Tetrahedron Letters
Synthesis of Actinomycetes natural products JBIR-94, JBIR-125, and
related analogues
Rafiq Taj a, John L. Sorensen b,
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a CanAm Bioresearch Inc., 9-1250 Waverley St., Winnipeg, Manitoba R3T 6C6, Canada
b Department of Chemistry, University of Manitoba, Winnipeg R3T 2N2, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of the natural products JBIR-94, DCP, DFP, and CFP is reported. A strategy for the coupling of
ferulic or coumaric acid to putrescine is described. We determined that EDCI was the most effective cou-
pling agent for this synthesis. In addition amide coupling with saturated cinnamic acids derivatives pro-
vided the best yield. The synthesis of JBIR-125 is accomplished through a novel synthesis of differentially
protected spermidine. Preliminary bioassay data demonstrated that all five compounds were active
against Pseudomonas aeruginosa.
Received 17 October 2015
Revised 5 November 2015
Accepted 8 November 2015
Available online 10 November 2015
Keywords:
Antibiotics
Ó 2015 Elsevier Ltd. All rights reserved.
Ferulic acid
Natural products
Putrescine
Actinomycetes
Introduction
Our synthetic route to 1 and 5 also gave us access to the struc-
turally related natural products N,N0-diferuloyl-putrescine (2), N,
Bacteria are a well-studied source of biologically active natural
products and within them the Gram-positive actinomycetes
are one of the most prolific producers of novel structures.1
Streptomyces is the largest genus of this class having more than
500 species as members and over two thirds of all clinically useful
antibiotics have been isolated from various strains of this group.2
The significant contribution of Streptomyces to pharmaceutical
industry is motivation to examine the synthesis of secondary
metabolites isolated from these strains as potential lead
compounds for further exploration.3 Two new phenolic compounds,
JBIR-94 (1) and JBIR-125 (5), have been recently reported from the
culture broth of a new species of Streptomyces (strain R56-07)
(Fig. 1)4 Both JBIR-94 (1) and JBIR-125 (5) have been tested for
their biological efficacy as radical scavenger against 1,10-diphe-
nyl-2-picrylhydrazyl (DPPH). It was observed that 1 gave an
N0-dicoumaroyl-putrescine (3), and N-p-coumaroyl-N0-feruloylpu-
trescine (4).
Compounds 2–4 have previously been isolated from corn bran5
and also demonstrate promising biological activities. In particular,
compound 4 has demonstrated promising biological activity as an
antidiuretic,6 an antioxidant7 and has also been shown to inhibit
aflatoxin biosynthesis.8 Recently the radical scavenging activity
of 2, and other similar polyamine conjugates, demonstrated
antioxidant activity in assays against DPPH, superoxide anion,
and hydroxyl radical.9 Despite the promising biological activity of
these polyamine-derived natural products there have, to date, been
no reported synthesis of molecules with this structural motif. Here
we report the synthesis of a series of related polyamine derived
natural products starting from ferulic acid and putrescine. The
key features of this work are the protection strategy for the synthe-
sis of the unsymmetrical compound CFP (4) as well as the synthesis
of differentially protected spermidine that was required for the
successful synthesis of JBIR-125 (5).
IC50value of 11.4 and 5 had an IC50 of 35.1 lM. Therefore these
compounds represent potential lead compounds in the develop-
ment of a series of novel biologically active molecules with antiox-
idant and other useful properties. Compounds 1 and 5 represent
the first examples of hydroxycinnamic acid amide derivatives
produced by actinomycetes that contain 1,4-diaminobutane
(putrescine) or N-(3-aminopropyl)-1,4-butanediamine (spermidine)
structural motifs.
Results and discussion
Our initial approach to the synthesis of JBIR-94 (1) involved the
attempted coupling of dihydroferulic acid (7) directly with putres-
cine (Scheme 1). The hydrogenation of feruic acid (6) gave 7 in
excellent yield. As part of this approach we conducted a very small
screen of carboxylic acid activating groups in the coupling step that
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Corresponding author. Tel.: +1 204 474 9504; fax: +1 204 474 7608.
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.