Catalytic enantioselective 1,3-dipolar cycloaddition of nitrones to cyclopent-1-enecarbaldehyde

Article abstract of DOI:10.1016/S0957-4166(02)00231-8

A variety of pyrrolidinium salts have been found to catalyse the reaction between nitrones and a cyclic α,β-unsaturated aldehyde furnishing bicyclic adducts with high diastereoselectivity and enantioselectivity.

Full text of DOI:10.1016/S0957-4166(02)00231-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 923–926
Catalytic enantioselective 1,3-dipolar cycloaddition of nitrones to
cyclopent-1-enecarbaldehyde
Staffan Karlsson* and Hans-Erik Ho¨gberg
Chemistry, Department of Natural and Environmental Sciences, Mid Sweden University, SE-851 70 Sundsvall, Sweden
Received 10 April 2002; accepted 8 May 2002
Abstract—A variety of pyrrolidinium salts have been found to catalyse the reaction between nitrones and a cyclic a,b-unsaturated
aldehyde furnishing bicyclic adducts with high diastereoselectivity and enantioselectivity. © 2002 Elsevier Science Ltd. All rights
reserved.
The enantioselective 1,3-dipolar cycloaddition of
nitrones to alkenes is one of the most efficient
approaches for the preparation of chiral non-racemic
isoxazolidines1,2 and these reactions can serve as routes
to building blocks for the construction of biologically
important compounds.3 Such 1,3-dipolar cycloaddition
reactions catalysed by chiral imidazolidinone salts and
involving acyclic a,b-unsaturated aldehydes furnish
cycloadducts with excellent diastereoselectivity and
enantioselectivity.4 In this case, the organocatalyst
works in the absence of metal salts because the catalytic
effect is due to activation of the a,b-unsaturated alde-
hyde by iminium salt formation between the catalyst
and the starting aldehyde, resulting in a decrease in the
LUMO energy of the alkene moiety.4
reaction occurred at ambient temperature. When the
catalyst 14 (Fig. 1, 13 mol%) was added, reaction took
place and after reduction of the bicyclic aldehyde
product to the corresponding alcohol, a low yield of
cycloadduct 12 was obtained in low e.e. together with
its diastereomer 13 (Table 1, entries 1 and 2).
These disappointing results prompted us to investigate
the catalytic performance of the chiral ammonium salts
Although, the imidazolidinone salts obviously serve as
excellent catalysts in the reaction between nitrones and
acyclic a,b-unsaturated aldehydes, enantioselective
organocatalytic 1,3-dipolar cycloaddition of nitrones to
cyclic a,b-unsaturated aldehydes have to our knowledge
not been investigated.
Figure 1. Catalysts for use in 1,3-dipolar cycloadditions of
nitrones.
We report herein our preliminary results from a study
of additions of acyclic nitrones to cyclopent-1-enecar-
baldehyde 10 (Scheme 1) catalysed by a variety of chiral
pyrrolidinium salts, resulting in highly enantio- and
diastereoselective
isoxazolidines.
formation
of
fused
bicyclic
When aldehyde 10 and nitrone 11 were mixed in either
CH3NO2 or DMF in the absence of a catalyst, no
Scheme 1.
* Corresponding author. E-mail: staffan.karlsson@mh.se
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00231-8

924
S. Karlsson, H.-E. Ho¨gberg / Tetrahedron: Asymmetry 13 (2002) 923–926
Table 1. 1,3-Dipolar cycloaddition between aldehyde 10 and nitrone 11 in DMF catalysed by a variety of catalysts (13
mol%) at +10°Ca
Entry
Catalyst
Salt (HX)
Time (h)
% Yieldb
D.r.c
e.e.d (%)
1e
1
1
2
3
4
4
5
6
7
8
8
9
9
9
9
9
9
9
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
HCl
2HCl
HCl
2HCl
2HClO4
2TFA
2HCl
2HCl
2HCl
120
144
72
48
120
96
72
48
96
144
72
144
72
120
72
120
120
144
7
19
59
39
61
45
0
–
0
–5
67
23
70
76
–
2e,f
3
86:14
83:17
89:11
80:20
72:28
–
4
5
6g
7e
8e
0
–
–
9e
12
26
50
44
49
44
31
23
21
70
80:20
95:5
93:7
95:5
97:3
80:20
84:16
93:7
97:3
95:5
68
85
89
91
92
78
85
93
91
91
10
11
12
13
14
15
16g
17h
18i
a The nitrone 11 (3.7 mmol) and a catalyst (0.48 mmol) were added to a solution of the aldehyde 10 (4.8 mmol) in DMF (15 mL) and H2O (86
mL). After the specified time, water (50 mL) and EtOAc (50 mL) were added. Extraction with EtOAc (2×25 mL), drying (Na2SO4) filtration and
concentration gave a residue, which was subjected to chromatography (silica gel, EtOAc/cyclohexane as eluent). All fractions containing the
desired product were collected and subjected to NaBH4 reduction. The resulting mixture of 12 and 13 was separated (silica gel, EtOAc/cyclohex-
ane as eluent). No regioisomers could be detected in any instance.
b Combined overall isolated yield of 12 and 13.
c Isolated diastereomeric ratio.
d Determined by GC-analysis on a chiral b-dex-325 column of the corresponding trifluoroacetate of 12.
e Performed at room temperature.
f CH3NO2 as solvent.
g Performed at −10°C.
h 1 mol% catalyst, 1:1 ratio 10:11.
i 1:2 ratio 10:11.
Formation of a protonated unreactive cyclic N–O ace-
tal from the aldehyde 10 and either catalyst 5 or 6 was
probably the reason why these catalysts were ineffective
(Scheme 2).11 On the other hand, when the proline
based diamines 812 and 912 (Fig. 1) were used as cata-
lysts in the reaction sequence above (Scheme 1), we
were pleased to see that the isoxazolidine 12 was
obtained with both very high diastereoselectivity and
enantioselectivity (entries 10 and 12). Because catalyst 9
gave a slightly higher enantioselectivity than 8, we
continued our study using this. When the dihydrochlo-
ride salt of 9 was used, excellent diastereoselectivity and
enantioselectivity were obtained although the yield was
moderate (entry 13). When performing the reaction at a
lower temperature, we observed no significant improve-
ment in the enantioselectivity (entry 16). The nature of
the counterion of the ammonium salt was important
of some azabicyclo[3.3.0]octanes in the cycloaddition
reaction above (Scheme 1). Compounds 2–4 (Fig. 1)
were prepared from the product of a 1,3-dipolar
cycloaddition. Thus, a chiral azomethine ylide was
added to a cyclic sulfur-containing dipolarophile.5 Fur-
ther transformations furnished compounds 2–4. Fortu-
nately, when these were used as catalysts in the reaction
sequence above (Scheme 1), the reduced cycloadduct 12
was obtained in reasonable yields and up to 76% e.e.
along with the separable diastereomer 13 (Table 1,
entries 3–6).6 When catalyst 2 was compared with its
methyl ether 3, it was evident (entry 3 versus 4) that the
free hydroxyl group in 2 was important for achieving
high enantioselectivity. When p-methoxy substituents
were introduced onto the phenyl groups the electron
density on the alcohol is increased, which resulted in a
slight improvement in the enantioselectivity (entry 3
versus 5).7
For comparison, we also investigated some proline-
based catalysts in the above reaction. Disappointingly,
no conversion was obtained when the alcohols 58 and
69 were tried as catalysts (entries 7 and 8). However,
albeit in low yield, the methyl ether 710 (i.e. methylated
5) yielded isoxazolidine 12 in high enantioselectivity
(entry 9).
Scheme 2.

S. Karlsson, H.-E. Ho¨gberg / Tetrahedron: Asymmetry 13 (2002) 923–926
925
(entries 14–15). Although the yield was low, when the
reagent:substrate loading was decreased to 1:1 and the
catalyst loading to 1 mol%, the enantioselectivity and
diastereoselectivity remained almost unchanged (entry
17). A good yield could, however, be obtained when
using an excess of the nitrone 11 (entry 18). Among all
the catalysts studied so far, 8 and 9 seemed to give the
highest enantioselectivity, while the fused bicyclic com-
pounds, in particular 4, gave the highest yields.
The relative configuration of the major diastereomer 12
was determined through 1D NOESY experiments (Fig.
2).
Scheme 3.
Thus, the minor diastereomer 13 displayed a 2% NOE
between the two methine protons shown. This NOE
was absent in the major diastereomer 12.13 However, a
strong NOE effect was observed for this isomer
using catalyst 1, McMillan et al. obtained a high enan-
tio- and diastereoselectivity in the reaction of croton-
aldehyde with nitrone 11.4 Having demonstrated the
utility of the catalysts 2–9 for a cyclic dipolarophile, we
also studied the reaction of crotonaldehyde and nitrone
11 in the presence of some of the catalysts 2–9. Interest-
ingly, although in low enantioselectivity compared to
catalyst 1,4 these catalysts showed reversed diastereose-
lectivity in the crotonaldehyde–nitrone reaction.
between the phenyl protons and the CH6 2-OH protons.
The assignment of relative configuration of the major
and minor diastereomer is also supported by the strong
shielding effect of the phenyl group resulting in a
upfield shift of the CH6 2-OH signals (3.27–3.42 ppm) of
the major diastereomer 12 relative to those of the minor
diastereomer 13 (3.56–3.75 ppm). Compound 12 was
transformed into one enantiomer of 2-benzyl-2-
(hydroxymethyl)cyclopentanol and tert-butyl-(1R)-1-
In summary, a variety of pyrrolidinium salts catalyse
the reaction between nitrones and cyclopent-1-enecarb-
aldehyde furnishing fused bicyclic isoxazolidines in
good yield and high diastereoselectivity and enantiose-
lectivity. The low loading of catalyst and substrate
necessary for achieving a reasonable yield of the
cycloadducts should make this process useful in prepar-
ing isoxazolidines containing a fused bicyclic substruc-
ture. The application of this methodology towards the
construction of a variety of heterocycles from other
nitrones and other cyclic a,b-unsaturated aldehydes is
currently being investigated.
benzyl-2-oxocyclopentanecarboxylate
of
known
absolute configuration14 was converted to (1S,2S)-2-
benzyl-2-(hydroxymethyl)cyclopentanol for compari-
son. These cyclopentanols displayed opposite signs of
specific rotation. Thus, the absolute configuration of 12
was assigned as 3R,3aR,6aR. Complete details will be
given in a full paper.
The low yields obtained under some conditions in the
reactions studied (Scheme 1, Table 1) could be due
partly to the fact that varying amounts of the
diastereomeric by-products 15 and 16 were formed
(Scheme 3).15
Acknowledgements
This work was supported by the Swedish Natural Sci-
ence Research Council (NFR) and the Mid Sweden
University. We are grateful to Dr. Kei Manabe for
supplying us with a sample of tert-butyl-(1R)-1-benzyl-
2-oxocyclopentanecarboxylate14 and Mr. Daniel Pet-
tersen (University of Go¨teborg, Department of Organic
Chemistry, Sweden) for a generous gift of compound 8.
Thus, under the wet conditions (DMF/H2O) applied in
these reactions,16 nitrone 11 underwent hydrolysis fol-
lowed by condensation of the corresponding hydroxyl-
amine with aldehyde 10. The resulting nitrone 14 could
now react with the aldehyde 10, which was activated by
the catalyst. Alternatively the nitrone 14 could react
with the double bond of the cyclopentenyl moiety of a
second molecule of this nitrone. The former pathway
was found to be the predominant one because the
reduced cycloadduct 15 was isolated as a by-product in
92% e.e. in one experiment (Table 1, entry 16). When
References
1. Karlsson, S.; Ho¨gberg, H.-E. Org. Prep. Proc. Int. 2001,
33, 103–172.
2. Gothelf, K. V.; Jensen, K. B.; Jo¨rgensen, K. A. Sci. Prog.
1999, 82, 327–350.
3. Frederickson, M. Tetrahedron 1997, 53, 403–425.
4. Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 9874–9875.
5. Karlsson, S.; Ho¨gberg, H.-E. J. Chem. Soc., Perkin
Trans. 1 2002, 1076–1082.
6. Some experiments revealed that DMF was the best sol-
vent in terms of enantioselectivity.
Figure 2.

926
S. Karlsson, H.-E. Ho¨gberg / Tetrahedron: Asymmetry 13 (2002) 923–926
7. It was obvious that a bulky tertiary alcohol and a sulfone
0.90–1.02 (m, 1H), 1.42–1.60 (m, 2H), 1.75–2.01 (m, 4H),
2.60 (s, 3H), 3.60 (dd, 1H, J=4.6, 10.9 Hz), 3.63 (s, 1H),
3.71 (dd, 1H, J=5.6, 10.9 Hz), 4.47–4.52 (m, 1H), 7.25–
7.40 (m, 5H). 13C NMR (CDCl3) l 25.4, 30.6, 35.1, 43.8,
64.1, 66.2, 77.7, 85.1, 127.4, 128.1, 128.3, 137.5. MS (EI):
m/z (%) 233 (M+, 63), 216 (2), 134 (100). Anal. calcd for
C14H19NO2: C, 72.1; H, 8.2; N, 6.0. Found: C, 72.3; H,
8.1; N, 5.9%.
functionality in the bicyclic catalysts were necessary for
achieving high enantioselectivity, because related cata-
lysts investigated, lacking those, gave much lower enan-
tioselectivity.
8. Guoqiang, L.; Hjalmarsson, M.; Ho¨gberg, H.-E.; Jernst-
edt, K.; Norin, T. Acta Chem. Scand. B 1984, 38, 795–
801.
9. Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem.
1988, 53, 2861–2863.
14. Manabe, K. Tetrahedron Lett. 1998, 39, 5807–5810.
15. Data for compound 15: e.e.=92%, mp 121–123°C, [h]2D5=
−128.6 (c 0.44, CHCl3) 1H NMR (CDCl3) l 1.35–1.99 (m,
8H), 2.23–2.48 (m, 5H), 2.58 (s, 3H), 2.74 (s, 1H), 3.43
(dd, 1H, J=6.1, 11.0 Hz), 3.60 (dd, 1H, J=3.5, 11.0 Hz),
4.40 (d, 1H, J=5.4 Hz), 5.66–5.70 (m, 1H). 13C NMR
(CDCl3) l 23.0, 24.0, 31.8, 32.4, 33.6, 34.8, 43.3, 63.1,
65.7, 78.1, 85.3, 127.6, 139.1. MS (EI): m/z (%) 223 (M+,
40), 125 (50), 68 (100). Anal. calcd for C13H21NO2: C,
69.9; H, 9.5; N, 6.3. Found: C, 69.8; H, 9.6; N, 6.2%.
Data for compound 16: 1H NMR (CDCl3) l 1.23–1.93 (m,
9H), 2.13–2.41 (m, 4H), 2.60 (s, 3H), 3.00 (s, 1H), 3.60 (d,
1H, J=10.8 Hz), 3.69 (d, 1H, J=10.8 Hz), 4.37 (t, 1H,
J=4.6 Hz), 5.60–5.66 (m, 1H). 13C NMR (CDCl3) l 23.3,
25.6, 30.7, 32.3, 34.7, 34.8, 44.3, 63.4, 67.0, 75.3, 85.2,
127.9, 139.7. MS (EI): m/z (%) 223 (M+, 100), 125 (20),
68 (31).
10. Bucher, C. B.; Linden, A.; Heimgartner, H. Helv. Chim.
Acta 1995, 78, 935–946.
11. Due to the rigid structure of the fused bicyclic catalysts 2
and 4, they are probably unable to form unreactive N–O
acetals with aldehyde 10 (see Scheme 2).
12. Hendrie, S. K.; Leonard, J. Tetrahedron 1987, 43, 3289–
3294.
13. Data for compound 12: e.e.=93%, mp 68–70°C, [h]2D5=
−153.1 (c 0.80, CHCl3) 1H NMR (CDCl3) l 1.26–1.32
(m, 1H, -OH), 1.46–1.65 (m, 2H), 1.76–2.06 (m, 4H), 2.57
(s, 3H), 3.23 (s, 1H), 3.31 (dd, 1H, J=6.7, 11.2 Hz), 3.39
(dd, 1H, J=4.9, 11.2 Hz), 4.30 (d, 1H, J=5.1 Hz),
7.28–7.38 (m, 5H). 13C NMR (CDCl3) l 24.0, 32.0, 33.6,
42.8, 64.0, 65.5, 81.2, 86.1, 127.3, 128.0, 128.8, 136.1. MS
(EI): m/z (%) 233 (M+, 57), 216 (2), 134 (100). Anal. calcd
for C14H19NO2: C, 72.1; H, 8.2; N, 6.0. Found: C, 72.2;
H, 8.3; N, 6.0%.
16. In the absence of water the reactions were very sluggish
and difficult to work-up.
1
Data for compound 13: mp 68–71°C, H NMR (CDCl3) l