Biomimetic cationic cyclization toward ent-Kaurene-type diterpenoids

Article abstract of DOI:10.1002/cjoc.201201029

Terpenoids comprise the largest family of natural products and include various structurally different genus which play important roles in living organisms. Biosynthetically, diterpenoids are derived from (E,E,E)- geranylgeranyl diphosphate (GGPP). From GGPP, diterpene cyclase catalyzes a sequence of carbocation-mediated cyclizations, rearrangements, and further oxidations, leading to a class of structurally unique ent-kaurenes, such as cafestol, gibberellin A3 and oridonin. According to the biosynthesis pathway of ent-kaurene, we designed a chiral acetal-enabled and SnCl₄-promoted biomimetic polyene cationic cyclization. With a following Birch reduction/alkylation cascade, a core skeleton of representative ent-kaurenes diterpenoids was completed. A chiral acetal-enabled and SnCl₄- promoted biomimetic polyene cationic cyclization was followed by oxidation and a cascade process of Birch reduction and alkylation to complete a core skeleton of representative ent-kaurene diterpenoids. Copyright

Full text of DOI:10.1002/cjoc.201201029

FULL PAPER
DOI: 10.1002/cjoc.201201029
Biomimetic Cationic Cyclization toward ent-Kaurene-type
Diterpenoids†
Lili Zhu and Ran Hong*
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chi-
nese Academy of Sciences, Shanghai 200032, China
Terpenoids comprise the largest family of natural products and include various structurally different genus
which play important roles in living organisms. Biosynthetically, diterpenoids are derived from
(E,E,E)-geranylgeranyl diphosphate (GGPP). From GGPP, diterpene cyclase catalyzes a sequence of carbocation-
mediated cyclizations, rearrangements, and further oxidations, leading to a class of structurally unique ent-kaurenes,
such as cafestol, gibberellin A3 and oridonin. According to the biosynthesis pathway of ent-kaurene, we designed a
chiral acetal-enabled and SnCl4-promoted biomimetic polyene cationic cyclization. With a following Birch reduc-
tion/alkylation cascade, a core skeleton of representative ent-kaurenes diterpenoids was completed.
Keywords diterpenoid, ent-kaurene, biomimetic synthesis, carbocation cyclization, Birch reduction/alkylation
cascade
Introduction
Scheme 1 ent-Kaurene and representative diterpenoids
The appealing creation of the processes that nature
builds natural products is astonishing. The quest for ef-
ficient chemical synthesis that mimics these routes is a
longstanding challenge.[1] Biomimetic synthesis of ter-
penoid natural products remains a thriving area of
chemical research.[2] Ent-Kaurene, one unique category
of diterpenoids, stems from geranylgeranyl diphosphate
(GGPP) catalyzed by cyclases, and always displays
pharmacologically significant activities in living organ-
ism.[3] For example, cafestol,[4] a typical ent-kaurene
diterpenoid as shown in Scheme 1, confers neuroprotec-
tion in Drosophila models of Parkinson's disease.[5] Ac-
cording to a recent study,[5c] cafestol seems partially
responsible for its neuro-protective effects, and activates
a protein produced by flies called Nrf2, blocking which
diminished coffee’s protective effect on dopamine neu-
rons. Since the first racemic synthesis achieved by the
Corey group[6] in 1987, an asymmetric synthesis re-
mains elusive. Gibberellin A3, discovered from Rhizo-
bium phaseoli in 1988, originally was only known to
fungi and plants, might represent the first report as bac-
terial diterpenoids.[7] Oridonin[8] and neotripterifordin[9]
are also exhibiting potent antitumor[8b-8g] and
anti-HIV[9a] activities, respectively. Developing efficient
biomimetic approach toward ent-kaurene is highly de-
sirable for future drug discovery and clinic usage.
OH
H
OH
O
C
D
OH
H
O
A
H
B
HO
O
H
H
COOH
H
cafestol
gibberellin A3
OH
ent-kaurene
OH
OMe
H
H
OH
O
O
OH
H
O
H
OH
oridonin
neotripterifordin
extensively.[10] Like all other diterpenoids derived from
GGPP, the proton-initiated cyclization of GGPP deliv-
ers ent-copalyl diphosphate (ent-CPP)[11] (Scheme 2).
From ent-CPP, loss of the diphosphate group enables a
carbocation-mediated cyclization. With the following
Wagner-Meerwein rearrangement, the [1,2]-alkyl mi-
gration switches the original secondary carbon cation to
the tertiary one, which results in a characteristic ring
skeleton of ent-kaurane. The subsequent deprotonation
of the methyl group generates the exocyclic double
bond of ent-kaurene. For the biomimetic synthesis of
ent-kaurene, the Wagner-Meerwein rearrangement step
is obviously a formidable challenge. When the cationic
cyclization took place, side reactions of [1,2]-H migra-
Biosynthesis of ent-kaurene has been investigated
*
E-mail: rhong@sioc.ac.cn; Tel.: 0086-021-54925161
Received October 21, 2012; accepted December 7, 2012; published online January 8, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201201029 or from the author.
Dedicated to the Memory of Professor Weishan Zhou.
†
Chin. J. Chem. 2013, 31, 111—118
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111

Zhu & Hong
FULL PAPER
tion and elimination were always encountered instead of
the Wagner-Meerwein rearrangement as Oikawa and
co-workers[2b] reported.
Results and Discussion
Our journey was started with commercially available
3-(3-methoxyphenyl)propanoic acid (5). Methylation
and DIBAL-H reduction of acid 5 gave the correspond-
ing aldehyde, which then was reacted with Grignard
reagent to afford allylic alcohol 7 (Scheme 4). With a
Johnson-Claisen rearrangement, the allylic alcohol was
converted to the unsaturated ester,[16] which was further
reduced with LiAlH4 to afford alcohol 8. Followed by
carbon homologation and DIBAL-H reduction, the re-
sulting aldehyde was efficiently masked with
(2R,3R)-2,3-butanediol to give a chiral acetal 10, which
was designed as the precursor for the subsequent enan-
tioseletive cationic cyclization.
Scheme 2 Biosynthesis pathway of ent-kaurene
OPP
+
GGPP
H
H
H
H
ent-CPP
H
+
Wager-
Meerwein
+
+
H
H
H
Scheme 4
H
H
H
OMe
CHO
MeO
a, b
c
ent-Kaurene
COOH
OMe
6
HO
Our group[12] has devoted to biomimetic synthesis of
bioactive natural products over the past several years,
ent-kaurene-type diterpenoids are very attractive targets
in terms of interesting biological activities and being a
platform to devise efficient biomimetic approach to ac-
cess to versatile and intriguing polycyclic structures.
Cationic cyclization has been extensively studied since
1960’s,[13] and especially the Johnson’s seminal work[14]
provides inspirations for our biomimetic study of
ent-kaurene. Based on the biosynthesis studies of
ent-kaurene, we envisioned that a Lewis acid-promoted
and acetal-initiated polyene cationic cyclization would
be feasible to serve as the quick establishment of
ent-kaurene skeleton as shown in Scheme 3. Therefore,
a substituted benzene ring is designed as the cation cap-
turer to achieve the 6/6/6 ring structure. The quarternary
carbon stereogenic center at C(10) can be stereoselec-
tively installed during the cyclization. Followed by a
Birch reduction/alkylation cascade,[15] the subsequent
5-exo-Trig radical cyclization will complete the D ring
to complete the core structure of ent-kaurene.
5
7
MeO
MeO
f, g
d, e
h, i
CN
OH
9
8
MeO
MeO
OMe
j
OH
OH
O
H
O
O
H
O
10
11
12
Reagents and conditions: (a) MeI, K2CO3, DMF, 99%; (b) DI-
o
BAL-H, CH2Cl2, −78 C, 93%; (c) isopropenylmagnesium bromide
1
(0.5 mol•L− in THF), THF, 0 ℃－r.t., 79%; (d) CH3C(OEt)3,
CH3CH2CO2H, 130 oC, 92%; (e) LiAlH4, THF, 0 oC－r.t., 79%; (f)
MsCl, Et3N, CH2Cl2, 0 oC－r.t.; (g) NaCN, Bu4NI, DMF, r.t. 92% for 2
o
steps; (h) DIBAL-H, CH2Cl2, −78 C, 72%; (i) (2R,3R)-2,3-butane-
diol, BF3•Et2O, CaSO4, THF, −78 oC, 95%; (j) SnCl4, toluene, –78 oC,
38% for 11, 56% for 12.
According to the Johnson’s seminal work,[14] it was
postulated that the acetal was only partially cleaved in
the transition state during the cyclization (Scheme 5).
When the acetal was opened, the configuration of oxo-
carbonium ion might adopt a planar, sp2-hybridized
geometry, with the departing oxygen lying in a roughly
perpendicular direction. On the assumption that attack
of the participating double bond took place at the least
sterically congested position, the departing oxygen
would favor to the formation of configuration II as seen.
The chiral acetal 10 was then treated with various Lewis
acids. It was found that SnCl4 afforded the best result in
which cationic cyclization produced the corresponding
tricyclic skeleton with a perfect stereochemistry control
at C(5) and C(10). However, the regioselectivity for the
aryl group was only 3∶2 (12/11) (Scheme 4).
Scheme 3 Biomimetic cation cyclization approach
MeO
Me
MeO
Me
cationic
cyclization
O
O
H
OR
2
1
Birch reduction/
akylation
O
O
radical
cyclization
Me
Me
8
3
10
5
H
H
OR
OR
4
3
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Chin. J. Chem. 2013, 31, 111—118

Biomimetic Cationic Cyclization toward ent-Kaurene-type Diterpenoids
Scheme 5 Proposed stereoselective pathway for the cationic
Scheme 6 Construction of C-ring
cyclization
MeO
MeO
MeO
Cl4Sn
Cl4Sn
Me
l
k
H
O
H
O
Me
-H
OMe
OH
O
O
O
H
H
H
O
O
Me
O
Me
O
O
OMe
Me
Me
I
II
11
13
14
MeO
The ortho-product 11 was then oxidized stepwise
with Swern oxidation followed by the treatment with
PDC and t-BuOOH to afford diketone 14.[17] Subse-
quently, various Birch reduction/alkylation conditions
were executed.[18] However, only bis-propygylated
product 15 was isolated as a major product in a moder-
ate yield (39%) along with the recovered starting mate-
rial 14 in 50% yield, no considerable mono-alkylation
product was obtained (Scheme 6).[19] The complete
stereochemistry assignment of product 15 was estab-
lished by the X-ray crystallographic analysis (Figure
1).[20] Since the chiral auxiliary was known as
(2R,3R)-2,3-butanediol, after the partial oxidation, the
remaining chiral center at the branched ketone-ether
was denoted as (R)-configuration. Therefore, the newly
generated stereogenic centers at C(6) and C(8) after cy-
clization, Birch reduction, and alkylation can be firmly
determined. It was delighted to find that three chiral
centers at the junction of A/B/C rings were consistent
with the corresponding absolute configurations in
ent-kaurenes. Therefore, chiral auxiliary-enabled enan-
tioselective cationic cyclization effectively delivered the
right stereoisomer. However, the second acetylenic
group was also introduced at α-position of ketone in
B-ring. Optimization of the reaction conditions was thus
undertaken. Unfortunately, the bis-alkylation product 15
was always dominated (Table 1). This phenomenon may
be attributed to the comparably enolizable reactivity at
C(5) to form the tertiary carbon center. To verify the
impact of the side chain at C(4), compound 13 was then
subjected to deprotection under the conditions of so-
dium in ether, however, the subsequent Birch reduc-
tion/alkylation cascade to deliver 17 did not occur
(Scheme 7).[21]
m
O
O
O
R
H
O
OMe
Me O
R
O
15
15
Reagents and conditions: (k) (COCl)2, DMSO, NEt3, CH2Cl2, 99%;
(l) PDC (4.0 equiv.), t-BuOOH (4.0 equiv.), Celite®, benzene, r.t.,
o
44%; (m) K (chunks), NH3(l), THF, t-BuOH, HC≡CCH2Br, –78 C,
39% (78%, brsm).
Scheme 7
MeO
(1) Na, Et2O
(2) TBSOTf, 2,6-lutidine
13
(3) PDC, t-BuOOH
O
H
OTBS
16
MeO
K, NH3(l)
t-BuOH, THF
O
Br
H
OTBS
17
Conclusions
In summary, a SnCl4-promoted enantioselective
cationic cyclization and the following Birch reduction/
alkylation cascade towards the construction of
ent-kaurene skeleton was presented. The double alky-
lated product was isolated as the major product although
the stereochemistry of quaternary carbon center at C(8)
was properly introduced. The current approach would
show the promising reaction sequence to access to the
complex ent-kaurene diterpenoids. However, the Birch
reduction/alkylation approach is required to further de-
velopment to deliver a requisite mono-alkylated product,
which may eventually lead to the complete synthesis of
ent-kaurene derivatives and is currently underway in
this laboratory.
Experimental
Melting points were measured on an SGW X-4A
1
melting point apparatus and are uncorrected. H NMR
and 13C NMR were recorded on Varian mercury-400
MHz spectrometers, Varian mercury-300 MHz spectro-
meters or Bruker AM-400 (400 MHz) spectrometers in
the CDCl3. IR spectra were recorded on a Perkin-Elmer
983, Digital FT-IR spectrometer or Bruker-Tensor
Figure 1 X-ray crystal structure of (–)-15 (hydrogen atoms are
omitted for clarity).
Chin. J. Chem. 2013, 31, 111—118
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113

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FULL PAPER
Table 1 Optimization of Birch reduction/alkylation cascade
MeO
MeO
(1) K, NH3(l), THF, t-BuOH,
8
(2)
8
Br
5
O
O
5
H
−78 oC
O
O
O
H
O
15
14
Entry
Solvent (0.75 mL)
Proton t-BuOH/equiv.
NH3(l)/mL
Additive (equiv.)
Yield of 15/%
Recovered 14/%
1
2
3
4
5
6
7
THF
THF
THF
Et2O
THF
THF
Et2O
1.0
1.5
1.0
1.0
1.0
1.0
1.0
10
10
20
10
10
5
—
—
39
Trace
15
50
—
79
73
69
80
62
—
—
21
LiBr (2.5)
—
20
8
10
LiBr (2.5)
14
27; frequencies are given in reciprocal centimeters
(cm−1) and only selected absorbance is reported; Mass
spectra were determined on an Agilent 5973N MSD (EI)
and a Shimadzu LCMS-2010EV (ESI) mass spectrome-
ter or an Agilent G6100 LC/MSD (ESI) single Quand
mass spectrometer. High resolution mass spectra were
recorded on a Waters Micromass GCT Premier (EI) and
a Bruker Daltonics, Inc. APEXIII 7.0 TESLA FTMS
(ESI) mass spectrometers.
colorless oil.[22] 1H NMR (400 MHz, CDCl3) δ: 9.82 (s,
1H), 7.21 (t, J＝7.8 Hz, 1H), 6.79－6.7 (m, 3H), 3.79 (s,
3H), 2.94 (t, J＝7.4 Hz, 2H), 2.77 (t, J＝7.6 Hz, 2H);
LRMS-EI m/z (%): 164 (43), 136 (71), 121 (100), 108
(19), 91 (39), 77 (22).
Preparation of 5-(3-methoxyphenyl)-2-methylpent-
1-en-3-ol (7)
To a solution of 6 (1.22 g, 7.44 mmol) in THF (20
mL) was slowly added isopropenylmagnesium bromide
(0.5 mol•L−1, 17.9 mL, 8.93 mmol) under Ar atmos-
phere at 0 ℃. The mixture was stirred at room tem-
perature. The reaction was finished in 4 h, then
quenched with saturated NH4Cl (aq.) at 0 ℃ and ex-
tracted with ethyl acetate. The combined organic layer
was washed with brine, then dried over Na2SO4 and
concentrated. The residue was purified by chromatog-
raphy on a silica-gel column eluted with PE-EtOAc
(V∶V＝10∶1) to afford compound 7 (1.21 g, 79%) as
colorless oil.[23] 1H NMR (400 MHz, CDCl3) δ: 7.20 (t,
J＝7.8 Hz, 1H), 6.80 (d, J＝7.6 Hz, 1H), 6.76－6.72 (m,
2H), 4.97 (s, 1H), 4.87 (s, 1H), 4.09 (t, J＝6.2 Hz, 1H),
3.79 (s, 3H), 2.70－2.61 (m, 2H), 1.90－1.83 (m, 2H),
1.74 (s, 3H).
Preparation of 3-(3-methoxyphenyl)propanal (6)
3-Methoxycinnamic acid (5.4 g, 30 mmol) and
K2CO3 (6.2 g, 45 mmol) were dissolved in dry DMF (30
mL) under N2 atmosphere, then methyl iodide (2.8 mL,
45 mmol) was added and the mixture was stirred at
room temperature until TLC indicated the complete
conversion of starting material 5 (10 h). The mixture
was poured into water and extracted with n-hexane/
ethyl acetate (V∶V＝50∶1). The combined organic
layer was dried over Na2SO4 and concentrated. The
residue was purified by chromatography on a silica-gel
column eluted with PE-EtOAc (V∶V＝20∶1) to afford
the ester (5.77 g, 99%) as colorless oil. To a solution of
the above ester (1.55 g, 8 mmol) in dry CH2Cl2 (45 mL)
was added DIBAL-H (1.0 mol•L−1, 8.8 mL, 8.8 mmol)
under Ar atmosphere at −78 ℃. The mixture was
stirred at –78 ℃ until TLC indicated the complete
conversion of starting material (0.5 h). The reaction was
quenched with MeOH and poured into an aqueous solu-
tion of potassium sodium tartrate (10 mL). The resulting
mixture was stirred and the organic phase was separated.
The aqueous layer was extracted with ethyl acetate (10
mL×3). The combined organic layers were washed
with brine, dried over Na2SO4 and concentrated. The
residue was subjected to purification by flash chroma-
tography on a silica-gel column eluted with PE-EtOAc
(V∶V＝20∶1) to afford compound 6 (1.22 g, 93%) as
Preparation of (E)-7-(3-methoxyphenyl)-4-methyl-
hept-4-en-1-ol (8)
Compound 7 (3.83 g, 18.6 mmol) and propionic acid
(0.14 mL, 1.86 mmol) were dispersed in triethyl or-
thoacetate (20 mL, 112 mmol) and the mixture was
heated to 130 ℃ until TLC indicated the complete
conversion of starting material 7 (20 h). The mixture
was cooled to room temperature and diluted with ethyl
acetate. The organic layer was washed sequentially with
1 mol•L−1 HCl (aq.), saturated NaHCO3 (aq.) solution
and brine, then dried over Na2SO4 and concentrated.
The residue was purified by chromatography on a silica-
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Biomimetic Cationic Cyclization toward ent-Kaurene-type Diterpenoids
gel column eluted with PE-EtOAc (V∶V＝50∶1) to
afford the ester (3.74 g, 79%) as colourless oil. 1H NMR
(400 MHz, CDCl3) δ: 7.19 (t, J＝8.2 Hz, 1H), 6.78 (d,
J＝7.6 Hz, 1H), 6.74－6.73 (m, 2H), 5.22 (t, J＝7.0 Hz,
1H), 4.12 (q, J＝7.1 Hz, 2H), 3.80 (s, 3H), 2.61 (t, J＝
7.6 Hz, 2H), 2.41－2.37 (m, 2H), 2.32－2.30 (m, 4H),
1.58 (s, 3H), 1.46 (t, J＝7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 173.53, 159.72, 143.93, 134.26, 129.28,
124.50, 120.99, 114.35, 111.11, 60.32, 55.20, 36.08,
34.75, 33.32, 29.84, 15.97, 14.34; FT-IR (film) ν: 2979,
2937, 1732, 1603, 1584, 1488, 1465, 1454, 1438, 1290,
1260, 1153, 1043, 851, 779, 695 cm−1; LRMS-ESI m/z:
299 ([M＋Na]＋); HRMS-ESI calcd for C17H24NaO3 ([M
＋Na]＋) 299.1618, found 299.1628.
chromatography on a silica-gel column eluted with
PE-EtOAc (V∶V＝20∶1) to afford compound 9 (816
mg, 92%) as colourless oil. 1H NMR (400 MHz, CDCl3)
δ: 7.19 (t, J＝8.2 Hz, 1H), 6.77 (d, J＝8.0 Hz, 1H), 6.73
－6.72 (m, 2H), 5.22 (t, J＝6.8 Hz, 1H), 3.79 (s, 3H),
2.63 (t, J＝7.8 Hz, 2H), 2.35－2.30 (m, 2H), 2.17 (t,
J＝7.2 Hz, 2H), 2.10 (t, J＝7.2 Hz, 2H), 1.74－1.67 (m,
2H), 1.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
159.71, 143.74, 133.20, 129.29, 126.00, 120.97, 119.86,
114.46, 111.05, 55.21, 38.25, 35.91; 29.70, 23.37, 16.14,
15.59; FT-IR (film) ν: 3047, 2938, 2855, 2836, 2245,
1601, 1584, 1488, 1454, 1261, 1152, 1051, 874, 780,
696 cm−1; LRMS-ESI m/z: 244 ([M＋ H]＋); HRMS-
ESI calcd for C16H21NO ([M＋H]＋) 244.1690, found
244.1696.
To a solution of LiAlH4 (274 mg, 7.2 mmol) in THF
(20 mL) was slowly added the above ester (1.1 g, 4.0
mmol) in THF (10 mL) at 0 ℃. The mixture was stirred
at room temperature until TLC indicated the complete
conversion of starting material (20 h). The reaction was
quenched with Na2SO4 crystal and stirred for 0.5 h. The
mixture was filtered through Celite and the filtrate was
concentrated. The residue was purified by chromatog-
raphy on a silica-gel column eluted with PE-EtOAc
(V∶V＝5∶1) to afford compound 8 (864 mg, 93%) as
Preparation of (4R,5R)-2-((E)-7-(3-methoxyphenyl)-
4-methylhept-4-enyl)-4,5-dimethyl-1,3-dioxolane (10)
To a solution of compound 9 (786 mg, 3.23 mmol)
in CH2Cl2 (20 mL) was added DIBAL-H (1.0 mol•L−1,
4.9 mL, 4.9 mmol) under Ar atmosphere at –78 ℃. The
mixture was stirred at –78 ℃ until TLC indicated the
complete conversion of starting material (0.5 h). The
reaction was quenched with MeOH (1 mL) and poured
into saturated NH4Cl (aq.)/ethyl acetate (V∶V＝1∶1)
10 mL. The mixture was added 1 mol•L−1 HCl (aq.)
until pH 3－4 and stirred for 20 min. The suspension
was then added potassium sodium tartrate solution (10
mL) until pH 7－8 and stirred to two-phase clear and
extracted with ethyl acetate. The combined organic layer
was washed with brine, then dried over Na2SO4 and
concentrated. The residue was purified by chromatog-
raphy on a silica-gel column eluted with PE-EtOAc
(V∶V＝20∶1) to afford the aldehyde (580 mg, 72%)
as colourless oil. 1H NMR (400 MHz, CDCl3) δ: 9.72 (s,
1H), 7.18 (t, J＝8.0 Hz, 1H), 6.77 (d, J＝7.6 Hz, 1H),
6.73－6.71 (m, 2H), 5.17 (t, J＝7.0 Hz, 1H), 3.78 (s,
3H), 2.62 (t, J＝7.8 Hz, 1H), 2.34－2.28 (m, 4H), 2.00
(t, J＝7.4 Hz, 1H), 1.74－1.67 (m, 2H), 1.54 (s, 3H);
13C NMR (100 MHz, CDCl3) δ: 202.72, 159.73, 143.95,
134.70, 129.29, 124.99, 121.02, 114.46, 111.07, 55.21,
43.19, 38.88, 36.09, 29.76, 20.22, 15.77; FT-IR (film) ν:
3053, 2936, 2858, 2716, 1723, 1601, 1584, 1488, 1455,
1260, 1151, 1043, 872, 779, 695 cm−1; LRMS-EI m/z:
246 ([M] ＋ ); HRMS-EI calcd for C16H22O2 (M ＋ )
246.1625, found 246.1624.
To a solution of above aldehyde (500 mg, 2.05 mmol)
in THF (17 mL) was sequentially added (2R,3R)-
(–)-2,3-butanediol (0.55 mL, 6.1 mmol) and calcium
sulfate (5 g). The mixture was cooled to –78 ℃ and
added boron fluoride ethyl ether (0.09 mL, 0.7 mmol).
The reaction was stirred at 0 ℃ for 8 h and quenched
with saturated Na2CO3 (aq.) solution. The aqueous
phase was extracted with ethyl acetate. The combined
organic layer was washed with brine, then dried over
Na2SO4 and concentrated. The residue was purified by
chromatography on a silica-gel column eluted with
PE-EtOAc (V∶V＝50∶1) to afford 10 (615 mg, 95%)
1
colourless oil. H NMR (400 MHz, CDCl3) δ: 7.20 (t,
J＝8.0 Hz, 1H), 6.79 (d, J＝7.2 Hz, 1H), 6.75－6.73 (m,
3H), 5.22 (t, J＝7.0 Hz, 1H), 3.80 (s, 3H), 3.60 (t, J＝
6.6 Hz, 3H), 2.63 (t, J＝7.8 Hz, 2H), 2.35－2.29 (m,
2H), 2.06 (t, J＝7.4 Hz, 2H), 1.69－1.58 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ: 159.67, 144.03, 135.51,
129.29, 124.18, 121.03, 114.43, 111.07, 62.75, 55.24,
36.15, 35.99, 30.80, 29.83, 15.94; FT-IR (film) ν: 3384,
3058, 2936, 2857, 1601, 1488, 1261, 1151, 1052, 872,
788, 695 cm−1; LRMS-ESI m/z: 257 ([M＋Na]＋);
＋
HRMS-ESI calcd for C15H22NaO2 ([M ＋ Na]
)
257.1515, found 157.1512.
Preparation of (E)-8-(3-methoxyphenyl)-5-methyl-
oct-5-enenitrile (9)
To a solution of compound 8 (864 mg, 3.70 mmol)
in CH2Cl2 (15 mL) was sequentially added triethyl-
amine (1.6 mL, 11.1 mmol) and mesyl chloride (0.43
mL, 5.54 mmol) at 0 ℃. The mixture was stirred at
room temperature until TLC indicated the complete
conversion of starting material (5 h). The reaction was
quenched with water, and extracted with CH2Cl2. The
combined organic layer was washed sequentially with 1
mol•L−1 HCl (aq.), saturated NaHCO3 (aq.) solution and
brine, then dried over Na2SO4 and concentrated to af-
ford pale yellow oil. The above crude product was dis-
solved in 15 mL dry DMF, and was sequentially added
with Bu4NI (683 mg, 1.85 mmol) and sodium cyanide
(272 mg, 5.55 mmol). The mixture was stirred at room
temperature until TLC indicated the complete conver-
sion of starting material, and then poured into water at 0
℃ and was extracted with ethyl ether. The combined
organic layer was washed with brine, then dried over
Na2SO4 and concentrated. The residue was purified by
Chin. J. Chem. 2013, 31, 111—118
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
115

Zhu & Hong
FULL PAPER
as colourless oil. [α]2D9 –7.2 (c 0.981, CHCl3); 1H
NMR (400 MHz, CDCl3) δ: 7.18 (t, J＝7.8 Hz, 1H),
6.75 (d, J＝7.6 Hz, 1H), 6.73－6.71 (m, 2H), 5.19 (t,
J＝6.8 Hz, 1H), 5.03 (t, J＝4.6 Hz, 1H), 3.79 (s, 3H),
3.62－3.57 (m, 2H), 2.60 (t, J＝7.6 Hz, 1H), 2.32－
2.26 (m, 2H), 2.00 (t, J＝7.4 Hz, 1H), 1.63－1.48 (m,
7H), 1.29 (d, J＝5.6 Hz, 1H), 1.22 (d, J＝5.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ: 159.76, 144.21, 135.64,
129.29, 124.07, 121.05, 114.34, 111.19, 103.45, 79.87,
78.23, 55.25, 39.61, 36.31, 34.40, 29.95, 22.30, 17.43,
17.13, 15.93; FT-IR (film) ν: 3054, 2973, 2931, 2866,
1732, 1602, 1584, 1488, 1382, 1261, 1151, 1122, 1080,
780, 696 cm−1; LRMS-EI m/z: 318 ([M]＋); HRMS-EI
calcd for C20H30O3 (M＋) 318.2195, found 318.2194.
1.26 (m, 2H), 1.21 (s, 3H), 1.18 (d, J＝6.4 Hz, 3H),
1.10 (d, J＝6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
159.01, 138.03, 136.56, 126.22, 122.56, 109.37, 77.48,
77.40, 71.34, 55.19, 47.49, 38.78, 36.10, 32.06, 29.21,
23.96, 20.54, 19.10, 18.46, 15.86; FT-IR (film) ν: 3569,
2965, 2929, 2874, 1608, 1499, 1453, 1374, 1277, 1253,
1149, 1079, 1039, 811, 738 cm−1; LRMS-ESI m/z: 341
([M＋Na]＋); HRMS-ESI calcd for C20H30NaO3 ([M＋
Na]＋) 318.2087, found 341.2089.
Preparation of (R)-3-(((1R,4aR,10aS)-5-methoxy-4a-
methyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-
yl)oxy)butan-2-one (13)
To a solution of oxalyl chloride (48.6 μL, 0.568
mmol) in CH2Cl2 (4 mL) was added DMSO (66.4 μL,
1.13 mmol) in CH2Cl2 (0.4 mL) under Ar atmosphere at
–78 ℃. The mixture was stirred for 5 min, then was
added 11 (120 mg, 0.377 mmol) in CH2Cl2 (0.4 mL)
and stirred for another 30 min. The reaction mixture was
then added triethylamine (0.26 mL, 1.89 mmol) and
slowly warmed to room temperature until TLC indi-
cated the complete conversion of starting material. The
reaction was quenched with water and extracted with
CH2Cl2. The organic layer was washed sequentially
with 1 mol•L−1 HCl (aq.), saturated NaHCO3 (aq.) solu-
tion and brine, then dried over Na2SO4 and concentrated.
The residue was purified by chromatography on a silica-
gel column eluted with PE-EtOAc (V∶V＝40∶1) to
afford ketone 13 (118 mg, 99%) as white solid. m.p. 84
General procedure for SnCl4-promoted cationic cy-
clization
To a solution of SnCl4 (1.0 mol•L−1 in CH2Cl2, 0.22
mL) in toluene (2.5 mL) was added compound 10 (35
mg, 0.11 mmol) in 2.5 mL toluene under Ar atmosphere
at –78 ℃. The mixture was stirred at –78 ℃ until
TLC indicated the complete conversion of starting ma-
terial (3 h). The reaction was quenched with aturated
NaHCO3 (aq.) solution and extracted with CH2Cl2. The
combined organic layer was washed with brine, then
dried over Na2SO4 and concentrated. The residue was
purified by chromatography on a silica-gel column
eluted with PE-EtOAc (V∶V＝40∶1) to afford 11
(10.8 mg, 31%, colourless oil) and 12 (20.4 mg, 58%,
colourless oil).
1
－85 ℃; [α]2D8 –134.2 (c 1.025, CHCl3); H NMR
(400 MHz, CDCl3) δ: 7.05 (t, J＝7.8 Hz, 1H), 6.69－
6.67 (m, 2H), 380－3.74 (m, 4H), 3.67－3.66 (m, 1H),
3.19 (d, J＝13.6 Hz, 1H), 3.01－2.91 (m, 1H), 2.87－
2.82 (m, 1H), 2.25 (s, 3H), 2.10－2.01 (m, 1H), 1.94－
1.84 (m, 2H), 1.60－148 (m, 4H), 1.44 (s, 3H), 1.42－
1.34 (m, 1H), 1.26 (d, J＝6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ: 212.14, 158.99, 137.93, 136.54, 126.23,
122.56, 109.40, 80.32, 80.04, 55.19, 47.67, 38.86, 36.13,
32.07, 29.89, 25.76, 24.10, 20.25, 18.35, 16.98; FT-IR
(film) ν: 2999, 2978, 2938, 2868, 1714, 1574, 1458,
(2R,3R)-3-((1R,4aR,10aS)-5-Methoxy-4a-methyl-
1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yloxy)but-
1
an-2-ol (11): [α]2D7 –163.1 (c 1.050, CHCl3); H NMR
(400 MHz, CDCl3) δ: 7.04 (t, J＝7.8 Hz, 1H), 6.68－
6.66 (m, 2H), 3.77 (s, 3H), 3.67－3.66 (m, 1H), 3.56－
3.53 (m, 1H), 3.19－3.15 (m, 2H), 3.00－2.91 (m, 1H),
2.86－2.81 (m, 1H), 2.70 (s 1H), 2.05－2.19 (m, 2H),
1.87－1.77 (m, 1H), 1.64－1.53 (m, 3H), 1.48 (dd, J＝
13.0, 7.0 Hz, 1H), 1.37 (s, 1H), 1.35－1.30 (m, 1H),
1.28－1.23 (m, 2H), 1.18 (d, J＝6.4 Hz, 3H), 1.09 (d,
J＝6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 157.31,
141.61, 136.59, 125.33, 113.73, 111.89, 77.52, 76.17,
71.32, 55.23, 45.01, 38.18, 36.37, 29.79, 29.09, 25.76,
23.19, 19.06, 18.17, 15.80; FT-IR (film) ν: 3571, 2971,
2928, 2864, 1574, 1454, 1437, 1249, 1080, 1053, 775,
737 cm−1; LRMS-ESI m/z: 341 ([M＋Na]＋); HRMS-
ESI calcd for C20H30NaO3 ([M＋Na]＋) 318.2087, found
341.2090.
1438, 1361, 1279, 1247, 1113, 1077, 1054, 1012, 994,
＋
779 cm−1; LRMS-ESI m/z: 339 ([M ＋ Na] );
＋
HRMS-ESI calcd for C20H28NaO3 ([M ＋ Na]
)
339.1931, found 339.1936.
Preparation of (1R,4aR,10aS)-5-methoxy-4a-methyl-
1-((R)-3-oxobutan-2-yloxy)-2,3,4,4a,10,10a-hexahy-
drophenanthren-9(1H)-one (14)
To a solution of the ketone 13 (118 mg, 0.373 mmol)
in benzene (5 mL) was added Celite (460 mg). The
mixture was sequentially added PDC (559 mg, 1.49
mmol) and t-BuOOH (0.27 mL, 1.49 mmol) at 0 ℃.
The reaction mixture was stirred at room temperature
until TLC indicated the complete conversion of starting
material (20 h). The mixture was diluted with excessive
ethyl ether and stirred vigorously for 1 h. The mixture
was filtered through Celite and the filtrate was concen-
trated. The residue was purified by flash chromatogra-
phy on a silica-gel column eluted with PE-EtOAc (V∶V
(2R,3R)-3-((1R,4aR,10aS)-7-Methoxy-4a-methyl-
1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yloxy)but-
1
an-2-ol (12): [α]2D7 –133.8 (c 1.015, CHCl3); H NMR
(400 MHz, CDCl3) δ: 7.15 (d, J＝8.8 Hz, 1H), 6.70 (dd,
J＝8.8, 2.8 Hz, 1H), 6.58 (d, J＝2.4 Hz, 1H), 3.76 (s,
3H), 3.63－3.62 (m, 1H), 3.57－3.54 (m, 1H), 3.19－
3.16 (m, 1H), 2.91 (dd, J＝9.0, 4.2 Hz, 1H), 2.62 (s,
1H), 2.29 (d, J＝12.8 Hz, 1H), 2.15－2.11 (m, 1H),
1.97 (d, J＝14.0 Hz, 1H), 1.85－1.76 (m, 1H), 1.66－
1.54 (m, 3H), 1.40 (dt, J＝13.2, 3.6 Hz, 1H), 1.36－
116
www.cjc.wiley-vch.de
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 111—118

Biomimetic Cationic Cyclization toward ent-Kaurene-type Diterpenoids
＝5∶1) to afford compound 14 (51.5 mg, 42%) as
white solid. m.p. 72－73 ℃; [α]2D8 –86.8 (c 1.015,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.73 (d, J＝7.6
Hz, 1H), 7.26 (t, J＝8.0 Hz, 1H), 7.07 (d, J＝7.2 Hz,
1H), 3.84 (s, 3H), 3.78 (q, J＝6.8 Hz, 1H), 3.63－3.62
(m, 1H), 3.26 (d, J＝13.6 Hz, 1H), 3.07 (dd, J＝16.0,
14.8 Hz, 1H), 2.37 (dd, J＝17.4, 2.2 Hz, 1H), 2.26 (s,
3H), 2.16－2.13 (m, 1H), 1.99－1.88 (m, 2H), 1.62－
1.58 (m, 1H), 1.53 (s, 3H), 1.43－1.34 (m, 2H), 1.28 (d,
J＝6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 210.96,
199.26, 158.21, 141.84, 133.34, 127.19, 120.36, 117.44,
80.34, 78.26, 55.72, 45.31, 39.81, 39.62, 35.79, 29.30,
25.78, 18.66, 17.94, 16.87; FT-IR (film) ν: 2998, 2935,
2864, 1717, 1687, 1596, 1570, 1453, 1437, 1302, 1284,
1116, 1041, 1016, 800, 747 cm−1; LRMS-ESI m/z: 353
([M＋Na]＋); HRMS-ESI calcd for C20H26NaO4 ([M＋
Na]＋) 253.1723, found 353.1713.
Sciences.
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4a-methyl-1-((R)-3-oxobutan-2-yloxy)-8a,10-di(prop-
2-ynyl)-2,3,4,4a,6,8a,10,10a-octahydrophenanthren-
9(1H)-one (15)
To a solution of 14 (50 mg, 0.015 mmol) in THF
(0.75 mL) was added t-BuOH (14 μL, 0.015 mmol), and
then the reaction mixture was cooled to –78 ℃. 10 mL
NH3(l) was collected and to the mixture was added po-
tassium (14.8 mg, 0.379 mmol), then stirred at –78 ℃
for 1 h. To the reaction mixture was then added
propargyl bromide (30 μL, 0.379 mmol) and stirred for
0.5 h. When the reaction finished, it was quenched with
NH4Cl (solid), and then the ammonia gas was evapo-
rated. The residue was added brine (3 mL) and extracted
with CH2Cl2. The organic layer was dried over Na2SO4
and concentrated. The residue was purified by chroma-
tography on a silica-gel column eluted with PE-EtOAc
(V∶V＝10∶1) to afford 15 (19.7 mg, 39%, 78% brsm)
as white solid. m.p. 42 ℃; [α]2D8 –23.9 (c 0.831,
1
CHCl3); H NMR (400 MHz, CDCl3) δ: 6.28 (dd, J＝
9.6, 2.4 Hz, 1H), 5.89 (ddd, J＝9.6, 4.4, 2.4 Hz, 1H),
3.97－3.96 (m, 1H), 3.80 (q, J＝6.8 Hz, 1H), 3.57 (s,
3H), 3.10－2.99 (m, 1H), 2.93 (d, J＝12.8 Hz, 1H),
2.84 (dd, J＝17.2, 2.8 Hz, 1H), 2.74－2.63 (m, 2H),
2.45－2.34 (m, 3H), 2.22 (s, 3H), 1.95－1.89 (m, 3H),
1.79－1.71 (m, 1H), 1.55－1.48 (m, 2H), 1.46 (s, 3H),
1.44－1.30 (m, 2H), 1.27 (d, J＝6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ: 211.22, 210.35, 152.35, 129.18,
123,26, 120.84, 81.32, 80.39, 80.22, 74.35, 71.05, 70.87,
55.37, 53.07, 44.81, 42.64, 38.77, 37.16, 32.30, 29.83,
28.69, 25.29, 20.26, 17.92, 17.40, 17.33; FT-IR (film) ν:
3289, 2931, 2120, 1712, 1682, 1434, 1355, 1221, 1115,
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1015, 722, 640 cm−1; LRMS-ESI m/z: 431 ([M＋Na]＋);
＋
HRMS-ESI calcd for C26H32NaO4 ([M ＋ Na]
)
431.2193, found 431.2202.
Acknowledgement
Financial support for this work is generously pro-
vided by the National Basic Research Program of China
(No. 2010CB833200) and the Chinese Academy of
[9] (a) Chen, K.; Shi, Q.; Fujioka, T.; Nakano, T.; Hu, C.-Q.; Jin, J.-Q.;
Chin. J. Chem. 2013, 31, 111—118
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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117

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reduced and the corresponding side product was isolated (＜10%
yield).
[20] CCDC 899271 (15) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
[21] Compound 12 was also oxidized to bis-ketone product like 14. The
ketone compound was subjected to Birch reduction/alkylation and a
complicated reaction was obtained, which afforded some unidenti-
fied products.
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(Zhao, C.)
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