Studies on Aculeines: Synthetic Strategy to the Fully Protected Protoaculeine B, the N-Terminal Amino Acid of Aculeine B

Article abstract of DOI:10.1021/acs.orglett.8b01331

A synthetic strategy for accessing protoaculeine B (1), the N-terminal amino acid of the highly modified peptide toxin aculeine, was developed via the synthesis of the fully protected natural homologue of 1 with a 12-mer poly(propanediamine). The synthesis of mono(propanediamine) analog 2, as well as core amino acid 3, was demonstrated by this strategy. New amino acid 3 induced convulsions in mice; however, compound 2 showed no such activity.

Full text of DOI:10.1021/acs.orglett.8b01331

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Studies on Aculeines: Synthetic Strategy to the Fully Protected
Protoaculeine B, the N‑Terminal Amino Acid of Aculeine B
Hiroki Shiozaki,† Masayoshi Miyahara,† Kazunori Otsuka,† Kei Miyako,‡ Akito Honda,‡
Yuichi Takasaki,† Satoshi Takamizawa,† Hideyuki Tukada,† Yuichi Ishikawa,† Ryuichi Sakai,‡
and Masato Oikawa*,†
†Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan
‡Faculty of Fisheries Sciences, Hokkaido University, Hakodate 041-8611, Japan
S
* Supporting Information
ABSTRACT: A synthetic strategy for accessing protoaculeine B (1), the N-
terminal amino acid of the highly modified peptide toxin aculeine, was
developed via the synthesis of the fully protected natural homologue of 1 with
a 12-mer poly(propanediamine). The synthesis of mono(propanediamine)
analog 2, as well as core amino acid 3, was demonstrated by this strategy. New
amino acid 3 induced convulsions in mice; however, compound 2 showed no
such activity.
culeines (ACUs, Figure 1) are modified peptide toxins
isolated from the marine sponge Axinyssa aculeata
A
Figure 1. Schematic structures of ACU-A, ACU-B, and the N-terminal
residues pACU-A and pACU-B (1).1,2
Figure 2. Protoaculeine B (1) and the artificial partial structures 2 and
3.
collected in Iriomote, Japan.1 To date, three ACUs (A−C)
have been isolated as the principle toxic compounds in the
sponge.1 ACU-A and ACU-B are comprised of a common 44-
amino acid ribosomal peptide, AcuPep, conjugated with highly
modified protoaculeine residues on their N-termini.
Protoaculeine B (pACU-B, 1, Figures 1 and 2) was isolated
from the same sponge in its free form and was readily identified
as an N-terminal amino acid derivative of ACU-B.2 Structurally,
1 is composed of a tryptophan-derived heterotricycle and a
long-chain polyamine (LCPA) that is a linearly extended 14-
mer of 1,3-propanediamine. ACUs are the first example of
peptides that are post-translationally modified by polyamine;
the exception to this is silaffin,3 which is a silica-depositing
protein bearing LCPA-modified lysine residues that was found
in the silica skeleton of a diatom.
membranes1 through the unique interaction between ACUs
and the plasma membrane; for example, ACU-A lysed
erythrocytes with greater potency than sodium dodecyl sulfate
(SDS), but its efficacy was less than 80% of that of the
detergent.1 This “partial” action of ACU-A suggested that the
membrane disruption by ACU-A was partly reversible; yet, its
detailed mechanism of action is yet to be determined.
Recently, independent of this study, LCPA was reported to
interact with lipid bilayers to form three-dimensional stacks on
the surface of artificial lipid membranes, but the stack formation
depended on the number of polyamine units in the LCPA.4
This observation suggests the possibility that the LCPA moiety
ACUs are toxic to various mammalian cells and show pro-
convulsant activity in mice. Interestingly, the mechanism of
these discrete actions stems from their ability to disrupt cell
Received: April 27, 2018
© XXXX American Chemical Society
A
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in the ACUs also plays a significant role in the unique
interactions between ACUs and cell membranes. Natural
ACUs, however, were obtained as an inseparable mixture of
homologues with different LCPA lengths.1 Thus, it has been
difficult to examine the above hypothesis using pure,
structurally defined compounds. Toward our ultimate goal of
a chemical synthesis of ACUs, various analogues, and model
compounds, herein, we developed a synthetic strategy for
accessing pACUs via the preparation of the fully protected
minor homologue of 1. We also discuss the bioactivity of the
unprotected core amino acid with mono(propanediamine) 2
and desLCPA analog 3.
racemization was observed here, when the synthesis started
with L-tryptophan. However, an enantioselective synthesis using
this route would be possible starting from L-tryptophanol, and
this is currently underway.7 Homologation of the C-ring carbon
chain by cross metathesis of 7 with tert-butyl acrylate mediated
by Zhan catalyst-1B8 gave α,β-unsaturated ester 8 in 65% yield.
Regioselective hydrogenation of 8 (H2, 5% Pd/C) afforded 9,
which was then treated with TFA to quantitatively form
carboxylic acid 10.
With carboxylic acid 10 in hand, a Friedel−Crafts-type
cyclization was attempted for the construction of the C-ring
(Scheme 2). Because O-acylphosphoric acid is known to be a
Retrosynthetically, 1 can be prepared from two fragments,
heterotricyclic N-Ns amine fragment A and hydroxylated LCPA
fragment B, which were expected to be assembled by a
Mitsunobu reaction (Figure 3). First, we synthesized mono-
Scheme 2. Formation of the C-Ring and Stereoselective
Elaboration of the (11S*)-Amino Group
Figure 3. Key fragments for our synthesis of pACU-B (1). PG =
protecting group.
(propanediamine) analog 2 in racemic form via fragment A,
featuring the stereoselective introduction of the C11-amino
group via an oxime. Then, we conducted an iterative synthesis
of poly(propanediamine) toward fragment B employing our
new strategy of using a photoremovable 1-(2-nitrophenyl)-
ethoxycarbonyl (NPEC) group for the temporary protection of
the amines. From fragments A and B, fully protected pACU-B
31 with the 12-mer polyamine was finally synthesized, and the
utility of our strategy for incorporating various polyamine side
chains into the desired amino acid is demonstrated, as follows.
First, we prepared phthalimide (Phth)-protected tryptophan
derivative 5, which was esterified to provide 6 in 91% yield
(Scheme 1).5 N-Allylation of 6 with allyl bromide and Cs2CO3
afforded 7 in 93% yield.6 It should be noted that complete
suitable intermediate when an indole derivative is used as the
substrate,9 we first used polyphosphoric acid, which gave
ketone 11 in 25% yield at 90 °C; however, the yield was
dramatically improved to 72% when P2O5 was employed in p-
xylene at reflux.10 The structure of 11 was confirmed using
NMR spectroscopy. To introduce a nitrogen-containing
functional group at the C11 position on the C-ring, we first
examined an Ir-catalyzed reductive amination;11 however, this
strategy only induced elimination across C11−C12 of 11. After
several trials, a multistep sequence via an oxime was found to be
the most practical strategy. Thus, ketone 11 was reacted with
NH2OH·HCl in pyridine to provide oxime 12 in excellent yield
(95%), which was then converted to N-Ac enamide 13. In this
transformation, following the report by Tang,12 Fe(OAc)2 and
Ac2O gave desired acetamide 13 in a satisfactory yield (65%)
accompanied by oxime O-acetate 13a (14%, see Scheme 2) and
ketone 11 (5%). Since enamide 13 was unstable even in
CDCl3, ketone 11 would have been generated by acidic
hydrolysis of 13. It was also found that oxime O-acetate 13a is
an intermediate, since it was converted to N-Ac enamide 13 in
53% yield upon exposure to the same reaction conditions used
for the conversion of 12 to 13 (Fe(OAc)2, Ac2O, AcOH, THF,
60 °C). A related observation has been reported by Bonderoff
et al.13
Scheme 1. Homologation of the C-Ring Carbon Chain
B
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Next, we attempted the regio- and stereoselective hydro-
genation of enamide 13 (Scheme 2). Due to the poor solubility
of 13 in EtOH, the reaction was conducted under dilute
conditions (0.03 M), and gratifyingly, the desired (9S*,11S*)
isomer of 14 was obtained as the major product (89% yield)
along with the (9S*,11R*) diastereomer of 15 (11%). The
stereochemistry of 14 was determined by single-crystal X-ray
analysis (Figure 4). The stereoselectivity is apparently
Scheme 3. Synthesis of the Mono(propanediamine) Analog
2
Figure 4. ORTEP drawing of conformer A of rac-14 with the
ellipsoids obtained from single-crystal X-ray diffraction measurements
at 183 K drawn at the 50% probability level.
controlled by the chiral center in the amino acid side chain
through remote asymmetric induction. In fact, the crystal
structure of product 14 (Figure 4) shows that the upper face is
sterically shielded by the Phth group. Thus, the hydrogen
atoms on the catalyst surface might only have approached from
the α-face of 13 during the hydrogenation.
With fully functionalized heterotricycle 14 in hand, some
protecting group manipulations were carried out in a stepwise
manner to prepare N-Ns amine 20 (Scheme 3), key
heterotricyclic fragment A. First, a Boc group was introduced
onto the acetamide (Boc2O, DMAP, THF, reflux) to give imide
16 in 79% yield, which was then treated with H2NNH2·H2O in
refluxing THF to induce simultaneous removal of the Phth14
and Ac15 groups, furnishing amine 17 in 85% yield. Then,
amine 17 was transformed into N-Ns amine 20. Thus, after
protection of amine 17 with an Alloc group (AllocCl, Et3N),
the Boc group was removed by Ohfune’s two-step procedure16
to give amine 19 (100% over two steps), and 19 was
immediately reprotected with NsCl to furnish desired N-Ns
amine 20 in 99% yield.
As we planned to employ a Mitsunobu reaction for the
coupling of the key fragments (Figure 3),17 the applicability of
this strategy was tested by synthesizing mono(propanediamine)
analog 2 from N-Ns amine 20 and alcohol 2118 (Scheme 3).
Although we expected the coupling at such a sterically crowded
N-Ns amine to be difficult, the reaction proceeded quite
smoothly by using DEAD and PPh3 in CH2Cl2, and 22 was
generated in 89% yield in 1 h. Coupling product 22 was found
to be stable, and no competing side reactions such as
elimination across the C11−C12 bond were observed. Finally,
fully protected pACU-B analog 22 with a mono(propane-
diamine) chain was subjected to sequential deprotection of the
Alloc group by Pd(0),19 Ns group by thiophenoxide,17b and
Boc group and methyl ester by acidic hydrolysis to furnish rac-2
in 91% yield over three steps. The overall yield was 9.5% for 20
total steps. desLCPA analog rac-3 was also synthesized from 17
by acidic hydrolysis (see Figure 2 and the Supporting
Information (SI)).
the 12-mer polyamine with 11 Ns groups by the Ns
strategy.17b,21 Unfortunately, the protected polyamine was
found to be insoluble in most generally used organic solvents
except for DMF and pyridine.22 We thus sought to reduce the
number of the Ns groups to improve the solubility. The
synthesis of the 12-mer polyamine 29 with four Ns groups by
our new strategy,23 which utilizes two persistent (Boc, Ns) and
one temporary (NPEC)24 protecting groups on the amines, is
shown in Scheme 4. Here, 3-mer polyamine 25 was designed as
the key building block for the iterative synthesis of 12-mer
polyamine 29, and 25 was prepared from 1,3-propanediamine
over five steps (see the SI). Photoirradiation of N-NPEC-N-Ns
amine 25 by a high-pressure Hg lamp (MeOH, 0 °C, 10 min)
provided N-Ns amine 26 in 94% yield without decomposition
of the Ns group. On the other hand, 25 was also converted to
alcohol 27 in 88% yield by the selective deprotection of the Tr
group by exposure to 2,2,2-trifluoroethanol (TFE) at reflux.
Mitsunobu coupling (DEAD, PPh3, PhH) of N-Ns amine 26
and as-prepared alcohol 27 gave 6-mer polyamine 28 in 82%
yield. 12-Mer polyamine 29 was synthesized similarly by the
coupling of two 6-mers derived from 28 by repetition of the
three-step sequence (split, deprotection, and coupling, see
Scheme 4). As expected, as-prepared 12-mer polyamine 29
showed satisfactory solubility in organic solvents such as PhH,
CHCl3, and EtOAc. The overall yield for 29 was 2.3% over nine
steps from 1,3-propanediamine.
Then, we turned our attention to LCPA fragment B (see
Figure 3),20 and we began our synthesis with the preparation of
C
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Scheme 4. Synthesis of Fully Protected pACU-B 31 with 12-mer LCPA
Finally, the coupling between heterotricyclic part A and long-
chain portion B was conducted, as follows (Scheme 4). First,
the Tr ether of 29 was cleaved with TFE to give alcohol 30
(90% brsm), which was then subjected to Mitsunobu coupling
with N-Ns amine 20. In the presence of excess DEAD (3
equiv), the reaction was complete in 3 h and furnished 31 in
63% yield as the fully protected conjugate of the modified
tryptophan and 12-mer LCPA. Although pACU-B (1) was
reported to bear 14-mer LCPA,2 minor homologues with
LCPA structures ranging from 12- to 15-mers were also
observed (see the SI). Thus, 12-mer 31 synthesized herein can
be regarded as the precursor to the natural form. Attempts
toward the final deprotection in a stepwise manner are
currently underway.
With unique amino acids 2 and 3 in their unprotected forms
in hand, we tested their biological activities. Since ACUs exhibit
potent convulsant activity in mice upon intracerebroventricular
(i.c.v.) injection, 2 and 3 were administered (i.c.v.) at 50 μg/
mouse. Interestingly, desLCPA analog 3 induced convulsions
including myoclonic convulsions, while mono(propane-
diamine) analog 2 did not cause noticeable behavioral changes
in the mice. Neither 2 nor 3 showed cytotoxicity or cell lysis
activity in cultured tumor cells (HeLa cells) at 100 μg/mL,
which suggests the importance of LCPA and/or AcuPep in
interacting with the cell membrane. Introducing even a short
polyamine unit onto desLCPA analog 3 can reduce the activity
of 3, which is consistent with our previous observation that 1
did not cause behavioral effects in mice. Since the behavioral
activity observed in 3 has obviously no relation to the inherent
cytotoxicity or the cell lysis activity of ACUs, detailed
evaluation of the activity of 3 against neuronal receptors is in
progress, and the results will be reported in due course.
In conclusion, we have developed pathways to synthesize
fully protected pACU-B 31, which is expected to pave the way
for the large-scale synthesis of 1 in a structurally defined
manner. The rapid synthesis of related compounds would be
possible on a polymer support if an NPEC group is employed
as a photocleavable linker.25 The putative neuronal activity
observed in rac-3 may suggest its potential interaction with
synaptic receptors.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01331.
Detailed experimental procedures and analytical data for
all new compounds (PDF)
Accession Codes
CCDC 1833350 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
D
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: moikawa@yokohama-cu.ac.jp.
ORCID
Yuichi Takasaki: 0000-0001-7377-817X
Ryuichi Sakai: 0000-0001-6490-0495
Masato Oikawa: 0000-0002-3919-811X
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by a Grant-in-Aid for
Scientific Research (15H04546 to R.S.) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
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