Cycloisomerization of 1,6-enynes in organoaqueous medium: An efficient and eco-friendly access to furan derivatives. Synthesis of a key intermediate of podophyllotoxin

Article abstract of DOI:10.1016/S0040-4020(01)00368-4

The first cycloisomerization of enynes catalyzed by Pd(TPPTS)₃ catalyst in aqueous medium to give functionalized furans is described. This new reaction has been applied to the synthesis of podophyllotoxin analog.

Full text of DOI:10.1016/S0040-4020(01)00368-4

TETRAHEDRON
Pergamon
Tetrahedron 57 /2001) 5137±5148
Cycloisomerization of 1,6-enynes in organoaqueous medium: an
ef®cient and eco-friendly access to furan derivatives.
Synthesis of a key intermediate of podophyllotoxin
p
Ã
Jean-Christophe Galland, Sonia Dias, Monique Savignac and Jean-Pierre Genet
 Á Â
Ecole Nationale Superieure de Chimie de Paris, Laboratoire de Synthese Selective Organique et Produits Naturels, UMR CNRS 7573, 11,
rue Pierre et Marie Curie, 75231 Paris, France
Dedicated to Professor Barry M. Trost on the occasion of his 60th birthday
Received 5 February 2001; revised 28 February 2001; accepted 1 March 2001
AbstractÐThe ®rst cycloisomerization of enynes catalyzed by Pd/TPPTS)3 catalyst in aqueous medium to give functionalized furans is
described. This new reaction has been applied to the synthesis of podophyllotoxin analog. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
isomerization; in the latter case, a catalytic amount of acetic
acid and of a phosphine is frequently required to run the
reaction correctly. Palladium-catalyzed cycloisomerization
can be applied to a large variety of 1,6-enynes substituted in
the four position by a carbon5 or another heteroelement
such as nitrogen6a or oxygen.6b Enediynes,7a triynes7b and
polyenynes7c may also be used to generate polycyclic
compounds. The reaction is tolerant towards various func-
tional groups including esters, alcohols, ethers and ketals.
Therefore, several natural products have been synthesized
using palladium-catalyzed cycloisomerization as a key step
and taking advantage of the resulting 1,3-dienic frame-
work.8 The most recent developments of the reaction deal
with the use of other transition metals including rhodium,9
ruthenium,10 platinum11 and titanium12 or the use of chiral
ligands to control the stereoselectivity.13
Green chemistry has emerged as a major concern in the ®eld
of chemistry and especially organic chemistry. In academic
and industrial laboratories, the idea to devise new processes
that are at the same time ef®cient, straightforward and
respectful of the environment has slowly asserted itself as
a natural way to conduct organic synthesis. Trost has given a
determining contribution to this new `eco-friendly' way of
thinking by introducing the principle of `atom economy';1
optimizing a chemical process by utilizing simple substrates
and minimizing the number of reactants can obviously lead
to a dramatic decrease of the wastes and ef¯uents. A striking
example of an `atom-economical' reaction is the palladium-
catalyzed cycloisomerization of enynes.2 In this process,
1,6- or 1,7-enynes can be directly converted to the corre-
sponding cyclic dienes as depicted in Scheme 1.
In the course of our studies on homogeneous catalysis in
organoaqueous medium,14 we thought it would be advan-
tageous to run the palladium-catalyzed cycloisomerization
of 1,6-enynes using a water-soluble catalyst. Indeed, the use
This reaction offers an ef®cient access to ®ve- or six-
membered rings by using easily accessible starting
materials. Both Pd/II)3 and Pd/0)4 can catalyze the cyclo-
Scheme 1.
Keywords: carbohydroxypalladation; organoaqueous medium; enynes; palladium; podophyllotoxin.
Corresponding author. Tel.: 133-1-4427-6743; fax: 133-1-4407-1062; e-mail: genet@ext.jussieu.fr
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020/01)00368-4

5138
J.-C. Galland et al. / Tetrahedron 57 02001) 5137±5148
of an `eco-friendly' solvent such as water and the ability to
recover the catalyst by a simple decantation offer two
supplementary economical and ecological assets.
Careful NMR analysis showed that this new product was the
4-a-hydroxyfuran derivative 2. The experimental condi-
tions were optimized in order to improve the yield of the
reaction. As can be seen in Table 1, the 3-exomethylene-4-
a-hydroxyfuran turned out to be very sensitive to acidic
media and consequently to the puri®cation conditions. Silica
gel or neutral alumina were too aggressive and led to an
extensive decomposition of the product. Fortunately,
Florisilw was suf®ciently neutral to isolate the furan in
good conditions. The solvent used concomitantly with
water appeared to have a great in¯uence on the activity of
the catalyst. The reaction turned out to be very sluggish
using DMF or THF /entries 1±3). A dramatic improvement
was obtained by using acetonitrile /entry 4) or 1,4-dioxane.
In the latter case, a temperature of 808C allowed us to
complete the reaction within 3 h and to obtain the expected
product in 85% yield after puri®cation on Florisilw /entry 6).
The use of the trisulfonated phosphine TPPTS15 is a wide-
spread way to make a catalyst soluble in an aqueous
medium. A remarkable example is the Rh/TPPTS `Rhurch-
16
Ã
emieÐRhone Poulenc' hydroformylation process. In the
case of Pd/TPPTS catalytic systems, many industrial appli-
cations such as carbonylation17b or oligomerization17c have
also been published recently.17a Our major contribution in
this ®eld has rather focused on the use of in situ water-
soluble palladium catalysts in ®ne chemical organic
reactions. We have developed a large number of cross-
coupling reactions such as Suzuki±Miyaura,18 `copper
free' Sonogashira,19 Tsuji±Trost20 or Heck reactions in
inter-19 and intramolecular21 versions under mild conditions.
The catalyst was proved to be a true Pd/0) species.22 Water-
soluble palladium catalysts have also been successfully
utilized in order to remove allyloxycarbonyl protective
group /Alloc) from acids, alcohols or amines.23
10% PdCl , 30% TPPTS
2
O
solvent/H O (6/1)
2
6 h, 80 ˚C
All these examples illustrate the possibility to conduct
classical organometallic reactions in aqueous media. By
applying this methodology to the cycloizomerization of
1,6-enynes, we thought it would be possible to associate
an environmentally benign process with an environmentally
friendly solvent.
1
OH
H
O
2. A new `carboxydroxypalladation' reaction24
2
Our ®rst attempt to carry out a cycloisomerization reaction
in an organoaqueous medium was directed towards the
easily accessible cinnamylpropargyl ether 1. The water-
soluble palladium catalyst was preformed from PdCl2 and
TPPTS in water /1 h at 808C) and the reaction was
conducted at 808C in a homogeneous mixture of acetonitrile
and water. After 6 h of reaction, we were pleased to ®nd that
the starting material had been mainly converted into a new
polar product which apparently was not the expected diene.
3. Structure determination
Compared to the classical cycloisomerization, several
features are noteworthy: the carbohydroxypalladation is
highly diastereoselective; the NMR spectra were consistent
with the presence of a unique diastereomer. This could
be con®rmed by derivatization of the crude alcohol with
/R)-/2)-a-methoxy-a-/tri¯uoromethyl)phenylacetic chloride
Table 1.
Entry
Solvent
Temperature /8C)
Time /h)
Puri®cation
Yield /%)
1
2
3
4
5
6
DMF
THF
THF
CH3CN
CH3CN
1,4-Dioxane
65
65
65
65
80
80
48
45
72
7
6
3
±
,10
28
62
44
66
85
Silica gel
Neutral alumina
Silica gel
Neutral alumina
Florisilw
Scheme 2.

J.-C. Galland et al. / Tetrahedron 57 02001) 5137±5148
5139
Scheme 3.
1
/Mosher's acid chloride). H and 13C NMR spectra of the
resulting ester 3 were characterized by two sets of signals of
equal intensity /Scheme 2). Unfortunately these two dia-
stereomers were inseparable by chromatography.
/2)-camphanic acid chloride afforded the optically pure
ester 5a as a crystalline derivative /Scheme 3). X-ray
diffraction studies showed an anti relationship for the
two hydrogen atoms a and b to the hydroxy group and
an /R,R) absolute con®guration could be deduced for 2a
from the /S) con®guration of the chiral camphanic moiety
/Fig. 1).
The carbohydroxypalladation reaction gives rise to 3-exo-
methylene-4-a-hydroxyfurans with a high level of stereo-
selectivity. In order to take advantage of this diastereoselec-
tivity in synthesis applications, the absolute con®guration of
the furan had to be unambiguously established. Since
Mosher's esters 3 could not be separated by column
chromatography, we looked for a more convenient chiral
auxiliary. /S)-/1)-a-Methoxyphenylacetic acid25 furnished
after coupling with 2 the oily diastereomers 4a and 4b separ-
able by careful silica gel chromatography. In order to obtain
crystallized derivatives, these diastereomers were cleanly
saponi®ed to the corresponding optically pure alcohols 2a
and 2b. Derivatization of the liquid alcohol 2a using /S)-
4. Scope and limitations
In order to evaluate the scope of this new reaction, various
1,6-enynes were tested using the optimized experimental
conditions /3 h in 1,4-dioxane, puri®cation on Florisilw).
The results are summarized in Table 2. The reaction can
be applied to a wide variety of propargylic ethers with
aromatic or ethylenic groups on the double bond, leading
to the corresponding hydroxyfurans with good yields and
diastereoselectivities. The starting materials may be substi-
tuted on the propargylic position although the reaction times
may be longer /entries 1 and 2). It is possible to use
substrates bearing a functionalized aromatic ring /entry 3)
or even a heteroaromatic nucleus such as thiophene /entry
4). In the case of compound 14 bearing an ethylenic group,
the reaction takes place but competes with a palladium-
catalyzed [412] cycloaddition process26 leading to the
bicyclic product 16.
Carbocycles such as compound 18 can also be obtained using
a carbohydroxypalladation but yields appear to be moderate
/entry 6). The reaction entails two major limitations:
² Substrates with an aliphatic chain on the double bond did
not give the expected secondary alcohol but a number of
unidenti®ed by-products: we assume that a complexation
between the palladium and an unsaturated group is neces-
sary to insure an ef®cient catalytic cycle.
² Propargylic amines did not undergo the reaction
Figure 1.

5140
J.-C. Galland et al. / Tetrahedron 57 02001) 5137±5148
Table 2.
Entry
Substrate
Product
Time /h)
10
Yield /%)a
1
2
85b /58/42)
7
82b /58/42)
3
4
5
5
47c
63c
18c
5
4.5
6d
10
35c
a
Isolated yields.
b
Two diastereomers /ratio).
Single diastereomer.
Performed in CH3CN, puri®cation by ¯ash chromatography on silica gel.
c
d
properly. Deallylation often competes as well as deacti-
vation of the Pd/0) species by the nitrogen atom.
However, a classical cycloisomerization to a cyclic diene
followed by a hydration cannot explain the diastereoselec-
tivity of the reaction. One proposal which is consistent with
the stereoselective introduction of the hydroxy group could
be a `Wacker-type' process in which intermediate A
undergoes a nucleophilic attack of water a to the aromatic
ring and anti to the palladium. Reductive elimination on
intermediate B yields the expected hydroxyfuran and
allows the regeneration of the starting Pd/0) catalyst
/Scheme 4).
Besides these two limitations, the new carbohydroxy-
palladation offers an ef®cient and `atom-economical' access
to valuable cyclic skeletons with a high level of diastereo-
selectivity.
5. Mechanistic proposals
The mechanism of the carbohydroxypalladation reaction is
not yet established. However, it is clear that it differs in the
last step from the catalytic cycle usually adopted for Trost's
cycloisomerizations in anhydrous medium. Carbohydroxy-
palladation does not require the use of acetic acid. We envi-
saged the formation of a hydroxypalladate species `H-Pd-
OH' in the ®rst step. This observation is consistent with the
formation of deuterated product 19 when the reaction was
carried out in D2O /see catalytic cycle). Syn addition on the
triple bond of the enyne and subsequent coordination of the
vinylpalladate give the intermediate A. The formation of a
secondary alcohol is obviously related to the use of water.
6. Application to the synthesis of the podophyllotoxin
isomer
Podophyllotoxin is the aglycone moiety of etoposide,27 an
important agent commonly used for the treatment of many
human malignancies. It is a powerful cytotoxic lignan
extracted from the roots and the rhizomes of Podophyllum
peltatum and Podophyllum emodi.28 Its chemical structure is
characterized by an aryltetralin skeleton including four
contiguous cycles A±D.

J.-C. Galland et al. / Tetrahedron 57 02001) 5137±5148
5141
Scheme 4.
®rst key step may be achieved by applying Mukaiyama's
procedure to oxidize furan ring a to the oxygen atom.30
Concerning the C ring, we decided to adopt a strategy
based on an intramolecular Friedel±Crafts reaction. This
kind of cyclization has been thoroughly studied31 and used
successfully by many authors in the synthesis of podophyl-
lotoxin derivatives32 /Scheme 5).
8. Synthesis of the precursor to the Friedel±Crafts
reaction
The requisite propargyl ether for the carbohydroxypallada-
tion reaction was prepared in three steps from piperonal
in 78% overall yield. Wittig reaction using commercial
/carbethoxymethylene)triphenylphosphorane led to the
expected unsaturated ester which was conveniently reduced
using diisobutylaluminum hydride /DIBAL) in excess.
O-Alkylation of the resulting primary alcohol under phase
transfer conditions furnished the appropriate propargyl ether
with an excellent yield /Scheme 6).
Since podophyllotoxin analog is currently used in the treat-
ment of severe forms of lung or testicle cancers, its synthesis
has continuously been a challenging matter of interest for
organic chemists.29
7. Disconnection strategy
Our new carbohydroxypalladation of propargyl cinnamyl
ether giving functionalized hydroxyfuran in good yield
with the correct trans relative con®guration of the hydrogen
at the C3 and C4 positions present in podophyllotoxin, we
envisaged a straightforward approach to this important
molecule as shown in the retrosynthetic Scheme 5. The
The optimized carbohydroxypalladation conditions were
successfully applied to substrate 22. The sensitive hydroxy-
furan was isolated in good yield of 84%. As expected, only
one diastereomer could be detected by NMR. The hydroxy
group was cleanly protected using triisopropylsilyl /TIPS)
Scheme 5.

5142
J.-C. Galland et al. / Tetrahedron 57 02001) 5137±5148
Scheme 6.
tri¯uoromethanesulfonate under mild conditions The exo-
double bound was converted into primary alcohol using a
classical hydroboration±oxidation sequence /Scheme 7).
moderate yield was increased to 59% by using three equiva-
lents of 3,4,5-trimethoxyphenyllithium /Scheme 8).
Ê
Treatment with PCC in the presence of 4 A molecular sieves
9. Cyclization attempts using an intramolecular Friedel±
Crafts reaction
yielded 81% of the corresponding aldehyde as a mixture of
two diastereomers /43/57). In accordance with Hannessian's
results, the C2 carbon could be partly epimerized under
basic conditions /DBU) to give an 84/16 mixture in favor
of the more stable C2,C3-trans furan ring. At this stage, it
was possible to introduce the E ring and generate the pre-
cursor to the Diels±Alder reaction by condensation of 3,4,5-
trimethoxyphenyllithium on aldehyde 26. The lithio deriva-
tive was prepared by halogen exchange from 1-bromo-
3,4,5-trimethoxybenzene33 using butyllithium at low
temperature. Under stoichiometric conditions, only 35%
of the expected secondary alcohol could be isolated. This
The intramolecular Friedel±Crafts reaction on alcohol 27
was ®rst attempted under acidic conditions. Unfortunately,
the use of a strong protic acid /CF3CO2H) or a Lewis acid
such as SnCl4 resulted in the decomposition of the starting
material without any trace of the cyclized product. The
Burgess reagent, successfully employed by Vandewalle34
in the synthesis of /^)-podophyllotoxin and /^)-epi-podo-
phyllotoxin, did not give satisfactory results. It seemed
likely that our secondary alcohol 27 was too sensitive to
acidic media since only degradation by-products resulting
Scheme 7.
Scheme 8.

J.-C. Galland et al. / Tetrahedron 57 02001) 5137±5148
5143
Scheme 9.
from deprotection of the TIPS group could be observed.
Taking into account this feature, we tried to undergo the
cyclization under basic conditions by using mesyl chloride
and triethylamine34 /Schemes 9 and 10).
11. Experimental
Tetrahydrofuran /THF) and diethyl ether /Et2O) were
distilled over sodium±benzophenone. Dichloromethane
/CH2Cl2) and dimethylformamide /DMF) were distilled
over CaH2. The other solvents /dioxane, acetonitrile, etc.)
were used without further puri®cation. All reactions were
conducted under argon atmosphere, unless obviously
unnecessary or otherwise speci®ed. Column chroma-
tography was performed using silica gel and thin-layer
chromatography was carried out on E. Merck ref. 5554
precoated silica gel 60 E254 plates. Melting points are uncor-
rected and were measured on a Ko¯er melting point appa-
ratus or on a Buchi apparatus. 1H and 13C NMR spectra were
recorded on a Brucker AM 200 using CDCl3 as solvent,
unless otherwise indicated /d ppm). Infrared spectra /IR,
cm21) were recorded on a Brucker IFS 48 Fourier transform
infrared spectrometer. Mass spectra were obtained on a
Hewlett±Packard HP 5989 A coupling with a Hewlett±
Packard HP 5890 gas chromatographs ®tted with a
Chrompack CPSi 15. Regional Microanalysis Service of
P. et M. Curie University performed elemental analyses.
Indeed, the intramolecular Friedel±Crafts took place with a
good yield. Surprisingly, careful analysis of the NMR spec-
tra showed that the cyclization had occurred on the C5
position of the aromatic ring leading to compound 28 with
the methylenedioxy group in the wrong position.
The reason for this unexpected regioselectivity is not estab-
lished yet, but we may assume that a steric hindrance due to
the bulky triisopropylsilyl group and the methylenedioxy
moiety brings about the rotation of the B ring and favors
the cyclization on the C5 position.
10. Conclusions
In this paper, we discuss a new reaction named carbohy-
droxypalladation which could have many applications in
synthesis of natural products containing a furan ring. We
have illustrated the interest of this methodology in an
economical approach of an analog of podophylotoxin.
However, the Friedel±Crafts cyclization affords the
wrong isomer. Other routes for the production of podo-
phyllotoxin itself which could have interesting biological
activity are underway using the valuable hydroxyfuran
intermediate 23.
11.1. General procedure for carbohydroxypalladation in
aqueous medium
All the solvents were degassed before used. A mixture of
PdCl2 /mol 10%), sodium triphenylphosphinosulfonate
/TPPTS) /mol 30% in water) and H2O /0.25 mL for 1023
mol) was heated at 808C for 30 min. The dark red solution
was cooled to 508C and a solution of propargyl ether
Scheme 10.

5144
J.-C. Galland et al. / Tetrahedron 57 02001) 5137±5148
/1 equiv.) in dioxane /1.5 mL per 1023 mol) was added
dropwise. The mixture was heated at 808C under stirring
and the evolution was monitored by TLC. After cooling to
room temperature, it was diluted with H2O /3 mL per 1023
mol) and extracted with Et2O /4£10 mL). Organic layer was
dried on Na2SO4, ®ltered and concentrated in vacuo. The
residue was ®ltered or subjected to ¯ash chromatography on
Florisil /eluent, EtOAc/cyclohexane: 1/9).
stereomer 4b: 3.2±3.1 /m, 1H), 3.40 /3H, s, CH3O), 3.86
3
/2H, d, Jˆ6.8 Hz, CH2), 4.26 /2H, s, CH2), 4.48 /1H, dd,
4
4Jˆ4.4 Hz, Jˆ2.3 Hz, CH2y), 4.80 /1H, s, CHO-CH3),
4
3
4.88 /1H, dd, Jˆ2,0 Hz, CH2y), 5.85 /1H, d, Jˆ7.3 Hz,
CHO), 7.4±6.9 /10H, m, Harom); 13C NMR d: diastereomer
4a: 49.0, 57.6, 70.5, 72.0, 76.4, 82.9, 107.2, 127.4, 127.7,
128.6, 128.7, 128.9, 129.2, 136.5, 138.6, 146.5, 169.9; dia-
stereomer 4b: 49.3, 57.7, 70.7, 72.1, 76.6, 82.9, 107.4, 127.0,
127.5, 128.3, 128.4, 128.9, 129.0, 136.2, 138.4, 146.6,
169.8; IR /neat): 3064, 3033, 1754, 1198, 1172, 1114,
1076; MS /DCI/NH3 m/z): 356 /M1NH4)1, 339 /M1H)1.
11.1.2. 4-Exomethylene-3-7hydroxy)7phenyl)methyltetra-
hydrofuran 72). 161 mg, 85% as orange oil; H NMR d:
1
2.41 /1H, d, 3Jˆ3.2 Hz, OH), 3.1±2.9 /1H, m, HC), 4.13 and
2
3
3
3.86 /2H, 2dd, Jˆ9 Hz, Jˆ4.9 Hz and Jˆ6.8 Hz, CH2),
11.1.5. 4-Exomethylene-3-7hydroxy)7phenyl)methyltetra-
hydrofuranyl 7S)-72)-camphanic ester 75a). To a solution
of alcohol 2a /48 mg, 0.252 mmol) and DMAP /308 mg,
2.52 mmol) in CH2Cl2 /1 mL) was added /S)-camphoric
acid chloride /82 mg, 0.378 mmol). The solution was stirred
overnight at room temperature and hydrolyzed with satu-
rated NaHCO3 solution /4 mL) and H2O /6 mL). After
extraction with Et2O /3£20 mL), the combined organic
layers were washed with saturated NaCl solution, dried
/Na2SO4) and concentrated in vacuo. The crude product
was puri®ed on silica gel chromatography /eluent, EtOAc/
cyclohexane: 3/7) to afford 89 mg of 5a /99%). Recrystalli-
zation from CCl4; Rfˆ0.28 /AcOEt/cyclohexane: 3/7); m.p.
4
4.4±4.2 /2H, m, CH2), 4.59 /2H, 2q, Jˆ2.1 Hz, H2Cy),
3
3
4.78 /1H, dd, Jˆ6.5 Hz, Jˆ2.1 Hz, HC-OH), 4.96 /1H,
4
q, Jˆ2.1 Hz, H2Cy), 7.4±7.2 /5H, m, Harom); 13C NMR
d: 51.0, 70.27, 71.82, 74.58, 106.23, 126.35, 127.64,
128.26, 142.38, 147.98; IR /neat): 3420, 1663, 1630,
1091, 1077, 1066; MS /DCI/NH3 m/z): 208 /M1NH41),
190 /M1NH42H2O)1, 173 /M2H2O1H)1. Anal calcd
for C12H14O2: C, 75.76; H, 7.42. Found: C, 72.82; H, 6.90.
11.1.3.
4-Exomethylene-3-[7S)-2-methoxy-2-tri¯uoro-
methyl-2-phenylacetoxy]7phenyl)methyltetrahydro-furan
73). To a solution of 2 /138 mg, 0.72 mmol) in CCl4 /5 mL)
were added pyridine /2.9 mL, 36.3 mmol) and Mosher acid
chloride /270 mL, 1.45 mmol) at 08C. After stirring over-
night at room temperature, the solution was neutralized with
3-dimethylamino-1-propargylamine /0.5 mL) and diluted
with Et2O. The organic layer was washed with 1 M HCl
solution, dried on Na2SO4, ®ltered, and concentrated in
vacuo to afford 247 mg of 3 /84%). Rfˆ0.42 /AcOEt/cyclo-
25
1
1328C; [a]D ˆ170 /cˆ1.03; CHCl3); H NMR d: 0.98,
0.81 /6H, 2s, 2CH3), 1.09 /3H, s, CH3), 1.8±1.6 /1H, m,
CH2cycle), 2.1±1.85 /2H, m, CH2cycle), 2.55±2.3 /1H, m,
3
CH2cycle), 3.35±3.2 /1H, m, CH), 3.98 /2H, d, Jˆ6.7 Hz,
CH2), 4.3 /2H, s, CH2), 4.46 /1H, m, 4Jˆ2.3 Hz, 4Jˆ2.1 Hz,
CH2) 4.91 /1H, q, 4Jˆ2.1 Hz, CH2), 5.91 /1H, d, 3Jˆ8.0 Hz,
CHO), 7.28 /5H, s, Harom); 13C NMR d: 9.5, 16.5, 28.8, 30.7,
48.8, 54.2, 54.7, 70.6, 71.7, 76.8, 90.8, 107.4, 127.2, 128.3,
138.0, 146.0, 166.5, 178.2; IR /KBr): 1778, 1747, 1065,
1045. MS /DCI/NH3 m/z): 388 /M1NH4)1.
1
hexane: 3/7); H NMR d diastereomers: 3.3±3.1 /1H, m,
CH), 3.42 /3H, d, Jˆ1.3 Hz, CH3O) and 3.51 /3H, d,
Jˆ1.3 Hz, CH3O), 3.9±3.7 /1H, m, CH2) and 3.95 /1H, d,
3Jˆ6.2 Hz, CH2), 4.21 /2H, s), 4.28 /2H, s), 4.85 /2H, d,
4Jˆ2.1 Hz, CH2y) and 4.92 /2H, d, 4Jˆ2.1 Hz, CH2y), 5.93
/1H, d, 3Jˆ7.8 Hz, CHO) and 5.95 /1H, d, 3Jˆ8.6 Hz,
11.1.6. 75S)-4-Exomethylene-5-methyl-3-7hydroxy)7phenyl)-
methyltetrahydrofuran 77). 175 mg, 85% as yellow oil as
3
1
3
CHO), 7.5±7.1 /8H, m, Harom), 8.62 /2H, d, Jˆ4.2 Hz,
diastereomers; H NMR d: 2.91 /1H, d, Jˆ3.2 Hz, OH),
Harom).
3.0±3.15 /1H, m, HC), 4.12 and 3.94 /2H, 2dd, 2Jˆ9.1 Hz,
3
3Jˆ4.8 Hz and Jˆ6.7 Hz, CH2), 4.15±4.4 /2H, m, CH2),
2
4
11.1.4. 73R)-4-Exomethylene-3-[7R)-[7S)-2-methoxy-2-
phenylacetoxy]7phenyl)methyl]tetrahydrofuran 74a). 73S)-
4-Exomethylene-3-[7S)-[7S)-2-mehoxy-2-phenylacetoxy]-
7phenyl)methyl] tetrahydrofuran 74b). To a solution of
4.68 /1H, dd, Jˆ2 Hz, and Jˆ2.4 Hz, H2Cy), 4.9±5.05
/2H, 2m, H2Cy and HC), 7.2±7.4 and 6.8±7.1 /3H, 2m,
Harom); 13C NMR d: 51.00, 70.48, 71.00, 71.76, 106.49,
124.49, 124.79, 126.46, 146.51, 147.49; IR /neat): 3394,
2855, 1734, 1664, 1439, 1302, 1235, 1066; MS /DCI/NH3
m/z): 214 /M1NH4)1, 196 /M1NH42H2O)1, 179
/M2H2O1H)1. Anal calcd for C13H16O2: C, 76.44; H,
7.89. Found: C, 76.09; H, 7.64.
alcohol
2
/292 mg, 1.54 mmol), DMAP /19 mg,
0.15 mmol) and /S)-/1)-a-methoxyphenylacetic acid in
CH2Cl2 /3 mL) was added EDC /323 mg, 1.69 mmol) at
08C. The solution was stirred for 1 h at 08C then concen-
trated in vacuo. The residue was hydrolyzed with H2O
/10 mL) and extracted with Et2O /3£30 mL). The combined
organic layers were washed successively with saturated
NaHCO3 and saturated NaCl solutions, dried /Na2SO4)
and concentrated in vacuo. The crude product was ®ltered
on silica gel chromatography /eluent, EtOAc/cyclohexane)
11.1.7. 4-Exomethylene-3-7hydroxy)7phenyl)methyl-5-
phenyltetrahydrofuran 79). 176 mg, 82% as yellow oil
as diastereomers; H NMR d: major diastereomer 2.4 /1H,
1
3
s, OH), 3.15±3.40 /1H, m, HC), 4.14 /2H, d, Jˆ 7.4 Hz,
3
CH2), 4.70±4.85 /2H, m, CH2y), 4.93 /1H, d, Jˆ 5.9 Hz,
1
to afford 85 mg of 4a and 109 mg of 4b; H NMR d: dia-
stereomer 4a: 3.05±3.15 /1H, m, CH), 3.40 /3H, s, CH3O),
HC-OH), 5.24 /1H, 4Jˆ2.0 Hz, HC), 7.7±7.0 /10H, m,
Harom); minor diastereomer 3.10±3.25 /1H, m, HC), 4.00
2
3
2
3
2
3.51 /1H, dd, Jˆ9.1 Hz, Jˆ5.9 Hz, CH2), 3.65 /1H, dd,
/1H, Jˆ9.2 Hz, Jˆ6.7 Hz, CH2), 4.60 /1H, Jˆ9.2 Hz,
3
2
4
2Jˆ9.1 Hz, Jˆ7.0 Hz, CH2), 3.90 /1H, dd, Jˆ13.1 Hz,
3Jˆ3.1 Hz, CH2), 4.52 /1H, t, Jˆ2.2 Hz, CH2y), 4.70±
4Jˆ2.1 Hz, CH2), 4.12 /1H, d, 2Jˆ13.1 Hz, CH2), 4.36
4.85 /1H, m, CH2y), 4.70±4.85 /1H, HC-OH); 13C NMR
d: 51.5 and 51.3, 68.8 and 69.3, 74.4 and 75.0, 84.0, 108.8,
126.2, 127.0, 127.8, 128.4, 140.7 and 140.9, 142.2 and
142.3, 151.9 and 151.1; MS /m/z): 248 /M2H2O)1.
4
4
4
/1H, dd, Jˆ4.4 Hz, Jˆ2.3 Hz, CH2y), 4.71 /1H, dd, Jˆ
4
4.1 Hz, Jˆ2.1 Hz, CH2y), 4.77 /1H, s, CHO-CH3), 5.87
3
/1H, d, Jˆ7.4 Hz, CHO), 7.5±7.25 /10H, m, Harom); dia-

J.-C. Galland et al. / Tetrahedron 57 02001) 5137±5148
5145
11.1.8. 4-Exomethylene-3-7hydroxy)72-methoxyphenyl)-
methyletrahydrofuran 711). 260 mg, 47% as orange oil;
1H NMR d: 2.73 /1H, d, 3Jˆ6.3 Hz), 3.1±3.3 /1H, m,
CH), 3.7±3.9 /4H, m, CH2, CH3), 4.16 /1H, dd, 2Jˆ
room temperature, diluted with Et2O and ®ltered. The
organic layer was washed, dried over MgSO4 and concen-
trated in vacuo. The crude product was puri®ed by ¯ash
chromatography /eluent CH2Cl21) to afford 3.88 g of a
3
2
3
9.0 Hz, Jˆ4.6 Hz, CH2), 4.27 /1H, d, Jˆ13.3 Hz, CH2),
yellow solid /88%), m.p. 628C; H NMR d: 1.26 /t, Jˆ
2
4
3
4.4 /1H, dq, Jˆ13.3 Hz, Jˆ1.9 Hz, CH2), 4.63 /1H, q,
4Jˆ2.2 Hz, HC), 4.9±5.05 /2H, m, H2CyCHOH), 6.7±7.0
/2H, m, Harom), 7.2±7.4 /2H, m, Harom); 13C NMR d: 49.2,
55.1, 70.4, 71.7, 71.8, 105.6, 110.2, 120.4, 127.7, 128.4,
130.1, 148.8, 156.3; IR /neat): 3410, 1605, 1590, 1050,
1070, 1066; MS /m/z): 220 /M)1, 202 /M2H2O)1. Anal
calcd for C13H16O3: C, 70.89; H, 7.32. Found: C, 69.68;
H, 7.09.
7.1 Hz, 3H), 4.18 /q, Jˆ7.1 Hz, 2H), 5.91 /s, 2H), 6.18
3
3
/d, Jtransˆ15.9 Hz, 1H), 6.71 /d, Jˆ7.9 Hz, 1H), 7.6±8.0
/m, 2H), 7.50 /d, Jtransˆ15.9 Hz, 1H); 13C NMR d: 14.2,
3
60.1, 101.4, 106.3, 108.3, 116.0, 124.2, 128.7, 144.0, 148.2,
149.4, 166.9; IR /KBr): 3052, 3031, 1703, 1642, 1611,
1504, 1175, 929. MS /m/z): 220 /M1), 175
/M2OCH2CH3)1, 148 /M2CO2Et1H)1.
11.1.14. 72E)-3-[73,4-Methylenedioxy)phenyl]prop-2-en-
1-ol 721). To a solution of ester 20 /3.68 g, 16.7 mmol) in
dry THF /60 mL) was added dropwise a DIBAL molar
solution /66.8 mL, 66.8 mmol) at 2788C. After stirring
the mixture for 2 h 30 min, it was hydrolyzed dropwise
with H2O /20 mL) stirring for 30 min at room temperature.
The gel was ®ltered and washed with Et2O. After extraction
of aqueous layer with Et2O, the combined organic layers
were washed with saturated NaCl solution, dried /MgSO4)
and concentrated in vacuo. The crude product was ®ltered
on silica gel chromatography to afford 2.74 g of 21 as a
natural solid. Rfˆ0.11 /AcOEt/cyclohexane: 2/8), m.p.
11.1.9. 4-Exomethylene-3-7hydroxy)7thien-2-yl)methyl-
tetrahydrofuran 713). 142 mg, 63% as orange oil; 1H
3
NMR d: 2.91 /1H, d, Jˆ3.9 Hz, OH) 3.0±3.15 /1H, m,
2
3
CHOH), 3.94 /1H, dd, Jˆ9.1 Hz, Jˆ6.7 Hz, CH2), 4.12
2
3
/1H, dd, Jˆ9.1 Hz, Jˆ4.8 Hz, CH2), 4.15±4.4 /2H, m,
4
4
CH2), 4.68 /1H, dd, Jˆ2.0 Hz, Jˆ2.2 Hz, H2Cy), 4.9±
5.05 /2H, m, H2Cy, CHOH), 6.8±7.1 /2H, m, Harom), 7.2±
7.4 /1H, m, Harom); 13C NMR d: 51.3, 70.5, 71.0, 71.8, 106.6,
124.8, 126.6, 146.6, 147.5; IR /neat): 3394, 1664, 1535,
1066; MS /DCI/NH3 m/z): 214 /M1NH4)1, 196
/M1NH42H2O)1. Anal calcd for C10H12O2S: C, 61.20;
H, 6.16. Found: C, 62.14; H, 6.02.
1
3
828C. H NMR d: 2.01 /s, 1H), 4.27 /d, Jˆ5.8 Hz, 2H),
5.94 /s, 2H), 6.18 /dt, 3Jtransˆ15.8 Hz, 3Jˆ5.8 Hz, 1H), 6.51
/d, 3Jtransˆ15.8 Hz, 1H), 6.7±7.0 /m, 3H). 13C NMR d: 63.4,
1100.9, 105.5, 108.1, 120.9, 126.5, 130.7, 130.9, 147.1,
47.8; IR /KBr) 3363, 3073, 3023, 1650, 1608, 1502, 1119,
1086, 1037, 1006, 926. MS /m/z): 178 /M1), 135 /M2CH-
CH2OH1H)1, 77 /C6H5)1. Anal calcd for C10H10O3: C,
67.41; H, 5.65. Found: C, 67.27; H, 5.72.
11.1.10. 4-Exomethylene-3-[7E)-1-hydroxybut-2-en-1-yl]-
tetrahydrofuran 715). 22 mg, 18% as a yellow oil. H
1
3
NMR d: 1.15 /3H, d, Jˆ7.4 Hz, CH3), 2.75±3.0 /1H, m,
2
3
CH), 3.2±3.3 /1H, dd, Jˆ7.1 Hz, Jˆ10.9 Hz, CH2), 4.21
2
2
/1H, t, Jˆ 3Jˆ7.1 Hz, CH2), 4.27 /1H, d, Jˆ12.1 Hz,
CH2), 4.44 /1H, dm, 2Jˆ12.1 Hz, CH2), 5.43 /1H, s,
HCy), 5.71 /2H, s, HCy); 13C NMR d: 21.6, 29.6, 39.4,
69.2, 72.1, 73.3, 120.9, 121.9, 133.7, 137.8.
11.1.15. 7E)-3-[73,4-Methylenedioxy)phenyl]prop-2-en-1-
yl propargyl oxide 722). 2.73 g of alcohol 21 /15.53 mmol)
was added dropwise to a solution of NaI /229 mg),
nBu4NHSO4 /2.08 g), and 1.88 mL of propargyl bromide
/16.8 mmol, 80% in toluene) in THF /30 mL). Amounts
of KOH were rapidly added in 1 h. After reaction was
completed /TLC control), the mixture was quenched with
H2O and the solution was extracted with AcOEt. The
organic layer was washed with saturated NaCl solution,
dried /Na2SO4) and concentrated in vacuo. The crude
product was puri®ed by ¯ash chromatography /AcOEt/cy-
clohexane: 2/8) to afford 3.17 g of 22 /96%). Rfˆ0.5
11.1.11. 3-Methyl-8-oxabicyclo[4.3.0]nona-172),4-diene
716). 25 mg, 23% as yellow oil; H NMR d: 1.75 /3H, d,
1
3
3Jˆ6.3 Hz, CH3), 2.75±2.9 /1H, m, CH), 4.0 /2H, dd, Jˆ
4
5.7 Hz, Jˆ2.2 Hz, CH2), 4.2±4.4 /3H, m, CH2, CHOH),
5.05±5.15 /2H, m, H2Cy), 5.53 /1H, ddm, 3Jtransˆ15.3 Hz,
3Jˆ6.7 Hz, HCy), 5.65±5.9 /1H, m, HCy); 13C NMR d:
22.0, 49.5, 70.0, 71.9, 73.3, 148.6, 131.6, 128.1, 105.8; IR
/neat): 3425, 1667, 1078; MS /DCI/NH3 m/z): 172
/M1NH4)1, 154 /M1NH42H2O)1.
1
4
11.1.12. 1,1-Bis7methoxycarbonyl)-4-exomethylene-3-
7hydroxy)7phenyl)methylcyclopentane 718). 37 mg, 35%
/AcOEt/cyclohexane: 2/8); H NMR d: 2.47 /1H, t, Jˆ
2.3 Hz, yCH), 4.15±4.3 /4H, m, CH2), 5.95 /2H, s,
1
as a yellow oil; H NMR d: 2.16 /1H, s, OH), 2.24 /1H, d,
3
O-CH2-O), 6.11 /1H, dt, Jtransˆ15.8 Hz, 3Jˆ6.3 Hz,
3
3
3Jˆ7.4 Hz, CH2), 2.28 /1H, d, Jˆ9.2 Hz, CH2), 2.9±3.15
CHy), 6.56 /1H, d, Jtransˆ15.8 Hz, CHy), 6.7±7.0 /3H,
/1H, m, CH), 3.0 /2H, s, CH2), 3.69 /3H, s, CH3), 3.73 /3H,
m, Harom); 13C NMR d: 56.9, 70.1, 74.4, 79.7, 101.0,
105.7, 108.2, 121.2, 123.1, 130.9, 133.1, 147.3, 147.9; IR
/neat): 3291, 2116, 1653, 1607, 1251, 1193; MS /m/z): 216
/M1), 177 /M2CH2C;CH)1, 119 /M2HC;C-CH2-O-
CH2-CHˆCH2 1 H)1. Anal calcd for C13H12O3: C, 72.21;
H, 5.59. Found: C, 72.08; H, 5.48.
s, CH3), 4.93 /1H, q, 4Jˆ2.3 Hz, CH2y), 5.0 /1H, d,
4
4Jˆ4.0 Hz, CHOH), 5.15 /1H, q, Jˆ2.3 Hz, H2Cy), 7.3±
7.5 /5H, m, Harom); 13C NMR d: 33.6, 42.0, 49.6, 52.7, 58.6,
73.9, 108.2, 125.7, 127.2, 128.2, 142.5, 148.8, 172.0; IR
/neat): 3582, 1734, 1661, 1602, 1261, 1066; MS /m/z):
286 /M2H2O)1, 227 /M2C6H5)1. Anal calcd for
C17H20O6: C, 67.09; H, 6.62. Found: C, 66.14; H, 6.47.
11.1.16. 4-Exomethylene-3-7hydroxy)[73,4-methylene-
dioxy)phenyl]methyltetrahydrofuran 723). As general
procedure described for carbohydroxypalladation, 108 mg
/0.5 mmol) of ether 21, 9 mg /mol 10%) of PdCl2 and
284 mg of TPPTS /mol 30%, 0.15 mmol) afforded 99 mg
of 23 as an orange oil /86%). Rfˆ0.13 /AcOEt/cyclohexane:
11.1.13. Ethyl 72E)-3-[73,4-methylenedioxy)phenyl]prop-
2-enoate 720). A solution of piperonal /3 g) in THF was
added to 3 g of /ethoxycarbonylmethylene)triphenyl-
phosphorane. The mixture was re¯uxed for 6 h, cooled to

5146
J.-C. Galland et al. / Tetrahedron 57 02001) 5137±5148
2/8); 1H NMR d: 2.12 /1H, d, 3Jˆ3.1 Hz, OH), 3.1±2.9 /1H,
solution of alcohol 25 /333 mg, 0.82 mmol) in CH2Cl2
Ê
/6.5 mL) with 4 A molecular sieves in powder /200 mg)
2
3
m, CH), 3.89 /1H, dd, Jˆ9.1 Hz, Jˆ6.8 Hz, CH2), 4.12
2
3
/1H, dd, Jˆ9.1 Hz, Jˆ4.7 Hz, CH2), 4.2±4.45 /2H, m,
was added PCC /352 mg, 1.63 mmol). The mixture was
stirred for 1 h at 08C and an additional amount of PCC
was added. After stirring 1 h at 08C, the mixture was ®ltered
on silica gel and eluted with CH2Cl2. The organic phase was
concentrated in vacuo to afford 270 mg of crude product as a
yellow oil /81%). The oil was dissolved in THF /2 mL) and
DBU /148 mL, 1 mmol) was added. The solution was
stirred for 24 h at room temperature, quenched with satu-
rated NH4Cl solution and extracted with Et2O /3£30 mL).
The combined organic layers were washed with saturated
NaCl solution /30 mL), dried /Na2SO4) and concentrated in
vacuo. The crude product was puri®ed by silica gel ¯ash
chromatography /eluent AcOEt/cyclohexane 25/75 and
1.5% NEt3) to afford 250 mg of 26 in 93% yield as a
4
3
CH2), 4.64 /1H, q, Jˆ2.1 Hz, CH2y), 4.71 /1H, dd, Jˆ
6.7 Hz, 3Jˆ3.1 Hz, CHOH), 4.98 /1H, q, 4Jˆ2.0 Hz,
CH2y), 5.97 /2H, s, O-CH2-O), 6.75±6.9 /3H, m, Harom);
13C NMR d: 51.0, 70.4, 71.8, 74.5, 100.9, 106.4, 106.8,
107.9, 119.8, 136.5, 146.9, 147.6, 147.8; IR /neat): 3413,
1653, 1096, 1039, 930; MS /DCI/NH3 m/z): 252
/M1NH4)1, 234 /M1NH42H2O)1, 217 /M1H2H2O)1.
11.1.17. 4-Exomethylene-3-[73,4-methylenedioxy)phenyl]-
7triisopropylsilyloxy)methyltetrahydrofuran 724). T o a
solution of 23 /2.3 g, 9.82 mmol) in CH2Cl2 /40 mL) were
added dropwise 2.3 mL of 2,6-lutidine then 3.95 mL
/14.7 mmol) of triisopropylsilyl tri¯ate. After stirring for
1 h at 2788C then for 3 h at 2108C, the mixture was
quenched with MeOH /2 mL) and concentrated in vacuo.
The crude product was puri®ed by ¯ash chromatography
/AcOEt/cyclohexane 1/9 and 2% NEt3) to give 2.8 g of 24
in 73% yield as yellow oil. Rf: 0.62 /AcOEt/cyclohexane: 3/
7); 1H NMR d: 0.8±1.1 /21H, m, iPr3), 2.8±3.0 /1H, m, CH),
1
yellow oil. Rfˆ0.31 /AcOEt/cyclohexane: 1/1); H NMR d
/diastereomers): 0.9±1.1 /21H, m, iPr3), 2.8±3.0 /2H, m,
CH), 3.75±3.95 /2H, m, CH2), 3.95±4.1 /2H, m, CH2),
3
4.69 /1H, d, Jˆ7.4 Hz, CH-O-), 5.98 /2H, s, OCH2O),
6.77 /2H, s, Harom), 6.87 /1H, s, Harom), 9.28 /1H, d,
3Jˆ2.2 Hz, CHO), 13C NMR d: 12.3, 17.8, 17.9, 50.8,
53.7, 69.9, 71.0, 101.0, 107.0, 107.8, 120.2, 136.6, 147.2,
147.8, 200.0; IR /neat): 1726, 1610, 1504, 1488, 1244, 1099,
1064; MS /m/z): 405 /M2H)1; 135 /M2ArCH1H)1; Anal
calcd for C22H34O5: C, 64.99; H 8.43. Found: C, 64.80; H,
8.41.
2
3
3.92 /1H, dd, Jˆ8.9 Hz, Jˆ6.5 Hz, CH2), 4.1±4.25 /3H,
4
m, CH2), 4.43 /1H, q, Jˆ1.9 Hz, CH2y), 4.64 /1H, d,
4
3Jˆ7.6 Hz, CHO), 4.84 /1H, q, Jˆ1.9 Hz, CH2y), 5.95
/2H, s, O-CH2-O), 6.72 /2H, s, Harom), 6.85 /1H, s, Harom);
13C NMR d: 12.4, 17.9, 53.1, 71.0, 71.8, 75.9, 100.8,
106.8, 107.3, 107.6, 120.8, 137.4, 146.7, 147.2, 147.5; IR
/neat): 3079, 1665, 1610, 1245, 1061, 1042, 935; MS
/DCI/NH3 m/z): 408 /M1NH4)1, 391 /M1H)1, 217
/M2OSiiPr3)1.
11.1.20.
73R)-3-7Hydroxy)[73,4,5-trimethoxy)phenyl]-
methyl-4-[73,4-methylenedioxy)phenyl]7triisopropylsilyl-
oxy)methyltetrahydrofuran 727). To a solution of 182 mg
of 1-bromo-3,4,5-trimethoxybenzene in THF /5.3 mL) were
added dropwise BuLi /285 mL, 0.713 mmol, 2.5 M hexane
solution) at 2788C. The mixture was stirred for 1 h at
2788C then 100 mg of 26 /0.246 mmol) in THF /4.5 mL)
were added dropwise for 10 min. After stirring 1 h at
2788C, the solution was quenched with H2O /20 mL) and
extracted with CH2Cl2 /3£50 mL). The combined organic
layers were washed with saturated NaCl solution, dried
/Na2SO4) and concentrated in vacuo. The crude product
was puri®ed by silica gel ¯ash chromatography /AcOEt/
cyclohexane 35/6511% NEt3) to give 83 mg of 27 in 59%
yield as a yellow oil. Rf27aˆ0.29; Rf27bˆ0.22 /AcOEt/cyclo-
11.1.18. 4-Hydroxymethyl-3-[73,methylenedioxy)phenyl]-
7triisopropylsilyloxy)methyltetrahydrofuran 725). T o a
solution of 24 /1.06 g, 2.71 mmol) in THF /8.5 mL) was
added dropwise a molar solution of BH3´THF /2.71 mL,
2.71 mmol) in THF at 08C. After stirring the mixture for
1 h at 08C, an additional amount of BH3´THF /1.35 mL,
1.35 mmol) was added. The solution was stirred for 1 h at
08C, quickly treated by 3N NaOH /2.84 mL) and a hydrogen
peroxide solution /30% in water) was added dropwise. The
mixture was stirred for 1 h at room temperature, quenched
with water /100 mL) and the aqueous layer was extracted
with Et2O /3£150 mL). The combined organic layers were
washed with saturated NaCl /150 mL), dried /Na2SO4) and
concentrated in vacuo. The crude product was puri®ed by
silica gel ¯ash chromatography /eluent AcOEt/cyclohexane:
4/6) to afford 1.06 g of 25 in 96% yield as a transparent oil.
1
hexane: 4/6); H NMR d: diastereomer 27a: 0.8±1.1 /21H,
m, iPr3), 1.67 /1H, s, OH), 2.3±2.5 /1H, m, CH), 2.55±2.8
/1H, m, CH), 3.82 /3H, s, p-CH3O), 3.85 /6H, s, CH3O),
3
3.4±4.1 /4H, m, CH2), 4.46 /1H, d, Jˆ7.8 Hz, CHOSi),
3
4.76 /1H, d, Jˆ4.9 Hz, CHOH), 5.98 /2H, d, Jˆ2.4 Hz,
1
Rfˆ0.31 /AcOEt/cyclohexane: 1/1); H NMR d: 0.75±1.1
O-CH2-O) 6.49 /2H, s, Harom), 6.71 /2H, s, Harom), 6.86
/1H, s, Harom); diastereomer 27b: 0.8±1.1 /21H, m, iPr3)
1.9±2.4 /2H, 2m, CH, OH), 2.5±2.7 /1H, m, CH), 3.79
/6H, s, CH3O), /3H, s, p-CH3O), 3.8±4.1 /4H, m, CH2),
/21H, m, iPr3), 1.8 /1H, s, OH), 1.8±1.95 /1H, m, CH), 2.7±
3.0 /1H, m, CH), 3.5±3.7 /2H, m, CH2-O), 3.7±3.9 /m, 1H,
2
2
CH2), 3.94 /2H, t, Jˆ3Jˆ8.9 Hz, CH2), 4.16 /1H, t, Jˆ
3Jˆ8.4 Hz, CH2), 4.76 /1H, d, Jˆ10.1 Hz, CH-O), 5.96
4.18 /1H, d, Jˆ7.2 Hz, CHOH), 4.34 /1H, d, Jˆ8.1 Hz,
CHOSi), 5.9±6.0 /2H, m, O-CH2-O), 6.25 /2H, s, Harom),
6.9±6.5 /3H, m, Harom); 13C NMR d: diastereomer 27a: 12.3,
17.8, 17.9, 48.3, 51.2, 55.8, 60.7, 70.7, 71.4, 75.3, 77.1,
101.1, 107.3103.1, 107.6, 120.4, 135.7, 137.4, 138.5,
146.9, 147.5, 153.0; diastereomer 27b: 12.4, 17.8, 17.9,
49.2, 51.3, 55.8, 60.7, 69.5, 70.6, 75.6, 76.7, 101.1, 102.7,
106.9, 107.0, 120.1, 137.1, 137.6, 138.8, 146.8, 147.6,
153.0; IR /neat): 3417, 1593, 1244, 1129, 1040, 924; MS
DCI/NH3 m/z): 592 /M1NH4)1, 574 /M1NH42H2O)1,
557 /M1H2H2O)1, 401 /M2iPr3SiO)1.
3
3
3
/2H, s, O-CH2-O), 6.7±7.0 /3H, m, Harom); 13C NMR d:
12.4, 17.8, 18.0, 42.3, 50.8, 61.1, 71.6, 71.9, 74.7, 100.9,
107.3, 107.7, 120.7, 137.9, 147.1, 147.6; IR /neat): 3420,
1245, 1084, 1041, 929; MS /DCI/NH3 m/z): 407 /M±H)1,
365 /M±iPr)1, 234 /M±OSiiPr3±H)1, 217 /M±OSiiPr3±
H2O)1; Anal calcd for C22H36O5Si: C, 64.67; H, 8.88.
Found: C, 64.60; H, 8.87.
11.1.19. 73R)-3-Formyl-4-[73,4-methylenedioxy)phenyl]-
7triisopropylsilyloxy)methyltetrahydrofuran 726). T o a

J.-C. Galland et al. / Tetrahedron 57 02001) 5137±5148
5147
12. Okamoto, S.; Livinghouse, T. Organometallics 2000, 19,
1449.
11.1.21. [3,4]-[[73,4)-Methylenedioxy]benzo]-2-triisopro-
pyloxy-5-[73,4,5)-trimethoxyphenyl]-8-oxabicyclo[4.3.0]-
nonane 728). To a solution of alcohol 27 /27.5 mg,
0.048 mmol) in CH2Cl2 /0.7 mL) were added dropwise
20 mL of NEt3 /0.143 mmol) then 9 mL of mesyl chloride
/0.116 mmol) at 2108C. After stirring for 1 h at 2108C, the
mixture was hydrolyzed with saturated NaHCO3 solution
and extracted with CH2Cl2 /3£10 mL). The combined
organic layers were washed with saturated NaCl solution,
dried /Na2SO4) and concentrated in vacuo. The crude
product was puri®ed on Florisil /eluent AcOEt/cyclohexane:
95/5) to provide 21 mg /81%). Rfˆ0.5 /AcOEt/cyclo-
hexane: 4/6); 1H NMR d: major diastereomer 0.8±1.1
/21H, m, iPr3), 2.15±2.3 /1H, m, CH), 2.3±2.45 /1H, m,
CH), 3.80 /6H, s, 2CH3O), 3.84 /3H, s, p-CH3O), 3.90
13. /a) Hatano, M.; Terada, M.; Mikami, K. Angew. Chem. Int. Ed.
Engl. 2001, 40, 249±253. /b) Cao, P.; Zhang, X. Angew.
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Chem. Soc. 1999, 121, 6183. /d) Trost, B. M.; Krische, M. J.
J. Am. Chem. Soc. 1999, 121, 6131. /e) Goeke, A.; Sawamura,
M.; Kuwano, R.; Ito, Y. Angew. Chem. Int. Ed. Engl. 1996, 35,
662.
Ã
14. Reviews: /a) Genet, J. P.; Savignac, M.; Lemaire-Audoire, S.
In Transition Metal Catalysed Reactions; Murahashi, S.-I.,
Davies, S. G., Eds.; Academic Press, 1999; pp. 55±79.
Ã
/b) Genet, J. P.; Savignac, M. J. Organomet. Chem. 1999,
576, 305±317.
2
/1H, t, Jˆ3Jˆ2.5 Hz, CH2), 3.8±3.9 /1H, m, CH2), 4.03
15. Kuntz, E. G.; Thorpe, T.; Brown, S. M.; Crosby, J.; Fitzjohn,
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references cited therein).
2
3
2
/1H, dd, Jˆ4.7 Hz, Jˆ2.5 Hz, CH2), 4.10 /1H dd, Jˆ
4.6 Hz, 3Jˆ2.2 Hz, CH2), 4.32 /1H d, 3Jˆ4.1 Hz, CH),
4.42 /1H, d, 3Jˆ4.2 Hz, CHOSi), 5.9±6.05 /2H, m,
O-CH2-O), 6.25 /2H, s, Harom), 6.4±6.8 /2H, m, Harom);
13C NMR d: major diastereomer 12.4, 17.8, 17.9, 50.7,
52.3, 55.9, 60.7, 66.2, 70.1, 70.7, 76.3, 101.2, 104.3,
106.7, 120.1, 135.5, 137.2, 137.7, 146.9, 147.7, 152.8,
153.2; IR /neat): 1592, 1242, 1127, 1040, 922; MS /DCI/
NH3 m/z): 557 /M2H)1, 401 /M1NH42iPr3SiO)1, 383
/M2iPr3SiO)1.
16. /a) Kuntz, E. G. Chem. Tech. 1987, 520. /b) Hermann, W. A.;
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à Á
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