A straight forward and first total synthesis of Penilumamides B–D

Article abstract of DOI:10.1016/j.tetlet.2017.07.027

A simple and straight forward first total synthesis of rare lumazine peptides, Penilumamide B, C and D isolated from the marine-derived fungi Aspergillus and Penicillium sp. is described from a common starting material, 1,3-dimethyllumazine-6-carboxylic acid. Penilumamide C was prepared from Penilumamide B by oxidation of the methionine residue to the corresponding sulphone.

Full text of DOI:10.1016/j.tetlet.2017.07.027

Accepted Manuscript
A straight forward and first total synthesis of Penilumamides B-D
Thirupathi Reddy Penjarla, Maheshwar Kundarapu, Syed Mohd. Baquer,
Anupam Bhattacharya
PII:
S0040-4039(17)30873-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.027
TETL 49109
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 May 2017
5 July 2017
7 July 2017
Please cite this article as: Reddy Penjarla, T., Kundarapu, M., Mohd. Baquer, S., Bhattacharya, A., A straight forward
and first total synthesis of Penilumamides B-D, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2
017.07.027
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A straight forward and first total synthesis of Penilumamides B-D
a,b
a
a*
b
Thirupathi Reddy Penjarla, Maheshwar Kundarapu, Syed Mohd. Baquer, Anupam Bhattacharya
a
Department of Medicinal Chemistry, GVK Biosciences Pvt. Ltd., Survey Nos: 125 (part) & 126, IDA,
Mallapur, Hyderabad 500076, India
b
BITS-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, Hyderabad, 500078, India
Corresponding author: Dr. Syed Mohd. Baquer; Tel: +91 40 67483452; Fax: +91 40 6748 3400
E-mail: baquer@gvkbio.com
Abstract: A simple and straight forward first total synthesis of rare lumazine peptides, Penilumamide B,
C and D isolated from the marine-derived fungi Aspergillus and Penicillium sp. is described from a
common starting material, 1,3-dimethyllumazine-6-carboxylic acid. Penilumamide C was prepared from
Penilumamide B by oxidation of the methionine residue to the corresponding sulphone.
Key words: Penilumamides, Lumazine peptides, Linear peptides, Total synthesis
Introduction
Peptides are important bioactive natural products which are present in many marine species
1
and these have been a subject of extensive research. Linear and cyclic peptides have always attracted
2
great attention for their unique structures and potent pharmacological activities. Penilumamides are
the first reported naturally occurring lumazine peptides, isolated from marine-derived fungi Penicillium
3
sp. and Aspergillus sp. These are the only reported linear peptides with an unusual 1,3
dimethyllumazine-6-carboxylic acid starter unit. Although lumazines are well known metabolites and are
frequently present in some synthetic molecules, natural products with an N–methylated lumazine
4
moieties are found rarely in natural products. Unfortunately no activity was reported for these linear
lumazine peptides.
Structural evaluation of Penilumamides (1-3) indicated N–methylated lumazine moiety linked to
3a
methionine, methionine sulphoxide and methionine sulphone residues. The sulphoxide (2) and
sulphone (3) analogues of Penilumamides are speculated to be formed as a result of oxidation during
the isolation, extraction process. In our ongoing interest in the synthesis of natural products, the rare
occurrence, structural uniqueness and similarity in the structure prompted us to undertake the total
synthesis of these compounds. Herein, we report the first, simple and straight forward total synthesis of
these linear peptides, Penilumamides B (1), C (3), & D (4).
1

Figure 1
Results and discussion
Retrosynthetic analysis of Penilumamide B (1), Penilumamide (2), Penilumamide C (3) revealed
the presence of N-methylated lumazine moiety with a methionine residue, methionine sulfoxide residue
and methionine sulfone residue respectively, coupled with anthranilic acid methyl ester. Whereas
Penilumamide D (4) indicated the presence of N-methylated lumazine moiety with alanine residue
coupled with anthranilamide.
Our synthetic efforts commenced with 1,3-dimethyllumazine-6-carboxylic acid (8) as the starting
5
material which was prepared following the protocol as reported in the literature. The synthetic strategy
is shown in scheme 1. Thus, commercially available 6-amino-1,3-dimethyl uracil (5) was treated with
aniline in presence of sodium nitrite under diazotization conditions to give 6-amino-1,3-dimethyl-5-
phenylazo-uracil (6) in 61 % yield. Treatment of 6 with diethyl acetylene dicarboxylate and 4-dimethyl
o
amino pyridine (DMAP) in DMF for 3h at 150 C gave 6,7-bis(ethoxycarbonyl)-1,3-dimethyllumazine (7)
in 74 % yield. Compound 7 was then hydrolyzed to 1,3-dimethyllumazine-6-carboxylic acid (8) in 85%
yield upon treatment with a refluxing mixture of conc. HCl and acetic acid for 16h. The spectral data was
5
compared with that of the data reported in the literature. The obtained acid 8 was then employed as a
common starting material for the preparation of Penilumamides B, C and D. L-Methionine was
6
converted to L-Methionine methyl ester HCl (10) by refluxing with thionyl chloride in MeOH. Compound
1
0 was coupled with the acid 8 in the presence of 1-[Bis(dimethylamino)methylene]-1H-1,2,3-
triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) in
DMF at room temperature overnight to give the amide 11 in 56 % yield. Efforts to hydrolyze the ester
7
1
1 under standard basic conditions proved futile as it resulted in the hydrolysis of the amide bond. After
screening several conditions, the hydrolysis of the ester was successfully achieved by using LiCl and TEA
in a mixture of acetonitrile and water (4:1) at 65 °C for 16 h, which gave the desired acid 12 in 81 %
8
yield. Completion of the synthesis then required a final coupling with methyl-2-amino benzoate (13).
After screening several coupling reagents, finally the acid 12 was successfully coupled with 13 in
presence of POCl and TEA in refluxing THF for 1h to furnish Penilumamide B in 51 % yield as a brown
3
9
solid. The spectral data was found to be well in agreement with that of the reported values of the
3a
natural product. Thus, a first total synthesis of Penilumamide B was successfully achieved from
commercially available starting materials.
2

Our next endeavor was the preparation of Penilumamide (2). The oxidation of Penilumamide B

was readily accomplished by treatment with Oxone in a mixture of acetonitrile and water (3:1) at rt for
2
h, which resulted directly in the formation of Penilumamide C (3) upon isolation and purification.
Compound 3 was isolated as a brown solid in 75% yield. However, Penilumamide 2, containing the
sulfoxide residue could not be isolated in the pure form as it might have oxidized easily to the
methionine sulfone residue to give Penilumamide C during the isolation and purification process as
previously reported. The spectral data was found to be in complete agreement with that of the values
reported in the literature.
3a
3

Scheme 1: Synthesis of Penilumamide B and C
Then we undertook the synthesis of Penilumamide D (scheme 2) from the acid 8. The acid 8 was
coupled with L-alanine methyl ester in the presence of HATU and DIPEA in DMF at room temperature
overnight to give the amide 14 in 74 % yield. Subsequent hydrolysis of the ester 14 using LiCl and TEA in
a mixture of acetonitrile and water at 65 °C overnight as previously performed gave the acid 15 in
quantitative yield. As a final step, the acid 15 was then coupled with anthranilamide in the presence of
®
Propylphosphonic anhydride (T3P ) and DIPEA in THF at rt for 24 h to produce Penilumamide D as a
10
white solid in 51 % yield. The spectral data of the synthetic compound was found to be in agreement
3a
with that of the reported values in the literature. Thus, we have accomplished a first total synthesis of
these lumazine peptides.
Scheme 2: Synthesis of Penilumamide D
In summary, an exceedingly efficient, simple and straight forward first total synthesis of the
lumazine peptides, penillulamide B (1), penillulamide C (3) and penillulamide D (4) was successfully
achieved by following sequential ester hydrolysis and amide coupling reactions from the key starting
material 8. Penilumamide C was prepared by the oxidation of the methionine residue of Penilumamide
B.
Acknowledgments
The authors are thankful to GVK Biosciences Pvt. Ltd. for the financial support and for the laboratory
facilities. The assistance from the analytical department is greatly acknowledged.
Supplementary data
Data includes experimental procedures and spectra of all new synthesized compounds.
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Highlights:



A first total synthesis of the rare lumazine peptides, Penilumamides B, C and D is achieved from
a common starting material.
Sequential saponification and peptide coupling were adapted for the preparation of these
compounds.
Oxidation of Penilumamide (B) directly gave Penilumamide (C) upon isolation and purification.
6

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A straight forward and first total synthesis of
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Penilumamides B-D
a,b
a
a
b
Thirupathireddy Penjarla, Maheshwar Kundarapu, Syed Mohd.Baquer, * Anupam Bhattacharya
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