Enantioselective total synthesis of novel diterpenoid pyrones (+)-sesquicillin and (-)-nalanthalide from fungal fermentations

Article abstract of DOI:10.3987/COM-08-S(S)2

We efficiently synthesized (+)-sesquicillin (a glucocorticoid antagonist) and (-)-nalanthalide (a potassium channel Kv1.3 blocker) in a convergent and unified manner starting from (+)-5-methyl-Wieland-Miescher ketone. The synthesis involved the following key steps: (i) a [2,3]-Wittig rearrangement of a stannylmethyl ether to install the stereogenic center at C9 and the exo-methylene functionality at C8 present in the tran/decalin portion, (ii) a coupling reaction of a trans-decalin portion with a γ-pyrone moiety to assemble the requisite whole carbon framework, and (iii) a conversion of a γ-pyrone moiety to an α-pyrone ring to produce (+)-sesquicillin. The present total synthesis has verified the absolute configuration of these natural products.

Full text of DOI:10.3987/COM-08-S(S)2

HETEROCYCLES, Vol. 80, No. 1, 2010
229
HETEROCYCLES, Vol. 80, No. 1, 2010, pp. 229 - 250. © The Japan Institute of Heterocyclic Chemistry
Received, 15th December, 2008, Accepted, 23rd February, 2009, Published online, 25th February, 2009
DOI: 10.3987/COM-08-S(S)2
ENANTIOSELECTIVE TOTAL SYNTHESIS OF NOVEL DITERPENOID
PYRONES (+)-SESQUICILLIN AND (–)-NALANTHALIDE FROM
FUNGAL FERMENTATIONS
Takamasa Oguchi, Kazuhiro Watanabe, Hideki Abe, and Tadashi Katoh*
Laboratory of Medicinal Synthetic Chemistry, Department of Chemical
Pharmaceutical Science, Tohoku Pharmaceutical University, Komatsushima,
Aoba-ku, Sendai 981-8558, Japan. E-mail: katoh@tohoku-pharm.ac.jp
Abstract – We efficiently synthesized (+)-sesquicillin (a glucocorticoid
antagonist) and (–)-nalanthalide (a potassium channel Kv1.3 blocker) in a
convergent and unified manner starting from (+)-5-methyl-Wieland–Miescher
ketone. The synthesis involved the following key steps: (i) a [2,3]-Wittig
rearrangement of a stannylmethyl ether to install the stereogenic center at C9 and
the exo-methylene functionality at C8 present in the trans-decalin portion, (ii) a
coupling reaction of a trans-decalin portion with a ꢀ-pyrone moiety to assemble
the requisite whole carbon framework, and (iii) a conversion of a ꢀ-pyrone moiety
to an ꢁ-pyrone ring to produce (+)-sesquicillin. The present total synthesis has
verified the absolute configuration of these natural products.
INTRODUCTION
In recent years, a number of diterpenoid pyrones and related compounds have been isolated from
1
–5
microorganisms, particularly from fungal strains. Several of these natural products have been reported
1
,2c
2d
to exhibit a wide variety of biological properties such as insecticidal,
antihypertensive,
2
d
2d
2d
2e
3–5
bronchospasmolytic, anti-inflammatory, laxative, anticancer, and immunosuppressive activities.
In most cases, however, further biological studies including structure-activity relationships are severely
restricted probably because of the scarcity of structural diversity of microorganisms. Consequently, the
development of efficient and flexible synthetic routes for this class of natural products and related
compounds is quite desirable and worthwhile from the viewpoint of medicinal chemistry and
This paper is dedicated to Professor Akira Suzuki on the occasion of his 80th birthday.

230
HETEROCYCLES, Vol. 80, No. 1, 2010
Me
O
Me
HO
Me
O
Me
Me
O
Me
3ꢀ
Me
O
O
16
O
Me
Me
H
O
Me
OMe
1
4
9
2
3
O
Me
H
10
8
7
OMe
5
Me
H
OMe
AcO
AcO
Me
6
H
Me
Me
Me
O
O
Me
HO
Me
Me
Me
R
Me
Me
sesquicillin (1)
nalanthalide (2)
candelalide A (3)
candelalide B (4) ( R = OH )
candelalide C (5) ( R = H )
Figure 1. Structures of sesquicillin (1), nalanthalide (2), and candelalides A (3), B (4), C (5).
pharmaceuticals.
2
a
In 1998, Erkel et al. reported the isolation and structural elucidation of a novel diterpenoid pyrone,
sesquicillin (1) (Figure 1), from the culture broth of Acremonium sp. This substance was first assigned as
2
a
an inhibitor of glucocorticoid-mediated signal transduction. It has also been reported that sesquicillin
2
b
strongly induced G1 phase arrest in human breast cancer cell lines. Recently, four additional and new
sesquicillin analogues (named sesquicillin B–E) were isolated from the culture broth of Albophoma sp.
2
c
and together with 1 (renamed sesquicillin A). These substances were reported to exhibit insecticidal and
2
c
cytotoxic activities. The gross structure and stereochemistry of 1 have been determined by extensive
2
a
NMR spectroscopic studies including COSY, HMQC, HMBC, and NOESY experiments, but the
absolute configuration has not been assigned. This natural product consists of a trans-decalin skeleton
2
connected to a fully substituted ꢀ-pyrone via a methylene linkage.
A closely related diterpenoid pyrone, nalanthalide (2), was isolated from the culture broth of
4
Nalanthamala sp. by the Merck research group in 2001. This substance was found to be a blocker of the
4
,6,7
voltage-gated potassium channel Kv1.3 for a novel molecular-targeted immunosuppressive agent. The
gross structure of 2 including stereochemistry, wherein the ꢀ-pyrone ring of 1 is replaced by a ꢁ-pyrone
4
ring, has been determined using detailed NMR spectroscopic analysis, however, the absolute
configuration has not been disclosed. Subsequently, the Merck research group reported the isolation and
structural determination of three novel diterpenoid pyrones, candelalides A (3), B (4), and C (5), from the
5
culture broth of Sesquicillium candelabrum in 2002. They found that these substances were also potential
5
Kv1.3 blocking immunosuppressive agents.
The attractive biological properties and unique structural features of 1–5 have made them intriguing
targets for total synthesis. To date, only one total synthesis of (±)-1 has been reported by Danishefsky and
8
9
Zhang in 2002. We have previously reported our preliminary results on the first total synthesis of (–)-2

HETEROCYCLES, Vol. 80, No. 1, 2010
231
1
0
and (–)-3 in enantiomerically pure forms, leading to the confirmation of their absolute configurations. In
1
1
addition, we also achieved an enatioselective total synthesis of candelalides B (4) and C (5). In this
paper, we describe the full details of our unified total synthesis of naturally occurring (+)-sesquicillin (1)
and (–)-nalanthalide (2).
RESULTS AND DISCUSSION
Synthetic plan for (+)-sesquicillin (1) and (–)-nalanthalide (2)
The synthetic plan for (+)-sesquicillin (1) and (–)-nalanthalide (2) is outlined in Scheme 1. The ꢀ-pyrone
moiety present in 2 is considered to be an equivalent to vinylogous ester; therefore, hydrolysis of this
moiety followed by its spontaneous tautomerization to ꢁ-pyrone would deliver sesquicillin (1). To the
best of our knowledge, the method for conversion of 2 to 1 was hitherto unknown, and hence this reaction
posed a considerable challenge from the synthetic viewpoint. Nalanthalide (2) would be produced through
a coupling reaction of the appropriately substituted trans-decalin segment 7 (accessible from alcohol 8)
1
0,11
with the fully substituted ꢀ-pyrone 6.
The advanced key intermediate 8, having both a hydroxymethyl
group at C9 and an exo-methylene moiety at C8, would be formed through the strategic [2,3]-Wittig
rearrangement of stannylmethyl ether 9, where we believed that the C9 stereogenic center and the C8
exo-methylene moiety in the product 8 would be established simultaneously. The intermediate 9 should,
1
0–12
in turn, be accessed from the known trans-decalone 10,
which is readily prepared in an
enantiomerically pure form from (+)-5-methyl-Wieland–Miescher ketone (11), by sequential functional
group manipulation and deprotection or vice versa.
Me
Me
Me
O
Me
HO
Me
O
Me
Snn-Bu
3
O
O
O
Li
X
O
Me
H
Me
H
9
OMe
6
Me
O
Me
H
OMe
8
TBSO
TBSO
AcO
AcO
Me
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
7
8
:
:
X = CHO
9
sesquicillin (1)
nalanthalide (2)
X = CH OH
2
O
O
Me
Me
H
ref. 10–12
O
O
O
Me
Me
11
10
Scheme 1. Synthetic plan for sesquicillin (1) and nalanthalide (2).

232
HETEROCYCLES, Vol. 80, No. 1, 2010
Synthesis of the substrate 9 for the [2,3]-Wittig rearrangement
As shown in Scheme 2, we initially pursued the synthesis of the intermediate 9, a substrate for the critical
1
0–12
[
2,3]-Wittig rearrangement, starting from the known enantiomerically pure trans-decalone 10
(>99%
ee). Our route to the allyl alcohol 22 from 10 was based on the procedures established by Danishefsky et
8
al. with some improvements in the reaction steps and conditions, which eventually allowed for an
increase of the total yield of 22 (49% overall yield in eleven steps versus 30% overall yield from those
same steps). Thus, stereoselective reduction of the C3 carbonyl group in 10 with lithium aluminum
hydride produced the desired ꢀ-alcohol 12 in 98% yield as a single stereoisomer. Subsequent
hydroboration of 12 (BH ·THF, THF, 0 °Cꢀrt) followed by hydrogen peroxide oxidation (30% aq. H O ,
3
2
2
3
M NaOH, 0 °Cꢀrt) delivered the requisite diol 13 in 85% yield. The two hydroxy groups in 13 were
simultaneously protected as the bis(tert-butyldimethylsilyl) (TBS) ethers to furnish the corresponding
disilyl ether 14 in quantitative yield. Compound 14 was then converted to the aldehyde 16 via a two-step
operation including selective deprotection of the TBS group on the C4 side chain and ethylene acetal
moiety at C9 by acid treatment [AcOH/THF/H O (3:1:1), 50 °C, 4 h, 90%], followed by Dess–Martin
2
1
3
oxidation (96%). To set up the requisite homoprenyl side chain at the C4 position, compound 16 was
subjected to a Wittig reaction using isopropylidene(triphenyl)phosphorane providing the desired product
1
7 in 86% yield.
O
O
Me
H
Me
H
O
O
Me
Me
H
O
9
8
O
O
d
g
a
b
4
4
3
3
RO
TBSO
O
HO
Me
Me
H
Me
Me
H
RO
X
10
12
1
3 : R = H
15 : X = OH, H
16 : X = O
c
e
f
14 : R = TBS
17 : X = CMe2
Snn-Bu
3
O
OR
OH OEE
Me
H
Me
H
Me
O
X
Me
H
9
9
i
j
l
4
TBSO
TBSO
TBSO
H
TBSO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
1
8 : R = H
20
21 : R = CHO
h
k
19 : R = EE
22 : R = CH OH
2
9
Scheme 2. Synthesis of the key intermediates 9. Reagents and conditions: (a) LiAlH , Et O, –45°C to rt, 1.5 h,
4
2
9
8%; (b) BH ·THF, THF, 0°C to rt, 1 h; 30% aq. H O , 3M NaOH, 0°C to rt, 1.5 h, 85%; (c) TBSOTf, 2,6-lutidine,
3 2 2
CH Cl , 0°C, 30 min, quant.; (d) AcOH/THF/H O (3:1:1), 50°C, 4 h, 90%; (e) Dess-Martin periodinane, CH Cl ,
2
2
2
2
2
rt, 96%; (f) Ph PCHMe I, n-BuLi, THF, 0°C, 1 h, 86%; (g) ethyl formate, NaH, THF, 0° to rt, 1 h, quant.; (g) ethyl
3
2
vinyl ether, PPTS, rt, 4 h, 91%; (i) NaBH , EtOH, 0°C to rt, 2 h, 92%; (j) MsCl, Et N, CH Cl , 0°C, 30 min, 94%
4
3
2
2
(
k) NaBH , EtOH, 0°C to rt, 30 min, quant.; (l) n-Bu SnCH I, KH, 18-crown-6, THF, 0°C to rt, 1 h, 98%
4 3 2

HETEROCYCLES, Vol. 80, No. 1, 2010
233
To introduce a formyl group at the C8 position, compound 17 was treated with ethyl formate in the
presence of sodium hydride to afford the enol 18 in quantitative yield, whose hydroxy group was then
protected as its ethoxyethyl (EE) ether to produce the enol ether 19 in 91% yield. Subsequent sodium
borohydride reduction of 19 provided the alcohol 20 in 92% yield as a single stereoisomer with respect to
the C9 position. Simultaneous dehydration of the C9 hydroxy function and deprotection of the EE group
within 20 was efficiently achieved by reaction with methanesulfonyl chloride (MsCl) in the presence of
triethylamine at 0 °C for 30 min, which provided the desired ꢀ,ꢁ-unsaturated aldehyde 21 in 94% yield.
Finally, compound 21 was converted to the requisite stannylmethyl ether 9 having 98% overall yield
through a two step sequence involving sodium borohydride reduction of the formyl group, followed by
1
4
stannylmethylation of the resulting alcohol 22 with iodomethyl tri-n-butyltin in the presence of
potassium hydride and 18-crown-6.
Synthesis of the trans-decalin segment 7
With the key intermediate 9 synthesized, we then conducted the synthesis of the trans-decalin segment 7
(
Table 1 and Scheme 3). The sequence involved the critical stereocontrolled [2,3]-Wittig
1
5,16
rearrangement
of 9 to construct the requisite decalin system 8, having both a hydroxymethyl group at
C9 with correct stereochemistry and an exo-methylene functionality at C8. After screening several
reaction conditions (Table 1), we found that the designed [2,3]-Wittig rearrangement of 9 proceeded
smoothly and cleanly in a completely stereoselective manner by treatment with n-butyllithium in hexane
from ꢀ50 to 0 °C for 12 h. The expected rearrangement product 8 was obtained in 92% yield as a single
stereoisomer with respect to the C9 position (entry 1). The structure and stereochemistry of 8 was
1
confirmed by extensive spectroscopic analysis including 600 MHz H NMR NOESY experiments. The
selected NOESY correlation of 8 is depicted in Figure 2.
Note that the use of hexane as the solvent was crucial in this reaction. When THF or Et O was used
2
instead of hexane, the yield of the desired rearrangement product 8 was reduced to 46–69% (entries 2 and
3
), and in addition, the undesired methyl ether 23 was obtained in 23–43% yield as a byproduct. The
byproduct 23 was probably formed by protonation of the intermediary carboanion 9A, generated in situ
by tin/lithium exchange; this reactive species might have brought about a proton abstraction from the
ethereal solvents such as THF and Et O because the methylene position adjacent to oxygen atom in those
2
solvents is relatively activated. To continue the synthesis (Scheme 3), the rearrangement product 8 was
1
3
then subjected to Dess–Martin oxidation to give the requisite trans-decalin segment 7 in quantitative
yield.

234
HETEROCYCLES, Vol. 80, No. 1, 2010
Table 1. [2,3]-Wittig rearrangement of the stannylmethyl ether 9.
Snn-Bu
3
H C
OH
2
OMe
O
O
Me
H
Me
H
Me 9
Me
H
n-BuLi
solvent
9
8
8
9
8
TBSO
+
TBSO
TBSO
TBSO
H
–50 ꢀ 0 °C
2 h
Me
Me
Me
Me
1
Me
Me
Me
Me
Me
Me
Me
Me
9
9A
8
23
Entry
Solvent
Yield [%][a]
8
23
1
2
3
hexane
THF
92
46
69
0
43
23
Et O
2
[a] Isolated yield.
NOEs
H
Me
Me
H
9
H
8
TBSO
H
H
H
H
OH
H
Me
Me
8
Figure 2. Selected NOESY correlation of 8.
OH
CHO
Me
H
Me
H
9
9
8
8
a
TBSO
TBSO
Me
Me
Me
Me
Me
Me
8
7
Scheme 3. Synthesis of the decalin segment (7). Reagents and conditions: (a) Dess-Martin periodinane, CH Cl ,
2
2
rt, 1 h, quant.
Synthesis of (–)-nalanthalide (2) and (+)-sesquicillin (1)
Having obtained the requisite trans-decalin segment 7 efficiently, we then investigated the synthesis of
the first target nalanthalide (2) by assembling the trans-decalin and ꢀ-pyrone segments (Scheme 4). The
1
0
crucial coupling reaction of 7 with the 3-lithio-ꢀ-pyrone 6 was successfully achieved by an initial
bromine/lithium exchange of 3-bromo-2-methoxy-5,6-dimethyl-4H-pyran-4-one and subsequent reaction

HETEROCYCLES, Vol. 80, No. 1, 2010
235
Me
Me
Me
O
Me
O
Me
O
Me
CHO
Me
H
X
O
O
O
9
8
Me
H
OMe
Me
OMe
Me
H
OMe
a
d
e
TBSO
Me
3
AcO
TBSO
HO
H
Me
Me
Me
Me
Me
Me
Me
Me
7
Me
Me
Me
2
4 : X = OH
nalanthalide (2)
b
c
27
25 : X = OC(S)SMe
6 : X = H
2
f
f
Me
Me
HO
RO
Me
Me
O
O
Me
O
Me
H
O
h
RO
AcO
H
Me
Me
Me
Me
Me
Me
2
2
8 : R = H
9 : R = Ac
sesquicillin (1)
g
Scheme 4. Synthesis of sesquicillin (1) and nalanthalide (2). Reagents and conditions: (a) 3-bromo-2-methoxy-
,6-dimethyl-4H-pyran-4-one, n-BuLi, THF, –78°C, 5 min; at –78°C, add 7, –78 to –55°C, 1 h, 87% (b)
NaN(SiMe ) , CS , MeI, THF, –78°C, 2 h (c) n-Bu SnH, AIBN, toluene, reflux, 6 h, 82% (2 steps); (d) BF ·Et O,
5
3
2
2
3
3
2
MeCN, 0°C to rt, 4 h, 95%; (e) Ac O, DMAP, pyridine, rt, 1 h, 86%; (f) 1M NaOH, MeOH, reflux, 12 h; (g)
2
Ac O, Et N, DMAP, 0°C, 1 h, 70% (2 steps); (h) 1M NaOH, THF, 0°C, 30 min, 88%
2
3
with 7 from ꢀ78 to ꢀ55 °C for 1 h. The desired coupling product 24 was obtained in 87% yield as a
1
mixture of epimeric alcohols (ca. 1:1 by 400 MHz H NMR) that was very difficult to separate. Note that
the regiochemical integrity of the sensitive exo-methylene moiety at C8 was maintained during the
coupling reaction. Removal of the sterically hindered hydroxy group in 24 was achieved smoothly by
1
7
applying the Barton–McCombie procedure with some improvements in the reaction conditions. Thus,
treatment of a mixture of 24 and carbon disulfide in THF with sodium bis(trimethylsilyl)amide
[
NaN(SiMe ) ] at ꢀ78 °C followed by addition of iodomethane at the same temperature provided the
3 2
corresponding methyl xanthate 25, which was further treated with tri-n-butyltin hydride and
,2’-azobis(isobutyronitrile) (AIBN) in refluxing toluene to produce the desired deoxygenated product 26
in 82% overall yield. The sterically congested TBS group in 26 was deprotected by exposure to BF ·Et O
2
3
2
in acetonitrile at room temperature, affording de-O-acetylnalanthalide (27) in 95% yield. When this
deprotection was performed using the conventional procedure (TBAF, THF, rtꢀreflux), the yield of the

236
HETEROCYCLES, Vol. 80, No. 1, 2010
desired product 27 was reduced to ~40% because the ꢀ-pyrone moiety was labile under these basic
conditions. Finally, acetylation of 27 under standard conditions (Ac O, pyridine, DMAP, rt) resulted in
2
1
13
the targeted (–)-nalanthalide (2) in 86% yield. The spectroscopic properties (IR, H and C NMR,
4
HRMS) of the synthetic sample 2 were identical to those of natural 2. The optical rotation of the
2
5
4
25
synthetic 2 {[ꢁ]D –48.3 (c 1.02, CHCl )} was in good agreement with that of natural 2 {lit., [ꢁ] –58.2
3
D
1
8
(
c 0.275, CHCl )}, leading to the assignment of the absolute configuration of natural 2.
3
Having successfully synthesized the first target nalanthalide (2), we next directed our attention to the
synthesis of the second target sesquicillin (1). Initial attempts to realize the direct conversion of 2 to 1
under conventional basic conditions (e.g. 1 M NaOH, MeOH, rtꢀreflux) were unsuccessful. The
expected hydrolysis of the ꢀ-pyrone moiety in 2 followed by tautomerization of the ꢀ-pyrone to ꢁ-pyrone
proceeded smoothly and cleanly at reflux temperature; however, unfavorable deprotection of the acetyl
group took place during the reaction, producing de-O-acetylsesquicillin (28) in good yield (83%).
Therefore, we decided to pursue the synthesis of 1 in a step-by-step manner from the intermediate 27.
Thus, hydrolysis of the ꢀ-pyrone moiety in 27 under basic conditions (1 M NaOH, MeOH, reflux, 12 h)
provided the desired 28, having an ꢁ-pyrone ring, whose two hydroxy groups were simultaneously
acetylated (Ac O, Et N, DMAP, 0 °C, 1 h) to form the corresponding diacetate 29 in 70% overall yield
2
3
from 27. Finally, chemoselective deprotection of the acetyl group on the pyrone ring in 29 under mild
basic conditions (1 M NaOH, THF, 0 °C, 30 min) resulted in the formation of (+)-sesquicillin (1) in 88%
1
13
yield. The spectroscopic properties (IR, H and C NMR, HRMS) of the synthetic sample 1 were
2
a
25
identical to those of natural 1. The optical rotation of the synthetic 1 {[ꢁ] +7.1 (c 0.36, CHCl )} was
D
3
2
a
22
18
essentially identical to that of natural 1 {lit., [ꢁ]
+10 (c 0.8, CHCl )}, verifying the absolute
3
D
configuration of natural 1.
CONCLUSION
We have accomplished the enantioselective total synthesis of (+)-sesquicillin (1) and (–)-nalanthalide (2)
in a convergent and unified manner starting from (+)-5-methyl-Wieland–Miescher ketone (11). The key
steps of the synthesis were (i) highly stereoselective [2,3]-Wittig rearrangement of stannylmethyl ether 9
to produce the requisite decalin portion 8, having both a hydroxymethyl group at C9 with the correct
stereochemistry and an exo-methylene functionality at C8 (9ꢀ8, Table 1), (ii) straightforward coupling
of the trans-decalin segment 7 with the ꢀ-pyrone segment 6 to construct the desired carbon framework 24
(7+6ꢀ24, Scheme 4), and (iii) strategic conversion of the ꢀ-pyrone moiety present in
de-O-acetylnalanthalide (27) to the corresponding ꢁ-pyrone 28 to approach sesquicillin (1) (27ꢀ28,
Scheme 4). This synthesis has verified the absolute configurations of these natural products. On the basis
of the present study, we are currently synthesizing the analogues of 1 and 2 with the aim of exploring

HETEROCYCLES, Vol. 80, No. 1, 2010
237
their structure–activity relationships and will report our results in the future.
EXPERIMENTAL
General Procedures: All reactions involving air- and moisture-sensitive reagents were carried out using
oven dried glassware and standard syringe-septum cap techniques. Routine monitoring of reaction were
carried out using glass-supported Merck silica gel 60 F254 TLC plates. Flash column chromatography was
performed on Kanto Chemical Silica Gel 60N (spherical, neutral 40–50 μm) with the solvents indicated
All solvents and reagents were used as supplied with following exceptions. Tetrahydrofuran (THF) and
Et O were freshly distilled from Na metal/benzophenone under argon. Toluene was distilled from Na
2
metal under argon. N,N-Dimethylformamide (DMF), CH Cl , pyridine, and hexane were distilled from
2
2
CaH under argon.Measurements of optical rotations were performed with a JASCO DIP-370 automatic
digital polarimeter. Melting points were taken on a Yanaco MP-3 micro melting point apparatus and are
1
13
uncorrected. H and C NMR spectra were measured with a JEOL AL-400 (400MHz) or a JEOL
JNM-LA600 (600 MHz) spectrometer. Chemical shifts were expressed in ppm using Me Si (ꢀ=0) as an
4
internal standard. The following abbreviations are used: singlet (s), triplet (t), quartet (q), multiplet (m),
and broad (br). Infrared (IR) spectra measurements were carried out with a JASCO FT/IR-4100
spectrometer. Low- and High-resolution mass (MS and HRMS) spectra were measured on a JEOL
JMS-DX 303/JMA-DA 5000 SYSTEM high resolution mass spectrometer.
(4aS,5S,6S,8aS)-5-Allyl-5,8a-dimethyl-6-(hydroxy)decahydronaphthalen-1-one 1-ethylene acetal
1
0,11
(12): A solution of 11
(4.54g, 16 mmol) in dry Et O (50 mL) was added to a stirred suspension of
2
LiAlH (683 mg, 18 mmol) in dry Et O (200 mL) at ꢀ45 °C under argon, and the mixture was warmed up
4
2
to rt over 1.5 h. The reaction was quenched by the successive addition of 1 M NaOH (0.7 mL), H O (0.7
2
mL), and brine (0.7 mL) at 0 °C. The resulting mixture was filtered through a pad of Celite. The filtrate
was concentrated in vacuo to afford a residue, which was purified by column chromatography
2
0
1
(
hexane/EtOAc, 6:1) to give 12 (4.49 g, 98%) as a colorless viscous oil. [ꢁ]D ꢀ11.5° (c 1.01, CHCl ); H
3
NMR (400 MHz, CDCl ): ꢀ 0.84 (3H, s), 1.07 (3H, s), 1.29–1.70 (11H, m), 2.02 (1H, dd, J = 7.8, 14.2
3
Hz), 2.30 (1H, dd, J = 7.3, 14.2 Hz), 3.46–3.50 (1H, m), 3.79–3.85 (1H, m), 3.88–3.94 (3H, m), 5.00–5.11
1
3
(
2H, m), 5.82–5.93 (1H, m); C NMR (100 MHz, CDCl ): ꢀ 15.8, 16.9, 20.3, 22.8, 26.8, 28.5, 30.4, 42.0,
3
4
1
2.6, 43.0, 43.5, 64.7, 65.3, 73.9, 113.2, 117.5, 135.2; IR (neat) 3443, 3072, 2945, 2872, 2677, 1636,
–
1
475, 1450, 1382, 1335, 1280, 1200, 1176, 1128, 1105, 1036, 907, 759, 732, 703 cm ; HREIMS (m/z)
+
calcd for C H O (M ), 280.2038, found 280.2038.
1
7
28
3
(4aS,5S,6S,8aS)-5,8a-Dimethyl-6-hydroxy-5-(3-hydroxypropyl)decahydronaphthalen-1-one-1-

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HETEROCYCLES, Vol. 80, No. 1, 2010
ethylene acetal (13): A solution of BH ·THF in THF (1.00 M solution, 32.3 mL, 32 mmol) was added
3
dropwise to a stirred solution of 12 (4.52 g, 16 mmol) in dry THF (160 mL) at 0 °C under argon. After 1 h,
3
0
M NaOH (16.1 mL, 48 mmol) and 30% aqueous H O (18.3 mL, 0.16 mol) was added to the mixture at
2 2
°C, and stirring was continued for 1.5 h at rt. The reaction was quenched with H O (160 mL) at 0°C,
2
and the resulting mixture was extracted with EtOAc (3 x 150 mL). The combined extracts were washed
with brine (2 x 50 mL), then dried over MgSO . Concentration of the solvent in vacuo afforded a residue,
4
which was purified by column chromatography (hexane/EtOAc, 1:2 ꢀ 0:1) to give 13 (4.09 g, 85%) as
2
0
a white solid. Recrystallization from acetone afford colorless needles, mp 138–139 °C; [ꢀ]D ꢀ9.6° (c
1
1
.00, CHCl ); H NMR (400 MHz, CDCl ): ꢁ 0.82 (3H, s), 1.07 (3H, s), 1.25–1.34 (2H, m), 1.38–1.47
3
3
(
4H, m), 1.50–1.61 (6H, m), 1.62–1.71 (3H, m), 1.67 (2H, br s), 3.46–3.50 (1H, m), 3.56–3.68 (2H, m),
1
3
3
2
1
.80–3.86 (1H, m), 3.88–3.94 (3H, m); C NMR (100 MHz, CDCl ): ꢁ 16.9, 17.1, 20.2, 23.0, 25.9, 26.9,
3
8.6, 30.4, 33.2, 40.8, 42.4, 42.9, 63.6, 64.8, 65.3, 73.0, 113.3; IR (KBr) 3359, 2941, 2871, 2308, 1684,
–
1
652, 1456, 1383, 1337, 1281, 1199, 1176, 1130, 1104, 1045, 907, 754 cm ; HREIMS (m/z) calcd for
+
C H O (M ), 298.2144, found 298.2144. Anal. Calcd for C H O : C, 68.42; H, 10.13. Found: C,
1
7
30
4
17 30
4
6
8.55; H, 10.59.
(
4aS,5S,6S,8aS)-6-(tert-Butyldimethylsiloxy)-5-(tert-butyldimethylsiloxypropyl)-5,8a-(dimethyl)-
decahydronaphthalen-1-one 1-ethylene acetal (14): tert-Butyldimethylsilyl trifluoromethanesulfonate
TBSOTf) (8.71 mL, 38 mmol) was added dropwise to a stirred solution of 13 (3.77 g, 13 mmol) in dry
CH Cl (150 mL) containing 2,6-lutidine (5.89 mL, 51 mmol) at 0 °C under argon. After 30 min, the
(
2
2
reaction was quenched with saturated aqueous NH Cl (100 mL) at 0 °C, and the resulting mixture was
4
extracted with CHCl (3 x 150 mL). The combined extracts were washed with brine (2 x 70 mL), then
3
dried over MgSO . Concentration of the solvent in vacuo afforded a residue, which was purified by
4
column chromatography (hexane/EtOAc, 50:1ꢀ30:1) to give 14 (6.65 g, 100%) as a colorless viscous
2
0
1
liquid. [ꢀ]D +2.4° (c 1.01, CHCl ); H NMR (400 MHz, CDCl ): ꢁ 0.02 (3H, s), 0.04 (9H, s), 0.76 (3H,
3
3
s), 0.87 (9H, s), 0.89 (9H, s), 1.06 (3H, s), 1.16–1.21 (1H, m), 1.27 (1H, dd, J = 3.9, 13.0 Hz), 1.33 (1H,
dt, J = 3.4, 12.7 Hz), 1.37–1.40 (6H, m), 1.45–1.50 (1H, m), 1.52–1.66 (5H, m), 3.44 (1H, dd, J = 4.9,
1
3
1
0.5 Hz), 3.47–3.51 (2H, m), 3.56–3.61 (1H, m), 3.78–3.84 (1H, m), 3.87–3.94 (2H, m); C NMR (100
MHz, CDCl ): ꢁ –5.29, –5.25, –4.9, –3.6, 17.1, 17.7, 18.1, 18.5, 20.3, 23.0, 25.9 (3 carbons), 26.1 (3
3
carbons), 26.4, 27.4, 28.5, 30.5, 33.0, 41.2, 42.3, 42.8, 64.3, 64.7, 65.3, 73.7, 113.5; IR (neat) 2950, 2858,
–
1
1
471, 1462, 1384, 1361, 1254, 1106, 1007, 908, 836, 773, 666 cm ; HREIMS (m/z) calcd for C H O Si
29 58 4 2
+
(
M ): 526.3874, found 526.3871.
(4aS,5S,6S,8aS)-6-(tert-Butyldimethylsiloxy)-5,8a-dimethyl-5-(3-hydroxypropyl)decahydro-

HETEROCYCLES, Vol. 80, No. 1, 2010
239
naphthalen-1-one (15): A solution of 14 (5.83 g, 11 mmol) in AcOH/THF/H O (3:1:1) (150 mL) was
2
stirred at 50 °C for 4 h. The reaction mixture was basified with 1 M NaOH (50 mL) at 0 °C, and the
resulting mixture was extracted with EtOAc (3 x 200 mL). The combine extracts were washed brine (2 x
1
00mL), then dried over MgSO . Concentration of the solvent in vacuo afforded a residue, which was
4
purified by column chromatography (hexane/EtOAc, 4:1ꢀ3:1) to give 15 (3.67 g, 90%) as a white solid.
2
0
1
Recrystallization from Et O afford colorless needles, mp 104–105 °C; [ꢀ]D ꢀ8.6° (c 1.01, CHCl ); H
2
3
NMR (400 MHz, CDCl ): ꢁ 0.02 (3H, s), 0.06 (3H, s), 0.88 (3H, s), 0.89 (9H, s), 1.16 (3H, s), 1.21–1.33
3
(
3H, m), 1.37–1.47 (1H, m), 1.50–1.72 (9H, m), 2.05–2.09 (1H, m), 2.17–2.22 (1H, m), 2.56 (1H, td, J =
1
3
6
.8, 13.7 Hz), 3.41 (1H, dd, J = 3.4, 5.4 Hz), 3.51–3.57 (1H, m), 3.60–3.65 (1H, m); C NMR (100 MHz,
CDCl ): ꢁ –5.0, –3.7, 17.9, 18.0, 19.0, 20.5, 25.8 (3 carbons), 26.1, 26.2, 27.0, 30.9, 32.9, 37.4, 42.1, 47.0,
3
4
8
8.2, 63.4, 73.0, 215.5; IR (KBr) 3426, 2939, 2859, 2247, 1756, 1471, 1383, 1253, 1113, 1099, 1075, 961,
–
1
+
36, 773, 669 cm ; HREIMS (m/z) calcd for C H O Si (M ), 368.2747, found 368.2729. Anal. Calcd for
2
1
40
3
C H O Si: C, 68.42; H, 10.94: C, 68.65; H, 11.46.
2
1
40
3
(
4aS,5S,6S,8aS)-6-(tert-Butyldimethylsiloxy)-5,8a-dimethyl-5-(3-oxopropyl)decahydronaphthalen-1-
one (16): Dess–Martin periodinane (5.60 g, 13 mmol) was added in small portions to a stirred solution of
6 (4.08 g, 11 mmol) in dry CH Cl (110 mL) containing NaHCO (9.28 g, 0.11 mmol) at rt. After 30 min,
1
2
2
3
the reaction was quenched with 10% aqueous Na S O (50 mL) at 0 °C, and the resulting mixture was
2
2
3
extracted with CHCl (3 x 100 mL). The combined extracts were washed with 1 M NaOH (50 mL) and
3
brine (2 x 50 mL), then dried over MgSO . Concentration of the solvent in vacuo afforded a residue,
4
which was purified by column chromatography (hexane/EtOAc, 50:1ꢀ10:1) to give 16 (3.89 g, 96%) as
2
0
a white solid. Recrystallization from Et O afford colorless needles, mp 83–84 °C; [ꢀ]D ꢀ17.0° (c 1.00,
2
1
CHCl ); H NMR (400 MHz, CDCl ): ꢁ 0.01 (3H, s), 0.06 (3H, s), 0.88 (9H, s), 0.94 (3H, s), 1.12 (1H, dd,
3
3
J = 2.4, 12.2 Hz), 1.17 (3H, s), 1.46–1.63 (5H, m), 1.65–1.69 (2H, m), 1.70–1.79 (1H, m), 1.86–1.94 (1H,
m), 2.05–2.17 (2H, m), 2.17–2.23 (1H, m), 2.26–2.35 (1H, m), 2.57 (1H, td, J = 6.8, 13.7 Hz), 3.33 (1H,
1
3
dd, J = 5.4, 9.8 Hz), 9.74 (1H, t, J = 2.0 Hz); C NMR (100 MHz, CDCl ): ꢁ ꢀ5.0, ꢀ3.6, 17.6, 18.0, 18.9,
3
2
3
0.5, 25.8 (3 carbons), 26.1, 26.9, 28.7, 30.9, 37.3, 37.9, 42.0, 47.2, 48.2, 73.0, 201.8, 214.9; IR (KBr)
430, 3395, 2951, 2882, 2858, 2713, 1726, 1713, 1471, 1385, 1253, 1113, 1005, 962, 900, 836, 773, 668
–
1
+
cm ; HREIMS (m/z) calcd for C H O Si (M ), 366.2590, found 366.2595. Anal. Calcd for C H O Si:
2
1
38
3
21 38
3
C, 68.80; H, 10.45: C, 68.98; H, 10.87.
(4aS,5S,6S,8aS)-6-(tert-Butyldimethylsiloxy)-5,8a-dimethyl-5-(4-methylpent-3-enyl)decahydro-
naphthalen-1-one (17): n-BuLi in hexane (1.58 M, 12 mL, 19 mmol) was added dropwise to a stirred
suspension of isopropyltriphenylphosphonium iodide (9.80 g, 23 mmol) in dry THF (70 mL) at 0 °C

240
HETEROCYCLES, Vol. 80, No. 1, 2010
under argon. After 30 min, a solution of 16 (2.76 g, 7.5 mmol) in dry THF (30 mL) was added dropwise
to the above mixture at 0 °C, and it was allowed to stand at rt for 1 h. The reaction was quenched with
saturated aqueous NH Cl (30 mL), and the resulting mixture was extracted with EtOAc (3 x 60 mL). The
4
combined extracts were washed with brine (2 x 50 mL), and dried over MgSO . Concentration of the
4
solvent in vacuo afforded a residue, which was purified by column chromatography (hexane/EtOAc,
1
00:1ꢀ50:1) to give 17 (2.54 g, 86%) as a white solid. Recrystallization from Et O afford colorless
2
2
0
1
needles, mp 63–64 °C; [ꢀ]D +5.7° (c 1.02, CHCl ); H NMR (400 MHz, CDCl ): ꢁ 0.02 (3H, s), 0.05
3
3
(
3H, s), 0.86 (3H, s), 0.88 (9H, s), 1.12–1.20 (1H, m), 1.16 (3H, s), 1.30 (1H, dd, J = 2.9, 11.7 Hz),
.46–1.60 (8H, m), 1.61–1.69 (6H, m), 1.72–1.82 (2H, m), 2.05–2.09 (1H, m), 2.20 (1H, dd, J = 4.4, 14.1
1
1
3
Hz), 2.57 (1H, td, J = 7.3, 13.9 Hz), 3.43–3.47 (1H, m), 5.00 (1H, t, J = 6.8 Hz); C NMR (100 MHz,
CDCl ): ꢁ ꢀ5.1, ꢀ3.7, 17.7, 17.9 18.0, 18.9, 20.7, 21.4, 25.7 (3 carbons), 25.8, 26.2, 27.1, 31.0, 36.9, 37.5,
3
4
1
3
2.4, 47.0, 48.3, 72.9, 124.4, 131.0, 215.5; IR (KBr) 2935, 2859, 2360, 1709, 1471, 1453, 1382, 1361,
–
1
+
253, 1099, 1067, 1006, 960, 836, 773 cm ; HREIMS (m/z) calcd for C H O Si (M ), 392.3111, found
2
4
44
2
92.3110. Anal. Calcd for C H O Si: C, 73.41; H, 11.29: C, 73.46; H, 11.66.
2
4
44
2
(Z)-(4aS,5S,6S,8aS)-6-(tert-Butyldimethylsiloxy)-5,8a-dimethyl-2-hydroxymethylene-5-(4-methyl-
pent-3-enyl)decahydronaphthalen-1-one (18): A solution of 17 (2.12 g, 5.4 mmol) in dry THF (20 mL)
containing ethyl formate (6.54 mL, 81 mmol) was added to a stirred suspension of NaH (60% dispersion
in mineral oil) (3.23 g, 81 mmol) in dry THF (40 mL) at 0 °C under argon, and stirring was continued at
rt for 1 h. The reaction was quenched with saturated aqueous NH Cl (20 mL) at 0 °C, and the resulting
4
mixture was extracted with EtOAc (3 x 100 mL). The combined extracts were washed with brine (2 x 50
mL), then dried over MgSO . Concentration of the solvent in vacuo afforded a residue, which was
4
purified by column chromatography (hexane/EtOAc, 50:1) to give 18 (2.27 g, 100%) as a pale yellow
2
0
1
viscous liquid. [ꢀ]D +36.2° (c 1.02, CHCl ); H NMR (400MHz, CDCl ): ꢁ 0.03 (3H, s), 0.06 (3H, s),
3
3
0
.80 (3H, s), 0.88 (9H, s), 1.22 (3H, s), 1.31–1.41 (2H, m), 1.47–1.62 (2H, m), 1.59 (3H, s), 1.66–1.74
(
3H, m), 1.68 (3H, s), 1.77–1.83 (2H, m), 2.01 (1H dt, J = 3.4, 13.7 Hz), 2.30–2.38 (1H, m), 2.45–2.50
1H, m), 3.52 (1H, dd, J = 6.3, 9.3 Hz), 5.01–5.05 (1H, m), 8.53–8.54 (1H, m), 14.66 (1H, d, J = 3.9 Hz);
(
1
3
C NMR (100 MHz, CDCl ): ꢁ ꢀ5.1, ꢀ3.7, 17.7, 17.9, 18.0, 18.1, 20.6, 21.5, 23.4, 25.7, 25.8 (3 carbons),
3
2
1
7.4, 31.9, 36.9, 41.3, 41.6, 42.5, 73.0, 105.8, 124.4, 131.0, 186.3, 193.7; IR (neat) 2953, 2857, 2735,
–
1
634, 1583, 1471, 1455, 1380, 1360, 1333, 1255, 1209, 1103, 1070, 1006, 942, 890, 836, 773, 669 cm ;
+
HREIMS (m/z) calcd for C H O Si (M ), 420.3060, found 420.3057.
2
5
44
3
(
Z)-(4aS,5S,6S,8aS)-6-(tert-Butyldimethylsiloxy)-2-(ethoxyethan-1-yl)oxymethylene-5,8a-dimethyl-5-
4-methylpent-3-enyl)decahydronaphthalen-1-one (19): Pyridinium p-toluenesulfonate (PPTS) (133
(

HETEROCYCLES, Vol. 80, No. 1, 2010
241
mg, 0.53 mmol) was added to a stirred solution of 18 (2.22 g, 5.3 mmol) in dry THF (60 mL) containing
ethyl vinyl ether (10.1 mL, 0.11 mmol) at rt. After 4 h, the reaction was quenched with saturated aqueous
NaHCO (40 mL) at 0 °C, and the resulting mixture was extracted with EtOAc (3 x 100 mL). The
3
combined extracts were washed with brine (2 x 50 mL), then dried over MgSO . Concentration of the
4
solvent in vacuo afforded a residue, which was purified by column chromatography (hexane/EtOAc,
4
0:1ꢀ10:1) to give 19 (1:1 diastereomeric mixture caused by the EE group) (2.37 g, 91%) as a pale
1
yellow viscous liquid. H NMR (400 MHz, CDCl ): ꢀ 0.03 (3H, s), 0.06 (3H, s), 0.83 (3H, s), 0.88 (9H, s),
3
1
.12 (3H, s), 1.208 (3/2H, t, J = 6.8 Hz), 1.213 (3/2H, t, J = 6.8 Hz), 1.24–1.27 (2H, m), 1.34–1.39 (1H,
m), 1.423 (3/2H, d, J = 5.3 Hz), 1.433 (3/2H, d, J = 5.3 Hz), 1.50–1.56 (3H, m), 1.59 (3H, s), 1.61–1.65
2H, m), 1.68 (3H, s), 1.79–1.82 (2H, m), 1.94 (1H, dt, J = 3.4, 13.7 Hz), 2.18–2.27 (1H, m), 2.72 (1H, dd,
(
1
3
J = 4.4, 16.6 Hz), 3.45–3.51 (2H, m), 3.67–3.75 (1H, m), 5.02–5.10 (2H, m), 7.43 (1H, s); C NMR (100
MHz, CDCl ): ꢀ ꢀ5.1, ꢀ3.7, 14.90, 14.94, 17.7, 17.9, 18.0, 19.5, 21.1, 21.6, 22.6, 25.7, 25.8 (3 carbons),
3
27.4, 32.4, 36.7, 42.1, 42.5, 46.0, 63.6 (1/2 carbon), 63.7 (1/2 carbon), 73.1, 103.5 (1/2 carbon), 103.7
(1/2 carbon), 113.7 (1/2 carbon), 113.9 (1/2 carbon), 124.6, 130.9, 151.5 (1/2 carbon), 151.7 (1/2 carbon),
2
8
06.3; IR (neat) 2934, 2858, 1681, 1594, 1454, 1381, 1360, 1253, 1207, 1103, 1071, 1042, 970, 950, 893,
–
1
+
36, 773, 667 cm ; HREIMS (m/z) calcd for C H O Si (M ), 492.3635, found 492.3630.
2
9
52
4
(Z)-(1R,4aS,5S,6S,8aS)-6-(tert-Butyldimethylsiloxy)-2-(ethoxyethan-1-yl)oxymethylene-5,8a-
dimethyl-5-(4-methylpent-3-enyl)decahydronaphthalen-1-ol (20): NaBH (954.4 mg, 25.23 mmol)
4
was added in small portions to a stirred solution of 19 (2.49 g, 5.1 mmol) in EtOH (50 mL) at 0 °C, and
stirring was continued at rt for 2 h. The reaction was quenched with 10% aqueous AcOH (30 mL) at 0 °C,
and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined extracts were washed
with saturated aqueous NaHCO (2 x 50 mL) and brine (2 x 50 mL), then dried over MgSO .
3
4
Concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography
(hexane/EtOAc, 30:1ꢀ5:1) to give 20 (1:1 diastereomeric mixture caused by EE group) (2.30 g, 92%) as
1
a colorless viscous liquid. H NMR (400 MHz, CDCl ): ꢀ 0.03 (3H, s), 0.05 (3H, s), 0.76 (3H, s), 0.78
3
(
(
(
(
3H, s), 0.88 (9H, s), 1.11–1.16 (3H, m), 1.20 (3/2H, t, J = 6.8 Hz), 1.21 (3/2H, t, J = 6.8 Hz), 1.22–1.28
1H, m), 1.36 (3H, d, J = 5.3 Hz), 1.45–1.62 (5H, m), 1.62 (3H, s), 1.67 (3H, s), 1.76–1.86 (3H, m), 2.91
1H, d, J = 14.5 Hz), 3.44–3.53 (2H, m), 3.63–3.65 (1H, m), 3.69–3.78 (1H, m), 4.87–4.93 (1H, m), 5.04
1
3
1H, t, J = 7.2 Hz), 6.24–6.25, (1H, m); C NMR (100 MHz, CDCl ): ꢀ ꢀ5.0, ꢀ3.7, 12.8, 15.1 (1/2
3
carbon), 15.2 (1/2 carbon), 17.70, 17.74 (1/2 carbon), 17.8 (1/2 carbon), 18.1, 20.46 (1/2 carbon), 20.54
1/2 carbon), 21.31 (1/2 carbon), 21.33 (1/2 carbon), 21.5, 24.2, 25.7, 25.8 (3 carbons), 27.7, 35.61 (1/2
carbon), 35.63 (1/2 carbon), 36.8, 40.1 (1/2 carbon), 40.2 (1/2 carbon), 41.5, 45.7, 62.2 (1/2 carbon), 62.4
1/2carbon), 73.6, 81.1, 100.8, 118.6 (1/2 carbon), 118.7 (1/2 carbon), 124.8, 130.8, 133.4 (1/2 carbon),
(
(

242
HETEROCYCLES, Vol. 80, No. 1, 2010
1
7
33.8 (1/2 carbon); IR (neat) 3490, 2935, 2857, 1685, 1451, 1382, 1253, 1147, 1102, 1056, 940, 893, 835,
–
1
+
72, 671 cm ; HREIMS (m/z) calcd for C H O Si (M ), 494.3791, found 494.3792.
2
9
54
4
(
4aR,5S,6S,8aR)-6-(tert-Butyldimethylsiloxy)-5,8a-dimethyl-5-(4-methylpent-3-enyl)-
,4,4a,5,6,7,8,8a-octahydronaphthlene-2-carbaldehyde (21): Methanesulfonyl chloride (MsCl) (3.41
mL, 44 mmol) was added dropwise to a stirred solution of 20 (2.18 g, 4.4 mmol) in dry CH Cl (50 mL)
3
2
2
containing Et N (7.38 mL, 53 mmol) at 0 °C under argon. After 30 min, the reaction was quenched with
3
saturated aqueous NH Cl (10 mL) at 0 °C, and the resulting mixture was extracted with CHCl (3 x 70
4
3
mL). The combined extracts were washed with brine (2 x 50 mL), then dried over MgSO . Concentration
4
of the solvent in vacuo afforded a residue, which was purified by column chromatography (hexane/EtOAc,
2
0
1
4
0:1ꢀ30:1) to give 21 (1.68 g, 94%) as a colorless viscous liquid. [ꢀ]D +43.8° (c 1.01, CHCl ); H
3
NMR (400 MHz, CDCl ): ꢁ 0.04 (3H, s), 0.06 (3H, s), 0.80 (3H, s), 0.90 (9H, s), 1.07, (3H, s), 1.18–1.28
3
(
2H, m), 1.31–1.49 (2H, m), 1.54–1.65 (2H, m), 1.58 (3H, s), 1.68 (3H, s), 1.71–1.82 (4H, m), 2.04–2.14
(1H, m), 2,42 (1H, dd, J = 5.9, 18.0 Hz), 3.55 (1H, dd, J = 4.9, 11.2 Hz), 5.01–5.05 (1H, m), 6.41 (1H, s),
1
3
9
2
2
6
.40 (1H, s); C NMR (100 MHz, CDCl ): ꢁ ꢀ5.1, ꢀ3.7, 17.4, 17.6 (2 carbons), 18.0, 20.7, 21.4, 22.8,
3
5.7, 25.8 (3 carbons), 27.6, 36.1, 36.3, 36.9, 41.4, 44.1, 73.2, 124.4, 131.0, 137.7, 162.0, 194.8; IR (neat)
928, 2856, 2711, 1692, 1683, 1643, 1471, 1379, 1254, 1188, 1102, 1066, 995, 949, 888, 836, 773, 723,
–
1
+
72 cm ; HREIMS (m/z) calcd for C H O Si (M ), 404.3111, found 404.3107.
2
5
44
2
(4aR,5S,6S,8aR)-6-(tert-Butyldimethylsiloxy)-5,8a-dimethyl-5-(4-methylpent-3-enyl)-
3
,4,4a,5,6,7,8,8a-octahydronaphthalene-2-methanol (22): NaBH (239 mg, 6.3 mmol) was added in
4
small portions to a stirred solution of 21 (1.70 g, 4.2 mmol) in EtOH (50 mL) at 0 °C, and stirring was
continued at rt for 30 min. The reaction was quenched with 10% aqueous AcOH (20 mL) at 0 °C, and the
resulting mixture was extracted with EtOAc (3 x 100 mL). The combined extracts were washed with
saturated aqueous NaHCO (2 x 50 mL) and brine (2 x 50 mL), then dried over MgSO . Concentration of
3
4
the solvent in vacuo afforded a residue, which was purified by column chromatography (hexane/EtOAc,
2
0
1
2
0:1ꢀ10:1) to give 22 (1.69 g, 100%) as a colorless viscous liquid. [ꢀ]D +31.9° (c 1.05, CHCl ); H
3
NMR (400 MHz, CDCl ): ꢁ 0.03 (3H, s), 0.05 (3H, s), 0.76 (3H, s), 0.88 (9H, s), 0.96 (3H, s), 1.16–1.26
3
(
(
3H, m), 1.42–1.57 (4H, m), 1.59 (3H, s), 1.62–1.74 (2H, m), 1.68 (3H, s), 1.78–1.84 (2H, m), 1.98–2.07
1H, m), 2.12 (1H, dd, J = 6.3, 17.6 Hz), 3.53 (1H, dd, J = 4.9, 11.2 Hz), 3.96 (2H, s), 5.04 (1H, t, J = 6.8
1
3
Hz), 5.36 (1H, s); C NMR (100 MHz, CDCl ): ꢁ ꢀ5.1, ꢀ3.7, 17.6, 17.7, 18.1, 18.3, 21.5, 21.8, 25.7, 25.9
3
(3 carbons), 27.1, 28.0, 34.6, 37.0, 37.3, 41.2, 44.4, 67.1, 73.6, 124.8, 130.7, 133.7, 136.4; IR (neat) 3315,
–
1
2
934, 2857, 1461, 1382, 1361, 1253, 1102, 1068, 998, 945, 887, 836, 772 cm ; HREIMS (m/z) calcd for
+
C H O Si (M ), 406.3267, found 406.3268.
2
5
46
2

HETEROCYCLES, Vol. 80, No. 1, 2010
243
(4aR,5S,6S,8aR)-6-(tert-Butyldimethylsiloxy)-2-(tri-n-butylstannylmethoxymethyl)-5,8a-dimethyl-5-
(4-methylpent-3-enyl)-3,4,4a,5,6,7,8,8a-octahydronaphthalene (9): KH (30% dispersion in mineral oil)
(1.63 g, 12 mmol), 18-crown-6 (3.17 g, 12 mmol), and iodomethyl tri-n-buthyltin (2.40 mL, 8.0 mmol)
were added successively to a stirred solution of 22 (1.63 g, 4.0 mmol) in dry THF (60 mL) at 0 °C under
argon, and stirring was continued at rt for 1 h. The reaction was quenched with saturated aqueous NH Cl
4
(
20 mL) at 0 °C, and the resulting mixture was extracted with EtOAc (3 x 70 mL). The combined extracts
were washed with brine (2 x 50 mL), then dried over MgSO . Concentration of the solvent in vacuo
4
afforded a residue, which was purified by column chromatography (hexane/EtOAc, 200:1) to give 9 (2.79
2
0
1
g, 98%) as a colorless viscous liquid. [ꢀ]D +16.9° (c 1.18, CHCl ); H NMR (400 MHz, CDCl ): ꢁ 0.03
3
3
(3H, s), 0.04 (3H, s), 0.76 (3H, s), 0.87–0.92 (24H, m), 0.97 (3H, s), 1.15–1.35 (10H, m), 1.39–1.54 (10H,
m), 1.59 (3H, s), 1.63–1.74 (1H, m), 1.68 (3H, s), 1.73–1.88 (2H, m), 1.91–2.00 (1H, m), 2.07 (1H, dd, J
=
5.9, 17.6 Hz), 3.53 (1H, dd, J = 4.9, 11.2 Hz), 3.61–3.72 (4H, m), 5.04 (1H, t, J = 6.8 Hz), 5.32 (1H, s);
1
3
C NMR (100 MHz, CDCl ): ꢁ ꢀ5.0, ꢀ3.7, 9.0 (3 carbons), 13.7 (3 carbons), 17.6, 17.7, 18.1, 18.3, 21.5,
3
2
6
1
7
1.9, 25.8, 25.9 (3 carbons), 27.3 (3 carbons), 27.4, 28.1, 29.2 (3 carbons), 34.8, 37.0, 37.4, 41.2, 44.4,
0.6, 73.7, 79.3, 124.9, 130.7, 131.2, 138.0; IR (neat) 2956, 2926, 2854, 1734, 1671, 1460, 1378, 1254,
–
1
+
186, 1102, 1065, 945, 887, 836, 773, 730, 666 cm ; HREIMS (m/z) calcd for C H O SiSn (M ),
3
8
74
2
10.4480, found 710.4478.
(
1R,4aR,5S,6S,8aS)-6-(tert-Butyldimethylsiloxy)-5,8a-dimethyl-2-methylene-5-(4-methylpent-3-
enyl)decahydronaphthalene-1-methanol (8) and (4aR,5S,6S,8aR)-6-(tert-butyldimethylsiloxy)-
-methoxymethyl-5,8a-dimethyl-5-(4-methylpent-3-enyl)-3,4,4a,5,6,7,8,8a-octahydronaphthalene
23): n-BuLi in hexane (1.57 M solution, 12.1 mL, 19 mmol) was added dropwise to a stirred solution of
(2.70 g, 3.8 mmol) in dry hexane (200 mL) at ꢀ50 °C under argon. The mixture was gradually warmed
2
(
9
up to 0 °C over 4 h, and stirring was continued at 0 °C for 8 h. The reaction was quenched with saturated
aqueous NH Cl (2 x 50 mL) at 0 °C, and the resulting mixture was extracted with EtOAc (3 x 150 mL).
4
The combined extracts were washed with brine (50mL), then dried over MgSO . Concentration of the
4
solvent in vacuo afforded a residue, which was purified by column chromatography (hexane/EtOAc,
1
:0ꢀ20:1) to give 8 (1.47 g, 92%) as a colorless viscous oil.
2
0
1
8
0
1
: [ꢀ]D +4.7° (c 1.02, CHCl ); H NMR (400 MHz, CDCl ): ꢁ 0.04 (3H, s), 0.05 (3H, s), 0.75 (3H, s),
3
3
.87 (9H, s), 0.98 (3H, s), 1.16–1.18 (1H, m), 1.20–1.28 (2H, m), 1.38–1.48 (3H, m), 1.51–1.60 (3H, m),
.60 (3H, s), 1.68 (3H, s), 1.73 (1H, dd, J = 2.9, 13.2 Hz), 1.81 (1H, d, J = 7.8 Hz), 1.84 (1H, d, J = 7.8
Hz), 1.93 (1H, dd, J = 5.4, 10.7 Hz), 2.05–2.13 (1H, m), 2.26–2.29 (1H, m), 3.46 (1H, dd, J = 4.9, 11.2
Hz), 3.55–3.61 (1H, m), 3.76 (1H, dt, J = 4.9, 9.8 Hz), 4.76 (1H, t, J = 1.9 Hz), 4.94 (1H, t, J = 1.9 Hz),

244
HETEROCYCLES, Vol. 80, No. 1, 2010
1
3
5
2
1
9
.04 (1H, t, J = 7.1 Hz); C NMR (100 MHz, CDCl ): ꢀ ꢀ5.0, ꢀ3.6, 17.7, 18.05, 18.07, 21.6, 22.7, 23.1,
3
5.7, 25.8 (3 carbons), 27.7, 31.0, 34.4, 36.9, 37.1, 39.9, 41.7, 59.0, 60.3, 73.8, 113.1, 124.7, 130.8,
46.8; IR (neat) 3398, 3067, 2928, 2884, 2857, 1641, 1471, 1452, 1384, 1361, 1254, 1099, 1065, 1024,
–
1
+
33, 891, 836, 773, 665 cm ; HREIMS (m/z) calcd for C H O Si (M ), 420.3424, found 420.3420.
2
6
48
2
When THF was used as a solvent instead of hexane, 8 and 23 were obtained in 46% and 43% yields,
respectively. In the case of using Et O as a solvent instead of hexane, 8 and 23 were obtained in 69% and
2
2
2
0
1
3
3% yields, respectively.
3: colorless viscous liquid. [ꢁ]D +30.6° (c 1.06, CHCl ); H NMR (400 MHz, CDCl ): ꢀ 0.03 (3H, s),
2
0
1
3
3
.05 (3H, s), 0.76 (3H, s), 0.88 (9H, s), 0.97 (3H, s), 1.51–1.27 (3H, m), 1.41–1.53 (4H, m), 1.59 (3H, s),
.61–1.74 (2H, m), 1.68 (3H, s), 1.73–1.88 (2H, m), 1.95–2.04 (1H, m), 2.10 (1H, dd, J = 5.9, 17.6 Hz),
1
3
.28 (3H, s), 3.53 (1H, dd, J = 4.9, 10.7 Hz), 3.74 (2H, s), 5.04 (1H, t, J = 6.8 Hz), 5.36 (1H, s); C NMR
100 MHz, CDCl ): ꢀ ꢀ5.0, ꢀ3.7, 17.6, 17.7, 18.1, 18.3, 21.5, 21.8, 25.8, 25.9 (3 carbons), 27.4, 28.1,
(
3
3
1
4.8, 37.0, 37.3, 41.2, 44.3, 57.6, 73.6, 76.9, 124.9, 130.7, 130.8, 138.5; IR (neat) 2934, 2856, 1471, 1451,
–
1
381, 1360, 1254, 1188, 1103, 1065, 1006, 943, 915, 887, 836, 773, 666 cm ; HREIMS (m/z) calcd for
+
C H O Si (M ), 420.3424, found 420.3437.
2
6
48
2
(1R,4aR,5S,6S,8aS)-6-(tert-butyldimethylsiloxy)-5,8a-dimethyl-2-methylene-5-(4-methylpent-3-
enyl)decahydronaphthalene-1-carbaldehyde (7): Dess–Martin periodinane (568 mg, 1.3 mmol) was
added in small portions to a stirred solution of 8 (282 mg, 0.67 mmol) containing NaHCO (563 mg, 6.70
3
mmol) in dry CH Cl (60 mL) at rt. After 1 h, the reaction was quenched with 10% aqueous Na S O (20
2
2
2
2
3
mL) at 0 °C, and the resulting mixture was extracted with CHCl (3 x 60 mL). The combined extracts
3
were washed with saturated aqueous NaHCO (2 x 30 mL), and brine (2 x 30 mL), then dried over
3
MgSO . Concentration of the solvent in vacuo afforded a residue, which was purified by column
4
2
0
chromatography (hexane/EtOAc, 100:1) to give 7 (281 mg, 100%) as a colorless viscous liquid. [ꢁ]D
1
+
46.2° (c 1.04, CHCl ); H NMR (400 MHz, CDCl ): ꢀ 0.03 (3H, s), 0.04 (3H, s), 0.77 (3H, s), 0.87 (9H,
3
3
s), 0.97 (3H, s), 1.15-1.23 (1H, m), 1.36–1.46 (1H, m), 1.47 (1H, dd, J = 4.4, 13.2 Hz), 1.51–1.59 (3H, m),
1
2
5
2
1
8
.60 (3H, s), 1.65-1.72 (2H, m), 1.68 (3H, s), 1.82–1.88 (3H, m), 2.22–2.45 (1H, m), 2.42–2.45 (1H, m),
.61 (1H, d, J = 3.9 Hz), 3.51 (1H, dd, J = 4.4, 10.7 Hz), 4.77 (1H, t, J = 2.0 Hz), 4.94 (1H, t, J = 2.0 Hz),
1
3
.02–5.06 (1H, m), 9.89 (1H, d, J = 3.9 Hz); C NMR (100 MHz, CDCl ): ꢀ ꢀ5.0, ꢀ3.7, 17.7, 17.9, 18.0,
3
1.6, 21.9, 22.5, 25.7, 25.8 (3 carbons), 27.7, 32.9, 35.0, 36.8, 38.8, 41.2, 41.8, 71.0, 73.5, 113.9, 124.6,
30.9, 142.1, 202.4; IR (neat) 2948, 2929, 2883, 2857, 1717, 1646, 1453, 1385, 1360, 1253, 1100, 1064,
–
1
+
91, 836, 773 cm ; HREIMS (m/z) calcd for C H O Si (M ), 418.3267, found 418.3277.
2
6
46
2
3
-[(1R,4aR,5S,6S,8aS)-6-(tert-Butyldimethylsiloxy)-5,8a-dimethyl-2-methylene-5-(4-methylpent-3-

HETEROCYCLES, Vol. 80, No. 1, 2010
245
enyl)decahydronaphthalen-1-yl]hydroxymethyl-5,6-dimethyl-2-methoxy-4H-pyran-4-one
(24):
n-BuLi in hexane (1.57 M solution, 0.59 mL, 0.93 mmol) was added dropwise to a stirred solution of
-bromo-2-methoxy-5,6-dimethyl-4H-pyran-4-one (231 mg, 0.99 mmol) in dry THF (15 mL) at ꢀ78 °C
3
under argon. After 5 min, a solution of 7 (83 mg, 0.20 mmol) in dry THF (5 mL) was added to the above
mixture at ꢀ78 °C, and the resulting mixture was warmed up to ꢀ55 °C over 1 h. The reaction was
quenched with saturated aqueous NH Cl (10 mL) at ꢀ55 °C, and the mixture was extracted with EtOAc (3
4
x 50 mL). The combined extracts were washed brine (2 x 40 mL), then dried over MgSO . Concentration
4
of the solvent in vacuo afforded a residue, which was purified by column chromatography (hexane/EtOAc,
1
4
:1) to give 24 (1:1 diastereomeric mixture) (101 mg, 87%) as a white amorphous powder. H NMR (400
MHz, CDCl ): ꢀ 0.04–0.52 (6H, m), 0.75 (3/2H, s), 0.76 (3/2H, s), 0.88 (9H, s), 0.92 (3/2H, s), 0.97 (3/2H,
3
s), 1.10–1.21 (1H, m), 1.26–1.49 (3H, m), 1.52–1.57 (2H, m), 1.60–1.70 (8H, m), 1.75–1.79 (1H, m),
1.86 (3/2H, s), 1.88 (3/2H, s), 1.91–2.04 (3H, m), 2.23–2.33 (1H, m), 2.26 (3/2H, s), 2.28 (3/2H, s),
1
3
2
.44–2.50 (1H, m), 3.55–3.61 (1H, m), 3.91 (3/2H, s), 3.97 (3/2H, s), 4.37–5.33 (5H, m); C NMR (100
MHz, CDCl ): ꢀ ꢀ5.1 (1/2 carbon), ꢀ5.0 (1/2 carbon), ꢀ3.7 (1/2 carbon), ꢀ3.6 (1/2 carbon), 9.4 (1/2
3
carbon), 9.6 (1/2 carbon), 16.9, 17.6, 17.7, 17.9 (1/2 carbon), 18.0 (1/2 carbon), 21.5 (1/2 carbon), 21.6
(
1/2 carbon), 22.9 (1/2 carbon), 23.0 (1/2 carbon), 23.1, 25.6 (1/2 carbon), 25.7 (1/2 carbon), 25.8 (3/2
carbon), 25.9 (3/2 carbon), 27.9 (1/2 carbon), 28.0 (1/2 carbon), 32.4 (1/2 carbon), 33.9 (1/2 carbon), 34.2
1/2 carbon), 35.1 (1/2 carbon), 37.0 (1/2 carbon), 37.1 (1/2 carbon), 37.8 (1/2 carbon), 37.9 (1/2 carbon),
9.2 (1/2 carbon), 39.5 (1/2 carbon), 41.5 (1/2 carbon), 41.8 (1/2 carbon), 55.4 (1/2 carbon), 55.5 (1/2
carbon), 61.4 (1/2 carbon), 64.4 (1/2 carbon), 67.0 (1/2 carbon), 67.6 (1/2 carbon), 73.8 (1/2 carbon), 73.9
1/2 carbon), 105.2 (1/2 carbon), 105.4 (1/2 carbon), 110.7 (1/2 carbon), 111.7 (1/2 carbon), 119.4 (1/2
(
3
(
carbon), 119.5 (1/2 carbon), 124.9 (1/2 carbon), 125.0 (1/2 carbon), 130.4 (1/2 carbon), 130.6 (1/2
carbon), 147.9 (1/2 carbon), 148.1 (1/2 carbon), 155.5 (1/2 carbon), 155.8 (1/2 carbon), 160.4 (1/2
carbon), 160.5 (1/2 carbon), 181.9 (1/2 carbon), 182.0 (1/2 carbon); IR (KBr) 3445, 2953, 2929, 2857,
–
1
1
669, 1592, 1463, 1423, 1377, 1319, 1253, 1151, 1097, 1063, 936, 888, 836, 772, 757, 665 cm ;
+
HREIMS (m/z) calcd for C H O Si (M ), 572.3897, found 572.3899.
3
4
56
5
3
-[(1R,4aR,5S,6S,8aR)-6-(tert-Butyldimethylsiloxy)-5,8a-dimethyl-2-methylene-5-(4-methylpent-3-
enyl)decahydronaphthalen-1-yl]methyl-5,6-dimethyl-2-methoxy-4H-pyran-4-one (26): NaN(SiMe3)2
in THF (1.0 M solution, 0.25 mL, 0.25 mmol) was added dropwise to a stirred solution of 24 (109 mg,
0
.19 mmol) in dry THF (8 mL) containing CS (0.12 mL, 1.90 mmol) at ꢀ78 °C under argon. After 1 h,
2
MeI (0.12 mL, 1.90 mmol) was added dropwise to the mixture at ꢀ78 °C, and the resulting solution was
further stirred at the same temperature for 2 h. The reaction was quenched with saturated aqueous NH Cl
4
(
5 mL) at ꢀ78 °C, and the resulting mixture was extracted with EtOAc (3 x 30 mL). The combined

246
HETEROCYCLES, Vol. 80, No. 1, 2010
extracts were washed with brine (2 x 20 mL), then dried over MgSO . Concentration of the solvent in
4
vacuo afforded crude methyl xanthate 25 (112 mg), which was used for the next reaction without
purification.
n-Bu SnH (0.15 mL, 0.55 mmol) and 2,2’-azobisisobutyronitrile (AIBN) (15.1 mg, 0.09 mmol) were
3
added successively to a stirred solution of the crude methyl xanthate 25 (112 mg, 0.17 mmol) in dry
toluene (5 mL) at rt. For the deaeration of the reaction mixture, it was frozen using liquid nitrogen, and
the reaction vessel was evacuated in vacuo for 30 min followed by filled with dry argon. The mixture was
heated at reflux for 2 h under argon. After cooling, the reaction mixture was concentrated in vacuo to
afford a residue, which was purified by column chromatography (benzene/EtOAc, 30:1) to give 26 (86
2
0
1
mg, 82%, 2 steps) as a colorless viscous liquid. [ꢀ]D ꢀ30.1° (c 1.01, CHCl ); H NMR (400 MHz,
3
CDCl ): ꢁ 0.04 (3H, s), 0.06 (3H, s), 0.75 (3H, s), 0.88 (9H, s), 0.93 (3H, s), 1.14–1.22 (1H, m),
3
1
1
2
4
.26–1.42 (4H, m), 1.50–1.54 (1H, m), 1.58–1.63 (2H, m), 1.64 (3H, s), 1.69 (3H, s), 1.73–1.77 (1H, m),
.80–1.85 (1H, m), 1.88–1.98 (2H, m), 1.90 (3H, s), 2.09 (1H, dd, J = 3.4, 14.0 Hz), 2.24 (3H, s),
.31–2.45 (2H, m), 2.69 (1H, dd, J = 3.4, 13.0 Hz), 3.52 (1H, dd, J = 4.8, 10.9 Hz), 3.83 (3H, s),
1
3
.17–4.18 (1H, m), 4.50 (1H, t, J = 2.4 Hz), 5.06–5.10 (1H, m); C NMR (100 MHz, CDCl ): ꢁ ꢀ5.0,
3
ꢀ
3.6, 10.0, 17.0, 17.7, 17.8, 18.1, 19.9, 21.8, 22.9, 23.1, 25.8, 25.9 (3 carbons), 28.0, 30.8, 34.0, 37.0,
3
2
7.5, 38.5, 41.6, 55.3, 55.9, 74.3, 103.5, 109.1, 118.6, 125.2, 130.6, 149.2, 154.9, 162.9, 180.4; IR (neat)
–
1
951, 2927, 2856, 1671, 1604, 1461, 1415, 1375, 1317, 1254, 1097, 1063, 1005, 934, 888, 836, 772 cm ;
+
HREIMS (m/z) calcd for C H O Si (M ), 556.3948, found 556.3961.
3
4
56
4
3
-[(1R,4aR,5S,6S,8aR)-5,8a-Dimethyl-2-methylene-5-(4-methylpent-3-enyl)-(6-hydroxy)decahydro-
naphthalen-1-yl]methyl-5,6-dimethyl-2-methoxy-4H-pyran-4-one (27): BF ·OEt (88 μL, 0.67 mmol)
3
2
was added dropwise to a stirred solution of 26 (74 mg, 0.13 mmol) in CH CN (4 mL) at 0 °C under argon,
3
and stirring was continued at rt for 4 h. The reaction was quenched with saturated aqueous NaHCO (10
3
mL) at 0 °C, and the resulting mixture was extracted with EtOAc (3 x 40 mL). The combined extracts
were washed with brine (2 x 30 mL), then dried over MgSO . Concentration of the solvent in vacuo
4
afforded a residue, which was purified by column chromatography (hexane/EtOAc, 2:1ꢀ1:1) to give 27
2
0
1
(
56 mg, 95%) as a colorless amorphous powder. [ꢀ]D ꢀ43.1° (c 1.02, CHCl ); H NMR (400 MHz,
3
CDCl ): ꢁ 0.79 (3H, s), 0.94 (3H, s), 1.25–1.42 (6H, m), 1.48–1.61 (2H, m), 1.64–1.75 (2H, m), 1.66 (3H,
3
s), 1.69 (3H, s), 1.90 (3H, s), 1.92–2.00 (3H, m), 2.08–2.13 (1H, m), 2.24 (3H, s), 2.32–2.45 (2H, m),
2
5
2
1
.69 (1H, dd, J = 3.4, 12.9 Hz), 3.56 (1H, t, J = 7.8 Hz), 3.84 (3H, s), 4.19 (1H, s), 4.51–4.52 (1H, m),
1
3
.14 (1H, t, J = 6.8 Hz); C NMR (100 MHz, CDCl ): ꢁ 10.0, 16.9, 17.0, 17.6, 19.9, 21.8, 22.85, 22.89,
3
5.7, 27.7, 30.7, 34.1, 37.5, 37.6, 38.9, 41.0, 55.3, 55.8, 73.9, 103.3, 109.2, 118.6, 125.0, 131.1, 148.9,
54.9, 162.9, 180.3; IR (KBr) 3419, 2928, 2871, 1669, 1588, 1462, 1419, 1376, 1319, 1256, 1163, 1149,

HETEROCYCLES, Vol. 80, No. 1, 2010
247
–
1
1
114, 1035, 996, 885, 731 cm ; HREIMS (m/z) calcd for C H O , 442.3083, found 442.3072.
28 42 4
3
-[(1R,4aR,5S,6S,8aR)-6-Acetoxy-5,8a-dimethyl-2-methylene-5-(4-methylpent-3-enyl)decahydro-
naphthalen-1-yl]methyl-5,6-dimethyl-2-methoxy-4H-pyran-4-one [(ꢀ)-nalanthalide] (2): Ac O (47
2
μL, 0.50 mmol) was added to a stirred solution of 27 (44.2 mg, 0.10 mmol) in CH Cl (2 mL) containing
2
2
Et N (97 μL, 0.70 mmol) and 4-dimethylaminopyridine (DMAP) (1.23 mg, 0.01 mmol) at 0 °C. After 1 h,
3
the reaction was quenched with 1 M aqueous HCl (2 mL) at 0 °C, and the resulting mixture was extracted
with EtOAc (3 x 40 mL). The combined extracts were washed with brine (2 x 20 mL), then dried over
MgSO . Concentration of the solvent in vacuo afforded a residue, which was purified by column
4
2
5
chromatography (hexane/EtOAc, 3:1) to give 2 (41.6 mg, 86%) as a colorless amorphous powder. [ꢀ]D
4
25
1
13
ꢀ
48.3° (c 1.02, CHCl ) {lit., [ꢀ] ꢀ58.2° (c 0.275, CHCl )}. The H and C NMR, IR, and MS spectra
3 D 3
1
(
see below) are identical to those of natural (ꢀ)-nalantalide. H NMR (400 MHz, CDCl ): ꢁ 0.87 (3H, s),
3
0
1
.96 (3H, s), 1.14–1.22 (1H, m), 1.26–1.33 (2H, m), 1.35–1.39 (2H, m), 1.50–1.54 (1H, m), 1.61 (3H, s),
.68 (3H, s), 1.71–1.78 (3H, m), 1.90 (3H, s), 1.92–2.00 (2H, m), 1.98 (1H, dd, J = 2.9, 11.7 Hz), 2.04
(
3H, s), 2.01–2.12 (1H, m), 2.24 (3H, s), 2.33–2.46 (2H, m), 2.68 (1H, dd, J = 3.4, 12.7 Hz), 3.85 (3H, s),
4
.20 (1H, t, J = 1.3 Hz), 4.52 (1H, t, J = 2.2 Hz), 4.82 (1H, dd, J = 7.3, 9.1 Hz), 5.07 (1H, t, J = 6.8 Hz);
1
3
C NMR (100 MHz, CDCl ): ꢁ 10.0, 16.9, 17.5, 18,1, 19.9, 21.3, 21.7, 22.7, 22.9, 24.1, 25.7, 30.7, 33.8,
3
3
1
8
7.4, 37.9, 39.2, 40.0, 55.3, 55.6, 76.3, 103.2, 109.4, 118.6, 124.6, 131.3, 148.7, 154.8, 162.8, 170.6,
80.3; IR (KBr) 2928, 2877, 1732, 1672, 1603, 1456, 1416, 1374, 1317, 1253, 1242, 1076, 1027, 983,
–
1
+
82 cm ; HREIMS (m/z) calcd for C H O (M ), 484.3189, found 484.3168.
3
0
44
5
3
-[(1R,4aR,5S,6S,8aR)-6-Acetoxy-5,8a-dimethyl-2-methylene-5-(4-methylpent-3-enyl)decahydro-
naphthalen-1yl]methyl-4-acetoxy-5,6-dimethyl-2H-pyran-2-one (29): 1 M NaOH (1.40 mL, 1.4 mmol)
was added dropwise to a stirred solution of 27 (33.8 mg, 76 mmol) in MeOH (2 mL) at rt. The mixture
was heated at reflux for 24 h. The reaction was quenched with 1 M HCl (1.40 mL) at 0 °C, and the
resulting mixture was extracted with CHCl (3 x 30 mL). The combined extracts were washed with brine
3
(
2 x 20 mL), then dried over MgSO . Concentration of the solvent in vacuo afforded the corresponding
4
ꢀ
-pyrone 28 (31.4 mg) as a colorless amorphous powder, which was used for the next reaction without
purification.
Ac O (36.0 μL, 0.38 mmol) was added to a stirred solution of the crude ꢀ-pyrone 28 (31.4 mg) in CH Cl
2
2
2
(
3 mL) containing Et N (74.0 μL, 0.54 mmol) and DMAP (0.80 mg, 6.6 μmol) at 0 °C, and stirring was
3
continued for 1 h at rt. The reaction was quenched with 1 M HCl (1 mL) at 0 °C, and the resulting
mixture was extracted with CHCl (3 x 30 mL). The combined extracts were washed with saturated
3
aqueous NaHCO (2 x 10 mL) and brine (2 x 10 mL), then dried over MgSO . Concentration of the
3
4

248
HETEROCYCLES, Vol. 80, No. 1, 2010
solvent in vacuo afforded a residue, which was purified by column chromatography (hexane/EtOAc, 2:1)
2
0
1
to give 29 (27.5 mg, 70%, 2 steps) as a colorless amorphous powder. [ꢀ]D ꢀ14.2° (c 0.352, CHCl ); H
3
NMR (400 MHz, CDCl ): ꢁ 0.87 (3H, s), 0.98 (3H, s), 1.14–1.22 (1H, m), 1.26–1.29 (2H, m), 1.32–1.43
3
(
1H, m), 1.53–1.57 (1H, m), 1.59 (3H, s), 1.62–1.64 (1H, m), 1.67 (3H, s), 1.73–1.88 (4H, m), 1.78 (3H,
s), 1.93–2.02 (1H, m), 2.04 (3H, s), 2.06–2.10 (1H, m), 2.14–2.18 (1H, m), 2.22 (3H, s), 2.30 (3H, s),
.32–2.46 (1H, m), 2.53–2.55 (2H, m), 4.36 (1H, s), 4.58 (1H, t, J = 2.0 Hz), 4.79 (1H, dd, J = 7.2, 8.2
2
1
3
Hz), 5.05 (1H, t, J = 7.2 Hz); C NMR (100 MHz, CDCl ): ꢁ 10.6, 17.41, 17.44, 18.1, 20.3, 21.2, 21.7,
3
2
2.5, 22.9, 24.0, 25.7, 30.67, 30.72, 34.0, 37.4, 37.8, 39.3, 39.9, 55.4, 76.0, 107.9, 111.0, 116.2, 124.2,
31.5, 147.2, 156.0, 159.4, 164.0, 167.0, 170.7; IR (KBr) 2931, 2872, 1773, 1723, 1651, 1579, 1454,
1
–
1
+
1
369, 1242, 1193, 1180, 1088, 1023, 893, 735 cm ; HREIMS (m/z) calcd for C H O (M ), 512.3138,
31 44 6
found 512.3146.
3
-[(1R,4aR,5S,6S,8aR)-6-Acetoxy-5,8a-dimethyl-2-methylene-5-(4-methylpent-3-enyl)decahydro-
naphthalene-1-yl]methyl-5,6-dimethyl-4-hydroxy-2H-pyran-2-one [(+)-sesquicillin] (1): 1 M NaOH
0.54 mL, 0.54 mmol) was added dropwise to a stirred solution of 29 (27.5 mg, 54 μmol) in THF (0.54
(
mL) at 0 °C. After 30 min, he reaction was quenched with 1 M HCl (0.6 mL) at 0 °C, and the resulting
mixture was extracted with CHCl (3 x 30 mL). The combined extracts were washed with brine (2 x 20
3
mL), then dried over MgSO . Concentration of the solvent in vacuo afforded the residue, which was
4
purified by column chromatography (hexane/EtOAc, 3:1) to give 1 (22.2 mg, 88%) as a colorless
2
5
2a
22
1
13
amorphous powder. [ꢀ]D +7.1° (c 0.36, CHCl ) {lit., [ꢀ] +10° (c 0.8, CHCl )}. The H and C NMR
3
D
3
2
a 1
spectra (see below) are identical to those reported. H NMR (400 MHz, CDCl ): ꢁ 0.87 (3H, s), 0.97 (3H,
3
s), 1.19 (1H, td, J = 4.9, 12.2 Hz), 1.24–1.32 (2H, m), 1.41 (1H, ddd, J = 4.4, 13.2, 25.9 Hz), 1.54–1.61
(
1H, m), 1.58 (3H, s), 1.67–1.78 (3H, m), 1.67 (3H, s), 1.83–1.89 (1H, m), 1.92 (3H, s), 1.95–1.99 (3H,
m), 2.04 (3H, s), 2.19 (3H, s), 2.22–2.25 (1H, m), 2.42 (1H, td, J = 5.4, 13.7 Hz), 2.54 (1H, dd, J = 10.7,
1
7
3
1
8
4.2 Hz), 2.75 (1H, dd, J = 3.4, 14.1 Hz), 4.45 (1H, s), 4.65 (1H, s), 4.80–4.84 (1H, m), 5.05 (1H, t, J =
1
3
.3 Hz); C NMR (100 MHz, CDCl ): ꢁ 9.9, 17.3, 17.5, 18.0, 21.2, 21.7, 22.1, 22.6, 22.8, 24.0, 25.7, 30.9,
3
3.8, 37.6, 37.8, 39.3, 40.0, 56.4, 76.2, 103.0, 106.1, 111.0, 124.4, 131.4, 148.9, 155.7, 164.3, 165.1,
70.8; IR (KBr) 3254, 2932, 2877, 1776, 1731, 1667, 1567, 1454, 1389, 1346, 1242, 1116, 1076, 1027,
–
1
+
87, 756 cm ; HREIMS (m/z) calcd for C H O (M ), 470.3032, found 470.3022.
2
9
42
5
ACKNOWLEDGEMENTS
We are especially grateful to Dr. Sheo B. Singh, Merck Research Laboratories, for providing us with
1
13
copies of the H and C NMR spectra of natural (ꢀ)-nalanthalide (2). This work was supported in part by
a Grant-in-Aid for Scientific Research (C) (No. 18590013), and a Grant-in-Aid for High Technology

HETEROCYCLES, Vol. 80, No. 1, 2010
249
Research Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan
MEXT).
(
REFERENCES AND NOTES
1
.
Viridoxins A and B, see: S. Gupta, S. B. Krasnoff, J. A. A. Renwick, D. W. Roberts, J. R. Steiner,
and J. Clardy, J. Org. Chem., 1993, 58, 1062.
2
.
Sesquicillins, see: (a) B. Engel, G. Erkel, T. Anke, and O. Sterner, J. Antibiot., 1998, 51, 518; (b)
H.–W. Jeong, H.–J. Lee, Y.–H. Kho, K.–H. Son, M. Y. Han, J.–S. Lim, M.–Y. Lee, D. C. Han, J.–H.
Ha, and B.–M. Kwon, Bioorg. Med. Chem., 2002, 10, 3129; (c) R. Uchida, R. Imasato, Y.
Yamaguchi, R. Masuma, K. Shiomi, H. Tomoda, and S. ꢀmura, J. Antibiot., 2005, 58, 397.
Sesquicillin (1) has been previously reported in patent literature, however, the structural elucidation
has not been described; (d) T. B. Hirschthal and T. H. Neuallschwil (Sandoz Ltd., Switzerland), DE
2
,316,429, October 11, 1973; (e) A. Kuwabara, S. Fujita, S. Kobayashi, and T. Nishigori (Nippon
Kayaku K. K. Japan), JP 8,092,119, April 9, 1996.
3
4
5
6
7
.
Subglutinols A and B, see: J. C. Lee, E. Lobkovsky, N. B. Pliam, G. Strobel, and J. Clardy, J. Org.
Chem., 1995, 60, 7076.
. Nalanthalide, see: M. A. Goetz, D. L. Zink, G. Denzeny, A. Dombrowski, J. D. Polishook, J. P. Felix,
R. S. Slaughter, and S. B. Singh, Tetrahedron Lett., 2001, 42, 1255.
.
.
.
Candelalides A–C, see: S. B. Singh, D. L. Zink, A. W. Dombrowski, G. Dezeny, G. F. Bills, J. P.
Felix, R. S. Slaughter and M. A. Goetz, Org. Lett., 2001, 3, 247.
8
6
+
It is reported that nalanthalide (2) blocked the Rb efflux in CHO-Kv1.3 cells with an IC value of
5
0
3
.9 μM (ref. 4).
For recent excellent reviews on the voltage-gated potassium chanel Kv1.3 as a novel therapeutic
target for autoimmune disorders, see: (a) H. Wulff and M. Pennington, Curr. Opin. Drug Discovery
Dev., 2007, 10, 438; (b) H. Wulff, B. Christine, and C. K. George, Curr. Opin. Drug Discovery Dev.,
2
003, 6, 640.
8
9
.
.
F. Zhang and S. J. Danishefsky, Angew. Chem. Int. Ed., 2002, 41, 1434.
T. Abe, K. Iwasaki, M. Inoue, T. Suzuki, K. Watanabe, and T. Katoh, Tetrahedron Lett., 2006, 47,
3
251.
0. K. Watanabe, K. Iwasaki, T. Abe, M. Inoue, K. Ohkubo, T. Suzuki, and T. Katoh, Org. Lett., 2005, 7,
745.
1
3
1
1
1
1. T. Oguchi, K. Watanabe, K. Ohkubo, H. Abe, and T. Katoh, Chem. Eur. J., in press.
2. H. Hagiwara and H. Uda, J. Chem. Soc., Perkin Trans. 1, 1991, 1803.
3. (a) R. E. Ireland and L. Liu, J. Org. Chem., 1993, 58, 2899; (b) D. B. Dess and J. C. Martin, J. Am.

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HETEROCYCLES, Vol. 80, No. 1, 2010
Chem. Soc., 1991, 113, 7277; (c) D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155.
1
1
4. (a) M. Balestra and J. Kallmerten, Tetrahedron Lett., 1988, 29, 6901; (b) W. C. Still and A. Mitra, J.
Am. Chem. Soc., 1978, 100, 1927.
5. For reviews on the [2,3]-Wittig rearrangement; see: (a) K. Tomooka, in the Chemistry of Functional
Groups: the Patai Series Vol. 104 (ed. by Z. Rappoport and I. Marek,), Wieley-VCH: Chichester,
2
004, pp. 749–828; (b) G. McGowan, Aust. J. Chem., 2002, 55, 799; (c) T. Nakai and K. Tomooka,
Pure Appl. Chem., 1997, 69, 595; (d) J. A. Marshall, in Comprehensive Organic Synthesis, Vol. 3
ed. by B. M. Trost and I. Fleming), Pergamon, Oxford, 1991, pp. 975–1014.
6. A related Eschenmoser–Claisen rearrangement has been reported for the total synthesis of
±)-sesquicillin (see ref. 8), while, to the best of our knowledge, this type of [2,3]-Wittig
(
1
(
rearrangement (cf. 9ꢀ8, Table 1) is unprecedented.
1
7. (a) M. Inoue, W. Yokota, and T. Katoh, Synthesis, 2007, 622; (b) T. Katoh, T. Izuhara, W. Yokota,
M. Inoue, K. Watanabe, A. Nobeyama, and T. Suzuki, Tetrahedron, 2006, 62, 1590; (c) M. Inoue,
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D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin Trans. 1, 1975, 1574.
8. Although the absolute value of the synthetic material is somewhat smaller than that of natural
product for some reason, we believe that the synthetic material is enantiomerically pure.
1