Rapid and stereocontrolled synthesis of racemic and optically pure highly functionalized pyrrolizidine systems via rearrangement of 1,3-dipolar cycloadducts derived from 2-azetidinone-tethered azomethine ylides

Article abstract of DOI:10.1021/jo005686s

This work describes a convenient procedure for the straightforward preparation of polyfunctionalized enantiopure pyrrolizidine systems. The methodology capitalizes on a HCl(g)-promoted reaction of the 1,3-dipolar cycloadducts derived from 2-azetidinone-tethered azomethine ylides, smoothly affording different types of highly functionalized bi- and tricyclic systems in racemic and optically pure forms. This process involves a selective bond cleavage of the four-membered ring, followed by a rearrangement under the reaction conditions. The synthetic route employed was shown to be compatible with a variety of 4-oxoazetidine-2-carbaldehydes, α-amino esters, or dipolarophiles, offering a versatile entry to pyrrolizidine systems.

Full text of DOI:10.1021/jo005686s

J . Org. Chem. 2001, 66, 1351-1358
1351
Ra p id a n d Ster eocon tr olled Syn th esis of Ra cem ic a n d Op tica lly
P u r e High ly F u n ction a lized P yr r olizid in e System s via
Rea r r a n gem en t of 1,3-Dip ola r Cycloa d d u cts Der ived fr om
2-Azetid in on e-Teth er ed Azom eth in e Ylid es
Benito Alcaide,* Pedro Almendros, J ose M. Alonso, and Moustafa F. Aly†
Departamento de Quı´mica Orga´nica I, Facultad de Quı´mica, Universidad Complutense,
28040 Madrid, Spain.
alcaideb@eucmax.sim.ucm.es
Received October 18, 2000
This work describes a convenient procedure for the straightforward preparation of polyfunctionalized
enantiopure pyrrolizidine systems. The methodology capitalizes on a HCl(g)-promoted reaction of
the 1,3-dipolar cycloadducts derived from 2-azetidinone-tethered azomethine ylides, smoothly
affording different types of highly functionalized bi- and tricyclic systems in racemic and optically
pure forms. This process involves a selective bond cleavage of the four-membered ring, followed by
a rearrangement under the reaction conditions. The synthetic route employed was shown to be
compatible with a variety of 4-oxoazetidine-2-carbaldehydes, R-amino esters, or dipolarophiles,
offering a versatile entry to pyrrolizidine systems.
In tr od u ction
synthesis. This usefulness is based on the impressive
variety of transformations that can be accomplished with
this system.7 The application of â-lactams in stereose-
lective synthesis may be divided into two groups, namely,
1,3-Dipolar cycloaddition employing azomethine ylides
is an important process in organic synthesis, acquiring
a prominent place of synthetic strategy for a variety of
targets, including natural products such as azasugars
and alkaloids.1 Natural products having the 1-azabicyclo-
[3.3.0]octane skeleton (pyrrolizidine alkaloids) are wide-
spread in nature, occurring in various plant species and
in insects. Their structural and stereochemical complex-
ity, coupled with their diverse and potent biological
activities,2 make pyrrolizidine alkaloids as well as struc-
turally related unnatural compounds very attractive
synthetic targets.3 In addition, angular fused tricycles
represent a structurally intriguing unit present in many
natural products, and among prominent targets of this
class of compounds are triquinanes.4 Moreover, function-
alized bicyclic lactams structurally related to pyrrolizi-
dine and indolizidine have been developed as conforma-
tionally restricted peptide mimetics,5 and a chiral
pyrrolizidine base has been used as a catalyst in the
asymmetric Baylis-Hillman reaction.6 On the other
hand, the importance of 2-azetidinones as synthetic
intermediates has been widely recognized in organic
(2) For selected recent references about the wide range of biological
activities (hepatotoxicity, antiviral activity, carcinogenic activity, DNA
cross-linker, etc.) displayed by the pyrrolizidine alkaloids, see: (a) Tepe,
J . J .; Williams, R. M. J . Am. Chem. Soc. 1999, 121, 2951. (b) Liddell,
J . R. Nat. Prod. Rep. 1998, 15, 363. (c) Michael, J . P. Nat. Prod. Rep.
1997, 14, 619. (d) Robins, D. J . Nat. Prod. Rep. 1995, 12, 413. (e)
Takahata, H.; Momose, T. The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York, 1993; Vol. 26, p 327. (f) Rizk, A. F. H. Naturally
Ocurring Pyrrolizidine Alkaloids; CRC Press: Boston, 1991. (g)
Huxtable, R. J . Human Health Implications of Pyrrolizidine Alkaloids
and Herbs Containing Them. In Toxicants of Plants Origin, Vol 1:
Alkaloids; Cheeke, P. R., Ed.; CRC Press: Boca Raton, FL, 1989; pp
41-86. (h) Molineux, R. J . In Alkaloids: Chemical and Biological
Perspective; Pelletier, S. W., Ed.; Wiley: New York, 1987; Vol. 5,
Chapter 1. (i) Howard, A. S.; Michael, J . P. The Alkaloids; Brossi, A.,
Ed.; Academic Press: New York, 1986; Vol. 28, p 183. (j) Mattocks, A.
R. Chemistry and Toxicology of Pyrrolizidine Alkaloids; Academic: New
York, 1986.
(3) For selected recent references, see: (a) Back, T. G.; Nakajima,
K. J . Org. Chem. 2000, 65, 4543. (b) Blakemore, P. R.; Schulze, V.;
White, J . D. Chem. Commun. 2000, 1263. (c) Yoda, H.; Asai, F.; Takabe,
K. Synlett 2000, 1001. (d) Denmark, S. E.; Hurd, A. R. J . Org. Chem.
2000, 65, 2875. (e) Marson, C. M.; Pink, J . H.; Smith, C.; Hursthouse,
M. B.; Malik, K. M. A. Tetrahedron Lett. 2000, 41, 127. (f) de Vicente,
J .; Go´mez-Arraya´s, R.; Can˜ada, J .; Carretero, J . C. Synlett 2000, 53.
(g) Ha, D.-C.; Yun, C.-S.; Lee, Y. J . Org. Chem. 2000, 65, 621. (h)
Despinoy, X. L.; McNab, H. Tetrahedron 2000, 56, 6359. (i) Williams,
R. M.; Tepe, J . J . Angew. Chem., Int. Ed. 1999, 38, 3501. (j)
Montgomery, J .; Tang, X.-Q. J . Am. Chem. Soc. 1999, 121, 6098. (k)
Riesinger, S. W.; Lo¨fstedt, J .; Pettersson-Fasth, H.; Ba¨ckvall, J .-E. Eur.
J . Org. Chem. 1999, 3277. (l) Himstra, H.; Speckamp, W. N. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon:
London, 1991; Vol. 2, pp 1047-1082.
†
Permanent adress: Department of Chemistry, Faculty of Science
at Qena, South Valley University, Qena, Egypt.
(1) For reviews, see: (a) Broggini, G.; Zecchi, G. Synthesis 1999,
905. (b) Gothelf, K. V.; J orgensen, K. A. Chem. Rev. 1998, 98, 863. (c)
Tsuge, O.; Kanemasa, S. Adv. Heterocycl. Chem. 1989, 45, 231. For
selected references, see: (d) Sebahar, P. R.; Williams, R. M. J . Am.
Chem. Soc. 2000, 122, 5666. (e) Dondas, H. A.; Grigg, R.; MacLachlan,
W. S.; MacPherson, D. T.; Markandu, J .; Sridharan, V.; Suganthan,
S. Tetrahedron Lett. 2000, 41, 967. (f) Huang, K. S.-L.; Lee, E. H.;
Olmstead, M. M.; Kurth, M. J . J . Org. Chem. 2000, 65, 499. (g) Muray,
E.; AÄ lvarez-Larena, A.; Piniella, J . F.; Branchadell, V.; Ortun˜o, R. M.
J . Org. Chem. 2000, 65, 388. (h) Novikov, M. S.; Khlebnikov, A. F.;
Sidorina, E. S.; Kostikov, R. R. J . Chem. Soc., Perkin Trans. 1 2000,
231. (i) Gonza´lez, G.; Mart´ın, M. V.; Paredes, M. C. Heterocycles 2000,
52, 237. (j) Tsuge, O.; Hatta, T.; Tashiro, H.; Kakura, Y.; Naeda, H.;
Kaheki, A. Tetrahedron 2000, 56, 7723. (k) Ayerbe, M.; Arrieta, A.;
Coss´ıo, F. P. J . Org. Chem. 1998, 63, 1795. (l) Denhart, D. J .; Griffith,
D. A.; Heathcock, C. H. J . Org. Chem. 1998, 63, 9616. (m) Enders, D.;
Meyer, I.; Runsink, J .; Raabe, G. Tetrahedron 1998, 54, 10733.
(4) For synthetic approaches to triquinanes, see: Mehta, G.; Srikrish-
na, S. Chem. Rev. 1997, 97, 671.
(5) (a) Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N. D.; Moeller, K. D.
J Org. Chem. 2000, 65, 2484. (b) Gosselin, F.; Lubell, W. D. J Org.
Chem. 2000, 65, 2163. (c) Li, W.; Hanau, C. E.; d'Avignon, A.; Moeller,
K. D. J Org. Chem. 1995, 60, 8155.
(6) Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem. Commun.
1998, 2533.
(7) For reviews, see: (a) Ojima, I. The Organic Chemistry of
â-lactams, Georg, G. I., Ed.; VCH Publishers: New York, 1993; p 197.
(b) Ojima, I. Adv. Asym. Synth. 1995, 1, 95. (c) Palomo, C.; Aizpurua,
J . M.; Ganboa, I.; Oiarbide, M. Amino Acids 1999, 16, 321.
10.1021/jo005686s CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/20/2001

1352 J . Org. Chem., Vol. 66, No. 4, 2001
Alcaide et al.
Sch em e 1
veniently synthesized as a single cis-enantiomer from
N-(4-methoxyphenyl)-(R)-2,3-O-isopropylidenepropan-
imine, through Staudinger reaction with methoxyacetyl
chloride in the presence of Et3N,17 followed by simple
transformations of the acetal moiety.14 Treatment of
aldehydes 1 with various R-amino esters in the presence
of 4 Å molecular sieves provided the corresponding
aliphatic aldimines 2. Imines 2 were obtained in quan-
titative yields and were used for next step without further
purification. The goal of this work has been to use
structurally diverse pyrrolidinyl-â-lactams, obtained from
2-azetidinone-tethered alanine (glycine)-derived azome-
thine ylides, as useful synthetic intermediates for the
straightforward entry to the final target, pyrrolizidine
systems. The 1,3-dipolar cycloaddition was achieved via
metal ion catalysis at room temperature. Treatment of
aldimines 2 with the appropriate dienophile (e.g., phe-
nylmaleimide, methyl acrylate, dimethyl fumarate, and
trans-â-nitrostyrene) in the presence of AgOAc/Et3N in
toluene at room temperature for 40 h gave with reason-
able diastereoselectivity mixtures of cycloadducts 3 and
4 (see Tables 1-3) in moderate to good yields (45-80%).18
Furthermore, the reaction with the unsymmetric mono-
activated alkene, methyl acrylate, proceeded with total
regioselectivity. The reaction with the less activated
dipolarophile dimethyl acetylenedicarboxylate was not
effective at room temperature and as a consequence the
adducts (+)-3k and (+)-4k were not obtained. However,
when the experiment was carried out at 40 °C a good
result was achieved (Scheme 2). Fortunately, in all cases
the diastereomeric cycloadducts 3 and 4 could be easily
separated by gravity flow chromatography, the isomeric
products 3 being the less polar compounds.
The steric properties of the C3 substituent on the
2-azetidinone ring appear to influence the stereoselec-
tivity of the cycloaddition, sterically less demanding
groups increasing the diastereoisomeric ratio (see Tables
1 and 2). In addition, no adducts were obtained placing
a tert-butyl group at C3 in the 2-azetidinone azomethine
ylide.
When DBU was used instead of Et3N complex mixtures
of unidentified products were obtained, whereas pyridine
gave erratic results. Besides, perfoming the reaction in
acetonitrile afforded poor yields of cycloadducts.
To successfully achieve our initial aim, we needed to
find an expedient transformation of the cycloadducts into
pyrrolizidine and diazatriquinane systems. First, sodium
methoxide was tested as reagent for the conversion of
adducts 3 or 4 into the framework of pyrrolizidine
alkaloids. In the event, the pyrrolizidine skeleton was
obtained from maleimide-derived cycloadduct 3a , afford-
ing compound 5 but after chemoselective epimerization
those processes based on transformation of the 2-azeti-
dinone by external reagents and those based on rear-
rangements of the four-membered ring. The first type of
reactivity is exemplified by the â-lactam synthon method.8
The second group of reactions is based on the building of
a conveniently functionalized 2-azetidinone to produce
different types of usually cyclic compounds by selective
bond breakage and rearrangement.9 Despite the versatil-
ity of the 2-azetidinone ring, there is little information
available on the use of â-lactams as chiral synthons for
the synthesis of pyrrolizidine alkaloids, with only Reus-
chling10 and Palomo11 having reported â-lactam routes
to simple pyrrolizidines. At the outset of the present
studies,12 no information was available regarding the 1,3-
dipolar cycloaddition reaction involving 4-oxoazetidine-
2-carbaldehydes-derived azomethine ylides.13 Our inter-
est in the use of 4-oxoazetidine-2-carbaldehydes as
substrates for addition reactions and cyclization pro-
cesses14 prompted us to evaluate the combination of the
[3 + 2] cycloaddition reaction of N-metalated azomethine
ylides with rearrangement reactions in the 2-azetidinone
ring as a route to complex pyrrolizidine derivatives. We
wish to report now full details of the straightforward
asymmetric synthesis of different highly functionalized
pyrrolizidine and diazatriquinane systems using â-lac-
tams as chiral building blocks. A brief retrosynthetic
analysis for the pyrrolizidine unit is illustrated in Scheme
1.
Resu lts a n d Discu ssion
Rearrangement precursors, 4-oxoazetidine-2-carbalde-
hydes 1, were prepared both in the racemic form and in
optically pure form using standard methodology. Racemic
compounds 1a -c were obtained as single cis-diastereoi-
somers, following our one-pot method from N,N-di-(p-
methoxyphenyl)glyoxal diimine.15 3-Unsubstituted â-lac-
tam 1d was obtained following a previously reported
procedure.16 Enantiopure 2-azetidinone (+)-1e was con-
(8) For a review, see: Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997,
26, 377.
(9) (a) Manhas, M. S.; Wagle, D. R.; Chiang, J .; Bose, A. K.
Heterocycles 1988, 27, 1755. (b) Alcaide, B.; Mart´ın-Cantalejo, Y.; Pe´rez-
Castells, J .; Sierra, M. A. J . Org. Chem. 1996, 61, 9156 and references
therein.
(10) Cavagna, F.; Linkies, A.; Pietsch, H.; Reuschling, D. Angew.
Chem., Int. Ed. Engl. 1980, 19, 129.
(11) Palomo, C.; Aizpurua, J . M.; Cuevas, C.; Roma´n, P.; Luque, A.;
Mart´ınez-Ripoll, M. Anal. Quim. Int. Ed. 1996, 92, 134.
(12) For a preliminary communication of a part of this work, see:
Alcaide, B.; Almendros, P.; Alonso, J . M.; Aly, M. F. Chem. Commun.
2000, 485.
(13) After the initiation of our efforts, a report appeared describing
the 1,3-dipolar cycloaddition of â-lactam imines with N-methylmale-
imide and methyl acrylate: Grigg, R.; Thornton-Pett, M.; Xu, J .; Xu,
L.-H. Tetrahedron 1999, 55, 13841.
(14) See, for instance: (a) Alcaide, B.; Almendros, P.; Salgado, N.
R. J . Org. Chem. 2000, 65, 3310. (b) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Org. Lett. 2000, 2, 1411. (c) Alcaide, B.; Aly, M. F.;
Rodr´ıguez, C.; Rodr´ıguez-Vicente, A. J . Org. Chem. 2000, 65, 3453.
(d) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Commun. 2000,
757. (e) Alcaide, B.; Sa´ez, E. Tetrahedron Lett. 2000, 41, 1647. (f)
Alcaide, B.; Almendros, P.; Aragoncillo, C.; Salgado, N. R. J . Org. Chem.
1999, 64, 9596.
(15) Alcaide, B.; Mart´ın-Cantalejo, Y.; Pe´rez-Castells, J .; Rodr´ıguez-
Lo´pez, J .; Sierra, M. A.; Monge, A.; Pe´rez-Garc´ıa, V. J . Org. Chem.
1992, 57, 5921.
(16) Palomo, C.; Coss´ıo, F. P.; Arrieta, A.; Odriozola, J . M.; Oiarbide,
M.; Ontoria, J . M. J . Org. Chem. 1989, 54, 5736.
(17) (a) Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of
â-lactams; Georg, G. I., Ed.; VCH: Weinheim, 1993; Chapter 3, p 295.
(b) Wagle, D. R.; Garai, C.; Chiang, J .; Monteleone, M. G.; Kurys, B.
E.; Strohmeyer, T. W.; Hedge, V. R.; Manhas, M. S.; Bose, A. K. J .
Org. Chem. 1988, 53, 4227.
(18) The origin of the facial selectivity of the reaction between
metalloazomethine ylides and dipolarophiles has been proposed as the
result of an endo-specific cycloaddition of the E,E-dipole generated
under kinetic control: see ref 13. The stereochemical outcome of the
[3 + 2] cycloaddition between N-metalated azomethine ylides and
nitroalkenes has been suggested as the result of a tandem Michael-
Henry process: see ref 1k.

Synthesis of Pyrrolizidine Systems
J . Org. Chem., Vol. 66, No. 4, 2001 1353
Ta ble 1. Syn th esis of Rea r r a n gem en t P r ecu r sor s, P yr r olid in yl-â-la cta m s 3a ,b a n d 4a ,ba
Ta ble 2. Syn th esis of Rea r r a n gem en t P r ecu r sor s, P yr r olid in yl-â-la cta m s 3c-h a n d 4c-h
entry
aldehyde
R1
R2
R3
R4
products
3/4 ratioa
yield 3/4 (%)b
1
2
3
4
5
6
1c
1d
(+)-1e
(+)-1e
(+)-1e
(+)-1e
vinyl
H
MeO
MeO
MeO
MeO
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
H
H
H
H
3c/4c
95:5
c
65:35
70:30e
58:42
79:21f
43/2
Me
Me
H
Me
H
3d c
48d
(+)-3e/(+)-4e
(+)-3f/(+)-4f
(+)-3g/(+)-4g
(+)-3h /(+)-4h
39/21
46/20
45/33
53/14
CO2Me
CO2Me
a
The ratio was determined by integration of well-resolved signals in the 1H NMR spectra of the crude reaction mixtures before
b
purification. PMP ) 4-MeOC6H4. Pyridine was used instead of Et3N for adducts 3c/4c. Yield of pure, isolated product with correct
analytical and spectral data. c The 1H NMR spectrum of the crude mixture showed mainly 3d together with unmeasurable traces of two
d
other isomers. Additional fractions containing the major cycloadduct together with traces of the minor isomers were isolated after column
chromatography, accounting for an overall 80% yield. e Two additional diastereoisomeric cycloadducts were detected in the 1H NMR
spectrum of the crude reaction mixture, accounting, respectively, for 7% and 4% of the products formed. f An additional diastereoisomeric
cycloadduct was detected in the 1H NMR spectrum of the crude reaction mixture, accounting for an 8% of the products formed.
at C4 in the former â-lactam ring (Scheme 3). However,
partial epimerization was observed for methyl acrylate
and dimethyl fumarate derived cycloadducts. This pre-
liminary result encouraged us to find a more convenient
reagent for this transformation. Then, attempts were
made to improve the method by using acidic conditions.
To our delight, when the reaction was conducted in a
saturated solution of HCl(g) in 2-propanol at room
temperature during 36 h, it gave rise to racemic and
optically pure pyrrolizidine systems 6 and 7 in moderate
to good yields and without byproducts (Schemes 4 and
5). However, some isopropyl transesterification was
observed by treatment of adducts (+)-3h and (+)-4f under
the usual conditions of HCl(g) in 2-propanol. The reaction
of pyrrolidinyl-â-lactam (+)-3h with HCl(g) in 2-propanol
afforded the transesterificated tricycle (+)-6f as the only
product. The obtention of bicycle (-)-7b was more ef-
ficiently achieved via reaction of adduct (+)-4f in a
saturated methanolic solution of HCl(g). The reaction of
compounds (+)-3f and (+)-3k in a saturated solution of
HCl(g) in methanol for 36 h gave in quantitative yield
compounds (+)-8 and (-)-9, respectively, as crude prod-
uct. Product (+)-8 has a monocyclic pyrrolidine structure,
which required 2 h of heating in toluene under PTSA
catalysis using a Dean-Stark apparatus to give the
expected pyrrolizidine system (+)-6d . By contrast, pyr-
roline (-)-9 under PTSA catalysis gave a complex reac-
tion mixture, bicycle (+)-10 being a very minor compo-
nent. Pyrrolidine (+)-8 slowly evolves on standing to the
tricycle (+)-6d . Tricycle (+)-6d and bicycle (+)-10 were
alternatively obtained in yields of 50% and 52%, respec-
tively, via heating overnight the adducts (+)-3f and (+)-
3k in methanol under 37% aqueous hydrochloric acid
catalysis (Scheme 6). Compound (+)-3i derived from
trans-â-nitrostyrene and alanine by treatment with HCl-
(g) failed to give the pyrrolizidine system, while reaction
of pyrrolidinyl-â-lactam (+)-3j derived from trans-â-
nitrostyrene and glycine, in a saturated 2-propanolic
solution of HCl(g), smoothly provided in 59% yield the
pyrrolizidine lactam (+)-11a . Cycloadduct (+)-4i was

1354 J . Org. Chem., Vol. 66, No. 4, 2001
Ta ble 3. Syn th esis of Rea r r a n gem en t P r ecu r sor s, P yr r olid in yl-â-la cta m s 3i,j a n d 4i,j
Alcaide et al.
entry
aldehyde
R
products
3/4 ratioa
yield 3/4 (%)b
1
2
(+)-1e
(+)-1e
Me
H
(+)-3i/(+)-4i
(+)-3j/(+)-4j
52:48c
82:18d
25/23
41/9
a
The ratio was determined by integration of well-resolved signals in the 1H NMR spectra of the crude reaction mixtures before
purification. PMP ) 4-MeOC6H4. b Yield of pure, isolated product with correct analytical and spectral data. c An additional diastereoisomeric
cycloadduct was detected in the 1H NMR spectrum of the crude reaction mixture accounting for 10% of the products formed. An additional
d
diastereoisomeric cycloadduct was detected in the 1H NMR spectrum of the crude reaction mixture accounting for 8% of the products
formed.
Sch em e 2
Sch em e 3
Sch em e 4
dissolved in 2-propanol and was converted in good yield
(70%) to pyrrolizidinone (+)-11b by treatment with HCl-
(g). Regiospecific epimerization at hydrogen R to the
bridge nitrogen atom (Hc) was observed on compound (+)-
11a , while chemospecific epimerization at hydrogen R to
the nitro moiety (Hd) was observed on compound (+)-11b
(Scheme 7 and Figure 3). The formation of pyrrolizidine
lactams 5-7 and 10 and 11 involves a selective C-N
bond cleavage at the four-membered ring, followed by a
rearrangement under the reaction conditions. The overall
transformation must be driven by relief of the strain
associated with the four-membered ring, on forming more
stable polycyclic systems. The relative anti-disposition
of the ester and amine moieties in bicycles 7 and 10 must
be responsible for the failure of the third cyclization to
occur, preventing the formation of a highly strained
tricyclic system.
Con figu r a tion a l Assign m en t for Bi- a n d Tr icyclic
System s. The polycyclic structures (by DEPT, HETCOR,
and COSY) and the stereochemistry (by vicinal proton
couplings and NOE experiments) of diazatriquinanes 6
and pyrrolizidines 5, 7, and 10 were established by NMR
one- and two-dimensional techniques. Taking into ac-
count that separated diastereomeric cycloadducts 3 and
4 could be obtained and cyclized, the stereochemistry for
compounds 3 and 4 was inmediately deduced by com-
parison with the NOE results of the polycyclic systems.19
Besides, the cis-stereochemistry of the four-membered
ring is set during the cyclization step to form the
2-azetidinone ring, and it is transferred unaltered during
the further synthetic steps, except for compound 5. NOE
irradiation of proton Hc on compound 5 gave enhance-
ments in the signals corresponding to Hd, methyl group
(R to the carboxymethyl moiety), and 4-methoxyphenyl
group (10%, 2%, and 7%, respectively), while NOE
irradiation of Hb resulted in 16% enhancement in the
signal corresponding to Ha. On the basis of these data a
syn-Ha-Hb/anti-Hb-Hc/syn-Hc-Hd/syn-He-CH3 relative ster-
eochemistry was assigned for compound 5 (Figure 1).

Synthesis of Pyrrolizidine Systems
J . Org. Chem., Vol. 66, No. 4, 2001 1355
Sch em e 5
Sch em e 6
F igu r e 1. Selected NOE effects and stereochemistry of
tricyclic compounds 5a , 6b, (+)-6c, and (+)-6d .
of 10% on Hc. Furthermore, NOE irradiation of Ha
resulted in a small enhancement of the signal corre-
sponding to Hb (1%). On the basis of these data, an anti-
Ha-Hb/syn-Hb-Hc/syn-Hc-Hd/syn-Hd-CH3 relative stereo-
chemistry was assigned. NOE irradiation of proton Hb
on compound (+)-6d resulted in 2% and 9% enhance-
ments of the signals corresponding to Ha and Hc, respec-
tively, while irradiation of Hc gave NOE enhancement
of 10% on Hb, being assigned an anti-Ha-Hb/syn-Hb-Hc
relative stereochemistry. Furthermore NOE irradiation
of proton Hc resulted in enhancements of the signals
corresponding to Hd and He (10% and 2%, respectively),
which is in agreement with the proposed stereochemistry
(Figure 1). Similar values were obtained when NOE
experiments were carried out in pyrrolizidine derivatives
6a ,b and 6e,f, being the stereochemistry immediately
deduced by comparison with the above results. NOE
irradiation of proton Hc on bicyclic compound (+)-10
resulted in 9% and 2% enhancements of the signals
corresponding to Hb and on the methyl group (R to the
carboxymethyl moiety), respectively, while irradiation of
Hb gave NOE enhancements of 1% and 9% in the signals
corresponding to Ha and Hc, respectively (Figure 2). On
the basis of these data, an anti-Ha-Hb/syn-Hb-Hc/syn-Hc-
CH3 relative stereochemistry was assigned.
Compounds 7a -d have a five-membered ring fused to
the γ-lactam. Absence of NOE enhancement was ob-
served on Ha and Hc for compound (-)-7a upon irradia-
tion of Hb, while NOE irradiation of Hc resulted in a 6%
and 5% enhancement of the signals corresponding to Hd
and the methyl group (R to the carboxymethyl moiety),
respectively. Thus, a relative anti-stereochemistry was
established for these moieties (Ha-Hb and Hb-Hc). Fur-
thermore, irradiation of Hd give NOE enhancement of 7%
on the signal corresponding to Hc and NOE enhancement
of 5% on He, being assigned a syn-relative disposition
between Hc and Hd. Irradiation of He on compound (-)-
7a gave NOE enhancement of 2% in the signal corre-
sponding to the methyl group (R to the carboxymethyl
moiety), which is in agreement with the proposed ster-
eochemistry (Figure 2). Absence of NOE enhancement
was observed on Ha and Hc for compound (-)-7b upon
irradiation of Hb being assigned an anti-Ha-Hb/anti-Hb-
Hc relative stereochemistry. The irradiation of the signal
Sch em e 7
For tricyclic compound (+)-6c, NOE irradiation of Hc
resulted in enhancement of the signals corresponding to
Hb and Hd (10% and 9%, respectively), while irradiation
of Hc gave NOE enhancement of 2% on the methyl group
(R to the carboxymethyl moiety) and NOE enhancement
(19) It should be noted that the relative 1H NMR chemical shift of
the â-lactamic protons for the 3 and 4 pyrrolidinyl-â-lactams is a useful
check of the relative stereochemistry. For any pair of 3 and
4
diastereoisomers, the â-lactamic hydrogens (H3 and H4) of the 3
isomers were ca. 0.2 ppm upfield of the analogous hydrogens of the 4
isomers. Besides, the chemical shift of H4 in the 3 isomer is always
smaller than the chemical shift of H3, and by contrast the chemical
shift of H3 in the 4 isomer is always smaller than the chemical shift
of H4. The vicinal coupling constants of the two protons (H4 in the
â-lactamic ring, hydrogen R to the nitrogen in the pyrrolidinic ring)
located at the single bond connecting the two rings were diagnostic
too for the 3 and 4 cycloadducts for the relative stereochemistry. The
vicinal coupling constants for the major 3 isomers are ca. 9.0 Hz,
suggesting a relative anti-stereochemistry for this connection, whereas
these vicinal coupling constants for the minor 4 isomers are ca. 5.0
Hz, suggesting a relative syn-stereochemistry: Heathcock, C. H. In
Asymmetric Synthesis; Morrison, J . D., Ed., Academic Press: London,
1984; Vol. 3, Part B, p 115.

1356 J . Org. Chem., Vol. 66, No. 4, 2001
Alcaide et al.
F igu r e 3. Selected NOE effects and stereochemistry of bicyclic
compounds (+)-11a and (+)-11b.
polycyclic systems must be the driving force of the overall
transformation. In addition, this methodology is very
versatile, offering the possibility of obtaining a variety
of conveniently functionalized pyrrolizidine derivatives
just by changing the substituents in readily available
4-oxoazetidine-2-carbaldehydes, R-amino esters, or dipo-
larophiles.
F igu r e 2. Selected NOE effects and stereochemistry of bicyclic
compounds (-)-7a , (-)-7b, and (+)-10.
corresponding to Hc showed NOE enhancement (7%) of
the neighboring Hd; while the irradiation of Hd resulted
in a 8% and 10% enhancement of the signals correspond-
ing to Hc and He, respectively. In addition, a 8% enhance-
ment of the signal corresponding to Hf on irradiating He
confirmed the proposed stereochemistry (Figure 2). Simi-
lar figures were observed when NOE experiments were
carried out in pyrrolizidines 7c,d , being the stereochem-
istry immediately deduced by comparison with the above
results.
Compounds 11 have a bicyclic pyrrolizidine lactam
structure. On compound (+)-11a , NOE irradiation of the
signal corresponding to He induced a 17% enhancement
of the Hf signal. NOE enhancements of Hc (13%) and the
phenyl group (14%) on irradiation of Hd and NOE
enhancements of Hd (13%) and the 4-methoxyphenyl
group (20%) on irradiation of Hc were detected, whereas
NOE enhancement could not be observed on the Hb signal
when Hc was irradiated. These results evidence an anti-
Hb-Hc/syn-Hc-Hd/anti-Hd-He/syn-He-Hf relative stereo-
chemistry. For pyrrolizidinone (+)-11b, an anti-Ha-Hb/
anti-Hb-Hc/syn-Hc-Hd relative stereochemistry was pro-
posed on the basis of absence of enhancement on Ha and
Hc upon NOE irradiation of Hb, together with a 16% NOE
enhancement in the signal corresponding to Hd when Hc
was irradiated. NOE irradiation of Hd give an enhance-
ment of 7% on the signal corresponding to Hc and NOE
enhancement of 7% on He, being assigned a syn-relative
disposition between Hc and Hd. Besides, irradiation of He
on compound (+)-11b gave 13% and 2% NOE enhance-
ment of the signals corresponding to Hc and methyl group
(R to the carboxymethyl moiety), respectively, which is
in agreement with the proposed relative syn-stereochem-
istry (Hd-He, and He-CH3) (Figure 3).
Exp er im en ta l Section
Gen er a l. General experimental data and procedures have
been previously reported.14a NMR spectra were recorded in
CDCl3 solutions, except when otherwise stated. Chemical shifts
are given in ppm relative to TMS (1H, 0.0 ppm), or CDCl3 (13C,
77.0 ppm). All commercially available compounds were used
without further purification.
Gen er a l P r oced u r e for th e Syn th esis of Cycloa d d u cts
3 a n d 4. A solution of the appropriate 4-azetidinone-2-
carbaldehyde 1 (1.00 mmol) in dichloromethane (7 mL) was
added dropwise to a stirred solution of 4 Å molecular sieves
(2.0 g) and the corresponding R-amino ester (1.50 mmol) in
dichloromethane (3 mL) at room temperature. After stirring
for 2 h at room temperature, the mixture was filtered through
a plug of Celite. The solvent was removed under reduced
pressure, giving imines 2 in quantitative yield. The crude
product was used for the next step without any further
purification.
To a solution of the appropriate imine 2 (1.00 mmol) in
toluene (6 mL) were sequentially added silver acetate (1.20
mmol), the dipolarophile (phenylmaleimide, methyl acrylate,
or dimethyl fumarate) (1.50 mmol), and triethylamine (1.20
mmol), and the reaction mixture was stirred at room temper-
ature for 40 h. Saturated aqueous NH4Cl (1 mL) was added,
and the mixture was partitioned between dichloromethane and
water. The organic extract was washed with brine, dried
(MgSO4), and concentrated under reduced pressure. Chroma-
tography of the residue eluting with ethyl acetate/hexanes or
acetate/dichloromethane mixtures gave analytically pure com-
pounds 3 and 4. Spectroscopic and analytical data for some
representative pure forms of 3 and 4 follow.20
Cycloa d d u ct 3d . From 240 mg (1.17 mmol) of the aldehyde
1d and 181 mg (1.77 mmol) of l-alanine methyl ester, after
column chromatography eluting with ethyl acetate/hexanes (3:
1), 210 mg (48%) of the compound 3d was obtained. Colorless
1
oil. H NMR (CDCl3): δ 1.28 (s, 3H), 1.86 (dd, 1H, J ) 13.5,
7.6 Hz), 2.62 (dd, 1H, J ) 13.5, 5.1 Hz), 2.65 (dd, 1H, J ) 15.2,
2.5 Hz), 3.03 (dd, 1H, J ) 15.2, 5.1 Hz), 3.05 (m, 1H), 3.59
(dd, 1H, J ) 9.0, 7.3 Hz), 3.62 (s, 3H), 3.70 and 3.71 (s, each
3H), 4.07 (m, 1H), 6.79 and 7.50 (d, each 2H, J ) 9.0 Hz). 13C
NMR (CDCl3): δ 176.3, 173.1, 164.5, 156.6, 131.3, 120.6, 114.2,
65.9, 65.5, 55.6, 54.3, 52.6, 52.1, 46.4, 40.7, 40.0, 27.3. IR
(CHCl3, cm-1): ν 3340, 1745. MS (CI), m/z: 364 (M+ + 1, 100),
301 (M+, 40). Anal. Calcd for C18H24N2O6: C, 59.33; H, 6.64;
N, 7.69. Found: C, 59.45; H, 6.54; N, 7.77.
Con clu sion s. We have demonstrated that combina-
tion of 1,3-dipolar cycloaddition of 2-azetidinone-tethered
azomethine ylides with rearrangement reactions on the
2-azetidinone ring is a powerful, hitherto unknown,
strategy for the asymmetric synthesis of different highly
functionalized enantiopure pyrrolizidine and diaza-
triquinane systems. The formation of pyrrolizidine lac-
tams involves a selective C(O)-N bond cleavage in the
four-membered ring, followed by a rearrangement under
the reaction conditions. The relief of the strain associated
with the four-membered ring on forming more stable
(20) Full spectroscopic and analytical data for compounds not
included in this Experimental Section are described in the Supporting
Information.

Synthesis of Pyrrolizidine Systems
J . Org. Chem., Vol. 66, No. 4, 2001 1357
P r ep a r a tion of Cycloa d d u cts (+)-3f a n d (+)-4f. From
708 mg (3.00 mmol) of the aldehyde (+)-1e and 485 mg (5.50
mmol) of glycine methyl ester, after column chromatography
eluting with ethyl acetate/dichloromethane (2:8), 540 mg (46%)
of the less polar compound (+)-3f and 235 mg (20%) of the
more polar compound (+)-4f were obtained.
118.9, 114.5, 83.5, 73.5, 63.2, 59.9, 59.7, 55.6, 52.8, 52.5, 52.2,
25.5. IR (CHCl3, cm-1): ν 3342, 1756, 1744. MS (CI), m/z: 463
(M+ + 1, 100), 462 (M+, 20). Anal. Calcd for C22H26N2O9: C,
57.14; H, 5.67; N, 6.06. Found: C, 56.98; H, 5.73; N, 6.10.
HCl(g)-P r om oted Rea ction of P yr r olid in yl-â-la cta m s
3 a n d 4. Gen er a l P r oced u r e for th e Syn th esis of Dia za -
tr iqu in a n es 6 a n d P yr r olizid in es 7. HCl(g) was bubbled,
during 1 h, through an unstirred solution of the appropriate
cycloadduct 3 or 4 (0.4 mmol) in 2-propanol (6 mL) and then
left in a sealed vessel for 36 h. The reaction mixture was
concentrated under reduced pressure, diluted with dichloro-
methane (10 mL), washed with saturated aqueous sodium
hydrogen carbonate and brine, dried (MgSO4), and concen-
trated under reduced pressure. After purification by flash
chromatography, eluting with hexanes/ethyl acetate, the ap-
propriate pyrrolizidinones 5 and 6 were obtained in analyti-
cally pure form.
Tr icycle 6b. From 144 mg (0.384 mmol) of adduct 3d , 90
mg (68%) of compound 6b was obtained as a colorless solid
after purification by flash chromatography (hexanes/ethyl
acetate 1/15). Mp 217-218 °C (hexanes/ethyl acetate). 1H NMR
(CDCl3): δ 1.25 (s, 3H), 1.74 (dd, 1H, J ) 14.0, 8.3 Hz), 2.05
(m, 2H), 2.45 (dd, 1H, J ) 8.3, 5.8 Hz), 2.76 (d, 1H, J ) 14.0
Hz), 3.32 and 3.42 (s, each 3H), 3.74 (t, 1H, J ) 5.2 Hz), 3.84
(m, 1H), 6.60 and 7.05 (m, each 2H). 13C NMR (CDCl3): δ
172.4, 172.3, 171.6, 170.3, 158.1, 129.3, 125.1, 114.7, 82.2, 63.1,
62.6, 62.1, 58.5, 55.5, 52.7, 45.3, 44.4, 24.2. IR (CHCl3, cm-1):
ν 1751, 1701. MS (CI), m/z: 344 (M+ + 1, 100), 374 (M+, 16).
Anal. Calcd for C18H20N2O5: C, 62.78; H, 5.85; N, 8.13.
Found: C, 60.88; H, 5.73; N, 8.05.
Cycloa d d u ct (+)-3f. Colorless oil. [R]D ) +170.9 (c 1.5,
1
CHCl3). H NMR (CDCl3): δ 2.33 (m, 2H), 3.29 (dd, 1H, J )
12.5, 6.6 Hz), 3.53 (dd, 1H, J ) 9.3, 6.6 Hz), 3.64 (s, 3H), 3.73
(m, 4H), 3.75 and 3.78 (s, each 3H), 4.42 (dd, 1H, J ) 9.3, 5.4
Hz), 4.57 (d, 1H, J ) 5.4 Hz), 6.85 and 7.54 (m, each 2H). 13C
NMR (CDCl3): δ 173.9, 173.6, 165.6, 156.8, 130.7, 120.3, 114.2,
83.2, 63.5, 60.5, 59.8, 59.3, 55.5, 52.3, 51.9, 44.9, 33.4. IR
(CHCl3, cm-1): ν 3333, 1744. MS (CI), m/z: 392 (M+ + 1, 100),
391 (M+, 50). Anal. Calcd for C19H23N2O7: C, 58.31; H, 5.92;
N, 7.16. Found: C, 58.43; H, 5.84; N, 7.08.
Cycloa d d u ct (+)-4f. Colorless solid. Mp 157-158 °C (hex-
anes/ethyl acetate). [R]D ) +95.0 (c 1.3, CHCl3). 1H NMR
(CDCl3): δ 2.34 (m, 2H), 2.88 (m, 1H), 3.59 (s, 3H), 3.66 (m,
4H), 3.73 (m, 4H), 3.77 (s, 3H), 4.64 (d, 1H, J ) 5.1 Hz), 4.80
(dd, 1H, J ) 5.9, 5.1 Hz), 6.85 and 7.30 (m, each 2H). 13C NMR
(CDCl3): δ 173.4, 173.0, 165.1, 157.1, 129.4, 121.0, 114.3, 83.7,
61.9, 59.4, 58.1, 57.4, 55.4, 52.1, 51.7, 44.7, 33.5. IR (CHCl3,
cm-1): ν 3335, 1743. MS (EI), m/z: 392 (M+ + 1, 42), 391 (M+,
100). Anal. Calcd for C20H26N2O7: C, 59.10; H, 6.45; N, 6.89.
Found: C, 59.18; H, 6.59; N, 6.99.
P r ep a r a tion of Cycloa d d u cts (+)-3h a n d (+)-4h . From
200 mg (0.851 mmol) of the aldehyde (+)-1e and 114 mg (1.28
mmol) of glycine methyl ester, after column chromatography
eluting with ethyl acetate/hexanes (1:1), 171 mg (53%) of the
less polar compound (+)-3h and 45 mg (14%) of the more polar
compound (+)-4h were obtained.
Cycloa d d u ct (+)-3h . Pale yellow oil. [R]D ) +38.0 (c 1.0,
CHCl3). 1H NMR (CDCl3): δ 3.57 (m, 2H), 3.64 (s, 3H), 3.74
(m, 4H), 3.76 and 3.77 (s, each 3H), 4.03 (dd, 1H, J ) 6.9, 6.6
Hz), 4.37 (dd, 1H, J ) 9.0, 5.1 Hz), 4.51 (d, 1H, J ) 5.1 Hz),
6.90 and 7.50 (m, each 2H). 13C NMR (CDCl3): δ 172.4, 172.3,
172.1, 165.5, 156.9, 130.6, 120.4, 114.3, 83.2, 63.0, 62.4, 60.3,
59.8, 55.6, 52.8, 52.6, 52.4, 50.7, 49.3. IR (CHCl3, cm-1): ν 3338,
1740. MS (EI), m/z: 451 (M+ + 1, 42), 450 (M+, 100). Anal.
Calcd for C21H26N2O9: C, 55.99; H, 5.82; N, 6.22. Found: C,
56.07; H, 5.74; N, 6.28.
Tr icycle (+)-6c. From 162.4 mg (0.4 mmol) of adduct (+)-
3e, 89.8 mg (60%) of compound (+)-6c was obtained as a
colorless oil after purification by flash chromatography (hex-
1
anes/ethyl acetate 1/1). [R]D ) +20.5 (c 1.0, CHCl3). H NMR
(CDCl3): δ 1.46 (s, 3H), 2.26 (dd, 1H, J ) 14.2, 7.8 Hz), 2.98
(d, 1H, J ) 14.2 Hz), 3.07 (dd, 1H, J ) 7.8, 5.6 Hz), 3.40 (s,
3H), 3.55 (s, 1H), 3.66 and 3.74 (s, each 3H), 4.46 (d, 1H, J )
4.6 Hz), 4.72 (dd, 1H, J ) 5.6, 4.6 Hz), 6.85 and 7.21 (m, each
2H). 13C NMR (CDCl3): δ 172.6, 171.4, 170.3, 158.1, 129.3,
125.1, 114.7, 82.2, 63.1, 62.6, 62.1, 58.5, 55.5, 52.7, 45.3, 44.4,
24.2. IR (CHCl3, cm-1): ν 1744, 1701. MS (EI), m/z: 375 (M+
+ 1, 18), 374 (M+, 100). Anal. Calcd for C19H22N2O6: C, 60.95;
H, 5.92; N, 7.48. Found: C, 60.83; H, 5.82; N, 7.56.
Cycloa d d u ct (+)-4h . Pale yellow solid. Mp 103-104 °C
1
(hexanes/ethyl acetate). [R]D ) +90.9 (c 0.8, CHCl3). H NMR
Tr icycle (+)-6d . From 108 mg (0.28 mmol) of adduct (+)-
3f, 60 mg (61%) of compound (+)-6d was obtained as a colorless
oil after purification by flash chromatography (hexanes/ethyl
(CDCl3): δ 3.37 (dd, 1H, J ) 7.3, 4.1 Hz), 3.57 (m, 1H), 3.63
and 3.66 (s, each 3H), 3.73 and 3.76 (s, each 3H), 3.78 (s, each
3H), 3.91 (m, 2H), 4.61 (d, 1H, J ) 5.1 Hz), 4.75 (dd, 1H, J )
5.1, 4.9 Hz), 6.86 and 7.32 (m, each 2H). 13C NMR (CDCl3): δ
172.7, 171.7, 171.4, 165.0, 157.0, 129.5, 120.4, 114.5, 83.7, 62.7,
60.5, 59.3, 56.8, 55.5, 52.6, 52.5, 52.2, 51.4, 49.5. IR (CHCl3,
cm-1): ν 3341, 1742. MS (CI), m/z: 451 (M+ + 1, 100), 450 (M+,
29). Anal. Calcd for C21H26N2O9: C, 55.99; H, 5.82; N, 6.22.
Found: C, 55.91; H, 5.76; N, 6.12.
1
acetate 1/3). [R]D ) +6.0 (c 1.1, CHCl3). H NMR (CDCl3): δ
2.70 (m, 2H), 3.05 (dd, 1H, J ) 6.1, 5.6 Hz), 3.39 (s, 3H), 3.56
(s, 1H), 3.70 and 3.74 (s, each 3H), 4.43 (dd, 1H, J ) 8.5, 3.4
Hz), 4.47 (d, 1H, J ) 4.4 Hz), 4.66 (dd, 1H, J ) 5.6, 4.4 Hz),
6.85 and 7.30 (m, each 2H). 13C NMR (CDCl3): δ 172.4, 171.3,
169.9, 158.3, 129.2, 125.6, 114.8, 82.1, 63.1, 62.9, 58.5, 56.6,
55.6, 52.7, 44.5, 35.5. IR (CHCl3, cm-1): ν 1751, 1701. MS (CI),
m/z: 361 (M+ + 1, 100), 360 (M+, 22). Anal. Calcd for
P r ep a r a tion of Cycloa d d u cts (+)-3k a n d (+)-4k . From
200 mg (0.851 mmol) of the aldehyde (+)-1e, 131 mg (1.28
mmol) of L-alanine methyl ester, and 182 mg (1.28 mmol) of
dimethyl acetylenedicarboxylate, by heating at 40 °C for 24 h
and after column chromatography eluting with dichloromethane/
ethyl acetate (10:1), 208 mg (47%) of the less polar compound
(+)-3k and 26 mg (6%) of the more polar compound (+)-4k
were obtained.
C
18H20N2O6: C, 59.99; H, 5.59; N, 7.77. Found: C, 60.13; H,
5.89; N, 7.71.
Tr icycle (+)-6e. From 100 mg (0.212 mmol) of adduct (+)-
3g, 76 mg (70%) of compound (+)-6e was obtained as a
colorless solid after purification by flash chromatography
(hexanes/ethyl acetate 1/2). Colorless solid. Mp 132-133 °C
1
(hexanes/ethyl acetate). [R]D ) +54.2 (c 0.8, CHCl3). H NMR
Cycloa d d u ct (+)-3k . Pale yellow oil. [R]D ) +145.4 (c 1.2,
CHCl3). 1H NMR (CDCl3): δ 1.57 (s, 3H), 3.51 and 3.61 (s, each
3H), 3.70 and 3.76 (s, each 3H), 3.85 (s, 3H), 4.51 (d, 1H, J )
4.9 Hz), 4.70 (m, 2H), 6.77 and 7.35 (m, each 2H). 13C NMR
(CDCl3): δ 172.4, 165.3, 164.5, 163.1, 156.3, 146.1, 139.3, 130.9,
119.8, 113.6, 82.3, 72.3, 64.5, 59.6, 59.4, 55.4, 52.5, 52.3, 52.1,
25.7. IR (CHCl3, cm-1): ν 3338, 1758, 1745. MS (EI), m/z: 463
(M+ + 1, 32), 462 (M+, 100). Anal. Calcd for C22H26N2O9: C,
57.14; H, 5.67; N, 6.06. Found: C, 57.22; H, 5.61; N, 5.98.
Cycloa d d u ct (+)-4k . Pale yellow oil. [R]D ) +56.2 (c 0.7,
CHCl3). 1H NMR (CDCl3): δ 1.57 (s, 3H), 3.40 and 3.54 (s, each
3H), 3.77 and 3.78 (s, each 3H), 3.81 (s, 3H), 4.61 (m, 2H),
4.90 (d, 1H, J ) 5.4 Hz), 6.85 and 7.30 (m, each 2H). 13C NMR
(CDCl3): δ 173.2, 165.3, 163.0, 156.6, 149.1, 145.0, 135.8, 130.7,
(CDCl3): δ 1.49 (s, 3H), 3.43 (s, 3H), 3.46 (d, 1H, J ) 5.4 Hz),
3.59 (s, 1H), 3.75 and 3.77 (s, each 3H), 3.79 (s, 3H), 3.99 (s,
1H), 4.53 (d, 1H, J ) 4.8 Hz), 4.97 (dd, 1H, J ) 5.7, 4.8 Hz),
6.93 and 7.23 (m, each 2H). 13C NMR (CDCl3): δ 171.3, 170.8,
170.1, 169.6, 158.2, 128.9, 125.1, 114.7, 82.0, 65.4, 62.4, 62.2,
58.4, 58.3, 55.4, 53.1, 52.4, 48.4, 19.5. IR (CHCl3, cm-1): ν 1746,
1703. MS (EI), m/z: 433 (M+ + 1, 32), 432 (M+, 100). Anal.
Calcd for C21H24N2O8: C, 58.33; H, 5.59; N, 6.48. Found: C,
58.39; H, 5.51; N, 6.40.
Tr icycle (+)-6f. From 80 mg (0.21 mmol) of adduct (+)-
3h , 45 mg (57%) of compound (+)-6f was obtained as a colorless
oil after purification by flash chromatography (hexanes/ethyl
1
acetate 1/1). [R]D ) +10.8 (c 0.4, CHCl3). H NMR (CDCl3): δ
1.29 and 1.31 (d, each 3H, J ) 6.6 Hz), 3.45 (s, 3H), 3.47 (d,

1358 J . Org. Chem., Vol. 66, No. 4, 2001
Alcaide et al.
1H, J ) 6.0 Hz), 3.62 (s, 1H), 3.82 (m, 4H), 3.84 (s, 3H), 4.37
(d, 1H, J ) 3.0 Hz), 4.55 (d, 1H, J ) 4.2 Hz), 4.83 (dd, 1H, J
) 6.0, 4.2 Hz), 5.09 (m, 1H, J ) 6.6 Hz), 6.95 and 7.32 (m,
each 2H). 13C NMR (CDCl3): δ 170.8, 170.7, 170.3, 168.5, 158.4,
128.8, 125.6, 114.7, 81.8, 77.2, 70.1, 62.9, 62.6, 60.1, 58.3, 55.5,
53.7, 52.9, 47.7, 21.6. IR (CHCl3, cm-1): ν 1751, 1707. MS (EI),
m/z: 447 (M+ + 1, 32), 446 (M+, 100). Anal. Calcd for
(dd, 1H, J ) 9.1, 8.4 Hz), 4.06 (dd, 1H, J ) 9.4, 9.1 Hz), 4.20
(d, 1H, J ) 9.1 Hz), 6.75 (s, 4H). 13C NMR (CDCl3): δ 169.9,
169.4, 168.7, 168.3, 153.0, 138.2, 115.8, 114.6, 77.5, 63.9, 61.5,
60.9, 55.5, 55.5, 53.1, 52.7, 52.4, 44.6, 42.8, 18.1. IR (CHCl3,
cm-1): ν 3342, 1747, 1718. MS (EI), m/z: 463 (M+ + 1, 31),
462 (M+, 100). Anal. Calcd for C22H26N2O9: C, 57.14; H, 5.67;
N, 6.06. Found: C, 57.06; H, 5.61; N, 6.16.
C
22H26N2O8: C, 59.19; H, 5.87; N, 6.27. Found: C, 59.11; H,
HCl(a q)-P r om oted Rea ction of P yr r olid in yl-â-la cta m
(+)-3j. Syn th esis of Bicycle (+)-10. To a solution of the
cycloadduct (+)-3k (126 mg, 0.272 mmol) in methanol (18 mL)
was added a catalytic amount (a few drops) of 37% aqueous
hydrochloric acid. The resulting solution was heated under
reflux for 18 h. The reaction mixture was allowed to cool to
room temperature and then concentrated under reduced
pressure. The mixture was diluted with dichloromethane (15
mL), washed with saturated aqueous sodium hydrogen car-
bonate and brine, dried (MgSO4), and concentrated under
reduced pressure. Chromatography of the residue eluting with
hexanes/ethyl acetate (1:1) gave 65 mg (52%) of the pyrroliz-
idinone (+)-10 as a colorless oil. [R]D ) +18.5 (c 0.8, CHCl3).
1H NMR (CDCl3): δ 1.69 (s, 3H), 3.51 and 3.68 (s, each 3H),
3.75 and 3.83 (s, each 3H), 3.89 (s, 3H), 4.27 (dd, 1H, J ) 12.4,
4.2 Hz), 4.44 (d, 1H, J ) 12.0 Hz), 5.56 (d, 1H, J ) 4.5 Hz),
6.60 and 6.77 (m, each 2H). 13C NMR (CDCl3): δ 172.2, 169.1,
162.1, 161.5, 153.2, 143.5, 139.8, 134.6, 115.9, 115.1, 85.8, 71.3,
70.6, 60.1, 58.5, 55.9, 53.7, 53.0, 52.7, 20.6. IR (CHCl3, cm-1):
ν 3240, 1736, 1720, 1711. MS (CI), m/z: 463 (M+ + 1, 100),
462 (M+, 20). Anal. Calcd for C22H26N2O9: C, 57.14; H, 5.67;
N, 6.06. Found: C, 57.08; H, 5.61; N, 6.00.
5.93; N, 6.37.
Bicycle (-)-7a . From 102 mg (0.250 mmol) of adduct (+)-
4e, 56 mg (55%) of compound (-)-7a was obtained as a
colorless oil after purification by flash chromatography (hex-
anes/ethyl acetate 2/1). [R]D ) -33.93 (c 1.0, CHCl3). 1H NMR
(CDCl3): δ 1.58 (s, 3H), 2.10 (dd, 1H, J ) 13.8, 7.8 Hz), 2.93
(d, 1H, J ) 13.8 Hz), 3.05 (t, 1H, J ) 7.8 Hz), 3.39 and 3.52 (s,
each 3H), 3.66 and 3.68 (s, each 3H), 3.88 (dd, 1H, J ) 8.4,
7.8 Hz), 3.94 (d, 1H, J ) 8.7 Hz), 4.35 (dd, 1H, J ) 8.7, 8.4
Hz), 6.71 (s, 4H). 13C NMR (CDCl3): δ 171.6, 170.6, 170.5,
168.2, 158.3, 129.2, 117.2, 114.7, 77.2, 64.0, 62.6, 61.3, 58.8,
55.6, 52.7, 43.1, 42.4, 22.8. IR (CHCl3, cm-1): ν 3340, 1740,
1711. MS (EI), m/z: 407 (M+ + 1, 20), 406 (M+, 100). Anal.
Calcd for C20H26N2O7: C, 59.10; H, 6.45; N, 6.89. Found: C,
59.00; H, 6.53; N, 6.81.
Bicycle (-)-7b. From 110 mg (0.281 mmol) of adduct (+)-
4f in methanol (5 mL), 82 mg (74%) of compound (-)-7b was
obtained as a colorless oil after purification by flash chroma-
tography (hexanes/ethyl acetate 1/1). [R]D ) -28.0 (c 1.2,
1
CHCl3). H NMR (CDCl3): δ 2.48 (ddd, 1H, J ) 13.9, 9.0, 7.6
Hz), 2.73 (ddd, 1H, J ) 13.9, 2.7, 2.2 Hz), 3.07 (ddd, 1H, J )
7.6, 7.3, 2.2 Hz), 3.39 and 3.52 (s, each 3H), 3.69 and 3.70 (s,
each 3H), 3.83 (dd, 1H, J ) 8.0, 7.3 Hz), 4.03 (d, 1H, J ) 8.5
Hz), 4.12 (dd, 1H, J ) 9.0, 2.7 Hz), 6.80 (s, 4H). 13C NMR
(CDCl3): δ 170.6, 169.4, 169.0, 153.2, 141.0, 116.3, 114.7, 88.5,
64.1, 61.2, 58.8, 55.6, 54.8, 52.6, 52.2, 41.9, 34.5. IR (CHCl3,
cm-1): ν 3344, 1744, 1705. MS (CI), m/z: 393 (M+ + 1, 100),
392 (M+, 34). Anal. Calcd for C19H24N2O7: C, 58.16; H, 6.16;
N, 7.14. Found: C, 58.28; H, 6.26; N, 7.08.
Ack n ow led gm en t. Support for this work by the
DGI-MCYT (Project BQU2000-0645) is gratefully ac-
knowledged. J .M.A. thanks the UCM for a predoctoral
grant.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
analytical data for isomerically pure compounds 3a -c, (+)-
3e, (+)-3g, (+)-3i, (+)-3j, 4a , 4b, (+)-4e, (+)-4g, (+)-4i, (+)-
4j, 5, 6a , (+)-8, (-)-9, (+)-11a , and (+)-11b. This material is
available free of charge via the Internet at http://pubs.acs.org.
Bicycle (-)-7c. From 80 mg (0.172 mmol) of adduct (+)-
4g, 59 mg (73%) of compound (-)-7c was obtained as a pale
yellow oil after purification by flash chromatography (hexanes/
ethyl acetate 1/1). [R]D ) -67.7 (c 0.7, CHCl3). 1H NMR
(CDCl3): δ 1.38 (s, 3H), 3.33 and 3.55 (s, each 3H), 3.70 and
3.75 (s, each 3H), 3.87 (s, 3H), 3.90 (d, 1H, J ) 8.4 Hz), 3.97
J O005686S