Kinetic Resolution of Cyclic Secondary Azides, Using an Enantioselective Copper-Catalyzed Azide-Alkyne Cycloaddition

Article abstract of DOI:10.1021/acs.orglett.9b01556

An enantioselective copper-catalyzed azide-alkyne cycloaddition (E-CuAAC) is reported by kinetic resolution. Chiral triazoles were isolated in high yield with limiting alkyne (up to 97:3 enantiomeric ratio (er)). A range of substrates were tolerated (>30 examples), and the reaction was scaled to >1 g. The er of a triazole product could be enhanced by recrystallization and the recovered scalemic azide could be racemized and recycled. Recycling the azide allows efficient use of the undesired azide enantiomer.

Full text of DOI:10.1021/acs.orglett.9b01556

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Kinetic Resolution of Cyclic Secondary Azides, Using an
Enantioselective Copper-Catalyzed Azide−Alkyne Cycloaddition
Juliana R. Alexander,† Amy A. Ott,† En-Chih Liu, and Joseph J. Topczewski*
Department of Chemistry, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, United States
S
* Supporting Information
ABSTRACT: An enantioselective copper-catalyzed azide−
alkyne cycloaddition (E-CuAAC) is reported by kinetic
resolution. Chiral triazoles were isolated in high yield with
limiting alkyne (up to 97:3 enantiomeric ratio (er)). A range of
substrates were tolerated (>30 examples), and the reaction was
scaled to >1 g. The er of a triazole product could be enhanced
by recrystallization and the recovered scalemic azide could be
racemized and recycled. Recycling the azide allows efficient use
of the undesired azide enantiomer.
he copper(I) catalyzed azide−alkyne cycloaddition
chiral triazoles, where the new stereocenter is alkyne-
derived.15,16,18,20,21 The original E-CuAAC reported by Fokin
and Finn is the state-of-the-art E-CuAAC kinetic resolution for
α-N-chiral triazole formation, where the new stereocenter is
derived from the azide component (Scheme 1a).14 The authors
T
reaction (CuAAC)1,2 is an important transformation.
Applications for CuAAC penetrate numerous subdisciplines,
including chemical biology, medicinal chemistry, and polymer
chemistry.3−5 This click reaction6 is operationally simple,
functional-group-tolerant, high yielding, and broad in scope.
Furthermore, the triazole ring is gaining recognition as a
protease-resistant peptidomimetic.4 Biologically active α-chiral
triazoles have been reported (Figure 1).7−12 Because of the
Scheme 1. Azide Kinetic Resolution by E-CuAAC
provided only two examples of kinetic resolution with a
selectivity factor (s) of 3.2 and 8, respectively (ca. 70:30 er and
84:16 er, assuming 40% conversion of the azide). Using the
same conditions, the desymmetrization of two bis-azides were
reported to result predominantly in the formation of bis-
triazole (not shown).
Our laboratory became interested in using the unique
properties of allylic azides to establish α-N-chiral centers
though dynamic kinetic resolution.23−25 Recently, we reported
the first E-CuAAC reaction that proceeded by dynamic kinetic
resolution.17 This work prompted an exploration of E-CuAAC
Figure 1. Representative bioactive α-N-chiral triazoles.
prevalence of α-amino acid-derived amides, an enantioselective
CuAAC (E-CuAAC) reaction would be useful for accessing α-
N-chiral triazoles. However, E-CuAAC has proven challenging
in part because (i) both cycloaddition components have linear
geometries, (ii) CuAAC does not require a ligand, and (iii) the
product triazole is a competent CuAAC ligand.13 Therefore, E-
CuAAC must kinetically outcompete the background CuAAC
reaction.
A few reports describe kinetic resolution,14−16 dynamic
kinetic resolution,17 or desymmetrization18−21 for E-CuAAC.22
The majority of successful E-CuAAC reactions generate α-C-
Received: May 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01556
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
by azide kinetic resolution for α-N-chiral triazole synthesis
(Scheme 1b). Reported herein is a successful expansion of the
kinetic resolution by E-CuAAC.
Our investigation began with azide 1a, alkyne 2a, and
commercially available PYBOX ligands (Table 1, entries 1−3).
With the optimized conditions in hand, the scope of the
alkyne coupling partner was investigated (Scheme 2). The
a
Scheme 2. Substrate Scope of Alkyne Coupling Partner
a
Table 1. E-CuAAC Optimization by Kinetic Resolution
b
temperature
yield
(%)
enantiomeric
c
entry
ligand
solvent
(°C)
ratio, er
d
1
2
3
4
5
(R)-L1
(R)-L2
(R)-L3
(R)-L4
(S)-L5
(S)-L5
(S)-L5
(S)-L5
(S)-L5
(S)-L5
(S)-L5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DME
rt
88 (35)
55 (22)
92 (37)
95 (38)
96 (38)
84 (34)
64 (26)
34 (14)
87 (35)
92 (37)
92 (37)
55:45
50:50
22:78
21:79
80:20
84:16
86:14
89:11
86:14
88:12
88:12
d
rt
d
rt
d
rt
d
rt
e
6
0
−15
−20
−15
−15
−15
e f
,
7
8
9
e g
,
e f
,
e f
,
10
e h
PhCF3
PhCF3
,
11
a
Reactions conducted with azide 1a (0.125 mmol) and alkyne 2a
(0.05 mmol) at 0.1 M in varying solvent with (CuOTf)2·PhMe (0.62
μmol) and varying ligand (2.5 μmol). All yield and er values reflect
b
the average of duplicate trials. Yield determined using calibrated GC
with triphenylmethane as an internal standard. The yield is calculated
based on either the alkyne (limiting reagent) or azide (kinetic
c
d
resolution component). Chiral HPLC was used to determine er. rt
e
f
= room temperature. Concentration was 0.125 M. Time = 72 h.
Time = 96 h. Time = 48 h.
g
h
Minimal enantioselectivity was observed with these ligands,
confirming the report from Fokin and Finn.14 A wide variety of
chiral ligands were screened consisting of numerous ligand
classes (see Table 1, entries 4 and 5, as well as the Supporting
Information). Only the aryl-PYBOX ligands provided reason-
able enantioselectivity, with ligand L5 providing the best
selectivity among the ligands screened. The data obtained are
reported here with er instead of the selectivity parameter s
because (i) er is more synthetically meaningful, (ii) er is
directly obtained by chiral HPLC, and (iii) several kinetic
assumptions are made when deriving s, which are likely faulty
for E-CuAAC, based on reported CuAAC kinetics.26,27 One
could convert the reported er to a presumed s by assuming
40% conversion for reactions approaching completion. Low-
ering the reaction temperature resulted in an increase in
enantioselectivity, albeit at the cost of conversion (Table 1,
entries 6−8). The reaction was faster in DME or PhCF3 as the
solvent, relative to CH2Cl2, and the enantioselectivity was
maintained. When using PhCF3 as the solvent, the reaction was
complete within 48 h (entry 11; see the Supporting
Information for additional optimization).
a
Isolated yields are reported. The yield is calculated based on either
the alkyne (limiting reagent) or azide (kinetic resolution component).
Enantiomeric ratio (er) was determined by chiral HPLC. Yield and er
values are the average of duplicate trials. b2.5 mol % (CuOTf)2·PhMe,
10 mol % (S,S)-4-F-Ph-PYBOX, and 0.1 M in PhCF3.
model substrate was isolated in comparable yield and er as
expected (3a). Other aryl alkynes were tolerated with electron-
rich (3b and 3c), electron-neutral (3d and 3e), and electron-
deficient substituents (3f−3h) on the arene. Substituents
positioned meta and ortho on the aryl alkyne provided good
enantioselectivity (3i−3l). Ethyl propiolate (3m), cycloalkyl
alkynes (3n and 3o), and a heterocyclic alkyne (entry 3p) were
tolerated, although several substrates required higher catalyst
loadings or longer reaction times to reach higher conversion.
Note that long reaction times are not uncommon for other E-
CuAAC reactions.15,18,19
The scope of the azide component that could be kinetically
resolved was explored (Scheme 3). Substituents on the
B
DOI: 10.1021/acs.orglett.9b01556
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope of Azide Coupling Partner
Scheme 4. Matched/Mismatched Experiment
Scheme 5. Gram-Scale Reaction and Racemization of
Recovered Azide
The azide could then be recycled and used in a subsequent
reaction. The ability to recycle the recovered azide improves
the overall efficiency of the reaction. The (R)-1a enantiomer
preferentially reacted with the catalyst derived from ligand
(S,S)-L5. This was determined by analyzing scalemic azide
recovered from the reaction. The scalemic azide was compared
to a sample of (S)-1a which was accessed via diazo transfer
from commercially available (S)-3,4-dihydro-2H-chromen-4-
amine. The same analysis was conducted with azide recovered
in the synthesis of triazoles 3j and 3p, which confirmed the
absolute configuration of the product. The configuration of the
other triazole products were assigned based on analogy.
This report describes an expanded scope for both the azide
and alkyne coupling partners in an E-CuAAC. The products of
this kinetic resolution are α-N-chiral triazoles and can be
obtained in up to 97% yield and up to 97:3 er. The reaction
can be conducted to isolate more than 1 g of product and the
excess azide can be recovered, racemized, and recycled. The er
of the product triazoles can be readily improved to 99:1 with a
single recrystallization.
a
Isolated yields are reported. The yield is calculated based on either
the alkyne (limiting reagent) or azide (kinetic resolution component).
Enantiomeric ratio (er) was determined by chiral HPLC. Yield and er
values are the average of duplicate trials.
chromane arene core were tolerated, including methyl (5a)
and halogens (5b−5d). Groups could also be added α to the
oxygen atom (5e). Azido-tetrahydroquinolines with various N-
protecting groups (5f−5h) and the free NH (5i) provided
triazoles in high yield and acceptable enantioselectivity. Azido-
thiochromanes (5j and 5k), azido-dihydrobenzofuran (5l), and
azido-indane (5m and 5n) could also be resolved. Substrates
5m and 5n are noteworthy because the original E-CuAAC
reported by Fokin and Finn described this as a problematic
substrate (s < 1.3).14 Acyclic substrate 5o provided slower
conversion and slightly reduced selectivity.
Chiral alkyne 6 was used to test for matched/mismatched
behavior (Scheme 4). Treating azide rac-1a with chiral alkyne
6 and either enantiomer of ligand L4 resulted in moderate
yield with opposite diastereoselectivity (14:1 and 1:13). This
reversal of diastereoselectivity indicates this reaction is under
catalyst control.
ASSOCIATED CONTENT
* Supporting Information
■
S
The kinetic resolution could be successfully scaled to
provide more than 1 g of triazole product (Scheme 5). The
initial enantioselectivity was 89:11 er, which corresponds to an
s = 13.5. The enantiopurity could be enhanced upon
recrystallization (99:1 er). The excess azide was recovered
(76:24 er) and racemized upon exposure to catalytic AgPF6.28
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01556.
Procedures, characterization, and spectral and chromato-
graphic data (PDF)
C
DOI: 10.1021/acs.orglett.9b01556
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(13) Rodionov, V. O.; Fokin, V. V.; Finn, M. G. Mechanism of the
Ligand-Free CuI-Catalyzed Azide-Alkyne Cycloaddition Reaction.
Angew. Chem., Int. Ed. 2005, 44, 2210−2215.
(14) Meng, J. C.; Fokin, V. V.; Finn, M. G. Kinetic Resolution by
Copper-Catalyzed Azide-Alkyne Cycloaddition. Tetrahedron Lett.
2005, 46, 4543−4546.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jtopczew@umn.edu.
ORCID
(15) Brittain, W. D. G.; Buckley, B. R.; Fossey, J. S. Kinetic
Resolution of Alkyne-Substituted Quaternary Oxindoles via Copper
Catalysed Azide-Alkyne Cycloadditions. Chem. Commun. 2015, 51,
17217−17220.
(16) Brittain, W. D. G.; Chapin, B. M.; Zhai, W.; Lynch, V. M.;
Buckley, B. R.; Anslyn, E. V.; Fossey, J. S. The Bull-James Assembly as
a Chiral Auxiliary and Shift Reagent in Kinetic Resolution of Alkyne
Amines by the CuAAC Reaction. Org. Biomol. Chem. 2016, 14,
10778−10782.
(17) Liu, E.-C.; Topczewski, J. J. Enantioselective Copper Catalyzed
Alkyne-Azide Cycloaddition by Dynamic Kinetic Resolution. J. Am.
Chem. Soc. 2019, 141, 5135−5138.
Amy A. Ott: 0000-0002-2018-3276
Joseph J. Topczewski: 0000-0002-9921-5102
Author Contributions
†These authors contributed equally.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
(18) Zhou, F.; Tan, C.; Tang, J.; Zhang, Y. Y.; Gao, W. M.; Wu, H.
H.; Yu, Y. H.; Zhou, J. Asymmetric Copper(I)-Catalyzed Azide-
Alkyne Cycloaddition to Quaternary Oxindoles. J. Am. Chem. Soc.
2013, 135, 10994−10997.
(19) Page, P.; Martin, J.; Stephenson, G.; Gaumont, A.-C.;
Deschamps, D.; Buttress, J.; Lancelot, M.; Sheldon, A.; Alayrac, C.
An Investigation of the Asymmetric Huisgen ‘Click’ Reaction. Synlett
2013, 24, 2723−2729.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Institute of
General Medical Sciences of the National Institutes of Health,
under Award No. R35GM124718. We also acknowledge NIH
Shared Instrumentation Grant No. S10OD011952.
(20) Zheng, Z.-J.; Song, T.; Xu, L.-W.; Deng, Y.; Xu, Z.; Zhou, W.;
Li, L. Enantioselective Copper-Catalyzed Azide-Alkyne Click Cyclo-
addition to Desymmetrization of Maleimide-Based Bis(Alkynes).
Chem. - Eur. J. 2015, 21, 554−558.
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DOI: 10.1021/acs.orglett.9b01556
Org. Lett. XXXX, XXX, XXX−XXX