Total synthesis of the dolabellane marine diterpenoids, claenone, palominol and dolabellatrienone

Article abstract of DOI:10.1016/S0040-4020(02)01474-6

The synthesis of marine dolabellane diterpenoids claenone, palominol and dolabellatrienone was conducted from D-mannitol. In each case, formation of the bicyclo[2.2.1]heptane derivative by sequential Michael reaction, preparation of the tetrasubstituted c

Full text of DOI:10.1016/S0040-4020(02)01474-6

Tetrahedron 59 (2003) 61–75
Total synthesis of the dolabellane marine diterpenoids, claenone,
palominol and dolabellatrienone
*
Hiroaki Miyaoka, Yutaka Isaji, Hidemichi Mitome and Yasuji Yamada
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 18 October 2002; accepted 11 November 2002
Abstract—The synthesis of marine dolabellane diterpenoids claenone, palominol and dolabellatrienone was conducted from D-mannitol. In
each case, formation of the bicyclo[2.2.1]heptane derivative by sequential Michael reaction, preparation of the tetrasubstituted cyclopentane
derivative by retro-aldol reaction and cyclization of sulfone were involved as key steps. q 2002 Elsevier Science Ltd. All rights reserved.
Dolabellane diterpenoid from sea hare was initially isolated
by Faulkner et al. in 19761 and subsequently, many others
were so mainly from marine sources.2,3 All dolabellane
diterpenoids share the unique feature of a trans-bicy-
clo[9.3.0]tetradecane nucleus and most express biological
activity.2,3 Claenone (1), isolated by the author’s group from
the Okinawan marine soft coral, Clavularia sp., is a
dolabellane diterpenoid (Fig. 1)4 and has been shown to
express ichthyotoxic activity toward killifish Oryzias latipes
(minimum lethal concentration: 10 mg/mL)4 and potent
cytotoxic activity toward human prostate cancer WMF
(GI50 2.42£1027 M) and RB cells (GI50 3.06£1027 M).5
Palominol (2)6,7a and 1(R), 11(S)-dolabella-3(E), 7(E),
12(18)-trien-13-one (dolabellatrienone, 3),6,7 isolated from
the gorgonian octocorals Eunicea calyculata and Eunicea
laciniata, are both dolabellane diterpenoids and express
week cytotoxic activity toward human colon (HCT 116) cell
line (IC50 10 mM, respectively).6a These features have
prompted research for the total synthesis of dolabellane
diterpenoids. Total synthesis8 of, and synthetic studies9 on,
dolabellane diterpenoid have been reported. The total
synthesis of claenone (1) appeared in a previous communi-
cation of the authors.8b The present paper presents the detail
of total synthesis of claenone (1) together with palominol
(2) and dolabellatrienone (3).
intermediate for the dolabellane diterpenoids (Fig. 2).
Diastereoselective sequential Michael reaction of cyclo-
pentenone F and chiral a,b-unsaturated ester G would
provide bicyclo[2.2.1]heptane derivative E. Bicyclic com-
pound E may possibly be converted to b-hydroxyketone D
and cleavage of C(14)–C(19) bond in D by a retro-aldol
reaction may produce tetrasubsutituted cyclopentane seg-
ment C.11 It was anticipated that compound C would be
converted to common synthetic intermediate B by
elongation of two side chains. Compound B may possibly
be converted to epoxy sulfone A and cyclization of epoxy
sulfone A would afford claenone (1). Cyclization of
compound B would afford palominol (2). Dolabellatrienone
(3) was considered to be obtained by oxidation of palominol
(2).8c
Sequential Michael reaction of enone 4 with chiral a,b-
unsaturated ester 5 was carried out. The lithium enolate of
enone 4 prepared with LDA was treated with a,b-
unsaturated ester 512 from D-mannitol in THF at 2788C to
afford bicyclo[2.2.1]heptane derivative 6a and its diaster-
eomer 6b (5.3:1) in 82% yield (Scheme 1).
The synthesis of natural products has been conducted at
author’s laboratory using a bicyclic compound prepared by
sequential Michael reaction as chiral building block.8a,b,10
The synthesis of the objective dolabellane diterpenoids was
also attempted in similar methodology. It was considered
that synthesis should be conducted via a common synthetic
Keywords: antitumour compounds; marine metabolites; terpenes and
terpenoids.
*
Corresponding author. Tel.: þ81-426-76-3063; fax: þ81-426-76-3048;
Figure 1. Dolabellane diterpenoids claenone (1), palominol (2) and
dolabellatrienone (3).
e-mail: yamaday@ps.toyaku.ac.jp
0040–4020/03/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01474-6

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H. Miyaoka et al. / Tetrahedron 59 (2003) 61–75
Scheme 2. Reagents and conditions: (a) AcOH–H2O (4:1), 408C, 83%; (b)
(1) TBSCl, imidazole, DMF, rt, 95%, (2) NaBH4, MeOH, 08C, (3) MOMCl,
iPr2NEt, CH2ClCH2Cl, 508C, (4) TBAF, THF, rt, 60% (three steps); (c) (1)
30% NaOH aq., reflux, (2) BOPCl, Et3N, CH2ClCH2Cl, rt, 38% (two steps).
catalyzed hydrolysis of acetonide in 6b followed by
NaIO4 oxidation-NaBH4 reduction gave alcohol (þ)-10,
[a]D¼þ19.88 (c 0.32, CHCl3), the enantiomer of (2)-10
from 6a. In this manner, relative configurations of
bicyclic compounds 6a and 6b were determined.
The ketone in bicyclic compound 6a was reduced by
treatment with NaBH4 (quantitative yield) followed by
protection of the secondary hydroxy group (quantitative
yield) to give TBS ether 11 (Scheme 4). The ester in 11 was
reduced by LiAlH4 (99% yield) and the primary hydroxy
group was protected as Bn ether (94% yield) to give benzyl
ether 12. Deprotection of the TBS group in 12 by treatment
with TBAF (quantitative yield) and acetylation of the
hydroxy group (99% yield) provided acetate 13. Acetate 13
was converted to b-hydroxyketone 14, corresponding to b-
hydroxyketone D in the synthetic strategy, in the following
five steps: (1) acid-catalyzed hydrolysis of acetonide and
MOM ether (80% yield), (2) NaIO4 oxidation of 1,2-diol
followed by NaBH4 reduction (88% yield), (3) protection of
the hydroxy group as TBS ether (96% yield), (4)
methanolysis of acetate (quantitative yield) and (5) PCC
oxidation of the secondary hydroxy group (90% yield).
C(14)–C(19) bond in b-hydroxyketone 14 was cleaved by
retro-aldol reaction in the presence of NaH and 15-crown-5
in toluene to produce tetrasubstituted cyclopentane deriva-
tive 15, having the desired chiral centers at C-1 and C-11
corresponding to claenone (1), in 86% yield. Selective
protection of the less hindered ketone in 15 was done as
follows: (1) deprotection of the TBS group by treatment
with 80% acetic acid (97% yield), (2) acetylation of the
hydroxy group (quantitative yield), and (3) treatment with
1,2-bis(trimethylsilyloxy)ethane in the presence of
TMSOTf14 (97% yield), giving monoketal 16. Deoxygena-
tion of C-14 position in 16 was carried out by (1) NaBH4
reduction of ketone (98% yield) and (2) dehydration by
treatment with N-phenylthiosuccinimide and nBu3P in
Figure 2. Synthetic strategy for claenone (1), palominol (2) and
dolabellatrienone (3).
The relative configuration of bicyclo compound 6a was
determined based on the NOESY spectrum of lactone 9,
obtained from bicyclo compound 6a via alcohols 7 and 8
(Scheme 2). Acid-catalyzed hydrolysis of acetonide in 6a
gave diol 7. Protection of the primary hydroxy group in diol
7 as TBS ether, reduction of ketone with NaBH4, protection
of two hydroxy groups as MOM ether and removal of TBS
group gave alcohol 8. Hydrolysis of ethyl ester in 8 followed
by treatment with bis(2-oxo-3-oxazolidinyl)phosphinic
chloride (BOPCl)13 and Et3N afforded lactone 9. NOESY
correlations were observed among the methine proton at C-
10, one of the methylene protons at C-13 and the methyl
protons at C-15.
The stereochemistry of bicyclic compound 6b was
determined by its chemical correlation with compound
6a (Scheme 3). Diol 7, obtained from 6a by hydrolysis
of acetonide, was oxidative cleaved by reaction with
NaIO4 and subsequent reduction with NaBH4 to give
alcohol (2)-10, [a]D¼219.88 (c 0.55, CHCl3). Acid-
Scheme 3. Reagents and conditions: (a) NaIO4, MeOH–H2O, 08C, then
NaBH4, 08C, 57%; (b) (1) AcOH–H2O (4:1), 408C, 73%, (2) NaIO4,
MeOH–H2O, 08C, then NaBH4, 08C, 74%.
Scheme 1. Sequential Michael reaction of enone 4 with a,b-unsaturated
ester 5.

H. Miyaoka et al. / Tetrahedron 59 (2003) 61–75
63
Scheme 4. Reagents and conditions: (a) (1) NaBH4, MeOH, 08C, quant., (2)
TBSCl, imidazole, DMF, rt, quant.; (b) (1) LiAlH4, Et2O, 08C, 99%, (2)
BnBr, NaH, DMF, rt, 94%; (c) (1) TBAF, THF, rt, quant., (2) Ac2O, Py, rt,
99%; (d) (1) AcOH–H2O (4:1), 658C, 80%, (2) NaIO4, (NH4)2SO4,
MeOH–H2O (1:1), 08C, then NaBH4, 08C, 88%, (3) TBSCl, imidazole,
˚
DMF, rt, 96%, (4) K2CO3, MeOH, rt, quant., (5) PCC, 4 A MS, CH2Cl2, rt,
90%; (e) NaH, 15-crown-5, toluene, rt, 86%; (f) (1) AcOH–H2O (4:1), rt,
97%, (2) Ac2O, Py, rt, quant., (3) 1,2-bis(trimethylsilyloxy)ethane,
TMSOTf, CH2Cl2, 2408C, 90%; (g) (1) NaBH4, MeOH, 08C, 98%, (2)
N-phenylthiosuccinimide, nBu3P, Py, 608C, 93%; (h) (1) K2CO3, MeOH, rt,
quant., (2) PhSSPh, nBu3P, Py, 608C, (3) OXONEw, THF–MeOH–H2O
(2:2:3), 08C, 85% (two steps).
Scheme 5. Reagents and conditions: (a) NBS, Ph3P, CH2Cl2, 08C, 80%; (b)
nBuLi, THF, 7788C, then 20, 278 to 2308C; (c) Na, liq. NH3, THF,
˚
2788C, 68% (two steps); (d) (1) PDC, 4 A MS, CH2Cl2, rt, (2)
Ph3PvCHOMe, THF, 08C, 84% (two steps), (3) PCC–Al2O3, benzene,
408C, 85%; (e) (1) DIBAH, toluene, 2788C, (2) (EtO)2P(O)CH(Me)CO2Et,
NaH, THF, 08C, 80% (two steps); (f) (1) TBAF, THF, rt, quant., (2)
PhSSPh, nBu3P, Py, 608C, 92%, (3) OXONEw, THF–MeOH–H2O (1:1:1),
pyridine (93% yield) to produce cyclopentene derivative 17.
The acetyl group in 17 was removed by K2CO3 in MeOH
(quantitative yield) to afford the primary alcohol, whose
hydroxy group was converted to phenyl sulfonyl group by
PhSSPh and nBu3P in pyridine and then OXONEw,15
affording sulfone 18 in 85% yield (two steps).
t
08C, 90%, (4) DIBAH, toluene, 2788C, 98%; (g) (1) BuOOH, (2)-DET,
i
Ti(O Pr)4, 4 A MS, CH2Cl2, 2208C, 95%, (2) MsCl, DMAP, CH2Cl2, rt,
˚
97%; (h) KHMDS, THF, 458C, 60% at 75% conversion; (i) (1) AcOH–H2O
(4:1), 458C, 93%, (2) K2CO3, MeOH, rt, quant., (3) MeLi, THF, 2788C,
˚
86%; (j) (1) Na-Hg, Na2HPO4, MeOH–THF (1:1), 08C, 83%, (2) PCC, 4 A
MS, CH2Cl2, rt, 63%.
Claenone (1) was synthesized from the cyclopentane core
18 by elongation of side chains and macrocyclization
(Scheme 5). Allylic alcohol 1916 was treated with NBS and
Ph3P to give allylic bromide 20, corresponding to the C-6–
C-9 segment, in 80% yield. Reaction of the lithio derivative
of sulfone 18 with allylic bromide 20 at 2788C to 2308C
gave the coupling product 21 as a diasereomeric mixture.
Treatment of sulfone 21 with Na in liq. NH3 gave alcohol 22
in 68% yield (two steps). The hydroxy group in 22 was
oxidized by PDC to give the aldehyde, which was reacted
with Wittig reagent (Ph3PvCHOMe) to produce methyl
enol ether in 80% yield (two steps). Oxidation of the methyl
enol ether by PCC–Al2O317 directly provided methyl ester
23 in 85% yield. Ester 23 was reduced with DIBAH to give
the aldehyde, whose reaction with Horner–Emons reagent
((EtO)2P(O)CHMeCO2Et) gave (E)-a,b-unsaturated ester
24 as the sole product in 80% yield (two steps). TBS ether
24 was converted to allylic alcohol 25 in four steps: (1)
removal of the TBS group with TBAF (quantitative yield),
(2) conversion of the hydroxy group to phenylthio group
(92% yield), (3) oxidation of the sulfide to sulfone by
OXONEw (90% yield) and (4) DIBAH reduction of the ester
to allylic alcohol (98% yield). Allylic alcohol 25 corre-
sponds to the common intermediate B in the synthetic
strategy. Stereoselective epoxidation of allylic alcohol 25
according to Sharpless procedure18 (95% yield) followed by
mesylation of hydroxy group gave mesylate 26 (97% yield)
corresponding compound A in the synthetic strategy. Regio-
selective macrocyclization of 26 was carried out by
treatment with KHMDS in THF (4.0£1023 M) to give
bicyclo[9.3.0]tetradecane derivative 27 as the sole product
in 60% yield based on recovery of 26. Bicyclic compound
27 was converted to allylic alcohol 28 in as follows: (1)
acid-catalyzed hydrolysis of acetal to give ketone (93%
yield), (2) isomerization of olefin to the enone (quantitative
yield) and (3) addition reaction with MeLi (86% yield). The
phenylsulfonyl group in 28 was removed by Na-Hg in
MeOH (83% yield) and oxidation of the tertiary allylic
alcohol with PCC19 to afford claenone (1), [a]D¼249.28 (c
0.42, CHCl3), mp 124–1258C, in 63% yield. Spectral data
and sign of optical rotation of synthetic claenone (1) were
identical to those of natural claenone, [a]D¼250.98 (c 1.25,
CHCl3), mp 124–1258C.4
The total synthesis of palominol (2) and dolabellatrienone
(3) was carried out from synthetic intermediate 25 (Scheme
6). Allylic alcohol 25 was treated with MsCl and DMAP in

64
H. Miyaoka et al. / Tetrahedron 59 (2003) 61–75
(37.0 mL, 47.0 mmol, 1.27 M in hexane). The mixture was
stirred at 08C for 30 min and was cooled to 2788C. A
solution of cyclopentenone 4 (5.60 g, 39.3 mmol) in THF
(10 mL) was added and the mixture was stirred at same
temperature for 10 min. A solution of a,b-unsaturated ester
5 (10.0 g, 46.7 mmol) in THF (15 mL) was added and the
mixture was stirred at same temperature for 2 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 purified by silica
gel column chromatography (eluted with hexane–
Et2O¼2:1) to give bicyclo[2.2.1]heptane 6a (9.60 g, 69%)
6b (1.80 g, 18%). 6a: colorless oil; [a]D¼214.98 (c 1.24,
CHCl3); IR (neat) 2986, 1755, 1719 cm21 1H NMR
;
(300 MHz, CDCl3) d ppm: 1.25 (3H, t, J¼7.0 Hz), 1.27
(3H, s), 1.38 (3H, s), 1.42 (3H, s), 1.92 (1H, dt, J¼10.0,
1.4 Hz), 2.37 (1H, m), 2.43 (2H, m), 2.60 (1H, m), 2.67 (1H,
m), 3.39 (3H, s), 3.68 (1H, dd, J¼7.0, 10.8 Hz), 4.07 (1H,
dd, J¼6.4, 8.2 Hz), 4.12 (1H, dq, J¼10.8, 7.0 Hz), 4.25 (1H,
ddd, J¼1.2, 6.4, 6.6 Hz), 4.77 (1H, d, J¼7.3 Hz), 4.83 (1H,
d, J¼7.3 Hz); 13C NMR (75 MHz, CDCl3) d ppm: 14.1,
16.9, 25.1, 26.4, 37.4, 45.0, 45.1, 49.5, 54.2, 55.4, 61.1,
68.6, 74.2, 85.1, 93.4, 109.1, 175.1, 211.0; EIMS (m/z): 356
(Mþ, 20), 341 (Mþ2CH3, 100); HREIMS: calcd for
C17H25O7 (Mþ2CH3): 341.1600; Found: 341.1588. 6b:
colorless oil; [a]D¼þ25.48 (c 1.62, CHCl3); IR (neat) 2985,
1756, 1720 cm21; 1H NMR (300 MHz, CDCl3) d ppm: 1.26
(3H, t, J¼7.1 Hz), 1.32 (3H, s), 1.35 (3H, s), 1.55 (3H, s),
1.92 (1H, dt, J¼10.7, 1.7 Hz), 2.11 (1H, m), 2.25 (1H, ddd,
J¼1.2, 4.2, 10.7 Hz), 2.39 (1H, dd, J¼4.2, 18.0 Hz), 2.57
(1H, dd, J¼1.2, 18.0 Hz), 2.67 (1H, m), 3.39 (3H, s), 3.67
(1H, ddd, J¼4.2, 10.7, 13.7 Hz), 4.09 (2H, m), 4.15 (1H, dq,
J¼11.3, 7.1 Hz), 4.20 (1H, dq, J¼11.3, 7.1 Hz), 4.75 (1H, d,
J¼7.3 Hz), 4.80 (1H, d, J¼7.3 Hz); 13C NMR (75 MHz,
CDCl3) d ppm: 14.1, 16.1, 25.8, 26.5, 37.3, 44.4, 46.3, 50.3,
54.3, 55.5, 61.1, 68.9, 75.4, 85.7, 93.4, 109.5, 174.6, 209.3;
EIMS (m/z): 356 (Mþ, 28), 341 (Mþ2CH3, 23), 325 (92);
HREIMS: calcd for C17H25O7 (Mþ2CH3): 341.1600;
Found: 341.1587.
Scheme 6. Reagents and conditions: (a) (1) MsCl, DMAP, CH2Cl2, rt, (2)
KHMDS, THF, 458C, 45% (two steps); (b) (1) Na-Hg, Na2HPO4, MeOH–
THF (1:1), 08C, 86%, (2) AcOH–H2O (4:1), 458C, 93%, (3) K2CO3,
MeOH, rt, quant.; (c) MeLi, THF, 2788C, 90%; (d) PDC, 4 A MS, CH2Cl2,
rt, 63%.
˚
THF to afford allylic chloride. Without purification,
macrocyclization of allylic chloride was carried out by
KHMDS in THF (4.0£1023 M) to give bicyclo[9.3.0]te-
tradecane derivative 29 in 45% yield (two steps). Bicyclic
compound 29 was converted to enone 30 in three steps: (1)
removal of the phenylsulfonyl group with Na-Hg in MeOH
(86% yield), (2) acid-catalyzed hydrolysis of acetal to give
ketone (93% yield) and (3) isomerization of olefin to the
enone (quantitative yield). Enone 30 was treated with MeLi
in THF at 2788C to produce palominol (2), [a]D¼224.78 (c
0.34, CHCl3) in 90% yield. Spectral data and sign of optical
rotation of the synthesized palominol (2) were identical to
those of natural palminol, [a]D¼2288 (c 0.7, CHCl3).7a
Palominol (2) was treated with PDC in CH2Cl2 to give
dolabellatrienone (3), [a]D¼þ29.98 (c 0.14, CHCl3) in 63%
yield. Spectral data and sign of optical rotation of the
synthesized dolabellatrienone (3) were identical to those of
natural dolabellatrienone, [a]D¼þ31.08 (c 0.88, CHCl3).7b
1. Experimental
1.1. 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 spectrometer, UV
spectra with a JASCO V-550 spectrophotometer and 1H and
13C NMR spectra with a Varian Gemini-300, a Bruker DPX-
400 or a Bruker DRX-500. Chemical shifts are given on a d
(ppm) scale with tetramethylsilane (TMS) 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. High resolution EIMS
(HREIMS) spectra was 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). Preparative TLC was conducted on a
Merck silica gel 60 F254 plate.
1.1.2. Ethyl (1R,2S,3R,4S)-3-((S)-1,2-dihydroxyethyl)-1-
methoxymethoxy-2-methyl-5-oxobicyclo[2.2.1]heptane-
2-carboxylate (7). A mixture of AcOH and H2O (4:1)
(20.0 mL) was added to keto ester 6a (2.00 g, 5.60 mmol)
and the mixture was stirred at rt for 72 h. The reaction
mixture was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(eluted with EtOAc) to give diol 7 (1.47 g, 83%). Colorless
oil; [a]D¼213.18 (c 0.65, CHCl3); IR (neat) 3439, 2939,
1748 cm21; 1H NMR (300 MHz, CDCl3) d ppm: 1.23 (3H,
t, J¼7.1 Hz), 1.50 (3H, s), 1.90 (1H, br d, J¼10.4 Hz), 2.24
(1H, br d, J¼2.8 Hz), 2.35 (1H, dd, J¼4.4, 18.2 Hz), 2.48
(1H, m), 2.62 (1H, d, J¼18.2 Hz), 2.68 (1H, br s), 3.30 (2H,
br s), 3.37 (3H, s), 3.51 (1H, dd, J¼7.5, 11.0 Hz), 3.60 (1H,
dd, J¼3.0, 11.0 Hz), 3.91 (1H, m), 4.10 (1H, dq, J¼10.8,
7.1 Hz), 4.16 (1H, dq, J¼10.8, 7.1 Hz), 4.76 (1H, d,
J¼7.4 Hz), 4.80 (1H, d, J¼7.4 Hz); 13C NMR (75 MHz,
CDCl3) d ppm: 14.1, 16.3, 37.8, 43.3, 45.1, 48.9, 54.9, 55.4,
61.2, 66.1, 66.1, 69.9, 84.9, 93.4, 175.7, 212.5; EIMS (m/z):
316 (Mþ, 9), 298 (16), 285 (100); Anal. calcd for C15H24O7:
C, 56.95; H, 7.65. Found: C, 57.14; H, 7.91.
1.1.1. Ethyl (1R,2S,3R,4S)-3-((S)-2,2-dimethyl-[1,3]diox-
olan-4-yl)-1-methoxymethoxy-2-methyl-5-oxobicy-
clo[2.2.1]heptane-2-carboxylate (6a) and ethyl
(1S,2R,3S,4R)-3-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-1-
methoxymethoxy-2-methyl-5-oxobicyclo[2.2.1]heptane-
i
2-carboxylate (6b). To a cold (08C) solution of Pr2NEt
n
(5.20 mL, 51.0 mmol) in THF (200 mL) was added BuLi

H. Miyaoka et al. / Tetrahedron 59 (2003) 61–75
65
1.1.3. Ethyl (1R,2S,3R,4S,5S)-3-[(S)-2-Hydroxy-1-meth-
oxymethoxyethyl]-1,5-bis(methoxymethoxy)-2-methyl-
bicyclo[2.2.1]heptane-2-carboxylate (8). To a solution of
diol 7 (1.00 g, 3.16 mmol) in DMF (6.32 mL) were added
imidazole (430 mg, 6.32 mmol) and TBSCl (530 mg,
3.48 mmol). After stirring at rt 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
purified by silica gel column chromatography (eluted with
hexane–EtOAc¼3:2) to give TBS ether (1.30 g, 95%).
Colorless oil; [a]D¼þ34.48 (c 1.00, CHCl3); IR (neat) 3420,
CDCl3) d ppm: 14.2, 16.6, 35.1, 37.3, 37.7, 40.0, 55.3, 55.5,
55.8, 56.4, 60,6, 66.3, 75.5, 83.1, 87.1, 93.3, 95.2, 97.8,
176.1; EIMS (m/z): 375 (Mþ2OCH3, 25), 343 (35), 126
(100); HREIMS: calcd for C18H31O8 (Mþ2OCH3):
375.2019; Found: 375.2027.
1.1.4. (1R,2S,6S,7R,8S,9S)-1,6,9-Tris(methoxymethoxy)-
2-methyl-4-oxatricyclo[6.2.1.02,7]undecan-3-one (9). An
aqueous solution of 30% NaOH (5.00 mL) was added to
ester 8 (8.0 mg, 18.7 mmol) and the mixture was refluxed for
14 h. The reaction mixture was diluted with Et2O, washed
with 1N HCl, H2O and saturated aqueous NaCl, dried over
anhydrous MgSO4 and concentrated under reduced pressure
to give crude carboxylic acid. The crude carboxylic acid
was used next reaction without purification.
1
2929, 1753, 1720 cm21; H NMR (300 MHz, CDCl3) d
ppm: 0.06 (6H, s), 0.88 (9H, s), 1.23 (3H, t, J¼7.2 Hz), 1.55
(3H, s), 1.89 (1H, br d, J¼10.2 Hz), 2.21 (1H, br s), 2.38
(1H, dd, J¼4.4, 18.2 Hz), 2.54 (1H, m), 2.60 (1H, br s), 2.61
(1H, br d, J¼18.2 Hz), 3.38 (3H, s), 3.44 (1H, t, J¼9.5 Hz),
3.55 (1H, dd, J¼3.8, 9.5 Hz), 3.97 (1H, m), 4.10 (1H, dq,
J¼10.9, 7.2 Hz), 4.16 (1H, dq, J¼10.9, 7.2 Hz), 4.77 (1H, d,
J¼7.3 Hz), 4.82 (1H, d, J¼7.3 Hz); 13C NMR (75 MHz,
CDCl3) d ppm: 14.1, 16.5, 18.2, 25.8, 38.3, 43.1, 45.2, 49.1,
55.1, 55.4, 61.0, 66.5, 69.6, 84.8, 93.4, 175.5; EIMS (m/z):
399 (Mþ2OCH3, 3), 373 (40), 341 (100); HREIMS: calcd
for C20H35O6Si (Mþ2OCH3): 399.2203; Found: 399.2194.
To a solution of the above crude carboxylic acid in CH2Cl2
(1.80 mL) were added Et3N (100 mL, 720 mmol) and
BOPCl (138 mg, 540 mmol). After stirring at rt for 16 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 purified by silica gel column chromatography
(eluted with EtOAc) to give lactone 9 (2.5 mg, 38%, two
steps). Colorless oil; [a]D¼238.48 (c 0.83, CHCl3); IR
1
To a cold (08C) solution of the above ketone (1.30 g,
3.02 mmol) in MeOH (30.0 mL) was added NaBH4
(230 mg, 6.04 mmol) and the mixture was stirred at 08C
for 15 min. 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. The crude alcohol was used next
reaction without purification.
(neat) 2927, 1752 cm21; H NMR (300 MHz, CDCl3) d
ppm: 1.36 (3H, s), 1.57 (1H, d, J¼11.0 Hz), 1.83 (1H, ddd,
J¼2.9, 5.0, 13.8 Hz), 2.08 (1H, dt, J¼11.0, 2.8 Hz), 2.29
(1H, s), 2.33 (1H, dd, J¼10.0, 13.8 Hz), 2.74 (1H, d,
J¼12.3 Hz), 3.36 (3H, s), 3.37 (3H, s), 3.41 (3H, s), 4.13
(1H, m), 4.15 (1H, m), 4.30 (1H, dd, J¼3.2, 12.9 Hz), 4.59
(1H, d, J¼6.9 Hz), 4.63 (1H, d, J¼6.9 Hz), 4.65 (2H, m),
4.74 (1H, dd, J¼7.0, 12.9 Hz), 4.75 (1H, d, J¼6.8 Hz), 4.95
(1H, d, J¼6.8 Hz); 13C NMR (75 MHz, CDCl3) d ppm:
13.9, 34.3, 35.8, 38.7, 41.5, 50.1, 56.2, 56.3, 56.3, 73.3,
76.3, 77.9, 86.0, 94.2, 95.2, 96.8, 173.1.
To a solution of the above crude alcohol in CH2ClCH2Cl
i
(6.00 mL) were added Pr2NEt (1.60 mL, 9.00 mmol) and
MOMCl (600 mL, 7.20 mmol). After stirring at 508C for
5 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 MOM ether. The crude MOM ether was used next
reaction without purification.
1.1.5. Ethyl (1R,2S,3R,4S,5S)-5-Hydroxy-3-hydroxy-
methyl-1-methoxymethoxy-2-methylbicyclo[2.2.1]hep-
tane-2-carboxylate ((2)-10). To a solution of diol 7
(57.3 mg, 181 mmol) in MeOH (1.8 mL) was added a
solution of NaIO4 (46.5 mg, 217 mmol) in H2O (500 mL) at
08C. After stirring at 08C for 30 min, NaBH4 (13.7 mg,
362 mmol) was added 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
purified by silica gel column chromatography (eluted with
EtOAc) to give alcohol (2)-10 (29.7 mg, 57%). Colorless
oil; [a]D¼214.18 (c 0.30, CHCl3); IR (neat) 3376,
To a solution of the above crude TBS ether in THF
(3.00 mL) was added TBAF (3.00 mL, 3.00 mmol, 1.0 M in
THF). After stirring at rt for 2 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 purified by silica gel
column chromatography (eluted with EtOAc) to give
alcohol 8 (730 mg, 60%, three steps). Colorless oil;
[a]D¼21.58 (c 0.85, CHCl3); IR (neat) 3442, 2927,
1715 cm21 1H NMR (300 MHz, CDCl3) d ppm: 1.27
;
(3H, t, J¼7.1 Hz), 1.31 (3H, s), 1.63 (1H, dt, J¼10.5,
1.7 Hz), 1.92 (1H, ddd, J¼1.8, 3.6, 10.5 Hz), 2.08 (1H, m),
2.29 (1H, dd, J¼10.9, 13.8 Hz), 3.01 (1H, dt, J¼1.7,
7.4 Hz), 3.35 (3H, s), 3.50 (1H, dd, J¼7.9, 10.6 Hz), 3.74
(1H, dd, J¼7.2, 10.6 Hz), 4.20 (3H, m), 4.65 (1H, d,
J¼7.1 Hz), 4.72 (1H, d, J¼7.1 Hz); 13C NMR (75 MHz,
CDCl3) d ppm: 14.2, 14.8, 37.5, 37.6, 41.0, 42.1, 54.8, 55.3,
61.3, 62.6, 70.1, 88.1, 93.0, 177.3.
1720 cm21 1H NMR (300 MHz, CDCl3) d ppm: 1.25
;
(3H, t, J¼7.2 Hz), 1.36 (3H, s), 1.49 (1H, dt, J¼14.0,
4.0 Hz), 1.56 (1H, dt, J¼10.2, 1.5 Hz), 2.08 (1H, ddd,
J¼2.1, 5.5, 10.2 Hz), 2.27 (1H, dd, J¼10.9, 13.7 Hz), 2.34
(1H, m), 2.95 (1H, dd, J¼1.4, 4.6 Hz), 3.34 (3H, s), 3.38
(3H, s), 3.62 (1H, m), 3.68 (1H, hept, J¼4.5 Hz), 3.78 (1H,
m), 4.06 (1H, dt, J¼10.9, 4.8 Hz), 4.15 (1H, dq, J¼10.8,
7.1 Hz), 4.19 (1H, dq, J¼10.8, 7.1 Hz), 4.56 (1H, d,
J¼6.6 Hz), 4.61 (1H, d, J¼6.6 Hz), 4.66 (1H, d,
J¼6.9 Hz), 4.69 (1H, d, J¼7.2 Hz), 4.74 (1H, d,
J¼6.9 Hz), 4.79 (1H, d, J¼7.2 Hz); 13C NMR (75 MHz,
1.1.6. Ethyl (1S,2R,3S,4R,5R)-5-Hydroxy-3-hydroxy-
methyl-1-methoxymethoxy-2-methylbicyclo[2.2.1]hep-
tane-2-carboxylate ((1)-10). A mixture of AcOH and H2O

66
H. Miyaoka et al. / Tetrahedron 59 (2003) 61–75
(4:1) (5.00 mL) was added to keto ester 6b (116 mg,
362 mmol) and the mixture was stirred at rt for 24 h. The
reaction mixture was concentrated under reduced pressure.
The residue was purified by silica gel column chromatog-
raphy (eluted with EtOAc) to give diol (75.4 mg, 73%).
Colorless oil; [a]D¼þ21.18 (c 0.80, CHCl3); IR (neat) 3442,
1752, 1715 cm21; 1H NMR (300 MHz, CDCl3) d ppm: 1.23
(3H, t, J¼7.2 Hz), 1.56 (3H, s), 1.88 (1H, br d, J¼10.6 Hz),
2.20 (1H, dd, J¼4.1, 10.6 Hz), 2.38 (1H, dd, J¼5.2,
13.1 Hz), 2.39 (1H, d, J¼18.0 Hz), 2.59 (1H, d,
J¼18.0 Hz), 3.31 (2H, br s), 3.36 (3H, s), 3.55 (1H, dd,
J¼5.0, 10.9 Hz), 3.65 (1H, m), 3.72 (1H, m), 4.12 (1H, dq,
J¼10.3, 7.2 Hz), 4.17 (1H, dq, J¼10.3, 7.2 Hz), 4.73 (1H, d,
J¼7.4 Hz), 4.78 (1H, d, J¼7.4 Hz); 13C NMR (75 MHz,
CDCl3) d ppm: 14.0, 16.1, 37.1, 44.1, 44.9, 49.4, 54.7, 55.4,
61.4, 65.0, 70.8, 85.1, 93.3, 176.0, 210.7; EIMS (m/z): 317
(MþþH, 14), 298 (9), 253 (100); HREIMS: calcd for
C15H22O6 (Mþ2H2O): 298.1416; Found: 298.1398.
residue was purified by silica gel column chromatography
(eluted with hexane–Et2O¼1:1) to give TBS ether 11
(63.0 g, quantitative yield). Colorless oil; [a]D¼223.08 (c
1.24, CHCl3); IR (neat) 2954, 1727 cm21 1H NMR
;
(400 MHz, CDCl3) d ppm: 0.00 (3H, s), 0.02 (3H, s), 0.86
(9H, s), 1.26 (3H, t, J¼7.1 Hz), 1.32 (3H, s), 1.33 (3H, s),
1.39 (3H, s), 1.41 (1H, dt, J¼3.5, 13.5 Hz), 1.53 (1H, dt,
J¼1.6, 10.2 Hz), 2.03 (1H, ddd, J¼2.0, 3.5, 10.2 Hz), 2.13
(1H, br d, J¼4.7 Hz), 2.22 (1H, dd, J¼10.4, 13.4 Hz), 3.07
(1H, dd, J¼1.5, 5.6 Hz), 3.38 (3H, s), 3.68 (1H, t,
J¼7.6 Hz), 4.05 (1H, dd, J¼6.4, 7.9 Hz), 4.10–4.20 (2H,
m), 4.27 (1H, dd, J¼6.5, 12.8 Hz), 4.70 (1H, d, J¼7.1 Hz),
4.81 (1H, d, J¼7.1 Hz); 13C NMR (75 MHz, CDCl3) d ppm:
24.9, 24.8, 14.2, 17.5, 17.9, 25.3, 25.7, 26.6, 36.9, 38.4,
40.1, 41.4, 55.2, 55.2, 60.3, 68.8, 70.3, 75.3, 87.4, 93.2,
108.5, 176.1; EIMS (m/z): 415 (Mþ2tBu, 9.5), 45 (100);
Anal. calcd for C24H44O7Si: C, 60.98; H, 9.38. Found: C,
60.84; H, 9.19.
To a solution of the above diol (64.7 mg, 205 mmol) in
MeOH (2.0 mL) was added a solution of NaIO4 (54.0 mg,
245 mmol) in H2O (600 mL) at 08C. After stirring at 08C for
30 min, NaBH4 (16.0 mg, 205 mmol) was added 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 purified by silica gel column
chromatography (eluted with EtOAc) to give alcohol (þ)-10
(43.2 mg, 74%). Colorless oil; [a]D¼þ14.28 (c 0.38,
CHCl3).
1.1.8. [(1S,2S,4R,5R,6R)-5-Benzyloxymethyl-6-((S)-2,2-
dimethyl[1,3]dioxolan-4-yl)-4-methoxymethoxy-5-
methylbicyclo[2.2.1]hept-2-yloxy]-tert-butyldimethylsi-
lane (12). To a cold (08C) solution of ester 11 (2.20 g,
48.7 mmol) in Et2O (460 mL) was added LiAlH4 (1.70 g,
48.0 mmol) and the mixture was stirred at 08C for 10 min.
The reaction mixture was diluted with Et2O and added with
saturated aqueous NaCl. After stirring for 20 min, organic
layer was dried over anhydrous MgSO4 and concentrated
under reduced pressure. The residue was purified by silica
gel column chromatography (eluted with hexane–
Et2O¼1:2) to give alcohol (2.07 g, 99%). Colorless oil;
;
1H NMR (400 MHz, CDCl3) d ppm: 0.03 (3H, s), 0.04 (3H,
s), 0.87 (9H, s), 1.15 (3H, s), 1.32 (3H, s), 1.36 (3H, s), 1.54
(1H, br d, J¼10.1 Hz), 1.61 (1H, dt, J¼3.5, 13.4 Hz), 2.01
(1H, dd, J¼0.9, 6.6 Hz), 2.05 (1H, ddd, J¼2.0, 3.5,
10.1 Hz), 2.12 (1H, dd, J¼10.5, 13.4 Hz), 2.19 (1H, m),
2.24 (1H, dd, J¼2.0, 7.9 Hz), 3.36 (3H, s), 3.45 (1H, dd,
J¼8.0, 10.6 Hz), 3.51 (1H, dd, J¼7.1, 7.7 Hz), 3.90 (1H, br
d, J¼10.6 Hz), 4.05 (1H, dd J¼6.4, 7.7 Hz), 4.15–4.20 (2H,
m), 4.65 (1H, d, J¼7.1 Hz), 4.71 (1H, d, J¼7.1 Hz); 13C
NMR (75 MHz, CDCl3) d ppm: 24.9, 24.8, 16.0, 18.0,
25.2, 25.8, 26.7, 36.6, 36.7, 41.4, 42.7, 46.8, 55.6, 69.1,
69.4, 70.1, 75.2, 89.4, 92.9, 108.4; EIMS (m/z): 430 (Mþ,
3.7), 415 ((Mþ2Me, 3.7), 45 (100); Anal. calcd for
C22H42O6Si: C, 61.36; H, 9.83. Found: C, 61.34; H, 9.72.
1.1.7. Ethyl (1R,2S,3R,4S,5S)-5-(tert-butyldimethylsila-
nyloxy)-3-((S)-2,2-dimethyl[1,3]dioxolan-4-yl)-1-meth-
oxymethoxy-2-methylbicyclo[2.2.1]heptane-2-carboxy-
late (11). To a cold (08C) solution of keto ester 6a (44.0 g,
124 mmol) in MeOH (600 mL) was added NaBH4 (2.30 g,
61.7 mmol) and the mixture was stirred at 08C for 15 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. The residue was purified by silica gel
column chromatography (eluted with hexane–EtOAc¼1:1)
to give alcohol (44.2 g, quantitative yield). Colorless oil;
[a]D¼15.28 (c 0.73, CHCl3); 1H NMR (400 MHz, CDCl3) d
ppm: 1.28 (3H, t, J¼7.1 Hz), 1.32 (3H, s), 1.34 (3H, s), 1.40
(3H, s), 1.58 (1H, br d, J¼2.1 Hz), 1.65 (1H, dd, J¼11.0,
13.8 Hz), 2.14 (1H, ddd, J¼1.9, 3.8, 10.2 Hz), 2.28 (1H, br
d, J¼5.0 Hz), 2.31 (1H, dd, J¼11.0, 13.8 Hz), 2.46 (1H, d,
J¼8.3 Hz), 2.95 (1H, dd, J¼1.7, 5.5 Hz), 3.37 (3H, s), 3.62
(1H, t, J¼7.7 Hz), 4.06 (1H, dd, J¼6.5, 8.0 Hz), 4.15–4.30
(4H, m), 4.69 (1H, d, J¼7.1 Hz), 4.73 (1H, d, J¼7.1 Hz);
13C NMR (75 MHz, CDCl3) d ppm: 14.1, 16.1, 25.2, 26.5,
38.0, 38.1, 40.2, 42.3, 55.2, 55.3, 61.1, 68.8, 69.9. 75.0.
87.9, 93.1, 108.7, 176.9; EIMS (m/z): 358 (Mþ, 5.1), 327
(Mþ2MeO, 5.2), 45 (100); Anal. calcd for C18H30O7: C,
60.32; H, 8.44. Found: C, 60.13; H, 8.39.
[a]D¼29.28 (c 0.43, CHCl3); IR (neat) 3495, 2931 cm21
To a cold (08C) solution of the above alcohol (75.8 g,
176 mmol) in DMF (141 mL) was added NaH (60%, 14.1 g,
350 mmol) and the mixture was stirred at 0 8C for 30 min.
BnBr (32.5 mL, 260 mmol) was added to the mixture and
the mixture was stirred at rt for 12 h. 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 purified by
silica gel column chromatography (eluted with hexane–
Et2O¼2:1) to give Bn ether 12 (86.0 g, 94%). Colorless oil;
To a solution of the above alcohol (49.0 g, 134 mmol) in
DMF (134 mL) were added imidazole (14.0 g, 200 mmol)
and TBSCl (24.0 g, 160 mmol). After stirring at rt for 10 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
[a]D¼26.18 (c 0.79, CHCl3); IR (neat) 2931 cm21
;
1H
NMR (400 MHz, CDCl3) d ppm: 0.00 (3H, s), 0.02 (3H, s),
0.86 (9H, s), 1.07 (3H, s), 1.32 (3H, s), 1.36 (3H, s), 1.43
(1H, dt, J¼3.3, 13.3 Hz), 1.48 (1H, br d, J¼10.1 Hz), 2.00
(1H, dd, J¼10.6, 13.3 Hz), 2.03 (1H, dt, J¼3.3, 10.1 Hz),
2.21 (1H, br d, J¼4.9 Hz), 2.29 (1H, dd, J¼1.2, 7.6 Hz),

H. Miyaoka et al. / Tetrahedron 59 (2003) 61–75
67
3.34 (3H, s), 3.43 (1H, d, J¼8.3 Hz), 3.52 (1H, d,
J¼8.3 Hz), 3.73 (1H, dd, J¼6.8, 7.9 Hz), 4.02 (1H, dd
J¼6.3, 8.0 Hz), 4.12 (1H, dd, J¼6.5, 13.9 Hz), 4.18 (1H,
ddd, J¼2.7, 4.9, 10.6 Hz), 4.48 (1H, d, J¼12.3 Hz), 4.55
(1H, d, J¼12.3 Hz), 4.63 (1H, d, J¼7.0 Hz), 4.70 (1H, d,
J¼7.0 Hz), 7.25–7.35 (5H, m); 13C NMR (100 MHz,
CDCl3) d ppm: 24.9, 16.3, 18.0, 25.4, 25.9, 26.8, 36.8,
41.2, 44.7, 46.3, 55.3, 69.4, 70.4, 73.6, 75.8, 76.7, 88.5,
93.1, 105.0, 127.3, 127.3, 128.3, 138.9; EIMS (m/z): 520
(Mþ, 1.0), 515 ((Mþ2Me, 1.0), 91 (100); Anal. calcd for
C29H48O6Si: C, 66.88; H, 9.29. Found: C, 66.78; H, 9.17.
dimethylsilanyloxymethyl)-4-hydroxy-5-methylbicy-
clo[2.2.1]heptan-2-one (14). A mixture of AcOH and H2O
(4:1) (200 mL) was added to acetate 13 (71.5 g, 160 mmol)
and the mixture was stirred at 658C for 12 h. The reaction
mixture was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(eluted with hexane–EtOAc¼1:4) to give triol (46.5 g,
80%) and acetate 13 (10.7 g, 15% recovered). Colorless oil;
[a]D¼212.68 (c 0.73, CHCl3); IR (neat) 3434, 2923,
1730 cm21 1H NMR (400 MHz, CDCl3) d ppm: 1.31
;
(3H, s), 1.43 (1H, br d, J¼4.4 Hz), 1.59 (1H, d, J¼4.1 Hz),
1.67 (1H, dt, J¼14.0, 3.6 Hz), 1.98 (3H, s), 2.06 (1H, dd,
J¼10.8, 14.0 Hz), 2.14 (1H, ddd, J¼2.0, 3.6, 10.2 Hz), 2.44
(1H, d, J¼4.4 Hz), 2.71 (1H, br s), 3.37 (1H, d, J¼8.7 Hz),
3.40 (1H, dd, J¼8.1, 10.8 Hz), 3.49 (1H, dd, J¼3.4,
10.8 Hz), 3.57 (1H, d, J¼8.7 Hz), 3.81 (1H, m), 4.48 (1H,
d, J¼11.9 Hz), 4.52 (1H, d, J¼11.9 Hz), 4.99 (1H, ddd,
J¼3.6, 4.4, 10.8 Hz), 7.25–7.40 (5H, m); 13C NMR
(100 MHz, CDCl3) d ppm: 16.2, 21.1, 38.0, 38.6, 39.6,
42.4, 45.6, 66.6, 70.5, 73.7, 74.0, 77.6, 83.9, 127.8, 127.9,
128.5, 137.6, 170.6; EIMS (m/z): 365 (Mþþ1, 3.6), 346
(Mþ2H2O, 0.7), 43 (100); HREIMS: calcd for C20H29O6
(MþþH): 365.1964; Found: 365.1962.
1.1.9. (1S,2S,4R,5R,6R)-5-Benzyloxymethyl-6-((S)-2,2-
dimethyl[1,3]dioxolan-4-yl)-4-methoxymethoxy-5-
methylbicyclo[2.2.1]hept-2-yl acetate (13). To a solution
of TBS ether 12 (83.1 g, 160 mmol) in THF (320 mL) was
added TBAF (240 mL, 240 mmol, 1.0 M in THF). After
stirring at rt for 2 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 purified by silica gel column
chromatography (eluted with hexane–EtOAc¼1:1) to give
alcohol (64.5 g, quantitative yield). Colorless oil;
[a]D¼26.08 (c 1.76, CHCl3); IR (neat) 3460, 2983 cm21
;
1H NMR (400 MHz, CDCl3) d ppm: 0.97 (3H, s), 1.32 (3H,
s), 1.40 (3H, s), 1.52 (1H, dt, J¼10.1, 1.4 Hz), 1.66 (1H, dt,
J¼13.4, 3.3 Hz), 1.72 (1H, br s), 2.04 (1H, ddd, J¼1.9, 3.7,
10.1 Hz), 2.10 (1H, dd, J¼11.0, 13.5 Hz), 2.29 (1H, br d,
J¼5.0 Hz), 2.38 (1H, dd, J¼1.5, 7.2 Hz), 2.57 (1H, d,
J¼7.1 Hz), 3.29 (1H, d, J¼9.3 Hz), 3.33 (3H, s), 3.64 (1H,
d, J¼9.3 Hz), 3.66 (1H, dd, J¼6.7, 8.0 Hz), 4.04 (1H, dd,
J¼6.3, 8.0 Hz), 4.16 (1H, dd J¼6.6, 13.5 Hz), 4.17 (1H, m),
4.48 (1H, d, J¼11.9 Hz), 4.57 (1H, d, J¼11.9 Hz), 4.64 (1H,
d, J¼7.0 Hz), 4.69 (1H, d, J¼7.0 Hz), 7.25–7.40 (5H, m);
13C NMR (100 MHz, CDCl3) d ppm: 17.1, 25.3, 26.8, 36.1,
37.0, 41.3, 41.7, 46.6, 55.3, 69.2, 70.1, 73.5, 75.4, 75.6,
88.2, 93.0, 108.3, 127.7, 127.8, 128.4, 137.8; EIMS (m/z):
406 (Mþ, 0.03), 391 ((Mþ2Me, 0.1), 91 (100); HREIMS:
calcd for C23H34O6 (Mþ): 406.2355; Found: 406.2379.
To a solution of the above triol (16.0 g, 44.2 mmol) in
MeOH (220 mL) was added (NH4)2SO4 (17.0 g,
133 mmol). A solution of NaIO4 (9.50 g, 44.2 mmol) in
H2O (220 mL) was added at 08C and the mixture was stirred
for 15 min. NaBH4 (840 mg, 22.0 mmol) was added and the
mixture was stirred for 5 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 purified by silica gel
column chromatography (eluted with hexane–EtOAc¼1:1)
to give diol (13.0 g, 88%). Colorless oil; [a]D¼211.18 (c
1
1.08, CHCl3); IR (neat) 3445, 2927, 1733 cm21; H NMR
(400 MHz, CDCl3) d ppm: 1.21 (3H, s), 1.42 (1H, br d,
J¼10.4 Hz), 1.67 (1H, dt, J¼14.0, 3.5 Hz), 1.91 (2H, m),
2.00 (3H, s), 2.05 (1H, dd, J¼10.9, 14.0 Hz), 2.12 (1H, br d,
J¼4.7 Hz), 2.53 (1H, br s), 3.43 (1H, d, J¼8.6 Hz), 3.49
(1H, m), 3.60 (1H, d, J¼8.6 Hz), 3.67 (1H, m), 4.51 (2H, s),
5.02 (1H, ddd, J¼3.3, 4.7, 10.1 Hz), 7.25–7.40 (5H, m); 13C
NMR (100 MHz, CDCl3) d ppm: 15.4, 21.1, 37.9, 38.6,
39.9, 43.8, 44.8, 62.2, 73.5, 73.7, 77.3, 84.3, 127.8, 127.9,
128.5, 137.7, 170.6; EIMS (m/z): 334 (Mþ, 0.2), 243
(Mþ2BnO, 2.4), 91 (100); HREIMS: calcd for C19H26O5
(Mþ): 334.1780; Found: 334.1764.
To a solution of the above alcohol (64.5 g, 160 mmol) in
pyridine (70.0 mL) was added Ac2O (20.0 mL). After
stirring at rt for 10 h, the reaction mixture was concentrated
under reduced pressure. The residue was purified by silica
gel column chromatography (eluted with hexane–
EtOAc¼3:1) to give acetate 13 (71.5 g, 99%). Colorless
oil; [a]D¼26.38 (c 0.91, CHCl3); IR (neat) 2985,
1736 cm21 1H NMR (400 MHz, CDCl3) d ppm: 1.08
;
(3H, s), 1.32 (3H, s), 1.37 (3H, s), 1.50–1.60 (2H, m), 1.90
(3H, s), 2.08 (2H, m), 2.16 (1H, dd, J¼10.8, 14.1 Hz), 2.47
(1H, br d, J¼4.8 Hz), 3.34 (3H, s), 3.36 (1H, d, J¼8.4 Hz),
3.47 (1H, d, J¼8.4 Hz), 3.85 (1H, dd, J¼5.9, 8.0 Hz), 4.03
(1H, d, J¼6.3, 8.0 Hz), 4.11 (1H, m), 4.49 (1H, d,
J¼12.4 Hz), 4.57 (1H, d, J¼12.4 Hz), 4.64 (1H, d,
J¼7.1 Hz), 4.70 (1H, d, J¼7.1 Hz), 4.95 (1H, ddd, J¼3.3,
4.8, 10.8 Hz), 7.25–7.35 (5H, m); 13C NMR (100 MHz,
CDCl3) d ppm: 16.3, 20.6, 25.4, 26.9, 33.5, 36.2, 38.6, 45.1,
46.4, 55.4, 69.0, 72.7, 73.4, 75.5, 76.0, 88.0, 93.2, 108.4,
127.5, 127.5, 128.3, 138.7, 170.5; EIMS (m/z): 448 (Mþ,
0.5), 433 (Mþ2Me, 1.5), 91 (100); Anal. calcd for
C25H36O7: C, 66.94; H, 8.09. Found: C, 66.98; H, 8.16.
To a solution of the above diol (4.13 g, 12.0 mmol) in DMF
(25.0 mL) were added imidazole (2.50 g, 36.0 mmol) and
TBSCl (2.70 g, 18.0 mmol). After stirring at rt for 5 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
purified by silica gel column chromatography (eluted with
hexane–Et2O¼3:1) to give TBS ether (5.16 g, 96%).
Colorless oil; [a]D¼210.88 (c 1.05, CHCl3); IR (neat)
1
3584, 2929, 1738 cm21; H NMR (400 MHz, CDCl3) d
ppm: 0.01 (3H, s), 0.02 (3H, s), 0.86 (9H, s), 1.20 (3H, s),
1.41 (1H, br d, J¼10.3 Hz), 1.68 (1H, dt, J¼13.8, 3.6 Hz),
1.77 (1H, br t, J¼7.7 Hz), 1.92 (1H, ddd, J¼2.0, 3.6,
10.3 Hz), 2.00 (3H, s), 2.05 (1H, dd, J¼10.9, 13.8 Hz), 2.12
(1H, br d, J¼4.6 Hz), 2.70 (1H, br s), 3.42 (1H, d,
1.1.10. (1S,4R,5R,6R)-5-Benzyloxymethyl-6-(tert-butyl-

68
H. Miyaoka et al. / Tetrahedron 59 (2003) 61–75
J¼9.0 Hz), 3.43 (1H, dd, J¼7.2, 10.0 Hz), 3.62 (1H, dd,
J¼7.7, 10.0 Hz), 3.64 (1H, d, J¼9.0 Hz), 4.47 (1H, d,
J¼11.8 Hz), 4.51 (1H, d, J¼11.8 Hz), 5.03 (1H, ddd, J¼3.4,
4.6, 10.9 Hz), 7.25–7.40 (5H, m); 13C NMR (100 MHz,
CDCl3) d ppm: 25.5, 25.4, 15.3, 18.0, 21.1, 25.8, 37.9,
38.4, 39.9, 43.5, 44.6, 62.7, 73.6, 73.7, 77.9, 84.5, 127.8,
127.8, 128.4, 137.8, 170.5; EIMS (m/z): 449 (Mþþ1, 1.0),
391 (Mþ2tBu, 10), 91 (100); HREIMS: calcd for
C25H37O5Si (Mþ2H): 449.2723; Found: 449.2712.
residue was purified by silica gel column chromatography
(eluted with hexane–Et2O¼3:1) to give diketone 15 (4.42 g,
86%). Colorless oil; [a]D¼þ47.38 (c 0.33, CHCl3); IR
(neat) 2930, 1746, 1714 cm21; 1H NMR (400 MHz, CDCl3)
d ppm: 0.02 (6H, s), 0.87 (9H, s), 0.92 (3H, s), 2.24 (3H, s),
2.48 (1H, dd, J¼10.7, 18.3 Hz), 2.54 (1H, dd, J¼8.1,
18.3 Hz), 2.92 (1H, m), 2.99 (1H, m), 3.34 (1H, d,
J¼8.8 Hz), 3.49 (1H, d, J¼8.8 Hz), 3.67 (1H, dd, J¼5.8,
10.4 Hz), 3.77 (1H, dd, J¼5.6, 10.4 Hz), 4.43 (1H, d,
J¼12.1 Hz), 4.48 (1H, d, J¼12.1 Hz), 7.25–7.35 (5H, m);
13C NMR (100 MHz, CDCl3) d ppm: 25.7, 25.7, 14.8,
18.2, 25.8, 29.5, 41.3, 46.3, 48.4, 52.6, 62.4, 73.3, 74.3,
127.4, 127.5, 128.3, 138.1, 209.1, 217.9; EIMS (m/z): 347
(Mþ2tBu, 0.6), 253, 91 (100); HREIMS: calcd for
C19H27O4Si (Mþ2tBu): 347.1678; Found: 347.1698.
To a solution of the above TBS ether (47.0 g, 105 mmol) in
MeOH (200 mL) was added K2CO3 (29.0 g, 210 mmol).
After stirring at rt for 2 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 diol (42.4 g, quantitative yield).
Colorless oil; [a]D¼þ9.58 (c 0.34, CHCl3); IR (neat) 3424,
2954 cm21; 1H NMR (400 MHz, CDCl3) d ppm: 0.02 (3H,
s), 0.03 (3H, s), 0.88 (9H, s), 1.18 (3H, s), 1.36 (1H, br d,
J¼9.9 Hz), 1.66 (1H, dt, J¼13.3, 3.5 Hz), 1.81 (1H, br s),
1.88 (1H, m), 1.90 (1H, ddd, J¼2.0, 3.5, 9.9 Hz), 1.97 (1H,
dd, J¼10.7, 13.3 Hz), 2.07 (1H, br t, J¼7.3 Hz), 2.61 (1H,
br s), 3.47 (1H, d, J¼9.0 Hz), 3.48 (1H, dd, J¼6.7, 9.9 Hz),
3.61 (1H, dd, J¼8.0, 9.9 Hz), 3.71 (1H, d, J¼9.0 Hz), 4.31
(1H, br d, J¼10.7 Hz), 4.46 (1H, d, J¼11.8 Hz), 4.53 (1H, d,
J¼11.8 Hz), 7.25–7.40 (5H, m); 13C NMR (100 MHz,
CDCl3) d ppm: 25.4, 25.3, 15.4, 18.2, 25.9, 39.3, 40.6,
41.9, 42.4, 45.0, 63.2, 71.4, 73.6, 77.7, 84.9, 127.7, 127.8,
128.5, 138.0; EIMS (m/z): 406 (Mþ), 257, 223, 91 (100);
Anal. calcd for C23H38O4Si: C, 67.94; H, 9.42. Found: C,
67.71; H, 9.41.
1.1.12. (1R,2R,5S)-2-Benzyloxymethyl-2-methyl-5-(2-
methyl[1,3]dioxolan-2-yl)-3-oxocyclopentylmethyl acet-
ate (16). A mixture of AcOH and H2O (4:1) (20.0 mL) was
added to TBS ether 15 (1.51 g, 3,72 mmol) and the mixture
was stirred at rt for 5 h. The reaction mixture was
concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluted with
hexane–EtOAc¼1:1) to give alcohol (1.05 g, 97%). Color-
less oil; [a]D¼þ83.78 (c 0.22, CHCl3); IR (neat) 3403,
1
2930, 1742, 1709 cm21; H NMR (400 MHz, CDCl3) d
ppm: 0.98 (3H, s), 2.27 (3H, s), 2.40 (1H, dd, J¼4.5,
18.4 Hz), 2.65 (1H, dd, J¼8.0, 18.4 Hz), 2.75–2.85 (2H,
m), 2.92 (1H, dt, J¼8.0, 11.2 Hz), 3.45 (1H, d, J¼9.1 Hz),
3.48 (1H, d, J¼9.1 Hz), 3.61 (1H, m), 3.68 (1H, m), 4.50
(1H, d, J¼12.0 Hz), 4.55 (1H, d, J¼12.0 Hz), 7.25–7.35
(5H, m); 13C NMR (75 MHz, CDCl3) d ppm: 14.6, 30.1,
41.1, 48.2, 48.3, 53.0, 61.5, 73.6, 74.0, 127.8, 127.9, 128.5,
137.2, 209.3, 216.5; EIMS (m/z): 272 (Mþ2H2O, 3.0), 166,
123, 91 (100); HREIMS: calcd for C17H22O4 (Mþ2H2O):
290.1518; Found: 290.1506.
To a solution of the above diol (2.18 g, 5.37 mmol) in
˚
CH2Cl2 (54.0 mL) were added 4 A molecular sieves
(1.70 g) and PCC (1.70 g, 8.05 mmol) at 08C. After stirring
at rt for 2 h, the reaction mixture was diluted with Et2O,
filtered through silica gel column and the filtrate was
concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluted with
hexane–EtOAc¼1:1) to give keto alcohol 14 (1.97 g, 90%).
Colorless oil; [a]D¼þ13.68 (c 0.13, CHCl3); IR (neat) 3451,
2929, 1751 cm21; 1H NMR (400 MHz, CDCl3) d ppm: 0.01
(3H, s), 0.02 (3H, s), 0.86 (9H, s), 1.29 (3H, s), 1.35 (1H, br
t, J¼7.2 Hz), 1.67 (1H, br d, J¼10.4 Hz), 2.21 (1H, dd,
J¼4.3, 10.4 Hz), 2.30 (1H, d, J¼18.8 Hz), 2.36 (1H, br s),
2.49 (1H, dd, J¼4.4, 17.9 Hz), 2.99 (1H, br s), 3.36 (1H, d,
J¼9.0 Hz), 3.42 (1H, d, J¼9.0 Hz), 3.56 (1H, dd, J¼6.3,
10.1 Hz), 3.69 (1H, dd, J¼7.9, 10.1 Hz), 4.47 (1H, d,
J¼11.8 Hz), 4.50 (1H, d, J¼11.8 Hz), 7.25–7.40 (5H, m);
13C NMR (100 MHz, CDCl3) d ppm: -5.5, -5.4, 15.4, 18.0,
25.8, 38.7, 44.2, 46.5, 48.1, 51.6, 62.3, 73.7, 78.2, 82.3,
127.8, 128.1, 128.6, 137.4, 212.6; EIMS (m/z): 347
(Mþ2tBu, 0.4), 255, 239, 91 (100); HREIMS: calcd for
C19H27O4Si (Mþ2tBu): 347.1678; Found: 347.1677.
To a solution of the above alcohol (1.05 g, 3.59 mmol) in
pyridine (5.00 mL) was added Ac2O (3.00 mL). After
stirring at rt for 5 h, the reaction mixture was concentrated
under reduced pressure. The residue was purified by silica
gel column chromatography (eluted with hexane–
Et2O¼1:5) to give acetate (1.19 g, quantitative yield).
Colorless oil; [a]D¼þ47.18 (c 0.20, CHCl3); IR (neat)
1
2863, 1743, 1716 cm21; H NMR (400 MHz, CDCl3) d
ppm: 0.89 (3H, s), 1.98 (3H, s), 2.25 (3H, s), 2.43 (1H, dd,
J¼11.0, 18.2 Hz), 2.61 (1H, dd, J¼7.9, 18.2 Hz), 2.97 (1H,
dt, J¼7.9, 11.0 Hz), 3.17 (1H, dt, J¼6.8, 11.0 Hz), 3.33 (1H,
d, J¼8.9 Hz), 3.53 (1H, d, J¼8.9 Hz), 4.11 (1H, dd, J¼7.1,
11.0 Hz), 4.23 (1H, dd, J¼6.4, 11.0 Hz), 4.44 (1H, d,
J¼12.3 Hz), 4.52 (1H, d, J¼12.3 Hz), 7.25–7.40 (5H, m);
13C NMR (100 MHz, CDCl3) d ppm: 14.8, 20.7, 29.6, 41.7,
42.5, 48.7, 52.6, 63.8, 73.4, 73.6, 127.6, 127.7, 128.4, 137.9,
170.6, 208.2, 216.5; EIMS (m/z): 332 (Mþ), 314, 200;
HREIMS: calcd for C19H24O5 (Mþ): 332.1624; Found:
332.1623.
1.1.11. (2R,3R,4S)-4-Acetyl-2-benzyloxymethyl-3-(tert-
butyldimethylsilanyloxymethyl)-2-methylcyclopenta-
none (15). To a solution of keto alcohol 14 (5.14 g,
12.7 mmol) in toluene (127 mL) were added 15-crown-5
(0.126 mL, 0.635 mmol) and NaH (60%, 0.61 g,
15.3 mmol). After stirring at rt for 1 h, the reaction mixture
was diluted with Et2O, filtered through silica gel column and
the filtrate was concentrated under reduced pressure. The
To a solution of the above diketone (4.70 g, 14.2 mmol) in
CH2Cl2 (70.0 mL) were added TMS–OTf (0.280 mL,
1.45 mmol) and 1,2-bis(trimethylsilyloxy)ethane (3.80 g,
15.6 mmol) at 2608C. After stirring at 2408C for 18 h,
pyridine (5.0 mL) was added to the reaction mixture. The
mixture was diluted with Et2O, washed with H2O and

H. Miyaoka et al. / Tetrahedron 59 (2003) 61–75
69
saturated aqueous NaCl, dried over anhydrous MgSO4 and
concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluted with
hexane–Et2O¼5:1) to give mono acetal 16 (5.00 g, 90%).
Colorless oil; [a]D¼þ34.68 (c 0.58, CHCl3); IR (neat) 2981,
1741 cm21; 1H NMR (400 MHz, CDCl3) d ppm: 0.90 (3H,
s), 1.33 (3H, s), 1.92 (3H, s), 2.20–2.35 (2H, m), 2.51 (1H,
dd, J¼7.8, 17.9 Hz), 2.99 (1H, dt, J¼4.0, 10.4 Hz), 3.35
(1H, d, J¼8.8 Hz), 3.59 (1H, d, J¼8.8 Hz), 3.90–4.05 (5H,
m), 4.40 (1H, d, J¼12.4 Hz), 4.52 (1H, d, J¼12.4 Hz), 4.69
(1H, dd, J¼4.0, 11.7 Hz), 7.25–7.40 (5H, m); 13C NMR
(75 MHz, CDCl3) d ppm: 14.9, 20.8, 21.7, 39.3, 41.3, 42.7,
53.6, 64.3, 64.4, 65.0, 73.1, 74.1, 110.6, 127.3, 127.4, 128.2,
138.3, 170.6, 218.8; EIMS (m/z): 376 (Mþ, 0.2), 358, 331,
87 (100); HREIMS: calcd for C21H28O6 (Mþ): 376.1886;
Found: 376.1899.
1.1.14. 2-((1S,4R,5S)-5-Benzenesulfonylmethyl-4-benzy-
loxymethyl-4-methylcyclopent-2-enyl)-2-methyl[1,3]-
dioxolane (18). To a solution of acetate 17 (16.2 g,
44.8 mmol) in MeOH (200 mL) was added K2CO3
(3.00 g, 21 mmol). After stirring at rt for 3 h, the reaction
mixture was diluted with Et2O and filtered through silica
gel. The filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatog-
raphy (eluted with hexane–EtOAc¼1:1) to give alcohol
(14.3 g, quantitative yield). Colorless oil; [a]D¼þ20.88 (c
0.25, CHCl3); IR (neat) 3457, 2875 cm21 1H NMR
;
(400 MHz, CDCl3) d ppm: 1.01 (3H, s), 1.29 (3H, s), 2.18
(1H, dd, J¼7.1, 15.3 Hz), 2.74 (1H, dt, J¼8.3, 1.5 Hz), 3.29
(1H, d, J¼8.6 Hz), 3.39 (1H, d, J¼8.6 Hz), 3.63 (1H, m),
3.75 (1H, m), 3.82 (1H, br t, J¼5.1 Hz), 3.90–4.00 (4H, m),
4.56 (1H, d, J¼12.1 Hz), 4.58 (1H, d, J¼12.1 Hz), 5.56 (1H,
dd, J¼2.0, 5.8 Hz), 5.58 (1H, dd, J¼1.4, 5.8 Hz), 7.25–7.35
(5H, m); 13C NMR (75 MHz, CDCl3) d ppm: 18.5, 21.6,
48.8, 52.1, 58.2, 63.0, 64.5, 64.8, 73.4, 77.2, 78.3, 110.9,
127.6, 128.4, 129.4, 137.9, 138.9; EIMS (m/z): 318 (Mþ,
0.1), 303 (0.1), 197, 87 (100); HREIMS: calcd for C19H26O4
(Mþ): 318.1831; Found: 318.1811.
1.1.13. (1R,2R,5R)-2-Benzyloxymethyl-2-methyl-5-(2-
methyl[1,3]dioxolan-2-yl)cyclopent-3-enylmethyl acet-
yate (17). To a cold (08C) solution of ketone 16 (44.0 g,
124 mmol) in MeOH (600 mL) was added NaBH4 (2.30 g,
61.7 mmol) and the mixture was stirred at 08C for 15 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. The residue was purified by silica gel
column chromatography (eluted with hexane–EtOAc¼1:1)
to give alcohol (44.0 g, 98%). Colorless oil; [a]D¼þ15.38 (c
To a solution of the above alcohol (340 mg, 1.06 mmol) in
pyridine (2.40 mL) were added PhSSPh (1.20 g, 5.30 mmol)
n
and Bu3P (3.80 g, 15.6 mmol) at 608C. After stirring for
5 h, the reaction mixture was diluted with Et2O, washed
with 5% NaOH aqueous solution, H2O and saturated
aqueous NaCl, dried over anhydrous MgSO4 and concen-
trated under reduced pressure to give crude sulfide. The
crude sulfide was used next reaction without purification.
1
0.55, CHCl3); IR (neat) 3457, 2969, 1738 cm21; H NMR
(400 MHz, CDCl3) d ppm: 0.95 (3H, s), 1.32 (3H, s), 1.64
(1H, m), 1.91 (3H, s), 2.05–2.15 (2H, m), 2.20 (1H, m), 3.41
(1H, br d, J¼7.9 Hz), 3.42 (1H, d, J¼8.8 Hz), 3.66 (1H, d,
J¼8.8 Hz), 3.84 (1H, ddd, J¼2.5, 5.1, 7.9 Hz), 3.95–4.05
(5H, m), 4.38 (1H, dd, J¼3.6, 11.1 Hz), 4.48 (1H, d,
J¼12.2 Hz), 4.59 (1H, d, J¼12.2 Hz), 7.25–7.35 (5H, m);
13C NMR (75 MHz, CDCl3) d ppm: 17.6, 20.9, 22.6, 34.3,
42.2, 46.9, 49.9, 64.7, 65.0, 73.3, 75.0, 79.4, 111.3, 127.4,
127.5, 128.3, 138.6, 170.8; EIMS (m/z): 363 (Mþ2Me, 0.5),
316, 225, 87 (100); HREIMS: calcd for C20H27O6
(Mþ2Me): 363.1808; Found: 363.1800.
To a cold (08C) solution of the above crude sulfide in THF–
MeOH (1:1, 255 mL) was added a solution of OXONEw
(55.0 g, 89.2 mmol) in H2O (190 mL). After stirring at rt for
3 h, the reaction mixture was diluted with Et2O, washed
with saturated aqueous NaHCO3, H2O and saturated
aqueous NaCl, dried over anhydrous MgSO4 and concen-
trated under reduced pressure. The residue was purified by
silica gel column chromatography (eluted with hexane–
Et2O¼1:1) to give sulfone 18 (16.8 g, 85%, two steps).
Colorless oil; [a]D¼þ26.58 (c 1.30, CHCl3); IR (neat) 2872,
1307, 1149 cm21; 1H NMR (400 MHz, CDCl3) d ppm: 1.07
(3H, s), 1.09 (3H, s), 2.66 (1H, dt, J¼8.9, 2.4 Hz), 2.81 (1H,
br t, J¼8.9 Hz), 3.41 (1H, dd, J¼10.8, 14.6 Hz), 3.64 (1H, d,
J¼9.1 Hz), 3.65–3.85 (6H, m), 4.58 (1H, d, J¼12.1 Hz),
4.63 (1H, d, J¼12.1 Hz), 5.49 (1H, dd, J¼1.7, 5.9 Hz), 5.72
(1H, dd, J¼2.4, 5.9 Hz), 7.25–7.40 (5H, m), 7.43 (2H, m),
7.57 (1H, m), 7.90 (2H, m); 13C NMR (75 MHz, CDCl3) d
ppm: 19.3, 21.5, 37.0, 51.4, 57.0, 59.0, 64.1, 64.8, 73.0,
76.2, 111.0, 126.9, 127.1, 127.3, 128.1, 128.3, 128.9, 133.3,
139.0, 139.8, 141.3; EIMS (m/z): 442 (Mþ, 0.1), 351, 300,
87 (100); Anal. calcd for C25H30O5S: C, 67.85; H, 6.83.
Found: C, 67.68; H, 6.83.
To a solution of the above alcohol (100 mg, 263 mmol) in
pyridine (420 mL) were added N-phenylthiosuccinimide
(272 mg, 1.32 mmol) and nBu3P (330 mL, 1.32 mmol).
After stirring at rt for 6 h, the reaction mixture was diluted
with Et2O, washed with 5% NaOH aqueous solution, H2O
and saturated aqueous NaCl, dried over anhydrous MgSO4
and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluted with
hexane–Et2O¼10:1) to give cyclopentene 17 (88.5 mg,
93%). Colorless oil; [a]D¼þ20.08 (c 0.20, CHCl3); IR
1
(neat) 2874, 1738 cm21; H NMR (400 MHz, CDCl3) d
ppm: 1.00 (3H, s), 1.30 (3H, s), 1.93 (3H, s), 2.40 (1H, ddd,
J¼4.5, 8.1, 10.0 Hz), 2.73 (1H, dt, J¼8.1, 2.1 Hz), 3.31 (1H,
d, J¼8.7 Hz), 3.39 (1H, d, J¼8.7 Hz), 3.90–4.00 (4H, m),
4.09 (1H, dd, J¼10.0, 11.0 Hz), 4.42 (1H, dd, J¼4.5,
11.0 Hz), 4.51 (1H, d, J¼12.4 Hz), 4.55 (1H, d, J¼12.4 Hz),
5.56 (1H, dd, J¼1.9, 5.8 Hz), 5.69 (1H, dd, J¼2.3, 5.8 Hz),
7.25–7.35 (5H, m); 13C NMR (75 MHz, CDCl3) d ppm:
18.7, 21.0, 21.8, 42.5, 52.1, 55.8, 64.5, 64.9, 65.1, 73.2,
78.0, 111.1, 127.3, 127.4, 128.2, 138.8, 140.0, 171.0; EIMS
(m/z): 345 (Mþ2Me, 0.1), 179, 151, 87 (100); HREIMS:
calcd for C20H25O5 (Mþ2Me): 345.1702; Found: 345.1692.
1.1.15. (4-Bromo-3-methylbut-2-enyloxy)-tert-butyldi-
methylsilane (20). To a cold (08C) solution of 4-(tert-
butyldimethylsilanyloxy)-2-methylbut-2-en-1-ol
(19)16
(14.4 g, 67.1 mmol) in CH2Cl2 (2.40 mL) were added
Ph3P (21.0 g, 80.5 mmol) and NBS (13.0 g, 73.8 mmol) at
08C. After stirring at 08C for 2 h, the reaction mixture was
diluted with Et2O and filtered through silica gel. The filtrate
was concentrated under reduced pressure. The residue was

70
H. Miyaoka et al. / Tetrahedron 59 (2003) 61–75
purified by distillation under reduce pressure (bp
1038C/3 mmHg) to give allylic bromide 20 (14.9 g, 80%).
phenylphosphonium chloride (15.0 g, 44.0 mmol) in THF
(27.0 mL) was added PhLi (34.6 mL, 35.3 mmol, 1.02 M in
cyclohexane–Et2O). The mixture was stirred at 08C for
30 min. A solution of the above crude aldehyde in THF
(5.00 mL) was added and stirred at 08C for 15 min. The
reaction mixture was diluted with Et2O and saturated
aqueous NH4Cl (10 mL) was added. After stirring at rt for
24 h, organic layer was washed with H2O and saturated
aqueous NaCl, dried over anhydrous MgSO4 and concen-
trated under reduced pressure. The residue was purified by
silica gel column chromatography (eluted with hexane–
Et2O¼10:1) to give the mixture (E/Z¼3:2) of methyl enol
ether (3.70 g, 84%, two steps). The mixture of geometric
isomers was used next reaction.
1
Colorless oil; IR (neat) 2954, 1474, 1254, 1101 cm21; H
NMR (300 MHz, CDCl3) d ppm: 0.08 (6H, s), 0.91 (9H, s),
1.77 (3H, br s), 3,96 (2H, br s), 4.21 (2H, br d, J¼6.2 Hz),
5.71 (1H, br t, J¼6.2 Hz); 13C NMR (75 MHz, CDCl3) d
ppm: 15.2, 18.5, 26.1, 26.1, 40.8, 60.2, 130.5, 132.5; EIMS
(m/z): 280 (Mþþ2, 10), 278 (Mþ, 10), 222 (10), 220 (10);
HREIMS: calcd for C10H20OSiBr (Mþ2CH3): 263.0467;
Found: 263.0454.
1.1.16. (E)-{5-Benzenesulfonyl-5-[(1R,2S,5R)-2-benzy-
loxymethyl-2-methyl-5-(2-methyl-[1,3]dioxolan-2-yl)-3-
cyclopentenyl]-(3-methyl-2-pentenyloxy)-tert-butyldi-
methylsilane (21). To a cold (2788C) solution of sulfone 18
n
(850 mg, 1.91 mmol) in THF (19.0 mL) was added BuLi
To a solution of the above enol ether (3.70 g, 8.55 mmol) in
benzene (85.5 mL) was added PCC–Al2O3 (21.4 g). After
stirring at 408C for 5 h, the reaction mixture was diluted
with Et2O, filtered through silica gel column and the filtrate
was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluted with
hexane–Et2O¼3:1) to give methyl ester 23 (3.25 g, 85%).
Colorless oil; [a]D¼þ30.08 (c 0.28, CHCl3); IR (neat) 2954,
1738 cm21; 1H NMR (400 MHz, CDCl3) d ppm: 0.07 (6H,
s), 0.90 (9H, s), 1.05 (3H, s), 1.27 (3H, s), 1.50–1.75 (3H,
m), 1.64 (3H, s), 1.94 (1H, m), 2.08 (2H, m), 2.40 (1H, d,
J¼13.7 Hz), 2.52 (1H, d, J¼13.7 Hz), 2.63 (1H, dt, J¼7.0,
2.1 Hz), 3.64 (3H, s), 3.90–4.00 (4H, m), 4.19 (2H, br d,
J¼6.3 Hz), 5.32 (1H, br t, J¼6.3 Hz), 5.53 (1H, dd, J¼2.0,
5.8 Hz), 5.73 (1H, dd, J¼2.2, 5.8 Hz); 13C NMR (75 MHz,
CDCl3) d ppm: 25.0, 16.4, 18.4, 21.5, 22.0, 26.0, 29.6, 38.9,
46.6, 49.7, 51.1, 51.2, 59.9, 60.3, 64.4, 64.7, 111.2, 124.1,
128.3, 137.4, 140.8, 172.4; EIMS (m/z): 452 (Mþ, 0.15),
437, 395 (0.1), 87 (100); HREIMS: calcd for C25H44O5Si
(Mþ): 452.2958; Found: 452.2957.
(1.47 mL, 2.30 mmol, 1.56 M in hexane). After stirring at
2788C for 30 min, a solution of allylic bromide 20 (1.05 g,
3.82 mmol) in THF (2.00 mL) was added and stirred at -
308C for 40 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 sulfone
21. The crude sulfone 21 was used next reaction without
purification.
1.1.17. [(1R,4S,5R)-5-[(E)-5-(tert-Butyldimethylsilany-
loxy)-3-methyl-3-pentenyl]-1-methyl-4-(2-methyl[1,3]-
dioxolan-2-yl)-2-cyclopentenyl]methanol (22). To a cold
(2788C) solution of crude sulfone 21 in THF (20.0 mL) and
NH3 (300 mL) was added Na (1.0 g). After stirring at
2788C for 1 h, NH4Cl (10 g) was added. After evaporation
of NH3 under atmospheric pressure, the residue was diluted
with Et2O, washed with H2O and saturated aqueous NaCl,
dried over anhydrous MgSO4 and concentrated under
reduced pressure. The residue was purified by silica gel
column chromatography (eluted with hexane–EtOAc¼2:1)
to give alcohol 22 (524 mg, 68%, two steps). Colorless oil;
1.1.19. Ethyl (E)-4-[(1R,4S,5R)-5-[(E)-5-(tert-butyldi-
methylsilanyloxy)-3-methyl-3-pentenyl]-1-methyl-4-(2-
methyl-[1,3]dioxolan-2-yl)-2-cyclopentenyl]-2-methyl-2-
butenoate (24). To a cold (2788C) solution of ester 23
(4.37 g, 9.67 mmol) in toluene (97.0 mL) was added
DIBAH (11.2 mL, 10.6 mmol, 0.95 M in hexane). After
stirring at 2788C for 10 min, EtOAc (1.0 mL) was added at
2788C. The reaction mixture was diluted with Et2O and
saturated aqueous NaCl was added. The mixture was stirred
at rt for 1 h. Organic layer was dried over anhydrous MgSO4
and concentrated under reduced pressure to give crude
aldehyde. The crude aldehyde was used next reaction
without purification.
[a]D¼þ36.78 (c 0.22, CHCl3); IR (neat) 3410, 2930 cm21
;
1H NMR (400 MHz, CDCl3) d ppm: 0.07 (6H, s), 0.90 (9H,
s), 0.97 (3H, s), 1.32 (3H, s), 1.60–1.70 (2H, m), 1.64 (3H,
br s), 2.00–2.10 (3H, m), 2.70 (1H, dt, J¼6.2, 2.0 Hz), 3.44
(1H, d, J¼9.5 Hz), 3.49 (1H, dd, J¼2.1, 5.8 Hz), 3.90–4.00
(4H, m), 4.19 (2H, d, J¼6.3 Hz), 5.32 (1H, br t, J¼6.3 Hz),
5.49 (1H, d, J¼12.1 Hz), 5.63 (1H, dd, J¼2.1, 5.8 Hz); 13C
NMR (75 MHz, CDCl3) d ppm: 25.0, 16.4, 18.4, 18.9, 22.6,
26.0, 30.3, 39.1, 41.7, 53.6, 60.3, 61.1, 64.6, 64.7, 70.9,
111.5, 124.2, 129.9, 137.6, 139.6; EIMS (m/z): 410 (Mþ,
0.02), 395 (Mþ2Me, 0.1), 380, 87 (100); HREIMS: calcd
for C22H39O4Si (Mþ2Me): 395.2617; Found: 395.2595.
To a cold (08C) solution of trietyl 2-phosphonopropionate
(2.60 mL, 12.0 mmol) in THF (40.0 mL) was added NaH
(390 mg, 9.60 mmol, 60%). After stirring at 08C for 20 min,
a solution of the above crude aldehyde in THF (10 mL) was
added at 08C and stirred for 1 h. The reaction mixture was
diluted with Et2O and saturated aqueous NaCl was added.
The mixture was stirred at rt for 1 h. The reaction mixture
was diluted with Et2O, was washed with H2O and saturated
aqueous NaCl, dried over anhydrous MgSO4 and concen-
trated under reduced pressure. The residue was purified by
silica gel column chromatography (eluted with hexane–
Et2O¼10:1) to give ethyl ester 24 (3.86 g, 80%, two steps).
Colorless oil; [a]D¼9.88 (c 0.57, CHCl3); IR (neat) 2930,
1.1.18. Methyl [(1R,4S,5R)5-[(E)-5-(tert-butyldimethylsi-
lanyloxy)-3-methyl-3-pentenyl]-1-methyl-4-(2-methyl-
[1,3]dioxolan-2-yl)-2-cyclopentenyl]acetate (23). To a
solution of alcohol 22 (4.10 g, 9.98 mmol) in CH2Cl2
˚
(100 mL) were added 4 A molecular sieves (5.6 g) and PDC
(5.60 g, 15.0 mmol). After stirring at rt for 5 h, the reaction
mixture was diluted with Et2O, filtered through silica gel
column and the filtrate was concentrated under reduced
pressure to give crude aldehyde. The crude aldehyde was
used next reaction without purification.
To a cold (2788C) suspension of (methoxymethyl)tri-

H. Miyaoka et al. / Tetrahedron 59 (2003) 61–75
71
1712 cm21; 1H NMR (400 MHz, CDCl3) d ppm: 0.06 (6H,
s), 0.90 (9H, s), 1.01 (3H, s), 1.26 (3H, s), 1.27 (3H, t,
J¼7.2 Hz), 1.55–1.65 (2H, m), 1.63 (3H, br s), 1.70–1.85
(2H, m), 1.83 (3H, br s), 1.95–2.15 (2H, m), 2.32 (1H, br d,
J¼8.0 Hz), 2.63 (1H, d, J¼7.4 Hz), 3.85–4.00 (4H, m),
4.10–4.25 (4H, m), 5.30 (1H, br t, J¼5.3 Hz), 5.54 (2H, m),
5.81 (1H, br t, J¼7.9 Hz); 13C NMR (75 MHz, CDCl3) d
ppm: 25.0, 12.7, 14.3, 16.4, 18.4, 21.8, 22.1, 26.0, 29.8,
39.3, 41.2, 46.2, 51.3, 60.1, 60.3, 64.4, 64.8, 111.7, 124.1,
128.8, 128.9, 137.5, 139.8, 141.2, 168.1; EIMS (m/z):
491 (Mþ2Me, 0.15), 449 (0.9), 87 (100); HREIMS:
calcd for C28H47O5Si (Mþ2Me): 491.3193; Found:
491.3183.
To a cold (08C) solution of the above sulfide (280 mg,
579 mmol) in THF–MeOH (1:1, 3.00 mL) was added a
solution of OXONEw (720 mg, 1.20 mmol) in H2O
(2.50 mL). After stirring at rt for 3 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 press-
ure. The residue was purified by silica gel column
chromatography (eluted with hexane–EtOAc¼1:2) to give
sulfone (269 mg, 90%). Colorless oil; [a]D¼29.78 (c 0.25,
1
CHCl3); IR (neat) 2937, 1707, 1648, 1307, 1151 cm21; H
NMR (400 MHz, CDCl3) d ppm: 0.93 (3H, s), 1.25 (3H, s),
1.27 (3H, t, J¼7.1 Hz), 1.33 (3H, br s), 1.48 (1H, m), 1.63
(1H, m), 1.77 (1H, m), 1.82 (3H, br s), 1.95–2.10 (2H, m),
2.29 (2H, d, J¼7.5 Hz), 2.61 (1H, d, J¼7.4 Hz), 3.79 (1H, d,
J¼8.0 Hz), 3.85–4.00 (4H, m), 4.10–4.20 (2H, m), 5.20
(1H, dt, J¼1.1, 8.0 Hz), 5.53 (1H, d, J¼7.0 Hz), 5.55 (1H, d,
J¼7.0 Hz), 6.81 (1H, dt, J¼1.3, 7.5 Hz), 7.52 (2H, m), 7.63
(1H, m), 7.86 (2H, m); 13C NMR (100 MHz, CDCl3) d ppm:
12.7, 14.3, 16.2, 21.7, 22.1, 29.8, 39.4, 41.1, 46.1, 51.3,
56.1, 60.2, 60.4, 64.4, 64.8, 110.1, 111.5, 128.6, 128.9,
133.5, 138.7, 139.5, 141.1, 147.1, 168.0; EIMS (m/z): 516
(Mþ, 0.8), 501, 87 (100); HREIMS: calcd for C29H40O6S
(Mþ): 516.2546; Found: 516.2547.
1.1.20. (E)-4-[(1R,4S,5R)-5-((E)-5-Benzenesulfonyl-3-
methyl-3-pentenyl)-1-methyl-4-(2-methyl-[1,3]dioxolan-
2-yl)-2-cyclopentenyl]-2-methyl-2-buten-1-ol (25). To a
solution of TBS ether 24 (321 mg, 0.634 mmol) in THF
(634 mL) was added TBAF (0.770 mL, 770 mmol, 1.0 M in
THF). After stirring at rt for 2 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 purified by silica gel
column chromatography (eluted with hexane–Et2O¼1:3) to
give alcohol (250 mg, quantitative yield). Colorless oil;
[a]D¼24.68 (c 0.57, CHCl3); IR (neat) 3402, 2935, 1707,
1647 cm21; 1H NMR (400 MHz, CDCl3) d ppm: 1.01 (3H,
s), 1.26 (3H, s), 1.27 (3H, t, J¼7.1 Hz), 1.55–1.65 (2H, m),
1.69 (3H, br s), 1.75 (1H, m), 1.83 (3H, br s), 1.85 (1H, m),
2.04 (1H, m), 2.12 (1H, m), 2.33 (2H, dd, J¼7.5, 0.6 Hz),
2.63 (1H, d, J¼7.5 Hz), 3.90–4.00 (4H, m), 4.13–4.23 (4H,
m), 5.41 (1H, dt, J¼1.3, 6.9 Hz), 5.54 (2H, m), 6.84 (1H, dt,
J¼1.4, 7.5 Hz); 13C NMR (75 MHz, CDCl3) d ppm: 12.7,
14.3, 16.3, 21.8, 22.2, 29.7, 39.0, 41.1, 45.7, 51.4, 59.4,
60.3, 60.4, 64.4, 64.8, 111.6, 123.3, 128.8, 129.0, 139.7,
140.1, 141.2, 168.1; EIMS (m/z): 377 (Mþ2Me, 0.1), 87
(100); HREIMS: calcd for C22H33O5Si (Mþ2Me):
377.2328; Found: 377.2323.
To a cold (2788C) solution of the above ester (1.00 g,
1.94 mmol) in toluene (20.0 mL) was added DIBAH
(6.00 mL, 5.70 mmol, 0.95 M in hexane). After stirring at
2788C for 15 min, the reaction mixture was diluted with
Et2O and saturated aqueous NaCl was added. The mixture
was stirred at rt for 1 h. Organic layer was dried over
anhydrous MgSO4 and concentrated under reduced press-
ure. The residue was purified by silica gel column
chromatography (eluted with hexane–EtOAc¼1:1) to give
allylic alcohol 25 (900 mg, 98%). Colorless oil;
[a]D¼þ19.48 (c 0.29, CHCl3); IR (neat) 3391, 2934,
1306, 1150 cm21 1H NMR (400 MHz, CDCl3) d ppm:
;
0.96 (3H, s), 1.25 (3H, s), 1.34 (3H, br s), 1.40–1.65 (3H,
m), 1.66 (3H, br s), 1.81 (1H, m), 1.95–2.15 (2H, m), 2.15
(2H, d, J¼7.5 Hz), 2.60 (1H, br d, J¼7.5 Hz), 3.80 (2H, d,
J¼7.9 Hz), 3.85–4.00 (4H, m), 4.00 (2H, br s), 5.21 (1H, dt,
J¼1.0, 7.9 Hz), 5.46 (1H, br d, J¼7.5 Hz), 5.45–5.55 (2H,
m), 7.52 (2H, m), 7.63 (1H, m), 7.86 (2H, m); 13C NMR
(100 MHz, CDCl3) d ppm: 14.1, 16.2, 22.0, 22.1, 29.8, 39.5,
39.9, 45.3, 51.5, 56.1, 60.4, 64.4, 64.8, 69.1, 110.0, 111.7,
123.4, 128.1, 128.6, 128.9, 133.5, 136.2, 138.8, 141.7,
147.2; EIMS (m/z): 459 (Mþ2Me, 0.04), 389 (7.3), 87
(100); HREIMS: calcd for C26H35O5S (Mþ2Me):
459.2205; Found: 459.2235.
To a solution of the above alcohol (250 mg, 638 mmol) in
pyridine (1.2 mL) were added PhSSPh (700 mg, 3.20 mmol)
n
and Bu3P (800 mL, 3.20 mmol) at 608C. After stirring for
2 h, the reaction mixture was diluted with Et2O, washed
with 5% NaOH aqueous solution, H2O and saturated
aqueous NaCl, dried over anhydrous MgSO4 and concen-
trated under reduced pressure. The residue was purified by
silica gel column chromatography (eluted with hexane–
Et2O¼10:1) to give sulfide (282 mg, 92%). Colorless oil;
[a]D¼210.38 (c 0.45, CHCl3); IR (neat) 2937, 1708,
1648 cm21 1H NMR (400 MHz, CDCl3) d ppm: 1.00
;
(3H, s), 1.26 (3H, s), 1.27 (3H, t, J¼7.1 Hz), 1.50–1.60 (2H,
m), 1.58 (3H, br s), 1.65–1.85 (2H, m), 1.83 (3H, br s),
1.95–2.15 (2H, m), 2.31 (2H, d, J¼7.4 Hz), 2.62 (1H, d,
J¼7.4 Hz), 3.54 (2H, d, J¼7.7 Hz), 3.85–4.00 (4H, m),
4.10–4.20 (2H, m), 5.32 (1H, dt, J¼1.1, 7.7 Hz), 5.53 (1H,
d, J¼6.8 Hz), 5.55 (1H, d, J¼6.8 Hz), 6.83 (1H, dt, J¼1.4,
7.4 Hz), 7.17 (1H, m), 7.25 (2H, m), 7.33 (2H, m); 13C NMR
(100 MHz, CDCl3) d ppm: 12.7, 14.3, 16.1, 21.8, 22.1, 29.9,
32.2, 39.2, 41.2, 46.1, 51.4, 60.2, 60.3, 64.4, 64.8, 111.6,
119.0, 126.0, 128.7, 128.8, 128.9, 129.9, 136.8, 139.7,
140.5, 141.1, 168.1; EIMS (m/z): 375 (Mþ2PhS, 0.8), 357,
87 (100); Anal. calcd for C29H40O4S: C, 71.86; H, 8.32.
Found: C,71.86; H, 8.36.
1.1.21. (2R,3R)-3-[(1R,4S,5R)-5-((E)-5-Benzenesulfonyl-
3-methyl-3-pentenyl)-1-methyl-4-(2-methyl-[1,3]dioxo-
lan-2-yl)-2-cyclopentenylmethyl]-2-methyloxiranyl-
methyl methanesulfonate (26). A mixture of powdered 4 A
molecular sieves (100 mg) and CH2Cl2 (2.10 mL) was
cooled to 2208C and then to which were added of Ti(OiPr)4
˚
(6.0 mL, 0.021 mmol) and
D-(2)-DET
(5.5 mL,
0.032 mmol). After stirring for 30 min, TBHP (140 mL,
0.420 mmol, 3.0 M in CH2Cl2) was added, followed by
stirring for 30 min and the addition of allylic alcohol 25
(99.0 mg, 0.210 mmol) in CH2Cl2 (0.5 mL). Stirring was
continued at 2208C for 6 h. The reaction mixture was
warmed to 08C, water (3.0 mL) was added and the mixture

72
H. Miyaoka et al. / Tetrahedron 59 (2003) 61–75
was stirred for 1 h. Aqueous solution of NaOH (30%) in
saturated with NaCl (0.10 mL) was added and the mixture
was stirred vigorously. After 1 h stirring, the mixture was
filtered through celite. The filtrate 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 purified by silica gel
column chromatography (eluted with hexane–EtOAc¼1:2)
to give epoxy alcohol (100 mg, 95%). Colorless oil;
[a]D¼þ16.98 (c 0.39, CHCl3); IR (neat) 3398, 2932,
1.36 (3H, br s), 1.41 (1H, dd, J¼11.0, 14.8 Hz), 1.46 (1H,
m), 1.55 (1H, m), 1.61 (1H, m), 1.80 (1H, dd, J¼1.8,
14.3 Hz), 1.84 (1H, m), 2.15 (1H, m), 2.27 (1H, m), 2.56
(1H, m), 2.60 (1H, dd, J¼4.3, 12.8 Hz), 2.86 (1H, dd,
J¼1.8, 11.0 Hz), 3.75–4.00 (5H, m), 5.03 (1H, dd, J¼1.0,
10.4 Hz), 5.35 (1H, dd, J¼1.9, 5.7 Hz), 5.46 (1H, dd, J¼2.4,
5.7 Hz), 7.54 (2H, m), 7.64 (1H, m), 7.85 (2H, m); 13C NMR
(100 MHz, CDCl3) d ppm: 16.5, 17.0, 21.3, 22.1, 32.4, 35.8,
37.5, 41.0, 50.0, 60.5, 61.9, 62.9, 64.2, 64.4, 66.2, 110.6,
116.9, 120.9, 126.5, 128.9, 129.1, 133.6, 137.6, 143.2,
144.6; EIMS (m/z): 472 (Mþ), 457 (0.1), 331 (0.2), 269, 87
(100); HREIMS: calcd for C27H36O5S (Mþ): 472.2283;
Found: 472.2280.
1306, 1150 cm21 1H NMR (400 MHz, CDCl3) d ppm:
;
1.01 (3H, s), 1.28 (3H, s), 1.29 (3H, s), 1.33 (3H, br s),
1.45–1.85 (4H, m), 2.00–2.10 (3H, m), 2.64 (1H, d,
J¼7.6 Hz), 3.11 (1H, dd, J¼6.8, 4.8 Hz), 3.58 (2H, d,
J¼7.0 Hz), 3.80 (2H, d, J¼7.9 Hz), 3.85–4.00 (4H, m),
5.21 (1H, br t, J¼7.9 Hz), 5.56 (2H, m), 7.53 (2H, m), 7.64
(1H, m), 7.86 (2H, m); 13C NMR (100 MHz, CDCl3) d ppm:
14.7, 16.2, 22.1, 22.5, 29.8, 39.4, 40.1, 45.5, 50.3, 56.1,
58.0, 60.0, 60.1, 64.4, 64.7, 66.0, 110.0, 111.5, 128.6, 128.8,
128.9, 133.5, 141.1, 147.1; EIMS (m/z): 490 (Mþ2Me,
0.03), 427 (0.1), 87 (100); HREIMS: calcd for C27H38O6S
(Mþ): 490.2389; Found: 490.2382.
1.1.23. (1S,2S,9R,10R)-(E)-2-(7-Benzenesulfonyl-1,5,9-
trimethyl-4-oxatricyclo[10.3.0.03,5]pentadeca-8,13-dien-
13-yl)-propan-2-ol (28). A mixture of AcOH and H2O (4:1)
(250 mL) was added to acetal 27 (5.0 mg, 10.6 mmol) and
the mixture was stirred at 458C for 30 min. The reaction
mixture was concentrated under reduced pressure. The
residue was purified by silica gel preparative TLC
(developed with hexane–Et2O¼5:1) to give ketone
(4.2 mg, 93%). Colorless oil; [a]D¼þ72.58 (c 0.16,
1
To a solution of the above epoxy alcohol (524 mg,
1.49 mmol) in CH2Cl2 (15.0 mL) were added DMAP
(364 mg, 3.00 mmol) and MsCl (170 mL, 2.20 mmol).
After stirring for 1.5 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 purified by silica gel
column chromatography (eluted with Et2O) to give
mesylate 26 (620 mg, 97%). Colorless oil; [a]D¼þ16.48
(c 0.76, CHCl3); IR (neat) 2937, 1357, 1306, 1176,
CHCl3); IR (neat) 2927, 1711, 1304, 1146 cm21; H NMR
(400 MHz, CDCl3) d ppm: 1.16 (3H, s), 1.19 (1H, m), 1.22
(3H, s), 1.32 (3H, s), 1.37 (1H, m), 1.50–1.65 (2H, m), 1.86
(1H, d, J¼14.0 Hz), 1.92 (1H, m), 2.12 (3H, s), 2.25 (1H,
m), 2.32 (1H, br d, J¼15.3 Hz), 2.62 (1H, dd, J¼4.1,
12.9 Hz), 2.85 (1H, dd, J¼0.9, 9.8 Hz), 3.23 (1H, dt, J¼2.1,
4.6 Hz), 3.96 (1H, ddd, J¼4.1, 10.3, 14.3 Hz), 5.07 (1H, br
d, J¼10.3 Hz), 5.49 (1H, dd, J¼2.2, 5.6 Hz), 5.53 (1H, dd,
J¼2.2, 5.6 Hz), 7.54 (2H, m), 7.64 (1H, m), 7.85 (2H, m);
13C NMR (100 MHz, CDCl3) d ppm: 16.4, 18.9, 20.7, 28.6,
32.0, 34.4, 37.7, 41.2, 41.6, 49.8, 60.7, 61.9, 62.0, 70.3,
116.5, 124.1, 129.0, 129.1, 133.7, 144.3, 144.8, 208.2;
EIMS (m/z): 287 (Mþ2PhSO2, 0.4), 245 (0.5), 43 (100);
HREIMS: calcd for C19H27O2 (Mþ2PhSO2): 287.2011;
Found: 287.2003.
1151 cm21 1H NMR (400 MHz, CDCl3) d ppm: 1.00
;
(3H, s), 1.27 (3H, s), 1.33 (3H, br s), 1.35 (3H, br s), 1.40–
1.80 (3H, m), 1.82 (1H, dd, J¼3.8, 14.6 Hz), 1.95–2.10
(3H, m), 2.63 (1H, dt, J¼7.5, 1.7 Hz), 3.02 (1H, dd, J¼3.8,
7.4 Hz), 3.04 (3H, s), 3.79 (2H, d, J¼7.9 Hz), 3.90–4.00
(4H, m), 4.05 (1H, d, J¼11.3 Hz), 4.23 (1H, d, J¼11.3 Hz),
5.21 (1H, dt, J¼1.1, 7.9 Hz), 5.50–5.60 (2H, m), 7.52 (2H,
m), 7.63 (1H, m), 7.86 (2H, m); 13C NMR (100 MHz,
CDCl3) d ppm: 14.3, 16.2, 22.1, 22.3, 29.7, 37.7, 39.9, 39.9,
45.5, 50.1, 56.1, 57.2, 58.9, 60.0, 64.4, 64.8, 74.0, 110.0,
111.3, 128.5, 128.9, 129.4, 133.5, 138.7, 140.7, 147.0;
EIMS (m/z): 568 (Mþ), 553 (0.2), 427 (0.33), 87 (100);
HREIMS: calcd for C28H40O8S2 (Mþ): 568.2165; Found:
568.2173.
A solution of 3% K2CO3 in MeOH (300 mL) was added to
the above ketone (8.0 mg, 18.7 mmol) and the mixture was
stirred at rt for 1 h. The reaction mixture was diluted with
Et2O and filtered through silica gel. The filtrate was
concentrated under reduced pressure to give enone
(8.0 mg, quantitative yield). Colorless oil; [a]D¼þ49.28 (c
0.42, CHCl3); IR (neat) 2927, 1662, 1618, 1305,
1147 cm21 1H NMR (400 MHz, CDCl3) d ppm: 1.05
;
(3H, s), 1.25–1.35 (2H, m), 1.33 (3H, s), 1.42 (1H, m), 1.49
(3H, br s), 1.56 (1H, m), 1.70 (1H, dd, J¼2.3, 13.7 Hz), 2.09
(1H, dd, J¼5.7, 12.8 Hz), 2.20 (1H, m), 2.22 (3H, s), 2.30
(1H, dt, J¼5.8, 13.1 Hz), 2.49–2.60 (2H, m), 2.62 (1H, dd,
J¼4.1, 12.8 Hz), 2.92 (1H, dd, J¼2.7, 11.2 Hz), 4.00 (1H,
ddd, J¼4.3, 10.4, 14.6 Hz), 4.98 (1H, d, J¼10.4 Hz), 6.58
(1H, br s), 7.54 (2H, m), 7.65 (1H, m), 7.87 (2H, m); 13C
NMR (100 MHz, CDCl3) d ppm: 15.4, 16.2, 21.7, 24.7,
26.7, 29.7, 37.5, 37.7, 40.9, 43.3, 43.9, 49.5, 60.4, 62.0,
62.9, 118.6, 128.9, 129.2, 133.7, 137.6, 142.2, 145.6, 148.9,
196.2; EIMS (m/z): 287 (Mþ2PhSO2, 3.6), 229, 171, 43
(100); HREIMS: calcd for C19H27O2 (Mþ2PhSO2):
287.2011; Found: 287.2020.
1.1.22. (1R,2R,9R,10R,13S)-(E)-7-Benzenesulfonyl-1,5,9-
trimethyl-13-(2-methyl-[1,3]dioxolan-2-yl)-4-oxatricy-
clo[10.3.0.03,5]pentadeca-8,14-diene (27). To a solution of
KHMDS (136 mL, 68.0 mmol, 0.5 M in toluene) in THF
(7.70 mL) was added a solution of mesylate 26 (16.0 mg,
28.1 mmol) in THF (2.0 mL) at 458C over 1.5 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
purified by silica gel preparative TLC (developed with
hexane–Et2O¼3:1) to give sulfone 27 (6.0 mg, 43%) and
mesylate 26 (4.0 mg, 25% recovered). Colorless oil;
[a]D¼þ66.88 (c 0.61, CHCl3); IR (neat) 3020, 2885,
1357, 1306, 1220, 1146 cm21
;
1H NMR (400 MHz,
To a cold (2788C) solution of the above enone (6.8 mg,
15.8 mmol) in THF (200 mL) was added MeLi (23.0 mL,
CDCl3) d ppm: 1.18 (3H, s), 1.20 (3H, s), 1.35 (3H, br s),

H. Miyaoka et al. / Tetrahedron 59 (2003) 61–75
73
23.7 mmol, 1.03 M in Et2O). After stirring at 2788C for
10 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. The residue was purified by silica gel
preparative TLC (developed with hexane–Et2O¼1:1) to
give alcohol 28 (6.0 mg, 86%) as a mixture of diastereomers
(1:1) at sulfonyl group. Alcohol 27 was used next reaction
without separation of diastereomers.
to give crude chloride. The crude chloride was used next
reaction without purification.
To a solution of the above crude chloride in THF (9.5 mL)
was added KHMDS (91.0 mL, 45.4 mmol, 0.5 M in toluene)
at 408C over 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. The residue was purified by silica gel preparative
TLC (developed with hexane–Et2O¼10:1) to give sulfone
29 (11.5 mg, 45%, two steps) as a mixture of diastereomers
(15:1) at sulfonyl group. Sulfone 29 was used next reaction
without separation of diastereomers.
Claenone (1). To a solution of sulfone 28 (6.2 mg,
14.0 mmol) in MeOH–THF (1:1, 300 mL) were added
NaH2PO4 (50 mg) and 5% Na-Hg (30 mg). 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 press-
ure. The residue was purified by silica gel preparative TLC
(developed with hexane–Et2O¼1:1) to give alcohol
(3.7 mg, 83%). Colorless needs; mp 117–1188C;
[a]D¼241.58 (c 0.27, CHCl3); IR (KBr) 3443,
1.1.25. 1-((3aR,12aS)-(5E,9E)-3a,6,10-Trimethyl-
3,3a,4,7,8,11,12,12a-octahydrocyclopentacycloundecen-
1-yl)ethanone (30). To a solution of sulfone 29 (6.0 mg,
13.4 mmol) in MeOH–THF (1:1, 300 mL) were added
NaH2PO4 (50 mg) and 5% Na-Hg (30 mg) at 08C. After
stirring at 08C 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. The residue was purified by silica gel preparative
TLC (developed with hexane–Et2O¼10:1) to give acetal
(3.6 mg, 86%). Colorless oil; [a]D¼þ29.38 (c 0.27, CHCl3);
2921 cm21 1H NMR (400 MHz, CDCl3) d ppm: 1.21
;
(3H, s), 1.25 (1H, m), 1.33 (3H, s), 1.34 (3H, s), 1.42 (3H, s),
1.40–1.55 (2H, m), 1.65 (1H, dd, J¼2.8, 13.7 Hz), 1.73
(3H, br s), 1.95 (1H, dd, J¼3.2, 16.5 Hz), 2.05–2.20 (4H,
m), 2.30–2.45 (3H, m), 2.47 (1H, br d, J¼11.5 Hz), 2.96
(1H, dd, J¼2.8, 11.3 Hz), 5.07 (1H, d, J¼11.4 Hz), 5.42
(1H, m); 13C NMR (100 MHz, CDCl3) d ppm: 15.8, 16.5,
22.7, 24.5, 25.4, 32.2, 32.3, 37.3, 38.9, 41.6, 43.8, 46.9,
49.2, 62.1, 64.0, 71.6, 122.4, 126.5, 134.3, 153.9; EIMS
(m/z): 304 (Mþ, 14.6), 286, 152 (100); HREIMS: calcd for
C20H32O2 (Mþ): 304.2402; Found: 304.2402.
1
IR (neat) 2927 cm21; H NMR (400 MHz, CDCl3) d ppm:
1.06 (3H, s), 1.29 (3H, s), 1.42 (1H, m), 1.54 (3H, br s), 1.54
(3H, br s), 1.63 (3H, br s), 1.70 (1H, m), 1.76 (1H, m), 1.85
(1H, br d, J¼13.5 Hz), 2.00–2.15 (3H, m), 2.15–2.35 (4H,
m), 2.59 (1H, d, J¼5.1 Hz), 3.90–4.00 (4H, m), 4.94 (1H, br
dd, J¼3.7, 8.3 Hz), 5.04 (1H, br d, J¼2.6, 11.4 Hz), 5.47
(1H, d, J¼6.0 Hz), 5.49 (1H, d, J¼6.0 Hz); 13C NMR
(100 MHz, CDCl3) d ppm: 15.6, 17.3, 21.5, 24.1, 29.7, 33.7,
36.0, 37.5, 39.6, 41.1, 41.2, 52.3, 53.0, 64.2, 64.4, 64.8,
111.3, 123.6, 125.5, 127.0, 134.4, 135.1, 143.6; EIMS (m/z):
316 (Mþ, 0.6), 301 (0.7), 235 (5), 87 (100); HREIMS: calcd
for C21H32O2 (Mþ): 316.2402; Found: 316.2409.
To a solution of the above alcohol (8.0 mg, 26.3 mmol) in
˚
CH2Cl2 (300 mL) were added 4 A molecular sieves (15 mg)
and PDC (15 mg, 39.5 mmol). After stirring at rt for 5 h, the
reaction mixture was diluted with Et2O, filtered through
silica gel column and the filtrate was concentrated under
reduced pressure. The residue was purified by ODS
preparative TLC (developed with MeOH) to give claenone
(1)4 (5.0 mg, 63%). Colorless needs; mp 124–1258C;
[a]D¼249.58 (c 0.25, CHCl3); IR (KBr) 2936, 1699,
A mixture of AcOH and H2O (4:1) (200 mL) was added to
the above acetal (8.0 mg, 25.3 mmol) and the mixture was
stirred at 458C for 30 min. The reaction mixture was
concentrated under reduced pressure. The residue was
purified by silica gel preparative TLC (developed with
hexane–Et2O¼5:1) to give ketone (6.5 mg, 93%). Colorless
oil; [a]D¼þ73.28(c 0.50, CHCl3); IR (neat) 2921,
1618 cm21 1H NMR (400 MHz, CDCl3) d ppm: 1.14
;
(3H, s), 1.27 (1H, m), 1.31 (1H, dd, J¼11.1, 13.7 Hz), 1.41
(3H, s), 1.49–1.60 (2H, m), 1.68 (1H, m), 1.71 (1H, dd,
J¼2.8, 13.7 Hz), 1.73 (3H, s), 1.84 (3H, s), 2.11 (1H, br d,
J¼18.3 Hz), 2.10–2.30 (2H, m), 2.20 (3H, m), 2.35–2.45
(2H, m), 2.41 (1H, d, J¼18.3 Hz), 2.94 (1H, br d,
J¼12.0 Hz), 2.98 (1H, dd, J¼2.9, 11.0 Hz), 5.13 (1H, br
d, J¼11.0 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 15.6,
16.7, 21.4, 23.4, 24.5, 24.6, 27.5, 37.3, 37.7, 38.6, 41.0,
42.5, 55.6, 61.5, 63.9, 128.4, 133.1, 137.3, 148.8, 206.2;
EIMS (m/z): 302 (Mþ, 11), 287 (7.3), 150 (100); HREIMS:
calcd for C20H30O2 (Mþ): 302.2246; Found: 302.2230.
1709 cm21 1H NMR (400 MHz, CDCl3) d ppm: 1.01
;
(3H, s), 1.43 (1H, m), 1.55 (3H, br s), 1.58 (3H, br s), 1.60
(1H, m), 1.74 (1H, m), 1.95 (1H, m), 2.00–2.10 (2H, m),
2.15–2.25 (4H, m), 2.16 (3H, s), 2.32 (1H, m), 3.25 (1H, br
dt, J¼2.1, 6.6 Hz), 4.97 (1H, br d, J¼10.5 Hz), 5.06 (1H, br
dd, J¼3.9, 11.3 Hz), 5.46 (1H, dd, J¼2.1, 5.6 Hz), 5.67 (1H,
dd, J¼2.2, 5.6 Hz); 13C NMR (100 MHz, CDCl3) d ppm:
15.5, 19.0, 20.9, 24.3, 27.9, 34.3, 34.9, 39.9, 41.2, 43.2,
52.3, 69.2, 122.4, 124.7, 125.9, 134.5, 135.7, 145.5, 200.7;
EIMS (m/z): 272 (Mþ, 3.6), 229 (10), 43 (100); HREIMS:
calcd for C19H28O (Mþ): 272.2140; Found: 272.2142.
1.1.24. 2-((1S,3aR,12aR)-(5E,9E)-8-Benzenesulfonyl-
3a,6,10-trimethyl-1,3a,4,7,8,11,12,12a-octahydrocyclo-
pentacycloundecen-1-yl)-2-methyl-[1,3]dioxolane (29).
To a solution of alcohol 25 (27.0 mg, 57.9 mmol) in
CH2Cl2 (580 mL) were added DMAP (35.0 mg,
0.290 mmol) and MsCl (9.0 mL, 0.120 mmol). After stirring
at rt 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
A solution of 3% K2CO3 in MeOH (300 mL) was added to
the above ketone (6.5 mg, 23.9 mmol) and the mixture was
stirred at rt for 2.5 h. The reaction mixture was diluted with
Et2O and filtered through silica gel. The filtrate was
concentrated under reduced pressure to give enone 30
(6.5 mg, quantitative yield). Colorless oil; [a]D¼223.58

74
H. Miyaoka et al. / Tetrahedron 59 (2003) 61–75
(c 0.51, CHCl3); IR (neat) 2914, 1667, 1617 cm21; H
NMR (400 MHz, CDCl3) d ppm: 1.19 (3H, s), 1.31 (1H,
m), 1.40 (3H, br s), 1.62 (1H, m), 1.78 (3H, br s),
2.00–2.30 (8H, m), 2.27 (3H, s), 2.41 (1H, m), 2.49
(1H, dt, J¼2.3, 18.8 Hz), 2.62 (1H, br d, J¼10.8 Hz),
4.80 (1H, br d, J¼11.6 Hz), 5.18 (1H, dd, J¼3.8,
11.0 Hz), 6.62 (1H, br t, J¼2.3 Hz); 13C NMR (75 MHz,
CDCl3) d ppm: 14.9, 15.4, 21.6, 24.3, 25.7, 26.9, 38.2,
40.3, 40.4, 43.3, 47.0, 48.6, 124.3, 128.3, 134.2, 136.4,
142.6, 149.6, 196.7; EIMS (m/z): 272 (Mþ, 60), 229
(35), 123 (100); HREIMS: calcd for C19H28O (Mþ):
272.2140; Found: 272.2145.
References
1
1. Ireland, C.; Faulkner, D. J.; Finer, J.; Clardy, J. J. Am. Chem.
Soc. 1976, 98, 4664–4665.
2. Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–48, and previous
paper in this series.
´ ´ ´
3. Rodrıguez, A. D.; Gonzalez, E.; Ramırez, C. Tetrahedron
1998, 54, 11683–11729.
4. Mori, K.; Iguchi, K.; Yamada, N.; Yamada, Y.; Inouye, Y.
Chem Pharm. Bull. 1988, 36, 2840–2852.
5. The cytotoxic activity was measured by National Cancer
Institute, USA.
´
6. (a) Rodrıguez, A. D.; Acosta, A. L.; Dhasmana, H. J. Nat.
´
Prod. 1993, 56, 1843–1849. (b) Caceres, J.; Rivera, M. E.;
Palominol (3). To a cold (2788C) solution of enone 30
(7.1 mg, 26.2 mmol) in THF (500 mL) was added MeLi
(30.0 mL, 30.9 mmol, 1.03 M in Et2O). After stirring at
2788C for 10 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. The residue was
purified by silica gel preparative TLC (developed with
hexane–Et2O¼1:3) to give palominol (3)7a (6.8 mg, 90%).
Colorless oil; [a]D¼224.78 (c 0.34, CHCl3); IR (neat) 3364,
2915 cm21; 1H NMR (400 MHz, CDCl3) d ppm: 1.17 (3H,
br s), 1.25 (1H, m), 1.38 (3H, br s), 1.43 (3H, br s), 1.51 (3H,
br s), 1.58 (1H, m), 1.63 (3H, br s), 1.94 (1H, dd, J¼3.1,
16.5 Hz), 1.95–2.15 (4H, m), 2.20–2.35 (5H, m), 2.38 (1H,
br d, J¼10.3 Hz), 4.86 (1H, br d, J¼10.6 Hz), 5.22 (1H, br
dd, J¼4.7, 11.5 Hz), 5.47 (1H, m); 13C NMR (100 MHz,
CDCl3) d ppm: 15.5, 16.2, 22.7, 24.4, 26.2, 31.9, 31.9, 38.2,
40.0, 40.7, 46.1, 47.4, 47.9, 71.6, 122.6, 125.4, 128.6, 133.4,
134.6, 154.1; EIMS (m/z): 288 (Mþ, 2.7), 270 (28), 133
(100); HREIMS: calcd for C20H32O (Mþ): 288.2453;
Found: 288.2449.
´
Rodrıguez, A. D. Tetrahedron 1990, 46, 341–348.
7. (a) Shin, J.; Fenical, W. J. Org. Chem. 1991, 56, 3392–3398.
(b) Look, S. A.; Fenical, W. J. Org. Chem. 1982, 47,
4129–4134.
8. (a) Miyaoka, H.; Baba, T.; Mitome, H.; Yamada, Y.
Tetrahedron Lett. 2001, 42, 9233–9236. (b) Miyaoka, H.;
Isaji, Y.; Kajiwara, Y.; Kunimune, I.; Yamada, Y. Tetrahe-
dron Lett. 1998, 39, 6503–6506. (c) Corey, E. J.; Kania, R. S.
Tetrahedron Lett. 1998, 39, 741–744. (d) Kato, N.; Higo, A.;
Wu, X.; Takeshita, H. Heterocycles 1997, 46, 123–127. (e)
Corey, E. J.; Kania, R. S. J. Am. Chem. Soc. 1996, 118,
1229–1230. (f) Jenny, L.; Borschberg, H.-J. Helv. Chim. Acta
1995, 78, 715–731.
9. (a) Zhu, Q.; Qiao, L.; Wu, Y.; Wu, Y.-L. J. Org. Chem. 2001,
66, 2692–2699. (b) Zeng, Z.; Xu, X. Tetrahedron Lett. 2000,
41, 3459–3461. (c) Zhu, Q.; Fan, K.-Y.; Ma, H.-W.; Qiao, L.-
X.; Wu, Y.-L.; Wu, Y. Org. Lett. 1999, 1, 757–759. (d) Zhu,
Q.; Qiao, L.-X.; Wu, Y.; Wu, Y.-L. J. Org. Chem. 1999, 64,
2428–2432. (e) Luker, T.; Whitby, R. J. Tetrahedron Lett.
1996, 42, 7661–7664. (f) Williams, D. R.; Coleman, P.
J. Tetrahedron Lett. 1995, 36, 39–42. (g) Kato, N.; Higo, A.;
Nakanishi, K.; Wu, X.; Takeshita, H. Chem. Lett. 1994,
1967–1970. (h) Mehta, G.; Karra, S. R.; Krishnamurthy, N.
Tetrahedron Lett. 1994, 35, 2761–2762. (i) Williams, D. R.;
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11654–11655. (j) Williams, D. R.; Coleman, P. J.; Navill,
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7895–7898.
Dolabellatrienone (2). To a solution of palominol (3)
˚
(8.0 mg, 26.3 mmol) in CH2Cl2 (300 mL) were added 4 A
molecular sieves (15 mg) and PDC (15 mg, 39.5 mmol).
After stirring at rt for 5 h, the reaction mixture was diluted
with Et2O, filtered through silica gel column and the filtrate
was concentrated under reduced pressure. The residue was
purified by silica gel preparative TLC (developed with
hexane–Et2O¼1:1) to give dolabellatrienone (2)7b (5.0 mg,
63%). Colorless oil; [a]D¼þ29.98(c 0.14, CHCl3); IR (neat)
2923, 1703 cm21; 1H NMR (400 MHz, CDCl3) d ppm: 1.23
(3H, s), 1.45 (3H, s), 1.45–1.50 (1H, m), 1.55–1.65 (2H,
m), 1.64 (3H, s), 1.83 (3H, s), 2.05–2.35 (8H, m), 2.22 (3H,
s), 2.38 (1H, d, J¼18.4 Hz), 2.83 (1H, br d, J¼12.2 Hz),
4.93 (1H, br d, J¼10.6 Hz), 5.24 (1H, dd, J¼5.0, 11.3 Hz);
13C NMR (100 MHz, CDCl3) d ppm: 15.6, 16.2, 21.4, 23.2,
24.3, 24.5, 28.0, 38.2, 39.9, 40.2, 41.1, 41.6, 54.9, 124.9,
130.4, 131.8, 135.7, 138.1, 148.3, 207.3; EIMS (m/z): 286
(Mþ, 23), 271 (15),150 (100); HREIMS: calcd for C20H30O
(Mþ): 286.2297; Found: 286.2299.
10. (a) Miyaoka, H.; Yokokura, T.; Okamura, T.; Nagaoka, H.;
Yamada, Y. Synlett 2002, 227–230. (b) Mitome, H.; Miyaoka,
H.; Yamada, Y. Tetrahedron Lett. 2000, 41, 8107–8110. (c)
Miyaoka, H.; Saka, Y.; Miura, S.; Yamada, Y. Tetrahedron
Lett. 1996, 37, 7107–7110. (d) Nagaoka, H.; Shibuya, K.;
Yamada, Y. Tetrahedron Lett. 1993, 34, 1501–1504. (e)
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Tetrahedron Lett. 1992, 33, 81–82. (f) Nagaoka, H.;
Kobayashi, K.; Yamada, Y. Tetrahedron Lett. 1988, 29,
5945–5946.
11. Numbering of all compounds is in accordance with that for
dolabellane diterpenoid in this paper.
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1989, 19, 3529–3534.
13. Diago-Meseguer, J.; Palomo-Coll, A. L.; Fernandez-Lizarbe,
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Acknowledgements
This work was supported in part by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology of Japan.
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