Facile synthesis of oxatricyclic systems with various ring sizes and substituents

Article abstract of DOI:10.1016/S0040-4020(00)00569-X

A series of α-diazo carbonyl compounds having cyclopentanone, cyclohexanone and substituted cyclohexanone units with different tether lengths have been synthesized using diazomethane solution or methanesulphonyl azide. The above synthesized α-diazo carbon

Full text of DOI:10.1016/S0040-4020(00)00569-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6307±6318
Facile Synthesis of Oxatricyclic Systems with Various Ring Sizes
and Substituents
*
Sengodagounder Muthusamy, Srinivasarao Arulananda Babu, Chidambaram Gunanathan,
Eringathodi Suresh, Parthasarathi Dastidar and Raksh Vir Jasra
Silicates and Catalysis Discipline, Central Salt and Marine Chemicals Research Institute, Bhavnagar 364-002, India
Received 13 March 2000; revised 26 May 2000; accepted 15 June 2000
AbstractÐA series of a-diazo carbonyl compounds having cyclopentanone, cyclohexanone and substituted cyclohexanone units with
different tether lengths have been synthesized using diazomethane solution or methanesulphonyl azide. The above synthesized a-diazo
carbonyl compounds with rhodium(II) acetate dimer furnish cyclic ®ve- or six-ring carbonyl ylide dipoles, which undergo facile 1,3-dipolar
cycloaddition with different dipolarophiles to furnish the substituted and functionalized oxatricyclic systems having various ring sizes. Two
X-ray crystallographic analyses of compounds 8b and 15a are reported to ®rmly establish the stereochemistry of the cycloadducts. q 2000
Elsevier Science Ltd. All rights reserved.
Introduction
Medium-size cyclic ethers are becoming increasingly recog-
nized as common structural units in naturally occurring
compounds such as the ionophores,1 the brevetoxins2 and
other marine natural products.3 Due to increasing interest in
these bio-active molecules and well recognized problems in
building medium-sized rings, the synthesis of such systems
is a challenging synthetic objective. Moreover, bridging
ethers confer structural rigidity to the carbon skeleton
which allows highly stereoselective transformations within
the six- and seven-membered carbocycles. Medium-size
cyclic ethers are generally assembled from an intramolec-
ular Diels±Alder reaction4 of a furan diene and dipolar
cycloaddition of pyrylium ylides.5 The 1,3-dipolar cyclo-
addition of carbonyl ylides with p bonds represent an attrac-
tive strategy6,7 for tetrahydrofuran formation. In medium-
size cyclic ethers particularly the oxatricylic ring system
is very important and present in several natural products
such as Ambrosic acid8 1, Smitopsin9 2 and Linearol10
3
Results and Discussion
etc. In our quest for the synthesis of sesquiterpenoids
containing bridging ethers, starting from cycloalkanone
carboxylic acids 4, we herein wish to report our detailed
preliminary studies on the synthesis of substituted and func-
tionalized oxatricyclic systems via ®ve or six-ring carbonyl
ylides involving carbocyclic carbonyl groups having
different ring sizes and substitutents with various dipolaro-
philes.
It was envisaged that the reaction of diazo ketones such as
6a±d and 6e±g/14a±d with rhodium(II) acetate dimer, can
in principle generate ®ve- and six-ring carbonyl ylides,
respectively. For investigating the intramolecular formation
and intermolecular cycloaddition of these carbonyl ylides 7
and 16, the requisite starting materials 6 and 14 were
assembled from commercially available materials.
Mild hydrolysis of 2-carbethoxy-2-methyl cyclopentanone
was carried out using 5% aqueous potassium hydroxide
solution at room temperature to afford 1-methyl-2-oxo-
cyclopentanecarboxylic acid 4a. Care was taken in the
Keywords: diazo compounds; carbonyl ylides; cycloaddition; rhodium ace-
tate catalyst.
* Corresponding author. Fax: 191-278-566970; e-mail: salt@csir.res.in
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00569-X

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S. Muthusamy et al. / Tetrahedron 56 (2000) 6307±6318
Scheme 1. Reagents for substrates a,b,e,f: (i) (a) (COCI)2, Ether; (b) i-PrMgBr, EtOOCCH2COOH, DCM/THF (1:5); (iii) MsN3, NEt3, DCM; (v) Rh2(OAc)4,
DMAD, C6H6; Reagents for substrates c,d,g: (ii) (COCl)2, Ether or ClCOOEt, NEt3, Ether; (iv) CH2N2, Ether; (vi) Rh2(OAc)4, DMAD, DCM.
preparation and further reactions of b-keto acids 4a,b due to
their instability under thermal conditions and possible ring
opening reactions. Treatment of 4a with oxalyl chloride
furnished the corresponding acid chloride, which on reac-
tion with excess Mg-complex of dianion of monoethyl
malonate in a mixture of DCM/THF (1:5) afforded the
active methylene compound 5a in moderate yield as
described in the literature.11 The diazo transfer reaction12
of 5a was carried out using mesyl azide-triethylamine to
give diazo compound 6a. The same sequence of reactions
on 2-carbethoxy-2-methyl cyclohexanone, ethyl 2-cyclo-
pentanoneacetate and ethyl 2-cyclohexanoneacetate
furnished a-diazo ketones 6b,e,f (Scheme 1), respectively
in very good yields. Treatment of 1-methyl-2-oxocyclo-
pentanecarboxylic acid (4a), 1-methyl-2-oxocyclohexane-
carboxylic acid (4b) and 2-oxocyclohexaneacetic acid (4f)
with ethyl chloroformate and triethylamine resulted in a
white suspension at room temperature and the resulting
mixed anhydride was then treated with freshly prepared
ethereal diazomethane at 0±108C to furnish a-diazo ketones
6c,d,g, respectively. In order to obtain a better yield of these
diazo compounds, the above acids 4a,b,f were treated with
Scheme 2.

S. Muthusamy et al. / Tetrahedron 56 (2000) 6307±6318
6309
oxalyl chloride at room temperature to afford the corre-
sponding acid chlorides. These crude acid chlorides were
treated with freshly prepared ethereal diazomethane
containing triethylamine at 08C and furnished the respective
a-diazo ketones 6c,d,g. Comparatively we obtained better
overall yields of diazo ketones from acids by the acid
chloride method than the mixed anhydride method. All
these diazo compounds were stable for chromatographic
puri®cation and spectroscopic characterization purposes.
After studying various ring systems, we were interested in
further illustrating the scope and synthetic utility of the
tandem cyclization±cycloaddition sequence. Thus, we
synthesized a-diazo ketones 14 in order to obtain oxatri-
cyclic systems with various subtituents. C-Alkylation of
ethyl 2-cyclohexanoneacetate with methyl iodide, ethyl
iodide was carried out by the Stork-enamine method as
described17 in the literature to afford ethyl 3-methyl-2-
cyclohexanoneacetate (11a) and ethyl 3-ethyl-2-cyclohexa-
noneacetate (11b), respectively. The above reaction was
carried out with 2-methylcyclohexanone and ethyl 2-bromo-
propionate to afford ethyl 2-(3-methyl-2-oxocyclohexyl)
propionate (11c). Hydrolysis of the above substrates
11a±c using 5% aqueous potassium hydroxide solution
afforded 3-methyl-2-cyclohexanoneacetic acid (12a),
3-ethyl-2-cyclohexanoneacetic acid (12b) and 2-(3-methyl-
2-oxocyclohexyl)propionic acid (12c), respectively. Further
reactions of acids 12a±c were carried out as described
above for substrate 6a to obtain a-diazo ketones 14a±c,
respectively (Scheme 2). Reaction of the acid chloride of
12a and diazoethane solution afforded diazo ketone 14d. In
these cases, the exclusive products were the exo-isomers of
the oxatricyclic compounds 15a±f in the presence of N-
phenylmaleimide as a dipolarophile. The assignment of
stereochemistry was made upon inspection of the 1H
NMR spectra; the bridgehead proton (R4ˆH) of compound
15e showed a singlet without any coupling. No products
resulting from potential competitive C±H insertion14 could
be detected.
We next investigated the Rh(II) catalyzed behavior of the
above synthesized a-diazo ketones 6. The reaction of 6a and
dimethyl acetylenedicarboxylate (DMAD) with 1 mol%
Rh2(OAc)4 catalyst in dry benzene was re¯uxed under an
argon atmosphere for 13 h followed by chromatographic
puri®cation, product 8a was obtained in 83% yield.
Typically the quantity of the catalyst was maintained at
1 mol% for performing all our experiments. The Rh(II) cata-
lyzed behavior of diazo compounds 6b±d and 6e±g was
also studied to form ®ve- and six-ring carbonyl ylides,
respectively, which further undergo 1,3-dipolar cyclo-
addition in the presence of DMAD to furnish the oxatri-
cyclic systems 8b±g in very good yield. The presence of a
singlet resonance around d 4.8 for the bridgehead proton in
the 1H NMR spectra, the presence of a signal around d 85 in
the 13C NMR spectra for the tertiary bridgehead carbon
atom of compounds 8c,d,g and the presence of oxygen
attached quaternary carbons around d 90 in all the products
in the 13C NMR spectra clearly established the oxatricyclic
system. The above tertiary bridgehead carbon signals are
deshielded in the range of d 7±8 when carbethoxy group
is present in compounds 8a,b,e,f.
All the active methylene compounds 5a,b,e,f and 13a±c
prepared in this work exist in 5±10% enolic form based
on the presence of characteristic peaks around d 5.0 (ole®-
nic proton) and d 12.0 (enol proton) in 1H NMR and around
d 90 for ole®nic carbon (CvCH) in 13C NMR. Typically,
the presence of strong absorption around 2100 cm21 in
infrared spectra, the singlet resonance around d 5.3 in
compounds 6c,d,g and 14e in 1H NMR spectra and a
quaternary carbon atom around d 75 in compounds
6a,b,e,f and 14a±c in 13C NMR spectra established the
presence of the diazo functionality. Due to very long relaxa-
tion times, the resonance for the above quaternary carbon
atom adjacent to the diazo functional group was usually less
intense for diazo compounds 6a,b,e,f and 14a±c.
Padwa13 observed a similar oxatricyclic ring system from
the decomposition of a diazo carbonyl compound, in which
the competition of ylide formation and C±H insertion takes
place in the presence of a dipolarophile. Under carefully
maintained experimental conditions, we could successfully
obtain only the oxatricyclic compound in very good yields
without forming any C±H insertion13,14 product 9 (expected
from compound 6b). Moreover, we have also not isolated
any 2:1 cycloadducts like 10 as described in the literature13
for rhodium catalyzed cycloaddition reactions with excess
amount of diazo ketone. We also failed to obtain 2:1
cycloadduct 10a,b by reacting the diazo compounds 6b as
well as 6d with isolated product 8b in the presence of
rhodium(II) acetate as a catalyst. It may be noted that the
rhodium(II) catalyzed reactions of diazo compounds with-
out carbonyl functionality in the cyclopentyl15 and cyclo-
hexyl16 ring furnished only a mixture of corresponding
cycloalkylacetic acids via Wolff rearrangement and
unexpected cycloalkylcarboxylic acids without forming
any C±H insertion product.
Figure 1. Ortep view of the compound 8b.

6310
S. Muthusamy et al. / Tetrahedron 56 (2000) 6307±6318
subjected to propargyl bromide in the presence of rhodium-
(II) catalyst affording the regioselective products 18a and
18b in moderate yield. The assigned regio- and stereo-
chemistry of the products follow from the above studies
and 1H NMR spectra, which showed a singlet for the bridge-
head proton (H-8) in products 17a, 17b and 18a. The
cycloaddition does proceed, however, with high regioselec-
tivity producing a single regioisomer in both cases.
The above results show that the mechanism by which 6a±d/
14e±f were converted into 8a±d/15e±f, respectively
involves rapid cyclization of the rhodium carbenoid onto
the neighboring ring carbonyl group to give ®ve-ring car-
bonyl ylides 7a±d and 16e±f. The length of the tether that
links the carbonyl and diazo ketone functionalities in
compounds 6e±g and 14a±d involves six-ring carbonyl
ylides as intermediates 7e±g/16a±d followed by a subse-
quent [312]-cycloaddition with dipolarophiles takes place.
Similar ef®ciency of this cyclization±cycloaddition strategy
was observed with both ®ve- or six-ring carbonyl ylides and
provides the basic sesquiterpenoids skeleton having a cyclic
ether bridge.
Figure 2. Ortep view of the compound 15a.
The diazo substrates 6a,b,e,f/14a±c and 14d were obtained
by diazo transfer reactions and diazoethane reactions. The
rhodium induced carbonyl ylide formation process is highly
dependent on the electronic nature18 of the substituent
attached to the diazo carbon atom. Irrespective of ®ve- or
six-ring carbonyl ylide formation, the yield of cycloadducts
8a,b,e,f and 15a±c,f increased when the electrophilicity of
the intermediate rhodium carbenoid was increased (when
R2ˆCOOEt in compounds 6 and R4ˆCOOEt in compounds
14). The methyl substituent in the diazo compounds 6a±d,
14e,f was required because the apparently highly stabilized
dipole 7a±d, 16e,f transfers a proton at a faster rate than
bimolecular cycloaddition. This phenomenon19 is not
observed in diazo substrates 6e±g and 14a±d.
In conclusion, we have demonstrated the high ef®ciency of
rhodium carbenoid induced cyclization of diazo ketones.
Coupled with the simplicity of the procedure, the method
promises to provide an effective route to a variety of the
substituted and functionalized oxatricyclic systems in a
single step operation. Further, the oxa-bridge serves as a
latent hydroxyl substitutent of de®ned stereochemistry
upon reductive cleavage to a targeted family of hydroxy-
lated bicyclic carbocyclic systems. As a consequence of its
practical simplicity and high ef®ciency, this method is
expected to have wide synthetic utility for the synthesis of
oxapolycyclic and carbocyclic systems. Currently, we are
investigating the application of this methodology in the
synthesis of natural products.
The stereochemical assignments of compounds 8b (Fig. 1)
and 15a (Fig. 2) were unambiguously established by X-ray
crystallography. The presence of the methyl group at the
ring juncture in the compound 8b, endo with respect to
the oxido bridge is tentatively assigned for other products
based on their similarity in spectral data. The angle of oxa-
bridge (C±O±C) was observed as 97.2 and 106.78 in six-
and seven-membered carbocyclic systems 8b and 15a,
respectively. The dihedral angle between H10 and C18
showed 88.58 in compound 15a and this prediction agrees
well with the absence of coupling between the H9 proton
and the bridgehead proton (H8) in compound 15e. More-
over, the crystal structure con®rms the complete diastereo-
selectivity and is the result of exo-cycloadduct 15a.
Experimental
Melting points are uncorrected. IR spectra were recorded on
a Perkin±Elmer Spectrum GX FT-IR spectrophotometer. 1H
NMR and 13C NMR spectra were recorded on a Bruker DPX
200 (200 and 50 MHz, respectively) spectrometer and refer-
enced to TMS. Carbon types were determined from DEPT
13C NMR experiments. Mass analyses were performed on a
Finnigan MAT 8230 mass spectrometer with an ionizing
voltage of 70 eV. Elemental analyses were performed on a
Perkin Elmer Model 2400 analyser. X-Ray crystallographic
analyses were carried out in a Enraf Nonius CAD-4 diffract-
ometer with Mo Ka radiation. All solvents were puri®ed by
distillation. Thin layer chromatography was performed on
silica or alumina plates and components were visualized by
observation under iodine or by sulphuric acid charring.
To widen the synthetic utility, the carbenoid cyclization±
cycloaddition sequence was extended to unsymmetrical
dipolarophiles, so as to probe the regiochemical aspects of
the reaction. To this end, diazo ketones 6b and 6d were
allowed to react with methyl methacrylate. Cycloaddition
products 17a,b and 17c,d were formed regioselectively as
diastereomeric mixtures (ratio of 1:5 and 1:2) in good
yields, respectively. The distereomeric mixtures were
separated by column chromatography for full spectral
characterization. The diazo ketones 6b and 6d were also

S. Muthusamy et al. / Tetrahedron 56 (2000) 6307±6318
6311
Column chromatography was performed on Silica Gel 100±
200 mesh and neutral alumina. All air sensitive reactions
were conducted in ¯ame-dried glassware under a positive
pressure of Argon with magnetic stirring. Reagents were
added via syringes through septa. Care has been taken to
avoid light during the course of reaction in the synthesis of
diazo compounds and its further conversion.
(20 ml). After cessation of carbon dioxide evolution the
clear solution was extracted with ethyl acetate, washed
with saturated sodium bicarbonate and brine solution. The
organic phase was dried over anhydrous MgSO4 and
concentrated under reduced pressure. The residue was
subjected to column chromatography on silica gel to afford
the corresponding active methylene compound.
To a solution containing 1 equiv. of the appropriate active
methylene compound and 1.2 equiv. of freshly distilled
methanesulphonyl azide in 5 ml of dry acetonitrile or
methylenechloride was added 2 equiv. of freshly distilled
triethylamine under an argon atmosphere at room tempera-
ture. The reaction was monitored by TLC till the dis-
appearance of the starting material. The solvent was
removed under reduced pressure at room temperature and
the residue subjected to short neutral alumina column
chromatography to get pure diazo ketone with 15% ethyl
acetate±hexane elution.
General procedure for the synthesis of diazo ketones 6
and 14
Acid chloride method: Cycloalkanone ester (12 mmol) was
carefully hydrolyzed using 5% aqueous potassium hydrox-
ide solution (20 ml) with stirring at room temperature. The
reaction was monitored by TLC and continued till the dis-
appearance of starting material. The reaction mixture was
extracted with ether, the aqueous layer acidi®ed and
extracted with ethyl acetate. The organic phase was concen-
trated under reduced pressure at room temperature to obtain
the corresponding keto acids 4. Freshly distilled oxalyl
chloride (20 mmol) was added dropwise to a stirring solu-
tion of 10 mmol of appropriate acid in 15 ml of dry ether at
258C, and the stirring was continued for 2 h under an argon
atmosphere. The solution was evaporated under reduced
pressure, the crude residual acid chloride was dissolved in
100 ml freshly prepared dry ether and used for next step
without further puri®cation. The crude acid chloride solu-
tion was added dropwise over a 0.5 h period to stirring
solution of 13 mmol of freshly prepared diazomethane and
10 mmol of freshly distilled triethylamine in 50 ml of dry
ether at 08C, and the stirring was continued for 2 h under an
argon atmosphere. The mixture was ®ltered and the ®ltrate
evaporated. Chromatography of the residue through a silica
gel column (prewashed by ethyl acetate) led to the
corresponding diazo ketone with 10% ethyl acetate±hexane
elution.
Preparation of 2-diazo-3-(1-methyl-2-oxocyclopentyl)-3-
oxopropanoic acid ethyl ester (6a). Hydrolysis of 2.5 g of
2-carbethoxy-2-methyl cyclopentanone was carried out for
5 h to afford the acid 4a (1.9 g) in 90% yield. Treatment of
1.5 g (10.6 mmol) of acid 4a with oxalyl chloride (2.2 ml,
21.2 mmol) furnished the crude acid chloride. Further
reaction of crude acid chloride with DCM/THF (1:5) solu-
tion of dianion of monoethyl malonate, prepared from
monoethyl malonate (3.5 g, 26.5 mmol) and isopropyl-
magnesium bromide (8.0 g, 53.0 mmol) gave active
methylene compound 5a (1.2 g) in 55% yield as a colorless
liquid; nmax (neat) 2978, 1741, 1708, 1648, 1459, 1408,
1320, 1263, 1157, 1029 cm21; dH (200 MHz, CDCl3) 4.16
(2H, q, Jˆ7.2 Hz, OCH2), 3.74 (1H, d, Jˆ16.0 Hz), 3.56
(1H, d, Jˆ16.0 Hz), 2.76±2.66 (1H, m), 2.39±2.30 (2H,
m), 2.00±1.85 (2H, m), 1.78±1.68 (1H, m), 1.34 (3H, s,
CCH3), 1.26 (3H, t, Jˆ7.2 Hz, CH2CH3); dC (50 MHz,
CDCl3) 217.0 (CvO), 201.0 (CvO), 168.0 (COO), 64.3
(CCH3), 61.9 (OCH2), 45.2 (CH2), 38.7 (CH2), 34.1
(CH2), 21.3 (CH3), 19.9 (CH2), 14.7 (CH2CH3).
Mixed anhydride method: To a solution containing 1 equiv.
of appropriate (10 mmol) keto acid in 100 ml of freshly
prepared dry ether was added 1.2 equiv. of freshly distilled
ethyl chloroformate followed by the slow addition of
1.5 equiv. of dry triethylamine. The resulting mixture was
stirred at room temperature for 45 min and the solid that
formed was ®ltered under inert atmosphere. The ®ltrate
was added to 20 mmol of freshly prepared ethereal diazo-
methane solution and then the mixture stirred for 12 h at
08C, after this duration allowed to warm till 108C for a
period of 2 h under an argon atmosphere. Then at the end
of this time the solvent was removed under reduced pressure
and the residue was puri®ed as described above.
The reaction of the compound 5a (330 mg, 1.6 mmol),
mesyl azide (230 mg, 1.7 mmol) and triethylamine
(0.44 ml, 3.2 mmol) afforded 6a (333 mg) in 90% yield as
a thick yellow oil; [Found: C, 55.61; H, 6.01; N, 11.70.
C11H14N2O4 requires C, 55.46; H, 5.92; N, 11.76%]; nmax
(neat) 2982, 2142, 1738, 1715, 1643, 1372, 1323,
1170 cm21; dH (200 MHz, CDCl3) 4.23 (2H, q, Jˆ7.2 Hz,
OCH2), 2.87±1.69 (6H, m), 1.30 (3H, s, CCH3), 1.29 (3H, t,
Jˆ7.2 Hz, CH2CH3); dC (50 MHz, CDCl3) 216.5 (CvO),
191.0 (CvO), 160.9 (COO), 76.0 (CvN2), 62.0 (OCH2),
61.7 (CCH3), 36.1 (CH2), 34.9 (CH2), 19.8 (CH3), 19.75
(CH2), 14.8 (CH3).
Diazo transfer method: To a solution of freshly distilled
monoethyl malonate (35 mmol) in dry dichloromethane
(8 ml) under an argon atmosphere was added dropwise a
solution of isopropylmagnesium bromide (70 mmol) in
tetrahydrofuran (50 ml) until propane has been evolved.
The temperature rises to 40±508C. The green-colored solu-
tion was then cooled in an ice/salt bath and crude appro-
priate acid chloride obtained from the corresponding acid
(14 mmol) in dichloromethane (2 ml) was added dropwise
with ef®cient stirring. The stirring was continued for an hour
after removing from the cooling bath and the resultant
mixture was poured into cold 10% hydrochloric acid
Preparation of 2-diazo-3-(1-methyl-2-oxocyclohexyl)-3-
oxopropanoic acid ethyl ester (6b). Hydrolysis of 2.0 g
of 2-carbethoxy-2-methyl cyclohexanone was carried out
for 6 h to afford the acid 4b (1.5 g) in 88% yield. Treatment
of 1.4 g (9.0 mmol) of acid 4b with oxalyl chloride (1.9 ml,
18.0 mmol) furnished the crude acid chloride. Further
reaction of crude acid chloride with DCM/THF (1:5)
solution of dianion of monoethyl malonate, prepared
from monoethyl malonate (3.0 g, 22.4 mmol) and

6312
S. Muthusamy et al. / Tetrahedron 56 (2000) 6307±6318
isopropylmagnesium bromide (7.0 g, 44.8 mmol) gave
active methylene compound 5b (1.3 g) in 63% yield as a
colorless liquid; nmax (neat) 2978, 1742, 1710, 1648, 1458,
1407, 1372, 1329, 1263, 1028 cm21; dH (200 MHz, CDCl3)
4.21 (2H, q, Jˆ7.2 Hz, OCH2), 3.52 (1H, d, Jˆ16.0 Hz),
3.42 (1H, d, Jˆ16.0 Hz), 2.58±2.38 (3H, m), 2.04±1.39
(5H, m), 1.31 (3H, s, CCH3), 1.27 (3H, t, Jˆ7.2 Hz,
CH2CH3); dC (50 MHz, CDCl3) 209.7 (CvO), 201.8
(CvO), 166.8 (COO), 63.9 (CCH3), 61.3 (OCH2), 44.6
(CH2), 41.0 (CH2), 36.1 (CH2), 27.0 (CH2), 21.8 (CH2),
20.4 (CH3), 13.9 (CH2CH3).
(1.5 g) in 92% yield as a thick yellow oil; [Found: C,
60.15; H, 6.67; N, 15.42. C9H12N2O2 requires C, 59.99; H,
6.71; N, 15.55%]; nmax (neat) 2942, 2870, 2110, 1757, 1721,
1453, 1355, 1266, 1126, 1018 cm21; dH (200 MHz, CDCl3)
5.27 (1H, s, CHN2), 2.59±2.41 (2H, m), 2.07±1.35 (6H, m),
1.24 (3H, s, CH3); dC (50 MHz, CDCl3) 211.0 (CvO),
193.7 (CvO), 61.9 (CCH3), 53.8 (CHN2), 41.8 (CH2),
37.3 (CH2), 27.6 (CH2), 22.8 (CH2), 22.7 (CH3).
Preparation of 2-diazo-4-(2-oxocyclopentyl)-3-oxobuta-
noic acid ethyl ester (6e). Hydrolysis of 4.0 g of ethyl
2-cyclopentanoneacetate was carried out for 8 h to afford
the acid 4e (3.2 g) in 96% yield. Treatment of 2.8 g
(19.7 mmol) of acid 4e with oxalyl chloride (4.0 ml,
39.4 mmol) furnished the crude acid chloride. Further
reaction of crude acid chloride with DCM/THF (1:5) solu-
tion of dianion of monoethyl malonate, prepared from
monoethyl malonate (6.5 g, 49.3 mmol) and isopropyl-
magnesium bromide (14.5 g, 98.6 mmol) gave active
methylene compound 5e (2.4 g) in 57% yield as a colorless
liquid; nmax (neat) 2977, 1738, 1715, 1643, 1447, 1371,
1322, 1190, 1133, 1054 cm21; dH (200 MHz, CDCl3) 4.19
(2H, q, Jˆ7.2 Hz, OCH2), 3.62 (1H, d, Jˆ16.1 Hz), 3.52
(1H, d, Jˆ16.1 Hz), 2.76±2.66 (1H, m), 2.48±2.03 (6H,
m), 1.84±1.58 (2H, m), 1.26 (3H, t, Jˆ7.2 Hz, CH3); dC
(50 MHz, CDCl3) 219.5 (CvO), 202.1 (CvO), 167.1
(COO), 61.2 (CH2), 50.1 (CH2), 46.2 (CH), 37.8 (CH2),
34.4 (CH2), 29.7 (CH2), 20.9 (CH2), 14.6 (CH3).
The reaction of the compound 5b (385 mg, 1.7 mmol),
mesyl azide (250 mg, 2.0 mmol) and triethylamine
(0.48 ml, 3.4 mmol) afforded 6b (355 mg) in 83% yield as
a thick yellow oil; [Found: C, 57.35; H, 6.13; N, 10.87.
C12H16N2O4 requires C, 57.13; H, 6.39; N, 11.10%]; nmax
(neat) 2947, 2876, 2147, 1712, 1646, 1453, 1375, 1320,
1156, 1031 cm21; dH (200 MHz, CDCl3) 4.21 (2H, q,
Jˆ7.2 Hz, OCH2), 2.45±2.19 (4H, m), 1.85±1.77 (3H, m),
1.62±1.56 (1H, m), 1.35 (3H, s, CCH3), 1.28 (3H, t,
Jˆ7.2 Hz, CH2CH3); dC (50 MHz, CDCl3) 209.0 (CvO),
192.7 (CvO), 161.2 (COO), 75.3 (CvN2), 61.3 (OCH2),
60.5 (CCH3), 37.7 (CH2), 34.3 (CH2), 24.0 (CH2), 20.5
(CH3), 20.1 (CH2), 13.5 (CH3).
Preparation of 1-diazo-2-(1-methyl-2-oxocyclopentyl)-
A
ethan-2-one (6c).
solution containing 600 mg
(4.2 mmol) of acid 4a in dry ether was treated with
0.48 ml (5.0 mmol) of ethyl chloroformate, 0.9 ml
(6.4 mmol) of triethylamine to afford the mixed anhydride
5c and followed by treatment with 8.5 mmol of diazo-
methane solution gave the diazo ketone 6c (440 mg) in
65% yield.
The reaction of the compound 5e (420 mg, 2.0 mmol),
mesyl azide (290 mg, 2.4 mmol) and triethylamine
(0.56 ml, 4.0 mmol) afforded 6e (395 mg) in 84% yield
as a thick yellow oil; [Found: C, 55.40; H, 5.89; N,
11.75%. C11H14N2O4 requires C, 55.46; H, 5.92; N,
11.76%]; nmax (neat) 2981, 2148, 1740, 1707, 1644, 1374,
1320, 1267, 1156, 1029 cm21; dH (200 MHz, CDCl3)
4.20 (2H, q, Jˆ7.1 Hz, OCH2), 2.72±2.61 (1H, m),
2.52±2.08 (6H, m), 1.89±1.50 (2H, m), 1.27 (3H, t,
Jˆ7.1 Hz, CH3); dC (50 MHz, CDCl3) 217.0 (CvO),
192.0 (CvO), 161.9 (COO), 75.9 (CvN2), 62.0 (OCH2),
46.1 (CH), 37.1 (CH2), 34.3 (CH2), 29.8 (CH2), 21.0 (CH2),
14.7 (CH3).
A solution containing 500 mg (3.5 mmol) of acid 4a in dry
ether was treated with 0.73 ml (7.0 mmol) of oxalyl chloride
to afford the acid chloride 5c which on treatment with
4.6 mmol diazomethane solution containing 0.5 ml
(3.5 mmol) of triethylamine gave the diazo ketone 6c
(497 mg) in 85% yield as a thick yellow bright oil;
[Found: C, 57.69; H, 6.05; N, 16.78. C8H10N2O2 requires
C, 57.82; H, 6.07; N, 16.85%]; nmax (neat) 2962, 2875,
2109, 1733, 1631, 1458, 1351, 1277, 1199, 1043 cm21; dH
(200 MHz, CDCl3) 5.65 (1H, s, CHN2), 2.52±2.31 (3H, m),
2.03±1.86 (3H, m), 1.30 (3H, s, CH3); dC (50 MHz, CDCl3)
216.1 (CvO), 194.0 (CvO), 56.2 (CCH3), 54.0 (CHN2),
38.0 (CH2), 36.3 (CH2), 19.8 (CH2), 19.7 (CH3).
Preparation of 2-diazo-4-(2-oxocyclopentyl)-3-oxobuta-
noic acid ethyl ester (6f). Hydrolysis of 4.0 g of ethyl
2-cyclohexanoneacetate was carried out for 7.5 h to afford
the acid 4f (3.2 g) in 94% yield. Treatment of 2.7 g
(17.3 mmol) of acid 4f with oxalyl chloride (3.5 ml,
34.6 mmol) furnished the crude acid chloride. Further reac-
tion of crude acid chloride with DCM/THF (1:5) solution of
dianion of monoethyl malonate, prepared from monoethyl
malonate (5.7 g, 43.3 mmol) and isopropylmagnesium
bromide (13.4 g, 86.5 mmol) gave active methylene
compound 5f (2.4 g) in 61% yield as a colorless liquid;
nmax (neat) 2976, 1739, 1712, 1456, 1409, 1373, 1317,
1209, 1148, 1020 cm21; dH (200 MHz, CDCl3) 4.19 (2H,
q, Jˆ7.2 Hz, OCH2), 3.58 (1H, d, Jˆ15.4 Hz), 3.48 (1H, d,
Jˆ15.4 Hz), 3.08±2.91 (2H, m), 2.45±2.16 (3H, m), 2.14±
2.07 (2H, m), 1.87±1.76 (1H, m), 1.75±1.32 (3H, m), 1.28
(3H, t, Jˆ7.2 Hz, CH3); dC (50 MHz, CDCl3) 211.8 (CvO),
202.8 (CvO), 167.9 (COO), 61.9 (OCH2), 50.5 (CH2), 47.4
(CH), 43.2 (CH2), 42.4 (CH2), 34.5 (CH2), 28.4 (CH2), 25.9
(CH2), 14.8 (CH3).
Preparation of 1-diazo-2-(1-methyl-2-oxocyclohexyl)-
ethan-2-one (6d).
A
solution containing 320 mg
(2.1 mmol) of acid 4b in dry ether was treated with
0.23 ml (2.5 mmol) of ethyl chloroformate, 0.43 ml
(3.2 mmol) of triethylamine to afford the mixed anhydride
5d and followed by treatment with 4.0 mmol of diazo-
methane solution gave the diazo ketone 6d (250 mg) in
68% yield.
A solution containing 1.4 g (8.9 mmol) of acid 4b in dry
ether was treated with 1.9 ml (17.9 mmol) of oxalyl chloride
to afford the acid chloride 5d which on treatment with
11.7 mmol diazomethane solution containing 1.3 ml
(8.9 mmol) of triethylamine gave the diazo ketone 6d

S. Muthusamy et al. / Tetrahedron 56 (2000) 6307±6318
6313
The reaction of the compound 5f (300 mg, 1.3 mmol),
mesyl azide (195 mg, 1.6 mmol) and triethylamine
(0.37 ml, 2.6 mmol) afforded 6f (298 mg) in 89% yield as
a thick yellow oil; [Found: C, 57.55; H, 6.33; N, 10.82.
C12H16N2O4 requires C, 57.13; H, 6.39; N, 11.10%]; nmax
(neat) 2949, 2148, 1714, 1646, 1375, 1320, 1125,
1031 cm21; dH (200 MHz, CDCl3) 4.20 (2H, q, Jˆ7.2 Hz,
OCH2), 3.04±2.93 (2H, m), 2.41±2.27 (3H, m), 2.16±2.08
(2H, m), 1.72±1.32 (4H, m), 1.28 (3H, t, Jˆ7.2 Hz, CH3);
dC (50 MHz, CD3CN) 211.8 (CvO), 202.8 (CvO), 167.9
(COO), 76.9 (CvN2), 62.0 (OCH2), 47.4 (CH), 43.2 (CH2),
42.4 (CH2), 34.6 (CH2), 28.4 (CH2), 25.8 (CH2), 14.8 (CH3).
(200 MHz, CDCl3) 4.20 (2H, q, Jˆ7.2 Hz, OCH2), 3.60
(1H, d, Jˆ15.4 Hz), 3.48 (1H, d, Jˆ15.4 Hz), 3.05±2.95
(2H, m), 2.47±2.08 (4H, m), 1.87±1.77 (2H, m), 1.42±
1.33 (2H, m), 1.28 (3H, t, Jˆ7.2 Hz, CH2CH3), 0.99 (3H,
d, Jˆ6.4 Hz); dC (50 MHz, CDCl3) 213.0 (CvO), 202.3
(CvO), 167.8 (COO), 61.8 (OCH2), 50.4 (CH2), 47.4
(CH), 45.8 (CH), 43.2 (CH2), 37.6 (CH2), 35.3 (CH2),
25.9 (CH2), 15.0 (CH3), 14.7 (CH3).
The reaction of the compound 13a (120 mg, 0.5 mmol),
mesyl azide (73 mg, 0.6 mmol) and triethylamine
(0.14 ml, 1.0 mmol) gave 14a (130 mg) in 98% yield as a
thick yellow oil; [Found: C, 58.65; H, 6.78; N, 10.48.
C13H18N2O4 requires C, 58.62; H, 6.81; N, 10.52%]; nmax
(neat) 2931 2137, 1714, 1654, 1368, 1304, 1169, 1137,
1031 cm21; dH (200 MHz, CDCl3) 4.17 (2H, q, Jˆ7.2 Hz,
OCH2), 3.04±2.94 (2H, m), 2.32±2.08 (4H, m), 1.87±1.77
(2H, m), 1.37±1.33 (2H, m), 1.28 (3H, t, Jˆ7.2 Hz,
CH2CH3), 0.99 (3H, d, Jˆ6.4 Hz); dC (50 MHz, CDCl3)
213.0 (CvO), 202.3 (CvO), 167.8 (COO), 76.0 (CvN2),
61.8 (OCH2), 47.3 (CH), 45.8 (CH), 43.2 (CH2), 37.6 (CH2),
35.3 (CH2), 25.9 (CH2), 15.0 (CH3), 14.7 (CH3).
Preparation of 1-diazo-3-(2-oxocyclohexyl)propan-2-one
(6g). A solution containing 1.0 g (6.4 mmol) of acid 4f in
dry ether was treated with 0.73 ml (7.7 mmol) of ethyl
chloroformate, 1.4 ml (9.6 mmol) of triethylamine to afford
the mixed anhydride 5g and followed by treatment with
12.8 mmol of diazomethane solution gave the diazo ketone
6g (810 mg) in 70% yield. A solution containing 1.0 g
(6.4 mmol) of acid 4f in dry ether was treated with 1.3 ml
(12.8 mmol) of oxalyl chloride to afford the acid chloride 5g
which on treatment with 8.3 mmol diazomethane solution
containing 0.9 ml (6.4 mmol) of triethylamine gave the
diazo ketone 6g (1.1 g) in 95% yield as a thick yellow bright
oil; [Found: C, 60.22; H, 6.66; N, 15.37. C9H12N2O2
requires C, 59.99; H, 6.71; N, 15.55%]; nmax (neat) 2938,
2864, 2108, 1713, 1450, 1371, 1277, 1132, 1030 cm21; dH
(200 MHz, CDCl3) 5.34 (1H, s, CHN2), 2.92±2.70 (2H, m),
2.43±2.35 (2H, m), 2.20±1.86 (3H, m), 1.79±1.38 (4H, m);
dC (50 MHz, CDCl3) 212.0 (CvO), 193.7 (CvO), 53.9
(CHN2), 47.5 (CH), 42.2 (CH2), 34.8 (CH2), 34.3 (CH2),
28.2 (CH2), 25.6 (CH2).
Preparation of 2-diazo-4-(3-ethyl-2-oxocyclohexyl)-3-
oxobutanoic acid ethyl ester (14b). Pyrrolidine enamine
of ethyl 2-cyclohexanoneacetate (4.0 g, 21.7 mmol) was
prepared as described above. To the crude enamine reaction
mixture in dry benzene (50 ml), ethyl iodide (2.6 ml,
32.5 mmol) was added at room temperature with stirring
and re¯uxed for 8 h. The reaction mixture was worked-up
as above to obtain ethyl 3-ethyl-2-cyclohexanoneacetate
11b (1.88 g) in 41% yield.
Hydrolysis of the ester 11b (1.0 g, 4.7 mmol) with 5%
aqueous potassium hydroxide solution for 5 h afforded the
acid 12b (798 mg) in 94% yield. Treatment of 525 mg
(2.9 mmol) of acid 12b with oxalyl chloride (0.6 ml,
5.8 mmol) furnished the crude acid chloride. Further
reaction with monoethyl malonate (950 mg, 7.2 mmol)
and isopropylmagnesium bromide (2.12 g, 14.4 mmol) as
described above gave active methylene compound 13b
(183 mg) in 58% yield as a colorless liquid; nmax (neat)
2978, 2975, 1737, 1712, 1458, 1433, 1376, 1346, 1262,
1200, 1149, 1108, 1028 cm21; dH (200 MHz, CDCl3) 4.19
(2H, q, Jˆ7.2 Hz, OCH2), 3.56 (1H, d, Jˆ16.0 Hz), 3.44
(1H, d, Jˆ16.0 Hz), 3.07±2.94 (2H, m), 2.39±1.98 (4H,
m), 1.85±1.77 (2H, m), 1.38±1.34 (2H, m), 1.27 (3H, t,
Jˆ7.2 Hz, CH2CH3), 1.03±0.96 (2H, m), 0.90 (3H, t,
Jˆ7.5 Hz, CH2CH3); dc (50 MHz, CDCl3) 212.9
(CvO), 202.0 (CvO), 167.8 (COO), 61.7 (OCH2),
50.3 (CH2), 47.4 (CH), 44.5 (CH), 43.9 (CH2), 37.5
(CH2), 35.2 (CH2), 26.0 (CH2), 15.1 (CH3), 14.9 (CH2),
14.7 (CH3).
Preparation of 2-diazo-4-(3-methyl-2-oxocyclohexyl)-3-
oxobutanoic acid ethyl ester (14a). A toluene solution
(50 ml) of ethyl 2-cyclohexanoneacetate (5.0 g, 27.2
mmol) and pyrrolidine (5.7 ml, 68.0 mmol) was re¯uxed
under a water separator in the presence of catalytic amount
of p-toluenesulphonic acid for 15 h. The solvent and excess
pyrrolidine were removed under reduced pressure and the
crude pyrrolidine enamine was taken in dry benzene
(50 ml). To the reaction mixture methyl iodide (2.5 ml,
41.0 mmol) was added at room temperature with stirring
and re¯uxed for 10 h. The solvent was removed and the
residue re¯uxed with 30 ml of water±methanol (1:5)
mixture for an hour. Removal of solvent and extraction
with ether, washing with dilute hydrochloric acid gave
ethyl 3-methyl-2-cyclohexanoneacetate (11a) (1.94 g) in
36% yield.
Hydrolysis of the ester 11a (370 mg, 1.9 mmol) with 5%
aqueous potassium hydroxide solution for 4 h afforded the
acid 12a (300 mg) in 96% yield. Treatment of 270 mg
(1.6 mmol) of acid 12a with oxalyl chloride (0.33 ml,
3.2 mmol) furnished the crude acid chloride. Further
reaction of crude acid chloride with DCM/THF (1:5) solu-
tion of dianion of monoethyl malonate, prepared from
monoethyl malonate (525 mg, 4.0 mmol) and isopropyl-
magnesium bromide (1.17 g, 8.0 mmol) gave active
methylene compound 13a (183 mg) in 48% yield as a color-
less liquid; nmax (neat) 2979, 1738, 1713, 1457, 1408, 1372,
1312, 1262, 1202, 1141, 1112, 1108, 1029 cm21; dH
The reaction of the compound 13b (300 mg, 1.2 mmol),
mesyl azide (172 mg, 1.4 mmol) and triethylamine
(0.33 ml, 2.4 mmol) afforded 14b (319 mg) in 96% yield
as a thick yellow oil; [Found: C, 59.86; H, 7.16; N, 10.06.
C14H20N2O4 requires C, 59.99; H, 7.19; N, 9.99%]; nmax
(neat) 2930, 2137, 1713, 1655, 1362, 1309, 1179, 1135,
1031 cm21; dH (200 MHz, CDCl3) 4.18 (2H, q, Jˆ7.2 Hz,
OCH2), 3.08±2.84 (2H, m), 2.38±2.00 (4H, m), 1.87±1.75
(2H, m), 1.38±1.35 (2H, m), 1.27 (3H, t, Jˆ7.2 Hz,

6314
S. Muthusamy et al. / Tetrahedron 56 (2000) 6307±6318
CH2CH3), 1.0±0.96 (2H, m), 0.91 (3H, t, Jˆ7.5 Hz); dC
(50 MHz, CDCl3) 213.0 (CvO), 202.3 (CvO), 167.7
(COO), 76.1 (CvN2), 61.9 (OCH2), 47.4 (CH), 45.9
(CH), 43.0 (CH2), 36.7 (CH2), 35.3 (CH2), 25.7 (CH2),
15.0 (CH3), 14.9 (CH2), 14.2 (CH3).
General procedure for the rhodium catalyzed cyclo-
addition reaction of diazo ketones 6 and 14 with
dipolarophiles
Method A: In a ¯ame-dried ¯ask, a solution containing
2 equiv. of dipolarophile and 1 mol% of rhodium acetate
dimer in 10 ml of dry dichloromethane (dried over phos-
phorous pentoxide) was degassi®ed under an argon atmos-
phere. To this reaction mixture a solution of 1 equiv. of
appropriate diazo ketone in dry dichloromethane was
added dropwise slowly for 1 h period under an argon atmos-
phere at room temperature. The reaction mixture was
allowed to stir and followed by TLC till the disappearance
of the starting material. The solvent was removed under
reduced pressure and the residue puri®ed by neutral
alumina/silica column to afford the respective cycloadduct.
Preparation of 2-diazo-4-methyl-4-(3-methyl-2-oxocyclo-
hexyl)-3-oxobutanoic acid ethyl ester (14c). Pyrrolidine
enamine of 2-methylcyclohexanone (5.0 g, 44.6 mmol)
was prepared as described above. To the crude enamine
reaction mixture in dry benzene (50 ml), ethyl 2-bromo-
propionate (11.6 ml, 89.2 mmol) was added at room
temperature with stirring and re¯uxed for 15 h. The
reaction mixture was worked-up as above to obtain ethyl
2-(3-methyl-2-oxocyclohexyl)propionate 11c (3.15 g) in
33% yield.
Hydrolysis of the ester 11c (2.0 g, 9.4 mmol) with 5%
aqueous potassium hydroxide solution for 8 h afforded the
acid 12c (1.57 g) in 90% yield. Treatment of 1.25 g
(6.8 mmol) of acid 12c with oxalyl chloride (1.4 ml,
13.6 mmol) furnished the crude acid chloride. Further reac-
tion with monoethyl malonate (2.25 g, 17.0 mmol) and
isopropylmagnesium bromide (5.0 g, 34.0 mmol) as
described above gave active methylene compound 13c
(810 mg) in 47% yield as a colorless liquid; nmax (neat)
2978, 1739, 1710, 1649, 1458, 1407, 1378, 1332, 1267,
1102 cm21; dH (200 MHz, CDCl3) 4.21 (2H, q, Jˆ7.2 Hz,
OCH2), 3.58 (1H, d, Jˆ15.5 Hz), 3.46 (1H, d, Jˆ15.5 Hz),
3.10±2.90 (2H, m), 2.59±2.10 (3H, m), 1.87±1.70 (2H, m),
1.42±1.33 (2H, m), 1.27 (3H, t, Jˆ7.2 Hz, CH2CH3), 1.17
(3H, d, Jˆ6.2 Hz), 0.98 (3H, d, Jˆ6.3 Hz); dC (50 MHz,
CDCl3) 213.2 (CvO), 202.8 (CvO), 167.5 (COO), 61.8
(OCH2), 53.2 (CH), 50.3 (CH2), 47.2 (CH), 39.6 (CH),
31.2 (CH2), 27.6 (CH2), 25.1 (CH2), 15.0 (CH3), 14.7
(CH3), 14.1 (CH3).
Method B: The procedure was followed as in method A
using dry benzene (dried over sodium) instead of dichloro-
methane. The diazo ketone was added dropwise over 1 h to
the re¯uxing reaction mixture under an argon atmosphere.
5-Methyl-6-oxo-10-oxatricyclo(5,2,1,01,5)dec-8-ene-7,8,9-
tricarboxylic acid 7-ethyl ester 8,9-dimethyl ester (8a). A
mixture of DMAD (180 mg, 1.3 mmol) and 2.8 mg of
Rh2(OAc)4 in benzene (5 ml) was allowed to react with a
benzene solution (2 ml) of diazo ketone 6a (150 mg,
0.6 mmol) for 15 h at re¯ux according to the general method
B to afford 184 mg (83%) of 8a as a white solid, mp 84±
868C (chloroform/hexane); [Found: C, 57.89; H, 5.76.
C17H20O8 requires C, 57.95; H, 5.72%]; nmax (KBr) 2961,
1782, 1747, 1728, 1659, 1443, 1262, 1179, 1016, 851 cm21
;
dH (200 MHz, CDCl3) 4.35 (2H, q, Jˆ7.2 Hz, OCH2), 3.86
(3H, s, OCH3), 3.80 (3H, s, OCH3), 2.77±2.68 (1H, m),
2.26±2.02 (4H, m), 1.76±1.66 (1H, m), 1.30 (3H, t,
Jˆ7.2 Hz, CH2CH3), 1.09 (3H, s, tert-CH3); dC (50 MHz,
CDCl3) 203.3 (CvO), 163.5 (COO), 163.0 (COO), 162.2
(COO), 145.6 (CvC), 141.1 (CvC), 102.0 (C±O), 92.1
(C±O), 63.3 (OCH2), 53.5 (OCH3), 53.3 (OCH3), 50.4
(C-5), 34.3 (CH2), 26.6 (CH2), 24.0 (CH2), 21.8 (CH3),
14.7 (CH3); m/z 352 (M1, 8), 308 (30), 251 (30), 149
(33), 112 (52), 85 (100%).
The reaction of the compound 13c (400 mg, 1.6 mmol),
mesyl azide (230 mg, 1.9 mmol) and triethylamine
(0.45 ml, 3.2 mmol) afforded 14c (425 mg) in 96% yield
as a thick yellow oil; [Found: C, 59.92; H, 7.23; N, 9.95.
C14H20N2O4 requires C, 59.99; H, 7.19; N, 9.99%]; nmax
(neat) 2942, 2139, 1716, 1658, 1362, 1348, 1307, 1183,
1029 cm21; dH (200 MHz, CDCl3) 4.19 (2H, q, Jˆ7.2 Hz,
OCH2), 3.12±2.89 (2H, m), 2.53±2.12 (3H, m), 1.92±1.73
(2H, m), 1.45±1.30 (2H, m), 1.28 (3H, t, Jˆ7.2 Hz,
CH2CH3), 1.18 (3H, d, Jˆ6.3 Hz), 0.99 (3H, d, Jˆ
6.3 Hz); dC (50 MHz, CD3CN) 212.0 (CvO), 203.0
(CvO), 167.9 (COO), 76.4 (CˆN2), 62.0 (OCH2), 53.3
(CH), 47.4 (CH), 39.8 (CH), 31.3 (CH2), 27.8 (CH2), 25.3
(CH2), 15.2 (CH3), 14.8 (CH3), 14.2 (CH3).
6-Methyl-7-oxo-11-oxatricyclo(6,2,1,01,6)undec-9-ene-8,9,
10-tricarboxylic acid 8-ethyl ester 9,10-dimethyl ester
(8b). A mixture of DMAD (225 mg, 1.6 mmol) and
3.5 mg of Rh2(OAc)4 in benzene (7 ml) was allowed to
react with a benzene solution (3 ml) of diazo ketone 6b
(200 mg, 0.8 mmol) for 18 h at re¯ux according to the
general method B to afford 253 mg (88%) of 8b as a
white solid, mp 82±838C (chloroform/hexane); [Found: C,
58.92; H, 6.01. C18H22O8 requires C, 59.01; H, 6.05%]; nmax
(KBr) 2941, 1779, 1752, 1727, 1634, 1441, 1320, 1268,
1183, 1011, 963 cm21; dH (200 MHz, CDCl3) 4.30 (2H, q,
Jˆ7.2 Hz, OCH2), 3.80 (3H, s, OCH3), 3.76 (3H, s, OCH3),
2.56±2.48 (1H, m), 2.20±2.08 (1H, m), 1.76±1.50 (6H, m),
1.27 (3H, t, Jˆ7.2 Hz, CH2CH3), 1.13 (3H, s, tert-CH3); dC
(50 MHz, CDCl3) 204.0 (CvO), 162.5 (COO), 162.4
(COO), 161.6 (COO), 144.0 (CvC), 143.4 (CvC), 92.0
(C±O), 91.3 (C±O), 62.5 (OCH2), 52.7 (OCH3), 52.5
(OCH3), 41.6 (C-6), 32.1 (CH2), 25.0 (CH2), 20.9 (CH2),
20.2 (CH2), 19.3 (CH3), 13.9 (CH3); m/z 366 (M1, 30),
334 (100), 306 (38), 274 (48), 251 (57), 232 (44%).
Preparation of 2-diazo-4-(3-methyl-2-oxocyclohexyl)-3-
oxobutane (14d).
A
solution containing 850 mg
(5.1 mmol) of acid 12a in dry ether was treated with
1.1 ml (10.6 mmol) of oxalyl chloride to afford the corre-
sponding acid chloride which on treatment with 6.5 mmol
diazoethane solution containing 0.7 ml (5.0 mmol) of
triethylamine gave the diazo ketone 14d (755 mg) in 71%
yield as a thick yellow bright oil; [Found: C, 63,27; H, 7.53;
N, 13.71. C11H16N2O2 requires C, 63.44; H, 7.74; N,
13.45%]; nmax (neat) 2953, 2083, 1710, 1640, 1382, 1228,
1123, 1028 cm21
.

S. Muthusamy et al. / Tetrahedron 56 (2000) 6307±6318
6315
5-Methyl-6-oxo-10-oxatricyclo(5,2,1,01,5)dec-8-ene-8,9-
dicarboxylic acid 8,9-dimethyl ester (8c). A mixture of
DMAD (170 mg, 1.2 mmol) and 2.7 mg of Rh2(OAc)4 in
dichloromethane (7.0 ml) was allowed to react with a
dichloromethane solution (3 ml) of diazo ketone 6c
(100 mg, 0.6 mmol) at room temperature for 5 h according
to the general method A to afford 125 mg (74%) of 8c as a
thick oil; [Found: C, 60.07; H, 5.98. C14H16O6 requires C,
59.99; H, 5.75%]; nmax (neat) 2960, 1764, 1727, 1632, 1439,
1325, 1271, 1145, 1117 cm21; dH (200 MHz, CDCl3) 4.82
(1H, s, CH), 3.79 (3H, s, OCH3), 3.75 (3H, s, OCH3), 2.24±
1.19 (6H, m), 1.02 (3H, s, tert-CH3); dC (50 MHz, CDCl3)
209.6 (CvO), 163.9 (COO), 161.9 (COO), 149.2 (CvC),
140.7 (CvC), 104.7 (C-1), 84.3 (C-7), 53.09 (OCH3), 53.04
(OCH3), 50.6 (C-5), 34.0 (CH2), 26.6 (CH2), 23.7 (CH2),
21.3 (CH3).
59.23; H, 6.26. C18H22O8 requires C, 59.01; H, 6.05%]; nmax
(neat) 2936, 1741, 1739, 1732, 1645, 1436, 1372, 1264,
1154, 1108, 1037 cm21; dH (200 MHz, CDCl3) 4.30 (2H,
q, Jˆ7.2 Hz, OCH2), 3.83 (6H, s, OCH3), 3.12 (1H, dd,
J1ˆ16.8 Hz, J2ˆ7.6 Hz), 2.41±2.28 (1H, m), 2.22±2.14
(1H, m), 2.09 (2H, d, Jˆ17.0 Hz), 1.84±1.63 (4H, m),
1.43±1.36 (2H, m), 1.31 (3H, t, Jˆ7.2 Hz, CH2CH3); dC
(50 MHz, CDCl3) 195.7 (CvO), 164.2 (COO), 164.1
(COO), 162.6 (COO), 143.2 (CvC), 140.2 (CvC), 94.4
(C±O), 90.1 (C±O), 63.0 (OCH2), 53.36 (OCH3), 53.34
(OCH3), 41.1 (CH2), 40.5 (CH), 31.9 (CH2), 31.0 (CH2),
25.8 (CH2), 21.3 (CH2), 14.6 (CH3), m/z 366 (M1, 40),
334 (95), 306 (84), 274 (95), 246 (44), 233 (100), 201
(48), 115 (29%).
8-Oxo-12-oxatricyclo(7,2,1,01,6)dodec-10-ene-10,11-dicar-
boxylic acid 10,11-dimethyl ester (8g). A mixture of
DMAD (475 mg, 3.3 mmol) and 7.3 mg of Rh2(OAc)4 in
dichloromethane (10 ml) was allowed to react with a
dichloromethane solution (5 ml) of diazo ketone 6g
(300 mg, 1.7 mmol) at room temperature for 5 h according
to the general method A to afford 348 mg (71%) of 8g as a
white solid, mp 84±868C (dichloromethane/hexane);
[Found; C, 61.11; H, 6.12. C15H18O6 requires C, 61.22; H,
6.16%]; nmax (KBr) 2930, 2861, 1731, 1654, 1440, 1273,
1200, 1142, 1013, 947 cm21; dH (200 MHz, CDCl3) 4.84
(1H, s), 3.90 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.02
(1H, dd, J1ˆ17.6 Hz, J2ˆ7.8 Hz), 2.33±2.21 (1H, m),
2.04 (2H, d, Jˆ16.4 Hz), 1.81±1.25 (7H, m); dC (50 MHz,
CDCl3) 200.3 (CvO), 164.7 (COO), 161.6 (COO), 148.6
(CvC), 135.6 (CvC), 90.5 (C-1), 86.8 (C-9), 53.22
(OCH3), 53.02 (OCH3), 40.8 (CH2), 38.4 (C-6), 31.9 (CH2),
30.9 (CH2), 25.6 (CH2), 20.9 (CH2); m/z 294 (M1, 5), 278 (38),
261 (48), 233 (76) 201 (57), 167 (33), 149 (100), 91 (32%).
6-Methyl-7-oxo-11-oxatricyclo(6,2,1,01,6)dec-9-ene-9,10-
dicarboxylic acid 9,10-dimethyl ester (8d). A mixture of
DMAD (475 mg, 3.3 mmol) and 7.3 mg of Rh2(OAc)4 in
dichloromethane (10 ml) was allowed to react with a
dichloromethane solution (5 ml) of diazo ketone 6d
(300 mg, 1.7 mmol) at room temperature for 3 h according
to the general method A to afford 371 mg (76%) of 8d as a
white solid, mp 87±888C (dichloromethane/hexane);
[Found: C, 61:05; H, 6.35. C15H18O6 requires C, 61.22; H,
6.16%];nmax (KBr) 2955, 1761, 1732, 1650, 1440, 1318,
1259, 1202, 1131 cm21; dH (200 MHz, CDCl3) 5.00 (1H,
s), 3.85 (3H, s, OCH3), 3.81 (3H, s, OCH3), 2.58±2.41 (1H,
m), 2.12±1.99 (1H, m), 1.83±1.51 (6H, m), 1.18 (3H, s, tert-
CH3); dC (50 MHz, CDCl3) 210.8 (CvO), 164.2 (COO),
161.5 (COO), 153.4 (CvC), 138.4 (CvC), 94.3 (C-1), 84.0
(C-8), 58.7 (C-6), 53.1 (OCH3), 53.0 (OCH3), 32.2 (CH2), 25.4
(CH2), 22.4 (CH2), 21.4 (CH2), 19.3 (CH3); m/z 294 (M1, 32),
262 (100), 234 (70), 202 (56), 179 (87), 166 (29), 91 (24%).
2-Methyl-8,11,13-trioxo-12-phenyl-15-oxa-12-azatetra-
cyclo[7.5.1.01,6.010,14]pentadecane-9-carboxylic acid ethyl
ester (15a). A mixture of N-phenyl maleimide (76 mg,
0.4 mmol) and 1.0 mg of Rh2(OAc)4 in dry benzene (7 ml)
was allowed to react with a benzene solution (3 ml) of diazo
ketone 14a (60 mg, 0.2 mmol) for 10 h at re¯ux according
to the general method B to afford 83 mg (92%) of 15a as a
white solid, mp 194±1968C (ethyl acetate/hexane); [Found:
C, 67.26; H, 6.03; N, 3.36. C23H25NO6 requires C, 67.14; H,
6.12; N, 3.40%]; nmax (KBr) 2965, 1774, 1741, 1715, 1499,
1452, 1212, 1074, 1017, 851 cm21; dH (200 MHz, CDCl3)
7.51±7.43 (3H, m, Arom-H), 7.27±7.25 (2H, m, Arom-H),
4.39 (2H, q, Jˆ7.2 Hz, OCH2), 3.87 (1H, d, Jˆ8.2 Hz), 3.57
(1H, d, Jˆ8.2 Hz), 2.90 (1H, dd, J1ˆ12.5 Hz, J2ˆ7.4 Hz),
2.34±2.20 (5H, m), 1.70±1.50 (4H, m), 1.34 (3H, t, Jˆ
7.2 Hz, CH2CH3), 0.96 (3H, d, Jˆ6.2 Hz, CH3); dC
(50 MHz, CDCl3) 197.9 (CvO), 175.1 (NCO), 175.0
(NCO), 172.5 (COO), 132.1 (quat-C), 129.9 (Arom-CH),
129.6 (Arom-CH), 126.8 (Arom-CH), 89.4 (C±O), 89.1
(C±O), 62.5 (OCH2), 53.7 (CH), 52.3 (CH), 49.5 (CH),
42.0 (CH2), 34.5 (CH), 32.9 (CH2), 29.6 (CH2), 25.5
(CH2), 17.1 (CH3), 14.6 (CH3); m/z 411 (M1, 32), 383
(40), 338 (25), 281 (43), 238 (100), 175 (83), 93 (37%).
7-Oxo-11-oxatricyclo(6,2,1,01,5)undec-9-ene-8,9,10-tri-
carboxylic acid 8-ethyl ester 9,10-dimethyl ester (8e). A
mixture of DMAD (300 mg, 2.1 mmol) and 4.6 mg of
Rh2(OAc)4 in benzene (10 ml) was allowed to react with a
benzene solution (3 ml) of diazo ketone 6e (250 mg,
1.1 mmol) for 14 h at re¯ux according to the general method
B to afford 330 mg (89%) of 8e as a thick oil; [Found: C,
58.08; H, 5.67. C17H20O8 requires C, 57.95; H, 5.72%]; nmax
(neat) 2958, 1740, 1733, 1728, 1645, 1435, 1263, 1096,
1029, 978, 782 cm21; dH (200 MHz, CDCl3) 4.31 (2H, q,
Jˆ7.2 Hz, OCH2), 3.84 (3H, s, OCH3), 3.82 (3H, s, OCH3),
2.99 (1H, dd, J1ˆ17.8 Hz, J2ˆ8.0 Hz), 2.67 (1H, dd,
J1ˆ17.9 Hz, J2ˆ4.0 Hz), 2.60±2.35 (2H, m), 2.15±1.94
(3H, m), 1.82±1.70 (2H, m), 1.33 (3H, t, Jˆ7.2 Hz, CH3);
dC (50 MHz, CDCl3) 194.6 (CvO), 163.3 (COO), 163.0
(COO), 161.8 (COO), 141.1 (CvC), 140.9 (CvC), 95.8
(C±O), 92.3 (C±O), 62.5 (OCH2), 52.61 (OCH3), 52.62
(OCH3), 44.2 (C-5), 40.2 (CH2), 33.0 (CH2), 32.9 (CH2),
24.1 (CH2), 13.9 (CH3).
8-Oxo-12-oxatricyclo(7,2,1,01,6)dodec-10-ene-9,10,11-tri-
carboxylic acid 9-ethyl ester 10,11-dimethyl ester (8f). A
mixture of DMAD (100 mg, 0.7 mmol) and 1.5 mg of
Rh2(OAc)4 in benzene (7 ml) was allowed to react with a
benzene solution (3 ml) of diazo ketone 6f (90 mg,
0.4 mmol) for 11 h at re¯ux according to the general method
B to afford 112 mg (86%) of 8f as a thick liquid; [Found: C,
2-Ethyl-8,11,13-trioxo-12-phenyl-15-oxa-12-azatetracyclo-
[7.5.1.01,6.010,14]pentadecane-9-carboxylic acid ethyl
ester (15b). A mixture of N-phenyl maleimide (90 mg,
0.5 mmol) and 1.2 mg of Rh2(OAc)4 in benzene (7 ml)

6316
S. Muthusamy et al. / Tetrahedron 56 (2000) 6307±6318
was allowed to react with a benzene solution (3 ml) of diazo
ketone 14b (75 mg, 0.3 mmol) for 8 h at re¯ux according to
the general method B to afford 98 mg (82%) of 15b as a
white solid, mp 204±2068C (ethyl acetate/hexane); [Found:
C, 67.61; H, 6.13; N, 3.20. C24H27NO6 requires C, 67.75; H,
6.39; N, 3.29%]; nmax (KBr) 2941, 1779, 1740, 1714, 1389,
1319, 1214, 1078, 1012, 996 cm21; dH (200 MHz, CDCl3)
7.48±7.36 (3H, m, Arom-H), 7.29±7.23 (2H, m, Arom-H),
4.38 (2H, q, Jˆ 7.2 Hz, OCH2), 3.87 (1H, d, Jˆ8.2 Hz),
3.57 (1H, d, Jˆ 8.2 Hz), 2.91 (1H, dd, J1ˆ14.2 Hz,
J2ˆ7.4 Hz), 2.32±2.08 (5H, m), 1.76±1.30 (4H, m), 1.34
(3H, t, Jˆ7.2 Hz, CH2CH3), 1.03±0.97 (2H, m), 0.92 (3H,
t, Jˆ7.5 Hz, CH3); dC (50 MHz, CDCl3) 198.0 (CvO),
175.1 (NCO), 172.5 (NCO), 169.8 (COO), 132.1 (quat-C),
130.1 (Arom-CH), 129.5 (Arom-CH), 126.9 (Arom-CH),
89.5 (C±O), 89.3 (C±O), 62.9 (OCH2), 53.9 (CH), 52.6
(CH), 47.6 (CH), 42.1 (CH2), 34.6 (CH), 33.0 (CH2), 29.7
(CH2), 25.6 (CH2), 16.0 (CH3), 14.9 (CH2), 14.2 (CH3).
6-Methyl-7,10,12-trioxo-11-phenyl-14-oxa-11-azatetra-
cyclo[6.5.1.01,6.09,13]tetradecane (15e). A mixture of N-
phenyl maleimide (105 mg, 0.6 mmol) and 1.3 mg of
Rh2(OAc)4 in dichloromethane (7 ml) was allowed to
react with a dichloromethane solution (3 ml) of diazo ketone
6d (55 mg, 0.3 mmol) at room temperature for 3 h accord-
ing to the general method A to afford 88 mg (88%) of 15e as
a white solid, mp 170±1728C (ethyl acetate/hexane);
[Found: C, 70.26; H, 5.83; N, 4.24. C19H19NO4 requires C,
70.14; H, 5.89; N, 4.30%]; nmax (KBr) 2934, 2864, 1768,
1709, 1595, 1498, 1385, 1199, 1160, 992 cm21; dH
(200 MHz, CDCl3) 7.51±7.42 (3H, m, Arom-H), 7.28±
7.23 (2H, m, Arom-H), 4.89 (1H, s, OCH), 3.21 (2H, s,
CH), 2.07±1.87 (2H, m), 1.80±1.59 (3H, m), 1.49±1.16
(3H, m), 1.09 (3H, s, tert-CH3); dC (50 MHz, CDCl3)
213.4 (CvO), 174.1 (NCO), 131.6 (quat-C), 129.2
(Arom-CH), 128.9 (Arom-CH), 126.4 (Arom-CH), 90.7
(C±O), 82.4 (OCH), 49.6 (CCH3), 47.9 (CH), 47.0 (CH),
30.4 (CH2), 25.7 (CH2), 21.9 (CH2), 19.9 (CH2), 16.2 (CH3).
2,7-Dimethyl-8,11,13-trioxo-12-phenyl-15-oxa-12-aza-
tetracyclo[7.5.1.01,6.010,14]pentadecane-9-carboxylic acid
ethyl ester (15c). A mixture of N-phenyl maleimide
(280 mg, 1.6 mmol) and 3.5 mg of Rh2(OAc)4 in dry ben-
zene (7 ml) was allowed to react with a benzene solution
(3 ml) of diazo ketone 14c (225 mg, 0.8 mmol) for 11 h at
re¯ux according to the general method B to afford 287 mg
(84%) of 15c as a white solid, mp 203±2048C (ethyl acetate/
hexane); [Found: C, 67.67; H, 6.32; N, 3.26. C24H27NO6
requires C, 67.75; H, 6.40; N, 3.29%]; nmax (KBr) 2933,
1775, 1742, 1716, 1652, 1393, 1319, 1218, 1028 cm21; dH
(200 MHz, CDCl3) 7.48±7.38 (3H, m, Arom-H), 7.29±7.23
(2H, m, Arom-H), 4.28 (2H, q, Jˆ7.2 Hz, OCH2), 3.89 (1H,
d, Jˆ8.3 Hz), 3.59 (1H, d, Jˆ8.3 Hz), 2.92±2.87 (1H, m),
2.38±2.09 (4H, m), 1.81±1.34 (4H, m), 1.37 (3H, t, Jˆ
7.2 Hz, CH2CH3), 1.23 (3H, d, Jˆ6.3 Hz), 0.95 (3H, d,
Jˆ6.2 Hz, CH3); dC (50 MHz, CDCl3) 198.3 (CvO),
176.1 (NCO), 173.0 (NCO), 168.2 (COO), 132.1 (quat-C),
130.2 (Arom-CH), 129.5 (Arom-CH), 127.2 (Arom-CH),
89.9 (C±O), 89.7 (C±O), 62.7 (OCH2), 53.8 (CH), 52.9
(CH), 48.2 (CH), 40.2 (CH), 35.3 (CH), 32.8 (CH2), 29.3
(CH2), 25.9 (CH2), 17.2 (CH3), 14.6 (CH3), 14.2 (CH3).
6-Methyl-7,10,12-trioxo-11-phenyl-14-oxa-11-azatetra-
cyclo[6.5.1.01,6.09,13]tetradecane-8-carboxylic acid ethyl
ester (15f). A mixture of N-phenyl maleimide (142 mg,
0.8 mmol) and 1.8 mg of Rh2(OAc)4 in benzene (7 ml)
was allowed to react with a benzene solution (3 ml) of
diazo ketone 6b (103 mg, 0.4 mmol) for 8 h at re¯ux
according to the general method B to afford 150 mg
(95%) of 15f as a white solid, mp 215±2178C (ethyl acetate/
hexane); [Found: C, 66.05; H, 5.81; N, 3.47. C22H23NO6
requires C, 66.49; H, 5.83; N, 3.52%]; nmax (KBr) 2933,
1774, 1741, 1715, 1393, 1317, 1212, 1074 cm21; dH
(200 MHz, CDCl3) 7.49±7.39 (3H, m, Arom-H), 7.26±
7.22 (2H, m, Arom-H), 4.40 (2H, q, Jˆ7.2 Hz, OCH2),
3.51 (1H, d, Jˆ8.0 Hz), 3.29 (1H, d, Jˆ8.0 Hz), 2.09±
1.67 (6H, m), 1.38 (3H, t, Jˆ7.2 Hz, CH2CH3), 1.46±1.34
(2H, m), 1.23 (3H, s, tert-CH3); dC (50 MHz, CDCl3) 207.6
(CvO), 173.5 (NCO), 172.4 (NCO), 163.3 (COO), 132.1
(quat-C), 129.7 (Arom-CH), 129.5 (Arom-CH), 127.0
(Arom-CH), 90.1 (C±O), 89.7 (C±O), 62.9 (OCH2), 50.4
(quat-C), 49.7 (CH), 49.1 (CH), 31.3 (CH2), 26.1 (CH2),
22.2 (CH2), 20.3 (CH2), 16.9 (CH3), 14.7 (CH3); m/z 397
(M1, 48), 351 (43), 305 (100), 204 (44), 175 (30), 149 (54),
115 (21), 98 (25%).
2,9-Dimethyl-8,11,13-trioxo-12-phenyl-15-oxa-12-aza-
tetracyclo[7.5.1.01,6.010,14]pentadecane (15d). A mixture
of N-phenyl maleimide (375 mg, 2.2 mmol) and 4.8 mg of
Rh2(OAc)4 in dichloromethane (15 ml) was allowed to react
with a dichloromethane solution (5 ml) of diazo ketone 14d
(225 mg, 1.1 mmol) at room temperature for 9 h according
to the general method A to afford 263 mg (69%) of 15d as a
white solid, mp 182±1838C (ethyl acetate/hexane); [Found:
C, 71.46; H, 6.43; N, 3.84. C21H23NO4 requires C, 71.37; H,
6.56; N, 3.96%]; nmax (KBr) 2938, 2863, 1768, 1707, 1598,
1493, 1386, 1237, 1120, 990 cm21; dH (200 MHz, CDCl3)
7.52±7.40 (3H, m, Arom-H), 7.28±7.24 (2H, m, Arom-H),
3.52 (1H, d, Jˆ8.0 Hz), 3.37 (1H, d, Jˆ8.0 Hz), 2.92 (1H,
dd, J1ˆ14.2 Hz, J2ˆ7.8 Hz), 2.40±2.01 (5H, m), 1.79±1.31
(4H, m), 1.51 (3H, s, CH3), 0.97 (3H, d, Jˆ6.4 Hz, CH3);
dC (50 MHz, CDCl3) 199.1 (CvO), 175.2 (NCO), 172.9
(NCO), 132.0 (quat-C), 129.9 (Arom-CH), 129.3
(Arom-CH), 126.6 (Arom-CH), 89.4 (C±O), 86.2 (C±O),
53.8 (CH), 52.3 (CH), 47.2 (CH), 42.2 (CH2), 34.7
(CH), 32.9 (CH2), 29.2 (CH2), 25.6 (CH2), 23.2 (CH3),
16.8 (CH3).
6,9-Dimethyl-7-oxo-11-oxatricyclo(6,2,1,01,6)undecane-
9-carboxylic acid 9-methyl ester (17a,b). A mixture of
methyl methacrylate (122 mg, 1.2 mmol) and 2.7 mg of
Rh2(OAc)4 in dichloromethane (7 ml) was allowed to
react with a dichloromethane solution (3 ml) of diazo ketone
6d (110 mg, 0.6 mmol) for 4 h according to the general
method A afforded the diasteromers 17a (16 mg, 10%)
and 17b (83 mg, 53%) as a thick liquid. 17a: [Found: C,
66.60; H, 7.82. C14H20O4 requires C, 66.65; H, 7.99%]; nmax
(neat) 2938, 2867, 1746, 1741, 1452, 1377, 1277, 1208,
1164, 1119, 998 cm21; dH (200 MHz, CDCl3) 4.12 (1H, s,
H-8), 3.68 (3H, s, OCH3), 2.70 (1H, d, Jˆ13.2 Hz), 1.93±
1.67 (6H, m), 1.63±1.26 (3H, m), 1.25 (3H, s, CH3), 1.09
(3H, s, CH3); dC (50 MHz, CDCl3) 216.8 (CvO), 176.5
(COO), 89.3 (C-1), 87.2 (C-8), 53.5 (OCH3), 51.5 (quat-
C), 50.3 (quat-C), 43.0 (CH2), 32.0 (CH2), 29.3 (CH2),
22.8 (CH2), 21.0 (CH2), 20.6 (CH3), 16.6 (CH3); 17b:
[Found: C, 66.59; H, 7.94. C14H20O4 requires C, 66.65; H,
7.99%]; nmax (neat) 2937, 2867, 1743, 1741, 1453, 1378,

S. Muthusamy et al. / Tetrahedron 56 (2000) 6307±6318
6317
1278, 1207, 1169, 1120, 995 cm21; dH (200 MHz, CDCl3)
4.64 (1H, s, H-8), 3.75 (3H, s, OCH3), 2.32 (1H, d,
Jˆ13.2 Hz), 1.90±1.78 (1H, m), 1.75±1.62 (6H, m),
1.43±1.25 (2H, m), 1.22 (3H, s, CH3), 1.08 (3H, s, CH3);
dC (50 MHz, CDCl3) 216.8 (CvO), 176.4 (COO), 89.2
(C-1), 87.3 (C-8), 53.4 (OCH3), 51.4 (quat-C), 50.3 (quat-
C), 42.6 (CH2), 31.3 (CH2), 29.2 (CH2), 22.8 (CH2), 20.9
(CH2), 20.6 (CH3), 16.5 (CH3).
mixture of propargyl bromide (108 mg, 0.9 mmol) and
2.0 mg of Rh2(OAc)4 in benzene (7 ml) was allowed to
react with a benzene solution (3 ml) of diazo ketone 6b
(113 mg, 0.5 mmol) for 13 h at re¯ux according to the
general method B to afford 97 mg (63%) of 18b as a thick
dark yellow liquid; [Found: C, 52.57; H, 5.61. C15H19BrO4
requires C, 52.49; H, 5.58%]; nmax (neat) 2935, 2868, 1743,
1650, 1459, 1383, 1327, 1267, 1124, 1087 cm21; dH
(200 MHz, CDCl3) 6.44 (1H, s, CvCH), 4.35 (2H, q,
Jˆ7.2 Hz, OCH2), 4.20 (2H, s, CH2Br), 2.22±2.15 (1H,
m), 1.95±1.52 (5H, m), 1.49±1.30 (2H, m), 1.38 (3H, t,
Jˆ7.2 Hz, CH2CH3), 1.09 (3H, s, CH3); dC (50 MHz,
CDCl3) 206.8 (CvO), 164.5 (COO), 143.7 (C-10), 142.2
(C-9), 92.0 (C±O), 89.0 (C±O), 62.9 (OCH2), 55.1 (C-6),
32.2 (CH2), 26.8 (CH2), 24.6 (CH2), 21.5 (CH2), 21.2 (CH3),
20.8 (CH2), 14.7 (CH3).
6,9-Dimethyl-7-oxo-11-oxatricyclo(6,2,1,01,6)undecane-
8,9-dicarboxylic acid 8-ethyl ester 9-methyl ester (17c,d).
A mixture of methyl methacrylate (60 mg, 0.6 mmol) and
1.32 mg of Rh2(OAc)4 in benzene (7 ml) was allowed to
react with a benzene solution (3 ml) of diazo ketone 6b
(75 mg, 0.3 mmol) for 11 h at re¯ux according to the
general method B afforded the diasteromers 17c (24 mg,
25%) and 17d (59 mg, 61%) as a thick liquid which solidi-
®ed on standing. 17c: mp 87±898C (dichloromethane/
hexane); [Found: C, 62.86; H, 7.37. C17H24O6 requires C,
62.95; H, 7.46%]; nmax (KBr) 2941, 2867, 1751, 1746, 1744,
1452, 1377, 1300, 1187, 1145 cm21; dH (200 MHz, CDCl3)
4.31 (2H, q, Jˆ7.2 Hz, OCH2), 3.72 (3H, s, OCH3), 2.59
(1H, d, Jˆ13.0 Hz), 1.91 (1H, d, Jˆ13.0 Hz), 1.79±1.33
(8H, m), 1.36 (3H, s, CH3), 1.31 (3H, t, Jˆ7.2 Hz,
CH2CH3), 1.27 (3H, s, CH3); dC (50 MHz, CDCl3) 209.3
(CvO), 173.6 (COO), 165.3 (COO), 94.4 (C±O), 87.6
(C±O), 62.4 (OCH2), 54.6 (C-6), 52.9 (OCH3), 49.9 (quat-
C), 46.8 (CH2), 32.4 (CH2), 29.5 (CH2), 22.7 (CH2), 22.0
(CH3), 20.8 (CH2), 16.4 (CH3), 14.7 (CH3); m/z 324 (M1, 5),
219 (100), 204 (11), 149 (21), 123 (11), 109 (25%). 17d: mp
86±888C (dichloromethane/hexane); [Found: C, 62.83; H,
7.45. C17H24O6 requires C, 62.95; H, 7.46%]; nmax (KBr)
2938, 2867, 1767, 1732, 1461, 1282, 1201, 1133, 1103,
1033, 960 cm21; dH (200 MHz, CDCl3) 4.34 (2H, q, Jˆ
7.2 Hz, OCH2), 3.71 (3H, s, OCH3), 2.17 (1H, d, Jˆ
13.4 Hz), 1.92 (1H, d, Jˆ13.4 Hz), 1.99±1.62 (5H, m),
1.44 (3H, s, CH3), 1.42±1.20 (3H, m), 1.34 (3H, t,
Jˆ7.2 Hz, CH2CH3), 1.05 (3H, s, CH3); dC (50 MHz,
CDCl3) 210.3 (CvO), 174.8 (COO), 165.9 (COO), 93.2
(C±O), 85.8 (C±O), 62.1 (OCH2), 53.6 (C-6), 53.2
(OCH3), 50.4 (quat-C), 45.7 (CH2), 31.6 (CH2), 28.9
(CH2), 22.4 (CH2), 21.2 (CH3), 20.7 (CH2), 16.7 (CH3),
14.7 (CH3).
X-Ray crystal structure analysis
Crystal data for the compound 8b: C18H22O8, Mˆ366.36,
3
Ê
0.30£0.25£0.30 mm , Triclinic, P-1, aˆ8.964(3) A, bˆ
Ê
Ê
9.955(4) A, cˆ11.952(5) A, aˆ74.98(3)8, bˆ76.96(3)8,
Ê 3
gˆ64.99(3)8, Vˆ925.3(6) A , Tˆ293(2) K, R1ˆ0.0956,
wR2ˆ0.2216 on observed data, zˆ2, Dcalc.ˆ1.315 Mg m23
,
,
F(000)ˆ388,
Absorption
coef®cientˆ0.104 mm21
Ê
lˆ0.7107 A, 2428 re¯ections were collected on a CAD-4
diffractometer, 1837 observed re¯ections (I$2s(I)). The
,
Ê 23
largest difference peak and holeˆ0.396 and 20.518e A
respectively. Crystal data for the compound 15a:
C23H25NO6, Mˆ411.44, 0.16£0.08£0.03 mm, Monoclinic,
Ê
Ê
Ê
P21/n, aˆ8.547(8) A, bˆ20.395(14) A, cˆ12.074(8) A,
Ê 3
bˆ106.49(7)8, Vˆ2018(3) A , Tˆ293(2) K, R1ˆ0.0603,
wR2ˆ0.1446 on observed data, zˆ4, Dcalc.ˆ1.354 Mg m23
,
F(000)ˆ872, Absorption coef®cientˆ0.098 mm21, lˆ
Ê
0.7107 A, 2613 re¯ections were collected on a CAD-4
diffractometer, 1636 observed re¯ections (I$2s(I)). The
,
Ê 23
largest difference peak and holeˆ0.450 and 20.383e A
respectively. The structure was solved by direct methods
and re®ned by full-matrix least squares on F2 using
shelx-97.20 All non-hydrogen atoms were re®ned aniso-
tropically. Some hydrogens were located on a difference
Fourier map and some were stereochemically ®xed. Atomic
coordinates, thermal parameters, bond lengths and angles
have been deposited at the Cambridge Crystallographic
Data Center.
9-Bromomethyl-6-methyl-7-oxo-11-oxatricyclo(6,2,1,01,6)-
undec-9-ene (18a). A mixture of propargyl bromide
(160 mg, 1.3 mmol) and 3.0 mg of Rh2(OAc)4 in dichloro-
methane (10 ml) was allowed to react with a dichloro-
methane solution (3 ml) of diazo ketone 6d (121 mg,
0.7 mmol) for 4.5 h according to the general method A to
afford 102 mg (56%) of 18a as a thick oil; [Found: C, 53.18;
H, 5.62. C12H15BrO2 requires C, 53.16; H, 5.58%]; nmax
(neat) 2935, 2869, 1734, 1651, 1458, 1384, 1327, 1268,
1128, 1088, 1036 cm21; dH (200 MHz, CDCl3) 6.43 (1H,
s, CvCH), 4.64 (1H, s, H-8), 4.21 (2H, s, CH2Br), 2.28±
2.15 (1H, m), 1.99±1.58 (5H, m), 1.40±1.39 (2H, m), 1.04
(3H, s, CH3); dC (50 MHz, CDCl3) 206.8 (CvO), 143.7
(C-10), 141.8 (C-9), 92.7 (C±O), 84.0 (C±O), 55.7 (C-6),
32.4 (CH2), 26.8 (CH2), 24.7 (CH2), 21.6 (CH2), 21.1 (CH3),
20.8 (CH2).
Acknowledgements
This research was supported in part by Department of
Science and Technology, New Delhi. We wish to thank
Dr P. K. Ghosh, Director for his encouragement shown in
this work. S. A. B. and C. G. wish to acknowledge the CSIR,
New Delhi for a fellowship.
References
1. (a) Westley, J. W. Polyether Antibiotics: Naturally Occurring
Acid Ionophores; Marcel Dekker: New York, 1982; Vol. I and II.
(b) Kishi, Y.; Schmid, G.; Fukuyama, T.; Akasaka, K. J. Am.
Chem. Soc. 1979, 101, 259.
9-Bromomethyl-6-methyl-7-oxo-11-oxatricyclo(6,2,1,01,6)-
undec-9-ene-8-carboxylic acid 8-ethyl ester (18b). A
2. (a) Lin, Y. Y.; Risk, M.; Ray, S. M.; Engen, D. V.; Clardy, J.;

6318
S. Muthusamy et al. / Tetrahedron 56 (2000) 6307±6318
Golik, J.; James, J. C.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103,
6773. (b) Shimizu, Y.; Chou, H. N.; Bando, H.; Duyne, G. V.;
Clardy, J. J. Am. Chem. Soc. 1986, 108, 514.
11. Pollet, P.; Gelin, S. Synthesis 1978, 142.
12. (a) Regitz, M.; Hecker, J.; Leidhergener, K. Org. Synth. Coll.
Vol. V; Wiley: New York, 1973; p 179. (b) Taber, D. F.; Ruckle,
R. E., Jr.; Hennesy, M. J. J. Org. Chem. 1986, 51, 1663.
13. Padwa, A.; Fryxell, G. E.; Zhi, L. J. Am. Chem. Soc. 1990, 112,
3100.
3. Moore, R. E. In Marine Natural Products: Chemical and Bio-
logical Perspectives, Scheuer, P. J., Ed.; Academic: New York,
1978; Vol. 1.
4. (a) Hunt, I. R.; Rogers, C.; Woo, S.; Rauk, A.; Keay, B. A. J. Am.
Chem. Soc. 1995, 117, 1049. (b) Harmata, M.; Elahmad, S.; Barnes,
C. L. J. Org. Chem. 1994, 59, 1241. (c) Toro, A.; Wang, Y.; Drouin,
M.; Deslongchamps, P. Tetrahedron Lett. 1999, 40, 2769.
5. Williams, D. R.; Benbow, J. W.; McNutt, J. G.; Allen, E. E.
J. Org. Chem. 1995, 60, 833.
14. (a) Doyle, M. P.; Shanklin, M. S.; Oon, S. M.; Pho, H. Q.; van
der Heide, F. R.; Veal, W. R. J. Org. Chem. 1988, 53, 3384. (b)
Doyle, M. P.; Tauton, J.; Pho, H. Q. Tetrahedron Lett. 1989, 30,
5397.
15. Malherbe, R.; Dahn, H. Helv. Chim. Acta 1974, 57, 2492.
16. House, H. O.; Fisher, W. F.; Gall, M.; McLaughlin, T. E.; Pect,
N. P. J. Org. Chem. 1971, 36, 3429.
6. 1,3-Dipolar Cycloaddition Chemistry, Padwa, A., Ed.; Wiley-
Interscience: New York, 1984.
17. Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.;
Terrell, R. J. Am. Chem. Soc. 1963, 85, 207.
7. (a) Padwa, A.; Carter, S. P.; Nimmesgern, H.; Stull, P. J. Am.
Chem. Soc. 1988, 110, 2894. (b) Padwa, A.; Weingarten, M. D.
Chem. Rev. 1996, 96, 223.
18. Dean, D. C.; Krumpe, K. E.; Padwa, A. J. Chem. Soc., Chem.
Commun. 1989, 921.
8. Inayama, S.; Ohkura, T.; Kawamata, T.; Yanagita, M. Chem.
Pharm. Bull. 1974, 22, 1435.
19. Lottes, A.; Landgreb, J. A.; Larsen, K. Tetrahedron Lett. 1989,
30, 4089.
9. Bohlmann, F.; Zdero, C. Chem. Ber. 1974, 107, 1409.
10. Ochi, M.; Miura, I.; Tokoroyama, T. J. Chem. Soc., Chem.
Commun. 1981, 100.
20. Sheldrick, M. shelx-97, Program for the solution of crystal
È
structures; University of Gottingen, Germany, 1997.