Total syntheses of (±)-(Z)- and (±)-(E)-9-(bromomethylene)-1, 5,5-trimethylspiro[5.5]undeca-1,7-dien-3-one and (±)-majusculone

Article abstract of DOI:10.1055/s-0030-1258412

A new total synthesis of the chamigrene sesquiterpenoids (Z)-9-(bromomethylene)-1,5,5-trimethylspiro[5.5]undeca-1,7-diene-3-one and its 15-E-epimer has been accomplished in 13 steps. In our sequence, a Diels-Alder reaction and subsequent reductive alkylat

Full text of DOI:10.1055/s-0030-1258412

PAPER
715
Total Syntheses of ( )-(Z)- and ( )-(E)-9-(Bromomethylene)-1,5,5-trimethyl-
spiro[5.5]undeca-1,7-dien-3-one and ( )-Majusculone
Total
S
ynt
i
heses
o
a
f
C
hamigre
-
ne Sesq
L
uiterpenoids iang Zhu,*a Po-Wei Huang,a Ruei-Yi You,a Fa-Yan Lee,a Sheng-Wei Tsao,a I-Chia Chenb
a
Department of Chemistry, National Dong Hwa University, Hualien 974, Taiwan, R. O. C.
Fax +886(3)8633570; E-mail: jlzhu@mail.ndhu.edu.tw
b
Department of Cosmetic Applications and Management, Cardinal Tien College of Healthcare and Management, Taipei, Taiwan, R. O. C.
Received 16 November 2010; revised 20 December 2010
derived from anisole to construct the spirocyclic skeleton.
In these synthetic routes, however, the key spirocyclic in-
termediates were produced either in a relatively low yield
(22%)6 or as an inseparable mixture with a tricyclic regio-
Abstract: A new total synthesis of the chamigrene sesquiterpe-
noids (Z)-9-(bromomethylene)-1,5,5-trimethylspiro[5.5]undeca-
1,7-diene-3-one and its 15-E-epimer has been accomplished in 13
steps. In our sequence, a Diels–Alder reaction and subsequent re-
ductive alkylation of the resulting adduct was utilized as the key isomer.7
strategy to create the A-ring and the quaternary spirocenter with the
suitable functionalities for accessing the B-ring. Additionally, from
Y
15
the advanced intermediate, a total synthesis of ( )-majusculone, a
nor-chamigrene natural product, was also readily achieved in two
steps.
12
1
15
O
X
9
9
B
7
8
1
A
7
6
5
6
3
3
13
Key words: chamigrenes, sesquiterpenes, majusculone, total syn-
theses, Diels–Alder reaction
O
O
14
1: X = Br, Y = H
2: X = H, Y = Br
3
Figure 1 Skeleton of chamigrene and structures of 1, 2, and 3
In the past years, over one hundred members of chami-
grene-type sesquiterpenoids have been isolated from nat-
ural sources.1 Structurally, these natural products are
characterized by a spiro[5.5]undecane skeleton with two
vicinal quaternary carbon centers at C-5 and C-6 positions
(Figure 1). Many chamigrenes, especially those being ha-
logenated by bromine and/or chlorine atom(s), have been
shown to possess a wide variety of interesting biological
activities1a such as antibacterial2b and antifungal2c proper-
ties, and the cytotoxicity against a range of cancer cell
lines.1b,f,g,j,2a Besides, this class of natural products has
also attracted considerable interest from synthetic com-
munity, as reflected by a number of documented examples
on their total syntheses.3
OH
OH
O
4 steps
CuCl2
OH
O
N2
O
O
6 steps
( )-1 and 2
O
OMe
5 steps
O
OH
4 steps
HCl
CHO
Belonging to the chamigrene family, (Z)-9-(bromometh-
ylene)-1,5,5-trimethylspiro[5.5]undeca-1,7-diene-3-one
(1) and its 15-E-epimer 2 (Figure 1) were both isolated
from the red algae Laurencia majuscula Harvey.4,5 Their
spirobicyclic framework is composed by an A-ring carry-
ing a C1–C3 enone moiety and a B-ring containing a C7–
C8 double bond conjugated with an exo-bromomethylene
functionality. Like many other chamigrenes, the intrigu-
ing structural features make 1 and 2 attractive targets for
total synthesis. In 1983, Iwata and co-workers reported
the first total synthesis of 1 and 2 by using a copper-cata-
lyzed cyclization of a phenolic a-diazo ketone to create
the core structure (Scheme 1).6 Following this, Niwa’s
group7 described the second total synthesis by employing
an acid-promoted spiroannulation of an enone aldehyde
Scheme 1 Iwata’s and Niwa’s synthetic approaches to 1 and 2
We herein wish to report the third total synthesis of ( )-1
and ( )-2 based on an approach to highly substituted cy-
clohexene system as recently developed by Liu’s and our
laboratories.8 In our synthetic sequence, a Diels–Alder re-
action of an a-cyano a,b-unsaturated ester and a lithium
naphthalenide (LN)-induced reductive alkylation of the
resulting adduct were employed as the key operations to
create the A-ring and the quaternary spirocenter of 1 and
2. In addition, a total synthesis of ( )-majusculone (3,
Figure 1), a naturally occurring 9-norchamigrene-type
metabolite first isolated with 2,1h,5 was also achieved from
an advanced intermediate leading to 1 and 2 through sim-
ple operations.
SYNTHESIS 2011, No. 5, pp 0715–0722
x
x
.
x
x
.2
0
1
1
As outlined in our initial retrosynthetic analysis
(Scheme 2), we envisioned that the Diels–Alder reaction
Advanced online publication: 18.01.2011
DOI: 10.1055/s-0030-1258412; Art ID: F20510SS
© Georg Thieme Verlag Stuttgart · New York

716
J.-L. Zhu et al.
PAPER
between 2-cyano-3-methylbut-2-enoic acid ethyl ester (4)
and the Danishefsky-type diene 5 could be used to create
the A-ring of 1 and 2 in a single step with the concomitant
introduction of the C-5 quaternary center and the C-1
methyl group. In addition, the silyl enol ether moiety of
the resulting adduct 6 would be easily converted into the
requisite enone functionality to afford the intermediate 7.
After protecting the carbonyl group of 7, the cyano group
would be elaborated into a but-3-enyl appendage through
a reductive alkylation operation to give the intermediate 8.
Then, the terminal vinyl moiety of 8 has to be changed
into a keto functionality while the ester moiety has to be
converted into a formyl group to afford the keto aldehyde
9. Subsequent intramolecular aldol condensation of 9
would allow the establishment of the spirocyclic core, by
giving rise to intermediate 10. Finally, Wittig reaction
of 10 with trimethylphosphonium bromomethylide
(Ph3P=CHBr) followed by the respective deprotection of
the resulting E- and Z-isomers would complete the total
synthesis of 1 and 2.
CN
CN
EtO2C
a
CN
b
EtO2C
EtO2C
OTBS
EtO2C
CN
66%
O
4
7
6 (50:50) (82%)
+
O
OTBS
11
H
H
OTBS
H
EtO2C
Me
2
≡
c or d
1
6
H
OTBS
EtO
12
O
Scheme 3 Reagents and conditions: (a) LiBr (5.0 equiv), MS 3Å,
acetone, reflux, 18 h; (b) 5 (5.0 equiv), ZnCl2 (1.0 equiv), toluene, 80
°C, 20 h; (c) LN (3.5 equiv), THF, –45 °C, 30 min, then
H2C=CHCH2CH2Br (4 equiv), r.t., 24 h, 57% of 12; (d) LN (3.5
equiv), THF, –45 °C, 30 min, then H2C=CHCH2CH2Br (4 equiv),
HMPA (4 equiv), r.t., 12 h, 70% of 12.
1 and 2
O
O
9
8
to the unfavorable electronic effect of the cyano group to
the cation intermediate. In this regard, it was decided to
reroute our original scheme by conducting the reductive
alkylation of 6 first, to replace its cyano group with a but-
3-enyl appendage. Following the previously established
reaction conditions,8 the reductive alkylation reaction was
initially performed by treating 6 with LN (3.5 equiv)13 in
THF at –45 °C for 30 minutes, followed by trapping the
resulting enolate from the reductive decyanation with 4-
bromobut-1-ene (4 equiv), affording the alkylated product
12 in 57% yield as a single diastereomer. The trans steric
relationship between C-1 butenyl and C-2 methyl groups
was verified by 2D NOESY correlations as illustrated in
EtO2C
7
OHC
OPG
OPG
OPG
8
9
10
PG = protecting group
CN
CN
EtO2C
CN
EtO2C
EtO2C
+
O
OTBS
OTBS
7
6
4
5
Scheme 2 Retrosynthetic analysis of 1 and 2
In a modified procedure, our synthetic effort began with Scheme 3. It was further discovered that a much better
the condensation of ethyl cyanoacetate with acetone to yield of 12 (70%) could be obtained by the use of hexa-
provide the known compound 49 in 66% yield(Scheme 3). methylphosphoramide (HMPA) (4 equiv) as an activating
After this, the Diels–Alder reaction of 4 with diene 510 reagent.
was carried out. It was observed that with the assistance of
With the cyano group having been replaced by the alkyl
zinc chloride, 4 could readily undergo the cycloaddition
group, treatment of 12 with DDQ (5 equiv) in benzene at
with 5 (5 equiv) in toluene at 80 °C, to afford the desired
80 °C for 24 hours could indeed affect the formation of the
adduct 6 as a diastereomeric mixture (ortho-like, 50:50) in
enone moiety as evidenced by the low yield (~10%) of 13
good yield (82%), together with the by-product 11 result-
obtained. To improve the yield of 13, we continued to ex-
ing from the self-addition of 5 (0.6 out of 5 equiv) as a sin-
amine several reaction conditions by combining DDQ re-
spectively with several bases, including K2CO3, 2,4,6-
gle diastereomer.11 As we designed, compound 6 should
be directly transformed into enone 7, and for this purpose,
two commonly employed reagent systems for converting
silyl enol ether into enone, including 2,3-dichloro-5,6-di-
cyanobenzoquinone (DDQ)/benzene12a and Pd(OAc)2/
Na2CO3/MeCN,12b were respectively attempted on 6 at
different temperatures (r.t. to reflux). However, these re-
actions only led to recovered starting material or complex
mixtures.
collidine,14 and 2,6-lutidine, in benzene. Among the bases
tested, the best result was obtained from the reaction of
DDQ (4.8 equiv) in 2,6-lutidine (5.1 equiv) affording 13
in 55% yield (brsm: 72%), plus 30% of recovered 12
(Scheme 4). Regarding the inherent instability of the
enone, we thought that the carbonyl group of 13 should be
protected before creating the B-ring. To this end, 13 was
first reduced under the Luche’s conditions to give the al-
We envisaged that the failure met with the transformation lyic alcohol 14 in 79% yield as a diastereomeric mixture
of 6 into 7 through the DDQ oxidation might be attributed (76:24). The formation of two isomers in this case should
Synthesis 2011, No. 5, 715–722 © Thieme Stuttgart · New York

PAPER
Total Syntheses of Chamigrene Sesquiterpenoids
717
EtO2C
a
2
EtO2C
EtO2C
c
b
3
12
55%
(brsm: 72%)
82%
79%
OTBS
15 (75:25)
OH
14 (76:24)
O
13
53%
(brsm: 63.5%)
d
O
OH
EtO2C
HOH2C
e
OTBS
16 (74:26)
OTBS
17 (77:23)
44% over 3 steps
Br
Br
f, g
h
O
i
90%
61%
OTBS
OH
OTBS
19 (61:21:15:5)
18 (83:17)
20 (60:22:13:5)
j
Y
X
O
( )-1: X = Br, Y = H (26%)
( )-2: X = H, Y = Br (53%)
Scheme 4 Reagents and conditions: (a) DDQ (4.8 equiv), 2,6-lutidine (5.1 equiv), benzene, r.t., 24 h, 30% of 12 was recovered; (b)
CeCl3·7H2O (1.5 equiv), NaBH4 (1.8 equiv), MeOH–CH2Cl2 (1:1), 0 °C, 1 h; (c) TBDMSCl (1.5 equiv), imidazole (2.5 equiv), DMF, r.t., 12
h; (d) PdCl2 (0.25 equiv), CuCl (1.4 equiv), O2, DMF–THF–H2O, r.t., 20 h, 20% of 15 was recovered; (e) LiAlH4 (6 equiv), THF, 0 °C to r.t.,
5 h; (f) PDC (3 equiv), CH2Cl2, r.t., 12 h; (g) KOH (1.6 equiv, 1.0 M in MeOH), THF, r.t., 3 h; (h) piperidine (2.94 equiv), n-BuLi (2.98 equiv),
BrCH2(Ph)3P+Br– (3.02 equiv), THF, 0 °C, 80 min; (i) TBAF (2.0 equiv), THF, r.t., 2 h; (j) PDC (2.0 equiv), CH2Cl2, r.t., 1 h.
be inconsequential to the final targets since the newly cre- with trimethylphosphonium bromomethylide generated
ated stereogenic center would be eventually eliminated. from (bromomethyl)triphenylphosphonium bromide and
Compound 14 was then subjected to the protection with lithium piperidide17 proceeded smoothly to afford the bro-
tert-butyldimethylsilyl chloride (TBDMSCl) in the pres- momethylene derivative 19 as an isomeric mixture (E-ma-
ence of imidazole to provide the silyl ether 15 (75:25) in jor/Z-major/E-minor/Z-minor = 61:21:13:5) in 61% yield.
82% yield.
Without separation, 19 was subsequently subjected to the
deprotection with tetra-n-butylammonium fluoride
(TBAF) in THF to afford the alcohol 20 (60:22:13:5) in an
almost quantitative yield (90%). At the end, oxidation of
20 with PDC furnished the final targets ( )-1 and its 15-E-
epimer ( )-2 in 26% and 53% yield, respectively. The
spectral data (1H and 13C NMR) of both products were
found to agree well with those reported in the literature.5,7
In an effort to access the spirocyclic core, the Wacker ox-
idation of 15 was first conducted under the standard reac-
tion conditions,15 to afford the keto ester 16 in 53% yield
(74:26) (brsm: 63.5%), along with 20% of recovered start-
ing material. Exposure of 16 to lithium aluminum hydride
(LiAlH4) in THF resulted in the formation of diol 17 with
1
only two isomers (77:23) as detected by the H NMR
spectrum of the crude 17. Without purification, the crude In addition to 1 and 2, the total synthesis of ( )-majuscu-
17 was immediately subjected to oxidation with pyridini- lone (3), a 9-nor-chamigrene natural product, was also
um dichromate (PDC), and the resulting keto aldehyde in- readily achieved from the advanced intermediate 18 in
termediate, still as a crude mixture, underwent the aldol two steps. As shown in Scheme 5, deprotection of 18 with
condensation smoothly on treatment with KOH in a THF– TBAF followed by treatment of the resulting crude alco-
MeOH solution,16 to yield the key spiro intermediate 18 in hol with PDC completed the synthesis of 3 in 82% yield
44% yield over three steps.
over two steps, the spectroscopic data of which were
found to be identical to both natural5 and synthetic prod-
ucts.18
With 18 in place, the remainder of the synthesis then pro-
ceeded smoothly. As we expected, Wittig reaction of 18
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718
J.-L. Zhu et al.
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4-(tert-Butyldimethylsilyloxy)-1-cyano-2,6,6-trimethylcyclo-
O
hex-3-enecarboxylic Acid Ethyl Ester (6) and 1-[(1R*,2S*,6S*)-
4-(tert-Butyldimethylsilyloxy)-2,6-dimethylcyclohex-3-
enyl]ethanone (11)
a, b
18
82% over 2 steps
O
To a flame-dried 100 mL round-bottom flask were added anhyd
ZnCl2 (804 mg, 5.9 mmol) and anhyd toluene (20 mL). The result-
ing suspension was stirred under a N2 atmosphere for 20 min before
treating with a solution of 4 (904 mg, 5.9 mmol) in anhyd toluene
(4 mL). After stirring for an additional 30 min, a solution of diene
( )-3
Scheme 5 Reagents and conditions: (a) TBAF (5.0 equiv), THF,
r.t., 3 h; (b) PDC (2.0 equiv, based on 24), CH2Cl2, r.t., 2 h.
5
10 (5.85 g, 29.5 mmol) in anhyd toluene (8 mL) was added to the
In summary, we have accomplished the total synthesis of mixture. The mixture was then stirred at 80 °C for 20 h, cooled to
r.t., and diluted with EtOAc (120 mL). The solution was successive-
ly washed with H2O (2 × 30 mL) and brine (20 mL), dried
(Na2SO4), filtered, and concentrated under reduced pressure. Chro-
1 and 2 in 13 steps through a novel synthetic approach. Al-
though the ultimate synthesis did not strictly follow the
initially designed scheme, our original goals of using the
matographic purification of the crude residue on silica gel (hexane–
Diels–Alder reaction to construct the A-ring and the re-
ductive alkylation of the Diels–Alder adduct to create the
spiro quaternary center with the suitable functionalities
for accessing the B-ring have been well realized. In the
synthetic sequence, some intermediates were produced as
the isomeric mixtures, but the separations of them were
shown to be unnecessary since all of the isomers could be
eventually converted into either of the targets. In compar-
ison with the previously reported syntheses (overall
yields: 0.31%6 and 4.51%7 for 1, 2.12%6 and 0.45%7 for
2, respectively), the current study did not result in a signif-
icant improvement on the overall yields of 1 (0.85%) and
2 (1.74%), but the synthetic route developed by us appears
to be more general and the generality has been demon-
strated by the ready achievement of ( )-majusculone (3)
EtOAc, 100:1, 60:1, and 40:1) afforded 1111 (500 mg, generated
from 0.6 out of 5 equiv of 5) as a colorless sticky oil, followed by 6
(1.7 g, 82%) as a mixture of two isomers (50:50).
6
IR (neat): 2960, 2931, 2857, 2242, 1739, 1671, 1463, 1363, 1259,
1207, 838, 781 cm–1.
1H NMR (400 MHz, CDCl3): d (isomer 1) = 4.57 (br s, 1 H), 4.35–
4.16 (m, 2 H), 3.04–2.95 (m, 1 H), 2.42 (br d, J = 17.5 Hz, 1 H),
1.76 (d, J = 17.5 Hz, 1 H), 1.33 (t, J = 7.2 Hz, 3 H), 1.18–1.05 (m,
9 H), 0.90 (s, 9 H), 0.15 (s, 3 H), 0.14 (s, 3 H); d (isomer 2) = 4.51
(br s, 1 H), 4.35–4.16 (m, 2 H), 2.90–2.82 (m, 1 H), 2.41 (d, J = 17.3
Hz, 1 H), 1.74 (d, J = 17.3 Hz, 1 H), 1.30 (t, J = 7.1 Hz, 3 H), 1.24
(s, 3 H), 1.16–1.05 (m, 6 H), 0.90 (s, 9 H), 0.14 (s, 3 H), 0.13 (s, 3
H).
13C NMR (100 MHz, CDCl3): d (isomer 1) = 167.7, 148.7, 117.6,
from the intermediate leading to 1 and 2. The application 105.6, 62.4, 58.9, 43.0, 37.6, 33.4, 27.1, 25.6, 22.0, 18.2, 17.9, 14.2,
–4.3, –4.6; d (isomer 2) = 165.9, 149.3, 119.8, 103.7, 61.9, 57.2,
of the same strategy for the syntheses of other members of
chamigrene family is the focus of our ongoing studies.
40.5, 37.0, 35.9, 26.8, 26.0, 25.6, 17.9, 17.3, 14.2, –4.3, –4.5.
HRMS-FAB: m/z calcd for C19H34NO3Si [M + H]+: 352.2308;
found: 352.2298.
Unless otherwise noted, all starting materials and reagents were
purchased from commercial suppliers and used without further pu-
rification. THF was distilled from sodium-benzophenone; toluene,
benzene, CH2Cl2, and DMF were distilled from CaH2 before use.
TLC analysis and preparative TLC were performed on Macherey-
Nagel DC-Fertigplatten. Durasil-25 UV254 glass-backed plates, and
visualized by UV, or KMnO4 or I2 treatment. All of the products
were purified by flash chromatography on Merck Kieselgel 60 (Art.
9385) (230–400 mesh) or neutral aluminum oxide. IR spectra were
recorded on a Jasco FT/IR 410 spectrometer. NMR spectra (1H, 13C,
DEPT, NOESY) were recorded on a Bruker Avance DPE-400 or a
Bruker Avance DPE-600 spectrometer using CDCl3 or C6D6 as sol-
vent. High-resolution mass spectra (HRMS) and low-resolution
mass spectra (LRMS) were recorded on a Finnigan/Thermo Quest
MAT 95XL spectrometer in a fast atom bombardment (FAB) mod-
el.
1111
IR (neat): 2958, 2929, 1712, 1673, 1253, 1195, 1180, 838, 779 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.87 (dd, J = 5.2, 1.8 Hz, 1 H),
2.63 (dd, J = 12.3, 6.5 Hz, 1 H), 2.51 (dd, J = 10.9, 5.3 Hz, 1 H),
2.19–2.10 (m, 1 H), 2.14 (s, 3 H), 2.07 (dd, J = 17.0, 5.9 Hz, 1 H),
1.75–1.68 (m, 1 H), 0.92 (d, J = 4.7 Hz, 3 H), 0.91 (s, 9 H), 0.80 (d,
J = 7.0 Hz, 3 H), 0.13 (s, 3 H), 0.12 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 210.8, 149.2, 109.1, 57.4, 37.9,
30.7, 30.6, 25.6, 24.8, 19.8, 18.0, 17.9, –4.3, –4.4.
HRMS-FAB: m/z calcd for C16H31O2Si [M + H]+: 283.2093; found:
283.2098.
(1S*,2S*)-1-But-3-enyl-4-(tert-butyldimethylsilyloxy)-2,6,6-tri-
methylcyclohex-3-enecarboxylic Acid Ethyl Ester (12)
To a solution of 6 (548 mg, 1.56 mmol) in anhyd THF (10 mL) pre-
cooled at –45 °C was added a THF solution of lithium naphthalen-
ide (0.34 M, 16.1 mL, 5.46 mmol)13 via syringe under the protection
of a N2 atmosphere. The resulting dark green solution was stirred at
–45 °C for 30 min and successively treated with 4-bromobut-1-ene
(0.63 mL, 6.24 mmol) and HMPA (1.09 mL, 6.24 mmol). The reac-
tion mixture was stirred at r.t. for 12 h, then poured into sat. aq
NH4Cl (10 mL), and extracted with EtOAc (2 × 60 mL). The com-
bined organic extracts were washed with H2O (2 × 15 mL) and brine
(15 mL), and concentrated. Chromatographic purification of the
crude mixture on silica gel (hexane–EtOAc, 100:1) afforded 12 as a
colorless oil (416 mg, 70%).
Ethyl 2-Cyano-3-methylbut-2-enoate (4)
This known compound was prepared by a modified procedure as
follows. LiBr (7.82 g, 0.09 mol) and molecular sieves 3Å (300 mg)
were added to a mixture of ethyl cyanoacetate (2.0 g, 0.018 mol)
and acetone (60 mL). The suspension was refluxed for 18 h, cooled
to r.t., filtered, and concentrated in vacuo. The residue was diluted
with EtOAc (300 mL), washed with H2O (2 × 50 mL) and brine (50
mL), and concentrated. The crude mixture was subjected to chro-
matographic purification on silica gel (hexane–EtOAc, 20:1) to
yield 4 (1.82 g, 66%).
IR (neat): 2958, 2929, 2902, 2857, 1735, 1673, 1641, 1149, 1130,
989, 939 cm–1.
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PAPER
Total Syntheses of Chamigrene Sesquiterpenoids
719
1H NMR [600 MHz, CDCl3 + C6D6 (1:1)]: d = 5.86–5.77 (ddt,
J = 17.3, 10.2, 6.6 Hz, 1 H), 5.05 (dm, J = 17.3 Hz, 1 H), 4.96 (dm,
J = 10.2 Hz, 1 H), 4.60 (br s, 1 H), 4.10–3.97 (m, 2 H), 2.47 (d,
J = 17.0 Hz, 1 H), 2.36–2.30 (m, 1 H), 2.29–2.19 (m, 2 H), 1.92–
1.85 (m, 1 H), 1.70–1.64 (m, 1 H), 1.60 (d, J = 17.0 Hz, 1 H), 1.12
(t, J = 7.0 Hz, 3 H), 1.05 (d, J = 7.0 Hz, 3 H), 1.03 (s, 3 H), 0.97 (br
s, 12 H), 0.18 (br s, 6 H).
13C NMR (100 MHz, CDCl3): d = 173.6, 148.0, 139.8, 114.1, 108.6,
59.6, 53.9, 44.6, 37.5, 35.9, 33.9, 31.8, 26.9, 25.8, 25.7, 18.8, 18.0,
14.4, –4.2, –4.4.
(1R*)-1-But-3-enyl-4-(tert-butyldimethylsilyloxy)-2,6,6-tri-
methylcyclohex-2-enecarboxylic Acid Ethyl Ester (15)
tert-Butyldimethylsilyl chloride (143 mg, 0.95 mmol) and imida-
zole (108 mg, 1.58 mmol) were successively added to a solution of
14 (168 mg, 0.63 mmol) in anhyd DMF (13 mL) under a N2 atmo-
sphere. The mixture was stirred for 12 h, then quenched with H2O
(13 mL), and extracted with EtOAc (2 × 40 mL). The combined or-
ganic layers were washed with H2O (10 mL) and brine (10 mL), and
concentrated. Flash chromatography of the crude residue on silica
gel (hexane–EtOAc, 100:1, 50:1, and 20:1) afforded 15 (197 mg,
82%) as a mixture of two isomers (75:25).
HRMS-FAB: m/z calcd for C22H41O3Si [M + H]+: 381.2825; found:
381.2815.
IR (neat): 2958, 2929, 1724, 1675, 1251, 1213, 1174, 1070, 836,
777 cm–1.
(1R*)-1-But-3-enyl-2,6,6-trimethyl-4-oxocyclohex-2-enecar-
boxylic Acid Ethyl Ester (13)
1H NMR (400 MHz, C6D6): d (major) = 5.77 (br s, 1 H), 5.67 (dm,
J = 16.8 Hz, 1 H), 4.94 (dm, J = 16.8 Hz, 1 H), 4.89 (dm, J = 10.2
Hz, 1 H), 4.42–4.34 (tm, J = 9.0 Hz, 1 H), 4.00–3.81 (m, 2 H), 2.20–
1.80 (m, 5 H), 1.77 (t, J = 1.4 Hz, 3 H), 1.59 (ddd, J = 12.5, 6.5, 1.0
Hz, 1 H), 1.11 (s, 3 H), 0.99 (s, 12 H), 0.92 (t, J = 7.1 Hz, 3 H), 0.10
(s, 3 H), 0.09 (s, 3 H); d (minor) = 5.79 (dm, J = 17.1 Hz, 1 H), 5.76
(br s, 1 H), 5.06 (dm, J = 17.1 Hz, 1 H), 4.99–4.94 (m, 1 H), 4.22–
4.16 (m, 1 H), 4.00–3.81 (m, 2 H), 2.20–1.80 (m, 5 H), 1.72 (t,
J = 1.4 Hz, 3 H), 1.68 (dd, J = 13.5, 5.9 Hz, 1 H), 1.15 (s, 3 H), 0.99
(s, 12 H), 0.91 (t, J = 7.1 Hz, 3 H), 0.11 (s, 3 H), 0.09 (s, 3 H).
13C NMR (100 MHz, C6D6): d (major) = 173.2, 138.9, 134.6, 130.7,
114.3, 66.3, 59.8, 57.2, 45.1, 36.8, 33.2, 31.3, 27.1, 26.3, 25.9, 21.7,
18.2, 13.9, –4.5, –4.6; d (minor) = 173.4, 139.3, 135.3, 129.0, 114.2,
65.4, 59.9, 57.2, 44.2, 36.1, 32.6, 31.4, 30.0, 28.2, 25.9, 22.1, 18.1,
13.9, –4.4, –4.6.
To a solution of DDQ (721 mg, 3.18 mmol) in anhyd benzene (7
mL) was added dropwise 2,6-lutidine (0.39 mL, 3.37 mmol) under
a N2 atmosphere. The resulting dark mixture was stirred for 20 min
before adding a solution of 12 (252 mg, 0.66mmol) in anhyd ben-
zene (2 mL). The reaction mixture was stirred at r.t. for 24 h, then
filtered through a Celite pad, washed with EtOAc (20 mL), and con-
centrated. The crude residue was subjected to chromatographic pu-
rification on silica gel (hexane–EtOAc, 40:1, 5:1) to provide 30% of
recovered 12 (76 mg), followed by 55% (brsm: 72%) of 13 (96 mg)
as a yellowish oil.
IR (neat): 2969, 2917, 1724, 1671, 1641, 1220, 1205, 1025 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.00 (s, 1 H), 5.81–5.71 (dm,
J = 17.1 Hz, 1 H), 5.03 (br d, J = 17.1 Hz, 1 H), 4.97 (br d, J = 10.3
Hz, 1 H), 4.30–4.14 (m, 2 H), 2.54 (d, J = 17.2 Hz, 1 H), 2.17 (d,
J = 17.2 Hz, 1 H), 2.17–2.00 (m, 3 H), 2.01 (s, 3 H), 1.96–1.91 (m,
1 H), 1.30 (t, J = 7.1 Hz, 3 H), 1.12 (s, 3 H), 1.02 (s, 3 H).
HRMS-FAB: m/z calcd for C22H41O3Si [M + H]+: 381.2825; found:
381.2837.
(1R*)-4-(tert-Butyldimethylsilyloxy)-2,6,6-trimethyl-1-(3-oxo-
butyl)cyclohex-2-enecarboxylic Acid Ethyl Ester (16)
To a solution of 15 (179 mg, 0.47 mmol) in DMF–THF–H2O (4:1:1,
6 mL) were successively added CuCl (65 mg, 0.66 mmol) and PdCl2
(21 mg, 0.12 mmol). O2 gas was bubbled through the mixture for 15
min and the mixture was stirred under an atmosphere of O2 for 18
h. The mixture was then diluted with sat. aq NH4Cl (6 mL) and ex-
tracted with EtOAc (2 × 50 mL). The combined organic layers were
washed with H2O (2 × 10 mL) and brine (15 mL). After concentra-
tion, the crude mixture was subjected to flash chromatography on
silica gel (hexane–EtOAc, 20:1, 10:1) to afford 16 as a pale yellow
oil (99 mg, 53%, 74:26) (brsm: 64%), along with 20% of recovered
15 (36 mg).
13C NMR (100 MHz, CDCl3): d = 198.0, 171.8, 160.7, 137.9, 128.5,
115.2, 60.9, 59.1, 49.7, 39.4, 33.4, 30.7, 27.1, 25.5, 24.0, 14.2.
HRMS-FAB: m/z calcd for C16H25O3 [M + H]+: 265.1804; found:
265.1805.
(1R*)-1-But-3-enyl-4-hydroxy-2,6,6-trimethylcyclohex-2-ene-
carboxylic Acid Ethyl Ester (14)
To a solution of 13 (219 mg, 0.83 mmol) in MeOH–CH2Cl2 (1:1, 16
mL) at 0 °C was added CeCl3·7H2O (463 mg, 1.24 mmol) and
NaBH4 (56 mg, 1.49 mmol). The reaction mixture was stirred at the
same temperature for 1 h, then diluted with EtOAc (80 mL), and
washed with H2O (2 × 15 mL) and brine (10 mL). After concentra-
tion, the crude mixture was purified by flash chromatography on sil-
ica gel (hexane–EtOAc, 5:1) to furnish 14 (174 mg, 79%) as an
isomeric mixture (76:24).
IR (neat): 2954, 2930, 2857, 1720, 1658, 1234, 1172, 1072, 836,
775 cm–1.
1H NMR (400 MHz, C6D6): d (major) = 5.74 (br s, 1 H), 4.42–4.31
(tm, J = 8.3 Hz, 1 H), 4.00–3.80 (m, 2 H), 2.45–2.05 (m, 4 H), 1.75
(br s, 3 H), 1.73–1.55 (m, 2 H), 1.55 (s, 3 H), 1.08 (s, 3 H), 0.98 (s,
9 H), 0.97 (s, 3 H), 0.91 (t, J = 7.2 Hz, 3 H), 0.09 (s, 6 H); d (minor)
= 5.66 (br s, 1 H), 4.25–4.18 (m, 1 H), 4.00–3.80 (m, 2 H), 2.45–
2.05 (m, 3 H), 1.91 (dd, J = 13.3, 6.3 Hz, 1 H), 1.71–1.57 (m, 2 H),
1.68 (s, 3 H), 1.64 (s, 3 H), 1.09 (s, 3 H), 0.99 (s, 9 H), 0.91 (s, 3 H),
0.90 (t, J = 7.1 Hz, 3 H), 0.12 (s, 3 H), 0.10 (s, 3 H).
13C NMR (100 MHz, C6D6): d (major) = 205.3, 173.0, 134.5, 130.8,
66.2, 59.9, 56.7, 45.0, 40.5, 36.7, 29.2, 27.1, 26.8, 26.4, 25.9, 21.5,
18.2, 13.9, –4.5, –4.6; d (minor) = 205.5, 173.3, 134.9, 129.7, 65.5,
60.1, 56.7, 44.2, 41.0, 36.5, 29.3, 28.0, 26.2, 25.9, 25.5, 22.0, 18.1,
13.9, –4.4, –4.5.
IR (neat): 3450, 2960, 2931, 1731, 1673, 1149, 1033, 838, 779 cm–1.
1H NMR (400 MHz, CDCl3): d (major) = 5.85–5.70 (m, 1 H), 5.68
(br s, 1 H), 5.02 (dm, J = 17.0 Hz, 1 H), 4.93 (dm, J = 10.2 Hz, 1
H), 4.30–4.21 (tm, J = 9.0 Hz, 1 H), 4.24–4.04 (m, 2 H), 2.19–1.75
(m, 5 H), 1.73 (t, J = 1.5 Hz, 3 H), 1.64–1.57 (m, 1 H), 1.54 (d,
J = 10.3 Hz, 1 H), 1.26 (t, J = 7.0 Hz, 3 H), 1.10 (s, 3 H), 0.88 (s, 3
H); d (minor) = 5.85–5.70 (m, 1 H), 5.69 (br s, 1 H), 5.02 (dm,
J = 17.0 Hz, 1 H), 4.93 (dm, J = 10.2 Hz, 1 H), 4.30–4.21 (tm,
J = 9.0 Hz, 1 H), 4.24–4.04 (m, 2 H), 2.19–1.75 (m, 5 H), 1.70 (t,
J = 1.5 Hz, 3 H), 1.64–1.57 (m, 1 H), 1.51 (d, J = 10.0 Hz, 1 H),
1.27 (t, J = 7.0 Hz, 3 H), 1.01 (s, 3 H), 1.00 (s, 3 H).
13C NMR (100 MHz, C6D6): d (major) = 173.2, 138.9, 134.8, 130.4,
114.4, 64.9, 59.8, 57.2, 44.6, 36.6, 33.1, 31.4, 26.9, 26.2, 21.6, 13.9;
d (minor) = 173.5, 139.3, 135.7, 129.3, 114.2, 64.5, 60.0, 57.2, 44.0,
36.3, 32.2, 31.4, 28.0, 25.6, 22.0, 13.9.
LRMS-FAB: m/z calcd for C21H37O4Si [M – CH3]+: 381; found:
381.
HRMS-FAB: m/z calcd for C16H27O3 [M + H]+: 267.1960; found:
267.1967.
Synthesis 2011, No. 5, 715–722 © Thieme Stuttgart · New York

720
J.-L. Zhu et al.
PAPER
(6R*)-9-(tert-Butyldimethylsilyloxy)-7,11,11-trimethyl-
spiro[5.5]undeca-1,7-dien-3-one (18)
IR (neat): 3066, 3027, 2956, 2856, 1735, 1654, 1577, 1257, 1068,
833, 777 cm–1.
A solution of 16 (137 mg, 0.35 mmol) in anhyd THF (3 mL) was
added to a stirred suspension of LiAlH4 (79 mg, 2.07 mmol) in an-
hyd THF (7 mL) under N2. The mixture was stirred at the same tem-
perature for 5 h and slowly diluted with EtOAc (80 mL), and
washed with aq 5% NaOH (15 mL), H2O (2 × 15 mL) and brine (15
mL), dried (Na2SO4), and concentrated to afford 139 mg of the
crude diol 17 (77:23).
1H NMR (400 MHz, CDCl3): d (E-isomer, major) = 6.27 (d,
J = 10.4 Hz, 1 H), 6.13 (br s, 1 H), 5.53 (d, J = 10.4 Hz, 1 H), 5.40
(br s, 1 H), 4.27–4.19 (m, 1 H), 2.66–2.28 (m, 2 H), 2.06–1.90 (m,
2 H), 1.76–1.51 (m, 2 H), 1.58 (br s, 3 H), 0.96–0.85 (m, 15 H), 0.09
(s, 3 H), 0.08 (s, 3 H); d (Z-isomer, major) = 6.69 (d, J = 10.5 Hz, 1
H), 5.88 (br s, 1 H), 5.75 (d, J = 10.5 Hz, 1 H), 5.36 (br s, 1 H), 4.27–
4.19 (m, 1 H), 2.66–2.28 (m, 2 H), 2.06–1.90 (m, 2 H), 1.76–1.51
(m, 5 H), 0.96–0.85 (m, 15 H), 0.07 (s, 3 H), 0.06 (s, 3 H); d (E-iso-
mer, minor) = 6.19 (d, J = 10.3 Hz, 1 H), 6.11 (br s, 1 H), 5.64 (d,
J = 10.3 Hz, 1 H), 5.34–5.33 (m, 1 H), 4.27–4.19 (m, 1 H), 2.66–
2.28 (m, 2 H), 2.06–1.90 (m, 2 H), 1.76–1.51 (m, 5 H), 0.96–0.85
(m, 15 H), 0.10–0.06 (m, 6 H); d (Z-isomer, minor) = 6.60 (d,
J = 10.4 Hz, 1 H), 6.33 (d, J = 10.4 Hz, 1 H), 5.83 (br s, 1 H), 5.34
(m, 1 H), 4.27–4.19 (m, 1 H), 2.66–2.28 (m, 2 H), 2.06–1.90 (m, 2
H), 1.76–1.51 (m, 5 H), 0.96–0.85 (m, 15 H), 0.10–0.06 (m, 3 H),
0.05 (s, 3 H).
17
1H NMR (400 MHz, CDCl3): d (major) = 5.53 (br s, 1 H), 4.24–4.16
(m, 1 H), 3.77–3.59 (m, 3 H), 1.73 (br s, 3 H), 1.67–1.38 (m, 8 H),
1.20 (d, J = 6.2 Hz, 3 H), 1.12–0.94 (m, 6 H), 0.90 (s, 9 H), 0.07 (s,
3 H), 0.06 (s, 3 H); d (minor) = 5.64 (br s, 1 H), 4.24–4.16 (m, 1 H),
3.77–3.59 (m, 3 H), 1.75 (br s, 3 H), 1.67–1.38 (m, 8 H), 1.19 (d,
J = 5.6 Hz, 3 H), 1.12–0.94 (m, 6 H), 0.89 (s, 9 H), 0.07 (s, 3 H),
0.05 (s, 3 H).
The crude 17 was dissolved in anhyd CH2Cl2 (10 mL) and treated
with pyridinium dichromate (395 mg, 1.05 mmol). The reaction
mixture was stirred under N2 for 12 h at r.t., then filtered through a
Celite pad, washed with CH2Cl2 (2 × 5 mL), and concentrated.
Without further purification, the crude keto aldehyde intermediate
was immediately dissolved in THF (4 mL) and added to methanolic
KOH solution (1.0 M, 0.56 mL, 0.56 mmol). The reaction mixture
was stirred at r.t. for 3 h, then diluted with EtOAc (60 mL), washed
with H2O (2 × 10 mL) and brine (10 mL), and concentrated. The
crude residue was purified by flash chromatography on silica gel
(hexane–EtOAc, 8:1) to provide 18 (83:17) as a pale yellow oil (51
mg, 44% from 12).
13C NMR (100 MHz, CDCl3): d (E-isomer, major) = 140.2, 138.9,
133.2, 128.6, 126.6, 105.2, 66.7, 45.6, 42.8, 38.8, 29.7, 27.4, 26.3,
26.0, 24.7, 21.1, 18.3, –4.4, –4.5; d (Z-isomer, major) = 140.2,
136.8, 134.1, 126.8, 126.5, 101.2, 66.6, 46.0, 42.9, 38.8, 29.6, 29.3,
29.1, 27.7, 26.0, 21.3, 14.1, –4.5; d (part of the signals of other two
isomers) = 139.3, 138.7, 137.8, 136.7, 133.0, 129.6, 128.4, 127.3,
127.2, 126.2, 110.9, 104.9, 66.1, 45.0, 43.3, 37.7, 31.9, 29.5, 25.4,
24.2, 22.7, 22.0, 18.3.
LRMS-FAB: m/z calcd for C21H3679BrOSi [M + H]+: 411; found:
411.
(6R*)-9-Bromomethylene-1,5,5-trimethylspiro[5.5]undeca-1,7-
dien-3-ol (20)
IR (neat): 2958, 2927, 1718, 1685, 1612, 1540, 1259, 1070, 1016,
833, 775 cm–1.
To a solution of 19 (63 mg, 0.15 mmol) in THF (1.5 mL) was added
Bu4NF (75 wt% in H2O, 0.082 mL, 0.30 mmol) The mixture was
stirred at r.t. for 1 h, then diluted with EtOAc (20 mL), and washed
with H2O (2 × 5 mL) and brine (5 mL). After concentration, the
crude mixture was purified by flash chromatography on silica gel
(hexane–EtOAc, 10:1) to afford 20 as a colorless oil (41 mg, 90%,
60:22:13:5).
1H NMR (400 MHz, CDCl3): d (major) = 6.62 (dd, J = 10.6, 0.9 Hz,
1 H), 6.17 (d, J = 10.6 Hz, 1 H), 5.48 (br s, 1 H), 4.32–4.21 (m, 1
H), 2.67–2.40 (m, 2 H), 2.27–2.00 (m, 2 H), 1.66 (br s, 3 H), 1.99–
1.55 (m, 2 H), 1.03 (s, 3 H), 0.98 (s, 3 H), 0.91 (s, 9 H), 0.07 (s, 3
H), 0.06 (s, 3 H); d (minor) = 6.74 (dd, J = 10.4, 1.0 Hz, 1 H), 6.09
(d, J = 10.4 Hz, 1 H), 5.40 (br s, 1 H), 4.45–4.35 (m, 1 H), 2.67–
2.40 (m, 2 H), 2.17–1.80 (m, 2 H), 1.74 (br s, 3 H), 1.80–1.43 (m, 2
H), 1.01 (s, 3 H), 0.96 (s, 3 H), 0.89 (s, 9 H), 0.07 (s, 3 H), 0.06 (s,
3 H).
IR (neat): 3345, 2952, 2923, 1733, 1716, 1654, 1558, 1243, 1025,
786, 738 cm–1.
1H NMR (400 MHz, CDCl3): d (E-isomer, major) = 6.28 (d,
J = 10.4 Hz, 1 H), 6.14 (br s, 1 H), 5.53 (d, J = 10.4 Hz, 1 H), 5.50
(t, J = 1.1 Hz, 1 H), 4.26–4.18 (m, 1 H), 2.63–2.54 (dm, J = 17.0
Hz, 1 H), 2.52–2.34 (m, 1 H), 2.01–1.90 (m, 1 H), 1.72–1.62 (m, 5
H), 1.61 (br s, 3 H), 0.95 (s, 1 H), 0.94 (s, 1 H); d (Z-isomer,
major) = 6.70 (d, J = 10.5 Hz, 1 H), 5.90 (br s, 1 H), 5.53 (d,
J = 10.5 Hz, 1 H), 5.51–5.54 (m, 1 H), 4.32–4.18 (m, 1 H), 2.63–
2.34 (m, 2 H), 2.01–1.83 (m, 1 H), 1.80–1.59 (m, 8 H), 0.97 (s, 3 H),
0.95 (s, 3 H); d (E-isomer, minor) = 6.23 (d, J = 10.3 Hz, 1 H), 6.07
(br s, 1 H), 5.60 (d, J = 10.3 Hz, 1 H), 4.32–4.18 (m, 1 H), 263–2.34
(m, 2 H), 2.01–1.83 (m, 1 H), 1.80–1.59 (m, 8 H), 0.93 (s, 3 H), 0.92
(s, 3 H); d (Z-isomer, minor) = 6.63 (d, J = 10.5 Hz, 1 H), 5.81 (br
s, 1 H), 5.68 (d, J = 10.7 Hz, 1 H), 4.32–4.26 (m, 1 H), 2.63–2.34
(m, 2 H), 2.01–1.83 (m, 1 H), 1.80–1.59 (m, 8 H), 0.90 (s, 3 H), 0.88
(s, 3 H).
13C NMR (100 MHz, CDCl3): d (E-isomer, major) = 141.8, 138.7,
132.8, 128.8, 125.6, 105.5, 66.0, 45.8, 42.6, 38.8, 29.7, 27.3, 26.3,
24.5, 21.2; d (Z-isomer, major) = 136.4, 133.5, 127.8, 126.9, 126.2,
101.5, 65.9, 43.1, 38.8, 31.9, 29.3, 29.2, 27.9, 22.7, 14.1; d (part of
the signals of other two isomers) = 136.7, 136.5, 125.5, 65.5, 29.6,
29.5, 21.3, 14.0.
13C NMR (100 MHz, C6D6): d (major) = 196.4, 151.5, 138.3, 131.0,
128.7, 66.2, 45.5, 42.7, 38.8, 35.6, 27.8, 26.7, 25.9, 24.2, 20.9, 18.1,
–4.6; d (minor) = 196.2, 151.6, 137.4, 129.8, 126.4, 65.8, 44.9, 42.5,
37.7, 35.6, 25.9, 23.8, 22.0, 21.4, 21.1, 18.0, –4.6, –4.8.
HRMS-FAB: m/z calcd for C20H34O2Si [M + H]+: 335.2406; found:
335.2395.
(6R*)-(9-Bromomethylene-1,5,5-trimethylspiro[5.5]undeca-
1,7-dien-3-yloxy)-tert-butyldimethylsilane (19)
To a stirred solution of piperidine (0.067 mL, 0.68 mmol) in anhyd
THF (2 mL) at 0 °C was added dropwise n-BuLi (1.6 M in hexane,
0.43 mL, 0.685 mmol) under a N2 atmosphere. The mixture was
stirred at 0 °C for 20 min and was dropwise added to a stirred sus-
pension of (bromomethyl)triphenylphosphonium bromide (303
mg, 0.69 mmol) in anhyd THF (2 mL) via a syringe. The resulting
orange solution was stirred for 20 min at 0 °C and a THF (1.5 mL)
solution of 18 (76 mg, 0.23 mmol) was added in one portion. After
stirring at 0 °C for 3 h, the mixture was diluted with EtOAc (70 mL)
and washed with H2O (2 × 10 mL) and brine (10 mL), and concen-
trated in vacuo. The crude residue was purified by flash chromatog-
raphy on silica gel (hexane, hexane–EtOAc, 100:1) to give 19 (57
mg, 61%) as a mixture of four isomers (61:21:15:5).
HRMS-FAB: m/z calcd for C15H2079BrO [M – H]+: 295.0698;
found: 295.0707.
Synthesis 2011, No. 5, 715–722 © Thieme Stuttgart · New York

PAPER
Total Syntheses of Chamigrene Sesquiterpenoids
721
( )-(Z)-9-(Bromomethylene)-1,5,5-trimethylspiro[5.5]undeca-
1,7-dien-3-one [( )-1] and ( )-(E)-9-(Bromomethylene)-1,5,5-
trimethylspiro[5.5]undeca-1,7-dien-3-one [( )-2]
1H NMR (400 MHz, CDCl3):18 d = 6.77 (d, J = 10.8 Hz, 1 H), 6.29
(d, J = 10.8 Hz, 1 H), 5.98 (s, 1 H), 2.68–2.30 (m, 6 H), 2.14–2.06
(m, 1 H), 1.98 (s, 3 H), 1.11 (d, J = 4.4 Hz, 6 H).
PDC (53 mg, 0.14 mmol) was added to a stirred solution of 20 (21
mg, 0.071 mmol) in anhyd CH2Cl2 (1 mL) under a N2 atmosphere.
The reaction mixture was stirred at r.t. for 1 h, then filtered through
a Celite pad, washed with CH2Cl2 (5 mL), and concentrated. The
crude mixture was purified by preparative TLC (hexane–EtOAc,
10:1) to afford ( )-1 (5 mg, 26%) and ( )-2 (11 mg, 53%) as color-
less oils.
13C NMR (100 MHz, CDCl3): d = 197.6, 197.4, 163.1, 149.8, 132.0,
127.4, 48.6, 47.4, 41.0, 35.1, 27.5, 25.6, 25.0, 23.1.
13C NMR (25 MHz, CDCl3):5 d = 197.5, 197.3, 163.0, 149.8, 131.9,
127.4, 48.6, 47.4, 41.0, 35.1, 27.5, 25.5, 25.0, 23.0.
HRMS-FAB: m/z calcd for C14H19O2 [M + H]+: 219.1385; found:
219.1387.
( )-1
IR (neat): 3066, 2871, 2852, 1668, 1616, 831 cm–1.
Supporting Information for this article is available online at
1H NMR (400 MHz, CDCl3): d = 6.82 (dd, J = 10.6, 1.0 Hz, 1 H),
6.01 (br s, 1 H), 5.90 (br s, 1 H), 5.88 (br d, J = 10.6 Hz, 1 H), 2.57–
2.40 (m, 3 H), 2.30–2.20 (dm, J = 16.8 Hz, 1 H), 2.15–2.04 (m, 1
H), 1.90 (d, J = 1.2 Hz, 3 H), 1.78–1.69 (m, 1 H), 1.06 (s, 3 H), 1.03
(s, 3 H).
1H NMR (90 MHz, CDCl3):7 d = 6.82 (dd, J = 10.8, 1.0 Hz, 1 H),
6.00 (br s, 1 H), 5.89 (br s, 1 H), 5.88 (br d, J = 10.8 Hz, 1 H), 2.6–
1.0 (m, 6 H), 1.88 (d, J = 1.1 Hz, 3 H), 1.04 (s, 3 H), 1.00 (s, 3 H).
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
We are grateful to the National Science Council of Republic of
China (Taiwan) and National Dong Hwa University for financial
support.
13C NMR (100 MHz, CDCl3): d = 198.0, 166.2, 135.5, 133.8, 128.8,
126.8, 103.4, 49.2, 47.2, 40.8, 29.1, 28.6, 25.4, 24.7, 23.7.
References
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893. (f) Rashid, M. A.; Gustafson, K. R.; Gardellina, J. H.;
Boyd, M. R. Nat. Prod. Lett. 1995, 6, 255. (g) Francisco,
M. E. Y.; Erickson, K. L. J. Nat. Prod. 2001, 64, 790.
(h) Davyt, D.; Fernandez, R.; Suescun, L.; Mombrú, A. W.;
Saldaña, J.; Dominguez, L.; Coll, J.; Fujii, M. T.; Manta, M.
J. Nat. Prod. 2001, 64, 1552. (i)Dorta, E.;Díaz-Marrero, A.
R.; Cueto, M.; D’Croz, L.; Maté, J. L.; Darias, J.
13C NMR (25 MHz, CDCl3):5 d = 198.0, 165.9, 135.4, 133.4, 128.1,
126.2, 102.9, 48.7, 47.6, 40.3, 28.5, 28.5, 25.4, 24.8, 23.3.
LRMS-FAB: m/z calcd for C15H2079BrO [M + H]+: 295 and
C15H2081BrO [M + H]+: 297; found: 297.
( )-2
IR (neat): 3029, 2962, 2933, 1668, 1577, 794 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.39 (d, J = 10.3 Hz, 1 H), 6.25
(br s, 1 H), 5.90 (d, J = 1.0 Hz, 1 H), 5.68 (d, J = 10.3 Hz, 1 H),
2.70–2.58 (m, 1 H), 2.56–2.42 (m, 2 H), 2.32–2.18 (dm, J = 16.6
Hz, 1 H), 2.14–2.03 (m, 1 H), 1.88 (d, J = 1.0 Hz, 3 H), 1.82–1.72
(m, 1 H), 1.04 (s, 3 H), 1.02 (s, 3 H).
1H NMR (90 MHz, CDCl3):7 d = 6.38 (d, J = 10.6 Hz, 1 H), 6.23 (br
s, 1 H), 5.88 (q, J = 1.0 Hz, 1 H), 5.66 (d, J = 10.6 Hz, 1 H), 1.0–2.7
(m, 6 H), 1.87 (d, J = 1.0 Hz, 3 H), 0.99 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 198.2, 166.3, 137.9, 130.3, 129.9,
126.5, 107.1, 48.8, 47.5, 40.3, 27.5, 25.7, 25.6, 25.0, 23.4.
13C NMR (25 MHz, CDCl3):5 d = 198.1, 166.1, 137.7, 130.1, 129.7,
126.2, 107.0, 48.6, 47.3, 40.2, 27.3, 25.5, 25.4, 24.9, 23.3.
Tetrahedron Lett. 2004, 45, 7065. (j) Chokpaiboon, S.;
Sommit, D.; Teerawatananond, T.; Muangsin, N.;
Bunyapaiboonsri, T.; Pudhom, K. J. Nat. Prod. 2010, 73,
1005; and references cited therein.
(2) (a) Tatsuo, H.; Snader, K. M. US Patent 4942180, 1990.
(b) Vairappan, C. S. Biomol. Eng. 2003, 20, 255. (c) König,
G. M.; Wright, A. D. J. Nat. Prod. 1997, 60, 967; and
references cited therein.
HRMS-FAB: m/z calcd for C15H2079BrO [M + H]+: 295.0698;
found: 295.0691.
(3) For lead references on the total syntheses of chamigrenes,
see: (a) Wolinsky, L. E.; Faulkner, D. J. J. Org. Chem. 1976,
41, 597. (b) Martin, J. D.; Pérez, C.; Ravelo, J. L. J. Am.
Chem. Soc. 1986, 108, 7801. (c) White, D. E.; Stewart, I. C.;
Crubbs, R. H.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130,
810. (d) Cui, Q.; Kang, L.; Yang, H. S.; Xu, X. H. Chin.
Chem. Lett. 2009, 554. (e) Srikrishna, A.; Lakshmi, B. V.;
Mathews, M. Tetrahedron Lett. 2006, 47, 2103.
( )-Majusculone [( )-3]
To a solution of 18 (54 mg, 0.16 mmol) in THF (2 mL) was added
Bu4NF (75 wt% in H2O, 0.22 mL, 0.80 mmol). The mixture was
stirred at r.t. for 3 h, then diluted with EtOAc (40 mL), and washed
with H2O (3 × 10 mL) and brine (10 mL). After concentration, the
crude alcohol was dissolved in anhyd CH2Cl2 (2 mL) and treated
with PDC (121 mg, 0.32 mmol). The mixture was stirred at r.t. for
2 h, then filtered through a Celite pad, washed with CH2Cl2 (10
mL), and concentrated. Chromatographic purification of the crude
residue on silica gel (hexane, hexane–EtOAc, 2:1) afforded ( )-3 as
a waxy solid (29 mg, 82% over two steps).
(f) Srikrishna, A.; Babu, R. R. Tetrahedron 2008, 64,
10501. (g) White, D. E.; Stewart, I. C.; Seashore-Ludlow, B.
A.; Grubbs, R. H.; Stoltz, B. M. Tetrahedron 2010, 66, 4668;
and references cited therein.
IR (neat): 3032, 2965, 1666, 1614, 904, 774 cm–1.
(4) (a) Suzuki, M.; Kurosawa, E. Tetrahedron Lett. 1978, 4805.
(b) Suzuki, M.; Furusaki, A.; Hashiba, N.; Kurosawa, E.
Tetrahedron Lett. 1979, 20, 879.
(5) Suzuki, M.; Kurasawa, E.; Kurata, K. Bull. Chem. Soc. Jpn.
1987, 60, 3795.
1H NMR (400 MHz, CDCl3): d = 6.77 (d, J = 10.6 Hz, 1 H), 6.29 (d,
J = 10.6 Hz, 1 H), 5.97 (br s, 1 H), 2.66–2.30 (m, 5 H), 2.11–2.05
(m, 1 H), 1.96 (br s, 3 H), 1.11 (s, 3 H), 1.10 (s, 3 H).
(6) Iwata, C.; Miyashita, K.; Koga, Y.; Shinoo, Y.; Yamada, M.;
Tanaka, Y. Chem. Pharm. Bull. 1983, 31, 2308.
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PAPER
(7) Niwa, H.; Yoshida, Y.; Hasegawa, T.; Yamada, K.
Tetrahedron 1991, 47, 2155.
(8) Amancha, P. K.; Lai, Y. C.; Chen, I. C.; Liu, H. J.; Zhu, J. L.
Tetrahedron 2010, 66, 871.
(12) (a) Fleming, I.; Paterson, I. Synthesis 1979, 736.
(b) Kakiuchi, K.; Nakamura, I.; Matsuo, F.; Nakata, M.;
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3318.
(9) Lynch, E. R.; McCall, E. B. J. Chem. Soc. 1960, 1254.
(10) Liu, H. J.; Wang, D. X.; Kim, J. B.; Browne, E. N. C.; Wang,
Y. Can. J. Chem. 1997, 75, 899.
(13) For preparing a stock solution of LN, see: Liu, H. J.; Yip, J.;
Shia, K. S. Tetrahedron Lett. 1997, 38, 2253.
(14) Zoretic, P. A.; Chambers, R. J. J. Org. Chem. 1985, 50,
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(15) Schmdit, D. R.; Park, P. K.; Leighton, J. L. Org. Lett. 2003,
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1988, 36, 2872.
(18) Taber, D. F.; Sikkander, M. I.; Storck, P. H. J. Org. Chem.
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(11) To resolve the stereochemistry of 11, we further converted it
into (3S*,5S*)-3,5-dimethyl-4-acetylcyclohexanone by
treating with TBAF in THF. Given with the fixed trans
relationship between the C-4 acetyl and C-3 methyl groups,
the relative steric relationships between the C-5 methyl and
the C-4 acetyl groups could be deduced from the coupling
constants of C-4 methine proton at d = 2.72 (dd, J = 9.1, 3.7
Hz) from the 1H NMR spectrum (see Supporting
Information).
Synthesis 2011, No. 5, 715–722 © Thieme Stuttgart · New York