Catalytic asymmetric formal [4 + 1] annulation leading to optically active cis -isoxazoline N -oxides

Article abstract of DOI:10.1021/ol102181r

The catalytic asymmetric synthesis of densely functionalized cis-isoxazoline N-oxides was realized with novel use of an organocatalyst, (S)-2-(azidodiphenylmethyl)pyrrolidine (4e) (Tan, B.; Zhu, D.; Zhang, L.; Chua, P. J.; Zeng, X.; Zhong, G. Chem.-Eur. J

Full text of DOI:10.1021/ol102181r

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5402-5405
Catalytic Asymmetric Formal [4 + 1]
Annulation Leading to Optically Active
cis-Isoxazoline N-Oxides
Zugui Shi, Bin Tan, Wendy Wen Yi Leong, Xiaofei Zeng, Min Lu, and
Guofu Zhong*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, 21 Nanyang Link, Singapore 637371
guofu@ntu.edu.sg
Received September 12, 2010
ABSTRACT
The catalytic asymmetric synthesis of densely functionalized cis-isoxazoline N-oxides was realized with novel use of an organocatalyst, (S)-
2-(azidodiphenylmethyl)pyrrolidine (4e) (Tan, B.; Zhu, D.; Zhang, L.; Chua, P. J.; Zeng, X.; Zhong, G. Chem.-Eur. J. 2010, 16, 3842; Olivares-
Romero, J. L.; Juaristi, E. Tetrahedron 2008, 64, 9992), via an elegant formal [4 + 1] annulation strategy using readily available 2-nitroacrylates
and r-iodoaldehydes.
Isoxazoline N-oxides are intriguing synthetic targets since
they can be readily converted into highly functionalized
γ-hydroxy-R-amino acids or γ-amino-R-hydroxy acids.1
Despite the fact that several synthetic methodologies have
been developed,2 only sporadic examples achieved asym-
metric versions by using stoichiometric amounts of chiral
reactants.3 As such, the catalytic asymmetric approach to
optically active isoxazoline N-oxides is still viewed as a
formidable synthetic challenge.4
Stereoselective construction of ring systems continues to
be considerably important in organic synthesis. In the past
few decades, the [4 + 1] annulation has proved to be a
powerful strategy in the construction of dihydrofurans,
cyclopentenes, cyclopentenones, and pyrrolidines.5 However,
the catalytic asymmetric version of the [4 + 1] annulation
was rarely documented, due to the difficulty in controlling
relative and absolute stereochemistry.6,7
(1) For references of synthetic utilities of isoxazoline N-oxides, see: (a)
Minter, A. R.; Fuller, A. A.; Mapp, A. K. J. Am. Chem. Soc. 2003, 125,
6846. (b) Fuller, A. A.; Chen, B.; Minter, A. R.; Mapp, A. K. J. Am. Chem.
Soc. 2005, 127, 5376. (c) Ja¨ger, V.; Schwab, W. Tetrahedron Lett. 1978,
19, 3129. (d) Ja¨ger, V.; Schwab, W. Tetrahedron Lett. 1978, 19, 3133. (e)
Schreiner, E. P.; Gstach, H. Synlett 1996, 1131. (f) Ashburn, S. P.; Coater,
R. M. J. Org. Chem. 1984, 49, 3127. (g) Manning, J. R.; Davies, H. M. L.
J. Am. Chem. Soc. 2008, 130, 8602. (h) Damkaci, F.; DeShong, P. J. Am.
Chem. Soc. 2003, 125, 4408. (i) Annunziata, R.; Cinquini, M.; Cozzi, F.;
Raimondi, L. Tetrahedron 1986, 42, 2129. (j) Righi, P.; Marotta, E.;
Landuzzi, A.; Rosini, G. J. Am. Chem. Soc. 1996, 118, 9446.
(3) For references of asymmetric synthesis of isoxazoline N-oxides using
chiral reactants, see: (a) Zhu, C.-Y.; Deng, X.-M.; Sun, X.-L.; Zheng, J.-
C.; Tang, Y. Chem. Commun. 2008, 738. (b) Zhu, C.-Y.; Sun, X.-L.; Deng,
X.-M.; Zheng, J.-C.; Tang, Y. Tetrahedron 2008, 64, 5583.
(4) Jiang, H.; Elsner, P.; Jensen, K. L.; Falcicchio, A.; Marcos, V.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2009, 48, 6844.
(5) For references of racemic [4 + 1] annulation reactions, see: (a)
Padwa, A.; Norman, B. H. Tetrahedron Lett. 1988, 29, 3041. (b) Dalton,
A. M.; Zhang, Y.; Davie, C. P.; Danheiser, R. L. Org. Lett. 2002, 4, 2465.
(c) Loebach, J. L.; Bennett, D. M.; Danheiser, R. L. J. Am. Chem. Soc.
1998, 120, 9690. (d) Chatani, N.; Oshita, M.; Tobisu, M.; Ishii, Y.; Murai,
S. J. Am. Chem. Soc. 2003, 125, 7812. (e) Rigby, J. H.; Wang, Z. Org.
Lett. 2002, 4, 4289. (f) Rigby, J. H.; Wang, Z. Org. Lett. 2003, 5, 263. (g)
Oshita, M.; Yamshita, K.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2005,
127, 761. (h) Giese, M. W.; Moser, W. H. Org. Lett. 2008, 10, 4215. (i)
Danheiser, R. L.; Bronson, K.; Okano, Son, S. J. Am. Chem. Soc. 1985,
107, 4579. (j) Lu, L.; Li, F.; An, J.; Zhang, J.; An, X.; Hua, Q.; Xiao,
W.-J. Angew. Chem., Int. Ed. 2009, 48, 9542.
(2) For selected synthetic approaches to racemic isoxazoline N-oxides,
see: (a) Kunetsky, R. A.; Dilman, A. D.; Ioffe, S. L.; Struchkova, M. A.;
Strelenko, Y.; Tartakovsky, V. A. Org. Lett. 2003, 5, 4907. (b) Clagett,
M.; Gooch, A.; Graham, P.; Holy, N.; Mains, B.; Strunk, J. J. Org. Chem.
1976, 41, 4033. (c) Kunetsky, R. A.; Dilman, A. D.; Struchkova, M. I.;
Belyakov, P. A.; Tartakovsky, V. A.; Ioffe, S. L. Synthesis 2006, 13, 2265.
(d) Snider, B. B.; Che, Q. Tetrahedron 2002, 58, 7821. (e) Khan, P. M.;
Wu, R.; Bisht, K. S. Tetrahedron 2007, 63, 1116. (f) Me´lot, J. M.; Texier-
Boullet, F.; Foucaud, A. Synthesis 1988, 558. (g) Zen, S.; Koyama, M.
Bull. Chem. Soc. 1971, 44, 2882.
10.1021/ol102181r  2010 American Chemical Society
Published on Web 10/19/2010

Inspired by organocatalytic enamine chemistry8 and our
previous study of the fluoroaldol reaction,9 we decided to
address these challenges. It was hypothesized that catalytic
asymmetric synthesis of isoxazoline N-oxides could be
achieved through [4 + 1] annulation between 2-nitroacryl-
ates10 and chiral enamines via elegant control of regio- and
chemoselectivity (Scheme 1, eq 1), thereby avoiding the
Table 1. Optimization of Reaction Parametersa
Scheme 1
.
Regio- and Chemoselectivities of Enamine
Cyclization
entry
4
Lg solvent t (h) yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
4a Cl TBME
4b Cl TBME
4a Br TBME
48
96
24
5
5
5
3
7
24
8
14
23
50
18
90
79
77
78
60
83
20
89
94
69
1:1.4
n.d.
1.3:1
1.8:1
4.5:1
2.2:1
6:1
9:1
3:1
11:1
11:1
9:1
70
0
99
96
96
95
95
98
n.d.
>99
>99
99
4a
4a
4c
4d
4e
4f
I
I
I
I
I
I
I
I
I
TBME
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
10e
11f
12g
4e
4e
4e
a Unless otherwise noted, reactions were performed at rt on a 0.1 mmol
scale, in 0.5 mL of solvent, with a molar ratio of R-iodohexanal/2-
nitroacyrate/DIPEA/4 ) 4:1:1.1:0.2. b The sum of both isomers. c dr ) cis/
trans, based on analysis of crude 1H NMR. d Determined by HPLC for the
cis-isomer. e TEA was employed. f Reaction was performed at 0.1 M
concentration. g 10 mol % 4e was used. n.d. ) not determined. DIPEA )
diisopropyl ethyl amine, TEA ) triethyl amine, Lg ) leaving group.
[2 + 1] pathway which would deliver cyclopropane adducts
(eq 2). Herein, we report our preliminary results of this
strategy, which gives rise to the formation of cis-isoxazoline
N-oxides. To our knowledge, this is the first example in
which cis-adducts are achieved.
Initial studies were focused on investigating suitable
enamine precursors (Table 1).11 Readily available R-halo-
genated hexanals were examined with methyl 2-nitro-3-
phenylacrylate (E/Z ) 2:1), in the presence of catalyst 4a,
which possessed high efficiency in enamine chemistry
(entries 1-4).12 The feasibility of our designed catalytic
system was first tested with R-chlorohexanal. To our delight,
the [4 + 1] annulation product was observed, without any
formation of cyclopropane, although unsatisfactory chemical
yield and stereoselectivity were obtained (entry 1). When
R-bromohexanal and R-iodohexanal were employed, the
yields were significantly increased to 90% and 79%, respec-
tively, and accompanied by excellent enantioselectivities
(99% and 96% ee’s), with the latter showing promising
diastereocontrol and highest reactivity (entries 3 and 4).
Replacing the solvent TBME with toluene led to better
diastereoselectivity (entry 5). In addition, ꢀ-elimination
would occur occasionally, hence requiring the use of a slight
excess of base as additive.11
Further catalyst screening with R-iodohexanal revealed that
catalyst 4e showed the best catalytic performance (entry 8).
The superior diastereocontrol achieved by 4e might have
resulted from the predominant formation of the Z-enamine
and electrostatic interaction between the azido moiety and
nitro group in 2-nitroacrylate. Subsequent screening of
additives indicated that use of triethyl amine provided the
best results (entry 10). Also, lower concentration led to higher
yield of the desired product (entry 11). It was found that the
catalyst loading could be decreased to 10 mol %, to achieve
acceptable chemical yield, as well as slightly lower diaste-
reoselectivity, while maintaining enantioselectivity (entry 12).
The scope of R-iodoaldehydes was next explored (Table
2). Under the optimized reaction conditions, R-iodoaldehydes
with linear alkyl substituents proceeded in the [4 + 1]
annulation smoothly to afford optically active isoxazoline
N-oxides 3 in good yields (64-94%), with excellent enan-
(6) For reference of asymmetric [4 + 1] annulation reactions using chiral
reactants, see: (a) Zheng, J.-C.; Zhu, C.-Y.; Sun, X.-L.; Tang, Y.; Dai, L.-
X. J. Org. Chem. 2008, 73, 6909. (b) Lu, L.-Q.; Zhang, J.-J.; Li, F.; Cheng,
Y.; An, J.; Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2010, 49, 4495.
(7) For reference of catalytic asymmetric [4 + 1] annulation reactions,
see: Son, S.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 1046.
(8) For reviews of enamine chemistry, see: (a) List, B. Acc. Chem. Res.
2004, 37, 548. (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem.
ReV. 2007, 107, 5471.
(9) Zhong, G.; Fan, J.; Barbas III, C. F. Tetrahedron Lett. 2004, 45,
5681.
(10) For general review of a nitro group, see: Ono, N. The Nitro Group
in Organic Synthesis; Wiley-VCH: New York, 2001.
(11) For more detailed optimization, see the Supporting Information.
(12) For selected references of chiral pyrrolidine derivative catalyzed
reactions, see: (a) Franze´n, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Kjrsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. (b)
Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed.
2005, 44, 4212. (c) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W. J. Am.
Chem. Soc. 2007, 129, 10886. (d) Enders, D.; Hu¨ttl, M. R. M.; Grondal,
C.; Raabe, G. Nature 2006, 441, 861. (e) Shibatomi, K.; Yamamoto, H.
Angew. Chem., Int. Ed. 2008, 47, 5796. (f) Zhu, D.; Lu, M.; Dai, L.; Zhong,
G. Angew. Chem., Int. Ed. 2009, 48, 60892. (g) Tan, B.; Zeng, X.; Lu, Y.;
Chua, P. J.; Zhong, G. Org. Lett. 2009, 11, 1927. (h) The catalyst 4e was
used in: Tan, B.; Zhu, D.; Zhang, L.; Chua, P. J.; Zeng, X.; Zhong, G.
Chem.-Eur. J. 2010, 16, 3842. (i) The catalyst 4e was prepared using a
modification of the method described in: Olivares-Romero, J. L.; Juaristi,
E. Tetrahedron 2008, 64, 9992.
Org. Lett., Vol. 12, No. 23, 2010
5403

rich substrates delivered higher yields compared to electron-
poor substrates, thus demonstrating that the electronic nature
of the aromatic substrates had drastic effects. However, longer
reaction times were needed (entries 2 and 3). Interestingly, for
all cases, comparable results were obtained, regardless of the
double bond geometry of the 2-nitroacrylate substrates. This
may be due to isomerization of the 2-nitroacrylate during
the course of the reaction,13 which was proved by the
detection of benzenaldehyde in the reaction system, and
subsequently resulted in relatively low yields of isoxazo-
line N-oxides for some cases. The absolute configuration
of the major diastereomer cis-3l was determined to be
(4S,5R) by X-ray crystallography (Figure 1).
Table 2. Scope of R-Iodoaldehydesa
entry
1 (R)
1a (ethyl)
yield (%)b
drc
ee (%)d
1
2
3
4
5
6
3a 64
3b 68
3c 94
3d 84
3e 75
3f 70
10:1
11:1
11:1
9:1
18:1
8:1
95
94
>99
92
99
99
1b (propyl)
1c (butyl)
1d (heptyl)
1e (benzyloxymethyl)
1f (benzyl)
a Unless otherwise noted, reactions were performed at rt on a 0.2 mmol
scale, in 2.0 mL of toluene, with a molar ratio of R-iodohexanal/2a/TEA/
4e ) 4:1:1.1:0.2. b The sum of both diastereoisomers. c dr ) cis/trans,
determined by H NMR. d Determined by chiral HPLC for cis-isomer.
1
tioselectivities (92 to >99% ee’s) and good diastereoselec-
tivities (9:1-11:1 dr, entries 1-4). Furthermore, aryl-
substituted R-iodoaldehydes proved to be good donors,
affording desired products in good yields and remarkable
stereocontrol (entries 5 and 6).
To further evaluate the versatility of this reaction, a variety
of 2-nitroacrylates were used (Table 3). Aromatic and
Table 3. Scope of 2-Nitroacrylatesa
entry
2 (R, E/Z)
2g (Ph, 1:1)
2h (o-MePh, 1.2:1)
2i (o-ClPh, 1.5:1)
2j (m-MePh, 1.8:1)
2k (m-ClPh, Z)
yield of 3 (%)b
drc
ee (%)d
Figure 1. Absolute configuration of cis-3l determined by X-ray
diffraction crystallography.
1
2
3
4
5
6
3g 87
3h 81
3i 64
3j 80
3k 63
3l 78
9:1 91
11:1 97
11:1 96
11:1 92
>20:1 96
14:1 94
Having established the catalytic asymmetric formal
[4 + 1] annulation methodology of 2-nitroacrylates and R-io-
doaldehydes, the synthetic utilities of these previously undocu-
mented cis-isoxazoline N-oxides were further explored. Apart
from the typical transformation of the chiral isoxazoline core
into numerous valuable synthons, such as ꢀ-amino acids,1
γ-hydroxy-R-amino acids, and amino alcohols,2 a concise
approach to a densely functionalized chiral γ-lactone 6, an
important building block in the synthesis of natural products
and biologically active compounds,14 was realized (Scheme 2).
2l (p-BrPh, Z)
7
8
2m (p-MePh, 2:1)
2n (p-MeOPh, 4:1)
2o (1-naphthyl, 1.5:1)
2p (2-naphthyl, 1.7:1)
3m 81
3n 73
3o 62
3p 74
3q 67
3r 61
10:1 92
13:1 91
12:1 94
9
10e
11:1 87 (>99)f
>20:1 85
11:1 84
11g 2q (3-furanyl, 2:1)
12
2r (2-furanyl, 1:1)
a Unless otherwise noted, reactions were performed at rt, on a 0.2 mmol
scale, in 2.0 mL of toluene, with a molar ratio of 1b/2/TEA/4e ) 4:1:1.1:
0.2, for 9-24 h. b The sum of both diastereoisomers. c dr ) cis/trans,
determined by 1H NMR. d Determined by chiral HPLC for cis-isomer.
e Methyl ester 2p was used. f After a simple recrystallization. g R-Iodohexanal
was employed.
(13) For selected reference of similar double bond geometric isomer-
ization, see: Wang, J.; Yu, F.; Zhang, X.; Ma, D. Org. Lett. 2008, 10, 2561.
(14) For selected references of biologically active natural products contain-
ing 2-amino-γ-lactones as core, see: (a) Matic, V.; Kosowska, K.; Bozdogan,
B.; Kelly, L. M.; Smith, K.; Ednie, L. M.; Lin, G.; Credito, K. L.; Clark,
C. L.; McGhee, P.; Pankuch, G. A.; Jacobs, M. R.; Appelbaum, P. C.
Antimicrob. Agents Chemother. 2004, 48, 4103. (b) Kosowska, K.; Credito,
K.; Pankuch, G. A.; Hoellman, D.; Lin, G.; Clark, C.; Dewasse, B.; McGhee,
P.; Jacobs, M. R.; Appelbaum, P. C. Antimicrob. Agents Chemother. 2004,
48, 4113. (c) Bringmann, G.; Gulder, T. A. M.; Schmitt, G.; Lang, S.; Sto¨hr,
R.; Wiese, J.; Nagel, K.; Imhoff, J. F. Mar. Drugs 2007, 5, 23.
heteroaromatic substrates were observed to be suitable
acceptors in this [4 + 1] annulation process. Systematic tuning
of electron-withdrawing and electron-donating substituents at
ortho-, meta- and para-positions of the aromatic ring gave rise
to densely functionalized isoxazoline N-oxides in good yields,
and with high stereoselectivities (entries 2-8). Notably, electron-
5404
Org. Lett., Vol. 12, No. 23, 2010

Scheme 2
.
Transformation of cis-Isoxazoline N-Oxide into
Densely Functionalized γ-Lactonea
Scheme 3
.
Proposed Mechanism of the Fomal [4 + 1]
Annulation Reaction
mediate 9 then proceeds via an intramolecular SN2-type
O-alkylation to complete the catalytic cycle.17
In conclusion, we have presented the first catalytic
asymmetric [4 + 1] annulation of 2-nitroacrylates and
R-iodoaldehydes for the highly stereoselective synthesis of
valuable cis-isoxazoline N-oxides with readily available
substrates with novel use of the catalyst 4e. Racemic
R-iodoaldehydes, which were rarely employed as nucleo-
philes, proved to be suitable donors for this enamine
cyclization process. Moreover, a concise synthetic approach
to the biologically and medicinally relevant building block,
chiral 2-amino-γ-lactone, has been developed. This catalytic
platform has opened up a new entry to the construction of
five-membered ring systems. Additional investigations of the
mechanism and other synthetic utilities of this protocol, such
as extension to three-membered ring formation as well as
total synthesis of natural products, are currently underway.
a TBS ) tert-butyldimethylsilyl, Boc ) tert-butoxycarbonyl.
Optically pure cis-isoxazoline N-oxide 3c was readily converted
to intermediate 5 by simple reduction and protection. A
deoxygenation was then carried out to provide isoxazoline 6 in
quantitative yield. This was followed by treatment of 6 with
nickel borohydride which was formed in situ, to give highly
substituted 2-amino-γ-lactone 7 as a single diastereoisomer in
good yield, albeit with slight loss of optical purity.
It is proposed that the tandem sequence15,16 is initiated
by condensation of R-iodoaldehyde 1 and catalyst 4e, to
generate enamine 8, which then undergoes a Michael addition
with 2-nitroacrylate 2 (Scheme 3). The oxyanion of inter-
Acknowledgment. Research support from the Ministry
of Education in Singapore (ARC12/07, #T206B3225) and
Nanyang Technological University (URC, RG53/07) is
gratefully acknowledged. We thank Dr. Yongxin Li in NTU
for the X-ray crystallographic analysis.
(15) For reviews of tandem reactions, see: (a) Nicolaou, K. C.; Edmonds,
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (b) Guo, H.;
Ma, J. Angew. Chem., Int. Ed. 2006, 45, 354. (c) Enders, D.; Grondal, C.;
Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 45, 1570. (d) Enders, D.;
Narine, A. J. Org. Chem. 2008, 73, 7857. (e) Sun, X.-L.; Tang, Y. Acc.
Chem. Res. 2008, 41, 937
.
(16) For selected references of tandem reactions, see: (a) Huang, Y.;
Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005,
127, 15051. (b) Tan, B.; Shi, Z.; Chua, P.; Li, Y.; Zhong, G. Angew. Chem.,
Int. Ed. 2009, 48, 758. (c) Lu, M.; Zhu, D.; Lu, Y.; Hou, Y.; Tan, B.;
Zhong, G. Angew. Chem., Int. Ed. 2008, 47, 10187. (d) Zhang, C.; De,
C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2007, 130, 416. (e) Zhu, D.;
Lu, M.; Chua, P. J.; Tan, B.; Wang, F.; Yang, X.; Zhong, G. Org. Lett.
2008, 10, 4585. (f) Wang, J.; Yu, F.; Zhang, X.; Ma, D. Org. Lett. 2008,
10, 5425. (g) Cao, C.; Zhou, Y.; Zhou, J.; Sun, X.; Tang, Y.; Li, Y.; Li, G.;
Sun, J. Chem.sEur. J. 2009, 15, 11384. (h) Belot, S.; Vogt, K. A.; Besnard,
Note Added after ASAP Publication. This paper was
published ASAP on October 19, 2010. References 12h and
12i were added, and changes to the text were made in the
abstract and the last paragraph. The revised paper was re-
posted on November 2, 2010.
Supporting Information Available: Experimental pro-
decures, characterization, spectra, chiral HPLC conditions,
and X-ray crystallographic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
C.; Krause, N.; Alexakis, A. Angew. Chem., Int. Ed. 2009, 48, 8923
.
(17) For selected references involving intramolecular nucleophilic
substitution, see: (a) Marigo, M.; Bertelsen, S.; Landa, A.; Jørgensen, K. A.
J. Am. Chem. Soc. 2006, 128, 5475. (b) Enders, D.; Wang, C.; Bats, J. W.
Angew. Chem., Int. Ed. 2008, 47, 7539. (c) Vignola, N.; List, B. J. Am.
Chem. Soc. 2004, 126, 450
.
OL102181R
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