Toward the synthesis of caraphenol C: Substituent effect on the Nazarov cyclization of 2-arylchalcones

Article abstract of DOI:10.1055/s-2008-1032065

A mild and versatile synthesis of cis-2,3-diarylindanones using a Nazarov cyclization strategy was reported. The substituent effect on the stereochemistry of the cyclization was discussed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032065

458
LETTER
Toward the Synthesis of Caraphenol C: Substituent Effect on the Nazarov
Cyclization of 2-Arylchalcones
T
oward th
u
e
Synthesis o
n
f
C
araphenol
C
Zhu,a Chen Zhong,a Hong-Fu Lu,a Guang-Yu Li,b Xun Sun*a
a
Department of Chemistry of Natural Drugs, School of Pharmacy, Fudan University, 138 Yixueyuan Road, Shanghai 200032,
P. R. of China
Fax +86(21)54237607; E-mail: sunxunf@shmu.edu.cn
b
Laboratory of Analytical Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, P. R. of China
Received 24 September 2007
3-methoxy-1,2,3-triphenylcyclopropene,2 cyclization of
2,3,3-triphenylpropanoyl chloride,3 or hydrogenation of
2,3-diarylindenone with palladium on charcoal.4 The Naz-
arov cyclization of 2-arylchalcone was recently realized
by the Marco and Flynn groups in which Lewis acid or
protic acid was utilized to give trans-2,3-diphenylindan-
1-one in excellent yield.5 In the context of total syntheses
of dimeric resveratrols, we envisioned that the Nazarov
cyclization could be a powerful approach to 2,3-substitut-
ed indanone moieties. We wish to present here mild and
versatile reaction conditions to pursue the stereoselective
synthesis of cis-2,3-diarylindanone moiety presented in
caraphenol C, and clarify the substituent effect on the ste-
reochemistry of the Nazarov cyclization.
Abstract: A mild and versatile synthesis of cis-2,3-diarylindanones
using a Nazarov cyclization strategy was reported. The substituent
effect on the stereochemistry of the cyclization was discussed.
Key words: caraphenol C, chalcone, 2,3-diarylindanone, Lewis ac-
id, Nazarov cyclization
The Nazarov cyclization is recognized as one of the most
powerful methods for the synthesis of five-membered car-
bocycles due to its prevalence in numerous natural prod-
ucts and bioactive compounds.1 To meet the need in
syntheses and structural modifications, the Nazarov cy-
clization has spurred efforts to realize the ring closure of
alkyl-substituted bisvinyl ketones. Surprisingly, a-aryl-
chalcone was scarcely subjected to this cyclization to
form 2,3-diarylindanone. In the literature, the synthesis of
2,3-diarylindanone was realized by a ring enlargement of
Caraphenol C was first isolated from the dry roots of Car-
agana sinica, a Chinese folk medicine for the treatment of
asthenia syndrome, vascular hypertension, leukorrhagia,
OH
OH
RO
7
7
OH
OH
HO
HO
8'
7'
8'
7'
OH
OH
OH
quadrangularin B (1a), R = Et (7S),
quadrangularin C (1b), R = Et (7R),
OH
leachianol F (1c), R = H (7S)
leachianol G (1d), R = H (7R)
OH
OH
quadrangularin A (1e)
OH
OH
O
7'
O
OR
OR
O
OR
OR
7
RO
RO
HO
8'
Nazarov
cyclization
OR
OR
OH
OH
OR
OR
OH
caraphenol C (1f)
2
3
Scheme 1 Selected resveratrol dimers and retrosynthetic analysis of caraphenol C
SYNLETT 2008, No. 3, pp 0458–0462
x
x.
x
x.
2
0
0
8
Advanced online publication: 03.01.2008
DOI: 10.1055/s-2008-1032065; Art ID: W17707ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Toward the Synthesis of Caraphenol C
459
O
X
LA
LA
O
Y
O
O
Y
H+
X
α
α'
X
2,3-cis-indane
X
H
H
H
β
Y
β'
Y
H
O
H+
conrotatory
electrocyclization
2-aryl chalcone
X
Y
2,3-trans-indane
Scheme 2 The mechanism of Nazarov cyclization
O
O
O
O
trans-6
PhCH2PPh2
BF3·OEt2
40 °C, 3 h or 35 h
72%
KOt-Bu, toluene
O
O
4
(E)-5
cis-6
Scheme 3 The Nazarov cyclization of (E)-2-phenylchalcone (5)
bruises, and contused wounds.6 The cis-configuration of er, after all the starting material was consumed, only the
C7¢ and C8¢ in caraphenol C differs from those of other trans-isomer 6 (3JH2–H3 = 4.7 Hz) was isolated, as reported
resveratrol dimers, such as quadrangularins A–C and lea- previously by Marco.5a Attempt to purify cis-indanone 6
chianols F, G (Scheme 1).7
was not successful due to its rapid epimerization to trans-
isomer of 6 on silica gel.
A recent biomimetic approach toward quadrangularin A
by Hou and co-workers represented a concise synthetic To further identify the stability of the 2,3-cis-indanone
strategy to construct the 2,3-trans-indane skeleton.8 How- during the cyclization event, a series of 2-arylchalcones
ever, the radical coupling only provided 2,3-trans-in- were synthesized and subjected to cyclization conditions
danes. From the mechanistic point of view, the 2,3-cis- as shown in Table 1. In order to promote the cyclization
indanone 2 skeleton in caraphenol C could be achieved of chalcones bearing electron-withdrawing groups at A
with a delicately controlled protonation step during the and B rings, such as 7a,b, AlCl3 was used as the promoter
Nazarov cyclization of 3 (Scheme 2).1,9 To this end, (E)- as BF3·OEt2 was ineffective. Only trans-products 8a,b
2-phenylchalcone 5, prepared from the Wittig–Horner re- were isolated after the chalcones 7a,b were consumed
action of benzil 4 with Ph2P(O)CH2Ph in the presence of (entries 1 and 2). The moderate isolated yields of 8a and
KOt-Bu in toluene, was subjected to the Nazarov cycliza- 8b were due to the considerable decomposition of sub-
tion in the presence of BF3·OEt2 (Scheme 3). Although stance under the harsher reaction conditions (AlCl3, 40
Marco reported the exclusive trans-indanone 6 was isolat- °C). On the other hand, electron-donating groups (OMe
ed when the 2-phenylchalcone trans-5 was treated with and Me) at the para positions of A and B rings enhanced
Lewis acid,5a another product (minor) was generated in the reaction efficiency to give higher yields of products 8c
our entry along with the trans-isomer of 6. This minor and 8d under milder reaction conditions (BF3·OEt2, en-
product was identified as the cis-isomer of 6 (3JH2–H3 = 8.1 tries 3 and 4, respectively). An interesting finding was
Hz) by 1H NMR analysis, which was identical with the lit- noted with the meta-methoxy in 7e. Boron trifluoride di-
erature data.10 This cis-isomer of 6 could be detected by ethyl etherate promoted cyclization of 7e to furnish the
TLC analysis when approximately 20% of the starting cis-product in 82% yield within 20 minutes (entry 5), but
material was consumed (monitored by 1H NMR). Howev- the trans-isomer was formed in 96% after prolonging the
Synlett 2008, No. 3, 458–462 © Thieme Stuttgart · New York

460
J. Zhu et al.
LETTER
Table 1 The Nazarov Cyclization of 2-Arylchalcones to 2-Arylindanones
R1
O
R2
O
B
R1–3
R1
R1–3
R3
A
Lewis acid
R2
C
R3
R4
cis/trans
R4
E/Z mixture
7a–g
R2
8a–g
Entry
Substrate
R1
H
H
H
H
R3
H
H
H
H
H
H
R4
H
Conditionsa
Time
70 h
Temp (°C)
Product (yield)e
1
2
3
4
5
6
7
8
9
10
7a
7b
7c
7d
7e
7e
7f
H
A (4 equiv)b
40c
40c
r.t.d
40
8a (trans, 24%)f
8b (trans, 50%)f
8c (trans, 89%)g
8d (trans, 90%)g
8e (cis, 82%)h
8e (trans, 96%)
8f (cis, 76%)h
H
H
A (10 equiv)
47 h
OMe
OMe
H
B
B
B
B
B
B
B
B
40 h
H
17 h
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
H
H
H
H
20 min
11 h
r.t.
40
H
OMe
OMe
OMe
OMe
H
13 min
11 h
r.t.
40
7f
H
8f (trans, 94%)
8g (cis, 94%)h
8g (trans, 85%)
7g
7g
OMe
OMe
7 min
12 h
r.t.
40
a Conditions A: 2-arylchalcone (1 equiv), AlCl3 (4 or 10 equiv), CH2Cl2. Conditions B: 2-arylchalcone (1 equiv), BF3·OEt2 (10 equiv), CH2Cl2.
b AlCl3 was added in portions by single equivalent until the reaction went into completion.
c No reaction at r.t.
d A comparable yield was achieved at 40 °C in 10 h.
e All the yields of trans-products were given after flash column chromatography while those of cis-products were obtained after trituration.
f Besides some degraded polar compounds, only trans-products were isolated in entries 1 and 2.
g The corresponding spot of cis-product could be observed on TLC within a short period of reaction time (together with the spot of trans-prod-
uct), but only trans-product remained when reaction went into completion. Even when the cis-product still remained, only trans-product could
be isolated after flash column chromatography.
h The minor trans-indanone can be removed by trituation, see ref.13 for detail.
reaction to 11 hours. For entries 7–10, more methoxy sented by, in this case, contributing resonance forms 7-II
groups were introduced to the A, B, and C phenyl rings. and 7-III or by the hybrid resonance form 7-I for simplic-
The faster cyclizations allowed us to isolate the cis-prod- ity. The electronic effect of substituted groups at phenyl
ucts 8f and 8g, and not surprisingly, epimerization to the rings A and B had a profound effect on reaction rate in the
trans-isomers was anticipated with an extended reaction Nazarov cyclization of 2-arylchalcones. Obviously, the
time (entries 7–10). The half-life of the cis-to-trans electron-donating groups that stabilize the developing
epimerization of 8g at 40 °C was approximately 155 min- positive-charge character will lower the energy of the in-
utes in the presence of BF3·OEt2 (10 equiv, Table 2). The termediate (and transition state), thereby enhancing the
para-methoxy in C ring of 7g (entry 9) gave a cis-in- rate of the cyclization. After cyclization, the second step
danone 8g which could be used as an intermediate toward is the tautomerization of ketone–enol to produce the cis-
an efficient synthesis of caraphenol C.
and trans-cyclopentenone products and the steric hin-
drance of the phenyl ring C at the b-position can affect the
stereochemical outcome of the cyclization. For example,
if R1 was a meta electron-donating group (such as in en-
tries 5, 7, and 9), the 2-arylchalcone cyclized faster and
the electronegativity at the a-postion of 8-I was enhanced
which made it easier to abstract a proton. Therefore the ki-
netic product cis-8 was generated as the major product
within a short time. As reaction time was prolonged, a
A possible mechanism for the electrocyclization of the 2-
arylchalcones was illustrated in Scheme 4. In the Nazarov
cyclization, the key step is believed to be the cyclization
of a 4p-electron system through a conrotatory (under ther-
mal conditions) electrocyclic process to form a five-mem-
bered ring.11 The mechanism of the Nazarov reaction is
well known at an experimental as well as theoretical lev-
el.12 It proceeds via a rate-determining electrocyclization
to a relatively high-energy intermediate that can be repre-
Synlett 2008, No. 3, 458–462 © Thieme Stuttgart · New York

LETTER
Toward the Synthesis of Caraphenol C
461
b-postion. Further investigations on the Nazarov cycliza-
tion of 2-arylchalcones in the context of total synthesis of
caraphenol C are currently under way.
Table 2 The Kinetics of cis-8g to trans-8g
Acknowledgment
Financial support by the National Natural Science Foundation of
China (20772017) and the Shanghai Municipal Committee of Sci-
ence and Technology (05JC14057 and 07DZ19713) is acknowled-
ged. We are grateful to Dr. Ran Hong of the Laboratory of Modern
Synthetic Organic Chemistry at Shanghai Institute of Organic Che-
mistry (CAS) for invaluable discussions.
Time (min)a
cis-8g (%)b
100
trans-8g (%)
References and Notes
(1) Reviews: (a) Pellissier, H. Tetrahedron 2005, 61, 6479.
(b) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577.
(2) Mueller, P.; Pautex, N. Helv. Chim. Acta 1991, 74, 55.
(3) Rockett, B. W.; Hauser, C. R. J. Org. Chem. 1964, 29, 1394.
(4) Pettit, W. A.; Wilson, J. W. J. Am. Chem. Soc. 1977, 99,
6372.
(5) (a) Marco, J. L. Synth. Commun. 1996, 26, 4225. (b) Kerr,
D. J.; Metje, C.; Flynn, B. L. Chem. Commun. 2003, 1380.
(6) Luo, H.-F.; Zhang, L.-P.; Hu, C.-Q. Tetrahedron 2001, 57,
4849.
(7) (a) Adesanya, S. A.; Nia, R.; Martin, M.-T.; Boukamcha, N.;
Montagnac, A.; Pais, M. J. Nat. Prod. 1999, 62, 1694.
(b) Ohyama, M.; Tanaka, T.; Iinuma, M. Phytochemistry
1995, 38, 733.
(8) Li, W.; Li, H.; Li, Y.; Hou, Z. Angew. Chem. Int. Ed. 2006,
45, 7609.
(9) Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126, 9544.
(10) Hiscock, M.; Porter, G. B. J. Chem. Soc. B 1971, 1631.
(11) See the reviews: (a) Denmark, S. E. Nazarov and Related
Cationic Cyclizations, In Comprehensive Organic Synthesis,
Vol. 5; Trost, B. M.; Fleming, I.; Paquette, L. A., Eds.;
Pergamon: Oxford, UK, 1991, 751–784. (b) Habermas, K.
L.; Denmark, S. E.; Jones, T. K. The Nazarov Cyclization, In
Organic Reactions, Vol. 45; Paquette, L. A., Ed.; Wiley:
New York, 1994, 1–158.
0
0
36
84
16
134
191
286
394
581
55.2
40
44.8
60
21.7
11.7
2.7
78.3
88.3
97.3
a Reaction conditions: To a solution of cis-8g (120 mg, 0.28 mmol) in
CH2Cl2 (10 mL) was added BF3·OEt2 (0.35 mL, 2.8 mmol) under a ni-
trogen atmosphere at 40 °C.
b The isomer ratios were measured with 1H NMR by comparing the
chosen proton peak area.
thermodynamic product trans-8 was finally obtained as a
result of its thermodynamic stability.13
In summary, the success formation of cis-2,3-diarylin-
danone was mainly relied on the electron-donating groups
at arenes and the steric hindrance of the substituent at the
O
LA
LA
LA
O
O
O
A
B
B
B
α
α'
B
H
H
H
A
A
A
β
β'
H
H
C
C
H
C
7-I
7-II
7-III
7 (E-isomer)
O
O
OH
α
A
B
B
A
B
β
A
H+
thermodynamic
kinetic
H
C
C
C
8-I
trans-8
cis-8
Scheme 4 Proposed mechanism for electrocyclization of 2-arylchalcones
Synlett 2008, No. 3, 458–462 © Thieme Stuttgart · New York

462
J. Zhu et al.
LETTER
Hz), 4.92 (d, 1 H, J = 7.8 Hz), 5.90–7.26 (m, 9 H) ppm. 13
NMR (75 MHz, CDCl3): d = 47.3, 55.1, 55.67, 55.7, 55.8,
61.9, 96.1, 99.3, 106.2, 108.4, 113.0, 129.3, 132.4, 136.7,
138.3, 139.0, 157.6, 158.0, 160.0, 161.7, 205.4 ppm. MS
(EI): m/z (%) = 434 (100) [M+] , 326 (25.54) [M+ – PhOCH3].
Compound trans-8g
(12) (a) Smith, D. A.; Ulmer, C. W. J. Org. Chem. 1991, 56,
4444. (b) Smith, D. A.; Ulmer, C. W. Tetrahedron Lett.
1991, 32, 725. (c) Smith, D. A.; Ulmer, C. W. J. Org. Chem.
1993, 58, 4118. (d) Smith, D. A.; Ulmer, C. W. J. Org.
Chem. 1997, 62, 5110. (e) Faza, O. N.; Lopez, C. S.;
Alvarez, R.; de Lera, A. R. Chem. Eur. J. 2004, 10, 4324.
(f) Cavalli, A.; Masetti, M.; Recanatini, M.; Prandi, C.;
Guarna, A.; Occhiato, E. G. Chem. Eur. J. 2006, 12, 2836.
(g) Polo, V.; Andres, J. J. Chem. Theory Comput. 2007, 3,
816.
C
To a solution of a-substituted chalcones 7g (3.21 g, 7.40
mmol) in CH2Cl2 (100 mL) was added dropwise BF3·OEt2
(9.38 mL, 74 mmol). After the reaction solution was stirred
for 40 h at r.t. under a nitrogen atmosphere, the reaction
mixture was quenched by the addition of H2O (80 mL). The
resulting mixture was extracted with CH2Cl2 (3 × 70 mL).
The combined organic phase was washed with brine and
dried over anhyd Na2SO4. After removal of solvent, the
residue was subjected to purification on silica gel by flash
column chromatography (PE–EtOAc, 5:1) to afford the pure
product trans-8g (2.68 g, 85%) as a white solid; mp 168–
169 °C. IR (KBr): nmax = 2937, 2840, 1711, 1610, 1514,
1202, 1156 cm–1. 1H NMR (300 MHz, CDCl3): d = 3.60 (d,
1 H, J = 3.0 Hz, 3-H), 3.66 (s, 3 H, OCH3), 3.73 (s, 6 H,
2 × OCH3), 3.78 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 4.51
(13) General Procedure for the Synthesis of 2-(3,5-
dimethoxyphenyl)-4,6-dimethoxy-3-(4-methoxyphenyl)-
2,3-dihydroinden-1-one
Compound cis-8g
To a solution of a-substituted chalcones 7g (2.78 g, 6.40
mmol) in CH2Cl2 (70 mL) was added dropwise BF3·OEt2
(8.11 mL, 64 mmol) via syringe. After the reaction mixture
was stirred at r.t. for 7 min under a nitrogen atmosphere, the
reaction was quenched by the addition of H2O (60 mL). The
resulting mixture was extracted with CH2Cl2 (3 × 60 mL).
The combined organic phase was washed with brine and
dried over anhyd Na2SO4. After removal of solvent, the
resulting yellow residue was washed by the solution of
EtOAc in PE (1–2%). The pure product cis-8g (2.6 g, 94%)
was obtained after trituration as a white solid; mp 146–
148 °C. IR (KBr): nmax = 2837, 1705, 1608, 1596, 1512,
1150 cm–1. 1H NMR (300 MHz, CDCl3): d = 3.56 (s, 6 H),
3.66 (s, 3 H), 3.71 (s, 3 H), 3.91 (s, 3 H), 4.27 (d, 1 H, J = 7.8
(d, 1 H, J = 3.0Hz, 2-H), 6.23–6.95 (m, 9 H, ArH) ppm. 13
NMR (75 MHz, CDCl3): d = 50.8, 55.2, 55.3, 55.6, 55.8,
65.3, 96.4, 98.9, 106.0, 106.6, 113.8, 127.9, 128.1, 135.4,
C
138.5, 141.5, 157.7, 158.1, 160.9, 161.9, 205.5. MS (EI):
m/z (%) = 434 (100) [M+] , 326 (22.59) [M+ – CH3OPhCH].
HRMS (EI): m/z calcd for C26H26O6: 434.1721; found:
434.1713.
Synlett 2008, No. 3, 458–462 © Thieme Stuttgart · New York

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