Synthesis of Cyclosiphonodictyol A and Its Bis(sulfato)

Article abstract of DOI:10.1021/acs.joc.9b03434

The first synthesis of the marine benzoxepane hydroquinone cyclosiphonodictyol A and its bis(sulfato) from commercial (+)-sclareolide is reported. The key steps of the synthetic sequence (11 steps, 46% global) are the nucleophilic attack of a hindered tertiary alkoxide, a ring-closing metathesis reaction, and the Diels-Alder cycloaddition of a dienol acetate.

Full text of DOI:10.1021/acs.joc.9b03434

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Article
Synthesis of Cyclosiphonodictyol A and its bis(Sulfato)
Juan A. Gil, Fabio Arias, Rachid Chahboun, and Enrique Alvarez-Manzaneda
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03434 • Publication Date (Web): 06 Feb 2020
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Synthesis of Cyclosiphonodictyol A and its
bis(Sulfato)
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Juan A. Gil, Fabio Arias, Rachid Chahboun* and Enrique Alvarez-Manzaneda*
Departamento de Química Orgánica, Facultad de Ciencias, Instituto de Biotecnología,
Universidad de Granada, 18071 Granada, Spain.
rachid@ugr.es ; eamr@ugr.es
ABSTRACT
The first synthesis of the marine benzoxepane hydroquinone cyclosiphonodictyol A and its
bis(sulfato) from commercial (+)-sclareolide is reported. The key steps of the synthetic sequence
(11 steps, 46% global) are the nucleophilic attack of a hindered tertiary alkoxide, a ring-closing
metathesis reaction and the Diels-Alder cycloaddition of a dienol acetate.
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INTRODUCTION
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Marine organisms are an important source of natural products which have aroused great
interest because of their structural variety and the wide range of biological activities that many of
them exhibit. One such organism is the tropical marine sponge Aka coralliphagum (or
Siphonodictyon coralliphagum), due to the considerable number of bioactive metabolites, usually
with a sesquiterpene hydroquinone structure,1 that have been isolated from it, such as liphagal2
and corallidictyals A-D.3
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Another important group of metabolites that have been isolated from this sponge are the
siphonodictyals, which have an aryl and an acyclic or bicyclic-sesquiterpene moiety and contain
aldehyde, carboxylic acid, imine or sulfate ester groups, among others. Siphonodictyal A (1) and
B (2) were the first compounds of this family to be isolated, by Faulkner et al. in 1981.4 The
same authors reported the isolation of siphonodictyal C (3) and E (7) a few years later.5
Subsequently, Köck et al. isolated siphonodictyals B1-B3 (4-6),6 and this was followed very
recently by siphonodictyals E1-E3 (8-10).7 Two structurally related metabolites are the
benzoxepane derivatives bis-(sulfato)cyclosiphonodictyol A (12), reported in 1995 by Wright et
al.,8 and the related hydroquinone cyclosiphonodictyol A (11), recently described (Figure 1).7
Some of the above metabolites exhibit significant biological activity. Compounds 1,4 24 and 3
inhibit the growth of Staphylococcus aureus and Bacillus subtilis, and the latter also inhibits the
marine bacterium Vibrio anguillarum5 and the CDK4/cyclin D1 complexation.9 Siphonodictyal
B1 (4) increases intracellular calcium to levels comparable to those of the Ca2+-ATPase (SRCA)
inhibitor thapsigargin,6b and siphonodictyal B3 (6) has a radical-scavenging activity that is
comparable with that of the known lipophylic antioxidant BHT.10
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Figure 1. Some representative siphonodictyals and related metabolites.
The development of synthetic processes for the above compounds is of interest, not only
because of the significant biological activity exhibited in some cases, but also because it allows
their structures to be established unequivocally. In this respect, siphonodictyal B (2) was first
isolated by Faulkner in 1981.4 The structure originally proposed for this compound was
subsequently revised by Faulkner and Clardy in 1986,5 and later revised again (in terms of its
configuration at C-8) to its correct structure 2, on the basis of George’s total synthesis.11
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Similarly, the structure of siphonodictyal C (3), described by Faulkner et al. as a desulfated
compound,5 was later revised as the correct structure 3.9 In this context, too, the structures
originally proposed for siphonodictyals B1-B3 (4-6) should probably be corrected to the
corresponding 8-epimers, in view of their spectroscopic similarities to compound 2.
The synthesis of siphonodictyals has been reported only recently, and for a limited number of
these compounds. For example, the preparation of a protected ( )-siphonodictyal C (3), by the
condensation of an aryllithium with ( )-drimenal, has been described; in this case, the aldehyde
group of target compounds was introduced in the final steps of the process.12 A similar strategy
has been utilized for the synthesis of (-)-siphonodictyal B (2), starting from a drimanal
synthesised from commercially available (+)-sclareolide.11,13 Very recently, a divergent synthesis
of compound 2 was reported, in which the meroterpene skeleton was obtained through a
palladium-catalysed direct cross-coupling reaction of a drimanal hydrazone, synthesised from
(+)-sclareolide, and an iodobenzaldehyde, and the subsequent iodine-promoted sunlight-induced
olefin Z/E isomerisation reaction.3c
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RESULTS AND DISCUSSION
The present study focuses on cyclosiphonodictyol A (11) and its bis-(sulfato) 12, which have not
previously been synthesised. These compounds contain an oxepanyl moiety frequently found in
nature, mainly in marine metabolites, such as cytotoxic aplysistatins and anti-inflammatory
palisadins.14 The retrosynthesis of natural benzoxepanes 11-12 is outlined in Scheme 1.
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Scheme 1. Retrosynthesis of benzoxepanes 11-12 from commercial (+)-sclareolide (17).
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The aromatic ring of phenol 13 is elaborated through the Diels-Alder cycloaddition of dienol
ester derived from methylketone 14, whose oxepane ring is formed via the ring-closing
metathesis of oxy-ketone 15, derived from alcohol 16, which is easily prepared from lactone 17.
To do this, the synthesis of ketone 15 was first attempted (Scheme 2). However, the treatment
of hydroxy alkene 16, resulting from the methylenation of lactol 18,15 with bromoketone 19 in
benzene, in the presence of n-BuLi and 18-crown-6 ether, did not provide the desired oxy-ketone
15. At room temperature the reaction did not take place; when the temperature was increased,
decomposition of the bromo derivative 19 was observed. In view of the low reactivity of tertiary
alcohol 16 and the lability of bromo ketone 19, the use of bromo ester 20, as an alkylating agent,
was then considered. This approach, under the above reaction conditions after refluxing for 12 h,
produced the desired oxy-ester 21 in good yield.
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Scheme 2. Synthesis of oxy ester 21 from commercial (+)-sclareolide (17).
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O
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OH
O
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DIBAL, CH2Cl2
Ph3P=CH2
H
H
H
OH
-78 ºC, 1 h
(94%)
THF, 0 ºC
1 h (89%)
H
H
H
17
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18
n-BuLi, 18-crown-6, 19
benzene, reflux
1) n-BuLi, 18-crown-6
20
2) reflux, 12 h (86%)
, benzene, 0 ºC, 30 min
R
Br
O
H
O
COOMe
H
O
19
20
R: COMe
R: COOMe
H
H
15
21
The construction of the oxepane ring was then investigated (Scheme 3). When the oxy ester 21
was treated with second-generation Grubbs catalyst,16 the desired oxepane ester 22 was obtained
in almost quantitative yield.
Scheme 3. Construction of the oxepane ring. Synthesis of ester 22.
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Next, the oxepane enone 14, a precursor of the target compounds, was synthesised from ester
22, via the corresponding Weinreb amide 23 (Scheme 4). After treating amide 23 with MeLi at -
78 ºC, ketone 14 resulted in a high yield.
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Scheme 4. Synthesis of enone 14 from ester 22.
Finally, the construction of the aromatic ring was undertaken (Scheme 5). To do so, enone 14
was treated with trans-1,2-bis(phenylsulfonyl)ethylene and isopropenyl acetate in the presence
of catalytic p-toluenesulphonic acid in a sealed tube for 5 h, which produced a mixture of
cycloadducts 24 in 90% yield.17 When these were treated with DBU in dichloromethane at room
temperature for 4 h, acetate 25 was resulted.18 This was converted into phenol 13 by heating a
solution in dioxane in the presence of concentrated hydrochloric acid. The further treatment of
compound 13 with Fremy’s salt gave 1,4-benzoquinone 26,19 which after reduction with sodium
hydrosulphite gave cyclosiphonodictyol A (11) in almost quantitative yield. This hydroquinone
is air sensitive, being slowly transformed into quinone. The NMR data obtained for the DMSO-
d6 solution of synthetic 11 were similar to that previously reported for the natural compound.7 In
fact, the 13C NMR data are identical. Compound 11 was finally converted into its bis(sulfato) 12,
after successive treatment with pyridine-sulphur trioxide and Na2CO3. The spectroscopic data of
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synthetic compound 12 were consistent with those reported for the natural product;8 however a
complete comparison was not feasible because of the low solubility of the synthetic bis(sulfato)
in CD3OD.
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Scheme 5. Synthesis of cyclosiphonodictyol A (11) and its bis(sulfato)(12).
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CONCLUSIONS
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In summary, the first synthesis of the marine metabolite cyclosiphonodictyol A (11) and its
bis-(sulfato) 12 from the commercially available lactone (+)-sclareolide (17) is reported. The
nucleophilic attack of a hindered tertiary alkoxide, a ring-closing metathesis reaction and the
Diels-Alder cycloaddition of a dienol acetate are the key steps of the synthetic sequence (11
steps, 46% global). This procedure can be utilized to achieve the synthesis of other
siphonodictyals, such as compound 1, that are not readily accessible.
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EXPERIMENTAL SECTION
General Procedures
Unless stated otherwise, reactions were performed in oven-dried glassware under an
argon atmosphere using dry solvents. Organic solvents were routinely dried and/or
distilled prior to use and stored over molecular sieves under argon. An oil bath was used
as the heating source for the reactions that require heating. Thin-layer chromatography
(TLC) was performed using F254 precoated plates (0.25 mm) and visualized by UV
fluorescence quenching and phosphomolybdic acid solution in ethanol staining. Flash
chromatography was performed on silica gel (230-400 mesh). Chromatography
separations were carried out by conventional column on silica gel 60 (230-400 Mesh),
using hexanes-AcOEt (AcOEt-hexane) or diethyl ether-hexanes (ether-hexane) mixtures
1 13
of increasing polarity. H and C NMR spectra were recorded at 500 and 400 MHz, and
at 125 and 100 MHz, respectively. Chemical shifts (δ H) are quoted in parts per million
(ppm) referenced to the appropriate residual solvent peak and tetramethylsilane. Data for
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1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling
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constant (Hz), integration), with the abbreviations s, br s, d, t, q and m denoting singlet,
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broad singlet, doublet, triplet, quartet and multiplet, respectively. J = coupling constant in
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Hertz (Hz). Data for C NMR spectra are reported in terms of chemical shift relative to
Me4Si (δ 0.0) and the signals were assigned utilizing DEPT experiments and on the basis
of heteronuclear correlations. Infrared spectra (IR) were recorded as thin films or as solids
on a FTIR spectrophotometer with samples between sodium chloride plates or as
potassium bromide pellets and are reported in frequency of absorption (cm–1). Only
selected absorbances (νmax) are reported. ([α]D) measurements were carried out in a
polarimeter; utilizing a 1dm length cell and CHCl3 as a solvent. Concentration is
expressed in mg/mL. HRMS were recorded on a spectrometer, utilizing a Q-TOF
analyzer, and ESI+ ionization.
Experimental Procedures
(1R,2R,4aS,8aS)-1-allyl-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol (16).
n-BuLi (2.5 M in n-hexane, 3.2 mL, 7.92 mmol) was added to a solution of MePPh3Br (2.89 g,
7.92 mmol) in dry THF (15 mL) at 0 ºC under Ar atmosphere and the mixture was stirred at this
temperature for 30 min. Then, a solution of 18 (1 g, 3.96 mmol) in dry THF (10 mL) was added
via cannula and the reaction was stirred for 1 h. At this time, TLC showed no starting material,
and H2O (10 mL) was added. The solvent was removed in vaccum and Et2O (50 mL) was added.
The organic layer was washed with H2O (2 x 20 mL) and brine (20 mL), dried over anhydrous
Na2SO4 and concentrate under vacuum. The crude was purified by flash chromatography (10%
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ether/hexane) to yield 882 mg of 16 (89%) as colourless syrup. [α]D25= -3.6 (c 5.5, CHCl3). H
NMR (400 MHz, CDCl3) δ: 5.96 (dddd, J = 16.6, 10.0, 7.9, 6.3 Hz, 1H), 5.05 (dd, J = 17.1, 1.7
Hz, 1H), 4.92 (dd, J = 10.1, 1.7 Hz, 1H), 2.29 – 2.15 (m, 2H), 1.84 (ddd, J = 12.5, 12.5, 3.2 Hz,
1H), 1.74 – 1.51 (m, 4H), 1.48 – 1.37 (m, 2H), 1.36 – 1.21 (m, 2H), 1.19 (s, 3H), 1.12 (dd, J =
13.5, 4.2 Hz, 1H), 0.94 (dd, J = 12.2, 2.5 Hz, 2H), 0.87 (s, 3H), 0.81 (s, 3H), 0.79 (s, 3H).13C
{1H} NMR (100 MHz, CDCl3) δ: 142.5 (CH), 114.3 (CH2), 74.5 (C), 61.4 (CH), 56.2 (CH), 44.1
(CH2), 42.0 (CH2), 40.2 (CH2), 39.0 (C), 33.6 (CH3), 33.4 (C), 30.0 (CH2), 24.5 (CH3), 21.7
(CH3), 20.4 (CH2), 18.7 (CH2), 15.5 (CH3). IR (film): 3409, 2923, 2867, 1636, 1462, 1387, 1083,
1000, 939, 906 cm-1. HRMS (ESI/TOF) m/z: [M+Na]+ calcd for C17H30ONa 273.2194, found
273.2187.
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Methyl
2-((((1R,2R,4aS,8aS)-1-allyl-2,5,5,8a-tetramethyldecahydronaphthalen-2-
yl)oxy)methyl)acrylate (21).
A solution of n-BuLi (2.5 M in n-hexane, 1.9 mL, 4.8 mmol) and ether/18-Crown-6 (1.3 g, 4.8
mmol) was added at 0º C to a solution of 16 (755 mg, 3.02 mmol) in dry benzene (15 mL). After
30 min stirring at 0 ºC, 20 (1.5 mL, 12 mmol) was added and the mixture was warmed to reflux.
After 12 h, TLC showed no starting material. Then, ice was added slowly to quench the reaction
and solvent was removed in vacuum. Ether (50 mL) was added to the crude product and the
organic phase was washed with H2O (2 x 20 mL) and brine (20 mL). The organic phase was
dried over anhydrous Na2SO4 and concentrate under vacuum to give a product which was
directly purified by flash chromatography (5% ether/hexane) to yield 904 mg of 21 (86%) as
colourless syrup. [α]D25= -5.9 (c 13.6, CHCl3). H NMR (400 MHz, CDCl3) δ: 6.23 (d, J = 2.0
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Hz, 1H), 5.92 (d, J = 2.0 Hz, 1H), 5.85 (m, 1H), 4.91 (dd, J = 17.1, 1.8 Hz, 1H), 4.82 (d, J = 10.0
Hz, 1H), 4.12 (ddd, J = 14.7, 14.7, 2.1 Hz, 1H), 4.04 (ddd, J = 14.7, 14.7 2.0 Hz, 1H), 3.75 (s,
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3H), 2.31 (m, 1H), 2.02 (m, 1H), 1.86 (dt, J = 12.2, 3.3 Hz, 1H), 1.72 – 1.62 (m, 2H), 1.61 – 1.48
(m, 2H), 1.48 – 1.32 (m, 2H), 1.32 – 1.19 (m, 2H), 1.15 (s, 3H), 0.97 – 0.87 (m, 3H), 0.86 (s,
6H), 0.79 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ: 166.8 (C), 142.5 (CH), 138.7 (C), 124.7
(CH2), 113.2 (CH2), 78.8 (C), 58.6 (CH), 58.4 (CH2), 56.1 (CH), 51.8 (CH3), 42.1 (CH2), 40.5
(CH2), 39.5 (C), 38.4 (CH2), 33.6 (CH3), 33.3 (C), 29.9 (CH2), 21.6 (CH3), 20.4 (CH3), 20.1
(CH2), 18.5 (CH2), 15.9 (CH3). IR (film): 2926, 1721, 1437, 1387, 1217, 1200, 1156, 1085, 772
cm-1. HRMS (ESI/TOF) m/z: [M+H]+ calcd for C22H37O3 349.2743, found 349.2748.
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Methyl
(5aR,7aS,11aS,11bR)-5a,8,8,11a-tetramethyl-1,4,5a,6,7,7a,8,9,10,11,11a,11b-
dodecahydronaphtho[2,1-b]oxepine-3-carboxylate (22).
To a solution of 21 (0.5 g, 1.43 mmol) in dry CH2Cl2 (20 mL) was added the second-generation
Grubbs catalyst (61 mg, 0.07 mmol) at room temperature under argon atmosphere. The mixture
was refluxed for 5 h and concentrated. The residue was purified by flash chromatography on
silica gel column (10% ether / hexane) to yield the product 22 (448 mg, 98 %) as colorless oil.
[α]D25= +47.8 (c 4.6, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.08 (m, 1H), 4.44 – 4.40 (m, 2H),
3.69 (s, 3H), 2.37 – 2.25 (m, 2H) , 1.73 (tt, J = 9.3, 2.8 Hz, 3H), 1.68 – 1.54 (m, 4H), 1.49 – 1.28
(m, 3H), 1.24 (s, 3H), 1.13 (td, J = 13.4, 4.2 Hz, 1H), 0.90 (d, J = 2.5 Hz, 1H), 0.87 (s, 3H), 0.79
(s, 3H), 0.79 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ: 167.1 (C), 144.9 (CH), 133.7 (C),
79.0 (C), 58.7 (CH2), 56.2 (CH), 55.7 (CH), 51.7 (CH3), 42.0 (CH2), 39.9 (CH2), 38.5 (C), 38.0
(CH2), 33.5 (C), 33.5 (CH3), 24.3 (CH2), 22.5 (CH3), 21.4 (CH3), 20.7 (CH2), 18.7 (CH2), 16.1
(CH3). IR (film): 2924, 1711, 1435, 1383, 1244, 1060, 774 cm-1. HRMS (ESI/TOF) m/z: [M+H]+
calcd for C20H33O3 321.2430, found 321.2427.
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(5aR,7aS,11aS,11bR)-N-methoxy-N,5a,8,8,11a-pentamethyl-1,4,5a,6,7,7a,8,9,10,11,11a,11b-
dodecahydronaphtho[2,1-b]oxepine-3-carboxamide (23).
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To a stirred solution of N,O-dimethyl-hydroxylamine HCl (0.84 g, 8.6 mmol) in dry THF (8 mL)
at -78 ºC was added a solution of n-BuLi (2.5 M in hexane, 6.7 mL, 16.8 mmol) under Ar
atmosphere. The reaction mixture was warmed to rt and stirred for 20 min. The solution of
lithium N,O-dimethyl hydroxylamine was recooled to -78 ºC, and a solution of 22 (0.45 g, 1.41
mmol) in dry THF (5 mL) at -78º C was added dropwise via cannula. After 20 min, TLC showed
no starting material. The reaction was quenched at -78º C with sat. aq. NH4Cl (10 mL) and
extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine (15
mL), dried over anhydrous Na2SO4 and the solvent was removed in vacuum. The residue was
purified by flash column chromatography on silica gel column (25% EtOAc / hexane) to afford
472 mg of Weinreb amide 23 (96%) as colorless syrup. [α]D25= +35.4 (c 15.7, CHCl3). 1H NMR
(400 MHz, , CDCl3) δ: 6.37 (dd, J = 7.5, 3.0, 1H), 4.48 (d, J = 16.4 Hz, 1H) , 4.10 (dd, J = 16.4,
2.0 Hz, 1H), 3.64 (s, 3H), 3.20 (s, 3H), 2.36 – 2.18 (m, 2H), 1.79 – 1.69 (m, 4H), 1.69 – 1.54 (m,
4H), 1.48 – 1.28 (m, 2H), 1.25 (s, 3H), 1.14 (ddd, J = 13.4, 13.4, 4.3 Hz, 1H), 0.91 (d, J = 2.5
Hz, 1H), 0.88 (s, 3H), 0.79 (s, 6H). C {1H} NMR (100 MHz, CDCl3) δ: 170.6 (C), 137.6 (C),
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137.6 (CH), 79.2 (C), 61.0 (CH3), 60.1 (CH2), 56.2 (CH), 55.8 (CH), 42.1 (CH2), 40.0 (CH2),
38.6 (C), 38.5 (CH2), 33.7 (CH3), 33.5 (C), 33.5 (CH3), 24.3 (CH2), 22.6 (CH3), 21.4 (CH3), 20.7
(CH2), 18.8 (CH2), 16.1 (CH3). IR (film): 2924, 1658, 1628, 1458, 1381, 1203, 1088, 1048, 772
cm-1. HRMS (ESI/TOF) m/z: [M+H]+ calcd for C21H35NO3 350.2695, found 350.2696.
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1-((5aR,7aS,11aS,11bR)-5a,8,8,11a-tetramethyl-1,4,5a,6,7,7a,8,9,10,11,11a,11b-
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dodecahydronaphtho[2,1-b]oxepin-3-yl)ethan-1-one (14).
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A solution of MeLi (1.6 M in diethyl ether, 0.53 mL, 0.85 mmol) was added dropwise to a
solution of 23 (270 mg, 0.77 mmol) in dry Et2O (6 mL) at -78 ºC under Ar atmosphere and
stirred for 5 min. At this time, TLC showed full consumption of starting material. The reaction
was quenched with water at -78 ºC. Ether (30 mL) was added and the organic phase was washed
with H2O (2 x 10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and the solvent was
removed in vacuum for purified the crude in flash column chromatography (5% AcOEt / hexane)
affording 220 mg of 14 (94%) as colorless syrup. [α]D25= +77.7 (c 12.1, CHCl3). 1H NMR (400
MHz, CDCl3) δ: 6.98 (dd, J = 8.0, 2.2 Hz, 1H), 4.51 (dd, J = 16.8, 2.1 Hz, 1H), 4.40 (d, J = 16.9
Hz, 1H), 2.56 – 2.30 (m, 2H), 2.29 (s, 3H), 1.82 – 1.71 (m, 3H), 1.70 – 1.61 (m, 4H), 1.53 – 1.33
(m, 3H), 1.27 (s, 3H), 1.17 (ddd, J = 13.5, 13.5, 4.3 Hz, 1H), 0.93 (m, 1H), 0.90 (s, 3H), 0.84 (s,
3H), 0.82 (s, 3H). C {1H} NMR (100 MHz, CDCl3) δ: 198.7 (C), 145.7 (CH), 143.4 (C), 78.9
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(C), 57.9 (CH2), 56.2 (CH), 55.5 (CH), 42.0 (CH2), 39.9 (CH2), 38.6 (C), 37.7 (CH2), 33.5 (C),
33.5 (CH3), 25.8 (CH3), 24.5 (CH2), 22.7 (CH3), 21.3 (CH3), 20.7 (CH2), 18.7 (CH2), 16.2 (CH3).
IR (film): 2923, 1662, 1384, 1243, 1219, 1104, 722 cm-1. HRMS (ESI/TOF) m/z: [M+H]+ calcd
for C20H33O2 305.2481, found 305.2477.
(4aS,6aR,13aR,13bS)-4,4,6a,13b-tetramethyl-11,12-bis(phenylsulfonyl)-
1,2,3,4,4a,5,6,6a,8,10,11,12,12a,13,13a,13b-hexadecahydrobenzo[e]naphtho[2,1-b]oxepin-9-
yl acetate (24).
trans-1,2-Bis(phenylsulfonyl)ethylene (250 mg, 0.79 mmol) and p-toluenesulfonic acid (14 mg,
0.07 mmol) were added to a solution of 14 (173 mg, 0.57 mmol) in isopropenyl acetate (4 mL),
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and the mixture was heated at 160 ºC for 5 h in a sealed tube. At this time, TLC showed no
remaining starting material. The reaction was allowed to rt and the crude was purified by flash
chromatography on silica gel (30% AcOEt / hexane), affording 336 mg of an irresolvable
mixture of adducts 24 (90%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 7.98 (dd, J = 3.6,
1.1 Hz, 2H), 7.96 (dd, J = 3.6, 1.5 Hz, 2H), 7.72 (m, 1H), 7.68 (m, 1H), 7.62 (d, J = 8.1 Hz, 2H),
7.59 (d, J = 7.3 Hz, 2H), 4.33 – 4.23 (m, 3H), 4.05 (d, J = 16.9 Hz, 1H), 4.00 (br s, 1H), 3.51 (m,
1H), 2.63 (m, 1H), 2.53 (m, 1H), 2.15 (m, 1H), 2.11 (s, 3H), 2.07 (m, 1H), 1.70 – 1.55 (m, 3H),
1.51 – 1.40 (m, 3H), 1.32 – 1.12 (m, 4H), 1.02 (ddd, J = 13.2, 13.2, 4.4 Hz, 1H), 0.93 (s, 3H),
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0.83 (s, 3H), 0.74 (s, 3H), 0.69 (s, 3H). C {1H} NMR (100 MHz, CDCl3) δ: 167.9 (C), 138.0
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(C), 137.2 (C), 135.7 (C), 134.4 (CH), 134.3 (CH), 129.7 (2 CH), 129.6 (2 CH), 129.3 (2 CH),
129.1 (2 CH), 124.3 (C), 79.0 (C), 60.7 (CH), 58.6 (CH2), 55.9 (CH), 55.9 (CH), 51.2 (CH),
41.7 (CH2), 39.8 (CH2), 38.5 (C), 38.5 (CH2), 33.5 (CH), 33.4 (C), 30.1 (CH3), 29.1 (CH2), 23.5
(CH3), 23.3 (CH2), 21.6 (CH3), 20.9 (CH3), 20.3 (CH2), 18.8 (CH2), 15.9 (CH3). IR (film): 1308,
1217, 1198, 1145, 1082, 752, 689, 564 cm-1. HRMS (ESI/TOF) m/z: [M+H]+ calcd for
C36H47O7S2 655.2763, found 655.2773.
(4aS,6aR,13aR,13bS)-4,4,6a,13b-tetramethyl-1,2,3,4,4a,5,6,6a,8,13,13a,13b-
dodecahydrobenzo[e]naphtho[2,1-b]oxepin-9-yl acetate (25).
To a solution of 24 (350 mg, 0.53 mmol) in dry CH2Cl2 (15 mL) was added dropwise at room
temperature DBU (0.16 mL, 1.07 mmol) and the reaction mixture was stirred for 4 h. At this
time, TLC showed full consumption of starting material. The solvent was evaporated and ether
(20 mL) was added. The organic layer was washed with H2O (2 x 8 mL) and brine (8 mL), dried
over anhydrous Na2SO4 and concentrated in vacuum. The crude product was purified by flash
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chromatography on silica gel (7% AcOEt / hexane), affording 179 mg (91%) of 25 as a white
solid. [α]D25= -57.8 (c 9.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.14 (t, J = 7.8 Hz, 1H), 7.01
(d, J = 7.5 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 4.65 (d, J = 15.0 Hz, 1H), 4.57 (d, J = 15.0 Hz, 1H),
2.98 (dd, J = 15.1, 9.7 Hz, 1H), 2.69 (d, J = 15.2 Hz, 1H), 2.28 (s, 3H), 1.91 (m, 1H), 1.79 – 1.45
(m, 5H), 1.42 (s, 3H), 1.40 – 1.23 (m, 3H), 1.11 (ddd, J = 13.5, 13.5, 4.3 Hz, 1H), 0.99 – 0.88
(m, 2H), 0.85 (s, 3H), 0.83 (s, 3H), 0.81 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3) δ: 169.8 (C),
148.0 (C), 145.2 (C), 132.1 (C), 127.9 (CH), 126.5 (CH), 119.6 (CH), 79.8 (C), 58.7 (CH), 57.8
(CH2), 55.9 (CH), 42.0 (CH2), 40.8 (CH2), 39.3 (CH2), 38.8 (C), 33.5 (C), 33.5 (CH3), 30.5
(CH2), 21.5 (2 x CH3), 21.0 (CH3), 20.4 (CH2), 18.7 (CH2), 15.8 (CH3). IR (film): 2924, 1763,
1463, 1367, 1204, 1039, 771 cm-1. HRMS (ESI/TOF) m/z: [M+H]+ calcd for C24H35O3 371.2586,
found 371.2584.
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(4aS,6aR,13aR,13bS)-4,4,6a,13b-tetramethyl-1,2,3,4,4a,5,6,6a,8,13,13a,13b-
dodecahydrobenzo[e]naphtho[2,1-b]oxepin-9-ol (13).
Conc. hydrochloric acid (0.5 mL) was added to a stirred solution of 25 (125 mg, 0.34 mmol) in
dioxane (4 mL) and the reaction mixture was warmed at 60 ºC. After 3 h TLC showed no starting
material remaining. Ether (30 mL) was added and the organic layer was washed with H2O (4 x
10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and the solvent was removed in
vacuum. The crude product was purified by flash chromatography (10% AcOEt / hexane) to
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yield 109 mg of 13 (98%) as a white solid. [α]D25= -33.4 (c 6.2, CHCl3). H NMR (500 MHz,
CDCl3) δ: 6.95 (t, J = 7.7 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 4.88 (d, J =
15.0 Hz, 1H), 4.72 (d, J = 15.0 Hz, 1H), 2.95 (dd, J = 15.1, 9.6 Hz, 1H), 2.62 (d, J = 15.1 Hz,
1H), 1.92 (dd, J = 12.8, 3.6 Hz, 1H), 1.82 – 1.47 (m, 4H), 1.44 (s, 3H), 1.41 – 1.24 (m, 4H), 1.11
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(ddd, J = 13.5, 13.5, 4.4 Hz, 1H), 0.96 – 0.87 (m, 2H), 0.85 (s, 3H), 0.83 (s, 3H), 0.81 (s, 3H).
13C {1H} NMR (125 MHz, CDCl3) δ: 152.8 (C), 145.5 (C), 127.9 (CH), 126.7 (C), 121.2 (CH),
113.4 (CH), 79.8 (C), 59.1 (CH), 57.1 (CH2), 56.0 (CH), 42.1 (CH2), 40.8 (CH2), 39.4 (CH2),
38.8 (C), 33.6 (C), 33.5 (CH3), 30.4 (CH2), 21.6 (CH3), 21.5 (CH3), 20.4 (CH2), 18.8 (CH2), 15.8
(CH3). IR (film): br 3273, 2924, 1738, 1466, 1366, 1217, 1031, 771 cm-1. HRMS (ESI/TOF) m/z:
[M+H]+ calcd for C22H33O2 329.2481, found 329.2480.
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(4aS,6aR,13aR,13bS)-4,4,6a,13b-tetramethyl-1,2,3,4,4a,5,6,6a,8,13,13a,13b-
dodecahydrobenzo[e]naphtho[2,1-b]oxepine-9,12-dione (26).
Potassium nitrosodisulfonate (350 mg, 1,3 mmol) was added to a stirred solution of 13 (70 mg,
0.21 mmol) in CH2Cl2 (20 mL), Na2HPO4/NaH2PO4 buffer (5 mL) and Aliquat336. After
overnight, TLC showed no starting material. Then, the solvent was evaporated and ether (30 mL)
was added. The organic layer was washed with H2O (2 x 10 mL) and brine (10 mL), dried over
anhydrous Na2SO4 and concentrated to give a crude product, which was purified by flash
chromatography on silica gel (5% AcOEt / hexane) to give 26 (64 mg, 89%) as a yellow oil.
[α]D25= +341.5 (c 9.1, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 6.71 (d, J = 10.0 Hz, 1H), 6.65 (d,
J = 10.0 Hz, 1H), 4.66 (dd, J = 18.0, 2.3 Hz, 1H), 4.56 (dd, J = 18.1, 4.2 Hz, 1H), 2.98 (d, J =
18.4 Hz, 1H), 2.33 (m, 1H), 1.89 – 1.73 (m, 3H), 1.69 – 1.55 (m, 5H), 1.50 – 1.31 (m, 2H), 1.29
(s, 3H), 1.25 (m, 1H), 1.11 (td, J = 13.5, 4.2 Hz, 1H), 0.87 (s, 6H), 0.80 (s, 3H). C {1H} NMR
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(100 MHz, CDCl3) δ: 187.4 (C)x2, 146.6 (C), 143.6 (C), 136.4 (CH), 136.1 (CH), 79.5 (C), 56.7
(CH2), 56.4 (CH), 55.5 (CH), 42.1 (CH2), 39.8 (CH2), 39.0 (C), 37.3 (CH2), 33.6 (C), 33.5 (CH3),
22.6 (CH3), 21.3 (CH3), 21.1 (CH2), 20.6 (CH2), 18.6 (CH2), 16.1 (CH3). IR (film): 2925, 1650,
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1454, 1386, 1298, 1217, 814, 771 cm-1. HRMS (ESI/TOF) m/z: [M+H]+ calcd for C22H31O3
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343.2273, found 343.2269.
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(4aS,6aR,13aR,13bS)-4,4,6a,13b-tetramethyl-1,2,3,4,4a,5,6,6a,8,13,13a,13b-
dodecahydrobenzo[e]naphtho[2,1-b]oxepine-9,12-diol (cyclosiphonodictyol A, 11).7
Na2S2O4 (224 mg, 1.1 mmol) was added to a suspension of quinone 26 (75 mg, 0.22 mmol) in 8
mL of H2O-CHCl3 (1:1) and the mixture was stirred for 4 h, at which time TLC showed no
starting material. CHCl3 was removed under vacuum and ether (15 mL) was added. The organic
layer was washed with H2O (2 x 5 mL) and brine (5 mL), dried over anhydrous Na2SO4 and
removed in vacuum to afford 69 mg of 11 (91%). The product could not purify because is
extremely air sensitive and back to quinone. 1H NMR (500 MHz, CDCl3) δ: 6.51 (d, J = 8.5 Hz,
1H), 6.43 (d, J = 8.5 Hz, 1H), 4.84 (d, J = 15.2 Hz, 1H), 4.73 (d, J = 15.2 Hz, 1H), 3.10 (d, J =
15.6 Hz, 1H), 2.54 (dd, J = 15.6, 9.6 Hz, 1H), 1.98 (ddd, J = 12.7, 12.7 3.7 Hz, 1H), 1.77 – 1.51
(m, 6H), 1.39 – 1.28 (m, 3H), 1.21 (m, 1H), 1.11 (ddd, J = 13.5, 13.5, 4.3 Hz, 1H), 0.96 – 0.88
(m, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.81 (s, 3H). 1H NMR (500 MHz, DMSO-d6) δ: 8.49 (s, 1H),
8.42 (s, 1H), 6.46 (d, J = 8.5 Hz, 1H), 6.39 (d, J = 8.5 Hz, 1H), 4.65 (d, J = 14.9 Hz, 1H), 4.51
(d, J = 14.9 Hz, 1H), 3.07 (d, J = 15.4 Hz, 1H), 2.34 (dd, J = 15.5, 9.5 Hz, 1H), 1.92 (d, J = 12.9
Hz, 1H), 1.66 – 1.58 (m, 3H), 1.49 – 1.36 (m, 3H), 1.35 (m, 1H), 1.33 (s, 3H), 1.20 (m, 1H), 1.09
(dt, J = 13.5, 4.2 Hz, 1H), 0.88 (m, 1H), 0.84 (s, 3H), 0.80 (s, 3H), 0.79 (s, 3H), 0.76 (m, 1H).
13C {1H} NMR (125 MHz, CDCl3) δ: 146.7 (C), 146.5 (C), 130.9 (C), 128.7 (C), 114.7 (CH),
113.6 (CH), 80.0 (C), 57.5 (CH2), 56.1 (CH), 55.5 (CH), 42.2 (CH2), 39.7 (CH2), 38.9 (C), 33.6
(C), 33.5 (CH3), 29.9 (CH2), 21.9 (CH3), 21.6 (CH2), 21.5 (CH3), 20.5 (CH2), 18.8 (CH2), 15.8
(CH3). IR (film): br 3334, 2923, 1738, 1365, 1259, 1217, 1024, 772 cm-1. C {1H} NMR (125
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MHz, DMSO-d6) δ: 146.5 (C), 146.4 (C), 129.9 (C), 127.7 (C), 113.7 (CH), 112.3 (CH), 78.5
(C), 58.1 (CH), 56.7 (CH2), 55.4 (CH), 41.6 (CH2), 40.1 (CH2), 39.4 (CH2), 38.2 (C), 33.1 (CH3),
33.1 (C), 21.6 (CH3), 21.2 (CH3), 20.8 (CH2), 19.8 (CH2), 18.2 (CH2), 15.3 (CH3). HRMS
(ESI/TOF) m/z: [M+Na]+ calcd for C22H32O3Na 367.2249, found 367.2246.
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The NMR spectra in DMSO-d6 are similar to that previously described for the natural product. In
fact, the 13C NMR data are identical.
Bis(sulfato)-cyclosiphonodictyol A (12). 8
To a solution of 11 (30 mg, 0.087 mmol) in dry pyridine (1 mL) was added SO3•Py (143 mg, 0.9
mmol) and the reaction mixture was heated to 80º C for 4 h. At this time, TLC showed no
starting material. The reaction was cooled to 0 ºC and quenched with a saturated solution of
Na2CO3 (1 mL) dropwise. The solvent was concentrated in vacuum and dried with Ar. The solid
residue was purified by column chromatography on silica gel (30% MeOH / CHCl3) to afford 39
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mg of disulfate 12 (82%) as a white solid. [α]D25= +12.3 (c 10.0, MeOH). H NMR (500 MHz,
DMSO-d6 ) δ: 7.08 (d, J = 8.9 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H), 4.72 (d, J = 15.3 Hz, 1H), 4.56
(d, J = 15.3 Hz, 1H), 3.24 (d, J = 15.9 Hz, 1H), 2.39 (dd, J = 15.9, 9.6 Hz, 1H), 1.99 (m, 1H),
1.69 – 1.53 (m, 4H), 1.47 – 1.32 (m, 2H), 1.31 (s, 3H), 1.24 (m, 1H), 1.14 – 1.03 (m, 2H), 0.95
(m, 1H) 0.83 (s, 3H), 0.80 (s, 3H), 0.78 (s, 3H), 0.74 (m, 1H). 13C {1H} NMR (125 MHz,
DMSO-d6) δ: 146.6 (C), 145.9 (C), 135.5 (C), 133.9 (C), 120.1 (CH), 119.2 (CH), 78.4 (C), 57.6
(CH2), 55.5 (CH), 48.6 (CH), 41.7 (CH2), 39.9 (CH2), 38.9 (CH2), 38.3 (C), 33.2 (CH3), 33.1 (C),
22.0 (CH2), 21.7 (CH3), 21.3 (CH3), 19.9 (CH2), 18.3 (CH2), 15.4 (CH3). IR (film): br 3431,
2924, 1462, 1219, 1059, 1032, 1000, 831, 782, 583 cm-1. HRMS (ESI/TOF) m/z: [M-2Na+H]-
calcd for C22H31O9S2 503.1409, found 503.1404.
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The NMR data for the DMSO-d6 solutions of synthetic compound are close to that reported for
the CD3OD solutions of the natural product. A complete comparison was not feasible due to the
low solubility of the synthetic bis(sulfato) in CD3OD.
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ASSOCIATED CONTENT
Supporting Information
Copies of 1H and 13C NMR spectra for all described compounds.
This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Tel: (+34) 958 248 089. E-mail: rachid@ugr.es; eamr@ugr.es
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors thank the Spanish Ministry of Economy and Competitiveness (Project CTQ2014-
56611-R/BQU) and the Regional Government of Andalucia (Project P11-CTS-7651) for
financial support and assistance provided to the FQM-348 group. J. A. Gil thanks the Spanish
Ministry of Education, Culture and Sports for the predoctoral grant provided.
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REFERENCES
7
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12
13
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15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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47
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50
51
52
53
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55
56
57
58
59
60
(1) Marcos, I. S.; Conde, A.; Moro, R. F.; Dies, D; Urones, J. G. Quinone/Hydroquinone
Sesquiterpenes. Mini-Reviews in Organic Chemistry, 2010, 7, 230-254.
(2) For the isolation and first total synthesis of liphagal, see: (a) Marion, F.; Williams, D. E.;
Patrick, B. O.; Hollander, I.; Mallon, R.; Kim, S. C.; Roll, D. M.; Feldberg, L.; Van Soest,
R.; Andersen, R. J. Liphagal, a Selective Inhibitor of PI3 Kinase α Isolated from the
Sponge Aka coralliphaga: Structure Elucidation and Biomimetic Synthesis. Org. Lett.
2006, 8, 321-324. For further total syntheses of liphagal, see: (b) Mehta, G.; Likhite, N. S.;
Kumar, C. S. A. A concise synthesis of the bioactive meroterpenoid natural product ( )-
liphagal, a potent PI3K inhibitor. Tetrahedron Lett. 2009, 50, 5260-5262. (c) George, J. H.;
Baldwin, J. E.; Adlington, R. M. Enantiospecific, Biosynthetically Inspired Formal Total
Synthesis of (+)-Liphagal. Org. Lett. 2010, 12, 2394-2397. (d) Alvarez-Manzaneda, E.;
Chahboun, R.; Alvarez, E.; Cano, M. J.; Haidour, A.; Alvarez-Manzaneda, R.
Enantioselective Total Synthesis of the Selective PI3 Kinase Inhibitor Liphagal. Org. Lett.
2010, 12, 4450-4453. (e) Day, J. J.; McFadden, R. M.; Virgil, S. C.; Kolding, H.; Alleva, J.
L.; Stoltz, B. M. The Catalytic Enantioselective Total Synthesis of (+)-Liphagal. Angew.
Chem., Int. Ed. 2011, 50, 6814-6818. (f) Kamishima, T.; Kikuchi, T.; Narita, K.; Katoh, T.
Biogenetically inspired total synthesis of (+)-liphagal: A potent and selective
phosphoinositide 3-kinase α (PI3Kα) inhibitor from the marine sponge Aka coralliphaga.
Eur. J. Org. Chem. 2014, 3443-3450.
(3) For the isolation of corallidictyals, see: (a) Chan, J. A.; Freyer, A. J.; Carte, B. K.;
Hemling, M. E.; Hofmann, G. A.; Mattern, M. R.; Mentzer, M. A.; Westley, J. W. Protein
21
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1
2
3
4
5
6
7
8
9
kinase C inhibitors: novel spirosesquiterpene aldehydes from a marine sponge Aka
(=Siphonodictyon) coralliphagum. J. Nat. Prod. 1994, 57, 1543-1548. (b) Grube, A.;
Assmann, M.; Lichte, E.; Sasse, F.; Pawlik, J. R.; Köck, M. Bioactive Metabolites from
the Caribbean Sponge Aka coralliphagum. J. Nat. Prod. 2007, 70, 504-509. For syntheses
of corallidictyals, see: (c) Cano, M. J.; Bouanou, H.; Tapia, R.; Alvarez, E.; Alvarez-
Manzaneda, R.; Chahboun, R.; Alvarez-Manzaneda, E. NIS-PPh3: A Selective Reagent for
the Spiroannulation of o-Allyl Phenols. Total Synthesis of Corallidictyal D. J. Org. Chem.
2013, 78, 9196-9204. (d) Dethe, D. H; Dherange, B.D; Ali, S.; Parsutkar, M. M.
Enantiospecific total syntheses of meroterpenoids (-)-F1839-I and (-)-corallidictyals B and
D. Org. Biomol. Chem. 2016, 15, 65-68. (e) Wang, J.-L.; Li, H.-J.; Wu, Y.-C. Divergent
Synthesis of Marine Natural Products Siphonodictyal B, Corallidictyals C/D, and Liphagal
Based on the Early Presence of an Aldehyde Group Instead of a Late-Stage Introduction. J.
Org. Chem. 2018, 83, 8716-8723. (f) Kuan, K. K. W.; Markwell-Heys, A. W.;
Cruickshank, M. C.; Tran, D. P.; Adlington, R. M.; Baldwin, J. E.; George, J.H.
Biomimetic synthetic studies on meroterpenoids from the marine sponge Aka coralliphaga:
Divergent total syntheses of siphonodictyal B, liphagal and corallidictyals A-D. Bioorg.
Med. Chem. 2019, 27, 2449-2465.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) Sullivan, B.; Djura, P.; McIntyre, D. E.; Faulkner, D. J. Antimicrobial constituents of the
sponge Siphonodictyon coralliphagum. Tetrahedron 1981, 37, 979-982.
(5) Sullivan, B. W.; Faulkner, D. J.; Matsumoto, G. K.; He, C.-H. Clardy, J. Metabolites of the
burrowing sponge Siphonodictyon coralliphagum. J. Org. Chem. 1986, 51, 4568-4573.
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2
3
4
5
6
7
8
9
(6) Bickmeyer, U.; Grube, A.; Klings, K.-W.; Pawlik, J. R.; Kock, M. Siphonodictyal B1 from
a Marine Sponge Increases Intracellular Calcium Levels Comparable to the Ca2+-ATPase
(SERCA) Inhibitor Thapsigargin. Mar. Biotechnol. 2010, 12, 267-272.
(7) Göthel, Q.; Köck, M. New sesquiterpene hydroquinones from the Caribbean sponge Aka
coralliphagum. Beilstein J. Org. Chem. 2014, 10, 613-621.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(8) Killday, K. B.; Wright, A. E.; Jackson, R.H.; Sills, M. A. Bis(sulfato)-cyclosiphonodictyol
A, a new disulfated sesquiterpene-hydroquinone from a deep water collection of the marine
sponge Siphonodictyon coralliphagum. J. Nat. Prod. 1995, 58, 958-960.
(9) Mukku, V. J. R. V.; Edrada, R. A.; Schmitz, F. J.; Shanks, M. K.; Chaudhuri, B.; Fabbro,
D. New sesquiterpene quinols from a Micronesian sponge, Aka sp. J. Nat. Prod.
2003, 66, 686-689.
(10) Shubina, L. K.; Kalinovsky, A. I.; Makarieva, T. N.; Fedorov, S. N.; Dyshlovoy, S. A.;
Dmitrenok, P. S.; Kapustina, I. I.; Mollo, E.; Utkina, N.K.; Krasokhin, V. B.; Denisenko,
V. A.; Stonik, V. A. New meroterpenoids from the marine sponge Aka coralliphaga. Nat.
Prod. Commun. 2012, 7, 487-490.
(11) Markwell-Heys, A. W.; Kuan, K. K. W.; George, J. H. Total Synthesis and Structure
Revision of (-)-Siphonodictyal B and Its Biomimetic Conversion into (+)-Liphagal.
Org. Lett. 2015, 17, 4228-4231.
(12) Laube, T.; Bernet, A.; Dahse, H.-M.; Jacobsen, I. D.; Karlheinz Seifert, K. Synthesis and
pharmacological activities of some sesquiterpene quinones and hydroquinones. Bioorg.
Med. Chem. 2009, 7, 1422-1427.
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7
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(13) Kikuchi, T.; Narita, K.; Saijo, K.; Ishioka, C.; Katoh, T. Enantioselective Total Synthesis
of (-)-Siphonodictyal B and (+)-8-epi-Siphonodictyal B with Phosphatidylinositol 3-Kinase
α (PI3Kα) Inhibitory Activity. Eur. J. Org. Chem.2016, 5659-5666.
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21
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45
46
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50
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58
59
60
(14) For a recent review concerning oxepane natural compounds see: Barbero, H.; Díez-Poza,
C.; Barbero, A. The oxepane motif in marine drugs. Mar. Drugs 2017, 15, 361/1-361/34.
(15) Margaros, I.; Montagnon, T.; Vassilikogiannakis, G. Spiroperoxy Lactones from Furans in
One Pot: Synthesis of (+)-Premnalane A. Org. Lett. 2007, 9, 5585-5588.
(16) For recent reviews concerning the ring-closing metathesis, see: (a) Yet, L. Olefin ring-
closing metathesis. Org. React. 2016, 89, 1-1303. (b) Lecourt, C.; Dhambri, S.; Allievi, L.;
Sanogo, Y.; Zeghbib, N.; Ben Othman, R.; Lannou, M.-I.; Sorin, G.; Ardisson, J. Natural
products and ring-closing metathesis: synthesis of sterically congested olefins. Nat. Prod.
Rep. 2018, 35, 105-124.
(17) A similar cycloadduct was previously synthesized in our laboratory, see: Fernández, A.;
Alvarez, E.; Alvarez-Manzaneda, R.; Chahboun, R.; Alvarez-Manzaneda, E. A short
synthetic route towards merosesquiterpenes with a benzoxanthene skeleton. Chem.
Commun. 2014, 50, 13100-13012.
(18) For some examples of the use of the non-nucleophilic base DBU to achieve
dehydrosulfonylation reactions, see: (a) Ballini, R.; Bosica, G.; Mercantoni, E. A New 1,4-
Elimination of Benzenesulfinic Acid from β-KetoPhenylsulphones Via Their
Tosylhydrazones. Tetrahedron 1996, 52, 10705-10710. (b) Giovannini, R.; Mercantoni;
Petrini, M. Claisen Rearrangement of γ-Hydroxyvinyl Sulfones via Ketene Acetal
Derivatives. A New Entry to Functionalized (2E, 4E)-Alkadienoic Esters. Tetrahedron
Lett. 1998, 39, 5827-5830. (c) Yu, L.; Tang, N.; Sheng, S.; Chen, R.; Liu, X.; Cai, M.
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Solid-Phase Organic Synthesis of Aryl Vinyl Ethers Using Sulfone-Linking Strategy. Chin.
J. Chem. 2012, 30, 1027-1030.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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(19) For some examples of the use of Fremy’s salt for the oxidation of phenol derivatives to p-
quinones, see: (a) Alvarez-Manzaneda, E.; Chahboun, R.; Cabrera, E.; Alvarez, E.;
Haidour, A.; Ramos, J.M.; Alvarez-Manzaneda, R.; Hmamouchi, M.; Es-Samti, H. A
thermal 6π electrocyclization strategy towards taiwaniaquinoids. First enantiospecific
synthesis of (-)-taiwaniaquinone G. Chem. Commun. 2009, 592–594. (b) Harjivan, S. G.;
Wanke, R.; Ferreira da Silva, J. L.; Marques, M. M.; Antunes, A. M. M. The phenolic
metabolites of the anti-HIV drug efavirenz: Evidence for distinct reactivities upon
oxidation with Fremy’s salt. Eur. J. Med. Chem. 2014, 74, 7-11. (c) Cao, Z.; Du, K.; Liu,
J.; Tang, W. Synthesis of triptoquinone H and its C-5 epimer via efficient asymmetric
dearomative cyclization. Tetrahedron 2016, 72, 1782-1786.
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