Synthetic studies toward zoapatanol

Article abstract of DOI:10.1016/j.tetlet.2007.12.088

The oxepane core of zoapatanol was efficiently synthesized from commercially available 1,2,4-butanetriol, and it was shown to be possible to introduce the angular methyl group at C2′ by the reaction of an intermediate butenolide with diazomethane.

Full text of DOI:10.1016/j.tetlet.2007.12.088

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1344–1347
Synthetic studies toward zoapatanol
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Isela Garcıa, Manuel Perez, Pedro Besada, Generosa Gomez , Yagamare Fall
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, Universidad de Vigo, 36200 Vigo, Spain
Received 6 November 2007; revised 12 December 2007; accepted 18 December 2007
Available online 23 December 2007
Abstract
The oxepane core of zoapatanol was efficiently synthesized from commercially available 1,2,4-butanetriol, and it was shown to be
possible to introduce the angular methyl group at C20 by the reaction of an intermediate butenolide with diazomethane.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Oxacyclic compounds; Singlet oxygen; Oxepanes; Stereoselective synthesis; Cycloaddition
O
Zoapatanol is a diterpenoid oxepane isolated from the
Mexican plant zoapatle (Montanoa tomentosa). For centu-
ries, Mexican women have used extracts of the leaves of
this plant to induce menses, labor, and early termination
of pregnancy.1 It is believed that it is zoapatanol and its
metabolites that are responsible for this antifertility activ-
ity.2 Since its structural elucidation in 1979 by Levine
et al.,3 several groups have described total syntheses of zoa-
patanol,4 and apparently viable alternative synthetic
approaches that were not pursued to completion have also
been reported.5 Most of these methods are racemic: to date,
only two enantioselective syntheses of zoapatanol have
been described.6 In this Letter, we report preliminary
results toward a new synthesis of racemic zoapatanol,
which could be used later to carry out the enantioselective
synthesis of zoapatanol by simply using chiral starting
material (Fig. 1).
O
2'
3'
OH
HO
H
1.Zoapatanol
Fig. 1. Structure of zoapatanol.
Protection of the C1 and C2 hydroxyl groups of 2 with
cyclohexanone afforded alcohol 38 (97%), which was easily
converted into iodide 48 in 93% yield. Lithiation of furan
(5) and reaction with 4 afforded the alkylated furan 68
(91%). Removal of the cyclohexylidene group of 6 using
Dowex 50W-X8 in methanol9 then gave an 89% yield of
diol 7,8 and protection of the primary hydroxy group of
7 afforded silylether 8,8 which was benzylated to furan 9.8
Oxidation of 9 with singlet oxygen, followed by treatment
with acetic anhydride in pyridine, afforded butenolide 108
in 96% yield (two steps), and treatment of 10 with TBAF
led to bicyclic lactone 11.8 The lactone ring of 11 was then
opened with LAH, and selective protection of the primary
hydroxy group of the resulting diol, followed by oxidation
of the secondary hydroxy group, afforded oxepanone 12.8
The nonenyl side chain of zoapatanol, and its exocyclic
double bond, can be introduced on 12 by known method-
ology,5d,6c but the angular methyl group at C20 cis to the
C30 hydroxy group is more challenging. To try to solve
It was anticipated that the oxepane core of 1 could be
prepared from commercially available butanetriol (2) using
our previously described method for the synthesis of oxa-
cyclic systems.7 Scheme 1 details the synthesis of the
advanced intermediate 12.
*
Corresponding authors. Tel.: +34 986 812320; fax: +34 986 81 22 62
(Y.F.).
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E-mail addresses: ggomez@uvigo.es (G. Gomez), yagamare@uvigo.es
(Y. Fall).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.088

I. Garcı´a et al. / Tetrahedron Letters 49 (2008) 1344–1347
1345
ii
OH
i
O
O
HO
O
O
OH
I
OH
2
4
3
iv
v
iii
HO
O
HO
O
O
7
O
O
6
5
BnO
HO
vi
vii
TBDPSO
TBDPSO
TBDPSO
O
9
O
8
BnO
O
viii
ix
O
BnO
O
MeO
O
O
OMe
10
11
O
2'
3'
OTBDPS
BnO
O
12
Scheme 1. Reagents and conditions: (i) cyclohexanone, BF3ꢀOEt2, Et2O, 0 °C to rt (97%); (ii) PPh3, imid, I2, THF (93%); (iii) 5, bipyridine, nBuLi, THF,
0 °C to rt (91%); (iv) Dowex 50W-X8, MeOH, rt, 20 h (89%); (v) TBDPSCl, imid, DMAP, DMF, rt (87%); (vi) NaH, DMF, BnBr, ꢁ78 °C to rt (75%);
1
(vii) (a) O2, MeOH, rose Bengal, hm; (b) Ac2O, py, DMAP (96%, two steps); (viii) TBAF, THF, rt (85%); (ix) (a) LAH, BF3ꢀOEt2 (97%); (b) TBDPSCl,
imid, DMAP, DMF, rt (43%); (c) TPAP, NMO, CH2Cl2 (91%).
the problem we used the more easily available tetrahydro-
pyran ring as a model system (Scheme 2).
experiments and proved to be the one required for
Zoapatanol.
Commercially available furan 13 was converted to bute-
nolide 14 following the procedure described previously.7b
Cycloaddition of 14 with diazomethane, followed by pyro-
lysis in refluxing dioxane, gave methylated furanone 16,8,10
and removal of the TBDPS group of 16 with cesium fluo-
ride in acetonitrile gave the bicyclic lactone 17,8 which
bears the desired angular methyl group, as a single product
(62%). The unambiguous elucidation of the stereochemis-
try of 17 by X-ray crystallography11 (Fig. 2) confirmed that
intramolecular Michael addition had given rise to a cis ring
junction.
In conclusion, we have shown that the oxepane core of
zoapatanol can be constructed starting from commercially
available butanetriol, and its angular methyl group intro-
duced by cycloaddition of diazomethane with the appropri-
ate butenolide. This preliminary study also provided
unambiguous proof that the intramolecular Michael addi-
tion of our furan approach to oxacyclic systems results in
the formation of a cis ring junction. Work is now in pro-
gress toward the total synthesis of natural (+)-(20S,30R)-
zoapatanol.
Opening of lactone 17 with LiAlH4 in the presence of
BF3ꢀOEt2 gave diol 18,8 which was selectively protected
with TBDPS. The resulting secondary alcohol, 19, was then
oxidized with TPAP to ketone 20,8 which on reaction with
sodium borohydride in MeOH–CH2Cl2 at ꢁ78 °C gave
alcohol 2112 as the major diastereoisomer (selectivity:
9/2.5). The relative stereochemistry of the two contiguous
stereocenters of alcohol 21 was established by NOE
Acknowledgments
This work was supported by grants from the Xunta de
Galicia (PGIDIT04BTF301031PR) and the Spanish Minis-
try of Education and Science (CTQ2007-61788). The work
of the NMR, MS, and X-ray divisions of the research sup-
port services of the University of Vigo (CACTI) is grate-
´
fully acknowledged. We thank Dr. S. Lopez (University

1346
I. Garcı´a et al. / Tetrahedron Letters 49 (2008) 1344–1347
i
O
TBDPSO
O
O
O
OEt
MeO
13
14
N
N
iii
TBDPSO
ii
TBDPSO
O
O
O
O
MeO
MeO
16
15
O
O
v
OH
O
iv
O
OMe
OH
17
18
O
O
vi
vii
OTBDPS
OTBDPS
O
O
OH
20
19
viii
O
O
OTBDPS
OH
OH
H
HO
H
21
Zoapatanol
Scheme 2. Reagents and conditions: (i) Ref. 7b; (ii) CH2N2, Et2O (81%); (iii) dioxane, 130 °C (67%); (iv) CsF, CH3CN, rt (62%); (v) LAH, BF3ꢀOEt2
(65%); (vi) TBDPSCl, imid, DMF, rt (50%); (vii) TPAP, NMO, CH2Cl2 (67%); (viii) NaBH4, CH2Cl2, MeOH, ꢁ78 °C (80%).
Compostela) for preliminary contributions to this study.
P.B. thanks the Xunta de Galicia for an Isidoro Parga Pon-
dal contract.
References and notes
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Fig. 2. X-ray structure of 17.
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˚
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7.68–7.66 (4H, m), 7.41 (6H, m), 3.75 (2H, dd, J = 7.05, J = 5.14),
3.60 (1H, m), 3.51 (2H, m), 3.19 (1H, m), 2.12 (1H, m), 1.80 (4H,
m), 1.50 (1H, m), 1.21 (3H, s), 1.04 (9H, s); 13C NMR (CDCl3), d
135.60 (CH), 135.59 (CH), 133.01 (C), 132.92 (C), 129.82 (CH),
127.77 (CH), 76.05 (C), 71.59 (CH), 60.79 (CH2), 60.31 (CH2), 36.85
(CH2), 26.98 (CH2), 26.76 (CH2), 22.30 (CH3), 26.98 [(CH3)3–],
19.01 (C).
´
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analytical, and/or high resolution mass spectral data.
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´
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