π-Facial Diastereoselection in [3 + 2]-Cycloadditions of Isomuenchnone Dipoles

Article abstract of DOI:10.1021/jo970625o

The Rh(II)-catalyzed reaction of 1-[diazo(methoxycarbonyl)acetyl]-2-oxopyrrolidine derivatives led to the formation of ring-fused isomuenchnone betaines which are trapped with various dipolarophiles to give the corresponding [3 + 2]-cycloadducts in excellent yield. The cycloaddition reaction proceeded with high levels of diastereoselectivity leading to the predominant formation of the exo dipolar cycloadduct. The influence of substituents on the stereoselectivity of the reaction was investigated. Diastereotopic facial selectivity by the dipolarophile on the mesoionic betaine was found to depend upon the nature of the stereogenic center. Inclusion of substituents at any position of the fused five-membered ring was found to enhance exo selectivity. Isomuenchnone dipoles derived from pyrrolidinones containing a carboalkoxy substituent in the 5-position of the ring afforded mainly exo-syn cycloadducts. In contrast, when a methyl group was present at the 3-position of the pyrrolidinone ring, the facial selectivity was reversed with the exo-anti adduct being the major product. A computational study was carried out to rationalize the observed product distribution.

Full text of DOI:10.1021/jo970625o

6842
J . Org. Chem. 1997, 62, 6842-6854
π-F a cia l Dia ster eoselection in [3 + 2]-Cycloa d d ition s of
Isom u1 n ch n on e Dip oles
Albert Padwa* and Michael Prein
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received April 7, 1997X
The Rh(II)-catalyzed reaction of 1-[diazo(methoxycarbonyl)acetyl]-2-oxopyrrolidine derivatives led
to the formation of ring-fused isomu¨nchnone betaines which are trapped with various dipolarophiles
to give the corresponding [3 + 2]-cycloadducts in excellent yield. The cycloaddition reaction
proceeded with high levels of diastereoselectivity leading to the predominant formation of the exo
dipolar cycloadduct. The influence of substituents on the stereoselectivity of the reaction was
investigated. Diastereotopic facial selectivity by the dipolarophile on the mesoionic betaine was
found to depend upon the nature of the stereogenic center. Inclusion of substituents at any position
of the fused five-membered ring was found to enhance exo selectivity. Isomu¨nchnone dipoles derived
from pyrrolidinones containing a carboalkoxy substituent in the 5-position of the ring afforded
mainly exo-syn cycloadducts. In contrast, when a methyl group was present at the 3-position of
the pyrrolidinone ring, the facial selectivity was reversed with the exo-anti adduct being the major
product. A computational study was carried out to rationalize the observed product distribution.
Developing methods that efficiently construct stere-
that the dipolar cycloaddition of isomu¨nchnones with
alkenes also occurred intramolecularly and that the
overall reaction represents an efficient way to synthesize
complex polyheterocyclic ring systems.14
ochemically rich polyheterocyclic ring systems are of
great interest in synthetic chemistry.1 In recent years,
much attention has been focused on reactions that affect
formation of heterocycles through [3 + 2]-cycloadditions.2
Among these, the dipolar cycloadditions of mesoionic
compounds occupy a uniquely important position due to
their synthetic as well as theoretical significance.3-10 Our
interest in the chemistry of mesoionic dipoles stems from
studies in our laboratory dealing with the rhodium(II)-
catalyzed reactions of R-diazo carbonyl compounds in the
presence of various heteroatoms.11 In earlier reports, we
showed that the isomu¨nchnone class of mesoionics can
easily be generated from the Rh(II)-catalyzed reaction of
R-diazo imides.12 This mesoionic dipole was found to
undergo cycloadditions with both electron-rich and elec-
tron-deficient dipolarophiles.13 We were able to show
Stereocontrolled 1,3-dipolar cycloadditions hold con-
siderable potential for the asymmetric synthesis of
complex heterocyclic molecules.15-17 One of today’s chal-
lenges in this field is to control the regio-, diastereo-, and
enantioselectivities of these reactions. Although some
synthetic equivalents of metalated dipoles have been
prepared, there are few examples known where Lewis
acids control the stereo- and/or regioselectivity of dipolar
cycloadditions21,22 as is typically encountered with Diels-
Alder chemistry.23 High stereochemical control in [3 +
2]-cycloadditions has generally been secured by the use
of chiral dipolarophiles18 or chiral dipoles.19,20 Most of
X Abstract published in Advance ACS Abstracts, September 15, 1997.
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S0022-3263(97)00625-7 CCC: $14.00 © 1997 American Chemical Society

[3 + 2]-Cycloadditions of Chiral Isomu¨chnone Dipoles
J . Org. Chem., Vol. 62, No. 20, 1997 6843
the available examples of asymmetric dipolar cycloaddi-
tions are limited to 1,3-dipoles such as nitrones,19 nitrile
oxides,24 or azomethine ylides.20 To the best of our
knowledge, there have been no reports concerning sub-
strate-controlled asymmetric 1,3-dipolar cycloadditions
using isomu¨nchnones as dipoles. Consequently, we initi-
ated a study designed to examine the extent to which an
asymmetric center on the mesoionic dipole can control
diastereoselective cycloaddition of ring-fused isomu¨nch-
nones with achiral dipolarophiles. In the present paper,
we report on the effect various substituents have on the
exo/endo and syn/anti selectivity of several isomu¨nchnone
betaines derived from cyclic amides.25
(18) For recent 1,3-dipolar cycloaddition reactions with chiral alk-
enes, see: (a) Olsson, T.; Stern, K.; Westman, G.; Sundell, S. Tetra-
hedron 1990, 46, 2473. (b) Ito, M.; Kibayashi, C. Tetrahedron 1991,
47, 9329. (c) Carruthers, W.; Coggins, P.; Weston, J . B. J . Chem. Soc.,
Chem. Commun. 1991, 117. (d) Takahashi, T.; Fujii, A.; Sugita, J .;
Hagi, T.; Kitano, K.; Arai, Y.; Koizzumi, T.; Shiro, M. Tetrahedron:
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trones, see: (a) Kiers, D.; Moffat, D.; Overton, K.; Tomanek, R. J . Chem.
Soc., Perkin Trans. 1 1991, 1041. (b) Brandi, A.; Cicchi, S.; Goti, A.;
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1991, 2, 1371. (d) McCraig, A. E.; Wightman, R. H. Tetrahedron Lett.
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Tamura, O. Helv. Chim. Acta 1994, 77, 554.
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ylides, see: (a) Padwa, A.; Chen, Y. Y.; Chiacchio, Y.; Dent, W.
Tetrahedron 1985, 41, 3529. (b) Deprez, P.; Royer, J .; Husson, H.-P.
Tetrahedron: Asymmetry 1991, 2, 1189. (c) Williams, R. M.; Zhai, W.;
Aldous, D. J .; Aldous, S. C. J . Org. Chem. 1992, 57, 6527. (d) Anslow,
A. S.; Harwood, L. M.; Phillips, H.; Watkin, D.; Wong, L. F. Tetrahe-
dron: Asymmetry 1991, 2, 1343. (e) Negron, G.; Roussi, G.; Zhang, J .
Heterocycles 1992, 34, 293. (f) Takano, S.; Moriya, M.; Ogasawara, K.
Tetrahedron: Asymmetry 1992, 3, 681. (g) Allway, P.; Grigg, R.
Tetrahedron Lett. 1991, 32, 5817. (h) Garner, P.; Dogan, O. J . Org.
Chem. 1994, 59, 4. (i) Kobach, M. E.; Fray, A. H.; Meyers, A. I. J . Am.
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E. J .; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J . Am. Chem. Soc. 1989,
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Resu lts a n d Discu ssion
The deprotonation of various pyrrolidinones with lithium
bis(trimethylsilyl)amide followed by reaction with dia-
zoethylmalonyl chloride12 was found to be a general and
high-yielding method for the preparation of the ester-
stabilized diazo compounds needed in this study. Using
this procedure, diazo imide 5 was prepared in a 80% yield
from pyrrolidin-2-one (4). The related acetyl-substituted
diazo imide 6 was synthesized by condensation of pyr-
rolidin-2-one with 2,2,6-trimethyl-4H-1,3-dioxin-4-one26
followed by a subsequent diazo transfer using methane-
sulfonyl azide (1.5 equiv) and triethylamine (2.0 equiv)27
in 81% overall yield (Scheme 1). Both of these diazo
imides were decomposed by heating in benzene in the
presence of an appropriate dipolarophile and a catalytic
quantity of rhodium(II) perfluorobutyro amidate
(Rh2(pfm)4). This choice of catalyst and solvent was found
to be the best set of conditions for the tandem cycliza-
tion-cycloaddition reaction since it gives a near quan-
titative yield of cycloadduct (g90%). Adduct ratios were
determined by careful integration of the 1H-NMR spectra
of the crude reaction mixture, and the results are shown
in Scheme 2. The endo cycloadducts exhibit a signal for
two aromatic protons at a field significantly higher (δ 7.13
ppm) than their exo counterparts (δ 7.23 ppm). In
addition, the exo cycloadducts possess a vicinal coupling
constant (J ) 6.6 Hz) for the two protons at the ring
fusion smaller than do the endo cycloadducts (J ) 8.4
Hz). This diagnostic difference in the NMR28 was en-
countered throughout the present study, and the stere-
ochemical assignment was further verified by an X-ray
analysis of one of the exo cycloadducts (vide infra). For
some of the minor cycloadducts we had to rely on an
analysis of trends in the NMR spectra in order to infer
the stereochemistry.
(25) Since submission of the manuscript for this paper, Harwood
and co-workers have reported on chirally templated isomu¨nchnone
dipolar cycloadditions. See: Angell, R.; Drew, M. G. B.; Fengler-Veith,
M.; Finch, H.; Harwood, L. M.; J ahans, A. W.; Tucker, T. T. Tetrahe-
dron Lett. 1997, 38, 3107. Angell, R.; Fengler-Veith, M.; Finch, H.;
Harwood, L. M.; Tucker, T. T. Tetrahedron Lett. 1997, 38, 4517. Drew,
M. G. B.; Fengler-Veith, M.; Harwood, L. M.; J ahans, A. W.
Tetrahedron Lett. 1997, 38, 4521.
(26) Sato, M.; Kanuma, N.; Kato, T. Chem. Pharm. Bull. 1982, 30,
1315.
(27) Regitz, M.; Hocker, J .; Leidhergergener, A. Organic Synthesis;
J ohn Wiley: New York, 1973; Collect. Vol. 4, p 179.
.
(24) (a) Curran, D. P. Advances in Cycloaddition; Curran, D. P., Ed.;
J AI Press: Greenwich, 1988; Vol. 1, pp 129-189. (b) Kanemasa, S.;
Tsuge, O. Heterocycles 1990, 30, 719. (c) Caramella, P.; Gru¨nanger,
P. In Nitrile Oxides and Imines; 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; J ohn Wiley & Sons: New York, 1984; Vol. 1, Chapter
3, pp 291-392.
(28) (a) Haddadin, M. J .; Kattarn, A. M.; Freeman, J . P. J . Org.
Chem. 1982, 47, 723. (b) Cava, M. M.; Pollack, N. M.; Manner, O. A.;
Mitchell, J . M. J . Org. Chem. 1971, 36, 3932.

6844 J . Org. Chem., Vol. 62, No. 20, 1997
Padwa and Prein
Ta ble 1. HOMO/LUMO En er gies a n d Or bita l
Coefficien ts
Sch em e 1
8 (X ) CO2Me)
HOMO LUMO HOMO LUMO HOMO LUMO
E (eV) -8.7 -0.9 -8.6 -0.9 -8.0 -0.5
0.70 0.30 0.70 0.35 0.67
9 (X ) COMe)
10 (X ) H)
C(1)
O(2)
C(3)
C(4)
N(5)
0.28
0.17
-0.73
-0.17
-0.17
-0.39
0.16
-0.72
-0.18
-0.18
-0.39
0.15
-0.72
-0.20
-0.21
-0.39
0.27
0.28
0.35
0.02
-0.39
-0.02
-0.42
0.06
-0.44
Sch em e 2
retical arguments.30 In order to probe the geometric
orientation and steric bulk of the substituent group X
with respect to the topography of the isomu¨nchnone
cycloaddition reaction, we carried out some molecular
orbital calculations. The mesoionic betaine intermediates
involved (i.e., 8-10) were optimized using the RHF/PM3
method, and the results are summarized in Table 1.
Almost identical values were obtained by carrying out
the calculations at the RHF/AM1 or ab initio RHF/3-21G
level. The fused mesoionic system adopts a planar
geometry. Both the HOMO and the LUMO show sig-
nificant contributions from N(5) and the carbonyl ylide
portion [C(1)-O(2)-C(3)], whereas C(4) corresponds to
a nodal point in the LUMO. The HOMO possesses the
largest orbital coefficient at C(3), while the LUMO is
polarized toward C(1) for all the mesoionic dipoles
examined. As expected, replacement of the hydrogen
atom in 10 with the electron-withdrawing acetyl (9) or
ester functionality (8) leads to a lowering of the HOMO
and LUMO energies (Table 1). The orbital coefficients
at the reactive centers are barely affected. The energies
of both of the transition states and corresponding prod-
ucts were also determined for the reaction of isomu¨nch-
nones 8-10 with N-methylmaleimide and were modeled
at the RHF/AM1 and RHF/PM3 level using the Spartan
software package.31 A concerted transition state model
based on a linear synchronous transit (LST)32 was used
as the initial input for the transition state geometry. Only
one transition state was located for each reaction and was
confirmed as a saddle point on the basis of frequency
analysis. Regardless of the method, the optimized ge-
ometries show nearly synchronous bond formation, con-
sistent with a concerted reaction. The calculated inter-
atomic distances for the newly formed bonds are listed
in Table 2 and generally show little variation.
Kinetically controlled [4 + 2]-cycloadditions generally
lead to the initial formation of the endo diastereomer29
which often can be equilibrated to the thermodynamically
more stable exo isomer. In keeping with previous studies
of Diels-Alder cycloaddition reactions, it was assumed
that the product distributions were kinetic. Experimen-
tal confirmation was provided by heating the dipolar
adducts above the cycloaddition temperature. In no
instance was there a hint of thermal equilibration. This
result establishes that the 1,3-dipolar cycloaddition is not
reversible under the reaction conditions used. In all of
the cycloadditions, the dipolarophile reacts preferentially
in an exo manner. However, the nature of the activating
group X present on the mesoionic dipole can subtly affect
the exo/endo ratio. Thus, the acetyl-substituted diazo
imide 6 exhibits an exo preference lower than both the
diazo imide ester 5 and the unsubstituted system 7.
Clearly, an all-embracing explanation that accounts for
the variation in ratio is not obvious.
The MO calculations suggest a slightly higher degree
of asymmetry for the exo transition states, but the
variation is quite small. The calculated difference in
transition state energies (Hqrel (Table 2)) reflects the low
exo/endo ratio observed for the keto system 9, but tends
to overemphasize the exo preference for the hydrogen-
substituted system 10. The ground state energies for the
(30) (a) Houk, K. N.; Moses, S. R.; Wu, Y. D.; Rondan, N. G.; J ager,
V.; Shohe, R.; Fronczek, F. R. J . Am. Chem. Soc. 1984, 106, 3880. (b)
Kahn, S. D.; Hehre, W. J . J . Am. Chem. Soc. 1987, 109, 663.
(31) Spartan version 4.0; copyright 1995; Wavefunction, Inc.
(32) Halgren, T. A.; Lipscomb, W. N. Chem. Phys. Lett. 1977, 49,
225.
Attempts to rationalize the relative topical preference
of [4 + 2]-cycloaddition reactions generally involve theo-
(29) Lee, M. W.; Herndon, W. C. J . Org. Chem. 1978, 43, 518.

[3 + 2]-Cycloadditions of Chiral Isomu¨chnone Dipoles
J . Org. Chem., Vol. 62, No. 20, 1997 6845
Ta ble 2. Ca lcu la ted Tr a n sition Sta te P a r a m eter s for th e Cycloa d d ition of Isom u1 n ch n on es 8-10
8 f 11 (X ) CO2Me)
exo endo
9 f 12 (X ) COMe)
exo endo
10 f 13 (X ) H)
exo endo
Hq (AM1)a
0
0.8
0
0.1
0
2.9
rel
d (C(1)-C(1′)) (Å)
d (C(3)-C(2′)) (Å)
Hrel (AM1)b
2.19
2.29
0
2.21
2.26
-0.2
1.1
2.19
2.29
0
2.20
2.26
-0.1
0.7
2.29
2.41
0
2.24
2.37
1.5
Hq (PM3)a
0
0
0
2.4
rel
d (C(1)-C(1′)) (Å)
d (C(3)-C(2′)) (Å)
Hrel (PM3)b
2.21
2.36
0
2.23
2.32
1.4
2.22
2.36
0
2.24
2.32
1.2
2.12
2.59
0
2.15
2.51
2.4
a
b
Transition state energy relative to the respective exo isomer in kcal/mol. Ground state energies of the cycloadducts 11-13 relative
to the respective exo isomer in kcal/mol.
Sch em e 3a
exo/endo cycloadducts 11-13 were also determined (Table
2). While the PM3 method predicts that the exo isomer
is more stable regardless of substitution, the energy
differences are quite small when the AM1 Hamiltonian
was used. Both semiempirical methods indicate that the
exo isomer should be formed preferentially in a kinetically
controlled process, which is in good agreement with the
experimental findings. The qualitative agreement of the
MO calculations with the experimental results for the
isomu¨nchnone reaction stands in contrast to the related
cycloaddition chemistry of mu¨nchnones,33 where semiem-
pirical methods failed to account for the regio- and
stereochemical findings.34
π-Facial selectivity in [4 + 2]-cycloadditions arises
when the addends possess two diastereotopic reactive
faces. Frequently, the presence of at least one center of
chirality imparts sufficient perturbation to influence the
diasterofacial selectivity.30 Incorporation of a stereogenic
center in the pyrrolidinone ring would be expected to
exert a significant directing effect on these isomu¨nchnone
cycloadditions. Important factors that will need to be
considered to rationalize the stereochemical outcome will
include steric effects, complexation between the dipole
and dipolarophile, secondary orbital interactions includ-
ing tilting and torsional effects, as well as polarizability
and electrostatic interactions. Prior to the present study,
no experimental evidence was available concerning π-fa-
cial selectivity in isomu¨nchnone cycloadditions. The first
system we examined involved diazo imide 16 which was
prepared in 65% yield from 3-methylpyrrolidin-2-one (14)
by malonation12 and subsequent diazo transfer. Treat-
ment of 16 with Rh2(pfm)4 in the presence of N-phenyl-
maleimide afforded a single diastereomer (90%) whose
structure was assigned as the exo-anti 20 isomer. The
other possible diastereomers were present only in trace
amounts (e5%) and could not be isolated (Scheme 3).
a
Reagents: (a) amide 14, LiN(SiMe3)2, EtO2CC(N2)COCl; (b)
amide 15, MeO2CCH2COCl, ∆; (c) p-NO2C6H4SO2N3, NEt3.
The absence of endo cycloadducts is probably related
to an unfavorable steric interaction in the transition state
for their formation. Anti attack by the dipolarophile is
to be expected due to steric interaction of the incoming
dipolarophile with the methyl group at C(3), which
shields the syn face. This rationale is consistent with
the MO calculations. Thus, the optimized exo-anti
transition state for the reaction of 18 with N-methylma-
leimide is favored over the exo-syn structure by 1.9 kcal/
mol (AM1) [2.7 kcal/mol (PM3)]. The transition state
energies reflect the relative stability of the exo cycload-
ducts, for which a ∆H of 1.1 kcal/mol (AM1) [1.4 kcal/
mol (PM3)] in favor of the exo-anti adduct was calcu-
lated.
Stereoelectronic effects of polar functional groups on
π-facial selectivity in Diels-Alder reactions have at-
tracted considerable attention in recent years.35-37 In a
few of these cycloadditions, the dienophile reacts pref-
erentially with the more sterically hindered synface of
the diene.38 In order to probe whether the stereochemical
(33) (a) Maryanoff, C. A.; Turchi, I. J . Heterocycles 1993, 35, 649.
(b) Coppola, B. P.; Noe, M. C.; Schwartz, D. J .; Abdon, R. L. H.; Trost,
B. M. Tetrahedron 1994 50, 93.
(34) Avalos, M.; Babiano, R.; Cabanillas, A.; Cintas, P.; J ime´nez, J .
L.; Palacios, J . C.; Aguilar, M. A.; Corchado, J . C.; Espinosa-Garc´ıa, J .
J . Org. Chem. 1996, 61, 7291. The same group, however, has been
more successful applying MO calculations to cycloaddition reactions
of thioisomu¨nchnones; see: Avalos, M.; Babiano, R.; Dia´nez, M. J .;
Espinosa, J .; Estrada, M. D.; J ime´nez, J . L.; Lo´pez-Castro, A.; Me´ndez,
M. M.; Palacios, J . C. Tetrahedron 1992, 48, 4193.

6846 J . Org. Chem., Vol. 62, No. 20, 1997
Padwa and Prein
Sch em e 4a
Sch em e 5
Sch em e 6
a
Reagents: (a) amides 22-25, LiN(SiMe3)2, THF, -78 °C,
EtO2CC(N2)COCl; (b) amide 26, CH3O2CCH2COCl, ∆, MsN3, NEt3;
(c) 2,2,6-trimethyl-1,3-dioxin-4-one, ∆, MsN3, NEt3; (d) Rh2(pfm)4,
N-phenylmaleimide.
course of isomu¨nchnone cycloadditions could be altered
by electronic interaction with polar substituents, we
prepared diazo ester 17 from the readily available
2-oxopyrrolidine-3-carboxylic acid methyl ester39 (15)
(Scheme 3). To our surprise, none of the expected dipolar
cycloadduct was formed when 17 was treated with
Rh2(pfm)4 in the presence of N-phenylmaleimide. In-
stead, the acidic proton at C(3) in the isomu¨nchnone
intermediate 19 was transferred, and the fused oxazoli-
dinone 21 was isolated in 77% yield (Scheme 3).
We next turned our attention to the Rh(II)-catalyzed
reaction of several diazo imides derived from 5-substi-
tuted pyrrolidin-2-ones. The stereogenic center in the
isomu¨nchnone dipole generated from this system is
further removed from the reacting dipole, and thus a
lesser steric effect is to be expected in the [3 + 2]-cy-
cloaddition reaction. Chiral diazo imides 27-32 were
prepared in good yield from readily available precursors.
The Rh(II)-catalyzed decomposition of 27-32 in benzene
in the presence of both cyclic (Scheme 4) and acyclic
(Schemes 5 and 6) dipolarophiles resulted in the forma-
tion of the expected cycloadducts in nearly quantitative
yield. Product distribution and yields are summarized
in Table 3. The major product obtained in all cases
corresponded to the exo cycloadduct. The Rh(II)-cata-
lyzed decomposition of the methyl-substituted derivative
27 afforded a 58:42 mixture of the syn/anti exo cycload-
ducts 33. This result is not totally unexpected, since
steric interaction of the incoming dipolarophile with the
methyl group at C(5) is not significant for an exo
transition state, and therefore, discrimination between
the two diastereotopic faces is poor.
Fortunately, the situation changes when an ester group
is located at the C(5) position. The reaction of diazo
imides 28-32 with Rh2(pfm)4 and N-phenylmaleimide in
refluxing benzene resulted in the formation of cycload-
ducts 34-35 and 39-41 with nearly complete exo/endo
selectivity as well as high π-facial selectivity. NMR
analysis of the crude reaction mixture indicated a near
quantitative yield of cycloadducts, with one of the two
exo adducts being formed as the dominant product in 90%
isolated yield. Endo cycloadducts were formed in less
than 3% yield. In view of the fact that the 5-methyl-
substituted isomu¨nchnone 27 did not discriminate be-
tween the two diastereotopic faces, the high stereoselec-
tivity encountered with the ester-substituted analog is
(35) (a) McDougal, P. G.; Rico, J . G.; VanDerveer, D. J . Org. Chem.
1986, 51, 4492. (b) Reitz, A. B.; J ordan, A. D., J r.; Maryanoff, B. E. J .
Org. Chem. 1987, 52, 4800.
(36) (a) Tripathy, R.; Franck, R. W.; Onan, K. D. J . Am. Chem. Soc.
1988, 110, 3257. (b) Adam, W.; Gla¨ser, J .; Peters, K.; Prein, M. J .
Am. Chem. Soc. 1995, 117, 9190.
(37) (a) Macaulay, J . B.; Fallis, A. G. J . Am. Chem. Soc. 1990, 112,
1136. (b) Ishida, M.; Aoyama, T.; Beniya, Y.; Yamabe, S.; Kato, S.;
Inagaki, S. Bull. Chem. Soc. J pn. 1993, 66, 3430. (c) Ishida, M.;
Beniya, Y.; Inagaki, S.; Kato, S. J . Am. Chem. Soc. 1990, 112, 8980.
(d) Coxon, J . M.; McDonald, D. G. Tetrahedron Lett. 1992, 33, 651. (e)
Ishida, M.; Kakita, S.; Inagaki, S. Chem. Lett. 1995, 469.
(38) Datta, S. C.; Franck, R. W.; Tripathy, R.; Quigley, G. J .; Huang,
L.; Chen, S.; Sihaed, A. J . Am. Chem. Soc. 1990, 112, 8472.
(39) (a) Lindstrom, K. L.; Crooks, S. L. Synth. Commun. 1990, 20,
2335. (b) Khouki, M.; Vaultier, M.; Carr´ıe, R. Tetrahedron Lett. 1986,
27, 1031.

[3 + 2]-Cycloadditions of Chiral Isomu¨chnone Dipoles
J . Org. Chem., Vol. 62, No. 20, 1997 6847
Ta ble 3. P r od u ct Distr ibu tion in th e Cycliza tion -Cycloa d d ition Sequ en ce of Dia zo Im id es 27-32
substrate
Y
X
dipolarophilea
product
yield (%)
exo/endo
syn/anti
27
28
29
29
29
29
29
29
29
30
31
32
Me
CO2Et
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
Me
NPM
NPM
NPM
NMM
MA
1,4-NQ
TCNE
MVK
1,1-DEE
NPM
NPM
NPM
33
34
35
36
37
38
42
43
44
39
40
41
86
85
g95:5
g95:5
g95:5
g95:5
g95:5
g95:5
58:42b
83:17
90:10
90:10
90:10
84:16
77:23
65:35d
65:35
85:15
87:13
88:12d
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
CO2allyl
CO2CH2Ph
CO2-t-Bu
84
74c
79c
80
74c
82
79:21
83
75c
91
g95:5
g95:5
92:8
95
a
NPM ) N-phenylmaleimide; NMM ) N-methylmaleimide; MA ) maleic anhydride; 1,4-NQ ) 1,4-naphthoquinone; TCNE )
tetracyanoethylene; MVK ) methyl vinyl ketone; 1,1-DEE ) 1,1-diethoxyethene. The stereochemistry was not assigned. c Only the major
cycloadduct was isolated. Syn/anti ratio of the exo cycloadducts.
b
d
quite surprising. The unexpected syn preference was
unambiguously established by an X-ray analysis of
cycloadduct 35.40
ical assignment was established by an acid-catalyzed
rearrangement to give the fused bicyclic anti/syn ring-
opened lactam 45. Although the exo/endo stereochemical
assignment is lost in the acid-catalyzed rearrangement,
the anti/syn selectivity is reflected in the anti/syn ratio
of lactam 45. Formation of the same lactam from the
minor exo adduct and the endo diastereomer indicates
that both cycloadducts are derived from anti attack of
the dipolarophile on the isomu¨nchnone intermediate.
The nature of the ester group present at the 5-position
of the pyrrolidinone ring showed little effect on the degree
of diastereoselectivity, with the bulky tert-butyl ester 29
giving the best results. The cycloaddition reaction of
benzyl ester 31 was examined in order to test the
possiblity of π-stacking between the phenyl ring and the
mesoionic system as a controlling factor, but no unusual
effect was encountered. Interestingly, in the case of allyl
ester 30, intramolecular cycloaddition across the olefinic
π-bond did not compete with bimolecular cycloaddition.
The scope and generality of the syn-directing effect of
the ester group was established from a study of the
cycloaddition of the tert-butyl ester 29 with a series of
dipolarophiles (Schemes 4-6). High yields of the dipolar
cycloadducts were obtained using electron-deficient (ma-
leic anhydride, tetracyanoethylene, 1,4-naphthoquinone,
methyl vinyl ketone) and electron-rich (1,1-diethoxyeth-
ylene) π-bonds. The regioselectivity observed using
methyl vinyl ketone (Scheme 6) or 1,1-diethoxyethylene
(Scheme 5) is consistent with FMO considerations.41 The
same stereochemical outcome was encountered for all the
[3 + 2]-cycloadditions examined, regardless of the reac-
tion partner. When unsymmetrical dipolarophiles were
used, the exo adduct was formed in preference to the endo
cycloadduct, which was only produced in trace quantities.
A syn/anti ratio of ca. 9:1 was observed in all cases, in
agreement with the results encountered when N-phenyl-
maleimide was used as the trapping reagent (Table 3).
However, with methyl vinyl ketone, a 51:28:21 mixture
of cycloadducts 44 was formed, with one of the diaster-
eomers corresponding to the endo cycloadduct. The major
exo adduct was assigned the syn stereochemistry in
accordance with its NMR spectrum. Formation of the
endo isomer occurs by anti attack of the dipolarophile
on the mesoionic betaine intermediate. This stereochem-
The above result is not surprising in view of the
transition state geometry of the cycloaddition reaction.
Exo approach of the dipolarophile proceeds with minimal
steric interaction with the substituent group at C(5). The
presence of the ester group promotes reaction at the
sterically more hindered syn face of the dipole. Possible
explanations to account for this syn selectivity involve
favorable secondary orbital interactions,42 electrostatic
attraction,30 or a Cieplak effect,43 in which face selectivity
is determined by a transition state bonding interaction
between a developing σ* orbital and the carboalkoxy
group. The endo-syn trajectory is severely hindered by
steric interaction of the acetyl group of methyl vinyl
ketone with the ester functionality at C(5), and therefore,
the endo-anti cycloadduct is the only endo isomer
formed. The lower π-facial selectivity encountered with
1,1-diethoxyethene (i.e., 43) (Scheme 4) probably origi-
nates from related steric interactions in the transition
state. This dipolarophile encounters an unfavorable
steric interaction in the syn transition state between the
ester functionality and the ethoxy group. Another factor
that may operate when 1,1-diethoxyethylene is used is
that the cycloaddition may be subject to a stereoelectronic
effect. The mesoionic dipole behaves as an electrophile
in the reaction with 1,1-diethoxyethylene, and the elec-
tronic factors that result in a syn preference with
electron-deficient dipolarophiles are no longer effective
in a “type III dipole controlled” process.41
(40) The authors have deposited atomic coordinates for cycloadduct
35 with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Centre, 12 Union Road, CB2 1EZ, UK.
(42) (a) Gleiter, R.; Ginsburg, D. Pure Appl. Chem. 1979, 51, 1301.
(b) Ginsburg, D. Tetrahedron 1983, 39, 2095.
(43) (a) Cieplak, A. S. J . Am. Chem. Soc. 1981, 103, 4540. (b)
Cieplak, A. S.; Tait, B. D.; J ohnson, C. R. J . Am. Chem. Soc. 1989,
111, 8447.
(41) Padwa, A.; Hertzog, D. L. Tetrahedron 1993, 49, 2589.

6848 J . Org. Chem., Vol. 62, No. 20, 1997
Padwa and Prein
Sch em e 7a
Ta ble 4. Rela tive Tr a n sition Sta te a n d P r od u ct
En er gies for th e Rea ction of 46 a n d N-Meth ylm a leim id ea
exo-syn
exo-anti
endo-syn
endo-anti
Hq (AM1)b
0
0
0
0
0.7
0.4
0.1
1.6
2.4
0.4
2.3
1.3
1.3
0.4
1.2
3.1
rel
a
Hrel (AM1)c
Reagents: (a) CH3O2CCH2COCl, ∆; (b) MsN3, NEt3.
Hq (PM3)b
rel
ical preferences are the consequence of a product-like
transition state. One possible explanation for the un-
usual contrasteric syn-directing effect of the ester group
is that the syn face of the dipole exhibits enhanced
electron density which is attributable to the electron-
accepting ester functionality residing on this face. Such
stereoelectronic effects have been invoked previously to
explain π-facial selectivity in Diels-Alder cycloadditions
as well as various electrophilic additions to π-systems.46
On the other hand, when the structure of the mesoionic
dipole or dipolarophile results in the formation of endo
adducts, steric control is the dominant factor and the anti
adduct becomes the preferred diastereomer. The general
order (exo-syn > exo-anti > endo-anti > endo-syn) is
nicely reflected in the calculated transition state energies
using semiempirical methods.
We also examined the tandem cyclization-cycloaddi-
tion chemistry of chiral diazo imides 50 and 51 which
were readily prepared from pyrrolidinones 48 and 49
(Scheme 7).47,48 In this case, placement of a substituent
group at C(4) would be expected to result in modest
π-facial selectivity, since the stereogenic center is too far
removed from the dipole site to efficiently direct dipo-
larophile attack either via steric or electronic interac-
tions. Indeed, the Rh(II)-catalyzed decomposition of 50
in the presence of N-methylmaleimide or N-phenylma-
leimide afforded a 2:1 mixture of two exo cycloadducts.
In view of the low diastereoselectivity, the relative
configuration of the two products (52 and 53) was not
established, but more than likely the major diastereomer
stems from attack of the dipolarophile on the sterically
less congested anti face of the isomu¨nchnone dipole. The
ester-substituted diazo imide 51 showed even lower
π-facial selectivity with N-methylmaleimide (45:55). Pre-
sumably, the weak syn-directing effect of the ester group
counteracts steric interactions in the transition state,
thereby resulting in a relatively unselective reaction.
Hrel (PM3)c
a
Calculated by RHF/PM3 or RHF/AM1 using the Spartan
b
program package. Transition state energies relative to the
respective exo-syn isomer in kcal/mol. c Ground state energies of
the cycloadducts 47 relative to the respective exo-syn isomer in
kcal/mol.
More than likely, this mechanistic analysis also holds
for the cycloaddition reaction of the acetyl-substituted
diazoimido ester 32. As was previously observed for
achiral substrates, the acetyl-stabilized isomu¨nchnone
shows a reduced exo/endo selectivity compared to its ester
analog 29. In addition to the formation of two exo
cycloadducts 41 (syn/anti ) 88:12), the endo-anti isomer
was also obtained, but only in 8% yield. The above
examples clearly demonstrate that an ester functionality
at C(5) acts as a stereodirecting group which guides the
incoming dipolarophile to the sterically more congested
syn face of the isomu¨nchnone dipole. It should be noted
that a related syn-directing effect of ester groups has been
observed in several enolate alkylations44 as well as Diels-
Alder reactions.45 This effect, however, is unprecedented
in dipolar cycloaddition chemistry. Consequently, a
computational study was initiated to rationalize the
observed product distribution. The geometry of the four
possible diastereomeric transition states from the reac-
tion of isomu¨nchnone 46 with N-methylmaleimide was
optimized using both RHF/AM1 and RHF/PM3 methods.
The relative energies are given in Table 4.
The calculated AM1 transition state energies nicely
reflect the experimental observations. Although the PM3
Hamiltonian correctly predicts the exo selectivity, it fails
to account for the observed syn preference in the exo
transition state. It should be noted that the ground state
energies of the cycloadducts do not correlate with the
observed experimental diastereoselectivities. This ob-
servation eliminates the argument that the stereochem-
(44) (a) Graham, C. L.; McQuillin, F. J . J . Chem. Soc. 1963, 4634.
(b) Bottom, F. H.; McQuillin, F. J . Tetrahedron Lett. 1967, 1975. (c)
Rao, H. S. P.; Reddy, K. S.; Balasubrahmanyam, S. N. Tetrahedron
Lett. 1994, 35, 1759.
(45) Sihida, M.; Tomohiro, S.; Shimzu, M.; Inagaki, S. Chem. Lett.
1995, 739.
(46) (a) Fisher, M. J .; Hehre, W. J .; Kahn, S. D.; Overman, L. E. J .
Am. Chem. Soc. 1988, 110, 4625. (b) Wu, Y.-D.; Li, Y.; Houk, K. N. J .
Am. Chem. Soc. 1993 58, 4625.
(47) Gutsche, C. D.; Tao, I. Y. C. J . Org. Chem. 1967, 32, 1778.
(48) Wu, Y.-H.; Feldkamp, R. F.; Corrigan, J . R.; Rhodes, H. J . J .
Org. Chem. 1961, 26, 1524.

[3 + 2]-Cycloadditions of Chiral Isomu¨chnone Dipoles
J . Org. Chem., Vol. 62, No. 20, 1997 6849
2-one (14) (700 mg, 7.1 mmol) and ethyldiazomalonyl chloride
(1.4 g, 7.8 mmol) were allowed to react according to the general
procedure. Flash silica gel chromatography of the crude
residue gave 1.43 g (85%) of 16 as a bright yellow oil: IR (neat)
2138, 1732, 1651, 1125, 1029, and 878 cm-1; 1H-NMR (CDCl3,
300 MHz) δ 1.20 (d, 3H, J ) 5.7 Hz), 1.26 (t, 3H, J ) 7.2 Hz),
1.60-1.74 (m, 1H), 2.21-2.32 (m, 1H), 2.54-2.67 (m, 1H), 3.67
(ddd, 1H, J )11.1, 9.6, and 7.2 Hz), 3.81 (ddd, 1H, J ) 11.1,
8.4, and 2.7 Hz), and 4.23 (q, 2H, J ) 7.2 Hz); 13C-NMR (CDCl3,
75 MHz) δ 14.2, 15.2, 26.4, 38.6, 44.1, 61.6, 160.9, 161.0, and
176.5; HRMS calcd for C10H13N3O4Li (M + Li)+ 246.1066, found
246.1073.
In conclusion, the present study has helped define the
stereochemical issues associated with the 1,3-dipolar
cycloaddition of ring-fused isomu¨nchnones. Exo transi-
tion states are generally preferred and the highest
selectivities encountered occur when the reactive dipole
contains an ester functionality. The inclusion of substit-
uents at any position of the fused five-membered ring
was found to enhance exo selectivity. Synthetically useful
π-facial selectivities were achieved by incorporating a
stereogenic center adjacent to C(2) of the dipole. Inter-
estingly, a contrasteric syn addition of the dipolarophile
occurred when an ester group was located adjacent to the
nitrogen atom of the mesoionic ring system. The experi-
mental results are reflected in the calculated transition
state energies using semiempirical FMO methods. Ex-
periments to determine the stereodirecting features of
other substituents and to exploit the methodology in the
stereocontrolled synthesis of chiral azapolycyclic systems
are presently underway in our laboratories.
1-[(Met h oxyca r b on yl)a cet yl]-2-oxop yr r olid in e-3-ca r -
boxylic Acid Meth yl Ester . A sample of 2-oxopyrrolidine-
3-carboxylic acid methyl ester (15)39 (3.0 g, 21.0 mmol) and
methylmalonyl chloride (3.2 g, 23.1 mmol) were allowed to
react according to the general procedure for 5 h. Flash silica
gel chromatography of the crude residue gave 4.68 g (92%) of
the corresponding malonate as a colorless oil: IR (neat) 2951,
1
1733, 1690, 1435, 1151, and 990 cm-1; H-NMR (CDCl3, 300
MHz) δ 2.29-2.47 (m, 2H), 3.62 (dd, 1H, J ) 9.0 and 8.1 Hz),
3.71 (s, 3H), 3.79 (s, 3H), 3.82 (d, 1H, J ) 13.8 Hz), 3.93-4.09
(m, 2H), and 3.97 (d, 1H, J ) 13.8 Hz); 13C-NMR (CDCl3, 75
MHz) δ 21.1, 43.5, 50.0, 52.1, 52.7, 165.9, 167.0, 168.4, and
170.4; HRMS calcd for C10H14NO6 (M + H)+ 244.0821, found
244.0816.
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed under an atmosphere of dry argon
in flame-dried glassware. Solutions were evaporated under
reduced pressure with a rotary evaporator, and the residue
was chromatographed on a silica gel column using an ethyl
acetate-hexane mixture as the eluent unless specified other-
wise. Methanesulfonyl azide and p-nitrobenzenesulfonyl azide
were prepared according to previously published procedures.49
Due to a very long relaxation time, the resonance for the
carbon atom next to the diazo functional group was usually
not detected for the diazo imides prepared in this study.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of r-Dia zo
Im id es. To a solution of the appropriate lactam (5.0 mmol)
in THF (30 mL) was added lithium bis(trimethylsilyl)amide
(1.0 equiv, 1.0 M in hexane) at -78 °C. The mixture was
stirred at -78 °C for 30 min, and ethyldiazomalonyl chloride12
(5.0 mmol) was added via syringe. The mixture was stirred
at -78 °C for 10 min and allowed to warm to rt. Evaporation
of the solvent afforded the crude diazo imide as orange oil,
which was purified by silica gel column chromatography. An
alternate method that was used involved heating a solution
of the appropriate lactam (5.0 mmol) with methylmalonyl
chloride (1.5 equiv) in benzene (30 mL) at reflux for 2.5-6 h.
Evaporation of the solvent afforded the crude malonate as a
colorless oil, which was purified by silica gel column chroma-
tography. To a solution of the above malonate (2.0 mmol) in
dichloromethane (25 mL) was added either mesyl azide or
p-methylbenzenesulfonyl azide (1.1-1.5 equiv) and triethy-
lamine (1.0-2.0 equiv). The mixure was stirred at rt for 2 h,
and the insoluble precipitate that had formed in the reaction
was removed by filtration. The solvent was removed under
reduced pressure to give the diazo imide, which was purified
by silica gel column chromatography.
1-[Dia zo(m et h oxyca r b on yl)a cet yl]-2-oxop yr r olid in e-
3-ca r boxylic Acid Meth yl Ester (17). To a solution of the
above malonate (1.4 g, 5.8 mmol) in dichloromethane (40 mL)
at -10 °C was added p-nitrobenzenesulfonyl azide (2.0 g, 8.6
mmol) and triethylamine (1.2 g, 11.5 mmol). The mixture was
stirred at -10 °C for 1 h and was stored at -20 °C overnight.
The precipitate that had formed was filtered, and the solvent
was removed under reduced pressure. The residue was
subjected to flash silica gel chromatography to give 980 mg
(63%) of diazo imide 17 as a bright yellow oil: IR (neat) 2135,
1
1756, 1697, 1646, 1041, and 750 cm-1; H-NMR (CDCl3, 300
MHz) δ 2.16-2.31 (m, 2H), 3.52 (dd, 1H, J ) 9.0 and 7.8 Hz),
3.63 (s, 3H), 3.64 (s, 3H), and 3.66-3.79 (m, 2H); 13C-NMR
(CDCl3, 75 MHz) δ 21.5, 44.3, 49.5, 52.2, 52.4, 70.0, 159.9,
160.9, 168.3, and 168.8; HRMS calcd for C10H12N3O6 (M + H)+
270.0726, found 270.0737.
2-Dia zo-3-(2-m eth yl-5-oxop yr r olid in -1-yl)-3-oxop r op i-
on ic Acid Eth yl Ester (27). A sample of 5-methylpyrrolidin-
2-one (22) (730 mg, 7.4 mmol) and ethyldiazomalonyl chloride
(1.4 g, 8.1 mmol) were allowed to react according to the general
procedure. Flash silica gel chromatography of the crude
residue gave 1.49 g (85%) of 27 as a bright yellow oil: IR (neat)
2139, 1733, 1652, 1371, 1133, and 1017 cm-1; 1H-NMR (CDCl3,
300 MHz) δ 1.22 (t, 3H, J ) 7.2 Hz), 1.27 (d, 3H, J ) 6.0 Hz),
1.59-1.69 (m, 1H), 2.15-2.25 (m, 1H), 2.34-2.53 (m, 2H), 4.18
(q, 2H, J ) 7.2 Hz), and 4.28-4.34 (m, 1H); 13C-NMR (CDCl3,
75 MHz) δ 14.0, 19.7, 25.9, 31.4, 54.1, 61.4, 71.3, 160.9, 161.3,
and 174.3. Anal. Calcd for C10H13N3O4: C, 50.21; H, 5.48; N,
17.56. Found: C, 49.91; H, 5.39; N, 17.55.
1-[Dia zo(et h oxyca r b on yl)a cet yl]-5-oxop yr r olid in e-2-
ca r boxylic Acid Eth yl Ester (28). A sample of 5-oxopyr-
rolidine-2-carboxylic acid ethyl ester (23) (880 mg, 5.6 mmol)
and ethyldiazomalonyl chloride (990 mg, 5.6 mmol) were
allowed to react according to the general procedure. Addition
of ethyl acetate to the crude mixture was followed by filtration
of the solution through a plug of silica gel. Evaporation of the
solvent gave 1.5 g (90%) of 28 as a yellow oil: IR (neat) 2129,
1752, 1652, 1197, and 1033 cm-1; 1H-NMR (CDCl3, 300 MHz)
δ 1.27 (t, 3H, J ) 7.2 Hz), 1.29 (t, 3H, J ) 7.2 Hz), 2.07-2.13
(m, 1H), 2.37-2.72 (m, 3H), 4.21 (m, 2H), 4.26 (q, 2H, J ) 7.2
Hz), and 4.71 (dd, 1H, J ) 8.7 and 3.9 Hz); 13C-NMR (CDCl3,
75 MHz) δ 13.9, 14.1, 21.9, 31.2, 58.6, 61.7, 61.8, 160.6, 170.5,
172.9, and 173.0; HRMS calcd for C12H16N3O6 (M + H)+
298.1039, found 298.1034.
2-Dia zo-3-(2-oxop yr r olid in -1-yl)-3-oxop r op ion ic Acid
Eth yl Ester (5). A sample of pyrrolidin-2-one (4) (1.04 g, 12.2
mmol) and ethyldiazomalonyl chloride (2.16 g, 12.2 mmol) were
allowed to react according to the general procedure. The crude
residue was subjected to flash silica gel chromatography to
give 2.2 g (80%) of 5 as a yellow oil: IR (neat) 2983, 2136,
1730, 1652, and 1126 cm-1; 1H-NMR (CDCl3, 300 MHz) δ 1.24
(t, 3H, J ) 7.2 Hz), 2.07 (m, 2H), 2.51 (t, 2H, J ) 7.8 Hz), 3.78
(t, 2H, J ) 7.2 Hz), and 4.20 (q, 2H, J ) 7.2 Hz); 13C-NMR
(CDCl3, 75 MHz) δ 14.1, 17.6, 32.6, 46.2, 61.5, 160.7, 160.9,
and 173.9. Anal Calcd. for C9H11N3O4: C, 48.00; H, 4.92; N,
18.66. Found: C, 48.06; H, 4.92; N, 18.65.
2-Dia zo-3-(4-m eth yl-5-oxop yr r olid in -1-yl)-3-oxop r op i-
on ic Acid Eth yl Ester (16). A sample of 3-methylpyrrolidin-
1-[Dia zo(et h oxyca r b on yl)a cet yl]-5-oxop yr r olid in e-2-
ca r boxylic Acid ter t-Bu tyl Ester (29). A sample of 5-ox-
opyrrolidine-2-carboxylic acid tert-butyl ester50 (24) (1.1 g, 6.0
(49) Reagan, M. T.; Nickon, A. J . Am. Chem. Soc. 1968, 90, 4096.
Taber, D. F.; Ruckle, R. E., J r.; Hennessy, M. J . J . Org. Chem. 1986,
51, 4077.
(50) Kolasa, T.; Miller, M. J . J . Org. Chem. 1990, 55, 1711.

6850 J . Org. Chem., Vol. 62, No. 20, 1997
Padwa and Prein
mmol) and ethyldiazomalonyl chloride (1.1 g, 6.0 mmol) were
allowed to react according to the general procedure. Evapora-
tion of the solvent gave 1.83 g (90%) of 29 as a yellow oil which
crystallized on standing: mp 97-98 °C; IR (KBr) 2136, 1759,
1723, 1645, and 1154 cm-1; 1H-NMR (CDCl3, 300 MHz) δ 1.36
(t, 3H, J ) 7.2 Hz), 1.49 (s, 9H), 2.02-2.09 (m, 1H), 2.36-2.69
(m, 3H), 4.29 (q, 2H, J ) 7.2 Hz), and 4.63 (dd, 1H, J ) 8.7
and 4.5 Hz); 13C-NMR (CDCl3, 75 MHz) δ 14.1, 21.9, 27.7, 31.2,
59.2, 61.6, 82.5, 160.5, 169.4, 172.9, and 173.0. Anal. Calcd
for C14H19N3O6: C, 51.69; H, 5.89; N, 12.92. Found: C, 51.43;
H, 5.86; N, 12.67.
according to the general procedure for 3 h at rt. Flash silica
gel chromatography of the crude residue gave 1.30 g (95%) of
32 as a viscous yellow oil: IR (neat) 2976, 2136, 1745, 1667,
and 1147 cm-1
;
1H-NMR (CDCl3, 300 MHz) δ 1.44 (s, 9H),
1.99-2.08 (m, 1H), 2.34-2.44 (m, 1H), 2.42 (s, 3H), 2.53-2.68
(m, 2H), and 4.62 (dd, 1H, J ) 8.7 and 5.1 Hz); 13C-NMR
(CDCl3, 75 MHz) δ 21.8, 27.8, 28.6, 31.5, 59.3, 82.8, 160.1,
169.5, 173.2, and 189.8. Anal. Calcd for C13H17N3O5: C, 52.88;
H, 5.80; N, 14.23. Found: C, 52.62; H, 5.79; N, 14.10.
3-(3-Meth yl-5-oxop yr r olid in -1-yl)-3-oxop r op ion ic Acid
Meth yl Ester . A mixture of 4-methylpyrrolidin-2-one (48)52
(2.2 g, 22 mmol) and methylmalonyl chloride (3.8 g, 28 mmol)
was allowed to react according to the general procedure for
2.5 h. Flash silica gel chromatography of the crude residue
gave 3.71 g (84%) of the desired imide as a colorless oil: IR
1-[Dia zo(et h oxyca r b on yl)a cet yl]-5-oxop yr r olid in e-2-
ca r boxylic Acid Allyl Ester (30). A sample of 5-oxopyrro-
lidine-2-carboxylic acid allyl ester51 (25) (1.0 g, 6.0 mmol) and
ethyldiazomalonyl chloride (1.1 g, 6.0 mmol) were allowed to
react according to the general procedure. Flash silica gel
chromatography of the crude residue gave 1.41 g (76%) of 30
as a yellow powder: mp 67-68 °C; IR (KBr) 2136, 1745, 1695,
1
(neat) 1738, 1695, 1339, 1211, 1014, and 898 cm-1; H-NMR
(CDCl3, 400 MHz) δ 1.08 (d, 3H, J ) 6.4 Hz), 2.18 (dd, 1H, J
) 17.6 and 8.0 Hz), 2.31-2.46 (m, 1H), 2.65 (dd, 1H, J ) 17.6
and 8.0 Hz), 3.31 (dd, 1H, J ) 11.6 and, 6.8 Hz), 3.65 (s, 3H),
3.79 (d, 1H, J ) 16.4 Hz), 3.85 (d, 1H, J ) 16.4 Hz), and 3.92
(dd, 1H, J ) 11.6 and 7.6 Hz); 13C-NMR (CDCl3, 100 MHz) δ
18.8, 25.4, 41.1, 43.7, 52.0, 52.1, 166.0, 167.5, and 175.1. Anal.
Calcd for C9H13NO4: C, 54.26; H, 6.58; N, 7.03. Found: C,
54.24; H, 6.60; N, 6.92.
2-Dia zo-3-(3-m eth yl-5-oxop yr r olid in -1-yl)-3-oxop r op i-
on ic Acid Meth yl Ester (50). A mixture of the above imide
(1.8 g, 8.8 mmol), mesyl azide (1.1 g, 8.8 mmol), and triethy-
lamine (1.8 g, 18 mmol) was allowed to react according to the
general procedure for 18 h at rt. Flash silica gel chromatog-
raphy of the crude residue gave 1.73 g (87%) of 50 as a yellow
oil: IR (neat) 2136, 1744, 1695, 1652, 1133, and 756 cm-1; 1H-
NMR (CDCl3, 300 MHz) δ 1.14 (d, 3H, J ) 6.8 Hz), 2.18 (dd,
1H, J ) 17.6 and 7.2 Hz), 2.42-2.50 (m, 1H), 2.67 (dd, 1H, J
) 17.6 and 8.0 Hz), 3.39 (dd, 1H, J ) 10.8 and 6.8 Hz), 3.78
(s, 3H), and 3.88 (dd, 1H, J ) 10.8 and 7.2 Hz); 13C-NMR
(CDCl3, 75 MHz) δ 18.7, 26.0, 40.7, 52.5, 53.0, 160.6, 161.5,
and 173.7. Anal. Calcd for C9H11N3O4: C, 48.00; H, 4.92; N,
18.66. Found: C, 48.05; H, 5.08; N, 18.83.
1652, and 1183 cm-1 1H-NMR (CDCl3, 300 MHz) δ 1.22 (t,
;
3H, J ) 7.2 Hz), 1.99-2.09 (m, 1H), 2.32-2.64 (m, 3H), 4.19
(q, 2H, J ) 7.2 Hz), 4.57 (dd, 2H, J ) 6.0 and 0.9 Hz), 4.67
(dd, 1H, J ) 8.4 and 3.9 Hz), 5.17 (dd, 1H, J ) 10.5 and 0.9
Hz), 5.26 (dd, 1H, J ) 15.6 and 0.9 Hz), and 5.75-5.88 (m,
1H); 13C-NMR (CDCl3, 75 MHz) δ 13.9, 21.8, 31.0, 58.3, 61.5,
65.9, 118.7, 131.0, 160.4, 170.1, 172.7, and 172.8. Anal. Calcd
for C13H15N3O6: C, 50.49; H, 4.89; N, 13.59. Found: C, 50.61;
H, 4.89; N, 13.32.
1-[(Met h oxyca r b on yl)a cet yl]-5-oxop yr r olid in e-2-ca r -
boxylic Acid Ben zyl Ester . A sample of 5-oxopyrrolidine-
2-carboxylic acid benzyl ester (26)51 (1.4 g, 6.4 mmol) and
methyl malonyl chloride (1.3 g, 9.6 mmol) were allowed to react
according to the general procedure for 6 h. Flash silica gel
chromatography of the crude residue gave 1.76 g (82%) of the
desired malonate as a colorless oil: IR (neat) 1748, 1699, 1393,
and 745 cm-1 1H-NMR (CDCl3, 300 MHz) δ 2.02-2.10, (m,
;
1H), 2.30-2.46 (m, 1H), 2.48-2.74 (m, 2H), 3.69 (s, 3H), 3.77
(d, 1H, J ) 16.5 Hz), 4.07 (d, 1H, J ) 16.5 Hz), 4.82 (dd, 1H,
J ) 9.3 and 2.7 Hz), 5.18 (s, 2H), and 5.30-5.38 (s, 5H); 13C-
NMR (CDCl3, 75 MHz) δ 21.2, 31.4, 43.4, 52.2, 57.7, 67.3,
128.1, 128.4, 128.5, 134.9, 166.0, 167.1, 170.3, and 174.4;
HRMS calcd for C16H18NO6 (M + H)+ 320.1134, found 320.1135.
1-[Dia zo(m et h oxyca r b on yl)a cet yl]-5-oxop yr r olid in e-
2-ca r boxylic Acid Ben zyl Ester (31). A sample of the above
imide (800 mg, 2.5 mmol), mesyl azide (304 mg, 2.5 mmol),
and triethylamine (250 mg, 2.5 mmol) were allowed to react
according to the general procedure for 5 h at rt. Flash silica
gel chromatography of the crude residue gave 813 mg (95%)
of 31 as a viscous yellow oil: IR (neat) 2141, 1742, 1645, 1438,
1-[(Meth oxyca r bon yl)a cetyl]-5-oxo-p yr r olid in e-3-ca r -
boxylic Acid Meth yl Ester . A sample of 5-oxopyrrolidine-
3-carboxylic acid methyl ester (49)53 (2.0 g, 14 mmol) and
methylmalonyl chloride (2.4 g, 18 mmol) were allowed to react
according to the general procedure for 3 h. Flash silica gel
chromatography of the crude residue gave 2.38 g (70%) of the
desired imide as a colorless oil: IR (neat) 1752, 1695, 1439,
1
1125, and 848 cm-1; H-NMR (CDCl3, 300 MHz) δ 2.81 (dd,
1H, J ) 18.0 and 9.2 Hz), 2.93 (dd, 1H, J ) 18.0 and 7.2 Hz),
3.20-3.27 (m, 1H), 3.69 (s, 3H), 3.73 (s, 3H), 3.81 (d, 1H, J )
16.4 Hz), 3.92 (d, 1H, J ) 16.4 Hz), 3.97 (dd, 1H, J ) 12.0 and
7.2 Hz), and 4.08 (dd, 1H, J ) 12.0 and 9.2 Hz); 13C-NMR
(CDCl3, 75 MHz) δ 34.6, 35.7, 43.6, 47.1, 52.3, 52.6, 165.9,
167.3, 172.2, and 172.9. Anal. Calcd for C10H13NO6: C, 49.38;
H, 5.39; N, 5.76. Found: C, 49.31; H, 5.33; N, 5.67.
1
and 1037 cm-1; H-NMR (CDCl3, 300 MHz) δ 2.00-2.06 (m,
1H), 2.24-2.67 (m, 3H), 3.74 (s, 3H), 4.72 (dd, 1H, J ) 8.7
and 4.2 Hz), 5.14 (s, 2H), and 7.26-7.33 (m, 5H); 13C-NMR
(CDCl3, 75 MHz) δ 21.6, 30.9, 52.2, 58.3, 67.1, 127.8, 128.2,
128.3, 134.8, 160.1, 160.8, 170.1, and 172.7; HRMS calcd for
C16H15N3O5Li (M + Li)+ 352.1121, found 352.1111.
1-[Dia zo(m et h oxyca r b on yl)a cet yl]-5-oxop yr r olid in e-
3-ca r boxylic Acid Meth yl Ester (51). A mixture of the
above imide (1.1 g, 4.6 mmol), p-methylbenzenesulfonyl azide
(920 mg, 4.6 mmol), and triethylamine (1.6 g, 16 mmol) was
allowed to react according to the general procedure for 18 h
at rt. Flash silica gel chromatography of the crude residue
gave 1.1 g (86%) of 51 as a yellow oil: IR (neat) 2143, 1737,
1-(1,3-Dioxobu tyl)-5-oxop yr r olid in e-2-ca r boxylic Acid
ter t-Bu tyl Ester . A mixture of 5-oxopyrrolidine-2-carboxylic
acid tert-butyl ester (24) (1.0 g, 5.4 mmol) and 2,2,6-trimethyl-
1,3-dioxin-4-one (845 mg, 5.9 mmol) in toluene (20 mL) was
placed in an oil bath at 160 °C and heated for 2.5 h. The
solvent was removed under reduced pressure, and the oily
residue was subjected to flash silica gel chromatography to
give 1.30 g (90%) of the desired keto imide as a colorless oil:
1
1652, 1133, and 756 cm-1; H-NMR (CDCl3, 400 MHz) δ 2.79
(dd, 1H, J ) 18.0 and 8.8 Hz), 2.90 (dd, 1H, J ) 18.0 and 7.2
Hz), 3.26 (m, 1H), 3.74 (s, 3H), 3.79 (s, 3H), 3.99 (dd, 1H, J )
11.6 and 6.8 Hz), and 4.05 (dd, 1H, J ) 11.6 and 8.4 Hz); 13C-
NMR (CDCl3, 100 MHz) δ 35.3, 35.4, 48.0, 52.5, 52.6, 160.3,
151.2, 171.5, and 172.0. Anal. Calcd for C10H11N3O6: C, 44.62;
H, 4.12; N, 15.61. Found: C, 44.70; H, 4.18; N, 15.55.
Gen er a l P r oced u r e for th e Rh od iu m (II)-Ca ta lyzed
Rea ction of r-Dia zo Im id es. To a solution of the R-diazo
imide (750 µmol) in benzene (10 mL) was added the appropri-
ate dipolarophile (1.0-2.0 equiv), and the mixture was placed
into an oil bath preheated to 90 °C. Rhodium perfluorobuty-
IR (neat) 1976, 2933, 1745, 1695, 1624, and 1154 cm-1 1H-
;
NMR (CDCl3, 300 MHz) δ 1.46 (s, 9H), 2.00-2.04 (m, 1H), 2.26
(s, 3H), 2.27-2.31 (m, 1H), 2.45-2.75 (m, 2H), 3.76 (d, 1H, J
) 16.2 Hz), 4.22 (d, 1H, J ) 16.2 Hz), and 4.64 (dd, 1H, J )
9.3 and 1.5 Hz); 13C-NMR (CDCl3, 75 MHz) δ 21.3, 27.8, 30.1,
31.6, 52.1, 58.5, 82.6, 166.7, 169.8, 174.8, and 200.8; HRMS
calcd for C13H19NO5Li (M + Li)+ 276.1423, found 276.1436.
1-(2-Dia zo-1,3-d ioxobu tyl)-5-oxop yr r olid in e-2-ca r box-
ylic Acid ter t-Bu tyl Ester (32). A mixture of the above imide
(1.3 g, 4.6 mmol), mesyl azide (620 mg, 5.1 mmol), and
triethylamine (520 mg, 5.1 mmol) was allowed to react
(52) Dunn, A. D.; Kinnear, K. I. J . Heterocycl. Chem. 1986, 23, 53.
(53) Wu, Y.-H.; Feldkamp, R . F.; Corrigan, J . R.; Rhodes, H. J . J .
Org. Chem. 1961, 26, 1524.
(51) Rigo, B.; Lespagnol, C.; Pauly, M. J . Heterocycl. Chem. 1988,
25, 49.

[3 + 2]-Cycloadditions of Chiral Isomu¨chnone Dipoles
J . Org. Chem., Vol. 62, No. 20, 1997 6851
roamidate [Rh2(pfm)4, 1 mg] was added, and the mixture was
heated at reflux until the starting material was completely
consumed. The solvent was removed under reduced pressure,
and the crude cycloadduct was purified by flash silica gel
chromatography.
(CDCl3, 300 MHz) δ 1.29 (d, 3H, J ) 6.6 Hz), 1.40 (t, 3H, J )
7.2 Hz), 1.85-1.89 (m, 1H), 2.29-2.49 (m, 2H), 2.76-2.82 (m,
1H), 3.50 (d, 1H, J ) 6.6 Hz), 3.90 (d, 1H, J ) 6.6 Hz), 4.07-
4.11 (m, 1H), 4.45 (q, 2H, J ) 7.2 Hz), 7.24 (d, 2H, J ) 7.2
Hz), and 7.37-7.49 (m, 3H); 13C-NMR (CDCl3, 75 MHz) δ 14.0,
20.5, 25.1, 33.2, 47.7, 52.6, 53.1, 62.6, 88.9, 103.5, 126.2, 128.9,
129.1, 131.1, 162.3, 168.6, 171.6, and 172.0. Anal. Calcd for
C20H20N2O6: C, 62.49; H, 5.24; N, 7.29. Found: C, 62.50; H,
5.26; N, 7.28.
Tet r a h yd r o-1,3,5-t r ioxo-2-p h en yl-7H -4,9a -ep oxy-1H -
p yr r olo[3,4-g]in d olizin e-4-ca r boxylic Acid Eth yl Ester
(11). Diazo imide 5 (310 mg, 1.4 mmol) and N-phenylmale-
imide (240 mg, 1.4 mmol) were allowed to react according to
the general procedure. Proton NMR analysis of the crude
product mixture showed the formation of two diastereomeric
cycloadducts identified as exo 11a and endo 11b (90%, dr 85:
15) which were separated by flash silica gel chromatography.
Cycloadduct exo 11a (398 mg, 78%): mp 183-184 °C; IR
(KBr) 1738, 1716, 1382, and 1204 cm-1; 1H-NMR (CDCl3, 300
MHz) δ 1.39 (t, 3H, J ) 7.2 Hz), 2.17-2.25 (m, 2H), 2.39-
2.45 (m, 1H), 2.56-2.66 (m, 1H), 3.22 (m, 1H), 3.51 (d, 1H, J
) 6.9 Hz), 3.70-3.75 (m, 1H), 3.86 (d, 1H, J ) 6.9 Hz), 4.46
(q, 2H, J ) 7.2 Hz), 7.22 (d, 2H, J ) 7.2 Hz), and 7.29-7.49
(m, 3H); 13C-NMR (CDCl3, 75 MHz) δ 14.1, 25.9, 26.7, 44.0,
47.9, 52.4, 62.8, 88.6, 103.7, 126.3, 129.0, 129.1, 131.1, 162.3,
169.1, 171.6, and 172.0. Anal. Calcd for C19H18N2O6: C, 61.62;
H, 4.90; N, 7.56. Found: C, 61.50; H, 4.94; N, 7.51.
Cycloadduct endo 11b (75 mg, 15%): mp 190-191 °C; IR
(KBr) 1780, 1745, 1716, 1197, and 1119 cm-1; 1H-NMR (CDCl3,
300 MHz) δ 1.38 (t, 3H, J ) 7.2 Hz), 2.13-2.22 (m, 2H), 2.45-
2.58 (m, 2H), 3.03 (m, 1H), 3.72 (d, 1H, J ) 8.4 Hz), 3.77-
3.82 (m, 1H), 4.04 (d, 1H, J ) 8.4 Hz), 4.42 (q, 2H, J ) 7.2
Hz), 7.16 (m, 2H), and 7.41-7.51 (m, 3H); 13C-NMR (CDCl3,
75 MHz) δ 14.0, 25.9, 27.9, 44.4, 48.8, 51.8, 63.0, 88.3, 103.3,
126.5, 129.0, 129.2, 131.1, 163.3, 168.6, 169.8, and 171.3. Anal.
Calcd for C19H18N2O6: C, 61.62; H, 4.90; N, 7.56. Found: C,
61.69; H, 4.92; N, 7.61.
The minor cycloadduct 33b (267 mg, 37%): mp 208-209
1
°C; IR (KBr) 1745, 1721, 1223, 1049, and 753 cm-1; H-NMR
(CDCl3, 300 MHz) δ 1.39 (t, 3H, J ) 7.2 Hz), 1.46 (d, 3H, J )
6.3 Hz), 1.87-2.04 (m, 1H), 2.35-2.51 (m, 2H), 2.62-2.80 (m,
1H), 3.47 (d, 1H, J ) 6.6 Hz), 3.81 (d, 1H, J ) 6.6 Hz), 3.83-
3.87 (m, 1H), 4.43 (q, 2H, J ) 7.2 Hz), 7.22 (d, 2H, J ) 7.2
Hz), and 7.36-7.47 (m, 3H); 13C-NMR (CDCl3, 75 MHz) δ 14.1,
17.5, 24.5, 34.4, 47.7, 52.5, 53.4, 62.7, 89.9, 104.9, 126.2, 129.0,
129.2, 131.1, 162.3, 166.6, 171.6, and 172.0. Anal. Calcd for
C20H20N2O6: C, 62.49; H, 5.24; N, 7.29. Found: C, 62.41; H,
5.23; N, 7.23.
Tet r a h yd r o-1,3,5-t r ioxo-2-p h en yl-7H -4,9a -ep oxy-1H -
p yr r olo[3,4-g]in d olizin e-4,7-d ica r boxylic Acid Dieth yl
Ester (34). Diazo imide 28 (360 mg, 1.2 mmol) and N-
phenylmaleimide (210 mg, 1.2 mmol) were allowed to react
according to the general procedure. Proton NMR analysis of
the crude product mixture showed the formation of two
diastereomeric cycloadducts identified as exo-syn 34a and
exo-anti 34b (90%, dr 83:17) which were separated by flash
silica gel chromatography.
Cycloadduct exo-syn 34a (375 mg, 71%): mp 187-189 °C;
IR (KBr) 1759, 1720, 1595, 1389, and 1040 cm-1
;
1H-NMR
(CDCl3, 300 MHz) δ 1.30 (t, 3H, J ) 7.2 Hz), 1.40 (t, 3H, J )
7.2 Hz), 2.33-2.43 (m, 2H), 2.54-2.64 (m, 1H), 2.67-2.79 (m
1H), 3.87 (d, 1H, J ) 6.9 Hz), 3.92 (d, 1H, J )6.9 Hz), 4.21 (q,
2H, J ) 7.2 Hz), 4.45 (q, 2H, J ) 7.2 Hz), 4.54 (d, 1H, J ) 8.1
Hz), 7.23 (m, 2H), and 7.39-7.51 (m, 3H); 13C-NMR (CDCl3,
75 MHz) δ 14.0, 14.1, 25.5, 30.9, 47.9, 52.4, 56.8, 62.1, 62.9,
88.5, 104.0, 126.3, 129.0, 129.1, 131.1, 162.1, 167.7, 170.3,
171.4, and 172.0. Anal. Calcd for C22H22N2O8: C, 59.73; H,
5.01; N, 6.22. Found: C, 59.65; H, 4.96; N, 6.26.
Tet r a h yd r o-9-m et h yl-1,3,5-t r ioxo-2-p h en yl-7H -4,9a -
epoxy-1H-pyr r olo[3,4-g]in dolizin e-4-car boxylic Acid Eth -
yl Ester (20). Diazo imide 16 (400 mg, 1.7 mmol) and
N-phenylmaleimide (290 mg, 1.7 mmol) were allowed to react
according to the general procedure. Proton NMR analysis of
the crude product mixture showed the predominant formation
of cycloadduct exo-anti 20 (90%). Flash silica gel chromatog-
raphy gave 552 mg (86%) of 20 as a white powder: mp 203-
Cycloadduct exo-anti 34b (78 mg, 14%): mp 170-171 °C;
204 °C; IR (KBr) 1756, 1718, 1393, 1197, 1116, and 754 cm-1
;
IR (KBr) 1752, 1709, 1496, 1382, and 749 cm-1 1H-NMR
;
1H-NMR (CDCl3, 400 MHz) δ 1.15 (d, 3H, J ) 6.9 Hz), 1.35 (t,
3H, J ) 7.2 Hz), 1.78-1.87 (m, 1H), 2.18-2.26 (m, 1H), 2.84-
2.92 (m, 1H), 3.05-3.13 (m, 1H), 3.42 (d, 1H, J ) 6.6. Hz),
3.63-3.70 (m, 1H), 3.82 (d, 1H, J ) 6.6 Hz), 4.39 (q, 2H, J )
7.2 Hz), 7.19 (d, 2H, J ) 7.2 Hz), and 7.35-7.46 (m, 3H); 13C-
NMR (CDCl3, 75 MHz) δ 12.1, 14.0, 33.8, 34.6, 42.6, 47.8, 52.5,
62.5, 87.9, 103.3, 126.2, 128.9, 129.1, 131.1, 162.3, 169.0, 171.7,
and 172.0. Anal. Calcd for C20H20N2O6: C, 62.49; H, 5.24; N,
7.29. Found: C, 62.52; H, 5.25; N, 7.28.
(CDCl3, 300 MHz) δ 1.25 (t, 3H, J ) 7.2 Hz), 1.37 (t, 3H, J )
7.2 Hz), 2.13-2.30 (m, 2H), 2.32-2.46 (m, 2H), 3.58 (d, 1H, J
) 6.9 Hz), 3.85 (d, 1H, J ) 6.9 Hz), 4.20 (q, 2H, J ) 7.2 Hz),
4.28 (dd, 1H, J ) 7.9 and 2.1 Hz), 4.41 (q, 2H, J ) 7.2 Hz),
7.22 (m, 2H), and 7.39-7.51 (m, 3H); 13C-NMR (CDCl3, 75
MHz) δ 13.9, 14.0, 23.6, 31.7, 47.6, 52.2, 56.0, 62.1, 62.7, 90.3,
103.9, 126.3, 129.0, 129.1, 131.1, 161.8, 166.5, 168.5, 171.5,
and 172.0. Anal. Calcd for C22H22N2O8: C, 59.73; H, 5.01; N,
6.33. Found: C, 59.53; H, 5.03; N, 6.27.
3-Oxo-2,3,5,6-t et r a h yd r op yr r olo[2,1-b]oxa zole-2,7-d i-
ca r boxylic Acid Dim eth yl Ester (21). To a solution of diazo
imide 17 (170 mg, 620 µmol) in benzene (5 mL) was added
Rh2(pfm)4 (1 mg), and the mixture was stirred overnight under
an atmosphere of argon. The solvent was removed under
reduced pressure, and the residue was subjected to flash silica
gel chromatography to give 115 mg (77%) of 21 as a colorless
oil; IR (neat) 1762, 1646, 1450, 1377, 1107, and 721 cm-1; 1H-
NMR (CDCl3, 400 MHz) δ 3.09-3.15 (m, 2H), 3.68 (s, 3H),
3.69-3.74 (m, 2H), 3.83 (s, 3H), and 5.51 (s, 1H); 13C-NMR
(CDCl3, 100 MHz) δ 30.1, 39.2, 51.2, 53.7, 80.7, 85.7, 159.5,
160.6, 163.3, and 163.9; HRMS calcd for C10H11NO6 (M + H)+
242.0665, found 242.0662.
Tet r a h yd r o-7-m et h yl-1,3,5-t r ioxo-2-p h en yl-7H -4,9a -
epoxy-1H-pyr r olo-[3,4-g]in dolizin e-4-car boxylic Acid Eth -
yl Ester (33). Diazo imide 27 (450 mg, 1.9 mmol) and
N-phenylmaleimide (330 mg, 1.9 mmol) were allowed to react
according to the general procedure. Proton NMR analysis of
the crude product mixture showed the formation of two
diastereomeric cycloadducts identified as exo-syn 33a and
exo-anti 33b (90%, dr 58:42) which were separated by flash
silica gel chromatography. The relative stereochemistry of
these cycloadducts could not be assigned.
Tet r a h yd r o-1,3,5-t r ioxo-2-p h en yl-7H -4,9a -ep oxy-1H -
p yr r olo[3,4-g]in d olizin e-4,7-d ica r boxylic Acid 4-Eth yl
Ester 7-ter t-Bu tyl Ester (35). Diazo imide 29 (200 mg, 620
µmol) and N-phenylmaleimide (110 mg, 620 µmol) were
allowed to react according to the general procedure. Proton
NMR analysis of the crude product mixture showed the
formation of two diastereomeric cycloadducts identified as exo-
syn 35a and exo-anti 35b (90%, dr 90:10). Flash silica gel
chromatography gave 242 mg (84%) of the major isomer exo-
syn 35a as a white powder: mp 191-192 °C; IR (KBr) 1752,
1709, 1496, 1389, and 1154 cm-1; 1H-NMR (CDCl3, 300 MHz)
δ 1.40 (t, 3H, J ) 7.2 Hz), 1.46 (s, 9H), 2.25-2.75 (m, 4H),
3.92 (d, 1H, J ) 6.6 Hz), 3.94 (d, 1H, J ) 6.6 Hz), 4.39-4.50
(m, 2H), 4.45 (d, 1H, J ) 8.7 Hz), 7.24 (d, 2H, J ) 7.2 Hz),
and 7.40-7.49 (m 3H); 13C-NMR (CDCl3, 75 MHz) δ 14.0, 25.4,
27.9, 31.0, 47.9, 52.4, 57.5, 62.9, 82.9, 88.6, 104.0, 126.3, 129.0,
129.1, 131.2, 162.1, 167.5, 169.4, 171.5, and 172.1. Anal.
Calcd for C24H26N2O8: C, 61.27; H, 5.27; N, 5.95. Found: C,
61.38; H, 5.60; N, 5.92.
Cycloadduct exo-anti 35b: 1H-NMR (CDCl3, 300 MHz) δ
1.41 (t, 3H, J ) 7.2 Hz), 1.49 (s, 9H), 2.25-2.75 (m, 4H), 3.55
(d, 1H, J ) 6.6 Hz), 3.86 (d, 1H, J ) 6.6 Hz), 4.22 (dd, 1H, J
) 8.4 and 1.5 Hz), 4.41-4.51 (m 2H), 7.24 (d, 2H, J ) 7.2 Hz),
and 7.40-7.49 (m, 3H); 13C-NMR (CDCl3, 75 MHz) δ 14.0, 23.5,
The major cycloadduct 33a (357 mg, 49%): mp 219-220 °C;
IR (KBr) 1749, 1713, 1206, 1136, and 1051 cm-1 1H-NMR
;

6852 J . Org. Chem., Vol. 62, No. 20, 1997
Padwa and Prein
27.7, 31.5, 47.5, 52.3, 56.9, 62.8, 83.1, 104.0, 126.0, 129.0, 129.1,
131.4, 162.2, 167.5, 169.7, 171.4, and 172.0.
Tet r a h yd r o-1,3,5-t r ioxo-2-p h en yl-7H -4,9a -ep oxy-1H -
p yr r olo[3,4-g]in d olizin e-4,7-d ica r boxylic Acid 4-Eth yl
Ester 7-Allyl Ester (39). Diazo imide 30 (180 mg, 590 µmol)
and N-phenylmaleimide (100 mg, 590 µmol) were allowed to
react according to the general procedure. Proton NMR analy-
sis of the crude product mixture showed the formation of two
diastereomeric cycloadducts identified as exo-syn 39a and
exo-anti 39b (90%, dr 85:15). Flash silica gel chromatography
gave 199 mg (75%) of the major exo-syn 39a isomer as a white
powder: mp 154-155 °C; IR (KBr) 1763, 1714, 1455, 1200,
1145, and 754 cm-1; 1H-NMR (CDCl3, 400 MHz) δ 1.37 (t, 3H,
J ) 7.2 Hz), 2.32-2.42 (m, 2H), 2.53-2.60 (m, 1H), 2.67-2.76
(m, 1H), 3.83 (d, 1H, J ) 6.8 Hz), 3.89 (d, 1H, J ) 6.8 Hz),
4.24-4.45 (m, 2H), 4.55 (d, 1H, J ) 8.4 Hz), 4.61-4.64 (m,
2H), 5.27 (d, 1H, J ) 11.6 Hz), 5.32 (d, 1H, J ) 17.2 Hz), 5.84-
5.94 (m, 1H), 7.20-7.22 (m, 2H), and 7.35-7.45 (m, 3H); 13C-
NMR (CDCl3, 100 MHz) δ 13.9, 25.3, 30.7, 47.7, 52.3, 56.6,
62.8, 66.3, 88.3, 103.8, 119.4, 126.2, 128.9, 129.0, 130.9, 131.0,
161.9, 167.6, 169.8, 171.4, and 171.9. Anal. Calcd for
C23H22N2O8: C, 60.79; H, 4.95; N, 6.03. Found: C, 60.77; H,
4.99; N, 5.99.
Tet r a h yd r o-1,3,5-t r ioxo-2-m et h yl-7H -4,9a -ep oxy-1H -
p yr r olo[3,4-g]in d olizin e-4,7-d ica r boxylic Acid 4-Eth yl
Ester 7-ter t-Bu tyl Ester (36). Diazo imide 29 (260 mg, 800
µmol) and N-methylmaleimide (90 mg, 800 µmol) were allowed
to react according to the general procedure. Proton NMR
analysis of the crude product mixture showed the formation
of two diastereomeric cycloadducts identified as exo-syn 36a
and exo-anti 36b (90%, dr 90:10). Flash silica gel chroma-
tography gave 241 mg (74%) of the major adduct exo-syn 36a
isomer: mp 162-163 °C; IR (KBr) 1752, 1720, 1439, 1389,
1154, and 1047 cm-1
;
1H-NMR (CDCl3, 400 MHz) δ 1.37 (t,
3H, J ) 7.2 Hz), 1.43 (s, 9H), 2.21-2.27 (m, 1H), 2.30 (ddd,
1H, J ) 14.8, 8.0, and 2.0 Hz), 2.45-2.55 (m, 1H), 2.61-2.69
(m, 1H), 2.93 (s, 3H), 3.70 (d, 1H, J ) 6.8 Hz), 3.76 (d, 1H, J
) 6.8 Hz), 4.37 (dd, 1H, J ) 6.8 and 1.6 Hz), and 4.37-4.45
(m, 2H); 13C-NMR (CDCl3, 100 MHz) δ 14.0, 25.2, 25.3, 27.8,
30.9, 47.8, 52.4, 57.3, 62.7, 82.8, 88.1, 103.6, 162.2, 167.5, 169.4,
172.3, and 173.0. Anal. Calcd for C19H24N2O8: C, 55.88; H,
5.92; N, 6.86. Found: C, 55.90; H, 5.90; N, 6.83.
Cycloadduct exo-anti 36b: 1H-NMR (CDCl3, 400 MHz) δ
1.41 (t, 3H, J ) 7.2 Hz), 1.44 (s, 9H), 2.35-2.83 (m, 4H), 2.97
(s, 3H), 3.41 (d, 1H, J ) 6.8 Hz), 3.73 (d, 1H, J ) 6.8 Hz), 4.18
(dd 1 H, J ) 8.4 and 1.6 Hz), and 4.37-4.46 (m, 2H).
Tetr a h yd r o-1,3,5-tr ioxo-7H-4,9a -ep oxy-1H-fu r a n o[3,4-
g]in d olizin e-4,7-d ica r boxylic Acid 4-Eth yl Ester 7-ter t-
Bu tyl Ester (37). Diazo imide 29 (140 mg, 430 µmol) and
maleic anhydride (40 mg, 430 µmol) were allowed to react
according to the general procedure. Proton NMR analysis of
the crude product mixture showed the formation of two
diastereomeric cycloadducts identified as exo-syn 37a and
exo-anti 37b (90%, dr 90:10). The major isomer exo-syn 37a
(134 mg, 79%) was a white powder: mp 136-137 °C; IR (KBr)
1780, 1732, 1695, 1368, and 1154 cm-1; 1H-NMR (CDCl3, 300
MHz) δ 1.41 (t, 3H, J ) 7.2 Hz), 1.48 (s, 9H), 2.29-2.72 (m,
4H), 4.08 (d, 1H, J ) 6.9 Hz), 4.12 (d, 1H, J ) 6.9 Hz), 4.46 (d,
1H, J ) 7.5 Hz), and 4.47 (q, 2H, J ) 7.2 Hz); 13C-NMR (CDCl3,
75 MHz) δ 13.9, 25.2, 27.7, 30.8, 49.0, 53.8, 57.5, 63.1, 83.2,
88.8, 104.3, 161.3, 166.2, 166.5, 167.0, and 169.2. Anal. Calcd
for C18H21NO9: C, 54.68; H, 5.35; N, 3.54. Found: C, 54.48;
H, 5.52; N, 3.27.
Cycloadduct exo-anti 39b showed the following spectral
properties: 1H-NMR (CDCl3, 400 MHz) δ 1.35 (t, 3H, J ) 7.2
Hz), 3.56 (d, 1H, J ) 6.4 Hz), 3.83 (d, 1H, J ) 6.4 Hz), 4.58
(dd, 1H, J ) 8.4 and 2.0 Hz), and 4.23-5.34 (m, 2H); 13C-NMR
(CDCl3, 100 MHz) δ 14.0, 23.5, 31.7, 47.5, 52.2, 55.8, 62.7, 66.5,
119.1, 126.2, 127.8, 131.1, 167.7, and 168.2.
Tet r a h yd r o-1,3,5-t r ioxo-2-p h en yl-7H -4,9a -ep oxy-1H -
p yr r olo[3,4-g]in d olizin e-4,7-d ica r boxylic Acid 4-Eth yl
Ester 7-Ben zyl Ester (40). Diazo imide 31 (130 mg, 380
µmol) and N-phenylmaleimide (72 mg, 410 µmol) were allowed
to react according to the general procedure. Proton NMR
analysis of the crude product mixture showed the formation
of two diastereomeric cycloadducts identified as exo-syn 40a
and exo-anti 40b (95%, dr 87:13) which were separated by
flash silica gel chromatography.
Cycloadduct exo-syn 40a (145 mg, 79%): mp 199-200 °C;
IR (KBr) 1759, 1716, 1455, 1388, 1200, 1141, and 754 cm-1
;
1H-NMR (CDCl3, 300 MHz) δ 2.32-2.76 (m, 4H), 3.83 (d, 1H,
J ) 6.9 Hz), 3.91 (d, 1H, J ) 6.9 Hz), 3.98 (s, 3H), 4.62 (dd,
1H, J ) 7.2 and 1.2 Hz), 5.19 (s, 2H), 7.23 (d, 2H, J ) 7.2 Hz),
and 7.35-7.51 (m, 8H); 13C-NMR (CDCl3, 75 MHz) δ 25.3, 30.7,
47.8, 52.2, 53.2, 56.8, 67.6, 88.5, 103.9, 126.2, 128.5, 128.6,
128.9, 129.0, 131.0, 134.6, 162.4, 167.5, 169.9, 171.5, and 171.9.
Anal. Calcd for C26H22N2O8: C, 63.67; H, 4.52; N, 5.71.
Found: C, 63.62; H, 4.55; N, 5.64.
Cycloadduct exo-anti 37b: 1H-NMR (CDCl3, 300 MHz) δ
1.45 (s, 9H), 3.72 (d, 1H, J ) 7.2 Hz), 4.02 (d, 1H, J ) 7.2 Hz),
and 4.22 (dd, 1H, J ) 8.1 and 1.5 Hz); 13C-NMR (CDCl3, 75
MHz) δ 13.8, 23.4, 27.7, 31.1, 48.8, 53.6, 56.8, 62.9, 83.3, 88.8,
104.4, 161.1, 165.9, 167.8, and 168.1.
Cycloadduct exo-anti 40b (21 mg, 12%): mp 193-194 °C;
IR (KBr) 1760, 1716, 1388, 1196, 1141, and 753 cm-1; 1H-NMR
(CDCl3, 300 MHz) δ 2.36-2.86 (m, 4H), 3.57 (d, 1H, J ) 6.9
Hz), 3.87 (d, 1H, J ) 6.9 Hz), 3.95 (s, 3H), 4.37 (dd, 1H, J )
8.1 and 2.1 Hz), 5.19 (s, 2H), 7.23 (d, 2H, J ) 7.2 Hz), and
7.31-7.48 (m, 8H); 13C-NMR (CDCl3, 75 MHz) δ 23.6, 31.8,
47.7, 52.2, 53.3, 56.0, 67.9, 90.5, 104.1, 126.3, 128.3, 128.5,
128.6, 129.0, 129.1, 131.1, 134.7, 162.2, 166.4, 168.3, 171.5,
and 171.9. Anal. Calcd for C26H22N2O8: C, 63.67; H, 4.52; N,
5.71. Found: C, 63.51; H, 4.57; N, 5.60.
Rh (II)-Ca ta lyzed Decom p osition of Dia zoim id e 29 in
th e P r esen ce of 1,4-Na p h th oqu in on e. Diazo imide 29 (135
mg, 415 µmol) and 1,4-naphthoquinone (70 mg, 415 µmol) were
allowed to react according to the general procedure. Proton
NMR analysis of the crude product mixture showed the
formation of two diastereomeric cycloadducts exo-syn 38a and
exo-anti 38b (95%, dr 84:16) which were separated by flash
silica gel chromatography.
Cycloadduct exo-syn 38a (126 mg, 67%): mp 199-200 °C;
IR (KBr) 1773, 1752, 1738, 1254, and 1154 cm-1 1H-NMR
;
4-Acetyltetr ah ydr o-1,3,5-tr ioxo-2-ph en yl-7H-4,9a-epoxy-
1H-p yr r olo[3,4-g]in d olizin e-7-ca r boxylic Acid ter t-Bu tyl
Ester (41). Diazo imide 32 (190 mg, 640 µmol) and N-
phenylmaleimide (110 mg, 640 µmol) were allowed to react
according to the general procedure. Proton NMR analysis of
the crude product mixture showed the formation of three
diastereomeric cycloadducts which were identified as exo-syn
41a , endo-anti 41b, and exo-anti 41c (95%, dr 81:8:11) and
were separated by flash silica gel chromatography.
(CDCl3, 300 MHz) δ 1.34 (t, 3H, J ) 7.2 Hz), 1.47 (s, 9H), 2.13
(dd, 1H, J ) 14.7 and 6.9 Hz), 2.24-2.43 (m, 2H), 2.71-2.75
(m, 1H), 3.90 (d, 1H, J ) 7.8 Hz), 3.99 (d, 1H, J ) 7.8 Hz),
4.30-4.40 (m, 2H), 4.40 (dd, 1H, J ) 8.4 and 1.5 Hz), 7.30-
7.40 (m, 2H), 7.90 (m, 1H), and 7.94 (m, 1H); 13C-NMR (CDCl3,
75 MHz) δ 13.9, 25.7, 27.8, 30.8, 52.0, 55.5, 57.7, 62.5, 82.7,
89.1, 104.9, 126.9, 134.7, 134.8, 135.9, 162.5, 168.1, 169.3,
191.6, and 191.7. Anal. Calcd for C24H25NO8: C, 63.29; H,
5.53; N, 3.08. Found: C, 63.42; H, 5.39; N, 2.97.
Cycloadduct exo-anti 38b (25 mg, 13%): mp 196-197 °C;
Cycloadduct exo-syn 41a (218 mg, 77%): mp 191-192 °C;
IR (KBr) 1775, 1750, 1738, 1389, and 1154 cm-1
;
1H-NMR
IR (KBr) 1730, 1716, 1389, 1198, and 1147 cm-1
;
1H-NMR
(CDCl3, 300 MHz) δ 1.37 (t, 3H, J ) 7.2 Hz), 1.40 (s, 9H), 2.25-
2.76 (m, 4H), 3.63 (d, 1H, J ) 7.8 Hz), 3.90 (d, 1H, J ) 7.8
Hz), 4.20 (dd, 1H, J ) 8.1 and 1.5 Hz), 4.33 (q, 2H, J ) 7.2
Hz), 7.72-7.75 (m, 2H), 7.91 (m, 1H), and 7.94 (m, 1H); 13C-
NMR (CDCl3, 75 MHz) δ 13.9, 23.8, 27.7, 31.1, 57.6, 56.2, 57.1,
62.4, 82.9, 89.0, 104.8, 126.9, 134.8, 134.9, 135.8, 162.3, 168.0,
169.1, 191.6, and 191.7. Anal. Calcd for C24H25NO8: C, 63.29;
H, 5.53; N, 3.08. Found: C, 63.17; H, 5.61; N, 3.11.
(CDCl3, 300 MHz) δ 1.48 (s, 9H), 2.26-2.75 (m, 4H), 2.62 (s,
3H), 3.94 (d, 1H, J ) 6.9 Hz), 2.99 (d, 1H, J ) 6.9 Hz), 4.44
(dd, 1H, J )8.1 and 1.2 Hz), 7.21 (d, 2H, J ) 7.2 Hz), and
7.26-7.47 (m, 3H); 13C-NMR (CDCl3, 75 MHz) δ 25.2, 27.7,
27.8, 31.0, 48.0, 52.8, 57.2, 83.0, 93.3, 103.4, 126.2, 129.1, 129.3,
131.0, 168.0, 169.3, 171.7, 172.0, and 196.3. Anal. Calcd for
C23H24N2O7: C, 62.72; H, 5.49; N, 6.36. Found: C, 62.56; H,
5.57; N, 6.29.

[3 + 2]-Cycloadditions of Chiral Isomu¨chnone Dipoles
Cycloadduct endo-anti 41b (22 mg, 8%): mp 194-195 °C;
J . Org. Chem., Vol. 62, No. 20, 1997 6853
400 MHz) δ 1.35 (t, 3H, J ) 7.2 Hz), 1.46 (s, 9H), 2.17-2.31
(m, 2H), 2.22 (s, 3H), 2.39 (dd, 1H, J ) 13.2 and 4.4 Hz), 2.45-
2.54 (m, 2H), 2.73 (dd, 1H, J ) 13.2 and 9.2 Hz), 3.58 (dd, 1H,
J ) 9.2 and 4.4 Hz); 4.31-4.40 (m, 2H), and 4.40 (dd, 1H, J )
7.2 and 2.0 Hz); 13C-NMR (CDCl3, 100 MHz) δ 14.1, 26.6, 27.8,
29.0, 31.2, 32.1, 57.0, 62.3, 82.5, 86.3, 104.0, 164.8, 170.0, 171.1,
and 205.0; HRMS calcd for C18H25NO7Li (M + Li)+ 374.1791,
found 374.1779.
Cycloadduct exo-anti 44b (76 mg, 21%): IR (neat) 1752,
1738, 1389, 1126, and 848 cm-1; 1H-NMR (CDCl3, 400 MHz) δ
1.34 (t, 3H, J ) 7.2 Hz), 1.45 (s, 9H), 2.20 (s, 3H), 2.37-2.50
(m, 5H), 2.61 (dd, 1H, J ) 13.2 and 8.8 Hz), 3.21 (dd, 1H, J )
8.8 and 4.4 Hz), 4.08 (dd, 1H, J ) 7.6 and 2.0 Hz), and 4.30-
4.41 (m, 2H); 13C-NMR (CDCl3, 100 MHz) δ 14.1, 25.0, 27.8,
28.6, 32.0, 32.2, 56.3, 57.3, 62.3, 82.9, 88.7, 104.1, 164.6, 167.9,
169.1, and 205.8; HRMS calcd for C18H25NO7Li (M + Li)+
374.1791, found 374.1776.
Cycloadduct endo-anti 44c (67 mg, 19%): IR (neat) 1773,
1759, 1730, 1389, and 948 cm-1; 1H-NMR (CDCl3, 400 MHz) δ
1.34 (t, 3H, J ) 7.2 Hz), 1.46 (s, 9H), 2.20 (s, 3H), 2.21-2.50
(m, 4H), 2.65-2.73 (m, 2H), 3.31 (dd, 1H, J ) 10.8 and 5.7
Hz), 4.10 (dd, 1H, J ) 8.7 and 5.7 Hz), and 4.30-4.42 (m, 2H);
13C-NMR (CDCl3, 100 MHz) δ 14.1, 26.5, 27.8, 30.2, 32.2, 32.3,
57.2, 57.4, 62.3, 82.6, 89.1, 104.0, 164.8, 168.3, 169.4, and
205.0. Anal. Calcd for C18H25NO7: C, 58.85; H, 6.86; N, 3.81.
Found: C, 58.60; H, 6.76; N, 3.74.
(3R*,6R*)-8-Acetyl-6-h yd r oxy-5-oxo-1,2,3,5,6,7-h exa h y-
d r oin d olizin e-3,6-d ica r boxylic Acid 3-ter t-Bu tyl Ester
6-Eth yl Ester (a n ti 45). To a solution of exo-syn 44a (75
mg, 200 µmol) in chloroform (2 mL) was added p-TsOH (1 mg),
and the mixture was stirred at rt for 18 h. The solvent was
removed under reduced pressure, and the residue was sub-
jected to flash silica gel chromatography to give 67 mg (89%)
of anti 45 as a colorless oil: IR (neat) 3438, 1738, 1695, 1602,
and 1147 cm-1; 1H-NMR (CDCl3, 400 MHz) δ 1.26 (t, 3H, J )
7.2 Hz), 1.41 (s, 9H), 2.06-2.13 (m, 1H), 2.25 (s, 3H), 2.25-
2.35 (m, 1H), 2.90 (d, 1H, J ) 16.4 Hz), 2.97-3.06 (m, 1H),
3.24-3.33 (m, 1H), 3.28 (d, 1H, J ) 16.4 Hz), 4.20-4.30 (m,
1H), 4.59 (br s, 1H), and 4.60 (dd, 1H, J ) 9.2 and 2.8 Hz);
13C-NMR (CDCl3, 100 MHz) δ 13.9, 26.5, 27.8, 29.2, 30.6, 33.0,
59.5, 63.0, 74.2, 82.4, 108.0, 150.4, 165.6, 168.9, 170.2, and
196.0; HRMS calcd for C18H26NO7 (M + H)+ 368.1709, found
368.1704.
IR (KBr) 1733, 1714, 1702, 1389, and 1148 cm-1 1H-NMR
;
(CDCl3, 300 MHz) δ 1.44 (s, 9H), 2.26-2.75 (m, 4H), 2.66 (s,
3H), 3.82 (d, 1H, J )8.4 Hz), 3.93 (d, 1H, J ) 8.4 Hz), 4.09
(dd, 1H, J ) 8.1 and 1.5 Hz), 7.13 (d, 2H, J ) 6.9 Hz), and
7.26-7.47 (m, 3H); 13C-NMR (CDCl3, 75 MHz) δ 26.5, 27.6,
27.8, 32.2, 48.3, 54.1, 57.1, 83.1, 94.6, 103.4, 126.5, 129.2, 129.3,
131.0, 167.3, 167.6, 170.5, 171.8, and 197.0. Anal. Calcd for
C23H24N2O7: C, 62.72; H, 5.49; N, 6.36. Found: C, 62.70; H,
5.49; N, 6.39.
Cycloadduct exo-anti 41c (27 mg, 10%): mp 184-185 °C;
IR (KBr) 1716, 1702, 1496, 1389, and 1154 cm-1 1H-NMR
;
(CDCl3, 300 MHz) δ 1.44 (s, 9H), 2.26-2.75 (m, 4H), 2.57 (s,
3H), 3.56 (d, 1H, J ) 6.6 Hz), 3.90 (d, 1H, J ) 6.6 Hz), 4.22
(dd, 1H, J ) 8.4 and 1.5 Hz), 7.29 (d, 2H, J ) 7.2 Hz), and
7.36-7.47 (m, 3H); 13C-NMR (CDCl3, 75 MHz) δ 23.5, 27.8,
27.9, 32.1, 47.7, 52.7, 56.9, 83.3, 95.2, 103.7, 126.3, 129.1, 129.2,
131.0, 167.3, 167.5, 171.6, 171.9, and 196.0. Anal. Calcd for
C23H24N2O7: C, 62.72; H, 5.49; N, 6.36. Found: C, 62.63; H,
5.50; N, 6.31.
6 -O x o -8 ,8 ,9 ,9 -t e t r a c y a n o -1 0 -o x a -5 -a z a t r i c y c l o -
[5.2.1.01,5]d eca n e-4,7-d ica r boxylic Acid 4-ter t-Bu tyl Ester
7-Eth yl Ester (42). Diazo imide 29 (180 mg, 570 µmol) and
tetracyanoethylene (70 mg, 570 µmol) were allowed to react
according to the general procedure. Proton NMR analysis of
the crude product mixture showed the predominant formation
of the syn cycloadduct 42a (90%, dr ) 77:23). Recrystallization
from dichloromethane/hexane gave 178 mg (74%) of 42a : mp
149-150 °C; IR (KBr) 1776, 1745, 1695, 1375, and 1154 cm-1
;
1H-NMR (CDCl3, 400 MHz) δ 1.48 (t, 3H, J ) 7.2 Hz), 1.49 (s,
9H), 2.64-4.65 (m, 4H), and 4.52-4.65 (m, 3H); 13C-NMR
(CDCl3, 75 MHz) δ 13.9, 26.8, 27.7, 28.9, 29.7, 59.6, 65.6, 84.8,
84.9, 107.1, 107.7, 108.2, 108.4, 108.8, 157.9, 163.2, and 166.1.
Anal. Calcd for C20H19N5O6: C, 56.47; H, 4.50; N, 16.46.
Found: C, 56.44; H, 4.39; N, 16.75.
8,8-Dieth oxy-6-oxo-10-oxa-5-azatr icyclo[5.2.1.01,5]decan e-
4,7-d ica r b oxylic Acid 4-ter t-Bu t yl E st er 7-E t h yl E st er
(43). Diazo imide 29 (200 mg, 610 µmol) and 1,1-diethoxy-
ethene (120 mg, 1.0 mmol) were allowed to react according to
the general procedure. Proton NMR analysis of the crude
product mixture showed the formation of two diastereomeric
cycloadducts identified as syn 43a and anti 43b (90%, dr 65:
35) which were separated by flash silica gel chromatography.
Cycloadduct syn 43a (177 mg, 56%): IR (neat) 1766, 1738,
(3R*,6S*)-8-Acetyl-6-h yd r oxy-5-oxo-1,2,3,5,6,7-h exa h y-
d r oin d olizin e-3,6-d ica r boxylic Acid 3-ter t-Bu tyl Ester
6-Eth yl Ester (Syn 45). To a solution of endo-anti 44c (50
mg, 140 µmol) in chloroform (2 mL) was added p-TsOH (1 mg),
and the mixture was stirred at rt for 18 h. The solvent was
removed under reduced pressure, and the residue was sub-
jected to flash silica gel chromatography to give 46 mg (92%)
of syn 45 as a colorless oil. The same product was also formed
(85%) from the exo-anti 44b isomer by treatment with
1
1389, 1154, and 855 cm-1; H-NMR (CDCl3, 400 MHz) δ 1.13
(t, 3H, J ) 7.2 Hz), 1.16 (t, 3H, J ) 7.2 Hz), 1.30 (t, 3H, J )
7.2 Hz), 1.42 (s, 9H), 2.07-2.22 (m, 2H), 2.29 (d, 1H, J ) 11.2
Hz), 2.29-2.43 (d, 2H), 2.49 (d, 1H, J ) 11.2 Hz), 3.42-3.55
(m, 2H), 3.62 (dq, 1H, J ) 9.6 and 7.2 Hz), 4.01 (dq, 1H, J )
9.2 and 7.2 Hz), 4.25-4.37 (m, 2H), and 4.39 (d, 1H, J ) 7.2
Hz); 13C-NMR (CDCl3, 100 MHz) δ 14.0, 14.8, 15.2, 27.5, 27.8,
30.2, 45.7, 57.3, 58.4, 59.4, 61.9, 82.1, 93.8, 101.6, 108.9, 163.0,
168.5, and 169.7; HRMS calcd for C20H32NO8 (M + H)+
414.2128, found 414.2121.
p-TsOH: IR (neat) 3445, 1740, 1695, 1602, and 1368 cm-1
;
1H-NMR (CDCl3, 400 MHz) δ 1.23 (t, 3H, J ) 7.2 Hz), 1.44 (s,
9H), 2.09-2.18 (m, 1H), 2.25 (s, 3H), 2.29-2.39 (m, 1H), 2.92
(dt, 1H, J ) 16.4 and 2.4 Hz), 2.97-3.11 (m, 1H), 3.20-3.31
(m, 1H), 3.32 (dt, 1H, J ) 16.4 and 1.6 Hz), 4.21 (q, 2H, J )
7.2 Hz), 4.63 (dd, 1H, J ) 9.2 and 3.2 Hz), and 5.09 (brs, 1H);
13C-NMR (CDCl3, 75 MHz) δ 14.0, 26.7, 27.8, 29.2, 30.5, 33.3,
59.5, 62.7, 74.3, 82.7, 107.8, 151.1, 166.4, 169.0, 170.0, and
196.0; HRMS calcd for C18H26NO7 (M + H)+ 368.1709, found
368.1720.
Cycloadduct anti 43b (83 mg, 27%): IR (neat) 1762, 1742,
1
1390, 1154, and 855 cm-1; H-NMR (CDCl3, 400 MHz) δ 1.13
(t, 3H, J ) 7.2 Hz, 1.17 (t, 3H, J ) 7.2 Hz), 1.30 (t, 3H, J )
7.2 Hz), 1.42 (s, 9H), 2.04-2.10 (m, 1H), 2.15 (d, 1H, J ) 11.2
Hz), 2.32-2.49 (m, 3H), 2.43 (d, 1H, J ) 11.2 Hz), 3.42-3.56
(m, 2H), 3.64 (dq, 1H, J ) 9.6 and 7.2 Hz), 4.07 (dq, 1H, J )
9.6 and 7.2 Hz), 4.14 (dd, 1H, J ) 8.0 and 2.0 Hz), and 4.27-
4.40 (m, 2H); 13C-NMR (CDCl3, 100 MHz) δ 14.1, 14.8, 15.2,
27.1, 27.8, 31.9, 46.2, 56.4, 58.5, 59.4, 61.7, 82.5, 95.9, 101.5,
108.8, 162.9, 166.8, and 168.5; HRMS calcd for C20H32NO8 (M
+ H)+ 414.2128, found 414.2133.
Tetr a h yd r o-8-m eth yl-1,3,5-tr ioxo-2-p h en yl-7H-4,9a -ep -
oxy-1H-p yr r olo[3,4-g]in d olizin e-4-ca r boxylic Acid Meth -
yl Ester (52). Diazo imide 50 (240 mg, 1.0 mmol) and
N-phenylmaleimide (180 mg, 1.0 mmol) were allowed to react
according to the general procedure. Proton NMR analysis of
the crude product mixture showed the formation of two
diastereomeric cycloadducts identified as exo-syn 52a and
exo-anti 52b (95%, dr 36:64) which were separated by flash
silica gel chromatography.
9-Acet yl-6-oxo-10-oxa -5-a za t r icyclo[5.2.1.01,5]d eca n e-
4,7-d ica r b oxylic Acid 4-ter t-Bu t yl E st er 7-E t h yl E st er
(44). Diazo imide 29 (320 mg, 970 µmol) and methyl vinyl
ketone (140 mg, 1.9 mmol) were allowed to react according to
the general procedure. Proton NMR analysis of the crude
product mixture showed the formation of the three diastere-
omeric cycloadducts identified as exo-syn 44a , exo-anti 44b,
and endo-anti 44c (90%, dr 51:21:28) which were separated
by flash silica gel chromatography.
Cycloadduct exo-syn 52a (123 mg, 32%): mp 198-199 °C;
IR (KBr) 1766, 1745, 1709, 1476, 1389, 1197, and 1140 cm-1
;
1H-NMR (CDCl3, 400 MHz) δ 1.17 (d, 3H, J ) 6.4 Hz), 2.24
(dd, 1H, J ) 14.8 and 11.2 Hz), 2.54 (dd, 1H, J ) 14.8 and 7.2
Hz), 2.60-2.74 (m, 1H), 2.80 (dd, 1H, J ) 11.6 and 10.4 Hz),
Cycloadduct exo-syn 44a (149 mg, 42%): IR (neat) 1773,
1
1752, 1730, 1453, 1154, 934, and 841 cm-1; H-NMR (CDCl3,

6854 J . Org. Chem., Vol. 62, No. 20, 1997
Padwa and Prein
3.52 (d, 1H, J ) 6.8 Hz), 3.85 (dd, 1H, J ) 11.6 and 7.2 Hz),
3.87 (d, 1H, J ) 6.8 Hz), 3.97 (s, 3H), 7.23-7.25 (m, 2H), and
7.38-7.48 (m, 3H); 13C-NMR (CDCl3, 100 MHz) δ 16.7, 34.7,
35.1, 47.9, 51.0, 52.8, 53.4, 88.0, 103.7, 126.3, 129.1, 129.2,
131.1, 162.8, 169.2, 171.6, and 171.9. Anal. Calcd for
C19H18N2O6: C, 61.62; H, 4.90; N, 7.56. Found: C, 61.61; H,
4.96; N, 7.54.
Tet r a h yd r o-1,3,5-t r ioxo-2-m et h yl-7H -4,9a -ep oxy-1H -
p yr r olo[3,4-g]in d olizin e-4,8-d ica r boxylic Acid Dim eth yl
Ester (54). Diazo imide 51 (300 mg, 1.1 mmol) and N-
methylmaleimide (120 mg, 1.1 mmol) were allowed to react
according to the general procedure. Proton NMR analysis of
the crude product mixture showed the formation of two
diastereomeric cycloadducts identified as exo-syn 54a and
exo-anti 54b (95%, dr 50:50) which were separated by flash
silica gel chromatography.
Cycloadduct exo-anti 52b (215 mg, 56%): mp 188-189 °C;
IR (KBr) 1759, 1745, 1715, 1595, 1496, 1382, 1197, and 749
1
cm-1; H-NMR (CDCl3, 400 MHz) δ 1.18 (d, 3H, J ) 6.8 Hz),
Cycloadduct exo-syn 54a (182 mg, 47%): mp 217-218 °C;
2.06 (dd, 1H, J ) 14.0 and 6.4 Hz), 2.71-2.81 (m, 1H), 2.86
(dd, 1H, J ) 14.0 and 6.8 Hz), 3.21 (dd, 1H, J ) 11.2 and 7.2
Hz), 3.46 (dd, 1H, J ) 11.2 and 7.2 Hz), 3.51 (d, 1H, J ) 6.8
Hz), 3.83 (d, 1H, J ) 6.8 Hz), 3.96 (s, 3H), 7.21-7.24 (m, 2H),
and 7.39-7.47 (m, 3H); 13C-NMR (CDCl3, 100 MHz) δ 18.9,
33.3, 34.9, 47.8, 49.6, 52.5, 53.3, 89.6, 103.7, 126.3, 129.0, 129.2,
131.1, 162.7, 167.7, 171.6, and 171.9. Anal. Calcd for
C19H18N2O6: C, 61.62; H, 4.90; N, 7.56. Found: C, 61.55; H,
4.95; N, 7.46.
IR (KBr) 1759, 1730, 1702, 1439, 1175, and 1133 cm-1
;
1H-
NMR (CDCl3, 400 MHz) δ 2.66 (dd, 1H, J ) 15.2 and 7.6 Hz),
2.89 (dd, 1H, J ) 15.2 and 10.0 Hz), 2.99 (s, 3H), 3.39-3.45
(m, 2H), 3.46 (d, 1H, J ) 6.8 Hz), 3.74 (d, 1H, J ) 6.8 Hz),
3.77 (s, 3H), 3.90-3.97 (m, 1H), and 3.99 (s, 3H); 13C-NMR
(CDCl3, 100 MHz) δ 25.5, 30.3, 43.5, 46.1, 47.7, 52.4, 52.6, 53.4,
87.9, 102.5, 162.6, 168.9, 171.4, 172.1, and 172.5. Anal. Calcd
for C15H16N2O8: C, 51.14; H, 4.58; N, 7.95. Found: C, 51.04;
H, 4.56; N, 7.92.
Tet r a h yd r o-2,8-d im et h yl-1,3,5-t r ioxo-7H -4,9a -ep oxy-
1H-p yr r olo[3,4-g]in d olizin e-4-ca r boxylic Acid Meth yl Es-
ter (53). Diazo imide 50 (230 mg, 1.0 mmol) and N-methyl-
maleimide (110 mg, 1.0 mmol) were allowed to react according
to the general procedure. Proton NMR analysis of the crude
product mixture showed the formation of two diastereomeric
cycloadducts identified as exo-syn 53a and exo-anti 53b (95%,
dr 32:68) which were separated by flash silica gel chromatog-
raphy.
Cycloadduct exo-syn 53a (94 mg, 30%): mp 177-178 °C;
IR (KBr) 1766, 1733, 1695, 1282, 1125, and 754 cm-1; 1H-NMR
(CDCl3, 400 MHz) δ 1.13 (d, 3H, J ) 6.8 Hz), 2.16 (dd, 1H, J
) 15.2 and 10.8 Hz), 2.44 (dd, 1H, J ) 15.2 and 7.2 Hz), 2.50-
2.64 (m, 1H), 2.74 (dd, 1H, J ) 11.6 and 10.8 Hz), 2.93 (s, 3H),
3.36 (d, 1H, J ) 6.8 Hz), 3.71 (d, 1H, J ) 6.8 Hz), 3.77 (dd,
1H, J ) 11.6 and 7.2 Hz), and 3.93 (s, 3H); 13C-NMR (CDCl3,
100 MHz) δ 14.1, 16.6, 25.4, 34.6, 35.0, 47.8, 50.8, 52.7, 53.2,
87.6, 103.3, 162.8, 169.1, 172.4, and 172.8. Anal. Calcd for
C14H16N2O6: C, 54.54; H, 5.23; N, 9.09. Found: C, 54.38; H,
5.21; N, 9.16.
Cycloadduct exo-anti 54b (178 mg, 46%): mp 209-210 °C;
IR (KBr) 1759, 1738, 1695, 1439, 1376, 1225, and 1133 cm-1
;
1H-NMR (CDCl3, 400 MHz) δ 2.78 (dd, 1H, J ) 15.6 and 4.4
Hz), 2.96 (dd, 1H, J ) 15.6 and 7.6 Hz), 2.98 (s, 3H), 3.39 (d,
1H, J ) 6.8 Hz), 3.40-3.46 (m, 2H), 3.72 (s, 3H), 3.73 (d, 1H,
J ) 6.8 Hz), 3.97 (s, 3H), and 4.05-4.11 (m, 1H); 13C-NMR
(CDCl3, 100 MHz) δ 25.5, 29.9, 44.0, 45.4, 47.7, 52.4, 52.8, 53.3,
88.5, 102.5, 162.4, 168.3, 171.3, 172.1, and 172.6. Anal. Calcd
for C15H16N2O8: C, 51.14; H, 4.58; N, 7.95. Found: C, 51.12;
H, 4.44; N, 7.95.
Ack n ow led gm en t. We gratefully acknowledge the
National Cancer Institute (CA-26751) for generous
support of this work. M.P. acknowledges the NATO for
a postdoctoral fellowship through the Deutscher Aka-
demischer Austauschdienst (DAAD). We also thank
Scott M. Sheehan for determining the X-ray crystal
structure of cycloadduct 35. The use of the high-field
NMR spectrometer used in these studies was made
possible through equipment grants from the NIH and
NSF.
Cycloadduct exo-anti 53b (191 mg, 61%): mp 161-162 °C;
IR (KBr) 1759, 1730, 1702, 1432, 1289, 1126, and 1054 cm-1
;
1H-NMR (CDCl3, 400 MHz) δ 1.19 (d, 3H, J ) 6.8 Hz), 2.02
(dd, 1H, J ) 14.0 and 6.4 Hz), 2.72-2.79 (m, 1H), 2.84 (dd,
1H, J ) 14.0 and 6.8 Hz), 2.98 (s, 3H), 3.20 (dd, 1H, J ) 10.8
and 6.0 Hz), 3.37 (d, 1H, J ) 6.8 Hz) 3.45 (dd, 1H, J ) 10.8
and 6.8 Hz), 3.71 (d, 1H, J ) 6.8 Hz), and 3.99 (s, 3H); 13C-
NMR (CDCl3, 100 MHz) δ 18.8, 25.4, 33.3, 35.0, 47.7, 49.5,
52.5, 53.3, 89.3, 103.4, 162.8, 167.6, 172.4, and 172.8. Anal.
Calcd for C14H16N2O6: C, 54.54; H, 4.23; N, 9.09. Found: C,
54.46; H, 5.18; N, 9.07.
Su p p or tin g In for m a tion Ava ila ble: 1H-NMR and 13C-
NMR spectra for new compounds lacking analyses together
with an ORTEP drawing for structure 35 (15 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O970625O