Sequential organocatalyzed michael addition/[3 + 2]-heterocyclization for the stereoselective synthesis of fused-isoxazoline precursors of enantiopure cyclopentanoids

Article abstract of DOI:10.1021/ol8023133

(Chemical Equation Presented) We propose an asymmetric synthesis of functionalized cyclopentanoids bearing up to four stereogenic centers from easily accessible nitroalkenes and unsaturated aldehydes. The overall sequence includes an enantioselective organocatalytic Michael addition and a [3 + 2]-heterocyclization between an in situ generated silylnitronate and the unactivated double bond. Finally, the fused isoxazoline can be further transformed to various cyclopentanoids.

Full text of DOI:10.1021/ol8023133

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5409-5412
Sequential Organocatalyzed Michael
Addition/[3 + 2]-Heterocyclization for
the Stereoselective Synthesis of
Fused-Isoxazoline Precursors of
Enantiopure Cyclopentanoids
Damien Bonne,* Lydie Salat, Jean-Pierre Dulce`re, and Jean Rodriguez*
Aix-Marseille UniVersite´, Institut des Sciences Mole´culaires de Marseille, iSm2 CNRS
UMR 6263, Centre Saint Je´roˆme, serVice 531, 13397 Marseille Cedex 20, France
jean.rodriguez@uniV-cezanne.fr
Received October 6, 2008
ABSTRACT
We propose an asymmetric synthesis of functionalized cyclopentanoids bearing up to four stereogenic centers from easily accessible nitroalkenes
and unsaturated aldehydes. The overall sequence includes an enantioselective organocatalytic Michael addition and a [3 + 2]-heterocyclization
between an in situ generated silylnitronate and the unactivated double bond. Finally, the fused isoxazoline can be further transformed to
various cyclopentanoids.
The development of enantioselective methods to access
functionalized cyclopentanoids is a challenging problem since
these valuable building blocks have found many applications
in organic chemistry and are precursors of a plethora of
natural products.1 Very recently, elegant asymmetric and
organocatalyzed cascade reactions2 have been described for
the synthesis of cyclopentanes, demonstrating the growing
interest for this type of structure.3 Although these methods
are very efficient because many stereogenic centers are
controlled in one single operation, the variety and diversity
of the substitution of the final cyclopentane ring is rather
limited. We have a long-standing and continuing interest in
the field of nitroolefins.4 Recently, we reported an efficient
diastereoselective synthesis of tetrahydrofurans and pyrro-
lidines based on a 1,3-dipolar cycloaddition between a
silylnitronate5 and an unactivated double bond (Scheme 1).6
The unsaturated ꢀ-heteronitroalkane 1 was obtained through
Scheme 1
.
Diastereoselective Synthesis of Tetrahydrofurans and
Pyrrolidines
(1) For reviews on the synthesis and applications of cyclopentanes, see:
(a) Silva, L. F. Tetrahedron 2002, 58, 9137–9161. (b) Ferrier, R. J.;
Middleton, S. Chem. ReV. 1993, 93, 2779–2831. (c) Trost, B. M. Angew.
Chem., Int. Ed. 1986, 25, 1–20.
(2) For a review on enantioselective cascade reactions, see: Yu, X.;
Wang, W. Org. Biomol. Chem. 2008, 6, 2037–2046.
(3) (a) Tan, B.; Chua, P. J.; Zeng, X.; Lu, M.; Zhong, G. Org. Lett.
2008, 10, 3489–3492. (b) Tan, B.; Shi, Z.; Chua, P. J.; Zhong, G. Org.
Lett. 2008, 10, 3425–3428. (c) Zu, L.; Li, H.; Xie, H.; Wang, J.; Jiang, W.;
Tang, Y.; Wang, W. Angew. Chem., Int. Ed. 2007, 46, 3732–3734.
10.1021/ol8023133 CCC: $40.75
Published on Web 11/06/2008
2008 American Chemical Society

a hetero-Michael reaction between the corresponding ni-
troolefin and an allylic alcohol or amine.
asymmetric conjugate addition via enamine activation (Fig-
ure 1).10
Because the cyclization step proceeds with total diaste-
reoselectivity,7 we reasoned that this useful methodology
could be in principle translated to a versatile enantioselective
carbocyclization version providing the control of the Michael
addition of a properly functionalized carbonucleophile 5 to
a simple nitroolefin 4 (Scheme 2). The resulting enantio-
Figure 1. Pyrrolidine-type organocatalysts.
Scheme 2
Therefore, in order to validate our strategy, we selected
nitrosyrene (4a) and 4-pentenal (5a) as test substrates to study
this reaction with different organocatalysts. The results are
summarized in Table 1. Various reaction conditions were
Table 1. Catalyst and Solvent Optimization for the
Enantioselective Michael Additiona
merically enriched unsaturated nitoalkanes 6 could be easily
cyclized stereoselectively to the corresponding fused-isox-
azoline precursor of the expected functionalized carbocycles.
Over recent years, very important developments of asym-
metric Michael addition of aldehydes to nitroolefins have
emerged.8,9 Chiral amines such as pyrrolidine analogues
constitute a broadly applicable class of organocatalysts for
entry
catalyst
2 mol %
2 mol %
20 mol %
20 mol %
solvent yield (%)b
drc
ee (%)d
1
2
3
4
A
A
B
C
water
water
iPrOH
DCM
97e
98f
95
92:8
91:9
10:1
98:2
99
99
40
95
92
(4) (a) Guillaume, M.; Dumez, E.; Rodriguez, J.; Dulce`re, J.-P. Synlett
2002, n/a, 1183–1185. (b) Dulce`re, J.-P.; Dumez, E. Chem. Commun. 1997,
971–972. (c) Dumez, E.; Rodriguez, J.; Dulce`re, J.-P. Chem. Commun. 1997,
n/a, 1831–1832. (d) Dumez, E.; Faure, R.; Dulce`re, J.-P. Eur. J. Org. Chem.
2001, 257, 7–2588.
a Reaction conditions: 1 mmol of 4a, 2 mmol of 5a and catalyst A, B,
or C in 2 mL of solvent at 0 °C. b Isolated yield by flash chromatography.
c Determined by proton NMR of the crude reaction product. d Determined
by HPLC on a chiral stationary phase. e 10 mol % of PhCO2H was used.
f 20 mol % of PhCO2H was used.
(5) For examples of the use of silylnitronate in synthesis, see: (a) Torssell,
K.; Zeuthen, O. Acta Chem. Scand. 1978, B33, 379. (b) Das, N. B.; Torssell,
K. B. G. Tetrahedron 1983, 39, 2227–2230. (c) Torsell, K. B. G.; Hazell,
A. C.; Hazell, R. G. Tetrahedron 1985, 41, 5569. (d) Uno, H.; Watanabe,
N.; Fujiki, S.; Suzuki, H. Synthesis 1987, n/a, 471–474. (e) Ishikawa, T.;
Shimizu, Y.; Kudoh, T.; Saito, S. Org. Lett. 2003, 5, 3879–3882. (f) Kudoh,
T.; Ishikawa, T.; Shimizu, Y.; Saito, S. Org. Lett. 2003, 5, 3875–3878.
(6) Roger, P.-Y.; Durand, A.-C.; Rodriguez, J.; Dulce`re, J.-P. Org. Lett.
2004, 6, 2027–2029.
tested, and it clearly appeared that catalyst A in combination
with benzoic acid as the additive in water9a (entries 1 and
2) and catalyst C in DCM9g (entry 4) were the best way to
achieve high levels of diastereoselectivity and enantioselec-
tivity along with excellent yields. Catalyst B9k was efficient
(yield ) 95%, entry 3) but showed only moderate enanti-
oselectivity. The best conditions for this enantioselective
transformation (entry 2) having been identified, they were
applied to diversely substituted nitroalkenes and different
unsaturated aldehydes. The resulting γ-nitroaldehydes
(6b-g) are represented in Figure 2. The aromatic-substituted
nitroolefins worked well in this reaction with high yields and
very good levels of diastereoselectivity and enantioselectivity,
except when 2-(2-nitrovinyl)furan 4d was engaged, which
resulted in the formation of 6d with slightly lower yield and
enantioselectivity. Aliphatic-substituted nitroolefin 4e and
ꢀ-nitroacrylate 4f are also suitable substrates for this
transformation, leading to 6e and 6f, respectively. Finally,
the variation in the aldehyde structure either by increasing
(7) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841–1860.
(8) For recent reviews on asymmetric organocatalyzed conjugate addi-
tions, see: (a) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–1716. (b)
Sulzer-Mosse´, S.; Alexakis, A. Chem. Commun. 2007, n/a, 3123–3135. (c)
Vicario, J. L.; Bad´ıa, D.; Carrillo, L. Synthesis 2007, 2065–2092. (d) Almasi,
D.; Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007, 18, 299–365
.
(9) For recent examples of conjugate additions between aldehydes and
nitroolefins with organocatalysts, see: (a) Zhu, S. L.; Yu, S. Y.; Ma, D. W.
Angew. Chem., Int. Ed. 2008, 3, 545–548. (b) Wiesner, M.; Revell, J. D.;
Wennemers, H. Angew. Chem., Int. Ed. 2008, 10, 1871–1874. (c) Barros,
M. T.; Phillips, A. M. F. Eur. J. Org. Chem. 2007, 17, 8–185. (d) McCooey,
S. H.; Connon, S. J. Org. Lett. 2007, 9, 599–602. (e) Hayashi, Y.; Gotoh,
H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 27, 4212–4215.
(f) Lalonde, M. P.; Chen, Y. G.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2006, 38, 6366–6370. (g) Palomo, C.; Vera, S.; Mielgo, A.; Gomez-Bengoa,
E. Angew. Chem., Int. Ed. 2006, 36, 5984–5987. (h) Mosse´, S.; Laars, M.;
Kriis, K.; Kanger, T.; Alexakis, A. Org. Lett. 2006, 8, 2559–2562. (i) Mase,
N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III
J. Am. Chem. Soc. 2006, 128, 4966. (j) Wang, J.; Li, J.; Lou, B.; Zu, L.;
Guo, H.; Wang, W. Chem. Eur. J. 2006, 12, 4321. (k) Wang, W.; Wang,
J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369. (l) Andrey, O.; Alexakis,
A.; Tomassini, A.; Bernardinelli, G. AdV. Synth. Catal. 2004, 346, 1147.
(m) Mase, N.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III Org. Lett.
2004, 6, 2527. (n) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611. (o)
(10) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV.
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Betancourt, J. M.; Barbas, C. F., III Org. Lett. 2001, 3, 3737
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5410
Org. Lett., Vol. 10, No. 23, 2008

Scheme 4. [3 + 2]-Heterocyclization to Fused Isoxazoline 8a
Figure 2. Synthesis of γ-nitroaldehydes.
cycles bearing three controlled stereogenic centers starting
from simple achiral acyclic substrates. After protection,16
the previous γ-nitroaldehydes 6b-6g were submitted to the
same cyclization conditions allowing the synthesis of di-
versely substituted five- and six-membered ring isoxazolines
8b-8f in good yields (Figure 3). With protected aldehyde
the length of the chain (6b) or by introducing a triple bond
(6g) had no apparent impact on the reaction outcome.
Having in hand a versatile enantioselective preparation of
a variety of functionalized unsaturated nitroalkanes (6a-g),
we next examined the feasibility of the cyclization step11
starting with 6a, which required prior protection of the
aldehyde function as cyclic acetal12 to afford compound 7a
(Scheme 3).13
Scheme 3. Protection of γ-Nitroaldehydes 6a
When the protected adduct 7a was engaged in the
cyclization step with the conditions recently used by our team
(DBU, Me2NTMS),4 we unfortunately did not observe the
formation of the expected isoxazoline 8a.
Nevertheless, when 7a was treated using conditions
developed by Hassner,14 the desired product 8a was formed
in 67% isolated yield (Scheme 4). As shown here, only one
stereoisomer could be detected, demonstrating the very high
diastereoselectivity of the cyclization step most probably
resulting from the 1,3-allylic strain allowing only one
conformation for the nitronate intermediate 9.7,4d The
absolute stereochemistry of 8a was unambiguously estab-
lished by analysis of the X-ray crystal structure.15
Figure 3. Synthesis of isoxazolines 8b-8f.
7b, the cyclization to the six-membered ring 8b proved to
be more difficult and less stereoselective, a mixture of two
diastereomers (2:1) being obtained.17 Nevertheless, in all
other cases, the cyclization proceeded with very high
diastereoselectivity as only one diasteromer was detected.
Interestingly, when compound 7g was engaged in the
cyclization reaction, we did not observe the formation of
the expected isoxazole 9, but rather the unsaturated aldehyde
10 was isolated in 28% yield (Scheme 5).18 This reactivity
of silylnitronates with alkynes has indeed already been
The present sequence (Michael addition, protection, cy-
clization) allows the rapid construction of bicyclic hetero-
(15) CCDC 704278 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.
(16) Yields of protected compounds 7a-f refers to pure single diaster-
eomers as they are separable by chromatography on silica gel. In all cases,
the minor diastereomer (3-7%) did not engage in the cyclization step.
(17) The major diastereomer can be obtained in pure form after
recristallization in EtOAc/PE; see Supporting Information.
(11) For a review, see: Torsell, K. B. G. Nitrile Oxides, Nitrones, and
Nitronates in Organic Synthesis; VCH Publishers: New York, 1988.
(12) Koreeda, M.; Brown, L. J. Org. Chem. 1983, 48, 2122–2124.
(13) Running the cyclization step without protection of the aldehyde
function led to lower yields and partial epimerization of the product; see
Supporting Information for details.
(14) Namboothiri, I. N.; Hassner, A.; Gottlieb, H. E. J. Org. Chem. 1997,
62, 485–492.
Org. Lett., Vol. 10, No. 23, 2008
5411

Scheme 5
.
Formation of Unsaturated Aldehyde 10
Scheme 6. Transformations of Fused Isoxazolines 8a and 8c
observed and exploited by Kurth et al. for the synthesis of
dihydrofuraldehydes and dihydropyranaldehydes.19
The isoxazolines are versatile masked structural entities
and allow easy access to γ-amino alcohols,20 ꢀ-hydroxy
ketones,21 or isoxazolidines,22 opening up a convenient and
useful entry into natural product synthesis. This behavior was
exploited, and several transformations were accomplished
with the possibility to introduce a fourth controlled stereo-
genic center (Scheme 6). For exemple, selective hydride
reduction of 8a can lead to 1,3-aminoalcohol 11 or bicyclic
isoxazolidine 12 in very good yields. Alternatively, direct
catalytic hydrogenation of 8c afforded trisubstituted cyclo-
pentanone 13 with 60% yield.
followed by [3 + 2]-heterocyclization allowing the rapid
access to diversely substituted fused isoxazolines with the
control of three stereogenic centers. These products were
further transformed in various cyclopentanoids bearing up
to four stereogenic centers, opening up a convenient, useful,
and complementary way to access a five-membered ring
system with a high level of complexity.
Acknowledgment. Financial support from the French
Research Ministry, the Universite´ Paul Ce´zanne and the
Centre National de la Recherche Scientifique (CNRS) is
gratefully acknowledged. We thank Dr. N. Vanthuyne (ISM2,
Chirosciences) for chiral HPLC analysis and M. Giorgi
(www.spectropole.fr) for X-ray structure.
In conclusion, we have developed a new enantioselective
and diastereoselective sequence including a Michael addition
(18) For exemples of intramolecular INOC reaction affording isoxazoles,
see: (a) Akritopoulou-Zanze, I.; Gracias, V.; Moore, J. D.; Djuric, S. W.
Tetrahedron Lett. 2004, 45, 3421–3423. (b) Hassner, A.; Dehaen, W. Chem.
Ber. 1991, 124, 1181–1186.
(19) Duffy, J. L.; Kurth, M. J. J. Org. Chem. 1994, 59, 3783–3785.
(20) (a) Fuller, A. A.; Chen, B.; Minter, A. R.; Mapp, A. K. J. Am.
Chem. Soc. 2005, 127, 5376–5383. (b) Kella-Bennani, A.; Soufjaoui, M.;
Kerbal, A.; Fkih-Tetouani, S.; Bitit, N. Tetrahedron 1995, 51, 10923–10928.
(21) (a) Tsantali, G. G.; Dimtsas, J.; Tsoleridis, C. A.; Takakis, I. M.
Eur. J. Org. Chem. 2007, n/a, 258–265. (b) Ferna´ndez-Mateos, A.; Coca,
G. P.; Gonza´lez, R. R. Tetrahedron 2005, 61, 8699–8704. (c) Tranmer,
G. K.; Tam, W. Org. Lett. 2002, 4, 4101–4104.
Supporting Information Available: Available Experi-
mental procedures, spectroscopic data for all new com-
pounds, and crystallographic data of 8a in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) (a) Itoh, T.; Watanabe, M.; Fukuyama, T. Synlett 2002, 1323–1325.
(b) Cerri, A.; Micheli, D.; Gandolfi, R. Synthesis 1974, 710–712.
OL8023133
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