Structure revision of the rare sponge metabolite echinosulfone A, and biosynthetically related echinosulfonic acids A–D

Article abstract of DOI:10.1016/j.tetlet.2020.151651

A short Friedel-Crafts mediated total synthesis has informed structure revision of the rare marine sponge natural product echinosulfone A (1a) and the biosynthetically related echinosulfonic acids A–D (2a–5a).

Full text of DOI:10.1016/j.tetlet.2020.151651

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Tetrahedron Letters
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Structure revision of the rare sponge metabolite echinosulfone A, and
biosynthetically related echinosulfonic acids A–D
1
2
⇑
Pratik Neupane , Angela A. Salim , Robert J. Capon
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A short Friedel-Crafts mediated total synthesis has informed structure revision of the rare marine sponge
natural product echinosulfone A (1a) and the biosynthetically related echinosulfonic acids A–D (2a–5a).
Ó 2020 Elsevier Ltd. All rights reserved.
Received 14 December 2019
Revised 7 January 2020
Accepted 17 January 2020
Available online xxxx
Keywords:
Marine natural product
Synthesis
Structure revision
Echinosulfone A
Introduction
data for 1–4 we speculated that the published structures were
incorrect. To test this hypothesis, we undertook a total synthesis
The bis-indole natural products echinosulfone A (1) and echi-
nosulfonic acids A–C (2–4) were first reported by Capon et al. in
1999 from a southern Australian marine sponge, Echinodictyum
sp., with structures assigned by detailed spectroscopic analysis
(Fig. 1) [1]. In addition to being unprecedented examples of bis-
indole sulfonic acids, the echinosulfonic acids displayed intriguing
chemical properties, undergoing rapid (equilibrium) solvolysis
during handling. This latter property proved particularly challeng-
ing during isolation and handling, which relied on the use of
hydroxylic solvents (viz., MeOH, EtOH and H2O). A subsequent
2006 report by Sévenet et al. described a related bis-indole, echi-
nosulfonic acid D (5) as a co-metabolite with echinosulfonic acid
B (3), from a new Caledonian sponge Psammoclemma sp. (Fig. 1)
[2]. Lacking the C-100 tertiary OH moiety pivotal to the solvolytic
instability of 2–4, echinosulfonic acid D (5) was stable to solvolysis
during handling.
of 1a, leading to a structure revision for both echinosulfone A,
and echinosulflonic acids A–D (Fig. 1).
Results and discussion
In a model synthesis, Friedel-Crafts acylation of indole [3] as
outlined in Scheme 1 (R = H) yielded a bis-indole ketone (60%),
Despite the discovery of a vast array of structurally diverse nat-
ural products from marine sources, especially sponges, published
examples of the echinosulfone/echinosulfonic acid structure class
are limited to 1–5, making them both very rare and unique to mar-
ine sponges. Re-examining authentic samples and spectroscopic
⇑
Corresponding author.
E-mail address: r.capon@uq.edu.au (R.J. Capon).
ORCID: 0000-0001-7947-1275.
ORCID: 0000-0002-8177-5689.
1
2
Fig. 1. Echinosulfone A and echinosulfonic acids A–D.
https://doi.org/10.1016/j.tetlet.2020.151651
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: P. Neupane, A. A. Salim and R. J. Capon, Structure revision of the rare sponge metabolite echinosulfone A, and biosynthetically
related echinosulfonic acids A–D, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151651

2
P. Neupane et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 2. Plausible biosynthetic relationship.
observations we propose the revised structure for echinosulfone
A as shown (Fig. 1).
Scheme 1. (a) DCM, SO2Cl2, cat. DMF, 25 °C 12 h, N2 gas; (b) DCE, indole, ZrCl4, 0 °C,
30 min, 30 °C, 5 h, N2 gas, (c) Py.SO3, pyridine, 120 °C 12 h.
A plausible biosynthetic relationship (Fig. 2) linking 1a with the
co-metabolite echinosulfonic acids A–C, supports the proposition
that their structures should be revised, from 2–5 to 2a–5a. This
relationship draws on the likely solvolysis mechanism, in which
an acid-mediated enamine-imine rearrangement centred on
10-NH catalyses the loss of H2O to yield a highly coloured interme-
diate. This transient species spontaneously reacts with available
nucleophiles (i.e., hydroxylic solvents), facilitating the equilibrium
observed between echinosulfonic acids A–C (2a–4a) (Fig. 2 blue
pathway).
In a parallel manner (Fig. 2 pink pathway), during the biosyn-
thetic process an enamine-imine rearrangement could initiate
the loss of HCO2Me, generating a highly reactive enol intermediate.
The latter could collapse via synchronised enol-keto and imine-
enamine rearrangements, linking echinosulfonic acids to echi-
nosulfone A (1a). Given this relationship, it seems plausible that
the structures for echinosulfonic acids A–C should be revised, to
bring them in line with that for echinosulfone A (Fig. 1).
Similarly, as echinosulfonic acid D was reported as a co-
metabolite with echinosulfonic acid B, its structure should also
be revised. All the revised structures for echinosulfonic acids A-D
are in full accord with the reported 1D and 2D NMR data.
which following sulfonation with pyridinium-sulfonate returned
didebromoechinosulfone A (1b) (38%). The structure for 1b was
confirmed by spectroscopic analysis (Table S1 and Figs. S1, S2).
With a successful synthetic methodology in hand, Friedel-Crafts
acylation of commercially available 6-bromoindole as outlined in
Scheme 1 (R = Br) yielded the corresponding brominated bis-indole
ketone (60%), which following sulfonation returned a product 1a
(20%), identical in all respects with an authentic sample of
echinosulfone A (Tables 1, S2 and Figs. S3, S4). Given these
Table 1
Comparison of 1D NMR (600 MHz, DMSO d6) data for synthetic and natural
echinosulfone (1a).
Pos.
Synthetic 1a
Natural 1a
dC
dH (J in Hz)
dC
dH (J in Hz)
2
3
3a
4
5
132.8
115.5
126.3
123.1
124.6
115.8
116.4
135.7
8.07, br s
132.7
115.4
126.2
122.9
124.4
115.6
116.4
135.6
8.08, s
8.13, d (8.1)
7.37, d (8.5)
8.13, d (8.6)
7.37, dd (8.6, 1.9)
6
7
Conclusion
8.02, br s
8.02, (d, 1.9)
7a
10-NH
20
Total synthesis of echinosulfone A has prompted the assign-
ment of revised structures for echinosulfone A (1a) and echinosul-
fonic acids A–D (2a–5a).
11.94, br s
8.16, d (2.7)
12.00, br s
8.15, br s
133.1
116.4
125.4
123.1
124.1
115.3
114.8
137.5
183.8
132.9
114.2
125.3
122.9
123.9
115.1
114.7
137.5
183.7
30
3a0
40
8.14, d (8.1)
7.32, d (8.5)
8.14, (d, 8.5)
7.32, dd (8.5, 1.7)
50
Declaration of Competing Interest
60
70
7.70, br s
7.70, (d, 1.7)
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
7a0
100
Please cite this article as: P. Neupane, A. A. Salim and R. J. Capon, Structure revision of the rare sponge metabolite echinosulfone A, and biosynthetically
related echinosulfonic acids A–D, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151651

P. Neupane et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Acknowledgments
References
[1] S.P.B. Ovenden, R.J. Capon, J. Nat. Prod. 62 (1999) 1246–1249.
[2] S. Rubnov, C. Chevallier, O. Thoison, C. Debitus, O. Laprevote, D. Guénard, T.
Sévenet, Nat. Prod. Res. 19 (2006) 75–79.
PN thanks the University of Queensland for a postgraduate
scholarship. This research was funded in part by The University
of Queensland, Institute for Molecular Bioscience.
[3] S.K. Guchhait, M. Kashyap, H. Kamble, J. Org. Chem. 76 (2011) 4753–4758.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151651.
Please cite this article as: P. Neupane, A. A. Salim and R. J. Capon, Structure revision of the rare sponge metabolite echinosulfone A, and biosynthetically
related echinosulfonic acids A–D, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151651