Total synthesis of 9-isocyanoneopupukeanane

Full text of DOI:10.1021/jo991115s

J . Org. Chem. 1999, 64, 8965-8967
8965
sealed tube at 450 °C for 1 h furnished directly the
desired tricyclic olefin 8 (54%), indicating the generation
of 7 as an intermediate.
Tota l Syn th esis of
9-Isocya n on eop u p u k ea n a n e
With the acquisition of 8 the functionalization of its
double bond was in order. We expected that hydrobora-
tion-oxidation would give rise to 9 predominantly be-
cause the formation of the regioisomeric alcohol 9a is less
favorable due to steric hindrance from the bridgehead
methyl substituents. Indeed, a separable mixture was
produced in 52% and 10% yield, respectively. By PCC
oxidation of the major alcohol 9 to afford ketone 10 (85%)
the work entered its last stage. Thus, after exposure of
10 to i-PrMgBr/CeCl316 (91%) and then Me3SiCN/H2SO4,17
the formamide 12 was obtained in 42.5% yield. Comple-
tion of our synthesis was attained by subjecting 12 to
TsCl-py at room temperature. 9-Isocyanoneopupukeanane
was isolated in 83% yield. The final product showed
spectral data in good agreement with the reported values.
In conclusion, this report delineates the first total
synthesis of isocyanoneopupukeanane. It is interesting
that we did not isolate the dimethyltwistene isomer from
the pyrolysate of 6b.
Tse-Lok Ho* and Gour Hari J ana
Department of Applied Chemistry, National Chiao Tung
University, Hsinchu, Taiwan, Republic of China
Received J uly 12, 1999
Sponges elaborate the largest number of bioactive
marine natural products, which often possess fascinating
structures of great varieties. Our involvement in this area
of chemistry has resulted in the synthesis of curcuphenol
and curcudiol,1 (-)-furodysin,2 (-)-furodysinin,3 the enan-
tiomer of herbasolide,4 and tavacpallescensin.5 More
recently, efforts in attaining the isocyanopupukeananes
also bore fruit;6 we now describe our approach to 9-iso-
cyanoneopupukeanane (1), which is a constituent of a
Ciocalypta sp.7 Besides the syntheses of 2-isocyanopu-
pukeanane (2a , Chart 1)8 and 9-isocyanopupukeanane
(2b),9,10 formal syntheses of the latter that terminated
at 9-pupukeanone11-13 have also been reported. On the
other hand, we are not aware of 1, which possesses a
rearranged skeleton, having been yielded to synthesis.
This work stemmed from our general interest in
synthesis design related to molecular symmetry.14 In a
retrosynthetic analysis of isocyanoneopupukeanane, the
disconnection of the isopropyl group and functional group
interchange at the isocyano-substituted center led to the
symmetrical ketone 10. Further tracking indicated the
tricyclic olefin 8, and the cyclohexadiene 7 to be useful
synthetic precursors. To secure these compounds, we
started from 3, which is readily available15 from a
reaction sequence consisting of Birch reduction of p-cresyl
methyl ether, Diels-Alder reaction with methyl acrylate
(after in situ conjugation), and Grignard reaction with
MeMgCl. Treatment of 3 with HClO4 led to enone 4
(63%), which was epoxidized at the side chain with
hydrogen peroxide-urea in acetic anhydride to give 5 in
70% yield (75% by using m-CPBA). Reduction of the
epoxy enone with lithium aluminum hydride afforded the
diol 6a (62%, inseparable diastereomers), which was
acetylated (Ac2O, py, DMAP) to provide diacetate 6b
(92%, inseparable diastereomers). Pyrolysis of 6b in a
Exp er im en ta l Section
Gen er a l Meth od s. NMR spectra were recorded with CDCl3
as solvent, at 300 and 74 MHz, respectively for 1H and 13C
absorptions. Chemicals shifts reported in ppm relative to 0 for
TMS. Electron impact mass spectra were measured at 70 eV.
Silica gel (70-230 mesh) for chromatography was a Merck
product. Melting points, determined with a Laboratory Devices
apparatus, were uncorrected.
4-Meth yl-4-(3-m eth yl-2-bu ten yl)-2-cycloh exen on e (4). To
a solution of the tertiary alcohol 3 (15.0 g, 71 mmol) in glacial
acetic acid (40 mL) was added 70% perchloric acid (1 mL), and
the mixture was stirred at room temperature for 45 min and
quenched with aqueous sodium bicarbonate. The product was
extracted into ether, which was washed with water and brine,
dried over anhydrous Na2SO4, and filtered. The residue obtained
on evaporation was passed through a silica gel column (eluent:
hexane) to afford the dienone 4 as an oil (8.0 g, 63%): IR (film)
1683 cm-1 1H NMR δ 1.04 (3H, s), 1.52 (3H, s), 1.70 (3H, s),
;
1.80-2.00 (1H, m), 2.15-2.20 (3H, m), 2.34-2.40 (2H, m), 5.08
(1H, t, J ) 7.2 Hz), 5.80 (1H, d, J ) 10.2 Hz), 6.60 (1H, d, J )
10.2 Hz); 13C NMR δ 17.8 (q), 24.6 (q), 25.9 (q), 33.4 (t), 34.1 (t),
36.5 (s), 39.0 (t), 119.0 (d), 127.3 (d), 135.0 (s), 159.1 (d), 199.6
(s); HRMS (EI) 178.1356 (178.1358 calcd for C12H18O).
4-Met h yl-4-(3-m et h yl-2,3-ep oxyb u t a n yl)-2-cycloh exen -
on e (5). A mixture of 4 (8.2 g, 46 mmol), urea-hydrogen
peroxide (13.0 g, 138 mmol), and acetic anhydride (37 mL) in
dichloromethane (130 mL) was refluxed for 4 h. The reaction
mixture was cooled to room temperature, neutralized with
saturated sodium carbonate, and separated into layers. The
aqueous solution was extracted with more dichloromethane. The
organic solutions were combined, dried over anhydrous Na2SO4,
and filtered. The residue obtained on evaporation was chro-
matographed over a silica gel column (eluent: hexane/ethyl
acetate 9:1) to furnish the oily epoxy enone 5 (6.2 g, 70%): IR
* To whom correspondence should be addressed. E-mail: tlho@
cc.nctu.edu.tw.
(1) Ho, T.-L.; Yang, P.-F. Tetrahedron 1995, 51, 181.
(2) Ho, T.-L.; Lee, K.-Y. Tetrahedron Lett. 1995, 36, 947.
(3) Ho, T.-L.; Chein, R.-J . Chem. Commun. 1996, 1147.
(4) Ho, T.-L.; Liang, F.-S. Chem. Commun. 1996, 1887.
(5) Ho, T.-L.; Lin, Y.-J . J . Chem. Soc., Perkin Trans. 1 1999, 1207.
(6) Some time ago we completed the first synthesis of 2-isocyano-
allopupukeanane which has another skeleton: Ho, T.-L.; Kung, L.-R.
Org. Lett. 1999, in press.
(7) Karuso, P.; Poiner, A.; Scheuer, P. J . J . Org. Chem. 1989, 54,
2095.
(8) Corey, E. J .; Ishiguro, M. Tetrahedron Lett. 1979, 2745.
(9) Corey, E. J .; Behforouz, M.; Ishiguro, M. J . Am. Chem. Soc. 1979,
101, 1608.
(10) Yamamoto, H.; Sham, H. L. J . Am. Chem. Soc. 1979, 101, 1609.
(11) Schiehser, G. A.; White, J . D. J . Org. Chem. 1980, 45, 1864.
(12) Piers, E.; Winter, M. Liebigs Ann. Chem. 1982, 973.
(13) Hsieh, S.-L., Chiu, C.-T.; Chang, N. C. J . Org. Chem. 1989, 54,
3820.
(14) Ho, T.-L. Symmetry. A Basis for Synthesis Design; Wiley: New
York, 1995.
(film) 1672 cm-1
1.80 (2H, m), 2.00-2.15 (2H, m), 2.25-2.32 (2H, m), 2.59-2.62
(1H, m), 5.70 (1H, d, J ) 10.5 Hz), 6.58 (1H, d, J ) 10.5 Hz); 13
;
1H NMR δ 1.21 (6H, s), 1.28 (3H, s), 1.40-
C
NMR δ 18.7/18.8 (q), 24.6/25.1/25.3 (q), 33.7/33.9 (t), 35.2/35.5
(s), 39.3 (t), 40.0 (t), 57.7 (s), 60.3/60.4 (d), 127.7 (d), 157.7/157.9
(d), 199.1 (s); HRMS (EI) 194.1304 (194.1307 calcd for C12H18O2).
(16) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392.
(17) Chen, H. G.; Goel, O. P.; Kesten, S.; Knobelsdorf, J . Tetrahedron
Lett. 1996, 37, 8129.
(15) Birch, A. J .; Hill, J . S. J . Chem. Soc. C 1966, 419.
10.1021/jo991115s CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/09/1999

8966 J . Org. Chem., Vol. 64, No. 24, 1999
Notes
Ch a r t 1
4-Meth yl-4-(3-h yd r oxy-3-m eth ylbu ta n yl)-2-cycloh exen -
ol (6a ). A solution of the epoxy enone 5 (0.97 g, 5 mmol) in
anhydrous ether (20 mL) was added to a suspension of lithium
aluminum hydride (0.19 g, 5 mmol) in ether (20 mL) at 0 °C
and then heated under reflux for 12 h. On cooling, the reaction
mixture was quenched with water, neutralized with 3 N sulfuric
acid, and separated into layers. The aqueous solution was
extracted with more ether, and the combined organic solutions
were dried over anhydrous Na2SO4 and filtered. The residue
obtained on evaporation was chromatographed over a silica gel
column (eluent: hexane/ethyl acetate 2:3) to furnish the diol 6a
as an oil (0.61 g, 62%). The spectral data indicated it to be a
mixture of diastereomers, but a sample of one isomer could be
obtained: IR (film) 3410 cm-1; 1H NMR δ 0.86 (3H, s), 1.12 (6H,
s), 1.15-1.95 (7H, m), 1.96 (1H, m), 2.48 (2H, m), 4.00-4.10 (1H,
m), 5.30-5.50 (2H, m); 13C NMR δ 26.5 (q), 28.9 (q), 31.4 (t),
34.1 (s), 36.4 (t), 37.6 (t), 66.2 (d), 70.7 (s), 129.0 (d), 138.3 (d);
MS (EI) 198 (M+, 3), 111 (100).
3,7-Dim eth yltr icyclo[5.3.1.03,8]u n d eca n -10-ol (9) a n d 3,7-
Dim eth yltr icyclo[5.3.1.03,8]u n d eca n -9-ol (9a ). A solution of
boron trifluoride etherate (0.23 g, 0.16 mmol) in THF (5 mL)
was slowly introduced to a stirred mixture of alkene 8 (0.650 g,
4 mmol) and sodium borohydride (0.045 g, 1.2 mmol) in THF
(10 mL) under nitrogen at room temperature. After 2 h, water
was added, which was followed by aqueous sodium hydroxide
(3 M, 5 mL) and hydrogen peroxide (28%, 5 mL). At the end of
4 h, the reaction mixture was diluted with water and extracted
with ether. On evaporation of the dried extracts, a mixture of
two alcohols was obtained. These were separated by silica gel
chromatography (eluent: hexane/ethyl acetate 9:1).
Alcohol 9 (0.375 g, 52%): IR (film) 3395 cm-1 1H NMR δ
;
0.80-0.83 (1H, m), 0.95 (3H, s), 1.03 (3H, s), 1.10-1.31 (2H, m),
1.34-1.40 (6H, m), 1.65-1.71 (3H, m), 1.95-2.10 (1H, m), 3.67-
3.72 (1H, m); 13C NMR δ 26.6 (q), 26.85 (t), 26.9 (q), 33.9 (d),
35.6 (t), 39.1 (s), 39.8 (s), 40.3 (t), 40.7 (t), 41.9 (t), 48.5 (d), 68.9
(d); HRMS (EI) 180.1520 (180.1515 calcd for C12H20O).
4-Meth yl-4-(3-a cetoxy-3-m eth ylbu ta n yl)-2-cycloh exen -1-
yl Aceta te (6b). A mixture of the diol isomers 6a (0.99 g, 5
mmol), acetic anhydride (5.0 mL, 50 mmol), pyridine (4.0 mL,
50 mmol), and 4-(N,N-dimethylamino)pyridine (0.061 g, 0.5
mmol) was stirred at room temperature for 12 h under nitrogen,
diluted with dichloromethane, and washed with aqueous sodium
carbonate, brine, and water. After drying (Na2SO4) and evapora-
tion, the product was isolated by silica gel chromatography
(eluent: hexane/ethyl acetate 1:1) to furnish the diastereomeric
mixture of the oily diacetate 6b (1.30 g, 92%): IR (film) 1733
cm-1; 1H NMR δ 0.88/0.94 (3H, s), 1.20-1.30 (4H, m), 1.34/1.35
(6H, s), 1.60-1.80 (4H, m), 1.89/1.90 (3H, s), 1.98/1.99 (3H, s),
5.10-5.17 (1H, m), 5.50-5.57 (2H, m); 13C NMR δ 21.3 (q), 22.3
(q), 25.0 (t), 25.9 (q), 30.2/31.0 (t), 33.9 (t), 34.0 (t), 34.6/34.7 (s),
35.3/35.4 (t), 67.6/69.0 (d), 141.7 (d), 170.2 (s), 170.7 (s); MS (EI)
282 (M+, 10), 180 (100).
3,7-Dim eth yltr icyclo[5.3.1.03,8]u n d ec-9-en e (8). Diacetate
6b (2.82 g, 10 mmol) and a trace amount of hydroquinone in
hexane (1 mL) was placed in a sealed tube and heated at 450
°C for 1 h. The cooled reaction product was filtered through a
short column of silica gel to provide the alkene 8 (0.87 g, 54%)
as a colorless liquid: 1H NMR δ 0.86 (6H, s), 1.04 (2H, d, J )
1.8 Hz), 1.05 (2H, d, J ) 1.8 Hz), 1.48-1.51 (4H, m), 1.76 (1H,
d, J ) 3.0 Hz), 2.34 (1H, m), 6.01 (1H, t, J ) 7.0 Hz), 6.30 (1H,
t, J ) 7.0 Hz); 13C NMR δ 28.5 (q), 31.0 (d), 39.3 (t), 42.0 (s),
44.3 (t), 54.7 (d), 129.2 (d), 135.3 (d); MS (EI) 162 (M+, 50), 93
(100). Anal. Calcd for C12H18: C, 88.88; H, 11.11. Found: C, 88.30;
H, 11.38.
Alcohol 9a (0.072 g, 10%): IR (film) 3480 cm-1 1H NMR δ
;
0.80-0.90 (2H, m), 0.97 (3H, s), 1.00-1.17 (2H, m), 1.18 (3H,
m), 1.19-1.80 (4H, m), 1.85-1.87 (2H, m), 1.90-1.98 (2H, m),
4.10-4.17 (1H, m); 13C NMR δ 26.2 (d), 27.1 (q), 29.6 (q), 38.2
(t), 39.6 (s), 40.7 (s), 40.8 (t), 41.7 (t), 42.9 (t), 43.8 (t), 54.3 (d),
66.9 (d); HRMS (EI) 180.1512 (180.1515 calcd for C12H20O).
3,7-Dim eth yltr icyclo[5.3.1.03,8]u n d eca n -10-on e (10). Al-
cohol 9 (0.360 g, 2 mmol) was added to a stirred suspension of
PCC (0.862 g, 4 mmol) in dichloromethane (6 mL) at room
temperature. After 3 h, the mixture was filtered through Celite
and evaporated. The residue was chromatographed over silica
gel (eluent: hexane/ethyl acetate 4:1) to give ketone 10 as a
colorless oil (0.303 g, 85%): IR (film) 1732 cm-1; 1H NMR δ 1.00
(6H, s), 1.30 (3H, m), 1.51-1.60 (8H, m), 2.00 (1H, m), 2.18-
2.19 (2H, m); 13C NMR δ 26.6 (q), 33.0 (t), 39.7 (s), 40.0 (t), 40.3
(t), 43.4 (d), 50.6 (d), 216.8 (s); HRMS (EI) 178.1362 (178.1358
calcd for C12H18O).
10-Isop r op yl-3,7-d im eth yltr icyclo[5.3.1.03,8]u n d eca n -10-
ol (11). Cerium trichloride heptahydrate (0.558 g, 1.5 mmol) was
dried at 150 °C/0.2 Torr for 4 h, cooled under nitrogen, and
suspended and stirred in THF (5 mL). A solution of isopropyl-
magnesium bromide prepared from Mg (0.048 g, 2 mmol) and
2-bromopropane (0.246 g, 2 mmol) in THF (10 mL) under
sonication was added to the cerium chloride at 0 °C. After 1.5
h, ketone 10 (0.178 g, 1 mmol) in THF (2 mL) was added, and
the reaction was allowed to proceed for 1 h. After addition of
10% acetic acid, the reaction mixture was extracted with ether
and the combined extracts were washed with brine and sodium

Notes
J . Org. Chem., Vol. 64, No. 24, 1999 8967
bicarbonate. Drying, filtration, and evaporation gave a crude
product which was purified by silica gel chromatography (elu-
ent: hexane/ethyl acetate 9:1) to afford alcohol 11 (0.202 g,
91%): IR (film) 3490 cm-1; 1H NMR δ 0.77 (3H, d, J ) 6.9 Hz),
0.93 (3H, d, J ) 6.9 Hz), 0.96 (3H, s), 1.05 (3H, s), 1.10-1.95
(13H, m); 13C NMR δ 16.05 (q), 16.07 (q), 26.3 (q), 27.0 (q), 32.1
(t), 34.1 (d), 37.6 (t), 38.77 (s), 38.83 (s), 39.6 (t), 41.0 (t), 41.0
(t), 49.4 (d), 72.8 (s); HRMS (EI) 222.1980 (222.1985 calcd for
C15H26O).
10-Isocya n o-10-isop r op yl-3,7-d im eth yltr icyclo[5.3.1.03,8]-
u n d eca n e (9-Isocya n on eop u p u k ea n a n e) (1). p-Toluenesul-
fonyl chloride (0.200 g, 1.05 mmol) was added to formamide 12
(0.110 g, 0.44 mmol) in pyridine (3.0 mL) at 0 °C. After a few
minutes, the ice bath was removed, and the mixture was stirred
at room temperature for 3 h, quenched with water (1 mL), and
extracted with hexane. The extracts were dried (Na2SO4),
filtered, evaporated, and chromatographed over silica gel (elu-
ent: hexane/ethyl acetate 19:1) to furnish 9-isocyanoneopuke-
N-F or m yl-10-isop r op yl-3,7-d im et h ylt r icyclo[5.3.1.03,8]-
u n d eca n -10-yla m in e (12). Concentrated sulfuric acid (0.25 mL,
4.5 mmol) was added in small portions to a stirred, ice-cooled
solution of alcohol 10 (0.111 g, 0.5 mmol) and cyanotrimethyl-
silane (0.4 mL, 2.5 mmol) in acetic acid (1.0 mL) under nitrogen.
The ice bath was removed, and the mixture was stirred at room
temperature for 24 h, neutralized with 10% sodium hydroxide,
and extracted with ethyl acetate. The product was purified by
silica gel chromatography (eluent: hexane/ethyl acetate 3:2) to
furnish the crystalline formamide 12 (0.053 g, 42.5%): mp 78-
80 °C. IR (film) 3213, 1683 cm-1; 1H NMR δ 0.74 (3H, d, J ) 6.6
Hz), 0.87 (3H, d, J ) 6.6 Hz), 0.96 (3H, s), 0.98 (3H, s), 1.15-
2.25 (4H, m), 1.30-1.42 (3H, m), 1.46-1.60 (2H, m), 1.74-1.80
(1H, m), 1.84-1.85 (1H, m), 6.30 (1H, br.s), 8.07 (1H, d, J )
12.0 Hz); 13C NMR δ 16.0 (q), 16.7 (q), 26.3 (q), 26.6 (q), 30.2 (t),
32.1 (d), 35.7 (d), 38.38 (t), 38.4 (t), 39.1 (s), 39.3 (s), 40.8 (t),
41.2 (t), 48.4 (d), 56.9 (s), 164.1 (d); HRMS (EI) 249.2101
(249.2094 calcd for C16H27NO).
anane (1) (0.085 g, 83%) as a colorless oil: IR (film) 2124 cm-1
;
1H NMR (C6D6) δ 0.55 (1H, m), 0.73 (3H, d, J ) 6.6 Hz), 0.74
(3H, s), 0.75-0.90 (2H, n), 0.95 (3H, d, J ) 6.6 Hz), 1.09 (3H, s),
1.20-1.60 (7H, m), 1.65-1.80 (2H, m), 2.00-2.10 (1H, m); 13C
NMR (C6D6) δ 16.5 (q), 17.0 (q), 26.3 (q), 26.7 (q), 31.4 (t), 33.2
(d), 34.6 (d), 38.0 (t), 38.7 (t), 39.0 (s), 39.1 (s), 40.1 (t), 48.3 (d),
64.4 (s), 157.0 (s); HRMS (EI) 231.1985 (231.1988 calcd for
C16H25N).
Ack n ow led gm en t. This research was generously
supported by the National Science Council, Republic of
China.
Su p p or tin g In for m a tion Ava ila ble: Copies of 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O991115S