Organocatalytic asymmetric 1,3-dipolar cycloaddition of nitrones to nitroolefins

Article abstract of DOI:10.1055/s-0028-1087300

The asymmetric 1,3-dipolar cycloaddition of nitrones to nitroolefins was investigated by employing novel thiourea-containing organocatalysts. This transformation exhibited excellent diastereoselectivities (generally >99:1 dr) and moderate to high enantioselectivities (up to 88% ee). A 2,3-diaminopropanol derivative with three contiguous chiral centers was efficiently prepared from one cycloaddition adduct. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087300

LETTER
2997
Organocatalytic Asymmetric 1,3-Dipolar Cycloaddition of Nitrones to
Nitroolefins
1
, 3-Dipola
r
Cycloadditi
e
on of
N
itron
i
e
s
to
N
itrool
D
efins u, Yan-Kai Liu, Lei Yue, Ying-Chun Chen*
Key Laboratory of Drug-Targeting and Drug Deliver System of Education Ministry, West China School of Pharmacy, Sichuan University,
Chengdu 610041, P. R. of China
Fax +86(28)85502609; E-mail: ycchenhuaxi@yahoo.com.cn; E-mail: ycchen@scu.edu.cn
Received 1 August 2008
thiourea compounds,13 we expected that the stereoselec-
Abstract: The asymmetric 1,3-dipolar cycloaddition of nitrones to
tivity of 1,3-dipolar cycloaddition between nitrones and
nitroolefins could be controlled by the use of chiral thio-
ureas.
nitroolefins was investigated by employing novel thiourea-contain-
ing organocatalysts. This transformation exhibited excellent diaste-
reoselectivities (generally >99:1 dr) and moderate to high
enantioselectivities (up to 88% ee). A 2,3-diaminopropanol deriva-
tive with three contiguous chiral centers was efficiently prepared
from one cycloaddition adduct.
A number of diversely structured thiourea catalysts
(Figure 1) were screened in the asymmetric 1,3-dipolar
cycloaddition of C,N-diphenyl nitrone (2a) and alkyl ni-
troolefin 3a (10 mol% catalyst, toluene, r.t., 4 Å MS).9,14
Key words: dipolar cycloaddition, nitrones, nitroolefins, thiourea,
orgaoncatalysis
As outlined in Table 1, almost no reaction occurred with-
out the thiourea catalyst (entry 1). To our gratification,
thiourea 1a12a smoothly promoted this transformation.
The desired cycloaddition product 4a was obtained in
moderate yield with excellent diastereoselectivity after 3
days (dr >99:1). However, the ee value was very disap-
pointing (entry 2). Poor results were attained when differ-
ent functionalized thioureas 1b,12e 1c,13e and 1d13e were
utilized (entries 3–5). Racemic 4a was obtained in the
presence of Jacobsen’s thiourea-pyrrole catalyst 1e (entry
6).15 While newly designed thiourea-pyrrole 1f from
chiral 1,2-diphenylethylenediamine still delivered an un-
acceptable ee value (entry 7),16 we were pleased to find
that the enantioselectivity could be dramatically improved
with thiourea-pyrrole 1g derived from (R,R)-1,2-diamino-
hexane (entry 8). Consequently, more modifications were
made on the pyrrole moiety. While the same ee was
The asymmetric 1,3-dipolar cycloaddition reaction is one
of the most important pericyclic reactions to generate op-
tically pure heterocycles in a very straightforward man-
ner.1 A number of 1,3-dipoles, such as azomethine ylides,2
azomethine imines,3 nitrile oxides,4 and others5 have been
widely applied in the cycloaddition with various alkenes
and alkynes. In particular, nitrones6 as 1,3-dipoles have
received special interest, because not only they are easily
handled compounds and readily available, but also be-
cause the resulting isoxazolidines can be smoothly con-
verted to 1,3-amino alcohols. These amino alcohols find
wide applications in the synthesis of natural products and
pharmaceutical compounds. An array of dipolarophiles,
including vinyl ether7 and various a,b-unsaturated car-
bonyl compounds,8 have been well represented in the
asymmetric 1,3-dipolar cycloaddition of nitrones. Never-
theless, the reaction of nitrones and nitroolefins has been
rarely explored,9 although nitroolefins have been identi-
fied as one of the most versatile electrophiles in organic
synthesis.10 To the best of our knowledge, its catalytic
asymmetric variant has not been provided to date. Here
we would like to report the first organocatalytic 1,3-dipo-
lar cycloaddition of nitrones to nitroolefins promoted by
thiourea-containing compounds. This reaction can be con-
ducted enantioselectively in the presence of new chiral
thiourea-pyrrole catalysts.
S
S
S
Ar1
Ar1
HN
Ar1
N
N
H
O
N
H
N
H
N
H
H
N
OH
N
O
1a
1b
F
F
S
S
1c
F
F
HN
NH
1d
HN Ar1
Ar1 NH
S
N
S
N
N
Recently, chiral thioureas have performed as powerful
Brønsted acid catalysts for a large number of asymmetric
reactions through hydrogen-bonding interaction.11 Nitro-
olefins have proved to be a suitable type of substrates with
thiourea catalysis since the pioneering work of Takemoto
in 2003.12 In our continuing catalytic studies based on
H
H
Ar1
Ph
N
O
N
N
H
Ph
Ar2
H
1e
N
Ar2
Ph
Ph
N
1g Ar2 = C6H5
1j Ar2 = 3,5-F2C6H3
S
Ph
1h Ar2 = 4-FC6H4
1i Ar2 = 4-MeC6H4
1k Ar2 = 3,5-(CF3)2C6H3
HN
Ph
1f
Ar1 = 3,5-(CF3)2C6H3
HN Ar1
SYNLETT 2008, No. 19, pp 2997–3000
x
x
.x
x
.2
0
0
8
Advanced online publication: 23.10.2008
DOI: 10.1055/s-0028-1087300; Art ID: W12008ST
Figure 1 Structures of various thiourea catalysts
© Georg Thieme Verlag Stuttgart · New York

2998
W. Du et al.
LETTER
when the reaction was conducted at 0 °C, but the time had
to be extended to obtain good yields (entries 13 and 14).
A decreased yield was isolated in the presence of 5 mol%
of 1j (entry 15). Unfortunately, the results could not be
improved by increasing the catalytic loading to 15 mol%
(entry 16). Subsequently, several solvents were investi-
gated with the superior catalyst 1j at 0 °C. While reduced
enantioselectivities were observed in some solvents (en-
tries 17–20), satisfactory data were afforded in less com-
mon solvents such as m-mesitylene and methyl tert-butyl
ether (MTBE) (entries 21 and 22). A simple recrystalliza-
tion from 2-PrOH–n-hexane provided isoxazolidine 4a in
an enantiopure form (entry 22, 99% ee).
Table 1 Screening Studies of Organocatalytic 1,3-Dipolar Cycload-
dition of Nitrone 2a and Nitroolefin 3aa
Ph
O
Ph
N
1 (10 mol%)
N
Ph
+
NO2
O
Ph
solvent, 4 Å MS
r.t., 3 d
O2N
2a
3a
4a
Entry
1
Catalyst 1
–
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
FPh
Yield (%)b ee (%)c
–
–
9
2
1a
1b
1c
1d
1e
1f
56
69
39
79
45
67
71
84
42
77
78
76
73
67
74
23
71
52
69
76
79 (58)
3
8
We then examined a spectrum of nitrones and nitroolefins
to explore the reaction generality.17 The reactions were
conducted with 10 mol% of catalyst 1j in MTBE at 0 °C
for 6 days. In general, excellent diastereoselectivities (dr
>99:1) were observed in the tested reactions. As summa-
rized in Table 2, for C,N-diphenyl nitrone (2a), good
enantioselectivities and isolated yields were obtained for
various aliphatic nitroolefins bearing a branched, linear,
or functionalized side chain (entries 1–7). On the other
hand, the reaction of diversely substituted nitrones with
b-ethyl nitroethene was investigated. Nitrones bearing
electron-donating substitutions afforded good results (en-
tries 8–10). Nitrones possessing electron-withdrawing
groups exhibited slightly poorer solubility in MTBE.
Modest yields were attained in the specific time, while the
enantioselectivities remained high (entries 11–14). A
good ee with modest yield was attained for a nitrone pos-
sessing a 2-furyl group (entry 15). In addition, a nitrone
with an N-o-anisyl substitution, which could be easily re-
moved through mild oxidative conditions, afforded a sat-
isfactory yield (entry 16). Moreover, good results were
also gained for the nitrone bearing an N-p-fluorophenyl
group (entry 17). The nitrone in situ formed from
PhNHOH and propionaldehyde showed high reactivity in
the 1,3-dipolar cycloaddition, but only moderate enantio-
selectivity could be achieved (entry 18).
4
24
23
0
5
6
7
11
60
60
37
66
64
74
70
73
72
32
63
67
72
80
82 (99)
8
1g
1h
1i
9
10
11
12
13d
14d
15d,e
16d,f
17d
18d
19d
20d
21d
22d
1j
1k
1j
1k
1j
1j
1j
1j
1j
CF3Ph
1j
m-Xylene
m-Mesitylene
MTBE
As illustrated in Scheme 1, enantiomerically pure isox-
azolidine 4a (99% ee, after recrystallization) could be di-
rectly converted to its 2,3-diaminopropanol derivative,
which was easily isolated as N-Boc-protected compound
5, without any racemization.18 Moreover, single crystals
suitable for X-ray crystallographic analysis were obtained
from an N-methanesulfonyl derivative 6 (Figure 2).19 In
this way, the absolute stereochemistry of cycloadduct 4a
was determined and the regioselectivity of the cycloaddi-
tion confirmed.
1j
1j
a Unless otherwise noted, reactions were performed with 0.1 mmol of
2a, 0.12 mmol of 3a, 10 mol% of 1, 50 mg 4 Å MS in 0.5 mL of sol-
vent at r.t. for 3 d.
b Isolated yields.
c Determined by chiral HPLC analysis, dr >99:1 in all cases. The ab-
solute configuration of 4a was determined by X-ray analysis after
some derivation (see Figure 2).
d At 0 °C for 6 d.
e With 5 mol% of 1j.
In conclusion, we have presented the first stereoselective
1,3-dipolar cycloaddition reaction of nitrones to b-alkyl
nitroolefins promoted by newly designed thiourea-pyrrole
catalysts. In general excellent diastereo- (dr >99:1) and
moderate to high enantioselectivities (up to 88% ee) could
be obtained for an array of substrates. Enantiopure 2,3-di-
aminopropanol derivatives with three contiguous chiral
centers could be efficiently prepared from the cycloaddi-
tion adducts obtained. Current studies are under way to in-
f With 15 mol% of 1j.
gained for catalyst 1h with a p-fluorophenyl substitution
(entry 9), the enantioselectivity was significantly de-
creased for 1i bearing an electron-donating group (entry
10). As a result, thiourea 1j and 1k possessing stronger
electron-withdrawing groups were prepared, which gave
rise to slightly better enantioselectivities as expected (en-
tries 11 and 12). The results could be further improved
Synlett 2008, No. 19, 2997–3000 © Thieme Stuttgart · New York

LETTER
1,3-Dipolar Cycloaddition of Nitrones to Nitroolefins
2999
Ph
Ph
Ph
Ph
N
NiCl2
(Boc)2O
Ph
91%
for two steps
Ph
O
OH
NHBoc
N
OH
N
NaBH4
H
H
O2N
NH2
5 99% ee
4a 99% ee
Scheme 1 Conversion of cycloadduct 4a to its corresponding 2,3-diaminopropanol derivative 5
Table 2 Asymmetric 1,3-Dipolar Cycloaddition of Nitrone 2 and
Nitroolefin 3
Ar
O
N
R1
N
1j (10 mol%)
NO2
R1
O
+
R2
Ar
MTBE, 4 Å MS
0 °C, 6 d
O2N
2
3
R2
4
Entry Ar
R1
R2
Yield
ee
(%)a
(%)b
82
83
87
84
80
84
82
88
86
80
82
87
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
i-Pr
4a 79
Cyclohexyl 4b 85
3
Et
4c 84
4d 93
4e 89
4f 72
4g 92
4h 78
4i 71
4j 93
4k 58
4l 54
4
n-Pr
Figure 2 X-ray crystallographic structure of enantiopure 6
5
i-Bu
6
n-Hexyl
Acknowledgment
7
2-BnOEt
We are grateful for the financial support from Natural Science
Foundation of China (20502018 and 20772084) and Chinesisch-
Deutsches Zentrum für Wissenschaftsförderung [GZ422 (362/6)].
8
4-MeOC6H4
4-MeC6H4
3-MeC6H4
4-FC6H4
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
9
References and Notes
10
11
12
13
14
15
16
17
18c
(1) (a) For a comprehensive review of 1,3-dipolar
cycloadditions, see: Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry toward Heterocycles and Natural
Products; Padwa, A.; Pearson, W. H., Eds.; John Wiley and
Sons: Hoboken NJ, 2003. For recent reviews of asymmetric
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Tetrahedron 2007, 63, 3235. (c) Gothelf, K. V.; Jørgensen,
K. A. Chem. Rev. 1998, 98, 863.
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Chem. Int. Ed. 2005, 44, 6272. (c) Pandey, G.; Banerjee, P.;
Gadre, S. R. Chem. Rev. 2006, 106, 4484.
4-ClC6H4
4-BrC6H4
2-ClC6H4
2-Furyl
4m 54 84
4n 78
4o 43
4p 91
4q 65
4r 84
84
83
81
84
40
2-MeOC6H4 Ph
4-FC6H4
Ph
Ph
Et
(3) For selected examples, see: (a) Shintani, R.; Fu, G. C. J. Am.
Chem. Soc. 2003, 125, 10778. (b) Suárez, A.; Downey,
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a Isolated yields.
b Determined by chiral HPLC analysis. Absolute stereochemistry of
4b–r assigned by analogy with 4a.
c With in situ formed nitrone; dr >90:10 by 1H NMR analysis.
vestigate the catalytic mechanism and expand the
synthetic utility of this catalytic system.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2008, No. 19, 2997–3000 © Thieme Stuttgart · New York

3000
W. Du et al.
LETTER
Kang, T.-R.; Hu, Z.-K.; Chen, Y.-C. J. Am. Chem. Soc.
2008, 130, 2456. (f) Tian, X.; Jiang, K.; Peng, J.; Du, W.;
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(14) b-Nitrostyrene exhibited very sluggish reactivity in the
catalytic 1,3-dipolar cycloaddition even at much higher
temperature (>50 °C).
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(k) Karlsson, S.; Högberg, H.-E. Eur. J. Org. Chem. 2003,
2782.
(16) Thiourea-pyrrole catalysts 1f–k were prepared in a similar
procedure as 1e, see ref. 14.
(17) General Procedure for the Asymmetric 1,3-Dipolar
Cycloaddition Reaction
Catalyst 1j (6.6 mg, 0.01 mmol, 10 mol%), nitrone 2a (20.0
mg, 0.1 mmol) and 4 Å MS (50 mg) were stirred in
redistilled MTBE (0.4 mL) at 0 °C. Then nitroolefin 3a (14.0
mg, 0.12 mmol) in MTBE (0.1 mL) was added. After 6 d,
product 4a was isolated by FC on SiO2 eluted with EtOAc–
PE as an oil; 24.5 mg, 79% yield; Rf = 0.5 (PE–EtOAc,
15:1); [a]D20 –101.3 (c 1.00 in CH2Cl2); 82% ee, determined
by HPLC analysis [Daicel chiralcel OD, n-hexane–i-PrOH
(95:5), 1.0 mL/min, l = 254 nm, tR(major) = 7.70 min,
tR(minor) = 11.16 min]. 1H NMR (400 MHz, CDCl3):
d = 7.44–7.41 (m, 2 H), 7.35–7.33 (m, 3 H), 7.21–7.17 (m,
2 H), 7.04–6.98 (m, 3 H), 5.29 (dd, J = 9.2, 7.2 Hz, 1 H), 4.80
(t, J = 7.2 Hz, 1 H), 4.74 (d, J = 9.2 Hz, 1 H), 2.08–2.03 (m,
1 H), 1.14 (d, J = 6.8 Hz, 3 H), 1.02 (d, J = 6.8 Hz, 3 H) ppm.
13C NMR (50 MHz, CDCl3): d = 148.1, 133.3, 129.2, 128.8,
128.7, 128.2, 124.1, 116.4, 94.5, 84.7, 73.0, 30.7, 19.0, 17.9
ppm. ESI-HRMS: m/z calcd for C18H20N2O3 + Na: 335.1372;
found: 335.1320.
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Eur. J. Org. Chem. 2002, 1877. (b) Tsogoeva, S. B. Eur. J.
Org. Chem. 2002, 1701.
(18) General Procedure for the Synthesis of 2,3-Diamino-
propanol 5
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Compound 4a (31 mg, 0.1 mmol, 99% ee) and NiCl2·6H2O
(100 mg, 0.4 mmol) were stirred in MeOH (1 mL) and THF
(0.5 mL) at r.t. for 10 min. Then NaBH4 (33 mg, 0.9 mmol)
was added in portions at 0 °C. After stirring for 5 min,
EtOAc (5 mL) and H2O (5 mL) were added. After filtration,
the filtrate was extracted with EtOAc (2 × 10 mL). The
combined organic layers were dried over Na2SO4 and
concentrated. The residue and (Boc)2O (26 mg, 0.12 mmol)
were dissolved in CH2Cl2 and stirred for 2 h. The solvent was
then removed in vacuo, and the residue was purified by flash
chromatography on SiO2 (EtOAc–PE) to give N-Boc-
diaminopropanol 5 as an oil; 35 mg, 91% yield for two steps;
Rf = 0.4 (PE–EtOAc, 5:1); [a]D20 +18.6 (c 0.70 in CH2Cl2);
99% ee, determined by HPLC analysis [Daicel chiralcel AD,
n-hexane–i-PrOH (90:10), 1.0 mL/min, l = 254 nm,
tR(minor) = 5.48 min, tR(major) = 9.32 min]. 1H NMR (400
MHz, CDCl3): d = 7.33–7.28 (m, 4 H), 7.23–7.21 (m, 1 H),
7.11–7.07 (m, 2 H), 6.70–6.67 (m, 1 H), 6.59–6.57 (m, 2 H),
5.46 (s, 1 H), 5.12 (d, J = 8.4 Hz, 1 H), 4.84–4.77 (m, 1 H),
4.03 (s, 1 H), 3.54 (s, 1 H), 1.86–1.84 (m, 1 H), 1.30 (s, 9 H),
1.06 (d, J = 6.8 Hz, 3 H), 1.02 (d, J = 6.4 Hz, 3 H) ppm.
13C NMR (50 MHz, CDCl3): d = 155.4, 147.0, 140.6, 129.1,
128.5, 127.1, 126.9, 118.3, 114.8, 79.6, 78.8, 58.6, 56.1,
29.9, 28.2, 19.4, 18.2 ppm. ESI-HRMS: m/z calcd for
C23H32N2O3 + H: 385.2491; found: 385.2453.
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(19) CCDC-700901 (6) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Synlett 2008, No. 19, 2997–3000 © Thieme Stuttgart · New York