Synthetic studies on polymaxenolides: Synthesis and structure elucidation of nominal epoxyafricanane and other africane-type sesquiterpenoids

Article abstract of DOI:10.1021/jo2010186

A racemic total synthesis of the sesquiterpenoid unit of the hybrid marine natural product polymaxenolide has been achieved based on a three-component assembly followed by ring-closing metathesis as the key steps. However, the spectral data of our product synthesized from Δ⁹⁽¹⁵⁾-africanene by epoxidation were not identical with those of the natural product named epoxyafricanane. The structure confirmation of the synthetic nominal epoxyafricanane is described.

Full text of DOI:10.1021/jo2010186

ARTICLE
pubs.acs.org/joc
Synthetic Studies on Polymaxenolides: Synthesis and Structure
Elucidation of Nominal Epoxyafricanane and Other
Africane-Type Sesquiterpenoids
Yutaka Matsuda, Yusuke Endo, Yoko Saikawa, and Masaya Nakata*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
S Supporting Information
b
ABSTRACT: A racemic total synthesis of the sesquiterpenoid
unit of the hybrid marine natural product polymaxenolide has
been achieved based on a three-component assembly followed
by ring-closing metathesis as the key steps. However, the
spectral data of our product synthesized from Δ9(15)-africanene
by epoxidation were not identical with those of the natural
product named epoxyafricanane. The structure confirmation of
the synthetic nominal epoxyafricanane is described.
’ INTRODUCTION
Polymaxenolide (1) is the first hybrid compound from the
marine environment isolated, by Slattery and co-workers in 2004,
from the hybrid soft coral Sinularia maxima  Sinularia poly-
dactyla collected from Piti Bomb Holes, Guam (Figure 1).1 The
relative configuration of 1 was determined by NMR experiments
and X-ray crystallography.1 This terpenoid is considered to be
biogenetically synthesized from the africane-type sesquiterpe-
noid unit 2 possessing the bicyclo[5.3.0]decane structure and the
cembranoid unit 3 (a diterpenoid) via CÀC coupling followed
by dehydrative cyclization (Figure 1).1 In 2009, Kamel, Slattery,
and co-workers isolated five new polymaxenolides from the same
hybrid soft coral.2 Their structures, including absolute config-
urations, were determined on the basis of detailed NMR and MS
Figure 1. Structures of polymaxenolide (1) and its proposed biosyn-
data analyses, experimental and theoretically calculated elec-
tronic circular dichroism, and X-ray crystallographic analysis.2
There has been no comment on the absolute configuration of 1.
However, one would expect that polymaxenolide (1) has the
absolute configuration as depicted in Figure 1 because of its
structural similarity to the six isolated polymaxenolides.1,2
The structural complexity and uniqueness of the polymax-
enolides, in conjunction with the proposed interesting biosynthe-
sis, prompted us to synthesize them. In this article, we report the
first racemic synthesis of the sesquiterpenoid unit 2, claimed to
have been isolated from the soft coral Sinularia dissecta in 1999 by
the Venkateswarlu group.3 We anticipated that 2 could be derived
from Δ9(15)-africanene (4)4,5 by a stereoselective epoxidation3
(Figure 2). Δ9(15)-Africanene (4) would be obtained from
ketone 5 by methylenation. In the original isolation studies,
natural Δ9(15)-africanene (4) was reversibly transformed into
ketone 5 by ozonolysis4a or by dihydroxylation followed by
oxidative scission4b in order to confirm the structure of 4. It was
necessary for us to synthesize some other africane-type natural
thetic precursors, i.e., the sesquiterpenoid unit 2 and the cembranoid
unit 3.
sesquiterpenoids, africane-9,15-diol 6,3,4b,6 another africane-
9,15-diol 7,6 leptographiol (8),7 and isoleptographiol (9),7 in
order to confirm the structure of 2 (Figure 2). The africanes, 4
and 6À9, were isolated from several soft coral Sinularia or woods
and have not become targets for total synthesis.8 The first
member of the africane-type sesquiterpenoids isolated from a
natural source was (+)-africanol (10), obtained from Lemnalia
africana in 1974 by the Braekman group (Figure 2).9 Biosyn-
thetic studies of the africane-type sesquiterpenoids and their
chemical synthesis along the proposed biosynthetic pathway
have been investigated.9À16 Among them, Shirahama’s synthesis13
of (()-africanol (10) from humulene in 1980 is the first example
Received: May 19, 2011
Published: June 24, 2011
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of the chemical synthesis of a natural africane. Following this
synthesis, Paquette and Ham succeeded in the synthesis of (()-
africanol (10) in 1986.17 In 1990, Tai and co-workers reported
the first chiral synthesis of (+)-africanol (10) and (+)-isoafrica-
nol (11);18 however, these were obtained as minor components
of the products. White,19 Cossy,20 and Marques21 also reported
the syntheses of (()-africanol (10) and/or (()-isoafricanol
(11). Paquette reported the synthesis of a diastereomer of (+)-
africanol (10) featuring ring-closing metathesis (RCM).22 Re-
cently, Hoveyda succeeded in the synthesis of (+)-africanol (10)
using asymmetric ring-opening metathesis/RCM.23
’ RESULTS AND DISCUSSION
The synthetic route to ketone 5 followed F€urstner’s synthesis24
of dactylol, which is based on a three-component assembly
followed by ring-closing metathesis (RCM) as the key steps
(Scheme 1). A similar strategy was recently applied to the
synthesis of bicyclo[5.3.0]decane and bicyclo[6.3.0]undecane
natural products.25 The three-component coupling of cyclopen-
tenone 12, 2-metallopropene derived from 2-bromopropene
(13), and the commercially available aldehyde 14 afforded
alcohol 15 as a single diastereomer in 86% yield. Mesylation of
15 gave olefin 16 directly in 89% yield. The relative configuration
of three consecutive stereocenters in 15 and the E-configuration
of the newly formed double bond in 16 were inferred from
Snider’s26 and Vanderwal’s25 precedents. Selective hydrogena-
tion of 16 with n-Bu3SnH in the presence of ZnCl2 and Pd(PPh3)4
provided 17 in 82% yield as a single diastereomer.24,25,27,28 This
reaction proceeded via palladium-catalyzed hydrostannation fol-
lowed by kinetic protonation, providing 2,3-trans-cyclopenta-
none.24,25,27,29 RCM of 17 using Grubbs’ second generation
Figure 2. Some africanes and ketone 5.
Scheme 1. Synthesis of Ketone 5
catalyst30 gave the bicyclo[5.3.0]decane derivative 18 in 53%
21,22,31
yield. Cyclopropanation of 18 with Et2ZnÀCH2I2
exclu-
sively afforded the desired ketone 5 in 62% yield. The data (1H
NMR, 13C NMR, and mp) of 5 were identical with those of the
naturally derived 5.4 The stereoselectivity of this cyclopropanation
can be explained by the steric hindrance of the lower face of the
trans bicyclic compound 18 caused by the 14-Me and H-8 groups.
The methylenation of 5 with Tebbe reagent32 afforded Δ9(15)
-
africanene (4) in 96% yield (Scheme 2). The data of the synthetic
4 were identical with those of natural 4.4,33 This is the first
synthesis of Δ9(15)-africanene (4), achieved in six steps and
20% overall yield without using any protecting groups. Epoxida-
tion of 4 with MCPBA gave a 2.5:1 inseparable mixture of the
Scheme 2. Synthesis of 2 and Some Other Africanes
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1.00 mmol) was added with stirring. After 15 min at rt, this dark
black solution was cooled to À78 °C, and cyclopentenone (0.164 mL,
2.00 mmol) was added with stirring. After 2 h at À78 °C, 2,2-dimethyl-4-
pentenal (0.114 mL, 1.00 mmol) was added at À78 °C, and the resulting
mixture was stirred at À78 °C for additional 3 h. Saturated aqueous
solution of NH4Cl was then added at 0 °C, and the mixture was extracted
with EtOAc. The organic layer was washed with saturated aqueous NaCl,
dried over Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel (10.2 g,
hexane/EtOAc = 10:1) to afford 15 (203 mg, 86%) as a colorless syrup:
Rf = 0.28 (hexane/EtOAc = 5:1); IR (neat, cmÀ1) 3457, 3074, 2964,
1732, 1640, 1466, 1404, 1285, 1145, 1054, 997, 910; 1H NMR (500 MHz,
CDCl3, TMS = 0.00) δ 0.82 (s, 3H), 0.89 (s, 3H), 1.72 (s, 3H), 1.82 (ddd,
J = 13.8, 11.7, 8.9 Hz, 1 H), 1.97 (dd, J = 13.5, 7.5 Hz, 1 H), 2.05 (ddd,
J = 13.8, 9.0, 7.4 Hz, 1H), 2.12 (dd, J = 13.5, 7.8 Hz, 1 H), 2.21 (ddd,
J = 18.9, 11.3, 8.9 Hz, 1 H), 2.29 (d, J = 11.7 Hz, 1 H), 2.38 (dd, J = 18.9,
8.9 Hz, 1 H), 2.56 (d, J = 11.5 Hz, 1 H), 2.82 (ddd, J = 11.7, 11.7, 6.3 Hz,
1 H), 3.31 (d, J = 11.5 Hz, 1 H), 4.90 (br s, 1H), 4.92 (br s, 1H), 5.03 (br d,
J = 15.5 Hz, 1H), 5.04 (br d, J = 10.9 Hz, 1H), 5.75 (m, 1H); 13C NMR
(125 MHz, CDCl3, CDCl3 = 77.00) δ 18.1, 22.9, 23.6, 25.5, 38.3, 38.5,
43.5, 51.1, 53.0, 77.4, 114.2, 117.4, 135.2, 144.0, 219.0; LRMS (EI) m/z
(M)+ 236.2; HRMS (EI) m/z (M)+ calcd for C15H24O2 236.1776, found
236.1776.
Figure 3. Representative NMR data of 2.
sesquiterpenoid unit 2 and its epimer 19 in 88% combined
yield.3,34 Surprisingly, the 1H NMR and 13C NMR spectra of our
synthetic 2 were not identical with those of the reported isolated
sample,3 especially in the epoxide region (Figure 3).35
Therefore, to confirm the structure of our synthetic 2, we
synthesized some additional africane-type natural sesquiterpe-
noids. First, Δ9(15)-africanene (4) was subjected to dihydroxyla-
tion using OsO4 and NMO, giving a separable mixture of af-
ricane-9,15-diol 6 and another africane-9,15-diol 7 in 77% and
18% yields, respectively34 (Scheme 2). The major diol 6 has been
isolated from a natural source3,6 and also derived from natural
4.3,4b,6 The minor diol 7 has also been isolated from a natural
source6 but has not yet been synthesized.36 The spectral data of 6
and 7 were identical with those of natural 6 and 7. In addition, the
relative configuration of 6 was confirmed by X-ray crystallo-
graphic analysis4b (see Supporting Information). With the pure
sample of 6 in hand, it was converted into the pure sample of 2 by
treatment with tosyl imidazole37 and NaH in 78% yield.38 Further-
more, the obtained 2 was converted into diol 6 by epoxide opening
with aqueous KOH in 58% yield. On the other hand, the
treatment of ketone 5 with MeLi gave leptographiol (8)7,39
and isoleptographiol (9)7 in 52% and 18% yields, respectively,34
the latter of which could be obtained from 2 by reductive opening
of the epoxide with LAH in 75% yield. All of these experimental
results confirm the structure of the synthetic sesquiterpenoid unit 2.
(()-(2E)-2-(2,2-Dimethylpent-4-enylidene)-3-(prop-1-en-
2-yl)cyclopentanone (16). To a solution of 15 (49.6 mg, 0.210 mmol)
in THF (5.25 mL) were added 4-(dimethylamino)pyridine (128 mg,
1.05 mmol) and methanesulfonyl chloride (0.041 mL, 0.532 mmol) at rt,
and the mixture was warmed to 60 °C (bath temperature). After 48 h at
60 °C, water was added at rt, and the mixture was extracted with hexane.
The organic layer was washed with saturated aqueous NaCl solution,
dried over Na2SO4, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel (1.50 g,
hexane/EtOAc = 10:1) to afford 16 (40.8 mg, 89%) as a colorless syrup:
Rf = 0.66 (hexane/EtOAc = 5:1); IR (neat, cmÀ1) 3075, 2960, 2927,
1
1742, 1640, 1467, 1409, 1386, 1368, 1146, 997, 893; H NMR (500
MHz, CDCl3, TMS = 0.00) δ 1.09 (s, 3H), 1.10 (s, 3H), 1.84 (s, 3H),
1.91À1.97 (m, 2H), 2.14 (br d, J = 7.5 Hz, 2H), 2.22 (m, 1 H), 2.30 (m, 1
H), 3.73 (br t, J = 3.7 Hz, 1H), 4.55 (br s, 1H), 4.82 (br s, 1H), 5.02 (br d,
J = 18.9 Hz, 1H), 5.03 (br d, J = 9.5 Hz, 1H), 5.71 (m, 1H), 6.63 (d, J =
1.7 Hz, 1H); 13C NMR (125 MHz, CDCl3, CDCl3 = 77.00) δ 22.1, 25.2,
25.8, 26.8, 34.4, 37.2, 45.3, 47.3, 111.8, 117.6, 134.6, 136.5, 146.2, 147.3,
208.4; LRMS (EI) m/z (M)+ 218.2; HRMS (EI) m/z (M)+ calcd for
C15H22O 218.1671, found 218.1679.
’ CONCLUSION
(()-(2S,3R)-trans-2-(2,2-Dimethylpent-4-enyl)-3-(prop-
1-en-2-yl)cyclopentanone (17). To a solution of 16 (269 mg,
1.23 mmol) in THF (4.13 mL) degassed with argon were added ZnCl2
(369 mg, 2.71 mmol) and (PPh3)4Pd (42.7 mg, 0.0369 mmol) at rt. This
solution was again degassed with argon, tributyltin hydride (0.716 mL,
2.46 mmol) was added at rt with stirring, and the resulting mixture was
stirred at rt for additional 1 h. Water was added at rt, and the mixture was
extracted with Et2O. The organic layer was washed with saturated
aqueous NaCl solution, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatography
on 10% w/w anhydrous K2CO3Àsilica gel (27.1 g, hexane/EtOAc =
10:1) to afford 17 (222 mg, 82%) as a colorless syrup: Rf = 0.62 (hexane/
EtOAc = 5:1); IR (neat, cmÀ1) 3075, 2960, 1742, 1640, 1466, 1409,
1368, 1282, 1146, 997, 911, 893; 1H NMR (500 MHz, CDCl3, TMS =
0.00) δ 0.81 (s, 3H), 0.85 (s, 3H), 1.15 (dd, J = 14.1, 2.6 Hz, 1H), 1.59
(dd, J = 14.1, 6.3 Hz, 1H), 1.74 (s, 3H), 1.83 (m, 1H), 1.90 (dd, J = 13.5,
7.5 Hz, 1H), 1.95À2.04 (m, 3H), 2.13 (ddd, J = 18.9, 10.1, 10.1 Hz, 1H),
2.34À2.42 (m, 2H), 4.83 (brs, 1H), 4.86 (brs, 1H), 4.98 (br d, J = 16.9,
1H), 5.00 (br d, J = 8.9, 1H), 5.82 (m, 1H); 13C NMR (125 MHz,
CDCl3, CDCl3 = 77.00) δ 18.5, 25.5, 26.7, 26.8, 33.2, 36.8, 40.5, 47.2,
49.1, 52.7, 113.2, 116.8, 135.7, 144.7, 220.0; LRMS (EI) m/z (M)+
We succeeded in the racemic total synthesis of the sesquiter-
penoid unit 2 of polymaxenolide (1), featuring the three-com-
ponent coupling of cyclopentenone 12, 2-metallopropene de-
rived from 2-bromopropene (13), and aldehyde 14 followed by
ring-closing metathesis, methylenation, and epoxidation. The
structure confirmation of 2 was realized by chemical correlation
between 2 and 6 and between 2 and 9. Although we are uncertain
about the structure of the compound isolated from the soft coral
Sinularia dissecta,3 our results indicate that the structure of the
natural product named epoxyafricanane was incorrectly assigned.
Progress toward the total synthesis of polymaxenolide (1) using
2, 4, or 5 as the sesquiterpenoid unit is now underway.40
’ EXPERIMENTAL SECTION
(()-(2R,3R)-2-(1-Hydroxy-2,2-dimethylpent-4-enyl)-3-(prop-
1-en-2-yl)cyclopentanone (15). To a solution of 2-bromopropene
(0.242 mL, 2.00 mmol) in Et2O (25.0 mL) was added a 1.60 M pentane
solution of t-BuLi (2.50 mL, 4.00 mmol) at À78 °C. After 30 min at
À78 °C, this yellow solution was warmed to rt, and CuI (190 mg,
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ARTICLE
220.2; HRMS (EI) m/z (M)+ calcd for C15H24O 220.1827, found
220.1833.
(40.0 mg, 0.196 mmol) in CH2Cl2 (0.980 mL) was added 3-chloroper-
oxybenzoic acid (78.1 mg, 0.294 mmol) at rt. After 1 h at rt, saturated
aqueous solution of NaHCO3 was added, and the mixture was extracted
with CHCl3. The organic layer was washed with saturated aqueous NaCl
solution, dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (1.00 g,
hexane/EtOAc = 10:1) to afford a 2.5:1 inseparable mixture (judged by
1H NMR spectrum) of 2 and 19 (38.0 mg 88% combined yield) as a
colorless syrup. Data for each are shown below.
(()-(3aR,8aS)-4,7,7-Trimethyl-3,3a,6,7,8,8a-hexahydro-
azulen-1-one (18). To a solution of 17 (57.2 mg, 0.260 mmol) in dry
CH2Cl2 (26.0 mL) degassed with argon was added the Grubbs second
generation catalyst (11.0 mg, 0.013 mmol). The resulting purple solution
was again degassed with argon and warmed to 40 °C (bath temperature).
After 1.5 h at 40 °C, the reaction mixture was cooled to rt, and the
solvent was removed under reduced pressure. The residue was purified
by column chromatography on silica gel (500 mg, hexane/EtOAc =
10:1) to afford 18 (26.4 mg, 53%) as a yellow syrup: Rf = 0.52 (hexane/
EtOAc = 5:1); IR (neat, cmÀ1) 2954, 1741, 1635, 1462, 1365, 1283,
1159, 1104, 1078; 1H NMR (500 MHz, CDCl3, TMS = 0.00) δ 0.85 (s,
3H), 0.96 (s, 3H), 1.22 (dd, J = 13.7, 13.0 Hz, 1H), 1.80 (br d, J = 1.5 Hz,
3H), 1.80À1.89 (m, 3H), 2.03 (ddd, J = 13.7, 2.7, 2.3 Hz, 1H), 2.08 (m,
1H), 2.09À2.16 (m, 2H), 2.40 (m, 1H), 2.71 (ddd, J = 12.9, 12.6, 4.9 Hz,
1H), 5.49 (m, 1H); 13C NMR (125 MHz, CDCl3, CDCl3 = 77.00) δ
21.3, 24.3, 24.7, 30.5, 33.4, 38.1, 40.7, 45.2, 45.8, 48.8, 124.8, 139.0,
221.1; LRMS (EI) m/z (M)+ 192.1; HRMS (EI) m/z (M)+ calcd for
C13H20O 192.1514, found 192.1519.
(()-Africane-9,15-diol (6) and (()-9-epi-Africane-9,15-
diol (7). To a solution of 4 (49.4 mg, 0.242 mmol) in acetone (2.18 mL)
and water (0.241 mL) were added OsO4 (6.2 mg, 0.024 mmol) and
4-methylmorpholine N-oxide (144 mg, 1.21 mmol) at rt. After 3 h at rt,
saturated aqueous solution of NaHCO3 was added, and the mixture was
extracted with EtOAc. The organic layer was washed with saturated
aqueous NaCl solution, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatography
on silica gel (10.0 g, hexane/EtOAc = 1:1) to afford 6 (44.4 mg, 77%)
and 7 (10.4 mg, 18%) as colorless solids. 6: Rf = 0.53 (hexane/EtOAc =
1:2); mp 112À114 °C (colorless crystals recrystallized from hexane; lit.
112À114 °C4b,6); IR (neat, cmÀ1) 3385, 3057, 2951, 2865, 1463, 1381,
1319, 1135, 1108, 1075, 1045, 912; 1H NMR (500 MHz, CDCl3, TMS =
0.00) δ 0.18 (dd, J = 4.3, 4.0 Hz, 1H), 0.47 (m, 1H), 0.55 (dd, J = 8.3, 4.0
Hz, 1H), 0.89 (s, 3H), 0.90 (m, 1H), 0.99 (s, 3H), 1.03 (m, 1H), 1.03 (s,
3H), 1.32 (m, 1H), 1.52À1.61 (m, 2H), 1.61 (ddd, J = 12.8, 2.8, 2.6 Hz,
1H), 1.76À1.82 (m, 3H), 1.85 (br s, 1H), 2.01 (ddd, J = 12.8, 9.9, 2.8 Hz,
1H), 2.08 (br s, 1H), 3.43 (d, J = 10.8 Hz, 1H), 3.58 (d, J = 10.8 Hz, 1H);
13C NMR (125 MHz, CDCl3, CDCl3 = 77.00) δ 19.7, 20.4, 21.7, 23.5,
23.6, 23.9, 33.5, 34.0, 36.7, 43.5, 44.3, 48.0, 50.0, 65.3, 82.5; LRMS (EI)
m/z (M)+ 238.2; HRMS (EI) m/z (M)+ calcd for C15H26O2 238.1933,
found 238.1922. 7: Rf = 0.51 (hexane/EtOAc = 1:2); mp 123À124 °C
(colorless crystals recrystallized from hexane/acetone; lit. 122À125 °C6);
IR (neat, cmÀ1) 3430, 2950, 2855, 1457, 1382, 1261, 1103, 1078, 1063,
1041, 805; 1H NMR (500 MHz, CDCl3, TMS = 0.00) δ 0.22 (dd, J = 4.3,
4.0 Hz, 1H), 0.48 (m, 1H), 0.54 (dd, J = 8.3, 4.0 Hz, 1H), 0.91 (s, 3H),
0.95 (s, 3H), 0.99 (s, 3H), 1.09 (dd, J = 14.6, 10.6 Hz, 1H), 1.17 (dd,
J = 12.9, 12.6 Hz, 1H), 1.42 (ddd, J = 12.9, 2.3, 2.3 Hz, 1H), 1.59À1.75
(m, 6H), 1.81 (ddd, J = 14.6, 6.3, 2.3 Hz, 1H), 3.46 (br d, J = 10.9 Hz,
1H), 3.57 (br d, J = 10.9 Hz, 1H); 13C NMR (125 MHz, CDCl3, CDCl3 =
77.00) δ 19.7, 20.2, 21.8, 23.6, 23.9, 24.3, 33.4, 34.0, 37.4, 43.3, 44.1, 44.4,
49.8, 68.8, 82.9; LRMS (EI) m/z (M)+ 238.2; HRMS (EI) m/z (M)+
calcd for C15H26O2 238.1933, found 238.1932.
Sesquiterpenoid Unit (()-2. To a solution of 6 (30.0 mg,
0.126 mmol) in THF (0.629 mL) were added sodium hydride (8.3 mg,
0.19 mmol, 55% dispersion in paraffin liquid) and 1-(p-toluenesulfo-
nyl)imidazole (56.0 mg, 0.252 mmol) at 0 °C, and the mixture was
warmed to rt. After 1 h at rt, saturated aqueous solution of NH4Cl was
added at 0 °C, and the mixture was extracted with EtOAc. The organic
layer was washed with saturated aqueous NaCl soluion, dried over
Na2SO4, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (1.00 g, hexane/EtOAc =
10:1) to afford 2 (21.7 mg, 78%) as a colorless syrup: Rf = 0.73 (hexane/
EtOAc = 5:1); IR (neat, cmÀ1) 2952, 1457, 1385, 1261, 1096, 1018, 954,
921, 875, 795; 1H NMR (500 MHz, CDCl3, TMS = 0.00) δ 0.20 (dd,
J = 4.3, 4.0 Hz, 1H), 0.50 (m, 1H), 0.56 (dd, J = 8.3, 4.0 Hz, 1H), 0.86 (s,
3H), 0.95 (s, 3H), 0.99 (m, 1H), 1.01 (s, 3H), 1.09 (dd, J = 14.6, 10.3 Hz,
1H), 1.33 (ddd, J = 12.9, 3.3, 3.3 Hz, 1H), 1.36 (ddd, J = 10.6, 10.6,
6.6 Hz, 1H), 1.62 (ddd, J = 13.2, 7.4, 2.3 Hz, 1H), 1.68 (m, 1H),
1.76À1.85 (m, 2H), 1.92 (ddd, J = 13.2, 11.5, 6.9 Hz, 1H), 2.07 (ddd,
J = 10.6, 10.3, 3.3 Hz, 1H), 2.61 (d, J = 4.6 Hz, 1H), 2.86 (d, J = 4.6 Hz,
1H); 13C NMR (125 MHz, CDCl3, CDCl3 = 77.00) δ 19.2, 20.2, 21.9,
23.3, 23.9, 26.0, 33.4, 33.90, 33.92, 41.0, 43.1, 47.5, 50.3, 52.4, 68.5;
LRMS (EI) m/z (M)+ 220.2; HRMS (EI) m/z (M)+ calcd for C15H24O
220.1827, found 220.1842.
(()-(1aS,4aS,7aR,7bR)-3,3,7b-Trimethyloctahydro-cyclo-
propa[e]azulen-5-one (5). To a solution of 18 (48.0 mg, 0.250 mmol)
in dry toluene (1.25 mL) were added 1.0 M hexane solution of diethylzinc
(2.50 mL, 2.50 mmol) and diiodomethane (1.34 mL, 5.00 mmol) at rt.
After 12 h at 80 °C (bath temperature), water was added at rt, the
reaction mixture was extracted with hexane, and the organic layer was
washed with saturated aqueous NaCl solution, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (10.3 g, hexane/EtOAc = 40:1) to afford
5 (32.0 mg, 62%) as colorless solids and the recovered 18 (2.6 mg, 15%)
as a colorless syrup: Rf = 0.55 (hexane/EtOAc = 5:1); mp 61À63 °C
(colorless crystalsrecrystallized frombenzene;lit. 63°C,4a 62À64°C4b);
IR (KBr, cmÀ1) 2989, 1739, 1456, 1385, 1240, 1139, 1019, 877, 757; 1H
NMR (500 MHz, CDCl3, TMS = 0.00) δ 0.27 (dd, J = 4.6, 4.4 Hz, 1H),
0.54 (m, 1H), 0.63 (dd, J = 8.3, 4.4 Hz, 1H), 0.91 (s, 3H), 0.95 (dd,
J = 13.1, 12.9 Hz, 1H), 1.00 (s, 6H), 1.06 (dd, J = 14.6, 10.8 Hz, 1H), 1.57
(ddd, J = 11.5, 11.5, 6.3 Hz, 1H), 1.77 (m, 1H), 1.86 (ddd, J = 14.6, 6.3,
2.6 Hz, 1H), 1.90 (ddd, J = 13.1, 2.9, 2.6 Hz, 1H), 1.97 (ddd, J = 12.6, 8.9,
6.3 Hz, 1H), 2.08À2.17 (m, 2H), 2.38 (dd, J = 18.6, 8.0 Hz, 1H); 13C
NMR (125 MHz, CDCl3, CDCl3 = 77.00) δ 18.8, 20.4, 22.0, 23.3, 23.48,
23.53, 33.2, 33.3, 38.9, 43.3, 45.7, 48.1, 49.7, 222.3; LRMS (EI) m/z (M)+
206.1; HRMS (EI) m/z(M)+ calcd for C14H22O 206.1671, found 206.1692.
(()-Δ9(15)-Africanene (4). To a solution of 5(52.0 mg, 0.252 mmol)
in THF (2.52 mL) was added 1.0 M toluene solution of the Tebbe
reagent (0.328 mL, 0.328 mmol) at 0 °C, and the mixture was warmed to
rt. After 10 min at rt, Et2O (5.04 mL) and 1.0 M aqueous solution of
NaOH (0.492 mL) were added at 0 °C, and the mixture was extracted
with Et2O. The organic layer was washed with saturated aqueous NaCl
solution, dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (1.00 g,
hexane) to afford 4 (49.4 mg, 96%) as a colorless syrup: Rf = 0.95
(hexane); IR (neat, cmÀ1) 3056, 2950, 1651, 1470, 1384, 1363, 1162,
1017, 875; 1H NMR (500 MHz, CDCl3, TMS = 0.00) δ 0.19 (dd, J = 4.0,
4.0 Hz, 1H), 0.46À0.55 (m, 2H), 0.89 (s, 3H), 0.95 (s, 3H), 1.03 (dd,
J = 13.1, 12.9 Hz, 1H), 1.04 (s, 3H), 1.10 (dd, J = 14.6, 10.5 Hz, 1H), 1.31
(ddd, J = 11.2, 11.0, 6.6 Hz, 1H), 1.55 (dddd, J = 12.1, 12.0, 11.2, 7.7 Hz,
1H), 1.67 (m, 1H), 1.73 (ddd, 1H, J = 13.5, 3.1, 2.3 Hz), 1.81 (ddd, 1H,
J = 14.6, 6.3, 2.3 Hz), 2.25 (m, 1H), 2.37À2.45 (m, 2H), 4.71 (br s, 1H),
4.87 (br s, 1H); 13C NMR (125 MHz, CDCl3, CDCl3 = 77.00) δ 19.0,
20.5, 22.1, 23.3, 24.1, 27.7, 33.6, 33.7, 33.9, 42.2, 43.2, 51.3, 52.7, 104.4,
158.5; LRMS (EI) m/z (M)+ 204.2; HRMS (EI) m/z (M)+ calcd for
C15H24 204.1878, found 204.1891.
Epoxidation of (()-Δ9(15)-Africanene (4) to Sesquiterpe-
noid Unit (()-2 and Its Epimer (()-19. To a solution of 4
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ARTICLE
From (()-2 to (()-Africane-9,15-diol (6). To a solution of 2
(10.0 mg, 0.0454 mmol) in DMSO (0.227 mL) and H2O (0.227 mL)
was added potassium hydroxide (3.8 mg, 0.068 mmol) at rt, and the
mixture was warmed to 50 °C (bath temperature). After 1 h at 50 °C,
saturated aqueous solution of NH4Cl was added at rt, and the mixture
was extracted with EtOAc. The organic layer was washed with saturated
aqueous NaCl solution, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatography
on silica gel (1.0 g, hexane/EtOAc = 2:1) to afford 6 (5.8 mg, 58%) as a
colorless syrup.
saturated aqueous solution of NH4Cl was added at 0 °C, and the mixture
was extracted with EtOAc. The organic layer was washed with saturated
aqueous NaCl solution, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatography
on silica gel (1.00 g, hexane/EtOAc = 5:1) to afford 9 (3.8 mg, 75%) as a
colorless syrup.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra of all
S
b
(()-19. To a solution of 7 (5.0 mg, 0.021 mmol) in THF (0.11 mL)
were added sodium hydride (1.4 mg, 0.031 mmol, 55% dispersion in
paraffin liquid) and 1-(p-toluenesulfonyl)imidazole (9.3 mg, 0.042 mmol)
at 0 °C and the mixture was warmed to rt. After 1 h at rt, saturated
aqueous solution of NH4Cl was added at 0 °C and the mixture was
extracted with EtOAc. The organic layer was washed with saturated
aqueous NaCl solution, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chromatography
on silica gel (1.0 g, hexane/EtOAc = 10:1) to afford 19 (3.5 mg, 75%) as
new compounds and crystallographic data of compound 6 in CIF
format. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: msynktxa@applc.keio.ac.jp.
a colorless syrup: Rf = 0.73 (hexane/EtOAc = 5:1); IR (neat, cmÀ1
)
1
’ ACKNOWLEDGMENT
2925, 2854, 1463, 1382, 1261 1075, 1038, 803; H NMR (500 MHz,
CDCl3, TMS = 0.00) δ 0.23 (dd, J = 4.3, 3.7 Hz, 1H), 0.51 (m, 1H), 0.56
(dd, J = 8.3, 3.7 Hz, 1H), 0.87 (s, 3H), 0.89 (m, 1H), 0.95 (s, 3H), 0.97
(s, 3H), 1.00 (m, 1H,), 1.09 (dd, J = 14.6, 10.6 Hz, 1H), 1.52 (ddd,
J = 10.6, 10.6, 6.9 Hz, 1H), 1.64 (m, 1H), 1.74À1.84 (m, 3H), 1.92 (m,
1H), 2.12 (ddd J = 11.3, 10.6, 3.4 Hz, 1H), 2.62 (d, J = 5.1 Hz, 1H), 2.80
(d, J = 5.1 Hz, 1H); 13C NMR (125 MHz, CDCl3, CDCl3 = 77.00)
δ 19.2, 20.4, 22.1, 23.3, 23.9, 25.3, 32.9, 33.0, 33.9, 38.9, 43.2, 44.2, 51.46,
51.52, 66.1; LRMS (EI) m/z (M)+ 220.2; HRMS (EI) m/z (M)+ calcd
for C15H24O 220.1827, found 220.1810.
We thank Professor Naoki Yoshioka and Dr. Chihiro Maeda,
Keio University, for X-ray crystallographic analysis.
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1463, 1382, 1262, 1075, 1017, 938, 920, 804; H NMR (500 MHz,
CDCl3, TMS = 0.00) δ 0.21 (dd, J = 4.3, 4.0 Hz, 1H), 0.45 (m, 1H), 0.53
(dd, J = 8.3, 4.0 Hz, 1H), 0.92 (s, 3H), 0.96 (s, 3H), 0.99 (s, 3H), 1.09
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803, 758; 1H NMR (500 MHz, CDCl3, TMS = 0.00) δ 0.17 (dd, 1H,
J = 4.6, 4.6 Hz), 0.46 (m, 1H), 0.53 (dd, J = 8.3, 4.0 Hz, 1H), 0.92 (dd,
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1.08 (s, 3H), 1.31 (ddd, J = 10.0, 10.0, 5.2 Hz, 1H), 1.52 (ddd, J = 12.6,
2.5, 2.3 Hz, 1H), 1.52 (m, 1H), 1.62 (ddd, J = 11.7, 11.7, 3.4 Hz, 1H),
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77.00) δ 19.7, 20.7, 21.8, 22.4, 22.9, 23.6, 24.1, 33.4, 34.0, 42.0, 43.5,
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(M)+ calcd for C15H26O 222.1984, found 222.1983.
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(5.0 mg, 0.023 mmol) in THF (0.23 mL) was added LiAlH4 (1.3 mg,
0.034 mmol) at 0 °C, and the mixture was warmed to rt. After 1 h at rt,
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ARTICLE
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