Asymmetric 1,3-dipolar cycloadditions of a chiral nonracemic glyoxylic azomethine imine

Article abstract of DOI:10.1016/j.tetlet.2004.02.088

The reactivity of a chiral nonracemic glyoxylic azomethine imine has been investigated. This species reacts with a wide range of dipolarophiles, with a complete regio- and facial stereoselectivity. The introduction of an electron-withdrawing substituent on the ylide leads to a lower endo selectivity with electron-withdrawing dipolarophiles, but to an improved exo selectivity with styrene derivatives when compared to the reactivity of aliphatic- or aromatic-substituted ylides.

Full text of DOI:10.1016/j.tetlet.2004.02.088

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3127–3130
Asymmetric 1,3-dipolar cycloadditions of a chiral nonracemic
glyoxylic azomethine imine
Florence Chung,a Ariane Chauveau,a Mohamed Seltki,b Martine Bonina,* and
Laurent Micouina,*
aLaboratoire de Chimie Thꢀerapeutique, UMR 8638 Associꢀee au CNRS et ꢁa l’Universitꢀe Renꢀe Descartes,
Facultꢀe des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l’Observatoire, 75270 Paris cedex 06, France
bLaboratoire de Cristallographie et RMN Biologiques (UMR 8015 CNRS), Facultꢁe des Sciences Pharmaceutiques et Biologiques,
4 Avenue de l’Observatoire, 75270 Paris cedex 06, France
Received 29 January 2004; revised 13 February 2004; accepted 17 February 2004
Abstract—The reactivity of a chiral nonracemic glyoxylic azomethine imine has been investigated. This species reacts with a wide
range of dipolarophiles, with a complete regio- and facial stereoselectivity. The introduction of an electron-withdrawing substituent
on the ylide leads to a lower endo selectivity with electron-withdrawing dipolarophiles, but to an improved exo selectivity with
styrene derivatives when compared to the reactivity of aliphatic- or aromatic-substituted ylides.
Ó 2004 Elsevier Ltd. All rights reserved.
1,3-Dipolar cycloadditions are reactions of considerable
interest in diversity-oriented synthesis (DOS),1 since
they can provide access to polyfunctional molecules with
overall good control of the relative configuration of
several consecutive asymmetric centres, under relatively
simple and scalable experimental procedures.2 In a series
of papers, we have reported that chiral nonracemic
cyclic hydrazine 1 reacts with aliphatic or aromatic
aldehydes, generating azomethine imine ylides capable
of undergoing highly regio- and stereoselective cyclo-
addition with a wide range of olefins, and delivering
polyfunctional pyrazolidines 2 in good yield (Scheme
1).3 We have also demonstrated that polyfunctional 1,3
diamines could be obtained from these intermediates in
a short synthetic sequence.4
We now report in this paper the results of our investi-
gations into the formation and reactivity of the ylide
Ph
R1CHO
O
Ph
BnCOHN
R1
NHCOBn
O
R1 = Alk, Ar
R1
N
N
O
*
*
N
*
*
R3
*
ref. 3
N
O
ref. 4
*
Ph
R2
R1
Ph
R2
R3
N
2
3
O
Ph
HN
O
N
H
O
O
EtO2C
N
1
O
*
*
EtO2CCHO
this work
N
N
O
*
R2
R3
4
CO2Et
Scheme 1.
Keywords: Cycloadditions; Azomethine imine; Asymmetric synthesis.
* Corresponding authors. Tel.: +33-1-53739751; fax: +33-1-43291403; e-mail addresses: martine.bonin@univ-paris5.fr; laurent.micouin@
univ-paris5.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.088

3128
F. Chung et al. / Tetrahedron Letters 45 (2004) 3127–3130
derived from the condensation of hydrazine 1 with ethyl
glyoxylate (Scheme 1).
Ph
Ph
O
O
N
N
7
8
EtO2C
c
N
O
EtO2C
N
9
O
While the use of aromatic and, in a lesser extent, ali-
phatic aldehydes is well documented for the generation
of azomethine ylides, reports on the preparation and
reactivity of ylides resulting from a condensation with
alkylglyoxylates are scarce.5 Works of the Harwoodꢀs
group have shown that good selectivity could be
achieved in some cases, despite a lower reactivity of the
ylide.5d
a
O
CO2Me
MeO2C
O
Ph
N
6
O
Ph
9
EtO2C
N
N
O
Ph
O
Ph
O
5
O
CO2Et
d.r. = 46/38/16
N
N
EtO2C
N
O
EtO2C
N
O
A more contrasted behaviour has been reported by the
group of Grigg5c and Risch and co-workers.5f In both
cases, only electron poor olefins were used as standard
dipolarophiles. On the contrary, good results have been
described with achiral azomethine imines by Khau and
Martinelli.5e
d
b
Me
MeO2C
CO2Me
MeO2C
8
7
Scheme 3. Reagents and conditions: (a) dimethyl maleate (3 equiv),
toluene, 80 °C, 8 days, 84%, de¼70%; (b) dimethyl fumarate (3 equiv),
toluene, 80 °C, 7 days, 71%, de¼32%; (c) N-phenyl maleimide
(4 equiv), toluene, 3 days, 80 °C, 73%, de¼49%; (d) methyl crotonate
(4 equiv), toluene, 11 days, 80 °C, 71%, de¼18%.
First attempts to perform the cycloaddition under
standard conditions proved to be unsuccessful, leading
mainly to starting material or degradation.6 We then
tried to prepare oxadiazolidine 5, in order to generate
the reactive ylide by a cycloreversion process. While
thermal or protic activation failed, we were pleased to
see that a diastereomeric mixture of 5 could be obtained
in good yield in the presence of magnesium bromide
etherate (Scheme 2).7
The tandem cycloreversion–cycloaddition was then
investigated in the presence of various electron poor
dipolarophiles, leading to cycloadducts 6–9 in 71–83%
yield (Scheme 3).
While the endo selectivity was usually excellent with
ylides generated from aliphatic or aromatic aldehydes, a
lower selectivity was observed in the glyoxylic series.
The approach of dimethylmaleate proved to be mostly
endo, as depicted by crystal structure X-ray analysis of
compound 6 (Fig. 1),8 whereas the use of dimethyl-
fumarate led to the exo adduct 7 as a major diastereo-
mer. In all the cases, the facial selectivity was excellent,
leading to a single epimer at the C7-position (Scheme 3),
as a result of a dipolarophile approach from the less
sterically hindered face of a S-shape ylide.
Figure 1. ORTEP diagram of compound 6.
tron-withdrawing group should lead to
a lower
HOMOdipole–LUMOdipolarophile control.9 This hypothesis
was confirmed by cycloadditions with styrene deriva-
tives (Scheme 4).
This loss of endo selectivity is not unexpected, since the
lowering of the HOMO level of the dipole by an elec-
With electron rich olefins, cycloadducts 10–12 could be
obtained in 48–65% yield, with diastereoselectivities
greater than 85%. In all cases, the reaction was com-
pletely regioselective and led to the exo adduct as a
major diastereomer. This stereoselectivity enhancement,
when compared to the results obtained with ylides pre-
pared from aliphatic or aromatic aldehydes, as well
as the regioselective formation of C7, C9 cis substi-
EtO2CCHO
degradation
toluene, 70 °C
Ph
tuted compounds, is typical for
a LUMOdipole–
O
Ph
HOMOdipolarophile controlled condensation, which can be
expected with ylides bearing an electron-withdrawing
substituent. These results are noteworthy, since they
enable a formal access to diamino substrates having an
ester and an aromatic substituent in a 1,3 arrangement,
whereas the use of aromatic aldehydes and unsaturated
esters should deliver diamines with these two function-
alities in a 1,2-position.
HN
O
N
H
O
EtO2C
N
N
O
EtO2CCHO
1
O
MgBr2.Et2O (excess)
THF, 65 °C, 7 h
71%
5
CO2Et
d.r. = 46/38/16
Scheme 2.

F. Chung et al. / Tetrahedron Letters 45 (2004) 3127–3130
3129
1990, 38, 1129–1135; (c) Grigg, R.; Rankovic, Z.; Thorn-
ton-Pett, M.; Somasunderam, M. Tetrahedron 1993, 49,
8679–8690; (d) Harwood, L. M.; Lilley, I. A. Tetrahedron:
Asymmetry 1995, 6, 1557–1560; (e) Khau, V. V.; Marti-
nelli, M. J. Tetrahedron Lett. 1996, 37, 4323–4326; (f)
Ph
Ph
O
O
N
N
7
8
EtO2C
N
O
EtO2C
N
9
O
a
c
€
Wittland, C.; Florke, U.; Risch, N. Synthesis 1997, 1291–
1295.
Ph
10
O
6. A 50% commercial toluene solution of ethylglyoxylate was
used in all experiments. 1H NMR of this solution (the high
concentration of the reagent enables the direct NMR of
the solution without the use of a deuterated solvent) shows
that this aldehyde exists mainly as a trimeric form, and
that the proportion of free aldehyde can be roughly
estimated to 10%.
12
CO2Me
EtO2C
N
N
O
O
Ph
O
5
CO2Et
d.r. = 46/38/16
N
EtO2C
N
O
7. Although the use of Lewis acid has been described to have
an effect on dipolar cycloadditions, the role of magnesium
bromide etherate in our case is not completely clear. It can
improve the reactivity of the aldehyde in the cycloaddi-
tion, but also catalyze the deoligomerization of this
reagent. For the use of MgBr2ÆEt2O in dipolar cycloaddi-
tions, see: Harwood, L. M.; Manage, A. C.; Robin, S.;
Hopes, S. F. G.; Watkin, D. J.; Williams, C. E. Synlett
1997, 777–780.
b
11
OMe
Scheme 4. Reagents and conditions: (a) styrene (10equiv), toluene,
7 days, 75 °C, 48%, de¼90%; (b) 4-vinylanisole (8 equiv), toluene,
12 days, 70 °C, 51%, de¼94%; (c) 4-vinyl-methylbenzoate (8 equiv),
toluene, 12 days, 70 °C, 65%, de¼85%.
8. Crystal data for 6: formula C19H22N2O8, orthorhombic,
space group P212121; a ¼ 7:936ð2Þ, b ¼ 10:650ð2Þ,
3
ꢂ
ꢂ
c ¼ 23:818ð4Þ A, V ¼ 2013:1ð7Þ A , Z ¼ 4, M ¼ 406:4 g,
In conclusion, the ylide derived from the condensation
of hydrazine 1 with ethyl glyoxylate can be generated by
a cycloreversion reaction, and reacts with a wide range
of dipolarophiles.10 The regio- and facial selectivity of
the cycloadditions are perfectly controlled in all of the
cases. When compared to the alkyl- or aromatic series,
the glyoxylic ylide led to a lower endo selectivity with
dipolarophiles bearing electron-withdrawing groups,
but to an improved exo selectivity with styrene deriva-
tives. These results broaden the scope of this three-
component asymmetric condensation, and increase the
molecular diversity that can be generated with this
reaction.
Dc ¼ 1:341 g cmÀ3
;
F ð000Þ ¼ 856. The structure was
solved by direct methods using SHELXS-97. Refinement,
based on F 2, was carried out by full matrix least squares
with SHELXL-97 software. An ORTEP diagram is given
in the figure. Non-hydrogen atoms were refined aniso-
tropically. The hydrogen atoms were positioned geomet-
rically and refined riding on their carrier atom with
isotropic thermal displacement parameters fixed at 1.2
times those of their parent atoms. Convergence was
reached at R1 ¼ 0:040 for 2153 reflections (I > 2rðIÞ),
wR2 ¼ 0:143 for all data and S ¼ 0:918 for 265 parame-
ters. The residual electron density in the final diffÀe3rence
ꢂ
Fourier does not show any feature above 0.156 e A and
À3
ꢂ
below )0.189 e A
. Crystallographic data (excluding
structure factors) have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion no. CCDC 225965 copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: +44 (0) 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgements
A.C. thanks the MENRT for financial support.
9. (a) Houk, K. N.; Sims, J.; Duke, R. E., Jr.; Stozier, R. W.;
Georges, J. K. J. Am. Chem. Soc. 1973, 95, 7287–7301; (b)
Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am.
Chem. Soc. 1973, 95, 7301–7315.
References and notes
10. Experimental procedure. The preparation of 6 is typical:
carbazate 1 (see Ref. 3 for the preparation of 1) (75 mg,
0.42 mmol), ethylglyoxylate (50% in toluene, 333 lL,
4 equiv) and MgBr2ÆEt2O (210 lL) were dissolved in
THF (5 mL) and stirred at 65 °C for 7 h. The crude
reaction mixture was concentrated, and purified by flash
chromatography on silica gel (EtOAc–cyclohexane¼3:7)
to give oxadiazolidine 5 as a mixture of three diastereo-
mers (110mg, 71%). A diastereomeric mixture of 5 (70mg,
0.19 mmol) and dimethylmaleate (72 lL, 3 equiv) were
dissolved in toluene (2 mL) and stirred at 80 °C for 8 days.
The reaction mixture was concentrated, and the de of the
crude was determined by NMR (de¼70%). Purification by
flash chromatography on silica gel (EtOAc–cyclohex-
ane¼3:7) gave one fraction (55 mg, 71%) of diastereomer-
ically pure pyrazolidine 6 and a second fraction (10mg) of
a diastereomeric mixture of 6 (global yield: 84%). Pyraz-
1. Schreiber, S. L. Science 2000, 287, 1964–1969.
2. For a recent example of the use of 1,3-dipolar cycloaddi-
tions in diversity-oriented synthesis: (a) Chen, C.; Li, X.;
Schreiber, S. J. Am. Chem. Soc. 2003, 125, 10174–10175;
(b) For reviews on asymmetric 1,3-dipolar cycloadditions:
Karlsson, S.; Hogberg, H. E. Org. Prep. Proceed. Int.
2001, 33, 105–172; (c) Gothelf, K. V.; Jorgensen, K. A.
Chem. Rev. 1998, 98, 863–909.
3. (a) Roussi, F.; Bonin, M.; Chiaroni, A.; Micouin, L.;
Riche, C.; Husson, H.-P. Tetrahedron Lett. 1999, 40,
3727–3730; (b) Roussi, F.; Chauveau, A.; Bonin, M.;
Micouin, L.; Husson, H.-P. Synthesis 2000, 1170–1179.
4. Chauveau, A.; Martens, T.; Bonin, M.; Micouin, L.;
Husson, H.-P. Synthesis 2002, 1885–1891.
5. (a) Jacobi, P. A.; Martinelli, M. J.; Polanc, S. J. Am.
Chem. Soc. 1984, 106, 5594–5598; (b) Katayama, H.;
Takatsu, N.; Kitano, H.; Shimaya, Y. Chem. Pharm. Bull.
olidine 6: white crystals, mp (Et2O)¼130–132 °C; ½aŠ
D
)155° (c 0.98, CHCl3). 1H NMR (300 MHz): d 7.40(m,

3130
F. Chung et al. / Tetrahedron Letters 45 (2004) 3127–3130
5H), 4.90(d, J ¼ 8:7 Hz, 1H), 4.45 (dd, J ¼ 10:9, 10.7 Hz,
NMR (75.43 MHz): d 169.6, 168.3, 167.1, 149.1, 132.3,
128.9–129.7, 72.2, 67.4, 65.5, 61.7, 59.7, 53.0, 52.7, 49.2,
13.5. MS (CI): 407 (MHþ). IR (cmÀ1): 1747, 1700.
Elemental analysis. Calcd: C, 56.15; H, 5.46; N, 6.89.
Found: C, 56.04; H, 5.49; N, 6.92.
1H), 4.15 (dd, J ¼ 11:2, 3.1 Hz, 1H), 4.09 (dd, J ¼ 10:5,
3.1 Hz, 1H), 4.09 (d, J ¼ 11:2 Hz, 1H), 3.85 (dd, J ¼ 11:2,
8.7 Hz, 1H), 3.80(s, 3H), 3.75 (m, 1H), 3.68 (s, 3H), 3.27
(dq, J ¼ 10:7, 7.1 Hz, 1H), 0.9 (t, J ¼ 7:1 Hz, 3H). 13C