Scandium Triflate Catalyzed Nazarov Cyclization of Arylvinyl Epoxides Derived from Alkoxides and Chloro(aryl)carbenes: A Facile Access to Resveratrol-Derived Natural Products

Article abstract of DOI:10.1055/s-0040-1705974

The reaction of arylvinyl alkoxides with chloro(aryl)carbenes provided the corresponding arylvinyl epoxides that underwent Nazarov cyclization in a catalytic amount of scandium triflate, providing easy access to several highly substituted indenes, includi

Full text of DOI:10.1055/s-0040-1705974

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–F
letter
A
en
N. Satish, G. Sudhakar
Letter
Synlett
Scandium Triflate Catalyzed Nazarov Cyclization of Arylvinyl Ep-
oxides Derived from Alkoxides and Chloro(aryl)carbenes: A Facile
Access to Resveratrol-Derived Natural Products
Nagam Satisha,b
Gangarajula Sudhakar*a,b
0
0
0
0
-
0
0
0
3
-
3
4
9
8
-
5
5
8
4
Ar
KH, KOtBu
CH2Cl2
Ar
OH
OH
R2
1)
MeO
R2
R1
a Department of Organic Synthesis & Process Chemistry, CSIR-
Indian Institute of Chemical Technology, Hyderabad-500007,
India
gsudhakar@iict.res.in
b Academy of Scientific and Innovative Research (AcSIR),
Ghaziabad-201002, UP, India
MeO
2) Sc(OTf)3, CH2Cl2, 0 °C
R1
OMe
• two C–C bonds
• highly substituted indenes
• up to 20 examples
• up to 96% yield
• synthesis of epi-camphenols
MeO
GDeMaenpagaiClarotgrmarsrjueeudnslahptaoSoknufaddOrih@rngagiakicnAatriu.rctehSsyo.inrnthesis
& Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India
Received: 14.09.2020
Accepted after revision: 15.10.2020
Published online: 13.11.2020
that overcome these natural products’ scarcity by isolation
were initial aims to address. Synthetic attempts based on
the proposed biosynthetic pathways were not satisfactory,
often giving unselective and natural and unnatural com-
pounds.10 However, some synthetic strategies addressed
these problems, and some managed to get a common inter-
mediate, thereby accessing a reasonable number of natural
products of this class.11
DOI: 10.1055/s-0040-1705974; Art ID: st-2020-r0502-l
Abstract The reaction of arylvinyl alkoxides with chloro(aryl)carben-
es provided the corresponding arylvinyl epoxides that underwent Nazarov
cyclization in a catalytic amount of scandium triflate, providing easy
access to several highly substituted indenes, including some resvera-
trol-derived natural products.
Given our ongoing interest in novel electrocyclization
precursors,12 we have reported converting arylvinyl ketones
into arylvinyl oxiranes and utilizing them to synthesize var-
ious highly substituted indenes.12e Further, the synthesis of
3, which was obtained from arylvinyl ketone 1 in 4 steps
(Scheme 1A), served as an advanced intermediate for the to-
tal synthesis of resveratrol-based natural products, (±)-iso-
ampelopsin D (I), and (±)-the proposed structure of cara-
phenol B (V).12e Nevertheless, in the present study, we have
envisioned that compound 3 could be obtained from 1 via
arylvinyl oxirane 2, if successful affording 3 only in two
steps, as illustrated in Scheme 1B. Herein we report a novel
method to access indene derivatives, including resveratrol-
based natural products, in a highly simplified manner.
Before we embark on precursors that yield resveratrol-
derived natural products, we have prepared a model sub-
strate 1a in two steps to evaluate the anticipated outcome.
First, reacting 3,5-dimethoxybezaldehyde (7) and (3-meth-
ylbut-2-en-2-yl)magnesium bromide followed by oxidation
of the resulted 8a afforded 1a (Scheme 2). Compound 1a
was also achieved from compound 9 via compound 10 fol-
lowing our previous report.12b
Key words Nazarov cyclization, arylvinyl alcohol, arylvinyl epoxides,
indenes, resveratrol-derived natural products, scandium triflate,
chloro(aryl)carbenes
Resveratrol and its oligomers are a highly diverse and
privileged class of natural products and are found to exhibit
a wide range of biological activities1 such as antioxidants,2
anticancer,3 antidiabetic,4 cardioprotective,5 and anti-aging
properties.6 Some Japanese and Chinese folk medicines,
which are in a high concentration of resveratrol related
compounds, are used to treat ailments related to the liver,
skin, heart, and lipid metabolism.7 The resveratrol mono-
mer is oligomerized to form dimers, trimers, tetramers, and
higher-order oligomers, generally up to 8 resveratrol units
and these polyphenolic metabolites mainly act as biological
defense agents similar to many other secondary metabo-
lites in plants.8 Pharmacological significance and dimeric
skeletons to architecturally complex oligomers from simple
resveratrol have been intriguing to the chemical communi-
ty, thriving to isolate more than 300 resveratrol oligomers
having dihydrobenzofuran and indane moieties and bicyclic
[3.2.1] and [3.3.0] ring systems.9 Out of all structural pat-
terns, an indane skeleton containing resveratrol-based nat-
ural products (I–XIV, Figure 1), originated from dimers or
substituted dimers of resveratrol, are given particular inter-
est from a synthetic standpoint. Understanding biosynthet-
ic pathways and developing general synthetic strategies
At the outset, treating compound 1a with benzal bro-
mide in a trap solvent system (THF/diethyl ether/pentane,
4:1:1)13 at –120 °C resulted in 2a with a lower yield (Table
1, entry 1). Whereas temperatures at –110 °C and –78 °C
provided little improved yields of 2a (entries 2 and 3). THF
or diethyl ether in place of trap solvent diminished the
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
N. Satish, G. Sudhakar
Letter
Synlett
Ph
O
OH
OH
OH
H
O
O
OH
H
MeO
MeO
MeO
PhCHBr2
HO
ref. 12b
HO
HO
OH
Table 1
entries 1–10
OH
OH
MeO
2a
MeO
1a
OH
MeO
Table 1
10
OH
OH
HO
OH
OH
OH
entries 16–23
ref. 12b
BrMg
HO
OH
Table 1
isoampelopsin D (I)
ampelopsin D (II)
quadrangularin A (III)
entries 11–15
Ph
OH
OH
HO
MeO
R
MeO
MeO
OH
OH
O
O
epoxidation
cyclization
H
HO
HO
OH
MeO
8a
MeO
MeO
OH
HO
OH
3a
7: R = CHO
9: R = COEt
OH
OH
HO
OH
OH
OH
OH
Scheme 2 Synthesis of 8a and 1a and converting them into 3a via 2a
HO
OH
proposed structure of
revised structure of
parthenocissin A (IV)
caraphenol B (V)
caraphenol B (VI)
We found an interesting report in the literature at this
stage, converting allylic or benzylic alcohols into an oxirane
using dichlorocarbene and chlorophenylcarbene.14 Inspired
by this work, we have envisioned that under similar reac-
tion conditions, 3a could be obtained directly from 8a. If
successful, this would further simplify the synthesis of ad-
vanced intermediate 3a or its analogues, allowing several
indane moiety resveratrol-based natural products. Gratify-
ingly, the subjection of 8a to benzal chloride (PhCHCl2)15 in
the presence of KH and KOt-Bu in THF at 0 °C provided 2a in
29% yield (Table 1, entry 11). Two equivalents of benzal
chloride under the same conditions doubled the 2a forma-
tion (entry 12) and obtained 2a in a similar yield (entry 13),
even doubling both benzal chloride and bases (KH and KOt-
Bu). Pleasingly, the optimum yield (90%) of 2a was obtained
with 2.5 equivalents of benzal chloride, KH, and KOt-Bu
(entry 14).16 However, additional excess equivalents of ben-
zal chloride and bases suppressed 2a yield (62%, entry 15),
likely the decomposition of formed product 2a due to ex-
cess base.
OH
OH
O
∗
OH
OH
HO
OH
OH
O
HO
HO
HO
OH
OH
OH
OH
OH
OH
OH
OH
OH
proposed structure of
caraphenol C (VII)
revised structure of
leachianol F *S (IX)
leachianol G *R (X)
caraphenol C (VIII)
HO
∗
OH
OH
C2H5O
OH
OH
MeO
HO
H
HO
H
OH
OH
OH
OH
H
HO
OH
OH
OH
OH
quadranfularin B *S (XII)
quadranfularin C *R (XIII)
HO
viniferaether B (XI)
OH
pallidol (XIV)
Figure 1 Resveratrol based natural products I–XIV
product formation (entries 4 and 5). Conversely, the reac-
tion in CH2Cl2 at –78 °C provided 2a in moderate yield (en-
try 6). In order to further improve the yield in CH2Cl2, we
have checked with raising the temperature (at 0 °C or 25 °C)
and changing the base from n-BuLi to s-BuLi and t-BuLi, but
observed only unsatisfactory yields (entries 7–10).
With optimized reaction conditions for 2a in hand, next,
we turned our attention to the conversion of 2a into 3a,
shown in Table 1 (entries 16–23). First, with Brønsted acid
TFA, 2a produced 3a in a 27% yield (Table 1, entry 16). The
HO
OMe
OMe
OMe
OMe
O
CHO
MeO
MeO
MeO
Step 3
Step 2
OMe
OMe
A
OMe
OMe
OMe
4
5
6
OMe
OMe
OMe
Step 4
MeO
Step 1
MeO
OMe
OMe
OH
OMe
OMe
O
OMe
OMe
MeO
MeO
O
MeO
B
OMe
OMe
OMe
OMe
1
2
3
OMe
OMe
Scheme 1 (A) Our previous synthetic plan; (B) present plan
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
N. Satish, G. Sudhakar
Letter
Synlett
Table 1 Optimization of Reaction Conditions for 2a and 3a
Entry
Substrates
Reagent (equiv)
Solvent
Temp (°C)
Time (min)
Yield of 2a and 3a (%)
1
2
1a and PhCHBr2 (1.2)
1a and PhCHBr2 (1.2)
1a and PhCHBr2 (1.2)
1a and PhCHBr2 (1.2)
1a and PhCHBr2 (1.2)
1a and PhCHBr2 (1.2)
1a and PhCHBr2 (1.2)
1a and PhCHBr2 (1.2)
1a and PhCHBr2 (1.2)
1a and PhCHBr2 (1.2)
8a and PhCHCl2 (1.0)
8a and PhCHCl2 (2.0)
8a and PhCHCl2 (2.0)
8a and PhCHCl2(2.5)
8a and PhCHCl2(3.0)
2a
n-BuLi (1.2)
tsa
–120
–110
–78
–78
–78
–78
0
5
5
2a (10)
2a (20)
2a (20)
2a (0)
n-BuLi (1.2)
tsa
3
n-BuLi (1.2)
tsa
5
4
n-BuLi (1.2)
THF
60
60
5
5
n-BuLi (1.2)
Et2O
2a (0)
6
n-BuLi (1.2)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
2a (40)
2a (20)
2a (15)
2a (15)
2a (10)
2a (29)b
2a (58)b
2a (59)b
2a (90)
2a (62)
3a (27)b
3a (50)
3a (20)
3a (45)b
3a (32)b
3a (96)
3a (92)
3a (90)
7
n-BuLi (1.2)
5
8
n-BuLi (1.2)
25
–78
–78
0
5
9
s-BuLi (1.2)
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
t-BuLi (1.2)
5
KH/KOt-Bu (1:1)
KH/KOt-Bu (1:1)
KH/KOt-Bu (2:2)
KH/KOt-Bu (2.5:2.5)
KH/KOt-Bu (3.0:3.0)
TFA (0.1)
10
10
10
10
10
10
10
10
50
10
45
45
45
THF
0
THF
0
THF
0
THF
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
2a
TiCl4 (0.1)
0
2a
BF3·OEt2 (0.1)
Cu(OTf)2 (0.1)
AlCl3 (0.1)
0
2a
0
2a
0
2a
Sc(OTf)3 (0.1)
Sc(OTf)3 (0.3)
Sc(OTf)3 (0.5)
0
2a
0
2a
0
a Compounds 1a, 8a, and 2a were used in 1 equiv each in appropriate solvents: trap solvent (ts) THF/diethyl ether/pentane (4:1:1), CH2Cl2, and THF in 0.3 M
concentration.
b Based on recovery of the starting material.
reaction of 2a with Lewis acids, TiCl4, and BF3·OEt2 provided
3a in 50% and 20% yields, respectively (entry 17 and 18).
Treatment of 2a with other Lewis acids, Cu(OTf)2 or AlCl3,
also provided similar yields (entries 19 and 20). However,
the subjection of 2a to Sc(OTf)3 dramatically improved
yield, affording 3a in 96% (entry 21).16 Increasing Sc(OTf)3
quantity slightly lowered the yields (entries 22 and 23).
Having had optimum reaction conditions for both key
reactions in hand, we have surveyed the substrate scope
with various benzal chlorides and different substitutions on
arylvinyl alcohols (R1 and R2), as depicted in Scheme 3. First,
reacting 3,5-dimethoxybenzal chloride with 8a under stan-
dard reaction conditions furnished the corresponding prod-
uct 3b in a 90% yield. Benzal chloride with electron-donat-
ing groups/atoms such as –OMe, -SMe, and -F at para posi-
tion lowered the yields, obtaining 3c–e in 74–76% yield
based on the recovery of the starting material (brsm). This
implies that chlorophenyl carbenes having electron-donat-
ing groups at the para position are less effective than the
simple phenyl in this reaction. Furthermore, under stan-
dard reaction conditions, electron-withdrawing groups
such as –NO2, –CN on benzal chloride failed to provide the
corresponding product 3, it appears that electron-with-
drawing groups are detrimental to this reaction. Nonethe-
less, various alkyl substitutions such as i-Pr, n-Bu, i-Bu, and
t-Bu at the para position delivered 3f–i in excellent yields
(91–97%). A phenyl substitution containing biphenyl deriv-
ative is also equally competitive in providing 3j in 90% yield.
Then, the substrate scope with substitutions on the R2 posi-
tion of arylvinyl alcohols 8 was verified. Either alkyl substi-
tutions (Me, Et, and i-Pr) or aryl (Ph) substitution delivered
the corresponding indene derivatives 3k–n in good yields.
Additionally, substrates without any substitution at R2 posi-
tion were also competitive to deliver expected indene de-
rivatives, affording 3o and 3p in comparable yields. More-
over, tricyclic frameworks 3q and 3r, which are more com-
plex indene derivatives in this series and structurally
similar to taiwaniaquinoids,17 were also achieved from this
method. Interestingly, tetracyclic framework compound 3s
was also accessed from the corresponding arylvinyl alcohol
in good yields (Scheme 3).
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
N. Satish, G. Sudhakar
Letter
Synlett
this problem, furnishing 3t in 89% yield. Spectral data of 3t
has well resembled with data reported previously,12e which
is becoming a formal synthesis for (±)-isoampelopsin D (I),
and the proposed structure of (±)-caraphenol B (V)/epi-car-
aphenol B.11d
Afterwards, similarly, 3u was prepared in 69% yield
from 8u. This advanced intermediate 3u was subjected to
DMP to give the corresponding enone 11 in 87% yield. Sub-
sequently, hydrogenation on compound 11 resulted in per-
methylated epi-caraphenol C 12 in 91% yield. The data of 12
is in good agreement with the data reported in the litera-
ture,11d which turns into a formal synthesis of the proposed
structure of (±)-caraphenol C (VII)/epi-caraphenol C.
In conclusion, we have developed a novel method to
highly substituted indenes from arylvinyl alcohols via aryl-
vinyl oxiranes. The method’s scope was demonstrated by
preparing several substrates including accessing some ad-
vanced intermediates of resveratrol-derived natural prod-
ucts in a highly efficient manner. Further application of this
method in a variety of other natural products is in progress.
Funding Information
We are grateful to the Science and Engineering Research Board, De-
partment of Science and Technology, New Delhi, India (SERB-DST,
Grant Number EMR/2016/002289) for the financial support and re-
search fellowship (N.S.). We thank Director, CSIR-Indian Institute of
Chemical Technology for the support (IICT/Pubs./2020/267).
S
cience
a
n
d
E
n
g
inerin
g
R
esearch
B
o
ard(E
M
R/2
0
1
6
/0
0
2
2
8
9)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1705974. Su
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
References and Notes
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Scheme 3 Substrate scope (synthesis of 3b–s). Reagents and condi-
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

E
N. Satish, G. Sudhakar
Letter
Synlett
MeO
MeO
MeO
MeO
OH
OMe
OMe
OMe
OH
OMe
OMe
O
b)
MeO
a)
OMe
OMe
3t (dr 1:0.1)
OMe
OMe
2t
8t
OMe
OMe
OMe
OMe
OMe
ref. 12e
(
)-isoampelopsin D, and ( )-epi-caraphenol B
MeO
OMe
MeO
MeO
OH
OH
MeO
O
OMe
OMe
MeO
a)
OMe
OMe
OMe
b)
OMe
8u
OMe
OMe
2u
OMe
3u (dr 1:0.1)
c)
MeO
HO
HO
OMe
OH
MeO
MeO
OMe
O
O
O
MeO
OMe
OH
d)
ref. 11d
OMe
OMe
OMe
OH
)-epi-caraphenol C
OMe
OH
OMe
12
11
(
Scheme 4 Formal synthesis of epi-caraphenol B, isoampelopsine D, and epi-caraphenol C. Reagents and conditions: a) p-MeOPhCHCl2, KH, KOt-Bu, THF,
0 °C, 73–79%; b) TiCl4, CH2Cl2, –78 °C, 89%; c) DMP, CH2Cl2, 0 °C to rt, 2 h, 87%; d) H2/Pd-C, MeOH, EtOAc, Et3N, 1 h, 91%.
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Raghavaiah, J.; Mahesh, G.; Singarapu, K. K. Org. Biomol. Chem.
(14) Harada, T.; Akiba, E.; Oku, A. J. Am. Chem. Soc. 1983, 105, 2771.
(15) (a) Chen, J.; Lin, J.-H.; Xiao, J.-C. Org. Lett. 2018, 20, 3061.
(b) Kaballa, G. W.; Wu, Z. Tetrahedron Lett. 2000, 41, 579.
(c) Han, G. Y.; Han, P. F.; Perkins, J.; McBay, H. C. J. Org. Chem.
1981, 46, 4695.
(16) Typical Procedure for the Synthesis of 2
To a mixed suspension of potassium hydride (2.5 equiv) and
potassium tert-butoxide (2.5 equiv) in THF was added a THF
(2.5 mL) solution of 8 (1.0 equiv), and the mixture was stirred at
0 °C under an argon atmosphere for 5 min after that was added
a THF (2.5 mL) solution of benzal chloride (2.5 equiv). After
completing the starting material, the reaction was quenched
with aq NH4Cl and extracted with EtOAc. The organic layer was
washed with aq NaCl, dried over Na2SO4, and concentrated
under reduced pressure. The crude product was purified by
using basic Al2O3 column chromatography to isolate 2.
Characterization Data of 2a
1
123.5 mg, 90% yield, dr 1:1 based on H NMR spectroscopy. 1H
NMR (500 MHz, CDCl3):  = 7.25–7.14 (m, 5 H), 6.41 (d, J = 2.3
Hz, 2 H), 6.22 (t, J = 2.3 Hz, 1 H), 4.37 (s, 1 H), 3.66 (s, 6 H), 2.08
(s, 3 H), 1.76 (s, 3 H), 1.74 (s, 3 H). 13C NMR (100 MHz, CDCl3):
 = 160.0, 139.1, 135.3, 128.9, 128.7, 127.8, 127.5, 126.7, 105.8,
99.2, 69.6, 68.3, 55.2, 22.5, 20.3, 15.0. IR (neat): max = 2927,
1594, 1454, 1425, 1345, 1202, 1152, 1063, 842, 737, 697. HRMS
(ESI): m/z calcd for C21H25O3 [M
+ H]: 325.1798; found:
325.1791.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

F
N. Satish, G. Sudhakar
Letter
Synlett
Typical Procedure for the Synthesis of 3
118 mg, 96% yield. 1H NMR (400 MHz, CDCl3):  = 7.44 (d, J = 7.6
Hz, 2 H), 7.3 (t, J = 7.6 Hz, 2 H), 7.2 (t, J = 7.6 Hz, 1 H), 6.34 (d, J =
2.0 Hz, 1 H), 6.15 (d, J = 2.0 Hz, 1 H), 5.93 (s, 1 H), 3.73 (s, 3 H),
3.58 (s, 3 H), 2.1 (br s, 1 H), 1.92 (s, 3 H), 1.32 (s, 3 H), 1.30 (s, 3
H). 13C NMR (125 MHz, CDCl3):  = 159.9, 155.7, 153.2, 143.2,
142.4, 134.2, 131.5, 128.3, 126.9, 125.7, 98.5, 95.2, 69.4, 55.4,
55.1, 50.3, 21.8, 21.2, 9.9. IR (neat): max = 3395, 2956, 2925,
2855, 1595, 1454, 1349, 1203, 1152, 1090, 699. HRMS (ESI): m/z
calcd for C21H23O2 [M – OH]: 307.1698; found: 307.1692.
To a stirred solution of above-obtained 2 (1.0 equiv) in dry
CH2Cl2 (3.7 mL) was added Sc(OTf)3 (0.1 equiv) at 0 °C, and stir-
ring was continued at the same temperature. After completing
the starting material, the reaction was quenched with water or
saturated aq NaHCO3 solution and extracted with CH2Cl2. The
organic layer was washed with aq NaCl solution, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by using silica gel column chroma-
tography (EtOAc/hexanes) to give 3.
(17) Majetich, G.; Shimkus, J. M. J. Nat. Prod. 2010, 73, 284.
Characterization Data of 3a
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F