Enantioselective Copper Catalyzed Alkyne-Azide Cycloaddition by Dynamic Kinetic Resolution

Article abstract of DOI:10.1021/jacs.9b01091

The copper(I) catalyzed alkyne-azide cycloaddition (CuAAC), a click reaction, is one of the most powerful catalytic reactions developed during the last two decades. Conducting CuAAC enantioselectively would add a third dimension to this reaction and would

Full text of DOI:10.1021/jacs.9b01091

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Communication
Enantioselective Copper Catalyzed Alkyne-Azide
Cycloaddition by Dynamic Kinetic Resolution
En-Chih Liu, and Joseph J. Topczewski
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b01091 • Publication Date (Web): 19 Mar 2019
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Enantioselective Copper Catalyzed Alkyne-Azide Cycloaddition by
Dynamic Kinetic Resolution
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En-Chih Liu, Joseph J. Topczewski*
Department of Chemistry, University of Minnesota Twin Cities, Minneapolis MN 55455
Supporting Information Placeholder
able to sense remote stereochemical information. Furthermore,
ABSTRACT: The copper(I) catalyzed alkyne-azide cycloaddition
even in the ideal sense, kinetic resolution proceeds with a
maximum theoretical yield of 50%.16 Others have attempted to use
bis-alkynes and/or bis-azides for E-CuAAC by desymmetrization
(Figure 1c).15,17–24 Reactions based on this approach are likewise
limited in scope and occur with modest chemoselectivity due to the
competitive formation of bis-triazoles.
(CuAAC), a click reaction, is one of the most powerful catalytic
reactions developed during the last two decades. Conducting
CuAAC enantioselectively would add a third dimension to this
reaction and would enable the direct synthesis of α-chiral triazoles.
Doing so is demanding because the two precursors have linear
geometries, and the triazole product is a flat heterocycle. Designing
a chiral catalyst is further complicated by the complex mechanism
of CuAAC. We report an enantioselective CuAAC (E-CuAAC),
enabled by dynamic kinetic resolution (DKR). The E-CuAAC is
high yielding and affords up to 99:1 er. The E-CuAAC can directly
generate α-chiral triazoles in a complex molecular environment.
Figure 1. CuAAC Reaction and Approaches to E-CuAAC
a
CuAAC Reaction
N
N
[Cu]
N
N
R
+
R
N
R'
N
R'
b Kinetic Resolution
Ph
The copper(I) catalyzed alkyne-azide cycloaddition (CuAAC)
has transformed many aspects of modern chemical synthesis since
it was first reported contemporaneously by Meldal, Sharpless, and
coworkers.1,2 The CuAAC reaction is robust, mild, high yielding,
and chemo-orthogonal.3–5 Applications for CuAAC have
permeated and transformed numerous fields including chemical
biology, material science, polymer chemistry, and medicinal
chemistry.5 Triazoles, formed by CuAAC, are now common
peptidomimetics and pharmaceutical building blocks.6 With the
tremendous utility of CuAAC, a versatile catalyst that could impart
enantioselectivity to the process would likely find numerous
applications, especially as examples of α-chiral triazoles are
emerging in active biological agents.7–11
N
Ph
N
N3
N3
N3
N
[Cu], Ligand
+
+
Ph
CH3
Ph
CH3
Ph
CH3
Ph
CH3
50% maximum theoretical yield
Limited scope
32% conversion, s = 6
c
Desymmetrization
N
N
N
BnN3
R
R
R
Bn
Bn
[Cu], Ligand
+
R'
R'
N
Bn
R'
N
N
N
N
N
competitive bis-triazole formation
d
Dynamic Kinetic Resolution
N
R'
R'
R'
N
R"
Facilitating an E-CuAAC reaction presents several fundamental
challenges. First, CuAAC uses an alkyne and an azide and forms a
triazole (Figure 1a). Alkynes and azides have a linear geometry and
the resulting triazole is a sp2 hybridized heterocycle. No new
stereogenic centers are formed in most Cu-AAC reactions.
Therefore, E-CuAAC requires the transmission of stereochemical
information beyond the forming triazole. Second, an E-CuAAC
reaction must outcompete the facile background CuAAC
reaction.12 This is non-trivial because the CuAAC reaction is an
extremely efficient process that proceeds by a complex and
dynamic reaction mechanism.13,14 Herein, we report that E-CuAAC
can be enabled by dynamic kinetic resolution (>95% yield and up
to 99:1 er).
[3,3]
N3
N3
N
R"
[Cu], Ligand
*
R
R
R
R
R
R
95% yield, 99:1 er
Our group has an interest in using dynamic kinetic resolution
(DKR)25–29 to enable enantioselective synthetic methods. A DKR
couples a pathway for racemization to an enantioselective
functionalization. Methods based on DKR use racemic starting
material and can result in both high yield and high
enantioselectivity. Our lab envisioned using allylic azides in DKR
because allylic azides spontaneously rearrange.30 The
rearrangement complicates using these intermediates but, a few
inspirational reports described successfully trapping allylic
azides.31–35 We hypothesized that allylic azides could be used to
enable an E-CuAAC reaction (Figure 1d). Herein, we report a DKR
enabled E-CuAAC that proceeds in yields exceeding 95%, with er
up to 99:1, which is compatible with a complex molecular
environment.
Fokin and Finn originally reported attempts at an E-CuAAC
through a kinetic resolution (Figure 1b).15 The results were
significantly limited in scope and proceeded with only a modest
selectivity (selectivity factor s up to 6). These early results implied
a twofold problem with E-CuAAC. First, the background CuAAC,
in the absence of a chiral ligand, is fast and must be outcompeted
or suppressed. Second, the catalyst’s ligand environment must be
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This study began with allylic azide 1a and tert-butyl propiolate
scaffold may promote dimerization, which is consistent with
crystallographic data on Cu(I)-PYBOX complexes.38,39
1
2
3
4
5
6
7
8
(2a, Table 1). We observed minimal enantioselectivity with copper
iodide (entry 1). Changing to a cationic copper(I) precatalyst had a
notable impact on both the rate and enantioselectivity of the
reaction (entry 2). A collection of ligands were screened that
included bidentate and tridentate phosphorous and nitrogen ligands
(entries 2 – 9 and Supporting Information). Based on these initial
results, aryl-PYBOX ligands appeared to be particularly effective
(entry 4 and 5). We hypothesized that increasing the ligand loading
would slow the background click reaction by saturating the copper
center. An increase in ligand loading enhanced the observed er to
88:12 (entry 10). Increasing the temperature had a notable positive
effect (entry 11), which resulted in a quantitative yield (>98%) and
high enantioselectivity (>99:1 er). The increased temperature likely
increases the relative rate of racemization via a sigmatropic
pathway.36 Other copper precatalysts were not as effective (entries
12 and 13) and the conditions outlined in entry 11 were selected as
being optimal.
Table 2. Scope of DKR E-CuAAC with Respect to Alkyne 2
1.25 mol%
N
PMP
PMP
PMP
N
(CuOTf)2PhMe
L4
N3
[3,3]
N3
R
N
R
5 mol%
+
*
DME, 20-48 h
40 °C
(±)-1a
2
3
(1 equiv)
(1.2 equiv)
N
9
N
PMP N
N
PMP
PMP N
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
PMP
N
CO2tBu
N
CH3
3a
95%, >99:1 er
N
3b
3c
89%, 93:7 er
91%, 93:7 er
N
N
PMP N
N
PMP N
N
PMP N
N
Ph
tBu
F
3d
3e
3f
96%, 92: 8 er
N
85%, 96:4 er
N
90%, 93:7 er
Table 1. Optimization of E-CuAAC by DKRa
CO2tBu
N
PMP N
N
PMP N
N
PMP N
N
Br
2a
(1.2 equiv)
N
PMP
N
CF3
PMP
PMP
Cl
2.5 mol% [Cu]
X mol% Ligand
CO2tBu
N
N3
N3
[3,3]
*
3g
3h
3i
DME, 24 h, temp
91%, 92:8 er
86%, 95:5 er
92%, 90:10 er
N
(±)-1a
3a
(1.0 equiv)
N
N
PMP N
N
PMP N
N
CH3
CH3
CH3
PMP N
N
Entry
[Cu] source
Ligand
Temp (˚C)
Yield (%)
80
er
NBoc
Cl
1
CuI
L1 (2.5%)
L1 (2.5%)
L2 (2.5%)
L3 (2.5%)
L4 (2.5%)
L5 (2.5%)
L6 (2.5%)
L7 (2.5%)
L8 (2.5%)
L4 (5.0%)
L4 (5.0%)
L4 (5.0%)
L4 (5.0%)
rt
57:43
60:40
53:47
86:14
76:24
51:49
52:48
52:48
52:48
88:12
99:1
3j
3k
3l
96%, 93:7 er
80%, 95:5 er
71%, 92:8 er
2
(CuOTf)2PhMe
(CuOTf)2PhMe
(CuOTf)2PhMe
(CuOTf)2PhMe
(CuOTf)2PhMe
(CuOTf)2PhMe
(CuOTf)2PhMe
(CuOTf)2PhMe
(CuOTf)2PhMe
(CuOTf)2PhMe
Cu(MeCN)4PF6
Cu(MeCN)4BF4
rt
>98
95
3
rt
N
N
N
OTBS
O
PMP N
N
PMP N
N
PMP N
N
4
rt
93
CH3
5
rt
80
3m
3n
3o
80%, 97:3 er
95%, 94:6 er
96%, 92:8 er
6
rt
58
Yields are reported for isolated and purified products. Enantiomeric ratio was
determined by chiral HPLC. Yield and er values reflect the average of duplicate trials.
See Supporting Information for details.
7
rt
87
8
rt
65
9
rt
>98
83
The scope of our E-CuAAC reaction was investigated with
respect to the alkyne (Table 2). Using the azide as the limiting
reagent, the model substrate 3a was isolated in 95% yield and >99:1
er. The scope of the alkyne was quite broad. Electron rich and
electron deficient aryl alkynes could participate in the E-CuAAC
(3b – 3i). A crystal of product 3h was suitable for diffraction
analysis, which unambiguously assigned the absolute configuration
of the product generated from the (S,S)-PYBOX/Cu catalyst as
having the (R)-configuration (see Supporting Information). The
configuration of the other products were assigned based on analogy
to product 3h. An ortho-substituted arene provided an acceptable
yield in high er (3j). An alkyne containing an aliphatic (3j),
heterocycle (3k), protected alcohol (3l), ketone (3m), and
cyclopropyl (3o) group could all be used in E-CuAAC.
10
11
12
13
rt
40
40
40
>98
73
90:10
91:9
82
Reactions conducted with allylic azide 1a (0.1 mmol), alkyne 2a (0.12 mmol), in
dimethoxyethane (0.2 M), with 2.5 mol% [Cu] and either 2.5 mol% or 5 mol%
ligand. Yields based on 1H NMR analysis using 1,3,5-trimethoxybenzene as an
internal standard. Chiral HPLC was used to determine er. All yield and er values
reflect the average of duplicate trials. See Supporting Information for full details.
O
O
O
Bn
O
O
O
N
N
N
N
N
N
N
Bn
Bn
Bn
L6
R
R
L5
i
L1
R = Pr
O
The azide component was varied (Table 3). The cyclohexyl-ring
could be contracted (3p), expanded (3q), or modified (3r – 3x). In
all of these cases, both the yield and enantioselectivity remained
acceptably high. The 2-aryl group is not required (3y and 3z) and
an acyclic substrate was tolerated (3aa).
F3C
t
L2
L3
L4
R = Bu
PPh2
O
O
R = Ph
O
N
R = 4-Cl-Ph
PPh2
N
tBu
L7
L8
O
To further demonstrate the features of this E-CuAAC reaction,
we conducted the reaction with (R)-1-phenyl-2-propyn-1-ol (4,
Scheme 1). Both enantiomers of the ligand were used to test for
We conducted a non-linear experiment by determining the effect
of varying the ligand’s enantiopurity on the enantiomeric excess of
the product.37 It has been reported that E-CuAAC by
desymmetrization can proceed with a posative19,24 or negative17
non-linear effect. A negative non-linear effect was observed for this
E-CuAAC reaction (see Supporting Information). The PYBOX
matched/mismatched
behavior
related
to
double
diastereoselectivity. Changing the ligand’s stereochemistry
reversed the diastereoselectivity (products 5a and 5b), indicating a
robust catalyst.
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Supporting Information
1
2
3
4
5
6
7
8
The Supporting Information is available free of charge on the ACS
Publications website. Experimental procedures and data.
Table 4. DKR E-CuAAC in a Complex Molecular Setting
1.25 mol%
Table 3. Scope of DKR E-CuAAC with Respect to Azide 1
1.25 mol%
N
PMP
PMP
N
(CuOTf)2PhMe
L4
complex
fragment
N
R
R
R
N
(CuOTf)2PhMe
L4
N3
N
complex
fragment
5 mol%
DME, 24 h, 40 °C
+
N3
[3,3]
N3
N
R"
R"
5 mol%
*
+
*
R'
DME, 24 h, 40 °C
R'
R'
R'
R'
R'
(±)-1a
2
(1 equiv)
(1.2 equiv)
CH3
6
(±)-1
2
3
(1 equiv)
(1.2 equiv)
PMP
O
9
N
N
CH3
CH3
N
N
N
N
CO2tBu
Ph
PMP
PMP
N
O
N
N
N
O
CO2tBu
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
*
N
N
AcO
H3C
CO2tBu
(H3C)2HC
H3C
O
OAc
H
CH3
3p
3q
3r
96%, 95:5 er
79%, 94:6 er
99%, 90:10 er
O
6a
92%, 97:3 dr
O
O
CF3
N
N
N
PMP
H
6b
*
99%, 90:10 dr
PMP
N
N
N
N
Ph
N
N
PMP N
N
N
N
H
H
CO2tBu
CO2tBu
Ph
OAc
*
N
N
N
N
O
AcO
AcO
N
O
*
6c
99%, 86:14 dr
H3C CH3
OAc
3s
3t
3u
85%, 96:4 er
96%, 94:6 er
85%, 96:4 er
CF3
PMP
6d
99%, 93:7 dr
*
N
N
N
Ph
Ph
O
N
N
N
N
N
N
N
PMP
CH3
Ph
CO2Et
CO2tBu
N
N
O
N
OBn
O
N
N
N
O
3xa
O
3v
3w
82%, 93:7 er
85%, 96:4 er
90%, 85:15 er
O
PMP
N
H3C
H3C
O
O
O
OH
*
N
N
N
OCH3
OCH3
I
Ph
N
N
N
N
N
CO2tBu
CO2tBu
CO2tBu
CH3
OCH3
N
6e
6f
98%, 93:7 er
99%, 97:3 dr
CH3 CH3
3za
3aa
92%, 86:14 er
3y
96%, 90:10 er
89%, 87:13 er
Yields are reported for isolated and purified products. Diastereomeric ratio or
enantiomeric ratio was determined by HPLC or 1H NMR. Yield, er, and dr values
reflect the average of duplicate trials. Substrate 6f was prepared using (R,R)-4-Cl-Ph-
PYBOX ligand (ent-L4). See Supporting Information for full details.
93:7 E:Z
Yields are reported for isolated and purified products. Enantiomeric ratio was
determined by chiral HPLC. Yield and er values reflect the average of duplicate trials.
aReaction used alkyne as limiting reagent. See Supporting Information for details.
AUTHOR INFORMATION
Scheme 1. Test for Matched/Mismatched Behavior
1.25 mol%
N
PMP
N
Corresponding Author
OH
(CuOTf)2PhMe
L4
N
5 mol%
*
*jtopczew@umn.edu
Ph
*
PMP
DME, 24 h, 40 °C
OH
1
N3
5a 95%, 95:5 dr
Notes
+
Ph
1.25 mol%
(CuOTf)2PhMe
5 mol% ent-
*
N
PMP
N
OH
The authors declare no competing financial interests.
(±)-1a
4
N
(1.0 equiv)
(1.2 equiv)
L4
*
*
Ph
DME, 24 h, 40 °C
ACKNOWLEDGMENT
5b 92%, 6:94 dr
We acknowledge the University of Minnesota and The American
Chemical Society’s Petroleum Research Fund (PRF #56505-
DNI1) for financial support. This research was supported by the
National Institute of General Medical Sciences of the National
Institutes of Health under Award Number R35GM124718.
Several additional examples demonstrate that the E-CuAAC is
viable in a complex molecular setting (Table 4). Derivatives of
vitamin E (6a), gibberellic acid (6b), esterone (6c), glucose (6d),
mycophenolate mofetil (6e), and moexipril (6f) could all be
successfully “clicked” by E-CuAAC in near perfect yield and
excellent selectivity. This illustrates that E-CuAAC is capable of
generating α-chiral triazoles in the presence of densely
functionalized molecules with robust stereochemical fidelity.
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