First total syntheses of bicyclic marine sesquiterpenoids drechslerines A and B

Article abstract of DOI:10.1016/j.tet.2011.04.007

The first total syntheses of the bicyclic sesquiterpenoids drechslerines A (1) and B (2), which were isolated from the algicolous fungus Drechslera dematioidea in the marine red alga Liagora viscida, has been accomplished starting from (S)-carvone (13) via three palladium-catalyzed reactions, namely, diastereoselective allylation, conjugate reduction, and carbon monoxide insertion, as the key reactions.

Full text of DOI:10.1016/j.tet.2011.04.007

Tetrahedron 67 (2011) 4061e4068
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First total syntheses of bicyclic marine sesquiterpenoids drechslerines A and B
,
a
a
b
b
Hisahiro Hagiwara a , Masakazu Fukushima , Kimihiko Kinugawa , Takuya Matsui , Takashi Hoshi ,
*
Toshio Suzuki b
a Graduate School of Science and Technology, Niigata University, 8050, 2-Nocho, Ikarashi, Nishi-ku, Niigata 950-2181, Japan
b Faculty of Engineering, Niigata University, 8050, 2-Nocho, Ikarashi, Nishi-ku, Niigata 950-2181, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total syntheses of the bicyclic sesquiterpenoids drechslerines A (1) and B (2), which were iso-
lated from the algicolous fungus Drechslera dematioidea in the marine red alga Liagora viscida, has been
accomplished starting from (S)-carvone (13) via three palladium-catalyzed reactions, namely, diaster-
eoselective allylation, conjugate reduction, and carbon monoxide insertion, as the key reactions.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 22 March 2011
Received in revised form 30 March 2011
Accepted 5 April 2011
Available online 9 April 2011
Keywords:
Bicyclic alicyclic compounds
Diastereoselective allylation
Carbon monoxide insertion
Sesquiterpenoid
Drechslerine
1. Introduction
2. Results and discussions
Marine organisms produce a large number of structurally in-
teresting and biologically unique natural products.1 Several poly-
cyclic sesquiterpenoids were recently isolated from the algicolous
fungus Drechslera dematioidea of leaf mold of the red algae Liagora
viscida.2 Among them were nor-sesquiterpenoids drechslerines A
(1) and C (3), and sesquiterpenoids drechslerines B (2), D (4), E (5), F
(6), and G (7). These compounds have the same carbon framework
as helminthosporal (8) isolated from the terrestrial fungus, having
a unique bicyclo[3.2.1]octane framework with an isopropyl group
in common. However, the absolute stereochemistries of drech-
slerines have not been fully discussed.2 Synthetic studies of ses-
quiterpenoids with the bicyclo[3.2.1]octane core have already been
conducted: first, in the total synthesis of helminthosporal (8)3 by
Corey and Nozoe in 1965,3a and subsequently by other groups in the
total synthesis of sativene (9),4 which has an antipodal core of
helminthosporal (8). Since then, synthetic studies in this area have
been interrupted over two decades because new natural products
have not been isolated. In the course of our synthetic study of
bridged carbocyclic compounds,4f,5 we re-visited the synthesis of
the functionalized bicyclo[3.2.1]octane core and describe here the
first total syntheses of drechslerines A (1) and B (2), thereby
establishing their absolute stereochemistries.
2.1. Synthesis of common intermediate 10
The retrosynthetic plan is outlined in Scheme 1. Enol triflate 10
was envisaged as an advanced common intermediate in the syn-
theses of drechslerines A (1) and B (2) by palladium-catalyzed
conjugate reduction, and carbon monoxide insertion, respectively,
which could be derived from bicyclic keto alcohol 11 via Wittig
olefination. The keto alcohol 11 in turn could be obtained by regio-
and diastereo-controlled allylation of optically active (S)-carvone
(13), followed by an intramolecular aldol reaction. Carvone (13) is
a classic but still useful chiral building block in the total synthesis of
natural products.
The (S)-enantiomer of carvone (13) was chosen as the starting
material. Reduction of the enone moietyof 13 with zinc inpotassium
hydroxide solution6 and subsequent reduction of the isopropenyl
group with platinum under hydrogen atmosphere led to tetrahy-
drocarvone (14) in 75% overall yield, although laborious workup to
remove zinc circumvented large-scale preparation. On the other
hand, hydrogenation of 13 with palladium on carbon resulted in
partialisomerization tocarvacrolalong with partialepimerization of
the isopropyl group, which was identified later by (S)-MTPA ester 23
(Fig. 2). These features made the hydrogenation protocols less at-
tractive. Fortunately, the hydrogenationissuewas solved bycatalytic
medium-pressure hydrogenation with rhodium on alumina to af-
ford a diastereomeric mixture of tetrahydrocarvone (14) in 96%
* Corresponding author. E-mail address: hagiwara@gs.niigata-u.ac.jp(H. Hagiwara).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.007

4062
H. Hagiwara et al. / Tetrahedron 67 (2011) 4061e4068
OH
O
O
O
O
H
a)
b)
6
2
OH
H-
OH
1
2
14
13
Pd(0)
CO
OTMS
O
O
c) or d)
CO2Me
+
TfO
15
12
16
OMe
10
O
OH
5
H
Ph2P
N
17
6
O
O
O
11
12
O
O
e)
f)
+
Pd(0)
O
O
18
19
13
OMe
H
OH
Scheme 1. Synthetic plan of drechslerines A (1) and B (2).
O
O
MeO
+
+
O
OH
O
O
OH
11
20
21
OH
OH
Scheme 2. Reagents and conditions: (a) H2 (4 MPa), Rh/Al2O3 (0.1 mol %), EtOH, rt,
3.5 h, 96%. (b) TMSCl, NaI, Et3N, MeCN, rt, 4 h, 99%. (c) MeLi, DME, ꢀ40 ꢁC then ally-
liodide, THF, ꢀ50 ꢁC, 22 h, 97% (12/16¼3.4:1). (d) TBAT, Pd2(dba)3, 17, THF, allyl car-
bonate, 78%, (12/16¼55:1). (e) O3, CH2Cl2, then Et3N, ꢀ78 ꢁC, 3 h, quant. (f) KOH, EtOH,
50 ꢁC, 13 h, 80%, recrystallization.
1
2
H
O
O
O
O
OH
HO
HO
3
4
flexibility and the lack of steric constraints in a monocyclic ring. In
the total synthesis of helminthosporal (8) by Corey and Nozoe,3a the
stereoselectivity in the introduction of the side chain at C-2 of the
tetrahydrocarvone derivative was 60% de. Although Mori et al. in
their synthesis of (þ)-sorokinianin already reported the synthesis
of the 5-hydroxy isomer of 11 by allylation at C-6 of tetrahy-
drocarvone (14) followed by ozonolysis and intramolecular aldol
reaction, an undesired diastereomer also appeared in 26% yield,
even under thermodynamically forced reaction conditions.7 On the
basis of these results, we anticipated that the allyl group could be
initially introduced to the thermodynamically stable enolate of
tetrahydrocarvone 14 from the same side of the isopropyl group by
kinetically controlled axial alkylation. Then, thermodynamically
stable tetrasubstituted silylenol ether 15 was prepared quantita-
tively by treatment with chlorotrimethylsilane in the presence of
sodium iodide and triethylamine. Silylenol ether 15 was cleaved
with methyllithium in dimethoxymethane (DME) at ꢀ40 ꢁC to give
the regioselective enolate. After fine tuning a variety of reaction
conditions, the chemical yield and diastereoselectivity of allylation
was optimized when allyliodide was employed and the reaction
mixture was allowed to stand at ꢀ50 ꢁC for 22 h. Fortunately, the
desired 2S-isomer 12 predominated in 78% de as an inseparable
mixture with 2R-isomer 16, in which the ratio of diastereomers was
estimated by the tertiary methyl peaks in NMR. The stereochem-
istry of the major 2S-isomer 12 was determined by NOE measure-
ment of silyl ether 22 after several subsequent transformations
(Fig. 2). A reversal of diastereoselectivity was observed when
hexamethylphosphoric triamide was added. Allylation proceeded
very slowly in diethyl ether.
O
HO
O
HO
O
5
6
OH
CHO
O
O
O
7
8
9
Fig. 1. Drechslerines A (1) and B (2) and their congeners.
6.3%
9.5%
OTBDMS
O—(S)-MTPA
H
H
H
H
O
O
22
23
Fig. 2. Determination of the relative stereochemistry and enantiomeric excess of the
intramolecular aldol product 11.
yield. Moreover, the catalyst could be re-used without loss of cata-
lytic activity (Scheme 2).
The control of regio- and diastereoselectivity in the alkylation of
a monocyclic carbonyl compound is not an easy task due to
The issue regarding diastereoselective allylation was solved via
palladium-catalyzed diastereoselective Tsuji allylation developed
by Behenna and Stoltz.8 In the presence of a catalytic amount of

H. Hagiwara et al. / Tetrahedron 67 (2011) 4061e4068
4063
bispalladium tris(benzylidene)acetone Pd2(dba)3, chiral ligand (S)-
tert-ButylPHOX 17, and tetrabutylammonium difluorotriphenyl-
silicate (TBAT), allylation of the silylenol ether 15 with allyl
carbonate proceeded under mild reaction conditions to give 2R-
isomer 12 and 2S-isomer 16 in 78% yield with 98% diaster-
eoselectivity in favor of the desired 2R-12.
Ozonolysis of the double bond of 12 and 16 was effected by
adding triethylamine to decompose ozonide.9 Without purification
of unstable aldehydes 18 and 19, an intramolecular aldol reaction
with potassium hydroxide in ethanol at 50 ꢁC afforded bicyclic
hydroxyketones 11 and 20 in 80% yield. In contrast, the aldol re-
action in methanol led to acetal 21, which regenerated keto alde-
hydes 18 and 19 by acid-catalyzed hydrolysis. The desired hydroxy
ketone 11 was separated by recrystallization from the diastereomer
20, in which the relative stereochemistry of the hydroxyl group of
11 was established (Fig. 2) by NOE measurement of ether 22. The
keto alcohol 11 was enantiomerically pure as evaluated by the NMR
spectrum of (S)-MTPA ester 23.
stereochemistry of 30 was determined by NOE measurements
(Fig. 3). The axial aldehyde 29 was epimerized into the equatorial
aldehyde 30 by treatment with morpholine and p-toluenesulfonic
acid (PTSA) in acetonitrile.12 Reduction of aldehyde 30 with diiso-
butylaluminum hydride in dichloromethane gave drechslerine A
(1), of which the spectral data and optical rotation value were
consistent with those of the natural product (1).
CO2Me
CO2Me
OMe
d)
TfO
a)
b)
OMe
10
28
CO2Me
CO2Me
+
CHO
With key keto alcohol 11 in hand, we investigated its trans-
formation into an advanced common intermediate (Scheme 3).
Jones oxidation of keto alcohol 11 provided 1,3-dicarbonyl com-
pound 24 in 95% yield, in which the carbonyl group at C-6 of the
diketone 24 was protected for the next transformation with sodium
bistrimethysilylamide (NaHMDS) and triisopropylsilylchloride as
triisopropylsilylenol ether 25 in 98% yield.
CHO
30
29
c)
OH
OH
1
OH
H
O
Scheme 4. Reagents and conditions: (a) Pd(OAc)2, HCO2H, PPh3, n-Bu3N, DMF, 50 ꢁC,
0.5 h, 96%. (b) HClO4, Et2O, rt, 97% (29/30¼1:2.5). (c) Morpholine, PTSA, MeCN, rt,
14.5 h, 94% (29/30¼1:2.3). (d) DIBAL, CH2Cl2, ꢀ78 ꢁC, 1 h, 89%.
a)
b)
O
O
24
11
TIPSO
O
Me
CO2
c), d)
e)
O
OMe
25
26
CO2Me
CO2Me
CHO
O
TfO
f)
H
H
3%
H
H
OMe
OMe
27
10
Scheme 3. Reagents and conditions: (a) Jones reagent, acetone, rt, 15 min, 95%. (b)
TIPSCl, NaHMDS, THF, ꢀ78 ꢁC, 1.5 h, 98%. (c) Ph3PCH2(OMe) Cl, n-BuLi, THF, 60 ꢁC, 4 h.
(d) TBAF, THF, 0 ꢁC, 1 h, 73% in two steps. (e) NaHMDS, CNCO2Me, THF, ꢀ78 ꢁC, 30 min,
87%. (f) NaHMDS, Tf2O, Et2O, ꢀ78 ꢁC, 1.5 h, 94%.
2.5%
30
Fig. 3. Relative stereochemistry of aldehyde 30.
Wittig methoxymethylenation of the remaining carbonyl group
at C-8 gave methyl enol ether, which was subsequently deprotected
by treatment with tetrabutylammonium fluoride to give ketone 26
in 73% yield in two steps. Methoxycarbonylation of 26 with methyl
cyanoformate10 selectively afforded C-acylated product 27 in 88%
yield, whereas methoxycarbonylation of diketone 24 under various
reaction condition gave a mixture of by-products. Treatment of
2.3. Synthesis of drechslerine B (2)
Then, we turned our attention on the synthesis of drechslerine
B (2). The enol triflate 10 was reduced with diisobutylalminum
hydride in dichloromethane to give hydroxy-triflate 31 in 95% yield
(Scheme 5). Palladium-catalyzed insertion of carbon monoxide to
the hydroxy-triflate 31 was not trivial, and we were forced to tune
the reaction conditions, which are summarized in Table 1.
An optimized result was obtained in the reaction with tetra-
kis(triphenylphosphine) palladium {Pd(PPh3)4} as a catalyst in the
presence of tri-n-butylamine in acetonitrile13 to give butenolide 32
in 88% yield (Table 1, entry 1). The addition of an external ligand,
such as 1,1-bis(diphenylphosphino)ferrocene (DPPF) was not ef-
fective (Table 1, entries 3 and 5). Palladium acetate gave moderate
yield (Table 1, entry 5).
b
-keto ester 27 with NaHMDS and triflic anhydride furnished the
advanced common intermediate, enol triflate 10 as a mixture of E/Z
isomers, in 95% yield.
2.2. Synthesis of drechslerine A (1)
The advanced common intermediate, enol triflate 10, was re-
duced with formic acid in the presence of palladium acetate, tri-
phenylphosphine, and tri-n-butylamine to give unsaturated ester
28 in 96% yield (Scheme 4).11 Hydrolysis of the enol ether with
ethereal perchloric acid provided 8R-aldehyde 29 and 8S-aldehyde
30 in 28% and 69% yields, respectively, in which the relative
Hydrolysis of the enol ether 32 by ethereal perchloric acid
proceeded preferentially from the exo-face of the enol ether to give
8R-aldehyde 33 and 8S-aldehyde 34 in 91% yield in a 14:1 ratio, in
which the relative stereochemistry of the 8R-aldehyde 33 was

4064
H. Hagiwara et al. / Tetrahedron 67 (2011) 4061e4068
Table 2
CO2Me
OMe
OH
Isomerization of the 8R-aldehyde 33a
TfO
O
TfO
a)
b)
Entry
Reagent (equiv)
Solvent
Time (h)
Yield (%)
8R 33/8S 34c
1
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (0.2)
K2CO3 (1)
Morpholine (0.3)/
PTSA (0.1)
MeOH
MeOH
MeOH
H2O/THF
CH2Cl2
3
3
18
12
21
70
60
26
11
58
1:2.6
1:3.1
1:2.7
5:1
2b
3
OMe
10
31
4
5
O
1:1
c)
6
Morpholine (0.1)/
PTSA (0.1)
MeCN
17
57
1:5
a
OMe
+
Reaction was carried out at rt.
Reaction was carried out at 45 ꢁC.
Ratio was determined by 1H NMR.
32
b
c
O
O
O
O
d), e)
decreased yields without changing the isomeric ratio. Although
treatment with morpholine and p-toluenesulfonic acid (PTSA) in
acetonitrile12 at room temperature provided 8S-aldehyde 34 pref-
erentially at a ratio of 5:1 (entry 6), the reaction was unpredictable.
Finally, reduction of a mixture of aldehydes 33 and 34 with sodium
borohydride provided a mixture of drechslerine B 214 and its
C-8 epimer in 90%, which were separated by medium-pressure LC
repeatedly to afford drechslerine B 2 in 44% yield. The spectral data
of synthetic 2 including optical rotation was completely identical
with that of natural 2, which unambiguously established the ab-
solute stereochemistry of 2 (Fig. 1).
CHO
CHO
33
34
O
O
e)
OH
2
Scheme 5. Reagents and conditions: (a) DIBAL, CH2Cl2, ꢀ78 ꢁC, 45 min, 95%. (b)
Pd(PPh3)4, CO atmosphere, LiCl, n-Bu3N, MeCN, 60 ꢁC, 4 h, 88%. (c) HClO4, Et2O, rt, 2 h,
91% (33/34¼14:1). (d) K2CO3, MeOH, rt, 3 h, 70% (33/34¼1:2.6). (e) NaBH4, MeOH, 0 ꢁC,
2 h, 44%.
3. Conclusion
Table 1
In summary, we have completed the first total syntheses of
drechslerines A (1) and B (2) by employing palladium-catalyzed
transformations of enol triflates 10 prepared from (S)-carvone 13,
which established the absolute stereostructures as described in Fig.1.
Insertion of carbon monoxide to triflate 31a
Entry Catalyst (equiv) Base (equiv) LiCl (equiv) Time (h) Yield (%)
Butenolide 32 Triflate 31
1
Pd(PPh3)4 (0.1) n-Bu3N (3) 1.5
4
18
18
18
17
88
40
43
3
n.d.
36
Trace
25
2b
3c
4
Pd(PPh3)4 (0.1) n-Bu3N (2)
Pd(PPh3)4 (0.2) n-Bu3N (2)
Pd(PPh3)4 (0.2) DIPEAd (3)
Pd(OAc)2 (0.5) Et3N (4.5)
1
1
1
4. Experimental section
4.1. General
5c
None
63
22
a
Reaction was carried out in acetonitrile at 60e65 ꢁC.
Reaction was carried out in DMF.
DPPF was added.
1H spectra were recorded on a Varian Unity 500 plus (500 MHz),
a Varian MR(400 MHz), ora JNM-Excalibur (270MHz) spectrometer.
13C NMR spectra were obtained for solutions in deuteriochloroform
with a Varian MR (100 MHz).1H and 13C chemical shifts are reported
b
c
d
Diisopropylethylamine.
determined rigorously by NOE measurement (Fig. 4). Although 8S-
aldehyde 34 is 3.44 kJ more stable than 8R-aldehyde 33, as esti-
mated by PM3 calculations, isomerization was sensitive due to the
instability of the aldehydes. The attempt at isomerization to give
the thermodynamically more stable 8S-aldehyde 34 is compiled in
Table 2. Treatment of a mixture of aldehydes 33 and 34 with po-
tassium carbonate in methanol led to an equilibrium mixture of
1:2.6 (entry 1). Prolonged reaction time or elevated temperature
in parts per million downfield from tetramethylsilane (TMS, d scale)
as an internal standard. The following abbreviations were used to
explain the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; br, broad. IR spectra were recorded on a JASCO FT/IR-
4200. Melting points (mp) were recorded on a Yanaco hot stage
apparatus and were uncorrected. Optical rotations were measured
on a Horiba SEPA-200 spectrophotometer. Mass spectra were
recorded on JMS GC-mate using EI method. Analytical TLC was car-
ried out on Kieselgel 60 F254 plates employing n-hexane/ethyl ace-
tate as the mobile phase. THF was distilled from sodium/
benzophenone ketyl. Toluene was distilled from sodium. Acetoni-
trile and dimethylformamide were distilled from CaH2.
O
O
W-type
2 Hz
H
4.1.1. (5S)-2-Methyl-5-(methylethyl)cyclohexan-1-one (14).
H
4.1.1.1. Reduction with zinc followed by hydrogenation catalyzed by Pd/
C. A solution of carvone (13) (53.6 g) in methanol (70 mL) was slowly
added to a refluxing solution of potassium hydroxide (24.9 g) and zinc
powder (69.8 g) in aqueous methanol (1:6, 400 mL) over 11 h. After
being refluxed for 62 h, the reaction was quenched by aqueous
ammonium chloride. Extraction with n-hexane, followed by evapo-
ration to dryness provided crude dihydrocarvone.
A solution of dihydrocarvone in ethyl acetate (100 mL) was
stirred in the presence of 10% palladium on carbon (1.50 g) under
hydrogen atmosphere at room temperature for 2 days. The catalyst
H
H
3%
7%
O
H
8%
2%
33
Fig. 4. Determination of relative stereochemistry of 33.

H. Hagiwara et al. / Tetrahedron 67 (2011) 4061e4068
4065
was removed by filtration through a silica gel column. Jones reagent
(6 mL) was added at 0 ꢁC. After being stirred for 20 min, the reaction
was quenched by the addition of sodium sulfite. Product was
extracted with n-hexane twice. The organic layer was washed with
dilute aqueous sodium hydroxide, water, and brine, and then dried
over anhydrous sodium sulfate. Evaporation of the solvent followed
by Kugelrohr distillation (95e100 ꢁC, 25 mmHg) provided tetra-
hydrocarvone (14) (39.39 g, 72%).
4.1.3.2. Allylation of thermodynamic enolate. Methyllithium (3 M
solution in dimethoxyethane, 13.5 mL, 39 mmol) was added to
a stirred solution of silylenol ether 15 (6.65 g, 30 mmol) in THF
(70mL)atꢀ40ꢁC. Afterstirringfor1h, allyliodide(8.23mL,90mmol)
was added at ꢀ50 ꢁC and the resulting solution was stirred at ꢀ50 ꢁC
for 19 h. The reactionwas quenched by aqueous ammonium chloride
and extracted with ethyl acetate. The extract was dried over anhy-
drous sodium sulfate and evaporated to dryness. Column chroma-
tography followed to give an inseparable mixture of 12 and 16 (5.51 g,
97%) at 3.4:1 (calculated from NMR of 2-methyl peaks).
4.1.1.2. Catalytic hydrogenation catalyzed by Rh/Al2O3. A solu-
tion of carvone (13) (7.49 g, 50 mmol) in ethanol (55 mL) was
hydrogenated in the presence of Rh/Al2O3 (0.203 g, 0.025 mmol)
at 4.2 MPa in an autoclave at room temperature for 3.5 h. After
filtration of the catalyst, evaporation of the solvent followed by
Kugelrohr distillation gave tetrahydrocarvone (14) (7.60 g, 99%).
4.1.4. (6S)-6-Hydroxy-1-methyl-4-(methylethyl)bicyclo[3.2.1]octan-
8-one (11). Ozone/oxygen was passed through a solution of 12 and
16 (201 mg) in dichloromethane (13 mL) at ꢀ78 ꢁC for 3 h, until the
colorof thesolutionwas blue. The reactionwas quenched byaddition
of triethylamine (0.42 mL, 3 mmol), and the solutionwas left to stand
until it reached room temperature. Evaporation of the solvent
followed by short column chromatography of the residue (eluent:
ethyl acetate/n-hexane¼1:3) provided 2-[(1S,4S)-1-methyl-4-
(methylethyl)-2-oxocyclohexyl]ethanal (18) (149 mg, 75% in two
[
a
]
21 ꢀ37.8 (c 1.32, CHCl3); IR (CHCl3) nmax/cmꢀ1 3013, 2963, 1702,
D
1457, 1369, 1315; 1H NMR (400 MHz, CDCl3)
d (ppm) 2.48e2.31
(m, 2H), 2.09 (m, 1H), 1.87 (m, 1H), 1.72e1.25 (m, 4H), 1.29 (ddd,
1H, J 25.8, 12.8, 3.2 Hz), 1.09 (d, 1.5H, J 6.8 Hz), 1.01 (d, 1.5H, J
6.4 Hz), 0.90 (dd, 3H, J 6.8, 6.0 Hz), 0.89 (dd, 3H, J 6.4, 3.6 Hz); 13C
NMR (100 MHz, CDCl3)
d
(ppm) 214.3, 212.8, 46.2, 44.9, 44.5,
steps). [a]
2D6ꢀ30.4 (c 1.05, CHCl3); IR (CHCl3) nmax/cmꢀ1 3024, 2963,
44.4, 43.9, 42.6, 34.7, 32.4, 31.0, 30.2, 28.5, 24.7, 19.7, 19.6, 19.2,
19.0, 15.4, 14.0; HRMS m/z calcd for C10H18O 154.1358, found
154.1359.
2873, 1719, 1704; 1H NMR (270 MHz, CDCl3)
d (ppm) 9.71 (t, 1H, J
2.2 Hz), 2.67 (dd, 1H, J 15.6, 1.8 Hz), 2.53 (dd, 1H, J 15.6, 2.7 Hz),
2.26e2.49 (m, 2H), 1.90e2.04 (m, 1H), 1.72e1.86 (m, 1H), 1.44e1.69
(m, 4H), 1.22 (s, 3H), 0.92 (s, 3H), 0.90 (s, 3H); 13C NMR (67.5 MHz,
4.1.2. 1-[(5S)-2-Methyl-5-(methylethyl)cyclohex-1-enyloxy]-1,1-di-
methyl-1-silaethane (15). Tetrahydrocarvone (14) (16.0 g, 0.10 mol)
in acetonitrile (60 mL) was added to a solution of sodium iodide
(31.2 g, 0.21 mol), chlorotrimethylsilane (26.5 mL, 0.21 mol), and
triethylamine (43.5 mL, 0.31 mol) in acetonitrile (100 mL), at room
temperature under nitrogen atmosphere. After being stirred for 4 h,
the reaction was quenched by the addition of water at 0 ꢁC. Product
was extracted with n-hexane. The extract was dried over anhydrous
sodium sulfate and evaporated to dryness. Purification by column
CDCl3) d (ppm) 213.6, 200.6, 50.3, 46.8, 45.4, 41.8, 37.5, 31.6, 24.1, 23.0,
19.8, 19.7; HRMS m/z calcd for C12H20O2 196.1463, found 196.1468.
A solution of aldehyde 18 (1.43 g, 7.3 mmol) and potassium hy-
droxide (335 mg, 5.1 mmol) in ethanol (100 mL) was heated at 50 ꢁC
for 13 h. After evaporation of ethanol in vacuo, aqueous ammonium
chloride was added. Product was extracted with ethyl acetate and
dried over anhydrous sodium sulfate. Evaporation of the solvent
followed by column chromatography of the residue (eluent: ethyl
acetate/n-hexane¼1:1) gave the desired diastereomer 11 (1.43 g,
chromatography (eluent: ethyl acetate/n-hexane¼1:10) provided
80%). Aldol 11 has mp 85.0e85.6 ꢁC; [
a]
2D3ꢀ25.88 (c 0.800, CHCl3); IR
21
silylenol ether 15 (23.4 g, 99%). [
a
]
ꢀ68.6 (c 0.966, CHCl3); IR
(CHCl3) nmax/cmꢀ1 3601, 2963, 2930, 1741, 1456, 1206, 1018; 1H NMR
D
(CHCl3) nmax/cmꢀ1 2959, 2924, 2877, 2836, 1691, 1464, 1173, 846; 1H
NMR (400 MHz, CDCl3) (ppm) 2.03e1.87 (m, 3H), 1.78 (m, 1H), 1.67
(270 MHz, CDCl3) d (ppm) 4.30 (dd,1H, J 7.8,1.7 Hz), 2.43 (s,1H), 2.40
d
(dd,1H, J 14.2, 8.0 Hz), 2.09 (br s,1H),1.46e1.83 (m, 6H),1.25 (td,1H, J
(ddt, 1H, J 13.2, 7.2, 1.6 Hz), 1.53 (s, 3H), 1.44 (dt, 1H, J 13.2, 6.4 Hz),
1.34 (m, 1H), 1.12 (ddd, 1H, J 24.0, 12.0, 6.4 Hz), 0.87 (d, 3H, J 3.6 Hz),
13.4, 6.1Hz),1.06 (s, 3H), 0.94(d, 3H, J 6.5 Hz), 0.93(d, 3H, J6.5Hz);13C
NMR (67.5 MHz, CDCl3) d (ppm) 221.6, 66.1, 58.3, 52.5, 47.7, 44.5, 42.0,
31.2, 24.4, 21.3, 19.0, 18.8; HRMS m/z calcd for C12H20O2 196.1463,
0.86 (d, 3H, J 3.6 Hz), 0.15 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
(ppm)
142.71, 111.43, 41.63, 34.01, 32.08, 30.24, 26.47, 19.95, 19.71, 16.09,
found 196.1459.
0.711; HRMS m/z calcd for C13H26OSi 226.1753, found 226.1768.
4.1.5. (1S,4R,5R)-1-Methyl-4-(methylethyl)bicyclo[3.2.1]octane-6,8-
dione (24). Jones reagent (11 mL, 2.67 M solution, 29.4 mmol) was
added drop wise to a stirred solution of keto alcohol 11 (1.71 g,
8.69 mmol) in acetone (20 mL) at 0 ꢁC, and the resulting solution was
stirred at room temperature for 15 min. The solutionwas diluted with
n-hexane and the reaction was quenched by the addition of isopropyl
alcohol. Product was extracted with ethyl acetate and dried over an-
hydrous sodium sulfate. Evaporation of the solvent followed by
column chromatography of the residue (eluent: ethyl acetate/n-
hexane¼1:3)afforded diketone 24 (1.60 mg, 95%)ascolorlesscrystals.
4.1.3. (2S,5S)-2-Methyl-5-(methylethyl)-2-prop-2-enylcyclohexan-1-
one (12) and (2R,5S)-2-methyl-5-(methylethyl)-2-prop-2-enylcyclo-
hexan-1-one (16).
4.1.3.1. Diastereoselective Tsuji allylation. A solution of tetrabu-
tylammonium difluorotriphenylsilicate (59 mg, 0.1 mmol),
Pd2(dba)3 (18 mg, 0.03 mmol), and (S)-tert-butylPHOX (17) (36 mg,
0.063 mmol) in THF (3 mL) was stirred at room temperature
under nitrogen for 25 min. Diallyl carbonate (160 mL, 1.1 mmol)
and then the silylenol ether 15 (227 mg, 1 mmol) in THF were
added. After stirring for 5 h, the solvent was evaporated to dry-
ness. Column chromatography (eluent: ethyl acetate/n-
hexane¼1:30) of the residue provided a mixture of allyl derivative
12 and 16 (201 mg) at a ratio of 55:1 (calculated from NMR of 2-
Mp 31.0 ꢁC; [
a]
D
25ꢀ87.6 (c 1.05, CHCl3); IR (CHCl3) nmax/cmꢀ1 3026,
2968, 2931, 2872, 1766, 1727, 1456, 1231, 1185; 1H NMR (270 MHz,
CDCl3) d (ppm) 2.95(s,1H), 2.61 (d,1H, J 19.2 Hz), 2.41 (d, 1H, J 19.2 Hz),
1.80e2.10 (m, 4H), 1.58e1.78 (m, 1H), 1.30e1.48 (m, 1H), 1.20 (s, 3H),
methyl peaks) in favor of 12. [
a
]
26 ꢀ113.2 (c 0.618, CHCl3); IR
1.00 (d, 3H, J 6.5 Hz), 0.90 (d, 3H, J 6.5 Hz); 13C NMR (67.5 MHz, CDCl3)
D
(CHCl3) nmax/cmꢀ1 3020, 2963, 2873, 1698, 1208; 1H NMR
d (ppm) 216.3, 209.0, 61.6, 56.8, 51.0, 49.6, 42.0, 30.6, 24.7, 21.2, 20.6,
(270 MHz, CDCl3)
d
(ppm) 5.54e5.72 (m, 1H), 5.08 (s, 1H), 5.03 (m,
18.5; HRMS m/z calcd for C12H18O2 194.1307, found 194.1307.
1H), 2.44 (dd, 1H, J 13.8, 7.2 Hz), 2.28 (br s, 1H), 2.25 (m, 1H), 2.15
(dd, 1H, J 13.8, 7.5 Hz), 1.87 (dd, 1H, J 13.4, 3.2 Hz), 1.36e1.76 (m,
5H), 1.01 (s, 3H), 0.91 (d, 3H, J 6.4 Hz), 0.90 (d, 3H, J 6.4 Hz); 13C
4.1.6. (1S,4R,5R)-6-[1,1-Bis(methylethyl)-2-methyl-1-silapropoxy]-1-
methyl-4-(methylethyl)bicyclo[3.2.1]oct-6-en-8-one
(25). Sodium
NMR (67.5 MHz, CDCl3)
41.4, 37.9, 32.6, 24.4, 22.1, 19.7, 19.5; HRMS m/z calcd for C13H22
194.1671, found 194.1669.
d
(ppm) 215.2, 132.8, 117.9, 48.1, 46.0, 42.2,
bistrimethylsilylamide (1 M solution inTHF,1.43 mL,14.3 mmol) was
added to a stirred solution of diketone 24 (2.55 g, 13 mmol) and
triisopropylsilylchloride (4.2 mL, 20.0 mmol) in THF (40 mL) at
O

4066
H. Hagiwara et al. / Tetrahedron 67 (2011) 4061e4068
ꢀ78 ꢁC under nitrogen atmosphere. After being stirred for 1.5 h, the
reaction was quenched by aqueous ammonium chloride. Ether was
added and the organic layer was separated by decantation, and dried
overanhydrous sodium sulfate. Evaporation of the solvents followed
by medium-pressure LC of the residue (eluent: ethyl acetate/
(c 1.09, CHCl3); IR (CHCl3) nmax/cmꢀ1 3010, 2933, 2871, 1748, 1727,
1435, 1120; 1H NMR (400 MHz, CDCl3)
(ppm) 5.85 (s, 1H), 3.67 (s,
d
3H), 3.59 (s, 3H), 3.55 (s, 1H), 3.00 (s, 1H), 1.91 (ddd, 1H, J 12.8, 5.3,
5.2 Hz), 1.90 (ddd, 1H, J 13.2, 6.1, 6.0 Hz), 1.62 (td, 2H, J 13.2, 6.0 Hz),
1.52 (m, 1H), 1.42 (m, 1H), 1.15 (s, 3H), 1.06 (d, 3H, J 6.4 Hz), 0.84 (d,
n-hexane¼1:10) gave TIPS enol ether 25 (4.52 g, 98%). [
a
]
24ꢀ80.8
3H, J 6.4 Hz); 13C NMR (100 MHz, CDCl3)
d (ppm) 210.3, 169.4, 137.0,
D
(c 1.15, CHCl3); IR (CHCl3) nmax/cmꢀ1 2962, 2928, 2869, 1748, 1617,
124.8, 64.7, 59.7, 51.7, 51.6, 50.6, 43.9, 43.3, 30.3, 25.3, 21.2, 20.3,
18.8; HRMS m/z calcd for C16H24O4 280.1674, found 280.1675.
1463, 1353, 1285, 1262, 1214, 883, 821; 1H NMR (270 MHz, CDCl3)
d
(ppm) 4.66(s,1H), 2.86(d,1H, J 1.6Hz),1.70e1.80 (m,1H),1.50e1.70
(m, 2H), 1.30e1.50 (m, 3H), 1.05e1.30 (m, 21H), 1.05 (s, 3H), 1.01 (d,
3H, J 6.5 Hz), 0.84 (d, 3H, J 6.5 Hz); 13C NMR (67.5MHz, CDCl3)
(ppm)
215.8,151.2,104.2, 55.4, 51.5, 47.8, 36.5, 32.3, 24.7, 21.2, 21.0,18.0,17.2,
12.5; HRMS m/z calcd for C23H42O2Si 350.2641, found 350.2645.
4.1.9. Methyl (1S,2R,5R)-8-(methoxymethylene)-5-methyl-2-(methy-
lethyl)-7-[(trifluoromethyl)sulfonyloxy]bicyclo[3.2.1]oct-6-ene-6-car-
boxylate (10). Sodium bistrimethylsilylamide (1 M solution in THF,
1.67 mL, 1.67 mmol) was added to a stirred solution of keto ester 27
(335 mg, 1.19 mmol) in ether (5 mL) at ꢀ78 ꢁC under nitrogen. After
d
4.1.7. (1S,4R,5S)-8-(Methoxymethylene)-1-methyl-4-(methylethyl)
bicyclo[3.2.1]octan-6-one (26). n-Butyllithium (1.63 M solution in
n-hexane, 1.9 mL, 3.10 mmol) was added to a stirred suspension of
methoxymethyltriphenylphosphonium chloride (1.27 g, 3.70 mmol)
in THF (5 mL) at 0 ꢁC under nitrogen atmosphere. After being stirred
for 50 min at room temperature, a solution of crude TIPS enol ether
25 (350 mg, 1.00 mmol) in THF (5 mL) was added. The resulting
solution was stirred at 60 ꢁC for 4 h. The reaction was quenched by
aqueous ammonium chloride. Product was extracted with n-hexane
twice. The organic layer was dried over anhydrous sodium sulfate
and evaporated todryness. Residue was passed through a short silica
gel column. Products were mixtures of E/Z isomers (6:1 by 1H NMR),
in which major the isomer separated by medium-pressure LC had
being stirred for 20 min, triflic anhydride (313 mL, 1.91 mmol) was
added. The solution was stirred for an additional 1.5 h. The reaction
was quenched by aqueous sodium hydrogencarbonate. After being
stirred for 5 h until room temperature, the product was extracted
with ethyl acetate twice. The organic layer was washed with water
and brine, and then dried over anhydrous sodium sulfate. Evapora-
tion of the solvent and subsequent medium-pressure LC (eluent:
ethyl acetate/n-hexane¼1:3) provided enol triflate 10 (463 mg, 94%).
Due to the instability of enol triflate 10, optical rotation and IR
spectrum were not measured. [
a]
2D3þ165.0 (c 0.552, CHCl3); IR
(CHCl3) nmax/cmꢀ1 2955, 2934, 1714, 1631, 1427, 1300, 1119; 1H NMR
(400 MHz, CDCl3) d (ppm)5.64 (s,1H), 3.85 (s,1H), 3.78(s, 3H), 3.57 (s,
3H), 1.95e1.88 (m, 2H), 1.40 (m, 1H), 1.29 (s, 3H), 1.31e1.10 (m, 3H),
[
a]
1D9 ꢀ95.6 (c 0.861, CHCl3); IR (CHCl3) nmax/cmꢀ1 2945, 2867, 1708,
1.03 (d, 3H, J 6.4 Hz), 0.85 (d, 3H, J 6.4 Hz); 13C NMR (100 MHz, CDCl3)
1619, 1462, 1253, 1163, 883; 1H NMR (270 MHz, CDCl3)
d
(ppm) 5.49
d (ppm) 162.2, 154.7,132.8,127.9,126.9,123.1,119.9,116.7, 113.5, 59.7,
(s, 0.14H), 5.43 (s, 0.86H), 4.36 (s, 0.86H), 4.28 (s, 0.14H), 3.51 (s,
2.6H), 3.46 (s, 0.4H), 3.41 (br s, 1H), 1.75 (dd, 1H, J 13.0, 5.9 Hz),
1.52e1.16 (m, 7H),1.14 (m, 21H),1.02 (s, 3H),1.01 (d, 3H, J 7.0 Hz), 0.84
51.4, 46.5, 45.1, 44.4, 35.6, 31.4, 25.0, 20.9, 20.6, 17.7; HRMS m/z calcd
for C17H23O6SF3S 412.1167, found 412.1162.
(d, 3H, J 7.0 Hz); 13C NMR (67.5 MHz, CDCl3)
d
(ppm) 155.0, 135.8,
4.1.10. Methyl (1R,2R,5R)-8-(methoxymethylene)-5-methyl-2-(methy-
lethyl)bicyclo[3.2.1]oct-6-ene-6-carboxylate (28). Formic acid (0.37
mL, 9.8 mmol) was added to a stirred solution of enol triflate 10
(406 mg, 0.98 mmol), palladium acetate (67 mg, 0.30 mmol), tri-
phenylphosphine (157 mg, 0.60 mmol), and tri-n-butylamine
(2.3 mL, 9.8 mmol) in dimethylformamide (15.0 mL) and the
resulting solution was heated at 50 ꢁC for 0.5 h. The reaction was
quenched by water. Product was extracted with ethyl acetate twice.
The organic layer was washed with water and brine, and then dried
over anhydrous sodium sulfate, before being passed through
a short silica gel column and evaporated to dryness. The residue
was purified by medium-pressure LC (eluent: ethyl acetate/
n-hexane¼1:5) to afford unsaturated ester 28 (481 mg, 96%).
128.9,106.8, 59.5, 45.8, 45.6, 44.0, 38.0, 32.0, 26.1, 21.7, 21.2, 21.1,18.1,
12.5; HRMS m/z calcd for C23H42O2Si 378.2954, found 378.2958.
TBAF (1.5 mL) was added to a solution of the crude methyl enol
ether in THF (5 mL) at room temperature. After being stirred for 1 h,
the reaction was quenched by addition of aqueous ammonium
chloride and the product was extracted with n-hexane twice. The
organic layer was washed with water and brine, and then dried over
anhydrous sodium sulfate. Evaporation of the solvent followed by
medium-pressure LC (eluent: ethyl acetate/n-hexane¼1:10) pro-
vided ketone 26 (174 mg, 73% in two steps) as a mixture of E/Z iso-
mers, in which the major enol ether has [
a
]
2D7ꢀ274.0 (c 1.89, CHCl3);
IR (CHCl3) nmax/cmꢀ1 3027, 3011, 2960, 2931, 2871, 1735, 1456, 1251,
1172, 1123; 1H NMR (270 MHz, CDCl3)
d
(ppm) 5.80 (s, 1H), 3.57 (s,
[
a
]
19 ꢀ122.0 (c 0.718, CHCl3); IR (CHCl3) nmax/cmꢀ1 2957, 2933,
D
3H), 3.42 (s,1H), 2.12 (d,1H, J 18.1 Hz), 2.01 (d,1H, J 18.1 Hz),1.88 (dt,
1H, J 18.3, 5.1 Hz), 1.74 (dd, 1H, J 12.7, 5.7 Hz), 1.44e1.64 (m, 2H),
1.28e1.44 (m,1H),1.18 (s, 3H),1.05e1.26 (m,1H),1.05 (d,1H, J 6.7 Hz),
2874, 2847, 1704, 1597, 1458, 1436, 1258, 1119; 1H NMR (400 MHz,
CDCl3) d (ppm) 6.82 (d, 1H, 3.0 Hz), 5.56 (s, 1H), 3.72 (s, 3H), 3.61 (t,
1H, J 1.0 Hz), 3.55 (s, 3H), 1.74 (dd, 1H, J 11.6, 6.4 Hz), 1.63 (dt, 1H, J
13.6, 4.8 Hz), 1.31e1.20 (m, 3H), 1.27 (s, 3H), 1.08 (ddd, 1H, J 12.8,
11.2, 5.6 Hz), 1.06 (d, 3H, J 6.4 Hz), 0.84 (d,3H, J 6.4 Hz); 13C NMR
0.84 (d,1H, J 6.8 Hz); 13C NMR (67.5 MHz, CDCl3)
d (ppm) 216.5,135.6,
127.2, 59.7, 52.2, 51.1, 51.0, 41.6, 40.1, 30.3, 25.7, 22.3, 21.5, 20.5; HRMS
m/z calcd for C14H22O2 222.1620, found 222.1621.
(100 MHz, CDCl3) d (ppm) 165.0, 143.0, 139.6, 134.3, 131.2, 59.5, 51.0,
46.4, 44.8, 42.7, 35.3, 32.6, 24.8, 21.0, 20.8, 17.8; HRMS m/z calcd for
4.1.8. Methyl (1S,2R,5S)-8-(methoxymethylene)-5-methyl-2-(meth-
ylethyl)-7-oxobicyclo[3.2.1]octane-6-carboxylate (27). Sodium bis-
trimethylsilylamide (1.0 M solution in THF, 0.33 mL, 0.33 mmol)
was added to a stirred solution of ketone 26 (48 mg, 0.22 mmol,
a mixture of E/Z isomer) in THF (1 mL) at ꢀ78 ꢁC under nitrogen
atmosphere. After being stirred for 10 min, methyl cyanoformate
(0.026 mL, 0.33 mmol) was added. The reaction was quenched by
aqueous ammonium chloride after being stirred for 30 min. Product
was extracted with ethyl acetate twice. The organic layer was
washed with water and brine, and then dried over anhydrous so-
dium sulfate. After evaporation of the solvent, the residue was
separated with medium-pressure LC (eluent: ethyl acetate/
C16H24O3 264.1725, found 264.1726.
4.1.11. Methyl (1R,2R,5R,8R)-8-formyl-5-methyl-2-(methylethyl)bi-
cyclo[3.2.1]oct-6-ene-6-carboxylate (29) and (1R,2R,5R,8S)-8-formyl-
5-methyl-2-(methylethyl)bicyclo[3.2.1]oct-6-ene-6-carboxylate
(30). Ethereal perchloric acid (2.0 mL), prepared by mixing
perchloric acid and ether at a ratio of 1:7, was added to a stirred
solution of enol ether 28 (248 mg, 0.94 mmol) in ether (10.0 mL).
The resulting solution was stirred at room temperature for 1 h.
Extra ethereal perchloric acid (0.5 mL) was added three times at 1 h
intervals. The reaction was quenched by the addition of sodium
hydrogencarbonate powder. Product was triturated with ethyl ac-
etate twice. The organic layer was passed through a short silica gel
n-hexane¼1:3) to provide keto ester 27 (53 mg, 87%). [
a
]
2D7ꢀ204.4

H. Hagiwara et al. / Tetrahedron 67 (2011) 4061e4068
4067
column and evaporated to dryness. Medium-pressure LC of the
residue (eluent: ethyl acetate/n-hexane¼1:5) gave a mixture of
aldehyde 29 and 30 (89 mg, 97%). Axial aldehyde 29 partially sep-
ester 10 (206 mg, 0.50 mmol) in dichloromethane (10 mL) at ꢀ78 ꢁC
under nitrogen atmosphere. After being stirred for 45 min, the
reaction was quenched by aqueous ammonium chloride. Product
was extracted with ethyl acetate twice. The organic layer was
washed with water and brine, and then dried over anhydrous so-
dium sulfate. Evaporation of solvent followed by medium-pressure
LC of the residue (eluent: ethyl acetate/n-hexane¼1:3) afforded
alcohol 31 (72 mg, 95%). Due to the instability of enol triflate, optical
rotation and IR spectrum were not measured. 1H NMR (270 MHz,
arated by medium-pressure LC had [
a
]
D
19þ147.3 (c 0.260, CHCl3); IR
(CHCl3) nmax/cmꢀ1 3027, 2958, 2872, 1712, 1602, 1460; 1H NMR
(400 MHz, CDCl3) d (ppm) 9.89 (d,1H, J 0.8 Hz), 6.83 (d, 1H, J 3.2 Hz),
3.75 (s, 3H), 3.18 (ddd, 1H, J 5.2, 2.8, 2.8 Hz), 2.55 (dd, 1H, 5.2,
0.8 Hz), 1.71 (ddd, 1H, J 13.2, 8.8, 3.6 Hz), 1.59 (dd, 1H, J 10.0, 3.6 Hz),
1.58 (dd, 1H, J 7.6, 2.0 Hz), 1.45 (s, 3H), 1.26 (m, 2H), 1.06 (m, 1H),
0.94 (d, 3H, J 6.4 Hz), 0.83 (d, 3H, J 6.4 Hz); 13C NMR (100 MHz,
CDCl3)
d (ppm) 5.58 (s, 1H), 4.21 (s, 2H), 3.74 (s, 1H), 3.56 (s, 3H),
CDCl3)
d
(ppm) 203.2, 164.9, 142.8, 140.9, 64.7, 51.2, 46.2, 42.6, 37.4,
1.85 (m, 1H), 1.71e1.57 (m, 1H), 1.31e1.13 (m, 4H), 1.21 (s, 3H), 1.04
(d, 3H, J 6.5 Hz), 0.85 (d, 3H, J 6.5 Hz); HRMS m/z calcd for
C16H23O5F3S 384.1218, found 384.1219.
32.5, 27.1, 24.6, 21.3, 20.9, 20.7; HRMS m/z calcd for C15H22O3
250.1569, found 250.1565.
4.1.12. Methyl (1R,2R,5S,8S)-8-formyl-5-methyl-2-(methylethyl)bi-
cyclo[3.2.1]oct-6-ene-6-carboxylate (30). A solution of aldehyde 29
(89 mg, 0.36 mmol), morpholine (15.5 mg, 0.18 mmol), and p-tol-
uenesulfonic acid (6.8 mg, 0.036 mmol) in acetonitrile (1 mL) was
stirred at room temperature for 14.5 h. The solution was diluted
with ethyl acetate and dried over anhydrous sodium sulfate, which
was filtered through a short silica gel column. Evaporation of the
solvent gave a residue, in which the ratio of 29 to 30 was de-
termined to be 1:0.2 by NMR measurement.
The residue (89 mg, 0.36 mmol) in acetonitrile (1 mL) was again
treated with morpholine (15.5 mg, 0.18 mmol) and p-toluenesulfonic
acid (6.8 mg, 0.036 mmol) at 40 ꢁC for12.5 h. The solutionwas diluted
with ethyl acetate and the organic layer was passed through a short
silica gel column. Evaporation of the solvent followed by medium-
pressure LC (eluent: ethyl acetate/n-hexane¼1:3) produced an in-
separable mixture of aldehydes 29 and 30 (84 mg, 94%) at a ratio of
1:2.3. Repeated medium-pressure LC produced pure 30. IR (CHCl3)
nmax/cmꢀ1 2959, 2874, 1713, 1605, 1453, 1279; 1H NMR (270 MHz,
4.1.15. (1S,7R,10R)-11-(Methoxymethylene)-7-methyl-10-(methyl-
ethyl)-4-oxatricyclo[5.3.1.02,6]undec-2(6)-en-3-one (32). A solution
of alcohol 31 (73 mg, 0.19 mmol), lithium chloride (13 mg,
0.29 mmol), palladium tetrakistriphenylphosphine (23 mg,
0.02 mmol), and tri-n-butylamine (0.136 mL, 0.57 mmol) in ace-
tonitrile (2 mL) was evacuated under water aspirator. After the
introduction of carbon monoxide, the solution was heated at 60 ꢁC
for 4 h. After aqueous ammonium chloride was added, the product
was triturated with n-hexane twice. The organic layer was dried
over anhydrous sodium sulfate and passed through a short silica gel
column. Evaporation of the solvent followed by medium-pressure
LC (eluent: ethyl acetate/n-hexane¼1:3) gave butenolide 32
(44 mg, 88%). [
a
]
19 ꢀ89.6 (c 0.170, CHCl3); IR (CHCl3) nmax/cmꢀ1
D
3017, 2961, 2872, 1749, 1635, 1454, 1120, 999; 1H NMR (270 MHz,
CDCl3) d (ppm) 5.61 (s, 1H), 4.86 (dd, 1H, J 18.1, 1.2 Hz), 4.74 (d, 1H, J
18.1 Hz), 3.88 (s, 1H), 3.58 (s, 3H), 1.84 (dt, 1H, J 14.1, 4.8 Hz), 1.66
(dd, 1H, J 12.5, 6.1 Hz), 1.48 (td, 1H, J 12.5, 6.0 Hz), 1.24 (s, 3H),
1.17e1.34 (m, 2H), 1.09 (d, 3H, J 6.0 Hz), 0.84e0.96 (m, 1H), 0.82 (d,
CDCl3)
d
(ppm) 9.69 (d,1H, J 3.9 Hz), 6.78 (d,1H, J 2.4 Hz), 3.73 (s, 3H),
3H, J 6.0 Hz); 13C NMR (67.5 MHz, CDCl3)
d (ppm) 117.6, 170.0, 135.9,
3.01 (br s, 1H), 2.11 (d, 3H, J 3.9 Hz), 1.71e1.82 (m, 1H), 1.66 (dd, 1H, J
13.2, 6.1 Hz),1.36 (s, 3H), 0.97e1.42 (m, 4H), 0.95 (d, 3H, J 6.6 Hz), 0.86
(d, 3H, J 6.6 Hz). Due to the instability of aldehyde 30, optical rotation
and 13C spectrum were not measured.
134.4, 132.2, 67.3, 59.8, 46.4, 44.7, 39.3, 36.3, 32.5, 25.7, 21.4, 20.7,
17.4; HRMS m/z calcd for C16H22O3 262.1569, found 262.1572.
4.1.16. (1R,7S,8R,11R)-1-Methyl-8-(methylethyl)-4-oxa-5-oxotricyclo
[5.3.1.02,6]undec-2(6)-ene-11-carbaldehyde (33) and (1R,7S,8S,11R)-
1-methyl-8-(methylethyl)-4-oxa-5-oxotricyclo[5.3.1.02,6]undec-2(6)-
ene-11-carbaldehyde (34). Ethereal perchloric acid (0.2 mL), which
was prepared from perchloric acid and ether at a ratio of 1:7, was
added to a stirred solution of enol ether 32 (48 mg, 0.18 mmol) in
ether (0.5 mL). After being stirred for 2 h at room temperature, the
reaction was quenched by adding sodium bicarbonate powder. After
the addition of ethyl acetate and subsequent decantation, the or-
ganic layer was dried over anhydrous sodium sulfate and passed
through a short silica gel column. Evaporation of the solvent fol-
lowed by medium-pressure LC (eluent: ethyl acetate/n-hexane¼1:1)
provided aldehydes 33 and 34 (14:1) (41 mg, 91%). Axial aldehyde 33
has IR (CHCl3) nmax/cmꢀ1 3030, 2962, 2870, 1753, 1720, 1642, 1003;
4.1.13. [(1S,2R,5R,8S)-7-(Hydroxymethyl)-1-methyl-4-(methylethyl)bi-
cyclo[3.2.1]oct-6-en-8-yl]methan-1-ol¼drechslerin A (1). Diisobutyl-
aluminum hydride (0.90
M solution in toluene, 0.58 mL,
0.52 mmol) was added to a stirred solution of aldehyde 30 (26 mg,
0.104 mmol) in dichloromethane (3 mL) at ꢀ78 ꢁC under nitrogen
atmosphere. After being stirred for 30 min, extra diisobutylalumi-
num hydride (0.23 mL) was added. After being stirred for 30 min,
the reaction was quenched by adding aqueous ammonium chloride.
Product was extracted with ethyl acetate twice. The organic layer
was washed with water and brine, and then dried over anhydrous
sodium sulfate. Evaporation of the solvent and subsequent
medium-pressure LC purification of the residue (eluent: ethyl
acetate/n-hexane¼4:1) afforded drechslerine A 1 (21 mg, 89%).
1H NMR (270 MHz, CDCl3)
d (ppm) 9.82 (s, 1H), 4.90 (d, 1H, J 18.1 Hz),
4.78 (d, 1H, J 18.1 Hz), 3.51 (d,1H, J 4.6 Hz), 3.02 (dd,1H, J 4.9, 2.2 Hz),
1.76e1.99 (m, 2H), 1.35e1.48 (m, 1H), 1.42 (s, 3H), 1.16e1.31 (m, 2H),
1.05 (d, 3H, J 5.1 Hz), 0.84e0.96 (m, 1H), 0.82 (d, 3H, J 5.1 Hz); 13C
Mp 128.1e128.9 ꢁC, lit.2 125 ꢁC; [
a
]
25ꢀ27.6 (c 0.098, CHCl3), lit.2
D
[
a
]
22 ꢀ25.0 (c 0.10, EtOH); IR (CHCl3) nmax/cmꢀ1 3612, 3446 (br),
D
2957, 2929, 1458, 1009; 1H NMR (400 MHz, CDCl3)
d (ppm) 5.55 (br
d, 1H, J 1.6 Hz), 4.05 (d, 1H, J 14.4 Hz), 4.02 (dd, 1H, J 14.4, 1.2 Hz),
3.64 (dd, 1H, J 10.4, 6.4 Hz), 3.36 (dd, 1H, J 10.4, 10.0 Hz), 2.80 (br s,
1H), 1.65 (m, 1H), 1.54 (dd, 1H, J 9.2, 4.8 Hz), 1.38 (m, 1H), 1.30e1.20
(m, 3H), 1.05 (m, 1H), 0.96 (s, 3H), 0.95 (d, 3H, J 6.4 Hz), 0.85 (d, 3H, J
NMR (67.5 MHz, CDCl3) d (ppm) 200.8, 178.4, 169.6, 134.3, 68.6, 67.1,
45.8, 39.2, 38.3, 32.2, 27.4, 25.2, 21.1, 20.5, 20.5; HRMS m/z calcd for
C15H20O3 248.1412, found 248.1414. Due to the instability of 33,
optical rotation was not measured.
6.4 Hz); 13C NMR (100 MHz, CDCl3)
d (ppm) 147.1, 124.2, 63.9, 62.7,
59.9, 47.7, 45.4, 43.9, 35.8, 33.8, 26.3, 21.6, 21.3, 19.0; HRMS m/z
calcd for C14H24O2 224.1776, found 224.1776.
4.1.17. (1R,7S,8R,11S)-1-Methyl-8-(methylethyl)-4-oxa-5-oxotricyclo
[5.3.1.02,6]undec-2(6)-ene-11-carbaldehyde (34). A solution of al-
dehydes 33 and 34 (23 mg, 0.09 mmol) and potassium carbonate
(2.5 mg, 0.018 mmol) in methanol (1.5 mL) was stirred at room
temperature for 3 h. After the addition of ammonium chloride
powder, the organic layer was dried over anhydrous sodium sul-
fate and passed through a short silica gel column. Evaporation of
4.1.14. (1R,4R,5S)-7-(Hydroxymethyl)-8-(methoxymethylene)-1-
methyl-4-(methylethyl)bicyclo[3.2.1]oct-6-en-6-yl (trifluoromethyl)
sulfonate (31). Diisobutylaluminum hydride (0.99 M solution in
toluene, 1.2 mL, 1.2 mmol) was added to a stirred solution of enol-

4068
H. Hagiwara et al. / Tetrahedron 67 (2011) 4061e4068
the solvent followed by medium-pressure LC (eluent: ethyl ace-
tate/n-hexane¼1:1) gave an inseparable mixture of aldehydes
(16 mg, 70%, 33/34¼1:2.6). NMR peaks of major isomer 34 are as
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.04.007.
follows: 1H NMR (270 MHz, CDCl3)
d (ppm) 9.69 (d, 1H, J 3.2 Hz),
4.91 (d, 1H, J 18.3 Hz), 4.76 (d, 1H, J 18.3 Hz), 3.33 (s, 1H), 2.52 (d,
1H, J 3.2 Hz), 1.84e2.01 (m, 2H), 1.58 (dd, 2H, J 9.5, 3.4 Hz),
1.17e1.36 (m, 1H), 1.32 (s, 3H), 1.06 (d, 3H, J 6.4 Hz), 0.86e1.13 (m,
References and notes
1H), 0.85 (d, 3H, J 6.4 Hz); 13C NMR (67.5 MHz, CDCl3)
d (ppm)
202.2, 176.6, 169.4, 134.4, 75.3, 67.2, 47.0, 42.9, 39.3, 34.2, 32.1, 25.7,
21.4, 20.6, 18.4; HRMS m/z calcd for C15H22O3 250.1569, found
250.1571. Due to the instability of 33 and 34, only NMR and mass
spectra were measured.
1. For example, Kornprobst, J.-M. Encyclopedia of Marine Natural Products; Wiley-
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(14 mg, 44%). [
a
]
2D0ꢀ40.6 (c 0.18, EtOH), lit.2 ꢀ42.0 (c 0.10, EtOH); IR
(CHCl3) nmax/cmꢀ1 3624, 2928, 2873, 1747; 1H NMR (500 MHz,
CDCl3)
d (ppm) 4.90 (dd, 1H, J 19.2, 1.2 Hz), 4.87 (d, 1H, J 18.3 Hz),
3.71 (dd, 1H, J 10.8, 5.2 Hz), 3.35 (dd, 1H, J 11.2, 9.6 Hz), 3.14 (br s,
1H), 2.01 (dd,1H, J 9.6, 5.2 Hz),1.88 (dddd,1H, J 14.0, 7.2, 4.1, 4.0 Hz),
1.58 (m, 1H), 1.56 (m, 1H), 1.24 (m, 1H), 1.19 (m, 1H), 1.13 (s, 3H), 1.03
(d, 3H, J 6.0 Hz), 0.88 (m, 1H), 0.84 (d, 3H, J 6.4 Hz); 13C NMR
(125 MHz, CDCl3)
d (ppm) 180.9, 173.8, 134.9, 69.3, 68.1, 61.8, 45.3,
41.3, 35.5, 33.7, 27.0, 21.8, 21.0, 17.8; HRMS m/z calcd for C15H22O3
250.1569, found 248.1568.
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Acknowledgements
14. Preliminary communication: Hagiwara, H.; Fukushima, M.; Kinugawa, K.;
We thank Mr. Ryusuke Tamaki for preliminary experiments.
Matsui, M.; Hoshi, T.; Suzuki, T. Nat. Prod. Commun. 2011, 6, 311e313.