Enantioselective Cu(I)-Catalyzed Cycloaddition of Prochiral Diazides with Terminal or 1-Iodoalkynes

Article abstract of DOI:10.1021/acs.orglett.9b04522

We report an unprecedented highly enantioselective desymmetric Cu(I)-catalyzed 1,3-dipolar cycloaddition of diazides with terminal alkynes and 1-iodoalkynes, affording tertiary alcohols bearing a 1,2,3-triazole moiety in high yield and excellent ee value. PYBOX ligands with a C4 shielding group once again show the promising ability to achieve higher enantioselectivity.

Full text of DOI:10.1021/acs.orglett.9b04522

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Letter
Enantioselective Cu(I)-Catalyzed Cycloaddition of Prochiral Diazides
with Terminal or 1‑Iodoalkynes
Cai Wang, Ren-Yi Zhu, Kui Liao, Feng Zhou,* and Jian Zhou*
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ABSTRACT: We report an unprecedented highly enantioselective
desymmetric Cu(I)-catalyzed 1,3-dipolar cycloaddition of diazides
with terminal alkynes and 1-iodoalkynes, affording tertiary alcohols
bearing a 1,2,3-triazole moiety in high yield and excellent ee value.
PYBOX ligands with a C4 shielding group once again show the
promising ability to achieve higher enantioselectivity.
lthough the Cu(I)-catalyzed azide−alkyne cycloaddition
bis(oxazolines) (PYBOX) ligands, substantial side achiral
ditriazole formation occurred. However, axially chiral multi-
stereogenic ligands with a deep chiral cavity, developed by Xu
et al, showed notable capacity of suppressing ditriazole
formation.6e,f Based on these meaningful studies, we recently
reported that PYBOX with a C4 bulky shielding group to
enhance the chiral pocket could effectively inhibit such side
reaction while achieving excellent enantioselectivity in the
desymmetrization of diethynylphosphine oxides (eq 3).6g
In contrast to the progress in accessing chiral alkynes via
CuAAC,6 limited attention was paid to the synthesis of chiral
azides, although Topczewskiet et al. recently made a
breakthrough in achieving a highly enantioslective dynamic
kinetic resolution of racemic azides via CuAAC as well as a
kinetic resolution of secondary azides.7 To our knowledge,
highly enantioselective desymmetrization of prochiral diazides
via CuAAC is unknown. In addition, reported desymmetric
CuAACs are all based on terminal alkynes, the use of 1-
iodoalkynes to access chiral 5-iodo-1,2,3-triazoles is unex-
plored.8 In view of the importance of optically active azides as
building blocks, along with the current interest in their catalytic
enantioselective synthesis,9 we explored the desymmetric
CuAAC of diazides. Here, we report a highly enantioselective
version to construct chiral 1,2-azido-alcohols, using both
terminal alkynes and 1-iodoalkynes (eq 4).
A
(CuAAC), independently discovered by Meldal1 and
Sharpless,2 has found numerous applications in many research
fields,3 its potential for the catalytic enantioselective synthesis
of chiral triazoles, alkynes, and azides remains largely
undeveloped.4 In 2005, Fokin and Finn pioneered asymmetric
CuAAC via the desymmetrization of gem-diazides and the
kinetic resolution of racemic α-azides (eq 1, Scheme 1).5 Later
Scheme 1. Desymmetric CuAAC Reactions
The desymmetrization10 of prochiral azides is a potentially
useful strategy to access multifunctional chiral azides, as shown
by intramolecular desymmetric cyclization of diazides to chiral
Received: December 17, 2019
in 2013, we reported the first highly enantioselective CuAAC
by desymmetrizing prochiral diynes to access quaternary
oxindoles (eq 2).6a The groups of Uozumi6c,d and
Stephenson6h elegantly demonstrated the potential of desym-
metric CuAAC of prochiral diynes to construct axial and planar
chirality, respectively. In these protocols using pyridine-2,6-
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© XXXX American Chemical Society
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5,6-dihydro-1,4-oxazin-2-ones developed by Gu et al.11
However, exploiting intermolecular desymmetrization of
diazides is very challenging because it is difficult to achieve
excellent enantiotopic group discrimination while suppressing
side difunctionalization, due to the linear shape of azide group
without bulky shielding group. This is clearly demonstrated by
the only precedent shown in eq 1.5,12 To examine whether our
recently developed PYBOX ligands bearing a bulky shielding
group offer a flexible solution to develop asymmetric
CuAAC,6a,g we first designed a prochiral diazido alcohol 1
for reaction development. It is worth mentioning that this
protocol constitutes an attractive method for catalytic
enantioselective synthesis of multifunctional tertiary alcohols
bearing both an azido and a triazole moiety.13,14 Notably,
chiral azido alcohols are valuable for the synthesis of
pharmaceutical products.15i,j While there are some catalytic
enantioselective methods to 1,2-azido alcohols,15 most are
based on asymmetric ring opening of epoxides with azides, and
importantly, few allowed access of tertiary alcohols bearing an
azido moiety.15f,6h The reaction of 1a with 1.0 equiv p-
bromophenylacetylene 2a was undertaken to evaluate the
potency of PYBOX with different C4 shielding groups, and
typical results are shown in Table 1.
of ligand L4 with a flexible OBn group obviously improved the
ee of 3a to 70% but afforded a poor 3a/4a of 1:1.7 (entry 4).
However, further increasing the steric hindrance of the
shielding group, by using ligand L5 and L6, led to poorer
results (entries 5 and 6), although both ligands were powerful
in the construction of P-chiralgenic center.6g We next varied
the phenyl group of the ligand to a 4-fluorophenyl group, and
the corresponding ligand L7 afforded slightly improved 77% ee
and a poor 3a/4a ratio of 1/1.4 (entry 7). These results are
generally unsatisfactory, further showing the challenging in
developing asymmetric desymmetrization of prochiral diazides.
To improve the outcome, we examined the solvent effects
(entries 8−10) and found that CH2Cl2 was the solvent of
choice, delivering 3a in 57% yield, 81% ee, and 2.8/1 3a/4a
ratio (entry 9). Screening of copper salts gave no better results
than CuCl (entries 11−13). Finally, increasing the usage of
alkyne 2a from 1.0 to 1.25 equiv with the addition of 10 mol %
PhCO2H, and the reaction performed at −50 °C could afford
chiral 3a in 66% yield with 92% ee, and 2.8/1 3a/4a ratio
(entry 14). For details of the condition optimization, see the
Supporting Information.
Under the above established conditions, we examined the
scope of this protocol, as shown in Table 2. First, diazido
Table 2. Reaction of Azides with Terminal Alkynes
Table 1. Optimization of Reaction Conditions
yield
a
ee of
b
of 3
3
c
entry
1
2
3
(%)
(%)
3/4
1
2
3
4
5
6
7
8
1a: R = C6H5
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
66
62
62
73
69
71
69
66
68
67
69
68
66
72
60
68
69
68
92
85
83
90
91
90
94
94
92
90
92
63
93
95
90
91
79
85
89
2.8:1
2.5:1
2.8:1
2.9:1
2.9:1
2.8:1
2.7:1
2.2:1
2.8:1
2.9:1
2.8:1
2.8:1
2.5:1
2.8:1
2.4:1
2.8:1
2.6:1
2.4:1
3.0:1
yield of
a
ee of
b
a
1b: R = 4-FC6H4
1c: R = 4-ClC6H4
1d: R = 4-CF3C6H4
1e: R = 4-MeC6H4
1f: R = 4-MeOC6H4
1g: R = 3-ClC6H4
1h: R = 3-MeC6H4
1i: R = 3,5-(MeO)2C6H3
1j: R = 2-naphthyl
1k: R = 2-thienyl
1l: R = CH2CH2Ph
1a: R = C6H5
1a: R = C6H5
1a: R = C6H5
1a: R = C6H5
1a: R = C6H5
1a: R = C6H5
1a: R = C6H5
entry
L
CuX
CuCl
solvent
3a (%)
3a (%) 3a/4a
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
L7
L7
L7
L7
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Et2O
CH2Cl2
DCE
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
26
25
15
19
15
24
22
34
57
55
53
28
54
66
57
60
53
70
53
65
77
80
81
81
78
79
80
92
1:1.1
1:1.3
1:1.7
1:1.7
1:2.5
1:1.6
1:1.4
2.4:1
2.8:1
2.7:1
2.2:1
1.6:1
2.7:1
2.8:1
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr
CuI
9
10
11
12
13
14
15
16
17
18
9
10
11
12
13
Cu(OAc)2
CuCl
c
14
a
Determined by 1H NMR using CH2Br2 as an internal standard.
Determined by chiral HPLC analysis. 0.3 mmol scale, 1.25 equiv of
2a, and 10 mol % PhCO2H were used at −50 °C for 96 h.
2g
2a
b
c
d
19
3a
73
c
a
b
Isolated yield. Determined by chiral HPLC. Determined by the
yield of 3/4. 1.0 mmol scale.
d
PYBOX L1, without a C4 shield group, was first examined.
Although it in combination with CuCl achieved excellent
enantioselectivity in the desymmetrization of oxindole-based
diyne (eq 2),6a it was insufficient in this reaction, because
chiral tertiary alcohol 3a was obtained in only 57% ee with 26%
yield as well as a poor ratio of mono- and ditriazole 3a/4a
(entry 1). With an electron-withdrawing group, either a chloro
or a bulkier CF3 substituent, ligands L2 and L3 gave a
diminished 3a/4a ratio (entries 2 and 3). Gratifyingly, the use
alcohols 1 with differently substituted phenyl rings were
studied. A wide range of functional groups at the para position
could be tolerated, no matter the electron-withdrawing F, Cl,
and CF3 group or electron-donating methyl and methoxyl
group, giving the desired products 3b−3f in 62−73% yield
with 83−91% ee and 2.5/1−2.9/1 M/D ratio (entries 2−6).
With meta-substituted phenyl rings, diazido alcohols 1g−i
B
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afforded the corresponding adducts 3g−i in slightly higher ee
values (entries 7−9). 2-Naphthyl- and 2-thienyl-substituted
diazides 1j−1k also furnished products 3j and 3k in 67% yield
and 90% ee, 69% yield, and 92% ee, respectively (entries 10
and 11). However, diazido alcohol 1l with an alkyl group gave
the corresponding product 3l in 68% yield and obviously lower
63% ee (entry 12). Second, terminal alkynes 2b−2e bearing
differently substituted phenyl rings were tried, and the
corresponding chiral products 3m−3p were obtained in 60−
72% yield, 90−95% ee, and 2.4−2.8/1 M/D ratio (entries 13−
16). In addition, the ester- and alkyl-substituted terminal
alkynes 2f and 2g were also workable, affording the
corresponding 3q and 3r in 69% yield, 79% ee with 2.6:1
M/D ratio, and 68% yield, 85% ee with 2.4:1 M/D ratio,
respectively (entries 17 and 18). Finally, the reaction could be
scaled up to 1.0 mmol, giving 3a in 73% yield with a slightly
decreased 89% ee, and a M/D ratio of 3.0:1 (entry 19). The
absolute configuration of 3a was determined to be S by X-ray
diffraction.
Scheme 2. Study of Reaction Mechanism
Encouraged by the above results, we next examined whether
1-iodoalkynes were viable substrates under this condition, as
shown in Table 3. To our delight, a variety of aryl diazido
and 2a catalyzed by L7/CuCl at 0 °C showed that the ee value
of 3a gradually increased with the proceeding of the reaction;
meanwhile, the 3a/4a ratio decreased sharply. This implied
that the formation of the achiral ditriazole 4a was helpful to
increase the enantioselectivity of 3a. In the presence of L7/
CuCl, the consumption of the minor enantiomer (R)-3a,
formed in the initial step of desymmetrization, was faster than
that of the major enantiomer (S)-3a (Scheme 2b). Therefore,
the reaction of 1a and 2a was a favorable scenario to obtain
(S)-3a with high ee value, where k1> k2 and k4 > k3.16
Table 3. Reaction of Azides with 1-Iodoalkynes
ee of
b
yield of
6
a
c
entry
1
5
6
6
(%) (%)
6/7
The thus-obtained chiral tertiary alcohols bearing a triazole
moiety are interesting targets for medicinal chemistry
research.17 In addition, they could be readily elaborated by
using the azido moiety as a synthetical handle. As shown in
Scheme 3, the 1,3-dipolar cycloaddition of 3a (99% ee after
1
2
3
4
5
6
7
8
1a: R = C6H5
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
6f
6g
6h
6i
65
93
92
93
96
93
91
92
74
92
97
82
93
2.4:1
2.8:1
2.6:1
2.2:1
2.7:1
2.8:1
2.5:1
2.6:1
2.7:1
2.8:1
2.7:1
2.5:1
1d: R = 4-CF3C6H4
1e: R = 4-MeC6H4
1f: R = 4-MeOC6H4
1i: R = 3,5-(MeO)2C6H3
1j: R = 2-naphthyl
1k: R = 2-thienyl
1l: R = CH2CH2Ph
1a: R = C6H5
68
65
60
63
67
64
60
65
67
64
Scheme 3. Synthetic Elaboration of 3a
9
10
11
12
1a: R = C6H5
1a: R = C6H5
1a: R = C6H5
6j
6k
6l
63
a
b
c
Isolated yield. Determined by chiral HPLC. Determined by the
yield of 6/7.
alcohols worked well with 1-iodoalkyne 5a to give the desired
chiral 1,2-azido alcohols 6a−6g in reasonable yield with
excellent enantioselectivity (entries 1−7). The reaction of alkyl
substituted 1l with1-iodoalkyne 5a gave a higher 74% ee than
the reaction with terminal alkyne 2a (entry 8). Good to
excellent enantioselectivity was also be achieved in the reaction
of 1a with 1-iodoalkynes 5b−5e bearing different phenyls
(entries 9−12). However, the electron-donating methoxyl
group seemed to be less favorable, resulting in a slightly lower
82% ee (entry 11). Notably, this presents the first
enantioselective Cu(I)-catalyzed 1,3-dipolar cycloaddition of
diazides with 1-iodoalkynes.
recrystallization) with 1-iodoalkyne 5a or TsCN delivered 8 or
9 in 99% and 50% yield, respectively. By a Staudinger reaction,
3a was easily reduced to 1,2-amino alcohol 10 in 99% yield; if
using the combination of CS2 and PPh3, the 1,3-oxazolidine-2-
thione 11 was obtained in 87% yield and 99% ee.
In conclusion, we have developed a highly enantioselective
desymmetric CuAAC of prochiral diazides for the synthesis of
β-azido tertiary alcohols bearing a 1,2,3-triazole moiety. Once
again, PYBOX ligands with a C4 shielding group on the
pyridine showed a promising ability to achieve higher
enantioselectivity. This process also features the first example
of using nonterminal alkynes for catalytic enantioselective
CuAAC. The development of new PYBOX ligands with
various shielding groups to develop enantioselective CuAAC
reactions for the diverse synthesis of chiral alkynes, azides, and
triazoles is ongoing in our laboratory.
The obtained high enantioselectivity was related to the
synergic combination of a desymmetrization and a kinetic
resolution, similar to Uozumi’s result.6d As shown in Scheme
2a, the time-dependent enantioselectivity of the reaction of 1a
C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04522.
■
sı
Experimental procedures, characterization data and
spectra (PDF)
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AsymmetricCopper-Catalyzed Azide-Alkyne Cycloadditions. ACS
Catal. 2016, 6, 3629−3636.
Accession Codes
CCDC 1968889 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
Feng Zhou − Shanghai Key Laboratory of Green Chemistry and
Chemical Process and Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, East
China Normal University, Shanghai 200062, China;
orcid.org/0000-0002-6729-1311; Email: fzhou@
chem.ecnu.edu.cn
Jian Zhou − Shanghai Key Laboratory of Green Chemistry and
Chemical Process and Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, East
China Normal University, Shanghai 200062, China; State Key
Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Shanghai 200032, China; orcid.org/
0000-0003-0679-6735; Email: jzhou@chem.ecnu.edu.cn
Authors
Cai Wang − Shanghai Key Laboratory of Green Chemistry and
Chemical Process, East China Normal University, Shanghai
200062, China
Ren-Yi Zhu − Shanghai Key Laboratory of Green Chemistry and
Chemical Process, East China Normal University, Shanghai
200062, China
Kui Liao − Shanghai Key Laboratory of Green Chemistry and
Chemical Process, East China Normal University, Shanghai
200062, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04522
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from NSFC (21672068, 21725203), the
Ministry of Education (PCSIRT), and the Fundamental
Research Funds for the Central Universities is highly
appreciated.
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