CuAAC macrocyclization: High intramolecular selectivity through the use of copper-tris(triazole) ligand complexes

Article abstract of DOI:10.1021/ol200861f

A range of multivalent heteroaryl ligands, copper sources, and solvent systems have been investigated for use in CuAAC-mediated macrocyclization reactions. These studies have revealed the key factors governing selectivity for macrocyclization versus dimerization and identified a simple but specific set of reaction conditions capable of efficiently generating a diverse series of drug-like macrocycles at modest dilution in up to 95% yield.

Full text of DOI:10.1021/ol200861f

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2754–2757
CuAAC Macrocyclization: High
Intramolecular Selectivity through the Use of
CopperÀTris(triazole) Ligand Complexes
Gagan Chouhan and Keith James*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92014, United States
kjames@scripps.edu
Received April 2, 2011
ABSTRACT
A range of multivalent heteroaryl ligands, copper sources, and solvent systems have been investigated for use in CuAAC-mediated macrocyclization
reactions. These studies have revealed the key factors governing selectivity for macrocyclization versus dimerization and identified a simple but specific
set of reaction conditions capable of efficiently generating a diverse series of drug-like macrocycles at modest dilution in up to 95% yield.
The design of macrocycles with drug-like structures and
properties is an area of growing interest.1 Consequently,
there is a need for efficient macrocyclization methodolo-
gies that are capable of generating drug-like structures at
reasonable scale without having to resort to high dilution
conditions. The copper-catalyzed azide-alkyne cycloaddi-
tion (CuAAC) reaction has emerged as an especially
valuable transformation,2 which generates a useful hetero-
cyclic product (a 1,4-substituted 1,2,3-triazole) and can
be used to close macrocyclic rings.3 However, CuAAC
macrocyclizations are still limited by the requirement for
high dilution conditions in order to avoid intermolecular
reactions, which is nonideal from practical, solvent con-
sumption, and reaction rate perspectives.
copper tube flow reactors,4 both of which aim to exploit a
pseudo-dilution effect associated with heterogeneous
(3) For recent selected examples of peptidic and nonpeptidic macro-
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Chem. Soc. Rev. 2007, 36, 1674–1689 and references therein. (b) Haridas,
V.; Lal, K.; Sharma, Y. K.; Upreti, S. Org. Lett. 2008, 10, 1645–1647. (c)
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Baranov, M. S.; Kazantsev, A. V.; Averin, A. D.; Lukashev, N. V.;
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Dandapani, S.; Duvall, J. R.; Gerard, B.; Kesavan, S.; Lee, M. D.; Liu,
H.; Lowe, J. T.; Marie, J.-C.; Mulrooney, C. A.; Pandya, B. A.; Rowley,
A.; Ryba, T. D.; Suh, B.-C.; Wei, J.; Young, D. W.; Akella, L. B.; Ross,
N. T.; Zhang, Y.-L.; Fass, D. M.; Reis, S. A.; Zhao, W.-N.; Haggarty,
S. J.; Palmer, M.; Foley, M. A. J. Am. Chem. Soc. 2010, 132, 16962–
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Recent approaches to address the issue of concentra-
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r
10.1021/ol200861f
Published on Web 04/28/2011
2011 American Chemical Society

Table 1. Impact of Multivalent Heteroaryl Ligands on Yield and
Product/Dimer Ratio for CuAAC Macrocyclizations
entry
ligand
none
yield (%)
2/dimera
NDb
9.8:1 (7.5:1)c
2.9:1
1
2
2.7
88 (72)c
67
TBTA
3
TTTA
4
DBTA
TDTA
BBTA
57
3.5:1
5
84
6.5:1
6
82
6.0:1
NDd
7
(Bim)3
BBTP
BTDE
BBMM
BTMM
PMDETA
23
8
40
2.6:1
9
57
2.9:1
10
11
12
53
1.7:1e
3.3:1e
1.2:1e
65
43
a Product-to-dimer ratio as determined by HPLC-MS analysis.
b Reaction yielded primarily oligomers, plus 18% unreacted 1. c Using
μW at 110 °C for 1 h, 14% unreacted 1. d Reaction yielded primarily
oligomers, plus 49% unreacted 1. e Using 5 mol % of Cu(CH3CN)4BF4.
Figure 1. Ligands examined in the CuAAC macrocyclization.
sources and solvent systems, with the aim of finding an
optimum set of conditions for effecting CuAAC-mediated
macrocyclizations.8a We now report the outcome of these
studies, which have revealed the key factors governing
macrocyclization versus dimerization, as well as identify-
ing a very specific but simple set of conditions capable of
efficiently generating a diverse series of drug-like macro-
cycles at modest dilution in useful yields.
Azido-alkyne 1, prepared in two steps from ephedrine,
had proven to be a useful substrate in an earlier study of
CuAAC-mediated macrocyclizations in flow4 and so was
used in a screen of homogeneous reaction conditions using
HPLC-MS analysis to determine product-to-dimer ratios
and yields (where the area under the dimer peak was
assumed to include both cyclic and acyclic dimers). An
initial survey of multivalent ligands was undertaken using
a standardized protocol of solvent, copper source, reaction
time, and temperature. Results are summarized in Table 1
(see Supporting Information for a comprehensive sum-
mary of conditions explored). The structures of the ligands
used are shown in Figure 1.
reaction conditions.5 However, these methods still have
limitations because they require either preparation and use
of large amounts of catalyst resin or specialized flow
equipment. Ideally, a methodology is required which uses
small quantities of commercially available catalyst and
which consistently produces a high ratio of intra- versus
intermolecular reaction at practical concentrations (e.g.,
0.02 M or above). This would facilitate both library
production and scale-up.
In a recent study of CuAAC macrocyclizations under
flow, using a copper tube reactor,4 we noted a beneficial
effectof tris(triazolyl) ligandssuchastris((1-tert-butyl-1H-
1,2,3-triazolyl)methyl)amine (TTTA) and tris((1-benzyl-
1H-1,2,3-triazolyl)methyl)amine (TBTA) on the macro-
cycle-to-dimer ratios observed in these reactions. While the
effect of these ligands on the rate of intermolecular
CuAAC reactions has been highlighted previously,6 and
there have been sporadic reports on their use in
macrocyclizations,7 no systematic study of their effective-
ness in facilitating CuAAC macrocyclizations has been
reported. We have therefore investigated a range of multi-
valent heteroaryl ligands, together with a variety of copper
Reaction in the absence of ligand yielded primarily
oligomeric products (Table 1, entry 1), whereas addition
of the tris(triazole) ligand TBTA produced a high product-
to-dimer ratio and a high isolated yield of macrocycle
(Table 1, entry 2), superior to those achieved with the
more hindered ligands TTTA6a and DBTA or flexible
alkyl-chain-substituted TDTA (Table 1, entries 3À5).8b
(4) Bogdan, A. R.; James, K. Chem.;Eur. J. 2010, 16, 14506–14512.
(5) Gonthier, E.; Breinbrauer, E. R. Mol. Diversity 2005, 9, 51–62.
(6) (a) Hein, J. E.; Krasnova, L. E.; Iwasaki, M.; Fokin, V. V. Org.
Synth. 2011, 88, 238–246. (b) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev.
2010, 39, 1302–1315. (c) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.;
Fokin, V. V. Org. Lett. 2004, 6, 2853–2855.
(8) (a) For review on various copper complexes and ligands used in
ꢀ
CuAAC reactions, see: Dıez-Gonzalez, S. Catal. Sci. Technol. 2011, DOI:
(7) Beierle, J. M.; Horne, W. S.; van Maarseveen, J. H.; Waser, B.;
Reubi, J. C.; Ghadiri, M. G. Angew. Chem., Int. Ed. 2009, 48, 4725–4729.
10.1039/c0cy00064g. (b) For review on various tripodal ligands, see: Blackman,
A. G. Polyhedron 2005, 24, 1–39.
Org. Lett., Vol. 13, No. 10, 2011
2755

Bis((1-benzyl-1H-1,2,3-triazolyl)methyl)amine (BBTA),9
a bidentate ligand, also achieved efficient macrocycliza-
tion, indicating that the third triazole moiety in the ligand
probably does not play a crucial role in the macrocycliza-
tion mechanism (Table 1, entry 6). In contrast, ligands
exhibiting stronger coordination to copper, such as the
benzimidazole-based system (Bim)3,9 showed low conver-
sion, low macrocycle yield, and primarily oligomers
(Table 1, entry 7). A possible explanation for this observa-
tion is that the ability of the ligand to enable free coordina-
tion sites on the copper ion, via decomplexation of the
weakly coordinated triazoles, might be a requirement for
efficient macrocyclization.
Table 2. Impact of Copper Source and Solvent on Yield and
Product/Dimer Ratio for CuAAC Macrocyclizationsa
entry
solvent
Cu source
yield (%)
2/dimera
To probe the role of the amine moiety in these ligands,
the carba analogue of BBTA, bis(1-benzyl-1H-1,2,3-
triazolyl)propane (BBTP), was evaluated. This resulted
in a modest yield and product-to-dimer ratio (Table 1,
entry 8), suggesting that the amine substituent in TBTA
and BBTA does play a role, perhaps acting as a base to
facilitate generation of a copper acetylide species. The
monodentate ligand BTDE produced a modest yield and
product-to-dimer ratio, suggesting that a ligand with at
least two triazole moieties is required for optimal macro-
cyclization efficiency (Table 1, entry 9). Finally, either
replacement of a triazole moiety with an amine (Table 1,
entries 10 and 11) or use of a polydentate amine ligand
(Table 1, entry 12) resulted in lower macrocycle-to-dimer
ratios.
To further explore the importance of free coordination
sites on the copper ion, we next examined the role of
solvent and counterion. Halide counterions produced only
modest product-to-dimer ratios and yields (Table 2, entries
1À3), consistent with coordination of the copper ion limit-
ing macrocyclization efficiency. In contrast, use of a non-
coordinating tetrafluoroborate counterion (Table 2, entry 4)
resulted in a high product-to-dimer ratio and yield,
comparable to the findings with the hexafluorophosphate
counterion (Table 1, entry 2). Use of solvents likely to
coordinate copper also reduced the product-to-dimer
ratio, with acetonitrile having the most dramatic effect
(Table 2, entries 5À7).
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
CuI
41
51
53
82
77
81
<5
93
78
1.2:1
1.3:1
1.9:1
11.7:1
4.9:1
6.4:1
ND
CuBr
CuCl
Cu(CH3CN)4BF4
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
dioxane
CH3CN
CH2Cl2
CH2Cl2
b
c
12.3:1
9.8:1
a Product-to-dimer ratio as determined byHPLC-MS. b With 5 mol %
of Cu(CH3CN)4BF4. c With 0.04 M substrate concentration, 5 mol % of
Cu(CH3CN)4BF4.
Our results are consistent with several recent reports
examining the sequence of steps in the CuAAC reaction
mechanism and the nature of ligands used toaccelerate this
reaction. Thus, interaction of the noncoordinating copper
salts with TBTA would be expected to yield a cop-
perÀligand complex that can readily release a free coordi-
nation site for reaction with the azido-alkyne substrate. A
recently reported X-ray structure of a CuBF4[CH3CN]4/
TBTA complex is essentially a symmetrical dimer of such a
species, where the free coordination site has been occupied
by a lone pair from the N-3 position of a triazole from a
second TBTA molecule.11 There is strong evidence from
IR studies of intermolecular CuAAC reactions indicating
thatthe first interaction withcopper isvia the alkyne rather
than the azide, and so we would expect this to be the case
with our azido-alkyne substrates.12 Further decomplexa-
tion of the copper by one of the triazole ligands,13 followed
by recomplexation with either the pendant azido group or
an azide from a second molecule, would then go on to yield
the macrocycle or a dimeric product, respectively. It seems
that, in comparison to the other ligands explored, the steric
environment of the copper in the TBTA/tetrafluorobo-
rate/alkyne complex preferentially favors reaction with
the pendant azide rather than an azide from a second
molecule.
Finally, having identified an optimal set of choices for
ligand, copper source, and solvent, we examined copper
and substrate concentrations. Increasing copper concen-
tration slightly, to achieve a 1:1 ratio of copper to ligand,
resulted in a slightly higher product-to-dimer ratio and an
excellent yield (Table 2, entry 8). Using these conditions, it
was also possible to increase substrate concentration to
0.04 M and still achieve a very good yield of macrocycle
(Table 2, entry 9). Our optimized conditions compare
favorably to several recently reported resin-supported
copper catalysts (for results with various resin-supported
copper catalyst, see Supporting Information).3b,10
(11) Donnelly, P. S.; Zanatta, S. D.; Zammit, S. C.; White, J. M.;
Williams, S. J. Chem. Commun. 2008, 2459–2461.
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complexes, see: (a) Eckenoff, W. T.; Pintauer, T. Inorg. Chem. 2010, 49,
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2756
Org. Lett., Vol. 13, No. 10, 2011

operationally very simple, and products could be iso-
lated following solvent evaporation and column
chromatography.
As illustrated in Figure 2, yields of macrocycles were
generally high, with the norephedrine-derived system 3
being produced in 95% yield. Several systems were pro-
duced in less than 50% yield, which we believe results either
from the stereochemical influence of substituent groups14
(e.g., comparing yield of pseudoephedrine-derived macro-
cycle 4 versus the diastereomeric ephedrine-derived
system 2) or from the presence of a trans-ring junction
(e.g., comparing the trans-aminoindanol-derived system 11
versus the cis-isomer 12). Macrocycles of up to 24-mem-
bered rings were prepared in very good yield (Figure 2,
example 13), and on the basis of related studies, even larger
rings are likely to be accessible. The macrocyclization
conditions were compatible with the inclusion of multiple
amino acid fragments, without any evidence of epimeriza-
tion (examples 7À10 and 13), although isolated yields were
slightly lower in some cases because of challenges with
solubility.
In conclusion, we have examined the parameters gov-
erning efficient macrocyclization via a CuAAC reaction
and identified a simple set of optimized conditions which
allow construction of novel macrocycles in up to 95% yield
at only a modest level of dilution. We have exemplified the
scope of this macrocyclization with a series of novel
macrocycles which incorporate features typically found
in biologically active agents. We expect this methodology
to find use in the growing area of macrocycle-based drug
design. We are currently investigating the use of this
protocol for the macrocyclization of substrates supported
on solid phase and will report our results in due course.
Figure 2. Substrate scope for CuAAC macrocyclization. Ring
size is denoted by figure within the macrocyclic ring. Numbers
in parentheses correspond to isolated yields after column chro-
matography. Macrocyclizations were conducted in CH2Cl2
at 55 °C, 0.02 M substrate concentration for 20 h, using TBTA
(5 mol %) and Cu(CH3CN)4BF4 (5 mol %).
Acknowledgment. This work was funded by Pfizer
Worldwide Research, where K.J. is employed. We are
grateful to Andrew Bogdan (The Scripps Research
Institute) for advice and assistance with HPLC-MS studies,
and Stanislav Presolski and M.G. Finn (The Scripps Re-
search Institute) for advice and gifts of ligands.
Having developed an optimized macrocyclization
protocol, we used this procedure to synthesize a small
library of novel, drug-like macrocycles in mostly good
to excellent yield, as illustrated in Figure 2. Macro-
cyclization substrates were available via short
synthetic sequences from readily available homo-
chiral starting materials (synthetic routes and full
experimental procedures are available in Supporting
Information). The macrocyclization procedure proved
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Lee, D.; Sello, J. K.; Schreiber, S. L. J. Am. Chem. Soc. 1999, 121,
10648–10649.
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