Total synthesis of pyripyropene A

Article abstract of DOI:10.1016/j.tet.2011.06.084

The total synthesis of pyripyropene A, a potent ACAT2 inhibitor with high isozyme selectivity, was completed. Key features of the synthetic strategy include Ti(III)-mediated radical cyclization and Peterson olefination for the construction of the AB ring

Full text of DOI:10.1016/j.tet.2011.06.084

Tetrahedron 67 (2011) 8195e8203
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of pyripyropene A
*
*
Atsuki Odani, Kaoru Ishihara, Masaki Ohtawa, Hiroshi Tomoda, Satoshi Omura , Tohru Nagamitsu
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 June 2011
Received in revised form 24 June 2011
Accepted 24 June 2011
Available online 28 July 2011
The total synthesis of pyripyropene A, a potent ACAT2 inhibitor with high isozyme selectivity, was
completed. Key features of the synthetic strategy include Ti(III)-mediated radical cyclization and
Peterson olefination for the construction of the AB ring segment and stereoselective dihydro-g-pyrone
formation (C-ring). The total synthesis provided pyripyropene A in 5.3% overall yield over 17 steps.
Ó 2011 Published by Elsevier Ltd.
Keywords:
Pyripyropene A
ACAT2 inhibitor
Total synthesis
1. Introduction
cholesterol-lowering or anti-atherosclerotic agents. We established
a cell-based assay using ACAT1- or ACAT2-expressing CHO cells and
Acyl-CoA:cholesterol acyltransferase (ACAT) plays important
roles in cholesterol metabolism in mammals. Therefore, a large
number of synthetic ACAT inhibitors, such as ureas, imidazoles, and
amides have been reported,1 although to date, no new types of
cholesterol-lowering or anti-atherosclerotic agents have come onto
the market.2 Recently, the development of avasimibe3 and pacti-
mibe4 has also failed.
During the course of our screening for ACAT inhibitors of natural
origin with a chemical structure different from the synthetic ones
developed from the 1990s, we discovered a number of new natural
products.5 Among them, the fungal metabolites, pyripyropenes,
were one of the most potent ACAT inhibitors in an enzyme assay
using rat liver microsomes.6e8 Accordingly, about 200 derivatives
were semisynthetically prepared from pyripyropene A (1) for a first
structureeactivity relationship (SAR) study. Certain derivatives
were more potent than PPPA (1), and proved to be active in re-
ducing cholesterol absorption in vivo from the intestines of
hamsters.9e14
studied the selectivity of microbial ACAT inhibitors we had pre-
viously discovered.20 Consequently, we confirmed that PPPA (1) is
a potent and selective inhibitor toward ACAT2. More recently, the
in vivo efficacy of PPPA in atherosclerosis has been also demon-
strated.21 PPPA derivatives synthesized previously were evaluated
in this cell-based assay to investigate their selective inhibition to-
ward the ACAT isozymes.22 Several PPPA derivatives showed more
potent ACAT2 inhibitory activity than PPPA (1), however, un-
fortunately, all synthesized PPPA derivatives showed much lower
isozyme selectivity than PPPA (1). This led us to embark on a second
SAR study for the development of new PPPA derivatives with higher
isozyme selectivity.23 Consequently, an efficient synthetic route for
PPPA and its derivatives was also necessary. Although the first total
synthesis of PPPA (1) has previously been reported by our group,24
it is not suitable for this task because of the presence of several
reactions that cannot be scaled up. We report herein another total
synthesis of pyripyropene A (1), which is a different approach to the
first one and a more practical synthesis for the SAR study.
Recent molecular biological studies revealed the presence of
two isozymes, ACAT1 and ACAT2.15e18 ACAT1 is ubiquitously
expressed, and high-level expression is observed in sebaceous
glands, steroidogenic tissues, and macrophages, while ACAT2 is
expressed predominantly in the liver and intestine.19 Therefore,
selective inhibitors toward ACAT2 are expected to have the po-
tential to be better drug candidates with fewer side-effects as
2. Results and discussion
2.1. Retrosynthetic analysis of pyripyropene A
Our retrosynthetic analysis of pyripyropene A (1) is shown in
Scheme 1. We adopted a reliable procedure reported by our group
previously13 for the conversion of intermediate 2 into 1. Dihydro-
g-
pyrone 2 could be prepared from diketoester 3 by stereoselective
intramolecular hetero-Michael addition and protonation, which
was expected to be obtained by a coupling between 4 and the
* Corresponding authors. Tel.: þ81 3 5791 6101; fax: þ81 3 3444 8360 (S.O.); tel.:
þ81 3 5751 6376; fax: þ81 3 3444 6762 (T.N.); e-mail addresses: omura-s@
kitasato-u.ac.jp (S. Omura), nagamitsut@pharm.kitasato-u.ac.jp (T. Nagamitsu).
0040-4020/$ e see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tet.2011.06.084

8196
A. Odani et al. / Tetrahedron 67 (2011) 8195e8203
LHMDS,
O
E
O
O
D
N
O
OMe
O
H
OMe
Stereoselective
Cl
N
HO
γ
O
H
dihydro- -pyrone
O
H
C
formation
O
O
O
O
O
A
O
H
1
see ref. 13
B
7
O
10
TBSO
TBSO
OTBS
TBSO
TBSO
OTBS
H
11
O
2
3
O
Pyripyropene A (1)
O
H
O
O
O
Ti(III)-mediated
radical cyclization
NC
O
TBSO
TBSO
OTBS
O
H
H
HO
4
5
6
(R)-Carvone
Scheme 1.
methyl acetoacetate unit. The
a
,
b
-unsaturated aldehyde 4 was en-
reductive opening produced a radical species, the stable chair-like
conformation of this intermediate would determine the stereo-
selectivity of the 6-exo-dig cyclization, in which the sterically hin-
dered titanoxy group would be oriented equatorially and might
also associate with the nitrile group by chelation.
Subsequent stereoselective reduction of C1-ketone in 5 was
accomplished by the Davis procedure27 (Scheme 3). Reaction of 5
with chlorodiisopropylsilane gave silyl ether 9 in 93% yield, which
was treated with Tin(IV) chloride to furnish the desired 10 as
visaged to be synthesized via functionalization of diketoalcohol 5 as
follows: stereoselective reduction of the C1-ketone (pyripyropene
A numbering), oxidation of the alkene, and one-carbon elongation
of another ketone. The trans-fused decaline unit of 5 could be
constructed by the Ti(III)-mediated radical cyclization of 6. The
epoxide 6 should be available from a commercially available (R)-
carvone.
a single isomer in 72% yield. We next attempted to install the C7-
hydroxy group by regioselective opening of the
silylene acetal 10 was oxidized with H2O2/6 M NaOH to give
b
-
2.2. Synthesis of the key intermediate 5
a
-epoxide. The
a
-
Synthesis of 5 commenced with methylation of (R)-carvone
epoxide 11 in 82% yield. The epoxide opening reactions of 11 under
various conditions using carboxylate and alkoxide anions were
investigated, but none proceeded. We next examined a bromohy-
drin reaction proceeding via the more reactive bromonium ion.
Consequently, treatment of 10 with NBS and 1 M HClO428 provided
bromohydrin 13 in 55% yield with hydrolysis of the silylene acetal.
The three hydroxy groups of 13 were protected as TBS ethers to
furnish 14 in 99% yield. At this stage, the stereochemistries of 14
were confirmed by NOE experiments (see Experimental section).
Wittig and Peterson olefinations of 14 were in turn attempted to
synthesize the desired key aldehyde 4, however, the unexpected
product 15 was obtained from each reaction in high yield, which
could be obtained via E2 elimination instead of the desired olefi-
nation reaction due to steric hindrance around the carbonyl group
of 14.
(Scheme
2).
Alkylation
of
the
resulting
725
with
3-bromopropionitrile gave 8 in 66% yield (98% brsm) stereo-
selectively, which was oxidized with mCPBA to produce a 10:1
diastereomixture of 6. Subsequent Ti(III)-mediated radical cycliza-
tion26 of 6 by treatment with Cp2TiCl2 and Zn proceeded smoothly
to afford the desired diketoalcohol 5 in 61% yield, accompanied by
the undesired 10-epi-diketoalcohol (20%). After an epoxide
O
O
LDA
LDA, MeI
3-bromopropionitrile
THF, –15 °C
90%
THF, –78 °C
66%
(98% brsm)
(R)-Carvone
7
To solve the steric problem, we intended to use b-epoxide 17 as
the new substrate for the olefination reactions, instead of 14
(Scheme 4). Treatment of 13 with DBU furnished 16 in quantitative
yield, which was protected with TBSOTf to give 17 in 90% yield. The
subsequent attempt of the Wittig reaction of 17 with
MeOCH2PPh3Cl/KHMDS was not successful, but the Peterson ole-
fination of 17 employing the Magnus protocol29 smoothly pro-
O
O
Cp2TiCl2, Zn
THF, rt
mCPBA
NC
NC
CH2Cl2, rt
97%
O
8
6
ceeded to afford the corresponding
g-hydroxy-a,b-unsaturated
(dr = 10 : 1)
aldehyde after acidic hydrolysis. The alcohol was protected as a TBS
ether to give rise to the key intermediate 4 in 71% yield over two
steps. As this aldehyde is susceptible to air oxidation to furnish the
corresponding carboxylic acid, which is identical to that derived
from 4 by Pinnick oxidation30 in all respects, the aldehyde 4 was
promptly subjected to the next reaction.
Synthesis of the key aldehyde 4 was accomplished however the
conversion of 5 into 16 was not suitable for the scale-up synthesis.
Therefore, another route for the synthesis of 16 was developed as
shown in Scheme 5. Evans reduction31 of 5 afforded the desired diol
O
OTi
OTi
C
N
O
10
N
H
HO
5
61%
Scheme 2.

A. Odani et al. / Tetrahedron 67 (2011) 8195e8203
8197
O
O
O
O
chlorodiisopropylsilane,
Et3N, DMAP
TBSOTf,
2,6-lutidine
DBU
Br
O
CH2Cl2, 0 °C
90%
CH2Cl2, rt
99%
DMF, 50 °C
93%
HO
HO
OH
HO
HO
O
O
H
H
H
H
H
HO
O
Si
13
16
5
9
O
1) TMSCH2OMe,
s-BuLi, t-BuOK,
THF, –60 °C to rt
then H+
SnCl4
O
CHO
CH2Cl2, 0 °C
72%
O
H
O
30% H2O2,
6 M NaOH,
MeOH, rt
82%
2) TBSCl, imidazole,
DMAP, DMF, 50 °C
71% (2 steps)
Si
O
TBSO
TBSO
TBSO
TBSO
OTBS
H
H
10
17
4
NBS,
1 M HClO4
dioxane,
H2O, 0 °C
55%
Scheme 4.
O
O
Br
O
HO
HO
HO
H
HO
OH
O
O
H
NBA,
Me4NBH(OAc)3
AgOAc
CH3CN, AcOH,
–40 °C
AcOH, rt
11
13
O
HO
HO
H
H
93%
TBSOTf,
2,6-lutidine
CH2Cl2, 0 °C
99%
HO
epoxide opening
with R'O–
5
18
O
O
O
O
See
Scheme 4
Br
K2CO3
OH
Br
OTBS
O
4
MeOH, rt
HO
HO
OAc
HO
HO
7
HO
HO
OR'
TBSO
TBSO
H
87%
H
H
H
(2 steps)
19
16
12
14
Scheme 5.
TMSCH2OMe,
s-BuLi, t-BuOK
then H+
77%
Lewis acids (Mg(OEt)2,33 MgCl2,34 SmCl335), however, the reactions
did not proceed. Reaction of lithium and sodium enolates of 21 with
acetyl chloride gave O-acylated product as a major product.
Next, the coupling reaction of 4 with the 5-iodo-1,3-dioxin-4-
one derivative 22 under conditions reported by Knochel et al.36
was investigated. Treatment of 22 with i-PrMgCl gave the corre-
sponding 5-magnesiated-1,3-dioxin-4-one derivative, which was
coupled with 4 to furnish 23. Subsequent DesseMartin oxidation
afforded 24 in 72% yield over two steps. To convert it to 3, solvolysis
was examined. Although methanolysis in the presence of NaH or
NaOMe led to decomposition, refluxing in MeOH without base gave
the desired 3 in 59% yield, accompanied by 7-hydroxy 3 in 24%
yield. Optimization then led to the methanolysis conditions
(MeOH/toluene (1:4) at 80 ꢀC) to produce 3 in 94% yield.
or
MeOCH2PPh3Cl
KHMDS, then H+
82%
CHO
O
TBSO
TBSO
OTBS
TBSO
TBSO
H
H
15
4
0 %
Scheme 3.
18 as the sole product in 93% yield. Treatment of 18 with NBA and
AgOAc in AcOH32 afforded 19, which was subjected to methanolysis
2.4. Synthesis of the dihydro-g-pyrone 2
to give the b-epoxide 16 in 87% yield over two steps. Then, the b-
epoxide 16 was converted to 4 according to Scheme 4. Thus, this
route provided the efficient synthesis of the key aldehyde 4.
With 3 in hand, the stage was set for the stereoselective syn-
thesis of dihydro- -pyrone by intramolecular cyclization. First, re-
g
actions with some Lewis acids, such as BF3$Et2O and SnCl4 were
attempted, but the desired cyclization did not proceed and only
TBS-deprotected mixtures were obtained. Therefore, cyclization
under basic conditions using DBU was investigated (Table 1).
Heating of 3 in the presence of DBU in DMF at reflux gave only
undesired product 25 formed by decarboxylation in 70% yield (run
1). The same reaction carried out at 100 ꢀC did not prevent the
decarboxylation (run 2). By changing to benzene as a solvent under
2.3. Synthesis of the diketoester 3
We next investigated an approach to the key synthetic in-
termediate 3 (Scheme 6). Aldol reaction of 4 with an enolate of
ethyl acetate afforded the b-hydroxy ester 20, which was oxidized
to give 21 in 67% yield over two steps. Subsequent C-acylation with
acetyl chloride was attempted under various conditions using

8198
A. Odani et al. / Tetrahedron 67 (2011) 8195e8203
O
OEt
O
OEt
O
H
HO
H
O
DMP
EtOAc, LHMDS
THF,
CH2Cl2, rt
67%
TBSO
TBSO
OTBS
TBSO
TBSO
OTBS
TBSO
TBSO
OTBS
–78 °C
H
H
(2 steps)
4
20
21
O
I
O
O
C-acylation
with AcCl
22, i-PrMgCl, THF, –30 °C to rt
O
OMe
O
O
O
O
O
O
HO
H
O
O
O
DMP
CH2Cl2, rt
OTBS
MeOH/toluene (1:4)
TBSO
TBSO
OTBS
TBSO
TBSO
TBSO
TBSO
OTBS
H
H
80 °C
94%
72%
(2 steps)
3
23
24
Scheme 6.
Table 1
Synthesis of the dihydro-g-pyrone 2 by intramolecular cyclization
O
OMe
O
O
O
H
OMe
O
O
H
O
DBU
O
+
TBSO
TBSO
OTBS
TBSO
TBSO
OTBS
TBSO
TBSO
OTBS
H
H
3
2
25
Run
Solvent
Temp
Time (h)
Yield (%)
2
25
3
1
2
3
4
5
6
7
DMF
DMF
Reflux
15
25
13
8
8
8
d
70
77
21a
7a
d
100 ꢀC
Reflux
Reflux
Reflux
100 ꢀC
60 ꢀC
Trace
53
11
Trace
68
50
d
Benzene
THF
C2H4Cl2
Toluene
Toluene
16a
46a
>90
12a
20
d
17a
d
156
a
Estimated by 1H NMR.
reflux conditions the desired 2 was afforded in 53% yield with an
inseparable mixture of unreacted 3 and 25 whose ratio was esti-
mated by 1H NMR (run 3). Use of THF and dichloroethane provided
inappropriate conditions (run 4 and 5). Thus, this cyclization
proved to be dependent on solvents and prefer aromatic hydro-
carbons, such as benzene. When the reaction was attempted at
a higher reaction temperature, toluene was selected. Consequently,
the reaction in toluene at 100 ꢀC gave the best yield to afford 2
(68%). Although the cyclization in toluene at 60 ꢀC also worked to
produce 2 in 50% yield accompanied by unreacted starting material
in 20% yield without the undesired decarboxylated product 25,
a longer reaction time was needed.
7).13 Enolization of 2 by LHMDS,
g-acylation with nicotinoyl chlo-
ride, and treatment with an additional portion of LHMDS leading to
intramolecular cyclization afforded 26 in 65% yield from 2 in one-
pot. A two-step sequence of protecting group manipulations pro-
vided 28, which was subjected to Luche reduction to furnish pyr-
ipyropene
A (1) in 88% yield over three steps. Synthetic
pyripyropene A (1) was completely identical to an authentic sample
in all respects (1H and 13C NMR, IR, FABMS, and ACAT2 inhibitory
activity and isozyme selectivity).
3. Conclusion
In conclusion, we have achieved a stereocontrolled total syn-
thesis of pyripyropene A (1). Key features of the synthetic strategy
included the intramolecular Ti(III)-mediated radical cyclization for
2.5. Completion of the total synthesis
The conversion of 2 to pyripyropene A (1) was obtained by
the construction of the A-ring, stereoselective
b-epoxide formation/
following the procedure reported by our group previously (Scheme
Peterson olefination for the preparation of the functional groups on

A. Odani et al. / Tetrahedron 67 (2011) 8195e8203
8199
resolution mass spectrometers. The melting points were recorded
on a Yanagimoto micro melting apparatus and are uncorrected.
MeO
O
O
N
4.1.1. (5S,6S)-6-(2-Isocyanoethyl)-2,6-dimethyl-5-(prop-1-en-2-yl)
cyclohex-2-enone (8). To a solution of diisopropylamine (3.46 mL,
24.7 mmol) in THF (22 mL) was added dropwise n-BuLi (1.59 M in
THF, 15.7 mL, 24.9 mmol) at ꢁ15 ꢀC. After being stirred for 0.5 h,
a solution of 724 (2.92 g, 17.8 mmol) in THF (30 mL) was added
dropwise. The resulting mixture was stirred for 5 h at ꢁ78 ꢀC and
treated with 3-bromopropionitrile (4.36 mL, 53.3 mmol). After
being stirred for an additional 16 h at ꢁ78 ꢀC, the reaction mixture
was quenched with a saturated aqueous NH4Cl solution. The
aqueous phase was extracted with EtOAc. The combined organic
extracts were dried over anhydrous Na2SO4 and concentrated in
vacuo. Flash chromatography (10:1 hexanes/EtOAc) afforded 8
O
1) LHMDS,
THF, rt
LHMDS
65%
O
2
2) nicotinoyl
chloride
H
TBSO
TBSO
OTBS
H
O
O
O
N
O
O
N
HO
H
NaBH4,
(2.47 g, 66%) as a colorless oil: ½a D26
ꢂ
ꢁ14.3 (c 1.0, CHCl3); IR (KBr)
CeCl3•7H2O
O
O
O
O
O
3021, 2927, 2857, 1663, 1443, 1380, 1217, 904, 759, 668 cmꢁ1
;
1H
H
H
H
MeOH,
–78 °C
88%
NMR (400 MHz, CDCl3)
d
6.66e6.63 (m, 1H), 4.90 (dq, J¼1.6 Hz, 1H),
RO
OR
O
4.79 (br s, 1H), 2.65 (t, J¼6.6 Hz, 1H), 2.49e2.45 (m, 2H), 2.41e2.26
(m, 2H), 2.07e1.99 (m, 1H), 1.92e1.84 (m, 1H), 1.77e1.76 (m, 3H),
1.71 (t, J¼0.6 Hz, 3H), 1.06 (s, 3H); 13C NMR (100 MHz, CDCl3)
(3 steps)
RO
O
O
26 R = TBS
27 R = H
AcCl,
d
202.8, 145.1, 143.2, 134.2, 120.3, 115.7, 49.5, 47.4, 32.8, 29.1, 22.6,
MeOH, rt
Pyripyropene A (1)
18.9, 16.6, 12.8; HRMS (ESI) [MþNa]þ calcd for C14H19NONa
Ac2O, Et3N,
240.1364, found 240.1361.
DMAP, CH2Cl2, rt
28 R = Ac
Scheme 7.
4.1.2. (5R,6S)-6-(2-Isocyanoethyl)-2,6-dimethyl-5-(2-methyloxiran-
2-yl)cyclohex-2-enone (6). To a solution of 8 (7.90 g, 36.4 mmol) in
CH2Cl2 (182 mL) was added mCPBA (10.6 g, 40.0 mmol). After being
stirred for 0.5 h at rt, additional mCPBA (10.6 g, 40.0 mmol) was
added. The resulting mixture was stirred for 0.5 h at rt and then
quenched with a saturated aqueous NaHCO3 solution. The aqueous
phase was extracted with CH2Cl2. The combined organic extracts
were dried over anhydrous Na2SO4 and concentrated in vacuo.
Flash chromatography (1:1 hexanes/EtOAc) afforded 6 (2.53 g, 97%)
(dr¼10:1) as a colorless oil: as a diastereomixture IR (KBr) 2979,
the B-ring, and stereoselective intramolecular cyclization for the
C-ring formation. Our second total synthesis provided 1 in 5.3%
overall yield over 17 steps. Extension of this chemistry to the syn-
thesis of structural analogs of 1 for the structureeactivity re-
lationship study is currently under way and will be reported in due
course.
4. Experimental section
4.1. General
2928, 2247, 1718,1665, 1447,1381, 1200, 1079,1035,1011, 866 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d 6.68e6.60 (m, 1H), 2.77e2.56 (m, 4H),
2.40e2.29 (m, 1H), 2.17e2.06 (m, 2H), 1.87e1.80 (m, 1H), 1.79e1.77
(m, 3H), 1.59 (dd, J¼6.1, 3.1 Hz, 1H), 1.16 (s, 3H), 1.10 (s, 3H); 13C NMR
All reactions were carried out in dried glassware under a nitro-
gen atmosphere employing standard techniques in handling air-
sensitive materials. Commercial reagents were used without fur-
ther purification unless otherwise indicated. Organic solvents were
distilled and dried over molecular sieves of 3 A or 4 A. Reactions
were performed in flame-dried glassware under positive Ar pres-
sure with stirring by a magnetic stirbar unless otherwise indicated.
Cold baths were generated as follows: 0 ꢀC, wet ice/water; ꢁ78 ꢀC,
dry ice/acetone. Flash chromatography was performed on silica gel
(75 MHz, CDCl3) d 201.7, 142.1, 134.1, 119.5, 58.0, 57.6, 50.2, 46.6,
33.9, 27.0, 19.3, 18.0, 16.3, 12.4; HRMS (ESI) [MþNa]þ calcd for
C14H19NNaO2 256.1314, found 256.1320.
ꢀ
ꢀ
4.1.3. (4aR,5R,8aS)-5-(Hydroxymethyl)-2,5,8a-trimethyl-4a,5,8,8a-
tetrahydronaphthalene-1,6(4H,7H)-dione (5). To
a
solution of
Cp2TiCl2 (2.14 g, 8.57 mmol) in THF (23 mL) was added Zn (2.12 g,
12.9 mmol). After being stirred for 1 h at rt, a solution of 6 (1.00 g,
4.29 mmol) in THF (20 mL) was added. The reaction mixture was
stirred for 45 min at rt and filtered through a pad of Celite. The
filtrate was concentrated in vacuo. The residue was dissolved with
EtOAc and washed with 2 N HCl solution. The organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo. Flash
chromatography (2:1 to 1:1 hexanes/EtOAc) afforded 5 (613 mg,
60 N (spherical, neutral, particle size 40e50 mm). TLC was per-
formed on 0.25 mm Merck silica gel 60 F254 plates and visualized by
UV (254 nm) and phosphomolybdic acid and p-anisaldehyde as TLC
Stains. Yields refer to chromatographically and spectroscopically
pure compounds, unless otherwise noted.
1H- and 13C-NMR spectra were recorded using an internal
deuterium lock on Varian Mercury-300, Varian Unity-400, and
Varian INOVA-600 spectrometers. All signals are reported in parts
per million with the internal reference of 7.26 ppm or 77.0 ppm for
chloroform as the standard. Data are presented as follows: multi-
plicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼mutiplet,
br¼broad, dd¼doublet of doublet), coupling constant (J/Hz) and
integration. Infrared spectra were recorded on a Horiba FT-710 in-
frared spectrometer. Absorptions are given in wavenumbers
(cmꢁ1). Optical rotations were recorded on a JASCO DIP-1000 po-
larimeter and reported as follows: ½aꢂTD, concentration (g/100 mL)
and solvent. High resolution mass spectra were obtained on JEOL
JMS-700 Mstation and JEOL JMS-T100LP with FAB and ESI high
61%) and 10-epi-5 (200 mg, 20%) as yellow solids: data for 5 ½a D26
ꢂ
ꢁ83.6 (c 1.0, CHCl3); IR (KBr) 3019, 2970, 1700, 1669, 1459, 1367,
1217, 1054, 1009, 752, 668, 462 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
6.73e6.70 (m, 1H), 3.75 (d, J¼11.7 Hz, 1H), 3.32 (d, J¼11.7 Hz, 1H),
2.73 (dt, J¼15.1, 5.7 Hz, 1H), 2.55 (dd, J¼11.3, 3.9 Hz, 1H), 2.48e2.19
(m, 4H), 2.18 (s, 1H), 1.84e1.76 (m, 1H), 1.78e1.77 (m, 3H), 1.31 (s,
3H), 1.13 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 216.5, 203.6, 143.1,
133.4, 65.3, 52.6, 43.9, 42.9, 34.9, 32.8, 24.1, 17.6, 17.1, 16.2; HRMS
(FAB, m-NBA) [MþH]þ calcd for C14H21O3 237.1491, found
237.1488. Data for 10-epi-5 ½a D27
ꢁ83.0 (c 1.0, CHCl3); IR (KBr) 3475,
ꢂ
2925, 1707, 1668, 1454, 1374, 1045, 1008 cmꢁ1 1H NMR (400 MHz,
;
CDCl3)
d
6.73e6.71 (m, 1H), 3.92 (d, J¼11.2 Hz, 1H), 3.70 (d,
J¼11.2 Hz, 1H), 2.61 (ddd, J¼16.0, 13.1, 6.5 Hz, 1H), 2.55e2.46 (m,

8200
A. Odani et al. / Tetrahedron 67 (2011) 8195e8203
2H), 2.38e2.30 (m, 1H), 2.25 (ddd, J¼14.3, 6.5, 3.3 Hz, 1H), 2.19 (dd,
J¼11.9, 4.1 Hz, 1H), 2.15 (s, 1H), 1.91 (dt, J¼14.1, 5.8 Hz, 1H),
1.77e1.76 (m, 3H), 1.19 (s, 3H), 1.17 (s, 3H); 13C NMR (100 MHz,
26.9, 22.3, 17.8, 16.7, 13.0; HRMS (ESI) [MþNa]þ calcd for
C14H22NaO4 277.1416, found 277.1406.
CDCl3)
d
215.2, 203.7, 143.6, 133.4, 65.9, 52.8, 50.1, 44.3, 35.1, 31.6,
4.1.7. (2R,3S,4aS,5R,6S,8aS)-2-Bromo-3,6-bis((tert-butyldime-
thylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2,5,8a-trime-
24.9, 21.2, 17.4, 16.4; HRMS (FAB, m-NBA) [MþH]þ calcd for
C14H21O3 237.1491, found 237.1490.
thyloctahydronaphthalen-1(2H)-one (14). To
(78.0 mg, 0.234 mmol) in CH2Cl2 (2.3 mL) at 0 ꢀC were added 2,6-
lutidine (271 L, 2.34 mmol) and TBSOTf (268 L, 1.17 mmol). The
a solution of 13
4.1.4. (4aR,5R,8aS)-5-(((Diisopropylsilyl)oxy)methyl)-2,5,8a-tri-
methyl-4a,5,8,8a-tetrahydronaphthalene-1,6(4H,7H)-dione (9). To
a solution of 5 (1.15 g, 4.87 mmol) in DMF (49 mL) were added Et3N
(3.39 g, 24.4 mmol), DMAP (2.97 g, 24.4 mmol), and chlor-
odiisopropylsilane (1.25 g, 7.31 mmol). The reaction mixture was
stirred for 0.5 h at 50 ꢀC, quenched with a saturated aqueous
NaHCO3 solution, and the aqueous phase was extracted with EtOAc.
The combined organic extracts were dried over anhydrous Na2SO4
and concentrated in vacuo. Flash chromatography (30:1 hexanes/
m
m
reaction was stirred for 1.5 h at 0 ꢀC, quenched with a saturated
aqueous NaHCO3 solution, and the aqueous phase was extracted
with CH2Cl2. The combined organic extracts were dried over an-
hydrous Na2SO4 and concentrated in vacuo. Flash chromatography
(200:1 hexanes/EtOAc) afforded 14 (156 mg, 99%) as a white solid:
½
a 2D8
1468, 1254, 1217, 1100, 899, 841, 756 cmꢁ1
CDCl3)
J¼10.0 Hz, 1H), 3.13 (d, J¼9.8 Hz, 1H), 2.28 (dd, J¼12.5, 4.5 Hz, 1H),
2.04e1.94 (m, 2H), 1.79 (s, 3H), 1.72e1.62 (m, 3H), 1.37 (dt, J¼13.7,
4.7 Hz,1H),1.20 (s, 3H), 0.91 (s, 9H), 0.88 (s, 9H), 0.87 (s, 9H), 0.69 (s,
3H), 0.14 (s, 6H), 0.06e0.04 (m, 12H); 13C NMR (100 MHz, CDCl3)
ꢂ
þ13.8 (c 1.0, CHCl3); IR (KBr) 2953, 2933, 2889, 2859, 1710,
;
1H NMR (400 MHz,
d
4.28 (t, J¼6.5 Hz, 1H), 3.70 (dd, J¼10.8, 5.5 Hz, 1H), 3.43 (d,
EtOAc) afforded 9 (1.59 g, 93%) as a colorless oil: ½a D26
ꢂ
ꢁ17.2 (c 1.0,
CHCl3); IR (KBr) 2926, 2865, 2095, 1710, 1672, 1464, 1097, 1003, 838,
804 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 6.76e6.73 (m, 1H), 4.08 (s,
1H), 3.97 (d, J¼9.8 Hz, 1H), 3.34 (d, J¼9.8 Hz, 1H), 2.80 (dd, J¼11.4,
4.5 Hz, 1H), 2.55 (ddd, J¼17.0, 13.3, 6.5 Hz, 1H), 2.46e2.35 (m, 2H),
2.28e2.25 (m, 1H), 2.21 (ddd, J¼14.1, 6.3, 3.5 Hz, 1H), 1.86 (dt,
J¼13.7, 5.7 Hz, 1H), 1.81e1.79 (m, 3H), 1.21 (s, 3H), 1.01 (s, 3H),
d
209.7, 77.6, 71.3, 68.6, 64.2, 46.9, 44.1, 36.1, 33.6, 28.9, 27.2, 26.0,
26.0, 25.9, 25.8, 19.1, 18.1, 18.1, 18.0, 13.0, ꢁ3.3, ꢁ4.3, ꢁ4.7, ꢁ4.8,
ꢁ5.2, ꢁ5.3; HRMS (ESI) [MþNa]þ calcd for C32H65BrNaO4Si3
699.3271, found 699.3288.
0.97e0.95 (m, 14H); 13C NMR (100 MHz, CDCl3)
d 213.2, 204.0,
143.6, 133.4, 68.5, 52.4, 43.9, 41.4, 35.2, 30.7, 29.8, 24.4, 18.6, 17.6,
17.5, 17.4, 17.4, 17.0, 16.4, 12.4; HRMS (ESI) [MþNa]þ calcd for
C20H34NaO3Si 373.2175, found 373.2168.
5.2%
4.4%
4.0%
O
4.4%
Br
OTBS
4.1.5. (4aS,6aS,10aS,10bR)-3,3-Diisopropyl-6a,8,10b-trimethyl-
4a,5,6,6a,10,10a-hexahydro-1H-naphtho[2,1-d][1,3,2]dioxasilin-
7(10bH)-one (10). To a solution of 9 (386 mg, 1.10 mmol) in CH2Cl2
TBSO
H
H
H
5.6% 4.4%
TBSO
(22 mL) was added SnCl4 (1.0 M in CH2Cl2, 22 mL, 22.0 mmol). The
reaction was stirred for 1 h at 0 ꢀC, quenched with a saturated
aqueous NaHCO3 solution, and the aqueous phase was extracted
with CH2Cl2. The combined organic extracts were dried over an-
hydrous Na2SO4 and concentrated in vacuo. Flash chromatography
(40:1 hexanes/EtOAc) afforded 10 (277 mg, 72%) as a colorless oil:
4.1.8. (4aS,5R,6S,8aS)-6-((tert-Butyldimethylsilyl)oxy)-5-(((tert-bu-
tyldimethylsilyl)oxy)methyl)-2,5,8a-trimethyl-4a,5,6,7,8,8a-hexahy-
dronaphthalen-1(4H)-one (15). To a solution of MeOCH2PPh3Cl
½
a 2D7
1047, 998, 885, 796 cmꢁ1
ꢂ
ꢁ29.9 (c 1.0, CHCl3); IR (KBr) 2945, 2866, 1673, 1465, 1095,
(23.0 mg, 66.6
(133 L, 66.6
14 (15.0 mg, 22.2
m
mol) in THF (100
mol) at 0 ꢀC. After being stirred for 0.5 h, a solution of
mol) in THF (120 L) was added dropwise. The
mL) was added dropwise KHMDS
;
1H NMR (400 MHz, CDCl3)
d
6.61e6.59
m
m
(m,1H), 3.82 (d, J¼10.4 Hz,1H), 3.69 (dd, J¼10.6, 4.7 Hz,1H), 3.65 (d,
J¼10.6 Hz, 1H), 2.40e2.32 (m, 1H), 2.06e1.99 (m, 1H), 1.96e1.91 (dt,
J¼13.9, 3.1 Hz, 1H), 1.75e1.66 (m, 2H), 1.74e1.71 (m, 3H), 1.58 (dd,
J¼11.5, 4.3 Hz, 1H), 1.51 (dt, J¼13.7, 5.3 Hz, 1H), 1.20 (s, 3H),
m
m
reaction was stirred for 3 h at rt, quenched with a saturated aqueous
NH4Cl solution, and the aqueous phase was extracted with CH2Cl2.
The combined organic extracts were dried over anhydrous Na2SO4
and concentrated in vacuo. Flash chromatography (150:1 hexanes/
1.07e1.04 (m, 17H); 13C NMR (100 MHz, CDCl3)
d 204.9, 142.6, 133.4,
79.6, 75.8, 45.5, 44.5, 41.5, 31.7, 26.6, 23.8, 18.1, 17.8, 17.6, 17.1, 17.1,
16.4, 12.7, 12.3, 12.2; HRMS (ESI) [MþNa]þ calcd for C20H34NaO3Si
373.2175, found 373.2171.
EtOAc) afforded 15 (8.5 mg, 82%) as a white solid: ½a D28
ꢁ3.87 (c 1.0,
ꢂ
CHCl3); IR (KBr) 3020, 2948, 2862, 1664, 1252, 1217, 1099, 843, 761,
672 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 6.66e6.64 (m,1H), 3.67e3.63
(m,1H), 3.43 (d, J¼10.0 Hz,1H), 3.13 (d, J¼10.0 Hz,1H), 2.30e2.11 (m,
2H), 2.09 (dd, J¼11.4, 4.1 Hz, 1H), 1.87 (dt, J¼14.0, 3.4 Hz, 1H),
1.74e1.73 (m, 3H), 1.69e1.58 (m, 2H), 1.45e1.37 (m, 1H), 1.04 (s, 3H),
0.87 (s, 9H), 0.83 (s, 9H), 0.76 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.01 (s,
4.1.6. (1aR,2aS,5S,6R,6aS,7aR)-5-Hydroxy-6-(hydroxymethyl)-
1a,2a,6-trimethyloctahydronaphtho[2,3-b]oxiren-2(1aH)-one
(11). To a solution of 10 (20.0 mg, 57.1
were added an aqueous NaOH solution (6 M in H2O, 3
and 30% H2O2 solution (22 L, 0.194 mmol). The reaction was stir-
mmol) in MeOH (1.0 mL)
m
L, 17.2 mol)
m
3H), 0.00 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 206.0, 143.6, 133.2,
m
71.5, 64.1, 44.4, 44.1, 41.0, 31.4, 27.2, 26.1, 26.0, 24.1, 18.3, 18.2, 17.8,
16.5, 13.0, ꢁ3.5, ꢁ4.8, ꢁ5.0, ꢁ5.5; HRMS (ESI) [MþNa]þ calcd for
C26H50NaO3Si2 489.3196, found 489.3205.
red for 20 h at rt, quenched with a saturated aqueous Na2S2O3 so-
lution and a saturated aqueous NaHCO3 solution, and the aqueous
phase was extracted with CH2Cl2. The combined organic extracts
were dried over anhydrous Na2SO4 and concentrated in vacuo.
Flash chromatography (1:1 hexanes/EtOAc) afforded 11 (11.9 mg,
4.1.9. (4aS,5R,6S,8aS)-6-Hydroxy-5-(hydroxymethyl)-2,5,8a-tri-
methyl-4a,5,6,7,8,8a-hexahydronaphthalen-1(4H)-one (18). To a so-
lution of Me4NBH(OAc)3 (5.57 g, 21.2 mmol) in CH3CN (2.1 mL) was
added dropwise acetic acid (16.8 mL). A solution of 5 (1.00 g,
4.23 mmol) in CH3CN (2.1 mL) was added to the mixture at ꢁ40 ꢀC.
The reactionwas stirred for 0.5 h at ꢁ40 ꢀC and quenched with 0.5 N
potassium sodium tartrate tetrahydrate. The resulting mixture was
carefully poured into a saturated aqueous NaHCO3 solution at 0 ꢀC
and the neutralized aqueous phase was extracted with CH2Cl2. The
combined organic extracts were dried over anhydrous Na2SO4 and
82%) as a white solid: ½a D28
ꢂ
þ45.3 (c 1.0, MeOH); IR (KBr) 3021, 2403,
1709, 1520, 1427, 1216, 1039, 929, 762, 673 cmꢁ1
;
1H NMR
(400 MHz, CDCl3)
d
3.54 (dd, J¼11.2, 5.1 Hz, 1H), 3.51 (d, J¼11.2 Hz,
1H), 3.43 (t, J¼2.0 Hz, 1H), 3.25 (d, J¼11.2 Hz, 1H), 2.20 (ddd, J¼14.7,
3.4, 2.7 Hz, 1H), 2.03 (ddd, J¼14.7, 12.7, 1.4 Hz, 1H), 1.92 (dd, J¼12.5,
3.7 Hz, 1H), 1.82 (dt, J¼13.9, 3.4 Hz, 1H), 1.71e1.58 (m, 2H), 1.41 (dt,
J¼13.1, 4.7 Hz, 1H), 1.36 (s, 3H), 1.08 (s, 3H), 0.81 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 209.9, 72.6, 65.7, 61.2, 57.3, 46.6, 43.6, 33.2, 32.0,

A. Odani et al. / Tetrahedron 67 (2011) 8195e8203
8201
concentrated in vacuo. Flash chromatography (1:1 hexanes/EtOAc)
18.1, 16.3, 12.2, ꢁ2.9, ꢁ3.6, ꢁ5.0, ꢁ5.7; HRMS (ESI) [MþNa]þ calcd
afforded 18 (935 mg, 93%) as awhite solid: ½a D27
ꢂ
ꢁ20.3 (c 1.0, MeOH);
for C26H50NaO4Si2 505.3145, found 505.3120.
IR (KBr) 3620, 3457, 3020, 2977, 1666, 1217, 1043, 771, 670 cmꢁ1; 1H
NMR (400 MHz, CDCl3)
d
6.82e6.79 (m,1H), 3.62e3.58 (m,1H), 3.53
4.1.12. (3S,4aR,5R,6S,8aS)-3,6-Bis((tert-butyldimethylsilyl)oxy)-5-
(((tert-butyldimethylsilyl)oxy)methyl)-2,5,8a-trimethyl-
3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carbaldehyde (4). To a so-
(d, J¼11.2 Hz, 1H), 3.27 (d, J¼11.2 Hz, 1H), 2.43e2.27 (m, 2H), 2.01
(dd, J¼10.9, 4.8 Hz, 1H), 1.86 (dt, J¼13.9, 3.4 Hz, 1H), 1.76e1.68 (m,
2H), 1.72e1.70 (m, 3H), 1.47e1.39 (m, 1H), 1.07 (s, 3H), 0.85 (s, 3H,);
lution of TMSCH2OMe (196 mL, 1.24 mmol) in THF (2.1 mL) was
13C NMR (100 MHz, CDCl3)
d
207.7,146.3,133.7, 72.5, 65.5, 45.5, 44.0,
added dropwise s-BuLi (1.0 M in THF, 1.24 mL, 1.24 mmol) at ꢁ23 ꢀC
and the reaction mixture was stirred for 0.5 h at ꢁ23 ꢀC. After
cooling to ꢁ78 ꢀC, the mixture was added dropwise to a solution of
17 (200 mg, 0.415 mmol) in THF (2.0 mL). The reaction mixture was
stirred for 0.5 h at ꢁ60 ꢀC before t-BuOK (184 mg, 1.63 mmol) was
added. The resulting mixture was gradually warmed up to rt over
1 h and quenched with a saturated aqueous NH4Cl solution. The
aqueous phase was extracted with CH2Cl2. The combined organic
extracts were dried over anhydrous Na2SO4, filtered, and concen-
trated in vacuo. This residue was employed in the next reaction
without further purification. The residue was dissolved in DMF
(4.2 mL) and to the solution were added imidazole (113 mg,
1.65 mmol), DMAP (cat.), and TBSCl (187 mg, 1.24 mmol). The
resulting solution was stirred for 30 min at 50 ꢀC before additional
TBSCl (187 mg, 1.24 mmol) was added. After being stirred for
30 min at 50 ꢀC, the reaction mixture was quenched with H2O, and
the aqueous phase was extracted with EtOAc. The combined or-
ganic extracts were dried over anhydrous Na2SO4 and concentrated
in vacuo. Flash chromatography (150:1 hexanes/EtOAc) afforded 4
42.6, 32.7, 27.2, 24.9, 18.2, 16.4, 12.9; HRMS (ESI) [MþNa]þ calcd for
C14H22NaO3 261.1467, found 261.1472.
4.1.10. (1aS,2aS,5S,6R,6aS,7aS)-5-Hydroxy-6-(hydroxymethyl)-
1a,2a,6-trimethyloctahydronaphtho[2,3-b]oxiren-2(1aH)-one
(16). To a solution of 18 (76.1 mg, 0.210 mmol) in acetic acid
(3.2 mL) at rt were added dropwise N-bromoacetamide (111 mg,
0.639 mmol) and silver acetate (107 mg, 0.639 mmol). The reaction
mixture was stirred for 6.5 h at rt, filtered through a pad of Celite,
and concentrated in vacuo. The residue 19 was dissolved with
CH2Cl2 and washed with an aqueous NaHCO3 solution. The organic
layer was dried over anhydrous Na2SO4 and concentrated in vacuo.
This residue was employed in the next reaction without further
purification. To a solution of the crude 19 in MeOH (3.2 mL) at rt
was added K2CO3 (133 mg, 0.959 mmol). The reaction was stirred
for 7 h at rt, quenched with H2O, and the aqueous phase was
extracted with CH2Cl2. The combined organic extracts were dried
over anhydrous Na2SO4 and concentrated in vacuo. Flash chroma-
tography (1:2 hexanes/EtOAc) afforded 16 (70.6 mg, 87%) as a white
solid: data for 19 (after purification by flash chromatography (1:2
(179 mg, two steps 71%) as a white solid: ½a D25
ꢁ22.6 (c 1.0, CHCl3);
ꢂ
IR (KBr) 2953, 2859, 1681, 1468, 1387, 1254, 1101, 1005, 838,
hexanes/EtOAc) of the above crude) ½a D26
ꢂ
þ4.12 (c 1.0, MeOH): IR
775 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
10.1 (s, 1H), 4.16 (dd, J¼9.2,
(KBr) 3374, 2931, 2077, 1711, 1455, 1381, 1222, 1033, 979, 757 cmꢁ1
;
7.6 Hz, 1H), 3.71 (dd, J¼10.7, 6.0 Hz, 1H), 3.42 (d, J¼9.8 Hz, 1H), 3.17
(d, J¼9.8 Hz, 1H), 2.44 (dt, J¼13.3, 3.5 Hz, 1H), 2.01 (s, 3H), 1.85 (dd,
J¼11.6, 7.3 Hz, 1H), 1.68e1.44 (m, 4H), 1.26 (s, 3H), 1.07e0.97 (m,
1H), 0.91 (s, 9H), 0.89 (s, 9H), 0.87 (s, 9H), 0.64 (s, 3H), 0.12 (s, 3H),
0.11 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.02 (s, 3H); 13C
1H NMR (400 MHz, CDCl3)
d
4.24 (dd, J¼8.5, 5.8 Hz, 1H), 3.60 (dd,
J¼9.3, 7.1 Hz, 1H), 3.56 (d, J¼11.2 Hz, 1H), 3.28 (d, J¼11.0 Hz, 1H),
2.08e1.98 (m, 2H), 1.93 (dt, J¼13.9, 3.5 Hz, 1H), 1.83e1.69 (m, 3H),
1.81 (s, 3H), 1.43e1.35 (m, 1H), 1.22 (s, 3H), 0.77 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d
211.2, 78.6, 73.9, 72.2, 65.7, 48.6, 44.1, 38.8, 35.0,
NMR (100 MHz, CDCl3) d 194.0, 153.6, 144.2, 74.2, 71.4, 64.2, 43.3,
28.6, 27.3, 25.9, 20.4, 12.9; HRMS (ESI) [MþNa]þ calcd for
39.8, 37.7, 34.1, 28.7, 27.8, 26.2, 26.1, 26.0, 20.5, 18.3, 18.2, 18.2, 15.2,
13.1, ꢁ3.1, ꢁ3.5, ꢁ4.7, ꢁ4.7, ꢁ5.0, ꢁ5.3; HRMS (ESI) [MþNa]þ calcd
for C33H66NaO4Si3 633.4167, found 633.4150.
C14H23BrNaO4 357.0677, found 357.0666. Data for 16 ½a D28
ꢁ12.6 (c
ꢂ
1.0, CHCl3); IR (KBr) 3408, 3018, 2978, 2941, 2878, 1701, 1471, 1447,
1383, 1217, 1063, 1043, 999, 761, 669 cmꢁ1
CDCl3)
;
1H NMR (400 MHz,
d
3.66 (d, J¼10.6 Hz,1H), 3.57 (dd, J¼11.2, 4.5 Hz,1H), 3.46 (d,
4.1.13. (3S,4aR,5R,6S,8aS)-3,6-Bis((tert-butyldimethylsilyl)oxy)-5-
(((tert-butyldimethylsilyl)oxy)methyl)-2,5,8a-trimethyl-
3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid (Pinnick
J¼5.5 Hz, 1H), 3.36 (d, J¼10.6 Hz, 1H), 2.18 (dd, J¼15.1, 12.9 Hz, 1H),
2.00 (dt, J¼15.3, 5.7 Hz, 1H), 1.80e1.62 (m, 4H), 1.50 (dt, J¼13.3,
3.9 Hz,1H),1.35 (s, 3H),1.24 (s, 3H), 0.91 (s, 3H); 13C NMR (100 MHz,
oxidation of 4). To a solution of 4 (27.0 mg, 44.3
mmol) in t-BuOH
CDCl3)
d
210.7, 73.9, 67.9, 64.2, 57.7, 45.3, 44.0, 43.2, 32.7, 26.2, 21.2,
(221 L) were added H2O (221 L) and 2-methyl-2-butene (19 m
m
m
L,
18.6, 16.3, 11.5; HRMS (ESI) [MþNa]þ calcd for C14H22NaO4 277.1416,
0.177 mmol) at rt and the reaction mixture was treated with
NaH2PO4$2H2O (21.0 mg, 0.133 mmol) and NaClO2 (12.0 mg,
0.133 mmol) at 0 ꢀC. After being stirred for 15 h at rt, the reaction
mixture was quenched with a saturated aqueous Na2S2O3 solution,
and the aqueous phase was extracted with CH2Cl2. The combined
organic extracts were dried over anhydrous Na2SO4 and concen-
trated in vacuo. Flash chromatography (10:1 hexanes/EtOAc) affor-
found 277.1429.
4.1.11. (1aS,2aS,5S,6R,6aS,7aS)-5-((tert-Butyldimethylsilyl)oxy)-6-
( ( ( t e r t - b u t y l d i m e t h y l s i l y l ) o x y ) m e t h y l ) - 1 a , 2 a , 6 -
trimethyloctahydronaphtho[2,3-b]oxiren-2(1aH)-one (17). To a solu-
tion of 16 (20.0 mg, 78.7
added 2,6-lutidine (55
m
mol) in CH2Cl2 (800
m
L) at 0 ꢀC were
L,
mL, 0.474 mmol) and TBSOTf (54
m
ded the carboxylic acid (17.0 mg, 61%) as a white solid: ½a D25
þ12.6 (c
ꢂ
0.237 mmol). The reaction was stirred for 0.5 h at 0 ꢀC, quenched
with a saturated aqueous NaHCO3 solution, and the aqueous phase
was extracted with CH2Cl2. The combined organic extracts were
dried over anhydrous Na2SO4 and concentrated in vacuo. Flash
chromatography (150:1 hexanes/EtOAc) afforded 17 (34.0 mg, 90%)
1.0, CHCl3); IR (KBr) 3018, 2949, 2891, 2862, 1696, 1254, 1217, 1097,
1056, 844 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
4.01 (t, J¼8.2 Hz, 1H),
3.73 (dd, J¼9.2, 7.1 Hz, 1H), 3.41 (d, J¼10.0 Hz, 1H), 3.18 (d, J¼9.8 Hz,
1H), 1.86 (dd, J¼11.6, 7.5 Hz, 1H), 1.72 (s, 3H), 1.69e1.49 (m, 5H),
1.38e1.32 (m, 1H), 1.29 (s, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.87 (s, 9H),
0.64 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.04 (s,
as a white solid: ½a D26
þ11.6 (c 1.0, CHCl3); IR (KBr) 3021, 2952, 2884,
ꢂ
2859, 1702, 1467, 1386, 1254, 1217, 1103, 1004, 886, 841, 810, 762,
3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 174.8, 139.2, 135.9,
671 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
3.55 (dd, J¼9.3, 6.9 Hz, 1H),
72.3, 71.4, 64.3, 43.3, 40.4, 37.0, 34.7, 29.3, 27.6, 26.1, 26.1, 26.1, 21.0,
18.4, 18.3, 18.3, 17.4, 13.0, ꢁ3.2, ꢁ3.6, ꢁ4.6, ꢁ4.7, ꢁ5.0, ꢁ5.3; HRMS
(ESI) [MþNa]þ calcd for C33H66NaO5Si3 649.4116, found 649.4099.
3.43 (d, J¼10.0 Hz, 1H), 3.41 (d, J¼5.1 Hz, 1H), 3.08 (d, J¼10.0 Hz,
1H), 2.09 (dd, J¼16.2, 14.3 Hz, 1H), 1.95e1.89 (m, 2H), 1.72 (dt,
J¼10.4, 3.5 Hz, 1H), 1.63e1.57 (m, 2H), 1.44e1.36 (m, 1H), 1.33 (s,
3H), 1.18 (s, 3H), 0.86 (s, 18H), 0.70 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H),
4.1.14. (Z)-Ethyl 3-((3S,4aR,5R,6S,8aS)-3,6-bis((tert-butyldimethyl-
silyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2,5,8a-tri-
methyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)-3-
0.03 (s, 3H), 0.01 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
211.0, 71.3,
64.3, 64.0, 57.2, 45.2, 44.4, 42.7, 32.5, 26.6, 25.9, 25.7, 21.2, 18.3, 18.1,

8202
A. Odani et al. / Tetrahedron 67 (2011) 8195e8203
hydroxyacrylate (21). To a solution of LHMDS (1.0 M in THF, 642
0.642 mmol) in THF (2.0 mL) was added dropwise EtOAc (52
m
m
L,
L,
trimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)(hydroxy)
methylene)-3-oxobutanoate (3). -Ketoester 24 (230 mg,
L).
b
0.602 mmol) at ꢁ78 ꢀC and the reaction mixture was stirred for 0.5 h
at ꢁ78 ꢀC. To the resulting mixture was added dropwise a solution of
4 (245 mg, 0.401 mmol) in THF (2.0 mL). The reaction mixture was
further stirred for 0.5 h at ꢁ78 ꢀC. The resulting mixture was then
quenched with a saturated aqueous NH4Cl solution. The aqueous
phase was extracted with CH2Cl2. The combined organic extracts
were dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. This residue was employed in the next reaction without fur-
ther purification. The crude 20 was dissolved in CH2Cl2 (4.0 mL) and
to the solution was added DMP (255 mg, 0.602 mmol). After being
stirred for 30 min at rt, the reaction mixture was quenched with
a saturated aqueous Na2S2O3 solution and a saturated aqueous
NaHCO3 solution, and the aqueous phase was extracted with CH2Cl2.
The combined organic extracts were dried over anhydrous Na2SO4
and concentrated in vacuo. Flash chromatography (150:1 hexanes/
0.307 mmol) was dissolved in toluene (2.5 mL) and MeOH (614 m
The reaction mixture was stirred for 5 h at 80 ꢀC, cooled to rt, and
concentrated in vacuo. Flash chromatography (150:1 hexanes/
EtOAc) afforded 3 (208 mg, 94%) as a white solid: ½a D25
þ31.3 (c 1.0,
ꢂ
CHCl3); IR (KBr) 2954, 2932, 2888, 2858, 1715, 1468, 1441, 1263,
1103, 1056, 841, 774, 708 cmꢁ1; enol form 1H NMR (600 MHz, CDCl3)
d
4.04 (ddd, J¼9.5, 7.0, 1.0 Hz, 1H), 3.73 (dd, J¼11.0, 5.0 Hz, 1H), 3.68
(s, 3H), 3.43 (d, J¼10.0 Hz, 1H), 3.19 (d, J¼10.0 Hz, 1H), 2.34 (s, 3H),
1.87 (dd, J¼13.0, 1.5 Hz, 1H), 1.86 (ddd, J¼13.0, 7.0, 1.5 Hz, 1H),
1.69e1.55 (m, 4H), 1.53 (s, 3H), 1.41 (ddd, J¼14.0, 5.0, 3.0 Hz, 1H),
1.32 (s, 3H), 0.92 (s, 9H), 0.89 (s, 9H), 0.86 (s, 9H), 0.65 (s, 3H), 0.09
(s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.03 (s,
3H); 13C NMR (150 MHz, CDCl3)
d 196.4, 194.1, 167.4, 141.2, 133.7,
111.1, 72.2, 71.4, 64.3, 51.7, 43.3, 39.3, 38.2, 32.8, 29.4, 27.3, 26.0,
25.9, 25.9, 25.9, 22.4, 18.3, 18.1, 18.1, 17.2, 12.8, ꢁ3.3, ꢁ3.8, ꢁ4.8,
ꢁ4.9, ꢁ5.1, ꢁ5.6; HRMS (ESI) [MþNa]þ calcd for C38H72NaO7Si3
747.4484, found 747.4450.
EtOAc) afforded 21 (186 mg, two steps 67%) as a white solid: ½a D25
ꢂ
þ13.1 (c 1.0, CHCl3); IR (KBr) 2954, 2932, 2890, 2858, 1612, 1468,
1252, 1218, 1100, 1056, 840, 754 cmꢁ1; enol form 1H NMR (600 MHz,
CDCl3)
d
12.2 (s, 1H), 4.91 (s, 1H), 4.21 (q, J¼7.1 Hz, 2H), 4.09 (br t,
4.1.17. (4aS,5S,6aR,7R,8S,10aS,10bR)-Methyl 5,8-bis((tert-butyldime-
thylsilyl)oxy)-7-(((tert-butyldimethylsilyl)oxy)methyl)-3,4a,7,10a-tet-
ramethyl-1-oxo-4a,5,6,6a,7,8,9,10,10a,10b-decahydro-1H-benzo[f]
J¼8.0 Hz,1H), 3.73 (dd, J¼10.0, 5.0 Hz,1H), 3.39 (d, J¼9.7 Hz,1H), 3.18
(d, J¼9.7 Hz,1H),1.84(ddd, J¼13.0, 8.0, 2.0 Hz,1H),1.75e1.44(m, 5H),
1.64 (s, 3H),1.31 (t, J¼7.2 Hz, 3H),1.19 (s, 3H), 0.90 (s, 9H), 0.89 (s, 9H),
0.86 (s, 9H), 0.63 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H), 0.05 (s, 3H), 0.04 (s,
chromene-2-carboxylate (2). To a solution of 3 (25.0 mg, 34.5
mmol)
in toluene (345 L) was added DBU (5 L, 34.5 mol). After being
m
m
m
3H), 0.02 (s, 3H), 0.02 (s, 3H); 13C NMR (150 MHz, CDCl3)
d
175.0,
stirred for 8 h at 100 ꢀC, the reaction mixture was quenched with
H2O. The aqueous phase was extracted with CH2Cl2. The combined
organic extracts were dried over anhydrous Na2SO4 and concen-
trated in vacuo. Flash chromatography (100:1 hexanes/EtOAc)
172.6, 140.6, 134.9, 92.9, 72.5, 71.2, 64.1, 60.0, 43.3, 40.5, 37.4, 35.0,
29.2, 27.5, 25.9, 25.9, 25.9, 21.3, 18.1, 18.1, 18.1, 17.1, 14.2, 12.8, ꢁ3.4,
ꢁ3.8, ꢁ4.9, ꢁ5.2, ꢁ5.5; HRMS (ESI)[MþNa]þ calcd for C37H72NaO6Si3
719.4534, found 719.4509.
afforded 2 (17.0 mg, 68%) as a white solid: ½a D25
þ12.1 (c 1.0, CHCl3);
ꢂ
IR (KBr) 2953, 2932, 2885, 2858, 1685, 1389, 1355, 1254, 1215, 1117,
4.1.15. 5-((3S,4aR,5R,6S,8aS)-3,6-Bis((tert-butyldimethylsilyl)oxy)-5-
(((tert-butyldimethylsilyl)oxy)methyl)-2,5,8a-trimethyl-
3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carbonyl)-2,2,6-trimethyl-
4H-1,3-dioxin-4-one (24). To a solution of 22 (198 mg, 0.739 mmol)
in THF (1.5 mL) at ꢁ30 ꢀC was added dropwise i-PrMgCl (2.0 M in
1060, 839, 753 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
3.84 (dd, J¼10.7,
5.0 Hz, 1H), 3.78 (s, 3H), 3.69 (dd, J¼11.5, 5.2 Hz, 1H), 3.41(d,
J¼9.8 Hz, 1H), 3.12 (d, J¼9.6 Hz, 1H), 2.60 (dt, J¼13.5, 3.5 Hz, 1H),
2.28 (s, 1H), 2.16 (s, 3H), 1.72e1.54 (m, 3H), 1.47e1.33 (m, 2H), 1.34
(s, 3H), 1.07 (s, 3H), 0.97e0.93 (m, 1H), 0.92 (s, 9H), 0.90 (s, 9H), 0.86
(s, 9H), 0.60 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.05 (s, 6H), 0.04 (s, 3H),
THF, 369
m
L, 0.739 mmol). After being stirred for 0.5 h at ꢁ30 ꢀC, to
the reaction mixture was added dropwise a solution of 4 (150 mg,
0.246 mmol) in THF (1.0 mL). The resulting mixture was warmed up
to rt, stirred for 0.5 h, and quenched with a saturated aqueous
NH4Cl solution. The aqueous phase was extracted with EtOAc. The
combined organic extracts were dried over anhydrous Na2SO4 and
concentrated in vacuo. This residue was employed in the next re-
action without further purification. The crude 23 was dissolved in
CH2Cl2 (2.5 mL) and DMP (156 mg, 0.369 mmol) was added. The
resulting solution was stirred for 15 min at rt and quenched with
a saturated aqueous Na2S2O3 solution and a saturated aqueous
NaHCO3 solution. The aqueous phase was extracted with CH2Cl2.
The combined organic extracts were dried over anhydrous Na2SO4
and concentrated in vacuo. Flash chromatography (150:1 hexanes/
0.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 189.5, 174.0, 166.6, 111.5,
88.4, 77.8, 71.6, 64.2, 61.2, 52.1, 43.6, 43.4, 37.1, 36.7, 28.9, 27.2, 26.2,
26.1, 26.0, 20.7, 18.4, 18.3,18.2, 16.0, 14.9, 12.9, ꢁ3.0, ꢁ4.1, ꢁ4.5, ꢁ4.7,
ꢁ5.0, ꢁ5.1; HRMS (ESI) [MþNa]þ calcd for C38H72NaO7Si3 747.4484,
found 747.4458. Data for 25 (after careful purification by SGC) ½a D24
ꢂ
þ44.3 (c 1.0, CHCl3); IR (KBr) 2947, 2862, 1596, 1468, 1383, 1254,
1219, 1093, 844, 761 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 5.43 (s, 1H),
4.11e4.07 (m, 1H), 3.74e3.70 (m, 1H), 3.40 (d, J¼9.8 Hz, 1H), 3.18 (d,
J¼9.8 Hz,1H), 2.10 (s, 3H),1.84 (ddd, J¼12.3, 7.0,1.4 Hz,1H),1.71 (dd,
J¼12.9, 1.4 Hz, 1H), 1.62e1.46 (m, 4H), 1.60 (s, 3H), 1.32e1.26 (m,
1H), 1.23 (s, 3H), 0.90 (s, 18H), 0.86 (s, 9H), 0.63 (s, 3H), 0.09 (s, 3H),
0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H); 13C
NMR (100 MHz, CDCl3)
d 192.3, 189.6, 142.7, 133.3, 103.4, 72.4, 71.3,
EtOAc) afforded 24 (133 mg, two steps 72%) as a white solid: ½a D27
ꢂ
64.1, 43.2, 40.5, 37.5, 35.1, 29.3, 27.5, 26.0, 26.0, 25.9, 25.6, 21.2, 18.2,
18.2, 18.1, 17.0, 12.8, ꢁ3.4, ꢁ3.8, ꢁ4.8, ꢁ4.9, ꢁ5.1, ꢁ5.5; HRMS (ESI)
[MþNa]þ calcd for C36H70NaO5Si3 689.4429, found 689.4395.
þ24.9 (c 1.0, CHCl3); IR (KBr) 2948, 2861, 1741, 1653, 1546, 1467,
1383, 1348, 1259, 1208, 1100, 844, 776, 741 cmꢁ1
;
1H NMR
4.12 (t, J¼8.4 Hz, 1H), 3.74 (dd, J¼10.9, 5.0 Hz,
(300 MHz, CDCl3)
d
1H), 3.39 (d, J¼9.8 Hz, 1H), 3.22 (d, J¼9.8 Hz, 1H), 2.39 (s, 3H), 2.05
(dd, J¼13.1, 1.6 Hz, 1H), 1.92e1.86 (m, 1H), 1.70 (s, 6H), 1.68e1.52 (m,
4H), 1.50 (s, 3H), 1.31 (s, 3H), 1.31e1.26 (m, 1H), 0.93 (s, 9H), 0.87 (s,
9H), 0.86 (s, 9H), 0.65 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H), 0.05 (s, 3H),
0.05 (s, 3H), 0.02 (s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz, CDCl3)
4.1.18. (3S,4R,4aR,6S,6aS,12aR,12bS)-3,6-Bis((tert-butyldimethylsilyl)
oxy)-4-(((tert-butyldimethylsilyl)oxy)methyl)-4,6a,12b-trimethyl-9-
(pyridin-3-yl)-1,3,4,4a,5,6,6a,12b-octahydrobenzo[f]pyrano[4,3-b]
chromene-11,12(2H,12aH)-dione (26). To
(1.0 M in THF,193 L, 0.193 mmol) in THF (193
dropwise a solution of 2 (14.0 mg, 19.3 mol) in THF (193 m
a
solution of LHMDS
L) at 0 ꢀC was added
L). The
m
m
d
197.3, 178.0, 157.6, 145.7, 131.4, 110.6, 105.7, 72.5, 71.4, 64.5, 43.3,
m
39.5, 38.6, 32.6, 29.5, 27.4, 26.0, 25.9, 25.9, 25.5, 25.3, 22.3, 21.4,18.2,
18.1, 18.1, 16.6, 12.7, ꢁ3.4, ꢁ3.7, ꢁ4.8, ꢁ4.8, ꢁ5.2, ꢁ5.3; HRMS (ESI)
[MþNa]þ calcd for C40H74NaO7Si3 773.4640, found 773.4630.
reaction mixture was warmed up to rt and stirred for 4 h. To the
mixture was added nicotinoyl chloride hydrochloride (9.0 mg,
57.9 mmol) expeditiously. The resulting mixture was stirred for 2 h
at rt, quenched with AcOH, and diluted with H2O. The aqueous
phase was extracted with CH2Cl2. The combined organic extracts
were dried over anhydrous Na2SO4 and concentrated in vacuo.
4.1.16. (Z)-Methyl
2-(((3S,4aR,5R,6S,8aS)-3,6-bis((tert-butyldime-
thylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2,5,8a-

A. Odani et al. / Tetrahedron 67 (2011) 8195e8203
8203
Flash chromatography (2:1 hexanes/EtOAc) afforded 26 (10.0 mg,
References and notes
65%) as a white solid: ½a D27
ꢂ
þ32.6 (c 1.0, CHCl3); IR (KBr) 2939, 2861,
1758, 1541, 1446, 1254, 1217, 1110, 844, 760 cmꢁ1
;
1H NMR
1. Roth, B. D. Drug Discovery Today 1998, 3, 19.
2. Kathawala, F. G.; Heider, J. C. In Antilipidemic Drugs; Witiak, D. T., Newman, H.
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Ibrahim, R.; Lesperance, J.; Blue, J.; Heinonen, T.; Rodes-Cabau, J. Circulation
2004, 110, 3372.
(400 MHz, CDCl3)
d
9.04 (s, 1H), 8.73 (d, J¼4.3 Hz, 1H), 8.20 (dd,
J¼8.0, 1.6 Hz, 1H), 7.47 (dd, J¼8.0, 4.9 Hz, 1H), 6.40 (s, 1H), 3.94 (dd,
J¼10.0, 5.5 Hz, 1H), 3.69 (dd, J¼11.5, 5.1 Hz, 1H), 3.42 (d, J¼9.8 Hz,
1H), 3.12 (d, J¼9.8 Hz, 1H), 2.66 (dt, J¼10.4, 3.5 Hz, 1H), 2.41 (s, 1H),
1.70e1.41 (m, 5H), 1.44 (s, 3H), 1.13 (s, 3H), 0.97e0.90 (m, 1H), 0.93
(s, 9H), 0.90 (s, 9H), 0.85 (s, 9H), 0.61 (s, 3H), 0.17 (s, 3H), 0.15 (s, 3H),
0.05 (s, 3H), 0.04 (s, 3H), 0.04 (s, 3H), 0.01 (s, 3H); 13C NMR
4. Nissen, S. E.; Tuzcu, E. M.; Brewer, H. B.; Sipahi, I.; Nicholls, S. J.; Ganz, P.;
Schoenhagen, P.; Waters, D. D.; Pepine, C. J.; Crowe, T. D.; Davidson, M. H.;
Deanfield, J. E.; Winsniewski, L. M.; Hanyok, J. J.; Kassalow, L. M. N. Engl. J. Med.
2006, 354, 1253.
ꢁ
(100 MHz, CDCl3)
d 187.4, 172.4, 161.9, 157.0, 152.0, 147.0, 134.4,
5. Tomoda, H.; Omura, S. Pharmacol. Ther. 2007, 115, 375.
ꢁ
6. Omura, S.; Tomoda, H.; Kim, Y. K.; Nishida, H. J. Antibiot. 1993, 46, 1168.
127.0, 124.1, 100.8, 98.0, 90.9, 71.5, 64.2, 62.7, 43.6, 43.3, 37.0, 37.0,
28.9, 27.2, 26.2, 26.1, 26.0, 18.3, 18.2, 18.2, 15.9, 15.5, 12.9, ꢁ3.0, ꢁ4.0,
ꢁ4.3, ꢁ4.7, ꢁ5.1, ꢁ5.1; HRMS (ESI) [MþNa]þ calcd for
C43H71NNaO7Si3 820.4436, found 820.4454.
ꢁ
7. Tomoda, H.; Kim, Y. K.; Nishida, H.; Masuma, R.; Omura, S. J. Antibiot.1994, 47,148.
8. Kim, Y. K.; Tomoda, H.; Nishida, H.; Sunazuka, T.; Obata, R.; Omura, S. J. Antibiot.
1994, 47, 154.
9. Obata, R.; Sunazuka, T.; Li, Z.; Tomoda, H.; Omura, S. J. Antibiot. 1995, 48, 749.
10. Obata, R.; Sunazuka, T.; Tomoda, H.; Harigaya, Y.; Omura, S. Bioorg. Med. Chem.
ꢁ
ꢁ
ꢁ
Lett. 1995, 5, 2683.
4.1.19. Pyripyropene A (1). Acetyl chloride (18 mL, 0.250 mmol) was
11. Obata, R.; Sunazuka, T.; Li, Z.; Tian, Z.; Harigaya, Y.; Tabata, N.; Tomoda, H.;
ꢁ
Omura, S. J. Antibiot. 1996, 49, 1133.
added to MeOH (0.1 mL), and the mixture was stirred at rt for
5 min. A solution of 26 (16.8 mg, 0.0250 mmol) in MeOH (0.4 mL)
was added to the resulting MeOH solution, and the mixture was
stirred at rt for 1 h. The reaction mixture was concentrated in
vacuo. A solution of crude triol in CH2Cl2 (0.5 mL) was treated with
ꢁ
12. Obata, R.; Sunazuka, T.; Kato, Y.; Tomoda, H.; Harigaya, Y.; Omura, S. J. Antibiot.
1996, 49, 1149.
ꢁ
13. Obata, R.; Sunazuka, T.; Tian, Z.; Tomoda, H.; Harigaya, Y.; Omura, S. J. Antibiot.
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ꢁ
14. Obata, R.; Sunazuka, T.; Tian, Z.; Tomoda, H.; Harigaya, Y.; Omura, S.; Smith, A.
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20747.
Ac2O (12 mL, 0.125 mmol), Et3N (35 mL, 0.250 mmol), and a catalytic
amount of DMAP, and the mixture was stirred at rt for 0.5 h. H2O
was added to the mixture and the aqueous layer was extracted with
EtOAc. The organic layer was combined, dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. A solution of crude
triacetate in MeOH (0.5 mL) was treated with CeCl3$7H2O (65.2 mg,
0.175 mmol) and NaBH4 (6.5 mg, 0.175 mmol), and the mixture was
stirred at ꢁ78 ꢀC for 0.5 h. Acetone was added to the mixture and
the resulting solution was diluted with EtOAc. The organic layer
was washed with H2O, dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by preparative TLC
(15:1 CH2Cl2/MeOH) to afford PPPA (1) (12.8 mg, 88% for three
16. Anderson, R. A.; Joyce, C.; Davis, M.; Reagan, J. W.; Clark, M.; Shelness, G. S.;
Rudel, L. L. J. Biol. Chem. 1998, 273, 26747.
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19. Parini, P.; Davis, M.; Lada, A. T.; Erickson, S. K.; Wright, T. L.; Gustafsson, U.;
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Sahlin, S.; Einarsson, C.; Eriksson, M.; Angelin, B.; Tomoda, H.; Omura, S.;
Willingham, M. C.; Rudel, L. L. Circulation 2004, 110, 2017.
20. (a) Lada, A. T.; Davis, M.; Kent, C.; Chapman, J.; Tomoda, H.; Omura, S.; Rudel, L.
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Tomoda, H. J. Antibiot. 2007, 60, 43.
steps) as a white solid: mp 153e154 ꢀC; ½a D24
þ71.5 (c 1.0, CHCl3); IR
ꢂ
21. Ohshiro, T.; Matusda, D.; Sakai, K.; Degirolamo, C.; Yagyu, H.; Rudel, L. L.;
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Omura, S.; Tomoda, H. Arterioscler., Thromb., Vasc. Biol. 2011, 31, 1108.
(KBr) 3424, 2946, 2862, 1738, 1702, 1413, 1272, 1027 cmꢁ1; 1H NMR
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(400 MHz, CDCl3)
d
9.01 (dd, J¼1.6, 0.4 Hz, 1H), 8.69 (ddd, J¼4.8, 1.6,
23. More recently, new PPPA derivatives with higher ACAT2 inhibitory activity and
isozyme selectivity than those of PPPA have been developed in our second SAR
study. They will be reported in due course.
0.8 Hz, 1H), 8.10 (ddd, J¼8.0, 1.6, 0.4 Hz, 1H), 7.40 (ddd, J¼8.0, 4.8,
0.8 Hz, 1H), 6.46 (s, 1H), 5.03e5.00 (m, 2H), 4.80 (dd, J¼11.6, 4.0 Hz,
1H), 3.79 (d, J¼12.0 Hz, 1H), 3.72 (d, J¼12.0 Hz, 1H), 2.94 (br s, 1H),
2.19e2.15 (m, 4H), 2.10 (s, 3H), 2.05 (s, 3H), 1.91e1.71 (m, 3H), 1.69
(s, 3H), 1.64e1.54 (m, 3H), 1.45 (s, 3H), 1.45e1.38 (m, 1H), 0.89 (s,
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Silvo, A. I.; Rubio Gonzalez, R. Synlett 2004, 1011; (b) Barrero, A. F.; Quílez del
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d 170.8, 170.3, 170.0, 164.0, 162.2,
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157.2, 151.4, 146.7, 133.2, 127.2, 123.7, 102.9, 99.4, 83.2, 77.6, 73.5,
64.9, 60.1, 54.7, 45.4, 40.3, 37.9, 36.1, 25.2, 22.6, 21.1, 21.1, 20.7, 17.4,
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Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search (C) (KAKENHI No. 22590011). We also thank Ms. N. Sato and
Dr. K. Nagai (Kitasato University) for kindly measuring NMR and MS
spectra.
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