1,3-Dipolar cycloaddition of 2-azetidinone-tethered azomethine ylides. Application to the rapid, stereocontrolled synthesis of optically pure highly functionalised pyrrolizidine systems

Article abstract of DOI:10.1039/b000249f

A new straightforward methodology to prepare polyfunctionalised enantiopure pyrrolizidine systems, based on the 1,3-dipolar cycloaddition of 2-azetidinone-tethered azomethine ylides as the key reaction, is presented.

Full text of DOI:10.1039/b000249f

1,3-Dipolar cycloaddition of 2-azetidinone-tethered azomethine ylides.
Application to the rapid, stereocontrolled synthesis of optically pure highly
functionalised pyrrolizidine systems
Benito Alcaide,* Pedro Almendros, Jose M. Alonso and Moustafa F. Aly†
Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040-Madrid,
Spain. E-mail: alcaideb@eucmax.sim.ucm.es
Received (in Liverpool, UK) 4th January 2000, Accepted 14th February 2000
A new straightforward methodology to prepare poly-
functionalised enantiopure pyrrolizidine systems, based on
the 1,3-dipolar cycloaddition of 2-azetidinone-tethered azo-
methine ylides as the key reaction, is presented.
provided the corresponding aliphatic aldimines 2. Imines 2 were
obtained in quantitative yields and were used for next step
without further purification
We sought to explore the reactivity of 2-azetidinone-tethered
azomethine ylides with cyclic and acyclic dienophiles such as
N-phenyl maleimide and methyl acrylate.‡ The 1,3-dipolar
cycloaddition was achieved via metal ion catalysis at room
temperature. Treatment of aldimines 2 with the appropriate
dienophile in the presence of AgOAc–Et3N in toluene at room
temp. for 40 h gave with reasonable diastereoselectivity
mixtures of cycloadducts 3 and 4 (Table 1) in moderate to
excellent yields (45–90%).§ Fortunately, in all cases the
diastereomeric cycloadducts were easily separated by flash
chromatography. Furthermore, the reaction with an unsym-
metric monoactivated alkene, methyl acrylate, proceeded with
total regioselectivity. The steric properties of the C3 substituent
on the 2-azetidinone ring influence the stereoselectivity of the
cycloaddition, sterically less demanding groups increasing the
diastereoisomeric ratio (Table 1). Next, our aim was to find an
expedient transformation of the cycloadducts into pyrrolizidine
systems. First we tested sodium methoxide as reagent for the
conversion of adducts 3 or 4 into the framework of pyrrolizidine
alkaloids. In the event, the pyrrolizidine skeleton was obtained.
Sodium methoxide works well in maleimide derived cycload-
ducts, however epimerization was observed in adducts coming
from methyl acrylate. This preliminary result encouraged us to
find a more convenient reagent for this transformation. To our
delight, when the reaction was conducted in a saturated solution
of HCl(g) in isopropanol at room temperature for 36 h, optically
pure pyrrolizidine systems 5 and 6 were obtained in moderate to
good yields and without by-products (Scheme 2).¶ However,
bicycle (2)-6b was more efficiently obtained in a saturated
methanolic solution of HCl(g), with some isopropyl transester-
ification being observed when adduct (+)-4d was treated with
HCl(g) in isopropanol. The reaction of (+)-3d in a saturated
solution of HCl(g) in methanol for 36 h gave a quantitative yield
of the monocyclic pyrrolidine (+)-7, which requires 2 h of
heating in toluene under PTSA catalysis to give the expected
tricyclic system (+)-5b.∑ The formation of pyrrolizidinones 5
and 6 involves a selective C–N bond cleavage of the four-
membered ring, followed by a rearrangement under the reaction
conditions. The relative anti-disposition of the ester and amine
moieties in bicycles 6 must be responsible for the failure of the
third cyclization to occur, preventing the formation of a highly
strained tricyclic system. The polycyclic structures (by DEPT,
HETCOR and COSY) and the stereochemistry (by vicinal
proton couplings and NOE experiments) of compounds 5 and 6
were established by one- and two-dimensional NMR tech-
niques.** Taking into account that separated diastereomeric
cycloadducts 3 and 4 could be obtained and cyclized, the
stereochemistry for compounds 3 and 4 was inmediately
deduced by comparison with the NOE results of the polycyclic
systems. Also, 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.
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 Pyrrolizidine
alkaloids occur in many natural products of potential use in
medicine and agriculture.2 In view of their potent and various
biological activities, pyrrolizidine alkaloids as well as structur-
ally related unnatural compounds are continuosly stimulating
new synthetic approaches.3 On the other hand, the importance
of 2-azetidinones as synthetic intermediates has been widely
recognized in organic synthesis. This usefulness is based on the
impressive variety of transformations which can be derived
from this system.4 The application of b-lactams in stereo-
selective synthesis may be divided into two groups, namely,
those processes based on transformation of the 2-azetidinone by
external reagents and those based on rearrangements of the
four-membered ring. The first type of reactivity is exemplified
by the b-lactam synthon method.5 The second group of
reactions is based on the building of a conveniently function-
alised 2-azetidinone to produce different types of, usually
cyclic, compounds by selective bond breakage and rearrange-
ment.6 Despite the versatility of the 2-azetidinone ring, there is
little information available on the use of b-lactams as chiral
synthons for the synthesis of pyrrolizidine alkaloids, just the
groups of Reuschling7 and Palomo8 have reported b-lactam
routes to simple pyrrolizidines. Our interest in the use of
4-oxoazetidine-2-carbaldehydes as substrates for addition reac-
tions and cyclization processes,9 prompted us to evaluate the
combination of the 1,3-dipolar cycloaddition of alanine (gly-
cine) derived iminoester ylides with rearrangement reactions on
the 2-azetidinone ring as a route to complex pyrrolizidine
alkaloids (Scheme 1). We report here, a straightforward
asymmetric synthesis of different kinds of highly fuctionalised
bi- and tri-cyclic pyrrolizidine systems using b-lactams as chiral
building blocks.
Cyclization precursors, 4-oxoazetidine-2-carbaldehydes 1,
were prepared both in the racemic form and in optically pure
form using standard methodology.9–12 Treatment of aldehydes 1
with various a-aminoesters in the presence of molecular sieves
Scheme 1
† Permanent address: Department of Chemistry, Faculty of Science at Qena,
South Valley University, Qena, Egypt.
DOI: 10.1039/b000249f
Chem. Commun., 2000, 485–486
This journal is © The Royal Society of Chemistry 2000
485

Table 1 1,3-Dipolar cycloaddition of 2-azetidinone-tethered azomethine ylides
¶ Representative experimental procedure for the synthesis of pyrrolizidine
systems: HCl(g) was bubbled, during 1 h, through an unstirred solution of
the appropriate cycloadduct 3 or 4 (0.4 mmol) in isopropyl alcohol (6 ml)
and the reaction solution left to stand 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 concentrated under reduced
pressure. After purification by flash chromatography, pyrrolizidinones 5
and 6 were obtained in analytically pure form.
∑ Tricycle (+)-5b was alternatively obtained via heating overnight the
adduct (+)-3d in methanol using 37% aqueous hydrochloric acid as a
catalyst.
** All new compounds were fully characterised by spectroscopic methods
and microanalysis and/or HRMS.
1 For reviews, see: G. Broggini and G. Zecchi, Synthesis, 1999, 905; K. V.
Gothelf and K. A. Jorgensen, Chem. Rev., 1998, 98, 863.
2 For reviews, see: J. R. Liddell, Nat. Prod. Rep., 1998, 15, 363; J. P.
Michael, Nat. Prod. Rep., 1997, 14, 619; H. Takahata and T. Momose,
The Alkaloids, ed. G. A. Cordell, Academic Press, New York, 1993,
vol. 26, p. 327; A. F. H. Rizk, Naturally Ocurring Pyrrolizidine
Alkaloids, CRC Press, Boston, MA, 1991; A. R. Mattocks, Chemistry
and Toxicology of Pyrrolizidine Alkaloids, Academic, New York,
1986.
3 A comprehensive investigation of the imine/azomethine ylide/cycload-
dition cascade process for the synthesis of pyrrolizidine-type alkaloids
has been carried out by Grigg. For recent references, see: R. Grigg, M.
Thornton-Pett and G. Yoganathan, Tetrahedron, 1999, 55, 8129; R.
Grigg, S. Hargreves, J. Redpath, S. Turchi and G. Yoganathan,
Synthesis, 1999, 441.
4 For reviews, see: I. Ojima, The Organic Chemistry of b-Lactams, ed.
G. I. Georg, VCH Publishers, New York, 1993, p. 197; I. Ojima, Adv.
Asym. Synth., 1995, 1, 95.
Scheme 2
In summary, we have demonstrated that the combination 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 types of highly functionalised pyrrolizi-
dine systems. In addition, this methodology is very versatile
offering the possibility of obtaining a variety of complex
pyrrolizidine derivatives just by changing the substituents in
readily available 4-oxoazetidine-2-carbaldehydes, a-amino-
esters or dipholarophiles.
We thank the DGES (MEC-Spain, grant PB96-0565) for
financial support. P. A. thanks the DGES (MEC, Spain) for a
‘Contrato de Incorporación’. J. M. A. thanks the UCM for a
predoctoral grant.
5 For a review, see: I. Ojima and F. Delaloge, Chem. Soc. Rev., 1997, 26,
377.
6 M. S. Manhas, D. R. Wagle, J. Chiang and A. K. Bose, Heterocycles,
1988, 27, 1755; B. Alcaide, Y. Martín-Cantalejo, J. Pérez-Castells and
M. A. Sierra, J. Org. Chem., 1996, 61, 9156 and references therein.
7 F. Cavagna, A. Linkies, H. Pietsch and D. Reuschling, Angew. Chem.,
Int. Ed. Engl., 1980, 19, 129.
8 C. Palomo, J. M. Aizpurua, C. Cuevas, P. Román, A. Luque and M.
Martínez-Ripoll, An. Quím. Int. Ed., 1996, 92, 134.
9 B. Alcaide, P. Almendros and C. Aragoncillo, Chem. Commun., 1999,
1913; B. Alcaide, I. M. Rodríguez-Campos, J. Rodríguez-López and A.
Rodríguez-Vicente, J. Org. Chem., 1999, 64, 5377; B. Alcaide and P.
Almendros, Tetrahedron Lett., 1999, 40, 1015.
10 B. Alcaide, Y. Martín-Cantalejo, J. Pérez-Castells, J. Rodríguez-López,
M. A. Sierra, A. Monge and V. Pérez-García, J. Org. Chem., 1992, 57,
5921.
11 C. Palomo, F. P. Cossío, A. Arrieta, J. M. Odriozola, M. Oiarbide and
J. M. Ontoria, J. Org. Chem., 1989, 54, 5736.
Notes and references
‡ During the evaluation of this manuscript a report appeared describing the
1,3-dipolar cycloaddition of closely related b-lactam azomethine ylides: R.
Grigg, M. Thornton-Pett and L.-H. Xu, Tetrahedron, 1999, 55, 13841.
§ When DBU was used instead of Et3N, complex mixtures of unidentified
products were obtained, whereas pyridine gave erratic results. Perfoming
the reaction in acetonitrile afforded poor yields of cycloadducts.
12 G. I. Georg and V. T. Ravikumar, in The Organic Chemistry of b-
Lactams, ed. G. I. Georg, VCH, Weinheim, 1993, ch. 3, p. 295.
Communication b000249f
486
Chem. Commun., 2000, 485–486