Total Synthesis of an Antifouling Marine Furanosesquiterpene

Article abstract of DOI:10.1055/s-0036-1588711

An antifouling sesquiterpene isolated from Sinularia sp. was synthesized from citronellyl acetate in eight steps and 9% overall yield. The furan moiety was constructed using a multifunctional sulfone reagent.

Full text of DOI:10.1055/s-0036-1588711

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–E
paper
A
C. N. Ungarean et al.
Paper
Synthesis
Total Synthesis of an Antifouling Marine Furanosesquiterpene
Chad N. Ungarean1
Jeremy D. Mason2
Benjamin R. Eyer
Nicholas S. Duca
Jaimie M. Mong
S. Shaun Murphree*
Department of Chemistry, Allegheny College,
520 North Main Street, Meadville, PA 16335,
USA
smurphre@allegheny.edu
Received: 03.11.2016
Accepted after revision: 19.01.2017
Published online: 10.02.2017
converting 1,3-diketones into 2,4-disubstituted furans.15
Using this approach (Figure 1), we envisioned that furoic
acid 1 could be accessed via diketone 2, which in turn could
be efficiently constructed from the readily available citro-
nellyl acetate (3).
DOI: 10.1055/s-0036-1588711; Art ID: ss-2016-z0777-op
Abstract An antifouling sesquiterpene isolated from Sinularia sp. was
synthesized from citronellyl acetate in eight steps and 9% overall yield.
The furan moiety was constructed using a multifunctional sulfone re-
agent.
HO2C
O
O
OAc
R
Key words furans, sulfones, natural products, total synthesis, hetero-
O
R
cycles
1
2
3
R =
Biofouling constitutes a significant economic challenge.
Fouling organisms are ubiquitous in marine habitats, and
they negatively impact shipping operations, water purifica-
tion, and aquatic recreation.3 Inorganic antifoulants have
been the first line of defense for many years,4 but increasing
environmental concerns prompted the International Mari-
time Organization to adopt a ban on the use of organotins
and other harmful antifouling systems in marine coatings
in 2001.5 Consequently, research into non-bioaccumulating,
environmentally benign fouling inhibitors has taken on a
renewed sense of urgency, and particular attention has
been devoted to natural products of marine origin.6
In this context, the furanosesquiterpene 1 has been iso-
lated from several subspecies of the soft coral Sinularia spe-
cies,7–11 and preliminary studies have estimated its efficacy
against the blue mussel (Mytilus edulis) at a loading of 0.2
mg/mL to be 74% that of copper(II) sulfate, a highly effective
(but environmentally persistent) inorganic antifoulant;12,13
moreover, at concentrations of 30 μM it exhibited moderate
(26%) inhibition of inducible NO synthase (iNOS) activity in
J774 macrophages.14 However, extraction of 1 from natural
sources yields low quantities, and to our knowledge a total
synthesis has not been reported previously. We were there-
fore intrigued with this compound as a target for our re-
cently reported sulfone-mediated preparative method for
Figure 1 Retrosynthetic strategy for furanosesquiterpene 1
For the construction of diketone 2, we took inspiration
from a synthesis of the insect pheromone methyl 2,6,10-
trimethyldodecanoate reported by Zarbin et al.,16 which
launched by subjecting citronellyl acetate (3) to selenium
dioxide mediated allylic oxidation to provide aldehyde 4
(Table 1). Using superstoichiometric quantities of SeO2, the
E-aldehyde 4 was isolated in 41% yield upon reflux in etha-
nol for 15 min (entry 1). Higher yields and shorter reaction
times could be achieved using a microwave protocol (entry
2), albeit with a somewhat more limited scalability. In both
of these approaches, a small amount of Z-isomer was ob-
served, which was difficult to remove by chromatography
without yield loss. In contrast, the use of substoichiometric
amounts of SeO2 adsorbed onto silica in dichloromethane at
room temperature in the presence of aqueous tert-butyl hy-
droperoxide as a terminal oxidant17 (entry 3) provided
practically exclusively the E-isomer in yields comparable to
those found in entry 1. However, with an eye toward scale-
up, we explored the possibility of isolating gram quantities
of aldehyde 4 without the high solvent demand associated
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

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C. N. Ungarean et al.
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Synthesis
with chromatography. The most effective alternative was
found to be Kugelrohr distillation (130 °C/2 Torr), which has
a higher throughput than a flash column and delivers the
product in significantly higher yield (entry 4). One draw-
back, however, is that a small amount of E/Z isomerization
occurs, which could not be circumvented. To take advantage
of its convenience and scalability, we nonetheless carried
the material forward with an eye toward removal of the Z-
isomer after the next step.
MePPh3Br
n-BuLi
OR
O
sIBX, BHT
4
THF
0 ° C, 2.5 h
rt, 12 h, 76%
t-BuOH
Δ, 25 min
quant.
7
5, R = Ac
6, R = H
K2CO3, MeOH
rt, 2 h, quant.
LDA
acetone
BHT
THF
–78 ° C
66%
Br
Table 1 Allylic Oxidation of Citronellyl Acetate (3)
R
O
Br
Y
X
SO2Ph
O
OAc
SeO2
NaOMe
3
MeOH
59%
O
11 (R = CH2SO2Ph)
1 (R = CO2H)
10 (X, Y = H, OH)
2 (X, Y = O)
KHMDS
O2, THF
50%
sIBX, BHT
EtOAc, Δ
97%
4
Entry SeO2
(equiv)
t-BuOOH Solvent
(equiv)
Time
T
(°C)
Yielda
(%)
Scheme 1 Synthesis of furan 1
1
2
3
4
5f
2.0
0
EtOH
15 min
78
41b
50b
39
2.0
0
EtOH
10 min
24 h
24 h
3 h
100c
r.t.
when the oxidation was carried out in the presence of 10
mol% 2,6-di-tert-butyl-4-methylphenol (BHT). Since the
conversion is practically quantitative, the BHT was carried
forward to avoid yield loss in purification.
0.5d
0.5d
0.5
2.5
2.5
3.0
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
r.t.
60e
40
r.t.
a Isolated by column chromatography unless otherwise stated.
b Approximately 2–4% Z-isomer present (by NMR).
c Microwave protocol.
The next step was to install the 1,3-diketone moiety
necessary for the sulfone-mediated furan formation, which
we envisioned to occur via an aldol-oxidation sequence on
aldehyde 7. We chose to optimize this reaction using com-
mercially available citronellal (8) (Table 2). As one of the
strategies surveyed, we examined the titanocene-catalyzed
Reformatsky addition of chloroacetone onto citronellal,
which has been previously reported to give a 91% yield of
hydroxy ketone 9 as a mixture of diastereomers,21 although
in our hands, the isolated yield was somewhat lower (entry
1). We also thought it prudent to explore some operational-
ly simpler alternatives. Toward this end, treating citronellal
with catalytic quantities of proline in a medium of ace-
tone/DMSO22 did provide a modest yield of the aldol 9, al-
though the chief product was the corresponding enone (en-
try 2). Results could be improved by using superstoichio-
metric amounts of proline and acetone as a solvent (entry
3).23 Similar yields (53%) could be obtained using catalytic
sodium methoxide in methanol at 5 °C24 (entry 4). Still bet-
ter results were achieved by changing the base to LDA and
using one equivalent of acetone in THF (entry 5).25
d Adsorbed onto silica.
e Isolated by bulb-to-bulb distillation. Z isomer also present.
f Results reported in ref. 16.
Methylenation of the aldehyde functionality was effect-
ed using standard Wittig chemistry. Thus, treatment of
methyltriphenylphosphonium bromide with n-butyllithi-
um, followed by addition of aldehyde 4 resulted in smooth
conversion into the corresponding E-diene acetate 5 in 76%
yield (Scheme 1). Subsequent deprotection of the alcohol
could be accomplished conveniently through potassium
carbonate promoted transesterification in methanol, which
afforded alcohol 6 in excellent yield on a variety of scales.
Among several protocols screened for the conversion of
the primary alcohol into aldehyde 7, oxidation with stabi-
lized IBX (sIBX)18 in tert-butyl alcohol proceeded with the
highest yield.19 Vexingly, a small amount (ca. 5%) of isomer-
ization was observed about the internal double bond under
these reaction conditions. It is unclear whether the E/Z
isomerization is induced by sIBX itself or results from traces
of iodine in the reagent. To our knowledge, the IBX-mediat-
ed isomerization of double bonds has not been reported, al-
though the iodine-promoted variant is well known, and
previous studies have shown the efficacy of radical scaven-
gers in retarding the iodine-catalyzed isomerization of
dienes.20 Thus, we were pleased to observe no Z-isomer
Gratifyingly, these conditions worked equally well on
substrate 7, providing aldol 10 in 66% yield. Subsequent ox-
idation to diketone 2 proceeded smoothly using stabilized
IBX,26 although the product degraded upon storage and was
used immediately for the next step. Again, the addition of
BHT was necessary to prevent E/Z isomerization during the
oxidation.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

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C. N. Ungarean et al.
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Synthesis
Table 2 Optimization of Aldol Condensation Using Citronellal (8)
h, and then filtered through a frit. The filtrate was concentrated in
vacuo to yield a yellow oil (3.58 g), which was purified by Kugelrohr
distillation (130 °C oven temperature/2 Torr) to afford aldehyde 4
(2.86 g, 60%) as a pale yellow oil comprised of a 96:4 mixture of E-
and Z-isomers. The E-isomer can be isolated using column chroma-
tography (30% Et2O/hexane) to give analytically pure material with
spectroscopic data identical to those reported in the literature.16
OH
O
O
8
9
(E)-3,7-Dimethylnona-6,8-dienyl Acetate (5)
To a stirred suspension of MePPh3Br (3.74 g, 10.5 mmol) in anhyd THF
(85 mL) at 0 °C was added dropwise 1.5 M n-BuLi in hexanes (6.8 mL,
10.2 mmol), whereupon the contents immediately turned yellow. The
mixture was warmed to 0 °C and allowed to stir for 2.5 h, after which
it was transferred dropwise via syringe to a solution of (E)-3,7-di-
methyl-8-oxooct-6-enyl acetate (4, 1.76 g, 8.29 mmol) in anhyd THF
(75 mL) at –78 °C. The cooling bath was removed and the yellow solu-
tion was stirred at r.t. overnight. The solvent was removed in vacuo,
and the resulting oil was passed through a small silica plug (ca. 3 in),
eluting with Et2O (250 mL). The eluent was concentrated in vacuo to
give an oil (1.62 g), which was purified by column chromatography
(10% EtOAc/hexane) to afford diene 5 (1.15 g, 76%) as a colorless oil
with spectroscopic data identical to those reported in the literature.16
Entry Conditions
Yield (%)
58
1
Cp2TiCl2 (2 equiv), Mn (8 equiv), chloroacetone (2 equiv),
2,4,6-collidine (8 equiv), TMSCl (4 equiv), THF
2
3
4
5
proline (0.3 equiv), 20% acetone/DMSO
proline (2 equiv), acetone
21a
49
53
63
NaOMe (0.33 equiv), acetone (3.6 equiv), MeOH
LDA (1.2 equiv), acetone (1.0 equiv), THF
a The corresponding enone was produced in 65% yield.
With diketone 2 in hand, the phenylsulfonylmethylfu-
ran 11 could be accessed by treatment with 2,3-dibromo-1-
(phenylsulfonyl)prop-1-ene in the presence of methanolic
sodium methoxide.15 The carboxylic acid functionality
could then be installed using an oxidative desulfonylation
strategy,27 in which the sulfonyl dianion formed using po-
tassium hexamethyldisilazanide is allowed to undergo oxi-
dation in dry air, providing the target furanosesquiterpene
1 in fair yield.
In summary, we have reported a convenient and scal-
able synthesis of the potential antifouling compound 1,
which is suitable for preparing gram quantities of the syn-
thetic target in 8 steps and 9% overall yield from the readily
available citronellyl acetate. Antifouling evaluation of com-
pound 1 is currently underway.
(E)-3,7-Dimethylnona-6,8-dien-1-ol (6)
To a solution of dienyl acetate 5 (1.26 g, 5.98 mmol) in HPLC grade
MeOH (19 mL) was added K2CO3 (826.5 mg, 5.98 mmol). The resulting
suspension was stirred for 2 h at r.t., after which the solid was re-
moved by filtration. The filtrate was concentrated in vacuo and the
residue was partitioned between water (100 mL) and Et2O (3 × 60
mL). The combined organic phases were washed with water (2 × 50
mL) and brine, dried (Na2SO4), and concentrated in vacuo to provide
alcohol 6 (1.00 g, quant.) as a pale straw-colored oil, which was im-
mediately used in the next step without further purification. Spectro-
scopic data were identical to those reported in the literature.16
(E)-3,7-Dimethylnona-6,8-dienal (7)
To a solution of dienol 6 (257 mg, 1.53 mmol) and BHT (33.8 mg, 0.15
mmol) in t-BuOH (23 mL) was added stabilized 2-iodoxybenzoic acid
(45 wt%, 1.9059 g, 3.06 mmol). The suspension was heated at reflux
for 25 min with stirring, after which the mixture was cooled, hexanes
(120 mL) were added, and the organics were washed with sat.
NaHCO3/brine (5 × 120 mL). The organic layer was dried (Na2SO4), and
concentrated in vacuo to provide an oil (289 mg) containing product 7
(254 mg, 99.6%), as well as residual BHT, which was used immediately
in the next step. A sample purified by chromatography (5% EtOAc/
hexanes) yielded analytically pure material with spectroscopic data
identical to those reported in the literature.16
THF was distilled first over CaH2 and then over Na/benzophenone ke-
tyl. Hexanes for chromatography were distilled over CaH2. MeOH,
EtOAc, acetone, and CH2Cl2 were purchased as HPLC grade and used
without further purification. n-BuLi was titrated against diphenyl-
acetic acid before use. All other reagents were purchased from Aldrich
Chemical Company and used as received.
Only diagnostic absorptions in the infrared spectrum are reported.
NMR spectra were recorded in CDCl3 (unless otherwise noted) using a
JEOL Eclipse 400+ FT-NMR spectrometer. Elemental analyses were
performed at Atlantic Microlabs in Norcross, GA. All air-sensitive re-
actions were performed under N2 atmosphere. Column chromatogra-
phy was carried out using SilicaFlash P60 silica gel (40–63 μm) pur-
chased from Silicycle.
4-Hydroxy-6,10-dimethylundec-9-en-2-one (9)
A solution of i-Pr2NH (0.87 mL, 6.2 mmol) in THF (6.0 mL) at –78 °C
was treated with 2.2 M n-BuLi (2.8 mL, 6.2 mmol) and allowed to stir
at –78 °C for 10 min. A solution of HPLC grade acetone (0.39 mL, 5.2
mmol) in THF (0.8 mL) was added to the LDA thus formed, and the
solution was stirred at –78 °C for 1 h. Citronellal (8, 0.864 mL, 4.8
mmol) in THF (1.0 mL) was then added over a period of 15 min. The
mixture was stirred for an additional 12 min at –78 °C, quenched by
the addition of sat. aq NH4Cl (3 mL), and partitioned between sat. aq
NH4Cl (40 mL) and Et2O (2 × 30 mL). The combined organic extracts
were washed with brine (2 ×), dried (Na2SO4), and concentrated in
vacuo to give an oil, which was purified by column chromatography
(E)-3,7-Dimethyl-8-oxooct-6-enyl Acetate (4)
To a stirred suspension of 5 wt% SeO2 on silica (15.0 g, 6.75 mmol) in
CH2Cl2 (135 mL) was added aq 70 wt% tBuOOH (4.9 mL, 34.1 mmol) as
a bolus followed by a solution of citronellyl acetate (3.0 mL, 2.7 g, 13.5
mmol) in CH2Cl2 (12.5 mL) added over a period of 15 min. The result-
ing suspension was stirred vigorously open to the atmosphere for 24
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C. N. Ungarean et al.
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Synthesis
(30% EtOAc/hexane) to afford product 9 (678 mg, 63%) as a straw-
colored oil with spectroscopic properties identical to those reported
in the literature.21
r.t., cooled again to 0 °C, after which 2,3-dibromo-1-(phenylsulfo-
nyl)prop-1-ene (555.9 mg, 1.64 mmol) was added in one portion. The
mixture was stirred at r.t. for 2.5 h, cooled to 0 °C, and treated with a
second portion of 0.5 M NaOMe solution (3.9 mL, 1.95 mmol). After
stirring for 16 h at r.t., the reaction was quenched with sat. NH4Cl (6
mL). MeOH was removed in vacuo and the mixture was poured into
sat. NH4Cl (35 mL), extracted with CH2Cl2 (3 × 15 mL), washed with
water (60 mL), and dried (Na2SO4). The organic layers were concen-
trated in vacuo to provide an oil (713 mg), which was purified by col-
umn chromatography (15% EtOAc/hexane) to afford phenylsulfonyl-
methylfuran 11 (376 mg, 59% from 10) as a light yellow oil.
(E)-4-Hydroxy-6,10-dimethyldodeca-9,11-dien-2-one (10)
A solution of i-Pr2NH (0.87 mL, 6.2 mmol) in THF (6.0 mL) at –78 °C
was treated with 2.2 M n-BuLi (2.8 mL, 6.2 mmol) and allowed to stir
at –78 °C for 10 min. A solution of HPLC grade acetone (0.39 mL, 5.2
mmol) in THF (0.8 mL) was added to the LDA thus formed, and the
solution was stirred at –78 °C for 1 h. Unpurified dienal 7 (922 mg,
792 mg aldehyde, 4.8 mmol) in THF (1.0 mL) was then added over a
period of 15 min. The mixture was stirred for an additional 12 min at
–78 °C, quenched by the addition of sat. aq NH4Cl (3 mL), and parti-
tioned between sat. aq NH4Cl (40 mL) and Et2O (2 × 30 mL). The com-
bined organic extracts were washed with brine (2 ×), dried (Na2SO4),
and concentrated in vacuo to give an oil, which was purified by col-
umn chromatography (30% EtOAc/hexane) to afford product 10 (708
mg, 66%) as a clear oil (mixture of diastereomers).
IR (neat, NaCl): 2956, 2924, 1447, 1320, 1156, 1086, 883, 688 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.77–7.69 (m, 2 H), 7.65–7.56 (m, 1 H),
7.47 (t, J = 7.8 Hz, 2 H), 7.05 (d, J = 1.0 Hz, 1 H), 6.36 (dd, J = 17.4, 10.7
Hz, 1 H), 5.88 (s, 1 H), 5.44 (t, J = 7.3 Hz, 1 H), 5.08 (d, J = 17.5 Hz, 1 H),
4.93 (d, J = 10.7 Hz, 1 H), 4.13 (s, 2 H), 2.54 (dd, J = 14.9, 6.0 Hz, 1 H),
2.38 (dd, J = 14.8, 7.7 Hz, 1 H), 2.24–2.04 (m, 2 H), 1.83–1.72 (m, 1 H),
1.73 (d, J = 1.2 Hz, 3 H), 1.45–1.30 (m, 1 H), 1.28–1.13 (m, 1 H), 0.86
(d, J = 6.7 Hz, 3 H).
IR (neat, NaCl): 3436, 3088, 2925, 1713, 1081 cm–1
.
13C NMR (CDCl3, 100 MHz): δ = 156.4, 141.6, 141.2, 137.9, 134.1,
133.8, 133.0, 129.0, 128.7, 113.1, 110.7, 108.0, 53.7, 36.1, 35.3, 32.3,
25.8, 19.5, 11.8.
1H NMR (CDCl3, 400 MHz): δ = 6.35 (dd, J = 17.4, 10.7 Hz, 1 H), 5.46 (t,
J = 7.3 Hz, 1 H), 5.06 (dd, J = 17.4, 2.9 Hz, 1 H), 4.91 (dd, J = 10.7, 2.9 Hz,
1 H), 4.22–4.06 (m, 1 H), 2.66–2.55 (m, 1 H), 2.55–2.44 (m, 1 H), 2.17
(s, 3 H), 2.23–2.01 (m, 2 H), 1.73 (m, 3 H), 1.65–1.00 (m, 5 H), 0.92 (d,
J = 6.6 Hz, 3 H).
Anal. Calcd for C21H26O3S: C, 70.36; H, 7.31. Found: C, 70.15; H, 7.17.
13C NMR (CDCl3, 100 MHz): δ = 210.1, 141.7, 134.0, 133.9, 133.3,
110.6, 110.5, 65.7, 65.3, 50.8, 50.2, 43.7, 37.4, 36.3, 30.9, 29.1, 28.8,
25.8, 25.6, 20.1, 19.1, 11.8, 11.7.
(E)-2-(2,6-Dimethylocta-5,7-dienyl)-4-furoic Acid (1)
To a solution of furan 9 (173.2 mg, 0.48 mmol) in anhyd THF (5.7 mL)
cooled to –78 °C was added dropwise 0.5 M KHMDS in toluene (2.4
mL). The solution was stirred for 45 min at –78 °C and thereafter
sparged with dry air through a 22-gauge needle for 2.5 h. The solu-
tion was warmed to r.t. and quenched with sat. NH4Cl (5 mL), diluted
with Et2O (40 mL), and washed with 0.1 M HCl (2 × 40 mL). The or-
ganic phase was dried (Na2SO4) and concentrated in vacuo to afford
an oil, which was purified using column chromatography (10%
MeOH/CH2Cl2) to afford natural product 1 (59.1 mg, 50%) as a light
straw-colored oil with spectroscopic properties identical to those re-
ported in the literature.
Anal. Calcd for C14H24O2: C, 74.95; H, 10.78. Found: C, 74.87; H, 10.57.
(E)-6,10-Dimethyldodeca-9,11-dien-2,4-dione (2)
Dienone (10, 645 mg, 2.87 mmol) and BHT (61.4 mg, 0.29 mmol)
were dissolved in HPLC grade EtOAc (25 mL). To the solution was add-
ed stabilized 2-iodoxybenzoic acid (45 wt%, 5.356 g, 8.61 mmol). The
suspension was heated at reflux for 50 min with stirring, after which
the mixture was cooled to r.t. and hexanes (323 mL) was added. The
organics were washed with sat. NaHCO3/brine (5 × 323 mL), dried
(Na2SO4), and concentrated in vacuo to provide an oil (680 mg) con-
taining product 2 (619 mg, 97%), as well as residual BHT. This unsta-
ble material was used immediately in the next step. An analytically
pure sample was obtained by column chromatography (5% EtOAc/
hexanes).
Acknowledgment
The authors gratefully acknowledge financial support from the Petro-
leum Research Fund (PRF 42382-B1), the Arnold and Mabel Beckman
Foundation, and the Shanbrom Fund of Allegheny College. We also
thank Doug Taber for stimulating discussion about this project.
IR (neat, NaCl): 2957, 2925, 1607, 1458, 1382, 1285, 1240, 990, 843,
777 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 15.54 (s, 1 H, enol tautomer), 6.35 (dd,
J1 = 17.5 Hz, J2 = 10.7 Hz, 1 H), 5.46 (s, 1 H, enol tautomer), 5.45 (t, J =
6.8 Hz, 1 H), 5.07 (d, J = 17.0 Hz, 1 H), 4.92 (d, J = 10.7 Hz, 1 H), 3.54 (s,
2 H, keto tautomer), 1.87–2.36 (m, 7 H), 1.72 (s, 3 H), 1.15–1.61 (m, 3
H), 0.93 (d, J = 6.4 Hz, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 192.9, 192.2, 141.6, 134.2, 132.8,
132.7, 110.7, 100.8, 58.4, 51.1, 45.6, 36.6, 36.4, 30.7, 28.7, 25.8, 25.3,
19.6, 11.7.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588711.
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References
Anal. Calcd for C14H22O2: C, 75.63; H, 9.97. Found: C, 75.45; H, 9.82.
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