SCHEME 4. Cyclization of Farnesal (1) under ClSO3H
Catalysis
not react with the electron-deficient C2-C3 double bond but
rather deprotonates to form the thermodynamically more stable
1e and 1f. The absence of 1a or 2 indicates that any 1d formed
by deprotonation of CI undergoes a faster isomerization to 1e/
1f than to give an intramolecular Prins-type reaction which leads
to the nanaimoal carbon skeleton.
The current synthesis of nanaimoal, using as a key reaction
a novel tandem cyclization promoted by NaY, exemplifies a
new biomimetic application of terpene cyclization under zeolite
confinement. To the best of our knowledge, we have presented
herein the first example of a tandem 1,5-cyclization/Prins-type
reaction that provides a direct access to 1,2,3,4,4a,5,6,7-
octahydronaphthalenes, the core skeleton of several terpenes
such as macfarlandins C and D24 and przewalskin B.25
In conclusion, we have presented a novel, simple, mild,
environmentally friendly and efficient biomimetic methodology
for the di-cyclization of farnesal, which provides a direct route
to nanaimoal. Further synthetic applications and mechanistic
studies of terpene cyclization under zeolite confinement condi-
tions are currently under investigation.
without obtaining any of the desired products. Furthermore, a
shorter approach for the isomerization of 1a to 2 by an attempted
I2-promoted isomerization of acetal 7 (obtained from 1a and
ethylene glycol) also failed, as the acetal undergoes deprotection
by the iodine. In addition, treatment of 1a with Lewis acids
such as BBr3 or MeAlCl2, which were efficient in catalyzing
Experimental Section
Intrazeolite Cyclization of Nanaimoal. A slurry of 1 g of NaY
(dried at 120 °C under vacuum for at least 6 h prior to use), 10 mL
of hexane, and 60 mg (0.27 mmol) of farnesal (1) was heated to
70 °C for 3 h. The solvent was removed by filtration, and the solid
residue was washed with methanol (2 × 10 mL) for 30 min each
time. The combined solvents were evaporated under reduced
pressure to afford 46 mg of 1a-c, in a relative ratio of 50/38/12.
The mixture was chromatographed using hexane/ethyl acetate )
50/1 to afford 18 mg of the less polar 1a11 and 17 mg of the mixture
of 1b,c. Under careful chromatographic conditions pure samples
the cyclization of a suitable precursor to â-georgywood,16
a
terpenoid structurally similar to 2, were disappointing. The
aldehyde disappeared, with accompanying formation of a
polymeric material. Finally, the attempted isomerization of 1a
to 2 using RhCl317 as catalyst also failed. A tricyclic dimethoxy
product (8, see Supporting Information) was formed almost
quantitatively, probably though a solvent (methanol) intercepted
intramolecular carbonyl-ene reaction. Further research is cur-
rently in progress18 to explore this novel reaction pathway.
We consider the current synthesis of nanaimoal as biomimetic.
In our opinion, nanaimoal might arise through the direct
isomerization of farnesal to 2 via a tandem reaction sequence,
such as the one provided by the zeolite environment. In addition,
the current synthesis is very fast and the overall yield is quite
acceptable (21%). There are four known literature syntheses of
nanaimoal,11,19-21 however, applying significantly more steps
compared to our approach. Engler and co-workers11 prepared
1d and attempted its cyclization upon treatment with several
Lewis acids, with varying degrees of success. Nanaimoal was
formed, among two other isomeric products, in up to 19% yield.
For comparison, we studied the cyclization of farnesal under
Bronsted acid catalysis (ClSO3H, 2-nitropropane, -78 °C).22
The two isomeric monocyclized products23 1e and 1f were
isolated in 81% yield, and in a ratio 1e/1f of ∼3/1 (Scheme 4).
Apparently, the mono-cyclized carbocation CI (Scheme 4) does
1
of 1b and 1c can be isolated. H NMR of the major diastereomer
of 2-2,5,5-trimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)-
acetaldehyde, 1a (500 MHz, CDCl3): δ 9.81 (dd, J ) 3.0 Hz, 1H),
5.33 (br. s, 1H), 2.29 (dd, J1 ) 14.5 Hz, J2 ) 3.0 Hz, 1H), 2.24
(dd, J1 ) 14.5 Hz, J2 ) 3.0 Hz, 1H), 2.09 (dd, J1 ) 13.0 Hz, J2 )
2.0 Hz, 1H), 1.97 (m, 2H), 1.90 (dd, J1 ) 13.0 Hz, J2 ) 2.0 Hz,
1H), 1.58 (m, 1H), 1.65-1.73 (m, 2H), 1.30-1.36 (m, 2H), 1.20-
1.27 (m, 2H), 1.07 (s, 3H), 0.91 (s, 3H), 0.84 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 204.1, 136.6, 121.2, 49.3, 48.9, 47.1, 38.2,
1
35.5, 34.8, 31.3, 28.9, 28.5, 24.7, 23.8, 22.7. H NMR of (E)-3-
methyl-5-(2,6,6-trimethylcyclohex-2-enyl)pent-2-enal, 1b (500 MHz,
CDCl3): δ 10.00 (d, J ) 8.0 Hz, 1H), 5.88 (d, J ) 8.0 Hz, 1H),
5.34 (br. s, 1H), 2.24 (m, 2H), 2.17 (s, 3H), 1.98 (m, 2H), 1.68 (s,
3H), 1.62 (m, 2H), 1.40 (m, 1H),1.27 (m, 1H), 1.17 (m, 1H), 0.93
(s, 3H), 0.88 (s, 3H). MS (EI): 220 (M+, 2%), 206 (1%), 176 (3%),
138 (29%), 121 (27%), 81 (51%), 55 (26%), 41 (100%). 1H NMR
of (Z)-3-methyl-5-(2,6,6-trimethylcyclohex-2-enyl)pent-2-enal, 1c
(500 MHz, CDCl3): δ 9.95 (d, J ) 8.0 Hz, 1H), 5.85 (d, J ) 8.0
Hz, 1H), 5.37 (br. s, 1H), 2.58 (m, 2H), 1.99 (s, 3H), 1.70 (s, 3H),
1.64 (m, 1H), 1.52 (m, 2H), 1.43-1.37 (m, 2H), 1.17-1.15 (m,
2H), 0.97 (s, 3H), 0.89 (s, 3H). MS (EI): 220 (M+, <1%), 206
(1%), 176 (2%), 149 (5%), 138 (17%), 121 (18%), 95 (21%), 81
(52%), 55 (27%), 41 (100%).
(16) Frater, G.; Schroder, F. J. Org. Chem. 2007, 72, 1112-1120.
(17) Grieco, P. A.; Nishizawa, M.; Marinovic, N.; Ehmann, W. J. J. Am.
Chem. Soc. 1976, 98, 7102-7104.
(18) We thank one of the reviewers for suggesting the use of RhCl3 as
an isomerization catalyst.
(19) Yamada, T.; Takabe, K. Chem. Lett. 1993, 29-30.
(20) Liu, H.-J.; Ly, T. W.; Tai, C.-L.; Wu, J.-D.; Liang, J.-K.; Gu, J.-C.;
Tseng, N.-W.; Shia, K.-S. Tetrahedron 2003, 59, 1209-1226.
(21) Omodani, T.; Shishido, K. Chem. Commun. 1994, 2781-2782.
(22) Linares-Palomino, P. J.; Salido, S.; Altarejos, J.; Sanchez, A.
Tetrahedron Lett. 2003, 44, 6651-6654.
(23) (a) Kojima, S.; Maki, S.; Hirano, T.; Ohmiya, Y.; Niwa, H.
Tetrahedron Lett. 2000, 41, 4409-4413. (b) Nakatsubo, F.; Kishi, Y.; Goto,
T. Tetrahedron Lett. 1970, 11, 381-382.
2-2,5,5-Trimethyl-1,2,3,4,4a,5,6,7-octahydronaphthalen-2-yl)-
ethanol (3). Alcohol 5 was prepared in 96% yield by reacting 16
mg (0.073 mmol) of aldehyde 1a with 25 µL (0.025 mmol) of
1
LiAlH4 (1 M in Et2O). H NMR of the major diastereomer of 3
(500 MHz, CDCl3): δ 5.29 (m, 1H), 3.65 (m, 2H), 1.97-1.92 (m,
4H), 1.80 (br. s, 1H), 1.60-1.49 (m, 3H), 1.36-1.30 (m, 2H),
(24) Molinski, T. F.; Faulkner, D. J.; Cun-Heng, H.; van Duyne, G. D.;
Clardy, J. J. Org. Chem. 1986, 51, 4564-4567.
(25) Xu, G.; Hou, A.-J.; Zheng, Y.-T.; Zhao, Y.; Li, X.-L.; Peng, L.-Y.;
Zhao, Q.-S. Org. Lett. 2007, 9, 291-293.
J. Org. Chem, Vol. 73, No. 7, 2008 2907