A microwave-assisted stereoselective synthesis of polyandrocarpamines A and B

Article abstract of DOI:10.1016/j.tetlet.2008.12.010

A stereoselective synthesis of the marine natural products, polyandrocarpamines A and B, has been achieved using a high-yielding one-step aldol condensation reaction under microwave conditions. The structures of both synthetic compounds were confirmed fol

Full text of DOI:10.1016/j.tetlet.2008.12.010

Tetrahedron Letters 50 (2009) 880–882
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A microwave-assisted stereoselective synthesis of polyandrocarpamines A and B
a
a
b
Rohan A. Davis a, , Paul S. Baron , Juliette E. Neve , Carleen Cullinane
*
a Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, QLD 4111, Australia
b Peter MacCallum Cancer Centre, St. Andrew’s Place, East Melbourne, VIC 3002, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective synthesis of the marine natural products, polyandrocarpamines A and B, has been
achieved using a high-yielding one-step aldol condensation reaction under microwave conditions. The
structures of both synthetic compounds were confirmed following 1D and 2D NMR, UV, IR and MS spec-
tral analysis, and by comparison with literature data. Both synthetic natural products were assigned Z
geometry about their exocyclic double bond on the basis of 13C/1H long-range coupling constants, which
were measured using a gHSQMBC experiment. Polyandrocarpamines A and B were evaluated for their
cytotoxicity towards the tumour cell lines, MCF-7 (breast), H460 (lung) and SF268 (central nervous sys-
tem). Polyandrocarpamine A displayed selective cytotoxicity towards the SF268 cell line with a GI50 value
Received 20 October 2008
Revised 24 November 2008
Accepted 3 December 2008
Available online 7 December 2008
of 65 lM.
Ó 2008 Elsevier Ltd. All rights reserved.
Marine organisms have proven to be a rich source of novel, and
structurally diverse metabolites that display a wide variety of bio-
logically significant activities.1–3 Examples include the anti-fouling
oroidin dimer, mauritiamine,4 the MEK-1 inhibitor, hymenialdi-
sine,5 the EGF inhibitor, purealidin K6 and the histaminergic antag-
onist, dispacamide A 3.7 All the marine metabolites listed above
belong to the 2-aminoimidazolone class of compounds, and all
have been isolated from marine sponges. Other marine organisms,
such as ascidians, have also yielded a small number of alkaloids
belonging to this structure class, although no bioactivity has been
reported.8 Polyandrocarpamines A 1 and B 2 are examples of ascid-
ian-derived 2-aminoimidazolones. These simple alkaloids were
first isolated and synthesized in 2002,9 and although sufficient
quantities of these molecules were obtained by total synthesis,
no biological activity was reported. Due to our interest in the syn-
thesis of bioactive natural products and their structural ana-
logues,10–15 we wished to obtain polyandrocarpamines A 1 and B
2 in sufficient quantities in order to undertake biological evalua-
tions. Herein, we report an alternative synthesis for polyandro-
carpamines A and B, along with their cytotoxicity profile against
three different tumour cell lines.
2-aminoimidazolones using tert-butyl hydroperoxide as an oxidant
in the presence of aqueous ammonia (Scheme 1).9,16,17 This meth-
od generally requires the protection of reactive groups (e.g., –OH)
and long reaction times (up to 72 h), which often result in variable
yields.9
An alternative synthetic route for the synthesis of 2-amin-
oimidazolones has been reported using glycocyamidine 5, or a
glycocyamidine derivative, in the presence of an aldehyde, NaOAc
and AcOH.17–19 This method uses a readily synthesized reagent
(i.e., 5), requires no protection chemistry and involves a one-step
condensation reaction that we thought might be suitable for
microwave chemistry. The sponge metabolite, leucettamine B 4,
O
MeO
HO
CHO
MeO
CHO
i
NH
N
O
O
O
Ac
S
ii
The previous synthesis of polyandrocarpamines A 1 and B 2
(Scheme 1),9 along with the related marine-derived imidazolones
dispacamide A 3,16 and leucettamine B 4,17 have all been reported
using the same methodology for the construction of the 2-amino-
imidazolone moiety (Fig. 1).9,16,17
The synthesis of the 2-aminoimidazolone component for 1-4 in-
volved the generation of an alkyl- or aryl-thiohydantoin, followed
by the facile conversion of the thiohydantoin to the corresponding
O
RO
HO
MeO
NH
iii
NH
N
HN
O
O
NH2
S
1
2
R = Me
R = H
iv
Scheme 1. Reagents and conditions for the original synthesis of polyandrocarp-
amines A and B:9 (i) pivaloyl chloride, pyridine, Ar, rt, 7 h; (ii) NaOAc, AcOH, reflux,
2 h; (iii) tert-butyl hydroperoxide, aq NH4OH, MeOH, rt, 72 h; (iv) BBr3ÁS(Me)2, DCE,
reflux, 15 min.
* Corresponding author. Tel.: +61 7 3735 6043; fax: +61 7 3735 6001.
E-mail address: r.davis@griffith.edu.au (R.A. Davis).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.010

R. A. Davis et al. / Tetrahedron Letters 50 (2009) 880–882
881
ines A and B.9 These differences were postulated to arise since
the isolated natural products were purified as their free bases.9
In order to confirm this hypothesis, a small amount of polyandro-
carpamine A TFA salt was purified on a base-stable C18 HPLC
column using aqueous NH4OH/MeOH. The free base of polyandro-
carpamine A was obtained, and NMR assignments were made fol-
lowing analysis of the 1D and 2D NMR spectra, and were shown to
be essentially identical to those of the natural product originally
reported.9
Polyandrocarpamines A and B were tested for their cytotoxic
activity against the tumour cell lines, H460 (lung), MCF-7 (breast),
and SF268 (central nervous system).26,27 Initial dosing at 10
lM for
72 h for both alkaloids showed no growth inhibition towards H460
and MCF-7; however, moderate cytotoxicity was identified to-
wards the cancer cell line, SF268. Further biological testing re-
vealed that 1 and 2 showed cytotoxicity towards this cell line
Figure 1. Chemical structures of marine natural products 1–4.
with GI50 values of 65 and >80 lM, respectively.
has been successfully synthesized using this glycocyamidine meth-
odology under reflux conditions, although the reaction generated a
Z/E mixture (9.5:0.5) of 4.17
In conclusion, we have successfully synthesized polyandrocarp-
amines A and B stereoselectively in high-yield using a microwave
reactor, and have shown that both natural products have selective
cytotoxicity towards the SF268 tumour cell line. With the synthesis
of large quantities of 1 and 2, these molecules will now be added to
the Queensland compound library (QCL)28 at the Eskitis Institute,
where they will be available for further biological evaluations. This
new synthetic route to polyandrocarpamines has substantially re-
duced the synthesis time, by up to 80 h, and uses less reagents
compared to the original procedure.9 This method makes this class
of marine alkaloids now more amenable to natural product-based
combinatorial synthesis.
In our laboratory, the HCl salt of glycocyamidine 5 was synthe-
sized using a microwave-modified literature preparation.20 This in-
volved the addition of glycocyamidine to a solution of H2O/32%
aqueous HCl (3:1) followed by heating under microwave condi-
tions at 160 °C for 30 min. Following purification by recrystallisa-
tion, the HCl salt of glycocyamidine 5 was condensed with 4-
hydroxy-3-methoxybenzaldehyde 6 or 3,4-dihydroxybenzaldehye
7 in a NaOAc/AcOH slurry under microwave conditions of 160 °C
for 30 min (Scheme 2). Purification of each separate reaction mix-
ture using C18 flash chromatography yielded the TFA salts of poly-
androcarpamines A21 1 (193 mg, 56%) and B22 2 (267 mg, 80%) in
high yields.
Acknowledgements
By comparing the overall yields for both 1 (31% vs 56%) and 2
(6% vs 80%) from the two different synthetic routes outlined in
Schemes 1 and 2, we showed that the new, faster and simpler
methodology also resulted in substantial yield improvements.
The structural confirmation and 1H/13C NMR assignments of
compounds 1 and 2 were performed following extensive 1D and
2D NMR spectroscopy (gCOSY, gHSQC, gHMBC and ROESY). The
geometry about the exocyclic double bonds of 1 and 2 was deter-
mined on the basis of 13C/1H long-range coupling constants, which
were measured using a gHSQMBC experiment.23 Analysis of each
gHSQMBC experiment identified that the coupling constant be-
tween the exocyclic protons [d 6.81 (H-6) for 1; d 6.79 (H-6) for
2] and the imidazolone carbonyl [d 165.2 ppm (C-4) for 1;
165.7 ppm (C-4) for 2] was 5.4 Hz for both molecules, which is con-
sistent with the Z geometry.24,25 Both synthetic 1 and 2 were ob-
tained solely as their Z isomers and no isomerisation about the
exocyclic double bond was observed during our studies.
The authors acknowledge financial support of this work by Grif-
fith University and the Eskitis Institute for Cell and Molecular Ther-
apies. We thank Hoan The Vu from Griffith University for acquiring
the HRESIMS measurements. One of us (P.S.B.) thanks Griffith Uni-
versity for an Honours scholarship. Alison Slater is acknowledged
for technical assistance in performing the cell culture assays.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.12.010.
References and notes
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O
5
9
7
RO
HO
RO
HO
CHO
i
NH
NH
NH2
3
N
N
1
11
NH2
1
6
R = Me
R = H
R = Me
R = H
5
7
2
Scheme 2. Reagents and conditions: (i) NaOAc, AcOH, lw, 160 °C, 20 min.

882
R. A. Davis et al. / Tetrahedron Letters 50 (2009) 880–882
H-12), 7.02 (1H, s, H-8); 13C NMR (125 MHz, CD3OD) d 117.0 (C-11), 118.0 (C-
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157.9 (C-2), 165.7 (C-4); (+)-LRESIMS m/z (rel. int.) 220 (100) [MÀCF3COO]+;
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240 (2.55), 357 (2.76) nm; IR mmax (KBr) 3500–2800, 1712, 1667, 1592, 1519,
1436, 1395, 1291, 1201, 1136, 1055, 1029, 840, 802, 723 cmÀ1 1H NMR
;
(500 MHz, CD3OD) d 3.91 (3H, s, 9-OCH3), 6.81 (1H, s, H-6), 6.87 (1H, d,
J = 8.5 Hz, H-11), 7.10 (1H, dd, J = 8.5, 1.5 Hz, H-12), 7.12 (1H, d, J = 1.5 Hz, H-8);
13C NMR (125 MHz, CD3OD) d 56.8 (9-OCH3), 114.3 (C-8), 116.9 (C-11), 119.7
(C-6), 123.6 (C-5), 124.8 (C-7), 125.8 (C-12), 149.5 (C-9), 150.6 (C-10), 157.6 (C-
2), 165.2 (C-4); (+)-LRESIMS m/z (rel. int.) 234 (100) [MÀCF3COO]+;
(+)-HRESIMS m/z 234.08709 (C11H12N3O3 [MÀCF3COO]+ requires 234.08732).
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(2.98), 250 (2.73), 359 (3.00) nm; IR mmax (KBr) 3500–2800, 1704, 1655, 1594,
1438, 1396, 1270, 1191, 1135, 841, 797, 722, 669 cmÀ1 1H NMR (500 MHz,
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28. www.griffith.edu.au/science/queensland-compound-library.
;