Total Synthesis of the Cyclic Carbonate-Containing Natural Product Aspergillusol B from d -(-)-Tartaric Acid

Article abstract of DOI:10.1021/acs.jnatprod.7b00303

A total synthesis of compound 3 from d-(-)-tartaric acid is reported, thereby establishing that the structure, including relative stereochemistry, originally assigned to the cyclic carbonate-containing natural product aspergillusol B is correct.

Full text of DOI:10.1021/acs.jnatprod.7b00303

Article
pubs.acs.org/jnp
Total Synthesis of the Cyclic Carbonate-Containing Natural Product
Aspergillusol B from D‑(−)-Tartaric Acid
Joshua N. Buckler, Tamaryn Meek, Martin G. Banwell,* and Paul D. Carr
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 2601, Australia
S
* Supporting Information
ABSTRACT: A total synthesis of compound 3 from D-(−)-tartaric acid is
reported, thereby establishing that the structure, including relative stereo-
chemistry, originally assigned to the cyclic carbonate-containing natural
product aspergillusol B is correct.
n 2014 Rukachaisirikul and co-workers reported1 on the
isolation and structural elucidation of a series of metabolites
from the culture broth of the fungus Aspergillus sp. PSU-
RSPG185 found in soil samples collected from Surat Thani
Province in Thailand. Among these were (+)-asperpentyn (1)2
and two novel cyclic carbonate-containing compounds, named
aspergillusols A and B, and to which structures 2 and 3,
respectively, were assigned.3,4
chirons that are likely to have broad applications in chemical
synthesis. Of course, the enantiomeric forms of these chirons will
be available by using D-(−)-tartaric acid and in order to showcase
the utility of our protocols, we now report on their use to prepare,
for the first time, compound 3 in enantiomerically pure form
from this abundant and enantiomerically pure starting material.
I
RESULTS AND DISCUSSION
■
The synthetic route shown in Scheme 1 was used to convert
D-(−)-tartaric acid (5) into a series of chiral cyclohexenes, and
this parallels, exactly, the one employed to make the
enantiomeric systems. Thus, compound 5 was treated with a
mixture of diacetyl, trimethyl orthoformate, and catalytic
amounts of p-toluenesulfonic acid monohydrate in hot methanol
to give the Ley diacetal 6 in 72% yield. Treatment of a toluene
solution of the latter compound with 2 molar equiv of di-
isobutylaluminum hydride (DIBAl-H) at −78 °C and then with
7 molar equiv of vinylmagnesium bromide afforded, after
allowing the reaction mixture to warm to ambient temperatures,
a diastereoisomeric mixture of the anticipated bis-allylic alcohols
in 85% yield. This mixture was subjected to ring-closing
metathesis using Grubbs-II catalyst in dichloromethane at ca.
40 °C and by such means the analogous mixture of cyclohexene
diols 8 was obtained in 94% combined yield. Twofold oxidation
of this mixture using the Dess−Martin periodinane (DMP) in
dichloromethane at 0 °C afforded the corresponding enedione 9
(86% yield). Unsurprisingly, and in keeping with earlier
observations, compound 9 was prone to aromatization to the
isomeric hydroquinone through a 2-fold enolization process.
Accordingly, this centrosymmetric species was immediately
reduced with just over 1 molar equiv of the Luche reagent in
methanol at −78 °C, thereby delivering the γ-hydroxycyclohex-
enone 10 completely stereoselectively and in 84% yield.
All the of IR, NMR, and mass spectral data acquired on this
The following year we detailed5 the syntheses of compound 1
and the enantiomer, ent-2, of the structure assigned to the first of
these cyclic carbonates. The enzymatically derived and enanti-
omerically pure cis-1,2-dihydrocatechol 46 was used as the
starting material in this work, and by such means we were able to
confirm the structures of (+)-asperpentyn (1) and aspergillusol A
save for the absolute stereochemistry of the latter. This ambiguity
arose because of the significant difference in the specific rotation
recorded for the synthetically derived compound ent-2 {[α]D =
+192.5 (c 0.2, methanol} and that reported for the natural product
{[α]D = −4.6 (c 0.49, methanol}.
Recently, we reported7 procedures that allow for the con-
version of L-(+)-tartaric acid into a range of cyclohexene-based
Received: April 8, 2017
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.7b00303
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Scheme 1. Elaboration of D-(−)-Tartaric Acid (5) to Homochiral Cyclohexenone Derivatives
Scheme 2. Conversion of Compound 10 into Cyclic Carbonate 3
last compound matched those reported7 for its enantiomer
derived from L-(+)-tartaric acid. Furthermore, the specific
rotation of compound 10 was of equal magnitude but opposite
sign to that recorded7 for its enantiomer (viz., ent-10).
The conversion the γ-hydroxycyclohexenone 10 into the
target cyclic carbonate 3 followed the reaction pathway shown
in Scheme 2. Thus, the former compound was engaged in a
Mitsunobu reaction using p-nitrobenzoic acid as nucleophile, and
the enone-ester 11 (99%) so-formed subjected to a Johnson
α-iodination reaction using molecular iodine and pyridine in
dichloromethane in the presence of a catalytic amound of
4-(N,N-dimethylamino)pyridine (DMAP). By such means
compound 12 (99%) was obtained. Luche reduction of enone
12 in methanol at −78 °C proceeded in a completely stereo-
selective manner and after the intermediate diol monoester
was saponified, using aqueous sodium hydroxide, diol 13 was
obtained in 87% yield. Cleavage of the Ley diacetal unit within
the last compound was achieved using a mixture of trifluoroacetic
B
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acid (TFA) and water in dichloromethane at 22 °C and by such
means the iodocondurtitol 14 (95%) was obtained. Tetra-ol 14 is
a known compound but because the reported8 spectral data did
not match those we acquired on this material a single-crystal
X-ray analysis was carried out (Figure 1).9 This served to confirm
spectral data acquired on this cyclic carbonate were in complete
accord with the assigned structure. Diol 3 was converted, under
standard conditions, into the crystalline bis p-nitrobenzoate 16
(87%). While the spectral data acquired on this derivative were
also in complete accord with the illustrated structure, all efforts to
secure a single-crystal X-ray analysis of this crystalline material
were unsuccessful.
A comparison of the spectral data derived from compound 3
with the equivalent data reported1 for aspergillusol B by
Rukachaisirikul and co-workers revealed a very good match
(see Table 1). Unfortunately, this group did not report a specific
rotation for the naturally derived material. Accordingly, while the
absolute stereochemistry of the synthetic material is as illustrated,
the corresponding configuration of the natural product cannot be
defined at the present time.
CONCLUSIONS
■
The studies reported herein not only serve to confirm the
structure assigned to aspergillusol B but also highlight the
capacities of our recently reported protocols7 to deliver a range of
synthetically useful homochiral polyoxygenated cyclohexenes in
either enantiomeric form from D- or L-tartaric acid, each of which
is an abundant material. Efforts to further demonstrate the utility
of such chirons are currently under way in our laboratories and
results will be reported in due course.
Figure 1. ORTEP derived from the single-crystal X-ray analysis of com-
pound 14 (CCDC 1533559) with labeling of selected atoms. Anisotropic
displacement ellipsoids display 30% probability levels. Hydrogen atoms
are drawn as circles with small radii, and the hydrogen-bonding linking the
two molecules in the unit cell is shown by a dotted line.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Unless otherwise specified,
proton (1H) and carbon (13C) NMR spectra were recorded at room
temperature in base-filtered CDCl3 on a Varian spectrometer operating
at 400 MHz for proton and 100 MHz for carbon nuclei. The signal due
to residual CHCl3 appearing at δH 7.26 and the central resonance of the
the illustrated structure (including absolute stereochemistry) for
compound 14 obtained by the present pathway. Following pro-
tocols established in our earlier studies,5,10 iodide 14 was engaged
in a Sonogashira cross-coupling reaction with commercially avail-
able 2-methylbut-1-en-3-yne using copper(I) iodide, PdCl2(PPh3)2
and triethylamine in dimethylformamide (DMF). In this way
the rather insoluble dienyne 15 (80%) was obtained. In the final
step of the reaction sequence, compound 15 was treated with
bis(trichloromethyl)carbonate (triphosgene) in the presence
of triethylamine and using tetrahydrofuran (THF) as solvent.
Compound 3 was thereby obtained as a white powder in 26%
yield [56% based on recovered starting material (brsm)]. All the
CDCl3 triplet appearing at δC 177.1(6) were used to reference 1H and 13
C
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 = triplet; q = quartet; m = multiplet or combinations of the above.
Infrared spectra (νmax) were recorded on a Perkin−Elmer 1800 Series
FTIR spectrometer. Samples were analyzed as either thin films or finely
divided solids. Low-resolution ESI mass spectra were recorded on a
single quadrupole liquid chromatograph−mass spectrometer, while
Table 1. Comparison of the 13C and 1H NMR Data Recorded for Synthetically Derived Compound 3 with Those Reported1 for
Aspergillusol B
13C NMR (δC)
1H NMR (δH)
a
b
c
d
aspergillusol B
compound 3
aspergillusol B
compound 3
6.13, br s, 1H
153.4
130.2
125.7
124.5
124.3
96.7
153.6
130.3
125.7
124.5
124.3
96.6
6.06, dd, J = 3.9 and 2.1 Hz, 1H
5.36, quintet, J = 3.9, and 1.8 Hz, 1H
5.34, quintet, J = 1.8 Hz, 1H
5.44, br s, 1H
5.38, br s, 1H
5.15, ddd, J = 7.8, 3.9, and 2.1 Hz, 1H
4.64, dd, J = 8.7 and 7.8 Hz, 1H
4.03, dt, J = 8.7 and 1.8 Hz, 1H
4.19, m, 1H
5.21, dd, J = 7.5 and 3.4 Hz, 1H
4.71, apt t, J = 8.5 Hz, 1H
4.09, d, J = 8.4 Hz, 1H
82.5
82.6
77.3
77.4
3.76, t, J = 8.7 Hz, 1H
3.83, br t, J = 8.7 Hz, 1H
e
f
73.0
72.9
1.88, t, J = 1.2 Hz, 3H
1.95, s, 3H
e
72.8
72.9
69.0
69.0
23.1
23.0
a
b
c
Data obtained from ref 1, recorded in CDCl3 at 125 MHz. Data recorded in CDCl3 containing 1% (H3C)4Si at 100 MHz. Data obtained from
d
e
ref 1, recorded in CDCl3 at 500 MHz. Data recorded in CDCl3 containing 1% (H3C)4Si at 400 MHz. When the 13C NMR spectrum of compound
3 was recorded in slightly acidic CDCl3, these signals appeared as distinct resonances at δC 73.2 and 73.0 ppm. Signals due to hydroxy group protons
f
not observed.
C
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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. Melting points were measured on an
Optimelt automated melting point system and are uncorrected.
Analytical thin-layer chromatography 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 phosphomo-
lybdic acid−ceric sulfate−sulfuric acid (conc)−water (37.5 g:7.5 g:37.5
g:720 mL) or potassium permanganate−potassium carbonate−5%
sodium hydroxide aqueous solution−water (3 g:20 g:5 mL:300 mL).
Flash chromatographic separations were carried out following protocols
defined by Still et al.11 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,
Merck, TCI, Strem, or Lancaster Chemicals and were used as supplied.
Drying agents and other inorganic salts were purchased from AJAX,
BDH, or Unilab Chemicals. THF, methanol, and dichloromethane
were dried using a Glass Contour solvent purification system that is
based upon a technology originally described by Grubbs et al.12 Where
necessary, reactions were performed under a nitrogen atmosphere.
Synthesis of 1,1′-((2R,3R,5S,6S)-5,6-Dimethoxy-5,6-dimeth-
yl-1,4-dioxane-2,3-diyl)bis(prop-2-en-1-ol) (7). The previously
reported13 diester 6 (3.41 g, 11.7 mmol), which is readily derived
from D-tartaric acid (5), was treated, successively, with di-isobutylalu-
minum hydride in toluene and then with vinyl magnesium bromide as
described6 for the reaction of compound ent-6. By such means com-
pound 7 (2.87 g, 85%) was obtained as a mixture of three diastereo-
Concentration of the relevant fractions (Rf = 0.3 in 1:19 v/v diethyl
ether/dichloromethane) afforded p-nitrobenzoate 11 (750 mg, 99%).
11: white, crystalline solid, mp 183−185 °C; [α]20 +156 (c 0.6,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.33 (m, 2H), 8.24 (m, 2H),
7.03 (dd, J = 10.1 and 5.8 Hz, 1H), 6.26 (d, J = 10.1 Hz, 1H), 5.83 (dd, J
= 5.8 and 3.8 Hz, 1H), 4.93 (d, J = 11.0 Hz, 1H), 4.24 (dd, J = 11.0 and
3.8 Hz, 1H), 3.37 (s, 3H), 3.27 (s, 3H), 1.43 (s, 3H), 1.25 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 193.5, 164.4, 150.9, 139.4, 135.5, 133.0,
131.1, 123.8, 100.5, 100.0, 70.3, 67.9, 67.3, 48.8, 48.4, 17.7, 17.6; IR νmax
2980, 1721, 1710, 1610, 1528, 1344, 1278, 1111, 1091, 1027, 721 cm−1;
MS (ESI, +ve) m/z 431 and 430 [(M + Na)+, 20 and 100%]; HRMS
calcd for C19H21NNaO9 430.1114, found 430.1118.
Synthesis of (2S,3S,4aR,5R,8aS)-7-Iodo-2,3-dimethoxy-2,3-
dimethyl-8-oxo-2,3,4a,-5,8,8a-hexahydrobenzo[b][1,4]dioxin-
5-yl 4-Nitrobenzoate (12). A solution of molecular iodine (415 mg,
1.64 mmol) in dichloromethane/pyridine (4 mL of a 1:1 v/v mixture)
was added over 0.25 h to a magnetically stirred solution of compound 11
(268 mg, 0.66 mmol) and DMAP (4 mg, 0.03 mmol) in dichloro-
methane/pyridine (10 mL of 7:3 v/v mixture) maintained at 0 °C. The
ensuing mixture was stirred for 16 h at 0 °C and after which time it was
allowed to warm to 22 °C. The resulting solution was diluted with ethyl
acetate (40 mL) and washed successively with HCl (2 × 10 mL of a 1 M
aqueous solution), water (1 × 10 mL) and Na2SO3 (2 × 10 mL of a
saturated aqueous solution). The combined aqueous phases were
extracted with ethyl acetate (3 × 10 mL), and combined organic phases
washed with brine (3 × 10 mL) then dried (Na2SO4), filtered, and
concentrated under reduced pressure. Heptane (20 mL) was added to
the ensuing residue and the mixture thus obtained concentrated under
reduced pressure (so as to remove any remaining traces of pyridine)
1
isomers. 7: clear, colorless oil; the H and 13C NMR spectral data
to give compound 12 (351 mg, 99%). 12: white foam; [α]20 −59.0
obtained on this material were identical with those reported7 for the
corresponding mixture of enantiomers.
D
1
(c 0.9, CHCl3); Rf 0.6 in 1:19 v/v diethyl ether/dichloromethane; H
NMR (400 MHz, CDCl3) δ 8.33 (m, 2H), 8.23 (m, 2H), 7.81 (d, J =
6.2 Hz, 1H), 5.68 (dd, J = 6.2 and 3.9 Hz, 1H), 4.98 (d, J = 11.0 Hz, 1H),
4.24 (dd, J = 11.0 and 3.9 Hz, 1H), 3.37 (s, 3H), 3.26 (s, 3H), 1.42
(s, 3H), 1.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 187.4, 164.2,
150.9, 147.3, 135.2, 131.2, 123.8, 110.3, 100.6, 99.9, 69.5, 69.1, 66.8,
48.9, 48.5, 17.6, 17.5; IR νmax 2952, 1718, 1607, 1528, 1342, 1264, 1141,
1101, 1035, 719 cm−1; MS (ESI, +ve) m/z 588 [(M + methanol + Na)+,
70%], 557 and 556 [(M + Na)+, 25 and 100], 430 (50); HRMS calcd for
C19H20INNaO9 556.0080, found 556.0081.
Synthesis of (2S,3S,4aR,8aR)-2,3-Dimethoxy-2,3-dimethyl-
2,3,4a,5,8,8a-hexa-hydrobenzo[b][1,4]dioxine-5,8-diol (8).
Compound 7 (5.50 g, 19.1 mmol) was subjected to ring-closing
metathesis using the Grubbs-II catalyst (in dichloromethane at 40 °C) in
the same manner as applied to its enantiomer (ent-7) and thereby
affording cyclohexene 8 (4.68 g, 94%) as a mixture of three
1
diastereoisomers. 8: white, amorphous solid; the H and 13C NMR
spectral data obtained on this material were identical with those
reported7 for the corresponding mixture of enantiomers.
Synthesis of (2S,3S,4aR,5R,8R,8aR)-6-Iodo-2,3-dimethoxy-
2,3-dimethyl-2,3,4a,- 5,8,8a -hexahydrobenzo[b][1,4]dioxine-
5,8-diol (13). Sodium borohydride (15 mg, 0.40 mmol) was added, in
portions over 0.08 h, to a magnetically stirred solution of enone 12
(100 mg, 0.19 mmol) and CeCl3·7H2O (70 mg, 0.19 mmol) in methanol
(5 mL) maintained at −78 °C. After 0.5 h the reaction mixture was
allowed to warm to 22 °C and water (0.5 mL) then added dropwise.
When evolution of hydrogen gas had subsided (ca. 0.25 h), NaOH
(0.5 mL of a 1 M aqueous solution) was added to the reaction mixture
and the resulting solution stirred for 2 h at 22 °C then diluted with ethyl
acetate (20 mL) and washed with NaHCO3 (2 × 5 mL of a saturated
aqueous solution). The combined aqueous washings were extracted
with ethyl acetate (3 × 5 mL) and then combined organic layers then
washed with brine (3 × 5 mL) before being dried (Na2SO4), filtered and
concentrated under reduced pressure. The residue thus obtained was
subjected to flash column chromatography (silica, dichloromethane →
1:9 v/v methanol/dichloromethane gradient elution) and concen-
tration of the relevant fractions (Rf = 0.2 in 1:19 v/v methanol/
Synthesis of (2S,3S,4aS,8aS)-2,3-Dimethoxy-2,3-dimethyl-
2,3,4a,8a-tetrahydrobenzo[b][1,4]dioxine-5,8-dione (9). Com-
pound 8 (1.26 g, 4.85 mmol) was subjected to 2-fold oxidation using
three molar equivalents of DMP in the same manner as employed for its
enantiomer (ent-8) and thus affording enedione 9 (1.07 g, 86%). 9: bright
yellow, crystalline solid, mp 162−165 °C, lit.7 mp (for enantiomer) 115−
117 °C (dec.); [α]D +115 (c 1.1 in CHCl3), lit.7 [α]D (for enantiomer)
−121.0 (c 0.9 in CHCl3); the 1H and 13C NMR spectral data obtained on
this material were identical with those reported7 for its enantiomer.
Synthesis of (2S,3S,4aS,8S,8aR)-8-Hydroxy-2,3-dimethoxy-
2,3-dimethyl-2,3,8,8a-tetrahydrobenzo[b][1,4]dioxin-5(4aH)-
one (10). Compound 9 (1.74 g, 6.77 mmol) was subjected to reduction
under the same conditions as used for its enantiomer (ent-9), viz. using a
slight excess of the Luche reagent, thus producing γ-hydroxyenone 10
(1.47 g, 84%). 10: white and crystalline solid, mp 171−172 °C; [α]D
+225.5 (c 1.0 in CHCl3), lit.7 [α]D (for enantiomer) −215.0 (c 0.5 in
CHCl3); the 1H and 13C NMR spectral data obtained on this material
were identical with those reported7 for its enantiomer.
Synthesis of (2S,3S,4aR,5R,8aS)-2,3-Dimethoxy-2,3-dimeth-
yl-8-oxo-2,3,4a,5,8,8a-hexahydrobenzo[b][1,4]dioxin-5-yl 4-Ni-
trobenzoate (11). A magnetically stirred solution of compound 10
(480 mg, 1.86 mmol), triphenylphosphine (585 mg, 2.23 mmol), and
p-nitrobenzoic acid (373 mg, 2.23 mmol) in dry THF (40 mL) was
cooled to 0 °C then diethyl azodicarboxylate (DEAD) (360 μL, 2.23
mmol) was added over 0.25 h. The resulting solution was stirred at 0 °C
for 0.5 h before being allowed to warm to 22 °C then stirred at this
temperature for another 1.5 h. The solution thus obtained was
concentrated under reduced pressure and the light yellow solid thus
obtained was subjected to flash chromatography (silica, dichloro-
methane → 1:19 v/v diethyl ether/dichloromethane gradient elution).
dichloromethane) afforded compound 13 (62 mg, 87%). 13: white,
1
amorphous solid; [α]20 +85.8 (c 0.4, CHCl3); H NMR (400 MHz,
D
CDCl3) δ 6.62 (dd, J = 5.8 and 1.8 Hz, 1H), 4.17−4.04 (complex m,
3H), 3.68 (dd, J = 10.8 and 4.1 Hz, 1H), 3.30 (s, 3H), 3.27 (s, 3H), 2.57
(br d, J = 1.7 Hz, 1H), 2.47 (d, J = 4.5 Hz, 1H), 1.34 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 137.1, 109.5, 99.8, 99.4, 74.5, 68.2, 67.5(1),
67.4(9), 48.3, 48.2, 17.9, 17.7; IR νmax 3429, 2949, 1376, 1115, 1028,
919, 849, 815, 656 cm−1; MS (ESI, +ve) m/z 409 [(M + Na)+, 100%];
HRMS calcd for C12H19INaO6 409.0124, found 409.0123.
Synthesis of (1R,2R,3S,4R)-5-Iodocyclohex-5-ene-1,2,3,4-tet-
raol (14). Water (200 μL) then trifluoroacetic acid (200 μL) were
added successively to a magnetically stirred solution of compound 13
D
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(66 mg, 0.17 mmol) in dichloromethane (3 mL) maintained under a
stream of nitrogen at 22 °C. The mixture thus obtained was allowed to
evaporate to dryness (ca. 0.25 h), the ensuing residue diluted with
dichloromethane (3 mL) and the resulting solution again treated with
water (200 μL) then trifluoroacetic acid (200 μL). After evaporation to
dryness (ca. 0.25 h) the residue was subjected to flash chromatography
(silica, 10:9:1 v/v hexane/ethyl acetate/methanol → 1:8:1 v/v hexane/
ethyl acetate/methanol gradient elution). Concentration of the
relevant fractions (Rf = 0.3 in 1:8:1 v/v hexane/ethyl acetate/methanol)
afforded compound 14 (44 mg, 95%). 14: white, crystalline solid, mp =
139−141 °C (from ethyl acetate−hexane), lit. mp8 145−149 (from
acetone/methanol); [α]20 −39.5 (c 0.6, methanol), lit.8 [α]20 −45
(5.1 mg, 0.022 mmol) and triethylamine (100 μL, 0.72 mmol) in dry
dichloromethane (2 mL) maintained at 0 °C was treated sequentially
with p-nitrobenzoyl chloride (16 mg, 0.086 mmol) and DMAP (one
crystal, ca. 0.1 mg). The ensuing mixture was allowed to warm to 22 °C,
stirred at this temperature for 4 h then diluted with diethyl ether (5 mL)
and quenched with phosphate buffer (5 mL of a 1 M, pH 7 aqueous
solution). The separated aqueous layer was extracted with diethyl ether
(3 × 1 mL) and the combined organic phases were then dried (Na2SO4),
filtered and concentrated under reduced pressure. The light yellow
residue thus obtained was subjected to flash chromatography (silica, 7:3
v/v hexane/ethyl acetate elution) and concentration of the relevant
fractions (Rf = 0.6) gave compound 16 (10 mg, 87%). 16: white,
D
D
1
amorphous solid; [α]20 +77.7 (c 0.5, CDCl3); H NMR (400 MHz,
(c 0.5, methanol); 1H NMR (400 MHz, CD3OD) δ 6.54 (dd, J = 5.3 and
1.2 Hz, 1H), 4.05 (dd, J = 5.4 and 4.1 Hz, 1H), 3.82−3.77 (complex m,
2H), 3.55 (m, 1H) (signals due to hydroxy group protons not
observed); 13C NMR (100 MHz, CD3OD) δ 139.5, 109.8, 78.5, 73.4,
72.1, 69.7; IR νmax 3279, 2907, 1618, 1264, 1089, 1066, 1046, 1019, 821
cm−1; MS (ESI, +ve) m/z 295 [(M + Na)+, 100%]; HRMS calcd for
C6H9INaO4 294.9443, found 294.9443.
D
CDCl3) δ 8.30−8.25 (complex m, 4H), 8.21−8.17 (complex m, 2H),
8.17−8.13 (complex m, 2H), 6.39 (dd, J = 4.1 and 1.8 Hz, 1H), 5.99
(ddd, J = 8.0, 1.8, and 1.3 Hz, 1H), 5.83 (dd, J = 8.1 and 8.0 Hz, 1H), 5.43
(ddd, J = 7.9, 4.1, and 1.3 Hz, 1H), 5.22 (app p, J = 1.3 Hz, 1H), 5.12
(br t, J = 1.3 Hz, 1H), 5.09 (dd, J = 8.1 and 7.9 Hz, 1H), 1.67 (app t, J =
1.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 163.8, 163.4, 152.5, 151.2,
133.9, 133.8, 131.2(4), 131.1(9), 126.9, 126.2, 125.4, 125.1, 123.9(4),
123.9(2), 97.2, 82.4, 74.2, 72.3, 71.0, 68.9, 22.7 (one signal obscured or
overlapping); IR νmax 3932, 2852, 1809, 1732, 1607, 1524, 1347, 1259,
1095, 1051, 907, 716 cm−1; MS (ESI, +ve) m/z 557 [(M + Na)+, 100],
337(70); HRMS calcd for C26H18N2NaO11 557.0803, found 557.0808.
Crystallographic Studies. Crystallographic Data. Compound 14:
C6H9IO4, M = 272.03, T = 150 K, monoclinic, space group P21, Z = 4, a
= 9.4654(3) Å, b = 7.09196(19) Å, c = 13.2976(5) Å; V = 835.51(5) Å3,
Dx = 2.163 g cm−3, 3355 unique data (2θmax = 147.8°), R = 0.081
[for 3304 reflections with I > 2.0σ(I)]; Rw = 0.225 (all data), S = 1.05.
Structure Determination. Diffraction images for compound 14 were
measured on a diffractometer (Cu Kα, mirror monochromator, λ =
1.54184 Å) fitted with an area detector, and the data extracted using the
DENZO/Scalepack package.14 The structure solution was solved by
direct methods (SIR92),15 then refined using the CRYSTALS program
package.16 Atomic coordinates, bond lengths and angles, and displace-
ment parameters have been deposited at the Cambridge Crystallo-
graphic Data Centre (CCDC no. 1533559). These data can be obtained
free-of-charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: +44 1223 336033.
Synthesis of (1R,2R,3R,4S)-5-(3-Methylbut-3-en-1-yn-1-yl)-
cyclohex-5-ene-1,2,3,4-tetraol (15). A magnetically stirred mixture
of iodide 14 (34 mg, 0.125 mmol) and triethylamine (2 mL) in DMF
(1 mL) maintained at 22 °C was degassed by sonication under an
atmosphere of nitrogen for 0.5 h, then treated with CuI (5 mg, 0.046
mmol), PdCl2(Ph3P)2 (21 mg, 0.030 mmol) and 2-methyl-1-buten-3-
yne (150 μL, 1.58 mmol). The resulting solution was stirred at 22 °C for
4 h and then the volatiles were removed under reduced pressure. The
residue thus obtained was dissolved in THF (1 mL) and subjected to
flash column chromatography (silica, 45:50:5 v/v hexane/ethyl acetate/
methanol → 23:70:7 v/v hexane/ethyl acetate/methanol gradient
elution). Concentration of the relevant fractions (Rf = 0.3 in 1:8:1 v/v
hexane/ethyl acetate/methanol) afforded compound 15 (50 mg, 80%).
15: white, amorphous solid; [α]20D −57.1 (c 0.6, methanol); 1H NMR
(400 MHz, CD3OD) δ 6.06 (dd, J = 5.2 and 1.8 Hz, 1H), 5.30 (m, 1H),
5.27 (m, 1H), 4.23 (app t, J = 4.4 Hz, 1H), 3.85 (dd, J = 7.2 and 1.8 Hz,
1H), 3.71 (dd, J = 9.8 and 7.2 Hz, 1H), 3.49 (dd, J = 9.8 and 4.4 Hz, 1H),
1.91 (app t, J = 1.3 Hz, 3H) (signals due to hydroxy group protons not
observed); 13C NMR (100 MHz, CD3OD) δ 134.1, 128.3(3), 128.3(1)
122.5, 92.5, 87.5, 74.4, 73.4, 72.1, 67.6, 23.5; IR νmax 3249, 2883, 1664,
1630, 1608, 1429, 1258, 1092, 1051, 898, 633 cm−1; MS (ESI, +ve) m/z
443 [(2 M + Na)+, 50%], 233 [(M + Na)+, 100]; HRMS calcd for
C11H14NaO4 233.0790, found 233.0790.
Synthesis of (3aS,4R,5S,7aR)-4,5-Dihydroxy-6-(3-methylbut-
3-en-1-yn-1-yl)-3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxol-2-one
(3). A magnetically stirred solution of tetraol 15 (37 mg, 0.18 mmol) in
THF (2 mL) maintained at −78 °C was treated with triethylamine
(90 μL, 0.65 mmol) and then with a solution of triphosgene (27 mg
0.09 mmol) in THF (1 mL). The resulting mixture was stirred at −78 °C
for 0.5 h then allowed to warm to 0 °C and stirred at this temperature
for another 0.5 h. The suspension thus obtained was poured into ice-
cold NH4Cl (10 mL of a saturated aqueous solution) and extracted with
ethyl acetate (3 × 5 mL). The combined organic phases were dried
(Na2SO4), filtered and concentrated under reduced pressure and the
residue thus obtained was subjected to flash chromatography (silica,
hexane → 65:35 v/v hexane/ethyl acetate gradient elution) to afford two
fractions, A and B. Concentration of fraction A (Rf = 0.3 in 10:9:1 v/v
hexane/ethyl acetate/methanol) afforded compound 3 (11 mg, 26% or
56% brsm). Concentration of fraction B (Rf = 0.1 in 10:9:1 v/v hexane/
ethyl acetate/methanol) afforded the starting material 15 (20 mg, 54%
recovery). The 1H and 13C NMR spectral data obtained on this material
were identical with those derived from an authentic sample. 3: white
powder, mp 115−117 °C (dec); [α]20D −12 (c 0.5, CDCl3); 1H NMR
(400 MHz, CDCl3) see Table 1; 13C NMR (100 MHz, CDCl3) see
Table 1; IR νmax 3412, 2957, 2922, 2199, 1791, 1628, 1357, 1169, 1046,
889, 772, 727 cm−1; MS (ESI, +ve) m/z 495 [(2 M + Na)+, 70%], 259
[(M + Na)+, 100], 102 (75); HRMS calcd for C12H12NaO5 259.0582,
found 259.0583.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.jnatprod.7b00303.
Data derived from the single-crystal X-ray analyses of
compound 14; 1H and 13C NMR spectra of compounds 3
and 11−16 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*Tel: +61-2-6125-8202. Fax: +61-2-6125-8114. E-mail: Martin.
Banwell@anu.edu.au.
ORCID
Martin G. Banwell: 0000-0002-0582-475X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Australian Research Council and the Institute of
Advanced Studies for financial support. J.N.B. is the grateful
recipient of an APA Scholarship provided by the Australian
Government.
Synthesis of (3aR,4R,5S,7aR)-6-(3-Methylbut-3-en-1-yn-1-yl)-
2-oxo-3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxole-4,5-diyl Bis(4-
nitrobenzoate) (16). A magnetically stirred solution of compound 3
E
DOI: 10.1021/acs.jnatprod.7b00303
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
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DOI: 10.1021/acs.jnatprod.7b00303
J. Nat. Prod. XXXX, XXX, XXX−XXX