Efficient diastereoselective synthesis of trifarane-type sesquiterpenes, trifarienols A and B

Article abstract of DOI:10.1021/jo900369t

Diastereoselective total synthesis of trifarienols A and B, trifarane-type sesquiterpenes isolated from the Malaysian Cheilolejeunea trifaria, was achieved via an intramolecular Hosomi - Sakurai reaction of the aldehyde to construct a substituted bicyclo[

Full text of DOI:10.1021/jo900369t

Efficient Diastereoselective Synthesis of Trifarane-Type
Sesquiterpenes, Trifarienols A and B
Kazunori Takahashi, Ryuichi Akao, and Toshio Honda*
Faculty of Pharmaceutical Sciences, Hoshi UniVersity, Ebara 2-4-41, Shinagawa-ku,
Tokyo 142-8501, Japan
honda@hoshi.ac.jp
ReceiVed February 18, 2009
Diastereoselective total synthesis of trifarienols A and B, trifarane-type sesquiterpenes isolated from the
Malaysian Cheilolejeunea trifaria, was achieved via an intramolecular Hosomi-Sakurai reaction of the
aldehyde to construct a substituted bicyclo[3.3.1]nonane skeleton having the exo-methylene moiety of
the target compounds in one step.
Introduction
Trifarienols A (1) and B (2) were isolated from the liverwort
Cheilolejeunea trifaria as trifarane-type sesquiterpenes having
a new carbon skeleton.
The structures of trifarienols A and B, including their absolute
configurations, were established by a combination of NMR, CD,
and X-ray crystallographic analyses as shown in Figure 1.1
Regarding the synthesis of those sesquiterpenes, there are two
reports to date. The first synthesis of trifarienols A and B was
achieved by Huang and Forsyth,2a in which antiselective R′-
intramolecular carbomercuration was involved as the key
reaction for the assembly of a bridged bicyclic system. In this
synthesis, trifarienols A and B were prepared from 2-methyl-
2-cyclohexenone in 16 steps and ca. 9% and 3% overall yields,
respectively. However, the synthesized target compounds were
both racemic forms. Although an enantioselective synthesis of
those terpenoids was developed by Tori and co-workers in
1999,2b the overall yields of trifarienols A and B starting from
the optically active (2RS,3R)-2,3-dimethylcyclohexanone were
1.8% and 1.4%, respectively. Thus, some improvement seemed
FIGURE 1. Structures of trifarienols A and B.
to be desired in terms of stereoselectivity and overall yields in
the synthesis of optically active trifarienols A and B.
Trifarienols are novel, naturally occurring sesquiterpene series
inbryophytesandcontainahighlysubstitutedbicyclo[3.3.1]nonane
system with an exo-methylene unit. The bicyclo[3.3.1]nonane
system is also present in several biologically attractive natural
products such as hyperforin,3 aristophenones,4 guttiferones,5
garsubellin A,6 papuaforin A,7 and upial.8 Moreover, this ring
system has received theoretical interest from the conformation
point of view.9
(3) Umek, A.; Kreft, S.; Kartnig, T.; Heydel, B. Planta Med. 1999, 65, 388–
390.
(4) Cuesta-Rubio, O.; Padron, A.; Castro, H. V.; Pizza, C.; Rastrelli, L. J.
Nat. Prod. 2001, 64, 973–975.
(5) Gustafson, K. R.; Blunt, J. W.; Munro, M. H. G.; Fuller, R. W.; McKee,
T. C.; Cardellina, J. H., II; McMahon, J. B.; Cragg, G. M.; Boyd, M. R.
Tetrahedron 1992, 48, 10093–10102.
(6) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm. Bull. 1997,
45, 947–949.
(7) Winkelmann, K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O. J. Nat.
Prod. 2001, 64, 701–706.
(8) Schulte, G.; Scheuer, P. J.; McConnell, O. J. J. Org. Chem. 1980, 45,
552–554.
* To whom correspondence should be addressed; Phone/fax: +81-3-5498-
5791.
(1) (a) Hashimoto, T.; Koyama, H.; Takaoka, S.; Tori, M.; Asakawa, Y.
Tetrahedron Lett. 1994, 35, 4787–4788. (b) Hashimoto, T.; Koyama, H.; Tori,
M.; Takaoka, S.; Asakawa, Y. Phytochemistry 1995, 40, 171–176.
(2) (a) Huang, H.; Forsyth, C. J. J. Org. Chem. 1995, 50, 5746–5747. (b)
Tori, M.; Hisazumi, K.; Wada, T.; Sono, M.; Nakashima, K. Tetrahedron:
Asymmetry 1999, 10, 961–971.
3424 J. Org. Chem. 2009, 74, 3424–3429
10.1021/jo900369t CCC: $40.75 2009 American Chemical Society
Published on Web 03/31/2009

Synthesis of Trifarane-Type Sesquiterpenes
SCHEME 1. Retrosynthesis of Trifarienols A and B
SCHEME 2. Preparation of Allylsilane
Due to the unique structural features of trifarienols, we are
interested in establishing a facile synthetic strategy for those
natural products, since stereocontrolled construction of highly
functionalized molecular frameworks with a high level of regio-,
stereo-, and enantioselectivity is one of the most challenging
aspects in organic synthesis.
Recently, we have developed a simple and convenient
methodology for the construction of a bicyclo[3.3.1]nonane ring
system with an exo-methylene moiety by employing an in-
tramolecular carbonyl-ene reaction, and we have reported its
application to the synthesis of (+)-upial.10
As part of our continuing work on enantioselective synthesis
of functionalized polycyclic carbocyclic systems from readily
available chiral starting material, we have developed a simple
and convenient methodology for the synthesis of target
compounds.
was able to be converted to enone 6 via Ito-Saegusa oxidation12
of silyl enol ether 5 in the usual manner. Subsequent Michael
addition of a vinyl group to enone 6 by treatment with
vinylmagnesium bromide in THF at -40 °C in the presence of
a higher ordered copper catalyst13 afforded ketone 7, as an
inseparable mixture, by constructing the quaternary carbon
center with the desired stereochemistry predominantly in 90%
yield (dr ) 83:17).
The configuration of the newly generated quaternary carbon
center of 7 was assumed to have an S configuration arising from
an axial attack of the vinyl group on enone.10 After treatment
of ketone 7 with Comins reagent14 and sodium hexamethyld-
isilazide (NaHMDS), the resulting triflate 8 was coupled with
trimethylsilylmethylmagnesium chloride in the presence of
tris(dibenzylideneacetone)dipalladium and tri-tert-butylphos-
phine to give allylsilane derivative 9,15 where removal of the
benzoyl group of 8 took place, simultaneously, and the
diastereoisomeric mixture could be separated at this stage. Swern
oxidation of alcohol 9 afforded the desired aldehyde in 98%
yield (Scheme 2).
Results and Discussion
Our basic strategy for the synthesis of trifarienols A and B
is outlined in Scheme 1.
We envisaged that the diol function could be installed at a
later stage of the synthesis by dihydroxylation of the corre-
sponding alkene A. A bicyclo[3.3.1]nonane skeleton would be
constructed by an intramolecular Hosomi-Sakurai reaction of
allylsilane-aldehyde B, which would be available from ketone
C by introducing a silylmethyl group by palladium-mediated
coupling of the corresponding triflate with a suitable Grignard
reagent. Construction of a quaternary carbon center with the
desired stereochemistry could be achieved by exploitation of
sequential stereoselective conjugate addition of a methyl group
and a vinyl group to enone D.
First, we attempted construction of a bicyclo[3.3.1]nonane
ring system by treatment of 10 with 0.05 equiv of p-toluene-
sulfonic acid in CHCl3, which was shown to be the best reaction
conditions for the synthesis of (+)-upial;10 however, the desired
product 11 was isolated in only 30% yield together with the
corresponding ethoxy derivative 12 in 48% yield (entry 1). Slight
improvement was observed with the use of 0.1 equiv of
p-toluenesulfonic acid in CHCl3 to give 11 in 42% yield (entry
2). The ethoxy function of compound 12 might be installed from
ethanol present in the solvent CHCl3 as a stabilizer. When this
The synthesis was started by Michael addition of a methyl
group to the known enone 311 that was previously prepared in
optically pure form by us.10
Treatment of enone 3 with methyllithium and copper(I) iodide
in THF brought about 1,4-conjugate addition of a methyl group
to give ꢀ-methyl compound 4 as the major product (dr ) 85:
15; the stereochemistry was depicted for the major product).
Similar stereoselectivity has already been observed in our
synthesis of (+)-upial.10 A mixture of the two diastereoisomers
(9) Peters, J. A.; Baas, J. M. A.; van de Graaf, B.; van der Toorn, J. M.; van
Bekkum, H. Tetrahedron 1978, 34, 3313–3323.
(10) Takahashi, K.; Watanabe, M.; Honda, T. Angew. Chem., Int. Ed. 2008,
47, 131–133.
(12) (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–1013.
(b) Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Halm, P.; Zhang, D.
Tetrahedron Lett. 1995, 36, 2423–2426.
(11) Compound 3 was prepared from methyl (3R)-3-[(1S)-1-methyl-2-
oxocyclohexyl]butanoate, which was derived by using an addition of the chiral
imine of 2-methylcyclohexanone to phenyl crotonate as the key step, according
to Pfau’s procedure, see: Javin, I.; Revial, G.; Tomas, A.; Lemoine, P.; Pfau,
M. Tetrahedron: Asymmetry 1995, 6, 1795–1812.
(13) Lipshutz, B. H.; Ellsworth, E. L.; Behling, J. R.; Campbell, A. L.
Tetrahedron Lett. 1988, 29, 893–896.
(14) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299–6302.
(15) Hara, R.; Furukawa, T.; Kashima, H.; Kusama, H.; Horiguch, I. Y.;
Kuwajima, I. J. Am. Chem. Soc. 1999, 121, 3072–3082.
J. Org. Chem. Vol. 74, No. 9, 2009 3425

Takahashi et al.
SCHEME 3. Formation of Ethoxy Derivative 12
FIGURE 2. Structure determination of compounds 11 and 12. Observed
NOEs are indicated by arrows.
TABLE 1. Synthesis of the Bicyclo[3.3.1]nonane System
cyclization was carried out with 0.1 equiv of p-toluenesulfonic
acid in CHCl3 containing amylene as a stabilizer, 11 was isolated
in 57% yield without formation of the ethoxy derivative (entry
3). Similar reaction with 0.1 equiv of p-toluenesulfonic acid in
the presence of water (5 equiv) instead of ethanol with the
expectation of obtaining a desired alcohol in better yield afforded
11 in 49% yield (entry 4). With the use of p-toluenesulfonic
acid, the cyclization of 10 to 11 required relatively longer
reaction times compared to the case observed in the synthesis
of upial,10 probably due to the steric repulsion between the
carbonyl group and the quaternary carbon center adjacent to
the reaction site of the starting aldehyde. Since the Hosomi-
Sakurai reaction will be competitive to acetal (or half acetal)
formation under the reaction conditions for entries 1 and 2, the
decreased reactivity of 10 by steric hindrance may lead to the
formation of the unfavorable ethoxy derivative (Scheme 3).
Thus, we attempted to use an alternative Lewis acid as an
initiator for the Hosomi-Sakurai reaction.
product yield (%)
acid
(equiv)
solvent additive reaction
stabilizer (equiv) time (h)
entry
11
12
1
2
3
4
5
p-TsOH (0.05) EtOH
p-TsOH (0.1) EtOH
p-TsOH (0.1) amylene
p-TsOH (0.1) amylene H2O (5)
3
0.5
12
12
0.5
30
42
57
49
93
48
25
0
0
0
ZnCl2 (1)
amylene
TABLE 2. Dihydroxylation of 13
Fortunately, we were able to find that the desired alcohol 11
was obtained as the sole product in 93% yield when aldehyde
10 was treated with zinc chloride (1 equiv) in refluxing CHCl3
for 0.5 h (entry 5). It is noteworthy that an intramolecular
Hosomi-Sakurai reaction of 10 proceeded in an entirely
stereoselective manner, and the newly generated stereogenic
center at the secondary hydroxyl group of 11 was unambigu-
ously determined by NOE experiments as depicted in Figure 2
(also see Table 1).
reagents
reaction time
additive
yield (%)
87
dr (14:15)
OsO4, NMO
AD-mix R
AD-mix ꢀ
3 days
7 days
7 days
1:3
MeSO2NH2 no reaction
MeSO2NH2 25a
1:2
Since the basic carbon framework of the target compounds
was thus constructed, our attention was focused on conversion
of 11 into natural products by installation of the diol function
and subsequent deoxygenation of the secondary hydroxyl group.
For deoxygenation of the secondary hydroxyl group, we decided
to exploit a radical reaction of the corresponding toluoyl group
originally developed by Marko´.16 Acylation of 11 with toluoyl
chloride in CH2Cl2 in the presence of TMEDA at room
temperature afforded ester 13 in 98% yield.
a 53% yield based on the consumed starting material.
SCHEME 4. Synthesis of Trifarienol B
Dihydroxylation of 13 was first carried out by using a catalytic
amount of OsO4 and 1.2 equiv of N-methylmorphorine N-oxide
(NMO) in t-BuOH-THF-H2O (5:5:1, v/v) at ambient temper-
ature for 3 days to give separable diols 14 and 15 in 23% and
64% yields, respectively. To obtain a better diastereoselectivity,
AD-mix R and ꢀ were applied to alkene 13; however, the
expected improvement was not observed and the reactivity was
decreased even for longer reaction times, unfortunately, as
shown in Table 2.
Since the configurations of diols could not be determined at this
stage, the major diol 15 was subjected to deoxygenation with
samarium diiodide to provide trifarienol B (2) in 25% yield
(Scheme 4). This conversion led to the determination of the
stereochemistry of diol 15 unambiguously. Although the reason
for the observed stereoselectivity in dihydroxylation of 13 leading
to diol 15 as a major isomer was not clear at present, we presumed
that the presence of a sterically bulky toluoyl group might prevent
the attack of OsO4 from the other side leading to diol 14.
Although the asymmetric synthesis of trifarienol B (2) was
achieved as above, the yield of the final deoxygenation step
was not sufficient. Thus, an alternative synthetic route to the
target compounds was examined as follows.
Diol 14 was converted to acetonides, which on hydrolysis of
the toluoyl group with methanolic NaOH solution gave the
corresponding alcohol. Treatment of alcohol with iodine in the
presence of triphenylphosphine and imidazole in THF at room
temperature afforded the corresponding olefin 16 in 58% yield
from 14 in three steps (Scheme 5). Finally, removal of acetonide
by acid treatment of 16, followed by site-selective hydrogenation
(16) Lam, K.; Marko´, I. E. Org. Lett. 2008, 10, 2773–2776.
3426 J. Org. Chem. Vol. 74, No. 9, 2009

Synthesis of Trifarane-Type Sesquiterpenes
SCHEME 5. Synthesis of Trifarienols A and B
subjected to column chromatography on silica gel. Elution with
n-hexane-AcOEt (9:1, v/v) afforded allylsilane 9 (82 mg, 83%)
as a colorless oil: [R]25D -15.2 (c 1.4, CHCl3); IR νmax 3369, 1213
1
cm-1; H NMR (CDCl3; 400 MHz) δ 5.69 (1H, dd, J ) 17.4 and
10.4 Hz), 5.06 (1H, s), 4.93 (1H, dd, J ) 17.4 and 2.0 Hz), 4.88
(1H, dd, J ) 10.4 and 2.0 Hz), 3.72-3.78 (1H, m), 3.56-3.63
(1H, m), 1.69-1.79 (2H, m), 1.25-1.56 (6H, m), 1.05-1.24 (2H,
m), 1.02 (3H, s), 0.97 (3H, s), 0.74 (3H, d, J ) 6.9 Hz), 0.05 (9H,
s); 13C NMR (CDCl3; 100 MHz) δ 147.2, 141.6, 129.7, 112.6, 62.6,
40.6, 39.2, 35.8, 33.8, 32.2, 29.8, 26.3, 24.1, 19.1, 14.9, 0.2 (3),
-29.8; MS (EI) 294 (M+); HRMS (EI) calcd for C18H34OSi
294.2379, found 294.2353.
(3R)-3-{(1S,4R)-1,4-Dimethyl-2-[(trimethylsilyl)methyl]-4-
vinylcyclohex-2-en-1-yl}butanal (10). To a stirred solution of
oxalyl chloride (83 µL, 0.582 mmol) in dry CH2Cl2 (2 mL) was
added a solution of DMSO (83 µL, 0.164 mmol) in dry CH2Cl2 (1
mL) dropwise at -78 °C under Ar, and the whole was stirred for
an additional 10 min. To this solution was added a solution of
alcohol 9 (57 mg, 0.194 mmol) in CH2Cl2 (2 mL) and the resulting
mixture was stirred at the same temperature for 2 h. After addition
of Et3N (135 µL, 0.97 mmol), the mixture was stirred at 0 °C for
30 min, and the whole was subjected to column chromatography
on silica gel. Elution with n-hexane:Et3N (99:1, v/v) gave aldehyde
of a carbon-carbon double bond of the diol over Crabtree’s
catalyst17 gave the desired product, trifarienol A (1), in 74%
yield from 16, whose spectroscopic data (1H and 13C NMR,
MS, IR) and TLC behavior, including its melting point and
specific optical rotation [mp 71-72 °C (lit.1a mp 59-60 °C,
lit.2b mp 82-82.5 °C); [R]D +11.5 (c 0.9, CHCl3) {lit.1a [R]D
+10.2 (c 0.63, CHCl3); lit.,2b [R]D +15 (c 0.57, CHCl3)}], were
similar to those reported in the literature.1
Similarly, diol 15 was transformed to alkene 17 in 58% yield,
which was further converted to trifarienol B (2), successfully,
in 94% yield from 17. Again, the spectroscopic data (1H and
13C NMR, MS, IR) and TLC behavior of the synthesized
compound, including its melting point and optical rotation [mp
99-100 °C (lit.1a mp 105-105.5 °C, lit.2b mp 108-109.5 °C);
[R]D -6.0 (c 1.53, CHCl3) {lit.1a [R]D -3.6 (c 1.62, CHCl3);
lit.,2b [R]D -3.5 (c 1.017, CHCl3)}], were comparable to those
reported in the literature.1
10 (55 mg, 98%) as a colorless oil: [R]24 -30.6 (c 2.1, CHCl3);
D
IR νmax 2957, 1728 cm-1; 1H NMR (CDCl3; 400 MHz) δ 9.77 (1H,
dd, J ) 3.2 and 1.8 Hz), 5.68 (1H, dd, J ) 17.3 and 10.4 Hz), 5.10
(1H, s), 4.93 (1H, dd, J ) 10.4 and 1.9 Hz), 4.86 (1H, dd, J )
17.3 and 1.9 Hz), 2.49 (1H, dd, J ) 16.2 and 1.8 Hz), 2.28-2.36
(1H, m), 2.10 (1H, ddd, J ) 16.2, 10.6, and 3.2 Hz), 1.54 (1H, dt,
J ) 13.3 and 3.2 Hz), 1.43-1.49 (3H, m), 1.39 (1H, dd, J ) 13.3
and 2.7 Hz), 1.34 (1H, d, J ) 15.6 Hz), 1.02 (3H, s), 0.97 (3H, s),
0.77 (3H, d, J ) 6.7 Hz), 0.05 (9H, s); 13C NMR (CDCl3; 100
MHz) δ 203.4, 147.0, 140.6, 130.3, 112.8, 45.9, 40.3, 39.2, 34.4,
32.0, 29.7, 26.6, 24.3, 19.1, 15.7, -0.3 (3); MS (EI) 292 (M+);
HRMS (EI) calcd for C18H32OSi 292.2222, found 292.2233.
(2S,4R,8R)-4,5,8-Trimethyl-9-methylene-8-vinylbicyclo-
[3.3.1]nonan-2-ol (11). To a stirred solution of aldehyde 10 (30
mg, 0.103 mmol) in CHCl3 (3.4 mL) was added ZnCl2 (0.5 M THF
solution; 0.2 mL, 0.103 mmol) at rt under Ar, and the resulting
mixture was heated at reflux for 30 min. The mixture was treated
with saturated aq NaHCO3 and extracted with AcOEt. The organic
layer was washed with brine and dried over Na2SO4. Evaporation
of the solvent gave a residue, which was subjected to column
chromatography on silica gel. Elution with n-hexane-AcOEt (9:
1, v/v) afforded alcohol 11 (21.2 mg, 93%) as white crystals: [R]26
Conclusions
In summary, we were able to establish a concise synthetic route
for trifarienols A (1) and B (2) by employing an intramolecular
Hosomi-Sakurai reaction of an allylsilane derivative as the key
reaction. In this synthesis, remarkable stereoselectivities and site-
selectivities were observed during the construction of a bicyclo-
[3.3.1]nonane ring system by the Hosomi-Sakurai reaction and
also in catalytic reduction of a carbon-carbon double bond. Finally,
trifarienols A and B were prepared from enone 3 in 15 steps in
2% and 9% yields, respectively. Further applications of this
methodology to various types of natural product synthesis are now
under investigation in our laboratory.
-17.6 (c 1.2, CHCl3); mp 63-65 °C; IR νmax 2927, 1220 cm-1D
;
1H NMR (CDCl3; 400 MHz) δ 5.84 (1H, dd, J ) 17.5 and 10.9
Hz), 5.01 (1H, dd, J ) 10.9 and 0.6 Hz), 4.98 (1H, dd, J ) 17.5
and 0.6 Hz), 4.94 (1H, d, J ) 1.6 Hz), 4.90 (1H, d, J ) 1.6 Hz),
3.91 (1H, br), 2.19-2.26 (1H, m), 2.05-2.14 (1H, m), 2.02 (1H,
s), 1.59-1.74 (4H, m), 1.45 (1H, d, J ) 15.3 Hz), 1.25-1.33 (1H,
m), 0.99 (6H, s), 0.95 (3H, d, J ) 7.3 Hz); 13C NMR (CDCl3; 100
MHz) δ 148.9, 147.7, 111.3, 110.8, 70.8, 59.5, 39.9, 39.7, 39.2,
38.7, 37.8, 29.9, 26.9, 25.1, 21.0; MS (CI) 221 (M + 1)+; HRMS
(CI) calcd for C15H24O + H 221.1905, found 221.1899. Anal. Calcd
for C15H24O: C, 81.76; H, 10.98. Found: C, 81.50; H, 10.93.
Experimental Section
(3R)-3-{(1S,4R)-1,4-Dimethy-2-[(trimethylsilyl)methyl]-4-
vinylcyclohex-2-en-1-yl}butan-1-ol (9). To a stirred solution of
triflate 8 (153 mg, 0.333 mmol) in THF (6.7 mL) were added
Pd2(dba)3 (15.3 mg, 16.7 µmol), tBu3P (4.4 M toluene solution; 19
µL, 83.3 µmol), and trimethylsilylmethylmagnesium chloride (1.0
M Et2O solution; 1.7 mL, 1.67 mmol) at rt under Ar, and the
resulting mixture was heated at reflux for 12 h. After treatment
with saturated aq ammonium chloride, the mixture was extracted
with AcOEt. The organic layer was washed with brine and dried
over Na2SO4. Evaporation of the solvent gave a residue, which was
(2R,4S,6R)-4-Ethoxy-1,2,6-trimethyl-9-methylene-6-vinylbi-
cyclo[3.3.1]nonane (12). [R]29D -8.8 (c 1.6, CHCl3); IR νmax 2975,
1119 cm-1; 1H NMR (CDCl3; 400 MHz) δ 5.84 (1H, dd, J ) 17.6
and 10.9 Hz), 5.00 (1H, dd, J ) 10.9 and 1.3 Hz), 4.96 (1H, dd, J
) 17.6 and 1.3 Hz), 4.81 (1H, d, J ) 1.9 Hz), 4.76 (1H, d, J ) 1.9
Hz), 3.45 (1H, dt, J ) 5.0 and 2.2 Hz), 3.31-3.43 (2H, m), 2.07
(1H, s), 1.93-2.02 (2H, m), 1.42-1.65 (2H, m), 1.25-1.36 (3H,
m), 1.11 (3H, t, J ) 7.0 Hz), 0.98 (3H, s), 0.96 (3H, s), 0.90 (3H,
d, J ) 8.2 Hz); 13C NMR (CDCl3; 100 MHz) δ 149.9, 148.4, 111.0,
108.9, 77.4, 63.0, 56.7, 40.1, 39.2, 38.8, 37.6, 35.1, 29.5, 26.4, 24.4,
19.5, 15.6; MS (EI) 248 (M+); HRMS (EI) calcd for C17H28O
248.2140, found 248.2144.
(17) (a) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Organomet. Chem. 1977,
141, 205–215. (b) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655–
2661.
J. Org. Chem. Vol. 74, No. 9, 2009 3427

Takahashi et al.
(2S,4R,8R)- 4,5,8-Trimethyl-9-methylene-8-vinylbicyclo[3.3.1]-
non-2-yl 4-Methylbenzoate (13). To a stirred solution of alcohol
11 (55 mg, 0.25 mmol) in CH2Cl2 (3 mL) were added TMEDA
(83 µL, 0.55 mmol) and p-toluoyl chloride (73 µL, 0.55 mmol) at
0 °C under Ar, and the resulting mixture was stirred at rt for 1 h.
The mixture was treated with saturated aq NaHCO3 and extracted
with AcOEt. The extract was washed with brine and dried over
Na2SO4. Evaporation of the solvent gave a residue, which was
subjected to column chromatography on silica gel. Elution with
n-hexane-AcOEt (50:1, v/v) afforded ester 13 (83 mg, 98%) as a
crude acetonide (16.6 mg), which without further purification was
used in the next reaction. A solution of acetonide obtained above
was dissolved in 4 M NaOH-MeOH (1:1) (2 mL), and the resulting
solution was heated at reflux for 12 h. The solution was carefully
acidified with 1 M HCl, and extracted with CHCl3. The extract
was washed with brine, dried over Na2SO4, and concentrated to
give alcohol (20.4 mg), which was used in the next reaction without
further purification. To a solution of alcohol obtained above in THF
(2 mL) were added imidazole (36 mg, 0.535 mmol), I2 (112 mg,
0.446 mmol), and PPh3 (117 mg, 0.446 mmol) at rt, and the whole
was stirred at the same temperature for 12 h. The mixture was
treated with 10% aq Na2S2O3, and extracted with AcOEt. The
extract was washed with brine and dried over Na2SO4. Evaporation
of the solvent gave a residue, which was subjected to column
chromatography on silica gel. Elution with n-hexane-AcOEt (50:
colorless oil: [R]20D +46.7 (c 1.6, CHCl3); IR νmax 1712, 1277 cm-1
;
1H NMR (CDCl3; 400 MHz) δ 7.89 (2H, d, J ) 8.1 Hz), 7.21 (2H,
d, J ) 8.1 Hz), 5.97 (1H, dd, J ) 17.6 and 10.9 Hz), 5.30 (1H, br),
5.09 (1H, dd, J ) 10.9 and 1.1 Hz), 5.05 (1H, dd, J ) 17.6 and
1.1 Hz), 4.88 (1H, d, J ) 1.8 Hz), 4.86 (1H, d, J ) 1.8 Hz), 2.47
(1H, ddd, J ) 16.0, 6.9, and 4.8 Hz), 2.39 (3H, s), 2.24 (1H, s),
2.18 (1H, dt, J ) 13.7 and 6.9 Hz), 1.59-1.82 (4H, m), 1.38 (1H,
dd, J ) 14.3 and 6.3 Hz), 1.04 (3H, s), 1.02 (3H, d, J ) 7.3 Hz),
1.01 (3H, s); 13C NMR (CDCl3; 100 MHz) δ 165.8, 148.3, 147.5,
143.2, 129.5 (2), 128.9 (2), 128.3, 111.6, 109.9, 74.4, 55.4, 40.0,
39.7, 39.5, 38.5, 34.7, 30.5, 27.0, 25.5, 21.6, 20.2; MS (EI) 338
(M+); HRMS (EI) calcd for C23H30O2 338.2246, found 338.2251.
(2S,4R,8S)-8-[(1S)-1,2-Dihydroxyethyl]-4,5,8-trimethyl-9-
methylenebicyclo[3.3.1]non-2-yl 4-Methylbenzoate (14) and
(2S,4R,8S)-8-[(1R)-1,2-Dihydroxyethyl]-4,5,8-trimethyl-9-
methylenebicyclo[3.3.1]non-2-yl 4-Methylbenzoate (15). To a
1, v/v) afforded diene 16 (7.2 mg, 58%) as a colorless oil: [R]19
D
-80.6 (c 1.6, CHCl3); IR νmax 2930, 1070 cm-1; 1H NMR (CDCl3;
400 MHz) δ 5.75 (1H, ddd, J ) 9.8, 5.7, and 1.5 Hz), 5.68 (1H,
dd, J ) 9.8 and 3.4 Hz), 4.80 (1H, d, J ) 1.8 Hz), 4.64 (1H, d, J
) 1.8 Hz), 3.95 (1H, dd, J ) 7.9 and 6.6 Hz), 3.83 (1H, dd, J )
7.9 and 6.6 Hz), 3.66 (1H, t, J ) 7.9 Hz), 2.69 (1H, d, J ) 5.7
Hz), 1.99-2.07 (1H, m), 1.44-1.68 (4H, m), 1.43 (3H, s), 1.34
(3H, s), 0.99 (3H, s), 0.91 (3H, s), 0.81 (3H, d, J ) 7.1 Hz); 13C
NMR (CDCl3; 100 MHz) δ 150.4, 136.2, 126.7, 108.3 105.9, 79.8,
65.1, 48.6, 43.8, 39.8, 39.4, 39.2, 27.4, 26.3, 25.2, 24.7, 17.6, 15.3;
MS (EI) 276 (M+); HRMS (EI) calcd for C18H28O2 276.2089, found
276.2116.
t
stirred solution of alkene 13 (63 mg, 0.186 mmol) in BuOH-
THF-H2O (5:5:1, 1.1 mL) were added NMO (26 mg, 0.223 mmol)
(4R)-2,2-Dimethyl-4-[(2S,6R)-2,5,6-trimethyl-9-methylenebi-
cyclo[3.3.1]non-7-en-2-yl]-1,3-dioxolane (17). Acetonide formation
of diol 15 (69 mg, 0.185 mmol), followed by subsequent hydrolysis
and elimination were carried out by the same procedure as described
for the preparation of 16 to give the corresponding diene 17 (29.7
mg, 58%) as a colorless oil: [R]17D -121.3 (c 2.0, CHCl3); IR νmax
t
and OsO4 (0.02 M BuOH solution; 0.9 mL, 18.6 µmol) at rt, and
the resulting solution was stirred for an additional 3 days. The
mixture was treated with Na2S2O5 and H2O, and extracted with
CHCl3. The extract was washed with brine and dried over MgSO4.
Evaporation of the solvent gave a residue, which was subjected to
column chromatography on silica gel. Elution with
n-hexane-AcOEt (2:1, v/v) afforded diol 14 (16 mg, 23%) as the
1
2933, 1219 cm-1; H NMR (CDCl3; 400 MHz) δ 5.68 (1H, dd, J
) 9.8 and 3.6 Hz), 5.54 (1H, ddd, J ) 9.8, 5.7, and 1.5 Hz), 4.74
(1H, d, J ) 1.6 Hz), 4.63 (1H, d, J ) 1.6 Hz), 3.91-3.97 (2H, m),
3.72-3.78 (1H, m), 2.21 (1H, d, J ) 5.7 Hz), 2.05-2.09 (1H, m),
1.78-1.87 (1H, m), 1.50-1.54 (2H, m), 1.40-1.45 (1H, m), 1.39
(3H, s), 1.33 (3H, s), 0.99 (3H, s), 0.88 (3H, s), 0.79 (3H, d, J )
7.1 Hz); 13C NMR (CDCl3; 100 MHz) δ 149.9, 136.7, 125.5, 108.5,
105.8, 82.2, 64.6, 50.0, 43.7, 40.0, 39.7, 39.2, 29.1, 26.3, 25.3, 24.7,
17.5, 15.6; MS (CI) 277 (M + 1)+; HRMS (CI) calcd for C18H28O2
+ H 277.2167, found 277.2148.
first eluate (colorless oil): [R]20 +27.9 (c 1.9, CHCl3); IR νmax
D
3446, 1708 cm-1; 1H NMR (CDCl3; 400 MHz) δ 7.89 (2H, d, J )
8.1 Hz), 7.23 (2H, d, J ) 8.1 Hz), 5.41(1H, d, J ) 5.4 Hz), 4.79
(2H, dd, J ) 16.7 and 1.6 Hz), 4.08 (1H, br), 3.88 (1H, dd, J )
8.8 and 2.5 Hz), 3.67 (1H, dd, J ) 11.0 and 8.8 Hz), 3.60 (1H, dd,
J ) 11.0 and 2.5 Hz), 2.70 (1H, br), 2.53-2.63 (1H, m), 2.41 (3H,
s), 1.59-1.89 (5H, m), 1.28-1.33 (2H, m), 1.11 (3H, d, J ) 7.2
Hz), 1.02 (3H, s), 0.87 (3H, s); 13C NMR (CDCl3; 100 MHz) δ
167.5, 147.0, 143.9, 129.6 (2), 129.1 (2), 127.4, 111.1, 77.9, 73.1,
62.8, 51.3, 40.0, 39.7, 39.6, 38.0, 34.8, 31.6, 25.6, 21.7, 19.9, 18.5;
MS (EI) 372 (M+); HRMS (EI) calcd for C23H32O4 372.2300, found
372.2295.
Trifarienol A (1). A solution of diene 16 (15 mg, 54.3 µmol)
in MeOH (2 mL) in the presence of p-TsOH (41 mg, 0.217 mmol)
was heated at reflux for 12 h. The mixture was treated with water
and extracted with CHCl3. The organic layer was washed with brine,
dried over Na2SO4, and concentrated to give diol (13.5 mg), which
was used in the next reaction without further purification. To a
stirred solution of diol obtained above in CH2Cl2 (2 mL) was added
Crabtree catalyst (4.4 mg, 5.43 µmol), and the resulting mixture
was stirred at rt under an atmospheric pressure of hydrogen for
12 h. Removal of the solvent gave a residue, which was subjected
to column chromatography on silica gel. Elution with
n-hexane-AcOEt (1:1, v/v) furnished trifarienol A (9.6 mg, 74%),
whose spectroscopic data, including its specific optical rotation,
were comparable to those reported: mp 71-72 °C (lit.1a mp 59-60
Further elution with n-hexane-AcOEt (1:1 v/v) afforded diol
15 (44 mg, 64%) as white crystals: [R]19 +27.5 (c 1.5, CHCl3);
mp 148-149 °C; IR νmax 3393, 1708 cm-D1; 1H NMR (CDCl3; 400
MHz) δ 7.87 (2H, d, J ) 8.1 Hz), 7.20 (2H, d, J ) 8.1 Hz), 5.50
(1H, br), 4.79 (2H, dd, J ) 10.9 and 1.6 Hz), 4.15 (1H, dd, J )
11.0 and 2.5 Hz), 3.83 (1H, dd, J ) 9.5 and 2.5 Hz), 3.55 (1H, dd,
J ) 11.0 and 9.5 Hz), 3.22 (2H, br), 2.57-2.64 (1H, m), 2.39 (3H,
s), 2.20 (1H, s), 1.89-1.99 (1H, m), 1.78-1.85 (1H, m), 1.57-1.69
(4H, m), 1.05 (3H, d, J ) 7.2 Hz), 1.02 (3H, s), 0.89 (3H, s); 13C
NMR (CDCl3; 100 MHz) δ 166.3, 148.0, 143.5, 129.6 (2), 129.0
(2), 127.9, 110.2, 78.1, 73.1, 62.3, 53.3, 40.3, 39.59, 39.55, 38.4,
34.8, 31.8, 25.7, 21.6, 20.5, 18.8; MS (EI) 372 (M+); HRMS (EI)
calcd for C23H32O4 372.2300, found 372.2278. Anal. Calcd for
C23H32O4: C, 74.16; H, 8.66. Found: C, 73.90; H, 8.70.
(4S)-2,2-Dimethyl-4-[(2S,6R)-2,5,6-trimethyl-9-methylenebi-
cyclo[3.3.1]non-7-en-2-yl]-1,3-dioxolane (16). To a stirred solution
of diol 14 (16.6 mg, 44.6 µmol) in acetone (2 mL) were added
2,2-dimethoxypropane (0.01 mL, 89.2 µmol) and p-TsOH (0.01
M acetone solution; 0.2 mL, 2.23 µmol) at rt, and the whole was
heated at reflux for 2 h. The mixture was treated with saturated aq
NaHCO3 and extracted with AcOEt. The extract was washed with
brine and dried over Na2SO4. Evaporation of the solvent gave a
°C, lit.2b mp 82-82.5 °C); [R]18D +11.5 (c 0.9, CHCl3) {lit.1a [R]20
D
+10.2 (c 0.63, CHCl3), lit.2b [R]21D +15 (c 0.5, CHCl3)}; MS (EI)
238 (M+); HRMS (EI) calcd for C15H26O2 238.1933, found
238.1929.
Trifarienol B (2): Method A: Trifarienol B (16.2 mg, 94%)
was synthesized from diene 17 (20 mg, 72.5 µmol) by the same
procedure as described for the preparation of trifarienol A.
Spectroscopic data of the synthesized compound, including its
specific optical rotation, were similar to those reported: mp 99-100
°C (lit.1a mp 105-105.5 °C, lit.2b mp 108-109.5 °C); [R]18D -6.0
(c 1.5, CHCl3) {lit.1a [R]20D -3.6 (c 1.62, CHCl3), lit.2b [R]20D -3.5
3428 J. Org. Chem. Vol. 74, No. 9, 2009

Synthesis of Trifarane-Type Sesquiterpenes
(c 1.01, CHCl3)}; MS (EI) 238 (M+); HRMS (EI) calcd for
C15H26O2 238.1933, found 238.1934.
Acknowledgment. This research was supported financially
in part by a grant for the Open Research Center Project and a
Grant-in-Aid from the Ministry of Education, Culture, Sports,
Science and Technology of Japan.
Method B: To a stirred solution of SmI2 (0.1 M THF solution;
6.8 mL, 0.68 mmol) was added HMPA (0.47 mL, 2.71 mmol) at
reflux under Ar. To this mixture was added a solution of ester 15
(41.4 mg, 0.113 mmol) in THF (1 mL), and the resulting mixture
was stirred for an additional 5 min. After treatment with saturated
aq ammonium chloride, the mixture was extracted with CHCl3. The
extract was washed with brine, dried over Na2SO4, and concentrated
to leave a residue, which was subjected to column chromatography
on silica gel. Elution with n-hexane-AcOEt (1:1, v/v) furnished
trifarienol B (6.7 mg, 25%), which was identical with the authentic
specimen obtained above.
Supporting Information Available: Complete synthetic
details and characterization for new compounds 4-8, as well
as copies of 1H and 13C NMR spectra for compounds 1, 2, and
4-17. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO900369T
J. Org. Chem. Vol. 74, No. 9, 2009 3429