Stereoselective synthesis of marine sesterterpenes, 16-deacetoxy- scalarafuran, (+)-scalarolide and their analogs

Article abstract of DOI:10.1016/j.tet.2011.05.092

The stereoselective synthesis of C12 oxygenated marine scalaranic sesterterpenes 16-deacetoxy-scalarafuran, (+)-scalarolide and their unnatural analogs were described. Three key transformations were involved in their synthesis, which are the ring-opening

Full text of DOI:10.1016/j.tet.2011.05.092

Tetrahedron 67 (2011) 5596e5603
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Tetrahedron
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Stereoselective synthesis of marine sesterterpenes, 16-deacetoxy-scalarafuran,
(þ)-scalarolide and their analogs
Wen-Yuan Fan, Zheng-Lin Wang, Zi-Gang Zhang, Hong-Chang Li, Wei-Ping Deng
*
Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 April 2011
Received in revised form 18 May 2011
Accepted 24 May 2011
Available online 30 May 2011
The stereoselective synthesis of C12 oxygenated marine scalaranic sesterterpenes 16-deacetoxy-scalar-
afuran, (þ)-scalarolide and their unnatural analogs were described. Three key transformations were
involved in their synthesis, which are the ring-opening rearrangement of epoxide, stereoselective
DielseAlder addition, and one-pot
natural (þ)-scalarolide and 16-deacetoxy-scalarafuran were confirmed.
Ó 2011 Elsevier Ltd. All rights reserved.
g-butenolide formation process, and the absolute configurations of
1. Introduction
O
OH
A range of scalarane sesterterpenoids,1 which display a variety
of biological activities, such as cytotoxicity,2 antifeedant activity,3
anti-inflammatory,4 and platelet-aggregation inhibitory effects,5
have been isolated from different marine organisms during past
three decades. Many members of this group of scalaranic ses-
terterpenes possess ABCDE pentacyclic fused ring skeletons I
OH
O
O
OH
O
OH
Sesterstatin 4
OH
19
O
(Fig. 1), which contain g-butenolide or furan as ring E moieties, as
12
18
E
20
well as C12 oxygenated functionality as common structural fea-
tures. Some representative compounds are depicted in Fig. 1:
(þ)-scalarolide was first isolated from sponge Spongia idia in
1980;3a sesterstatins 4e5 and scalarafuran have been found to have
potent cytotoxic6 and HIV-1 integrase inhibiting activities;7 16-
deacetoxy-scalarafuran, isolated from genus Spongia, was repor-
ted to have the cytotoxicity against HeLa cells.8 16-Deacetoxy-12-
epi-scalarafuran acetate has the cytotoxicity against brine shrimp.9
Due to their important ecological roles, interesting biological
properties and unique structural skeleton, many efforts10 have been
developed for the construction of the scalarane framework, such as:
(i) biomimetic cyclization sequence of suitably constructed ali-
phatic11 or bicyclic12 C25 substrates; (ii) DielseAlder addition
constructing of the D ring from an ABC tricyclic ring precursor.13
However, to the best of our knowledge, all the above-mentioned
synthetic methods end up with the construction of the tetracyclic
ring skeleton, none of them has been successfully utilized to pro-
duce the scalarane sesterterpenes containing C12 oxygenated
group, which is supposed to be a prerequisite maintaining the bi-
ological activity.
11
C
13
Sesterstatin 5
(+)-Scalarolide
17
16
1
D
2
3
8
B
14
9
7
15
A
6
10
O
O
4
OH
OAc
5
I
OAc
O
OH
Scalarafuran
16-deacetyl-12-epi-
scalarafuran acetate
16-deacetoxy-
scalarafuran
Fig. 1. Representative scalaranic sesterterpenes.
Recently, we reported the first synthesis of marine scalaranic
sesterterpene (þ)-scalarolide,14 and sesterstatins 4/5,15 re-
spectively, through different strategies. For the synthesis of
(þ)-scalarolide, DielseAlder addition was employed as the key step
to construct the ring D; for the latter, a reductive Heck cyclization
was employed as the key step to afford the ring D. In the continu-
ation of our efforts to the synthesis of small library of marine sca-
laranic sesterterpenes for the marine lead compound discovery, we
further elaborated former synthetic route, and one new member of
this series, 16-deacetoxy-scalarafuran and two unnatural analogues
* Corresponding author. Tel./fax: þ86 021 64252431; e-mail address:
weiping_deng@ecust.edu.cn (W.-P. Deng).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.092

W.-Y. Fan et al. / Tetrahedron 67 (2011) 5596e5603
5597
of (þ)-scalarolide were synthesized. Herein, we would like to de-
scribe our recent achievement on the synthesis of 16-deacetoxy-
scalarafuran, (þ)-scalarolide and their derivatives in details.
With the success of the establishment of C12 hydroxy group on
the tricyclic ring skeleton, we then focused on the stereoselective
DielseAlder addition. As shown in Scheme 2, Wittig olefination of
enal 6 provided the 12
a consecutive oxidation with PDC and stereoselective Luche re-
duction to produce the 12 -OH diene 10, which can be also pre-
a-OH diene 8 in 79% yield, followed by
2. Results and discussion
b
pared through Wittig reaction of 7 in one-step. The benzyl
protection of 10 with benzyl bromide gave diene 11, which was
then subjected to DielseAlder addition with DMAD in sealed tube
at 110 ꢀC. As expected, the DielseAlder addition afforded desired 12
in 26% yield and undesired 13 in 52% yield. The 2D NOESY spectra of
12 and 13 established the above stereochemical assignment due to
an obvious crosspeak between newly formed angular methyl group
and the axial proton at C12 for 13, while the absence of such
a crosspeak for 12. This stereochemical result is different from that
of previous report.13b Unfortunately, many attempts to improve the
stereoselectivity by changing the benzyl protecting group to other
group, such as MOM, Acyl, and TBS turned out unsuccessful.
With two diastereoisomers 12 and 13 in hands, we initially try to
reduce the diester group to form furan ring using major isomer 13
as model substrate. Interestingly, reduction of diester 13 with LAH
(0.75 equiv) in ether resulted in the regioselective reduction of less
hindered methyl ester group, and spontaneous lactonization
A retrosynthetic analysis of 16-deacetoxy-scalarafuran is shown
in Fig. 2. The furan moiety could be synthesized from the diester
compound, which could be prepared from the DielseAlder addition
of tricyclic diene with DMAD to construct the ring D. The 12-OH
group can be introduced from an epoxide via epoxidation of tri-
cyclic methyl ent-isocopalate, which can be easily synthesized us-
ing sclareol 1 as starting material according to a published
method.12b,13a,16,17
disconnection
OP
O
OP
COOMe
COO Me
D-A
OH
D
D
16-deacetoxy
scalarafuran
afforded
g-butenolide 14 in 80% yield. This one-pot process of
O
regioselective construction of
g-butenolide moiety is superior to
OH
that of previously reported synthetic route of (þ)-12-
deoxyscalarolide.19 Further hydrogenation of 14 using 10% Pd/C
accomplished the synthesis of 25-epi-scalarolide 15 in 95% yield.
However, if an excess of LAH was used (10 equiv), both two esters of
13 were reduced to afford diol 16 in 69% yield, and further oxidation
with pyridinium chlorochromate afforded the expected furan 17 in
92% yield. Finally, deprotection of benzyl group and reduction of
double bond catalyzed by 10% Pd/C in ethyl acetate in one step
afforded 25-epi-16-deacetoxy-scalarafuran 18, an epimer of natural
16-deacetoxy-scalarafuran in 86% yield (Scheme 3).
COOMe
CHO
OH
sclareol 1
Fig. 2. The retrosynthetic analysis of 16-deacetoxy-scalarafuran.
Tricyclic intermediate 2 was prepared by a published proce-
dure12b,13a,16 from readily available sclareol 1. LAH reduction of 2
and subsequent Swern oxidation afforded aldehyde 4, which was
subjected to an epoxidation to generate the epoxide 5a as major
product in 70% yield, accompanied by a minor product 5b in 15%
yield (Scheme 1). The epoxide 5a underwent smoothly a ring-
Encouraged by the success of model reaction, we then turned to
the transformation of minor, but desired isomer 12. Using the
above-mentioned methods, g-butenolide 19 was synthesized via
opening rearrangement to afford 12
hyde 6 using pyrrolidine as base in ether at room temperature.18 It
was notable that 12 -OH- -unsaturated aldehyde 7 can be also
a-OH-a, b-unsaturated alde-
the LAH (0.75 equiv) reduction of 12, followed by debenzylation
and hydrogenation with 10% Pd/C to obtain 20 in high yield.
b
a, b
Comparisons of specific optical rotation ([a 18
]
þ23.6, c 0.13, CH2Cl2)
D
synthesized from compound 5b under the same condition (Scheme
1). Therefore, the both epimers of 6 and 7 were prepared via the
same procedure and can be utilized for further synthesis.
20
versus ([
a
]
D
þ26.3, c 0.15, CH2Cl2 of lit.2b), 1H NMR, 13C NMR, and
HRMS data of our synthetic 20 established the structural identity
with the natural (þ)-scalarolide isolated by Youssef2b and Faul-
kner.3a Likewise, when the amount of LAH was increased to
10 equiv, the diol 21 was afforded in 65% yield, which was then
oxidized by pyridinium chlorochromate to form the furan 22 in 90%
yield. Unfortunately, hydrogenation of compound 22 led to the
reduction of the furan to form a saturated furan ring, which differs
from the transformation of 17 to 18. Fortunately, when DIBAL-H
1) LiAlH4, Et2O, r.t.
R
COOCH3
97%
2) Swern Oxidation
96%
2
3
R = CH2OH
2)
4 R = CHO
was used instead of LAH for the reduction of the
g-butenolide 20,
O
O
the product 24 was obtained in 65% yield (Scheme 4). Comparisons
18
25
of specific optical rotation ([
a
]
D
ꢁ6.8, c 0.08, CHCl3) versus ([
a]
D
ꢁ9.1, c 0.076, CHCl3 of lit.8a), 1H NMR, 13C NMR, and HRMS data of
our synthetic 24 established the structural identity with the natural
16-deacetoxy-scalarafuran isolated by Tsukamoto.8a
m-CPBA, CH2Cl2
CHO
CHO
0 oC, 85%
5b (15%)
5a
(70%)
OH
3. Conclusion
OH
In summary, the first stereoselective synthesis of 16-deacetoxy-
scalarafuran 24 was finished in 20 steps with overall yield of 2.9%,
and also a series of scalaranic unnatural compounds, such as 25-
epi-scalarolide 15 and 25-epi-16-deacetoxy-scalarafuran 18 etc.,
were synthesized in an efficient way. It is believed that the de-
veloped synthetic method will be of benefit to the synthesis of
other sesterterpenes containing C12 oxygenated functionality,
Pyrrolidine
Et2O, r.t.
CHO
CHO
+
7
6
5a
5b
from
93%
from
83%
Scheme 1. The establishment of C12 hydroxy group.

5598
W.-Y. Fan et al. / Tetrahedron 67 (2011) 5596e5603
O
OH
OH
PDC, CH2Cl2
MePPh3Br, n-BuLi, THF
0 oC-r.t., 8 h, 79%
r.t., 4 h, 96%
CHO
9
8
6
NaBH4, CeCl3 ·7H2O
0 oC, 1 h, 95%
OBn
OH
OH
NaH, BnBr, THF
MePPh3Br, n-BuLi, THF
0 oC-r.t., 8 h, 75%
oC-r.t., overnight
96%
CHO
0
11
10
7
OBn CO2Me
OBn CO2Me
CO2Me
CO2Me
DMAD, 110 o
C
N2, sealed tube
24 h, 78%
12
(26%)
13
(52%)
Scheme 2. Synthesis of DielseAlder adducts 12 and its stereoisomer 13.
Scheme 3. Synthesis of 25-epi-16-deacetoxy-scalarafuran 18.
Scheme 4. Synthesis of (þ)-scalarolide 20 and 16-deacetoxy-scalarafuran 24.

W.-Y. Fan et al. / Tetrahedron 67 (2011) 5596e5603
5599
which will further facilitate the pharmacological evaluation of
corresponding marine natural or unnatural scalaranic products.
Further investigations are currently underway to extend this new
synthetic method to generate more analogs of 16-deacetoxy-sca-
larafuran and corresponding investigation of their pharmacological
properties.
aldehyde 4 (1.95 g, 96%). The procedure of Nakano et al. was
used.13a Rf¼0.4, petroleum ether/EtOAc (50/1). 1H NMR (400 MHz,
CDCl3):
d
9.70 (d, J¼5.1 Hz, 1H), 5.66 (s, 1H), 2.60 (s, 1H), 2.04e1.95
(m, 2H), 1.79e1.73 (m, 1H), 1.68e1.63 (m, 1H), 1.62 (s, 3H), 1.59e1.52
(m, 2H), 1.44e1.31 (m, 4H), 1.18e1.06 (m, 2H), 1.05 (s, 3H), 0.92 (s,
3H), 0.86 (s, 3H), 0.85e0.82 (m, 1H), 0.81 (s, 3H), 0.81e0.75 (m, 1H).
13C NMR (100 MHz, CDCl3):
d 206.9, 127.6, 125.2, 68.0, 56.4, 53.9,
4. Experimental
41.8, 41.8, 39.8, 37.5, 37.3, 33.4, 33.2, 22.6, 21.7, 21.5, 18.4, 18.3, 16.6,
15.9. The data is in agreement with that reported by Nakano et al.13a
4.1. General methods
4.4. Preparation of compounds 5a and 5b
Melting points were obtained in open capillary tubes using
a micro melting point apparatus SGW X-4, which were uncorrected.
Mass spectra were recorded by the HP5989A service; HRMS (EI)
spectra were obtained on a Finigann MAT8401 instrument. Optical
rotations were measured on a AUTOPOLO III polarimeter operating
To an ice-cooled solution of 4 (2.00 g, 6.93 mmol) in dry CH2Cl2
(60 mL) was added m-CPBA (85%, 1.55 g, 7.63 mmol), the mixture
was stirred at 0 ꢀC for 12 h. The CH2Cl2 solution was filtered, and the
filtrate was washed successively with saturated Na2SO3 (40 mL),
then washed with 0.1 N NaOH (3ꢂ20 mL) and saturated brine, dried
over Na2SO4, and concentrated in vacuo to give a solid residue,
which was purified by column chromatography (5%, EtOAc/petro-
leum ether) to give 5a (1.47 g, 70%) and 5b (316 mg, 15%). Rf¼0.20
for 5a and 0.25 for 5b, petroleum ethþer/1EtOAc (30/1). Data for 5a:
mp: 139e141 ꢀC. EI(MS) m/z 304.1 [M] . H NMR (400 MHz, CDCl3):
at the sodium D line (589 nm) and are reported as follows: [a
]DT,
concentration (g/100 mL), and solvent. 1H nuclear magnetic reso-
nance (NMR) spectra were recorded using an internal deuterium
lock for the residual protons in CDCl3
(
dH¼7.26) at ambient tem-
peratures on the following instruments: Bruker AVANCE DPX-400
(400 MHz). Data are presented as follows: chemical shift (in ppm
on the scale relative to dTMS¼0), integration, multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, and m¼multiplet), coupling con-
stant (J/Hz), and interpretation. 13C NMR spectra were recorded by
broadband spin decoupling using an internal deuterium lock for
d
9.83 (d, J¼5.3 Hz, 1H), 3.09 (s, 1H), 2.24 (d, J¼5.2 Hz, 1H), 2.09 (dd,
J¼4.4, 15.2 Hz, 1H), 1.82e1.72 (m, 1H), 1.68e1.37 (m, 6H), 1.34 (s,
3H), 1.31e1.20 (m, 2H), 1.15 (s, 3H), 1.13e1.07 (m, 1H), 0.99 (dd,
J¼4.7, 12.5 Hz, 1H), 0.92 (s, 3H), 0.84 (s, 3H), 0.83e0.81 (m, 1H), 0.80
CDCl3
(
d
¼77.2) at ambient temperatures on the following in-
(s, 3H), 0.79e0.76 (m, 1H). 13C NMR (100 MHz, CDCl3):
d 203.6, 67.2,
struments: Bruker AVANCE DPX-400 (100.6 MHz). Chemical shift
values are reported in parts per million on the scale (dTMS¼0). In-
frared spectra were recorded on NICOLET 5SXC instrument as thin
film, frequencies are given as wavenumbers (cmꢁ1). All reagents
and solvents were used as purchased if not otherwise stated.
60.4, 56.1, 55.7, 49.2, 41.6, 41.1, 39.3, 37.3, 36.2, 33.4, 33.1, 22.8, 21.6,
21.6, 18.3, 18.2, 17.0,þ16.0. Data for 5b: mp: 183e185 ꢀC. HRMS(EI)
calcd for C20H32O2 [M]þ 304.2402, found 304.2402. 1H NMR
(400 MHz, CDCl3):
d
9.69 (d, J¼4.8 Hz, 1H), 3.18 (t, J¼1.9 Hz, 1H),
2.14e2.09 (m, 1H), 1.94 (d, J¼4.8 Hz, 1H), 1.81e1.64 (m, 3H),
1.54e1.48 (m, 2H), 1.47e1.44 (m, 1H), 1.41e1.39 (m, 1H), 1.38e1.36
(m, 1H), 1.34 (s, 3H), 1.32e1.27 (m, 2H), 1.26 (s, 1H), 0.96 (s, 3H), 0.92
(s, 3H), 0.89e0.87 (m, 1H), 0.85 (s, 3H), 0.82 (s, 3H), 0.81e0.79 (m,
4.2. Preparation of compound 3
To a solution of 2 (420 mg,1.32 mmol) in dry Et2O (30 mL) LiAlH4
(50 mg, 1.32 mmol) was added at 0 ꢀC, and the reaction was stirred
at 0 ꢀC for 6 h. Once the reaction was finished as judged by TLC,
water (2 mL) was added to quench the unreacted LiAlH4. The
mixture was then extracted with CH2Cl2 (3ꢂ10 mL), and the organic
phase was washed with saturated NaCl, dried over Na2SO4, con-
centrated in vacuo, and purified by column chromatography (10%,
EtOAc/petroleum ether) to give 3 (372 mg, 97%) as a white solid.
Rf¼0.2, petroleum ether/EtOAc (20/1). 1H NMR (400 MHz, CDCl3):
1H). 13C NMR (100 MHz, CDCl3):
d 203.9, 62.6, 59.2, 57.3, 56.5, 44.6,
41.7, 39.6, 38.4, 37.1, 34.6, 33.4, 33.2, 24.8, 22.7, 21.8, 21.7, 18.4, 18.3,
16.2.
4.5. Preparation of compound 6
To a solution of 5a (150 mg, 0.49 mmol) in Et2O (30 mL) was
added pyrrolidine (0.1 mL, 1.09 mmol) at room temperature, and
the reaction was stirred over night. Once the reaction was finished
as judged by TLC, water (5 mL) was added. The mixture was
extracted with EtOAc (3ꢂ10 mL), the organic layer washed suc-
cessively with brine, dried over Na2SO4, concentrated in vacuo, and
purified by column chromatography (10%, EtOAc/petroleum ether)
to give 6 (139 mg, 93%) as a white solid. Rf¼0.2, petroleum ether/
d
5.50 (s, 1H), 3.88e3.82 (m, 1H), 3.76e3.69 (m, 1H), 2.07 (dt, J¼3.2,
12.6 Hz, 1H), 1.95e1.83 (m, 3H), 1.78 (s, 3H), 1.67e1.57 (m, 2H),
1.55e1.51 (m,1H),1.43e1.31 (m, 3H),1.25e1.07 (m, 4H), 0.89 (s, 3H),
0.86 (s, 3H), 0.84 (s, 3H), 0.82 (s, 3H), 0.81e0.78 (m, 1H). 13C NMR
(100 MHz, CDCl3):
d 132.7, 123.8, 60.8, 57.8, 56.2, 54.8, 41.9, 41.5,
39.9, 37.2, 36.2, 33.4, 33.1, 22.6, 21.9, 21.7, 18.8, 18.5, 15.8, 15.8.
EtOAc (6/1). Mp: 134e135 ꢀC. 1H NMR (400 MHz, CDCl3):
d 10.08 (s,
1H), 4.05 (d, J¼4.1 Hz, 1H), 2.49 (dt, J¼3.2, 12.9 Hz, 1H), 2.13 (s, 3H),
1.82 (d, J¼14.2 Hz, 1H), 1.72e1.58 (m, 4H), 1.47e1.36 (m, 3H), 1.27
(dd, J¼1.8,12.9 Hz,1H),1.17 (s, 3H),1.16e1.08 (m, 2H), 0.92e0.89 (m,
1H), 0.88 (s, 3H), 0.87e0.85 (m, 1H), 0.84 (s, 3H), 0.82 (s, 3H). 13C
4.3. Preparation of compound 4
A solution of dimethyl sulfoxide (1.2 mL, 15.2 mmol) in CH2Cl2
(4 mL) was added dropwise to a stirred solution of oxalyl chloride
(0.7 mL, 7.6 mmol) in CH2Cl2 (25 mL) under dry nitrogen at ꢁ60 ꢀC.
After 3 min at ꢁ60 ꢀC, a solution of the alcohol 3 (2.0 g, 6.9 mmol) in
CH2Cl2/dimethyl sulfoxide (3/1; 10 mL) was added dropwise over
5 min. The reaction mixture was stirred for a further 20 min, trie-
thylamine (4.8 mL, 36.1 mmol) was added at ꢁ60 ꢀC, and stirring
was continued for a further 10 min. The cooling bath was removed,
water was added at room temperature, and the product was
extracted with ether (3ꢂ10 mL). The ether was evaporated off and
the remaining dimethyl sulfoxide was removed under reduced
pressure, yielding a crude product as a gum. Chromatography on
silica gel using 3% EtOAc/petroleum ether as the eluant afforded the
NMR (100 MHz, CDCl3):
d 194.3, 148.4, 145.0, 70.7, 56.5, 56.3, 50.3,
42.0, 39.6, 38.9, 37.6, 37.0, 33.2, 27.1, 21.2, 19.8, 18.5, 18.4, 16.8, 16.5.
4.6. Preparation of compound 7
To a solution of 5b (150 mg, 0.49 mmol) in Et2O (30 mL) was
added pyrrolidine (0.1 mL, 1.09 mmol) at room temperature, and
the reaction was stirred over night. Once the reaction was finished
as judged by TLC, water (5 mL) was added. The mixture was
extracted with EtOAc (3ꢂ10 mL), the organic layer washed suc-
cessively with brine, dried over Na2SO4, concentrated in vacuo, and
purified by column chromatography (10%, EtOAc/petroleum ether)

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W.-Y. Fan et al. / Tetrahedron 67 (2011) 5596e5603
to give 7 (125 mg, 83%) as a white solid and was directly used for
the next step. Rf¼0.2, petroleum ether/EtOAc (6/1). Mp:
183e184 ꢀC. EIMS m/z 304.3 [M]þ. 1H NMR (400 MHz, CDCl3):
0.86 (s, 3H), 0.84 (s, 3H), 0.81 (s, 3H), 0.80e0.75 (m, 1H). 13C NMR
(100 MHz, CDCl3): 145.5, 134.4, 128.5, 119.6, 73.6, 56.3, 54.0, 42.1,
39.6, 39.4, 39.0, 37.2, 33.2, 33.2, 28.6, 21.3, 21.1, 18.5, 18.5, 16.6, 16.4.
IR (film): 3247, 2996, 2932, 2850, 1377, 1013, 918 cmꢁ1
d
d
10.06 (s, 1H), 4.15 (dd, J¼8.0, 16.7 Hz, 1H), 2.52 (dt, J¼3.2, 12.9 Hz,
.
1H), 2.18e2.11 (m, 1H), 2.10 (s, 3H), 1.75e1.62 (m, 2H), 1.58e1.54 (m,
1H), 1.49e1.33 (m, 4H), 1.26 (s, 3H), 1.18e1.05 (m, 3H), 0.88 (s, 3H),
0.84 (br s, 4H), 0.81 (s, 3H), 0.80e0.73 (m, 1H).
4.10. Preparation of compound 10 from 7
To suspension of methyltriphenylphosphonium bromide
a
4.7. Preparation of compound 8
(411 mg, 1.15 mmol) in THF (25 mL), a solution of n-BuLi in hexane
(1.6 M, 0.6 mL, 0.96 mmol) was added dropwise at 0 ꢀC under
nitrogen atmosphere. The solution was stirred for a further 40 min,
then a solution of aldehyde 7 (158 mg, 0.52 mmol) in THF (5 mL)
was added dropwise. Then the mixture was stirred at room tem-
perature for 8 h, then quenched with aqueous NH4Cl (2 mL), and
extracted with Et2O (3ꢂ10 mL). The organic layer was washed with
saturated brine and dried over Na2SO4. The residue was obtained
after removing the solvent and was purified by chromatography
(5%, EtOAc/petroleum ether) afforded 10 (118 mg, 75%) as a white
solid.
To
a suspension of methyltriphenylphosphonium bromide
(411 mg, 1.15 mmol) in THF (25 mL) at 0 ꢀC under nitrogen atmo-
sphere, a solution of n-BuLi in hexane (1.6 M, 0.6 mL, 0.96 mmol)
was added dropwise. The solution was stirred for a further 40 min,
then a solution of aldehyde 6 (158 mg, 0.52 mmol) in THF (5 mL)
was added dropwise at 0 ꢀC. The mixture was stirred at room
temperature for 8 h, then quenched with aqueous NH4Cl (2 mL),
and extracted with Et2O (3ꢂ10 mL). The organic layer was washed
with saturated brine and dried over Na2SO4. The residue was
obtained after removing the solvent and purified by chromatog-
raphy (5%, EtOAc/petroleum ether) afforded 8 (124 mg, 79%) as
4.11. Preparation of compound 11
a
white solid. Rf¼0.3, petroleum ether/EtOAc (20/1). Mp:
130e132 ꢀC. 1H NMR (400 MHz, CDCl3):
d
6.11 (dd, J¼11.3, 17.7 Hz,
To a solution of NaH (220 mg, 5.5 mmol) in 15 mL dry THF was
added BnBr (0.66 mL) under N2 atmosphere at 0 ꢀC. After stirring at
room temperature for 10 min, Bu4NBr (35.5 mg 0.11 mmol) was
added at 0 ꢀC, and the reaction was stirred for another 10 min. Then
a solution of compound 10 (165 mg, 0.55 mmol) in 10 mL dry THF
was added dropwise to the solution. The reactant was warmed to
35 ꢀC. Once the reaction was finished as judged by TLC, water was
added to quench any unreacted NaH. The mixture was extracted
with CH2Cl2 (3ꢂ10 mL), and the organic phase was washed with
saturated NaCl, dried over Na2SO4, concentrated in vacuo, and
purified by column chromatography (1%, EtOAc/petroleum ether)
to give 11 (207 mg, 96%) as a white solid. Rf¼0.3, petroleum ether/
EtOAc (100/1). EIMS m/z 392.3 [M]þ. 1H NMR (400 MHz, CDCl3):
1H), 5.30 (dd, J¼2.6, 11.3 Hz, 1H), 4.96 (dd, J¼2.6, 17.7 Hz, 1H), 4.00
(d, J¼3.8 Hz, 1H), 1.79 (s, 3H), 1.77e1.72 (m, 2H), 1.71e1.68 (m, 1H),
1.67e1.60 (m, 1H), 1.58e1.54 (m, 1H), 1.50 (s, 1H), 1.47e1.41 (m, 1H),
1.40e1.34 (m, 2H), 1.33e1.28 (m, 1H), 1.23e1.09 (m, 2H), 0.97 (s,
3H), 0.92e0.87 (m, 2H), 0.86 (s, 3H), 0.84 (s, 3H), 0.81 (s, 3H). 13C
NMR (100 MHz, CDCl3):
42.1, 39.6, 39.3, 38.8, 37.0, 33.3 (2C), 27.5, 21.3, 19.4, 18.7, 18.6, 18.5,
16.5. IR (film): 3414, 2996, 2932, 1623, 1401, 1200, 967, 917 cmꢁ1
d 146.2, 134.3, 127.1, 119.2, 70.5, 56.5, 50.2,
.
4.8. Preparation of compound 9
To a solution of 8 (120 mg, 0.40 mmol) in CH2Cl2 (20 mL) was
added PDC (752 mg, 2.0 mmol), and the solution was stirred at
room temperature for 4 h. Once the reaction was finished, PDC was
filtered, and the solvent was concentrated in vacuo to give a solid
residue, which was purified by column chromatography (3%, EtOAc/
petroleum ether) to give 9 (114 mg, 96%) as a white solid. Rf¼0.3,
petroleum ether/EtOAc (40/1). Mp: 116e118 ꢀC. EI(MS) m/z 300.2
d
7.34 (m, 5H), 6.10 (dd, J¼11.3, 17.5 Hz, 1H), 5.27 (dd, J¼2.5, 11.2 Hz,
1H), 4.97 (dd, J¼2.5, 11.2 Hz, 1H), 4.63 (d, J¼11.4 Hz, 1H), 4.49 (d,
J¼11.4 Hz, 1H), 3.95 (t, J¼8.4 Hz, 1H), 2.10 (dd, J¼7.4, 12.2 Hz, 1H),
1.78e1.74 (m, 1H), 1.73 (s, 3H),1.68e1.57 (m, 2H), 1.53e1.41 (m, 2H),
1.37e1.34 (m, 1H), 1.28e1.22 (m, 1H), 1.22e1.11 (m, 3H), 1.11e1.08
(m, 1H), 1.05 (s, 3H), 0.88 (s, 3H), 0.87e0.85 (m, 1H), 0.84 (s, 3H),
[M]þ. 1H NMR (400 MHz, CDCl3):
d
6.30 (dd, J¼11.7, 17.7 Hz, 1H),
0.81 (s, 3H), 0.80e0.75 (m, 1H). 13C NMR (100 MHz, CDCl3):
d 146.2,
5.48 (dd, J¼2.0, 11.7 Hz, 1H), 5.12 (dd, J¼2.0, 17.7 Hz, 1H), 2.48 (dd,
J¼4.2, 17.6 Hz, 1H), 2.37 (dd, J¼13.9, 17.6 Hz, 1H), 1.86e1.80 (m, 1H),
1.78 (s, 3H), 1.72e1.58 (m, 4H), 1.54 (s, 2H), 1.47e1.35 (m, 4H), 1.12
(s, 3H), 0.93 (s, 3H), 0.91e0.87 (m, 1H), 0.86 (s, 3H), 0.83 (s, 3H). 13C
139.1, 134.5, 128.3, 127.8, 127.6, 127.4, 119.5, 80.4, 69.9, 56.4, 53.9,
42.1, 39.6, 39.5, 38.8, 37.3, 33.3, 33.2, 24.1, 21.3, 21.0, 18.6, 18.5, 17.1,
16.4. IR (film): 3431, 2996, 2851, 1621, 1452, 1376, 1068, 918, 741,
697 cmꢁ1
.
NMR (100 MHz, CDCl3):
41.9, 39.9, 39.1, 38.9, 37.3, 34.4, 33.2, 33.1, 21.4, 19.2, 18.5, 18.3, 15.8,
13.2. IR (film): 3445, 2958, 2929, 1656, 936, 804 cmꢁ1
d 200.9,165.0, 133.2,128.7,120.8, 56.0, 54.2,
4.12. Preparation of compounds 12 and 13
.
A mixture of the diene 11 (100 mg, 0.25 mmol) and freshly
distilled DMAD (0.5 mL, 4.1 mmol) was heated under nitrogen at-
mosphere in a seal tube at 110 ꢀC for 24 h. Then the reaction was
cooled to room temperature, DMAD was removed under reduced
pressure. The residue was purified by column chromatography (4%
EtOAc/petroleum ether) to give compounds 12 (35 mg, 26%) and 13
(70 mg, 52%) as white solid. Rf¼0.15 for 13 and 0.10 for 12, petro-
leum ether/EtOAc (30/1). Data for 12: mp: 69e71 ꢀC. 1H NMR
4.9. Preparation of compound 10 from 9
To a solution of 9 (123 mg, 0.41 mmol) in MeOH (10 mL) and
CH2Cl2 (3 mL) at 0 ꢀC was added CeCl3$7H2O (167 mg, 0.45 mmol),
followed by NaBH4 (17.0 mg, 0.45 mmol). Once the reaction was
finished as judged by TLC, the solvent was removed in vacuo.
CH2Cl2 was added, the organic solution was washed with saturated
NaCl, dried over Na2SO4, concentrated in vacuo, and purified by
column chromatography (10%, EtOAc/petroleum ether) to give 10
(115 mg, 95%) as a white solid. Rf¼0.3, petroleum ether/EtOAc (20/
1). Mp: 159e161 ꢀC. HRMS-EI calcd for C21H34Oþ [M]þ 302.2610,
(400 MHz, CDCl3):
d 7.34e7.30 (m, 4H), 7.25e7.20 (m, 1H), 5.61 (d,
J¼3.6 Hz,1H), 4.65 (d, J¼12.2 Hz,1H), 4.26 (d, J¼12.2 Hz,1H), 3.70 (s,
3H), 3.64 (dd, J¼4.5, 11.3 Hz, 1H), 3.34 (s, 3H), 3.09 (dd, J¼5.6,
22.5 Hz, 1H), 2.83 (dd, J¼1.7, 22.5 Hz, 1H), 2.13 (dd, J¼3.6, 12.6 Hz,
1H), 1.97 (d, J¼11.5 Hz, 1H), 1.75e1.58 (m, 3H), 1.54e1.49 (m, 1H),
1.47 (s, 3H), 1.44e1.41 (m, 1H), 1.41e1.30 (m, 3H), 1.21 (s, 3H),
1.18e1.08 (m, 1H), 0.91e0.87 (m, 1H), 0.86 (s, 3H), 0.85 (s, 3H), 0.82
found 302.2614. 1H NMR (400 MHz, CDCl3):
d
6.11 (dd, J¼11.7,
17.2 Hz, 1H), 5.30 (dd, J¼2.6, 11.2 Hz, 1H), 4.96 (dd, J¼2.6, 17.7 Hz,
1H), 4.09 (m, 1H), 2.08 (dd, J¼7.2, 12.3 Hz, 1H), 1.80e1.75 (m, 1H),
1.73 (s, 3H), 1.72e1.69 (m, 1H), 1.66e1.60 (m, 1H), 1.57e1.53 (m, 1H),
1.46e1.34 (m, 5H), 1.27e1.19 (m, 1H), 1.19e1.11 (m, 2H), 1.04 (s, 3H),
(s, 3H), 0.80e0.74 (m, 2H). 13C NMR (100 MHz, CDCl3):
166.3, 151.8, 148.6, 139.4, 128.1 (2C), 126.8, 126.4 (2C), 124.8, 116.4,
d 169.8,

W.-Y. Fan et al. / Tetrahedron 67 (2011) 5596e5603
5601
80.7, 68.3, 56.1, 53.1, 52.0, 51.9, 46.0, 41.9, 41.2, 40.5, 39.8, 37.8, 33.2
4.15. Preparation of compound 16
(2C), 26.7, 25.6, 21.9, 21.5, 21.4, 18.7, 18.6, 16.2. IR (film): 3438, 2945,
2929, 2864, 1730, 1258, 738, 689 cmꢁþ1. Data for 13: mp: 86e88 ꢀC.
HRMS (ESI) calcd for C34H46O5NH4 [MþNa]þ 552.3689, found
To a solution of compound 13 (20 mg, 0.037 mmol) in dry ether
(10 mL) was added LiAlH4 (14.2 mg, 0.37 mmol) at 0 ꢀC. The reaction
mixture was stirred at 0 ꢀC for 1 h. Once the reaction was finished as
judged by TLC, water was added to quench any unreacted LiAlH4.
The mixture was extracted with Et2O (3ꢂ5 mL), and the organic
phase was washed successively with brine, dried over Na2SO4. The
residue was purified by column chromatography to give 16
(12.2 mg, 69%) as a white solid. Rf¼0.2, petroleum ether/EtOAc (3/
552.3677. 1H NMR (400 MHz, CDCl3):
d 7.31e7.26 (m, 4H), 7.24e7.18
(m, 1H), 5.71 (d, J¼5.3 Hz, 1H), 4.62 (d, J¼11.9 Hz, 1H), 4.16 (d,
J¼11.9 Hz, 1H), 4.00 (d, J¼7.8 Hz, 1H), 3.71 (s, 3H), 3.64 (s, 3H), 3.26
(dd, J¼5.9, 22.5 Hz, 1H), 2.77 (d, J¼22.6 Hz, 1H), 2.14 (d, J¼11.7 Hz,
1H), 2.01e1.90 (m, 1H), 1.77 (m, 1H), 1.65e1.60 (m, 1H), 1.58e1.50
(m, 3H), 1.46e1.40 (m, 1H), 1.39 (s, 4H), 1.38e1.33 (m, 2H), 1.20 (s,
3H), 1.17e1.08 (m, 1H), 0.94e0.87 (m, 1H), 0.85 (s, 3H), 0.84 (s, 3H),
þ
1). Mp: 87e89 ꢀC. HRMS (EI) calcd for C32H46O3 [M]þ 478.3447,
0.81 (s, 3H), 0.80e0.76 (m, 1H). 13C NMR (100 MHz, CDCl3):
d
168.8,
found 478.3446. 1H NMR (400 MHz, CDCl3):
d 7.35e7.27 (m, 5H),
168.0, 153.5, 145.9, 138.6, 131.8, 128.1 (2C), 126.9 (2C), 116.6, 70.5,
56.7, 52.1, 51.5, 48.8, 44.2, 43.4, 42.0, 39.7, 39.2, 37.9, 33.3, 33.1, 28.0,
27.1, 26.1, 21.9, 21.5, 19.3, 18.5, 15.8. IR (film): 3450, 2946, 2929,
5.72 (dd, J¼2.6, 5.2 Hz, 1H), 4.83 (d, J¼11.2 Hz, 1H), 4.27 (dd, J¼3.5,
11.5 Hz, 2H), 4.15 (s, 2H), 4.11e4.07 (m, 1H), 4.00 (d, J¼11.9 Hz, 1H),
2.90e2.74 (m, 2H), 2.69e2.40 (br, 2H), 2.20e2.13 (m, 1H), 2.02e1.96
(m, 2H), 1.73e1.61 (m, 4H), 1.48e1.36 (m, 4H), 1.26 (t, J¼7.2 Hz, 1H),
1.22 (s, 3H), 1.19e1.13 (m, 1H), 1.11 (s, 3H), 0.94 (s, 3H), 0.88 (s, 3H),
2881, 1725, 1253, 736, 701 cmꢁ1
.
0.84 (s, 3H), 0.83e0.79 (m, 1H). 13C NMR (100 MHz, CDCl3):
d 152.8,
4.13. Preparation of compound 14
142.1, 137.2, 136.6, 128.6, 128.1, 127.9, 118.1, 78.9, 69.9, 63.7, 57.8,
56.8, 48.8, 43.5, 43.5, 42.0, 39.8, 39.3, 37.9, 33.3, 33.2, 31.0, 27.9,
26.4, 21.5, 21.5, 19.4, 18.5, 16.0. IR (film): 3386, 2929, 1593, 1459,
To a solution of compound 13 (56 mg, 0.105 mmol) in 5 mL Et2O
was added LiAlH4 (3.0 mg, 0.079 mmol) at 0 ꢀC. Then the reaction
was refluxed for 1 h. Once the reaction was finished, water was
added to quench the LiAlH4. The mixture was extracted with Et2O
(3ꢂ5 mL), and the organic phase was washed successively with
brine, dried over Na2SO4. The residue was purified by column
chromatography to give 14 (40 mg, 80%) as a white solid. Rf¼0.2,
petroleum ether/EtOAc (10/1). Mp: 69e72 ꢀC. 1H NMR (400 MHz,
1052, 748, 702 cmꢁ1
.
4.16. Preparation of compound 17
PCC (205 mg, 0.95 mmol) was added to a solution of compound
16 (30 mg, 0.06 mmol) in CH2Cl2 (8 mL). The reaction mixture was
stirred at room temperature for 0.5 h. PCC was filtrated, the reaction
was evaporated in vacuo to get the crude product, which was pu-
rified by column chromatography (2% EtOAc/petroleum ether) to
get the product compound 17 (26 mg, 92%) as a white solid. Rf¼0.3,
petroleum ether/EtOAc (50/1). Mp: 144e146 ꢀC. HRMS (EI) calcd for
CDCl3):
d
7.29e7.26 (m, 1H), 7.25e7.18 (m, 4H), 5.68 (dd, J¼2.4,
4.8 Hz, 1H), 4.70e4.57 (m, 4H), 4.47 (d, J¼11.2 Hz, 1H), 3.02e2.85
(m, 2H), 2.16e2.10 (m, 1H), 2.06e1.96 (m, 1H), 1.79e1.67 (m, 2H),
1.66e1.54 (m, 4H), 1.47e1.34 (m, 4H), 1.32 (s, 3H), 1.23 (s, 3H),
1.19e1.09 (m, 1H), 0.88 (s, 3H), 0.86 (s, 3H), 0.83 (s, 3H), 0.82e0.76
þ
C32H42O2 [M]þ 458.3185, found 458.3183. 1H NMR (400 MHz,
(m, 1H). 13C NMR (100 MHz, CDCl3):
d
172.4, 157.3, 154.7, 139.3,
CDCl3):
d
7.32e7.23 (m, 5H), 7.12 (s, 1H), 6.79 (d, J¼1.3 Hz, 1H), 5.80
132.9, 128.2, 128.1, 127.1, 115.7, 76.3, 71.6, 70.4, 57.0, 48.7, 43.5, 42.0,
40.1, 39.9, 39.7, 37.8, 33.3, 33.2, 27.3, 26.8, 25.7, 22.6, 21.5, 19.4, 18.5,
(dd, J¼2.1, 6.1 Hz,1H), 4.67 (d, J¼11.9 Hz,1H), 4.46 (d, J¼11.9 Hz,1H),
3.89 (d, J¼7.3 Hz, 1H), 3.22 (dd, J¼6.2, 20.0 Hz, 1H), 3.08 (dt, J¼1.9,
20.0 Hz, 1H), 2.20e2.13 (m, 1H), 2.07e1.96 (m, 1H), 1.94e1.85 (m,
1H),1.82e1.73 (m, 1H), 1.66e1.58 (m, 3H),1.49e1.35 (m, 4H), 1.33 (s,
1H), 1.28 (s, 3H), 1.24 (s, 3H), 1.19e1.10 (m, 1H), 0.93 (s, 3H), 0.86 (s,
3H), 0.84 (s, 3H), 0.83e0.79 (m, 1H). 13C NMR (100 MHz, CDCl3):
16.1. IR (film): 3446, 1753, 1450, 1062, 991, 697 cmꢁ1
.
4.14. Preparation of compound 15
d
152.9,137.2,134.7,133.4,130.8,127.4,127.2,126.4,119.3,117.0, 77.0,
To a solution of compound 14 (10 mg, 0.021 mmol) in MeOH
(5 mL) 10% Pd/C (30 mg) was added under hydrogen atmosphere.
The reaction mixture was stirred at room temperature for 8 h. Once
the reaction was finished as judged by TLC, Pd/C was filtrated, and
the solvent was evaporated in vacuo to obtain the crude product,
which was purified by column chromatography (20% EtOAc/pe-
troleum ether) to get compound 15 (7.7 mg, 95%) as a white solid.
Rf¼0.2, petroleum ether/EtOAc (6/1). Mp: >300 ꢀC. HRMS (EI) calcd
for C25H38O3þ [M]þ 386.2829, found 386.2825. 1H NMR (400 MHz,
69.8, 55.9, 48.0, 42.7, 41.0, 38.8, 38.7, 38.4, 37.1, 32.3, 32.2, 30.5, 25.5,
21.3, 20.5, 20.1, 18.4, 17.5, 15.0.
4.17. Preparation of compound 18
This procedure was the same as for the preparation of the
compound 15 with the solvent of ethyl acetate. After column
chromatography and evaporated in vacuo, product 18 was obtained
in 86% yield as white solid. Rf¼0.2, petroleum ether/EtOAc (30/1).
þ
CDCl3):
d
5.80 (d, J¼12.1 Hz, 1H), 4.79 (d, J¼17.5 Hz, 1H), 4.61 (d,
Mp: 152e154 ꢀC. HRMS (EI) calcd for C25H38O2 [M]þ 370.2872,
J¼17.5 Hz, 1H), 3.30 (td, J¼12.0, 3.6 Hz, 1H), 2.43 (dd, J¼6.1, 8.7 Hz,
2H), 2.17e2.00 (m, 2H), 1.96e1.90 (m, 1H), 1.85 (dt, J¼3.2, 12.6 Hz,
1H), 1.72 (d, J¼12.6 Hz, 1H), 1.61e1.51 (m, 2H), 1.47e1.31 (m, 5H),
1.30 (s, 3H), 1.29e1.24 (m, 1H), 1.16e1.06 (m, 1H), 1.01e0.88 (m, 2H),
0.83 (s, 3H), 0.81e0.79 (m,1H), 0.78 (s, 3H), 0.76 (s, 3H), 0.61 (s, 3H).
found 370.2875. 1H NMR (400 MHz, CDCl3):
d
7.50 (d, J¼1.2 Hz, 1H),
7.09 (d, J¼1.3 Hz, 1H), 3.65 (dd, J¼4.6, 11.2 Hz, 1H), 2.64 (m, 2H),
2.02e1.94 (m, 2H), 1.87 (dt, J¼3.2, 12.7 Hz, 2H), 1.75e1.66 (m, 3H),
1.64e1.60 (m, 1H), 1.52e1.48 (m, 1H), 1.44e1.36 (m, 2H), 1.33 (s, 1H),
1.28 (s, 3H), 1.22 (t, J¼4.0 Hz, 1H), 1.16e1.09 (m, 1H), 0.97e0.91 (m,
1H), 0.91e0.86 (m, 2H), 0.84 (s, 3H), 0.77 (s, 3H), 0.75 (s, 3H), 0.55 (s,
1H NMR (400 MHz, CDCl3 add D2O):
d
5.82 (d, J¼12.0 Hz, 0.3H), 4.79
(d, J¼17.5 Hz, 1H), 4.61 (d, J¼17.5 Hz, 1H), 3.30 (d, J¼12.0 Hz, 1H),
2.43 (dd, J¼6.1, 8.7 Hz, 2H), 2.17e2.00 (m, 2H), 1.96e1.90 (m, 1H),
1.85 (dt, J¼3.2, 12.6 Hz, 1H), 1.72 (d, J¼12.6 Hz, 1H), 1.61e1.51 (m,
2H), 1.47e1.31 (m, 5H), 1.30 (s, 3H), 1.29e1.24 (m, 1H), 1.16e1.06 (m,
1H), 1.01e0.88 (m, 2H), 0.83 (s, 3H), 0.81e0.79 (m, 1H), 0.78 (s, 3H),
3H). 13C NMR (100 MHz, CDCl3):
d 136.8, 136.6, 126.2, 121.4, 81.1,
58.2, 56.7, 54.9, 42.4, 42.1, 40.3, 39.7, 39.2, 37.3, 33.3, 33.3, 30.2, 27.0,
21.3,18.6,18.2,16.7,16.5,16.2,15.8. IR (film): 3405, 2929,1640,1395,
1026, 614 cmꢁ1
.
0.76 (s, 3H), 0.61 (s, 3H). 13C NMR (100 MHz, CDCl3):
d
175.6, 166.2,
4.18. Preparation of compound 19
131.6, 79.9, 72.7, 59.2, 56.6, 55.0, 42.3, 42.0, 41.8, 40.1, 39.4, 37.3,
33.3, 33.2, 28.9, 28.6, 21.9, 21.2, 18.5, 18.1, 17.5, 16.9, 15.8. IR (film):
This procedure was the same as for the preparation of the
compound 14. After column chromatography and evaporated in
3425, 2921, 1708, 1645, 1459, 1054, 788 cmꢁ1
.

5602
W.-Y. Fan et al. / Tetrahedron 67 (2011) 5596e5603
vacuo, product 19 was obtained in 88% yield as white solid. Rf¼0.2,
petroleum etþher/EtOAc (10/1). Mp: 207e209 ꢀC. HRMS (ESI) calcd
for C32H42O3 [M]þ 474.3134, found 474.3136. 1H NMR (400 MHz,
4.22. Preparation of compound 23
This procedure was the same as for the preparation of com-
pound 18. After column chromatography and evaporated in vacuo,
product 23 was obtained in 86% yield as white solid. Rf¼0.2, pe-
troleum ether/EtOAc (4/1). Mp: 179e181 ꢀC EI/MS m/z 374.3 [M]þ.
CDCl3):
d
7.42 (d, J¼7.3 Hz, 2H), 7.30 (t, J¼7.3 Hz, 2H), 7.22 (t,
J¼7.3 Hz, 1H), 5.59 (t, J¼3.6 Hz, 1H), 4.67 (d, J¼11.6 Hz, 1H), 4.58 (s,
2H), 4.47 (d, J¼11.5 Hz, 1H), 3.33 (dd, J¼4.5, 11.2 Hz, 1H), 2.95 (m,
2H), 1.97e1.77 (m, 2H), 1.66e1.62 (m, 1H), 1.62e1.57 (m, 3H), 1.51 (s,
3H), 1.46e1.41 (m, 2H), 1.40e1.34 (m, 2H), 1.18 (s, 3H), 1.14e1.07 (m,
1H), 0.86 (s, 3H), 0.85 (s, 3H), 0.82 (s, 3H), 0.78e0.72 (m, 3H). 13C
1H NMR (400 MHz, CDCl3):
d
4.35 (dd, J¼2.1, 9.2 Hz, 1H), 3.85e3.79
(m, 2H), 3.41 (dd, J¼7.9, 10.2 Hz, 1H), 3.33 (m, 1H), 2.36 (br, 1H), 1.93
(t, J¼6.0 Hz, 1H), 1.77 (dt, J¼3.0, 12.5 Hz, 1H), 1.71e1.59 (m, 5H),
1.55e1.34 (m, 8H), 1.26 (s, 1H), 1.19e1.07 (m, 2H), 0.97 (s, 3H),
0.93e0.87 (m, 2H), 0.86 (s, 3H), 0.84 (s, 3H), 0.83 (s, 3H), 0.80 (s,
NMR (100 MHz, CDCl3):
d 171.2, 157.7, 153.5, 139.3, 132.3, 128.3,
128.1, 127.1, 113.7, 83.5, 71.5, 69.2, 56.5, 54.7, 43.2, 42.0, 41.9, 40.8,
39.6, 38.1, 33.3, 33.2, 26.0, 24.4, 23.5, 21.4, 21.3, 18.9, 18.6, 16.0. IR
(film): 3424, 2945, 1753, 1400, 993, 705 cmꢁ1
3H), 0.79e0.77 (m,1H). 13C NMR (100 MHz, CDCl3):
d 84.8, 72.1, 71.7,
58.8, 56.7, 56.4, 53.1, 42.1, 41.7, 41.1, 39.9, 37.9, 37.6, 37.4, 33.3 (2C),
27.8, 24.3, 21.3, 18.6, 18.2, 17.5, 16.4 (2C), 11.7. IR (film): 3433, 2926,
2842, 1462, 1379, 1058, cmꢁ1. The data is in agreement with that
reported by Kamel et al.20
4.19. Preparation of compound 20
This procedure was the same as for the preparation of com-
pound 15. After column chromatography and evaporated in vacuo,
product 20 was obtained in 92% yield as white solid. Rf¼0.2, pe-
4.23. Preparation of compound 24
troleum ether/EtOAc (6/1). Mp: >300 ꢀC. [a 18
]
þ23.6 (c 0.13, CH2Cl2)
To a solution of compound 20 (5 mg, 0.013 mmol) in dry toluene
was added DIBAL-H (1 M in hexane, 0.06 mL, 0.06 mmol,) dropwise
at ꢁ78 ꢀC under nitrogen atmosphere. After 2 h at ꢁ78 ꢀC, the re-
action was gradually rised up to room temperature. Once the re-
action was finished as judged by TLC, saturated NH4Cl (1 mL) was
added, and the mixture was extracted with CH2Cl2 (3ꢂ5 mL). The
organic phase was washed successively with brine, dried over
Na2SO4. The residue was purified by column chromatography (3%,
EtOAc/petroleum ether) to give 24 (3.1 mg, 65%) as a white solid.
D
versus [aþ
]
þ26.3 (c 0.15, CH2Cl2 of lit.2b). HRMS (ESI) calcd for
20
D
C25H39O3 [MþH]þ 387.2899, found 387.2896. 1H NMR (400 MHz,
CDCl3):
d
5.94 (s, 1H), 4.75e4.65 (m, 2H), 3.67 (dd, J¼5.2, 10.9 Hz,
1H), 2.49e2.40 (m, 1H), 2.33e2.16 (m, 1H), 1.97e1.78 (m, 3H),
1.78e1.61 (m, 3H), 1.57e1.42 (m, 4H), 1.42e1.24 (m, 3H), 1.13 (s, 3H),
1.12e1.04 (m, 2H), 0.89 (s, 3H), 0.84 (s, 6H), 0.81 (s, 3H), 0.80e0.74
(m, 2H). 13C NMR (100 MHz, CDCl3):
d 176.0, 162.1, 135.9, 75.6, 72.1,
58.0, 56.7, 55.2, 42.2, 42.1, 41.7, 39.7, 37.4, 37.3, 33.3, 31.0, 25.8, 25.3,
Rf¼0.1, petroleum ether/EtOAc (20/1). [a 18
ꢁ6.8 (c 0.08, CHCl3)
]
21.3, 18.6, 18.3, 17.2, 16.8, 16.5, 16.0. IR (film): 3393, 2929, 1711, 1442,
versus [aþ25
]
D
ꢁ9.1 (c 0.076, CHCl3 of lit.8aD). HRMS (EI) calcd for
1387, 1061 cmꢁ1
.
C25H38O2 [M]þ 370.2872, found 370.2873. 1H NMR (400 MHz,
4.20. Preparation of compound 21
CDCl3):
d
7.53 (br s, 1H), 7.04 (br s, 1H), 3.64 (m, 1H), 2.75 (dd, J¼5.8,
16.0 Hz, 1H), 2.41 (m, 1H), 1.86 (dt, J¼3.2, 12.5 Hz, 1H), 1.83e1.75 (m,
2H), 1.73e1.65 (m, 2H), 1.65e1.57 (m, 2H), 1.51e1.42 (m, 2H),
1.42e1.33 (m, 3H),1.20 (s, 3H),1.14e1.10 (m, 2H), 0.97e0.91 (m, 2H),
0.89 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3H), 0.82 (s, 3H), 0.79e0.77 (m,1H).
This procedure was the same as for the preparation of com-
pound 16. After column chromatography and evaporated in vacuo,
product 21 was obtained in 65% yield as white solid. Rf¼0.2, pe-
troleum ether/EtOAc (3/1). Mp: 122e124 ꢀC. HRMS (EI) calcd for
13C NMR (100 MHz, CDCl3):
d 137.4, 136.2, 134.6, 120.0, 80.0, 58.8,
þ
C32H46O3 [M]þ 478.3447, found 478.3441. 1H NMR (400 MHz,
56.7, 55.8, 42.1, 41.7, 40.4, 39.9, 37.5, 37.5, 33.3, 33.3, 28.0, 21.3, 21.0,
19.2, 18.6, 18.2, 17.7, 17.6, 16.3.
CDCl3):
d
7.41e7.29 (m, 5H), 5.65 (t, J¼3.9 Hz,1H), 4.81 (d, J¼11.2 Hz,
1H), 4.48 (m, 2H), 4.20 (d, J¼1.8 Hz, 2H), 4.15e4.09 (m,1H), 3.65 (dd,
J¼4.7, 11.2 Hz, 1H), 2.82 (d, J¼3.6 Hz, 2H), 2.23 (dd, J¼4.2, 12.6 Hz,
1H), 1.99 (m, 1H), 1.81e1.58 (m, 5H), 1.50e1.31 (m, 5H), 1.27 (s, 3H),
1.22 (s, 3H), 1.15e1.08 (m, 1H), 0.89 (s, 3H), 0.85 (s, 3H), 0.83 (s, 3H),
Acknowledgements
This work was financially supported by the Natural Science
Foundation of China (No. 20972047), the ‘Shu Guang’ project of
Shanghai Municipal Education Commission, Shanghai Education
Development Foundation (No. 09SG28), the New Century Excellent
Talents in University, the Ministry of Education, China (No. NCET-
07-0283), and ‘111’ Project (No. B07023).
0.81e0.78 (m, 1H). 13C NMR (100 MHz, CDCl3):
d 154.5, 142.0, 137.9,
135.3, 128.6, 127.9, 118.0, 84.1, 69.5, 63.2, 59.1, 56.1, 53.2, 44.6, 42.0,
41.5, 40.4, 39.9, 37.8, 33.3, 33.2, 30.8, 25.9, 23.7, 22.1, 21.4, 18.8, 18.6,
16.2. IR (film): 3425, 2918, 2359, 1621, 1395, 1062, 975 cmꢁ1
.
4.21. Preparation of compound 22
Supplementary data
This procedure was the same as for the preparation of com-
pound 17. After column chromatography and evaporated in vacuo,
product 22 was obtained in 90% yield as white solid. Rf¼0.3, pe-
troleum ether/EtOAc (50/1). Mp: 85e87 ꢀC. HRMS (EI) calcd for
The 1H NMR and 13C NMR copies of all compounds were at-
tached as Supplementary data. Supplementary data associated
with this article can be found, in the online version, at doi:10.1016/
j.tet.2011.05.092.
þ
C32H42O2 [M]þ 458.3185, found 458.3181. 1H NMR (400 MHz,
CDCl3):
d
7.47 (d, J¼1.4 Hz, 1H), 7.46e7.36 (m, 4H), 7.34e7.30 (m,
1H), 7.14 (s, 1H), 5.76 (dd, J¼2.4, 5.6 Hz, 1H), 4.84 (d, J¼11.8 Hz, 1H),
4.54 (d, J¼11.9 Hz, 1H), 3.50 (dd, J¼4.2, 10.5 Hz, 1H), 3.26 (dd, J¼5.6,
10.6 Hz, 1H), 3.12 (dt, J¼1.9, 20.5 Hz, 1H), 2.15 (dd, J¼2.8, 12.6 Hz,
1H), 2.04e1.96 (m, 1H), 1.77 (d, J¼12.4 Hz, 1H), 1.73e1.60 (m, 3H),
1.53e1.47 (m, 1H), 1.45 (s, 3H), 1.43e1.36 (m, 2H), 1.25 (s, 3H),
1.18e1.08 (m, 1H), 0.95e0.93 (m, 1H), 0.92 (s, 3H), 0.88 (s,3H), 0.85
(s, 3H), 0.91e0.89 (m, 1H), 0.82e0.76 (m, 2H). 13C NMR (100 MHz,
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