Azedaralide: total synthesis, relative and absolute stereochemical assignment

Article abstract of DOI:10.1016/j.tet.2006.05.030

Azedaralide, a potentially advanced intermediate for the total synthesis of various tetranortriterpenes, was constructed utilising the Fernández-Mateos protocol and assigned both relative and absolute stereochemistries. Both asymmetric aldol and classical

Full text of DOI:10.1016/j.tet.2006.05.030

Tetrahedron 62 (2006) 7355–7360
Azedaralide: total synthesis, relative and absolute
stereochemical assignment
a
b
Luke A. Baker,a Craig M. Williams,a, Paul V. Bernhardt and Gary W. Yanik
*
aSchool of Molecular and Microbial Sciences, University of Queensland, Brisbane, 4072 Queensland, Australia
bPDR-Chiral Inc., 1331A South Killian Drive, Lake Park, FL 33403, USA
Received 11 March 2006; revised 27 April 2006; accepted 11 May 2006
Available online 9 June 2006
Abstract—Azedaralide, a potentially advanced intermediate for the total synthesis of various tetranortriterpenes, was constructed utilising the
´
Fernandez-Mateos protocol and assigned both relative and absolute stereochemistries. Both asymmetric aldol and classical chiral resolution
attempts failed to deliver pure enantiomers whereas preparative chiral chromatography resolved racemic azedaralide with ease.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Azedaralide 1, isolated from Melia azedarach (1.7 mg from
1.5 kg root bark) by Nakatani et al.,1 displays antifeedant
and ichthyotoxic properties, and is to date the only d-lactone
degraded limonoid isolated from M. azedarach.1 In addition,
azedaralide 1 appears to have the required connectivity to act
as an advanced intermediate for total syntheses studies of the
tetranortriterpenes (limonoids) andirobin 2 and mexicano-
lide 3 (Fig. 1).2 In this regard two distinctly different ap-
proaches to viable quantities of azedaralide 1 were
investigated, the results of which are described herein.
Due to the large amount of work already conducted on the
total synthesis of dl-pyroangolensolide3–7 4, the most sim-
plistic, yet logically direct approach to azedaralide 1, that
being exocyclic allylic oxidation was examined in the first
instance. Numerous methods to effect allylic oxidation were
exhaustively investigated, for example, SeO2/t-BuO2H,8
Pd(OAc)2 and Hg(OAc)2,10 but in all cases these proce-
9
dures provided epoxide 5 and/or starting material 4. How-
ever, selenium dioxide or selenious acid in dioxane11
afforded azedaralide 112 in 17% yield along with the cor-
responding aldehyde 6 (28%), resulting from over oxidation
(Fig. 2).
O
Although access to 1 using the selenium dioxide protocol
was rapid, the disappointing yield and purity indicated
that an alternative strategy was required. Of the procedures
O
O
1
HO
O
O
O
O
O
O
O
O
O
O
O
O
H
4
5
O
O
H
MeO2C
O
O
O
O
2
3
CO2Me
O
O
H
O
Li
Figure 1.
O
R
O
7 (lk)
6
* Corresponding author. Tel.: +61 7 3365 3530; fax: +61 7 3365 4299;
e-mail: c.williams3@uq.edu.au
Figure 2.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.030

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L. A. Baker et al. / Tetrahedron 62 (2006) 7355–7360
1) LDA
Base
HCHO
TBDMSCl
90%
1) LDA
2) MeI
64%
2)
OHC
O
O
O
O
10
HO
TBDMSO
TBDMSO
8
9
77%
O
O
O
O
O
1) Ac2O (92%)
2) LDA (69%)
SOCl2
pyr
72%
TBAF
O
O
O
OH
92%
O
O
O
O
OH
1
12
11
HO
TBDMSO
TBDMSO
TBDMSO
Scheme 1.
available for the construction of dl-pyroangolensolide3–7
O
O
7
´
4, Fernandez-Mateos maintains an unrivalled sequence
(stereospecific, four steps, 62% overall yield). On closer
inspection of the proposed transition state13 [lk approach,
7 (R¼H)] the allylic methyl group seems not to play a role
in the stereochemical outcome of the reaction, hence, addi-
tional functionality, for example, an ether unit (7, R¼OR0)
should be easily accommodated without transition state
disruption (Fig. 2).
O
O
HO
O
O
O
O
O
S
O
O
O
13
O
14
Figure 4.
Installation of the oxygen functionality was best achieved
using the El Gaıed (DMAP or imidazole)14 Baylis–Hillman
variants (Scheme 1). Alcohol 8 was then protected as
a t-BDMS ether (i.e., 9) (90%) and methylated (i.e., 10)
and (+)-Mosher’s ester17 derivatives. Although the dia-
stereomers could be easily seen by NMR analysis separation
was not achieved. Non-covalent methods, for example, treat-
ing the phthalate derivative 13 with a-methylbenzylamine18
(and brucine) did not yield crystals (Fig. 4). Lipases, both
acetylase (lipase PS) and deacetylase (lipase PS)19,20 proto-
cols failed to react with either the alcohol 11 or correspond-
ing acetate.
¨
´
(64%). The Fernandez-Mateos stereospecific aldol pro-
ceeded without incident, as predicted, giving 11 in 77%
yield, which was routinely acetylated (92%) and cyclised
affording the hydroxylactone 12 (69%). Elimination (72%)
and deprotection (92%) revealed azedaralide 1 [19% overall
yield, eight steps], as confirmed by X-ray crystal structure
analysis of the racemate (Fig. 3).
Preparative chiral chromatography on the other hand com-
pletely resolved the mixture of azedaralide enantiomers.
This task including transpacific transportation required only
days in comparison to months investigating failed asym-
metric and classical protocols described above. The (+)-
enantiomer was then converted to the crystalline sulfonate
14 (Fig. 4) using 1S-(+)-10-camphorsulfonyl chloride,21
which gave the X-ray crystal structure shown in Figure 5.
Considering the predetermined absolute stereochemistry of
the camphorsulfonyl chloride [via the sulfonic acid (R,S)]
the absolute stereochemistry of the (+)-enantiomer, as dem-
onstrated in the X-ray crystal structure, must be R,R. The
(+)-enantiomer has a rotation of +385.0, which is at variance
with that reported rotation (+165)1 for the isolated natural
product. Considering that only 1.7 mg of the isolated natural
product were obtained and that the 1H NMR of the material
revealed impurities,12 we are inclined to accept our optical
rotation value as more accurate.
In an attempt to introduce asymmetry into the racemic
sequence seen in Scheme 1, both asymmetric aldol and
classical chiral resolution type protocols were investigated.
For example, asymmetric aldol reactions with 10 and 3-fur-
aldehyde failed (e.g., DIP-Cl15), and difficulties were also
encountered in converting 10 into the SAMP derivative.16
Classical chiral resolution using covalent chiral auxiliaries
was attempted by converting 11 to the (–)-menthoxy acetate
Figure 3. ORTEP3 view of 1 crystallised as a racemate (30% probability
ellipsoids).
Figure 5. ORTEP3 view of 14 (30% probability ellipsoids shown).

L. A. Baker et al. / Tetrahedron 62 (2006) 7355–7360
7357
3. Conclusion
were heated at reflux in 1,4-dioxane (34 mL) for 20 h. A col-
our change from pale yellow to dark brown was observed
after 5–10 min. On cooling the solvent was removed under
high vacuum and the residue was redissolved in dichloro-
methane and filtered. The filtrate was washed with 2 M
hydrochloric acid, water and brine followed by drying
(Na2SO4) and evaporation in vacuo. The residue was then
reacted under the same conditions as above and after work
up was subjected to column chromatography (2:1 diethyl
ether/petroleum spirit) which afforded two fractions.
In conclusion, capitalising on the ingenious stereospecific
´
Fernandez-Mateos protocol has allowed a direct synthesis
of azedaralide 1 in viable quantities. Furthermore, the cur-
rent sequence (eight steps, 19% overall yield) is a near 70
fold improvement in overall yield on the only tetranortriter-
pene advanced intermediate 15 reported5 so far (15 steps,
0.27% overall yield) (Fig. 6). Chiral chromatography in con-
junction with X-ray crystal structure analysis was paramount
for elucidating and confirming Nakatani’s proposed config-
uration of azedaralide 1.
Fraction 1 afforded aldehyde 6 (148 mg, 28%) as white crys-
tals. mp 147–149 ꢁC.
O
O
1H NMR (400 MHz, CDCl3) d: 1.02 (s, 3H), 1.42–1.51 (m,
1H), 1.56–1.62 (m, 1H), 2.47–2.58 (m, 1H), 2.62–2.75 (m,
1H), 5.14 (s, 1H), 6.43–6.44 (m, 1H), 7.17–7.19 (m, 1H),
7.21 (s, 1H), 7.41–7.42 (m, 1H), 7.46–7.48 (m, 1H); 13C
NMR (100 MHz, CDCl3) d: 16.0, 23.5, 29.1, 36.9, 80.2,
109.9, 115.1, 120.0, 133.1, 141.2, 143.1, 151.4, 158.4,
BnO
O
15
ꢂ
165.1, 191.7; MS (EI) m/z (%): 258 (M+ , 2), 214 (1), 178
Figure 6.
(1), 162 (100), 147 (14), 134 (27), 119 (21), 105 (16), 91
(25). Anal. Calcd for C15H14O4: C, 70.03; H, 5.09. Found:
C, 70.08; H, 5.45%.
4. Experimental
4.1. General
Fraction 2 afforded azedaralide 1, which contained an un-
identified impurity (<10%) (92 mg, 17%). Characterisation
data below.
1H and 13C NMR spectra were recorded on Bruker AV400
(400.13 MHz; 100.62 MHz), AV300 (300.13 MHz; 75.47
MHz) and DRX (or AV) 500 (500.13 MHz; 125.77 MHz) in-
struments in deuteriochloroform (CDCl3). Coupling con-
stants are given in Hertz and chemical shifts are expressed
as d values in parts per million. High and low resolution
EI mass spectral data were obtained on a KRATOS MS 25
RFA. Electrospray mass spectrometry was performed on
a Finnigan MAT 900 XL-Trap. Microanalyses were per-
formed by the University of Queensland Microanalytical
Service. Melting points were determined on an Electrother-
mal melting point apparatus and are uncorrected. Chiral
chromatography was performed on a Berger Multigram
SFC (Mettler–Toledo) using a Chiralpak AS-H-SFC column
2.1 diaꢀ25 cm long (Chiral Technologies) and a K-2501 UV
detector (Knauer) with an eluent mixture of CO2/MeOH 80/
20 flowing at 25 mL/min. Injection, detection and collection
were controlled by AutoPrep software (PDR-Chiral). IR
spectra were obtained on a Perkin Elmer FTIR Spectrometer,
Spectrum 2000.
4.2.2. 2-[(tert-Butyldimethylsilyloxy)methyl]-2-cyclo-
hexenone 9. 2-Hydroxymethyl-2-cyclohexenone 8 (5 g,
40.32 mmol) was dissolved in anhydrous dichloromethane
(100 mL) and anhydrous triethylamine (13.25 mL) under
an argon atmosphere. To this was added in one portion,
tert-butyldimethylsilyl chloride (7.17 g, 47.56 mmol) and
the mixture was allowed to stir for 24 h at room temperature.
The reaction mixture was poured into a separatory funnel
containing saturated sodium hydrogen carbonate (25 mL),
and the organic layer partitioned. The aqueous layer was
extracted with dichloromethane (3ꢀ30 mL) and the com-
bined organic phases were washed with water, dried
(Na2SO4), evaporated and the residue subjected to column
chromatography (2:1 petroleum spirit/diethyl ether), yield-
ing the titled compound 9 as a pale yellow oil (8.56 g, 90%).
1H NMR (500 MHz, CDCl3) d: 0.05 (s, 6H), 0.90 (s, 9H),
1.98 (p, J¼6.3 Hz, 2H), 2.37–2.41 (m, 4H), 4.33 (AB, 2H),
6.97–6.99 (m, 1H); 13C NMR (75 MHz, CDCl3) d: ꢃ5.5,
ꢃ3.6, 18.3, 22.9, 25.55, 25.6, 25.9, 38.3, 60.0, 138.3,
143.9, 199.0; Near IR (Neat) n (cmꢃ1) 1671, 1461, 1399;
4.2. X-ray crystallography
ꢂ
Data for all compounds were collected at 293 K on an
Enraf–Nonius CAD4 diffractometer. Data reduction, direct
methods structure solution and full least squares refinement
(SHELX9722) were performed with the WINGX package.23
Drawings of all molecules were created with ORTEP3.24
Data in CIF format have been deposited with the Cambridge
Crystallographic Data Centre (CCDC deposition numbers
601060 and 601061). Copies of the data can be obtained
free of charge upon request to deposit@ccdc.cam.ac.uk.
MS (EI) m/z (%): 240 (M+ , 1), 225 (4), 193 (3), 183 (100),
167 (1), 151 (9), 142 (1), 127 (2), 117 (1), 109 (1), 101 (1),
91 (3); HRMS calcd for C13H24O2Si 240.1545, Found
240.1548.
4.2.3. 2-[(tert-Butyldimethylsilyloxy)methyl]-6-methyl-
2-cyclohexenone 10. To a cold (0 ꢁC) stirring solution of
diisopropylamine (6.16 mL, 43.7 mmol) in anhydrous tetra-
hydrofuran (50 mL) under an argon atmosphere, was added
n-butyl lithium (1 M in hexanes, 31.5 mL, 41.6 mmol) over a
period of 10 min. After a further 45 min, 2-[(tert-butyl-
dimethylsilyloxy)methyl]-2-cyclohexenone 9 (10 g, 41.6
mmol) in tetrahydrofuran (50 mL) was added dropwise via
4.2.1. Reaction of pyroangolensolide 4 with selenium
dioxide. dl-Pyroangolensolide 4 (500 mg, 2.05 mmol) and
freshly sublimed selenium dioxide (341 mg, 3.07 mmol)

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L. A. Baker et al. / Tetrahedron 62 (2006) 7355–7360
cannula. The reaction was stirred at 0 ꢁC for a further
60 min, before dropwise addition of iodomethane (7.8 mL,
125 mmol). Saturated sodium hydrogen carbonate (40 mL)
was added to the cold solution after 30 min, and the suspen-
sion was allowed to warm to room temperature (2 h).
Extraction with petroleum spirit (4ꢀ100 mL), followed by
washing with brine, drying (Na2SO4) and evaporation re-
sulted in an oily residue. Column chromatography (5:1
petroleum spirit/diethyl ether) afforded 10 as an orange-
brown oil (6.8 g, 64%).
column chromatography (2:1 petroleum spirit/diethyl ether)
affording the titled compound as a yellow oil (2.59 g, 92%).
1H NMR (500 MHz, CDCl3) d: 0.05 (s, 6H), 0.89 (s, 9H),
1.16 (s, 3H), 1.79–1.91 (m, 2H), 2.05 (s, 3H), 2.39 (br s,
2H), 4.21–4.32 (m, 2H), 6.28 (s, 1H), 6.33 (s, 1H), 6.87
(br s, 1H), 7.28 (s, 1H), 7.30 (s, 1H); 13C NMR (125 MHz,
CDCl3) d: ꢃ5.53, ꢃ5.49, 18.3, 18.6, 20.9, 22.1, 25.9, 29.2,
48.9, 60.1, 71.6, 110.1, 122.2, 137.0, 140.6, 142.0, 142.5,
169.7, 200.4; HRMS calcd for C21H32O5NaSi 415.1916,
Found 415.1923.
1H NMR (500 MHz, CDCl3) d: 0.05 (s, 6H), 0.90 (s, 9H),
1.11 (d, J¼6.83 Hz, 3H), 1.66–1.74 (m, 1H), 2.00–2.06
(m, 1H), 2.37–2.41 (m, 2H), 4.29–4.35 (m, 2H), 6.91–6.92
(br m, 1H); 13C NMR (75 MHz, CDCl3) d: ꢃ5.4, 1.0,
15.0, 18.4, 25.0, 25.9, 29.7, 31.0, 41.7, 60.2, 137.7, 143.0,
4.2.6. 5-[(tert-Butyldimethylsilyloxy)methyl]-1-(furan-3-
yl)-4a-hydroxy-8a-methyl-4,4a,8,8a-tetrahydro-1H-iso-
chromen-3(7H)-one 12. To a stirred solution of diisopropyl-
amine (8.67 mL, 6.18 mmol) in anhydrous tetrahydrofuran
(15 mL) at 0 ꢁC under an argon atmosphere, was added
n-butyl lithium (1.32 M in hexanes, 4.46 mL) dropwise over
a period of 4 min. After 30 min at 0 ꢁC, the solution was
cooled to ꢃ78 ꢁC and a solution of 2-[(tert-butyldimethyl-
silyloxy)methyl]-6-[(furan-3-yl)-acetoxymethyl]-6-methyl-
2-cyclohexenone (2 g, 5.10 mmol) in tetrahydrofuran
(15 mL) was added dropwise. The reaction was stirred
at ꢃ78 ꢁC for 5 h, before quenching with saturated ammo-
nium chloride solution (15 mL). After warming to room
temperature (12 h), the mixture was transferred to a separa-
tory funnel, extracted with dichloromethane (4ꢀ20 mL) and
washed successively with water and brine. The extracts
were then dried (Na2SO4), evaporated and subjected to col-
umn chromatography (2:1 diethyl ether/petroleum spirit)
affording the titled compound 12 (1.37 g, 69%) as a white,
crystalline solid.
ꢂ
201.6; MS (EI) m/z (%): 254 (M+ , 1), 239 (4), 225 (5),
211 (2), 207 (6), 197 (99), 193 (6), 183 (100), 167 (6), 155
(7), 153 (9), 151 (12), 127 (5), 117 (2), 105 (7), 91 (8);
HRMS calcd for C14H26O2Si 254.1702, Found 254.1699.
4.2.4. 2-[(tert-Butyldimethylsilyloxy)methyl]-6-[(furan-
3-yl)hydroxymethyl]-6-methyl-2-cyclohexenone 11. To a
stirred solution of diisopropylamine (5 mL, 35.7 mmol) in
anhydrous tetrahydrofuran (100 mL) at 0 ꢁC under an argon
atmosphere, was added n-butyl lithium (1.32 M in hexanes,
25.8 mL, 34.1 mmol) dropwise over a period of 5 min. After
25 min at 0 ꢁC, the solution was cooled to ꢃ78 ꢁC and a
solution of 2-[(tert-butyldimethylsilyloxy)methyl]-6-methyl-
2-cyclohexenone 10 (5 g, 19.7 mmol) in anhydrous tetra-
hydrofuran (25 mL) was added via cannula (3 min). The re-
action was stirred for 3 h at ꢃ78 ꢁC before quenching with
saturated ammonium chloride solution (30 mL) and slow
warming to room temperature (12 h). The organic layer
was partitioned and the aqueous layer extracted with di-
chloromethane (4ꢀ50 mL). The combined organic layers
were washed with water and brine, dried (Na2SO4) and evap-
orated. Column chromatography of the residue (5:1 petro-
leum spirit/diethyl ether) afforded the desired product 11 as
a pale yellow oil (5.3 g, 77%).
1
Mp 121–123 ꢁC; H NMR (500 MHz, CDCl3) d: 0.10 (s,
3H), 0.12 (s, 3H), 0.90 (s, 9H), 1.01 (s, 3H), 1.31–1.36 (m,
1H), 1.88–1.93 (m, 1H), 2.09–2.16 (m, 2H), 3.02 (AB,
2H), 3.69 (br s, 1H), 4.10 (d, J¼11.6 Hz, 1H), 4.47 (d,
J¼11.6 Hz, 1H), 5.21 (s, 1H), 5.87 (br s, 1H), 6.43 (s, 1H),
7.40 (d, J¼1.6 Hz, 1H), 7.43 (s, 1H); 13C NMR (125 MHz,
CDCl3) d: ꢃ5.57, ꢃ5.58, 15.0, 18.0, 21.8, 25.8, 27.3, 39.5,
39.9, 66.4, 71.5, 77.7, 109.8, 121.2, 128.5, 137.0, 140.6,
143.0, 170.3; HRMS calcd for C21H32O5NaSi 415.1916,
Found 415.1919.
1H NMR (400 MHz, CDCl3) d: 0.06 (s, 6H), 0.90 (s, 9H),
1.17 (s, 3H), 1.49–1.53 (m, 1H), 1.69–1.75 (m, 1H), 2.37–
2.41 (br m, 2H), 4.25–4.39 (m, 2H), 4.89 (s, 1H), 6.36 (s,
1H), 6.97 (br s, 1H), 7.35 (d, J¼1.5 Hz, 1H), 7.36 (s, 1H);
13C NMR (125 MHz, CDCl3) d: ꢃ5.5, 14.5, 18.3, 22.3,
25.9, 31.1, 47.5, 60.1, 71.5, 110.1, 123.9, 136.6, 140.5,
142.5, 144.1, 206.2; Near IR (Neat) n (cmꢃ1) 3444, 1651,
1503, 1461; HRMS ESI calcd for C19H30O4NaSi
373.1811, Found 373.1809.
4.2.7. 5-[(tert-Butyldimethylsilyloxy)methyl]-1-(furan-3-
yl)-8a-methyl-8,8a-dihydro-1H-isochromen-3(7H)-one.
To a solution of 12 (1.00 g, 2.55 mmol) in anhydrous di-
chloromethane (15 mL), was added anhydrous pyridine
(825 mL, 10.2 mmol) under an argon atmosphere. The reac-
tion flask was cooled in an ice-bath, and thionyl chloride
(372 mL, 5.10 mmol) added dropwise. After 20 min, water
(10 mL) was added and the mixture was allowed to warm
to room temperature over 1 h. The reaction mixture was
extracted with dichloromethane (2ꢀ30 ml), washed with
saturated sodium hydrogen carbonate and brine then dried
(Na2SO4). Evaporation followed by column chromato-
graphy of the residue (1:1 petroleum spirit/diethyl ether)
gave the titled compound as a white, crystalline solid
(690 mg, 72%).
4.2.5. 2-[(tert-Butyldimethylsilyloxy)methyl]-6-[(furan-
3-yl)acetoxymethyl]-6-methyl-2-cyclohexenone. Acetic
anhydride (8.7 mL) was added dropwise to a cold (0 ꢁC)
solution of 11 (2.5 g, 7.14 mmol) in pyridine (8.7 mL) under
an argon atmosphere. The cold bath was removed and stir-
ring continued at room temperature for 4 h, followed by
addition of iced water (20 mL). On warming to room tem-
perature, the mixture was transferred to a separatory funnel
and extracted with dichloromethane (4ꢀ20 mL). The
combined extracts were washed successively with sodium
hydrogen carbonate, water and brine, dried (Na2SO4) and
evaporated. Excess pyridine was removed in vacuo prior to
1
Mp 93.5–94.5 ꢁC; H NMR (500 MHz, CDCl3) d: 0.07 (s,
6H), 0.90 (s, 9H), 1.01 (s, 3H), 1.41–1.50 (m, 2H), 2.28–
2.37 (m, 2H), 4.30 (AB, 2H), 5.11 (s, 1H), 5.79 (s, 1H),

L. A. Baker et al. / Tetrahedron 62 (2006) 7355–7360
7359
6.43 (br s, 2H), 7.40 (d, J¼1.5 Hz, 1H), 7.46 (s, 1H); 13C
NMR (125 MHz, CDCl3) d: ꢃ5.38, ꢃ5.35, 15.9, 18.3,
22.0, 25.9, 29.9, 37.1, 62.4, 80.7, 109.3, 110.1, 120.2,
132.2, 134.7, 141.1, 142.9, 157.3, 165.8; Near IR (Neat)
n (cmꢃ1) 1704, 1635, 1597; HRMS calcd for C21H30O4NaSi
397.1811, Found 397.1817; Anal. Calcd for C21H30O4Si:
C, 67.34; H, 8.07. Found: C, 67.37; H, 8.26%.
1H), 7.41–7.42 (m, 1H), 7.47 (s, 1H); 13C NMR
(100 MHz, CDCl3) d: 15.9, 19.7, 19.8, 22.4, 24.9, 26.9,
29.3, 37.2, 42.5, 42.7, 48.0, 48.1, 58.0, 69.4, 80.5, 110.0,
111.3, 119.9, 127.8, 141.2, 142.5, 143.0, 156.0, 165.1,
ꢂ
214.5; MS (EI) m/z (%): 474 (M+ , 2), 410 (1), 378 (1),
294 (1), 260 (9), 242 (3), 215 (15), 178 (3), 164 (85), 146
(46), 118 (100), 109 (34), 91 (29); HRMS calcd for
C25H33O7S 474.1712, Found 474.1712.
4.2.8. 1-(Furan-3-yl)-5-hydroxymethyl-8a-methyl-8,8a-
dihydro-1H-isochromen-3(7H)-one (azedaralide) 1.
Tetrabutylammonium fluoride (1 M in tetrahydrofuran,
2.67 mL, 2.67 mmol) was added dropwise to a 0 ꢁC solu-
tion of5-[(tert-butyldimethylsilyloxy)methyl]-1-(furan-3-yl)-
8a-methyl-8,8a-dihydro-1H-isochromen-3(7H)-one (500 mg,
1.34 mmol) in anhydrous tetrahydrofuran (25 mL). The solu-
tion was stirred at this temperature for 20 min, before dilution
with ethyl acetate (10 mL) and hydrochloric acid (1 M,
10 mL). The reaction was extracted with ethyl acetate
(3ꢀ30 mL). The combined organic phases were washed
with brine (40 mL) and dried (Na2SO4). Evaporation and col-
umn chromatography of the residue (diethyl ether) afforded
azedaralide (1) as a pale yellow, crystalline solid (320 mg,
92%). After chiral chromatography (+)-azedaralide [a]D
+385.0 (c 1.59, MeOH) and (ꢃ)-azedaralide [a]D ꢃ391.9
(c 1.47, MeOH) at 27 ꢁC.
Acknowledgements
The authors thank the following people for their assistance
with this body of research. Professor Munehiro Nakatani
for providing 400 MHz 1H NMR spectra of isolated azedar-
alide 1 and the University of Queensland for providing
support to this work. We are indebted to Charlene Olle at
PDR-Chiral for technical assistance.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.05.030.
1
Mp 108–108.5 ꢁC; H NMR (500 MHz, CDCl3) d: 1.02 (s,
References and notes
3H), 1.41–1.51 (m, 3H), 2.25–2.39 (m, 2H), 4.33 (q,
J¼12.8 Hz, 2H), 5.13 (s, 1H), 5.94 (s, 1H), 6.43 (br s, 1H),
7.41 (t, J¼1.5 Hz, 1H), 7.47 (s, 1H); 13C NMR (125 MHz,
CDCl3) d: 16.0, 22.0, 29.7, 37.1, 62.8, 80.7, 110.0, 110.2,
120.1, 132.5, 136.7, 141.2, 143.0, 157.3, 165.8; MS (EI)
1. Nakatani, M.; Huang, R. C.; Okamura, H.; Iwagawa, T.;
Tadera, K. Phytochemistry 1998, 49, 1773–1776.
2. Mulholland, D. A.; Parel, B.; Coombes, P. H. Curr. Org. Chem.
2000, 4, 1011–1054; (b) Taylor, D. A. H. Fortschr. Chem. Org.
Naturst. 1984, 45, 1–102; (c) Deyer, D. L. Fortschr. Chem. Org.
Naturst. 1968, 26, 190–244.
3. Fukuyama, Y.; Tokoroyama, T.; Kubota, T. Tetrahedron Lett.
1973, 4869–4872.
4. Drewes, S. E.; Grieco, P. A.; Huffman, J. C. J. Org. Chem.
1985, 50, 1309–1311.
ꢂ
m/z (%): 260 (M+ , 2), 216 (1), 183 (2), 173 (2), 164 (100),
149 (15), 135 (3), 119 (38), 105 (11), 99 (13), 91 (14);
Near IR [(+)-azedaralide] (Neat) n (cmꢃ1) 3429, 1676,
1629, 1591; HRMS calcd for C15H16O4 260.1049, Found
260.1050; Anal. Calcd for C15H16O4: C, 69.22; H, 6.20.
Found: C, 69.37; H, 6.32%.
5. Liu, H.-J.; Dieck-Abularach, T. Heterocycles 1987, 25, 245–
249.
4.2.9. [(1R,8aR)-1-(furan-3-yl)-8a-methyl-3-oxo-3,7,8,8a-
tetrahydro-1H-isochromen-5-yl]methyl (1S,4R)-7,7-
dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl methane-
sulfonate 14. (+)-Azedaralide (20 mg, 0.077 mmol) was
dissolved in anhydrous tetrahydrofuran (5 mL) under an
atmosphere of argon. Anhydrous triethylamine (25 mL,
0.18 mmol) was added and the reaction vessel cooled in an
ice-bath, prior to dropwise addition of (+)-camphorsulfonyl
chloride (29 mg, 0.12 mmol). The solution was then allowed
to warm slowly to room temperature. After 21 h the solvent
was removed in vacuo, and the residue taken up into di-
chloromethane (10 mL), before washing with hydrochloric
acid (2 M), and water. The organic phase was dried
(Na2SO4), and evaporated. The residue was subjected to
column chromatography (diethyl ether) to yield the desired
sulfonate (32 mg, 88%) as an amorphous solid, which was
recrystallised (ethyl acetate) affording white needles. [a]D
+260.1 (c 1.45, CDCl3) at 27 ꢁC.
´
6. Fernandez Mateos, A.; de la Fuente Blanco, J. A. J. Org. Chem.
1991, 56, 7084–7092.
´
7. Fernandez-Mateos, A.; Grande Benito, M.; Pascual Coca, G.;
Rubio Gonzalez, R.; Tapia Hernandez, C. Tetrahedron 1995,
´
´
51, 7521–7526.
8. (a) Warpehoski, M. A.; Chabaud, B.; Sharpless, K. B. J. Org.
Chem. 1982, 47, 2897–2900; (b) Umbreit, M. A.; Sharpless,
K. B. J. Am. Chem. Soc. 1977, 99, 5526–5528.
9. Kitching, W.; Rappoport, Z.; Winstein, S.; Young, W. G. J. Am.
Chem. Soc. 1966, 88, 2054–2055.
10. Rappoport, Z.; Sleezer, P. D.; Winstein, S.; Young, W. G.
Tetrahedron Lett. 1965, 3719–3728.
11. (a) Connolly, J. D.; MacLellan, M.; Okorie, D. A.; Taylor,
D. A. H. J. Chem. Soc., Perkin Trans. 1 1976, 1993–1996;
(b) Adesogan, E. K.; MacLachlan, L. K.; Taylor, D. A. H.
S. Afr. J. Chem. 1987, 40, 25–29.
12. The 1H NMR spectrum of azedaralide 1 provided by M.
Nakatani, et al.1 is identical in all respects to our data. The
13C NMR spectrum is in slight disagreement; we observed
an additional peak at 110.0 ppm, whereas M. Nakatani,
et al.1 reports overlapping peaks at 157.2 ppm. A visual com-
Mp 160.5 ꢁC; 1H NMR (400 MHz, CDCl3) d: 0.86 (s, 3H),
1.03 (s, 3H), 1.09 (s, 3H), 1.43–1.50 (m, 3H), 1.60–1.65
(m, 1H), 1.92–2.12 (m, 3H), 2.34–2.44 (m, 4H), 3.01 (d,
1H, J¼15 Hz), 3.57 (dd, 1H, J¼15, 1 Hz), 4.93 (AB, m,
2H), 5.14 (s, 1H), 5.95 (s, 1H), 6.43 (s, 1H), 6.59–6.60 (m,
1
parison of the H NMR spectra can be made from the sup-
porting information.

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L. A. Baker et al. / Tetrahedron 62 (2006) 7355–7360
´
13. Fernandez-Mateos, A.; Pascual Coca, G.; Perez Alonso, J. J.;
Rubio Gonzalez, R.; Tapia Hernandez, C. Tetrahedron Lett.
´
18. Sato, K.; Nakayama, T.; Mori, K. Agric. Biol. Chem. 1979, 43,
1571–1575.
´
´
1995, 36, 961–964.
14. (a) Gatri, R.; El Gaıed, M. M. Tetrahedron Lett. 2002, 43,
19. Takanami, T.; Tokoro, H.; Kato, D.-I.; Nishiyama, S.; Sugai, T.
Tetrahedron Lett. 2005, 46, 3291–3295.
¨
7835–7836; (b) Rezgui, F.; El Gaied, M. M. Tetrahedron
Lett. 1998, 39, 5965–5966.
20. Luna, A.; Astorga, C.; Fulop, F.; Goto, V. Tetrahedron:
¨ ¨
Asymmetry 1998, 9, 4483–4487.
15. Mickel, S. J.; Daeffler, R.; Prikoszovich, W. Org. Prog. Res.
Dev. 2005, 9, 113–120.
16. Lio, H.; Monden, M.; Okada, K.; Tokoroyama, T. J. Chem.
Soc., Chem. Commun. 1987, 358–359.
21. Brown, R. J.; Annis, G.; Casalnuovo, A.; Chan, D.; Shapiro, R.;
Marshall, W. J. Tetrahedron 2004, 60, 4361–4375.
22. Sheldrick, G. M. SHELX97. Programs for Crystal Structure
Analysis; University of Gottingen: Germany, 1997.
¨
17. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543–2549.
23. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837–838.
24. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.