Enantioselective total synthesis and absolute stereostructure of hippospongic acid A

Article abstract of DOI:10.1016/S0040-4020(00)01129-7

A compound having the structure proposed for hippospongic acid A, a triterpene that specifically inhibits gastrulation of starfish embryos, was synthesized enantioselectively. The synthetic compound was not identical to the natural product. Comparison of the NMR spectra of the natural and synthetic compounds led us to propose an alternative structure, which was confirmed by enantioselective synthesis. The present synthesis established that the natural product has the (R)-configuration.

Full text of DOI:10.1016/S0040-4020(00)01129-7

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1235±1246
Enantioselective total synthesis and absolute stereostructure of
hippospongic acid A
Hideaki Hioki,a Hidenori Ooi,a Masayo Hamano,a Yumi Mimura,a Suzuyo Yoshio,a
Mitsuaki Kodama,a,p Shinji Ohta,b Mihoko Yanaib and Susumu Ikegamic
aFaculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
bInstrument Center for Chemical Analysis, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526, Japan
cDepartment of Applied Biochemistry, Hiroshima University, 1-4-4 Kagamiyama, Higashi-Hiroshima 739-8528, Japan
Received 8 November 2000; accepted 1 December 2000
AbstractÐA compound having the structure proposed for hippospongic acid A, a triterpene that speci®cally inhibits gastrulation of star®sh
embryos, was synthesized enantioselectively. The synthetic compound was not identical to the natural product. Comparison of the NMR
spectra of the natural and synthetic compounds led us to propose an alternative structure, which was con®rmed by enantioselective synthesis.
The present synthesis established that the natural product has the (R)-con®guration. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
pyran ring was assigned by Ohta et al. on the basis of spec-
tral analysis.1 Although the proposed structure contains six
isoprenoid units, the carbon framework is unusual for a
triterpene skeleton because it was apparently biosynthesized
by the tail-to-tail coupling of a geranylgeranyl unit and a
geranyl unit instead of two farnesyl units. Rhopaloic acid A
isolated from the marine sponge, Rhopaloeides sp., has a
related norsesterterpene structure 2 and exhibits potent cyto-
toxicity against some human tumor cell lines and inhibitory
activity in gastrulation of star®sh embryos.2 Structure 2 has
been established by unequivocal synthesis by Ohkata et al.3
Later rhopaloic acids B (3) and C (4) were isolated from the
same marine sponge as more potent gastrulation inhibitors.4
The biologic activity and the report of a new triterpene
carbon skeleton led us to investigate the enantioselective
total synthesis of hippospongic acid A to determine the
absolute con®guration. The synthesized compound having
structure 1, however, was not spectroscopically identical to
the natural product.5 Reinvestigation of the structure of
hippospongic acid A suggested that the structure of the
natural product should be 5, possessing the normal triter-
pene carbon skeleton. The new structure for hippospongic
acid A and its absolute con®guration were established by
enantioselective synthesis.6 We present the full details of the
results in this report (Fig. 1).7
Hippospongic acid A is a triterpene isolated from the marine
sponge, Hippospongia sp.1 This natural product is a very
interesting compound because it speci®cally inhibits gastru-
lation of star®sh embryos, a fundamental process that occurs
during embryonic development of multicellular animals.
Structure 1 (except for the stereochemistry) having a hydro-
2. Results and discussion
Figure 1.
2.1. Synthesis of (R)-1
Keywords: enantioselective synthesis; baker's yeast reduction; triterpene
ether; gastrulation inhibitory activity; absolute stereostructure.
* Corresponding author. Fax: 181-88-655-3051;
Our synthetic strategy towards (R)-1 consists of coupling a
geranylgeranyl unit (A) and a hydropyran ring unit (B) as
e-mail: kodama@ph.bunri-u.ac.jp
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01129-7

1236
H. Hioki et al. / Tetrahedron 57 (2001) 1235±1246
Scheme 1.
illustrated in Scheme 1. Unit B could be derived from the
tetraol derivative D via the hydropyran derivative C. To
introduce the chiral center at C-20 of (R)-1, we used the
baker's yeast reduction8 of a-hydroxyketone 7, readily
available from myrcene (8).
Thus, myrcene (8) was ®rst converted into a-hydroxyke-
tone 7 in three steps in 52% overall yield. Treatment of 7
with baker's yeast at room temperature yielded (1)-6 in
96% yield.8 The (R)-con®guration of (1)-6 was determined
using a modi®ed Mosher method9 (Fig. 2). Gas chromato-
graphy (GC) analysis using a chiral stationary column
Figure 2. Dd values between (S)-MTPA ester and (R)-MTPA ester of
(1)-6.
Scheme 2.

H. Hioki et al. / Tetrahedron 57 (2001) 1235±1246
1237
Scheme 3.
Table 1. Comparison of 13C NMR between natural and synthetic compounds (chemical shifts in CDCl3)
C-50, 500, 900, 1300, 1700 C-100, 400, 800, 1200, 1600 C-200, 300, 700, 1100, 1500
C-600, 1000, 1400
Naturala
Synthetic 1b 135.8 135.0 134.9 132.6 131.2 123.5 125.0 124.4 124.2 124.2 26.6 26.8 26.8 27.3 28.2 39.7 39.7 39.7
Dd 11.5 20.2 10.4 20.1 21.8 20.1 10.9 10.1 21.0
134.3 135.2 134.9 132.2 131.3 125.3 125.0 124.4 124.3 124.2 25.7 26.8 26.7 28.3 28.2 39.7 39.7 39.7
0
0
0
0
0
0
0
0
0
a Measured at 125 MHz.
b Measured at 150 MHz.
revealed that the optical purity of (1)-6 was more than 98%
ee. The diol in (1)-6 was protected as an acetonide and the
resulting 10 was subjected to photosensitized oxidation in
DMF using hematoporphyrin as a sensitizer. The endo-
peroxide 11 thus obtained in moderate yield was so stable
that it could be fully characterized and reduction with
NaBH4 to 1,4-diol 12 required a high temperature. The
diol in 12 was protected as bisbenzoate and the acetonide
group was hydrolyzed. The resulting 1,2-diol 14 was then
converted into epoxide 15 through mesylate. Hydrolysis of
the benzoyl groups in 15 with alkali resulted in the con-
comitant formation of a hydropyran ring to give the diol
16 (87% from 14). Although two inversion processes were
involved in the hydropyran ring formation, GC analysis of
16 using a chiral stationary column revealed that no race-
mization took place during the process. After the primary
alcohol was protected as benzoate to give 17, dehydration of
the tertiary alcohol was attempted. The usual dehydration
method using SOCl2 or POCl3 in pyridine, or elimination of
mesylate, however, produced a low yield (,41%) of the
desired exomethylene derivative 18. Epoxidation of 18
with mCPBA afforded the epoxide 19 as a diastereomeric
mixture. Protection by an ester group is essential in this
regioselective epoxidation. When the reaction was
performed on the compound protected by ether, non-
regioselective epoxidation occurred, resulting in the forma-
tion of a complex mixture. After the protecting group in 19
was changed to p-methoxybenzyl (MPM) ether, the epoxide
ring of 21 was opened with aluminum triisopropoxide in
re¯uxing toluene to give allylic alcohol 22 in high
selectivity. The hydroxy group in 22 was protected as silyl
ether and the resulting 23 was converted into chloride 25
using Corey's method10 via the allylic alcohol 24
(Scheme 2).
using the Bouveault±Blanc conditions. Deprotection of
the silyl ether followed by puri®cation by AgNO3-impreg-
nated silica gel chromatography yielded the alcohol 28 as
the major product. Finally, the allylic alcohol in 28 was
oxidized to carboxylic acid in two steps to yield (R)-1 in
68% overall yield. Thus, we achieved the enantioselective
synthesis of a compound having the structure reported for
hippospongic acid A (Scheme 3).
1
The H and 13C NMR spectra of the synthetic compound
were similar to those of the natural product. Although a
signal assigned to H-200 was clearly observed at 2.15 ppm
as a multiplet in the H NMR spectrum (500 MHz) of the
1
natural product, a corresponding signal was not observed in
the spectrum (600 MHz) of the synthetic compound, prob-
ably due to overlapping with a large signal at 1.95±2.1 ppm.
Moreover, the chemical shifts of 13C NMR spectra were
different between the natural product and the synthetic
compound, as shown in Table 1. These ®ndings indicated
that the structures of natural product and synthetic
compound were quite similar, but not identical. Table 1
shows that a large difference was observed in the chemical
shifts of one tetrasubstituted and one trisubstituted double
bond carbons and two methylene carbons. Because these
carbons can be assigned to C-500, C-400, C-200, and C-300,
the alternative structure 5, which has a normal triterpene
carbon skeleton possessing the methyl group on C-400
instead of C-500, is a highly possible alternative structure
for hippospongic acid A.
2.2. Reinvestigation of the structure of hippospongic acid
A
Because the reported structure 1 for hippospongic acid A
was determined to be incorrect by the unequivocal synthe-
sis, we decided to reinvestigate the structure of natural
hippospongic acid A. To obtain the natural product in
large quantity, we ®rst investigated various species of
marine sponge and found that the sponge Rhopaloeides
Thus, the obtained chloride 25 was reacted with the lithio-
anion of geranylgeranyl phenyl sul®de11 (26) in the presence
of 1,4-diazabicyclo[2.2.2]octane (DABCO). The resulting
coupling product 27 was subjected to desulfurization

1238
H. Hioki et al. / Tetrahedron 57 (2001) 1235±1246
Figure 3. Mass spectral fragmentation of dodecahydrohippospongic acid A methyl ester.
group. These ®ndings strongly supported the location of the
methyl group at C-400.
2.3. Synthesis and absolute con®guration of natural
hippospongic acid A
The evidence described above indicated that 5 is the most
probable structure for hippospongic acid A. To con®rm the
structure, synthesis of compound 5 with the (R)-con®gura-
tion was attempted using a similar route as the synthesis of
(R)-1. The known allylic alcohol12 32 was converted into
sul®de 33 using Hata's method.13 The lithio-anion of 33 was
reacted with the chloride 25 to afford the coupling product
34, desulfurization of which followed by deprotection
produced 35 and its regioisomer14 36 of double bond in
ca. 1:1 ratio. These were separated using chromatography
with AgNO3-impregnated silica gel. Finally, the allylic
alcohol in 35 was oxidized using the same procedure
described above to furnish the desired 5 (Scheme 4).
Figure 4. HMBC correlation in hippospongic acid.
sp., the same sponge that contains rhopaloic acids, was a
rich source of hippospongic acid A. Thus, we isolated 15 mg
of the natural product from 250 g of the sponge using the
procedure described previously.4 The mass spectrum of
dodecahydrohippospongic acid A methyl ester (30) showed
a fragment ion peak with moderate intensity at m/z 153,
which is implied to be produced by the cleavage shown in
Fig. 3. The corresponding fragment ion peak at m/z 167,
which would be expected had the natural product furnished
31 upon hydrogenation, was not observed. In addition, in the
HMBC spectrum (Fig. 4) a cross peak was observed
between H-100 (5.23 ppm) and a methylene carbon at
39.7 ppm (C-300). If the methyl group is present at C-500 as
in 1, the C-300 carbon signal should appear at a higher ®eld
(around 26 ppm) due to the steric compression of the methyl
The IR and 1H NMR spectra of 5 were identical to those of
the natural hippospongic acid A. 13C NMR signals of C-1,
C-2, and C-20 had concentration-dependent behavior as
shown in Table 2, probably due to the difference in
Scheme 4.

H. Hioki et al. / Tetrahedron 57 (2001) 1235±1246
Table 2. Comparison of 13C NMR chemical shifts (d (ppm) in CDCl3
solution)
1239
Table 3. Inhibitory activity on gastrulation of star®sh embryos
Compound
IC50 (mM)
C-1
C-2
C-20
Rhopaloic acid A (2)a
Rhopaloic acid B (3)a
Rhopaloic acid C (4)a
Hippospongic acid A (5) (natural)
Hippospongic acid A (5) (synthetic)
(R)-1
0.52
0.40
0.52
14.0
11.0
11.0
0.12
Conc.a
0.01
168.0
168.0
0.1
170.0
169.9
0.01
140.2
140.1
0.1
140.7
140.6
0.01
76.2
76.3
0.1
75.6
75.7
Naturalb
Synthetic 5c
a Mol/L.
b Measured at 125 MHz.
c Measured at 150 MHz.
(R)-38
a Ref. 4.
hydrogen bonding. The chemical shifts of these carbons
were identical to each other, however, at the same concen-
tration. As the synthetic compound ([a]Dˆ141.48) has the
same sign of optical rotation as the natural product
([a]Dˆ1378), the natural hippospongic acid A was deter-
mined to have the (R)-con®guration.
natural product has the (R)-con®guration. We also synthe-
sized a related compound that more potently inhibits
gastrulation of star®sh embryos.
4. Experimental
2.4. Synthesis of hippospongic acid A analogue and
gastrulation inhibitory activity
4.1. General methods
Rhopaloic acids and hippospongic acid A speci®cally
inhibit gastrulation of embryos, a very important process
during embryonic development of multicellular animals.
In order to obtain a compound possessing more potent
inhibitory activity for gastrulation, we synthesized a simpler
analogue (R)-38, the lipophilic part of which is much
smaller than that of hippospongic acid A. The synthetic
route for (R)-38 is essentially the same as that of (R)-1
except for the use of geranylphenyl sul®de instead of
geranylgeranylphenyl sul®de (Scheme 5).
1H NMR spectra were recorded on Varian Unity 200,
Gemini 200, or Unity 600 instruments. 13C NMR spectra
were recorded on Varian Unity 200 (50 MHz) or Varian
Unity 600 (150 MHz) instruments. Chemical shifts (d) are
expressed in ppm from Me4Si as internal standard and
coupling constants (J) in Hz. IR spectra were measured on
a JASCO FT±IR 5300 spectrometer. Mass spectra were
recorded on a JEOL AX-500 mass spectrometer (70 eV).
Methane was used for CI-MS unless otherwise stated.
Optical rotations were recorded on a JASCO DIP-1000
polarimeter. Tetrahydrofuran (THF) was distilled from
sodium benzophenone ketyl and CH2Cl2 from CaH2 prior
to use.
The bioassay was performed using the procedure estab-
lished by the Hiroshima group.4 The IC50 values of natural
and synthetic compounds are listed in Table 3. (R)-1 has the
same inhibitory effect as hippospongic acid A, revealing
that the position of the methyl group is not important for
the activity. (R)-38 had the strongest activity, revealing that
the length of the lipophilic portion in¯uences the inhibitory
activity.
4.1.2. 2-Hydroxy-2-methyl-6-methyleneoct-7-en-3-one (7).
To an ice-cooled solution of myrcene (10.00 g, 0.0734 mol)
in CH2Cl2 (100 mL) was added mCPBA (16.00 g,
0.074 mol) in small portions under stirring. After 5 min,
2 M aq. NaOH solution was added and the reaction mixture
was extracted with CH2Cl2 (3£300 mL). The combined
organic layers were washed with water and then brine,
and dried over MgSO4. Evaporation of solvent yielded
epoxide 9 as a colorless oil (10.7 g, 95.2%): 1H NMR
(CDCl3) d 6.38 (1H, dd, Jˆ10.6, 17.6 Hz), 5.25 (1H, d,
Jˆ17.6 Hz), 5.09 (1H, d, Jˆ10.6 Hz), 5.05 (1H, br. s),
5.04 (1H, br. s), 2.76 (1H, t, Jˆ6.3 Hz), 2.41 (1H, m),
2.36 (1H, m), 1.75 (2H, m), 1.31 (3H, s), 1.26 (3H, s).
3. Conclusions
We ®rst synthesized a compound corresponding to that
reported for hippospongic acid A and then compared it to
natural hippospongic acid A in an optically active form.
Using the present syntheses, we revised the reported struc-
ture of hippospongic acid A to be 5 and established that the
Scheme 5.

1240
H. Hioki et al. / Tetrahedron 57 (2001) 1235±1246
The crude epoxide 9 (10.7 g, 0.07 mol) was dissolved in
THF:H2O (3:1, 100 mL). To the solution was added 70%
HClO4 at 08C until pH of the solution became 1±2. After
stirring at rt for 1.5 h, the mixture was neutralized by satu-
rated NaHCO3 solution. Most of THF was evaporated in
vacuo and the residual mixture was extracted with EtOAc
(3£300 mL). The combined organic layers were washed
with water and then brine, dried over Na2SO4 and concen-
trated. The residue was puri®ed by column chromatography
on silica gel (EtOAc:hexaneˆ1:1) to afford (^)-6 (10.3 g,
82% for 2 steps) as a colorless oil: IR (neat, cm21) n 3424,
1595; 1H NMR (CDCl3) d 6.39 (1H, dd, Jˆ10.6, 17.6 Hz),
5.27 (1H, d, Jˆ17.6 Hz), 5.09 (1H, d, Jˆ10.6 Hz), 5.05 (2H,
br.s), 3.42 (1H, dd, Jˆ2.1, 10.4 Hz), 2.55 (1H, m), 2.29 (1H,
m), 1.60 (2H, m), 1.21 (3H, s), 1.17 (3H, s); MS (CI2NH3)
m/z 188 (M11NH3), 170 153 (base peak); HRMS
(CI2NH3) calcd for C10H22O2N 188.1650, found 188.1664.
tion. The reaction mixture was diluted with water and
extracted with hexane (3£400 mL). The combined organic
layers were washed with water and then brine. After drying
over Na2SO4, solvent was evaporated in vacuo. The residue
was puri®ed by column chromatography on silica gel
(EtOAc:hexaneˆ1:30) to afford 10 (13.81 g, 84%) as a
22
colorless oil: [a]D ˆ10.938 (c 1.0, CHCl3); IR (neat,
cm21) n 1595, 1217; H NMR (CDCl3) d 6.39 (1H, dd,
1
Jˆ10.6, 17.6 Hz), 5.28 (1H, d, Jˆ17.6 Hz), 5.08 (1H, d,
Jˆ10.6 Hz), 5.06 (2H, br. s), 3.73 (1H, dd, Jˆ3.1,
9.5 Hz), 2.49 (1H, m), 2.28 (1H, m), 1.68 (1H, m), 1.58
(1H, m), 1.44 (3H, s), 1.35 (3H, s), 1.25 (3H, s), 1.11 (3H,
s); MS (CI) m/z 211 (M11H), 195, 167, 153 (base peak);
HRMS calcd for C13H23O2 (M11H) 211.1698, found
211.1690.
4.1.5. Photosensitized oxidation of 10. A solution of the
acetonide 10 (6.20 g, 29.50 mmol) and hematoporphyrine
(0.26 g) in DMF (200mL) was irradiated with ¯uorescent
arc lamp (30 W£3) in the atmosphere of oxygen at rt for
22 h. The solvent was evaporated in vacuo and the residue
was puri®ed by column chromatography on silica gel
(EtOAc:hexaneˆ1:20) to afford the peroxide 11 (4.00 g,
56%) and recovered 10 (1.75 g, 28%). Colorless oil;
A solution of oxalyl chloride (0.71 mL, 8.10 mmol) and
DMSO (0.76 mL, 10.73 mmol) in dry CH2Cl2 (2 mL) was
cooled to 2788C under argon. To the solution was added
under argon a solution of (^)-6 (0.69 g, 4.05 mmol) in dry
CH2Cl2 (10 mL) and the mixture was stirred at 2788C for
1 h. Triethylamine (4.12 mL, 29.57 mmol) was added to the
solution and the temperature was gradually elevated to 08C.
After the addition of saturated NH4Cl solution (60 mL), the
mixture was extracted three times with EtOAc. The
combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The residue was puri®ed by column
chromatography on silica gel (EtOAc:hexaneˆ1:6!1:4) to
yield 7 (0.44 g, 64.0%) as a colorless oil; IR (neat, cm21) n
26
[a]D ˆ10.938 (c 1.00, CHCl3); IR (neat, cm21) n 2980,
2934, 2881; 1H NMR (CDCl3) d 5.70 (1H, m), 4.59 (2H, m),
4.53 (2H, m), 3.69 (1H, dd, Jˆ3.3, 9.5 Hz), 2.30 (1H, m),
2.12 (1H, m), 1.46±1.78 (2H, m), 1.42 (3H, s), 1.33 (3H, s),
1.26 (3H, s), 1.11 (3H, s); MS (CI) m/z 243 (M11H), 227
(base peak), 209; HRMS calcd for C13H23O4 243.1596,
found 243.1584.
1
3476, 3090, 1711, 901;: H NMR (CDCl3) d 6.39 (1H, dd,
Jˆ10.6, 17.6 Hz), 5.25 (1H, d, Jˆ17.6 Hz), 5.10 (1H, d,
Jˆ10.6 Hz), 5.05 (1H, br. s), 5.01 (1H, br. s), 3.76 (1H,
s), 2.76 (2H, m), 2.56 (2H, m), 1.38 (6H, s); MS (CI) m/z
169 (M11H), 151 (base peak), 123, 110, 59.
4.1.6. (R)-(Z)-2-[2-(2,2,5,5-Tetramethyl-[1,3]-dioxolan-4-
yl)ethyl]but-2-ene-1,4-diol (12). The peroxide 11 (100 mg,
0.41 mmol) in MeOH (4 mL) was treated with NaBH4
(65 mg, 1.72 mmol) at 45±558C. The reaction mixture
was diluted with water and extracted with EtOAc
(3£50 mL). The combined organic layers were washed
with water and then brine, dried over MgSO4, and evapo-
rated in vacuo. The residue was puri®ed by column chro-
matography on silica gel (EtOAc) to afford the diol 12
4.1.3. (R)-2-Methyl-6-methyleneoct-7-ene-2,3-diol [(1)-
6]. To a solution of glucose (230.8 g) in water (1000 mL)
was added baker's yeast (purchased from Kyowa Hakko
Ind. Corp., 232 g) in water (1300 mL) and the mixture
was stirred at rt for 30 min (preincubation). A solution of
the ketol 7 (7.69 g, 45.5 mmol) in EtOH (230 mL) was
added and the mixture was stirred at rt for 15.5 h. To the
reaction mixture were added EtOAc (1500 mL) and celite
(109 g). After stirring vigorously for 1 h, the mixture was
®ltered through a celite pad and the precipitates were
washed well with EtOAc. The combined ®ltrates were
extracted with EtOAc (3£400 mL). The combined organic
layers were dried over Na2SO4 and evaporated in vacuo. The
residue (9.82 g) was puri®ed by column chromatography on
silica gel (EtOAc:hexaneˆ1:3) to afford (1)-6 (7.45 g,
96%) as a colorless oil. Enantiomeric purity was determined
by GC analysis using SPELCO beta-DEXTM 120 at 1358C.
Retention time: (1)-6: 14.6 min, (2)-6: 13.8 min;
20
(99 mg, 98%) as a colorless oil: [a]D ˆ27.548 (c 1.02,
1
CHCl3); IR (neat, cm21) n 3401, 2934, 2870, 1980; H
NMR (CDCl3) d 5.69 (1H, t, Jˆ7.0 Hz), 4.2±4.5 (4H, m),
3.69 (1H, dd, Jˆ3.3, 9.2 Hz), 2.30 (2H, m), 1.60 (2H, m),
1.42 (3H, s), 1.33 (3H, s), 1.25 (3H, s), 1.10 (3H, s); MS (CI)
m/z 245 (M11H), 229, 211, 169 (base peak), 151; HRMS
calcd for C13H25O4 245.1735, found 245.1742.
4.1.7. (R)-(Z)-2-[2-(2,2,5,5-Tetramethyl-[1,3]-dioxolan-4-
yl)ethyl]but-2-ene-1,4-diol bisbenzoate (13). To an ice-
cooled solution of 12 (832 mg, 3.4 mmol) in pyridine
(10 mL) was added benzoyl chloride (0.9 mL, 7.75 mmol).
After stirring at rt for 2 h, the reaction mixture was diluted
with saturated NaHCO3 solution and extracted with hexane
(3£100 mL). The combined organic layers were washed
with brine, dried over MgSO4, and evaporated in
vacuo. The residue was puri®ed by column chromato-
graphy on silica gel (EtOAc:hexaneˆ1:10) to give
bisbenzoate 13 (1.507 g, 98%) as a colorless oil:
22
[a]D ˆ137.48 (c 1.0, CHCl3). The spectroscopic data
were identical to those for (^)-6.
4.1.4. (R)-2,2,4,4-Tetramethyl-5-(3-methylenepent-4-enyl)-
[1,3]dioxolane (10).
A
mixture of (1)-6 (13.39 g,
20
78.66 mmol), 2,2-dimethoxypropane (50 mL), and PPTS
(0.42 g) was stirred under argon at rt for 3.5 h. The reaction
was quenched by the addition of saturated NaHCO3 solu-
[a]D ˆ24.798 (c 1.02, CHCl3); IR (neat, cm21) n 2980,
1721; 1H NMR (CDCl3) d 8.03 (4H, m), 7.56 (2H, m), 7.42
(4H, m), 5.83 (1H, t, Jˆ6.9 Hz), 5.05 (1H, d, Jˆ12.8 Hz),

H. Hioki et al. / Tetrahedron 57 (2001) 1235±1246
1241
5.03 (2H, d, Jˆ6.9 Hz), 4.98 (1H, d, Jˆ12.8 Hz), 3.68 (1H,
dd, Jˆ3.3, 9.4 Hz), 2.50 (1H, m), 2.32 (1H, m), 1.65 (2H,
m), 1.40 (3H, s), 1.30 (3H, s), 1.21 (3H, s), 1.08 (3H, s);
HRMS calcd for C27H33O6 (M11H) 453.2277, found
453.2267.
solution of 16 (4.44 g, 24.1 mmol) in CH2Cl2 (100 mL)
were added triethylamine (5 mL, 36.6 mmol) and benzoyl
chloride (3.1 mL, 26.5 mmol) and the mixture was stirred at
rt for 12 h. Saturated NH4Cl solution (200 mL) was added
and the mixture was extracted with EtOAc (3£400 mL).
The combined organic layers were washed with saturated
NH4Cl solution, dried over MgSO4, and concentrated. The
residue was puri®ed by column chromatography on silica
gel (EtOAc:hexaneˆ1:3) to yield the benzoate 17 (6.63 g,
4.1.8. (R)-(Z)-2-(3,4-Dihydroxy-4-methylpentyl)but-2-ene-
1,4-diol bisbenzoate (14). A solution of the bisbenzoate 13
(1.28 g, 2.83 mmol) and p-TsOH (37 mg) in MeOH
(20 mL)±H2O (1 mL) was stirred at rt for 41 h and then at
508C for 3 h. The reaction mixture was diluted with satu-
rated NaHCO3 solution and extracted with EtOAc
(3£100 mL). The combined organic layers were washed
with brine, dried over MgSO4, and evaporated. The residue
was puri®ed by column chromatography on silica gel
(EtOAc:hexaneˆ1:5!1:2) to provide the 1,2-diol 14
20
95%) as a colorless oil: [a]D ˆ117.88 (c 1.03, CHCl3); IR
(neat, cm21) n 3501, 1719, 1273, 1086, 713; H NMR
1
(CDCl3) d 8.04 (2H, m), 7.54 (1H, m) 7.45 (2H, m), 5.54
(1H, t, Jˆ7.3 Hz), 4.84 (2H, d, Jˆ7.3 Hz), 4.79 (1H, d,
Jˆ13.2 Hz), 3.91 (1H, d, Jˆ13.2 Hz), 3.26 (1H, dd,
Jˆ2.2, 11.4 Hz), 2.24±2.52 (2H, m), 1.78 (1H, m), 1.43
(1H, m), 1.20 (3H, s), 1.15 (3H, s); MS (DI-CI) m/z 291
(M11H), 273, 231, 168, 151, 105 (base peak); HRMS calcd
for C17H23O4 291.1652, found 291.1624.
20
(1.06 g, 91%) as a colorless oil: [a]D ˆ110.48 (c 1.00,
CHCl3); IR (neat, cm21) n 3428, 2973, 1719, 1603, 1453,
1269; 1H NMR (CDCl3) d 8.03 (4H, m), 7.56 (2H, m), 7.42
(4H, m), 5.81 (1H, t, Jˆ7.0 Hz), 5.05 (1H, d, Jˆ12.4 Hz),
5.00 (2H, d, Jˆ7.0 Hz), 4.97 (1H, d, Jˆ12.4 Hz), 3.37 (1H,
br.d, Jˆ10.3 Hz), 2.52 (1H, m), 2.36 (1H, m), 1.60 (2H, m),
1.19 (3H, s), 1.15 (3H, s); MS (CI) m/z 413 (M11H), 395,
291, 273 (base peak), 231, 151, 123, 105; HRMS calcd for
C24H29O6, 413.1964, found 413.1986.
4.1.11. (R)-(Z)-2-(6-Isopropenyldihydropyran-3-ylidene]-
ethyl benzoate (18). To a solution of 17 (881 mg,
3.04 mmol), 4-dimethylaminopyridine (37 mg, 0.3 mmol),
and triethylamine (3.1 mL) in CH2Cl2 (30 mL) was added
MsCl (1.17 mL, 15.0 mmol) dropwise at 08C. After stirring
at rt for 2 h, saturated NH4Cl solution was added and the
mixture was extracted with EtOAc (3£100 mL). The
combined organic layers were dried over Na2SO4 and
evaporated in vacuo. The residue was puri®ed by column
chromatography on silica gel (EtOAc:hexaneˆ1:8) to afford
4.1.9. (R)-(Z)-2-[5-(2-Hydroxyethylidene)tetrahydropyran-
2-yl]propan-2-ol (16). To an ice-cooled solution of 14
(1.10 g, 2.67 mmol) in pyridine (20 mL) was added MsCl
(0.3 mL, 3.88 mmol) and the mixture was stirred at rt for
15 h. After addition of saturated NH4Cl solution (100 mL),
the reaction mixture was extracted with EtOAc (3£70 mL).
The combined organic layers were washed with brine, dried
over Na2SO4. Evaporation of solvent yielded mesylate
21
18 (344 mg, 41%) as a colorless oil: [a]D ˆ149.78 (c 1.01,
CHCl3); IR (neat, cm21) n 1719, 1452, 1271, 1113, 1092,
1
712; H NMR (CDCl3) d 8.04 (2H, m), 7.54 (1H, m), 7.43
(2H, m), 5.54 (1H, t, Jˆ7.3 Hz), 4.99 (1H, m), 4.87 (1H, m),
4.87 (2H, d, Jˆ7.3 Hz), 4.79 (1H, d, Jˆ13.2 Hz), 3.95 (1H,
d, Jˆ13.2 Hz), 3.88 (1H, d, Jˆ10.2 Hz), 2.42 (2H, m), 1.87
(1H, m), 1.76 (3H, s), 1.62 (1H, m); MS (CI) m/z 273
(M11H), 255, 151 (base peak), 133, 123, 105; HRMS
calcd for C17H21O3 273.1491, found 273.1479.
1
(1.179 g) as a colorless oil: H NMR (CDCl3) d 8.04 (4H,
m), 7.56 (2H, m), 7.42 (4H, m), 5.83 (1H, t, Jˆ7.0 Hz), 5.00
(4H, m), 4.58 (1H, dd, Jˆ3.5, 9.0 Hz), 3.08 (3H, s), 2.56 (1H,
m), 2.38 (1H, m), 1.82 (2H, m), 1.23 (3H, s), 1.22 (3H, s).
To a solution of the crude mesylate (1.179 g) in MeOH
(40 mL) was added K2CO3 (845 mg, 6.11 mmol) at 08C
and the mixture was stirred at rt for 1.5 h. To the reaction
mixture was added 1 M NaOH solution (100 mL) and the
mixture was stirred at rt for 20 h. The reaction mixture was
extracted with EtOAc (3£60 mL). The combined organic
layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The crude product was puri®ed by
column chromatography on silica gel (EtOAc:hexaneˆ1:5)
to afford 16 (0.432 g, 87% from 14) as a colorless oil.
Enantiomeric purity was con®rmed by GC analysis using
SPELCO alpha-DEXTM 120 at 1508C. Retention time: (1)-
4.1.12. Epoxidation of 18. To a solution of benzoate 18
(2.00 g, 7.37 mmol) in CH2Cl2 (100 mL) was added
mCPBA (1.27 g, 5.15 mmol) at 2108C and the mixture
was stirred at the same temperature for 72 h. After dilution
with saturated NaHCO3, the mixture was extracted with
CH2Cl2 (3£100 mL). The combined organic layers were
washed with water, dried over Na2SO4, and evaporated in
vacuo. The residue was chromatographed on silica gel
(EtOAc:hexaneˆ1:8!1:4) to afford the epoxide 19
(1.23 g, 58%) and the starting material 18 (0.86 g). The
recovered starting material 18 was treated again with
mCPBA similarly. The total amount of 19 (ca. 2:1 mixture
of diastereomers) was 1.94 g (91%). Colorless oil: IR (neat,
cm21) n 1719, 1451, 1273, 1086, 713; MS (CI) m/z 289
(M11H), 271, 167 (base peak), 149, 105; 1H NMR
(CDCl3) d 8.04 (2H, m), 7.57 (1H, m), 7.44 (2H, m), 5.55
(1H, t, Jˆ7.3 Hz), 4.83 (2H, d, Jˆ7.3 Hz), 4.79 (1H, d,
Jˆ13.2 Hz), 3.89 (1H, d, Jˆ13.2 Hz), 3.28 (major isomer,
1H, dd, Jˆ2.6, 11.0 Hz), 3.32 (minor isomer, 1H, dd, Jˆ2.6,
11.0 Hz), 2.81 (1H, d, Jˆ5.1 Hz), 2.62 (major isomer, 1H, d,
Jˆ5.1 Hz), 2.60 (minor isomer, 1H, d, Jˆ5.1 Hz), 2.24±
2.52 (2H, m), 1.83 (1H, m), 1.64 (1H, m), 1.33 (major
isomer, 3H, s), 1.35 (minor isomer, 3H, s); HRMS calcd
for C17H21O4 289.1440, found 289.1439.
20
16: 31.7 min, (2)-16: 30.6 min; [a]D ˆ16.928 (c 1.00,
1
CHCl3); IR (neat, cm21) n 3378, 1084; H NMR (CDCl3)
5.49 (1H, t, Jˆ6.2 Hz), 4.71 (1H, d, Jˆ12.5 Hz), 4.23 (1H,
dd, Jˆ6.2, 12.5 Hz), 4.04 (1H, dd, Jˆ6.2, 12.5 Hz), 3.82
(1H, d, Jˆ12.5 Hz), 3.25 (1H, dd, Jˆ1.8, 11.4 Hz), 2.10±
2.30 (2H, m), 1.78 (1H, m), 1.53 (1H, m), 1.21 (3H, s), 1.14
(3H, s); MS (CI) m/z 187 (M11H), 169, 151 (base peak),
123, 83; HRMS calcd for C10H19O3 187.1334, found
187.1332.
4.1.10. (R)-(Z)-2-[6-(1-Hydroxy-1-methyl-ethyl)-dihydro-
pyran-3-ylidene]ethyl benzoate (17). To an ice-cooled

1242
H. Hioki et al. / Tetrahedron 57 (2001) 1235±1246
4.1.13. (60R,100RS)-(2Z)-2-[60-(100-Methyloxiranyl)dihydro-
pyran-30-ylidene]ethanol (20). To a solution of epoxide 19
(1.943 g, 6.74 mmol) in THF (20 mL) were added MeOH
(10 mL) and 1 M NaOH aq. solution (20 mL) and the
mixture was stirred at rt for 1 h. After dilution with water,
the mixture was extracted with EtOAc (3£100 mL). The
combined organic layers were washed with brine, dried
over Na2SO4, and then concentrated. The residue was
puri®ed by column chromatography on silica gel (EtOAc:
hexaneˆ1:1) to afford 20 (1.18 g, 95%) as a colorless oil: IR
4.41 (1H, d, Jˆ11.7 Hz), 4.22 (1H, d, Jˆ12.8 Hz), 4.14 (1H,
d, Jˆ12.8 Hz), 4.11 (1H, dd, Jˆ2.9, 11.0 Hz), 3.99 (2H, d,
Jˆ6.6 Hz), 3.85 (1H, d, Jˆ13.2 Hz), 3.81 (3H, s), 2.40 (2H,
m), 1.82 (1H, m), 1.72 (1H, m); MS (CI) m/z 305 (M11H),
241, 166, 121 (base peak); HRMS calcd for C18H25O4
305.1751, found 305.1722.
4.1.16. (R)-(50Z)-Triisopropyl{2-[50-[200-(4000-methoxybenzyl-
oxy)ethylidene)tetrahydro-pyran-20-yl]allyloxy}silane (23).
To a solution of 22 (173 mg, 0.57 mmol) in DMF (5 mL)
were added imidazole (251 mg, 3.7 mmol) and triisopropyl-
silyl chloride (365 ml, 1.7 mmol) at 08C under argon. After
stirring at rt for 7 h, the reaction was quenched by addition
of saturated NH4Cl solution. The mixture was extracted
with hexane (3£50 mL). The combined organic layers
were washed with brine, dried over MgSO4, and then evapo-
rated. The residue was puri®ed by column chromatography
on silica gel (EtOAc:hexaneˆ1:20) to afford 23 (261 mg,
1
(neat, cm21) n 3420, 1440, 1383, 1082, 1018; H NMR
(CDCl3) 5.48 (1H, t, Jˆ7.0 Hz), 4.66 (1H, d, Jˆ13.2 Hz),
4.21 (1H, dd, Jˆ7.0, 12.5 Hz), 4.09 (1H, dd, Jˆ7.0,
12.5 Hz), 3.81 (1H, d, Jˆ13.2 Hz), 3.27 (major isomer,
1H, dd, Jˆ2.2, 11.4 Hz), 3.29 (minor isomer, 1H, dd,
Jˆ2.6, 11.4 Hz), 2.80 (1H, d, Jˆ5.1 Hz), 2.62 (major
isomer, 1H, d, Jˆ5.1 Hz), 2.59 (minor isomer, 1H, d,
Jˆ5.1 Hz), 2.20±2.46 (2H, m), 1.83 (1H, m), 1.60 (1H,
m), 1.32 (major isomer, 3H, s), 1.33 (minor isomer, 3H,
s); MS (CI) m/z 185 (M11H), 167 (base peak), 149;
HRMS calcd for C10H17O3 185.1177, found 185.1156.
21
100%) as a colorless oil: [a]D ˆ137.28 (c 1.07, CHCl3);
IR (neat, cm21) n 1515, 1464, 1250, 1113, 1072, 1045, 818;
1H NMR (CDCl3) d 7.26 (2H, d, Jˆ8.8 Hz), 6.88 (1H, d,
Jˆ8.8 Hz), 5.44 (1H, t, Jˆ7.3 Hz), 5.22 (1H, m), 5.10 (1H,
m), 4.59 (1H, d, Jˆ13.2 Hz), 4.42 (2H, s), 4.27 (2H, s), 4.02
(1H, d, Jˆ11.0 Hz), 3.99 (2H, d, Jˆ7.3 Hz), 3.84 (1H, d,
Jˆ13.2 Hz), 3.81 (3H, s), 2.38 (2H, m), 1.88 (1H, m), 1.67
(1H, m), 1.09 (21H, m); MS (CI) m/z 461 (M11H) (base
peak) 389, 323, 121; HRMS calcd for C27H45O4 461.3087,
found 461.3057.
4.1.14. (2R,20RS)-(5Z)-5-[200-(4000-Methoxybenzyloxy)ethyl-
idene]-2-(20-methyloxiranyl)tetrahydropyran (21). To an
ice-cooled solution of NaH (605 mg of 60% mineral oil
dispersion, 25.2 mmol) in DMF (300 mL) was added a
solution of 20 (2.33 g, 12.6 mmol) and 4-methoxybenzyl
chloride (2.23 mL, 16.4 mmol) in DMF (50 mL) under
argon. After stirring at rt for 7 h, the reaction mixture was
diluted with saturated NH4Cl solution and extracted with
hexane (3£100 mL). The combined organic layers were
washed with brine, dried over MgSO4, and concentrated.
The residue was puri®ed by column chromatography on
silica gel (EtOAc:hexaneˆ1:6) to afford MPM-ether 21
(3.80 g, 99%) as a colorless oil: IR (neat, cm21) n 1612,
1512, 1248, 1082, 1035, 819; 1H NMR (CDCl3) 7.26 (2H, d,
Jˆ8.8 Hz), 6.88 (2H, d, Jˆ8.8 Hz), 5.45 (1H, t, Jˆ7.0 Hz),
4.60 (1H, d, Jˆ12.8 Hz), 4.43 (2H, s), 3.97 (2H, d,
Jˆ7.0 Hz), 3.80 (3H, s), 3.78 (1H, d, Jˆ12.8 Hz), 3.25
(1H, dd, Jˆ2.6, 11.4 Hz), 2.80 (major isomer, 1H, d,
Jˆ4.8 Hz), 2.78 (minor isomer, 1H, d, Jˆ4.8 Hz), 2.61
(major isomer, 1H, d, Jˆ4.8 Hz), 2.59 (minor isomer, 1H,
d, Jˆ4.8 Hz), 2.24±2.46 (2H, m), 1.82 (1H, m), 1.62 (1H,
m), 1.31 (major isomer, 3H, s), 1.33 (minor isomer, 3H, s);
MS m/z 304 (M1), 241, 166, 121 (base peak); HRMS calcd
for C18H24O4 304.1674, found 304.1662.
4.1.17. (R)-(50Z)-2-[60-(100-Triisopropylsilyloxymethyl-
vinyl)dihydropyran-30-ylidene]ethenol (24). To a solution
of 23 (318 mg, 0.689 mmol) in CH2Cl2 (10 mL) were added
water (0.2 mL) and DDQ (223 mg, 0.982 mmol) and the
mixture was stirred at rt for 2 h. After addition of saturated
NaHCO3 solution, the reaction mixture was extracted with
EtOAc. The combined organic layers were washed with
brine, dried over MgSO4, and concentrated. The residue
was puri®ed by column chromatography on silica gel
(EtOAc:hexaneˆ1:5) to afford 24 (211 mg, 90%) as a color-
less oil: [a]D ˆ123.08 (c 1.07, CHCl3); IR (neat, cm21) n
21
1
3383, 2943, 2866, 1464, 1116, 1078; H NMR (CDCl3) d
5.48 (1H, t, Jˆ7.4 Hz), 5.22 (1H, m), 5.10 (1H, m), 4.66
(1H, d, Jˆ13.0 Hz), 4.26 (2H, s), 4.23 (1H, dd, Jˆ7.4,
12.4 Hz), 4.08 (1H, dd, Jˆ7.4, 12.4 Hz), 4.00 (1H, br.d,
Jˆ11.0 Hz), 3.85 (1H, d, Jˆ13.0 Hz), 2.38 (2H, m), 1.90
(1H, m), 1.65 (1H, m), 1.07 (21H, m); MS (CI) m/z 341
(M11H), 323, 297, 149 (base peak), 131; HRMS calcd
for C19H37O3Si 341.2512, found 341.2524.
4.1.15. (R)-(50Z)-2-{50-[200-(4000-Methoxybenzyloxy)ethyl-
idene]tetrahydropyran-20-yl}prop-2-en-1-ol (22).
A
solution of 21 (1.55 g, 5.08 mmol) and aluminum tri-
isopropoxide (5.18 g, 25.4 mmol) in dry toluene (50 mL)
was heated under re¯ux for 36 h. After addition of saturated
potassium sodium tartrate aq. solution, the mixture was
stirred at rt until becoming clear solution and extracted
with EtOAc (3£120 mL). The combined organic layers
were washed with brine, dried over MgSO4, and then evapo-
rated. The residue was puri®ed by column chromatography
on silica gel (EtOAc:hexaneˆ1:3!1:1) to afford 22
CHCl3); IR (neat, cm21) n 3426, 1613, 1514, 1248, 1069,
1034, 820; 1H NMR (CDCl3) d 7.28 (2H, d, Jˆ8.4 Hz), 6.88
(2H, d, Jˆ8.4 Hz), 5.47 (1H, t, Jˆ6.6 Hz), 5.14 (1H, s), 5.11
(1H, s), 4.60 (1H, d, Jˆ13.2 Hz), 4.47 (1H, d, Jˆ11.7 Hz),
4.1.18.
(R)-(Z)-{2-[5-(2-Chloroethylidene)tetrahydro-
pyran-2-yl]allyloxy}triisopropyl-silane (25). A solution
of NCS (68 mg, 0.51 mmol) in CH2Cl2 (5 mL) was cooled
to 2308C under argon and dimethylsul®de (35 mg,
0.56 mmol) was added. The resulting suspension was
warmed to 08C and stirred for 5 min. The mixture was
cooled to 2308C again and alcohol 24 (87 mg,
0.255 mmol) in CH2Cl2 (5 mL) was added dropwise. After
stirring at 08C for 0.5 h, the mixture was diluted with water
and extracted with hexane. The combined organic layers
were washed with brine, dried over MgSO4, and concen-
trated. The residue was chromatographed on silica gel
(EtOAc:hexaneˆ1:30) to afford 25 (85 mg, 93%) as a color-
21
(1.205 g, 78%) as a colorless oil: [a]D ˆ156.98 (c 0.74,
less oil: [a]D ˆ155.58 (c 1.00, CHCl3); IR (neat, cm21) n
21

H. Hioki et al. / Tetrahedron 57 (2001) 1235±1246
1243
2944, 2892, 2866, 1462, 1256, 1117, 1080, 912, 883, 810,
682; 1H NMR (CDCl3) d 5.49 (1H, t, Jˆ7.4 Hz), 5.22 (1H,
m), 5.11 (1H, m), 4.66 (1H, d, Jˆ13.0 Hz), 4.27 (2H, s),
4.12 (1H, dd, Jˆ7.4, 11.7 Hz), 4.06 (1H, dd, Jˆ7.4,
11.7 Hz), 4.01 (1H, br.d, Jˆ10.8 Hz), 3.88 (1H, d,
Jˆ13.0 Hz), 2.40 (2H, m), 1.88 (1H, m), 1.68 (1H, m),
1.08 (21H, m); MS (CI) m/z 359 (M11H) 315 (base
peak), 279, 199, 149; HRMS calcd for C19H36O2SiCl
359.2171, found 359.2174.
4.1.21. (R)-(50Z,400E,800E,1200E)-2-[50-(500,900,1300,1700-Tetra-
methyloctadeca-400,800,1200,1600-tetraenylidene)tetrahydro-
pyran-20-yl]propenal (29). A mixture of 28 (75 mg,
0.17 mmol) and active MnO2 (151 mg, 0.95 mmol) in
hexane (5 mL) was stirred at rt for 16 h. The reaction
mixture was directly chromatographed on silica gel
(EtOAc:hexaneˆ1:15) to give 29 (59 mg, 78%) as a color-
less oil: [a]D ˆ147.48 (c 0.59, CHCl3); IR (neat, cm21) n
23
1
1694, 1443, 1275, 1088; H NMR (CDCl3) d 9.54 (1H, s),
6.54 (1H, s), 6.07 (1H, s), 5.24 (1H, br.t, Jˆ7.0 Hz), 5.16±
5.06 (4H, m), 4.70 (1H, d, Jˆ12.5 Hz), 4.34 (1H, d,
Jˆ11.0 Hz), 3.87 (1H, d, Jˆ12.5 Hz), 2.34 (2H, m), 1.90±
2.18 (16H, m), 1.69 (3H, br.s), 1.60 (12H, br.s), 1.20±1.40
(2 H, m); MS m/z 438 (M1), 369, 301, 259, 149, 137, 121,
95, 81, 69 (base peak); HRMS calcd for C30H46O2 438.3498,
found 438.3509.
4.1.19. Coupling of 25 and 26. A solution of 26 (964 mg,
2.52 mmol) and freshly sublimed DABCO (283 mg,
2.52 mmol) in dry THF (20 mL) was cooled to 2788C
under argon and n-BuLi (1.6 mL of 1.6 M hexane solution,
2.59 mmol) was added. To the yellow colored solution was
added 25 (566 mg, 1.58 mmol) in dry THF (20 mL) drop-
wise. After stirring at 2788C for 2 h, the reaction was
quenched by addition of saturated NH4Cl solution
(20 mL). The reaction mixture was diluted with water
(100 mL) and extracted with hexane (3£100 mL). The
combined organic layers were dried over Na2SO4 and
evaporated in vacuo. The residue was puri®ed by column
chromatography on silica gel (hexane: benzeneˆ1:1) to
give coupling product 27 (1.042 g, 94%) as a colorless oil.
This product was a ca. 1:1 mixture of diastereomers and
used for the next step without separation. 1H NMR
(CDCl3) d 7.41 (2H, m), d 7.22 (3H, m), 5.0±5.25 (7H,
m), 4.56 (1H, d, Jˆ12.8 Hz), 4.25 (2H, s), 3.65±4.00 (3H,
m), 2.30 (2H, m), 1.80±2.15 (20H, m), 1.68 (3H, s), 1.60
(12H, s),1.08 (21H, m).
4.1.22. (R)-(50Z,400E,800E,1200E)-2-[50-(500,900,1300,1700-Tetra-
methyloctadeca-400,800,1200,1600-tetraenylidene)tetrahydro-
pyran-20-yl]propenoic acid [(R)-1]. To a solution of
aldehyde 29 (56 mg, 0.127 mmol) in t-BuOH (4 mL) were
added water (1 mL), 2-methyl-2-butene (1 mL), NaClO2
(70%%, 58 mg, 0.45 mmol), and NaH2PO4´2H2O (99 mg,
0.64 mmol) and the mixture was stirred at rt for 2 h. The
reaction mixture was cooled to 08C and NaHSO3 powder
(13 mg, 0.126 mmol) was added. After dilution with satu-
rated NaH2PO4 solution (50 mL), the mixture was extracted
with EtOAc (3£50 mL). The combined organic layers were
washed with brine, dried over Na2SO4, and then evaporated.
The residue was puri®ed by column chromatography on
silica gel (EtOAc: hexaneˆ1:2) to yield 1 (51 mg, 87%)
21
4.1.20. (R)-(50Z,400E,800E,1200E)-2-[50-(500,900,1300,1700-Tetra-
methyloctadeca-400,8001200,1600-tetraenylidene)tetrahydro-
pyran-20-yl]prop-2-en-1-ol (28). To a re¯uxing solution of
sul®de 27 (612 mg, 0.87 mmol) in n-BuOH (50 mL) was
added sodium metal (250 mg) in small portions under
argon. The reaction was monitored by TLC and additional
621 mg of sodium metal was added during 40 min in small
portions. After cooling to rt, the reaction mixture was
diluted with saturated NH4Cl solution and extracted with
hexane (3£100 mL). The combined organic layers were
dried over Na2SO4 and evaporated in vacuo. The crude
product was subjected to desilylation without further
puri®cation.
as a colorless oil; [a]D ˆ147.18 (c 0.253, CHCl3); IR
1
(neat, cm21) n 3400±2500, 1695, 1628, 1439, 1082; H
NMR (CDCl3) d 6.34 (1H, s), 5.97 (1H, s), 5.26 (1H, t,
Jˆ7.0 Hz), 5.14±5.07 (4H, m), 4.72 (1H, d, Jˆ12.6 Hz),
4.32 (1H, d, Jˆ10.1 Hz), 3.90 (1H, d, Jˆ12.6 Hz), 2.41±
2.31 (2H, m), 2.12±2.01 (11H, m), 2.01±1.95 (6H, m), 1.68
(3H, s), 1.60 (12H, s), 1.43 (1H, m); 13C NMR (CDCl3) d
170.1 (C-1), 140.6 (C-2), 135.8, 135.0, 134.9 (C-500, C-900,
C-1300), 132.0 (C-50), 131.2 (C-1700), 127.1 (C-3), 125.0
(C-100), 124.4, 124.2£2, 123.5 (C-400, C-800, C-1200, C-1600),
75.6 (C-20), 67.1 (C-60), 39.7£3 (C-600, C-1000, C-1400), 33.7
(C-30), 32.9 (C-40), 28.2, 27.3 (C-200, C-300), 26.8, 26.7, 26.6
(C-700, C-1100, C-1500), 25.7 (C-1800), 17.7 (C-2200), 16.1,
16.0, 16.0 (C-1900, C-2000, C-2100); MS m/z 454 (M1), 317,
81, 61 (base peak); HRMS calcd for C30H46O3 454.3447,
found 454.3448.
To a solution of the crude desulfurized product in THF
(3 mL) was added n-Bu4NF (1.9 mL of 1 M THF solution,
1.9 mmol) at rt under argon. After stirring at rt for 0.5 h, the
reaction was quenched by the addition of brine (30 mL) and
extracted with EtOAc (3£50 mL). The combined organic
layers were dried over Na2SO4 and concentrated. The resi-
due was separated by column chromatography on 10%
AgNO3-impregnated silica gel (EtOAc:hexaneˆ1:1) to
afford 28 (248 mg, 65% for 2 steps) as a colorless oil:
4.1.23. Methyl ester of dodecahydrohippospongic acid A.
A solution of hippospongic acid A (1 mg) and 10% Pd/C
(2 mg) in EtOAc (1 mL) was stirred at rt in the atmosphere
of H2 for 2 h. The catalyst was ®ltered off and the ®ltrate was
evaporated in vacuo. After treatment with Me3SiCHN2, the
residue was puri®ed by column chromatography on silica
gel (EtOAc:hexaneˆ1:9) to afford methyl ester 30 (1 mg)
as a colorless oil: IR (neat, cm21) n 1740, 1460, 1377, 1073;
MS m/z 480 (M1), 465, 420, 393 (base peak), 171, 153,
143, 130; HRMS calcd for C31H60O3 480.4542, found
480.4548.
24
[a]D ˆ123.68 (c 0.45, CHCl3); IR (neat, cm21) n 3420,
1
1659, 1442, 1381, 1074, 1030; H NMR (CDCl3) d 5.24
(1H, br.t, Jˆ7.8 Hz), 5.16±5.06 (6H, m), 4.65 (1H, d,
Jˆ12.8 Hz), 4.30±4.02 (3H, m), 3.83 (1H, d, Jˆ12.8 Hz),
2.38 (2H, m), 1.90±2.18 (16H, m), 1.80 (1H, m), 1.68 (1H,
m), 1.68 (3H, br.s), 1.60 (12H, br.s); MS m/z 440 (M1), 422,
371, 353, 303, 261, 137, 135, 121, 107, 95, 93, 81, 89 (base
peak); HRMS calcd for C30H48O2 440.3654, found
440.3654.
4.1.24. (2E,6E,10E)-2,7,11,15-Tetramethyl-1-phenylthio-
hexadeca-2,6,10,14-tetraene (33). To an ice-cooled solu-
tion of 32 (163 mg, 0.563 mmol) and PhSSPh (615 mg,

1244
H. Hioki et al. / Tetrahedron 57 (2001) 1235±1246
2.815 mmol) in pyridine (16 mL) was added Bu3P (570 mg,
2.19 mmol) under argon. After stirring at rt for 1.5 h,
the reaction was quenched by addition of water (30 mL).
The mixture was extracted with hexane (3£50 mL) and the
combined organic layers were washed with brine, dried over
Na2SO4, and evaporated in vacuo. The residue was puri®ed
by column chromatography on silica gel (EtOAc:hexaneˆ
1:100) to give 33 (194 mg, 90%) as a colorless oil: IR (neat,
AgNO3-impregnated silica gel (EtOAc:hexaneˆ1:1) to
give 35 (11 mg, 48%) and its isomer 36 (9 mg, 39%). 35:
22
Colorless oil; [a]D ˆ126.98 (c 1.00, CHCl3); IR (neat,
1
cm21) n 3418, 2922, 1433, 1074; H NMR (CDCl3) d
5.2±5.0 (7H, m), 4.57 (1H, d, Jˆ12.8 Hz), 4.17 (1H, d,
Jˆ12.6 Hz), 4.05 (1H, d Jˆ12.6 Hz), 4.01 (1H, br.d,
Jˆ10.8 Hz), 3.75 (1H, d, Jˆ12.8 Hz), 2.25 (2H, m), 1.84±
2.08 (16H, m), 1.74 (2H, m), 1.61 (3H, s), 1.53 (12H, s); MS
(CI) m/z 440 (M1), 166 (base peak), 136, 81, 69; HRMS
calcd for C30H48O2 440.3652, found 440.3654. 36: Colorless
oil; IR (neat, cm21) n 3420, 1074, 909; 1H NMR (CDCl3) d
5.2±5.0 (7H, m), 4.58 (1H, d, Jˆ12.8 Hz), 4.22±3.96 (3H,
m), 3.78 (1H, d, Jˆ12.8 Hz), 2.64 (1H, t, Jˆ7.4 Hz), 2.25
(2H, m), 1.84±2.08 (14H, m), 1.74 (2H, m), 1.61 (3H, s),
1.53 (12H, s); MS (CI) m/z 441 (M11H), 395, 353, 333
(base peak), 199, 155, 137; HRMS calcd for C30H49O2
441.3730, found 441.3721.
1
cm21) n 2920, 2855, 1439, 784, 691; H NMR (CDCl3) d
7.38±7.12 (5H, m), 5.25 (1H, t, Jˆ6.8 Hz), 5.08 (3H, m),
3.50 (2H, s), 2.08±1.85 (12H, m), 1.73 (3H, s), 1.68 (3H, s),
1.60 (6H, s), 1.57 (3H, s); MS (CI) m/z 383 (M11H), 273,
177 (base peak); HRMS calcd for C26H39S 383.2771, found
383.2772.
4.1.25. Coupling of 25 and 33. The solution of 33 (169 mg,
0.44 mmol) and freshly sublimed DABCO (50 mg,
0.44 mmol) in dry THF (3.5 mL) was cooled to 2788C
under argon and n-BuLi (963 ml of 1.6 M hexane solution,
1.54 mmol) was added. To the yellow colored solution was
added 25 (99 mg, 0.276 mmol) in dry THF (3.5 mL) drop-
wise. After stirring at 2788C for 5 h, the reaction was
quenched by addition of saturated NH4Cl solution
(15 mL). The mixture was extracted with hexane
(3£50 mL). The combined organic layers were washed
with brine, dried over Na2SO4, and evaporated in vacuo.
The residue was puri®ed by column chromatography on
silica gel (hexane:benzeneˆ3:1) to give coupling product
34 (ca. 1:1 mixture of diastereomers, 103 mg, 53%) as a
colorless oil: IR (neat, cm21) n 2942, 2866, 1076, 784,
4.1.27. (R)-(50Z,400E,800E,1200E)-2-[50-(400,900,1300,1700-Tetra-
methyloctadeca-400,800,1200,1600-tetraenylidene)tetrahydro-
pyran-20-yl]propenal (37). A mixture of 35 (22 mg,
0.048 mmol) and active MnO2 (76 mg, 0.48 mmol) in
hexane (3 mL) was stirred at rt for 11 h. The reaction
mixture was directly chromatographed on silica gel
(EtOAc:hexaneˆ1:12) to give 37 (19 mg, 87%) as a color-
less oil: [a]D ˆ146.78 (c 1.00, CHCl3); IR (neat, cm21) n
20
1
2920, 1694, 1088; H NMR (CDCl3) d 9.47 (1H, s), 6.47
(1H, s), 6.00 (1H, s), 5.2±5.0 (5H, m), 4.62 (1H, d,
Jˆ12.8 Hz), 4.27 (1H, d, Jˆ11.0 Hz), 3.80 (1H, d,
Jˆ12.8 Hz), 2.25 (2H, m), 1.84±2.08 (16H, m), 1.61 (3H,
s), 1.53 (12H, s), 1.26 (2H, m); MS (CI) m/z 438 (M1), 370,
271, 164, 137, 69 (base peak); HRMS calcd for C30H46O2
438.3498, found 438.3495.
1
691; H NMR (CDCl3) d 7.18±7.34 (5H, m), 4.98±5.24
(7H, m), 4.58 (1H, d, Jˆ12.8 Hz), 4.27 (2H, s), 3.96 (1H,
br.d, Jˆ11.4 Hz), {3.82 (d, Jˆ12.8 Hz), 3.79 (d,
Jˆ12.8 Hz), 1H}, 3.55 (1H, m), 2.24±2.44 (2H, m), 1.8±
2.1 (16H, m), 1.53±1.70 (15H, m), 1.08 (21H, m); MS (CI)
m/z 705 (M11H), 661, 595, 553, 551, 421, 381, 309, 131,
111 (base peak); HRMS calcd for C45H73O2SSi 705.5096,
found 705.5100.
4.1.28. Hippospongic acid A (5). To a solution of aldehyde
37 (16 mg, 0.037 mmol) in t-BuOH (2 mL) were added
water (0.5 mL), 2-methyl-2-butene (0.35 mL), NaClO2
(17 mg, 0.15 mmol), and NaH2PO4´2H2O (29 mg,
0.15 mmol) and the mixture was stirred at rt for 0.5 h. The
reaction mixture was cooled to 08C and NaHSO3 powder
(15 mg, 0.15 mmol) was added. After dilution with satu-
rated NaH2PO4 solution (15 mL), the mixture was extracted
with EtOAc (70 mL). The combined organic layers were
washed with brine, dried over Na2SO4, and then evaporated.
The residue was puri®ed by column chromatography on
silica gel (EtOAc:hexaneˆ1:4) to give 5 (13 mg, 76%) as
4.1.26. (R)-(50Z,400E,800E,1200E)-2-[50-(400,900,1300,1700-Tetra-
methyloctadeca-400,800,1200,1600-tetraenylidene)tetrahydro-
pyran-20-yl]prop-2-en-1-ol (35). To a re¯uxing solution of
34 (53 mg, 0.075 mmol) in n-BuOH (16 mL) was added
sodium metal (183 mg, 2.25 mmol). The reaction was moni-
tored by TLC and 75 mg of sodium was added three times
further. After cooling to rt, the reaction mixture was diluted
with saturated NH4Cl solution (20 mL) and extracted with
hexane (3£70 mL). The combined organic layers were
washed with brine, dried over MgSO4, and evaporated in
vacuo. The residue was puri®ed by column chromatography
on silica gel (hexane:tolueneˆ5:1) to yield the desulfurized
product (31 mg, 69%) as a ca. 1:1 mixture of geometrical
isomers of double bond. The mixture was used for the next
step without separation.
20
a colorless oil; [a]D ˆ141.48 (c 1.00, CHCl3); IR (neat,
cm21) n 3200±2500 (br), 2922, 1697, 1082; 1H NMR
(CDCl3) d 6.40 (1H, s), 5.95 (1H, s), 5.23 (1H, br.t,
Jˆ7.2 Hz), 5.18±5.04 (4H, m), 4.72 (1H, d, Jˆ10.0 Hz),
4.32 (1H, d, Jˆ11.0 Hz), 3.90 (1H, d, Jˆ10.0 Hz), 2.36
(2H, m), 2.15 (1H, m), 1.69 (3H, br.s), 1.60 (12H,
br.s),1.43 (1H, m); 13C NMR (CDCl3) d 169.9 (s), 140.6
(s), 135.2 (s), 134.9 (s), 134.4 (s), 132.4 (s), 131.2 (s),
125.0 (d), 124.9 (d), 124.2 (d), 75.7 (d), 67.1 (t), 39.7 (t),
33.7 (t), 32.9 (t), 28.3 (t), 28.2 (t), 26.8 (t), 26.6 (t), 25.7 (q),
25.6 (t), 17.7 (q), 16.1 (q), 16.0 (q); MS (CI) m/z 455
(M11H, base peak), 453, 437, 191, 180, 137; HRMS (EI)
calcd for C30H46O3 454.3447, found 454.3448.
To a solution of the mixture (31 mg, 0.052 mmol) in THF
(5 mL) was added n-Bu4NF (0.21 mL of 1 M THF solution,
0.21 mmol) at rt under argon. After stirring at rt for 0.5 h,
the reaction was quenched by the addition of saturated
NH4Cl solution (10 mL) and extracted with EtOAc
(3£30 mL). The combined organic layers were washed
with brine, dried over MgSO4, and concentrated. The resi-
due was separated by column chromatography on 10%
4.1.29. Coupling of 25 and 39. To a solution of geranyl-
phenyl sul®de 39 (133 mg, 0.54 mmol) and freshly
sublimed DABCO (60 mg, 0.54 mmol) in dry THF

H. Hioki et al. / Tetrahedron 57 (2001) 1235±1246
1245
(3.5 mL) was added n-BuLi (0.5 mL of 1.6 M hexane solu-
tion, 0.81 mmol) at 2788C under argon. To the yellow-
colored solution was added a solution of 25 (86 mg,
0.24 mmol) in dry THF (2 mL) dropwise at 2788C. After
stirring at the same temperature for 1.5 h, the reaction was
quenched by the addition of saturated NH4Cl solution. The
mixture was extracted with hexane (3£30 mL). The
combined organic layers were washed with brine, dried
over Na2SO4, and then evaporated. The residue was puri®ed
by column chromatography on silica gel (hexane:
benzeneˆ20:1) to give 40 (ca. 1:1 mixture of diastereomers,
121 mg, 89%) as a colorless oil: IR (neat, cm21) n 2942,
2866, 1439, 1254, 1115, 1076, 883, 691; 1H NMR (CDCl3)
d 7.37 (2H, m), 7.20 (3H, m), 5.22 (2H, m), 5.00±5.09 (3H,
m), 4.54 (1H, d, Jˆ12.8 Hz), 4.28 (2H, s), 3.73±3.99 (3H,
m), 2.10±2.30 (4H, m), 1.78±2.06 (6H, m), 1.68 (3H, s),
1.59 (3H, s), 1.42 (3H, s), 1.08 (21H, m); MS (CI) m/z 569
(M11H), 525, 459, 415 (base peak), 309, 285, 267, 245, 69;
HRMS calcd for C35H56O2SSi 568.3767, found 568.3767.
mixture of 42 (29 mg, 0.094 mmol) and active MnO2
(149 mg, 0.94 mmol) in hexane (4.5 mL) was stirred at rt
for 14 h. The reaction mixture was directly chromato-
graphed on silica gel (EtOAc:hexaneˆ1:20) to give alde-
1.00, CHCl3); IR (neat, cm21) n 2917, 2853, 1694, 1088; 1H
NMR (CDCl3) d 9.54 (1H, s), 6.54 (1H, s), 6.07 (1H, s), 5.24
(1H, t, Jˆ6.8 Hz), 5.11 (2H, m), 4.70 (1H, d, Jˆ12.6 Hz),
4.34 (1H, d, Jˆ11.0 Hz), 3.87 (1H, d, Jˆ12.6 Hz), 2.30 (2H,
m), 1.92±2.14 (9H, m), 1.68 (3H, s), 1.60 (6H, s), 1.32 (1H,
m); MS (CI) m/z 302 (M1), 285, 109, 95, 81, 69 (base peak);
HRMS calcd for C20H30O2 302.2244, found 302.2246.
19
hyde 43 (20 mg, 70%) as a colorless oil: [a]D ˆ174.08 (c
4.1.33. (R)-(50Z,400E)-2-[50-(500,900-Dimethyldeca-400,800-di-
enylidene)tetrahydropyran-20-yl]propenoic acid [(R)-
38]. To a solution of aldehyde 43 (20 mg, 0.066 mmol) in
t-BuOH (2.5 mL) were added water (0.5 mL), 2-methyl-2-
butene (0.35 mL), NaClO2 (31 mg, 0.26 mmol), and
NaH2PO4´2H2O (52 mg, 0.33 mmol) and the mixture was
stirred at rt for 1.5 h. The reaction mixture was cooled to
08C and NaHSO3 powder (28 mg, 0.26 mmol) was added.
After dilution with saturated NaH2PO4 solution (15 mL), the
mixture was extracted with EtOAc (80 mL). The combined
organic layers were washed with brine, dried over Na2SO4,
and then evaporated. The residue was puri®ed by column
chromatography on silica gel (hexane:benzeneˆ1:2) to give
4.1.30. {2-[5-(5,9-Dimethyldeca-4,8-dienylidene)tetra-
hydropyran-2-yl]allyloxy}triethyl-silane (41). To a solu-
tion of 40 (117 mg, 0.21 mmol) in n-BuOH (10 mL) was
added sodium metal (47 mg, 2.1 mmol) at 908C under
argon. Additional sodium metal (total 317 mg) was added
in small portions during 1 h. After cooling to rt, the reaction
mixture was diluted with saturated NH4Cl solution and
extracted with hexane (150 mL). The combined organic
layers were washed with brine, dried over MgSO4, and
concentrated. The residue was puri®ed by column
chromatography on 10% AgNO3-impregnated silica gel
(hexane:tolueneˆ3:1) to afford 41 (56 mg, 60%) as a color-
20
(R)-38 (16 mg, 76%) as a colorless oil; [a]D ˆ174.28 (c
1.00, CHCl3); IR (neat, cm21) n 3400±2600 (br), 2967,
1
2920, 2853, 1695, 1439, 1082, 1046; H NMR (CDCl3) d
6.40 (1H, s), 5.98 (1H, s), 5.25 (1H, br.t, Jˆ6.5 Hz), 5.18±
5.02 (2H, m), 4.72 (1H, d, Jˆ12.6 Hz), 4.32 (1H, d,
Jˆ10.6 Hz), 3.90 (1H, d, Jˆ12.6 Hz), 2.33 (2H, m), 1.93±
2.14 (9H, m), 1.69 (3H, s), 1.60 (6H, s), 1.44 (1H, m); MS
(CI) m/z 318 (M1), 109, 95, 81, 69 (base peak); HRMS calcd
for C20H30O3 318.2193, found 318.2195.
less oil: [a]D ˆ119.48 (c 1.00, CHCl3); IR (neat, cm21) n
20
2942, 2866, 1076; 1H NMR (CDCl3) d 5.06±5.24 (3H, m),
5.21 (1H, br.s), 5.09 (1H, br.s), 4.63 (1H, d, Jˆ12.8 Hz),
4.28 (2H, s), 3.96 (1H, br.d, Jˆ10.8 Hz), 3.80 (1H, d,
Jˆ12.8 Hz), 2.33 (2H, m), 1.80±2.08 (10H, m), 1.68 (3H,
br.s), 1.59 (6H, br.s), 1.08 (21H, m); MS (CI) m/z 461
(M11H), 417, 269, 69 (base peak); HRMS calcd for
C29H53O2Si 461.3812, found 461.3815.
Acknowledgements
This work was partially supported by a Grant-in-Aid for
Scienti®c Research (No. 08680642) from the Ministry of
Education, Science and Culture of Japan
4.1.31. (R)-(50Z,400E)-2-[50-(500,900-Dimethyldeca-400,800-
dienylidene)tetrahydropyran-20-yl] prop-2-en-1-ol (42).
To a solution of 41 (48 mg, 0.10 mmol) in THF (8 mL)
was added n-Bu4NF (418 ml of 1 M THF solution,
0.42 mmol) at rt under argon. After stirring at rt for
15 min, saturated NH4Cl solution was added and the
mixture was extracted with EtOAc (150 mL). The combined
organic layers were washed with brine, dried over MgSO4,
and concentrated. The residue was puri®ed by column chro-
matography on silica gel (EtOAc:hexaneˆ1:10) to afford 42
References
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22
(28 mg, 87%) as a colorless oil: [a]D ˆ137.68 (c 1.00,
CHCl3); IR (neat, cm21) n 3399, 2924, 1443, 1074, 909;
1H NMR (CDCl3) d 5.24 (1H, br.t, Jˆ6.5 Hz), 5.16±5.05
(4H, m), 4.65 (1H, d, Jˆ12.8 Hz), 4.24 (1H, d, Jˆ13.2 Hz),
4.12 (1H, d, Jˆ13.2 Hz), 4.06 (1H, br.d, Jˆ10.8 Hz), 3.82
(1H, d, Jˆ12.8 Hz), 2.35 (2H, m), 1.96±2.11 (9H, m), 1.80
(1H, m), 1.68 (3H, br.s), 1.60 (6H, br.s); MS (CI) m/z 305
(M11H), 304, 287, 269, 230, 135, 109, 95, 81, 69 (base
peak); HRMS calcd for C20H32O2 304.2402, found 304.2402.
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enylidene)tetrahydropyran-20-yl] propenal (43). The

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H. Hioki et al. / Tetrahedron 57 (2001) 1235±1246
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1
2.64 ppm in the H NMR spectrum.
9. (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakizawa, H. J. Am.