Stereo- and regioselectivity of cyclization reactions in conformationally restricted epoxy ketones: Evaluation of C- versus O-alkylation process

Article abstract of DOI:10.1016/S0040-4020(01)00817-1

The intramolecular addition reaction of metal enolates of ketones to oxiranes has been applied to a series of epoxy ketones derived from cyclohexene oxide. γ-Hydroxy ketones (γ-HKs, C-alkylation products) or hydroxy enol ethers (HEEs, O-alkylation products) are obtained, depending on the nature of the cyclic transition state in each case involved and the application of the Fu?rst-Plattner rule. The formation of HEEs by reaction of the same epoxy ketones under acid conditions is also described. In some cases, regioconvergent or chemoselective processes are conveniently obtained.

Full text of DOI:10.1016/S0040-4020(01)00817-1

TETRAHEDRON
Pergamon
Tetrahedron 57 .2001) 8559±8572
Stereo- and regioselectivity of cyclization reactions in
conformationally restricted epoxy ketones: evaluation of C- versus
O-alkylation process
Paolo Crotti,p Fabrizio Badalassi, Valeria Di Bussolo, Lucilla Favero and Mauro Pineschi
Á
Dipartimento di Chimica Bioorganica e Biofarmacia, Universita di Pisa, Via Bonanno 33, I-56126 Pisa, Italy
Received 10 May 2001; revised 6July 2001; accepted 2 August 2001
AbstractÐThe intramolecular addition reaction of metal enolates of ketones to oxiranes has been applied to a series of epoxy ketones
derived from cyclohexene oxide. g-Hydroxy ketones .g-HKs, C-alkylation products) or hydroxy enol ethers .HEEs, O-alkylation products)
are obtained, depending on the nature of the cyclic transition state in each case involved and the application of the FuÈrst±Plattner rule. The
formation of HEEs by reaction of the same epoxy ketones under acid conditions is also described. In some cases, regioconvergent or
chemoselective processes are conveniently obtained. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
subjected to conformational constrains, with the only
requirement of an anti addition fashion: monocyclic C-
.g-HKs) or O-alkylation products .hydroxy enol ethers,
HEEs) were so obtained, depending on the structure of the
starting epoxide .Scheme 1, eq. 2).2
The metal-salt catalyzed addition of lithium enolates of
ketones to 1,2-epoxides has turned out to be an ef®cient
route to substituted g-hydroxy ketones .g-HKs).1 This
epoxide addition reaction was examined both in an inter-
molecular version .addition reaction of lithium enolates of
acetophenone and propiophenone to cyclohexene oxide and
propene oxide, Scheme 1, eq. 1)1a and in an intramolecular
one .cyclization reaction of non-cyclic epoxy ketones such
as 1, Scheme 1, eq. 2).2 In epoxy ketones of type 1, the
oxirane moiety is inserted at the end of a carbonyl-contain-
ing aliphatic chain and the possible reaction with the corre-
sponding enolate portion, as shown in 2, is substantially
In order to evaluate the potential of this addition reaction in
epoxy ketones systems in which the conformational require-
ments of the addition reaction could play a more decisive
role, we have extended the intramolecular version of this
reaction to some epoxy ketones in which the carbonyl-
containing aliphatic chain .a phenone of different length)
is differently disposed with respect to the oxirane function-
ality inserted into a cyclohexane ring. Some 3,4-, 4,5-, 5,6-
Scheme 1.
Keywords: epoxy ketones; cyclization reactions; C- and O-alkylation; enolates.
Corresponding author. Tel.: 139-50-44074; fax: 139-50-43321; e-mail: crotti@farm.unipi.it
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020.01)00817-1

8560
P. Crotti et al. / Tetrahedron 57 )2001) 8559±8572
and 6,7-epoxy ketones derived from cyclohexene oxide
were thus prepared: the 6,7-epoxy ketones 3 and 5, the
5,6-epoxy ketones 4 and 6, the 4,5-epoxy ketone 7 and the
3,4-epoxy ketone 8. Epoxides 3, 4 and 7 are regioisomers in
which the distance between the carbonyl and the oxirane
functionality is progressively reduced. In the pairs 3 and
5, and 4 and 6, the distance between the two functionalities
is formally the same, but there is a difference in the position
and length of the carbonyl-containing aliphatic chain. In 8,
the two reactive functional groups are at the lowest possible
distance allowing the presence of an active methylene group
between them. Epoxy ketones 3 and 4 were prepared and
used as a mixture of the corresponding diastereoisomers cis
.c-3 and c-4) and trans .t-3 and t-4) .see below).
2. Results
Enones 31±36, necessary for the synthesis of epoxy ketones
3±8 were prepared as follows .Schemes 2 and 3): .i) enones
31±34 were prepared by alkylation of the corresponding
iodides 9±12 with the lithium enolate derived from N,N-
dimethyl hydrazone of acetophenone .26) to give the corre-
sponding N,N-dimethylhydrazones 27±30, followed by
deprotection with acid resin .Amberlyst 15); .ii) enones
35 and 36 were prepared by PhMgBr addition to nitriles
21 and 17, respectively, followed by hydrolysis .HCl/
H2O) of the intermediate imino salt .Scheme 3).
case of 17) or basic conditions .NaOH/H2O/THF, re¯ux in
the case of 21) followed by LAH reduction of the inter-
mediate ester 18 and carboxylic acid 22, respectively.
When the hydrolysis of nitrile 21 was carried out under
acid conditions as for 17 .H2SO4/MeOH, re¯ux), the
spiro lactone 25 turned out to be the only reaction
product. Nitrile 21 was prepared by NaCN/MeCN SN2
displacement reaction on the corresponding iodide 11.
Alcohol 13 and nitrile 17 are commercially available
.Scheme 2).
The necessary iodides 9±12 were prepared by NaI/acetone
SN2 displacement reaction on the corresponding tosylates 14
and 16, and mesylates 20 and 24 prepared from alcohols 13,
15, 19, and 23, respectively .Scheme 2). Alcohol 15 was
prepared by allylic hydroxymethylation [TMEDA/BuLi/
.CH2O)n] of cyclohexene, as previously described;3 alcohols
19 and 23 were prepared by hydrolysis of the corresponding
nitriles 17 and 21 under acid .H2SO4/MeOH, re¯ux, in the
Scheme 2. a: MsCl .or TsCl)/Py; b: NaI/acetone, re¯ux; c: .1) BuLi/TMEDA, .2) .CH2O)n; d: MeOH/H2SO4, re¯ux; e: LiAlH4/Et2O; f: NaCN/MeCN, 808C;
g: .1) NaOH/EtOH, 808C, .2) HCl.

P. Crotti et al. / Tetrahedron 57 )2001) 8559±8572
8561
Scheme 3. a: Amberlyst 15/acetone; b: .1) NBS/THF±H2O, .2) NaOH±H2O; c: m-CPBA±KF/CH2Cl2; d: m-CPBA/NaHCO3; e: .1) PhMgBr/Et2O, .2) HCl±
H2O.
Treatment of enones 31, 32 and 34 with NBS in THF/H2O
reasonably afforded mixtures of the corresponding regio-
isomeric trans bromohydrins which were not separated,
but directly cyclized under basic conditions .aqueous
NaOH) to the corresponding epoxy ketones 3, 4, and 6.
Epoxy ketones 3 and 4 were obtained as a 25:75 mixture
of the corresponding cis .c-3 and c-4) and trans diastereo-
isomers .t-3 and t-4) which turned out to be not separable
under any chromatographic procedure tried. Epoxy ketones
5, 7 and 8 were prepared by m-CPBA oxidation of the
corresponding enones 33, 35 and 36 in the presence of
KF4a .in the case of 33 and 35) or NaHCO3 .in the case of
36), respectively .Scheme 3).4b
quent nucleophilic attack on the O-metal-coordinated .basic
conditions) or O-protonated oxirane ring .acid conditions),
is reasonably admitted. It is to be stressed that while, on the
one hand, O-alkylation products are reasonably possible
both under alkaline .LHMDS or EtONa) and acid conditions
.Amberlyst 15/CH2Cl2), on the other hand C-alkylation
products are possible only under alkaline conditions, as
tentatively shown for epoxy ketone t-4 in Scheme 4.
The trans-diaxial requirement .FuÈrst±Plattner rule)5 for the
intramolecular addition reaction of the metal enolate or enol
form of epoxy ketones 3±8 to the corresponding semi-rigid
cyclohexane-derived oxirane ring could be decisive in
these systems not only in determining, in accordance with
or opposite to Baldwin's rule,6 the oxirane carbon to be
3. Discussion
Epoxy ketones 3±8 have been subjected to several cycliza-
tion procedures both under basic and acid reaction condi-
tions: .i) the recently introduced LHMDS/Sc.OTf)3/toluene
protocol1a,2 and the more common EtONa/EtOH protocol as
examples of cyclization reactions under basic conditions,
and .ii) treatment with acid resin .Amberlyst 15) in an
aprotic polar solvent .CH2Cl2), as an example of cyclization
reaction under acid conditions. As shown in Scheme 4, only
for epoxy ketone t-4, taken as an example, the incursion of
the corresponding metal enolate .4a) or enol form .4b)
under basic and acid conditions, respectively, with subse-
Scheme 4.

8562
P. Crotti et al. / Tetrahedron 57 )2001) 8559±8572
Scheme 5.
nucleophilically attacked, but also in affecting the nature of
the addition product .C- or O-alkylation product).
diastereoisomer c-3) with LHMDS in the presence of
Sc.OTf)3 afforded the g-HK 45 .a C-alkylation product),
as the only reaction product .Scheme 6). The exclusive
formation of 45 is reasonably justi®ed by means of a
5-membered transition state .TS) .a favored 5-exo cycliza-
tion process)6 in which a favorable anti arrangement
between the unsaturated system of the corresponding .Z)-
enolate portion and the C±C oxirane bond is nicely
achieved,2 as shown in anti .Z)-37a. The same result
.lower yield) is obtained also by application of the alter-
native EtONa/EtOH alkaline protocol. Because of the
necessary incursion, at least, of a 7-membered TS [dotted
arrows in .Z)-37b, Scheme 6], O-alkylation products are
never observed with epoxy ketone t-3, either under alkaline
or acid reaction conditions. Accordingly, application of the
acid protocol to the 75:25 mixture of t-3 and c-3, leads only
to recovery of unreacted starting epoxides.
Epoxy ketones 3±8 afford, under basic conditions, only the
corresponding metal .Z)-enolates 37±42 .Schemes 6±11).
Evidence of this behavior was obtained by treating epoxy
ketone 6 with LHMDS at 08C for 1 h, then quenching the
reaction with Me3SiCl: only silyl enol ether .SEE) .Z)-43
1
was obtained, as substantiated by H NMR spectroscopic
evidence.7 The same control reaction carried out on epoxy
ketone 4 .a 25:75 mixture of c-4 and t-4) yielded a 24:76
mixture of the corresponding SEEs .Z)-c-44 and .Z)-t-44, in
accordance with the diastereoisomeric ratio of the starting
epoxide .Scheme 5).
For strictly structural reasons, also substantiated by
examination of molecular models, in the pairs of diastereo-
isomeric epoxides c-3 and t-3 and c-4 and t-4, only the
corresponding metal .Z)-enolate .in alkaline conditions) or
.Z)-enol .under acid conditions) derived from t-3 and t-4,
can intramolecularly react with the oxirane functionality in
the required trans-diaxial fashion. Accordingly, in the reac-
tion carried out on epoxides 3 and 4, as mixtures of cis and
trans diastereoisomers, while one isomer .reasonably the
trans isomer), corresponding to the one present in a larger
amount .75%) in the starting mixture, is largely consumed,
the other isomer .reasonably the cis isomer) greatly enriches
in the ®nal reaction mixture .GC).9
Consistently different is the behavior of the regioisomeric
trans epoxide t-4 .in the 75:25 mixture with diastereoisomer
c-4). In this case, the C-alkylation pathway is not possible in
either of the two reactive conformations .Z)-38a and .Z)-
38b of the corresponding metal .Z)-enolate .Scheme 7),
because of the implication of a 4-membered TS [.Z)-38a,
pathway a] or the unsurmontable distance between the two
reactive centers [.Z)-38b, pathway b]. All this makes an
O-alkylation pathway highly competitive to the point that
HEE 46 is the only reaction product with attack of the
nucleophile [enolate .Z)-38] on the C.2) oxirane carbon
through a 6-membered TS .a favored 6-exo cyclization
Treatment of epoxide t-3 .in the 75:25 mixture with
Scheme 6.

P. Crotti et al. / Tetrahedron 57 )2001) 8559±8572
8563
Scheme 7.
process),6 as shown in .Z)-38a .pathway c). Nucleophilic
attack on the C.1) oxirane carbon and the alternative
formation of the regioisomeric HEE 47, through .Z)-38b
.pathway d) and a reasonably less stable 7-membered cyclic
TS .a 7-endo cyclization process),6 has been ruled out by
structural evidences .see below). HEE 46 is also obtained by
the alternative basic protocol .EtONa/EtOH) and under acid
conditions [incursion of the protonated enol .Z)-38-H], thus
giving an example of a regioconvergent process .Scheme 7).
a disfavored 6-endo cyclization process) .95%) and the
spiro g-HK 49 .through a favored 5-exo cyclization
process)6 .5%), by nucleophilic attack on C.1) and C.2)
oxirane carbon, respectively. The decidedly larger amount
of the bicyclic compound 48 in this reaction is consistent
with the preferential TS anti .Z)-39a if compared with the
alternative TS gauche .Z)-39b, reasonably less stable,
leading to the spiro compounds 49. The EtONa/EtOH proto-
col is ineffective and leads only to the recovery of the
unreacted starting epoxide. No O-alkylation products are
observed either under acid or alkaline conditions, probably
due to the extremely large cyclic TS .7- or 8-membered
ring) which would necessarily be involved in their forma-
tion. As a consequence, the acid protocol leads only to
In the case of the epoxy ketone 5, the long carbonyl-contain-
ing side chain allows an easy reactivity, under the alkaline
protocols, of the corresponding enolate .Z)-39a,b to give
only C-alkylation products, the bicyclic g-HK 48 .through
Scheme 8.
Scheme 9.

8564
P. Crotti et al. / Tetrahedron 57 )2001) 8559±8572
Scheme 10.
isomerization products, the diketone 50 and the oxo-
aldehyde 51 in a 95:5 ratio .Scheme 8).
Diastereoisomeric spiro g-HKs 54 and 55 arise from a
reactivity of the epoxide 7-derived metal enolate .Z)-41
.from LHMDS) in the two possible conformations a and
b, through a highly favored 3-membered TS .a 3-exo
cyclization process) .Scheme 10).6 The higher amount of
54 so far obtained under the LHMDS/Sc.OTf)3 protocol
.54/55 ratioˆ76:24) may be reasonably justi®ed on the
basis of a chelation process, through a metal species .Li1
and/or Sc13) present in the aprotic reaction solvent
.toluene), between the enolate and oxirane oxygens, only
possible in .Z)-41a. Accordingly, when the same reaction is
carried out using the alternative alkaline protocol .EtONa/
EtOH), an inverted stereoselectivity was obtained and the
`non-chelation' product, the g-HK 55, turned out to be the
main reaction product .54/55 ratioˆ14:86), as a result of a
strongly diminished chelation capability of the enolate
counterion .Na1) in the protic solvent .EtOH).
Due to the appropriate length of the side chain, epoxides 6
and 7 are the only epoxy ketones so far studied that show a
chemoselective behavior depending on the reaction condi-
tions. In fact, while C-alkylation products, the g-HK 52
from 6 and the g-HKs 54 and 55 from 7, are obtained
under alkaline conditions, O-alkylation products, the
HEEs 53 from 6 and 56 from 7 are, respectively, observed
under acid conditions .Schemes 9 and 10). The g-HK 52
comes from a classically favored TS such as anti .Z)-40a,
through a 5-endo cyclization process, which, even if dis-
favored by Baldwin's rule,6 is the only possible one in
these conditions, considering that the formation of
4-membered cyclic products has never been observed
under our experimental conditions .Scheme 9).2 The
EtONa/EtOH protocol is ineffective and the starting epoxide
is recovered completely unreacted. As shown in .Z)-40-H,
when the reactivity is transferred to the corresponding enol
form .acid conditions), a 6-membered TS may easily be
obtained and the HEE 53 is obtained as the only reaction
product. In this case, the acid-induced ring opening process
of the oxirane ring toward the tertiary C.2) oxirane carbon
may play an important role in directing the attack of the
nucleophile .Scheme 9).
Under acid conditions, epoxide 7 affords the bicyclic HEE
56, reasonably through the 6-membered TS .Z)-41c-H,
which, even if disfavored by Baldwin's rule .a 6-endo cycli-
zation process), is, for structural reasons and application of
the FuÈrst±Plattner rule, the only one reasonably possible in
this system .Scheme 10).
Epoxy ketone 8, both under alkaline and acid conditions,
Scheme 11.

P. Crotti et al. / Tetrahedron 57 )2001) 8559±8572
8565
affords the tetrahydrobenzofurane derivative 57, as a conse-
quence of a cyclization process in which the primary
reaction product, the HEE 58 .or 58-H), undergoes an
easy elimination process to give the corresponding aromatic
system .Scheme 11). The HEE 58 .or 58-H), an O-alkyl-
ation product, is the only product allowed, for structural
reasons, by a cyclization process in this system through
enolate .Z)-42a, under alkaline conditions, and enol .Z)-
42a-H, under acid conditions, respectively. The chemical
behavior so far observed with epoxide 8, even if interesting,
had already been previously observed in other related
systems.10
system, as independently stated by considerations based on
the reaction mechanism.
The presence of a tertiary hydroxyl group in g-HKs 48 and
52 was clearly con®rmed by their recovering completely
unreacted when subjected both to acetylation and oxidation
procedures.
5. Conclusion
The cyclization reactions of cyclohexene oxide-derived
epoxy ketones 3±8 have indicated that the FuÈrst±Plattner
rule mostly drives the nature of the cyclization product in
these epoxy ketone systems to the point that, if a C-alkyl-
ation process is not possible for strictly structural reasons or
for reasons linked to the incursion of a 4-membered or
strained 5-membered cyclic TS, the alternative constantly
less-strained O-alkylation pathway takes place. Under
alkaline conditions, where the LHMDS/Sc.OTf)3/toluene
protocol appears superior and more generally applicable
than the alternative EtONa/EtOH one, when a clear C-alkyl-
ation process is allowed, the alternative O-alkylation
process is not observed. In these conditions, the combina-
tion of the FuÈrst±Plattner rule and the favored anti TS
determines the nature .bicyclic or spiro) of the g-HK
obtained in each case.
4. Structures and con®gurations
The structures and con®gurations of the bicyclic and spiro
compounds, the g-HKs 45, 48, 49, 52, 54 and 55 and the
HEEs 46, 53 and 56, were determined by examination of the
1
corresponding IR and H NMR spectra, with appropriate
double resonance experiments, and by considerations
based on the reaction mechanism and application of the
FuÈrst±Plattner rule. While the contemporary presence of
an OH and CvO stretching band in the IR spectra of the
reaction product reasonably indicated the obtainment of a
C-alkylation product .a g-HK), the presence of an OH and
the contemporary absence of a CvO stretching band in the
IR spectra and the presence of a vinyl proton in the corre-
sponding 1H NMR spectra were taken as diagnostic tools to
indicate the obtainment of an O-alkylation product .an
HEE).
Under acid conditions, O-alkylation products are classically
obtained, with the only exception of epoxides t-3 and 5, and
in some cases, depending on the corresponding behavior
under alkaline conditions, a nice regioconvergent or chemo-
selective procedure may be achieved by using alkaline or
acid cyclization reaction conditions. On its own, the acid
cyclization process appears to be sensitive to stereo-
electronic effects and the attack of the nucleophilic enol
oxygen on the more substituted oxirane carbon, when
allowed by strain effects and the FuÈrst±Plattner rule, is
highly favored. Even if allowed by the previous considera-
tions, 4- and 7-membered cyclic products are never
observed under any conditions.
The secondary nature of the hydroxyl group present in the
bicyclic g-HK 45 and HEE 46, in the spiro g-HKs 49, 54
and 55, and in the oxaspiro HEE 53 was demonstrated by
acetylation .Ac2O/Py): 1H NMR spectra of the correspond-
ing acetates .45-46-Ac, 49-Ac, and 53±55-Ac) showed the
down®eld shift of only one proton, the hydrogen a to the
newly introduced carbonyl group. In the case of the HEEs
46 and 53, the oxidation to the corresponding ketones 59
and 60, respectively, was taken as a further con®rmation of
their structure .Scheme 12). In particular, the multiplicity of
the signal of proton H1 .a doublet at d 4.54) and the low
value of the corresponding coupling constant .Jˆ3.9 Hz) in
In all cases, interesting bicyclic, oxabicyclic, spiro and/or
oxaspiro compounds, not easy to prepare by alternative
synthetic procedures, are obtained in a high to complete
stereo- and regioselective fashion, starting from easily avail-
able precursors .the epoxy ketones) by means of quite
simple protocols. Moreover, simple considerations based
on the reaction mechanism and the reaction conditions
adopted may be used in order to predict the nature of the
cyclization product.
1
the H NMR spectrum of ketone 59 made it possible to
exclude for the starting HEE 46 the regioisomeric structure
47 .Scheme 7) and to con®rm the cis junction in this bicyclic
6. Experimental
6.1. General
Melting points were determined on a Ko¯er apparatus and
1
are uncorrected. H and 13C NMR spectra were determined
with a Bruker AC 200 spectrometer on CDCl3 solution using
tetramethylsilane as the internal standard. IR spectra for
comparison between compounds were registered on a
Mattson 3000 FTIR spectrophotometer. All reactions were
Scheme 12.

8566
P. Crotti et al. / Tetrahedron 57 )2001) 8559±8572
followed by TLC on Alugram SIL G/UV254 silica gel sheets
.Machery-Nagel) with detection by UV and/or by a 10%
phoshomolybdic acid in EtOH. Silica gel 60 .Machery-
Nagel 230±400 mesh) was used for ¯ash chromatography.
All the reactions with compounds sensitive to air and/or
humidity were carried out under a nitrogen or argon
atmosphere and reagents were added via syringe or cannula.
Anhydrous solvents were distilled under a nitrogen
atmosphere immediately prior to use: THF and toluene
from sodium/benzophenone ketyl, and CH2Cl2 from CaH2.
Acetylation protocol: the product .0.050 g) in anhydrous
pyridine .0.8 mL) was treated at 08C with Ac2O .0.5 mL)
and the resulting reaction mixture was left for 18 h at rt.
After dilution with toluene, all solvents were removed
under vacuum .rotating evaporator). 2-Cyclohexen-1-
methanol .15),3 and N,N-dimethylhydrazone of aceto-
phenone .26)2 were prepared as previously described.
3-Cyclohexen-1-methanol .13) and .1-cyclohexenyl)-aceto-
nitrile .17) are commercially available.
.28 mL) was treated with solid KOH .4.60 g, 82.0 mmol)
and the resulting reaction mixture was stirred at 80±908C
for 18 h. After cooling, the reaction mixture was diluted
with Et2O and acidi®ed with aqueous 6N HCl. Evaporation
of the separated organic solution afforded a crude product
.2.40 g) consisting of the corresponding carboxylic acid
22.15
A solution of 22 .2.40 g, 15.56mmol) in anhydrous Et 2O
.60 mL) was treated at rt with LiAlH4 .1.0 g) and the reac-
tion mixture was stirred for 18 h at the same temperature.
Water and 10% aqueous NaOH were added in order to
destroy the excess of hydride. Evaporation of the organic
solvent afforded the practically pure alcohol 23 .2.14 g,
98% yield).16
6.1.5. Lactone 25. Following the procedure described above
for the preparation of ester 18, a solution of nitrile 21
.1.80 g, 13.3 mmol) in MeOH .8 mL) was re¯uxed 24 h in
the presence of 96% H2SO4 .1.3 mL). The usual treatment
afforded a crude reaction product .1.40 g) which was
subjected to ¯ash chromatography. Elution with an 8:2
hexane/AcOEt mixture afforded pure 1-oxaspiro[4,5]-
decan-2-one .25) .1.20 g, 59% yield), as a liquid.17
6.1.1. Methyl 01-cyclohexenyl)-acetate 018). A solution of
.1-cyclohexenyl)-acetonitrile .17) .10.0 g, 82.52 mmol) in
MeOH .47 mL) containing 96% H2SO4 .8 mL) was re¯uxed
for 72 h. After cooling, the reaction mixture was diluted
with water and extracted with ether. Evaporation of the
washed .10% aqueous Na2CO3 and saturated aqueous
NaCl) ether extracts afforded a crude liquid .12.60 g, 99%
yield) consisting of practically pure ester 1811 which was
directly utilized in the next step without any further
puri®cation.
6.1.6. Tosylates 14 and 16 and mesylates 20 and 24. Typi-
cal procedure. A solution of 3-cyclohexen-1-methanol .13)
.10.0 g, 89.15 mmol) in anhydrous pyridine .100 mL) was
treated at 08C with TsCl .18.81 g, 98.66 mmol) and the
resulting reaction mixture was stirred at 58C for 24 h. Dilu-
tion with CH2Cl2 and evaporation of the washed .10%
aqueous HCl, saturated aqueous NaHCO3 and H2O) organic
solution afforded a crude reaction product consisting of
practically pure 4-tosyloxymethyl-1-cyclohexene .14)
.18.0 g, 76% yield),18 as a liquid which was directly utilized
in the next step .Found: C, 63.34; H, 6.48. C14H18O3S
requires C, 63.13; H, 6.81%): IR n 1354 and 1177 cm21
6.1.2. 3-01-Cyclohexenyl)propanonitrile 021). A solution
of iodide 11 .3.31 g, 14.0 mmol) in anhydrous MeCN
.20 mL) in the presence of NaCN .2.75 g, 56.0 mmol) was
stirred at 808C for 72 h. After cooling, dilution with Et2O
and evaporation of the washed .saturated aqueous NaHCO3
and H2O) organic solution afforded a crude reaction product
consisting of practically pure nitrile 21 .1.78 g, 94%
yield),12 as a liquid, which was directly utilized in the
next step without any further puri®cation.
1
.SvO); H NMR d 7.76±7.81 .m, 2H), 7.34±7.38 .d, 2H,
Jˆ8.8 Hz), 5.55±5.69 .m, 2H), 3.91 .d, 2H, Jˆ6.8 Hz), 2.45
.s, 3H), 1.90±2.11 .m, 4H), 1.64±1.87 .m, 2H), 1.16±1.36
.m, 1H). 13C NMR d 144.79, 133.09, 129.92, 127.92,
127.03, 125.01, 74.47, 33.18, 27.60, 24.72, 24.08, 21.68.
6.1.3. 2-01-Cyclohexenyl)-1-ethanol 019). A solution of
ester 18 .6.51 g, 42.2 mmol) in anhydrous Et2O .56mL)
was added at 08C to a suspension of LiAlH4 .1.60 g,
42.2 mmol) in anhydrous Et2O .160 mL). After 3 h stirring
at rt, the reaction mixture was diluted with Et2O and treated
with H2O and 10% aqueous NaOH in order to destroy the
excess of hydride. Evaporation of the ether solution afforded
a crude liquid product .5.30 g) consisting of alcohol 19
which was puri®ed by ¯ash chromatography. Elution with
an 8:2 hexane/AcOEt mixture yielded pure alcohol 19
.3.30 g, 62% yield), as a liquid.13
The same reaction carried out on alcohol 15 .4.85 g,
43.24 mmol) afforded 3-tosyloxymethyl-1-cyclohexene
.16) .10.40 g, 90% yield), as a liquid.19
The same reaction carried out on alcohol 19 .4.60 g,
36.5 mmol) with MsCl .5.0 g, 43.8 mmol) afforded 1-)2-
mesyloxyethyl)-1-cyclohexene .20) .5.29 g, 71% yield), as
a liquid .Found: C, 52.61; H, 7.64. C9H16O3S requires C,
1
52.92; H, 7.89%): IR n 1345 and 1176cm 21 .SvO); H
NMR d 5.52±5.58 .m, 1H), 4.28 .t, 2H, Jˆ6.8 Hz, 2H), 3.01
.s, 3H), 2.34±2.41 .m, 2H), 1.95±2.00 .m, 4H), 1.55±1.68
.m, 4H). 13C NMR d 132.30, 124.65, 68.71, 37.38, 28.28,
25.19, 22.74, 22.13.
Following a previously described procedure,14 alcohol 19
was also prepared by adding 2-phenyl-1-ethanol .12.20 g,
0.10 mol) to a suspension of Li .4.16g, 0.60 g-atoms) in
anhydrous PrNH2 .140 mL). The crude liquid reaction
product .10.80 g) was distilled to give pure alcohol 19
.6.04 g, 48% yield), bp 1308C .35 mm) [lit.14 bp 74±758C
.2 mm)].
The same reaction carried out on alcohol 23 .2.19 g,
15.62 mmol) with MsCl .1.50 g, 13.09 mmol) in anhydrous
pyridine .15 mL) for two days at 08C afforded pure 1-)3-
mesyloxypropyl)-1-cyclohexene .24) .2.47 g, 73% yield), as
a liquid .Found: C, 54.78; H, 8.49. C10H18O3S requires C,
6.1.4. 3-01-Cyclohexenyl)-1-propanol 023). A solution of
nitrile 21 .2.50 g, 18.5 mmol) in a 1:1 EtOH/H2O mixture
1
55.02; H, 8.31%): IR n 1354 and 1174 cm21 .SvO); H

P. Crotti et al. / Tetrahedron 57 )2001) 8559±8572
8567
1
NMR d 5.41±5.46.m, 1H), 4.22 .t, 2H, Jˆ6.3 Hz), 3.02 .s,
3H), 1.82±2.09 .m, 8H), 1.52±1.69 .m, 4H). 13C NMR d
135.95, 122.52, 70.08, 37.59, 33.84, 28.38, 27.25, 25.43,
23.15, 22.60.
79.64; H, 9.44; N, 10.93%): IR n 1586cm 21 .CvN); H
NMR d 7.60±7.72 .m, 2H), 7.30±7.40 .m, 3H), 5.50±5.70
.m, 2H), 2.90 .t, 2H, Jˆ7.4 Hz), 2.60 .s, 6H), 1.90±2.10 .m,
1H), 1.94 .m, 2H), 1.55±1.93 .m, 2H) 1.35±1.50 .m, 2H).
13C NMR d 169.08, 138.30, 137.28, 131.54, 128.59, 127.26,
126.63, 48.14, 36.21, 33.73, 30.81, 28.99, 26.51, 25.59,
21.69.
6.1.7. Iodides 9±12. Typical procedure. A solution of
tosylate 14 .6.40 g, 24.0 mmol) in acetone .100 mL)
containing NaI .10.80 g, 72.05 mmol) was re¯uxed for
24 h. After cooling, dilution with Et2O and evaporation of
the washed .10% aqueous Na2S2O3 and H2O) organic
solution afforded a crude liquid product .3.98 g) mostly
consisting of iodide 9 which was puri®ed by ®ltration on a
silica gel column. Elution with petroleum ether afforded
pure 4-)iodomethyl)-1-cyclohexene .9), as a liquid .3.21 g,
60% yield).20
The same reaction carried out on iodide 12 .2.30 g,
9.20 mmol) afforded pure 5-)1-cyclohexenyl)-pentano-
phenone DMH .29) .1.70 g, 65% yield), as a liquid
.Found: C, 80.56; H, 9.69; N, 9.54. C19H28N2 requires C,
80.23; H, 9.92; N, 9.85%): IR n 1671 cm21 .CvN); H
1
NMR d 7.40±7.66 .m, 2H), 7.30±7.39 .m, 3H), 5.32±
5.37 .m, 1H), 2.64±2.93 .m, 2H), 2.56 .s, 6H), 1.85±2.36
.m, 6H), 1.40±1.65 .m, 8H). 13C NMR d 168.91, 138.30,
137.64, 129.29, 128.45, 127.21, 121.21, 48.03, 37.69, 28.65,
28.34, 27.79, 26.86, 25.41, 23.20, 22.76.
The same reaction carried out on tosylate 16 .5.70 g,
21.4 mmol) afforded pure 3-)iodomethyl)-1-cyclohexene
.10) .3.0 g, 63% yield), as a liquid.21
The same reaction carried out on iodide 11 .4.0 g,
16.94 mmol) afforded pure 4-)1-cyclohexenyl)-butyro-
phenone DMH .30) .3.51 g, 77% yield), as a liquid
.Found: C, 79.73; H, 9.42; N, 10.22. C18H26N2 requires C,
The same reaction carried out on mesylate 20 .8.30 g,
40.63 mmol) afforded pure 1-)2-iodoethyl)-1-cyclohexene
.11) .5.20 g, 54% yield), as a liquid.18
1
79.95; H, 9.69; N, 10.36%): IR n 1602 cm21 .CvN); H
The same reaction carried out on mesylate 24 .2.47 g,
11.31 mmol) afforded pure 1-)3-iodopropyl)-1-cyclohexene
.12) .2.30 g, 81% yield), as a liquid .Found: C, 43.01; H,
5.69. C9H15I requires C, 43.22; H, 6.04%): IR n 1199 cm21
.CH2I); 1H NMR d 5.45±5.49 .m, 1H), 3.18 .t, 2H,
NMR d 7.60±7.65 .m, 2H), 7.26±7.38 .m, 3H), 5.31±5.43
.m, 1H), 2.85±2.95 .m, 2H), 2.50 .s, 6H), 1.80±2.00 .m,
4H), 1.50±1.60 .m, 8H).
6.1.9. Enones 31±34. Typical procedure. A solution of
DMH 27 .3.50 g, 13.65 mmol) in acetone .70 mL) was
treated with Amberlyst 15 .4.0 g) and the resulting suspen-
sion was stirred for 24 h at rt. Dilution with Et2O and
evaporation of the ®ltered organic solution afforded pure
3-)3-cyclohexenyl)-propiophenone .31) .2.49 g, 85%
yield), as a liquid.23
Jˆ7.3 Hz), 1.88±2.06.m, 8H), 1.59±1.76 .m, 4H).
13C
NMR d 135.87, 122.44, 38.69, 31.68, 28.38, 25.41, 23.13,
22.67.
6.1.8. N,N-Dimethyl hydrazones 0DMH) 27±30. Typical
procedure.22 A solution of acetophenone DMH .26)2
.2.32 g, 14.30 mmol) in anhydrous THF .5 mL) was added
dropwise at 08C under N2 to a solution of LDA [20 mmol,
from diisopropylamine .2.24 mL) and 1.6M BuLi in hexane
.10 mL)] in anhydrous THF .24 mL) and the reaction
mixture was stirred at the same temperature for 2 h. A solu-
tion of iodide 9 .4.44 g, 20.0 mmol) in anhydrous THF
.5 mL) was added at 08C and the resulting reaction mixture
was left to warm to rt, then stirred for 24 h at this tempera-
ture. Et2O and saturated aqueous NH4Cl were added and
stirring was prolonged for 2 h. Evaporation of the washed
.saturated aqueous NH4Cl and H2O) organic solution
afforded a crude liquid reaction product mostly consisting
of DMH 27 .3.59 g) which was puri®ed by ¯ash chromato-
graphy. Elution with an 8:2 hexane/AcOEt mixture yielded
pure 3-)3-cyclohexenyl)-propiophenone DMH .27) .2.75 g,
75% yield), as a liquid .Found: C, 79.44; H, 9.13; N, 11.21.
C17H24N2 requires C, 79.64; H, 9.44; N, 10.93%): IR n
The same reaction carried out on DMH 28 .4.36g,
17.0 mmol) afforded, after ¯ash chromatography and
elution with an 8.5:1.5 hexane/AcOEt mixture, pure 3-)2-
cyclohexenyl)-propiophenone .32), as a liquid .2.28 g, 62%
yield) .Found: C, 84.28; H, 8.51. C15H18O requires C, 84.07;
H, 8.47%): IR n 1685 cm21 .CvO); 1H NMR d 7.93±7.97
.m, 2H), 7.40±7.58 .m, 3H), 5.55±5.73 .m, 2H), 3.0 .t, 2H,
Jˆ7.8 Hz), 2.08±2.19 .m, 1H), 1.96±2.00 .m, 2H), 1.24±
1.85 .m, 6H). 13C NMR d 210.03, 138.45, 134.56, 132.35,
129.38, 128.34, 127.56, 37.29, 36.37, 31.25, 29.31, 26.37,
22.36.
The same reaction carried out on DMH 29 .1.71 g,
6.0 mmol) afforded, after ¯ash chromatography and elution
with a 9:1 hexane/AcOEt mixture, pure 5-)1-cyclohexenyl)-
pentanophenone .33), as a liquid .1.0 g, 69% yield) .Found:
C, 84.39; H, 8.98. C17H22O requires C, 84.25; H, 9.15%): IR
n 1685 cm21 .CvO); 1H NMR d 7.93±7.98 .m, 2H), 7.42±
7.59 .m, 3H), 5.39±5.43 .m, 1H), 2.98 .t, 2H, Jˆ7.1 Hz),
1.90±2.01 .m, 7H), 1.44±1.79 .m, 7H). 13C NMR d 200.69,
137.65, 137.36, 133.06, 128.75, 128.29, 121.30, 38.74,
38.02, 28.46, 27.54, 25.49, 24.30, 23.26, 22.83.
1
1591 cm21 .CvN); H NMR d 7.60±7.66 .m, 2H), 7.25±
7.38 .m, 3H), 5.63±5.65 .m, 2H), 2.97 .t, 2H, Jˆ7.6Hz),
2.55 .s, 6H), 2.00±2.10 .m, 3H), 1.66±1.83 .m, 4H), 1.34±
1.45 .m, 2H). 13C NMR d 169.55, 138.69, 129.82, 128.98,
127.66, 126.97, 48.52, 34.58, 34.47, 32.30, 29.26, 26.88,
25.84, 23.09.
The same reaction carried out on iodide 10 .3.0 g,
13.51 mmol) afforded pure 3-)2-cyclohexenyl)-propio-
phenone DMH .28) .2.80 g, 81% yield), as a liquid
.Found: C, 79.37; H, 9.11; N, 10.81. C17H24N2 requires C,
The same reaction carried out on DMH 30 .4.30 g,
15.90 mmol) afforded, after ®ltration on a short silica gel
column and elution with petroleum ether, pure 4-)1-cyclo-
hexenyl)-butyrophenone .34), as a liquid .1.80 g, 50% yield)

8568
P. Crotti et al. / Tetrahedron 57 )2001) 8559±8572
.Found: C, 84.01; H, 8.66. C16H20O requires C, 84.16; H,
8.83%): IR n 1687 cm21 .CvO); 1H NMR d 7.95±7.98 .m,
2H), 7.42±7.56.m, 3H), 5.40±5.44 .m, 1H), 2.94 .t, 2H,
Jˆ7.3 Hz), 1.81±2.03 .m, 8H), 1.26±1.64 .m, 4H). 13C
NMR d 201.12, 137.71, 137.50, 133.47, 129.14, 128.65,
122.37, 38.57, 38.11, 28.72, 25.85, 23.58, 23.15, 22.81.
2.10 .m, 5H), 0.90±1.40 .m, 3H), 0.70±0.85 .m, 1H). 13C
NMR d 200.49, 137.48, 133.73, 129.27, 128.66, 56.69,
56.01, 53.44, 36.89, 36.35, 34.82, 28.76, 28.42, 27.92,
25.72, 25.42, 24.50, 20.43, 17.80. Epoxides c-4 and t-4
turned out not to be separable by any of the chromato-
graphic procedures tried.
6.1.10. Enones 35 and 36. Typical procedure. A solution of
nitrile 17 .2.0 g, 16.50 mmol) in anhydrous Et2O .100 mL)
was added in 15 min at rt to a solution of PhMgBr [prepared
from Mg .0.80 g, 32.91 g-atoms) and bromobenzene
.5.17 g, 32.91 mmol)] in anhydrous Et2O .7.5 mL) and the
resulting reaction mixture was re¯uxed for 3 h. After cool-
ing, anhydrous THF .80 mL) was added and the reaction
mixture was cooled at 08C and acidi®ed by addition of 10%
aqueous HCl. The reaction mixture was then stirred over-
night at rt. Dilution with AcOEt and evaporation of the
washed .saturated aqueous NaHCO3 and H2O) organic solu-
tion afforded a crude product .3.60 g) consisting of enone 36
which was subjected to ¯ash chromatography. Elution with
a 97:3 petroleum ether/AcOEt mixture yielded pure 2-)1-
cyclohexenyl)-acetophenone .36) .1.10 g, 33% yield), as a
liquid.24
The same reaction carried out on enone 34 .2.70 g,
11.82 mmol) afforded pure 4-)1,2-epoxycyclohexyl)-butyro-
phenone .6) .1.87 g, 65% yield), as a solid, mp 38±418C
.Found: C, 78.33; H, 8.01. C16H20O2 requires C, 78.65; H,
1
8.25%): IR n 1685 cm21 .CvO); H NMR d 7.96.d, 2H,
Jˆ6.8 Hz), 7.31±7.59 .m, 3H), 2.97±3.04 .m, 3H), 1.76±
2.04 .m, 6H), 1.57±1.64 .m, 2H), 1.22±1.46 .m, 4H). 13C
NMR d 199.98, 136.94, 133.01, 128.59, 128.01, 59.95,
58.33, 38.32, 37.19, 27.66, 24.83, 20.18, 19.63, 19.37.
6.1.12. Epoxy ketones 5 and 7. Typical procedure.
Anhydrous KF .1.34 g, 23.07 mmol) was added under
nitrogen to a solution of m-CPBA .2.84 g, 16.46 mmol) in
CH2Cl2 .100 mL), previously dried on MgSO4, and the
reaction suspension was stirred at rt for 30 min.4a After cool-
ing at 08C, a solution of enone 35 .1.0 g, 4.67 mmol) in
anhydrous CH2Cl2 .20 mL) was added dropwise and the
reaction mixture was stirred for 1 h at rt. Dilution with
CH2Cl2 and evaporation of the ®ltered and washed
.saturated aqueous NaHCO3, 10% aqueous Na2S2O3 and
saturated aqueous NaCl) organic solution afforded 3-)1,2-
epoxycyclohexyl)-propiophenone .7) .1.05 g, 98% yield),
practically pure, as a liquid .Found: C, 78.54; H, 8.04.
C15H18O21requires C, 78.23; H, 7.88%): IR n 1685 cm21
.CvO); H NMR d 7.93±7.96.m, 2H), 7.40±7.54 .m,
3H), 3.05 .t, 2H, Jˆ7.8 Hz), 2.96±2.98 .m, 1H), 1.66±
The same reaction carried out on nitrile 21 .2.10 g,
15.53 mmol) afforded pure 3-)1-cyclohexenyl)-propiophe-
none .35) .2.10 g, 63% yield),25 as a liquid .Found: C,
84.31; H, 8.58. C15H18O requires C, 84.07; H, 8.47%): IR
n 1685 cm21 .CvO); 1H NMR d 7.95±7.98 .m, 2H), 7.42±
7.60 .m, 3H), 5.43±5.48 .m, 1H), 3.07 .t, 2H, Jˆ7.6Hz),
2.32±2.40 .m, 2H), 1.95±2.00 .m, 4H), 1.58±1.64 .m, 4H).
13C NMR d 200.80, 137.70, 137.18, 133.52, 129.18, 128.69,
122.05, 37.73, 32.99, 29.18, 25.86, 23.58, 23.09.
2.16.m, H6 ), 1.24±1.40 .m, 4H).
13C NMR d 199.74,
6.1.11. Epoxy ketones 3, 4 and 6. Typical procedure. A
solution of enone 31 .2.42 g, 11.3 mmol) in a 3:1 THF/
H2O mixture .100 mL) was treated with NBS .2.31 g,
13.0 mmol) and the reaction mixture was left in the dark
for 24 h at rt. 10% Aqueous NaOH .6.8 mL) was added
dropwise in the presence of phenolphthalein and the
reaction mixture was stirred for an additional 1 h. Dilution
with saturated aqueous NaCl, extraction with Et2O and
evaporation of the washed .saturated aqueous NaCl) ether
extracts afforded a crude liquid product consisting of a
mixture of epoxides c-3 and t-3 .1.55 g) which was
subjected to ¯ash chromatography. Elution with an 8:2
hexane/AcOEt mixture yielded a 25:75 mixture .GC) of
cis )c-3) and trans 3-)3,4-epoxycyclohexyl)-propiophenone
)t-3) .1.43 g, 55% yield), as a liquid: IR n 1684 cm21
133.14, 128.70, 128.14, 125.12, 59.56, 58.76, 33.37,
31.64, 28.38, 24.85, 20.23, 19.17.
The same reaction carried out on enone 33 .0.30 g,
1.24 mmol) afforded pure 5-)1,2-epoxycyclohexyl)-
pentanophenone .5) .0.29 g, 91% yield), as a liquid
.Found: C, 78.91; H, 8.29. C17H22O2 requires C, 79.03;
1
H, 8.58%): IR n 1685 cm21 .CvO); H NMR d 7.92±
7.96.m, 2H), 7.38±7.58 .m, 3H), 2.97 .t, 2H, Jˆ7.1 Hz),
2.93±2.97 .m, 1H), 1.67±1.92 .m, 6H), 1.24±1.58 .m, 8H).
13C NMR d 200.37, 137.16, 133.06, 128.70, 128.15, 60.21,
58.79, 38.54, 37.73, 27.86, 24.97, 24.59, 24.45, 20.32,
19.80.
6.1.13. Epoxy ketone 8. A solution of enone 36 .1.20 g,
6.0 mmol) in CH2Cl2 .24 mL) was added dropwise at 08C
to a vigorously stirred two-phase system composed of a
solution of m-CPBA .1.63 g, 9.45 mmol) in CH2Cl2
.80 mL) and saturated aqueous NaHCO3 .60 mL) and the
resulting reaction mixture was stirred for 1 h at the same
temperature. Evaporation of the washed .saturated aqueous
NaHCO3, 10% aqueous Na2S2O3 and H2O) afforded a crude
reaction product consisting of practically pure 2-)1,2-epoxy-
cyclohexyl)-acetophenone .8) .1.23 g, 95% yield), as a
liquid .Found: C, 77.98; H, 7.60. C14H16O2 requires C,
1
.CvO); H NMR d 7.91±7.95 .m, 2H), 7.41±7.58 .m,
3H), 3.13±3.17 .m, 2H), 2.94 .t, 2H, Jˆ7.3 Hz), 0.80±
2.10 .m, 9H). 13C NMR d 200.91, 137.58, 133.67, 129.27,
128.70, 53.73, 53.23, 52.54, 52.38, 36.81, 36.28, 32.85,
32.44, 31.61, 31.20, 31.09, 30.16, 27.80, 25.88, 24.94,
24.14. Epoxides c-3 and t-3 turned out not to be separable
by any of the chromatographic procedures tried.
The same reaction carried out on enone 32 .2.98 g,
13.91 mmol) afforded a 25:75 mixture of cis )c-4) and
trans 3-)2,3-epoxycyclohexyl)-propiophenone )t-4) .1.98 g,
62% yield), as a solid, mp 33±368C: IR n 1682 cm21
1
77.75; H, 7.46%): IR n 1682 cm21 .CvO); H NMR d
7.93±7.96.m, 2H), 7.3±67.16 .m, 3H), 3.48 .d, 1H,
Jˆ16.6 Hz), 3.05±3.15 .m, 1H), 2.97 .d, 1H, Jˆ16.6 Hz),
1.86±1.95 .m, 4H), 1.25±1.64 .m, 4H). 13C NMR d 198.27,
1
.CvO); H NMR d 7.94±7.98 .m, 2H), 7.40±7.55 .m,
3H), 2.90±3.13 .m, 3H), 2.86.d, 1H, Jˆ3.9 Hz), 1.50±

P. Crotti et al. / Tetrahedron 57 )2001) 8559±8572
8569
137.60, 133.99, 129.31, 128.90, 59.42, 58.30, 48.10, 29.22,
25.38, 20.79, 19.80.
75:25 mixture of diastereoisomers t-4 and c-4, 0.43 mmol)
afforded a crude reaction product .0.10 g) which was
subjected to preparative TLC .a 9:1 hexane/AcOEt mixture
was used as the eluant). Extraction of the two most intense
bands afforded a 6:4 mixture of the starting epoxides c-4 and
t-4 .GC) .0.025 g) and pure rel-)1R,6S,10R)-3-phenyl-2-
oxabicyclo[4.4.0]dec-3-en-10-ol .46) .0.060 g, 61%
yield), as a liquid .Found: C, 78.53; H, 8.05. C15H18O2
6.1.14. Reaction of epoxy ketones 4 and 6 with LHMDS
and Me3SiCl. A solution of epoxy ketone 4 .0.10 g of a
75:25 mixture of diastereoisomers t-4 and c-4, 0.43 mmol)
in anhydrous toluene .1.8 mL), was added at 08C under
nitrogen to stirred 1 M LHMDS in hexane .0.54 mL) and
the resulting reaction mixture was stirred at the same
temperature for 1 h. Me3SiCl .0.069 mL, 0.54 mmol) was
dropwise added and stirring was prolonged for 1 h. After
dilution with Et2O and ice-water, evaporation of the washed
.saturated aqueous NaHCO3 and H2O) organic solution
afforded a crude reaction product consisting of a 74:26
mixture of silyl enol ethers .Z)-t-44 and .Z)-c-44 .0.12 g,
1
requires C, 78.23; H, 7.88%): IR n 3417 cm21 .OH); H
NMR d 7.54±7.58 .m, 2H), 7.25±7.49 .m, 3H), 5.29±
5.35 .m, 1H), 4.00±4.05 .m, 2H), 2.26±2.34 .m, 2H),
1.44±1.66 .m, 8H). 13C NMR d 136.52, 129.27, 128.83,
128.43, 124.88, 96.75, 79.54, 68.05, 31.22, 30.11, 28.30,
24.97, 19.78. Acetate .46-Ac), a liquid .Found: C, 74.81;
H, 7.23. C17H20O3 requires C, 74.97; H, 7.40%): IR n
1
1
92% yield): H NMR d 7.88±7.99 .m, 2H), 7.10±7.55 .m,
1732 cm21 .CvO); H NMR d 7.47±7.57 .m, 2H), 7.25±
3H), 5.33 [t, Jˆ7.3 Hz, vinyl proton of .Z)-c-44], 5.24 [t,
Jˆ7.3 Hz, vinyl proton of .Z)-t-44], 2.99±3.18 [m, two
oxirane protons of .Z)-t-44], 2.91 [dd, Jˆ13.1, 3.8 Hz,
two oxirane protons of .Z)-c-44], 1.07±2.34 .m, 10H),
0.75±1.00 .m, 1H), 0.11 [TMS group of .Z)-c-44] 0.096
[TMS group of .Z)-t-44].
7.36.m, 3H), 5.29±5.33 .m, 1H), 5.17±5.22 .m, 1H), 4.09
.dd, 1H, Jˆ5.0, 3.0 Hz), 2.10 .s, 3H), 1.35±2.48 .m, 9H).
When the reaction was repeated in the absence of Sc.OTf)3,
the starting epoxy ketones c-4 and t-4 were recovered
completely unreacted.
The same reaction carried out on epoxy ketone 6 .0.10 g,
0.41 mmol) in anhydrous toluene .1.8 mL) afforded silyl
enol ether .Z)-43 .0.12 g, 92% yield): H NMR d 7.56±
The same reaction carried out on epoxy ketone 5 .0.15 g,
0.58 mmol) afforded a crude reaction product .0.14 g)
consisting of a 95:5 mixture of g-HKs 48 and 49 which
was subjected to ¯ash chromatography. Elution with an
8:2 hexane/AcOEt mixture afforded pure g-HKs 48
.0.090 g, 60% yield) and 49 .0.004 g).
1
7.61 .m, 2H), 7.23±7.40 .m, 3H), 5.28 .t, 1H, Jˆ7.1 Hz),
3.02±3.10 .m, 2H), 1.23±2.11 .m, 12H), 0.20 .s, 9H).
6.1.15. Reaction of epoxy ketones 3±8 by the LHMDS/
Sc0OTf)3 protocol. Typical procedure.2,3 A solution of 1 M
LHMDS in hexane .1.34 mL) was added at 08C to a stirred
solution of epoxy ketone 3 .0.20 g of a 75:25 mixture of
diastereoisomers t-3 and c-3, 0.87 mmol) in anhydrous
toluene .5 mL). After 1 h stirring at the same temperature,
Sc.OTf)3 .0.080 g, 20 mol%) was added and the resulting
reaction mixture was stirred for 18 h at rt. Et2O and satu-
rated aqueous NH4Cl were added and stirring was prolonged
for 30 min. Evaporation of the washed .saturated aqueous
NaHCO3 and H2O) organic solution afforded a crude reac-
tion product which was subjected to ¯ash chromatography.
Elution with an 8:2 hexane/AcOEt mixture afforded a 53:47
mixture of the starting epoxides t-3 and c-3 .GC) .0.070 g)
and rel-)1R, 2S, 5R, 7R)-7-benzoyl-bicyclo[3.2.1]octan-2-ol
.45) .0.11 g, 55% yield), as a solid, mp 64±658C .Found: C,
78.01; H, 7.62. C15H18O2 requires C, 78.23; H, 7.88%): IR n
Rel-)1R,5S,6R)-5-benzoyl-bicyclo[4.4.0]decan-1-ol .48), as
a liquid .Found: C, 78.89; H, 8.30. C17H22O2 requires C,
79.03; H, 8.58%): IR n 3498 .OH) and 1670 cm21
1
.CvO); H NMR .CD3OD) d 7.98±8.02 .m, 2H), 7.47±
7.62 .m, 3H), 3.83 .dt, 1H, Jˆ10.6, 3.4 Hz), 1.08±2.12
.m, 15H). 13C NMR .CD3OD) d 206.16, 138.79, 134.46,
130.01, 129.32, 72.17, 46.18, 44.88, 41.67, 33.59, 31.68,
25.67, 23.80, 22.76, 22.15. Compound 48 turned out to be
stable under acetylation conditions .Ac2O/Py).
Rel-)1R,5S,6S)-1-benzoyl-spiro[4,5]decan-6-ol .49), as a
liquid .Found: C, 79.21; H, 8.76. C17H22O2 requires C,
79.03; H, 8.58%): IR n 3461 .OH) and 1689 cm21
1
.CvO); H NMR d 8.01±8.08 .m, 2H), 7.41±7.59 .m,
3H), 4,27 .dd, 1H, Jˆ10.2, 6.9 Hz), 3.34 .dd, 1H, Jˆ10.5,
3.5 Hz), 0.77±1.93 .m, 14H). 13C NMR d 203.46, 139.47,
132.94, 128.70, 73.34, 52.40, 50.26, 33.69, 32.85, 29.79,
28.78, 24.62, 24.07, 21.88. Acetate .49-Ac), a liquid
.Found: C, 75.70; H, 8.41. C19H24O3 requires C, 75.97; H,
1
3385 .OH) and 1683 cm21 .CvO); H NMR d 7.95±7.96
.m, 2H), 7.44±7.57 .m, 3H), 4.03±4.07 .m, 1H), 3.46±3.53
.m, 1H), 2.49±2.53 .m, 1H), 2.17±2.35 .m, 2H), 1.42±1.94
.m, 8H). 13C NMR d 201.29, 137.01, 133.50, 129.24,
129.07, 70.05, 48.33, 46.31, 35.68, 31.40, 31.01, 28.40,
27.41. Acetate .45-Ac), a liquid .Found: C, 74.68; H,
7.35. C17H20O3 requires C, 74.97; H, 7.40%): IR n 1728
1
8.05%): IR n 1734 and 1672 cm21 .CvO); H NMR d
7.83±7.91 .m, 2H), 7.40±7.58 .m, 3H), 4.66 .dd, 1H,
Jˆ10.6, 4.4 Hz), 3.82 .dd, 1H, Jˆ8.6, 7.2 Hz), 2.14 .s,
3H), 0.75±2.10 .m, 14H). 13C NMR d 203.21, 170.84,
139.16, 133.18, 128.96, 128.47, 77.59, 51.05, 51.01,
33.93, 32.43, 29.80, 29.39, 25.03, 24.11, 22.20, 21.71.
1
and 1668 cm21 .CvO); H NMR d 7.95±7.98 .m, 2H),
7.44±7.56.m, 3H), 4.98±5.03 .m, 1H), 3.48±3.55 .m,
1H), 2.58±2.64 .m, 1H), 2.10±2.37 .m, 2H), 2.06 .s, 3H),
1.65±1.85 .m, 5H), 1.25±1.51 .m, 2H).
The same reaction carried out on epoxy ketone 6 .0.10 g,
0.41 mmol) afforded pure rel-)1R,6R,7S)-7-benzoyl-
bicyclo[4.3.0]nonan-1-ol .52) .0.090 g, 90% yield), as a
liquid .Found: C, 78.33; H, 8.42. C16H20O2 requires C,
78.65; H, 8.25%): IR n 3435 .OH) and 1677 cm21
The same reaction carried out in the same conditions with-
out adding Sc.OTf)3, afforded the same product, the g-HK
45, but in a lower yield .0.022 g, 11% yield).
1
.CvO); H NMR d 7.90±7.94 .m, 2H), 7.24±7.51 .m,
3H), 3.50±3.60 .m, 2H), 1.81±2.17 .m, 5H), 1.50±1.77
The same reaction carried out on epoxy ketone 4 .0.10 g of a

8570
P. Crotti et al. / Tetrahedron 57 )2001) 8559±8572
.m, 5H), 1.10±1.37 .m, 3H). 13C NMR d 199.82, 137.27,
133.23, 128.87, 128.29, 60.06, 58.38, 38.51, 37.44, 28.08,
25.20, 20.55, 20.03, 19.63.
6.1.16. Reaction of epoxy ketones 3±8 by the EtONa/
EtOH protocol. Typical procedure. Epoxy ketone 3
.0.12 g of a 75:25 mixture of diastereoisomers t-3 and c-3,
0.52 mmol) was added to a solution of EtONa [from Na
.0.046g, 2.0 g-atoms)] in EtOH .3 mL) and the reaction
mixture was stirred at rt for 72 h. Dilution with saturated
aqueous NaCl, extraction with Et2O and evaporation of the
washed .saturated aqueous NaCl) organic solution afforded
a crude reaction product .0.080 g) which was subjected to
preparative TLC .an 8:2 hexane/AcOEt mixture was used as
the eluant). Extraction of the two most intense bands
afforded pure g-HK 45 .0.015 g, 13% yield) and a mixture
of the starting unreacted epoxides .0.007 g).
When the same reaction was repeated in the absence of
Sc.OTf)3, a complex reaction mixture was obtained.
The same reaction carried out on epoxy ketone 7 .0.10 g,
0.43 mmol) afforded a crude reaction product .0.094 g)
consisting of a 76:24 mixture of g-HKs 54 and 55
.1H NMR) which was subjected to preparative TLC .a
99:1 CH2Cl2/acetone mixture was used as the eluant).
Extraction of the two most intense bands afforded pure
g-HKs 54 .0.060 g, 61% yield) and 55 .0.010 g, 10%
yield).
The same reaction carried out on epoxy ketone t-4 .0.20 g of
a 75:25 mixture of diastereoisomers c-4 and t-4, 0.87 mmol)
afforded a crude reaction product .0.20 g) which was
subjected to preparative TLC .an 8:2 hexane/AcOEt
mixture was used as the eluant). Extraction of the two
most intense bands afforded pure HEE 46 .0.10 g, 50%
yield) and an almost 1:1 mixture of the unreacted starting
epoxides .0.040 g).
Rel-)1R,3S,4S)-1-benzoyl-spiro[2.5]octan-4-ol .54),
liquid .Found: C, 78.56; H, 7.94. C15H18O2 requires C,
a
78.23; H, 7.88%): IR n 3430 .OH) and 1666 cm21
.CvO); H NMR d 7.97±8.00 .m, 2H), 7.42±7.59 .m,
1
3H), 3.65 .dd, 1H, Jˆ7.1, 3.7 Hz), 2.87 .dd, 1H, Jˆ7.6,
5.6Hz), 1.25±1.98 .m, 9H), 1.14 .dd, 1H, Jˆ7.8, 3.9 Hz).
13C NMR d 198.32, 138.89, 132.79, 128.72, 128.32, 73.02,
38.25, 34.49, 28.11, 26.03, 25.40, 23.09, 16.33. Acetate .54-
Ac), a liquid .Found: C, 75.11; H, 7.71. C17H20O3 requires
C, 74.97; H, 7.40%): IR n 1726 and 1666 cm21 .CvO); 1H
NMR d 8.04±8.07 .m, 2H), 7.45±7.61 .m, 3H), 4.92 .broad
s, 1H), 2.59 .dd, 1H, Jˆ5.9, 7.4 Hz), 2.19±2.31 .m, 1H),
1.98 .s, 3H), 1.55±1.83 .m, 6H), 0.97±1.10 .m, 3H). 13C
NMR d 197.08, 170.34, 138.52, 132.97, 128.78, 128.38,
70.88, 35.48, 33.31, 31.47, 29.96, 25.23, 21.50, 20.72,
20.44.
The same reaction carried out on epoxy ketone 7 .0.050 g,
0.22 mmol) afforded a crude reaction product consisting of
an 86:14 mixture of g-HKs 55 and 54 .1H NMR) .0.048 g,
96% yield).
The same reaction carried out on epoxy ketone 8 .0.10 g,
0.46mmol) afforded a crude reaction product .0.090 g)
which was subjected to preparative TLC .an 8:2 hexane/
Et2O mixture was used as the eluant). Extraction of the
most intense band afforded tetrahydrobenzofurane deriva-
tive 57 .0.055 g, 60% yield).
Rel-)1R,3R,4R)-1-benzoyl-spiro[2.5]octan-4-ol .55),
a
solid, mp 97±988C .Found: C, 78.12; H, 7.52. C15H18O2
requires C, 78.23; H, 7.88%): IR n 3440 .OH) and
The same reaction carried out on epoxy ketones 5 and 6
.0.10 g) led only to the recovery of the completely unreacted
starting material. When the same reaction was carried out at
808C for 6h, a complex reaction mixture was obtained in
both cases.
1
1664 cm21 .CvO); H NMR d 8.00±8.04 .m, 2H), 7.44±
7.60 .m, 2H), 3.78 .t, 1H, Jˆ3.9 Hz), 2.56.dd, 2H, Jˆ7.6,
5.6Hz), 1.99±2.13 .m, 1H), 1.15±1.83 .m, 8H), 1.07 .dd,
1H, Jˆ7.8, 3.9 Hz). 13C NMR d 199.53, 138.86, 133.08,
128.81, 128.43, 67.53, 38.74, 33.91, 32.90, 32.15, 25.51,
20.86, 20.62. Acetate .55-Ac), a liquid .Found: C, 75.27;
H, 7.68. C17H20O3 requires C, 74.97; H, 7.40%): IR n 1735
6.1.17. Reaction of epoxy ketones 3±8 by the Amberlyst
15/CH2Cl2 protocol. Typical procedure. A solution of
epoxy ketone 4 .0.10 g of a 75:25 mixture of diastereo-
isomers t-4 and c-4, 0.43 mmol) in CH2Cl2 .5 mL) was
treated with Amberlyst 15 .0.070 g) and the resulting
suspension was stirred for 24 h at rt. Solid NaHCO3 was
added and, after 30 min stirring, evaporation of the ®ltered
organic solution afforded a crude reaction product .0.054 g,
54% yield) consisting of HEE 46, practically pure.
1
and 1670 cm21 .CvO); H NMR d 7.96±8.00 .m, 2H),
7.45±7.59 .m, 3H), 4.81 .dd, 1H, Jˆ6.1, 3.2 Hz), 2.63
.dd, 1H, Jˆ7.6, 5.7 Hz), 2.11 .s, 3H), 1.82±1.94 .m, 4H),
1.42±1.78 .m, 4H), 1.17±1.26.m, 2H). 13C NMR d 197.57,
170.86, 138.63, 132.94, 128.81, 128.29, 75.19, 35.83, 31.12,
28.46, 25.84, 25.06, 22.63, 21.48, 17.12.
The same reaction carried out on epoxy ketone 8 .0.10 g,
0.46mmol) afforded pure 2-phenyl-4,5,6,7-tetrahydro-
benzofuran .57)26 .0.080 g, 88% yield), as a liquid
.Found: C, 84.89; H, 7.46. C14H14O requires C, 84.81; H,
7.12%): 1H NMR d 7.54 .d, 2H, Jˆ7.32 Hz), 7.23±7.31 .m,
2H), 7.08±7.18 .m, 1H), 6.40 .s, 1H), 2.56±2.61 .m, 2H),
2.36±2.42 .m, 2H), 1.62±1.85 .m, 4H). 13C NMR d 152.26,
151.46, 132.11, 129.22, 127.20, 123.91, 119.63, 106.67,
23.96, 23.82, 22.84.
The same reaction carried out on epoxy ketone 6 .0.10 g,
0.41 mmol) afforded a crude reaction product .0.087 g)
which was puri®ed by ¯ash chromatography. Elution with
an 8:2 hexane/AcOEt mixture containing NEt3 .1½)
afforded pure rel-)6R,7S)-2-phenyl-1-oxaspiro[5.5]undec-
2-en-7-ol .53) .0.064 g, 64% yield), as a liquid .Found: C,
78.83; H, 8.61. C16H20O2 requires C, 78.65; H, 8.25%): IR n
3500 cm21 .OH); 1H NMR d 7.54±7.59 .m, 2H), 7.25±7.40
.m, 3H), 5.30 .t, 1H, Jˆ3.9 Hz), 3.83±3.89 .m, 1H), 2.11±
2.24 .m, 4H), 1.32±2.05 .m, 4H), 1.30±1.78 .m, 4H). 13C
NMR d 149.95, 137.04, 128.64, 128.26, 125.00, 96.96,
78.80, 73.80, 30.72, 29.88, 23.38, 22.86, 22.34, 18.36.
When the reaction was repeated in the absence of Sc.OTf)3,
the same cyclization product, the tetrahydrobenzofurane
derivative 57 was obtained in a similar yield.

P. Crotti et al. / Tetrahedron 57 )2001) 8559±8572
8571
Acetate .53-Ac), a liquid .Found: C, 75.19; H, 7.48.
C18H22O31requires C, 75.50; H, 7.74%): IR n 1726cm 21
.CvO); H NMR d 7.56±7.60 .m, 2H), 7.22±7.35 .m,
3H), 5.35 .t, 1H, Jˆ3.9 Hz), 5.08 .dd, 1H, Jˆ4.8, 3.0 Hz)
2.09 .s, 3H), 1.69±1.79 .m, 6H), 1.53±1.60 .m, 6H).
.0.080 g) which was subjected to ¯ash chromatography.
Elution with a 7:3 hexane/Et2O mixture yielded pure rel-
)1R, 6S)-3-phenyl-2-oxabiciylo[4.4.0]dec-3-en-10-one .59)
.0.060 g, 60% yield), as a liquid .Found: C, 78.79; H, 6.84.
C15H16O21requires C, 78.92; H, 7.06%): IR n 1724 cm21
.CvO); H NMR d 7.55±7.61 .m, 2H), 7.27±7.38 .m,
3H), 5.30 .t, 1H, Jˆ4.1 Hz), 4.50 .d, 1H, Jˆ3.9 Hz),
2.65±2.74 .m, 1H), 2.24±2.53 .m, 3H), 1.76±2.11 .m, 5H).
The same reaction carried out on epoxy ketone 7 .0.10 g,
0.43 mmol) afforded a crude reaction product .0.096g)
essentially consisting of HEE 56 which was puri®ed by
¯ash chromatography. Elution with a 7:3 hexane/AcOEt
mixture containing NEt3 .1%) yielded rel-)1R,6S)- 4-phen-
yl-5-oxabicylo[4.4.0]dec-3-en-1-ol .56) .0.070 g, 70%
yield), as a liquid .Found: C, 78.10; H, 8.12. C15H18O2
The same reaction carried out on HEE 53 .0.060 g,
0.25 mmol) in CH2Cl2 .15 mL) with PCC .0.083 g, 0.39
mmol) in the presence of AcONa .0.025 g, 0.30 mmol)
and molecular sieves .0.24 g) afforded a crude reaction
product .0.077 g) essentially consisting of ketone 60
which was puri®ed by ¯ash chromatography. Elution with
a 7:3 hexane/AcOEt mixture yielded pure rel-)6R,7S)-2-
phenyl-1-oxaspiro[5.5]undec-2-en-7-one .60) .0.042 g,
69% yield), as a liquid .Found: C, 79.58; H, 7.61.
C16H18O21requires C, 79.31; H, 7.49%): IR n 1725 cm21
.CvO); H NMR d 7.60±7.63 .m, 2H), 7.25±7.55 .m,
3H), 5.38 .t, 1H, Jˆ4.4 Hz), 2.86.td, 1H, Jˆ11.7,
5.9 Hz), 1.51±2.46.m, 11H). 13C NMR d 211.12, 149.38,
131.10, 128.41, 128.04, 124.46, 98.03, 81.60, 39.90, 39.10,
29.91, 29.13, 27.08, 18.65.
1
requires C, 78.23; H, 7.88%): IR n 3441 cm21 .OH); H
NMR d 7.52±7.59 .m, 2H), 7.24±7.48 .m, 3H), 5.24 .t,
1H, Jˆ3.9 Hz), 3.92 .dd, 1H, Jˆ8.0, 3.7 Hz), 2.44 .dd,
2H, Jˆ18.0, 3.9 Hz), 1.38±2.21 .m, 8H). HEE 56 turned
out to be stable under acetylation conditions .Ac2O/Py).
The same reaction carried out on epoxy ketone 8 .0.10 g,
0.46mmol) afforded a crude reaction product essentially
consisting of tetrahydrobenzofurane derivative 57
.0.090 g, 98% yield).
The same reaction carried out on epoxy ketone 3 .0.10 g of a
75:25 mixture of diastereoisomers t-3 and c-3) was
ineffective and the starting epoxides were recovered
completely unreacted.
Acknowledgements
Á
This work was supported by the Universita di Pisa and the
Ministero della Universita e della Ricerca Scienti®ca e
Tecnologica .MURST), Roma. P. C. gratefully acknowl-
edges Merck for the generous ®nancial support derived
from the 2000 ADP Chemistry Award.
The same reaction carried out on epoxy ketone 5 .0.098 g,
0.38 mmol) afforded a crude reaction product consisting of a
95:5 mixture of diketone 50 and oxoaldehyde 51 which
were subjected to ¯ash chromatography. Elution with an
8:2 hexane/AcOEt mixture afforded pure 50 .0.080 g, 81%
yield) and 51 .0.004 g, 4% yield).
Á
References
5-)2-Oxocyclohexyl)-pentanophenone .50), a liquid .Found:
C, 79.25; H, 8.89. C17H222O1 2 requires C, 79.03; H, 8.58%):
IR n 1706and 1686cm
.m, 2H), 7.43±7.60 .m, 3H), 3.00 .t, 2H, Jˆ7.3 Hz), 2.13±
2.37 .m, 5H), 1.69±1.91 .m, 5H), 1.25±1.47 .m, 5H). 13C
NMR d 213.57, 200.66, 137.33, 133.15, 128.81, 128.29,
50.82, 42.30, 38.66, 34.21, 29.48, 28.29, 27.14, 25.17,
24.60.
1. .a) Crotti, P.; Di Bussolo, V.; Favero, L.; Macchia, F.;
Pineschi, M.; Pasero, M. J. Org. Chem. 1996, 61, 9548±
9552. .b) Crotti, P.; Di Bussolo, V.; Favero, L.; Macchia, F.;
Pineschi, M. Tetrahedron Lett. 1994, 35, 6537±6540.
.c) Chini, M.; Crotti, P.; Favero, L.; Pineschi, M. Tetrahedron
Lett. 1991, 32, 7583±7586. .d) Taylor, S. K. Tetrahedron
2000, 56, 1149±1163.
1
.CvO); H NMR d 7.94±7.99
2. Crotti, P.; Di Bussolo, V.; Favero, L.; Macchia, F.; Pineschi,
M.; Napolitano, E. Tetrahedron 1999, 55, 5853±5866.
3. Chini, M.; Crotti, P.; Flippin, L. A.; Gardelli, C.; Macchia, F.
J. Org. Chem. 1992, 57, 1713±1718.
1-)4-Benzoylbutyl)-1-cyclopentanecarbaldehyde .51),
liquid .Found: C, 78.79; H, 8.19. C17H22O2 requires C,
a
79.03; H, 8.58%): IR n 1718 and 1684 cm21 .CvO); H
1
NMR d 9.45 .s, 1H), 7.90±7.95 .m, 2H), 7.41±7.55 .m,
3H), 2.95 .t, 2H, Jˆ7.3 Hz), 1.24±1.71 .m, 14H). 13C
NMR d 220.20, 200.36, 137.22, 133.11, 128.78, 128.25,
53.87, 39.01, 38.55, 36.26, 29.87, 25.92, 25.20, 24.80,
24.60.
4. .a) Bellucci, G.; Catelani, G.; Chiappe, C.; D'Andrea, F.
Tetrahedron Lett. 1994, 35, 8433±8436. .b) No by-products
arising from a competitive Bayer±Villiger side-reaction have
been observed in the crude oxidation reaction product.
5. .a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley: New York, 1994; p 730. .b) FuÈrst, A.;
Plattner, P. A. Abstract of papers, 12th International Congress
of Pure and Applied Chemistry 1951, p 409.
6.1.18. Oxidation reaction of HEEs 46 and 53. A solution
of HEE 46 .0.10 g, 0.43 mmol) in anhydrous CH2Cl2 .2 mL)
was added dropwise at 08C under nitrogen to a stirred
suspension of PCC .0.14 g, 0.65 mmol), AcONa .0.040 g,
6. Baldwin, J. E. Chem. Commun. 1976, 734±736.
7. The .Z)-con®guration of SEEs 43 and c-44 and t-44 was
clearly de®ned on the basis of the chemical shift of the vinyl
proton in the 1H NMR spectra of these compounds .d 5.28 for
43, 5.33 for c-44 and 5.24 for t-44, Scheme 5), if compared
with the corresponding values found in .Z)- and .E)-SEE of
propiophenone .d 5.33 and 5.11 cm21, respectively).8
Ê
0.49 mmol), 4 A molecular sieves .0.38 g) in anhydrous
CH2Cl2 .4 mL) and the resulting reaction mixture was stir-
red at rt for 1 h. After dilution with Et2O, stirring was
prolonged for 30 min. Evaporation of the ®ltered .Celite-
Fluorisil) organic solution afforded a crude reaction product

8572
P. Crotti et al. / Tetrahedron 57 )2001) 8559±8572
Foscolos, G. B. J. Org. Chem. 1981, 46, 3091±3097.
8. Heathcock, C. H.; Davidsen, S. K.; Hug, K. T.; Flippin, L. A.
J. Org. Chem. 1986, 51, 3027±3037.
Â
.c) Canonne, P.; Foscolos, G. B.; Belanger, D. J. Org.
Chem. 1980, 45, 1828±1835.
9. In the absence of any other direct evidence, the observation
that in the two pairs of diastereoisomeric epoxides c-3 and t-3
and c-4 and t-4, only one reacts in our conditions was utilized
as a demonstration of its relative trans con®guration. A cis
con®guration was consequently assigned to the other
diastereoisomer.
18. Wilcox, C. F.; Chibber, S. S. J. Org. Chem. 1962, 27, 2332±
2338.
19. Blancou, H.; Casadevall, E. Tetrahedron 1976, 32, 2907±
2913.
20. Mash, E. A.; Gregg, T. M. J. Org. Chem. 1995, 60, 6180±
6182.
10. Cornier, R. A.; Francis, M. D. Synth. Commun. 1981, 11, 36 5±
369.
21. Atkinson, P. H.; Cambie, R. C.; Dixon, G.; Noall, W. I.;
Rutledge, P. S.; Woodgate, P. D. Perkin Trans. 1 1977,
230±238.
11. Kikukawa, K.; Sakai, K.; Asada, K.; Matsuda, T. J. Organo-
met. Chem. 1974, 77, 131±145.
22. .a) Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993,
115, 830±846. .b) Arseniyadis, S.; Laurent, A.; Mison, P.
Bull. Soc. Chim. Fr. 1980-II, 233±245. .c) Corey, E. J.;
Enders, D. Tetrahedron Lett. 1976, 3±6.
12. Wittekind, R. R.; Weissman, C.; Farber, S.; Meltzer, R. I.
J. Heterocycl. Chem. 1967, 143±145.
13. Jackson, A. C.; Goldman, B. E.; Snider, B. B. J. Org. Chem.
1984, 49, 3988±3994.
23. Lewis, F. D.; Johnson, R. W.; Ruden, R. A. J. Am. Chem. Soc.
1972, 94, 4292±4297.
14. Benkeser, R. A.; Arnold, Jr., C.; Lambert, R. F.; Thomas, O. H.
J. Am. Chem. Soc. 1955, 77, 6042±6045 and references
therein.
24. Katritzky, A.; Harris, P. A. Tetrahedron 1990, 46, 987±996.
25. Ghera, E.; Perry, D. M.; Shoua, S. Chem. Commun. 1973,
858±859.
15. Costantino, A.; Linstrumelle, G.; Julia, S. Bull. Soc. Chim. Fr.
1970, 907±912.
26. Hagiwara, H.; Uda, H. Perkin Trans. 1 1984, 91±94.
16. Chen, L.; Gill, B.; Pattenden, G.; Simonian, H. Perkin Trans. 1
1996, 31±43.
17. .a) Alonso, D.; Font, J.; OrtunÄo, R. M. J. Org. Chem. 1991, 56,
Â
5567±5572. .b) Canonne, P.; Belanger, D.; Lemay, G.;