Chemoenzymatic total synthesis of the phytotoxic geranylcyclohexentriol (-)-phomentrioloxin

Article abstract of DOI:10.1021/np4002866

The enantiomeric form, 1R, of the structure (1S) assigned to the phytotoxic natural product phomentrioloxin has been synthesized in seven steps from the homochiral cis-1,2-dihydrocatechol 3. These studies reveal that the true structure of phomentrioloxin

Full text of DOI:10.1021/np4002866

Note
pubs.acs.org/jnp
Chemoenzymatic Total Synthesis of the Phytotoxic
Geranylcyclohexentriol (−)-Phomentrioloxin
Xinghua Ma, Martin G. Banwell,* and Anthony C. Willis
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra ACT 0200, Australia
S
* Supporting Information
ABSTRACT: The enantiomeric form, 1R, of the structure (1S)
assigned to the phytotoxic natural product phomentrioloxin has
been synthesized in seven steps from the homochiral cis-1,2-
dihydrocatechol 3. These studies reveal that the true structure of
phomentrioloxin is represented by 1R and not by 1S.
he rapidly increasing resistance of weeds and related pests
to those herbicides currently used for crop protection is a
shown in the ORTEP derived from the above-mentioned X-ray
analysis.6
T
source of great concern and has prompted the search for new
lead compounds.1,2 Natural products continue to offer
considerable potential in this regard.3 Various studies have
shown that species of the genus Phomopsis produce phytotoxic
metabolites.4 Furthermore, it has been suggested that a form of
this fungal pathogen found associated with symptomatic saffron
thistle (Carthamus lanatus) could be a useful source of
mycoherbicides for the biocontrol of this noxious weed which
causes economically significant crop and pasture losses in
Australia.5,6 On that basis, Evidente and co-workers recently
reported6 the isolation of the phytotoxic agent phomentrioloxin
(1S, Figure 1) from liquid cultures of a Phomopsis sp. and
Various biological evaluations of phomentrioloxin (1)
revealed6 that on application (at a concentration of 6.85
mM) to the leaves of both host and nonhost plants it causes
necrotic spots, inhibition of tomato rootlet elongation, ca. 90%
reduction of chlorophyll content, and a 50% reduction in the
fresh weight of the fronds of Lemna minor (common
duckweed), a potentially invasive species. In addition it was
shown that the compound was inactive as an antifungal or
antibacterial agent and nontoxic to brine shrimp larvae. The
above mentioned Mosher esters were similarly inactive. These
features, coupled with the observed variation in biological
activity as a function of structural modification,6 suggest that
phomentrioloxin (1) represents a useful lead for the develop-
ment of new, natural, and environmentally acceptable
herbicides.
The biological features of phomentrioloxin (1) prompted us
to establish an analogue development program using
modifications of the protocols we employed in our recently
completed synthesis of the structurally related epoxyquinol
tricholomenyn A (2).7 The starting material used for this
purpose was the cis-1,2-dihydrocatechol 3, a compound
obtained in enantiomerically pure and stereochemically well-
defined form through the whole-cell biotransformation of
iodobenzene.8 Herein we report the conversion of this same
metabolite into compound 1R, thereby establishing the
absolute stereochemistry of the title natural product.
The synthetic sequence leading to target 1R is shown in
Scheme 1 and begins with the conversion of diol 3 into the
corresponding and previously reported9 acetonide 4 (100%)
through treatment of the former compound with 2,2-
dimethoxypropane (2,2-DMP) in the presence of p-toluene-
sulfonic acid (p-TsOH) at 18 °C for 1 h. Dihydroxylation of the
Figure 1. Structures of compounds 1S, 2, and 3.
established its structure, including relative stereochemistry,
using a combination of spectroscopic techniques, most notably
single-crystal X-ray analysis. They also showed that the
compound was readily converted into the corresponding
acetonide and that the remaining free hydroxy group could
then be derivatized as the corresponding (+)- or (−)-Mosher
ester. Analysis of the differences in chemical shifts between
relevant resonances in the 1H NMR spectra of these
diastereomeric esters resulted in the illustrated absolute
configuration being assigned to the natural product. Curiously,
however, the other enantiomeric form (1R) of the compound is
Received: April 4, 2013
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
dx.doi.org/10.1021/np4002866 | J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Note
Scheme 1. Synthesis of (−)-Phomentrioloxin (1R) from the
cis-1,2-Dihydrocatechol 3
Figure 2. ORTEP derived from the single-crystal X-ray analysis of
compound 7 with labeling of selected atoms. Anisotropic displacement
ellipsoids display 30% probability levels. Hydrogen atoms are drawn as
circles with small radii.
diethylamine resulted in the formation of the desired trienyne
10, which was obtained as a viscous, light yellow oil in 88%
yield. Finally, treatment of compound 10R with 4:1 v/v acetic
acid−water at 70 °C for 5 h resulted in hydrolytic cleavage of
the acetonide group and formation of phomentrioloxin (1R),
which was obtained in 79% yield as a white, crystalline solid.13
A single-crystal X-ray analysis of this material revealed that it
was the same, in terms of structure (including relative
stereochemistry), as that reported by Evidente.6,10
Interestingly, the specific ordering of the steps associated
with the closing stages of the synthesis was not critical to
success. So, for example, if the cleavage of the acetonide group
within compound 8 was carried out first (Scheme 2), then the
resulting triol 11 (89%) could be engaged in a Sonogashira
cross-coupling reaction with terminal alkyne 9 to give target 1R
Scheme 2. Alternate Coupling Regimes for Obtaining
(−)-Phomentrioloxin (1R)
nonhalogenated and more electron-rich double bond within
diene 4 using the Upjohn protocol [involving OsO4 and N-
methylmorpholine N-oxide (NMO)] proceeded in a diastereo-
selective fashion to give the previously reported9 diol 5 (62%),
the allylic hydroxyl group of which could be selectively
protected as the corresponding triisopropylsilyl (TIPS) ether
upon reaction with TIPSOTf and 2,6-lutidine in dichloro-
methane (DCM) between −78 and 18 °C. The ether 6 (84%)
so-formed was treated with methyl iodide in the presence of
sodium hydride at 0 °C, thereby generating the desired and
crystalline bis-ether 7 in 90% yield. In order to ensure that the
required arrangement of ether residues had been established in
the course of the conversion 5 → 6 → 7, we undertook a
single-crystal X-ray analysis of the last compound.10 The
derived ORTEP is shown in Figure 2, and this served to
confirm the illustrated structure, including absolute stereo-
chemistry, for compound 7.
Treatment of bis-ether 7 with tetra-n-butylammonium
fluoride in THF at 18 °C for 2 h resulted in cleavage of the
TIPS group and the formation of the allylic alcohol 8 in 94%
yield. Subjection of the latter compound to Sonogashira cross-
coupling7,11 with the readily accessible terminal alkyne 912
using copper(I) iodide in the presence of PdCl2(Ph3P)2 and
B
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Journal of Natural Products
Note
in 88% yield. Similarly, Sonogashira cross-coupling reaction of
the fully protected cyclohexene-tetraol 7 with terminal alkyne 9
gave the anticipated product 12 (96%), which upon treatment
with 70% v/v aqueous acetic acid afforded triol 1R in 57% yield.
For the purposes of comparison with the previously reported6
derivative, compound 1R was converted into the corresponding
triacetate 13 (88%) under standard conditions.
configuration of the natural product phomentrioloxin was
incorrectly assigned. Accordingly, we deduce that the true
structure of phomentrioloxin is represented by 1R (and not by
1S). The discrepancy in the magnitudes of the two sets of
specific rotations shown in Table 2 remains unclear. The
possibility that naturally derived phomentrioloxin is a mixture
of R and S enantiomers (with the former predominating)
cannot be discounted at the present time.
The work reported here serves to further emphasize the
utility of enzymatically derived and stereochemically well-
defined cis-1,2-dihydrocatechols as starting materials in the
unambiguous total synthesis of various chiral, nonracemic
natural products.14,15
The 1H and 13C NMR spectroscopic data obtained on
compound 1R were completely consistent with the assigned
structure. They also proved to be a good match with those
reported6 for the natural product apart from a minor
discrepancy in the 13C NMR data set (Table 1). In particular,
Table 1. Comparison of the 13C NMR Data Recorded for
Synthetically Derived Compound 1R with Those Reported
for the Natural Product Phomentrioloxin
EXPERIMENTAL SECTION
General Experimental Procedures. Unless otherwise specified,
proton (1H) and carbon (13C) NMR spectra were recorded at 18 °C
in base-filtered CDCl3 on a Varian spectrometer operating at 400 MHz
■
δC
1
carbon
a
synthetically derived
naturally derived
c
for proton and 100 MHz for carbon nuclei. For H NMR spectra,
b
entry
no.
compound 1R
phomentrioloxin
Δδ
signals arising from the residual protio-forms of the solvent were used
as the internal standards. 1H 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. The
signal due to residual CHCl3 appearing at δH 7.26 and the central
resonance of the CDCl3 “triplet” appearing at δC 77.0 were used to
reference 1H and 13C NMR spectra, respectively. Infrared spectra
(νmax) were recorded on a Perkin−Elmer 1800 Series FTIR
spectrometer. Samples were analyzed as thin films on KBr plates.
Low-resolution ESI mass spectra were recorded on a Micromass LC-
ZMD single quadrupole liquid chromatograph−mass spectrometer,
while high-resolution measurements were conducted on an LCT
Premier time-of-flight instrument. Low- and high-resolution EI mass
spectra were recorded on an Autospec Premier Micromass magnetic-
sector machine. Optical rotations were recorded in CHCl3 at 20 °C on
a Perkin−Elmer model 343 polarimeter. Melting points were
measured on an Optimelt automated melting point system and are
uncorrected. Analytical thin-layer chromatography (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−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.16
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 chemical companies and were used as supplied. Drying
agents and other inorganic salts were purchased from the AJAX, BDH,
or Unilab chemical companies. Tetrahydrofuran (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.17 Where necessary, reactions were
performed under an argon atmosphere.
1
6
134.7
132.3
130.9
123.9
123.1
122.1
91.5
135.4
135.3
131.5
124.4
123.8
123.1
92.4
−0.7
−3.0
−0.6
−0.5
−0.7
−1.0
−0.9
−0.5
−0.6
−0.5
−0.5
−0.8
−0.8
−0.7
−0.7
−0.8
−0.7
2
5
3
3′
6′
8′
7′
2′
1′
3
4
5
6
7
8
86.8
87.3
9
78.5
79.1
10
11
12
13
14
15
16
17
1
68.4
69.1
2
67.4
67.9
4
64.0
64.8
OMe
4′
9′
10′
5′
58.5
59.3
37.2
37.9
26.7
27.4
25.6
26.4
17.7
b
18.4
a
Assignments from ref 6. Recorded in CDCl3 at 100 MHz and
referenced against the central peak of the “triplet” due to solvent (δC
77.0). Recorded in CDCl3 at 100 MHz and referenced against TMS
(δC 0.0).
c
and as highlighted in entry 2 of Table 1, the chemical shift
difference between the signals due to C5 is much larger than
the rest. The origins of this discrepancy remain unclear.
The specific rotations recorded on our samples of diol 1R,
the precursor acetonide 10R, and the derived triacetate 13R are
presented in Table 2 and compared with those reported6 for
their enantiomers. Clearly, each pair of compounds has the
same sign, and given that the chirality of the starting material 3
is well-defined, these results suggest that the absolute
Table 2. Comparison of the Specific Rotations Recorded for
Synthetically Derived Compounds 1R, 10R, and 13R with
Those Reported for Their Naturally Derived Counterparts
Compound 5. A magnetically stirred solution of diol 318 (2.00 g,
8.40 mmol) in 2,2-dimethoxypropane (25 mL) was treated with p-
toluenesulfonic acid (40 mg, 0.21 mmol). After stirring at 18 °C for 1
h, the reaction mixture was quenched with triethylamine (1 mL) and
then concentrated under reduced pressure. The residue thus obtained
was dissolved in CH2Cl2 (25 mL), and the resulting solution treated
with NH4Cl (50 mL of a saturated aqueous solution). The separated
aqueous phase was extracted with CH2Cl2 (1 × 10 mL), and the
combined organic phases were washed with NaHCO3 (1 × 50 mL of a
saturated aqueous solution) before being dried (MgSO4), filtered, and
then concentrated under reduced pressure. The residue so-formed,
and presumed to contain acetonide 4,9 was dissolved in acetone−water
a
bc
,
de
,
compound
[α]D
compound
[α]D
f
1R
−65 (c 0.5)
+34 (c 0.5)
−236 (c 0.2)
1S
−23 (c 0.4)
+21 (c 0.2)
−132 (c 0.3)
f
10R
13R
10S
f
13S
a
b
c
All optical rotations recorded in CHCl3. This work. Recorded at 20
°C. Obtained from ref 6. Recorded at 25 °C. Stereochemistry as
originally reported in ref 6.
d
e
f
C
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Journal of Natural Products
Note
(48 mL of an 83:17 v/v mixture), and the ensuing solution cooled to 0
°C and then treated with N-methylmorpholine N-oxide (NMO) (2.50
g, 21.34 mmol) and osmium tetroxide (21 mg, 0.08 mmol).19 Stirring
was continued for 18 h, during which time the reaction mixture was
allowed to warm to 18 °C and then treated with sodium metabisulfite
(5 mL of a saturated aqueous solution). After being allowed to stir at
18 °C for 1 h NH4Cl (80 mL of a saturated aqueous solution) was
added to the reaction mixture. The separated aqueous phase was
extracted with ethyl acetate (4 × 40 mL), and the combined organic
phases were then dried (MgSO4), filtered, and concentrated under
reduced pressure. Subjection of the light yellow oil thus obtained to
flash chromatography (silica, 1:50:50 v/v/v methanol−ethyl acetate−
hexane elution) and concentration of the appropriate fractions (Rf =
0.3 in 8:2.5:5.5 v/v/v ethyl acetate−CH2Cl2−hexane) afforded the title
compound 59 (1.63 g, 62% over two steps) as a white, crystalline solid:
mp 139−142 °C (lit.9 mp 139−141 °C); [α]D +25 (c 0.5, CHCl3)
{lit.9 [α]D +28 (c 0.62, CHCl3)}; 1H NMR (CDCl3, 400 MHz) δ 6.43
(m, 1H), 4.64 (d, J = 5.3 Hz, 1H), 4.40 (t, J = 5.3 Hz, 1H), 4.33 (m,
1H), 4.23 (m, 1H), 2.47 (m, 2H), 1.43 (s, 3H), 1.40 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 139.0, 110.0, 100.5, 78.3, 76.1, 69.3, 67.8,
27.6, 26.3; IR νmax 3503, 3380, 2984, 2923, 2884, 1633, 1447, 1369,
1233, 1156, 1131, 1079, 1052, 1025, 943, 895, 855 cm−1; MS (EI, 70
eV) m/z 312 (M+•, 14%), 297 (50), 254 (40), 110 (65), 101 (100);
HRMS M+• calcd for C9H13IO4 311.9859, found 311.9859.
Compound 6. Triisopropylsilyl trifluoromethanesulfonate (1.60
mL, 5.95 mmol) was added, dropwise, to a magnetically stirred
solution of compound 5 (982 mg, 3.15 mmol) and 2,6-lutidine (1.5
mL, 12.90 mmol) in CH2Cl2 (30 mL) maintained at −78 °C under a
nitrogen atmosphere. The ensuing mixture was allowed to warm to 18
°C over 3 h, then treated with NH4Cl (60 mL of a saturated aqueous
solution). The separated aqueous phase was extracted with CH2Cl2 (1
× 20 mL), and the combined organic phases were dried (MgSO4),
filtered, and concentrated under reduced pressure. The resulting light
yellow oil was subjected to flash chromatography (silica, 3:100 v/v
ethyl acetate−hexane elution) to give, after concentration of the
appropriate fractions (Rf = 0.3 in 0.5:2.5:5.5 v/v/v ethyl acetate−
CH2Cl2−hexane), compound 6 (1.24 g, 84%) as a white, crystalline
solid: mp 77−78 °C; [α]D −24 (c 0.5, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 6.28 (t, J = 1.7 Hz, 1H), 4.61 (m, 1H), 4.46−4.40 (complex
m, 2H), 4.27 (m, 1H), 2.67 (br s, 1H), 1.40 (s, 3H), 1.38 (s, 3H),
1.19−1.03 (complex m, 21H); 13C NMR (CDCl3, 100 MHz) δ 138.8,
109.7, 100.7, 77.8, 75.7, 69.1, 68.7, 27.5, 26.3, 17.9, 12.3, 12.1; IR νmax
3561, 2943, 2893, 2867, 1631, 1463, 1381, 1370, 1235, 1079, 1053,
947, 882, 862, 836 cm−1; MS (EI, 70 eV) m/z 453 [(M − CH3·)+,
4%], 367 (62), 240 (100), 131 (47); HRMS (M − CH3·)+ calcd for
C18H33IO4Si 453.0958, found 453.0959.
nitrogen atmosphere was treated with tetra-n-butylammonium fluoride
(3 mL of a 1.0 M solution in THF, 3.00 mmol). After 2 h the reaction
mixture was concentrated under reduced pressure and the residue so-
formed subjected to flash chromatography (silica, 1:2 v/v ethyl
acetate−hexane elution) to provide, after concentration of the
appropriate fractions (Rf = 0.4 in 4:2.5:5.5 v/v/v ethyl acetate−
CH2Cl2−hexane), compound 8 (620 mg, 94%) as a white, crystalline
solid: mp 65−66 °C; [α]D +51 (c 0.5, CHCl3); 1H NMR (CDCl3, 400
MHz) δ 6.42 (m, 1H), 4.57 (d, J = 4.9 Hz, 1H), 4.47 (t, J = 4.9 Hz,
1H), 4.27 (br s, 1H), 3.80 (t, J = 4.4 Hz, 1H), 3.53 (s, 3H), 2.72 (br s,
1H), 1.41 (s, 3H), 1.39 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
140.0, 109.9, 100.1, 78.5, 78.2, 73.6, 66.9, 59.2, 27.5, 26.3; IR νmax
3455, 2985, 2933, 2830, 1631, 1456, 1380, 1372, 1230, 1108, 1076,
1039, 959, 867 cm−1; MS (EI, 70 eV) m/z 326 (M+•, 7%), 311 [(M −
CH3·)+, 12], 223 (9), 115 (100), 43 (15); HRMS (M − CH3·)+ calcd
for C10H15IO4 310.9780, found 310.9781.
Compound 10R. CuI(I) (23 mg, 0.12 mmol) and PdCl2(Ph3P)2
(56 mg, 0.08 mmol) were added to a magnetically stirred solution of
compounds 8 (258 mg, 0.79 mmol) and 912 (212 mg, 1.58 mmol) in
diethylamine (10 mL) maintained at 18 °C under a nitrogen
atmosphere. After 3 h the reaction mixture was concentrated under
reduced pressure, and the residue thus obtained subjected to flash
chromatography (silica, 2:5 v/v ethyl acetate−hexane elution).
Concentration of the appropriate fractions (Rf = 0.5 in 4:2.5:5.5 v/
v/v ethyl acetate−CH2Cl2−hexane) afforded compound 10R6 (233
mg, 88%) as a clear, light yellow oil: [α]D +34 (c 0.5, CHCl3) {lit.6
1
[α]D (for 10S) +21 (c 0.2, CHCl3)}; H NMR (CDCl3, 400 MHz) δ
6.12 (d, J = 3.4 Hz, 1H), 5.36 (d, J = 2.0 Hz, 1H), 5.26 (m, 1H), 5.11
(m, 1H), 4.58 (d, J = 5.8 Hz, 1H), 4.49 (m, 1H), 4.40 (dd, J = 3.4 and
7.3 Hz, 1H), 3.68 (t, J = 4.4 Hz, 1H), 3.54 (s, 3H), 2.61 (d, J = 8.3 Hz,
1H), 2.24−2.17 (complex m, 4H), 1.69 (s, 3H), 1.62 (s, 3H), 1.43 (s,
3H), 1.40 (s, 3H); 13C NMR (CDCl3−TMS, 100 MHz) δ 135.6,
132.2, 131.2, 123.4, 122.5, 121.7, 109.7, 90.6, 87.3, 79.6, 73.7, 73.1,
64.7, 58.9, 37.3, 27.6, 26.7, 26.0, 25.7, 17.7; IR νmax 3456, 2984, 2932,
1632, 1605, 1453, 1379, 1232, 1107, 1076, 1039, 897, 873 cm−1; MS
(EI, 70 eV) m/z 317 [(M − CH3·)+, 6%], 257 (10), 185 (14), 115
(100); HRMS (M − CH3·)+ calcd for C20H28O4 317.1573, found
317.1570.
Compound 11. Compound 7 (208 mg, 0.43 mmol) was treated
with acetic acid−water (10 mL of a 7:3 v/v mixture), and the resulting
solution was heated at 70 °C for 18 h and then cooled and
concentrated under reduced pressure. Subjection of the residue thus
obtained to flash chromatography (silica, 1:6:3 v/v/v methanol−ethyl
acetate−hexane elution) delivered, after concentration of the
appropriate fractions (Rf = 0.4 in 1:7:2 v/v/v methanol−ethyl
acetate−hexane), compound 11 (110 mg, 89%) as a white, crystalline
solid: mp 145−147 °C; [α]D −82 (c 0.5, CHCl3); 1H NMR
[(CD3)2SO, 400 MHz)] δ 6.23 (d, J = 3.4 Hz, 1H), 5.16 (dd, J = 1.9
and 9.3 Hz, 1H), 4.94 (d, J = 4.9 Hz, 1H), 4.86 (d, J = 7.3 Hz, 1H),
4.19 (m, 1H), 3.92 (m, 2H), 3.42 (m, 1H), 3.36 (s, 3H); 13C NMR
[(CD3)2SO, 400 MHz)] δ 140.4, 105.6, 79.8, 72.3, 68.3, 66.7, 58.2; IR
νmax 3412, 3351, 3306, 2994, 2925, 1630, 1446, 1289, 1117, 1097,
1078, 1034, 995, 914, 822 cm−1; MS (ES, 70 eV) m/z 309 [(M +
Na)+, 100%]; HRMS (M + Na)+ calcd for C7H11IO4 308.9600, found
308.9600.
Compound 7. Sodium hydride (300 mg of a 60% dispersion in
mineral oil, 7.5 mmol) was added to a magnetically stirred solution of
compound 6 (1.16 g, 2.48 mmol) and iodomethane (460 μL, 7.39
mmol) in dry THF (25 mL) maintained at 0 °C under a nitrogen
atmosphere. Stirring was continued for 2 h at 0 °C then the reaction
mixture was treated with ice−water (60 mL). The separated aqueous
phase was extracted with ethyl acetate (1 × 25 mL), and the combined
organic phases were then dried (MgSO4), filtered, and concentrated
under reduced pressure. The ensuing light yellow oil was subjected to
flash chromatography (silica, 1:50 v/v ethyl acetate−hexane elution)
to give, after concentration of the appropriate fractions (Rf = 0.4 in
0.5:2.5:5.5 v/v/v ethyl acetate−CH2Cl2−hexane), compound 7 (1.07
g, 90%) as a white, crystalline solid: mp 81−83 °C; [α]D −36 (c 0.5,
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 6.43 (d, J = 3.0 Hz, 1H), 4.62
(dd, J = 1.2 and 5.3 Hz, 1H), 4.53 (ddd, J = 1.2, 2.9, and 4.1 Hz, 1H),
4.39 (m, 1H), 3.73 (m, 1H), 3.53 (s, 3H), 1.40 (s, 3H), 1.38 (s, 3H),
1.15−1.05 (complex m, 21H); 13C NMR (CDCl3, 100 MHz) δ 141.1,
109.5, 98.9, 80.2, 79.0, 75.0, 68.8, 59.7, 27.5, 26.0, 18.0, 12.2; IR νmax
2940, 2888, 2865, 1635, 1461, 1382, 1335, 1240, 1221, 1197, 1138,
1122, 1081, 954, 880, 858, 681 cm−1; MS (EI, 70 eV) m/z 467 [(M −
Compound 12. CuI(I) (9 mg, 0.05 mmol) and PdCl2(Ph3P)2 (22
mg, 0.03 mmol) were added to a magnetically stirred solution of
compounds 7 (150 mg, 0.31 mmol) and 9 (75 mg, 0.56 mmol) in
diethylamine (6 mL) maintained at 18 °C under a nitrogen
atmosphere. After 5 h the reaction mixture was concentrated under
reduced pressure, and the residue so formed was subjected to flash
chromatography (silica, 1:50 v/v ethyl acetate−hexane elution) to
give, after concentration of the appropriate fractions (Rf = 0.4 in
0.5:2.5:5.5 v/v/v ethyl acetate−CH2Cl2−hexane), compound 12 (146
1
mg, 96%) as a clear, light yellow oil: [α]D −46 (c 0.5, CHCl3); H
NMR (CDCl3, 400 MHz) δ 6.14 (m, 1H), 5.35 (d, J = 2.0 Hz, 1H),
5.24 (m, 1H), 5.13−5.09 (complex m, 1H), 4.62 (m, 2H), 4.42 (m,
1H), 3.63 (m, 1H), 3.53 (s, 3H), 2.25−2.16 (complex m, 4H), 1.68 (s,
3H), 1.62 (s, 3H), 1.41 (s, 3H), 1.38 (s, 3H), 1.20−1.04 (complex m,
21H); 13C NMR (CDCl3, 100 MHz) δ 137.6, 132.1, 131.3, 123.4,
•
CH3•)+, 2%], 439 (55), 254 (100), 222 (44), 145 (63); HRMS (M −
CH3 )+ calcd for C19H35IO4Si 467.1115, found 467.1116.
Compound 8. A magnetically stirred solution of compound 7 (972
mg, 2.02 mmol) in THF (10 mL) maintained at 18 °C under a
D
dx.doi.org/10.1021/np4002866 | J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Note
121.5, 121.4, 109.3, 90.1, 87.8, 81.3, 74.3, 74.2, 66.8, 59.4, 37.4, 27.4,
26.8, 25.7, 25.5, 18.0, 17.7, 12.3; IR νmax 2942, 2867, 1629, 1605, 1463,
1380, 1369, 1235, 1137, 1080, 882, 858, 680 cm−1; MS (EI, 70 eV) m/
z 488 (M+•, 3%), 445 (17), 439 (23), 387 (44), 254 (52), 145 (83),
117 (74), 115 (100), 75 (73); HRMS M+• calcd for C29H48O4Si
488.3322, found 488.3304.
ASSOCIATED CONTENT
* Supporting Information
Data derived from the single-crystal X-ray analyses of
compounds 1R and 7; 1H and 13C NMR spectra of compounds
1R, 6−8, 10R, 11, 12, and 13R. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
Compound 1R. Method A: Compound 10R (59 mg, 0.18 mmol)
was treated with acetic acid−water (5 mL of a 4:1 v/v mixture), and
the solution thus obtained was heated at 70 °C for 5 h and then cooled
and concentrated under reduced pressure. Subjection of the ensuing
light yellow residue to flash chromatography (silica, 1:6:3 v/v/v
methanol−ethyl acetate−hexane elution) delivered, after concentra-
tion of the appropriate fractions (Rf = 0.5 in 1:7:2 v/v/v methanol−
ethyl acetate−hexane), compound 1R6 (41 mg, 79%) as a white,
crystalline solid: mp 71−73 °C; [α]D −65 (c 0.5, CHCl3) {lit.6 [α]D
(for 1S) −23 (c 0.4, CHCl3)}; 1H NMR (CDCl3−TMS, 400 MHz) δ
6.15 (d, J = 4.4 Hz, 1H), 5.38 (d, J = 1.4 Hz, 1H), 5.28 (s, 1H), 5.10
(m, 1H), 4.49 (m, 1H), 4.32 (d, J = 3.4 Hz, 1H), 4.18 (m, 1H), 3.68
(m, 1H), 3.53 (s, 3H), 2.93 (br s, 1H), 2.86 (br s, 1H), 2.65 (br s, 1H),
2.20 (s, 4H), 1.69 (s, 3H), 1.62 (s, 3H); 13C NMR, see Table 1; IR
νmax 3402, 2965, 2915, 2191, 1671, 1632, 1604, 1444, 1377, 1244,
1106, 989, 910 cm−1; MS (EI, 70 eV) m/z 292 (M+•, <1%), 277 (8),
259 (12), 227 (16), 199 (35), 185 (72), 175 (63), 91 (71), 69 (100);
HRMS M+• calcd for C17H24O4 292.1675, found 292.1673.
Method B: CuI(I) (12 mg, 0.06 mmol) and PdCl2(Ph3P)2 (29 mg,
0.04 mmol) were added to a magnetically stirred solution of
compound 11 (118 mg, 0.41 mmol) and compound 9 (163 mg,
1.21 mmol) in diethylamine (10 mL) maintained under a nitrogen
atmosphere at 18 °C. After 3 h the reaction mixture was concentrated
under reduced pressure, and the residue thus formed was subjected to
flash chromatography (silica, 1:6:3 v/v/v methanol−ethyl acetate−
hexane elution). Concentration of the appropriate fractions (Rf = 0.5
in 1:7:2 v/v/v methanol−ethyl acetate−hexane) afforded compound
1R6 (107 mg, 88%) as a white, crystalline solid. This material was
identical in all respects with that obtained via method A as detailed
above.
AUTHOR INFORMATION
Corresponding Author
*Tel: +61-2-6125-8202. Fax: +61-2-6125-8114. E-mail: mgb@
rsc.anu.edu.au.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Australian Research Council and the Institute of
Advanced Studies for generous financial support.
■
REFERENCES
■
(1) Mortensen, D. A.; Egan, J. F.; Maxwell, B. D.; Ryan, M. R.; Smith,
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(10) CCDC 924849 and 924850 contain the crystallographic data for
1R and 7, respectively. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Method C: Compound 12 (197 mg, 0.40 mmol) was treated with
acetic acid−water (10 mL of a 7:3 v/v mixture), and the resulting
solution heated at 70 °C for 18 h then cooled and concentrated under
reduced pressure. Subjection of the residue thus obtained to flash
chromatography (silica, 1:6:3 v/v/v methanol−ethyl acetate−hexane
elution) delivered, after concentration of the appropriate fractions (Rf
= 0.5 in 1:7:2 v/v/v methanol−ethyl acetate−hexane), compound 1R6
(67 mg, 57%) as a white, crystalline solid. This material was identical
in all respects with that obtained via method A as detailed above.
Compound 13R. A magnetically stirred solution of compound 1R
(120 mg, 0.41 mmol) in pyridine (8 mL) maintained at 18 °C under a
nitrogen atmosphere was treated with acetic anhydride (0.5 mL, 5.29
mmol) and 4-(N,N-dimethylamino)pyridine (11 mg, 0.09 mmol).
Stirring was continued at 18 °C for 4 h then the reaction mixture was
concentrated under reduced pressure. The residue thus obtained was
subjected to flash chromatography (silica, 3:10 v/v ethyl acetate−
hexane elution) to give, after concentration of the appropriate fractions
(Rf = 0.5 in 4:2.5:5.5 v/v/v ethyl acetate−CH2Cl2−hexane),
compound 13R6 (136 mg, 88%) as a clear, colorless oil that solidified
on standing: [α]D −236 (c 0.2, CHCl3) {lit.6 [α]D (for 13S) −132 (c
́
(11) Kurti, L.; Czako, B. Strategic Applications of Named Reactions in
̈
Organic Synthesis; Elsevier: Amsterdam, 2005; pp 424−425.
(12) Miller, M. W.; Johnson, C. R. J. Org. Chem. 1997, 62, 1582−
1583.
(13) The melting range for this material was 71−73 °C. No
equivalent data appear to have been reported for the natural product.
(14) (a) Schwartz, B. D.; Jones, M. T.; Banwell, M. G.; Cade, I. A.
Org. Lett. 2010, 12, 5210−5213. (b) Schwartz, B. D.; White, L. V.;
Banwell, M. G.; Willis, A. C. J. Org. Chem. 2011, 76, 8560−8563.
(15) Palframan, M. J.; Kociok-Kohn, G.; Lewis, S. E. Org. Lett. 2011,
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13, 3150−3153.
(16) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923−
1
2925.
0.3, CHCl3)}; H NMR (CDCl3−TMS, 400 MHz) δ 6.13 (d, J = 4.4
(17) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518−1520.
(18) Compound 3 was obtained from Questor, Queen’s University of
Belfast, Northern Ireland. Questor Centre Contact Page: http://
questor.qub.ac.uk/Contact/ (accessed April 2, 2013).
(19) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973−1976.
Hz, 1H), 5.79 (d, J = 4.4 Hz, 1H), 5.71 (m, 1H), 5.46 (m, 1H), 5.32
(m, 1H), 5.28 (m, 1H), 5.07 (br s, 1H), 3.79 (dd, J = 4.4 and 8.8 Hz,
1H), 3.47 (s, 3H), 2.15−2.06 (complex m, 13H), 1.68 (s, 3H), 1.61 (s,
3H); 13C NMR (CDCl3−TMS, 100 MHz) δ 170.4, 170.0, 169.9,
132.4, 132.0, 130.7, 123.4, 123.1, 122.7, 92.4, 85.5, 74.8, 68.0, 67.9,
66.3, 59.1, 37.1, 26.7, 25.7, 21.0, 20.9, 20.7, 17.8; IR νmax 2931, 2854,
2256, 1749, 1637, 1605, 1436, 1370, 1226, 1118, 1043, 914, 733 cm−1;
MS (ESI) m/z 441 [(M + Na)+, 100%]; HRMS (M + Na)+ calcd for
C23H30O7 441.1889, found 441.1890.
E
dx.doi.org/10.1021/np4002866 | J. Nat. Prod. XXXX, XXX, XXX−XXX