Acid-Promoted Cascade Cyclization to Produce 2-(4′-Alkoxyaryl)-3,4-Fused Tricyclic Dihydrobenzopyrans via a Vinylidene para-Quinone Methide Intermediate

Article abstract of DOI:10.1002/ejoc.201800013

We developed a novel method for synthesizing 2-(4-hydroxyaryl)-3,4-fused tricyclic dihydrobenzopyrans with 2,3-syn and 3,4-syn motif based on the acid-promoted cascade cyclization via vinylidene para-quinone methide intermediates. Using easily prepared li

Full text of DOI:10.1002/ejoc.201800013

A Journal of
Accepted Article
Title: Acid Promoted-Cascade Cyclization to Produce 2-(4'-
Alkoxyaryl)-3,4-Fused Tricyclic Dihydrobenzopyrans via a
Vinylidene para-Quinone Methide Intermediate
Authors: Dongil Choi, Naoki Shiga, Robert Franzén, and Tetsuhiro
Nemoto
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800013
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800013
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10.1002/ejoc.201800013
European Journal of Organic Chemistry
COMMUNICATION
Acid Promoted-Cascade Cyclization to Produce 2-(4’-Alkoxyaryl)-
3,4-Fused Tricyclic Dihydrobenzopyrans via a Vinylidene para-
Quinone Methide Intermediate
Dongil Choi,[a] Naoki Shiga,[a] Robert Franzén,[b] and Tetsuhiro Nemoto*[a,c]
Abstract: We developed a novel method for synthesizing 2-(4-
hydroxyaryl)-3,4-fused tricyclic dihydrobenzopyrans with 2,3-syn
and 3,4-syn motif based on the acid-promoted cascade cyclization
via vinylidene para-quinone methide intermediates. Using easily
prepared linear substrates, TFA-promoted cascade cyclization
proceeded in the presence of triethylsilane, affording a series of
five to seven-membered ring-fused dihydrobenzopyran derivatives
in moderate to excellent yield in a highly diastereoselective manner.
The developed method provided new access to potent and
selective ERb agonists.
addition of the indole to the para-quinone methide intermediate
(Scheme 1a).[4b,6] The reaction sequence of this process is
potentially applicable to the construction of the core structure of
2-aryl-3,4-fused tricyclic dihydrobenzopyrans, leading us to
examine an acid-promoted cascade cyclization using 1 as the
substrate. The reaction gave a mixture of diastereomers 2a
and 2b in 82% yield and compound 2a bearing a 2,3-anti and
3,4-syn structure was obtained as a major isomer (2a:2b =
1.85:1) (Scheme 1b). In Eli Lilly’s synthesis, reductive
cyclization of a 1,2-cis-disubstituted cyclopentane derivative
was used to construct three contiguous stereocenters. We thus
hypothesized that diastereoselective construction of the 2,3-
syn and 3,4-syn motif could be realized by designing a cascade
reaction using a vinylidene para-quinone methide intermediate,
which have been rarely explored in organic synthesis.[7] Herein
we report our results.
Introduction
Flavan (i.e., 2-aryl dihydrobenzopyran) skeletons are
ubiquitous structures in various bioactive natural products. In
particular, highly oxygenated flavans typified by catechin and
related compounds exhibit a wide variety of bioactivities, such
as anticancer activity and antioxidant activity, and are
recognized as useful scaffolds for drug discovery studies.
Therefore, the development of an efficient and flexible synthetic
method to produce functionalized flavan derivatives is an
attractive research topic in the field of synthetic organic and
medicinal chemistry.[1, 2]
Binding Affinity
R1
R2
5
4
ERβ (nM)
ERα (nM)
6
3
R2
+
51 11
–
+
267 112
–
H
6-OH
H
2
O
4’
R1
+
+
22.1 7.3
–
OH
40 27
–
OH 6-OH
OH 5-OH
0.47
0.66
4.34
0.35
2-Aryl-3,4-fused tricyclic
dihydrobenzopyrans
In 2006, researchers at Eli Lilly and Company reported that
3,4-cyclopentane-fused 2-(4-hydroxyaryl)-dihydrobenzopyrans
exhibit potent estrogen receptor (ER) agonist activity (Figure
1).[3] Structure activity relationship studies revealed that phenol
groups on the aromatic rings are important for the binding
affinity, as well as the selectivity of ER subtypes. Removing the
phenolic hydroxyl group at the 4’-position dramatically affects
the affinity for ERs, indicating the importance of this phenol in
the ER pharmacophore.
Figure 1. 2-(4-Hydroxyaryl)-3,4-Fused Tricyclic Dihydrobenzopyrans with an
Estrogen Receptor Agonist Activity.
(a) Previous work
Ts
Ts
N
N
HO
TFA
(8 equiv)
As part of our ongoing studies aimed at developing acid-
OMe
CH2Cl2
0 °C
N
promoted cascade reactions based on
a
phenol
N
OMe
Boc
dearomatization process,[4,5] we recently reported the synthesis
of fused-polycyclic indole derivatives via an intramolecular ene-
type addition of the double bond of para-alkoxystyrene to 3-
alkylidene indolenium cations followed by Friedel-Crafts-type
Boc
62% yield
(b) Initial trial
O
TFA
HO
(5 equiv)
2a
OMe
OMe
[a]
D. Choi, N, Shiga, Prof. Dr. T. Nemoto
OH
CH2Cl2
0 °C, 1 h
Graduate School of Pharmaceutical Sciences, Chiba University
1-8-1, Inohana, Chuo-ku, Chiba 260-8675 (Japan)
E-mail: tnemoto@faculty.chiba-u.jp
URL: http://www.p.chiba-u.jp/lab/yakka/reserch,eng.html
Prof. Dr. R. Franzén
Department of Chemistry, University of Turku
Vatselankatu 2, 20014 Turku (Finland)
Prof. Dr. T. Nemoto
OMe
1
82% yield
(2a:2b = 1.85:1)
O
[b]
[c]
2b
Scheme 1. Initial Trial based on the Previous Work.
Molecular Chirality Research Center, Chiba University
1-33, Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
Supporting information for this article is given via a link at the end of
the document.
Results and Discussion
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10.1002/ejoc.201800013
European Journal of Organic Chemistry
COMMUNICATION
Our synthetic plan for the synthesis of 2-aryl-3,4-fused tricyclic
dihydrobenzopyranes with a 2,3-syn and 3,4-syn structure is
outlined in Scheme 2. We envisioned that compound I could be
constructed by an acid-promoted reduction of enol ether
derivative II, which in turn would be obtained by 1,6-addition of
phenol to vinylidene para-quinone methide intermediate III.
This intermediate could be prepared from compound IV by
intramolecular dearomative nucleophilic addition of 4-
alkynylphenol to ortho-quinone methide generated from the
ortho-hydroxy benzylalcohol moiety. Both processes are
promoted by an acid promoter, indicating that the target
transformation can be performed in a cascade manner.
in 69% yield (entry 3). The yield was further improved to 87%
yield using 5 equiv of triethylsilane (entry 5). The use of other
hydride sources such as triisopropylsilane and triphenylsilane
gave less satisfactory results (entries 7 and 8). We thus
selected the reaction conditions in entry 5 as optimal for this
cascade process. Interestingly, the present cascade reaction
also proceeded in the absence of triethylsilane, affording 6a in
moderate yield (entry 9). To specify the hydride source in the
reaction without triethylsilane, compound 5a-D was prepared
and treated with 5 equiv of TFA in CH2Cl2 at 0 °C (Scheme 2).
Product 6a-D bearing two deuterium atoms in the C2 and C4
positions was obtained in 37% yield, revealing that the
disproportionation reaction of 2 molecules of 7 into 6a-D and 8
unexpectedly promoted the reaction, even in the absence of
triethylsilane.
Acid-promoted
reduction
4
1,6-Addition
OR
3
Table 1. Optimization of the Reaction Conditions.
H+ promoter
R3SiH
O
2
O
I
II
Acid promoter
R3SiH
OR
HO
OH
OMe
CH2Cl2
Formation of
vinylidene para-
quinone methide
O
·
0 °C, 45 min
HO
5a
Acid Promoter
6a
OMe
OH
OH
OR
OR
Entry
R3SiH
Yield[a]
H+ promoter
III
IV
1
2
3
4
5
6
7
8
9
TFA (1 equiv)
TFA (3 equiv)
TFA (5 equiv)
TFA (5 equiv)
TFA (5 equiv)
TFA (5 equiv)
TFA (5 equiv)
TFA (5 equiv)
TFA (5 equiv)
Et3SiH (1 equiv)
0% (65%)[b]
37%
Scheme 2. Reaction Design.
Et3SiH (1 equiv)
Et3SiH (1 equiv)
Et3SiH (2 equiv)
Et3SiH (5 equiv)
Et3SiH (10 equiv)
i-Pr3SiH (2 equiv)
Ph3SiH (2 equiv)
–
69%
Our investigation started with the synthesis of a model
substrate (Scheme 3). 4-Iodoanisole was first coupled with 5-
hexyn-1-ol in the presence of 5 mol % of PdCl2(PPh3)2 and 5
mol % of CuI in triethylamine, providing compound 3a in 94%
yield. After oxidation of the primary alcohol, the obtained 4a
was reacted with 2 equiv of aryllithium reagent generated from
2-bromophenol to give compound 5a in 80% yield from 3a.
82%
87%
87%
32%
37%
37% (42%)[c]
I
b
a
OMe
94% yield
[a] Isolated yield. [b] Recovery of 5a. [c]Reaction time: 2 h.
OH
c
OMe
3a
HO
H
D
TFA
(5 equiv)
OH
OMe
80% yield
(2 steps)
HO
O
OMe
4a
5a
D
OH
OMe
CH2Cl2
O
0 °C, 2 h
D
5a-D
6a-D
OMe
Scheme 3. Synthesis of Model Substrate. (a) 5-hexyn-1-ol (1.2 equiv), CuI
(5 mol %), PdCl2(PPh3)2 (5 mol %), NEt3 (0.2 M), rt, 2.5 h; (b) Dess-Martin
Reagent (1.6 equiv), CH2Cl2 (0.1 M), 0 °C to rt, 1.5 h; (c) 2-bromophenol (2
equiv), n-BuLi (4.0 equiv), Et2O (0.1 M), –20 °C, 0.5 h.
D
8
CF3COOH
O
O
6a-D
7
OMe
The reaction conditions were optimized using 5a as a
substrate (Table 1). We first examined the reaction using 1
equiv of trifluoroacetic acid (TFA) and 1 equiv of triethylsilane
in CH2Cl2 at 0 °C. The desired product 6a, however, was not
obtained and 65% of 5a was recovered (entry 1). Increasing
the amount of TFA improved the yield of 6a. When the reaction
was performed using 5 equiv of TFA, the product was obtained
OMe
(2 molecules)
CF3COO
Scheme 4. Deuterium Labelling Study.
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10.1002/ejoc.201800013
European Journal of Organic Chemistry
COMMUNICATION
With the optimized reaction conditions in hand, we next
examined the scope and limitations using various substrates
(Scheme 5). In addition to model substrate 5a, TBS-protected
4-alkynyl phenol derivatives were effective substrates for this
reaction. Treatment of 5b under the optimized conditions led to
the corresponding product 6b in 86% yield. The TBS group
could be removed using tetrabutylammonium fluoride (TBAF),
of TBAF and 4.4 equiv of AcOH, and the resulting mixture of 6h
and 6h’ was then allowed to react with 10 equiv of TFA and 5
equiv of triethylsilane, producing compound 7h in 71% yield for
2
steps. Moreover, substrates with substituents on the
alkynylphenyl moiety were examined. When ortho-
dimethylphenol-type substrate 5i was used, the corresponding
product 6i was obtained in 99% yield, and could be
transformed into compound 7i in 90% yield. Naphthol
derivatives 5j and 5k were also examined. The acid-promoted
cascade reactions proceeded in the presence of 10 equiv of
Et3SiH, affording the corresponding products 6i and 6k in 62%
yield and 52% yield, respectively, accompanied by the
formation of a small amount of the naphthol unit-epimerized
product (dr = 20:1). Substrates 9 and 11 bearing a longer
tether were also examined (Scheme 6). Both substrates were
treated with the optimum conditions and the corresponding
products with a six-membered ring or a seven-membered ring
10 and 12 were obtained in 63% yield and 63% yield,
respectively, in a highly diastereoselective manner.
affording
2-(4-hydroxyphenyl)-3,4-fused
tricyclic
dihydrobenzopyran derivative 7b in 73% yield. Substrates with
a substituent on the R1 position 5c–f reacted under the same
reaction conditions to give the corresponding products 6c–f in
54%–89% yield. Treatment of compound 6f with 2.2 equiv of
TBAF afforded product 7f, the potent and selective ERb
agonist shown in Figure 1, in 84% yield. A substrate with a
methoxy group in R2 was also applicable to this process,
providing 6g in 51% yield. Although substrate 5h bearing a t-
butyldimethylsiloxy group in the R3 position was prepared
according to the general procedure in Scheme 3, separation of
compounds 5h from 5h’ and 6h from 6h’ by a silica gel column
chromatography was difficult in each reaction. Therefore, the
obtained mixture of 5h and 5h’ was first treated with 4.4 equiv
R3
R4
R3
R1
R2
HO
R3
R1
R1
TBAF
(1.1 equiv)
TFA (5 equiv)
Et3SiH (5 equiv)
R4
R4
OR5
OH
O
R2
O
THF
0 °C, 1 h
CH2Cl2 (0.02 M)
0 °C, 1 h
OR5
5
6
7
OH
R2
Me
MeO
O
O
O
O
OMe
OR
OR
OR
6a: 87% yield
6b (R = TBS): 86% yield
7b (R = H): 73% yield
6c (R = TBS): 82% yield
7c (R = H): 95% yield
6d (R = TBS): 89% yield
7d (R = H): 95% yield
OH
F
RO
O
O
MeO
O
O
OR
OR
OMe
OH
6e (R = TBS): 54% yield
7e (R = H): 70% yield
6f (R = TBS): 68% yield
7f (R = H): 84% yield
(2.2 equiv of TBAF was used.)
6g: 51% yield
7h: 71% yield (2 steps)
(10 equiv of TFA)
(0 °C, 1h then rt, 2 h)
OR
Me
OR
O
O
O
OR
OMe
OH
Me
6j (R = TBS): 62% yield
(10 equiv of Et3SiH was used.)
7j (R = H): 66% yield
6k: 52% yield
(10 equiv of Et3SiH
was used.)
5h’: R = TBS
6h’: R = H
6i (R = TBS): 99% yield
7i (R = H): 90% yield
Scheme 5. Scope and Limitations.
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10.1002/ejoc.201800013
European Journal of Organic Chemistry
COMMUNICATION
[2]
For recent representative examples of the synthesis of
dihydrobenzopyran derivatives, see: a) S. B. Bharate, R. Mudududdla,
J. B. Bharate, N. Battini, S. Battula, R. R. Yadav, B. Singh, R. A.
Vishwakarma, Org. Biomol. Chem. 2012, 10, 5143; b) Y. Wang, R.
Franzén, Synlett 2012, 23, 925; c) R. R. R. Taylor, R. A. Batey, J. Org.
Chem. 2013, 78, 1404; d) X.-G. Song, S.-F. Zhu, X.-L. Xie, Q.-L. Zhou,
Angew. Chem. 2013, 125, 2615; Angew. Chem. Int. Ed. 2013, 52,
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2014, 136, 10834; g) J. E. Lee, T. H. Kwon, S. J. Gu, D.-H. Lee, B. M.
kim, J. Y. Lee, J. K. Lee, S. H. Seo, A. N. Pae, G. Keum, Y. S. Cho,
S.-J. Min, Org. Biomol. Chem. 2014, 12, 5669; h) Z.-C. Geng, S.-Y.
Zhang, N.-K. Li, N. Li, J. Chen, H.-Y. Li, X.-W. Wang, J. Org. Chem.
2014, 79, 10772; i) V. V. Pagar, C.-C. Tseng, R.-S. Liu, Chem. Eur. J.
2014, 20, 10519; j) P. Saha, A. Biswas, N. Molleti, V. K. Singh, J. Org.
Chem. 2015, 80, 11115; k) W. Yang, Y. Liu, S. Zhang, Q. Cai, Angew.
Chem. 127, 8929; Angew. Chem. Int. Ed. 2015, 54, 8805; l) K.
Tangdenpaisal, K. Chuayboonsong, P. Sukjarean, V. Katesampao, N.
Noiphrom, S. Ruchirawat, P. Ploypradith, Chem. Asian. J. 2015, 10,
1050; m) A. Kebberg, P. Metz, Angew. Chem. 2016, 128, 1173;
Angew. Chem. Int. Ed. 2016, 55, 1160; n) A. Kebberg, P. Metz, Org.
Lett. 2016, 18, 6500; o) N. Shiraishi, M. Kumazoe, S. Fuse, H.
Tachibana, H. Tanaka, Chem. Eur. J. 2016, 22, 13050; p) A. G. K.
Reddy, J. Krishna, G. Satyanarayana, ChemistrySelect 2016, 6, 1151;
q) M. A. Arai, Y. Yamaguchi, M. Ishibashi, Org. Biomol. Chem. 2017,
15, 5025; r) S. Shee, B. Paul, D. Panja, B. C. Roy, K. Chakrabarti, K.
Ganguli, A. Das, G. K. Das, S. Kundu, Adv. Synth. Catal. 2017, 359,
3888; s) K. Tangdenpaisal, K. Chuayboonsong, S. Ruchirawat, P.
Ploypradith, J. Org. Chem. 2017, 82, 2672.
n
n
TFA (5 equiv)
Et3SiH (5 equiv)
OH
OMe
CH2Cl2 (0.02 M)
0 °C, 1 h
O
HO
OMe
9 (n = 1)
11 (n = 2)
10 (n = 1): 63% yield
12 (n = 2): 63% yield
Scheme 6. Substrate Scope.
Conclusions
In conclusion, we developed a novel method for synthesizing 2-
(4-hydroxyaryl)-3,4-fused tricyclic dihydrobenzopyrans with 2,3-
syn and 3,4-syn motifs based on the acid-promoted cascade
cyclization via vinylidene para-quinone methide intermediates.
Using easily prepared linear substrates, a series of five to
seven-membered ring-fused dihydrobenzopyran derivatives
were obtained in moderate to excellent yield in a highly
diastereoselective manner. The developed method provided
new access to potent and selective ERb agonists. The present
work demonstrated the synthetic utility of vinylidene para-
quinone methide intermediates. Further studies on the
application of this intermediate to complex molecule synthesis
are in progress.
[3]
a) B. H. Norman, J. A. Dodge, T. I. Richardson, P. S. Borromeo, C. W.
Lugar, S. A. Jones, K. Chen, Y. Wang, G. L. Durst, R. J. Barr, C.
Montrose-Rafizadeh, H. E. Osborne, R. M. Amos, S. Guo, A.
Boodhoo, V. Krishnan, J. Med. Chem. 2006, 49, 6155; b) T. I.
Richardson, B. H. Norman, C. L. Lugar, S. A. Jones, Y. Wang, J. D.
Durbin, V. Krishnan, J. A. Dodge, Bioorg. Med. Chem. Lett. 2007, 17,
3570.
Experimental Section
General Procedure for the Acid-Promoted Cascade Cyclization
(Table 1, entry 5): To a stirred solution of 5a (29.6 mg, 0.1 mmol) in
CH2Cl2 (5.0 mL) at 0 °C was added Et3SiH (80 µL, 0.5 mmol) and TFA
(38 µL, 0.5 mmol). After being stirred for 1 h at 0 °C, the reaction
mixture was concentrated in vacuo. The residue was purified by silica
gel column chromatography to give the desired products 6a (24.7 mg)
in 87% yield. IR (ATR) ν 2952, 2869, 1612, 1582, 1455, 1303, 1175,
1034, 993, 823 cm-1; 1H NMR (400 MHz, CDCl3): d 7.39 (2H, d, J = 8.8
Hz), 7.18 (1H, d, J = 8.0 Hz), 7.10 (1H, ddd, J = 8.4, 8.4, 2.0 Hz), 6.96–
6.88 (4H, m), 5.13 (1H, d, J = 2.4 Hz), 3.82 (3H, s), 3.52 (1H, ddd, J =
8.0, 8.0, 2.4 Hz), 2.64–2.55 (1H, m), 2.20–2.09 (1H, m), 1.88–1.80 (1H,
m), 1.70–1.59 (1H, m), 1.53–1.35 (3H, m); 13C NMR (100 MHz, CDCl3):
d 158.7, 155.4, 133.4, 129.1, 127.4, 126.8 (2C), 126.7, 121.3, 117.1,
113.6 (2C), 77.2, 55.3, 45.3, 39.6, 34.9, 23.7, 23.5; HRMS (ESI-TOF):
m/z: Calcd. for C19H19O2– [M-H] –: 279.1391; found: 279.1400.
[4]
a) T. Yokosaka, T. Nemoto, Y. Hamada, Chem. Commun. 2012, 48,
5431; b) T. Yokosaka, H. Nakayama, T. Nemoto, Y. Hamada, Org.
Lett. 2013, 15, 2978; c) T. Yokosaka, T. Nemoto, Y. Hamada,
Tetrahedron Lett. 2013, 54, 1562; d) T. Yokosaka, T. Kanehira, H.
Nakayama, T. Nemoto, Y. Hamada, Tetrahedron 2014, 70, 2151; e) T.
Yokosaka, N. Shiga, T. Nemoto, Y. Hamada, J. Org. Chem. 2014, 79,
3866; f) T. Yokosaka, T. Nemoto, H. Nakayama, N. Shiga, Y. Hamada,
Chem. Commun. 2014, 50, 12775; g) Y. Suzuki, T. Nemoto, S.
Nakano, Z. Zhao, Y. Yoshimatsu, Y. Hamada, Tetrahedron Lett. 2014,
55, 6726.
[5]
[6]
[7]
For reviews on the synthetic methods using a phenol dearomatization
process, see: a) L. Pouysegu, D. Deffieux, S. Quideau, Tetrahedron
2010, 66, 2235; b) Q. Ding, Y. Ye, R. Fang, Synthesis 2013, 45, 1; c)
W. Sun, G. Li, L. Hong, R. Wang, Org. Biomol. Chem. 2016, 14, 2164;
d) W.-T. Wu, L. Zhang, S.-L. You, Chem. Soc. Rev. 2016, 45, 1570.
For reviews on the synthetic methods using quinone methide
intermediates, see: a) T. P. Pathak, M. S. Sigman, J. Org. Chem.
2011, 76, 9210; b) M. S. Singh, A. Nagaraju, N. Anand, S. Chowdhury,
RSC Adv. 2014, 4, 55924; c) W.-J. Bai, J. G. David, Z.-G. Feng, M. G.
Weaver, K.-L. Wu, T. R. R. Pettus, Acc. Chem. Res. 2014, 47, 3655.
Vinylidene ortho-quinone methide intermediates in organic synthesis,
see: a) M. Furusawa, K. Arita, T. Imahori, K. Igawa, K. Tomooka, R.
Irie, Tetrahedron Lett. 2013, 54, 7107; b) X. Wu, L. Xue, D. Li, S. Jia,
J. Ao, J. Deng, H. Yan, Angew. Chem. 2017, 129, 13910; Angew.
Chem. Int. Ed. 2017, 56, 13722.
Acknowledgements
This work was supported financially by JSPS KAKENHI Grant
Number 15K07850, and Chiba University.
Keywords: Cascade reaction • dihydrobenzopyrans • synthetic
method
[1]
For reviews, see: a) K. Oyama, K. Yoshida, T. Kondo, Curr. Org.
Chem. 2011, 15, 2567; b) K. Ohmori, Chem. Rec. 2011, 11, 252; b) T.
Asakawa, Y. Hamashima, T. Kan, Curr. Pharm. Des., 2013, 19, 6207.
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10.1002/ejoc.201800013
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
n
n
We developed a novel method
Cascade Reaction*
Y
TFA
Et3SiH
Y
for
synthesizing
2-(4-
HO
·
Dongil Choi, Naoki Shiga, Robert
Franzén, and Tetsuhiro Nemoto *
hydroxyaryl)-3,4-fused tricyclic
dihydrobenzopyrans with 2,3-
syn and 3,4-syn motifs based
on the acid-promoted cascade
cyclization via vinylidene para-
OH
OH
OR
X
OR
X
Formation of vinylidene para-
quinone methide intermediate
Page No. – Page No.
Acid
Promoted-Cascade
Diastereo-
selective
reduction
n
X
n
Cyclization to Produce 2-(4’-
Alkoxyaryl)-3,4-Fused Tricyclic
Dihydrobenzopyrans
Vinylidene para-Quinone
Methide Intermediate
quinone
methide
X
1,6-Addition
intermediates. The developed
method provided new access
to potent and selective ERb
agonists from a simple linear
Y
Y
O
O
via
a
OR
OR
· Cascade process
· Highly diastereoselective
· Efficient access to estrogen receptor agonist
51–99% yield
(13 examples)
(n = 1 ~ 3)
substrate in
reaction.
a
single-step
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