Synthesis of Heterocycle-Bridged Peptidic Macrocycles through 1,3-Diyne Transformations

Article abstract of DOI:10.1002/ejoc.201601215

Macrocyclic tetrapeptide analogues containing a 1,3-diyne moiety were synthesized by a Glaser–Hay-type macrocyclization. The obtained 1,3-diyne was evaluated as a handle to introduce heterocycles into the macrocyclic structure. It was shown that the macrocyclic 1,3-diynes were successfully transformed into various heterocycles by nucleophilic attack of (bis)nucleophiles to the diyne moiety. Treatment with NaHS or H₂O as nucleophiles gave rise to 2,5-bridged thiophenes or furans, whereas the use of hydrazines and hydroxylamine gave rise to the corresponding pyrazole- and isoxazole-containing macrocycles. In addition, a thermoreversible Diels–Alder cycloaddition of a cyclopeptidic bridged furan was demonstrated.

Full text of DOI:10.1002/ejoc.201601215

DOI: 10.1002/ejoc.201601215
Communication
Peptide Diyne Transformations
Synthesis of Heterocycle-Bridged Peptidic Macrocycles through
1,3-Diyne Transformations
Steven Verlinden,[a] Steven Ballet,[a] and Guido Verniest*[a]
Abstract: Macrocyclic tetrapeptide analogues containing a 1,3- (bis)nucleophiles to the diyne moiety. Treatment with NaHS or
diyne moiety were synthesized by a Glaser–Hay-type macro- H2O as nucleophiles gave rise to 2,5-bridged thiophenes or
cyclization. The obtained 1,3-diyne was evaluated as a handle furans, whereas the use of hydrazines and hydroxylamine gave
to introduce heterocycles into the macrocyclic structure. It was rise to the corresponding pyrazole- and isoxazole-containing
shown that the macrocyclic 1,3-diynes were successfully trans- macrocycles. In addition, a thermoreversible Diels–Alder cyclo-
formed into various heterocycles by nucleophilic attack of addition of a cyclopeptidic bridged furan was demonstrated.
Introduction
tential of 1,3-diynes include reactions with guanidines or acet-
amidines to give amino- or alkylpyrimidines[24,25] and formal
[4+2] reactions with pyrrole towards indoles.[26] In addition to
these monoheterocycles, the formation of polyheterocyclic
compounds has been described by intramolecular reactions be-
tween nucleophiles and 1,3-diynes.[27,28]
In continuation of our previous work regarding the synthesis
of macrocyclic 1,3-diynes from tetrapeptides containing O-
propargylated serine residues (Scheme 1),[1] we hereby report
on the condensation of peptidic 1,4-dialkyl-1,3-diynes and 1-
Alkyne–alkyne coupling reactions are currently being evaluated
in peptide chemistry as promising tools to cyclize or functional-
ize peptidic backbones.[1–4] Cyclic peptides containing a 1,3-
diyne moiety can be prepared by either derivatization of pept-
ide side chains with difunctionalized 1,3-diynes[5] or by Glaser–
Hay-type oxidative alkyne–alkyne coupling reactions of α,ω-di-
alkynylated peptides.[1,2] To date, there are no examples in the
known literature for which postcyclization transformations of
the 1,3-diyne linker of a macrocyclic peptide have been applied.
Interestingly, starting from one parent structure the reaction of
such diynes with nucleophiles could lead to a set of different
cyclic peptides that contain a heterocyclic tether, which in turn
could be of value in structure–activity relationship studies. 1,3-
Diynes have for a long time been considered as versatile build-
ing blocks,[6] and currently, they are receiving revived interest
in organic synthesis.[7] The reaction of 1,3-diynes with S-nucleo-
philes can lead to thioenynes or thiophenes,[8–16] and analo-
gous hydration or hydroamination reactions give rise to
furans[15–18] or pyrroles.[12,15,17–20] Unfortunately, in many cases
a high reaction temperature is needed, and these transforma-
tions are mostly reported by using arylated 1,3-diynes. It has
been shown that related reactions of alkyl-substituted 1,3-di-
ynes often result in a drastic drop in yield relative to those
obtained for aromatic substituted thiophenes[8] or furans.[17,18]
Also, 1,2-bisnucleophiles such as hydrazine and hydroxylamine
have been used to prepare pyrazoles[21,22] and isoxazoles,[23]
but such conversions have never been applied on peptidic sub-
strates. Very recent examples that further demonstrate the po-
[a] Research group of Organic Chemistry, Department of Chemistry
and Department of Bio-engineering Sciences, Faculty of Science and
Bio-engineering Sciences, Vrije Universiteit Brussel (VUB),
Pleinlaan 2, 1050 Brussels, Belgium
E-mail: gvernies@vub.ac.be
http://we.vub.ac.be/en/organic-chemistry
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201601215.
Scheme 1. Residue incorporating R1:
D-Pro or D
-Ala; residue incorporating R2:
L
-Pro or -Ala. Boc = tert-butoxycarbonyl.
L
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alkyl-4-aryldiynes with nucleophiles leading to a variety of
heterocycle-bridged macrocycles.
The formation of a thiophene from a S-nucleophile and a
diyne requires the introduction of two protons. Whereas NaHS
has only one proton available, the mixture becomes more basic
during the reaction. To counter this, it was decided to add
NH4OAc as a buffer instead of using H2S. Under these condi-
tions, clean conversion (70–92 %) towards thiophene deriva-
tives 5a–c was observed at room temperature. Whereas peptide
derivatives 5a and 5b only required a reaction time of 2 h, 5c
required a reaction time of 24 h to reach 90 % conversion for
reasons that remain unclear. Compounds 5a–c were isolated by
preparative reverse-phase (RP) HPLC or C18 silica gel chroma-
tography in moderate yields (28–50 %).
Results and Discussion
To explore the possibility of forming thiophenes through dou-
ble nucleophilic addition of a sulfur anion to macrocyclic 1,3-
diynes, compounds 4a–c were prepared from linear peptides
3a–c (Scheme 2). The latter result from the coupling of corre-
sponding dipeptides 1a,b and 2a,b.[1] In a first evaluation to
transform macrocyclic diynes into the corresponding thio-
phenes, 4c was treated with Na2S·9H2O (2 equiv.) in DMF at
room temperature. This resulted in a complex mixture of prod-
In a next transformation of 1,3-diynes 4a–c, water was evalu-
ucts, and only a minor amount of the envisaged thiophene was ated as a nucleophile. Without activation of the alkyne moiety
observed after LC–MS analysis. A switch to NaHS as the nucleo- no reaction took place, even at elevated temperatures. How-
phile, which is more soluble in organic solvents, resulted in bet- ever, if SPhosAuNTf2 was used as an alkyne activating cata-
ter conversion of the diyne into the thiophene, but in this case, lyst,[17] desired furans 6a–c were obtained but more side prod-
concomitant N-Boc deprotection occurred.
ucts were formed than in the formation of thiophenes 5a–c.[29]
Scheme 2. Synthesis of thiophenes 5a–c and furan derivatives 6a–c and cycloadduct 7. Yields of isolated products are indicated. In the case of 6a, SPhosAuCl
(1 equiv.), AgNTf2 (1 equiv.), and H2O (20 equiv.) were added. HOAt = 1-hydroxy-7-azabenzotriazole, EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,
HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, SPhos = 2-dicyclohexylphosphino-2′,6′-dimethoxy-
biphenyl, AgNTf2 = silver bis(trifluoromethanesulfonyl)imide.
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The transformation of 4b and 4c towards 6b and 6c required ing studies at a distant site from the potential recognition do-
only a catalytic amount of the gold catalyst to reach good HPLC main within peptide macrocycles.
conversions (60–90 %), but the formation of 6a proceeded slug-
gishly and 1 equivalent of the catalyst and 20 equivalents of
H2O were needed to promote the reaction. This led to a rather
complex mixture, from which 6a was isolated in low yield.
The introduction of furans into peptidic structures through
transformation of the 1,3-diyne linker can expand the current
toolbox for reversible furan-based peptide labeling tech-
niques.[30] Having peptide-bridged furans 6 in hand, Diels–Alder
reactions with maleimides were therefore evaluated in a model
study. After heating macrocycle 6c in toluene at 40 °C in the
Transformations of diynes into pyrroles by using amines as
nucleophiles have been described and could provide the nitro-
gen analogues of compounds 5 and 6. Unfortunately, in many
cases harsh reaction conditions are required to accomplish
this.[17–20] In an attempt to reach pyrrole derivatives, the reac-
tion of macrocycles 4a–c with amines was evaluated (>10 dif-
ferent reaction conditions, see the Supporting Information), but
did not result in any pyrrole formation, and only complex reac-
tion mixtures were obtained.
All of the above-described transformations gave rise to
presence of an excess amount of N-methylmaleimide, cyclo- quasi-symmetrically substituted heterocycles. In contrast, the
adduct 7 (both diastereomers) was obtained after 40 h in a use of hydrazines or hydroxylamines can result in different
nearly peak-to-peak HPLC conversion. Subsequently, obtained regioisomers depending on whether position 1 or 4 of the 1,3-
and isolated 7 was heated to verify whether a retro-Diels–Alder diynes is attacked first by these bisnucleophiles. To evaluate if
transformation was possible without affecting the peptidic the nature and conformation of the macrocycles could direct
linker. Although at first no conversion seemed to occur upon the incoming nucleophile and give regioselective reactions with
heating 7 in toluene at 80 °C, the addition of furan as a trapping bisnucleophiles, compound 4c was separately treated with
agent for the formed N-maleimide at this temperature com- hydrazine, hydroxylamine, and N-methylhydrazine (Scheme 3).
pletely shifted the equilibrium towards starting peptide 6c in In these cases, no or low regioselectivity was observed and mix-
clean conversion, as observed by HPLC. This conversion pro- tures of pyrazole regioisomers 8 and 9 and isoxazoles 10 were
vides proof-of-principle for the reversible linkage of macro- obtained. Pyrazoles 8 and isoxazoles 10 could not be separated
cycle-bridged furans of type 6c and opens a gateway for label- and were obtained as a mixture of two regioisomers in 1:1 and
Scheme 3. Synthesis of pyrazole derivatives 8 and 9 and isoxazoles 10. Compound 8 was isolated as a mixture of two regioisomers (1:1 ratio); compound 9
was isolated as a mixture of three regioisomers (3:1:1 ratio); compound 10 was isolated as a mixture of two regioisomers (2:1 ratio).
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2:1 ratios, respectively, as shown by NMR spectroscopy. The re- 13a–c by using the optimized Glaser–Hay coupling reaction
action of N-methylhydrazine with 4c gave rise to a mixture of conditions.[1]
three regioisomers in a 3:1:1 ratio.[31]
For the cyclization of linear peptide 12a, DMF was used as
The reason for the observed lack of selectivity is most proba-
bly due to the quasi-symmetric nature of the 1,3-diyne moiety
in substrate 4c. This could change drastically if 1-aryl-4-alkyl-
1,3-diynes are used, as an electronic bias (aryl conjugation) is
present in such cases. To verify this, the synthesis of macrocyclic
substrates 13a–c was envisaged. Instead of using two prop-
argylated serine residues, one serine residue was exchanged
with an ethynylated phenylalanine residue. Sonogashira cou-
pling of 2-, 3-, and 4-iodinated Boc-Phe-OMe with TMS-acet-
ylene resulted in the corresponding trimethylsilyl-protected 2-,
the solvent instead of EtOH, as the use of the latter required
much longer reaction times and generated more side products.
Unfortunately, full consumption of 12a still took 7 days in DMF
with 5 equivalents of Cu(OAc)2·H2O and NiCl2, and concomi-
tantly, more side products were formed than in reactions with
12b,c. This long reaction time and low yield is most probably
due to the large ring strain in obtained macrocycle 13a, be-
cause both a para-phenylene and a 1,3-diyne structure are
bridged by a peptidic macrocycle. Less strained peptide ana-
logues 12b,c cyclized within 4 h at 60 °C. Obtained arylated
diynes 13a–c were then treated with hydrazine in DMSO for
15 h at 60 °C, which resulted in the formation of single regio-
isomers 14a–c, as observed by HPLC and NMR spectroscopy.
1H–13C HSQC analysis clearly shows one singlet for pyrazole
proton Hx (see Scheme 4), which corresponds with one carbon
3-, and 4-ethynyl-
yield. Simultaneous silyl deprotection and saponification of the
methyl esters with a 1 NaOH solution afforded ethynylated
L-phenylalanine methyl esters in 54 to 92 %
M
Phe derivatives, which were used as the first amino acid in a
solution-phase peptide synthesis strategy.
Coupling of ethynylated Boc-Phe-OH with H-D-Ala-OMe us- atom. The fact that the two methylene units within the tether
1
1
ing HATU in DMF and subsequent saponification afforded di- do not couple with each other in the H–13C HMBC and H–1H
peptides 11a–c. Coupling of 11a–c with H-Ala-Ser(O-prop- COSY NMR spectra and the fact that the newly formed CH2
argyl)-OBn by using N,N′-diisopropylcarbodiimide (DIC)/HOAt in protons show cross peaks with the benzene and pyrazole ring
DMF resulted in linear tetrapeptides 12a–c in good yields (67– proves the formation of only one regioisomer. This is in agree-
82 %). Next, these were cyclized to corresponding peptides ment with the expected reactivity, for which the first nucleo-
Scheme 4. Synthesis of cyclic peptides 13a–c and pyrazoles 14a–c. Peptide 14a was not purified owing to the low amount of isolated 13a but was used as
an initial test reaction.
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tR = 16.6 min. HMRS: calcd. for [C34H44N4O9S + Na+] 707.2721; found
707.2723.
philic attack occurs at the 4-position of the 1-aryl-1,3-diyne. Al-
though this concurs with previous literature data, often mix-
tures of regioisomers are reported if nonsymmetric alkyl- and
aryl-substituted 1,3-diynes are used,[22,23] which is clearly not
the case upon using peptides 13a–c.
Synthesis of Furan Peptide 6a: SPhosAuCl (0.03 mmol) and
AgNTf2 (0.03 mmol) were weighed into a vial and THF (0.2 mL) was
added. The mixture was stirred for 15 min at r.t. Compound 4a
(0.03 mmol) was dissolved in THF (0.2 mL) and added to the mix-
ture. Subsequently, MilliQ water (0.60 mmol, 33 μL) was added
while stirring. The mixture was stirred at 60 °C for 5 h and concen-
trated in vacuo. The obtained residue was purified by preparative
RP-HPLC to obtain 6a (1.2 mg, 6 %) as a white powder. tR = 16.7 min.
HMRS: calcd. for [C34H44N4O10 + Na+] 691.2950; found 691.2949.
Conclusions
In conclusion, the synthesis of various peptide macrocycles with
heterocycle-bearing tethers (thiophene 5, furan 6, cycloadduct
7, pyrazole 8, N-methylpyrazole 9, and isoxazole 10) was real-
ized under mild reaction conditions. In addition, it was shown
that a nonsymmetric arylated 1,3-diyne linker (i.e., 13a–c) gave
rise to the regioselective formation of the corresponding pyr-
azoles upon treatment with hydrazine. Further application of
these methods to larger peptide sequences and the potential
for reversible linking of such macrocycles through Diels–Alder
reactions is currently being evaluated and will be reported in
due course.
Synthesis of Pyrazole Peptide 8: A representative procedure is
given for the synthesis of 8. Compound 4c (0.033 mmol) was dis-
solved in DMSO (0.5 mL). NH2NH2·H2O (0.083 mmol) was added,
and the mixture was stirred at 60 °C for 15–48 h. DMSO was evapo-
rated under a stream of pressurized air, and the crude mixture was
purified by preparative RP-HPLC to obtain 8 (4.0 mg, 20 %) as two
regioisomers as a white powder. tR = 14.0 min. HRMS: calcd. for
[C30H42N6O9 + H+] 631.3086; found 631.3084.
Synthesis of Pyrazole Peptide 14b: A representative procedure is
given for the synthesis of 14b. Compound 13b (0.020 mmol) was
dissolved in DMSO (0.5 mL) and NH2NH2·H2O (0.08 mmol, 3 μL) was
added. The mixture was stirred at 60 °C for 15 h. The mixture was
lyophilized to obtain 10b (12.8 mg, 99 %) as a yellow powder. 1H
NMR (500 MHz, [D6]DMSO): δ = 8.10 (d, J = 8.0 Hz, 1 H), 7.79 (d, J =
8.0 Hz, 0 H), 7.74 (d, J = 7.1 Hz, 1 H), 7.27–7.40 (m, 5 H), 7.15–7.22
(m, 1 H), 7.08–7.14 (m, 1 H), 6.98–7.07 (m, 1 H), 6.94 (d, J = 7.5 Hz,
1 H), 6.65 (d, J = 6.6 Hz, 1 H), 5.99 (s, 1 H), 5.06–5.16 (m, 2 H), 4.53–
4.59 (m, 1 H), 4.39 (s, 2 H), 4.22 (t, J = 1.0 Hz, 1 H), 4.06–4.14 (m, 1
H), 3.99–4.06 (m, 1 H), 3.81–3.93 (m, 3 H), 3.61–3.70 (m, 2 H), 2.85
(t, J = 6.1 Hz, 2 H), 1.25–1.38 (m, 9 H), 1.16–1.23 (m, 4 H), 0.96 ppm
(d, J = 6.9 Hz, 2 H). 13C NMR (126 MHz, [D6]DMSO): δ = 171.9, 171.7,
171.5, 170.6, 169.8, 145.0, 139.2, 137.2, 135.8, 129.0, 128.3, 128.2,
127.9, 127.6, 127.5, 126.9, 103.7, 78.4, 68.7, 65.9, 65.6, 55.7, 52.3,
48.3, 48.1, 37.4, 32.1, 28.1, 17.2, 17.1 ppm. HRMS: calcd for
[C35H44N6O8 + Na+] 699.3113; found 699.3118.
Experimental Section
General Methods: Column chromatography purifications were con-
ducted on silica gel 60 (40–63 μm; Grace Davisil) or with a Grace
Reveleris X2 Flash Chromatography System on silica gel (prepacked
40 μm; Grace Reveleris) or C18 silica gel (prepacked 40 μm, Grace
Reveleris). TLC was performed on glass plates precoated with silica
gel 60F254 (Merck); the spots were visualized under UV light (λ =
254 nm) and/or KMnO4 (aq.) was used as the revealing system.
Preparative HPLC was conducted by using a Gilson semipreparative
HPLC system equipped with a Supelco Discovery Bio Wide Pore C18
column. Samples were analyzed with an Agilent 1100 Series HPLC
equipped with a Supelco Discovery Bio Wide Pore C18 column
(15 cm × 2.1 mm × 3 μm). The solvent system consisted of 0.1 %
trifluoroacetic acid (TFA) in water and 0.1 % TFA in acetonitrile. The
samples were then eluted through the column by using a gradient
ranging from 3 % acetonitrile to 97 % acetonitrile over 20 min (stan-
dard gradient) at a flow rate of 0.3 mL min–1. Melting points were
acquired with a Büchi Melting Point B-540. IR absorption spectra
were recorded with a Thermo Nicolet 700 FTIR spectrophotometer.
NMR measurements were performed with a Bruker Avance II spec-
trometer operating at 1H and 13C frequencies of 500.13 and
125.76 MHz, respectively. The sample temperature was set to
298.2 K. The deuterated solvent is mentioned in the analysis section
and tetramethylsilane was used as an internal standard. Chemical
shifts (δ) are given in parts per million (ppm), and coupling con-
stants (J) are given in Hertz (Hz). High-resolution mass spectrometry
was conducted with a Waters Micromass QTof in ESI+ mode by
using reserpine as the reference. Commercial amino acids and cou-
pling reagents were purchased from Novabiochem and Chem-Im-
pex. All other used reagents and chemicals were purchased from
Sigma–Aldrich and were used without further purification unless
otherwise specified.
Acknowledgments
The Vrije Universiteit Brussel (VUB) is acknowledged for finan-
cial support. M. Sc. Karolien Van Imp is acknowledged for her
contribution to the research.
Keywords: Cyclization · Diynes · Heterocycles · Nucleophilic
addition · Peptides
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Received: September 27, 2016
Published Online: ■
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Peptide Diyne Transformations
S. Verlinden, S. Ballet,
G. Verniest* .......................................... 1–7
Synthesis of Heterocycle-Bridged
Peptidic Macrocycles through 1,3-
Diyne Transformations
Macrocyclic tetrapeptides containing a cleophiles. This results in a variety of
1,3-diyne tether are synthesized by us- corresponding macrocycles bearing a
ing a mild Glaser–Hay-type coupling heterocycle in the cyclic core structure.
and are subsequently treated with nu- Boc = tert-butoxycarbonyl.
DOI: 10.1002/ejoc.201601215
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