Highly enantioselective nitrone cycloadditions with 2-alkenoyl pyridine N-oxides catalyzed by Cu

Article abstract of DOI:10.1021/ol102716e

Enantioselective nitrone cycloadditions with 2-alkenoyl pyridine N-oxides as dipolarophiles have been reported. The reaction is catalyzed by Cu (II)-BOX complexes to give the expected isoxazolidine products with high diastereo-and enantioselectivity.

Full text of DOI:10.1021/ol102716e

ORGANIC
LETTERS
2011
Vol. 13, No. 3
402-405
Highly Enantioselective Nitrone
Cycloadditions with 2-Alkenoyl Pyridine
N-Oxides Catalyzed by Cu(II)-BOX
Complexes
Santiago Barroso,† Gonzalo Blay,*,† M. Carmen Mun˜oz,‡ and Jose´ R. Pedro*,†
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica, UniVersitat de Vale`ncia,
C/Dr. Moliner, 50, E-46100 Burjassot, Vale`ncia, Spain, and Departamento de F´ısica
Aplicada, UniVersidad Polite´cnica de Valencia, E-46071 Valencia, Spain
gonzalo.blay@uV.es; jose.r.pedro@uV.es
Received November 9, 2010
ABSTRACT
Enantioselective nitrone cycloadditions with 2-alkenoyl pyridine N-oxides as dipolarophiles have been reported. The reaction is catalyzed by
Cu(II)-BOX complexes to give the expected isoxazolidine products with high diastereo- and enantioselectivity.
The 1,3-dipolar cycloaddition reaction is an important and
atom-economic synthetic tool for the preparation of five-
membered heterocycles, which are present in a large number
of bioactive compounds. Several compounds have been used
as 1,3-dipoles in this kind of reaction, nitrones being among
the most studied substrates. The isoxazolidine products
obtained from these reactions are valuable precursors to
biologically active γ-amino acids, γ-aminoalcohols, ꢀ-lac-
tams, amino sugars, and alkaloids.1 In recent years, a number
of enantioselective Lewis acid catalyzed nitrone cycloaddi-
tions with either electron-deficient (normal-electron demand)
or electron-rich alkenes (inverse-electron demand) have been
reported,2 some of them using copper complexes with chiral
ligands as catalysts.3 With respect to the copper-catalyzed
nitrone cycloadditions with electron-deficient alkenes, only
a limited number of substrates have been successfully used
as dipolarophiles. First examples were described by Saito,
using 3-(2-alkenoyl)-1,3-oxazolidin-2-ones as chelating di-
polarophiles together with bis-imine and BOX complexes.4
(2) For recent reviews, see: (a) Gothelf, K. V. In Cycloaddition Reactions
in Organic Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH:
Weinheim, 2001; pp 211-248. (b) Pellissier, H. Tetrahedron 2007, 63,
3235–3285. For recent examples, see: (c) Badoiu, A.; Bernardinelli, G.;
Ku¨ndig, E. P. Synthesis 2010, 2207–2212. (d) Phomkeona, K.; Takemoto,
T.; Ishima, Y.; Shibatomi, K.; Iwasa, S.; Nishiyama, H. Tetrahedron 2008,
64, 1813–1822. (e) Carmona, D.; Lamata, M. P.; Viguri, F.; Rodriguez,
R.; Oro, L. A.; Lahoz, F. J.; Balana, A. I.; Tejero, T.; Merino, P. J. Am.
Chem. Soc. 2005, 127, 13386–13398. (f) Suga, H.; Nakajima, T.; Itoh, K.;
Kakehi, A. Org. Lett. 2005, 7, 1431–1434. (g) Iwasa, S.; Maeda, H.;
Nishiyama, K.; Tsushima, S.; Tsukamoto, Y.; Nishiyama, H. Tetrahedron
2002, 58, 8281–8287. (h) Jensen, K. B.; Roberson, M.; Jørgensen, K. A. J.
Org. Chem. 2000, 65, 9080–9084.
† Universitat de Vale`ncia.
‡ Universidad Polite´cnica de Valencia.
(1) (a) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley:
New York, 1984; Vol. 1. (b) 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984; Vol. 2. (c) Torssell, K. B. G. Natural
Product Chemistry; VCH: Weinheim, 1988. (d) 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, 2002.
(3) For a recent review on copper-catalyzed 1,3-dipolar cycloadditions,
see: Stanley, L. M.; Sibi, M. P. Chem. ReV. 2008, 108, 2887–2902.
10.1021/ol102716e  2011 American Chemical Society
Published on Web 12/22/2010

In these cases, the dipolarophile is able to form a chelate
with the metal ion of the chiral complex which is responsible
for the high stereoselectivities observed. Other chelating
dipolarophiles have been also used as reaction substrates.
Thus, Palomo5 introduced R′-hydroxy enones in BOX-Cu(II)-
catalyzed reactions to obtain the endo adducts, and Sibi
reported the BOX-Cu(II) catalyzed reaction using 1-sub-
stituted 2-alkenoyl-5,5-dimethyl-3-pyrazolidones6 and acyclic
alkenoylimides7 as dipolarophiles, which favored the forma-
tion of the corresponding exo adducts. Also, very recently
Ishihara has described the use of propioloyl- and acry-
loylpyrazoles as dipolarophiles in nitrone cycloadditions.8
Jørgensen introduced the 2-acylpyridine N-oxide moiety as
a new chelating scaffold for Cu(II)-BOX-catalyzed reactions.9
Inspired by this work, we developed 2-alkenoylpyridine N-
oxides as efficient chelating substrates for asymmetric catalysis.
We have used these substrates as dienophiles in Diels-Alder
reactions10 and as heterodienes in inverse-electron demand
hetero-Diels-Alder reactions.11 These substrates have also been
used by Singh et al. in Mukaiyama-Michael reactions12 and
Friedel-Crafts alkylations.13 As we and Singh have shown,
these substrates are much more reactive and afford higher
enantioselectivities in asymmetric Cu(II)-BOX-catalyzed14
reactions than the corresponding nonoxidized 2-alkenoylpy-
ridines. In this communication we present the use of the
2-alkenoylpyridineN-oxidesasdipolarophilesfortheCu(II)-BOX-
catalyzed 1,3-dipolar cycloaddition reactions with nitrones
(Scheme 1).15
) R2 ) Ph) was used for the screening of ligands and
conditions (Table 1). Initially, we tested this reaction under
the optimized conditions for the Diels-Alder reaction,9 using
Cu(OTf)2 and Ph-BOX ligand (S,S)-4, in dichloromethane
(entry 1). To our surprise, low yields of racemic compounds
were obtained. The use of Zn(OTf)2 instead of Cu(OTf)2 gave
even worse results (entry 2).
Table 1. Optimization of the Reaction of Dipolarophile 1a (R )
Ph) with Nitrone 2a (R1 ) R2 ) Ph): Screening of Ligandsa
,
entry
MX2
L
yield(%)b endo/exo ee (%)endoc d
1e
2e
3
5
4
Cu(OTf)2 (S,S)-4
Zn(OTf)2 (S,S)-4
Cu(OTf)2 (S,S)-4
Cu(OTf)2 (S,S)-5
Cu(OTf)2 (4R,5S)-6
Cu(OTf)2 (4R,5S)-7
Cu(OTf)2 (S,S)-8
<10f
<5f
94
85
90
n.d.
n.d.
0
0
62:38
92:8
80:20
82:18
85:15
(S)10
(R)89
(S)59
0
6
7
79
86
0
a All experiments were carried out under nitrogen: 1a (0.25 mmol), 2a
(0.3 mmol), MX2 (0.025 mmol, 10 mol %), L (0.025 mmol, 10 mol %),
MS 4 Å (100 mg), CH2Cl2 (1.5 mL), rt, 5 h. b Purified by flash
chromatography. c Determined by HPLC on a Chiralcel OD-H column. d The
absolute configuration of the carbon R to carbonyl is in parentheses. e No
MS were used. f Yield after 24 h.
Then, we tested the use of additives. It has been described
that the addition of molecular sieves significantly influences
the results of 1,3-dipolar cycloadditions.16 Effectively, when
we carried out the reaction in the presence of 4 Å molecular
sieves (400 mg/mmol 1a), the reaction was complete in 5 h,
providing a 62:38 endo/exo mixture of diastereomers in 94%
yield, although in only 10% ee for the endo diastereomer.
Encouraged by this result, we tested different BOX ligands
5-8, and to our delight, ligand (S,S)-5 afforded the desired
compound 3aa with 89% ee and high diatereoselectivity
(endo/exo 92:8). Ligands (S,S)-4 and (S,S)-5 afforded op-
posite enantiomers in a similar way as it has been observed
in other Cu(II)-catalyzed reactions with these ligands.13
Ligand (4R,5S)-7, bearing an unsubstituted central methylene,
and the pyBOX ligand (S,S)-8 gave racemic mixtures. Further
optimization with ligand (S,S)-5 was achieved by changing
solvents and the amounts of MS (Table 2). Both nitromethane
and EtOAc performed better than other solvents in terms of
diastereo- and enantioselectivity, although EtOAc gave a
better yield (entry 5). The type of MS was also tested
although it did not show a very important effect (entries
5-7): 4 Å MS gave better diastereoselectivities than 3 and
5 Å MS, although with 3 Å MS a slightly better enantiose-
Scheme 1. Nitrone 1,3-Dipolar Cycloadditions to Alkenoyl
Pyridine N-Oxides and BOX Ligands Evaluated in This Study
(5) Palomo, C.; Oiarbide, M.; Arceo, E.; Garc´ıa, J. M.; Lopez, R.;
Gonzalez, A.; Linden, A. Angew. Chem., Int. Ed. 2005, 44, 6187–6190.
(6) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc. 2004, 126,
718–719.
The reaction between cinnamoylpyridine N-oxide (1a, R
) Ph) and nitrone 2a (R1 ) R2 ) Ph) to give 3aa (R ) R1
(7) Sibi, M. P.; Ma, Z.; Itoh, K.; Prabagaran, N.; Jasperse, C. P. Org.
Lett. 2005, 7, 2349–2352.
(8) Sakakura, A.; Hori, H.; Fushimi, M.; Ishihara, K. J. Am. Chem. Soc.
2010, 132, 15550–15552.
(4) (a) Saito, T.; Yamada, Y.; Miyazaki, S.; Otani, T. Tetrahedron Lett.
2004, 45, 9585–9587. (b) Saito, T.; Yamada, Y.; Miyazaki, S.; Otani, T.
Tetrahedron Lett. 2004, 45, 9581–9584. See also: (c) Desimoni, G.; Faita,
G.; Toscanini, M.; Boiocchi, M. Chem.sEur. J. 2009, 15, 9674–9677.
(9) (a) Landa, A.; Minnkila¨, A.; Blay, G.; Jørgensen, K. A. Chem.sEur.
J. 2006, 12, 3472–3483. (b) Landa, A.; Richter, B.; Johansen, R. L.;
Minkkila¨, A.; Jørgensen, K. A. J. Org. Chem. 2007, 72, 240–245.
(10) Barroso, S.; Blay, G.; Pedro, J. R. Org. Lett. 2007, 9, 1983–1986.
Org. Lett., Vol. 13, No. 3, 2011
403

Table 2. Optimization of the Reaction of Dipolarophile 1a (R )
Ph) with Nitrone 2a (R1 ) R2 ) Ph) Using Ligand (S,S)-5:
Effect of Solvent and MSa
Table 3. 1,3-Dipolar Cycloadditions of 2-Alkenoyl Pyridine
N-Oxide 1a (R ) Ph) with Nitrones 2a-g Using Ligand
(S,S)-5a
MS
(Å/mg)
time yield
(h)
ee (%)d
(%)b endo/exoc endo/exo
entry
solvent
CH2Cl2
1
4/100
Toluene 4/100
CH3NO2 4/100
5
5.5
5
29
5
5
85
85
86
20
100
81
92
97
86
94
96
92:8
87:13
93:7
79:21
94:6
89:11
86:14
90:10
91:9
89/12
85/18
92/28
78/32
92/9
96/33
91/32
95/36
93/17
95/61
98/41
2
3
4
5
6
CH3CN
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
4/100
4/100
3/100
5/100
4/50
4/200
4/75
4/75
time
R2 (h)
yield
(%)b endo/exoc endo/exo
(%)d
entry
2
R1
3
7
8
9
5
1
2
3
4
5
6
7
a
b
c
d
e
f
Ph
4-MeOC6H4 Ph 24 ab 77
4-BrC6H4 Ph 24 ac 81
4-NO2C6H4 Ph 48 ad 36
cyclohexyl Ph 24 ae 16
Ph 10 aa 94
94:6
86:14
91:9
95/61
90/42
94/45
89/79
60/29
88/78
80/75
21
21
10
24
10
94:6
91:9
94:6
11e
74:26
66:34
61:39
a All experiments were carried out under nitrogen: 1a (0.25 mmol), 2a
(0.3 mmol), Cu(OTf)2 (0.025 mmol), (S,S)-5 (0.025 mmol), MS, solvent
(1.5 mL), rt. b Purified by flash chromatography. c Determined by 1H NMR.
d Determined by HPLC on a Chiralcel OD-H column. e Reaction carried
out at 0 °C.
Ph
Me 48 af
59
g
Ph
Bn 48 ag 62
a All experiments were carried out under nitrogen: 1a (0.25 mmol), 2a
(0.3 mmol), Cu(OTf)2 (0.025 mmol, 10 mol %), (S,S)-5 (0.025 mmol, 10
mol %), MS 4 Å (75 mg), EtOAc (1.5 mL), rt. b Purified by flash
chromatography. c Determined by 1H NMR. d Determined by HPLC on
chiral stationary phase columns.
lectivity was obtained. However, it was possible to arrive at
a compromise between diastereo- and enantioselectivity by
adjusting the amount of 4 Å MS to 300 mg/mmol of
dipolarophile (entry 10). The ee could be slightly increased
by carrying out the reaction at 0 °C, although this required
a longer reaction time (entry 11) and the diastereoselectivity
was lower.
Table 4. 1,3-Dipolar Cycloadditions of 2-Alkenoyl Pyridine
N-Oxides 1a-h with Nitrone 2a (R1 ) R2 ) Ph) Using Ligand
(S,S)-5a
With these optimized conditions in hand, we investigated
the scope of the reaction. First, we studied the reaction of
alkenoyl pyridine N-oxide 1a (R ) Ph) as a dipolarophile
with different nitrones (Table 3). In general, N-phenyl
nitrones (entries 1-5) gave better results than N-methyl or
N-benzyl nitrones (entries 6 and 7). N-Phenyl nitrones
derived from aromatic aldehydes gave the corresponding
cycloadducts with good yields as well as diastereo- (near
9:1 favoring the endo isomer) and enantioselectivities (above
90% ee), except in the case of nitrone 1d derived from
p-nitrobenzaldehyde that reacted with low yield, although
with good stereoselectivity. However, nitrone 1e, derived
from alicyclic cyclohexancarbaldehyde was poorly reactive
and gave cycloadduct 3ae with fair diastereoselectivity but
only 60% ee.
time
(h)
yield
(%)b endo/exoc endo/exo
ee (%)d
entry
1
R
3
1
2
3
4
5
6
7
8
9e
a
b
c
d
e
f
g
h
a
Ph
10
24
10
1.5 da
24
24
aa
ba
ca
94
69
82
56
43
68
52
98
94:6
93:7
90:10
87:13
>99:1
94:6
95/61
96/nd
96/22
96/21
95/-
91/nd
93/33
86/45
92/35
4-MeOC6H4
4-BrC6H4
4-NO2C6H4
2-furyl
ea
fa
ga
ha
2-thienyl
(E)-PhCH)CH- 24
93:7
92:8
t-Bu
Ph
1
24
aa 100
90:10
a All experiments were carried out under nitrogen: 1a (0.25 mmol), 2a
(0.3 mmol), Cu(OTf)2 (0.025 mmol, 10 mol %), (S,S)-5 (0.025 mmol, 10
mol %), MS 4 Å (75 mg), EtOAc (1.5 mL), rt. b Purified by flash
chromatography. c Determined by 1H NMR. d Determined by HPLC on
chiral stationary phase columns. e 1a (3.0 mmol), 2a (2.5 mmol), Cu(OTf)2
(0.125 mmol, 5% mol), 5 (0.125 mmol, 5 mol %), MS 4 Å (750 mg), EtOAc
(7 mL), rt.
Then, we performed the reaction of differently substituted
dipolarophiles 1 with nitrone 2a (R1 ) R2 ) Ph). The results
are gathered in Table 4. The R group on the double bond of
the dipolarophile 1 was amenable to variation. When R was
(11) Barroso, S.; Blay, G.; Mun˜oz, M. C.; Pedro, J. R. AdV. Synth. Catal.
2009, 351, 107–111.
a substituted phenyl group, high diastereoselectivities (near
9:1 favoring the endo cycloadduct) and enantiomeric excesses
(above 95% ee for the endo diastereomer) were obtained,
regardless of the electronic nature of the substituent; again,
the 4-nitrophenyl derivative gave the corresponding cycload-
duct only in moderate yield. R can be also a five-membered
heterocyle (entries 5 and 6). In these cases the reaction was
a little bit slow. The furyl-containing compound 1f afforded
(12) Singh, P. K.; Singh, V. K. Org. Lett. 2008, 10, 4121–4124.
(13) Singh, P. K.; Singh, V. K. Org. Lett. 2010, 12, 80–83.
(14) For a review on BOX-catalyzed reactions, see: Desimoni, G.; Faita,
G.; Jørgensen, K. A. Chem. ReV. 2006, 106, 3561–3651.
(15) A few days after the submission of our manuscript we noticed a
related paper by Faita describing one example of this reaction: Livieri, A.;
Boiocchi, M.; Desimoni, G.; Faita, G. Chem.sEur. J., DOI: 10.1002/
chem.201002017.
(16) Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 1998,
63, 5483–5488.
404
Org. Lett., Vol. 13, No. 3, 2011

the highest diastereoselectivity, although the yield dropped
considerably. Similar results were obtained with compound
1g bearing an alkene. Dipolarophile 1h, bearing a bulky tert-
butyl group, showed a very high reactivity and gave
cycloadduct 3ah with good yield, fair diastereoselectivity,
and 86% ee. Experiments also showed that the amount of
catalyst can be reduced to as low as 5 mol %, and the reaction
scaled up at least ten times without noticeable effect on the
yield and stereoselectivity (entry 9).
Suitable crystals for X-ray analysis of compound endo-
3fa could be obtained upon crystallization from EtOAc,
which allowed establishing the absolute stereochemistry for
this compound (Figure 1). For the remaining cycloadducts,
(left) of the ligand. On the other hand, the endo approach
would minimize the interactions between the R1 group of
the nitrone and the other tert-butyl group (right) of the ligand.
This model is in good agreement with the recent findings
by Faita,15 who has isolated a complex of compound 1a,
Cu(OTf)2, and a related bis-oxazoline ligand having an
elongated square-bipyramidal structure, with two triflate
anions occupying the axial positions. Since it is not clear
whether these two anions are present also in solution, and
for clarity, we have omitted them in Figure 2.
Figure 2. Proposed stereochemical model for the 1,3-dipolar
cycloaddition between 2-alkenoyl pyridine N-oxides and nitrones.
In conclusion, we have shown that 2-alkenoyl pyridine
N-oxides are efficient dipolarophiles for 1,3-dipolar cycload-
ditions of nitrones catalyzed by chiral Cu(II)-BOX com-
plexes. This kind of substrates enlarges the range of electron-
deficient alkenes that can be used in these cycloaddition
reactions to favor formation of the endo adducts. Isoxazo-
lidines bearing a pyridine-containing substituent are obtained
with yields as well as diastereo- and enantioselectivities from
good to excellent.
Figure 1. ORTEP plot for the X-ray structure of compound 3fa.
Flack parameter 0.1(12).
the absolute configuration was assigned on the assumption
of a uniform stereochemical mechanistic pathway.
Acknowledgment. Financial support from the Ministerio
de Ciencia e Innovacio´n and FEDER (CTQ2006-14199 and
CTQ2009-13083) and from Generalitat Valenciana (ACOMP/
2009/338) is acknowledged. S.B. thanks the Universitat de
Valencia for a predoctoral grant (V Segles program).
The stereochemistry of the products indicates the prefer-
ence of the nitrone to approach the dipolarophile from the
R-re face of the double bond. Following previous studies13
on BOX-Cu(II) catalyzed reactions, we suggest that a
distorted square-planar complex is formed by the dipolaro-
phile 1, ligand 5, and metal center, with the dipolarophile
coordinating to two positions of the copper ion, with the
carbonyl and N-oxide moieties. The dipolarophile would
adopt the more stable s-cis conformation, and in this way
the approach of the nitrone from the R-si face of the double
bond would be hampered by one of the tert-butyl groups
Supporting Information Available: Experimental pro-
cedures, characterization data and copies of NMR spectra,
and chiral HPLC analysis for compounds 3. X-ray structure
plot and CIF file for compound 3fa. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL102716E
Org. Lett., Vol. 13, No. 3, 2011
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