Synthesis toward the lindenane-type sesquiterpenoid monomer of Chlorahololide A

Article abstract of DOI:10.1002/cjoc.201200695

An investigation toward the synthesis of the lindenane-type sesquiterpenoid monomer of Chlorahololide A using a Yamamoto rearrangement, intramolecular cyclopropanation reaction, 1,3-dipolar cyclization, and an intramolecular Heck reaction gave the pivotal intermediate 20. This gives a practical synthetic route that could generate further natural products of the Chloranthaceae family. Starting from alcohol (2), and on the basis of Yamamoto rearrangement, intramolecular cyclopropanation reaction, 1,3-dipolar cyclization, and intramolecular Heck reaction, the Lindenane-type sesquiterpenoid fragement (20) of Chlorahololide A (1) has been synthesized in a linear sequence of 21 steps and an overall yield of 1.8%. The flexible synthetic route could generate further natural products of the Chloranthaceae family. Copyright

Full text of DOI:10.1002/cjoc.201200695

FULL PAPER
DOI: 10.1002/cjoc.201200695
Synthesis toward the Lindenane-type Sesquiterpenoid
Monomer of Chlorahololide A†
Haizhen Zhang and Fajun Nan*
Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Mate-
ria Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China
An investigation toward the synthesis of the lindenane-type sesquiterpenoid monomer of Chlorahololide A using
a Yamamoto rearrangement, intramolecular cyclopropanation reaction, 1,3-dipolar cyclization, and an intra-
molecular Heck reaction gave the pivotal intermediate 20. This gives a practical synthetic route that could generate
further natural products of the Chloranthaceae family.
Keywords lindenane-type sesquiterpenoid, intramolecular Heck reaction, Julia-Kocienski methylenation
Introduction
Results and Discussion
Chlorahololide A (1), a highly complex lindenane-
type sesquiterpenoid dimer, was first isolated by Yue
and co-workers in 2007 from South China Chloranthus
holostegius.[1] It exhibits potent and selective inhibition
of the delayed rectifier (IK) K＋ current with an IC50 of
10.9 μmol/L, which is 96-fold more potent than the
positive control, tetraethylammonium chloride (IC50＝
1.05 mmol/L), a classical blocker of the delayed rectifier
(IK) K＋ current. However, the unique octacyclic core
that is characteristic of Chlorahololide A is unprece-
dented among known natural products.
The obvious synthetic challenge posed by chlora-
hololide A coupled with its impressive biological activ-
ity has generated significant interest from the synthetic
community. Chlorahololide A was proposed as a Diels-
Alder cycloaddition product of two lindenane-type ses-
quiterpenoids in a biogenic reaction. Several efforts to-
ward the total synthesis of Chlorahololide A have fo-
cused on the stereoselective synthesis of lindenane-type
sesquiterpenoids,[2] while some efforts have been re-
ported to construct the core structure through Diels-
Alder cycloaddition.[3] In our previous paper,[2a] we re-
ported the synthesis of pivotal intermediate 21. Com-
pared with the desired key intermediate 20 for the syn-
thesis of Chlorahololide A, its 14-methyl group is epim-
eric. Herein, we would like to present our efforts to
construct a lindenane-type sesquiterpenoid framework
of Chlorahololide A with all configurations correct
through a flexible synthetic strategy, which we believe
may be applied to the synthesis of other members of the
intriguing Chloranthaceae family.
In line with the previous work by Kawabata’s
group[4] and Yue’s group,[1] our retrosynthetic analysis
of Chlorahololide A is outlined in Scheme 1. Chlora-
hololide A could be assembled using segment 22 with
expedient and practical conversion via a suitable func-
tional group transformation and Diels-Alder cycloaddi-
tion, followed by oxidation and rearrangement. Com-
pound 22 would be accessed from compound 20 in view
of the chemical reactivity of the butenolide.[5] Further
disconnection of this pivotal intermediate, using an in-
tramolecular Heck reaction, 1,3-dipolar cyclization, in-
tramolecular cyclopropanation, and Yamamoto rear-
rangement led to intermediate 3, which could be dis-
connected to give 3-butyn-1-ol as the starting material.
As shown in Scheme 2, our synthesis commenced
with alcohol 2, which was prepared from commercially
accessible 3-butyn-1-ol according to the literature in six
steps.[6] According to the protocol reported by Yama-
moto and co-workers,[7] rearrangement of silyl ether 3,
catalyzed by MABR (methylaluminum bis(4-bromo-
2,6-di(tert-butyl)phenoxide)), the (R)-configured β-si-
loxy aldehyde 4 was obtained in 94% yield over two
steps. Then Wittig methylenation of 4 could afford 5 in
95% yield. Treatment of 5 with TBAF in THF at room
temperature gave alcohol 6 in 96% yield, which was
then transformed to 7 using glyoxylic acid chloride
p-toluenesulfonyl hydrazone[8] in 81% yield over two
steps. Copper-catalyzed intramolecular cyclopropan-
ation of diazoacetate 7 afforded the important interme-
diate bicyclic lactone 8a as the main product (8a∶8b＝
2∶1, which are inseparable in this step)[9] in 74% over-
*
E-mail: fjnan@mail.shcnc.ac.cn; Tel.: 0086-021-50800954
Received July 9, 2012; accepted August 6, 2012; published online December 11, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200695 or from the author.
Dedicated to the Memory of Professor Weishan Zhou.
†
84
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 84—92

Synthesis toward the Lindenane-type Sesquiterpenoid Monomer of Chlorahololide A
Scheme 1 Retrosynthetic analysis of chlorahololide A (1)
MeO2C
O
O
O
O
O
O
O
O
O
O
H
O
OH
Chlorahololide A (1)
22
20
21
OBn
O
O
N
O
Br
O
O
OH
OH
O
18a
O
16a
8a
14a
OTBS
O
HO
OR
HO
BnO
3 R = OTBS
2 R = OH
5
Scheme 2 Preparation of intermediate 8a
OTBS
c
b
ref. [6]
O
BnO
OR
BnO
HO
O
2 R = H
4
a
3 R = TBS
OBn
OBn
OBn
f
OR
d
O
e
O
BnO
O
O
N2
O
O
5 R = TBS
6 R = H
8b
8a
7
Reagents and conditions: (a) TBSCl, imidazole, DMF, r.t., 5 h; (b) MABR, CH2Cl2, −78 to −40 ℃, 2 h, 94% over two steps; (c) Ph3PCH3Br,
n-BuLi, THF, −78 ℃ to r.t., overnight, 95%; (d) 1 mol/L TBAF in THF, THF, r.t., 3 h, 96%; (e) p-TsNHNHCOCl, dimethylaniline, CH2Cl2, then
Et3N, 0 ℃ to r.t., 30 min, 81% over two steps; (f) Cu(TBS)2, PhMe, reflux, 30 min, 74%.
all yield (Scheme 2). It is worth mentioning that the
cis-cyclopropane was constructed in a cyclic stereocon-
trolled manner without the use of a chiral catalyst.
11 in 81% yield over two steps. Subsequent DIBAL-H
reduction[11] of the Weinreb amide gave aldehyde 12
and oxime formation with hydroxylamine hydrochloride
in pyridine[12] gave oxime 13. Oxime 13 underwent in-
tramolecular [3＋2] cycloaddition to give a mixture of
the two diastereomeric isoxazolines 14a and 14b in 79%
yield over three steps. Isoxazolines 14a and 14b were
transformed to α-hydroxy ketones 15a and 15b by cata-
lytic hydrogenation over 10% Pd/C in a 4∶l mixture of
methanol and water containing 3 equiv. of boric acid[13]
in 76% yield. After debenzylation of α-hydroxy ketones
15a and 15b, ready acetylation and careful saponifica-
tion led to the primary alcohol 16a in 78% yield over
three steps. Swern oxidation of 16a led to aldehyde 17
in excellent yield. Then aldehyde 17 was treated with
Once the desired bicyclic lactone 8a was available,
the crucial lactone opening was attempted. Initially, we
intended to selectively transform it to the hydroxy acid
23. However, the transformation was problematic, al-
though several attempts were made. Finally, the ring
opening occurred smoothly with methoxymethylamine
[10]
hydrochloride in the presence of AlMe3 to afford the
Weinreb amides 9a and 9b (9a and 9b could be sepa-
rated by silica gel column chromatography in this step)
in 98% yield based on 62% conversion (Scheme 3).
DMP (Dess-Martin periodinane) oxidation of alco-
hol 9a followed by a Wittig methylenation yielded ene
Chin. J. Chem. 2013, 31, 84—92
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85

Zhang & Nan
FULL PAPER
Scheme 3 Preparation of the pivotal intermediate 18
OBn
OBn
OBn
OBn
OBn
g
HO
HO
R
N
R
O
O
N
O
O
O
O
O
O
O
8b
9b
8a
23
9a R = CH2OH
h
10 R = CHO
i
OBn
OBn
N
N
O
O
O
O
O
j, k
l
s
u
O
N
OR
OBn
OBn
N
14a
O
O
HO
28
13
11
14b
26 R = Bn
27 R = H
t
m
O
Br
O
O
O
OH
OH
Br
n
p
O
O
18a
Br
R
O
OBn
COOEt
OBn
Br
24
16a R = CH2OH
17 R = CHO
15a
15b
o
O
O
18b
Reagents and conditions: (g) MeNHOMe•HCl, AlMe3, CH2Cl2, r.t., 98% (62%, BORSM); (h) DMP, CH2Cl2, 3 h, r.t., 90%; (i) Ph3PCH3Br,
NaHMDS, THF, 0 ℃, 1 h, 90%; (j) DIBAL-H, THF, −78 ℃, 1 h; (k) H2NOH•HCl, Pyr., r.t.; (l) 5% NaClO, CH2Cl2, r.t., 79% over three steps; (m)
H2, 10% Pd/C, H3BO3, MeOH/H2O (4∶1), r.t., 76%; (n) H2, 10%Pd/C, MeOH, then Ac2O, DMAP, Et3N, CH2Cl2, then Na2CO3, MeOH/H2O
(2∶1), r.t., 78% over three steps; (o) (COCl)2, DMSO, Et3N, CH2Cl2, −78 ℃, 30 min then r.t. 30 min; (p) 24, i-PrMgCl, THF, −78 ℃, 30 min,
then 0 ℃, 3 h, 63% over two steps; (s) Raney Ni, AcOH, MeOH/H2O (4∶1), r.t.; (t) H2, 10% Pd/C, MeOH; (u) p-TsOH, Benzene, reflux,
overnight, 95%.
Grignard reagent which was derived from 24[14] to af-
ford the precursors of the intramolecular Heck reaction
18a and 18b in 63% overall yield over two steps (di-
astereomer ratio ＞3∶1), which could be separated by
silica gel column chromatography (Scheme 3).
With the desired precursors 18 in hand, we then
turned our attention to assembling the skeleton of the
lindenane-type sesquiterpenoid. Although an exo-type
intramolecular Heck reaction is impossible for this sub-
strate,[15] the endo-type ring closure was still problem-
atic. After screening many reaction conditions, tetra-
cyclic ketone 19 was produced in 31% yield based on
69% conversion under ligand-free conditions. Finally,
the methylenation reaction was achieved under modified
Julia-Kocienski conditions[2c,16] in moderate yield to
give compound 20, which possesses a typical lindenane-
type sesquiterpenoid framework (Scheme 4).
which was derived from isoxazoline 14a as outlined in
Scheme 3. Isoxazoline 14a was transformed to α-meth-
oxy ketone 26 by catalytic hydrogenation over Raney Ni
and acetic acid in a 4∶l mixture of methanol and water.
After debenzylation, demethylation and spontaneous
cyclization of 27 led to the solid 28, which was crystal-
lized from petroleum and ethyl acetate.
Experimental
Starting materials, reagents and solvents were pur-
chased from commercial suppliers and used without
further purification unless otherwise noted. Anhydrous
THF, toluene, benzene and CH2Cl2 were obtained from
a distillation over sodium wire or CaH2. All non-aqueous
reactions were run under an inert atmosphere (nitrogen
or argon) with rigid exclusion of moisture from reagents
and all reaction vessels were oven-dried. The progress
of reactions was monitored by silica gel thin layer
The stereochemistry of the final product was con-
firmed by the X-ray crystallographic analysis of 28,
86
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Chin. J. Chem. 2013, 31, 84—92

Synthesis toward the Lindenane-type Sesquiterpenoid Monomer of Chlorahololide A
Scheme
framework 20
4
Preparation of lindenane-type sesquiterpenoid
7.37－7.28 (m, 5H), 4.50 (s, 2H), 3.82－3.68 (m, 2H),
3.60－3.55 (m, 2H), 2.988 (t, J＝5.4 Hz, 1H), 1.99－
1.89 (m, 1H), 1.85－1.78 (m, 1H), 1.29 (s, 3H), 0.90 (s,
9H), 0.06 (s, 6H); 13C NMR (75 MHz, CDCl3) δ: 138.52,
128.62, 127.86, 127.83, 73.28, 66.84, 63.45, 62.47,
59.27, 38.61, 26.14, 18.56,17.58, −4.92, −5.08; HR-
ESIMS calcd for C19H32O3SiNa＋ [M＋Na]＋ 359.2018,
found 359.2031.
O
O
Br
q
r
O
O
O
O
18a
19
(R)-4-(Benzyloxy)-2-((tert-butyldimethylsilyloxy)-
methyl)-2-methylbutanal (4) To a soln. of meth-
ylaluminum bis(4-bromo-2,6-di(tert-butyl)phenoxide),
which was prepared from 4-bromo-2,6-di(tert-butyl)
phenol (53.6 g, 0.188 mol) and Me3Al (94 mL, 0.094
mol; 1.0 mol/L in hexane) in 300 mL of CH2Cl2 at 0 ℃,
was added a soln. of 3 (15.8 g, 0.047 mol) at −78 ℃
over a period of 30 min. The mixture was then stirred at
−78 ℃ for 1 h then at −40 ℃ for 1 h. The resulting
mixture was carefully poured into 1 mol/L HCl solution
and then stirred vigorously for 30 min at r.t. The org.
phase was washed with sat. aq. NaCl soln. (50 mL×3)
and then dried (Na2SO4). The solvent was removed un-
der reduced pressure, and the crude product was puri-
fied by flash chromatography on silica gel (PE∶EtOAc
＝100∶1 to 30∶1) to afford 4 (14.82 g) as a yellow oil
O
O
20
H
H
N N
O
N
O
SO2CH3
O
N
O
t-Bu
Shizukanolide A
Chloranthalactone A
25
Reagents and conditions: (q) Pd(OAc)2, Et3N, DMF, 80 ℃, 4 h,
31% (69%, BORSM); (r) Julia’s reagent 25, NaHMDS, THF, −78 ℃,
6 h, 47%.
chromatography (TLC) plates, visualized under UV and
charred using phosphomolybdic acid solution followed
by heating. Products were purified by flash column
chromatography (FCC) on 200－400 mesh silica gel.
Petroleum ether refers to the fraction with boiling range
60－90 or 30－60 ℃. Proton nuclear magnetic reso-
nance spectra (1H NMR) were recorded on a spec-
trometer operating at 300 MHz. Data is reported as fol-
lows: chemical shift, multiplicity (s ＝ singlet, d ＝
doublet, dd＝double doublet, t＝triplet, q＝quartet,
br＝broad, m＝multiplet), integration. Carbon nuclear
magnetic resonance spectra (13C NMR) were recorded
on a spectrometer operating at 75 MHz.
1
in 94% yield. [α]D20 ＝2.4 (c＝1.35, CHCl3); H NMR
(300 MHz, CDCl3) δ: 9.57 (s, 1H), 7.34－7.27 (m, 5H),
4.44 (s, 2H), 3.63 (dd, J＝28.0, 9.9 Hz, 2H), 3.53－3.46
(m, 2H), 2.06－1.96 (m, 1H), 1.79－1.68 (m, 1H), 1.06
(s, 3H), 0.86 (s, 9H), 0.014 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ: 205.77, 138.34, 128.57, 127.86, 127.79,
73.31, 67.24, 66.28, 50.39, 33.26, 25.97, 18.38, 16.55,
−5.44, −5.46; HR-ESIMS calcd for C19H32O3SiNa＋ [M
＋Na]＋ 359.2018, found 359.2006.
(S)-(2-(2-(Benzyloxy)ethyl)-2-methylbut-3-enyloxy)-
(tert-butyl)dimethylsilane (5) To a stirred suspension
of (methyl)(triphenyl) phosphonium Bromide powder
(56.94 g, 0.1593 mol) in 600 mL of dry THF at −78 ℃
was added n-BuLi (90 mL, 0.1434 mol; 1.6 mol/L in
hexane) over 1 h, then slowly warmed to −40 ℃ (ca.
1.5 h). Then a soln. of 4 (29.8 g, 0.0885 mol) in 50 mL
of THF was added dropwise over 30 min, and the re-
sulting mixture was stirred for 2 h and warm to r.t.
naturally. Acetone (3 mL) was added to the mixture to
consume the excess Wittig reagent. The mixture was
treated with sat. aq. NH4Cl soln. and extracted with
EtOAc (100 mL×3). The org. phase was washed with
sat. aq. NaCl soln. (50 mL×3) and then dried (Na2SO4).
The solvent was removed under reduced pressure, and
the crude product was purified by flash chromatography
on silica gel (PE∶EtOAc＝50∶1) to afford 5 (28.07 g)
((2R,3R)-3-(2-(Benzyloxy)ethyl)-3-methyloxiran-
2-yl)methanol (2) Colorless liquid, [α]2D0 ＝5.1 (c＝
1
4.61, CHCl3); H NMR (300 MHz, CDCl3) δ: 7.39－
7.28 (m, 5H), 4.51 (s, 2H), 3.86－3.81 (m, 1H), 3.72－
3.66 (m, 1H), 3.60－3.55 (m, 2H), 3.06－3.03 (m, 1H),
1.93－2.01 (m, 2H), 1.33 (s, 3H); HR-ESIMS calcd for
C13H18O3Na＋ [M＋Na]＋ 245.1168, found 245.1154.
(((2R,3R)-3-(2-(Benzyloxy)ethyl)-3-methyloxiran-
2-yl)methoxy)(tert-butyl)dimethylsilane (3)
To a
soln. of alcohol 2 (13.9 g, 62.6 mmol) and 1H-imidazole
(9.38 g, 137.7 mmol) in 75 mL of DMF was added a
soln. of TBSCl (10.38 g, 68.8 mmol) in 25 mL of DMF
over a period of 25 min, and the mixture was then
stirred at r.t. for 5 h. The reaction was quenched with
250 mL of H2O, and the mixture was stirred for 30 min
at r.t. The mixture was then poured into 150 mL of
EtOAc. The org. phase was washed with sat. aq. NaCl
soln. (50 mL×3) and then dried (Na2SO4). The solvent
was removed under reduced pressure, and the crude
product was purified by flash chromatography on silica
gel (PE∶EtOAc＝100∶1 to 60∶1) to afford 3 (21.0 g)
as a colorless oil in quantitative yield. [α]2D0 ＝−10.32
1
as a yellow oil in 95% yield. H NMR (300 MHz,
CDCl3) δ: 7.34－7.28 (m, 5H), 5.79 (dd, J＝17.5, 10.9
Hz, 1H), 4.98 (t, J＝13.6 Hz, 2H), 4.46 (s, 2H), 3.48 (t,
J＝7.4 Hz, 2H), 3.33 (q, J＝9.4 Hz, 2H), 1.74 (q, J＝
9.4 Hz, 2H), 0.98 (s, 3H), 0.87 (s, 9H), 0.07 (s, 6H);
HR-ESIMS calcd for C20H34O2SiNa ＋ [M ＋ Na] ＋
357.2225, found 357.2214.
1
(c＝3.42, CHCl3); H NMR (300 MHz, CDCl3) δ:
(S)-2-(2-(Benzyloxy)ethyl)-2-methylbut-3-en-1-ol
Chin. J. Chem. 2013, 31, 84—92
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87

Zhang & Nan
FULL PAPER
(6) To a soln. of 5 (28.2 g, 0.0843 mol ) in 300 mL of
THF was added TBAF (101 mL, 0.101 mol; 1 mol/L in
THF) at 0 ℃. The mixture was stirred at r.t. for 3 h.
After the completion of the reaction, The mixture was
treated with sat. aq. NH4Cl soln. and extracted with
EtOAc (100 mL×2). The org. phase was washed with
sat. aq. NaCl soln. (30 mL×3) and then dried (Na2SO4).
The solvent was removed under reduced pressure, and
the crude product was purified by flash chromatography
on silica gel (PE∶EtOAc＝30∶1 to 10∶1) to afford 6
(17.83 g) as a colorless oil in 96% yield. [α]2D0 ＝−3
reduced pressure and then purified by flash chromatog-
raphy (PE∶EtOAc＝5∶1 to 3∶1) to give 1.04 g of an
inseparable 1.9∶1.0 mixture of 8 as a yellow oil in 74%
yield. The stereochemistry of 8a and 8b (separated by
reverse semi-preparative column: Agilent 1200HPLC
using an Agilent 20RBAX Eclipse XDB-C18, 5 μm
reversed-phase column measuring 4.6 mm×150 mm
with 50% MeOH∶50% H2O over 30 min. tR(8a)＝
11.32 min, tR(8b)＝12.42 min) was determined by ex-
tensive spectroscopic studies along with a single crystal
1
X-ray diffraction analysis of relate compoud. H NMR
1
(c＝2.36, CHCl3); H NMR (300 MHz, CDCl3) δ:
(300 MHz, CDCl3) δ: 7.41－7.26 (m, 5H), 4.48 (s, 2H),
3.90 (dd, J＝17.6, 7.0 Hz, 1H), 3.80－3.68 (m, 1H),
3.61 (dt, J＝15.6, 4.8 Hz, 2H), 1.91－1.80 (m, 2H),
1.67 (dd, J＝11.2, 5.2 Hz, 1H), 1.64－1.55 (m, 1H),
1.33 (dd, J＝10.3, 5.6 Hz, 1H), 1.06 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ: 171.62, 138.44, 128.68, 128.62,
127.96, 127.83, 73.43, 73.29, 73.15, 72.26, 66.71, 66.40,
37.72, 37.65, 31.22, 30.77, 26.18, 26.03, 23.74, 22.04,
16.36, 15.82, 9.07, 8.28; HR-ESIMS calcd for
C16H21O＋3 [M＋H]＋ 261.1491, found 261.1480.
7.36－7.28 (m, 5H), 5.80 (dd, J＝17.7, 11.1 Hz, 1H),
5.06 (ddd, J＝12.9, 11.4, 1.2 Hz, 2H), 4.50 (s, 2H), 3.55
(t, J＝5.9 Hz, 2H), 3.47－3.33 (m, 2H), 2.70 (t, J＝6.9
Hz, 1H), 1.74－1.68 (m, 2H), 1.02 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ: 144.53, 138.20, 128.69, 127.98,
113.55, 73.43, 69.90, 67.25, 41.45, 37.32, 21.70;
HR-EIMS calcd for C14H20O＋2 [M＋] 220.1463, found
220.1464.
(S)-2-(2-(Benzyloxy)ethyl)-2-methylbut-3-enyl-
2-diazoacetate (7) A suspension of glyoxylic acid
p-toluenesulfonyl hydrazone (4.95 g, 20.43 mmol) in a
solution of 50 mL of anhydrous benzene and 4.45 mL of
thionyl chloride (61.29 mmol) was refluxed with stirring
for 2 h under an argon atmosphere. The solvent was
placed on a high-vacuum line for 1 h to remove residual
thionyl chloride. This material was used immediately
without purification. The crude glyoxylic acid chloride
p-toluenesulfonyl hydrazone in 40 mL of CH2Cl2 was
dropped into a solution of 6 (3.0 g, 13.62 mmol) in 130
mL of anhydrous CH2Cl2 in an ice bath under an argon
atmosphere. Dimethylaniline (2.42 mL,19.07 mmol) in
17 mL of CH2Cl2 was added with stirring for 15 min
prior to addition of Et3N (3.8 mL, 27.24 mmol) in 15
mL of CH2Cl2. The resulting dark orange solution was
stirred for 10 min at 0 ℃ and then 20 min at room tem-
perature. The CH2Cl2 solution was evaporated. Flash
column chromatography (PE∶EtOAc＝40∶1 to 20∶1)
provided 7 (3.18 g) as a yellow oil in 81% yield over
two steps. [α]2D0 ＝7.04 (c＝2.4, CHCl3); 1H NMR (300
MHz, CDCl3) δ: 7.37－7.27 (m, 5H), 5.75 (dd, J＝17.6,
10.9 Hz, 1H), 5.05 (dd, J＝18.7, 14.2 Hz, 2H), 4.73 (s,
1H), 4.47 (s, 2H), 4.01 (q, J＝15.1 Hz, 2H), 3.49 (t, J＝
7.2 Hz, 2H), 1.75 (t, J＝7.2 Hz, 2H), 1.02 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ: 142.88, 138.58, 128.62,
127.80, 114.17, 73.27, 71.40, 67.04, 46.37, 39.76, 37.03,
21.16; HR-ESIMS calcd for C16H20N2O3Na＋ [M＋Na]＋
311.1372, found 311.1391.
(1S,2R)-2-((S)-4-(Benzyloxy)-1-hydroxy-2-methyl-
butan-2-yl)-N-methoxy-N-methylcyclopropanecarbo-
xamide (9a) and (1R,2S)-2-((S)-4-(benzyloxy)-1-
hydroxy-2-methylbutan-2-yl)-N-methoxy-N-methyl-
cyclopropanecarboxamide (9b) Trimethylaluminum
(26.7 mL, 26.7 mmol; 1 mol/L in heptane) was slowly
added over 20 min to N,O-dimethyl hydroxylamine hy-
drochloride (2.608 g, 26.73 mmol) in 70 mL anhydrous
CH2Cl2 at 0 ℃. The bath was removed, and the solution
was allowed to stir at r.t. for 1 h. Upon cooling the solu-
tion to 0 ℃, 8 (2.32 g, 8.91 mmol) in 50 mL anhydrous
CH2Cl2 was cannulated in over a 30 min period. The
cooling bath was removed, and the solution was stirred
for several hours. The solution was cooled to 0 ℃, then
treated with sat. aq. Rochelle’s soln. and extracted with
EtOAc (30 mL×2). The org. phase was washed with
sat. aq. NaCl soln. (10 mL×3) and then dried (Na2SO4).
The solvent was removed under reduced pressure, and
the crude product was purified by flash chromatography
on silica gel (PE∶EtOAc＝5∶1 to 2∶1) to afford 9
(1.73 g) as a yellow oil in 98% yield based on 0.892 g 8
recovery (62%, BORSM).
9a and 9b were separated by normal semi-prepara-
tive column: Agilent 1200HPLC using an Agilent
20RBAX Zorbax SB-C18, 5 μm normal-phase column
measuring 4.6 mm×250 mm with 90% hexane∶10%
isopropyl alcohol over 50 min; tR(9b)＝16.18 min,
tR(9a)＝20.52 min.
(1S,5S,6R)-5-(2-(Benzyloxy)ethyl)-5-methyl-3-
oxabicyclo[4.1.0]heptan-2-one (8) To a refluxing
solution of bis(tert-butylsalicylal diminato)copper(II)
[Cu(TBS)2] (116.6 mg, 0.281 mmol) in 240 mL anhy-
drous, deoxygenated toluene was added a solution of 7
(1.62 g, 5.62 mmol) in 60 mL deoxygenated toluene
over 5 h under an argon atmosphere. The resulting mix-
ture was refluxed for a further 30 min and then allowed
to cool to room temperature. It was concentrated under
9a Colorless liquid, [α]2D0 ＝ −35.46 (c ＝ 0.43,
CHCl3); 1H NMR (300 MHz, CDCl3) δ: 7.34－7.28 (m,
5H), 4.50 (s, 3H), 3.75 (s, 3H), 3.65－3.57 (m, 2H),
3.35 (s, 3H), 3.19 (s, 3H), 1.94 (br, 1H), 1.81－1.66 (m,
3H), 1.36－1.21 (m, 2H), 0.92 (td, J＝8.1, 3.6 Hz, 1H),
0.79 (s, 3H); 13C NMR (75 MHz, CDCl3) δ: 137.95,
128.67, 128.03, 127.97, 73.48, 70.69, 67.10, 61.58,
39.37, 34.12, 38.26, 29.75, 20.51, 17.70, 7.91; 13C
NMR-dept (75 MHz, CDCl3) δ: 128.67, 128.03, 127.97,
88
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 84—92

Synthesis toward the Lindenane-type Sesquiterpenoid Monomer of Chlorahololide A
73.48, 70.69, 67.10, 61.58, 39.37, 34.12, 29.75, 20.51,
17.70, 7.91; HR-ESIMS calcd for C18H27NO4Na＋ [M＋
Na]＋ 344.1838, found 344.1835.
duced pressure, and the crude product was purified by
flash chromatography on silica gel (PE∶EtOAc ＝
20∶1 to 5∶1) to afford 11 (3.8 g) as a yellow oil in
1
9b Colorless liquid, [α]2D0 ＝63.4 (c＝0.9, CHCl3);
1H NMR (300 MHz, CDCl3) δ: 7.38－7.24 (m, 5H),
4.51 (s, 2H), 3.72 (d, J＝1.8 Hz, 3H), 3.60 (dddd, J＝
13.7, 12.2, 8.2, 4.1 Hz, 2H), 3.34 (s, 3H), 3.18 (s, 2H),
1.99 (d, J＝25.6 Hz, 2H), 1.86－1.73 (m, 2H), 1.59
(ddd, J＝14.9, 6.7, 4.0 Hz, 1H), 1.44 (t, J＝6.9 Hz, 1H),
1.39 (ddd, J＝12.3, 6.2, 4.3 Hz, 1H), 0.95－0.85 (m,
1H), 0.83 (s, 3H); 13C NMR (75 MHz, CDCl3) δ: 137.95,
128.68, 128.04, 128.01, 73.53, 70.54, 67.16, 61.48,
38.33, 37.98, 33.26, 30.00, 21.10, 17.22, 8.62; 13C
NMR-dept (75 MHz, CDCl3) δ: 128.68, 128.04, 128.01,
73.53, 70.54, 67.16, 61.48, 38.33, 33.26, 30.00, 21.10,
17.22, 8.62.
90% yield. [α]2D0 ＝−28.8 (c＝0.08, CHCl3); H NMR
(300 MHz, CDCl3) δ: 7.37－7.28 (m, 5H), 5.80 (dd, J＝
17.4, 10.9 Hz, 1H), 4.95－4.87 (m, 2H), 4.47 (s, 2H),
3.71 (s, 3H), 3.57－3.50 (m, 2H), 3.16 (s, 3H), 1.89－
1.75 (m, 2H), 1.37－1.23 (m, 2H), 1.01 (s, 3H), 0.93－
0.84 (m, 1H); 13C NMR (75 MHz, CDCl3) δ: 145.79,
128.56, 127.82, 127.69, 111.60, 73.16, 67.54, 61.40,
42.43, 38.79, 32.09, 31.16, 21.82, 18.03, 8.21.
HR-ESIMS calcd for C19H27NO3Na ＋ [M ＋ Na] ＋
340.1889, found 340.1877.
(1aS,3aS,4R,5aR)-4-(2-(Benzyloxy)ethyl)-4-methyl-
1a,3a,4,5a-tetrahydrocyclopropa-3H-cyclopenta[c]-
isoxazole (14a) and (1aS,3bS,4R,5aR)-4-(2-(benzyloxy)-
ethyl)-4-methyl-1a,3b,4,5a-tetrahydrocyclopropa-3H-
(1S,2R)-2-((S)-4-(Benzyloxy)-2-methyl-1-oxobutan-
2-yl)-N-methoxy-N-methylcyclopropanecarboxamide
(10) Alcohol 9a (4.75 g, 14.78 mmol) was dissolved
in 200 mL CH2Cl2, then treated with DMP (7.522 g,
17.73 mmol) at 0 ℃, the solution became cloudy im-
mediately until a colourless emulsion formed. The bath
was removed, and the solution was allowed to stir at r.t.
for 3 h, then hydrolysis was achieved by addition of 150
mL of a 1∶1 mixture of sat. aq NaHCO3 soln. and sat.
aq Na2S2O3 soln. The mixture was stirred until two clear
layers formed. The organic layer was separated and the
aqueous layer was washed with CH2Cl2 (50 mL×2).
The org. phase was washed with sat. aq. NaCl soln. (20
mL×3) and then dried (Na2SO4). The solvent was re-
moved under reduced pressure, and the crude product
was purified by flash chromatography on silica gel
(PE∶EtOAc＝2∶1) to afford 10 (4.26 g) as a yellow
cyclopenta[c]isoxazole (14b)
To the cyclopropyl
amide 11 (3.8 g, 11.97 mmol) in dry THF (120 mL)
under nitrogen at −78 ℃, DIBAL-H (15.6 mL, 15.6
mmol; 1 mol/L in hexane) was added. The reaction was
completed in 2 h. Reaction mixture was poured into a
sat. aq. potassium sodium tartarate soln. (10 mL) and
stirred for 1 h, then extracted with EtOAc (40 mL×2).
The combined organic solution was washed with brine
(20 mL×2) and dried over Na2SO4, concentrated to
give 3.09 g (quantitative) of yellow liquid 12.
Hydroxylamine hydrochloride (1.0 g, 14.36 mmol)
was added to a solution of the aldehyde 12 in pyridine
(36 mL). The reaction mixture was stirred at room tem-
perature until the disappearance of the aldehyde as
shown on TLC. Concentration of the solvent under re-
duced pressure and then purification with flash chroma-
tography on silica gel (PE∶EtOAc＝5∶1) to remove
pyridinium chloride gave 3.2 g of colorless liquid oxime
13.
To a stirred solution of oxime 13 (3.2 g, 11.7 mmol)
in CH2Cl2 (140 mL) was added an aqueous NaClO soln.
(17.5 mmol, 25 mL) and the mixture was stirred at room
temperature for 9 h. The reaction was diluted with water
and extracted with CH2Cl2 (30 mL×2), The org. phase
was washed with sat. aq. NaCl soln. (10 mL×3) and
then dried (Na2SO4). The solvent was removed under
reduced pressure, and the crude product was purified by
flash chromatography on silica gel (PE∶EtOAc ＝
10∶1 to 5∶1) to afford 14 (2.58 g) as a yellow oil in
79% yield over three steps.
1
oil in 90% yield. [α]2D0 ＝−20 (c＝0.3, CHCl3); H
NMR (300 MHz, CDCl3) δ: 9.49 (s, 1H), 7.35－7.22 (m,
5H), 4.45 (s, 2H), 3.71 (s, 3H), 3.57 (t, J＝6.5 Hz, 2H),
3.16 (s, 3H), 2.02 (dd, J＝14.2, 7.1 Hz, 1H), 1.83 (dt,
J＝14.2, 6.0 Hz, 1H), 1.37 (dt, J＝12.4, 6.6 Hz, 2H),
1.12 (s, 3H), 1.03 (dd, J＝7.9, 4.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ: 203.30, 172.61, 138.44, 128.58,
127.85, 113.80, 73.26, 66.53, 61.65, 37.33, 32.92, 28.41,
20.49, 16.54, 9.47. HR-ESIMS calcd for C18H25NO4Na＋
[M＋Na]＋ 342.1681, found 342.1669.
(1S,2R)-2-((R)-5-(Benzyloxy)-3-methylpent-1-en-
3-yl)-N-methoxy-N-methylcyclopropanecarboxamide
(11) To a stirred suspension of (methyl)(triphenyl)
phosphonium Bromide powder (11.91 g, 33.25 mmol)
in 100 mL of dry THF at 0 ℃ was added NaHMDS
(29.9 mL, 29.9 mmol; 1.0 mol/L in THF) over 30 min.
The bath was removed, and the solution was allowed to
stir at r.t. for 30 min. Upon cooling the solution to −78
℃, a soln. of 10 (4.26 g, 13.3 mol) in 60 mL of THF
was added dropwise over 30 min, and the resulting
mixture was stirred at 0 ℃ for another 1 h. Then the
mixture was treated with sat. aq. NH4Cl soln. and ex-
tracted with EtOAc (50 mL×3). The org. phase was
washed with sat. aq. NaCl soln. (20 mL×3) and then
dried (Na2SO4). The solvent was removed under re-
14a Colorless liquid, [α]2D0 ＝ 47.8 (c ＝ 0.45,
CHCl3); 1H NMR (300 MHz, CDCl3) δ: 7.35－7.27 (m,
5H), 4.50 (s, 2H), 4.26 (dd, J＝11.0, 8.4 Hz, 1H), 3.99
(dd, J＝12.0, 8.4 Hz, 1H), 3.62 (tdd, J＝7.2, 4.2, 1.4 Hz,
2H), 3.24－3.14 (q, J＝12 Hz, 1H), 2.09－2.04 (m, 2H),
1.78－1.70 (m, 2H), 1.13 (s, 3H), 1.03 (dd, J＝9.0, 4.5
Hz, 2H); 13C NMR (75 MHz, CDCl3) δ: 170.39, 138.42,
128.65, 128.01, 127.88, 127.86, 73.39, 69.31, 66.67,
59.41, 38.36, 36.75, 35.63, 24.82, 14.83, 10.26; 13C
NMR-dept (75 MHz, CDCl3) δ: 128.65, 127.86, 73.39,
69.31, 66.67, 59.41, 36.75, 35.63, 24.82, 14.83, 10.26.
Chin. J. Chem. 2013, 31, 84—92
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
89

Zhang & Nan
FULL PAPER
＋
HR-ESIMS calcd. for C17H22 NO＋2 [M ＋ H]
mmol) in 50 mL of CH2C12 was added acetic anhydride
(1.39 mL, 14.72 mmol) at −20 ℃. The reaction mixture
was stirred for 3 h and warmed to 0 ℃, before being
quenched with sat. aq. NaHCO3 soln. (10 mL). The
aqueous phase was extracted with CH2C12 (20 mL×2),
and the combined organic phases were washed with
H2O (10 mL×2) and NaCl soln. (10 mL), then dried
over MgSO4, filtered and the solvent was removed un-
der reduced pressure to afford M2, which was directly
subjected to hydrolysis.
272.2651, found 272.1654.
14b 1H NMR (300 MHz, CDCl3) δ: 7.36－7.28 (m,
5H), 4.48 (s, 2H), 4.13－4.00 (m, 2H), 3.62－3.49 (m,
2H), 2.05－1.93 (m, 2H), 1.91－1.84 (m, 2H), 1.15－
1.01 (m, 2H), 0.94－0.88 (m, 1H), 0.87 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ: 171.84, 138.24, 128.70,
128.00, 127.96, 127.88, 73.56, 73.40, 71.86, 70.17,
67.66, 67.51, 43.92, 37.57, 37.42, 19.48, 15.92, 12.74;
13C NMR-dept (75 MHz, CDCl3) δ: 128.70, 128.00,
127.96, 73.56, 73.40, 71.86, 70.17, 67.66, 43.92, 37.42,
19.48, 15.92, 12.74.
To a solution of M2 in MeOH (48 mL) and H2O (16
mL) was added Na2CO3 (96 mg, 9.814 mmol) in 8 mL
of H2O at room temperature. The resulting mixture was
stirred for 1.5 h. Then methanol was removed under
reduced pressure, and the residue was extracted with
EtOAc (20 mL×2). The org. phase was washed with
sat. aq. NaCl soln. (10 mL×2) and then dried (Na2SO4).
The solvent was removed under reduced pressure, and
the crude product was purified by flash chromatography
on silica gel (PE∶EtOAc＝2∶1) to afford 16a (634
mg) as a colorless oil in 78% yield over three steps.
(1S,3R,4S,5R)-4-(2-(Benzyloxy)ethyl)-3-(hydroxy-
methyl)-4-methylbicyclo[3.1.0]hexan-2-one (15a) and
(1S,3S,4S,5R)-4-(2-(benzyloxy)ethyl)-3-(hydroxy-
methyl)-4-methylbicyclo[3.1.0]hexan-2-one
(15b)
To a solution of isoxazoline 14 (607 mg, 2.229 mmol)
in MeOH (28 mL) and water (7 mL) were added H3BO3
(346 mg, 5.572 mmol) and Pd/C (10%, 61 mg, 10% wt).
The reaction flask was evacuated and refilled with H2
five times, and stirring was continued at room tempera-
ture for 1.5 h. The reaction mixture was filtered through
a pad of Celite, the organic solvents were removed un-
der vacuum, and the aqueous layer was extracted with
EtOAc (10 mL×3). The combined organic phases were
washed with sat. aq. NaHCO3 soln. (10 mL×2) and NaCl
soln. (10 mL), then dried (Na2SO4). The solvent was
removed under reduced pressure, and the crude product
was purified by flash chromatography on silica gel
(PE∶EtOAc＝5∶1 to 3∶1) to afford hydroxyketone
15 (465 mg) as a colorless liquid in 76% yield.
1
[α]2D0 ＝31.43 (c＝0.7, CHCl3); H NMR (300 MHz,
CDCl3) δ: 5.96 (s, 1H), 5.19 (s, 1H), 3.72－3.58 (m,
2H), 2.01 (br, 1H, OH), 1.99－1.89 (m, 2H), 1.77 (ddd,
J＝8.0, 6.6, 2.9 Hz, 2H), 1.20 (s, 3H), 1.19－1.11 (m,
1H), 0.71－0.66 (m, 1H); 13C NMR (75 MHz, CDCl3) δ:
204.09, 151.21, 119.19, 59.18, 46.03, 42.44, 29.43,
26.90, 23.38, 13.34. HR-EIMS calcd for C10H14O＋2
[M＋] 166.0994, found 166.0987.
(S)-4-Bromo-3-methyl-5-(((1R,2S,5S)-2-methyl-3-
methylene-4-oxobicyclo[3.1.0]hexan-2-yl)methyl)-
furan-2(5H)-one (18a) and (R)-4-bromo-3-methyl-
5-(((1R,2S,5S)-2-methyl-3-methylene-4-oxobicyclo-
15a
Colorless liquid, [α]2D0 ＝ −14 (c ＝ 0.29,
CHCl3); 1H NMR (300 MHz, CDCl3) δ: 7.34－7.27 (m,
5H), 4.47 (s, 2H), 3.87 (ddd, J＝14.0, 8.4, 4.1 Hz, 1H),
3.57 (m, 3H), 2.82－2.74 (m, 1H), 2.11－2.01 (m, 2H),
1.90－1.80 (m, 1H), 1.65 (dt, J＝14.8, 7.3 Hz, 2H),
1.19 (s, 3H), 1.19－1.10 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ: 138.29, 128.63, 127.90, 122.30, 73.40, 66.83,
59.10, 52.39, 39.44, 37.39, 30.84, 27.60, 24.41, 13.53;
[3.1.0]hexan-2-yl)methyl)furan-2(5H)-one
(18b)
DMSO (0.42 mL, 6 mmol) in CH2Cl2 (10 mL) was
slowly added to oxalyl chloride (0.29 mL, 3 mmol) in
CH2Cl2 (20 mL) at −78 ℃. After stirring for 20 min,
alcohol 16a (332 mg, 2 mmol) in CH2Cl2 (20 mL) was
cannulated into the solution over a 5 min period. The
heterogeneous solution was stirred for 60 min, where-
upon triethylamine (1.4 mL, 10 mmol) was added. The
resulting mixture was stirred for 30 min then warmed to
room temperature and stirred for another 30 min. Then
the mixture was treated with sat. aq. NH4Cl soln. and
extracted with EtOAc (20 mL×2). The org. phase was
washed with sat. aq. NaCl soln. (10 mL×2) and then
dried (Na2SO4). After concentration, the oil was diluted
with CH2Cl2 and Et2O and then filtered through silica
gel. This solution was concentrated again to afford al-
dehyde 17, which was directly subjected to the next re-
action.
i-PrMgCl (3.36 mL, 6.71 mmol) in THF (20 mL)
was slowly added to dibromo ester 24 (1.921 g, 7.064
mmol) in THF (40 mL) at 0 ℃. After stirring for 30
min, the reaction mixture was cooled to −78 ℃, alde-
hyde 17 (580 mg, 3.532 mmol) in THF (20 mL) was
cannulated into the solution over a 5 min period, the
reaction mixture was stirred for 30 min and warmed to 0
＋
＋
HR-ESIMS calcd for C17H22O3Na
297.1467, found 297.1472.
[M ＋ Na]
15b 1H NMR (300 MHz, CDCl3) δ: 7.37－7.27 (m,
5H), 4.47 (s, 2H), 3.87 (dd, J＝14.2, 5.4 Hz, 0.5H), 3.77
－3.68 (m, 0.5H), 3.64－3.50 (m, 3H), 2.46 (s, OH),
2.26 (t, J＝6.0 Hz, 1H), 1.95－1.80 (m, 4H), 1.66 (dd,
J＝13.9, 7.2 Hz, 1H), 1.13 (s, 3H), 1.10－1.05 (m, 1H).
(1S,4S,5R)-4-(2-Hydroxyethyl)-4-methyl-3-meth-
ylenebicyclo[3.1.0]hexan-2-one (16) Pd/C (10%, 270
mg, 20% wt) was suspended in a solution of hy-
droxyketone 15 (1.346 g, 4.906 mmol) in MeOH (50
mL). The reaction flask was evacuated and refilled with
H2 five times, and stirring was continued at room tem-
perature for 8 h. The reaction mixture was filtered
through a pad of Celite, the organic solvents were re-
moved under vacuum to afford diol M1 as an oil. The
diol M1 was taken directly to the next reaction.
To a solution of diol M1 (904 mg, 4.907 mmol),
DMAP (120 mg, 0.981 mmol), and Et3N (4.1 mL, 29.44
90
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 84—92

Synthesis toward the Lindenane-type Sesquiterpenoid Monomer of Chlorahololide A
℃. After 3 h, the mixture was quenched with sat. aq.
NH4Cl soln. and extracted with EtOAc (20 mL×2). The
org. phase was washed with sat. aq. NaCl soln. (10
mL×2) and then dried (Na2SO4). The solvent was re-
moved under reduced pressure, and the crude product
was purified by flash chromatography on silica gel
(PE∶EtOAc＝6∶1 to 4∶1) to afford 18 (745 mg) as a
yellow solid in 63% yield over two steps.
with sat. aq. NH4Cl soln. and extracted with EtOAc (5
mL×2). The org. phase was washed with sat. aq. NaCl
soln. (2 mL×2) and then dried (Na2SO4). The solvent
was removed under reduced pressure, and the crude
product was purified by flash chromatography on silica
gel (PE∶Benzene＝1∶2 to PE∶EtOAc＝12∶1) to
1
afford 20 (14 mg) as a white solid in 47% yield. H
NMR (300 MHz, CDCl3) δ: 6.535 (s, 1H), 5.337 (s, 1H),
5.126 (s, 1H), 5.033－4.985 (m, 1H), 2.43 (dd, J＝11.5,
5.0 Hz, 2H), 1.99－1.91 (m, 2H), 1.90 (s, 3H), 1.467－
1.568 (m, 2H), 1.264 (s, 3H), 0.78 (td, J＝7.7, 5.4 Hz,
2H), 0.14 (dd, J＝8.4, 4.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ: 174.90, 156.44, 154.93, 149.63, 119.54,
113.65, 107.21, 77.00, 40.14, 28.62, 26.21, 20.51, 12.20,
8.73; 13C NMR-dept (75 MHz, CDCl3) δ: 113.65,
18a White solid, [α]2D0 ＝88.9 (c＝0.09, CHCl3);
1H NMR (300 MHz, CDCl3) δ: 6.11 (s, 1H), 5.35 (s,
1H), 4.90 (d, J＝10.2 Hz, 1H), 2.15－2.07 (m, 2H),
2.07－2.02 (m, 1H), 1.89 (s, 3H), 1.69－1.59 (m, 2H),
1.38 (s, 3H), 1.28－1.19 (m, 2H), 0.81－0.75 (m, 1H);
13C NMR (75 MHz, CDCl3) δ: 202.93, 170.91, 149.99,
144.79, 129.39, 120.68, 81.01, 79.75, 47.32, 44.76,
42.97, 29.97, 26.50, 22.43, 13.74, 10.50; HR-ESIMS
calcd for C14H15O3NaBr＋ [M＋Na]＋ 333.0102, found
333.0111.
107.21, 77.00, 45.65, 40.14, 28.62, 26.21, 20.51, 12.20,
8.73; HR-EIMS calcd for C15H16O2 [M＋] 228.1150,
＋
found 228.1154.
18b White solid, [α]2D0 ＝24.6 (c＝0.24, CHCl3);
1H NMR (300 MHz, CDCl3) δ: 6.16 (s, 1H), 5.36 (s,
1H), 4.73 (d, J＝10.5 Hz, 1H), 2.27－2.19 (m, 2H),
2.18－2.09 (m, 2H), 1.89 (d, J＝1.8 Hz, 3H), 1.68 (dd,
J＝9.6, 5.2 Hz, 1H), 1.33 (s, 3H), 1.29－1.23 (m, 1H),
0.79－0.73 (m, 1H).
(4aS,5R,6S,7aS)-4a-Methyl-4a,5,5a,6,6a,7a-hexahy-
drocyclopropa[2,3]cyclopenta[c]pyran-7(3H)-one (28)
1
[α]2D0 ＝25.8 (c＝0.24, CHCl3); H NMR (300 MHz,
CDCl3) δ: 4.25 (d, J＝12.1 Hz, 1H), 3.72 (dd, J＝11.5,
4.0 Hz, 1H), 3.41 (dd, J＝12.1, 4.0 Hz, 1H), 3.31 (dd,
J＝11.3, 1.5 Hz, 1H), 1.86 (ddd, J＝7.7, 6.7, 4.0 Hz,
2H), 1.80－1.66 (m, 1H), 1.58－1.50 (m, 2H), 1.28 (s,
3H), 1.22－1.13 (m, 1H), 1.13－1.05 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ: 211.19, 77.74, 77.31, 76.89,
63.54, 61.23, 45.49, 37.57, 35.20, 33.05, 26.53, 22.21,
13.05; HR-EIMS calcd for C10H14O＋2 [M＋] 166.0994,
found 166.0985.
(4aS,5aS,6aR,6bS,7aS)-3,6b-Dimethyl-6,6a,7,7a-
tetrahydrocyclopropa[2,3]indeno[5,6-b]furan-2(6bH)-
one (19) A solution of 18a (160 mg, 0.514 mmol),
Pd(OAc)2 (34.6 mg, 30 mol%) and Et3N (0.15 mL, 1.03
mmol) in DMF (10 mL) was stirred at 80 ℃ for 4 h
under arogon atmosphere. The reaction mixture was
allowed to cool to room temperature, quenched with
water (10 mL), and extracted with EtOAc (20 mL×2).
The org. phase was washed with water (5 mL×2) and
sat. aq. NaCl soln. (10 mL×2) and then dried (Na2SO4).
The solvent was removed under reduced pressure, and
the crude product was purified by flash chromatography
on silica gel (PE∶EtOAc＝6∶1 to 3∶1) to afford 19
(26 mg) as a yellow solid in 31% yield based on 50 mg
18 recovery (69%, BORSM). [α]2D0 ＝−16.5 (c＝0.2,
Conclusions
In summary, we have developed a practical synthesis
of the lindenane-type sesquiterpenoid framework 20 in a
linear sequence of 21 steps and an overall yield of 1.8%
from easily accessible starting materials. The flexible
synthetic route could generate further natural products
of the Chloranthaceae family such as Shizukanolides A
and Chloranthalactone A[17] (Scheme 4).
1
CHCl3); H NMR (300 MHz, CDCl3) δ: 6.91 (s, 1H),
5.28－5.19 (m, 1H), 2.60 (dd, J＝11.3, 4.7 Hz, 1H),
2.19－2.12 (m, 2H), 1.98 (s, 3H), 1.95－1.90 (m, 1H),
1.76－1.68 (m, 1H), 1.32 (s, 3H), 1.31－1.21 (m, 1H),
0.86－0.67 (m, 1H); 13C NMR (75 MHz, CDCl3) δ:
200.56, 154.50, 153.61, 127.76, 119.76, 109.39, 77.01,
44.66, 39.75, 29.90, 29.64, 24.05, 14.86, 9.40; 13C
NMR-dept (75 MHz, CDCl3) δ: 119.76, 109.39, 77.01,
44.66, 29.90, 29.64, 24.05, 14.86, 9.40; HR-ESIMS
calcd for C14H14O3Na＋ [M＋Na]＋ 253.0840, found
253.0845.
(4aS,5aS,6aR,6bS,7aS)-3,6b-Dimethyl-5,5a,6,6a,7,
7a-hexahydrocyclopropa[2,3]indeno[5,6-b]furan-
2(6bH)-one (20) NaHMDS (0.2 mL, 0.2 mmol; 1.0
mol/L in THF)) was slowly added to a solution of ke-
tone 19 (30 mg, 0.13 mmol) and Julia’s reagent 25 (37.2
mg, 0.182 mmol) in THF (2.5 mL) under argon. The
mixture was stirred for 6 h at −78 ℃, then quenched
Acknowledgement
This work was supported by The National Natural
Science Foundation of China (Nos. 30725049,
81021062, 81072652).
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