Stereoselective syntheses of four diastereomers of 3,9,12- trihydroxycalamenene via a benzobicyclo[3.3.1] intermediate

Article abstract of DOI:10.1021/jo1008349

The highly stereoselective syntheses of four diastereomers of natural 3,9,12-trihydroxycalamenene are described. The syntheses highlight the utility of an unusual framework of benzobicyclo[3.3.1] lactones, which were accomplished via an intramolecular Friedel-Crafts-type Michael addition of α,β-unsaturated lactones.

Full text of DOI:10.1021/jo1008349

pubs.acs.org/joc
Stereoselective Syntheses of Four Diastereomers of
3,9,12-Trihydroxycalamenene via a Benzobicyclo[3.3.1] Intermediate
Yongquan Sun, Binxun Yu, Xiaolei Wang, Shibing Tang, Xuegong She,* and
Xinfu Pan*
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University,
Lanzhou, 730000, People’s Republic of China
shexg@lzu.edu.cn; panxf@lzu.edu.cn
Received April 7, 2010
The highly stereoselective syntheses of four diastereomers of natural 3,9,12-trihydroxycalamenene
are described. The syntheses highlight the utility of an unusual framework of benzobicyclo[3.3.1]
lactones, which were accomplished via an intramolecular Friedel-Crafts-type Michael addition of
R,β-unsaturated lactones.
Introduction
Since the late 1990s, a large number of aromatic diterpenes
with a serrulatane or amphilectane framework have been
isolated from marine soft corals, especially Pseudopterogor-
gia elisabethae. Many members of them exhibit substantial
biological activities such as anti-inflammatory, anticancer,
antitubercular, and antibacterial agents. The biological acti-
vity and commercial potential of the compounds stimulated
a number of approaches to their synthesis.1,2 From a syn-
thetic perspective, a major challenge associated with their
FIGURE 1. Frameworks of serrulatane and amphilectane and
structures of 1, 2, and 3.
(1) For a general review on the isolation, synthesis, and biosynthesis of
these natrual products, see: (a) Berrue, F.; Kerr, R. G. Nat. Prod. Rep. 2009,
26, 681. (b) Heckrodt, T. J.; Mulzer, J. Top. Curr. Chem. 2005, 244, 1.
(2) Some representative examples for the synthesis: (a) Davies, H. M. L.;
Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2485. (b) Harmata, M.;
Hong, X.; Schreiner, P. R. J. Org. Chem. 2008, 73, 1290. (c) Nicolau, K. C.;
Vassilikogiannakis, G.; Magerlein, W.; Kranich, R. Angew. Chem., Int. Ed.
2001, 40, 2482. (d) Boezio, A. A.; Jarvo, E. R.; Lawrence, B. M.; Jacobsen,
E. N. Angew. Chem., Int. Ed. 2005, 44, 6046. (e) Johnson, T. W.; Corey, E. J.
J. Am. Chem. Soc. 2001, 123, 4475. (f) Chow, R.; Kocienski, P. J.; Kuhl, A.;
LeBrazidec, J. Y.; Muir, K.; Fish, P. J. Chem. Soc., Perkin Trans. 1 2001,
2344. (g) Kocienski, P. J.; Pontiroli, A.; Qun, L. J. Chem. Soc., Perkin Trans.
1 2001, 2356. (h) Uemura, M.; Nishimura, H.; Minami, T.; Hayashi, Y. J.
Am. Chem. Soc. 1991, 113, 5402.
syntheses has been the control of the three stereocenters
marked in Figure 1, because there are no convenient neigh-
boring functional groups available to assist in their stereo-
control. Therefore, it is very desirable to develop a strategy
to the highly stereoselective installation of this array of
stereocenters.
In 2006, three new aromatic cadinane sesquiterpenes,
3,9,12-trihydroxycalamenenes 1, 2, and 3,12-dihydroxycala-
menene 3, were isolated by bioassay-guided fractionation
4224 J. Org. Chem. 2010, 75, 4224–4229
Published on Web 05/19/2010
DOI: 10.1021/jo1008349
r
2010 American Chemical Society

Sun et al.
JOCArticle
SCHEME 1. Retrosynthetic Analysis of 3,9,12-Trihydroxy-
calamenene 1
TABLE 1. Examples of Intramolecular Friedel-Crafts-Type Michael
Addition of r,β-Unsaturated Lactone 7a
from Phomopis cassiae, an endophytic fungus (Figure 1).3 As
new members of important precursors for the synthesis of the
diterpenes mentioned above,2b,e-g they attracted our inter-
est. The structures of 1 and 2 differ from that of 3 by the
presence of a C9-hydroxyl group. Moreover, their undeter-
mined stereochemistry at C11 inspired us to find a common
path for the stereoselective installation of the three stereo-
centers. Herein we report a highly efficient construction of
benzobicyclo[3.3.1] framework, and based on this frame-
work, four diastereomers of 3,9,12-trihydroxycalamenene
were synthesized.
Results and Discussion
To develop a potentially general and diversity-oriented
strategy to the flexible and stereoselective installation of the
three stereocenters, the rigid benzobicyclo[3.3.1] lactone4 was
envisioned to be the key intermediate that was expected to be
obtained via an intramolecular Friedel-Crafts-type Michael
addition of the corresponding R,β-unsaturated lactone. On the
basis of this strategy, the retrosynthetic analysis of 3,9,12-
trihydroxycalamenene 1 was outlined in Scheme 1. We envi-
sioned that the bridged lactone 4 was a very desirable precursor
to 1, and 4 was expected to be derived from an intramolecular
Friedel-Crafts-type Michael addition of R,β-unsaturated lac-
tone 5. As for the preparation of 5, it was easily obtained from
R-methyl phenyl acetaldehyde 6.
Even though the dual activated R,β-unsaturated com-
pounds easily facilitated the inter- or intramolecular Friedel-
Crafts-type Michael addition under Lewis acid conditions,5
there were few examples of R,β-unsaturated lactones to be
applied in the reaction. To test the feasibility, a model
reaction was carried out with m-methoxy-substituted lactone
7a as the substrate (eq 1). After several unsuccessful attempts
under Lewis acid conditions (TiCl4, SnCl4, F3B-OEt2, AlCl3),
triflic acid, a strong organic protic acid, was found to be the
efficient reagent to promote this reaction, while the relative
aUnless otherwise indicated, all reactions were performed on a 0.5
mmol scale at 0.1 M in CH2Cl2 for 24 h at room temperature. bIsolated
yield. cReaction time: 12 h. dQuantitative recovery of the starting
material. eIsolated yield based on the recovery of 20% of starting
material. fA 1:1 diastereomeric mixture of 7h or 8h was illustrated.
weaker acids (TsOH, TFA) did not play any role at all. In this
process, 2.5 equiv of triflic acid was essential.
(3) Silva, G. H.; Teles, H. L.; Zanardi., L. M.; Young, M. C. M.; Eberlin,
M. N.; Hadad, R.; Pfenning, L. H.; Costa-Neto, C. M.; Castro-Gamboa, I.;
^
Bolzani, V. S.; Araujo, A. R. Phytochemistry 2006, 67, 1964.
ꢀ
(4) (a) Williams, D. R.; Ihle, D. C.; Brugel, T. A.; Patnaik, S. Heterocycles
2006, 70, 77. (b) Kawamura, M.; Ogasawara, K. Tetrahedron Lett. 1995, 36,
3369. (c) Broka, C. A.; Chan, S.; Peterson, B. J. Org. Chem. 1988, 53, 1584.
(d) Takano, S.; Masuda, K.; Hatakeyama, S.; Ogasawara, K. Heterocycles
1982, 19, 1407.
(5) (a) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030. (b)
Yamazaki, S.; Iwata, Y. J. Org. Chem. 2006, 71, 739. (c) Liu, H. J.; Tran,
D. D. P. Tetrahedron Lett. 1999, 40, 3827.
With the optimized conditions in hand, several sub-
strates were investigated (Table 1). 3,5-Dimethoxy- and
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SCHEME 2. Allylation of R-Methyl Phenyl Acetaldehyde 6
endo isomer 13,11 the endo isomer 13 was prepared via a two-
step procedure in 75% yield: (i) R-methylenation of 4 with
sodium hydride and paraformaldehyde in a sealed tube12 and
(ii) stereoselective hydrogenation of the resulting product
with 10% Pd/C in EtOAc. After deprotection with BBr3 and
LAH reduction, the serial products 1a and 1b were obtained
in high yields (Scheme 4). However, the spectral data of
synthetic 1a or 1b are not in agreement with those of natural
product.3,13 And the solubility of our synthetic products in
CHCl3 was very weak (<1 mg/mL), while the isolated
natural product exhibited good solubility in CHCl3 (3 mg/
mL in CHCl3). Hence what we have accomplished are the
syntheses of the proposed structure 1.
Subsequently, another two diastereomers 19 and 20 were
furnished by using compound 10 as starting material
through the same route (Scheme 5). Thus, four diastereo-
mers, bearing four different combinations of stereochemistry
at C7, C10, and C11, were achieved from the same starting
material and similar route.
3,4,5-trimethoxy-substituted substrates (entries 2 and 5) pro-
ceeded smoothly under these conditions, while 2,4-dimethoxy-
and 2,3,4-trimethoxy-substituted substrates (entries 3 and 6) did
not react. This indicated that the methoxy group located at the
meta position to the reaction site would reduce the activity of the
reaction site, which was not favored for the reaction. This could
be confirmed by the reaction of 3,4-dimethoxy-substituted
substrates which afforded 8d in 62% yield (recovery of 20%
of 7d, entry 4). The reaction time was shortened if more electron-
donating substituents were attached to the aromatic ring (entries
2, 7, and 8). And to our delight, the substrates 7g and 7h could
also react well to give the products 8g and 8h bearing bridge-
head quaternary carbon and bridge methyl group, respectively
(entries 7 and 8).
Having established the method to construct the key
benzobicyclo[3.3.1] framework, attention was then directed
toward the syntheses of 3,9,12-trihydroxycalamenenes,
which began with the allylation of the R-methyl aryl acet-
aldehyde 6 (Scheme 2). Under the cooperation of allylindium
sesquibromide and lithium neopentoxide at -78 °C, com-
pound 10 was obtained as the major product (Felkin-Ahn
product) in satisfactory diastereoselectivity (8.5:1) and yield
(95%).6 Otherwise, the anti-Felkin-Ahn product 9 was
obtained from aldehyde 6 through a three-step sequence in
74% overall yield (allylation,7 oxidation, and L-Selectride
reduction8).
The esterification reaction between homoallyl alcohol 9
and acryloyl chloride afforded the ring-closing-metathesis
precursor 11 in 93% yield (Scheme 3). Treatment of 11 with
Grubbs catalyst first under high dilution in CH2Cl2 at reflux
furnished the R,β-unsaturated lactone 5 in 86% yield.9 With
5 in hand, the intramolecular Friedel-Crafts-type Michael
addition was executed under the above-mentioned condi-
tions at 0 °C to construct the bridged lactone 4 in 78%
yield.10
Then a stereocontrolled methylation reaction was per-
formed to establish the stereochemistry at C11. After treat-
ment of bridged lactone 4 with LDA in THF at -78 °C, a
mixture of methyl iodide/HMPA in THF was injected to trap
the enolate to give the exo isomer 12 as a single product in
92% yield.4b-d The stereochemical outcome of this reaction
was confirmed by X-ray crystallographic analysis. Due to the
insufficiency of direct transformation of exo isomer 12 to
Conclusion
In summary, we have achieved the syntheses of four
diastereomers of 3,9,12-trihydroxycalamenene in 28-45%
yields over 7-10 steps. The stereochemical controls are
accomplished by an unusual framework of benzobicyclo-
[3.3.1] lactones, which are prepared via an intramolecular
Friedel-Crafts-type Michael addition of R,β-unsaturated
lactones. This strategy reveals a potentially flexible and
stereoselective installation of the three stereocenters em-
bedded in the aromatic diterpenes with a serrulatane or
amphilectane skeleton. Further improvements and applica-
tions are underway and will be reported in due time.
Experimental Section
Typical Procedure for Intramolecular Friedel-Crafts-Type
Michael Addition (Compound 8a). To a solution of compound
7a (118 mg, 0.5 mmol) in 5 mL of CH2Cl2 was added triflic acid
(0.11 mL, 1.25 mmol, 2.5 equiv) at room temperature, and the
mixture was stirred at this temperature open to the air for 24 h. A
solution of saturated NaHCO3 was added to the above mixture
and the mixture was extracted with CH2Cl2, then the combined
organic fractions were washed with brine followed by drying
over Na2SO4, filtered, and concentrated. Purification by flash
chromatography provided 85 mg of compound 8a in 72% yield
as a white solid: mp 109-111 °C. 1H NMR (400 MHz, CDCl3) δ
7.03 (d, J = 8.4 Hz, 1H), 6.77 (dd, J = 8.4, 2.4 Hz, 1H), 6.63 (d,
J = 2.0 Hz, 1H), 5.11 (d, J = 1.2 Hz, 1H), 3.78 (s, 3H), 3.21-
3.25 (m, 2H), 3.08 (dd, J = 17.6, 4.0 Hz, 1H), 2.80 (dd, J = 18.0,
5.6 Hz, 1H), 2.61 (dt, J = 17.6, 2.0 Hz, 1H), 2.30 (dt, J = 13.6,
2.4 Hz, 1H), 2.11 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 169.9, 158.9, 132.0, 130.4, 129.6, 114.1, 113.6, 74.5,
55.3, 40.2, 36.5, 30.4, 28.1; HRMS (ESI) calcd for C13H18NO3
[M þ NH4]þ 236.1287, found 236.1282.
anti-2-(3-Methoxy-4-methylphenyl)hex-5-en-3-ol (9). To a solu-
tion of aldehyde 6 (356 mg, 2 mmol) in 2 mL of saturated aqueous
ammonium chloride and 0.4 mL of THF were added allyl bromide
(6) Reetz, M. T.; Haning, H. J. Organomet. Chem. 1997, 541, 117.
(7) Wilson, S. R.; Guazzaroni, M. E. J. Org. Chem. 1989, 54, 3087.
(8) Yamamoto, Y.; Matsuoka, K.; Nemoto., H. J. Am. Chem. Soc. 1988,
110, 4475.
(11) The 1H NMR data showed that about 70% conversion was obtained
after the treatment of 12 with LDA; howerver, the two diastereomers were
unseparable.
€
(9) D’Annibale, A.; Ciaralli, L.; Bassetti, M.; Pasquini, C. J. Org. Chem.
2007, 72, 6067.
(10) The reaction of 5 at room temperature resulted to the decomposition
of starting material. The reason might be the presence of the benzyl methyl
group.
(12) (a) Merten, J.; Hennig, A.; Schwab, P.; Frohlich, R.; Tokalov, S. V.;
Gutzeit, H. O.; Metz, P. Eur. J. Org. Chem. 2006, 1144. (b) Noya, B.; Paredes,
M. D.; Ozores, L.; Alonso, R. J. Org. Chem. 2000, 65, 5960.
(13) Comparisons of the spectral data of compounds 1a and 1b with those
of the isolated compound 1 are listed in the Supporting Information.
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SCHEME 3. Synthesis of Bridged Lactone 4
SCHEME 4. Completion of Syntheses of 3,9,12-Trihydroxycalamenene Diastereomers 1a and 1b
SCHEME 5. Syntheses of Another Two 3,9,12-Trihydroxycalamenene Diastereomers 19 and 20
(484 mg, 0.346 mL, 4 mmol) and zinc dust (256 mg, 4 mmol). The
mixture was stirred at room temperature open to the air for 1 h,
the suspension was then extracted with Et2O, and the ether layer
was dried over Na2SO4. Evaporation of the organic solvent
at reduced pressure and purification by flash chromatography
yielded 422 mg (96%) of the products in a ratio of 1:2 of
antiproduct 9:syn-product 10.
To a mixture of PCC (1.24 g, 5.76 mmol) and silica gel (1.24 g)
in 20 mL of CH2Cl2 was added the resulting products (422 mg, 1.92
mmol) in the above procedure at 0 °C. After being stirred overnight,
the mixture was filtered directly by silica gel and then purification by
flash chromatography provided 377 mg of ketone in 90% yield.
A solution of ketone (377 mg, 1.73 mmol) in 20 mL of THF
was treated with 1 M L-Selectride (2.59 mL, 2.59 mmol) at
-78 °C under argon atmosphere. After being stirred at the same
temperature for 2 h, the mixture was treated with 3 M NaOH
and 30% H2O2. The reaction mixture was warmed to room
temperature and stirred for 12 h before being extracted with
Et2O. The organic layer was washed with brine then dried over
Na2SO4, filtered, and concentrated. Purification by flash chro-
matography provided 288 mg of the antiproduct 9 exclusively in
84% yield. 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 7.6 Hz,
1H), 6.77 (dd, J = 7.6, 1.2 Hz, 1H), 6.74 (s, 1H), 5.88-5.99 (m,
1H), 5.17 (dd, J = 17.6, 1.2 Hz, 1H), 5.16 (d, J = 10.0 Hz, 1H),
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Sun et al.
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3.86 (s, 3H), 3.72-3.77 (m, 1H), 2.70-2.82 (m, 1H), 2.41-2.47
(m, 1H), 2.22 (s, 3H), 2.13-2.21 (m, 1H), 1.63 (d, J = 3.6 Hz,
1H), 1.31 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 157.7, 142.1, 135.1, 130.6, 124.8, 119.5, 117.5, 109.9, 75.0,
55.2, 45.4, 38.9, 17.9, 15.8; HRMS (ESI) calcd for C14H24NO2
[M þ NH4]þ 238.1807, found 238.1805.
rel-(()-(7S,9S,10R)-4,10-Dimethyl-3-methoxybenzobicyclo-
[3.3.1]lactone (4).14 Following the procedure described above
for the preparation of compound 8a at 0 °C, 191 mg of
compound 4 was obtained in 78% yield as a white solid: mp
130-132 °C. 1H NMR (400 MHz, CDCl3) δ 6.85 (s, 1H), 6.68
(s, 1H), 4.83-4.86 (m, 1H), 3.81 (s, 3H), 3.18 (s, 1H), 3.05-3.11
(m, 1H), 2.80 (dd, J = 17.6, 5.6 Hz, 1H), 2.62 (dt, J = 17.6, 2.0
Hz, 1H), 2.31 (ddd, J = 13.6, 5.2, 2.4 Hz, 1H), 2.17 (s, 3H),
2.10-2.16 (m, 1H), 1.50 (d, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 170.0, 157.4, 134.5, 130.4, 129.5, 125.8, 108.8,
79.1, 55.4, 40.7, 38.9, 31.1, 29.0, 17.2, 15.7; HRMS (ESI) calcd
for C15H22NO3 [M þ NH4]þ 264.1600, found 264.1598.
rel-(()-(7S,9S,10R,11R)-3-Methoxy-4,10,11-trimethylbenzo-
bicyclo[3.3.1]lactone (12). To a stirred solution of lithium diiso-
propylamide, prepared from diisopropylamine (71 mg, 0.10 mL,
0.7 mmol) and n-butyllithium (1.79 M in hexane, 0.34 mL,
0.6 mmol) in THF, was added compound 4 (123 mg, 0.5 mmol)
in 1 mL of THF under argon at -78 °C. After being stirred at the
same temperature for 1 h, a solution of methyl iodide (284 mg,
0.23 mL, 2 mmol) and HMPA (89 mg, 0.5 mmol) in 0.5 mL
of THF was added and the temperature was allowed to rise to
-30 °C. After being stirred at the same temperature for 2 h, the
reaction mixture was quenched by addition of saturated NH4Cl
solution. It was then extracted with Et2O and the combined
organic fractions were washed with brine then dried over
Na2SO4, filtered, and concentrated. Purification by flash chro-
matography provided 120 mg of the product 12 in 92% yield
as a white solid: mp 144-146 °C. 1H NMR (400 MHz, CDCl3) δ
6.85 (s, 1H), 6.68 (s, 1H), 4.80-4.82 (m, 1H), 3.81 (s, 3H),
3.06-3.10 (m, 1H), 2.85 (d, J = 1.6 Hz, 1H), 2.71 (ddt, J = 14.8,
7.6, 1.2 Hz, 1H), 2.49 (ddd, J = 13.6, 5.2, 2.4 Hz, 1H), 2.18 (s,
3H), 1.99 (ddd, J = 13.6, 3.2, 1.2 Hz, 1H), 1.50 (d, J = 7.6 Hz,
3H), 1.46 (d, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
173.8, 157.3, 134.4, 130.5, 125.9, 108.7, 79.1, 55.4, 44.9, 38.8,
37.7, 24.3, 19.0, 17.2, 15.7 (1 C not observed due to overlap);
HRMS (ESI) calcd for C16H24NO3 [M þ NH4]þ 278.1756,
found 278.1757.
syn-2-(3-Methoxy-4-methylphenyl)hex-5-en-3-ol (10). To a
stirred suspension of indium powder (230 mg, 2 mmol) in
2 mL of THF was added allyl bromide (362 mg, 0.26 mL,
3 mmol) under argon atmosphere, and the indium metal is
consumed within 0.5 h in an exothermic reaction, affording a
slightly cloudy solution of allyl sesquibromide. At -78 °C, a
solution of lithium neopentoxide, which is prepared by adding 4
mmol of BuLi to 4 mmol of neopentyl alcohol in 5 mL of THF at
0 °C for 20 min, was added to the above prepared reagent. After
the resulting mixture was stirred for 30 min at -78 °C, a solution
of compound 6 (356 mg, 2 mmol) in 1 mL of THF was added.
After 2 h at -78 °C, the temperature is gradually allowed to
reach room temperature, and the reaction was terminated by
treatment with saturated aqueous NH4Cl solution. It was
extracted with Et2O and the combined organic fractions were
washed with brine and then dried over Na2SO4, filtered, and
concentrated. Purification by flash chromatography provided
418 mg (95%) of the products in a ratio of 1:8.5 of antiproduct 9:
syn-product 10. 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 7.6
Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.69 (s, 1H), 5.78-5.89 (m,
1H), 5.14 (d, J = 10.8 Hz, 1H), 5.13 (d, J = 16.4 Hz, 1H), 3.85 (s,
3H), 3.71-3.74 (m, 1H), 2.73-2.80 (m, 1H), 2.23-2.27 (m, 1H),
2.21 (s, 3H), 2.04-2.11 (m, 1H), 1.72 (d, J = 2.8 Hz, 1H), 1.36
(d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.7,
143.3, 135.2, 130.5, 124.6, 119.3, 118.0, 109.6, 75.0, 55.2, 45.3,
39.5, 16.3, 15.8; HRMS (ESI) calcd for C14H24NO2 [M þ NH4]þ
238.1807, found 238.1806.
anti-2-(3-Methoxy-4-methylphenyl)hex-5-en-3-yl Acrylate (11).
To a stirred solution of compound 9 (220 mg, 1 mmol) in 10 mL of
CH2Cl2 at 0 °C was added diisopropylethylamine (516 mg, 0.69 mL,
4 mmol) and acryloyl chloride (181 mg, 0.162 mL, 2 mmol), and the
mixture was stirred for 2 h. Water was added and the mixture was
extracted with CH2Cl2, then the combined organic fractions were
washed with brine followed by drying over Na2SO4, filtered, and
concentrated. Purification by flash chromatography provided 255
mg of the ester 11 in 93% yield. 1H NMR (400 MHz, CDCl3) δ 7.06
(d, J = 7.6 Hz, 1H), 6.74-6.77 (m, 2H), 6.35 (dd, J = 17.2, 1.2 Hz,
1H), 6.07 (dd, J = 17.2, 10.4 Hz, 1H), 5.71-5.81 (m, 2H), 5.23 (dt,
J = 7.2, 5.6 Hz, 1H), 5.06 (dd, J = 15.6, 1.2 Hz, 1H), 5.05 (d, J =
11.6 Hz, 1H), 3.83 (s, 3H), 3.01-3.08 (m, 1H), 2.26-2.36 (m, 2H),
2.20 (s, 3H), 1.31 (d, J =7.2Hz, 3H);13C NMR (100 MHz, CDCl3)
δ 165.7, 157.4, 141.3, 133.8, 130.3, 130.2, 128.7, 124.7, 119.9, 117.7,
110.1, 76.8, 55.2, 42.7, 36.1, 17.4, 15.8; HRMS (ESI) calcd for
C17H26NO3 [M þ NH4]þ 292.1913, found 292.1912.
rel-(()-(7S,9S,10R,11S)-3-Methoxy-4,10,11-trimethylbenzo-
bicyclo[3.3.1]lactone (13). To a solution of the lactone 4 (49 mg,
0.2 mmol) in THF (5 mL) in a sealed tube was added para-
formaldehyde (180 mg, 6 mmol) and NaH (29 mg, 1.2 mmol).
The colorless mixture was stirred at 100 °C for ca. 40 min. A
change in the color of the mixture to yellowish brown within this
time period indicates termination of the reaction, and the
heating source was removed immediately. The resulting solu-
tion was cooled to room temperature and quenched by water.
Then it was extracted with Et2O and the combined organic
fractions were washed with brine then dried over Na2SO4,
filtered, and concentrated. Purification was by flash chroma-
tography and the crude product was dissolved in EtOAc. After
adding 10% Pd/C, the resulting suspension was stirred under
H2 atmosphere for 4 h at room temperature. Then it was filtered
and concentrated and purified by flash chromatography to
anti-5,6-Dihydro-6-(1-(3-methoxy-4-methylphenyl)ethyl)pyran-
2-one (5). To a solution of Grubbs catalyst first (82 mg, 0.10
mmol) in 200 mL of CH2Cl2 was added a solution of the ring-
closing metathesis precursor 11 (548 mg, 2 mmol) in 2 mL of
CH2Cl2 under argon atmosphere. The mixture was warmed to
reflux and stirred for 12 h. After evaporation of the organic
solvent at reduced pressure and purification by flash chromatog-
1
provide 39 mg of the product 13 in 75% yield for 2 steps. H
NMR (300 MHz, CDCl3) δ 6.80 (s, 1H), 6.71 (s, 1H), 4.81-4.83
(m, 1H), 3.81 (s, 3H), 3.04-3.08 (m, 1H), 2.99 (s, 1H), 2.75-2.83
(m, 1H), 2.46 (ddd, J = 13.5, 4.8, 1.8 Hz, 1H), 2.23 (d, J = 4.2
Hz, 1H), 2.18 (s, 3H), 1.49 (d, J = 7.2 Hz, 3H), 1.18 (d, J = 6.9
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.8, 157.4, 135.0,
132.5, 125.9, 124.4, 108.8, 79.1, 55.3, 42.8, 39.4, 36.8, 31.3, 17.3,
15.8, 15.1; HRMS (ESI) calcd for C16H24NO3 [M þ NH4]þ
278.1756, found 278.1758.
rel-(()-(7S,9S,10R,11R)-3,9,12-Trihydroxycalamenene (1a).
To a solution of compound 12 (20 mg, 0.077 mmol) in 3 mL
of CH2Cl2 was added BBr3 (1 M in CH2Cl2, 0.23 mL, 0.23
mmol) solution under argon atmosphere at -78 °C, and the
resulting solution was allowed to rise to -20 °C. After being
stirred at the same temperature for 12 h, the reaction mixture
1
raphy, 423 mg of the product 5 was obtained in 86% yield. H
NMR (400 MHz, CDCl3) δ 7.07 (d, J = 7.6 Hz, 1H), 6.81-6.85
(m, 1H), 6.74-6.76 (m, 2H), 5.97 (dd, J = 9.6, 2.0 Hz, 1H), 4.59
(dt, J = 12.4, 4.4 Hz, 1H), 3.83 (s, 3H), 3.06-3.13 (m, 1H),
2.25-2.34 (m, 1H), 2.21 (s, 3H), 2.14-2.19 (m, 1H), 1.44 (d, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.4, 157.7, 145.4,
140.0, 130.4, 125.2, 121.1, 120.0, 110.2, 81.5, 55.3, 43.3, 26.4, 16.2,
15.8; HRMS (ESI) calcd for C15H22NO3 [M þ NH4]þ 264.1600,
found 264.1594.
(14) Note that it was just relative configuration.
4228 J. Org. Chem. Vol. 75, No. 12, 2010

Sun et al.
JOCArticle
was quenched by water. Then it was extracted with CH2Cl2 and
the combined organic fractions were washed with brine then
dried over Na2SO4, filtered, and concentrated. Purification by
flash chromatography provided the crude product.
rel-(()-(7R,9R,10R,11S)-3,9,12-Trihydroxycalamenene (19).
Following the procedure described above for the preparation of
compound 1a, product 19 was obtained in 82% yield for 2 steps.
1H NMR (300 MHz, acetone-d6) δ 7.81 (d, J = 3.0 Hz, 1H), 7.01
(s, 1H), 6.74 (s, 1H), 3.86 (t, J = 4.5 Hz, 1H), 3.35-3.43 (m, 2H),
3.22-3.35 (m, 2H), 2.80-2.93 (m, 1H), 2.46-2.56 (m, 1H),
2.28-2.35 (m, 1H), 2.15 (s, 3H), 2.07-2.12 (m, 1H), 1.37-1.48
To a suspension of LiAlH4 (8.7 mg, 0.23 mmol) in 2 mL of
THF was added the resulting crude product at 0 °C, and the
mixture was allowed to rise to room temperature. After being
stirred for 3 h at room temperature, the mixture was quenched
by water. It was extracted with EtOAc and the combined
organic fractions were washed with brine then dried over
Na2SO4, filtered, and concentrated. Purification by flash chro-
matography provided 16 mg of the product 1a in 83% yield for 2
(m, 1H), 1.30 (d, J = 6.9 Hz, 3H), 1.06 (d, J = 6.9 Hz, 3H); 13
C
NMR (75 MHz, acetone-d6) δ 154.3, 140.5, 130.0, 129.8, 122.3,
113.7, 74.0, 64.3, 42.5, 41.4, 40.3, 34.7, 17.6, 16.2, 16.1; IR (KBr)
3353, 1695, 1617, 1451, 1415, 1257, 1030 cm-1; HRMS (ESI)
calcd for C15H22NaO3 [M þ Na]þ 273.1467, found 273.1458.
rel-(()-(7R,9R,10R,11R)-3,9,12-Trihydroxycalamenene (20).
Following the procedure described above for the preparation of
compound 1a, product 20 was obtained in 79% yield for 2 steps.
1H NMR (400 MHz, acetone-d6) δ 7.83 (d, J = 2.0 Hz, 1H), 6.95
(s, 1H), 6.76 (s, 1H), 3.87 (t, J = 5.2 Hz, 1H), 3.72 (s, 1H),
3.49-3.58 (m, 2H), 3.31-3.38 (m, 1H), 3.18-3.23 (m, 1H),
2.45-2.55 (m, 1H), 2.40-2.44 (m, 1H), 2.15 (s, 3H), 1.94-2.00
(m, 1H), 1.42 (q, J = 7.6 Hz, 1H), 1.32 (d, J = 6.8 Hz, 3H), 0.59
(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, acetone-d6) δ 154.2,
140.9, 130.2, 129.2, 122.5, 113.7, 73.8, 66.2, 42.5, 39.8, 38.0,
32.8, 17.5, 16.1, 11.2; IR (KBr) 3352, 1695, 1619, 1505, 1462,
1415, 1256, 1038 cm-1; HRMS (ESI) calcd for C15H22NaO3
[M þ Na]þ 273.1467, found 273.1463.
1
steps. H NMR (300 MHz, acetone-d6) δ 7.83 (s, 1H), 7.03 (s,
1H), 6.52 (s, 1H), 3.84-3.91 (m, 1H), 3.71 (d, J = 4.2 Hz, 1H),
3.34-3.40 (m, 1H), 3.25-3.32 (m, 2H), 2.88-2.94 (m, 1H),
2.78-2.85 (m, 1H), 2.35-2.40 (m, 1H), 2.14 (s, 3H), 1.76-1.83
(m, 1H), 1.50-1.63 (m, 1H), 1.12 (d, J = 6.6 Hz, 3H), 1.10 (d,
J = 6.9 Hz, 3H); 13C NMR (75 MHz, acetone-d6) δ 154.2, 142.1,
129.9, 129.0, 123.1, 115.8, 69.9, 64.2, 41.5, 40.9, 40.4, 28.1, 16.8,
16.2 (1 C not observed due to overlap); IR (KBr) 3343, 1694,
1619, 1458, 1416, 1256, 1029 cm-1; HRMS (ESI) calcd for
C15H22NaO3 [M þ Na]þ 273.1467, found 273.1460.
rel-(()-(7S,9S,10R,11S)-3,9,12-Trihydroxycalamenene (1b).
Following the procedure described above for the preparation
of compound 1a, 14 mg of product 1b was obtained in 79% yield
for 2 steps. 1H NMR (300 MHz, acetone-d6) δ 7.80 (s, 1H), 6.97
(s, 1H), 6.52 (s, 1H), 3.89-3.95 (m, 1H), 3.71 (d, J = 4.2 Hz,
1H), 3.64 (t, J = 5.1 Hz, 1H), 3.52-3.57 (m, 2H), 3.20 (ddd, J =
11.1, 7.5, 3.6 Hz, 1H), 2.79-2.86 (m, 1H), 2.42-2.47 (m, 1H),
2.14 (s, 3H), 1.54-1.67 (m, 2H), 1.12 (d, J = 7.2 Hz, 3H), 0.61
(d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, acetone-d6) δ 154.0,
142.5, 129.5, 129.2, 123.2, 115.8, 69.6, 66.2, 40.8, 39.9, 38.0, 25.9,
17.0, 16.2, 11.2; IR (KBr) 3341, 1695, 1619, 1462, 1415, 1256,
1030 cm-1; HRMS (ESI) calcd for C15H22NaO3 [M þ Na]þ
273.1467, found 273.1461.
Acknowledgment. We are grateful for the generous finan-
cial support by the MOST (2010CB833200) and the NSFC
(20872054, 20732002).
Supporting Information Available: Experimental procedures
and spectral data for all new products, X-ray crystallographic data
(CIF), and ORTEP diagrams for compounds 12. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 12, 2010 4229