Total synthesis and biological evaluation of auripyrones A and B

Article abstract of DOI:10.1246/bcsj.20120162

The total synthesis of auripyrones was achieved by using a novel aldol-type reaction of γ-pyrone as a key step. From this synthetic work, we have established the stereostructure and absolute configuration of auripyrone B. Furthermore, the cytotoxicities o

Full text of DOI:10.1246/bcsj.20120162

© 2012 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 85, No. 10, 1077-1092 (2012) 1077
BCSJ Award Article
Total Synthesis and Biological Evaluation of Auripyrones A and B
Ichiro Hayakawa,1 Takuma Takemura,1,2 Emi Fukasawa,1 Yuta Ebihara,1 Natsuki Sato,1
Takayasu Nakamura,1 Kiyotake Suenaga,1,³ and Hideo Kigoshi*1
1Department of Chemistry, Graduate School of Pure and Applied Sciences,
University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571
2Japan Society for the Promotion of Science (JSPS)
Received June 4, 2012; E-mail: kigoshi@chem.tsukuba.ac.jp
The total synthesis of auripyrones was achieved by using a novel aldol-type reaction of £-pyrone as a key step. From
this synthetic work, we have established the stereostructure and absolute configuration of auripyrone B. Furthermore, the
cytotoxicities of auripyrones against a panel of 39 human cancer cell lines (termed JFCR39) at the Japanese Foundation
for Cancer Research were investigated. The patterns of the differential cytotoxicities of auripyrones were COMPARE
negative, suggesting that they inhibit cancer cell proliferation through a novel mechanism.
A number of significant biologically active £-pyrone-
27
28
containing compounds from marine animals have been report-
ed.1 The structural features of these £-pyrone-containing
compounds are asymmetric centers at the neighboring positions
of the £-pyrone part. In 1996, Yamada and co-workers reported
the isolation of auripyrones A (1) and B (2) from the sea hare
Dolabella auricularia (Aplysiidae), which exhibit cytotoxicity
against HeLa S3 cells with IC50 values of 0.26 and 0.48
¯g mL¹1, respectively (Figure 1).2 The relative stereochemistry
of the core unit of auripyrones A (1) and B (2) was determined
by an extensive analysis of coupling constants and the NOESY
correlations. The main structural features of auripyrones are a
£-pyrone ring and a spiroacetal moiety. The unique structures
of auripyrones, in conjunction with their biological activities,
have made them attractive synthetic targets. Several groups
have reported approaches to the synthesis of auripyrones. In
2006, Perkins and Lister were the first to achieve the total
synthesis of auripyrone A (1), featuring spiroacetalization.3
This synthesis established the absolute configuration of
auripyrone A (1). In 2009, Jung and Salehi-Rad achieved the
total synthesis of auripyrone A (1) by using a tandem non-aldol
aldol/Paterson aldol process.4 The next year, we preliminarily
reported the total synthesis of auripyrones A (1) and B (2) by
using a novel diastereoselective aldol-type reaction of 2,6-
diethyl-3,5-dimethyl-4-pyrone (8).5 From this synthetic work,
we determined the absolute configuration of auripyrone B (2).
Very recently, Jung and co-workers reported the total synthesis
5'
20
17
O
O
26
O
O
5
1'
4'
4'
25
21
auripyrone A (1) : R1
=
22
13
24
O
9
O
2'
*
1
auripyrone B (2) : R1 =
3
7
11
O
OR1
1'
23
5'
Figure 1. Structures of auripyrones A (1) and B (2).
of auripyrone B (2) using their previous strategy.6 We describe
herein the detailed synthesis of auripyrones A (1) and B (2) and
their cytotoxicities against a panel of 39 human cancer cell
lines.
Results and Discussion
Our retrosynthetic analyses of auripyrones A (1) and B (2)
are shown in Scheme 1. Auripyrones A (1) and B (2) can
be obtained from triketone 3 by using spiroacetalization. Tri-
ketone 3 can be derived from C1-C13 segment 4 and C14-C20
segment 5 by using the aldol coupling reaction. Asymmetric
centers at C11 and C12 of C1-C13 segment 4 can be constructed
from aldehyde 7 by asymmetric crotylboration. Aldehyde 7,
which possesses an asymmetric center at the neighboring posi-
tion of £-pyrone, can be synthesized from 2,6-diethyl-3,5-
dimethyl-4-pyrone (8) and the optically active aldehyde 9 by
diastereoselective aldol-type reaction as a key step.7,8
Synthesis of C1-C13 Segment. Previously, we reported
diastereoselective aldol-type reaction of £-pyrone (8) with
NaHMDS7 and the Mukaiyama aldol-type reaction of silyl enol
³ Present address: Department of Chemistry, Faculty of Science
and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama, Kanagawa 223-8522
Published on the web September 29, 2012; doi:10.1246/bcsj.20120162

1078 Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) BCSJ AWARD ARTICLE
spiroacetalization
O
O
O
O
O
13 O
11
OH OR1
O
O
O
O
9
13
OR1
O
9
11
14
3
aldol reaction
auripyrone A (1) : R1
=
=
O
auripyrone B (2) : R1
*
O
OR2 OR1
O
OR3
12
11
+
CHO
13
O
14
20
C1–C13 segment 4
C14–C20 segment 5
crotylboration
O
O
OR2 OH
11
OR2
9
CHO
O
O
O
12
8
6
aldol-type reaction
of -pyrone
7
γ
OR4
9
OHC
+
O
8
8
9
Scheme 1. Retrosynthetic analyses of auripyrones A (1) and B (2).
ether of £-pyrone 8.8 These approaches have the benefits of
straightforward access even to complex molecules and of the
construction of two stereogenic centers at once. Therefore, we
planned the synthesis of auripyrones A (1) and B (2) starting
from this aldol-type reaction between £-pyrone (8) and optically
active aldehyde 10.9 First, we tried the aldol-type reaction
with NaHMDS to afford the desired compound 11 in 47% yield
along with other diastereomers (21%) (Scheme 2). Although we
attempted a Mukaiyama aldol-type reaction between the silyl
enol ether of £-pyrone 8 and aldehyde 10 by using TiCl4 to give
the desired aldol adduct 11, the yield and diastereoselectivity
were low (desired aldol adduct 11: 17% yield, other diaster-
eomers: 21%). The configuration of 11 was determined from
1H NMR of the corresponding acetonide derivative A including
NOESY correlations (Scheme 3). Protection of the secondary
hydroxy group in aldol adduct 11 gave a TBS ether, which
was transformed into aldehyde 12 by removal of the trityl
group and oxidation of the resulting primary hydroxy group.
Aldehyde 12 was converted into homoallylic alcohol 14 as a
single diastereomer via Brown crotylation using the (E)-crotyl
boronate 13.10 The stereochemistry of 14 was determined as
follows. Homoallylic alcohol 14 was converted into 1,3-
acetonide B, the stereochemistry of which was confirmed to
be syn by the 13C chemical shifts of two acetonide methyls (¤C
19.2 and 29.8) (Scheme 4).11 Furthermore, 1,3-acetonide B was
converted into 1,3-acetonide C, and the configuration at C11
1
and C12 in C was determined by H-1H coupling constants
and NOESY correlations. Introduction of the isovaleryl group
at C11 in homoallylic alcohol 14 and dihydroxylation of
the terminal olefin afforded a diol, which was converted into
aldehyde 15 as a C1-C13 segment. This two-step procedure
was superior to the direct Lemieux-Johnson conditions12 in
both yield and reproducibility because of the instability of
aldehyde 15.
Synthesis of C14-C20 Segment. Next, we prepared C14-
C20 segment 17 (Scheme 5). Oxidation of commercially
available (S)-2-methy-1-butanol gave aldehyde 16.13 The aldol
reaction of aldehyde 16 and 3-pentanone with LDA followed
by the protection of the resulting secondary hydroxy group as
the TES ether gave C14-C20 segment 17 as a diastereomeric
mixture. This segment 17 was used for the next reaction
without separation of diastereomers because the configurations
of these newly generated stereocenters were lost by oxidation
and epimerization in subsequent steps.
Total Synthesis of Auripyrone A. With C1-C13 segment
15 and C14-C20 segment 17 in hand, we next tried the aldol
coupling reaction between two segments. First, we attempted
the aldol coupling reaction between model compounds 18 and
17 with LDA, LHMDS, and NaHMDS, but the yields were low
(9-43%) (Table 1). We then examined the deuteration of C14-

I. Hayakawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) 1079
O
O
OTr
OH OTr
NaHMDS
OHC
O
8
O
THF, –78 °C
10
11
47%
other diastereomers
21%
1) TBSCl, imidazole
DMF, 70 °C, 99%
O
O
2) HCO2H, Et2O, RT
B
2
3) 25% NH3 aq., MeOH, RT
92% over two steps
OTBS
CHO
13
4) (COCl)2, DMSO, i-Pr2NEt
CH2Cl2, –78 °C then 0 °C, 99%
·
BF3 OEt2, THF, –78 °C
then NaOH, H2O2, 71%
12
1) isovaleryl chloride
DMAP, py, RT, quant
2) OsO4, NMO
O
O
O
TBS
O
TBS
O
OH
11
O
O
1
acetone–H2O, RT, 90%
CHO
O
11
13
3) NaIO4
acetone–H2O, 72%
15
C1–C13 segment
14
Scheme 2. Synthesis of C1-C13 segment 15.
O
O
1) HCO2H, AcOEt, rt
2) 25% NH3 aq., MeOH
rt, 93% in 2 steps
O
O
OH OTr
O
O
3) Me2C(OMe)2, PPTS
acetone, rt, 96%
11
A
10.1 Hz
O
O
Me
O
H
Me
10
R=
H
R
Me
8
9
Me
H
O
H
H
1.7 Hz
2.8 Hz
2.8 Hz
JH, H
(500 MHz, CDCl3)
NOE
(500 MHz, CDCl3)
Scheme 3. Determination of stereochemistry of 11.
C20 segment 17, as depicted in Table 2. Interestingly, treat-
ment of 17 with LDA or LHMDS, followed by the addition of
D2O, did not give the deuterated compound 20 (Entries 1 and
2). In Entries 3 and 4, the enolate of 17 prepared with KHMDS
and NaHMDS, respectively, gave a deuterated compound 20
in 70% yields in both cases. However, as we reported that £-
pyrone 8 is easily deprotonated by using metal bis(trimethyl-
silyl)amides (deuteration yield: >95%),7,8 model compound 18
(C2 position) was expected to be more easily deprotonated at
the C2 position of £-pyrone than C14-C20 segment 17 was at
the C14 position, reducing the yield of the aldol adduct.
Therefore, we attempted an aldol reaction with a weaker base.
The Mukaiyama Sn(II)-promoted aldol reaction14 between
C1-C13 segment 15 and C14-C20 segment 17 using Sn(OTf)2
and Et3N afforded coupling compound 21 in 99% yield as a
diastereomeric mixture (Scheme 6).
Next, we tried to synthesize auripyrone A (1) from coupling
compound 21 (Scheme 7). Selective removal of the TES group
in 21 gave a diol, which was oxidized into triketone 22 as an
equilibrium mixture of the keto and enol forms. Removal of the
TBS group in triketone 22 by HF¢py was accompanied by
spiroacetalization to give auripyrone A (1) as a single isomer.
The synthetic auripyrone A (1) is identical in all respects to the
natural product.2
Stereocontrol in the spiroacetalization to auripyrone A (1)
can be explained as follows (Figure 2). Triketone 22 was
converted into hemiacetals 23a and 23b. The stereochemistry
of spiro carbon (C13) in 23a and 23b was controlled by the
double anomeric effect. The C14 methyl group in hemiacetal
23a was epimerized into the equatorial position (hemiacetal
23b) so as to avoid a 1,3-diaxial interaction between the C12
and C14 methyl groups in 23a via ¢-diketone form 22.

1080 Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) BCSJ AWARD ARTICLE
13C NMR (67.8 MHz, CDCl3)
δ = 19.2 and 29.8 ppm
O
O
TBS
1) HF·py
O
OH
O
9
O
THF–py, rt, 71%
12
12
9
11
11
O
O
2) Me2C(OMe)2, PPTS
acetone, rt, 88%
14
B
O
1) OsO4, NMO, THF, H2O, then NaIO4, rt
2) NaBH4, EtOH, rt
OH
9
O
O
12
3) PPTS, MeOH, H2O, rt, 67% in 3 steps
4) Me2C(OMe)2, PPTS, acetone, rt, 57%
11
13
O
C
11.5 Hz
5.0 Hz
O
Me
O
H
H
OH
O
R=
10
11
H
O
R
Me
13
Me
Me
H
H
JH, H
(500 MHz, CDCl3
NOE
(500 MHz, CDCl3)
)
Scheme 4. Determination of stereochemistry of 14.
(COCl)2
DMSO
OH
i-Pr2NEt
O
O
OHC
TBS
O
O
CH2Cl2, –78 °C
then 0 °C, 30%
O
O
OTES
1
(S)-2-methyl-1-butanol
16
CHO
13
14
11
2
20
O
OTES
17
1) LDA, 3-pentanone
C1–C13 segment 15
C14–C20 segment 17
16
THF, –78 °C, 89%
14
20
2) TESCl, imidazole
DMF, RT, 95%
C14–C20 segment 17
O
TBS
O
OH
Sn(OTf)2
Et3N
Scheme 5. Synthesis of C14-C20 segment 17.
O
O
O
OTES
17
O
13
CH2Cl2
–78 °C, 99%
21
Table 1. Study of Aldol Coupling Reactiona)
O
Scheme 6. Aldol coupling reaction between C1-C13 seg-
ment 15 and C14-C20 segment 17.
TBS DMBOM
O
O
O
OTES
1
CHO
13
14
O
11
2
20
Table 2. Deuteration of Ketone 17
model compound 18
C14–C20 segment 17
O
OTES
O
OTES
1) base (1.1 equiv)
O
TBS
DMBOM
THF, –78 °C
D 14
14
O
O
OH
O
OTES
17
20
20
2) D2O
–78 °C to rt
base
C14–C20 segment 17
20
O
13
THF, –78 °C
Recovered
ketones
Yield of deuterated
compound 20/%a)
19
Entry
Base
Entry
Base
LDA
LHMDS
Yield/%
1
2
3
4
LDA
quant.
quant.
quant.
quant.
0
0
70
70
1
2
3
9
17
43
LHMDS
KHMDS
NaHMDS
NaHMDS
1
a) DMBOM: [(3,4-dimethoxybenzyl)oxy]methyl.
a) The deuteration yield was calculated by H NMR.

I. Hayakawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) 1081
O
Total Synthesis of (2¤S)- and (2¤R)-Auripyrones B. We
next tried the synthesis of (2¤S)- and (2¤R)-auripyrones B to
determine the absolute structure of auripyrones B (2). Therefore,
we planned the conversion of auripyrone A (1) into B (2) by
removal of the isovaleryl group at C11 in auripyrone A (1) and
subsequent esterification with optically active 2-methylbutanoic
acid. Thus, hydrolysis of the isovaleryl group of auripyrone A (1)
with LiOH in aqueous methanol was attempted (Scheme 8).
However, we could not obtain the desired deacyl derivative 24,
but a bis(pyrone) compound 25. Bis(pyrone) compound 25 was
thought to be produced by deprotonation at C14 and elimination.
On the other hand, Jung and co-workers reported that the
hydrolysis of auripyrone A (1) under similar conditions
(KOH(aq)/THF) gave the C14-epimerized elimination com-
pounds 26 and 27 (Scheme 9).6 From these results, auripyrone
A (1) was shown to be easily deprotonated at the C14 position
under basic conditions, causing side reactions.
OH OR1
O
O
O
12
14
18
9
13
15
17
O
O
22
R1 =
Me
Me
H
H
γ-pyrone
γ-pyrone
9
9
Me
Me
O
O
OH
17 R2
OH
17 R2
OR1
OR1
12
14
12
13
13
O
O
14
Me
Me
Me
O
O
Me
R2 =
Me
Me
18
23a
23b
1) AcOH
THF–H2O
RT, 73%
O
Me
H
TBS
O
Me
H
O
OH
γ-pyrone
γ-pyrone
O
O
OTES
17
9
9
2) Dess–Martin
periodinane
CH2Cl2, RT, 83%
Me
Me
O
13
O
O
R2
R2
OR1
O
13 OR1
O
17
17
13
21
12
12
14
14
Me
Me
15
15
Me
O
O
Me
Me
Me
O
O
TBS
O
O
O
O
O
O
HF·py
17
THF–py
60 °C, 22%
O
15
O
14
22
13
O
O
O
12
11
O
O
O
9
O
O
O
O
O
auripyrone A (1)
O
Figure 2. Spiroacetalization of triketone 22.
auripyrone A (1)
Scheme 7. Total synthesis of auripyrone A (1).
15
O
O
O
O
O
14
O
O
LiOH
O 13
O
O
MeOH–H2O, RT
9
11 O
O
OH
11
24
auripyrone A (1)
base
O
O
O
O
15
O
O
14
14
13
O
OH OH
O
9
11
O
11 OH
25
81%
Scheme 8. Hydrolysis of auripyrone A (1).

1082 Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) BCSJ AWARD ARTICLE
O
O
O
14
O
O
15
O
11
O
O
14
O
26
53%
+
O
9
O
13
KOH aq
THF
11
O
O
O
O
14
auripyrone A (1)
O
O
11
27
22%
Scheme 9. Hydrolysis of auripyrone A (1) by Jung and co-workers.
Therefore, we attempted the synthesis of auripyrone B (2) by
using our synthetic strategy for auripyrone A (1) (Scheme 10).
Esterification between homoallylic alcohol 14 and (S)-2-
methylbutanoic (28)15 by using Yamaguchi conditions16 gave
compound 29. The terminal olefin in 29 was transformed into a
diol, which was oxidatively cleaved to afford aldehyde 30. The
coupling reaction between aldehyde 30 and C14-C20 segment
17 via the Mukaiyama Sn(II)-promoted aldol reaction14 gave
the coupling product 31 as a diastereomeric mixture. Removal
of the TES group in 31 and subsequent oxidation of the diol
group afforded triketone 32 as a mixture of the keto and enol
forms, a precursor of spiroacetalization. Removal of the TBS
group in triketone 32 by HF¢py and a spontaneous spiroace-
talization gave (2¤S)-auripyrone B (33).
IC50 values of synthetic auripyrones A (1) and B (33) were
about 10-fold larger (less cytotoxic) than the reported IC50
values of natural auripyrones,2 maybe because of the condition
of the HeLa S3 cells. 2¤-epi Auripyrone B (36) showed
cytotoxicity, with an IC50 of 3.4 ¯g mL¹1. From these results,
the structure of the O11-acyl group in auripyrones was shown to
be unimportant for cytotoxicity. On the other hand, bis(pyrone)
compound 25 showed no cytotoxicity even at 10 ¯g mL¹1. This
result suggested that the spiro structure of auripyrones is
essential for their cytotoxicity.
The cytotoxicities of synthetic auripyrones A (1) and B (33)
were evaluated against a panel of 39 human cancer cell lines
(termed JFCR39) at the Japanese Foundation for Cancer
Research (Table 4). Auripyrones A (1) and B (33) each showed
broad cytotoxicity in the panel, respectively. On the basis of the
COMPARE analysis,17 the patterns of the differential cyto-
toxicities of auripyrones A (1) and B (33) suggested that they
inhibited cancer cell proliferation through a novel mechanism.
Also, (2¤R)-auripyrone B (36) was synthesized from homo-
allylic alcohol 14 in the same manner with (R)-2-methyl-
butanoic (34) (Scheme 11).
Determination of the Absolute Configuration of Auri-
pyrone B. With both diastereomers (2¤S)-auripyrone B (33)
and (2¤R)-auripyrone B (36) in hand, the determination of
configuration of C2¤ in auripyrone B was determined by com-
Conclusion
In conclusion, we have achieved the total synthesis of
auripyrones A (1) (2.6% overall yield in 13 steps) and B (2)
(2.8% overall yield in 13 steps), featuring a diastereoselective
aldol-type reaction between 2,6-diethyl-3,5-dimethyl-4-pyrone
(8) and optically active aldehyde 10 to construct three con-
tiguous stereocenters. From this synthetic work, we have
established the stereostructure and absolute configuration of
auripyrone B (2). Furthermore, we have investigated the
cytotoxicities of auripyrones against a panel of 39 human
cancer cell lines. Auripyrones A (1) and B (2) were COMPARE-
negative, suggesting that they inhibit cancer cell proliferation
through a novel mechanism. Further studies on the synthesis
of O11-modified probe molecules of auripyrones for use in the
search for target biomolecules are currently in progress.
1
paring the H NMR spectra of synthetic samples with those
reported for the natural auripyrone B (2) (Figure 3). The
chemical shifts of protons in the acyl group (H4¤, H5¤) in (2¤S)-
auripyrone B (33) were different from those of (2¤R)-auripyrone
1
B (36). The H NMR data of (2¤S)-auripyrone B (33) were in
good agreement with those of the natural one. Furthermore,
comparison of the optical rotations of synthetic (2¤S)-auri-
pyrone B (33) and natural auripyrone B (2) determined the
absolute configuration of auripyrone B (2): The optical rotation
25
of synthetic (2¤S)-auripyrone B (33) {½¡ꢀD = +43 (c = 0.29,
CHCl3)} was in accordance with that of the natural one2
25
{½¡ꢀD = +39 (c = 0.14, CHCl3)} to clarify the absolute con-
figuration of auripyrone B (2) as depicted in Figure 4.
Biological Evaluation of Auripyrones A and B. Table 3
shows the cytotoxic activities of auripyrones A (1) and B (2),
2¤-epi auripyrone B (36), and bis(pyrone) compound 25 against
HeLa S3 cells. Auripyrones A (1) showed an IC50 value of
cytotoxic activity equivalent to that of auripyrone B (2). The
Experimental
General.
All reagents and dry solvents were used as
obtained from commercial supplies unless otherwise noted.
Organic solvents for moisture-sensitive reactions were distilled

I. Hayakawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) 1083
O
S
OH
O
O
O
TBS
O
TBS
O
O
28
OH
11
O
1
(89% ee)
13
O
2,4,6-trichlorobenzoyl
chloride, Et3N, DMAP
toluene, –78 °C to 0 °C, 93%
14
29
1) OsO4, NMO
acetone–H2O
RT, 94%
O
TBS
O
O
O
O
OTES
1
CHO
2) NaIO4
acetone–H2O
14
O
11
13
20
82%
30
17
C1–C13 segment
C14–C20 segment
O
1) AcOH
THF–H2O
RT, 90%
TBS
O
O
OH
Sn(OTf)2
Et3N
O
O
OTES
17
13
O
CH2Cl2, –78 °C
2) Dess–Martin
periodinane
CH2Cl2, RT, 95%
99%
31
O
O
TBS
O
O
O
O
O
O
HF·py
THF–py
60 °C, 17%
32
O
O
O
O
O
2'
O
O
(2'S)-auripyrone B (33)
Scheme 10. Total synthesis of (2¤S)-auripyrone B (33).
O
R
OH
O
O
O
O
TBS
O
TBS
O
O
34
OH
11
O
1
(87% ee)
2,4,6-trichlorobenzoyl chloride
Et3N, DMAP, toluene
14
35
–78 °C to 0 °C, 94%
O
O
O
O
O
O
11
2'
O
(2'R)-auripyrone B (36)
Scheme 11. Total synthesis of (2¤R)-auripyrone B (36).
by standard procedure. Column chromatography was per-
formed using silica gel (75-200 or 45-75 ¯m). All moisture-
sensitive reactions were performed under an atmosphere of
argon or nitrogen, and the starting materials were azeotropi-
cally dried with benzene before use. Optical rotations were
measured on digital polarimeter at room temperature, using

1084 Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) BCSJ AWARD ARTICLE
Table 4. GI50 Values of Auripyrones A (1) and B (33)
against 39 Human Cancer Cell Lines
GI50a),b)/¯M
Cell line
Auripyrone Auripyrone
A (1)
B (33)
Breast
HBC-4
BSY-1
HBC-5
MCF-7
4.3
2.0
5.2
4.5
4.3
4.5
15>
3.9
12
3.1
8.5
2.6
3.4
3.3
4.6>
3.4
3.5
4.6
2.4
4.7
5.1
3.5
3.5
5.5
2.9
3.6
10>
6.7
13
7.3
5.7
4.4
2.8
2.1
3.0
2.8
2.6
20>
3.5
¹5.35
0.36
1
3.5
1.9
3.6
3.7
2.5
3.0
4.5
2.9
2.4
2.0
3.4
1.8
2.6
2.8
2.6
2.3
2.9
3.8
1.8
3.2
3.2
2.4
2.2
2.2
2.1
2.8
3.7
3.6
3.7
3.0
3.5
3.7
2.5
2.3
2.5
2.3
2.6
4.4
2.9
¹5.55
0.19
0.4
MDA-MB-231
Central nervous U251
system
Colon
Lung
SF-268
SF-295
SF-539
SNB-75
SNB-78
HCC2998
KM-12
HT-29
HCT-15
HCT-116
NCI-H23
NCI-H226
NCI-H522
NCI-H460
A549
DMS273
DMS114
LOX-IMVI
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
SK-OV-3
RXF-631L
ACHN
St-4
MKN1
MKN7
MKN28
MKN45
MKN74
DU-145
PC-3
Figure 3. Partial 1H NMR spectra (600 MHz, C6D6) of
synthetic auripyrone B and of the natural one.
O
Melanoma
Ovary
O
O
O
O
2'
5'
O
O
4'
auripyrone B (2)
Kidney
Figure 4. Absolute stereochemistry of auripyrone B (2).
Stomach
Table 3. Cytotoxicities of Auripyrones and Their Analogues
Against HeLa S3 Cells
¹1
IC50 values/¯g mL
Auripyrone A (1)
Auripyrone B (33)
2¤-epi Auripyrone B (36)
Bis(pyrone) compound 25
3.1 (lit. 0.26)
3.1 (lit. 0.48)
3.4
Prostate
MG-MIDc)
Deltad)
Rangee)
>10
a) Concentrations for the inhibition of cell growth at 50%
relative to control. b) Cell growth was determined according
to the sulforhodamine B assay. c) Mean GI50 value in all of
the cell lines tested. d) Difference in the GI50 value between
the most-sensitive cells and the MG-MID value. e) Difference
in the log GI50 value between the most- and least-sensitive
cells.
the sodium D line. Infrared (IR) spectra were recorded on a
FT IR system and only selected peaks are reported. 1H and 13
C
nuclear magnetic resonance (NMR) spectra were run at various
field strengths as indicated. The 1H and 13C chemical shifts (¤)
are reported in parts per million (ppm) downfield relative to
tetramethylsilane (TMS), CDCl3 (¤H 7.26 and ¤c 77.0) or C6D6
(¤H 7.16 and ¤c 128.0). Coupling constants (J) are reported in
Hz. Multiplicities are reported using the following abbrevia-
tions: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet. High-resolution mass spectra (HRMS) were recorded
by electrospray ionization (ESI)/time-of-flight (TOF) experi-
ments. Melting points are uncorrected.
Aldol 11. To a stirred solution of 2,6-diethyl-3,5-dimethyl-
4-pyrone (8) (200 mg, 1.11 mmol) in THF (1.5 mL) was added
NaHMDS (1.0 M solution in THF, 1.15 mL, 1.15 mmol) at
¹78 °C. After being stirred at ¹78 °C for 1.5 h, a solution of

I. Hayakawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) 1085
aldehyde 10 (275 mg, 0.832 mmol) in THF (1.5 mL) was added
via cannula. The mixture was stirred at ¹78 °C for 2.3 h,
diluted with saturated aqueous NH4Cl (10 mL), and extracted
with EtOAc (3 © 20 mL). The combined extracts were washed
with brine, dried over Na2SO4, filtered, and concentrated. The
residual oil was purified by column chromatography on silica
gel (30 g, hexane-EtOAc 7:1 ¼ 3:1) to give a diastereomeric
mixture of aldols (290 mg, 68%) and recovered 2,6-diethyl-3,5-
dimethyl-4-pyrone (8) (74.5 mg, 37%). Further purification of
the diastereomeric mixture of aldols by column chromatog-
raphy on silica gel (FL-60D, 26 g, benzene-acetone 20:1;
FL-60D, 12 g, benzene-acetone 20:1) gave aldol 11 (199 mg,
47%) and an inseparable mixture of undesired diastereomers
(90.6 mg, 21%) as colorless powder, respectively: Rf = 0.33
mixture was stirred at room temperature for 20 min, concen-
trated, diluted with half-saturated brine (10 mL), and extracted
with EtOAc (3 © 10 mL). The combined extracts were dried
over Na2SO4, filtered, and concentrated. The residual oil was
purified by column chromatography on silica gel (10 g,
hexane-EtOAc 5:1 ¼ 3:1 ¼ 1:1) to give alcohol 11b (92.7
mg, 92%) as a colorless oil: Rf = 0.37 (1:1 hexane/EtOAc);
24
½¡ꢀD ¹2.2 (c 0.815, CHCl3); IR (CHCl3): 3416, 1653, 1592,
¹1
1463, 1378 cm
;
1H NMR (270 MHz, CDCl3): ¤ 4.12 (dd,
J = 9.0, 1.6 Hz, 1H), 3.62-3.45 (m, 2H), 3.20 (dq, J = 9.0,
7.0 Hz, 1H), 2.68 (dq, J = 15.2, 7.6 Hz, 1H), 2.55 (dq, J =
15.2, 7.6 Hz, 1H), 2.05-1.85 (m, 1H), 1.97 (s, 3H), 1.95 (s,
3H), 1.23 (t, J = 7.4 Hz, 3H), 1.15 (d, J = 6.8 Hz, 3H), 0.93
(d, J = 7.0 Hz, 3H), 0.80 (s, 9H), 0.02 (s, 3H), ¹0.40 (s, 3H),
A signal due to one proton (OH) was not observed; 13C NMR
(67.8 MHz, CDCl3): ¤ 179.8, 165.0, 163.9, 119.3, 117.9, 73.1,
65.0, 39.9, 38.6, 25.9 (3C), 24.7, 18.1, 15.2, 11.4, 9.8, 9.5, 9.4,
¹4.8 (2C); HRMS (ESI): m/z 405.2461, calcd for C21H38O4-
SiNa [M + Na]+ 405.2437.
23
(1:1 hexane/EtOAc); mp 136-138 °C; ½¡ꢀD ¹7.2 (c 0.90,
¹1
CHCl3); IR (CHCl3): 3500 (br), 1655, 1595 cm
;
1H NMR
(270 MHz, CDCl3): ¤ 7.45-7.40 (m, 6H), 7.34-7.20 (m, 9H),
4.10 (dd, J = 9.7, 3.2 Hz, 1H), 3.36-3.19 (m, 2H), 3.07 (dq,
J = 9.7, 7.2 Hz, 1H), 2.62 (q, J = 7.6 Hz, 2H), 2.10-1.80 (m,
1H), 1.96 (s, 3H), 1.93 (s, 3H), 1.22 (t, J = 7.6 Hz, 3H), 1.12
(d, J = 7.2 Hz, 3H), 1.02 (d, J = 7.1 Hz, 3H), A signal due to
one proton (OH) was not observed; 13C NMR (67.8 MHz,
CDCl3): ¤ 179.5, 164.7, 163.7, 143.6 (3C), 128.4 (6C), 127.7
(6C), 126.9 (3C), 119.1, 117.6, 86.7, 74.1, 67.2, 38.8, 34.8,
24.7, 14.7, 11.2, 9.6, 9.5, 9.2; HRMS (ESI): m/z 533.2664,
calcd for C34H38O4Na [M + Na]+ 533.2668.
To a stirred solution of oxalyl chloride (70.0 ¯L, 0.800
mmol) in CH2Cl2 (0.4 mL) was added DMSO (4.0 M solution
in CH2Cl2, 0.500 mL, 2.00 mmol) at ¹78 °C. The mixture was
stirred at ¹78 °C for 30 min, and a solution of alcohol 11b
(151 mg, 0.394 mmol) in CH2Cl2 (1.0 mL) was added via
cannula. The mixture was stirred at ¹78 °C for 15 min, and
diisopropylethylamine (0.280 mL, 1.61 mmol) was added. The
resulting mixture was stirred at ¹78 °C for 15 min, warmed to
0 °C, and stirred for an additional 15 min. The mixture was
diluted with pH 6.8 phosphate buffer (5 mL) and extracted
with EtOAc (3 © 10 mL). The combined extracts were washed
with brine, dried over Na2SO4, filtered, and concentrated.
The residual oil was purified by column chromatography on
silica gel (6.5 g, hexane-EtOAc 3:1 ¼ 1:1) to give aldehyde
12 (149 mg, 99%) as a colorless oil: Rf = 0.53 (1:1 hexane/
Aldehyde 12. To a stirred solution of aldol 11 (1.61 g,
3.16 mmol) in DMF (3 mL) were added imidazole (2.10 g,
30.1 mmol) and tert-butyldimethylsilyl chloride (2.40 g, 15.9
mmol) at room temperature. The mixture was stirred at 70 °C
for 22 h, diluted with H2O (30 mL) at room temperature, and
extracted with Et2O (3 © 50 mL). The combined extracts were
washed with brine, dried over Na2SO4, filtered, and concen-
trated. The residual oil was purified by column chromatography
on silica gel (60 g, hexane-EtOAc 10:1 ¼ 5:1 ¼ 1:1) to give
tert-butyldimethylsilyl ether 11a (1.95 g, 99%) as a yellow
amorphous solid; Rf = 0.73 (1:1 hexane/EtOAc); mp 37-
25
EtOAc); ½¡ꢀD +29.0 (c 0.813, CHCl3); IR (CHCl3): 2827,
¹1
2786, 1728, 1655, 1595, 1463, 1426, 1377 cm
;
1H NMR
(270 MHz, CDCl3): ¤ 9.71 (s, 1H), 4.54 (dd, J = 8.9, 1.9 Hz,
1H), 3.20 (dq, J = 8.9, 7.1 Hz, 1H), 2.70 (dq, J = 15.2, 7.6 Hz,
1H), 2.57 (dq, J = 15.2, 7.6 Hz, 1H), 2.52 (dq, J = 1.9, 6.8 Hz,
1H), 1.97 (s, 3H), 1.95 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H), 1.22
(d, J = 6.8 Hz, 3H), 1.17 (d, J = 7.1 Hz, 3H), 0.74 (s, 9H),
¹0.09 (s, 3H), ¹0.34 (s, 3H); 13C NMR (67.8 MHz, CDCl3): ¤
203.9, 179.6, 163.9, 163.5, 119.8, 118.2, 72.3, 49.8, 40.1, 25.7
(3C), 24.8, 18.0, 15.1, 11.5, 9.9, 9.6, 6.4, ¹4.4, ¹4.9; HRMS
(ESI): m/z 403.2275, calcd for C21H36O4SiNa [M + Na]+
403.2281.
Homoallylic Alcohol 14. To a stirred solution of potassium
tert-butoxide (455 mg, 4.05 mmol) in THF (1.3 mL) were added
trans-2-butene (1.20 mL, 12.9 mmol) and n-BuLi (1.57 M
solution in hexane, 2.55 mL, 4.00 mmol) at ¹78 °C. After the
mixture was stirred at ¹40 °C for 1 h, a solution of (¹)-B-
methoxydiisopinocampheylborane (2.10 g, 6.64 mmol) in THF
(2.1 mL) was added via cannula at ¹78 °C. After 40 min, boron
trifluoride diethyl etherate (0.754 mL, 6.00 mmol) and a solu-
tion of aldehyde 12 (780 mg, 2.05 mmol) in THF (2.3 mL) were
added successively. The mixture was stirred at ¹40 °C for 8.3 h
and diluted with a 1:1 mixture of Et2O and EtOH (10 mL). The
mixture was warmed up to room temperature and treated with a
1:1 mixture of 20% H2O2 and 20% NaOH (10 mL). After being
25
39 °C; ½¡ꢀD +4.1 (c 0.405, CHCl3); IR (CHCl3): 1655,
1
1595 cm¹1; H NMR (270 MHz, CDCl3): ¤ 7.45-7.36 (m, 6H),
7.35-7.20 (m, 9H), 4.06 (d, J = 8.9 Hz, 1H), 3.20-3.00 (m,
3H), 2.68 (dq, J = 15.2, 7.6 Hz, 1H), 2.56 (dq, J = 15.2,
7.6 Hz, 1H), 2.05-1.88 (m, 1H), 1.94 (s, 3H), 1.94 (s, 3H), 1.25
(t, J = 7.6 Hz, 3H), 1.13 (d, J = 7.0 Hz, 3H), 0.94 (d, J =
6.8 Hz, 3H), 0.63 (s, 9H), ¹0.35 (s, 3H), ¹0.48 (s, 3H);
13C NMR (67.8 MHz, CDCl3): ¤ 179.6, 164.7, 163.6, 144.1
(3C), 128.5 (6C), 127.5 (6C), 126.7 (3C), 119.3, 117.9, 86.5,
73.6, 66.6, 40.3, 36.8, 25.8 (3C), 24.7, 18.1, 15.1, 11.3, 10.1,
9.8, 9.5, ¹4.6, ¹4.7; HRMS (ESI): m/z 647.3532, calcd for
C40H52O4SiNa [M + Na]+ 647.3533; Anal. Found: C, 76.47;
H, 8.47%. Calcd for C40H52O4: C, 76.88; H, 8.39%.
To a stirred solution of tert-butyldimethylsilyl ether 11a
(165 mg, 0.265 mmol) in Et2O (3 mL) was added formic acid
(6 mL) at room temperature. The mixture was stirred at room
temperature for 10 min, poured into saturated aqueous NaHCO3
(150 mL) at 0 °C, and extracted with Et2O (3 © 20 mL). The
combined extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated to afford a crude formate. The crude
formate was dissolved in methanol (9 mL), and 25% aqueous
NH3 (3 mL) was added to the mixture at room temperature. The

1086 Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) BCSJ AWARD ARTICLE
stirred for 13 h, the mixture was extracted with EtOAc (3 ©
15 mL). The combined extracts were washed with brine, dried
over Na2SO4, filtered, and concentrated. The residual oil was
purified by column chromatography on silica gel (FL-60D,
25 g, hexane-EtOAc 7:1; FL-60D, 25 g, hexane-EtOAc 7:1;
FL-60D, 25 g, hexane-EtOAc 7:1 ¼ 5:1 ¼ 3:1) to give homo-
allylic alcohol 14 (636 mg, 71%) as colorless powder: Rf =
(dd, J = 8.4, 6.8 Hz, 1H), 4.07 (dd, J = 7.5, 2.4 Hz, 1H), 3.75-
3.64 (m, 2H), 3.47-3.40 (m, 1H), 3.23 (dq, J = 7.5, 7.3 Hz,
1H), 2.70-2.55 (m, 3H), 2.30-2.05 (m, 6H), 1.99 (s, 3H), 1.95
(s, 3H), 1.24 (t, J = 7.6 Hz, 3H), 1.22 (d, J = 7.3 Hz, 3H), 0.97
(d, J = 6.2 Hz, 6H), 0.92 (d, J = 7.0 Hz, 3H), 0.86 (s, 9H), 0.83
(d, J = 6.8 Hz, 3H), 0.06 (s, 3H), ¹0.23 (s, 3H); 13C NMR
(67.8 MHz, CDCl3): ¤ 180.0, 172.6, 164.8, 164.4, 119.5, 118.0,
77.0, 73.4, 72.0, 64.3, 43.6, 40.9, 38.0, 37.6, 26.0 (3C), 25.4,
24.8, 22.5 (2C), 18.2, 14.9, 12.9, 11.4, 10.2, 10.0, 9.6, ¹3.9,
¹4.3; HRMS (ESI): m/z 577.3533, calcd for C30H54O7SiNa
[M + Na]+ 577.3537.
26
0.57 (1:1 hexane/EtOAc); mp 24-26 °C; ½¡ꢀD +9.7 (c 0.600,
CHCl3); IR (CHCl3): 3429, 1653, 1593, 1463, 1428,
¹1
1378 cm
;
1H NMR (270 MHz, CDCl3): ¤ 5.76 (ddd, J =
17.0, 10.5, 8.6 Hz, 1H), 5.15-5.05 (m, 2H), 4.03 (dd, J = 8.1,
2.4 Hz, 1H), 3.40 (t, J = 6.0 Hz, 1H), 3.28 (dq, J = 8.1, 7.0 Hz,
1H), 2.75-2.50 (m, 2H), 2.45-2.30 (m, 1H), 2.05-1.90 (m, 1H),
1.97 (s, 3H), 1.95 (s, 3H), 1.24 (t, J = 7.6 Hz, 3H), 1.17 (d,
J = 7.0 Hz, 3H), 1.02 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 7.0 Hz,
3H), 0.81 (s, 9H), 0.02 (s, 3H), ¹0.28 (s, 3H), A signal due
to one proton (OH) was not observed; 13C NMR (67.8 MHz,
CDCl3): ¤ 179.6, 164.7, 163.6, 139.7, 119.2, 117.9, 116.2,
75.3, 75.0, 41.6, 40.9, 39.0, 26.0 (3C), 24.8, 18.1, 17.5, 14.9,
11.4, 9.9, 9.6, 9.0, ¹4.1, ¹4.6; HRMS (ESI): m/z 459.2922,
calcd for C25H44O4SiNa [M + Na]+ 459.2907.
To a stirred solution of diol 14b (138 mg, 0.249 mmol) in
acetone (1 mL) and H2O (1 mL) was added NaIO4 (103 mg,
0.390 mmol). The mixture was stirred at room temperature for
15 min, diluted with half-saturated brine (5 mL), and extracted
with EtOAc (3 © 10 mL). The combined extracts were dried
over Na2SO4, filtered, and concentrated. The residual oil was
purified by column chromatography on silica gel (8 g, hexane-
EtOAc 3:1 ¼ 2:1 ¼ 1:1) to give C1-C13 segment 15 (94.3
mg, 72%) as a colorless oil and recovered diol 14b (18.1 mg,
26
13%); 15: Rf = 0.66 (1:1 hexane/EtOAc); ½¡ꢀD +17.7 (c
C1-C13 Segment 15. To a stirred solution of homoallylic
alcohol 14 (120 mg, 0.275 mmol) in pyridine (1 mL) were
added dimethylaminopyridine (3.70 mg, 30.3 ¯mol) and iso-
valeryl chloride (0.200 mL, 1.64 mmol) at room temperature.
The mixture was stirred at room temperature for 18 h, poured
into saturated aqueous NaHCO3 (50 mL) at 0 °C, and extracted
with EtOAc (3 © 10 mL). The combined extracts were washed
with brine, dried over Na2SO4, filtered, and concentrated. The
residual oil was purified by column chromatography on silica
gel (10 g, hexane-EtOAc 10:1 ¼ 5:1 ¼ 3:1; 10 g, hexane-
EtOAc 10:1 ¼ 5:1) to give ester 14a (143 mg, quant) as a
0.951, CHCl3); IR (CHCl3): 1725, 1653, 1594, 1463, 1427,
1377 cm¹1; 1H NMR (270 MHz, CDCl3): ¤ 9.67 (d, J = 3.2 Hz,
1H), 5.26 (dd, J = 8.9, 3.2 Hz, 1H), 4.06 (dd, J = 8.4, 2.1 Hz,
1H), 3.19 (dq, J = 8.4, 6.8 Hz, 1H), 2.80-2.55 (m, 3H), 2.26-
2.04 (m, 4H), 1.97 (s, 3H), 1.95 (s, 3H), 1.26 (t, J = 7.1 Hz,
3H), 1.15 (d, J = 6.5 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H), 0.98 (d,
J = 6.2 Hz, 6H), 0.96 (d, J = 6.8 Hz, 3H), 0.82 (s, 9H), 0.03 (s,
3H), ¹0.32 (s, 3H); 13C NMR (67.8 MHz, CDCl3): ¤ 202.8,
179.5, 172.3, 164.0, 163.8, 119.5, 118.1, 75.1, 73.4, 47.6, 43.3,
40.5, 38.8, 26.0 (3C), 25.5, 24.8, 22.5 (2C), 18.1, 15.3, 11.8,
11.4, 10.1, 9.9, 9.6, ¹3.9, ¹4.5; HRMS (ESI): m/z 545.3268,
calcd for C29H50O6SiNa [M + Na]+ 545.3274.
27
colorless oil: Rf = 0.77 (1:1 hexane/EtOAc); ½¡ꢀD +19.7 (c
1.445, CHCl3); IR (CHCl3): 1727, 1654, 1594, 1463, 1377
C14-C20 Segment 17. To a stirred solution of LDA (5.21
mmol) prepared from diisopropylamine (0.730 mL, 5.21 mmol)
and n-BuLi (1.63 M solution of in hexane, 3.20 mL, 5.22
mmol) in THF (6.0 mL) was added 3-pentanone (0.5 mL, 4.73
mmol) at ¹78 °C. After the mixture was stirred at ¹78 °C for
40 min, a solution of (S)-2-methylbutyraldehyde 16 (493 mg,
5.72 mmol) in THF (3.0 mL) was added via cannula. The
mixture was stirred at ¹78 °C for 1 h, diluted with saturated
aqueous NH4Cl (10 mL), and extracted with Et2O (3 © 10 mL).
The combined extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated. The residual oil was
purified by column chromatography on silica gel (FL-60D,
50 g, hexane-Et2O 10:1 ¼ 7:1) to give a diastereomeric mix-
ture of aldol 16a (728 mg, 89%) as a colorless oil: Rf = 0.63,
0.38 (1:1 hexane/EtOAc); IR (CHCl3): 3494, 1699, 1603,
¹1
cm
;
1H NMR (270 MHz, CDCl3): ¤ 5.73 (ddd, J = 17.5,
10.1, 6.8 Hz, 1H), 5.10-4.95 (m, 3H), 4.04 (d, J = 8.4 Hz, 1H),
3.16 (dq, J = 8.4, 7.1 Hz, 1H), 2.70-2.50 (m, 3H), 2.30-2.05
(m, 3H), 2.10-1.90 (m, 1H), 1.96 (s, 3H), 1.93 (s, 3H), 1.26 (t,
J = 7.6 Hz, 3H), 1.09 (d, J = 7.1 Hz, 3H), 0.98 (d, J = 6.2 Hz,
9H), 0.89 (d, J = 7.0 Hz, 3H), 0.83 (s, 9H), 0.07 (s, 3H), ¹0.34
(s, 3H); 13C NMR (67.8 MHz, CDCl3): ¤ 179.6, 172.5, 164.5,
163.6, 138.7, 119.4, 118.0, 115.9, 76.4, 72.6, 43.5, 40.6, 40.2,
37.9, 26.0 (3C), 25.4, 24.8, 22.6, 22.5, 18.2, 18.1, 15.4, 11.3,
9.9, 9.5, 9.3, ¹3.9, ¹4.5; HRMS (ESI): m/z 543.3486, calcd
for C30H52O5SiNa [M + Na]+ 543.3482.
To a stirred solution of ester 14a (143 mg, 0.186 mmol) in
acetone (1 mL) and H2O (1 mL) were added N-methylmorpho-
line oxide (103 mg, 0.879 mmol) and osmium tetroxide (0.1 M
solution in tert-butanol, 0.500 mL, 50.0 ¯mol) at room temper-
ature. The mixture was stirred at room temperature for 17 h,
diluted with saturated aqueous NaHSO3 (5 mL) at 0 °C, and
extracted with EtOAc (3 © 10 mL). The combined extracts
were washed with brine, dried over Na2SO4, filtered, and
concentrated. The residual oil was purified by column chroma-
tography on silica gel (10 g, hexane-EtOAc 1:1 ¼ 0:1) to give
a diastereomeric mixture of diol 14b (ca. 6:1) (138 mg, 90%) as
a colorless oil: Rf = 0.20 (major), 0.13 (minor) (1:1 hexane/
EtOAc); IR (CHCl3): 3421, 1726, 1651, 1592, 1464, 1378
1
1460, 1409, 1380 cm¹1; H NMR (270 MHz, CDCl3): ¤ 3.69
(ddd, J = 8.1, 5.9, 3.0 Hz, 0.51H), 3.61 (ddd, J = 6.7, 2.8,
2.8 Hz, 0.26H), 3.26 (ddd, J = 7.6, 5.9, 5.9 Hz, 0.23H), 2.88 (d,
J = 3.0 Hz, 0.3H), 2.87-2.63 (m, 1.2H), 2.63-2.36 (m, 2H),
2.27 (d, J = 5.9 Hz, 0.5H), 1.88-1.65 (m, 0.6H), 1.65-1.38 (m,
1.7H), 1.38-1.20 (m, 0.7H), 1.20-1.10 (m, 6H), 0.96-0.75 (m,
6H); 13C NMR (67.8 MHz, CDCl3): ¤ 217.1, 216.6, 216.5,
78.3, 75.7, 74.4, 48.6, 47.4, 47.0, 37.7, 36.8, 36.6, 36.2, 36.0,
34.8, 26.8, 24.9, 23.3, 16.1, 14.9, 14.1, 12.3, 11.8, 11.6, 10.9,
9.2, 7.7, 7.5, 7.5; HRMS (ESI): m/z 195.1359, calcd for
C10H20O2Na [M + Na]+ 195.1361.
1
cm¹1; H NMR (270 MHz, CDCl3) for major isomer: ¤ 5.05

I. Hayakawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) 1087
To a stirred solution of aldol 16a (322 mg, 1.87 mmol) and
imidazole (389 mg, 5.71 mmol) in DMF (4.6 mL) was added
triethylsilyl chloride (0.470 mL, 2.81 mmol) at room temper-
ature. The mixture was stirred at room temperature for 75 min,
diluted with H2O (15 mL), and extracted with Et2O (2 © 10
mL). The combined extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated. The residual oil was purified
by column chromatography on silica gel (15 g, hexane-Et2O
200:1 ¼ 100:1 ¼ 20:1) to give a diastereomeric mixture of
C14-C20 segment 17 (507 mg, 95%) as a yellow oil: Rf = 0.78
(3:1 hexane/EtOAc); IR (CHCl3): 1712, 1459, 1412, 1380
cm¹1; 1H NMR (270 MHz, CDCl3): ¤ 3.89 (dd, J = 8.5, 1.8 Hz,
0.21H), 3.88 (dd, J = 6.8, 1.9 Hz, 0.66H), 3.84 (dd, J = 8.9,
5.4 Hz, 0.13H), 2.86-2.65 (m, 1H), 2.65-2.35 (m, 2H), 1.55-
1.30 (m, 2H), 1.30-1.10 (m, 1H), 1.10-0.80 (m, 21H), 0.65-
0.45 (m, 6H); 13C NMR (67.8 MHz, CDCl3): ¤ 214.4, 214.2,
214.0, 78.6, 77.5, 77.0, 49.9, 49.7, 49.3, 40.3, 38.3, 37.9, 37.1,
36.8, 35.4, 26.9, 24.7, 23.7, 15.8, 14.2, 14.0, 13.4, 12.7, 12.5,
12.4, 12.3, 7.8, 7.5, 7.4, 7.1, 7.1, 5.5, 5.4, 5.3; HRMS (ESI): m/z
309.2206, calcd for C16H34O2SiNa [M + Na]+ 309.2226.
room temperature for 6.5 h. The mixture was poured into
saturated aqueous NaHCO3 (70 mL) at 0 °C and extracted with
EtOAc (3 © 20 mL). The combined extracts were washed
with brine, dried over Na2SO4, filtered, and concentrated. The
residual oil was purified by column chromatography on silica
gel (6 g, hexane-EtOAc 3:1 ¼ 2:1 ¼ 1:1) to give a diastereo-
meric mixture of diol 21a (76.4 mg, 73%) as a colorless oil:
Rf = 0.74, 0.65, 0.58, 0.48 (1:1 hexane/EtOAc); IR (CHCl3):
¹1
3503, 1724, 1653, 1593, 1463, 1427, 1378 cm
;
1H NMR
(270 MHz, CDCl3): ¤ 5.12 (d, J = 9.1 Hz, 1H), 4.28 (d, J =
8.4 Hz, 1H), 3.94 (d, J = 9.5 Hz, 1H), 3.70-3.55 (m, 1H), 3.20-
3.10 (m, 1H), 3.15-2.80 (m, 3H), 2.70-2.50 (m, 4H), 2.30-2.05
(m, 5H), 1.96 (s, 3H), 1.95 (s, 3H), 1.55-1.40 (m, 2H), 1.30-
1.20 (m, 6H), 1.20-1.10 (m, 9H), 1.05-0.95 (m, 9H), 0.95-0.80
(m, 15H), 0.04 (s, 3H), ¹0.31 (s, 3H); 13C NMR (67.8 MHz,
CDCl3): ¤ 220.7, 219.5, 179.7, 179.5, 173.1, 172.6, 165.0,
164.0, 163.9, 163.6, 119.5, 119.3, 119.2, 118.0, 117.9 (2C),
77.2, 76.4, 76.3 (2C), 74.7, 74.1, 73.1, 72.6, 70.4, 51.1, 49.1,
47.0, 45.7, 43.7, 43.6, 43.4, 41.2, 40.5, 37.9, 37.8, 37.3, 36.3,
36.1, 34.7, 26.8, 26.7, 26.0 (2C), 25.5 (2C), 25.4, 24.9, 24.7,
22.6, 22.5 (2C), 18.3, 18.2, 18.1 (2C), 15.4, 15.3, 15.2, 14.9,
13.6, 12.0 (2C), 11.9, 11.5, 11.2, 11.1, 10.0 (2C), 9.9, 9.8,
9.5, 9.3, 9.1, 8.7, 7.1, ¹3.9, ¹4.0, ¹4.2, ¹4.3, ¹4.5; HRMS
(ESI): m/z 717.4735, calcd for C39H70O8SiNa [M + Na]+
717.4738.
Aldol 21.
To a stirred solution of Sn(OTf)2 (75.0 mg,
0.180 mmol) in CH2Cl2 (0.6 mL) were added triethylamine
(27.0 ¯L, 0.200 mmol) and a solution of C14-C20 segment 17
(40.0 mg, 0.140 mmol) in CH2Cl2 (0.4 mL) at ¹78 °C, and the
mixture was stirred at ¹78 °C for 1.3 h. After a solution of C1-
C13 segment 15 (21.9 mg, 0.042 mmol) in CH2Cl2 (0.4 mL) was
added via cannula, the reaction mixture was stirred at ¹78 °C
for 3 h and diluted with pH 6.8 phosphate buffer (5 mL). The
mixture was filtered through a pad of Celite, and the Celite was
rinsed with EtOAc (4 © 5 mL). The filtrate and rinses were
combined, and the layers were separated. The aqueous layer was
extracted with EtOAc (3 © 10 mL). The organic layer and
extracts were washed with brine, dried over Na2SO4, filtered,
and concentrated. The residual oil was purified by column
chromatography on silica gel (4 g, hexane-EtOAc 10:1 ¼
3:1 ¼ 2:1) to give a diastereomeric mixture of aldol 21 (33.6
mg, 99%) as a colorless oil: Rf = 0.73, 0.70, 0.64 (1:1 hexane/
EtOAc); IR (CHCl3): 3503, 1725, 1653, 1592, 1462, 1426,
1378 cm¹1; 1H NMR (270 MHz, CDCl3): ¤ 5.12 (d, J = 9.5 Hz,
1H), 4.38 (d, J = 8.4 Hz, 1H), 4.04 (d, J = 9.5 Hz, 1H), 3.93-
3.75 (m, 2H), 3.74-3.70 (m, 1H), 3.33-2.55 (m, 7H), 2.25-2.05
(m, 4H), 1.96 (s, 3H), 1.94 (s, 3H), 1.30-1.19 (m, 6H), 1.18-
1.06 (m, 6H), 1.05-0.92 (m, 21H), 0.90-0.80 (m, 15H), 0.59
(q, J = 8.1 Hz, 6H), 0.02 (s, 3H), ¹0.38 (s, 3H), A signal due
to one proton (OH) was not observed; 13C NMR (67.8 MHz,
CDCl3): ¤ 220.0, 219.1, 216.5, 179.7 (3C), 179.6, 172.7 (2C),
172.6, 165.3 (2C), 165.2, 164.4, 164.1, 163.4, 119.6, 119.2
(2C), 117.9 (2C), 79.2, 78.5, 78.1, 77.2, 76.5, 75.7, 74.3, 73.0
(2C), 71.8, 71.1, 70.2, 69.6, 51.2, 49.0, 48.9, 48.3, 48.0, 46.8,
43.6, 43.5 (2C), 41.3, 41.2, 40.0, 39.9, 38.6, 38.1, 38.0 (2C),
37.9, 35.6, 35.3 (2C), 35.0, 26.8, 26.2, 26.0, 25.5 (2C), 25.4,
24.9, 24.7, 24.4, 22.6, 18.3, 18.2 (2C), 16.4, 15.9, 15.6 (2C),
15.3, 15.1, 15.0, 14.9, 14.8, 14.2, 14.1, 13.8, 13.5 (2C), 12.6,
12.5, 12.3, 11.7, 11.1 (2C), 10.0, 9.9 (2C), 9.8, 9.6, 9.0, 8.7,
7.8, 7.1, 7.0, 5.5, 5.4 (3C), 5.2, ¹3.7, ¹3.9, ¹4.1, ¹4.3; HRMS
(ESI): m/z 831.5604, calcd for C45H84O8Si2Na [M + Na]+
831.5602.
To a stirred solution of diol 21a (76.4 mg, 0.110 mmol) in
CH2Cl2 (3.0 mL) was added Dess-Martin periodinane (184 mg,
0.434 mmol) at room temperature. The mixture was stirred
at room temperature for 20 min; diluted with a 1:1:2 mixture
of saturated aqueous NaHCO3, saturated aqueous Na2S2O3, and
H2O (4 mL); and extracted with Et2O (2 © 10 mL). The com-
bined extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated. The residual oil was purified by
column chromatography on silica gel (6 g, hexane-EtOAc
5:1 ¼ 3:1 ¼ 1:1) to give a keto-enol equilibrium mixture of
triketone 22 (63.7 mg, 83%) as a colorless amorphous solid:
25
Rf = 0.61 (1:1 hexane/EtOAc); mp 26-28 °C; ½¡ꢀD +16.9
(c 0.586, CHCl3); IR (CHCl3): 1724, 1653, 1593, 1463,
1
1378 cm¹1; H NMR (270 MHz, CDCl3): ¤ 16.93 (s, 0.06H),
16.80 (s, 0.04H), 16.66 (s, 0.10H), 5.50-5.39 (m, 0.3H), 5.32-
5.22 (m, 0.4H), 5.20-5.08 (m, 0.3H), 4.15-3.66 (m, 2H), 3.50-
3.30 (m, 0.5H), 3.25-3.00 (m, 1.5H), 2.80-2.50 (m, 2.8H),
2.25-1.80 (m, 13H), 1.40-0.70 (m, 39H), 0.10-0.05 (m, 3H),
{(¹0.10)-(¹0.32)} (m, 3H); 13C NMR (67.8 MHz, CDCl3):
¤ 210.1, 207.9, 206.2, 203.9, 202.8, 198.9, 198.4, 197.6,
195.0, 193.6, 193.5, 191.7, 191.4, 190.2, 189.5, 179.6, 179.5
(2C), 174.1, 172.3 (2C), 172.1, 172.0 (2C), 171.8, 171.7,
166.2, 165.7, 164.7, 164.6, 164.5 (2C), 164.4, 164.2 (2C),
164.0 (2C), 163.9, 128.1, 119.6 (2C), 119.5 (2C), 119.4
(2C), 117.8 (3C), 117.7, 109.5, 108.4, 105.8, 105.4, 105.0,
104.4, 104.2, 103.8, 103.5, 75.5, 75.4, 74.8, 74.6, 74.5, 74.3,
74.1, 73.9, 73.8, 73.6, 73.5, 58.2, 58.1, 57.7, 57.1, 53.2, 52.6,
51.8, 50.5, 47.3, 47.2, 46.9, 46.6, 46.5, 46.2, 46.0, 45.9 (2C),
45.8, 44.7, 43.4, 43.3 (2C), 43.2, 41.9, 40.3, 40.2 (2C), 40.1,
39.9, 39.8, 39.7, 39.5, 39.4, 39.3, 38.7, 38.6, 38.4, 38.3, 26.8,
26.7, 26.1, 25.9, 25.7 (2C), 25.4, 25.3 (2C), 25.0, 24.9, 22.5,
22.4, 20.9, 18.2, 18.1, 18.0, 16.9, 16.3, 16.0, 15.9, 15.8, 15.6,
15.4, 15.2, 14.4, 14.2, 14.1, 14.0, 13.9, 13.8, 13.5, 13.3, 13.2
(2C), 13.0, 12.5, 12.2 (2C), 12.1, 11.7, 11.6, 10.7, 10.4, 10.3,
Triketone 22. Aldol 21 (122 mg, 0.151 mmol) was treated
with a 4:4:1 mixture of acetic acid, H2O, and THF (4.5 mL) at

1088 Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) BCSJ AWARD ARTICLE
10.0, 9.5, 9.3, 9.0, 7.6, ¹3.7, ¹3.9, ¹4.0, ¹4.2, ¹4.7; HRMS
(ESI): m/z 713.4419, calcd for C39H66O8SiNa [M + Na]+
713.4425.
and triethylamine (0.602 mL, 4.53 mmol) in toluene (18 mL)
was added 2,4,6-trichlorobenzoyl chloride (0.742 mL, 4.75
mmol) at ¹78 °C. The mixture was stirred at 0 °C for 1.3 h,
diluted with saturated aqueous NaHCO3 (15 mL) at 0 °C, and
extracted with EtOAc (3 © 10 mL). The combined extracts
were washed with brine, dried over Na2SO4, filtered, and
concentrated. The residual oil was purified by column chroma-
tography on silica gel (10 g, hexane-EtOAc 5:1 ¼ 3:1) to give
ester 29 (104 mg, 93%) as a colorless oil: Rf = 0.77 (1:1
Auripyrone A (1). A solution of triketone 22 (32.5 mg,
47.0 ¯mol) in a 5:3:7 mixture of HF¢pyridine, pyridine, and
THF (5.0 mL) was stirred at 60 °C for 14.3 h. The mixture was
poured into saturated aqueous NaHCO3 (150 mL) at 0 °C and
extracted with EtOAc (3 © 20 mL). The combined extracts
were washed with brine, dried over Na2SO4, filtered, and
concentrated. The residual oil was purified by column chroma-
tography on silica gel (5 g, hexane-EtOAc 5:1 ¼ 2:1 ¼ 1:1)
and by preparative HPLC [Develosil ODS-HG-5 (250 © 20
mm), flow rate 5 mL min¹1; detection, UV 215 nm, solvent
80% aqueous MeOH] to give auripyrone A (1) (5.9 mg, 22%)
25
hexane/EtOAc); ½¡ꢀD +21.5 (c 1.316, CHCl3); IR (CHCl3):
1724, 1654, 1594, 1462, 1426, 1378 cm¹1; 1H NMR (270 MHz,
CDCl3): ¤ 5.78 (ddd, J = 17.3, 10.0, 7.8 Hz, 1H), 5.12-4.99
(m, 3H), 4.08 (d, J = 8.6 Hz, 1H), 3.17 (dq, J = 8.6, 7.3 Hz,
1H), 2.72-2.52 (m, 3H), 2.45-2.30 (m, 1H), 2.00-1.92 (m, 1H),
1.97 (s, 3H), 1.96 (s, 3H), 1.73 (ddq, J = 14.0, 7.0, 7.0 Hz, 1H),
1.48 (ddq, J = 14.0, 7.0, 7.0 Hz, 1H), 1.26 (t, J = 7.6 Hz, 3H),
1.20 (d, J = 7.3 Hz, 3H), 1.09 (d, J = 7.3 Hz, 3H), 0.98 (d,
J = 6.8 Hz, 3H), 0.94 (t, J = 7.6 Hz, 3H), 0.89 (d, J = 6.8 Hz,
3H), 0.83 (s, 9H), 0.07 (s, 3H), ¹0.33 (s, 3H); 13C NMR
(67.8 MHz, CDCl3): ¤ 179.6, 176.0, 164.4, 163.5, 138.7, 119.4,
118.0, 116.0, 76.2, 72.6, 41.6, 40.6, 40.3, 37.9, 26.6, 26.0 (3C),
24.8, 18.2, 18.1, 17.2, 15.5, 11.9, 11.4, 9.9, 9.5, 9.3, ¹3.8,
¹4.4; HRMS (ESI): m/z 543.3485, calcd for C30H52O5SiNa
[M + Na]+ 543.3482.
25
as a colorless solid: Rf = 0.37 (1:1 CH2Cl2/Et2O); ½¡ꢀD +47.3
(c 0.390, CHCl3); IR (CHCl3): 1725, 1655, 1623, 1598, 1462,
1
1387 cm¹1; H NMR (600 MHz, C6D6): ¤ 4.92 (dd, J = 3.3,
3.3 Hz, 1H), 3.96 (dd, J = 10.3, 2.1 Hz, 1H), 2.75 (dq,
J = 10.3, 7.0 Hz, 1H), 2.32 (q, J = 7.0 Hz, 1H), 2.31 (dq, J =
15.0, 7.5 Hz, 1H), 2.25 (ddq, J = 7.5, 7.5, 3.8 Hz, 1H), 2.21-
2.16 (m, 1H), 2.16-2.11 (m, 2H), 2.09 (dq, J = 15.0, 7.5 Hz,
1H), 2.03 (s, 3H), 1.98 (s, 3H), 1.85-1.80 (m, 2H), 1.64 (s, 3H),
1.56-1.48 (m, 1H), 1.40-1.33 (m, 1H), 1.12 (d, J = 7.0 Hz,
3H), 0.99 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.2 Hz, 3H), 0.90 (d,
J = 6.5 Hz, 3H), 0.89 (t, J = 7.6 Hz, 3H), 0.83 (t, J = 7.5 Hz,
3H), 0.77 (d, J = 7.0 Hz, 3H), 0.73 (d, J = 7.0 Hz, 3H), 0.63 (d,
J = 7.1 Hz, 3H); 13C NMR (150 MHz, C6D6): ¤ 191.8, 178.5,
172.0, 166.2, 162.1, 161.5, 121.3, 118.1, 107.8, 105.0, 75.2,
70.5, 44.5, 44.0, 37.2, 36.6, 34.1, 31.7, 26.4, 26.3, 24.7, 22.5,
22.3, 16.0, 12.1, 12.0, 11.9, 11.0, 10.8, 9.7, 9.5, 9.0, 8.1;
HRMS (ESI): m/z 581.3446, calcd for C33H50O7Na [M + Na]+
581.3454.
C1-C13 Segment 30. To a stirred solution of ester 29
(65.8 mg, 0.126 mmol) in acetone (1 mL) and H2O (1 mL) were
added N-methylmorpholine oxide (55.0 mg, 0.469 mmol) and
osmium tetroxide (0.1 M solution in tert-butanol, 0.300 mL,
30.0 ¯mol) at room temperature. The mixture was stirred at
room temperature for 14 h, diluted with saturated aqueous
NaHSO3 (10 mL) at 0 °C, and extracted with EtOAc (3 ©
10 mL). The combined extracts were washed with saturated
aqueous NaHSO3 and brine, dried over Na2SO4, filtered, and
concentrated. The residual oil was purified by column chroma-
tography on silica gel (7 g, hexane-EtOAc 1:1 ¼ 0:1) to give a
diastereomeric mixture of diol 29a (ca. 6:1) (65.5 mg, 94%) as
a colorless oil: Rf = 0.18 (major), 0.10 (minor) (1:1 hexane/
EtOAc); IR (CHCl3): 3424, 1724, 1651, 1591, 1462, 1380
Bis(pyrone) Compound 25.
To a stirred solution of
auripyrone A (1) (2.5 mg, 4.5 ¯mol) in MeOH (2 mL) was
added 1 M aqueous LiOH (2 mL) at room temperature. The
mixture was stirred at room temperature for 3.5 h, diluted with
saturated aqueous NH4Cl (5 mL) at 0 °C, and extracted with
EtOAc (3 © 20 mL). The combined extracts were washed with
brine, dried over Na2SO4, filtered, and concentrated. The
residual oil was purified by column chromatography on silica
gel (0.6 g, hexane-EtOAc 1:1 ¼ 0:1) to give bis(pyrone)
compound 25 (1.7 mg, 81%) as colorless crystals: Rf = 0.38
1
cm¹1; H NMR (270 MHz, CDCl3) for major isomer: ¤ 5.07
(dd, J = 8.6, 3.5 Hz, 1H), 4.10 (dd, J = 8.1, 1.9 Hz, 1H), 3.80-
3.62 (m, 2H), 3.50-3.38 (m, 1H), 3.24 (dq, J = 8.1, 7.3 Hz,
1H), 2.64 (dq, J = 7.6, 3.0 Hz, 2H), 2.63-2.55 (m, 1H), 2.43-
2.05 (m, 4H), 1.99 (s, 3H), 1.95 (s, 3H), 1.72 (ddq, J = 14.0,
7.0, 7.0 Hz, 1H), 1.47 (ddq, J = 14.0, 7.0, 7.0 Hz, 1H), 1.24 (t,
J = 7.3 Hz, 3H), 1.19 (d, J = 7.3 Hz, 3H), 1.18 (d, J = 7.0 Hz,
3H), 0.93 (t, J = 7.0 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.85 (s,
9H), 0.82 (d, J = 7.3 Hz, 3H), ¹0.18 (s, 3H), ¹0.24 (s, 3H);
13C NMR (67.8 MHz, CDCl3): ¤ 179.9, 176.1, 164.8, 164.4,
119.5, 118.0, 76.9, 73.3, 71.9, 64.4, 41.6, 40.9, 38.0, 37.6, 26.6,
26.0 (3C), 24.8, 18.2, 17.1, 15.1, 12.9, 11.9, 11.4, 10.2, 10.0,
9.6, ¹3.9, ¹4.3; HRMS (ESI): m/z 577.3558, calcd for
C30H54O7SiNa [M + Na]+ 577.3537.
To a stirred solution of diol 29a (88.2 mg, 0.159 mmol) in
acetone (1 mL) and H2O (1 mL) was added NaIO4 (73.2 mg,
0.277 mmol). The mixture was stirred at room temperature for
15 min, diluted with half saturated brine (5 mL), and extracted
with EtOAc (3 © 10 mL). The combined extracts were washed
with saturated aqueous NaHSO3 and brine, dried over Na2SO4,
filtered, and concentrated. The residual oil was purified
25
(1:1 hexane/acetone); ½¡ꢀD +21.7 (c 0.138, CHCl3); IR
1
(CHCl3): 3422, 1653, 1593, 1460, 1426, 1381 cm¹1; H NMR
(600 MHz, CDCl3): ¤ 4.01 (dd, J = 13.8, 9.7 Hz, 2H), 3.23-
3.16 (m, 2H), 3.02 (br s, 1H), 2.96-2.85 (m, 2H), 2.68 (dq,
J = 15.2, 7.6 Hz, 1H), 2.62 (dq, J = 15.2, 7.6 Hz, 1H), 2.00-
1.90 (m, 1H), 2.00 (s, 3H), 1.99 (s, 3H), 1.96 (s, 3H), 1.94 (s,
3H), 1.70-1.55 (m, 2H), 1.25 (t, J = 7.6 Hz, 3H), 1.23 (d,
J = 7.6 Hz, 3H), 1.19 (d, J = 7.0 Hz, 3H), 1.18 (d, J = 6.8 Hz,
3H), 1.05 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H);
13C NMR (150 MHz, CDCl3): ¤ 179.7, 179.6, 165.9, 164.2,
163.5, 163.4, 120.1, 119.8, 118.3, 118.1, 79.0, 78.8, 39.3 (2C),
37.0, 34.5, 27.7, 24.8, 17.9, 14.6, 14.4, 11.9, 11.4, 9.7 (2C), 9.5
(2C), 3.8; HRMS (ESI): m/z 497.2882, calcd for C28H42O6Na
[M + Na]+ 497.2879.
Ester 29. To a stirred solution of homoallylic alcohol 14
(94.2 mg, 0.216 mmol), dimethylaminopyridine (1.00 g, 8.19
mmol), (S)-2-methylbutanoic acid (28) (0.234 mL, 2.15 mmol),

I. Hayakawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) 1089
by column chromatography on silica gel (8 g, hexane-EtOAc
3:1 ¼ 2:1 ¼ 1:1) to give C1-C13 segment 30 (68.0 mg, 82%)
as a colorless oil: Rf = 0.73 (1:1 hexane/EtOAc); ½¡ꢀD +16.2
(45.9 mg, 90%) as a colorless oil: Rf = 0.67, 0.60, 0.50 (1:1
hexane/EtOAc); IR (CHCl3): 3523, 1723, 1652, 1592, 1462,
25
¹1
1427, 1379 cm ;
1H NMR (270 MHz, CDCl3): ¤ 5.10 (d,
(c 1.000, CHCl3); IR (CHCl3): 1725, 1654, 1594, 1462, 1426,
1378 cm¹1; 1H NMR (270 MHz, CDCl3): ¤ 9.69 (d, J = 3.2 Hz,
1H), 5.26 (dd, J = 9.5, 3.5 Hz, 1H), 4.07 (dd, J = 8.4, 2.2 Hz,
1H), 3.20 (dq, J = 8.4, 7.0 Hz, 1H), 2.80-2.30 (m, 4H), 2.17-
2.06 (m, 1H), 1.98 (s, 3H), 1.95 (s, 3H), 1.71 (ddq, J = 14.4,
7.2, 7.2 Hz, 1H), 1.47 (ddq, J = 14.4, 7.2, 7.2 Hz, 1H), 1.26 (t,
J = 7.6 Hz, 3H), 1.19 (d, J = 7.3 Hz, 3H), 1.15 (d, J = 8.1 Hz,
3H), 1.12 (d, J = 6.5 Hz, 3H), 0.96 (d, J = 7.0 Hz, 3H), 0.94 (t,
J = 7.3 Hz, 3H), 0.82 (s, 9H), 0.04 (s, 3H), ¹0.32 (s, 3H);
13C NMR (67.8 MHz, CDCl3): ¤ 202.7, 179.5, 175.9, 164.0,
163.8, 119.6, 118.1, 75.0, 73.6, 47.7, 41.4, 40.4, 38.8, 26.5,
26.0 (3C), 24.8, 18.2, 17.1, 15.5, 11.8, 11.7, 11.4, 10.0, 9.9,
9.6, ¹3.9, ¹4.5; HRMS (ESI): m/z 523.3432, calcd for
C29H50O6Si [M + H]+ 523.3455.
J = 9.5 Hz, 1H), 4.32-4.24 (m, 1H), 3.95 (d, J = 8.9 Hz, 1H),
3.70-3.55 (m, 1H), 3.25-3.10 (m, 1H), 3.08-2.75 (m, 2H),
2.75-2.50 (m, 4H), 2.50-2.28 (m, 1H), 1.95 (s, 3H), 1.93 (s,
3H), 1.80-1.62 (m, 2H), 1.58-1.35 (m, 2H), 1.30-1.05 (m,
15H), 1.05-0.75 (m, 27H), 0.03 (s, 3H), ¹0.33 (s, 3H);
13C NMR (67.8 MHz, CDCl3): ¤ 227.9, 220.8, 179.7, 176.1
(2C), 165.1, 165.0, 164.9, 163.6 (3C), 119.6, 119.2, 117.9,
117.7, 78.1, 77.2, 74.7, 74.3, 73.0, 70.2, 52.6, 50.2, 47.1, 46.9,
45.7, 45.5, 45.3, 44.7, 43.8, 41.6, 41.2, 41.1, 37.9, 37.3, 37.0,
36.4 (2C), 34.6, 33.7, 26.6, 26.1, 25.9, 25.0, 24.8, 18.3 (2C),
18.2, 17.2, 15.5, 15.4, 15.2, 15.0, 14.8, 12.5, 11.9, 11.2, 11.1
(2C), 10.0, 9.9 (2C), 9.6, 9.1, 8.7, ¹3.9, ¹4.2, ¹5.3; HRMS
(ESI): m/z 717.4725, calcd for C39H70O8SiNa [M + Na]+
717.4738.
Aldol 31.
To a stirred solution of Sn(OTf)2 (220 mg,
To a stirred solution of diol 31a (34.0 mg, 48.9 ¯mol) in
CH2Cl2 (1.5 mL) was added Dess-Martin periodinane (86.6
mg, 204 ¯mol) at room temperature. The mixture was stirred at
room temperature for 25 min; diluted with a 1:1:2 mixture of
saturated aqueous NaHCO3, saturated aqueous Na2S2O3, and
H2O (4 mL); and extracted with Et2O (2 © 10 mL). The
combined extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated. The residual oil was purified by
column chromatography on silica gel (10 g, hexane-EtOAc
5:1 ¼ 3:1 ¼ 1:1) to give a keto-enol equilibrium mixture of
triketone 32 (32.1 mg, 95%) as a colorless amorphous solid:
0.528 mmol) in CH2Cl2 (1.4 mL) were added triethylamine
(0.0700 mL, 0.527 mmol) and a solution of C14-C20 segment
17 (110 mg, 0.384 mmol) in CH2Cl2 (0.7 mL) at ¹78 °C. After
the mixture was stirred at ¹78 °C for 1.3 h, a solution of
aldehyde 30 (68.0 mg, 0.130 mmol) in CH2Cl2 (0.7 mL) was
added via cannula. The reaction mixture was stirred at ¹78 °C
for 2.5 h, diluted with pH 6.8 phosphate buffer (10 mL), and
filtrated through a pad of Celite. This Celite was rinsed with
EtOAc (4 © 5 mL). The filtrate and rinses were combined, and
the layers were separated. The aqueous layer was extracted
with EtOAc (3 © 10 mL). The organic layer and extracts were
washed with brine, dried over Na2SO4, filtered, and concen-
trated. The residual oil was purified by column chromatography
on silica gel (10 g, hexane-EtOAc 10:1 ¼ 3:1 ¼ 2:1) to give
a diastereomeric mixture of aldol 31 (104 mg, 99%) as a
25
Rf = 0.63 (1:1 hexane/EtOAc); ½¡ꢀD +15.9 (c 1.325, CHCl3);
¹1
IR (CHCl3): 1724, 1652, 1593, 1462, 1427, 1379 cm
;
1H NMR (270 MHz, CDCl3): ¤ 16.93 (s, 0.06H), 16.81 (s,
0.04H), 16.66 (s, 0.10H), 5.52-5.36 (m, 0.3H), 5.35-5.21 (m,
0.3H), 5.20-5.06 (m, 0.4H), 4.15-3.60 (m, 1.8H), 3.58-3.00
(m, 2H), 2.80-2.45 (m, 3H), 2.40-2.18 (m, 1H), 2.20-1.55
(m, 12H), 1.55-1.14 (m, 11H), 1.14-0.75 (m, 28H), {(0.10)-
(¹0.06)} (m, 3H), {(¹0.10)-(¹0.35)} (m, 3H); 13C NMR (67.8
MHz, CDCl3): ¤ 210.1, 206.1, 204.0, 203.9, 198.6, 197.6,
195.1, 194.0, 193.7, 191.4 (2C), 179.7, 179.6, 179.5, 177.8
(2C), 176.0, 175.9, 175.7 (2C), 175.6, 164.9, 164.8, 164.7
(2C), 164.6 (2C), 164.5 (2C), 164.4, 164.3 (2C), 164.2, 164.1,
164.0, 119.7, 119.6, 119.5 (2C), 119.4, 117.8 (3C), 109.4,
108.2, 106.0, 105.6, 105.1, 104.3, 104.0, 103.8, 103.5, 75.5,
75.4, 74.7, 74.4, 73.9, 73.7, 73.1, 57.6, 52.7, 50.4, 47.2, 46.8,
46.6, 46.2, 46.1, 46.0, 45.9, 44.8, 44.7, 42.0, 41.5, 41.4, 41.3
(2C), 41.2, 41.1, 40.3, 40.0, 39.8, 39.6 (2C), 39.5, 39.4 (2C),
39.3, 39.1, 38.7, 38.6, 38.5 (2C), 38.2, 26.9, 26.7 (2C), 26.5
(2C), 26.1, 26.0, 25.6, 24.9, 21.0, 18.4, 18.3, 18.2, 18.1, 16.9,
16.8, 16.4, 16.3, 16.1, 16.0, 14.6, 14.2, 14.0, 13.9, 13.8, 13.3,
13.2, 13.1, 13.0, 12.6, 12.2, 12.0, 11.9, 11.8 (2C), 11.6 (2C),
10.7, 10.5 (2C), 10.1 (2C), 10.0, 9.6, 9.3, 7.7, ¹3.5, ¹3.7,
¹3.8, ¹4.0, ¹4.4; HRMS (ESI): m/z 713.4432, calcd for
C39H66O8SiNa [M + Na]+ 713.4425.
colorless oil: Rf = 0.83, 0.77 (1:1 hexane/EtOAc); IR (CHCl3):
3509, 1723, 1653, 1592, 1461, 1426, 1379 cm
;
1H NMR
¹1
(270 MHz, CDCl3): ¤ 5.11 (d, J = 10.3 Hz, 1H), 4.39 (d, J =
8.6 Hz, 1H), 4.06 (d, J = 9.5 Hz, 1H), 4.02-3.80 (m, 1H), 3.76-
3.65 (m, 1H), 3.20-3.05 (m, 1H), 2.95-2.25 (m, 6H), 2.13-2.06
(m, 1H), 1.95 (s, 3H), 1.93 (s, 3H), 1.80-1.60 (m, 1H), 1.52-
1.33 (m, 2H), 1.30-1.00 (m, 15H), 1.00-0.85 (m, 18H), 0.85-
0.70 (m, 15H), 0.60 (q, J = 7.8 Hz, 6H), 0.55-0.48 (m, 2H),
0.01 (s, 3H), ¹0.39 (s, 3H); 13C NMR (67.8 MHz, CDCl3): ¤
220.0, 179.7, 179.5, 176.1, 175.8, 165.2, 163.9, 163.8, 163.4,
119.5, 119.1, 118.0, 117.9, 79.0, 78.1, 77.2, 75.7, 75.6, 72.9,
70.1, 60.3, 48.9, 46.9, 41.6, 41.4, 41.3, 40.3, 40.0, 38.7, 37.8,
35.4, 26.8, 26.6, 26.5, 26.0, 25.9, 24.8, 24.7, 24.4, 21.0, 18.3,
18.1, 17.2, 16.4, 15.6, 15.5, 15.0, 14.2, 12.2, 11.9, 11.7, 11.4,
11.1, 10.0, 9.9, 9.8, 9.5, 8.6, 8.2, 7.1, 7.0, 5.5, 5.4, 5.3, 5.2,
¹3.9, ¹4.3, ¹4.5; HRMS (ESI): m/z 831.5596, calcd for
C45H84O8Si2Na [M + Na]+ 831.5602.
Triketone 32. Aldol 31 (59.6 mg, 73.6 ¯mol) was treated
with a 4:4:1 mixture of acetic acid, H2O, and THF (4.5 mL) at
room temperature for 13.3 h. The mixture was poured into
saturated aqueous NaHCO3 (70 mL) at 0 °C and extracted with
EtOAc (3 © 20 mL). The combined extracts were washed with
saturated aqueous NaHCO3 and brine, dried over Na2SO4,
filtered, and concentrated. The residual oil was purified by
column chromatography on silica gel (10 g, hexane-EtOAc
3:1 ¼ 2:1 ¼ 1:1) to give a diastereomeric mixture of diol 31a
(2¤S)-Auripyrone B (Natural-Type Auripyrone B) (33).
A solution of triketone 32 (26.5 mg, 38.3 ¯mol) in a 5:3:7
mixture of HF¢pyridine, pyridine, and THF (10.0 mL) was
stirred at 60 °C for 17 h. The mixture was poured into saturated
aqueous NaHCO3 (150 mL) at 0 °C and extracted with EtOAc
(3 © 20 mL). The combined extracts were washed with satu-
rated aqueous NaHCO3 and brine, dried over Na2SO4, filtered,

1090 Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) BCSJ AWARD ARTICLE
and concentrated. The residual oil was purified by column
chromatography on silica gel (6 g, hexane-EtOAc 5:1 ¼
2:1 ¼ 1:1) and by preparative HPLC [Develosil ODS-HG-5
(250 © 20 mm), flow rate 5 mL min¹1; detection, UV 215 nm,
solvent 80% aqueous MeOH] to give (2¤S)-auripyrone B
(natural-type auripyrone B) (33) (3.6 mg, 17%) as colorless
concentrated. The residual oil was purified by column chroma-
tography on silica gel (7 g, hexane-EtOAc 1:1 ¼ 0:1) to give a
diastereomeric mixture of diol 35a (ca. 9:1) (84.5 mg, 85%) as
a colorless oil: Rf = 0.18 (major), 0.10 (minor) (1:1 hexane/
EtOAc); IR (CHCl3): 3422, 1724, 1651, 1591, 1462, 1380
cm¹1; 1H NMR (270 MHz, CDCl3): ¤ 5.05 (dd, J = 8.9, 3.5 Hz,
1H), 4.09 (dd, J = 9.7, 4.0 Hz, 1H), 3.75-3.64 (m, 2H), 3.47-
3.38 (m, 1H), 3.23 (dq, J = 7.6, 7.6 Hz, 1H), 2.64 (dq, J = 7.8,
3.5 Hz, 2H), 2.50-2.25 (m, 2H), 2.20-2.05 (m, 1H), 1.99 (s,
3H), 1.95 (s, 3H), 1.75 (ddq, J = 14.0, 7.0, 7.0 Hz, 1H), 1.45
(ddq, J = 14.0, 7.0, 7.0 Hz, 1H), 1.20 (d, J = 7.0 Hz, 3H), 1.17
(d, J = 8.1 Hz, 3H), 1.14 (d, J = 7.0 Hz, 3H), 0.89 (d, J =
7.3 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H), 0.81 (s, 9H), 0.80 (d,
J = 8.4 Hz, 3H), 0.04 (s, 3H), ¹0.28 (s, 3H), signals due to
two protons (OH) were not observed; 13C NMR (67.8 MHz,
CDCl3): ¤ 180.0, 176.1, 164.9, 164.4, 119.5, 118.0, 76.9,
73.3, 71.9, 64.4, 41.5, 40.9, 38.0, 37.5, 26.7, 26.0 (3C), 24.8,
18.2, 16.9, 15.0, 13.0, 11.8, 11.3, 10.1, 9.9, 9.6, ¹3.9, ¹4.3;
HRMS (ESI): m/z 555.3722, calcd for C30H55O7Si [M + H]+
555.3717.
25
crystals: Rf = 0.33 (1:1 CH2Cl2/Et2O); ½¡ꢀD +43.4 (c 0.293,
CHCl3); IR (CHCl3): 1726, 1655, 1623, 1597, 1462, 1387
1
cm¹1; H NMR (600 MHz, C6D6): ¤ 4.91 (dd, J = 3.4, 3.4 Hz,
1H), 3.97 (dd, J = 10.3, 2.1 Hz, 1H), 2.74 (dq, J = 10.3,
7.0 Hz, 1H), 2.43 (ddq, J = 7.0, 7.0, 7.0 Hz, 1H), 2.32 (q,
J = 7.0 Hz, 1H), 2.32-2.24 (m, 2H), 2.09 (dq, J = 15.0, 7.5 Hz,
1H), 2.03 (s, 3H), 1.98 (s, 3H), 1.88-1.70 (m, 3H), 1.66 (s,
3H), 1.58-1.45 (m, 1H), 1.43-1.38 (m, 1H), 1.37-1.30 (m, 1H),
1.16 (d, J = 7.0 Hz, 3H), 1.13 (d, J = 7.0 Hz, 3H), 0.99 (d,
J = 6.8 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H), 0.87 (t, J = 7.6 Hz,
3H), 0.83 (t, J = 7.5 Hz, 3H), 0.77 (d, J = 7.0 Hz, 3H), 0.72 (d,
J = 7.0 Hz, 3H), 0.63 (d, J = 7.1 Hz, 3H); 13C NMR (150 MHz,
C6D6): ¤ 191.8, 178.5, 175.9, 166.2, 162.0, 161.5, 121.3, 118.1,
107.8, 105.1, 75.2, 70.6, 44.5, 41.6, 37.2, 36.6, 34.1, 31.7,
27.4, 26.4, 24.7, 16.9, 15.9, 12.1, 12.0, 11.8, 11.8, 10.8, 10.7,
9.7, 9.4, 9.0, 8.2; HRMS (ESI): m/z 581.3472, calcd for
C33H50O7Na [M + Na]+ 581.3454.
To a stirred solution of diol 35a (144 mg, 0.264 mmol) in
acetone (1.5 mL) and H2O (1.5 mL) was added NaIO4 (120 mg,
0.445 mmol). The mixture was stirred at room temperature for
10 min, diluted with half saturated brine (5 mL), and extracted
with EtOAc (3 © 10 mL). The combined extracts were dried
over Na2SO4, filtered, and concentrated. The residual oil was
purified by column chromatography on silica gel (8 g, hexane-
EtOAc 3:1 ¼ 2:1 ¼ 1:1) to give aldehyde 35b (96.8 mg, 70%)
Ester 35. To a stirred solution of homoallylic alcohol 14
(149.5 mg, 0.342 mmol), dimethylaminopyridine (660 mg, 5.40
mmol), (R)-2-methylbutanoic acid (34) (0.123 mL, 1.13 mmol),
and triethylamine (0.317 mL, 2.39 mmol) in toluene (9 mL) was
added 2,4,6-trichlorobenzoyl chloride (0.374 mL, 2.39 mmol)
at ¹78 °C. The mixture was stirred at 0 °C for 2.5 h, diluted
with saturated aqueous NaHCO3 (15 mL) at 0 °C, and extracted
with EtOAc (3 © 10 mL). The combined extracts were washed
with brine, dried over Na2SO4, filtered, and concentrated. The
residual oil was purified by column chromatography on silica
gel (10 g, hexane-EtOAc 5:1 ¼ 3:1) to give ester 35 (182 mg,
25
as a colorless oil: Rf = 0.73 (1:1 hexane/EtOAc); ½¡ꢀD +11.0
(c 1.000, CHCl3); IR (CHCl3): 1726, 1654, 1594, 1462, 1426,
1378 cm¹1; 1H NMR (270 MHz, CDCl3): ¤ 9.68 (d, J = 3.5 Hz,
1H), 5.26 (dd, J = 9.1, 5.8 Hz, 1H), 4.07 (dd, J = 8.4, 1.0 Hz,
1H), 3.19 (dq, J = 8.4, 7.0 Hz, 1H), 2.80-2.35 (m, 4H), 2.18-
2.05 (m, 1H), 1.97 (s, 3H), 1.95 (s, 3H), 1.72 (ddq, J = 14.4,
7.2, 7.2 Hz, 1H), 1.49 (ddq, J = 14.4, 7.2, 7.2 Hz, 1H), 1.26 (t,
J = 7.6 Hz, 3H), 1.18 (d, J = 7.3 Hz, 3H), 1.14 (d, J = 7.0 Hz,
3H), 1.12 (d, J = 6.5 Hz, 3H), 0.95 (d, J = 7.6 Hz, 3H), 0.94 (t,
J = 7.3 Hz, 3H), 0.82 (s, 9H), 0.04 (s, 3H), ¹0.32 (s, 3H);
13C NMR (67.8 MHz, CDCl3): ¤ 202.7, 179.5, 175.8, 163.9,
163.8, 119.5, 118.1, 75.0, 73.3, 47.6, 41.3, 40.4, 38.9, 26.7,
26.0 (3C), 24.8 (2C), 18.2, 16.7, 15.4, 11.8, 11.4, 10.0, 9.9, 9.5,
¹3.9, ¹4.5; HRMS (ESI): m/z 523.3436, calcd for C29H51O6Si
[M + H]+ 523.3455.
25
quant) as a colorless oil: Rf = 0.77 (1:1 hexane/EtOAc); ½¡ꢀD
+14.7° (c 1.228, CHCl3); IR (CHCl3): 1724, 1654, 1594, 1462,
1426, 1378 cm¹1; H NMR (270 MHz, CDCl3): ¤ 5.73 (ddd,
1
J = 17.0, 10.0, 7.0 Hz, 1H), 5.10-4.97 (m, 3H), 4.08 (d,
J = 8.4 Hz, 1H), 3.16 (dq, J = 8.1, 7.6 Hz, 1H), 2.72-2.52 (m,
3H), 2.40 (q, J = 6.8 Hz, 1H), 2.00-1.90 (m, 1H), 1.96 (s, 3H),
1.94 (s, 3H), 1.75 (ddq, J = 14.0, 7.0, 7.0 Hz, 1H), 1.46 (ddq,
J = 14.0, 7.0, 7.0 Hz, 1H), 1.25 (t, J = 7.6 Hz, 3H), 1.21 (d,
J = 7.6 Hz, 3H), 1.08 (d, J = 7.0 Hz, 3H), 0.97 (d, J = 6.5 Hz,
3H), 0.94 (t, J = 7.3 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H), 0.82
(s, 9H), 0.06 (s, 3H), ¹0.35 (s, 3H); 13C NMR (67.8 MHz,
CDCl3): ¤ 179.6, 176.0, 164.4, 163.5, 138.7, 119.5, 118.1,
116.0, 76.3, 72.6, 41.6, 40.7, 40.2, 38.0, 26.8, 26.0 (3C),
24.8, 18.2, 18.1, 16.9, 15.5, 11.9, 11.4, 9.9, 9.5, 9.2, ¹3.8,
¹4.4; HRMS (ESI): m/z 543.3471, calcd for C30H52O5SiNa
[M + Na]+ 543.3482.
C1-C13 Segment 35b. To a stirred solution of ester 35
(93.5 mg, 0.180 mmol) in acetone (1 mL) and H2O (1 mL) were
added N-methylmorpholine oxide (70.0 mg, 0.598 mmol) and
osmium tetroxide (0.1 M solution in tert-butanol, 0.400 mL,
40.0 ¯mol) at room temperature. The mixture was stirred at
room temperature for 7 h, diluted with saturated aqueous
NaHSO3 (15 mL) at 0 °C, and extracted with EtOAc (3 © 20
mL). The combined extracts were washed with saturated
aqueous NaHSO3 and brine, dried over Na2SO4, filtered, and
Aldol 35c. To a stirred solution of Sn(OTf)2 (320 mg,
0.768 mmol) in CH2Cl2 (2 mL) were added triethylamine
(0.100 mL, 0.753 mmol) and a solution of C14-C20 segment
17 (162 mg, 0.565 mmol) in CH2Cl2 (1 mL) at ¹78 °C. After
the mixture was stirred at ¹78 °C for 1 h, a solution of aldehyde
35b (96.8 mg, 0.185 mmol) in CH2Cl2 (1 mL) was added via
cannula. The reaction mixture was stirred at ¹78 °C for 3.5 h,
diluted with pH 6.8 phosphate buffer (15 mL), and filtered
through a pad of Celite. This Celite was rinsed with EtOAc
(4 © 5 mL). The filtrate and rinses were combined, and the
layers were separated. The aqueous layer was extracted with
EtOAc (3 © 10 mL). The organic layer and extracts were
washed with brine, dried over Na2SO4, filtered, and concen-
trated. The residual oil was purified by column chromatography
on silica gel (10 g, hexane-EtOAc 10:1 ¼ 3:1 ¼ 2:1) to give
a diastereomeric mixture of aldol 35c (139 mg, 93%) as a

I. Hayakawa et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) 1091
colorless oil: Rf = 0.87, 0.81 (1:1 hexane/EtOAc); IR (CHCl3):
(¹0.05)} (m, 3H), {(¹0.10)-(¹0.40)} (m, 3H); 13C NMR
(67.8 MHz, CDCl3): ¤ 210.1, 209.8, 198.5, 195.0, 193.7, 191.5
(2C), 190.5, 179.6, 179.5 (2C), 177.7 (2C), 175.7, 175.6,
164.8, 164.7, 164.6, 164.5, 164.4, 164.3, 164.2, 164.1, 119.7,
119.6 (2C), 119.5 (2C), 117.9 (2C), 117.8 (2C), 109.4, 108.3,
105.6, 105.1, 104.4, 104.0, 103.8, 103.5, 100.5, 77.7, 77.3,
77.2, 76.7, 74.8, 74.4, 47.0, 46.6, 46.1, 46.0, 45.9, 44.8, 41.4
(3C), 41.3, 40.4, 40.0, 39.9, 39.8, 39.7, 39.6, 39.7, 39.3, 38.7,
38.6, 38.4, 26.9, 26.6, 26.5, 26.3, 26.2, 26.1, 26.0, 25.7, 24.9,
18.4, 18.3, 18.1, 16.0, 11.7 (2C), 11.6, 10.0, 9.6, ¹3.7 (2C);
HRMS (ESI): m/z 713.4423, calcd for C39H66O8SiNa
[M + Na]+ 713.4425.
¹1
3507, 1723, 1694, 1653, 1592, 1462, 1426, 1379 cm
;
1H NMR (270 MHz, CDCl3): ¤ 5.12 (d, J = 10.0 Hz, 1H),
4.41 (d, J = 8.4 Hz, 1H), 4.06 (d, J = 9.5 Hz, 1H), 4.02-3.82
(m, 1H), 3.75-3.70 (m, 1H), 3.13 (t, J = 7.6 Hz, 1H), 3.00-2.25
(m, 5H), 2.12-2.05 (m, 1H), 1.96 (s, 3H), 1.94 (s, 3H), 1.82-
1.65 (m, 1H), 1.52-1.30 (m, 2H), 1.30-1.00 (m, 15H), 1.00-
0.70 (m, 36H), 0.58 (q, J = 8.0 Hz, 6H), 0.02 (s, 3H), ¹0.38 (s,
3H); 13C NMR (67.8 MHz, CDCl3): ¤ 220.0, 217.1, 179.7 (2C),
176.1 (2C), 165.3, 165.1, 163.5 (2C), 119.2, 119.1, 117.9 (2C),
78.3, 78.1, 77.2, 75.7, 73.0, 72.9 (2C), 70.1, 49.7, 48.9, 48.6,
47.4, 46.9, 41.6, 41.3, 41.2, 40.0, 38.0, 37.8, 36.6, 36.2, 36.0,
35.3, 26.8, 26.2, 26.1, 26.0, 25.9, 24.7, 24.4, 23.3, 18.3, 16.9,
16.2, 15.6, 15.0, 14.9, 14.1 (2C), 12.4 (2C), 12.3, 12.2 (2C),
11.9, 11.1, 11.0, 9.8, 9.6, 7.6, 7.5, 7.4, 7.0, 6.9, 6.6, 5.9, 5.5,
5.4, 5.3, 5.3, ¹3.8, ¹4.3; HRMS (ESI): m/z 831.5591, calcd
for C45H84O8Si2Na [M + Na]+ 831.5602.
(2¤R)-Auripyrone B (2¤-epi-Auripyrone B) (36). A solu-
tion of triketone 35e (51.8 mg, 75.1 ¯mol) in a 5:3:7 mixture of
HF¢pyridine, pyridine, and THF (10.0 mL) was stirred at 60 °C
for 19.5 h. The mixture was poured into saturated aqueous
NaHCO3 (150 mL) at 0 °C and extracted with EtOAc (3 ©
20 mL). The combined extracts were washed with saturated
aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and
concentrated. The residual oil was purified by column chroma-
tography on silica gel (6 g, hexane-EtOAc 5:1 ¼ 2:1 ¼ 1:1)
and by preparative HPLC [Develosil ODS-HG-5 (250 © 20
mm), flow rate 5 mL min¹1; detection, UV 215 nm, solvent
80% aqueous MeOH] to give (2¤R)-auripyrone B (2¤-epi-
auripyrone B) (36) (10.3 mg, 25%) as colorless crystals:
Triketone 35e. Aldol 35c (82.5 mg, 102 ¯mol) was treated
with a 4:4:1 mixture of acetic acid, H2O, and THF (4.5 mL) at
room temperature for 13 h. The mixture was poured into
saturated aqueous NaHCO3 (70 mL) at 0 °C and extracted with
EtOAc (3 © 20 mL). The combined extracts were washed with
saturated aqueous NaHCO3 and brine, dried over Na2SO4,
filtered, and concentrated. The residual oil was purified by
column chromatography on silica gel (10 g, hexane-EtOAc
3:1 ¼ 2:1 ¼ 1:1) to give a diastereomeric mixture of diol
35d (60.2 mg, 84%) as a colorless oil: Rf = 0.68, 0.61, 0.45
(1:1 hexane/EtOAc); IR (CHCl3): 3493, 1723, 1652, 1592,
25
Rf = 0.37 (1:1 CH2Cl2/Et2O); ½¡ꢀD +35.7 (c 0.837, CHCl3);
¹1
IR (CHCl3): 1726, 1655, 1623, 1461, 1426, 1386 cm
;
1H NMR (600 MHz, C6D6): ¤ 4.90 (dd, J = 3.4, 3.4 Hz, 1H),
3.95 (dd, J = 10.3, 2.2 Hz, 1H), 2.74 (dq, J = 10.3, 7.0 Hz,
1H), 2.43 (ddq, J = 7.0, 7.0, 7.0 Hz, 1H), 2.35-2.11 (m, 3H),
2.09 (dq, J = 15.0, 7.4 Hz, 1H), 2.02 (s, 3H), 1.97 (s, 3H),
1.88-1.65 (m, 3H), 1.64 (s, 3H), 1.58-1.48 (m, 1H), 1.43-1.32
(m, 2H), 1.13 (d, J = 7.0 Hz, 3H), 1.11 (d, J = 7.0 Hz, 3H),
0.99 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H), 0.88 (t,
J = 7.6 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H), 0.77 (d, J = 7.1 Hz,
3H), 0.71 (d, J = 7.0 Hz, 3H), 0.63 (d, J = 7.1 Hz, 3H);
13C NMR (150 MHz, C6D6): ¤ 191.9, 178.6, 175.8, 166.3,
162.2, 161.6, 121.4, 118.2, 107.9, 105.1, 75.1, 70.7, 44.6, 42.0,
37.3, 36.6, 34.1, 31.8, 27.0, 26.3, 24.8, 17.0, 16.0, 12.2, 12.0
(2C), 11.9, 11.0, 10.8, 9.8, 9.5, 9.0, 8.2; HRMS (ESI): m/z
581.3443, calcd for C33H50O7Na [M + Na]+ 581.3454.
Cytotoxic Activity Assay. Stock cultures of HeLa S3 cells
were maintained in Eagle’s Minimum Essential Medium
containing Earle’s Balanced Salts and 10% fetal bovine serum
(DS Pharma Biomedical Co., Ltd.) and 1% antibiotic-anti-
mycotic mixed stock solution {penicillin (10000 units mL¹1),
streptomycin (10 mg mL¹1), and amphotericin B (25 ¯g mL¹1)}
at 37 °C under 5% CO2.
1
1462, 1427, 1379 cm¹1; H NMR (270 MHz, CDCl3): ¤ 5.12
(d, J = 9.5 Hz, 1H), 4.32 (d, J = 8.1 Hz, 1H), 3.96 (d, J =
8.9 Hz, 1H), 3.70-3.55 (m, 1H), 3.25-3.10 (m, 1H), 3.05-2.75
(m, 2H), 2.70-2.30 (m, 4H), 2.20-2.00 (m, 1H), 1.97 (s, 3H),
1.94 (s, 3H), 1.80-1.65 (m, 2H), 1.60-1.35 (m, 2H), 1.30-1.05
(m, 15H), 1.05-0.75 (m, 27H), 0.04 (s, 3H), ¹0.31 (s, 3H);
13C NMR (67.8 MHz, CDCl3): ¤ 220.8, 179.7, 176.2, 165.0,
163.6, 119.3, 118.0, 77.2, 74.8, 73.1, 70.3, 47.1, 47.0, 45.7,
41.6, 41.2, 39.9, 39.1, 38.1, 37.4, 36.3, 36.1, 34.4, 33.3, 30.6,
26.8 (2C), 26.1, 26.0, 25.9, 25.0, 24.8, 18.3 (3C), 17.1, 16.9,
16.8, 15.4, 15.2, 14.9, 14.8 (2C), 11.9 (2C), 11.2, 9.8, 9.6,
¹3.9, ¹4.2; HRMS (ESI): m/z 717.4747, calcd for C39H70O8-
SiNa [M + Na]+ 717.4738.
To a stirred solution of diol 35d (60.2 mg, 86.6 ¯mol) in
CH2Cl2 (2 mL) was added Dess-Martin periodinane (260 mg,
471 ¯mol) at room temperature. The mixture was stirred at
room temperature for 35 min; diluted with a 1:1:2 mixture
of saturated aqueous NaHCO3, saturated aqueous Na2S2O3
and H2O (4 mL); and extracted with Et2O (2 © 10 mL). The
combined extracts were washed with brine, dried over Na2SO4,
filtered, and concentrated. The residual oil was purified by
column chromatography on silica gel (6 g, hexane-EtOAc
5:1 ¼ 3:1 ¼ 1:1) to give a keto-enol equilibrium mixture of
triketone 35e (51.8 mg, 87%) as a colorless oil: Rf = 0.66 (1:1
For the purpose of the experiment, 2 © 103 cells suspended
in 100 ¯L of medium per well were plated in a 96-well plate.
After 12 h incubation at 37 °C under 5% CO2 to allow cell
attachment, compounds in 100 ¯L of medium were added to the
25
hexane/EtOAc); ½¡ꢀD +23.4 (c 1.036, CHCl3); IR (CHCl3):
wells at different concentrations and incubated for 96 h under
1724, 1653, 1593, 1462, 1427, 1379 cm¹1; 1H NMR (270 MHz,
CDCl3): ¤ 16.94 (s, 0.07H), 16.81 (s, 0.06H), 16.67 (s, 0.18H),
5.55-5.39 (m, 0.3H), 5.32-5.25 (m, 0.4H), 5.20-5.08 (m,
0.3H), 4.15-3.60 (m, 1.69H), 3.55-3.30 (m, 0.7H), 3.30-3.00
(m, 1.3H), 2.80-2.45 (m, 3H), 2.45-2.20 (m, 1H), 2.20-1.55
(m, 12H), 1.50-1.05 (m, 18H), 1.05-0.70 (m, 21H), {(0.10)-
the same conditions. After 3 h of the MTT (1.44 mg mL ,
¹1
50 ¯L) addition to each well, the medium/MTT mixtures were
removed, and the formazan crystals formed were dissolved in
150 ¯L of DMSO per well. After 30 min, optical absorbance at
540 nm were measured with a microplate reader. The cytotoxic
effects of each compound were obtained as IC50 values.

1092 Bull. Chem. Soc. Jpn. Vol. 85, No. 10 (2012) BCSJ AWARD ARTICLE
2560.
4
48, 8766.
We thank Dr. Takao Yamori (Screening Committee of
Anticancer Drugs supported by Grant-in-Aid for Scientific
Research on Priority Area “Cancer” from The Ministry of
Education, Culture, Sports, Science and Technology, Japan) for
screening in the human cancer cell line panel. We also thank
Kaneka Corporation for their gift of methyl D-(R)-¢-hydroxy-
isobutanoate. We appreciate technical assistance from Mr. Ikuo
Iida and Ms. Maiko Matsuki (University of Tsukuba). This
work was supported by Grants-in-Aid for Scientific Research,
from the Ministry of Education, Culture, Sports, Science and
Technology (MEXT), Japan; by a grant from the Uehara
Memorial Foundation (H.K.); and by a grant from the
University of Tsukuba, Strategic Initiatives (A), Center for
Creation of Functional Materials (CCFM). I.H. thanks The
Society of Synthetic Organic Chemistry, Japan (Meiji Seika
Award in Synthetic Organic Chemistry, Japan) and the Suntory
Institute for Bioorganic Research (SUNBOR GRANT) for their
financial support.
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