Accessing skeletal diversity using catalyst control: Formation of n and n + 1 macrocyclic triazole rings

Article abstract of DOI:10.1021/ol900562u

A regioselective intramolecular Huisgen cycloaddition was performed on various azido alkyne substrates giving rise to macrocyclic triazole rings. Using catalyst control, a common intermediate has been converted to two structurally unique macrocycles with

Full text of DOI:10.1021/ol900562u

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2257-2260
Accessing Skeletal Diversity Using
Catalyst Control: Formation of n and
n + 1 Macrocyclic Triazole Rings
Ann Rowley Kelly, Jingqiang Wei, Sarathy Kesavan, Jean-Charles Marie´,
Nicole Windmon, Damian W. Young, and Lisa A. Marcaurelle*
Chemical Biology Platform, Broad Institute of MIT and HarVard, 7 Cambridge Center,
Cambridge, Massachusetts 02142
lisa@broad.mit.edu
Received March 17, 2009
ABSTRACT
A regioselective intramolecular Huisgen cycloaddition was performed on various azido alkyne substrates giving rise to macrocyclic triazole
rings. Using catalyst control, a common intermediate has been converted to two structurally unique macrocycles with either a 1,5- or a
1,4-triazole resulting in an n or n + 1 ring size. This is the first example of an intramolecular ruthenium-catalyzed Huisgen cycloaddition.
The preparation and screening of small molecules constitutes
a powerful strategy for the discovery of biological probes
and pharmaceutical agents.1-3 Diversity of structure within
a particular compound collection is key to the discovery of
hits over a wide range of biological areas. It has recently
been shown that even large screening collections that lack
diversity are insufficient to provide lead compounds against
a range of antibacterial targets.4 A current strategy for
achieving diverse compound collections through diversity-
oriented synthesis (DOS) focuses on the use of functional
group pairing.5,6 By using scaffolds with multiple functional
group “handles” and joining them in a pairwise, intramo-
lecular, and chemoselective fashion, both skeletal diversity
and rigidity are achieved. A complementary approach for
generating structural diversity is known as “reagent-based”
diversification.7 This strategy involves the preparation of a
singular scaffold that, when subjected to different reaction
conditions, selectively yields different products.1,8 To further
develop this strategy, robust methodologies that allow for
reagent-based differentiation must be developed.
The Huisgen 1,3-dipolar cycloaddition is a widely utilized
reaction in DOS.9,10 This “click” reaction results from the
ligation of azides and alkynes to give a triazole moiety. This
reaction has been shown to be effective in the formation of
a variety of macrocyclic rings.11 A key point of interest for
us was the regioselectivity of the cycloaddition. We surmised
that a reagent-based diversity approach could be applied to
generate both possible regioisomers from a common substrate
as shown in Scheme 1. While many advances have been
made in the formation of 1,4-triazoles using copper(I)
catalysis,9 the formation of 1,5-triazole rings using ruthe-
nium(II) catalysis has only recently been reported and has
(1) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43,
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Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127, 15998
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48
10.1021/ol900562u CCC: $40.75
Published on Web 04/30/2009
 2009 American Chemical Society

tion. First, we examined the ruthenium(II)-catalyzed forma-
tion of the 1,5-triazole. When Cp*RuCl(COD) (Table 1,
Scheme 1. Use of Huisgen Cycloaddition for Divergent Pairing
Table 1. Optimization of Ru-Catalyzed Cycloaddition tTo
Yield 4aa
mol
%
T
conc
monomer/
dimer
entry
catalyst
(°C) (M)
% convb
been demonstrated in an intermolecular fashion and in a
much more limited scope.10,12
1
2
3
4
5
6
7
8
Cp*RuCl(COD) 15
Cp*RuCl(COD) 15
Cp*RuCl(PPh3) 15
25 0.002
65 0.002 dec
80 0.002 60
40 0.002 100
80 0.002 100
60 0.010 100
60 0.005 100
80 0.002 100 (58)c
0
With this in mind, we sought to expand the existing
Huisgen methodology to make macrocyclic triazole rings
regioselectively. This method is ideally suited to the prepara-
tion of small-molecule libraries because one compound can
be converted into two structurally unique macrocycles that
have an n or n + 1 ring size (Scheme 1). Access to
macrocyclic triazoles that are different yet structurally related
could provide insight into antibacterial and cytotoxic biologi-
cal activity, two areas in which triazole-containing small
molecules have shown promise.13,14
50:50
60:40
80:20
40:60
50:50
80:20
[Cp*RuCl]4
[Cp*RuCl]4
[Cp*RuCl]4
[Cp*RuCl]4
[Cp*RuCl]4
15
15
5
5
5
a Reactions were run as a solution in toluene for 30 min at the indicated
concentrations. b Conversion was determined by LCMS analysis. c Isolated
yield of 4a after silica gel chromatography.
entries 1 and 2) was employed as the catalyst,9 the reaction
yielded no product even at elevated temperatures, most likely
due to catalyst thermal instability.12 More encouraging results
were achieved with Cp*RuCl(PPh3) (Table 1, entry 3);
however, 50% dimer formation was observed and purification
of the desired product proved difficult due to the presence
of phosphine oxide. Improved results were obtained with the
[Cp*RuCl]4 catalyst (Table 1, entries 4-8) which yielded
improved monomer to dimer ratios (entries 5 and 8) and a
more straightforward purification. Using 5% [Cp*RuCl]4
(Table 1, entries 6-8), we found that higher temperatures
(80 °C) and lower concentrations (0.002 M) (entry 8) led to
optimal monomer to dimer ratios. With our optimized
protocol in hand, we obtained the desired 1,5-macrocyclic
triazole 4a in 58% isolated yield and confirmed the structure
as the 1,5-regioisomer via X-ray crystallography (Figure 1).15
To explore the substrate scope of this divergent pairing
strategy, we synthesized various alkynyl azides embedded
within different structural frameworks (Scheme 2). The first
Scheme 2
.
Substrate Synthesis and Intramolecular Ru-Catalyzed
Cycloaddition
pairing partner was provided by coupling an amino alcohol
(1a) to an azido acyl chloride, resulting in the amide (2a).
The second requisite functional group, the alkyne, was added
via propargylation of the alcohol (3a). This general synthesis
was applied to all of our substrates except in the synthesis
of the linear (3e-g) and cyclohexyl substrates (3j-k), in
which we observed bisacylation. In this instance, protection
of the alcohol as a silyl ether was necessary to avoid ester
formation.15
Figure 1. X-ray crystal structures of representative macrocyclic
triazoles (4a and 5f).
Using the pyrrolidine azido alkyne substrate (3a), different
conditions were screened for the macrocyclic triazole forma-
To the best of our knowledge, this is the first demonstration
of a ruthenium-catalyzed intramolecular 1,5-triazole forma-
tion.
Using the same pyrrolidine substrate (3a), we attempted
to find the best conditions for the formation of the 1,4-
(12) Boren, B. C.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao, H.;
Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 8923
.
(13) (a) Reck, F.; Zhou, F.; Girardot, M.; Kern, G.; Eyermann, C. J.;
Hales, N. J.; Ramsay, R. R.; Gravestock, M. B. J. Med. Chem. 2005, 48,
499. (b) Horne, W. S.; Olsen, C. A.; Beierle, J. M.; Montero, A.; Ghadiri,
M. R. Angew. Chem., Int. Ed. 2009, 48, ASAP
.
(14) Odlo, K.; Hentzen, J.; Chabert, J. F. d.; Ducki, S.; Gani, O. A. B. S.
M.; Sylte, I.; Skrede, M.; Flørenesd, V. A.; Hansena, T. V. Bioorg. Med.
Chem. 2008, 16, 4829
.
(15) See the Supporting Information.
2258
Org. Lett., Vol. 11, No. 11, 2009

triazole. Starting with Cu(CN)4PF6, we ran the reaction
at 0.01 M in toluene at 60 °C and saw complete
consumption of starting material but no desired product
(Table 2, entry 1). It was determined this was due to the
with a slight increase in yield for the desired product (Table
2, entry 4). These observations were consistent with pseudodi-
lution.17
With these optimized conditions in hand, the effect of
substrate specificity, conformation, and ring size on these
metal-catalyzed macrocyclizations was investigated. The
results of these experiments are shown in Table 3. The same
Table 2. Optimization of Intramolecular Cu-Catalyzed
Cycloaddition
Table 3. Results for Intramolecular Cycloadditions with Linear
and Carbocyclic Substratesa
a Isolated yield of 5a after silica gel chromatography.
intermolecular formation of dimers and oligomers; there-
fore, we decreased the concentration of the reaction to
favor the intramolecular reaction. Gratifyingly, by chang-
ing the reaction concentration from 0.01 to 0.002 M we
were able to obtain the 1,4-triazole 5a in 50% yield (Table
2, entry 2). Although encouraged by these results, such
dilute conditions were not suitable for the scalability of
our protocol, so we sought to optimize the reaction further.
A recent publication by Girard and co-workers showcased
the utility of CuI loaded on Amberlyst resin as a catalyst
for an intermolecular Huisgen cycloaddition.16 We envi-
sioned utilizing this technology to facilitate pseudodilution
and suppress dimer formation in the intramolecular Huisgen
reaction.17 First, we examined the exact conditions reported
in the manuscript, Amberlyst-21 and CuI at 0.2 mmol/g
loading (Table 2, entry 3). The monomeric 1,4-triazole was
obtained; however, there was evidence of iodine incorpora-
tion.15 While this observation is not uncommon in the use
of solution phase CuI, it was not reported by Girard with
the solid-phase catalyst. In light of this problem, we applied
the Girard protocol to the generation of a CuPF6 Amberlyst.
We chose CuPF6 (as opposed to CuBr) due to its high
solubility in CH3CN, the solvent used in the preparation of
the solid-supported copper reagents. We were pleased to find
that using this catalyst (0.2 mmol/g loading) we were able
to achieve a 5-fold increase in reaction concentration along
a Ru conditions: 5 mol % of [Cp*RuCl]4, 80 °C, toluene, 0.002 M, 10
min. Cu conditions: 0.2 mmol/g Amberlyst-CuPF6, 60 °C, toluene, 0.01
M, 16 h.Thermal conditions: 110 °C, toluene, 0.01 M, 16 h (nd ) not
determined). b Structure confirmed by X-ray crystallography. c For the Ru-
and Cu-catalyzed entries, only the major regioisomer was detected by
LCMS.
pyrrolidine system was examined with an additional meth-
ylene group in the azido acid side chain (Table 3, entries
4-6). The isolated yields for the formation of the 12- and
13-membered rings were slightly higher than that of the 11-
and 12-membered rings, a trend which is consistent with
thermodynamic arguments.18
Since the pyrrolidine substrates (3a,b) assume a pseudo-
axial position, the piperidine azido alkynes (3c,d) were
(16) Girard, C.; Onen, E.; Aufort, M.; Beauviere, S.; Samson, E.;
Herscovici, J. Org. Lett. 2006, 8, 1689.
(17) For an example of pseudodilution, see: Gonthier, E.; Breinbauer,
R. Mol. DiVersity 2005, 9, 51.
(18) Galli, C.; Mandolini, L. Eur. J. Org. Chem. 2000, 3117.
Org. Lett., Vol. 11, No. 11, 2009
2259

synthesized in order to examine the effect of a true axial
substituent on ring closure. The resulting yields of the
cycloaddition were slightly lower than that of their pyrro-
lidine counterparts (Table 3, entries 7-12). The drop in yield
is most likely due to the difficulty of the cycloaddition. We
hypothesize that the axial substituent places the alkyne and
the azide further apart and leads to greater dimer and
oligomer formation.
Table 4. Influence of Stereochemistry on Intramolecular
Cycloadditionsa
Three linear substrates (3e-g) were then tested to see if
the rigidity imparted by the pyrrolidine ring was facilitating
macrocyclization. The results of the metal-catalyzed cycliza-
tions were very similar to that of the pyrrolidine substrate;
however, the inherent bias in the system, determined by the
thermal reaction, seemed to be less specific. When exposed
to the thermal conditions the pyrrolidine substrates formed
the 1,5-triazole products almost exclusively; whereas, the
linear substrates gave a 4:1 ratio of the 1,5- to 1,4-triazoles
(Table 3, entries 3 and 6 vs 15 and 18). We also compared
substrates derived from 1,2-amino alcohols (3e,f) to sub-
strates derived from 1,3-amino alcohols (3g) to determine if
the position of the oxygen in the macrocyclic ring had any
effect on the cycloaddition. The 1,3-amino alcohols (Table
3, entries 19 and 20) were only slightly higher in yield than
their 1,2-amino alcohol counterparts (entries 16 and 17) and
their thermal ratios were quite similar (entries 18 and 21).
From these observations, it would not seem that the position
of the alcohol has a dramatic effect on the macrocyclization.
During the course of our work an X-ray crystal structure
was obtained for one of the 1,4-triazoles (5f, Figure 1).
With the general reaction conditions established for the
regioselective triazole pairing reactions, we chose to further
explore conformational effects, as well as examine stereo-
chemical effects on the macrocyclic triazole ring formation.
Our results of these experiments are shown in Table 4. The
first system that we examined was the planar 2-aminophenol
derivatives (Table 4, entries 1-6). To better understand the
system, we studied both the primary (Table 4, entries 1-3)
and secondary amides (entries 4-6), however, no trend was
observed. Both of these substrates gave moderate yields in
all cases except for the copper-catalyzed primary amide
(Table 4, entry 2). Next, we examined a saturated system of
the cis- and trans-cyclohexyl amino alcohol compounds
(Table 4, entries 7-12). Surprisingly, the cis or trans
configuration had little effect for the ruthenium-catalyzed
reaction (Table 4, entries 7 and 10); however, the trans
system showed a remarkable loss in yield for the copper-
catalyzed case (Table 4, entry 8). Optimization of this
reaction for this substrate was effected by a 5-fold dilution,
leading to a significant increase in yield, from 17% to 46%
(Table 4, entry 8).
a Ru conditions: 5 mol % of [Cp*RuCl]4, 80 °C, toluene, 0.002 M, 10
min. Cu conditions: 0.2 mmol/g of Amberlyst-CuPF6, 60 °C, toluene, 0.01
M, 16 h. Thermal conditions: 110 °C, toluene, 0.01 M, 16 h (nd ) not
determined). b Reaction was run at a concentration of 0.002 M. c For the
Ru- and Cu-catalyzed entries, only the major regioisomer was detected by
LCMS.
catalyzed intramolecular cyclization. Furthermore, as a result
of this study, we have developed an understanding of which
substrates and ring sizes provide the best yields. The
performance of these regioisomeric triazoles in a wide variety
of biological screens is currently under investigation. We
are also following up these substrate examples with a more
comprehensive library synthesis, the results of which will
be reported in due course.
Acknowledgment. We gratefully acknowledge Marie
Harton for help with characterization and Dr. Peter Mueller
for X-ray analysis. This work was funded in part by the
NIGMS-sponsored Center of Excellence in Chemical Meth-
odology and Library Development (Broad Institute CMLD;
P50 GM069721).
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and X-ray crystal-
lographic information files. This material is available free
of charge via the Internet at http://pubs.acs.org.
In conclusion, we have expanded on the existing Huisgen
cycloaddition methodology, showing the utility of pseudodi-
lution and performing the first example of a ruthenium-
OL900562U
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Org. Lett., Vol. 11, No. 11, 2009