Studies on the synthesis of (±)-pathylactone A, a nor-sesquiterpene lactone isolated from marine sources

Article abstract of DOI:10.1016/S0040-4020(02)00058-3

An approach to the synthesis of a highly substituted carbon skeleton exhibited by some unusual nor-sesquiterpenes isolated from marine sources, is described. Our strategy was applied for the total synthesis of pathylactone A, which has now been prepared by an unambiguous route and found to be different from the natural product.

Full text of DOI:10.1016/S0040-4020(02)00058-3

TETRAHEDRON
Pergamon
Tetrahedron 58 12002) 1647±1656
Studies on the synthesis of ꢀ^)-pathylactone A,
a nor-sesquiterpene lactone isolated from marine sources
Fernando Coelhop and Gaspar Diaz
 à  Â
Depto. de Quõmica Organica, Instituto de Quõmica, Universidade Estadual de Campinas ꢀUNICAMP), Cidade Universitaria Zeferino Vaz,
P.O. Box 6154, 13083-970, Campinas, SP, Brazil
Received 13 November 2001; accepted 15 January2002
AbstractÐAn approach to the synthesis of a highly substituted carbon skeleton exhibited by some unusual nor-sesquiterpenes isolated from
marine sources, is described. Our strategy was applied for the total synthesis of pathylactone A, which has now been prepared by an
unambiguous route and found to be different from the natural product. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
total synthesis of some marine natural products, we describe
herein a studyaimed at the total synthesis of 1 ^)-pathyl-
actone A 11). Our interest was focused on the development
of a simple and straightforward method, which would allow
us to prepare not onlythe natural product but some non-
natural derivatives, directed towards the studyof the bio-
logical pro®le of this kind of spirolactone nor-sesquiterpene.
Pathylactone A 11) is an unusual and denselysubstituted
nor-sesquiterpene isolated bySu et al., in 1991 from the
soft coral Paralemnalia thyrsoides, found in the South
China Sea. Theyassigned the structure and relative stereo-
chemistrydepicted in Fig. 1, based on one- and two-
dimensional NMR data.
1
From our point of view, 1 could be prepared from the spiro-
ether 3 through two sequential oxidation steps, e.g. Wacker
oxidation of the allyl moiety and oxidation of the cyclic
ether to furnish the spirolactone unit. The preparation of
the spiroether moietywith the correct stereochemistryat
C6 1pathylactone-A numeration, Scheme 1) could be
secured bythe regioselective opening of the epoxide 4.
The latter could be easilyobtained bythe epoxidation reac-
tion of alkene 5, which can be prepared bya regioselective
dehydration reaction of a tertiary alcohol. The addition of a
suitablyfunctionalized organometallic reagent to a-allyl
cyclohexenone 6 could furnish the tertiaryalcohol neces-
saryfor the dehdyration step 1Scheme 1). The required
ketone 6 could be stereoselectivelyprepared through a
conjugate addition of lithium dimethylcuprate to the double
bond of 2-methylcyclohexenone 17), followed bythe
trapping of the copper enolate intermediate with allyl bro-
mide. The control of the relative stereochemistryof the
methyl groups at C4 and C5 1pathylactone-A numeration)
should be secured in this step 1Scheme 1). Finally, ketone 7
could be easily prepared from methylcyclohexanol.
A year later, Scheuer et al.2 reported the isolation and
chemical characterization of napalilactone 12), another
example of this class of nor-sesquiterpene, from the soft
coral Lemnalia africana.
The biological activityof these spirolactone nor-sesquiter-
penes remains unknown, but their unusual and stereo-
chemicallycomplex structures make them challenging
synthetic targets.
As part of a current research program directed towards the
The onlydoubt concerning the stereochemical control of
this strategyrelies on the stereoselectivityobtained in the
epoxidation step, although this has been proved not to be
crucial. However, it would be important to us to separate
these diastereoisomeric epoxides. We thought that the
opening of the a-oriented epoxide with chloride ion as
nucleophile could be used as a keystep in the total synthesis
Figure 1. Structures of pathylactone A and napalilactone.
Keywords: pathylactone A; epi-pathylactone A; natural products; total
synthesis.
p
Corresponding author. Tel.: 155-19-788-3085; fax: 111-55-19-788-
3023; e-mail: coelho@iqm.unicamp.br
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020102)00058-3

1648
F. Coelho, G. Diaz / Tetrahedron 58 ꢀ2002) 1647±1656
Scheme 1. Retrosynthesis for the preparation of pathylactone A.
of napalilactone 12, Scheme 1), while the b-oriented isomer
could be used as a substrate in the total synthesis of pathyl-
actone A, as depicted in Fig. 2. According to the Baldwin
rules, the favored cyclization should preferentially lead to
the spiro compound.3 Depending on the success attained
with this strategy, some additional modi®cations should
allow us to synthesize 2, in its racemic form.
dimethylcuprate to 2-methylcyclohexenone,5 followed by
the regioselective alkylation of the copper enolate inter-
mediate with allyl bromide, gave the allyl ketone 6a/b
1cis:trans 20:80), as a diastereoisomeric mixture 1GC analy-
sis), readilyseparated bycolumn chromatography1Scheme
2). Although, Boeckman reported a diastereoselection ratio
of 10:90 1cis:trans), we, as well as others,6 were unable to
reproduce this result.
We tried to con®rm the stereochemical assignments of 6a/b
byNOE experiments, through the irradiation of the methyl
group protons at C4 and C5.7 Unfortunately, the results were
not conclusive, mainlydue to saturation of the methyl group
protons at C4, when the C5 methyl group protons were
irradiated, and vice versa.
2. Results and discussions
Our synthesis started with the preparation of the 2-methyl-
cyclohexenone 7, which was obtained using a standard
procedure4 in three steps and 73% overall yield from
commercial 2-methylcyclohexanol.
To prepare the spiro g-butyrolactone moiety at C6, it was
necessaryto add a suitablyfunctionalized three carbon
residue 1fragment C7±C9) to ketone 6b. This fragment
To obtain the carbonyl compound 6 we decided to take
advantage of the greater stereoselectivityand generally
greater yields of 1,4-addition products obtained using
organocopper reagents. Boeckman5 has described a method
based on a stereo- and regioselective double alkylation of
a,b-unsaturated ketones. The 1,4-addition of lithium
could be readilyobtained from 1,3-propanediol byusing
the method recentlydescribed byForsyth et al.,
8
and Chen
and Reamer.9
Figure 2. Preparation of 1 and 2 from diastereoisomeric epoxides.

F. Coelho, G. Diaz / Tetrahedron 58 ꢀ2002) 1647±1656
1649
Scheme 2. Preparation of the spiroethers 3a and b. 1a): 1i) 1CH3)2CuLi, ether, 08C; 1ii) DME, allyl bromide, rt, 15 min, 16a/b, 1:4), 77%; 1b) I1CH2)2CH2OPMB
110), t-BuLi, ether, 2238C, 1 h, 92% 1based on recovered starting material); 1c) POCl3, DBU, Py, rt, 24 h, 78%; 1d) MCPBA, CH2Cl2, 08C, 8 h, 88%; and
1e) DDQ, CH2Cl2:H2O 118:1), 3 h, 94%.
Thus, 1,3-propanediol was treated with sodium hydride in
THF at 08C, followed byaddition of p-methoxybenzyl
chloride to furnish, a PMB/ether alcohol intermediate, in
84% yield. The mesylation of the alcohol, followed by
substitution with NaI, provided iodide 10, in 98% yield
for the two steps.
The epoxides 4a/b were treated with DDQ in a mixture of
dichloromethane/water 118:1) in order to remove the PMB
group. These conditions gave spiroethers 3a/b in 94% yield.
Most probably, formation of spiroethers 3a/b arise due to a
decrease of the pH of the reaction mixture when the quinone
is reduced. There are other examples of this kind of cycli-
zation reaction, in the literature, which are characterized by
a high level of stereoselectivity.8,11 Fortunatelythe spiro-
ethers were readilyseparated bycolumn chromatography
1Scheme 2).
The ketone trans-6b was treated at 2238C with the organo-
lithium compound derived from iodide 10 1generated in situ
bytreatment with an ethereal solution of t-butyllithium) to
furnish the tertiaryalcohol 11, as a mixture of diastereo-
isomers 1ratio 11a/b; 50:50) 1Scheme 2).10
To have additional information about the stereochemical
assignments of these compounds 13a/b), we decided to
establish the relative stereochemistrybywayof an
NOESY experiment 1Fig. 3). Irradiation of 3a at 3.75 ppm
1multiplet attributed to carbinolic hydrogen) showed an
increment of 4.0 and 2.72% on signals at 5.0 and
5.99 ppm, attributed to the vinylic methylene and the
ole®nic methylene, respectively. An increase in the signal
attributed to the axial hydrogen at C3 was also observed.
Irradiation of the protons of the quaternarymethyl group
showed an increase in the absorption attributed to the C8,
C9 and vicinal methyl group protons. When the same
experiment was performed with the epoxide 3b, we
observed an increment onlyin methly group protons.
These results clearlyindicated that the spiroether 3a had
the correct stereochemical arrangement for the preparation
of 1.
The treatment of the mixture of alcohols 11a/b with POCl3/
DBU in the presence of pyridine gave the alkene 5, in 88%
yield, contaminated with a trace of the exocyclic alkene,
onlydetectable bygas chromatography1HP5 column,
#5%). Thus, alkene 5 was treated with MCPBA in dichloro-
methane at 08C, to provide regioselectivelythe a- and
b-oriented epoxides 4a/b in 82% yield, in a 57:43 mixture
ratio 1determined byanalysis of the 500 MHz 1H NMR
spectrum).
We were unable to separate the diastereoisomeric epoxides
4a/b, despite various attempts 1preparative HPLC, column
chromatography, preparative thin-layer chromatography).
As we are interested in having some non-natural derivatives
of these spirolactone sesquiterpenes, we decided to continue
our synthesis with the mixture of epoxides.
To ®nish the total synthesis of pathylactone A, it was neces-
sary to oxidize the spiroether and the allyl moiety. To avoid
problems with the secondary hydroxyl group at C1 during
these oxidation steps, we ®rst protected it as a TBS ether
1Scheme 3). This reaction sequence was carried out sepa-
ratelyon spiroethers 3a and b.
Thus, treatment of 3a or b with TBS tri¯ate in the presence
of triethylamine in dichloromethane gave the silyl ethers 12
and 15 in 94 and 92% yield, respectively. To avoid the
removal of the silyl protecting group, a modi®ed Wacker12
Figure 3. NOE experiments with spiroether 3a.

1650
F. Coelho, G. Diaz / Tetrahedron 58 ꢀ2002) 1647±1656
Scheme 3. Preparation of pathylactone A. 1a) TBSTf, Et3N, CH2Cl2, rt 194% for 12 and 92% for 14); 1b) PdCl2, Cu1OAc)2, N,N-dimethylacetamide/water
17:1), 50% 1for 13 and 15); 1c) RuCl3´H2O 110% aq. sol.), NaIO4, AcOEt, rt, 23 h; and 1d) HF, CH3CN, rt, 3 h 176% for the two steps for 1 and 16).
reaction was carried out, to give the corresponding methyl-
ketones 113 and 16) in 50% yield. Subsequent oxidation
with RuCl3´H2O in the presence of NaIO4 led to the spiro-
lactones 14 and 17 in 84% yield for both cases. To remove
the silyl group the spirolactone 14 was treated with a solu-
tion of HF 148% in water) to provide pathylactone A in 90%.
When the spirolactone 17 was treated with HF in CH3CN,
1H NMR analysis revealed the formation of a different type
of product. Some spectral features of this new compound
drew our attention. First, the absorption at 2.46 ppm, attri-
buted to methylene of the methylketone moiety dis-
appeared. Associated to that was the disappearance of the
carbonyl carbon absorption at 209.8 ppm. The absorption at
2.23 ppm attributed to methyl unit of the methylketone
moiety, shifted to 1.75 ppm, associated with the appearance
of an absorption at 4.12 ppm, which integrating to one
hydrogen. The 13C NMR spectrum showed an additional
CH group and the disappearance of a CH2. Analysis of the
IR spectrum showed the disappearance of the ketone
carbonyl absorption at 1712 cm21 and the appearance of
an absorption at 1778 cm21, con®rming the presence of
the spirolactone unity. All the spectral data is compatible
with the structure proposed for 18. The formation of this
unusual structure is onlypossible if the hydroxyl group and
the methylketone moiety were on the same face of the
molecule. This result proves that compound 3b has an a
stereochemical arrangement at C1.
To con®rm the relative stereochemistryof 1, we carried out
several NOESY experiments according to those described
bySu et al. 1 Thus, we irradiated several hydrogens in order
to observe the NOE effects in other points of the structure.
The results are shown in Fig. 4. The incremental values
observed in the NOESY experiments point out unam-
biguouslythat the relative stereochemistryof all stereo-
centers was correctlycontrolled and it was totallyin
1
accordance with that proposed bySu et al.
With these data in hand, we carefullycompared our spectral
data 11H and 13C NMR) with those described bySu et al.
However, to our surprise, NMR data of synthetic 1 shows
some discrepancies with those described for the natural
product, e.g. a singlet had been attributed to the methylene
of the methylketone unit 1C10, Scheme 1), in the synthetic
product this methylene appears as two duplets centered at
2.77 ppm 1Jˆ15.5 Hz). The carbinolic proton in our product
appeared at 3.99 ppm 1double doublets, Jˆ10.9 and
4.27 Hz), with two coupling constants, the major one clearly
indicating that this proton was in an axial position, as
proposed bySu et al.
The NMR data obtained by us for the synthetic pathyl-
actone A did not match that published for the natural
product. We tried to understand these discrepancies by
performing a careful re-examination of all synthetic steps
and the spectral data obtained for the intermediates,
however all NOESY experiments indicated unambigu-
ouslythat the relative stereochemistries of all stereocenters
exhibited bythe synthesized molecule were adequately
controlled.
For the natural product the absorption of the carbinolic
proton was attributed at 4.33 ppm. In the 13C NMR of the
natural product, the carbon at C1 appears at 63.7 ppm.
Surprisingly, this carbon is shifted to down®eld with a
difference of almost 9 ppm from the synthetic product.
The absorption value 11H and 13C NMR) found for the
Figure 4. NOESY experiments with synthetic pathylactone A.

F. Coelho, G. Diaz / Tetrahedron 58 ꢀ2002) 1647±1656
1651
Table 1. NMR spectral data for pathylactone A 1natural and synthetic) and epi-pathylactone A 120)
Carbon
No.
13C NMR 1100 MHz, CDCl3)
1H NMR 1500 MHz, CDCl3)
NMR 1500 MHz, CDCl3)
for epi-pathylactone A 120)
Natural
63.7
Synthetic
71.1
Natural
Synthetic
13C
1H
1
4.33 1dd, Jˆ10.9 and 3.9 Hz)
3.99 1dd, Jˆ10.9 and
65.0
4.27 1m, 1H)
4.2 Hz)
1.60±1.90
2
3
4
5
6
7
8
9
10
28.6
26.7
33.0
45.9
91.8
175.5
29.1
24.5
46.6
27.0
25.7
33.7
45.1
93.1
177.3
29.4
23.4
47.6
1.90±2.06
1.44±1.80
2.39
27.0
26.0
33.7
45.3
92.0
177.0
29.0
24.0
47.0
1.78±2.0
1.44±1.79
2.38
±
1.44±1.78
2.41±2.33
±
±
±
±
±
±
±
±
2.46±2.71
2.21±2.33
2.50±2.65
2.32
2.69 1s)
2.48±2.67
2.30
2.80±2.73
2.77±2.69
1two doublet, Jˆ15.5 Hz)
1two doublet, Jˆ15.1 Hz)
11
12
13
14
207.6
32.6
15.4
17.7
208.7
32.9
15.9
17.2
±
2.10
±
2.17
207.0
32.2
15.9
17.2
±
2.09
0.94 1d, Jˆ7.8 Hz)
0.98 1d, Jˆ7.5 Hz)
0.96 1d, Jˆ7.7 Hz)
1.12 1s)
1.14 1s)
1.12 1s)
The synthetic product is a solid melting at 43±458C 1the natural product melt at 44.5±47.08C)1. epi-Pathylactone melting at 46±498C. All the NMR spectra
1
were recorded using an INOVA NMR equipment at 500 MHz for H and 125 MHz for 13C using CDCl3 as solvent and TMS as internal standard.1,15
natural product could suggest that the hydroxyl group at C1
was not in an axial position, but in an equatorial one.
a proton in an equatorial position 1di-equatorial and axial-
equatorial coupling constants).
Under normal circumstances, a carbon bearing an equatorial
hydroxyl group shows an absorption between 70±71 ppm,13
which agrees with our synthetic product. In the natural
product, this carbon apparentlyshows an unusual protec-
tion.
All the data obtained from 1H and 13C NMR spectra 1Table
1) were compatible for the structure of the synthetic epi-
pathylactone A 120). When the absorption at 4.27 ppm,
attributed to the equatoriallyoriented carbinolic proton,
was irradiated, we observed NOE increments in axial hydro-
gens at C2, hydrogens of the methyl group at C4 and protons
at C9 1Fig. 5). The spectral data for this non-natural
compound showed some similarityto those described for
natural pathylactone A, however the data obtained from
the NOESY experiments were different from those
described for the natural product.
In Table 1, the NMR 11H and 13C) data for synthetic and
natural pathylactone A are shown.
In order to propose an alternative structure for pathylactone
A, based on the possibility of the hydroxyl bearing in an
axial position, we prepared epimeric pathylactone A 1at C1),
as outlined in Scheme 4.
These data pointed out clearlythat the carbinolic proton was
not in an equatoriallyposition in the natural product.
Mitsunobu reaction16 with 1 furnished acetate 19 in 62%
yield. The presence of some elimination product was also
detected bygas chromatography110±15%). All spectral
data obtained for 19 were compatible with the structure.
The acetate 19 was then treated with LiOH in a mixture
THF/water to furnish epi-pathylactone A 120) in 68% yield.
Based on all data we have 11H, 13C NMR and NOESY
experiments, MM2 calculations) for the synthetic products
1pathylactone A and epi-pathylactone A), we believe that
C
1
the structure proposed bySu is correct, but some H and 13
The carbinolic proton in epi-pathylactone A 120) appeared
at 4.27 ppm 1as a multiplet), with two similar coupling
constants 1Jˆ4.2 and 2.9 Hz), which is in agreement with
Scheme 4. Preparation of epi-pathylactone A 120). 1a) DEAD, PPh3, AcOH,
CH2Cl2, 3 h, 62%; and 1b) LiOH, THF:H2O 13:1), rt, 8 h, 68%.
Figure 5. NOESY experiments with synthetic epi-pathylactone A.

1652
F. Coelho, G. Diaz / Tetrahedron 58 ꢀ2002) 1647±1656
NMR data were incorrectlyassigned, particularlythose for
the carbinolic group.
washed with a 10% solution of NH4OH 150 mL) and
distilled water 1100 mL). The organic phase was dried
over anhydrous MgSO4 and the solvent was removed
under reduced pressure. The oilyresidue was puri®ed by
¯ash column chromatography1silica gel 230±400 mesh,
hexane/ethyl acetate 50:1 v/v) to furnish ketone cis-6a
10.68 g, 15%) and ketone trans-6b 12.74 g, 62%), as color-
less oils. Ketone cis-6a: IR 1nmax, cm21, ®lm) 3073, 2964,
2938, 2871, 2353, 1708 1CO), 1641, 1458, 1386, 1319,
3. Conclusion
In conclusion, this simple and direct approach has allowed
us to construct the highlyfunctionalized carbon skeleton of
a rare type of nor-sesquiterpene from marine origin, in nine
steps from 2-methylcyclohexenone, with an overall yield of
10%. Our results suggest that the spectral data proposed for
natural pathylactone needs to be revised.
1
1141, 1034, 939, 909, 808; H NMR 1500 MHz, CDCl3) d
5.61±5.54 1m, 1H), 5.07±5.0 1m, 2H), 2.49 1dd, Jˆ14.0 and
7.6 Hz, 1H), 2.42±2.38 1m, 1H), 2.34±2.30 1m, 1H), 2.11
1dd, Jˆ14.0 and 7.0 Hz, 1H), 2.03±1.97 1m, 1H), 1.75±1.64
1m, 4H), 1.09 1s, 3H), 0.98 1d, Jˆ6.6 Hz, 3H); Ketone trans-
6b: IR 1nmax, cm21, ®lm) 3073, 2960, 2924, 2871, 2353,
1706 1CO), 1634, 1456, 1385, 1319, 1141, 1034, 909,
The above synthesis exempli®es a ¯exible approach that can
be applied to the preparation of a number of derivatives of
this class of sesquiterpenes.
1
808; H NMR 1CDCl3, 300 MHz) d 5.80±5.66 1m, 1H),
5.07±5.0 1m, 2H), 2.52 1dd, Jˆ14.0 and 8.4 Hz, 1H),
2.47±2.28 1m, 2H), 2.17 1dd, Jˆ14.0 and 8.4 Hz), 2.0±
1.87 1m, 2H), 1.85±1.75.4 1m, 1H), 1.74±1.65 1m, 1H),
1.64±1.50 1m, 1H), 1.0 1s, 3H), 0.91 1d, Jˆ7.0 Hz, 3H);
13C NMR 175.4 MHz, CDCl3) d 216.2, 135.4, 117.6, 52.3,
40.8, 38.5, 38.4, 29.1, 24.3, 18.9, 15.2; MS 170 eV, m/z):
166 1M1, 30%), 151 1100%), 133 115%), 123 145%), 109
165%), 95 162%), 70 183%), 61 192%); HRMS 1M1) Calcd
for C11H18O 166.13577; Found 166.13587.
Additional modi®cations to this strategyare ongoing in our
laboratory, aiming at the total synthesis of 1^)-napali-
lactone 12) and other non-natural spirolactone nor-sesquiter-
penes.
4. Experimental
4.1. General
1
The H and 13C NMR spectra were recorded on a Varian
4.1.2. 1-[ꢀ4-Methoxybenzyl)oxy)]-3-propyl iodide ꢀ10).
To a suspension of NaH 11.6 g, 39.6 mmol, 60% in mineral
oil, washed with dryhexane before use) in dryTHF
1220 mL), at 08C, under argon, was added 1,3-propanediol
11.3 g, 33 mmol). The resulting mixture was warmed to
room temperature and stirred for 1 h. After this time, the
mixture was cooled to 08C and, to the cooled suspension,
was added tetrabutylammonium iodide 12.44 g, 6.61 mmol)
and p-methoxybenzylchloride 1PMBCl, 5.4 mL, 39.6
mmol). The reaction mixture was warmed again to room
temperature and stirred for 24 h. The reaction mixture was
subsequently hydrolysed by the addition of a saturated
solution of NH4Cl 1100 mL) and extracted with ethyl ether
12£250 mL). The organic phase was washed with a satu-
rated solution of NH4Cl 175.4 mL), distilled water 12£
75.4 mL), brine 12£75.4 mL) and dried over anhydrous
Na2SO4. After evaporation of the solvent under reduced
pressure, the residue was puri®ed bycolumn chroma-
tography to furnish 1-[14-methoxybenzyl)oxy)]-3-propanol
15.43 g, 84%), as a colorless oil. IR 1nmax, cm21, ®lm): 3412,
3007, 2948, 2871, 2062, 1997, 1896, 1622, 1468, 1373,
Gemini BB-300 at 300 and 75.4 MHz, respectively. 1H and
13C NMR spectra were also recorded on an Inova 500 and
100 MHz, respectively. The mass spectra were recorded
using a HP model 5988 A CG/MS or an Autospec±Micro-
mass±EBE±high resolution equipment. The melting points
were measured in open capillarytubes using an electro-
thermal apparatus, model 9100, and are uncorrected.
Puri®cations and separations bycolumn chromatography
were performed on silica gel, using normal or ¯ash chroma-
tography. Ether and THF were distilled from benzophenone
ketyl under nitrogen. Dichloromethane was distilled from
CaH2. TLC visualization was achieved byspraying with
5% ethanolic phosphomolybdic acid and heating. All the
organolithium reagents were purchased from Aldrich
Chemical Co.
4.1.1. ꢀ^)-2-Allyl-2,3-dimethylcyclohexan-1-one ꢀ6a/b).
To a suspension of CuI 17.79 g, 41.0 mmol) in anhydrous
ether 190 mL) was added an ethereal solution of methyl-
lithium 165 mL, 82.0 mmol, ca. 1.25 mol dm3), at 08C,
under N2 atmosphere. After 15 min at 08C, a solution of 7
13.0 g, 27.27 mmol) in anhydrous ether 130 mL) was added
to the ethereal solution of lithium dimethylcuprate. After
60 min at 08C, the solvent was removed under reduced
pressure. 1Caution: Avoid drying the reaction media
completely as it is well known in the literature14 that some
dry RCu compounds can explode.) To the resulting wet
yellow solid was added DME 165 mL) under a N2 atmos-
phere, giving rise to a greenish black solution, to which allyl
bromide 119.0 mL, 218 mmol) was added, at 08C. The ®nal
solution was stirred for 15 min. After that, the reaction was
quenched with a saturated solution of NaHCO3 1200 mL),
1
1313, 1260, 1177, 1087, 1034, 832; H NMR 1300 MHz,
CDCl3) d 7.25 1d, Jˆ8.8 Hz, 2H), 6.87 1d, Jˆ8.8 Hz, 2H),
4.44 1s, 2H), 3.79 1s, 3H), 3.75 1t, Jˆ6.0 Hz, 2H), 3.62 1t,
Jˆ6.0 Hz), 2.65±2.25 1bs, 1H, exchangeable with D2O),
1.84 1quint, Jˆ6.0 Hz, 2H); 13C NMR 175.4 MHz,
CDCl3): d 159.2, 130.1, 129.2, 113.8, 72.8, 68.9, 61.7,
55.2, 32.0.
To a solution of the alcohol obtained above 13.0 g,
13.3 mmol) in drydichloromethane 1105 mL) was slowly
added, at 08C, triethylamine 12.3 mL, 16.8 mmol) and mesyl
chloride 11.55 mL, 20 mmol). To the resulting mixture was
added a solution of 4-dimethylaminopyridine 1DMAP) in
drydichloromethane 15 mL). The ®nal solution was stirred
for 2 h at room temperature, after which cold water
followed bythe addition of a 10% solution of NH OH
4
145 mL). The blue aqueous phase was extracted with pen-
tane 13£200 mL). The combined organic layers were

F. Coelho, G. Diaz / Tetrahedron 58 ꢀ2002) 1647±1656
1653
1100 mL) was added to the reaction and the mixture was
extracted with ethyl acetate 12£100 mL). The combined
organic layers were washed with HCl 10.1 mol dm3,
50 mL), NaHCO3 5% 12£50 mL) and brine 150 mL). The
organic layer was dried over anhydrous Na2SO4 and the
solvent was evaporated under reduced pressure. The residue
14.18 g, quantitative yield) was suf®ciently pure 1by TLC) to
be used in the next step without puri®cation.
11b: IR 1nmax, cm21, ®lm): 3459, 3079, 2954, 2936, 2859,
1616, 1527, 1468, 1367, 1307, 1248, 1183, 1111, 1046, 927,
826; 1H NMR 1300 MHz, CDCl3) d 7.26 1d, Jˆ8.8 Hz, 2H),
6.87 1d, Jˆ8.8 Hz, 2H), 6.14 1m, 1H), 5.08 1m, 1H), 5.01 1m,
1H), 4.43 1s, 2H), 3.80 1s, 3H), 3.50±3.40 1m, 2H), 2.37 1dd,
Jˆ10.0 and 9.5 Hz, 1H), 2.25±2.13 1m, 2H), 1.95 1sl,
exchangeable with D2O, 1H), 1.79±1.22 1m, 10H), 0.85
1d, Jˆ6.6 Hz, 3H), 0.78 1s, 3H); 13C NMR 175.4 MHz,
CDCl3) d 159.0, 138.8, 130.6, 129.2, 116.2, 113.7, 77.4,
72.3, 70.8, 55.2, 44.7, 39.9, 33.3, 31.8, 31.5, 30.2, 23.4,
21.1, 17.3, 16.1; MS 170 eV, m/z): 346 1M1, 3%), 287
12%), 207 16%), 121 1100%), 77 17%); HRMS 1M1)
Calcd for C22H34O3 346.25080; Found: 346.25072.
To a solution of the mesylate 14.10 g, 15.0 mmol) in acetone
1156 mL) was added sodium iodide 111.25 g, 75.4 mmol).
The resulting mixture was re¯uxed, under argon, for 6 h.
After cooling to room temperature, distilled water 1260 mL)
was added and the mixture was extracted with ethyl ether
12£200 mL). The combined organic layers were washed
with brine 12£130 mL). The aqueous phases were combined
and extracted with more ethyl ether 12£200 mL). The
organic layers were combined and dried over anhydrous
Na2SO4. After evaporation of the solvent, the residue was
puri®ed bycolumn chromatographyto furnish iodide 11
14.5 g, 98%). IR 1nmax, cm21, ®lm) 3001, 2936, 2894,
2865, 1616, 1581, 1521, 1462, 1373, 1307, 1248, 1177,
4.1.4. ꢀ^)-6-Allyl-1-[3-ꢀ4-methoxybenzyloxy)propyl]-5,6-
dimethylcyclohex-1-ene ꢀ5). To a stirred solution of the
diastereoisomeric alcohols 11a/b 10.34 g, 1.0 mmol) in dry
pyridine 16 mL) was added 1,8-diazabicyclo[4.3.0]undec-7-
ene 1DBU, 0.28 mL, 3.0 mmol) and phosphorus oxychloride
1POCl3, 0.45 mL, 3.0 mmol), at 08C. The resulting mixture
was stirred at room temperature for 24 h, after which the
reaction was cooled to 08C and acetyl acetate 130 mL) and
cold water 130 mL) were then carefullyadded. The organic
phase was separated, washed successivelywith water
11£20 mL), and brine 11£20 mL) and dried over MgSO4.
After evaporation of the solvent, the residue was puri®ed by
column chromatographyto furnish alkene 5 10.25 g, 78%),
contaminated with a small amount of the exo alkene 1#5%,
as determined byGC on a HP column). Alkene 5 was used
in the next step without puri®cation. IR 1nmax, cm21, ®lm)
3079, 2966, 2924, 2853, 1616, 1521, 1474, 1248, 1093,
1
1093, 1034, 826; H NMR 1300 MHz, CDCl3) d 7.26 1d,
Jˆ8.8 Hz), 6.88 1d, Jˆ8.8 Hz, 2H), 4.44 1s, 2H), 3.80 1s,
3H), 3.51 1t, Jˆ6.0 Hz, 2H), 3.29 1t, Jˆ6.7 Hz, 2H), 2.07
1quint, Jˆ6.0 Hz, 2H); 13C NMR 175.4 MHz, CDCl3) d
159.2, 130.3, 129.3, 113.8, 72.7, 69.3, 55.2, 33.5, 3.5.
4.1.3. ꢀ^)-2-Allyl-1-[3-ꢀ4-methoxybenzyloxy)propyl]-2,3-
dimethylcyclohexan-1-ol ꢀ11a/b). To a stirred solution of
the iodide 10 10.91 g, 3.0 mmol) in anhydrous ether 120 mL)
was added t-butyllithium 14.48 mL, 3.0 mmol) at 2238C,
under a N2 atmosphere. The resulting solution was stirred
for 20 min at 2238C and allowed to warm to 08C, before a
solution of the ketone 6b 10.33 g, 2.0 mmol) in anhydrous
ether 120 mL) was slowlyadded 1via canula). The ®nal solu-
tion was stirred for 60 min at 08C. The reaction medium was
quenched with a saturated solution of NH4Cl 113 mL) and
extracted with ether 12£65 mL). The combined organic
layers were washed with a saturated solution of NH4Cl
140 mL), distilled water 12£40 mL) and ®nallybrine
12£40 mL). The combined aqueous layers were extracted
twice with ether 165 mL). The combined organic layers
were dried over MgSO4, and the solvent was removed
under reduced pressure. The mixture of diastereoisomeric
alcohols 150:50 ratio byCG) was easilyseparated by¯ash
column chromatography1silica gel 230±400 mesh, hexane/
ethyl acetate 99:1 and 95:5 v/v) to furnish the alcohol 11a
10.24 g, 46% based on the recovered starting material) and
the alcohol 11b 10.24 g, 46% based on the recovered starting
material). Alcohol 11a: IR 1nmax, cm21, ®lm) 3459, 3079,
2936, 2871, 1616, 1515, 1474, 1373, 1313, 1248, 1183,
1
1040, 820; H NMR 1300 MHz, CDCl3) d 7.26 1d, Jˆ
8.8 Hz, 2H), 6.87 1d, Jˆ8.8 Hz, 2H), 5.67±5.53 1m, 1H),
5.43 1bs, 1H), 5.03±4.94 1m, 2H), 4.43 1s, 2H), 3.79 1s, 3H),
3.46 1t, Jˆ6.6 Hz, 2H), 2.32±2.24 1m, 1H), 2.12 1dd,
Jˆ14.8 and 8.4 Hz, 1H), 2.05±1.92 1m, 4H), 1.79±1.63
1m, 3H), 1.53±1.31 1m, 2H), 0.87 1s, 3H), 0.84 1d, Jˆ
7 Hz, 3H); 13C NMR 175.4 MHz, CDCl3) d 159.0, 142.1,
135.9, 130.7, 129.2, 121.8, 116.2, 113.7, 72.4, 70.1, 55.2,
41.4, 40.7, 33.9, 28.8, 26.9, 26.5, 24.9, 20.8, 15.7; MS
170 eV, m/z): 328 1M1, 2%), 287 12%), 207 16%), 121
1100%), 77 17%); HRMS 1M1) Calcd for C22H32O2
328.24043; Found: 328.25042.
4.1.5. ꢀ^)-2-Allyl-1-[ꢀ3-methoxybenzyloxy)propyl)]-2,3-
dimethyl-7-oxabicyclo[4.1.0]heptane ꢀ4). To a stirred
solution of alkene 5 10.3 g, 0.91 mmol) in dichloromethane
115 mL) was added m-chloroperbenzoic acid 1MCPBA,
77%; 0.225 g, 1.0 mmol) at 08C. The reaction mixture was
then stirred at 08C for 8 h, after which, a 2 mol21 solution of
potassium hydroxide 13.0 mL) was added and the organic
phase separated. The aqueous phase was re-extracted with
dichloromethane 13£10 mL). The combined organic layers
were dried over MgSO4, and the solvent was removed under
reduced pressure. The residue was puri®ed bysilica gel
column chromatography1ethly acetate/hexane, 2:98) to
furnish the epoxides 4a and b, as a mixture of diastereo-
isomers 10.276 g, 88%). IR 1nmax, cm21, ®lm) 3073, 2954,
1
1099, 1046, 915, 826, 749; H NMR 1300 MHz, CDCl3) d
7.26 1d, Jˆ8.8 Hz, 2H), 6.88 1d, Jˆ8.8 Hz, 2H), 6.10 1m,
1H), 5,.07 1m, 1H), 5.02 1m, 1H), 4.44 1s, 2H), 3.80 1s, 3H),
3.49±3.45 1m, 2H), 2.24±2.11 1m, 2H), 2.0±1.92 1m, 1H),
1.81±1.67 1m, 2H), 1.64±1.43 1m, 2H), 1.39±1.21 1m, 2H),
1.0 1s, 3H), 0.84 1d, Jˆ6.6 Hz, 3H); 13C NMR 175.4 MHz,
CDCl3) d 159.1, 138.3, 130.7, 129.1, 116.5, 113.7, 77.3,
72.3, 70.7, 55.2, 45.1, 41.5, 37.5, 30.8, 30.3, 30.1, 23.3,
22.0, 16.6, 13.0; MS 170 eV, m/z): 346 1M1, 3%), 287
12%), 207 16%), 121 1100%), 77 17%); HRMS 1M1)
Calcd for C22H34O3 346.25080; Found: 346.25072; Alcohol
1
2936, 2853, 1640, 1616, 1587, 1509; H NMR 1300 MHz,
CDCl3) d 7.24 1d, Jˆ8.8 Hz, 2H), 6.87 1d, Jˆ8.8 Hz, 2H),
6.04±5.90 1m, 1H), 5.84±5.71 1m, 1H), 5.09±4.98 1m, 2H),
4.41 1s, 2H), 3.79 1s, 3H), 3.58 1dd, Jˆ13.4 and 7.0 Hz, 1H),
3.48±3.34 1m, 2H), 3.08 1bs, 1H), 2.40±2.12 1m, 3H), 2.04±

1654
F. Coelho, G. Diaz / Tetrahedron 58 ꢀ2002) 1647±1656
1.08 1m, 10H), 0.89 1s, 3H), 0.76 1d, Jˆ6.0 Hz, 3H), 0.74 1d,
Jˆ6.0 Hz, 3H); 13C NMR 175.4 MHz, CDCl3) d 159.0,
134.0, 131.0, 129.5, 121.8, 117.5, 114.0, 72.2, 71.5, 64.0,
59.0, 42.0, 40.0, 39.5, 34.5, 29.5, 28.5, 27.5, 24.5, 24.0,
22.0, 18.5, 17.5; MS 170 eV, m/z): 344 1M1, 2%), 303
12%), 223 12%), 167 112%), 138 117%), 121 1100%);
HRMS 1M1) Calcd for C22H32O2 344.23515; Found:
344.23548.
silica gel column chromatography1hexane/ethly acetate
95:5) to give 12 10.153 g, 92%), as a colorless oil. IR
1nmax, cm21, ®lm): 3071, 2957, 2930, 2887, 1637, 1484,
1
1382, 1257, 1062, 910, 839, 785; H NMR 1300 MHz,
CDCl3) d 6.10±5.96 1m, 1H), 4.96±4.88 1m, 2H), 3.85±
3.66 1m, 2H), 3.55 1m, 1H), 2.26 1m, 1H), 2.17±1.26 1m,
10H), 2.0±1.78 1m, 5H), 0.93 1s, 3H), 0.91 1s, 9H), 0.84 1d,
Jˆ6.9 Hz, 3H); 0.06 1s, 6H). 13C NMR 175.4 MHz, CDCl3)
d 138.1, 114, 89.7, 72.8, 67.9, 43.5, 41.7, 34.7, 29.4, 26,
25.9, 25.6, 18.1, 17.6, 16.3, 24.1; MS 170 eV, m/z): 338
1M1, 90%), 281 190%), 239 126%), 165 180%), 115
1100%), 75 192%); HRMS 1EI): m/z Calcd for C20H38O2Si
[M]1 338.26411; Found 338.26416.
4.1.6. ꢀ^)-10-Allyl-9,10-dimethyl-1-oxaspiro[4.5]decan-
6-ol ꢀ3a/b). To a stirred solution of epoxyether 4a/b
1276 mg, 0.8 mmol) in a mixture of CH2Cl2 120 mL) and
H2O 11.11 mL) was added DDQ 10.274 g, 1.2 mmol). The
reaction medium was stirred at room temperature for 2.5 h.
The reaction mixture was then diluted byaddition of a satu-
rated solution of NaHCO3 120 mL) and the aqueous phase
was extracted with ethyl ether 13£50 mL). The organic layer
was separated and washed successivelywith a saturated
solution of NaHCO3, and then NaCl and dried over
MgSO4. After evaporation under reduced pressure, the resi-
due was puri®ed bysilica gel 1230±400 mesh) column
chromatography1hexane/ethly acetate 95:5) to provide
ethers 3a and b 10.088 and 0.070 g, respectively, 88%
4.1.8. 1-[ꢀ^)-10-t-Butyldimethylsilyloxy-6,7-dimethyl-1-
oxaspiro[4.5]dec-1-yl]acetone ꢀ13). To a stirred solution
of silyl spiroether 12 10.131 g, 0.19 mmol) in N,N-dimethyl-
acetamide 10.58 mL) were added PdCl2 10.034 g, 0.19
mmol), Cu1OAc)2´H2O 10.078 g, 0.39 mmol) and water
10.083 mL). The resulting suspension was stirred at room
temperature, under an enriched oxygen atmosphere, for 3
days. The reaction mixture was then quenched with a
3 mol21 solution of hydrogen chloride 10.5 mL) and
extracted with ethyl ether 15£20 mL). The combined
organic layers were washed successively with a solution
of NaHCO3 12£25 mL) and brine 12£30 mL), dried over
MgSO4 and the solvent was evaporated under reduced
pressure. The residue was puri®ed bysilica gel column
chromatography1ethyl acetate/hexane 20:80) to furnished
methyl ketone 13 10.077 g, 56%), as a colorless oil. IR
1nmax, cm21, ®lm): 2956, 2932, 2886, 2857, 1709, 1470,
yield), as colorless oils. Spiroether 3a: IR 1nmax, cm21
,
®lm): 3446, 3072, 2941, 2879, 1634, 1459, 1391, 1067,
1
1036, 911; H NMR 1300 MHz, CDCl3) d 5.99±5.85 1m,
1H), 5.01±4.97 1m, 1H), 4.95±4.94 1m, 1H), 3.86±3.79 1m,
2H), 3.75 1t, Jˆ7.5 Hz, 1H), 2.35 1dd, Jˆ14.6, 7.3 Hz, 1H),
2.24 1dd, Jˆ14.6 and 7.3 Hz, 1H), 2.10±1.79 1m, 6H), 1.65±
1.36 1m, 3H), 0.93 1s, 3H), 0.89 1d, 3H, Jˆ7.3 Hz); 13C
NMR 175.4 MHz, CDCl3) d 137.1, 115.6, 90.2, 72.4, 68.4,
43.9, 40.7, 34.4, 28.0, 27.9, 27.0, 25.6, 18.4, 15.8; MS
170 eV, m/z): 224 1M1, 30%), 183 110%), 165 130%), 113
1100%), 97 120%), 71 132%), 55 156%); HRMS 1EI): m/z
Calcd for C14H24O2 [M]1 224.17763, Found 224.17721;
Calcd for C14H24O2 74.95; H 10.78%, Found C 74.91; H
10.74%. Spiroether 3b: IR 1nmax, cm21, ®lm): 3442, 3073,
1
1366, 1256, 1134, 1058, 942, 838; H NMR 1300 MHz,
CDCl3) d 3.74±3.67 1m, 1H), 3.61±3.53 1m, 2H), 2.41±
2.24 1m, 3H), 2.12 1s, 2H), 2.05±1.78 1m, 5H), 1.66±1.26
1m, 3H), 0.98 1s, 3H), 0.89 1s, 9H), 0.88 1d, Jˆ6.6 Hz, 3H),
0.05 1s, 6H); 13C NMR 175.4 MHz, CDCl3) d 207.5, 89.23,
70.9, 66.8, 49.8, 46.9, 34.2, 31.9, 29.1, 28.0, 25.9, 25.6,
24.51£2), 18.6, 16.9, 24.2, 25.1; MS 170 eV, m/z): 354
1M1, 17%), 297 150%), 239 1100%), 198 125%), 153
145%), 111 185), 75 190%); Calcd for C20H38O3Si [M]1
354.25902; Found 354.25907.
1
2972, 2938, 2878, 1635, 1467, 1386, 1064, 909; H NMR
1300 MHz, CDCl3) d 6.05±5.91 1m, 1H), 5.0±4.9 1m, 2H),
3.98±3.91 1m, 2H), 3.87 1t, 1H, Jˆ7 Hz), 2.19 1dd, Jˆ15.0
and 7.3 Hz, 1H), 2.06 1dd, Jˆ15.0 and 7.3 Hz, 1H), 2.0±
1.78 1m, 5H), 1.53±1.27 1m, 4H), 0.90 1s, 3H), 0.85 1d, 3H,
Jˆ6.6 Hz). 13C NMR 175.4 MHz, CDCl3) d 137.4, 114.6,
92.3, 76.6, 69.8, 44.6, 41.1, 37.5, 30.5, 28.7, 27.1, 24.9,
15.9, 13.9; MS 170 eV, m/z): 224 1M1, 55%), 209 15%),
183 18%), 165 196%), 153 110%), 113 1100%), 97 130%),
85 125%), 71 153%), 55 145%); HRMS 1EI): m/z Calcd for
C14H24O2 [M]1 224.17763; Found 224.17790. Calcd for
C14H24O2 74.95%, H 10.78%; Found C 74.94%, H 10.77%.
4.1.9. ꢀ^)-10-Hydroxy-6,7-dimethyl-6-ꢀ2-oxopropyl)-1-
oxaspiro[4,5]decan-2-one ꢀ1). To a stirred solution of
silyl methylketone 13 10.057 g, 0.16 mmol) in ethyl acetate
10.6 mL) were added RuCl3´H2O 10.007 g, 0.032 mmol) and
a 10% aqueous solution of NaIO4 11.71 mL, 0.8 mmol). The
suspension was stirred at room temperature for 23 h, after
which, the reaction mixture was quenched with a saturated
solution of Na2S2O3 and extracted with ethyl acetate
13£20 mL). The combined organic layers were dried over
Na2SO4, and the solvent was evaporated under reduced
pressure. The residue was puri®ed bysilica gel column
chromatography1hexane/ethyl acetate 90:10) to furnish a
4.1.7. ꢀ^)-6-tert-Butyldimethylsilyloxy-10-allyl-9,10-di-
methyl-1-oxaspiro[4.5]-decan-6 ꢀ12). To a stirred solution
of spiroether 3a 10.11 g, 0.49 mmol) in dichloromethane
was added triethylamine 1275.4 mL, 2.0 mmol) at 08C.
The resulting solution was stirred for 5 min, after which
t-butyldimethylsilane tri¯ate 1TBSOTf, 226 mL, 0.98
mmol) was added and the reaction mixture was allowed to
warm to room temperature and then stirred for 1 h. After
that, the reaction mixture was quenched with a saturated
solution of ammonium chloride 114 mL) and extracted
with dichloromethane 13£20 mL). The combined organic
layers were dried over MgSO4 and the solvent was evapo-
rated under reduced pressure. The residue was puri®ed by
spirolactone 14 10.0495 g, 88%), as an oil. IR 1nmax, cm21
,
®lm): 2955, 2931, 2883, 2859, 1777, 1705, 1471, 1259,
1
1255, 1189, 1057, 1020, 840, 780; H NMR 1500 MHz,
CDCl3) d 3.94 1dd, Jˆ10.0 and 5.0 Hz, 1H), 2.73 1d, Jˆ
14.0 Hz, 1H), 2.58 1d, Jˆ14.0 Hz, 1H), 2.52±2.15 1m, 4H),
2.17 1s, 3H), 1.81±1.46 1m, 5H), 1.09 1s, 3H), 0.97 1d, Jˆ
7.3 Hz, 3H), 0.88 1s, 9H), 0.08 1s, 3H), 0.06 1s, 3H); 13C
NMR 1125 MHz, CDCl3) d 208.5, 176.4, 92.3, 72.2, 48.1,
45.4, 34.1, 32.9, 29.1, 28.1, 25.8, 25.7, 23.7, 17.9, 17.1,

F. Coelho, G. Diaz / Tetrahedron 58 ꢀ2002) 1647±1656
1655
1
16.2, 24.4, 25.0; MS 170 eV, m/z): 368 1M1, 10%), 311
120%), 253 1100%), 171 113%), 119 117%), 75 143%), 74
138%); HRMS 1EI): m/z Calcd for C20H36O4Si 368.23829;
Found 368.23823; Calcd for C20H36O4Si C 65.17, H 9.84%;
Found C 65.12, H 9.81%.
1081, 840; H NMR 1300 MHz, CDCl3) d 3.86±3.79 1m,
2H), 3.63±3.56 1m, 1H), 2.5±2.25 1m, 2H), 2.18 1s, 3H),
2.13±1.6 1m, 5H), 1.39±1.26 1m, 4H), 1.19 1s, 3H), 0.88 1s,
9H), 0.82 1d, Jˆ6.6 Hz, 3H), 0.06 1s, 6H); 13C NMR
175.4 MHz, CDCl3) d 208.7, 91.3, 74.2, 69.0, 52.8, 47.5,
38.4, 31.6, 29.8, 28.2, 26.6, 26.0, 25.3, 18.1, 16.1, 15.7,
24.4; MS 170 eV, m/z): 354 1M1, 20%), 297 150%), 239
195%), 198 118%), 111 180%), 75 195%), 74 1100%); HRMS
1EI): m/z Calcd for C14H38O3Si 354.25902; Found
354.25899.
A stirred solution of silyl spirolactone 14, prepared as
described earlier 10.041 g, 0.11 mmol) in a mixture of aceto-
nitrile/hydrogen ¯uoride 1CH3CN:HF, 1:1; 2 mL, 48% w/v
of HF in water), was stirred, at room temperature, for 2 h.
After that, the reaction mixture was diluted with distilled
water 13 mL) and a saturated solution of NaHCO3 12 mL).
Then, the aqueous phase was extracted with dichloro-
methane 12£10 mL). The combined organic phases were
dried over Na2SO4 and evaporated under reduced pressure.
The residue was puri®ed bysilica gel 170±230 mesh)
column chromatography1hexane/ethly acetate 70:30) to
provide 1 10.026 g, 90%) as a viscous oil, which slowly
crystallizes on standing. Mp 43±458C 1recrystallized from
cold hexane); IR 1nmax, cm21, ®lm): 3460, 2932, 2886, 1778
1O±CvO), 1709 1CvO), 1470, 1360, 1256, 1232, 1198,
4.1.12.
ꢀ^)-30,50,60-Trimethyl-3,4-dihydro-5H-spiro-
[furan-2,90-[2]oxabicyclo[3.3.1]non[3]en]-5-one ꢀ18). To
a stirred solution of 16 10.03 g, 0.08 mmol) in ethyl acetate
10.3 mL) was added RuCl3´H2O 10.004 g, 0.016 mmol) and
a 10% aqueous solution of NaIO4 10.9 mL, 0.4 mmol). The
suspension was stirred at room temperature for 23 h, after
which, the reaction mixture was quenched with a saturated
solution of Na2S2O3 and extracted with ethyl acetate
13£10 mL). The combined organic phases were dried over
Na2SO4 and the solvent was evaporated under reduced
pressure. The residue was puri®ed bysilica gel column
chromatography1hexane/ethyl acetate 90:10) to furnish 17
10.026 g, 84%), as an oil. IR 1nmax, cm21, ®lm): 2953, 2927,
2856, 2859, 1776, 1700, 1466, 1259, 1221, 1098, 1014, 839,
781, 671; 1H NMR 1500 MHz, CDCl3) d 3.82±3.78 1m, 1H),
2.73 1d, Jˆ14.0 Hz, 1H), 2.58 1d, Jˆ14.0 Hz, 1H), 2.52±
2.15 1m, 4H), 2.17 1s, 3H), 1.81±1.46 1m, 5H), 1.09 1s, 3H),
0.97 1d, Jˆ7.3 Hz, 3H), 0.88 1s, 9H), 0.08 1s, 3H), 0.06 1s,
3H); 13C NMR 1125 MHz, CDCl3) d 209.8, 177.2, 93.0,
72.2, 53.5, 46.6, 37.5, 31.8, 31.3, 30.4, 27.8, 21.8, 17.9,
15.7, 15.3, 24.9; MS 170 eV, m/z): 368 1M1, 5%), 311
190%), 253 1100%), 185 140%), 123 190%), 75 195%);
HRMS 1EI): m/z Calcd for C14H22O4 368.23829; Found
368.23807.
1
1006; H NMR 1500 MHz, CDCl3) d 3.99 1dd, Jˆ10.9
and 4.27 Hz, 1H), 2.77 1d, Jˆ15.5 Hz, 1H), 2.67 1d, Jˆ
15.5 Hz, 1H), 2.71±2.64 1m, 1H), 2.58±2.46 1m, 1H),
2.41±2.33 1m, 2H), 2.29 1bs, 1H), 2.26±2.21 1m, 1H),
2.17 1s, 3H), 1.90±1.84 1m, 1H), 1.78±1.73 1m, 1H),
1.68±1.60 1m, 1H), 1.50±1.44 1m, 1H), 1.14 1s, 3H), 0.98
1d, Jˆ7.5 Hz, 3H). 13C NMR 1125 MHz, CDCl3) d 208.7,
177.3, 93.1, 71.1, 47.6, 45.1, 33.7, 32.9, 29.4, 27.0, 25.7,
23.4, 17.2, 15.9; MS 170 eV, m/z): 254 15%), 236 112%),
221 13%), 197 130%), 179 177%), 167 185%), 152 150%),
149 155%), 125 130%), 115 125%), 111 113%), 85 123%), 71
120%), 57 135%); HRMS 1EI): m/z Calcd for C14H22O4
254.151809; Found 254.151805; Calcd for C14H22O4
66.12, H 8.72%; Found C 66.10, H 8.70%.
C
4.1.10. ꢀ^)-6-Allyl-10-t-butyldimethylsilyloxy-6,7-dimethyl-
1-oxaspiro[4.5]decane ꢀ15). This compound was prepared
using the same experimental protocol described earlier for
compound 13, using spiroether 3b 10.05 g, 0.223 mmol) as
starting material. Chromatographic puri®cation 1hexane/
ethyl acetate 90:10) furnished 0.071 g 194%) of 15, as a
colorless oil. IR 1nmax, cm21, ®lm): 3072, 2954, 2929,
A solution of silyl spirolactone 17 10.020 g, 0.05 mmol) in a
mixture of acetonitrile/hydrogen ¯uoride 1CH3CN:HF, 1:1;
1 mL, 48% w/v of HF in water) was stirred, at room
temperature, for 2 h. After that, the reaction mixture was
diluted with distilled water 13 mL) and a saturated solution
of NaHCO3 12 mL). Then, the aqueous phase was extracted
with dichloromethane 12£10 mL). The combined organic
phases were dried over Na2SO4 and evaporated under
reduced pressure. The residue was puri®ed bysilica gel
170±230 mesh) column chromatography1hexane/ethly
acetate 70:30) to provide 18 10.011 g, 90%) as a viscous
oil. IR 1nmax, cm21, ®lm): 2966, 2929, 2873, 1777, 1677,
1453, 1383, 1204, 1036, 818; 1H NMR 1300 MHz, CDCl3) d
4.1 1d, Jˆ0.7 Hz, 1H), 3.89 1bs, 1H), 2.56±2.49 1m, 2H),
2.32±2.22 1m, 1H), 2.18±1.96 1m, 2H), 1.75 1d, Jˆ0.7 Hz,
3H), 1.66±1.46 1m, 2H), 1.35±1.21 1m, 2H), 1.13 1d, Jˆ
7.3 Hz, 3H), 0.98 1s, 3H); 13C NMR 175.4 MHz, CDCl3) d
176.6, 150.6, 103.5, 86.3, 76.3, 40.0, 39.0, 28.2, 27.7, 25.0,
24.9, 19.3, 18.8, 16.3; Calcd for C14H20O3 C 71.16, H
8.53%; Found C 71.12, H 8.50%.
1
2885, 2860, 1634, 1466, 1248, 1092, 837, 675; H NMR
1500 MHz, CDCl3) d 6.03±5.94 1m, 1H), 4.96±4.88 1m,
2H), 3.86±3.82 1m, 3H), 2.24±2.21 1m, 1H), 2.08±2.03
1m, 2H), 1.92±1.86 1m, 1H), 1.84±1.69 1m, 3H), 1.50±
1.26 1m, 4H), 0.9 1s, 3H), 0.88 1m, 9H), 0.85 1d, Jˆ
6.6 Hz, 3H), 0.06 1s, 6H); 13C NMR 1125 MHz, CDCl3) d
137.8, 114.2, 91.4, 74.0, 69.0, 44.7, 41.3, 37.6, 29.5, 28.7,
26.9, 25.9, 25.7, 18.0, 16.1, 14.1, 24.6; MS 170 eV, m/z):
338 1M1, 24%), 281 190%), 239 130%), 211 15%), 190
140%), 165 185%), 147 170%), 75 1100%); HRMS 1EI):
m/z Calcd for C14H38O2Si 338.26411; Found 338.26415.
4.1.11. 1-[ꢀ^)-10-Ethoxy-6,7-dimethyl-1-oxaspiro[4.5]-
dec-6-yl]acetone ꢀ16). This compound was prepared
following the same experimental protocol described earlier
for compound 13, using the silyl spiroether 15 10.061 g,
0.18 mmol) as starting material. Chromatographic puri®-
cation 1hexane/ethyl acetate 80:20) gave methylketone 16
10.032 g, 50%) as a colorless oil. IR 1nmax, cm21, ®lm):
2955, 2931, 2889, 2859, 1707, 1459, 1357, 1255, 1093,
4.1.13. ꢀ^)-epi-Pathylactone A ꢀ20). To a stirred solution
of 1 15 mg, 0.0196 mmol), at 08C, in drydichloromethane
11.5 ml) was added PPh3 11 mg, 0.039 mmol), diethyl azo-
dicarboxylate 1DEAD, 6 mg, 6 mL, 0.039 mmol) and acetic
acid 12 mg, 2.5 mL, 0.039 mmol). The resulting solution
was stirred at room temperature for 6 h, after which the

1656
F. Coelho, G. Diaz / Tetrahedron 58 ꢀ2002) 1647±1656
reaction mixture was diluted with dichloromethane
110 mL). The organic phase was washed with brine
12£5 mL), dried over Na2SO4 and was evaporated under
reduced pressure. The residue was puri®ed bysilica gel
column chromatography1hexane/ethly acetate 90:10) to
furnish 19 13.6 mg, 62%), as a viscous yellow tinged oil.
IR 1nmax, cm21, ®lm): 2953, 2927, 1776, 1721, 1710, 1238,
1014; 1H NMR 1500 MHz, CDCl3) d 4.72 1dd, Jˆ10.1 and
3.9 Hz, 1H), 2.73 1d, Jˆ14.0 Hz, 1H), 2.58 1d, Jˆ14.0 Hz,
1H), 2.52±2.15 1m, 4H), 2.2 1s, 3H), 2.17 1s, 3H), 1.81±1.46
1m, 5H), 1.09 1s, 3H), 0.97 1d, Jˆ7.3 Hz, 3H), 0.88 1s, 9H),
0.08 1s, 3H), 0.06 1s, 3H); 13C NMR 1125 MHz, CDCl3) d
209.8, 177.2, 170.3, 98.0, 72.2, 53.5, 50.8, 46.6, 37.5, 31.8,
31.3, 30.4, 27.8, 21.8, 17.9, 15.7; MS 170 eV, m/z): 296
1M1, 5%), 281 123%), 254 190%), 237 170%), 43 1100%);
HRMS 1EI): m/z Calcd for C16H24O5 296.1623; Found
296.1620.
References
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mixture of THF/water 13:1, 1.5 mL), at room temperature,
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tion mixture was evaporated and dissolved in ethyl acetate
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evaporated under reduced pressure. The residue was puri-
®ed bysilica gel 170±230 mesh) column chromatography
1hexane/ethyl acetate 80:20) to provide 20 12.2 mg, 72%) as
an amorphous solid. Mp 44±478C 1recrystallized from cold
hexane) IR 1nmax, cm21, ®lm): 2966, 2929, 2873, 1777,
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1
1707, 1453, 1383, 1204, 1036, 818; H NMR 1500 MHz,
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CDCl3) d 4.27 1m, 1H), 2.80±2.73 1two doublet, Jˆ
15.1 Hz, 2H), 2.67±2.48 1m, 2H), 22.38 1m, 1H), 2.30
1m, 2H), 2.09 1s, 3H), 2.0±1.78, 1m, 2H), 1.79±1.44 1m,
2H), 0.96 1d, Jˆ7.7 Hz, 3H), 1.12 1s, 3H); 13C NMR
175.4 MHz, CDCl3) d 207.0, 177.0, 92.0, 65.0, 47.0, 45.3,
33.7, 32.2, 29.0, 27.0, 26.0, 24.0, 17.2, 15.9; MS 170 eV,
m/z): 254 115%), 236 112%), 221 13%), 197 130%), 179
177%), 167 185%), 152 150%), 149 155%), 125 130%), 115
125%), 111 113%), 85 123%), 71 120%), 57 135%); HRMS
1EI): m/z Calcd for C14H22O4 254.151809; Found
254.151805.
12. Smith, A. B.; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett.
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13. Prestch, E.; Simon, W.; Clerc, T.; Bieman, T. In Table of
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14. Posner, G. H. Org. React. 1972, 9, 1.
15. All attempts to get copies of the spectra 11H and 13C NMR)
and/or a sample of natural product failed.
16. Mitsunobu, O. Synthesis ꢀStuttgart) 1981, 1, 1±28.
The 1H 1500 MHz) and 13C NMR 1125 MHz) spectra of 1 is
provided as SupplementaryMaterial.
Acknowledgements
We thank CNPq for fellowships to G. D. and F. C. 1301369/
87-9) and FAPESP for a grant 1#1996/04293-2). We thank
Professor C. Collins for the revision of this text.