A novel route towards cycle-tail peptides using oxime resin: Teaching an old dog a new trick

Article abstract of DOI:10.1039/c8ob01868e

Two anabaenopeptins, Schizopeptin 791 and anabaenopeptin NZ825, have similar structural features and have been synthesized via a novel acid-catalyzed head-to-side-chain concomitant cyclization/cleavage reaction on oxime resin. The methodology gave rapid access to the anabaenopeptin scaffold by taking advantage of a combined solid-phase/solution-phase synthetic strategy. Also, as side-products of the synthesis, large C₂-symmetric 38-member cyclic peptides ring bearing two endocyclic lysine side-chains were isolated, constituting a novel cyclic peptide scaffold.

Full text of DOI:10.1039/c8ob01868e

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A novel route towards cycle-tail peptides using oxime resin: Teaching an old dog a
new trick
Christopher Bérubé, Alexandre Borgia, Normand Voyer
1Département de Chimie and PROTEO, Université Laval, Pavillon AlexandreꢀVachon,
Faculté des sciences et de génie, 1045 avenue de la Médecine, Québec, QC, Canada,
G1V 0A6
Keywords : cyclic peptide, oxime resin, anabaenopeptin, cyclization
Abstract
Two anabaenopeptins, Schizopeptin 791 and anabaenopeptin NZ825, have similar structural
features and have been synthesized via a novel acidꢀcatalyzed headꢀtoꢀsideꢀchain concomitant
cyclization/cleavage reaction on oxime resin. The methodology gave rapid access to the
anabaenopeptin scaffold by taking advantage of a combined solidꢀphase/solutionꢀphase synthetic
strategy. Also, as sideꢀproducts of the synthesis, large C2ꢀsymmetric 38ꢀmember cyclic peptides
ring bearing two endocyclic lysine sideꢀchains were isolated, constituting a novel cyclic peptide
scaffold.

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Introduction:
The identification of new natural products with useful bioactivities is a growing field of research,
driven by the needs of drug companies for compounds with unique structures.1 Cyanobacteria are
organisms that produce a rich diversity of secondary metabolites with a variety of biological
activities.2 Their secondary metabolites contain abundant variable peptide scaffolds, which are
often cyclic and usually contain nonproteinogenic and endocyclic amino acids.3
A significant number of cyanobacteria peptides share the common feature of a macrocyclic
depsipeptide core linked to a linear peptide chain.4 Among the diverse peptides that
microorganisms produce, cycleꢀtail peptides are a privileged scaffold. Well known cycleꢀtail
peptides such as daptomycin5 and polymyxin6 are widely used antibiotics on the market. Among
phytochemical cyclic peptides, the secondary metabolites known as anabaenopeptins (hereafter
APs) are characterized by a 19ꢀmembered ring with endocyclic DꢀLysine or Lꢀlysine.7
Natural macrocyclic products obtained by the lactamization between a terminal carboxylic acid
and the epsilon primary amine of the Nꢀterminus of a lysine have an exocyclic αꢀamine linked to
different substituents, such as an ureido chain (tail), as exemplified by schizopeptin 7917t and
similarlyꢀstructured anabaenopeptin NZ8257e, isolated from cyanobacteria Schizotrix sp. and
Anabaena sp. respectively (Figure 1). In addition to their unique structure, APs are of great
interest due to their inhibition of proteolytic enzymes and protein phosphatases. Interestingly,
schizopeptin 791 inhibited the serine protease trypsin with an IC50 of 45.0 ꢀg/mL. In contrast, no
activity have been reported for anabaenopeptin NZ825, most probably due to its very low
availability. Therefore, there is a need to develop a rapid synthetic procedure towards these
compounds. In fact, few synthetic methodologies have been developed towards anabaenopeptin
scaffold.8
By exploiting the nucleophilic cleavage susceptibility of the Kaiser/DeGrado oxime resin,9 we
achieved a convergent onꢀresin headꢀtoꢀsideꢀchain concomitant cyclization/cleavage to access the
AP scaffold. This strategy relies on the selective deprotection of orthogonally protected amino
acids (Boc/Cbz), then uses the free side chain amino group as a cleavage nucleophile. Indeed, as
the oxime ester linkage is stable in both acidic and nonꢀnucleophilic basic conditions, anchoring
linear peptides by an oxime ester bond allows peptide elongation on solidꢀsupport media with a
Boc strategy. After NꢀBoc removal, the susceptibility of the oxime resin to nucleophile attack
allows an easy release of the protected peptide via acidꢀcatalyzed Nꢀterminal macrocyclization.

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Though oxime resin has been used to prepare a rich diversity of small10 and large11 cyclic headꢀ
toꢀtail peptide rings, the onꢀresin synthetic method we report here is a new way to rapidly access
the AP scaffold by a headꢀtoꢀsideꢀchain concomitant cyclization/cleavage reaction.
L-Ile (4)
L-Ile (4)
O
H
O
O
O
L-Hph (3)
N
H
H
H
NH
NH
O
O
L-Hph (3)
N
N
N
H
H
NH
NH
HO
O
N
N
HO
O
O
N
O
L-Ile (6)
N
O
D-Lys (5)
NMe-Gly (2)
NMe-L-Ala (2)
D-Lys (5)
L-Phe (6)
O
HN
HN
O
O
L-Hph (1)
L-Phe (1)
Schizopeptin 791 (1)
Anabaenopeptin NZ825 (2)
Figure 1: Chemical structures of schizopeptin 791 and anabaenopeptin NZ825 (red: endocyclic
lysine)
Results and discussion
We designed our method to give a rapid and convergent synthesis of the AP scaffold. Our
retrosynthetic approach is described in Figure 2. We envisioned that APs could be prepared by
an exocyclic lateꢀstage ligation of a pꢀnitrophenylcarbamate amino benzyl ester and the free αꢀ
amino group appendage of AP’s cyclic peptide core.
The latter compound can be obtained by onꢀresin acidꢀcatalyzed headꢀtoꢀtail concomitant
cyclization/cleavage on oxime resin using the epsilonꢀamino group of a lysine as a nucleophile.
The strategy used orthogonally protected Dꢀlysine and NꢀBoc protected amino acids as starting
materials. The linear peptide chain elongation involves the use of NꢀBoc protected amino acids
coupled together using wellꢀknown coupling strategies to assemble the first four amino acids on
the resin. The key step is the insertion of ZꢀDꢀLys(Boc)ꢀOH at the fifth position, which allows
selective sideꢀchain lysine NꢀBoc deprotection. The free epsilonꢀamino group can then participate
in the headꢀtoꢀsideꢀchain cyclization/cleavage reaction, while the Nꢀterminal amine is unreactive
due to the benzyloxycarbonyl (Cbz) protection, thus making it impervious to undesired headꢀtoꢀ
tail cyclization side products.

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Exocyclic amine group
functionalization
O
H
O
O
N
NH
H
O
O
H2N
N
H
H
NH
O
N
N
HO
O2N
O
O
R3
N
+
R3
O
N
O
D-Lys
R2
O
N
COOBn
D-Lys
Urea formation
Side chain ligation
H
R2
O
NH
R1
3 steps
HN
NH
R1
HN
O
O
Anabaenopeptin scaffold
1. Lactamization
2. Hydrogenolysis
Cyclization site
O
O
R2
O
NHBoc
H
N
H
CbzHN
N
N
O
N
H
N
N
HO
O
O
R1
+
SPPS
Ph
CbzHN
COOH
R1 = Ph or Bn
R2 = H or Me
NH2
Oxime resin
Orthogonally protected D-lysine
On-resin head-to-side chain concomitant cyclization/cleaveage
Figure 2: Retrosynthetic approach towards the AP scaffold
Following the retrosynthetic pathway, all peptides were prepared on oxime resin with a low
substitution level (0.3 mmol/g) using the protocols illustrated in Figure 3 (see ESI for details).
Low oxime functionalization on polystyrene has been used as higher resin loadings increase the
undesired oligomerization process.12 Briefly, the first amino acid was coupled for three hours
using diisopropylcarbodiimide (DIC) as a coupling reagent. The NꢀBoc protecting group was
removed using a mixture of 1:1 trifluoroacetic acid (TFA)/dichloromethane, while the second
amino acid was activated with 6ꢀchloroꢀ1ꢀhydroxybenzotriazole (6ꢀClꢀHOBt) and 1ꢀ
[Bis(dimethylamino)methylene]ꢀ1Hꢀ1,2,3ꢀtriazolo[4,5ꢀb]pyridinium 3ꢀoxid hexafluorophosphate
(HCTU). The Kaiser test showed that each coupling step on the resin was quantitative. After the
appropriate deprotection step, the linear peptide was simultaneously cyclized and cleaved from
the resin in the presence of diisopropylethylamine (DIEA; 2.5 equiv) and acetic acid (AcOH; 5
equiv) in dichloromethane at a respectable 10ꢀ2 M precursor concentration according to the
starting loading of the resin, leading to high macrocyclization yield (72ꢀ74%) of Cbzꢀprotected
cyclic peptides 3 and 4. As reported in the literature, incorporating a flexible aliphatic chain (we
used lysine) facilitated the peptide folding and thus the macrocyclization process.13

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The crude cyclization/cleavage compounds contained mainly the desired cyclized peptides but
also a proportion of cyclic peptide dimers. The C2ꢀsymmetric cyclic dimers originate from the
amino group attacking a neighboring monomer on the resin as the initial step. Then, the terminal
lysine amino group cyclized on the resin to provide the cyclic dimers. Hence, lowering the resin
loading could potentially decrease this side reaction. Although, more work is needed to confirm
this hypothesis. The separation of the desired products from the cyclic dimers was difficult at this
stage due to solubility problems. We decided to proceed with the next step towards the AP, the
exocyclic amine deprotection by hydrogenolysis.
Peptides 3 and 4 were deprotected by catalytic palladium hydrogenation using mild conditions in
EtOH with 1 atm of hydrogen to yield the two desired cyclic peptides 5 and 6. HPLCꢀTOFꢀmass
spectrometry was used to distinguish between the desired protected compounds 5 and 6 and their
cyclic dimers, as reported previously.11d In both cases, only two peaks were revealed, both with
identical masses (see ESI for details). However, the first peak possesses an isotopic m/z ratio
equal to one, while the second peak has an isotopic m/z ratio equal to 0.5. The isotopic ratio
distribution analysis confirms that the first peaks corresponded to the desired cyclic monomers 5
and 6, while the second peaks of the chromatograms corresponded to the cyclic dimers 7 and 8.
The 38ꢀmember macrocyclic peptide sideꢀproducts were obtained in 22% and 33% with
dimerization followed by cyclization/cleavage.

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Figure 3: Synthesis of APs cyclic peptides 5 and 6 and their cyclic dimers isolated.
At this stage, RPꢀHPLC preparative purification was used to separate the cyclic monomer from
the cyclic dimer formed in the cyclization process. Unfortunately, this step required long
purification times and had high losses, yielding small quantities of the desired compounds.
However, we have developed a powerful normalꢀphase chromatography method that allows the
separation of 5 and 6 from their cyclic dimers. The purification was performed using mediumꢀ

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pressure liquid chromatography system equipped with a SiliaSep Premium (169 x 27 mm i.d.)
flash cartridge loaded with silica as the stationary phase (25 µm). We used gradients of
dichloromethane and methanol as eluents to afford the desired pure peptides 5 and 6 with
satisfying isolated yields of 60% and 58% respectively. Also, we isolated the C2ꢀsymmetric
dimers 7 and 8 in 11% and 13% yield respectively. These cyclodimers possess a novel 38ꢀ
membered macrocyclic peptides incorporating two endocyclic lysine sideꢀchains. To the best of
our knowledge, this is the first report of large C2ꢀsymmetric 38ꢀmember macrocyclic peptides
from in situ dimerization/cyclization/cleavage on oxime resin.

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Figure 4: ESI mass spectrum of cyclized peptide 5 obtained (above) and cyclic dimer 7 (below)
with calculated monomer (5) and dimer (7) isotopic (inserts).
In producing APs, the penultimate step is the ligation between the cyclic peptides 5 or 6 and the
protected pꢀnitrophenyl carbamate 9 or 10. The final synthetic steps to obtain APs 1 and 2 are
illustrated in Figure 5. The pꢀnitrophenylcarbamate amino acid benzyl esters 11 and 12 were
prepared in three steps from commercially available NꢀBoc isoleucine or NꢀBoc phenylalanine.
Carboxylic acid benzylation of NꢀBoc isoleucine and phenylalanine using benzyl bromide led to
compounds 9 and 10 in 82% and 90% yields, respectively. After NꢀBoc removal using pꢀTsOH,
the free amine was treated with pꢀnitrophenylchloroformate in the presence of Et3N to give
compounds 11 and 12 in 75% and 80% yields. Compound 12 was difficult to purifiy from traces
of pꢀnitrophenol. Since it is used in excess in the tail ligation reaction, we decided to use it as is.
Notably, exocyclic ligation of cyclic peptides 5 or 6 with the pꢀnitrophenylcarbamate amino
benzyl esters 11 or 12 in DCM or in THF provided the desired intermediates 13 and 14 in poor
yields. However, same reaction between cyclic peptides 5 or 6 and 11 or 12 had good yields (55%
and 51% respectively) using optimized conditions in DMF with the presence of DMAP (0.1
equiv.) and Et3N (10 equiv.). Interestingly, performing the reaction without DMAP afforded
intermediates 13 and 14 in low 24% and 20% yields respectively. Finally, hydrogenolysis using
palladium on activated carbon in EtOH provided a 91% yield of schizopeptin 791 (1) and a 90%
yield of anabaenopeptin NZ825 (2). HPLC semiꢀpreparative purification afforded pure
schizopeptin 791 (1) and anabaenopeptin NZ825 (2); their spectroscopic data matched perfectly
with those reported for the isolated natural products (see ESI for details), confirming the first total
synthesis of schizopeptin 791 (1) and anabaenopeptin NZ825 (2). Chemical shifts are identical
within ± 0.05. The largest differences observed for NH chemical shifts are due to a concentration
effect or to traces of water.

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1. p-TsOH
DCM/EtOH 1:1, 30 min, r.t.
R3
R3
BnBr, K2CO3
MeCN, r.t., 16h.
BocHN
COOH
BocHN
COOBn
2. p-NO2chloroformate, pyridine,
(9) : R3 = sec-butyl, 82%
(10) : R3 = Ph, 90%
DCM, -10 oC to 5 oC, 3h.
(11) : R3 = sec-butyl, 75%
(12) : R3 = Ph, 80%
O
H
DMAP, Et3N
DMF, 48h, r.t.
O
O
N
O2N
H
H
NH
O
O
R3
N
N
BnO
O
5 or 6
N
COOBn
R3
O
H
N
O
(13) : R1 = Ph, R2 = Me, R3 = sec-butyl 55%
(14) : R1 = Bn, R2 = H, R3 = Bn, 51%
R2
NH
R1
HN
O
O
H
O
O
N
H2 1 atm, 10% Pd/C
H
H
NH
N
N
Schizopeptin 791 (1) : R1 = Ph, R2 = Me, R3 = sec-buty, 91%
Anabaenopeptin NZ825 (2) : R1 = Bn, R2 = H, R3 = Bn 90%
HO
EtOH/THF 1:1, 24h, r.t.
O
R3
O
N
O
R2
NH
R1
HN
O
Figure 5: Sideꢀchain synthesis, exocyclic ureamidation and deprotection procedures for the
synthesis of 1 and 2.
Conclusions
We achieved the first total synthesis of schizopeptin 791 (1) and anabaenopeptin NZ8257e7e (2)
with high overall yields between 22% to 19%. The synthesis is based on the use of orthogonally
protected lysine to graft endocyclic lysine by acidꢀcatalyzed onꢀresin headꢀtoꢀsideꢀchain
cyclization/cleavage. Linear precursor cyclization proceeded in excellent yields with up to 78%
and 67% of the desired cyclic monomers. Hydrogenolysis gave the exocyclic free amine,
followed by tail ligation and final deprotection, rapidly yielding 1 and 2. In addition, we reported
the first synthesis of a novel cyclic peptide scaffold, large C2ꢀsymmetric 38ꢀmembered cyclic
peptides bearing two endocyclic lysines. Overall, the work described can be applied to the
preparation of a rich diversity of anabaenopeptins and other cycleꢀtail peptides. Evidently,
performing the complete synthesis onto solidꢀphase is a very attractive and alternative synthetic
approach towards natural cycleꢀtail peptides. We are exploring currently such approach using
Alloc protected lysine for selective side chain deprotection. However, results have been
disappointing so far.

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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful to NSERC of Canada and to FRQNT of Québec for financial support. CB also
thanks FRQNT for a graduate scholarship and PROTEO for a travel award. The authors wish to
thank François Otis for his technical assistance with chiral HPLC, and Pierre Audet for mass
spectrometry analysis.
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Organic & Biomolecular Chemistry
Page 12 of 12
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DOI: 10.1039/C8OB01868E
Graphical Abstract:
O
O
O
R2
O
H
O
O
H
N
H
N
H
H
CbzHN
NH
N
N
N
N
N
H
N
O
HO
O
O
O
R1
R3
O
1. Hydrogenolysis
2. Side-chain ligation
3. Final deprotection
Oxime resin
N
Ph
R2
R1 = Ph or Bn
NH2
R
2 = H or Me
O
NH
R1
HN
Schizopeptin 791 (1) : Overall yield : 22 %
Anabaenopeptin NZ825 (2) : Overall yield : 19 %
O
On-resin head-to-side chain concomitant cyclization/cleaveage
In this paper, two anabaenopeptins cycleꢀtail peptides were synthesized via a novel acidꢀcatalyzed
headꢀtoꢀsideꢀchain concomitant cyclization/cleavage reaction on oxime resin.