Asymmetric total synthesis of (+)-curcutetraol and (+)-sydonol

Article abstract of DOI:10.1016/j.tet.2008.08.012

The asymmetric total syntheses of (+)-curcutetraol and (+)-sydonol, phenolic bisabolane-type sesquiterpenoids having chiral tertiary alcohol moiety in the o-position of a phenol, were achieved in high enantiomeric excesses (99% ee). The chiral tertiary benzylic alcohol moiety of these compounds was constructed by an asymmetric synthesis using an easily available chiral aminal, (-)-(2R,5S)-2-methoxycarbonyl-3-phenyl-1,3-diazabicyclo[3.3.0]octane. The absolute configurations of both (+)-curcutetraol and?(+)-sydonol have been assumed to be S-configuration based on the stereochemical course of the well established asymmetric synthesis used in the syntheses.

Full text of DOI:10.1016/j.tet.2008.08.012

Tetrahedron 64 (2008) 9879–9884
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric total synthesis of (þ)-curcutetraol and (þ)-sydonol
*
Suguru Ito, Chenxia Zhang, Naoya Hosoda, Masatoshi Asami
Department of Advanced Materials Chemistry, Graduate School of Engineering, Yokohama National University, Tokiwadai 79-5, Hodogaya-ku, Yokohama 240-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2008
Received in revised form 2 August 2008
Accepted 6 August 2008
Available online 9 August 2008
The asymmetric total syntheses of (þ)-curcutetraol and (þ)-sydonol, phenolic bisabolane-type sesqui-
terpenoids having chiral tertiary alcohol moiety in the o-position of a phenol, were achieved in high
enantiomeric excesses (99% ee). The chiral tertiary benzylic alcohol moiety of these compounds was
constructed by an asymmetric synthesis using an easily available chiral aminal, (ꢀ)-(2R,5S)-2-methoxy-
carbonyl-3-phenyl-1,3-diazabicyclo[3.3.0]octane. The absolute configurations of both (þ)-curcutetraol
and (þ)-sydonol have been assumed to be S-configuration based on the stereochemical course of the well
established asymmetric synthesis used in the syntheses.
Keywords:
Curcutetraol
Sydonol
Ó 2008 Elsevier Ltd. All rights reserved.
Sesquiterpene
Asymmetric total synthesis
HO
HO
1. Introduction
OH
OH
OH
Many phenolic sesquiterpenoids of the bisabolane family, pos-
sessing one or two stereogenic centers, have been isolated from both
terrestrial and marine organisms. They often display characteristic
biological activities1–9 in contrast with non-phenolic sesquiterpe-
noids. For example, (þ)-curcuphenol, isolated from sponges (the
subgenus Mycale (Arenochalina) and the genera Didiscus, Epipolasis,
and Myrmekioderma),1 strongly inhibits the activity of gastric H, K-
ATPase.1b On the other hand, (ꢀ)-curcuphenol, isolated from the
gorgonian coal (Pseudopterogorgia rigida) and the terrestrial plant
(Lasianthaea podocephata),2 exhibits antibacterial activities against
Staphylococcus aureus and Vibrio anguillarum.2a Thus, a number of
studies have been carried out to date on syntheses of both racemic
and chiral curcuphenol.10 Meanwhile, there has been few reports on
biological activities of curcutetraol (1),5 sydonol (2),6 sydonic acid,7
waraterpol,8 ligustiphenol,9 and curcutriolamide,5 which contain
a tertiary benzylic alcohol moiety in the o-position of a phenol
(Fig.1), and there was no report on their asymmetric synthesis to the
best of our knowledge.
HO
HO
HO
(+)-curcutetraol (1)
(+)-sydonol (2)
HO
OH
HO
O
(+)-curcuphenol
( )-sydonic acid
Figure 1. Phenolic bisabolane sesquiterpenoids.
compound.5 The absolute configuration of its tertiary benzylic
alcohol moiety was proposed to be S by the comparison of its ex-
perimental CD spectrum with the calculated one.5 The S-configu-
ration of (þ)-1 was also assumed by an asymmetric synthesis of
(þ)-1 as shown in our preliminary communication.11
50-Deoxygenated curcutetraol is known as sydonol (2).
(þ)-Sydonol (2) was isolated from a strain of Aspergillus sp. by
Nukina and co-workers in 1981 and exhibited antifungal activity
against Cochliobolus lunata (IFO 6299). The structure of (þ)-2 was
characterized by comparison of the spectral properties and chro-
matographic behavior of natural 2 with a compound synthesized
from (ꢁ)-sydonic acid.6 The absolute stereochemistry of natural 2
has not been determined yet although natural 2 was isolated in
optically active form. Thus, we undertook an asymmetric synthesis
of (þ)-sydonol (2) by employing similar reaction sequences used in
the synthesis of (þ)-1. Herein, we report the asymmetric total
(þ)-Curcutetraol (1) was isolated from the marine bacterium
CNH-741 and fungus CNC-979 by Lindel and co-workers in 2005. It
is the first bisabolane sesquiterpenoid with a tertiary benzylic al-
cohol moiety as a single stereogenic center in the o-position of
a phenol isolated from the marine environment. The structure of
(þ)-1 was determined on the basis of an extensive NMR spectro-
scopic analysis and confirmed by synthesis of the racemic
* Corresponding author. Tel./fax: þ81 45 339 3968.
E-mail address: m-asami@ynu.ac.jp (M. Asami).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.012

9880
S. Ito et al. / Tetrahedron 64 (2008) 9879–9884
syntheses of (þ)-1 and (þ)-2 by applying an asymmetric synthesis
(TIPS) ether), which could be easily cleaved under mild condi-
tions by fluoride ion, were chosen as protective groups of the
hydroxy groups of aryl Grignard reagent 7. Protected aryl bro-
mides were prepared from 2-bromo-5-hydroxymethylphenol
(8)14 and TESCl, TBDMSCl, or TIPSCl in the presence of imid-
azole in DMF, respectively. Unfortunately, the corresponding
Grignard reagents were not prepared from those protected aryl
bromides by treating with activated magnesium turnings in the
presence of iodine or 1,2-dibromoethane in Et2O or THF. Then,
2-(trimethylsilyl)ethoxymethyl (SEM) ether, which also could be
cleaved by fluoride ion, was examined as an alternative pro-
tective group. Bromide 9 was prepared from 8 and SEMCl in the
presence of NaH in THF in 78% yield (Scheme 3). The corre-
sponding Grignard reagent 7a was successfully prepared from 9
by using activated magnesium turnings in the presence of 1,2-
dibromoethane in refluxing THF. A THF solution of acetyl aminal
(ꢀ)-6 was added dropwise to Grignard reagent 7a at ꢀ78 ꢂC
and the mixture was stirred at the same temperature for 1 h.
The resulting crude hydroxy aminal 10 was treated with 2%
of an
a
-hydroxy aldehyde using a chiral aminal, (ꢀ)-(2R,5S)-2-
methoxycarbonyl-3-phenyl-1,3-diazabicyclo[3.3.0]octane (3).12
2. Results and discussion
Our synthetic plan for the synthesis of (þ)-curcutetraol (1) and
(þ)-sydonol (2) is shown in Scheme 1. The bisabolane skeleton of
(þ)-1 and (þ)-2 would be synthesized by the regioselective ring-
opening reaction of (R)-epoxide 4. Required (R)-4 could be
obtained from (R)-a-hydroxy aldehyde 5, a key intermediate of
this synthetic plan. (R)-Configuration of 5 should be constructed
by the reaction of acetyl aminal 6 and aryl Grignard reagent 7
based on the stereochemical course of the reaction reported
previously.12
RO
R
O
(+)-1
(+)-2
+
BrMg
aqueous HCl in Et2O at 0 ꢂC for 15 h to afford
a-hydroxy alde-
ꢀ61.8 (c 1.0, CHCl3)), a key intermediate for
RO
29
hyde (ꢀ)-5a ([
a
]
(R = OR' or H)
D
4
a synthesis of (þ)-1 and (þ)-2, in 82% yield.
Reduction of (ꢀ)-5a with sodium borohydride in ethanol at
RO
OH
CHO
RO
25
room temperature for 30 min gave diol (ꢀ)-11 ([
a]
ꢀ3.1 (c 1.0,
D
MgBr
CHCl3)) in 83% yield. The enantiomeric excess of (ꢀ)-11 was 99% by
chiral HPLC analysis (Daicel Chiralcel OD-H). When the corre-
sponding lithium reagent 7b, prepared from bromide 9 and
RO
RO
5
7
butyllithium in Et2O at ꢀ78 ꢂC, was used in place of Grignard re-
+
22
agent 7a, (ꢀ)-5a ([
a
]
ꢀ49.2 (c 1.0, CHCl3)) was obtained in 74%
D
yield with 82% ee.
N
N
O
N
N
O
Primary hydroxy group of diol (ꢀ)-11 (99% ee) was tosylated by
TsCl in pyridine at room temperature for 4.5 h. The resulting crude
mono-tosylate was treated with NaH in THF at 0 ꢂC for 12 h affor-
ded almost pure epoxide 4a, which was used in the next step
without purification. When epoxide 4a was treated with 3-methyl-
3-triethylsiloxybutylmagnesium bromide (12a)15 in the presence of
CuI in THF at ꢀ10 ꢂC for 1 h, a mixture of bis-SEM ether 13a and
mono-SEM ether 14a was obtained. The mixture was separated by
column chromatography to give (þ)-13a and (þ)-14a in 52% and
47% yields from (ꢀ)-11, respectively.
Ph
Ph
H
H
OMe
(−)-3
Me
(−)-6
Scheme 1. Retrosynthetic analysis of (þ)-curcutetraol (1) and (þ)-sydonol (2).
The synthetic route of (þ)-1 is summarized in Scheme 2. Acetyl
aminal (ꢀ)-612 was obtained in 88% yield by the reaction of
methoxycarbonyl aminal (ꢀ)-3 and MeMgBr in the presence of
MgCl2 in THF at ꢀ78 ꢂC for 15 min.
Since the tertiary benzylic alcohol moiety at o-position of
a phenol is labile under acidic conditions,13 silyl ethers (tri-
ethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), or triisopropylsilyl
Removal of the SEM group and triethylsilyl (TES) group of
each (þ)-13a and (þ)-14a with an excess amount of
MgBr
OSEM
Ph
CHO
Me
CH2OH
HO Me
N
H
N
OSEM
7a
HO
N
N
OSEM
OSEM
a
c
d
N
N
HO
Me
O
O
Ph
Ph
b
OSEM
H
H
OMe
(–)-3
Me
OSEM
(–)-5a
[α]D29–61.8(c 1.0, CHCl3)
OSEM
(–)-11 99% ee
25–3.1(c 1.0, CHCl3)
(–)-6
OSEM
10
[α]D
OTES
BrMg
SEMO
RO
OH
OTES
h
HO
OH
OH
e, f
12a
O
g
SEMO
HO
SEMO
(+)-13a (R = SEM) [α]D21+6.1 (c 1.0, CHCl3)
4a
(+)-curcutetraol (1)
[α]D23+5.9 (c 0.74, MeOH)
+
(+)-14a (R = H)
[α]D20+3.55 (c 1.0, CHCl3)
Scheme 2. Reagents and conditions: (a) MgCl2, THF, reflux, 1 h, then MeMgBr, THF, ꢀ78 ꢂC, 88%; (b) 7a, THF, ꢀ78 ꢂC, 1 h; (c) 2% aq HCl, Et2O, 0 ꢂC, 15 h, 82% (from (ꢀ)-6); (d) NaBH4,
EtOH, rt, 30 min, 83%; (e) TsCl, pyridine, rt, 4.5 h; (f) NaH, THF, 0 ꢂC, 12 h; (g) 12a, CuI, THF, ꢀ10 ꢂC, 1 h, 99% (from (ꢀ)-11; (þ)-13a, 52% and (þ)-14a, 47%); (h) TBAF, MS 4 Å, THF,
reflux, 4–5 h, 80% from (þ)-13a and 87% from (þ)-14a.

S. Ito et al. / Tetrahedron 64 (2008) 9879–9884
9881
Br
Br
4. Experimental
4.1. General
OH
OH
OSEM
ref. 14
SEMCl, NaH
THF, rt, 24 h
All air-sensitive experiments were carried out under an atmo-
sphere of argon. IR spectra were recorded on an HORIBA FT-730
spectrometer. 1H and 13C NMR spectra were recorded on JEOL JNM-
EX-270 spectrometer using tetramethylsilane as an internal
standard. Optical rotations were measured on a JASCO P-1000 au-
tomatic polarimeter. HPLC analyses were carried out on JASCO in-
struments (pump, PU-2080 plus; detector, UV-2075). Elemental
analyses were carried out on a Vario EL III Elemental analyzer. TLC
analyses were done on silica-gel 60 F254-precoated aluminum
backed sheets (E. Merck). Preparative TLC was performed on silica-
gel-coated plates (Wakogel B-5F, 20 cmꢃ20 cm). Wakogel C-200
O
OH
OH
OSEM
78%
8
9
Scheme 3. Preparation of bromide 9.
tetrabutylammonium fluoride (TBAF) in the presence of MS 4 Å
(crushed, activated) in refluxing THF for 4–5 h gave (þ)-1 in 80%
and 87% yields, respectively. Addition of 4 Å molecular sieves was
effective to reduce the formation of the corresponding ethoxy-
methyl ether.16 The spectroscopic data (1H and 13C NMR, IR) of
23
synthetic (þ)-1 ([ D þ5.9 (c 0.74, MeOH)) were in good accordance
a
]
and Silica gel 60N (spherical, neutral, 63–210
column chromatography.
mm) were used for
20
with those reported for the natural (þ)-1 ([
a]
þ5.24 (c 0.74,
D
MeOH)5).
According to the similar procedure used in the reaction of ep-
oxide 4a and 12a, bis-SEM ether (þ)-13b and mono-SEM ether
(þ)-14b were obtained in 28% and 49% yields from (ꢀ)-11 (99% ee),
respectively, using 3-methylbutylmagnesium bromide (12b) in
place of 12a (Scheme 4). Removal of the SEM group of (þ)-14b with
an excess amount of TBAF (DMPU, 80 ꢂC, 1.5 h) gave (þ)-2 in 47%
yield. In this case, the addition of 4 Å molecular sieves in THF or the
reaction in DMPU was not effective to reduce the formation of the
corresponding ethoxymethyl ether (ca. 40%).16 The spectroscopic
data (1H and 13C NMR, IR) of synthetic (þ)-2 were in good accor-
4.2. 1-Bromo-2-(2-trimethylsilylethoxymethoxy)-4-(2-
trimethylsilylethoxymethoxymethyl)benzene (9)
To a stirred suspension of sodium hydride (60% mineral oil
dispersion, 0.720 g, 18.0 mmol), washed with hexane prior to use,
in THF (5.0 mL), 2-bromo-5-hydroxymethylphenol (8)14 (1.22 g,
6.0 mmol) in THF (8.0 mL) was added through a syringe at 0 ꢂC. The
reaction mixture was stirred at 0 ꢂC for 1 h. A solution of 2-trime-
thylsilylethoxymethyl chloride (2.50 g, 16.5 mmol) in THF (7.0 mL)
was added dropwise through a syringe to the solution. After the
reaction mixture was stirred at room temperature for 24 h, water
was added to the reaction mixture at 0 ꢂC. The organic layer was
separated and the aqueous layer was extracted with Et2O three
times. The combined organic layer was washed with brine, and
dried over anhydrous Na2SO4. After removal of the solvent under
reduced pressure, crude product was purified by silica-gel column
chromatography (hexane/CH2Cl2¼1:1) to give bromide 9 (2.17 g,
78%) as a colorless oil. IR (neat): nmax 2953, 2895, 1582, 1484, 1397,
dance with those reported for the natural (þ)-2,6 although the
24
specific rotation of the synthetic (þ)-2 ([
a
]
þ9.0 (c 1.0, MeOH))
D
20
was slightly larger than that of natural (þ)-2 ([
a
]
þ7.2 (c 1.0,
D
MeOH)6). The enantiomeric excess of (þ)-2 was confirmed to be
99% by chiral HPLC analysis (Daicel Chiralcel OD-H) of (þ)-15, de-
rived from (þ)-2 with TBDMSCl in the presence of imidazole in
DMF (54% yield). The enantiomeric excess of (þ)-15, derived from
22
(ꢀ)-5a ([
a]
ꢀ49.2 (c 1.0, CHCl3), 82% ee), was 82% by chiral HPLC
D
analysis (Daicel Chiralcel OD-H). These results showed that no ra-
cemization at the chiral tertiary benzylic alcohol moiety occurred in
this synthetic route.
1250 cmꢀ1
;
1H NMR (270 MHz, CDCl3):
d
(ppm) 7.50 (d, J¼7.9 Hz,
1H), 7.16 (d, J¼1.8 Hz, 1H), 6.88 (dd, J¼1.8, 7.9 Hz, 1H), 5.30 (s, 2H),
4.75 (s, 2H), 4.54 (s, 2H), 3.78–3.84 (m, 2H), 3.63–3.69 (m, 2H),
0.92–0.99 (m, 4H), 0.02 (s, 9H), 0.00 (s, 9H); 13C NMR (67.8 MHz,
CDCl3):
d (ppm) 153.7, 138.8, 133.0, 122.0, 115.3, 111.7, 94.2, 93.4,
3. Conclusion
68.6, 66.7, 65.3, 18.2, 18.0, ꢀ1.28. Anal. Calcd for C19H35BrO4Si2: C,
49.23; H, 7.61. Found: C, 49.17; H, 7.76.
In conclusion, the asymmetric total syntheses of (þ)-curcute-
traol (1) and (þ)-sydonol (2), phenolic bisabolane-type sesqui-
terpenoids, were accomplished with high enantiomeric excesses
4.3. (2R,5S)-2-Acetyl-3-phenyl-1,3-diazabicyclo-
(99% ee). The chiral tertiary benzylic alcohol moiety of
a
-hydroxy
[3.3.0]octane (6)
aldehyde (ꢀ)-5a, a key intermediate of the synthesis of (þ)-1 and
(þ)-2, was constructed by a stereoselective Grignard reaction of
acetyl aminal (ꢀ)-6, derived from easily available chiral methoxy-
carbonyl aminal (ꢀ)-3. Although the absolute configuration of
(ꢀ)-5a has not been determined directly, it is reasonable to assume
that the absolute configurations of both (þ)-1 and (þ)-2 are S by
analogy to results reported previously.12
A solution of methoxycarbonyl aminal (ꢀ)-3 (0.246 g, 1.0 mmol)
in THF (10 mL) was added to anhydrous magnesium chloride
(0.105 g, 1.1 mmol, dried prior to use at 100 ꢂC for 1 h under vac-
uum) through a syringe and the mixture was refluxed for 1 h. Then,
the reaction mixture was cooled to ꢀ78 ꢂC, and an Et2O solution
(1.4 M) of methylmagnesium bromide (1.4 mL, 2.0 mmol) was
BrMg
HO
SEMO
RO
OH
OH
d
a, b
12b
O
(−)-11
c
RO
SEMO
SEMO
[α]2D4+9.0 (c 1.0, MeOH)
(+)-13b (R = SEM) [α]D27+5.3 (c 1.0, CHCl3)
(+)-sydonol (2) (R = H)
(+)-15 (R = TBDMS) [α]D20+4.7 (c 1.0, CHCl3)
4a
e
+
(+)-14b (R = H)
[α]D27+3.9 (c 1.0, CHCl3)
Scheme 4. Reagents and conditions: (a) TsCl, pyridine, rt, 4.5 h; (b) NaH, THF, 0 ꢂC, 12 h; (c) 12b, CuI, THF, ꢀ10 ꢂC, 30 min, 77% (from (ꢀ)-11; (þ)-13b, 28% and (þ)-14b, 49%); (d)
TBAF, DMPU, 80 ꢂC, 1.5 h, 47% (from (þ)-14b); (e) TBDMSCl, imidazole, DMF, rt, 30 min, 54%.

9882
S. Ito et al. / Tetrahedron 64 (2008) 9879–9884
added dropwise through a syringe. The reaction was monitored
carefully by TLC and saturated aqueous NH4Cl was added to the
reaction mixture quickly after the disappearance of (ꢀ)-3 by TLC
(about 15 min after the end of the addition of the Grignard reagent).
The reaction mixture was then warmed to room temperature. After
the organic layer was separated, the aqueous layer was extracted
with Et2O three times. The combined organic layer was washed
with water and brine, and dried over anhydrous Na2SO4. After re-
moval of the solvent under reduced pressure, the crude product
was purified by silica-gel (spherical, neutral) column chromatog-
layer became <7. The organic layer was separated and the aqueous
layer was extracted with Et2O three times. The combined organic
layer was washed with water and brine, and dried over anhydrous
Na2SO4. After removal of the solvent under reduced pressure, the
crude product was purified by preparative TLC (hexane/Et2O¼1:2)
25
to afford diol (ꢀ)-11 (94.8 mg, 83%) as a colorless oil. [
a
]
ꢀ3.1 (c
D
1.0, CHCl3); IR (neat): nmax 3435, 2952, 2896, 1615, 1577, 1409, 1401,
1377, 1249 cmꢀ1 1H NMR (270 MHz, CDCl3):
;
d
(ppm) 7.42 (d,
J¼7.9 Hz, 1H), 7.15 (d, J¼1.5 Hz, 1H), 7.01 (dd, J¼7.9, 1.5 Hz, 1H), 5.32
(d, J¼6.9 Hz, 1H), 5.30 (d, J¼6.9 Hz, 1H), 4.75 (s, 2H), 4.56 (s, 2H),
3.97 (dd, J¼10.9, 5.3 Hz, 1H), 3.96 (s, 1H), 3.73–3.79 (m, 2H), 3.63–
3.70 (m, 3H), 2.03 (dd, J¼6.9, 5.3 Hz, 1H), 1.56 (s, 3H), 0.93–1.00 (m,
raphy (hexane/Et2O¼1:10) to give acetyl aminal (ꢀ)-6 (0.203 g,
25
88%) as a pale yellow oil. [
a
]
ꢀ46.9 (c 1.0, CHCl3); IR (neat): nmax
D
2965, 2872, 1713, 1599, 1505, 1351, 1157 cmꢀ1
CDCl3):
;
1H NMR (270 MHz,
4H), 0.02 (s, 9H), 0.00 (s, 9H); 13C NMR (67.8 MHz, CDCl3):
d (ppm)
d
(ppm) 7.21 (dd, J¼7.9, 7.6 Hz, 2H), 6.75 (t, J¼7.6 Hz, 1H),
154.4, 138.7, 131.6, 127.4, 121.0, 113.7, 94.1, 92.7, 75.1, 69.1, 68.8, 66.8,
6.48 (d, J¼7.9 Hz, 2H), 4.37 (s, 1H), 3.93 (ddd, J¼13.8, 7.3, 4.6 Hz,1H),
3.75–3.82 (m, 1H), 3.17–3.25 (m, 1H), 3.13 (dd, J¼8.6, 6.6 Hz, 1H),
2.81–2.86 (m, 1H), 2.12 (s, 3H), 2.10–2.14 (m, 1H), 1.67–1.97 (m, 3H);
65.2, 24.3, 18.1, 18.0, ꢀ1.31, ꢀ1.36. Anal. Calcd for C22H42O6Si2: C,
57.60; H, 9.23. Found: C, 57.24; H, 9.27.
25
The enantiomeric excess of (ꢀ)-11 ([
a
]
ꢀ3.1 (c 1.0, CHCl3)) was
D
13C NMR (67.8 MHz, CDCl3):
d
(ppm) 207.8, 145.5, 129.3, 117.5, 112.4,
99% by HPLC analysis using a chiral column (Daicel Chiralcel OD-H
(25 cmꢃ0.46 cm i.d.); 254 nm UV detector; eluent hexane/i-
PrOH¼97:3; flow rate 0.5 mL/min; tmajor 29.8 min, tminor 35.9 min).
86.5, 62.9, 55.0, 53.2, 30.5, 25.1, 24.33. Anal. Calcd for C14H18N2O: C,
73.01; H, 7.88; N, 12.16. Found: C, 73.29; H, 8.07; N, 12.06.
4.4. (L)-2-Hydroxy-2-[2-(2-trimethylsilylethoxymethoxy)-4-
(2-trimethylsilylethoxymethoxymethyl)phenyl]propanal (5a)
4.6. (D)-6-Triethylsilyloxy-6-methyl-2-[2-(2-trimethyl-
silylethoxymethoxy)-4-(2-trimethylsilylethoxymethoxy-
methyl)phenyl]heptan-2-ol (13a) and (D)-2-
To a stirred THF solution of 2-(2-trimethylsilylethoxymethoxy)-
4-(2-trimethylsilylethoxymethoxymethyl)phenylmagnesium bro-
mide (7a) prepared from bromide 9 (0.545 g, 1.2 mmol) and Mg
turnings (37.4 mg, 1.5 mmol) in refluxing THF (2.4 mL) for 30 min in
(1-hydroxy-5-triethylsilyloxy-1,5-dimethylhexyl)-5-(2-
trimethylsilylethoxymethoxymethyl)phenol (14a)
p-Toluenesulfonyl chloride (0.203 g, 1.06 mmol) was added to
a stirred solution of diol (ꢀ)-11 (0.244 g, 0.53 mmol) in pyridine
(1.1 mL). The reaction mixture was stirred at room temperature for
4.5 h. Water and saturated aqueous CuSO4 were added to the re-
action mixture. The mixture was extracted with Et2O three times.
The combined organic layer was washed with water (twice) and
brine, and dried over anhydrous Na2SO4. After removal of the sol-
vent under reduced pressure, the crude mono-tosylate was
obtained as a colorless oil (0.349 g) and used next step without
further purification.
To a stirred suspension of sodium hydride (60% mineral oil
dispersion, 64.2 mg, 1.6 mmol), washed with hexane prior to use, in
THF (1.0 mL), the crude mono-tosylate (0.349 g) in THF (4.5 mL)
was added through a syringe at 0 ꢂC. The reaction mixture was
stirred at 0 ꢂC for 12 h. Water was added to the reaction mixture,
and the organic layer was separated. The aqueous layer was
extracted with Et2O three times. The combined organic layer was
washed with brine, and dried over anhydrous Na2SO4. After re-
moval of the solvent under reduced pressure, almost pure epoxide
4a (0.235 g) was obtained as a yellow oil and used next step
without further purification.
To a stirred suspension of copper iodide (0.101 g, 0.53 mmol) in
THF (1.0 mL), an Et2O solution of 3-methyl-3-triethylsiloxy-
butylmagnesium bromide (12a), prepared from (3-bromo-1,1-
dimethylpropoxy)triethylsilane (1.49 g, 5.3 mmol) and Mg turnings
(0.154 g, 6.4 mmol) in Et2O (5.5 mL, containing a catalytic amount
of iodine) for 2 h,15 was added dropwise through a syringe at
ꢀ10 ꢂC. After the mixture was stirred at ꢀ10 ꢂC for 30 min, epoxide
4a (0.235 g) in THF (3.2 mL) was added dropwise through a syringe.
The reaction mixture was stirred at ꢀ10 ꢂC for 1 h. Saturated
aqueous NH4Cl and water were added to the reaction mixture. After
separation of the organic layer, the aqueous layer was extracted
with Et2O three times. The combined organic layer was washed
with brine, and dried over anhydrous Na2SO4. After removal of the
solvent under reduced pressure, the crude product was purified by
silica-gel column chromatography (hexane/Et2O¼from 5:1 to 1:1)
to afford bis-SEM ether (þ)-13a (0.176 g) in 52% overall yield from
diol (ꢀ)-11 as a colorless oil and mono-SEM ether (þ)-14a (0.128 g)
in 47% overall yield from diol (ꢀ)-11 as a colorless oil. Compound
the presence of
a small amount of 1,2-dibromoethane (ca.
0.3 mmol), acetyl aminal (ꢀ)-6 (0.136 g, 0.6 mmol) in THF (1.5 mL)
was added dropwise through a syringe at ꢀ78 ꢂC. The reaction
mixture was stirred at ꢀ78 ꢂC for 2 h. Saturated aqueous NH4Cl and
water were added to the reaction mixture. The aqueous layer was
extracted with Et2O three times. The combined organic layer was
washed with water and brine, and dried over anhydrous Na2SO4.
After removal of the solvent under reduced pressure, crude hydroxy
aminal 10 was obtained as a yellow oil. Dilute hydrochloric acid (2%,
6.0 mL) was added to a stirred solution of the resulting crude hy-
droxy aminal 10 in Et2O (6.0 mL), and stirring was continued at 0 ꢂC
for 15 h. The organic layer was separated and the aqueous layer was
extracted with Et2O three times. The combined organic layer was
washed with water and brine, and dried over anhydrous Na2SO4.
After removal of the solvent under reduced pressure, the residue
was purified by silica-gel column chromatography (hexane/
Et2O¼2:1) to afford -hydroxy aldehyde (ꢀ)-5a (0.220 g) in 82%
a
29
overall yield from (ꢀ)-6 as a colorless oil. [
IR (neat): nmax 3450, 2952, 2896, 1739 cmꢀD1
a]
ꢀ61.8 (c 1.0, CHCl3);
;
1H NMR (270 MHz,
CDCl3):
d
(ppm) 9.76 (s, 1H), 7.47 (d, J¼7.9 Hz, 1H), 7.13 (d, J¼1.6 Hz,
1H), 7.03 (dd, J¼7.9, 1.6 Hz, 1H), 5.25 (d, J¼6.9 Hz, 1H), 5.23 (d,
J¼6.9 Hz, 1H), 4.74 (s, 2H), 4.57 (s, 2H), 4.06 (s, 1H), 3.63–3.74 (m,
4H), 1.65 (s, 3H), 0.91–0.98 (m, 4H), 0.01 (s, 9H), ꢀ0.01 (s, 9H); 13
C
NMR (67.8 MHz, CDCl3):
d (ppm) 200.7, 154.1, 140.2, 128.5, 127.2,
121.1, 113.4, 94.2, 92.8, 78.0, 68.7, 66.8, 65.3, 21.7, 18.2, 18.0, ꢀ1.31,
ꢀ1.36. Anal. Calcd for C22H40O6Si2: C, 57.85; H, 8.83. Found: C,
57.99; H, 9.09.
4.5. (L)-2-[2-(2-Trimethylsilylethoxymethoxy)-4-
(2-trimethylsilylethoxymethoxymethyl)phenyl]-
propane-1,2-diol (11)
Sodium borohydride (10.1 mg, 0.28 mmol) was added to a stir-
red solution of
a
-hydroxy aldehyde (ꢀ)-5a (0.114 g, 0.25 mmol) in
ethanol (0.75 mL) at room temperature. The reaction mixture was
stirred at the same temperature for 15 min. Water was added to
quench the reaction. The mixture was diluted with Et2O and dilute
hydrochloric acid (about 0.7%) was added until pH of the aqueous

S. Ito et al. / Tetrahedron 64 (2008) 9879–9884
9883
21
(þ)-13a: [
2875, 1614, 1577, 1502, 1460, 1380, 1250 cmꢀ1
CDCl3):
a
]
þ6.1 (c 1.0, CHCl3); IR (neat): nmax 3469, 2953, 2911,
a colorless oil and mono-SEM ether (þ)-14b (72.2 mg) in 49%
D
;
1H NMR (270 MHz,
overall yield from diol (ꢀ)-11 as a colorless oil. Compound (þ)-13b:
27
d
(ppm) 7.27 (d, J¼7.9 Hz, 1H), 7.13 (d, J¼1.6 Hz, 1H), 6.95
[a
]
þ5.3 (c 1.0, CHCl3); IR (neat): nmax 3503, 2953, 2898,
D
(dd, J¼7.9, 1.6 Hz, 1H), 5.32 (d, J¼7.1 Hz, 1H), 5.29 (d, J¼7.1 Hz, 1H),
4.75 (s, 2H), 4.55 (s, 2H), 3.91 (s, 1H), 3.74–3.81 (m, 2H), 3.63–3.70
(m, 2H), 1.80–1.90 (m, 2H), 1.57 (s, 3H), 1.22–1.34 (m, 4H), 1.13 (s,
3H), 1.12 (s, 3H), 0.93–1.01 (m, 4H), 0.88 (t, J¼7.9 Hz, 9H), 0.50 (q,
J¼7.9 Hz, 6H), 0.03 (s, 9H), 0.00 (s, 9H); 13C NMR (67.8 MHz,
1250 cmꢀ1
;
1H NMR (270 MHz, CDCl3):
d
(ppm) 7.28 (d, J¼7.9 Hz,
1H), 7.13 (d, J¼1.6 Hz, 1H), 6.96 (dd, J¼7.9, 1.6 Hz, 1H), 5.32 (d,
J¼7.1 Hz, 1H), 5.29 (d, J¼7.1 Hz, 1H), 4.75 (s, 2H), 4.56 (s, 2H), 3.82 (s,
1H), 3.74–3.80 (m, 2H), 3.63–3.71 (m, 2H),1.73–1.99 (m, 2H), 1.56 (s,
3H),1.42–1.53 (m, 1H),1.08–1.27 (m, 4H), 0.93–1.01 (m, 4H), 0.81 (d,
J¼6.6 Hz, 6H), 0.03 (s, 9H), 0.00 (s, 9H); 13C NMR (67.8 MHz, CDCl3):
CDCl3):
d (ppm) 154.6, 137.9, 134.4, 126.7, 120.8, 113.6, 94.1, 92.8,
75.1, 73.3, 68.9, 66.8, 65.2, 45.4, 42.9, 29.9, 29.8, 27.4, 19.4, 18.2,
d (ppm) 154.6, 138.0, 134.5, 126.8, 120.8, 113.7, 94.2, 92.8, 75.1, 69.0,
18.0, 7.21, 6.80, ꢀ1.28. Anal. Calcd for C33H66O6Si3: C, 61.63; H,
66.8, 65.3, 42.6, 39.5, 27.9, 27.7, 22.7, 22.3, 18.2, 18.1, ꢀ1.26, ꢀ1.29.
20
10.34. Found: C, 61.85; H, 10.73. Compound (þ)-14a: [
a]
þ3.55
Anal. Calcd for C27H52O5Si2: C, 63.23; H, 10.22. Found: C, 63.31; H,
D
27
(c 1.0, CHCl3); IR (neat): nmax 3271, 2953, 2912, 2876, 1629, 1577,
10.34. Compound (þ)-14b: [
a
]
þ3.9 (c 1.0, CHCl3); IR (neat): nmax
D
1512, 1458, 1381, 1250 cmꢀ1 1H NMR (270 MHz, CDCl3):
;
d
(ppm)
3273, 2952, 1577, 1374, 1250, 1158, 1104 cmꢀ1
;
1H NMR (270 MHz,
9.31 (s, 1H), 6.95 (d, J¼7.9 Hz, 1H), 6.82 (d, J¼1.6 Hz, 1H), 6.77 (dd,
J¼7.9, 1.6 Hz, 1H), 4.73 (s, 2H), 4.50 (s, 2H), 3.63–3.69 (m, 2H),
3.03 (s, 1H), 1.75–1.95 (m, 2H), 1.61 (s, 3H), 1.30–1.48 (m, 4H), 1.16
(s, 3H), 1.15 (s, 3H), 0.86–0.99 (m, 11H), 0.52 (q, J¼7.8 Hz, 6H), 0.02
(s, 9H); 13C NMR (67.8 MHz) 155.9, 138.5, 128.9, 126.1, 118.6, 116.8,
94.0, 78.7, 73.4, 68.7, 65.2, 44.8, 42.8, 30.0, 29.8, 29.0, 18.9, 18.2,
7.18, 6.77, ꢀ1.29. Anal. Calcd for C27H52O5Si2: C, 63.23; H, 10.22.
Found: C, 63.23; H, 10.60.
CDCl3):
d
(ppm) 9.21 (s, 1H), 6.96 (d, J¼7.9 Hz, 1H), 6.83 (d, J¼1.6 Hz,
1H), 6.79 (dd, J¼7.9, 1.6 Hz, 1H), 4.73 (s, 2H), 4.51 (s, 2H), 3.64–3.70
(m, 2H), 2.72 (s, 1H), 1.71–1.89 (m, 2H), 1.61 (s, 3H), 1.46–1.51 (m,
1H), 1.09–1.35 (m, 4H), 0.93–0.99 (m, 2H), 0.83 (d, J¼6.6 Hz, 6H),
0.03 (s, 9H); 13C NMR (67.8 MHz, CDCl3):
d (ppm) 155.9,138.6,128.9,
126.1, 118.6, 116.8, 94.0, 78.6, 68.8, 65.3, 42.9, 39.1, 29.1, 27.8, 22.7,
22.6, 21.8, 18.2, ꢀ1.28. Anal. Calcd for C21H38O4Si: C, 65.92; H, 10.01.
Found: C, 65.73; H, 10.35.
4.7. (D)-Curcutetraol (1)
4.9. (D)-Sydonol (2)
Tetrabutylammonium fluoride hydrate (0.524 g) in benzene
(2 mL) was evaporated under reduced pressure five times to
remove water azeotropically and dried under vacuum. A crushed
4 Å MS (ca. 60 mg), activated at 120 ꢂC under vacuum for 5 h, and
THF (0.5 mL) were added. A solution of bis-SEM ether (þ)-13a
(0.129 g, 0.20 mmol) in THF (1.5 mL) was added to the mixture at
room temperature and the mixture was refluxed for 5 h. After
water and Et2O were added to the reaction mixture and the organic
layer was separated, the aqueous layer was extracted with Et2O four
times. The combined organic layer was washed with brine, and
dried over anhydrous Na2SO4. After removal of the solvent under
reduced pressure, crude product was purified by silica-gel (spher-
ical, neutral) column chromatography (Et2O to Et2O/MeOH¼5:1) to
afford (þ)-curcutetraol (1) (42.7 mg, 80%) as a brownish oil. When
mono-SEM ether (þ)-14a (51.5 mg, 0.10 mmol) was treated with
tetrabutylammonium fluoride hydrate (0.264 g, water was re-
moved in the same manner as described above) for 4 h in the same
Tetrabutylammonium fluoride hydrate (0.799 g) in benzene
(2 mL) was evaporated under reduced pressure three times to
remove water azeotropically and dried under vacuum. A solution of
mono-SEM ether (þ)-14b (72.2 mg, 0.19 mmol) in 1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (1.9 mL) was
added through a syringe to tetrabutylammonium fluoride. The re-
action mixture was stirred at 80 ꢂC for 1.5 h. Water and Et2O were
added to the reaction mixture. The organic layer was separated and
the aqueous layer was extracted with Et2O three times. The com-
bined organic layer was washed with water and brine, and dried
over anhydrous Na2SO4. After removal of the solvent under reduced
pressure, crude product was purified by silica-gel column chro-
matography (hexane/Et2O¼1:3) to afford (þ)-sydonol (2) (47.6 mg,
24
47%) as a colorless oil. [
a
]
þ9.0 (c 1.0, MeOH); IR (neat): nmax 3305,
D
2952, 1628, 1577, 1512 cmꢀ1 1H NMR (270 MHz, CDCl3):
; d (ppm)
6.97 (d, J¼7.6 Hz, 1H), 6.73–6.83 (m, 2H), 4.56 (s, 2H), 1.73–1.97 (m,
2H), 1.62 (s, 3H), 1.36–1.58 (m, 1H), 1.09–1.36 (m, 4H), 0.83 (d,
way, (þ)-1 (23.4 mg, 87%) was obtained as a brownish oil.
J¼6.6 Hz, 6H); 13C NMR (67.8 MHz, CDCl3):
d (ppm) 155.8, 141.4,
129.1, 126.3, 117.9, 115.9, 78.5, 64.8, 42.9, 39.1, 28.9, 27.9, 22.6, 21.8.
Anal. Calcd for C15H24O3: C, 71.39; H, 9.59. Found: C, 71.48; H, 9.89.
23
(þ)-Curcutetraol (1): [
a]
þ5.9 (c 0.74, MeOH); IR (neat): nmax 3337,
D
2971, 1625, 1577, 1513, 1376, 1297, 1266, 1167, 1021 cmꢀ1
(270 MHz, CD3OD):
;
1H NMR
d
(ppm) 7.10 (d, J¼7.7 Hz, 1H), 6.78 (d, J¼1.6 Hz,
1H), 6.75 (br s, 1H), 4.50 (s, 2H), 1.70–1.98 (m, 2H), 1.57 (s, 3H), 1.20–
4.10. (D)-2-(1-Hydroxy-1,5-dimethylhexyl)-5-tert-
butyldimethylsiloxymethylphenol (15)
1.48 (m, 4H), 1.10 (s, 3H), 1.09 (s, 3H); 13C NMR (67.8 MHz, CD3OD):
d
(ppm) 156.7, 142.6, 131.1, 127.4, 118.6, 116.0, 77.9, 71.4, 64.8, 45.1,
44.4, 29.1, 20.1.
To a solution of (þ)-2 (27.2 mg, 0.11 mmol) in DMF (1.1 mL),
imidazole (23.3 mg, 0.32 mmol) was added at 0 ꢂC and the mixture
was stirred at room temperature for 10 min. Then a solution of tert-
butyldimethylsilyl chloride (TBDMSCl) (51.1 mg, 0.34 mmol) in
DMF (0.6 mL) was added to the mixture. The reaction mixture was
stirred at room temperature for 30 min. Water and Et2O were
added to the reaction mixture, and the organic layer was separated.
The aqueous layer was extracted with Et2O three times. The com-
bined organic layer was washed with water and brine, and dried
over anhydrous Na2SO4. After removal of the solvent under reduced
pressure, crude product was purified by silica-gel column chro-
4.8. (D)-6-Methyl-2-[2-(2-trimethylsilylethoxymethoxy)-4-
(2-trimethylsilylethoxymethoxymethyl)phenyl]heptan-2-ol
(13b) and (D)-2-(1-hydroxy-1,5-dimethylhexyl)-5-(2-
trimethylsilylethoxymethoxymethyl)phenol (14b)
3-Methylbutylmagnesium bromide (12b) was prepared from
1-bromo-3-methylbutane (1.51 g, 10 mmol) and Mg turnings
(0.268 g, 11 mmol) in Et2O (10 mL) for 3 h in the presence of a small
amount of iodine.
According to the similar procedure used for the preparation of
(þ)-13a and (þ)-14a, almost pure epoxide 4a (0.159 g) prepared
from diol (ꢀ)-11 (0.176 g, 0.38 mmol) was treated with 3-methyl-
butylmagnesium bromide (12b) (0.78 mL). The crude product was
purified by preparative TLC (hexane/Et2O¼2:1) to afford bis-SEM
ether (þ)-13b (55.9 mg) in 28% overall yield from diol (ꢀ)-11 as
matography (hexane/Et2O¼3:1) to afford (þ)-15 (21.5 mg, 54%) as
20
a colorless oil. [
a]
þ4.7 (c 1.0, CHCl3); IR (neat): nmax 3300, 2953,
D
2858, 1629, 1578, 1512, 1462 cmꢀ1 1H NMR (270 MHz, CDCl3):
;
d
(ppm) 9.08 (s, 1H), 6.95 (d, J¼7.9 Hz, 1H), 6.83 (d, J¼2.0 Hz, 1H),
6.78 (dd, J¼7.9, 2.0 Hz, 1H), 4.67 (s, 2H), 2.24 (s, 1H), 1.73–1.94 (m,
2H), 1.64 (s, 3H), 1.43–1.55 (m, 1H), 1.10–1.37 (m, 4H), 0.94 (s, 9H),

9884
S. Ito et al. / Tetrahedron 64 (2008) 9879–9884
0.83 (d, J¼6.6 Hz, 6H), 0.10 (s, 6H); 13C NMR (67.8 MHz, CDCl3):
Rajbhandari, I.; Gerwick, W.; Hamann, M.; Nagle, D. J. Nat. Prod. 2003, 66,
605–608.
d
(ppm) 155.8, 142.2, 127.9, 125.9, 116.8, 115.0, 78.8, 64.5, 42.9, 39.1,
4. (a) Imai, S.; Morikiyo, M.; Furihata, K.; Hayakawa, Y.; Seto, H. Agric. Biol. Chem.
1990, 54, 2367–2371; (b) Nanba, R.; Isozaki, M.; Endo, I.; Yomo, Y. Jpn. Kokai
Tokkyo Koho, Jpn. Pat. Appl. JP 89-60236 19890313; Chem. Abstr. 1990, 114,
121718; (c) Aguilar, M.; Delgado, G. Nat. Prod. Lett. 1995, 7, 155–162; (d) Aguilar,
M. I.; Delgado, G.; Hernanadez, M.; Villarreal, M. L. Nat. Prod. Lett. 2001, 15, 93–
101; (e) Kim, S.; Hong, K.; Chung, W.; Hwang, J.; Park, K. Toxicol. Appl. Phar-
macol. 2004, 196, 346–355.
29.1, 27.9, 26.1, 22.7, 22.6, 21.8,18.6, ꢀ5.1. Anal. Calcd for C21H38O3Si:
C, 68.80; H, 10.45. Found: C, 68.74; H, 10.54.
The enantiomeric excess of (þ)-15 was determined to be 99% by
chiral HPLC analysis (Daicel Chiralcel OD-H (25 cmꢃ0.46 cm i.d.);
254 nm UV detector; eluent hexane/i-PrOH¼98.5:1.5; flow rate
0.5 mL/min; tmajor 18.7 min, tminor 24.3 min).
5. Mu¨lhaupt, T.; Kaspar, H.; Otto, S.; Reichert, M.; Bringmann, G.; Lindel, T. Eur.
J. Org. Chem. 2005, 334–341.
6. Nukina, M.; Sato, Y.; Ikeda, M.; Sassa, T. Agric. Biol. Chem. 1981, 45, 789–790.
7. Hamasaki, T.; Nagayama, K.; Hatsuda, Y. Agric. Biol. Chem. 1978, 42, 37–40.
8. (a) Henne, P.; Thiericke, R.; Grabley, S.; Hu¨tter, K.; Wink, J.; Jurkiewicz, E.; Zeeck,
A. Liebigs Ann. Chem. 1993, 565–571; (b) Zeeck, A.; Henne, P.; Grabley, S.; Wink,
J; Hutter, K.; Thiericke, R.; Haenel, H. Ger. Offen. DE 4231451, 1994; Chem. Abstr.
1994, 121, 7444.
9. Yu, D. Q.; Xie, F. Z.; Chen, Y.; Huang, Y. H. Chin. Chem. Lett. 1996, 7, 721–722.
10. (a) Fuganti, C.; Serra, S. J. Chem. Soc., Perkin Trans. 1 2000, 3758–3764; (b) Ono,
M.; Ogura, Y.; Hatogai, K.; Akita, H. Chem. Pharm. Bull. 2001, 12, 1581–1585; (c)
Kimachi, T.; Takemoto, Y. J. Org. Chem. 2001, 66, 2700–2704; (d) Singh, V.;
Khurana, A.; Kaur, I.; Sapehiyia, V.; Kad, G.; Singh, J. J. Chem. Soc., Perkin Trans. 1
2002, 1766–1768; (e) Harmata, M.; Hong, X.; Barnes, C. Tetrahedron Lett. 2003,
44, 7261–7264; (f) Lu, J.; Xie, X.; Chen, B.; She, X.; Pan, X. Tetrahedron: Asym-
metry 2005, 16, 1435–1438; (g) Kim, S. G.; Kim, J.; Jung, H. Tetrahedron Lett.
2005, 46, 2437–2439; (h) Kamal, A.; Malik, M. S.; Shaik, A. A.; Azeeza, S. Tet-
rahedron: Asymmetry 2007, 18, 2547–2553.
11. Zhang, C.; Ito, S.; Hosoda, N.; Asami, M. Tetrahedron Lett. 2008, 49, 2552–2554.
12. Mukaiyama, T.; Sakito, Y.; Asami, M. Chem. Lett. 1979, 705–708.
13. Miyazaki, H.; Honda, K.; Asami, M.; Inoue, S. J. Org. Chem. 1999, 64, 9507–9511.
14. (a) Buehler, C. A.; Harris, J. O.; Shacklett, C.; Block, B. P. J. Am. Chem. Soc. 1946, 68,
574–577; (b) Canceill, J.; Collet, A. New J. Chem. 1986, 10, 17–23.
15. (a) Taber, D. F.; Joerger, J.-M. J. Org. Chem. 2007, 72, 3454–3457; (b) Fall, Y.;
Vitale, C.; Mourin˜o, A. Tetrahedron Lett. 2000, 41, 7337–7340; (c) Andrews,
D. R.; Barton, D. H. R.; Hesse, R. H.; Pechet, M. M. J. Org. Chem. 1986, 51, 4819–
4828.
Acknowledgements
We wish to thank Professor Manabu Nukina (Yamagata Uni-
versity) for providing spectra of natural (þ)-sydonol (2). We are
grateful to Mr. Shinji Ishihara (Instrumental Analysis Center of
Yokohama National University) for his technical assistance in the
elemental analyses.
References and notes
1. (a) Wright, A. E.; Pomponi, S. A.; McConnell, O. J.; Kohmoto, S.; McCarthy, P. J.
J. Nat. Prod. 1987, 50, 976–978; (b) Fusetani, N.; Sugano, M.; Matsunaga, S.;
Hashimoto, K. Experientia 1987, 43, 1234–1235; (c) Butler, M. S.; Capon, R. J.;
Nadeson, R.; Beveridge, A. A. J. Nat. Prod. 1991, 54, 619–623; (d) El Sayed, K. A.;
Yousaf, M.; Hamann, M. T.; Avery, M. A.; Kelly, M.; Wipf, P. J. Nat. Prod. 2002, 65,
1547–1553; (e) Peng, J.; Franzblau, S. G.; Zhang, F.; Hamann, M. T. Tetrahedron
Lett. 2002, 43, 9699–9702; (f) Tasdemir, D.; Bugni, T. S.; Mangalindan, G. C.;
Concepcion, G. P.; Harper, M. K.; Ireland, C. M. Turk. J. Chem. 2003, 27, 273–279.
2. (a) McEnroe, F. J.; Fenical, W. Tetrahedron 1978, 34, 1661–1664; (b) Bohlmann,
F.; Lonitz, M. Chem. Ber. 1978, 111, 843–852; (c) Ghisalberti, E. L.; Jefferies, P. R.;
Stuart, A. D. Aust. J. Chem. 1979, 32, 1627–1630; (d) D’Armas, H. T.; Mootoo, B. S.;
Reynolds, W. F. J. Nat. Prod. 2000, 63, 1593–1595.
16. (a) Lipshutz, B. H.; Miller, T. A. Tetrahedron Lett. 1989, 30, 7149–7152; (b) Kan, T.;
Hashimoto, M.; Yanagiya, M.; Shirahama, H. Tetrahedron Lett. 1988, 29, 5417–
5418.
3. (a) Gul, W.; Hammond, N. L.; Yousaf, M.; Peng, J.; Holley, A.; Hamann, M. T.
Biochim. Biophys. Acta 2007, 1770, 1513–1519; (b) Takamatsu, S.; Hodges, T.;