Chemical Synthesis Study Establishes the Correct Structure of the Potent Anti-Inflammatory Agent Myrsinoic Acid F

Article abstract of DOI:10.1021/acs.jnatprod.8b00778

A total synthesis of compound 3 from p-bromophenol is reported and thereby establishing that this, rather than its cyclodehydrated counterpart 1 (as postulated originally), is the correct structure of the natural product myrsinoic acid F. The biological evaluation of compound 3 in a mouse-ear edema assay established that it is a significantly more potent anti-inflammatory agent than the NSAID indometacin.

Full text of DOI:10.1021/acs.jnatprod.8b00778

Article
Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
pubs.acs.org/jnp
Chemical Synthesis Study Establishes the Correct Structure of the
Potent Anti-Inflammatory Agent Myrsinoic Acid F
†
†
‡,§
,†,‡
Jiri Mikusek, Jeremy Nugent, Ping Lan,
and Martin G. Banwell*
†Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, Australian Capital
Territory 2601, Australia
‡
Institute of Advanced and Applied Chemical Synthesis, Jinan University, Zhuhai 519070, People’s Republic of China
§
Department of Food Science and Engineering, Jinan University, Guangzhou 510632, People’s Republic of China
*
S Supporting Information
ABSTRACT: A total synthesis of compound 3 from p-
bromophenol is reported and thereby establishing that this, rather
than its cyclodehydrated counterpart 1 (as postulated originally), is
the correct structure of the natural product myrsinoic acid F. The
biological evaluation of compound 3 in a mouse-ear edema assay
established that it is a significantly more potent anti-inflammatory
agent than the NSAID indometacin.
1
n 2002, Hirota and co-workers reported the isolation and
anti-inflammatory agent, as determined in a mouse-ear edema
assay. However, neither of them corresponds to the structure
of MA-F. Clearly, then, the question arises as to the correct
structure of MA-F. In considering this matter and the
similarities of the physical data for certain acyclic precursors
(i.e., ones lacking the dihydrobenzofuran ring) to compound 1
with those reported for the natural product, the possibility
arose that the p-hydroxybenzoic acid 3 (Figure 2) represents
I
structural elucidation of a series of anti-inflammatory agents,
named myrsinoic acids, from the fresh leaves and twigs of
Myrsine seguinii, a hardwood of the Myrsinaceae family found in
various parts of Asia from Myanmar to Japan. The most active
of these compounds was myrsinoic acid F (MA-F) and to
1
which structure 1 (Figure 1) was assigned on the basis of a
Figure 2. Revised structure 3 proposed for myrsinoic acid F.
Figure 1. Originally proposed structure of myrsinoic acid (1) and its
Z-isomer (2).
the correct structure. It is conceivable that the molecular ion
for such a species would not be observed in the electron-
impact mass spectrum (because of its facile dehydration under
the conditions involved) and so leading to an erroneous
range of NMR spectroscopic and mass spectrometric studies.
This compound and various structurally related co-metabolites
have since been encountered in certain other plants (e.g.,
Rapanea ferruginea and Myrsine coriacea) found in several parts
of the globe, and a number of these have been shown to exhibit
potentially useful biological properties including selective
5
structural assignment. Interestingly, compound 3 has been
6
reported in the patent literature as a natural product isolated
from the aerial parts of the Southern African tree Rapanaea
melanophloeos, but we have been unable to secure copies of the
spectral data for this material. Accordingly, we sought to adapt
our syntheses of compounds 1 and 2 to the preparation of
2
cytotoxic, anti-microbial, and anti-leishmanial effects. The
anti-inflammatory properties of these compounds may arise
3
through their inhibition of DNA polymerase λ.
4
Recently, we reported total syntheses of compound 1 and
Received: September 12, 2018
its Z-isomer 2. Each of these compounds proved to be a potent
©
XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.8b00778
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
target 3 in order to compare its spectral data with those
reported for MA-F. The outcomes of such studies are reported
here together with the results of evaluating the anti-
inflammatory properties of compound 3 and certain synthetic
analogues in a mouse-ear edema assay.
Scheme 2. Direct Synthesis of Alkenyl Iodide 10
RESULTS AND DISCUSSION
Synthetic Studies. The successful synthesis of compound
from p-bromophenol used the first two steps involved in the
■
3
preparation of dihydrobenzofuran 1 as well as minor variations
4
on the third and fourth ones. Thus, as shown in Scheme 1,
followed by conventional workup gave the light-sensitive
iodide 10 in 91% yield. This material was identical in all
respects with a sample prepared by the earlier route.
As shown in Scheme 3, the conversion of compound 8 into
target 3 proved to be a relatively straightforward process. Thus,
Scheme 1. Conversion of p-Bromophenol (4) into Aryl
Acetaldehyde 8
4
Scheme 3. Conversion of Compound 8 into the Correct
Structure (3) of Myrsinoic Acid F
reaction of p-bromophenol (4) with prenyl bromide in the
7
presence of sodium hydride afforded the known, C-alkylated
product 5 (64%). Formylation of product 5 using paraformal-
dehyde in the presence of Et N and MgCl gave compound 6
3
2
(
68%) that was subjected to Wittig olefination using the ylide
3
Ph P=CH(OMe) in the presence of triethylsilyl chloride
(
TES-Cl) and potassium tert-butoxide. As a result, the
previously unreported enol ether 7 (67%) was obtained, and
its hydrolysis with trifluoroacetic acid (TFA) as catalyst gave
the arylated acetaldehyde 8 in 94% yield.
the alkenyllithium obtained by treating an ethereal solution of
iodide 10 with t-BuLi was treated, in situ, with aldehyde 8 and
4
The known alkenyl iodide required for completion of the
assembly of the geranyl-type side-chain associated with target 3
was synthesized by the more concise and higher yielding route
thus affording, after aqueous workup, the allylic alcohol 11 in
64% yield. Reaction of the latter compound with TES-Cl in the
presence of imidazole afforded the bis-ether 12 (95%), and this
served as the immediate precursor to target 3. Treatment of a
THF solution of compound 12 maintained at −78 °C with t-
BuLi led to the anticipated metal-for-bromine exchange, and
the ensuing aryllithium was trapped with dry, gaseous carbon
dioxide. The resulting mixture was treated with aqueous AcOH
and heated at 50 °C for 36 h. After cooling, extractive workup,
and flash column chromatography, carboxylic acid 3 was
obtained in 75% yield as a clear, light-yellow oil.
8
shown in Scheme 2. This employed the Bond modification of
the Shapiro reaction as the key step and allowed for the direct
introduction of the halogen. Thus, acetone 2,4,6-triisopropyl-
4
benzenesulfonylhydrazone (9) was treated with n-BuLi, and
then prenyl bromide was added at −78 to −60 °C. The
intermediate was treated in situ, again at −78 °C, with a
second aliquot of n-BuLi, and the ensuing anion was allowed to
warm to 0 °C at which point gas evolution was observed. Once
this had ceased (after ca. 0.5 h), the reaction mixture was
recooled to −78 °C before being treated with 1,2-diiodo-
ethane. Quenching the reaction with sodium thiosulfate
The NMR and MS data derived from acid 3 were in
complete accord with the assigned structure. Of particular
note, the 70 eV electron-impact mass spectrum of this
B
DOI: 10.1021/acs.jnatprod.8b00778
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
compound did not display a molecular ion at m/z 358. In
contrast, in the ESI mass spectrum (run in negative mode) a
molecular-associated ion was observed at m/z 357. Further-
notable difference between the two data sets centered on the
chemical shifts of the resonances due to the hydroxycarbonyl
group carbons (δ 172.5 for 3 vs 170.9 reported for MA-F), a
C
1
13
more, comparisons of the H and C NMR spectroscopic data
sets derived from the synthetic material proved to be identical
feature that can be attributed to minor variations in the pH of
the media in which the two data sets were acquired.
1
with those reported for MA-F (see Tables 1 and 2). The only
In order to assist with the development of a structure−
activity relationship (SAR) profile for MA-F related com-
pounds, the monoether 11 was subjected to desilylation by
treating a THF solution with aqueous AcOH at 50 °C for 18 h
1
Table 1. Comparison of the H NMR Spectroscopic Data
1
Recorded for Compound 3 with Those Reported for
4
Myrsinoic Acid F (MA-F)
(Scheme 4) and thereby forming the known bromo-analogue,
a
,
b
b
,
c
,
de
compound 3 δH
MA-F δH
7.77 (s, 1H)
7.67 (s, 1H)
assignment
Scheme 4. Synthesis of the Bromo-Analogue 13 of
Myrsinoic Acid F
7
7
5
5
5
4
3
3
.80 (d, J = 2.1 Hz, 1H)
.68 (d, J = 2.1 Hz, 1H)
.42 (m, 1H)
H-6
H-4
5.42 (t, J = 6.2 Hz, 1H)
5.34 (broad s, 1H)
5.04 (t, J = 6.8 Hz, 1H)
4.35 (d, J = 8.5 Hz, 1H)
3.37 (d, J = 6.5 Hz, 2H)
H-2′
H-2″
H-4′
H-2
H-1″
H-3
.33 (m, 1H)
.03 (m, 1H)
.35 (d, J = 8.8 Hz, 1H)
.38 (d, J = 7.3 Hz, 2H)
.04
3.03
(
dd, J = 14.7, 9.1 Hz, 1H)
(dd, J = 14.2, 9.3 Hz, 1H)
2
2
1
1
1
1
1
.76 (d, J = 14.7 Hz, 1H)
.71 (t, J = 7.3 Hz, 2H)
.76 (s, 3H)
.74 (s, 3H)
.73 (s, 3H)
2.76 (d, J = 14.2 Hz, 1H)
2.71 (t, J = 6.8 Hz, 2H)
1.75 (s, 3H)
H-3
H-3′
H-4″
H-7′ or H-5″
H-5″ or H-7′
H-6′
1
3 (80%), of compound 3. All the spectroscopic data derived
from this product were in complete accord with the illustrated
structure and matched those recorded earlier.
Biological Studies. With significant quantities of the
synthetically derived compounds 3, 7, 8, 12, and 13 to hand,
and in order to begin developing an SAR profile for the class,
each of these was assayed in the same mouse-ear edema assay
used to evaluate the anti-inflammatory properties of com-
1.73 (s, 6H)
4
.69 (s, 3H)
.62 (s, 3H)
1.69 (s, 3H)
1.62 (s, 3H)
H-8′
a
b
Spectrum recorded in CDCl at 400 MHz. Signals due to the
3
c
carboxylic acid and hydroxy group protons not observed. Spectrum
recorded in CDCl at 500 MHz. These assignments derived from ref
d
3
4
e
pounds 1 and 2. These tests revealed, as shown in the
1. See Figure 2 for atom numbering.
Supporting Information, that MA-F (3) is a significantly more
potent anti-inflammatory agent than the widely prescribed
NSAID indometacin and even more active than its cyclic
Table 2. Comparison of the 13C NMR Chemical Shifts of
Compound 3 with Those Reported for Myrsinoic Acid F
1
4
congener 1 (that showed activities similar to indometacin in
(
MA-F)
the same assay). Similarly, the bromo-analogue 13 displayed
significant anti-inflammatory effects, while the structurally
simpler congeners also possessed some activity. The perhaps
counterintuitive observation that the less concentrated samples
of certain of the test compounds showed greater inhibition
rates is not uncommon in animal tests. This could be
attributed, in relevant cases, to partial cleavage of the
associated TES-ether moiety under the assay conditions.
In conclusion, the studies reported herein serve to establish
the correct structure, 3, of the potent anti-inflammatory natural
product myrsinoic acid F and provide a rational basis for the
original misassignment as the dihydrobenzofuran 1. The
synthetic sequences established in the course of both the
a
b
,
cd
compound 3 δC
MA-F δC
Δδ
assignment
1
1
1
1
1
1
1
1
1
1
1
1
1
8
3
2
2
2
2
1
1
1
72.5
59.2
36.1
33.4
32.5
31.9
31.0
29.9
25.9
25.8
22.1(0)
22.0(6)
20.7
0.2
8.5
8.9
6.7
6.0
5.8
8.0
7.9
2.2
170.9
159.0
136.0
133.2
132.4
131.8
130.9
129.8
125.8
125.6
122.0
121.9
120.4
80.2
38.4
28.8
26.6
25.8
25.7
17.9
17.7
12.1
+1.6
+0.2
+0.1
+0.2
+0.1
+0.1
+0.1
+0.1
+0.1
+0.2
+0.1
+0.1
+0.3
0
+0.1
+0.1
+0.1
+0.2
+0.1
+0.1
+0.2
+0.1
CO
C-7a
C-1′
C-5′
C-3″
C-4
C-6
C-7
C-2′
C-3a
C-2″
C-4′
C-5
4
present and earlier studies are likely to provide effective
means for accessing other members of the myrsinoic acid class
of natural product as well as various analogues. They should
also enable syntheses of related and biologically active natural
C-2
C-3
9
C-1″
C-3′
C-4″
C-6′
C-5″
C-8′
C-7′
products such as the amorfrutins.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Unless otherwise specified,
1
13
H and C NMR spectra were recorded at room temperature in base-
filtered CDCl on a Bruker spectrometer operating at 400 MHz for
3
proton and 100 MHz for carbon nuclei. The signal due to residual
a
b
CHCl appearing at δ 7.26 and the central resonance of the CDCl
3
H
3
Spectrum recorded in CDCl at 100 MHz. Spectrum recorded in
CDCl at 125 MHz. Assignments derived from ref 1. See Figure 2
for atom numbering.
1
13
3
c
d
triplet appearing at δC 77.1(6) were used to reference H and
C
3
1
NMR spectra, respectively. H NMR data are recorded as follows:
chemical shift (δ) [multiplicity, coupling constant(s) J (Hz), relative
integral] where multiplicity is defined as s = singlet; d = doublet; t =
C
DOI: 10.1021/acs.jnatprod.8b00778
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
+
triplet; q = quartet; m = multiplet or combinations of the above. IR
spectra were recorded, using neat samples, on an attenuated total
reflectance (ATR) infrared spectrometer. Samples were analyzed as
either thin films or finely divided solids. Low-resolution ESI mass
spectra were recorded on a single quadrupole mass spectrometer,
while high-resolution measurements were conducted on a time-of-
flight instrument. Low- and high-resolution EI mass spectra were
recorded on a magnetic-sector machine. Analytical TLC was
performed on aluminum-backed 0.2 mm thick silica gel 60 F254
plates as supplied by Merck. Eluted plates were visualized using a 254
nm UV lamp and/or by treatment with a suitable dip followed by
heating. These dips included phosphomolybdic acid:Ce(SO ) :H SO
(100 and 95), 399 and 397 [M + H] (both <1), 373 (18), 301 (10),
+
147 (7); HRMS (TOF ESI, + ve) m/z 397.1194 [M + H] (calcd for
7
9
C H BrO Si, 397.1193).
1
9
30
2
(E)-2-Iodo-6-methylhepta-2,5-diene (10). A magnetically stirred
4
solution of hydrazone 9 (2.00 g, 5.91 mmol) in THF (30 mL) was
cooled to −78 °C and treated with n-BuLi (5.33 mL of 2.38 M
solution in hexanes, 12.7 mmol). The resulting orange solution was
stirred at −78 °C for 1 h and treated dropwise with prenyl bromide
(820 μL, 7.11 mmol). The yellow solution was allowed to warm to
−60 °C over 1 h, recooled to −78 °C, and treated with n-BuLi (2.70
mL of 2.38 M solution in hexanes, 6.43 mmol). The solution turned
orange and was stirred at −78 °C for 0.25 h, warmed to 0 °C, and
maintained at this temperature for 0.5 h during which time gas
evolution was observed. The reaction was then recooled to −78 °C
and treated with 1,2-diiodoethane (2.08 g, 7.40 mmol). After 0.3 h at
−78 °C the reaction mixture was warmed to 22 °C, stirred at this
temperature for 0.5 h, and treated with Na S O (50 mL of a
4
2
2
4
(
conc.):H O (37.5 g:7.5 g:37.5 g:720 mL) or KMnO :K CO :5%
2
4
2
3
NaOH aqueous solution:H O (3 g:20 g:5 mL:300 mL). Flash
2
chromatographic separations were carried out following protocols
10
defined by Still et al. with silica gel 60 (40−63 μm) as the stationary
phase and using the AR- or HPLC-grade solvents indicated. Starting
materials and reagents were generally available from Sigma−Aldrich
2
2
3
saturated aqueous solution) before being extracted with EtOAc (3 ×
100 mL). The combined organic phases were dried (Na SO ),
(Sydney, Australia) and were used as supplied. Drying agents and
2
4
other inorganic salts were purchased from the AJAX Finechem
Melbourne, Australia). THF, MeOH, and CH Cl were dried using a
filtered, and concentrated under reduced pressure. The residue thus
obtained was subjected to flash chromatography (silica, cyclohexane
(
2
2
Glass Contour solvent purification system that is based upon a
technology originally described by Pangborn et al. Where necessary,
reactions were performed under a nitrogen atmosphere.
elution) to afford, after concentration of the appropriate fractions (R
f
11
4
= 0.9 in hexanes), iodide 10 (1.27 g, 91%) as a clear, pink-orange and
1
light-sensitive oil. H NMR (400 MHz, CDCl ) δ 6.11 (m, 1H), 5.07
3
Specific Chemical Transformations. (E)-[4-Bromo-2-(2-me-
thoxyvinyl)-6-(3-methylbut-2-en-1-yl)phenoxy]triethylsilane (7). A
magnetically stirred suspension of methoxymethyltriphenylphospho-
nium chloride (7.64 g, 22.3 mmol) in dry THF (150 mL) was cooled
to −40 °C and treated with a solution of t-BuOK (3.76 g, 33.5 mmol)
in dry THF (30 mL). The ensuing mixture was maintained at this
temperature for 0.3 h, and the resulting dark-red reaction mixture was
treated with a solution of benzaldehyde 6 (2.79 g, 10.4 mmol) in dry
THF (30 mL) before being warmed to 0 °C, stirred at this
temperature for 1 h, treated with TES-Cl (4.45 mL, 26.5 mmol),
(m, 1H), 2.70 (t, J = 7.5 Hz, 2H), 2.39 (s, 3H), 1.69 (s, 3H), 1.61 (s,
1
3
3H); C NMR (100 MHz, CDCl ) δ 139.9, 133.2, 120.1, 93.6, 29.8,
3
27.6, 25.8, 17.9. This material was identical, in all respects, with a
4
sample prepared as described earlier.
(E)-1-{5-Bromo-3-(3-methylbut-2-en-1-yl)-2-[(triethylsilyl)oxy]-
phenyl}-3,7-dimethylocta-3,6-dien-2-ol (11). A magnetically stirred
solution of iodide 10 (1.00 g, 4.24 mmol) in dry Et O (20 mL) was
2
4
cooled to −78 °C, treated dropwise with t-BuLi (3.67 mL of a 1.5 M
solution in hexanes, 5.51 mmol), maintained at this temperature for 1
h, and treated with a solution of aldehyde 8 (1.12 g, 2.82 mmol) in
stirred at 0 °C for 1 h, then treated with NH Cl (100 mL of a
dry Et O (5 mL). The ensuing mixture was maintained at −78 °C for
4
2
saturated aqueous solution), and extracted with EtOAc (3 × 100 mL).
The combined organic phases were dried (Na SO ), filtered, and
1 h before being diluted with brine (20 mL), warmed, and extracted
with EtOAc (3 × 15 mL). The combined organic phases were dried
(Na SO ), filtered, and concentrated under reduced pressure, and the
2
4
concentrated under reduced pressure, and the residue was subjected
to flash chromatography (silica, 95:5 v/v hexanes/toluene elution).
2
4
residue was subjected to flash chromatography (silica, 98:2 → 95:5 v/
v hexanes/EtOAc elution). Concentration of the appropriate fractions
Concentration of the appropriate fractions (R = 0.9 in 9:1 v/v
f
hexanes/EtOAc) afforded enol ether 7 (2.86 g, 67%) as a clear, light-
(R = 0.4 in 9:1 v/v hexanes/EtOAc) gave compound 11 (1.11 g,
f
1
1
yellow oil. H NMR (400 MHz, CDCl ) δ 7.93 (d, J = 2.6 Hz, 1H),
64%) as a light-yellow oil. H NMR (400 MHz, CDCl ) δ 7.13 (d, J =
3
3
7
1
3
.01 (d, J = 2.6 Hz, 1H), 6.17 (d, J = 7.2 Hz, 1H), 5.39 (d, J = 7.2 Hz,
H), 5.25 (m, 1H), 3.77 (s, 3H), 3.24 (d, J = 7.2 Hz, 2H), 1.77 (s,
H), 1.67 (s, 3H), 0.96 (t, J = 7.9 Hz, 9H), 0.75 (q, J = 7.9 Hz, 6H);
2.6 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 5.36 (t, J = 7.3 Hz, 1H), 5.24
(m, 1H), 5.05 (m, 1H), 4.21 (m, 1H), 3.25 (d, J = 7.3 Hz, 2H), 2.82
(dd, J = 13.8 and 8.7 Hz, 1H), 2.75−2.67 (complex m, 3H), 1.79 (m,
1H), 1.78 (s, 3H), 1.70 (s, 3H), 1.69 (s, 3H), 1.67 (s, 3H), 1.62 (s,
1
3
C NMR (100 MHz, CDCl ) δ 149.6, 148.4, 134.0, 133.7, 129.9,
3
1
3
1
29.6, 129.2, 121.9, 114.2, 99.9, 60.9, 28.8, 25.9, 18.0, 6.9, 5.8; IR
3H), 0.96 (t, J = 7.9 Hz, 9H), 0.76 (q, J = 7.9 Hz, 6H); C NMR
(
ATR) ν 2957, 2913, 1648, 1433, 1262, 1096, 1004, 907, 822, 740
(100 MHz, CDCl ) δ 151.7, 136.4, 134.5, 134.1, 132.0, 131.7, 131.2,
130.5, 126.1, 122.6, 121.7, 114.2, 77.6, 37.3, 28.9, 26.8, 25.9, 25.8,
max
3
−
1
+
cm ; MS (ESI, + ve) m/z (%) 435 and 433 [M + Na] (100 and 92),
13 (18), 332 (20), 147 (19); HRMS (TOF ESI, + ve) m/z 433.1171
4
18.0, 17.9, 11.7, 6.9, 5.8; IR (ATR) ν 3391, 2958, 2913, 2877,
max
+
79
31
−1
[
M + Na] (calcd for C H BrO SiNa, 433.1174).
1452, 1267, 1198, 910, 816, 739 cm ; MS (ESI, + ve) m/z (%) 531
2
0
2
+
2
-{5-Bromo-3-(3-methylbut-2-en-1-yl)-2-[(triethylsilyl)oxy]-
and 529 [M + Na] (73 and 70), 130 (100), 88 (14); HRMS (TOF
+
79
phenyl}acetaldehyde (8). A magnetically stirred solution of enol
ether 7 (370 mg, 0.90 mmol) in CH Cl (10 mL) containing water
ESI, + ve) m/z 529.2113 [M + Na] (calcd for C H BrO SiNa
27 43 2
2
2
529.2113).
(
50 μL) was treated with TFA (250 μL, 3.26 mmol) and maintained
at 22 °C for 0.5 h. The resulting mixture was quenched with NaHCO3
10 mL of a saturated aqueous solution) before being extracted with
CH Cl (3 × 15 mL). The combined organic phases were dried
(E)-{4-Bromo-2-[3,7-dimethyl-2-((triethylsilyl)oxy)octa-3,6-dien-
1-yl]-6-(3-methylbut-2-en-1-yl)phenoxy}triethylsilane (12). A mag-
netically stirred solution of compound 11 (430 mg, 0.85 mmol) and
imidazole (157 mg, 2.30 mmol) in CH Cl (15 mL) was cooled to 0
(
2
2
2
2
(
Na SO ), filtered, and concentrated under reduced pressure, and the
°C and treated with TES-Cl (0.31 mL, 1.82 mL). The resulting
2
4
residue was subjected to flash chromatography (silica, 99:1 → 95:5 v/
solution was allowed to warm to 22 °C, stirred at this temperature for
v hexanes/EtOAc elution) to afford, after concentration of the
16 h, treated with NaHCO (10 mL of a saturated aqueous solution),
3
appropriate fractions (R = 0.8 in 9:1 v/v hexanes/EtOAc), aldehyde 8
and extracted with EtOAc (3 × 15 mL). The combined organic
f
1
(
337 mg, 94%) as a clear, colorless oil. H NMR (400 MHz, CDCl )
phases were dried (Na SO ), filtered, and concentrated under
3
2
4
δ 9.65 (t, J = 2.1 Hz, 1H), 7.17 (d, J = 2.6 Hz, 1H), 7.10 (d, J = 2.6
Hz, 1H), 5.26 (m, 1H), 3.59 (d, J = 2.1 Hz, 2H), 3.27 (d, J = 7.3 Hz,
reduced pressure, and the residue was subjected to flash
chromatography (silica, hexanes →95:5 v/v hexanes/EtOAc elution).
2
7
1
H), 1.79 (s, 3H), 1.68 (s, 3H), 0.96 (t, J = 7.8 Hz, 9H), 0.75 (q, J =
Concentration of the appropriate fractions (R = 0.9 in 9:1 v/v
f
.8 Hz, 6H); 13C NMR (100 MHz, CDCl ) δ 199.4, 151.9, 135.0,
hexanes/EtOAc) afforded compound 12 (499 mg, 95%) as a clear,
3
1
34.5, 131.8, 131.4, 125.4, 121.3, 114.4, 45.6, 28.8, 25.9, 18.0, 6.9, 5.8;
light-yellow oil. H NMR (400 MHz, CDCl ) δ 7.12 (d, J = 2.6 Hz,
3
IR (ATR) ν 2958, 1728, 1455, 1271, 1200, 1006, 911, 817, 742
cm ; MS (ESI, + ve) m/z (%) 453 and 451 [M + Na + MeOH]
1H), 7.02 (d, J = 2.6 Hz, 1H), 5.24 (m, 2H), 5.05 (m, 1H), 4.14 (m,
1H), 3.23 (m, 2H), 2.73−2.55 (complex m, 4H), 1.77 (s, 3H), 1.69
max
−
1
+
D
DOI: 10.1021/acs.jnatprod.8b00778
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
(
9
s, 3H), 1.67 (s, 3H), 1.66 (s, 3H), 1.62 (s, 3H), 0.94 (t, J = 7.9 Hz,
H), 0.82−0.68 (complex m, 15H), 0.46−0.27 (complex m, 6H); C
Notes
1
3
The authors declare no competing financial interest.
NMR (100 MHz, CDCl ) δ 151.5, 137.4, 134.1, 133.6, 132.4, 132.1,
3
1
2
2
31.8, 129.8, 125.0, 122.7, 122.1, 113.6, 78.2, 38.1, 28.9, 26.7, 25.9,
ACKNOWLEDGMENTS
■
5.8, 18.0, 17.8, 11.1, 7.0, 6.9, 5.8, 4.8; IR (ATR) ν 2956, 2912,
max
−
1
We thank the Australian Research Council, the Institute of
Advanced Studies, Jinan University, the Pearl River Scholar
Program of Guangdong Province, and the Famous Foreign
Supervisor Program (Grant 2018-HWMS001) of the Ministry
of Education, People’s Republic of China for financial support.
The continued interest of Drs. Alison Findlay and Jonathan
Foot (Pharmaxis Ltd., Sydney, Australia) in this work is
gratefully acknowledged.
877, 1455, 1270, 1200, 1065, 1004, 812, 740 cm ; MS (ESI, + ve)
+
m/z (%) 645 and 643 [M + Na] (100 and 90), 121 (10); HRMS
+
(
TOF ESI, + ve) m/z 643.2974 [M + Na] (calcd for
79
C H BrO Si Na, 643.2978).
33
57
2
2
(
E)-4-Hydroxy-3-(2-hydroxy-3,7-dimethylocta-3,6-dien-1-yl)-5-
(3-methylbut-2-en-1-yl)benzoic Acid (3). A magnetically stirred
solution of compound 12 (200 mg, 0.32 mmol) in THF (5 mL)
was cooled to −78 °C and treated with t-BuLi (0.53 mL of 1.5 M
solution in hexanes, 0.80 mmol). The resulting yellow solution was
stirred at −78 °C for 0.75 h, and then dry CO (g) was bubbled into
2
REFERENCES
the reaction mixture for 0.5 h. The resulting clear, colorless solution
was treated with AcOH (2 mL of a 50% v/v aqueous solution), heated
at 50 °C for 36 h before being cooled to 22 °C, treated with TLC-
grade silica gel (500 mg), and concentrated under reduced pressure.
The resulting free-flowing powder was subjected to flash chromatog-
raphy (silica, 8:2 → 1:1 v/v hexanes/EtOAc elution) to afford, after
■
(1) Hirota, M.; Miyazaki, S.; Minakuchi, T.; Takagi, T.; Shibata, H.
Biosci., Biotechnol., Biochem. 2002, 66, 655.
(2) (a) Amaro-Luis, J. M.; Koteich-Khatib, S.; Carrillo-Rodríguez,
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concentration of the appropriate fractions (R = 0.5 in 3:2 v/v
f
hexanes/EtOAc), carboxylic acid 3 (86 mg, 75%) as a clear, light-
1
13
yellow oil. H NMR (400 MHz, CDCl ) δ see Table 1; C NMR
3
(
1
−
3
100 MHz, CDCl ) δ see Table 2; IR (ATR) ν 2965, 2915, 1679,
3 max
−
1
600, 1408, 1263, 1214, 776 cm ; MS (ESI, −ve) m/z (%) 357 [M
−
H] (100), 101 (71), 62 (21); HRMS (TOF ESI, −ve) m/z
−
57.2051 [M − H] (calcd for C H O , 357.2060).
2
2
29
4
(
E)-4-Bromo-2-(2-hydroxy-3,7-dimethylocta-3,6-dien-1-yl)-6-(3-
methylbut-2-en-1-yl)phenol (13). A magnetically stirred solution of
allylic alcohol 11 (100 mg, 0.20 mmol) in THF (2 mL) was treated
F.; dos Santos Silva, B.; Gimenez, A.; Gutierrez-Yapu, D.; Salamanca,
́
E.; Malheiros, A. Evid. Based Complement. Alternat. Med. 2013, 2013,
265025.
with AcOH/H O (2 mL of a 1:1 v/v aqueous solution), and the
2
resulting mixture was heated at 50 °C for 18 h, cooled, and treated
(
3) Mizushina, Y.; Hirota, M.; Murakami, C.; Ishidoh, T.; Kamisuki,
with NaHCO (5 mL of a saturated aqueous solution) before being
3
S.; Shimazaki, N.; Takemura, M.; Perpelescu, M.; Suzuki, M.; Yoshida,
H.; Sugawara, F.; Koiwai, O.; Sakaguchi, K. Biochem. Pharmacol. 2003,
66, 1935.
extracted with EtOAc (3 × 20 mL). The combined organic phases
were dried (Na SO ), filtered, and concentrated under reduced
2
4
pressure. The residue was subjected to flash chromatography (silica,
5:5 v/v hexanes/EtOAc elution) to afford, after concentration of the
appropriate fractions (R = 0.8 in 9:1 v/v hexanes/EtOAc), diol 13
(
4) Mikusek, J.; Nugent, J.; Ward, J. S.; Schwartz, B. D.; Findlay, A.
9
D.; Foot, J. S.; Banwell, M. G. Org. Lett. 2018, 20, 3984.
(5) We thank a reviewer of our earlier paper for first suggesting this
possibility.
6) Sauer, S.; Weidner, C.; Kliem, M.; Schroeder, F. C.; Micikas, R.
J. WO 2014/177593 A1, 29 April, 2014.
7) Bates, R. W.; Gabel, C. J. Tetrahedron Lett. 1993, 34, 3547.
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61, 141.
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Wowro, S. J.; Siems, K.; Hetterling, G.; Kliem, M.; Schroeder, F. C.;
f
1
(
8
63 mg, 80%) as a light-yellow oil. H NMR (400 MHz, CDCl ) δ
3
.18 (s, 1H), 7.11 (d, J = 2.5 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 5.41
(
(
(
=
m, 1H), 5.29 (m, 1H), 5.05 (m, 1H), 4.30 (d, J = 9.3 Hz, 1H), 3.32
d, J = 7.3 Hz, 2H), 2.98 (m, 1H), 2.71 (t, J = 7.3 Hz, 2H), 2.61 (d, J
(
(
14.5 Hz, 1H), 2.30 (s, 1H), 1.76 (s, 3H), 1.71 (m, 9H), 1.63 (s,
3
1
3
H). 13C NMR (100 MHz, CDCl ) δ 152.7, 136.1, 133.3, 132.4,
3
31.9, 131.2, 130.8, 127.9, 125.8, 121.9(2), 121.8(6), 111.8, 80.3,
(
8.0, 28.7, 26.6, 25.8, 25.7, 17.8, 17.7, 12.0. These data matched those
4
recorded on an authentic sample.
Sauer, S. J. Nat. Prod. 2016, 79, 2.
(
10) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
ASSOCIATED CONTENT
(11) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
■
Timmers, F. J. Organometallics 1996, 15, 1518.
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.8b00778.
Biological evaluations of 3, 7, 8, and 10, and 12;
1
13
references; and H and C NMR spectra of 3, 7, 8, and
0−13 (PDF)
1
AUTHOR INFORMATION
■
*
Corresponding Author
Phone: +61-2-6125-8202. Fax: +61-2-6125-8114. E-mail:
Martin.Banwell@anu.edu.au.
ORCID
Ping Lan: 0000-0002-9285-3259
Martin G. Banwell: 0000-0002-0582-475X
E
DOI: 10.1021/acs.jnatprod.8b00778
J. Nat. Prod. XXXX, XXX, XXX−XXX