Synthesis and 1,3-dipolar cycloadditions of a new enantiopure cyclic nitrone

Article abstract of DOI:10.1016/S0040-4039(02)02587-X

A new enantiopure cyclic nitrone has been efficiently synthesized from a D-glyceraldehyde derivative. Its 1,3-dipolar cycloaddition to different classes of dipolarophiles show complete antifacial selectivity, furnishing highly functionalized enantiopure bicyclic isoxazolidines.

Full text of DOI:10.1016/S0040-4039(02)02587-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 523–525
Synthesis and 1,3-dipolar cycloadditions of a new enantiopure
cyclic nitrone
Ramo´n Alibe´s,a Pilar Blanco,a Pedro de March,a Marta Figueredo,a,* Josep Font,a
b
b
´
´
Angel Alvarez-Larena and Juan F. Piniella
aDepartament de Qu´ımica, Universitat Auto`noma de Barcelona, E-08193 Bellaterra, Spain
bUnitat de Cristal·lografia, Universitat Auto`noma de Barcelona, E-08193 Bellaterra, Spain
Received 4 November 2002; accepted 14 November 2002
Abstract—A new enantiopure cyclic nitrone has been efficiently synthesized from a
D-glyceraldehyde derivative. It’s 1,3-dipolar
cycloaddition to different classes of dipolarophiles show complete antifacial selectivity, furnishing highly functionalized enantio-
pure bicyclic isoxazolidines. © 2002 Elsevier Science Ltd. All rights reserved.
The utility of nitrones in synthetic organic chemistry
has been widely illustrated.1 The main reactions involv-
ing such compounds are nucleophilic addition, and
1,3-dipolar cycloaddition to olefins and acetylenes.
Both of these processes have been used as key steps in
the preparation of diverse target molecules containing
nitrogen. A very important aspect of these reactions is
the control of the configuration of the newly generated
stereogenic centers and, although noticeable efforts
have been devoted to this end,2 there is still a need for
further practical solutions in this field.
1,3-dipolar cycloaddition to several kind of
dipolarophiles.
The synthesis of nitrone 5, outlined in Scheme 1, starts
from di-O-benzyl-
readily prepared from
D
-glyceraldehyde, 1, which can be
D
-mannitol.6 Reaction of 1 with
the Grignard reagent 27 furnishes a ca. 1:1 mixture of
the syn and anti alcohols 3 in 67% yield. The propor-
tion of the syn isomer can be increased by in situ
generation of the corresponding cuprate species,8 but
the inability of separating the diastereomeric alcohols
makes it more practical to oxidize the mixture and then
reduce the resulting ketone with L-Selectride®. This
procedure renders exclusively the alcohol syn-3 in 55%
overall yield from 1. Mesylation of syn-3, followed by
hydrolysis of the acetal and then treatment with
hydroxylamine provides the target nitrone 5, [h]D=−37
Up to now, the enantioselective catalysis in reactions
involving nitrones2,3 has reached quite limited success
and good results have been found mainly in reactions
involving aromatic nitrones as substrates. Alternatively,
preparations of several enantiopure nitrones from start-
ing materials of the chiral pool have been
described,2a,b,4 and currently the use of such substrates
seems the most practical choice for nitrone based
stereoselective synthesis. Among them, five membered
cyclic nitrones have received particular attention, prin-
cipally due to their utility as precursors of pyrrolizidine
alkaloids, and several groups including ours have devel-
oped methodologies to access differently substituted
pyrrolidine N-oxides in enantiopure form.4a,b,e,f,g,j,k,5
Here we present a very efficient and stereoselective
synthesis of the new nitrone 5 and an overview of it’s
Scheme 1. Reagents and conditions: (a) THF, rt, 4 h, 67%; (b)
Dess–Martin, CH2Cl2, 2 h, 95%; (c) L-Selectride®, THF,
−78°C, 87%; (d) MsCl/pyr., CH2Cl2, rt, 3 days, 89%; (e) 2 M
HCl/THF, 50°C, 16 h, 96%; (f) NH2OH·HCl/pyr., BuOH,
80°C, 4 days, 67%.
Keywords: enantiopure cyclic nitrone; dipolar cycloaddition; facial
selectivity.
* Corresponding author. Tel.: +34-93-5811853; fax: +34-93-5811265;
e-mail: marta.figueredo@uab.es
t
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02587-X

524
R. Alibe´s et al. / Tetrahedron Letters 44 (2003) 523–525
(c 1.8, CHCl3), in 57% yield. This sequence may be
easily performed in a multi-gram scale and batches of
up to 4 g of 5 have been prepared in a single operation.
The relative configuration of the newly generated
stereogenic centers in the isolated cycloadducts was
determined by 1H NMR analyses, including NOE
experiments, while an X-ray analysis of a single crystal
of compound 149 (Fig. 2) provided evidence for the
relative configuration of the chiral centers already
present in the starting nitrone. Consequently, the abso-
lute stereochemistry of all the new compounds 3–5 and
12–20 was undoubtedly secured.
The enantiomeric purity of alcohol syn-3 was estab-
1
lished by H NMR analysis of the diastereomeric corre-
sponding Mosher esters, while the absolute
configuration of nitrone 5 was confirmed by X-ray
analysis of a derivative (vide infra).
The 1,3-dipolar cycloaddition of 5 to a series of dipo-
larophiles 6–11 (Fig. 1) was then investigated, with the
aim of determining the scope of this chiral nitrone as
asymmetric inductor in such processes. The results of
this study are summarized in Table 1.
The endo/exo selectivity followed the expected bias1,2a,b
and it was very high in all cases, except for vinylene
carbonate, 11, which showed a moderate preference for
the exo reaction course. Among the cases studied, this
dipolarophile was also the single one to afford a
Figure 1. Compounds 6–11 were used as dipolarophiles in cycloaddition reactions to the enantiopure nitrone 5. The cycloadducts
12–20 were isolated from these reactions.
Table 1. 1,3-Dipolar cycloaddition of nitrone 5 to dipolarophiles 6–11
Dipolarophilea
Solventb
Timec
endo–antid
exo–antid
exo–synd
6
7
8
9
10
11
CHCl3
30 min
2 h
2 h
2 h
4 h
12 (89%)e
–
12 (89%)e
13 (87%)
14 (89%)
16 (7%)
17 (89%)
19 (36%)
–
–
–
–
Toluene
Toluene
Toluene
CHCl3
–
15 (83%)f
–
–
Toluene
20 h
18 (23%)
20 (11%)
a A 10% excess of dipolarophile was used in all runs, except for 11 which was used in a five molar excess.
b The reactions were performed at the reflux temperature.
c The reactions were run until complete consumption of nitrone 5 according to TLC analysis.
d Yields are referred to isolated pure products.
e endo/exo selectivity does not apply to this case.
f endo related to the ester substituent of the starting olefin.

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525
Merchan, F. L.; Tejero, T. Synlett 2000, 442–454; (e)
Lombardo, M.; Trombini, C. Synthesis 2000, 759–774.
3. (a) Bayo´n, P.; de March, P.; Espinosa, M.; Figueredo, M.;
Font, J. Tetrahedron: Asymmetry 2000, 11, 1757–1765; (b)
Bayo´n, P.; de March, P.; Figueredo, M.; Font, J.;
Medrano, J. Tetrahedron: Asymmetry 2000, 11, 4269–4278;
(c) Jensen, K. B.; Roberson, M.; Jørgensen, K. A. J. Org.
Chem. 2000, 65, 9080–9084; (d) Ding, X.; Taniguchi, K.;
Ukaji, Y.; Inomata, K. Chem. Lett. 2001, 468–469; (e)
Mita, T.; Ohtsuki, N.; Ikeno, T.; Yamada, T. Org. Lett.
2002, 4, 2457–2460; (f) Lo, M. M.-C.; Fu, G. C. J. Am.
Chem. Soc. 2002, 124, 4572–4573; (g) Viton, F.; Bernar-
dinelli, G.; Ku¨ndig, E. P. J. Am. Chem. Soc. 2002, 124,
4968–4969.
4. (a) Hall, A.; Meldrum, K. P.; Therond, P. R.; Wightman,
R. H. Synlett 1997, 123–125; (b) Closa, M.; de March, P.;
Figueredo, M.; Font, J. Tetrahedron: Asymmetry 1997, 8,
1031–1037; (c) Merino, P.; Franco, S.; Merchan, F. L.;
Tejero, T. Tetrahedron: Asymmetry 1997, 8, 3489–3496; (d)
Closa, M.; Wightman, R. H. Synth. Commun. 1998, 28,
3443–3450; (e) Murahashi, S.-I.; Ohtake, H.; Imada, Y.
Tetrahedron Lett. 1998, 39, 2765–2766; (f) Cicchi, S.;
Nunes, J., Jr.; Goti, A.; Brandi, A. Eur. J. Org. Chem.
1998, 419–421; (g) Goti, A.; Cacciarini, M.; Cardona, F.;
Brandi, A. Tetrahedron Lett. 1999, 40, 2853–2856; (h)
Chiacchio, U.; Corsaro, A.; Gumina, G.; Rescifina, A.;
Iannazzo, D.; Piperno, A.; Romeo, G.; Romeo, R. J. Org.
Chem. 1999, 64, 9321–9327; (i) Carda, M.; Portole´s, R.;
Murga, J.; Uriel, S.; Marco, J. A.; Domingo, L. R.;
Zaragoza´, R. J.; Ro¨per, H. J. Org. Chem. 2000, 65,
7000–7009; (j) Cordero, F. M.; Gensini, M.; Goti, A.;
Brandi, A. Org. Lett. 2000, 2, 2475–2477; (k) Busque´, F.;
de March, P.; Figueredo, M.; Font, J.; Gallagher, T.;
Mila´n, S. Tetrahedron: Asymmetry 2002, 13, 437–445.
5. (a) Golik, J.; Wong, H.; Krishnan, B.; Vyas, D. M.; Doyle,
T. W. Tetrahedron Lett. 1991, 32, 1851–1854; (b) Ballini,
R.; Marcantoni, E.; Petrini, M. J. Org. Chem. 1992, 57,
1316–1318; (c) Oppolzer, W.; Bochet, C. G.; Merifield, E.
Tetrahedron Lett. 1994, 35, 7015–7018; (d) Cicchi, S.; Goti,
A.; Brandi, A. J. Org. Chem. 1995, 60, 4743–4748; (e)
Ishikawa, T.; Tajima, Y.; Fukui, M.; Saito, S. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1863–1864.
Figure 2. Molecular structure of 14.
detectable amount of a cycloadduct derived from a
synfacial approach.
In conclusion, we have accomplished a very efficient
synthesis of the new enantiopure pyrrolidine N-oxide 5,
through a very practical sequence, easily scalable, and
we have studied its 1,3-dipolar activity towards
diversely substituted dipolarophiles. The cycloaddition
reactions of nitrone 5 occur with very high yields and
stereoselectivity, providing access to a series of densely
functionalized enantiopure compounds, demonstrating
its high potential in asymmetric synthesis.
Acknowledgements
We thank Generalitat de Catalunya for the award of
predoctoral fellowships to P.B. This research was sup-
ported by the DGES (project BQU2001-2600) and the
CIRIT (project 2001SGR 00178).
References
6. Ashton, W. T.; Canning, L. F.; Reynolds, G. F.; Tolman,
R. L.; Karkas, J. D.; Liou, R.; Davies, M.-E. M.; DeWitt,
C. M.; Perry, H. C.; Field, A. K. J. Med. Chem. 1985, 28,
926–933.
7. Bu¨chi, G.; Wu¨est, H. J. Org. Chem. 1969, 34, 1122–1123.
8. Mead, K.; MacDonald, T. L. J. Org. Chem. 1985, 50,
422–424.
1. (a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chem-
istry; John Wiley & Sons: New York, 1984; Vol. 2, Chap-
ter 9; (b) Torssell, K. B. G. In Nitrile Oxides, Nirones, and
Nitronates in Organic Synthesis; VCH Verlagsgesellschaft:
Weinheim, 1988; (c) Bloch, R. Chem. Rev. 1998, 98, 1407–
1438.
9. Crystallographic data (excluding structure factors) for the
structure have been deposited within the Cambridge Crys-
tallographic Data Centre as supplementary publication
number CCDC 196484.
2. (a) Frederickson, M. Tetrahedron 1997, 53, 403–425; (b)
Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98,
863–909; (c) Gothelf, K. V.; Jørgensen, K. A. Chem.
Commun. 2000, 1449–1458; (d) Merino, P.; Franco, S.;