Total synthesis of curvulone B and a proposed structure for dothiorelone B; Determination of the configuration of curvulone B and structural revision of phomopsin A

Article abstract of DOI:10.1016/j.tetasy.2012.06.009

The total synthesis of curvulone B was achieved, and its absolute configuration unambiguously established, as had been determined by TD-DFT ECD calculations on the computed solution conformers. Key features of the synthesis were an olefin cross-metathesis of an α,β-unsaturated ketone as a common key building block with (R)-6-triethylsilyloxyhept-1-ene, and an intramolecular oxy-Michael addition of the hydroxyl enone obtained therefrom. An intermolecular metathesis of the enone with (S)-5-benzyloxyhept-ene also enabled us to prepare a proposed structure for dothiorelone B, thus leading to the confirmation of the structural revision of phomopsin A, a novel nine-membered cyclic phenol ether.2012 Elsevier Ltd.

Full text of DOI:10.1016/j.tetasy.2012.06.009

Tetrahedron: Asymmetry 23 (2012) 952–958
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of curvulone B and a proposed structure for dothiorelone
B; determination of the configuration of curvulone B and structural revision
of phomopsin A
⇑
Shunya Takahashi , Yuki Akita, Takemichi Nakamura, Hiroyuki Koshino
RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 April 2012
Accepted 6 June 2012
The total synthesis of curvulone B was achieved, and its absolute configuration unambiguously estab-
lished, as had been determined by TD-DFT ECD calculations on the computed solution conformers. Key
features of the synthesis were an olefin cross-metathesis of an
a,b-unsaturated ketone as a common
key building block with (R)-6-triethylsilyloxyhept-1-ene, and an intramolecular oxy-Michael addition
of the hydroxyl enone obtained therefrom. An intermolecular metathesis of the enone with (S)-5-benzyl-
oxyhept-ene also enabled us to prepare a proposed structure for dothiorelone B, thus leading to the
confirmation of the structural revision of phomopsin A, a novel nine-membered cyclic phenol ether.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
A 208 should also be revised to 2 from the originally proposed oxo-
nine derivative. However, the fact that both data reported for 20
Marine microorganisms have proven to be rich sources of novel
secondary metabolites with biological activities such as antitumor,
antifungal, and cytotoxic effects.1 Among them, certain plant-asso-
ciated fungi produce a series of 2-alkyl-(3,5-dihydroxy)phenylace-
tic acid derivatives.2
and 2 were not completely identical still made this proposal
ambiguous.10 For confirmation of this, the synthesis of 2 and its
extensive NMR analysis were necessary. Described herein is the to-
tal synthesis of curvulone B 1 and 2 via a common key intermedi-
ate 7, thus establishing the absolute configuration of 1 as well as a
confirmation of the structural revision of phomopsin A 20 into 2.
Curvulone B 1 is the first derivative to be reported that bears a
tetrahydropyran (THP) ring, which was isolated from Curvularia sp.
obtained from the marine alga Gracilaria folifera by Krohn and
Kurtán et al. (Fig. 1).3 The planar structure was determined by
2D NMR spectra, while the absolute configuration was deduced
by comparison of the experimental ECD spectra in acetonitrile with
the Boltzmann-averaged spectrum calculated using a TD-DFT
method4 for the solution conformers.5 Compound 1 shows strong
antibacterial and antifungal activities, and potency is reported to
be comparable to those of curvularin macrolides. Dothiorelone B
was isolated from the mangrove endophytic fungus Dothiorella
sp. HTF3 by Su et al.6,7 and its structure was reported to be 2, based
on NMR and MS analyses. This compound was shown to have cyto-
toxicity against KB, Raji, and Mg-63 cancer cells but no significant
antibacterial activities.
2. Results and discussion
2.1. Synthetic plan
In the synthetic study of 1, the construction of the cis-tetrahy-
dropyran ring was the key step. Since the ether ring is located at
the b-position of the keto carbonyl group, we planned to utilize
an intramolecular oxy-Michael addition of e-hydroxy a,b-unsatu-
rated enone 3 (Scheme 1). This compound would be synthesized
by the olefin cross-metathesis11 of vinyl ketone 7 with a terminal
olefin 5. Removal of a C2 carbon unit from 7 and reduction of the
carbonyl function led to the known benzaldehyde derivative 8.
Recently, we achieved the total synthesis of the proposed struc-
ture for phomopsin B,8 and revealed that its real structure was not
a 4,5,6,7-tetrahydro-2H-benzo[b]oxecin-8(3H)-one derivative but
a phenylacetic acid derivative carrying a long side chain such as
2.9 In that paper, we suggested that the structure of phomopsin
HO
O
HO
O
15
11
14
O
2
CO2Me
2
CO2Et
OH
HO
HO
1
2
⇑
Corresponding author. Fax: +81 48 462 4627.
E-mail address: shunyat@riken.jp (S. Takahashi).
Figure 1. Curvulone B 1 and a proposed structure 2 for dothiorelone B.
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.06.009

S. Takahashi et al. / Tetrahedron: Asymmetry 23 (2012) 952–958
953
CO2Me
CH(OMe)2
CHO
HO
O
HO
O
vinyl MgCl,
THF, 0 °C
CO2Me
O
CO2Me
CO2Et
OH
98%
HO
HO
HO
OH
BnO
OBn
1
2
8
9
OTES
MeO
MeO
MeO
5
BnO
O
BnO
O
HO
MeO
TPAP, NMMO,
Grubbs cat. 2nd,
CH2Cl2, 45 °C
MS 4Å, CH2Cl2, rt
O
OH
OBn
CH(OMe)2 OBn
CH(OMe)2
84%
78%
BnO
O
BnO
BnO
OBn
BnO
3
5
4
10
7
TESO
OTES
12
MeO
MeO
MeO
BnO
OBn
6
MeO
HO
CH(OMe)2
a) TBAF, THF, rt
63%
O
O
BnO
7
BnO
OBn
BnO
OBn
11
a) and b)
3
HO
(without separation)
CO2Me
CO2Me
MeO
MeO
MeO
HO
MeO
O
O
8
1) Jones'oxidation, 0 °C
2) CH2N2, Et2O, rt
O
O
+
Scheme 1. Synthetic plan for 1 and 2.
75%
BnO
OBn
BnO
OBn
34%
12
31%
13
b) t-BuOK, THF, rt, 87%
Similarly, retrosynthetic analysis of structure 2 can revert it to the
corresponding dimethylacetal 4, and then 7 and 6. Considering the
fact that both the absolute configuration of the natural product and
its specific rotation value were not reported, we tentatively se-
lected (S)-6 as the terminal olefin part because the chiral olefin
MeO2C
BnO
O
HO
O
20% Pd(OH)2,
H2, EtOAc, rt
88%
O
O
seemed to be obtainable from L-malic acid.
CO2Me
OBn
HO
2.2. Total synthesis of curvulone B
14
1
Scheme 2. Total synthesis of curvulone B 1.
The synthesis of 1 began with the vinylation of aldehyde 9,
which was prepared from 8 according to a method described pre-
viously (Scheme 2).9 The resulting alcohol 10 was oxidized with
tetra-n-propylammonium perruthenate (TPAP) in the presence of
N-methylmorpholine N-oxide (NMO) to give the key intermediate
7 in good yield. Olefin cross-metathesis of 7 with a (R)-hept-6-en-
2-ol derivative was examined under a variety of conditions. Since
this coupling reaction did not proceed for the hydroxy-free olefin,
an acyl or silyl group was employed for hydroxy protection with
the expectation of deprotection followed by the oxy-Michael reac-
tion under basic conditions. We found that triethylsilyl (TES) was
the protecting group of choice for this purpose.12 The coupling
reaction of 7 and the TES derivative 513 in dichloromethane was
performed in the presence of Grubbs 2nd generation catalyst14 at
45 °C, giving the desired product 11 in good yield. Due to the low
reactivity of the cross-conjugated enone 7 and a facile formation
of the homo-dimer of 5, the addition of 5 (0.5 equiv) and the cata-
lyst (0.025 equiv) at 0.5 h intervals was required for a highly effi-
cient conversion. As expected, the deprotection reaction of the
TES group with TBAF in tetrahydrofuran was accompanied by an
oxy-Michael reaction to provide a mixture of trans-THP derivative
12 and its cis-isomer 13 in moderate yield (60–70%) with a ratio of
ca. 2:1 (trans/cis) after a few hours.15 We found that a prolonged
reaction time promoted epimerization at the C-11 position and
that the ratio reached ca. 1:1 after 18 h. The use of the TBAF solu-
tion dried over MS 4 Å16 dramatically shortened the reaction time
(30 min) but the yield was not improved. Each stereoisomer could
be separated by chromatography on silica gel, and the stereochem-
istry was established by the NMR analyses together with the differ-
ence NOE experiments.17 Brief treatment of 12 with t-BuOK caused
an isomerization to efficiently give 13 as a single isomer. Ulti-
mately, the stereoisomeric mixture obtained by TBAF treatment
of 11 was, without separation, isomerized with the base, to give
the cis-isomer 13 in good overall yield. The transformation of the
dimethylacetal moiety in 13 into the corresponding carboxylic acid
group in a one pot manner was achieved by Jones reagent in ace-
tone to furnish the corresponding methyl ester 14 after methyla-
tion with diazomethane. Finally, 14 was hydrogenated over
Pd(OH)2 under a hydrogen atmosphere to give 1 in high yield.
The spectroscopic data and physical properties were identical to
those of the natural product, thus establishing the absolute config-
uration of natural curvulone B 1.
2.3. Synthesis of (S)-2 and structural revision of phomopsin A 20
The synthesis of (S)-2 started from preparation of (S)-6
(Scheme 3). Initially, the epoxide 1518 obtained from
L-malic acid
was submitted to allylation,19 and the resulting compound 16
was transformed into alcohol 17 via a protection-deprotection se-

954
S. Takahashi et al. / Tetrahedron: Asymmetry 23 (2012) 952–958
allyltributyltin, MeLi, LiCl,
CuCN, THF, -78 -> -40 °C
of the C–C double bond at the side chain, a stepwise procedure was
adopted. Thus, the dimethylacetal moiety was hydrolyzed with
lithium tetrafluoroborate in aq acetonitrile, and the resulting alde-
hyde was oxidized with sodium chlorite to provide ethyl ester 19
after ethylation. Finally, all benzyl groups were removed by
hydrogenolysis to give (S)-2. We carried out extensive NMR analy-
ses of it and the results are listed in Table 1. By comparison of its
NMR data with those of the natural product reported, it was re-
vealed that there were some inconsistent signals. In the 1H NMR
data of the natural product, there were no signals corresponding
to the methylene protons at the b-position of the C-9 carbonyl in
the acyclic side chain,20 which would be observed at ca.
1.72 ppm based on the chemical shifts for H-11 of (S)-2. In the
13C NMR data of natural dothiorelone B, there were two missing
signals for C-11 at d 24.7 and C-18 at d 14.1 of (S)-2, and an addi-
tional signal at 29.7 ppm for the two carbons of C-15 and 18.21 The
assignments for C-5 and 7 were opposite to our results. Based on
the present data, it should be mentioned that the real structure
of dothiorelone B closely resembles that of (S)-2. However, there
is a discrepancy in the NMR data for the natural product and com-
pound (S)-2. These results prevent us from unequivocally stating
that the structure of natural dothiorelone B is 2. In order to clarify
this, a direct comparison of our synthetic sample with the authen-
tic natural product is necessary. On the other hand, the NMR data
of (S)-2 matched well with those of the compound reported as pho-
mopsin A 20. Although the molecular formula of natural phomop-
sin A was determined to be C18H24O5 by HR-EIMS at m/z 320.1610
(calcd 320.1618), the data would be explained as being those of the
corresponding dehydration product,22 thus establishing that the
structure of phomopsin A is that of 2 (a proposed structure for
dothiorelone B) as suggested by us previously.9
83%
O
OH
OTBDPS
OTBDPS
15
16
1) benzyl 2,2,2-trichloroacetimidate,
TfOH, c-hex-CH2Cl2, 0 °C
2) TBAF, THF, rt
LiBHEt3, THF, 0 °C -> rt
80%
74%
BnO
17
OR
: R = H
: R = Ts
p-TsCl, pyridine,
0 °C, 85%
18
(MeO)2HC
O
Grubbs cat. 2nd, CH2Cl2, 45 °C
84%
+
OBn
BnO
OBn
(S)-6
7
(MeO)2HC
O
1) LiBF4, aq. MeCN, rt
2) Jones oxidation, 0 °C
3) EtI, Cs2CO3, DMF, rt
71%
OBn
BnO
BnO
HO
OBn
O
(S)-4
BnO
HO
20% Pd(OH)2, H2, EtOAc, rt
96%
CO2Et
19
OBn
OH
EtO2C
O
2
O
7
HO
5
14
CO2Et
(S)-
O
2
phomopsin A 20
Scheme 3. Total synthesis of (S)-2.
3. Conclusion
In conclusion, the absolute configuration of 1 was unambigu-
ously established by total synthesis. Our synthesis of (S)-2 revealed
that its spectroscopic data were consistent with those reported for
phomopsin A 20, thus leading us to conclude that the structure of
quence. Tosylation followed by deoxygenation of 18 led to (S)-6.
Treatment of 7 with (S)-6 and Grubbs catalyst 2nd generation as
described for the preparation of 11 afforded enone (S)-4 in good
yield. Since its direct oxidation with Jones reagent caused cleavage
Table 1
1H and 13C NMR (CDCl3) of dothiorelone B, phomopsin A, and (S)-2
No.a
1H NMR
13C NMR
Dothiorelone Bb
Phomopsin Ac
(S)-2
Dothiorelone Bb
Phomopsin Ac
(S)-2
1
2
3
4
5
6
7
8
–
–
–
171.2
41.6
171.7
41.4
171.4
41.6
3.77 s
–
6.25 s
–
6.26 s
–
–
–
2.85 t (7.2)
1.45
1.25
1.42
3.55
1.25 m
0.93 t (7.4)
4.18 q (7.2)
3.76 s
–
6.24 d (2.4)
–
6.25 d (2.4)
–
–
3.80 s
–
6.25 d (2.5)
–
6.26 d (2.5)
–
136.5
112.6
163.6
103.1
160.4
116.9
206.6
43.2
25.1
30.1
36.4
73.2
136.4
112.5
160.4
103.0
163.0
117.1
206.7
43.2
24.6
25.1
36.3
73.2
136.6
112.5
160.3
103.1
163.8
116.9
206.6
43.2
24.7
25.2
36.4
73.2
–
–
9
–
10
11
12
13
14
15
16
17
18
5-OH
7-OH
15-OH
2.85 t (7.2)
1.73 m
1.46 m
1.47 m
3.55 m
1.48 m
0.93 t (7.2)
4.18 q (7.2)
1.26 t (7.2)
–
2.86 t (7.4)
1.69 m, 1.75 m
1.38 m, 1.49 m
1.43 m, 1.49 m
3.56 m
1.45 m, 1.51 m
0.94 t (7.3)
4.19 q (7.1)
1.27 t (7.1)
6.48 s
29.7
9.9
61.5
29.7
30.1
9.8
61.5
14.1
30.2
9.9
61.5
14.1
1.25 t (7.2)
–
–
–
11.32 s
–
11.67 s
a
b
c
The carbon numbering system is according to the one shown in Figure 1 and Scheme 3.
Ref. 6.
Ref. 8.

S. Takahashi et al. / Tetrahedron: Asymmetry 23 (2012) 952–958
955
phomopsin A should be revised to proposed structure 2 for dothi-
orelone B.
37.2; HRMS (EI+) calcd for C27H28O5 [M]+ 432.1937, found
432.1937.
4.4. (R,E)-1-(2,4-Bis(benzyloxy)-6-(2,2-dimethoxyethyl)-
phenyl)-7-(triethylsilyloxy)oct-2-en-1-one 11
4. Experimental section
4.1. General procedures
To a stirred mixture of 7 (104 mg, 0.24 mmol) and 5 (82.2 mg,
0.36 mmol) in dichloromethane (19 mL) was added Grubbs 2nd
All reactions were carried out under an argon atmosphere, un-
less otherwise noted. IR spectra were recorded with a JASCO VA-
LOR-III spectrophotometer by ATR method. Proton (1H) and
carbon (13C) NMR spectra were obtained using a Varian NMR sys-
tem 500 (500 MHz) or JEOL ECA600 (600 MHz) spectrometers as
solutions in CDCl3 unless otherwise noted. Chemical shifts are re-
ported in ppm downfield from tetramethylsilane with the solvent
resonance as the internal standard (dH 7.26 ppm or dC 77.0 ppm).
Column chromatography was performed on Kanto silica gel 60 N
generation catalyst (20.4 mg, 24.0
red at 45 °C for 0.5 h. More 5 (41.1 mg, 0.18 mmol) and the Grubbs
catalyst (5.1 mg, 6.0 mol) were then added to the mixture, and
lmol), and the mixture was stir-
l
stirring was further continued for 0.5 h. This operation was re-
peated twice. After cooling, Florisil was added with stirring, and
the resulting mixture was filtered through a pad of Celite. The fil-
trate was concentrated to give a syrup, which was purified by chro-
matography on silica gel (n-hexane–ethyl acetate = 4:1) to give 11
(119 mg, 78%) as a colorless oil; ½a D24
¼ ꢀ3:1 (c 0.65, CHCl3); IR
ꢁ
(spherical, neutral; 40–100 lm). Merck precoated silica gel 60
(film) 2954, 2831, 1653, 1600, 1456, 1280, 1155, 1121, 1066,
F254 plates, 0.25 mm thickness, was used for analytical thin-layer
chromatography. The solvent extracts were dried with magnesium
sulfate, and the solutions were evaporated under reduced pressure
at 35–40 °C.
831 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.43–7.31 (10H, m), 6.63
;
(1H, dt, J = 15.6, 6.6 Hz), 6.57 (1H, d, J = 2.0 Hz), 6.48 (1H, d,
J = 2.0 Hz), 6.39 (1H, d, J = 15.6 Hz), 5.04 (2H, s), 5.00 (2H, s), 4.47
(1H, t, J = 5.7 Hz), 3.73 (1H, m), 3.28 (6H, s), 2.78 (1H, d,
J = 5.7 Hz), 2.21–2.17 (2H, m), 1.52–1.34 (4H, m), 1.08 (3H, d,
J = 6.1 Hz), 0.93 (9H, t, J = 8.0 Hz), 0.56 (6H, q, J = 8.0 Hz); 13C
4.2. 1-(2,4-Bis(benzyloxy)-6-(2,2-dimethoxyethyl)phenyl)prop-
2-en-1-ol 10
NMR (125 MHz, CDCl3):
d 197.1, 159.9, 157.0, 149.8, 137.3,
136.59, 136.57, 132.8, 128.6, 128.4, 128.1, 127.8, 127.6, 126.8,
123.7, 108.8, 105.3, 99.0, 70.2, 70.1, 68.1, 53.97, 53.96, 39.3, 37.3,
32.5, 24.2, 23.8, 6.9, 4.9; HRMS (EI+) calcd for C38H52O6Si [M]+
632.3533, found 632.3526.
To a stirred solution of 9 (233 mg, 0.57 mmol) in tetrahydrofu-
ran (2.4 mL) was added dropwise a 1.36 M solution of vinylmagne-
sium chloride in tetrahydrofuran (0.63 mL, 0.86 mmol) at 0 °C, and
the mixture was stirred at the same temperature for 1 h. After
being quenched with addition of saturated aqueous NH4Cl, the
resulting mixture was extracted with ether. The combined organic
layers were washed successively with water, and brine. After re-
moval of the solvent, the residue was chromatographed on silica
gel (n-hexane–ether = 1:1) to give 10 (243 mg, 98%) as a colorless
oil; IR (film) 3450, 3030, 2923, 1602, 1457, 1149, 1120, 1074,
4.5. 1-(2,4-Bis(benzyloxy)-6-(2,2-dimethoxyethyl)phenyl)-2-
((2S,6R)-6-methyltetrahydro-2H-pyran-2-yl)ethanone 12 and 1-
(2,4-bis(benzyloxy)-6-(2,2-dimethoxyethyl)phenyl)-2-((2R,6R)-
6-methyltetrahydro-2H-pyran-2-yl) ethanone 13
(i) To a stirred solution of 11 (62.8 mg, 99.2 lmol) in tetrahy-
1058, 737 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.42–7.32 (10H,
;
drofuran (1.5 mL) was added dropwise a 1.0 M solution of tetrabu-
tylammonium fluoride (TBAF) in tetrahydrofuran (0.15 mL,
0.15 mmol) at rt. After 15 h, the mixture was diluted with ethyl
acetate, and washed with brine. After removal of the solvent, the
residue was purified by preparative TLC (n-hexane–ethyl ace-
tate = 4:1, 2 developments) to give 12 (17.4 mg, 34%) and 13
m), 6.54 (1H, d, J = 2.4 Hz), 6.48 (1H, d, J = 2.4 Hz), 6.17 (1H, ddd,
J = 15.7, 10.3, 4.7 Hz), 5.56 (1H, m), 5.16 (1H, dt, J = 15.7, 1.7 Hz),
5.08 (1H, dt, J = 10.3, 1.7 Hz), 5.02 (4H, s), 4.49 (1H, dd, J = 6.3,
4.7 Hz), 3.89 (1H, d, J = 9.5 Hz), 3.32 (3H, s), 3.29 (3H, s), 3.14
(1H, dd, J = 14.0, 6.3 Hz), 2.84 (1H, dd, J = 14.0, 4.7 Hz); 13C NMR
(125 MHz, CDCl3): d 158.5, 157.7, 140.9, 137.0, 136.8, 136.2,
128.7, 128.6, 128.2, 128.1, 127.6, 122.6, 113.6, 109.0, 105.4, 99.6,
70.6, 70.0, 69.7, 54.5, 53.1, 37.4; HRMS (EI+) calcd for C27H30O5
[M]+ 434.2093, found 434.2083.
(15.9 mg, 31%). To a stirred solution of 12 (4.7 mg, 9.1
rahydrofuran (0.2 mL) was added potassium tert-butoxide (2.5 mg,
18.1 mol) at rt, and the mixture was then stirred at rt for 3 h.
lmol) in tet-
l
After being quenched by the addition of saturated aqueous NH4Cl,
the resulting mixture was extracted with ethyl acetate. The com-
bined organic layers were washed successively with water, and
brine. After removal of the solvent, the residue was chromato-
graphed on silica gel (benzene-ether = 20:1) to give 13 (4.1 mg,
87%) as a single isomer.
4.3. 1-(2,4-Bis(benzyloxy)-6-(2,2-dimethoxyethyl)phenyl)prop-
2-en-1-one 7
To a stirred suspension of 10 (204 mg, 0.47 mmol), N-methyl-
morpholine N-oxide (98.3 mg, 0.84 mmol) and MS 4 Å (380 mg)
in dichloromethane (3.1 mL) was added tetra-n-propylammonium
perruthenate (TPAP) (19.6 mg, 55.9 lmol), and the mixture was
stirred at rt for 2 h. After dilution with dichloromethane, the result-
(ii) To a stirred solution of 11 (62.8 mg, 99.2 lmol) in tetrahy-
drofuran (1.6 mL) was added dropwise a 1.0 M solution of TBAF/
tetrahydrofuran (0.11 mL, 0.11 mmol) which was dried over MS
4 Å for 2 d at rt, and the mixture was stirred at rt for 30 min.
ing mixture was directly poured onto a column of silica gel (dichlo-
Work-up as described above gave
a syrup (116.0 mg; cis/
romethane). Elution with n-hexane–ether = 1:1 afforded
(204 mg, 84%) as a colorless oil; IR (film) 3032, 2937, 2831, 1661,
1600, 1580, 1455, 1432, 1334, 1283, 1160, 1076, 833 cmꢀ1 1H
7
trans = 1/2) which was dissolved in tetrahydrofuran (2.0 mL). To
this solution was added potassium tert-butoxide (5.5 mg,
0.15 mmol), and the mixture was stirred at rt for 3 h. According
to the method described above, 13 (32.4 mg, 63% from 11) was ob-
tained as a single isomer.
;
NMR (500 MHz, CDCl3): d 7.42–7.30 (10H, m), 6.66 (1H, dd,
J = 17.6, 10.5 Hz), 6.57 (1H, d, J = 2.2 Hz), 6.49 (1H, d, J = 2.2 Hz),
6.05 (1H, dd, J = 17.6, 1.4 Hz), 5.86 (1H, dd, J = 10.5, 1.4 Hz), 5.05
(2H, s), 5.01 (2H, s), 4.47 (1H, t, J = 5.4 Hz), 3.27 (6H, s), 2.79 (1H,
d, J = 5.4 Hz); 13C NMR (125 MHz, CDCl3): d 197.1, 160.2, 157.4,
138.7, 137.7, 136.5, 136.4, 129.3, 128.7, 128.5, 128.3, 128.1,
127.9, 127.6, 127.0, 123.0, 109.1, 105.3, 99.0, 70.3, 70.1, 53.9,
Compound 12. Colorless oil; ½a D24
¼ þ10:8 (c 0.41, CHCl3); IR
ꢁ
(film) 3033, 2933, 1679, 1600, 1574, 1455, 1432, 1373, 1282,
1157, 1121, 1048, 833, 738, 700 cmꢀ1
7.41–7.30 (10H, m), 6.56 (1H, d, J = 2.2 Hz), 6.48 (1H, d,
J = 2.2 Hz), 5.04 (2H, s), 5.01 (2H, s), 4.56 (1H, t, J = 5.6 Hz), 4.31
;
1H NMR (500 MHz, CDCl3):
d

956
S. Takahashi et al. / Tetrahedron: Asymmetry 23 (2012) 952–958
(1H, m), 3.77 (1H, m), 3.31 (6H, s), 3.09 (1H, d, J = 16.4, 7.6 Hz), 2.99
(1H, d, J = 16.4, 6.1 Hz), 2.84 (1H, d, J = 13.7, 5.4 Hz), 2.76 (1H, d,
J = 13.7, 5.4 Hz), 1.63–1.45 (4H, m), 1.26–1.18 (2H, m), 1.05 (3H,
t, J = 6.4 Hz); 13C NMR (125 MHz, CDCl3): d 205.3, 159.9, 157.1,
137.6, 136.5, 136.2, 128.62, 128.60, 128.2, 128.1, 127.6, 127.5,
125.0, 109.3, 105.7, 98.8, 70.6, 70.1, 68.0, 67.2, 54.10, 54.06, 48.6,
37.6, 31.5, 31.0, 29.7, 19.6, 18.3; HRMS (EI+) calcd for C32H38O6
[M]+ 518.2668, found 518.2657.
30.72, 23.11, 21.50; HRMS (EI+) calcd for C17H22O6 [M]+
322.1416, found 322.1417.
4.8. (R)-1-(tert-Butyldiphenylsilyloxy)hept-6-en-3-ol 16
According to the method described in the literature,19 16 was
prepared from 15 in 83% yield; ½a D22
ꢁ
¼ þ8:0 (c 1.12, CHCl3) {lit.19
:
½
a 2D2
ꢁ
¼ ꢀ4:3 (c 1.05, CHCl3) for (S)-16}; IR (ZnSe) 3482, 3072,
Compound 13. Colorless oil; ½a D24
ꢁ
¼ ꢀ1:3 (c 0.82, CHCl3); IR
2930, 2857, 1641, 1471, 1427, 1234, 1083, 882, 821, 735,
(film) 3032, 2931, 2861, 1680, 1600, 1576, 1456, 1373, 1283,
701 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.70–7.68 (4H, m), 7.47–
;
1155, 1078, 738, 698 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d 7.42–
7.39 (6H, m), 5.85 (1H, ddt, J = 16.9, 10.3, 6.8 Hz), 5.05 (1H, ddt,
J = 16.9, 2.0, 1.7 Hz), 4.97 (1H, ddt, J = 10.3, 2.0, 1.2 Hz), 3.93 (1H,
m), 3.92–3.83 (2H, m), 3.28 (1H, br s), 2.23 (1H, m), 2.15 (1H, m),
1.77–1.60 (3H, m), 1.54 (1H, m), 1.06 (9H, s); 13C NMR (125 MHz,
CDCl3): d 138.6, 135.58, 135.56, 133.0, 132.9, 129.88, 129.85,
127.8, 114.6, 71.3, 63.6, 38.3, 36.6, 29.2, 26.8, 19.0; HRMS (EI+)
calcd for C19H23O2Si [M-C4H9]+ 311.1467, found 311.1467.
7.32 (10H, m), 6.56 (1H, d, J = 2.2 Hz), 6.47 (1H, d, J = 2.2 Hz),
5.04 (2H, s), 5.02 (2H, s), 4.56 (1H, t, J = 5.7 Hz), 3.83 (1H, m),
3.37 (1H, m), 3.32 (3H, s), 3.31 (3H, s), 2.99 (1H, d, J = 16.4,
7.1 Hz), 2.92 (1H, d, J = 16.4, 5.6 Hz), 2.84 (1H, d, J = 13.7, 5.7 Hz),
2.77 (1H, d, J = 13.7, 5.4 Hz), 1.74–1.68 (1H, m), 1.58–1.43 (4H,
m), 1.15–1.02 (1H, m), 1.09 (3H, d, J = 6.1 Hz); 13C NMR
(125 MHz, CDCl3): d 205.5, 159.9, 157.1, 137.3, 136.6, 136.2,
128.62, 128.57, 128.1, 127.6, 127.5, 125.3, 109.2, 105.8, 98.7,
74.5, 74.0, 70.5, 70.1, 54.2, 54.1, 51.7, 37.5, 33.0, 31.1, 23.6, 22.1;
HRMS (EI+) calcd for C32H38O6 [M]+ 518.2668, found 518.2679.
4.9. (R)-3-(Benzyloxy)hept-6-en-1-ol 17
To a stirred solution of 16 (1.35 g, 3.65 mmol) and benzyl 2,2,2-
trichloroacetimidate (0.75 mL, 4.02 mmol) in c-hexane–dichloro-
methane (2:1; 7.5 mL) was added dropwise a saturated solution
of trifluoromethanesulfonic acid (TfOH) in dichloromethane
(0.45 mL) at 0 °C. After 1.5 h, more TfOH solution (0.50 mL) was
added, and stirring was continued at 0 °C for an additional 1.5 h.
The reaction mixture was then filtered through a pad of Celite,
and the filtrate was washed successively with saturated aqueous
NaHCO3, water, and brine. After removal of the solvent, the residue
(1.73 g) was dissolved in tetrahydrofuran (51 mL). To the solution
was added a 1.0 M solution of TBAF in tetrahydrofuran (5.5 mL,
5.5 mmol) with stirring. The mixture was stirred at rt for 62 h, di-
luted with ethyl acetate, and washed with brine. After removal of
the solvent, the residue was chromatographed on silica gel (ben-
zene–ether = 90:1 ? 5:1) to give 17 (598 mg, 74% from 16) as a
4.6. Methyl 2-(3,5-bis(benzyloxy)-2-(2-((2R,6R)-6-methyl
tetrahydro-2H-pyran-2-yl)ethanoyl)phenyl)ethanoate 14
To a stirred solution of 13 (20.7 mg, 39.9 lmol) in acetone
(1.0 mL) was added dropwise a 2.7 M solution of Jones’ reagent
(ca. 0.12 mL) at 0 °C and the mixture was stirred at 0 °C for
30 min. After the addition of 2-methyl-2-propanol, the resulting
mixture was extracted with dichloromethane. The combined or-
ganic layers were washed successively with water, and brine. After
removal of the solvent, the residue (15.4 mg) was dissolved in
ether (1.0 mL) and an ether solution of diazomethane was added
dropwise until a yellow color persisted. The resulting mixture
was concentrated to give a syrup, which was chromatographed
on silica gel (n-hexane–ethyl acetate = 40:1) to give 14 (15.1 mg,
colorless syrup; ½a D23
ꢁ
¼ ꢀ34:2 (c 0.80, CHCl3); IR (ZnSe) 3390,
75%) as a colorless oil; ½a D23
ꢁ
¼ ꢀ0:7 (c 0.71, CHCl3); IR (ZnSe)
3068, 3031, 2921, 1640, 1453, 1235, 1086, 870, 735 cmꢀ1 1H
;
2921, 2851, 1736, 1684, 1601, 1434, 1317, 1159, 1082, 883, 842,
NMR (500 MHz, CDCl3): d 7.38–7.31 (5H, m), 5.83 (1H, ddt,
J = 17.1, 10.2, 6.6 Hz), 5.04 (1H, ddt, J = 17.1, 1.8, 1.5 Hz), 4.99
(1H, ddt, J = 10.2, 1.9, 1.2 Hz), 4.60 (1H, d, J = 11.5 Hz), 4.51 (1H,
d, J = 11.5 Hz), 3.81 (1H, ddd, J = 10.7, 7.1, 4.6 Hz), 3.74 (1H, ddd,
J = 10.7, 6.4, 4.9 Hz), 3.68 (1H, m), 2.45 (1H, br s), 2.14 (2H, m),
1.88–1.74 (3H, m), 1.65 (1H, m); 13C NMR (125 MHz, CDCl3): d
138.3, 128.50, 128.46, 127.9, 127.8, 114.8, 77.8, 71.0, 60.6, 35.8,
32.7, 29.4; HRMS (EI+) calcd for C14H20O2 [M]+ 220.1463, found
220.1453.
737 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.47–7.30 (10H, m), 6.51
;
(1H, d, J = 2.0 Hz), 6.50 (1H, d, J = 2.0 Hz), 5.033 (2H, s), 5.027
(2H, s), 3.82 (1H, m), 3.70 (3H, s), 3.60 (2H, s), 3.37 (1H, m), 3.01
(1H, dd, J = 16.2, 7.6 Hz), 2.94 (1H, dd, J = 16.2, 5.6 Hz), 1.74–1.68
(1H, m), 1.59–1.42 (4H, m), 1.14–1.06 (1H, m), 1.08 (3H, d,
J = 6.1 Hz); 13C NMR (125 MHz, CDCl3): d 204.5, 171.8, 160.5,
157.9, 136.3, 136.1, 135.0, 128.7, 128.6, 128.19, 128.16, 127.61,
127.55, 124.5, 109.1, 99.3, 74.7, 73.8, 70.7, 70.2, 52.0, 51.4, 38.8,
33.0, 31.1, 29.7, 23.5, 22.1; HRMS (EI+) calcd for C31H34O6 [M]+
502.2355, found 502.2357.
4.10. (R)-3-(Benzyloxy)hept-6-en-1-yl p-toluenesulfonate 18
4.7. Curvulone B 1
To a stirred solution of 17 (106 mg, 0.48 mmol) in pyridine
(0.50 mL) was added p-TsCl (138 mg, 0.72 mmol) at 0 °C, and the
mixture was stirred at 0 °C for 15 h. After the addition of ice-water,
the resulting mixture was vigorously stirred at rt for 1 h, and ex-
tracted with ether. The combined organic layers were washed suc-
cessively with cold 5% HCl, water, saturated aqueous NaHCO3,
water, and brine. After removal of the solvent, the residue was
chromatographed on silica gel (n-hexane–ether = 10:1) to give 18
A mixture of 14 (15.1 mg, 30.0 lmol) and 20% Pd(OH)2 (7.5 mg)
in ethyl acetate (1.5 mL) was stirred at rt under a hydrogen atmo-
sphere for 7.5 h, filtered through a pad of Celite, and then concen-
trated. The residue was chromatographed on silica gel (n-hexane–
ethyl acetate = 1:1) to give 1 (8.5 mg, 88%) as a colorless oil;
½
a 2D3
ꢁ
¼ ꢀ15:1 (c 0.52, EtOH) {lit.3: ½a D25
¼ ꢀ22 (c 0.27, EtOH)}; IR
ꢁ
(film) 3350, 2940, 2855, 1717, 1615, 1585, 1340, 1275, 1165,
(154 mg, 85%) as a colorless oil; ½a D23
¼ ꢀ19:2 (c 0.67, CHCl3); IR
ꢁ
1080, 850 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d 9.79 (1H, s), 6.27
(ZnSe) 3065, 3031, 2917, 2850, 1639, 1598, 1454, 1359, 1175,
(1H, d, J = 2.4 Hz), 6.21 (1H, d, J = 2.4 Hz), 5.88 (1H, br s), 4.15
(1H, brtt, J = 10.3, 3.2 Hz), 3.92 (1H, d, J = 16.6 Hz), 3.70 (3H, s),
3.55 (1H, m), 3.51 (1H, d, J = 16.6 Hz), 3.31 (1H, dd, J = 14.5,
10.3 Hz), 2.55 (1H, dd, J = 14.5, 3.2 Hz), 1.85 (1H, m), 1.68–1.51
(3H, m), 1.41 (1H, m), 1.25 (1H, m), 1.17 (6H, d, J = 6.1 Hz); 13C
NMR (125 MHz, CDCl3): d 204.26, 172.31, 159.41, 159.22, 135.80,
120.95, 111.58, 104.06, 77.96, 74.91, 52.08, 49.02, 39.70, 32.68,
1087, 892, 814, 736 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.78 (1H,
;
d, J = 8.3 Hz), 7.32–7.24 (5H, m), 7.24 (1H, d, J = 8.3 Hz), 5.78 (1H,
ddt, J = 16.4, 10.3, 7.1 Hz), 5.00 (1H, ddt, J = 16.4, 1.5, 1.5 Hz), 4.96
(1H, ddt, J = 10.3, 1.8, 1.5 Hz), 4.47 (1H, d, J = 11.3 Hz), 4.31 (1H,
d, J = 11.3 Hz), 4.19 (1H, ddd, J = 10.6, 8.3, 5.6 Hz), 4.13 (1H,
J = 10.6, 5.3, 5.1 Hz), 3.54 (1H, m), 2.42 (3H, s), 2.11–2.06 (2H, m),
1.89 (1H, m), 1.83 (1H, m), 1.65 (1H, m), 1.55 (1H, m); 13C NMR

S. Takahashi et al. / Tetrahedron: Asymmetry 23 (2012) 952–958
957
(125 MHz, CDCl3): d 144.8, 138.3, 138.1, 133.0, 129.9, 128.4, 127.9,
127.7, 127.6, 114.9, 74.5, 71.3, 67.6, 33.5, 33.0, 29.2, 21.6; HRMS
(EI+) calcd for C21H26O4S [M]+ 374.1552, found 374.1547.
(0.16 mL, 0.39 mmol), and the resulting mixture was stirred at rt
for 15 h, diluted with water, and extracted with ether. The com-
bined organic layers were washed successively with water, and
brine. After removal of the solvent, the residue was chromato-
graphed on silica gel (n-hexane–ethyl acetate = 2:1) to give 19
4.11. (S)-5-(benzyloxy)hept-1-ene 6
(43.0 mg, 71% from (S)-4) as a colorless oil; ½a D25
¼ þ4:9 (c 0.66,
ꢁ
To a stirred solution of 18 (1.95 g, 2.80 mmol) in tetrahydrofu-
ran (10.5 mL) was added dropwise a 1.0 M solution of lithium tri-
ethylborohydride (5.6 mL, 5.6 mmol) in tetrahydrofuran at 0 °C.
The mixture was stirred at 0 °C for 30 min and then at rt for
1.5 h. After being quenched by the addition of saturated aqueous
NH4Cl, the resulting mixture was extracted with ether. The com-
bined organic layers were washed successively with water, and
brine. After removal of the solvent, the residue was chromato-
graphed on silica gel (n-hexane–ethyl acetate = 5:1) to give a syrup
(606 mg), which was distilled under reduced pressure {2–3 mmHg,
120 °C (bath temperature)} to give (S)-6 (460 mg, 80%) as a color-
CHCl3); IR (ZnSe) 3080, 2934, 2875, 1733, 1650, 1601, 1454,
1318, 1285, 1166, 1028, 735 cmꢀ1 1H NMR (500 MHz, CDCl3): d
;
7.42–7.26 (15H, m), 6.71 (1H, dt, J = 15.6, 7.1 Hz), 6.53 (2H, s),
6.43 (1H, dt, J = 15.6, 1.5 Hz), 5.04 (2H, s), 5.00 (2H, s), 4.45 (1H,
d, J = 11.7 Hz), 4.37 (1H, d, J = 11.7 Hz), 4.10 (2H, q, J = 7.3 Hz),
3.58 (2H, s), 3.28 (1H, m), 2.29 (1H, m), 2.22 (1H, m), 1.65–1.45
(4H, m), 1.21 (3H, t, J = 7.3 Hz), 0.88 (3H, t, J = 7.6 Hz); 13C NMR
(125 MHz, CDCl3): d 195.9, 171.1, 160.4, 157.7, 149.3, 138.8,
136.4, 134.9, 132.4, 128.7, 128.5, 128.3, 128.2, 127.9, 127.7,
127.6, 127.5, 126.9, 123.4, 108.7, 99.6, 79.2, 70.8, 70.3, 70.2, 60.9,
38.7, 31.6, 28.3, 26.1, 14.2, 9.4; HRMS (EI+) calcd for C39H42O6
[M]+ 606.2981, found 606.2994.
less syrup; ½a 2D4
¼ þ11:7 (c 2.07, CHCl3); IR (ZnSe) 3067, 3030,
ꢁ
2965, 2921, 2875, 1640, 1454, 1234, 1087, 888, 733, 696 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d 7.37–7.27 (5H, m), 5.82 (1H, m),
5.01 (1H, dq, J = 17.1, 1.7 Hz), 4.95 (1H, ddd, J = 10.0, 1.7, 1.0 Hz),
4.52 (1H, d, J = 11.8 Hz), 4.47 (1H, d, J = 11.8 Hz), 3.36 (1H, m),
2.18 (1H, m), 2.12 (1H, m), 1.69–1.53 (4H, m), 0.93 (3H, d,
J = 7.4 Hz); 13C NMR (125 MHz, CDCl3): d 139.0, 138.8, 128.3,
127.8, 127.4, 114.4, 79.5, 70.8, 32.6, 29.7, 26.2, 9.5; HRMS (EI+)
calcd for C14H20O [M]+ 204.1514, found 204.1505.
4.14. Preparation of (S)-2
Treatment of 19 (3.2 mg, 5.3
l
mol) as described for the prepa-
ration of afforded (S)-2 (1.7 mg, 96%) as
1
a
white solid;
½
a 2D4
ꢁ
¼ þ4:9 (c 0.39, CHCl3); IR (ZnSe) 3226, 2930, 2858, 1705,
1590, 1457, 1370, 1260, 1160, 1024 cmꢀ1; EI-MS m/z (rel. int.):
338 (1.9), 320 (18.6), 292 (4.0), 263 (9.2), 248 (21.1), 205 (29.6),
196 (50.0), 167 (100); HRMS (EI+) calcd for C18H26O6 [M]+
338.1729, found 338.1731.
4.12. (S,E)-6-(Benzyloxy)-1-(2,4-bis(benzyloxy)-6-(2,2-
dimethoxyethyl)phenyl)oct-2-en-1-one 4
Acknowledgments
Treatment of
7 (113 mg, 0.26 mmol) and (S)-6 (160 mg,
0.78 mmol) as described for the preparation of 11 afforded (S)-4
We are grateful to Drs. T. Kurtán (University of Debrecen) and L.
M. Abreu (Federal University of Minas Gerais) for providing the
spectra of curvulone B and dothiorelone B, respectively. This work
was supported in part by the Chemical Genomics Project (RIKEN).
(133 mg, 84%) as a colorless oil; ½a D22
¼ þ5:2 (c 0.43, CHCl3); IR
ꢁ
(film) 3031, 2934, 2875, 1653, 1601, 1456, 1281, 1160, 1120,
1066, 737 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.43–7.26 (15H,
;
m), 6.64 (1H, dt, J = 15.9, 6.8 Hz), 6.57 (1H, d, J = 2.2 Hz), 6.48
(1H, d, J = 2.2 Hz), 6.38 (1H, d, J = 15.9 Hz), 5.05 (2H, s), 4.99 (2H,
s), 4.48 (1H, t, J = 5.4 Hz), 4.46 (1H, d, J = 11.5 Hz), 4.37 (1H, d,
J = 11.5 Hz), 3.28 (6H, s), 2.77 (1H, d, J = 5.4 Hz), 2.38–2.28 (1H,
m), 2.27–2.18 (1H, m), 1.69–1.45 (4H, m), 0.88 (3H, d, J = 7.6 Hz);
13C NMR (125 MHz, CDCl3): d 197.1, 159.9, 157.0, 149.8, 138.8,
137.2, 136.6, 136.5, 132.9, 128.6, 128.4, 128.3, 128.1, 127.8,
127.7, 127.6, 127.5, 126.9, 123.6, 108.8, 105.3, 99.0, 79.2, 70.8,
70.2, 70.1, 54.0, 37.3, 31.7, 28.3, 26.1, 9.4; HRMS (EI+) calcd for
References
1. (a) Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 1; (b) Faulkner, D. J. Nat. Prod. Rep.
2001, 18, 1.
2. (a) Brady, S. F.; Wagenaar, M. M.; Singh, M. P.; Janso, J. E.; Clardy, J. Org. Lett.
2000, 2, 4043; (b) Paranagama, P. A.; Kithsiri Wijeratne, E. M.; Leslie
Gunatilaka, A. A. J. Nat. Prod. 2007, 70, 1939.
3. Dai, J.; Krohn, K.; Flörke, U.; Pescitelli, G.; Kerti, G.; Papp, T.; Kövér, K. E.; Bényei,
A. C.; Draeger, S.; Schulz, B.; Kurtán, T. Eur. J. Org. Chem. 2010, 6927.
4. Guo, Y. W.; Kurtán, T.; Krohn, K.; Pescitelli, G.; Zhang, W. Chirality 2009, 21, 561.
5. Krohn and Kurtán et al.3 suggested that the 7-OH in the lowest-energy
conformer was bonded to the THP oxygen by computational calculations. The
result was also supported by the ROESY spectra in which strong ROE was
observed between 7-OH and 10a-H.
C
39H44O6 [M]+ 608.3138, found 608.3129.
4.13. (S,E)-Ethyl 2-(3,5-bis(benzyloxy)-2-(6-(benzyloxy) oct-2-
enoyl)phenyl)ethanoate 19
6. Xu, Q.; Wang, J.; Huang, Y.; Zheng, Z.; Song, S.; Zhang, Y.; Su, W. Acta Oceanolog.
Sin. 2004, 23, 541.
7. After Su’s report, several groups isolated this natural product from a similar
endophytic fungus (a) Huang, Z.; Guo, Z.; Yang, R.; Yin, X.; Li, X.; Luo, W.; She,
Z.; Lin, Y. Chem. Nat. Comp. 2009, 45, 625; (b) Xu, J.; Kjer, J.; Sendker, J.; Wray,
V.; Guan, H.; Edrada, R.; Mueller, W. E. G.; Bayer, M.; Lin, W.; Wu, J.; Proksch, P.
Bioorg Med. Chem. 2009, 17, 7362; In this paper, the erroneous name
‘dothiorelone B’ is used for dothiorelone A (c) Abreu, L. M.; Phipps, R. K.;
Pfenning, L. H.; Gotfredsen, C. H.; Takahashi, J. A.; Larsen, T. O. Tetrahedron Lett.
2010, 51, 1803.
8. Huang, Z.; Cai, X.; Shao, C.; She, Z.; Xia, X.; Chen, Y.; Yang, J.; Zhou, S.; Lin, Y.
Phytochemistry 2008, 69, 1604.
9. Izuchi, Y.; Koshino, H.; Hongo, Y.; Kanomata, N.; Takahashi, S. Org Lett. 2011, 13,
3360.
10. As shown in Table 1, the signals of H-11 to 13 and 15 of dothiorelone B showed
ca. 0.2–0.3 ppm of upfield shift rather than those of phomopsin A in the 1H
NMR spectra, and the signals of C-5, -7, -11, -12, -15, and -18 of the natural
product deviated by 0.4–15.6 ppm compared with the respective signals of
phomopsin A in the 13C NMR spectra.
11. Grubbs, R. H. In Handbook of Metathesis; Wiley-VCH, 2003; Vols. 1–3,
12. The reaction of 7 with the TBS analogue of 5 also gave the corresponding enone
in good yield. However, removal of the TBS group by TBAF or KF required a
longer time (2–4 d) for complete deprotection, resulting in a low yield of the
desired products. The use of the TMS or trichloroacetyl group as the protecting
To a stirred solution of (S)-4 (60.8 mg, 99.9 lmol) in acetoni-
trile–water (50:1; 1.8 mL) was added a 1.0 M solution of lithium
tetrafluoroborate in acetonitrile (0.2 mL) at rt. After 1 h, the mix-
ture was diluted with ether, washed successively with saturated
aqueous NaHCO3, water, and brine. After removal of the solvent,
the residue (61.0 mg) was dissolved in tetrahydrofuran/2-methyl-
2-propanol/water (8:3:1; 1.3 mL), and NaH2PO4ꢂ2H2O (78.0 mg,
0.50 mmol) and 2-methyl-2-butene (0.32 mL, 3.00 mmol) were
added. To the above mixture was added dropwise a solution of so-
dium chlorite (45.2 mg, 0.50 mmol) in water (0.13 mL) at 0 °C with
stirring, and the resulting mixture was stirred at the same temper-
ature for 0.5 h. After the addition of saturated aqueous Na2S2O3,
the resulting mixture was extracted with ethyl acetate. The com-
bined organic layers were washed successively with water, and
brine. After removal of the solvent, the residue (74.9 mg) was dis-
solved in N,N-dimethylformamide (1.0 mL). To this solution were
added cesium carbonate (35.8 mg, 0.11 mmol) and iodoethane

958
S. Takahashi et al. / Tetrahedron: Asymmetry 23 (2012) 952–958
group was also ineffective for the preparation of the corresponding enones
19. Robinson, J. E.; Brimble, M. A. Org. Biomol. Chem. 2007, 5, 2572.
20. We could find such signals at 1.70–1.80 ppm in the 1H NMR spectra kindly
provided by Dr. L. M. Abreu.
because of the decomposition of the starting olefin during the reaction.
13. Compound 5: ½a D21
ꢁ
¼ ꢀ9:5 (c 1.23, CHCl3); HRMS (CI+) calcd for C11H23OSi [M-
C2H5]+ 199.1518, found 199.1514. For the antipode, see Hinkle, R. J.; Lian, Y.;
Litvinas, N. D.; Jenkins, A. T.; Burnette, D. C. Tetrahedron 2005, 61, 11679.
14. As other catalysts, Grubbs catalyst 1st generation, Grubbs–Hoveyda 1st and
2nd generation catalysts were employed.
21. The peak for the C-18 methyl group at d 29.7 would be misassignment
obviously because its chemical shift value is different from that of the typical
methyl carbon23 of an ethoxy carbonyl group; for example, the C-18 of (S)-2 is
observed at 14.1 ppm. Taking into account the proton signal at 1.25 ppm
assigned to H-15 and 18 of the natural product, the signal at 29.7 ppm might be
derived from contaminated grease or its related compound. For the signals
deriving from common contaminants in the use of NMR, see; Gottlieb, H. E.;
Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512.
15. We confirmed that 15-hydroxyenone 3 was not included in the crude product
by NMR analysis. Although the reaction mechanism is unclear, 12-hydroxy-
a
,b-epoxy ketone derivatives of 3 were isolated as major side-products (ꢃ10%).
16. Kan, T.; Hashimoto, M.; Yanagiya, M.; Shirahama, H. Tetrahedron Lett. 1988, 29,
5417.
22. The fragment ion peak (m/z 320 [M-H2O]+) derived from the corresponding
dehydration product was also observed by EI-MS measurement of S-2. Relative
intensities for m/z 338 [M]+ and m/z 320 were 1.9:18.6 in the spectra.
23. Kalinowski, H. -O.; Berger, S.; Braun, S. In Carbon-13 NMR Spectroscopy, John
Wiley & Sons: 1988, p 203.
17. The data of NOE are as follows; 12: H-15 ? H-10a; 13: H-11 ? H-15, H-
15 ? H-11 (irradiation of the proton on the left of the allow caused NOE of the
one on the right).
18. Nakata, T.; Suenaga, T.; Oishi, T. Tetrahedron Lett. 1989, 30, 6525.