Enantioposition-selective copper-catalyzed azide-alkyne cycloaddition for construction of chiral biaryl derivatives

Article abstract of DOI:10.1021/ol502778j

A highly enantioposition-selective copper-catalyzed azide-alkyne cycloaddition (CuAAC) of dialkynes bearing prochiral biaryls has been developed for the construction of 1,2,3-triazoles bearing axially chiral biaryl groups in up to 76% yield and up to 99% ee.

Full text of DOI:10.1021/ol502778j

Letter
pubs.acs.org/OrgLett
Enantioposition-Selective Copper-Catalyzed Azide−Alkyne
Cycloaddition for Construction of Chiral Biaryl Derivatives
Takao Osako† and Yasuhiro Uozumi*,†,‡
†Institute for Molecular Science (IMS), Okazaki, Aichi 444-8787, Japan
‡Riken Advanced Science Institute, Wako, Saitama 351-0198, Japan
S
* Supporting Information
ABSTRACT: A highly enantioposition-selective copper-catalyzed
azide−alkyne cycloaddition (CuAAC) of dialkynes bearing
prochiral biaryls has been developed for the construction of
1,2,3-triazoles bearing axially chiral biaryl groups in up to 76%
yield and up to 99% ee.
he copper-catalyzed azide−alkyne cycloaddition
reaction to the desymmetrization of Cs-symmetric achiral
T(CuAAC) reaction, also known as the Huisgen reaction, biaryls might provide a new method for enantioselective
has been recognized as a click reaction1 and is widely used in
construction of axially chiral biaryls. Here, we report the
development of enantioposition-selective copper-catalyzed
azide−alkyne cycloaddition of azides with dialkynes bearing
prochiral biaryl groups to give 1,2,3-triazoles bearing axially
chiral biaryl groups with high enantioselectivities.
the construction of 1,2,3-triazoles in the synthesis of a wide
variety of functional molecules.2 Compared with the
significant development of the CuAAC, scant attention has
been paid to the asymmetric version of this reaction. Fokin
and Finn reported a kinetic resolution of α-benzylic azides and
the asymmetric desymmetrization of gem-diazides through an
enantioposition-selective CuAAC with a modest level of the
enantioselectivity.3 Recently, Zhou and co-workers achieved a
highly enantioposition-selective CuAAC of prochiral oxindole
group-containing 1,6-heptadiynes to give the 1,2,3-triazoles
containing quaternary stereogenic carbon centers in the
oxindole moiety in high yields and excellent enantioselectiv-
ities (84−98% ee).4 However, despite the considerable
potential of CuAAC to achieve asymmetric induction, the
range of substrates with which highly enantioselective CuAAC
can occur remains limited to oxindole-based 1,6-heptadiynes.
Therefore, enantioselective CuAAC is still an immature re-
action and major challenges remain in broadening its synthetic
utility.
Axially chiral biaryl derivatives are important and useful
compounds and are widely found in valuable organic
compounds, including biologically active compounds, chiral
ligands, and chiral Brønsted acids.5 Because of their versatility
as excellent chiral units, much effort has been devoted to the
development of efficient methods for constructing axially
chiral biaryl derivatives.6−8 Asymmetric desymmetrization of
Cs-symmetric achiral biaryls is a particularly efficient strategy
for the construction of axially chiral biaryl derivatives.8 As part
of our continuing efforts to develop copper catalysis,9 we
hypothesized that the application of the asymmetric CuAAC
We chose 1-(2,6-diethynylphenyl)naphthalene (1a) as a
model substrate for the enantioposition-selective copper-
catalyzed azide−alkyne cycloaddition (CuAAC) of achiral
biaryls, and we screened the effects of various chiral ligands
(Scheme 1). The reaction of diyne 1a with benzyl azide (2a)
in the presence of CuOTf·(C6H6)0.5 (20 mol %) and a chiral
phosphine ligand L1−4 (40 mol %) in 1,2-dichloroethane
(1,2-DCE) at 60 °C for 24 h gave the desired monotriazole
3a in 20−67% yield with low enantioselectivity (≤14% ee).
The reaction in the presence of the chiral bidentate
bisoxazoline (Box) ligand L5 also showed low enantioselec-
tivity. We then screened the effects of a series of tridentate
bis(oxazolinyl)pyridine (PyBox) ligands L6−9. Whereas the
isopropyl-substituted PyBox L6 was not effective in
asymmetric induction, the use of a phenyl-substituted PyBox
improved the enantioselectivity toward 3a to 60% ee. The use
of more sterically congested PyBox ligands L8 and L9 did not
enhance the enantioselectivity. Reaction in the presence of the
L-serine-derived PyBox ligand L1010 gave monotriazole 3a in
55% yield and 3% ee, together with a 19% yield of bistriazole
4a. Protection of the hydroxy groups of L10 as tert-
butyl(dimethyl)silyl (TBS) groups in L1110 significantly
improved both the yield and enantioselectivity. The desired
Received: September 19, 2014
© XXXX American Chemical Society
A
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a
a
Scheme 1. Chiral Ligand Screening
Table 1. Condition Optimization
3a
4a
b
c
b
entry Cu (mol %) L11 (mol %) yield (%) ee (%) yield (%)
1
2
3
4
5
6
7
8
20
10
5
40
20
10
11
30
20
20
20
67
65
60
52
65
72
65
64
79
78
70
70
73
84
80
91
16
14
10
19
17
14
11
32
10
10
10
10
10
d
e
f
a
Reaction conditions: 1a (0.125 mmol), 2 (0.125 mmol), CuOTf·
(C6H6)0.5, L11, 1,2-DCE, 60 °C, 24 h, unless otherwise noted.
b
c
Isolated yield. The ee values were determined by HPLC on a chiral
stationary column (DAICEL CHIRALPAK IA). The absolute
configuration of 3a was tentatively determined to be R (see below).
d
e
The reaction was performed at 25 °C. The reaction was performed
f
at 25 °C for 3 h. The reaction was performed at 25 °C for 3 h. 2a
(0.188 mmol, 1.5 equiv) was used.
a
We then examined the substrate scope for dialkynes 1 in the
enantioposition-selective CuAAC under the optimized con-
ditions (Scheme 2). 1-(2,6-Diethynylphenyl)naphthalenes
1b−f bearing electron-donating substituents such as methoxy,
phenoxy, or alkyl groups on the phenyl rings underwent the
enantioposition-selective CuAAC to give the corresponding
chiral monotriazoles 3b−f in 56−66% yield and 78−91% ee.
Substituents such as chloro and nitro on the phenyl rings (1g
and 1h) were also tolerated in the reaction, and chiral
monotriazoles 3g and 3h were obtained in 68% and 54%
yield and 91% and 87% ee, respectively. Dialkynes 1i−l bearing
prochiral biphenyl groups [2,6-diethynyl-2′,4-dimethyl-
biphenyls] also underwent the enantioposition-selective
CuAAC to provide the corresponding monotriazoles 3i−l
bearing axially chiral biphenyl groups in 63−76% yield and
97−99% ee.11
The absolute stereochemistry of chiral monotriazole 3g was
determined to have an R-configuration by means of X-ray
crystallographic analysis (Scheme 3).12 The chiral monotriazole
3g was converted into the asymmetric bistriazole 5 by CuAAC
with 4-methylbenzyl azide. The crystal structure of 5 showed
that the conformation of the axial chirality was retained during
the CuAAC.
Reaction conditions: 1a (0.125 mmol), 2a (0.125 mmol), CuOTf·
(C6H6)0.5 (20 mol %), L1−11 (40 mol %), 1,2-DCE, 60 °C, 24 h.
Isolated yields are reported. The ee values were determined by
HPLC on a chiral stationary column (DAICEL CHIRALPAK IA).
The absolute configuration of 3a was tentatively determined to be R
(see below).
monotriazole 3a was then obtained in 67% yield and 79% ee,
together with a 16% yield of bistriazole 4a.
Having identified the optimal chiral ligand (L11), we
further screened the reaction conditions for the enantioposi-
tion-selective CuAAC (Table 1). When the reaction of
dialkyne 1a with azide 2a was performed in the presence of
a combination of CuOTf·(C6H6)0.5 (10 mol %) and L11
(20 mol %), the chiral mono(triazole) 3a was obtained in 65%
yield with retention of enantioselectivity (78% ee; Table 1,
entry 2). Further reductions in the loading of both copper and
the ligand (5 mol % for Cu and 10 mol % for L11) resulted
in a slight loss of enantioselectivity (entry 3). Changing the
Cu/L11 ratio to 1:1.1 or 1:3 afforded 3a in 70% and 73% ee,
respectively (entries 4 and 5). The reaction at 25 °C improved
both the yield and ee, giving 3a in 72% yield and 84% ee
(entry 6). The reaction time could be reduced to 3 h without
significant loss of yield and enantioselectivity (65% yield and
80% ee, entry 7). The use of 1.5 equiv of benzyl azide (2a)
further improved the ee of 3a to 91% ee with an acceptable
yield (64%), although the yield of 4a increased to 32%
(entry 8).
The resulting axially chiral monotriazoles 3 can be used as
synthetic intermediates. For example, monotriazole 3a was
readily converted into the optically active ethyl derivative 6
without loss of the enantioselectivity by catalytic hydro-
genation in the presence of an amphiphilic resin dispersion of
platinum (ARP-Pt), and the phenylethynyl derivative 7 was
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a
Scheme 2. Substrate Scope for Dialkynes 1
Scheme 3. Determination of the Absolute Structure
Scheme 4. Derivatization of Chiral Mono(triazole) 3a
ASSOCIATED CONTENT
* Supporting Information
■
S
1
Experimental procedures, analytical and spectroscopic data, H
and 13C{1H} NMR and HPLC spectra, and crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: uo@ims.ac.jp.
Notes
a
Reaction conditions: 1 (0.125 mmol), 2a (0.188 mmol), CuOTf·
(C6H6)0.5 (10 mol %), L11 (20 mol %), 1,2-DCE, 25 °C, 3 h. Isolated
yields are reported. The ee values were determined by HPLC on a
chiral stationary column. The absolute configuration of 3g was
determined to be R by X-ray crystallographic analysis, and those of
3a−l were tentatively assigned based on the mechanistic similarity of
the asymmetric induction.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the JST-CREST (Creation of
Innovative Functions of Intelligent Materials on the Basis of
Element Strategy). We appreciate the partial funding from the
JSPS (Grant-in-Aid for Scientific Research on Innovative Area
No. 2105; Grant-in-Aid for Young Scientists (B) Nos.
22750141, 26810099) and from Shionogi & Co., Ltd.
(Shionogi Award in Synthetic Organic Chemistry).
prepared enantioselectively by the Sonogashira reaction
(Scheme 4).
In conclusion, we have developed a highly enantioposition-
selective copper-catalyzed azide−alkyne cycloaddition
(CuAAC) of benzyl azide with dialkynes bearing prochiral
biaryl groups to give 1,2,3-triazoles bearing axially chiral biaryl
groups in up to 76% yield and up to 99% ee. This asymmetric
transformation provides a novel and efficient method for the
construction of axially chiral biaryl derivatives. Further
investigation for the substrate scope and the mechanistic
study will be reported elsewhere.
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■
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D
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