Stereoselective synthesis of chiral polyfunctionalized cyclohexane derivatives. Palladium(II)-mediated reaction between cyclohexenones and diazomethane

Article abstract of DOI:10.1016/S0040-4020(00)01061-9

Several chiral polyfunctionalyzed cyclohexanones and cyclohexenones have been synthesized through Diels-Alder cycloadditions, stereoselectivity being stated by X-ray structural analysis and NOE experiments. The chemoselectivity in the palladium(II)-catalyzed reaction between cyclohexenones and diazomethane has been investigated. Thus, in those enones bearing an amide function on the γ-carbon, the preferential addition occurs at the carbonyl giving epoxides which, under acid conditions, rearrange to tetrahydrobenzoxazoles. The other cyclohexenones afford cyclopropanes as a result of addition to the C=C bond. A mechanistic approach to explain the whole process is proposed.

Full text of DOI:10.1016/S0040-4020(00)01061-9

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1025±1034
Stereoselective synthesis of chiral polyfunctionalized cyclohexane
derivatives. Palladium(II)-mediated reaction between
cyclohexenones and diazomethane
a
Cristobal Rodrõguez-Garcõa, Javier Ibarzo, Angel Alvarez-Larena, VicencË Branchadell,
a
b
a
Â
Â
Â
Â
Â
Antoni Olivaa and Rosa M. OrtunÄoa,p
a
 Á
Departament de Quõmica, Universitat Autonoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
Á
Unitat de Cristal.logra®a, Universitat Autonoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
b
Received 4 August 2000; revised 25 October 2000; accepted 7 November 2000
AbstractÐSeveral chiral polyfunctionalyzed cyclohexanones and cyclohexenones have been synthesized through Diels±Alder cyclo-
additions, stereoselectivity being stated by X-ray structural analysis and NOE experiments. The chemoselectivity in the palladium(II)-
catalyzed reaction between cyclohexenones and diazomethane has been investigated. Thus, in those enones bearing an amide function on the
g-carbon, the preferential addition occurs at the carbonyl giving epoxides which, under acid conditions, rearrange to tetrahydrobenzoxazoles.
The other cyclohexenones afford cyclopropanes as a result of addition to the CvC bond. A mechanistic approach to explain the whole
process is proposed. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
was treated with diazomethane trying to produce a pyrazo-
line that, under photolysis, would provide the corresponding
cyclopropane. Then, we performed the reaction of cyclo-
hexenone 1 with excess diazomethane under catalysis of
palladium(II) acetate. Surprisingly, conjugated epoxide 2,
in a single isomeric form, was obtained instead of the
expected cyclopropane (Scheme 1). Compound 2 was an
unstable product that rearranged during chromatography
on silica gel, with concomitant formation of an oxazolidine
ring, to afford 3 in 75% yield for the two steps (Scheme 1).10
On the other hand, we realized that the presence of the CvC
bond was required since treatment of the saturated ketone 4
with diazomethane, under similar conditions, led to the total
recovery of the starting material.
Polyfunctional cyclohexenones and cyclohexanones have
been used as powerful building blocks in the synthesis of
a wide variety of compounds including terpenes,1 amino
acids,2 and cyclohexene carbocyclic nucleosides.3 In par-
ticular, chiral cyclohexenones can undergo, among other
reactions, thermal4 or photochemical5 cycloadditions, to
afford cyclohexanone derivatives in which the con®guration
of the new stereogenic centers is determined by the chirality
of the precursors. Moreover, a highly functionalized cyclo-
hexenone unit has been recently described to be the
common structural feature of many natural products with
antibiotic and antitumor activity.6
Palladium-catalyzed reactions between diazoalkanes and
ole®nic substrates have been used as an ef®cient method
for the cyclopropanation of a,b-unsaturated carbonyl
compounds including cyclohexenones11,12 and cyclopente-
nones.11 The generally accepted mechanism involves the
formation of a metal-carbene complex as intermediate
which adds to the CvC bonds.12±14 Nevertheless, there
was not precedent in the literature on the chemoselective
methylenation of carbonyls in cyclohexenones by using this
procedure.
According to our research project on the synthesis of carbo-
cyclic compounds,7 we envisaged the stereoselective
synthesis of polyfunctional cyclohexane derivatives as
precursors to a variety of products with potential biological
activity. One of our synthetic goals was the creation of
bicylo[3.1.0]hexane8 and bicyclo[4.1.0]heptane skeletons.
To synthesize the later, we intended the cyclopropanation
of enone 1 (Scheme 1) by using the Corey±Chaykovsky
protocol,9 which led, in our case, to the total recovery of
the starting material. The same result was obtained when 1
Therefore, owing to the novelty of this process and the
interest of the resulting oxazolidine derivative as a versatile
synthetic intermediate,15,16 we decided to investigate this
reaction from different points of view. We report in this
paper the obtained results. The ®rst goal was to study the
Keywords: benzoxazole; chemoselectivity; cyclohexanones; cyclohexe-
nones; cyclopropanation; diazomethane; Diels±Alder reactions; oxiranes;
palladium diacetate.
* Corresponding author. Tel.: 134-93-581-16-02; fax: 134-93-581-12-65;
e-mail: rosa.ortuno@uab.es
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01061-9

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C. Rodrõguez-Garcõa et al. / Tetrahedron 57 (2001) 1025±1034
1026
Scheme 1.
in¯uence on the reactivity of several conditions, such as the
metal used as catalyst, the substrate-catalyst stoichiometry,
solvent, and temperature. Secondly, we investigated the
effect of the neighboring substituents on the chemoselective
approach of the reagent, that is, the scope of the process.
The third objective was to postulate a mechanistic pathway
according to the experimental ®ndings. To achieve these
purposes, we chose cyclohexenones 5±11 as convenient
substrates (Chart 1). Compounds 5±7, as well as 1, bear
the benzamide and ester functions at C-4, but differ in the
substituents at C-5 which are of increasing size from 5 to 7.
Cyclohexenone 8 shows the same substitution as 1 but only
the dioxolane ring is in the same relative position.
Compounds 9 and 10 should be useful to discern if the
presence of the amide, the ester or both is required for
the chemoselective methylenation of the carbonyl. Finally,
the obtained results were contrasted with the reaction of
cyclohexenone itself, 11. The synthesis of compounds 1,
5±10 was carried out through Diels±Alder cycloadditions
of heterosubstituted dienes to suitable dienophiles.
Compounds 5, 6, 8, and 9 were previously unknown.
Regarding their synthesis, endo/exo diastereoselectivity of
the corresponding reactions is not relevant since the corre-
sponding stereogenic center is destroyed concomitantly to
the formation of the CvC bond. Nevertheless, we investi-
gated the stereoselectivity of these cycloadditions since the
alcohols or ethers, precursors to the enones, present a great
synthetic interest because they are highly functionalized
Chart 1.
Scheme 2.

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C. Rodrõguez-Garcõa et al. / Tetrahedron 57 (2001) 1025±1034
1027
Scheme 3.
cyclohexanes bearing three chiral centers of determined
relative con®guration. Moreover, facial diastereoselection
in the cycloadditions of chiral dienophiles leading to
optically pure ketones, 1,17 8, and 9 was unambiguously
established by X-ray structural analysis of these com-
pounds.
2. Results and discussion
2.1. Synthesis of the cyclohexenones and the precursor
cyclohexanones
Ketone 1 had been previously synthesized in our labora-
tory,17 and the syntheses of 718 and 1019 were described in
the literature. Ketones 5 and 6 resulted from Diels±Alder
cycloaddition of Danishefsky diene, 12, to (Z)-methyl- and
(Z)-t-butylazlactone, 13 and 17, respectively (Schemes 2
and 3). Thus, reaction between 12 and known azlactone
1320 in boiling toluene for 24 h, followed by acid hydrolysis,
afforded a 1:2 mixture of endo/exo diastereomers 14a,b
(67% yield) whose con®guration was elucidated by differen-
tial NOE experiments. Treatment of the mixture with DBU
in dry methanol at 08C overnight allowed methanol elimi-
nation to produce the CvC bond, as well as methanolysis of
the azlactone, giving cyclohexenone 5 in 81% yield.
Azlactone 17 was prepared in 26% yield following a modi-
È
21
®cation of the Erlenmeyer±Plochl method (Scheme 3).
Thus, reaction of pivalaldehyde, 15, with hippuric acid 16,
in the presence of acetic anhydride and lead diacetate,
afforded 17 in 26% yield. The Z con®guration of 17 was
assessed by spectroscopic methods by comparison with 13.
Figure 1. Structure of compounds 18a and 22 as determined by X-ray
structural analysis.
Scheme 4.

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C. Rodrõguez-Garcõa et al. / Tetrahedron 57 (2001) 1025±1034
1028
Scheme 5.
Subsequent cycloaddition of diene 12 to azlactone 17 led, in
69% yield, to a 2:3 mixture of endo/exo diastereomers
18a,b. Stereochemistry was unambiguously stated by
X-ray structural analysis of 18a (Fig. 1) and corroborated
by signi®cant NOE enhancements in 18b (Scheme 3). Reac-
tion of these compounds with DBU in methanol, as above,
failed. exo Isomer 18b was inert under treatment with
MeONa/MeOH, whereas endo 18a afforded cyclohexenone
6 in only 33% yield. In 18b, the steric congestion induced by
the bulky t-butyl group precludes a conformation suitable
for methanol elimination through a E2-mechanism, since it
would force both methoxyl and t-butyl groups to be axial.
2.2. Reactions of the cyclohexenones with diazomethane
Table 1 summarizes the experiments carried out on ketone
1. Firstly, we realized that the presence of a catalyst was
required for reaction to take place. Solvent played an impor-
tant role since addition was less ef®cient in THF and was not
observed to occur in dichloromethane, these results pointing
towards a solvated polar transition state for this process
where the steric factors should be noticeable. Addition
was not observed when Rh2(OAc)4, either in ether or in
dichloromethane, was used as catalyst. The same result
was obtained when Cu(OTf)2 was employed.
The synthesis of ketone 8 was undertaken from alcohol 19
(Scheme 4). This compound, as a mixture of endo/exo
isomers, resulted from the Diels±Alder cycloaddition of
1-trimethylsilyloxy-1,3-butadiene to a chiral azlactone.17
Treatment of 19 with sodium methoxide in methanol, at
room temperature for 24 h, afforded 20 in 67% yield as
the single exo isomer, as established by NMR. This is,
presumably, the thermodynamically most stable diastereo-
mer. Oxidation of allylic alcohol 20 with PDC in dichloro-
methane produced quantitatively ketone 8.
Then, we decided to explore the behavior of the parent
compound 11. After a preliminary communication on this
work was published,10 Denmark described the cyclopropa-
nation of 11 with diazomethane and a bis(oxazoline)palla-
dium(II) complex to afford 23 (Scheme 6) in 71% yield as
the only reaction product.12 Our most signi®cant results are
listed in Table 1. In no case addition to carbonyl was
observed, compound 23 being the only de®ned product
when Pd(OAc)2 in ether (85% yield) or Rh2(OAc)4 in
dichloromethane (60% yield) were used as catalysts,
whereas Cu(OTf)2 promoted only a very low conversion.
Another noticeable difference between the behaviour of 1
and 11 lies on the fact that the substrate/catalyst ratio, as
well as solvent and temperature, does not have a remarkable
effect on the reactivity of 11 towards cyclopropanation
(entries 5±8, Table 1).
Finally, the synthesis of enone 9 was envisioned as depicted
in Scheme 5. Thus, reaction between diene 12 and the
nitroole®n 21,22 in toluene at 608C for 24 h, and subsequent
acid hydrolysis, afforded compound 22 in 35% yield, as a
single isomer whose stereochemistry was assigned by X-ray
crystallography (Fig. 1). Attempts to reduce the nitro group
by reaction with hydrogen, in the presence of Pd(OH)2 and
under several atmospheres pressure, failed. The use of
ammonium formate or cyclohexene, as sources of hydrogen,
did not afford satisfactory results neither. These facts,
jointly with the low yield in the cycloaddition and hydro-
lysis steps, prompted us to give up the attempted synthesis
of 9.
From all these results, we concluded that Pd(OAc)2 was the
catalyst of choice, in good agreement with Denmark's ®nd-
ings,12 ether being the best solvent for addition to the car-
bonyl group. The reagent addition order was also crucial.
For instance, cyclopropane derivative 23 was obtained from
cyclohexenone, 11, in ca 10% yield, when diazomethane
was added to a suspension of Pd(OAc)2 in ether, the mixture
Table 1. Selected reactions of enones 1 and 11 with diazomethane under several conditions
Entry
Enone
Catalyst (eq)
Solvent
Temperature (8C)
Time (h)
Product
Yield
1
2
3
4
5
6
7
8
9
10
1
1
1
1
11
11
11
11
11
11
Pd(OAc)2 (0.02)
Pd(OAc)2 (1)
Pd(OAc)2 (1)
ether
ether
THF
CH2Cl2
ether
ether
0
0
0
0
0
4
4
4
4
2
2
2
2
2
2
2
2
57
70
63
±
77
85
76
88
10
60
2
±a
Pd(OAc)2 (1)
Pd(OAc)2 (0.02)
Pd(OAc)2 (0.02)
Pd(OAc)2 (1)
Pd(OAc)2 (0.02)
Rh2(OAc)4 (0.01)
Rh2(OAc)4 (0.01)
23
23
23
23
23
23
25b
0
ether
CH2Cl2
ether
CH2Cl2
25b
25b
25b
a Enone 1 is recovered.
b Diazomethane was added at 08C, then the reaction mixture was warmed to 258C.

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C. Rodrõguez-Garcõa et al. / Tetrahedron 57 (2001) 1025±1034
1029
Scheme 6.
was stirred for 15 min, then enone 11 was added and the
®nal mixture was stirred for 16 h at room temperature. In
contrast, compound 23 was obtained in 90% yield when the
enone was added prior to diazomethane.
and two singlets at 1.35 and 1.37 ppm due to the methoxyl
group in each isomer. GC±MS showed two peaks that
produced the same molecular ion (182) and identical ionic
fragments, being relevant those at m/e 123 (loss of CO2Me)
and 81 (C6H9).
The study of this process was also extended to the other
cyclohexenones. The obtained results can be grouped in
two sets, depending on the presence or the absence of the
amide group at the allylic g-position. Thus, ketone 5 was
reacted with diazomethane and 1 equiv. Pd(OAc)2 in ether
at 08C for 4 h affording, after ¯ash chromatography on silica
gel, a mixture of oxazolidine 24 (38% yield) and cyclo-
propane 25 (8% yield). Ketones 6 and 7 remained unaltered
under similar conditions suggesting that steric hindrance
prevents these substrates to react.
All these results reinforce the hypothesis that the neigh-
boring benzamide group assists the methylene addition to
the carbonyl of enones 1 and 5 reversing the chemoselec-
tivity from the CvC attack to the CvO attack. This is an
example of 1,2-/1,4-dichotomy, presumably controlled by
chelation. Thus, it is reasonable to assume that, under
normal circumstances, the metallocarbene PdvCH2
species12±14 attacks the conjugated double bond with Pd
approaching the a-carbon (and the CH2 group approaching
the b-carbon) (Scheme 7a).23 In enones such as 1 and 5, it
may well be that coordination of the electrophilic palladium
to the Lewis-basic amide carbonyl will actually alter the
geometry of approach, forcing Pd to approach the b-carbon
(Scheme 7b). Then, palladium would coordinate simul-
taneously to the amide carbonyl and to the double bond.
Several conformations of enone 8 have been studied through
theoretical calculations using the semiempirical PM3
method24 implemented in the chem3d program.25 Fig. 2
presents the most stable structure obtained in this
study. The relative orientation of the CvC and amide
CvO groups shows that the formation of a chelate Pd
complex seems feasible. From this species, methylene can
be delivered intramolecularly through the attack of the
On the other hand, cyclopropanation products (mixtures of
stereoisomers) were the only compounds obtained from
ketones 8 and 10 under similar conditions (Scheme 6).
Thus, 26 resulted from enone 8 in 50% yield, after 10
days reaction with excess diazomethane. Enone 10 reacted
very smoothly to afford compound 27, but conversion was
never higher than ca 15%, either at 08C for 4 h or at 258C
overnight. This low reactivity may be attributed to the steric
congestion produced by the presence of the methyl group at
the allylic g-position of 10. The presence of compound 27 in
the reaction mixture was detected by 1H NMR and MS. The
former showed a complex absorption between 1.1 and
1.3 ppm, attributable to the cyclopropane-ring protons,

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C. Rodrõguez-Garcõa et al. / Tetrahedron 57 (2001) 1025±1034
1030
Scheme 7.
metallocarbene carbon to the electrophilic carbon of the
CvO group (rather than to the a-carbon). In this way,
the formation of the oxirane-ring is diastereoselective and
the presence of the CvC bond is required to link the palla-
dium species. In contrast, when the benzamido group is
absent, the cyclopropanation of the CvC bond occurs in
the usual way. Steric hindrance produced by the substituents
can prevent the attack of the reagents. Thus, reactivity of
enones 8 and 10 is decreased with respect to cyclohexenone
11.
selective Diels±Alder cycloadditions. The transition-metal
catalyzed reactions of some cyclohexenones with diazo-
methane have been investigated. Thus, while cyclohexe-
none itself reacts fairly under rhodium(II) or palladium(II)
catalysis, affording the corresponding cyclopropane deriva-
tive in good yield, the other cyclohexenones led to cyclo-
propanes or oxiranes as the main products, depending on the
substitution at the g-carbon. Thus, those cyclohexenones
bearing an amide function at g-position underwent addition
to the carbonyl to give a conjugated epoxide which rear-
ranged under acid conditions to a tetrahydrobenzoxazole
derivative. The other cyclohexenones gave cyclopropanes
in variable yields, as a result of addition to the CvC bond.
In both cases, steric hindrance markedly decreased the reac-
tivity of the substrates considered.
Finally, in the cases of addition to carbonyl, rearrangement
of the resultant conjugated epoxide takes place under acid
catalysis to afford the tetrahydrobenzoxazole nucleus
(Scheme 7c).
3. Concluding remarks
4. Experimental
4.1. General
Several chiral polyfunctionalized cyclohexanones and
cyclohexenones have been synthesized through stereo-
Flash column chromatography was carried out on silica gel
(240±400 mesh) unless otherwise stated. Melting points
were determined on a hot stage and are uncorrected. H
1
NMR and 13C NMR spectra were recorded at 250 and
62.5 MHz, respectively, unless otherwise stated.
Ketones 1,17 7,18 and 1019 were synthesized according to the
previously described procedures. Commercially available
palladium(II) acetate and dimeric rhodium(II) acetate were
used without further treatment.
4.1.1. X-Ray diffraction analysis of 18a. Suitable crystals
were obtained by crystallization from EtOAc±pentane.
Crystal dimensions: 0.18£0.14£0.14 mm. Empirical
formula C19H23NO4. Molecular weight 329.38. Crystal
system: monoclinic. Space group Cc (No. 9). Lattice para-
Figure 2. PM3 optimized structure of enone 8 indicating the approximate
position that Pd would occupy in a chelate complex. Hydrogen atoms have
been omitted for clarity.
Ê
Ê
Ê
meters: aˆ18.020(6) A, bˆ8.293(4) A, cˆ12.844(6) A,

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C. Rodrõguez-Garcõa et al. / Tetrahedron 57 (2001) 1025±1034
1031
Ê 3
bˆ116.60(4)8, Vˆ1716.2(13) A . Zˆ4. Calculated density
dryness, the residue was poured into dichloromethane
(20 mL). The resultant solution was washed with brine
(2£20 mL), and with saturated aqueous sodium bicarbonate
(20 mL). The organic phase was dried (MgSO4) and solvent
was removed to afford a 1:2 mixture of 14a/14b (500 mg,
67% yield) as determined from its H NMR spectrum: H
NMR (CDCl3) 0.82 (d, 3H); 0.90 (d, 3H); 2.13±2.95
(complex absorption, 10H), 3.24 (s, 3H); 3.34 (s, 3H);
3.70 (m, 1H); 3.79 (m, 1H); 7.4±8.1 (m, 10H). Anal.
Calcd for C16H17NO4: C, 66.89; H, 5.96; N, 4.89. Found:
C, 66.74; H, 6.13; N, 4.75.
1.275 g cm23
293(2) K on an Enraf Nonius CAD4 diffractometer using
.
F(000)ˆ704. Data were collected at
Ê
MoKa radiation (lˆ0.71069 A) yielding 1504 independent
re¯ections. The structure was solved by direct methods
(shelxs-86)26 and re®ned by least-squares on F2 for all
re¯ections (shelxl-97).27 Non-hydrogen atoms were
re®ned anisotropically. Hydrogen were placed in calculated
positions with isotropic displacement parameters 1.5
(methyl H) or 1.2 (the rest) times the Ueq values of corre-
sponding carbons. Re®ned parameters 217. Goodness-of-®t
on F2: 0.818. R(F)ˆ0.071 for re¯ections with I.2s(I),
Rw(F2)ˆ 0.172 for all data.
1
1
Column chromatography (mixtures of ethyl acetate±hexane)
of the mixture 14a/14b allowed the isolation and characteri-
zation of the major isomer, (3S,4S,5R)-5-methyl-4-
spiro{40[20-phenyl-50(4H)-oxazolone]}-3-methoxycyclo-
hexan-1-one, 14b, as a solid. Crystals, mp 118±1198C
4.1.2. X-Ray diffraction analysis of 22. Suitable crystals
were obtained by crystallization from EtOAc±pentane.
Crystal dimensions: 0.58£0.36£0.25 mm. Empirical
formula C12H19NO6. Molecular weight 273.28. Crystal
system: orthorhombic. Space group P212121 (No. 19).
(from EtOAc±pentane); IR (KBr) 1845, 1812, 1727 cm21
;
400-MHz 1H NMR (CDCl3) 0.82 (d, JMe-5ˆ4.1, CH3); 2.30
(m, H51H6ax); 2.60 (t, J6eq±6axˆJ6eq±5ˆ14.7 Hz, H6eq); 2.81
(m, H2ax1H2eq); 3.24 (s, OCH3); 3.79 (dd, J3±2eqˆ11.5 Hz,
J3±2axˆ5.7 Hz, H3); 7.3±8.1 (m, Ph); 100-MHz 13C NMR
(CDCl3) 17.2 (CH3); 36.3 (C5); 44.6, 46.7 (C21C6); 59.4
(OCH3); 82.8 (C4); 127.4, 130.2, 130.7, 134.9 (Ph); 163.7
(NC(Ph)O); 180.8 (COO); 207.9 (CO). Anal. Calcd for
C16H17NO4: C, 66.89; H, 5.96; N, 4.89. Found: C, 66.84;
H, 6.03; N, 4.67.
Ê
Ê
Lattice parameters: aˆ7.561(3) A, bˆ9.571(3) A, cˆ
Ê
Ê 3
19.425(10) A, Vˆ1405.7(10) A . Zˆ4. Calculated density
1.291 g cm23
293(2) K on an Enraf Nonius CAD4 diffractometer using
.
F(000)ˆ584. Data were collected at
Ê
MoKa radiation (lˆ0.71069 A) yielding 1442 independent
re¯ections. The structure was solved by direct methods
(shelxs-86)26 and re®ned by least-squares on F2 for all
re¯ections (shelxl-97).27 Non-hydrogen atoms were
re®ned anisotropically. Hydrogen were placed in calculated
positions with isotropic displacement parameters 1.5
(methyl H) or 1.2 (the rest) times the Ueq values of corre-
sponding carbons. Re®ned parameters 172. Goodness-of-®t
on F2: 0.927. R(F)ˆ 0.040 for re¯ections with I.2s(I),
Rw(F2)ˆ0.103 for all data.
4.1.5. Methyl (1R,6R)-1-benzoylamino-6-methyl-4-oxo-
2-cyclohexene-1-carboxylate, 5. A mixture of 14a/14b
(500 mg, 1.8 mmol) and DBU (0.3 g, 1.8 mmol) in
methanol (36 mL) was stirred at 08C for 17 h. Solvent was
removed and the residue was chromatographed (1:1 ethyl
acetate±hexane) to afford enone 5 as a white solid (405 mg,
81% yield). Crystals, mp 125±1268C (from EtOAc±
4.1.3. Methyl (1S,2R)-1-benzoylamino-2-[(40S)-40-(20,20-
dimethyl-10,30-dioxolo)]-4-oxocyclohexane-1-carboxylate,
4. Enone 117 (396 mg, 1,1 mmol) in methanol (35 mL) was
hydrogenated at atmospheric pressure in the presence of
20% Pd(OH)2/C (20 mg). The suspension was ®ltered
through celite, solvent was evaporated under vacuo and
the residue was chromatographed (4:1 ethyl acetate±
hexane) to afford quantitatively ketone 4 (398 mg) as a
dense oil, [a]Dˆ248.6 (c 0.37, CHCl3); IR (®lm) 1735,
pentane); IR (KBr) 1740, 1694, 1635, 1607 cm21 1H
;
NMR (CDCl3) 1.06 (d, JMe-6ˆ6.58 Hz, CH3); 2.52 (m,
H5ax1H5eq); 2.75 (m, H6); 3.74 (s, OCH3); 6.03 (d,
J2±3ˆ10.25 Hz, H3); 7.05 (broad s, NH); 7.13 (d,
J3±2ˆ10.25 Hz, H2); 7.3±7.9 (m, Ph); 13C NMR (CDCl3)
15.8 (CH3); 35.8 (C6); 41.7 (C5); 53.2 (OCH3); 61.2 (C1);
127.1, 128.6, 129.5, 132.0, 133.4 (Ph1C2); 145.8 (C3);
167.7 (CONH), 171.5 (COO); 197.8 (CO). Anal. Calcd for
C16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found: C, 66.78; H,
5.97; N, 4.88.
1715, 1673 cm21; H NMR (CDCl3) 1.35 (s, CH3), 1.48
1
(s, CH3), 2.25±2.46 (complex absorption, 5H), 2.68 (dd,
Jˆ16.0 Hz, J0ˆ13.1 Hz, 1H), 3.46 (m, 1H), 3.65 (dd,
Jˆ8.8 Hz, J0ˆ5.8 Hz, 1H), 3.75 (s, OCH3), 4.02 (dd,
JˆJ0ˆ8.8 Hz, 1H), 4.34 (m, 1H), 7.38±7.54 (complex
absorption, 3H), 7.78±7.82 (complex absorption, 2H),
7.90 (broad s, 1H); 13C NMR (CDCl3) 24.6, 25.8, 30.6,
35.5, 36.4, 45.0, 52.9, 63.3, 66.8, 74.5, 110.5, 126.9,
128.5, 131.8, 134.3, 168.3, 172.7, 208.6. Anal. Calcd for
C20H25NO6: C, 64.06; H, 6.72; N, 3.74. Found: C, 64.12;
H, 6.70; N, 3.68
4.1.6. Synthesis of azlactone 17 and its Diels±Alder reac-
tion with diene 12: Compounds 18a and 18b. A mixture of
pivalaldehyde, 15 (600 mg, 7.4 mmol), hippuric acid, 16
(900 mg, 4.9 mmol), lead diacetate (900 mg, 2.5 mmol)
and acetic anhydride (2 mL) was stirred at 1308C for 72 h.
Then, absolute ethanol (100 mL) was added and the
resultant azeotropic mixture was distilled. The residue was
chromatographed (1:4 ethyl acetate±hexane) to afford
(Z)-2-phenyl-4-tert-butyliden-(4H)-oxazolone, 17 (300
mg, 26% yield) which was identi®ed by its spectral data.
4.1.4. Diels±Alder reaction between diene 12 and
azlactone 13, and subsequent hydrolysis of adducts:
Compounds 14a and 14b. Diene 12 (500 mg, 2.9 mmol)
and azlactone 13 (500 mg, 2.7 mmol) in anhydrous toluene
(30 mL) were heated to re¯ux for 24 h under nitrogen
atmosphere. Solvent was evaporated at reduced pressure, a
4:1 mixture of 0.05% HCl±THF (20 mL) was added, and
the solution was stirred for 3 h. After concentration to
1
IR (KBr) 1807, 1747, 1720, 1665, 1597 cm21; H NMR
(CDCl3) 1.35 (s, 3£CH3); 6.65 (s, 1H), 7.4±8.0 (complex
absorption, Ph); 13C NMR (CDCl3) 29.88 (t-Bu); 34.8 (q,
t-Bu); 125.8, 128.1, 128.8, 133.0, 133.8 (C21Ph); 148.2
(C1), 161.8 (NH(CO)Ph); 167.6 (COO); 203.6 (CO).
A solution of azlactone 17 (400 mg, 1.5 mmol) and diene 12

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C. Rodrõguez-Garcõa et al. / Tetrahedron 57 (2001) 1025±1034
1032
(300 mg, 1.5 mmol) in anhydrous toluene (20 mL) was
heated to re¯ux for 24 h. Solvent was removed and a 4:1
solution of 0.05% HCl±THF was added. The resultant
mixture was stirred at rt for 30 min, solvent was evaporated
and the residue was diluted with dichloromethane (20 mL).
The solution was washed with brine (2£20 mL) and satu-
rated aqueous sodium bicarbonate (20 mL), and dried
(MgSO4). Solvent was removed to afford a 2:3 mixture of
diastereomeric ketones 18a and 18b (500 mg, 69% yield)
which were isolated after column chromatography (1:3
ethyl acetate±hexane). (3S,4S,5R)-5-tert-Butyl-4-spiro-
{40[20-phenylÐ50(4H)-oxazolone]}-3-methoxycyclohexan-
1-one, 18a. Crystals, mp 138±1398C (from EtOAc±pen-
tane); IR (KBr) 1817, 1723, 1653 cm21; 400-MHz 1H
NMR (CDCl3) 0.90 (s, 3£CH3); 2.54±2.90 (complex
absorption, H2ax, H2eq, H5, H6ax, H6eq); 3.32 (s, OCH3);
3.50 (dd, J3±2eqˆ6.6 Hz, J3±2axˆ3.6 Hz, H3); 7.4±8.0 (m,
Ph); 100-MHz 13C NMR (CDCl3) 30.5 (t-Bu); 36.0 (q,
t-Bu); 41.5, 41.6 (C21C6); 49.1 (C5); 60.3 (OCH3); 75.7
(C4); 84.3 (C3); 127.7, 130.0, 130.8, 135.0 (Ph); 163.1
(NC(Ph)O); 180.1 (COO); 210.2 (CO); MS, m/e (%) 329
(M1, 1), 77 (27), 105 (100). (3R,4S,5R)-5-tert-Butyl-4-
spiro{40[20-phenylÐ50(4H)-oxazolone]}-3-methoxycyclo-
hexan-1-one, 18b. Oil; IR (®lm) 1827, 1713, 1618,
graphed (1:7 ethyl acetate±hexane) to afford 20 as a solid in
a single isomeric form (70 mg, 67% yield). Crystals, mp
154±1558C (from EtOAc±pentane); [a]Dˆ268.0 (c 1.79,
CHCl3); IR (KBr) 3374, 3253, 1746, 1736 1661, 1602 cm21
;
1H NMR (CDCl3) 1.36 (s, CH3), 1.46 (s, CH3), 2.29±2.33
(m, H5ax,H5eq), 2.70 (dd, J6±5axˆJ6±5eqˆ1.5 Hz, H6), 3.76
0
0
0
0
0
(dd, J5 a,5 bˆ6.6 Hz, J5 a,4 ˆ3.7 Hz, H5 a), 3.80 (s, OCH3),
0
0
0
0
0
0
0
4.05 (dd, J5 b,5 aˆ7.3 Hz, J5 b,4 ˆ7.1, H5 b), 4.28 (t, J4 ,5 a
ˆ
0
0
0
J4 ,5 bˆ6.6 Hz, H4 ), 4.72 (m, H2), 5.69 (complex absorption,
H3,H4), 6.98 (broad, NH), 7.38±7.83 (m, Ph); 13C NMR
(CDCl3) 21.9, 24.9, 27.0, 29.6, 40.3, 53.0, 66.8, 68.9,
71.8, 75.3, 110.3, 125.6, 127.9, 128.5, 129.7, 131.9, 134.3,
168.4, 171.8. Anal. Calcd for C20H25NO6: C, 63.99; H, 6.71;
N, 3.73. Found: C, 64.00; H, 6.61; N, 3.72.
4.1.9. Methyl (1S,6R)-1-benzoylamino-6-[(40S)-40-(20,20-
dimethyl-10,30-dioxolo)]-2-oxocyclohex-3-ene-1-carboxy-
late, 8. A mixture of alcohol 20 (200 mg, 0.5 mmol) and
PDC (300 mg, 0.7 mmol) in dry dichloromethane (25 mL)
was stirred at 408C for 70 h. Solvent was removed and the
residue was chromatographed (1:1 ethyl acetate±hexane) to
afford 19 mg of recovered 20 and 180 mg of 8 (100% yield
on reacted 20) as a solid. Crystals, mp 123±1248C (from
EtOAc±pentane); [a]Dˆ2186.3 (c 1.1, CHCl3); IR (KBr)
1
1
1579 cm21; 400-MHz H NMR (CDCl3) 0.87 (s, 3£CH3);
3385, 1745, 1702, 1674 cm21; H NMR (CDCl3) 1.19 (s,
2.14 (dd, J5±6axˆ4.38 Hz, J5±6eqˆ13.25 Hz, H5); 2.53 (dd,
CH3), 1.29 (s, CH3), 2.69 (m, H5a), 3.20 (m, H5b), 3.49 (m,
0
0
0
0
0
J6ax±5ˆ4.38 Hz, J6ax±6eqˆ13.8 Hz, H6ax); 2.77 (d, J2ax±2eq
ˆ
H6), 3.66 (dd, J5 a,5 bˆJ5 a,4 ˆ8.9 Hz, H5 a), 3.66 (s, OCH3),
0
0
0
0
0
0
J2±3ˆ8.75 Hz, H2ax1H2eq); 2.87 (dd, J6eq±6axˆ14.0 Hz,
3.98 (dd, J5 b,5 aˆJ5 b,4 ˆ8.8 Hz, H5 b), 4.23 (m, H4 ), 6.08
(m, H3), 6.94 (m, H4), 7.41±7.85 (m, Ph), 7.94 (s, 1H,
NH); 13C NMR (CDCl3) 24.3, 25.0, 25.9, 41.1, 53.2, 67.3,
67.9, 73.9, 109.4, 125.3, 127.2, 128.6, 132.1, 133.1, 151.5,
166.9, 167.8, 189.6. Anal. Calcd for C20H23NO6: C, 64.33;
N, 3.75; H, 6.21. Found: C, 64.37; N, 3.53; H, 6.11.
J6eq±5ˆ14.0 Hz, H6eq); 3.21 (s, OCH3), 3.67 (dd, J3±2eq
ˆ
J3±2axˆ8.75 Hz, H3); 7.4±8.1 (m, Ph). 100-MHz 13C NMR
(CDCl3): 28.8 (t-Bu); 34.2 (q,t-Bu); 40.2 (C6); 42.4 (C2);
47.8 (C5); 57.8 (OCH3); 76.1 (C4); 83.0 (C3); 125.8, 128.1,
128.7, 132.7 (Ph); 161.0 (NC(Ph)O); 180.1 (COO); 206.8
(CO); MS, m/e (%) 329 (M1, 1), 77 (24), 105 (100). Anal of
the mixture 18a/18b. Calcd for C19H23NO4: 69.28; H, 7.04;
N, 4.25. Found: C, 69.13; H, 6.99; N, 4.28.
4.1.10. (3S,4S)-3-Methoxy-5-[(40S)-40-(20,20-dimethyl-10,30-
dioxolo)]-4-nitrocyclohexan-1-one, 22. Nitroole®n 21
(170 mg, 10. 0 mmol) and diene 12 (200 mg, 10.9 mmol)
in toluene (40 mL) were stirred at 608C for 24 h. Solvent
was removed and a 1:4 solution of 0.05% HCl±THF was
added to the residue. The mixture was stirred at room
temperature for 1 h, then concentrated to dryness. The resi-
due was chromatographed (1:2 ethyl acetate±hexane) to
afford ketone 22 as a white solid (65 mg, 35% yield). Crys-
tals, mp 117±1188C (from EtOAc±pentane); [a]Dˆ225.5
4.1.7. Methyl (1R,6R)-1-benzoylamino-6-tert-butyl-4-oxo-
2-cyclohexene-1-carboxylate, 6. Compound 18a (300 mg,
1.0 mmol), and NaOMe (100 mg, 2.0 mmol) in anhydrous
methanol (40 mL) were stirred at 08C for 72 h. Then 0.1%
HCl was added to reach neutral pH, and the mixture was
concentrated to dryness. The residue was poured into
dichloromethane (50 mL), ®ltered, and the solvent was
removed. After column chromatography (mixtures of ethyl
acetate±hexane), pure enone 6 was obtained in 33% yield (g)
as a solid. Crystals, 124±1258C (from EtOAc±pentane); IR
1
(c 1.02, CHCl3); H NMR (CDCl3) 1.28 (s, CH3); 1.39 (s,
CH3); 2.37±2.48 (complex absorption, H2a,H3,H6a,H6b);
2.93 (dd, J2a,2bˆ14.8 Hz, J2b±3ˆ4.9 Hz, H2b); 3.32 (s,
1
(KBr) 1732, 1675, 1581 cm21; H NMR (CDCl3) 0.93 (s,
OCH3); 3.60 (dd, J5 a,5 bˆ8.3 Hz, J5 a,4 ˆ5.1 Hz, H5 a);
0
0
0
0
0
0
0
3£CH3); 2.63 (dd, J6±5eqˆ17.5 Hz, J6±5axˆ5.1 Hz, H6); 2.76
(complex absorption, H5eq); 3.43 (dd, J5ax±5eqˆ13.8 Hz,
J5ax±6ˆ5.1 Hz, Hax); 3.81 (s, OCH3); 6.17 (m, H2), 6.60 (m,
H3); 7.3±7.9 (m, Ph); 13C NMR (CDCl3) 28.65 (t-Bu); 34.2
(q, t-Bu); 37 (C5); 47.4 (C6); 53.6 (OCH3); 63.2 (C1), 126.8,
128.6, 129.7, 131.9, 133.8 (Ph1C3); 150.9 (C2); 165.14
(CONH); 171.3 (COO); 198.9 (CO). Anal. Calcd for
C19H23NO4: C, 69.28; H, 7.04; N, 4.25. Found: C, 69.14;
H, 6.95; N, 4.30.
4.10±3.89 (complex absorption, H4 ,H5 b,H3); 4.85±4.78
(m, H4); 13C NMR (CDCl3) 24.3 and 25.7 (2£CH3), 37.4
0
(C6), 39.1 (C3), 43.7 (C2), 57.4 (OCH3), 65.9 (C5 ), 73.1
0
0
(C4 ), 78.3 (C3), 89.8 (C4), 100.0 (C2 ). Anal. Calcd for
C12H19NO6: C, 52.74; H, 7.01; N, 5.13. Found: C, 52.88;
H, 6.90; N, 5.14.
4.1.11. Reaction of enone 1 with diazomethane and palla-
dium acetate: Methyl (1S,4R,6R)-1-benzoylamino-6-
[(40S)-4-(20,20-dimethyl-10,30-dioxolo)]-4-oxaspiro[2.5]-
2-octene-1-carboxylate, 2, and [(3aR,4R,7aS)]-4-[(40S)-
40-(20,20-dimethyl-10,30-dioxolo)]-6-hydroxymethyl-3a-
methoxycarbonyl-2-phenyl-3a,4,5,7a-tetrahydrobenzoxa-
zole, 3. Palladium diacetate (79 mg, 0.3 mmol) was added to
an ice-cooled solution of enone 1 (130 mg, 0.35 mmol) in
4.1.8. Methyl (1S,2S,6R)-1-benzoylamino-2-hydroxy-6-
[(40S)-40-(20,20-dimethyl-10,30-dioxolo)]cyclohex-3-ene-1-
carboxylate, 20. Azlactone 19 (100 mg, 0.3 mmol) and
NaOMe (10 mg) in methanol (15 mL) was stirred at rt for
24 h. Solvent was removed and the residue was chromato-

 Â
C. Rodrõguez-Garcõa et al. / Tetrahedron 57 (2001) 1025±1034
1033
ether (10 mL). On the resultant suspension was distilled an
ethereal solution of diazomethane (prepared from N-methyl-
N-nitroso-p-toluenesulfonamide (2.2 g, 10.0 mmol) and
KOH (0.4 g, 7.1 mmol) in 30 mL ether). The light-protected
mixture was stirred at 08C for 4 h, then ®ltered through
celite, and concentrated to dryness. The residue was ¯ash-
chromatographed on ¯orisil (3:1 ether±hexane) to afford
17 mg of alcohol 3 and 81 mg of epoxide 2 (75% total
yield) as an oil which was identi®ed by its spectroscopic
data, as follows. IR (®lm) 3381, 1743, 1665 cm21; 1H NMR
(CDCl3) 1.35 (s, CH3), 1.47 (s, CH3), 2.32±2.57 (complex
absorption, H5,H4a,H4b), 2.87 (d, J6a,6bˆ5.1 Hz, H6a), 2.92
(d, J6b,6aˆ5.1 Hz, H6b), 3.71±3.77 (complex absorption,
excess diazomethane was distilled onto the mixture,
previously cooled at 08C. The resultant solution was
allowed to warm to rt and stirred for 2 h, then ®ltered
through celite, and concentrated to dryness. The residue
was chromatographed (mixtures of ethyl acetate±hexane)
to afford 23 (130 mg, 57% yield). Compound 23 was iden-
ti®ed by its spectroscopic data, as follows. 1H NMR (CDCl3)
0.98 (m, 1H), 1.10 (m, 1H), 1.49±1.66 (complex absorption,
3H), 1.78±2.01 (complex absorption, 3H), 2.14 (dd, Jˆ
J0ˆ4.4 Hz, 1H), 2.21 (dd, Jˆ5.1 Hz, J0ˆ4.4 Hz, 1H); 13C
NMR (CDCl3) 10.0, 17.3, 17.6, 21.1, 25.6, 36.6, 209.1. MS,
m/e (%) 110 (M, 61), 82 (43), 81 (37), 68 (34), 67 (72), 55
(71), 54 (100).
0
0
0
OCH31H5 a), 4.08 (m, H5 b), 4.59 (m, H4 ), 5.39 (d,
J3,2ˆ10.2 Hz, H3), 6.91 (d, J2,3ˆ10.2 Hz, H2), 7.43 (m,
4.1.13. Palladium(II)-catalyzed reaction of enone 5 with
diazomethane. A light-protected ethereal-solution of enone
5 (100 mg, 3.5 mmol), Pd(OAc)2 (80 mg, 3.5 mmol) and
excess diazomethane (prepared from 3.0 g of N-methyl-N-
nitroso-p-toluenesulfonamide) was stirred at 08C for 4 h.
After the usual working-up and chromatography (1:2 ethyl
acetate±hexane), fractions enriched in oxazole 24 (43 mg,
38%) and in cyclopropane 25 (10 mg, 8%) were obtained
and identi®ed by their spectroscopic data. (3aR,4R,7aS)-4-
Methyl-3a-methoxycarbonyl-2-phenyl-6-hydroxymethyl-
3a,4,5,7a-tetrahydrobenzoxazole, 24. IR (®lm) 3381,
1
3H) and 7.77 (m, 2H) (Ph), 8.23 (broad s, NH); H NMR
(acetone-d6) 1.36 (s, CH3), 1.51 (s, CH3), 2.45±2.58
(complex absorption, H4a,H4b), 2.86 (d, J6a,6bˆ5.1 Hz,
H6a), 2.94 (d, J6b,6aˆ5.1 Hz, H6b), 3.40 (m, H5), 3.70±3.85
0
0
0
(complex absorption, OCH31H5 a), 4.15 (dd, J5 b,5 a
ˆ
0
0
0
0
8.2 Hz, J
ˆ5.9 Hz, H5 b), 4.70 (m, H4 ), 5.44 (d, J3,2ˆ
5 b,4
10.2 Hz, H3), 6.75 (d, J2,3ˆ10.2 Hz, H2), 7.50 (m, 3H) and
7.84 (m, 2H) (Ph), 8.35 (broad s, NH); 13C NMR (acetone-
d6) 24.5, 25.7, 26.3, 41.2, 53.8, 54.1, 61.2, 65.6, 67.7, 74.5,
109.9, 127.3, 127.6, 128.9, 131.9, 134.9, 166.8, 172.3, MS,
m/e (%) 387 (M, 6), 372 (M-15, 6), 329 (43), 122 (35), 105
(100), 77 (31).
1
1732, 1644 cm21; H NMR (CDCl3) 1.17 (d, Jˆ7.3 Hz,
CH3); 1.61 (m, 2£H5); 2.51 (m, H4); 3.76 (s, OCH3); 4.02
(broad s, CH2OH); 5.28 (m, H7a); 5.79 (broad s, H7); 7.65
(m, Ph); 13C NMR (CDCl3) ; GC-MS, m/e (%) 301 (M, 1),
242 (83), 139 (98), 105 (100), 104 (27), 93 (44), 77 (77).
(1Rp,2R,3R,6Sp)-2-Benzoylamino-3-methyl-6-methoxy-
carbonylbicyclo[4.1.0]heptan-5-one, 25. 1H NMR (CDCl3)
0.95 (d, Jˆ7.2 Hz, CH3); 1.26 (complex absorption, 2£H7),
2.44 (m, H1, H3, H4eq,H4ax, H6); 7.55 (m, Ph); 13C NMR
(CDCl3) 16.1, 30.7, 32.4, 41.6; 44.4, 45.1, 53.44, 70.7,
129.1, 129.3, 129.8, 132., 162.2, 175.5, 206.1; GC-MS,
m/e (%) 301 (M, 1), 212 (74), 105 8100), 77 (42).
When epoxide 2 was eluted through a silica gel column (3:1
ether±hexane), alcohol 3 was obtained and fully character-
ized. Crystals, mp 41±438C (from ethyl acetate±pentane);
[a]Dˆ296.5 (c 1.14, CHCl3); IR (KBr) 3451±3381 (broad),
1729, 1644 cm21; 1H NMR (CDCl3) 1.24 (s, CH3), 1.34 (s,
CH3), 2.06 (dd, J5a,5bˆ16.8 Hz, J5a,4ˆ4.4 Hz, H5a), 2.30 (dd,
J5b,5aˆ16.8 Hz, H5b), 2.66 (m, H4), 3.71±3.78 (complex
0
0
0
0
0
absorption, OCH31H5 a), 3.97 (dd, J5 b,5 aˆ8.0 Hz, J5 b,4
ˆ
0
0
5.8 Hz, H5 b), 4.07±4.11 (complex absorption, H4 , H8a,H8b),
5.29 (d, J7a,7ˆ4.4 Hz, H7a), 5.95 (m, H7), 7.41 (m, 3H) and
7.93 (m, 2H) (Ph); 1H NMR (acetone-d6) 1.25 (s, CH3), 1.31
(s, CH3), 2.11±2.17 (complex absorption, H5a,5b), 2.66 (m,
4.1.14. Palladium(II)-catalyzed reaction of enone 10 with
diazomethane: (1Rp,3R,4R,6Rp)-3-Benzoylamino-4-[(40S)-
40-(20,20-dimethyl-10,30-dioxolo)]-3-methoxycarbonylbi-
cyclo[4.1.0]heptan-2-one, 26. An ethereal solution of
excess diazomethane was distilled onto a stirred mixture
of enone 8 (110 mg, 3.2 mmol) and Pd(OAc)2 (65 mg,
3.2 mmol) in ether (15 mL) for ®ve times throughout a 2.5
days period. Each time, the reaction mixture was cooled at
08C before diazomethane addition, later stirred at room
temperature. The mixture was ®ltered through celite,
solvent was removed and the residue was chromatographed
(mixtures of ethyl acetate±hexane) to afford compound 26
as a 4:1 diastereoisomeric mixture (56 mg, 50% yield). The
major isomer was an oil which could be characterized by its
spectroscopic data. 1H NMR (CDCl3) 1.19 (m, H7a), 1.25 (s,
CH3), 1.36 (s, CH3), 1.50 (m, H7b), 1.93 (m, H6), 2.26±2.07
(complex absorption, 2£H5), 2.42 (m, H1), 2.70 (m, H4),
0
0
0
0
H4), 2.86 (broad s, OH), 3.70 (dd, J5 a,5 bˆ8.1 Hz, J5 a,4
ˆ
0
0
0
5.1 Hz, H5 a), 3.77 (s, OCH3), 3.93 (dd, J5 b,5 aˆ8.1 Hz,
0
0
0
0
J5 b,4 ˆ5.8 Hz, H5 b), 4.04 (broad s, 2£H8), 4.20 (m, H4 ),
5.31 (d, J7a,7ˆ4.4 Hz, H7a), 5.93 (m, H7), 7.59 (m, 3H) and
(7.98 (m, 2H) (Ph); 13C NMR (acetone-d6) 25.4, 26.1, 26.9,
43.2, 53.0, 65.2, 69.0, 76.9, 77.7, 80.9, 107.9, 116.3, 128.5,
129.1, 129.3, 132.7, 145.9, 165.7, 174.8; MS, m/e (%) 372
(M-15, 3), 105 (100), 77 (38), 43 (33). Anal. Calcd for
C21H25NO6: C, 65.18; H, 6.51; N, 3.62. Found: C, 65.15;
H, 6.59; N, 3.56.
4.1.12. Metal-catalyzed reaction of cyclohexenone, 11,
with diazomethane: Bicyclo[4.1.0]heptan-2-one, 23.28
Method A: Pd(II) as a catalyst and ether as a solvent. Work-
ing as described above, reaction of 11 (200 mg, 2.1 mmol)
in ether (20 mL) with excess diazomethane in the presence
of palladium acetate (10 mg, 0.04 mmol) at 08C for 2 h
afforded, after chromatography (mixtures of ethyl acetate±
hexane), 185 mg (80% yield) of cyclopropane 23. Method
B: Rh(II) as a catalyst and dichloromethane as a solvent.
Rhodium diacetate (5.0 mg, 0.02 mmol) was added to a
solution of cyclohexenone, 11, (200 mg, 2.1 mmol) in
dichloromethane (20 mL). Then, an ethereal solution of
0
0
3.24 (m, H5 a), 3.78 (s, OCH3), 3.94 (m, H5 b), 4.08 (m,
H4 ), 7.70 (m, Ph), 8.24 (broad s, NH). 13C NMR (CDCl3)
0
13.3, 19.0, 20.9, 21.5, 25.6, 25.7, 26.4, 26.9, 27.1, 30.6,
39.2, 42.5, 47.6, 54.0, 54.8, 68.0, 68,1, 68.7, 74.4, 76.4,
109.4, 128.1, 128.2, 129.6, 129.7, 132.9, 133.0, 134.1,
134.3, 167.8, 201.8. MS, m/e (%) 387 (M, 1), 105 (100),
77 (26). Calcd for C21H25NO6£1/2H2O: C, 63.32; H, 6.61;
N, 3.53. Found: C, 63.09; H, 6.55; N, 3.14.

 Â
C. Rodrõguez-Garcõa et al. / Tetrahedron 57 (2001) 1025±1034
1034
Â
(e) Rife, J.; OrtunÄo, R. M.; Lajoie, G. J. Org. Chem. 1999,
Â
64, 8958. (f) Rife, J.; OrtunÄo, R. M. Org. Lett. 1999, 1, 1221.
4.1.15. Palladium(II)-catalyzed reaction of enone 10 with
diazomethane. Several experiments were carried out in
order to state the in¯uence of the temperature and the reac-
tion time. In all cases, results were similar and conversion
never was higher than ca 15%. For instance, an ice-cooled
ethereal solution of 10 (80 mg, 0.48 mmol), palladium
acetate (108 mg, 0.48 mmol) and excess diazomethane
was stirred for 4 h. After the usual working-up and subse-
quent chromatography, 65 mg (85% recovery) of 10 and
16 mg (15% total yield) of a 1:1 diastereomeric mixture
Â
8. (a) Dõaz, M.; OrtunÄo, R. Tetrahedron: Asymmetry 1995, 6,
Â
1845. (b) Dõaz, M.; OrtunÄo, R. M. Tetrahedron: Asymmetry
1996, 7, 3465.
9. (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84,
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10. OrtunÄo, R. M.; Ibarzo, J.; Alvarez-Larena, A.; Piniella, J. F.
Tetrahedron Lett. 1996, 37, 4059.
1
11. For a pioneering work, see: Mende, U.; RaduÈchel, B.;
Skuballa, W.; VorbruÈggen, H. Tetrahedron Lett. 1975, 629.
12. For a recent and very interesting work, see: Denmark, S. E.;
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1997, 62, 3375. See also the references cited therein.
13. Doyle, M. P. Chem. Rev. 1986, 86, 919.
of 27a/27b were obtained. Signi®cant selected H NMR
data for the mixture 27a/27b and 10 (CDCl3): 1.10±1.30
(complex absorption, 4H, cyclopropane-ring protons,
27a127b), 1.35 (s, CH3, 27a), 1.37 (s, CH3, 27b), 1.44 (s,
CH3, 10). GC-MS, (a) Compound 27a, retention time
6.68 min, m/e (%) 182 (M, 40), 150 (52), 123 (100), 122
(51), 95 (83), 94 (36), 81 (92), 79 (50), 67 (47), 55 (68), 41
(36). (b) Compound 27b, retention time 6.80 min, m/e (%)
182 (M, 68), 154 (61), 126 (42), 123 (88), 122 (51), 95 (94),
94 (47), 81 (100), 79 (56), 67 (53), 55 (78), 41 (35).
14. Doyle, M. P. In Comprehensive Organometallic Chemistry 2,
Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon:
New York, 1995; Vol. 12, pp 387.
15. (a) Chandler, M.; Bamford, M. J.; Conroy, R.; Lamont, B.;
Patel, V. K.; Steeples, I. P.; Storer, R.; Weir, N. G.; Wright, M.;
Williamson, C. J. Chem. Soc., Perkin Trans. 1 1995, 1173.
(b) Bamford, M.; Castro-Pichel, J.; Husman, W.; Patel, B.;
Storer, R.; Weir, N. G. J. Chem. Soc., Perkin Trans. 1 1995,
1181. (c) Chandler, M.; Conroy, R.; Cooper, A. W. J.;
Lamont, R. B.; Scicinski, J. J.; Smart, J. E.; Storer, R.;
Weir, N. G.; Wilson, R. D.; Wyatt, P. G. J. Chem. Soc., Perkin
Trans. 1 1995, 1189.
Acknowledgements
C. R.-G. thanks the U.A.B. for a pre-doctoral fellowship.
Financial support from the DGESIC (PB97-0214) and the
CIRIT (SGR99 00092) is gratefully acknowledged.
16. Clerici, F.; Gelmi, M. L.; Gambini, A. J. Org. Chem. 1999, 64,
5764.
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