
EIMS (m/z): 360 (M1, 0.04), 315 (M12MOM, 2), 45
(100); HREIMS: Calcd for C20H27O3 (M12MOM)
315.1960; Found: 315.1972.
(1S,4S,5S,6R)-4-Formyl-6-(methoxymethyl)oxy-3-oxabi-
cyclo[3.3.0]octan-2-one (18). To a solution of MPM ether
17 (764 mg, 2.27 mmol) in acetonitrile±H2O (9:1)
(23.0 mL) was added CAN (1.87 g, 3.41 mmol) followed
by stirring at rt for 1 h. The reaction mixture was diluted
with CHCl3, washed with H2O and saturated aqueous NaCl,
dried over anhydrous MgSO4 and concentrated under
reduced pressure. The residue was puri®ed by silica gel
column chromatography (eluted with hexane±acetoneˆ1:1)
to give alcohol (430 mg, 88%) as white crystals. mp 115±
1178C; [a]Dˆ21.18 (cˆ1.00, CHCl3); IR (KBr) 3446,
1
2955, 1762 cm21; H NMR (300 MHz, CDCl3) d ppm:
1.60 (1H, m), 2.10 (3H, m), 2.81 (1H, ddd, Jˆ9.6, 6.4,
4.6 Hz), 3.17 (1H, m), 3.36 (3H, s), 3.92 (1H, ddd, Jˆ
12.1, 8.0, 4.1 Hz), 4.20 (1H, m), 4.27 (1H, ddd, Jˆ12.1,
7.5, 4.4 Hz), 4.60 (1H, d, Jˆ6.8 Hz), 4.64 (1H, d, Jˆ
6.8 Hz), 4.71 (1H, td, Jˆ7.5, 4.1 Hz); 13C NMR (75 MHz,
CDCl3) d ppm: 23.8, 32.1, 44.3, 47.2, 56.0, 61.5, 78.6, 78.7,
81.3, 94.9, 180.0; EIMS (m/z): 217 (M111, 0.2), 185
(M12MeOH, 9), 45 (100); Anal. Calcd for C10H16O5:C,
55.55; H, 7.46. Found: C, 55.33; H, 7.75.
A mixture of AcOH and conc.HCl (50:1) (810 mL) was
added to 5-O-methoxymethylbacillariolide II (29.2 mg,
81.0 mmol) and stirred at 408C for 6 h. The reaction mixture
was diluted with Et2O, washed with saturated aqueous
NaHCO3, H2O and saturated aqueous NaCl, dried over
anhydrous MgSO4 and concentrated under reduced pres-
sure. The residue was puri®ed by preparative silica gel
TLC (developed with hexane±EtOAcˆ2:1, Rf 0.3) to give
bacillariolide II (2) (24.8 mg, 97%) as a colorless oil.
[a]Dˆ258.58 (cˆ0.33, MeOH); IR (CHCl3) 3528, 2964,
1
To a cold (2788C) solution of oxalyl chloride (129 mL,
1.48 mmol) in CH2Cl2 (2.0 mL) was added DMSO
(131 mL, 1.85 mmol) in CH2Cl2 (300 mL). The mixture
was stirred at 2788C for 15 min, treated with a solution of
the above alcohol (80.0 mg, 370 mmol) in CH2Cl2
(1.40 mL) and stirred for 15 min and then with Et3N
(309 mL, 2.22 mmol). The mixture was stirred for 15 min
and warmed to rt and stirred for 20 min. The reaction
mixture was diluted with Et2O±benzene (5:1), washed
with H2O, saturated aqueous NaHCO3 and saturated
aqueous NaCl, dried over anhydrous MgSO4 and concen-
trated under reduced pressure. The residue was puri®ed by
1763 cm21; H NMR (300 MHz, CD3OD) d ppm: 0.97
(3H, t, Jˆ7.5 Hz), 1.65 (1H, m), 1.82 (1H, m), 2.0±2.2
(4H, m), 2.77 (1H, ddd, Jˆ9.3, 6.0, 3.5 Hz), 2.83 (2H, t,
Jˆ5.8 Hz), 2.88 (2H, t, Jˆ5.7 Hz), 2.95 (2H, m), 3.19 (1H,
dt, Jˆ5.1, 9.5 Hz), 4.21 (1H, t, Jˆ3.0 Hz), 5.25±5.35 (6H,
m), 5.50 (1H, m), 5.64 (1H, ddt, Jˆ11.0, 1.4, 7.6 Hz), 6.05
(1H, ddt, Jˆ11.0, 8.3, 1.6 Hz); 13C NMR (75 MHz, CD3OD)
d ppm: 14.7, 21.5, 25.5, 26.4, 26.5, 27.0, 36.9, 45.3, 52.6,
73.4, 77.7, 127.5, 128.1, 128.4, 128.8, 129.6, 129.9,
132.9, 133.1, 183.6; EIMS (m/z): 316 (M1,0.01), 67 (100);
HREIMS: Calcd for C20H28O3 (M1) 316.2038; Found:
316.2034.

8092
H. Miyaoka et al. / Tetrahedron 56 (2000) 8083±8094
(1S,2S,4S,5S,6R)-2-Methoxy-6-(methoxymethyl)oxy-4-
{[(400-methoxyphenyl)methyl]oxy}methyl-3-oxabicyclo-
[3.3.0]octane (19). To a cold (2788C) solution of lactone 17
(1.60 g, 4.76 mmol) in toluene (48.0 mL) was added
DIBAL-H (5.51 mL, 5.24 mmol, 0.95 M in hexane). The
mixture was stirred for 1 h, treated with MeOH (1.0 mL),
diluted with Et2O, treated with saturated aqueous NaCl
and stirred at rt for 6 h. The organic layer was dried over
anhydrous MgSO4 and concentrated under reduced pressure
to give a crude anomeric mixture of hemiacetals (about 7:1)
for use in the reaction below without puri®cation. A portion
of a crude hemiacetals was puri®ed for spectral analysis by
silica gel column chromatography (eluted with hexane±
EtOAcˆ1:1). Colorless oil; IR (neat) 3418, 2948,
1142 cm21; EIMS (m/z): 338 (M1, 0.2), 320 (M12H2O,
1), 121 (100); Anal. Calcd for C18H26O6: C, 63.89; H,
(1H, m), 4.23 (1H, dd, Jˆ13.2, 6.3 Hz), 4.67 (1H, d, Jˆ
6.6 Hz), 4.68 (1H, d, Jˆ6.6 Hz), 4.74 (1H, s); 13C NMR
(75 MHz, CDCl3) d ppm: 25.9, 30.6, 45.7, 48.0, 53.9,
55.5, 61.4, 80.3, 81.2, 95.8, 110.4; EIMS (m/z): 201
(M12OMe, 8), 45 (100); Anal. Calcd for C11H20O5: C,
56.88; H, 8.68. Found: C, 56.77; H, 8.61.
To a cold (2788C) solution of oxalyl chloride (158 mL,
1.81 mmol) in CH2Cl2 (3.0 mL) was added DMSO
(160 mL, 2.26 mmol) in CH2Cl2 (500 mL). The mixture
was stirred at 2788C for 15 min, treated with a solution of
the above alcohol (105 mg, 452 mmol) in CH2Cl2 (1.00 mL)
and stirred for 15 min and then with Et3N (378 mL,
2.71 mmol). The mixture was stirred for 15 min and
warmed to rt and stirred for 20 min. The reaction mixture
was diluted with Et2O±benzene (5:1), washed with H2O,
saturated aqueous NaHCO3 and saturated aqueous NaCl,
dried over anhydrous MgSO4 and concentrated under
reduced pressure. The residue was puri®ed by silica gel
column chromatography (eluted with hexane±EtOAcˆ
4:1) to give aldehyde 20 (79.0 mg, 96%) as a colorless oil.
1
7.74. Found: C, 63.76; H, 7.93; major isomer: H NMR
(300 MHz, CDCl3) d ppm: 1.58±1.90 (4H, m), 2.60±2.80
(2H, m), 3.30 (3H, s), 3.79 (3H, s), 3.85 (1H, dd, Jˆ10.6,
3.1 Hz), 3.93 (1H, dd, Jˆ10.6, 8.4 Hz), 4.00 (1H, td, Jˆ6.3,
4.2 Hz), 4.47 (1H, d, Jˆ11.5 Hz), 4.55 (1H, d, Jˆ6.7 Hz),
4.57 (1H, d, Jˆ6.7 Hz), 4.58 (1H, d, Jˆ11.5 Hz), 4.59 (1H,
m), 5.29 (1H, s), 6.87 (2H, m), 7.27 (2H, m); 13C NMR
(75 MHz, CDCl3) d ppm: 26.3, 32.1, 47.7, 49.8, 50.5,
55.1, 55.5, 69.7, 72.7, 79.2, 80.4, 95.5, 98.8, 104.5, 113.5,
113.6, 113.7, 129.3, 129.4, 130.0, 158.9.
[a]Dˆ13.28 (cˆ0.87, CHCl3); IR (neat) 2954, 1729 cm21
;
1H NMR (400 MHz, CDCl3) d ppm: 1.64 (2H, m), 1.87 (2H,
m), 2.67 (1H, dd, Jˆ15.5, 8.8 Hz), 3.27 (1H, m), 3.31 (3H,
s), 3.34 (3H, s), 4.06 (1H, m), 4.40 (1H, d, Jˆ7.4 Hz), 4.48
(1H, d, Jˆ6.8 Hz), 4.56 (1H, d, Jˆ6.8 Hz), 4.89(1H, s), 9.86
(1H, s); 13C NMR (75 MHz, CDCl3) d ppm:27.1, 32.6, 49.9,
52.1, 54.7, 55.9, 79.0, 82.4, 95.8, 110.5, 200.6; EIMS (m/z):
201 (M12CHO, 2), 45 (100); HREIMS: Calcd for C9H13O4
(M12CHO±Me) 185.0813; Found: 185.0808.
A solution of PPTS in MeOH (0.1%, 23.8 mL) was added to
the above hemiacetals and stirred at rt for 3 h. The reaction
mixture was diluted with Et2O, washed with H2O and
saturated aqueous NaCl, dried over anhydrous MgSO4 and
concentrated under reduced pressure. The residue was
puri®ed by silica gel column chromatography (eluted with
hexane±EtOAcˆ3:1) to give methyl acetal 19 (1.66 g, 99%,
2 steps) as a colorless oil. [a]Dˆ134.38 (cˆ1.00, CHCl3);
(1S,2S,4R,5S,6R)-4-Formyl-2-methoxy-6-(methoxymethyl)-
oxy-3-oxabicyclo[3.3.0]octane (21). A solution of K2CO3
in MeOH (0.5%, 13.1 mL) was added to aldehyde 20
(302 mg, 1.31 mmol) and the mixture was stirred at rt for
6 h. The reaction mixture was diluted with Et2O±CHCl3
(5:1), washed with H2O and saturated aqueous NaCl, dried
over anhydrous MgSO4 and concentrated under reduced
pressure. The residue was puri®ed by silica gel column
chromatography (eluted with hexane±EtOAcˆ3:1) to give
aldehyde 21 (246 mg, 82%) as a colorless oil. [a]Dˆ
1
IR (neat) 2948 cm21; H NMR (400 MHz, CDCl3) d ppm:
1.60 (2H, m), 1.85 (2H, m), 2.61 (1H, ttd, Jˆ8.9, 5.0,
0.9 Hz), 2.71 (1H, dt, Jˆ8.9, 6.4 Hz), 3.31 (3H, s), 3.34
(3H, s), 3.80 (3H, s), 3.91 (1H, dd, Jˆ10.9, 3.7 Hz), 3.95
(1H, dd, Jˆ10.9, 7.2 Hz), 4.02 (1H, td, Jˆ6.0, 4.5 Hz), 4.38
(1H, dt, Jˆ7.2, 3.7 Hz), 4.45 (1H, d, Jˆ11.6 Hz), 4.55 (1H,
d, Jˆ6.8 Hz), 4.59 (1H, d, Jˆ6.8 Hz), 4.62 (1H, d, Jˆ
11.6 Hz), 4.78 (1H, s), 6.87 (2H, m), 7.28 (2H, m); 13C
NMR (75 MHz, CDCl3) d ppm: 26.4, 32.3, 47.9, 49.1,
54.3, 54.9, 55.5, 69.6, 72.5, 79.2, 80.3, 95.4, 110.8, 113.4,
129.1, 130.4, 158.8; EIMS (m/z): 352 (M1, 0.2), 320
(M12MeOH, 2), 121 (100); Anal. Calcd for C19H28O6: C,
64.75; H, 8.01. Found: C, 64.69; H, 8.07.
1
1198.58 (cˆ0.52, CHCl3); IR (neat) 2953, 1732 cm21; H
NMR (400 MHz, CDCl3) d ppm: 1.58 (2H, m), 1.73 (1H,
m), 1.81 (1H, m), 2.56 (1H, td, Jˆ7.5, 2.7 Hz), 3.12 (1H, td,
Jˆ7.5, 2.8 Hz), 3.35 (3H, s), 3.38 (3H, s), 4.14 (1H, m), 4.63
(1H, d, Jˆ2.8 Hz), 4.64 (1H, d, Jˆ6.6 Hz), 4.67 (1H, d,
Jˆ6.6 Hz), 4.85 (1H, s), 9.70 (1H, s); 13C NMR (75 MHz,
CDCl3) d ppm: 25.7, 30.4, 46.3, 47.9, 55.2, 55.6, 78.4, 83.9,
95.6, 112.9, 204.4; EIMS (m/z): 231 (M111, 1), 45 (100);
HREIMS: Calcd for C10H17O4 (M12CHO) 201.1127;
Found: 201.1122.
(1S,2S,4S,5S,6R)-4-Formyl-2-methoxy-6-(methoxymethyl)-
oxy-3-oxabicyclo[3.3.0]octane (20). To a solution of MPM
ether 19 (43.0 mg, 122 mmol) in CH2Cl2±H2O (20:1)
(1.20 mL) was added DDQ (33.0 mg, 146 mmol) and stirred
at rt for 1 h. The reaction mixture was diluted with CHCl3,
washed with H2O and saturated aqueous NaCl, dried over
anhydrous MgSO4 and concentrated under reduced
pressure. The residue was puri®ed by preparative silica
gel TLC (developed with hexane±EtOAcˆ1:3, Rf 0.4) to
give alcohol (26.0 mg, 92%) as a colorless oil. [a]Dˆ
(10Z,40Z,70Z,100Z)-(1S,2S,4R,5S,6R)-2-Methoxy-6-(meth-
oxymethyl)oxy-4-trideca-10,40,70,100-tetraenyl-3-oxabi-
cyclo[3.3.0]octane (22). To a cold (08C) suspension of
phosphonium iodide 7 (177 mg, 3.21 mmol) in THF
(13.5 mL) was added BuLi (1.33 mL, 2.14 mmol, 1.61 M
in hexane). The mixture was stirred at 08C for 20 min to
give Wittig reagent. To a cold (2788C) solution of aldehyde
21 (246 mg, 1.07 mmol) and HMPA (1.86 mL, 10.7 mmol)
in THF (40.0 mL) was added the prepared above Wittig
reagent and the mixture was stirred at 2788C for 10 min.
The reaction mixture was diluted with Et2O, washed with
1
275.58 (cˆ1.00, CHCl3); IR (neat) 3479, 2947 cm21; H
NMR (400 MHz, CDCl3) d ppm: 1.64±1.83 (4H, m), 2.63
(1H, m), 2.82 (1H, dd, Jˆ15.0, 7.4 Hz), 3.13 (1H, t, Jˆ
7.1 Hz), 3.30 (3H, s), 3.38 (3H, s), 3.99 (2H, m), 4.07

H. Miyaoka et al. / Tetrahedron 56 (2000) 8083±8094
8093
H2O and saturated aqueous NaCl, dried over anhydrous
MgSO4 and concentrated under reduced pressure. The
residue was puri®ed by silica gel column chromatography
(eluted with hexane±EtOAcˆ10:1) to give ole®n 22
(400 mg, 99%) as a colorless oil. [a]Dˆ140.58 (cˆ1.00,
was diluted with Et2O, washed with saturated aqueous
NaHCO3, H2O and saturated aqueous NaCl, dried over
anhydrous MgSO4 and concentrated under reduced pres-
sure. The residue was puri®ed by preparative silica gel
TLC (developed with hexane±EtOAcˆ1:1, Rf 0.4) to give
bacillariolide I (1) (9.2 mg, 90%) as a colorless oil.
[a]Dˆ223.68 (cˆ0.55, MeOH); IR (CHCl3) 3474, 2968,
CHCl3); IR (neat) 2961 cm21
;
1H NMR (400 MHz,
CDCl3) d ppm: 0.96 (3H, t, Jˆ7.6 Hz), 1.53±1.89 (4H,
m), 2.08 (2H, qd, Jˆ7.6, 7.0 Hz), 2.64±3.05 (8H, m), 3.30
(3H, s), 3.34 (3H, s), 4.13 (1H, dt, Jˆ9.6, 6.2 Hz), 4.60 (2H,
s), 4.73 (1H, s), 5.15 (1H, dd, Jˆ9.5, 3.1 Hz), 5.28±5.43
(7H, m), 5.56 (1H, ddt, Jˆ10.8, 9.5, 1.6 Hz); 13C NMR
(75 MHz, CDCl3) d ppm: 14.2, 20.4, 25.3, 25.3, 25.4,
25.5, 29.6, 48.6, 51.0, 54.0, 55.2, 76.0, 78.9, 95.4, 112.1,
126.7, 127.7, 127.8, 128.3, 128.4, 128.8, 131.8, 133.3;
EIMS (m/z): 376 (M1, 0.1), 45 (100); HREIMS: Calcd for
C22H32O3 (M12MeOH) 344.2351; Found: 344.2369.
1
1760 cm21; H NMR (400 MHz, CD3OD) d ppm: 0.97
(3H, t, Jˆ7.5 Hz), 1.62 (1H, m), 1.84 (1H, m), 1.99 (2H,
dd, Jˆ14.3, 6.9 Hz), 2.09 (2H, dq, Jˆ7.5, 7.5 Hz), 2.65 (1H,
ddd, Jˆ9.6, 6.5, 2.6 Hz), 2.83 (2H, t, Jˆ6.0 Hz), 2.88 (2H, t,
Jˆ5.4 Hz), 3.00 (2H, m), 3.18 (1H, dt, Jˆ9.6, 6.5 Hz), 4.30
(1H, dt, Jˆ6.5, 5.0 Hz), 5.26±5.46 (6H, m), 5.49±5.61 (3H,
m); 13C NMR (100 MHz, CD3OD) d ppm: 14.7, 21.5, 26.4,
26.5, 26.9, 27.2, 34.6, 44.7, 51.8, 74.5, 76.5,128.1, 128.2,
128.8, 129.6, 130.1, 130.1, 132.8, 133.0, 183.4; EIMS (m/z):
316 (M1, 2.5), 91 (100); HREIMS: Calcd for C20H28O3
(M1): 316.2038; Found: 316.2020.
Bacillariolide I (1). A mixture of AcOH and H2O (4:1)
(5.00 mL) was added to methyl acetal 22 (35.8 mg,
95.1 mmol) and the mixture was stirred at rt for 12 h. The
reaction mixture was concentrated under reduced pressure.
The residue was puri®ed by preparative silica gel TLC
(developed with hexane±EtOAcˆ4:1, Rf 0.2) to give an
anomeric mixture of hemiacetals (30.0 mg, 87%) as a color-
less oil. IR (neat) 3408, 2962 cm21; EIMS (m/z): 299
(M12MOM, 6), 45 (100); HREIMS: Calcd for C22H32O3
(M12H2O) 344.2351; Found 344.2363; major isomer: 1H
NMR (400 MHz, CDCl3) d ppm: 0.97 (3H, t, Jˆ7.6 Hz),
1.58±1.94 (4H, m), 2.07 (2H, qd, Jˆ7.6, 6.9 Hz), 2.51±3.05
(9H, m), 3.34 (3H, s), 4.16 (1H, dt, Jˆ9.5, 6.4 Hz),
4.60 (2H, t, Jˆ6.9 Hz), 5.15 (1H, dd, Jˆ9.4, 4.4 Hz),
5.27±5.49 (8H, m), 5.66 (1H, ddt, Jˆ10.8, 9.4, 1.6 Hz);
13C NMR (75 MHz, CDCl3) d ppm: 14.2, 20.4, 25.1,
25.3, 25.4, 25.5, 25.9, 49.5, 51.1, 55.2, 76.1, 78.8, 95.3,
105.6, 126.9, 127.7, 127.8, 128.3, 128.5, 129.2, 131.9,
133.2.
(10Z)-(1S,4R,5S,6R)-2-Methoxy-6-(methoxymethyl)oxy-
4-[(50-methoxycarbonyl)pent-10-enyl]-3-oxabicyclo[3.3.0]-
octane (23). To a suspension of phosphonium bromide 9
(214 mg, 484 mmol) in THF (1.40 mL) was added LiHMDS
(518 mL, 518 mmol, 1.0 M in THF) at 08C. The mixture was
stirred at 08C for 20 min, added with HMPA (291 mL,
1.67 mmol) and cooled to 2788C. A solution of aldehyde
21 (38.5 mg, 167 mmol) in THF (0.30 mL) was added to the
mixture, warmed to 08C and stirred at 08C for 30 min. The
reaction mixture was diluted with Et2O, washed with H2O
and saturated aqueous NaCl, dried over anhydrous MgSO4
and concentrated under reduced pressure. The residue was
puri®ed by silica gel column chromatography (eluted with
hexane±EtOAcˆ5:1) to give ole®n 23 (50.0 mg, 95%) as a
colorless oil. [a]Dˆ168.78 (cˆ0.87, CHCl3); IR (neat)
1
2952, 1739 cm21; H NMR (400 MHz, CDCl3) d ppm:
1.53±1.77 (3H, m), 1.86 (1H, m), 2.38 (2H, m), 2.44 (1H,
m), 2.52 (1H, m), 3.29 (3H, s), 3.34 (3H, s), 3.67 (3H, s),
4.13 (1H, dt, Jˆ9.3, 6.1 Hz), 4.60 (1H, d, Jˆ6.7 Hz), 4.61
(1H, d, Jˆ6.7 Hz), 4.72 (1H, s), 5.11 (1H, dd, Jˆ9.4,
2.8 Hz), 5.38 (1H, dt, Jˆ10.8, 6.7 Hz), 5.57 (1H, ddt,
Jˆ10.8, 9.4, 1.3 Hz); 13C NMR (75 MHz, CDCl3) d ppm:
22.5, 25.3, 29.6, 33.8, 48.5, 51.1, 51.4, 54.0, 55.2, 75.9,
79.0, 95.4, 112.1, 128.4, 134.4, 173.3; EIMS (m/z): 314
(M1, 0.4), 299 (M12Me, 1), 45 (100); HREIMS: Calcd
for C15H23O6 (M12Me): 299.1495; Found: 299.1519.
To a cold (08C) solution of the above hemiacetals (162 mg,
447 mmol) in acetone (4.47 mL) was added Jones reagent
(300 mL), followed by stirring for 10 min and treatment
with 2-propanol (1.0 mL). After stirring for 10 min, the
reaction mixture was diluted with Et2O, washed with H2O
and saturated aqueous NaCl, dried over anhydrous MgSO4
and concentrated under reduced pressure. The residue was
puri®ed by silica gel column chromatography (eluted with
hexane±EtOAcˆ4:1) to give 5-O-methoxymethylbacillar-
iolide I (144 mg, 89%) as a colorless oil. [a]Dˆ223.58
Bacillariolide III (3). A mixture of AcOH and H2O (4:1)
(3.00 mL) was added to methyl acetal 23 (50.0 mg,
159 mmol) and stirred at rt for 12 h. The reaction mixture
was concentrated under reduced pressure. The residue was
puri®ed by preparative silica gel TLC (developed with
hexane±EtOAcˆ3:1, Rf 0.3) to give an anomeric mixture
of hemiacetals (32.0 mg, 67%) as a colorless oil. IR (neat)
3445, 2954, 1733 cm21; EIMS (m/z): 283 (M12OH, 1), 45
(100); HREIMS: Calcd for C13H18O4 (M12MOM±OH)
238.1205; Found 238.1163; major isomer: 1H NMR
(400 MHz, CDCl3) d ppm: 1.55±1.93 (4H, m), 2.36±2.78
(6H, m), 3.34 (3H, s), 3.67 (3H, s), 4.13 (1H, m), 4.60 (2H,
s), 5.10 (1H, dd, Jˆ9.4, 4.8 Hz), 5.25 (1H, d, Jˆ2.7 Hz),
5.48 (1H, m), 5.68 (1H, ddt, Jˆ10.9, 9.4, 1.5 Hz); 13C
NMR (75 MHz, CDCl3) d ppm: 22.5, 25.0, 29.6, 33.8,
49.4, 51.2, 51.4, 55.2, 75.9, 78.9, 95.4, 105.5, 128.6,
134.3, 173.2.
1
(cˆ1.36, CHCl3); IR (neat) 2925, 1771 cm21; H NMR
(400 MHz, CDCl3) d ppm: 0.97 (3H, t, Jˆ7.5 Hz), 1.69
(1H, m), 1.93 (2H, m), 2.08 (3H, m), 2.75 (1H, ddd,
Jˆ9.8, 7.2, 3.0 Hz), 2.81 (2H, t, Jˆ6.7 Hz), 2.84 (2H, t,
Jˆ6.5 Hz), 2.96 (2H, m), 3.09 (1H, br td, Jˆ9.8, 2.3 Hz),
3.35 (3H, s), 4.20 (1H, m), 4.61 (1H, d, Jˆ6.7 Hz), 4.65
(1H, d, Jˆ6.7 Hz), 5.27±5.63 (9H, m); 13C NMR (75 MHz,
CDCl3) d ppm: 14.1, 20.4, 25.4, 25.5, 25.8, 26.3, 30.5, 42.9,
48.5, 55.4, 74.4, 78.8, 95.5, 126.7, 126.7, 127.4, 128.6,
128.7, 129.0, 132.0, 132.3, 180.0; EIMS (m/z): 360 (M1,
0.3), 45 (100); HREIMS: Calcd for C20H27O3 (M1):
315.1960; Found: 315.1950.
A mixture of AcOH and conc. HCl (50:1) (3.00 mL) was
added to 5-O-methoxymethylbacillariolide I (11.6 mg,
32.3 mmol) and stirred at rt for 1 h. The reaction mixture

8094
H. Miyaoka et al. / Tetrahedron 56 (2000) 8083±8094
To a cold (08C) solution of the above hemiacetals (32.0 mg,
107 mmol) in acetone (2.00 mL) was added Jones reagent
(70.0 mL), stirred for 10 min and treated with 2-propanol
(0.5 mL). After stirring for 10 min, the reaction mixture
was diluted with Et2O, washed with H2O and saturated
aqueous NaCl, dried over anhydrous MgSO4 and concen-
trated under reduced pressure. The residue was puri®ed by
silica gel column chromatography (eluted with hexane±
EtOAcˆ3:1) to give 5-O-methoxymethylbacillariolide III
methyl ester (32.0 mg, quantitative yield) as a colorless
oil. [a]Dˆ29.88 (cˆ0.82, CHCl3); IR (neat) 2952, 1766,
1737 cm21 1H NMR (400 MHz, CDCl3) d ppm: 1.68
;
lide III sodium salt (15.6 mg, 95%) as a white amorphous
solid. [a]Dˆ243.68 (cˆ0.16, H2O); IR (KBr) 3541, 1769,
1
1577, 1413 cm21; H NMR (400 MHz, D2O) d ppm:1.69
(1H, m), 1.94 (2H, m), 2.10 (1H, m), 2.30 (1H, dt, Jˆ
14.3, 7.9 Hz), 2.31 (1H, dt, Jˆ14.3, 6.4 Hz), 2.46 (2H, m),
2.82 (1H, ddd, Jˆ9.6, 6.3, 2.6 Hz), 3.37 (1H, td, Jˆ9.6,
3.2 Hz), 4.43 (1H, td, Jˆ6.3, 4.7 Hz), 5.58±5.64 (2H, m),
5.74 (1H, m); 13C NMR (100 MHz, D2O) d ppm:26.4, 27.8,
34.7, 39.3, 45.7, 52.5, 75.6, 79.0, 130.1, 136.3, 184.6, 187.1;
EIMS (m/z): 222 (M12NaOH, 63), 127 (100); FABMS
(m/z): 263 (M1, 50), 135 (100); HREIMS: Calcd for
C12H14O4 (M12NaOH): 222.0892; Found: 222.0893.
(1H, m), 1.94 (2H, m), 2.08 (1H, m), 2.39±2.48 (3H, m),
2.53 (1H, m), 2.73 (1H, ddd, Jˆ9.6, 7.1, 3.3 Hz), 3.08 (1H,
td, Jˆ9.6, 2.7 Hz), 3.36 (3H, s), 3.67 (3H, s), 4.20 (1H, ddd,
Jˆ8.5, 7.1, 5.1 Hz), 4.63 (1H, d, Jˆ6.8 Hz), 4.65 (1H, d,
Jˆ6.8 Hz), 5.45 (1H, dd, Jˆ9.0, 3.4 Hz), 5.49 (1H, m), 5.58
(1H, m); 13C NMR (75 MHz, CDCl3) d ppm: 22.9, 26.3,
30.6, 33.4, 42.9, 48.6, 51.5, 55.5, 74.4, 78.9, 95.5, 129.8,
131.9, 172.9, 180.0; EIMS (m/z): 299 (M111, 2), 45 (100);
HREIMS: Calcd for C13H17O5 (M12MOM) 253.1076;
Found: 253.1064.
Acknowledgements
The authors are grateful to Prof. Yuzuru Shimizu, College
of Pharmacy, University of Rhode Island, for providing the
NMR spectra of bacillariolides. This work was supported in
part by a grant-in-aid for Scienti®c Research (Grant No.
05771939) from the Ministry of Education, Science, Sports
and Culture of Japan.
Method A (puri®cation with preparative silica gel TLC). A
solution of 5-O-methoxymethylbacillariolide III methyl
ester (22.5 mg, 75.4 mmol) in 1N HCl (754 mL) was stirred
at 608C for 6 h. The reaction mixture was extracted with
CHCl3. The organic layer was dried over anhydrous
MgSO4 and concentrated under reduced pressure. The resi-
due was puri®ed by preparative silica gel TLC (developed
with hexane±THF±AcOHˆ10:10:0.1, Rf 0.4) to give bacil-
lariolide III (3) (14.6 mg, 70%) as a colorless oil. [a]Dˆ
254.28 (cˆ0.31, MeOH); IR (CHCl3) 3029, 2977, 1758,
References
1. (a) Gerwick, W. H. Chem. Rev. 1993, 93, 1807±1823.
(b) Gerwick, W. H. Biochim. Biophys. Acta 1994, 1211, 243±255.
2. The designation previously given to this organism, Nitzschia
pungens f. multiseries, has been recently changed to Pseudo-
nitzschia multiseries.
3. Wright, J. L. C.; Boyd, R. K.; de Freitas, A. S. W.; Falk, M.;
Foxall, R. A.; Jamieson, W. D.; Laycock, M. V.; McCulloch, A.
W.; McInnes, A. G.; Odense, P.; Pathak, V. P.; Quilliam, M. A.;
Ragan, M. A.; Sim, P. G.; Thibault, P.; Walter, J. A.; Gilgan, M.;
Richard, D. J. A.; Dewar, D. Can. J. Chem. 1989, 67, 481±490.
4. Wang, R.; Shimizu, Y. J. Chem. Soc., Chem. Commun. 1990,
413±414.
1
1719 cm21; H NMR (400 MHz, CD3OD) d ppm: 1.63
(1H, m), 1.82 (1H, m), 1.99 (2H, m), 2.41 (2H, m), 2.48
(2H, m), 2.64 (1H, ddd, Jˆ9.6, 6.4, 1.7 Hz), 3.18 (1H, dt,
Jˆ9.6, 6.6 Hz), 4.32 (1H, ddd, Jˆ11.4, 5.1, 1.7 Hz), 5.54±
5.67 (3H, m); 13C NMR (100 MHz, CD3OD) d ppm: 24.1,
27.1, 34.6, 34.6, 44.6, 52.0, 74.5, 76.4, 131.1, 133.0, 176.6,
183.4; EIMS (m/z): 241 (M1, 1), 45 (100); HREIMS: Calcd
for C12H14O4 (M12H2O): 222.0892; Found: 222.0906.
5. Zheng, N.; Shimizu, Y. Chem. Commun. 1997, 399±400.
6. Wang, R.; Shimizu, Y.; Steiner, J. R.; Clardy, J. J. Chem. Soc.,
Chem. Commun. 1993, 379±380.
7. Shimizu, Y. Annu. Rev. Microbiol. 1996, 50, 431±465.
8. Miyaoka, H.; Tamura, M.; Yamada, Y. Tetrahedron Lett. 1998,
39, 621±624.
Method B (puri®cation with ODS column chromatography).
A solution of 5-O-methoxymethylbacillariolide III methyl
ester (40.3 mg, 135 mmol) in 1N HCl (1.35 mL) was stirred
at 608C for 6 h. The reaction mixture was extracted with
CHCl3. The organic layer was dried over anhydrous
MgSO4 and concentrated under reduced pressure. The resi-
due was puri®ed by ODS column chromatography (eluted
with H2O±acetonitrile±AcOHˆ90:10:0.5) to give bacillar-
iolide III (3) complex (25.1 mg) as a colorless oil. [a]Dˆ
9. Miyaoka, H.; Shigemoto, T.; Shinohara, I.; Suzuki, A.;
Yamada, Y. Tetrahedron 2000, 56, 8077±8081.
10. Miyaoka, H.; Shigemoto, T.; Yamada, Y. Tetrahedron Lett.
1996, 37, 7407±7408. Miyaoka, H.; Shigemoto, T.; Yamada, Y.
Heterocycles 1998, 47, 415±428.
11. Numbering of compounds is in accordance with that for
bacillariolide.
1
247.98 (cˆ0.28, MeOH); H NMR (400 MHz, CD3OD) d
12. Jeffery, T.; Gueugnot, S.; Linstrumelle, G. Tetrahedron Lett.
1992, 33, 5757±5760.
ppm: 1.62 (1H, m), 1.83 (1H, m), 1.99 (2H, br dd, Jˆ13.9,
6.5 Hz), 2.35 (2H, t, Jˆ7.1 Hz), 2.47 (2H, m), 2.64 (1H,
ddd, Jˆ9.5, 6.5, 1.8 Hz), 3.18 (1H, dt, Jˆ9.5, 6.4 Hz), 4.32
(1H, dd, Jˆ11.5, 6.4 Hz), 5.54 (2H, m), 5.63 (1H, dt, Jˆ9.3,
7.4 Hz); 13C NMR (100 MHz, CD3OD) d ppm: 24.8, 27.1,
34.6, 36.2, 44.6, 51.9, 74.5, 76.5, 130.7, 133.6, 183.2, 183.4.
13. Lapitskaya, M. A.; Vasiljeva, L. L.; Pivnitsky, K. K. Synthesis
1993, 65±66.
14. Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.;
Nomizu, S.; Moriwake, T. Chem. Lett. 1984, 1389±1392.
15. Ban®, L.; Cascio, G.; Guanti, G.; Manghisi, E.; Narisano, E.;
Riva, R. Tetrahedron 1994, 41, 11967±11982.
Bacillariolide III sodium salt. An aqueous solution of
bacillariolide III (3) (15.1 mg, 62.8 mmol) was passed
through Chelex 100 Na1 form. The aqueous solution was
concentrated under reduced pressure to give the bacillario-
16. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
S.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765±5780.
17. Personal communication from Professor Yuzuru Shimizu
(University of Rhode Island).