Total synthesis of (±)-2-pupukeanone

Article abstract of DOI:10.1021/jo9603338

A synthesis of (±)-2-pupukeanone (4) is described in which the pupukeanane skeleton is assembled by means of intramolecular cyclization of tosylate 11 and then the attachment of an isopropyl group at the appropriate position of the tricyclic ring system. The key intermediate 11 was constructed via a sequence beginning from readily available ketone 5 and proceeding through bicyclo[3.2.1]ketone 8 by regioselective ring expansion.

Full text of DOI:10.1021/jo9603338

J . Org. Chem. 1996, 61, 4967-4970
4967
Tota l Syn th esis of (()-2-P u p u k ea n on e
Nein-Chen Chang* and Chi-Kang Chang
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung, Taiwan 804, Republic of China
Received February 16, 1996X
A synthesis of (()-2-pupukeanone (4) is described in which the pupukeanane skeleton is assembled
by means of intramolecular cyclization of tosylate 11 and then the attachment of an isopropyl group
at the appropriate position of the tricyclic ring system. The key intermediate 11 was constructed
via a sequence begining from readily available ketone 5 and proceeding through bicyclo[3.2.1]ketone
8 by regioselective ring expansion.
Sch em e 1
9-Isocyanopupukeanane (1) and 2-isocyanopupukeanane
(2), which are produced by a sponge (Hymeniacidon sp.)
and serve certain nudibranchs as defensive substances,
were isolated by Scheuer et al.1 Independent syntheses
of 1,2 2,3 and of their degradation products 9-pu-
pukeanone (3)4 and 2-pupukeanone (4)5 have been
Sch em e 2
achieved. In this report, we describle a new approach to
the synthesis of 2-pupukeanone (4), a key intermediate
in Corey’s synthesis3 of 2. Our strategy is outlined in
Scheme 1. The crucial steps include (1) ring expansion
of the bicyclo[2.2.1]ketone 7 to the bicyclo[3.2.1]ketone
8; (2) intramolecular cyclization of tosylate 11 to 12.
Resu lts a n d Discu ssion
The synthesis began (see Scheme 2) with acid-cata-
lyzed hydrolysis of the readily available ketone 5.6
Subsequent treatment of the intermediate aldehyde with
(methoxymethylene) triphenylphosphorane produced
methyl enol ether 6 in 76% yield.7 In order to obtain
better regioselectivity in the following ring expansion
procedure, a large group attached at C-7 is required to
X Abstract published in Advance ACS Abstracts, J uly 1, 1996.
(1) Burreson, B. J .; Scheuer, P. J .; Finer, J .; Clardy, J . J . Am. Chem.
Soc. 1975, 97, 4763.
(2) (a) Corey, E. J .; Behforouz, M.; Ishiguro, M. J . Am. Chem. Soc.
1979, 101, 1608. (b) Yamamoto, H.; Sham, H. L. J . Am. Chem. Soc.
1979, 101, 1609.
(3) Corey, E. J .; Ishiguro, M. Tetrahedron Lett. 1979, 2745.
(4) (a) Schiehser, G. A.; White, J . D. J . Org. Chem. 1980, 45, 1864.
(b) Hsieh, S. L.; Chiu, C. T.; Chang, N. C. J . Org. Chem. 1989, 54,
3820.
(5) Frater, G.; Wenger, J . Helv. Chim. Acta 1984, 64, 1702.
(6) (a) Brown, E. D.; Clarkson, R.; Leeney, T. J .; Robinson, G. E. J .
Chem. Soc., Perkin Trans. 1, 1978, 1507. (b) Chang, N. C.; Lu, W. F.;
Tseng, C. Y. J . Chem. Soc., Chem. Commun. 1988, 182. (c) Chang, N.
C.; Chiu, C. T. J . Chin. Chem. Soc. 1993, 40, 379.
(7) Ibuka, T.; Hayashi, K.; Minakata, H.; Ito, Y.; Inubushi, Y. Can.
J . Chem. 1979, 57, 1579.
block the exo face of ketone 6. This was accomplished
by methanolysis of 6 using catalytic amount of p-TsOH
in methanol to afford dimethyl acetal 7 in 96% yield. With
7 in hand, we then turned our attention to the construc-
tion of bicyclo[3.2.1]octenone 8. Treatment of 7 with
dimethylsulfoxonium methylide, followed by ammonoly-
sis of the resulting epoxide gave a â-amino alcohol.
Without purification, reaction of the â-amino alcohol with
S0022-3263(96)00333-7 CCC: $12.00 © 1996 American Chemical Society

4968 J . Org. Chem., Vol. 61, No. 15, 1996
Chang and Chang
Sch em e 3
It now seemed that the conversion of 15 to 4 would be
quite straightforward; however, it was initially problem-
atic. Dehydration of 15 by using methanesulfonyl
chloride2b or thionyl chloride,11 under basic conditions,
disappointingly did not afford diene 16 but rather the
product of an SN2′ reaction with chloride ion. After
considerable effort, it was found that reaction of 15 with
pyridinium p-toluenesulfonate in 1,2-dichloroethane gave
16 in 77% yield.12 Finally, conversion of 16 into the
target molecule 4 was accomplished by sequential hy-
drogenations of 16 using iridium black catalyst2b followed
1
by Adams’ catalyst.4a,13 The H and 13C NMR spectra of
4 are identical to those reported by Professor Frater.14
The above procedure constitutes a new approach to the
synthesis of 2-isocyanopupukeanane (2).
Exp er im en ta l Section
Gen er a l. Diethyl ether and tetrahydrofuran (THF) were
distilled prior to use from a deep-blue solution of sodium-
benzophenone ketyl. All other reagents and solvents were
obtained from commerical sources and used without further
purification. Reactions were routinely carried out under an
atmosphere of dry nitrogen with magnetic stirring. Solutions
of products in organic solvents were dried with anhydrous
MgSO4 before concentration in vacuo. Crude products were
purified by preparative TLC or column chromatography on
silica gel. All reported temperatures are uncorrected. El-
emental analyses were performed by a Heraeus CHN-O-Rapid
Analyzer. 1H and 13C NMR spectra were recorded on either a
Varian EM 390 or a VXR 300-MHz instrument. The purity
of all titled compounds was established to be >90% by
inspection of 1H and 13C NMR spectra unless otherwise stated.
7-(2-Meth oxyeth en yl)-1-m eth ylbicyclo[2.2.1]h ep t-5-en -
2-on e (6). To 10.50 g (53.57 mmol) of acetal 5 was added 40
mL of acetone and 20 mL of 2 N hydrochloric acid. The
reaction mixture was stirred at room 25 °C for 2 h. Acetone
was then removed under reduced pressure, and the residue
was extracted with ether (4 × 50 mL). The organic layer was
washed with brine, dried, and evaporated in vacuo. Chroma-
tography on silica gel (elution with 2:1 n-hexane/ethyl acetate)
afforded the aldehyde (7.39 g, 92%) corresponding to 5 as a
yellowish oil: 1H NMR (300 MHz, CDCl3) δ 9.71 (d, J ) 1.5
Hz, 1 H), 6.55 (dd, J ) 3.0, 5.4 Hz, 1 H), 5.84 (d, J ) 5.4 Hz,
1 H), 3.42 (m, 1 H), 2.08-2.05 (m, 2 H), 1.33 (s, 3 H); 13C NMR
(75 MHz, CDCl3) δ 212.4, 200.4, 141.4, 136.3, 74.9, 60.3, 39.7,
34.4, 10.2; HRMS calcd for C9H10O2 150.0681, found 150.0676.
To a suspension of (methoxymethyl)triphenylphosphonium
chloride (9.60 g, 28.00 mmol) in dry THF (40 mL) at -30 °C
was added a 1.6 M solution of n-butyllithium in hexane (16.8
mL, 26.83 mmol). After the mixture was stirred for 20 min
at -30 °C, a solution of above aldehyde (3.50 g, 23.33 mmol)
in dry THF (10 mL) was added. The mixture was then stirred
for 30 min at 0 °C, quenched with saturated aqueous NH4Cl
(15 mL), and extracted with ethyl acetate (3 × 50 mL). The
combined organic extracts were washed with brine, dried with
anhydrous MgSO4, and filtered. Removal of the solvent from
the filtrate gave an oil which was flash chromatographed on
silica gel (elution with 16:1 n-hexane/ethyl acetate) to yield
methyl enol ether 6 (3.45 g, 83%) as a colorless oil: 1H NMR
(300 MHz, CDCl3) δ 6.58 (dd, J ) 2.4, 5.4 Hz, 1 H), 6.46 (d, J
) 12.6 Hz, 1 H), 5.84 (d, J ) 5.4 Hz, 1 H), 4.48 (dd, J ) 9.6,
12.6 Hz, 1 H), 3.50 (s, 3 H), 2.88-2.87 (m, 2 H), 2.19 (dd, J )
3.6, 17.1 Hz, 1 H), 1.97 (dd, J ) 3.0, 17.1 Hz, 1 H), 1.10 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 216.8, 150.8, 143.1, 136.2,
nitrous acid furnished the ring-expanded ketone 8 in 75%
yield.8 Methylation of 8 was effected by deprotonation
with lithium diisopropylamide and treatment of the
lithium enolate intermediate with methyl iodide. Work-
up gave rise to a single alkylation product 9 in 92% yield.
The assignment of the stereochemistry of ketone 9 was
based on the expection that steric shielding by C-7
substituent would favor the approach of the alkylating
agent from the R side of the molecule. Hydrolysis of the
acetal group in 9 and selective reduction of the resulting
aldehyde with sodium borohydride gave alcohol 10 in 77%
yield.9 In order to effect ring closure, hydroxy ketone 10
was converted into the corresponding tosylate 11 in
nearly quantitative yield.
As shown in Scheme 3, intramolecular cyclization of
11 was carried out in the presence of LDA in THF.
Under this condition, tricyclo[4.3.1.03,7]decanone 12 was
obtained in 86% yield. Having established the tricyclic
carbon skeleton, the remaining challenge in the synthesis
of 2-pupukeanone (4) involved regio- and stereoselective
introduction of the isopropyl group.
Regioselective hydroboration of 12 with 9-BBN fol-
lowed by hydrogen peroxide oxidation of the correspond-
ing borane afforded alcohol 13 in 83% yield.4b Further
oxidation of alcohol 13 with PCC gave diketone 14 in 85%
yield. Treatment of 14 with isopropenyllithium or the
corresponding Grignard reagent failed to give the addi-
tion product. The conversion of 14 into its enolate anion
by deprotonation at C-4 by the basic reagents may
explain these results. This problem was solved by adding
cerium trichloride to the solution of 14 before the injec-
tion of isopropenylmagnesium bromide.10 Since the car-
bonyl group at C-2 in 14 is next to two neopentyl centers
and sterically hindered, the addition reaction occurred
exclusively at C-5 and furnished ketol 15 as the only
product in 95% yield.
(11) Schwartz, A.; Madan, P. J . Org. Chem. 1986, 51, 5463.
(12) (a) Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J . Org. Chem.
1977, 42, 3772. (b) Rosen, T.; Taschner, M. J .; Thomas, J . A.;
Heathcock, C. H. J . Org. Chem. 1985, 50, 1190.
(13) Hydrogenation process furnished only one product 4 as judged
by NMR spectra.
(8) Hsu, L. F.; Chang, C. P.; Chang, N. C. J . Org. Chem. 1993, 58,
4756.
(9) Sell, C. S. Aust. J . Chem. 1975, 28, 1383.
(10) Paquette, L. A.; DeRussy, D. T.; Pegg, N. A.; Taylor, R. T.;
Zydowsky, T. M. J . Org. Chem. 1989, 54, 4576.
(14) We thank professor G. Frater for providing us the NMR, IR,
and mass spectra for comparison.

Total Synthesis of (()-2-Pupukeanone
J . Org. Chem., Vol. 61, No. 15, 1996 4969
98.2, 66.0, 59.8, 56.0, 43.9, 34.7, 9.8; IR (neat, cm-1) 1742;
HRMS calcd for C11H14O2 178.0994, found 178.0993.
with water, and the solvent was removed under reduced
pressure. The residue was taken up in 10 mL of water and
extracted with ethyl acetate (3 × 30 mL). The combined
organic extracts were washed with brine, dried, filtered, and
concentrated to afford crude 9. Purification on silica gel
(elution with 8:1 n-hexane/ethyl acetate) afforded 1.55 g (92%)
of 9 as a yellowish oil: 1H NMR (300 MHz, CDCl3) δ 6.27 (dd,
J ) 3.0, 5.7 Hz, 1 H), 5.58 (d, J ) 5.7 Hz, 1 H), 4.43 (dd, J )
4.8, 6.6 Hz, 1 H), 3.33 (s, 3 H), 3.31 (s, 3 H), 2.71-2.69 (m, 1
H), 2.41-2.25 (m, 3 H), 1.79-1.70 (m, 1 H), 1.56-1.45 (m, 1
H), 1.38-1.34 (m, 1 H), 1.22 (d, J ) 7.5 Hz, 3 H), 1.13 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 212.4, 139.9, 136.8, 103.4, 59.9,
7-(2,2-Dim et h oxyet h yl)-1-m et h ylb icyclo[2.2.1]h ep t -5-
en -2-on e (7). A solution of methyl enol ether 6 (4.01 g, 22.52
mmol) in methanol (40 mL) was treated with p-toluenesulfonic
acid (0.23 g, 1.34 mmol). The reaction mixture was stirred at
room temperature for 8 h. Methanol was then removed under
reduced pressure, and the crude product was purified by flash
chromatography on silica gel (elution with 4:1 n-hexane/ethyl
acetate) to give 7 as a colorless oil in 96% yield: 1H NMR (300
MHz, CDCl3) δ 6.59 (dd, J ) 3.3, 5.7 Hz, 1 H), 5.82 (d, J ) 5.7
Hz, 1 H), 4.41 (t, J ) 5.4 Hz, 1 H), 3.32 (s, 3 H), 3.31 (s, 3 H),
3.00 (m, 1 H), 2.46-2.41 (m, 1 H), 2.11 (dd, J ) 3.0, 16.8 Hz,
1 H), 1.93 (dd, J ) 2.4, 16.8 Hz, 1 H), 1.63-1.55 (m, 1 H),
1.41-1.31 (m, 1 H), 1.13 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 216.7, 143.7, 136.6, 103.2, 61.8, 61.5, 53.1, 52.3, 40.9, 33.9,
29.3, 9.5; IR (neat, cm-1) 1742; HRMS calcd for C12H18O3
210.1256, found 210.1249. Anal. Calcd for C12H18O3: C, 68.55;
H, 8.63. Found: C, 68.51; H, 8.68.
8-(2,2-Dim eth oxyeth yl)-1-m eth ylbicyclo[3.2.1]oct-6-en -
2-on e (8). A suspension of 0.89 g (37.08 mmol) of dry-nitrogen-
blanketed sodium hydride in 250 mL of dry THF and 8.59 g
(38.93 mmol) of trimethylsulfoxonium iodide was heated at 67
°C for 3 h. The solution was cooled to 0 °C, and the reaction
mixture was stirred for 10 min before adding 5.77 g (27.47
mmol) of ketone 7 in 5 mL of THF. Stirring was continued at
0 °C for 6 h before extracting with ethyl acetate (3 × 125 mL).
The combined organic extracts were washed with brine, dried,
filtered, and evaporated in vacuo to afford the crude product
which was purified by flash chromatography on silica gel
(elution with 4:1 n-hexane/ethyl acetate) to afford 5.72 g (93%)
of epoxy acetal as a colorless oil: 1H NMR (300 MHz, CDCl3)
δ 6.33 (dd, J ) 3.3, 5.7 Hz, 1 H), 5.86 (d, J ) 5.7 Hz, 1 H),
4.40 (t, J ) 5.7 Hz, 1 H), 3.32 (2s, 6 H), 2.72 (m, 1 H), 2.63 (d,
J ) 4.2 H, 1 H), 2.58 (d, J ) 4.2 Hz, 1 H), 1.98-1.93 (m, 1 H),
1.89 (dd, J ) 3.6, 13.2 Hz, 1 H), 1.76-1.68 (m, 3 H), 0.92 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 140.7, 139.9, 103.8, 66.1, 60.5,
52.8, 52.4, 52.0, 46.1, 43.0, 32.3, 29.4, 9.2; HRMS calcd for
C13H20O3 224.1413, found 224.1404.
To a stirred solution of 5.72 g (23.83 mmol) of the above
epoxy acetal in 5 mL of 1,4-dioxane was added 6 mL of 28%
aqueous ammonia solution. The mixture was heated in a
sealed tube at 120 °C for 2.5 h to afford the corresponding
â-amino alcohol. After the solvent was removed, the reside
was diluted with 50 mL of water. The solution was cooled to
0 °C, 1.6 mL (30.72 mmol) of acetic acid was added with
stirring, and a solution of 2.12 g (30.72 mmol) of sodium nitrite
in 20 mL of water was added over a period of 2 h. Stirring
was continued at 0 °C for 1 h and then for an additional 5 h
with no further external cooling. The reaction mixture was
then neutralized with a cold saturated aqueous solution of
sodium bicarbonate. The product was extracted with ethyl
acetate (4 × 100 mL), and combined organic extracts were
washed with brine, dried, filtered, and evaporated in vacuo to
afforded crude 8. Flash column chromatography on silica gel
(elution with 4:1 n-hexane/ethyl acetate) afforded 4.63 g (81%)
of 8 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 6.24 (dd,
J ) 3.3, 6.0 Hz, 1 H), 5.76 (d, J ) 6.0 Hz, 1 H), 4.42 (dd, J )
6.9, 4.8 Hz, 1 H), 3.32 (s, 3 H), 3.31 (s, 3 H), 2.77-2.75 (m, 1
H), 2.69-2.57 (m, 1 H), 2.41-2.34 (m, 1 H), 2.19 (dd, J ) 17.4,
7.8 Hz, 1 H), 2.08-1.97 (m, 1 H), 1.70-1.62 (m, 2 H), 1.45-
1.33 (m, 1 H), 1.09 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 211.9,
138.5, 137.6, 103.1, 60.3, 53.3, 53.1, 52.4, 41.5, 34.5, 28.7, 21.6,
15.2; IR (neat, cm-1) 1708; HRMS calcd for C13H20O3 224.1413,
found 224.1403. Anal. Calcd for C13H20O3: C, 69.61; H, 8.99.
Found: C, 68.66; H, 9.02.
53.2, 52.4, 51.6, 41.5, 40.4, 29.7, 28.8, 25.2, 15.5; IR (neat, cm-1
1704; HRMS calcd for C14H22O3 238.1569, found 238.1558.
)
8-(2-Hyd r oxyeth yl)-1,3-d im eth ylbicyclo[3.2.1]oct-6-en -
2-on e (10). To 1.21 g (5.08 mmol) of acetal 9 was added 10
mL of acetone and 5 mL of 2 N hydrochloric acid. The reaction
mixture was stirred at 25 °C for 2 h. Acetone was then
removed under reduced pressure and the residue extracted
with ether (4 × 30 mL). The organic layer was washed with
brine, dried, and evaporated to produce the crude aldehyde.
Chromatography on silica gel (elution with 2:1 n-hexane/ethyl
acetate) afforded the aldehyde (0.87 g, 89%) as a colorless oil:
1H NMR (300 MHz, CDCl3) δ 9.83 (dd, J ) 1.8, 1.2 Hz, 1 H),
6.30 (dd, J ) 3.0, 5.7 Hz, 1 H), 5.63 (d, J ) 5.7 Hz, 1 H), 2.85-
2.79 (m, 2 H), 2.57 (dd, J ) 4.2, 17.0 Hz, 1 H), 2.46-2.36 (m,
2 H), 2.22-2.14 (m, 1 H), 1.40 (dd, J ) 1.8, 17.0 Hz, 1 H), 1.25
(d, J ) 7.8 Hz, 3 H), 1.13 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 211.7, 200.5, 139.7, 136.4, 59.6, 49.3, 41.3, 40.6, 40.4, 29.4,
25.3, 15.3; IR (neat, cm-1) 1724, 1697; HRMS calcd for
C12H16O2 192.1151, found 192.1150.
To a stirred solution of above aldehyde (1.20 g, 6.25 mmol)
in EtOH (10 mL) was added sodium borohydride (60.5 mg, 1.60
mmol) at 0 °C, and the mixture was stirred for 30 min at 0
°C. After pouring into H2O, the mixture was thoroughly
extracted with ethyl acetate. The extract was washed with
brine, dried, and evaporated. Chromatography on silica gel
(elution with 2:1 n-hexane/ethyl acetate) afforded alcohol 10
(1.05 g, 87%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
6.28 (dd, J ) 5.4, 3.0 Hz, 1 H), 5.60 (d, J ) 5.4Hz, 1 H), 3.80-
3.62 (m, 2 H), 3.72-3.68 (m 1 H), 2.43-2.36 (m, 2 H), 2.32-
2.23 (m, 1 H), 1.94 (br, 1 H), 1.78-1.69 (m, 1 H), 1.60-1.43 (m,
1 H), 1.37 (dd, J ) 1.5, 14 Hz, 1 H), 1.23 (d, J ) 7.8 Hz, 3 H),
1.14 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 212.9, 139.8, 137.0,
61.5, 60.0, 52.7, 41.3, 40.5, 29.5, 28.9, 25.3, 15.5; IR (neat, cm-1
1697; HRMS calcd for C12H18O2 194.1307, found 194.1302.
)
8-[2-(Tosyloxy)et h yl]-1,3-d im et h ylb icyclo[3.2.1]oct -6-
en -2-on e (11). A round-bottomed flask was charged sequen-
tially with alcohol 10 (1.65 g, 8.51 mmol), methylene chloride
(10 mL), and triethylamine (4 mL). p-Toluenesulfonyl chloride
(1.79 g, 9.36 mmol) dissolved in 5 mL of methylene chloride
was added dropwise at 0 °C. The mixture was stirred at 0 °C
for 30 min and then stirred at 25 °C for 10 h. Precipitates
were separated from the reaction mixture by filtration and
washed with ethyl acetate (2 × 20 mL). The filtrate was
concentrated to dryness. The residue was chromatographed
on silica gel (elution with 4:1 n-hexane/ethyl acetate) to give
tosylate 11 (2.84 g, 96%) as a yellowlish oil: 1H NMR (300
MHz, CDCl3) δ 7.79 (d, J ) 7.8 Hz, 2 H), 7.36 (d, J ) 7.8 Hz,
2 H), 6.24 (dd, J ) 3.0, 5.4 Hz, 1 H), 5.56 (d, J ) 5.4 Hz, 1 H),
4.09 (t, J ) 7.0 Hz, 2 H), 2.66-2.59 (m, 1 H), 2.46 (s, 3 H),
2.35-2.27 (m, 2 H), 2.19-2.18 (m, 1 H), 1.80-1.74 (m, 1 H),
1.62-1.50 (m, 1 H), 1.34 (dd, J ) 1.5, 14 Hz, 1 H), 1.21 (d, J )
7.8 Hz, 3 H), 1.08 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 211.9,
144.9, 139.6, 136.8, 132.9, 129.9, 127.8, 69.0, 59.8, 52.1, 40.9,
40.4, 29.3, 25.4, 25.2, 21.6, 15.3; IR (neat, cm-1) 1704, 1361,
1177; HRMS calcd for C19H24O4S 348.1396, found 348.1405.
1,3-Dim eth yltr icyclo[4.3.1.03,7]d ec-4-en -2-on e (12). To
a solution of lithium diisopropylamide, prepared from 0.23 mL
(1.73 mmol) of diisopropylamine in 10 mL of freshly distilled
THF and 1.1 mL (1.73 mmol) of n-butyllithium (1.60 M in
hexane) at -78 °C, was added a solution of 0.40 g (1.15 mmol)
of tosylate 11 in 3 mL of THF. The reaction mixture was
stirred at -78 °C for 0.5 h, warmed to 25 °C over 0.5 h, and
stirred for an additional 6 h. The reaction mixture was
quenched with water and extracted with ether (3 × 30 mL).
8-(2,2-Dim eth oxyeth yl)-1,3-d im eth ylbicyclo[3.2.1]oct-
6-en -2-on e (9). To a solution of lithium diisopropylamide,
prepared from 1.1 mL (8.1 mmol) diisopropylamine in 30 mL
of freshly distilled THF and 4.9 mL (7.8 mmol) of n-butyl-
lithium (1.60 M in hexane) at -78 °C, was added a solution of
1.60 g (7.1 mmol) of keto ketal 8 in 5 mL of THF. After stirring
this mixture for an additional 30 min at -78 °C, 0.67 mL (10.7
mmol) methyl iodide was added. The reaction mixture was
stirred at -78 °C for 1 h, warmed to 25 °C over 1 h, and stirred
at 25 °C for an additional 4 h. The reaction was quenched

4970 J . Org. Chem., Vol. 61, No. 15, 1996
Chang and Chang
The combined organic extracts were washed with brine, dried,
and concentrated to afford crude 12. Purification on silica gel
(elution with n-hexane) afforded 0.17 g (86%) of 12 as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 6.11 (dd, J ) 3.3,
5.4 Hz, 1 H), 5.54 (d, J ) 5.4 Hz, 1 H), 2.71-2.65 (m, 1 H),
2.34-2,31 (m, 1 H), 1.90-1.83 (m, 3 H), 1.78-1.61 (m, 2 H),
at 0 °C. The reaction mixture was stirred overnight at 0 °C
before being quenched with saturated NH4Cl solution (5 mL)
and extracted with ethyl acetate (3 × 25 mL). The combined
extracts were dried, filtered, and evaporated, and the residue
was purified by column chromatography on silica gel (elution
with 2:1 n-hexane/ethyl acetate) to give 15 (240 mg, 95%) as
a colorless oil: 1H NMR (300 MHz, CDCl3) δ 4.93 (s, 1 H), 4.86
(s, 1 H), 2.39 (dd, J ) 4.8, 9.6 Hz, 1 H), 2.12-2.06 (m, 2 H),
2.00-1.98 (m, 1 H), 1.85 (s, 3 H), 1.77-1.52 (m, 7 H), 1.13 (s,
3 H), 0.99 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 221.6, 150.3,
109.9, 80.8, 52.9, 49.4, 45.1, 44.7, 41.9, 33.4, 29.2, 20.1, 19.2,
18.6, 17.1; IR (neat, cm-1) 1708; HRMS calcd for C15H22O2
234.1620, found 234.1632.
1.48 (dd, J ) 3.0, 13.2 Hz, 1 H), 1.22 (s, 3 H), 0.94 (s, 3 H); 13
C
NMR (75 MHz, CDCl3) δ 214.3, 139.5, 135.4, 58.4, 50.5, 46.0,
41.2, 40.0, 35.4, 21.4, 17.0, 15.3; IR (neat, cm-1) 1712; HRMS
calcd for C12H16O 176.1202, found 176.1209.
5-H yd r oxy-1,3-d im e t h ylt r icyclo[4.3.1.03,7]d e ca n -2-
on e (13). To a stirred solution of ketone 12 (0.51 g, 2.90 mmol)
in THF (20 mL) was added 9-BBN/THF (0.5 M, 18 mL) via
syringe under N2. The mixture was heated at 60 °C for 2 h.
Oxidation was carried out by dropwise addition of a solution
of 18 mL of 30% H2O2/0.5 N NaOH/H2O (vol: 4:4:1). The
mixture was held an additional 1 h at reflux temperature,
cooled, and extracted with ethyl acetate (3 × 20 mL). After
separation, the organic layer was dried, filtered, and concen-
trated. Chromatography on silica gel (elution with 2:1 n-
hexane/ethyl acetate) afforded alcohol 13 (0.47 g, 83%) as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.85 (dd, J ) 2.1,
6.9 Hz, 1 H), 2.29-2.22 (m, 3 H), 1.90-1.78 (m, 3 H), 1.65-
1.49 (m, 4 H), 1.19 (s, 3 H), 1.05 (d, J ) 13.8 Hz, 1 H), 0.91 (s,
3 H); 13C NMR (75 MHz, CDCl3) δ 221.8, 78.4, 54.0, 47.5, 46.2,
42.8, 42.6, 35.4, 33.4, 20.3, 18.7, 16.6; IR (neat, cm-1) 1710;
HRMS calcd for C12H18O2 194.1307, found 194.1303.
5-Isop r op en yl-1,3-d im eth yltr icyclo[4.3.1.03,7]d ec-4-en -
2-on e (16). To a solution of 0.21 g (0.90 mmol) of alcohol 15
in 1,2-dichloroethane (10 mL) was added 23 mg (0.09 mmol)
of pyridinium p-toluenesulfonate. The reaction mixture was
heated at reflux for 6 h and then diluted with ether (20 mL)
and washed with brine. The organic phase was dried, filtered,
and concentrated. The crude product was purified by chro-
matography on silica gel (elution with 50:1 n-hexane/ethyl
acetate) to obtain 0.15 g (77%) of diene 16 as a colorless oil:
1H NMR (300 MHz, CDCl3) δ 5.47 (s, 1 H), 4.97 (s, 2 H), 2.96
(dd, J ) 5.4, 8.4 Hz, 1 H), 2.39-2.36 (m, 1 H), 1.97 (dd, J )
8.4, 12.9 Hz, 1 H), 1.90-1.56 (m, 5 H), 1.85 (s, 3 H), 1.25 (s, 3
H), 0.93 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 215.1, 152.7,
137.5, 130.3, 113.6, 59.4, 50.5, 44.6, 41.6, 39.6, 35.5, 21.3, 19.9,
1,3-Dim eth yltr icyclo[4.3.1.03,7]decan e-2,5-dion e (14). To
alcohol 13 (0.47 g, 2.41 mmol) was added a mixture of
pyridinium chlorochromate (0.80 g, 3.62 mmol) and 4-Å
molecular sieve powder (1.60 g) in 20 mL of methylene
chloride. After being stirred at 25 °C for 3 h, the mixture was
diluted with ethyl acetate and filtered through a short silica
gel column. The filtrate was washed with water (3 × 30 mL),
dried, and concentrated. The reside was purified by flash
chromatography on silica gel (elution with 3:1 n-hexane/ethyl
acetate) to give diketone 14 (0.40 g, 85%) as a colorless solid:
mp: 45-46 °C; 1H NMR (300 MHz, CDCl3) δ 2.68 (dd, J )
4.8, 10.8 Hz, 1 H), 2.35 (d, J ) 18.6 Hz, 1 H), 2.27-2.24 (m, 1
H), 2.11 (dd, J ) 0.9, 18.6 Hz, 1 H), 2.07-1.88 (m, 3 H), 1.72-
1.66 (m, 2 H), 1.40 (d, J ) 14.7 Hz, 1 H), 1.31 (s, 3 H), 0.96 (s,
3 H); 13C NMR (75 MHz, CDCl3) δ 219.4, 217.4, 52.3, 48.8,
48.6, 43.2, 42.3, 32.5, 20.1, 18.6, 16.1; IR (neat, cm-1) 1747,
1720; HRMS calcd for C12H16O2 192.1151, found 192.1150.
Anal. Calcd for C12H16O2: C, 74.97; H, 8.39. Found: C, 74.72;
H, 8.31.
17.0, 15.7; IR (neat, cm-1) 1712; HRMS calcd for C15H20
216.1515, found 216.1524.
O
2-P u p u k ea n on e (4). Diene 16 (0.081 g, 0.37 mmol) in 10
mL of ethanol was hydrogenolyzed over iridium black (20 mg)
at atmospheric pressure for 12 h. The catalyst was removed
by filtration, and the filtrate was concentrated. The residue
was added to 20 mg of platinum(IV) oxide in ethanol (10 mL)
and stirred under hydrogen for another 12 h. The catalyst
was filtrated off as mentioned above and the solvent evapo-
rated. The crude product was purified by flash chromatogra-
phy (elution with 50:1 n-hexane/ethyl acetate) to give 0.077 g
(95%) of 4 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 2.32
(m, 1 H), 1.85-1.52 (m, 9 H), 1.42-1.38 (m, 1 H), 1.31 (dd, J
) 7.8, 14.0 Hz, 1 H), 1.14 (s, 3 H), 0.92 (s, 3 H), 0.85 (d, J )
5.4 Hz, 3 H), 0.83 (d, J ) 5.4 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 223.1, 53.9, 49.3, 47.2, 42.0, 41.5, 38.7, 33.9, 29.9,
29.3, 21.7, 21.6, 20.4, 19.0, 17.5; IR (neat, cm-1) 1716; HRMS
calcd for C15H24O 220.1828, found 220.1833.
5-Hydr oxy-5-isopr open yl-1,3-dim eth yltr icyclo[4.3.1.03,7]-
d eca n -2-on e (15). Cerium trichloride heptahydrate (491 mg,
1.31 mmol) was dried at 150 °C and 0.2 Torr for 4 h and
blanketed with nitrogen while being allowed to cool. Dry THF
(4 mL) was introduced, and the slurry was stirred at room
temperature for 10 min. A solution of diketone 14 (210 mg,
1.09 mmol) in THF (5 mL) was added, and the mixture was
stirred for 0.5 h at 0 °C. Then a solution of isopropenylmag-
nesium bromide, prepared from 0.14 mL (1.31 mmol) of
isopropenyl bromide and 78 mg (3.27 mmol) of Mg in THF (15
mL), was transferred via cannula into the above slurry also
Ack n ow led gm en t. We thank the National Science
Council of the Republic of China for financial support.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra (40 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O9603338