A cyclooligomerisation approach to backbone-modified cyclic peptides bearing guanidinium arms

Article abstract of DOI:10.1055/s-0029-1219155

Cyclooligomerisation of the pentafluorophenyl ester derivatives of oxazoles, derived from dipeptides containing protected ornithine, diaminobutanoic acid and diaminopropionic acid residues, gives the cyclic trimers as the major products. Deprotection and treatment with guanidinylating agents provides efficient access to backbone rigidified cyclic peptides with guanidinium functionalised side chains. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1219155

LETTER
551
A Cyclooligomerisation Approach to Backbone-Modified Cyclic Peptides
Bearing Guanidinium Arms
Synthesis of
Guai
c
m
F
unction
h
alised
C
yclic
a
Peptide
s
rd J. G Black, Victoria J. Dungan, Rebecca Y. T. Li, Philip G. Young, Katrina A. Jolliffe*
School of Chemistry, The University of Sydney, 2006, NSW, Australia
Fax +61(2)93513329; E-mail: jolliffe@chem.usyd.edu.au
Received 9 November 2009
Dedicated to Professor Gerry Pattenden on the occasion of his 70th birthday.
12 and 13) and this has led to their incorporation in numer-
ous anion receptors and enzyme mimics.9 Cyclic peptide
scaffolds bearing guanidinium arms should find applica-
tion as anion receptors, enzyme mimics9 and, given their
Abstract: Cyclooligomerisation of the pentafluorophenyl ester de-
rivatives of oxazoles, derived from dipeptides containing protected
ornithine, diaminobutanoic acid and diaminopropionic acid resi-
dues, gives the cyclic trimers as the major products. Deprotection
and treatment with guanidinylating agents provides efficient access cationic peptide structure, may have antibiotic or other bi-
to backbone rigidified cyclic peptides with guanidinium functiona-
ological activity.
lised side chains.
Key words: peptides, macrocycles, cyclisation, heterocycles,
amides
NH
O
HN
NH2
O
n
R
The Lissoclinum class of natural products (e.g.,
westelliamide1 and ascidiacyclamide2) consists of cyclic
hexa-, hepta- and octapeptides that are characterised by
the presence of azole heterocycles derived from serine,
threonine or cysteine residues, alternating with amino acid
residues.3 These molecules often exhibit interesting bio-
logical activities (e.g., cytotoxic, antibiotic or immuno-
regulatory activity) and this has led to great interest in
their synthesis.3,4 It is well established that the alternating
pattern of heterocycles and amide bonds in the backbone
of these naturally occurring macrocycles results in a net-
work of bifurcated hydrogen bonds between the azole ni-
trogen atoms and the amide protons. This hydrogen-
bonding network is strongest in the hexapeptide
derivatives5 and holds the macrocyclic backbone of the
compounds relatively flat. If all side chains are of the
same configuration, they are presented on the same face of
the macrocycle in a convergent manner. This, together
with the development of efficient syntheses of analogues
of the natural products,1,5,6 has led to recent interest in the
use of such molecules as molecular scaffolds for the de-
velopment of molecular receptors, chiral ligands, artificial
proteins and combinatorial libraries.7 Whereas syntheses
of cyclic peptide scaffolds incorporating oxazoles, thiaz-
oles and/or imidazoles with a variety of side chains have
been reported, there are relatively few reports in the liter-
ature of their functionalisation with moieties capable of
molecular recognition.7b,m,8 We report here the efficient
synthesis of Lissoclinum analogues bearing guanidinium
arms (1–4; Figure 1). Guanidinium groups offer both hy-
drogen-bonding and electrostatic interactions over a wide
pH range, as a result of their high pKa (typically between
N
H
R
O
NH2
N
N
HN
N
H
NH
HN
O
n
N
O
n
O
NH
R
H2N
NH
1 n = 2, R = Me
2 n = 1, R = H
3 n = 0, R = H
NH
HN
NH2
O
n
NH2
O
O
HN
N
H
HN
N
N
N
O
n
NH
HN
O
n
N
NH
H2N
H
N
NH
O
O
O
n
H2N
NH
NH
4 n = 2
Figure 1 Structures of the guanidinium functionalised cyclic pepti-
des 1–4
There are two synthetic approaches to guanidinium-func-
tionalised lissoclinamide analogues. The first of these in-
volves synthesising the oxazole building blocks with a
protected guanidinium group in place, followed by cy-
clooligomerisation to give the required macrocycles; in
cyclooligomerisations of this type, the cyclic trimer and
SYNLETT 2010, No. 4, pp 0551–0554
0
1.
0
3.
2
0
1
0
Advanced online publication: 22.12.2009
DOI: 10.1055/s-0029-1219155; Art ID: D31609ST
© Georg Thieme Verlag Stuttgart · New York

552
R. J. Black et al.
LETTER
NHCbz
cyclic tetramer are normally the major products, with the
trimer/tetramer ratio dependent on the side chain structure
and normally favouring the cyclic trimer.5,6,7a The second
approach involves post-functionalisation of the side arms
attached to a prepared cyclic peptide scaffold. Our initial
approach to the target guanidinium compounds used the
former strategy, that is, via cyclooligomerisation of an ox-
azole amino acid building block derived from arginine.
Dipeptide 5, which was prepared by coupling Cbz-
Arg(Boc)2-OH with NH2-Thr-OBn under standard solu-
tion-phase peptide coupling conditions, was converted
into the corresponding oxazole 6, using a well-established
two-step (cyclodehydration followed by oxidation) proce-
dure (Scheme 1).10
NHCbz
n
O
n
H
N
O
i, ii
BocHN
BocHN
OMe
R
N
O
R
OH
CO2Me
10 n = 2, R = Me
11 n = 1, R = H
12 n = 0, R = H
13 n = 2, R = Me
14 n = 1, R = H
15 n = 0, R = H
iii, vi
iii, iv
NHCbz
NHCbz
O
n
n
F3C
O
BocN
NHBoc
O
O
BocN
NHBoc
BocHN
H3N
R
R
N
N
NH
O
NH
CO2Pfp
CO2H
16 n = 2, R = Me
17 n = 1, R = H
18 n = 0, R = H
25 n = 2, R = Me
26 n = 1, R = H
27 n = 0, R = H
O
i, ii
H
N
R1HN
CbzHN
OBn
OH
N
O
iv
CO2R2
5
v
6: R1 = Cbz, R2 = Bn
7: R1 = R2 = H
iii
NHCbz
O
Scheme 1 Synthesis of an arginine-derived oxazole. Reagents and
conditions: (i) DAST, CH2Cl2, –78 °C, then K2CO3, H2O; (ii) DBU,
BrCCl3, CH2Cl2, 0 °C, 60% over 2 steps; (iii) H2, Pd/C, MeOH, 90%.
n
F3C
O
19 + 22
20 + 23
21 + 24
O
vii
H3N
R
N
CO2Pfp
The N- and C-terminal protecting groups were then re-
moved in a single hydrogenolysis step to provide oxazole
7 in 90% yield. Unfortunately, all attempts to cyclooligo-
merise 7 gave only traces of the required cyclic trimer 8 or
cyclic tetramer 9 (see Scheme 3 for structures of 8 and 9).
We therefore decided to synthesise these compounds us-
ing the alternative strategy, commencing from the corre-
sponding amino-functionalised cyclic peptides derived
from ornithine (Orn). In addition, we prepared amino-
functionalised cyclic peptides derived from diamino-
butanoic acid (Dab) and diaminopropionic acid (Dpr), in
which the number of methylene units between the oxazole
and the amine group was varied, to provide molecular
scaffolds with functional groups at different distances
from the peptide scaffold. This was undertaken to investi-
gate the effect this distance has on anion binding of the
corresponding guanidinium derivatives, since it has previ-
ously been shown that similar macrocycles can bind an-
ions through the amide protons.11 Hence, the orthogonally
protected Boc-Orn(Cbz)-OH was coupled with threonine
methyl ester, while the similarly protected amino acids
with shortened side chains, Boc-Dab(Cbz)-OH and Boc-
Dpr(Cbz)-OH, were each coupled with serine methyl
ester, under standard peptide coupling conditions to give
the dipeptides 10–12, respectively (Scheme 2).
28 n = 2, R = Me
29 n = 1, R = H
30 n = 0, R = H
Scheme 2 Synthesis of cyclic peptides 19–24. Reagents and condi-
tions: (i) DAST, CH2Cl2, –78 °C then K2CO3, H2O; (ii) DBU, BrCCl3,
CH2Cl2, 0 °C, 59–90% over 2 steps; (iii) NaOH, MeOH, H2O, 66–
100%; (iv) TFA, CH2Cl2, 95–100%; (v) FDPP, DIPEA, DMF, 0.05
M, 11–21%; (vi) pentafluorophenyl 2,2,2-trifluoroacetate, CH2Cl2,
DMF, 51–98%; (vii) DIPEA, DMF, 0.05 M, 24–51%.
sponding oxazoles 13–15. Hydrolysis of the methyl
esters, followed by treatment with trifluoroacetic acid to
remove the Boc protecting groups, furnished the amino
acids 16–18 as the trifluoroacetate salts. Cyclooligomeri-
sation of 16–18 was attempted using a variety of peptide
coupling reagents (DPPA, FDPP, HBTU), with FDPP
giving the best yields of cyclic trimers 19–21 and cyclic
tetramers 22–24 in each case. However, in all cases, puri-
fication of these compounds from the coupling reagent
by-products (in particular, diphenylphosphinic acid) was
problematic. Therefore, we investigated an alternative
method of cyclooligomerisation in which the oxazoles
13–15 were converted into the corresponding pentafluo-
rophenyl esters 25–27 after ester hydrolysis and treatment
with pentafluorophenyl acetate.12 Selective removal of the
Boc protecting groups from 25–27 was achieved by treat-
ment with trifluoroacetic acid to give the amines 28–30,
which were immediately subjected to cyclooligomerisa-
tion in DMF, in the presence of diisopropylethylamine
The dipeptides were then treated with DAST to give the
intermediate oxazolines, which were not isolated but im-
mediately treated with DBU/BrCCl3 to give the corre-
Synlett 2010, No. 4, 551–554 © Thieme Stuttgart · New York

LETTER
Synthesis of Guanidinium Functionalised Cyclic Peptides
553
NHCbz
(DIPEA). In all cases, this procedure gave significantly
higher yields of the cyclic trimers 19–21 and cyclic tet-
ramers 22–24 than were obtained from the acids 16–18,
respectively, using any of the coupling reagents; further-
more, the pentafluorophenol by-product was easily re-
moved by a base washing.13 Notably, cyclooligo-
merisation of the pentafluorophenyl ester 30 gave cyclic
trimer 21 in 41% yield, which is more than twice the yield
(19%) previously obtained when DPPA was used as a
coupling agent to cyclise 18 in its free-base form.6k The
cyclic oligomers obtained from the pentafluorophenyl es-
ters were readily separated by either flash column chro-
matography or preparative reverse-phase HPLC. In all
cases, the cyclic trimers were the major products (24–
42%), with only trace amounts of the cyclic tetramers iso-
lated in most cases.
Br
NH3
n
n
O
i
N
O
N
H
R
H
N
R
N
O
O
m
m
19 n = 2, m = 3, R = Me
20 n = 1, m = 3, R = H
21 n = 0, m = 3, R = H
22 n = 2, m = 4, R = Me
23 n = 1, m = 4, R = H
24 n = 0, m = 4, R = H
31 n = 2, m = 3, R = Me
32 n = 1, m = 3, R = H
33 n = 0, m = 3, R = H
34 n = 2, m = 4, R = Me
ii
NH2
NBoc
X
The cyclic trimers 19–21 and the cyclic tetramer 22 were
treated with a solution of HBr in acetic acid to provide the
amines 31–34, respectively, as their hydrobromide salts
(Scheme 3). Several reagents were then investigated for
the conversion of the amines 31–34 into the correspond-
ing guanidine derivatives 8, 35, 36 and 9, respectively.
We found that this was best achieved in a two-step proce-
dure by guanidinylation with either N,N¢-bis(tert-butoxy-
carbonyl)-1H-pyrazole-1-carboxamidine14 or the more
HN
NH2
HN
NHBoc
n
n
iii or iv
O
O
N
N
H
H
R
R
N
O
N
O
m
m
1 n = 2, m = 3, R = Me
2 n = 1, m = 3, R = H
3 n = 0, m = 3, R = H
4 n = 2, m = 4, R = Me
8
n = 2, m = 3, R = Me
35 n = 1, m = 3, R = H
36 n = 0, m = 3, R = H
active
N,N¢-bis(tert-butoxycarbonyl)-N¢¢-triflylguani-
dine15 (with the latter generally giving higher yields),16
followed by removal of the Boc protecting groups upon
treatment with either trifluoroacetic acid or tin(IV) chlo-
ride in ethyl acetate to provide the guanidinium deriva-
tives 1–4 as the trifluoroacetate or chloride salts,
respectively. Yields for the guanidinylation reaction were
found to decrease as the length of spacer between the cy-
clic peptide scaffold and the amine to be guanidinylated
was shortened. Given the bulky nature of the Boc-protect-
ed guanidinylation reagents, this is most likely a result of
an increase in steric crowding about the macrocycles as
the side chains become shorter.
9
n = 2, m = 4, R = Me
Scheme 3 Synthesis of cyclic peptides 1–4. Reagents and conditi-
ons: (i) HBr, AcOH, quant.; (ii) N,N¢-bis(tert-butoxycarbonyl)-1H-
pyrazole-1-carboxamidine, DIPEA, DMF, 23–57% or N,N¢-bis(tert-
butoxycarbonyl)-N¢¢-triflylguanidine, DIPEA, CH2Cl2, 42–82%; (iii)
TFA, CH2Cl2, 90–100%, X– = CF3CO2 ; (iv) SnCl4, EtOAc, 81–
–
100%, X– = Cl–.
Acknowledgment
We thank Prof. T. C. Sorrell and N. Pantarat (University of Sydney
at Westmead Hospital) for performing the antifungal and antibacte-
rial assays and the Australian Research Council for financial sup-
port.
The tris- and tetra-guanidinium compounds 1–4 were test-
ed for their activity against three fungal strains (C. albi-
cans, A. fumigatus and C. neoformans) and four bacteria
(E. coli, P. aeruginosa, S. aureus and MRSA) but none
showed any significant antifungal or antibacterial activity
against any of the pathogens tested. This is in striking con-
trast to antibacterial activity observed for similar com-
pounds in which four guanidinium groups are attached to
calixarene scaffolds17 and is most likely a result of the
lack of amphipathicity in the cyclic peptide structures.18
References and Notes
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Chemical and Biological Perspectives, Vol. 12; Pelletier,
S. W., Ed.; Elsevier: Amsterdam, 1998, 187. (b) Wipf, P.
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9506.
In summary, the backbone-modified cyclic peptides 1–4
have been efficiently synthesised via the cyclooligomeri-
sation of Orn, Dab and Dpr derived oxazoles, followed by
deprotection and guanidinylation. We are currently inves-
tigating the ability of 1–4 to bind anions and the results of
these studies will be reported in due course.
Supporting Information for this article containing all experi-
mental prodedures is available online at http://www.thieme-
connect.com/ejournals/toc/synlett.
Synlett 2010, No. 4, 551–554 © Thieme Stuttgart · New York

554
R. J. Black et al.
LETTER
(5) Bertram, A.; Blake, A. J.; Gonzaléz-López de Turiso, F.;
Hannam, J. S.; Jolliffe, K. A.; Pattenden, G.; Skae, M.
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foam. This was dissolved in EtOAc–hexane (1:2) and passed
down a silica plug (EtOAc–hexane, 1:2→2:1) to give a
mixture of cyclic oligomers. These were then separated by
preparative HPLC {gradient 50→100% B [MeCN–TFA
(100:0.1)] in A [H2O–MeCN–TFA (95:5:0.1)] over 60
mins} to give the cyclic trimer 19, tR = 28.0 min (225 mg,
42%) and cyclic tetramer 22, tR = 30.1 min (58 mg, 9%) as
colourless foams. Data for 19: [a]D20 –21.6 (c 1.0, CHCl3).
1H NMR (200 MHz, CDCl3): d = 8.33 (d, J = 4.4 Hz, 3 H),
7.42–7.24 (m, 15 H), 5.22 (m, 3 H), 5.14 (m, 3 H), 5.06 (s,
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6 H), 3.24 (m, 6 H), 2.63 (s, 9 H), 2.12–1.90 (m, 12 H). 13
C
NMR (75 MHz, CDCl3): d = 160.79, 160.75, 156.4, 153.9,
136.5, 128.3, 128.2, 127.9, 127.8, 66.4, 47.5, 40.5, 32.0,
25.2, 11.5. MS (ESI): m/z = 1010 [M + Na]+. HRMS (ESI):
m/z [M + Na]+ calcd. for C51H57N9O12Na: 1010.4019; found:
1010.3999. Data for 22: [a]D20 –73.3 (c 0.9, CHCl3). 1H
NMR (400 MHz, CDCl3): d = 7.40 (d, J = 9.0 Hz, 4 H),
7.31–7.27 (m, 20 H), 5.36 (app dt, J = 9.0, 7.5 Hz, 4 H), 5.12
(m, 4 H), 5.04 (s, 8 H), 3.23 (m, 8 H), 2.60 (s, 12 H), 2.08
(m, 4 H), 1.95 (m, 4 H), 1.62–1.60 (m, 8 H). 13C NMR (100
MHz, CDCl3): d = 161.1, 161.0, 156.7, 154.3, 136.5, 128.6,
128.4, 128.2, 128.1, 66.7, 45.7, 40.6, 31.2, 26.3, 11.8. MS
(ESI): m/z (%) = 1339 (100) [M + Na]+. HRMS: m/z [M +
Na]+ calcd for C68H76N12NaO16: 1339.5395; found:
1339.5407.
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Chem. 1998, 63, 3804.
(16) Representative guanidinylation procedure: To a suspension
of 31 (0.12 g, 0.15 mmol) in CH2Cl2 (5 mL), DIPEA (0.14
mL, 0.75 mmol) was added and the solution was stirred at r.t.
for 15 min. N,N¢-di-Boc-N¢¢-triflylguanidine (0.32 g, 0.83
mmol) in CH2Cl2 (2 mL) was added via cannula and the
reaction mixture was stirred at r.t. for 21 h. The mixture was
diluted with CH2Cl2 (10 mL) and washed with 2 M NaHSO4
(10 mL), NaHCO3 (10 mL), brine (10 mL), dried (MgSO4)
and concentrated under reduced pressure to give a pale-
brown foam. The crude material was purified by flash
chromatography (hexane–EtOAc, 2:3) to give 9 as a
colourless foam (0.16 g, 82%); [a]D20 –1.0 (c 3.5, CHCl3). 1H
NMR (400 MHz, CDCl3): d = 11.49 (s, 3 H), 8.32 (s, 3 H),
8.31 (s, 3 H), 5.14 (m, 3 H), 3.47–3.45 (m, 6 H), 2.66 (s,
9 H), 2.15 (m, 3 H), 1.98 (m, 3 H), 1.81 (m, 3 H), 1.55 (m,
3 H), 1.48 (s, 54 H). 13C NMR (100 MHz, CDCl3): d = 161.0,
160.8, 156.1, 154.2, 153.3, 128.5, 83.3, 79.5, 47.8, 40.6,
32.1, 28.3, 28.1, 24.7, 11.7. MS (ESI): m/z (%) = 1312 (100)
[M + H]+, 1334 (20) [M + Na]+. HRMS: m/z [M + H]+ calcd
for C60H94N15O18: 1312.6896; found: 1312.6900.
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(13) Representative cyclooligomerisation procedure: Compound
25 (1.19 g, 1.95 mmol) was dissolved in CH2Cl2 (5 mL) and
TFA (15 mL) was added in one portion. The reaction
mixture was stirred at r.t. for 2 h and the solvents were
removed to give the trifluoroacetate salt 28 as a yellow foam.
This was dissolved in DMF (39 mL) and DIPEA (1.5 mL,
8.78 mmol) was added in one portion. The pale-orange
solution was stirred at r.t. for 3 d, then the DMF was
removed in vacuo to give an orange oil. This was redissolved
in EtOAc (50 mL) and washed with 1 M NaOH (2 × 3 mL),
brine (2 × 7 mL) and H2O (2 × 7 mL), dried (Na2SO4) and
concentrated under reduced pressure to give a dark-orange
Synlett 2010, No. 4, 551–554 © Thieme Stuttgart · New York