Total synthesis of (-)-heliespirone a and (+)-heliespirone C

Article abstract of DOI:10.1002/ejoc.201402420

Total syntheses of the spiro-epimeric natural products (-)-heliespirone A and (+)-heliespirone C are described. The successful strategy involved an aromatic Claisen rearrangement, a diastereoselective Sharpless asymmetric dihydroxylation (AD) reaction, and an intramolecular oxa-Michael addition.

Full text of DOI:10.1002/ejoc.201402420

Job/Unit: O42420
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FULL PAPER
DOI: 10.1002/ejoc.201402420
Total Synthesis of (–)-Heliespirone A and (+)-Heliespirone C
Philip Norcott[a] and Christopher S. P. McErlean*[a]
Keywords: Total synthesis / Natural products / Asymmetric synthesis / Sigmatropic rearrangement / Michael addition /
Spiro compounds
Total syntheses of the spiro-epimeric natural products (–)-
heliespirone A and (+)-heliespirone C are described. The
successful strategy involved an aromatic Claisen rearrange-
ment, a diastereoselective Sharpless asymmetric dihydrox-
ylation (AD) reaction, and an intramolecular oxa-Michael ad-
dition.
Macías to propose a biosynthetic route to these compounds
from the co-isolate, heliannuol C (5).[1b] All three of the re-
ported total syntheses of heliespirones A and C (1 and 2)
use this conjugate addition strategy for the spirocyclization
step. The novelty of previous synthetic approaches is there-
fore confined to the generation of the quinone 4.
In the first asymmetric approach (Scheme 1), Liu and co-
worker used a palladium-catalysed conjugate addition of
arylboronic acid 6 onto unsaturated lactone 7.[4] Synthetic
manipulations then unveiled quinone ent-4 en route to ent-
Introduction
Competition between plant species for limited natural re-
sources has provided evolutionary pressure for the develop-
ment of allelochemicals that function as naturally occurring
herbicides. One attractive branch of research looks to dis-
cover new agrochemicals by identifying the allelochemical
components that are responsible for specific plant–plant (or
plant–microbe) interactions. It was in this setting that helie-
spirones A, C, and B (1–3) were first isolated by Macías
and co-workers from a sunflower cultivar, H. annuus L. cv.
SH-222 (Figure 1).[1] Initially described as the 6,6-spiro
compound,[1a,2] the structure of heliespirone A (1) was re-
vised to the spiro epimer of the 6,5-spiro compound helie-
spirone C (2).[1b,3] The natural occurrence of both dia-
stereomers 1 and 2 suggests a biosynthesis involving an oxa-
Michael addition onto a quinone 4, and this prompted
Figure 1. Heliespirone natural products.
[a] School of Chemistry,
The University of Sydney, NSW 2006, Australia
E-mail: christopher.mcerlean@sydney.edu.au
http://sydney.edu.au/science/chemistry/~mcerlean
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402420.
Scheme 1. Strategies for the synthesis of the heliespirones. TMS =
trimethylsilyl.
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P. Norcott, C. S. P. McErlean
FULL PAPER
1 and ent-2. Pettus and co-workers also reported syntheses
of ent-1 and ent-2.[5] They accessed quinone ent-4 via chro-
man 10, which they generated using a [4+2] cycloaddition
on an o-quinone methide generated in situ from 9.[5] Finally,
Shishido and co-workers used an intramolecular Hosomi–
Sakurai reaction to generate the carbon–carbon bond of
the spirocentre and give quinone 4.[6] As such, Shishido and
co-workers were able to complete the first total synthesis of
the naturally occurring enantiomers (–)-1 and (+)-2.
Our continuing interest in discovering efficient protocols
for the generation of quinone natural products[7] led us to
take on the challenge of synthesizing heliespirones A (1)
and C (2). At the outset, we hoped to use an on-water-
catalysed[8] aromatic Claisen rearrangement to give diene
14,[9] and that the stereocentre generated in this process
would create a matched–mismatched scenario in which a
simple Sharpless asymmetric dihydroxylation (AD) would
result in a kinetic resolution.[10]
Scheme 2. Synthesis of Claisen rearrangement precursor 13. Rea-
gents and conditions: (a) nBuLi, CuI, (CH3)2CCHCH2Br, 89%;
(b) LiAlH4, 94%; (c) 18, PPh3, DIAD (diisopropyl azodicarboxyl-
ate), 80%.
whether 13 would participate in an on-water-catalysed aro-
matic Claisen rearrangement.
Results and Discussion
As shown in Table 1, attempted on-water rearrangement
Our synthesis began with the construction of diene 13. of 13 at either room temperature (Table 1, Entry 1) or 80 °C
As shown in Scheme 2, propargyl alcohol 15 was deproton- (Table 1, Entry 2) led to recovery of the starting material
ated with excess butyllithium, and subsequent treatment with no observed rearrangement. Increasing the tempera-
with prenyl bromide gave enyne 16 in good yield. Chemo- ture to 150 °C in a sealed tube was similarly unproductive
and diastereoselective reduction was carried out with lith- (Table 1, Entry 3). With an experimentally measured iso-
ium aluminium hydride to give (E)-configured diene 17. electric point between pH = 3 and 4, interfacial water has
Mitsunobu coupling with 4-methoxy-m-cresol (18)[11]gave an acidity comparable to that of carboxylic acids.[15] We
13, the substrate for the planned aromatic Claisen re- therefore attempted a Brønsted-acid-catalysed rearrange-
arrangement.
ment with benzoic acid (pKa = 4.2; Table 1, Entry 4). Un-
We have previously shown that on-water catalysis results surprisingly, compound 13 did not undergo rearrangement
from the acidic nature of interfacial water in oil-in-water under those conditions. Using a stronger carboxylic acid,
emulsions.[12] On-water catalysis has been successfully used trifluoroacetic acid (pKa = 0.23; Table 1, Entry 5), did not
by us[12b,13] and others[8,14] to facilitate aromatic Claisen re- lead to rearrangement, but it did allow the trisubstituted
arrangements of a variety of substrates by protonation of alkene to participate in a hydration reaction upon aqueous
the ether oxygen atom and subsequent charge-accelerated workup to give undesired compound 19. It was clear from
rearrangement. However, substrate 13 represents an exam- this data that the oxygen atom of the allyl phenyl ether por-
ple in which there is a competing site for protonation. The tion of 13 could not be protonated by interfacial water or
methyl ether of 13 is sterically less congested and less hydro- by Brønsted acids of comparable acidity. Attempted ther-
phobic than the alternative ether, so it was not clear mal rearrangement was also unproductive (Table 1, En-
Table 1. Claisen rearrangement of compound 13.
Entry
Acid
Solvent
Temperature [°C]
Yield of 14 [%][a]
Yield of 19 [%][a]
1
2
–
–
on-H2O
on-H2O
H2O
CH2Cl2
CH2Cl2
25
80
150
25
25
216
–78 Ǟ 0
0
0
0
0
0
0
93
0
0
0
0
12
0
3[b]
4
–
benzoic acid
trifluoroacetic acid
–
5[c]
6
7
N,N-diethylaniline
n-pentane
Me2AlCl
0
[a] Isolated after chromatography. [b] Sealed tube. [c] Containing Ͻ3% v/v H2O.
2
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Total Synthesis of (–)-Heliespirone A and (+)-Heliespirone C
try 6), with compound 13 being consumed, but with none the reason for this undesired outcome, we masked the
of the desired compound (i.e., 14) being isolated. We there- phenol unit with an electron-withdrawing acetate group to
fore resorted to Lewis acid catalysis.[14a,16] Treatment of give compound 20. Sharpless AD of 20 proceeded
compound 13 with dimethylaluminium chloride at low tem- smoothly. We were gratified to observe that the desired
perature gave smooth conversion to the desired product compound (i.e., 21) was produced in a 5:1 ratio with the
(i.e., 14; Table 1, Entry 7).[17]
undesired diastereomer (i.e., 22). Removal of the acetate
With compound 14 in hand, our attention turned to the group allowed the diastereomers (i.e., 23 and 24) to be sepa-
kinetic resolution using Sharpless AD reaction rated by simple silica gel chromatography.
(Scheme 3). We anticipated that the more electron-rich tri- As shown in Scheme 4, the synthesis was completed by
a
substituted alkene would react in preference to the terminal oxidation of 23 with ceric ammonium nitrate to give pro-
alkene or the aromatic ring. In the event, reactions of 14 posed biosynthetic intermediate 4. Finally, treatment of 4
with commercially sourced AD-mixtures (or other osmium- with cesium carbonate in dichloromethane facilitated an in-
based oxidants) led to intractable mixtures. Imagining that tramolecular oxa-Michael addition to give the easily sepa-
interference by the relatively electron-rich aromatic ring was rable diastereomers (–)-heliespirone A (1) in 22% yield and
(+)-heliespirone C (2) in 20% yield.
Table 2. Comparison of natural and synthetic samples of heliespi-
rone A and heliespirone C.
(–)-Heliespirone A
Synthetic[a]
Natural[b]
Difference
ΔδH ΔδC
Carbon no.
δH
δC
δH
δC
1
2
3
4
5
6
–
–
6.61
–
–
87.7
201.3
137.2
153.6
195.6
51.9
–
–
6.61
–
–
87.6
201.5
137.0
153.4
195.5[c]
51.8
–
–
0.00
–
–
0.1
–0.2
0.2
0.2
0.1
0.1
3.24,
2.96
5.31
2.92
2.15,
1.97
4.04
–
1.10
1.33
5.06,
4.96
1.97
3.23,
2.95
5.29
2.91
2.14,
1.96
4.03
–
1.09
1.32
5.06,
4.96
1.96
0.01,
0.01
0.02
0.01
0.01,
0.01
0.01
–
0.01
0.01
0.00,
0.00
0.01
7
8
9
135.5
57.2
32.0
135.3
57.1
31.9
0.2
0.1
0.1
10
11
12
13
14
86.8
70.3
28.5
25.4
118.6
86.7
70.1
28.3
25.3
118.4
0.1
0.2
0.2
0.1
0.2
Scheme 3. Kinetic resolution by Sharpless asymmetric dihydrox-
ylation. Reagents and conditions: (a) Ac2O, Et3N, DMAP [4-(di-
methylamino)pyridine], 100%; (b) AD-mix-α, CH3SO2NH2, 53%;
(c) CH3OH, K2CO3, 70% (23) and 14% (24).
15
16.0
15.9
0.1
(+)-Heliespirone C
Synthetic[a] Natural[b]
Difference
Carbon no.
δH
δC
δH δC
ΔδH
ΔδC
1
2
3
4
5
6
–
–
6.68
–
–
87.0
196.8
137.1
151.9
196.3
48.8
–
–
6.63
–
–
86.9
196.5
136.9
151.7
196.3
48.5
–
–
0.05
–
–
0.1
0.3
0.2
0.2
0.0
0.3
2.95,
2.83
5.62
3.28
2.05,
1.93
3.95
–
1.13
1.24
5.13,
5.09
1.99
2.95,
2.83
5.61
3.26
2.04,
1.92
3.95
–
1.12
1.23
5.12,
5.09
1.98
0.00,
0.00
0.01
0.02
0.01,
0.01
0.00
–
0.01
0.01
0.01,
0.00
0.01
7
8
9
134.7
47.1
32.5
134.6
47.0
32.4
0.1
0.1
0.1
10
11
12
13
14
86.8
70.4
27.7
24.6
119.9
86.7
70.3
27.5
24.5
119.6
0.1
0.1
0.2
0.1
0.3
15
16.3
16.1
0.2
[a] 1H NMR (300 MHz, CDCl3), 13C NMR (75 MHz, CDCl3).
[b] 1H NMR (400 MHz, CDCl3), 13C NMR (100 MHz, CDCl3).
[c] See ref.[4] for the correction of a typographical error found in
the isolation paper.
Scheme 4. Synthesis of heliespirones A and C. (a) Ce(NH4)2(NO3)6,
35%; (b) Cs2CO3, 22% (1) and 20% (2).
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P. Norcott, C. S. P. McErlean
FULL PAPER
51.6 (CH2), 25.7 (CH3), 18.1 (CH2), 17.8 (CH3) ppm. MS (APCI):
As expected, the chemical shifts of the synthetic products
were in close agreement with those of the originally isolated
compounds (Table 2).
m/z (%) = 123 (100) [M – H+], 93 (34) [M – CH2OH].
(E)-6-Methylhepta-2,5-dien-1-ol (17): A solution of 6-methylhept-5-
en-2-yn-1-ol (689 mg, 5.5 mmol) in THF (2 mL) was added drop-
wise to a suspension of lithium aluminium hydride (335 mg,
8.8 mmol, 1.6 equiv.) in dry THF (12 mL) at 0 °C. The reaction
mixture was heated to reflux for 8 h, then it was cooled again to
0 °C and quenched with hydrochloric acid (1 m; 30 mL). The mix-
ture was extracted with diethyl ether (3ϫ 30 mL), the combined
organic extracts were washed with brine (30 mL) and dried with
Na2SO4, and the solvent was removed in vacuo. The residue was
purified by flash chromatography on silica (ethyl acetate/light pe-
troleum, 1:9) to give 17 (659 mg, 94%) as a colourless oil. Rf =
Conclusions
We have completed the synthesis of the quinone natural
products (–)-heliespirone A (1) and (+)-heliespirone C (2).
The key steps in this straightforward approach were an aro-
matic Claisen rearrangement and
Sharpless asymmetric dihydroxylation.
a diastereoselective
0.17 (ethyl acetate/light petroleum, 1:9). IR: ν = 3311, 2916, 2857,
˜
1438, 1376, 1090 cm–1. 1H NMR (300 MHz, CDCl3): δ = 5.67–5.62
(m, 2 H), 5.16–5.10 (m, 1 H), 4.08 (d, J = 3.9 Hz, 2 H), 2.72 (m, 2
H), 1.70 (d, J = 0.9 Hz, 3 H), 1.61 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 133.0 (C), 132.0 (CH), 129.0 (CH), 121.7
(CH), 63.9 (CH2), 31.0 (CH2), 25.8 (CH3), 17.8 (CH3) ppm.
Experimental Section
General: Reagent-grade dichloromethane and triethylamine were
freshly distilled from calcium hydride. Tetrahydrofuran and meth-
anol were collected using an Innovative Technology Inc. PureSolv™
solvent purification system. All other solvents and reagents were
used as received from commercial sources. Melting points were de-
termined using a Stanford Research Systems Optimelt automated
melting point system and are uncorrected. Infrared spectra were
acquired neat with a Bruker Alpha-E ATR spectrometer. UV/Vis
absorption spectra were recorded with a Varian Cary 50 spectro-
photometer, and absorption maxima are expressed in wavenumbers
(cm–1). 1H and 13C NMR spectra were recorded with a Bruker
Avance DPX300 (1H frequency 300 MHz; 13C frequency 75 MHz).
1H chemical shifts are expressed as parts per million (ppm) with
residual chloroform (δ = 7.26 ppm) or residual methanol (δ =
3.31 ppm) as reference and are reported as chemical shift (δH); rela-
tive integral; multiplicity (s = singlet, br. = broad, d = doublet, t =
triplet, dd = doublet of doublets, dt = doublet of triplets, q = quar-
tet, m = multiplet); and coupling constants (J) reported in Hz. 13C
NMR chemical shifts are expressed as parts per million (ppm) with
residual chloroform (δ = 77.1 ppm) or residual methanol (δ =
49.0 ppm) as internal reference and are reported as chemical shift
(δC); and multiplicity (assigned from DEPT experiments). High-
resolution mass spectra were recorded with a Bruker ApexII Fou-
rier Transform Ion Cyclotron Resonance mass spectrometer with a
7.0 T magnet, fitted with an off-axis analytical electrospray source.
Column chromatography was performed using Grace Davidson 40–
63 µm (230–400 mesh) silica gel using distilled solvents. Analytical
thin layer chromatography was performed using preconditioned
plates (Merck TLC silica gel 60 F254 on aluminium) and visualised
using UV light (254 nm and 365 nm) and ethanolic anisaldehyde.
(E)-1-Methoxy-2-methyl-4-[(6-methylhepta-2,5-dien-1-yl)oxy]benz-
ene (13): 4-Methoxy-3-methylphenol (570 mg, 4.13 mmol, 2 equiv.),
6-methylhepta-2,5-dien-1-ol (260 mg, 2.06 mmol, 1 equiv.), and tri-
phenylphosphine (1.08 g, 4.12 mmol, 2 equiv.) were dissolved in
THF (7 mL), and the mixture was cooled to 0 °C. Diisopropyl azo-
dicarboxylate (820 μL, 4.16 mmol, 2 equiv.) was added, and the re-
action mixture was allowed to return to room temperature over-
night. The reaction mixture was quenched by addition of water
(15 mL) and extracted with ethyl acetate (2ϫ 20 mL). The com-
bined organic extracts were dried with Na2SO4 and concentrated
in vacuo. The residue was purified by flash chromatography on
silica (ethyl acetate/light petroleum, 1:19) to give 13 (404 mg, 80%)
as a yellow oil. R = 0.74 (ethyl acetate/light petroleum, 1:9). IR: ν
˜
f
= 2926, 1499, 1463, 1441, 1377, 1280, 1215, 1181, 1162, 1036 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.82–6.81 (m, 1 H, ArH), 6.76–
6.75 (m, 2 H, ArH), 5.91–5.71 (m, 2 H, CH=CH), 5.24 (t, J =
7.3 Hz, 1 H, CH), 4.46 (dd, J = 5.7, 0.9 Hz, 2 H, OCH2), 3.82 (s,
3 H, OCH3), 2.84 (dd, J = 6.3, 6.3 Hz, 2 H, CH2), 2.27 (s, 3 H,
ArCH3), 1.79 (s, 3 H, CH3), 1.69 (s, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 152.6 (C), 152.1 (C), 133.5 (CH), 132.9 (C),
127.7 (C), 125.3 (CH), 121.5 (CH), 118.1 (CH), 111.9 (CH), 110.8
(CH), 69.3 (CH2), 55.7 (CH3), 31.0 (CH2), 25.7 (CH3), 17.7 (CH3),
16.4 (CH3) ppm. HRMS (ESI): calcd. for C16H23O2 [M + H]+
247.1693; found 247.1694.
4-Methoxy-5-methyl-2-(6-methylhepta-1,5-dien-3-yl)phenol (14): Di-
methylaluminium chloride (1 m solution in hexanes; 2.1 mL,
1 equiv.) was added to a solution of (E)-1-methoxy-2-methyl-4-[(6-
methylhepta-2,5-dien-1-yl)oxy]benzene (500 mg, 2.0 mmol) in n-
pentane (20 mL) at –78 °C. The reaction mixture was stirred at
–78 °C for 30 min, then it was warmed to 0 °C over 15 min, and
then quenched by addition of water (10 mL). The mixture was ex-
tracted with ethyl acetate (2ϫ 20 mL), and the combined organic
extracts were dried with Na2SO4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica (ethyl acet-
ate/light petroleum, 1:19) to give 14 (465 mg, 93%) as a colourless
6-Methylhept-5-en-2-yn-1-ol (16): n-Butyllithium (2.2 m in hexanes;
7.3 mL, 16 mmol) was added dropwise to a solution of propargyl
alcohol (475 μL, 8.0 mmol) in THF (20 mL) at 0 °C. After 1 h, cu-
prous iodide (170 mg, 0.89 mmol) was added. After a further
30 min, a solution of prenyl bromide (1.21 g, 8.1 mmol) in THF
(20 mL) was added slowly, and the reaction mixture was allowed
to return to room temperature overnight. Saturated ammonium
chloride solution (30 mL) was added. The mixture was extracted
with diethyl ether (3ϫ 30 mL) and dried with Na2SO4, and the
solvent was removed in vacuo. The residue was purified by flash
chromatography on silica (ethyl acetate/light petroleum, 1:9) to give
16 (881 mg, 89%) as a pale yellow oil. Rf = 0.31 (ethyl acetate/light
oil. R = 0.33 (ethyl acetate/light petroleum, 1:9). IR: ν = 3422,
˜
f
2973, 2927, 1513, 1450, 1407, 1376, 1197, 1157, 1099, 1019 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.63 (s, 1 H, ArH), 6.61 (s, 1 H,
ArH), 6.05 (ddd, J = 17.0, 10.6, 6.4 Hz, 1 H), 5.17–5.10 (m, 3 H),
4.71–4.70 (m, 1 H), 3.79 (s, 3 H), 3.54 (dt, J = 7.2, 7.2 Hz, 1 H),
2.55–2.38 (m, 2 H), 2.17 (s, 3 H), 1.69 (s, 3 H), 1.60 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 152.2 (C), 147.2 (C), 141.1 (CH),
petroleum, 1:9). IR: ν = 3318, 2915, 1446, 1376, 1288, 1135, 1093,
˜
1
1005 cm–1. H NMR (300 MHz, CDCl3): δ = 5.17 (tsept, J = 6.9,
1.4 Hz, 1 H), 4.24 (s, 2 H), 2.91 (br. d, J = 6.9 Hz, 2 H), 1.70 (d, J
= 1.2 Hz, 3 H), 1.68 (br. s, 1 H, OH), 1.62 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 134.3 (C), 118.8 (CH), 85.4 (C), 78.0 (C), 133.3 (C), 127.1 (C), 125.9 (C), 122.4 (CH), 119.0 (CH), 115.0
4
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Total Synthesis of (–)-Heliespirone A and (+)-Heliespirone C
(CH2), 111.2 (CH), 56.3 (CH3), 44.1 (CH), 32.4 (CH2), 25.9 (CH3), 5,6-dihydroxy-6-methylhept-1-en-3-yl]-4-methoxy-5-methylphenyl
18.0 (CH3), 15.9 (CH3) ppm. HRMS (ESI): calcd. for C16H22O2Na
acetate (mixture of diastereomers; 65 mg, 0.20 mmol) in methanol
(3 mL). The reaction mixture was stirred vigorously for 1 h, then it
was diluted with methanol (10 mL) and filtered. The filtrate was
concentrated in vacuo, and the resulting residue was purified by
flash chromatography on silica (ethyl acetate/light petroleum, 2:3)
to give 23 (39 mg, 70%, 17% ee) as a colourless solid and 24 (8 mg,
14%) as a colourless oil. 23: Rf = 0.25 (ethyl acetate/light petro-
[M + Na]+ 269.1512; found 269.1514.
4-Methoxy-5-methyl-2-(6-methylhepta-1,5-dien-3-yl)phenyl Acetate
(20): A solution of acetic anhydride (260 μL, 2.75 mmol, 2 equiv.)
and triethylamine (380 μL, 2.72 mmol, 2 equiv.) in dichlorometh-
ane (12 mL) was added to a mixture of 4-methoxy-5-methyl-2-(6-
methylhepta-1,5-dien-3-yl)phenol (337 mg, 1.37 mmol) and 4-(di-
methylamino)pyridine (17 mg, 0.14 mmol), and the reaction mix-
ture was stirred at room temperature overnight. The mixture was
then concentrated in vacuo, and the residue was purified by flash
chromatography on silica (ethyl acetate/light petroleum, 1:19) to
give 20 (395 mg, 100%) as a colourless oil. Rf = 0.64 (ethyl acetate/
leum, 1:1). m.p. 157–159 °C. [α]D = –8.0 (c = 0.40, MeOH). IR: ν
˜
= 3398 (br.), 2964, 2929, 1706, 1639, 1512, 1462, 1408, 1376, 1365,
1323, 1199, 1162, 1119, 1073, 1021, 1005 cm–1 1H NMR
.
(300 MHz, [D4]methanol): δ = 6.65 (s, 1 H), 6.56 (s, 1 H), 6.03
(ddd, J = 17.4, 9.9, 8.4 Hz, 1 H), 5.14–5.02 (m, 2 H), 3.92–3.84 (m,
1 H), 3.73 (s, 3 H), 3.44 (ddd, J = 10.2, 1.2 Hz, 1 H), 2.15–2.06 (m,
4 H, CH, CH3), 1.53 (ddd, J = 14.1, 10.8, 3.3 Hz, 1 H), 1.17 (s, 3
H), 1.14 (s, 3 H) ppm. 13C NMR (75 MHz, [D4]methanol): δ =
152.6 (C), 148.8 (C), 142.2 (CH), 130.6 (C), 125.9 (C), 119.0 (CH),
115.2 (CH2), 111.9 (CH), 77.1 (CH), 73.8 (C), 56.6 (CH3), 41.6
(CH), 37.5 (CH2), 25.8 (CH3), 25.0 (CH3), 15.9 (CH3) ppm. HRMS
(ESI): calcd. for C16H24O4Na [M + Na]+ 303.1567; found 303.1567.
Enantiomeric excess was determined by HPLC analysis [CHI-
RALCEL OD-H column, 2% ethanol/hexane, 0.7 mL/min, reten-
tion times 49.3 (minor) and 53.9 (major)]. 24: Rf = 0.32 (ethyl acet-
light petroleum, 1:9). IR: ν = 2927, 1757, 1503, 1464, 1398, 1368,
˜
1256, 1212, 1191, 1174, 1023 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 6.83 (s, 1 H, ArH), 5.96 (ddd, J = 17.1, 10.2, 6.6 Hz, 1 H),
5.13–5.02 (m, 3 H), 3.82 (s, 3 H), 3.44 (dt, J = 7.2, 7.2 Hz, 1 H),
2.47–2.35 (m, 2 H, CH2), 2.29 (s, 3 H), 2.20 (s, 3 H), 1.69 (s, 3 H),
1.61 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.9 (C),
155.6 (C), 141.5 (C), 140.6 (CH), 133.6 (C), 132.7 (C), 125.6 (C),
124.5 (CH), 122.2 (CH), 114.6 (CH2), 109.6 (CH), 55.6 (CH3), 43.3
(CH), 33.1 (CH2), 25.8 (CH3), 21.0 (CH3), 17.9 (CH3), 15.9 (CH3)
ppm. HRMS (ESI): calcd. for C18H24O3Na [M + Na]+ 311.1618;
found 311.1618.
ate/light petroleum, 1:1). [α]D = –19.62 (c = 0.52, CHCl ). IR: ν =
˜
3
3376 (br.), 2972, 2926, 1705, 1637, 1501, 1463, 1410, 1364, 1200,
1
1165, 1079, 1023, 1001 cm–1. H NMR (300 MHz, [D4]methanol):
2-[(3R,5S)-5,6-Dihydroxy-6-methylhept-1-en-3-yl]-4-methoxy-5-
methylphenyl Acetate (21) and 2-[(3S,5S)-5,6-Dihydroxy-6-meth-
ylhept-1-en-3-yl]-4-methoxy-5-methylphenyl Acetate (22): Water
(10 mL) and tert-butyl alcohol (10 mL) were added to a mixture of
AD-mix-α (2.74 g, Aldrich, 1.4 g per mmol of olefin) and methane-
sulfonamide (232 mg, 2.44 mmol). The mixture was stirred vigor-
ously until complete dissolution had taken place, then the solution
was cooled to 0 °C. A solution of 4-methoxy-5-methyl-2-(6-meth-
ylhepta-1,5-dien-3-yl)phenyl acetate (555 mg, 1.92 mmol) in water
(10 mL) and tert-butyl alcohol (10 mL) was then added. The reac-
tion mixture was stirred at 0 °C for 1 h, then it was allowed to
return to room temperature, and stirred for a further 24 h. The
mixture was diluted with water (25 mL), then sodium sulfite (1.0 g)
was added, and the mixture was stirred for a further 1 h. The mix-
ture was extracted with dichloromethane (3ϫ 50 mL), and the
combined organic extracts were dried with Na2SO4 and concen-
trated in vacuo. The residue was purified by flash chromatography
on silica (ethyl acetate/light petroleum, 1:1) to give a mixture of 23
and 24 (329 mg, 53%) as a pale pink oil. Rf = 0.35 (ethyl acetate/
δ = 6.61 (s, 1 H), 6.59 (s, 1 H), 6.12 (ddd, J = 17.1, 10.2, 6.6 Hz, 1
H), 5.06–4.95 (m, 2 H), 3.96–3.89 (m, 1 H), 3.72 (s, 3 H), 3.06 (dd,
J = 10.5, 1.2 Hz, 1 H), 2.12–2.03 (m, 4 H, CH, CH3), 1.68 (ddd, J
= 14.1, 10.8, 3.9 Hz, 1 H), 1.12 (s, 3 H), 1.08 (s, 3 H) ppm. 13C
NMR (75 MHz, [D4]methanol): δ = 152.8 (C), 149.6 (C), 143.9
(CH), 128.0 (C), 126.3 (C), 119.1 (CH), 113.3 (CH2), 112.3 (CH),
77.1 (CH), 73.7 (C), 56.5 (CH3), 40.9 (CH), 37.3 (CH2), 25.4 (CH3),
25.2 (CH3), 15.9 (CH3) ppm. HRMS (ESI): calcd. for C16H24O4Na
[M + Na]+ 303.1567; found 303.1568.
2-[(3R,5S)-5,6-Dihydroxy-6-methylhept-1-en-3-yl]-5-methylcyclo-
hexa-2,5-diene-1,4-dione (4): A solution of cerium ammonium
nitrate (153 mg, 0.28 mmol, 2 equiv.) in water (1 mL) was added
dropwise to a stirred mixture of (3S,5R)-5-(2-hydroxy-5-methoxy-
4-methylphenyl)-2-methylhept-6-ene-2,3-diol (39 mg, 0.14 mmol) in
acetonitrile (1 mL) at 0 °C. The mixture was stirred at 0 °C for
5 min, then it was diluted with water (10 mL), and extracted with
ethyl acetate (3 ϫ 10 mL). The combined organic extracts were
dried with Na2SO4 and concentrated in vacuo. The residue was
purified by flash chromatography on silica (ethyl acetate/light pe-
troleum, 1:1) to give 4 (13 mg, 35%) as a yellow oil. Rf = 0.39 (ethyl
acetate/light petroleum, 1:1). [α]D = –15.0 (c = 0.29 CHCl3) [ref.[6]
light petroleum, 1:1). [α]D = –5.87 (c = 0.47, CHCl ). IR: ν = 3466,
˜
3
2976, 2931, 1736, 1503, 1465, 1398, 1370, 1218, 1192, 1176, 1070,
1
1044, 1025 cm–1. H NMR (300 MHz, CDCl3): δ = 6.77–6.60 (m,
2 H, ArH), 5.94–5.82 (m, 1 H, HC=CH2), 5.13–4.94 (m, 2 H,
HC=CH2), 3.78–3.66 (m, 4 H, OCH3, CH), 3.42 (d, J = 10.2 Hz,
1 H, major isomer CH), 3.08 (d, J = 10.2 Hz, 1 H, minor isomer
CH), 2.83 (br. s, 1 H, OH), 2.78 (br. s, 1 H, OH), 2.28 (s, 3 H,
major isomer CH3), 2.26 (s, 3 H, minor isomer CH3), 2.16 (s, 3 H,
minor isomer CH3), 2.15 (s, 3 H, major isomer CH3), 1.83–1.75 (m,
1 H, CH), 1.60–1.51 (m, 1 H, CH), 1.16 (s, 3 H, CH3), 1.10 (s, 3
H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.9, 170.5,
155.8, 155.6, 141.9, 141.5, 140.9, 139.5, 134.3, 131.9, 126.0, 125.6,
124.4, 115.8, 113.8, 109.2, 75.8, 75.3, 72.9, 72.7, 55.5, 39.8, 39.1,
36.6, 35.8, 26.1, 23.4, 23.2, 20.8, 15.7 ppm. HRMS (ESI): calcd. for
C18H26O5Na [M + Na]+ 345.1673; found 345.1673.
[α]D = –63.2 (c = 0.38 CHCl )]. IR: ν = 3431 (br.), 2975, 2926,
˜
3
1651, 1609, 1442, 1301, 1351, 1257, 1239, 1135, 1070, 1005 cm–1.
1
UV: λ (ε) = 329 (sh, 420), 414 (sh, 60 Lmol–1 cm–1) nm. H NMR
(300 MHz, CDCl3): δ = 6.59 (q, J = 1.6 Hz, 1 H), 6.53 (d, J =
0.9 Hz, 1 H), 5.77 (ddd, J = 17.9, 9.8, 8.6 Hz, 1 H), 5.24–5.18 (m,
2 H), 3.72 (td, J = 9.2, 3.7 Hz, 1 H), 3.45 (d, J = 10.5 Hz, 1 H),
2.33 (br. s, 1 H, OH), 2.03 (d, J = 1.2 Hz, 3 H), 1.77–1.69 (m, 1
H), 1.53 (ddd, J = 14.2, 10.6, 3.9 Hz, 1 H), 1.20 (s, 3 H), 1.14 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 188.4 (C), 187.3 (C),
151.5 (C), 145.5 (C), 137.5 (CH), 133.9 (CH), 132.0 (CH), 118.2
(CH2), 76.1 (CH), 73.0 (C), 39.6 (CH), 35.9 (CH2), 26.5 (CH3),
23.7 (CH3), 15.5 (CH3) ppm. HRMS (ESI): calcd. for C15H20O4Na
[M + Na]+ 287.1254; found 287.1255.
(3S,5R)-5-(2-Hydroxy-5-methoxy-4-methylphenyl)-2-methylhept-6-
ene-2,3-diol (23) and (3S,5S)-5-(2-Hydroxy-5-methoxy-4-meth-
ylphenyl)-2-methylhept-6-ene-2,3-diol (24): Potassium carbonate
(84 mg, 0.61 mmol, 3 equiv.) was added to a solution of 2-[(5S)-
(–)-Heliespirone A (1) and (+)-Heliespirone C (2): Cesium carbonate
(295 mg, 0.91 mmol, 5 equiv.) was added to a solution of 2-
[(3R,5S)-5,6-dihydroxy-6-methylhept-1-en-3-yl]-5-methylcyclo-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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/KAP1
Date: 01-07-14 18:02:56
Pages: 8
P. Norcott, C. S. P. McErlean
FULL PAPER
hexa-2,5-diene-1,4-dione (50 mg, 0.19 mmol) in dichloromethane
(6.5 mL) at 0 °C. The reaction mixture was allowed to return to
room temperature and then stirred for 1 h. The mixture was then
diluted with water (10 mL) and extracted with dichloromethane
(2 ϫ 10 mL). The combined organic extracts were dried with
Na2SO4 and concentrated in vacuo. The residue was purified by
flash chromatography on silica (ethyl acetate/light petroleum, 1:3)
1:1). rac-24: Rf = 0.32 (ethyl acetate/light petroleum, 1:1). Other
spectroscopic data were consistent with those obtained from en-
antioenriched 23 and 24.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra.
to give 1 (11 mg, 22%) as a colourless solid and 2 (10 mg, 20%) as Acknowledgments
a colourless solid. 1: Rf = 0.61 (ethyl acetate/light petroleum, 1:1).
M.p. 106–107 °C (ref.[6] m.p. 105–106 °C). [α]D = –28.0 (c = 0.1
P. N. gratefully acknowledges receipt of an Australian Postgraduate
Award and a John A. Lamberton Research Scholarship. This work
was funded by the Australian Research Council (DP120102466).
CHCl3) [ref.[6] [α]D = –55.2 (c = 0.13, CHCl )]. IR: ν = 3458 (br.),
˜
3
2972, 2925, 2854, 1681, 1780, 1348, 1242, 1128, 1062, 1005 cm–1.
1H NMR (300 MHz, CDCl3): δ = 6.61 (q, J = 1.4 Hz, 1 H), 5.31
(dt, J = 16.8, 9.6 Hz, 1 H), 5.06 (ddd, J = 16.8, 1.3, 0.7 Hz, 1 H),
4.96 (dd, J = 10.0, 1.3 Hz, 1 H), 4.80 (br. s, 1 H), 4.04 (dd, J =
10.8, 5.3 Hz, 1 H), 3.24 (d, J = 15.6 Hz, 1 H), 2.96 (d, J = 15.6 Hz,
1 H), 2.92 (ddd, J = 12.6, 9.1, 6.6 Hz, 1 H), 2.15 (td, J = 12.7,
10.8 Hz, 1 H), 2.01–1.93 (m, 1 H), 1.97 (d, J = 1.5 Hz, 3 H), 1.33
(s, 3 H), 1.10 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 201.3
(C), 195.6 (C), 153.6 (C), 137.2 (CH), 135.5 (CH), 118.6 (CH2),
87.7 (C), 86.8 (CH), 70.3 (C), 57.2 (CH), 51.9 (CH2), 32.0 (CH2),
28.5 (CH3), 25.4 (CH3), 16.0 (CH3) ppm. HRMS (ESI): calcd. for
C15H20O4Na [M + Na]+ 287.1254; found 287.1255. 2: Rf = 0.48
(ethyl acetate/light petroleum, 1:1). M.p. 68–71 °C (ref.[6] m.p. 74–
75 °C). [α]D = +13.0 (c = 0.1 CHCl3) [ref.[6] [α]D = +50.4 (c = 0.4
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CHCl )]. IR: ν = 3459 (br.), 2975, 2928, 1685, 1622, 1378, 1351,
˜
3
1248, 1181, 1115, 1068, 1031, 1006 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 6.68 (q, J = 1.5 Hz, 1 H), 5.62 (m, 1 H), 5.13 (m, 1
H), 5.09 (d, J = 5.8 Hz, 1 H), 3.95 (dd, J = 10.7, 5.3 Hz, 1 H), 3.28
(m, 1 H), 2.95 (d, J = 16.3 Hz, 1 H), 2.83 (d, J = 16.3 Hz, 1 H),
2.05 (m, 1 H), 1.99 (d, J = 1.5 Hz, 3 H), 1.93 (m, 1 H), 1.84 (br. s,
1 H, OH), 1.24 (s, 3 H), 1.13 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 196.8 (C), 196.3 (C), 151.9 (C), 137.1 (CH), 134.7
(CH), 119.9 (CH2), 87.0 (C), 86.8 (CH), 70.4 (C), 48.8 (CH), 47.1
(CH2), 32.5 (CH2), 27.7 (CH3), 24.6 (CH3), 16.3 (CH3) ppm.
HRMS (ESI): calcd. for C15H20O4Na [M + Na]+ 287.1254; found
287.1254.
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rac-2-(5,6-Dihydroxy-6-methylhept-1-en-3-yl)-4-methoxy-5-methyl-
phenyl Acetate (rac-21 and rac-22): Potassium osmate(VI) dihydrate
(0.7 mg, 0.002 mmol, 0.5 mol-%) and N-methylmorpholine N-oxide
(50 mg, 0.43 mmol, 1.1 equiv.) were added to a solution of 4-meth-
oxy-5-methyl-2-(6-methylhepta-1,5-dien-3-yl)phenyl acetate
(112 mg, 0.39 mmol) in tBuOH/H2O (1:1; 0.76 mL). The reaction
mixture was stirred at room temperature for 24 h, then it was ex-
tracted with ethyl acetate (3ϫ 10 mL). The combined organic ex-
tracts were dried with Na2SO4 and concentrated in vacuo. The resi-
due was purified by flash chromatography on silica (ethyl acetate/
light petroleum, 2:3) to give a mixture of rac-21 and rac-22 (60 mg,
48%) as a colourless oil. Rf = 0.35 (ethyl acetate/light petroleum,
1:1). Other spectroscopic data were consistent with those obtained
from enantioenriched 21 and 22.
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anti-5-(2-Hydroxy-5-methoxy-4-methylphenyl)-2-methylhept-6-ene-
2,3-diol (rac-23) and syn-5-(2-Hydroxy-5-methoxy-4-methylphenyl)-
2-methylhept-6-ene-2,3-diol (rac-24): Potassium carbonate (122 mg,
0.88 mmol, 3 equiv.) was added to a solution of 2-(5,6-dihydroxy-
6-methylhept-1-en-3-yl)-4-methoxy-5-methylphenyl acetate (mix-
ture of diastereomers; 94 mg, 0.29 mmol) in methanol (4.5 mL).
The reaction mixture was stirred vigorously for 1 h, then it was
diluted with methanol (20 mL) and filtered. The filtrate was con-
centrated in vacuo, and the resulting residue was purified by flash
chromatography on silica (ethyl acetate/light petroleum, 2:3) to give
rac-23 (31 mg, 38%) as a colourless solid and rac-24 (25 mg, 31%)
as a colourless oil. rac-23: Rf = 0.25 (ethyl acetate/light petroleum,
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6
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Job/Unit: O42420
/KAP1
Date: 01-07-14 18:02:56
Pages: 8
Total Synthesis of (–)-Heliespirone A and (+)-Heliespirone C
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Received: April 15, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42420
/KAP1
Date: 01-07-14 18:02:56
Pages: 8
P. Norcott, C. S. P. McErlean
FULL PAPER
Total Synthesis
Total syntheses of the epimeric natural
products (–)-heliespirone A and (+)-helie-
spirone C are described. The successful
strategy involved an aromatic Claisen re-
arrangement, a diastereoselective Sharpless
asymmetric dihydroxylation (AD) reaction,
and an intramolecular oxa-Michael ad-
dition.
P. Norcott, C. S. P. McErlean* ......... 1–8
Total Synthesis of (–)-Heliespirone A and
(+)-Heliespirone C
Keywords: Total synthesis / Natural prod-
ucts / Asymmetric synthesis / Sigmatropic
rearrangement / Michael addition / Spiro
compounds
8
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