Approaches to the synthesis of arisugacin A

Article abstract of DOI:10.1016/j.tet.2007.02.085

Approaches to the synthesis of the important acetylcholinesterase inhibitor, arisugacin A, are described. Two different routes to?the key AB ring system are described: the first utilizes an intramolecular Diels-Alder reaction on a furan substrate and the

Full text of DOI:10.1016/j.tet.2007.02.085

Tetrahedron 63 (2007) 3682–3701
Approaches to the synthesis of arisugacin A
*
Michael E. Jung and Sun-Joon Min
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1569, United States
Received 19 January 2007; revised 20 February 2007; accepted 21 February 2007
Available online 24 February 2007
Abstract—Approaches to the synthesis of the important acetylcholinesterase inhibitor, arisugacin A, are described. Two different routes
to the key AB ring system are described: the first utilizes an intramolecular Diels–Alder reaction on a furan substrate and the second
a 6p-electrocyclization of a substituted triene followed by cycloaddition with singlet oxygen. The successful synthesis of a fully functional-
ized AB ring system of arisugacin A, the tetraol 52 from hydroxy-b-ionone 22 in 16 steps and 9.3% overall yield is described. Several useful
synthetic transformations to this molecule and its analogues are reported, e.g., the formation of the furan Diels–Alder cycloadduct 14 and its
conversion into the oxa-bridged structures 17 and 21, the preparation of the dienes 25 and 26 and the conversion of the later into the endo-
peroxide 30 and its diol 36, the preparation of the endoperoxide 40 and the oxa-bridged system 42, and finally the use of the enelactone 43 and
its ultimately successful conversion into 52. In addition, several novel rearrangements are described, producing the unusual compounds 62, 65,
and 67. Finally, the successful coupling of the pyrone unit to the AB ring system is described to give compounds 70 and 71. The novel
reduction of these compounds to the cyclic ether 74 is described.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the angular methyl and hydroxyl groups at the AB and BC
ring junctures having the trans–anti–trans relationship.
With respect to its three-dimensional structure, a docking
simulation of arisugacin A with AChE showed that this rel-
atively flat compound when stretched out as a long sheet
appeared to reside in the extended narrow active site of
AChE.1b Because of its structural complexity, its therapeutic
significance, and limited supply from natural sources,
synthetic chemists have been attracted to this compound.
Arisugacin A (1a), a compound isolated in 1997 from a strain
of Penicillium sp. FO-4259, is a potent and specific inhibitor
of acetylcholinesterase (AChE), which may be clinically
useful for the treatment of Alzheimer’s disease (AD), the
most common form of dementia.1 The inhibitory activity
of arisugacin A reduces the rate of hydrolysis of acetyl-
choline (ACh), a neurotransmitter in the cholinergic neuron
system, thereby increasing the amount of ACh in the brain.2
Moreover, this compound shows a higher selectivity for
AChE in the nervous system than for butyrylcholinesterase
(BuChE), which should reduce the unfavorable side effects
associated with non-specific inhibitors such as tacrine.3
˜
Recently, both the Omura and Hsung groups have
independently reported total syntheses of arisugacin A using
a formal [3+3] cycloaddition strategy to construct the
dihydro-pyranopyrone ring system.4
In our retrosynthetic analysis of arisugacin A (Scheme 1),
we envisioned a coupling of the pyrone unit with the ad-
vanced AB ring system at a late synthetic stage. The highly
As shown in Figure 1, arisugacin A consists structurally of
a tetracyclic ring core possessing four contiguous stereocen-
ters and an aryl group connected to an a-pyrone moiety with
oxygenated decalin system
3
would derive from
R3
R2
R1
R1
R2
R3
Arisugacin A (1a)
H
OMe
OMe
OMe
H
O
O
Arisugacin B (1b)
Territrem A (1c)
Territrem B (1d)
Territrem B (1e)
H
-OCH2O-
OMe
OMe
OMe
OMe
OMe
O Me
12b
6a
O
Me
OMe
OH
12a
4a
OH
OH
Me
Me
Figure 1. Arisugacin A and its family.
* Corresponding author. Tel.: +1 310 825 7954; fax: +1 310 206 3722; e-mail: jung@chem.ucla.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.085

M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
3683
O
O
Ar
OH
O
CO2R
Me
O
O
Me Me
OR
Me Me
OH
Me
OH
1
OH
OH
OH
OH
OH
Me Me
3
Me Me
4
Me Me
2
Route A
O
O
Z
Me
Me
Z
Me
O
Me
Me
4
O
O
Intramolecular
DA reaction
7
Me Me
5 Z = CN, COOBn
Me Me
6 Z = CN, COOBn
Route B
R'O
CO2R
R'O
CO2R
Me
Me
R'O
CO2R
Me
Me
Me
Me
4
OH
O
OH
Me Me
8
O
Me Me
9
Me Me
Singlet oxygen
10
HO
R'O
Me
Me
O
Me
Electrocyclization
CO2R
Me Me
12
Me Me
Me
11
Scheme 1. Retrosynthetic analysis.
dihydroxylation of the advanced intermediate 4, which
would be formed via two different approaches. First, we
could construct the oxa-bridged compound 5 using an intra-
molecular Diels–Alder reaction of furan (IMDAF), which
has already been studied in our group (Route A).5,6 In this
case, one would expect the stereochemistry of the fused
ring juncture in the AB ring system to be trans since (1)
the exo cycloadduct (keto group in the exo position) would
be favored over the endo cycloadduct and (2) the trans
ring juncture is much more stable in these systems. The
key feature of the second approach (Route B) is the construc-
tion of the bicyclic core by a 6p-electrocyclization7 of the
triene 11 followed by cycloaddition with singlet oxygen.8 We
assumed that the stereochemical outcome in the reaction of
the diene 10 with singlet oxygen would be controlled by the
steric interaction between the angular methyl group and the
incoming oxygen, which would also lead to the trans fused
decalin system. Herein, we describe the synthesis of the
highly oxygenated AB ring system of arisugacin A and our
approach toward the total synthesis of the natural product.
afforded the desired cycloadduct 14 as
a
single
diastereomer in 91% yield in the presence of dimethylalumi-
num chloride (Scheme 2). Diimide reduction9 of the endo-
cyclic double bond of 14 gave the ketone, which was
selectively converted to the b-alcohol in 64% yield using
lithium in ammonia. We conducted the sequence of hydro-
boration and oxidation as described below to afford the
free or PMB protected hydroxy aldehydes 17 and 21ab al-
though their yields were not optimized. Unfortunately, all at-
tempts to open the oxygen-bridged ring of compounds 17
and 21ab to the corresponding trans fused decalin system us-
ing bases such as DBU, NaOH or LDAwere unsuccessful. In
fact, we could observe only epimerization of the proton a to
the aldehyde. Presumably, the oxa-tricyclic starting mate-
rials 17 and 21ab are more stable than the hydroxy enal
products 18 and 19 under these basic conditions because the
1,3-diaxial interaction between the angular and C2 methyl
groups is somewhat reduced when C1 and C8 are linked
by the oxygen bridge. However, although we were unable
to synthesize the desired compounds 18 or 19 via this
route, we used the oxa-bridged compounds 17 and 21a as
the coupling material in subsequent reactions. This will be
discussed in a later section.
2. Results and discussion
2.1. Synthesis of AB ring system using an IMDAF
reaction
2.2. Synthesis of AB ring system via electrocyclization/
singlet oxygen cycloaddition
In recent work in our laboratory,5 we demonstrated the
construction of oxygen-bridged bicyclic ring systems using
the IMDAF reaction. IMDAF reactions of the precursors to
the AB ring system having alkene dienophiles, e.g., the
ester 6a and the nitrile 6b, gave the expected cycloadducts
5ab in low yields, presumably due to a facile retro Diels–
Alder reaction.5 However, the analogous allenic ketone 13
The second approach toward the AB ring system began by
investigating the key electrocyclization. Thus, we first syn-
thesized the two triene precursors having different electron-
withdrawing groups, i.e., the ester and nitrile (Scheme 3).
Hydroxy b-ionone 22, easily prepared in two steps from
a-ionone,10 was protected as the tert-butyldimethylsilyl

3684
M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
R
O
O
Me
Me
R
MeAlCl2
Me
O
O
Me
O
Me
ref 5
Me Me
Me Me
6a R = CO2Bn
6b R = CN
6%
5a R = CO2Bn
5b R = CN
11%
O
CH2
O
HO
C
Me
Me
Me
Me
Me
O
b,c
a
Me
Me
O
O
O
ref 5
HO
Me Me
14
Me Me
15
Me Me
13
OH
H
RO
CHO
Me
HO
CHO
Me
Me
O
Me
8
Me
Me
d
e
O
2
1
OH
Me Me
Me Me
16a ( -H)
16b ( -H)
Me Me
17
18 R = H
19 R = PMB
PMBO
CHO
Me
PMBO
Me
Me
Me
g,h
f
O
O
15
Me Me
Me Me
20
21a ( -H)
21b ( -H)
Scheme 2. Reagents and conditions: (a) Me2AlCl, CH2Cl2, ꢀ20 ꢁC, 91%; (b) KO2CN]NCO2K, AcOH, CH2Cl2, ꢀ78 ꢁC to 23 ꢁC; (c) Li/NH3, Et2O, MeOH,
ꢀ33 ꢁC, 64% (+12% starting material); (d) BH3$DMS, H2O2, NaOH, 77% (16a/16b¼2.2:1); (e) Dess–Martin periodinane, CH2Cl2, 72% (from 16a); (f)
PMBOC(NH)CCl3, TfOH, Et2O, 89%; (g) BH3$DMS, H2O2, NaOH, 25%; (h) Dess–Martin periodinane, CH2Cl2, 85% (21a/21b¼2.1:1).
TBSO
OH
TBSO
R
Me
Me
Me
Me
d
a,b or c
O
R
Me Me
Me Me
Me
Me Me
Me
22
23 R = CO2Et
24 R = CN
25 R = CO2Et
26 R = CN
TBSO
CN
HO
CO2Et
Me
Me
Me
Me
e
25 R = CO2Et
Me Me
Me Me
25a
27
Scheme 3. Reagents and conditions: (a) TBSCl, imid, DMF, 96%; (b) (EtO)2P(O)CH2CO2Et, NaH, Et2O, 90% (E/Z¼7.2:1); (c) (MeO)2P(O)CH2CN, BuLi,
THF, ꢀ78 ꢁC, 87% (E/Z¼2.0:1); (d) see Table 1; (e) HF, CH3CN, 86%.
(TBS) ether 22a.11 Horner–Wadsworth–Emmons reaction of
this silyl ether afforded the corresponding trienes 2312 and
2413 in 90% and 87%, respectively, favoring the E stereoiso-
mers. Presumably, the small size of the nitrile group in com-
pound 24 resulted in the low stereoselectivity of this
reaction as compared to the ester (2:1 vs 7.2:1). As shown
in Table 1, we explored the electrocyclization of the trienes
23 and 24 by modifying the reported reaction procedure.7a
The triene 23 was first isomerized to the Z-isomer by way
of sodium lamp irradiation in the presence of benzanthrone
and subsequently cyclized thermally to give the diene 25 in
56% yield as a single diastereomer. We improved the yield to
64% when the Z-isomer was isolated by flash column chro-
matography before cyclization. It should be noted that mi-
crowave reaction of the substrate 23 significantly reduced
the reaction time, but the yield of the desired product did
not increase. The structure of the cyclized product 25 was
confirmed by its conversion into the known alcohol 25a
(and eventually into the lactone 38, see Scheme 7) and com-
parison of the spectroscopic data of those two compounds
with that reported previously in the literature for the
Table 1. Triene electrocyclization studies
Entry Compd Conditions
Results
1
2
23
23
(i) hn, benzanthrone, THF,
5 h; (ii) DMF, 154 ꢁC, 3 d
(i) hn, benzanthrone, THF,
5 h; (ii) mw, DMF, 250 ꢁC,
5 min
mw, DMF, 250 ꢁC, 5 min
(i) hn, benzanthrone, THF,
5 h; (ii) DMF, 154 ꢁC, 3 d
25, 64%
25, 44%
3
4
23
24
Complex mixtures
26+27, 62% (3:2)

M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
3685
Me
Me
Me
Me
Me
Me
OTBS
OTBS
H
H
H
H
R
R
Me
Me
23 or 24
25 R = CO2Et
26 R = CN
Me
Me
OTBS
TBSO
Me
TBSO
R
R
H
Me
Me
H
OTBS
H
Me
Me
Me
Me
H
H
R
H
Me
Me
Me
Me
R
H
Me
Me
Me
26' R = CN
27 R = CN
Scheme 4.
alcohol7d and lactone.7c,d We explain this stereospecificity
based on the assumption that the 6p-electrocyclization takes
place preferentially via one of the two possible transition
states, namely from the face opposite to the silyloxy group,
to avoid an unfavorable steric interaction (Scheme 4). On the
other hand, the electrocyclization of the nitrile substrate 24
gave an inseparable mixture of the desired diene 26 and
the isomerized compound 27 in which one double bond
was conjugated with the nitrile group. Presumably, the steric
effect of the small nitrile group allowed the reaction to occur
via both transition states to produce both possible com-
pounds 26 and 260. This latter compound 260 then isomerized
to the more stable unsaturated nitrile 27 in which the steric
interaction between the nitrile group and OTBS group is
eliminated.
the starting material 26 and the intact isomer 27. An X-ray
crystallographic analysis of the endoperoxide 30 (see Sup-
plementary data for ORTEP drawing of 30) indicated that
the OTBS group is located in the equatorial position and
that the angular methyl group and the bridgehead oxygen
have a trans relationship. Therefore, we were convinced that
the singlet oxygen reaction of the diene nitrile 26 occurred
from the face syn to the nitrile substituent to circumvent
the steric interaction between the C-8 methyl group and
the incoming singlet oxygen.
Despite the low yield of the endoperoxide 30, we continued
the synthesis because we were able to obtain a reasonable
amount of material by repeating the singlet oxygen reaction
several times using the recovered starting material. We next
attempted to both reduce the endocyclic alkene and cleave
the endoperoxide O–O bond in one step using palladium-
catalyzed hydrogenation. While most attempts gave various
side products, it was noteworthy that the endoperoxide 30
was converted to the diepoxide 31 via palladium-catalyzed
isomerization, an interesting reaction, which has already
been reported in the literature (Scheme 6).15 Alternatively,
a series of stepwise reductions were tried. The initial cleav-
age of the peroxide bond by treatment of compound 30 with
zinc/acetic acid produced the alkenes 32 and 33, in which
the nitrile group was simultaneously hydrolyzed to give the
carboxylic acid or the acetyloxy amide. However, all further
efforts toward reduction of the endocyclic alkene moiety in
the acid 32 failed. Instead, we successfully reduced both the
double bond and the peroxide bond in 30 by changing the
sequence of reduction steps. First, diimide reduction of the
endoperoxide 30 afforded the reduced endoperoxide 35 in
good yield after five iterative reactions (overall 98%). To
increase the amount of the reduced product 35, it was crucial
to select the proper combination of solvents, i.e., a 2:1 ratio
of methanol and tetrahydrofuran. Finally, the peroxide bond
was cleaved by zinc/acetic acid to give an 84% yield of
a 1:2.7 mixture of the dihydroxy nitrile 36 along with the
hydrolyzed amide 37.
We next examined the cycloaddition14 of the cyclized dienes
25 and 26 with singlet oxygen (Scheme 5). We performed
photoperoxidation of a solution of the diene 25 in deuterated
chloroform using methylene blue as a sensitizer under irra-
diation with a tungsten lamp (GE, 300 W), while keeping
1
the temperature around 0 ꢁC. Unfortunately, the H NMR
analysis of the product indicated that it was not the expected
endoperoxide 29, but the hydroperoxide 28, which was ap-
parently generated via the ene reaction of the less hindered
alkene of the diene with singlet oxygen. It is likely that the
axial ethyl ester group sterically prevented the proximal
approach of singlet oxygen from the bottom face of the
compound. However, when we applied the same reaction
to a mixture of the isomeric diene nitriles 26 and 27, we ob-
tained the desired endoperoxide 30 along with a mixture of
TBSO
CO2Et
TBSO
CO2Et
TBSO
CO2Et
Me
Me
Me
Me
Me
a
O
OOH
O
Me Me
25
Me Me
29
not observed
Me Me
28
TBSO
CN
8
Me
At this point, even though we obtained the desired com-
pounds 36 and 37 as planned, the synthetic difficulty as
well as the low efficiency prompted us to search for a new
route to overcome these problems. Corey had reported that
the cycloaddition of singlet oxygen to the lactone 38 pro-
duced the endoperoxide 40 in excellent yield in the total syn-
thesis of forskolin (Scheme 7).14 Thus, we transformed the
ester 25 to the corresponding lactone 38 by modifying the
Me
O
b
26 and 27
A mixture of 26 and 27
O
Me Me
30
Scheme 5. Reagents and conditions: (a) hn, O2, methylene blue, CHCl3,
0 ꢁC, 3.5 h, 51%; (b) hn, O2, methylene blue, CHCl3, 0 ꢁC, 20 h, 28%
(59% of a recovered mixture of 26 and 27).

3686
M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
TBSO
CN
Me
TBSO
Me
CN
Me
Me
O
Me
O
a
O
O
Me
Me
Me
31
30
TBSO
R1
Me
TBSO
CO2H
Me
Me
OR2
Me
b
OH
OH
Me
OH
Me
Me Me
32 R1 = CO2H, R2 = H
34
33 R1 = CONH2, R2 = Ac
TBSO
R
TBSO
CN
Me
Me
Me
OH
Me
O
c
d
OH
Me Me
36 R = CN
37 R = CONH2
O
Me Me
35
Scheme 6. Reagents and conditions: (a) H2, Pd/C, MeOH, 1 d, 46% (19% SM); (b) Zn, AcOH, 1.5 h, 32 (70%), 33 (9%); (c) KO2CN]NCO2K, AcOH, MeOH/
THF (2:1), ꢀ78 ꢁC to 23 ꢁC, 18 h, 98% (1:20¼30/35 after five times); (d) Zn, AcOH, 84% (36/37¼1:2.7).
previously reported work of Cha,7c which involved remov-
ing the TBS group to give the alcohol 25a, Swern oxidation
to the ketone 25b, and NaBH4 reduction. The last reduction
step afforded a 2.5:1 mixture of the lactone 38 and the lactol
39, which were easily separated by column chromatography.
Since the hydride addition to the ketone occurs preferen-
tially from the b-face, this implies that the 1,3-steric interac-
tion of the axial ester is more dominant than the 1,2- or
1,4-steric interaction of the axial methyl groups. The cyclo-
addition of singlet oxygen to the lactone 38 afforded the
desired endoperoxide 40 as a single isomer in 99%
yield. Following the same procedures we had applied previ-
ously, we carried out the two consecutive reductions of the
endoperoxide 40 with diimide followed by zinc/acetic acid
to produce the dihydroxy lactone 41 in 96% yield without
any difficulty.
Next, we needed to regioselectively eliminate the b-hydroxy
group of the dihydroxy lactone 41 while retaining the other
hydroxyl group at the ring juncture. As illustrated in Table 2,
the elimination reactions of the dihydroxy lactone 41 did not
proceed under basic conditions, with only starting material
being recovered.16 Treatment of the lactone 41 with thionyl
chloride gave the epimeric tertiary alcohol 45 (38%) along
with a mixture of the two rearranged lactones 44 and 46 in
25% yield. The formation of 45 is perhaps due to a retro-
aldol aldol process with 45 being more stable than 41 due
to the lack of one 1,3-diaxial methyl–methyl interaction.
Acetylation produced the rearranged lactone 47 in 61% yield
without any dehydration. However, it was noted that the
oxa-bridged compound 42 was generated under either mesyl-
ation (entry 6, 21%) or acidic conditions (entry 9, 64%).
Encouraged by this result, we investigated a practical
R1
O
R2
Me
TBSO
CO2Et
O
O
Me
Me
Me
Me
Me
O
d
a,b,c
O
40
Me Me
25
Me Me
Me Me
38 R1,R2 = O
39 R1,R2 = OH, H
O
O
CH2
O
O
HO
O
Me
Me
Me Me
OH
Me
e,f
O
OH
Me Me
43
OH
Me Me
41
Me Me
44
O
O
Me
Me
g
h
O
Me Me
42
Scheme 7. Reagents and conditions: (a) HF, CH3CN, 86%; (b) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC, 97%; (c) NaBH4, 95% (38/39¼2.5:1); (d) hn, O2,
methylene blue, CHCl3, 0 ꢁC, 5.5 h, 99%; (e) KO2CN]NCO2K, AcOH, CH2Cl2, ꢀ78 ꢁC to 23 ꢁC; (f) Zn, AcOH, 96% (two steps); (g) see Table 2; (h)
LDA, THF, ꢀ78 ꢁC, 96% (43/44¼4.6:1).

M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
3687
Table 2. Elimination reaction of 41
the desired oxa-bridged compound 42 cleanly in 80% yield.
Finally, we opened the bridged oxygen of this lactone 42
with lithium diisopropylamide at low temperature. In this
case, the rearranged lactone 44 was also produced as
a side product. As shown in Scheme 8, we believe that the
mechanism for the formation of 44 involves the initial proton
abstraction from one of the methyl protons (Hb), which gen-
erated the tertiary alkoxide anion I by b-elimination. The ad-
dition of the resulting alkoxide to the nearby lactone group
formed the tetrahedral intermediate II, which was rear-
ranged to afford the less strained lactone 44.
O
O
O
O
Me Me
OH
Me
OH
Me
OH
Me Me
Me Me
41
43
O
Me
Me
Me
AcO
HO
O
OH
O
other products:
Me
Me Me
OH
O
O
O
38, 42, and 44
OH
Me Me
45
Me Me
47
Me Me
46
Our final goal was the conversion of the key intermediate 43
to the tetraol 52 having the four contiguous stereogenic cen-
ters and all of the functional groups of the AB ring system
(Scheme 9). Thus, we first reduced the hydroxy lactone to
the triol 48, which was protected as the TBS ether 49.
Although oxidation of the sterically hindered secondary
alcohol in 49 by Dess–Martin periodinane failed, the alcohol
was converted to the ketone 50 in 95% yield by Ley’s
method (TPAP/NMO). Dihydroxylation of the endocyclic
alkene 50 with stoichiometric osmium tetroxide in pyridine
occurred from the less hindered a-face to furnish the triol 51
in 83% yield. Careful removal of the silyl protecting group
using TBAF afforded the desired tetraol 52, which existed
as the hemiketal form 52. Thus, the synthesis of the highly
oxygenated AB ring system of arisugacin Awas successfully
completed. It converts hydroxy-b-ionone 22 into 52 in 16
steps and 9.3% overall yield.
Entry Conditions
Results
1
2
3
4
5
6
7
8
9
10
KOH, dioxane, 85 ꢁC, 20 h
LiOH, MeOH, 23 ꢁC, 2 d
KOH, MeOH, 23 ꢁC, 12 h
SOCl2, pyr, 0 ꢁC, 1 h
No reaction
No reaction
No reaction
45 (38%), 44+46 (25%)
Ac2O, DMAP, Et3N, THF, 23 ꢁC, 20 h 47 (61%)
MsCl, DMAP, pyr, CH2Cl2, 23 ꢁC, 7 d 42 (21%)
H2SO4, CH2Cl2, 23 ꢁC, 16 h
38 (81%)
BF3$Et2O, CH2Cl2, ꢀ78 to 23 ꢁC, 3 h No reaction
ꢁ
˚
TsOH, MS 4 A, PhH, 90 C, 20 h
HF/pyr, KI, 23 ꢁC, 15 min
42 (64%), 38 (24%)
42 (80%), 38 (trace)
procedure to transform the dihydroxy lactone 41 to the oxa-
bicyclic compound 42. We thought it might be possible to
take advantage of the release of the ring strain of the oxa-
bridged ring system as the driving force in a subsequent
elimination step later in the synthesis. It has been reported
that 1,4-cyclohexanediol could be dehydrated to produce
the corresponding oxabicyclic compound under mild acidic
conditions.17 Following this literature protocol, we treated
the dihydroxy lactone 41 with HF/pyridine in the presence
of potassium iodide for a short period of time and obtained
2.3. The synthesis of 6-aryl-4-hydroxy-2-pyrones
The preparation of the 6-aryl-pyrone was carried out using
the procedure reported by Hua18a (Scheme 10). Ethyl aceto-
acetate 53 was treated with lithium diisopropylamide (LDA)
Me
Me
Me
Me
Me
Me
CH2
O
HO
Me
Me
Me
Me
Ha
O
O
O
O
O
O
Hb
O
_
Me Me
O
42
O
B
O
I
II
44
Scheme 8.
O
OH
OTBS
Me
O
HO
HO
Me
OH
Me
OH
Me
Me
Me
a
b
OH
Me Me
49
Me Me
Me Me
43
48
OTBS
Me
OTBS
Me Me
O
O
O
HO
Me Me
OH
OH
Me
OH
OH
c
d
e
OH
OH
OH
Me Me
52
Me Me
Me Me
51
50
Scheme 9. Reagents and conditions: (a) DIBAL, THF, ꢀ78 ꢁC to 23 ꢁC, 6 h, 83%; (b) TBSCl, Et3N, DMAP, CH2Cl2, 84%; (c) TPAP, NMO, CH2Cl2, 95%; (d)
OsO4, pyr, 83%; (e) TBAF, THF, 89%.

3688
M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
OMe
OMe
the corresponding mesylate 60, but only the bicyclic furan
62 in 95% yield (Scheme 11). Alternatively, when we tried
to oxidize the compound 52 to the corresponding aldehyde
61, we again isolated the same unexpected furan 62. The
structure of 62 was confirmed on the basis of spectroscopic
evidence such as the proton NMR spectrum (especially the
olefinic singlet at d 7.08), four olefinic carbons in the carbon
NMR spectrum and the carbonyl stretch in the IR spectrum.
In addition, we realized that this undesired compound 62
was easily formed when a small amount of acid was present
in the deuterated chloroform used in the NMR sample. We
explain the formation of this furan 62 as shown in Scheme 11.
The severe steric interaction among the three axial methyl
groups would promote a retro aldol reaction20 in the presence
of base, namely the alkoxide I would open the bicyclic ring to
afford the ketone enolate II. b-Elimination to give the hy-
droxymethylenone III followed by cyclization would give
the hydroxy dihydrofuran IV, which would rapidly aromatize
via dehydration to generate the highly strained bicyclic furan
62. The formation of 62 under acidic condition could be
explained by a similar acid-promoted mechanism.21 Conse-
quently, the conversion of the highly functionalized tetraol
52 to the advanced intermediate 60 or 61 was unsuccessful.
Thinking that the tertiary hydroxyl group at the ring juncture
of 52 had caused the problems observed during acidic or
basic treatment, we decided to select less functionalized
and more stable AB ring systems as substrates.
O
O
b,c
a
O
O
EtO2C
OEt
53
54
OMe
OMe
OMe
OMe
O
O
O
O
e,f or g
R1
R1
OH
OR2
55 R1 = H
57 R1 = H, R2 = Bn
58 R1 = H, R2 = Me
59 R1 = Br, R2 = Bn
d
56 R1 = Br
Scheme 10. Reagents and conditions: (a) LDA, THF, TMEDA, methyl 3,4-
dimethoxybenzoate, 55%; (b) KOH, MeOH/H2O; (c) TFAA, 72% (two
steps); (d) Br2, AcOH, 95%; (e) BnBr, K2CO3, CH3CN, 90 ꢁC, 48%; (f)
Me2SO4, K2CO3, 83%; (g) BnBr, K2CO3, CH3CN, 90 ꢁC, 78% (from 56).
followed by the addition of methyl 3,4-dimethoxybenzoate
to afford the diketoester 54 in 55% yield. Since the Claisen
condensation of the diketoester 54 required high temperature
at low pressure in the literature,18 milder reaction conditions
were required to synthesize the pyrone 55 on a large scale.
Thus, the hydrolysis of the diketoester 54 afforded the corre-
sponding acid, which was cyclized using trifluoroacetic
anhydride to give the desired pyrone 55 in good yield.19
Although this hydroxy pyrone 55 can be used directly for
coupling reactions, we also prepared several other useful py-
rone derivatives. We brominated the 4-hydroxy-2-pyrone 55
in acetic acid to furnish the 3-bromo-2-pyrone 56 in 95%
yield. Both the pyrone 55 and the 3-bromo-2-pyrone 56
were protected by benzyl and methyl groups to give the
ethers 57–59. However, all attempts to introduce silyl pro-
tecting groups on the C4 hydroxyl group of the pyrones 55
and 56 failed due either to the low reactivity of hydroxy
pyrones or the instability of the products.
2.5. Attempted addition of nucleophilic pyrones to the
AB ring system
We then considered other AB ring systems as substrates for
the coupling reaction with the various pyrones to overcome
the problems associated with tetraol 52. Consequently, we
turned our attention to the strained lactone 47 with the
idea that anionic pyrone nucleophiles would add easily to
the carbonyl group of such a strained lactone to afford the
coupled ketone. Furthermore, we decided to try to utilize
some derivatives of the triol 48, since the lack of the ketone
function would be an effective solution to preventing the
retro aldol reaction since the required b-hydroxy ketone
would not be present. First, the primary alcohol of the triol
48 was selectively oxidized to give the aldehyde 63 in
81% yield (Scheme 12). However, when we attempted to
prepare derivatives of 48 containing good leaving groups
such as tosylate, mesylate or bromide, e.g., 64, only the
2.4. First coupling attempt—unexpected rearrangement
Our initial plan for the connection of a fully functionalized
AB ring system 52 with the pyrones 57–59 involved
transition metal promoted coupling reactions. Thus, it was
necessary to transform the advanced intermediate 52 into
an electrophilic partner, e.g., either a mesylate or an alde-
hyde. However, mesylation of the tetraol 52 did not give
O
R
O
O
Me Me
Me
OH
HO
Me Me
OH
OH
OH
a or b
OH
OH
Me
OH
Me Me
Me Me
52
O
Me Me
60 R = CH2OMs
61 R = CHO
62
not observed
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OH
O
O
O
O
O
OH
O
OH
O
OH
O
HO
HO
HO
HO
OH
II
OH
I
III
IV
Scheme 11. Reagents and conditions: (a) MsCl, DMAP, pyr, 3 h, 23 ꢁC, 95%; (b) TPAP, NMO, CH2Cl2, 23 ꢁC, 74%.

M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
3689
OH
give the rearranged lactone 45, or which undergoes an intra-
molecular Michael reaction to produce the oxatricyclic lac-
tone 42. We also tried chromium mediated reactions23
because it is well known that organochromium species can
tolerate many different functional groups.24 However, the
reactions gave only the novel very strained acetal 67 as the
major product. The structure of this unusual compound was
HO
HO
CHO
Me
Me
OH
Me
Me
TPAP
NMO
81%
OH
Me Me
63
Me Me
48
X
HO
HO
1
Me
O
Me
tentatively assigned by a careful analysis of the H NMR,
MsCl or
TsCl or
base
Me
Me
13C NMR, and IR spectra. In particular, the proton at
5.21 ppm and the carbon at 103.5 ppm indicated that the
compound 67 must be acetal. Therefore, we concluded that
protection of the hydroxyl group at the ring juncture is neces-
sary to prevent the formation of the side products.
SN2'
48
O
Me Me
Me Me
65
:Base
H
64 X = OMs, OTs, Br
Scheme 12.
2.6. Indium catalyzed coupling reactions
oxatricyclic compound 65 was produced as a single product.
Presumably, the first intermediate 64 is formed and cyclizes
to 65 via an SN20-type displacement of the allylic leaving
group with the internal tertiary alkoxide. This process indi-
cates the ease of formation of this oxa-bridged system, pre-
sumably a result of the steric interaction of the A ring methyl
groups. As a result, we were able to investigate the coupling
reactions of nucleophilic pyrones with only the lactone 43
and the aldehyde 63. As illustrated in Table 3, the lithiated
pyrone anions, generated via either treatment of the pyrones
55, 57, or 58 with LDA or butyllithium or metal–halogen ex-
change of the bromo pyrone 59, did not react with the lac-
tone 43 or the aldehyde 63. A Reformatsky-type reaction22
of the bromide 59 using a large excess of zinc also did not
provide the desired product 66. Instead, we obtained previ-
ously isolated compounds such as the lactone 45 or the
oxa-bridged lactone 42 as major products. It appears that
the pyrone anion is not nucleophilic enough to attack the hy-
droxy lactone, but only acts as a base to generate the tertiary
alkoxide, which subsequently attacks the lactone carbonyl to
Since it is clear that a free hydroxyl group at the ring juncture
of an AB ring precursor caused some problems during the
coupling reactions, we speculated that the oxa-bridged com-
pound 42 would be a good substrate since it is a protected
form of the tertiary alcohol, which could be unmasked later
in the synthesis. On the other hand, Lee reported an efficient
synthesis of a 2H-pyran by the indium(II) catalyzed reaction
of 4-hydroxycoumarins with a,b-unsaturated aldehydes.25
In this synthesis, the initial condensation between the alde-
hyde and a 4-hydroxycoumarin provided an oxatriene inter-
mediate, which was subsequently cyclized to afford a pyran.
In order to apply this protocol to our system, the oxa-bridged
compound 42 had to be converted to a compound containing
an aldehyde functionality. Thus, we reduced the oxatricyclic
lactone 42 to the lactol 68 by lithium aluminum hydride at
0 ꢁC in excellent yield (Scheme 13). Then, coupling reaction
of the lactol 68 with the hydroxy pyrone 55 in the presence of
indium trichloride successfully furnished the desired cou-
pled product 70 as a single diastereomer. The structure of
Table 3. Study of pyrone coupling
O
O
Me
Me
OMe
OMe
O
O
Ar
O
X
O
Z
OH
Y
Me
Me
Me Me
HO
43
OR
Me
Me
OR
Me
or
55 X = H R = H
57 X = H, R = Bn
58 X = H, R = Me
59 X = Br, R= Bn
HO
CHO
O
O
Me
Me
Me
OH
Me Me
H
67
66 Y,Z = O or H, OH
OH
Me Me
63
R = H, Me, Bn
Entry
Compd
Conditions
Results
1
2
3
4
5
6
7
8
43
43
43
43
43
63
63
63
63
63
63
3.0 equiv LDA, 1.5 equiv 55, THF, ꢀ78 to 23 ꢁC, 5 h
3.0 equiv n-BuLi, 3.0 equiv 57, THF, ꢀ78 to 0 ꢁC, 1 h
3.0 equiv t-BuLi, 1.5 equiv 59, THF, ꢀ78 to 0 ꢁC, 1.5 h
3.0 equiv n-BuLi, 3.0 equiv 59, THF, ꢀ78 to 0 ꢁC, 1.5 h
10 equiv Zn, 3.0 equiv 59, benzene/THF, 85 ꢁC, 18 h
6.0 equiv t-BuLi, 3.0 equiv 59, THF/HMPA, ꢀ78 to 0 ꢁC, 1 h
3.0 equiv t-BuLi, 1.5 equiv 59, THF, ꢀ78 to 0 ꢁC, 1 h
3.0 equiv n-BuLi, 3.0 equiv 59, THF, ꢀ78 to 0 ꢁC, 1 h
45 (67%)
42 (63%)
No reaction
42a
No reaction
Complex mixtures
Complex mixtures
Complex mixtures
No reaction
67 (39%)
9
10
11
5.0 equiv CrCl2, 1.0 equiv NiCl2, 3.0 equiv 59, DMF, ꢀ60 to 23 ꢁC, 24 h
3.0 equiv CrCl2, 2.0 equiv 59, THF, 23 ꢁC, 18 h
3.0 equiv LDA, 3.0 equiv 58, THF/HMPA, ꢀ78 to 23 ꢁC, 14 h
No reaction
a
The yield was not determined.

3690
M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
the compound 70 was determined by a comparison of the
spectroscopic data with that of the same compound pub-
lished by Hsung et al.26 Unlike the mechanism reported in
the literature, we believe that the formation of the coupled
compound 70 involves the generation of the oxocarbonium
intermediate 69 followed by the addition of the pyrone
nucleophile 55 from the less hindered b-face.
acids.27 We postulate that the acids must preferentially coor-
dinate with the carbonyl group of the pyrone moiety to gen-
erate the stabilized protonated pyrone intermediate and thus
make the pyrone a better leaving group than the strained
ether. Thus, we protected the hydroxyl group of the pyrone
moiety as the methyl ether 71 and carried out reduction of
compound 71 under the same conditions. Unfortunately, it
produced the same compound 74 and the 4-methoxy pyrone
58 with none of the desired alcohol 73.
OH
H
O
O
O
Me
Me
O
Me
In contrast to the lactol 68, in which the C5 oxygen is in the
axial position, we assumed that the b-hydroxy aldehyde 17
with the opposite stereochemistry at C5 would react with
the hydroxy pyrone 55 in the presence of the indium catalyst
to afford the coupled product 75 without any bond formation
between the two groups since they would now be in a trans
orientation. In addition, the PMB protected alcohol 21a
could be a more stable precursor in order to prevent the for-
mation of the ethereal carbon–oxygen bond. Thus, we tested
this idea using the two aldehydes 17 and 21a, which were
synthesized via the first IMDAF approach. The coupling re-
action of the aldehyde 17 with the hydroxy pyrone 55 was
attempted under the same conditions as above, but the reac-
tion did not proceed at all (Scheme 14). The PMB protected
aldehyde 21a was also subjected to the coupling reaction
with the pyrone 55 in the presence of indium(III) chloride,
but only the starting material 21a was recovered. Unlike
the case of the lactol 68, it seems that the activation of the
aldehyde 17 or 21a by indium catalyst did not occur perhaps
due to the steric congestion around the aldehyde moiety.
Thus the formation of an oxocarbonium intermediate such
as 69 seems to be required for this coupling to proceed well.
Me
b
a
O
Me Me
68
Me Me
42
O
H
O
Ar
H
O
O
Me
H
OH
Me
Me
O
Me
O
Me Me
70 Ar = 3,4-(OMe)2C6H3
Me Me
69
Scheme 13. Reagents and conditions: (a) LiAlH4, THF, 0 ꢁC, 100%; (b) 55,
InCl3, CH3CN, THF, 80 ꢁC, 73%.
For further transformation of the compound 70 toward arisu-
gacin A, we needed to cleave the strained carbon–oxygen
bond of compound 70 to provide the corresponding reduced
compound 72. As shown in Table 4, however, only the car-
bon–carbon bond next to the pyrone moiety was cleaved to
give the ether 74 and the simple pyrone 55 when compound
70 was treated with triethylsilane in the presence of several
Table 4. Study of reduction of coupled pyrone substrate
O
H
O
Ar
O
O
O
Ar
H
O
OH
Me
O
Me
H
OR
Me
H
OR
Me
Me
O
Ar
Me
O
O
O
Ar = 3,4-(OMe)2C6H3
Me2SO4, K2CO3
Me Me
74
Me Me
OR
Me Me
70 R = H
55 R = H
72 R = H
58 R = Me
73 R = Me
71 R = Me
not observed
Entry
Substrates
Conditions
Results
1
2
3
4
5
70
70
70
70
71
Et3SiH, TFA, CH2Cl2, 23 ꢁC, 6 h
Et3SiH, TFA, DCE, 60 ꢁC, 44 h
Et3SiH, CF3SO3H, CH2Cl2, 23 ꢁC, 2.5 h
Et3SiH, BF3$Et2O, CH2Cl2, 23 ꢁC, 24 h
Et3SiH, BF3$Et2O, CH2Cl2, 23 ꢁC, 18 h
No reaction
70+55+74a
Decomposed
55+74 (68%)
58+74 (quant)
a
The yield was not determined.
O
O
O
Ar
O
O
Ar
O
O
Ar
RO
CHO
Me
RO
Me Me
O
RO
Me
Me Me
O
5
OH
OH
O
55
a
Me Me
Me Me
75 Ar = 3,4-(OMe)2C6H3
Me Me
76 R = H
77 R = PMB
17 R = H
21a R = PMB
Scheme 14. Reagents and conditions: (a) 55, InCl3, CH3CN, THF, 80 ꢁC.

M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
3691
3. Conclusion
gel (10:1 hexane/ethyl acetate) to provide the reduced com-
pound 14a (430 mg, 87%) as a white solid. 1H NMR (CDCl3,
500 MHz) d: 4.98 (s, 1H), 4.84 (s, 1H), 2.64 (ddd, J¼15.3,
13.2, 6.0 Hz, 1H), 2.40 (ddd, J¼15.2, 4.9, 3.7 Hz, 1H),
2.12 (ddd, J¼13.4, 13.4, 3.5 Hz, 1H), 1.81–1.78 (m, 2H),
1.62–1.56 (m, 3H), 1.43 (s, 3H), 1.36 (s, 3H), 1.15 (s, 3H),
1.12 (s, 3H). 13C NMR (CDCl3, 125 MHz) d: 210.5, 158.6,
103.6, 93.5, 84.6, 62.1, 38.2, 35.9, 35.0, 33.7, 25.9, 25.7,
23.7, 22.9, 18.3. IR (neat): 3082, 2973, 2871, 1716, 1665,
1475, 1450, 1420, 1383, 1324, 1248, 1223, 1180, 1102,
1063, 1031, 1014, 922, 888, 828, 780 cmꢀ1. HRMS (EI)
m/z found for M+ 234.1629, calcd for C15H22O2 234.1620.
We have studied the synthesis of the AB ring system of ari-
sugacin A using two synthetic methodologies. The first
approach was based on an intramolecular Diels–Alder
reaction of furan (IMDAF) and gave the synthetically useful
intermediates 17 and 21a even though we did not open the
oxa-bridged ring to give the hydroxy enals. We then synthe-
sized the highly oxygenated AB ring system using two cru-
cial methods, namely electrocyclization and singlet oxygen
reaction, in 16 steps in 9.3% overall yield starting from
hydroxy b-ionone. Finally, coupled products, such as the
cyclic ether 70, were obtained via an indium catalyzed
reaction; however arisugacin A could not be prepared from
this compound. Synthetic studies of other coupling reactions
between various AB ring systems and pyrone units are
currently underway and will be reported in due course.
4.1.3. ( )-(1R,5R,6S,8R)-2,2,6,8-Tetramethyl-7-methyl-
ene-11-oxatricyclo[6.2.1.01,6]undecan-5-ol (15). To a pre-
formed solution of lithium (30 mg, 4.32 mmol) in
ammonia (3 mL) was added a solution of the ketone 14a
(50 mg, 0.21 mmol) and methanol (8 mL, 0.20 mmol) in di-
ethyl ether (1 mL), and the resulting mixture was allowed to
stir for 5 h at ꢀ33 ꢁC. The mixture was poured into aqueous
ammonium chloride solution (10 mL) and diluted with di-
ethyl ether (10 mL). After extraction with diethyl ether
(3ꢂ10 mL), the combined organic layers were washed
with brine, dried over magnesium sulfate, and concentrated
under reduced pressure. The crude product was purified by
column chromatography on silica gel (4:1 to 1:1 hexane/di-
ethyl ether) to yield the alcohol 15 (32 mg, 64%) along with
4. Experimental section
4.1. General
4.1.1. ( )-(1R,6R,8R)-2,2,6,8-Tetramethyl-7-methylene-
11-oxatricyclo[6.2.1.01,6]-9-undecen-5-one (14). To
a
solution of the allenic ketone 135 (455 mg, 1.96 mmol) in
dichloromethane (20 mL) cooled to ꢀ78 ꢁC was added a so-
lution of dimethylaluminum chloride (2.15 mL, 2.15 mmol,
1.0 M in hexane). After stirring for 30 min, the reaction mix-
ture was allowed to warm to ꢀ20 ꢁC and stirred for an addi-
tional 3 h. The mixture was quenched with saturated sodium
bicarbonate (30 mL), extracted with dichloromethane
(3ꢂ25 mL), washed with brine, dried over magnesium sul-
fate, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica
gel (10:1 hexane/ethyl acetate) to give the oxatricyclic com-
pound 14 (416 mg, 91%) as a solid. 1H NMR (CDCl3,
500 MHz) d: 6.30 (d, J¼5.6 Hz, 1H), 6.19 (d, J¼5.6 Hz,
1H), 5.07 (s, 1H), 4.99 (s, 1H), 2.72 (ddd, J¼15.9, 13.6,
6.1 Hz, 1H), 2.42 (ddd, J¼15.9, 4.7, 3.1 Hz, 1H), 2.08
(ddd, J¼13.6, 13.6, 4.7 Hz, 1H), 1.59 (ddd, J¼13.6, 6.1,
3.1 Hz, 1H), 1.54 (s, 3H), 1.35 (s, 3H), 1.25 (s, 3H), 1.09
(s, 3H). 13C NMR (CDCl3, 125 MHz) d: 210.2, 154.4,
140.0, 133.7, 105.3, 96.8, 86.6, 59.2, 35.1, 34.4, 32.5, 27.1,
25.4, 23.5, 15.6. IR (neat): 3081, 2967, 2931, 2869, 1712,
1476, 1452, 1384, 1370, 1319, 1250, 1201, 1164, 1124,
1083, 1066, 1011, 943, 886, 758 cmꢀ1. HRMS (EI) m/z
found for M+ 232.1459 calcd for C15H20O2 232.1463.
1
the starting material 14a (6 mg, 12%). H NMR (CDCl3,
500 MHz) d: 4.76 (s, 1H), 4.69 (s, 1H), 3.61 (dd, J¼9.1,
6.6 Hz, 1H), 1.80–1.69 (m, 4H), 1.66–1.61 (m, 2H), 1.58–
1.49 (m, 2H), 1.48 (s, 3H), 1.38 (ddd, J¼13.3, 3.4, 3.4 Hz,
1H), 1.16 (s, 3H), 1.02 (s, 3H), 0.97 (s, 3H). 13C NMR
(CDCl3, 125 MHz) d: 165.0, 98.9, 92.6, 85.3, 73.0, 53.3,
38.6, 36.5, 33.8, 27.0, 26.2, 26.1, 24.1, 18.6, 14.6. HRMS
(EI) m/z found for M+ 236.1775, calcd for C15H24O2
236.1776.
4.1.4. ( )-(1R,5R,6S,7R,8R)-7-(Hydroxymethyl)-2,2,6,8-
tetramethyl-11-oxatricyclo[6.2.1.01,6]-5-undecanol (16a)
and ( )-(1R,5R,6S,7S,8R)-7-(hydroxymethyl)-2,2,6,8-
tetramethyl-11-oxatricyclo[6.2.1.01,6]-5-undecanol (16b).
To a solution of the alkene 15 (23 mg, 0.097 mmol) in di-
chloromethane (1 mL) cooled to 0 ꢁC was added borane/
dimethyl sulfide complex (28 mL, 0.30 mmol). The reaction
mixture was allowed to warm to 23 ꢁC and stirred for 3 h.
The solution was again cooled to 0 ꢁC and treated with
15% sodium hydroxide (0.2 mL) and 30% hydrogen per-
oxide (0.2 mL). The reaction mixture was allowed to warm
to 23 ꢁC and stirred for another 24 h. Ammonium chloride
(5 mL) and ethyl acetate (5 mL) were added to the reaction
mixture. The organic layer was separated and the aqueous
layer was extracted with ethyl acetate (3ꢂ5 mL). The com-
bined organic layers were washed with brine, dried over
magnesium sulfate, and concentrated under reduced pres-
sure. The residue was purified by column chromatography
on silica gel (1:1 hexane/ethyl acetate) to give the alcohol
16a (13 mg, 53%) and its epimer 16b (6 mg, 24%). Com-
pound 16a: 1H NMR (CDCl3, 500 MHz) d: 4.12 (dd,
J¼11.0, 4.7 Hz, 1H), 3.87 (dd, J¼11.9, 11.6 Hz, 1H), 3.68
(dd, J¼11.6, 4.2 Hz, 1H), 3.07 (br s, 2H), 1.93 (ddd,
J¼13.2, 9.2, 6.3 Hz, 1H), 1.79–1.69 (m, 4H), 1.65–1.59
(m, 2H), 1.40–1.27 (m, 2H), 1.25 (s, 3H), 1.22 (s, 3H),
0.97 (s, 3H), 0.93 (s, 3H). 13C NMR (CDCl3, 125 MHz)
4.1.2. ( )-(1R,6R,8R)-2,2,6,8-Tetramethyl-7-methylene-
11-oxatricyclo[6.2.1.01,6]-5-undecanone (14a). To a sus-
pension of 14 (0.491 g, 2.11 mmol) and dipotassium azodi-
carboxylate28 (1.642 g, 8.45 mmol) in dichloromethane
(20 mL) cooled to ꢀ78 ꢁC was slowly added a solution of
acetic acid (0.97 mL, 16.0 mmol) in dichloromethane
(2 mL). The reaction mixture was stirred at ꢀ78 ꢁC for 2 h
and then slowly warmed to 23 ꢁC. Stirring was continued un-
til the suspension became white and then the solvent was re-
moved under reduced pressure. The residue was diluted with
ether (30 mL) and the residual potassium acetate was filtered
off through a pad of Celite. The solvent was completely re-
moved under reduced pressure to yield the crude product,
which was purified by column chromatography on silica

3692
M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
d: 92.5, 82.9, 71.6, 61.7, 59.2, 53.0, 41.2, 35.8, 34.1, 27.9,
26.8, 26.5, 24.0, 18.2, 17.9. HRMS (EI) m/z found for M+
254.1897, calcd for C15H26O3 254.1892. Compound 16b:
1H NMR (CDCl3, 500 MHz) d: 3.60 (dd, J¼11.6, 4.3 Hz,
1H), 3.57 (dd, J¼10.2, 10.2 Hz, 1H), 3.53 (dd, J¼10.2,
4.2 Hz, 1H), 2.02 (br s, 2H), 1.81 (ddd, J¼17.8, 9.4, 4.7 Hz,
1H), 1.81–1.78 (m, 1H), 1.74 (ddd, J¼13.6, 13.6, 3.5 Hz,
1H), 1.67 (ddd, J¼12.8, 12.8, 4.8 Hz, 1H), 1.67–1.62 (m,
1H), 1.58 (ddd, J¼12.6, 3.9, 3.9 Hz, 1H), 1.45 (ddd, J¼
12.3, 9.2, 4.8 Hz, 1H), 1.42 (s, 3H), 1.38 (ddd, J¼13.3, 3.4,
3.4 Hz, 1H), 1.29 (ddd, J¼9.5, 4.7, 2.2 Hz, 1H), 1.10 (s, 3H),
1.00 (s, 3H), 0.95 (s, 3H).
16.2. IR (neat): 3075, 2984, 2933, 2868, 2835, 1613, 1514,
1463, 1382, 1302, 1248, 1172, 1086, 1039, 887, 822 cmꢀ1
.
4.1.7. ( )-(1R,5R,6S,7S,8R)-5-[(4-Methoxyphenyl)meth-
oxy]-2,2,6,8-tetramethyl-11-oxatricyclo[6.2.1.01,6]unde-
cane-7-carboxaldehyde (21a) and ( )-(1R,5R,6S,7R,8R)-
5-[(4-methoxyphenyl)methoxy]-2,2,6,8-tetramethyl-11-
oxatricyclo[6.2.1.01,6]undecane-7-carboxaldehyde (21b).
Following the same procedure as that used for the synthesis
of 16ab, the reaction of the alkene 20 (200 mg, 0.56 mmol)
and borane/dimethyl sulfide complex (0.11 mL, 1.16 mmol)
gave a mixture of the corresponding alcohols (52 mg, 25%)
after purification by column chromatography on silica gel
(6:1 hexane/ethyl acetate).
4.1.5. ( )-(1R,5R,6S,7S,8R)-5-Hydroxy-2,2,6,8-tetra-
methyl-11-oxatricyclo[6.2.1.01,6]undecane-7-carboxalde-
hyde (17). To a solution of the alcohol 16a (6.9 mg,
0.027 mmol) in dichloromethane (3 mL) under argon was
added the Dess–Martin periodinane (13 mg, 0.030 mmol).
The suspension was stirred at 23 ꢁC for 1 h, and then a solu-
tion of sodium thiosulfate in saturated sodium bicarbonate
(5 mL) was added. The mixture was stirred vigorously until
the organic layer was clear. The organic layer was separated.
The aqueous layer was extracted with diethyl ether
(3ꢂ10 mL). Both layers were washed with saturated sodium
bicarbonate and brine. The combined organic layer was then
dried over magnesium sulfate and concentrated under re-
duced pressure. The crude product was purified by column
chromatography on silica gel (4:1 to 2:1 hexane/ethyl
Following the same procedure as that used for the synthesis
of 17, the reaction of the mixture of the alcohols (52 mg,
0.14 mmol) and Dess–Martin periodinane (71 mg,
0.17 mmol) gave the aldehyde 21a (30 mg, 58%) and the al-
dehyde 21b (14 mg, 27%) after purification by column chro-
matography on silica gel (10:1 hexane/ethyl acetate).
1
Compound 21a: H NMR (CDCl3, 500 MHz) d: 9.48 (d,
J¼6.1 Hz, 1H), 7.20 (d, J¼8.6 Hz, 2H), 6.85 (d, J¼8.6 Hz,
2H), 4.49 (d, J¼11.0 Hz, 1H), 4.17 (d, J¼11.0 Hz, 1H),
3.96 (dd, J¼11.8, 3.6 Hz, 1H), 3.79 (s, 3H), 2.10 (d,
J¼6.1 Hz, 1H), 1.96 (ddd, J¼12.8, 7.0, 3.5 Hz, 1H), 1.90
(ddd, J¼13.2, 9.2, 6.0 Hz, 1H), 1.78 (ddd, J¼12.6, 12.6,
3.5 Hz, 1H), 1.74 (ddd, J¼13.6, 13.6, 3.5 Hz, 1H), 1.66–1.61
(m, 1H), 1.58–1.53 (m, 1H), 1.48–1.42 (m, 2H), 1.39 (s, 3H),
1.25 (s, 3H), 1.04 (s, 3H), 0.96 (s, 3H). 13C NMR (CDCl3,
125 MHz) d: 203.7, 158.8, 130.3, 128.9, 113.5, 93.2, 84.2,
77.3, 69.0, 68.7, 57.2, 55.1, 41.0, 36.3, 34.2, 26.6, 26.5,
1
acetate) to give the hydroxy aldehyde 17 (5 mg, 72%). H
NMR (CDCl3, 500 MHz) d: 9.72 (d, J¼6.2 Hz, 1H), 4.33
(dd, J¼11.6, 4.2 Hz, 1H), 2.07 (d, J¼6.2 Hz, 1H), 1.90
(ddd, J¼13.2, 9.2, 6.2 Hz, 1H), 1.83–1.77 (m, 2H), 1.73
(ddd, J¼11.7, 2.3, 2.3 Hz, 1H), 1.68–1.62 (m, 1H), 1.61
(ddd, J¼12.6, 7.8, 3.8 Hz, 1H), 1.54 (br s, 1H), 1.44 (ddd,
J¼12.2, 12.2, 6.2 Hz, 1H), 1.40 (ddd, J¼13.1, 3.3, 3.3 Hz,
1H), 1.40 (s, 3H), 1.21 (s, 3H), 1.03 (s, 3H), 0.94 (s, 3H).
13C NMR (CDCl3, 125 MHz) d: 204.5, 93.2, 84.3, 70.1,
69.1, 56.9, 41.0, 36.4, 34.0, 27.5, 26.8, 26.5, 24.2, 18.3, 16.8.
IR (neat): 3450, 2979, 2938, 2871, 1708, 1477, 1460, 1383,
1
24.4, 21.4, 18.3, 18.2. Compound 21b: H NMR (CDCl3,
500 MHz) d: 9.69 (d, J¼2.9 Hz, 1H), 7.23 (d, J¼8.5 Hz,
2H), 6.87 (d, J¼8.5 Hz, 2H), 4.63 (d, J¼11.6 Hz, 1H),
4.30 (d, J¼11.6 Hz, 1H), 3.79 (s, 3H), 3.36 (dd, J¼11.9,
3.7 Hz, 1H), 2.12 (dd, J¼2.9, 2.5 Hz, 1H), 1.97 (ddd,
J¼12.9, 9.2, 4.0 Hz, 1H), 1.86 (ddd, J¼13.0, 9.2, 5.5 Hz,
1H), 1.82 (ddd, J¼12.8, 7.0, 3.5 Hz, 1H), 1.73 (ddd, J¼
12.7, 12.7, 4.0 Hz, 1H), 1.68 (ddd, J¼13.6, 13.6, 3.1 Hz,
1H), 1.54 (dddd, J¼13.0, 13.0, 13.0, 3.0 Hz, 1H), 1.42 (ddd,
J¼13.3, 3.2, 3.2 Hz, 1H), 1.38 (dddd, J¼12.4, 12.4, 5.5,
2.4 Hz, 1H), 1.31 (s, 3H), 1.26 (s, 3H), 1.00 (s, 3H), 0.96
(s, 3H). 13C NMR (CDCl3, 125 MHz) d: 204.2, 159.1, 130.8,
129.2, 113.7, 93.7, 84.9, 84.8, 70.5, 68.9, 55.2, 52.2, 36.5,
34.4, 32.6, 27.2, 26.5, 24.7, 21.9, 21.7, 14.0.
1103, 1046, 1008, 994 cmꢀ1
.
4.1.6. ( )-(1R,5R,6S,8R)-5-((4-Methoxyphenyl)-
methoxy)-2,2,6,8-tetramethyl-7-methylene-11-oxatri-
cyclo[6.2.1.01,6]undecane (20). To a solution of the alcohol
15 (200 mg, 0.85 mmol) in diethyl ether (8 mL) were added
p-methoxybenzyl trichloroacetimidate (478 mg, 1.69 mmol)
and trifluoromethanesulfonic acid (2 mL, 0.02 mmol) at
23 ꢁC. The reaction mixture was stirred for 15 min and
then quenched with aqueous sodium bicarbonate (10 mL).
The mixture was extracted with diethyl ether (3ꢂ15 mL),
and the combined organic layer was washed with brine,
dried over magnesium sulfate, and concentrated under re-
duced pressure. The residue was purified by column chroma-
tography on silica gel (15:1 hexane/diethyl ether) to yield the
PMB ether 20 (267 mg, 89%). 1H NMR (CDCl3, 500 MHz)
d: 7.25 (d, J¼8.8 Hz, 2H), 6.85 (d, J¼8.8 Hz, 2H), 4.87
(s, 1H), 4.71 (s, 1H), 4.49 (d, J¼11.1 Hz, 1H), 4.31 (d,
J¼11.1 Hz, 1H), 3.80 (s, 3H), 3.37 (dd, J¼11.8, 3.7 Hz,
1H), 1.82–1.68 (m, 4H), 1.57–1.49 (m, 3H), 1.48 (s, 3H),
1.37 (ddd, J¼13.2, 13.2, 3.1 Hz, 1H), 1.23 (s, 3H), 1.02 (s,
3H), 0.97 (s, 3H). 13C NMR (CDCl3, 125 MHz) d: 163.8,
158.8, 131.4, 129.0, 113.4, 100.1, 92.7, 85.2, 81.1, 72.0,
55.1, 52.6, 38.3, 36.5, 33.8, 26.8, 26.2, 24.1, 23.5, 18.9,
4.1.8. ( )-(E)-4-[1-(3-[(1,1-Dimethylethyl)dimethylsilyl-
oxy]-2,6,6-trimethyl-1-cyclohexenyl)]-3-buten-2-one
(22a).11 To a solution of the hydroxy ketone 22 (3.403 g,
16.3 mmol) in dimethylformamide (16 mL) at 0 ꢁC were
added imidazole (1.668 g, 24.5 mmol) and tert-butyldi-
methylsilyl chloride (3.694 g, 24.5 mmol). The reaction mix-
ture was stirred for 1.5 h and quenched with aq ammonium
chloride (40 mL). The organic layer was separated and the
aqueous layer was extracted with diethyl ether (3ꢂ50 mL).
The combined organic layers were washed with water and
brine, dried over magnesium sulfate, and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel (15:1 pentane/ethyl acetate) to
give the silyl ether 22a11 (5.162 g, 98%) as an oil. 1H NMR
(CDCl3, 500 MHz) d: 7.19 (d, J¼16.4 Hz, 1H), 6.11 (d,
J¼16.4 Hz, 1H), 4.01 (dd, J¼5.5, 5.5 Hz, 1H), 2.28 (s, 3H),

M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
3693
1.84–1.77 (m, 1H), 1.74 (s, 3H), 1.68–1.62 (m, 2H), 1.42–
1.37 (m, 1H), 1.06 (s, 3H), 1.01 (s, 3H), 0.89 (s, 9H), 0.08 (s,
3H), 0.08 (s, 3H). 13C NMR (CDCl3, 125 MHz) d: 198.4,
143.2, 137.9, 135.7, 132.8, 70.9, 35.4, 34.5, 28.9, 28.4,
28.3, 27.2, 25.8, 18.4, 18.1, ꢀ4.2, ꢀ4.7. IR (neat): 2955,
4.1.11. ( )-(1R,8R,8aR)Ethyl-8-[(1,1-dimethylethyl)di-
methylsilyloxy]-2,5,5,8a-tetramethyl-1,5,6,7,8,8a-hexa-
hydronaphthalene-1-carboxylate (25). Procedure A: The
triene 23 (351 mg, 0.89 mmol) and benzanthrone (309 mg,
1.34 mmol) were dissolved in tetrahydrofuran (30 mL).
The solution was stirred for 5 h under the irradiation of a
medium-pressure mercury lamp (Hanovia model 73A36,
550 W). The solvent was removed under reduced pressure
and the benzanthrone was filtered off through Celite with
the aid of hexane. The solvent was again removed under
reduced pressure to give the isomerized products, which
were dissolved in dimethylformamide (2.5 mL). The reaction
solution was stirred for 3 d at 154–160 ꢁC. After the mixture
was cooled to 23 ꢁC, the solvent was removed under reduced
pressure to give the crude product, which was purified by col-
umn chromatography on silica gel (25:1 to 20:1 hexane/di-
ethyl ether) to yield the cyclized product 25 (197 mg, 56%)
as an oil.
2857, 1695, 1675, 1463, 1360, 1253, 1085, 1050, 837 cmꢀ1
.
4.1.9. ( )-(2E,4E)Ethyl-5-[1-(3-[(1,1-dimethylethyl)di-
methylsilyloxy]-2,6,6-trimethyl-1-cyclohexenyl)]-3-
methyl-2,4-pentadienoate (23a).12 To a suspension of
sodium hydride (3.18 g, 73.0 mmol, 55% in mineral oil) in
diethyl ether (50 mL) cooled to 0 ꢁC was slowly added a so-
lution of triethyl phosphonoacetate (12.6 mL, 63.3 mmol) in
diethyl ether (10 mL). After the reaction mixture was stirred
for 1 h at 0 ꢁC, a solution of the enone 22a (15.13 g,
46.9 mmol) in diethyl ether (10 mL) was added. The reac-
tion was allowed to warm to 23 ꢁC and stirred for 18 h.
The mixture was quenched with aq ammonium chloride, ex-
tracted with diethyl ether, washed with brine, dried over
magnesium sulfate, and concentrated. The crude product
was purified by column chromatography on silica gel
(20:1 to 15:1 hexane/ethyl acetate) to give a 7.2:1 mixture
of the ethyl dienoates 23a12 and 23b (16.66 g, 90%) as an
Procedure B: Procedure A was used, but the crude material
(the isomerized intermediate) was purified by column chro-
matography on silica gel.
1
oil. Compound 23a: H NMR (CDCl3, 500 MHz) d: 6.51
Procedure C: Following procedure A, the crude isomerized
products were prepared. They were stirred for 5 min at
250 ꢁC under microwave heating. The solvent was removed
under reduced pressure and the crude material was purified
by column chromatography on silica gel.
(d, J¼16.1 Hz, 1H), 6.11 (d, J¼16.1 Hz, 1H), 5.75 (br s,
1H), 4.17 (q, J¼7.1 Hz, 2H), 4.02 (dd, J¼5.5, 5.5 Hz, 1H),
2.32 (s, 3H), 1.85–1.75 (m, 1H), 1.72 (s, 3H), 1.69–1.61
(m, 2H), 1.42–1.37 (m, 1H), 1.29 (t, J¼7.1 Hz, 3H), 1.02
(s, 3H), 0.98 (s, 3H), 0.91 (s, 9H), 0.09 (s, 3H), 0.09 (s,
3H). 13C NMR (CDCl3, 125 MHz) d: 167.2, 152.4, 139.5,
137.0, 133.3, 132.6, 118.6, 71.1, 59.6, 35.3, 34.7, 29.2,
28.4 (2C), 25.9, 18.4, 18.2, 14.3, 13.6, ꢀ4.2, ꢀ4.6. IR
(neat): 2956, 2932, 2857, 1714, 1609, 1471, 1463, 1362,
Procedure D: A solution of the triene 23 in dimethylform-
amide was stirred for 10 min at 250 ꢁC under microwave
heating. The solvent was removed under reduced pressure
and the crude material was purified by column chromato-
graphy on silica gel.
1352, 1252, 1234, 1153, 1083, 1048, 836, 773 cmꢀ1
.
4.1.10. ( )-(2E,4E)-5-[1-(3-[(1,1-Dimethylethyl)dime-
thylsilyloxy]-2,6,6-trimethyl-1-cyclohexenyl)]-3-methyl-
2,4-pentadienenitrile (24a).13 To a solution of diethyl
cyanomethylphosphonate (0.75 mL, 4.64 mmol) in tetrahy-
drofuran (30 mL) cooled to ꢀ78 ꢁC was added n-butyl-
lithium (1.92 mL, 2.5 M in pentane). After the mixture
stirred for 20 min, a solution of the enone 22 (1.002 g,
3.11 mmol) in tetrahydrofuran (10 mL) was added and the
resulting solution was allowed to warm to 23 ꢁC. The reac-
tion mixture was stirred for 16 h and quenched with aqueous
ammonium chloride (40 mL). The organic layer was sepa-
rated and the aqueous layer was extracted with diethyl ether
(3ꢂ50 mL). The combined organic layers were washed with
brine, dried over magnesium sulfate, and concentrated. The
crude product was purified by column chromatography on
silica gel (20:1 to 15:1 hexane/ethyl acetate) to yield a
2.0:1 mixture of the trienenitriles 24a13 and 24b (0.935 g,
87%) as an oil. Compound 24a: 1H NMR (CDCl3,
500 MHz) d: 6.51 (d, J¼16.1 Hz, 1H), 6.15 (d, J¼16.1 Hz,
1H), 5.17 (br s, 1H), 4.00 (dd, J¼5.4, 5.4 Hz, 1H), 2.19 (d,
J¼1.1 Hz, 3H), 1.81–1.76 (m, 1H), 1.71 (s, 3H), 1.67–1.61
(m, 2H), 1.41–1.36 (m, 1H), 1.02 (s, 3H), 0.98 (s, 3H),
0.90 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H). 13C NMR (CDCl3,
125 MHz) d: 156.9, 138.8, 135.4, 133.64, 133.57, 96.9,
70.9, 35.2, 34.6, 29.0, 28.4, 28.3, 25.8, 18.4, 18.1, 16.4,
ꢀ4.3, ꢀ4.7 (one low field carbon not observed). IR (neat):
2956, 2857, 2211, 1618, 1586, 1471, 1463, 1389, 1361,
Compound 25: 1H NMR (CDCl3, 500 MHz) d: 5.69 (s, 2H),
4.17–4.11 (m, 1H), 4.01–3.96 (m, 2H), 2.83 (s, 1H), 1.84 (s,
3H), 1.75 (dddd, J¼13.3, 13.0, 11.4, 3.7 Hz, 1H), 1.61
(dddd, J¼13.0, 4.4, 4.0, 3.5 Hz, 1H), 1.49 (ddd, J¼13.6,
13.3, 3.5 Hz, 1H), 1.41 (ddd, J¼13.6, 4.0, 3.7 Hz, 1H),
1.22 (t, J¼7.2 Hz, 3H), 1.13 (s, 3H), 1.11 (s, 6H), 0.89 (s,
9H), 0.04 (s, 3H), 0.00 (s, 3H). 13C NMR (CDCl3,
125 MHz) d: 171.5, 150.0, 128.7, 121.7, 116.8, 74.2, 59.6,
54.6, 43.4, 37.2, 34.5, 32.2, 31.1, 27.9, 25.9, 22.6, 18.0,
17.9, 14.2, ꢀ3.6, ꢀ5.3.
4.1.12. ( )-(1R,8R,8aR)-8-[(1,1-Dimethylethyl)dimethyl-
silyloxy]-2,5,5,8a-tetramethyl-1,5,6,7,8,8a-hexahydro-
naphthalene-1-carbonitrile (26) and ( )-(8S,8aS)-8-[(1,1-
dimethylethyl)dimethylsilyloxy]-2,5,5,8a-tetramethyl-
3,5,6,7,8,8a-hexahydronaphthalene-1-carbonitrile (27).
Following procedure A as used for the synthesis of 25, the
reaction of the triene 24 (935 mg, 2.71 mmol) and benz-
anthrone (934 mg, 4.06 mmol) gave a 3:2 mixture of the
cyclized products 26 and 27 (579 mg, 62%) as an oil. Com-
pound 26: 1H NMR (CDCl3, 500 MHz) d: 5.89 (d, J¼5.8 Hz,
1H), 5.82 (dq, J¼5.8, 1.5 Hz, 1H), 4.10 (dd, J¼11.2, 4.6 Hz,
1H), 2.94 (s, 1H), 1.91 (d, J¼1.5 Hz, 3H), 1.82–1.75
(m, 1H), 1.69 (dddd, J¼13.0, 4.6, 4.0, 4.0 Hz, 1H), 1.61–
1.58 (m, 1H), 1.50–1.47 (m, 1H), 1.15 (s, 3H), 1.10 (s,
3H), 1.03 (s, 3H), 0.91 (s, 9H), 0.17 (s, 3H), 0.13 (s, 3H).
1
Compound 27: H NMR (CDCl3, 500 MHz) d: 5.59 (t, J¼
1351, 1252, 1083, 1049, 1005 cmꢀ1
.
3.7 Hz, 1H), 4.01 (br d, J¼2.1 Hz, 1H), 2.72 (m, 2H), 2.04

3694
M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
(d, J¼14.3, 14.3, 4.0, 1.8 Hz, 1H), 1.98 (s, 3H), 1.78–1.73
(m, 1H), 1.50–1.45 (m, 1H), 1.32 (s, 3H), 1.20 (ddd,
J¼12.8, 3.4, 3.4 Hz, 1H), 1.16 (s, 3H), 1.12 (s, 3H), 0.79
(s, 9H), 0.13 (s, 3H), 0.05 (s, 3H).
50.5, 49.2, 45.3, 41.1, 35.5, 33.9, 27.5, 26.4, 25.8, 25.5,
24.4, 18.2, 18.0, ꢀ3.9, ꢀ4.9. HRMS (EI) m/z found for
(M+H)+ 378.2467, calcd for C21H36NO3Si 378.2464.
4.1.15.2. ( )-(1S,2R,4aR,8R,8aS)-8-[(1,1-Dimethylethyl)-
dimethylsilyloxy]-2,4a-dihydroxy-2,5,5,8a-tetramethyl-
1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid
(32) and ( )-(1S,2R,4aR,8R,8aS)-8-[(1,1-dimethylethyl)-
dimethylsilyloxy]-2-acetyloxy-4a-hydroxy-2,5,5,8a-tetra-
methyl-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carbox-
amide (33). A solution of the endoperoxide 30 (20 mg,
0.053 mmol) in acetic acid (0.2 mL) was cooled in an ice
bath until the acetic acid just began to crystallize. The ice
bath was removed and zinc dust (18 mg, 0.28 mmol) was
added all at once with vigorous stirring. After 1.5 h, the ex-
cess zinc dust was filtered off through a pad of Celite and the
resulting solution was treated with water (5 mL), extracted
with dichloromethane (3ꢂ5 mL), washed with aq sodium bi-
carbonate and brine, and dried over magnesium sulfate. The
solvent was removed under reduced pressure and the result-
ing residue was purified by column chromatography on
silica gel (2:1 to 1:3 hexane/ethyl acetate) to give the
dihydroxy acid 32 (14 mg, 70%) and the acetate 33 (2 mg,
4.1.13. ( )-(1R,3R,8R,8aR)Ethyl-8-[(1,1-dimethylethyl)-
dimethylsilyloxy]-3-hydroperoxy-5,5,8a-trimethyl-2-
methylene-1,2,3,5,6,7,8,8a-octahydronaphthalene-1-
carboxylate (28). To a solution of the dienes 25 (31 mg,
0.079 mmol) in chloroform (3.5 mL) was added methylene
blue (0.3 mg). The reaction mixture was cooled to 0 ꢁC. Oxy-
gen gas was bubbled into the reaction mixture, which was
stirred for 3 h at 0 ꢁC under the irradiation of a high-pressure
sodium lamp (GE Lucalox LU-400/BU, 400 W). The sol-
vent was removed under reduced pressure. The resulting resi-
due was purified by column chromatography on silica gel
(8:1 to 4:1 hexane/ethyl acetate) to give the hydroperoxide
1
28 (17 mg, 51%). H NMR (CDCl3, 500 MHz) d: 7.84 (s,
1H), 5.50 (d, J¼4.3 Hz, 1H), 5.39 (s, 2H), 4.61 (d,
J¼4.3 Hz, 1H), 4.38 (dd, J¼11.3, 4.8 Hz, 1H), 4.09 (q,
J¼7.2 Hz, 1H), 4.08 (q, J¼7.2 Hz, 1H), 3.24 (s, 1H), 1.79
(dddd, J¼13.3, 13.0, 11.3, 3.4 Hz, 1H), 1.63 (dddd,
J¼13.0, 4.8, 3.7, 3.6 Hz, 1H), 1.57 (ddd, J¼13.5, 13.3,
3.6 Hz, 1H), 1.45 (ddd, J¼13.5, 3.7, 3.4 Hz, 1H), 1.24 (t,
J¼7.2 Hz, 1H), 1.15 (s, 3H), 1.11 (s, 3H), 1.06 (s, 3H),
0.89 (s, 9H), 0.03 (s, 3H), ꢀ0.03 (s, 3H). 13C NMR
(CDCl3, 125 MHz) d: 171.1, 159.5, 139.5, 120.5, 114.3,
81.2, 72.6, 60.4, 54.9, 44.5, 37.1, 35.5, 31.3, 31.2, 27.6,
25.8, 23.0, 18.0, 14.1, ꢀ3.8, ꢀ5.3. IR (neat): 3463, 2964,
2932, 2858, 1782, 1730, 1678, 1463, 1395, 1253, 1107,
838 cmꢀ1. HRMS (MALDI) m/z found for (M+Na)+
447.2549, calcd for C23H40O5NaSi 447.2537.
1
9%). Compound 32: H NMR (CDCl3, 500 MHz) d: 5.94
(d, J¼9.8 Hz, 1H), 5.77 (dd, J¼9.8, 1.8 Hz, 1H), 3.67 (dd,
J¼10.9, 4.5 Hz, 1H), 2.65 (d, J¼1.8 Hz, 1H), 1.79–1.72
(m, 2H), 1.56–1.53 (m, 1H), 1.42 (s, 3H), 1.32–1.29 (m,
1H), 1.15 (s, 3H), 1.01 (s, 3H), 0.96 (s, 3H), 0.88 (s, 9H),
0.07 (s, 3H), 0.05 (s, 3H). Compound 33: 1H NMR
(CDCl3, 500 MHz) d: 6.18 (br s, 1H), 5.87 (d, J¼5.7 Hz,
1H), 5.71 (dd, J¼5.7, 1.5 Hz, 1H), 4.92 (br s, 1H), 3.90
(dd, J¼11.3, 4.7 Hz, 1H), 2.84 (br s, 1H), 1.83 (s, 3H),
1.76 (dddd, J¼13.4, 12.7, 11.3, 3.5 Hz, 1H), 1.65 (dddd,
J¼12.7, 4.7, 4.0, 3.8 Hz, 1H), 1.56 (s, 3H), 1.46–1.35 (m,
2H), 1.15 (s, 3H), 1.14 (s, 3H), 0.91 (s, 9H), 0.13 (s, 3H),
0.07 (s, 3H).
4.1.14. ( )-(1R,5R,6R,7R,8R)-5-[(1,1-Dimethylethyl)-
dimethylsilyloxy]-2,2,6,8-tetramethyl-9,10-dioxatri-
cyclo[6.2.2.01,6]dodec-11-ene-7-carbonitrile (30). Following
the same procedure as that used in the synthesis of 28, the
reaction of a mixture of the dienes 26 and 27 (365 mg,
1.05 mmol) in chloroform (6 mL) in the presence of methyl-
ene blue (5 mg) and oxygen at 0 ꢁC for 20 h gave the endo-
peroxide 30 (110 mg, 28%) along with a mixture of 26
and 27 (217 mg, 59%). 1H NMR (CDCl3, 500 MHz) d: 6.58
(d, J¼8.6 Hz, 1H), 6.41 (d, J¼8.6 Hz, 1H), 4.55 (dd,
J¼11.2, 4.5 Hz, 1H), 2.27 (s, 1H), 1.85–1.78 (m, 2H), 1.71–
1.66 (m, 1H), 1.58 (s, 3H), 1.30–1.25 (m, 1H), 1.16 (s, 3H),
1.05 (s, 3H), 0.97 (s, 3H), 0.92 (s, 9H), 0.23 (s, 3H), 0.15
(s, 3H). 13C NMR (CDCl3, 125 MHz) d: 134.0 (2C),
118.3, 84.3, 73.7, 73.2, 47.3, 46.1, 35.4, 33.5, 28.3, 27.0,
26.3, 25.0, 23.6, 20.2, 18.4, ꢀ2.7, ꢀ4.6. IR (neat): 2952,
2931, 2894, 2857, 2240, 1657, 1632, 1463, 1380, 1254,
1125, 1097, 1069 cmꢀ1. HRMS (MALDI) m/z found for
(M+Na)+ 400.2269, calcd for C21H35NO3NaSi 400.2278.
4.1.15.3.
ethyl)dimethylsilyloxy]-2,2,6,8-tetramethyl-9,10-dioxa-
tricyclo[6.2.2.01,6]dodecane-7-carbonitrile (35). To
( )-(1R,5R,6S,7R,8R)-5-[(1,1-Dimethyl-
a
suspension of the endoperoxide 30 (360 mg, 0.95 mmol)
and dipotassium azodicarboxylate (926 mg, 4.77 mmol) in
methanol (10 mL) and tetrahydrofuran (5 mL) cooled to
ꢀ78 ꢁC was slowly added acetic acid (0.56 mL, 9.78 mmol).
The reaction mixture was stirred at ꢀ78 ꢁC for 2 h and then
slowly warmed to 23 ꢁC. Stirring was continued until the
suspension became white and then the solvent was removed
under reduced pressure. The residue was diluted with water
(30 mL) and diethyl ether (30 mL). The organic layer was
separated and the aqueous layer was extracted with diethyl
ether (2ꢂ30 mL). The combined organic layers were washed
with brine and dried over magnesium sulfate. The solvent
was removed under reduced pressure to yield a mixture of
30 and 35. The procedure was repeated five times to give
a 1:20 mixture of 30 and 35 (356 mg, 98%). 1H NMR
(CDCl3, 500 MHz) d: 4.51 (dd, J¼11.5, 4.4 Hz, 1H), 2.52
(s, 1H), 2.13 (ddd, J¼14.2, 11.0, 8.3 Hz, 1H), 2.04–1.93
(m, 2H), 1.72–1.66 (m, 3H), 1.59–1.56 (m, 1H), 1.36 (s,
3H), 1.24 (s, 3H), 1.21 (ddd, J¼13.1, 13.1, 3.6 Hz, 1H),
1.02 (s, 3H), 0.98 (s, 3H), 0.91 (s, 9H), 0.22 (s, 3H), 0.13
(s, 3H). 13C NMR (CDCl3, 125 MHz) d: 118.8, 83.1, 74.8,
74.7, 49.9, 45.1, 36.9, 35.1, 28.6, 27.7, 26.6, 26.2, 25.9,
23.2, 21.5, 21.3, 18.3, ꢀ3.0, ꢀ4.6.
4.1.15. Side products in Scheme 6.
4.1.15.1. ( )-(1R,2S,3R,4S,4aR,8R,8aS)-(2,3:4,4a)Bis-
epoxy-8-[(1,1-dimethylethyl)dimethylsilyloxy]-2,5,5,8a-tet-
ramethyl-decahydronaphthalene-1-carbonitrile (31). H
1
NMR (CDCl3, 500 MHz) d: 4.04 (dd, J¼7.8, 7.8 Hz, 1H),
3.32 (d, J¼2.6 Hz, 1H), 3.23 (d, J¼2.6 Hz, 1H), 2.82 (s,
1H), 1.77–1.72 (m, 2H), 1.61–1.55 (m, 1H), 1.46 (s, 3H),
1.44 (ddd, J¼14.0, 3.4, 3.4 Hz, 1H), 1.19 (s, 3H), 1.12 (s,
3H), 0.89 (s, 9H), 0.75 (s, 3H), 0.18 (s, 3H), 0.12 (s, 3H).
13C NMR (CDCl3, 125 MHz) d: 116.8, 74.0, 67.1, 55.1,

M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
3695
4.1.15.4.
( )-(1R,2R,4aR,8R,8aS)-8-[(1,1-Dimethyl-
mixture.
After
30 min,
triethylamine
(2.15 mL,
ethyl)dimethylsilyloxy]-2,4a-dihydroxy-2,5,5,8a-tetra-
methyldecahydronaphthalene-1-carbonitrile (36). 1H NMR
(CDCl3, 500 MHz) d: 4.49 (dd, J¼8.7, 7.0 Hz, 1H), 2.98 (br
s, 1H), 2.77 (s, 1H), 2.33 (br s, 1H), 2.11–2.04 (m, 1H),
1.89–1.82 (m, 2H), 1.73–1.64 (m, 4H), 1.44 (s, 3H), 1.20
(ddd, J¼13.6, 3.5, 3.5 Hz, 1H), 1.14 (s, 3H), 1.00 (s, 3H),
0.89 (s, 3H), 0.88 (s, 9H), 0.18 (s, 3H), 0.11 (s, 3H). 13C
NMR (CDCl3, 125 MHz) d: 120.4, 77.9, 73.7, 69.3, 52.3,
46.9, 38.0, 34.4, 33.3, 30.3, 28.0, 26.5, 26.3, 25.9, 24.0, 21.6,
18.1, ꢀ3.5, ꢀ4.8. IR (neat): 3446, 2954, 2856, 2240, 1471,
1389, 1252, 1090, 1061, 1029, 836, 776 cmꢀ1. HRMS
(MALDI) m/z found for (M+Na)+ 404.2594, calcd for
C21H39NO3NaSi 404.2591.
15.4 mmol) was added and then the dry ice bath was re-
moved. After the reaction mixture was stirred for another
1 h, it was quenched with aqueous ammonium chloride
(40 mL), extracted with diethyl ether (3ꢂ40 mL), washed
with brine, and dried over magnesium sulfate. The solvent
was removed under reduced pressure. The resulting residue
was purified by column chromatography on silica gel (8:1
hexane/ethyl acetate) to give the ketone 25b6c (829 mg,
1
97%) as an oil. H NMR (CDCl3, 400 MHz) d: 5.68 (dq,
J¼5.7, 1.3 Hz, 1H), 5.65 (d, J¼5.7 Hz, 1H), 4.01 (q,
J¼7.1 Hz, 2H), 3.22 (s, 1H), 2.57–2.54 (m, 2H), 1.92 (d,
J¼1.3 Hz, 3H), 1.87–1.76 (m, 2H), 1.23 (s, 3H), 1.22 (s,
3H), 1.20 (s, 3H), 1.17 (t, J¼7.1 Hz, 3H). 13C NMR
(CDCl3, 100 MHz) d: 214.7, 171.0, 147.4, 129.0, 121.0,
116.4, 60.3, 54.4, 49.1, 35.4, 34.6, 34.4, 30.1, 29.9,
23.6, 23.0, 14.0. IR (neat): 3036, 2969, 2934, 2869, 1728,
1709, 1448, 1366, 1327, 1210, 1181, 1145, 1030, 841,
4.1.15.5.
( )-(1S,2R,4aR,8R,8aS)-8-[(1,1-Dimethyl-
ethyl)dimethylsilyloxy]-2,4a-dihydroxy-2,5,5,8a-tetra-
methyldecahydronaphthalene-1-carboxamide (37). 1H
NMR (CDCl3, 500 MHz) d: 6.36 (br s, 2H), 3.57 (dd,
J¼10.3, 4.7 Hz, 1H), 2.59 (s, 1H), 1.98 (br s, 1H), 1.87–
1.80 (m, 3H), 1.74–1.67 (m, 2H), 1.64–1.58 (m, 1H),
1.52–1.48 (m, 1H), 1.42 (s, 3H), 1.24–1.22 (m, 1H), 1.19
(s, 3H), 0.97 (s, 3H), 0.89 (s, 3H), 0.86 (s, 9H), 0.06 (s,
3H), 0.02 (s, 3H). 13C NMR (CDCl3, 125 MHz) d: 173.9,
94.1, 74.1, 68.3, 61.1, 50.2, 35.6, 35.2, 34.9, 28.0, 26.7,
26.2, 25.7, 24.9, 22.8, 17.9, 15.6, ꢀ3.9, ꢀ5.0. IR (neat):
3271, 2953, 2857, 1682, 1556, 1472, 1392, 1254, 1107,
829 cmꢀ1
.
4.1.18. ( )-(2aR,8aS,8bR)-3,6,6,8b-Tetramethyl-
2a,6,7,8,8a,8b-hexahydro-2H-naphtho(1,8-bc)furan-2-one
(38)6c and ( )-(2S,2aR,8aS,8bR)-3,6,6,8b-tetramethyl-
2a,6,7,8-hexahydro-2H-naphtho(1,8-bc)furan-2-ol (39).6c
To a solution of the ketone 25b (510 mg, 1.85 mmol) in eth-
anol (20 mL) cooled to 0 ꢁC was added sodium borohydride
(349 mg, 9.23 mmol) in portions. The reaction mixture was
stirred for 16 h and the solvent was mostly removed under
reduced pressure. The residue was diluted with diethyl ether
(20 mL) and then aqueous ammonium chloride was added.
The organic layer was separated and the aqueous layer was
extracted with diethyl ether (3ꢂ25 mL). The combined or-
ganic layers were washed with brine, dried over magnesium
sulfate, and concentrated. The resulting residue was purified
by column chromatography on silica gel (5:1 to 2:1 hexane/
ethyl acetate) to give the lactone 386c (290 mg, 68%) and the
lactol 396c (113 mg, 27%). Compound 38: 1H NMR (CDCl3,
500 MHz) d: 5.86 (d, J¼5.8 Hz, 1H), 5.82 (dq, J¼5.7,
1.1 Hz, 1H), 4.41 (dd, J¼2.7, 2.7 Hz, 1H), 2.64 (s, 1H),
2.09–2.03 (m, 2H), 1.98 (d, J¼1.1 Hz, 3H), 1.52 (ddd,
J¼13.6, 13.3, 5.2 Hz, 1H), 1.30 (ddd, J¼13.6, 3.5, 3.5 Hz,
1H), 1.21 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H). 13C NMR
(CDCl3, 125 MHz) d: 176.4, 141.8, 127.6, 120.8, 119.8,
85.0, 56.3, 43.1, 34.5, 33.0, 30.4, 27.9, 22.6, 22.1, 21.4. IR
(neat): 3054, 2963, 2934, 1771, 1453, 1382, 1367, 1251,
1053, 995 cmꢀ1
. HRMS (MALDI) m/z found for
(M+NaꢀH2O)+ 404.2595, calcd for C21H39NO3NaSi
404.2591.
4.1.16. ( )-(1R,8R,8aR)Ethyl-8-hydroxy-2,5,5,8a-tetra-
methyl-1,5,6,7,8,8a-hexahydronaphthalene-1-carboxyl-
ate (25a).6c To a solution of the silyl ether 25 (1.409 g,
3.60 mmol) in acetonitrile (35 mL) was added dropwise
concentrated hydrofluoric acid (1.5 mL, 49%). The reaction
mixture was stirred for 18 h and quenched with aqueous so-
dium bicarbonate (30 mL). The organic layer was separated
and the aqueous layer was extracted with diethyl ether
(3ꢂ50 mL). The combined organic layers were washed
with brine, dried over magnesium sulfate, and concentrated
under reduced pressure. The crude product was purified by
column chromatography on silica gel (3:1 hexane/ethyl
acetate) to give the alcohol 25a6c (859 mg, 86%) as an oil.
1H NMR (CDCl3, 500 MHz) d: 5.74 (s, 2H), 4.19–4.13 (m,
1H), 4.08–4.01 (m, 1H), 3.66 (dd, J¼4.5, 11.3 Hz, 1H),
2.90 (s, 1H), 2.01 (br s, 1H), 1.75 (dddd, J¼13.0, 12.7,
11.3, 4.2 Hz, 1H), 1.75 (s, 3H), 1.69 (dddd, J¼13.0, 4.5,
4.2, 4.1 Hz, 1H), 1.47 (ddd, J¼13.6, 4.2, 4.1 Hz, 1H), 1.39
(ddd, J¼13.6, 12.7, 4.2 Hz, 1H), 1.21 (t, J¼7.1 Hz, 3H),
1.14 (s, 3H), 1.10 (s, 3H), 1.09 (s, 3H). 13C NMR (CDCl3,
125 MHz) d: 172.2, 147.8, 128.3, 121.6, 117.8, 74.1, 60.4,
56.1, 44.3, 37.6, 34.6, 32.5, 31.3, 26.5, 22.6, 18.3, 14.2. IR
(neat): 3493, 3044, 2960, 2938, 2869, 1717, 1464, 1364,
1
1162, 973, 964 cmꢀ1. Compound 39: H NMR (CDCl3,
500 MHz) d: 5.72–5.69 (m, 2H), 5.08 (d, J¼6.3 Hz, 1H),
4.24 (dd, J¼2.6, 2.6 Hz, 1H), 3.63 (br s, 1H), 2.04 (d,
J¼6.3 Hz, 1H), 1.91–1.80 (m, 2H), 1.87 (d, J¼1.0 Hz,
3H), 1.54 (ddd, J¼13.3, 13.3, 4.3 Hz, 1H), 1.26–1.20 (m,
1H), 1.09 (s, 3H), 1.08 (s, 3H), 1.06 (s, 3H).
4.1.19. ( )-(3R,3aS,5aS,8aR,8bS)-3a,5a,6,7,8,8b-Hexahy-
dro-3,8,8,8b-tetramethyl-4H-3,8a-etheno-3H-furo[4,3,2-
de]-1,2-benzodioxin-4-one (40).11 Following the procedure
that was used in the synthesis of 28, the reaction of the
diene 38 (290 mg, 1.25 mmol), methylene blue (5 mg,
0.01 mmol), and oxygen at 0 ꢁC for 6 h gave the endoper-
1239, 1178, 1158, 1132, 1040, 827 cmꢀ1
.
4.1.17. ( )-(1R,8aR)Ethyl-2,5,5,8a-tetramethyl-8-oxo-
1,5,6,7,8,8a-hexahydronaphthalene-1-carboxylate
(25b).6c To a solution of oxalyl chloride (0.54 mL,
6.19 mmol) in dichloromethane (40 mL) cooled to ꢀ78 ꢁC
was added dimethyl sulfoxide (0.88 mL, 12.4 mmol). After
15 min, a solution of the alcohol 25a (859 mg, 3.09 mmol)
in dichloromethane (5 mL) was added to the reaction
1
oxide 4011 (326 mg, 99%) as a solid. H NMR (CDCl3,
500 MHz) d: 6.63 (d, J¼8.6 Hz, 1H), 6.39 (d, J¼8.6 Hz,
1H), 4.32 (dd, J¼6.2, 6.2 Hz, 1H), 2.13 (s, 1H), 2.09–2.02
(m, 2H), 1.68 (ddd, J¼13.6, 8.8, 4.2 Hz, 1H), 1.62 (s, 3H),
1.27 (ddd, J¼13.6, 8.7, 4.2 Hz, 1H), 1.17 (s, 3H), 1.14 (s,

3696
M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
3H), 0.96 (s, 3H). 13C NMR (CDCl3, 125 MHz) d: 174.2,
136.7, 131.9, 83.8, 81.7, 74.3, 54.0, 46.6, 34.4, 30.4,
27.6, 26.3, 26.0, 22.8, 18.4. IR (neat): 3054, 2936, 2875,
1770, 1466, 1370, 1269, 1206, 1179, 1036, 1005, 951,
4.1.22. Side products in Table 2.
4.1.22.1. ( )-(1R,5S,6S,7R)-5-Hydroxy-2,2,6-trimethyl-
8-methylene-11-oxatricyclo[5.3.2.01,6]dodecan-12-one (44).
1H NMR (CDCl3, 500 MHz) d: 4.89 (br d, J¼1.6 Hz, 1H),
4.86 (br d, J¼1.6 Hz, 1H), 3.69 (dd, J¼2.7, 2.7 Hz, 1H),
3.04 (s, 1H), 2.67 (m, 1H), 2.38–2.34 (m, 2H), 2.14 (ddd, J¼
14.5, 14.4, 3.2 Hz, 1H), 2.03–1.99 (m, 1H), 1.97 (dddd, J¼
14.5, 14.4, 3.1, 2.9 Hz, 1H), 1.91–1.75 (m, 1H), 1.68 (ddd,
J¼14.5, 5.6, 3.2 Hz, 1H), 1.12 (ddd, J¼13.8, 3.3, 3.3 Hz,
1H), 1.09 (s, 3H), 1.00 (s, 3H), 0.96 (s, 3H). 13C NMR
(CDCl3, 125 MHz) d: 177.4, 140.0, 112.4, 92.2, 73.2, 59.4,
48.3, 35.3, 29.8, 27.1, 26.4, 25.7, 25.5, 24.0, 20.1. IR (neat):
3434, 2969, 2945, 1755, 1652, 1459, 1384, 1365, 1287,
1253, 1180, 1030, 944 cmꢀ1. HRMS (MALDI) m/z found
for (M+Na)+ 273.1461, calcd for C15H22O3Na 273.1461.
903 cmꢀ1
.
4.1.20. ( )-(2aS,3R,5aR,8aS,8bR)-3,5a-Dihydroxy-
3,6,6,8b-tetramethyldecahydronaphtho-[1,8-bc]furan-
2-one (41). Following the procedure that was used in the
synthesis of 35, the reaction of the endoperoxide 40 (317 mg,
1.20 mmol), dipotassium azodicarboxylate (1.165 g,
6.00 mmol), and acetic acid in dichloromethane with only
one repetition gave the crude 40a, which was used directly
1
in the next step. H NMR (CDCl3, 500 MHz) d: 4.28 (dd,
J¼4.3, 3.0 Hz, 1H), 2.34 (s, 1H), 2.14 (ddd, J¼13.2, 9.1,
8.9 Hz, 1H), 2.04 (dddd, J¼15.4, 7.2, 4.1, 4.1 Hz, 1H),
1.94–1.97 (m, 3H), 1.81 (ddd, J¼13.3, 4.2, 4.0 Hz, 1H),
1.74 (ddd, J¼13.6, 10.4, 8.8 Hz, 1H), 1.46 (s, 3H), 1.35 (s,
3H), 1.02 (ddd, J¼13.6, 4.2, 3.9 Hz, 1H), 1.003 (s, 3H),
0.997 (s, 3H). 13C NMR (CDCl3, 125 MHz) d: 175.0, 82.5,
82.4, 75.7, 56.5, 42.7, 35.5, 30.3, 29.2, 25.9, 25.2, 24.0,
21.1 (2C), 20.1. IR (neat): 2937, 1770, 1455, 1370, 1266,
1180, 1027, 997 cmꢀ1. To a suspension of the crude 40a
and zinc dust (756 mg, 11.6 mmol) in dichloromethane
(25 mL) at 0 ꢁC was added acetic acid (0.17 mL,
2.97 mmol). After 2.5 h, excess zinc was filtered off through
a pad of Celite. The resulting solution was washed with so-
dium bicarbonate and water, dried over magnesium sulfate,
and concentrated. The recrystallization (hexane/dichloro-
methane) gave the dihydroxy lactone 41 (310 mg, 96% two
4.1.22.2. ( )-(2aS,3S,5aR,8aS,8bS)-3,5a-Dihydroxy-
3,6,6,8b-tetramethyldecahydronaphtho[1,8-bc]furan-2-
1
one (45). H NMR (CDCl3, 500 MHz) d: 4.25 (dd, J¼5.5,
5.5 Hz, 1H), 2.54 (s, 1H), 2.44 (dddd, J¼9.7, 9.5, 7.2, 7.1 Hz,
1H), 2.34 (dd, J¼15.4, 9.7 Hz, 1H), 2.21–2.15 (m, 2H), 2.06–
1.99 (m, 2H), 1.93 (ddd, J¼14.1, 14.0, 4.0 Hz, 1H), 1.72 (s,
3H), 1.58 (br s, 1H), 1.33 (s, 3H), 1.26 (br s, 1H), 1.23
(ddd, J¼14.1, 7.6, 4.4 Hz, 1H), 1.10 (s, 3H), 1.07 (s, 3H).
13C NMR (CDCl3, 125 MHz) d: 172.8, 89.6, 81.7, 77.3,
60.5, 44.4, 36.9, 32.7, 30.7, 30.0, 26.3, 24.9, 24.6, 23.2, 21.9.
4.1.22.3. ( )-(1R,5S,6S,7R)-5-Hydroxy-2,2,6,8-tetra-
methyl-11-oxatricyclo[5.3.2.01,6]dodec-8-en-12-one (46).
1H NMR (CDCl3, 500 MHz) d: 5.43 (m, 1H), 3.75 (m,
1H), 2.68 (br s, 1H), 2.38–2.37 (m, 2H), 2.12–2.09 (m,
1H), 2.04–1.96 (m, 2H), 1.85 (s, 3H), 1.67 (dddd, J¼11.6,
2.9, 2.9, 2.9 Hz, 1H), 1.13 (ddd, J¼14.1, 3.4, 3.4 Hz, 1H),
1.09 (s, 3H), 1.04 (s, 3H), 1.03 (s, 3H). 13C NMR (CDCl3,
125 MHz) d: 176.0, 131.8, 120.5, 90.3, 72.5, 54.7, 45.2,
35.1, 30.7, 29.6, 26.4, 25.5, 24.3, 22.9, 18.3. IR (neat):
3437, 2932, 1748, 1459, 1383, 1261, 1204, 1175, 1056,
1012, 960 cmꢀ1. HRMS (MALDI) m/z found for (M+Na)+
273.1461, calcd for C15H22O3Na 273.1461.
1
steps) as a solid. H NMR (CDCl3, 500 MHz) d: 4.67 (br
s, 1H), 4.33 (br s, 1H), 4.27 (dd, J¼5.3, 3.3 Hz, 1H), 2.33
(s, 1H), 2.16–2.11 (m, 1H), 2.05–1.93 (m, 4H), 1.74–1.65
(m, 2H), 1.47 (s, 3H), 1.27 (s, 3H), 1.08 (ddd, J¼13.3, 4.3,
3.6 Hz, 1H), 0.98 (s, 3H), 0.95 (s, 3H). 13C NMR (CDCl3,
125 MHz) d: 178.5, 83.5, 75.3, 68.5, 59.8, 45.6, 35.4, 33.6,
32.2, 30.4, 26.1, 25.6, 24.8, 23.9, 21.5. HRMS (MALDI)
m/z found for (M+Na)+ 291.1561, calcd for C15H24O4Na
291.1567.
4.1.21. ( )-(2R,2aS,4aS,7aR,7bS)Hexahydro-2,7,7,7b-
tetramethyl-3H-3,7a-ethano-3H-furo[4,3,2-cd]-1-benzo-
furan-3-one (42). The dihydroxy lactone 41 (250 mg,
0.92 mmol) was added to a stirred solution of HF$pyridine
(2.5 mL) containing potassium iodide (309 mg, 1.86 mmol)
in a polyethylene bottle. The reaction mixture was stirred at
23 ꢁC for 15 min, quenched by pouring onto ice water, and
extracted with diethyl ether (3ꢂ25 mL). The ether extract
was washed with aqueous sodium thiosulfate, dried over
magnesium sulfate, and poured through a short column of
alumina. The solvent was removed under reduced pressure
and the residue was purified by column chromatography
on silica gel (4:1 hexane/ethyl acetate) to give the oxa-
4.1.22.4. ( )-(1R,5S,6S,7R,8R)-5-Acetyloxy-8-hydroxy-
2,2,6,8-tetramethyl-11-oxatricyclo[5.3.2.01,6]dodecan-12-
1
one (47). H NMR (CDCl3, 500 MHz) d: 4.84 (dd, J¼2.9,
2.9 Hz, 1H), 2.88 (br s, 1H), 2.13 (m, 1H), 2.06 (s, 3H),
2.05–1.95 (m, 3H), 1.82 (ddd, J¼14.6, 12.3, 6.0 Hz, 1H),
1.70–1.59 (m, 3H), 1.46 (s, 3H), 1.34 (s, 3H), 1.15 (ddd,
J¼12.3, 5.2, 2.8 Hz, 1H), 1.10 (s, 3H), 0.96 (s, 3H). 13C
NMR (CDCl3, 125 MHz) d: 177.6, 170.6, 91.3, 73.5, 69.4,
59.8, 47.0, 36.4, 34.9, 30.3, 27.9, 26.4, 24.5, 22.8, 22.2,
21.1, 20.9. IR (neat): 3366, 2949, 2877, 1748, 1457, 1243,
1177, 1134, 1021, 1004 cmꢀ1. HRMS (MALDI) m/z found
for (M+Na)+ 333.1673, calcd for C17H26O5Na 333.1672.
1
bridged compound 42 (187 mg, 80%). H NMR (CDCl3,
4.1.23. ( )-(5aR,8aS,8bS)-5a-Hydroxy-3,6,6,8b-tetra-
methyl-4,5,5a,6,7,8,8a,8b-octahydronaphtho[1,8-
bc]furan-2-one (43). To a solution of diisopropylamine
(0.17 mL, 1.21 mmol) in tetrahydrofuran (10 mL) cooled
to ꢀ78 ꢁC was added n-butyllithium (0.50 mL, 2.5 M in
hexane). After the mixture stirred for 30 min, a solution of
the oxabridged compound 42 (207 mg, 0.83 mmol) was
added to the LDA solution at ꢀ78 ꢁC. After the reaction
mixture was stirred for 1 h, it was quenched with aqueous
ammonium chloride and warmed up to 23 ꢁC. The organic
500 MHz) d: 4.29–4.27 (m, 1H), 2.33 (s, 1H), 2.02–1.98
(m, 1H), 1.99–1.87 (m, 2H), 1.84–1.76 (m, 2H), 1.72–1.63
(m, 2H), 1.53 (s, 3H), 1.36 (s, 3H), 1.27–1.10 (m, 1H),
1.06 (s, 3H), 0.98 (s, 3H). 13C NMR (CDCl3, 125 MHz) d:
175.9, 92.3, 85.1, 84.0, 63.8, 47.3, 36.4, 33.2, 30.6, 27.6,
26.0, 24.4, 24.1, 22.8, 18.5. IR (neat): 2936, 1760, 1478,
1456, 1385, 1366, 1269, 1214, 1188, 1093, 1021,
967 cmꢀ1. HRMS (MALDI) m/z found for (M+Na)+
273.1470, calcd for C15H22O3Na 273.1461.

M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
3697
layer was separated and the aqueous layer was extracted with
diethyl ether (3ꢂ25 mL). The combined organic layers were
washed with brine, dried over magnesium sulfate, and con-
centrated under reduced pressure. The residue was purified
by column chromatography on silica gel (1:1 hexane/ethyl
acetate) to yield the hydroxy lactone 43 (164 mg, 79%)
and the rearranged lactone 44 (36 mg, 17%). 1H NMR
(CDCl3, 500 MHz) d: 4.26 (dd, J¼10.9, 7.3 Hz, 1H), 2.53
(dddd, J¼20.1, 10.0, 1.2, 1.2 Hz, 1H), 2.33–2.26 (m, 2H),
2.23 (s, 3H), 2.04 (ddd, J¼14.6, 10.0, 5.3 Hz, 1H), 1.93–
1.88 (m, 1H), 1.64–1.59 (m, 2H), 1.35 (ddd, J¼14.6, 1.1,
1.1 Hz, 1H), 1.32 (br s, 1H), 1.21 (s, 3H), 1.08 (s, 3H),
1.06 (s, 3H). 13C NMR (CDCl3, 125 MHz) d: 169.0, 150.7,
127.7, 84.8, 77.2, 44.9, 35.7, 34.7, 29.6, 28.8, 27.5 (2C),
26.4, 24.4, 18.3. IR (neat): 3489, 2977, 2936, 2871, 1714,
1663, 1467, 1448, 1368, 1350, 1312, 1271, 1206, 1150,
1055, 1020, 993 cmꢀ1. HRMS (MALDI) m/z found for
(M+Na)+ 273.1460, calcd for C15H22O3Na 273.1461.
1.72–1.64 (m, 2H), 1.69 (s, 3H), 1.05 (br ddd, J¼13.7, 3.4,
3.4 Hz, 1H), 1.01 (s, 3H), 0.99 (s, 6H), 0.89 (s, 9H), 0.13
(s, 3H), 0.12 (s, 3H). 13C NMR (CDCl3, 125 MHz) d:
136.4, 132.3, 76.3, 73.2, 58.6, 45.8, 38.3, 30.4, 29.9, 28.0,
25.7, 25.1, 24.55, 24.51, 23.3, 19.3, 18.1, ꢀ5.5, ꢀ5.7. IR
(neat): 3420, 2956, 2931, 2890, 2859, 1471, 1461, 1420,
1388, 1253, 1018, 996, 983, 837, 778 cmꢀ1. HRMS
(MALDI) m/z found for (M+Na)+ 391.2647, calcd for
C21H40O3SiNa 391.2639.
4.1.26. ( )-(4aR,8aR)-4a-Hydroxy-8-[(1,1-dimethyl-
ethyl)dimethylsilyloxymethyl]-4,4,7,8a-tetramethyl-
3,4,4a,5,6,8a-hexahydro-2H-naphthalen-1-one (50). The
dihydroxy TBS ether 49 (35 mg, 0.10 mmol) was dissolved
in dichloromethane (0.8 mL) including N-methylmorpho-
˚
line N-oxide (NMO, 17 mg, 0.15 mmol) and 4 A molecular
sieves (15 mg). Tetrapropylammonium perruthenate (TPAP,
2 mg, 0.006 mmol) was added to the reaction mixture and it
was stirred for 2.5 h at 23 ꢁC. The solvent was removed in
vacuo and then flash column chromatography on silica gel
(8:1 hexane/ethyl acetate) was performed to afford the
hydroxy ketone 50 as a white solid (33 mg, 95%). Mp
4.1.24. ( )-(1S,4aR,8aS)-8-Hydroxymethyl-4,4,7,8a-
tetramethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalene-1,4a-
diol (48). To a solution of the hydroxy ketone 43 (98 mg,
0.39 mmol) in tetrahydrofuran (3 mL) cooled to ꢀ78 ꢁC
was slowly added diisobutylaluminum hydride (DIBAL,
1.96 mL, 1.0 M in tetrahydrofuran). The reaction mixture
was slowly warmed up to 0 ꢁC for 6 h and then quenched
with aqueous potassium sodium tartrate. The resulting solu-
tion was vigorously stirred until it became clear. The organic
layer was separated and the aqueous layer was extracted with
ethyl acetate (3ꢂ15 mL). The combined organic layers were
washed with brine, dried over magnesium sulfate, and con-
centrated. The residue was purified by column chromato-
graphy on silica gel (2:1 hexane/ethyl acetate) to give the
triol 48 (83 mg, 83%) as a solid. The spectroscopic data of
48 were identical with those reported in the literature.4b 1H
NMR (CDCl3, 500 MHz) d: 4.67 (br s, 3H), 4.33 (d, J¼
12.2 Hz, 1H), 4.06 (m, 1H), 3.97 (d, J¼12.2 Hz, 1H), 2.18
(ddd, J¼18.7, 9.3, 9.3 Hz, 1H), 2.06–1.92 (m, 3H), 1.77–
1.63 (m, 3H), 1.76 (s, 3H), 1.10–1.07 (m, 1H), 1.01 (s, 3H),
0.99 (s, 3H), 0.97 (s, 3H). 13C NMR (CDCl3, 125 MHz) d:
134.6, 134.5, 77.9, 73.2, 57.2, 46.0, 38.1, 30.2, 28.7, 27.7,
25.5, 25.0, 24.5, 23.3, 19.2. IR (neat): 3385, 2946, 1476,
1
108–109 ꢁC. H NMR (CDCl3, 500 MHz) d: 4.44 (d, J¼
12.4 Hz, 1H), 3.99 (d, J¼12.4 Hz, 1H), 2.94 (ddd, J¼14.9,
14.9, 8.9 Hz, 1H), 2.23–2.10 (m, 4H), 2.04 (dd, J¼17.9,
7.2 Hz, 1H), 1.88 (ddd, J¼13.4, 13.4, 6.8 Hz, 1H), 1.71 (s,
3H), 1.70–1.60 (m, 2H), 1.54 (s, 3H), 1.20 (s, 3H), 1.01 (s,
3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H). 13C NMR
(CDCl3, 125 MHz) d: 214.7, 133.9, 133.7, 80.8, 61.4, 60.7,
38.8, 37.8, 35.8, 28.4, 26.8, 25.9, 24.9, 23.4, 23.3, 20.1,
18.2, ꢀ5.5, ꢀ5.6. IR (neat): 3674, 3527, 3393, 3053, 2958,
2706, 2306, 1704, 1661, 1471, 1254, 973, 847, 773,
679 cmꢀ1. HRMS (MALDI) m/z found for (M+Na)+
389.2481, calcd for C21H38O3SiNa 389.2482.
4.1.27. ( )-(4aR,7R,8S,8aS)-8-[(1,1-Dimethylethyl)di-
methylsilyloxymethyl]-4a,7,8-trihydroxy-4,4,7,8a-tetra-
methyloctahydronaphthalen-1-one (51). Osmium tetroxide
(33 mg, 0.082 mmol) was added to the solution of the hy-
droxy ketone 50 (34 mg, 0.13 mmol) in pyridine (0.5 mL)
at 23 ꢁC. The solution was stirred for 18 h and quenched
with saturated sodium bisulfite (1.5 mL). The mixture was
stirred for an additional 2.5 h and extracted with ethyl ace-
tate (5ꢂ10 mL). The combined organic layers were washed
with saturated sodium chloride, dried over magnesium sul-
fate, and concentrated under vacuum. The resulting residue
was purified by column chromatography on silica gel (4:1
hexane/ethyl acetate) to give the triol 51 (30 mg, 83%) as
1457, 1384, 1305, 1138, 1086, 1012, 993, 919 cmꢀ1
.
4.1.25. ( )-(1S,4aR,8aS)-8-[(1,1-Dimethylethyl)dimethyl-
silyloxymethyl]-4,4,7,8a-tetramethyl-1,2,3,4,4a,5,6,8a-
octahydronaphthalene-1,4a-diol (49). To the solution of
the triol 48 (52 mg, 0.20 mmol) in dichloromethane (1 mL)
were added triethylamine (0.11 mL, 0.79 mmol), 4-(di-
methylamino)pyridine (2 mg, 0.016 mmol) and tert-butyldi-
methylsilyl chloride (68 mg, 0.45 mmol) at 23 ꢁC. The
solution was stirred for 20 h and quenched with saturated
aq ammonium chloride. The mixture was extracted with di-
chloromethane (3ꢂ10 mL), washed with saturated sodium
chloride (15 mL), dried over magnesium sulfate, and con-
centrated under vacuum. The residue was purified by flash
column chromatography (10:1 hexane/ethyl acetate) to give
the dihydroxy TBS ether 49 as a white solid (63 mg, 84%).
Mp 98–99 ꢁC. 1H NMR (CDCl3, 500 MHz) d: 5.61 (m, 1H),
5.23 (m, 1H), 4.37 (d, J¼11.2 Hz, 1H), 4.07 (d, J¼
11.2 Hz, 1H), 4.01 (m, 1H), 2.33 (ddd, J¼18.0, 9.6, 9.6 Hz,
1H), 2.07 (ddd, J¼14.1, 14.1, 4.1 Hz, 1H), 1.97 (m, 1H),
1.89 (dd, J¼18.0, 6.3 Hz, 1H), 1.75 (dm, J¼14.0 Hz, 1H),
a
white solid. Mp 134–137 ꢁC. 1H NMR (CDCl3,
500 MHz) d: 4.30 (s, 1H), 4.18 (s, 1H), 3.77 (d, J¼
11.0 Hz, 1H), 3.70 (d, J¼11.0 Hz, 1H), 2.90 (ddd, J¼16.3,
9.7, 9.0 Hz, 1H), 2.74 (m, 1H), 2.32 (ddd, J¼16.3, 4.5,
4.5 Hz, 1H), 2.10 (ddd, J¼13.8, 13.8, 4.7 Hz, 1H), 1.89
(ddm, J¼14.5, 14.5 Hz, 1H), 1.79 (m, 2H), 1.67 (ddd,
J¼14.5, 4.3, 2.3 Hz, 1H), 1.57 (s, 3H), 1.36 (ddd, J¼13.8,
4.3, 2.3 Hz, 1H), 1.18 (s, 3H), 1.11 (s, 3H), 1.08 (s, 3H),
0.89 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H). 13C NMR (CDCl3,
125 MHz) d: 219.6, 78.5, 77.3, 74.3, 67.3, 60.4, 37.3, 37.1,
35.4, 31.2, 28.0, 27.9, 25.8, 25.5, 24.5, 21.1, 18.2, ꢀ5.8,
ꢀ6.0. IR (neat): 3470, 3383, 2956, 2930, 2858, 1686, 1472,
1408, 1372, 1326, 1256, 1072, 1054, 840, 781 cmꢀ1
.
HRMS (MALDI) m/z found for (M+Na)+ 423.2539, calcd
for C21H40O5SiNa 423.2537.

3698
M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
4.1.28. ( )-(2aR,3R,5aR,8aR,8bS)-3,6,6,8b-Tetramethyl-
decahydronaphtho[1,8-bc]furan-2a,3,5a,8a-tetraol (52).
A solution of tetrabutylammonium fluoride (0.22 mL,
1.0 M in THF) was added to the solution of the triol 51
(30 mg, 0.07 mmol) in THF (0.5 mL) at 23 ꢁC. The reaction
mixture was stirred for 30 min and diluted with ethyl acetate
(10 mL). The solution was washed with saturated aq ammo-
nium chloride (5 mL) and the organic layer was set aside.
The aqueous layer was extracted with dichloromethane
(2ꢂ5 mL). The combined organic layers were dried over
magnesium sulfate, concentrated under vacuum, and the res-
idue was purified by column chromatography on silica gel
(1:1 hexane/ethyl acetate) to afford the tetraol 52 (19 mg,
combined organic layer was washed with brine, dried over
magnesium sulfate, and concentrated under reduced pres-
sure to give the crude acid 54a18a (173 mg, 97%), which
was used directly in the next step without further purifica-
1
tion. H NMR (CDCl3, 500 MHz) d: 9.95 (br s, 1H), 7.51
(d, J¼8.4 Hz, 1H), 7.42 (s, 1H), 6.90 (d, J¼8.4 Hz, 1H),
3.94 (s, 3H), 3.93 (s, 3H), 3.91 (s, 2H), 3.52 (s, 2H). 13C
NMR (CDCl3, 125 MHz) d: 183.3, 153.3, 149.0, 126.4,
121.6, 110.5, 109.6, 104.6, 96.1, 56.3, 56.04, 55.98, 44.4.
4.1.31. 6-(3,4-Dimethoxyphenyl)-4-hydroxy-2-pyrone
(55).18 To a suspension of the crude acid 54a (173 mg,
0.65 mmol) in diethyl ether (3 mL) was added trifluoroacetic
anhydride (0.14 mL, 0.99 mmol) at 23 ꢁC. After stirring for
1.5 h, the reaction mixture was filtered to collect the crude
yellow solids, which were washed with diethyl ether and dried
under vacuum to give the pyrone 55 (120 mg, 72%, two steps
from 54). The spectroscopic data of 55 were consistent with
those reported in the literature.15 1H NMR (DMSO,
500 MHz) d: 11.75 (br s, 1H), 7.40 (dd, J¼8.5, 1.9 Hz, 1H),
7.31 (d, J¼1.9 Hz, 1H), 7.04 (d, J¼8.5 Hz, 1H), 6.68 (d,
J¼1.7 Hz, 1H), 5.30 (d, J¼1.7 Hz, 1H), 3.80 (s, 3H), 3.78 (s,
3H). 13C NMR (DMSO, 125 MHz) d: 171.2, 163.5, 160.6,
151.5, 149.2, 123.8, 119.2, 112.0, 108.8, 97.4, 89.0, 55.98, 55.96.
1
89%) as a white solid. Mp 127–129 ꢁC. H NMR (CDCl3,
500 MHz) d: 4.37 (m, 1H), 4.20 (dd, J¼9.2, 1.3 Hz, 1H),
4.16 (m, 1H), 3.94 (d, J¼9.2 Hz, 1H), 3.48 (d, J¼2.8 Hz,
1H), 2.27 (ddd, J¼13.2, 13.2, 4.8 Hz, 1H), 2.03–1.87 (m,
4H), 1.64–1.57 (m, 2H), 1.48–1.44 (m, 2H), 1.32 (s, 3H),
1.21 (s, 3H), 1.09 (s, 3H), 0.97 (s, 3H). 13C NMR (CDCl3,
125 MHz) d: 108.7, 84.7, 77.1, 76.6, 72.2, 53.6, 38.0, 33.9,
32.9, 29.5, 27.5, 25.7, 27.3, 22.3, 15.4. IR (KBr): 3451,
3368, 2981, 2963, 1455, 1372, 1221, 1044, 996, 650 cmꢀ1
.
4.1.29. Ethyl-5-(3,4-dimethoxyphenyl)-3,5-dioxopenta-
noate (54).18a To a solution of diisopropylamine (LDA,
8.90 mL, 63.5 mmol) in tetrahydrofuran (THF, 100 mL)
cooled to ꢀ20 ꢁC was added n-butyllithium (49.1 mL,
1.1 M in hexane). The solution was stirred for 45 min. In
a separate flask, freshly distilled ethyl acetoacetate 53
(3.33 g, 25.6 mmol) and THF (50 mL) were added and the
resulting solution was cooled to ꢀ78 ꢁC. To this solution
was added the solution of LDA via cannula followed by
the addition of tetramethylethylenediamine (TMEDA,
3.84 mL, 25.4 mmol), and the solution was stirred at 0 ꢁC
for 3 h. To this dianion solution was added a solution of
methyl 3,4-dimethoxybenzoate (5.01 g, 25.5 mmol) in
THF (15 mL) and then the reaction mixture was warmed
to 23 ꢁC. After stirring for 48 h, the reaction mixture was
treated with acetic acid and stirred for an additional
10 min. HCl (1 N, 200 mL) was added to the reaction mix-
ture, which was extracted with diethyl ether (3ꢂ200 mL).
The organic layer was washed with brine, dried over magne-
sium sulfate, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel
(3:1 to 1:1 hexane/ethyl acetate) to give the diketo acid 54
(4.10 g, 55%) as an oil. The spectroscopic data of 54 were
consistent with those reported in the literature.18a 1H NMR
(CDCl3, 500 MHz) d: 7.44–7.41 (m, 1H), 7.36–7.35 (m,
1H), 6.83–6.80 (m, 1H), 6.18–6.17 (m, 1H), 4.17–4.11 (m,
2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.38–3.37 (m, 2H), 1.24–
1.17 (m, 3H). 13C NMR (CDCl3, 125 MHz) d: 186.1,
183.8, 167.5, 152.8, 148.8, 126.8, 121.2, 110.3, 109.3,
95.7, 61.2, 55.8, 55.7, 44.9, 13.9.
4.1.32. 6-(3,4-Dimethoxyphenyl)-4-phenylmethoxy-2-
pyrone (57). To a suspension of the pyrone 55 (100 mg,
0.40 mmol) in acetonitrile (5 mL) were added anhydrous
potassium carbonate (167 mg, 1.21 mmol) and benzyl bro-
mide (0.14 mL, 1.18 mmol) at 23 ꢁC. The reaction mixture
was refluxed at 85 ꢁC for 6 h and quenched with ammonium
chloride. The mixture was extracted with dichloromethane
(3ꢂ15 mL), washed with brine, dried over magnesium sul-
fate, and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel (3:2
hexane/ethyl acetate) to give the benzyloxy pyrone 57
(65 mg, 48%) as a yellow solid. 1H NMR (CDCl3,
500 MHz) d: 7.41–7.36 (m, 6H), 7.27 (d, J¼1.9 Hz, 1H),
6.87 (d, J¼8.5 Hz, 1H), 6.38 (d, J¼2.0 Hz, 1H), 5.56 (d, J¼
2.0 Hz, 1H), 5.03 (s, 2H), 3.90 (s, 3H), 3.89 (s, 3H). 13C
NMR (CDCl3, 125 MHz) d: 170.3, 164.2, 160.2, 151.3,
149.0, 134.3, 128.72, 128.70, 127.8, 123.7, 119.0, 110.9,
108.2, 96.7, 88.6, 70.7, 55.93, 55.88.
4.1.33. 6-(3,4-Dimethoxyphenyl)-4-methoxy-2-pyrone
(58).29
A suspension of the pyrone 55 (100 mg,
0.40 mmol), dimethyl sulfate (0.19 mL, 2.00 mmol), and po-
tassium carbonate (278 mg, 2.01 mmol) in acetone (4 mL)
was stirred at 23 ꢁC for 1 h. Water (2 mL) was added, and
the resulting solution was stirred at 23 ꢁC for 24 h. After
addition of aqueous ammonium chloride, the mixture was
extracted with ethyl acetate (3ꢂ10 mL). The organic layers
were washed with water and brine, dried over magnesium
sulfate, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica
gel (1:1 hexane/ethyl acetate) to give the known 4-methoxy
pyrone 5829 (88 mg, 83%) as a pale yellow solid. 1H NMR
(CDCl3, 500 MHz) d: 7.39 (dd, J¼8.5, 2.0 Hz, 1H), 7.30
(d, J¼2.0 Hz, 1H), 6.90 (d, J¼8.5 Hz, 1H), 6.33 (d, J¼
2.0 Hz, 1H), 5.50 (d, J¼2.0 Hz, 1H), 3.94 (s, 3H), 3.92 (s,
3H), 3.85 (s, 3H). 13C NMR (CDCl3, 125 MHz) d: 171.5,
164.4, 160.2, 151.4, 149.1, 123.8, 119.1, 111.0, 108.4,
96.7, 87.7, 56.1, 55.99, 55.96.
4.1.30. 5-(3,4-Dimethoxyphenyl)-3,5-dioxopentanoic acid
(54a).18a To a solution of potassium hydroxide (188 mg,
3.35 mmol) in ethanol (7.5 mL) and water (1.5 mL) was
added the diketoester 54 (197 mg, 0.67 mmol) at 23 ꢁC. Af-
ter the mixture was stirred for 15 h, about 80% of the solvent
was removed by heating under reduced pressure. The residue
was diluted with ethyl acetate and quenched with 1 N HCl
(10 mL). The organic layer was separated and the aqueous
layer was extracted with ethyl acetate (3ꢂ15 mL). The

M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
3699
4.1.34. 3-Bromo-6-(3,4-dimethoxyphenyl)-4-phenyl-
methoxy-2-pyrone (59). To a solution of the pyrone 55
(100 mg, 0.40 mmol) in acetic acid (0.4 mL) was added
dropwise bromine (23 mL, 0.45 mmol) at 23 ꢁC. After stir-
ring for 1 h, the reaction mixture was diluted with ice water
(2 mL) and the precipitated solid was filtered, washed with
water, and dried under vacuum. The crude bromo pyrone
56 (125 mg, 95%) was used directly in the next step without
pressure, and the residue was purified by column chromato-
graphy on silica gel (1:1 hexane/ethyl acetate) to give the al-
dehyde 63 (12 mg, 81%) as an oil. The proton NMR data
seem to indicate that this compound exists as the lactol
1
63a. H NMR (CDCl3, 500 MHz) d: 6.39 (s, 1H), 5.38 (m,
1H), 5.09 (m, 1H), 3.96 (br s, 1H), 2.44 (m, 1H), 2.26–
1.43 (m, 6H), 1.73 (br s, 3H), 1.13 (s, 3H), 1.05 (m, 1H),
0.96 (s, 6H).
1
further purification. H NMR (DMSO, 500 MHz) d: 7.35
(dd, J¼8.5, 2.0 Hz, 1H), 7.23 (d, J¼2.0 Hz, 1H), 7.06 (d,
J¼8.5 Hz, 1H), 6.66 (s, 1H), 3.80 (s, 3H), 3.79 (s, 3H).
13C NMR (DMSO, 125 MHz) d: 167.2, 160.1, 158.7,
151.8, 149.3, 123.0, 119.3, 112.2, 108.7, 96.6, 85.9, 56.0,
55.9. To a suspension of the bromo pyrone 56 (15 mg,
0.046 mmol) in acetonitrile (1 mL) were added anhydrous
potassium carbonate (19 mg, 0.14 mmol) and benzyl bro-
mide (15 mL, 0.13 mmol) at 23 ꢁC. The reaction mixture
was refluxed at 90 ꢁC for 24 h and quenched with ammo-
nium chloride. The mixture was extracted with dichloro-
methane (3ꢂ8 mL), washed with brine, dried over
magnesium sulfate, and concentrated under reduced pres-
sure. The residue was purified by column chromatography
on silica gel (2:1 to 1:1 hexane/ethyl acetate) to give the ben-
zyloxy pyrone 59 (15 mg, 78%) as a yellow solid. 1H NMR
(CDCl3, 500 MHz) d: 7.46–7.38 (m, 5H), 7.34 (dd, J¼8.4,
2.0 Hz, 1H), 7.25 (d, J¼2.0 Hz, 1H), 6.90 (d, J¼8.4 Hz,
1H), 6.53 (s, 1H), 5.36 (s, 2H), 3.93 (s, 3H), 3.92 (s, 3H).
13C NMR (CDCl3, 125 MHz) d: 166.4, 160.4, 160.3,
152.0, 149.3, 134.7, 129.0, 128.8, 126.9, 123.3, 119.4,
111.1, 108.6, 92.2, 89.7, 71.8, 56.2, 56.1.
4.1.37. ( )-(1R,5S,6R,8R)-2,2,6,8-Tetramethyl-7-methyl-
ene-11-oxatricyclo[6.2.1.01,6]-5-undecanol (65). To
solution of the known triol 48 (5 mg, 0.020 mmol) in
dichloromethane (0.3 mL) was added triethylamine (8 mL,
a
0.057 mmol),
4-(dimethylamino)pyridine
(0.3 mg,
0.002 mmol), and p-toluenesulfonyl chloride (6 mg,
0.031 mmol). The reaction mixture was stirred for 2 h and
the solvent was removed under reduced pressure. The residue
was purified by column chromatography on silica gel (5:1
1
hexane/ethyl acetate) to give alcohol 65 (2 mg, 43%). H
NMR (CDCl3, 500 MHz) d: 4.94 (s, 1H), 4.73 (s, 1H), 3.70
(br s, 1H), 3.45 (m, 1H), 1.99 (ddd, J¼14.1, 14.1, 3.5 Hz,
1H), 1.89 (dddd, J¼14.4, 14.4, 3.0, 3.0 Hz, 1H), 1.79 (ddd,
J¼12.6, 11.0, 5.2 Hz, 1H), 1.71 (ddd, J¼14.3, 6.5, 3.0 Hz,
1H), 1.68 (ddd, J¼12.7, 9.2, 5.4 Hz, 1H), 1.62–1.54 (m,
2H), 1.49 (s, 3H), 1.20 (s, 3H), 1.20–1.18 (m, 1H), 1.06 (s,
3H), 0.99 (s, 3H). 13C NMR (CDCl3, 125 MHz) d: 162.8,
100.2, 93.1, 85.9, 75.6, 51.8, 38.2, 33.5, 30.7, 26.8, 26.3,
25.5, 24.4, 22.2, 17.7. IR (neat): 3503, 3072, 2935, 2866,
1668, 1475, 1410, 1382, 1292, 1201, 1161, 1085, 1057,
1018, 975, 953, 921 cmꢀ1. HRMS (EI) m/z found for M+
236.1782, calcd for C15H24O2 236.1776.
4.1.35. ( )-(R)-2-Hydroxy-2,6,6,12-tetramethyl-10-oxa-
bicyclo[7.2.1]dodeca-1(11),9(12)-dien-5-one (62). To the
solution of the tetraol 52 (12 mg, 0.04 mmol) in pyridine
(0.2 mL) cooled to 0 ꢁC were added 4-(dimethylamino)pyr-
idine (DMAP, 0.5 mg, 0.004 mmol) and methanesulfonyl
chloride (5 mL, 0.06 mmol). After the solution had stirred
for 2.5 h, it was diluted with dichloromethane (0.5 mL)
and poured into aqueous ammonium chloride (1 mL). The
mixture was extracted with dichloromethane (3ꢂ5 mL)
and ethyl acetate (5 mL). The combined organic layers
were dried over magnesium sulfate and concentrated. Flash
column chromatography (2:1 hexane/ethyl acetate) afforded
the furan 62 (10 mg, 95%). 1H NMR (CDCl3, 500 MHz) d:
7.08 (s, 1H), 2.95 (m, 1H), 2.64 (ddd, J¼13.0, 13.0,
4.2 Hz, 1H), 2.53 (ddd, J¼13.2, 13.2, 4.1 Hz, 1H), 2.29 (s,
3H), 2.18 (dd, J¼12.2, 12.2 Hz, 1H), 1.62–1.57 (m, 3H),
1.59 (s, 3H), 1.43 (ddd, J¼13.1, 4.1, 1.8 Hz, 1H), 1.26 (s,
3H), 0.89 (s, 3H). 13C NMR (CDCl3, 125 MHz) d: 205.7,
153.8, 138.9, 127.5, 118.7, 73.5, 45.8, 45.4, 41.9, 32.0,
31.1, 28.9, 22.3, 21.6, 15.2. IR (neat): 3462, 2960, 2926,
1678, 1612, 1542, 1458, 1411, 1363, 1327, 1240, 1106,
1040, 893, 731 cmꢀ1. HRMS (EI) m/z found for M+
250.1560, calcd for C15H22O3 250.1569.
4.1.38. ( )-(1R,2R,4S,8S,12S)-7,7,11,12-Tetramethyl-
3,13-dioxatetracyclo[6.3.1.12,8.04,12]tridec-10-ene (67).
To a mixture of the aldehyde 63 (11 mg, 0.044 mmol) and
chromium(II) chloride (16 mg, 0.13 mmol) in THF
(0.5 mL) was added a solution of the bromo pyrone 59
(36 mg, 0.086 mmol) in THF (0.5 mL) at 23 ꢁC. The reac-
tion mixture was stirred for 18 h and then quenched with
cold water (5 mL). The organic layer was separated and
the aqueous layer was extracted with diethyl ether
(3ꢂ5 mL). The combined organic layers were washed with
brine, dried over magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by column chro-
matography on silica gel (4:1 hexane/ethyl acetate) to afford
the acetal 67 (4 mg, 39%) as a side product. 1H NMR
(CDCl3, 500 MHz) d: 5.38 (m, 1H), 5.21 (s, 1H), 3.96 (m,
1H), 2.21 (ddd, J¼18.1, 2.2, 2.2 Hz, 1H), 2.12 (ddd,
J¼13.5, 13.5, 4.5 Hz, 1H), 2.10–2.05 (m, 1H), 2.06 (s,
1H), 1.82 (ddd, J¼14.5, 6.5, 4.0 Hz, 1H), 1.76–1.70 (m,
1H), 1.74 (d, J¼0.9 Hz, 3H), 1.13 (s, 3H), 1.40 (ddd,
J¼13.5, 4.3, 2.5 Hz, 1H), 0.96 (s, 6H). 13C NMR (CDCl3,
125 MHz) d: 130.0, 120.2, 103.5, 84.5, 80.3, 59.4, 44.3,
34.8, 31.0, 29.8, 26.4, 23.3, 22.2, 22.1, 13.5. IR (neat):
2962, 2923, 2876, 1451, 1381, 1270, 1175, 1066, 1041,
4.1.36. ( )-(4aR,8S,8aS)-4a,8-Dihydroxy-2,5,5,8a-tetra-
methyl-3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carb-
oxaldehyde (63).4b To a solution of the triol 48 (15 mg,
0.059 mmol) and N-methylmorpholine N-oxide (NMO,
8 mg, 0.068 mmol) in dichloromethane (0.5 mL) was
added tetrapropylammonium perruthenate (TPAP, 1 mg,
0.003 mmol) at 23 ꢁC. After the reaction mixture was stir-
red for 30 min, the solvent was removed under reduced
1026, 987, 927, 850 cmꢀ1
.
4.1.39. ( )-(2R,2aS,3S,4aS,7aR,7bS)-3-[Hexahydro-
2,7,7,7b-tetramethyl-3H-2,7a-ethano-3H-furo[4,3,2-dc]-
1-benzo-3-furanyl]-6-(3,4-dimethoxyphenyl)-4-hydroxy-
2-pyrone (70). To a solution of the lactone 42 (20 mg,
0.080 mmol) in THF (0.5 mL) cooled to 0 ꢁC was added lith-
ium aluminum hydride (12 mg, 0.32 mmol). After the

3700
M. E. Jung, S.-J. Min / Tetrahedron 63 (2007) 3682–3701
reaction mixture was stirred for 1 h, it was quenched with
one drop of water and one drop of 15% sodium hydroxide
solution. Magnesium sulfate was added and the mixture
was stirred for additional 10 min. Filtration and concentra-
tion gave the crude product, which was dried in vacuum to
give the lactol 68 (20 mg, 100%). The product 68 was
reduced pressure to give the crude residue, which was puri-
fied by column chromatography on silica gel (1:1 hexane/
ethyl acetate) to afford the reduced oxatetracyclic compound
1
74 (1 mg, 68%) and the pyrone 55 (1 mg, 65%). H NMR
(CDCl3, 500 MHz) d: 4.08 (dd, J¼10.0, 1.0 Hz, 1H), 3.57
(dd, J¼10.0, 7.1 Hz, 1H), 3.56 (dd, J¼3.0, 3.0 Hz, 1H),
1.96 (ddd, J¼13.8, 13.8, 3.8 Hz, 1H), 1.90 (ddd, J¼14.9,
6.5, 2.8 Hz, 1H), 1.84–1.76 (m, 3H), 1.71 (ddd, J¼12.2,
12.0, 6.2 Hz, 1H), 1.61 (ddd, J¼12.0, 8.8, 6.1 Hz, 1H),
1.55 (ddd, J¼14.9, 14.5, 3.5 Hz, 1H), 1.38 (s, 3H), 1.29 (s,
3H), 1.05 (ddd, J¼13.1, 3.8, 3.5 Hz, 1H), 1.04 (s, 3H),
0.95 (s, 3H).
1
used in the next step without further purification. H NMR
(CDCl3, 500 MHz) d: 5.44 (s, 1H), 4.19 (dd, J¼3.0,
3.0 Hz, 1H), 2.45 (br s, 1H), 1.95–1.91 (m, 1H), 1.93 (s,
1H), 1.86–1.83 (m, 2H), 1.80–1.63 (m, 3H), 1.55 (ddd,
J¼12.0, 12.0, 3.3 Hz, 1H), 1.44 (s, 3H), 1.36 (s, 3H), 1.05
(ddd, J¼13.5, 3.5, 3.5 Hz, 1H), 1.04 (s, 3H), 0.95 (s, 3H).
13C NMR (CDCl3, 125 MHz) d: 99.2, 90.9, 82.5, 82.1,
70.0, 50.5, 36.9, 33.6, 30.7, 27.5, 26.4, 23.7, 23.4, 22.1,
19.3. IR (neat): 3228, 2947, 2870, 1460, 1379, 1345, 1138,
1088, 1070, 995, 953, 919 cmꢀ1. To a solution of the lactol
68 (18 mg, 0.071 mmol) and the pyrone 55 (18 mg,
0.072 mmol) in acetonitrile (0.8 mL) and THF (0.2 mL)
was added indium(III) chloride (8 mg, 0.036 mmol) at
23 ꢁC. The reaction mixture was stirred for 4 h at 85 ꢁC
and then cooled to 23 ꢁC. The solvent was removed under re-
duced pressure to give the crude product, which was purified
by column chromatography on silica gel (1:1 hexane/ethyl
acetate) to yield the coupled product 70 (25 mg, 73%).
The spectroscopic data of 70 were consistent with those
reported in the literature.23 1H NMR (CDCl3, 500 MHz)
d: 11.06 (s, 1H), 7.37 (dd, J¼8.5, 2.1 Hz, 1H), 7.29 (d,
J¼2.1 Hz, 1H), 6.91 (d, J¼8.5 Hz, 1H), 6.29 (br s, 1H),
5.37 (d, J¼2.4 Hz, 1H), 3.99 (dd, J¼2.9, 2.9 Hz, 1H), 3.92
(s, 6H), 2.60 (d, J¼2.4 Hz, 1H), 2.04–1.98 (m, 1H), 1.90–
1.87 (m, 2H), 1.80–1.71 (m, 3H), 1.66–1.61 (m, 1H), 1.61
(s, 3H), 1.28 (s, 3H), 1.08 (s, 3H), 0.97 (s, 3H). 13C NMR
(CDCl3, 125 MHz) d: 167.1, 162.9, 159.4, 151.3, 149.1,
123.9, 118.8, 111.0, 108.1, 99.7, 97.3, 90.4, 85.6, 84.6,
80.6, 67.9, 56.01, 56.00, 51.0, 36.3, 33.7, 30.6, 27.9, 26.5,
24.7, 23.9, 22.5, 19.6.
Acknowledgements
We thank the National Science Foundation (CHE 0314591
and CHE 0614591) for generous support of this work.
Supplementary data
A general experimental section, the proton and carbon NMR
spectra, and some infrared spectra for all new compounds
and the ORTEP drawing and the CIF file for the X-ray
crystal structure of compound 30. Supplementary data asso-
ciated with this article can be found in the online version, at
doi:10.1016/j.tet.2007.02.085.
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