A concise total synthesis of (S)-zearalenone and zeranol

Article abstract of DOI:10.1055/s-0030-1260058

A convergent total synthesis of the naturally occurring, 14-membered macrolides (S)-zearalenone and zeranol has been achieved through application of the Diels-Alder reaction, Jacobsen kinetic resolution, Mitsunobu coupling, ring-closing metathesis, and hy

Full text of DOI:10.1055/s-0030-1260058

PAPER
2117
A Concise Total Synthesis of (S)-Zearalenone and Zeranol
T
otal
S
ynt
.
hesis of
(
S
)-Z
S
earalenone an
.
d
Zeranol Yadav,*a,b P. Vishnu Murthya
a
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad – 500 607, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
King Saud University, Riyadh 11451, Saudi Arabia
b
Received 25 March 2011; revised 14 April 2011
from a common intermediate 3, which, in turn, could be
obtained from Mitsunobu and RCM reaction of aromatic
acid 4 and alcohol 5. Aromatic acid 4 was to be obtained
from Diels–Alder reaction of diene 6 and dienophile 7.
Fragments 5 and 7 could be derived from commercially
available 5-hexene-1-ol and homopropargyl alcohol, re-
spectively.
Abstract: A convergent total synthesis of the naturally occurring,
14-membered macrolides (S)-zearalenone and zeranol has been
achieved through application of the Diels–Alder reaction, Jacobsen
kinetic resolution, Mitsunobu coupling, ring-closing metathesis,
and hydrogenation as key steps.
Key words: Diels–Alder reaction, Jacobsen resolution, Mitsunobu
reaction, ring-closing metathesis, macrolide
OH
O
OH
O
O
The b-resorcylic macrolides are a class of naturally occur-
ring 12- and 14-membered macrolides1 (Figure 1). (S)-
Zearalenone is a 14-membered macrolactone of this type
that exhibits anabolic, estrogenic, uterotropic, and anti-
bacterial activity.2 Zearalenone was first isolated from the
mycelium of the fungus Gibberella zeae (Fusarium
graminearum) growing as a mould on corn.3 Zeranol also
belongs to this class of macrolide and is closely related to
(S)-zearalenone. Zeranol is a non-steroidal estrogen ago-
nist and animal growth-promoting agent and is under clin-
ical trials as a potential treatment for menopausal and
post-menopausal syndrome.4 Our synthetic strategy in-
volved an intermolecular Diels–Alder reaction to con-
struct the resorcylic acid moiety and esterification of two
appropriately functionalized components under Mitsunobu
conditions, followed by ring-closing metathesis mediated
by Grubbs' second-generation catalyst to afford the target
compounds.
O
HO
O
O
HO
OH
1
2
(S)-zearalenone
zeranol
OMe
O
MeO
OH
3
OMe
O
OH
OTHP
OH
5
MeO
4
OMe
OH
9
MeO
O
6
OMe
TBSO
H
O
7
O
O
O
O
(R)
(R)
(R)
Cl
(S)
H
OH
HO
HO
8
O
O
Scheme 1 Retrosynthetic analysis
OH
OH
cis-resorcylide
radicicol
OH
O
Dienophile 7 was prepared from homopropargyl alcohol
8, which was protected as the tert-butyldimethylsilyl
(TBS) ether with tert-butyldimethylsilyl chloride in the
presence of imidazole and a catalytic amount of 4-(N,N-
dimethylamino)pyridine (DMAP) in dichloromethane.
Treatment with n-butyllithium and reaction with methyl
chloroformate (ClCO2Me) afforded 7 in 80% yield. The
Diels–Alder5 reaction between diene 6 and acetylenic di-
enophile 7 in a sealed tube at 180 °C for 48 hours in the
presence of a catalytic amount of N,N-dimethylaniline
gave the aromatic product 12 (40% yield). Silyl ether
deprotection with HF·Py in acetonitrile afforded 13; fur-
ther iodination with triphenylphosphine and iodine in a
OH
O
(S)
O
(S)
O
HO
OH
HO
O
zearalenone (1)
zeranol (2)
Figure 1
In our retrosynthetic analysis (Scheme 1), we envisaged
that the target molecules 1 and 2 could be synthesized
SYNTHESIS 2011, No. 13, pp 2117–2124
Advanced online publication: 26.05.2011
x
x.
x
x
.
2
0
1
1
DOI: 10.1055/s-0030-1260058; Art ID: Z04511SS
© Georg Thieme Verlag Stuttgart · New York

2118
J. S. Yadav, P. V. Murthy
PAPER
O
mixture of acetonitrile and diethyl ether (1:2), yielded
iodo compound 14 in 85% yield. Compound 14, upon
treatment with potassium tert-butoxide, afforded olefin
15, and hydrolysis of the ester (LiOH·H2O6 in MeOH–
H2O) furnished acid 4 in 80% yield over two steps
(Scheme 2).
(ii)
OR1
(iii)
OTHP
9 R1 = H
(i)
16 R1 = THP
17
OR2
O
(iv)
(vi)
(ix)
OTHP
OTHP
18
19 R2 = H
20 R2 = TBDPS
(v)
OTBDPS
The synthesis of segment 5 began from the known 5-hex-
ene-1-ol (9). Thus, protection of the hydroxyl group with
2,3-dihydropyran7 in the presence of a catalytic amount of
p-toluenesulfonic acid (PTSA) in dichloromethane gave
the tetrahydropyranyl ether 16 in 90% yield.
R3
OH
OTBDPS
(viii)
R4
23
21 R3 = H, R4 = OH
22 R3, R4 = O
(vii)
OTBDPS
OTHP
OTBS
OH
OTHP
OH
(i)
(ii)
(x)
8
11
24
5
OMe
O
O
Scheme 3 Reagents and conditions: (i) DHP, PPTS, CH2Cl2, r.t.,
95%; (ii) MCPBA, CH2Cl2, r.t., 90%; (iii) (S,S)-Jacobsen catalyst,
AcOH, H2O, toluene, 40%; (iv) LAH, THF, 0 °C to r.t., 90%; (v)
TBDPSCl, imidazole, CH2Cl2, 90%; (vi) PPTS, EtOH, 94%; (vii)
IBX, DMSO, CH2Cl2, 89%; (viii) 4-pentenyl bromide, Mg, THF,
0 °C to r.t., 80%; (ix) DHP, PPTS, CH2Cl2, 90%; (x) TBAF, THF,
90%.
OMe
OR
(v)
OMe
(iii)
MeO
TBSO
7
12 R = TBS
13 R = H
(iv)
OMe
O
OMe
O
We then attempted to couple the two fragments 4 and 5 to
construct a 14-membered ring by ring-closing metathesis.
Accordingly, the Mitsunobu protocol [use of diethyl
azodicarboxylate (DEAD) and Ph3P]9 was explored to af-
ford ester 25 in 80% yield. Removal of the tetrahydropyr-
anyl group with PPTS delivered alcohol 26, which, on
ring-closing metathesis with Grubbs' second-generation
catalyst (5 mol%), afforded intermediate 3. Oxidation of
OR
OMe
I
(vi)
MeO
MeO
15 R = Me
4 R = H
14
(vii)
Scheme 2 Reagents and conditions: (i) TBSCl, imidazole, DMAP,
CH2Cl2, r.t., 95%; (ii) n-BuLi, ClCO2Me, THF, –78 °C, 80%; (iii) 6,
neat, N,N-dimethylaniline (cat.), 180 °C, 48 h, 40%; (iv) HF·Py,
MeCN, r.t., 90%; (v) I2, Ph3P, MeCN–Et2O (1:2), r.t., 95%; (vi) t-
BuOK, THF, r.t., 90%; (vii) LiOH–H2O, MeOH–H2O (3:1), reflux,
85%.
3
with IBX afforded ketone 27, and further
demethylation10 using freshly prepared triiodoaluminum
at 10 °C for 45 minutes gave (S)-zearalenone (1) in 70%
yield (Scheme 4).
OMe
O
OR1
Epoxidation of 16 with m-chloroperoxybenzoic acid in
dichloromethane gave 17 in 85% yield. A kinetic resolu-
tion of racemic epoxide 17 with (S,S)-Jacobsen catalyst8
furnished the optically active epoxide 18 (42%, 99% ee).
The reduction of 18 with lithium aluminum hydride7 in
tetrahydrofuran at room temperature afforded secondary
alcohol 19, which was protected as its silyl ether using
tert-butyldiphenylsilyl chloride, imidazole, and DMAP
(cat.) in dichloromethane. Removal of the tetrahydropyr-
anyl group with a catalytic amount of pyridinium p-tolue-
nesulfonate (PPTS) in dichloromethane afforded 21 in
85% yield. The primary hydroxyl group was oxidized to
aldehyde 22 with 2-iodoxybenzoic acid (IBX), and further
coupling with the Grignard reagent, prepared from 4-pen-
tenyl bromide and magnesium in tetrahydrofuran, yielded
secondary alcohol 23 in 80% yield. Protection of the alco-
hol as the tetrahydropyranyl ether and further deprotec-
tion of the TBDPS group with tetrabutylammonium
fluoride (TBAF) in tetrahydrofuran at room temperature
furnished the required alcohol fragment 5 (80%;
Scheme 3).
(i)
O
+
4
5
MeO
25 R1 = THP
26 R1 = H
(ii)
OMe
O
O
(iii)
(v)
R2
R3
1
MeO
3 R2 = H, R3 = OH
27 R2, R3 = O
(iv)
Scheme 4 Reagents and conditions: (i) DEAD, Ph3P, Et2O, r.t.,
90%; (ii) PPTS, EtOH, 85%; (iii) [(PCy)3Cl2Ru=CHPh], toluene, re-
flux, 80%; (iv) IBX, DMSO, CH2Cl2, r.t., 85%; (v) AlI3, TBAI, ben-
zene, 70%.
Hydrogenation of compound 3 with hydrogen (1 atm)
over Pd/C in ethanol, followed by demethylation fur-
nished zeranol (2) in 70% yield (Scheme 5). The physical
characteristics of the synthetic products were consistent
with those reported in the literature.11
Synthesis 2011, No. 13, 2117–2124 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (S)-Zearalenone and Zerano
2119
column chromatography (hexane–EtOAc, 9:1) to afford the title
compound.
OMe
O
(i)
O
(ii)
3
2
Yield: 24.2 g (95%); light-yellow oil; Rf = 0.9 (EtOAc–PE, 10%).
IR (neat): 3312, 2931, 1468, 1255, 1219, 914, 839, 773, 635 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.76–3.68 (m, 2 H), 2.57–2.40 (m,
2 H), 1.91 (s, 1 H), 0.85 (s, 9 H), 0.07 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 81.0, 69.2, 61.6, 25.8, 22.7,
18.2, –5.3.
MeO
OH
28
Scheme 5 Reagents and conditions: (i) Pd/C, H2, EtOH, r.t., 80%;
(ii) AlI3, TBAI, benzene, 70%.
In conclusion, the total synthesis of (S)-zearalenone and
zeranol has been accomplished using the inexpensive and
commercially available starting materials homopropargyl
alcohol and 5-hexene-1-ol. The stereochemistry of the al-
cohol was established by Jacobsen resolution. The aro-
matic acid framework was constructed through the Diels–
Alder approach. This synthetic strategy may also be appli-
cable to the synthesis of other complex natural products.
MS (ESI): m/z = 185 [M + H]+.
HRMS: m/z calcd for C10H20ONaSi: 207.1175; found: 207.1181.
Methyl 5-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-2-pentynoate (7)
Alkyne 11 (10 g, 54.24 mmol) was taken in anhydrous THF
(120 mL) and cooled to –78 °C under nitrogen. To this, n-BuLi
(1 M in hexane, 54.2 mL, 54.2 mmol) was added dropwise over 30
min. After 30 min, methyl chloroformate (5.02 mL, 65.07 mmol)
was added slowly at the same temperature. The reaction was stirred
for a further 30 min (the reaction was monitored by TLC), then
quenched with sat. aq NH4Cl (30 mL) and extracted with EtOAc
(2 × 100 mL). The combined organic extracts were washed with
brine (60 mL), dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by silica gel flash column chro-
matography (hexane–EtOAc, 95:5) to give the title compound 7.
Reactions were conducted under N2 in anhydrous solvents such as
CH2Cl2, THF, and toluene. All reactions were monitored by TLC
(silica-coated plates visualized under UV light). Light petroleum
ether (PE; bp 60–80 °C) was used. Yields refer to chromatographi-
cally and spectroscopically (1H, 13C NMR) homogeneous material.
Air-sensitive reagents were transferred by syringe or double-ended
needle. Evaporation of solvents was performed at reduced pressure
on a Büchi rotary evaporator. 1H and 13C NMR spectra of samples
in CDCl3 were recorded with Varian FT-200 MHz (Gemini) or
Bruker UXNMR FT-300 MHz (Avance) spectrometers. Chemical
shifts (d) are reported relative to TMS (d = 0.0 ppm) as internal
standard. Mass spectra were recorded under EI conditions at 70 eV
with an LC-MSD (Agilent technologies) spectrometer. Column
chromatography was performed on silica gel (60–120 mesh) sup-
plied by Acme Chemical Co., India. TLC was performed on Merck
60 F-254 silica gel plates. Optical rotations were measured with a
JASCO DIP-370 Polarimeter at 20 °C.
Yield: 10.5 g (80%); oily liquid; Rf = 0.9 (EtOAc–PE, 10%).
IR (neat): 2954, 2858, 2243, 1753, 1466, 1256, 1111, 838, 778
cm–1.
1H NMR (200 MHz, CDCl3): d = 3.81 (d, J = 5.8 Hz, 2 H), 3.75 (s,
3 H), 2.55 (t, J = 6.5 Hz, 2 H), 0.85 (s, 9 H), 0.01 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 153.7, 73.4, 68.0, 63.5, 52.9, 25.9,
22.6, 18.31, –5.2.
MS (ESI): m/z = 265 [M + Na]+.
HRMS: m/z calcd for C12H22O3NaSi: 265.1229; found: 265.1236.
Methyl 2-(2-[1-(tert-Butyl)-1,1-dimethylsilyl]oxyethyl)-4,6-
dimethoxybenzoate (12)
A mixture of acetylenic ester 7 (5 g, 41.27 mmol), diene 6 (8.6 g,
61.42 mmol) and N,N-dimethylaniline (cat.) was heated in a sealed
tube at 180 °C for 48 h (TLC indicated completion of reaction). The
residue was purified by silica gel column chromatography (hexane–
EtOAc, 9:1) to give the title compound 12.
2,5-Dihydro-3-methoxyanisole (6)
A solution of 3-methoxy anisole (17.5 mL, 140 mmol) in anhydrous
Et2O (50 mL) and liquid NH3 (500 mL) was treated by slow addition
of lithium (4.5 g, 5 equiv). After stirring for 15 min, anhydrous
EtOH (30 mL) was added over 30 min (the color of the mixture
changed from blue to colorless). Excess ammonia was allowed to
evaporate and the crude mixture was extracted with Et2O (100 mL).
The organic layers were washed with brine (30 mL), dried over an-
hydrous Na2SO4, and concentrated under reduced pressure. Purifi-
cation by silica gel column chromatography (hexane–EtOAc, 99:1)
afforded the product 6.
Yield: 3.2 g (40%); Rf = 0.7 (EtOAc–PE, 10%).
IR (neat): 3003, 2953, 2893, 2856, 1727, 1605, 1463, 1428, 1332,
1273, 12092, 1159, 1097, 835 cm–1.
1H NMR (200 MHz, CDCl3): d = 6.38 (d, J = 15.8 Hz, 2 H), 3.92 (s,
3 H), 3.87–3.76 (m, 8 H), 2.83–2.72 (m, 2 H), 0.94 (s, 9 H), 0.05 (s,
6 H).
13C NMR (75 MHz, CDCl3): d = 168.5, 161.2, 158.1, 139.1, 116.7,
106.8, 96.8, 63.8, 55.2, 51.9, 37.5, 25.8, 18.2, –5.1.
Yield: 12.9 g (84%); clear oil; Rf = 0.9 (EtOAc–PE, 10%).
IR (neat): 2944, 2829, 1665, 1604, 1445, 1395, 1206, 1147, 1016,
949, 775 cm–1.
1H NMR (200 MHz, CDCl3): d = 4.57 (t, J = 3.3 Hz, 2 H), 3.54 (s,
6 H), 2.85–2.77 (m, 2 H), 2.73–2.67 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 151.6, 90.1, 53.4, 30.6, 24.6.
MS (ESI): m/z = 141 [M + H]+.
MS (ESI): m/z = 377 [M + Na]+.
HRMS: m/z calcd for C18H30O5NaSi: 377.1755; found: 377.1760.
Methyl 2-(2-Hydroxyethyl)-4,6-dimethoxybenzoate (13)
To a stirred solution of 12 (3 g, 8.46 mmol) in anhydrous MeCN (15
mL), HF·Py (1 M in THF, 1.59 mL, 12.69 mmol) was added at 0 °C.
The reaction mixture was warmed to r.t. and stirred for 5 h, then
quenched by addition of sat. aq NaHCO3 (4 mL). The mixture was
extracted with EtOAc (3 × 30 mL), washed with brine (20 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo. The resi-
due was purified by flash column chromatography (hexane–EtOAc,
8:2) to afford the title compound.
tert-Butyl(3-butynyloxy)dimethylsilane (11)
To a solution of alcohol 8 (10 g, 142.8 mmol) in CH2Cl2 (60 mL),
imidazole (19.4 g, 285.7 mmol) and TBSCl (25.8 g, 171.1 mmol)
were added at 0 °C and the solution was stirred at r.t. for 1 h. The
reaction mixture was quenched with sat. NH4Cl (30 mL) and the or-
ganic layer was dried over anhydrous Na2SO4, filtered, and the fil-
trate was concentrated in vacuo. The residue was purified by flash
Synthesis 2011, No. 13, 2117–2124 © Thieme Stuttgart · New York

2120
J. S. Yadav, P. V. Murthy
PAPER
Yield: 1.82 g (90%); clear oil; Rf = 0.6 (EtOAc–PE, 20%).
(25 mL), dried over Na2SO4 and concentrated to give the crude acid.
The crude product was purified by silica gel column chromatogra-
phy (hexane–EtOAc, 7:3) to afford the product 4.
IR (neat): 3430, 2949, 2843, 1722, 1604, 1461, 1323, 1271, 1204,
1159, 1101 cm–1.
Yield: 1 g (85%); pale-yellow solid; mp 156–159 °C; Rf = 0.6
(EtOAc–PE, 60%).
1H NMR (200 MHz, CDCl3): d = 6.33 (d, J = 11.2 Hz, 2 H), 3.90 (s,
3 H), 3.82–3.77 (m, 8 H), 2.89 (d, J = 7.5 Hz, 2 H).
IR (neat): 3247, 3041, 2991, 1752, 1696, 1533, 1481, 1370, 1242,
1068, 898 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.22–7.09 (m, 1 H), 6.64 (s, 1 H),
6.43 (s, 1 H), 5.63 (d, J = 17.1 Hz, 1 H), 5.34 (d, J = 10.9 Hz, 1 H),
3.92 (s, 3 H), 3.84 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 168.2, 160.7, 157.4, 138.5, 115.6,
105.5, 95.9, 62.2, 55.0, 54.4, 51.4, 36.1.
MS (ESI): m/z = 263 [M + Na]+.
HRMS: m/z calcd for C12H16O5Na: 263.0887; found: 263.0895.
13C NMR (75 MHz, CDCl3): d = 169.2, 162.2, 158.8, 141.4, 135.4,
Methyl 2-(2-Iodoethyl)-4,6-dimethoxybenzoate (14)
116.8, 103.6, 98.1, 56.3, 55.4.
To a stirred solution of alcohol 13 (1.8 g, 7.49 mmol) in a mixture
of anhydrous Et2O (20 mL) and anhydrous MeCN (10 mL), was
added Ph3P (3.92 g, 14.98 mmol), imidazole (1.52 g, 22.48 mmol)
and iodine (3.8 g, 14.98 mmol) at 0 °C. The resulting mixture was
stirred at r.t. for 1 h. The reaction mixture was diluted with hexane
(30 mL), the solid was filtered, washed with EtOAc–hexane (10%),
and the filtrate was concentrated in vacuo. The crude product was
dissolved in Et2O (60 mL) and washed with aq sodium thiosulfate
(10%, 10 mL), brine (15 mL) and dried over Na2SO4. Concentration
of solvent under reduced pressure and purification by silica gel col-
umn chromatography afforded the iodo compound 14.
MS (ESI): m/z = 231 [M + Na]+.
HRMS: m/z calcd for C11H12O4Na: 231.0628; found: 231.0633.
2-(5-Hexenyloxy)tetrahydro-2H-pyran (16)
To a stirred solution of 5-hexen-1-ol (9; 5 g, 49.92 mmol) in CH2Cl2
(100 mL) at 25 °C was added 2,3-dihydro-2H-pyran (5.43 mL, 59.9
mmol) and PPTS (0.627 g, 2.49 mmol) and the reaction was stirred
at 25 °C for 30 min. The reaction mixture was quenched with sat.
NaHCO3 (5 mL), extracted with CH2Cl2 (2 × 50 mL), and the com-
bined organic extracts were dried over Na2SO4, concentrated under
reduced pressure and purified by silica gel column chromatography
(hexane–EtOAc, 9:1) to afford the product 16.
Yield: 2.49 g (95%); viscous liquid; Rf = 0.8 (EtOAc–PE, 20%).
IR (neat): 2921, 2875, 1735, 1701, 1625, 1495, 1385, 1225, 1104,
1059 cm–1.
Yield: 8.27 g (95%); clear oil; Rf = 0.9 (EtOAc–PE, 5%).
1H NMR (200 MHz, CDCl3): d = 6.33 (d, J = 12 Hz, 2 H), 3.92 (s,
3 H), 3.84 (s, 6 H), 3.32 (t, J = 8.3 Hz, 2 H), 3.10 (t, J = 8.3 Hz, 2 H).
IR (neat): 3075, 2937, 2865, 1640, 1445, 1352, 1263, 1127, 1074,
990, 870 cm–1.
13C NMR (75 MHz, CDCl3): d = 169.5, 160.4, 158.4, 146.8, 117.5,
1H NMR (300 MHz, CDCl3): d = 5.86–5.70 (m, 1 H), 5.04–4.85 (m,
2 H), 4.56 (d, J = 3.9 Hz, 1 H), 3.87–3.62 (m, 2 H), 3.50–3.28 (m,
2 H), 2.13–2.00 (m, 2 H), 1.93–1.35 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 138.7, 114.4, 98.7, 67.3, 62.3, 62.2,
33.5, 30.7, 29.1, 25.4, 19.5.
111.4, 95.2, 55.2, 52.0, 38.7, 7.8.
MS (ESI): m/z = 372 [M + Na]+.
HRMS: m/z calcd for C12H15IO4Na: 372.9908; found: 372.9913.
Methyl 2,4-Dimethoxy-6-vinylbenzoate (15)
MS (ESI): m/z = 207 [M + Na]+.
To a stirred solution of iodo compound 14 (2.4 g, 6.85 mmol) in an-
hydrous THF was added t-BuOK (1.15 g, 10.28 mmol) at 0 °C. The
resulting mixture was stirred at 25 °C for 2 h, then the reaction mix-
ture was quenched by the addition of H2O (5 mL) and the solvent
was evaporated. The residue was taken in EtOAc (30 mL) and the
organic layer was washed with H2O (30 mL), brine (30 mL), and
dried over anhydrous Na2SO4. The solvent was evaporated under re-
duced pressure and the residue was purified by flash chromatogra-
phy (hexane–EtOAc, 9:1) to afford the pure product 15.
HRMS: m/z calcd for C11H20O2Na: 207.1356; found: 207.1361.
2-[4-(2-Oxiranyl)butoxy]tetrahydro-2H-pyran (17)
A solution of alkene 16 (8.27 g, 44.87 mmol) in CH2Cl2 (150 mL)
was cooled to 0 °C and freshly prepared MCPBA (11.61 g, 67.31
mmol) was added portionwise to the reaction mixture. The reaction
mixture was stirred at ambient temperature for 2 h, then diluted with
CH2Cl2 (100 mL) and sat. aq NaHCO3 (50 mL) and sat. aq NaHSO3
(50 mL) were added. The crude product was extracted with CH2Cl2
(3 × 80 mL), and the combined organic extracts were dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane–EtOAc, 8:2) to afford 17.
Yield: 1.37 g (90%); pale-yellow solid; mp 131–133 °C; Rf = 0.7
(EtOAc–PE, 30%).
IR (neat): 3086, 2925, 2847, 2092, 1830, 1723, 1599, 1425, 1330,
1269, 915 cm–1.
Yield: 8.08 g (90%); clear oil; Rf = 0.6 (EtOAc–PE, 20%).
1H NMR (200 MHz, CDCl3): d = 6.72–6.64 (m, 1 H), 6.58 (s, 1 H),
6.33 (s, 1 H), 5.60 (d, J = 17.5 Hz, 1 H), 5.28 (d, J = 11.7 Hz, 1 H),
3.87–3.77 (m, 9 H).
13C NMR (75 MHz, CDCl3): d = 168.2, 161.4, 158.0, 137.7, 133.7,
116.9, 101.4, 98.0, 55.8, 55.3, 52.1.
IR (neat): 2940, 2867, 1727, 1452, 1354, 1256, 1126, 1029, 984,
868 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.49 (d, J = 3.7 Hz, 1 H), 3.83–
3.63 (m, 2 H), 3.47–3.37 (m, 2 H), 2.86–2.79 (m, 1 H), 2.69–2.63
(m, 1 H), 2.41–2.34 (m, 1 H), 1.86–1.41 (m, 12 H).
MS (ESI): m/z = 245 [M + Na]+.
13C NMR (75 MHz, CDCl3): d = 98.6, 67.1, 62.1, 52.0, 46.8, 32.1,
30.5, 29.3, 25.3, 22.6. 19.3.
HRMS: m/z calcd for C12H14O4Na: 245.0789; found: 245.0790.
MS (ESI): m/z = 223 [M + Na]+.
2,4-Dimethoxy-6-vinylbenzoic Acid (4)
HRMS: m/z calcd for C11H20O3Na: 223.1306; found: 223.1312.
To a stirred solution of ester 15 (1.3 g, 5.85 mmol) in MeOH–H2O
(3:1, 10 mL) was added LiOH·H2O (0.84 g, 35.13 mmol) and the
mixture was heated to 70 °C for 24 h. The solvent was evaporated
and the aqueous solution was extracted with Et2O (2 × 15 mL). The
aqueous solution was acidified with 2N HCl (20 mL) and extracted
with EtOAc (2 × 15 mL). The organic layer was washed with brine
4-[(2S)-Oxiran-2-yl]butoxytetrahydro-2H-pyran (18)
A mixture of (S,S)-N,N¢-bis(3,5-di-tert-butylsalicylidene)-1,2-cy-
clohexane-diamino cobalt(III) complex (0.121 g, 0.2 mmol), tolu-
ene (5 mL) and AcOH (0.02 mL, 0.363 mmol) was stirred at r.t. in
Synthesis 2011, No. 13, 2117–2124 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (S)-Zearalenone and Zerano
2121
open air for 1 h. The solvent was removed in a rotary evaporator un-
der reduced pressure and the brown residue [(S,S)-N,N¢-bis(3,5-di-
tert-butylsalicylidene)-1,2-cyclohexanediamino cobalt(III) acetate,
(salen)-Co(III)(OAc) complex] was dried under vacuum. The
brown residue was then added to 17 (8.08 g, 40.34 mmol) and the
stirred mixture was then cooled in an ice-water bath. Distilled H2O
(0.39 mL, 22.19 mmol) was slowly added over 1 h, keeping the bath
temperature below 15 °C. When the addition was complete, the ice-
water bath was removed and the reaction mixture was stirred at r.t.
for 18 h. The crude reaction mixture was purified by column chro-
matography (hexane–EtOAc, 8:2) to afford 18.
1H NMR (300 MHz, CDCl3): d = 7.72–7.60 (m, 4 H), 7.39–7.26 (m,
6 H), 4.52 (br, 1 H), 3.87–3.55 (m, 4 H), 3.48–3.36 (m, 1 H), 3.31–
3.20 (m, 1 H), 1.84–1.29 (m, 11 H), 1.11–0.96 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 135.8, 129.3, 127.4, 127.3, 98.6,
69.4, 67.4, 62.0, 39.2, 30.6, 29.6, 26.9, 26.5, 25.4, 23.1, 21.9, 19.5.
MS (ESI): m/z = 463 [M + Na]+.
HRMS: m/z calcd for C27H40O3NaSi: 463.2639; found: 463.2644.
(5R)-5-[1-(tert-Butyl)-1,1-diphenylsilyl]oxyhexan-1-ol (21)
Compound 20 (5.87 g, 13.32 mmol) was dissolved in EtOH (50 mL)
and stirred with a catalytic amount of pyridinium p-toluene-
sulfonate (PPTS; 0.167 g, 0.66 mmol) at 60 °C for 1 h. The mixture
was quenched by addition of sat. aq NaHCO3 (10 mL). EtOH was
evaporated under reduced pressure and the aqueous phase was ex-
tracted with EtOAc (2 × 30 mL). The organic extracts were washed
with brine (30 mL) and dried over anhydrous Na2SO4. After evapo-
rating the solvent, the crude product was purified by column chro-
matography (hexane–EtOAc, 8:2) to afford pure alcohol 21.
Yield: 3.23 g (40%); light-brown oil; Rf = 0.6 (EtOAc–PE, 20%);
93% ee; [a]D20 +3.2 (c 2.75, CHCl3).
IR (neat): 2939, 2865, 1728, 1449, 1352, 1260, 1128, 1075, 982,
870 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.51 (d, J = 3.6 Hz, 1 H), 3.84–
3.67 (m, 2 H), 3.51–3.31 (m, 2 H), 2.84–2.76 (m, 1 H), 2.65–2.61
(m, 1 H), 2.43–2.41 (m, 1 H), 1.72–1.47 (m, 12 H).
20
13C NMR (75 MHz, CDCl3): d = 98.6, 67.1, 62.1, 51.9, 46.8, 32.1,
30.5, 29.3, 25.3, 22.6, 19.4.
Yield: 4.46 g (94%); clear oil; Rf = 0.6 (EtOAc–PE, 20%); [a]D
–1.8 (c 1.3, CHCl3).
MS (ESI): m/z = 223 [M + Na]+.
IR (neat): 3355, 3068, 2933, 2859, 1589, 1465, 1375, 1186, 1053,
997 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.74–7.60 (m, 4 H), 7.45–7.31 (m,
6 H), 3.88–3.78 (m, 1 H). 3.55 (t, J = 6.4 Hz, 2 H), 1.63–1.21 (m,
6 H), 1.97–1.11 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 135.8, 129.4, 127.5, 69.3, 62.8,
39.0, 32.6, 27.0, 23.1, 21.3, 19.2.
HRMS: m/z calcd for C11H20O3Na: 223.1310; found: 223.1316.
(2R)-6-(Tetrahydro-2H-2-pyranyloxy)hexan-2-ol (19)
To a suspension of LAH (0.938 g, 24.7 mmol) in anhydrous THF
(60 mL) under a nitrogen atmosphere at 0 °C, was added 18 (5 g,
24.7 mmol) in anhydrous THF (70 mL) and the mixture was stirred
at r.t. for 4 h. The reaction mixture was cooled to 0 °C, diluted with
wet Et2O and the excess LAH was quenched by addition of sat. aq
Na2SO4 (15 mL). When the effervescence subsided, the reaction
mixture was filtered through a pad of Celite and washed with hot
EtOAc (60 mL). The filtrate was evaporated under vacuum and the
residue was purified by column chromatography (hexane–EtOAc,
8:2) to furnish compound 19.
MS (ESI): m/z = 379 [M + Na]+.
HRMS: m/z calcd. for C22H32O2NaSi: 379.2061; found: 379.2069.
(5R)-5-[1-(tert-Butyl)-1,1-diphenylsilyl]oxyhexanal (22)
To a stirred clear solution of IBX (5.38 g, 18.76 mmol) in anhydrous
DMSO (10 mL) under a nitrogen atmosphere was added alcohol 21
(4.46 g, 12.5 mmol) in anhydrous CH2Cl2 (5 mL) at r.t. The reaction
mixture was stirred for 30 min and diluted with an excess of Et2O
and filtered through a Celite pad. The filtrate was washed with sat.
aq NaHCO3 (20 mL), H2O (20 mL) and brine (20 mL). The organic
layer was dried over Na2SO4 and concentrated in vacuo. The residue
was purified by flash column chromatography (hexane–EtOAc,
9:1) to afford the title compound 22.
20
Yield: 4.5 g (90%); brown oil; Rf = 0.5 (EtOAc–PE, 20%); [a]D
+2.7 (c 3.4, CHCl3).
IR (neat): 3423, 2939, 2867, 1638, 1457, 1322, 1261, 1076, 904,
870 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.56 (br, 1 H), 3.86–3.65 (m, 3 H),
3.52–3.30 (m, 2 H), 1.88–1.36 (m, 13 H), 1.18 (d, J = 6.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 98.7, 67.7, 67.4, 62.2, 38.9, 30.6,
29.5, 25.3, 23.3, 19.5.
Yield: 3.94 g (89%); light-yellow oil; Rf = 0.9 (EtOAc–PE, 10%);
[a]D20 +2.7 (c 1.5, CHCl3).
MS (ESI): m/z = 225 [M + Na]+.
IR (neat): 3065, 2934, 2860, 1710, 1464, 1375, 1107, 1042, 821,
740 cm–1.
1H NMR (300 MHz, CDCl3): d = 9.62 (s, 1 H), 7.68–7.60 (m, 4 H),
7.41–7.30 (m, 6 H), 3.87–3.78 (m, 1 H), 2.28–2.21 (m, 2 H), 1.64–
1.56 (m, 2 H), 1.48–1.37 (2 H), 1.09–1.02 (m, 12 H).
HRMS: m/z calcd for C11H22O3Na: 225.1461; found: 225.1467.
tert-Butyl[(1R)-1-methyl-5-(tetrahydro-2H-2-pyranyloxy)pen-
tyl]oxydiphenylsilane (20)
To a solution of 19 (2.93 g, 14.48 mmol) in CH2Cl2 (40 mL), imi-
dazole (1.47 g, 21.61 mmol) and TBDPSCl (1.67 mL, 6.4 mmol)
were added sequentially at 0 °C. A catalytic amount of DMAP was
added and the reaction mixture was stirred for 4 h at 25 °C. The re-
action mixture was quenched with sat. aq NH4Cl (6 mL) and ex-
tracted with CH2Cl2 (3 × 30 mL). The organic extract was dried
over anhydrous Na2SO4 and concentrated under vacuum. Column
chromatographic separation on silica gel (hexane–EtOAc, 9:1) af-
forded pure compound 20.
13C NMR (75 MHz, CDCl3): d = 202.5, 135.8, 130.1, 127.3, 68.9,
43.6, 38.6, 26.9, 23.0, 17.7.
MS (ESI): m/z = 393 [M + K]+.
HRMS: m/z calcd. for C22H30O2NaSi: 377.19.8; found: 377.1913.
(10R)-10-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-1-undecen-6-ol
(23)
To a stirred solution of Mg (0.541 g, 22.26 mmol) in THF (10 mL),
4-pentenyl bromide (3.31 g, 22.2 mmol) was added at r.t. After stir-
ring for 30 min at 25 °C, aldehyde 22 (3.94 g, 11.11 mmol) in THF
(5 mL) was added and reaction mixture was stirred for 1 h. The mix-
ture was quenched by addition of sat. aq NH4Cl (5 mL) and extract-
ed with EtOAc (2 × 60 mL). The organic extracts were washed with
brine (30 mL) and dried over anhydrous Na2SO4. After evaporating
20
Yield: 5.87 g (90%); clear oil; Rf = 0.9 (EtOAc–PE, 10%); [a]D
+3.5 (c 2.1, CHCl3).
IR (neat): 3069, 2934, 2894, 2858, 1589, 1468, 1362, 1261, 860,
738 cm–1.
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2122
J. S. Yadav, P. V. Murthy
PAPER
HRMS: m/z calcd for C16H30O3Na: 293.2087; found: 293.2093.
the solvent, the product was purified by column chromatography
(hexane–EtOAc, 8:2) to afford pure alcohol 23.
(1S)-1-Methyl-5-(tetrahydro-2H-2-pyranyloxy)-9-decenyl 2,4-
Dimethoxy-6-vinylbenzoate (25)
Yield: 3.77 g (80%); light-yellow liquid; Rf = 0.6 (EtOAc–PE,
20%); [a]D20 +2.1 (c 1.1, CHCl3).
To a well-stirred solution of alcohol 5 (0.6 g, 2.21 mmol) and Ph3P
(1.16 g, 4.43 mmol) in anhydrous Et2O (4 mL) at r.t., was added a
pre-stirred solution of acid 4 (0.461 g, 2.21 mmol) and DEAD (0.66
mL, 4.19 mmol) in benzene (3 mL). The mixture was stirred for
14 h, then the solvent was evaporated and the residue was washed
with anhydrous Et2O (10 mL) and filtered through a sintered funnel
with a Celite pad. The filtrates were dried over anhydrous Na2SO4
and the solvent was evaporated. Purification by column chromatog-
raphy (hexane–EtOAc, 9:1) afforded pure ester 25.
IR (neat): 3358, 3070, 2932, 2858, 1640, 1462, 1375, 1187,
1050 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.65–7.57 (m, 4 H), 7.38–7.26 (m,
6 H), 5.80–5.66 (m, 1 H), 5.00–4.87 (m, 2 H), 3.84–3.75 (m, 1 H),
3.45–3.39 (m, 1 H), 2.05–1.97 (m, 2 H), 1.57–1.50 (m, 11 H), 1.08–
0.96 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 138.7, 135.8, 129.4, 127.4, 114.5,
71.5, 69.4, 39.3, 37.3, 33.7, 27.0, 24.8, 23.2, 21.2, 19.2.
MS (ESI): m/z = 447 [M + Na]+.
Yield: 0.918 g (90%); light-yellow oil; Rf = 0.8 (EtOAc–PE, 30%);
[a]D20 +1.9 (c 1.8, CHCl3).
HRMS: m/z calcd for C27H40O2NaSi: 447.2687; found: 447.2695.
IR (neat): 2920, 2851, 1723, 1600, 1460, 1370, 1262, 1158, 917,
832 cm–1.
tert-Butyl[(1R)-1-methyl-5-(tetrahydro-2H-2-pyranyloxy)-9-
decenyl]oxydiphenylsilane (24)
1H NMR (300 MHz, CDCl3): d = 6.71–6.64 (m, 1 H), 6.58 (s, 1 H),
6.35 (s, 1 H), 5.83–5.62 (m, 2 H), 5.29 (d, J = 10.2 Hz, 2 H), 5.13
(br, 1 H), 5.02–4.87 (m, 2 H), 4.60 (br, 1 H), 3.84 (s, 3 H), 3.80 (s,
3 H), 3.63–3.55 (m, 1 H), 3.48–3.39 (m, 1 H), 2.09–2.00 (m, 2 H),
1.18–1.25 (m, 19 H).
13C NMR (75 MHz, CDCl3): d = 167.4, 161.1, 157.7, 138.8, 137.2,
133.6, 116.8, 114.3, 101.2, 98.1, 97.4, 76.2, 62.6, 55.3, 36.0, 33.8,
31.1, 29.6, 25.4, 24.2, 19.9.
To a stirred solution of alcohol 23 (3.77 g, 8.87 mmol) in CH2Cl2
(30 mL) at r.t., was added 2,3-dihydro-2H-pyran (0.965 mL, 10.65
mmol), and PPTS (0.111 g, 0.443 mmol) and the solution was
stirred at r.t. for 30 min. The reaction mixture was quenched by ad-
dition of sat. NaHCO3 (10 mL), extracted with CH2Cl2 (3 × 50 mL)
and the organic layer was washed with H2O (30 mL). The combined
organic extracts were dried over Na2SO4, concentrated under re-
duced pressure and purified by silica gel column chromatography
(hexane–EtOAc, 9: 1) to afford the product 24.
MS (ESI): m/z = 483 [M + Na]+.
HRMS: m/z calcd. for C27H40O6Na: 483.2718; found: 483.2723.
20
Yield: 3.69 g (90%); clear oil; Rf = 0.9 (EtOAc–PE, 10%); [a]D
+1.1 (c 1.4, CHCl3).
(1S)-5-Hydroxy-1-methyl-9-decenyl 2,4-Dimethoxy-6-vinylben-
zoate (26)
IR (neat): 3070, 2934, 2858, 1639, 1461, 1376, 1197, 1025, 997,
869 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.69–7.58 (m, 4 H), 7.41–7.31 (m,
6 H), 5.82–5.67 (m, 1 H), 5.02–4.87 (m, 2 H), 4.62–4.50 (m, 1 H),
3.89–3.72 (m, 2 H), 3.53–3.33 (m, 2 H), 2.02–1.97 (m, 2 H), 1.54–
1.18 (m, 15 H), 1.06–0.96 (m, 12 H).
13C NMR (75 MHz, CDCl3): d = 136.0, 129.1, 127.6, 127.4, 99.3,
76.6, 76.2, 76.0, 63.0, 62.4, 39.3, 34.7, 33.5, 33.0, 29.5, 27.6, 27.0,
25.2, 24.9, 23.6, 21.0, 20.3, 19.5.
Compound 25 (0.8 g, 1.73 mmol) was dissolved in EtOH (7 mL)
and stirred with a catalytic amount of PPTS (0.021 g, 0.08 mmol) at
60 °C for 1 h. The mixture was quenched by the addition of sat. aq
NaHCO3 (50 mL). EtOH was evaporated under reduced pressure
and the aqueous phase was extracted with EtOAc (2 × 20 mL). The
organic extracts were washed with brine (10 mL) and dried over an-
hydrous Na2SO4. After evaporating the solvent, the product was pu-
rified by column chromatography (hexane–EtOAc, 8:2) to afford
pure alcohol 26.
MS (ESI): m/z = 531 [M + Na]+.
Yield: 0.55 g (85%); colorless liquid; Rf = 0.7 (EtOAc–PE, 30%);
[a]D20 +3.5 (c 1.1, CHCl3).
HRMS: m/z calcd for C32H48O3NaSi: 531.3265; found: 531.3270.
IR (neat): 3449, 2922, 2855, 1716, 1603, 1461, 1266, 1160, 1087,
968 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.77–6.65 (m, 1 H), 6.57 (s, 1 H),
6.33 (s, 1 H), 5.81–5.61 (m, 2 H), 5.29 (d, J = 10.2 Hz, 1 H), 5.13
(br, 1 H), 5.01–4.87 (m, 2 H), 3.82 (s, 3 H), 3.80 (s, 3 H), 3.56 (br,
1 H), 2.09–2.01 (m, 2 H), 1.50–1.30 (m, 14 H).
13C NMR (75 MHz, CDCl3): d = 167.1, 160.7, 157.3, 138.3, 136.8,
133.2, 116.4, 100.8, 97.6, 71.3, 71.1, 55.4, 54.9, 36.7, 35.4, 35.2,
33.2, 29.2, 24.4, 20.9, 19.5.
(2R)-6-(Tetrahydro-2H-2-pyranyloxy)-10-undecen-2-ol (5)
To a solution of 24 (3.69 g, 7.25 mmol) in anhydrous THF (25 mL),
TBAF (1 M in THF, 8.7 mL, 8.66 mmol) was added at 0 °C. The re-
action mixture was warmed to r.t. and stirred for 5 h then the reac-
tion was quenched by addition of sat. aq NH4Cl (10 mL), extracted
with EtOAc (3 × 40 mL), washed with brine (30 mL), and dried
over anhydrous Na2SO4. After evaporating the solvent, the product
was purified by column chromatography (hexane–EtOAc, 8:2) to
afforded pure alcohol 5.
MS (ESI): m/z = 399 [M + Na]+.
Yield: 1.96 g (90%); light-yellow oil; Rf = 0.6 (EtOAc–PE, 20%);
[a]D20 +2.5 (c 1.2, CHCl3).
HRMS: m/z calcd for C22H32O5Na: 399.2141; found: 399.2147.
IR (neat): 3417, 2925, 2853, 1640, 1459, 1374, 1116, 1023, 908,
607 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.82–5.69 (m, 1 H), 5.02–4.88 (m,
2 H), 4.64–4.52 (m, 1 H), 3.92–3.70 (m, 2 H), 3.63–3.54 (m, 1 H),
3.48–3.40 (m, 1 H), 2.11–1.99 (m, 2 H), 1.61–1.32 (m, 17 H), 1.15
(d, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 138.8, 114.4, 98.4, 76.9, 76.5, 76.3,
63.1, 62.6, 39.4, 34.6, 33.8, 33.3, 29.6, 25.4, 24.8, 23.4, 21.1, 20.2,
19.8.
(3S)-7-Hydroxy-14,16-dimethoxy-3-methyl-3,4,5,6,7,8,9,10-oc-
tahydro-1H-2-benzoxacyclotetradecin-1-one (3)
To a solution of the Grubbs catalyst [(Cy3P)2Cl2Ru=CHPh] (0.045
g, 0.053 mmol) in anhydrous toluene (100 mL) was added a solution
of 26 (0.2 g, 0.53 mmol) in toluene (5 mL) under nitrogen. The re-
action mixture was stirred at 80 °C under nitrogen for 23 h. The re-
action mixture was concentrated under reduced pressure and the
resulting residue was purified by column chromatography (hexane–
EtOAc, 8:2) to afford pure product 3.
MS (ESI): m/z = 293 [M + Na]+.
Synthesis 2011, No. 13, 2117–2124 © Thieme Stuttgart · New York

PAPER
Total Synthesis of (S)-Zearalenone and Zerano
2123
20
Yield: 0.157 g (80%); clear oil; Rf = 0.6 (EtOAc–PE, 30%); [a]D
+7.5 (c 1.1, CHCl3).
13C NMR (75 MHz, CDCl3): d = 211.6, 171.3, 165.4, 160.6, 143.9,
133.1, 132.5, 108.4, 103.7, 102.4, 73.4, 42.9, 36.6, 34.7, 31.0, 22.2,
20.9, 20.8.
IR (neat): 3449, 2922, 2855, 1716, 1603, 1461, 1266, 1160, 1087,
968 cm–1.
MS (ESI): m/z = 341 [M + Na]+.
1H NMR (500 MHz, CDCl3): d = 6.52 (s, 1 H), 6.52–6.40 (m, 1 H),
6.38 (d, J = 16.2 Hz, 1 H), 6.28 (s, 1 H), 6.19–5.99 (m, 1 H), 5.33–
5.15 (m, 1 H), 3.82–3.79 (s, 6 H), 3.71–3.57 (m, 1 H), 2.37–2.15
(m, 2 H), 1.81–1.28 (m, 13 H).
13C NMR (75 MHz, CDCl3): d = 167.8, 161.1, 157.4, 133.3, 127.8,
126.6, 101.4, 101.0, 97.5, 70.7, 69, 55.9, 55.3, 36.6, 34.8, 32.5,
30.3, 22.8, 20.3, 19.3.
HRMS: m/z calcd for C18H22O5: 341.1372; found: 341.1365.
(3S)-7-Hydroxy-14,16-dimethoxy-3-methyl-
3,4,5,6,7,8,9,10,11,12-decahydro-1H-2-benzoxacyclotetradecin-
1-one (28)
To a well-stirred solution of alcohol 3 (0.025 g, 0.72 mmol) in an-
hydrous EtOH (4 mL) at r.t., was added a catalytic amount of Pd/C
and a hydrogen balloon was attached. The mixture was stirred at r.t.
for 2 h. After completion of reaction, the reaction mixture was fil-
tered through a pad of Celite and the filtrate was concentrated in
vacuo. The residue was purified by flash column chromatography
(hexane–EtOAc, 7:3) to afford the title compound 28.
MASS (ESI): m/z = 371 [M + Na]+.
HRMS: m/z calcd for C20H28O5Na: 371.1841; found: 371.1834.
(3S)-14,16-Dimethoxy-3-methyl-3,4,5,6,7,8,9,10-octahydro-1H-
2-benzoxacyclotetradecine-1,7-dione (27)
Yield: 0.02 g (80%); light-yellow solid; mp 125–129 °C; Rf = 0.7
(EtOAc–PE, 20%); [a]D20 +12 (c 0.9, MeOH).
To a stirred clear solution of IBX (0.123 g, 0.43 mmol) in anhydrous
DMSO (1 mL) under a nitrogen atmosphere, was added alcohol 3
(0.1 g, 0.287 mmol) in anhydrous CH2Cl2 (5 mL) at r.t. The reaction
mixture was stirred for 30 min, diluted with an excess of Et2O and
filtered through a Celite pad. The filtrate was washed with sat. aq
NaHCO3 (5 mL), H2O (5 mL) and brine (5 mL). The organic layer
was dried over Na2SO4 and concentrated in vacuo. The residue was
purified by flash column chromatography (hexane–EtOAc, 8:2) to
afford the title compound 27.
IR (neat): 3449, 2922, 2855, 1716, 1603, 1461, 1266, 1160, 1087,
968 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.38 (s, 1 H), 6.30 (s, 1 H), 5.33–
5.18 (m, 1 H), 3.83–3.73 (m, 7 H), 2.80–2.64 (m, 1 H), 2.55–2.35
(m, 1 H), 1.78–1.31 (m, 17 H).
13C NMR (75 MHz, CDCl3): d = 168.8, 161.0, 142.0, 128.7, 105.5,
96.4, 70.6, 69.7, 55.8, 55.3, 34.7, 34.2, 33.5, 33.0, 29.9, 29.2, 27,
22.7, 19.8.
Yield: 0.084 g (85%); white solid; mp 105–107 °C; Rf = 0.6
(EtOAc–PE, 30%); [a]D20 +23 (c 1, CHCl3).
MS (ESI): m/z = 373 [M + Na]+.
IR (neat): 2922, 2855, 1720, 1710, 1603, 1580, 1461, 1270, 1210,
1160, 1087, 968 cm–1.
HRMS: m/z calcd for C20H30O5: 373.1998; found: 373.1991.
1H NMR (300 MHz, CDCl3): d = 6.51 (s, 1 H), 6.42–6.28 (m, 2 H),
6.01–5.85 (m, 1 H), 5.35–5.19 (m, 1 H), 3.82 (s, 3 H), 3.80 (s, 3 H),
2.73–2.60 (m, 2 H), 2.43–2.24 (m, 3 H), 2.19–2.00 (m, 2 H), 1.83–
1.48 (m, 5 H), 1.33 (d, J = 6.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 211.4, 167.5, 161.2, 157.6, 136.7,
133.1, 128.9, 101.2, 97.7, 71.8, 55.9, 55.4, 44.0, 37.5, 35.1, 31.2,
29.6, 21.7.
(3S)-7,14,16-Trihydroxy-3-methyl-3,4,5,6,7,8,9,10,11,12-
decahydro-1H-2-benzoxacyclotetradecin-1-one (2)
To a stirred solution of AlI3 in benzene [prepared in situ from Al
(0.117 g, 4.35 mmol) and I2 (0.77 g, 3.043 mmol) in anhydrous ben-
zene (5 mL) at 80 °C for 1 h] was added 28 (0.03 g, 0.087 mmol) in
anhydrous benzene (2 mL) at 10 °C. The reaction mixture was
stirred for 30 min then the reaction was quenched by addition of aq
NH4Cl (2 mL) and aq Na2S2O3·5H2O (2 mL) and extracted with
EtOAc (3 × 6 mL). The combined organic layers were collected,
dried over Na2SO4 and concentrated in vacuo. The residue was pu-
rified by flash column chromatography (hexane–EtOAc, 7:3) to af-
ford zeranol (2).
MS (ESI): m/z = 347 [M + H]+.
HRMS: m/z calcd for C20H27O5: 347.1858; found: 347.1848.
(3S)-14,16-Dihydroxy-3-methyl-3,4,5,6,7,8,9,10-octahydro-1H-
2-benzoxacyclotetradecine-1,7-dione (1)
Yield: 0.019 g (70%); white solid; mp 176–180 °C; Rf = 0.6
(EtOAc–PE, 50%); [a]D20 +27 (c 1.2, MeOH).
To a stirred solution of AlI3 in benzene [prepared in situ from Al
(0.117 g, 4.35 mmol) and I2 (0.77 g, 3.043 mmol) in anhydrous ben-
zene (5 mL) at 80 °C for 1 h] was added 27 (0.03 g, 0.087 mmol) in
anhydrous benzene (2 mL) at 10 °C. The reaction mixture was
stirred for 30 min then the reaction was quenched by the addition of
aq NH4Cl (2 mL) and aq Na2S2O5 (2 mL) and extracted with EtOAc
(3 × 6 mL). The combined organic layers were collected, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
flash column chromatography (hexane–EtOAc, 7:3) to afford (S)-
zearalenone (1).
IR (neat): 3358, 2921, 2851, 1707, 1644, 1458, 1353, 1312, 1257,
1204, 1167, 1120, 972, 758 cm–1.
1H NMR (300 MHz, CDCl3): d = 11.62 (s, 1 H), 6.29–6.21 (m, 2 H),
3.91–3.77 (m, 1 H), 3.31–3.19 (m, 1 H), 2.64–2.53 (m, 1 H), 2.18–
2.12 (m, 1 H), 1.83–1.17 (m, 17 H).
13C NMR (75 MHz, DMSO-d6): d = 171.2, 163.6, 161.5, 147.3,
110.6, 110.2, 100.8, 69.3, 67.2, 35.3, 34.5, 30.8, 29.0, 27.7, 26.5,
20.7, 20.4.
Yield: 0.019 g (70%); white solid; mp 161–163 °C; Rf = 0.45
(EtOAc–PE, 50%); [a]D20 –127 (c 1, MeOH).
MS (ESI): m/z = 345 [M + Na]+.
HRMS: m/z calcd. for C18H26O5Na: 345.1677; found: 345.1671.
IR (neat): 3447, 2921, 2851, 1707, 1644, 1458, 1353, 1312, 1257,
1204, 1167, 1120, 972, 758 cm–1.
1H NMR (300 MHz, CDCl3): d = 12.04 (s, 1 H), 7.01 (dd, J = 12.2,
1.2 Hz, 1 H), 6.40 (d, J = 2.4 Hz, 1 H), 6.34 (d, J = 2.4 Hz, 1 H),
5.72–5.63 (m, 1 H), 5.03–4.95 (m, 1 H), 2.90–2.80 (m, 1 H), 2.66–
2.57 (m, 1 H), 2.41–2.29 (m, 1 H), 2.26–2.08 (d, J = 6.4 Hz, 3 H).
Acknowledgment
P.V.M. thanks CSIR, New Delhi for the award of a Fellowship.
Author acknowledges partial support from King Saud University
for Global Research Network for Organic Synthesis (GRNOS).
Synthesis 2011, No. 13, 2117–2124 © Thieme Stuttgart · New York

2124
J. S. Yadav, P. V. Murthy
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Synthesis 2011, No. 13, 2117–2124 © Thieme Stuttgart · New York