Synthesis of Highly Enantio-Enriched Heliespirones A and C by a Diastereoselective Aromatic Claisen Rearrangement

Article abstract of DOI:10.1071/CH18019

Computational methods were used to investigate the stereochemical course of the extra-annular Claisen rearrangement. The stereochemical fidelity of the synthetic strategy and comparison of the optical properties support the hypothesis that the heliespirones are scalemic natural products.

Full text of DOI:10.1071/CH18019

CSIRO PUBLISHING
Aust. J. Chem. 2018, 71, 366–372
Full Paper
https://doi.org/10.1071/CH18019
Synthesis of Highly Enantio-Enriched Heliespirones A and C
by a Diastereoselective Aromatic Claisen Rearrangement
A
A B
,
Philip Norcott and Christopher S. P. McErlean
A
School of Chemistry, University of Sydney, Sydney, NSW 2006, Australia.
Corresponding author. Email: christopher.mcerlean@sydney.edu.au
B
Computational methods were used to investigate the stereochemical course of the extra-annular Claisen rearrangement.
The stereochemical fidelity of the synthetic strategy and comparison of the optical properties support the hypothesis that
the heliespirones are scalemic natural products.
Manuscript received: 12 January 2018.
Manuscript accepted: 7 March 2018.
Published online: 9 April 2018.
Introduction
Asymmetric total synthesis of both 4 and 5 has confirmed that
these compounds exist naturally in highly enantio-enriched
forms.[4]
Mac´ıas and coworkers reported the isolation of heliespirone A
(1) and heliespirone C (2) from a sunflower cultivar in 1998 and
2006 respectively (Fig. 1).[1,2] The source plant has demon-
strated natural herbicidal activity against the seedling growth of
several common weeds, and consequently, it has been exploited
as a potential source of new agrichemicals. Mac´ıas suggested
that the spiro-epimeric heliespirones may ultimately derive
from the co-isolate, heliannuol C (4), which possesses the same
absolute configuration.[2,3] Another possible biosynthetic pro-
genitor is the six-membered variant, heliannuol E (5), which
possesses the opposite configuration at the cyclic ether.
The heliespirones have attracted significant synthetic inter-
est, with four total syntheses reported to date, either of the
naturally occurring enantiomers[5,6] or their antipodes.[7,8] Our
recently reported synthesis utilized an aromatic Claisen rear-
rangement, followed by a Sharpless asymmetric dihydroxyla-
tion (AD) reaction to generate the key intermediate 8
(Scheme 1).[5] However, the Sharpless AD reaction does not
perform well on compounds such as 7,[9,10] and in that instance,
the level of enantiomeric excess (ee) that could be induced in the
process was only 17 %. When this material was advanced
through the synthetic sequence, we were very surprised to find
that both our synthetic heliespirone A (1) and heliespirone C (2)
had the same values of optical rotation as the isolated com-
pounds. A range of values for the optical rotation of synthetic
heliespirones have been reported in the literature (see Supple-
mentary Material) and, in particular, Shishido reported that the
O
O
O
(S)
O
(S)
O
O
HO
HO
2
1
OMe
Non-selective
Claisen
(ϩ)-heliespirone C
(Ϫ)-heliespirone A
Kinetic resolution
Sharpless AD
rearrangement
O
Previous
work
OH
7
OMe
OMe
proposed
biosynthesis
OH
O
Stereocontrolling
centre?
3
O
OH
OH
OH
OH
HO
6
OMe
OH
8
Current
work
HO
HO
(S)
OH
(R)
O
O
Stereoselective
Claisen
rearrangement
OH
Enantioselective
Sharpless AD
4
5
O
heliannuol C
heliannuol E
9
Fig. 1. Heliespirones A (1) and C (2), and some possible biosynthetic
Scheme 1. Pathways to the proposed biosynthetic intermediate 8.
progenitors.
Journal compilation Ó CSIRO 2018
www.publish.csiro.au/journals/ajc

Synthesis of Heliespirones A and C
367
enantiomerically pure samples possessed significantly higher
specific rotations.[6] Given that heliespirone A (1) and heliespir-
one C (2) were isolated independently, it is unlikely that
co-incident measurement errors were responsible for the apparent
low ee. If an inadvertent resolution had occurred during our
reported synthetic sequence, it is improbable (though not impos-
sible) that the optical rotation data would individually match both
of the natural products. Does this mean that the naturally occurring
heliespirones exist as scalemic mixtures?[11,12] To clarify the
situation, we devised a second-generation strategy to the helie-
spirones, which is reported below.
(Scheme 3). The remote stereogenic centre imposed a substrate-
controlled reaction that produced a 2 : 1 mixture of diastereomers
14 and 8.[19] Inopposition toexpectation, the desiredisomer8 was
the minor componentof the mixture. Single-crystal X-ray analysis
served to unambiguously demonstrate the relative stereochemis-
try of compound 8 (Fig. 4). Other Lewis and protic acids were
screened for this transformation, as well as simple heating, but in
all instances, elimination of the stereochemically defined alcohol
was observed. Enantioselective HPLC analysis of compound 8
demonstrated that the absolute stereochemical integrity of the
molecule remained intact (Fig. 5).
Results and Discussion
OMe
HO
OH
Asshowninthe lowersection ofScheme1, weplanned toperform
the Sharpless AD reaction on compound 6 to give compound 9.
We then hoped that the newly installed stereogenic centre would
influence the stereochemical outcome of a subsequent Claisen
rearrangement and give compound 8 in a stereoselective fashion.
The projected stereo-directing centre is two carbons removed
from the newly forming bond, and resides on a flexible carbon
chain. To the best of our knowledge, there are no examples in the
literature of an aromatic Claisen rearrangement being influenced
by such a remote extra-annular stereocentre.[13–16]
O
enantioenriched
In analogy to our previous work, the synthesis began with
Friedel–Crafts acylation of 2-methylanisole (10) in the presence
of anhydrous aluminium trichloride to give compound 11[17]
(Scheme 2). Baeyer–Villiger oxidation with m-chloroperoxy-
benzoic acid and acidic hydrolysis gave 4-methoxy-m-cresol
(12) in high yield.[13] This was coupled with the known alcohol
13[5] under Mitsunobu conditions to give the desired compound
6, which was expected to perform well under Sharpless AD
reaction conditions.[9,10] Pleasingly, treatment of 6 with com-
mercial AD-mix-a gave compound 9 in moderate yield but,
importantly, with excellent enantioselectivity, .97 % ee.
(Fig. 2). Compound 9 was the substrate for the planned diaster-
eoselective aromatic Claisen rearrangement.
Racemic
Co-injection
The aromatic Claisen rearrangement is known to proceed
preferentially through a chair-like transition state.[18] We hoped
that a chelating Lewis acid would sequester the diol unit, and
that minimization of A1,3-strain would result in one face of the
alkene being shielded by the geminal methyl groups (Fig. 3).
When subjected to the action of 2 equivalents of Me2AlCl at low
temperature in a non-polar solvent, compound 9 did undergo
a moderately stereoselective aromatic Claisen rearrangement
0
10
20
30
40
Elution time [min]
Fig. 2. Enantioselective HPLC traces of (ꢀ)-9 and (ꢁ)-9.
M
O
O
O
H
H
MeO
OMe
Most
accessible
face
OMe
OMe
CH3COCl,
AlCl3
mCPBA,
then HCl
Minimized
1,3-strain
82 %
76 %
Fig. 3. Anticipated complex between Me2AlCl and compound (ꢀ)-9.
M ¼ metal atom.
O
OH
10
11
12
HO
OH
13
13, PPh3
OH
OMe
HO
OMe
OMe
DIAD,
80 %
Me2AlCl
dr 2:1
OMe
OMe
ϩ
HO
AD-mix-α,
MeSO2NH2
O
OH
OH
OH
OH
OH
OH
52 %
8
14
38 %
9
O
O
19 %
6
9
Scheme 3. Diastereoselective aromatic Claisen rearrangement. d.r. ¼ dia-
Scheme 2. Synthesis of compound 9.
stereomeric ratio.

368
P. Norcott and C. S. P. McErlean
C(15)
O(4)
C(16)
C(10)
C(11)
C(8)
O(1)
C(9)
C(6)
C(7)
C(5)
C(4)
O(3)
C(1)
C(12)
C(13)
C(2)
C(3)
O(2)
C(14)
Fig. 4. ORTEP representation of diastereomer 8.
OMe
OH
OH
OH
TS15a
TS15b
ΔΔG ϭ ϩ8.4 kJ molϪ1
(m ϭ 5.81 D)
ΔΔG ϭ ϩ20.3 kJ molϪ1
(m ϭ 6.24 D)
TS15c
TS15d
ΔΔG ϭ ϩ3.8 kJ molϪ1
(m ϭ 7.33 D)
ΔΔG ϭ 0 kJ molϪ1
(m ϭ 6.07 D)
0
20
40
60
Elution time [min]
Fig. 6. Transition-state structures for the aromatic Claisen rearrangement
of intermediate 15. Purple ¼ Al; red ¼ O; grey ¼ C; white ¼ H. Dipole
moment (m) in debyes (D).
Fig. 5. Enantioselective HPLC traces of (ꢀ)-8 and (ꢁ)-8.
Ϫ
Al
ϩ
O
Ϫ
H
Al
OMe
OMe
H
O
ϩ
B3LYP/6–31G* level of theory, with inclusion of solvent
effects using the C-PCM (conductor-like polarizable continuum
model) method. As displayed in Fig. 6, all four transition-state
structures possessed common features: (1) A1,3-strain was
minimized between the hydrogen atoms attached to C-4 and
C-6 during the rearrangement; (2) the C-3 stereocentre was
oriented with the smallest substituent (the H atom) projecting
over the C-5–C-6 alkene; and (3) the methoxy substituent on the
aromatic ring rotated to minimize steric interactions.
Me2AlCl
pentane
O
O
2
3
4
1
9
5
6
O
O
15
16
Scheme 4. Relative energies of possible precursors for the aromatic
Claisen rearrangement.
Transition-state structures TS15a and TS15c possess chair-
like conformations and, as predicted at the outset of the synthe-
sis, the lower-energy structure TS15c leads to the naturally
occurring (R)-configuration at the newly formed stereocentre of
compound 8. In contrast, transition-state structures TS15b and
TS15d possess boat-like conformations, but surprisingly,
TS15d proved to be on the lowest-energy pathway for the
aromatic Claisen rearrangement, giving compound 14. The
preference for TS15d results from not only a minimization of
steric interactions (TS15a versus TS15d), but also from a
Because there was no literature precedent for this type of
diastereoselective extra-annular aromatic Claisen rearrange-
ment, we investigated the transformation using computational
methods. Based on the relative pKa values of secondary and
tertiary alcohols, we anticipated that reaction between diol 9 and
Me2AlCl would yield intermediate 15 in preference to interme-
diate 16 (Scheme 4).
The transitions state structures (TS15a–d) for the aromatic
Claisen rearrangement of intermediate 15 were calculated at the

Synthesis of Heliespirones A and C
369
O
OMe
Table 1. Comparison of enantiomeric excess from second-generation
synthesis
CAN
35 %
Compound
Measured ee [%] Specific optical rotation
OH
OH
O
OH
OH
Compound 8
98A
97B
–
ꢀ16.4 (c 0.29, CHCl3)
ꢀ107 (c 0.55, CHCl3)
ꢀ29 (c 0.1, CHCl3)
ꢀ47 (c 0.12, CHCl3)
ꢀ55.2 (c 0.13, CHCl3)
þ14.4 (c 0.1, CHCl3)
þ48 (c 0.09, CHCl3)
þ50.4 (c 0.4, CHCl3)
3
8
Compound 3
OH
Natural heliespirone A (1)
Synthetic heliespirone A
Shishido’s heliespirone A[6]
Natural heliespirone C (2)
Synthetic heliespirone C
Shishido’s heliespirone C[6]
Cs2CO3
95C
–
O
O
–
97D
ϩ
–
O
O
AMeasured on a Chiralcel OD-H column, 8 % isopropanol in hexane.
BMeasured on a Chiralcel OD-H column, 4 % ethanol in hexane.
CMeasured on a Chiralcel OD-H column, 8 % isopropanol in hexane.
DMeasured on a Chiralcel OD-H column, 4 % isopropanol in hexane.
O
O
1
2
HO
HO
22 %
20 %
Scheme 5. Synthesis of the heliespirones 1 and 2.
determined using a Stanford Research Systems Optimelt auto-
mated melting point system and are uncorrected. Infrared
spectra were acquired neat on a Bruker Alpha-E attenuated total
reflectance (ATR) spectrometer (cmꢀ1). UV-vis absorption
spectra were recorded on a Varian Cary 50 spectrophotometer
and absorption maxima are expressed in wavenumbers. 1H and
13C NMR spectra were recorded on 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 (7.26 ppm) or residual methanol (3.31 ppm) as ref-
erence and are reported as chemical shift (dH); relative integral;
multiplicity (s ¼ singlet, br ¼ broad, d ¼ doublet, t ¼ triplet,
dd ¼ doublet of doublets, dt ¼ doublet of triplets, q ¼ quartet,
m ¼ multiplet), and coupling constants (J) reported in hertz.
13C NMR chemical shifts are expressed as parts per million
(ppm) with residual chloroform (77.1 ppm) or residual methanol
(49.0 ppm) as internal reference and are reported as chemical
shift (dC); multiplicity (assigned from DEPT experiments).
High-resolution mass spectra (HRMS) were recorded on a
Bruker ApexII Fourier-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-mm (230–400 mesh)
silica gel using distilled solvents. Analytical thin layer chro-
matography was performed using preconditioned plates (Merck
TLC silica gel 60 F254 on aluminium) and visualized using UV
light (254 and 365 nm) and ethanolic anisaldehyde.
minimization of the structure’s overall dipole moment (TS15c
versus TS15d). As such, the nature of the solvent is likely to play
a crucial role in the stereochemical outcome of this and related
reactions. Although the calculated difference in activation
energies between TS15c and TS15d does not exactly predict
the observed 2 : 1 ratio of product diastereomers, it does predict
the predominant isomer. The calculated energies starting from
compound 16 also showed favoured production of the observed
stereoisomer (Supplementary Material). It is important to note
that charge acceleration and the nature of the counter-ion were
not included in these calculations.
To complete the total synthesis, compound 8 was converted
into the quinone 3 (Scheme 5), and subsequently treated with
Cs2CO3 gave the desired products (ꢀ)-heliespirone A (1) and
(þ)-heliespirone C (2). Again, analysis by enantioselective
HPLC demonstrated that the reaction sequence had not affected
the absolute stereochemistry of the compounds (see Supplemen-
tary Material). As outlined in Table 1, the heliespirone natural
products were produced in a highly enantio-enriched fashion, and
the observed specific rotations were in good agreement with
Shishido’s values.[6] This demonstrated that an inadvertent reso-
lution had not taken place during our first generation synthesis,
and that naturally occurring heliespirone A (1) and heliespirone C
(2) possess enantiomeric excesses lower than 20 %.
Conclusion
Density functional theory (DFT) calculations were carried
out with the Spartan ’16 program.[24] Geometries and energies
of transition states and intermediates were obtained using the
B3LYP functional with the 6–31G* basis set. The vibrational
frequencies of stationary points were inspected to ensure that
they corresponded to minima on the potential energy surface.
All relative energies are reported uncorrected at 298 K in kilo-
joules per mole.
Crystallographic data for compound 8 have been deposited
with the Cambridge Crystallographic Data Centre (CCDC) and
can be obtained free of charge on quoting the depository number
CCDC 1825691 (http://www.ccdc.cam.ac.uk).
This article describes a second-generation synthesis of the plant-
derived natural products (ꢀ)-heliespirone A (1) and (þ)-helie-
spirone C (2). The improved route is not only shorter than our
previous approach (eight steps for the longest linear synthesis)
but features a diastereoselective aromatic Claisen rearrange-
ment in which the stereocontroling unit is distal to the rearran-
ging bonds. Both natural products were obtained with excellent
enantiopurity, and the outcomes of this work suggest that the
heliespirones occur naturally as scalemic mixtures.[20–23]
Experimental
General Experimental
40-Methoxy-30-methylacetophenone 11[17]
Reagent-grade dichloromethane and triethylamine were freshly
distilled from calcium hydride. Tetrahydrofuran and methanol
were collected using an Innovative Technology Inc. PureSolvTM
solvent purification system. All other solvents and reagents were
used as received from commercial sources. Melting points were
Toamixtureofanhydrousaluminiumchloride(2.4g,18mmol)in
CH2Cl2 (4mL) was added slowly a solution of 2-methylanisole
(3.4g, 28mmol) in CH2Cl2 (4mL), then acetyl chloride (2.3mL,
32 mmol) in CH2Cl2 (2mL). The mixture was heated to reflux for

370
P. Norcott and C. S. P. McErlean
2 h, then cooled, quenched with aqueous HCl (3 M, 3 mL) and
extracted with diethyl ether (2ꢂ 20 mL), washed with brine
(10 mL), dried over Na2SO4, and concentrated under vacuum.
Flash chromatography on silica gel, eluting with 20 % ethyl
acetateinlightpetroleum, gave11 (3.5 g, 76 %) as acolourlessoil;
Rf 0.32 (20 % ethyl acetate in light petroleum). nmax (oil)/cmꢀ1
2958, 2840, 1671, 1599, 1581, 1502, 1414, 1356, 1295, 1254,
1174, 1129, 1082, 1025.dH (300MHz, CDCl3) 7.77–7.73(2H, m,
ArH), 6.77 (1 H, d, J 8.4, ArH), 3.82 (3 H, d, J 2.1, OCH3), 2.49
(3 H, d, J 2.4, CH3CO), 2.21 (3 H, s, CH3). dC (75MHz, CDCl3)
196.4 (C), 161.4 (C), 130.4 (CH), 129.5 (C), 128.2 (CH), 126.3
(C), 108.8 (CH), 55.1 (CH3), 25.8 (CH3), 15.8 (CH3).
ArH), 5.91–5.71 (2 H, m, CH=CH), 5.24 (1 H, t, J 7.3, CH), 4.46
(2 H, dd, J 5.7, 0.9, OCH2), 3.82 (3 H, s, OCH3), 2.84 (2 H, dd,
J 6.3, 6.3, CH2), 2.27 (3 H, s, ArCH3), 1.79 (3 H, s, CH3), 1.69 (3
H, s, CH3). dC (75 MHz, CDCl3) 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). m/z (electrospray ionization
(ESI) HRMS) 247.1694 [MHþ]. C16H23O2þ requires 247.1693.
(3S, 5E)-7-(4-Methoxy-3-methylphenoxy)-2-methylhept-
5-ene-2,3-diol (ꢀ)-9
To a mixture of AD-mix-a (1.4 g) and methanesulfonamide
(114 mg, 1.20 mmol) was added water (5 mL) and tert-butanol
(5 mL). The mixture was stirred vigorously until complete dis-
solution, then cooled to 08C. Compound 6 (250 mg, 1.0 mmol)
was added and the reaction mixture was stirred at 08C for 1 h,
then at room temperature overnight. Sodium sulfite (500 mg)
was added and the mixture was stirred for a further 20 min, then
diluted with water (10 mL), extracted with ethyl acetate
(3 ꢂ 20 mL), dried over Na2SO4, and concentrated under vac-
uum. Flash chromatography on silica gel, eluting with 40 %
ethyl acetate in light petroleum, gave (2)-9 (148 mg, 52 %, 98 %
ee) as a colourless oil; Rf 0.26 (50 % ethyl acetate in light
4-Methoxy-3-methylphenol 12[17]
To a solution of 11 (3.5 g, 21 mmol) in CH2Cl2 (15 mL) at 08C
was added meta-chloroperbenzoic acid (m-CPBA) (85 % with
chlorobenzoic acid; 7.8 g, 38 mmol) and the reaction mixture
was heated to reflux overnight. The mixture was cooled, then
quenched with saturated Na2S2O3 solution (10 mL), extracted
with ether (2 ꢂ 20 mL), and washed successively with further
saturated Na2S2O3 solution (10 mL), saturated NaHCO3 solu-
tion (10 mL), water (10 mL), and brine (10 mL), then dried over
Na2SO4, and concentrated under vacuum. Purification by flash
chromatography on silica gel, eluting with 5 % ethyl acetate in
light petroleum, gave 4-methoxy-3-methylphenylacetate (3.2 g,
83 %) as a light yellow oil; Rf 0.69 (20 % ethyl acetate in light
petroleum). nmax (oil)/cmꢀ1 2952, 2837, 1754, 1497, 1368,
1223, 1196, 1176, 1150, 1118, 1031, 1014. dH (300 MHz,
CDCl3) 6.92–6.87 (2 H, m, ArH), 6.81–6.78 (1 H, m, ArH), 3.80
(3 H, s, OCH3), 2.27 (3 H, s, CH3), 2.24 (3 H, s, CH3). dC
(75 MHz, CDCl3) 169.7 (C), 155.3 (C), 143.7 (C), 127.6 (C),
123.5 (CH), 119.0 (CH), 110.1 (CH), 55.4 (CH3), 20.8 (CH3),
16.1 (CH3). A mixture of 4-methoxy-3-methylphenylacetate
(2.0 g, 11 mmol) in THF (10 mL) and aqueous HCl (3 M, 3 mL)
was heated to reflux overnight. The reaction mixture was
allowed to cool, then diluted with water (30 mL), extracted with
diethyl ether (2 ꢂ 30 mL), washed with water (10 mL) and brine
(10 mL), dried over Na2SO4, and concentrated under vacuum.
Flash chromatography on silica gel, eluting with 10 % ethyl
acetate in light petroleum, gave 12 (1.5 g, 99 %) as a light yellow
oil; Rf 0.45 (20 % ethyl acetate in light petroleum). nmax
(oil)/cmꢀ1 3325, 2951, 2833, 1500, 1464, 1430, 1286, 1212,
1178, 1154, 1119, 1033. dH (300 MHz, CDCl3) 6.81 (1 H, br s,
OH), 6.68–6.67 (3 H, m, ArH), 3.75 (3 H, s, OCH3), 2.17 (3 H, s).
dC (75 MHz, CDCl3) 151.8 (C), 149.2 (C), 128.1 (C), 118.1
(CH), 112.8 (CH), 111.8 (CH), 56.1 (CH3), 16.2 (CH3).
20
petroleum). ½aꢃD ꢀ16.4 (c 0.29, CHCl3). nmax (oil)/cmꢀ1 3409
(br), 2971, 1667, 1500, 1217, 1064. dH (300 MHz, CDCl3) 6.73–
6.65 (3 H, m), 5.93–5.75 (2 H, m), 4.42 (2 H, d, J 4.9), 3.77 (3 H,
s), 3.43 (1 H, dd, J 10.0, 1.6), 2.62 (1 H, br s, OH), 2.46 (1 H, br s,
OH), 2.36–2.09 (2 H, m), 2.19 (3 H, s), 1.21 (3 H, s), 1.16 (3 H,
s). dC (75 MHz, CDCl3) 152.3 (C), 152.2 (C), 131.8 (CH), 128.2
(CH), 127.8 (C), 118.1 (CH), 112.0 (CH), 110.9 (CH), 77.4
(CH), 72.8 (C), 69.1 (CH2), 55.9 (CH3), 35.0 (CH2), 26.4 (CH3),
23.6 (CH3), 16.4 (CH3). m/z (ESI HRMS) 303.1567 [MNaþ].
C16H24O4Naþ requires 303.1567. Enantiomeric excess was
determined by HPLC analysis (Chiralcel OD-H column, 8 %
iso-propanol/hexane, 0.7 mL minꢀ1, retention times 24.9 min
(major) and 31.5 min (minor)).
(ꢁ)-(E)-7-(4-Methoxy-3-methylphenoxy)-2-methylhept-
5-ene-2,3-diol (ꢁ)-9
To a solution of 6 (250 mg, 1.0 mmol) in tert-butanol (5 mL) and
water (5 mL) was added potassium osmate(VI) dihydrate (2 mg,
5 mmol, 0.5 mol-%) and N-methylmorpholine-N-oxide (129 mg,
1.1 mmol). The reaction mixture was stirred at room tempera-
ture for 24 h, then diluted with water (10 mL), extracted with
ethyl acetate (3 ꢂ 10 mL), dried over Na2SO4, and concentrated
under vacuum to give (ꢁ)-9.
(E)-1-Methoxy-2-methyl-4-((6-methylhepta-2,5-dien-1-yl)
oxy)benzene 6[5]
(3S,5S)-5-(2-Hydroxy-5-methoxy-4-methylphenyl)-2-
methylhept-6-ene-2,3-diol (ꢀ)-14 and (3S, 5R)-5-(2-
Hydroxy-5-methoxy-4-methylphenyl)-2-methylhept-6-
ene-2,3-diol (ꢀ)-8
To a solution of 12 (570 mg, 4.13 mmol), 6-methylhepta-2,5-
dien-1-ol (13) (260 mg, 2.06 mmol) and triphenylphosphine
(1.08 g, 4.12 mmol) in THF (7 mL) at 08C was added
di-isopropyl azodicarboxylate (820 mL, 4.16 mmol) and the
reaction mixture was allowed to return to room temperature
overnight. The reaction was quenched by addition of water
(15 mL), and the mixture was extracted with ethyl acetate
(2 ꢂ 20 mL), dried over Na2SO4, and concentrated under vac-
uum. Flash chromatography on silica gel, eluting with 5 % ethyl
acetate in light petroleum, gave 6 (404 mg, 80 %) as a yellow oil;
Rf 0.74 (10 % ethyl acetate in light petroleum). nmax (oil)/cmꢀ1
2926, 1499, 1463, 1441, 1377, 1280, 1215, 1181, 1162, 1036. dH
(300 MHz, CDCl3) 6.82–6.81 (1 H, m, ArH), 6.76–6.75 (2 H, m,
To a solution of compound 9 (88 mg, 0.31 mmol) in CH2Cl2
(7 mL) at ꢀ788C was added dimethylaluminium chloride (1 M
in hexanes; 0.7 mL, 0.7 mmol). The reaction mixture was
allowed to return to room temperature, stirred for a further 6 h,
and was then quenched by the addition of water (5 mL). The
solvent was removed under vacuum and the residue purified by
flash chromatography on silica gel, eluting with 40 % ethyl
acetate/0.5 % acetic acid in light petroleum, to give 14 (33 mg,
38 %) as a colourless oil; Rf 0.32 (50 % ethyl acetate in light
20
petroleum). ½aꢃD ꢀ52.3 (c 0.49, MeOH), nmax (oil)/cmꢀ1 3376
(br), 2972, 2926, 1705, 1637, 1501, 1463, 1410, 1364, 1200,

Synthesis of Heliespirones A and C
371
1165, 1079, 1023, 1001. dH (300 MHz, CDCl3) 6.61 (1 H, s),
6.59 (1 H, s), 6.12 (1 H, ddd, J 17.1, 10.2, 6.6), 5.06–4.95 (2 H,
m), 3.96–3.89 (1 H, m), 3.72 (3 H, s), 3.06 (1 H, dd, J 10.5, 1.2),
2.12–2.03 (4 H, m, CH þ CH3), 1.68 (1 H, ddd, J 14.1, 10.8, 3.9),
1.12 (3 H, s), 1.08 (3 H, s). dC (75 MHz, CDCl3) 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). m/z (ESI HRMS)
303.1568 [MNaþ]. C16H24O4Naþ requires 303.1567; and
Compound 8 (17 mg, 19 %, 97 % ee) as a colourless solid;
Rf 0.25 (50 % ethyl acetate in light petroleum); mp 157–
1128, 1062, 1005. dH (300 MHz, CDCl3) 6.61 (1 H, q, J 1.4),
5.31 (1 H, dt, J 16.8, 9.6), 5.06 (1 H, ddd, J 16.8, 1.3, 0.7), 4.96
(1 H, dd, J 10.0, 1.3), 4.80 (1 H, br s), 4.04 (1 H, dd, J 10.8, 5.3),
3.24 (1 H, d, J 15.6), 2.96 (1 H, d, J 15.6), 2.92 (1 H, ddd, J 12.6,
9.1, 6.6), 2.15 (1 H, td, J 12.7, 10.8), 2.01–1.93 (1H, m), 1.97 (3H,
d, J 1.5), 1.33 (3 H, s), 1.10 (3 H, s). dC (75 MHz, CDCl3) 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). m/z (ESI HRMS) 287.1255
[MNaþ]. C15H20O4Naþ requires 287.1254. Enantiomeric excess
was determined by HPLC analysis (Chiralcel OD-H column, 8 %
iso-propanol/hexane, 0.7 mL minꢀ1, retention times 20.0 min
(major) and 27.6 min (minor)); and
20
1598C.½aꢃD ꢀ107.3 (c 0.55, CHCl3). nmax (film)/cmꢀ1 3398
(br), 2964, 2929, 1706, 1639, 1512, 1462, 1408, 1376, 1365,
1323, 1199, 1162, 1119, 1073, 1021, 1005. dH (300 MHz,
CDCl3) 6.65 (1 H, s), 6.56 (1 H, s), 6.03 (1 H, ddd, J 17.4, 9.9,
8.4), 5.14–5.02 (2 H, m), 3.92–3.84 (1 H, m), 3.73 (3 H, s), 3.44
(1 H, ddd, J 10.2, 1.2), 2.15–2.06 (4 H, m, CH þ CH3), 1.53 (1 H,
ddd, J 14.1, 10.8, 3.3), 1.17 (3 H, s), 1.14 (3 H, s). dC (75 MHz,
CDCl3) 152.6 (C), 148.8 (C), 142.2 (CH), 130.6 (C), 125.9 (C),
119.1 (CH), 115.2 (CH2), 111.9 (CH), 77.1 (CH), 73.8 (C), 56.6
(CH3), 41.7 (CH), 37.5 (CH2), 25.8 (CH3), 25.0 (CH3), 15.9
(CH3). m/z (ESI HRMS) 303.1567 [MNaþ]. C16H24O4Naþ
requires 303.1567. Enantiomeric excess was determined by
HPLC analysis (Chiralcel OD-H column, 4 % ethanol/hexane,
0.7 mL minꢀ1, retention times 31.5 min (minor) and 35.0 min
(major)).
(þ)-Heliespirone C (2) (10 mg, 20 %, 97 % ee) as a colour-
less solid; Rf 0.48 (50 % ethyl acetate in light petroleum); mp
20
68–718C (lit. mp 74–758C[6]); ½aꢃD þ48.0 (c 0.09, CHCl3) (lit.
20
½aꢃD þ50.4 (c 0.4, CHCl3)[6]). nmax (film)/cmꢀ1 3459 (br), 2975,
2928, 1685, 1622, 1378, 1351, 1248, 1181, 1115, 1068, 1031,
1006. dH (300 MHz, CDCl3) 6.68 (1 H, q, J 1.5), 5.62 (1 H, m),
5.13 (1 H, m), 5.09 (1 H, d, J 5.8), 3.95 (1 H, dd, J 10.7, 5.3), 3.28
(1 H, m), 2.95 (1 H, d, J 16.3), 2.83 (1 H, d, J 16.3), 2.05 (1 H, m),
1.99 (3 H, d, J 1.5), 1.93 (1 H, m), 1.84 (1 H, br s, OH), 1.24 (3 H,
s), 1.13 (3 H, s). dC (75 MHz, CDCl3) 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). m/z (ESI HRMS) 287.1254 [MNaþ].
C15H20O4Naþ requires 287.1254. Enantiomeric excess was
determined by HPLC analysis (Chiralcel OD-H column, 4 %
iso-propanol/hexane, 0.7 mL minꢀ1, retention times 21.5 min
(minor) and 22.9 min (major)).
2-((3R,5S)-5,6-Dihydroxy-6-methylhept-1-en-3-yl)-5-
methylcyclohexa-2,5-diene-1,4-dione 3
To a stirred mixture of 8 (39 mg, 0.14 mmol) in acetonitrile (1 mL)
at08Cwasaddeddropwise asolutionofcerium ammoniumnitrate
(153mg, 0.28 mmol) in water (1mL). After stirring at 08C for
5 min, the mixture was diluted with water (10 mL) and extracted
with ethyl acetate (3ꢂ 10 mL), dried over Na2SO4, and concen-
trated under vacuum. Flash chromatography on silica gel, eluting
with 50 % ethyl acetate in light petroleum, gave 3 (13 mg, 35%)
as a yellow oil; Rf 0.39 (50% ethyl acetate in light petroleum).
Supplementary Material
1H and 13C NMR spectra for all synthesized compounds,
Cartesian coordinates and absolute energies of calculated
structures, and enantioselective HPLC traces of compounds 1
and 2 are available on the Journal’s website.
20
½aꢃD ꢀ61.2 (c 0.34, CHCl3). nmax (oil)/cmꢀ1 3431 (br), 2975,
Conflicts of Interest
2926, 1651, 1609, 1442, 1301, 1351, 1257, 1239, 1135, 1070,
1005. dH (300 MHz,CDCl3) 6.59 (1 H,m), 6.53(1H, s),5.77(1H,
ddd, J 17.9, 9.8, 8.6), 5.23–5.17 (2 H, m), 3.72 (1 H, td, J 9.2, 3.7),
3.45 (1 H, d, J 10.5), 2.35 (1 H, br s, OH), 2.05–1.95 (4 H, m,
CH3 þ OH), 1.77–1.69 (1 H, m), 1.53 (1 H, ddd, J 14.2, 10.6, 3.9),
1.20 (3 H, s), 1.14 (3 H, s). dC (75 MHz, CDCl3) 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). m/z (ESI HRMS) 287.1255
[MNaþ]. C15H20O4Naþ requires 287.1254.
The authors declare no conflicts of interest.
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