Synthesis of derivatives of podocarpane-type diterpenoids through Diels-Alder cycloaddition and photo-decarbonylation from unmasked ortho-benzoquinone

Article abstract of DOI:10.1016/j.tet.2017.02.032

Derivatives of podocarpane-type diterpenoids, including cassane-type, abietane-type and totarane-type diterpenoids, are either widely distributed natural products or common intermediates in synthetic and medicinal chemistry. Although unmasked ortho-benzoquinone has been used in [4+2] cycloadditions in sparse cases due to its multiple reactivity as diene, dienophile, heterodiene and heterodienophile, applications of this motif in cycloadditions of complex molecules are very rare. We report herein that this [4+2] process can be successfully extended to various polycyclic substrates, followed by a photo-decarbonylation, to generate versatile derivatives of podocarpane-type diterpenoids. Racemic synthesis of isolophanthins A & B and abietatrien-3β-ol was accomplished on the basis of this methodology.

Full text of DOI:10.1016/j.tet.2017.02.032

Accepted Manuscript
Synthesis of derivatives of podocarpane-type diterpenoids through Diels-Alder
cycloaddition and photo-decarbonylation from unmasked ortho-benzoquinone
Guili Zhu, Bo Liu
PII:
S0040-4020(17)30164-3
10.1016/j.tet.2017.02.032
TET 28473
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 August 2016
Revised Date: 13 February 2017
Accepted Date: 15 February 2017
Please cite this article as: Zhu G, Liu B, Synthesis of derivatives of podocarpane-type diterpenoids
through Diels-Alder cycloaddition and photo-decarbonylation from unmasked ortho-benzoquinone,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.02.032.
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Graphical Abstract
Synthesis of derivatives of podocarpane-type
diterpenoids through Diels-Alder
Leave this area blank for abstract info.
cycloaddition and photo-decarbonylation
from unmasked ortho-benzoquinone
Guili Zhu, Bo Liu*
Key Laboratory of Green Chemistry & Technology of the Ministry of Education, College of Chemistry, Sichuan
University, Chengdu, Sichuan 610064, China

ACCEPTED MANUSCRIPT
Tetrahedron
1
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of derivatives of podocarpane-type diterpenoids through Diels-Alder
cycloaddition and photo-decarbonylation from unmasked ortho-benzoquinone
Guili Zhua , Bo Liua, b,
a Key Laboratory of Green Chemistry & Technology of the Ministry of Education, College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, China
b State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Derivatives of podocarpane-type diterpenoids, including cassane-type, abietane-type and
totarane-type diterpenoids, are either widely distributed natural products or common
intermediates in synthetic and medicinal chemistry. Although unmasked ortho-benzoquinone
has been used in [4+2] cycloadditions in sparse cases due to its multiple reactivity as diene,
dienophile, heterodiene and heterodienophile, applications of this motif in cycloadditions of
complex molecules are very rare. We report herein that this [4+2] process can be successfully
extended to various polycyclic substrates, followed by a photoreaction-decarbonylation, to
generate versatile derivatives of podocarpane-type diterpenoids. Racemic synthesis of
Available online
Keywords:
Diels-Alder cycloaddition
photoreaction
isolophanthins A & B and abietatrien-3β-ol was accomplished on the basis of this methodology.
decarbonylation
podocarpane
ortho-benzoquinone
1. Introduction
efficient way to access complex multisubstituted benzene
derivatives of podocarpane-type diterpenoids (Figure 1c). By
following this methodology, we accomplished the racemic
synthesis of isolophanthin A,3 isolophanthin B,5 and abietatrien-
Phenylic diterpenes with a multisubstituted benzene ring,
represented as structure A in Figure 1a, are metabolites isolated
from a variety of plants. Structurally, they are composed of
podocarpane-type, cassane-type, abietane-type and totarane-type
diterpenoids, but all can be considered as derivatives of
podocarpane-type diterpenoids.1-5 Some of these derivatives are
biogenetic precursors of medicinally important compounds,
while many of them exhibit intriguing bioactivities as natural
products. Therefore, structural features and bioactivities of these
molecules have garnered interest from synthetic chemists,
cultivating numerous total syntheses and partial syntheses.6
3β
-ol,1b,2,4 and the architecture of antiochic acid was constructed
as well.1f
Herein we report
a
synthetic methodology aiming at
podocarpane-type derivatives with different phenyl substituents.
Unmasked ortho-benzoquinone (UMOB) shows versatile
reactivity, behaving as a carbodiene, heterodiene, dienophile and
heterodienophile in cycloaddition reactions. Notably, when
alkynes as the dienophiles undergo [4+2] cycloaddition with
UMOB,7 photochemical decarbonylation can take place facilely
to deliver a benzene ring with various substituents.7d-h,8 However,
to the best of our knowledge, this cycloaddition/decarbonylation
sequence has never been applied in complex polycyclic
molecules. In the process of our recent total synthesis of atisane-
type diterpenoids (Figure 1b),9 we observed that the [4+2]
cycloadducts from podocarpane-type UMOB were unstable with
exposure to light and led to aromatization after releasing two
Figure 1
molecules of carbon monoxide. We realized that this might be an
———
Corresponding author. Tel. & fax: +86-28- 8541-3712; e-mail: chembliu@scu.edu.cn

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2
Tetrahedron
2. Results and discussion
three steps based on our previously developed procedure,9 was
reacted with various alkynes in dichloromethane and the solution
was heated in a sealed tube at 140 or 160 ꢀ to undergo thermal
[4+2] cycloaddition. Notably, presence of MnO2 as oxidant in the
reaction was necessary to prevent compound 1 from being
reduced to compound 1′ at high temperature. After reacting rac-1
with different alkynes, the resultant regiomers in this
cycloaddition were further converted into compounds 3 and 3′ in
photochemical conditions (Table 1).10 After the two-step
sequence, aromatic alkynes afforded compounds 3a-3c as the
major products, whose regioselectivity is in accordance with our
previous findings.9 This chemistry might be applied in the
synthesis of podocarpane-type diterpenoid homodimers or
heterodimers.11
In our previous attempts on Diels-Alder cycloaddition of
podocarpane-type unmasked ortho-benzoquinone toward
bicyclo[2.2.2]octane skeletons,9 we wrapped reaction tubes in
aluminum foil to prevent the cycloadducts from light-driven
decarbonylation and subsequent aromatization. However,
decarbonylation and aromatization took place inevitably for some
substrates in the course of workup. Thus it is a convenient way to
achieve derivatives of podocarpane-type diterpenoids by utilizing
photo-decarbonylation
and
aromatization
from
the
bicyclo[2.2.2]octane cycloadducts, which facilitates convenient
introduction of versatile functional groups on the benzene ring
and divergent synthesis of different aromatically substituted
natural product-like analogs. Accordingly, racemic 1, prepared in
Table 1
Scope of the reaction of 1 and alkynes to generate multisubstituted benzene derivatives.a, b, c
R1
R2
O
OH
OH
R2
R1
R1
i) MnO2, CH2Cl2, 3-7 h
140 oC or 160 o
C
O
HO
HO
ii) PhCH3, rt, 2-4 h
26 W lamp
R2
HO
H
HO
H
H
H
1
3
2
3'
1'
HO
F
HO
HO
OMe
HO
H
H
H
H
3c
3dd
3b
3a
30%
79% (2:1)
81% (6:1)
80% (2:1)
TMS
TMS
TMS
TMS
HO
HO
HO
HO
HO
HO
H
H
H
H
3f
3hd
3ee
3g
74% (>50:1)
32% (2:1)
53%
76% (4:1)
O
TMS
O
NO2
O
O
HO
HO
HO
H
H
H
H
3id
3l
3j
3k
59% (3:1)
63% (6:1)
69% (3:1)
53% (3:1)
OH
OTBS
OTBS
Br
TMS
HO
HO
HO
H
H
H
H
3pd
3mf
3n
3o
31% (2:1)
71% (15:1)
62% (>30:1)
22%
a Unless otherwise stated, cycloaddition reactions were carried out with 1 (1.0 equiv.) and 2a-p (20.0 equiv.) in dichloromethane in sealed tubes at 140 ꢀ for
3-7 hours in the presence of freshly activated MnO2 (4.0 equiv.). Then dichloromethane was removed under reduced pressure after filtration and the residue
was dissolved in toluene. The resultant solution was irradiated with 26 W lamp for 2-4 hours. b Isolated yields combining 3 and 3’. c The ratios of 3 to 3′ in
d
e
parenthesis were determined by LC/MS analysis of the crude reaction mixture. These reactions were performed at 160 ꢀ. See ref. 9 for details on
f
cycloaddition. Norbornadiene was used to in situ generate acetylene as the dienophile.

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Tetrahedron
3
Symmetric disubstituted alkynes, i.e. 1,2-diphenyl acetylene,
benzyne and acetylene generated in situ, led to the corresponding
aromatized products 3d, 3e and 3m in medium to good yields.
The bulkiness of 1,2-diphenyl acetylene might result in low yield
of 3d even at higher temperature during cycloaddition, compared
to higher yields for compounds 3a-3c from substituted
phenylacetylenes. While trimethylsilyl acetylene and aliphatic
terminal alkynes showed different regioselectivity to aromatic
terminal alkynes in cycloaddition,9 we observed similar
preference for compounds 3f-3h, 3l, 3n-3p. Disubstituted
aliphatic alkynes showed typically lower reactivity to afford 3h
and 3n because of steric hindrance. Interestingly, the diynes and
the ynone substituted with trimethylsilyl group afforded the
corresponding products, 3g, 3l and 3o, in satisfactory yields with
enhanced regioselectivities (6:1->50:1) with both TMS and other
conjugative groups, which was much better than the
regioselectivites (3:1-4:1) obtained for 3f, 3j and 3k from
monosubstituted alkynes.
synthesis of these natural products in a concise and efficient
manner.
OH
p-TsOH.H2O
PhMe, reflux
HO
HO
0.5 h
H
H
3p
8
(rac-isolophanthin A)
Pd/C, MeOH
HCOONH4, 66 oC
81% for 2 steps
HO
OH
H
rac-abietatrien-3 β-ol
OMe
DDQ, MeOH
rt, 80%
HO
HO
A
plausible mechanism of this cycloaddition/photo-
H
H
3p
(rac-isolophanthin A)
aromatization process is shown in Scheme 1. First, thermal Diels-
Alder cycloaddition takes place between unmasked ortho-
benzoquinone 1 and alkyne 2 to generate the bicyclo[2.2.2]octane
intermediate, i.e. diketone 4. Then, one of the two carbonyls in 4
is irradiated to produce the diradical species 5, which triggers
allylic C-C cleavage to afford 6. Subsequently, the diradical
species 6 is transformed to compound 7 by releasing one
molecule of CO. Finally, the second CO is released to afford
compound 3 via aromatization. The regioselectivity of this
sequential process is controlled by the thermal Diels-Alder
cycloaddition. Other possibilities involving C-C cleavage
between two carbonyls from 5 cannot be ruled out.
rac-isolophanthin B
Scheme 2 Conversion of 3p to other racemic abietane-type natural products.
3. Conclusion
In summary, we reported herein a useful sequential process
involving thermal Diels-Alder cycloaddition of podocarpane-type
unmasked ortho-benzoquinones with alkynes and light-driven
decarbonylation to generate a variety of multisubstituted benzene
ring derivatives embracing the podocarpane-type substructure.
The potential of this methodology was demonstrated through the
concise synthesis of several natural abietane-type diterpenoids,
albeit in racemic form.
4. Experimental Section
4.1. General information
All solvents were purified according to standard methods prior
to use, except the directly used commercial MeOH. All
anhydrous reactions were carried out under a positive atmosphere
of argon in dried sealed tube unless otherwise indicated.
Materials were obtained from commercial suppliers and used
without further purification except those otherwise noted.
Compounds 2i, 2o and 2n were prepared according to the
procedures described in the literature.13,14 Flash chromatography
was performed using silica gel (200-300 mesh). Reactions were
monitored by thin layer chromatography (TLC). Visualization
was achieved under a UV lamp (254 nm and 365 nm), I2 and by
developing the plates with p-anisaldehyde, phosphomolybdic
acid (PMA) or Cerium Ammonium Molybdate (CAM). NMR
Scheme 1 Proposed reaction mechanism.
1
spectra were recorded for H NMR at 400 MHz and 13C NMR at
100 MHz. For 1H NMR, tetramethylsilane (TMS) served as
To demonstrate potential synthetic applications of this
methodology, compound 3p, a racemic form of sessilifol J3a and
isolophanthin A3b belonging to natural abietane-type diterpenoid,
was treated with a catalytic amount of para-toluenesulfonic acid
to deliver compound 8 through dehydration. Hydrogenation
internal standard (δ= 0). The data were calibrated using residual
1
undeuterated solvent as an internal reference (CDCl3: H NMR =
7.26, 13C NMR = 77.16) and reported in the following order:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q
=
quartet, m=multiplet, br=broad), integration. Coupling
catalyzed by palladium converted 8 into racemic abietatrien-3β-
constants (J) are reported in Hertz. LC/MS data was obtained
using Agilent Technologies 6224 TOF LC/MS system. High
resolution mass spectra (HRMS) were recorded by using FTMS-
7 spectrometers. Infrared (IR) spectra were recorded on a
NEXUS 670 FT-IR Spectrophotometer and are reported in
wavenumbers (cm-1).
ol.2 Alternatively, compound 3p could be smoothly converted
into racemic isolophanthin B, another natural abietane-type
diterpenoid,3b with DDQ as reagent.12 Characterization data of all
our synthetic samples were in good accordance with those of the
natural samples. Application of this methodology enables total

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4
Tetrahedron
4.2. General procedure for the sequential process involving
Diels-Alder cycloaddition between ortho-benzoquinone 1 and
alkynes 2, and decarbonylation toward derivatives of
podocarpane-type diterpenoid 3 (3a-d, 3f-p).
CDCl3) δ 7.35 (d, J = 8.0 Hz, 1H), 7.25 – 7.20 (m, 2H), 7.16 (t, J
= 8.0 Hz, 2H), 7.10 – 6.96 (m, 7H), 3.34 (dd, J = 10.8, 4.8 Hz,
1H), 2.56 (m, 2H), 2.41 (d, J = 12.8 Hz, 1H), 1.82 (m, 3H), 1.66
(m, 2H), 1.37 (d, J = 12.0 Hz, 1H), 1.31 (s, 3H), 1.04 (s, 3H),
0.90 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 148.9, 142.0, 140.8,
140.3, 138.8, 133.6, 130.5, 130.5, 129.9 (2C), 127.9, 127.8, 127.6,
127.4 (2C), 126.3, 126.0, 124.0, 78.8, 49.4, 39.0, 38.1, 37.5, 30.8,
28.2, 28.2, 25.2, 19.1, 15.5. HRMS (ESI): m/z calcd for C29H32O,
[M+Na]+, 419.2359; found, 419.2351.
A mixture of the ortho-benzoquinone 1 (27.4 mg, 0.10 mmol,
1.0 equiv.) and freshly activated MnO2 (0.40 mmol, 4.0 equiv.)
was added into a dried sealed tube under argon atmosphere. Then
a solution of the alkynes 2 (2.00 mmol, 20.0 equiv.) in
dichloromethane (2.0 mL) was added. The reaction mixture was
heated at 140ꢀ or 160ꢀ in an oil bath until the substrate 1
disappeared (monitored by TLC). Then MnO2 was filtered off
through a plug of silica gel and washed with EtOAc-petroleum
(v/v=1.5:1). The resulting filtrate was concentrated to afford the
crude product, which was dissolved in 2.0 mL of toluene and
irradiated with a 26W lamp (UVB). After the reaction was
completed, the mixture was purified directly by flash
chromatography on silica gel with EtOAc-Petroleum (1:5 or 1:3
v/v) as eluent to afford compounds 3 and 3′.
4.2.5. 1,1,4a-trimethyl-1,2,3,4,4a,11,12,12a-octahydrochrysen-
2-ol (3e)
To the mixture of ortho-benzoquinone 1 (27.3 mg, 0.10 mmol,
1.0 equiv.), anhydrous KF (14.5 mg, 0.25 mmol, 2.5 equiv.) and
18-crown-6 (67.9 mg, 0.25 mmol, 2.5 equiv.) in a reaction tube
was added 1.0 mL of THF under argon atmosphere. Then the
mixture was cooled to 0 ꢀ. To the resultant dark-red solution
was added 2-(trimethylsilyl)phenyl trifluoromethanesulfonate
(30.0 µL, 0.12 mmol, 1.2 equiv.) dropwise. When TLC analysis
showed completion of the reaction after 3 hours, the reaction
mixture was quenched with 20 mL of water at 0ꢀ. The aqueous
layer was extracted with EtOAc (20 mL×3). The combined
organic extracts were dried over anhydrous Na2SO4 and
concentrated to give the crude product, which was dissolved in
2.0 mL of toluene and irradiated with a 26W lamp (UVB). After
the reaction was completed, the reaction mixture was purified by
flash chromatography on silica gel with EtOAc-Petroleum
(v/v=1:5) as eluent to afford the product 3e (15.5 mg). Yield:
53%, white solid, 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.4
Hz, 1H), 7.82 – 7.76 (m, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.53 –
7.41 (m, 3H), 3.39 (dd, J = 17.6, 6.4 Hz, 1H), 3.36 – 3.28 (m, 1H),
3.21 – 3.07 (m, 1H), 2.43 (dt, J = 13.2, 3.6 Hz, 1H), 2.12 (dd, J =
13.2, 7.6 Hz, 1H), 1.92 – 1.79 (m, 3H), 1.61 – 1.51 (m, 1H), 1.43
(dd, J = 12.4, 1.6 Hz, 1H), 1.30 (s, 3H), 1.13 (s, 3H), 0.95 (s, 3H).
4.2.1. 1,1,4a-trimethyl-8-phenyl-1,2,3,4,4a,9,10,10a-octahydro-
phenanthren-2-ol (3a)
Yield: 80%, white solid, IR (thin film): 3447, 2930, 2857,
1583, 1444, 1032, 796, 702cm-1; 1H NMR (400 MHz, CDCl3) δ
7.42 (t, J = 7.2 Hz, 2H), 7.38 – 7.29 (m, 4H), 7.23 (t, J = 7.6 Hz,
1H), 7.04 (d, J = 7.2 Hz, 1H), 3.35 (dd, J = 10.4, 5.2 Hz, 1H),
2.73 (t, J = 7.8 Hz, 2H), 2.41 (d, J = 12.8 Hz, 1H), 1.86 (m, 3H),
1.68 (m, 2H), 1.39 (d, J = 12.0 Hz, 1H), 1.30 (s, 3H), 1.09 (s, 3H),
0.93 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 149.8, 142.6, 142.2,
132.9, 129.3 (2C), 128.2 (2C), 127.2, 126.8, 125.7, 124.0, 78.8,
49.6, 39.1, 38.3, 37.5, 30.0, 28.2 (2C), 25.2, 19.0, 15.5. HRMS
(ESI): m/z calcd for C23H28O, [M+Na]+, 343.2038; found,
343.2033.
4.2.2. 8-(4-methoxyphenyl)-1,1,4a-trimethyl-1,2,3,4,4a,9,10,10a-
octahydrophenanthren-2-ol (3b)
13C NMR (100 MH
Z, CDCl3) δ 146.1, 132.3, 131.7, 129.7, 128.3,
126.5, 126.0, 125.1, 123.5, 123.4, 78.8, 50.0, 39.0, 38.1, 37.3, 28.3,
28.2, 28.1, 24.5, 18.8, 15.5. HRMS (ESI): m/z calcd for C21H26O,
[M+Na]+, 317.1881; found, 317.1885.
Yield: 81%, white solid, IR (thin film): 3440, 2930, 2857,
1610, 1513, 1243, 797cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39 –
7.12 (m, 4H), 7.06 – 6.87 (m, 3H), 3.85 (s, 3H), 3.32 (dd, J =
10.8, 5.2 Hz, 1H), 2.85 – 2.61 (m, 2H), 2.37 (d, J = 12.8 Hz, 1H),
1.82 (m, 3H), 1.69 – 1.56 (m, 2H), 1.35 (d, J = 12.0 Hz, 1H), 1.25
(s, 3H), 1.05 (s, 3H), 0.89 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
158.5, 149.8, 141.8, 135.0, 133.2, 130.3 (2C), 127.5, 125.6, 123.9,
113.6 (2C), 78.7, 55.4, 49.6, 39.1, 38.2, 37.5, 30.1, 28.2, 28.2,
25.1, 19.0, 15.5. HRMS (ESI): m/z calcd for C24H30O2, [M+Na]+,
373.2143; found, 373.2144.
4.2.6. 1,1,4a-trimethyl-7-(trimethylsilyl)-1,2,3,4,4a,9,10,10a-oct-
ahydrophenanthren-2-ol (3f)
Yield: 76%, white solid, IR (thin film): 3408, 2949, 2854,
1451, 1384, 1247, 1090, 1065, 873, 838, 818, 755cm-1;1H NMR
(400 MHz, CDCl3) δ 7.28 (d, J = 7.8 Hz, 1H), 7.25 – 7.18 (m,
2H), 3.29 (dd, J = 10.8, 5.2 Hz, 1H), 2.98 (dd, J = 16.8, 6.4 Hz,
1H), 2.93 – 2.81 (m, 1H), 2.35 – 2.28 (m, 1H), 1.95 – 1.86 (m,
1H), 1.86 – 1.70 (m, 3H), 1.61 – 1.50 (td, J=12.8, 4.4 Hz, 1H),
1.33 (dd, J = 12.0, 1.2 Hz, 1H), 1.20 (s, 3H), 1.07 (s, 3H), 0.90 (s,
3H), 0.24 (d, J = 1.2 Hz, 9H). 13C NMR (100 MHz, CDCl3) δ
150.1, 137.0, 134.4, 134.3, 130.9, 124.0, 78.9, 49.8, 39.2, 37.7,
36.9, 30.8, 28.3, 28.1, 24.9, 19.0, 15.5, -0.9 (3C). HRMS (ESI):
m/z calcd for C20H32OSi, [M+Na]+, 339.2120; found, 339.2116.
4.2.3. 8-(4-fluorophenyl)-1,1,4a-trimethyl-1,2,3,4,4a,9,10,10a-
octahydrophenanthren-2-ol (3c)
Yield: 79%, white solid, IR (thin film): 3422, 2928, 2957,
1560, 1511, 1223, 1032, 798cm-1; 1H NMR (400 MHz, CDCl3) δ
7.29 (d, J = 8.0 Hz, 1H), 7.25 – 7.14 (m, 3H), 7.06 (t, J = 8.4 Hz,
2H), 6.96 (d, J = 7.2 Hz, 1H), 3.31 (dd, J = 10.8, 4.8 Hz, 1H),
2.64 (t, J = 8.0 Hz, 2H), 2.37 (d, J = 12.8 Hz, 1H), 1.89 – 1.73 (m,
3H), 1.73 – 1.54 (m, 2H), 1.34 (d, J = 12.4 Hz, 1H), 1.24 (s, 3H),
1.04 (s, 3H), 0.89 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.9
(d, J=243.7 Hz), 149.9, 141.2, 138.4 (d, J=3.3 Hz), 132.9, 130.8,
130.7, 127.3, 125.7, 124.2, 115.1, 114.9, 78.8, 49.5, 39.1, 38.2,
37.5, 30.0, 28.2, 28.2, 25.1, 19.0, 15.5. HRMS (ESI): m/z calcd
for C23H27FO, [M+Na]+, 361.1944; found, 361.1946.
4.2.7. 1,1,4a-trimethyl-7-(trimethylsilyl)-8-((trimethylsilyl)ethyn-
yl)-1,2,3,4,4a,9,10,10a-octahydrophenanthren-2-ol (3g)
Yield: 74%, white solid, IR (thin film): 2958, 2360, 2145,
1248, 1036, 883, 863, 758cm-1; 1H NMR (400 MHz, CDCl3) δ
7.26 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 3.29 (dd, J =
10.8, 4.8 Hz, 1H), 3.17 (dd, J = 18.4, 6.0 Hz, 1H), 2.93 – 2.77 (m,
1H), 2.30 (dt, J = 13.2, 3.2 Hz, 1H), 1.98 (dd, J = 13.2, 8.0 Hz,
1H), 1.86 – 1.67 (m, 3H), 1.50 (td, J = 12.8, 4.8 Hz, 1H), 1.42 (s,
1H), 1.29 (dd, J = 12.4, 2.0 Hz, 1H), 1.18 (s, 3H), 1.08 (s, 3H),
0.90 (s, 3H), 0.35 (s, 9H), 0.25 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ 150.4, 139.8, 138.0, 131.4, 128.0, 124.1, 105.4, 102.8,
4.2.4. 1,1,4a-trimethyl-7,8-diphenyl-1,2,3,4,4a,9,10,10a-octahy-
drophenanthren-2-ol (3d)
Yield: 30%, white solid, IR (thin film): 2968, 2930, 2851,
1467, 1442, 1372, 1082, 1034, 764, 700cm-1;1H NMR (400 MHz,

ACCEPTED MANUSCRIPT
Tetrahedron
5
78.7, 49.3, 39.1, 37.8, 37.0, 30.0, 28.3, 28.0, 24.9, 18.8, 15.5, 0.0
7,8,8a,9,10-octahydrophenanthren-1-yl)ethan-1-one (3l)
(3C), -1.0 (3C). HRMS (ESI): m/z calcd for C25H40OSi2, [M+H]+,
413.2690; found, 413.2696.
Yield: 63%, white solid, IR (thin film): 2944, 1696, 1249,
1097, 1072, 1031, 840, 752cm-1; 1H NMR (400 MHz, CDCl3) δ
7.36 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 3.30 (dd, J =
11.2, 5.2 Hz, 1H), 2.88 – 2.71 (m, 2H), 2.50 (s, 3H), 2.32 (dt, J =
13.2, 3.6 Hz, 1H), 1.95 – 1.87 (m, 1H), 1.87 – 1.67 (m, 3H), 1.58
– 1.48 (m, 1H), 1.32 (dd, J = 12.4, 2.0 Hz, 1H), 1.19 (s, 3H), 1.06
(s, 3H), 0.89 (s, 3H), 0.24 (s, 9H). 13C NMR (100 MHz, CDCl3) δ
210.4, 150.8, 148.9, 132.7, 132.0, 128.8, 124.7, 78.7, 49.3, 39.1,
38.2, 37.1, 33.0, 28.2, 28.2, 28.1, 24.9, 18.7, 15.5, 0.3 (3C).
HRMS (ESI): m/z calcd for C22H34O2Si, [M+Na]+, 381.2226;
found, 381.2222.
4.2.8. 1,1,4a,8-tetramethyl-7-(trimethylsilyl)-1,2,3,4,4a,9,10,10a-
octahydrophenanthren-2-ol (3h)
Yield: 32%, white solid, IR (thin film): 2924, 2852, 1591,
1458, 1372, 1252, 1043, 837, 815cm-1; H NMR (400 MHz,
1
CDCl3) δ 7.29 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 3.33
– 3.23 (m, 1H), 2.83 (dd, J = 17.2, 6.4 Hz, 1H), 2.71 – 2.58 (m,
1H), 2.37 – 2.28 (m, 4H), 1.98 (dd, J = 13.2, 7.6 Hz, 1H), 1.84 –
1.71 (m, 3H), 1.58 – 1.49 (m, 1H), 1.40 (s, 1H), 1.31 (dd, J =
12.4, 2.0 Hz, 1H), 1.22 (s, 3H), 1.08 (s, 3H), 0.90 (s, 3H), 0.31 (s,
9H). 13C NMR (100 MHz, CDCl3) δ 150.7, 142.2, 135.5, 133.6,
132.0, 121.6, 78.9, 49.1, 39.1, 37.9, 37.3, 29.0, 28.3, 28.2, 25.1,
20.3, 19.0, 15.5, 0.4 (3C). HRMS (ESI): m/z calcd for C21H34OSi,
[M+Na]+, 353.2277; found, 353.2275.
4.2.13. 1,1,4a-trimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanth-
ren-2-ol (3m)
Yield: 22%, white solid, IR (thin film): 3414, 2934, 2855,
1456, 1376, 1091, 1032, 761, 722cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.24 (d, J = 7.6 Hz, 1H), 7.14 – 7.03 (m, 3H), 3.31 (dd,
J = 10.8, 4.8 Hz, 1H), 2.97 (dd, J = 16.4, 6.0Hz, 1H), 2.93 – 2.81
(m, 1H), 2.33 (dt, J = 12.8, 3.2 Hz, 1H), 1.95 – 1.75 (m, 1H),
1.85 – 1.72 (m, 3H), 1.60 – 1.49 (m, 1H), 1.34 (dd, J = 12.4, 2.0
Hz, 1H), 1.20 (s, 3H), 1.08 (s, 3H), 0.91 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 149.5, 135.2, 129.1, 125.9, 125.6, 124.6, 78.8,
49.9, 39.2, 37.8, 37.0, 30.8, 28.3, 28.1, 25.0, 19.0, 15.5. HRMS
(ESI): m/z calcd for C17H24O, [M+Na]+, 267.1725; found,
267.1727.
4.2.9. (7-hydroxy-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahydro-
phenanthren-2-yl)methyl 4-nitrobenzoate (3i)
Yield: 53%, light brown oil, IR (thin film): 2917, 2849, 1719,
1528, 1347, 1101, 720cm-1; 1H NMR (400 MHz, CDCl3+D2O)
for 2:1 mixture of diastereomers: δ 8.32 – 8.20 (m, 4H), 7.36 –
7.10 (m, 3H), 5.39 (dd, J = 18.4, 12.8 Hz, 0.7H), 5.32 (s, 1.3H),
3.35 – 3.26 (m, 1H), 3.01 (td, J = 16.0, 6.0 Hz, 1H), 2.90 (dd, J =
11.2, 7.2 Hz, 0.5H), 2.88 – 2.77 (m, 0.5H), 2.38 – 2.29 (m, 1H),
2.03 – 1.88 (m, 1H), 1.88 – 1.71 (m, 3H), 1.60 – 1.49 (m, 1H),
1.38 – 1.29 (m, 1H), 1.23 (s, 1H), 1.20 (s, 2H), 1.09 (s, 1H), 1.08
(s, 2H), 0.91 (s, 3H). 13C NMR (100 MHz, CDCl3) for mixture of
diastereomers: δ 164.8, 150.7, 150.4, 150.1, 135.8, 135.7, 135.7,
134.2, 132.9, 132.3, 131.0, 129.4, 126.8, 126.2, 126.1, 125.7,
125.1, 123.7, 123.6, 78.7, 67.7, 66.2, 49.8, 49.3, 39.1, 39.1, 38.0,
37.8, 37.4, 37.0, 30.7, 28.3, 28.1, 28.0, 27.6, 25.2, 25.0, 18.8,
18.7, 15.5. HRMS (ESI): m/z calcd for C25H29NO5, [M+Na]+,
446.1943; found, 446.1937.
4.2.14. 8-bromo-7-(((tert-butyldimethylsilyl)oxy)methyl)-1,1,4a-
trimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-2-ol (3n)
Yield: 31%, white solid, IR (thin film): 2928, 1470, 1255, 838,
777, 537, 408cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.0
Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.70 (s, 2H), 3.30 (dd, J = 11.2,
4.8 Hz, 1H), 3.02 (dd, J = 18.0, 6.4 Hz, 1H), 2.83 – 2.65 (m, 1H),
2.32 (dt, J = 13.2, 3.2 Hz, 1H), 1.97 (dd, J = 13.2, 8.0 Hz, 1H),
1.89 – 1.68 (m, 3H), 1.53 (td, J = 13.2, 4.8 Hz, 1H), 1.34 – 1.28
(m, 1H), 1.20 (s, 3H), 1.08 (s, 3H), 0.96 (s, 9H), 0.90 (s,3H), 0.12
(s, 6H). 13C NMR (100 MHz, CDCl3) δ 150.3, 138.0, 134.4,
124.9, 124.4, 123.6, 78.7, 65.2, 49.3, 39.1, 38.0, 37.4, 32.4, 28.3,
28.2, 26.1 (3C), 25.1, 19.0, 18.6, 15.5, -5.2 (2C). HRMS (ESI):
m/z calcd for C24H39O2BrSi, [M+Na]+, 489.1800; found,
489.1799.
4.2.10. 1-(7-hydroxy-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octahy-
drophenanthren-2-yl)ethan-1-one (3j)
Yield: 59%, white solid, IR (thin film): 2924, 2854, 1680,
1361, 1227, 1087, 903, 682cm-1; H NMR (400 MHz, CDCl3) δ
1
7.40 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 8.0 Hz, 1H), 3.31 (dd, J =
10.8, 5.2 Hz, 1H), 3.18 – 2.99 (m, 2H), 2.54 (s, 3H), 2.32 (dt, J =
12.8, 3.6 Hz, 1H), 1.97 – 1.88 (m, 1H), 1.86 – 1.76 (m, 2H), 1.75
– 1.63 (m, 1H), 1.53 (td, J = 12.8, 4.8 Hz, 1H), 1.31 (dd, J = 12.4,
2.0 Hz, 1H), 1.21 (s, 3H), 1.07 (s, 3H), 0.90 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 203.7, 151.0, 138.9, 134.7, 128.1, 126.1,
125.6, 78.7, 49.1, 39.0, 38.4, 37.6, 30.6, 29.2, 28.2, 28.1, 25.1,
18.8, 15.5. HRMS (ESI): m/z calcd for C19H26O2, [M+Na]+,
309.1830; found, 309.1824.
4.2.15. 7-(((tert-butyldimethylsilyl)oxy)methyl)-1,1,4a-trimethyl-
8-((trimethylsilyl)ethynyl)-1,2,3,4,4a,9,10,10a-octahydrophenan-
thren-2-ol (3o)
Yield: 71%, colorless oil, IR (thin film): 2962, 2392, 2132,
1761, 1629, 1252, 1116, 1043, 824cm-1; H NMR (400 MHz,
1
CDCl3) δ 7.31 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 4.83
(s, 2H), 3.27 (dd, J = 10.8, 4.8 Hz, 1H), 3.14 (dd, J = 17.6, 6.4 Hz,
1H), 2.89 – 2.74 (m, 1H), 2.30 (d, J = 12.8 Hz, 1H), 2.00 – 1.91
(m, 1H), 1.85 – 1.65 (m, 3H), 1.54 – 1.43 (m, 1H), 1.27 (d, J =
12.8 Hz, 1H), 1.16 (s, 3H), 1.07 (s, 3H), 0.95 (s, 9H), 0.89 (s, 3H),
0.25 (s, 9H), 0.11 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 147.9,
141.2, 137.2, 124.9, 123.2, 119.3, 104.6, 101.4, 78.8, 63.5, 49.6,
39.1, 37.7, 37.2, 30.0, 28.3, 28.1, 26.2 (3C), 25.0, 18.8, 18.7, 15.5,
0.3 (3C), -5.2 (2C). HRMS (ESI): m/z calcd for C29H48O2Si2,
[M+Na]+, 507.3091; found, 507.3088.
4.2.11. 1,1,4a-trimethyl-8-(prop-1-en-2-yl)-1,2,3,4,4a,9,10,10a-
octahydrophenanthren-2-ol (3k)
Yield: 69%, white solid, IR (thin film): 3069, 2964, 2855,
1457, 1374, 1095, 1033, 1007, 894, 796, 726cm-1; 1H NMR (400
MHz, CDCl3) δ 7.20 – 7.17 (m, 1H), 7.11 (t, J = 7.6 Hz, 1H),
6.91 (dd, J = 7.2, 1.2 Hz, 1H), 5.17 – 5.13 (m, 1H), 4.80 (dd, J =
2.0, 0.8 Hz, 1H), 3.32 (dd, J = 10.8, 5.2 Hz, 1H), 2.94 (ddd, J =
17.6, 6.4, 1.6 Hz, 1H), 2.84 – 2.72 (m, 1H), 2.33 (dt, J = 13.2, 3.6
Hz, 1H), 2.01 (s, 3H), 1.94 – 1.67 (m, 4H), 1.62 – 1.52 (m, 1H),
1.34 (dd, J = 12.4, 2.4 Hz, 1H), 1.22 (s, 3H), 1.08 (s, 3H), 0.91 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 149.6, 146.6, 144.1, 131.8,
125.6, 125.4, 123.4, 114.5, 78.9, 49.6, 39.1, 38.2, 37.4, 28.5, 28.3,
28.2, 25.1, 24.6, 19.0, 15.6. HRMS (ESI): m/z calcd for C20H28O,
[M+Na]+, 307.2038; found, 307.2039.
4.2.16. 7-(2-hydroxypropan-2-yl)-1,1,4a-trimethyl-1,2,3,4,4a,9,
10,10a-octahydrophenanthren-2-ol (3p/ rac-isolophanthin A)
Yield: 62%, white solid, 1H NMR (400 MHz, CDCl3+D2O) δ
7.21 (m, 2H), 7.16 (s, 1H), 3.28 (dd, J = 11.2, 5.2 Hz, 1H), 2.97
(dd, J = 17.2, 6.8 Hz, 1H), 2.92 – 2.80 (m, 1H), 2.31 (dt, J = 13.2,
3.6 Hz, 1H), 1.90 (dd, J = 13.2, 7.2 Hz, 1H), 1.86 – 1.73 (m, 3H),
4.2.12. 1-(7-hydroxy-4b,8,8-trimethyl-2-(trimethylsilyl)-4b,5,6,

ACCEPTED MANUSCRIPT
6
Tetrahedron
1.55 (s, 6H), 1.54 – 1.49 (m, 1H), 1.32 (dd, J = 12.4, 2.0 Hz, 1H),
1.19 (s, 3H), 1.07 (s, 3H), 0.90 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 148.0, 146.2, 134.9, 125.0, 124.5, 122.2, 78.9, 72.4,
50.0, 39.2, 37.5, 37.1, 31.8 (2C), 31.0, 28.3, 28.2, 25.0, 19.0, 15.5.
HRMS (ESI): m/z calcd for C20H30O2, [M+Na]+, 325.2143; found,
325.2149.
support from the Open Fund of State Key Laboratory of Natural
Medicines in China Pharmaceutical University is acknowledged
(SKLNMKF201601).
Supplementary Material
The supplementary data associated with this article can be
found in the online version.
4.3. Syntheses of rac-abietatrien-3β-ol and rac-isolophanthin
B.
4.3.1. 7-isopropyl-1,1,4a-trimethyl-1,2,3,4,4a,9,10,10a-octahy-
drophenanthren-2-ol (rac-abietatrien-3 -ol)
References and notes
β
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J.-F. J. Nat. Prod. 2015, 78, 1635-1646. (b) Yang, L.-b.; Li, L.;
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To a flask containing 3p (15.5 mg, 0.05 mmol) was added p-
TsOH•H2O (19.6 mg, 0.10 mmol) and toluene (5.0 mL). After
the reaction mixture was refluxed for 30 minutes, it was
quenched with sat. NaHCO3 (30 mL). The aqueous layer was
extracted with EtOAc (20×3 mL), dried over anhydrous Na2SO4
and concentrated under reduced pressure to afford the crude
product, which was purified by flash chromatography on silica
gel with EtOAc-petroleum (v/v=1:8) as eluent to afford
compound 8. To the solution of 8 in 5.0 mL of methanol was
added Pd/C (2.5 mg, 5% wt) and HCOONH4 (98.6 mg, 0.64
mmol). The mixture was heated at 66 ꢀ overnight. Then the
reaction mixture was filtered through a pad of silica gel and
concentrated to give a residue, which was purified by flash
chromatography on silica gel with EtOAc-petroleum (v/v=1:8) as
eluent to give rac-abietatrien-3β-ol (11.8 mg). Yield 81% for 2
steps; white solid; IR (thin film): 3435, 2959, 2927, 2868, 1459,
1
1378, 1086, 1034, 821cm-1; H NMR (400 MHz, CDCl3) δ 7.15
(d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.90 (s, 1H), 3.30
(dd, J = 10.4, 4.8 Hz, 1H), 2.95 (dd, J = 16.4, 6.0 Hz, 1H), 2.89 –
2.78 (m, 2H), 2.30 (dt, J = 13.2, 3.6 Hz, 1H), 1.94 – 1.86 (m, 1H),
1.84 – 1.69 (m, 3H), 1.61 – 1.49 (m, 1H), 1.33 (dd, J = 12.4, 2.4
Hz, 1H), 1.22 (d, J = 7.2 Hz, 6H), 1.19 (s, 3H), 1.07 (s, 3H), 0.90
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 147.0, 145.9, 134.9,
126.9, 124.5, 124.1, 79.0, 50.0, 39.2, 37.5, 37.1, 33.6, 30.9, 28.3,
28.2, 25.1, 24.1, 19.1, 15.5.
4. Céspedes, C. L.; Salazar, J. R.; Ariza-Castolo, A.; Yamaguchi, L.;
Ávila, J. G.; Aqueveque, P.; Kubo, I.; Alarcón, J. Environ. Res.
2014, 132, 391–406.
5. Xie, C.; Sun, L.; Liao, K.; Liu, S.; Wang, M.; Xu, J.; Bartlam, M.;
Guo, Y. J. Nat. Prod. 2015, 78, 2800-2807.
4.3.3. 7-(2-methoxypropan-2-yl)-1,1,4a-trimethyl-1,2,3,4,4a,9,
10,10a-octahydrophenanthren-2-ol (rac-isolophanthin B)
6. For recent examples, see: (a) Zhao, Y.-J.; Loh, T.-P. Org. Lett.
2008, 10, 2143-2145. (b) Wang, Y.-Y.; Gao, Y.-X.; Gao, W.; Xu,
Y.; Xu, Y.-Z.; Wang, Y.-J.; Chang, S.; Yu, L.-G.; Zhang, L.-Y.;
Liao, H.; Yang, L.-F.; Pang, T.; Qiu, W.-W. Eur. J. Med. Chem.
2015, 103, 396-408. (c) Marcos, I. S.; Beneitez, A.; Casta ñeda, L;
Moro, R. F.; Basabe, P.; Diez, D.; Urones, J. G. Synlett 2007,
1589-1590. (d) Alvarez-Manzaneda, E.; Chahboun, R.; Cabrera,
E.; Alvarez, E.; Alvarez-Manzaneda, R.; Hmamouchi, M.; Es-
Samti, H. Tetrahedron Lett. 2007, 48, 8930-8934. (e) Mahdjour,
S.; Harche-Kaid, M.; Haidour, A.; Chahboun, R.; Alvarez-
Manzaneda, E. Org. Lett. 2016, 18, 5964-5967. (f) Fischer, M.;
Harms, K.; Koert, U. Org. Lett. 2016, 18, 5692-5695. (g) Onyango,
E. O.; Fu, L.; Gribble, G. W. Org. Lett. 2014, 16, 322-324. (h)
Marcos, I. S.; Beneitez, A.; Moro, R. F.; Basabe, P.; Diez, D.;
Urones, J. G. Tetrahedron 2010, 66, 7773-7780. (i) Tada, M.;
Kurabe, J.; Yasue, H.; Ikuta, T. Chem. Pharm. Bull. 2008, 56,
287-291.
7. (a) Bryce-Smith, D.; Gilbert, A. Chem. Commun. 1968, 1319-
1320. (b) Krebs, A.; Born, W.; Kaletta, B.; Nickel, W.-U.; Rüger,
W. Tetrahedron Lett. 1983, 24, 4821-4824. (c) Borrmann, A.;
Fatunsin, O.; Dommerholt, J.; Jonker, A. M.; Löwik, D. W. P. M.;
Hest, J. C. M.; Delft, F. L. Bioconjug. Chem. 2015, 26, 257-261.
(d) Kumar, V.; Ramanathan, S.; Sang, D.; Chen, X.; Lemal, D. M.
J. Org. Chem. 2012, 77, 966-970. (e) Thomas, A.; Anikumar, G.;
Nair, V. Tetrahedron 1996, 52, 2481-2488. (f) Meier, H.; Molz, T.;
Merkle, U.; Echter, T.; Lorch, M. Liebigs Ann.
Chem. 1982, 5, 914-923. (g) Liao, C. C.; Lin, H. S.; Lin, J. T. J.
Chinese Chem. Soc. 1980, 27, 87-95. (h) Pyle, J. L.; Shaffer, A. A.;
Cantrell, J. S. J. Org. Chem. 1981, 46, 115-118.
To a solution of 3p (25.4 mg, 0.08 mmol) in 2.0 mL of
methanol was added DDQ (66.8 mg, 0.29 mmol) at room
temperature. After the reaction was stirred overnight, the reaction
mixture was diluted with petroleum ether (15.0 mL) and filtered
through a pad of silica gel. The filtrate was concentrated and
purified by flash chromatography on silica gel with EtOAc-
petroleum (v/v=1:6) as eluent to give rac-isolophanthin B (21.2
mg). Yield 80%, white solid; IR (thin film): 3440, 2971, 2935,
2860, 1458, 1406, 1380, 1264, 1172, 1034, 1006, 934, 825,
798cm-1; 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.4 Hz, 1H),
7.14 (dd, J = 8.4, 1.6 Hz, 1H), 7.05 (s, 1H), 3.31 (dd, J = 10.4,
4.4 Hz, 1H), 3.06 (s, 3H), 2.97 (dd, J = 16.8, 6.0 Hz, 1H), 2.92 –
2.81 (m, 1H), 2.32 (dt, J = 12.8, 3.2 Hz, 1H), 1.95 – 1.87 (m, 1H),
1.86 – 1.71 (m, 3H), 1.57 (dd, J = 12.8, 4.8 Hz, 1H), 1.49 (s, 6H),
1.42 (s, 1H), 1.34 (dd, J = 12.4, 2.4 Hz, 1H), 1.19 (s, 3H), 1.08 (s,
3H), 0.90 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 148.0, 142.9,
134.7, 126.3, 124.4, 123.5, 78.9, 76.7, 50.8, 50.0, 39.2, 37.6, 37.1,
31.0, 28.3, 28.2, 28.1, 28.0, 25.0, 19.1, 15.5. HRMS (ESI): m/z
calcd for C21H32O2, [M+Na]+, 339.2300; found, 339.2309.
Acknowledgments
We appreciate the financial support from the National Natural
8.
(a) Wasserfallen, D.; Kastler, M.; Pisula, W.; Hofer, W. A.; Fogel,
Science Foundation of China (21290180,
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