Concise total synthesis of (±)-pisiferin

Article abstract of DOI:10.1016/j.tet.2015.10.032

A concise total synthesis of (±)-pisiferin has been accomplished from commercially available compounds α-cyclocitral (9) and 4-bromo-2-isopropylphenol (10) via Suzuki coupling and F-C alkylation as key reaction in five steps with an overall yield of 22%. The feature of this concise synthesis is a convergent strategy coupled by Suzuki reaction. This work not only provides a strategy to approach the total synthesis of pisiferin itself but also serves as an additional correlation origin to which many related icetaxane-type diterpenes can be referred.

Full text of DOI:10.1016/j.tet.2015.10.032

Accepted Manuscript
Concise total synthesis of (±)-pisiferin
Yulong Li, Liqi Li, Yueming Guo, Zhixiang Xie
PII:
S0040-4020(15)30132-0
10.1016/j.tet.2015.10.032
TET 27204
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 June 2015
Revised Date: 9 October 2015
Accepted Date: 12 October 2015
Please cite this article as: Li Y, Li L, Guo Y, Xie Z, Concise total synthesis of (±)-pisiferin, Tetrahedron
(2015), doi: 10.1016/j.tet.2015.10.032.
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Concise total synthesis of (±)-pisiferin
Yulong Li, Liqi Li, Yueming Guo and Zhixiang Xie*
Leave this area blank for abstract info.
State Key Laboratory of Applied Organic Chemistry & College of Chemistry and Chemical Engineering,
Lanzhou University, 222 Tianshui South Road, Lanzhou, Gansu 730000, China
Br
OH
OAc
OH
10
+
Pisiferin (3)
CHO
11b
9

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Concise total synthesis of (±)-pisiferin
Yulong Li, Liqi Li, Yueming Guo and Zhixiang Xie
State Key Laboratory of Applied Organic Chemistry & College of Chemistry and Chemical Engineering, Lanzhou University, 222 Tianshui South Road,
Lanzhou, Gansu 730000, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A concise total synthesis of (±)-pisiferin has been accomplished from commercially available
compounds α-cyclocitral (9) and 4-bromo-2-isopropylphenol (10) via Suzuki coupling and F-C
alkylation as key reaction in five steps with an overall yield of 22%. The feature of this concise
synthesis is a convergent strategy coupled by Suzuki reaction. This work not only provides a
strategy to approach the total synthesis of pisiferin itself but also serves as an additional
correlation origin to which many related icetaxane-type diterpenes can be referred.
Available online
Keywords:
2014 Elsevier Ltd. All rights reserved
.
icetaxane-type diterpenes
total synthesis
pisiferin
Suzuki coupling
F-C alkylation
1. Introduction
(±)-pisiferin was reported by Majetich and co-workers by using
cyclialkylation reaction as key reaction.7 The total synthesis of
(±)-isopisiferin was also reported by Liu and Shia3a and Ghatak8.
Previous efforts directed toward the synthesis of pisiferin and
other congeners fall into more steps, more complicated methods
and produced isomers.5-7 It was notable, most of isomers were
inseparable, for example pisiferin and isopisiferin.6,7 The
particular interests on the biogenetic synthesis relationship of
ictexane diterpene and other diterpene led us to choose Pisiferin
as our synthetic target molecule. Herein we describe the
realization of this goal.
The icetaxane diterpenoid natural products exhibit an array of
interesting biological activities, which coupled with their unique
structural features. Thus they have generated significant interests
from the isolation and synthetic community.1 Recently more and
more icetaxane and dimeric icetexane diterpenoids have been
isolated from a variety of terrestrial plant sources.2 Most of those
compounds in this family exhibit significant cytotoxicities
against human cancer lines, such as compounds 1 and 22a,
premnalatifolin A2b and przewalskone2d (Figure 1).
Scheme 1. Retrosynthetic Analysis of pisiferin
Figure 1. Selected member of icetaxane diterpenoid natural products
Our retrosynthetic analysis of pisiferin is shown in scheme 1.
Of the many possible disconnection of the 6, 7, 6-tricyclic
backbone, we chose a two-step procedure. We envisioned that
pisiferin could be synthesized from compound 6 via a Lewis-acid
catalyzed F-C alkylation. In previous paper, isomer of pisiferin
(isopisiferin) was produced in cleavage of the methyl ether or
under strong acidic conditions. Thus the F-C alkylation condition
should be controlled in order to exclusively obtain the target
molecular. The compound 6 would be derived from 7 and 8 by
New, simple or enantioselective synthesis of the icetaxane
products have also been reported.3 Our target molecule pisiferin
(3) is a subclass of the icetaxane family which has been isolated
from the leaves and the seeds of Chamaecyparis pisifera.4 The
first total synthesis of (±)-pisiferin was reported by Matsumoto5
and co-workers in 1986, which was also the first example for
synthesis of an icetexane diterpenoid. The second total synthesis
of (±)-pisiferin and the first total synthesis of (±)-isopisiferin was
reported by Honda and co-workers.6 The third total synthesis of
———
Corresponding author. e-mail: xiezx@lzu.edu.cn

2
Tetrahedron
using a Suzuki-coupling, and then an allylic oxidation. Further
the phenol would complicate the coupling reaction. Thus, it
ACCEPTED MANUSCRIPT
retrosynthetic disconnection of compounds 7 and 8 were
envisioned to follow a Wittig reaction to prepare the diene 7 from
racemic α-cyclocitral (9) and to prepare the bromide derivative 8
from 10. This retrosynthesis of the target molecule was concise
and novel compared to the reported works by other chemists.5-7
needs a protecting group before the coupling procedure.
With these realizations in mind, two tenets were confirmed
that (i) the protect group must tolerate the ambient which the
Suzuki reaction needs and (ii) the condition of deprotection
should be non-acid and easily to deprotect the hydroxyl group.
Therefore, the acetyl group was then taken into consideration and
chosen as the protecting group. Therefore, the compound 8 was
prepared in by acetylating of 10 with AcCl and pyridine (Table
1).11 Under the condition12 stated as Table 1 entry 5, we firstly
got the desired coupling product in 19% yield. In order to
improve the yield of this reaction, different Pd-catalyst, base and
solvents were screen. When Pd(PPh3)4 was subjected to the
reaction instead of Pd(OAc)2 and SPhos, the desired product
cannot be obtained no matter using DMF and THF as solvents or
THF and H2O (Table 1 entry 6, 7). Changing the base as CsF, the
desired coupling product was obtained in 17% yield (Table 1
entry 8). When we changed the solvent to THF, the reaction
resulted in 7% of 11a and 58% of 11b (entry 9). This could be
rationlized by the better solubility of the base CsF in THF. By
utilization a considerable weak base, CsF, the acetyl group was
envisioned to be maintained during Suzuki coupling reaction.
However, changing the base as KF, the desired product was not
obtained (Table 1 entry 10).
2. Results and Discussion
In the forward direction, compounds 9 and 10 are commercial
available. The diene 7 was prepared via Wittig reaction from
racemic aldehyde 9 in 87% yield.9 (Shown in Scheme 2)
Scheme 2. Synthesis of compound 7.
With compound 7 in hand, we want to try the Suzuki coupling
with phenol 10 without protecting the phenol group, concerned
on the green chemistry principle. However the Suzuki coupling
of 10 and the borohydride diene 7 did not work as expected under
the typical Suzuki coupling condition.10 (Table 1, entry 1) A
screen of the bases and solvents for Suzuki coupling were taken
into consideration to accomplish the coupling procedure (Table
1, entry 2 ~4). The complex products were obtained in these
conditions, which strongly suggested that the hydroxyl group of
Table 1. Conditions of the Suzuki coupling a
Entry
1
Aryl halides
catalysts
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
base
solvents
THF
Yields b
10
10
10
10
8
3N NaOH (5.0 equiv)
K3PO4·3H2O (3.0 equiv)
K3PO4·3H2O (3.0 equiv)
K3PO4 (3.0 equiv)
K3PO4 (3.0 equiv)
K3PO4 (3.0 equiv)
K3PO4 (3.0 equiv)
CsF (3.0 equiv)
Complex product
Complex product
Complex product
Complex product
19 %
2
THF : H2O = 40 : 3
THF : H2O = 5 : 1
DMF : THF = 1 : 1
DMF : THF = 1 : 1
DMF : THF = 1 : 1
THF : H2O = 5 : 1
DMF : THF = 1 : 1
THF
3
4 c
5 c
6
8
Undesired product
Undesired product
17 %
7
8
8
8
9
8
CsF (3.0 equiv)
11a 7%; 11b 58 %
Undesired product
10
8
KF (3.0 equiv)
THF
a All reactions were carried out under the following conditions, unless otherwise noted: alkenylboranes were generate in situ from the diene 7 (2.0 mmol, 1.5
equiv) heated with 9-BBN. And 1.0 equiv of aryl halides, catalysts (0.1 equiv) refluxed for 3 h under Ar atmosphere.
b Isolated yield.
c Add the ligand 0.2 equiv of SPhos.
With this optimized condition in hand, the Suzuki coupling
was utilized to generate 11b. This convergent synthesis of 11b
was operated in one-pot procedure. Diene 7 was mixed with 9-
BBN stirred over night at r.t. then stirred for another 6h at 70 oC.
This hydroboration product was used without any purification to
accomplish the Suzuki coupling.13 Then the coupled compound
11b and the deprotection compound 11a was achieved. (Shown
in Scheme. 3) As expected, most of the acetyl group remained.
Moreover, the compound 11a was transformed to 11b in 89%
yield by use of AcCl and Et3N.
When we finally got this coupling compound 11a, we were
able to move on and approach to the target molecule. As it was
shown in the retrosynthesis the compound 11a was needed to be
transformed to 6 for F-C alkylation to construct the 6, 7, 6-fused
tricycles. At this time the construction of compound 6 was the
key. In order to accomplish this transformation, an allylic

3
oxidation of 11a was first conducted with SeO2.14 However, only
4. Experimental section
ACCEPTED MANUSCRIPT
few desired product was obtained in company with other isomers
in this case. As a result we chose a two-step procedure to finish
this transformation. The compound 11a was first treated with m-
CPBA to generate the corresponding epoxide product 12
(diastereoisomer mixture) in 83%, which following
rearrangement of the formed epoxide yielded diol 6 in 89% with
4.1. General
All moisture-sensitive reactions were performed under an
atmosphere of Ar. Glassware was flame dried prior to use. THF
was dried by distillation over Na/K. CH2Cl2 was dried by
distillation over CaH2. Unless otherwise stated, solvents and
reagents were used as received. Column chromatography was
generally performed on silica gel (200-300 mesh) and TLC
inspections were on silica gel GF254 plates. 1H NMR spectra were
recorded at 400 MHz spectrometers. Chemical shifts (δ) are
reported in ppm downfield from Si(CH3)4 with the partially-
deuterated solvent as the internal standard (CDCl3 δ 7.26). Data
are reported as follows: chemical shift, multiplicity (s = singlet, d
= doublet, t = triplet, dd = doublet of doublet, b = broad, q =
quartet, m = multiplet). 13C NMR spectra were recorded at 100
MHz spectrometers. Chemical shifts are reported in ppm from
tetramethylsilane with the solvent as the internal standard (CDCl3
δ 77.0). IR spectra were recorded on a Nicolet 670 FTIR
spectrophotometer and reported in wave numbers (cm-1). HRMS
data were determined on a Bruker Daltonics APEXII 47e FT-ICR
spectrometer.
o
addition of Al(Oi-Pr)3 at 130 C.15 (Shown in Scheme 3) And
with this two-step procedure we accomplished the transformation
as expected. As the temperature of the rearrangement step was a
little severe, another condition of open epoxide rearrangement
was utilized. We tried to use iodine to accomplish this
transformation.16 However the result was disappointing. So we
did not change the condition. In these steps the new chiral centers
were generated. But all these generated chirality would dismiss in
the final step. So the diastereoisomer mixture 12 and 6 were not
separated. The diol 6 was pursued a F-C alkylation under Lewis-
acid catalyzed condition10 to construct the 7-member ring. When
using BF3·Et2O as Lewis-acid catalyst, the target molecule,
pisiferin (along its 10% isomer) was obtained in 60%. (Shown in
Scheme 3) The reaction time need be controlled, when the
reaction mixture was turned to a pale-purple, then the reaction
was quenched with saturated NaHCO3 (aq), extracted with ethyl
acetate. In order to reduce the ratio of the isomer or obtain the
target exclusively, with the BF3·Et2O as the Lewis acid the
reaction was conducted under the low temperature such as -78 oC,
4.2. Experimental procedures and data of synthetic
intermediates
4.2.1. 1,5,5-trimethyl-6-vinylcyclohex-1-ene (7)
o
o
-48 C, - 10 C, all these efforts resulted in no reaction. The
weaker Lewis acid such as FeCl3 was also tried, but the
cyclization did not occur either. When we chose the other
transition metal Lewis acid such as Sc(OTf)3, the result was the
same as the BF3·Et2O condition. As result, pisiferin (along with
the isomer 10% detected) was achieved in 22% yield with only 5
steps from the commercially available 10. It was disappointed
that the control of the reaction time did not result in giving the
pisiferin exclusively. The isomer of the pisiferin was still existed
in the product mixture according to the NMR result. This fact
strongly suggested that the Lewis acid promoted F-C alkylation
would cause the isomerization of the pisiferin.
To a 50 ml round bottom flask equipped with a stir bar was
added CH3P(Ph3)I (4.85 g, 12 mmol, 1.2 equiv). Then 20 ml THF
was added under Ar atmosphere. This solution was cooled to 0oC,
upon which n-BuLi (2.5 M in THF; 4.4 ml, 11 mmol, 1.1 equiv)
was added dropwise via syringe, resulted a yellow mixture and a
solution of aldehyde 9 (1.35 g, 8.9 mmol, 1.0 equiv) in THF (12
ml) was added successfully. The result mixture was warmed to
room temperature and stirred for 2 h. Then the reaction was
quenched with saturated NH4Cl (aq). The resulting mixture was
o
extracted with petroleum ether (bp. 30-60 C). The organic layer
was washed with water followed by brine, and dried over Na2SO4.
The extraction was filtered and concentrated in vacuo. The
resulted residue was purified by column chromatography
(petroleum ether bp.30-60 oC), provided diene 7 (1.17 g, 87%) as
a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 5.70 – 5.49 (m,
1H), 5.40 (s, 1H), 5.09 – 4.98 (m, 2H), 4.98 – 4.93 (m, 1H), 2.10
(d, J = 9.4 Hz, 1H), 2.00 (m, 2H), 1.59 (d, J = 1.7 Hz, 3H), 1.49 –
1.35 (m, 1H), 1.17 (d, J = 13.2 Hz, 1H), 0.89 (s, 3H), 0.83 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 140.13, 134.69, 121.71, 121.68,
116.56, 78.12, 77.80, 77.48, 56.58, 32.48, 32.41, 28.19, 27.75,
23.87, 23.55. IR(film): 3389, 2925, 1720, 1656, 1458, 1374,
1253, 1122, 917, 502 cm-1.
4.2.3. 4-bromo-2-isopropylphenyl acetate (8)11
To a 25 ml round bottom flask equipped with a stir bar were
added 4-bromo-2-isopropylphenol 10 (913.7 mg, 4.248 mmol, 1
equiv) and DCM (10 ml). This solution was stirred at room
temperature, then pyridine (0.68 ml, 8.496 mmol, 2.0 equiv) was
added dropwise via syringe. After addition of the pyridine, acetyl
chloride (0.57 ml, 8.071 mmol, 1.9 equiv) was added dropwise
via syringe, resulted in a pale yellow mixture. After stirring for 3
h, the reaction was quenched with saturated NH4Cl (aq). The
resulting mixture was extracted with ethyl acetate. The organic
layer was washed with water followed by brine, and dried over
Na2SO4. It was filtered and concentrated in vacuo. The residue
was purified by column chromatography (8:1 petroleum
ether/ethyl acetate), provided 4-bromo-2-isopropylphenyl acetate
(8) (951.8 mg, 87%) as a pale yellow liquid. 1H NMR (400 MHz,
CDCl3) δ 7.42 (d, J = 2.2 Hz, 1H), 7.31 (dd, J = 8.5, 2.3 Hz, 1H),
Scheme 3. Synthesis of pisiferin
3. Summary
Even though this strategy did not give the pisiferin without its
isomers as expected, the strategy we designed to approach the
backbone of pisiferin is concise. And this elegant strategy can be
referred as an additional correlation origin to which many related
icetaxane-type diterpenes. Our work also can give some light on
the construction of the 6-7-6 backbone of the icetaxane-type
diterpenes. Further studies on synthesis of icetaxane-type
diterpenes by new strategy of construction the 7-member ring are
ongoing in our group.

4
Tetrahedron
ACCEPTED MANUSCRIPT
6.88 (d, J = 8.5 Hz, 1H), 2.98 (dt, J = 13.8, 6.9 Hz, 1H), 2.32 (s,
0.90 (s, 3H), 0.81 (d, J = 12.9 Hz, 4H); 13C NMR (101 MHz,
3H), 1.20 (d, J = 6.9 Hz, 7H); 13C NMR (100 MHz, CDCl3) δ
169.45, 147.20, 142.63, 130.08, 129.78, 124.21, 119.66, 77.48,
77.16, 76.84, 27.70, 22.90, 21.02. IR(film): 2967, 1765, 1688,
1369, 1207, 1177, 1095, 758 cm-1.
CDCl3) δ 169.83, 146.02, 141.14, 139.67, 126.68, 126.57, 121.94,
77.32, 77.00, 76.68, 60.15, 59.55, 47.03, 35.50, 31.50, 29.71,
27.81, 27.51, 27.35, 26.92, 26.89, 22.99, 22.96, 22.12, 20.95;
IR(film): 3449, 3023, 2978, 2934, 2368, 1736, 1374, 1246, 1098,
1047, 758, 668 cm-1; HRMS (ESIMS) calculated for C22H32O3 [M
+ Na]+ 367.2249, found 367.2244.
4.2.4. 2-isopropyl-4-(2-(2,6,6-trimethylcyclohex-2-en-1-yl)ethyl)
phenol (11a) and 2-isopropyl-4-(2-(2,6,6-trimethylcyclohex-2-en-
1-yl)ethyl)phenyl acetate (11b)
4.2.6. 4-(2-(5-hydroxy-2,2-dimethyl-6-methylenecyclohexyl)ethyl)
-2-isopropylphenol (6)
To a 10 ml round bottom flask equipped with a stir bar was
added diene 7 (295 mg, 1.967 mmol, 1.5 equiv) and 9-BBN (0.5
M in THF; 5.25 ml, 2.62 mmol, 2.0 equiv) under Ar atmosphere.
The resulted reaction mixture was stirred at room temperature
overnight, then heated to 70 oC for another 6 h. To another 25 ml
two neck round bottom flask equipped with a stir bar was added
CsF (611.8 mg, 4.03 mmol, 3.1 equiv) which was flame dried,
and Pd(PPh3)4 (150.9 mg, 0.1306 mmol, 0.1 equiv) under Ar
atmosphere. Then a solution of phenyl acetate 8 (335.6 mg, 1.31
mmol, 1.0 equiv) in 4 ml THF was added to this flask, followed
by addition of the 9-BBN and diene 7 reaction mixture which
To a 25 ml two neck round bottom flask equipped a stir bar
was added Al(O-iPr)3 (353.0 mg, 1.728 mmol, 3.0 equiv). And a
solution of the corresponding epoxide 12 (198.4 mg, 0.5759
mmol, 1.0 equiv) in 10 ml toluene was added to this flak via
syringe under Ar atmosphere. The resulted mixture was heated to
130 oC and refluxed for 3h. The reaction was then quenched with
saturated NH4Cl, extracted with ethyl acetate. The organic layer
was washed with water followed by brine, and dried over Na2SO4.
The extraction was filtered and concentrated in vacuo. The
residue was purified by column chromatography (8:1 then 4:1
petroleum ether/ethyl acetate), provided diol 6 (154.9 mg, 89%)
as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 7.00 (s, 1H),
6.88 (d, J = 6.3 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 5.42 – 5.04 (m,
2H), 4.84 (d, J = 28.0 Hz, 1H), 4.26 (s, 1H), 4.00 (d, J = 9.7 Hz,
1H), 3.59 (q, J = 10.6 Hz, 1H), 3.23 (dt, J = 12.7, 6.3 Hz, 1H),
2.74 (dt, J = 14.1, 7.1 Hz, 1H), 2.67 – 2.48 (m, 1H), 2.36 (dt, J =
13.6, 8.3 Hz, 1H), 2.14 – 2.01 (m, 1H), 2.01 – 1.87 (m, 1H), 1.80
(dd, J = 14.1, 7.8 Hz, 2H), 1.71 (d, J = 6.3 Hz, 1H), 1.65 – 1.52
(m, 1H), 1.52 – 1.34 (m, 3H), 1.27 (d, J = 6.8 Hz, 7H), 1.12 (s,
1H), 1.04 (s, 1H), 0.95 (s, 2H), 0.89 (d, J = 9.6 Hz, 1H), 0.72 (s,
2H); 13C NMR (101 MHz, CDCl3) δ 169.83, 146.02, 141.14,
139.67, 126.68, 126.57, 121.94, 77.32, 77.00, 76.68, 60.15, 59.55,
47.03, 35.50, 31.50, 29.71, 27.81, 27.51, 27.35, 26.92, 26.89,
22.99, 22.96, 22.12, 20.95; IR(film): 3365, 2960, 2868, 1505,
1461, 1431, 1258, 1216, 1170, 1081, 1036, 1022, 901, 756, 668
cm-1; HRMS (ESIMS) calculated for C20H30O2 [M + Na]+
325.2143, found 325.2584.
o
was already prepared. The resulted mixture was heated to 80 C,
refluxed for 3 h and 30 min. The reaction mixture was then
quenched with saturated NH4Cl (aq), extracted with ethyl acetate.
The organic layer was washed with water followed by brine, and
dried over Na2SO4. The extraction was filtered and concentrated
in vacuo, resulted a brownish black liquid. The residue was
purified by column chromatography (30:1 petroleum ether/ethyl
acetate), provided phenyl acetate 11b (246 mg, 58%) and phenol
11a (31.2 mg, 7%).
11a : 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 2.4 Hz, 1H),
7.16 (dd, J = 8.5, 2.4 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 4.75 (s,
1H), 3.27 – 3.05 (m, 1H), 2.46 – 2.33 (m, 1H), 1.88 (s, 1H), 1.64
– 1.48 (m, 4H), 1.24 (d, J = 6.9 Hz, 6H).
11b : 1H NMR (400 MHz, CDCl3) δ 7.08 (s, 1H), 7.00 (d, J =
8.2 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 5.31 (s, 1H), 2.99 (dt, J =
13.8, 6.9 Hz, 1H), 2.63 (t, J = 8.4 Hz, 2H), 2.28 (s, 3H), 1.97 (s,
2H), 1.72 (dd, J = 13.5, 7.9 Hz, 1H), 1.53 – 1.41 (m, 2H), 1.20 (d,
J = 6.9 Hz, 6H), 0.97 (s, 3H), 0.88 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 169.66, 145.96, 140.99, 139.60, 136.34, 126.41, 126.40,
121.90, 120.17, 77.32, 77.00, 76.68, 48.90, 36.21, 33.12, 32.53,
31.56, 27.47, 27.43, 27.41, 23.39, 22.99, 22.90, 20.82; IR(film):
3400, 2962, 2926, 2855, 1767, 1737, 1603, 1451, 1413, 1261,
1097, 1023, 797, 700 cm-1; HRMS (ESIMS) calculated for
C22H32O2 [M + Na]+ 351.2300, found 351.2295.
4.2.7. Pisiferin (3)
To a 25 ml round bottom flask equipped with a stir bar was
added a solution of diol 6 (35.1 mg, 0.1160 mmol, 1.0 equiv) in 6
o
ml DCE under Ar. The solution was cooled to 0 C, upon which
BF3•Et2O (49.4 mg, 0.3481 mmol, 3.0 equiv) was added via
microsyringe under Ar atmosphere. The resulted mixture was
o
stirred for 3h 20min at 0 C, resulted a pale-purple like mixture.
Then the reaction was quenched with saturated NaHCO3 (aq),
extracted with ethyl acetate. The organic layer was washed with
brine and dried over Na2SO4. The resulted extraction was filtered
and concentrated in vacuo. The residue was purified by column
chromatography (20:1 then 16:1 petroleum ether/ethyl acetate),
provided pisiferin (19.7 mg, 60%) as a colorless liquid. The
resulted pisiferin contained a inseparable isomer with 10:1
(pisiferin/isopisiferin). The NMR spectrum was complicated by
4.2.5. 2-isopropyl-4-(2-(1,3,3-trimethyl-7-oxabicyclo[4.1.0]
heptan-2-yl)ethyl)phenyl acetate (12)
To a 50 ml round bottom flask equipped with a stir bar was
added the phenyl acetate 9 (246.0 mg, 0.7489 mmol, 1 equiv) and
o
10 ml DCM. The solution was cooled to 0 C, upon which m-
CPBA (197.9 mg, 1.147 mmol, 1.5 equiv) was added. The
o
resulted mixture was stirred for 2h and 10 min at 0 C. Then the
1
the existing isomer of the pisiferin. H NMR (400 MHz, CDCl3)
reaction was quenched with saturated NaHCO3 (aq), extracted by
DCM. The organic layer was washed with water followed by
brine, and dried over Na2SO4. Then the resulted extraction was
filtered, concentrated in vacuo. The residue was purified by
column chromatography (8:1 petroleum ether/ethyl acetate),
provided epoxide (204.1 mg, 83%) as pale yellow liquid. And the
1H NMR analysis suggested that the epoxide 12 was a racemic
mixture. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 1.5 Hz, 1H),
7.07 (dd, J = 8.2, 1.8 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 3.10 –
2.94 (m, 2H), 2.94 – 2.83 (m, 1H), 2.70 – 2.50 (m, 1H), 2.32 (s,
3H), 2.05 – 1.90 (m, 1H), 1.90 – 1.75 (m, 1H), 1.67 (ddd, J =
12.9, 10.6, 5.8 Hz, 2H), 1.57 (d, J = 2.3 Hz, 1H), 1.45 (dd, J =
8.8, 5.2 Hz, 1H), 1.35 (d, J = 10.8 Hz, 3H), 1.32 – 1.13 (m, 7H),
δ 6.90 (s, 1H), 6.54 (s, 1H), 5.43 (s, 1H), 4.50 (s, 1H), 3.26 (s,
2H), 3.14 (dt, J = 13.8, 6.9 Hz, 1H), 2.80 (dd, J = 13.0, 4.5 Hz,
2H), 2.15 – 1.95 (m, 2H), 1.90 (d, J = 17.9 Hz, 1H), 1.79 (d, J =
11.7 Hz, 1H), 1.24 (t, J = 6.9 Hz, 10H), 0.91 (d, J = 11.5 Hz, 7H);
13C NMR (151 MHz, CDCl3) δ 150.80, 139.84, 138.42, 133.70,
131.06, 127.02, 121.23, 114.99, 77.21, 77.00, 76.79, 51.76, 44.70,
42.31, 37.27, 35.90, 35.72, 34.48, 32.12, 31.93, 31.25, 31.10,
30.92, 30.52, 30.46, 29.70, 27.81, 27.73, 27.14, 26.74, 25.90,
24.19, 23.20, 22.88, 22.69, 22.52, 21.98, 21.81, 20.11, 17.67,
14.11; HRMS (ESIMS) calculated for C20H30O2 [M + H]+
285.2140, found 285.2213.

5
A.;Reddy, S. C. K.; Kuncha, M.; M. V. P. S. V. V.; Kulkarni, P.;
Acknowledgments
ACCEPTED MANUSCRIPT
Janaswamy, M. R.; Sistla, R. Phytomedicine 2014, 21, 497-505.
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This work is financially supported by, the National Natural
Science Foundation of China (Grant Nos. 21272104, 21202069
and 21202075), the Program for Changjiang Scholars and
Innovative Research Team in University (PCSIRT: IRT1138),
the Research Fund for the Doctoral Program of Higher Education
of China (No. 20110211110009), the Program for New Century
Excellent Talents in University (NCET-12-0247 and lzujbky-
2012-56), and the Fundamental Research Funds for the Central
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