Total synthesis of (±)-Scrodentoid A

Article abstract of DOI:10.1016/j.tet.2019.130774

An efficient total synthesis of scrodentoid A was accomplished starting from a Hagemann's ester and a substituted (2-bromoethyl)benzene. Key reactions in this synthesis include C-alkylation of the Hagemann's ester, 6-endo-Trig cationic cyclization of an enone and Lewis acid promoted isomerization of a cis-fused ketone.

Full text of DOI:10.1016/j.tet.2019.130774

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of ( )-Scrodentoid A
,
Shao-Dong Lv a b, Tian Tian a, Liu-Qiang Zhang b, Si-Yu Xu a, Dong-Hai Zhao a,
,
,
, c, *
Jun-Jie Wang a, Jian-Guo Fu a **, Yi-Ming Li b ***, Chen-Guo Feng a
a The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine,
Shanghai, 201203, China
b School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
c Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Shanghai Jiao Tong University, Shanghai, 200240, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient total synthesis of scrodentoid A was accomplished starting from a Hagemann's ester and a
substituted (2-bromoethyl)benzene. Key reactions in this synthesis include C-alkylation of the Hage-
mann's ester, 6-endo-Trig cationic cyclization of an enone and Lewis acid promoted isomerization of a cis-
fused ketone.
Received 20 July 2019
Received in revised form
2 November 2019
Accepted 6 November 2019
Available online xxx
© 2019 Elsevier Ltd. All rights reserved.
Keywords:
Scrodentoid
Total Synthesis
Cationic Cyclization
1. Introduction
scrodentoid A (see Fig. 1).
As depicted in Scheme 1, scrodentoid A (1) may be synthesized
Abiatane diterpenoids [1] are widely distributed natural prod-
ucts in the plant kingdom which exhibit a wide range of biological
activities. Scrodentoid A (1) [2], the 19(4 / 3)-abeo-abietane
diterpenoid, was firstly isolated by Li et al. in 2015 from the whole
plant of Scrophularia dentata. [3] The absolute configuration of
scrodentoid A was established by 2D NMR and X-ray crystallo-
graphic analysis. It significantly inhibited ConA-induced splenocyte
proliteration and showed indiscernible cytotoxic activity against
B16 or MCF-7 cells.
from the key precursor 3 via several simple operations including
benzylic oxidation, diastereoselective -alkylation of ketone and
Wittig reaction. The subsequent bond disconnection of 3 leads to
enone 4, which may go through an intramolecular cationic cycli-
zation and be generated from Hagemann's ester 6 [8] and
substituted (2-bromoethyl)benzene 5 via C-alkylation.
a
2. Results and discussion
A number of synthetic studies of aromatic abietane diterpenoids
have been reported since the first isolation in the late 1930s. [4]
Most of the synthetic studies toward aromatic abietane diterpe-
noids have been focused on the synthesis of ferruginol (2) [5,6], and
the polyene cyclization is the most used strategy. [7] The total
synthesis of scrodentoid A (1) has not been reported yet. In this
paper, we attempted to accomplish the first total synthesis of
The synthesis began with a four-step preparation of the (2-
bromoethyl)benzene 5 (Scheme 2). The commercial reagent 2-
isopropylphenol 7 was O-methylated with Me2SO4 to yield 2-
isopropylanisole 8 in 85% yield. Bromination of electron-rich aro-
matic compound 8 with LiBr/(NH4)2Ce(NO3)6 selectively yielded 4-
* Corresponding author. The Research Center of Chiral Drugs, Innovation
Research Institute of Traditional Chinese Medicine, Shanghai University of Tradi-
tional Chinese Medicine, Shanghai, 201203, China.
** Corresponding author.
*** Corresponding author.
E-mail address: fengcg@shutcm.edu.cn (C.-G. Feng).
Fig. 1. Abirtane numbering system and scrodentoid A (1).
https://doi.org/10.1016/j.tet.2019.130774
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Table 1
Synthesis of 3 from enone 4 via 6-endo-Trig cyclizationa
.
Entry
Acid
Solvent
T (oC)
Combined yield (%)b
cis/transc
1
2
3
4
5
6
7
BF3ꢁEt2O
TMSOTf
TBDPSCl
TMSCl
Ph3B
H3PO4
DCM
rt ~ 100
rt ~ 160
rt ~ 160
rt ~ 160
rt ~ 160
190
N.R.
N.R.
N.R.
N.R.
N.R.
46
-
-
-
-
toluene
toluene
toluene
toluene
xylene
toluene
-
2.3/1
2/1
Scheme 1. Retrosynthesis for scrodentoid A (1).
TBDMSOTf
160
65
a
Reaction conditions: enone 4 (1.0 equiv), acid (2.0 equiv), 8 h. N.R. ¼ no reaction
b
c
Isolated yield.
Determined by 1H NMR analysis.
with the undesired cis-decalin
3 as the major isomer (cis/
trans ¼ 2.3/1) (entry 6). [14] This result was improved by using
TBDMSOTf (entry 7).
Methylation of the lithium anion of mixture 3 with MeI resulted
in three diastereoisomers (12A/12B/12C ¼ 2/1.4/1) in a combined
yield of 90% (Scheme 4). [15] The stereochemistry of di-
astereoisomers were assingned by 2D NMR analysis. Unfortunately,
the desired ketone 12D was not observed. Therefore, several
isomerization conditions were tested to generate ketone 12D
(Table 2). TMSOTf catalysis at room temperature proved to be the
optimal reaction conditions, and the desired 12D was generated in
37% isolated yield from an equilibration of diastereomers (12A/12B/
12D ¼ 0.5/1.5/1) (Table 2, entry 3).
Scheme 2. Synthesis of substituted (2-bromoethyl)benzene 5.
bromo-2-isopropylanisole 9 in 84% yield. [9] Addition of ethylene
oxide to the lithium anion of 9 formed alcohol 10 in 76% yield, [10]
which was followed by a bromination with PPh3/CBr4 to afford (2-
bromoethyl)benzene 5 in 88% yield. [11] Next, C-alkylation of the
Hagemann's ester 6 with (2-bromoethyl)benzene 5 in the presence
of t-BuOK afforded 11 in 66% yield, [12] and the subsequent
decarboxylation of 11 by treatment with aqueous KOH delivered
enone 4 in 71% yield (Scheme 3).
In order to execute the planned intramolecular cationic cycli-
zation, a number of acidic activation conditions were screened
(Table 1). [13] This 6-endo-Trig cyclization is rather difficult, and the
recovery of the starting material 4 was observed in most cases
Reaction of 12D with Mg/TiCl4 delivered olefin 13 in 53% yield,
[16] which was followed by oxidation of 13 with CrO3 in AcOH to
provide compound 14 in 85% yield. [17] Finally, deprotection of
methoxyl group occurred by treatment with EtSNa in DMF under
110 ꢀC to afford ( )-scrodentoid A (1) in 85% yield (Scheme 5). [18]
In the meantime, an alternative synthetic route to the inter-
mediate 12D was also examined, where the Lewis acid promoted
cyclization of 1,3-dithiolane 15 was the key step. The desired trans-
decalin 16 as the major was furnished in the presence of TMSOTf via
a highly diastereoselective 6-endo-Trig cyclization (trans/cis ¼ 9/1)
in 65% yield. [13] Deportection of the dithiolane 16 by PIFA (bis-
trifluoroacetoxyiodobenzene) afforded the trans-3. Then methyl-
ation of the lithium anion of trans-3 with MeI formed undesired
12C exclusively, which may be explained by the steric effect of the
(entries 1e5), which may be attributed to the low reactivity of b-
methyl substituted enone 4. To our delight, the desired cyclization
took place when it was treated by H3PO4 in xylene under 190 ꢀC,
Scheme 3. Synthesis of enone 4.
Scheme 4. Methylation of the mixture 3.
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S.-D. Lv et al. / Tetrahedron xxx (xxxx) xxx
3
Table 2
3. Conclusion
Synthesis of 12D via isomerizationa
.
In conclusion, the total synthesis of ( )-scrodentoid A was
achieved in 8 steps starting from 5 and the Hagemann's ester 6 with
a total yield of 3.8%. C-alkylation of the Hagemann's ester, 6-endo-
Trig cationic cyclization of an enone and Lewis acid promoted
isomerization of a cis-fused ketone were key steps for this
synthesis.
4. Experimental section
Entry
Additive
Solvent
T (oC)
A/B/C/Db
4.1. General
1
2
3
4
BF3ꢁEt2O
MeONa
TMSOTf
TMSOTf
DCM
MeOH
DCM
DCM
40
rt
rt
0.8/2.7/1/0
2.5/3.8/1/1
0.5/1.5/0/1
0.5/2.0/0/1
All non-aqueous reactions were run under a positive pressure of
nitrogen. Anhydrous solvents were obtained using standard drying
techniques. Commercial grade reagents were used without further
purification. Flash chromatography was performed on 300e400
mesh silica gel with the indicated solvent systems. 1H and 13C NMR
spectras were recorded on a Brüker Avance-600 HD spectrometer
or Brüker Avance-400 HD spectrometer at ambient temperature.
High-resolution mass spectras were determined on a Aglient 6545
Accurate-Mass Q-TOF spectrometer or JMS-HX 110 spectrometer.
60
a
Reaction conditions: 12 (1.0 equiv), additive (1.5 equiv).
b
Determined by 1H NMR analysis.
4.2. Typical procedure for the synthesis of scrodentoid A (1) [19]
4.2.1. 1-isopropyl-2-methoxybenzene (8)
To a solution of 2-isopropylphenol 7 (27.24 g, 200 mmol) in H2O
(100 mL) was added 23% aq. solution of sodium hydroxide (24.00 g,
600 mmol) in H2O (80 mL) dropwise at 0 ꢀC and the mixture was
stirred at room temperature for 1 h. Dimethylsulfate (50.44 g,
400 mmol) was added slowly for 10 min, and the mixture was
stirred for 24 h at 120 ꢀC and then allowed to cool to room tem-
perature. A solution of dilute hydrochloric acid was added until the
pH reached 7 and the mixture was extracted with ethyl acetate for
three times. The combine organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was subject to column chromatog-
raphy on silica gel (PE) to give 8 (25.50 g) as colorless oil in 85%
Scheme 5. Synthesis of ( )-scrodentoid A.
methyl group. Isomerization of 12C in the presence of TMSOTf also
gave the same diastereomer ratio (12A/12B/12D ¼ 0.5/1.5/1) as
starting from the above mixture of 12, which showed that a ther-
modynamic equilibrium was established under the reaction con-
ditions (Scheme 6).
yield. 1H NMR (600 MHz, CDCl3)
d
7.21 (dd, J ¼ 7.5, 1.5 Hz, 1H), 7.16
(td, J ¼ 7.5, 1.4 Hz,1H), 6.92 (td, J ¼ 7.5, 1.2 Hz, 1H), 6.84 (d, J ¼ 8.1 Hz,
1H), 3.82 (s, 3H), 3.32 (hept, J ¼ 7.0 Hz, 1H), 1.21 (d, J ¼ 7.0 Hz, 6H);
EI-MS (m/z): 150 (Mþ).
4.2.2. 4-bromo-2-isopropyl-1-methoxybenzene (9)
LiBr (28.71 g, 330 mmol) and (NH4)2Ce(NO3)6 (180.84 g,
330 mmol) were added to an oven-dried flask under N2 and then
acetonitrile (300 mL) was added at 0 ꢀC. The mixture was stirred at
0 ꢀC for 1 h. The flask was flushed with N2 and a solution of 8
(45.00 g, 300 mmol) in acetonitrile (80 mL) was added slowly and
the reaction was stirred at room temperature for 12 h. The solvent
was removed under reduce pressure. The residual was diluted with
water and extracted with ethyl acetate for three times. The combine
organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was subject to column chromatography on silica gel (PE) to
afford 9 (57.50 g) in 84% yield as colorless oil. 1H NMR (600 MHz,
CDCl3)
d
7.28 (d, J ¼ 2.5 Hz, 1H), 7.24 (dd, J ¼ 8.6, 2.5 Hz, 1H), 6.70 (d,
J ¼ 8.6 Hz, 1H), 3.80 (s, 3H), 3.27 (hept, J ¼ 6.9 Hz, 1H), 1.18 (d,
J ¼ 6.9 Hz, 6H); EI-MS (m/z): 228 (Mþ).
4.2.3. 2-(3-isopropyl-4-methoxyphenyl)ethan-1-ol (10)
To a solution of 9 (52.70 g, 230 mmol) in THF (150 mL) was
added n-butyllithium (1.6 M in hexanes, 287.5 ml, 460 mmol)
dropwise at ꢂ78 ꢀC and the mixture was stirred at the temperature
for 2 h on oven-dried flask under N2. Ethylene oxide (23 mL,
Scheme 6. A second synthetic route to the intermediate 12D.
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S.-D. Lv et al. / Tetrahedron xxx (xxxx) xxx
460 mmol) in THF (80 mL) was added dropwise about 1 h and the
solution was stirred for 1 h. Raising the temperature slowly, the
mixture was allowed to stir at ꢂ10 ꢀC for 2 h. The mixture was then
quenched with saturated aq. solution of NH4Cl (140 mL) at 0 ꢀC.
Then it was extracted with ethyl acetate, washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatog-
raphy on silica gel (PE/EA ¼ 5/1) to give 10 (33.90 g) as colorless oil
C
12H31O4 (M þ H)þ: 359.2217, found: 359.2228.
4.2.7. 2-(3-isopropyl-4-methoxyphenethyl)-3-methylcyclohex-2-
en-1-one (4)
To a solution of 11 (15.04 g, 42 mmol) in EtOH (84 mL) was
added KOH (13.17 g, 253.2 mmol) and H2O (13 mL) with condenser
under N2 at room temperature. The mixture was allowed to reflux
for 30 h. A solution of dilute hydrochloric acid was added until the
pH reached 6 at 0 ꢀC. The residual was diluted with water and
extracted with ethyl acetate for three times. The combine organic
layers were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
subject to column chromatography on silica gel (PE/EA ¼ 5/1) to
give 4 (8.52 g) as a yellow solid in 71% yield. 1H NMR (400 MHz,
in 76% yield. 1H NMR (600 MHz, CDCl3)
d
7.05 (d, J ¼ 2.2 Hz,1H), 7.01
(dd, J ¼ 8.2, 2.2 Hz, 1H), 6.79 (d, J ¼ 8.2 Hz, 1H), 3.82 (t, J ¼ 6.6 Hz,
2H), 3.81 (s, 3H), 3.30 (hept, J ¼ 6.9 Hz, 1H), 2.80 (t, J ¼ 6.6 Hz, 2H),
1.59 (s, 1H), 1.20 (d, J ¼ 6.9 Hz, 6H); EI-MS (m/z): 194 (Mþ).
4.2.4. 4-(2-bromoethyl)-2-isopropyl-1-methoxybenzene (5)
A solution of CBr4 (44.92 g, 135.3 mmol) and 10 (23.86 g,
123 mmol) in DCM (114 mL) was added to an oven-dried flask at
0 ꢀC for 20 min and then PPh3 (35.44 g,135.3 mmol) in DCM (40 mL)
was added slowly for 10 min. Then the mixture was stirred at room
temperature for overnight. The solvent was removed under reduce
pressure. The residual was diluted with water and extracted with
ethyl acetate for three times. The combine organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was subject to
column chromatography on silica gel (PE) to afford 5 (29.50 g) as
CDCl3)
d
6.99e6.94 (m, 2H), 6.75 (d, J ¼ 8.3 Hz,1H), 3.80 (s, 3H), 3.29
(hept, J ¼ 6.9 Hz, 1H), 2.55 (br s, 4H), 2.40 (t, J ¼ 6.1 Hz, 2H), 2.28 (t,
J ¼ 6.1 Hz, 2H), 1.97e1.89 (m, 2H), 1.69 (s, 3H), 1.19 (d, J ¼ 6.9 Hz, 6H)
13C NMR (100 MHz, CDCl3)
d 198.9, 156.2, 154.9, 136.6, 134.7, 134.1,
126.4, 126.4, 111.3, 55.5, 38.0, 34.4, 32.9, 27.8, 26.6, 22.8, 22.8, 22.3,
21.1; LRMS (ESI): 287 (M þ H)þ; HRMS (ESI): calcd for C19H27O2
(M þ H)þ: 287.2006, found: 287.2012 .
4.2.8. 7-isopropyl-6-methoxy-4a-methyl-3,4,4a,9,10,10a-
hexahydrophenanthren-1(2H)-one (3)
light yellow oil in 93% yield. 1H NMR (600 MHz, CDCl3)
d
7.03 (d,
To a solution of 4 (572 mg, 2 mmol) in toluene (10 mL) under N2
was added TBDMSOTf (0.92 ml, 4 mmol) in a 35 ml of sealed tube at
room temperature. Then the mixture was stirred at 160 ꢀC for 8 h.
The mixture was quenched with a saturated aq. solution of NaHCO3
(10 mL) at 0 ꢀC. It was extracted with ethyl acetate, washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by column
chromatography on silica gel (PE/EA ¼ 15/1) to give 3 (372 mg) as
brown oily mixture in 65% yield. Data for trans-3: 1H NMR
J ¼ 2.2 Hz, 1H), 7.00 (dd, J ¼ 8.2, 2.2 Hz, 1H), 6.79 (d, J ¼ 8.2 Hz, 1H),
3.81 (s, 3H), 3.53 (t, J ¼ 7.8 Hz, 2H), 3.30 (hept, J ¼ 6.9 Hz,1H), 3.10 (t,
J ¼ 7.8 Hz, 2H), 1.20 (d, J ¼ 6.9 Hz, 6H); EI-MS (m/z): 256 (Mþ).
4.2.5. ethyl 2-methyl-4-oxocyclohex-2-ene-1-carboxylate (6)
t-BuOK (2.80 g, 25 mmol) and paraformaldehyde (7.50 g,
250 mmol) were added to a 1L oven-dried three-necked round
bottom flask equip with thermometer and condenser under N2 and
then t-BuOH (250 mL) was added at room temperature. Ethyl ace-
toacetate (63.2 ml, 500 mmol) was added to the mixture at 0 ꢀC for
1 h and then t-BuOK (7.00 g, 62.5 mmol) was added. The solution
was allowed to reflux for 24 h. A solution of dilute hydrochloric acid
was added until the pH reached 7 at 0 ꢀC. The residual was diluted
with water and extracted with ethyl acetate for three times. The
combine organic layers were washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was subject to reduced pressure distillation to give 6
(31.40 g) as colorless oil in 69% yield. 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
d 6.89 (s, 1H), 6.74 (s, 1H), 3.81 (s, 3H), 3.24 (dt,
J ¼ 13.8, 6.9 Hz, 1H), 2.88e2.69 (m, 2H), 2.60 (d, J ¼ 12.4 Hz, 1H),
2.49e2.35 (m, 3H), 2.20e2.11 (m, 1H), 2.08e1.98 (m, 2H), 1.92e1.72
(m, 2H), 1.19 (d, J ¼ 6.9 Hz, 3H), 1.18 (d, J ¼ 6.9 Hz, 3H), 1.07 (s, 3H);
13C NMR (100 MHz, CDCl3)
d 212.7, 155.2, 143.4, 135.1, 127.0, 126.6,
107.0, 55.6, 55.5, 42.6, 40.9, 37.2, 28.2, 26.5, 23.6, 22.8, 22.7, 22.6,
17.7; LRMS (ESI): 287 (M þ H)þ; HRMS (ESI): calcd for C19H27O2
(M þ H)þ: 287.2006, found: 287.2011. Data for cis-3: 1H NMR
(400 MHz, CDCl3)
d 6.86 (s, 1H), 6.69 (s, 1H), 3.79 (s, 3H), 3.22 (dt,
J ¼ 13.8, 6.9 Hz, 1H), 2.88e2.69 (m, 2H), 2.60 (dd, J ¼ 12.4, 2.5 Hz,
1H), 2.49e2.35 (m, 3H), 2.20e2.11 (m, 1H), 2.08e1.98 (m, 2H),
1.92e1.72 (m, 2H), 1.35 (s, 3H), 1.19 (d, J ¼ 6.9, 3H), 1.18 (d, J ¼ 6.9,
d
5.96 (s, 1H), 4.22 (q, J ¼ 7.1 Hz, 2H), 3.27 (t, J ¼ 4.9 Hz, 1H),
2.62e2.50 (m, 1H), 2.39e2.31 (m, 2H), 2.26e2.17 (m, 1H), 2.03 (s,
3H), 1.30 (t, J ¼ 7.1 Hz, 3H); EI-MS (m/z): 182 (Mþ).
3H); 13C NMR (100 MHz, CDCl3)
d 214.4, 155.3, 141.2, 135.1, 127.0,
126.7, 107.5, 57.3, 55.5, 40.6, 38.9, 36.5, 29.7, 29.1, 27.9, 22.8, 22.8,
4.2.6. ethyl 3-(3-isopropyl-4-methoxyphenethyl)-2-methyl-4-
oxocyclohex-2-ene-1-carboxylate (11)
22.6, 21.7; LRMS (ESI): 287 (M þ H)þ; HRMS (ESI): calcd for
C
19H27O2 (M þ H)þ: 287.2006, found: 287.2011.
t-BuOK (7.39 g, 66 mmol) were added to a oven-dried round
bottom flask equip with condenser under N2 and then t-BuOH
(220 mL) was added at room temperature. 6 (12.00 g, 66 mmol) was
added and stirred for 1 h. Then 5 (15.40 g, 60 mmol) was added at
room temperature and the mixture was stirred at 75 ꢀC for 18 h. The
residual was diluted with water and extracted with ethyl acetate for
three times. The combine organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was subject to column chromatog-
raphy on silica gel (PE/EA ¼ 5/1) to give 11 (14.18 g) as yellow oil in
4.2.9. 7-isopropyl-6-methoxy-2,4a-dimethyl-3,4,4a,9,10,10a-
hexahydrophenanthren-1(2H)-one (12)
To a solution of LiHMDS (1M in THF, 7.15 ml, 7.15 mmol)
at ꢂ78 ꢀC under N2 was added a solution of 3 (1.86 g, 6.5 mmol) in
THF (7 mL) .The mixture was stirred for 1 h at ꢂ78 ꢀC and then MeI
was added. The solution was stirred at room temperature for 5 h.
The mixture was then quenched with a saturated aq. solution of
NH4Cl (10 mL) at 0 ꢀC. Then it was extracted with ethyl acetate,
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was pu-
rified by column chromatography on silica gel (PE/EA ¼ 15/1) to
give 12A (800 mg, 41%),12B (560 mg, 28.7%), 12C (400 mg, 20.3%) as
66% yield. 1H NMR (600 MHz, CDCl3)
d
7.00 (d, J ¼ 2.1 Hz, 1H), 6.96
(dd, J ¼ 8.2, 2.1 Hz, 1H), 6.75 (d, J ¼ 8.2 Hz, 1H), 4.19 (q, J ¼ 7.1 Hz,
2H), 3.79 (s, 3H), 3.29 (d, J ¼ 6.9 Hz, 1H), 3.24 (t, J ¼ 4.9 Hz, 1H),
2.65e2.53 (m, 5H), 2.38 (dt, J ¼ 16.9, 5.2 Hz, 1H), 2.29e2.24 (m, 1H),
2.21e2.15 (m, 1H), 1.80 (s, 3H), 1.27 (t, J ¼ 7.1 Hz, 3H), 1.20 (d,
J ¼ 6.9 Hz, 6H); LRMS (ESI): 359 (M þ H)þ; HRMS (ESI): calcd for
a yellow solid. Data for 12A: 1H NMR (600 MHz, CDCl3)
d 6.88 (s,
1H), 6.71 (s,1H), 3.82 (s, 3H), 3.25 (hept, J ¼ 7.1 Hz,1H), 3.09 (m,1H),
2.65 (dd, J ¼ 17.1, 6.8 Hz, 1H), 2.59 (dt, J ¼ 14.2, 3.2 Hz, 1H),
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S.-D. Lv et al. / Tetrahedron xxx (xxxx) xxx
5
2.46e2.43 (m, 1H), 2.41e2.35 (m, 2H), 2.04e1.87 (m, 3H), 1.44 (s,
4.2.12. (2S*,4aS*,10aS*)-7-isopropyl-6-methoxy-2,4a-dimethyl-1-
3H), 1.32 (dd, J ¼ 13.0, 2.8 Hz, 1H), 1.23 (d, J ¼ 7.1 Hz, 3H), 1.22 (d,
methylene-2,3,4,4a,10,10a-hexahydrophenanthren-9(1H)-one (14)
J ¼ 7.1 Hz, 3H), 0.98 (d, J ¼ 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3)
To a solution of CrO3 (30 mg) in acetic acid (0.8 mL) under N2
was added a solution of 13 (60 mg, 0.2 mmol) in acetic acid (1.5 mL)
at room temperature. The mixture was stirred at room temperature
for 6 h. The residual was diluted with water and extracted with
ether for three times. The combine organic layers were sequentially
washed with saturated aq. solution of NaHCO3 and brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatog-
raphy on silica gel (PE/EA ¼ 25/1) to give 14 (54 mg) as a white solid
d
212.2, 155.0, 138.3, 134.9, 128.4, 127.1, 106.2, 55.4, 54.1, 44.8, 42.3,
37.6, 34.1, 30.3, 26.4, 25.0, 22.7, 22.5, 18.4, 14.6; LRMS (ESI): 301
(M þ H)þ; HRMS (ESI): calcd for C20H29O2 (M þ H)þ: 301.2162,
found: 301.2159. Data for 12B: 1H NMR (600 MHz, CDCl3)
d 6.87 (s,
1H), 6.69 (s, 1H), 3.80 (s, 3H), 3.23 (hept, J ¼ 6.9 Hz, 1H), 2.79e2.75
(m, 2H), 2.55 (m, 1H), 2.44 (dd, J ¼ 12.5, 1.3 Hz, 1H), 2.16 (td, J ¼ 13.8,
4.2 Hz, 1H), 2.08e1.93 (m, 2H), 1.85e1.77 (m, 2H), 1.60 (qd, J ¼ 13.3,
3.8 Hz,1H), 1.29 (s, 3H), 1.20 (t, J ¼ 6.9 Hz, 3H), 1.19 (t, J ¼ 6.9 Hz, 3H),
1.06 (d, J ¼ 6.5 Hz, 3H); 13C NMR (150 MHz, CDCl3)
d
216.4, 155.3,
in 85% yield. 1H NMR (400 MHz, CDCl3)
d 7.95 (s, 1H), 6.81 (s, 1H),
142.5,134.9,126.4,126.2,107.8, 58.6, 55.4, 40.8, 40.7, 36.3, 31.0, 29.3,
26.8, 26.4, 24.9, 22.7, 22.6, 14.5; LRMS (ESI): 301 (M þ H) þ; HRMS
(ESI): calcd for C20H29O2 (M þ H)þ: 301.2162, found: 301.2157. Data
4.92 (d, J ¼ 1.6 Hz, 1H), 4.71 (d, J ¼ 1.6 Hz, 1H), 3.90 (s, 3H), 3.26
(hept, J ¼ 6.9 Hz, 1H), 2.79e2.58 (m, 3H), 2.35e2.29 (m, 1H),
2.15e2.03 (m, 1H), 1.93e1.74 (m, 2H), 1.42 (qd, J ¼ 13.1, 3.9 Hz, 1H),
1.23 (d, J ¼ 5.8 Hz, 3H),1.21 (d, J ¼ 5.8 Hz, 3H), 1.13 (d, J ¼ 6.5 Hz, 3H),
for 12C: 1H NMR (600 MHz, CDCl3)
d 6.90 (s, 1H), 6.75 (s, 1H), 3.81
(s, 3H), 3.24 (hept, J ¼ 6.9 Hz, 1H), 2.87e2.73 (m, 3H), 2.62e2.56 (m,
1H), 2.27e2.19 (m, 2H), 2.16e2.08 (m, 1H), 2.02e1.95 (m, 1H),
1.85e1.72 (m, 2H), 1.23 (d, J ¼ 7.4 Hz, 3H), 1.20 (d, J ¼ 6.9 Hz, 3H),
1.19 (d, J ¼ 6.9, Hz, 3H), 1.07 (s, 3H); 13C NMR (150 MHz, CDCl3)
1.09 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 197.3, 161.6, 154.0, 152.0,
135.6, 125.7, 124.0, 105.6, 105.4, 55.4, 47.5, 39.8, 38.1, 38.0, 37.8, 32.5,
26.6, 22.5, 22.4, 21.1, 18.3; LRMS (ESI): 299 (M þ H)þ; HRMS (ESI):
calcd for C21H29O2 (M þ H)þ: 313.2162, found: 313.2161.
d
216.4, 155.1, 143.6, 135.0, 126.9, 126.4, 106.9, 55.5, 50.5, 43.5, 42.5,
32.7, 28.6, 28.1, 26.4, 23.7, 22.8, 22.6, 18.3, 17.5; LRMS (ESI): 301
(M þ H)þ; HRMS (ESI): calcd for C20H29O2 (M þ H)þ: 301.2162,
found: 301.2151.
4.2.13. (2S*,4aS*,10aS*)-6-hydroxy-7-isopropyl-2,4a-dimethyl-1-
methylene-2,3,4,4a,10,10a-hexahydrophenanthren-9(1H)-one
(scrodentoid A, 1)
A
solution of 14 (63 mg, 0.2 mmol) and NaSEt (185 mg,
4.2.10. (2S*,4aS*,10aR*)-7-isopropyl-6-methoxy-2,4a-dimethyl-
3,4,4a,9,10,10a-hexahydrophenanthren-1(2H)-one (12D)
2.2 mmol) in DMF (3 mL) was stirred at 110 ꢀC for 4 h. The mixture
was diluted with water and extracted with ethyl acetate for three
times. The combine organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatog-
raphy on silica gel (PE/EA ¼ 5/1) to give scrodentoid A (1) (51 mg)
To a solution of the mixture of 12 (900 mg, 3 mmol) in DCM
(6 mL) was added TMSOTf (0.81 ml, 4.5 mmol) at room tempera-
ture. After being stirred for 18 h, the mixture was quenched with a
saturated aq. solution of NaHCO3 (10 mL) at 0 ꢀC. Then it was
extracted with ethyl acetate, washed with brine, dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified by column chromatography on
silica gel (PE/EA ¼ 150/1) to give 12D (333 mg) as a yellow solid in
as a white solid in 85% yield. 1H NMR (400 MHz, CDCl3)
d 7.99 (s,
1H), 6.84 (s, 1H), 4.91 (s, 1H), 4.68 (s, 1H), 3.27e3.15 (m, 1H),
2.77e2.61 (m, 3H), 2.20 (dt, J ¼ 12.9, 3.4 Hz, 1H), 2.11e1.98 (m, 1H),
1.87e1.81 (m, 1H), 1.72 (td, J ¼ 13.3, 4.3 Hz, 1H), 1.41e1.34 (m, 1H),
1.28 (d, J ¼ 6.8 Hz, 3H),1.27 (d, J ¼ 6.8 Hz, 3H), 1.11 (d, J ¼ 6.5 Hz, 3H),
37% yield. 1H NMR (400 MHz, CDCl3)
d 6.89 (s, 1H), 6.73 (s, 1H), 3.81
(s, 3H), 3.31e3.18 (m, 1H), 2.88e2.69 (m, 2H), 2.63e2.58 (m, 1H),
2.52e2.43 (m, 1H), 2.36 (ddd, J ¼ 13.3, 4.3, 2.5 Hz, 1H), 2.24e2.16
(m, 1H), 2.03e1.93 (m, 2H), 1.88e1.63 (m, 2H), 1.20 (d, J ¼ 3.4 Hz,
1.04 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 198.2, 159.1, 154.3, 151.9,
133.4, 126.7, 124.0, 111.2, 105.5, 47.4, 39.4, 38.0, 37.9, 37.6, 32.5, 26.8,
22.4, 22.3, 21.1, 18.3; LRMS (ESI): 321 (M þ Na)þ; HRMS (ESI): calcd
for C20H26O2Na (M þ Na)þ: 321.1825, found: 321.1819.
3H), 1.18 (d, J ¼ 3.4 Hz, 3H), 1.06 (d, J ¼ 6.4 Hz, 3H), 1.02 (s, 3H); 13
C
NMR (100 MHz, CDCl3)
d 213.6, 155.1, 143.6, 135.0, 126.9, 126.5,
106.9, 55.5, 55.2, 44.4, 43.1, 37.4, 32.0, 28.2, 26.4, 23.6, 22.8, 22.6,
4.2.14. 6-(3-isopropyl-4-methoxyphenethyl)-7-meth yl-1,4-
dithiaspiro [4.5]dec-6-ene (15)
17.9, 14.4; LRMS (ESI): 301 (M þ H)þ; HRMS (ESI): calcd for
C
20H29O2 (M þ H)þ: 301.2162, found: 301.2157.
To a solution of 5 (1.14 g, 4 mmol) in DCM (20 mL) was added
1,2-ethanedithiol (1.0 mL, 12 mmol) and indium (III) tri-
fluoromethanesulfonate (899 mg, 1.6 mmol) successively at room
temperature. After being stirred for 24 h, the mixture was
quenched with H2O (10 mL). Then it was extracted with dichloro-
methane for three times. The combined organic extracts were
washed with brine, dried over anhydrous Na2SO4 and filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography on a silica gel (PE/EA ¼ 20/1) to give 15 as
4.2.11. (2S*,4aS*,10aS*)-7-isopropyl-6-methoxy-2,4a-dimethyl-1-
methylene-1,2,3,4,4a,9,10,10a-octahydrophenanthrene (13)
To a suspension of Mg (77 mg, 3.2 mmol), TiCl4 (88 mL, 0.8 mmol)
and DCM (1.6 mL) was added a solution of 12D (120 mg, 0.4 mmol)
in DCM (1.2 mL) and THF (0.8 mL) at 0 ꢀC. After being stirred for 1 h
at 0 ꢀC, the resulting green-black mixture was stirred for overnight
at room temperature. The reaction mixture was cooled to 0 ꢀC.
Saturated potassium carbonate solution (5 mL) was added and the
mixture was diluted with ether (5 mL). The organic layer was
separated, dried, evaporated and purified by chromatography on
silica gel (PE) to 13 (63 mg) as colorless oil in 53% yield. 1H NMR
colorless oil (1.23 g, 85%). 1H NMR (600 MHz, CDCl3):
d 7.10 (d,
J ¼ 8.5 Hz, 1H), 7.04 (dd, J ¼ 8.3 Hz, 2.0 Hz, 1H), 6.77 (d, J ¼ 8.3 Hz,
1H), 3.80 (s, 3H), 3.36e3.28 (m, 5H), 2.84e2.80 (m, 2H), 2.53e2.49
(m, 2H), 2.24e2.21 (m, 2H), 1.99 (t, J ¼ 6.2 Hz, 2H), 1.82e1.78 (m,
2H), 1.74 (s, 3H),1.21 (d, J ¼ 6.9 Hz, 6H); 13C NMR (150 MHz, CDCl3):
(400 MHz, CDCl3)
d
6.89 (s, 1H), 6.76 (s, 1H), 4.82 (d, J ¼ 1.4 Hz, 1H),
4.67 (d, J ¼ 1.4 Hz, 1H), 3.80 (s, 3H), 3.23 (hept, J ¼ 6.9 Hz, 1H),
2.86e2.81 (m, 2H), 2.25e2.17 (m, 2H), 2.12e2.03 (m, 1H), 1.86e1.75
(m, 3H), 1.67 (td, J ¼ 13.1, 4.3 Hz, 1H), 1.38 (qd, J ¼ 13.1, 4.1 Hz, 1H),
1.20 (d, J ¼ 4.9 Hz, 3H), 1.19 (d, J ¼ 4.9 Hz, 3H), 1.10 (d, J ¼ 6.5 Hz, 3H),
d 154.9, 136.8, 135.3, 134.3, 130.9, 126.0, 125.8, 110.3, 72.1, 55.5, 44.4,
40.2, 36.2, 33.8, 31.7, 26.8, 22.8, 22.5, 20.9; EI-MS (m/z, %): 362 (Mþ,
6.2), 301 (100), 163 (82.5); HRMS (EI): m/z calcd for C21H30OS2:
362.1738, found: 362.1743.
0.98 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 155.0, 154.7, 145.2, 134.4,
126.7, 126.5, 107.6, 103.8, 55.5, 48.7, 39.7, 38.7, 38.3, 32.9, 29.6, 26.5,
22.9, 22.8, 22.7, 22.0, 18.2; LRMS (ESI): 299 (M þ H)þ; HRMS (ESI):
calcd for C21H31O (M þ H)þ: 299.2369, found: 299.2378.
4.2.15. (4aS*,10aR*)-7-isopropyl-6-methoxy-4a-methyl-3,4,4a,9,
10,10a-hexahydro-2H-spiro[phenanthrene-1,2'-[1,3]dithiolane] (16)
To a solution of 15 (73 mg, 0.2 mmol) in DCM (10 mL) was added
Please cite this article as: S.-D. Lv et al., Total synthesis of ( )-Scrodentoid A, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130774

6
S.-D. Lv et al. / Tetrahedron xxx (xxxx) xxx
(c) L.F. Fieser, W.P. Campbell, J. Am. Chem. Soc. 61 (1939) 2528e2539;
TMSOTf (54 mL, 0.3 mmol) at room temperature. After being stirred
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(e) T. Matsumoto, Y. Ohsuga, S. Harada, K. Fukui, Bull. Chem. Soc. Jpn. 50
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(g) H. Akita, T. Oishi, Chem. Pharm. Bull. 29 (1981) 1567e1579;
for 24 h, the mixture was quenched with H2O (5 ml). Then it was
extracted with dichloromethane for three times. The combined
organic extracts were washed with brine, dried over anhydrous
Na2SO4 and filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on a silica gel (PE/
EA ¼ 20/1) to give 16 as colorless oil (47 mg, 65%). 1H NMR
ꢀ
ꢀ
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(h) I. Cordova-Guerrero, L. San Andres, A.E. Leal-Orozco, J.M. Padron,
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J.M. Cornejo-Bravo, F. Leon, Tetrahedron Lett 54 (2013) 4479e4482;
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~
(j) I.S. Marcos, A. Beneitez, L. Castaneda, R.F. Moro, P. Basabe, D. Diez,
(600 MHz, CDCl3): d 6.86 (s, 1H), 6.70 (s, 1H), 3.78 (s, 3H), 3.36e3.31
J.G. Urones, Synlett 10 (2007) 1589e1590;
(m, 1H), 3.30e3.19 (m, 3H), 3.15e3.09 (m, 1H), 2.92e2.79 (m, 2H),
2.36e2.22 (m, 2H), 2.25 (d, J ¼ 12.5 Hz, 1H), 2.08 (d, J ¼ 11.8 Hz, 1H),
1.98e1.84 (m, 3H), 1.73 (d, J ¼ 12.8 Hz, 1H), 1.49 (d, J ¼ 12.8 Hz, 1H),
(k) I.S. Marcos, A. Beneitez, R.F. Moro, P. Basabe, D. Diez, J.G. Urones, Tetra-
hedron 66 (2010) 7773e7780;
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(n) R.E. Ireland, R.C. Kierstead, J. Org. Chem. 31 (1966) 2543e2559;
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(p) T. Matsumoto, S. Usui, T. Morimoto, Bull. Chem. Soc. Jpn. 50 (1977)
1575e1579;
1.18 (s, 3H),1.21e1.16 (m, 6H); 13C NMR (150 MHz, CDCl3):
d 155.0,
146.0, 134.5, 126.8, 126.6, 106.5, 72.9, 55.5, 51.4, 46.7, 40.6, 39.6,
38.4, 37.9, 29.6, 26.4, 24.8, 22.8, 22.6, 21.9, 21.6; EI-MS (m/z, %): 362
(Mþ, 100), 347 (21.0), 131 (43.1); HRMS (EI): m/z calcd for
(q) S. Torii, K. Uneyama, K. Hamada, Bull. Chem. Soc. Jpn. 50 (1977)
2503e2504;
C
21H30OS2: 362.1738, found: 362.1732.
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4758e4762;
4.2.16. (4aS*,10aR*)-7-isopropyl-6-methoxy-4a-methyl-3,4,4a,9,
10,10a-hexahydrophenanthren-1(2H)-one (trans-3)
To a solution of 16 (47 mg, 0.13 mmol) in a mixture of acetoni-
trile (0.65 mL) and water (0.65 mL) was added trifluoroacetic acid
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room temperature. After being stirred for 3 h, the mixture was
quenched with H2O (5 mL). Then it was extracted with DCM for
three times. The combined organic extracts were washed with
brine, dried over sodium sulfate and filtered, and concentrated
under reduced pressure. The residue was purified by flash chro-
matography on a silica gel (PE/EA ¼ 15/1) to give trans-3 as colorless
oil (32 mg, 85%).
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Acknowledgments
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This work was supported by the National Natural Science
Foundation of China (21772216), the STCSM (18401933500), the
SMEC (2019-01-07-00-10-E00072) and Shanghai E-institute of
bioactive constituents in Traditional Chinese Medicine.
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NMR.
Appendix A. Supplementary data
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Supplementary data to this article can be found online at
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Please cite this article as: S.-D. Lv et al., Total synthesis of ( )-Scrodentoid A, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130774