Total synthesis of modified pentapeptide, caldoramide

Article abstract of DOI:10.1016/j.tetlet.2018.06.045

Total synthesis of modified pentapeptide, caldoramide, a cytotoxic linear pentapeptide from the marine cyanobacterium Caldora penicillate is described. Notable features of the route include the efficient preparation of three key fragments and final assemb

Full text of DOI:10.1016/j.tetlet.2018.06.045

Accepted Manuscript
Total synthesis of modified pentapeptide, Caldoramide
Kishore Kumar Anantoju, Thirumala Chary Maringanti, Syed Mohd. Baquer
PII:
S0040-4039(18)30799-8
https://doi.org/10.1016/j.tetlet.2018.06.045
TETL 50083
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 April 2018
21 May 2018
18 June 2018
Please cite this article as: Anantoju, K.K., Maringanti, T.C., Baquer, S.M., Total synthesis of modified pentapeptide,
Caldoramide, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.06.045
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Graphical Abstract
Total synthesis of modified pentapeptide,
Leave this area blank for abstract info.
Caldoramide
a, b
b
a,
Kishore Kumar Anantoju , Thirumala Chary Maringanti , Syed Mohd. Baquer *

1
Tetrahedron Letters
Total synthesis of modified pentapeptide, Caldoramide
a,b
b
a,
Kishore Kumar Anantoju , Thirumala Chary Maringanti , Syed Mohd. Baquer 
a
Discovery Chemistry, GVK Biosciences Pvt. Ltd., Survey Nos: 125 (part) & 126, IDA, Mallapur, Hyderabad 500076, India
Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, 500 085, India
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Total synthesis of modified pentapeptide, caldoramide, a cytotoxic linear pentapeptide from the
marine cyanobacterium Caldora penicillate is described. Notable features of the route include
the efficient preparation of three key fragments and final assembly to the natural product via
sequential amide couplings. The spectral data of the synthetic compound was found to be in
comparison with that of the isolated natural product.
Available online
Keywords:
Natural Product
Anti-cancer
Peptides
2009 Elsevier Ltd. All rights reserved.
Cytotoxic
Total synthesis
Introduction
other deviations were observed in the spectral data. We herein
report an efficient total synthesis of caldoramide (1), a new
Peptides are important bioactive natural products which are
present in many marine species and these have been a subject of
extensive research. Both linear and cyclic peptides have always
closely related structural analogue of belamide A and dolastatin
5.
1
1
attracted great attention for their unique structures and potent
pharmacological activities. In addition, peptides have also
Results and discussion
2
played an important role as therapeutic agents and key mediators
of biological function due to their low toxicity and high
specificity. Caldoramide (1) is
a marine derived linear
pentapeptide natural product, isolated from cyanobacterium
3
Caldora penicillata by Luesch and coworkers in 2016.
Structurally it comprises of a peptidic backbone bearing a
dimethylated N-terminal amino acid and C-terminal benzyl
pyrrolinone moiety. It has structural similarities to belamide A
4
5,6
7,8
9
(
(
2), dolastatin 15 (3), dolastatin 10 (4), and simplostatin (5)
Fig 1) which are potential anti-cancer agents, advanced to
clinical trials. Caldoramide has shown moderate cytotoxicity
1
0
similar to that of belamide. In particular, dolastatins 10 (4) and
1
5 (3) have exhibited extraordinary cytotoxicity to cancer
11,12
cells.
Their interesting biological activities have aroused
synthetic efforts which resulted in several drug leads that have
1
3
advanced to clinical trials.
In continuation of our interest in the total synthesis of
biologically active natural products, the similarity in structure of
caldoramide with the potential anti-cancer agents prompted us to
undertake the total synthesis of caldoramide (1). Recently
Wunder A. et al have reported the first total synthesis of
1
4
caldoramide, but the optical rotation was not found to be in
comparison with that of the isolated natural product and some
—
——
Scheme 1. Retrosynthetic strategy of Caldoramide (1)

Corresponding author. Tel.: +91-40-6748-3452; fax: +91-40-6748-3400; e-mail: baquer@gvkbio.com

2
Tetrahedron Letters
Retrosynthetic analysis (scheme 1) of caldoramide revealed
the presence of a linear peptide chain linked to 3-methoxy-4-
benzylpyrrolinone ring at the C-terminus similar to that of
belamide A and N,N-dimethyvaline at the N-terminus of the
peptide chain. Linked to the pyrrolinone ring was found a linear
chain of amino acids containing N-Me-isoleusine residue, N-Me-
valine and valine which was finally linked to the N-terminal,
N,N-dimethyvaline residue. We envisaged that caldoramide (1)
could be assembled in a rapid and convergent manner by the
sequential coupling of the pyrrolidone 6, with the above
mentioned amino acid residues.
Scheme 2. Synthesis of 3-methoxy-4-benzyl pyrrolinone
N,N-dimethylvaline 9 residue present at the N-terminus as
1
6
reported in the literature.
With the fragments 6, 8 and 9 now in our hand, the
construction of the linear pentapeptide, caldoramide was
achieved sequentially from the C-terminus to the N-terminus as
depicted in the scheme 3.
Commercially available N-Boc isoleucine (13) was taken as
the starting material and treated with sodium hydride and methyl
iodide in THF to give the corresponding N-methylated acid
derivative (14) in 85 % yield. Then compound 14 was converted
to the pentafluorophenyl ester 15 (76 % yield) by treatment with
perflourophenyl-2,2,2 triflouroacetate in the presence of DIPEA
in methylene chloride. The activated ester 15 was reacted with
o
the anion of 6 generated by treatment with BuLi in THF at -78 C
which gave compound 16 in 65% yield. Subsequent removal of
Boc group by treatment of 16 with TFA in methylene chloride
gave compound 17 in quantitative yield. Amide coupling of
fragment 17 with the previously prepared peptide 8 was carried
out using 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TBTU) in acetonitrile in the presence of
DIPEA which gave compound 18 in 51 % yield. Removal of the
Boc group with TFA in methylene chloride gave compound 19 in
quantitative yield. Completion of the synthesis then required a
coupling with compound 9 prepared earlier. Then as a final step,
compound 19 was coupled with the acid 9 using EDC.HCl in
presence of HOBT and DIPEA in DMF to produce caldoramide
in 71 % yield. Gratifyingly, the physical and the spectroscopic
Fig 1. Stucturally related natural products
L
which was condensed with Meldrum’s acid
using
N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide
hydrochloride (EDC) and 4-(dimethylamino) pyridine (DMAP).
Subsequent reflux in ethyl acetate facilitated the anticipated
thermal cyclization to the desired pyrrolinone (11) in 72% yield
1
13
data obtained for the synthetic caldoramide 1 ( H and C NMR)
2
5
diisopropyl azodicarboxylate (DIAD), triphenylphosphine
and the measured specific rotation, [α] +8.4 (c 0.36, MeOH)
D
(
TPP) and methanol selectively ge
cf. + 11.1 were in good agreement with that provided for the
isolated natural product, providing convincing evidence that the
3
absolute configuration of 1 is identical to those reported by
Luesch and co-workers (see the supporting information).
Having successfully prepared the pyrrolidinone moiety (6) our
attention turned towards the synthesis of the peptide fragments 8
and 9 (scheme 1). The known peptide fragment 8 was prepared
following the reported procedures. The spectral data of the
4
prepared compound was correlated with the reported values, and
found to be in complete agreement.

3
Scheme 3: Synthetic Scheme for the preparation of Caldoramide
References and notes
In summary, we have completed the total synthesis of the
cyano bacterium-derived linear pentapeptide natural product,
caldoramide. It is anticipated that the synthetic route described
can be useful to prepare related class of compounds. This
convergent synthesis outlines the preparation of the key
fragments, an efficient and rapid coupling to yield the natural
product.
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Acknowledgments
2
The authors are thankful to GVK Biosciences Pvt. Ltd, India
for the financial support and for the laboratory facilities. The
assistance from the analytical department is greatly
acknowledged.
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Highlights:




Total
synthesis
of
a
modified
pentapeptide, Caldoramide.
The total synthesis involved
convergent approach
a
Sequential amide couplings were
adapted to prepare the natural product.
The spectral data was in good
agreement with the reported values.