Formal Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides to (S)-2-p-Tolylsulfinyl-2-cyclopentenone

Article abstract of DOI:10.1021/jo035369w

Azomethine ylides, derived from iminoesters 1 and DBU in the presence of silver salts, react with (S)-2-p-tolylsulfinyl-2-cyclopentenone 2 in a completely regio- and endoselective manner but with a low facial selectivity, affording a mixture of two cycloa

Full text of DOI:10.1021/jo035369w

F or m a l Asym m etr ic 1,3-Dip ola r Cycloa d d ition of Azom eth in e
Ylid es to (S)-2-p-Tolylsu lfin yl-2-cyclop en ten on e†
J ose´ Luis Garc´ıa Ruano,* Amelia Tito,* and M. Teresa Peromingo
Departamento de Qu´ımica Orga´nica, Universidad Auto´noma, Cantoblanco, 28049 Madrid, Spain
joseluis.garcia.ruano@uam.es
Received September 17, 2003
Azomethine ylides, derived from iminoesters 1 and DBU in the presence of silver salts, react with
(S)-2-p-tolylsulfinyl-2-cyclopentenone 2 in a completely regio- and endoselective manner but with
a low facial selectivity, affording a mixture of two cycloadducts 3 and 4. When the ylides were
prepared with LHMDS, only one diastereoisomer 3 was obtained in an almost quantitative yield.
A nucleophilic addition/ring closure process easily accounts for the stereochemical results.
Compounds 3 were transformed into optically pure 4-oxocyclopenta[c]dihydropyrroles and tetra-
hydropyrroles by elimination of the sulfinyl group.
1. In tr od u ction
investigated its Diels-Alder reactions,10,11 with excellent
stereochemical results in most of the cases. However, its
reactions with dipoles have not been previously studied.
On the basis of these precedents, we decided to explore
the behavior of compound 2 as a chiral dipolarophile. As
dipoles we choose azomethine ylides,12 intensively inves-
tigated by Grigg,13 Kanemasa,14 and other authors.15 This
election was based on the interest of obtaining adducts
Asymmetric 1,3-dipolar cycloadditions offer a powerful
and reliable synthetic methodology to access five-
membered heterocyclic rings in a regio- and stereocon-
trolled fashion.1 Most of the reported studies concern the
use of acrylates as chiral dipolarophiles. Enantiomerically
pure vinyl sulfoxides, widely used as dienophiles,2 have
been much less investigated as homochiral dipolaro-
philes.2 Several years ago we initiated a research pro-
gram to explore the scope and limitations of vinyl
sulfoxides in asymmetric 1,3-dipolar cycloadditions. In
this field, we have already reported the behavior of some
sulfinyl ethylenes in reactions with diazoalkanes,3 nitrile
oxides,4 and azomethine ylides.5 All of these studies
revealed the sulfinyl group as a good chiral auxiliary in
1,3-dipolar reactions, as well as the possibilities of the
sulfinylated adducts as valuable synthetic intermediates.
R-Sulfinylcyclopentenone 2 has been widely used in
asymmetric synthesis because of the structural interest
of the resulting compounds. Thus, Posner,6 Paquette,7
and Tokoroyama8 studied its Michael additions; Toru9
explored its behavior in radical additions; and our group
(6) Posner, G. H.; Hulce, M.; Mallamo, J . P. J . Org. Chem. 1981,
46, 5244. (b) Posner, G. H.; Mallamo, J . P.; Miura, K. J . Am. Chem.
Soc. 1981, 103, 2886. (c) Posner, G. H.; Asirvatham, E. J . Org. Chem.
1985, 50, 2589. (d) Posner, G. H. Acc. Chem. Res. 1987, 20, 72. (d) See
also: Posner, G. H. In The Chemistry of Sulphones and Sulphoxides;
Patai, S., et al., Eds.; Wiley: New York, 1988; Vol. 16, p 823.
(7) Paquette, L. A.; Tae, J .; Arrington, M. P.; Sadoun, A. H. J . Am.
Chem. Soc. 2000, 122, 2742.
(8) Pan, L. R.; Tokoroyama, T. Tetrahedron Lett. 1992, 33, 1469.
(9) Mase, N.; Watanabe, Y.; Ueno, Y.; Toru, T. J . Org. Chem. 1997,
62, 7794.
(10) Alonso, I.; Carretero, J . C.; Garc´ıa Ruano, J . L. Tetrahedron
Lett. 1989, 30, 3853.
(11) Alonso, I.; Carretero, J . C.; Garc´ıa Ruano, J . L.; Mart´ın
Cabrejas, L. M.; Lo´pez-Solera, I.; Raithby, P. R. Tetrahedron Lett. 1994,
35, 9461.
(12) Broggini, G.; Zecchini, G. Synthesis 1999, 905. (b) Harwood, L.
M.; Vickers, R. J . In Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; Padwa, A.,
Pearson, H., Eds.; Wiley: Huboken, NJ , 2003; pp 169-252.
(13) Barr, D. A.; Grigg, R.; Gunaratne, H. Q. N.; Kemp, J .; Mc-
Meekin, P.; Sridharan, V. Tetrahedron 1988, 44, 557. (b) Grigg, R.;
Sridharan, V. In Advances in Cycloaddition; Curran, D. P., Ed.; J AI:
London, 1993; Vol. 3, pp 161-204. (c) Barr, D. A.; Dorrity, M. J .; Grigg,
R.; Malone, J . F.; Montgomery, J .; Rajviroongit, S.; Stevenson, P.
Tetrahedron Lett. 1990, 31, 6569. (d) Copper, D. M.; Grigg, R.;
Hargreaves, S.; Kennewell, P.; Redpath, J . Tetrahedron 1995, 51, 7791.
(e) Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2475 (and references
therein). (f) Grigg, R.; Montgomery, J .; Somasunderan, A. Tetrahedron
1992, 48, 10431.
(14) Tsuge, O.; Kanemasa, S.; Yoshioka, M. J . Org. Chem. 1988,
53, 1384. (b) Kanemasa, S.; Yoshioka, M.; Tsuge, O. Bull. Chem. Soc.
J pn. 1989, 62, 869. (c) Kanemasa, S.; Tsuge, O. In Advances in
Cyloaddition; Curran, D. P., Ed.; J AI: London, 1993; Vol. 3, pp 99-
159. (d) Kanemasa, S.; Yamamoto, H.; Wada, E.; Sakurai, T.; Urushido,
K. Bull. Chem. Soc. J pn. 1990, 63, 2857. (e) Kanemasa, S.; Hayashi,
T.; Yamamoto, H.; Sakurai, T. J . Org. Chem. 1991, 56, 4473.
(15) Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L.; Pilati,
T. Tetrahedron: Asymmetry 1991, 2, 1329. (b) Galley, G.; Liebscher,
J .; Pa¨tzel, M. J . Org. Chem. 1995, 60, 5005.
† Dedicated to the memory of Prof. J esu´s H. Rodr´ıguez Ramos.
(1) Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products; Padwa, A., Pearson, H.,
Eds.; Wiley: Huboken, NJ , 2003. (b) Golthelf, K. V.; J orgensen, K. A.
Chem. Rev. 1998, 98, 863. (c) Karlsson, S.; Ho¨gberg, H. E. Asymmetric
1,3-Dipolar Cycloadditions for the Construction of Enantiomerically
Pure Heterocycles, A Review. Org. Prep. Proced. Int. 2001, 33, 103-
172. (d) Nadin, A. J . Chem. Soc., Perkin Trans. 1 1998, 3493. (e) Najera,
C.; Sansano, J . M. Curr. Org. Chem. 2003, 7, 1105.
(2) Garc´ıa Ruano, J . L.; Cid, B. In Topics in Current Chemistry; Page,
P. C. B., Ed.; Springer: Berlin, 1999; Vol. 204, pp 1-126 (and
references therein).
(3) Garc´ıa Ruano, J . L.; Bercial, F.; Gonza´lez, G.; Mart´ın Castro, A.
M.; Mart´ın, M. R. Tetrahedron: Asymmetry 2002, 13, 1993. (b) Garc´ıa
Ruano, J . L.; Fraile, A.; Mart´ın, M. R. Tetrahedron: Asymmetry 1996,
7, 1943. (c) Garc´ıa Ruano, J . L.; Fraile, A.; Gonza´lez, G.; Mart´ın, M.
R.; Clemente, F. R.; Gordillo, R. J . Org. Chem. 2003, 68, 6522.
(4) Garc´ıa Ruano, J . L.; Fraile, A.; Mart´ın, M. R. Tetrahedron 1999,
55, 14491.
(5) Garc´ıa Ruano, J . L.; Tito, A.; Peromingo, M. T. J . Org. Chem.
2002, 67, 981.
10.1021/jo035369w CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/22/2003
J . Org. Chem. 2003, 68, 10013-10019
10013

Garc´ıa Ruano et al.
TABLE 1. F or m a l Asym m etr ic 1,3-Dip ola r Cycloa d d ition of N-Meta la ted Azom eth in e Ylid e Gen er a ted fr om Im in oester s
1a -d w ith 2
iminoester
Ar
conditions
solvent
product ratioa (b)
entry
R
salt/base (equiv)
T (°C)
t (h)
3
4
1
2
3
4
5
6
7
8
1a
1a
1b
1c
1d
1d
1d
1d
1d
1c
1c
1d
1d
1d
1d
1a
1b
1c
Ph
Ph
Ph
H
H
Me
H
Me
Me
Me
Me
Me
H
AgOAc/DBU (1.5/1.0)
AgOAc/DBU (0.075/0.6)
AgOAc/DBU (0.075/0.6)
AgOAc/DBU (0.075/0.6)
AgOAc/DBU (0.075/0.6)
AgOAc/DBU (0.075/0.6)
AgOAc/DBU (0.075/0.6)
AgOAc/DBU (0.075/0.6)
DBU (1.0)
AgOAc/Et3N (1.5/1.0)
AgOAc/Et3N (0.075/0.6)
LDA (1.1)
LHMDS (1.1)
NaHMDS (1.1)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
rt
rt
rt
0
rt
0
rt
0
0
rt
rt
-78
-78
-78
-78
-78
-78
-78
0.20
0.25
0.42
1.50
0.80
1.00
0.25
1.00
0.75
1.20
1.20
inst
inst
inst
inst
inst
inst
inst
52 (42)
50 (37)
50 (12)
58 (42)
51 (34)
50 (22)
57 (13)
50 (19)
52 (17)
55 (12)
52 (20)
90 (72)
>98 (91)
68 (48)
75 (54)
>98 (89)
>98 (91)
>98 (93)
48 (38)
50 (37)
50 (12)
42 (31)
49 (33)
50 (22)
43 (10)
50 (19)
48 (16)
45 (10)
48 (18)
10 (8)
<2
2-Naph
2-Naph
2-Naph
2-Naph
2-Naph
2-Naph
2-Naph
2-Naph
2-Naph
2-Naph
2-Naph
2-Naph
Ph
THF
9
MeCN
MeCN
MeCN
THF
THF
THF
THF
THF
THF
THF
10
11
12
13
14
15
16
17
18
H
Me
Me
Me
Me
H
32 (23)
25 (18)
<2
<2
<2
KHMDS (1.1)
LHMDS (1.1)
LHMDS (1.1)
LHMDS (1.1)
Ph
2-Naph
Me
H
a
b
Determined by 1H NMR from the reaction crude. Isolated yield (%).
containing the skeleton of 4-oxocyclopenta[c]pyrrolidine,
which is present in compounds exhibiting interesting
pharmacological properties as protease inhibitors16 and
analgesics,17 as well as in some intermediates in the
synthesis of kainic acid.18 Moreover, to the best of our
knowledge, the cyclopentenone ring has never been used
as a dipolarophile in asymmetric 1,3-dipolar cycloaddi-
tions with azomethine ylides.19 In this paper, we report
the results obtained in the reactions of compound 2 with
iminoesters under different conditions, as well as some
chemical transformation of the resulting adducts involv-
ing the elimination of the sulfinyl group.
the standard conditions for 1,3-dipolar cycloadditions
reported by Grigg (DBU or Et3N in the presence of either
a silver or lithium salt).13 The results are indicated in
Table 1.
The reaction of 1a in acetonitrile with DBU (1.0 equiv)
in the presence of AgOAc (1.5 equiv), at room tempera-
ture, afforded an almost equimolecular mixture of only
two adducts, 3a and 4a (entry 1). Similar results were
obtained by using the base and the silver salt in catalytic
amounts21 (entry 2). The latter conditions were then used
in reactions of 2 with 1b-d (entries 3-5). The structure
of the dipole has scarce influence on the stereoselectivity,
which is similar in all of the cases, but the reactivity is
lower for 1b and 1d (R ) Me). Both polymerization of
the dipolarophile and hydrolysis of the dipoles contrib-
uted to lowering of the overall isolated yields when the
2. Resu lts a n d Discu ssion
We first studied the reactions of the R-sulfinylcyclo-
pentenone 2, prepared following previously reported
methods,9,20 with the N-metalated azomethine ylides
generated from the corresponding iminoesters 1 under
22
temperature reaction was under 0 °C.
We have studied the influence of the factors that were
allowed to modify the stereoselectivity of the reactions
of the ylides with 2-p-tolylsulfinyl acrylates,5 but none
of them improved our results.23 Thus, the use of THF as
a solvent (which provoked an inversion of the facial
selectivity) decreases the reaction rate and therefore the
yield (entries 7 and 8), but the stereoselectivity was
scarcely modified. The same results were obtained when
the reactions were conducted in the absence of the silver
(16) Babine, R. E.; Chen, S. H.; Lamar, J . E.; Snyder, N. J .; Sun, X.
D.; Tebbe, M. J .; Victor, F.; Wang, Q. M.; Yip, Y. Y. M.; Collado, I.;
Garcia-Paredes, C.; Parker, R. S., III; J in, L.; Guo, D.; Glass, J . I. PCT
Int. Appl. 2002, 424 pp (Patent No. WO 0218369).
(17) Carmosin, R. J .; Carson, J . R.; Pitis, P. M. (Ortho Pharmaceuti-
cal Corp.). U.S. Patent 5541217, 1996, 9 pp.
(18) Monn, J . A. (Eli Lilly Co.). U.S. Patent 5352799, 1994, 11 pp.
(b) Parsons, A. F. Tetrahedron 1996, 52, 4149. (c) Monn, J . A.; Valli,
M. J . J . Org. Chem. 1994, 59, 2773. (d) Cantrell, B. E.; Zimmerman,
D. M.; Monn, J . A.; Kamboj, R. K.; Hoo, K. H.; Tizzano, J . P.; Pullar,
I. A.; Farrell, L. N.; Bleakman, D. J . Med. Chem. 1996, 39, 3617. (e)
Lorthiois, E.; Marek, I.; Normant, J . F. J . Org. Chem. 1998, 63, 2442.
(f) Baldwin, J . E.; Fryer, A. M.; Pritchard, G. J . J . Org. Chem. 2001,
66, 2588.
(20) Posner, G. H. Org. Synth. 1985, 64, 196. (b) Geng, F.; Liu, J .;
Paquette, L. A. Org. Lett. 2002, 4, 71.
(21) Galley, G.; Liebscher, J .; Pa¨tzel, M. J . Org. Chem. 1995, 60,
5005.
(19) Husinec, S.; Porter, A. E. A.; Roberts, J . S.; Stracgan, C. H. J .
Chem. Soc., Perkin Trans 1 1984, 2517. (b) Panandora-Yambolieva,
K. V. Bulg. Chem. Commun. 1992, 25, 315. (c) Ishii, K.; Shimada, Y.;
Sugiyama, S.; Noji, M. J . Chem. Soc., Perkin Trans. 1 2000, 3022. (d)
Butler, R. N.; Coine´, A. G.; Cunningham, W. J .; Luke, A. J Chem. Soc.,
Perkin Trans. 2 2002, 1807.
(22) At temperatures under 0 °C, polymerization of the dipolarophile
is almost quantitative.
(23) We have also studied the influence of Lewis acids such as
EtAlCl2 or ZnBr2 (which substantially modified the stereochemical
results of the Diels-Alder reactions of compound 210,11), but we did
not detect any changes in the composition of the reaction mixtures.
10014 J . Org. Chem., Vol. 68, No. 26, 2003

1,3-Dipolar Cycloaddition of Azomethine Ylides
noester 1a to 2-cyclohexenone),27 we observed the im-
mediate formation of a mixture of the same two com-
pounds, 3d and 4d , but the stereoselectivity was sub-
stantially increased (80% de, entry 12, Table 1). This
excellent result prompted us to optimize the reaction. The
best conditions involved the use of LHMDS as the base,
which yielded 3d in an almost quantitative yield (entry
13). We have also studied the behavior of 1d in the
presence of NaHMDS and KHMDS (entries 14 and 15).
In both cases, the reactions were more sluggish and
slower, affording almost equimolecular mixtures of 3d
and 4d . These results suggest that the essential role of
the lithium cation is for achieving very high or complete
stereoselectivity.28 Finally, the iminoesters 1a -d were
treated with LHMDS and then with 2, yielding only one
diastereoisomer (3a -d ) in isolated yields higher than
90% (entries 13 and 16-18).
All of these results can be explained by assuming that
these reactions take place according to a nucleophilic
addition/ring closure (NARC) process, in which the
lithium acts as a tether between the reagent and the
substrate (Figure 3). In the first step, the lithium of the
dipole is associated with the sulfinyl oxygen at the
electrophile. This species can evolve to the 1,4-addition
product through two transition states, TS-A and TS-B,
resulting from the approach of the nucleophile to each
face of the sulfinylcyclopentenone (Figure 3). The strong
steric interactions produced by the p-tolyl group to the
approach of the nucleophile to the upper face of the
cyclopentenone (TS-B) would explain that compounds
3a -d , resulting from TS-A, were clearly favored. After
the formation of the C-C bond, the stereochemistry of
the ring closure (second step of the process) is imposed
by the rigidity of the system (only the fusion cis is
possible) and the stereochemistry of the CdN (E in all
cases; Figure 3).
When sodium or potassium bases were used (these
metals cannot act as a tether), the approaches of the syn
dipole took place in a intermolecular manner. TS-B′
would be the transition state resulting from the attack
to the upper face (the steric interactions destabilizing
TS-B do not exist), whereas TS-A′, which is identical to
TS-A but without lithium (it has not been depicted in
Figure 3), would be formed in the approach to the bottom
face. Both new transition states exhibit similar stability,
which justifies the observed low facial selectivity. A
similar explanation can also account for the results
obtained in the reactions conducted with DBU in the
presence of silver salts. Seemingly, 2 does not react with
azomethine ylides according to a concerted 1,3-dipolar
cycloaddition. Instead, it reacts in a stepwise mechanism
involving a NARC process.29
F IGURE 1. NOESY experiments for 3d and 4d .
salt (entry 9) or by using Et3N instead of DBU as the
base24 (entries 10 and 11).
The relative stereochemistry of the substituents Ar and
CO2Me for the adducts 3 and 4 was established as cis on
the basis of NOESY experiments (Figure 1). The absolute
configuration of the four new stereocenters was unequivo-
cally assigned by single-crystal X-ray analysis25 in the
case of compounds 3d and 4d .
On the basis of the configurational assignment of the
cycloadducts 3 and 4, we can conclude that all of the
reactions are completely regio- and endoselective (with
respect to the carbonyl group at the dipolarophile). By
contrast, the π-facial selectivity is very poor in all of the
conditions studied. The formation of diastereoisomers 3
and 4 can be explained by assuming the endo approach
of the syn dipole to both faces of the dipolarophile, which
adopts in each case a different conformation around the
C-S bond in order to minimize their steric interactions
with the dipole (Figure 2).
The higher stability of the syn configuration for dipoles,
as a consequence of the association of the metal to both
oxygen and nitrogen, is easily understandable. However,
the strong interactions between the syn dipole and the
methylene groups at the cyclopentenone ring (Figure 2)
are not easily compatible with the complete endoselec-
tivity observed in these cycloadditions. In other ways, the
scarce influence of the different factors considered in this
study (temperature, solvent, Lewis acids, etc.) on the
stereochemical results is also difficult to rationalize in
terms of a concerted cycloaddition.26
At this point, we decided to study the reactions of the
iminoesters 1 and 2 in the presence of stronger bases.
When 1d was treated with LDA at -78 °C and then 2-p-
tolylsulfinylcyclopentenone (2) was added (the standard
reaction conditions for the Michael addition of the imi-
The adducts 3 and 4 were independently transformed
into 4-oxocyclopenta[c]pyrrole derivatives by desulfiny-
(24) The reactions do not work by using highly hindered bases such
as 2,2,6,6-tetramethylpiperidine.
(25) The authors have deposited atomic coordinates for 3d and 4d
with the Cambridge Crystallographic Data Centre (Deposit Nos.
218777 and 218778, respectively). The coordinates can be obtained,
upon request, from the Director, Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.
(26) To check that the obtained mixture (3 + 4) could be the result
of thethermodynamic equilibration, because it had been observed in
the reactions of 1 with sulfinyl acrylates under certain conditions (ref
5), we studied the behavior of both diastereoisomers after their
chromatographic separation under the same conditions as those
indicated in Table 1. All of the resulting trials were unfruitful because
we recovered the unaltered starting materials. This suggests that the
retro-1,3-dipolar reaction is not taking place under such conditions.
(27) Stork, G.; Leong, A. Y. W.; Touzin, A. M. J . Org. Chem. 1976,
41, 3491.
(28) On the basis of the results obtained by Posner in the Michael
addition of 2 with Grignard reagents and lithium enolates,6 we have
also studied the reaction of 1d with 2 in the presence of ZnBr2 by using
LDA as a base. Under these conditions, we observed the completely
stereoselective evolution into 3d instead of the expected inversion of
the facial selectivity.
(29) Ayerbe, A.; Arrieta, A.; Cossio, F. P. J . Org. Chem. 1998, 63,
1795. (b) Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.;
Linden, A.; Cossio, F. P. J . Am. Chem. Soc. 2000, 122, 6078.
J . Org. Chem, Vol. 68, No. 26, 2003 10015

Garc´ıa Ruano et al.
F IGURE 2. Favored endo approaches accounting for the formation of compounds 3 and 4.
F IGURE 3. Stereochemical evolution of the substrates according to the NARC process.
lation. Thus, the hydrogenolysis of the C-S bond of
compounds 3a -d with Raney nickel at -20 °C afforded
enantiomerically pure tetrahydropyrroles (-)-5a -d ,
whereas their enantiomers (+)-5a -d were exclusively
obtained from 4a -d (Scheme 1). Activated powdered
zinc30 simultaneously effected desulfinylation and hy-
drogenolysis of the benzylic C-N bond when R ) Me or
aromatization when R ) H. Thus, compounds 3b,d and
4b,d evolved respectively into each enantiomer of the
monocyclic R-aminoesters 6b,d , whereas compounds 3a ,c
and 4a ,c evolved into the corresponding aromatic rings
8a ,c. Finally, pyrolytic desulfinylation of 3b,d and 4b,d
at refluxing toluene afforded respectively the enantio-
mers of 4-oxocyclopenta[c]dihydropyrrole 7 (Scheme 1),
with an unusual bicyclic skeleton31 potentially useful as
a chiral synton. Under similar conditions, 3a and 4a were
transformed into the same aromatic compound 8a . Analo-
gously, 3c and 4c (R ) H, Ar ) 2-Naph) were converted
into 8c. In all cases, the yields were very high, and the
specific rotation results of the obtained enantiomers were
identical but with the opposite sign, which supports their
homochiral integrity.
In summary, the synthesis of the optically pure 4-oxo-
cyclopenta[c]pyrrolidine derivatives can be achieved by
reaction of 2 with N-metalated azomethine ylides, fol-
lowed by desulfinylation with Raney nickel of the result-
ing adducts. The stereoselectivity depends on the reaction
conditions becoming complete when LHMDS is used as
the base. A NARC stepwise mechanism accounts for the
observed stereoselectivity under the different conditions.
Pyrolytic desulfinylation of the adducts affords 4-oxocy-
clopenta[c]dihydropyrroles when R ) Me.
3. Exp er im en ta l Section
Gen er a l Meth od s. All moisture-sensitive reactions were
performed in flame-dried glassware equipped with rubber
septa under positive pressure of argon. THF and diethyl ether
were distilled from sodium-benzophenone under argon and
CH2Cl2 over P2O5. Lewis acids were commercially available
and were used without further purification. ZnBr2 was flame-
dried in the reaction flask prior to use. Flash chromatography
was carried out with silica gel Merck 60 (230-400 mesh,
American Society for Testing and Materials). NMR spectra
were determined in CDCl3 solutions at 300 and 75 MHz for
(30) Holton, R. A.; Crouse, D. J .; Williams, A. D.; Kennedy, R. M. J .
Org. Chem. 1987, 52, 2317.
(31) Barluenga, J .; Fan˜anas, F. J .; Sanz, R.; Ignacio, J . M. Eur. J .
Org. Chem. 2003, 771.
10016 J . Org. Chem., Vol. 68, No. 26, 2003

1,3-Dipolar Cycloaddition of Azomethine Ylides
SCHEME 1
1H and 13C NMR, respectively; J values are given in hertz.
Melting points were measured using a Gallenkamp apparatus
in open capillary tubes and are uncorrected. The optical
rotations were measured at room temperature (20-23 °C)
using a Perkin-Elmer 241 MC polarimeter (concentration in
g/100 mL). The compounds 1 and 2 were synthesized and
purified according to the procedure described in refs 13 and
14 and refs 9 and 20, respectively.
1H), 4.22 (d, 1H, J ) 7.0), 3.85 (s, 3H), 3.49 (m, 1H), 2.51 (bs,
1H), 2.37 (s, 3H), 2.20-2.03 (m, 1H), 1.82-1.59 (m, 1H), 1.32-
1.18 (m, 2H); 13C NMR δ 210.1, 174.5, 142.1, 136.1, 136.0,
129.7, 128.4, 128.3, 127.6, 125.5, 83.8, 67.2, 63.8, 52.3, 41.5,
40.5, 22.5, 21.4; MS (electrospray+) m/z 398.2 (MH+). Anal.
Calcd for C22H23NO4S: C, 66.48; H, 5.83; N, 3.52; S, 8.07.
Found: C, 66.31; H, 5.65; N, 3.68; S, 8.05.
Met h yl (+)-(1S,3S,3a S,6a S,SS)-4-Oxo-3-p h en yl-3a -p -
t olylsu lfin yloct a h yd r ocyclop en t a [c]p yr r ole-1-ca r b oxy-
la te (4a ): yellow oil; [R]D +161 (c 0.5, CHCl3); IR (CHCl3) 3428,
Meth od A: Rea ction s w ith DBU. Gen er a l P r oced u r e.
A solution of the corresponding iminoester 1 (1 equiv) in the
appropriate solvent (5.5 mL/0.5 mmol) and AgOAc (amounts
indicated in Table 1) was stirred for 10 min, and base (amounts
indicated in Table 1) was added to the above solution. The
reaction mixture was stirred for 10 min before addition of 2
(1 equiv) in the appropriate solvent (5.5 mL/0.5 mmol) at the
temperature indicated in Table 1. When the reaction was
completed (monitored by TLC ethyl acetate-hexane, 1:2),
saturated aqueous ammonium chloride was added. The prod-
ucts were extracted with diethyl ether. The combined organic
extracts were washed with brine. The organic layer was dried
(Na2SO4) and concentrated under vacuum. The residue was
purified by flash column chromatography (ethyl acetate-
hexane, 1:5) to give a mixture of cycloadducts 3 and 4.
Meth od B: Rea ction s w ith LHMDS. Gen er a l P r oce-
d u r e. To a 1 M solution of LHMDS (0.25 mmol, 1.1 equiv) in
THF (1.8 mL) at -78 °C was added a solution of the corre-
sponding iminoester 1 (1.5 equiv) in THF (6.8 mL). The
mixture was stirred at -78 °C for 30 min, and a solution of 2
(0.23 mmol, 1 equiv) in THF (6.8 mL) was added. After 5 min,
the reaction was quenched at -78 °C with a saturated aqueous
solution of NH4Cl (12 mL) and extracted with ethyl acetate (2
× 10 mL). The organic extracts were washed with brine (7
mL) and dried (MgSO4). The solvent was removed under
vacuum and the crude purified by flash chromatography (ethyl
acetate-hexane, 1:5) to give only cycloadduct 3.
1
1758, 1739 cm-1; H NMR δ 7.61-7.21 (m, 9H), 4.95 (s, 1H),
4.15 (d, 1H, J ) 7.0), 3.86 (s, 3H), 3.52 (m, 1H), 2.52 (bs, 1H),
2.39 (s, 3H), 2.0-2.01 (m, 1H), 1.80-1.59 (m, 1H), 0.97-0.86
(m, 2H); 13C NMR δ 207.3, 171.5, 143.5, 137.2, 136.0, 129.3,
128.4, 128.1, 127.3, 125.5, 79.9, 67.5, 63.9, 52.0, 41.3, 40.5, 22.3,
21.4; MS (electrospray+) m/z 398.2 (MH+). Anal. Calcd for
C
22H23NO4S: C, 66.48; H, 5.83; N, 3.52; S, 8.07. Found: C,
66.62; H, 5.98; N, 3.74; S, 8.39.
Meth yl (-)-(1R,3R,3a R,6a R,SS)-1-Meth yl-4-oxo-3-p h en -
yl-3a -p -t olylsu lfin yloct a h yd r ocyclop en t a [c]p yr r ole-1-
ca r boxyla te (3b): yellow oil; [R]D -69.8 (c 0.5, CHCl3); IR
(CHCl3) 3425, 1730, 1725 cm-1; 1H NMR δ 7.53-7.28 (m, 9H),
5.08 (s, 1H), 3.82 (s, 3H), 3.03 (dd, 1H, J ) 9.4, J ) 3.4), 2.41
(s, 3H), 2.31 (bs, 1H), 2.20-2.07 (m, 1H), 1.73 (s, 3H), 1.60-
1.47 (m, 2H), 1.09-0.96 (m, 2H); 13C NMR δ 211.3, 174.7,
142.3, 136.5, 136.4, 129.8, 128.4, 128.3, 127.6, 125.5, 85.5, 68.3,
64.9, 52.1, 48.6, 40.4, 25.2, 24.5, 21.3; MS (FAB) m/z 412.6
(MH+). Anal. Calcd for C23H25NO4S: C, 67.13; H, 6.12; N, 3.40;
S, 7.79. Found: C, 67.35; H, 5.98; N, 3.52; S, 7.65.
Meth yl (+)-(1S,3S,3a S,6a S,SS)-1-Meth yl-4-oxo-3-p h en -
yl-3a -p -t olylsu lfin yloct a h yd r ocyclop en t a [c]p yr r ole-1-
ca r boxyla te (4b): yellow oil; [R]D +167 (c 0.5, CHCl3); IR
(CHCl3) 3385, 1745, 1730 cm-1; 1H NMR δ 7.60-7.21 (m, 9H),
4.97 (s, 1H), 3.77 (s, 3H), 2.85 (dd, 1H, J ) 8.0, J ) 8.0), 2.41
(bs, 1H), 2.39 (s, 3H), 2.08-1.87 (m, 1H), 1.63-1.49 (m, 2H),
1.42 (s, 3H), 0.87-0.80 (m, 1H); 13C NMR δ 207.9, 173.9, 143.0,
137.2, 136.6, 129.8, 128.2, 128.0, 127.9, 126.6, 79.7, 68.0, 66.1,
52.2, 51.8, 40.8, 24.6, 24.3, 21.4; MS (FAB) m/z 412.6 (MH+).
Met h yl (-)-(1R,3R,3a R,6a R,SS)-4-Oxo-3-p h en yl-3a -p -
t olylsu lfin yloct a h yd r ocyclop en t a [c]p yr r ole-1-ca r b oxy-
la te (3a ): yellow oil; [R]D -65.3 (c 0.5, CHCl3); IR (CHCl3)
3502, 1739, 1718 cm-1; 1H NMR δ 7.52-7.21 (m, 9H), 5.05 (s,
J . Org. Chem, Vol. 68, No. 26, 2003 10017

Garc´ıa Ruano et al.
Anal. Calcd for C23H25NO4S: C, 67.13; H, 6.12; N, 3.40; S, 7.79.
Found: C, 67.45; H, 6.38; N, 3.68; S, 7.63.
Meth yl (-)-(1R,3S,3a R,6a S)-1-Meth yl-4-oxo-3-p h en yl-
octa h yd r ocyclop en ta [c]p yr r ole-1-ca r boxyla te (5b): yield
86%; yellow oil; [R]D -58 (c 1.7, CHCl3); IR (CHCl3) 3441, 1752,
Meth yl (-)-(1R,3R,3a R,6a R,SS)-3-(2-Na p h th yl)-4-oxo-
3a -p-tolylsu lfin ylocta h yd r ocyclop en ta [c]p yr r ole-1-ca r -
boxyla te (3c): yellow needles (ethyl ether-hexane); mp 132-
134 °C; [R]D -85 (c 0.5, CHCl3); IR (CHCl3) 3484, 1735, 1729
cm-1; 1H NMR δ 7.99-7.25 (m, 11H), 5.18 (s, 1H), 4.25 (d, 1H,
J ) 7.0), 3.87 (s, 3H), 3.52 (m, 1H), 2.55 (bs, 1H), 2.38 (s, 3H),
1694 cm-1 1H NMR δ 7.59-7.31 (m, 5H), 4.89 (d, 1H, J )
;
10.0), 3.81 (s, 3H), 3.24-3.17 (dd, 1H, J ) 10.0, J ) 8.0), 2.94-
2.87 (dd, 1H J ) 15.0, J ) 8.0), 2.41 (bs, 1H), 2.18-2.00 (m,
3H), 1.87-1.78 (m, 1H); 13C NMR δ 211.0, 175.1, 135.4, 134.1,
127.4, 125.5, 63.8, 60.4, 53.1, 50.0, 41.4, 34.3, 23.4; MS (EI)
m/z 273.4 (M+). HRMS (EI) C16H19NO3 required 273.1365,
found 273.1369.
Meth yl (+)-(1S,3R,3a S,6a R)-1-Meth yl-4-oxo-3-p h en yl-
octa h yd r ocyclop en ta [c]p yr r ole-1-ca r boxyla te (5b): yield
83%; yellow oil; [R]D +61 (c 1.7, CHCl3).
Met h yl (-)-(1R,3S,3a R,6a S)-3-(2-Na p h t h yl)-4-oxooc-
ta h yd r ocyclop en ta [c]p yr r ole-1-ca r boxyla te (5c): yield
85%; yellow needles (ethyl ether-hexane); mp 105-107 °C;
[R]D -61 (c 1.9, CHCl3); IR (CHCl3) 3448, 1753, 1694 cm-1; 1H
NMR δ 7.82-7.34 (m, 7H), 4.88 (d, 1H, J ) 9.0), 3.97 (d, 1H,
J ) 2.0), 3.81 (s, 3H), 3.34-3.27 (m, 1H), 2.91-2.85 (m, 1H),
2.41-2.10 (m, 4H); 13C NMR δ 218.4, 174.2, 135.4, 135.2, 133.4,
128.6, 128.4, 128.2, 126.5, 126.3, 126.2, 125.9, 67.2, 66.4, 55.6,
53.0, 44.9, 39.9, 28.8; MS (EI) m/z 309.6 (M+). Anal. Calcd for
2.20-2.05 (m, 1H), 1.80-1.63 (m, 1H), 1.40-1.25 (m, 2H); 13
C
NMR δ 211.0, 171.2, 142.0, 136.0, 134.0, 133.4, 133.2, 129.8,
128.1, 127.9, 127.8, 126.5, 126.1, 126.0, 125.8, 125.7, 84.2, 67.5,
63.9, 52.0, 41.6, 40.4, 22.5, 21.4; MS (electrospray+) m/z 448.2
(MH+). Anal. Calcd for C26H25NO4S: C, 69.78; H, 5.63; N, 3.13;
S, 7.16. Found: C, 69.62; H, 5.69; N, 3.38; S, 7.45.
Meth yl (+)-(1S,3S,3a S,6a S,SS)-3-(2-Na p h th yl)-4-oxo-3a -
p-tolylsu lfin ylocta h yd r ocyclop en ta [c]p yr r ole-1-ca r box-
yla t e (4c): yellow needles (ethyl ether-hexane); mp 135-
137 °C; [R]D +164 (c 0.5, CHCl3); IR (CHCl3) 3418, 1741, 1735
cm-1; 1H NMR δ 7.91-7.18 (m, 11H), 4.96 (s, 1H), 4.12 (d, 1H,
J ) 7.0), 3.88 (s, 3H), 3.62 (m, 1H), 2.41 (s, 3H), 2.39 (bs, 1H),
2.20-2.00 (m, 1H), 1.80-1.60 (m, 1H), 0.98-0.81 (m, 2H); 13
C
NMR δ 207.5, 170.2, 143.1, 137.1, 134.1, 133.4, 133.1, 129.8,
128.0, 127.7, 127.5, 126.3, 126.0, 125.9, 125.4, 125.3, 79.7, 67.1,
63.8, 51.8, 40.8, 40.0, 22.7, 21.4; MS (electrospray+) m/z 448.4
(MH+). Anal. Calcd for C26H25NO4S: C, 69.78; H, 5.63; N, 3.13;
S, 7.16. Found: C, 69.71; H, 5.71; N, 3.31; S, 7.25.
C
19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C, 73.66; H,
6.37; N, 4.45.
Met h yl (+)-(1S,3R,3a S,6a R)-3-(2-Na p h t h yl)-4-oxooc-
ta h yd r ocyclop en ta [c]p yr r ole-1-ca r boxyla te (5c): yield
83%; yellow needles (ethyl ether-hexane); mp 108-111 °C;
[R]D +65 (c 2.0, CHCl3).
Meth yl (-)-(1R,3R,3aR,6aR,SS)-1-Meth yl-3-(2-n aph th yl)-
4-oxo-3a -p-tolylsu lfin ylocta h yd r ocyclop en ta [c]p yr r ole-
1-ca r boxyla te (3d ): yellow needles (ethyl ether-hexane); mp
138-140 °C; [R]D -94 (c 0.5, CHCl3); IR (CHCl3) 3415, 1732,
Meth yl (-)-(1R,3S,3a R,6a S)-1-Meth yl-3-(2-n a p h th yl)-4-
oxooct a h yd r ocyclop en t a [c]p yr r ole-1-ca r b oxyla t e (5d ):
yield 86%; yellow needles (ethyl ether-hexane); mp 111-113
1
1728 cm-1; H NMR δ 7.95-7.25 (m, 11H), 5.21 (s, 1H), 3.82
(s, 3H), 3.01 (dd, 1H, J ) 3.9, J ) 8.9), 2.45 (bs, 1H), 2.37 (s,
3H), 2.21-2.01 (m, 1H), 1.73 (s, 3H), 1.70-1.58 (m, 1H), 1.20-
0.98 (m, 2H); 13C NMR δ 211.2, 174.8, 142.4, 136.5, 134.1,
133.4, 133.2, 129.8, 129.7, 128.1, 127.9, 127.8, 126.6, 126.1,
126.0, 125.9, 125.6, 85.6, 68.4, 65.0, 52.2, 48.8, 40.4, 25.3, 24.6,
21.4; MS (electrospray+) m/z 462.1 (MH+). Anal. Calcd for
°C; [R]D -64 (c 1.7, CHCl3); IR (CHCl3) 3441, 1736, 1684 cm-1
;
1H NMR δ 7.86-7.34 (m, 7H), 4.91 (d, 1H, J ) 9.0), 3.84 (s,
3H), 3.21-3.15 (dd, 1H, J ) 10.3, J ) 8.0), 2.98-2.90 (dd, 1H,
J ) 15.0, J ) 8.0), 2.20-2.02 (m, 3H), 1.92-1.82 (m, 1H); 13
C
NMR δ 217.2, 174.7, 136.7, 133.3, 133.1, 127.9, 127.7, 127.6,
125.9, 125.8, 125.7, 125.4, 69.3, 62.5, 55.9, 52.1, 50.2, 39.2 (2C),
25.0; MS (EI) m/z 323.6 (M+). HRMS (EI) C20H21NO3 required
323.1521, found 323.1523.
C
27H27NO4S: C, 70.26; H, 5.90; N, 3.03; S, 6.95. Found: C,
70.51; H, 5.81; N, 3.25; S, 7.12.
Meth yl (+)-(1S,3S,3a S,6a S,SS)-1-Meth yl-3-(2-n a p h th yl)-
4-oxo-3a -p-tolylsu lfin ylocta h yd r ocyclop en ta [c]p yr r ole-
1-ca r boxyla te (4d ): yellow needles (ethyl ether-hexane); mp
145-147 °C; [R]D +168 (c 0.5, CHCl3); IR (CHCl3) 3428, 1731,
Meth yl (+)-(1S,3R,3a S,6a R)-1-Meth yl-3-(2-n a p h th yl)-4-
oxooct a h yd r ocyclop en t a [c]p yr r ole-1-ca r b oxyla t e (5d ):
yield 88%; yellow needles (ethyl ether-hexane); mp 112-110
°C; [R]D +67 (c 2.0, CHCl3).
1
1729 cm-1; H NMR δ 7.90-7.23 (m, 11H), 5.14 (s, 1H), 3.82
Met h od B: To a solution of the corresponding cyclo-
adduct 3 or 4 (1 equiv) in THF (7 mL/0.5 mmol) was added
activated powdered Zn (2 g/0.5 mmol) and saturated aqueous
ammonium chloride (7 mL/0.5 mmol). The mixture was stirred
vigorously at room temperature under argon for 30 min and
diluted with a 1:1 mixture of ethyl acetate and hexane (100
mL/0.5 mmol). The organic layer was washed with a saturated
aqueous solution of NaHCO3 (3 × 20 mL/0.5 mmol), dried
(Na2SO4), and evaporated. The crude mixture was purified by
flash chromatography (ethyl acetate-hexane, 1:2) to give the
compound 6. In these reaction conditions, compounds 3a ,c and
4a ,c evolved into the corresponding aromatic rings, 8a ,c,
respectively.
(s, 3H), 2.99 (dd, 1H, J ) 8.2, J ) 8.2), 2.41 (s, 3H), 2.38 (bs,
1H), 2.15-2.05 (m, 1H), 1.73 (s, 3H), 1.62-1.52 (m, 1H), 0.98-
0.83 (m, 2H); 13C NMR δ 208.0, 174.1, 143.0, 136.6, 134.9,
133.2, 133.1, 129.9, 128.2, 128.1, 127.7, 126.8, 126.7, 126.3,
126.2, 125.9, 125.8, 82.3, 68.1, 66.0, 52.2, 40.9, 24.8, 24.5, 21.5;
MS (electrospray+) m/z 462.1 (MH+). Anal. Calcd for C27H27
-
NO4S: C, 70.26; H, 5.90; N, 3.03; S, 6.95. Found: C, 70.31; H,
5.93; N, 3.24; S, 7.02.
Desu lfin yla tion . Meth od A: To a solution of the corre-
sponding cycloadduct 3 or 4 in THF (2 mL/0.2 mmol) was
added a suspension of activated Raney nickel in THF. The
reaction was stirred at -20 °C for 30 min. The reaction mixture
was filtered through a Celite pad, and the filtrate was con-
centrated under reduced pressure. The residue was purified
by flash chromatography (ethyl acetate-hexane, 1:2) to
give 5.
Meth yl (-)-(2R)-2-Am in o-2-[(1S,2S)-2-ben zyl-3-oxocy-
clop en tyl]p r op a n oa te (6b): yield 84%; yellow oil; [R]D -57
1
(c 1.9, CHCl3); IR (CHCl3) 3438, 1737, 1699 cm-1; H NMR δ
7.52-7.28 (m, 5H), 3.64 (s, 3H), 3.20-3.04 (m, 2H), 2.75-2.69
(m, 1H), 2.47-2.40 (m, 1H), 2.38-2.29 (m, 1H), 2.05-1.93 (m,
1H), 1.85-1.59 (m, 5H), 1.20 (s, 3H); 13C NMR δ 221.1, 176.2,
136.8, 130.9, 128.2, 127.6, 61.2, 60.0, 50.8, 46.8, 37.7, 37.0, 25.0,
22.3; MS (EI) m/z 275.4 (M+). HRMS (EI) C16H21NO3 required
275.1521, found 275.1525.
Meth yl (-)-(1R,3S,3a R,6a S)-4-Oxo-3-p h en ylocta h yd r o-
cyclop en ta [c]p yr r ole-1-ca r boxyla te (5a ): yield 82%; yellow
oil; [R]D -55 (c 1.6, CHCl3); IR (CHCl3) 3452, 1741, 1682 cm-1
;
1H NMR δ 7.58-7.34 (m, 5H), 4.85 (d, 1H, J ) 9.0), 3.94 (d,
1H, J ) 9.0), 3.79 (s, 3H), 3.32-3.25 (m, 1H), 2.88-2.82 (m,
1H), 2.38-2.08 (m, 4H); 13C NMR δ 206.3, 173.5, 133.0, 131.4,
125.4, 123.1, 64.0, 63.1, 52.6, 51.4, 41.2, 36.8, 25.1; MS (EI)
m/z 259.2 (M+). Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61;
N, 5.40. Found: C, 69.52; H, 6.81; N, 5.35.
Meth yl (+)-(2S)-2-Am in o-2-[(1R,2R)-2-ben zyl-3-oxocy-
clop en tyl]p r op a n oa te (6b): yield 82%; yellow oil; [R]D +59
(c 1.8, CHCl3).
Meth yl (-)-(2R)-2-Am in o-2-[(1S,2S)-2-(2-n a p h th ylm eth -
Meth yl (+)-(1S,3R,3a S,6a R)-4-Oxo-3-p h en ylocta h yd r o-
cyclop en ta [c]p yr r ole-1-ca r boxyla te (5a ): yield 84%; yellow
oil; [R]D +59 (c 1.8, CHCl3).
yl)-3-oxocyclop en tyl]p r op a n oa te (6d ): yield 85%; yellow
oil; [R]D -68 (c 2, CHCl3); IR (CHCl3) 3441, 1736, 1705 cm-1
;
1H NMR δ 7.83-7.27 (m, 7H), 3.64 (s, 3H), 3.23-3.01 (m, 2H),
10018 J . Org. Chem., Vol. 68, No. 26, 2003

1,3-Dipolar Cycloaddition of Azomethine Ylides
2.77-2.68 (m, 1H), 2.46-2.38 (m, 1H), 2.31-2.27 (m, 1H),
2.09-1.88 (m, 1H), 1.85-1.56 (m, 5H), 1.20 (s, 3H); 13C NMR
δ 220.7, 175.2, 136.4, 133.5, 132.2, 129.8, 128.5, 128.1, 127.9,
127.6, 126.0, 125.5, 61.8, 61.0, 50.4, 46.3, 37.4, 36.5, 25.5, 22.4;
MS (EI) m/z 325.5 (M+). Anal. Calcd for C20H23NO3: C, 73.82;
H, 7.12; N, 4.30. Found: C, 73.69; H, 7.23; N, 4.35.
Meth yl (+)-(2S)-2-Am in o-2-[(1R,2R)-2-(2-n aph th ylm eth -
yl)-3-oxocyclop en tyl]p r op a n oa te (6d ): yield 81%; yellow
oil; [R]D +71 (c 1.8, CHCl3).
Meth od C: A solution of 3b,d or 4b,d in toluene (2 mL/0.2
mmol) was refluxed for 2.5 h. The solvent was evaporated
under vacuum, and the residue was purified by column
chromatography (ethyl acetate-hexane, 1:3). Under these
reaction conditions, compounds 3a ,c and 4a ,c evolve into the
corresponding aromatic rings, 8a ,c, respectively.
Meth yl (-)-(1S,3S)-1-Meth yl-3-p h en yl-4-oxo-1,2,3,4,5,6-
h exa h yd r ocyclop en ta [c]p yr r ole-1-ca r boxyla te (7b): yield
92%; yellow oil; [R]D -52 (c 1.0, CHCl3); IR (CHCl3) 3458, 1737,
1712 cm-1; 1H NMR δ 7.54-7.31 (m, 5H), 4.64 (s, 1H), 3.71 (s,
3H), 2.64-2.57 (m, 2H), 2.12-1.84 (m, 2H), 1.35 (s, 3H); 13C
NMR δ 205.1, 173.0, 146.1, 137.5, 134.6, 128.9, 128.3, 125.9,
77.2, 56.0, 55.3, 44.5, 25.6, 23.4; MS (EI) m/z 271.9 (M+).
HRMS (EI) C16H17NO3 required 271.1208, found 271.1210.
Meth yl (+)-(1R,3R)-1-Meth yl-3-p h en yl-4-oxo-1,2,3,4,5,6-
h exa h yd r ocyclop en ta [c]p yr r ole-1-ca r boxyla te (7b): yield
93%; yellow oil; [R]D +57 (c 1.1, CHCl3).
133.1, 132.8, 127.8, 127.3, 127.0, 126.8, 125.9, 125.4, 125.1,
72.3, 59.2, 54.2, 42.9, 26.1, 23.8; MS (EI) m/z 321.7 (M+). Anal.
Calcd for C20H19NO3: C, 74.75; H, 5.96; N, 4.36. Found: C,
74.92; H, 6.12; N, 3.47.
Meth yl (+)-(1R,3R)-1-Meth yl-3-(2-n a p h th yl)-4-oxo-1,2,-
3,4,5,6-h e xa h yd r ocyclop e n t a [c]p yr r ole -1-ca r b oxyla t e
(7d ): yield 92%; yellow oil; [R]D +63 (c 1.2, CHCl3).
Meth yl 4-Oxo-3-p h en yl-2,4,5,6-tetr a h yd r ocyclop en ta -
[c]p yr r ole-1-ca r boxyla te (8a ): yield 95%; yellow needles
(ethyl ether-hexane); mp 125-127 °C; IR (CHCl3) 3452, 1734,
1
1705 cm-1; H NMR δ 7.51-7.24 (m, 5H), 3.81 (s, 3H), 2.82-
2.71 (m, 2H), 2.58-2.49 (m, 2H); 13C NMR δ 212.1, 160.6,
137.5, 131.5, 131.1, 125.4, 125.3, 124.9, 124.7, 124.2, 123.5,
119.3, 51.8, 43.6, 16.8; MS (EI) m/z 255.9 (M+). Anal. Calcd
for C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.35;
H, 5.12; N, 5.58.
Meth yl 3-(2-Na p h th yl)-4-oxo-2,4,5,6-tetr a h yd r ocyclo-
p en t a [c]p yr r ole-1-ca r b oxyla t e (8c): yield 96%; yellow
needles (ethyl ether-hexane); mp 129-130 °C; IR (CHCl3)
3449, 1744, 1712 cm-1; 1H NMR δ 7.81-7.27 (m, 7H), 3.80 (s,
3H), 2.85-2.76 (m, 2H), 2.61-2.52 (m, 2H); 13C NMR δ 210.1,
165.1, 137.9, 136.7, 136.1, 132.7, 129.2, 129.1, 126.5, 126.1,
125.8, 125.4, 125.0, 123.9, 123.2, 117.0, 52.3, 43.1, 15.4; MS
(EI) m/z 305.6 (M+). HRMS (EI) C19H15NO3 required 305.1052,
found 305.1049.
Meth yl (-)-(1S,3S)-1-Meth yl-3-(2-n a p h th yl)-4-oxo-1,2,-
3,4,5,6-h e xa h yd r ocyclop e n t a [c]p yr r ole -1-ca r b oxyla t e
(7d ): yield 96%; yellow oil; [R]D -59 (c 1.3, CHCl3); IR (CHCl3)
3440, 1741, 1735 cm-1; 1H NMR δ 7.68-7.23 (m, 7H), 4.68 (s,
1H), 3.73 (s, 3H), 2.69-2.51 (m, 2H), 2.18-1.81 (m, 2H), 1.31
Ack n ow led gm en t. We thank Direccio´n General de
Investigacio´n Cient´ıfica y Te´cnica for financial support
(Grant BQU2003-04012).
(s, 3H); 13C NMR
δ
209.4, 179.6, 148.5, 135.8, 133.4,
J O035369W
J . Org. Chem, Vol. 68, No. 26, 2003 10019