Efficient construction of proline-containing β-turn mimetic cyclic tetrapeptides via CuAAC macrocyclization

Article abstract of DOI:10.1021/ol303572t

A range of macrocyclic β-turn mimetic tetrapeptides was prepared by efficient copper-tris(triazole) ligand complex catalyzed azide-alkyne "click" macrocyclizations in good to high yields. Preliminary conformational studies using X-ray crystallography and NMR spectroscopy demonstrated the presence of intramolecular H-bonds characteristic of β-turns in these cyclic tetrapeptides.

Full text of DOI:10.1021/ol303572t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Efficient Construction of Proline-
Containing β‑Turn Mimetic Cyclic
Tetrapeptides via CuAAC
Macrocyclization
Gagan Chouhan and Keith James*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, United States
kjames@scripps.edu
Received January 12, 2013
ABSTRACT
A range of macrocyclic β-turn mimetic tetrapeptides was prepared by efficient copper-tris(triazole) ligand complex catalyzed azideꢀalkyne “click”
macrocyclizations in good to high yields. Preliminary conformational studies using X-ray crystallography and NMR spectroscopy demonstrated
the presence of intramolecular H-bonds characteristic of β-turns in these cyclic tetrapeptides.
Peptide-based molecules are of considerable interest
within the pharmaceutical industry as potential therapeu-
tic agents,1 particularly for the modulation of challenging
molecular targets such as proteinꢀprotein interactions
(PPIs).2 However, the conformational flexibility of simple,
linear peptides can limit their target selectivity and render
them susceptible to degradation by peptidases/proteases.3
Consequently, embedding bioactive peptide sequences with-
in a macrocyclic framework represents an attractive strategy
for circumventing these issues, provided that the bioactive
conformation of the peptide is present among the low
energy conformations of the macrocycle.4 Such macro-
cyclic peptides may possess fewer rotatable bonds, lack
charged termini, and, in some cases, can conceal their
polarity in hydrophobic environments through the ability
to establish intramolecular H-bonds, thereby enabling
them to partition across cell membranes.5 Not surprisingly
therefore, in light of these potential pharmacological and
physicochemical advantages, there has been considerable
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r
10.1021/ol303572t
XXXX American Chemical Society

interest in new methods for the efficient construction of
macrocyclic peptidomimetic motifs.6
(CuAAC) reaction has proved to be especially popular in
the construction of peptide-based macrocyles.11
β-Turns represent a particularly important element of
secondarystructureintherecognition ofbioactivepeptides
and proteins by their cognate receptors, and so the ability
to successfully stabilize this motif is a key strategy in the
design of peptidomimetics.7 Notably, β-turns are also the
mostcommon type ofreverse turnfoundinmany naturally
occurring bioactive cyclic peptides, such as the clinically
important cyclosporin A and gramicidin S.
Given the importance of both naturally occurring8 and
synthetic cyclic peptides in the design and development of
new peptide-based theraputics,6,9 many approaches have
been developed to generate turn mimetic cyclic peptides.6,9,10
Of these, the Cu-catalyzed azideꢀalkyne cycloaddition
However, most of the methods described to date require
highdilutionconditions, stoichiometricamountsofcopper
catalyst and/or additives (bases), harsh reaction conditions,
and, in some cases, syringe pump addition, while providing
only low to moderate yields of the desired cyclic peptides.12
Thus, these methods are both inefficient and impractical in a
drug discovery and development setting in terms of solvent
consumption, reaction rate, and catalyst loading. Therefore,
to fully exploit the potential of this approach to the con-
struction of macrocyclic turn-mimetic peptides, a general,
mild, and catalytic method is required which can generate
these systems in high yield. In this regard, we have recently
reported a very efficient method for the synthesis of di-
versely functionalized triazole-containing macrocyles using
the CuAAC reaction,13 and here we further describe the
application of the methodology to the efficient construction
of a series of turn-mimetic cyclic tetrapeptides.
Linear tetrapeptidic macrocyclic precursors were syn-
thesized using standard peptide coupling conditions via a
fragment condensation strategy (for full synthetic details,
see Supporting Information (SI)). The optimal length of
alkynylamide and azidoalkanoyl groups at the C- and
N-termini of the tetrapeptide precursors was selected after
computational analysis of the product macrocycles for the
likely presence of a turn structure and characteristic in-
tramolecular H-bond. The azido-alkyne containing linear
tetrapeptide FPFG 1 was used as a model system for
comparison of available macrocyclization methodologies,
the results of which are outlined in Table 1.
The combination of dichloromethane as solvent and
Cu(CH3CN)4BF4 as a Cu source had proven optimal in
our earlier study of CuAAC macrocyclizations, and so we
chose to examine reaction with Cu(CH3CN)4BF4 (5 mol %)
alone at rt for 24 h. This provided a low yield of macrocycle
2 and gave primarily dimers/oligomers (Table 1, entry 1).
As anticipated from our earlier studies,13 the yield of 2 was
improved dramatically by heating and addition of a cataly-
tic amount of the ligand tris((1-benzyl-1H-1,2,3-triazolyl)-
methyl)amine (TBTA) (Table 1, entry 2). Although we had
previously examined systems containing one or two amino
acid residues,13 we were extremely gratified to demonstrate
the efficient macrocyclization of this more challenging tetra-
peptide substrate.
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We compared this reaction outcome with several other
known literature methods employing stoichiometric amounts
of copper. None of these conditions offered comparable
yields (Table 1, entries 3ꢀ5).12aꢀc
€
Maekawa, H.; Ge, N.-H.; Gorbitz, C. H.; Rongved, P.; Ottersen, O. P.;
To demonstrate the scope of this peptide CuAAC-
macrocyclization protocol, a series of azido-alkyne con-
taining linear tetrapeptides were synthesized and subjected
Amiry-Moghaddam, M.; Klaveness, J. J. Org. Chem. 2011, 76, 1228.
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M. R.; Singh, E. K.; Wahyudi, H.; Alexander, L. D.; Kunicki, J. B.;
Nazarova, L. A.; Fairweather, K. A.; Giltrap, A. M.; Jolliffe, K. A.;
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O.; Karoyan, P.; Guianvarc’h, D.; Lavielle, S. J. Pept. Sci. 2011, 17, 632.
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A. G.; Lokey, R. S. Org. Lett. 2007, 9, 5011–4.
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(14) We also screened a range of other organic bases and solid
supported bases such as PS-TBD (Polystyrene-supported bicyclic
guanidine) in this macrocyclization reaction, and none was found to
be efficient (for more details, see HPLC/ESI MS chromatograms in the
SI). For use of a heterogenous catalyst in CuAAC, see: Dervaux, B.; Du
Prez, F. E. Chem. Sci. 2012, 3, 959.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of CuAAC Macrocyclizations14
condition
(mol %)
t
time
(h)
yield
(%)
2/dimer/
entry
1
(°C)
oligomera
Cu(CH3CN)4BF4
(5)
rt
24
12
24
17
7
38
80
53
67
59
1.5:1.4:1
13:2.3:1
2:0.74:1
5.2:1.5:1
3.3:1.3:1
2
3
4
5
(Cu(CH3CN)4BF4
(5), TBTA (5)
Cu(CH3CN)4PF6
(100)b,12a
55
rt
Amberlite-21-
CuPF6 (100)c,12b
CuBr (100), DBU
(300)12c
55
rt
Figure 1. Substrate scope for CuAAC macrocyclization of
tetrapeptides. Numbers in parentheses correspond to isolated
yields after column chromatography.
a Ratio determined by integration of peaks in HPLC-MS trace
(λ = 210 nm, see SI). b Reaction run in MeOH:toluene (4:1). c Reaction
run in toluene.
2
cis-amides) a PSA score of 62 A is achieved, suggesting
˚
that this system has the potential to show membrane
permeability, despite a molecular weight of 678.
Additionally, 3-butenyl glycine was incorporated at
positions i and i þ 3 for eventual generation of the
corresponding macrobicyclic peptide via a ring closing
metathesis reaction (Figure 1, 10).16
to the optimized conditions. Results are summarized in
Figure 1. A small library of proline-based cyclic tetrapep-
tides, incorporating alternative amino acids at residues i,
i þ 3, and i þ 4, were generated in good to high yields.
Notably, >200 mg of macrocyclic product could readily
be generated in a 0.01 M scale reaction, employing just
50 mL of solvent. Further diversity could be introduced via
incorporation of D-amino acids (Figure 1, 4, 9, 10, and 11).
It was also possible to prepare N-methylated cyclic
tetrapeptides, since this maneuver is known to improve
membrane permeability by the reduction of polar surface
area (PSA) (Figure 1, 6ꢀ10).15
Finally, although most of the macrocyclic peptides were
bridged via cycloaddition between a C-terminal N-propar-
gyl group and an N-terminal azido-pentanoyl group, we
were able to demonstrate that the methodology was
equally applicable to alternative bridge configurations
(Figure 1, 4). We were able to grow crystals of several of
these cyclic tetrapeptides and determine their structure by
X-ray crystallography (Figure 2 A and B), which clearly
illustrated the presence of a β-turn secondary structure,
with a H-bond between the carbonyl of phenylalanine at
i and the NH of glycine at i þ 3. It is noteworthy that two
intermolecular H-bonds were also observed in the unit cell
of 6 (Figure 2C), one of which involved a triazole N-atom.
We had included a mimic of the turn portion of the
naturally occurring antimicrobial cyclic decapeptide Gra-
micidin S in our substrate scope (Figure 1, 11), and its
conformation was studied using 1D, 2D, and variable
temperature (VT)-1H NMR spectroscopy (see SI for addi-
tional details).17 The VT experiments show the presence of
secondary structure in 11 which is stabilized by H-bonds
involving amide protons of Val and Phe (low ΔδNH/ΔT)
To examine whether these systems show lower PSA
scores, we calculated this property for the lowest energy
conformations (generated using Schrodinger’s MacroMo-
del software; see SI) of several members of the library,
using the X-ray structure of cyclosporin A (CsA) as a
2
˚
reference point (PSA = 74 A ), since this N-methylated
cyclic peptide is known to cross cell membranes. Whereas
2
˚
2, 3, and 6 exhibit PSA scores in the 99ꢀ114 A range,
example 10, containing two N-methylated amide residues,
2
begins to approach the PSA score for CsA (PSA = 81 A ).
˚
When a D-proline residue is employed at i þ 1 (Figure 1, 9,
establishing a clear trans-amide bond within the turn,
according to modeling studies; cf. Figure1, 6ꢀ8 showing
(15) (a) Ovadia, O.; Greenberg, S.; Chatterjee, J.; Laufer, B.;
Opperer, F.; Kessler, H.; Gilon, C.; Hoffman, A. Mol. Pharm. 2011, 8,
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McEwen, C. M.; Gelev, V. M.; Turner, R. A.; Linington, R. G.; Leung,
S. S. F.; Kalgutkar, A. S.; Bauman, J. N.; Zhang, Y.; Liras, S.; Price,
D. A.; Mathiowetz, A. M.; Jacobson, M. P.; Lokey, R. S. Nat. Chem.
Biol. 2011, 7, 810. (d) Beck, J. G.; Chatterjee, J.; Laufer, B.; Kiran,
M. U.; Frank, A. O.; Neubauer, S.; Ovadia, O.; Greenberg, S.; Gilon, C.;
Hoffman, A.; Kessler, H. J. Am. Chem. Soc. 2012, 134, 12125 and
references therein.
(16) (a) Hanessian, S.; Angiolini, M. Chem.;Eur. J. 2002, 8, 111. (b)
Giovannoni, J.; Didierjean, C.; Durand, P.; Marraud, M.; Aubry, A.;
Renaut, P.; Martinez, J.; Amblard, M. Org. Lett. 2004, 6, 3449.
(17) (a) Ripka, W. C.; De Lucca, G. V.; Bach, A. C., II; Pottorf, R. S.;
Blaney, J. M. Tetrahedron 1993, 49, 3609. (b) Trabocchi, A.; Sladojevich,
F.; Guarna, A. Chirality 2009, 21, 584. (c) Zhang, K.; Schweizer, F.
Carbohydr. Res. 2010, 345, 1114. (d) Jennotte, G.; Lubell, W. D. J. Am.
Chem. Soc. 2004, 126, 14334.
Org. Lett., Vol. XX, No. XX, XXXX
C

Figure 3. (A) Variable temperature NMR experiments of 11 in
1
CDCl3. (B) Schematic structure of 11 showing key 1Hꢀ H
ROESY cross-peaks (red arrows) and potential H-bonds from
temperature coefficient experiments.
Figure 2. X-ray crystal structure of macrocyclic tetrapeptide 6
(A) and 8 (B) and the two molecules in the unit cell in the crystal
structure of the cyclic tetrapeptide 6 showing inter- and intra-
molecular H-bonding (C, dashed line).
1
Figure 4. (A) Schematic diagram of 3 showing key 1Hꢀ H
ROESY cross-peaks (blue arrows) and potential H-bonds from
temperature coefficient experiments. (B) Lowest energy con-
former of 3 generated using the OPLS 2005 force field and the
mixed-torsional/low-mode conformational search in MacroModel.
(Figure3A).18 The cross peaks in the ROESY spectrum of 11
clearly suggested the presence of β and γ turns (Figure 3B).5b
To gain additional insight into the conformation of
these macrocyclic tetrapeptides, we performed VT and
2D NMR studies on cyclic peptide 3 in CDCl3 (see SI).
This agent differs from analogs 6 and 8, for which we have
X-ray crystallographic structures, by virtue of a leucine, as
opposed to a phenylalanine derivative, at i. The characteristic
ROE correlations in 3 are shown in Figure 4A.
macrocyclizations to generate a library of β-turn mimetic
tetrapeptides in good to high yields. We have demon-
strated the presence of secondary structure in these CTPs
by some preliminary solution NMR and conformational
search studies. We are currently pursuing the detailed
NMR conformational and membrane permeability prop-
erties of these systems and also preparing various other
macrocycles/macrobicycles utilizing azide and alkyne de-
rived R-amino acids.20
NMR studies show the presence of only one conformer
of 3 in CDCl3 at rt (2 and 5 show cis/trans amide mixtures
on the NMR time scale), and the low temperature co-
efficients for NH12 and NH15 suggest intramolecular
H-bonding, which is consistent with the lowest energy
conformation generated via a MacroModel conforma-
tional search (Figure 4B).19 Strong ROEs were observed
between NH12 and NH7, NH15 and the R and β positions
of the leucine at i þ 2. These results suggest that 3 shows
two consecutive β-turns in solution; in the first turn proline
occupies the i þ 1 position, and in the second, the leucine2
occupies i þ 1.
Acknowledgment. This work was funded by Pfizer
Worldwide Research. The authors would like to thank
Curtis Moore and Arnold Rheingold (UCSD Small-
Molecule Lab) for crystallographic data.
Supporting Information Available. Experimental pro-
cedures, X-ray crystal structure (data and CIF files),
HPLC and NMR data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have demonstrated the utility of a
copperꢀtris(triazole) ligand complex in peptide CuAAC
(20) Johansson, H.; Pedersen, D. S. Eur. J. Org. Chem. 2012, 23,
4267.
(18) Cierpicki, T.; Otlewski, J. J. Biomol. NMR 2001, 21, 249.
(19) We also performed conformational analysis by simulated an-
nealing using the DISCOVER (Molecular Simulations, Inc.) program
within the molecular modeling package Insight II (for details on
computer simulations, see SI).
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX