An efficient oxidative coupling method for synthesis of novel diastereomeric biaryl diols derived from estrone

Article abstract of DOI:10.1016/j.tetlet.2012.11.109

An efficient oxidative coupling of estrogen derivatives was developed. Several 2-substitutent-17-deoxyestrones were applied to the aerobic oxidative coupling reactions catalyzed by CuCl₂/TMEDA. The products were obtained as diastereoisomers wit

Full text of DOI:10.1016/j.tetlet.2012.11.109

Accepted Manuscript
An Efficient Oxidative Coupling Method for Synthesis of Novel Diastereomeric
Biaryl Diols Derived from Estrone
Jie Feng, Xin-Bin Yang, Shuai Liang, Ji Zhang, Xiao-Qi Yu
PII:
S0040-4039(12)02072-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2012.11.109
TETL 42205
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
21 May 2012
7 November 2012
13 November 2012
Please cite this article as: Feng, J., Yang, X-B., Liang, S., Zhang, J., Yu, X-Q., An Efficient Oxidative Coupling
Method for Synthesis of Novel Diastereomeric Biaryl Diols Derived from Estrone, Tetrahedron Letters (2012), doi:
http://dx.doi.org/10.1016/j.tetlet.2012.11.109
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An Efficient Oxidative Coupling Method for Synthesis of Novel
Diastereomeric Biaryl Diols Derived from Estrone
Jie Feng, Xin-Bin Yang, Shuai Liang, Ji Zhang,* Xiao-Qi Yu*
1

An Efficient Oxidative Coupling Method for Synthesis of Novel
Diastereomeric Biaryl Diols Derived from Estrone
Jie Feng,a Xin-Bin Yang,b Shuai Liang,a Ji Zhang,a* Xiao-Qi Yua*
a Department of Chemistry, Key Laboratory of Green Chemistry and Technology (Ministry of Education),
Sichuan University, Chengdu, 610064, P. R. China
b Rongchang Campus, Southwest University, Chongqing 402460, P. R. China
Fax: +86 28 85415886; E-mail: xqyu@scu.edu.cn (X.-Q. Yu), jzhang@scu.edu.cn(J. Zhang)
Abstract:
An efficient oxidative coupling of estrogen derivatives was developed. Several
2-substitutent-17-deoxyestrones were applied to the aerobic oxidative coupling reactions
catalyzed by CuCl2/TMEDA. The products were obtained as the diastereoisomers with
moderate to good yields. As chiral ligands, three couples of diastereoisomers were applied to
the asymmetric HDA reaction to investigate their chemical properties.
Keywords: oxidative coupling, estrogen derivatives, substituent, diastereoisomers
Axially chiral biaryl diols play important roles in asymmetric synthesis since the diols or
their derivatives can induce high enantioselectivity.1 In the past several decades, much
attentions have been paid to the effective synthesis of these axially chiral diols, especially
binaphthol and its derivatives.2 Oxidative coupling of 2-naphthol derivatives represents a well
established method for the preparation of binaphthols. Various oxidizing metal salts such as
Fe,3 Cu,4 V,5 Ru6 or Re7 have been used for the coupling of 2-naphthol derivatives to give
binaphthols with high yields or enatioselectivities. However, limited researches were focused
on the oxidative coupling of tetrahydronaphthalen-2-ol and its analogues, which have been
proved to be inactive in oxidative coupling reactions.
In 1977, Ius and co-workers firstly reported that K3Fe(CN)6 could catalyze the coupling
reaction of 17β-estradiol,8 which is a typical analogue of tetrahydronaphthalen-2-ol. The mixed
ortho-coupled products were obtained with low yields and low selectivity. In 2004, Riva and
co-workers applied a copper-containing enzymatic catalyst laccase to the oxidative coupling
2

reactions of tetrahydronaphthalen-2-ol and 17β-estradiol.9 Both of the substrates converted to
dimeric products with low yields and improved selectivity. Afterwards, another
peroxidase-H2O2-MnO2 catalytic system was developed to catalyze the dimerization of
17β-estradiol by Pezalla.10 The dimeric product with axial symmetry was isolated only with 2%
yield from eight different dimeric or trimeric products. To our knowledge, there was rare
successful synthesis of axially symmetric dimmers through the coupling reaction from
H4-naphthol’s derivatives with high reactivity and selectivity. Herein, we report an efficient
method of the oxidative coupling reactions of a series of chiral estrogen derivatives. These
chiral substrates (S-2) as precursors of axially chiral biaryl diols are attractive because the diol
products (S, S-3) could be easier for separation due to their diastereoisomerism.
The original challenge was the competition of reactive positions between C-2 and C-4 of
estrogen in oxidative coupling reaction. Taylor and co-workers have used the tert-butyl as
protecting group at C-2 of estrogen for the purpose of selective functionalization at C-4
position.11 Inspired by this report, to block C-2 position of estrogen, a series of 2-alkyl or
2-aryl-17-deoxyestrones (2a-2h) were synthesized starting from estrone through different
pathways (Scheme 1).12
13
2
t
4
S-
S-
Scheme 1. Synthesis of a series of 2-alkyl or aryl substituted 17-deoxyestrones
2-ethyl-17-deoxyestrone (2a) was then chosen as model substrate to optimize the aerobic
oxidative coupling conditions, and the results are summarized in Table 1. Firstly, the use of
three common oxidative metal salts exhibited no activity in the coupling reactions (Entries 1-3),
and only trace target product could be observed when the reaction was catalyzed by copper salt.
Then several ligands were investigated to improve the efficiency of metal catalyst used in the
model reaction (Entries 4-6). To our delight, the dimeric product was obtained in 57 % yield in
3

the reaction catalyzed by CuCl2 in the presence of tetramethylethylenediamine (TMEDA,
entry 5). This is the highest yield of estrogen’s dimerization ever studied. Any changes of
copper salts or solvents led to no reaction (Entries 7-11), and slightly decreased yield was
obtained by using anhydrous CuCl2 instead of CuCl2 2H2O as catalyst (Entry 12). Neither the
increase of catalyst loading nor reaction temperature could increase the yield (Entries 13, 14).
In addition, the special aerobic oxidative method is vital for the reaction, and the desired
product could only be obtained in the reaction with atmosphere bubbling through the reaction
mixture (Entry 15). However, pure oxygen bubbling did not improve the yield of reaction.
Table 1. Optimization of the reaction conditions.[a]
Entry
1
Metal salt
FeCl3 6H2O
MnO2
Ligand
---
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
Acetone
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Isolated yield (%)
N.R.
N.R.
Trace
22
2[b]
---
3
CuCl2 2H2O
CuCl2 2H2O
CuCl2 2H2O
CuCl2 2H2O
CuSO4 5H2O
Cu(NO3)2 3H2O
Cu(acac)2
---
4
N-methylimidazole
TMEDA
ethanediamine
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
5
57
6
Trace
N.R.
N.R.
N.R.
N.R.
N.R.
48
7
8
9
10
11
12
13[c]
14[d]
15[e]
CuCl2 2H2O
CuCl2 2H2O
CuCl2
CuCl2 2H2O
CuCl2 2H2O
CuCl2 2H2O
56
40
Trace
[a] Reaction conditions: 2a (1 mmol), metal salt (20 mol %), ligand (20 mol %), solvent (15 mL),
atmosphere was bubbled through the mixture at room temperature for 72h. [b] Reaction was performed with
MnO2 (100 mol %). [c] Reaction was performed with CuCl2·2H2O (40 mol %) and TMEDA (40 mol %). [d]
Reaction was performed at 40 °C. [e] Reaction was performed not with bubbling atmosphere.
4

Substrates 2a-2h were then employed for the oxidative coupling under optimized conditions
(Table 2). It’s notable that the catalytic activities were strongly depended on the substituents at
C-2 of estrogen. For example, the substrates with 2-ethyl and 2-methyl substituent (2a and 2b)
gave the dimeric products with moderate yields, comparing with no product in the reaction
involving 2-t-butyl-17-deoxyestrone 2c (Entries 1-3). Not only the alkyl groups but also
several aryl substituents have different effects on the oxidative coupling. Electron-withdrawing
group might benefit the reaction, and the deoxyestrones substituted by 3,
5-di(trifluromethyl)-phenyl at C-2 could give the dimeric product 3e smoothly with up to 75%
yield (Entry 5), which was distinctly higher than that obtained by using phenyl substituted
substrate 2d (58%, entry 4). In contrast, there was no reaction when the electron-donating aryl
groups were introduced to the substrates (Entries 6, 7). Further, substrate with more bulky
naphthalene group (2h) could also convert to the desired product with 22% yield (Entry 8).
These results demonstrate that both electronic effect and steric effect of the substituents
influence the oxidative coupling reaction remarkably.
Table 2. Oxidative reactions of several 2-substituted-17-deoxyestrone.[a]
R
CuCl2 6H2O
TMEDA
HO
HO
R
air
CH2Cl2
HO
R
2
S-
3
S,S-
Entry
Substrate
R
Isolated yield of 3 (%)[b]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
ethyl
57
68
methyl
t-butyl
phenyl
N.R.
58
3,5-di(trifluromethyl)-phenyl
4-methoxyphenyl
75
N.R.
N.R.
22
2g
2h
2,4,6-trimethoxyphenyl
1-naphthyl
[a] Reaction conditions: substrate 2 (1 mmol), CuCl2·2H2O (34 mg, 0.2 mmol), TMEDA (30 mg, 0.2 mmol),
CH2Cl2 (15 mL), atmosphere was bubbled through the mixture at room temperature for 72h. [b]
Diastereoisomers (Rax, S, S- and Sax, S, S-) were obtained in 1 : 1 ratio.
5

The 4, 4’-linked biaryl diols S, S-3a-3h were obtained as 1 : 1 mixtures of two
diastereoisomers (Rax, S, S- and Sax, S, S-, Figure 1). Among these diastereoisomers, 3a, 3b and
3d could respectively be separated to a couple of axially chiral biaryl diols (3a1 and 3a2, 3b1
and 3b2, 3d1 and 3d2) by column chromatography. The pure diastereoisomers were
1
characterized by H NMR, 13C NMR and HRMS respectively, and the results for each couple
were almost the same. However, every couple of compounds displayed mirror image on CD
spectra (Figure 2). The CD spectra supported our assumption that the chiral properties of these
diastereoisomers are mainly determined by the bis-estrogenic axis.
Figure 1. The axially chiral structure of the diastereoisomers
20
20
10
0
20
10
3d1
3b1
10
0
3a1
0
-10
-20
-30
-10
3a2
3b2
-10
3d2
-20
-20
220
220
240
260
280
300
320
240
260
280
300
320
220
240
260
280
300
320
Wavelength/nm
Wavelength/nm
Wavelenghth/nm
Figure 2. CD spectra of diastereoisomers of 3a, 3b and 3d
Subsequently, asymmetric hetero-Diels-Alder (HDA) reaction was chosen for examining the
chemical properties of the diastereoisomers. As shown in Table 3, three couples of ligands
exhibited different catalytic activities in the model HDA reaction between
trans-1-methoxy-2-methyl-3-trimethylsiloxybuta-1, 3-diene and 4-nitrobenzaldehyde.13 The
reactions were carried out in the presence of diastereomeric ligand (25 mol %) and Ti(OiPr)4
(20 mol %) in CH2Cl2 at 0 ºC for 72 h. Interestingly, the HDA reactions involving
6

ethyl-containing 3a and afforded 5-Methyl-2-(4-nitrophenyl)-2, 3-dihydro-4H-pyran-4-one
with much higher yields and ee values than those using other two couples of ligands 3b and 3d.
Meanwhile, the absolute configurations of the products were confirmed, and the opposite
enantiomers were given in the reactions catalyzed by the ligands with different axial chirality.
Table 3. Investigation of chemical properties of several diastereometric ligands.[a]
Product
Entry
Ligand
Yield (%) [b]
ee (%) [c]
Configuration
1
2
3
4
5
6
3a1
3a2
3b1
3b2
3d1
3d2
99
98
75
82
74
77
93
96
57
48
25
32
S
R
S
R
S
R
[a] Reaction conditions: 4-nitrobenzaldehyde 0.2 mmol, diene 4 (2 mmol), Ti(OiPr)4 0.04 mmol, ligand 0.05
mmol at 0 ºC for 72 h, then added TFA 0.1 mL at R.T. overnight. [b] Isolated yields. [c] The ee values were
determined by HPLC using chiralcel OD-H column.
In summary, we described an oxidative coupling of estrogen derivatives catalyzed by
CuCl2/TMEDA system. Key to the high selectivity and activity was the introduction of
substituted groups with suitable steric and electronic properties at 2-position of estrogen. The
catalytic products 3a, 3b and 3d were separated to three couples of diastereoisomers. All of
them were examined as chiral ligands in asymmetric HDA reaction. Further studies to find
widespread application in asymmetric catalytic reactions are currently under investigation.
Acknowledgements: This work was financially supported by the National Science Foundation
of China (Nos. 21021001, 20972104). We also thank the Sichuan University Analytical and
Testing Center for NMR spectroscopic analysis.
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An Efficient Oxidative Coupling Method for Synthesis of Novel
Diastereomeric Biaryl Diols Derived from Estrone
Jie Feng, Xin-Bin Yang, Shuai Liang, Ji Zhang,* Xiao-Qi Yu*
8