Solid phase total synthesis of callipeltin e isolated from marine sponge Latrunculia sp.

Article abstract of DOI:10.1016/j.tetlet.2011.05.062

Solid phase total synthesis of callipeltin E (1), truncated linear peptide isolated from marine sponge, Latrunculia sp. was achieved. Our strategy based on traditional Fmoc-SPPS was in common use TFA-treatment final deprotection to reach callipeltin E (1) contained acid-sensitive βMeOTyr.

Full text of DOI:10.1016/j.tetlet.2011.05.062

Tetrahedron Letters 52 (2011) 3872–3875
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Tetrahedron Letters
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Solid phase total synthesis of callipeltin E isolated from marine sponge
Latrunculia sp.
Mari Kikuchi a, Kazuto Nosaka b, Kenichi Akaji c, Hiroyuki Konno a,
⇑
a Department of Biochemical Engineering, Graduate School of Science and Technology, Yamagata University, Yonezawa 982-8510, Japan
b Department of Chemistry, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan
c Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Solid phase total synthesis of callipeltin E (1), truncated linear peptide isolated from marine sponge,
Latrunculia sp. was achieved. Our strategy based on traditional Fmoc-SPPS was in common use
TFA-treatment final deprotection to reach callipeltin E (1) contained acid-sensitive bMeOTyr.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 15 April 2011
Revised 11 May 2011
Accepted 13 May 2011
Available online 27 May 2011
Keywords:
Unusual amino acid
Marine sponge
Callipeltin
Solid phase synthesis
Callipeltin E (1) is an acyclic hexapeptide isolated from the
marine sponge Latrunculia sp. by D’Auria and co-workers in
2002.1 Callipeltin E (1) was shown to be a truncated, open-chain
derivative of callipeltin A (2) (Fig. 1). Callipeltin A (2), isolated from
the shallow water sponge Callipelta,2,3 is the first natural peptide
found to act against HIV and shows antifungal activity and potent
cytotoxicity against several human carcinoma cell lines.4,5,6 Calli-
peltin E (1) is composed of unique amino acids: N-methylalanine
(MeAla), b-methoxytyrosine (bMeOTyr), N-methylglutamine
(MeGln), leucine (Leu),
D-arginine (D-Arg), and D-allothreonine
(D-alloThr). The configuration of bMeOTyr, which could not be
determined in Minale’s isolation study,3 was determined as 2R,3R
by D’Auria and co-workers7 using chemical degradation of callipel-
tin A (2) and derivatization of the resulting amino acids, and also
by Konno et al.8 using NMR comparison of four diastereoisomeric
tripeptides, independently. On the other hand, by employing
quantum mechanical calculation of coupling constants, it was
suggested by Bifulco and co-workers9 that both of the threonine
residues in callipeltin A (2) have a
these reports, callipeltin E (1) was determined to have the struc-
ture H- -alloThr- -Arg-Leu-N-MeGln-(2R,3R)-bMeOTyr-N-MeAla-
D-allo configuration. Based on
D
D
OH. Lipton reported the solid phase synthesis and confirmation
of the configurational assignment of callipeltin E (1).10 Although
Lipton did not use acidic conditions in the study due to the acid-
sensitive nature of the bMeOTyr residue, we recently reported that
⇑
Corresponding author.
E-mail address: konno@yz.yamagata-u.ac.jp (H. Konno).
Figure 1. Callipeltin E (1) and calliepltin A (2).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.062

M. Kikuchi et al. / Tetrahedron Letters 52 (2011) 3872–3875
3873
bMeOTyr was not decomposed by TFA treatment.8 The results were
a major advantage to construct the depsipeptide such as callipel-
tins and similar complex molecules in the point of permission to
employ the traditional Fmoc-solid phase peptide synthesis
(Fmoc-SPPS).
For the solid phase total synthesis of callipeltin A (2) and its
analogues using the traditional Fmoc-SPPS strategy, we decided
to synthesize callipeltin E (1) as a model peptide. Herein, we report
the efficient solid phase synthesis of callipeltin E (1) based on the
Fmoc-SPPS strategy.
Our approach to the synthesis of callipeltin E (1) employed
traditional Fmoc-SPPS, that is, both Fmoc deprotection using
piperidine and TFA-mediated final deprotection. Prior to the total
synthesis of callipeltin E (1), the necessary four unusual amino
acids with protecting groups, Fmoc-MeAla-OH (3), Fmoc-
bMeOTyr(OMEM)-OH (4), Fmoc-MeGln-OH (5), and Fmoc-
D-all-
oThr-OH (8) were synthesized (Scheme 1).
The required residue Fmoc-(2R,3R)-bMeOTyr(OMEM)-OH (4)
was synthesized from the previously reported aziridine derivative
(9) in three steps with 94% overall yield8,11 (Scheme 2). In the
previous report,8 aziridine was opened using catalytic BF3ÁEt2O
and 10 equiv of MeOH in CH2Cl2, but the diastereoselectivity of
the ring opening was moderate (3:1). In an attempt to improve
diastereoselectivity, we found that treatment of aziridine (9) with
a catalytic amount of BF3ÁEt2O in MeOH at room temperature gave
anti-methoxyamine, and then an ethoxycarbonyl group was
saponified to afford the amino acid (10). It was noted that MeOH
for methoxy source was effective to use as a solvent. Under these
conditions, anti-substitution was observed, leading to no loss of
Scheme 2. Preparation of Fmoc-(2R,3R)-bMeOTyr(OMEM)-OH (4).
diastereoselectivity (>20:1). The amino acid (10) was protected
with Fmoc-OSu to yield Fmoc-(2R,3R)-bMeOTyr(OMEM)-OH (4)
in quantitative yield.
a
a
Fmoc-N -MeAla-OH (3) and Fmoc-N -MeGln-OH (5) were
a
prepared from commercially available Fmoc-N -Ala-OH and
a
Nd-trityl-N -Fmoc-Gln-OH via the oxazolidinone intermediates
employing Freidinger’s procedure12 in 93% and 75% overall yields,
respectively (Scheme 3).
Fmoc-
reported by Yajima et al.13
using salicylaldehyde to give a diastereomeric mixture of
D
-alloThr-OH (8) was prepared from
-Thr was subjected to epimerization
-Thr
L-Thr in the study
L
L
Scheme 3. Preparation of Fmoc-N-MeAla-OH (3) and Fmoc-N-MeGln-OH (5).
Scheme 1. Synthetic plan for callipeltin E (1).
Scheme 4. Preparation of Fmoc-D-alloThr-OH (8).

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M. Kikuchi et al. / Tetrahedron Letters 52 (2011) 3872–3875
Scheme 5. Solid phase synthesis of callipeltin E (1).
and D-alloThr in a molar ratio of 1:0.6. After acetylation of the
Acknowledgements
amino group followed by converting the ammonium salt, separa-
tion of Ac- -alloThr-OH ammonium salt as a soluble in EtOH and
Ac- -Thr-OH ammonium salt as a less-soluble diastereomeric salt
by filtration obtained Ac- -alloThr-OH as 50% de. The sequence
of hydrolysis, recrystallization and Fmoc protection gave pure
Fmoc- -alloThr-OH (8) in 9% overall yield (Scheme 4).
D
We thank Dr. Nobutaka Fujii and Dr. Shinya Oishi (Kyoto Uni-
versity) for the measurement of mass spectra. This work was sup-
ported in part by the Japan Science Society (23-324) in Japan, and a
Grant-in-Aid for Scientific Research from the Japan Society for the
Promotion of Science (Grant 21689004 to H. K.)
L
D
D
Callipeltin E (1) was synthesized by Fmoc-based SPPS according
to the route shown in Scheme 5. As a solid support, 2-chlorotrityl
chloride resin was selected. Fmoc-N-MeAla-OH (3) was reacted
with 2-chlorotrityl chloride resin in DMF in the presence of iPr2-
NEt. The Fmoc group of the resulting resin was removed with
20% piperidine/DMF and Fmoc-(2R,3R)-bMeOTyr(OMEM)-OH (4)
was condensed by HATU14/HOAt15 in the presence of iPr2NEt. The
same deprotection/condensation procedure was repeated for the
introduction of Fmoc-N-MeGln-OH (5), Fmoc-Leu-OH (6), Fmoc-
References and notes
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