Total Synthesis of (+)-Antrocin and Its Diastereomer and Clarification of the Absolute Stereochemistry of (-)-Antrocin

Article abstract of DOI:10.1021/acs.joc.7b01600

Using 2,2-dimethyl cyclohexanone as the starting compound, (+)-antrocin and its diastereomer have been synthesized. The absolute stereochemistry of (-)-antrocin, a natural sesqui-terpenoid and an antagonist in some types of cancer cells, was clarified using the character data of (+)-antrocin. The synthetic procedure involved two key steps: (1) the reaction of vinyl magnesium bromide with 2,2-dimethyl-6-t-butyl-dimethyl-silyoxy-methyl-1-cyclo-hexanone to give a vinyl cyclohexanol derivative and (2) a highly stereoselective intramolecular Diels-Alder (IMDA) reaction of the camphanate-containing triene intermediate. The relative energy levels of the possible transition states of the IMDA reaction of the camphanate-containing triene were obtained from density functional theory calculations, proving the stereospecific formation of the target molecule.

Full text of DOI:10.1021/acs.joc.7b01600

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Article
Total Synthesis of (+)-Antrocin and Its Diastereomer and
Clarification of the Absolute Stereochemistry of (-)-Antrocin
Sheng-Han Huang, Kai-Hsiang Liang, Jia-Syun Lu, Wei-Sheng Chang, Ming-Der Su, and Te-Fang Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01600 • Publication Date (Web): 21 Aug 2017
Downloaded from http://pubs.acs.org on August 22, 2017
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Total Synthesis of (+)-Antrocin and Its Diastereomer and Clarifica-
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‡
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ShengꢀHan Huang, KaiꢀHsiang Liang, JiaꢀSyun Lu, WeiꢀSheng Chang,
,‡,§
,†
MingꢀDer Su,* and TeꢀFang Yang*
†
Department of Applied Chemistry, National Chi Nan University, 1 University Road, Puli, 545 Nantou, Taiwan
Department of Applied Chemistry, National Chiayi University, 60004 Chiayi, Taiwan
‡
§
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 80708 Kaohsiung, Taiwan
O
O
O
O
O
O
O
O
O
O
O
IMDA reaction
O
O
O
high diastereoselectivity
H
iso-(+)-Antrocin
O
H
O
(+)-Antrocin
ABSTRACT: Using 2,2ꢀdimethyl cyclohexanone as the starting compound, (+)ꢀantrocin and its diastereomer have been syntheꢀ
sized. The absolute stereochemistry of (ꢀ)ꢀantrocin, a natural sesquiꢀterpenoid and an antagonist in some types of cancer cells, was
clarified using the character data of (+)ꢀantrocin. The synthetic procedure involved two key steps: (1) the reaction of vinyl magneꢀ
sium bromide with 2,2ꢀdimethylꢀ6ꢀtꢀbutylꢀdimethylꢀsilyoxyꢀmethylꢀ1ꢀcycloꢀhexanone to give a vinyl cyclohexanol derivative and
(2) a highly stereoselective intramolecular DielsꢀAlder (IMDA) reaction of the camphanateꢀcontaining triene intermediate. The
relative energy levels of the possible transition states of the IMDA reaction of the camphanateꢀcontaining triene were obtained from
density functional theory calculations, proving the stereospecific formation of the target molecule.
1
1
tion of molecule C, which is expected to be prepared from inꢀ
termediate D. After molecule E is obtained, intermediate D can be
prepared through the reaction of E with a Grignard reagent, folꢀ
lowed by conversion of a functional group. Thus, the commercialꢀ
ly available compound F should be the precursor of the target
molecule. Herein, we report the total synthesis of (+)ꢀantrocin as
well as a clarification of the absolute stereochemistry of (ꢀ)ꢀ
antrocin, a natural bioactive sesquiꢀterpenoid.
INTRODUCTION
Traditionally, Antrodia camphorate (also called “NiuꢀZarng
Jee”), a fungus that uniquely grows on the withered inner shell of
a Taiwanese lauraceous tree called “NiuꢀZarng”, is utilized as a
multiꢀfunctional folk medicine for the treatment of various diseasꢀ
1ꢀ6
es. Two decades ago, (ꢀ)ꢀantrocin (1, Fig. 1), one of the terpeꢀ
1,7
noids contained in Antrodia camphorata, was first isolated by
5
Chiang et al., who further identified its relative molecular stereoꢀ
structure based on its ORTEP diagram. Recently, antrocin was
proven to be a potent antagonist in several types of cancer cells,
3
especially in MDAꢀMBꢀ231 breast cancer cells. Currently, altꢀ
6
hough Antrodia camphorata is highly valuable in east Asia,
“
8
NiuꢀZarng” trees are not readily available for several reasons,
creating an urgent need for the synthesis of antrocin, which has
9
demonstrated significant biological activity. In 2011, Yang and
coꢀworkers reported the synthesis of racemic antrocin via a casꢀ
cade reaction of a 1,7ꢀdiyne analog with nucleophiles, using gold
10
as the catalyst. To obtain enantiomerically pure antrocin for
medicinal purposes, we designed a synthetic route for the target
product, and this retroꢀsynthesis is illustrated in Figure 2.
Figure 1. Molecular structures of some terpenoids isolated from
the fruit of Antrodia camphorata.
The tricyclic molecule B is one of the key intermediates and
may be furnished by the intramolecular DielsꢀAlder (IMDA) reacꢀ
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hydroxyl ester 14. Dehydration of 14 under the same conditions as
RESULTS AND DISCUSSION
for that of 9 furnished the triene 15. The lactone 16, a stereoisoꢀ
mer of 11, was then obtained from the IMDA reaction of 15. Simꢀ
ilar to the case of intermediate 10, none of the stereoisomers of 16
was detected after the reaction.
As shown in Scheme 1, formylation of commercially available
2,2ꢀdimethyl cyclohexanone (3, i.e., compound F shown in Fig. 2)
1
2
gave ketoꢀenol 4. Reduction of 4 by sodium borohydride proꢀ
vided a diol, of which the primary hydroxyl group was then proꢀ
tected with TBSCl to give secondary alcohol 5. Oxidation of 5
with PCC furnished the cyclohexanone derivative 6. Reaction of
O
O
13
vinyl magnesium bromide with 6 afforded the tertiary alcohol 7.
O
O
The hydroxyl aldehyde 8 was then obtained after removal of the
tertꢀbutyl dimethyl silyl group in 7, followed by oxidation of the
O
HO
O
O
O
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HO
primary hydroxyl group.
8a
8b
O
O
O
O
O
OR
O
Figure 3. Molecular structures of 8a and 8b.
Scheme 2. Synthesis of lactone 11.
OR
A
B
C
O
OH
OH
OPG
O
O
F
D
E
Figure 2. Retroꢀsynthetic analysis of antrocin
.
The formyl group on 8 was further oxidized to a carboxylic acꢀ
15
id (Scheme 2), which immediately underwent esterification with
1
6,17
Eꢀ2ꢀbutenol camphanate (8a, Fig. 3)
in the presence of DCC
to produce the βꢀhydroxyl ester 9. Thionyl chloride was then emꢀ
ployed for the dehydration of 9 to provide the key intermediate
1
0. The IMDA reaction of 10, using TEMPO as the catalyst, gave
18
the lactone 11 as a single product in good yield. Notably, none
of the stereoisomers of 11 was detected after the IMDA reaction.
Hydrogenation of 11 in methanol smoothly afforded the lactone
12 (Scheme 3). The individual absolute stereoꢀstructures of 11
and 12 were confirmed by Xꢀray crystallography of the correꢀ
sponding single crystals. Treatment of 12 with sodium carbonate
furnished the hydroxyl lactone 13. Iodination of 13 followed by
an elimination produced alkene 2, which turned out to be a diaꢀ
stereomer of (ꢀ)ꢀantrocin.
Scheme 3. Synthesis of alkene 2.
O
O
O
O
O
O
H2, Pd/C
K2CO3, MeOH
rt, 95 %
O
O
OH
1
1
MeOH, rt, 95%
H
H
1
2
13
Scheme 1. Synthesis of the aldehyde 8.
O
O
1. I2, PPh3, imidazole, CH2Cl2, rt
1. NaBH4
HCO2Et,
NaOMe
MeOH
0 oC to rt
2. tꢀBuOK, THF, rt
OH
OTBS
OH
65% for 2 steps
H
0 oC to rt
2. TBSCl, im
DMF, rt
92% for 2 steps
O
O
7
3%
2
3
4
5
For the hydrogenation of 16, the same conditions as for that of
1 were employed at first. Unexpectedly, however, the lactone 17
1
PCC, Al2O3
NaOAC
OTBS
Vinyl MgBr
THF, rt, 80%
OTBS
OH
(Scheme 5) was exclusively obtained in good yield. Starting from
CH2Cl2
rt, 86%
O
17, compound 2 was then again provided in three steps: hydrolyꢀ
19
20
sis, iodination and elimination. Thus, at this stage, platinum
dioxide instead of Pd/C was adopted as the catalyst for the hydroꢀ
6
7
2
0(d)
O
genation of 16 in order to obtain the exact target molecule.
1. TBAF
THF, rt
H
OH
Indeed, the reaction smoothly afforded the lactone 18 as the only
product. Diastereospecific hydrogenations of compounds 11 and
16 in the presence of Pd/C to give 12 and 17, respectively, could
be attributed to a directing effect between the catalyst and the
2
. PDC,
CH2Cl2, rt
73% for 2 steps
8
2
0(c)
lactone moiety, which is oriented βꢀface.
On the other hand,
Although compound 2 was not the original target molecule, our
synthetic strategy for the natural product appeared to be feasible.
hydrogenation of 16 in the presence of PtO to give stereospecific
2
18 was probably due to the steric hindrance caused on the βꢀface
16
20
Thus, to obtain natural (ꢀ)ꢀantrocin, Zꢀ2ꢀbutenol camphanate
8b, Fig. 3) was adopted as one of the reactants for the preparation
of the new key intermediate. As shown in Scheme 4, reaction of
b with the crude acid given by the oxidation of 8 provided the βꢀ
by the substituents on the ring. Finally, the target molecule,
(
compound (+)ꢀ1, was furnished after the same three reactions
were carried out starting from 18. Surprisingly, the sign of the
optical rotation of product (+)ꢀ1 was found to be positive, whereas
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the HꢀNMR and CꢀNMR spectral data of (+)ꢀ1 were in excelꢀ
butene moiety is the dienophile, might be attributable to the spaꢀ
tial features of transition states TS5 ~ TS8 illustrated in Figure
5(b). It is speculated that TS7 and TS8 should not exist because of
the large steric effect caused by the chiral auxiliary (Xc) and the
vinyl moiety of diene, and the repulsion effect between the two
carbonyl groups. Therefore, iso-16 could not be obtained at all
from the reaction, and the reaction exclusively provided 16 via
TS5, a predominant conformer compared to TS6.
lent agreement with those of the natural product reported in the
5
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literature.
As illustrated in Figure 4, upon comparison of the
optical rotation ([α] = ꢀ112, C1.0, CHCl ) of antrocin isolated by
D
3
5
Chang and coworkers with that ([α]D = +116, C0.6, CHCl ) of
3
product (+)ꢀ1 synthesized by us, the absolute stereoꢀstructure of
each of the two isomers was accordingly clarified.
To gain a better understanding about each of the IMDA reacꢀ
tions of 10 and 15, which can afford the corresponding stereospeꢀ
cific products, the density functional theory (DFT) was thus perꢀ
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Scheme 4. Synthesis of intermediate 16.
23
formed. It has to be mentioned here that a recent paper reported
by Liptrot and Power demonstrated that the London dispersion
forces could considerably influence the stability, structure and
24
reactivity of molecules bearing large substituents. Since it is
25
wellꢀknown that the B97ꢀD3 functional can describe nonꢀ
covalent interactions (for instance, the London dispersion) sucꢀ
24
cessfully, computations were thus performed using the disperꢀ
23
sionꢀcorrected B97ꢀD3/6ꢀ311G(d,p). For each IMDA reaction,
as illustrated in Figure 6, the diene and dienophile moieties on the
reactant could interact at two different pairs of relative positions,
constructing one transition state with high free energy and the
other with low free energy. During the reaction of 10, according
to the calculation, the activation energy (16.8 kcal/mol) required
to produce 11 was much lower than that (30.7 kcal/mol) required
to produce iso-11, which was higher in Gibb’s free energy than
the former (11) by 0.9 kcal/mol as illustrated in Figure 6(a). On
the other hand, for the reaction of 15, compound 16 was excluꢀ
sively furnished via the pathway possessing transition state
TS(15-16), which was lower in free energy than transition state
TS(15-iso-16) by 12.1 kcal/mol as illustrated in Figure 6(b). Furꢀ
thermore, compound 16 was lower in Gibb’s free energy than
compound iso-16 by 1.6 kcal/mol. In addition, it is speculated that
there are two possible reasons for the difference in energy (Fig. 6)
between TS(10-11) and TS(10-iso-11): (1) in the latter, a signifiꢀ
cant steric repulsion caused by the dienophile, which is connected
to the camphanate moiety, and the diene, which is attached to the
twisted sixꢀmembered ring (TS3 or TS4), as shown in Figure 5,
and (2) a large torsion of the dienophile moiety in TS(10-iso-11).
Two reasons, which are similar to the above, are for the difference
in energy (Fig. 6) between TS(15-16) and TS(15-iso-16). Furꢀ
thermore, on the basis of the selfꢀconsistent reaction field (SCRF)
Scheme 5. Synthesis of (+)ꢀantrocin 1.
2
6
23
To explore the theoretical basis for why only one isomer was
furnished by the IMDA reaction of the triene 10, on which an (E)ꢀ
method (SCRF = PCM) in Gaussian programs, corrections for
solvation in dielectric medium with the toluene dielectric constant
27
2
ꢀbutene moiety is the dienophile, the spatial features of all possiꢀ
(ε = 2.38) were utilized, whose theoretical data are also collectꢀ
ed in Figure 6. As shown in Figure 6, it is apparent that the relaꢀ
tive energies calculated with two methods for different systems,
i.e., B97ꢀD3/6ꢀ311G(d,p) and B97ꢀD3/6ꢀ311G(d,p) + PCM (solꢀ
vent = toluene)//B97ꢀD3/6ꢀ311G(d,p) are quite similar to each
other. As a consequence, the relative activation energy levels
obtained computationally were in excellent agreement with the
aforesaid relative free energy levels of the possible transition
states illustrated in Figure 5, confirming the extremely high steꢀ
reoꢀselectivity of each reaction.
ble transition states (TS1 ~ TS4) were considered and are illusꢀ
trated in Figure 5(a). Conformations TS2 and TS3 are unstable
because of the Aꢀstrain. In addition, TS4 is also unstable due to
the steric effect between the chiral auxiliary (Xc) and ring methꢀ
ylene moiety, and/or that between Xc and pseudoꢀequatorial meꢀ
thyl group. It was hypothesized that TS1 exclusively exists in exoꢀ
2
2
cycloaddition mode. Thus, the diastereomer 11 rather than iso-
1
1 was furnished by the reaction.
O
O
O
O
CONCLUSIONS
In conclusion, by starting with commercially available comꢀ
pound, we achieved the total synthesis of (+)ꢀantrocin and its
diastereomer. The highly stereoꢀselective IMDA reaction of each
triene intermediate (10 or 15) containing a camphanate group was
one of the crucial steps leading to the target molecule. DFT calcuꢀ
lations of the activation energy of both reactions confirmed the
rationale for the formations of the stereoꢀspecific products 11 and
H
H
natural (-)-1
synthetic (+)-1
o
o
[α]
D
= ꢀ112
[α]
D
= +116
(
c 1.0, CHCl
3
)
(c 0.6, CHCl )
3
Figure 4. Comparison of the absolute stereoꢀstructure of natural
(ꢀ)ꢀ1 with that of synthetic (+)ꢀ1.
1
6. The absolute stereoꢀstructure of natural (ꢀ)ꢀantrocin was finalꢀ
ized based on the optical rotation of (+)ꢀantrocin, Xꢀray crystalꢀ
On the other hand, the stereospecific formations of product 16
obtained from the IMDA reaction of triene 15, on which a (Z)ꢀ2ꢀ
28,29
lography of the key intermediates and NMR spectra.
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Figure 5. Structures of the possible transition states of the IMDA reactions of 10 and 15.
Figure 6. Potential energy surfaces of the reactants (10 and 15), transition states, and cycloaddition products (11 and 16) at the B97ꢀD3/6ꢀ
11G(d,p) level of theory. The solvent effect (SCRF= PCM, solvent = toluene) was utilized for the B97ꢀD3/6ꢀ311G(d,p) + PCM (solvent =
toluene)//B97ꢀD3/6ꢀ311G(d,p) method, whose computational data are given in the parentheses. (For more information, see the text).
3
EXPERIMENTAL SECTION
coupling constant in Hz (Hertz), integration. Highꢀresolution mass
spectra were determined on a Jasco JMSꢀHX 110 spectrometer.
Reactions were monitored by thin layer chromatography (TLC) on
General Procedures. Reactions were carried out in round botꢀ
tom flasks fitted with rubber septa under argon. Crude product
TM
Silicycle siliaplate G TLC plates (Fꢀ254 indicator). The optical
solutions were dried on Na SO and concentrated with a rotary
20
2
4
rotation ([α] D) were recorded with a Jasco Pꢀ2000 polarimeter at
o
evaporator below 40 C at ~ 30 Torr. Silica gel column chromaꢀ
tography was performed employing 230 ꢀ 400 mesh silica gel.
5
89 nm (sodium dꢀline) using thermostable optical glass cell (10
mm path length). HRMS measurements were performed using a
magnetic sector mass analyzer.
1
Proton nuclear magnetic resonance ( H NMR) and carbon nuclear
1
3
magnetic resonance ( C NMR) spectra were obtained using
Bruker Avance II (300 MHz) NMR spectrometer. Chemical shifts
(δ scale) are expressed in parts per million downfield from tetraꢀ
methylsilane (δ = 0.00). 1H NMR data are presented as follows:
chemical shift, multiplicity (s = singlet, br = broad singlet, d =
doublet, t = triplet, m = multiplet and/or multiple resonances),
12
(
Z)-6-(Hydroxymethylene)-2,2-dimethylcyclohexanone (4)
.
To a stirred suspension of NaOMe (16.3 g, 302.85 mol) in dry
toluene (300 mL) was added dropwise 2,2ꢀdimethylcycloꢀ
hexanone (20 g, 158.49 mmol) during 30 min at room temperature,
the mixture being stirred throughout this period. To this was added
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dropwise HCO Et (34.9 mL, 406.58 mol) during 15 min at 0 C
2
anhydrous MgSO , and concentrated in vacuo. Purification by
silica gel flash column chromatography (EAꢀhexanes, 1:50) gave
4
and the reaction mixture stirred for 12 h at room temperature beꢀ
fore being poured into ice cooled water. The reaction mixture was
acidified with 10% HCl aq, extracted with EA (3 x 100 mL),
washed with water (3 x 50 mL). The combined organic phases
were washed with brine (100 mL), dried over anhydrous MgSO4,
and concentrated in vacuo. Purification by silica gel flash column
7 (16.2 g, 80%): IR (KBr): 2936, 2860, 1471, 1464, 1389, 1257,
ꢀ
1 1
1084 cm ; H NMR (300 MHz, CDCl ): δ 5.86 (dd, J = 17.1, 10.8
3
Hz, 1H), 5.43 (dd, J = 17.1, 2.4 Hz, 1H), 5.21 (dd, J = 10.5, 2.4
Hz, 1H), 3.98 (d, J = 2.7 Hz, 1H), 3.95 (s, 1H), 3.47 (dd, J = 9.6,
2.1 Hz, 1H), 2.05－1.79 (m, 2H), 1.68－1.50 (m, 3H), 1.40－1.33
chromatography (EAꢀhexanes, 1:20) gave 4 (17.8 g, 73%):
(
m, 1H), 1.13－1.07 (m, 1H), 0.92 (s, 3H), 0.89 (s, 9H), 0.80 (s,
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
H NMR (200 MHz, CDCl ): δ 8.68 (s, 1H), 2.32 (t, J = 6.3 Hz,
3
3
1
H), 0.02 (s, 3H), 0.01 (s, 3H); C NMR (75 MHz, CDCl ): δ
3
2
H), 1.62－1.70 (m, 2H), 1.52－1.56 (m, 2H), 1.19 (s, 6H);
41.5, 114.6, 79.5, 67.0, 39.9, 37.6, 36.1, 25.9, 24.7, 24.6, 23.5,
12(b)
+
[
lit.
NMR (CDCl ): δ 14.40 (1H, broad, s), 8.54 (1H, s),
3
21.7, 18.2, ꢀ5.6, ꢀ5.7; HRMS (EI/magnetic sector) m/z: [M] calcd
for C H O Si 298.2328; found 298.2329.
13
1
1
.5~2.4 (6H), 1.18 (6H, s)]. C NMR (50 MHz, CDCl ): δ 190.4,
3
17
34
2
88.8, 107.2, 37.4, 27.0, 24.3, 19.5.
Hydroxyl aldehyde 8. To a stirred solution of 7 (1.59 g, 5.33
mmol) in THF (80 mL) was added TBAF (1 M in THF, 10.6 mL,
10.6 mmol) at room temperature. The reaction mixture was stirred
for 12 h, then concentrated under reduced pressure. Purification
by silica gel flash column chromatography (EAꢀhexanes, 1:4)
gave corresponding alcohol S-1 (8.8 g, 80%): IR (KBr): 3322,
Alcohol 5. To a stirred solution of 4 (15 g, 97.34 mmol) in
o
MeOH (150 mL) at 0 C was added NaBH4 (5.5 g, 145.91
o
mol).The reaction mixture was allowed to stir for 1 h at 0 C and
quenched with water. The reaction mixture was extracted with EA
(3 x 50 mL). The organic layers were combined, dried with anhyꢀ
ꢀ
1
1
drous MgSO and concentrated. The crude product was used for
4
2980, 2865 1459, 1385, 1249, 1071, 1004cm ; H NMR (300
the next step without purification. To a stirred solution of crude
diol (11.14 g, 70.38 mmol) in DMF (150 mL) was added imidazꢀ
ole (9.58 g, 140.71 mol) and TBDMSCl (15.9 g, 105.56 mol) at 0
MHz, CDCl ): δ 5.91 (dd, J = 17.4, 10.8 Hz, 1H), 5.37 (dd, J =
3
1
1
1
7.4, 1.8 Hz, 1H), 5.25 (dd, J = 10.8, 1.8 Hz, 1H), 3.89 (dd, J =
0.8, 2.1 Hz, 1H), 3.54 (d, J = 10.8 Hz, 1H), 2.77 (s, 1H), 2.30 (br,
H), 1.90－1.84 (m, 1H), 1.81－1.71 (m, 2H), 1.64－1.55 (m,
o
C. After stirring at room temperature for 5 h. The reaction mixꢀ
ture was dilutes with water followed by extraction with EtOAc (3
x 50 mL). The combined organic layers were washed with brine
2H), 1.53－1.47 (m, 1H), 1.20－1.14 (m, 1H), 0.95 (s, 3H), 0.79
13
(s, 3H); C NMR (75 MHz, CDCl ): δ 141.0, 114.4, 80.1, 65.6,
3
(
100 mL), dried over anhydrous MgSO , and concentrated in vacꢀ
4
40.0, 37.6, 36.0, 24.3, 24.2, 23.5, 21.3; HRMS (EI/magnetic secꢀ
uo. Purification by silica gel flash column chromatography (EAꢀ
hexanes, 1:20) gave 5 (24.3 g, 92% for 2 steps): IR (KBr): 3399,
+
tor) m/z: [M] calcd for C H O 184.1463; found 184.1462.
11
20
2
To a stirred solution of the alcohol S-1 (4.4 g, 24.16 mmol) in
ꢀ
1
1
2
954, 2929, 2857, 1461, 1251, 1096 cm ; H NMR (300 MHz,
CH Cl (150 mL) was added PDC (36 g, 95.69 mmol) at room
2
2
CDCl ): δ 4.09 (s, 1H), 3.68 (dd, J = 9.9, 3.9 Hz, 1H), 3.56 (t, J =
3
temperature. The reaction mixture was stirred for 4 h. The reaction
mixture was diluted with CH Cl (240 mL) and washed with water
9
Hz, 1H), 3.18 (d, J = 9 Hz, 1H), 1.73－1.60 (m, 1H), 1.53－1.36
2
2
(m, 4H), 1.16－1.11 (m, 2H), 1.00 (s, 3H), 0.90 (s, 12H), 0.08 (s,
(3 x 80 mL). The organic layer was dried over anhydrous MgSO4,
13
6H); C NMR (75 MHz, CDCl ): δ 83.1, 69.7, 40.5, 39.2, 35.5,
3
and concentrated in vacuo. Purification by silica gel flash column
chromatography (EAꢀhexanes, 1:5) gave 8 (3.9 g, 91%): IR (KBr):
29.2, 27.7, 26.0, 20.9, 18.6, 18.2, ꢀ5.4; Anal calcd for C H O Si:
15
32
2
ꢀ
1
1
C, 66.11; H, 11.84; found: C, 66.35; H, 11.88.
2
937, 2868, 1713, 1455, 1388, 1195 cm ; H NMR (300 MHz,
Ketone 6. To a stirred solution of 5 (9 g, 33.24 mmol) in CH Cl2
2
CDCl ): δ 9.72 (s , 1H), 5.99 (dd, J = 17.4, 7.4 Hz, 1H), 5.29 (m,
3
(100 mL) was added pyridinium chlorochromate (28.6 g, 132.94
mol) at room temperature. Stirring was continued at room temperꢀ
ature until the starting material was disappeared on TLC. The
reaction mixture was diluted with CH Cl (100 mL) and washed
2
H), 2.73 (m, 1H), 1.76－1.61 (m, 5H), 1.26－1.21 (m, 1H), 0.99
13
(s, 3H), 0.86 (s, 3H); C NMR (75 MHz, CDCl ): δ 206.3, 139.9,
3
1
15.2, 77.0, 52.0, 37.2, 35.3, 23.7, 23.1, 21.8, 20.3; HRMS (EI/
2
2
+
with water (3 x 50 mL). The organic layer was dried over anhyꢀ
magnetic sector) m/z: [M] calcd for C11
182.1305.
H O 182.1307; found
18 2
drous MgSO , and concentrated in vacuo. Purification by silica
4
gel flash column chromatography (EAꢀhexanes, 1:40) gave 6 (7.7
Butenol camphanate 8a. To a stirred solution of transꢀ2ꢀ
buteneꢀ1,4ꢀdiol (1.7 g, 19.29 mmol) in CH Cl (50 mL) was added
g, 86%): IR (KBr): 2954, 2930, 2884, 2857, 1703, 1471, 1463,
ꢀ
1
1
2
2
1254, 1122, 1103, 1090 cm ; H NMR (300 MHz, CDCl ): δ 3.97
3
(1S)ꢀ(ꢀ)ꢀcamphanic chloride (4 g, 18.51 mmol) at room temperaꢀ
(dd, J = 10.5, 4.5 Hz, 1H), 3.50 (dd, J = 10.2, 8.4 Hz, 1H), 2.78－
2.67 (m, 1H), 2.38－2.29 (m, 1H), 1.87－1.63 (m, 3H), 1.59－
1.50 (m, 1H), 1.34－1.24 (m, 1H), 1.18 (s, 3H), 1.02 (s, 3H), 0.88
ture. The mixture was stirred at room temperature for 4 h and
quenched with water (50 mL). The aqueous layer was extracted by
CH Cl (3 x 50 mL). The combined organic layers were washed
2 2
1
3
(s, 9H), 0.05 (s, 6H); C NMR (75 MHz, CDCl ): δ 216.2, 62.9,
3
with brine (100 mL), dried over anhydrous MgSO , and concenꢀ
4
8.5, 45.5, 41.8, 31.8, 26.0, 25.4, 25.2, 21.2, 18.4, ꢀ5.2, ꢀ5.3;
4
+
HRMS (EI/magnetic sector) m/z: [M] calcd for C H O Si
trated in vacuo. Purification by silica gel flash column chromatogꢀ
raphy (EAꢀhexanes, 1:5) gave 8a (4.2 g, 82%): IR (KBr):3662,
15 30
2
2
70.2015; found 270.2012.
Vinly alcohol 7. To a solution of 6 (17.9 g, 66.32 mmol) in
THF (100 mL) was added vinyl magnesium bromide (12.54 g,
5.59 mmol). The mixture was stirred at room temperature for 1 h
ꢀ
1
1
2
971, 1783, 1736, 1450, 1311, 1228 cm ; H NMR (300 MHz,
CDCl ): δ 6.00 – 5.93 (m , 1H), 5.88 – 5.81 (m, 1H), 4.73 (d, J =
3
9
5
.7 Hz, 2H), 4.17 (d, J = 4.8 Hz, 2H), 2.42 (td, J = 11.4, 4.8 Hz,
and quenched with saturated aqueous NH Cl solution (50 mL) at 0
4
1H), 2.07－1.95 (m, 2H), 1.93－1.87 (m, 1H), 1.72－1.63 (m,
o
C. The system was extracted by CH Cl (3 x 50 mL). The comꢀ
13
2
2
1H), 1.10 (s, 3H), 1.05 (s, 3H), 0.95 (s, 3H); C NMR (75 MHz,
bined organic layers were washed with brine (100 mL), dried over
CDCl ): δ 178.1, 167.1, 134.7, 123.5, 91.0, 65.2, 62.2, 54.6, 54.1,
3
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5
5
5
5
5
6
+
30.5, 28.7, 16.6, 9.5; HRMS (EI/magnetic sector) m/z: [M] calcd
gel flash column chromatography (EtOAcꢀhexanes, 1:10) gave 11
ꢀ
1
for C H O 268.1311; found 268.1304.
(0.4 g, 72%): IR (KBr): 2929, 1787, 1459, 1313, 1273, 1171 cm ;
14
20
5
20
1
Hydroxyl ester 9. To a stirred solution of 8 (3 g, 16.47 mmol)
in acetone/H O = 3:1 (40 mL) was added 2ꢀmethylꢀbutene (7 mL,
65.87 mmol), NaH PO (2.27 g, 16.45 mmol), and NaClO (4.4 g,
49.42 mmol), and the mixture was stirred at room temperature for
4 h. Then the reaction mixture was diluted with EA (50 mL),
washed with ice cooled aqueous 0.1 M HCl and brine, then dried
[α]
= +51.8 (c 0.1, CHCl ); H NMR (300 MHz, CDCl ): δ
D 3 3
2
5.82ꢀ5.81 (m, 1H), 4.46－4.40 (m, 1H), 4.33－4.24 (m, 3H), 2.48
－2.39 (m, 1H), 2.30－2.47 (m, 2H), 2.10－1.90 (m, 6H), 1.75－
2
4
2
1
3
3
1
3
.66 (m, 2H), 1.60－1.53 (m, 1H), 1.46－1.40 (m, 1H), 1.36 (s,
H), 1.27 (m, 1H), 1.17 (s, 3H), 1.13(s, 3H), 1.06 (s, 3H), 0.96 (s,
13
H); C NMR (75 MHz, CDCl ): δ 177.8, 177.1, 167.3, 139.9,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
over anhydrous MgSO and concentrated in vacuo to give a crude
4
21.9, 90.8, 66.7, 66.4, 54.5, 54.0, 47.6, 45.7, 45.6, 40.2, 36.0,
acid, which was directly used in next step.
5.0, 32.8, 32.0, 30.4, 28.8, 28.6, 27.0, 18.1, 16.5, 9.4; HRMS (EI/
To a stirred solution of the crude acid (2.44 g, 12.32 mmol) in
CH Cl (80 mL) was added 8a (3.04 g, 11.34 mmol), N,N’ꢀ
dicyclohexylcarbodiimide (4.6 g, 22.29 mmol), and DMAP (0.13
g, 1.06 mmol), and the mixture was stirred at room temperature
for 4 h. The mixture was filtered through celite and rinsed with
CH Cl (3 x 25 mL). The filtrate was washed with water (3 x 50
mL), brine (100 mL), dried over anhydrous MgSO , and concenꢀ
trated in vacuo. Purification by silica gel flash column chromatogꢀ
raphy (EAꢀhexanes, 1:30) gave 9 (6.2 g, 73% for 2 steps): IR
KBr): 3088, 2941, 1790, 1731, 1522, 1447, 1266 cm ; H NMR
300 MHz, CDCl ): δ 5.87 (m , 3H), 5.30 (dd, J = 17.4, 1.5 Hz,
H), 5.15 (dd, J = 10.8, 1.5 Hz, 1H), 4.73 (m, 2H), 4.55 (m, 2H)
.66 (s, 1H), 2.83 (dd, J = 12.9, 3.9 Hz, 1H), 2.49－2.39 (m, 1H),
.08－2.04 (m, 1H), 1.94－1.87 (m, 3H), 1.74－1.70 (m, 2H),
.61－1.55 (m, 2H), 1.19 (m, 1H), 1.13 (s, 3H), 1.07 (s, 3H), 0.97
+
magnetic sector) m/z: [M] calcd for C H O 430.2355; found
25
34
6
2
2
4
30.2359.
Tricyclic camphanate 12. To a stirred solution of 11 (0.2 g,
0
.46mmol) in MeOH (50 mL) was added 10% Pd/C (0.02 g, 10
mol%), and the mixture was stirred at room temperature under a
hydrogen atmosphere for 48 h. Then the mixture was filtered
through a celiteꢀsintered funnel and extracted with EA (3 x 20
mL). The organic layers were combined, dried with anhydrous
MgSO4 and concentrated in vacuo gave 12 (0.19 g, 95%): IR
2
2
4
ꢀ
1 1
(
ꢀ1
20
(
0
4
KBr): 2927, 2854, 1782, 1667, 1626, 1457cm ; [α] = +80.2 (c
D
(
1
3
.15, CHCl ); H NMR (300 MHz, CDCl ): δ 4.39ꢀ4.34 (m, 1H),
3
3
1
3
2
1
.23ꢀ4.19 (m, 2H), 4.13ꢀ4.09 (m, 1H),2.49－2.20 (m, 1H) 2.18
(m, 1H), 1.99－1.86 (m, 5H), 1.74－1.60 (m, 3H), 1.40－1.34 (m,
5H), 1.13 (s, 3H), 1.07 (s, 3H), 1.02(s, 3H), 0.98 (s, 3H), 0.96 (s,
13
3
6
3
H); C NMR (75 MHz, CDCl ): δ 181.3, 177.9, 167.7, 91.0,
3
1
3
(s, 3H), 0.94 (s, 3H), 0.87 (s, 3H); C NMR (75 MHz, CDCl ): δ
177.9, 176.2, 167.1, 140.1, 128.7, 127.2, 115.3, 90.9, 75.9, 64.7,
63.6, 54.7, 54.2, 46.4, 36.8, 35.0, 30.6, 28.8, 25.2, 24.5, 22.9,
3
9.7, 68.4, 54.7, 54.2, 46.7, 42.6, 40.2, 38.8, 36.4, 33.7, 31.7,
0.6, 28.8, 27.1, 23.3, 22.0, 18.6, 16.8, 16.7, 9.6; HRMS
EI/magnetic sector) m/z: [M] calcd for C H O 432.2512;
+
(
2
5
36
6
+
20.7, 16.7, 9.6; HRMS (EI/magnetic sector) m/z: [M] calcd for
found 432.2518.
Tricyclic alcohol 13. To a stirred solution of 12 (0.2 g, 0.46
C H O 448.2461; found 448.2465.
2
5
36
7
Triene 10. To a stirred solution of 9 (1.5 g, 3.39 mmol) in pyriꢀ
dine (50 mL) was added SOCl (0.72 mL, 9.92 mmol). The mixꢀ
ture was stirred at room temperature for 2 h and quenched with
saturated aqueous NaHCO solution (50 mL) at 0 C. The mixture
layer was extracted by CH Cl (3 x 20 mL). The organic layers
were combined, washed with brine (100 mL), dried over anhyꢀ
drous MgSO , and concentrated in vacuo. Purification by silica
gel flash column chromatography (EtOAcꢀhexanes, 1:4) gave 10
1.29 g, 89%): IR (KBr): 3082, 2934, 1790, 1731, 1639, 1453 cm
H NMR (300 MHz, CDCl ): δ 6.36 (ddt, J = 17.4, 11.1, 1.8 Hz,
H), 5.89 (m, 2H), 5.06 (ddd, J = 20.7, 17.4, 1.8 Hz, 2H), 4.74 (d,
J = 4.2 Hz, 2H), 4.58 (d, J = 4.2 Hz, 2H), 2.44 (ddd, J = 12.3,
mmol) in MeOH (20 mL) was added K CO (0.1 g, 0.72 mmol).
2
3
2
The mixture was stirred at room temperature for 4 h and quenched
with water (20 mL). The mixture was extracted by CH Cl (3 x 10
2
2
o
3
mL). The organic layers were combined, washed with brine (100
2
2
mL), dried over anhydrous MgSO , and concentrated in vacuo.
4
Purification by silica gel flash column chromatography (EtOAcꢀ
4
hexanes, 1:5) gave 13 (0.11 g, 95%): IR (KBr): 3686, 2918, 2857,
ꢀ1
20
1
1
762, 1453, 1373cm ; [α]
= +90.6 (c 0.13, CHCl ); H NMR
D 3
ꢀ
(
(
300 MHz, CDCl ): δ 4.34 (dd, J = 9.3, 4.5 Hz, 1H), 4.13 (d, J =
3
1
1
;
3
9
1
3
.3 Hz, 1H), 3.64 (d, J = 4.5 Hz, 2H),2.28－2.23 (m, 1H), 1.95－
.84 (m, 3H), 1.69 (br, 1H), 1.60－1.56 (m, 2H), 1.51－ 1.46 (m,
1
13
H), 1.37－1.32 (m, 4H), 1.06 (s, 3H), 1.00 (s, 3H); C NMR (75
1
2
0.5, 3.9 Hz, 1H), 2.27 (td, J = 7.2, 1.8 Hz, 2H), 2.09－1.89 (m,
MHz, CDCl ): δ 181.9, 70.2, 66.3, 46.7, 42.6, 40.3, 38.9, 38.7,
3
H), 1.75－1.63 (m, 3H), 1.52－1.48 (m, 2H), 1.12 (s, 3H), 1.06
33.7, 31.8, 31.7, 27.2, 23.0, 22.1, 18.6; HRMS (EI/magnetic secꢀ
1
3
(
s, 9H), 0.97 (s, 3H); C NMR (75 MHz, CDCl ): δ 177.9, 170.6,
67.1, 148.8, 135.4, 129.3, 127.0, 126.8, 117.6, 90.9, 64.9, 63.5,
4.7, 54.2, 38.2, 34.0, 30.6, 28.8, 27.9, 27.4, 18.4, 16.7, 9.6;
+
3
tor) m/z: [M] calcd for C H O 252.1725; found 252.1720.
15
24
3
1
5
Tricyclic alkene 2. To a stirred solution of 13 (80 mg, 0.31
mmol) in DCM (10 mL) was added PPh (0.13 g, 0.49 mmol),
3
+
HRMS (EI/magnetic sector) m/z: [M] calcd for C H O
2
5
34
6
imidazole (69 mg, 1.01 mmol), and I (160 mg, 0.63 mmol) at 0
2
4
30.2355; found 430.2364.
Lactone 11. To a stirred solution of 10 (0.56 g, 1.30 mmol) in
anhydrous degassed toluene (5 mL) was added TEMPO (0.05 g,
0 mol%) and heated in a sealed tube under argon at 185 C for 5
d. The reaction mixture was cooled to room temperature. The
reaction mixture was diluted with CH Cl (100 mL) and washed
o
C. The reaction mixture was stirred for 2 h at room temperature,
quenched with saturated aqueous Na S O solution (15 mL), and
2
2
3
extracted with EA (3 x 10 mL). The organic layers were comꢀ
o
1
bined, dried with anhydrous MgSO and concentrated in vacuo.
4
Purification by silica gel flash column chromatography (EtOAcꢀ
2
2
hexanes, 1:6) gave corresponding lactone S-2 (0.11 g, 82%): IR
with water (3 x 50 mL). The organic layer was dried over anhyꢀ
drous MgSO , and concentrated in vacuo. Purification by silica
ꢀ1
20
(
KBr): 2929, 1769, 1481, 1455, 1367, 1195cm ; [α] = 78.1 (c
D
4
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6
0.3, CHCl ); H NMR (300 MHz, CDCl ): δ 4.34 (dd, J = 9.3, 4.2
3
3
vacuo. Purification by silica gel flash column chromatography
(EtOAcꢀhexanes, 1:5) gave 14 (7.78 g, 79% for 2 steps): IR
(KBr): 3060, 2967, 1790, 1715, 1639, 1447, 1379 cm ; H NMR
Hz, 1H), 3.99 (d, J = 9.3 Hz, 1H), 3.38－3.25 (m, 2H), 2.22 (dd, J
10.2, 4.2 Hz, 1H), 1.97－1.91 (m, 2H), 1.85 (m, 1H), 1.64－
ꢀ
1 1
=
(300 MHz, CDCl ): δ 5.90－5.72 (m , 3H), 5.31－5.12 (m, 2H),
3
1
3
4
1
.52 (m, 5H), 1.48－1.41 (m, 1H), 1.39－1.31(m, 3H), 1.07 (s,
13
4.81 (d, J = 5.4 Hz, 2H), 4.66 (d, J = 5.1 Hz, 2H), 3.62 (s, 1H),
H), 1.05 (s, 3H); C NMR (75 MHz, CDCl ): δ 181.3, 69.4,
3
2
.80 (dd, J = 12.9, 3.9 Hz, 1H), 2.83 (dd, J = 12.1, 3.9 Hz, 1H),
6.9, 42.6, 42.3, 40.1, 37.8, 33.6, 31.9, 31.8, 27.3, 26.9, 22.0,
+
2.06－2.01 (m, 1H), 1.98－1.82 (m, 3H), 1.73－1.66 (m, 3H),
8.7, 14.7; HRMS (EI/magnetic sector) m/z: [M] calcd for
1
3
1
5
2
.58 (m, 1H), 1.18 (m, 1H), 1.17 (s, 3H), 1.05 (s, 3H), 0.95 (s,
C H IO 362.0743; found 362.0746.
1
5
23
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
H), 0.93 (s, 3H), 0.86 (s, 3H); C NMR (75 MHz, CDCl ): δ
To a stirred solution of Lactone S-2 (70 mg, 0.15 mmol) in THF
10 mL) was added tꢀBuOK (50 mg, 0.45 mmol). The mixture was
3
77.8, 176.2, 167.2, 140.1, 128.6, 127.3, 115.2, 90.8, 75.9, 60.7,
9.7, 54.7, 54.2, 46.4, 36.8, 35.0, 30.5, 28.8, 25.1, 24.5, 22.8,
(
stirred at room temperature for 4 h and quenched with water (20
mL). The mixture was extracted by CH Cl (3 x 10 mL). The orꢀ
+
0.7, 16.6, 9.6; HRMS (EI/ magnetic sector) m/z: [M] calcd for
2
2
C H O 448.2461; found 448.2452.
ganic layers were combined, washed with brine (50 mL), dried
25 36
7
Triene 15. To a stirred solution of 14 (2 g, 4.46 mmol) in pyriꢀ
over anhydrous MgSO , and concentrated in vacuo. Purification
4
dine (50 mL) was added SOCl (0.94 mL, 13.05 mmol). The mixꢀ
by silica gel flash column chromatography (EtOAcꢀhexanes, 1:6)
2
ture was stirred at room temperature for 2 h and quenched with
gave tricyclic alkene 2 (20 mg, 78%): IR (KBr): 2930, 2361,
o
ꢀ
1
20
1
saturated aqueous NaHCO solution (50 mL) at 0 C. The mixture
1
768, 1647, 1275, 1158 cm ; [α] = +120.3 (c 0.1, CHCl ); H
3
D
3
was extracted with CH Cl (3 x 20 mL). The organic layers were
NMR (300 MHz, CDCl ): δ 4.84 (d, J = 15.6 Hz, 2H), 4.24ꢀ4.21
2
2
3
combined, washed with brine (100 mL), dried over anhydrous
(m, 1H), 2.83 (t, J = 7.5 Hz, 1H), 2.25－2.13 (m, 3H), 1.97－1.91
MgSO , and concentrated in vacuo. Purification by silica gel flash
4
(m, 1H), 1.84 (m, 1H), 1.52－1.35 (m, 5H), 1.08 (s, 3H), 0.86 (s,
13
column chromatography (EtOAcꢀhexanes, 1:4) gave 15 (1.53 g,
3H); C NMR (75 MHz, CDCl ): δ 182.1, 143.9, 112.0, 68.9,
3
ꢀ
1
1
8
0%)l: IR (KBr): 3079, 2934, 1790, 1731, 1639, 1453 cm ; H
NMR (300 MHz, CDCl ): δ 6.37 (dd, J = 17.4, 11.4 Hz, 1H), 5.83
5.74 (m, 2H), 5.08 (ddd, J = 13.2, 11.4, 2.1 Hz, 2H), 4.85 (d, J
50.7, 46.3, 41.6, 36.0, 33.7, 29.8, 29.6, 29.2, 29.0, 23.9, 18.3;
+
3
HRMS (EI/magnetic sector) m/z: [M] calcd for C H O
15
22
2
－
234.1620; found 234.1626.
Butenol camphanate 8b. To a stirred solution of cisꢀ2ꢀbuteneꢀ
= 5.7 Hz, 2H), 4.70 (d, J = 5.4 Hz, 2H), 2.44 (td, J = 10.8, 4.5 Hz,
1H), 2.27 (td, J = 6.3, 2.1 Hz, 2H), 2.09－1.89 (m, 2H), 1.75－
1.66 (m, 3H), 1.52－1.50 (m, 2H), 1.22 (s, 3H), 1.07 (s, 9H), 0.97
1
,4ꢀdiol (2 g, 22.69 mmol) in CH Cl (50 mL) was added (ꢀ)ꢀ
2
2
camphanic chloride (4.7 g, 21.77 mmol). The mixture was stirred
at room temperature for 4 h and quenched with water (50 mL).
The mixture was extracted by CH Cl (3 x 50 mL). The organic
13
(s, 3H); C NMR (75 MHz, CDCl ): δ 178.0, 170.7, 167.2, 148.8,
3
135.4, 128.9, 127.0, 117.7, 90.9, 61.0, 59.7, 54.7, 54.2, 38.3, 34.0,
30.6, 29.6, 28.3, 28.0, 27.5, 18.5, 16.7, 9.6; HRMS (EI/magnetic
2
2
layers were combined, washed with brine (100 mL), dried over
+
anhydrous MgSO , and concentrated in vacuo. Purification by
sector) m/z: [M] calcd for C H O 430.2355; found 430.2364.
4
25 34
6
silica gel flash column chromatography (EAꢀhexanes, 1:5) gave
Lactone 16. To a stirred solution of 15 (0.8 g, 1.85 mmol) in
8
1
5
2
1
b (4.8 g, 80%): IR (KBr): 3661, 2971, 1788, 1736, 1450, 1312,
anhydrous degassed toluene (5 mL) was added TEMPO (0.08 g,
ꢀ1
1
o
228 cm ; H NMR (300 MHz, CDCl ): δ 5.92－5.87 (m , 1H),
10 mol%) and heated in a sealed tube under argon at 185 C for 5
3
d. The reaction mixture was cooled to room temperature. The
reaction mixture was diluted with CH Cl (100 mL) and washed
.69－5.64 (m, 1H), 4.85 (d, J = 6.9 Hz, 2H), 4.29 (d, J = 6.3 Hz,
2
2
H), 2.43 (td, J = 12.1, 4.2 Hz, 1H), 2.08－1.88 (m, 3H), 1.73－
13
with water (3 x 50 mL). The organic layer was dried over anhyꢀ
.65 (m, 1H), 1.12 (s, 3H), 1.05 (s, 3H), 0.95 (s, 3H); C NMR
drous MgSO , and concentrated in vacuo. Purification by silica
4
(
75 MHz, CDCl ): δ 177.9, 167.3, 134.3, 124.1, 90.8, 61.0, 58.1,
3
gel flash column chromatography (EtOAcꢀhexanes, 1:10) gave 16
5
4.6, 54.1, 30.3, 28.7, 16.5, 16.5, 9.4; HRMS (EI/magnetic sector)
ꢀ1
+
(0.42 g, 76%): IR (KBr): 2929, 1787, 1760, 1459, 1274, 1017 cm ;
m/z: [M] calcd for C H O 268.1311; found 268.1300.
14 20
5
20
1
[
α]
= +41.1 (c 0.4, CHCl ); H NMR (300 MHz, CDCl ): δ
D 3 3
Hydroxyl ester 14. To a stirred solution of 8 (4 g, 21.96 mmol)
5
3
.78 (d, , J = 6.3 Hz, 1H), 4.23－4.13 (m, 4H), 2.58－2.38 (m,
H), 2.18－1.98 (m, 6H), 1.81－1.66 (m, 2H), 1.53－1.45 (m,
in acetone/H O = 3:1 (44 mL) was added 2ꢀmethylꢀbutene (9.3 g,
2
87.82 mmol), NaH PO (3.02 g, 21.93 mmol), and NaClO (5.96
2
4
2
g, 65.89 mmol) at room temperature. After 4 h, the reaction mixꢀ
ture was diluted with EtOAc (20 mL), washed with ice cooled
2H), 1.27－1.17 (m, 1H), 1.17 (s, 3H), 1.12(s, 3H), 1.10 (s, 3H),
13
1.06 (s, 3H), 0.96 (s, 3H); C NMR (75 MHz, CDCl ): δ 179.1,
3
aqueous 0.1 M HCl and brine, dried over anhydrous MgSO and
177.9, 167.5, 141.9, 121.4, 91.0, 67.1, 64.7, 54.8, 54.3, 46.9, 45.5,
45.4, 41.1, 37.9, 36.6, 32.7, 30.8, 30.4, 28.9, 26.4, 24.5, 18.6, 16.9,
4
concentrated in vacuo to give a crude acid, which was directly
used in next step.
+
9.7; HRMS (EI/magnetic sector) m/z: [M] calcd for C H O
2
5
34
6
To a stirred solution of the crude acid (3 g, 15.14 mmol) in
CH Cl (50 mL) was added 8b (3.74 g, 13.94 mmol), N,N’ꢀ
430.2355; found 430.2348.
Tricyclic camphanate 17. To a stirred solution of 16 (0.3 g,
0.69 mmol) in MeOH (50 mL) was added 10% Pd/C (0.03, 10
mol%), and the mixture was stirred at room temperature under a
hydrogen atmosphere for 48 h. Then the mixture was filtered
through a celiteꢀsintered funnel and extracted with EA (3 x 20
mL). The organic layers were combined, dried with anhydrous
2
2
dicyclohexylcarbodiimide (5.6 g, 27.4 mmol), and DMAP (0.15 g,
1.3 mmol), and the mixture was stirred at room temperature for 4
h. The mixture was filtered through celite and rinsed with CH Cl2
2
(3 x 25 mL). The filtrate was washed with water (3 x 50 mL) and
brine (100 mL), dried over anhydrous MgSO , and concentrated in
4
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The Journal of Organic Chemistry
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
MgSO and concentrated in vacuo. Purification by silica gel flash
were in excellent agreement with those of tricyclic alkene 2 obꢀ
tained from tricyclic alcohol 13.
Tricyclic camphanate 18. To a stirred solution of 16 (0.1 g,
4
column chromatography (EtOAcꢀhexanes, 1:5) gave 17 (0.29 g,
ꢀ
1
20
98%): IR (KBr): 2928, 2854, 1782, 1627, 1450, 1175 cm ; [α]
D
1
= +58.1 (c 0.14, CHCl ); H NMR (300 MHz, CDCl ): δ 4.3 (td, J
0.23 mmol) in MeOH (20 mL) was added 10% PtO (0.01, 10
3
3
2
= 9.3, 1.8 Hz, 1H), 4.08 (m, 3H), 2.47－2.40 (m, 2H), 2.30 (m,
mol%), and the mixture was stirred at room temperature under a
hydrogen atmosphere for 48 h. Then the mixture was filtered
through a celiteꢀsintered funnel and extracted with EA (3 x 20
mL). The organic layers were combined, dried with anhydrous
1
5
3
6
3
H), 2.07－1.88 (m, 4H), 1.74－1.66 (m, 3H), 1.64－1.48 (m,
H), 1.44 (m, 2H) 1.28 (s, 6H), 1.27 (s, 3H), 1.05(s, 3H), 0.95 (s,
13
H); C NMR (75 MHz, CDCl ): δ 181.8, 177.8, 167.3, 90.8,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MgSO and concentrated in vacuo. Purification by silica gel flash
4
7.2, 64.3, 54.6, 54.1, 46.0, 45.9, 43.6, 41.6, 33.9, 33.7, 32.3,
column chromatography (EtOAcꢀhexanes, 1:5) gave 18 (0.09 g,
1.9, 30.6, 28.7, 28.1, 27.4, 23.8, 22.9, 18.1, 16.6, 9.5; HRMS (EI/
ꢀ
1
+
90%): IR (KBr): 2926, 2864, 1785, 1740, 1630, 1422, 1116 cm ;
magnetic sector) m/z: [M] calcd for C H O 432.2512; found
2
5
36
6
20
1
[
α]
= +64.4 (c 0.4, CHCl ); H NMR (300 MHz, CDCl ): δ
D 3 3
4
32.2514.
Tricyclic alkene 2 (from 17). To a stirred solution of 17 (30
mg, 0.06 mmol) in MeOH (10 mL) was added K CO (20 mg,
4
.32－4.08 (m, 4 Hz, 1H), 2.47－2.29 (m, 3H), 2.15－2.02 (m,
2H), 1.99－1.90 (m, 1H), 1.81－1.80 (m, 1H), 1.76－1.56 (m,
5H), 1.52－1.44 (m, 2H) 1.41－1.37 (m, 2H), 1.26 (m, 1H), 1.19
2
3
0
.14 mmol). The mixture was stirred at room temperature for 4 h
and quenched with water (20 mL). The mixture was extracted
with CH Cl (3 x 10 mL). The organic layers were combined,
13
(
s, 3H), 1.13 (s, 3H), 1.06 (s, 3H), 0.96 (s, 6H); C NMR (75
2
2
MHz, CDCl ): δ 178.8, 177.9, 167.3, 908, 66.3, 64.8, 54.6, 54.1,
3
washed with brine (100 mL), dried over anhydrous MgSO , and
4
46.8, 46.7, 46.3, 43.5, 41.8, 37.3, 33.2, 33.0, 32.1, 30.6, 28.7, 22.0,
+
concentrated in vacuo. Purification by silica gel flash column
chromatography (EAꢀhexanes, 1:3) gave S-3 (16 mg, 93%): IR
2
1.0, 19.0, 18.3, 16.6, 9.5; HRMS (EI/magnetic sector) m/z: [M]
calcd for C H O 432.2512; found 432.2514.
25 36
6
ꢀ
1
20
(
+
KBr): 3435, 2933, 2870, 1762, 1627, 1457, 1268 cm ; [α]
=
D
(+)-Antrocin (1). To a stirred solution of 18 (50 mg, 0.1 mmol)
1
109.8 (c 0.05, CHCl ); H NMR (300 MHz, CDCl ): δ 4.29 (t, J
3 3
in MeOH (20 mL) was added K CO (4 mg, 0.28 mmol). The
2
3
=
9 Hz, 1H), 4.14 (d, J = 8.7 Hz, 1H), 3.57－3.50 (m, 2H), 2.42－
mixture was stirred at room temperature for 4 h and quenched
with water (20 mL). The mixture was extracted by CH Cl (3 x 10
mL). The organic layers were combined, washed with brine (100
2.38 (m, 2H), 1.92－1.87 (m, 2H), 1.69－1.59 (m, 4H), 1.53 (m,
2
2
13
2
H), 1.44 (m, 1H), 1.39 (m, 1H), 1.14 (s, 3H), 0.91 (s, 3H);
C
mL), dried over anhydrous MgSO , and concentrated in vacuo.
NMR (75 MHz, CDCl ): δ 182.9, 65.1, 64.8, 46.0, 43.7, 42.0,
4
3
Purification by silica gel flash column chromatography (EtOAcꢀ
3
5.2, 34.0, 33.9, 28.2, 27.5, 23.9, 23.2, 21.0, 18.3; HRMS
+
hexanes, 1:3) gave corresponding alcohol S-5 (20 mg, 95%): IR
(EI/magnetic sector) m/z: [M] calcd for C H O 252.1725;
15 24 3
ꢀ
1
20
(KBr): 3447, 2932, 2870, 1762, 1636, 1457, 1097 cm ; [α]
=
D
found 252.1729.
To a stirred solution of S-3 (40 mg, 0.15 mmol) in DCM (10
1
+101.9 (c 0.2, CHCl ); H NMR (300 MHz, CDCl ): δ 4.35－4.23
3 3
mL) was added PPh (60 mg, 0.22 mmol), imidazole (30 mg, 0.45
(m, 2H), 3.67－3.51 (m, 2H), 2.42－2.36 (m, 1H), 2.14－2.10 (m,
3
o
mmol), and I (76 mg, 0.30 mmol) at 0 C. The reaction mixture
2
2H), 1.86－1.70 (m, 4H), 1.58－1.50 (m, 3H), 1.49－1.38 (m,
was stirred for 2 h at room temperature, quenched with saturated
aqueous Na S O solution (10 mL), and extracted with EA (3 x 10
13
2
H), 1.32－1.29 (m, 1H), 1.18 (s, 3H), 0.94 (s, 3H); C NMR (75
2
2
3
MHz, CDCl ): δ 175.9, 70.8, 62.1, 58.8, 55.5, 51.0, 50.5, 47.1,
3
mL). The organic layers were combined, dried with anhydrous
4
2.2, 39.0, 38.5, 33.9, 32.7, 28.9, 21.3, 20.3, 18.6; HRMS (EI/
MgSO and concentrated in vacuo. Purification by silica gel flash
+
4
magnetic sector) m/z: [M] calcd for C H O 252.1725; found
15
24
3
column chromatography (EtOAcꢀhexanes, 1:6) gave S-4 (5 mg,
2
52.1733.
To a stirred solution of alcohol S-5 (21 mg, 0.08 mmol) in
ꢀ1
20
7
5%): IR (KBr): 2924, 1769, 1481, 1455, 1367, 1195 cm ; [α]
D
1
=
+88.1 (c 0.16, CHCl ); H NMR (300 MHz, CDCl ): δ 4.18－
3
3
DCM (10 mL) was added PPh (35 mg, 0.13 mmol), imidazole
3
4
2
1
.09 (m, 2H), 3.09－3.04 (m, 1H), 2.89 (t, J = 9.9 Hz, 1H), 2.47－
.45 (m, 2H), 1.89－1.82 (m, 3H), 1.58－1.48 (m, 4H), 1.43－
o
(
18 mg, 0.27 mmol), and I (43 mg, 0.17 mmol) at 0 C. The reacꢀ
2
tion mixture was stirred for 2 h at room temperature, quenched
with saturated aqueous Na solution (10 mL), and extracted
13
.25 (m, 3H), 1.16－1.12 (m, 1H), 1.04 (s, 3H), 0.88 (s, 3H);
C
S O
2 2 3
with EA (3 x 20 mL). The organic layers were combined, dried
NMR (75 MHz, CDCl ): δ 179.1, 64.1, 49.4, 46.9, 43.1, 42.0,
3
with anhydrous MgSO and concentrated in vacuo. Purification by
37.5, 35.9, 33.2, 33.0, 24.9, 22.1, 19.6, 18.4, 8.6; HRMS
4
+
silica gel flash column chromatography (EtOAcꢀhexanes, 1:6)
(EI/magnetic sector) m/z: [M] calcd for C H IO 362.0743;
1
5
23
2
gave corresponding lactone S-6 (22 mg, 73%): IR (KBr): 2928,
found 362.0741.
ꢀ
1
20
1
769, 1481, 1455, 1195, 1127 cm ; [α]
D
= +85.9 (c 0.2, CHCl3);
To a stirred solution of S-4 (50 mg, 0.10 mmol) in THF (10
mL) was added tꢀBuOK (46 mg, 0.40 mmol). The mixture was
stirred at room temperature for 4 h and quenched with water (20
mL). The mixture was extracted with CH Cl (3 x 15 mL). The
1
H NMR (300 MHz, CDCl ): δ 4.31 (dd, J = 10.5, 7.5 Hz, 1H),
3
4.10 (dd, J = 10.2, 1.8 Hz, 1H), 3.25 (dd, J = 10.2, 6.3 Hz, 1H),
2.95 (t, J = 10.2 Hz, 1H), 2.45 (t, J = 6.3 Hz, 1H), 2.23－2.21 (m,
2H), 1.84－1.70 (m, 3H), 1.53－1.52 (m, 2H), 1.49－1.40 (m,
2
2
organic layers were combined, washed with brine (50 mL), dried
13
over anhydrous MgSO , and concentrated in vacuo. Purification
4
3H), 1.38－1.28 (m, 2H), 1.18 (s, 3H), 0.94 (s, 3H); C NMR (75
by silica gel flash column chromatography (EtOAcꢀhexanes, 1:20)
gave tricyclic alkene 2 (0.02 g, 79%). All the characterized data
MHz, CDCl ): δ 179.2, 64.3, 49.5, 47.0, 43.2, 42.1, 37.6, 36.1,
3
3
3.4, 33.2, 25.1, 22.2, 19.8, 18.6, 8.8; HRMS (EI/magnetic sector)
+
m/z: [M] calcd for C H IO 362.0743; found 362.0748.
15
23
2
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The Journal of Organic Chemistry
1
2
To a stirred solution of lactone S-6 (20 mg, 0.06 mmol) in THF
(10 mL) was added tꢀBuOK (18 mg, 0.17 mmol). The mixture was
(5) Chiang, H. ꢀC.; Wu, D. ꢀP.; Cherng, I. ꢀW.; Ueng, C. ꢀH. Phytochemꢀ
istry, 1995, 39, 613ꢀ616.
6) Chen, J. C. “King of Ganoderma: Antrodia Camphorata in Taiwan”,
Yuen Chi Jai Book Publishing: Taipei, Taiwan, 2 Ed. 2008.
(7) (a) Chen, C. ꢀC.; Shiao, Y. ꢀJ.; Lin, R. ꢀD.; Shao, Y. ꢀY.; Lai, M. ꢀN.;
Lin, C. ꢀC.; Ng, L. ꢀT.; Kuo, Y. ꢀH. J. Natural Products. 2006, 69, 689ꢀ
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
stirred at room temperature for 4 h and quenched with water (20
mL). The mixture was extracted with CH Cl (3 x 15 mL). The
nd
2
2
organic layers were combined, washed with brine (50 mL), dried
8
91. (b) Han, B. H.; Yang, H. O.; Kang, Y. H.; Suh, D. Y.; Go, H. J.;
over anhydrous MgSO , and concentrated in vacuo. Purification
4
Song, W. J.; Kim, Y. C.; Park, M. K. J. Med. Chem. 1998, 41, 2626ꢀ2630.
(c) Chiang, Y. M.; Liu, H. K.; Lo, J. M.; Chien, S. C.; Chan, Y. F.; Lee, T.
H.; Su, J. K.; Kuo, Y. H. J. Chin. Chem. Soc. 2003, 50, 161ꢀ166. (d) Rojas,
E. T.; RodriguezꢀHahn, L. Phytochemistry, 1978, 17, 574ꢀ575.
by silica gel flash column chromatography (EtOAcꢀhexanes, 1:20)
gave (+)-1 (11 mg, 78%): IR (KBr): 2922, 1769, 1459, 1366, 1158
ꢀ
1
20
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
cm ; [α]
= +116.1 (c 0.6, CHCl3); H NMR (300 MHz,
D
(8) Wu, S. ꢀH.; Ryvarden, L.; Chang, T. ꢀT. Botanical Bulletin of Acaꢀ
CDCl ): δ 4.83 (d, J = 10.2 Hz, 2H), 4.48 (dd, J = 9.3, 6.6 Hz,
3
demia Sinica. 1997, 38, 273ꢀ275.
(9) Cragg, G. M.; Grothaus, P. G.; Newman, D. J. Chem. Rev. 2009, 109,
3012ꢀ3043.
1
H), 4.16 (dd, J = 9.6, 1.2 Hz, 1H), 2.68 (d, J = 6.6 Hz, 1H), 2.41
2.22 (m, 2H), 2.20－2.14 (m, 1H), 1.86－1.74 (m, 2H), 1.58－
.49 (m, 2H), 1.48－1.44 (m, 1H), 1.40－1.33 (m, 2H), 1.27－
－
(10) Shi, H.; Fang, L.; Tan, C.; Shi, L.; Zhang, W.; Li, C.ꢀC.; Luo T.;
1
1
Yang, Z. J. Am. Chem. Soc. 2011, 133, 14944ꢀ14947.
1
3
(11) For examples of the intramolecular DielsꢀAlder (IMDA) reaction,
please see : (a) Lilly, M. J.; Sherburn, M. S. Chem. Commun. 1997, 967ꢀ
968. (b) Suzuki, Y.; Ohara, A.; Sugaya, K.; Takao, K. ꢀi.; Tadano, K. ꢀi.
Tetrahedron, 2001, 57, 7291ꢀ7301. (c) Suzuki, Y.; Nishimaki, R.;
Ishikawa, M.; Murata, T.; Takao, K. ꢀi.; Tadano, K. ꢀi. J. Org. Chem.,
.22 (m, 1H), 1.19 (s, 3H), 0.95 (s, 3H); C NMR (75 MHz,
CDCl ): δ 178.4, 146.7, 111.2, 69.4, 54.2, 48.5, 46.6, 42.0, 36.8,
3
3
3.3, 33.2, 30.4, 22.4, 22.2, 18.7; HRMS (EI/magnetic sector)
+
m/z: [M] calcd for C H O 234.1620; found 234.1614.
1
5
22
2
2
000, 65, 8595ꢀ8607. (d) Ishihara, J.; Yamamoto, Y.; Kanoh, N.; Murai, A.
Tetrahedron Lett. 1999, 40, 4387ꢀ4390. (e) Usui, K.; Suzuki, T.; Nakada,
M. Tetrahedron Lett. 2015, 56, 1247ꢀ1251. (f) Chackalamannil, S.;
Davies, R. J.; Wang, Y.; Asberom, T.; Doller, D.; Wong, J.; Leone, D. J.
Org. Chem. 1999, 64, 1932ꢀ1940. (g) Jauch, J. Angew. Chem. Int. Ed.
ASSOCIATED CONTENT
Supporting Information
2
000. 39, 2764ꢀ2765. (h) Zhao, Y. ꢀM.; Maimone, T. J. Angew. Chem. Int.
NMR spectra for all the new compounds, Xꢀray crystallographic
data
Ed. 2015, 54, 1223ꢀ1226.
(12) (a) Bourdron, J.; Commeiras, L.; Audran, G.; Vanthuyne, N.;
Hubaud, J. C.; Parrain, J. ꢀL. J. Org. Chem. 2007, 72, 3770ꢀ3775. (b) Kaꢀ
wanobe, T.; Kogami, K.; Hayashi, K.; Matsui, M. Agric. Biol. Chem. 1984,
Crystallographic data of 11
Crystallographic data of 12
Crystallographic data of 16
Crystallographic data of 1
4
8, 461ꢀ464.
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M.; de Arellano, C. R. J. Org. Chem. 2000, 65, 4189ꢀ4192.
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(
6
270ꢀ6273.
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T. S.; Silverman, R. B. Bioorg. Med. Chem. 2010, 18, 1124ꢀ1134.
16) Compounds 8a and 8b were obtained from the individual reactions
AUTHORS’ INFORMATION
Corresponding Authors
(
of (1S)ꢀ(ꢀ)ꢀcamphanic chloride with transꢀ2ꢀbuteneꢀ1,4ꢀdiol and cisꢀ2ꢀ
buteneꢀ1,4ꢀdiol (Fig. 3), respectively. See the Experimental Section for the
procedure.
(17) For the reaction of (1S)ꢀ(ꢀ)ꢀcamphanic chloride with alcohols,
please see: (a) Bieliunas, V.; Rackauskaite, D.; Orentas, E.; Stoncius, S.
J. Org. Chem. 2013, 78, 5339ꢀ5348. (b) Nicolaou, K. C.; Yang, Z.; Liu, J.
* Email: tfyang@ncnu.edu.tw
* Email: midesu@mail.ncyu.edu.tw
Notes:
The authors declare no competing financial interest.
ꢀ
J. Nantermet, P. G.; Claiborne, C. F.; Renaud, J.; Guy, R. K.; Shibayama,
K. J. Am. Chem. Soc. 1995, 117, 645ꢀ652.
18) For the example of utilizing TEMPO as catalyst for IMDA reaction,
ACKNOWLEDGMENTS
(
see Chackalamannil, S.; Davies, R. J.; Wang, Y,; Asberom, T.; Doller, D.;
Wong, J.; Leone, D. J. Org. Chem. 1999, 64, 1932ꢀ1940.
(19) Imuta, S.; Tanimoto, H.; Momose, M. K. N. Chida, Tetrahedron
2006, 62, 6926ꢀ6944.
This work was supported by the National Science Council,
Taiwan (Grant NSC 99ꢀ2119ꢀMꢀ260ꢀ002ꢀMY2), which is grateꢀ
fully acknowledged. The authors also thank the Instrumental Cenꢀ
ter at National Taiwan University and the Regional Instruments
Center at National ChungꢀHsing University for highꢀresolution
mass spectrometry and Xꢀray crystallography analyses. The auꢀ
thors are grateful to the National Center for HighꢀPerformance
Computing of Taiwan for providing massive computing resources
to facilitate this research. We also thank the Ministry of Science
and Technology of Taiwan for the financial support.
(
20) (a) Tapia, R.; Bouanou, H.; Alvarez, E.; AlvarezꢀManzaneda, R.;
Chahboun, R.; AlvarezꢀManzaneda, E. J. Org. Chem. 2014, 79, 4405ꢀ
413. (b) Cheung, W. S.; Wong, H. N. C. Tetrahedron 1999, 55, 11001ꢀ
11016.
c) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655ꢀ2661.
4
(
(
d) The hydrogenation of lactone 11 in the presence of PtO
2
gave exactly
the same product (12) as that in the presence of Pd/C did.
(21) The chemical shift difference between their corresponding C NMR
signals was found to be < 0.2 ppm.
13
(22) Usui, K.; Kanbe, M.; Nakada, M. Org. Lett. 2014, 16, 4734ꢀ4737.
REFERENCES AND NOTES
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(29) It has to be noted that the absolute stereoꢀstructure of synthetic (+)ꢀ1
(Fig. 4) is exactly the same as that of synthetic (ꢀ)ꢀ1 reported in the literaꢀ
ture (ref. 28). Thus, it is worth emphasis that the absolute configuration of
(+)ꢀ1 (Fig. 4) was determined in terms of the Xꢀray crystallography of
intermediates 11 (Scheme 2), 12 (Scheme 3) and 16 (Scheme 4), in which
the absolute configuration of (ꢀ)ꢀcamphanic moiety was known. Please see
the Supporting Information for all the CIF data of 11, 12, 16 and (+)ꢀ1
(Scheme 5).
(
(
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