Synthesis of the racemic forms of carbon-carbon double bond locked analogues of strobilurins which are characterized by a 2-arylcyclopropane ring cis-substituted at C-1 by the methyl (E)-3-methoxypropenoate unit

Article abstract of DOI:10.1016/S0040-4020(02)00334-4

The racemic forms of three new carbon-carbon double bond locked analogues of strobilurins, which are characterized by a 2-arylcyclopropane ring cis-substituted at C-1 by the methyl (E)-3-methoxypropenoate unit, have been synthesized according to a strateg

Full text of DOI:10.1016/S0040-4020(02)00334-4

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 3673±3680
Synthesis of the racemic forms of carbon±carbon double bond
locked analogues of strobilurins which are characterized
by a 2-arylcyclopropane ring cis-substituted at C-1
by the methyl ꢀE)-3-methoxypropenoate unit
Adriano Carpita,p Arianna Ribecai, Renzo Rossip and Paolo Stabile
Dipartimento di Chimica e Chimica Industriale, University of Pisa, Via Risorgimento 35, I-56126 Pisa, Italy
Received 21 January 2002; accepted 22 March 2002
AbstractÐThe racemic forms of three new carbon±carbon double bond locked analogues of strobilurins, which are characterized by a
2-arylcyclopropane ring cis-substituted at C-1 by the methyl (E)-3-methoxypropenoate unit, have been synthesized according to a strategy
which involves the palladium-catalyzed synthesis of methyl (E)-3-methoxy-2-[(Z)-2-(aryl)ethenyl]propenoates and their stereospeci®c
cyclopropanation. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
the methyl (E)-3-methoxypropenoate unit, is linked to a
substituted cyclopentenyl ring3d,e and, more recently,
concise procedures6 for the stereocontrolled preparation of
compounds (1Rp,2Rp)-6, (1Rp,2Rp)-7a, (1Rp,2Rp)-7b and
(1Rp,2Rp)-7c, which do not contain carbon±carbon double
bond in their lipophilic subunit and are characterized by a
trans-1,2-disubstituted cyclopropane ring, have also been
reported.
Strobilurins 1 are a group of metabolites isolated from
cultures of Basidiomycetes1 which served as leads for the
design and development of photostable structural analogues
able to control the major classes of fungi which affect
crops.2 These analogues, which differ from the lead struc-
tures in their pharmacophore and/or their lipophilic sub-
units, include agricultural fungicides of general formula
2±4, which are characterized by a suitably ortho-substituted
aromatic ring attached to the methyl (E)-3-methoxy-
propenoate unit,3 the methyl (E)-O-methyloximinoacetate
group4 or the (E)-O-methyloximino-N-methylacetamide
group, respectively.2,5
As regards the bioactivity of compounds 1 and their ana-
logues, it should also be noted that naturally-occurring
strobilurins D,7 E8 and F7 have been found to exhibit power-
ful cytostatic activities in addition to antifungal properties
and that, recently, we found that some analogues of 1, which
had been synthesized in our laboratory, such as com-
pounds 2a,3e 2b,3e 3a,4 (1Rp,2Rp)-7a,6 (1Rp,2Rp)-7b6 and
ꢀ1Rp; 2Rp†-7c,6 are signi®cantly active in the National
Cancer Institute (NCI) 3-cell line, one dose primary anti-
cancer assay at a 1.00£1024 M concentration.9 Neverthe-
less, these last compounds showed limited cytotoxicity
against the NCI 60-cell line panel.
However, attention has also been paid to the synthesis of
photostable carbon±carbon double bond locked analogues
of 1 of general formula 5 in which their pharmacophore, i.e.
Keywords: strobilurin; carbon±carbon double bond; methoxy propenoate.
Corresponding authors. Tel.:139-50-918275; fax: 139-50-918260;
p
e-mail: adricar@dcci.unipi.it. Tel.: 139-50-918214; fax: 139-50-
918260; e-mail: rossi@dcci.unipi.it
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00334-4

3674
A. Carpita et al. / Tetrahedron 58 -2002) 3673±3680
Scheme 1. Retrosynthetic analysis for compounds (1Rp,2Sp)-8a±c.
Scheme 3. (a) CHBr3 (3.00 equiv.), BnEt3N1Cl2 (1.6 mol%), NaOH
(4.00 equiv.), H2O, 608C, 2 h; (b) Zn/Cu (7.83 equiv.), THF and H2O,
room temperature, 18 h; (c) MPLC on silica gel; (d) BuLi (1.02 equiv.),
THF, hexane, 2908C, 1.5 h; (e) ZnBr2 (1.20 equiv.), THF, 2908C to room
temperature; (f) (Z)-13 (0.83 equiv.), Pd(PPh3)4 (5.0 mol%), THF, re¯ux,
8 h.
which involves the preparation and use of the methyl (E)-3-
methoxy-2-[(Z)-2-(aryl)ethenyl]propenoates (E,Z)-18a±c.
More recently, as part of a project aimed at developing
concise and ef®cient protocols for the selective synthesis
of analogues of natural products which are potentially cyto-
toxic against human tumor cell lines,10,11 we decided to
develop a general procedure for the synthesis of carbon±
carbon double bond locked analogues of 1, which are
characterized by a 2-arylcyclopropane ring cis-substituted
at C-1 by the methyl (E)-3-methoxypropenoate unit, and to
evaluate their cytotoxic properties. To our knowledge, this
type of analogue of 1 has not been described so far. Thus, we
examined the possibility of accessing the racemic forms of
three of these analogues, i.e. compounds (1Rp,2Sp)-8a,
(1Rp,2Sp)-8b and (1Rp,2Sp)-8c, by a chemistry similar to
that we used to prepare compounds (1Rp,2Rp)-7a±c.6 In
particular, we speculated that compounds (1Rp,2Sp)-8a±c
might be prepared by a reaction sequence based on the
retrosynthetic analysis depicted in Scheme 1, in which a
key step is the palladium-catalyzed cross-coupling reaction
between easily available methyl (Z)-2-iodo-3-methoxy-
propenoate [(Z)-13]3a,e and the 1-[2-(aryl)cyclopropyl]zinc
bromides (1Rp,2Sp)-12a±c.
We now wish to describe and comment on the results of
these synthetic studies and to report the results of tests to
evaluate the cytotoxic activities exhibited by compounds
(1Rp,2Sp)-8a±c against the NCI 3-cell line panel.
2. Results and discussion
We began our synthetic studies by turning our attention to
the synthesis of compound (1Rp,2Sp)-8a according to the
retrosynthetic analysis depicted in Scheme 1. Thus, a pos-
sible precursor to this compound, i.e. 1,1-dibromo-2-
phenylcyclopropane (10a), which was prepared from
styrene (9a)12 in 88% yield, was converted according to
the literature13 into a stereoisomeric mixture of (1Rp,2Sp)-
and (1Rp,2Rp)-11a by treatment with a freshly prepared
zinc±copper couple in THF and water at room temperature
(Scheme 3).
Puri®cation of this mixture by MPLC on silica gel allowed
isolation of pure (1Rp,2Sp)-11a in 35% yield. This
compound was then converted into the corresponding orga-
nozinc bromide (1Rp,2Sp)-12a by the procedure used in the
literature for the stereospeci®c synthesis of 2-(hetero)aryl-1-
phenylcyclopropanes from a stereoisomeric mixture of
1-bromo-2-phenylcyclopropane and (hetero)aryl halides.12
In particular, (1Rp,2Sp)-11a was reacted with 1.02 equiv.
of butyllithium in THF and hexane at 2908C for 1.5 h and
the resulting mixture was added to a solution of 1.2 equiv. of
ZnBr2 in THF maintained at 2908C, which was then
allowed to warm up to 208C. Finally, 0.83 equiv. of iodide
(Z)-13 and 5 mol% Pd(PPh3)4 were added and the mixture
re¯uxed for 8 h. Unexpectedly, this palladium-catalyzed
reaction provided a mixture of the desired cross-coupled
product (1Rp,2Sp)-8a and methyl (E)-3-methoxy-2-[(E)-3-
phenyl-2-propen-1-yl]propenoate [(E,E)-19], where this
last compound was the major component (Scheme 3). Puri®-
cation of this mixture by MPLC on silica gel allowed
Moreover, we considered the possibility to synthesize alter-
natively compounds (1Rp,2Sp)-8a±c by a reaction sequence
based on the retrosynthetic analysis reported in Scheme 2,
Scheme 2. Alternative retrosynthetic analysis for compounds (1Rp,2Sp)-
8a±c.

A. Carpita et al. / Tetrahedron 58 -2002) 3673±3680
3675
stereospeci®cally (Z)-16c, a mixture of (Z)- and (E)-16c in
a 72:28 molar ratio, respectively, was obtained in 95% yield.
It should also be noted that attempts to prepare stereoiso-
merically pure (Z)-16c from (Z)-15c by stereospeci®c
iodine±silicon exchange with IPy2BF4/HBF4 in acetonitrile
16
or CH2Cl2 under various experimental conditions were
fruitless. In fact, this ipso-substitution reaction provided
mixtures of (Z)- and (E)-16c in 72±40:28±60 molar ratios,
which were also contaminated by 1±7% of 6-methoxy-2-
ethenylnaphthalene derived from protodesilylation of
(Z)-15c. It should also be noted that we did not succeed in
obtaining stereoisomerically pure (Z)-16c even by chro-
matographic puri®cation of mixtures of (Z)- and (E)-16c
in which (Z)-16c was the major component.
Scheme 4. (a) Me3Si±u±MgBr (21)(1.13 equiv.), Pd(PPh3)4 (3.4 mol%),
THF, C6H6, re¯ux, 4.0±5.5 h; (b) HAl(i-Bu)2 (1.00±1.05 equiv.),
N-methylpyrrolidine (1.00±1.05 equiv.), hexane, 60±648C, 70±142 h then
08C, H2O; (c) NIS (2.0 equiv.), CH3CN, room temperature, 35±50 min; (d)
(Z)-17 (1.50 equiv.), Pd(PPh3)4 (5 mol%), THF, 558C, 16.5±22 h; (e)
CF3COOZnCH2I (1.85±4.00 equiv.), CH2Cl2, 0±208C, 1±4 h, then H3O1.
As shown in Scheme 4, compounds (Z)-16a and (Z)-16b as
well as a mixture of (Z)- and (E)-16c in 72:28 molar ratio,
respectively, were then reacted with 1.5 equiv. of TMEDA-
complexed
(Z)-2-methoxy-1-(methoxycarbonyl)ethenyl-
isolation of (1Rp,2Sp)-8a and (E,E)-19 in 6 and 23% yield,
respectively.
zinc iodide [(Z)-17]3e in THF at 558C in the presence of
5 mol% Pd(PPh3)4. Puri®cation by MPLC on silica gel of
the resulting crude cross-coupled products allowed isolation
of methyl (E)-3-methoxy-2-[(Z)-2-(phenyl)ethenyl]pro-
penoate [(E,Z)-18a], methyl (E)-3-methoxy-2-[(Z)-2-(2-
naphthyl)-ethenyl]propenoate [(E,Z)-18b] and methyl
(E)-3-methoxy-2-[(Z)-2-(6-methoxy-2-naphthyl)ethenyl]-
propenoate [(E,Z)-18c] in 41, 72 and 35% yield, respec-
tively. Compounds (E,Z)-18a and (E,Z)-18b were
stereoisomerically pure and (E,Z)-18c had stereoisomeric
purity higher than 97%.
Taking into account this unsatisfactory result, we thought it
right to drop the idea to prepare compounds (1Rp,2Sp)-8b
and (1Rp,2Sp)-8c via the retrosynthetic approach indicated
in Scheme 1 and to verify if the rapid synthesis of
compounds (1Rp,2Sp)-8a±c might be conveniently and
ef®ciently performed using the reaction sequence reported
in Scheme 4, which is based on the retrosynthetic analysis
depicted in Scheme 2.
Whereas one of the possible precursors to compounds
(1Rp,2Sp)-8a±c, i.e. 14a, was commercially available, the
2-aryl-1-trimethylsilylacetylenes 14b and c were prepared
in 88 and 98% yield, respectively, by reaction of aryl
bromides 20b and c with trimethylsilyl-ethynylmagnesium
bromide (21) in THF/benzene in the presence of a catalytic
amount of Pd(PPh3)4. Compounds 14a±c were then
converted into the corresponding (Z)-2-aryl-1-trimethylsilyl-
ethenes (Z)-15a, (Z)-15b and (Z)-15c in 66, 79 and 65%
yield, respectively, by cis-hydroalumination with diisobutyl-
aluminum hydride (DIBAH) and N-methylpyrrolidine in
hexane at 60±648C followed by hydrolysis.14 Treatment of
(Z)-15a and (Z)-15b with 2.0 equiv. of N-iodosuccinimide
(NIS) in acetonitrile at room temperature according to the
method described by Kishi and co-workers15 allowed iso-
lation, in 89 and 86% yield, of iodides (Z)-16a and (Z)-16b
having stereoisomeric purity higher than 97% (Scheme 4).
However, when a similar procedure was used to prepare
Finally, compounds (E,Z)-18a±c were stereospeci®cally
cyclopropanated according to the general procedure which
involves treatment of a CH2Cl2 solution of an alkene with
2.0±4.0 equiv. of the organozinc species generated by
reaction of ZnEt2 with equimolar amounts of tri¯uoroacetic
acid and CH2I2.17 In particular, the cyclopropanation reac-
tion of (E,Z)-18a and (E,Z)-18b required 4.0 equiv. of
CF3COOZnCH2I, occurred at room temperature in 1.5±4 h
and provided pure compounds (1Rp,2Sp)-8a and (1Rp,2Sp)-
8b in 71 and 75% yield, respectively. However, when a
similar molar excess of CF3COOZnCH2I was used for
cyclopropanation of (E,Z)-18c, a complex reaction mixture,
which contained (1Rp,2Sp)-8c, a stereoisomer of this
compound as well as signi®cant amounts of two byproducts
having a molecular ion peak higher by 28 mass units than
(1Rp,2Sp)-8c, was formed.
Nevertheless, it was found that, when the cyclopropanation
Table 1. Results of the cytotoxicity tests for compounds (1Rp,2Sp)-8a±c and (1Rp,2Rp)-6 in the NCI 3-cell line, one dose primary anticancer assay
Entry
Compound
Growth percentage
MCF-7 (Breast)
Activity
SF-269 (CNS)
NCI-H460 (Lung)
1
2
(1Rp,2Sp)-8a
(1Rp,2Sp)-8b
(1Rp,2Sp)-8c
(1Rp,2Rp)-6
83
16
91
67
82
12
106
69
98
3
130
86
Inactive
Active
Inactive
Inactive
3
4a
In the protocol used, each cell line was inoculated and preincubated on a microtiter plate. Tests agents were then added at 1.00£1024 M concentration in DMSO
and the culture incubated for 48 h. End point determinations were made with alamar blue.
See Ref. 9.
a

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A. Carpita et al. / Tetrahedron 58 -2002) 3673±3680
reaction of (E,Z)-18c was performed at 08C for 1 h using
1.85 equiv. of CF3COOZnCH2I, the reaction went to
completion and the amount either of the two above
mentioned byproducts or of the stereoisomer of (1Rp,2Sp)-
8c was minimized. Puri®cation of the crude reaction
mixture allowed us to isolate stereoisomerically pure
(1Rp,2Sp)-8c in 70% yield.
toxic in the NCI 3-cell line, one dose primary anticancer
assay.
4. Experimental
4.1. General
It should also be noted that an attempt to perform alterna-
tively the cyclopropanation reaction of (E,Z)-18a by the
procedure involving treatment of this compound with
4.0 equiv. of diazomethane in diethyl ether at 0±58C in
the presence of a catalytic amount of Pd(OAc)218 was unsuc-
cessful. In fact, this reaction did not provide (1Rp,2Sp)-8a
and compound (E,Z)-18a could be completely recovered
from the reaction mixture.
Melting points and boiling points are uncorrected. Precoated
aluminum silica gel sheets Merck 60 F254 were used for TLC
analyses. GLC analyses were performed on a Dani GC 1000
instrument with a PTV injector, which was equipped with a
Dani data station 86.01. Two types of capillary columns
were used: an Alltech AT-1 bonded FSOT column
(30 m£0.25 mm i.d.) and an Alltech At-35 bonded FSOT
column (30 m£0.25 mm i.d.). Puri®cations by MPLC on
silica gel (Merck silica gel 60, particle size 0.015±
0.040 mm) were performed on a BuÈchi B-680 system
using a Knauer K-2400 differential refractometer as
detector. GLC/MS analyses were performed using a
Perkin±Elmer Q-Mass 910 Mass Spectrometer (quadrupole
mass spectrometer) interfaced with a Perkin±Elmer 8500
gas-chromatograph. NMR spectra were recorded on a
Varian Gemini 200 MHz spectrometer or on a Bruker
AMX 600 spectrometer using TMS and CDCl3 as an
internal standard. The structure of compound (E,E)-19
With compounds (1Rp,2Sp)-8a±c now readily available,
their evaluation in the NCI 3-cell line, one dose primary
anticancer assay at a 1.00£1024 M concentration was
performed. This 3-cell line panel consisted of SF-269
(CNS), MCF-7 (Breast) and NCI-H460 (Lung). The results
for each test agent are reported in Table 1 as percent of
growth of the treated cells when compared to the untreated
control cells. As shown from the data reported in this table,
where the cytotoxicity values of compounds (1Rp,2Sp)-8a±c
are compared to those recently found for (1Rp,2Rp)-6,9
whereas compounds (1Rp,2Sp)-8a, (1Rp,2Rp)-6 and
(1Rp,2Sp)-8c were inactive, compound (1Rp,2Sp)-8b, which
represents an analogue of strobilurin A in which the Z and E
double bonds of the lipophilic subunit of this natural product
are locked in a cis-1,2-disubstituted cyclopropane ring and
in an aromatic ring of a 2-naphthyl system, respectively,
was found to be signi®cantly cytotoxic against the NCI-3-
cell line panel. Thus, these data seem to indicate that: (i) the
presence of a 2-naphthyl ring linked at C-2-of a cyclo-
propane ring cis-substituted at C-1 by the methyl (E)-3-
methoxypropenoate unit is bene®cial to cytotoxicity of
analogues of strobilurins, which are characterized by a
cis-1,2-disubstituted cyclopropane ring; (ii) the introduction
of a 6-methoxy-2-naphthyl group in place of the 2-naphthyl
group abolishes cytotoxicity.
1
was assigned on the basis of its H NMR and 13C NMR
spectra at 600 and 150 MHz, respectively, and by a combi-
1
nation of NMR techniques which included H±1H COSY,
NOESY (mixing time: 400 ms), Heteronuclear Multiple
Quantum Coherence (HMQC) and HMBC (Heteronuclear
Multiple Bond Correlation). All reactions of air and water
sensitive materials were performed in ¯ame dried glassware
under an atmosphere of nitrogen or argon using standard
syringe, cannula and septa techniques. Solvents were dried
and distilled before use. The following compounds were
prepared by published procedures: (Z)-13,3a,e 10a,12
Pd(PPh3)4,19 (Z)-17,3e and diazomethane.20 All the other
reagents are commercially available and were used as
purchased.
4.1.1. ꢀ1Rp,2Sp)-1-Bromo-2-phenylcyclopropane [ꢀ1Rp,2Sp)-
11a]. To a stirred solution of glacial acetic acid (125 ml) and
Cu(OAc)2 (2.50 g, 12.5 mmol), which was heated to 1108C,
was added zinc powder (25.0 g, 382.0 mmol) rapidly. The
mixture was stirred for an additional 1 min and then ®ltered
hot. The resulting couple was washed with acetic acid
(30 ml) and diethyl ether (2£30 ml) and heated under
vacuum (1208C, 0.05 mbar) for 3 h. After cooling to room
temperature, THF (155 ml) was added to the couple and the
mixture was stirred while 1,1-dibromo-2-phenylcyclo-
propane (10a) (13.47 g, 48.8 mmol) and deaerated water
(12.5 ml) were added rapidly. The resulting reaction
mixture was stirred overnight and then ®ltered through
Celite. The ®ltrate was concentrated under reduced pressure
(200 mbar) and the residue was puri®ed by MPLC on silica
gel using hexane as eluant to give (1Rp,2Sp)-11a (3.35 g,
35% yield) as a colorless liquid. Bp 748C/1 mbar (lit.21 bp
60±628C/0.8 Torr). MS, m/z (%): 118 (10), 117 (100), 116
(11), 115 (56), 91 (23), 89 (7), 77 (3). 1H NMR (200 MHz,
CDCl3): d 7.29±7.25 (5H, m), 3.30 (1H, ddd, Jˆ8.0, 7.0,
5.0 Hz), 2.30 (1H, ddd, Jˆ9.5, 8.0, 7.0 Hz), 1.56 (1H, ddd,
Jˆ9.5, 7.0, 6.5 Hz), 1.31 ppm (1H, ddd, Jˆ7.0, 6.5, 5.0 Hz).
3. Conclusions
In this study, we developed a concise procedure for the
synthesis of the racemic forms of three carbon±carbon
double bond locked analogues of naturally-occurring
strobilurins 1, which are characterized by a 2-arylcyclopro-
pane ring cis-substituted at C-1 by the methyl (E)-3-meth-
oxypropenoate unit. The strategy used to prepare these
compounds, which involves the palladium-catalyzed syn-
thesis of methyl (E)-3-methoxy-2-[(Z)-2-(aryl)ethenyl]-
propenoates and their stereospeci®c cyclopropanation, is
very ¯exible and appears to be suitable for the synthesis
of a large variety of analogues of 1 in which the Z and E
carbon±carbon double bonds present in the lipophilic
subunit of these natural substances are locked in a cis-1,2-
disubstituted cyclopropane ring and in an aromatic ring,
respectively. Finally, it should be noted that one of the
analogues of 1, which was prepared in this study, i.e.
compound (1Rp,2Sp)-8b, proved to be signi®cantly cyto-

A. Carpita et al. / Tetrahedron 58 -2002) 3673±3680
3677
The spectral properties of this compound were in agreement
with those reported in the literature.21
mixture was re¯uxed for 5.5 h, then cooled to room
temperature, poured into a cold saturated aqueous NH4Cl
solution (250 ml) and extracted with diethyl ether
(4£70 ml). The organic extract was washed with brine,
dried over Na2SO4 and concentrated under reduced
pressure. The residue was puri®ed by MPLC on silica gel,
using hexane as eluant, to give 14b (11.58 g, 88% yield) as a
colorless solid. Mp 45±478C (lit.22 mp 44±44.58C). MS, m/z
(%): 224 (25), 210 (21), 209 (100), 179 (12), 155 (13), 104
4.1.2. Conversion of ꢀ1Rp,2Sp)-11a into the correspond-
ing organozinc bromide, ꢀ1Rp,2Sp)-12a, and palladium-
catalyzed reaction between this organometallic
compound and methyl ꢀZ)-2-iodo-3-methoxypropenoate
[ꢀZ)-13]. A 1.77 M hexane solution of butyllithium
(4.75 ml, 8.57 mmol) was added over 5 min to a solution
of (1Rp,2Sp)-11a (1.65 g, 8.40 mmol) in THF (6 ml), which
was stirred at 2908C. After stirring for 1.5 h, a solution of
ZnBr2 (2.27 g, 10.1 mmol) in THF (10 ml), which was
cooled to 2508C, was added and the mixture was stirred
for 1 h while the temperature was allowed to reach room
temperature. A solution of compound (Z)-13 (1.70 g,
7.00 mmol) in THF (10 ml) and Pd(PPh3)4 (404 mg,
0.350 mmol) were then added sequentially and the resulting
mixture was stirred at room temperature for 27 h. It was then
poured into a cold saturated aqueous NH4Cl solution
(100 ml) and extracted with benzene (4£30 ml). A GLC
analysis of the organic extract, which was washed with
H2O (2£10 ml) and dried with Na2SO4, showed the presence
of two new compounds in a ca. 1:3.7 molar ratio. The
organic extract was concentrated under reduced pressure
and the residue was puri®ed by MPLC on silica gel using
benzene as eluant. Concentration of the ®rst eluted chroma-
tographic fractions allowed us to obtain methyl (E)-3-meth-
oxy-2-[(E)-(3-phenyl-2-propen-1-yl]propenoate [(E,E)-19]
(0.40 g, 23% yield) as a pale yellow liquid. MS, m/z (%):
232 (1), 201 (11), 200 (55), 141 (87), 128 (68), 115 (100), 91
1
(29), 90 (13). H NMR (200 MHz, CDCl3): d 7.99 (1H, br
s), 7.83±7.72 (3H, m), 7.53±7.42 (3H, m), 0.28 ppm (9H, s).
4.1.4. 1-ꢀ6-Methoxy-2-naphthyl)-2-trimethylsilylacetyl-
ene ꢀ14c). This compound was prepared in 98% yield start-
ing from 2-bromo-6-methoxynaphthalene (20c) according
to the same procedure used for the synthesis of 14b from
20b. Compound 14c was a colorless solid. Mp 99±1028C.
MS, m/z (%): 254 (54), 239 (100), 224 (5), 196 (14), 166 (5),
119 (8), 98 (5). IR (KBr): n 2154, 1247, 1031, 857,
1
839 cm21. H NMR (200 MHz, CDCl3): d 7.92 (1H, d,
Jˆ2.0 Hz), 7.68 (1H, d, Jˆ8.5 Hz), 7.64 (1H, d, Jˆ
8.0 Hz), 7.46 (1H, dd, Jˆ8.5, 2.0 Hz), 7.14 (1H, dd, Jˆ
8.0, 2.0 Hz), 7.09 (1H, d, Jˆ2.0 Hz), 3.91 (3H, s),
0.20 ppm (9H, s). Anal. calcd for C16H18OSi: C, 75.54; H,
7.13. Found: C, 75.73; H, 7.21.
4.1.5. ꢀZ)-1-Phenyl-2-trimethylsilylethene [ꢀZ)-15a]. A
1 M hexane solution of diisobutylaluminum hydride
(DIBAH) (57.5 ml, 57.5 mmol) was added dropwise to
N-methylpyrrolidine (4.89 g, 57.5 mmol). The resulting
solution was then added dropwise to a stirred solution of
1-phenyl-2-trimethylsilylacetylene (14a) (10.02 g, 57.5
mmol) in hexane (40 ml) and the mixture was heated for
142 h at 60±648C. After cooling to room temperature, water
(25 ml) was cautiously added. Potassium sodium tartrate
tetrahydrate (10.0 g) and hexane (100 ml) were then added
to the suspension and the mixture was stirred for 0.5 h and
then ®ltered. The ®ltrate was extracted with hexane
(2£40 ml) and the organic extract was dried over Na2SO4
and concentrated under reduced pressure (260 mbar). The
residue was fractionally distilled to give a mixture of
(Z)-15a and 14a (8.80 g) in a ca. 73:27 molar ratio, respec-
tively. This mixture was dissolved in methanol (30 ml),
treated with a 1 M KOH solution (20.0 ml, 20.0 mmol)
and the resulting solution was stirred for 3 h at room
temperature. It was then extracted with pentane (5£30 ml)
and the organic extract was washed with brine, dried
over Na2SO4 and concentrated under reduced pressure
(260 mbar). The residue was fractionally distilled to give
pure (Z)-15a (6.63 g, 66% yield) as a colorless liquid. Bp
638C/2 mbar (lit.14 bp 43±448C/0.2 Torr). MS, m/z (%): 176
(18), 161 (100), 146 (13), 145 (85), 135 (42), 115 (12), 77
1
(58). IR (®lm): n 1708, 1646, 1195, 1247, 1107 cm21. H
NMR (600 MHz, CDCl3): d 7.35, (1H, s), 7.32 (2H, d,
Jˆ7.5 Hz), 7.25 (2H, t, Jˆ7.5 Hz), 7.16 (1H, t, Jˆ
7.5 Hz), 6.40 (1H, dt, Jˆ16.0, 2.0 Hz), 6.21 (1H, dt,
Jˆ16.0, 6.5 Hz), 3.82 (3H, s), 3.71 (3H, s), 3.13 ppm (2H,
dd, Jˆ6.5, 2.0 Hz). 13C NMR (150 MHz, CDCl3): d 168.5,
159.2, 137.8, 130.0, 128.3 (2C), 127.7, 126.8, 126.0 (2C),
108.8, 61.4, 51.2, 27.3 ppm. Anal. calcd for C14H16O3: C,
72.39; H, 6.94. Found: C, 72.15; H, 6.77.
On the other hand, concentration of the last eluted chroma-
tographic fraction allowed isolation of methyl (E) (1Rp,2Sp)-
3-methoxy-2-[2-(phenyl)cyclopropyl]propenoate [(1Rp,2Sp)-
8a] (0.11 g, 6% yield) as a pale yellow liquid. MS, m/z (%):
200 (63), 141 (100), 129 (60), 128 (82), 115 (83), 91 (43), 75
1
(41). IR (®lm): n 1712, 1640, 1245, 1113, 1078 cm21. H
NMR (200 MHz, CDCl3): d 7.35 (1H, s), 7.22±6.98 (5H, br
m), 3.64 (3H, s), 3.48 (3H, s), 2.30 (1H, pseudo-dt, Jˆ8.5,
6.0 Hz), 1.83 (1H, pseudo-ddt, Jˆ8.5, 6.0, 1.5 Hz), 1.51
(1H, pseudo-q, Jˆ6.0 Hz), 1.31 ppm (1H, pseudo-dt, Jˆ
8.5, 6.0 Hz). 13C NMR (50.3 MHz, CDCl3): d 168.9,
161.2, 139.3, 127.5 (2C), 127.3 (2C), 125.2, 106.6, 61.4,
50.9, 22.4, 16.7, 11.1 ppm. Anal. calcd for C14H16O3: C,
72.39; H, 6.94. Found: C, 72.21; H, 7.06.
1
(11). IR (®lm): n 1604, 1469, 1252, 851, 780 cm21. H
NMR (200 MHz, CDCl3): d 7.36 (1H, d, Jˆ15.0 Hz),
7.22 (5H, s), 5.83 (1H, d, Jˆ15.0 Hz), 0.03 ppm (9H, s).
The spectral properties of this compound were in agreement
with those previously reported.23
4.1.3. 1-ꢀ2-Naphthyl)-2-trimethylsilylacetylene ꢀ14b).
Trimethylsilylacetylene (6.71 g, 68.3 mmol) was slowly
added to a 1.30 M THF solution of ethylmagnesium bro-
mide (52.5 ml, 68.3 mmol) and the resulting mixture was
maintained for 1 h under gentle re¯ux. It was then cooled to
room temperature and added to a solution of 2-bromo-
naphthalene (20b) (12.52 g, 60.46 mmol) and Pd(PPh3)4
(2.40 g, 2.10 mmol) in benzene (70 ml). The resulting
4.1.6. ꢀZ)-1-ꢀ2-Naphthyl)-2-trimethylsilylethene [ꢀZ)-15b].
Compound 14b (11.58 g, 51.61 mmol) was reacted with
a 1 M hexane solution of DIBAH (54.2 ml, 54.2 mmol)
and N-methylpyrrolidine (4.62 g, 54.2 mmol) for 70 h
at 60±648C according to the same procedure for

3678
A. Carpita et al. / Tetrahedron 58 -2002) 3673±3680
cis-hydroalumination of 14a. The crude reaction product,
which was obtained after hydrolysis of the reaction mixture
followed by extraction with hexane (5£70 ml) and concen-
tration of the organic extract under reduced pressure, was
puri®ed by MPLC on silica gel, using hexane as eluant, to
give (Z)-15b (9.18 g, 79% yield) as a colorless liquid. MS,
m/z (%): 226 (39), 211(100), 195 (74), 155 (14), 152 (32),
127 (8), 99 (7). IR (®lm): n 1603, 1588, 1247, 857,
4.1.9. ꢀZ)-1-Iodo-2-ꢀ2-naphthyl)ethene [ꢀZ)-16b]. This
compound, having stereoisomeric purity higher than 97%,
was prepared in 86% yield from (Z)-15b according to
the same procedure used for the synthesis of (Z)-16a from
(Z)-15a. Compound (Z)-16b was a yellow solid. Mp
66±688C. MS, m/z (%): 280 (1), 153 (4), 152 (76), 151
(100), 126 (44), 125 (15), 75 (54). IR (KBr): n 1587,
1
1354, 1310, 862, 822 cm21. H NMR (200 MHz, CDCl3):
840 cm21
.
1H NMR (200 MHz, CDCl3): d 7.87±7.68
d 8.10 (1H, br s), 7.91±7.69 (3H, m), 7.57±7.40 (4H, m),
6.65 ppm (1H, d, Jˆ8.5 Hz). 13C NMR (50.3 MHz, CDCl3):
d 149.8, 138.5, 134.1, 128.4, 128.2, 127.8, 127.7 (2C),
126.4, 126.3, 125.8, 79.7 ppm. Anal. calcd for C12H9I: C,
51.45; H, 3.24. Found: C, 51.57; H, 3.44.
(4H, m), 7.55±7.34 (4H, m), 5.92 (1H, d, Jˆ15.0 Hz),
0.09 ppm (9H, s). Anal. calcd for C15H18Si: C, 79.57; H,
8.01. Found: C, 79.67; H, 7.89. GLC/MS analysis showed
that (Z)-15b was chemically pure and had 96% stereo-
isomeric purity.
4.1.10. ꢀZ)-1-Iodo-2-ꢀ6-methoxy-2-naphthyl)ethene [ꢀZ)-
16c]. Some attempts were made to prepare (Z)-16c having
high stereoisomeric purity by reaction of (Z)-15c with NIS
in acetonitrile at room temperature or at 08C using a
NIS:(Z)-15c molar ratio of 2 or 5. The best result was
obtained using the following modi®cation of the procedure
used to prepare (Z)-16a and (Z)-16b. A solution of (Z)-15c
(1.50 g, 5.85 mmol) in acetonitrile (13.5 ml) was added in
30 min to a solution of NIS (2.63 g, 11.7 mmol) in aceto-
nitrile (15 ml) and the resulting mixture was stirred at room
temperature for 35 min. It was then poured into a saturated
aqueous Na2S2O3 solution (50 ml) and the mixture was
stirred for 10 min and then extracted with a 1:1 mixture of
hexane and AcOEt (5£40 ml). The organic extract was
washed with 0.5N aqueous NaOH and brine, dried over
Na2SO4 and concentrated under reduced pressure. GLC/
MS analysis of the residue showed the presence of two
compounds in a ca. 28:72 molar ratio, which were subse-
quently identi®ed as (E)- and (Z)-16c, respectively. The
residue was puri®ed by MPLC on silica gel, using a mixture
of hexane and benzene (85:15) as eluant, to give (Z)-16c
contaminated by ca. 28% of the corresponding (E)-stereo-
isomer (1.72 g, 95% yield) as a pale yellow solid. Mp 88±
958C. Some MS data for (Z)-16c are as follows. MS, m/z
(%): 310 (100), 183 (24), 168 (19), 152 (13), 140 (32), 139
(48), 114 (11). Some MS data for (E)-16c are as follows.
MS, m/z (%): 310 (100), 183 (21), 168 (18), 152 (12), 140
4.1.7.
ꢀZ)-1-ꢀ6-Methoxy-2-naphthyl)-2-trimethylsilyl-
ethene [ꢀZ)-15c]. Compound 14c (12.00 g, 47.17 mmol)
was reacted with a 1 M hexane solution of DIBAH
(49.5 ml, 49.5 mmol) and N-methylpyrrolidine (4.20 g,
49.5 mmol) for 137 h at 60±648C according to the same
procedure used for cis-hydroalumination of 14a. T he
crude reaction product, which was obtained by hydrolysis
of the reaction mixture followed by extraction with diethyl
ether (5£70 ml) and concentration of the dried organic
extract, was puri®ed by MPLC on silica gel, using a mixture
of petroleum ether and benzene (95:5) as eluant, to give
98% chemically pure (Z)-15c (7.83 g, 65% yield) as a color-
less solid. Mp 64±678C. MS, m/z (%): 256 (83), 242 (22),
241 (100), 225 (44), 215 (26), 152 (12), 139 (19). IR (KBr):
n 1626, 1605, 1586, 1251, 837 cm21. H NMR (200 MHz,
1
benzene-d6): d 7.68 (1H, br s), 7.53 (1H, d, Jˆ15.0 Hz),
7.54±7.42 (2H, m), 7.22±7.12 (2H, m), 6.90 (1H, d, Jˆ
2.5 Hz), 5.93 (1H, d, Jˆ15.0 Hz), 3.38 (3H, s), 0.15 ppm
(9H, s). Anal. calcd for C16H20OSi: C, 74.94; H, 7.87.
1
Found: C, 75.09; H, 7.76. GLC/MS and H NMR analyses
showed that (Z)-15c was stereoisomerically pure. It
should be noted that, when the 1H NMR spectrum of
(Z)-15c was recorded in CDCl3, this compound underwent
stereomutation after few minutes at room temperature.
4.1.8. ꢀZ)-1-Iodo-2-phenylethene [ꢀZ)-16a]. N-iodosuc-
cinimide (NIS) (15.29 g, 67.94 mmol) was added to a solution
of (Z)-15a (5.99 g, 34.0 mmol) in acetonitrile (35 ml) and
the resulting mixture was stirred for 40 min at room
temperature. It was then poured into a cold saturated
aqueous Na2S2O3 solution (50 ml) and the mixture was
stirred for 10 min and then extracted with a 1:1 mixture of
hexane and AcOEt (4£40 ml). The organic extract was
washed with 1N aqueous NaOH and brine, dried over
Na2SO4 and concentrated under reduced pressure
(100 mbar). The residue was fractionally distilled to give
chemically pure (Z)-16a (6.91 g, 89% yield) as a yellow
liquid. Bp 578C/0.5 mbar (lit.24 60.58C/0.5 Torr). MS, m/z
(%): 230 (54), 128 (10), 127 (72), 103 (100), 102 (25), 77
(53), 76 (12). IR (®lm): n 1599, 1493, 1298, 1262,
1
(30), 139 (46), 114 (10). The H NMR data for (Z)-16c
contaminated by (E)-16c are as follows. 1H NMR
(200 MHz, CDCl3): d 8.04 (0.72H, br s), 7.77 (0.28H, br
s), 7.75±7.55 (3H, m), 7.53 (0.28H, d, Jˆ15.0 Hz), 7.43
(0.72H, d, Jˆ8.5 Hz), 7.18±7.06 (2H, m), 6.86 (0.28H, d,
Jˆ15.0 Hz), 6.56 (0.72H, d, Jˆ8.5 Hz), 3.92 (2.16H, s),
3.91 ppm (0.84H, s). The 13C NMR data for (E)-16c are as
follows. 13C NMR (50.3 MHz, CDCl3):d 158.1, 144.9,
134.2, 132.9, 129.6, 128.5, 127.1, 126.4, 125.9, 119.2,
105.7, 75.5, 55.3 ppm. The 13C NMR data for (Z)-16c are
as follows. 13C NMR (50.3 MHz, CDCl3):d 158.1, 138.4,
134.2, 131.8, 129.7, 128.3, 127.7, 126.4, 123.2, 119.1,
105.6, 78.4, 55.3 ppm. IR (KBr): n 1480, 1311, 1242,
1166, 854 cm21. Anal. calcd for C13H11IO: C, 50.35; H,
3.58. Found: C, 50.21; H, 3.65.
817 cm21. H NMR (200 MHz, CDCl3): d 7.67±7.59 (2H,
1
m), 7.38±7.32 (3H, m), 7.31 (1H, d, Jˆ8.5 Hz), 6.56 (1H, d,
1
128.6 (2C), 128.5, 128.3 (2C), 79.3 ppm. GLC/MS and H
NMR analyses showed that (Z)-16a had stereoisomeric
purity higher than 97%. The spectral properties of this
compound were in agreement with those reported in the
literature.25
Jˆ8.5 Hz). 13C NMR (50.3 MHz, CDCl3): d 138.8, 136.9,
4.1.11. Methyl ꢀE)-3-methoxy-2-[ꢀZ)-2-ꢀphenyl)ethenyl]-
propenoate [ꢀE,Z)-18a]. A 0.44 M THF solution of
TMEDA-complexed (Z)-2-methoxy-1-(methoxycarbonyl)-
ethenylzinc iodide [(Z)-17]3e (98.6 ml, 43.4 mmol) was
added to a solution of (Z)-16a (6.65 g, 28.9 mmol) and
Pd(PPh3)4 (1.67 g, 1.45 mmol) in THF (84 ml), which was

A. Carpita et al. / Tetrahedron 58 -2002) 3673±3680
3679
prepared immediately prior to use, and the resulting mixture
was stirred for 20 h at 558C. The crude reaction product,
which was obtained after usual workup, was puri®ed by
MPLC on silica gel, using benzene as eluant, to give pure
(E,Z)-18a (2.57 g, 41% yield) as a yellow liquid. MS, m/z
(%): 218 (20), 186 (17), 155 (19), 144 (18), 128 (21), 115
(100), 75 (63). IR (®lm): n 1708, 1632, 1606, 1245,
1109 cm21. 1H NMR (200 MHz, CDCl3): d 7.25±7.17 (6H,
m), 6.56 (1H, d, Jˆ12.0 Hz), 6.15 (1H, dd, Jˆ12.0, 1.0 Hz),
3.66 (3H, s), 3.48 ppm (3H, s). 13C NMR (50.3 MHz,
CDCl3): d 167.9, 159.3, 138.4, 131.7, 127.9 (2C), 127.7
(2C), 126.8, 119.6, 108.5, 61.6, 51.3 ppm. Anal. calcd for
C13H14O3: C, 71.54; H, 6.46. Found: C, 71.49; H, 6.79.
tri¯uoroacetic acid (1.96 g, 17.2 mmol) in freshly distilled
CH2Cl2 (8 ml) was added over 20 min to a stirred mixture of
a 1 M hexane solution of ZnEt2 (17.2 ml, 17.2 mmol) and
CH2Cl2 (17 ml), which was stirred at 08C under argon. Upon
stirring for 20 min at 08C, a solution of CH2I2 (4.61 g,
17.2 mmol) in CH2Cl2 (7 ml) was added. After an additional
20 min at 08C a solution of (E,Z)-18a (1.00 g, 4.30 mmol) in
CH2Cl2 (6 ml) was added and the resulting suspension was
stirred at room temperature for 4 h. It was then poured into a
cold saturated aqueous NH4Cl solution (60 ml) and
extracted with benzene (3£50 ml). The organic extract
was washed with water, dried over Na2SO4 and concentrated
under reduced pressure. The residue was puri®ed by MPLC
on silica gel, using benzene as eluant, to give pure (1Rp,2Sp)-
8a (0.75 g, 71% yield) as a pale yellow liquid. The spectral
properties of this compound were in good agreement with
those of (1Rp,2Sp)-8a prepared by palladium-catalyzed
reaction between (1Rp,2Sp)-12a and (Z)-13.
4.1.12. Methyl ꢀE)-3-methoxy-2-[ꢀZ)-2-ꢀ2-naphthyl)-
ethenyl]propenoate [ꢀE,Z)-18b]. Compound (Z)-16b
(4.92 g, 17.6 mmol) was reacted with a 0.44 M THF solu-
tion of (Z)-17 (59.9 ml, 26.4 mmol) at 558C for 16.5 h in the
presence of Pd(PPh3)4 (1.02 g, 0.88 mmol) according to the
same procedure used to prepare (E,Z)-18a. The crude reac-
tion product, which was obtained after usual workup, was
puri®ed by MPLC on silica gel, using benzene as eluant, to
give pure (E,Z)-18b (3.41 g, 72% yield) as a yellow liquid.
MS, m/z (%): 268 (51), 237 (30), 209 (22), 193 (11), 178
(42), 165 (100), 75 (43). IR (®lm): n 1706, 1633, 1606,
4.1.15. Methyl ꢀE)ꢀ1Rp,2Sp)-3-methoxy-2-[2-ꢀ2-naph-
thyl)-cyclopropyl]propenoate [ꢀ1Rp,2Sp)-8b]. An ice
cooled solution of CF3COOZnCH2I was prepared from a
1 M hexane solution of ZnEt2 (26.1 ml, 26.1 mmol),
tri¯uoroacetic acid (2.97 g, 26.1 mmol), CH2I2 (6.99 g,
26.1 mmol) and CH2Cl2 (38 ml) according to the procedure
employed for the preparation of (1Rp,2Sp)-8a. This solution
was stirred under argon at 08C for 20 min, then a solution of
(E,Z)-18b (1.75 g, 6.52 mmol) in freshly distilled CH2Cl2
(9 ml) was added and the resulting mixture was stirred for
1.5 h at room temperature. The crude reaction product,
which was obtained after usual workup, was puri®ed by
MPLC on silica gel, using a mixture of hexane and diethyl
ether (80:20) as eluant, to give pure (1Rp,2Sp)-8b (1.38 g,
75% yield) as a pale yellow solid. Mp 64±668C. MS, m/z
(%): 282 (13), 250 (81), 191 (100), 178 (59), 165 (63), 141
(27), 89 (30). IR (KBr): n 1707, 1632, 1243, 1111,
1
1244, 1102 cm21. H NMR (200 MHz, CDCl3): d 7.83±
7.58 (3H, m), 7.67 (1H, s), 7.50±7.34 (3H, m), 7.26 (1H,
s), 6.72 (1H, d, Jˆ12.0 Hz), 6.24 (1H, d, Jˆ12.0 Hz), 3.61
(3H, s), 3.46 ppm (3H, s). 13C NMR (50.3 MHz, CDCl3): d
167.9, 159.5, 136.0, 133.1, 132.3, 131.6, 127.9, 127.4,
127.2, 127.1, 125.9, 125.8, 125.6, 119.9, 108.6, 61.6,
51.3 ppm. Anal. calcd for C17H16O3: C, 76.10; H, 6.01.
Found: C, 76.05; H, 6.26.
4.1.13. Methyl ꢀE)-3-methoxy-2-[ꢀZ)-2-ꢀ6-methoxy-2-
naphthyl)ethenyl]propenoate [ꢀE,Z)-18c]. A mixture of
(Z)- and (E)-16c (Z/Eˆ72:28; 8.34 g, 26.9 mmol) was
reacted at 558C for 22 h with a 0.44 M THF solution of
(Z)-17 (91.6 ml, 40.3 mmol) in the presence of Pd(PPh3)4
(1.55 g, 1.34 mmol) according to the same procedure used
to prepare (E,Z)-18a. The crude reaction product, which was
obtained after usual workup, was puri®ed by MPLC on
silica gel, using a mixture of toluene and AcOEt (94:6) as
eluant. The chromatographic fractions which contained
(E,Z)-18c were collected and concentrated under reduced
pressure and the residue was puri®ed by MPLC on silica
gel, using a mixture of toluene and AcOEt (94:6) as eluant,
to give 97% stereoisomerically pure (E,Z)-18c (2.78 g, 35%
yield) as a pale yellow solid. Mp 98±1008C. MS, m/z (%):
298 (100), 267 (57), 235 (29), 208 (51), 195 (76), 152 (60),
75 (38). IR (KBr): n 1694, 1599, 1265, 1224, 1104 cm21. 1H
NMR (200 MHz, CDCl3): d 7.72±7.56 (3H, m), 7.41 (1H,
dd, Jˆ8.5, 1.5 Hz), 7.26 (1H, d, Jˆ1.0 Hz), 7.09 (1H, dd,
Jˆ8.5, 2.5 Hz), 7.07 (1H, s), 6.69 (1H, d, Jˆ12.0 Hz), 6.19
(1H, dd, Jˆ12.0, 1.0 Hz), 3.90 (3H, s), 3.65 (3H, s),
3.48 ppm (3H, s). 13C NMR (50.3 MHz, CDCl3): d 168.0,
159.3, 157.6, 133.8, 133.5, 131.7, 129.4, 128.6, 127.1,
126.5, 125.9, 119.0, 118.6, 108.8, 105.6, 61.6, 55.2,
51.4 ppm. Anal. calcd for C18H18O4: C, 72.46; H, 6.08.
Found: C, 72.66; H, 6.10.
1080 cm21 1H NMR (200 MHz, CDCl3): d 7.82±7.64
.
(3H, m), 7.48±7.36 (3H, m), 7.26 (1H, dd, Jˆ8.5, 1.5 Hz),
7.17 (1H, d, Jˆ1.0 Hz), 3.65 (3H, s), 3.49 (3H, s), 2.50 (1H,
pseudo-dt, Jˆ8.5, 6.5 Hz), 1.96 (1H, pseudo-ddt, Jˆ9.0, 6.5
1.0 Hz), 1.75 (1H, pseudo-q, Jˆ6.5 Hz), 1.42 ppm (1H,
pseudo-dt, Jˆ8.5, 6.0 Hz). 13C NMR (50.3 MHz, CDCl3):
d 168.9, 161.2, 137.1, 133.1, 131.8, 127.3 (2C), 127.2,
126.6, 125.5, 125.4, 124.7, 106.5, 61.5, 51.0, 22.7, 17.2,
11.0 ppm. Anal. calcd for C18H18O3: C, 76.57; H, 6.43.
Found: C, 76.40; H, 6.38.
4.1.16. Methyl ꢀE)ꢀ1Rp,2Sp)-3-methoxy-2-[2-ꢀ6-methoxy-
2-naphthyl)-cyclopropyl]propenoate [ꢀ1Rp,2Sp)-8c]. An
ice cooled solution of CF3COOZnCH2I was prepared from
a 1 M hexane solution of ZnEt2 (7.0 ml, 7.0 mmol), tri-
¯uoroacetic acid (0.52 ml, 7.0 mmol), CH2I2 (1.87 g,
7.0 mmol) and CH2Cl2 (13 ml) according to the procedure
employed for the preparation of (1Rp,2Sp)-8a. This solution
was stirred under argon at 08C for 20 min, then a solution of
(E,Z)-18c (1.13 g, 3.80 mmol) in freshly distilled CH2Cl2
(5 ml) was added and the resulting mixture was stirred for
1 h at 08C. The crude reaction product, which was obtained
after usual workup, was puri®ed by MPLC on silica gel,
using a mixture of toluene and AcOEt (96:4) as eluant, to
give pure (1Rp,2Sp)-8c (0.827 g, 70% yield) as a pale yellow
solid. Mp 81±82.58C. MS, m/z (%): 312 (54), 280 (68), 221
(100), 195 (34), 178 (26), 165 (49), 141 (25). IR (KBr): n
4.1.14. Methyl ꢀE)ꢀ1Rp,2Sp)-3-methoxy-2-[2-ꢀphenyl)-
cyclopropyl]propenoate [ꢀ1Rp,2Sp)-8a]. A solution of

3680
A. Carpita et al. / Tetrahedron 58 -2002) 3673±3680
1
1702, 1630, 1250, 1112, 1082 cm21. H NMR (200 MHz,
CDCl3): d 7.64±7.52 (2H, m), 7.35 (1H, br s), 7.19 (1H, dd,
Jˆ8.5, 1.5 Hz), 7.13 (1H, d, Jˆ1.5 Hz), 7.10±7.04 (1H, m),
7.05 (1H, s), 3.88 (3H, s), 3.61 (3H, s), 3.46 (3H, s), 2.43
(1H, pseudo-dt, Jˆ8.5, 6.5 Hz), 1.89 (1H, pseudo-ddt,
Jˆ9.0, 6.5, 1.0 Hz), 1.68 (1H, pseudo-dt, Jˆ6.5, 5.5 Hz),
1.36 ppm (1H, pseudo-dt, Jˆ8.5, 5.5 Hz). 13C NMR
(50.3 MHz, CDCl3): d 168.9, 161.0, 156.8, 134.6, 132.7,
128.8, 128.5, 127.7, 125.5, 125.3, 118.2, 106.6, 105.4,
61.4, 55.2, 50.9, 22.5, 16.8, 10.8 ppm. Anal. calcd for
C19H20O4: C, 73.06; H, 6.45. Found: C, 73.36; H, 6.48.
5. (a) Fredenhagen, A.; KuÈhn, A.; Peter, H. H.; Cuomo, V.;
Giuliano, U. J. Antibiot. 1990, 43, 655±660. (b) Fredenhagen,
A.; Hug, P.; Peter, H. H. J. Antibiot. 1990, 43, 661±667.
(c) Masuko, M. Annu. Rep. Shionogi Res. Lab. 1997, 47,
33±57.
6. Rossi, R.; Carpita, A.; Ribecai, A.; Mannina, L. Tetrahedron
2001, 57, 2847±2856.
7. Weber, W.; Anke, T.; Bross, M.; Steglich, W. Planta Med.
1990, 56, 446±450.
8. Weber, W.; Anke, T.; Steffan, B.; Steglich, W. J. Antibiot.
1990, 43, 207±212.
9. Rossi, R.; Carpita, A.; Ribecai, A. Unpublished results.
10. Bellina, F.; Anselmi, C.; Viel, S.; Mannina, L.; Rossi, R.
Tetrahedron 2001, 57, 9997±10007.
Acknowledgements
11. Bellina, F.; Anselmi, C.; Rossi, R. Tetrahedron Lett. 2002, 43,
2023±2027.
This work was supported by the Ministero dell'Istruzione,
Á
dell'Universita e della Ricerca (MIUR) and the University
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1
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 Â
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