Enantioselective synthesis of the 3C-protease inhibitor (-)-thysanone by a Staunton-Weinreb annulation strategy

Article abstract of DOI:10.1055/s-0029-1217390

The total synthesis of (-)-thysanone is described. The key step involves the addition of an o-toluate anion to a lactone to create the naphthopyran framework (Staunton-Weinreb annulation). This synthesis further confirms the absolute stereochemistry of th

Full text of DOI:10.1055/s-0029-1217390

PAPER
2561
Enantioselective Synthesis of the 3C-Protease Inhibitor (–)-Thysanone by a
Staunton–Weinreb Annulation Strategy
E
nantiosel
o
e
ctive Synth
n
e
sis of (–)-T
a
Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland 1142, New Zealand
Fax +64(9)3737422; E-mail: m.brimble@auckland.ac.nz
Received 27 February 2009
on the cyanophthalide coupling partner prevented suc-
Abstract: The total synthesis of (–)-thysanone is described. The
key step involves the addition of an o-toluate anion to a lactone to
create the naphthopyran framework (Staunton–Weinreb annula-
tion). This synthesis further confirms the absolute stereochemistry
of the natural product to be 1R,3S.
cessful annulation with a variety of electrophiles.7e Upon
further examination of this reaction, it was noted that a
parallel annulation reaction was published in the same pa-
per by Hauser,8a in which the annulation of 2-(ethoxycar-
bonyl)benzyl phenyl sulfoxide with several Michael
acceptors was reported. A notable difference is the oxy-
genation pattern produced in the products using this meth-
od. In contrast to the naphthalenediol products that are
produced by the reaction of stabilised phthalides with
electrophiles (the Hauser–Kraus annulation), the reaction
of sulfoxides with a variety of Michael acceptors furnish-
es naphthol products that are much more amenable to fac-
ile purification (Scheme 1). Based on these observations,
our revised retrosynthesis hinged on the annulation be-
tween a sulfoxide 2 or sulfone 3 with the lactone (S)-para-
sorbic acid (4), a natural product isolated from mountain
ash berries Sorbus aucuparia L.10 (Scheme 2).
Key words: thysanone, Staunton–Weinreb annulation, total syn-
thesis, natural products, polycycles
Human rhinoviruses (HRVs) are a leading cause of the
common cold in the Western world. At present, only
symptomatic treatments are available to treat the common
cold and the search for pharmaceutical agents aimed at
preventing HRV infections are of major pharmaceutical
interest.1,2
Thysanone (1, Figure 1) is a pyranonaphthoquinone anti-
biotic that was discovered by chemists at Merck upon
screening the fermentation broths of the fungus Thysano-
phora penicilloides.3 It was subsequently shown to be the
first inhibitor of HRV-3C protease to be identified by
screening (IC50 = 13 mg/mL), hence making thysanone an
ideal lead compound for the rational design of small mol-
ecule HRV-3C-protease inhibitors. Due to the interesting
biological activity exhibited by thysanone together with
our ongoing interest in the synthesis of pyranonaphtho-
quinone antibiotics,4 we aimed to execute an efficient syn-
thesis of thysanone that would be amenable to the
production of analogues.5–7
O
R1 = CN,
O
OH
OH
O
SO2Ph
R1
base
O
Michael
acceptor
OH
O
OH
OH
O
1
O
base
3
CO2Me
R2 = SOPh,
HO
O
1
SO2Ph
R2
Figure 1 (–)-Thysanone, shown with 1R,3S stereochemistry
Scheme 1 Hauser–Kraus annulation and variants
Our initial thoughts were focused on construction of the
central ring of thysanone using a Hauser–Kraus annula-
tion.8,9 Unfortunately, our initial work adopting this ap-
proach showed that the 4,6-dimethoxy substitution pattern
SYNTHESIS 2009, No. 15, pp 2561–2569
x
x.
x
x
.
2
0
0
9
Advanced online publication: 08.06.2009
DOI: 10.1055/s-0029-1217390; Art ID: P03209SS
© Georg Thieme Verlag Stuttgart · New York

2562
J. Sperry et al.
PAPER
OMe
O
O
OH
CO2Me
(ii)
(i)
O
O
lactone
reduction
OH
O
O
OH
MeO
R
8
4
1
O
2 R = SOPh
3 R = SO2Ph
3
Scheme 4 Reagents and conditions: (i) H2C=CHCOCl, Et3N,
CH2Cl2, 0 °C to r.t.; (ii) Grubbs II catalyst, CH2Cl2, reflux, 3 h, 60%
(over 2 steps).
HO
+
lactone
annulation with
sulfoxide/sulfone
O
1
O
Unfortunately, attempted annulation of sulfone 2 or sulf-
oxide 3 with lactone 4 by our standard cyanophthalide-
based Hauser–Kraus annulation conditions (t-BuOK or
t-BuOLi in DMSO) failed to deliver any of the desired an-
nulation product. Upon screening several reaction condi-
tions, it was found that upon treatment of sulfoxide 2 and
sulfone 3 with lithium diisopropylamide, both species
formed a bright red colour, indicative of anion formation,
but only the sulfoxide 2 underwent successful annulation
with lactone 8 to deliver (S)-semivioxanthin methyl
ether16 (9) in a poor 29% yield (Scheme 5).
4 (S)-parasorbic acid
Scheme 2 Retrosynthetic analysis of (–)-thysanone
With this strategy in mind, the synthesis of both the sulf-
oxide 2 and sulfone 3 were conducted as follows: diphe-
nol 5 was prepared from methyl acetoacetate by slight
modification of a route described by Jouillé.11 Facile di-
alkylation of diphenol 5 delivered aromatic 6,12 which un-
derwent smooth toluate anion addition to diphenyl
disulfide, furnishing the sulfide 7.13 Monooxidation was
accomplished with sodium periodate, to deliver sulfoxide
2, and further oxidation was achieved with catalytic quan-
tities of ammonium molybdate tetrahydrate in the pres-
ence of hydrogen peroxide, affording the desired sulfone
3 (Scheme 3).
OMe
CO2Me
OMe OH
O
MeO
2 R = SOPh
3 R = SO2Ph
(i)
R
O
29% from 2
0% from 3
MeO
OMe
OR
O
9
CO2Me
SPh
CO2Me
(ii)
O
MeO
RO
(i)
5 R = H
7
4
(iii)
(iv)
6 R = Me
Scheme 5 Reagents and conditions: (i) LDA, THF, –78 °C to r.t.,
1 h.
OMe
OMe
CO2Me
SO2Ph
CO2Me
Due to the unpredictable nature of this annulation and its
poor yields, it was next decided to pursue an alternative
annulation to access thysanone. Thus, the addition of tol-
uate anions to enone electrophiles, also known as the
Staunton–Weinreb annulation7d,17 was deemed a viable al-
ternative to the Hauser–Kraus annulation (Scheme 6).
MeO
MeO
SOPh
2
3
Scheme 3 Reagents and conditions: (i) K2CO3, Me2SO4, TBAI,
acetone–DMF, 60 °C, 16 h, 91%; (ii) LDA, THF, then Ph2S2, –78 °C
to r.t., 16 h, 64%; (iii) NaIO4, MeOH–H2O, r.t., 16 h, 80%; (iv)
(NH4)2MoO4·4H2O, H2O2, EtOH, 0 °C to r.t., 20 h, 56%.
OMe
CO2Me
With both sulfoxide 2 and sulfone 3 annulation partners in
hand, attention turned to the synthesis of (S)-parasorbic
acid (4) (Scheme 4). By modification of a literature syn-
thesis by Brown,14 commercially available (S)-pent-4-en-
2-ol was treated with acryloyl chloride to deliver the vol-
atile diene 8. Smooth ring-closing metathesis was
achieved with the Grubbs second generation catalyst, to
furnish (S)-parasorbic acid (4) in good overall yield
{[a]D24 +199.8 (c 2.5, EtOH)} (Scheme 4).
lactone
reduction
OH
O
O
OH
MeO
6
1
O
+
3
HO
O
o-toluate
anion addition
(Staunton–Weinreb
annulation)
1
O
MeO
10
Scheme 6 Modified retrosynthesis of (–)-thysanone
Synthesis 2009, No. 15, 2561–2569 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of (–)-Thysanone
2563
O
OMe
OMe OH
O
CO2Me
(i)
O
O
+
MeO
MeO
MeO
(ii)
6
10
9
OMe
O
OMe OH
OMe OH OH
(iii)
O
O
O
MeO
MeO
MeO
12
O
13
11
(iv)
O
OH
O
OH
O
O
(–)-thysanone (1)
HO
MeO
O
O
15
14
Scheme 7 Reagents and conditions: (i) LDA, THF, –78 °C to r.t., 1 h, 56%; (ii) BH3·SMe2, THF, 0 °C to r.t., 16 h, 58%; (iii) salcomine, MeCN,
O2, r.t., 16 h, 84%; (iv) AlCl3, CH2Cl2, r.t., 6 h, then reflux, 4 h, 48%.
The revised aromatic annulation partner 6 was readily ac- bonate delivered the dialkylated diol 16, which gratifying-
cessible, as it was an intermediate in the previous synthe- ly underwent smooth annulation with lactone 10 in the
ses of sulfoxide 2 and sulfone 3. Lactone 10 was, in turn, presence of lithium diisopropylamide, to deliver the naph-
obtained from commercially available (S)-ethyl-3-hy- thol 17 in moderate yield (Scheme 8). Smooth borane-
droxybutyrate by a three-step procedure reported by mediated lactone reduction gave 18, which underwent ox-
Müller.18
idation in presence of salcomine and oxygen, delivering
the pyranonaphthoquinone 19 in excellent yield. Gratify-
ingly, facile removal of both isopropyl protecting groups
was easily achieved by treatment of 19 with aluminium
trichloride in dichloromethane at room temperature, fur-
nishing 146 in excellent yield. Boron trichloride only de-
livered moderate yields of 14 (45–55%) in this instance.
Finally, following the procedure of Gill,6 a solution of 14
in carbon tetrachloride in the presence of molecular bro-
mine was irradiated at 40 °C with a 60-watt desk lamp for
one hour. Hydrolysis of the resulting diastereomeric bro-
mides in aqueous tetrahydrofuran delivered (–)-thysanone
1, which was identical in all aspects to the synthetic thys-
anone obtained by Donner and Gill6 (Scheme 8, Figure 2,
Table 1), and a similar anomaly in our recorded optical ro-
Gratifyingly, the o-toluate anion addition of 6 with lac-
tone 10 proceeded smoothly, delivering (S)-semivioxan-
thin methyl ether (9)16 in an acceptable 56% yield,
together with recovery of both starting materials
(Scheme 7). At this stage, reduction of the lactone to the
lactol 11 could not be achieved with diisobutylaluminum
hydride, so complete reduction was envisaged, with the
aim of installing the lactol at a later stage of the synthesis.
Thus, treatment of lactone 9 with borane–dimethyl sulfide
complex gave the reduced pyran 12 in moderate yield.
Next, salcomine-mediated oxidation of naphthol 12 pro-
ceeded in excellent yield, delivering the pyranonaphtho-
quinone
13.
Disappointingly,
the
seemingly
straightforward removal of both methyl groups to give 14
was not successful. Despite subjecting 13 to a plethora of
Lewis acid and nucleophile based deprotection conditions
(e.g., BBr3, BCl3, AlCl3, TMSI, BF3·OEt2, MsOH/
methionine, K2CO3/PhSH), only the monodeprotected
product 156b was ever isolated, along with degradation be-
ing observed if the reaction was subjected to harsher con-
ditions (Scheme 7). Disappointingly, at this stage a new
protecting group strategy had to be implemented.
24
tation {[a]D –21.2 (c 0.005, MeOH)} was also evident.
As noticed by Donner and Gill, the optical rotation of syn-
24
thetic (1R,3S)-thysanone ({[a]D
–29.7 (c 0.002,
MeOH)}, was of opposite sign to that reported in the iso-
lation paper3 {[a]D24 +29 (c 1.62, MeOH)}. By extensive
comparison of their synthetic sample with an authentic
sample of the natural product, Donner and Gill concluded
that the optical rotation extensively fluctuates at higher
concentrations, and hence was inaccurately recorded in
the isolation paper. It was therefore concluded unequivo-
cally that the stereochemistry of thysanone was, in fact,
1R,3S.6b Our own synthesis further confirms this observa-
tion.
It is well established that isopropyl ethers are more labile
than methyl ethers.19 Thus, it was decided to return to the
start of the synthesis and use an isopropyl ether protecting
group instead of a methyl ether. Treatment of diphenol 5
with 2-bromopropane in the presence of potassium car-
Synthesis 2009, No. 15, 2561–2569 © Thieme Stuttgart · New York

2564
J. Sperry et al.
PAPER
system with a circular single mode and focused waves was used, re-
sulting in formation of a homogeneous field pattern surrounding the
sample.
OH
9
O
OH
10a
4a
9a
5a
8
1
10
5
O
3
4
7
HO
Methyl 2,4-Dihydroxy-6-methylbenzoate (5)11
6
O
In a 500-mL round-bottom flask equipped with a condenser and
side arm, a soln of a 60% dispersion of NaH in mineral oil (11 g,
258.4 mmol) in THF (100 mL) was cooled to 0 °C. A freshly dis-
tilled soln of methyl acetoacetate (21.6 mL, 172.2 mmol) in THF
(25 mL) was added dropwise over 30 min. Upon completion of the
addition, the resulting suspension was stirred at 0 °C for 30 min, and
1
Figure 2
In conclusion, we have achieved a convergent, enantiose-
lective synthesis of (–)-thysanone with a longest linear se- then cooled to –78 °C. A 1.6 M soln of n-BuLi in pentane (103 mL,
163.6 mmol) was added slowly via cannula over 30 min, and the re-
quence of eight steps, hence confirming the absolute
sulting soln was allowed to reach r.t. over 20 h. The resulting bright
stereochemistry of the natural product. We envisage this
red soln was then heated to reflux for 24 h and cooled to 0 °C, and
will provide a sound basis for the rapid synthesis of ana-
logues, with the intention of increasing the HRV-3C pro-
its pH was adjusted to 1–2 by careful addition of concd aq HCl. The
mixture was diluted with H2O (300 mL) and then extracted with
CH2Cl2 (3 × 200 mL). The combined organic extracts were washed
with brine (200 mL), dried (MgSO4), filtered, and concentrated in
vacuo. Purification by flash chromatography (pre-loading of sample
onto silica; silica gel, hexanes–EtOAc, 5:1) gave 5.
tease activity of this class of pyranonaphthoquinones.
All reactions were carried out in oven-dried or flame-dried glass-
ware under a N2 atmosphere unless otherwise stated. Analytical
TLC was performed on 0.2-mm Kieselgel F254 (Merck) silica
plates and compounds were visualised under 365-nm UV irradia-
tion followed by staining with either alkaline permanganate or
Yield: 8.53 g (55%); strong-smelling beige solid; mp 131–132 °C
(Lit.11 136–138 °C).
ethanolic vanillin soln. IR spectra of samples prepared as thin films
between NaCl plates were obtained on a Perkin-Elmer Spectrum
One FT-IR spectrometer. Optical rotations were measured on a
Perkin-Elmer 341 polarimeter at l = 598 nm. Melting points were
recorded on an Electrothermal melting point apparatus and are un-
corrected. NMR spectra were recorded on either a Bruker DRX-400
spectrometer (1H, 400 MHz; 13C, 100 MHz) or a Bruker Avance 300
spectrometer (1H, 300 MHz; 13C, 75 MHz). The 1H NMR chemical
shifts are reported relative to the TMS peak recorded as d = 0.00 in
CDCl3/TMS solvent, the residual CHCl3 peak at d = 7.25, or the re-
sidual acetone peak at d = 2.05. The 13C NMR values were refer-
enced to the residual CHCl3 peak at d = 77.0 or the residual acetone
peak at d = 29.8. Assignments are made with the aid of DEPT 135,
COSY, NOESY, and HSQC experiments. HRMS was carried out
on a VG-70SE mass spectrometer at a nominal accelerating voltage
of 70 eV. For all microwave-assisted reactions, the CEM Discover
The spectroscopic data were consistent with those previously re-
ported in the literature.11
Methyl 2,4-Dimethoxy-6-methylbenzoate (6)12
K2CO3 (8.7 g, 63 mmol) and TBAI (100 mg, 0.3 mmol), followed
by Me2SO4 (3.98 mL, 42 mmol), were added to a soln of diphenol
5 (1.6 g, 10.5 mmol) in acetone (40 mL) and DMF (2 mL), and the
reaction mixture was heated to reflux for 16 h. A 1 M soln of aq HCl
(100 mL) was added and the mixture was extracted with CH2Cl2
(3 × 50 mL). The combined organic extracts were washed with
brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo.
Purification by flash chromatography (silica gel, hexanes–EtOAc,
4:1) gave 6.
Yield: 2.02 g (91%); colourless oil that crystallised upon standing;
mp 39–40 °C (Lit.12 41.6 °C).
O
O
OiPr
10
OH
MeO
CO2Me
(i)
CO2Me
(ii)
iPrO
HO
5
16
OiPr OH
O
OiPr
O
O
OiPr OH
O
(iii)
(iv)
O
O
iPrO
iPrO
iPrO
17
18
19
OH
O
O
OH
O
OH
(vi)
(v)
O
O
HO
HO
O
14
1
Scheme 8 Reagents and conditions: (i) i-PrBr, K2CO3, TBAI, acetone–DMF, 60 °C, 16 h, 91%; (ii) LDA, THF, –78 °C to r.t., 1 h, 47%; (iii)
BH3·SMe2, THF, 0 °C to r.t., 16 h, 61%; (iv) salcomine, MeCN, O2, r.t., 16 h, 91%; (v) AlCl3, CH2Cl2, r.t., 1 h, 95%; or BCl3, CH2Cl2, –78 °C
to r.t., 3 h, 53%; (vi) Br2, Bz2O2, CCl4, 60-W lamp, 40 °C, 1 h, then THF–H2O, 45 min, 89%.
Synthesis 2009, No. 15, 2561–2569 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of (–)-Thysanone
2565
Table 1 1H and 13C NMR Data for Natural and Synthetic Thysanone (1)a
Positionb
Natural thysanone from T. penicilloides3
Synthetic thysanone (ref. 6)
Synthetic thysanone (this work)
1H (d)
13C (d)
1H (d)
13C (d)
1H (d)
13C (d)
1
5.84 (s)
86.5
62.0
5.90 (s)
86.6
62.1
5.93 (s)
86.8
62.2
3
4.21 (m)
4.30 (m)
4.30–4.36 (m)
4ax
2.05 (dd, J = 19.4, 11.0 29.9
Hz)
2.10 (dd, J = 19.4, 11.3 30.0
Hz)
2.11–2.17 (dd, J =
18.1, 11.1 Hz)
obscured by acetone
4eq
2.62 (dd, J = 19.4, 3.5
Hz)
2.65 (dd, J = 19.4, 3.5 Hz)
2.66–2.73 (dd, J =
18.1, 3.5 Hz)
4a
–
144.0
184.2
134.6
108.7
165.2
108.4
165.1
109.5
187.3
142.0
21.4
–
–
144.1
184.4
134.7
108.8
165.5
108.4
165.2
109.5
187.4
142.2
21.3
–
–
–
–
144.5
184.2
135.1
5
–
–
5a
–
–
6
6.97 (d, J = 2.3 Hz)
7.02 (d, J = 2.4 Hz)
7.07 (d, J = 2.3 Hz) 108.8
165.4
7
–
–
8
6.53 (d, J = 2.3 Hz)
6.57 (d, J = 2.4 Hz)
6.62 (d, J = 2.3 Hz) 108.5
9
–
–
–
–
–
–
165.4
109.5
187.6
142.0
9a
–
–
10
–
–
10a
3-Me
1-OH
7-OH
9-OH
–
–
1.25 (d, J = 6.3 Hz)
not observed
not observed
12.10 (s)
1.28 (d, J = 6.2 Hz)
not observed
not observed
12.23 (s)
1.30 (d, J = 6.5 Hz) 21.6
not observed
9.73–10.31 (br s)
12.26 (s)
–
–
–
–
–
–
–
a Solvent: acetone-d6.
b See Figure 2 for the atom-numbering of compound 1.
The spectroscopic data were consistent with those previously re-
ported in the literature.12
Methyl 2,4-Dimethoxy-6-[(phenylsulfinyl)methyl)]benzoate (2)
NaIO4 (0.5 g, 2 mmol) was added in one portion to a soln of 7 (0.6
g, 2 mmol) in MeOH–H2O (16 mL, 4:1). The reaction mixture was
stirred overnight at r.t., concentrated in vacuo, and then diluted with
H2O (50 mL). The aqueous phase was extracted with CH2Cl2
(3 × 30 mL). The combined organic phases were washed with brine
(20 mL), dried (MgSO4), filtered, and concentrated in vacuo. Puri-
fication by flash chromatography (silica gel, hexanes–EtOAc, 2:1)
gave 2.
Methyl 2,4-Dimethoxy-6-[(phenylsulfanyl)methyl]benzoate
(7)13
A soln of 6 (2.3 g, 11 mmol) in THF (4.5 mL) was added dropwise
over 5 min to a freshly prepared soln of LDA (20 mmol) in THF (20
mL) at –78 °C [prepared from 1.6 M n-BuLi in pentane (12.5 mL,
20 mmol) and i-Pr2NH (2.7 mL, 20 mmol) in THF (20 mL) at 0 °C],
and the bright red mixture was stirred for 1 h at –78 °C. A soln of
Ph2S2 (2.6 g, 12 mmol) in THF (4 mL) was added and the reaction
mixture was left to warm to r.t. overnight. The soln was quenched
by the addition of H2O (40 mL) and extracted with CH2Cl2 (3 × 30
mL). The combined organic extracts were washed with sat. aq
NaHCO3 (30 mL) and brine (30 mL), dried (MgSO4), filtered, and
concentrated in vacuo. Purification by flash chromatography (silica
gel, hexanes–EtOAc, 9:1) gave 7.
Yield: 0.5 g (80%); colourless solid; mp 56–58 °C.
IR (film): 3053, 2985, 1710, 1604, 1461, 1433, 1331, 1265, 1204,
1163, 670 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.70 (s, 3 H, OMe), 3.81 (s, 3 H,
OMe), 3.87 (s, 3 H, OMe), 4.14 (s, 2 H, SCH2), 6.12 (d, J = 2.1 Hz,
1 H, ArH), 6.43 (d, J = 2.1 Hz, 1 H, ArH), 7.46–7.55 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = 52.3 (OMe), 55.5 (OMe), 56.1
(OMe), 63.1 (SCH2), 99.3 (CH), 107.8 (CH), 124.3 (2 CH), 129.0
(2 CH), 131.2 (C), 131.8 (C), 143.6 (C), 159.3 (C), 161.6 (C), 167.7
(C=O), 1 C not observed.
Yield: 2.2 g (64%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 3.61 (s, 3 H, OMe), 3.70 (s, 3 H,
OMe), 3.81 (s, 3 H, OMe), 4.10 (s, 2 H, SCH2), 6.31 (m, 2 H, ArH),
7.17 (m, 3 H, ArH), 7.30 (m, 2 H, ArH).
MS–FAB: m/z (%) = 335 [M + H+] (29), 303 (30), 209 (42), 195 (3),
178 (14), 165 (6), 120 (12), 89 (21), 77 (21).
The spectroscopic data were consistent with those previously re-
ported in the literature.13
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2566
J. Sperry et al.
PAPER
HRMS–FAB: m/z [M + H+] calcd for C17H19O5S: 335.0953; found:
335.0953.
The spectroscopic data were consistent with those previously re-
ported in the literature.15
Methyl 2,4-Dimethoxy-6-[(phenylsulfonyl)methyl]benzoate (3)
(NH4)2MoO4·4H2O (0.09 g, 0.07 mmol) was added to 27% aq H2O2
(2.8 mL) at 0 °C, and the mixture was stirred for 15 min. The result-
ing bright yellow mixture was added dropwise to a soln of 7 (0.5 g,
2 mmol) in EtOH (15 mL) at 0 °C. The reaction mixture was stirred
for 20 h at r.t., and filtered through a pad of silica, which was
washed successively with EtOAc (30 mL) and Et2O (30 mL). The
combined organic extracts were diluted with H2O (20 mL) and the
aqueous layer was further extracted with EtOAc (3 × 20 mL). The
combined organic extracts were dried (MgSO4), filtered, and con-
centrated in vacuo. Purification by flash chromatography (silica gel,
hexanes–EtOAc, 1:2) gave 3.
(S)-Semivioxanthin Methyl Ether (9)16
A soln of sulfoxide 2 (400 mg, 1.2 mmol) in THF (2 mL) was added
dropwise to a freshly prepared soln of LDA (3 mmol) in THF (10
mL) at –78 °C [prepared from 1.6 M n-BuLi in pentane (1.9 mL, 3
mmol) and i-Pr2NH (421 mL, 3 mmol) in THF (3 mL) at 0 °C]. The
resulting bright red soln was stirred for 30 min, and then a soln of
lactone 4 (134 mg, 1.2 mmol) in THF (1 mL) was added dropwise,
before the reaction mixture was warmed to r.t. and stirred for 1 h.
Sat. aq NH4Cl (20 mL) was added and the mixture was extracted
with CH2Cl2 (3 × 20 mL). The combined organic extracts were
washed with brine (20 mL), dried (MgSO4), filtered, and concen-
trated in vacuo. Purification by flash chromatography (silica gel,
hexanes–EtOAc, 5:1) gave 9.
Yield: 0.3 g (56%); colourless solid; mp 146–148 °C.
IR (film): 1705, 1605, 1463, 1317, 1162 cm–1.
Yield: 101 mg (29%); colourless solid; mp 104–106 °C (Lit.16 130–
24
24
131 °C); [a]D –16.1 (c 0.5, CHCl3) [Lit.16 [a]D –18 (c 0.3,
CHCl3)].
1H NMR (300 MHz, CDCl3): d = 3.73 (s, 3 H, OMe), 3.75 (s, 3 H,
OMe), 3.78 (s, 3 H, OMe), 4.57 (s, 2 H, SCH2), 6.31 (d, J = 2.2 Hz,
1 H, ArH), 6.44 (d, J = 2.2 Hz, 1 H, ArH), 7.45 (t, J = 7.5 Hz, 2 H,
ArH), 7.61 (t, J = 7.5 Hz, 1 H, ArH), 7.69 (d, J = 7.5 Hz, 2 H, ArH).
IR (neat): 3577, 2990, 1667, 1602, 1576, 1412, 1352, 1332, 1281,
1263, 1187, 1154, 1011, 910 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.53 (d, J = 6.3 Hz, 3 H, Me), 2.97
(dd, J = 1.7, 6.1 Hz, 2 H, CH2), 3.91 (s, 3 H, OMe), 4.02 (s, 3 H,
OMe), 4.68–4.85 (m, 1 H, CH), 6.47 (d, J = 2.3 Hz, 1 H, ArH), 6.58
(d, J = 2.3 Hz, 1 H, ArH), 6.85 (s, 1 H, ArH), 13.15 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 52.2 (OMe), 55.5 (OMe), 56.2
(OMe), 59.7 (CH2), 99.7 (CH), 108.4 (CH), 117.1 (C), 128.6 (2
CH), 129.0 (2 CH), 129.4 (C), 133.7 (CH), 138.4 (C), 159.2 (C),
161.5 (C), 167.3 (C=O).
13C NMR (75 MHz, CDCl3): d = 20.8 (Me), 35.1 (CH2), 55.4
(OMe), 56.2 (OMe), 75.6 (CH), 98.3 (CH), 98.9 (CH), 100.7 (C),
110.7 (C), 115.2 (CH), 134.3 (C), 141.5 (C), 160.6 (C), 161.8 (C),
164.1 (C), 171.2 (C=O).
MS (EI, 70 eV): m/z (%) = 350 [M+] (19), 319 (9), 286 (5), 209
(100), 178 (10), 165 (6), 148 (6), 135 (7), 77 (10), 51 (6).
HRMS (EI): m/z [M+] calcd for C17H18O6S: 350.0824; found:
350.0824.
MS–FAB: m/z (%) = 289 [M + H+] (100), 271 (11), 154 (64), 136
(50), 107 (20), 89 (21), 77 (24).
(S)-Parasorbic Acid (4)
A modification of a literature procedure14 was used for the synthesis
of 4. Isolation10 and NMR data were reported previously.15
HRMS–FAB: m/z [M + H+] calcd for C16H17O5: 289.1076; found:
289.1081.
A soln of (S)-(+)-pent-4-en-2-ol (Aldrich, >95% ee; 2.5 g, 30 mmol)
in CH2Cl2 (80 mL) was cooled to 0 °C. Freshly distilled Et3N (10
mL) was added followed by H2C=CHCOCl (3.5 mL, 44 mmol). The
reaction mixture was warmed to r.t., stirred for 4 h, and then
quenched by the addition of 1 M aq HCl (100 mL). The organic lay-
er was removed and the aqueous layer was extracted with CH2Cl2
(3 × 50 mL). The combined organic extracts were washed with
brine (50 mL), dried (MgSO4), filtered, and carefully concentrated
in vacuo at r.t.; this gave the crude, volatile acrylate ester product 8
(ca. 4.3 g), which was taken up in freshly distilled CH2Cl2 (750 mL).
The Grubbs II catalyst (0.2 mol%, 0.06 mmol, 51 mg) was added
and the reaction mixture was heated to reflux for 3 h. Concentration
in vacuo followed by column chromatography (silica gel, hexanes–
EtOAc, 3:1, then 1:1, then 1:3) gave 4.
The spectroscopic data were consistent with those previously re-
ported in the literature.16
(S)-4-Methoxy-6-methyl-5,6-dihydro-2H-pyran-2-one (10)
Compound 10 was prepared by following a reported procedure.18
1H NMR (300 MHz, CDCl3): d = 1.39 (d, J = 6.2 Hz, 3 H, Me),
2.26–2.44 (m, 2 H, CH2-3), 3.68 (s, 3 H, OMe), 4.40–4.51 (m, 1 H,
CH-2), 5.06 (d, J = 1.2 Hz, 1 H, CH-2).
The spectroscopic data were consistent with those previously re-
ported in the literature.18
(S)-Semivioxanthin Methyl Ether (9)
A soln of benzoate 6 (947 mg, 4.51 mmol) in THF (2 mL) was add-
ed dropwise to a freshly prepared soln of LDA (9 mmol) in THF (8
mL) at –78 °C [prepared from 1.6 M n-BuLi in pentane (5.6 mL, 9
mmol) and i-Pr2NH (1.3 mL, 9 mmol) in THF (8 mL) at 0 °C], and
the reaction mixture was stirred for 15 min. To the resulting bright
red soln at –78 °C was added lactone 10 (640 mg, 4.5 mmol) in THF
(2 mL), and the reaction mixture was warmed to r.t. with stirring
over 1 h. Sat. aq NH4Cl (50 mL) was added and the mixture was ex-
tracted with CH2Cl2 (3 × 30 mL). The combined organic extracts
were washed with brine (50 mL), dried (MgSO4), filtered, and con-
centrated in vacuo. Purification by flash chromatography (silica gel,
hexanes–EtOAc, 3:1) gave 9.
Yield: 2.02 g (60% over 2 steps); pale yellow oil; [a]D24 +199.8 (c
2.5, EtOH) [Lit.10 [a]D24 +210 (EtOH)].
IR (neat): 2983, 2911, 1725, 1390, 1262, 1249, 1109, 1055, 911,
734 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.43 (d, J = 5.9 Hz, 3 H, Me),
2.28–2.36 (m, 2 H, 5-CH2), 4.53–4.60 (m, 1 H, 6-H), 5.98–6.02
(ddd, J = 9.7, 2.7, 1.1 Hz, 1 H, 3-H), 6.83–6.89 (ddd, J = 2.7, 5.7,
9.7 Hz, 1 H, 4-H).
13C NMR (75 MHz, CDCl3): d = 20.7 (Me), 30.9 (CH2), 74.3 (CH),
121.1 (CH), 145.1 (CH), 164.5 (C=O).
Yield: 723 mg (56%).
MS (EI, 70 eV): m/z (%) = 112 [M+] (4), 108 (10), 68 (100), 55 (24),
41 (26), 29 (35).
The spectroscopic data were consistent with those previously re-
ported in the literature.16
HRMS (EI): m/z [M+] calcd for C6H8O2: 112.0524; found:
112.0524.
Synthesis 2009, No. 15, 2561–2569 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of (–)-Thysanone
2567
(S)-7,9-Dimethoxy-3-methyl-3,4-dihydro-1H-benzo[g]iso-
chromen-10-ol (12)
uo. Purification by flash chromatography (silica gel, hexanes–
EtOAc, 5:1) gave 15.
BH3·SMe2 (3.06 mmol, 300 mL) was added to a soln of lactone 9
(220 mg, 0.76 mmol) in THF (5 mL) at 0 °C, and the reaction mix-
ture was warmed to r.t. over 16 h. Sat. aq NH4Cl soln (10 mL) was
added and the mixture was extracted with CH2Cl2 (3 × 15 mL). The
combined organic extracts were washed with brine (10 mL), dried
(MgSO4), filtered, and concentrated in vacuo. Purification by flash
chromatography (silica gel, hexanes–EtOAc, 5:1) gave 12.
Yield: 11 mg (48%); orange solid; mp 108–110 °C (Lit.6b 161–
162 °C); [a]D24 +60.5 (c 1.3, CH2Cl2).
IR (neat): 3090, 2980, 2936, 1686, 1618, 1442, 1393, 1349, 1289,
1233, 1204, 1053, 991, 856, 842 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.29 (d, J = 6.3 Hz, 3 H, Me),
2.20–2.25 (dddd, J = 18.9, 9.2, 3.8, 2.6 Hz, 1 H, Hax-4), 2.59–2.66
(ddd, J = 18.9, 3.8, 2.6 Hz, 1 H, Heq-4), 3.57 (m, 1 H, CH), 3.82 (s,
3 H, OMe), 4.39–4.46 (ddd, J = 18.8, 4.3, 3.3 Hz, 1 H, Hax-1), 4.72–
4.80 (dd, J = 18.8, 2.8 Hz, 1 H, Heq-1), 6.53 (d, J = 2.5 Hz, 1 H,
ArH), 7.10 (d, J = 2.5 Hz, 1 H, ArH), 12.04 (s, 1 H, OH).
Yield: 121 mg (58%); colourless solid; mp 117–119 °C; [a]D24 –9.9
(c 0.12, MeOH).
IR (neat): 3410, 1638, 1364, 1204, 829 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.37 (d, J = 6.2 Hz, 3 H, Me), 2.79
(m, 2 H, CH2-4), 3.08–3.84 (m, 1 H, CH), 3.88 (s, 3 H, OMe), 4.01
(s, 3 H, OMe), 4.75 (dd, J = 15.2, 3.1 Hz, 1 H, Hax-1), 5.13 (dd, J =
15.2, 2.6 Hz, 1 H, Heq-1), 6.38 (d, J = 2.0 Hz, 1 H, ArH), 6.61 (d,
J = 2.0 Hz, 1 H, ArH), 6.95 (s, 1 H, ArH), 9.20 (s, 1 H, OH).
13C NMR (100 MHz, CDCl3): d = 21.2 (Me), 29.6 (CH2), 56.0
(OMe), 63.0 (CH2), 69.6 (CH), 106.0 (CH), 108.1 (CH), 133.4 (C),
142.3 (C), 142.8 (C), 164.3 (C), 166.0 (C), 182.9 (C=O), 186.7
(C=O), 1 C not observed.
MS (EI, 70 eV): m/z (%) = 274 [M+] (100), 259 (12), 245 (20), 230
(55), 202 (18), 122 (12), 43 (13).
13C NMR (100 MHz, CDCl3): d = 21.6 (Me), 36.1 (Me), 55.3
(OMe), 56.1 (OMe), 64.8 (CH2), 70.4 (CH), 97.0 (CH), 98.6 (CH),
115.0 (C), 116.5 (CH), 135.0 (C), 135.6 (C), 149.2 (C), 157.1 (C),
157.2 (C), 1 C not observed.
HRMS (EI): m/z [M+] calcd for C15H14O5: 274.0841; found:
274.0834.
1H and 13C NMR and MS data are consistent with those reported in
the literature.6b
MS (EI, 70 eV): m/z (%) = 274 [M+] (100), 230 (96), 215 (12), 187
(12), 115 (11).
HRMS (EI): m/z [M+] calcd for C16H18O4: 274.1205; found:
274.1207.
Methyl 2,4-Diisopropoxy-6-methylbenzoate (16)
K2CO3 (4.2 g, 30.3 mmol) and TBAI (100 mg, 0.3 mmol), followed
by i-PrBr (8 mL, 86 mmol) were added to a soln of diphenol 5 (1.15
g, 7.57 mmol) in acetone (20 mL) and DMF (2 mL), and the reaction
mixture was heated to reflux for 16 h. A 1 M soln of aq HCl (50 mL)
was added and the mixture was extracted with CH2Cl2 (3 × 30 mL).
The combined organic extracts were washed with brine (30 mL),
dried (MgSO4), filtered, and concentrated in vacuo. Purification by
flash chromatography (silica gel, hexanes–EtOAc, 4:1) gave 16.
(S)-7,9-Dimethoxy-3-methyl-3,4-dihydro-1H-benzo[g]iso-
chromene-5,10-dione (13)
Salcomine (26 mg, 0.08 mmol, 25 mol%) was added to a soln of
naphthol 12 (90 mg, 0.31 mmol) in MeCN (4 mL), and the reaction
mixture was stirred under an atmosphere of O2 for 16 h. Concentra-
tion in vacuo followed by flash chromatography (silica gel, hexane–
EtOAc, 3:1) gave 13.
Yield: 1.83 g (91%); colourless oil that crystallised upon standing;
mp 29–32 °C.
Yield: 75 mg (84%); orange solid; mp 193–195 °C; [a]D24 +112.5 (c
1.3, CH2Cl2).
IR (neat): 2976, 1724, 1600, 1430, 1383, 1372, 1316, 1265, 1182,
1156, 1136, 1110, 1093, 1016, 833 cm–1.
IR (neat): 2933, 1648, 1635, 1592, 1557, 1466, 1330, 1311, 1274,
1150, 1033, 938, 845 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.42–1.46 (m, 12 H, 2 CHMe2)
2.39 (s, 3 H, ArMe), 3.98 (s, 3 H, Me), 4.57–4.67 (m, 2 H, 2
CHMe2), 6.43 (s, 2 H, 2 ArH).
1H NMR (400 MHz, CDCl3): d = 1.35 (d, J = 5.6 Hz, 3 H, Me),
2.20–2.28 (m, 1 H, Hax-4), 2.64–2.69 (ddd, J = 16.2, 9.0, 1.9 Hz, 1
H, Heq-4), 3.62–3.67 (m, 1 H, CH), 3.94 (s, 3 H, OMe), 4.44–4.50
(dt, J = 18.8, 3.1 Hz, 1 H, Hax-1), 4.80–4.84 (dd, J = 18.8, 2.1 Hz, 1
H, Heq-1), 6.70 (d, J = 2.0 Hz, 1 H, ArH), 7.25 (m, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 19.8 (Me), 21.0 (Me), 22.1 (Me),
51.8 (Me), 69.8 (CH), 71.3 (CH), 100.4 (CH), 108.9 (CH), 117.8
(C), 137.9 (C), 156.6 (C), 159.4 (C), 169.0 (C=O).
13C NMR (100 MHz, CDCl3): d = 21.2 (Me), 29.1 (CH2), 55.9
(OMe), 56.4 (OMe), 63.7 (CH2), 69.5 (CH), 103.4 (CH), 104.0
(CH), 114.0 (C), 135.9 (C), 138.9 (C), 144.3 (C), 161.9 (C), 164.6
(C), 181.8 (C=O), 183.9 (C=O).
MS (EI, 70 eV): m/z (%) = 266 [M]+ (22), 235 (12), 224 (10), 192
(28), 182 (16), 150 (100), 122 (11), 43 (16).
HRMS (EI): m/z [M+] calcd for C15H22O4: 266.1518; found:
266.1520.
MS (EI, 70 eV): m/z (%) = 288 [M+] (100), 273 (31), 259 (25), 255
(13), 106 (11), 43 (14).
(S)-10-Hydroxy-7,9-diisopropoxy-3-methyl-3,4-dihydro-1H-
benzo[g]isochromen-1-one (17)
HRMS (EI): m/z [M+] calcd for C16H16O5: 288.0998; found:
288.0999.
A soln of benzoate 16 (1.03 g, 3.9 mmol) in THF (2 mL) was added
dropwise to a freshly prepared soln of LDA (9.8 mmol) in THF (10
mL) at –78 °C [prepared from 1.6 M n-BuLi in pentane (6.1 mL, 9.8
mmol) and i-Pr2NH (1.4 mL, 9.8 mmol) in THF (10 mL) at 0 °C],
and the reaction mixture was stirred for 15 min. To the resulting
bright red soln at –78 °C was added lactone 10 (550 mg, 3.9 mmol)
in THF (2 mL), and the reaction mixture was warmed to r.t. with
stirring over 1 h. Sat. aq NH4Cl (50 mL) was added and the mixture
was extracted with CH2Cl2 (3 × 30 mL). The combined organic ex-
tracts were washed with brine (30 mL), dried (MgSO4), filtered, and
concentrated in vacuo. Purification by flash chromatography (silica
gel, hexanes–EtOAc, 3:1) gave 17.
(S)-9-Hydroxy-7-methoxy-3-methyl-3,4-dihydro-1H-ben-
zo[g]isochromene-5,10-dione (15)6b
Compound 15 was obtained from the reaction of 13 with BBr3,
AlCl3, BCl3, or TMSI. The experimental details of the reaction with
AlCl3 are provided, as this method afforded the best yield.
AlCl3 (144 mg, 1.08 mmol) was added to a soln of 13 (26 mg, 0.09
mmol) in CH2Cl2 (2 mL) at –78 °C, and the reaction mixture was
warmed to r.t. for 6 h, before being heated to reflux for 4 h. Sat. aq
NH4Cl (2 mL) was added, and the mixture was extracted with
CH2Cl2 (3 × 5 mL). The combined organic extracts were washed
with brine (5 mL), dried (MgSO4), filtered, and concentrated in vac-
Synthesis 2009, No. 15, 2561–2569 © Thieme Stuttgart · New York

2568
J. Sperry et al.
PAPER
Yield: 630 mg (47%); colourless solid; mp 48–50 °C; [a]D24 +26.4
(c 2.5, CH2Cl2).
CHMe2), 4.80–4.86 (dd, J = 2.0, 18.9 Hz, 1 H, Heq-1), 6.65 (d, J =
2.3 Hz, 1 H, ArH), 7.20 (d, J = 2.3 Hz, 1 H, ArH).
IR (neat): 3558, 2978, 1631, 1602, 1576, 1437, 1373, 1332, 1289,
1272, 1187, 1114, 1030, 910, 831 cm–1.
13C NMR (100 MHz, CDCl3): d = 21.2 (Me), 21.9 (2 CHMe2), 29.1
(CH2), 63.8 (CH2), 69.5 (CH), 70.7 (CH), 71.2 (CH), 104.9 (CH),
107.7 (CH), 114.4 (CH), 135.9 (C), 138.7 (C), 144.3 (C), 160.6 (C),
162.9 (C), 181.5 (C=O), 184.1 (C=O).
1H NMR (300 MHz, CDCl3): d = 1.29–1.55 (m, 15 H, 2 CHMe2, 3-
Me), 2.97–2.90 (m, 2 H, CH2-4), 4.60–4.72 (m, 3 H, 2 CHMe2, CH-
1), 6.46 (d, J = 2.4 Hz, 1 H, ArH), 6.55 (d, J = 2.4 Hz, 1 H, ArH),
6.78 (s, 1 H, ArH), 12.79 (s, 1 H, OH).
MS (EI, 70 eV): m/z (%) = 344 [M]+ (70), 329 (12), 302 (34), 261
(15), 260 (95), 245 (22), 242 (22), 231 (24), 216 (100), 200 (11),
188 (15), 43 (49).
13C NMR (75 MHz, CDCl3): d = 20.7 (Me), 21.9 (4 Me), 35.2
(CH2), 69.9 (CH), 72.3 (CH), 75.4 (CH), 100.6 (C), 101.0 (CH),
102.5 (CH), 111.4 (C), 115.0 (CH), 134.2 (C), 141.3 (C), 158.9 (C),
159.8 (C), 164.1 (C), 170.4 (C=O).
HRMS (EI): m/z [M+] calcd for C20H24O5: 344.1624; found:
344.1624.
(S)-7,9-Dihydroxy-3-methyl-3,4-dihydro-1H-benzo[g]iso-
chromene-5,10-dione (14)
MS (EI, 70 eV): m/z (%) = 344 [M]+ (51), 302 (39), 260 (100), 242
(36), 216 (26), 213 (19), 43 (32).
AlCl3 (52 mg, 0.39 mmol, 3 equiv) was added portionwise over 5
min to a soln of quinone 19 (43 mg, 0.13 mmol) in CH2Cl2 (2 mL),
cooled to 0 °C. The reaction mixture was slowly warmed to r.t.,
stirred for 1 h, and diluted with CH2Cl2 (5 mL). Sat. aq NH4Cl (10
mL) was added and the organic layer was removed. The aqueous
layer was extracted with CH2Cl2 (2 × 10 mL) and then EtOAc
(2 × 10 mL), and the combined organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo. Purification by flash
chromatography (silica gel, hexanes–EtOAc, 1:1, then 1:2) gave 14.
HRMS (EI): m/z [M+] calcd for C20H24O5: 344.1624; found:
344.1620.
(S)-7,9-Diisopropoxy-3-methyl-3,4-dihydro-1H-benzo[g]iso-
chromen-10-ol (18)
A soln of lactone 17 (80 mg, 0.23 mmol) in THF (4 mL) was cooled
to 0 °C. BH3·SMe2 (50 mL, 0.48 mmol, 2 equiv) was added drop-
wise and the reaction mixture was warmed to r.t. with stirring for 16
h. The reaction mixture was diluted with CH2Cl2 (5 mL), sat. aq
NH4Cl (10 mL) was added, and the organic layer was removed. The
aqueous layer was extracted with CH2Cl2 (2 × 3 mL) and the com-
bined organic extracts were washed with brine (2 mL), dried
(MgSO4), filtered, and concentrated in vacuo. Purification by flash
chromatography (silica gel, hexanes–EtOAc, 3:1) gave 18 as a vis-
cous oil.
Yield: 31 mg (95%); orange solid; mp 176–178 °C (Lit.6b 171–
173 °C); [a]D24 +149.2 (c 0.15, MeOH) [Lit.6b [a]D24 +160.0 (c 0.28,
MeOH)].
IR (neat): 3416, 2925, 2852, 1643, 1615, 1401, 1320, 1241, 1153,
1125, 1039, 773 cm–1.
1H NMR (400 MHz, acetone-d6): d = 1.30 (d, J = 6.0 Hz, 3 H, 3-
Me), 2.19–2.27 (m, 1 H, Hax-4), 2.59–2.69 (m, 1 H, Heq-4), 3.68 (m,
1 H, H-3), 4.42–4.47 (dd, J = 18.9, 3.2 Hz, 1 H, Hax-1), 4.69–4.74
(m, 1 H, Heq-1), 6.57 (d, J = 2.6 Hz, 1 H, ArH), 7.06 (m, J = 2.6 Hz,
1 H, ArH), 9.96 (br s, 1 H, OH), 12.09 (s, 1 H, OH).
Yield: 46 mg (61%); [a]D24 +14.2 (c 0.06, CH2Cl2).
IR (neat): 3383, 2974, 2932, 1637, 1614, 1582, 1467, 1362, 1308,
1183, 1153, 1135, 1108, 1082, 1021, 906, 848, 824 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.37–1.39 (m, 9 H, CHMe2, 3-
Me), 1.49 (m, 6 H, CHMe2), 2.79 (m, 2 H, CH2-4), 3.75–3.83 (m, 1
H, CHMe2), 4.61–4.67 (m, 1 H, CHMe2), 4.75–4.82 (m, 2 H, Hax-1,
CH-3), 5.13–5.10 (dt, J = 18.8, 2.6 Hz, 1 H, Heq-1), 6.37 (d, J = 1.7
Hz, 1 H, ArH), 6.60 (d, J = 1.7 Hz, 1 H, ArH), 6.90 (s, 1 H, ArH),
9.65 (s, 1 H, OH).
13C NMR (100 MHz, acetone-d6): d = 20.7 (3-Me), 62.5 (CH2), 69.5
(CH), 107.3 (CH), 108.8 (CH), 112.9 (CH), 134.1 (C), 142.3 (C),
142.6 (C), 164.3 (C), 164.6 (C), 182.5 (C=O), 187.1 (C=O), 1 CH2
obscured by acetone.
MS (EI, 70 eV): m/z (%) = 260 [M]+ (100), 245 (10), 231 (22), 216
(60), 188 (30), 108 (22), 41 (45).
13C NMR (100 MHz, CDCl3): d = 21.6 (Me), 21.98 (2 Me), 22.01
(2 Me), 36.1 (CH2), 64.8 (CH2), 69.7 (CH), 70.5 (CH), 72.5 (CH),
100.2 (CH), 100.7 (CH), 109.5 (C), 114.5 (C), 116.3 (CH), 134.7
(C), 135.8 (C), 149.5 (C), 155.2 (C), 155.3 (C).
HRMS (EI): m/z [M+] calcd for C14H12O5: 260.0685; found:
260.0685.
The spectroscopic data were consistent with those previously re-
ported in the literature.6b
MS (EI, 70 eV): m/z (%) = 330 [M]+ (100), 314 (10), 288 (50), 246
(52), 202 (95), 186 (20), 173 (20), 43 (42).
(–)-Thysanone (1)3
HRMS (EI): m/z [M+] calcd for C20H26O4: 330.1831; found:
330.1827.
A 1 M soln of Br2 in CCl4 (30 mL, 0.030 mmol) and Bz2O2 (1 crys-
tal) were added to a soln of quinone 14 (8 mg, 0.030 mmol) in CCl4
(7 mL), and the reaction mixture was irradiated with a 60-W lamp
at 40 °C for 1 h. The cooled reaction mixture was concentrated in
vacuo and taken up in THF (2 mL). H2O (1 mL) was added and the
reaction mixture was stirred for 1 h before being diluted with
CH2Cl2 (8 mL). H2O (5 mL) was added and the organic layer was
removed. The aqueous layer was extracted with CH2Cl2 (2 × 3 mL),
and the combined organic extracts were washed with brine (2 mL),
dried (MgSO4), filtered, and concentrated in vacuo. Purification by
preparative TLC (silica gel, hexanes–EtOAc, 1:1, then 1:2) gave 1.
(S)-7,9-Diisopropoxy-3-methyl-3,4-dihydro-1H-benzo[g]iso-
chromene-5,10-dione (19)
Salcomine (12 mg, 15 mol%) was added to a soln of naphthol 18 (96
mg, 0.29 mmol) in MeCN (3 mL), and the reaction mixture was
stirred under an atmosphere of O2 for 4 h. Concentration in vacuo
followed by flash chromatography (silica gel, hexanes–EtOAc, 1:1)
gave 19.
Yield: 89 mg (91%); orange solid; mp 127–128 °C; [a]D24 +102.2 (c
0.09, CH2Cl2).
Yield: 7 mg (89%); orange solid; mp 201–202 °C (Lit. isolation3
24
205–206 °C, Lit. synthesis6b 197–198 °C); [a]D –21.2 (c 0.005,
IR (neat): 2976, 1654, 1590, 1555, 1431, 1305, 1275, 1164, 1104,
1038, 908, 843, 724 cm–1.
MeOH) [Lit. isolation3 [a]D +29 (c 1.62, MeOH), Lit. synthesis6b
[a]D –29.7 (c 0.002, MeOH)].
1H NMR (400 MHz, CDCl3): d = 1.33–1.46 (m, 15 H, 2 CHMe2, 3-
Me), 2.19–2.27 (m, 1 H, Hax-4), 2.62–2.67 (dt, J = 18.6, 2.6 Hz, 1
H, Heq-4), 3.60–3.65 (m, 1 H, H-3), 4.43–4.50 (dt, J = 19.0, 3.4 Hz,
1 H, Hax-1), 4.57–4.63 (m, 1 H, CHMe2), 4.70–4.76 (m, 1 H,
IR (neat): 3368, 2925, 1648, 1615, 1412, 1327, 1279, 1174, 1011
cm–1.
Synthesis 2009, No. 15, 2561–2569 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of (–)-Thysanone
2569
1H NMR (300 MHz, acetone-d6): d = 1.30 (d, J = 6.5 Hz, 3 H, 3-
Me), 2.11–2.17 (dd, J = 18.8, 11.1 Hz, 1 H, Hax-4), 2.66–2.73 (dd,
J = 19.4, 3.5 Hz, 1 H, Heq-4), 4.30–4.36 (m, 1 H, H-3), 5.93 (s, 1 H,
H-1), 6.62 (d, J = 2.3 Hz, 1 H, ArH), 7.07 (d, J = 2.3 Hz, 1 H, ArH),
9.73–10.31 (br s, 1 H, OH), 12.26 (s, 1 H, OH).
(7) For analogue syntheses of thysanone, see: (a) Brimble, M.
A.; Elliott, R. J. R.; McEwan, J. F. Aust. J. Chem. 2000, 53,
571. (b) Brimble, M. A.; Elliott, R. J. R. Tetrahedron 2002,
58, 183. (c) Kraus, G. A.; Ogutu, H. Tetrahedron 2002, 58,
7391. (d) Bulbule, V. J.; Koranne, P. S.; Deshpande, V. H.;
Borate, H. B. Tetrahedron 2007, 63, 166. (e) Brimble, M.
A.; Houghton, S. I.; Woodgate, P. D. Tetrahedron 2007, 63,
880. (f) For a formal synthesis of thysanone, see: Bachu, P.;
Sperry, J.; Brimble, M. A. Tetrahedron 2008, 64, 4827.
(g) Sawant, R. T.; Waghmode, S. B. Tetrahedron 2009, 65,
1599.
13C NMR (75 MHz, acetone-d6): d = 21.6 (Me), 62.2 (CH), 86.8
(CH), 108.5 (CH), 108.8 (CH), 109.5 (C), 135.1 (C), 142.0 (C),
144.5 (C), 165.4 (C), 165.8 (C), 184.2 (C=O), 187.6 (C=O), 1 CH2
obscured by acetone.
MS (EI, 70 eV): m/z (%) = 276 [M]+ (4), 258 (50), 229 (10), 129
(10), 97 (40), 83 (50), 55 (100).
(8) (a) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178.
(b) Kraus, G. A.; Sugimoto, H. Tetrahedron Lett. 1978, 19,
2263.
HRMS (EI): m/z [M+] calcd for C14H12O6: 276.0634; found:
276.0634.
(9) For recent reviews on the Hauser–Kraus annulation, see:
(a) Rathwell, K.; Brimble, M. A. Synthesis 2007, 5, 643.
(b) Mal, D.; Pahari, P. Chem. Rev. 2007, 107, 1892.
(10) Kuhn, R.; Kum, K. Chem. Ber. 1962, 95, 2009.
(11) Chiarello, J.; Jouillé, M. M. Tetrahedron 1988, 44, 41.
(12) Drochner, D.; Hüttel, W.; Bode, S. E.; Müller, M.; Karl, U.;
Nieger, M.; Steglich, W. Eur. J. Org. Chem. 2007, 1749.
(13) Hauser, F. M.; Rhee, R. P.; Prassana, S.; Weinreb, S. M.;
Dodd, J. H. Synthesis 1980, 72.
The spectroscopic data were consistent with those previously re-
ported in the literature (see Table 1).3,6b
Acknowledgment
We thank the Royal Society of New Zealand Marsden fund for fi-
nancial support.
(14) Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C.
Tetrahedron Lett. 2000, 41, 583.
References
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Synthesis 2009, No. 15, 2561–2569 © Thieme Stuttgart · New York