A novel biomimetic synthesis of (S)-(-)-zearalenone: Via macrocyclization and transannular aromatization

Article abstract of DOI:10.1016/j.tet.2010.05.084

On heating, a hydroxy-keto-dioxinone underwent retro-Diels-Alder fragmentation and the resultant α,γ-diketo-ketene was efficiently trapped intramolecularly by a secondary alcohol to provide a macrocyclic triketo-lactone. Following ketal hydrolysis, transannular aromatization gave the resorcylate natural product, (S)-(-)-zearalenone.

Full text of DOI:10.1016/j.tet.2010.05.084

Tetrahedron 66 (2010) 6331e6334
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Tetrahedron
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A novel biomimetic synthesis of (S)-(ꢀ)-zearalenone: via macrocyclization and
transannular aromatization
*
Hideki Miyatake-Ondozabal, Anthony G.M. Barrett
Department of Chemistry, Imperial College, London SW7 2AZ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
On heating, a hydroxy-keto-dioxinone underwent retro-DielseAlder fragmentation and the resultant a,
Received 1 March 2010
Received in revised form 13 May 2010
Accepted 21 May 2010
g
-diketo-ketene was efficiently trapped intramolecularly by a secondary alcohol to provide a macrocyclic
triketo-lactone. Following ketal hydrolysis, transannular aromatization gave the resorcylate natural
product, (S)-(ꢀ)-zearalenone.
Available online 4 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Resorcylic acid lactones
Retro-DielseAlder
Intramolecular ketene trapping
Transannular aromatization
Biomimetic synthesis
1. Introduction
ester 5 was constructed by intermolecular trapping of a ketene
derived from diketo-dioxinone
4 followed by aromatization
The
b
-resorcylate unit 1 occurs in a wide range of resorcylic acid
(Scheme 1). This strategy was also employed in our syntheses of
lactones including the potent estrogen agonist (S)-(ꢀ)-zearalenone
(2),1 isolated from microfungus Fusarium graminearum (Fig. 1).2
Several total syntheses of both racemic and naturally occurring
(S)-(ꢀ)-zearalenone (2) have been reported,3aee including a recent
synthesis by our group in which the 6-alkyl-2,4-dihydroxybenzoic
the potent anti-malarial agent aigialomycin D (3),4 and marine anti-
fungal agents 15G256i, 15G256b . In all our
, and 15G256p 3c
syntheses, either a late-stage ring-closing metathesis (RCM) or
Yamaguchi macrolactonization were utilized to construct the
macrocyclic structure.
OH
O
OH
O
1) retro-Diels-Alder
R2OH
O
O
O
O
OR2
O
R1
O
2) aromatization
HO
R1
HO
β-resorcylate unit 1
OH
O
4
5
O
Scheme 1. Intermolecular ketene trapping approach to elaborate the 6-alkyl-2,4-di-
hydroxybenzoic ester 5.3c
HO
OH
Inspired by Boeckman’s elegant application of dioxinones as
OH
O
precursors for
u-hydroxy-ketene generation and trapping to pro-
(3)
aigialomycin D (3)
OH
duce macrocyclic natural products,5 we examined intramolecular
ketene trapping and aromatization to produce resorcylate macro-
cyclic lactones. This route provides a convenient alternative to
macrocyclization using ring closing metathesis.
O
HO
O
(S)-(−)-zearalenone (2)
Figure 1. Examples of resorcylate natural products.
2. Results and discussion
Our retrosynthetic analysis is illustrated in Scheme 2. (S)-
(ꢀ)-Zearalenone (2) should be available by late-stage transannular
* Corresponding author. Tel.: þ44 020 7594 5766; fax: þ44 020 7594 5805;
e-mail address: agm.barrett@imperial.ac.uk (A.G.M. Barrett).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.084

6332
H. Miyatake-Ondozabal, A.G.M. Barrett / Tetrahedron 66 (2010) 6331e6334
1) CDI, THF, 23 o
OH
O
O
C
O
2) EtOAc, LiNi-Pr2,
THF, −78 oC to 0 o
C
CO2H
HO
O
O
2
10
CO2Et
11
Late-stage
HOCH2CH2OH,
p-TSA, HC(OEt)3,
PhMe, 23 o
aromatization
C
O
O
O
O
O
O
O
FVP
O
O
O
580 oC,
0.18 mbar
OEt
13 (70%)
6
O
CO2Et
12 (70% over 2 steps)
Intramolecular
ketene trapping
1) KOH, EtOH, 45 oC,
2) 14, EDC HCl, CH2Cl2, 23 oC
.
HN
N
O
O
OH
O
O
O
O
O
O
N
14
O
7
O
O
O
O
O
O
Cross-metathesis
16
9 (63%)
N
N
LiN(SiMe3)2, ZnCl2,
THF, −78 oC to 0 o
N
C
OH
O
O
O
O
O
O
15 (70%)
O
Scheme 3. Synthesis of olefin 9.
8
9
Scheme 2. Retrosynthetic analysis.
Subsequent cross-metathesis of dioxinone 9 with alcohol 8
using the second generation Grubbs catalyst proceeded with
excellent E/Z selectivity and gave the desired E-alkene 7 (75%)
(Scheme 4). Hydroxy protection was not required during this
transformation. Thermolysis of dioxinone 7 resulted in a retro-
DielseAlder reaction9 to produce ketene 17, which was efficiently
trapped intramolecularly by the alcohol to provide the 18-
membered macrocyclic lactone 18. Finally, ketal deprotection
gave triketo-ester 19, which was subjected to transannular aro-
matization using cesium carbonate followed by acidification to
give (S)-(ꢀ)-zearalenone (2) (46% over four steps).10 The sample
of (S)-(ꢀ)-zearalenone (2) displayed identical physical and
spectroscopic data to an authentic sample.
aromatization of macrocylic triketo-ester 6, which in turn could be
prepared by the intramolecular trapping of the ketene derived from
dioxinone 7. We considered that olefin 7 could be generated by the
cross-metathesis reaction between alcohol 8 and dioxinone 9.
Alcohol 8 (>99% ee) was prepared by a modification3c of
Fürstner’s original synthesis.3d Alkene 9 was synthesized in seven
steps from commercially available (ꢁ)-norbornene-2-carboxylic
acid (10) (endo/exo 3:1) (Scheme 3). Claisen condensation between
ethyl acetate and the acyl imidazolide from acid 10 gave keto-ester
11, which was transformed into ketal 12 in 70% yield over two steps.
Flash vacuum pyrolysis (FVP) of norbornene 12 gave olefin 13 (70%),
which was converted into benzotriazole derivative 15 over two
steps.6 Subsequent Claisen condensation with the lithium enolate
Grubbs II (10% mol)
CH2Cl2, 40 o
OH
O
O
O
O
PhMe
110 oC
O
OH
O
O
O
O
O
O
O
O
O
8
9
O
C
C
7 (75%)
17
> 20:1 E/Z
O
O
O
O
O
O
1) Cs2CO3, MeOH
p-TSA, H2O,
Me2CO, 23 o
2 (46% over 4 steps)
O
O
2) AcOH, then
1 M aq. HCl
C
O
O
O
O
O
O
18
19
Scheme 4. Synthesis of (S)-(ꢀ)-zearalenone (2).
from dioxinone 16 in the presence of zinc chloride provided keto-
dioxinone 9 in 63% yield. We found that the presence of zinc
chloride enhanced selectivity for C-acylation over O-acylation via
Lewis acid coordination.7 In the absence of zinc chloride, the
reaction proceeded in lower yields (35e50%). The enone func-
3. Conclusion
In summary, we report a novel synthesis of (S)-(ꢀ)-zearalenone
(2) where macrolactonization and aromatization are carried out
consecutively. It is noteworthy that this intramolecular ketene
trappingdlate-stage aromatization strategy closely mimics the
biosynthesis of resorcylate natural products such as (S)-
tionality in 13 was protected since g,d-unsaturated-b-keto-esters
are known to be relatively labile.8

H. Miyatake-Ondozabal, A.G.M. Barrett / Tetrahedron 66 (2010) 6331e6334
6333
(ꢀ)-zearalenone (2). Further applications toward more complex
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
endo 169.7, 135.9, 132.4,
resorcylates are currently under investigation.
110.4, 65.5, 64.4 60.4, 50.4, 46.1, 44.1, 43.2, 42.3, 28.3, 14.2; d exo
169.7, 137.8, 137.2, 111.1, 65.6, 64.9, 60.5, 46.6, 46.0, 43.5, 43.1, 41.6,
28.3, 14.1; m/z (EI) 252 (Mþ); HRMS (EI): Mþ, found 252.1359;
C14H20O4 requires 252.1362; found: C, 66.56; H, 7.91. C14H20O4
requires C, 66.65; H, 7.99%.
4. Experimental section
4.1. General remarks
All solvents and reagents were obtained from commercial
suppliers and used without further purification unless otherwise
stated. The following reaction solvents were distilled under nitro-
gen: Et2O and THF from Ph2CO/Na; PhMe from Na; CH2Cl2 and Et3N
from CaH2. MeOH was dried by reflux over Mg/I2, followed by
distillation from CaH2 under N2. Flash column chromatography was
performed using silica gel 60, and compounds were visualized by
UV light (254 nm and 350 nm).
4.1.3. Ethyl 2-(2-ethenyl-1,3-dioxolan-2-yl)acetate (13)12. Flash
vacuum pyrolysis (FVP) of norbornene 12 (24.0 g, 95 mmol) using
a carbolite furnace at 580 ꢂC under 0.18 mbar pressure gave a crude
product, which was chromatographed (Et2O/hexanes 1:9 to 1:4) to
give ester 13 (12.1 g, 70%) as a pale yellow liquid: Rf (Et2O/hexanes
1:4) 0.20; nmax (liquid film) 1733s, 1405m, 1369m, 1208m, 1174m,
1118m, 1032s cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
5.92 (dd, J¼17.2,
10.6 Hz, 1H), 5.46 (dd, J¼17.1, 1.7 Hz, 1H), 5.22 (dd, J¼10.6, 1.5 Hz,
1H), 4.17 (q, J¼7.2 Hz, 2H), 4.05e3.91 (m, 4H), 2.79 (s, 2H), 1.28 (t,
4.1.1. Ethyl 3-(bicyclo[2.2.1]hept-5-en-2-yl)-3-oxopropanoate (11)11
endo/exo¼3:1. Carbonyl diimidazole (32.3 g, 199 mmol) was
added portionwise with stirring to (ꢁ)-norbornene-2-carboxylic
acid (10) (22.1 mL, 181 mmol) in THF (600 mL) at 23 ꢂC. After 18 h,
the solvent was reduced to approximately 60 mL in volume and the
clear yellow solution was used directly in the next step. EtOAc
(53 mL, 544 mmol) was added dropwise with stirring to freshly
prepared LDA (544 mmol) in THF (600 mL) at ꢀ78 ꢂC. After 30 min,
the crude acyl imidazolide (w60 mL) was added dropwise with
stirring at ꢀ78 ꢂC. After 20 min, the mixture was allowed to warm
to 23 ꢂC over 2.5 h and aqueous HCl (1 M; 150 mL) was added. The
mixture was extracted with Et2O (2ꢃ200 mL), the combined
organic layers were washed with saturated aqueous NaHCO3
(3ꢃ100 mL) and dried (MgSO4). Rotary evaporation gave the crude
keto-ester 11 (32 g) as a dark orange oil, which was used on the
following step without further purification. A small amount of the
endo and exo isomers was separated by chromatography (Et2O/
hexanes 1:9 to 1:4) for authentication: Rf (Et2O/hexanes 1:4) 0.26;
nmax (liquid film) 1740s, 1707s, 1367m, 1337m, 1307m, 1252m,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 168.9, 136.6, 116.1, 106.4,
64.8 (2C), 60.6, 43.9, 14.2; m/z (ESI) 187 (MþH)þ; HRMS (ESI):
(MþH)þ, found 187.0962; C9H15O4 requires 187.0970.
4.1.4. 1-(1H-Benzo[d][1,2,3]triazol-1-yl)-2-(2-ethenyl-1,3-dioxolan-
2-yl)ethanone (15). KOH (950 mg, 17 mmol) in EtOH (10 mL) was
added with stirring to ester 13 (2.0 g, 10.8 mmol) in EtOH (10 mL) at
23 ꢂC. After 1.5 h at 45 ꢂC, rotary evaporation gave a sticky yellow
solid, which was triturated with Et2O (20 mL) to give the corre-
sponding potassium salt as a white solid (2.1 g). The crude salt was
dissolved in H2O (15 mL) and acidified carefully to pH 3 using
aqueous HCl (1 M). The aqueous layer was extracted with Et2O
(2ꢃ25 mL) and the combined organic layers were dried (MgSO4)
and rotary evaporated to leave the corresponding carboxylic acid as
a colorless oil (1.6 g). The crude material was used in the following
step without further purification. Benzotriazole 14 (1.3 g,
11.1 mmol) in CH2Cl2 (8 mL) was added with stirring to the crude
carboxylic acid (1.6 g, 10.1 mmol) and EDC$HCl (2.1 g, 11.1 mmol) in
CH2Cl2 (40 mL) at 23 ꢂC. After 18 h, CH2Cl2 (60 mL) was added and
the solution was washed with aqueous HCl (1 M; 25 mL) and pH 9
buffer (2ꢃ30 mL). The organic layer was dried (MgSO4) and rotary
evaporated to give acyl triazole 15 (1.9 g, 70% over two steps) as
a white solid: mp 97e101 ꢂC; Rf (Et2O/hexanes 1:1) 0.67; nmax
1093s,1030s, 715s cmꢀ1; 1H NMR (400 MHz, CDCl3)
d endo 6.21 (dd,
J¼5.6, 3.1 Hz, 1H), 5.90 (dd, J¼5.7, 2.7 Hz, 1H), 4.23 (q, J¼7.2 Hz, 2H),
3.53 (d, J¼15.2 Hz, 1H), 3.46 (d, J¼15.2 Hz, 1H), 3.28 (br s, 1H),
3.21e3.18 (m, 1H), 2.95 (br s, 1H), 1.85e1.78 (m, 1H), 1.56e1.35 (m,
3H),1.30 (t, J¼7.2 Hz, 3H);
d
exo 6.20 (dd, J¼5.6, 2.9 Hz,1H), 6.14 (dd,
(liquid film) 1743s, 1621w, 1375s, 1367s, 1195s, 1172s, 1059s cmꢀ1
1H NMR (400 MHz, CDCl3)
;
J¼5.6, 3.1 Hz, 1H), 4.25e4.19 (q, J¼7.2 Hz, 2H), 3.58 (d, J¼15.2 Hz,
1H), 3.54 (d, J¼15.4 Hz, 1H), 3.06 (br s, 1H), 2.95 (br s, 1H),
2.53e2.49 (m,1H),1.94 (dt, J¼11.2, 4 Hz,1H),1.43e1.33 (m, 2H),1.30
d
8.34 (d, J¼8.4 Hz, 1H), 8.15 (d, J¼8.4 Hz,
1H), 7.70e7.67 (m, 1H), 7.56e7.52 (m, 1H), 6.07 (dd, J¼17.2, 10.6 Hz,
1H), 5.56 (dd, J¼17.1, 1.7 Hz, 1H), 5.28 (dd, J¼10.6, 1.5 Hz, 1H),
(t, J¼7.2 Hz, 3H), 1.30 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
endo
4.11e3.97 (m, 4H), 3.96 (s, 2H); 13C NMR (100 MHz, CDCl3)
d 167.7,
203.0, 167.4, 138.1, 131.1, 61.3, 52.0, 49.9, 48.7, 45.9, 42.7, 27.6, 14.1;
m/z (EI) 208 (Mþ); HRMS (EI): Mþ, found 208.1098; C12H16O3
requires 208.1099; found: C, 69.18; H, 7.74. C12H16O3 requires C,
69.21; H, 7.74%.
146.3, 136.4, 131.1, 130.4, 126.2, 120.2, 116.7, 114.6, 106.7, 65.0 (2C),
43.8; m/z (EI) 259 (Mþ); HRMS (EI): Mþ, found 259.0955;
C13H13N3O3 requires 259.0957; found: C, 60.27; H, 5.13; N, 16.26.
C13H13N3O3 requires C, 60.22; H, 5.05; N, 16.21%.
4.1.2. Ethyl 2-((bicyclo[2.2.1]hept-5-en-2-yl)-1,3-dioxolan-2-yl)ace-
4.1.5. 2,2-Dimethyl-6-(2-oxo-3-(2-ethenyl-1,3-dioxolan-2-yl)pro-
pyl)-4H-1,3-dioxin-4-one (9). Dioxinone 16 (540 mg, 3.8 mmol) in
THF (2 mL) was added dropwise with stirring to freshly prepared
LiN(SiMe3)2 (3.8 mmol) in THF (15 mL) at ꢀ78 ꢂC. After 1 h, ZnCl2 in
Et2O (1 M; 3.8 mL) was added and stirring continued for 15 min.
Benzotriazole 15 (350 mg, 1.27 mmol) in THF (2 mL) was added
dropwise and the mixture was warmed to 0 ꢂC over 1.5 h, turning
bright yellow in color. Saturated aqueous NH4Cl (20 mL) was added
and the aqueous layer was acidified to pH 2 using aqueous HCl
(1 M). The aqueous layer was extracted with Et2O (2ꢃ25 mL) and
the organic phase was dried (MgSO4), rotary evaporated and
chromatographed (Et2O/hexanes 1:1 to 1:0) to give dioxinone 9
(225 mg, 63%) as an amber oil: Rf (Et2O) 0.35; nmax (liquid film)
tate (12): endo/exo¼3:1. Triethyl orthoformate (50.4 mL,
303 mmol) was added dropwise with stirring to b-keto ester 11
(21.0 g, 101 mmol), ethylene glycol (16.9 mL, 303 mmol) and p-TSA
(1.9 g, 10 mmol) in PhMe (200 mL) at 23 ꢂC. After 18 h, rotary
evaporation and chromatography (Et2O/hexanes 1:9 to 1:4) gave
ketal 12 (21 g, 70% over two steps) as a colorless oil: Rf (Et2O/hex-
anes 1:4) 0.22; nmax (liquid film) 1733s, 1369m, 1332m, 1217m,
1091m, 1043s, 719s cmꢀ1 1H NMR (400 MHz, CDCl3)
; d endo 6.13
(dd, J¼5.6, 3.1 Hz, 1H), 5.94 (dd, J¼5.7, 2.7 Hz, 1H), 4.18 (q, J¼7.2 Hz,
2H), 4.09e3.90 (m, 4H), 2.99 (br s,1H), 2.81 (br s,1H), 2.75e2.71 (m,
1H), 2.64 (s, 2H), 1.91e1.85 (m, 1H), 1.41e1.38 (m, 1H), 1.30 (t,
J¼7.2 Hz, 3H), 1.28e1.27 (m, 1H), 0.99 (ddd, J¼11.3, 8.1, 2.5 Hz, 1H);
d
exo 6.19 (dd, J¼5.6, 2.9 Hz, 1H), 6.10 (dd, J¼5.6, 3.1 Hz, 1H), 4.16 (q,
1719s, 1637m, 1391m, 1374s, 1271m, 1200s, 1013s cmꢀ1
;
1H NMR
J¼7.2 Hz, 2H), 4.11e3.94 (m, 4H), 2.87 (br s, 1H), 2.82 (br s, 1H), 2.72
(d, J¼14.2 Hz,1H), 2.67 (d, J¼14.2 Hz,1H),1.96e1.92 (m,1H),1.69 (br
d, J¼8.0 Hz, 1H), 1.55e1.51 (m, 1H), 1.29e1.26 (m, 2H), 1.28 (t,
(400 MHz, CDCl3)
1.1 Hz, 1H), 5.34 (s, 1H), 5.26 (dd, J¼10.7, 1.2 Hz, 1H), 4.04e3.92 (m,
d
5.78 (dd, J¼17.3, 10.7 Hz, 1H), 5.45 (dd, J¼17.3,
4H), 3.50 (s, 2H), 2.92 (s, 2H), 1.73 (s, 6H); 13C NMR (100 MHz,

6334
H. Miyatake-Ondozabal, A.G.M. Barrett / Tetrahedron 66 (2010) 6331e6334
CDCl3)
d
199.5, 164.7, 160.8, 136.2, 116.8, 107.2, 106.5, 96.8, 64.6 (2C),
144.0, 133.2, 132.5, 108.4, 103.9, 102.5, 73.5, 42.9, 36.7, 34.7, 31.0,
22.3, 21.0, 20.8; m/z (ESI) 319 (MþH)þ; HRMS (ESI): (MþH)þ, found
319.1540; C18H23O5 requires 319.1545; found: C, 68.03; H, 7.00.
C18H22O5 requires C, 67.91; H, 6.97%.
51.3, 48.2, 25.1 (2C); m/z (ESI) 565 (2MþH)þ, 587 (2MþNa)þ; HRMS
(ESI): (2MþH)þ, found 565.2271; C28H37O12 requires 565.2285;
found: C, 59.67; H, 6.37. C14H18O6 requires C, 59.57; H, 6.43%.
The 1H NMR and 13C NMR spectra were identical with those of
an authentic sample purchased from the Aldrich Chemical Co.
4.1.6. (S,E)-6-(3-(2-(5-(2-(4-Hydroxypentyl)-1,3-dioxolan-2-yl)
pent-1-enyl)-1,3-dioxolan-2-yl)-2-oxopropyl)-2,2-dimethyl-4H-1,3-
dioxin-4-one (7). Alcohol 8 (122 mg, 0.54 mmol) in CH2Cl2 (1 mL)
Acknowledgements
was added dropwise with stirring to dioxinone
9 (75 mg,
0.27 mmol) and Grubbs II (24 mg, 0.03 mmol) in CH2Cl2 (3 mL) at
reflux over 10 min. After 18 h, rotary evaporation and chromatog-
raphy (Et2O; EtOAc/hexanes 4:1) gave dioxinone 7 (97 mg, 75%) as
We thank P.R. Haycock and R.N. Sheppard (Imperial College
London) for high-resolution NMR spectroscopy and the Engineer-
ing and Physical Sciences Research Council (EPSRC) for grant sup-
port (to H.M.-O.).
25
a dark brown oil: Rf (Et2O) 0.17; [
a
]
þ3.6 (c 1.0, CH2Cl2); nmax
D
(liquid film) 3458m, 1720s, 1638m, 1391m, 1374m, 1271m, 1202s,
1015s cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
5.85 (dt, J¼15.5, 6.9 Hz,
Supplementary data
1H), 5.40 (d, J¼15.5 Hz, 1H), 5.34 (s, 1H), 4.01e3.90 (m, 8H),
3.85e3.78 (m, 1H), 3.49 (s, 2H), 2.89 (s, 2H), 2.09e2.04 (m, 2H), 1.73
(s, 6H), 1.66e1.42 (m, 10H), 1.21 (d, J¼6.1 Hz, 3H); 13C NMR
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.05.084. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
(100 MHz, CDCl3)
d 199.7, 164.8, 160.8, 132.9, 128.5, 111.5, 107.1,
106.5, 96.7, 67.9, 64.9 (2C), 64.5 (2C), 51.7, 48.1, 39.4, 36.9, 36.5, 31.7,
25.0 (2C), 23.5, 23.0, 20.0; m/z (ESI) 505 (MþNa)þ; HRMS (ESI):
(MþNa)þ, found 505.2397; C25H38NaO9 requires 505.2414; found:
C, 62.10; H, 8.03. C25H38O9 requires C, 62.22; H, 7.94%.
References and notes
4.1.7. (S)-(ꢀ)-Zearalenone (2)3c. Dioxinone 7 (75 mg, 0.15 mmol) in
PhMe (4 mL) was added dropwise with stirring to PhMe (12 mL) at
reflux over 20 min. After a further 20 min, rotary evaporation gave
macrocycle 18 (60 mg) as a yellow oil. p-TSA (37 mg, 0.19 mmol) in
Me2CO (2 mL) and H2O (1.5 mL) was added with stirring. After 3 h
at 23 ꢂC, H2O (6 mL) was added and the mixture was extracted with
Et2O (2ꢃ20 mL). The combined organic layers were dried (MgSO4)
and rotary evaporated to give triketo-ester 19 (55 mg) as a bright
yellow oil. The crude material was used directly in the following
step without further purification. Triketo-ester 19 (55 mg) in MeOH
(4 mL) was allowed to react with Cs2CO3 (560 mg, 1.7 mmol) at
23 ꢂC. The reaction mixture immediately turned dark yellow and
was stirred for 45 min. AcOH (1 mL, 17.0 mmol) was added and
stirring was continued for 3 h, after which aqueous HCl (2 M; 2 mL)
was added and the mixture was stirred for further 1.5 h. Rotary
evaporation left an oil, which was partitioned between EtOAc
(20 mL) and H2O (15 mL). The organic layer was washed with H2O
(2ꢃ10 mL), dried (MgSO4), rotary evaporated, and chromato-
graphed (Et2O/hexanes 3:7 to 1:1) to give (S)-(ꢀ)-zearalenone (2)
1. Winssinger, N.; Barluenga, S. Chem. Commun. 2007, 22.
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6. Accurate pH monitoring was crucial during hydrolysis to obtain a good yield
since the use of excess acid resulted in competitive ketal deprotection and
polymerization.
(23 mg, 46% over four steps) as a white solid: mp 162e163 ꢂC, lit.13
€
7. Navarro, I.; Poverlein, C.; Schlingmann, G.; Barrett, A. G. M. J. Org. Chem. 2009,
25
164ꢀ166 ꢂC; Rf (Et2O/hexanes 1:1) 0.38; [
a]
ꢀ130 (c 1.0, MeOH),
D
74, 8139.
lit.14 ꢀ134 (c 1.0, MeOH); nmax (liquid film) 3306m, 1689s, 1645s,
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second less reactive ketal group.
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1618s, 1579s, 1312s, 1260s, 1195s, 1167s, 1143s, 1101s, 1074m cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
12.09 (s, 1H), 7.05 (dd, J¼15.3, 1.7, 1H),
6.45 (d, J¼2.5 Hz,1H), 6.39 (d, J¼2.5 Hz,1H), 5.75e5.68 (m,1H), 5.37
(br s, 1H), 5.07e4.99 (m, 1H), 2.90 (ddd, J¼18.6, 12.1, 2.1 Hz, 1H),
2.67e2.62 (m, 1H), 2.42e2.38 (br m, 1H), 2.27e2.14 (br m, 4H),
1.85e1.74 (m, 2H), 1.73e1.63 (m, 2H), 1.58e1.48 (m, 1H), 1.41 (d,
J¼6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
211.7, 171.3, 165.5, 160.6,
14. Kalivretenos, A.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1991, 56, 2883.