Cationic Polyene Cyclization for Taiwaniaquinoid Construction

Article abstract of DOI:10.1002/ejoc.201601349

An acid-catalyzed polyene cyclization has been used to rapidly generate the 6/5/6-fused ring system of the taiwaniaquinoid natural products. The cis-fused diastereomer was formed selectively, which enabled a step-efficient synthesis of (±)-5-epi-taiwaniaq

Full text of DOI:10.1002/ejoc.201601349

DOI: 10.1002/ejoc.201601349
Full Paper
Cationic Polyene Cyclizations
Cationic Polyene Cyclization for Taiwaniaquinoid Construction
Marlowe Graham,[a] Robert W. Baker,[a] and Christopher S. P. McErlean*[a]
Abstract: An acid-catalyzed polyene cyclization has been used formed selectively, which enabled a step-efficient synthesis of
to rapidly generate the 6/5/6-fused ring system of the taiwania-
( )-5-epi-taiwaniaquinone G.
quinoid natural products. The cis-fused diastereomer was
Introduction
taiwaniaquinone G (6) in just 14 steps. Demonstrating the diffi-
culty of applying biomimetic strategies, Alvarez-Manzaneda
subsequently reported a biomimetically inspired synthesis from
(+)-abietic acid (8) that gave (–)-taiwaniaquinone G (6) in 23
steps overall.[3c] The cis-fused isomer, ( )-5-epi-taiwaniaquinone
The taiwaniaquinoids are a family of 18 rearranged abietane-
type diterpenes possessing a 4a-methyltetrahydrofluorene skel-
eton, i.e., a 6/5/6-ring system (Figure 1).[1] This ring system oc-
curs in nature much less frequently than the corresponding
6/6/6-fused system,[2] and this has led to speculation that
taiwaniaquinoid biosynthesis involves a ring contraction.[3] Sev-
eral elegant biomimetic syntheses that exploit such a ring con-
traction have been reported.[4] Most members of the family
contain a trans-fused 5/6-ring system (e.g., 1 and 2), but there
are several taiwaniaquinones that have a cis-fused 5/6-ring
junction (e.g., 4 and 5). Our particular attention was taken by
the norditerpene taiwaniaquinone G (6).[5] This molecule has
not only undergone biosynthetic excision of a carbon atom, but
it also lacks the unsaturation and/or oxygen functionality that
would be immediately amenable to biomimetic chemistry.
G
(9), has also been synthesized on three occasions
(Scheme 1).[7] In each case, hydrogenation of an alkene precur-
sor installed the cis-5/6-ring junction: Alvarez-Manzaneda and
coworkers hydrogenated compound 10;[3c] Chang, Song, and
coworkers hydrogenated compound 11;[7b] and Bisai and co-
workers reported the hydrogenation of compound 12.[7a]
Scheme 1. Previous syntheses of taiwaniaquinone G (6) and 5-epi-taiwania-
quinone G (9).
Figure 1. Taiwaniaquinones A–F (1–5) and G (6).
We wondered whether the trans-fused 5/6-ring system could
be installed directly from an appropriate geranylbenzene deriv-
ative such as 13 (Scheme 1) by using a cationic polyene cycliza-
tion.[8] Surprisingly, this particular polyene cyclization has not
been reported. Longer polyene systems have been cyclized to
give 6/5/6/6-ring systems[9] and steroidal frameworks with ex-
cellent trans selectivity.[10] Our strategy was to initiate a polyene
cyclization by using simple Brønsted- or Lewis-acid catalysis.
Taiwaniaquinone G (6) has been the target of two previous
syntheses (Scheme 1). The first approach by Alvarez-Manzaneda
and coworkers in 2009 used (+)-sclareolide (7) as a chiral-pool
source with the necessary trans configuration.[6] Installation of
the quinone ring by using an electrocyclization delivered (–)-
[a] School of Chemistry, The University of Sydney,
New South Wales 2006, Australia
E-mail: christopher.mcerlean@sydney.edu.au
Results and Discussion
We planned to install the required polyene unit by using a
Suzuki coupling, so geraniol (14) was converted into the corre-
http://sydney.edu.au/science/chemistry/~mcerlean
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201601349.
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sponding boronate ester 16 (Scheme 2).[11] The synthesis of the the reaction consisted of a mixture of monocyclized products,
second coupling partner is shown in Scheme 3.
alkene-rearranged products, and the cleaved aromatic unit 19.
Table 1. Polyene cyclization conditions.
Entry
Catalyst[a]
Solvent
Temp.
[°C]
Yield of 21 + 22
[%][b]
1
2
3
4
5
6
7
8
TsOH
TsOH
toluene
EtNO2
EtNO2
EtNO2
EtNO2
EtNO2
EtNO2
THF
EtNO2
THF
EtNO2
THF
110
112
100
80
60
40
decomp.
decomp.
33
33
27
4
0
n.r.
0
n.r.
50
n.r.
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
AlCl3
AlCl3
BF3·OEt2
BF3·OEt2
room temp.
Scheme 2. Synthesis of cyclization polyene chain 16. pin = pinacolato.
66
r.t.
r.t.
r.t
9
10
11
12
r.t.
[a] 10 mol-% catalyst loading, reaction time 18 h. [b] Yield of isolated prod-
ucts. n.r. = no reaction.
NMR spectroscopic analysis of the 6/5/6-containing com-
pound 21 demonstrated that the cyclization had produced a
6.7:1 mixture of diastereomers at the ring junction. Surprisingly,
NOESY experiments unambiguously demonstrated that the pre-
dominant product 21 had
a cis-fused 5/6-ring junction
(Scheme 4). This result contrasts with the work of Xie, She, and
coworkers, who reported the cyclization of the extended poly-
ene 23 during their synthesis of (–)-walsucochin B.[9a] In that
instance, compound 24, with a trans-fused 5/6-ring junction,
was the exclusive product; the authors rationalized this result
on the basis of a chair-like transition state. Similarly Anderson
and coworkers reported the cationic polyene cyclization of 25;
they obtained the trans-fused compound 26.[9b] Friedel–Crafts
alkylation of the cation generated from compound 27 also gave
a trans-fused 5/6-ring junction. The fact that 19, 22, and mono-
cyclized compounds were isolated from the reaction of 13 to
Scheme 3. Synthesis of cyclization substrate 13. TMEDA = tetramethylethyl-
enediamine.
3-Methoxyanisole (17) underwent ortho-lithiation and reac-
tion with acetone to give 18. Elimination and in-situ transfer
hydrogenation gave compound 19, which was smoothly con-
verted into aryl bromide 20. An sp2–sp3 Suzuki coupling with
16 gave the desired cyclization precursor 13 in good yield.
Our attempts to effect the polyene cyclization are detailed
in Table 1. Cyclization with tosic acid was ineffective, regardless
of the solvent used (Table 1, entries 1 and 2). In contrast, bis-
muth triflate initiated the desired polyene cyclization to give
tricyclic products 21 and 22 in modest yield when a polar sol-
vent was used (contrast Table 1, entries 3 and 8). Lowering the
reaction temperature proved detrimental, and below 40 °C cy-
clization was not observed (Table 1, entries 4–7). Aluminium
trichloride was ineffective (Table 1, entries 9 and 10), but we
were delighted to observe a 50 % combined yield of tricyclic
products 21 and 22 when boron trifluoride diethyl etherate was
used (Table 1, entry 11). Again, this reaction proved to be sol-
vent specific, with no cyclization occurring in the less polar THF
(Table 1, entry 12). HSQC and HMBC 2D NMR spectroscopic
analysis of the tricyclic products revealed that the polyene cycli-
zation had indeed delivered the desired 6/5/6-ring system as a
2:1 mixture of 21 and the rearranged product 22 (Scheme 3),[12]
which were separated by laborious HPLC. The mass balance of
Scheme 4. Cyclizations to give 6/5/6- and 6/5/6/6-fused systems.
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give 21 suggests that the reaction is not a concerted process, state leading to 32. These results indicate that the reaction pro-
but that it occurs in a stepwise manner. To further understand ceeds through intermediate 30.
the stereochemical outcome of the cyclization we turned to
computational methods.
As shown in Scheme 5, an initial alkene cyclization would
give cyclohexyl cation 29, which can then be transformed into
each of the observed reaction products. Friedel–Crafts alkyl-
ation meta to both methoxy groups can lead to the cis-config-
ured Wheland intermediates 30 and 31, or to the trans-config-
ured intermediates 32 and 33. Gas-phase DFT calculations us-
ing the ωB97X-D/6-31G* functional/basis set combination indi-
cated that the endo transition states 30 and 32 were substan-
tially lower in energy than the corresponding exo transition
states 31 and 33.[13] Calculations carried out with the inclusion
of solvation effects by using the CPCM (conductor-like polariza-
ble continuum model) method, indicated two steric interactions
that destabilized the transition state leading to the trans config-
ured diastereomer 32 relative to that leading to its cis counter-
part 30. In the transition state leading to 32, the hydrogen
atom on the aromatic ring comes within the Van der Waals
radius of the hydrogen atom at the ring junction (Figure 2).
Additionally, the 1,3-diaxial interaction between the angular
methyl groups at the 5/6-ring junction and one of the gem-
dimethyl groups is slightly more pronounced in the transition
Figure 2. Calculated energies for solvated transition states leading to interme-
diates 30 and 32.
Compound 21 has the same relative stereochemistry at the
5/6-ring junction as ( )-5-epi-taiwaniaquinone G (9), and the
synthesis of that compound is shown in Scheme 6. Treatment
of compound 21 with BBr3 resulted in an unselective demethyl-
ation, and the crude reaction mixture was exposed to the ac-
tion of salcomine under an atmosphere of oxygen to give ( )-
5-epi-taiwaniaquinone G (9) in just seven steps from methoxy-
anisole (14). Although this approach was concise, it suffered
Scheme 5. Calculated gas-phase energies for transition states leading to pre-
dicted reaction intermediates 30–33.
Scheme 6. Initial synthesis of 5-epi-taiwaniaquinone G (9).
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from two limitations: the nontrivial separation of 21 and 22,
and the unselective demethylation of 21, which resulted in sig-
nificant material loss.
To circumvent those issues, a second approach was pursued.
As shown in Scheme 7, the 2:1 mixture of 21 and 22 that re-
sulted from the polyene cyclization of 13 was globally demeth-
ylated, and the diols 36 and 37 were separated. Oxidation of
36 with Fremy's salt gave quinone 38. Methylation of 38 gave
( )-5-epi-taiwaniaquinone G (9) in a total of eight steps from
methoxyanisole (17). A chemical-shift comparison between
compound 9 synthesized by a cationic polyene cyclization and
the literature data reported for 5-epi-taiwaniaquinone G[7a] re-
veals only minor differences as shown in Figures 3 and 4 and
thus confirms the structure. In an analogous manner, diol 37
was transformed into the new quinone 40.
Figure 4. 13C NMR chemical-shift differences between 9 and literature data
reported for 5-epi-taiwaniaquinone G.[7a]
Conclusions
In contrast to published results involving longer polyene sys-
tems, the cationic cyclization of geranylbenzene derivative 13
preferentially gave the cis-fused 5/6-ring-containing compound
21. We used this polyene cyclization to complete a concise syn-
thesis of ( )-5-epi-taiwaniaquinone G (9). Our approach is the
first to install the cis ring junction of this compound by means
other than hydrogenation. While this approach is relevant for
the synthesis of several taiwaniaquinoid natural products, the
exclusive production of a trans-fused ring junction would re-
quire an additional stereocontrolling group (mimicking a fused
ring) that would alter the conformation of the six-membered
ring to avoid undesired H–H interactions, and favour the trans-
selective Friedel–Crafts alkylation. Efforts to achieve this goal
are currently underway.
Experimental Section
(E)-2-(3,7-Dimethylocta-2,6-dien-1-yl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (16):[11] Compound 15 (79 mg, 0.14 mmol), geraniol
(14; 0.46 g, 3.0 mmol), and bis(pinacolato)diborane (1.46 g,
5.75 mmol) were dissolved in methanol (6.0 mL) and DMSO
(6.0 mL). p-Toluenesulfonic acid (29 mg, 0.17 mmol) was added, and
the solution was heated to 50 °C for 20 h. The reaction mixture was
cooled to room temperature, and water (10 mL) was added. The
mixture was extracted with diethyl ether (3 × 15 mL), and the com-
bined organic extracts were washed with water (15 mL) and satu-
rated brine (15 mL), and dried with Na2SO4. The solvent was re-
moved in vacuo to give a crude yellow oil. Flash chromatography
(eluting with 2 % diethyl ether in hexanes) gave 16 (0.75 g, 95 %)
as a pale yellow oil. IR (film): ν = 2956, 2928, 2872, 2835, 1595,
˜
1484, 1452, 1415, 1377, 1358, 1346, 1250, 1105, 1053 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 5.24 (m, 1 H), 5.10 (m, 1 H), 2.06–1.99 (m, 4
H), 1.68–1.58 (m, 2 H), 1.67 (s, 3 H), 1.59 (s, 3 H), 1.58 (s, 3 H), 1.25
(s, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 135.1, 131.1, 124.5,
118.5, 83.0, 39.8, 26.8, 25.7, 24.7, 24.6, 17.7, 15.9 ppm.
Scheme 7. Synthesis of 5-epi-taiwaniaquinone G (9) and quinone 40.
2-(2,6-Dimethoxyphenyl)propan-2-ol (18):[14] 1,3-Dimethoxy-
benzene (9.4 mL, 72 mmol) was dissolved in THF (200 mL). Tetra-
methylethylenediamine (12.0 mL, 80 mmol) was added, and the
solution was cooled to –78 °C. n-Butyllithium (1.90
M in hexanes;
40 mL, 76 mmol) was added over 40 min, then the mixture was
stirred at –78 °C for 2.5 h. Acetone (6.4 mL, 87 mmol) was added
over 20 min, and the mixture was stirred at –78 °C for 30 min.
Saturated aqueous ammonium chloride (40 mL) was added slowly,
then the solution was warmed to room temperature and stirred
overnight. The layers were separated, and the aqueous phase was
Figure 3. 1H NMR chemical-shift differences between 9 and literature data
reported for 5-epi-taiwaniaquinone G.[7a]
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extracted with ethyl acetate (3 × 150 mL). The combined organic
layers were washed with brine (2 × 100 mL), dried with Na2SO4, and
concentrated in vacuo to give 18 (8.76 g, 62 %). H NMR (300 MHz,
Compounds 36 and 37: Compound 16 (790 mg, 2.5 mmol) was
dissolved in nitroethane (20 mL). The solution was cooled to 0 °C,
and boron trifluoride diethyl etherate (0.70 mL, 0.57 mmol) was
added. The mixture was stirred for 18 h, then it was warmed to
1
CDCl3): δ = 7.14 (t, J = 8.4 Hz, 1 H), 6.60 (d, J = 8.4 Hz, 2 H), 5.74
(br. s, 1 H), 3.82 (s, 6 H), 1.65 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): room temperature. The reaction was quenched with saturated
δ = 157.9, 127.6, 124.4, 106.0, 74.1, 56.1, 31.1 ppm. MS (ESI): m/z aqueous sodium hydrogen carbonate (10 mL). The mixture was di-
(%) = 179 (100) [M – OH]+.
luted with water (40 mL) and ethyl acetate (40 mL), then extracted
with ethyl acetate (2 × 30 mL). The organic layer was dried with
sodium sulfate, and concentrated in vacuo to yield a crude yellow
oil.
2-Isopropyl-1,3-dimethoxybenzene (19):[14] Compound 18
(7.76 g, 39.5 mmol) was dissolved in glacial acetic acid (85 mL).
Palladium on carbon (10 wt.-%; 0.59 g, 0.55 mmol) was added, and
then ammonium formate (12.5 g, 199 mmol) was added portion-
wise. The suspension was slowly heated to 100 °C (gas evolution
was observed). The mixture was kept at 100 °C for 1.5 h, then it
was cooled to room temperature. The suspension was filtered
through Celite, eluting with ethyl acetate (3 × 50 mL). The filtrate
was washed with water (3 × 200 mL) and saturated brine (200 mL),
and was then dried with Na2SO4. The solvent was removed in vacuo
to give 19 (7.12 g, 99 %) as a pale yellow oil. 1H NMR (300 MHz,
CDCl3): δ = 7.17 (t, J = 8.4 Hz, 1 H), 6.61 (d, J = 8.4 Hz, 2 H), 3.86 (s,
This crude oil was dissolved in dichloromethane (70 mL). The result-
ing solution was cooled to 0 °C, and boron tribromide (1.0
M solu-
tion in CH2Cl2; 7.5 mL, 7.5 mmol) was added dropwise. The solution
was warmed to room temperature, and stirred for 4 h. It was then
cooled to 0 °C, and ice-cold water (10 mL) was added. The mixture
was diluted with ethyl acetate (50 mL) and water (50 mL), and the
layers were separated. The aqueous layer was extracted with ethyl
acetate (2 × 50 mL), and the combined organic layers were dried
with sodium sulfate and concentrated in vacuo. The crude red resi-
due was passed through a short silica plug (eluting with ethyl acet-
ate/pentane, 3:7). Product-containing fractions were concentrated
in vacuo to give a dark yellow oil (330 mg). This was further purified
by HPLC (water/acetonitrile, 35:65, isocratic, Sunfire C18) to give cis-
6 H), 3.71 (septet, J = 7.2 Hz, 1 H), 1.38 (d, J = 7.2 Hz, 6 H) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 158.8, 126.6, 124.6, 104.7, 55.8, 24.2,
20.8 ppm. MS (ESI): m/z (%) = 203 (10) [M + Na]+, 219 (55) [M + K]+.
1-Bromo-3-isopropyl-2,4-dimethoxybenzene (20):[14] Compound
19 (4.53 g, 25.1 mmol) was disolved in DMF (55 mL), and N-bromo-
succinimide (4.54 g, 25.5 mmol) was added. The resulting solution
was stirred in the dark for 42 h. The mixture was then poured into
water (200 mL), and extracted with a hexanes/diethyl ether mixture
(2:3; 3 × 100 mL). The organic extracts were washed with water
(100 mL) and saturated brine (100 mL), and dried with Na2SO4. The
solvent was removed in vacuo to give 20 (6.37 g, 98 %) as an or-
diol 36 (149 mg, 21 %) as a yellow oil. IR (film): ν = 3425, 2953,
˜
2926, 2866, 1710, 1623, 1596, 1437, 1376, 1362, 1328, 1301, 1274,
1
1253, 1220, 1146, 1120, 1024 cm–1. H NMR (400 MHz, CDCl3): δ =
6.11 (s, 1 H), 5.10–3.00 (br., 2 H, OH), 3.42 (septet, J = 7.2 Hz, 1 H),
2.63 (dd, J = 14.3, 7.9 Hz, 1 H), 2.51 (dd, J = 14.3, 10.8 Hz, 1 H), 1.86
(dd, J = 10.6, 8.2 Hz, 1 H), 1.62–1.53 (m, 1 H), 1.45–1.14 (m, 5 H),
1.37 (s, 3 H), 1.35 (d, J = 7.2 Hz, 6 H), 1.10 (s, 3 H), 0.95 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 153.83, 153.81, 150.8, 118.2, 117.8,
102.1, 57.5, 45.7, 36.4, 35.2, 32.2, 31.2, 29.5, 29.2, 25.4, 24.7, 21.12,
21.10, 19.0 ppm. HRMS (ESI): calcd. for C19H28NaO2 [M + Na]+
311.19815; found 311.19829.
1
ange-yellow oil. H NMR (300 MHz, CDCl3): δ = 7.31 (d, J = 8.7 Hz,
1 H), 6.55 (d, J = 8.7 Hz, 1 H), 3.79 (app. s, 6 H), 3.52 (septet, J =
7.2 Hz, 1 H), 1.32 (d, J = 7.2 Hz, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 159.2, 155.2, 131.9, 130.4, 108.9, 108.8, 61.6, 55.7, 26.3,
21.0 ppm. MS (ESI): m/z (%) = 259/261 (10) [M + H]+, 281/283 (30)
[M + Na]+.
And rearranged diol 37 (91 mg, 13 %) as a yellow oil. IR (film): ν =
˜
3425, 2929, 2868, 1710, 1617, 1587, 1459, 1421, 1376, 1314, 1256,
1213, 1196, 1145, 1097 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.31 (s,
1 H), 4.90–4.20 (br., 2 H, OH), 3.43 (septet, J = 6.9 Hz, 1 H), 2.42 (d,
J = 16.1 Hz, 1 H), 2.36 (d, J = 16.0 Hz, 1 H), 1.61–1.45 (m, 3 H), 1.36
(d, J = 7.1 Hz, 6 H), 1.32–1.27 (m, 1 H), 1.24 (s, 3 H), 1.23–1.06 (m, 3
H), 1.01 (d, J = 6.9 Hz, 3 H), 1.01 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 152.4, 151.0, 144.5, 117.3, 116.1, 104.7, 42.8, 39.4, 38.4,
34.6, 34.0, 32.8, 31.2, 25.5, 24.8, 21.2, 21.1, 20.5, 9.3 ppm. HRMS (ESI):
calcd. for C19H27O2 [M – H]– 287.20165; found 287.20203.
(E)-1-(3,7-Dimethylocta-2,6-dien-1-yl)-3-isopropyl-2,4-dimeth-
oxybenzene (13): A mixture of 16 (0.37 g, 1.4 mmol), 20 (0.75 g,
2.8 mmol), powdered sodium hydroxide (1.12 g, 28 mmol), and
tetrakis(triphenylphosphine)palladium(0) (0.086 g. 0.074 mmol) was
placed under an argon atmosphere. Toluene (30 mL) and water
(7.5 mL) were added, and the mixture was stirred at 90 °C for 20 h.
The mixture was cooled to room temperature, and diluted with
hexane (30 mL) and water (20 mL). The layers were separated, and
the aqueous layer was extracted with diethyl ether (20 mL). The
Compound 38: A solution of Fremy's salt (265 mg, 988 μmol) and
potassium dihydrogenphosphate (78.0 mg, 573 μmol) in water
combined organic extracts were filtered through Celite, and the (26 mL) was added to a solution of cis-diol 36 (126 mg, 437 μmol)
solvent was removed in vacuo. The residue was diluted with diethyl
ether (10 mL) and passed through a short plug of silica gel, before
being subjected to preparative reverse-phase HPLC [water/aceto-
nitrile/0.1 % TFA (trifluoroacetic acid), gradient elution over 55 min]
in acetone (63.0 mL) at 0 °C. The solution was stirred overnight in
the dark. The mixture was diluted with ethyl acetate (100 mL) and
water (100 mL), and the layers were separated. The aqueous layer
was extracted with ethyl acetate (2 × 50 mL), and the combined
organic layers were dried with sodium sulfate and concentrated in
vacuo to give a crude orange oil. The crude mixture was passed
to give 13 (0.33 g, 73 %) as a pale yellow oil. IR (film): ν = 2956,
˜
2928, 2872, 2835, 1596, 1483, 1453, 1414, 1377, 1345, 1250, 1215,
1195, 1149, 1105, 1053, 899, 801 cm–1 1H NMR (300 MHz, CDCl3): through a silica plug (eluting with 3 % ethyl acetate/pentane) to
.
δ = 6.98 (d, J = 8.4 Hz, 1 H), 6.63 (d, J = 8.4 Hz, 1 H), 5.32 (td, J =
7.2, 1.2 Hz, 1 H), 5.13 (m, 1 H), 3.80 (s, 3 H), 3.72 (s, 3 H), 3.50 (septet,
give 38 (130 mg, 98 %) as an orange oil. UV/Vis (MeCN): λmax (ε,
L mol–1 cm–1) = 286 (8780) nm. IR (film): ν = 3377, 2958, 2929, 2871,
˜
J = 7.1 Hz, 1 H), 3.34 (d, J = 7.2 Hz, 2 H), 2.05–2.15 (m, 4 H), 1.73 (s, 1637, 1610, 1459, 1372, 1317, 1284, 1201, 1173, 1121, 1099,
3 H), 1.70 (s, 3 H), 1.62 (s, 3 H), 1.36 (d, J = 7.1 Hz, 6 H) ppm. 13C
1081 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.03 (s, 1 H), 3.17 (septet,
NMR (75 MHz, CDCl3): δ = 158.2, 156.4, 135.9, 131.5, 129.5, 127.2, J = 7.1 Hz, 1 H), 2.71 (dd, J = 18.5, 8.1 Hz, 1 H), 2.39 (dd, J = 18.5,
127.0, 124.5, 123.6, 107.6, 61.7, 55.5, 39.9, 27.9, 26.8, 25.8, 25.7, 21.2,
17.8, 16.2 ppm. HRMS (ESI): calcd. for C21H32O2Na [M + Na]+
339.2295; found 339.2292.
11.4 Hz, 1 H), 1.85 (dt, J = 13.4, 3.6 Hz, 1 H), 1.77 (dd, J = 11.4,
8.1 Hz, 1 H), 1.69–1.55 (m, 1 H), 1.53 (s, 3 H), 1.48–1.35 (m, 1 H),
1.30 (dd, J = 8.3, 3.7 Hz, 2 H), 1.26–1.17 (m, 1 H), 1.22 (d, J = 7.0 Hz,
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3 H), 1.21 (d, J = 7.1 Hz, 3 H), 1.08 (s, 3 H), 0.93 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 186.9, 182.1, 151.4, 149.8, 149.6, 124.2,
55.2, 47.7, 35.0, 34.3, 31.9, 31.8, 31.2, 29.6, 24.5, 24.1, 20.1, 20.0,
18.0 ppm. HRMS (ESI): calcd. for C19H26NaO3 [M + Na]+ 325.17742;
found 325.17770.
23.0, 20.8, 20.7, 20.5, 8.2 ppm. HRMS (ESI): calcd. for C20H28NaO3
[M + Na]+ 339.19307; found 339.19330.
Acknowledgments
M. G. gratefully acknowledges receipt of an Australian Postgrad-
uate Award.
Compound 39: This compound was prepared in the same manner
described above for the synthesis of 38, but starting from 37
(68 mg, 240 μmol), to give 39 (52 mg, 73 %) as an orange oil. UV/
Keywords: Cyclization · Fused-ring systems · Carbocycles ·
Diastereoselectivity · Natural products
Vis (MeCN): λmax (ε, L mol–1 cm–1) = 280 (8820) nm. IR (film): ν =
˜
3365, 2929, 2870, 1635, 1609, 1456, 1395, 1380, 1362, 1328, 1271,
1
1258, 1242, 1210, 1157, 1105 cm–1. H NMR (400 MHz, CDCl3): δ =
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7.20 (s, 1 H), 3.16 (septet, J = 7.1 Hz, 1 H), 2.39 (d, J = 20.4 Hz, 1 H),
2.35 (d, J = 20.4 Hz, 1 H), 1.56–1.44 (m, 2 H), 1.50–1.37 (m, 2 H),
1.47–1.38 (m, 1 H), 1.40–1.33 (m, 1 H), 1.38 (s, 3 H), 1.22 (d, J =
7.1 Hz, 3 H), 1.21 (d, J = 7.1 Hz, 3 H), 1.21–1.15 (m, 1 H), 0.97 (d, J =
7.0 Hz, 3 H), 0.95 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.0,
183.3, 150.8, 148.4, 143.2, 123.9, 44.0, 40.7, 38.9, 33.8, 32.3, 30.2,
28.6, 24.2, 23.1, 20.8, 20.1, 20.0, 8.2 ppm. HRMS (ESI): calcd. for
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C
19H25O3 [M – H]– 301.18092; found 301.18125.
( )-5-epi-Taiwaniaquinone G (9):[7a] Compound 38 (110 mg,
360 μmol) was dissolved in acetonitrile (8.0 mL). Potassium carb-
onate (270 mg, 1.90 mmol) and methyl iodide (300 μL, 4.80 mmol)
were added. The mixture was stirred in the dark for 18 h, then
saturated aqueous sodium hydrogen carbonate (15 mL) and ethyl
acetate (15 mL) were added, and the mixture was stirred for 30 min.
The layers were separated, and the aqueous layer was extracted
with ethyl acetate (2 × 15 mL). The combined organic layers dried
with sodium sulfate, and concentrated in vacuo to give a crude
orange oil. The crude material was purified by chromatography on
neutral alumina (pentane/ethyl acetate, 99:1) to give
9
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(40 mg, 130 μmol, 35 %) as an orange oil. UV/Vis (MeCN): λmax (ε,
L mol–1 cm–1) = 280 (6780) nm. IR (film): ν = 2930, 2869, 1730, 1647,
˜
1592, 1459, 1377, 1319, 1287, 1260, 1199, 1160, 1147 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 3.92 (s, 3 H), 3.19 (septet, J = 7.1 Hz, 1 H),
2.64 (dd, J = 18.0, 8.1 Hz, 1 H), 2.35 (dd, J = 18.0, 11.5 Hz, 1 H), 1.88
(td, J = 13.5, 3.5 Hz, 1 H), 1.73 (dd, J = 11.3, 8.1 Hz, 1 H), 1.62–1.53
(m, 1 H), 1.51 (s, 3 H), 1.45–1.39 (m, 1 H), 1.30–1.15 (m, 3 H), 1.20
(d, J = 7.0 Hz, 3 H), 1.18 (d, J = 6.9 Hz, 3 H), 1.07 (s, 3 H), 0.92 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.4, 182.7, 156.7, 152.5,
146.3, 136.8, 61.1, 55.1, 48.1, 35.0, 34.3, 31.8, 31.2, 31.1, 29.5, 24.6,
24.4, 20.7, 20.6, 18.0 ppm. HRMS (ESI): calcd. for C20H28NaO3 [M +
Na]+ 339.19307; found 339.19331.
Compound 40: This compound was prepared in the same manner
described above for the synthesis of 9, but starting from 38 (52 mg,
170 μmol), to give 40 (18 mg, 57 μmol, 33 %) as an orange oil.
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6620.
UV/Vis (MeCN): λmax (ε, L mol–1 cm–1) = 276 (4690) nm. IR (film): ν =
˜
2929, 2870, 1729, 1704, 1644, 1603, 1457, 1376, 1294, 1268, 1252,
1142 cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.88 (s, 3 H), 3.17 (septet,
J = 6.9 Hz, 1 H), 2.37 (d, J = 20.8 Hz, 1 H), 2.24 (d, J = 20.8 Hz, 1 H),
1.75–1.69 (m, 1 H), 1.51–1.13 (m, 6 H), 1.30 (s, 3 H), 1.20 (d, J =
7.0 Hz, 3 H), 1.17 (d, J = 7.0 Hz, 3 H), 0.96 (d, J = 7.0 Hz, 3 H), 0.94
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.7, 184.3, 156.9,
146.7, 144.6, 135.2, 60.6, 44.1, 39.8, 39.2, 33.9, 32.2, 30.2, 28.9, 24.5,
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2091.
Received: October 25, 2016
Eur. J. Org. Chem. 2017, 908–913
www.eurjoc.org
913
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