Formal homoiodo allylsilane annulations: Dual total syntheses of (±)-hirsutene and (±)-capnellene

Article abstract of DOI:10.1021/jo4009854

Dual total syntheses of (±)-hirsutene and (±)-capnellene, two typical linear triquinane sesquiterpenes, were achieved via a formal [3 + 2] annulation strategy, as illustrated schematically. Cyclic homoiodo allylsilanes were employed as key bifunctional synthons in the synthesis, which were readily prepared from the corresponding cyclopropanated cyclopentenones. A formal [3 + 3] annulation approach for the elaboration of the bicyclic framework of the Eudesmane sesquiterpenoids based on this type of synthon was also developed.

Full text of DOI:10.1021/jo4009854

Article
pubs.acs.org/joc
Formal Homoiodo Allylsilane Annulations: Dual Total Syntheses of
( )-Hirsutene and ( )-Capnellene
Shou-Jie Shen† and Wei-Dong Z. Li*,†,‡
†State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
‡Innovative Drug Research Centre, Chongqing University, Chongqing 401331, P. R. China
S
* Supporting Information
ABSTRACT: Dual total syntheses of ( )-hirsutene and ( )-capnellene, two
typical linear triquinane sesquiterpenes, were achieved via a formal [3 + 2]
annulation strategy, as illustrated schematically. Cyclic homoiodo allylsilanes were
employed as key bifunctional synthons in the synthesis, which were readily
prepared from the corresponding cyclopropanated cyclopentenones. A formal [3 +
3] annulation approach for the elaboration of the bicyclic framework of the
Eudesmane sesquiterpenoids based on this type of synthon was also developed.
Our own interest in the total synthesis of 1 and 2 via a
unified annulation strategy2 shown in Figure 1 stemmed from
our previous methodological development for the synthesis of
cyclic homoiodo allylsilanes 5a and 5b as bifunctional synthons
from the corresponding cyclopropanated cyclopentenone
derivatives 6a and 6b, respectively.5 The intramolecular
Hosomi−Sakurai type cyclization of enone allylsilanes 3 and
4 would establish the triquinone skeleton of 1 and 2,
respectively. Cyclization precursors 3 and 4 can be prepared
by alkylation of homoiodo allylsilanes 5a and 5b with the
respective enolates of the substituted cyclopentenones. This
Article describes the detailed experimental results of these
studies.
INTRODUCTION
■
Hirsutene (1) and capnellene (2) are two representative
members of the linearly fused triquinane sesquiterpene family
(Figure 1). The inspiring molecular architectures of 1 and 2
have captured the imagination of synthetic chemists for several
decades, as evidenced by the flourishing novel strategies and
methodologies for their total syntheses.1−4
RESULTS AND DISCUSSION
■
The total synthesis of ( )-hirsutene (1) commenced from
cyclopentenone derivatives 6a6 and 87 and is outlined in
Scheme 1. Homoiodo allylsilane 5a (along with chromato-
graphically inseparable cyclohexenyl iodosilane 7a), prepared
from 6a according to a two-step sequence previously developed
in our laboratory5 in 68% overall yield (with a ratio of 2:1
determined by GC), was alkylated with the lithium enolate of
5,5-dimethylcyclopentenone (8) in a solvent mixture of THF
and HMPA. The purification of the crude product by standard
silica gel chromatography furnished desired α-alkylation
product 3 in 30% yield. It is worth noting that the presence
of HMPA in the solvent mixture is critical for direct α-
alkylation of enone 8 in modest yield. Alternative protocols8 for
Figure 1. Formal homoiodo allylsilane annulation strategy toward the
linear triquinane sesquiterpenes.
Received: May 5, 2013
© XXXX American Chemical Society
A
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Scheme 1
Scheme 2
derivative 13 was obtained as the sole isolated product in 42%
yield. It is notable that diastereomer 4β is unreactive under the
TiCl4-mediated conditions, presumably because of the
unfavorable overlapping conformation (Scheme 3, diastereomer
4α exhibits a favorable off-set conformation instead).16d The
methylation17 of triquinone 13 according to a known procedure
gave triquinone derivative 14 in good yield. The standard
reductive deoxygenation2e,13 of compound 14 via the
aforementioned procedures produced ( )-capnellene (2),
which was identical spectroscopically to previous reports.3e,f
In sharp contrast, the TBAF-mediated cyclization10,16d of 4
resulted in the formation of protodesilylated10b,c enone
derivative 16a (38% yield) and cis-syn-cis triquinone derivative
16b10 in 45% yield after silica gel chromatographic purification
(Scheme 4). Interestingly, the TBAF-mediated cyclization of
allylsilane 4 prefers the diastereomer 4β instead.
We have previously prepared via an analogous procedure
cyclic homoiodo allylsilane 18 from readily available
(+)-carvone derivative 17.5 Facile coupling of 18 with methyl
acrylate was effectively mediated by a Ni(0)−pyridine complex
(in situ generated via Zn reduction)18 to afford allylsilane 19 in
80% yield (Scheme 5). The hydride reduction of the ester
function of 19 with DIBAL-H in toluene gave corresponding
aldehyde 20 smoothly. Exposure of 20 to freshly distilled SnCl4
in a chlorinated solvent (CH2Cl2 or ClCH2CH2Cl) at
temperatures below −78 °C furnished epimeric bicyclic alcohol
products 21a and 21b in good yield.19 Oxidation of 21a or 21b
with PCC in CH2Cl2 led to identical bicyclic ketone 22 with
yield of 95%, which bears the typical ring framework of the
Eudesmane sesquiterpene.20 Interestingly, cyclization mediated
by SnCl4 at −20 °C afforded the sole product 21a in 61%
isolated yield.19a
indirect alkylation of derivatives of 5,5-dimethylcyclopentenone
(8) are less efficient. The intramolecular cyclization9 of
allylsilane 3 mediated by TBAF10 in a solvent mixture of
DMF and HMPA at ambient temperature led to the production
of an equal amount of cis-anti-cis triquinone derivative 9 and cis-
syn-cis triquinone derivative11 9a in 60% overall yield, which
were readily separated by flash silica gel chromatography. The
stereostructure of 9a was confirmed unambiguously by the X-
ray crystallography of corresponding carbamate derivative 9c
(Scheme 2).12 The reductive deoxygenation of triquinone
derivative 9 by a standard Barton−McCombie procedure2e,13
via corresponding xanthate 10 gave ( )-hirsutene (1), which
was identical spectroscopically to previous reports.2
The detailed synthesis sequence for ( )-capnellene (2)
commenced from cyclopentenone derivatives 6b6 and 1114 and
is depicted in Scheme 3. Homoiodo allylsilane 5b (along with
chromatographically inseparable cyclohexenyl iodosilane 7b),
prepared from 6b via the standard procedures as aforemen-
tioned in 65% overall yield (with a ratio of 2.3:1 determined by
GC), was alkylated with the lithium enolate of 3-ethoxy-2,5-
dimethylcyclopentenone (11) smoothly to afford desired
allylsilane 1215 in 70% yield as a chromatographically
inseparable mixture of diastereomers. The hydride reduction
of 12 with DIBAL-H followed by aqueous workup (hydrolysis)
furnished desired cyclization precursor 415a in 82% yield. The
cyclization of allylsilane 4 was conducted in CH2Cl2 at −78 °C
by brief exposure to freshly distilled TiCl4.16 After aqueous
workup and silica gel chromatographic purification, triquinone
The hydride reduction of bicyclic ketone 22 with LiAlH4 in
Et2O at 0 °C gave kinetically favorable product 21a in 92%
yield (whose skeletal and stereostructure were established
unambiguously by X-ray crystallography of a dihydroxylation
derivative 23a) (Scheme 6).12
CONCLUSIONS
■
We have demonstrated in this Article that readily accessible
cyclic homoiodo allylsilanes 5a, 5b, and 18 could be employed
as useful synthons for a formal [3 + 2] or [3 + 3] annulation in
B
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Scheme 3
Scheme 4
10 steps from cyclopentenone in an overall yield of ca. 2.8%.
Eudesmane sesquiterpene framework (e.g., 21a) was estab-
lished in 5 steps from (+)-carvone in an overall yield of ca. 20%.
The features of this synthesis approach include the facile
incorporation of an angular substituent (e.g., methyl) and the
versatile allylsilane cyclization mode and reaction conditions.21
EXPERIMENTAL SECTION
■
General Procedures. For product purification by flash column
chromatography, silica gel (200−300 mesh) and light petroleum ether
(bp 60−90 °C) were used unless otherwise noted. All solvents were
purified and dried by standard techniques and distilled prior to use.
Other commercially available reagents were used as received without
further purification unless otherwise indicated. All organic extracts
were dried over anhydrous sodium sulfate or magnesium sulfate. All
moisture-sensitive reactions were carried out under an atmosphere of
organic synthesis (Figure 2), as exemplified here in a short and
convergent total synthesis of ( )-hirsutene and ( )-capnellene.
The total synthesis of ( )-hirsutene (1) was achieved in 8 steps
from 2-methyl cyclopentenone in an overall yield of ca. 1.5%,
and the total synthesis of ( )-capnellene (2) was achieved in
nitrogen in glassware that was flame-dried under vacuum. H and 13C
1
NMR spectra were recorded on a 300, 400, or 600 MHz spectrometer
with TMS as the internal reference and CDCl3 as the solvent unless
otherwise indicated. IR spectra were recorded on an FT-IR
C
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Scheme 5
Figure 2. Homoiodo allylsilane annulation synthons.
General Procedure for the Preparation of Homoiodo
Allylsilanes from Cyclopropyl Ketones. (1) Freshly dried (1
mmHg at 150 °C for 7 h from the heptahydrate) CeCl3 (815 mg, 3.30
mmol) was suspended in 10 mL of anhydrous THF, and the mixture
was stirred vigorously for 2 h at room temperature. The resultant
solution was cooled to 0 °C by an ice bath, and a stock solution of
(trimethylsilyl)methylmagnesium chloride in diethyl ether (1.0 M, 3.3
mL, 3.30 mmol) was added dropwise at the same temperature. After
the mixture was stirred for 1 h at 0 °C, cyclopropyl ketone6 (2.00
mmol) in 3 mL of THF was added, and the resulting mixture was
warmed gradually to room temperature. When the consumption of the
starting ketone was complete (monitored by TLC), the reaction
mixture was cooled to 0 °C and quenched with water (1 mL). The
organic layer was separated, and the aqueous phase was extracted with
diethyl ether. The organic layers were washed with water and brine
and dried (MgSO4). The solvent was evaporated carefully in vacuo at 0
°C to give the cyclopropyl carbinol adduct as a yellowish oil.
(2) The crude cyclopropyl carbinol was taken in anhydrous diethyl
ether (10 mL) under a nitrogen atmosphere, the mixture was stirred at
0 °C, and a freshly prepared MgI2·Et2O (3.00 mmol, 0.25 M) solution
mixture in Et2O−benzene (1:1) was added dropwise. The resulting
mixture was stirred for 10−15 min at 0 °C, quenched with saturated
NaHCO3, and extracted with diethyl ether. The organic extract was
washed with a 10% sodium thiosulfate solution, water, and brine and
dried (MgSO4). The solvent was evaporated in vacuo to give an oily
residue, which was purified by flash silica gel chromatography, eluting
with a mixture of diethyl ether−petroleum ether (bp 30−60 °C) to
afford the homoiodo allylsilane product as a colorless oil.
Scheme 6
((3-(Iodomethyl)-2-methylcyclopent-1-en-1-yl)methyl)-
trimethylsilane (5a) and ((4-Iodo-2-methylcyclohex-1-en-1-yl)-
methyl)trimethylsilane (7a). Compounds 5a and 7a were prepared
using the above general procedure in an overall yield of 68% as a
chromatographically inseparable mixture. The ratio was determined by
GC−MS to be 2.0:1 (GC−MS conditions: DB-5MS chromatographic
column (30 m × 0.25 mm × 0.25 μm); flow rate = 1.0 mL/min;
source temperature 250 °C; injection port 220 °C, 40 °C/3 min).
Colorless oil: Rf = 0.60 (petroleum ether); IR (film) νmax = 2952, 2848,
1
1663, 1417, 1247, 1164, 853, 841, 692 cm−1; H NMR (400 MHz,
CDCl3) δ 4.49−4.48 (m, compound 7a, 0.4H), 3.40 (dd, compound
5a, 1H, J = 3.2, 10.0 Hz), 3.18 (dd, compound 5a, 1H, J = 7.2, 9.6 Hz),
2.67−2.62 (m, 2H), 2.30−2.24 (m, 1H), 2.14−1.93 (m, 5H), 1.57−
1.52 (m, 7H), 1.42−1.39 (m, 1.6H), 0.02 (s, 12H); 13C NMR (100
MHz, CDCl3) δ 136.6, 128.7, 126.9, 121.4, 51.3, 44.3, 36.5, 35.6, 32.8,
29.3, 28.8, 24.0, 19.8, 19.5, 16.5, 12.2, −0.5, −0.7; EI-MS (m/z) M+
308 (5.9%), 181 (25%), 93 (30%), 73 (100%).
((3-(Iodomethyl)cyclopent-1-en-1-yl)methyl)trimethylsilane (5b)
and ((4-Iodocyclohex-1-en-1-yl)methyl)trimethylsilane (7b). Com-
pounds 5b and 7b were prepared using the above general procedure in
an overall yield of 65% as a chromatographically inseparable mixture.
The ratio was determined by GC−MS spectra to be 2.3:1 (GC−MS
conditions: DB-5MS chromatographic column (30 m × 0.25 mm ×
0.25 μm); flow rate =1.0 mL/min; source temperature 250 °C;
injection port 220 °C, 40 °C/3 min.). Colorless oil; Rf = 0.60
spectrometer as liquid film, and the data are reported in reciprocal
centimeters (cm−1). HRMS were determined on a FT-ICR
spectrometer. For liquid secondary ion mass spectrometry (LSIMS),
a Cs+ ion beam (2 mA) was employed at 10 000 V, and the analytical-
cell vacuum was 2 × 10−9 mbar. Melting points were measured on a
hot stage and are uncorrected.
D
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(petroleum ether); IR (film) νmax = 2952, 2921, 1636, 1248, 1168, 844
for 30 min at 0 °C, the reaction mixture was quenched with 1 mL of
water and extracted with ether. The organic layer was washed
successively with water and brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash silica gel
column chromatography (petroleum ether/EtOAc = 5:1) to give
hydroxyl olefin 9b (18 mg, 83%) as a colorless oil: Rf = 0.31
(petroleum ether/EtOAc = 3:1); IR (film) νmax = 3360, 2944, 2856,
1650, 1457, 1671, 1072, 1028, 876 cm−1; 1H NMR (400 MHz,
CDCl3) δ 4.95 (s, 1H), 4.64 (s, 1H), 3.59 (d, 1H, J = 6.4 Hz), 2.93−
2.84 (m, 1H), 2.58−2.49 (m, 1H), 2.37 (t, 2H, J = 8.8 Hz), 2.25−2.18
(m, 1H), 1.78−1.70 (m, 1H), 1.69−1.57 (m, 3H), 1.33−1.22 (m, 2H),
1.15 (s, 3H), 0.98 (s, 3H), 0.92 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 159.7, 105.7, 80.7, 56.0, 55.0, 54.4, 49.9, 44.7, 42.0, 34.6, 30.7, 30.0,
28.2, 27.6, 24.2; HRMS (ESI) m/z [M + H]+ calcd for C15H25O,
221.1900; found, 221.1903.
(1R,3aS,3bR,6aR,7aS)-2,2,3b-Trimethyl-4-methylenedecahydro-
1H-cyclopenta[a]pentalen-1-ol (9c). To a mixture of compound 9b
(20 mg, 0.09 mmol) in dry benzene (1 mL) were added 4-
bromophenylisocyanate (22 mg, 0.11 mmol) and Et3N (0.10 mL, 0.70
mmol) at 0 °C. The resulting mixture was stirred at room temperature
overnight and quenched with 1 mL of water. The reaction mixture was
extracted with ether, and the organic layer was washed successively
with water and brine, dried over Na2SO4, and concentrated in vacuo.
The residue was purified by flash silica gel column chromatography
(petroleum ether/EtOAc = 10:1) to give 9c (38 mg, 78%) as a
colorless solid: Rf = 0.58 (petroleum ether/EtOAc = 10:1); mp 123−
125 °C; IR (film) νmax = 3320, 2957, 2867, 1735, 1459, 1379, 1129,
1094, 912, 743 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.40 (d, 2H, J =
8.8 Hz), 7.29 (d, 2H, J = 8.8 Hz), 6.56 (br s, 1H), 4.96 (s, 1H), 4.65 (s,
1H), 4.62 (d, 1H, J = 6.0 Hz), 2.59−2.52 (m, 1H), 2.50−2.36 (m,
3H), 2.22−2.12 (m, 2H), 1.75−1.70 (m, 1H), 1.64−1.60 (m, 1H),
1.55−1.47 (m, 2H), 1.13 (s, 3H), 1.04 (s, 3H), 0.95 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.4, 153.3, 137.2, 131.9 (2C), 127.6, 120.1,
115.7, 105.6, 83.7, 55.6, 54.8, 54.3, 49.0, 43.9, 43.1, 34.7, 31.3, 30.6,
28.1, 27.6, 24.4; HRMS (ESI) m/z [M + H]+ calcd for C22H29BrNO2,
418.1376; found, 418.1380. X-ray crystallographic data of 9c:
C22H28BrNO2, monoclinic, space group: Cc, a = 11.002 (4) Å, b =
24.264 (8) Å, c = 9.485 (3) Å, β = 123.324 (14) °, Z = 4, dcalcd = 1.313
g/cm3, R1(I > 2σ(I)) = 0.0633, wR2 = 0.0766.
1
cm−1; H NMR (300 MHz, CDCl3) δ 5.05 (s, compound 5b, 1H),
5.02 (s, compound 7b, 0.3H), 4.52−4.45 (m, compound 7b, 0.4H),
3.19 (dd, compound 5b, 1H, J = 6.8, 12.0 Hz), 3.10 (dd, compound
5b, 1H, J = 9.6, 12.0 Hz), 3.00−2.98 (m, 1H), 2.80−2.61 (m, 1H),
2.31−2.17 (m, 2H), 2.13−1.98 (m, 3H), 1.57−1.49 (m, 3H), 0.03 (s,
13H); 13C NMR (75 MHz, CDCl3) δ 144.7, 134.9, 124.5, 116.7, 48.3,
38.2, 36.9, 35.0, 31.5, 31.2, 29.7, 28.1, 27.9, 21.7, 15.6, −1.1, −1.3; EI−
MS (m/z) M+ 294 (1.9%), 167 (39%), 79 (35%), 73 (100%).
5,5-Dimethyl-2-((2-methyl-3-((trimethylsilyl)methyl)cyclopent-2-
en-1-yl)methyl)cyclopent-2-enone (3). To a stirred mixture of
diisopropylamine (0.34 mL, 2.40 mmol) in dry THF (4 mL) was
added n-BuLi (1.6 M in hexane, 1.38 mL, 2.20 mmol) dropwise at 0
°C under N2, and the mixture was stirred for 30 min. The resulting
LDA solution was cooled to −78 °C, and a mixture of 8 (220 mg, 2.00
mmol) and HMPA (1.0 mL, 5.40 mmol) in dry THF (3 mL) was
added dropwise, and the solution was stirred for 30 min. A mixture of
5a and 7a (2:1 (GC), 940 mg, 3.00 mmol) in 5 mL of THF was added
dropwise over 10 min via syringe at −78 °C. The reaction mixture was
warmed gradually to room temperature over 1 h, quenched with 1 mL
of saturated aqueous NH4Cl, and extracted with diethyl ether. The
ethereal layer was washed successively with water and brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by flash
silica gel column chromatography (petroleum ether/EtOAc = 10:1) to
give compound 3 (104 mg, 30%) as a colorless oil: Rf = 0.65
(petroleum ether/EtOAc = 8:1); IR (film) νmax = 2956, 2867, 1704,
1440, 1247, 1146, 1022, 841, 692 cm−1; 1H NMR (400 MHz, CDCl3)
δ 7.19 (s, 1H), 2.72 (br s, 1H), 2.49−2.42 (m, 2H), 2.21−2.11 (m,
2H), 1.96−1.85 (m, 2H), 1.55 (s, 3H), 1.49−1.47 (m, 2H), 1.34−1.26
(m, 2H), 1.12 (s, 6H), −0.00 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
214.3, 154.7, 142.7, 133.6, 130.5, 47.9, 43.7, 43.0, 36.9, 29.3, 28.4, 25.2,
25.1, 19.4, 12.6, −0.8 (3C, −Si(CH3)3); HRMS (ESI) m/z [M + H]+
calcd for C18H31OSi, 291.2139; found, 291.2135.
(3aR,3bR,6aR,7aR)-2,2,3b-Trimethyl-4-methylenedecahydro-1H-
cyclopenta[a]pentalen-1-one (9) and (3aS,3bR,6aR,7aS)-2,2,3b-
Trimethyl-4-methylenedecahydro-1H-cyclopenta[a]pentalen-1-one
(9a). To a mixture of TBAF trihydrate (62 mg, 0.24 mmol) in dry
DMF (3 mL) was added powdered 4 Å molecular sieves (50 mg).
After stirring for 15 min, the mixture was filtered, and the resulting
filtrate was transferred to a reaction vessel containing 100 mg of 4 Å
molecular sieves and HMPA (0.40 mL, 2.16 mmol). After stirring for
15 min at room temperature, a solution of allylsilane 3 (63 mg, 0.22
mmol) in 1 mL of dry DMF was added to the above slurry over 30
min via a syringe pump. The reaction mixture was stirred at room
temperature for 12 h, quenched with 1 mL of water, and extracted with
ether. The organic layer was washed successively with water and brine,
dried over Na2SO4, and concentrated in vacuo. The residue was
purified by flash silica gel column chromatography (petroleum ether/
EtOAc = 10:1) to give compounds 9 (15 mg, 30%) and 9a (15 mg,
30%) as colorless oils, respectively. Compound 9: Rf = 0.55
(petroleum ether/EtOAc = 8:1); IR (film) νmax = 2956, 2867, 1735,
1459, 1378, 1093, 879, 743 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.90
(s, 1H), 4.85 (d, 1H, J = 2.4 Hz), 2.76−2.68 (m, 2H), 2.66−2.52 (m,
1H), 2.49−2.40 (m, 2H), 2.33−2.30 (m, 1H), 1.93−1.86 (m, 2H),
1.80−1.73 (m, 1H), 1.65−1.60 (m, 2H), 1.54−1.41 (m, 1H), 1.10 (s,
3H), 1.06 (s, 3H), 1.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
224.8, 161.5, 104.7, 57.6, 50.7, 49.2, 48.9, 47.1, 40.4, 34.5, 31.5, 28.4,
24.6, 24.3, 22.3; HRMS (ESI) m/z [M + H]+ calcd for C15H23O,
219.1743; found, 219.1746. Compound 9a: Rf = 0.54 (petroleum
ether/EtOAc = 8:1); IR (film) νmax = 2962, 2867, 1740, 1329, 1129,
(1R,3aR,3bR,6aR,7aR)-2,2,3b-Trimethyldecahydro-1H-
cyclopenta[a]pentalen-1-ol (9d). Compound 9d was prepared by a
procedure analogous to that for compound 9b in 81% yield as a
colorless oil: Rf = 0.31 (petroleum ether/EtOAc = 3:1); IR (film) νmax
1
= 3503, 2933, 2867, 1713, 1427, 1363, 1222, 1091, 901 cm−1; H
NMR (400 MHz, CDCl3) δ 4.83 (s, 1H), 4.77 (d, 1H, J = 2.4 Hz),
3.22 (d, 1H, J = 7.6 Hz), 2.61 (q, 1H, J = 9.6 Hz), 2.51−2.46 (m, 2H),
2.45−2.37 (m, 1H), 2.24−2.15 (m, 1H), 2.13−2.04 (m, 1H), 1.76−
1.70 (m, 1H), 1.65−1.61 (m, 1H), 1.60−1.48 (m, 2H), 1.47−1.40 (m,
1H), 1.01 (s, 3H), 0.91 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
161.7, 104.1, 87.8, 55.8, 50.0, 49.5, 47.6, 42.4, 41.0, 35.5, 29.9, 26.7,
25.4, 22.1, 19.4; HRMS (ESI) m/z [M + H]+ calcd for C15H25O,
221.1900; found, 221.1904.
S-Methyl O-((1R,3aR,3bR,6aR,7aR)-2,2,3b-Trimethyldecahydro-
1H-cyclopenta[a]pentalen-1-yl) Carbonodithioate (10). A mixture
of compound 9d (25 mg, 0.11 mmol), NaH (18 mg, 0.75 mmol), and
imidazole (2 mg, 0.03 mmol) in dry THF (2 mL) in a 10 mL three-
necked flask was refluxed with stirring for 3 h under nitrogen, and a
mixture of carbon disulfide (0.30 mL, 5.00 mmol) in 1 mL of THF was
added dropwise. After refluxing for 45 min, methyl iodide (0.50 mL,
8.00 mmol) was added to the reaction mixture and refluxed for
another 30 min. The reaction mixture was quenched with acetic acid
(0.15 mL), diluted with water, and extracted with ether. The ethereal
layer was washed with water, dried over Na2SO4, and concentrated in
vacuo. The residue was purified by flash silica gel column
chromatography (petroleum ether/EtOAc = 15:1) to give xanthate
derivative 10 (28 mg, 81%) as a colorless oil: Rf = 0.70 (petroleum
ether/EtOAc = 10:1); IR (film) νmax = 2947, 2867, 1649, 1460, 1370,
1
1094, 912, 756 cm−1; H NMR (400 MHz, CDCl3) δ 4.94 (s, 1H),
4.65 (s, 1H), 2.49−2.35 (m, 4H), 2.22−2.09 (m, 2H), 1.73−1.70 (m,
1H), 1.56−1.42 (m, 4H), 1.12 (s, 3H), 0.98 (s, 3H), 0.87 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 223.9, 158.2, 105.8, 56.8, 55.5, 53.1, 49.5,
47.7, 41.7, 35.3, 34.0, 29.9, 29.2, 24.9, 24.4; HRMS (ESI) m/z [M +
H]+ calcd for C15H23O, 219.1743; found, 219.1745.
(1R,3aS,3bR,6aR,7aS)-2,2,3b-Trimethyl-4-methylenedecahydro-
1H-cyclopenta[a]pentalen-1-ol (9b). To a suspension of LiAlH4 (20
mg, 0.53 mmol) in dry Et2O (1.5 mL) at 0 °C was added compound
9a (25 mg, 0.11 mmol) in dry Et2O (1.5 mL) under N2. After stirring
1
1222, 1058, 964, 880 cm−1; H NMR (400 MHz, CDCl3) δ 5.52 (d,
1H, J = 6.4 Hz), 4.83 (s, 1H), 4.78 (d, 1H, J = 2.4 Hz), 2.74−2.69 (m,
1H), 2.58−2.52 (m, 1H), 2.54 (s, 3H), 2.49−2.44 (m, 2H), 2.20−2.16
E
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The Journal of Organic Chemistry
Article
(m, 1H), 1.95−1.89 (m, 1H), 1.78−1.70 (m, 1H), 1.62−1.57 (m, 1H),
1.53−1.46 (m, 3H), 1.06 (s, 6H), 0.96 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 216.2, 161.7, 104.2, 96.7, 55.7, 49.8, 49.6, 47.6, 43.9, 41.7,
35.9, 30.4, 27.3, 26.2, 22.4, 21.8, 18.8; HRMS (ESI) m/z [M + H]+
calcd for C17H27OS2, 311.1498; found, 311.1504.
42.4, 42.3, 37.3, 37.1, 33.6, 33.3, 27.4, 27.0, 21.4, 9.9, 9.9, −1.3, −1.3;
HRMS (ESI) m/z [M + H]+ calcd for C17H29OSi, 277.1982; found,
277.1986.
(3S,3aS,3bS,6aS,7aR)-3,7a-Dimethyl-4-methyleneoctahydro-1H-
cyclopenta[a]pentalen-2(3bH)-one (13). To a mixture of compound
4 (55 mg, 0.20 mmol) in dry CH2Cl2 (2 mL) was added titanium
tetrachloride (1.0 M in CH2Cl2, 0.30 mL, 0.30 mmol) at −78 °C
under N2. After stirring for 1 min at −78 °C, the reaction mixture was
quenched with 0.5 mL of saturated aqueous NaHCO3. The reaction
mixture was extracted with ether (20 mL), and the organic layer was
washed successively with water and brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash silica gel
column chromatography (petroleum ether/EtOAc = 8:1) to give
compound 13 (20 mg, 42%) as a colorless oil: Rf = 0.53 (petroleum
ether/EtOAc = 8:1); IR (film) νmax = 2933, 2866, 1739, 1655, 1455,
(3aR,3bR,6aR,7aS)-2,2,3b-Trimethyl-4-methylenedecahydro-1H-
cyclopenta[a]pentalene (1). A mixture of tri-n-butyltin hydride (41
mg, 0.14 mmol) and AIBN (2 mg, 0.01 mmol) in dry benzene (2 mL)
was brought to 80 °C, and a mixture of xanthate 10 (15 mg, 0.05
mmol) in dry benzene (1 mL) was introduced. After refluxing for 6 h,
the reaction mixture was evaporated in vacuo, and the residual oil was
charged on an AgNO3-impregnated silica gel column. An elution with
petroleum ether removed the organotin impurities. Further elution
with n-hexane gave hydrocarbon 1 (8 mg, 42%) as a colorless oil: Rf =
0.95 (petroleum ether); IR (film) νmax = 2921, 2862, 1660, 1585, 1456,
1
1248, 1162, 872 cm−1; H NMR (400 MHz, CDCl3) δ 4.82 (s, 1H),
1
1376, 1182, 880 cm−1; H NMR (400 MHz, CDCl3) δ 4.86 (s, 1H),
4.77 (s, 1H), 2.63−2.57 (m, 1H), 2.53−2.44 (m, 3H), 2.17−2.11(m,
1H), 1.78−1.71 (m, 1H), 1.65 (ddd, 2H, J = 2.0, 8.4, 10.4 Hz), 1.48−
1.40 (m, 4H), 1.29−1.19 (m, 1H), 1.05 (s, 3H), 1.04−0.98 (m, 1H),
0.92 (s, 3H), 0.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.9,
103.5, 56.0, 53.5, 50.0, 49.0, 44.3, 41.9, 40.9, 38.6, 30.9, 29.7, 27.3,
26.8, 23.2.
4.69 (s, 1H), 2.68−2.55 (m, 2H), 2.48−2.38 (m, 1H), 2.28−2.22 (m,
1H), 2.08−2.04 (m, 1H), 2.07 (s, 2H), 1.98−1.94 (m, 1H), 1.77−1.67
(m, 2H), 1.52−1.49 (m, 1H), 1.38−1.33 (m, 1H), 1.18 (s, 3H), 1.15
(d, 3H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 220.6, 157.7,
105.4, 60.3, 49.4, 48.0, 47.4, 47.3, 46.2, 42.7, 33.0, 30.4, 26.6, 11.5;
HRMS (ESI) m/z [M + H]+ calcd for C14H21O, 205.1587; found,
205.1582.
(5R)-3-Ethoxy-2,5-dimethyl-5-((3-((trimethylsilyl)methyl)-
cyclopent-2-en-1-yl)methyl)cyclopent-2-enone (12). To a stirred
solution of diisopropylamine (0.34 mL, 2.40 mmol) in dry THF (4
mL) was added n-BuLi (1.6 M in hexane, 1.38 mL, 2.20 mmol) at 0 °C
under N2, and the mixture was stirred for 30 min. The resulting LDA
solution was cooled to −78 °C, and a mixture of compound 11 (308
mg, 2.00 mmol) and HMPA (1.0 mL, 5.41 mmol) in dry THF (4 mL)
was added dropwise. After stirring for 30 min at −78 °C, a mixture of
compounds 5b and 7b (2.3:1 (GC), 470 mg, 1.60 mmol) in 3 mL of
THF was added over 10 min. The reaction mixture was warmed to
room temperature over 3 h and quenched with 1 mL of saturated
aqueous NH4Cl. The mixture was extracted with 100 mL of EtOAc,
and the organic layer was washed successively with water and brine,
dried over Na2SO4, and concentrated in vacuo. The residue was
purified by flash silica gel column chromatography (petroleum ether/
EtOAc = 10:1) to give compound 12 (250 mg, 70%) as a colorless oil.
The diastereoisomeric ratio of compound 12 was determined by GC−
MS spectra to be 1:1 (GC−MS conditions: DB-5MS chromatographic
column (30 m × 0.25 mm × 0.25 μm); flow rate = 1.0 mL/min;
source temperature 250 °C; injection port 220 °C, 15 °C/min): Rf =
0.51 (petroleum ether/EtOAc = 4:1); IR (film) νmax = 2953, 2921,
(3aR,3bS,6aS,7aR)-3,3,7a-Trimethyl-4-methyleneoctahydro-1H-
cyclopenta[a]pentalen-2(3bH)-one (14). To a suspension of NaH
(4.8 mg, 0.20 mmol) in dry THF (1 mL) was added a solution of
compound 13 (33 mg, 0.16 mmol) in dry THF (1 mL) at room
temperature. After stirring for 30 min, methyl iodide (0.23 mL, 3.75
mmol) in THF (1 mL) was added to the reaction mixture. The
reaction mixture was stirred for 2 h and quenched with saturated
aqueous NH4Cl. The resulting mixture was extracted with EtOAc. The
organic layer was washed successively with water and brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by flash
silica gel column chromatography (petroleum ether/EtOAc = 20:1) to
give compound 14 (25 mg, 76%) as a colorless oil: Rf = 0.58
(petroleum ether/EtOAc = 8:1); IR (film) νmax = 2943, 2868, 1737,
1
1653, 1454, 1380, 877 cm−1; H NMR (400 MHz, CDCl3) δ 4.93 (s,
1H), 4.77 (d, 1H, J = 1.6 Hz), 2.82 (br d, 1H, J = 8.0 Hz), 2.61−2.46
(m, 2H), 2.39−2.33 (m, 1H), 2.31 and 2.23 (ABq, each 1H, J = 18.4
Hz), 2.03 (d, 1H, J = 3.6 Hz), 1.84−1.71 (m, 2H), 1.57−1.50 (m, 1H),
1.38 (dd, 1H, J = 9.6, 13.2 Hz), 1.26 (s, 3H), 1.90 (s, 3H), 1.11 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 223.9, 158.2, 105.4, 66.3, 51.5,
49.8, 49.2, 46.8, 46.4, 43.5, 32.1, 30.0, 29.3, 28.3, 23.3; HRMS (ESI)
m/z [M + H]+ calcd for C15H23O, 219.1743; found, 219.1740.
(2R,3aR,3bS,6aS,7aR)-3,3,7a-Trimethyl-4-methylenedecahydro-
1H-cyclopenta[a]pentalen-2-ol (14a). Compound 14a was prepared
by a procedure analogous to that of compound 9b in 82% yield as a
colorless oil: Rf = 0.31 (petroleum ether/EtOAc = 3:1); IR (film) νmax
1
1690, 1637, 1382, 1336, 1246, 1011, 847 cm−1; H NMR (400 MHz,
CDCl3) δ 4.94 (s, 0.5H, α isomer), 4.92 (s, 0.5H, β isomer), 4.19−
4.16 (m, 2H), 2.66 and 2.33 (ABq, each 1H, J = 17.2 Hz), 2.61−2.51
(m, 1H), 2.14−2.05 (m, 4H), 1.61 (s, 3H), 1.48 (s, 2H), 1.53−1.42
(m, 2H), 1.39−1.35 (m, 3H), 1.10 (s, 3H), −0.04 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 210.1, 210.0, 181.4, 181.3, 141.8, 141.5, 126.7,
126.5, 114.2, 113.7, 65.0, 46.9, 46.7, 44.9, 44.6, 42.2, 42.2, 39.6, 39.1,
37.2, 37.1, 33.1, 32.5, 25.0, 24.0, 21.4, 21.3, 15.3, 6.2, 6.1, −1.4, −1.4;
HRMS (ESI) m/z [M + H]+ calcd for C19H33O2Si, 321.2244; found,
321.2245.
(4R)-2,4-Dimethyl-4-((3-((trimethylsilyl)methyl)cyclopent-2-en-1-
yl)methyl)cyclopent-2-enone (4). To a mixture of 12 (110 mg, 0.34
mmol) in 2 mL of toluene at −20 °C was added dropwise DIBAL-H
(1.2 M in n-hexane, 0.57 mL, 0.68 mmol). After stirring for 30 min, the
reaction mixture was quenched with 0.5 mL of water and extracted
with ether. The ethereal layer was washed successively with water and
brine, dried over Na2SO4, and concentrated in vacuo. The residue was
purified by flash silica gel column chromatography (petroleum ether/
EtOAc = 10:1) to give compound 4 (78 mg, 82%) as a colorless oil: Rf
= 0.62 (petroleum ether/EtOAc = 8:1); IR (film) νmax = 2954, 2920,
1708, 1248, 848 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.08 (d, 0.5H, J
= 1.2 Hz, α isomer), 7.06 (d, 0.5H, J = 1.2 Hz, β isomer), 4.96 (s, 1H,
α/β = 1:1), 2.59−2.56 (m, 1H), 2.41 and 2.17 (ABq, each 1H, J = 18.8
Hz, OCCH2−), 2.15−1.94 (m, 3H), 1.74 (s, 3H), 1.71−1.64 (m,
1H), 1.55−1.45 (m, 2H), 1.53 (s, 2H), 1.45−1.31 (m, 2H), 1.18 (s,
3H), −0.21 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 209.9, 167.6,
167.4, 142.0, 141.9, 139.1, 139.0, 126.7, 126.5, 48.8, 48.6, 48.1, 47.9,
1
= 3360, 2944, 2865, 1650, 1457, 1371, 1073, 1028, 876 cm−1; H
NMR (400 MHz, CDCl3) δ 4.91 (s, 1H), 4.77 (s, 1H), 3.77 (dd, 1H, J
= 6.4, 10.0 Hz), 2.71−2.68 (m, 2H), 2.50−2.44 (m, 1H), 2.40−2.37
(m, 1H), 1.91−1.78 (m, 3H), 1.69−1.50 (m, 2H), 1.34−1.21 (m, 2H),
1.11 (s, 3H), 1.07 (s, 3H), 0.86 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 158.6, 105.1, 80.9, 68.3, 51.5, 48.3, 48.2, 47.5, 46.3, 44.5, 32.6, 31.8,
29.7, 28.5, 17.5; HRMS (ESI) m/z [M + H]+ calcd for C15H25O,
221.1900; found, 221.1905.
S-Methyl O-((2R,3aR,3bS,6aS,7aR)-3,3,7a-Trimethyl-4-methyle-
nedecahydro-1H-cyclopenta[a]pentalen-2-yl) Carbonodithioate
(15). Compound 15 was prepared by a procedure analogous to that
of compound 10 as a colorless oil (79%): Rf = 0.71 (petroleum ether/
EtOAc = 10:1); IR (film) νmax = 2949, 2866, 1650, 1454, 1221, 1057,
1
963, 877 cm−1; H NMR (400 MHz, CDCl3) δ 5.56 (t, 1H, J = 6.4
Hz), 4.92 (d, 1H, J = 1.6 Hz), 4.78 (d, 1H, J = 1.6 Hz), 2.87−2.85 (m,
1H), 2.76−2.71 (m, 1H), 2.56 (s, 3H), 2.52−2.48 (m, 1H), 2.41−2.38
(m, 1H), 2.17−2.12 (m, 1H), 1.86−1.73 (m, 4H), 1.56−1.50 (m, 1H),
1.31−1.27 (m, 1H), 1.25 (s, 3H), 1.15 (s, 3H), 1.09 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 215.4, 158.6, 105.4, 92.7, 68.5, 52.0, 49.7, 48.4,
45.7, 45.6, 45.0, 32.5, 31.8, 29.4, 29.2, 20.3, 18.8; HRMS (ESI) m/z [M
+ H]+ calcd for C17H27OS2, 311.1498; found, 311.1502.
F
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(R)-2,4-Dimethyl-4-(((S)-3-methylcyclopent-2-en-1-yl)methyl)-
cyclopent-2-enone (16a) and (3S,3aS,3bR,6aR,7aR)-3,7a-Dimethyl-
4-methyleneoctahydro-1H-cyclopenta[a]pentalen-2(3bH)-one
(16b). A mixture of powdered 4 Å molecular sieves (50 mg) and
TBAF trihydrate (31 mg, 0.12 mmol) in dry DMF (1.5 mL) was
stirred at room temperature for 15 min. The mixture was filtered, and
the resulting filtrate was transferred to a reaction vessel containing 100
mg of powdered 4 Å molecular sieves and HMPA (0.20 mL, 1.07
mmol). The resulting mixture was stirred for 15 min, and a solution of
allylsilane 4 (33 mg, 0.12 mmol) in dry DMF (0.50 mL) was added
dropwise over 30 min via a syringe pump. The resulting mixture was
stirred at room temperature for 12 h and quenched with 0.5 mL of
water. The mixture was extracted with ether, and the organic layer was
washed successively with water and brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography (petroleum ether/EtOAc = 10:1) to give 16a (9 mg,
38%) and 16b (11 mg, 45%) as colorless oils, respectively. Compound
16a: Rf = 0.47 (petroleum ether/EtOAc = 8:1); IR (film) νmax = 2960,
2923, 1704, 1441, 1379, 1011, 835 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.05 (d, 1H, J = 1.2 Hz), 5.10 (d, 1H, J = 1.6 Hz), 2.55−2.52
(m, 1H), 2.37 and 2.13 (ABq, each 1H, J = 18.8 Hz), 2.16−2.11 (m,
1H), 2.01−1.96 (m, 1H), 1.72 (d, 3H, J = 0.8 Hz), 1.69−1.64 (m,
2H), 1.67 (s, 3H), 1.48−1.29 (m, 2H), 1.15 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 209.7, 167.1, 140.3, 139.1, 129.2, 48.4, 47.5, 42.3,
42.3, 36.5, 33.4, 27.4, 16.5, 9.9; HRMS (ESI) m/z [M + H]+ calcd for
C14H21O, 205.1587; found, 205.1594. Compound 16b: Rf = 0.53
(petroleum ether/EtOAc = 8:1); IR (film) νmax = 2937, 2869, 1738,
1456, 1156, 887 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.02 (t, 1H, J =
1.4 Hz), 4.77 (s, 1H), 3.38 (t, 1H, J = 9.2 Hz), 3.00−2.90 (m, 1H),
2.39 and 2.10 (ABq, each 1H, J = 18.8 Hz), 2.31−2.27 (m, 2H), 2.04−
1.93 (m, 2H), 1.77−1.68 (m, 3H), 1.50−1.45 (m, 1H), 1.19 (s, 3H),
1.10 (d, 3H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 222.2, 153.0,
108.1, 59.7, 50.2, 50.0, 48.2, 46.6, 45.0, 44.8, 35.0, 30.0, 26.1, 17.2;
HRMS (ESI) m/z [M + H]+ calcd for C14H21O, 205.1587; found,
205.1592.
(3aS,3bS,6aS,7aS)-3,3,7a-Trimethyl-4-methylenedecahydro-1H-
cyclopenta[a]pentalene (2). A mixture of tri-n-butyltin hydride (33
mg, 0.14 mmol) and AIBN (2 mg, 0.01 mmol) in dry benzene (2 mL)
was brought to 80 °C, and a mixture of xanthate 15 (15 mg, 0.05
mmol) in dry benzene (1 mL) was added. After refluxing for 6 h, the
resulting mixture was evaporated in vacuo, and the residual oil was
charged on an AgNO3-impregnated silica gel column. An elution with
petroleum ether removed the organotin impurities. Further elution
with hexane provided hydrocarbon 2 (8 mg, 41%) as a colorless oil: Rf
= 0.96 (petroleum ether); IR (film) νmax = 2942, 2864, 1651, 1459,
1370, 876 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.89 (s, 1H), 4.78 (s,
1H), 2.66−2.64 (m, 1H), 2.57−2.44 (m, 2H), 2.38−2.36 (m, 1H),
1.71−1.65 (m, 3H), 1.68−1.61 (m, 2H), 1.56−1.47 (m, 3H), 1.46−
1.42 (m, 2H), 1.22−1.19 (m, 1H), 1.15 (s, 3H), 1.08 (s, 3H), 0.95 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 159.0, 104.9, 69.0, 53.3, 52.3,
47.9, 46.0, 42.3, 41.6, 40.5, 31.8, 31.5, 30.8, 29.0, 26.0.
room temperature, and halide 18 (1.81 g, 5.00 mmol) in pyridine (5
mL) was added dropwise. After stirring for 1 h, the reaction mixture
was filtered with a short plug of Celite (elution with 100 mL Et2O).
The filtrate was washed with HCl (1 N), water, and brine, dried over
MgSO4, filtered, and concentrated. The crude product was purified by
flash silica gel column chromatography to give compound 19 (1.29 g,
80%) as a colorless oil: Rf = 0.58 (petroleum ether/EtOAc = 10:1);
[α]2D0 = +50 (c = 2.4, CHCl3); IR (film) νmax = 2950, 1742, 1438, 1246,
1198, 844 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.69 (s, 2H), 3.66 (s,
3H), 2.37−2.29 (m, 2H), 2.24−2.17 (m, 1H), 1.92−1.83 (m, 3H),
1.80−1.68 (m, 2H), 1.75 (s, 3H), 1.58 (s, 3H), 1.59−1.50 (m, 1H),
1.53 (s, 2H), 1.48−1.38 (m, 2H), 1.35−1.24 (m, 1H), −0.00 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 174.1, 150.2, 127.9, 125.7, 108.3, 51.4,
40.8, 38.0, 36.8, 34.3, 32.4, 31.3, 24.0, 23.7, 20.7, 18.5, −0.5; HRMS
(ESI) m/z [M + H]+ calcd for C19H35O2Si, 323.2401; found,
323.2396.
4-((1R,5R)-2-Methyl-5-(prop-1-en-2-yl)-3-((trimethylsilyl)methyl)-
cyclohex-2-en-1-yl)butanal (20). To a mixture of compound 19 (102
mg, 0.32 mmol) in CH2Cl2 (1.5 mL) was added DIBAL-H (0.29 mL,
0.34 mmol, 1.2 M in hexane) dropwise at −20 °C. After stirring for 2
h, the reaction was quenched with 0.5 mL of water and extracted with
ether (100 mL). The ethereal layer was washed with water and brine,
dried over MgSO4, filtered, and concentrated. The solution was
evaporated, and the residue was purified by flash silica gel column
chromatography (petroleum ether/EtOAc = 10:1) to give aldehyde 20
(83 mg, 90%) as a colorless oil: Rf = 0.75 (petroleum ether/EtOAc =
8:1); [α]2D0 = +53 (c = 1.7, CHCl3); IR (film) νmax = 2923, 1729, 1447,
1247, 1090, 844 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.77 (d, 1H, J =
1.2 Hz), 4.70 (s, 2H), 2.49−2.37 (m, 2H), 2.21−2.20 (m, 1H), 1.93−
1.83 (m, 3H), 1.78−1.70 (m, 2H), 1.73 (s, 3H), 1.57−1.49 (m, 2H),
1.55 (s, 3H), 1.52 (s, 2H), 1.38−1.25 (m, 2H), 0.00 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 202.6, 150.2, 128.1, 125.5, 108.4, 44.1, 40.9,
38.0, 36.9, 32.5, 31.3, 24.0, 20.8, 20.7, 18.5, −0.5; HRMS (ESI) m/z
[M + Na]+ calcd for C18H32NaOSi, 315.2115; found, 315.2117.
(1R,4aR,6R,8aR)-8a-Methyl-8-methylene-6-(prop-1-en-2-yl)-
decahydronaphthalen-1-ol (21a). To a stirred mixture of aldehyde
20 (120 mg, 0.41 mmol) in 1,2-dichloroethane (1 mL) was added a
stock solution of freshly distilled stannic tetrachloride (1.0 M in 1,2-
dichloroethane, 0.82 mL, 0.82 mmol) dropwise at −20 °C. After
stirring for 10 min, the reaction mixture was quenched with saturated
aqueous NaHCO3, diluted with ether (100 mL), and washed with
saturated NaHCO3 (5 mL) and brine (5 mL). The ethereal phase was
dried over MgSO4, filtered, and concentrated. The crude residue was
purified by flash silica gel column chromatography to give compound
21a (62 mg, 61%) as a colorless oil: Rf = 0.24 (petroleum ether/
EtOAc = 10:1); [α]D20 = +15 (c = 1.0, CHCl3); IR (film) νmax = 3416,
1
2928, 1641, 1452, 1373, 1038, 906, 888 cm−1; H NMR (400 MHz,
CDCl3) δ 5.18 (s, 1H), 5.02 (s, 1H), 4.71 (s, 2H), 3.50 (dd, 1H, J =
4.4, 12.0 Hz), 2.29 (d, 2H, J = 2.8 Hz), 2.23−2.00 (m, 2H), 1.87−1.79
(m, 1H), 1.79−1.71 (m, 2H), 1.75 (s, 3H), 1.60−1.54 (m, 2H), 1.51−
1.45 (m, 2H), 1.34 (s, 3H), 1.27−1.24 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 149.8 (2C), 111.9, 108.5, 80.7, 45.2, 43.8, 40.6, 39.4, 32.4,
30.2, 28.2, 25.1, 24.5, 20.7; HRMS (ESI) m/z [M + Na]+ calcd for
C15H24NaO, 243.1719; found, 243.1724.
(((3R,5R)-3-(Iodomethyl)-2-methyl-5-(prop-1-en-2-yl)cyclohex-1-
en-1-yl)methyl)trimethylsilane (18). Compound 18 was prepared5,6
from (+)-carvone in 56% yield as a colorless oil: Rf = 0.95 (petroleum
ether); [α]2D0 = +45 (c = 0.8, CHCl3); IR (film) νmax = 2954, 2921,
(1S,4aR,6R,8aR)-8a-Methyl-8-methylene-6-(prop-1-en-2-yl)-
decahydronaphthalen-1-ol (21b). To a stirred mixture of 20 (120
mg, 0.41 mmol) in dichloromethane (1 mL) was added dropwise a
stock solution of freshly distilled stannic tetrachloride (1.0 M in
dichloromethane, 0.82 mL, 0.82 mmol) at −90 °C. After stirring for 10
min, the reaction mixture was quenched with saturated aqueous
NaHCO3, diluted with ether (100 mL), and successively washed with
saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The ethereal
phase was dried over MgSO4, filtered, and concentrated. The crude
residue was purified by flash silica gel column chromatography to give
compounds 21a (35 mg, 13%) and 21b (12 mg, 39%) as colorless oils.
1
1645, 1446, 1248, 847 cm−1; H NMR (400 MHz, CDCl3) δ 4.74 (d,
2H, J = 6.4 Hz), 3.47 (dq, 1H, J = 1.2, 10.0 Hz), 3.03 (t, 1H, J = 10.4
Hz), 2.36 (br d, 1H, J = 7.6 Hz), 2.19−2.14 (m, 1H), 2.19 (d, 1H, J =
13.2 Hz), 1.89−1.79 (m, 2H), 1.76 (s, 3H), 1.64 (s, 3H), 1.61 (s, 2H),
1.53−1.49 (m, 1H), 0.02 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
149.2, 131.7, 122.7, 108.8, 44.3, 38.2, 36.1, 32.1, 24.3, 20.9, 18.7, 12.0,
−0.5; EI−MS (m/z) M+ 362 (2.2%), 235 (19%), 161 (11%), 73
(100%).
Methyl-4-((1R,5R)-2-methyl-5-(prop-1-en-2-yl)-3-((trimethylsilyl)-
methyl)cyclohex-2-en-1-yl) Butanoate (19). To a stirred slurry of
zinc dust (1.07 g, 16.50 mmol) in pyridine (5 mL) was added methyl
acrylate (1.35 mL, 15.00 mmol) at room temperature. Powdered
nickel(II) chloride hexahydrate (1.19 g, 5.00 mmol) was added to the
above slurry mixture. The resulting suspension was brought to 50 °C
and stirred for 20 min. The resulting red-brown mixture was cooled to
Compound 21b: Rf = 0.24 (petroleum ether/EtOAc = 10:1); [α]D20
=
−22 (c = 0.2, CHCl3); IR (film) νmax = 3440, 2928, 1639, 1448, 1082,
1
890 cm−1; H NMR (400 MHz, CDCl3) δ 4.95 (d, 1H, J = 0.8 Hz),
4.79 (s, 2H), 4.77 (s, 1H), 3.98 (br s, 1H), 2.47−2.43 (m, 1H), 2.37
(d, 2H, J = 11.2 Hz), 1.93−1.92 (m, 1H), 1.84−1.83 (m, 1H), 1.79−
G
dx.doi.org/10.1021/jo4009854 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1.69 (m, 2H), 1.72 (s, 3H), 1.68−1.56 (m, 4H), 1.49−1.46 (m, 1H),
1.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.8, 148.5, 110.8,
110.1, 70.0, 44.1, 43.8, 40.6, 39.4, 37.0, 31.2, 28.2, 27.7, 24.5, 21.7;
HRMS (ESI) m/z [M + Na]+ calcd for C15H24NaO, 243.1719; found,
243.1727.
(4aR,6R,8aR)-8a-Methyl-8-methylene-6-(prop-1-en-2-yl)-
octahydronaphthalen-1(2H)-one (22). To a stirred mixture of
compounds 21a and 21b (diastereoisomers, 17 mg, 0.08 mmol) in
dry DCM (1 mL) was added SiO2 (20 mg). After stirring for 5 min,
powdered PCC (30 mg, 0.14 mmol) was added in one portion to the
above suspension. After stirring for 15 min, the reaction mixture was
filtered through a short pad of Celite, eluting with ether. The resulting
filtrate was concentrated, and the residue was purified by flash silica gel
column chromatography (petroleum ether/EtOAc = 1:1) to give
compound 22 (15 mg, 95%) as a colorless oil: Rf = 0.70 (petroleum
program and the scholars program of Chongqing University are
gratefully acknowledged.
REFERENCES
■
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ether/EtOAc = 10:1); [α]2D0 = +79 (c = 2.0, CHCl3); IR (film) νmax
=
2934, 1705, 1640, 1453, 1373, 1235, 1112, 895 cm−1; H NMR (400
MHz, CDCl3) δ 4.86 (s, 1H), 4.76 (s, 1H), 4.75 (s, 1H), 4.34 (s, 1H),
2.67 (td, 1H, J = 6.4, 14.4 Hz), 2.45−2.35 (m, 2H), 2.28−2.26 (m,
2H), 2.02−1.96 (m, 1H), 1.92−1.84 (m, 3H), 1.81 (s, 3H), 1.75−1.52
(m, 3H), 1.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 214.4, 149.1,
149.1, 111.2, 109.1, 55.9, 45.3, 40.0, 39.6, 37.3, 32.4, 28.4, 26.0, 22.0,
20.6; HRMS (ESI) m/z [M + H]+ calcd for C15H23O, 219.1743;
found, 219.1748.
1
(3) For recent reports on the total synthesis of hirsutene (since
1998), see: (a) Anger, T.; Graalmann, O.; Schroder, H.; Gerke, R.;
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Kaiser, U.; Fitjer, L.; Noltemeyer, M. Tetrahedron 1998, 54, 10713.
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(R)-2-((2R,4aR,5R,8aR)-5-Hydroxy-4a-methyl-4-methylenedeca-
hydronaphthalen-2-yl)propane-1,2-diol (23a). To a stirred mixture
of compound 21a (62 mg, 0.28 mmol) in dry acetone (2 mL) and N-
methylmorpholine N-oxide (31 mg, 0.26 mmol) was added OsO4 (5.0
mg, 0.02 mmol) in 1 mL of i-PrOH at 0 °C under N2. After stirring for
2 h, the reaction mixture was quenched with 2 mL of saturated
aqueous NaHSO3 and extracted with ether. The organic layer was
washed successively with water and brine, dried over Na2SO4, and
concentrated in vacuo. The solid residue was purified by
recrystallization from a solvent mixture of petroleum ether/EtOAc
(2:1) to give diastereomer 23a (15 mg, 43%) as colorless crystals: Rf =
0.15 (petroleum ether/EtOAc = 1:1); [α]2D0 = −15 (c = 0.2, CHCl3);
mp 136−138 °C; IR (film) νmax = 3394, 2931, 2859, 1703, 1638, 1454,
1041, 908 cm−1; 1H NMR (600 MHz, CDCl3) δ 5.17 (s, 1H), 5.05 (s,
1H), 3.57−3.50 (m, 2H), 3.41 (dd, 1H, J = 9.0, 16.2 Hz), 2.29−2.17
(m, 2H), 2.07−1.98 (m, 1H), 1.94−1.84 (m, 1H), 1.80−1.77 (m, 2H),
1.76−1.66 (m, 2H), 1.55−1.43 (m, 1H), 1.43−1.34 (m, 2H), 1.31 (s,
3H), 1.30−1.22 (m, 1H), 1.13 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 150.2, 112.2, 80.2, 74.4, 68.4, 45.1, 43.1, 39.7, 35.2, 34.0, 30.1, 28.2,
26.9, 25.1, 20.2; HRMS (ESI) m/z [M + H]+ calcd for C15H27O3,
255.1955; found, 255.1958. X-ray crystallographic data of 23a:
C15H26O3, monoclinic, space group: C2, a = 19.18 (5) Å, b = 9.99
(3) Å, c = 7.58 (2) Å, β = 94.11 (3)°, Z = 4, dcalcd = 1.166 g/cm3, R1(I
> 2σ(I)) = 0.0631, wR2 = 0.3156.
̀
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ASSOCIATED CONTENT
* Supporting Information
■
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J., Jr.; Dong, Y. Tetrahedron 1993, 49, 7931.
S
X-ray crystallographic data for compounds 9c and 23a, GC−
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1
NMR spectra for compounds 1−4, 9, 10, 12−15, 18−20, 22,
5a, 7a, 5b, 7b, 9a−d, 14a, 16a, 16b, 21a, 21b, and 23a, and CIF
files for 9c and 23a. This material is available free of charge via
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AUTHOR INFORMATION
Corresponding Author
*E-mail: wdli@cqu.edu.cn. Fax/Phone: 0086-(0)23-65678459.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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N.; Fujimoto, T.; Tominaga, N.; Morita, H. J. Org. Chem. 1992, 57,
7175. (b) Jung, M. E.; Rayle, H. L. J. Org. Chem. 1997, 62, 4601.
We thank the National Natural Science Foundation
(21132006) for financial support. The Cheung Kong Scholars
H
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The Journal of Organic Chemistry
Article
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I
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