Total synthesis of attenols A and B

Article abstract of DOI:10.1016/S0040-4020(02)00056-X

The enantioselective synthesis of attenols A and B, cyclic polyethers of marine origin, was accomplished on a semigram scale by using diastereoselective hydroboration, coupling with lithium acetylide, Lindlar reduction and acid-catalyzed acetal formation. The configuration of the remaining undetermined spiro acetal carbon was unambiguously determined to be 11S using this ample supply of attenol A. The antitumor activities of synthetic attenol A were also examined.

Full text of DOI:10.1016/S0040-4020(02)00056-X

TETRAHEDRON
Pergamon
Tetrahedron 58 42002) 1983±1995
Total synthesis of attenols A and B
²
Keisuke Araki, Kiyotake Suenaga, Tetsuya Sengoku and Daisuke Uemurap
Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
Received 22 October 2001; accepted 10 December 2001
AbstractÐThe enantioselective synthesis of attenols A and B, cyclic polyethers of marine origin, was accomplished on a semigram scale by
using diastereoselective hydroboration, coupling with lithium acetylide, Lindlar reduction and acid-catalyzed acetal formation. The con-
®guration of the remaining undetermined spiro acetal carbon was unambiguously determined to be 11S using this ample supply of attenol A.
The antitumor activities of synthetic attenol A were also examined. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
showed signi®cant acute toxicity against mice, with LD99s
of 100 and 8 mg/kg, respectively.
Marine bivalves are rich sources of various unique bioactive
compounds. Shell®sh of the genus Pinna live mainly in
shallow areas of the temperate and tropical zones of the
Indian and Paci®c oceans. The adductor muscle of this
bivalve is eaten in Japan and China, and food poisoning
frequently occurs from its ingestion. In our continuing
search for toxic compounds, we have reported the isolation
and structural determination of toxic compounds, pinna-
toxins 43),1 and an alkaloidal marine toxin, pinnamine
44),2 from the Okinawan bivalve Pinna muricata 4Fig. 1).
Pinnatoxins are amphoteric carbocyclic compounds which
contain 6,7-spiro, 5,6-bicyclo and 6,5,6-trispiro ketal rings.
Pinnatoxin A 43a)1a is the major toxic component in Pinna
sp. and a Ca21 channel activator. The absolute stereo-
structure was con®rmed by its total synthesis by Kishi and
co-workers.3 Pinnatoxins B 43b) and C 43c), extremely
minor components 41:1 ratio) from Pinna sp., are the most
potent toxic components in the pinnatoxin series, and their
isolation and structural determination were reported by our
laboratory.1d We achieved the total synthesis of pinnamine
44), an alkaloid that contains a dihydropyrone ring and
which induces characteristic toxic symptoms, such as
scurrying around.4 We also isolated pinnaic acid 45),
which has cPLA2 inhibitory activity, from the same
Okinawan bivalve P. muricata.5 Furthermore, we have
isolated toxic compounds, pteriatoxins 46),6 from another
bivalve, Pteria penguin, and their structures are similar to
those of pinnatoxins. Although pteriatoxin A 420 mg) and
pteriatoxins B and C in a 1:1 mixture 48 mg) exist as minute
components in viscera 482 kg) of P. penguin, these toxins
In the course of extensive studies on shell®sh poisons, we
observed that the CH2Cl2-soluble fraction of the EtOH
extract of the Chinese bivalve Pinna attenuata exhibited
moderate cytotoxicity against P388 cells, and isolated
attenols A 41) and B 42), cyclic polyethers that exhibit cyto-
toxicity against P388 cells with IC50 values of 24 and 12 mg/
mL, respectively.7 The absolute stereostructures of these
attenols were determined by NMR analysis and a modi®ed
Mosher's method. The main structural features of attenol A
41) are a spiro acetal ring, three contiguous stereocenters and
Z-disubstituted and terminal ole®ns. Attenol B 42) was
determined to be an isomeric polyether of attenol A 41)
with a 6,8-dioxabicyclo[3.2.1]octane ring. However, their
natural scarcity has prevented further biological studies.
Recently, we achieved the total synthesis of attenols A 41)
and B 42) to con®rm their absolute stereostructures and to
evaluate their biological activities.8 In this paper, we
describe an enantioselective and practical synthesis of
attenols A 41) and B 42) and biological studies on attenol
A 41) based on a good supply of synthetic material. We were
able to unambiguously con®rm the con®guration of the
remaining undetermined spiro acetal carbon.
2. Results and discussion
2.1. Synthetic plan
Scheme 1 outlines our strategy for synthesizing attenols A
41) and B 42).
Keywords: enantioselective synthesis; semigram scale; diastereoselective
hydroboration; stereochemistry of spiro acetal ring; biological studies.
Since acid treatment of attenol A 41) gave a mixture of 1 and
2 43:1), 1 and 2 were synthesized simultaneously by acetal
ring formation of a ketone 47) in the ®nal step. Ketone 47)
was constructed by a Julia coupling reaction9 between the
C1±C11 segment 48) and the C12±C21 segment 49). The
p
Corresponding author. Tel./fax: 181-52-789-3654;
e-mail: uemura@chem3.chem.nagoya-u.ac.jp
²
Present address: School of Pharmaceutical Sciences, University of
Shizuoka, Yada, Shizuoka 422-8526, Japan.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020402)00056-X

1984
K. Araki et al. / Tetrahedron 58 ,2002) 1983±1995
Figure 1. Bioactive compounds isolated from the bivalve Pinna sp. and Pteria penguin.
Scheme 1. Retrosynthesis of attenols A and B.

K. Araki et al. / Tetrahedron 58 ,2002) 1983±1995
1985
Z-disubstituted ole®n was introduced by Lindlar reduction
of the disubstituted acetylene, which was prepared from
alcohol 410) and 4-tert-butyldimethylsilyloxy-1-butyne
411).10 The stereochemistry of the C8 methyl groupon
attenols was introduced by diastereoselective hydroboration
of the ole®n 412). The ole®n 412) was prepared using 2,3-O-
isopropylidene-d-threitol as a starting material. The C12±
C21 segment 49) was derived from anti-1,3-diol, which was
used to introduce the stereochemistry of the C16 hydroxy
groupon attenols by stereoselective reduction of b-hydroxy
ketone 413). The b-hydroxy ketone 413) was prepared using
1,3-dithiane as a starting material.
Figure 2. Observed NOE 4arrow) and coupling constants 4dashed line, in
Hz) of 19.
2.2. Synthesis of the C1±C11 segment
Synthesis of the C1±C11 segment 8 began with monosilyl-
ation of 2,3-O-isopropylidene-d-threitol to give silyl ether
14 497%) 4Scheme 2), Swern oxidation11 of which afforded
aldehyde 15 491%). Addition of Me2CuLi to aldehyde 15
gave a diastereomeric mixture of secondary alcohol 16
490%), which was oxidized to methyl ketone 17 496%).
Wittig reaction of 17 with the phosphorus ylide derived
from methyltriphenylphosphonium bromide and n-butyl-
lithium afforded ole®n 12 in 95% yield. Diastereoselective
hydroboration of ole®n 12 with 9-BBN followed by oxida-
tion with H2O2 provided alcohol 18 499%, a/bˆ8/1). Since
it was dif®cult to separate the diastereomers at this stage, the
Figure 3. Preferential orientation in diastereoselective hydroboration
governed predominantly by steric effects.
of C8 was determined to be R based on coupling constants
and NOE experiments for the derived acetonide 19 4Fig. 2).
1
The stereoselectivity of hydroboration can be explained by
considering that 9-BBN approached the less-hindered side
of ole®n 12, which adopted the conformation shown in Fig. 3
to minimize allylic strain.12
stereoselectivity was determined by H NMR 4800 MHz).
The minor b-isomer could be separated by chromatography
at a later stage in the synthesis. To determine the stereo-
chemistry of the C8 methyl group, alcohol 18 was trans-
formed into acetonide 19 4Scheme 3). The stereochemistry
Oxidation of alcohol 18 with Dess±Martin periodinane13
gave aldehyde 20 481%) 4Scheme 4), which in the
Horner±Emmons reaction with 4EtO)2P4O)CH2COOEt
and t-BuOK afforded conjugated ester 21 484%). Hydro-
genation of 21 gave ester 22 487%) and the minor diastereo-
mer regarding C8, which was separated by chromatography
at this stage. Reduction of 22 with DIBAL±H and then
NaBH4 afforded alcohol 23 490% in 2 steps). The one-step
reduction of 22 to 23 with DIBAL±H or LiAlH4 at a higher
temperature led to cleavage of the TBS ether. Protection of
the hydroxyl groupin 23 as a p-methoxybenzyl 4MPM)
ether group4 24, 82%) followed by desilylation with
n-Bu4NF gave alcohol 10 499%). Although we initially
attempted a coupling reaction of iodide 25 prepared from
alcohol 10, with acetylene 11, an elimination product was
mainly obtained. Using EtMgBr as a base, the same result
was observed. Coupling reaction using tri¯uoromethane-
sulfonate 26 gave disubstituted acetylene 27 in good yield
482% in 2 steps).14 Lindlar reduction of 27 afforded Z-ole®n
28 quantitatively. The Z-stereochemistry of the C3±C4
double-bond in 28 was con®rmed by the coupling constant
410.9 Hz) between H3 and H4 in 1H NMR 4270 MHz). The
MPM groupon 28 was removed with 2,3-dichloro-5,6-
dicyano-p-benzoquinone 4DDQ) to give alcohol 29 496%),
oxidation of which with Dess±Martin periodinane provided
C1±C11 segment 8 499%). The overall yield of the C1±C11
segment 8 was 24% in 18 steps.
Scheme 2. Synthesis of C1±C11 segmentÐ1. 4a) TBSCl, NaH, DME,
08C!rt; 4b) 4COCl)2, DMSO, CH2Cl2, 2788C, then Et3N, 2788C!08C;
4c) MeLi, CuI, Et2O, 2788C!08C; 4d) 4COCl)2, DMSO, CH2Cl2, 2788C,
then Et3N, 2788C!08C; 4e) Ph3PCH3Br, n-BuLi, 2408C!08C.
2.3. Synthesis of the C12±C21 segment
Scheme 3. Transformation to 19 to determine the stereochemistry of the C8
methyl group.
Synthesis of the C12±C21 segment 9 began with alkylation

1986
K. Araki et al. / Tetrahedron 58 ,2002) 1983±1995
Scheme 4. Synthesis of C1±C11 segmentÐ2. 4a) Dess±Martin periodinane, CH2Cl2, rt; 4b) 4EtO)2P4O)CH2COOEt, tert-BuOK, THF, 2788C!08C; 4c) H2,
5% Rh-Al2O3, EtOAc, rt; 4d) 4i) DIBAL±H, CH2Cl2, 2788C, 4ii) NaBH4, EtOH, 08C; 4e) MPMCl, NaH, DMF, 2208C; 4f) n-Bu4NF, THF, rt; 4g) I2, PPh3,
imidazole, toluene, rt; 4h) 4-tert-butyldimethylsilyloxy-1-butyne 411), n-BuLi, HMPA, THF, 2788C, then iodide 425), 08C!108C; 4i) 11, n-BuLi, HMPA,
THF, 2788C, then 25, 2358C!08C!rt; 4j) Tf2O, 2,6-di-tert-butyl-4-methylpyridine, CH2Cl2, 2208C; 4k) 11, EtMgBr, THF, 2788C, then 26, 2358C!rt;
4l) H2, Lindlar catalyst, MeOH, rt; 4m) DDQ, CH2Cl2-tert-BuOH-phosphate buffer 4pH 6); 4n) Dess±Martin periodinane, CH2Cl2, rt.
of 1,3-dithiane with 5-bromo-1-pentene to afford ole®n 30
498%) 4Scheme 5). Further alkylation of 30 with 4R)-benzyl
glycidyl ether provided alcohol 31 480%), the dithiane
groupof which was hydrolyzed 15 to give b-hydroxy ketone
13 486%). Stereoselective reduction of b-hydroxy ketone
13 with tetramethylammonium triacetoxyborohydride16
afforded anti-1,3-diol 32a 488%, 32a/32bˆ8.8/1), the
stereochemistry of which was determined as follows. Two
hydroxyl groups of 32a were protected as an acetonide
4100%), the 13C NMR chemical shifts of which revealed
that the stereochemistry at C16 was S.17 The benzyl group
of 33 was removed with sodium in liquid ammonia to give
alcohol 34 499%). The corresponding tosylate derived from
34 was coupled with the carbanion of methyl phenyl sulfone
to give C12±C21 segment 9 486% in 2 steps). The overall
yield of the C12±C21 segment 9 was 27% in 8 steps.
2.4. Synthesis of attenols A and B
The Julia coupling reaction between C1±C11 segment 8 and
the carbanion generated from C12±C21 segment 9 4n-BuLi,
THF, 2788C) gave a diastereomeric mixture of hydroxy
sulfones, which was oxidized 4Dess±Martin periodinane,
pyridine, CH2Cl2, rt) and subsequently reduced with sodium
amalgam 45% Na±Hg, Na2HPO4, MeOH, 08C) to afford
ketone 7 485% from 8) 4Scheme 6). Finally, removal of
the protecting groups and acetal formation with p-TsOH
in MeOH at room temperature gave attenols A 41, 55%)
and B 42, 11%). We synthesized 180 mg of attenol A to
evaluate its biological activity. Synthetic attenols A 41)
and B 42) were identical to natural 1 and 2 in all respects,
including spectral data 4IR, 1H and 13C NMR, HRMS, thin-
layer chromatography 4TLC), [a]D).
Scheme 5. Synthesis of C12±C21 segment. 4a) 4i) n-BuLi, 4ii) 5-bromo-1-pentene, THF, 2788C!rt; 4b) 4i) n-BuLi, 4ii) 4R)-benzyl glycidyl ether, THF,
2788C!rt; 4c) CuCl2, CuO, acetone/H2O, rt; 4d) Me2C4OMe)2, CSA, acetone, rt; 4e) Na, Liq. NH3/THF, 2788C; 4f) p-TsCl, pyridine, 08C; 4g) MeSO2Ph,
n-BuLi, THF, re¯ux.

K. Araki et al. / Tetrahedron 58 ,2002) 1983±1995
1987
Scheme 6. Synthesis of attenols A and B. 4a) 9, n-BuLi, THF, 2788C, then 8, 2788C; 4b) Dess±Martin periodinane, pyridine, CH2Cl2, rt; 4c) 5% Na±Hg,
Na2HPO4, MeOH, 08C.
Scheme 7. Synthesis of tribenzoate 435).
2.5. Determination of the stereochemistry at the spiro
acetal carbon )C11)
4dH 5.55, 5.7%). Irradiation of the signals at H16 4dH 5.55)
enhanced the signals for H7 4dH 3.80, 0.8%) and H14 4dH
4.13, 2.9%). Irradiation of the signals at H7 4dH 3.80)
enhanced the signals for H22 4dH 0.87, 2.8%). Irradiation
of the signals at H22 4dH 0.87) enhanced the signals for H9a
4dH 1.48, 2.7%). The NOESY correlations H7/H9b, H8/22
and H9b/22 were observed. A detailed analysis of cross-
peaks revealed the stereochemistry of the spiro acetal
moiety as shown in Fig. 4, which is based on a reasonable
anomeric effect on both the ®ve-membered ring and the six-
membered ring.
Since the stereochemistry of the spiro acetal carbon 4C11) of
natural attenol A 41) could not be determined by NOE
1
experiments due to overlap of the H NMR signals, the
stereochemistry of C11 was deduced as shown in Fig. 1
based on an empirical consideration of the anomeric effect.
A suf®cient amount of synthetic attenol A 41) enabled us to
synthesize derivatives, which resolved the con®guration of
C11 as follows. Tribenzoate 435) derived from synthetic
1
attenol A 41) solved the problem of the overlap of the H
NMR signals 4Scheme 7). In NOE experiments 4600 MHz)
on tribenzoate 435), irradiation of the signals at H15b 4dH
2.11) enhanced the signals for H7 4dH 3.80, 1.3%) and H16
2.6. Examination of the biological activities of synthetic
attenol A
We screened the antitumor activity of synthetic attenol A.
Although attenol A exhibited inhibitory activity against
P388 cells, it did not appear to inhibit polymerization of
tubulin or enzymatic degradation in metastasis. In addition,
attenol A did not exhibit antibacterial activity against Gram-
negative bacterium. Further biological studies are currently
in progress.
3. Conclusion
In conclusion, the enantioselective synthesis of attenols A
41) and B 42) was achieved with overall yields of 11% and
2.3% in 22 steps, respectively. The C8-stereochemistry was
introduced by diastereoselective hydroboration. Finally,
Figure 4. Determination of stereochemistry at the spiro acetal carbon
4C11), based on NOE and NOESY correlations.

1988
K. Araki et al. / Tetrahedron 58 ,2002) 1983±1995
acid-catalyzed spiroketalization gave attenols A and B
simultaneously. The spectral data 41H and 13C NMR, [a]D,
IR, HRFAB, TLC) of the synthetic attenols were identical to
those of the natural products. The stereochemistry of the
spiro acetal moiety was unambiguously determined by
NOE experiments with tribenzoate 435), which was derived
from synthetic attenol A 41). We synthesized 180 mg of
attenol A to evaluate its biological activity. Further bio-
logical studies on attenols are currently in progress.
colorless oil: TLC, Rf 0.38 4hexane/EtOAc, 4:1);
[a]27 ˆ25.4 4c 0.67, CHCl3); IR 4CHCl3) 3600, 3560±
D
3280 4br), 1260, 1078, 840 cm21
;
1H NMR 4270 MHz,
CDCl3) d 3.98 4dt, Jˆ7.9, 4.6 Hz, 1H), 3.91±3.84 4m,
2H), 3.80±3.63 4m, 3H), 2.36 4dd, Jˆ7.9, 4.6 Hz, 1H),
1.41 4s, 3H), 1.40 4s, 3H), 0.90 4s, 9H), 0.08 4s, 6H); 13C
NMR 467.8 MHz, CDCl3) d 109.1, 80.2, 78.1, 63.7, 62.7,
27.0, 26.9, 25.8 43C), 18.3, 25.5 42C); MS 4FAB) m/z 299
4M1Na)1; HRMS 4FAB) calcd for C13H28O4SiNa
4M1Na)1 299.1654, found 299.1654.
4.1.2. Aldehyde 15. To a solution of oxalyl chloride
44.90 mL, 56.1 mmol) in dry CH2Cl2 440 mL) cooled to
2788C was added a solution of DMSO 48.00 mL,
112 mmol) in CH2Cl2 440 mL) dropwise. The reaction
mixture was stirred at 2788C for 15 min. A solution of
silyl ether 14 47.78 g, 28.1 mmol) in CH2Cl2 440 mL) was
added dropwise and the mixture was stirred at 2788C for an
additional 15 min. Triethylamine 423.6 mL, 169 mmol) was
added, and the mixture was stirred at 2788C for 15 min and
at 08C for 30 min. The reaction was quenched with water
450 mL) and extracted with a 3:1 mixture of benzene and
ether 4400 mL12£100 mL). The combined extracts were
washed with saturated aqueous NH4Cl 4150 mL) and brine
4150 mL), dried 4Na2SO4) and concentrated. The residual oil
was puri®ed by column chromatography on silica gel
4200 g, benzene/acetone, 64:1!4:1) to give 15 47.38 g,
91%) as a colorless oil: TLC, Rf 0.25±0.43 4hexane/
4. Experimental
4.1. General
Unless otherwise noted, materials were obtained from
commercial sources and used without further puri®cation.
All solvents were puri®ed by standard procedures before
use. The starting materials were azeotropically dried with
benzene before use. p-Toluenesulfonyl chloride,18 Dess±
Martin periodinane,13,19 and copper4I) iodide20 were
prepared according to procedures in the literature. All
reactions involving organometallic reagents were conducted
under a nitrogen atmosphere. Fuji Silysia silica gel BW-820
MH, Fuji Silysia silica gel FL-60D and Nacalai Tesque
Cosmosil 75C18-OPN were used for column chromato-
graphy unless otherwise noted. Merck precoated silica gel
60 F254 plates were used for TLC. Visualization was accom-
plished with UV light, phosphomolybdic acid, or p-anis-
aldehyde solution followed by heating. Optical rotations
were measured with a JASCO DIP-1000 polarimeter. IR
spectra were recorded on a JASCO FT/IR-230 spectrometer
EtOAc, 4:1); [a]30 ˆ110 4c 0.35, CHCl3); IR 4CHCl3)
D
1
2715, 1735, 1258, 1078, 838 cm21; H NMR 4270 MHz,
CDCl3) d 9.77 4d, Jˆ1.7 Hz, 1H), 4.33 4dd, Jˆ7.3,
1.7 Hz, 1H), 4.12 4dt, Jˆ7.3, 4.3 Hz, 1H), 3.80 4d,
Jˆ4.3 Hz, 2H), 1.47 4s, 3H), 1.39 4s, 3H), 0.90 4s, 9H),
0.08 4s, 6H); 13C NMR: 467.8 MHz, CDCl3) d 200.8,
111.4, 82.0, 77.6, 62.9, 26.8, 26.3, 25.8 43C), 18.4, 25.5
42C); MS 4FAB) m/z 297 4M1Na)1; HRMS 4FAB) calcd for
C13H27O4Si 4M1H)1 275.1679, found 275.1666.
1
in chloroform. H NMR spectra were recorded on a JEOL
JNM-EX270 4270 MHz), JEOL JNM-A400 4400 MHz),
JEOL JNM-A600 4600 MHz) or JEOL JNM-ECP800
4800 MHz) instrument. Chemical shifts are reported in
ppm from internal standards [tetramethylsilane 40.00 ppm)
for deuteriochloroform 4CDCl3)] and J values are in Hertz.
13C NMR spectra were recorded on a JEOL JNM-EX270
467.8 MHz), a JEOL JNM-A400 4100 MHz), a JEOL JNM-
A600 4150 MHz) or a JEOL JNM-ECP800 4201 MHz)
instrument using deuteriochloroform 4CDCl3) or benzene-
d6 4C6D6) as a solvent. Chemical shifts are reported in ppm
from the central peak of deuteriochloroform 477.0 ppm) or
benzene-d6 4128.0 ppm). Mass spectra 4FABMS, GCEI)
were recorded on a JEOL JMS LG2000 spectrometer. The
matrix used in FABMS analysis was m-nitrobenzyl alcohol.
Elemental analyses were performed with a LECO CHN-900
elemental analyzer.
4.1.3. Secondary alcohols 16. To a suspension of copper4I)
iodide 44.88 g, 25.6 mmol) in dry Et2O 450 mL) cooled to
2238C was added a 1.06 M solution of MeLi in Et2O
450 mL, 53 mmol) dropwise. The mixture was stirred at
2238C for 30 min and cooled to 2788C, and then a solution
of aldehyde 15 43.13 g, 11.4 mmol) in Et2O 420 mL) was
added dropwise. The mixture was stirred at 2788C for 1 h
and at 08C for 30 min. The reaction was quenched by adding
a 2:1 mixture of saturated aqueous NH4Cl and concentrated
aqueous NH3 490 mL). The resulting mixture was warmed
to room temperature, stirred for 1 h, and extracted with Et2O
43£90 mL). The combined extracts were washed with
water 490 mL) and brine 490 mL), dried 4Na2SO4) and
concentrated. The residual oil was puri®ed by column
chromatography on silica gel 480 g, benzene/acetone,
32:1!8:1!0:1) to give a diastereomeric mixture of second-
ary alcohols 16 42.97 g, 90%) as a colorless oil, which was
used in the next experiment without separation of the
diastereomers: TLC, Rf 0.55 4major), 0.61 4minor) 4hexane/
EtOAc, 2:1); IR 4CHCl3) 3600±3280 4br), 1258, 1080,
4.1.1. Silyl ether 14. To a stirred solution of 2,3-O-iso-
propylidene-d-threitol 45.00 g, 30.8 mmol) in dry DME
450 mL) cooled to 08C was added NaH 41.23 g of 60%
dispersion in mineral oil, 30.8 mmol). The mixture was
stirred at 08C for 30 min. tert-Butyldimethylsilylchloride
44.74 g, 30.5 mmol) was added, and the mixture was stirred
at 08C for 30 min and at room temperature for 3 h. The
reaction was quenched by adding water 450 mL) and Et2O
450 mL). The mixture was extracted with Et2O 43£100 mL).
The combined extracts were washed with brine 450 mL),
dried 4Na2SO4) and concentrated. The residual oil was
puri®ed by column chromatography on silica gel 4100 g,
hexane/EtOAc, 5:1!0:1) to give 14 48.25 g, 97%) as a
1
838 cm21; H NMR 4270 MHz, CDCl3) [noted only the
signal of the major diastereomer] d 3.96±3.64 4m, 5H),
2.35 4d, Jˆ6.6 Hz, 1H), 1.42 4s, 3H), 1.40 4s, 3H), 1.23 4d,
Jˆ6.3 Hz, 3H), 0.90 4s, 9H), 0.08 4s, 6H); 13C NMR
467.8 MHz, CDCl3) [noted only the signal of the major

K. Araki et al. / Tetrahedron 58 ,2002) 1983±1995
1989
diastereomer] d 108.8, 82.7, 80.5, 66.9, 64.3, 27.1 42C),
25.9 43C), 18.4, 25.4, 25.5; MS 4GCEI) m/z 275
4M12CH3, 17), 233 4M12C4H9, 16), 175 4M12C6H15Si,
38), 131 4100); HRMS 4FAB) calcd for C14H30O4SiNa
4M1Na)1 327.1968, found 327.1951.
temperature for 15 h. After the solution was re-cooled to
08C, 10 mL of ethanol, 34 mL of saturated aqueous sodium
acetate and 11 mL of 30% hydrogen peroxide were added in
that order. The mixture was stirred at 08C for 1 h and at
room temperature for 5 h, and then the solution was diluted
with Et2O 4300 mL), washed with water 42£150 mL),
saturated aqueous sodium bicarbonate 4150 mL), and
saturated aqueous NH4Cl 4150 mL), dried 4Na2SO4) and
concentrated. The residual oil was puri®ed by column
chromatography on silica gel [4200 g, CHCl3/EtOAc,
32:1!16:1!8:1!4:1!0:1) and 4100 g, hexane/CHCl3/
EtOAc, 20:1:1!20:2:1!0:0:1)] to give 18 42.57 g, 99%)
as a colorless oil: TLC, Rf 0.16 4hexane/EtOAc, 6:1); IR
4.1.4. Methyl ketone 17. To a solution of oxalyl chloride
41.78 mL, 20.4 mmol) in dry CH2Cl2 414 mL) cooled to
2788C was added a solution of DMSO 42.89 mL,
40.8 mmol) in CH2Cl2 414 mL) dropwise. The reaction
mixture was stirred at 2788C for 15 min. A solution of
secondary alcohols 16 42.96 g, 10.2 mmol) in CH2Cl2
414 mL) was added dropwise and the mixture was stirred
at 2788C for an additional 15 min. Triethylamine 48.59 mL,
61.1 mmol) was added, and the mixture was then stirred at
2788C for 15 min and at 08C for 30 min. The reaction was
quenched with water 430 mL) and extracted with a 3:1
mixture of benzene and ether 428 mL). The combined
extracts were washed with water 42£60 mL) and brine
460 mL), dried 4Na2SO4) and concentrated. The residual
oil was puri®ed by column chromatography on silica gel
430 g, hexane/Et2O, 16:1!8:1!4:1!0:1) to give 17
42.83 g, 96%) as a colorless oil: TLC, Rf 0.68 4hexane/
1
4CHCl3) 3600±3280 4br), 1258, 1080, 838 cm21; H NMR
4270 MHz, CDCl3) [noted only the signal of the major dia-
stereomer] d 3.96±3.64 4m, 2H), 3.93±3.87 4m, 2H), 3.74
4d, Jˆ4.0 Hz, 2H), 2.82 4dd, Jˆ6.6, 5.0 Hz, 1H), 1.94 4m,
1H), 1.42 4s, 3H), 1.38 4s, 3H), 0.94 4d, Jˆ6.9 Hz, 3H), 0.90
4s, 9H), 0.08 4s, 6H); 13C NMR 467.8 MHz, CDCl3) [noted
only the signal of the major diastereomer] d 108.8, 82.7,
80.5, 66.9, 64.3, 38.5, 27.4, 27.1, 25.9 43C), 18.4, 13.3,
25.4, 25.5; MS 4FAB) m/z 327 4M1Na)1. HRMS 4FAB)
calcd for C15H32O4SiNa 4M1Na)1 327.1951, found
327.1951.
EtOAc, 4:1); [a]31 ˆ218 4c 0.31, CHCl3); IR 4CHCl3)
D
1
1718, 1258, 1220, 1190, 910, 840, 480 cm21; H NMR
4270 MHz, CDCl3) d 4.31 4d, Jˆ7.6 Hz, 1H), 4.05 4ddd,
Jˆ8.1, 7.6, 7.3 Hz, 1H), 3.87 4dd, Jˆ11.3, 8.1 Hz, 1H),
3.75 4dd, Jˆ11.3, 7.3 Hz, 1H), 2.28 4s, 3H), 1.45 4s, 3H),
1.42 4s, 3H), 0.90 4s, 9H), 0.08 4s, 6H); 13C NMR
467.8 MHz, CDCl3) d 208.5, 110.7, 81.5, 78.8, 63.0, 26.9,
26.5, 26.4, 25.9 43C), 18.4, 25.3, 25.4; MS 4GCEI) m/z 273
4M12CH3, 4), 231 4M12C4H9, 18), 173 4M12C6H15Si,
46), 117 4100); HRMS 4FAB) calcd for C14H29O4Si
4M1H)1 289.1835, found 289.1834.
4.1.7. Acetonide 19. To a stirred solution of alcohol 18
497.2 mg, 319 mmol) in dry acetone 410 mL) was added
p-toluenesulfonic acid 41.2 mg, 6.39 mmol). The mixture
was stirred at room temperature for 22 h. Saturated aqueous
NaHCO3 42 mL) was added and the resulting mixture was
extracted with EtOAc 43£10 mL). The combined extracts
were washed with water 410 mL) and brine 410 mL), dried
4Na2SO4) and concentrated. The residual oil was puri®ed by
column chromatography on silica gel 45 g, hexane/EtOAc,
6:1!5:1!4:1!0:1) to give 19 414.5 mg, 20%) as a color-
4.1.5. Ole®n 12. To a stirred solution of methyltriphenyl-
phosphonium bromide 47.49 g, 21.0 mmol) in dry THF
445 mL) cooled to 2408C was added dropwise a 1.49 M
solution of n-BuLi in hexane 413.8 mL, 20.5 mmol) to
give a yellow solution. After 1 h, a solution of methylketone
17 42.82 g, 9.78 mmol) in THF 420 mL) was added. The
reaction mixture was stirred at 2408C for 30 min and at
room temperature for 12 h and then diluted with ether
465 mL). The solution was washed with 5% aqueous
NH4Cl 465 mL), water 42£50 mL) and brine 450 mL),
dried 4Na2SO4) and concentrated. The residual oil was
puri®ed by column chromatography on silica gel 480 g,
hexane/Et2O, 16:1!8:1!4:1) to give 12 42.66 g, 95%) as
less oil: TLC, Rf 0.65 4hexane/EtOAc, 2:1); [a]31 ˆ282
D
4c 0.15, CHCl3); IR 4CHCl3) 1460, 1380, 1370, 1230,
1
1160, 1060 cm21; H NMR 4270 MHz, CDCl3) d 4.26 4dt,
Jˆ6.9, 2.6 Hz, 1H), 3.99 4dd, Jˆ12.2, 6.9 Hz, 1H), 3.94 4dd,
Jˆ12.2, 6.9 Hz, 1H), 3.72 4dd, Jˆ10.6, 5.3 Hz, 1H), 3.49 4t,
Jˆ10.6 Hz, 1H), 3.44 4dd, Jˆ10.6, 2.6 Hz, 1H), 2.05 4tqd,
Jˆ10.6, 6.6, 5.3 Hz, 2H), 1.42 4s, 3H), 1.40 4s, 3H), 1.39 4s,
3H), 1.37 4s, 3H), 0.83 4d, Jˆ6.6 Hz, 3H); 13C NMR
467.8 MHz, CDCl3) d 109.3, 98.3, 75.3, 73.9, 65.9, 64.9,
30.3, 29.3, 25.9, 25.8, 19.2, 12.7; MS 4FAB) m/z 253
4M1Na)1; HRMS 4FAB) calcd for C12H22O4Na
4M1Na)1 253.1416, found 253.1434.
a
colorless oil: TLC, Rf 0.64 4hexane/Et2O, 6:1);
4.1.8. Aldehyde 20. To a stirred solution of alcohol 18
42.43 g, 7.99 mmol) in dry CH2Cl2 470 mL) was added
Dess±Martin periodinane 44.04 g, 9.53 mmol) at room
temperature. The mixture was stirred at room temperature
for 1.5 h, and the reaction was quenched by adding saturated
aqueous Na2S2O3 450 mL), saturated aqueous NaHCO3
450 mL), water 450 mL) and Et2O 4290 mL). The resulting
mixture was stirred at room temperature for 1 h and
extracted with Et2O 43£100 mL). The combined extracts
were washed with water 4100 mL) and brine 4100 mL),
dried 4Na2SO4) and concentrated. The residual oil was
puri®ed by column chromatography on silica gel 4100 g,
hexane/Et2O, 16:1!12:1!8:1) to give 20 41.95 g, 81%)
as a colorless oil: TLC, Rf 0.56 4hexane/Et2O, 3:1); IR
[a]32 ˆ0.94 4c 0.021, CHCl3); IR 4CHCl3) 1220, 1205,
D
790, 723, 670 cm21; H NMR 4270 MHz, CDCl3) d 5.05
1
4br s, 1H), 4.95 4br s, 1H), 4.36 4d, Jˆ8.3 Hz, 1H), 3.85±
3.66 4m, 3H), 1.78 4s, 3H), 1.44 4s, 3H), 1.42 4s, 3H), 0.90 4s,
9H), 0.07 4s, 6H); 13C NMR 467.8 MHz, CDCl3) d 142.0,
114.0, 108.9, 81.1, 80.0, 62.8, 27.1 42C), 25.9 43C), 18.4,
17.4, 25.3, 25.4; MS 4FAB) m/z 309 4M1Na)1; HRMS
4FAB) calcd for C15H31O3Si 4M1H)1 287.2042, found
287.2051.
4.1.6. Alcohol 18. To a stirred solution of ole®n 12 42.44 g,
8.53 mmol) in dry THF 454 mL) cooled to 08C was added a
0.5 M solution of 9-BBN in THF 468 mL, 34 mmol). The
reaction mixture was stirred at 08C for 1 h and at room
4CHCl3) 2730, 1725, 1255, 1210, 1085, 840 cm21 1H
;

1990
K. Araki et al. / Tetrahedron 58 ,2002) 1983±1995
NMR 4270 MHz, CDCl3) [noted only the signal of the major
diastereomer] d 9.78 4d, Jˆ2.3 Hz, 1H), 4.14 4dd, Jˆ7.3,
6.3 Hz, 1H), 4.00±3.68 4m, 3H), 2.62 4m, 1H), 1.39 4s, 6H),
1.16 4d, Jˆ6.9 Hz, 3H), 0.90 4s, 9H), 0.07 4s, 6H); 13C NMR
467.8 MHz, CDCl3) [noted only the signal of the major
diastereomer] d 203.3, 109.3, 79.5, 79.2, 63.8, 48.9, 27.2,
27.0, 25.9 43C), 18.3, 10.9, 25.4, 25.5; MS 4FAB) m/z 325
4M1Na)1; HRMS 4FAB) calcd for C15H30O4SiNa
4M1Na)1 325.1811, found 325.1815.
4.1.11. Alcohol 23. To a stirred solution of ester 22
4360 mg, 961 mmol) in CH2Cl2 47.0 mL) cooled to 2788C
was added a 0.95 M solution of diisobutylaluminum hydride
in hexane 45.5 mL, 5.23 mmol) dropwise. The mixture was
stirred at 2788C for 3 h and the reaction was quenched by
adding MeOH 41.0 mL). The resulting mixture was warmed
to room temperature. Ether 4120 mL), brine 42.0 mL), and
MgSO4 45.0 g) were added, and the mixture was stirred at
room temperature for 2 h. The mixture was ®ltered through
a pad of Celite, and the residue was washed with Et2O
470 mL). The ®ltrate and the washings were combined and
concentrated to give an aldehyde 4318 mg) as a colorless oil,
which was used in the next experiment without puri®cation.
To a stirred solution of the aldehyde 4318 mg) in EtOH
45.0 mL) cooled to 08C was added sodium borohydride
444 mg, 1.15 mmol). The mixture was stirred at 08C for
30 min. The reaction was quenched by adding acetone
41.0 mL), and the resulting mixture was stirred at room
temperature for 20 min. Saturated aqueous NH4Cl
43.0 mL) was added, and the mixture was extracted with
Et2O 45.0 mL). The combined extracts were washed with
water 415 mL) and brine 415 mL), dried 4Na2SO4) and
concentrated. The residual oil was puri®ed by column chro-
matography on silica gel 44 g, hexane/EtOAc, 2:1!0:1) to
give 23 4287 mg, 90%) as a colorless oil: TLC, Rf 0.42
4.1.9. Conjugated ester 21. To a stirred solution of diethyl-
4ethoxycarbonyl)methylphosphonate 41.50 g, 6.69 mmol) in
THF 410 mL) cooled to 08C was added potassium tert-
butoxide 4746 mg, 6.64 mmol), and the resulting solution
was stirred at room temperature for 1 h. The solution was
cooled to 2788C, and a solution of aldehyde 20 4498 mg,
1.65 mmol) in THF 46.0 mL) was added. After the
reaction mixture was stirred at 2788C for 1 h and at 08C
for 2 h, ether 415 mL) and saturated aqueous NH4Cl
415 mL) were added. The resulting mixture was extracted
with Et2O 43£15 mL) and the combined extracts were
washed with water 415 mL) and brine 415 mL), dried
4Na2SO4) and concentrated. The residual oil was puri®ed
by column chromatography on silica gel 435 g, hexane/
Et2O, 20:1!10:1!5:1!0:1) to give 21 4513 mg, 84%) as
a colorless oil: TLC, Rf 0.41 4hexane/Et2O, 3:1); IR
4hexane/EtOAc, 2:1); [a]32 ˆ111 4c 0.27, CHCl3); IR
D
4CHCl3) 1715, 1255, 1085, 840 cm21
;
1H NMR
4CHCl3) 3620, 3580±3280 4br), 1250, 1050, 840 cm21; H
1
4270 MHz, CDCl3) d 7.01 4dd, Jˆ15.8, 7.9 Hz, 0.87H),
6.91 4dd, Jˆ15.8, 7.9 Hz, 0.13H), 5.87 4dd, Jˆ15.8,
1.0 Hz, 0.13H), 5.84 4d, Jˆ15.8, 1.0 Hz, 0.87H), 4.19
4q, Jˆ6.9 Hz, 2H), 3.94±3.62 4m, 4H), 2.61 4m, 1H),
1.379 4s, 3H), 1.377 4s, 3H), 1.29 4t, Jˆ6.9 Hz, 3H), 1.15
4d, Jˆ6.9 Hz, 3H), 0.90 4s, 9H), 0.07 4s, 6H); 13C NMR
467.8 MHz, CDCl3) [noted only the signal of the major
diastereomer] d 166.4, 149.6, 122.1, 108.9, 81.4, 79.1,
64.0, 60.2, 39.2, 27.2 42C), 25.9 43C), 18.3, 16.6, 14.3,
25.4, 25.5; MS 4FAB) m/z 395 4M1Na)1; HRMS 4FAB)
calcd for C19H36O5SiNa 4M1Na)1 395.2229, found
395.2231.
NMR 4270 MHz, CDCl3) d 3.85 4dt, Jˆ6.9, 4.3 Hz, 1H),
3.78±3.68 4m, 5H), 1.78±1.48 4m, 5H), 1.39 4s, 3H), 1.37 4s,
3H), 1.24 4m, 1H), 0.94 4d, Jˆ6.9 Hz, 3H), 0.90 4s, 9H),
0.07 4s, 6H); 13C NMR 467.8 MHz, CDCl3) d 108.4, 82.1,
79.9, 64.6, 63.2, 36.1, 30.1, 28.7, 27.5, 27.3, 25.9 43C), 18.4,
15.8, 25.3, 25.4; MS 4FAB) m/z 355 4M1Na)1; HRMS
4FAB) calcd for C17H36O4SiNa 4M1Na)1 355.2264, found
355.2264.
4.1.12. p-Methoxybenzyl ether 24. To a stirred solution of
alcohol 23 4799 mg, 2.40 mmol) in dry DMF 41.2 mL)
cooled to 2208C were added p-methoxybenzyl chloride
40.39 ml, 2.88 mmol) and NaH 4106 mg of 60% dispersion
in mineral oil, 2.65 mmol). The mixture was stirred at
2208C for 4 days, and the reaction was quenched by adding
saturated aqueous NH4Cl 410 mL). The mixture was
extracted with EtOAc 43£30 mL). The combined extracts
were washed with brine 430 mL), dried 4Na2SO4) and
concentrated. The residual oil was puri®ed by column
chromatography on silica gel 490 g, hexane/EtOAc,
16:1!8:1!2:1!0:1) to give 24 4894 mg, 82%) as a color-
4.1.10. Ester 22. A mixture of conjugated ester 21 4642 mg,
1.72 mmol) and 5% Rh on alumina 466 mg) in EtOAc
417 mL) was stirred under a hydrogen atmosphere at room
temperature for 4 h. The reaction mixture was ®ltered
through a pad of Celite, and the residue was washed with
EtOAc 450 mL). The ®ltrate and the washings were
combined and concentrated. The residual oil was puri®ed
by column chromatography on silica gel [480 g, hexane/
Et2O, 32:1!16:1!12:1!8:1!0:1) and 4FL-60D, 30 g,
hexane/Et2O, 32:1!16:1!8:1)] to give 22 4561 mg, 87%)
as a colorless oil: TLC, Rf 0.58 4hexane/Et2O, 2:1);
less oil: TLC, Rf 0.58 4hexane/Et2O, 2:1); [a]31 ˆ121 4c
D
0.29, CHCl3); IR 4CHCl3) 1615, 1515, 1250, 1210, 1085,
840 cm21 1H NMR 4270 MHz, CDCl3) d 7.26 4br d,
;
[a]31 ˆ111 4c 0.28, CHCl3); IR 4CHCl3) 1725, 1255,
Jˆ8.6 Hz, 2H), 6.87 4br d, Jˆ8.6 Hz, 2H), 4.43 4s, 2H),
3.80 4s, 3H), 3.85±3.41 4m, 6H), 1.80±1.51 4m, 4H), 1.38
4s, 3H), 1.37 4s, 3H), 1.21 4m, 1H), 0.92 4d, Jˆ6.9 Hz, 3H),
0.89 4s, 9H), 0.08 4s, 6H); 13C NMR 467.8 MHz, CDCl3) d
159.1, 130.8, 129.2 42C), 113.8 42C), 108.3, 82.0, 79.7,
72.6, 70.4, 64.7, 55.3, 36.1, 29.0, 27.5, 27.3, 25.9 43C),
18.4, 15.7, 14.2, 25.3, 25.4; MS 4FAB) m/z 475
4M1Na)1; HRMS 4FAB) calcd for C25H44O5SiNa
4M1Na)1 475.2856, found 475.2831.
D
1
1110, 840 cm21; H NMR 4270 MHz, CDCl3) d 4.12 4q,
Jˆ6.9 Hz, 2H), 3.86 4ddd, Jˆ6.9, 4.0, 4.0 Hz, 1H), 3.76
4t, Jˆ6.9 Hz, 1H), 3.73 4dd, Jˆ10.9, 4.0 Hz, 1H), 3.67
4dd, Jˆ10.9, 4.0 Hz, 1H), 2.43±2.28 4m, 2H), 1.96 4m,
1H), 1.72 4m, 1H), 1.48 4m, 1H), 1.39 4s, 3H), 1.37 4s,
3H), 1.25 4t, Jˆ6.9 Hz, 3H), 0.93 4d, Jˆ6.9 Hz, 3H), 0.90
4s, 9H), 0.07 4s, 6H); 13C NMR 467.8 MHz, CDCl3) d 173.7,
108.5, 82.0, 79.8, 64.5, 60.2, 35.8, 32.1, 28.0, 27.4, 27.3,
25.9 43C), 18.4, 15.7, 14.2, 25.3, 25.4; MS 4FAB) m/z 375
4M1H)1; HRMS 4FAB) calcd for C19H38O5SiNa 4M1Na)1
397.2386, found 397.2392.
4.1.13. Alcohol 10. To a stirred solution of p-methoxy-
benzyl ether 24 41.17 g, 2.59 mmol) in dry THF 46.25 mL)

K. Araki et al. / Tetrahedron 58 ,2002) 1983±1995
1991
was added a 1.0 M solution of tetrabutylammonium ¯uoride
45.07 mL, 5.07 mmol) in THF at room temperature. The
mixture was stirred at room temperature for 1 h. Ether
425 mL) and saturated aqueous NH4Cl 46.5 mL) were
added, and the mixture was extracted with EtOAc
43£35 mL). The combined extracts were washed with
brine 435 mL), dried 4Na2SO4) and concentrated. The
residual oil was puri®ed by column chromatography on
silica gel 4150 g, benzene/acetone, 20:1) to give 10
4869 mg, 99%) as a colorless oil: TLC, Rf 0.41 4hexane/
4.1.15. Z-Ole®n 28. A mixture of acetylene 27 43.6 mg,
7.13 mmol) and Lindlar cat. 40.3 mg) in MeOH 40.20 mL)
was stirred under a hydrogen atmosphere at room tempera-
ture for 6 h. The reaction mixture was ®ltered through a pad
of Celite, and the residue was washed with EtOAc 45.0 mL).
The ®ltrate and the washings were combined and concen-
trated. The residual oil was puri®ed by column chromato-
graphy on silica gel 4500 mg, hexane/Et2O, 8:1!5:1) to
give 28 43.6 mg, 100%) as a colorless oil: TLC, Rf 0.47
4hexane/EtOAc, 5:1); [a]27 ˆ117 4c 0.20, CHCl3); IR
D
1
EtOAc, 1:1); [a]32 ˆ10.44 4c 0.20, CHCl3); IR 4CHCl3)
4CHCl3) 1610, 1515, 1250, 1220, 1090, 840, 670 cm21; H
D
3590, 3000, 1610, 1515, 1250, 1215, 1095, 1035 cm21
;
NMR 4400 MHz, CDCl3) d 7.26 4br d, Jˆ8.6 Hz, 2H), 6.87
4br d, Jˆ8.6 Hz, 2H), 5.57 4m, 1H), 5.51 4m, 1H), 4.43 4s,
2H), 3.83 4ddd, Jˆ7.1, 7.1, 4.2 Hz, 1H), 3.80 4s, 3H), 3.61 4t,
Jˆ7.1 Hz, 2H), 3.51 4dd, Jˆ7.1, 7.1 Hz, 1H), 3.44 4t,
Jˆ6.6 Hz, 2H), 2.42±2.22 4m, 4H), 1.78±1.42 4m, 4H),
1.38 4s, 3H), 1.36 4s, 3H), 1.22 4m, 1H), 0.92 4d,
Jˆ6.8 Hz, 3H), 0.89 4s, 9H), 0.05 4s, 6H); 13C NMR
467.8 MHz, CDCl3) d 159.1, 130.7, 129.2 42C), 128.0,
126.8, 113.8 42C), 107.9, 84.7, 78.7, 72.6, 70.4, 62.8,
55.3, 36.0, 32.3, 31.4, 29.1, 27.4, 27.3 42C), 26.0 43C),
18.4, 15.8, 25.3 42C); MS 4FAB) m/z 529 4M1Na)1;
HRMS 4FAB) calcd for C29H50O5SiNa 4M1Na)1
529.3325, found 529.3331.
1H NMR 4270 MHz, CDCl3) d 7.26 4br d, Jˆ8.6 Hz, 2H),
6.87 4br d, Jˆ8.6 Hz, 2H), 4.43 4s, 2H), 3.90 4ddd, Jˆ7.6,
5.3, 3.0 Hz, 1H), 3.80 4s, 3H), 3.78 4ddd, Jˆ11.9, 6.3,
3.0 Hz, 1H), 3.68 4t, Jˆ7.6, 7.6 Hz, 1H), 3.58 4ddd,
Jˆ11.9, 6.3, 5.3 Hz, 1H), 3.44 4t, Jˆ6.3 Hz, 2H), 1.92
4t, Jˆ6.3 Hz, 1H), 1.78±1.51 4m, 5H), 1.40 4s, 6H), 1.22
4m, 1H), 0.91 4d, Jˆ6.9 Hz, 3H); 13C NMR 467.8 MHz,
CDCl3) d 159.1, 130.7, 129.3 42C), 113.8 42C), 108.5,
80.9, 79.6, 72.6, 70.3, 63.6, 55.3, 36.2, 29.4, 27.3, 27.23,
27.16, 15.3; MS 4FAB) m/z 361 4M1Na)1; HRMS
4FAB) calcd for C19H30O5Na 4M1Na)1 361.1991, found
361.1995.
4.1.14. Acetylene 27. To a solution of alcohol 10 415.4 mg,
45.5 mmol)
4.1.16. Alcohol 29. To a stirred solution of Z-ole®n 28
4105 mg, 207 mmol) in dry CH2Cl2 432 mL), tert-butyl
alcohol 43.2 mL), and 1 M phosphate buffer 4pH 6,
3.2 mL) cooled to 08C was added 2,3-dichloro-5,6-
dicyano-p-benzoquinone 4DDQ) 4219 mg, 869 mmol). The
mixture was warmed to room temperature, and stirring was
continued for 1.5 h. The reaction was quenched by adding
saturated aqueous NaHCO3 418 mL), and the resulting
mixture was stirred at room temperature for 10 min. The
mixture was extracted with CHCl3 43£40 mL), and the
combined extracts were washed with brine 440 mL), dried
4Na2SO4) and concentrated. The residual oil was puri®ed by
column chromatography on silica gel 47 g, hexane/EtOAc,
5:1!4:1!1:1) to give 29 476.6 mg, 96%) as a colorless oil:
and
2,6-di-tert-butyl-4-methylpyridine
440.6 mg, 198 mmol) in dry CH2Cl2 40.70 mL) cooled to
2308C was added tri¯uoromethanesulfonic anhydride
420 mL, 118 mmol). The reaction mixture was warmed to
2108C, stirred at 2108C for 40 min, and then concentrated
in vacuo to give the desired tri¯ate 26 as a clear oil. To a
solution of 4-tert-butyldimethylsilyloxy-1-butyne 4103 mg,
559 mmol) in dry THF 43.5 mL) cooled to 2788C were
added HMPA 480 mL, 1.04 mmol) and a 1.56 M solution
of n-BuLi 40.30 mL, 468 mmol) in hexane. The mixture
was stirred at 2788C for 30 min, warmed to 2358C, and
kept at this temperature for 10 min. In the meantime, the
tri¯ate 26 described above was dissolved in dry THF
40.8 mL), and the resulting solution was added dropwise
to the acetylide solution at 2358C. This solution was
allowed to warm to room temperature over 5 h. The reaction
was quenched with 1:1 saturated aqueous NH4Cl/water
43.0 mL) and extracted with EtOAc 43£5 mL). The
combined extracts were washed with water 45 mL) and
brine 45 mL), dried 4Na2SO4), and concentrated. The
residual oil was puri®ed by column chromatography on
silica gel 414 g, hexane/EtOAc, 12:1!8:1!1:1!0:1) to
give 27 418.8 mg, 82%) as a colorless oil; TLC, Rf 0.39
TLC, Rf 0.13 4hexane/EtOAc, 4:1); [a]29 ˆ120 4c 0.20,
D
CHCl3); IR 4CHCl3) 3615, 1460, 1380, 1255, 1090, 1050,
1
840, 660 cm21; H NMR 4270 MHz, CDCl3) d 5.61±5.49
4m, 2H), 3.84 4dt, Jˆ4.2, 7.3 Hz, 1H), 3.64±3.50 4m, 3H),
3.62 4t, Jˆ7.1 Hz, 1H), 3.52 4t, Jˆ7.1 Hz, 1H), 2.42±2.22
4m, 4H), 1.76±1.49 4m, 4H), 1.46 4br s, 1H), 1.38 4s, 3H),
1.37 4s, 3H), 1.22 4m, 1H), 0.93 4d, Jˆ6.9 Hz, 3H), 0.90 4s,
9H), 0.05 4s, 6H); 13C NMR 467.8 MHz, CDCl3) d 128.1,
126.7, 108.0, 84.7, 78.9, 63.1, 62.8, 36.0, 32.3, 31.4, 30.1,
28.8, 27.4, 27.3, 26.0 43C), 18.4, 16.0, 25.3 42C); MS
4FAB) m/z 409 4M1Na)1; HRMS 4FAB) calcd for
C21H42O4SiNa 4M1Na)1 409.2750, found 409.2768.
4hexane/EtOAc, 5:1); [a]28 ˆ114 4c 0.21, CHCl3); IR
D
1
4CHCl3) 1610, 1515, 1250,1090, 840, 730 cm21; H NMR
4270 MHz, CDCl3) d 7.26 4br d, Jˆ8.6 Hz, 2H), 6.87 4br d,
Jˆ8.6 Hz, 2H), 4.43 4s, 2H), 3.88 4dt, Jˆ6.6, 5.3 Hz, 1H),
3.80 4s, 3H), 3.69 4t, Jˆ6.6 Hz, 1H), 3.69 4t, Jˆ7.3 Hz, 2H),
3.44 4t, Jˆ6.6 Hz, 2H), 2.58±2.33 4m, 4H), 1.80±1.46 4m,
4H), 1.40 4s, 3H), 1.38 4s, 3H), 1.20 4m, 1H), 0.94 4d,
Jˆ6.6 Hz, 3H), 0.89 4s, 9H), 0.06 4s, 6H); 13C NMR
467.8 MHz, CDCl3) d 159.1, 150.2, 130.7, 129.2 42C),
113.8 42C), 108.4, 84.3, 79.2, 77.1, 72.6, 70.3, 62.2, 55.3,
35.7, 28.9, 27.5, 27.4, 27.3, 25.9 43C), 24.4, 23.2, 18.3, 15.8,
25.3 42C); MS 4FAB) m/z 527 4M1Na)1; HRMS 4FAB)
calcd for C29H48O5SiNa 4M1Na)1 527.3169, found
527.3170.
4.1.17. C1±C11 segment 8. To a stirred solution of alcohol
29 418.0 mg, 46.6 mmol) in dry CH2Cl2 41.0 mL) and dry
pyridine 40.40 mL) was added Dess±Martin periodinane
447.2 mg, 111 mmol) at room temperature. The mixture
was stirred at room temperature for 1 h, and the reaction
was quenched by adding saturated aqueous Na2S2O3
41.0 mL), saturated aqueous NaHCO3 41.0 mL) and Et2O
45.0 mL). The resulting mixture was stirred at room
temperature for 30 min and extracted with Et2O
43£15 mL). The combined extracts were washed with a
1:1 mixture of water and saturated aqueous NaHCO3

1992
K. Araki et al. / Tetrahedron 58 ,2002) 1983±1995
410 mL) and brine 410 mL), dried 4Na2SO4) and con-
centrated. The residual oil was puri®ed by column
chromatography on silica gel 42 g, hexane/EtOAc,
10:1!4:1!2:1!0:1) to give 8 417.8 mg, 99%) as a color-
4H), 2.25 4dd, Jˆ15.2, 8.3 Hz, 1H), 2.15±1.84 4m, 7H),
1.72±1.48 4m, 2H); 13C NMR 467.8 MHz, CDCl3) d
138.2, 137.8, 128.4 42C), 127.7 43C), 115.0, 74.4, 73.3,
67.6, 52.1, 41.3, 39.0, 33.7, 26.3, 26.0, 25.0, 23.2; MS
4FAB) m/z 375 4M1Na)1; HRMS 4FAB) calcd for
C19H28O2NaS2 4M1Na)1 375.1429, found 375.1399.
less oil: TLC, Rf 0.74 4hexane/EtOAc, 2:1); [a]27 ˆ116 4c
D
0.20, CHCl3); IR 4CHCl3) 2740, 1720, 1460, 1380, 1260,
1090, 1060, 840 cm21; 1H NMR 4270 MHz, CDCl3) d 9.78
4t, Jˆ2.0 Hz, 1H), 5.63±5.47 4m, 2H), 3.85 4dt, Jˆ4.6,
7.3 Hz, 1H), 3.62 4t, Jˆ7.3 Hz, 2H), 3.49 4t, Jˆ7.3 Hz,
1H), 2.62±2.24 4m, 4H), 2.05±1.83 4m, 2H), 1.72±1.48
4m, 2H), 1.40 4s, 3H), 1.38 4s, 3H), 1.26 4m, 1H), 0.92 4d,
Jˆ6.6 Hz, 3H), 0.89 4s, 9H), 0.05 4s, 6H); 13C NMR
467.8 MHz, CDCl3) d 202.5, 128.2, 126.5, 108.2, 84.5,
79.1, 62.7, 41.5, 35.9, 32.3 42C), 31.4, 27.34, 27.27, 26.0
43C), 25.3, 16.1, 25.3 42C); MS 4FAB) m/z 407 4M1Na)1;
HRMS 4FAB) calcd for C21H40O4SiNa 4M1Na)1 407.2593,
found 407.2620.
4.1.20. Ketone 13. To a solution of alcohol 31 450.3 mg,
143 mmol) in 99% aqueous acetone 41.5 mL) were added
CuCl2 438.1 mg, 283 mmol) and CuO 445.5 mg, 572 mmol).
The mixture was stirred at room temperature for 1 h. The
reaction mixture was ®ltered through a Celite pad and the
Celite was washed with Et2O. The combined ®ltrate and
washings were concentrated under reduced pressure and
the residue was diluted again with acetone 450 mL). The
solution was concentrated and diluted with EtOAc
415 mL) and 5% aqueous NaHCO3 solution 415 mL). The
aqueous layer was extracted with EtOAc 43£15 mL). The
combined extracts were dried 4Na2SO4) and concentrated.
The residual oil was puri®ed by column chromatography on
silica gel 42 g, hexane/EtOAc, 5:1!2:1!0:1) to give 13
432.4 mg, 86%) as a colorless oil: TLC, Rf 0.34 4hexane/
4.1.18. Ole®n 30. To a stirred solution of 1,3-dithiane
45.00 g, 41.6 mmol) in dry THF 4125 mL) cooled to
2208C was added a 1.64 M solution of n-BuLi in hexane
426.5 mL, 43.5 mmol). The reaction mixture was stirred at
2208C for 1 h. After cooling to 2788C, a solution of
5-bromo-1-pentene 45.07 mL, 42.8 mmol) was added drop-
wise over 5 min, and the mixture was warmed to room
temperature over 3 h. The reaction was quenched with
water 430 mL) and extracted with Et2O 43£50 mL). The
combined extracts were washed with water 450 mL) and
brine 450 mL), dried 4Na2SO4) and concentrated. The
residual oil was puri®ed by column chromatography on
silica gel 4150 g, hexane/benzene, 10:1!5:1!1:1) to give
30 47.66 g, 98%) as a colorless oil: TLC, Rf 0.57 4hexane/
Et2O, 4:1); IR 4CHCl3) 1640, 1425, 1270, 1215, 1175, 990,
920 cm21; 1H NMR 4270 MHz, CDCl3) d 5.79 4ddt, Jˆ16.8,
11.2, 6.6 Hz, 1H), 5.02 4br d, Jˆ16.8 Hz, 1H), 4.95 4br d,
Jˆ11.2 Hz, 1H), 4.05 4t, Jˆ6.9 Hz, 1H), 2.94±2.78 4m, 4H),
2.17±2.04 4m, 3H), 1.94±1.71 4m, 3H), 1.68±1.58 4m, 2H);
13C NMR 467.8 MHz, CDCl3) d 138.1, 115.0, 47.5, 34.8,
33.2, 30.4 42C), 26.0, 25.8; MS 4GCEI) m/z 188 4M)1;
HRMS 4GCEI) calcd for C9H16S2 4M)1 188.0694, found
188.0702.
EtOAc, 2:1); [a]28 ˆ115 4c 0.41, CHCl3); IR 4CHCl3)
D
3580, 3520±3200 4br.), 1715, 1640, 1455, 1360, 1125,
1090, 990, 915 cm21 1H NMR 4270 MHz, CDCl3) d
;
7.39±7.26 4m, 5H), 5.75 4ddt, Jˆ16.8, 11.2, 6.6 Hz, 1H),
5.05±4.95 4m, 2H), 4.55 4s, 2H), 4.26 4m, 1H), 3.49 4dd,
Jˆ9.6, 4.6 Hz, 1H), 3.44 4dd, Jˆ9.6, 5.9 Hz, 1H), 2.99 4d,
Jˆ4.3 Hz, 1H), 2.66 4dd, Jˆ16.8, 6.9 Hz, 1H), 2.58 4dd,
Jˆ16.8, 5.0 Hz, 1H), 2.45 4t, Jˆ7.3 Hz, 2H), 2.05 4br q,
Jˆ6.6 Hz, 2H), 1.73±1.62 4m, 2H); 13C NMR 467.8 MHz,
CDCl3) d 210.7, 137.9, 137.8, 128.4 42C), 127.7 43C),
115.3, 73.4, 73.3, 66.9, 45.7, 42.8, 33.0, 22.5; MS 4FAB)
m/z 285 4M1Na)1; HRMS 4FAB) calcd for C16H22O3Na
4M1Na)1 285.1665, found 285.1665.
4.1.21. anti-1,3-Diol 32a. To a stirred solution of tetra-
42.32 g,
methylammonium
triacetoxyborohydride
8.82 mmol) in dry acetonitrile 43.0 mL) and acetic acid
43.0 mL) cooled to 2408C was added alcohol 13 4323 mg,
1.23 mmol). The mixture was stirred at 2408C for 1 h,
warmed to 2308C, and kept at this temperature for 20 h.
The reaction was quenched by adding 1 M aqueous
potassium sodium tartrate 425 mL), and the mixture was
extracted with EtOAc 43£50 mL). The combined extracts
were washed with saturated aqueous NaHCO3 450 mL),
dried 4Na2SO4) and concentrated. The residual oil was
puri®ed by column chromatography on silica gel [4FL-
60D, 15 g, benzene/acetone, 10:1!9:1!2:1), 4FL-60D,
15 g, benzene/acetone, 10:1!9:1!2:1), and 4FL-60D,
7 g, benzene/acetone, 10:1!9:1!2:1)] to give anti-isomer
32a 4282 mg, 88%) and syn-isomer 32b 435.3 mg, 11%) as a
colorless oil: 32a; TLC, Rf 0.14 4hexane/EtOAc, 2:1);
4.1.19. Alcohol 31. To a stirred solution of ole®n 30 47.54 g,
40.0 mmol) in dry THF 460 mL) cooled to 2208C was
added a 1.64 M solution of n-BuLi in hexane 425 mL,
41.0 mmol). The reaction mixture was cooled to 2788C.
A solution of 4R)-42)-benzyl glycidyl ether 46.84 g,
41.7 mmol) in dry THF 440 mL) was added and the mixture
was warmed to room temperature over 5 h. The reaction was
quenched with saturated aqueous NH4Cl 460 mL) and
extracted with Et2O 43£150 mL). The combined extracts
were washed with brine 4150 mL), dried 4Na2SO4) and
concentrated. The residual oil was puri®ed by column chro-
matography on silica gel [4100 g, hexane/EtOAc,
20:1!10:1!8:1!4:1!0:1) and 4100 g, hexane/EtOAc,
20:1!8:1!4:1)] to give 31 412.5 g, 80%) as a colorless
[a]31 ˆ13.5 4c 0.27, CHCl3); IR 4CHCl3) 3590±3240
D
1
4br), 1640, 1495, 1455, 1365, 1090, 995, 915 cm21; H
NMR 4400 MHz, CDCl3) d 7.39±7.26 4m, 5H), 5.80 4ddt,
Jˆ13.5, 10.2, 6.6 Hz, 1H), 5.00 4br d, Jˆ13.5 Hz, 1H), 4.95
4br d, Jˆ10.2 Hz, 1H), 4.56 4s, 2H), 4.30 4m, 1H), 3.90 4m,
1H), 3.50 4dd, Jˆ9.2, 3.6 Hz, 1H), 3.43 4dd, Jˆ9.2, 7.6 Hz,
1H), 2.73 4d, Jˆ4.0 Hz, 1H), 2.43 4d, Jˆ4.6 Hz, 1H), 2.07
4br q, Jˆ6.6 Hz, 2H), 1.70±1.37 4m, 6H); 13C NMR
467.8 MHz, CDCl3) d 138.6, 137.8, 128.5 42C), 127.9,
127.8 42C), 114.6, 74.4, 73.4, 68.8, 68.1, 39.0, 37.0, 33.6,
oil: TLC, Rf 0.10 4hexane/EtOAc, 10:1); [a]27 ˆ117 4c
D
0.39, CHCl3); IR 4CHCl3) 3590, 1640, 1600, 1490, 1360,
1
1275, 1240, 1100, 990, 915 cm21; H NMR 4270 MHz,
CDCl3) d 7.38±7.26 4m, 5H), 5.79 4ddt, Jˆ16.8, 11.2,
6.6 Hz, 1H), 5.02 4br d, Jˆ16.8 Hz, 1H), 4.97 4br d,
Jˆ11.2 Hz, 1H), 4.58 4s, 2H), 4.15 4m, 1H), 3.45 4d,
Jˆ5.6 Hz, 2H), 3.17 4d, Jˆ2.6 Hz, 1H), 3.01±2.72 4m,

K. Araki et al. / Tetrahedron 58 ,2002) 1983±1995
1993
25.0; MS 4FAB) m/z 287 4M1Na)1; HRMS 4FAB) calcd for
C16H24O3Na 4M1Na)1 287.1623, found 287.1629. 32b;
1.56±1.40 4m, 5H), 1.38 4s, 3H), 1.36 4s, 3H); 13C NMR
467.8 MHz, CDCl3) d 138.6, 114.6, 100.4, 92.5, 67.5, 66.6,
65.5, 35.3, 33.8, 33.6, 24.9, 24.7; MS 4FAB) m/z 237
4M1Na)1; HRMS 4FAB) calcd for C12H22O3Na
4M1Na)1 237.1467, found 237.1459.
TLC, Rf 0.16 4hexane/EtOAc, 2:1); [a]31 ˆ114 4c 0.15,
D
CHCl3); IR 4CHCl3) 3590±3440 4br), 1640, 1495, 1455,
1380, 1200, 1170, 1110, 995, 915 cm21
;
1H NMR
4400 MHz, CDCl3) d 7.38±7.25 4m, 5H), 5.80 4ddt,
Jˆ17.1, 10.2, 6.8 Hz, 1H), 4.99 4br d, Jˆ17.1 Hz, 1H),
4.94 4br d, Jˆ10.2 Hz, 1H), 4.60 4br d, Jˆ12.2 Hz, 1H),
4.54 4br d, Jˆ12.2 Hz, 1H), 4.08 4m, 1H), 3.83 4m, 1H),
3.51 4dd, Jˆ10.0, 5.9 Hz, 1H), 3.37 4dd, Jˆ10.0, 5.1 Hz,
1H), 2.05 4br q, Jˆ6.8 Hz, 2H), 1.54±1.13 4m, 8H); 13C
NMR 4100 MHz, CDCl3) d 138.7, 137.3, 128.4 42C),
127.8 42C), 127.6, 114.5, 73.7, 73.5, 68.6, 68.5, 35.9,
33.6, 30.2, 24.3; MS 4FAB) m/z 287 4M1Na)1; HRMS
4FAB) calcd for C16H24O3Na 4M1Na)1 287.1623, found
287.1622.
4.1.24. C12±C21 segment 9. To a stirred solution of alco-
hol 34 445.0 mg, 210 mmol) in pyridine 41.0 mL) cooled to
08C was added p-toluenesulfonyl chloride 487.6 mg,
460 mmol). The mixture was stirred at 08C for 3.5 h, and
the reaction was quenched by adding water 42.0 mL). The
resulting mixture was extracted with Et2O 45.0 mL). The
combined extracts were dried 4Na2SO4) and concentrated
to give tosylate 480.5 mg) as a colorless oil, which was
used in the next experiment without puri®cation. To a stir-
red solution of methyl phenyl sulfone 4163 mg, 853 mmol)
in dry THF 47.0 mL) and cooled to 2308C was added a
1.56 M solution of n-BuLi in hexane 40.50 mL,
780 mmol). The mixture was warmed to room temperature
and kept at this temperature for 40 min. After adding a
solution of tosylate 480.5 mg) in THF 41.0 mL), the mixture
was stirred at re¯ux temperature for 22 h. The reaction was
quenched by adding saturated aqueous NH4Cl 42.0 mL), and
the mixture was extracted with Et2O 43£15 mL). The
combined extracts were washed with water 410 mL) and
brine 410 mL), dried 4Na2SO4) and concentrated. The
residual oil was puri®ed by column chromatography on
silica gel [44 g, hexane/EtOAc, 8:1!6:1!4:1!0:1) and
4.1.22. Acetal 33. To a stirred solution of anti-1,3-diol 32a
43.07 g, 11.6 mmol) in dry acetone 41.0 mL) were added
2,2-dimethoxypropane 428.5 mL, 232 mmol) and d-10-
camphorsulfonic acid 4136 mg, 585 mmol). The mixture
was stirred at room temperature for 2 days. EtOAc
426 mL) and saturated aqueous NaHCO3 426 mL) were
added and the mixture was extracted with EtOAc
43£60 mL). The combined extracts were washed with
brine 460 mL), dried 4Na2SO4) and concentrated. The
residual oil was puri®ed by column chromatography on
silica gel 4150 g, hexane/EtOAc, 20:1!10:1!0:1) to give
33 43.52 g, 100%) as a colorless oil: TLC, Rf 0.73 4hexane/
42 g, hexane/EtOAc, 7:1!6:1!5:1!2:1)] to give
9
EtOAc, 2:1); [a]27 ˆ13.7 4c 0.43, CHCl3); IR 4CHCl3)
463.6 mg, 86%) as a colorless oil: TLC, Rf 0.48 4hexane/
D
1640, 1600, 1495, 1455, 1380, 1220, 1170, 1090,
EtOAc, 2:1); [a]28 ˆ117 4c 0.36, CHCl3); IR 4CHCl3)
D
1
915 cm21; H NMR 4270 MHz, CDCl3) d 7.35±7.26 4m,
1710, 1640, 1585, 1445, 1380, 1310, 1225, 1150, 1085,
5H), 5.80 4ddt, Jˆ13.5, 10.2, 6.6 Hz, 1H), 5.02 4br d,
Jˆ13.5 Hz, 1H), 4.94 4br d, Jˆ10.2 Hz, 1H), 4.62 4d,
Jˆ12.2 Hz, 1H), 4.55 4d, Jˆ12.2 Hz, 1H), 3.77 4m, 1H),
3.50 4dd, Jˆ10.6, 4.3 Hz, 2H), 3.43 4dd, Jˆ10.6, 6.6 Hz,
1H), 2.06 4br q, Jˆ6.6 Hz, 2H), 1.71±1.34 4m, 6H), 1.38
4s, 3H), 1.37 4s, 3H); 13C NMR 467.8 MHz, CDCl3) d 138.7,
138.3, 128.4 42C), 127.7 42C), 127.6, 114.5, 100.3, 73.3,
72.7, 66.4, 66.3, 35.3, 34.8, 33.6, 24.8 42C), 24.7; MS
4FAB) m/z 305 4M1H)1; HRMS 4FAB) calcd for
C19H28O3Na 4M1Na)1 327.1936, found 327.1917.
1000, 915, 820 cm21 1H NMR 4270 MHz, CDCl3) d
;
7.94±7.90 4m, 2H), 7.70±7.54 4m, 3H), 5.79 4ddt, Jˆ17.2,
10.2, 6.6 Hz, 1H), 4.99 4m, 1H), 4.94 4m, 1H), 4.14±3.69
4m, 2H), 3.31 4ddd, Jˆ14.2, 10.6, 5.3 Hz, 1H), 3.09 4ddd,
Jˆ14.2, 10.2, 5.3 Hz, 1H), 2.10±2.00 4m, 2H), 2.00±1.79
4m, 2H), 1.64±1.22 4m, 6H), 1.28 4s, 3H), 1.27 4s, 3H); 13C
NMR 467.8 MHz, CDCl3) d 139.2, 138.6, 133.7, 129.3,
128.1, 114.6, 100.4, 66.4, 65.0, 53.1, 38.3, 35.2, 33.6,
28.8, 24.7 42C), 24.5; MS 4FAB) m/z 353 4M1H)1;
HRMS 4FAB) calcd for C19H28O4SNa 4M1Na)1
375.1606, found 375.1607.
4.1.23. Alcohol 34. Sodium 40.79 g, 34.4 mmol) was added
to a stirred solution of acetal 33 4251 mg, 824 mmol) in THF
44 mL) and liquid NH3 430 mL) cooled to 2788C. After the
mixture was stirred at 2788C for 30 min, NH4Cl 410 g) was
added. The mixture was allowed to warm to room tempera-
ture and then stirred for 1 h. EtOAc 430 mL) and water
450 mL) were added, and the mixture was extracted with
EtOAc 43£80 mL). The combined extracts were washed
with brine 450 mL), dried 4Na2SO4) and concentrated. The
residual oil was puri®ed by column chromatography on
silica gel 414 g, hexane/EtOAc, 10:1!2:1!1:1!0:1) to
give 34 4174 mg, 99%) as a colorless oil: TLC, Rf 0.27
4.1.25. Hydroxy sulfones. To a stirred solution of the C12±
C21 segment 9 467.0 mg, 190 mmol) in THF 40.60 mL)
cooled to 2788C was added a 1.56 M solution of n-BuLi
in hexane 40.10 mL, 156 mmol) dropwise. The mixture was
stirred at 2788C for 30 min, and a solution of the C1±C11
segment 8 414.0 mg, 36.4 mmol) in THF 40.50 mL) was
added dropwise. The resulting mixture was stirred at
2788C for 2 h. The reaction was quenched by adding satu-
rated aqueous NH4Cl 41.0 mL) and EtOAc 45.0 mL), and the
mixture was extracted with EtOAc 43£5.0 mL). The
combined extracts were washed with water 45.0 mL) and
brine 45.0 mL), dried 4Na2SO4), and concentrated. The
residual oil was puri®ed by column chromatography on silica
gel 44 g, hexane/EtOAc, 20:1!10:1!6:1!5:1!4:1) and by
ODS column chromatography 43.5 g, MeOH/H2O,
1:1!2:1!3:1!5:1!7:1!11:1!1:0) to give a diastereo-
meric mixture of hydroxy sulfones 431.0 mg) as a colorless
oil. The hydroxy sulfones were used in the next experiment
without separation of the diastereomers.
4hexane/EtOAc, 2:1); [a]32 ˆ130 4c 0.34, CHCl3); IR
D
4CHCl3) 3590, 3570±3250 4br), 1640, 1460, 1380, 1220,
1
1170, 1080, 1010, 915 cm21; H NMR 4270 MHz, CDCl3)
d 5.80 4ddt, Jˆ17.1, 10.5, 6.6 Hz, 1H), 5.00 4br d,
Jˆ17.1 Hz, 1H), 4.95 4br d, Jˆ10.5 Hz, 1H), 3.95 4m,
1H), 3.76 4m, 1H), 3.62 4ddd, Jˆ11.6, 7.8, 3.6 Hz, 1H),
3.51 4ddd, Jˆ11.6, 7.8, 3.8 Hz, 1H), 2.06 4br q, J, 2H),
1.95 4br s, 1H), 1.65 4ddd, Jˆ12.3, 9.3, 5.6 Hz, 1H),

1994
K. Araki et al. / Tetrahedron 58 ,2002) 1983±1995
4.1.26. Keto sulfones. To a stirred solution of hydroxy
sulfones 431.0 mg) in dry CH2Cl2 41.0 mL) and dry pyridine
40.4 mL) was added Dess±Martin periodinane 435.2 mg,
83.0 mmol) at room temperature. The mixture was stirred
at room temperature for 2 h, and the reaction was quenched
by adding saturated aqueous Na2S2O3 415 mL), saturated
aqueous NaHCO3 41.5 mL) and EtOAc 47.0 mL). The
resulting mixture was stirred at room temperature for
50 min and extracted with EtOAc 43£15 mL). The
combined extracts were washed with saturated aqueous
NaHCO3 410 mL) and brine 410 mL), dried 4Na2SO4) and
concentrated. The combined residual oil was puri®ed by
column chromatography on silica gel [44 g, hexane/
EtOAc, 8:1!7:1!6:1!0:1) and 4500 mg, hexane/EtOAc,
16:1!12:1!10:1!6:1)] to give keto sulfones 423.8 mg,
89% from 8) as a colorless oil. The keto sulfones were
used in the next experiment without separation of the
diastereomers.
[a]28 ˆ28.0 4c 0.38, CHCl3)]; IR 4CHCl3) 3460, 1460,
D
1440 cm21
;
1H NMR 4400 MHz, CDCl3) d 5.81 4ddt,
Jˆ17.0, 10.2, 6.0 Hz, 1H), 5.69 4m, 1H), 5.54 4m, 1H),
5.01 4br. d, Jˆ17.0 Hz, 1H), 4.96 4br. d, Jˆ10.2 Hz, 1H),
4.32 4m, 1H), 3.83 4m, 1H), 3.72 4br. s, 1H), 3.72±3.68 4m,
2H), 3.65 4m, 1H), 3.32 4dd, Jˆ10.1, 1.5 Hz, 1H), 2.58 4br.
s, 1H), 2.52 4br. dt, Jˆ14.3, 8.8 Hz, 1H), 2.42 4m, 1H), 2.29
4m, 1H), 2.14±2.08 4m, 3H), 2.04±1.99 4m, 2H), 1.84 4m,
1H), 1.77±1.70 4m, 5H), 1.66±1.64 4m, 2H), 1.60±1.42 4m,
6H), 0.88 4d, Jˆ6.2 Hz, 3H); 13C NMR 4100 MHz, CDCl3)
d 138.7, 129.6, 128.0, 114.6, 106.4, 78.04, 77.98, 70.1, 69.6,
62.0, 43.6, 38.5, 36.6, 33.9, 33.7, 33.0, 30.9, 30.8, 30.4,
29.0, 25.1, 17.3; MS 4FAB) m/z 405 4M1Na)1; HRMS
4FAB) calcd for C22H38O5Na 4M1Na)1 405.2617, found
405.2635; Anal. calcd for C22H38O5´H2O: C, 65.97; H,
10.07. Found: C, 65.98; H, 9.694. 2; TLC, Rf 0.14 4benzene/
acetone, 3:1); [a]29 ˆ134 4c 0.073, CHCl3) [natural attenol
D
B: [a]28 ˆ31 4c 0.065, CHCl3)]; IR 4CHCl3) 3400, 1460,
D
1440 cm21
;
1H NMR 4600 MHz, CDCl3) d 5.81 4ddt,
4.1.27. Ketone 7. To a stirred solution of the diastereomeric
mixture of keto sulfones 41.8 mg, 2.45 mmol) in MeOH
40.20 mL) cooled to 08C were added Na2HPO4 451.0 mg,
359 mmol) and 5% sodium amalgam 456.7 mg), and the
mixture was stirred at 08C for 2.5 h. The mixture was diluted
with saturated aqueous NH4Cl 41.0 mL) and EtOAc
42.5 mL), stirred at room temperature for 1 h, and extracted
with EtOAc 43£5.0 mL). The combined extracts were
washed with brine 45.0 mL), dried 4Na2SO4), and con-
centrated. The residual oil was puri®ed by column
chromatography on silica gel 4500 mg, hexane/EtOAc,
8:1!4:1!2:1!0:1) to give 7 41.4 mg, 96%) as a colorless
Jˆ17.2, 10.2, 6.8 Hz, 1H), 5.56±5.49 4m, 2H), 5.02 4br. d,
Jˆ17.2 Hz, 1H), 4.95 4br. d, Jˆ10.2 Hz, 1H), 4.09 4t,
Jˆ6.8 Hz, 1H), 4.04 4br. s, 1H), 4.00±3.83 4m, 2H), 3.93
4s, 1H), 3.63±3.59 4m, 2H), 3.39 4br. s, 1H), 2.62 4br. s, 1H),
2.44±2.35 4m, 2H), 2.35±2.24 4m, 2H), 2.10±2.04 4m, 2H),
2.02 4m, 1H), 1.94±1.75 4m, 3H), 1.75±1.48 4m, 8H), 1.48±
1.40 4m, 2H), 1.34 4dd, Jˆ15.2, 5.7 Hz, 1H), 1.11 4d,
Jˆ7.1 Hz, 3H); 13C NMR 4150 MHz, CDCl3) d 138.8,
128.5, 127.8, 114.5, 109.6, 83.1, 80.1, 70.2, 69.2, 61.9,
42.5, 36.9, 34.5, 33.74, 33.69, 31.3, 31.2, 30.3 42C), 25.0,
23.1, 16.9; MS 4FAB) m/z 405 4M1Na)1; HRMS 4FAB)
calcd for C22H38O5Na 4M1Na)1 405.2617, found 405.2636;
Anal. calcd for C22H38O5´H2O: C, 65.97; H, 10.07. Found:
C, 65.61; H, 9.628.
oil: TLC, Rf 0.46 4hexane/EtOAc, 4:1); [a]29 ˆ120 4c
D
0.20, CHCl3); IR 4CHCl3) 1710, 1640, 1460, 1380, 1225,
1090, 1005, 915, 840 cm21; 1H NMR 4400 MHz, CDCl3) d
5.80 4ddt, Jˆ17.1, 10.3, 6.8 Hz, 1H), 5.59±5.49 4m, 2H),
5.00 4br d, Jˆ17.1 Hz, 1H), 4.94 4br d, Jˆ10.3 Hz, 1H),
3.84 4dt, Jˆ4.2, 7.3 Hz, 1H), 3.79±3.69 4m, 2H), 3.61 4t,
Jˆ7.1 Hz, 2H), 3.48 4t, Jˆ7.1 Hz, 1H), 2.59±2.25 4m, 8H),
2.05 4br. q, Jˆ6.8 Hz, 2H), 1.92±1.25 4m, 11H), 1.37
4s, 3H), 1.36 4s, 3H), 1.32 4s, 3H), 1.31 4s, 3H), 0.90
4d, Jˆ4.9 Hz, 3H), 0.89 4s, 9H), 0.05 4s, 6H); 13C NMR
467.8 MHz, CDCl3) d 210.6, 152.2, 138.7, 128.1, 126.6,
114.5, 108.1, 100.2, 84.6, 78.9, 77.2, 66.5, 66.0, 62.7,
40.3, 38.8, 38.7, 35.8, 35.3, 33.6, 32.3, 31.4, 29.7,
27.4, 27.3, 26.9, 25.9 43C), 24.8, 18.3, 16.0, 25.3
42C); MS 4FAB) m/z 617 4M1Na)1; HRMS 4FAB)
calcd for C34H62O6SiNa 4M1Na)1 617.4213, found
617.4229.
4.1.29. Tribenzoate 35. To a stirred solution of attenol A
41) 47.2 mg, 18.8 mmol) in pyridine 40.3 mL) cooled to 08C
was added benzoyl chloride 40.1 mL, 861 mmol), and the
mixture was stirred at 08C for 1 h and at room temperature
for 34 h. The reaction mixture was diluted with toluene
41.0 mL) and concentrated in vacuo. The residual oil was
puri®ed by column chromatography on silica gel 42 g,
hexane/EtOAc, 10:1!10:1!8:1) to give 35 413.1 mg,
100%) as a colorless oil: [a]29 ˆ121 4c 0.42, CHCl3); IR
D
4CHCl3) 1708, 1600, 1450, 1120 cm21; 1H NMR 4600 MHz,
C6D6) d 8.28 4br. d, Jˆ8.2 Hz, 2H), 8.22 4br. d, Jˆ8.2 Hz,
2H), 8.14 4br. d, Jˆ8.2 Hz, 2H), 7.12±7.02 4m, 9H), 5.72
4m, 1H), 5.71 4m, 1H), 5.70 4m, 1H), 5.55 4m, 1H), 5.45 4br.
dt, Jˆ10.8, 7.3 Hz, 1H), 5.00 4br. d, Jˆ9.4 Hz, 1H), 4.95
4br. d, Jˆ18.2 Hz, 1H), 4.21 4dt, Jˆ10.8, 6.8 Hz, 1H), 4.15
4dt, Jˆ10.8, 6.8 Hz, 1H), 4.14 4m, 1H), 3.80 4dd, Jˆ9.5,
1.6 Hz, 1H), 3.00 4br. dt, Jˆ14.6, 7.3 Hz, 1H), 2.61 4br.
dt, Jˆ14.6, 7.3 Hz, 1H), 2.52 4br. dq, Jˆ13.6, 6.8 Hz,
1H), 2.44 4br. dq, 1H), 2.11 4ddd, Jˆ14.3, 8.2, 4.6 Hz,
1H), 2.03 4dd, Jˆ12.3, 7.0 Hz, 1H), 1.99 4q, Jˆ7.1 Hz,
2H), 1.94 4ddd, Jˆ14.3, 7.7, 4.4 Hz, 1H), 1.88 4m, 1H),
1.79 4m, 1H), 1.76 4m, 1H), 1.71 4m, 1H), 1.60 4m, 1H),
1.58 4m, 1H), 1.57 4m, 1H), 1.52 4m, 1H), 1.48 4m, 1H), 1.45
4m, 1H), 1.41 4m, 1H), 1.40 4m, 1H), 0.87 4d, Jˆ6.1 Hz,
3H); 13C NMR 4150 MHz, C6D6) d 166.2, 166.1, 166.0,
138.6, 132.9, 132.8, 132.7, 129.9 46C), 128.6, 128.5,
128.5, 128.3 46C), 128.2, 127.7, 115.0, 106.2, 77.8, 76.5,
73.5, 73.3, 64.2, 42.7, 39.0, 34.44, 34.37, 31.5, 31.1, 30.0,
29.4, 27.4, 25.0, 17.3; MS 4FAB) m/z 717 4M1Na)1;
4.1.28. Attenol A )1) and attenol B )2). To a stirred solu-
tion of ketone 7 4284 mg, 477 mmol) in MeOH 415 mL) was
added p-toluenesulfonic acid 421.0 mg, 122 mmol), and the
mixture was stirred at room temperature for 18 h. The reac-
tion mixture was diluted with pyridine 423 mL) and toluene
45 mL) and concentrated. This procedure was performed
again using the ketone 4240 mg, 404 mmol), p-toluenesulfo-
nic acid 414.0 mg, 69.7 mmol), MeOH 413 mL), pyridine
418 mL) and toluene 45 mL). The combined crude product
was puri®ed by column chromatography on silica gel 4FL-
60D, 40 g, benzene/acetone, 4:1!3:1!5:2) to give attenol
A 41) 4187 mg, 55%) and attenol B 42) 434.9 mg, 11%) as a
colorless oil: 1; TLC, Rf 0.24 4benzene/acetone, 3:1);
[a]28 ˆ29.7 4c 0.35, CHCl3) [natural attenol A:
D

K. Araki et al. / Tetrahedron 58 ,2002) 1983±1995
1995
HRMS 4FAB) calcd for C22H38O5Na 4M1Na)1 717.3403,
found 717.3403.
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42, 7469±7471.
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6. Takada, N.; Umemura, N.; Suenaga, K.; Uemura, D.
Tetrahedron Lett. 2001, 42, 3495±3497.
Acknowledgements
This work was supported in part by Wako Pure Chemical
Industries Ltd, by Banyu Pharmaceutical Co., Ltd, and by
Grants-in-Aid 4Nos. 11558079 and 12045235) for Scienti®c
Research from the Ministry of Education, Science, Sports,
and Culture, Japan. We thank Dr T. Yamori 4Screening
Committee of New Anticancer Agents supported by a
Grant-in Aid for Scienti®c Research on Priority Area
`Cancer' from the Ministry of Education, Science, Sports,
and Culture, Japan) for help with screening the human
cancer cell line panel.
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H.-S.; Uemura, D. Chem. Lett. 1999, 1025±1026.
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