A Ring-Distortion Strategy from Marine Natural Product Ilimaquinone Leads to Quorum Sensing Modulators

Article abstract of DOI:10.1002/ejoc.201800047

We report herein a ring-distortion strategy applied to marine natural substances ilimaquinone and 5-epi-ilimaquinone. A chemically diverse library of molecules was synthesised that included rearrangements of the sesquiterpene moiety and original reorganisations of the quinone ring. Chemoinformatic analyses evaluated the rise of structural diversity and the exploration of chemical space. Some focussed biological activities of this library were also investigated; quorum sensing activity of Vibrio harveyi was envisaged and some of the new compounds were shown to be good quorum sensing inhibitor candidates, whereas others were activators. Toxicities were also evaluated and some products showed micromolar activities against human umbilical vein endothelium, human hepatocellular carcinoma and human lung carcinoma (A549) cells.

Full text of DOI:10.1002/ejoc.201800047

DOI: 10.1002/ejoc.201800047
Full Paper
Marine Natural Products | Very Important Paper |
A Ring-Distortion Strategy from Marine Natural Product
Ilimaquinone Leads to Quorum Sensing Modulators
Laurent Evanno,*[a] David Lachkar,[a] Assia Lamali,[a] Asmaa Boufridi,[a]
Blandine Séon-Méniel,[a] Florent Tintillier,[b] Denis Saulnier,[c] Stéphanie Denis,[a]
Grégory Genta-Jouve,[d] Jean-Christophe Jullian,[a] Karine Leblanc,[a]
Mehdi A. Beniddir,[a] Sylvain Petek,[e] Cécile Debitus,[e] and Erwan Poupon*[a]
Abstract: We report herein a ring-distortion strategy applied this library were also investigated; quorum sensing activity of
to marine natural substances ilimaquinone and 5-epi-ilimaquin- Vibrio harveyi was envisaged and some of the new compounds
one. A chemically diverse library of molecules was synthesised were shown to be good quorum sensing inhibitor candidates,
that included rearrangements of the sesquiterpene moiety and whereas others were activators. Toxicities were also evaluated
original reorganisations of the quinone ring. Chemoinformatic and some products showed micromolar activities against
analyses evaluated the rise of structural diversity and the explo- human umbilical vein endothelium, human hepatocellular carci-
ration of chemical space. Some focussed biological activities of noma and human lung carcinoma (A549) cells.
Introduction
are some examples of compounds that went through the strat-
egy to generate structural diversity. To date, no marine natural
product has been investigated by this approach. As part of a
program of valorisation of French Polynesia biodiversity, a DOS
project from an abundant marine natural product was selected.
Isolated in high yields from Dactylospongia metachromia, ilima-
quinone (1)[11] and its isomer 5-epi-ilimaquinone (2)[12] were
chosen as suitable starting materials because the sponge is
common all over the French Polynesian atolls.[13,14] Notably,
ilimaquinone (1) is a highly bioactive molecule that displays
cytotoxic,[15] anti-HIV[16] and anti-inflammatory activities;[17] in
addition it causes an impressive fragmentation of Golgi appara-
tus.[18]
The design of small-molecule libraries with structural diversity
is a current challenge for drug discovery. Natural products are
an impressive source of complex scaffolds and inspiration for
the discovery of new lead structures for future small molecule
based drugs.[1,2] Complementary to natural products isolation[3]
and total synthesis,[4] synthetic methods have been developed,
such as diversity-oriented synthesis (DOS),[5] biology-oriented
synthesis,[6] skeletal diversifications or synthesis of natural
product inspired scaffolds. Recently, Hergenrother and co-work-
ers developed an elegant ring distortion strategy, called “com-
plexity-to-diversity (CtD)”, based on efficient and straightfor-
ward reaction sequences to alter molecular ring systems.[7] This
strategy ideally generates libraries of complex molecules
through ring contraction, ring aromatisation, ring fusion, ring
expansion and ring cleavage reactions from readily available
natural products. Gibberellic acid, adrenosterone, quinine,
pleuromutilin, abietic acid,[8] sinomenine[9] and yohimbine[10]
[a] BioCIS, Université Paris-Sud, Université Paris-Saclay, CNRS,
92290 Châtenay-Malabry, France
E-mail: laurent.evanno@u-psud.fr
erwan.poupon@u-psud.fr
http://www.biocis.u-psud.fr/
[b] EIO, UPF-IRD-Ifremer, Institut Louis Malardé, IRD,
BP529, 98713 Papeete, Tahiti, Polynésie française
[c] EIO, IRD-UPF-Ifremer, Institut Louis Malardé, Ifremer,
BP 49, 98719 Taravao, Tahiti, Polynésie française
[d] Dr Grégory Genta-Jouve, Laboratoire de Chimie-Toxicologie Analytique et
Cellulaire (C-TAC), Université Paris Descartes, UMR CNRS 8638 COMETE,
4 Avenue de l'observatoire 75006 Paris, France
[e] LEMAR, IRD-UBO-CNRS-IFREMER, IUEM,
rue Dumont d'Urville, 29280 Plouzané, France
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800047.
Figure 1. Isolation of ilimaquinone (1) and 5-epi-ilimaquinone (2) and diversi-
fication plans. * isolation ratio varies depending on the sample collection
area (see ref.[13a]).
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Figure 2. Overview of scaffolds generated from ilimaquinone (1) and 5-epi-ilimaquinone (2).
Compounds 1 and 2 were obtained on a gram scale from hydroxide in ethanol at reflux temperatures gave O-desmethyl-
the freeze-dried sponge through a solid-liquid extraction with ilimaquinone (15) in quantitative yield. As we will discuss below,
ethyl acetate, a single flash chromatography with silica gel and this compound presents enhanced reactivity relative to 1. Treat-
further resolution of the two diastereomers by using 2 %/w sil- ment of 15 with dimethyl sulfoxide (DMSO) and acetic an-
ver nitrate impregnated silica gel (Figure 1).[13a,19] Structurally, hydride produced stable π-delocalised sulfur-ylide 3 in 50 %
ilimaquinone (1) and 5-epi-ilimaquinone (2) are made up of a
sesquiterpene domain connected to a penta-substituted quin-
one. The CtD strategy was applied to ilimaquinone (1)[20] and
5-epi-ilimaquinone (2) to generate a library of molecules with
modified scaffolds in a limited number of steps (3 maximum).
The quinone moiety was modified furnishing π-delocalised
sulfur ylide 3, zwitterionic biscyanine 4 and aromatic rings 5
and 6 (Figure 2). Special attention was paid to the original react-
ivities that led to ring contractions of the quinone ring (com-
pounds 7 and 8). The sesquiterpene moiety was cleaved by
using a one-pot ozonolysis/Baeyer–Villiger reaction followed by
a saponification (compounds 9 and 10). It was also possible to
fuse the decalin and quinone rings by using Wagner–Meerwein
shifts (compound 11). Combined modifications of both the
quinone and the decalin moieties were also performed (com-
pounds 12 and 13). More than thirty compounds were synthe-
sised and evaluated for their biological properties against
human umbilical vein endothelium (HUVEC), human
hepatocellular carcinoma (Hep-G2) and human lung carcinoma
(A549) cells. Importantly, some of these new compounds were
good quorum sensing modulators in specific screening in con-
nection with marine environment issues.
Results and Discussion
Scheme 1. Synthesis of aromatic and π-delocalised rings from 1 and 2. Reac-
tion conditions: a) aq. NaOH (2 M), EtOH, reflux, 97 %; b) Ac2O, DMSO, 70 °C,
Quinone Substitutions
50 %; c) Ac2O, Zn, NEt3, 40 °C, 67 %; d) Ac2O, Zn, NEt3, 40 °C, (6: 80 %, 16:
16 %); e) CH3CN/NH3(35 %) 1:1, 55 °C (smenospongine: 16 %, 4: 65 %);
f) R1NH2 (1 equiv.), CH3CN, 35 °C (85–90 %); g) R2NH2 (1 equiv.), CH3CN, 35 °C
(22: 86 %); h) oxone®, CH3CN, H2O (80 %, 2 steps); i) RNH2 (2 equiv.), CH3CN,
35 °C (85–90 %).
To start our investigations (Scheme 1), the quinone ring of 1
or 2 was reduced into an aromatic ring or converted into π-
delocalised ring systems. The demethylation of 1 by sodium
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yield.[21,22] Reduction of this ylide by zinc powder in acetic an- ilimaquinone (15) into tetronic acids 7 and 26–28. During the
hydride (catalytic amount of trimethylamine)[23] resulted in the reaction, ozonolysis of 15 might produce keto-acid I that under-
formation of thio-substituted aromatic compound 5. Similar re- goes oxidative decarbonylation (pathway i, intermediate II).[28]
duction performed on 2, furnished compounds 6 and 16 in Then, cyclisation of intermediate II might explain the formation
80 and 16 % yield, respectively. During the investigation of the of 7 and 26. Formation of 27 and 28 is explained by a cyclisa-
quinone reactivity, it was discovered that treatment of 1 with tion that occurs before the decarbonylation process (pathway
aqueous ammonia in acetonitrile resulted in the isolation of an ii, intermediate III). To the best of our knowledge, this result is
original π-delocalised blue dye 4 in 63 % yield.[24]
the first example of a ring contraction of a quinone with
ozone.[29] Performed on blue dye 4 the quinone ring is com-
pletely truncated and furnishes 29 and smenospongic acid
(14).[30] Acid 14 clearly opens prospects for the introduction
of alternative aromatic rings through, for example, the Barton-
Motherwell reaction.[31]
Recently, by using 4 as a “phishing probe”, we reported the
isolation of zwitterionic dactylocyanines A–H (17–24) from D.
metachromia by using a “molecular networking” based derepli-
cation approach.[25] Natural products 17–24 could be synthe-
sised from 4 by sequential transamination followed by an ox-
one®-mediated oxidation of a thioether side chain for com-
pounds 23 and 24.
Ring Fusions
During attempts towards quinone reorganisation of 1 induced
by sodium azide in sulfuric acid,[32] a ring-fusion phenomenon
was observed (Scheme 3). Cyclosmenospongine (11),[33] 31 and
32 were formed stepwise by means of a Wagner–Meerwein
shift[34]/olefin addition with a 30 % global yield. Notably, by us-
ing Faulkner's conditions, postulated intermediate 30 was iso-
lated[13a,34] alongside ortho-quinone 33.[35] Compound 33 was
then converted into two steps into smenaqualone (34). Ring
fusion performed on 2 in the presence of triflic acid at low
temperatures (–50 °C) produced directly smenoqualone (34)[36]
and isomer 35 through a Wagner–Meerwein shift followed by
the direct trapping of the transient carbocation.
Ozone-Mediated Transformations
Inspired by the structures of dactylolactones,[26] we sought to
modify the quinone moiety by ozonolysis (Scheme 2). The reac-
tion was investigated on compounds 1, 4 and 15. Performed
on ilimaquinone (1), the reaction led to formation of ketone 25
and lactone 9 in 49 and 15 % yield, respectively. Formation of
“abnormal” ozonolysis product 9 is rationalised by a Baeyer–
Villiger oxidation of ketone 25.[27] Then, saponification of lact-
one 9 with sodium hydroxide in ethanol furnished compound
10 to achieve the A ring opening. Simple demethylation of 1
completely modifies the reactivity of the quinone ring. Contrary
to the results observed with 1, ozone oxidises O-desmethyl-
Scheme 3. Ring fusions from 1 and 2. Reaction conditions: a) 1, NaN3, H2SO4
conc., (11: 13 %, 31: 13 %, 32: 4 %); b) 1, Et2O·BF3, benzene, (30: 58 %, 33:
21 %); c) i) NaOH aq. (10 %), EtOH, reflux, ii) Me2SO4, acetone, 80 %; d) 2,
CF3SO3H, CH2Cl2, – 50 °C, (34: 30 %, 35: 40 %).
Further Ring Contractions
Pursuing the modifications of the quinone ring (Scheme 4),
ilimaquinone (1) was subjected to the action of phenyliodine(III)
diacetate (PIDA) but no reaction was observed. Notably, key
intermediate 15 that presents an enhanced reactivity reacts
with PIDA in dichloromethane, followed by heating at reflux
temperatures in acetonitrile to produce cyclopentenedione 8[37]
related to dactylospongenones[17] and smenohaimines.[38] The
postulated mechanism suggests reaction between PIDA and 15
Scheme 2. Ozonolysis of 1, 4 and 15. Reaction conditions: a) ozone stream,
CH2Cl2, –78 °C, then Me2S, room temp. (9: 15 %, 25: 49 %); b) aq. NaOH (2 M),
EtOH, 65 %; c) ozone stream, CH2Cl2/MeOH, 1:1, –78 °C, then Me2S, room
temp. (7: 6 %, 26: 2 %, 27: 13 %, 28: 4 %); d) ozone stream, MeOH, –78 °C,
then Me2S, room temp. (29: 38 %, 14: 31 %).
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in dichloromethane forms a phenyliodonium zwitterionic inter- diones 8, 12 as two close clusters of structures. Calculations
mediate I. Then heating at reflux temperature in acetonitrile also revealed that isomerisation of the decalin produced a more
causes the elimination of iodobenzene, which leads to keto- important structure diversification than the quinone contrac-
carbene II that undergoes a ring contraction. Then, ketene III tion induced by PIDA or ozone as reflected by the localisation
reacts with water (intermediate IV) and decarboxylates to afford of the clusters of structures and the distance index (d 1–34 =
contracted compound 8.[37b,39] The method is also applicable 0.45; d 1–8 = 0.33; d 1–26 = 0.36). The chemolibrary analysis is
to compounds 25 (after demethylation) and 31 as products
12 and 13 were obtained in 20 and 48 % yield, respectively,
which achieves a noteworthy modification of both quinone and
decalin rings.
Figure 3. Molecular fingerprint similarity analysis, distance: (1.00 – tanimoto
similarity coefficient). Generated with the ChemMine Tools.[40a]
Scheme 4. Ring contraction of 15, 25 and 31. Reaction conditions: a) PIDA,
CH2Cl2,0 °C then CH3CN, reflux, (8: 37 %, 12: 20 %, 13: 48 %); b) aq. NaOH
(2 M), EtOH, reflux, 94 %.
Diversity Analysis
A molecular fingerprint of structural distances of the chemo-
library based on Tanimoto coefficient was calculated through
chemoinformatic analyses (Figure 3).[40] The average distance
for the entire library is 0.57 in a range from 0.14 to 0.85, which
reflects a fair structural diversity. The distance matrix was also
vectorised into a 3D map by an all-against-all analysis of com-
pounds (Figure 4) that allows us to visualise both the chemical
space explored and the clusters of structures. Prepared mol-
ecules only share the connectivities of the non-reactive hydro-
carbon moiety present in starting material 1. Aromatic com-
pounds 5, 6 and 25, π-delocalised rings 3, 4 and dactylo-
cyanines A-H (17–25) constitute localised clusters of structures
quite distant from parent molecule 1. The chemoinformatic
analysis identified tetronic acids 7, 26–28 and cyclopentene-
Figure 4. Chemical space of the chemolibrary based on structural distances.
Generated with the ChemMine Tools.[40a]
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based on the chemical connectivities without consideration of quorum sensing communication may be evidenced by a bio-
stereochemistry, which explains the failure to identify the 3D luminescence phenomenon of the Vibrio harveyi strain.[44] Mol-
distance for structures 32, 34 and 35 (distance index = 0).
ecules of the chemolibrary (50 μg mL–1) were evaluated as quo-
rum sensing inhibitors. Inhibition was determined by measur-
ing the delay time for the onset of bioluminescence in Vibrio
harveyi cultures by using a Leucetta chagosensis extract as a
positive control (Table 2).[45] Ilimaquinone (1) and 5-epi-ilima-
quinone (2) proved to be good quorum sensing inhibitors but
are also cytotoxic (Table 1). The best delay value (150 min) is
observed for molecule 15 that arises from its antibiotic activity.
Biological Evaluation: Toxicity
Compounds 1–19, 21, 23–29 and 31–32 were evaluated in vi-
tro for their cytotoxic activities against three human cell lines
(HUVEC, Hep-G2 and A549) by using doxorubicin as a positive
control. Some products showed micromolar cytotoxicities and
Table 2. Quorum sensing inhibition evaluations (50 μg mL–1).[a]
significant IC50 values (<50 μM) are reported in Table 1. Relative
to ilimaquinone (1) and 5-epi-ilimaquinone (2), the modification
of the quinone ring as π-delocalised ring systems (compound
3, 4 and dactylocyanines B, C, E: 18, 19 and 21) moderately
decreases cytotoxicities. Aromatisation of the quinone ring and
demethylation (compounds 5, 6, 15 and 16) does not affect
significantly the cytotoxicity and IC50 are in the same range.
When the decalin moiety is modified as found in lactone 9,
acid 10, ketone 25 or rearranged compounds 11, 31 and 32,
cytotoxicities significantly decrease and some of those products
are considered barely cytotoxic. Truncated compounds 14 and
29, tetronic acids 7 and 26–28 and contracted products 8, 12
Compound
Bacterial growth
inhibition
Bioluminescence
lag time [min]
Leucetta sp.
control [min]
1
2
5
6
7
8
9
10
11
12
13
15
16
17
18
19
21
23
24
25
27
31
32
–
–
–
–
–
–
–
–
40
30
–20
–10
–30
30
40
–10
20
40
20
150
60
–20
10
10
10
–30
–20
10
–40
10
70
70
70
40
50
70
40
70
70
70
70
40
70
40
70
70
40
50
50
40
50
70
70
–
–
–
and 13, are not active against the three cell lines (IC50 > 50 μM).
inhibition
–
–
–
–
–
–
–
–
–
–
–
Table 1. Cytotoxicity evaluations, (IC50 in μM).
Compound
HUVEC[a]
Hep-G2[b]
A549[c]
1
3.9
6.0
3.3
2
4.7
7.1
4.5
3
4
5
27.8
28.3
3.6
42.3
33.6
4.9
30.0
24.6
4.3
6
0.9
1.9
1.2
9
18.0
24.8
5.9
43.3
24.6
8.8
6.5
–
24.1
17.8
13.0
>50
8.3
40.5
>50
>50
>50
11.2
7.0
10
11
15
16
17
18
19
21
23
24
25
31
32
[a] Vibrio haveyi BB120 wild-type strain.
4.5
3.6
Compounds 9 and 16 are the best quorum sensing inhibitors
of the chemolibrary (Table 2) associated with moderate toxicity
for 9 (Table 1). The most promising quorum sensing inhibitor
candidates are cyclopentenediones 8, 12 and 13 because they
are equally as good quorum sensing inhibitors as 1 (40 min for
12), are not cytotoxic and do not display any antibiotic activity.
Notably, mono-alkylated dactylocyanines 18, 19 and 21 are
barely inhibitors, whereas di-alkylated members 17, 23, and 24
stimulate the bioluminescence phenomenon. Tetronic acids 7
and 27 significantly stimulate quorum sensing by shortening
the onset of bioluminescence with advance values of 30 and
40 minutes, respectively. The identification of quorum sensing
activators is potentially valuable in strategies that aim to stimu-
late the host immune system when the pathogen bacterial
population is low[46] or as “artificial autoinducers” to study ex-
11.9
29.3
17.3
11.3
>50
8.2
10.0
47.2
29.0
10.0
24.3
18.4
13.6
13.5
8.1
30.0
>50
>50
[a] HUVEC, doxorubicin (10 μ
M): 30 % cell survival. [b] Hep-G2, doxorubicin
(10 μ ): 30 % cell survival. [c] A549, doxorubicin (10 μ
M
M): 30 % cell survival.
Biological Evaluation: Activities Against Vibrio harveyi
Quorum Sensing
Vibrio harveyi is an opportunistic pathogen bacterium of tropi- tracellular communication in a chemical ecology context. Com-
cal marine organisms. This bacterium is known to induce severe pounds 9, 12 and 16 with the best inhibitions values were cho-
economic losses in aquacultured species including farmed bat sen and further investigated on three derived mutants kindly
fish (Platax orbicularis) and pearl oysters (Pinctada margaritifera) provided by Prof. Bassler,[45,47] each of them expresses one of
in French Polynesia.[41] Quorum sensing is an intercellular com- three pathways that control luminescence activity. The selected
munication[42] used by many bacteria that facilitates a collective compounds display better activity on Vibrio specific auto-indu-
organisation and a concerted production of e.g. virulence cers pathways (CAI-1 and HAI-1), especially compound 16,
factors by the population of cells.[43] The establishment of a which is more active than the reference extract, but all display
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preparative C18 columns (150 × 30 mm; i.d. 5 μ
XBridge® preparative C18 columns (150 × 46 mm; i.d. 5 μM, Waters)
were used for preparative HPLC separations by using a Waters Delta
Prep equipped with a binary pump (Waters 2525), a UV/Visible di-
ode array detector (190–600 nm, Waters 2996). Medium pressure
chromatography was run with an Armen-Spot-Prep® purification
M
, Waters) and
mild activity on the more general AI-2 pathway (see inhibitions
values on Vibrio harveyi double mutants in the Supporting in-
formation).
Conclusions
system with Grace® flash cartridges (330 g and 40 g; i.d. 40 μM). For
silica-gel chromatography, the flash chromatography technique was
used, with Merck silica gel 60 (230–400 mesh) and p.a. grade. Ana-
lytical and preparative TLC were performed with Merck silica gel
F254 (230–400 mesh) plates and analysed by direct observation or
UV light or by staining upon heating with a vanillin solution (2 g of
vanillin, 1 mL of conc. H2SO4, 100 mL of EtOH).
In summary, a ring distortion strategy was applied to ilimaquin-
one (1) and 5-epi-ilimaquinone (2) isolated in high yields from
the sponge D. metachromia. A chemically diversified chemo-
library was prepared that afforded already known natural prod-
ucts (11, 14, 15, 30 and 34), recently described new natural
products (17–24), known semisynthetic products (29, 31–33)
and, most importantly, original structures (3–10, 12, 13, 16, 25–
28 and 35; see references in the Supporting information,
Table 1). Products were synthesised in quantities that ranged
from 10 mg to 1 gram; a prerequisite to carry out the multistep
sequences and biological evaluations. Chemo-informatic calcu-
lations of the structure distances based on Tanimoto coefficient
indicates a fair diversification with a 0.57 average distance for
the entire library. The terpene moiety that contained an olefin
as the sole reactive function was modified by a formal Baeyer–
Villiger strategy or Wagner–Meerwein shifts to afford a set of
diastereomeric fused decalins. The quinone moiety was modi-
fied to aromatic or π-delocalised ring systems. In addition, the
action of PIDA and ozone shed light on original reactivities of
the quinone ring and afforded contracted five-membered rings.
Although some chemical transformations, such as Wagner–
Meerwein shifts (e.g. 11) or quinone reductions (e.g. 6), seemed
to reduce reactivity, the introduction of a ketone on the decalin
(e.g. 25) and contracted products (e.g. 7, 8) improves the mo-
lecular profiles by introducing new patterns of reactivity relative
to sparsely functionalised ilimaquinone (1). Further prospects
could start from these more reactive functionalities introduced
on the ilimaquinone scaffold. Cytotoxicity evaluations indicated
that compounds with quinone, aromatic or π-delocalised rings
systems display IC50 values in the micromolar range. Without a
quinone moiety compounds lose their cytotoxicity. Compounds
of the chemolibrary were also evaluated as quorum sensing
inhibitors of an economically important pathogen in French
Polynesia. The cyclopentenedione series proved to be as good
inhibitors as ilimaquinone (1), whereas tetronic acid derivatives
significantly stimulated quorum sensing.
Isolation of Ilimaquinone (1) and 5-epi-Ilimaquinone (2) from
Dactylospongia metachromia: Freeze-dried sponge collected from
Tetiaroa atoll (300 g) is extracted by stirring in ethyl acetate (1.5 L)
for 2 h. The operation is repeated twice on the grounds and com-
bined extracts are concentrated to dryness. The crude extract (≈
40 g) is fractionated by medium pressure chromatography [Grace®
flash cartridges 330 g, eluent gradient: petroleum ether/dichloro-
methane/methanol, 20:80:0 → 0:1:0 → 0:99:1 (2.5 L, 62 min, 40 mL/
min)]. Fraction (≈ 12 g) that contains ilimaquinone (1) and 5-epi-
ilimaquinone (2) is purified by flash chromatography with 2 %w-
silver nitrate impregnated silica gel (elution gradient: petroleum
ether/dichloromethane/methanol, 20:80 → 0:1) to afford 5-epi-
ilimaquione (2; 3.3 g, 1.1 %) and ilimaquinone (1; 5.0 g, 1.6 %).
Ilimaquinone (1): Rf: (SiO2, CH2Cl2) = 0.45; (AgNO3-SiO2, CH2Cl2) =
1
0.12. IR (neat): ν
= 3331, 2921, 1657, 1642, 1609, 1434 cm–1. H
˜
max
NMR (400 MHz, [D]chloroform): δ = 7.51 (s, OH), 5.83 (s, 1 H, 19-H),
4.42 (br. s, 1 H, 11-H), 4.40 (br. s, 1 H, 11-H), 3.84 (s, 3 H), 2.52 (d,
J = 13.7 Hz, 1 H, 15-H), 2.45 (d, J = 13.7 Hz, 1 H, 15-H), 2.30 (m, 1
H), 2.02–2.09 (m, 2 H), 1.84 (m, 1 H), 1.31–1.51 (m, 5 H), 1.11–1.19
(m, 2 H), 1.02 (s, 3 H), 0.95 (d, J = 6.4 Hz, 3 H), 0.82 (s, 3 H), 0.75
(dd, J = 12; 1.8 Hz, 1 H) ppm. 13C NMR (101 MHz, [D]chloroform):
δ = 182.3 (C-17), 182 (C-20), 161.6 (C-18), 160.4 (C-4), 153.3 (C-21),
117.3 (C-16), 102.4 (C-11), 101.9 (C-19), 56.8 (OCH3), 50.0 (C-10), 43.2
(C-9), 40.4 (C-5), 38.0 (C-8), 36.6 (C-6), 32.9 (C-3), 32.3 (C-15), 28.6 (C-
2), 27.9 (C-7), 23.1 (C-1), 20.5 (C-12), 17.8 (C-13), 17.3 (C-14) ppm.
HRMS (ESI): m/z calcd. for C22H29O4 [M + H]+ 357.2071; found
+
357.2071.
5-epi-Ilimaquinone (2): Rf: (SiO2, CH2Cl2) = 0.45; (AgNO3-SiO2,
CH2Cl2) = 0.42. IR (neat): νmax = 3330, 2929, 1662, 1642, 1601, 1458,
˜
1433 cm–1. 1H NMR (400 MHz, [D]chloroform): δ = 7.45 (s, OH), 5.88
(s, 1 H, 19-H), 4.69 (br. s, 1 H, 11-H), 4.66 (br. s, 1 H, 11-H), 3.87 (s, 3
H), 2.59 (d, J = 13.7 Hz, 1 H, 15-H), 2.49 (d, J = 13.7 Hz, 1 H, 15-H),
2.43 (m, 1 H), 2.16–2.08 (m, 2 H), 2.0 (m, 1 H), 1.91–1.63 (m, 3 H),
1.48 (m, 1 H), 1.23–1.17 (m, 3 H), 1.1 (dd, J = 13.9, 3.2 Hz, 1 H), 1.05
(s, 3 H), 0.92 (d, J = 6.2 Hz, 3 H), 0.87 (s, 3 H) ppm. 13C NMR
(101 MHz, [D]chloroform): δ = 182.4 (C-17, C-20), 161.7 (C-18),
[153.5, 153.3 (C-4, C-21)], 117.6 (C-16), 105.7 (C-11), 102.0 (C-19),
56.8 (C-22), 48.5 (C-10), 44.9 (C-9), 39.5 (C-5, C-8), 37.9 (C-6), 33.2 (C-
12), 32.7 (C-15), 32.0 (C-3), 27.8 (C-7), 24.9 (C-2), 22.5 (C-1), 18.6 (C-
Experimental Section
All reactions were carried out under an argon atmosphere. Dichloro-
methane was distilled under argon over calcium hydride. Tetra-
hydrofuran was distilled under argon over sodium and benzo-
phenone. Unless otherwise noted, all reagent-grade chemicals and
other solvents were obtained from commercial suppliers and were
used as received. IR spectra were recorded with a Vector 22 Bruker
spectrometer. The NMR spectra were recorded with a Bruker
14), 18.2 (C-13) ppm. HRMS (ESI): m/z calcd. for C22H29O4 [M + H]+
+
357.2071; found 357.2071.
O-Desmethyl-ilimaquinone (15): To a solution of ilimaquinone (1;
200 mg, 0.56 mmol) in ethanol (20 mL) is added NaOH (2 M, 12 mL).
Avance-300 (300 MHz) and Avance-400 (400 MHz) apparatus with The reaction mixture is heated to reflux temperatures for 1 h. After
[D]chloroform, [D4]MeOH, [D3]acetonitrile, and [D6]DMSO as sol- cooling, the reaction mixture is quenched with HCl (1 , 50 mL)
vents. HRMS and LC/MS were obtained by using Electrospray Ionisa- and extracted with ethyl acetate (2 × 50 mL). The combined extracts
M
tion (ESI) on a Thermoquest TLM LCQ Deca ion-trap spectrometer
with a Sunfire® analytical C18 column (150 × 2.1 mm; 3.5 μ , Waters)
or with a XBridge® C18 column (150 × 2.1 mm; i.d. 3.5 μ ). Sunfire®
are dried with Na2SO4, filtered and concentrated under reduced
pressure to afford the title compound as a red solid (186 mg, 97 %).
M
M
IR (neat): νmax = 3119, 3289, 2921, 2860, 2445, 1704, 1639, 1601,
˜
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1449 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 11.10, (br. s, 1 H, OH),
5.79 (s, 1 H, 19-H), 4.41 (s, 1 H, 11-H), 4.39 (s, 1 H, 11-H), 3.36 (br. s,
1 H, OH), 2.40 (d, J = 13.5 Hz, 1 H, 15-H), 2.32 (d, J = 13.6 Hz, 1 H,
1,4,5-Triacetoxy-2-methoxy-6-[(5R,9R,10R)-14(4→5),15(10→9)-
bisabeo-driman-4(13)-en-11-yl]benzene (6): IR (neat): νmax
=
˜
2985, 2902, 2854, 1767, 1482, 1464, 1443, 1426 cm–1 1H NMR
.
15-H), 2.24 (dt, J = 17.0, 8.7 Hz, 1 H), 2.08–1.97 (m, 2 H), 1.76 (m, 1 (300 MHz, [D]Chloroform): δ = 6.73 (s, 1 H, 19-H), 4.70 (s, 1 H, 11-
H), 1.58–1.10 (m, 5 H), 0.99 (s, 3 H, 12-H), 0.92 (d, J = 6.3 Hz, 3 H, H), 4.66 (s, 1 H, 11-H), 3.79 (s, 3 H, OMe), 2.44 (d, J = 4.4 Hz, 2 H,
12-H), 0.78 (s, 3 H, 14-H), 0.73 (m, 1 H) ppm. 13C NMR (101 MHz,
[D6]DMSO): δ = 159.3 (C-4), 115.4 (C-16), 103.6 (C-19), 102.9 (C-11),
49.5 (C-10), 42.4 (C-9), 39.8 (C-2), 37.5, 36.3, 32.4, 27.9, 27.5, 22.7,
15-H), 2.31 (s, 3 H, OAc), 2.29 (s, 3 H, OAc), 2.26 (s, 3 H, OAc), 2.17–
1.99 (m, 3 H), 1.93–1.84 (m, 1 H), 1.74–1.63 (m, 3 H), 1.49–1.45 (m,
3 H), 1.10 (s, 3 H, CH3), 0.89 (s, 3 H, CH3), 0.81 (d, J = 5.9 Hz, 3 H,
20.1 (C-12), 18.0 (C-13), 17.1 (C-14) ppm. HRMS (ESI): m/z calcd. for CH3) ppm. 13C NMR (75 MHz, [D]Chloroform): δ = 168.2 (2 × C=O),
21H27O4 [M + H]+ 343.1915; found 343.1911. [α]2D0 = –184 (c = 168.1 (C=O), 153.5 (C-4), 149.1,140.2,137.5,135.5,128.9,106.2 (C-11),
+
C
0.038, CHCl3).
105.3 (C-19), 56.4 (OCH3), 50.2 (C-10), 45.0 (C-9), 41.4 (C-8), 39.9 (C-
5), 38.5 (CH2), 37.9 (CH2), 32.1 (C-12), 28.2 (CH2), 25.1 (CH2), 23.4
(CH2), 21.0 (3CH3 OAc), 20.9 (CH2), 19.0 (C-14), 17.9 (C-13) ppm.
HRMS (ESI): m/z calcd. for C28H38O7Na+ [M + Na]+ 509.2510; found
509.2523. [α]2D0 = –43 (c = 0.046, CHCl3).
3-(Dimethyl–λ4–sulfanylidene)-5-hydroxy-6-[(5S,9R,10R)-
14(4→5),15-(10→9)-bisabeodriman-4(13)en-11-yl]cyclohex-5-
ene-1,2,4-trione (3): A solution of ilimaquinone (1, 20 mg,
0.058 mmol) in a mixture of DMSO and acetic anhydride (6:4 v/v,
1 mL) was heated to 70 °C for 1 h. After cooling, the reaction mix-
ture is quenched with water (5 mL), pH is adjusted to 8 with
Na2CO3, and extracted with CH2Cl2 (2 × 10 mL). The combined or-
ganic extracts are dried with Na2SO4, filtered and concentrated un-
der reduced pressure. Purification by preparative TLC with silica gel
(eluent: dichloromethane/methanol, 95:5) afforded the title com-
1,4-Diacetoxy-5-hydroxy-2-methoxy-6-[(5R,9R,10R)-
14(4→5),15(10→9)-bis-abeodriman-4(13)-en-11-yl]benzene
(16): IR (neat): νmax = 2924, 2852, 1767, 1712, 1486, 1464, 1442 cm–
˜
1. 1H NMR (300 MHz, [D]Chloroform): δ = 6.63 (s, 1 H, 19-H), 5.73 (s,
1 H, OH), 4.70 (s, 1 H, 11-H), 4.66 (s, 1 H, h-11), 3.86 (s, 3 H, OMe),
2.57 (s, 2 H, 10-H), 2.29 (s, 3 H, OAc), 2.25 (s, 3 H, OAc), 2.12–1.87
(m, 4 H), 1.65–1.46 (m, 6 H), 1.09 (s, 3 H, CH3), 0.90 (s, 3 H, CH3),
0.85 (d, J = 5.7 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, [D]Chloroform):
δ = 1 6 8 . 9 ( C = O ) , 1 6 8 . 8 ( C = O ) , 1 5 3 . 8 ( C - 4 ) ,
143.7,143.4,136.2,134.5,120.9,105.9 (C-11), 103.8 (C-19), 56.4 (CH3
OMe), 49.5 (C-10), 44.9 (C-9), 40.4 (C-8), 39.9 (C-5), 37.8 (CH2), 36.8
(CH2), 32.2 (C-12), 28.3 (CH2), 25.3 (CH2), 23.4 (CH2), 20.9 (2 × OAc),
20.8 (CH2), 19.2 (C-14), 18.2 (C-13) ppm. HRMS (ESI): m/z calcd. for
pound as a yellow oil (11.8 mg, 50 %). IR (neat): νmax = 2921, 2852,
˜
1668, 1634, 1620, 1575 cm–1. 1H NMR (300 MHz, [D]chloroform): δ =
8.32 (br. s, 1 H, OH), 4.43 (s, 1 H, 11-H), 4.42 (s, 1 H, 11-H), 3.10 (s, 3
H, SCH3), 3.09 (s, 3 H, SCH3), 2.54 (d, J = 13.5 Hz, 1 H, 15-H), 2.48 (d,
J = 13.5 Hz, 1 H, 15-H), 2.38–2.27 (m, 2 H), 2.18–2.04 (m, 2 H), 1.86
(m, 1 H), 1.68–1.59 (m, 2 H), 1.49 (m, 1 H), 1.42–1.35 (m, 2 H), 1.04
(s, 3 H, CH3), 0.99 (d, J = 6.1 Hz, 3 H, CH3), 0.84 (s, 3 H, CH3) ppm.
13C NMR (75 MHz, [D]chloroform): δ = 175.1, 162.8, 162.5, 161.2 (Cq,
C-4′), 157.3, 117.9 (C-18), 102.4 (C-11), 50.1 (C-8), 43.4 (C-5), 40.7 (C-
9), 38.1 (C-10), 36.9 (CH2), 33.2 (CH2), 33.0 (CH2), 28.4 (CH2), 28.2
(CH2), 26.3 (2 SCH3), 23.4 (CH2), 20.9 (H-12), 18.1 (H-13), 17.7 (H-
14) ppm. HRMS (ESI): m/z calcd. for C23H33O4S+ [MH]+ 405.2104;
found 405.2094. [α]2D0 = –366 (c = 0.030, CHCl3).
C
26H36O6Na+ [M + Na]+ 467.2404; found 467.2410. [α]2D0 = +19 (c =
0.054, CHCl3).
(5S,9R,10R)-(2-Hydroxy-5-amino-1-imino-quinon-3-yl)-
14(4→5),15(10→9)-bisabeodriman-4(13)-ene (4): A solution of il-
imaquinone (1; 600 mg, 1.75 mmol) in a 1:1 mixture of aqueous
ammonia (35 %) and acetonitrile (5 mL) is heated to 35 °C for 16 h.
The reaction mixture is diluted with ethyl acetate (50 mL) and
washed with water (15 mL). The organic extract is dried with
MgSO4, filtered and concentrated under reduced pressure. Purifica-
tion by flash chromatography with silica gel (eluent: dichloro-
methane/methanol, 95:5 then 85:15) affords smenospongine
(100 mg, 16 %) and then the title compound as a deep blue solid
1,2,4,5-Tetracetoxy-3-(methylthio)-5-hydroxy-6-[(5S,9R,10R)-
14(4→5),15(10→9)bisabeo-driman-4(13)-en-11-yl]benzene (5):
To a solution of 3 (12.5 mg, 0.046 mmol) in acetic anhydride
(0.50 mL) are added zinc dust (36 mg, 0.55 mmol) and trimethylam-
ine (20 μL). The reaction mixture is heated to 45 °C for 1 h. After
cooling, the reaction mixture is filtered and concentrated to dry-
ness. Purification by flash chromatography with silica gel (eluent:
dichloromethane/methanol, 1:0 then 9:1) affords the title com-
(390 mg, 65 %). IR (neat): νmax = 3385, 2927, 1739, 1684, 1433,
˜
1205 cm–1
.
1H NMR (400 MHz, [D6]DMSO): δ = 9.03 (s, 2 H, NHa),
pound as a colourless oil (17.2 mg, 67 %). IR (neat): νmax = 2926,
˜
8.33 (s, 2 H, NHb), 5.55 (s, 1 H, 19-H), 4.36 (s, 1 H, 11-Ha), 4.34 (s, 1
H, 11-Hb), 2.37 (d, J = 10.3 Hz, 1 H, 7-H), 2.29 (d, J = 13.5 Hz, 1 H,
15-H), 2.25 (m, 1 H, 3-H), 2.20 (d, J = 13.5 Hz, 1 H, 2–15), 1.96 (d, J =
13.9 Hz, 1 H, 3-H), 1.68 (m, 1 H, 1-H), 1.39 (d, J = 10.9 Hz, 1 H, 6-H),
1.32–1.15 (m, 5 H), 0.98–0.95 (m, 7 H, 10-H 12-H 13-H), 0.83 (d, J =
10.2 Hz, 1 H, 8-H), 0.71 (s, 3 H, 14-H) ppm. 13C NMR (101 MHz,
[D6]DMSO): δ = 171.8 (C-17, C21), 160.1 (C-4), 159.9 (C-18, C-20),
107.7 (C-16), 102.4 (C-11), 85.4 (C-19), 48.7 (C-8), 41.9 (C-9), 39.8 (C-
5), 37.0 (C-10), 36.7 (C-6), 32.7 (C-3 C-15), 28.5 (C-1), 27.8 (C-2), 22.7
(C-7), 20.2 (C-12), 18.4 (C-13), 17.6 (C-14) ppm. HRMS (ESI): m/z calcd.
2859, 1785, 1769, 1634, 1426 cm–1
.
1H NMR (300 MHz, [D]Chloro-
form): δ = 4.49 (s, 2 H, 11-H), 2.51–2.46 (m, 1 H), 2.33–2.23 (m, 15
H, 4 OAc, CH3S), 2.14–2.07 (m, 2 H), 1.88–1.81 (m, 1 H), 1.50–1.42
(m, 5 H), 1.38–1.25 (m, 3 H), 1.04 (s, 3 H, CH3), 0.85 (s, 3 H, CH3),
0.70 (d, J = 6.0 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, [D]Chloroform):
δ = 167.6 (2 × C=O), 167.5 (C=O), 167.4 (C=O), 160.2 (C-4), 143.2,
141.1 (2 C), 130.4, 124.1, 116.1 (C-16), 103.2 (C-11), 54.6 (C-8), 44.0
(C-5), 41.0 (C-9), 40.9 (C-10), 39.7 (CH2), 37.0 (CH2), 33.1 (CH2), 29.1
(CH2), 28.7 (CH2), 24.0 (CH2), 20.9 (OAc), 20.8 (OAc), 20.7 (OAc), 20.5
(OAc), 18.7 (C-12), 18.5 (C-13), 18.3 (C-14), 15.8 (CH3S) ppm. HRMS
(ESI): m/z calcd. for C30H44NO8S+ [M + NH4]+ 578.2782; found
578.2798. [α]2D0 = –9 (c = 0.104, CHCl3).
for C21H31N2O2 [M + H]+ 343.2380; found 343.2382. [α]2D0 = –51
+
(c = 0.04, MeOH).
Reduction of 2 to Afford 6 and 16: To a solution of 5-epi-ilima- Transaminations of 4 to Afford Dactylocyanines A-H (17–24): To
quinone (2; 20.0 mg, 0.057 mmol) in acetic anhydride (0.50 mL) are
added zinc dust (21 mg, 0.32 mmol) and trimethylamine (20 μL).
The reaction mixture was heated to 40 °C for 1 h. After cooling, the
reaction mixture is filtered and concentrated to dryness. Purification
a solution of 4 (50 mg, 0.15 mmol) in acetonitrile (2 mL) is added
the corresponding amine R1-NH2 (for 17 and 20: 0.30 mmol,
2 equiv.; for 18, 19, 21 and S-i: 0.15 mmol, 1 equiv.). The reaction
mixture is heated to 35 °C (20–24 h) and concentrated to dryness.
by flash chromatography with silica gel (eluent: dichloromethane/ Purification by flash chromatography with silica gel (eluent: CH2Cl2/
methanol, 1:0) affords 16 as a white powder (4.0 mg, 16 %) and
then 6 as a white power (21.8 mg, 80 %).
MeOH, 98:2 then 95:5) affords the title compounds as deep blue
solids (85–90 %). To a solution of 18 (20 mg), or 19 (40 mg) or S-i
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(20 mg; 1 equiv.) in acetonitrile (2 mL) is added the corresponding
amine R2-NH2 [(S)-2-methylbututylamine or 3-(methylthio)propyl-
amine] [1 equiv. (100 μL of a solution of 10 equiv. of amine in
1.00 mL of acetonitrile)]. For compound 22: The reaction mixture is
heated to 35 °C (24 h) and concentrated to dryness. Purification by
flash chromatography with silica gel (eluent: CH2Cl2/MeOH, 98:2)
affords 22 as a deep blue solid (40 mg, 86 %). For compound 23
and 24: the reaction mixture is heated to 35 °C (24 h) and then
water (0.5 mL) and oxone® (50 mg, 0.162 mmol) are added. After
35 min of stirring, the reaction mixture is diluted with water (5 mL)
and extracted with ethyl acetate (2 × 15 mL). The combined extracts
are dried with Na2SO4, filtered and concentrated under reduced
pressure. Purification by preparative TLC with silica gel (eluent: di-
chloromethane/methanol, 95:5) affords title compounds as deep
blue solids (23/24, both 80 %).[25]
δ = 182.4, 182.2 (C-17, C-21), 175.9 (C-4), 161.9 (C-18), 154.1 (C-21),
116.3 (C-16), 102.3 (C-19), 86.5 (C-5), 57.1 (OMe), 50.2 (C-10), 44.7
(C-9), 41.7 (CH2), 37.5 (C-8), 37.2 (CH2), 31.6 (CH2), 28.3 (CH2), 27.0
(CH2), 24.2 (CH2), 22.0 (CH3), 17.8 (CH3), 16.4 (CH3) ppm. HRMS (ESI):
+
m/z calcd. for C21H28O6Na [M + H]+ 399.1778; found 399.1771.
[α]2D0 = –64 (c = 0.110, CHCl3).
4-{(1S,3S,6S)-2-[(3,6-Dihydroxy-quinon-2-yl)methyl]-6-hydroxy-
2,3,6-trimethylcyclohexyl}butanoic Acid (10): To a solution of
lactone 9 (44 mg, 0.012 mmol) in ethanol (4.5 mL) is added a solu-
tion of NaOH (2
for 1 h. After cooling, the reaction mixture is quenched with HCl
solution (1 , 50 mL) and extracted with ethyl acetate (2 × 50 mL).
M, 2.5 mL). The reaction mixture is heated to reflux
M
The combined extracts are dried with Na2SO4, filtered and concen-
trated under reduced pressure. Solubilisation in chloroform and pre-
cipitation by the addition of petroleum ether afford the title com-
(5S,9R,10R)-[2-Hydroxy-5-(2-phenylethylamino)-1-imino-
quinon-3-yl]-14(4→5),15(10→9)-bisabeodriman-4(13)-ene (S-i):
pound as a brown solid (29 mg, 65 %). IR (neat): νmax = 3310, 2923,
˜
2853, 2360, 2340, 1703, 1647, 1625 cm–1
.
1H NMR (300 MHz, [D3]-
IR (neat): νmax = 3300, 2977, 2921, 2856, 1655, 1554, 1535, 1527 cm–1
.
acetonitrile): δ = 8.52–8.39 (br. s, 2 H, 2OH), 5.94 (s, 1 H, 19-H), 2.51
˜
1H NMR (400 MHz, [D]chloroform): δ = 7.31 (dd, J = 8.0, 6.3 Hz, 2 (d, J = 2.5 Hz, 2 H, 15-H), 1.62–1.53 (m, 3 H), 1.44–1.34 (m, 4 H),
H, H-o), 7.24 (m, 1 H, H-p), 7.19–7.14 (m, 2 H, H-m), 5.32 (s, 1 H, 19-
H), 4.42 (s, J = 1.7 Hz, 2 H, 11-H), 3.53 (t, J = 7.1 Hz, 2 H, H-ꢀ), 2.95
(t, J = 7.2 Hz, 2 H, H-α), 2.45 (d, J = 13.7 Hz, 1 H, H-15), 2.39 (d, J =
14.2 Hz, 1 H, H-15), 2.37–2.23 (m, 2 H), 2.05 (dt, J = 12.9, 2.9 Hz, 1
H), 1.81 (dd, J = 12.1, 4.9 Hz, 1 H), 1.51 (tt, J = 11.4, 5.4 Hz, 1 H),
1.43–1.22 (m, 3 H), 1.36 (s, 3 H), 1.17 (qd, J = 12.6, 10.6, 6.4 Hz, 1
H), 1.02 (s, 3 H), 1.01 (d, J = 4.5 Hz, 3 H), 0.88 (dd, J = 11.5, 2.0 Hz,
1 H), 0.79 (s, 3 H). 13C NMR (101 MHz, [D]chloroform): δ = [171.7,
171.0 (C-17, C-21)], 161.5 (C-4), 159.6 (C-20), 156.9 (C-18), 136.9 (C-
ipso), 129.0, 128.6, 127.2, 110.7 (C-16), 101.9 (C-11), 83.6 (C-19), 49.9
(C-8), 44.6 (C-ꢀ), 42.7 (C-5), 40.5 (C-9), 38.0 (C-10), 36.9, 34.7 (C-α),
33.3, 33.2, 29.0, 28.1, 23.4, 20.6 (C-12), 18.2 (C-13), 17.4 (C-14) ppm.
1.32–1.27 (m, 3 H), 1.10 (s, 3 H, CH3), 0.87 (d, J = 6.3 Hz, 3 H, CH3),
0.74 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, [D4]MeOH): δ = 179.1 (C-
4), 178.7 (C-17, C-20), 134.9 (C-18, C-21), 117.4 (C-16), 104.5 (C-19),
75.4 (C-5), 55.0 (C-10), 45.7 (C-9), 44.3 (CH2), 40.5 (C-8), 36.7 (CH2),
34.2 (CH2), 30.9 (CH2), 29.3 (CH2), 28.5 (CH2), 23.5 (C-12), 18.6 (C-13),
16.4 (C-14) ppm. HRMS (ESI): m/z calcd. for C20H28O7Na+ [M + Na]+
379.1762; found 379.1761. [α]2D0 = –125 (c = 0.048, CHCl3).
Ozonolysis of 15 Affording 7, 26–28: A solution of 15 (265 mg,
0.77 mmol) in a 3:1 mixture of dichloromethane and methanol
(30 mL) cooled to –78 °C is subjected to an ozone stream (0.3 NL/
min) for 2 min. The reaction mixture is quenched by the addition
of dimethyl sulfide (1.0 mL, 13.5 mmol). After 16 h stirring at room
temp. the reaction mixture is concentrated under reduced pressure.
Purification by preparative HPLC (Sunfire® preparative C18 columns
150 × 30 mm; i.d. 5 μm, Waters) 20 % to 100 % MeCN in H2O (0.2 %
HRMS (ESI): m/z calcd. for C29H39N2O2 [M + H]+ 447.3011; found
+
447.3011. [α]2D0 = –129 (c = 0.007, CHCl3).
Ozonolysis of 1 Affording 9 and 25: A solution of ilimaquinone
(126 mg, 0.35 mmol) in dichloromethane (25 mL) cooled to –78 °C HCOOH) over 20 min at 42 mL/min affords 27 (RT = 8.40 min, 35 mg,
is subjected to an ozone stream (0.3 NL/min, 5 × 15 s, TLC monitor-
ing) and then Me2S (0.20 mL) is added. After 16 h of stirring, the
reaction mixture is concentrated under reduced pressure. Purifica-
tion by flash chromatography with silica gel (eluent: dichloro-
methane/methanol, 199:1 → 99:1 → 98:2) affords recycled ilima-
quinone (1; 8 mg, 6 %), then ketone 25 as yellow solid (62 mg,
49 %) and lactone 9 as a yellow solid (20 mg, 15 %).
13 %), 7 (RT = 10.25 min, 16 mg, 6 %), 28 (RT = 13.10 min, 13.0 mg,
4 %), and 26 (RT = 15.30 min, 3 mg, 2 %). See NMR spectroscopy
data charts in the Supporting information.
2-Hydroxy-3-[(5S,9R,10R)-4-oxo-13-nor-14(4→5),15(10→9)-bis-
abeo-driman-11-yl]-2-butenolide-4-carboxylic Acid (27): IR
(neat): νmax = 2935, 1774, 1744, 1668 cm–1; 3:2 diastereomeric mix-
˜
ture: 1H NMR (400 MHz, [D]chloroform, diastereomer A): δ = 6.71
(br. m, 2 H), 5.10 (s, 1 H), 2.65 (d, J = 13.5 Hz, 1 H), 2.57 (m, 1 H),
2.22 (d, J = 13.5 Hz, 1 H), 2.19 (m, 1 H), 2.19–2.00 (m, 3 H), 1.69 (m,
2-Hydroxy-5-methoxy-3-[(5S,9R,10R)-4-oxo-13-nor-14(4→5),15-
(10→9)-bisabeodriman-11-yl]quinone (25): IR (neat): νmax = 3343,
˜
1
2975, 2930, 1721, 1701, 1665, 1642, 1609 cm–1. H NMR (300 MHz, 1 H), 1.63–1.44 (m, 3 H), 1.44–1.30 (m, 2 H), 1.24 (m, 1 H), 1.15 (s, 3
[D]chloroform): δ = 7.65 (s, 1 H, OH), 5.84 (s, 1 H, 19-H), 3.84 (s, 3 H,
OMe), 2.60–2.43 (m, 3 H, 15-H), 2.20 (m, 1 H), 2.08 (dt, J = 14.3, [D]chloroform): δ = 217.3, 169.80, 169.4, 141.0, 127.3, 78.8, 49.4,
3.5 Hz, 1 H), 1.97 (m, 1 H), 1.63–1.55 (m, 2 H), 1.49–1.15 (m, 5 H), 49.2, 44.1, 37.6, 37.3, 33.0, 32.31, 26.6, 25.6, 20.9, 18.8, 17.7,
H), 0.97 (d, J = 5.0 Hz, 3 H), 0.90 (s, 3 H) ppm. 13C NMR (101 MHz,
1
1.11 (s, 3 H, CH3), 1.10 (m, 1 H), 0.94 (d, J = 6.1 Hz, 3 H, CH3), 0.88 16.8 ppm. H NMR (400 MHz, [D]chloroform), δ (ppm; diastereomer
(s, 3 H, CH3) ppm. 13C NMR (75 MHz, [D]chloroform): δ = 216.7 (C-
4), 182.2 (C-17, C-21), 161.8 (C-18), 153.8 (C-21), 116.7 (C-16), 102.3
(C-19), 57.0 (OMe), 49.5 (C-8), 49.4 (C-10), 43.6 (C-5), 37.6 (CH2), 37.4
B): 6.71 (br. m, 2 H), 5.28 (s, 1 H), 2.76 (d, J = 13.5 Hz, 1 H), 2.62 (m,
1 H), 2.13 (d, J = 13.5 Hz, 1 H), 2.26 (m, 1 H), 2.19–2.00 (m, 3 H),
1.78 (m, 1 H), 1.63–1.44 (m, 3 H), 1.44–1.30 (m, 2 H), 1.19 (m, 1 H),
(C-9), 32.5 (CH2), 32.3 (CH2), 27.1 (CH2), 26.1 (CH2), 22.2 (CH2), 19.0 1.15 (s, 3 H), 0.97 (d, J = 5.0 Hz, 3 H), 0.90 (s, 3 H). 13C NMR (101 MHz,
(CH3), 17.9 (2 × CH3) ppm. HRMS (ESI): m/z calcd. for C21H28O5Na+ [D]chloroform): δ = 218.0, 169.84, 169.80, 140.4, 127.6 78.9, 49.8,
[M + Na]+ 383.1829; found 383.1842. [α]D20 = –125 (c = 0.024, CHCl3). 49.2, 44.1, 38.2, 37.3, 32.8, 32.35, 26.6, 25.5, 21.3, 18.9, 17.7, 16.3.
HRMS (ESI): m/z calcd. for C19H26O6Na+ [M + Na]+ 373.1627; found
2-Hydroxy-5-methoxy-4,5-epoxy-3-[(5S,9R,10R)-4-oxo-13-nor-
14(4→5),15(10→9)-bisabeodriman-11-yl]quinone (9): IR (neat):
373.1616. [α]2D0 = +10 (c = 0.100, CHCl3).
νmax = 2934, 2886, 1778, 1712, 1661, 1643, 1609 cm–1
.
1H NMR 2-Hydroxy-3-[(5S,9R,10R)-4-oxo-13-nor-14(4→5),15(10→9)-bis-
abeo-driman-11-yl]-2-butenolide-4-carboxylic Acid (7): IR (neat):
νmax = 3300, 2931, 1782, 168 cm–1 1H NMR (400 MHz, [D]chloro-
˜
(300 MHz, [D]chloroform): δ = 7.68 (s, 1 H, OH), 5.90 (s, 1 H, 19-H),
3.87 (s, 3 H, OMe), 2.74–2.43 (m, 5 H), 1.98–1.80 (m, 2 H), 1.62–1.58
(m, 2 H), 1.48 (s, 3 H, CH3), 1.34–1.13 (m, 3 H), 0.99 (d, J = 6.1 Hz, 3
H, CH3), 0.77 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, [D]chloroform):
.
˜
form, diastereomer A): δ = 3.83 (s, 3 H), 2.57 (td, J = 14.0, 7.3 Hz, 1
H), 2.37 (d, J = 16.0 Hz, 1 H), 2.34 (d, J = 16.0 Hz, 1 H), 2.18 (dd, J =
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14.0, 4.7 Hz, 1 H), 2.03–1.90 (m, 2 H), 1.70–1.42 (m, 3 H), 1.40–1.22
(m, 4 H), 1.13 (s, 3 H), 0.86 (s, 3 H), 0.85 (m, 3 H) ppm. 13C NMR
(101 MHz, [D]chloroform): δ = 216.8, 168.8, 167.4, 143.0, 125.8,
100.9, 54.5, 49.0, 49.0, 42.7, 37.9, 37.4, 34.3, 32.4, 26.7, 25.5, 21.3,
18.7, 17.6, 16.6 ppm. 1H NMR (400 MHz, [D]chloroform, diastereo-
mer B): 3.83 (s, 3 H), 2.57 (td, J = 14.0, 7.3 Hz, 1 H), 2.37 (d, J =
16.0 Hz, 1 H), 2.34 (d, J = 16.0 Hz, 1 H), 2.18 (dd, J = 14.0, 4.7 Hz, 1
H), 2.03–1.90 (m, 2 H),1.70–1.38 (m, 5 H), 1.38–1.27 (m, 2 H), 1.13 (s,
3 H), 0.86 (s, 3 H), 0.85 (m, 3 H). 13C NMR (101 MHz, [D]chloroform):
δ = 216.9, 168.8, 167.4, 143.3, 125.7, 100.9, 54.5, 49.2, 49.0, 42.7,
37.3, 37.1, 34.5, 32.2, 26.7, 25.3, 21.3, 18.7, 17.7, 16.9. HRMS (ESI):
m/z calcd. for C20H28O7Na+ [M + Na]+ 403.1733; found 403.1735.
[α]2D0 = –29 (c = 0.070, CHCl3).
49.02 (C-5), 42.6 (C-15), 41.4 (C-9), 37.45 (C-3), 37.43 (C-8), 32.7 (C-
6), 26.5 (C-7), 25.6 (C-2), 21.3 (C-1), 19.0 (C-12), 17.5 (C-14), 16.2 (C-
13) ppm. HRMS (ESI): m/z calcd. for C15H24O3Na+ [M + Na]+
275.1623; found 275.1628. [α]2D0 = –125 (c = 0.024, MeOH).
Rearrangement of 1 to Afford 11 and 31–32: To a solution of
ilimaquinone (1; 515 mg, 1.44 mmol) in concentrated sulfuric acid
(13.0 mL) cooled to –10 °C is added sodium azide (105.5 mg,
1.62 mmol). After 2 h of stirring at 10 °C, the reaction mixture is
quenched with ice and extracted with dichloromethane (2 × 10 mL).
The combined organic extracts are dried with Na2SO4, filtered and
concentrated under reduced pressure. Purification by preparative
HPLC (Xbridge® preparative C18 columns 150 × 46 mm; i.d. 5 μm,
Waters) 65 % to 100 % MeCN in H2O (0.1 % HCOOH) over 20 min
at 42 mL/min affords 11 as a red oil (RT = 7.70 min, 62 mg, 13 %),
31 as a green oil (RT = 9.90 min, 65 mg, 13 %) and 32 as a brown
oil (RT = 11.50 min, 10 mg, 2 %).
2-Hydroxy-3-[(5S,9R,10R)-14(4→5),15(10→9)-bisabeodrim-
4(13)-en-11-yl]-2-butenolide-4-carboxylic Acid (26): IR (neat):
νmax = 3390, 2924, 2860, 1781, 1739, 1663 cm–1. 1H NMR (400 MHz,
˜
[D]chloroform, diastereomer A): δ = 5.89 (s br., H), 5.14 (s br., 1 H),
4.49 (s, 1 H), 4.47 (s, 1 H), 3.85 (s, 3 H), 2.47 (d, J = 15.3 Hz, 1 H),
2.34 (d, J = 15.3 Hz, 1 H), 2.34–2.25 (m, 1 H), 2.14–2.05 (m, 1 H),
1.85–1.75 (m, 3 H), 1.60–1.30 (m, 5 H), 1.19 (m, 1 H), 1.03 (s, 3 H),
1.02 (m, 1 H), 0.87 (s, 3 H), 0.80 (s, 3 H) ppm. 13C NMR (101 MHz,
[D]chloroform): δ = 169.0, 167.3, 160.2, 142.5, 126.2, 102.6, 100.9,
54.5, 49.6, 42.5, 40.3, 38.6, 36.7, 34.6, 32.9, 28.2, 27.6, 22.5, 20.4, 17.3,
16.7 ppm. 1H NMR (400 MHz, [D]chloroform, diastereomer B): δ =
5.89 (s br., H), 5.14 (s br., 1 H), 4.49 (s, 1 H), 4.47 (s, 1 H), 3.85 (s, 3
H), 2.47 (d, J = 15.3 Hz, 1 H), 2.34 (d, J = 15.3 Hz, 1 H), 2.34–2.25
(m, 1 H), 2.14–2.05 (m, 1 H), 1.85–1.75 (m, 3 H), 1.60–1.30 (m, 5
H),1.19 (m, 1 H),1.19 (m, 1 H), 1.03 (s, 3 H), 1.02 (m, 1 H), 0.87 (s, 3
H), 0.80 (s, 3 H) ppm. 13C NMR (101 MHz, [D]chloroform): δ = 169.0,
167.3, 160.1, 142.4, 125.8, 102.7, 100.9, 54.6, 49.5, 42.5, 40.3, 37.7,
36.4, 34.3, 32.7, 28.2, 27.7, 22.4, 20.4, 17.4, 17.0 ppm. HRMS (ESI):
m/z calcd. for C21H30O6Na+ [M + H]+ 401.1940; found 401.1918.
[α]2D0 = –36 (c = 0.055, CHCl3).
Smenospongamine (11): IR (neat): νmax = 3471, 2958, 2250, 1666,
˜
1
1596, 1555 cm–1. H NMR (300 MHz, [D]chloroform): δ = 6.16–5.77
(br. s, 2 H, NH2), 5.60 (s, 1 H, 19-H), 2.56 (d, J = 18.6 Hz, 1 H, 15-H),
1.99 (d, J = 18.7 Hz, 1 H, 15-H), 1.84–1.79 (m, 2 H), 1.68–1.45 (m, 5
H), 1.40–1.24 (m, 3 H), 1.02 (s, 3 H, 11-H), 0.97 (2s, 6 H, 14-H 12-H),
0.78 (d, J = 6.3 Hz, 3 H, 13-H) ppm. 13C NMR (75 MHz, [D]chloro-
form): δ = 181.5 (C-20), 177.0 (C-17), 154.3 (C-21), 153.9 (C-18), 113.3
(C-16), 97.5 (C-19), 88.6 (C-10), 45.8 (C-5), 41.0 (C-3), 37.6 (C-9), 33.3
(C-4), 32.4 (C-12), 32.3 (C-8), 30.2 (C-7), 29.1 (C-1), 26.8 (C-15), 22.6
(C-11), 22.1 (C-6), 17.8 (C-2), 17.2 (C-14), 16.4 (C-13) ppm. HRMS (ESI):
m/z calcd. for C21H29O3NNa+ [M + Na]+ 366.2040; found 366.2039.
[α]2D0 = –312 (c = 0.032, CHCl3).
2,10′-Epoxy-5-hydroxy-3-[(5R,9R,10S)-15(10→9)-abeodriman-
11-yl]quinone (31): IR (neat): νmax = 2960, 2360, 2255, 1665,
˜
1
1640 cm–1. H NMR (300 MHz, [D]chloroform): δ = 7.41–7.35 (br. s,
1 H, OH), 5.89 (s, 1 H, 19-H), 2.55 (d, J = 18.6 Hz, 1 H, 15-H), 2.02 (d,
J = 18.6 Hz, 1 H, 15-H), 1.72–1.53 (m, 5 H), 1.50–1.27 (m, 5 H), 1.16
(s, 3 H, 11-H), 0.97 (s, 3 H, 14-H), 0.93 (s, 3 H, 12-H), 0.78 (d, J =
6.2 Hz, 3 H, 13-H) ppm. 13C NMR (75 MHz, [D]chloroform): δ = 182.4
(C-20), 181.7 (C-17), 155.4 (C-21), 154.9 (C-18), 113.0 (C-16), 105.0
(C-19), 87.6 (C-10), 45.9 (C-5), 41.8 (C-3), 37.4 (C-9), 33.7 (C-4), 32.7
(C-12), 32.6 (C-8), 30.4 (C-7), 29.9 (C-1), 26.5 (C-15), 22.3 (C-11), 22.1
(C-6), 18.0 (C-2), 17.1 (C-14), 16.6 (C-13) ppm. HRMS (ESI): m/z calcd.
for C21H28O4Na+ [M + Na]+ 367.1880; found 367.1901. [α]2D0 = –220
(c = 0.050, CHCl3).
Ozonolysis of 4 Affording 14 and 29: A solution of 4 (35 mg,
0.10 mmol) in a 1:1 mixture of dichloromethane and methanol
(20 mL) cooled to –78 °C is subjected to an ozone stream (0.3 mL/
min) for 20 seconds. The reaction mixture is quenched by the addi-
tion dimethyl sulfate (1.0 mL, 13.5 mmol). After 16 h of stirring at
room temp. the reaction mixture is concentrated under reduced
pressure. Purification by flash chromatography with silica gel (elu-
ent: dichloromethane/methanol: 98:2) affords 14 as an off white
solid (8 mg; 31 %) and then 29 as an off white solid (10 mg; 38 %).
2,10′-Epoxy-5-methoxy-3-[(5R,9R,10S)-15(10→9)-abeodriman-
Smenospongic Acid (14): IR (neat): νmax = 2921, 2859, 1730,
˜
1448 cm–1. 1H NMR (400 MHz, [D]chloroform): δ = 4.50 (s, 2 H), 2.40
(d, J = 13.5 Hz, 1 H, 15-H), 2.29 (m, 1 H, 3-H), 2.28 (d, J = 13.5 Hz, 1
H, 15-H), 2.10 (m, 1 H, 3-H), 1.92–1.70 (m, 3 H), 1.61–1.53 (m, 2 H,
6-H), 1.52–1.40 (m, 3 H), 1.31 (m, 2 H, 1-H), 1.04 (s, 3 H), 0.91 (d, J =
6.8 Hz, 3 H), 0.80 (s, 3 H) ppm. 13C NMR (101 MHz, [D]chloroform):
δ = 176.5 (C=O), 156.0 (C-11), 102.8 (C-4), 49.9 (C-10), 42.7 (C-15),
41.4 (C-9), 40.2 (C-5), 37.8 (C-8), 36.9 (C-6), 33.0 (C-3), 28.2 (C-2), 27.4
(C-7), 22.5 (C-1), 20.7 (C-12), 17.2 (C-14), 16.4 (C-13) ppm. HRMS (ESI):
m/z calcd. for C16H26O2Na+ [M + H]+ 272.1830; found 272.1989. [α]
˜
11-yl]quinone (32): IR (neat): ν
= 2959, 2939, 2362, 2251, 1659,
max
1639, 1599, 1458 cm–1. H NMR (300 MHz, [D]chloroform): δ = 5.74
(s, 1 H, 19-H), 3.81 (s, 3 H, OMe), 2.57 (d, J = 18.6 Hz, 1 H, 15-H),
2.00 (d, J = 18.7 Hz, 1 H, 15-H), 1.72–1.68 (m, 1 H), 1.49–1.31 (m, 9
H), 1.17 (s, 3 H, 11-H), 0.96 (s, 3 H, 14-H), 0.93 (s, 3 H, 12-H), 0.77 (d,
J = 6.4 Hz, 3 H, 13-H) ppm. 13C NMR (75 MHz, [D]chloroform): δ =
181.7 (C-20), 181.5 (C-17), 159.7 (C-21), 152.9 (C-18), 115.3 (C-16),
105.1 (C-19), 86.6 (C-10), 56.6 (OMe), 45.9 (C-5), 41.9 (C-3), 37.4 (C-
9), 33.7 (C-4), 32.6 (C-12 C-8), 30.5 (C-7), 29.6 (C-1), 26.9 (C-15), 22.4
(C-11), 22.1 (C-6), 18.0 (C-2), 17.1 (C-14), 16.5 (C-13) ppm. HRMS (ESI):
1
20
= –36 (c = 0.028, MeOH).
D
+
m/z calcd. for C22H30O4Na [M + Na]+ 381.2036; found 381.2048;.
(5S,9R,10R)-4-Oxo-13-nor-14(4→5),15(10→9)-bisabeodriman-
[α]2D0 = –42 (c = 0.048, CHCl3).
11-carboxylic Acid (29): IR (neat): νmax = 3338, 2927, 2863,
˜
1702 cm–1. 1H NMR (400 MHz, [D]chloroform): δ = 2.55 (td, J = 14.0,
Rearrangements of 1 Affording 30 and 33: To a solution of ilima-
6.9 Hz, 1 H, 3-H), 2.43 (d, J = 13.7 Hz, 1 H, 15-H), 2.35 (d, J = 13.7 Hz, quinone (1; 1.90 g, 5.30 mmol) in benzene (200 mL) cooled to 0 °C
1 H, 15-H), 2.21 (ddt, J = 14.0, 4.3, 1.7 Hz, 1 H, 3-H), 2.05 (m, 1 H, 2-
H), 1.92 (dd, J = 13.0, 3.2 Hz, 1 H, 1-H), 1.74–1.64 (m, 2 H), 1.63–1.54
(m, 4 H), 1.50 (m, 1 H, 7-H), 1.37 (m, 1 H, 7-H), 1.13 (s, 3 H, H12),
0.91 (d, J = 6.7 Hz, 3 H, 13-H), 0.87 (s, 3 H, 14-H) ppm. 13C NMR
(101 MHz, [D]chloroform): δ = 215.7 (C-4), 176.0 (C=O), 49.08 (C-10),
is added Et2O·BF3 (3.20 mL, 25.94 mmol). After 10 min of stirring at
0 °C, the reaction mixture is quenched with water (150 mL) and
extracted with dichloromethane (2 × 150 mL). The combined or-
ganic extracts are dried with Na2SO4, filtered and concentrated un-
der reduced pressure. Purification by flash chromatography with
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silica gel (eluent: dichloromethane/methanol: 1:0 → 98:2) affords organic extracts are dried with Na2SO4, filtered and concentrated
neo-mamanutaquinone (30) as a yellow-brown solid (1.10 g; 58 %)
and then 33 as orange crystals after further crystallisation from hex-
ane (400 mg; 21 %).
under reduced pressure. Purification by flash chromatography with
silica gel (eluent: dichloromethane) affords smenoqualone 34 as a
yellow oil (15 mg; 30 %) and then 35 a yellow oil (20 mg; 40 %).
Neo-Mamanuthaquinone (30): IR (neat): νmax = 2925, 1632 cm–1
.
2,10′-epoxy-5-methoxy-3-[(5S,9R,10R)-15(10→9)-abeodriman-
˜
1H NMR (300 MHz, [D]chloroform): δ = 7.36 (s, 1 H, OH), 5.84 (s, 1
H, 19-H), 3.85 (s, 3 H, OCH3), 2.70 (d, J = 13.2 Hz, 1 H, 15-H), 2.56
11-yl]quinone (35): IR (neat): νmax = 3050–2850, 1653, 1621, 1592,
˜
1384, 1353 cm–1
.
1H NMR (300 MHz, [D]chloroform): δ = 5.63 (s, 1
(d, J = 13.2 Hz, 1 H, 15-H), 2.20–2.03 (m, 2 H), 2.03–1.79 (m, 3 H), H, 19-H), 3.83 (s, 3 H, OMe), 2.55 (d, J = 18.5 Hz, 1 H, 15-H), 1.97 (d,
1.63–1.53 (m, 3 H), 1.45–1.27 (m, 3 H), 0.99 (s, 3 H, 11-H), 0.95 (s, 3 J = 18.5 Hz, 1 H, 15-H), 1.82–1.67 (m, 2 H), 1.64–1.33 (m, 8 H), 1.33–
H, 12-H), 0.83 (s, 3 H, 14-H), 0.77 (d, J = 6.8 Hz, 3 H, 13-H) ppm. 13C 1.15 (m, 2 H), 1.04 (s, 3 H, 11-H), 0.94 (s, 3 H, 13-H), 0.93 (s, 3 H, 12-
NMR (75 MHz, [D]chloroform): δ = 182.6 (C-20), 182.2 (C-17), 161.4
(C-18), 152.9 (C-21), 135.0 (C-5), 131.4 (C-10), 118.0 (C-16), 102.1 (C-
H), 0.76 (d, J = 6.3 Hz, 3 H, 14-H) ppm. 13C NMR (75 MHz, [D]chloro-
form): δ = 179.9 (C-20), 178.3 (C-17), 164.6 (C-18), 156.3 (C-21), 112.6
19), 56.8 (OMe), 42.8 (C-9), 39.9 (C-3), 34.6 (C-8), 34.3 (C-4), 32.2 (C- (C-16), 101.5 (C-19), 87.8 (C-10), 56.8 (OMe), 45.7 (C-5), 41.6 (C-3),
15), 28.9 (C-12), 28.0 (C-11), 26.5 (C-7), 25.9 (C-1), 22.0 (C-14), 20.8 37.2 (C-9), 33.4 (C-4), 32.5 (C-8, C-12), 30.3 (C-7), 29.7 (C-1), 26.7 (C-
(C-6), 20.0 (C-2), 15.4 (C-13) ppm. HRMS (ESI): m/z calcd. for 15), 22.1 (C-6), 21.8 (C-11), 18.0 (C-3), 17.0 (C-14), 16.4 (C-13) ppm.
C
22H31O4Na+ [M + Na]+ 381.2036; found 381.2039. [α]D20 = +22 (c = HRMS (ESI): m/z calcd. for C22H31O4H+ [M + H]+ 359.2217; found
0.047, CHCl3).
359.2214. [α]2D0 = –39 (c = 0.051, CHCl3).
4,10′-Epoxy-5-methoxy-3-[(5S,9R,10S)-15(10→9)-abeodriman-
4-Hydroxy-5-[(5S,9R,10R)-14(4→5),15(10→9)-bisabeodrim-
4(13)-en-11-yl]cyclopent-4-en-1,3-dione (8): To a solution of 15
11-yl]-ortho-quinone (33): IR (neat): ν
= 2984, 2935, 2871,
˜
max
16666, 1652, 1625, 1599, 1400, 1376 cm–1 1H NMR (300 MHz, (20 mg, 0.058 mol) in dichloromethane (1.0 mL) cooled to 0 °C is
.
[D]chloroform): δ = 5.63 (s, 1 H, 19-H), 3.85 (s, 3 H, OMe), 2.83 (d, added PIDA (18.7 mg, 0.058). After 30 min of stirring the reaction
J = 18.2 Hz, 1 H, 15-H), 2.08–1.90 (m, 3 H), 1.84 (m, 2 H), 1.79–1.82 mixture is concentrated under reduced pressure. Acetonitrile
(m, 2 H), 1.62–1.31 (m, 5 H), 1.18 (m, 1 H), 1.08 (d, J = 7.5 Hz, 3 H, (1.0 mL) is added and mixture is heated to reflux for 3 h. After
13-H), 1.03 (s, 3 H), 0.87 (s, 3 H, 14-H), 0.85 (s, 3 H) ppm. 13C NMR
cooling, the reaction mixture is concentrated to dryness. Purifica-
(75 MHz, [D]chloroform): δ = 180.1 (C-21), 178.4 (C-20), 164.4 (C-18), tion by flash chromatography with silica gel (eluent: dichloro-
155.2 (C-17), 112.6 (C-16), 101.6 (C-19), 89.4 (C-10), 56.8 (OMe), 45.4 methane/methanol, 95:5 then 9:1) affords 8 as a red oil (6.7 mg,
(C-5), 39.1 (C-8), 37.9 (C-9), 33.8 (C-4), 33.5 (C-3), 32.0 (C-14), 30.7 (C- 37 %). IR (neat): νmax = 2923, 2855, 1745, 1685, 1635, 1448 cm–1. 1H
˜
15), 29.1, 29.1, 27.7 (C-7), 22.6, 20.1 (C-13), 18.3, 17.2 (C-13) ppm. NMR (300 MHz, [D]chloroform): δ = 4.46 (s, 1 H, 11′-H), 4.43 (s, 1 H,
HRMS (ESI): m/z calcd. for C22H31O4H+ [M + H]+ 359.2217; found
359.2214. [α]2D0 = +132 (c = 0.062, CHCl3).
11′-H), 2.93 (s, 2 H, 2-H), 2.53 (d, J = 13.2 Hz, 1 H, 15′-H), 2.41 (d, J =
13.2 Hz, 1 H, 15′-H), 2.30 (m, 1 H), 2.12–2.04 (m, 2 H), 1.90–1.86 (m,
2 H), 1.55–1.51 (m, 2 H), 1.48–1.46 (m, 1 H), 1,43–1.39 (m, 2 H), 1.04
(s, 3 H, CH3), 1.01 (d, J = 6.3 Hz, 3 H, CH3), 0.88 (s, 3 H, CH3) ppm.
13C NMR (75 MHz, [D]chloroform): δ = 196.6 (C=O), 196.5 (C=O),
166.0 (C-4), 160.5 (C-4′), 134.6 (C-5), 102.9 (C-11′), 50.6 (C-10′), 44.1
(C-9′), 40.6 (C-5′), 40.3 (C-2), 38.9 (C-8), 37.0 (C-6′), 33.1 (C-3′), 31.7
(C-15′), 28.7 (C-7′), 27.9 (C-1′), 23.0 (C-12′), 20.8 (C-12′), 17.7 (C-13′),
Smenoqualone (34): To a solution of 33 (50 mg, 0.14 mmol) in
ethanol (5 mL) is added a solution of NaOH (2
mixture is heated to reflux for 1 h. After cooling the reaction mix-
ture is quenched with a HCl solution (1 , 12 mL) and extracted
M, 3 mL). The reaction
M
with ethyl acetate (2 × 15 mL). The combined extracts are dried
with Na2SO4, filtered and concentrated under reduced pressure.
Crude product is dissolved in acetone (5.0 mL) and potassium carb-
onate (200 mg, 1.45 mmol) and dimethylsulfate (100 μL, 1.06 mmol)
are added. After 16 h of stirring reaction mixture is concentrated to
dryness and then partitioned between dichloromethane (2 ×
15 mL) and water (10 mL). The combined extracts are dried with
17.5 (C-14′) ppm. HRMS (ESI): m/z calcd. for C20H29O3 [M + H]+
+
317.2111; found 317.2113. [α]2D0 = –15 (c = 0.068, CHCl3).
2,5-Hydroxy-3-[(5S,9R,10R)-4-oxo-13-nor-14(4→5),15(10→9)-
bis-abeodriman-11-yl]quinone (36): To a solution of 25 (52 mg,
0.144 mmol) in ethanol (5.1 mL) is added a solution of NaOH (2 M,
Na2SO4, filtered and concentrated under reduced pressure. Purifica- 3.1 mL). The reaction mixture is heated to reflux for 1 h. After cool-
tion by flash chromatography with silica gel (eluent: dichloro- ing, the reaction mixture is quenched with a HCl solution (1
methane/methanol, 99:1) affords 34 as a yellow oil (40 mg, 80 %). 10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined
IR (neat): νmax = 2962, 2935, 2872, 1665, 1644, 1601, 1219 cm–1. H extracts are dried with Na2SO4, filtered and concentrated under re-
M,
1
˜
NMR (300 MHz, [D]chloroform): δ = 5.71 (s, 1 H, 19-H), 3.81 (s, 3 H,
duced pressure to afford the title compound as a red solid (47 mg,
OMe), 2.85 (d, J = 18.7 Hz, 1 H, 15-H), 2.16 (m, 1 H), 1.94 (d, J = 94 %). IR (neat): νmax = 2996, 2926, 2861, 1702, 1689, 1649,
˜
1
18.7 Hz, 1 H, 15-H), 1.85 (d, J = 3.8 Hz, 1 H), 1.82–1.68 (m, 3 H),
1.60–1.43 (m, 2 H), 1.43–1.31 (m, 2 H), 1.30–1.18 (m, 2 H), 1.09 (d,
J = 7.5 Hz, 3 H, 14-H), 1.00 (s, 3 H, 12-H), 0.85 (s, 3 H, 13-H), 0.83 (s,
3 H, 12-H) ppm. 13C NMR (75 MHz, [D]chloroform): δ = 181.6 (C-17,
C-20), 159.6 (C-18), 151.2 (C-21), 115.4 (C-16), 104.8 (C-19), 87.9 (C-
1625 cm–1. H NMR (300 MHz, [D]chloroform): δ = 6.03 (s, 1 H, 19-
H), 2.61–2.45 (m, 3 H), 2.25–2.13 (m, 2 H), 2.09–2.00 (m, 1 H), 1.77–
1.64 (m, 2 H), 1.52–1.32 (m, 4 H), 1.14 (s, 3 H, CH3), 0.97 (d, J =
5.9 Hz, 3 H, CH3), 0.91 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, [D]chlo-
roform): δ = 216.8 (C-4), 114.3 (C-16), 102.5 (C-19), 49.6 (C-10), 49.4
10), 56.5 (OMe), 45.2 (C-5), 39.2 (C-8), 38.1 (C-9), 33.9 (C-4), 33.6 (C- (C-8), 43.6 (C-5), 37.6 (CH2), 37.5 (C-9), 32.6 (CH2), 32.5 (CH2), 27.2
3), 32.1 (C-12), 30.8 (C-15), 29.9 (C-11), 29.1 (C-1), 27.9 (C-7), 22.6 (C-
(CH2), 26.2 (CH2), 22.3 (CH2), 19.1 (CH3), 17.9 (2 × CH3) ppm. HRMS
6), 20.2 (C-14), 18.4 (C-2), 17.3 (C-13) ppm. HRMS (ESI): m/z calcd. (ESI): m/z calcd. for C20H25O5 [M + H]+ 345.1707; found 345.1706.
+
for C22H31O4H+ [M + H]+ 359.2217; found 359.2201. [α]2D0 = +144 [α]D20 = –63 (c = 0.032, CHCl3).
(c = 0.083, CHCl3).
4-Hydroxy-5-[(5S,9R,10R)-4-oxo-13-nor-14(4→5),15(10→9)-bis-
Rearrangements of 2 Affording 34 and 35: To a solution of 5-epi-
ilimaquinone (2; 50 mg, 0.14 mmol) in CH2Cl2 (1.5 mL) cooled to
–78 °C is added triflic acid (62 μL, 0.71 mmol). After 4 h of stirring
at –50 °C, the reaction mixture is quenched with water (100 mL)
and extracted with dichloromethane (2 × 10 mL). The combined
abeo-drim-11-yl]cyclopent-4-en-1,3-dione (12): To a solution of
36 (20.0 mg, 0.058 mmol) in dichloromethane (1.3 mL) cooled to
0 °C is added PIDA (25.5 mg, 0.058 mmol). After 30 min of stirring
the reaction mixture is concentrated under reduced pressure.
Acetonitrile (1.3 mL) is added and mixture is heated to reflux for
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3 h. After cooling, the reaction mixture is concentrated to dryness. bioassays by Becton Dickinson Co. (Le Pont de Claix, France). The
Purification by flash chromatography with silica gel (eluent: di-
strains used for this bioassay are V. harveyi BB120 wild type (ATCC
chloromethane/methanol, 0:1 → 95:5 → 9:1) to afford 12 as a yel-
BAA-1116) and its derived double mutants (JAF 375, JMH 597 and
low oil (3.7 mg, 20 %). IR (neat): νmax = 2960, 2918, 2854, 1746, JMH 612) obtained from Bassler's laboratory.[47] BB120 strain was
˜
1
1690, 1649, 1451 cm–1. H NMR (300 MHz, [D]chloroform): δ = 2.93
shown to exhibit strong virulence in brine shrimp Artemia francis-
(s, 2 H, 2-H), 2.64–2.43 (m, 3 H), 2.28–2.03 (m, 3 H), 1.79–1.66 (m, 2 cana whereas the use of HAI-1, AI-2 and CAI-1-deficient mutants
H), 1.57–1.50 (m, 1 H), 1.46–1.33 (m, 3 H), 1.14 (s, 3 H), 1.01 (d, J =
abolished virulence of V. harveyi to brine shrimp.[48] Twenty four
6.0 Hz, 3 H), 0.95 (s, 3 H) ppm. 13C NMR (75 MHz, [D]chloroform): hour old bacteria colonies were suspended in Lennox broth (5 mL,
δ = 216.5 (C-4′), [196.7, 196.1 (C-1/C-3)], 160.1 (C-4), 133.7 (C-5′), InvitrogenTM 12780–052) prepared in artificial sea water 3.5 % w/v
49.9 (C-10′), 49.5 (C-9′), 44.1 (C-5′), 40.3 (C-2), 38.2 (C-8′), 37.6 (CH2),
and incubated for 16 h whilst stirring at 27 °C. The optical absorb-
ance (OD) of each bacterial culture at wavelength λ = 600 nm was
32.7 (CH2), 31.6 (CH2), 27.0 (CH2), 26.1 (CH2), 21.9 (CH2), 19.1 (CH3),
18.0 (CH3), 17.3 (CH3) ppm. HRMS (ESI): m/z calcd. for C19H26O4Na+ adjusted at 0.012 (approx. 107 bacteria mL–1 after numeration on a
[M + Na]+ 341.1723; found 341.1736. [α]D20 = –29 (c = 0.034, CHCl3). Malassez cell) by dilution in Zobell media (0.5 % w/v BactoTM pep-
tone, 0.1 % w/v yeast extract in artificial sea water). The compounds
4,10′-Epoxy-5-[(5S,9R,10S)-15(10→9)-abeodriman-11-yl]cyclo-
were dissolved in ethanol and deposited in the 96 wells plates and
pent-4-en-1,3-dione (13): To a solution of 31 (32.5 mg,
dried. Bacterial suspension (200 μL, final concentration of com-
0.094 mmol) in dichloromethane (1.6 mL) cooled to 0 °C is added
pounds: 50 μg mL–1) was added in the wells and incubated at 27 °C
PIDA (30.4 mg, 0.094 mmol). After 30 min of stirring the reaction
in a BMG FLUOstarOPTIMA microplate reader (Labtech), in which
mixture is concentrated under reduced pressure. Acetonitrile
luminescence and absorbance at 600 nm wavelength were meas-
(1.6 mL) is added and mixture is heated to reflux for 3 h. After
ured every 10 min after 5 min of double orbital stirring during 11 h
cooling, the reaction mixture is concentrated to dryness. Purifica-
50 min (71 cycles). At the end of the incubation time, the absence
tion by flash chromatography with silica gel (eluent: dichloro-
of bacterial growth inhibition due to the tested compounds was
methane/methanol, 95:5 then 9:1) affords 13 as a yellow oil
verified by OD600 measurements and comparison with the control
(14.2 mg, 48 %). IR (neat): νmax = 2958, 2941, 2905, 2870, 1746, 1695,
˜
experiment performed without tested compound. A Spearman's
1633, 1460 cm–1
.
1H NMR (400 MHz, [D]chloroform): δ = 2.81 (s, 2
rank correlation test was used to determine the correlation between
OD600 measurements. Every compound was tested in quadruplicate,
for both luminescence production (relative luminescence units) and
antibiotic or bacteriostatic activity (OD600). An extract (CH2Cl2/
CH3OH, 1:1) of free dried Leucetta Chagosensis (50 μg mL–1) was
used as positive control. For each strain, luminescence and absorb-
ance values were obtained after subtracting the background signal
obtained with media and compounds sterility tests to the raw data.
H, 2-H), 2.47 (d, J = 18.8 Hz, 1 H, 15′-H), 1.97 (d, J = 18.8 Hz, 1 H,
15′-H), 1.60–1.50 (m, 3 H), 1.47–1.38 (m, 3 H), 1.36–1.10 (m, 4 H),
1.01 (s, 3 H, 11′-H), 0.93 (s, 3 H, 14-H), 0.86 (s, 3 H, 12′-H), 0.71 (d,
J = 6.2 Hz, 3 H, 13′-H) ppm. 13C NMR (101 MHz, [D]chloroform): δ =
195.7 (C=O), 193.7 (C=O), 166.3 (C-4), 132.8 (C-5), 89.9 (C-10′), 45.8
(C-5′), 42.3 (C-2), 41.6 (C-3′), 37.9 (C-9′), 33.7 (C-4′), 32.6 (C-8′/C-12′),
30.4 (C-7′), 29.5 (C-1′), 26.2 (C-15′), 22.4 (C-11′), 21.9 (C-6′), 17.8 (C-
2′), 17.5 (C-14′), 16.5 (C-3′) ppm. HRMS (ESI): m/z calcd. for
+
C
20H29O3 [M + H]+ 317.2111; found 317.2121. [α]2D0 = –31 (c = Contributions: L. E., E. P. and C. D. conceived the project. D. L., L. E.
0.064, CHCl3).
and A. L. performed the synthetic experimental work. A. B. per-
formed prospective experiments. D. L., A. B., B. S. M, L. E., M. A. B.
and A. L. extracted ilimaquinone and 5-epi-ilimaquinone. S. P. and
C. D. collected sponges. K. L. developed conditions for analytical
and preparative HPLC. M. A. B. and L. E. reported the discovery of
dactylocyanines series. G. G.-J. advised on chemoinformatic aspects.
L. E. performed chemoinformatic analysis. J.-C. J. recorded 400 MHz
NMR spectra. S. D. performed cytotoxicity evaluations. F. T., D. S.
and C. D. performed quorum sensing inhibition evaluations. L. E.
and E. P. wrote the manuscript with the help of D. L.
Cell Proliferation Assay: The in vitro cytotoxic activity of com-
pounds 1–19, 21, 23–29, 31–32 was evaluated by using the 3-[4,5-
dimethylthiazol-2-yl]-3,5-diphenyltetrazolium bromide (MTT) test.
Cells were seeded in growth medium (100 μL; HUVEC: 5 × 103
cells mL–1; Hep-G2: 5 × 103 cells mL–1; A549: 5 × 103 cells mL–1), in
96-well plates (TPP), and incubated for 24 h. Cells were then treated
with test compounds (DMSO 100 μL) at a series of concentrations
and incubated at 37 °C for 48 h. The initial cell densities and incuba-
tion times were determined to allow the cells to remain in exponen-
tial growth. At the end of the incubation period, MTT (Sigma–
Aldrich; 5 mg mL–1 solution in phosphate buffered saline; 20 μL)
was added to each well. After 1 to 4 h of incubation at 37 °C, the
culture medium was removed and replaced by DMSO (200 μL) to
dissolve the formazan crystals. After 5 min of stirring, the absorb-
ance of the solubilized dye was measured spectrophotometrically
with a microplate reader (LAB System Original Multiscan MS) at
570 nm. The percentage of viable cells for each treatment was cal-
culated from the ratio of the absorbance of the well containing the
treated cells versus the average absorbance of the control wells (i.e.,
untreated cells). All experiments were set up in triplicate to deter-
mine means and standard deviations. To circumscribe the IC50 val-
ues cells were treated with test compounds at a series of concentra-
Acknowledgments
Camille Dejean (Université Paris-Sud) is gratefully acknowl-
edged for assistance with NMR spectroscopy. This project was
supported by the ANR (11-EBIM-006-01 Netbiome project
POMARE). We gratefully acknowledge the French Polynesian au-
thorities and Délégation à la Recherche-France in Tahiti for their
help and support in the sponge survey in French Polynesia and
collection of samples. We thank IRD and GOPS for funding the
sampling trip aboard R/V ALIS, her crew, and IRD's diving team
for their on-field help. Prof. Bonnie L. Bassler is gratefully ac-
knowledged for Vibrio harveyi mutant strains she provided.
tions: 0.5, 1.0, 5.0, 10.0, 20.0, 30.0 and 50.0 μ
2.5, 7.5 and 12.5 μ
M and if necessary at
M.
Quorum sensing Inhibition Screenings: Artificial sea water was Keywords: Synthetic methods · Ilimaquinone ·
purchased by SIGMA, S9883 (St. Quentin Fallavier, France); Lennox
broth (InvitrogenTM, 12780–052) by Life technologies (Saint Aubin,
France); BactoTM Peptone and yeast extract for Zobell liquid media
Ring-distortion · Quinones · Molecular diversity ·
Quorum sensing
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[1]
[2]
[25] N. Bonneau, G. Chen, D. Lachkar, A. Boufridi, J.-F. Gallard, P. Retailleau, S.
Petek, C. Debitus, L. Evanno, M. A. Beniddir, E. Poupon, Chem. Eur. J.
2017, 23, 14454–14461.
a) G. M. Cragg, D. J. Newman, Biochim. Biophys. Acta BBA - Gen. Subj.
2013, 1830, 3670–3695; b) D. J. Newman, G. M. Cragg, J. Nat. Prod. 2016,
79, 629–661; c) K. Hübel, T. Leßmann, H. Waldmann, Chem. Soc. Rev.
2008, 37, 1361–1374; d) A. Reayi, P. Arya, Curr. Opin. Chem. Biol. 2005, 9,
240–247.
[26] H. Mitome, T. Nagasawa, H. Miyaoka, Y. Yamada, R. W. M. van Soest, J.
Nat. Prod. 2003, 66, 46–50.
[27] P. R. Story, J. R. Burgess, Tetrahedron Lett. 1968, 9, 1287–1292.
[28] E. Mvula, S. Naumov, C. von Sonntag, Environ. Sci. Technol. 2009, 43,
6275–6282.
[29] a) E. Bernatek, Acta Chem. Scand. 1954, 8, 1943–1943; b) E. Bernatek,
K. N. Straumsgård, Acta Chem. Scand. 1959, 13, 178–185; c) E. Bernatek,
K. Valen, Acta Chem. Scand. 1960, 14, 224–226.
[30] M. D. López, E. Quiñoá, R. Riguera, S. Omar, J. Nat. Prod. 1994, 57, 992–
996.
[31] T. Ling, E. Poupon, E. J. Rueden, E. A. Theodorakis, Org. Lett. 2002, 4,
819–822; T. Ling, E. Poupon, E. J. Rueden, S. H. Kim, E. A. Theodorakis, J.
Am. Chem. Soc. 2002, 124, 12261–12267.
a) A. A. Shelat, R. K. Guy, Nat. Chem. Biol. 2007, 3, 442–446; b) M. Garcia-
Castro, S. Zimmermann, M. G. Sankar, K. Kumar, Angew. Chem. Int. Ed.
2016, 55, 7586–7605; Angew. Chem. 2016, 128, 7712.
[3]
[4]
S. Sasidharan, Y. Chen, D. Saravanan, K. M. Sundram, L. Y. Latha, Afr. J.
Tradit. Complement. Altern. Med. 2011, 8, 1–10.
a) K. C. Nicolaou, S. A. Snyder, Proc. Natl. Acad. Sci. USA 2004, 101, 11929–
11936; b) E. A. Crane, K. Gademann, Angew. Chem. Int. Ed. 2016, 55,
3882–3902; Angew. Chem. 2016, 128, 3948.
[5]
[6]
[7]
D. R. Spring, Org. Biomol. Chem. 2003, 1, 3867–3870.
H. van Hattum, H. Waldmann, J. Am. Chem. Soc. 2014, 136, 11853–11859.
[32] H. W. Moore, H. R. Shelden, D. W. Deters, R. J. Wikholm, J. Am. Chem. Soc.
R. W. Huigens III, K. C. Morrison, R. W. Hicklin, T. A. Flood Jr., M. F. Richter,
P. J. Hergenrother, Nat. Chem. 2013, 5, 195–202.
1970, 92, 1675–1681.
[33] N. K. Utkina, V. A. Denisenko, O. V. Scholokova, A. E. Makarchenko, J. Nat.
Prod. 2003, 66, 1263–1265.
[34] S. Urban, R. J. Capon, Aust. J. Chem. 1994, 47, 1023–1029.
[35] T. Katoh, S. Atsumi, R. Saito, K. Narita, T. Katoh, Eur. J. Org. Chem. 2017,
3837–3849.
[36] M.-L. Bourguet-Kondracki, M.-T. Martin, M. Guyot, Tetrahedron Lett. 1992,
33, 8079–8080.
[8]
R. J. Rafferty, R. W. Hicklin, K. A. Maloof, P. J. Hergenrother, Angew. Chem.
Int. Ed. 2014, 53, 220–224; Angew. Chem. 2014, 126, 224.
[9]
A. Garcia, B. S. Drown, P. J. Hergenrother, Org. Lett. 2016, 18, 4852–4855.
[10]
N. G. Paciaroni, R. Ratnayake, J. H. Matthews, V. M. Norwood, A. C. Arnold,
L. H. Dang, H. Luesch, R. W. Huigens, Chem. Eur. J. 2017, 23, 4327–4335.
[11]
R. T. Luibrand, T. R. Erdman, J. J. Vollmer, P. J. Scheuer, J. Finer, J. Clardy,
Tetrahedron 1979, 35, 609–612.
[37] a) E. Malamidou-Xenikaki, S. Spyroudis, M. Tsanakopoulou, J. Org. Chem.
2003, 68, 5627–5631; b) N. A. Calandra, S. M. King, S. B. Herzon, J. Org.
Chem. 2013, 78, 10031–10057.
[12]
B. Carte, C. B. Rose, D. J. Faulkner, J. Org. Chem. 1985, 50, 2785–2787.
[13] For the 1/2 ratio distribution, see: a) A. Boufridi, D. Lachkar, D. Erpenbeck,
M. A. Beniddir, L. Evanno, S. Petek, C. Debitus, E. Poupon, Aust. J. Chem.
2017, 70, 743–750; For further reading about similar anomalies, see: b)
J. M. Finefield, D. H. Sherman, M. Kreitman, R. M. Williams, Angew. Chem.
Int. Ed. 2012, 51, 4802–4836; Angew. Chem. 2012, 124, 4886.
[14] C. Debitus, TUAM′2011 cruise, RV Alis, 2011, https://doi.org/10.17600/
11100010.
[15] M.-L. Kondracki, M. Guyot, Tetrahedron 1989, 45, 1995–2004.
[16] S. Loya, R. Tal, Y. Kashman, A. Hizi, Antimicrob. Agents Chemother. 1990,
34, 2009–2012.
[38] P. V. Kiem, L. T. Huyen, D. T. Hang, N. X. Nhiem, B. H. Tai, H. L. T. Anh, P. V.
Cuong, T. H. Quang, C. V. Minh, N. V. Dau, Y.-A. Kim, L. Subedi, S. Y. Kim,
S. H. Kim, Bioorg. Med. Chem. Lett. 2017, 27, 1525–1529.
[39] E. G. Bakalbassis, S. Spyroudis, C. A. Tsipis, Eur. J. Org. Chem. 2008, 1783–
1788.
[40] a) T. W. H. Backman, Y. Cao, T. Girke, Nucleic Acids Res. 2011, 39, W486–
W491; b) D. Bajusz, A. Rácz, K. Héberger, J. Cheminf. 2015, 7, 20.
[41] L. Owens, N. Busico-Salcedo in Biol. Vibrios (Eds.: F. L. Thompson, B. Aus-
tin, J. Swings), American Society of Microbiology, 2006, pp. 266–280.
[42] J. A. Shapiro, Annu. Rev. Microbiol. 1998, 52, 81–104.
[43] H. L. Swaminath Srinivas, X. H. Guoli Gong, J. Bacteriol. Parasitol. 2013,
04, https://doi.org/10.4172/2155–9597.1000172.
[17] D. M. Kushlan, D. J. Faulkner, L. Parkanyi, J. Clardy, Tetrahedron 1989, 45,
3307–3312.
[18] F. A. Barr, G. Warren, Semin. Cell Dev. Biol. 1996, 7, 505–510.
[19] K. W. L. Yong, A. Jankam, J. N. A. Hooper, A. Suksamrarn, M. J. Garson,
Tetrahedron 2008, 64, 6341–6348.
[20] A. Boufridi, S. Petek, L. Evanno, M. A. Beniddir, C. Debitus, D. Buisson, E.
Poupon, Tetrahedron Lett. 2016, 57, 4922–4925.
[21] T. Rosenau, K. Mereiter, C. Jäger, P. Schmid, P. Kosma, Tetrahedron 2004,
60, 5719–5723.
[22] H. W. Moore, R. J. Wikholm, Tetrahedron Lett. 1968, 9, 5049–5052.
[23] R. H. Thomson, J. Chem. Soc. Resumed 1951, 1237–1239.
[24] F. B. Tamboura, C. S. J. Cazin, R. Pattacini, P. Braunstein, Eur. J. Org. Chem.
2009, 3340–3350.
[44] K. H. Nealson, T. Platt, J. W. Hastings, J. Bacteriol. 1970, 104, 313–322.
[45] T. Mai, F. Tintillier, A. Lucasson, C. Moriou, E. Bonno, S. Petek, K. Magré,
A. Al Mourabit, D. Saulnier, C. Debitus, Lett. Appl. Microbiol. 2015, 61,
311–317.
[46] a) G. D. Geske, J. C. O'Neill, H. E. Blackwell, ACS Chem. Biol. 2007, 2, 315–
320; b) W. R. J. D. Galloway, J. T. Hodgkinson, S. Bowden, M. Welch, D. R.
Spring, Curr. Trends Microbiol. 2012, 20, 949–958; c) W. R. J. D. Galloway,
J. T. Hodgkinson, S. D. Bowden, M. Welch, D. R. Spring, Chem. Rev. 2011,
111, 28–67.
[47] J. M. Henke, B. L. Bassler, J. Bacteriol. 2004, 186, 6902–6914.
[48] T. Defoirdt, P. Sorgeloos, ISME J. 2012, 6, 2314–2319.
Received: January 11, 2018
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Marine Natural Products
A ring-distortion strategy is applied to
ilimaquinone and 5-epi-ilimaquinone.
A diverse compound library was syn-
thesised that included rearrangements
of the sesquiterpene moiety and the
quinone ring. Quorum sensing activity
of Vibrio harveyi was evaluated and
some of the new compounds were
shown to be good quorum sensing in-
hibitor candidates.
L. Evanno,* D. Lachkar, A. Lamali,
A. Boufridi, B. Séon-Méniel, F. Tintillier,
D. Saulnier, S. Denis, G. Genta-Jouve,
J.-C. Jullian, K. Leblanc, M. A. Beniddir,
S. Petek, C. Debitus,
E. Poupon* ........................................ 1–13
A Ring-Distortion Strategy from Ma-
rine Natural Product Ilimaquinone
Leads to Quorum Sensing Modula-
tors
DOI: 10.1002/ejoc.201800047
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