N-benzyl aspartate nitrones: Unprecedented single-step synthesis and [3 + 2] cycloaddition reactions with alkenes

Article abstract of DOI:10.1021/ol8017243

(Chemical Equation Presented) N-Benzyl aspartate nitrones 2, prepared by addition of N-benzylhydroxylamine to dialkyl acetylenedicarboxylates 1, underwent [3 + 2] thermal cycloaddition with a wide range of alkenes to afford isoxazolidines 4 bearing a polyfunctionalized quaternary center. Under these uncatalyzed conditions, the trans stereocontrol observed with vinyl ethers is higher than that obtained with all acyclic activated nitrones reported to date. The first asymmetric access to a type-4 pure adduct was achieved starting from the chiral aspartate nitrone derived from (S)-α-methylbenzylhydroxylamine.

Full text of DOI:10.1021/ol8017243

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4493-4496
N-Benzyl Aspartate Nitrones:
Unprecedented Single-Step Synthesis
and [3 + 2] Cycloaddition Reactions
with Alkenes
Thanh Binh Nguyen, Arnaud Martel, Robert Dhal, and Gilles Dujardin*
UCO2M UMR 6011 & IRIM2F FR 2575 CNRS, UniVersite´ du Maine,
72085, Le Mans, France
gilles.dujardin@uniV-lemans.fr
Received July 28, 2008
ABSTRACT
N-Benzyl aspartate nitrones 2, prepared by addition of N-benzylhydroxylamine to dialkyl acetylenedicarboxylates 1, underwent [3 + 2] thermal
cycloaddition with a wide range of alkenes to afford isoxazolidines 4 bearing a polyfunctionalized quaternary center. Under these uncatalyzed
conditions, the trans stereocontrol observed with vinyl ethers is higher than that obtained with all acyclic activated nitrones reported to date.
The first asymmetric access to a type-4 pure adduct was achieved starting from the chiral aspartate nitrone derived from
(S)-r-methylbenzylhydroxylamine.
Nitrones represent attractive synthetic intermediates since
they undergo 1,3-dipolar cycloaddition (1,3-DC) reactions
with a wide range of alkenes and alkynes to afford versatile
isoxazolidine and isoxazoline products, respectively.1 These
cycloadducts could be opened by N-O bond cleavage via
reduction,2 alkylation,3 and even oxidation to other nitrones.4
Condensation of aldehydes/ketones with N-substituted hy-
droxylamines,5 oxidation of N,N-disubstituted amine6/hy-
droxylamines7/imines,8 thermal cycloreversion9 of isoxazo-
lidines, N-alkylation of O-trimethylsilyl oximes,10 and
fragmentation of N-hydroxyamino sulfonates11 represent the
most common methods for the synthesis of nitrones. R,R-
Dialkylnitrones are synthetically important as they could be
involved in 1,3-DC reactions to create a quaternary center,
(5) (a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; John Wiley & Sons: New York, 1984. (b) Confalone, P. N.; Huie,
E. M. Org. React. 1988, 36, 1. (c) Torssell, K. B. G. Nitrile Oxides, Nitrones,
and Nitronates in Organic Synthesis; Feuer, H., Ed.; VCH Publishers: New
York, 1988.
(1) (a) Frederickson, M. Tetrahedron 1997, 53, 403. (b) Gothelf, K. V.;
Jorgensen, K. A. Chem. ReV. 1998, 98, 863.
(2) (a) LeBel, N. A.; Balasubramanian, N. J. Am. Chem. Soc. 1989,
111, 3363. (b) Cicchi, S.; Goti, A.; Guarna, A.; De Sarlo, F. Tetrahedron
Lett. 1990, 31, 3351.
(6) (a) Murahashi, S.-I.; Shiota, T. Tetrahedron Lett. 1987, 28, 2383.
(b) Zajac, W. W., Jr.; Walters, T. R.; Darcy, M. G. J. Org. Chem. 1988,
53, 5856. (c) Murray, R. W.; Singh, M. J. Org. Chem. 1990, 55, 2954. (d)
Murahashi, S.-I.; Shiota, T.; Imada, Y. Org. Synth. 1998, 70, 265. (e) Goti,
A.; Cardona, F.; Soldaini, G. Org. Synth. 2005, 81, 204.
(7) (a) Cicchi, S.; Corsi, M.; Goti, A. J. Org. Chem. 1999, 64, 7243.
(b) Cicchi, S.; Marradi, M.; Goti, A.; Brandi, A. Tetrahedron Lett. 2001,
42, 6503.
(3) (a) DeShong, Ph.; Dicken, C. M.; Staib, R. R.; Freyer, A. J.; Weinreb,
St. M. J. Org. Chem. 1982, 47, 4397. (b) Murahashi, S-I.; Kodera, Y.;
Hosomi, T. Tetrahedron Lett. 1988, 29, 5949. (c) Casuscelli, F.; Chiacchio,
U.; Rescifina, A.; Romeo, G.; Romeo, R.; Tomassini, S.; Uccella, N.
Tetrahedron 1995, 51, 2979. (d) Meske, M. J. Prakt. Chem. 1997, 339,
426. (e) Bayon, P.; de March, P.; Figueredo, M.; Font, J. Tetrahedron 1998,
54, 15691. (f) Defoin, A.; Chevrier, C. Synthesis 2003, 8, 1221. (g) Nguyen,
T. B.; Martel, A.; Dhal, R.; Dujardin, G. J. Org. Chem. 2008, 73, 2621.
(4) (a) LeBel, N. A.; Spurlock, L. A. J. Org. Chem. 1964, 29, 1337. (b)
Holmes, A. B.; Hughes, A. B.; Smith, A. L. Synlett 1991, 1, 47. (c) de
March, P.; Figueredo, M.; Font, J.; Milan, S.; Alvarez-Larena, A.; Piniella,
J. F.; Molins, E. Tetrahedron 1997, 53, 2979. (d) Yang, S-H; Caprio, V.
Synlett 2007, 8, 1219.
(8) Soldaini, G.; Cardona, F.; Goti, A. Org. Lett. 2007, 9, 473.
(9) Tufariello, J. J.; Mullen, G. B.; Tegler, J. J.; Trybulski, E. J.; Wong,
S. C.; Ali, S. A. J. Am. Chem. Soc. 1979, 101, 2435.
(10) LeBel, N. A.; Balasubramanian, N. Tetrahedron Lett. 1985, 26,
4331.
(11) LeBel, N. A.; Caprathe, B. W. J. Org. Chem. 1985, 50, 3940.
10.1021/ol8017243 CCC: $40.75
Published on Web 09/12/2008
2008 American Chemical Society

but the 1,3-DC reactions of nitrones containing two differ-
ently functionalized side chains were rarely reported.12 The
access to this kind of nitrone such as 2a,b was described by
Winterfeldt by Michael addition of N-alkylhydroxylamines
to dimethyl acetylenedicarboxylate (Scheme 1).13 Attempts
one set of these signals was observed). Considering the
absence of a NOESY correlation peak between HCH2Ph and
HCH2COOMe, we thought that these nitrones would adopt a
stable E configuration. This hypothesis could agree with the
fact that the Z-isomer encounters two unfavorable interactions
including steric interaction between N-benzyl and CH2COOR
moieties and repulsion between two negatively charged
oxygen atoms of nitrone and 1-carboxylate groups (Figure
1). In contrast, the E-isomer appears to be more stable as its
Scheme 1. Synthesis of Nitrones 2c,d
Figure 1. Rationale for the stability of the E-isomer.
structure could minimize these unfavorable interactions.
With 2c,d in hand, we investigated the cycloaddition
reactions with representative alkenes (Table 1) as dipolaro-
philes: simple alkenes 3a,b, functionalized alkenes 3c-e,
electron-deficient alkenes 3f,g, and electron-rich alkenes
3h-k. In most cases, cycloaddition of nitrones 2c,d gave
high yields of expected isoxazolidines 4 (except toward 3b,k)
and exhibited a total regioselectivity.
Not surprisingly, reaction times varied considerably de-
pending on the substrate. In general, electron-deficient
dipolarophiles 3f,g reacted most rapidly, leading to comple-
tion of the reaction after only 4-16 h at 80 °C (entries 6
and 7). Simple alkene 3a (entry 1) and electron-rich alkenes
3h-j reacted notably more slowly (entries 8-10). Allyl
alcohol 3c gave total conversion only after 10 h at 80 °C
(entry 3), more rapidly than its acetate ester 3d (entry 4) or
its homologue 3e (entry 5). This enhanced reactivity would
be possibly due to the formation of a hydrogen bond between
the OH group of 3c and ester oxygens of 2c in the transition
state that could reduce the activation barrier. When the OH
group is located further from the reaction site, this assistance
would be less effective. Cyclic alkenes 3b,k failed to react
probably because of unfavorable steric interaction in the
transition state (entries 2 and 13).
The diastereoselectivity was moderate in most cases but,
interestingly, very high in the case of alkyl vinyl ethers 3i,j
(entries 9-12, Table 1). The corresponding adducts 4i-l
were thus obtained as a mixture 92:8 to 98:2 in which the
major adducts possess a trans relationship between COOR
and alkoxy moieties, possibly resulting from an exo-selective
1,3-DC reaction involving the nitrones 2c,d in an E config-
uration.
to prepare N-aryl derivatives by the same procedure led to
unstable nitrones.14 We report herein the first extensive study
on the reactivity of type-2 nitrones toward a wide range of
alkenes.15 In this study, we selected N-benzyl nitrones 2c,d
with the aim to obtain N-protected-3,3-disubstituted isox-
azolidines.
The dimethyl and di-t-butyl acetylenedicarboxylates 1a,b
werechosenasthestartingmaterialtoreactwithBnNHOH·HCl
since all these compounds are commercially available and
the N-benzyl group is convenient to handle for the following
manipulation. Addition of a stoichiometric amount of Bn-
NHOH to the alkyne in sodium acetate-buffered methanolic
medium was achieved in less than 5 min at rt (Scheme 1).
The intermediate 2-(N-benzyl-N-hydroxyamino)butendioate
underwent a rapid N-hydroxy-enamine-nitrone tautomer-
ization to afford nitrone 2c,d which could be obtained as an
oily liquid stable at rt. When a sample of 2c was heated under
argon in toluene for 3 days at 110 °C, no decomposition
was detected by 1H NMR. Interestingly, nitrones 2c,d exist
at rt in solution of CDCl3 as a unique isomer as shown by
1H NMR (all H-C sp3 proton signals are singlet, and only
(12) For the only example of 1,3-DC reaction to our knowledge, between
2a and 1-tridecene, see: Chiacchio, U.; Piperno, A.; Rescifina, A.; Romeo,
G.; Uccella, N. Tetrahedron 1998, 54, 5695. For the formal 1,3-DC reaction
of an R,R-disubstituted nitrone to alkynes, see: (a) Cantagrel, F.; Pinet, S.;
Gimbert, Y.; Chavant, P. Y. Eur. J. Org. Chem. 2005, 2694. (b) Pernet-
Poil-Chevrier, A.; Cantagrel, F.; Le Jeune, K.; Philouze, C.; Chavant, P. Y.
Tetrahedron: Asymmetry 2006, 17, 1969.
This common relative configuration was readily assigned
on the basis of spectral data, including 2D COSY and
NOESY NMR spectra, as exemplified in Figure 2 for major
adduct 4i. The presence of three NOESY correlation peaks
between H-5 and H-4ꢀ, H-4R and H-1, and H-4R and H-2,
together with the absence of a correlation peak between H-5
and H-4ꢀ, and between H-4ꢀ and H-2 helped to deduce the
(13) Winterfeldt, E.; Krohn, W.; Stracke, H. Chem. Ber. 1969, 102, 2346.
(14) (a) Huntress, E. H.; Leslie, T. E.; Hearon, W. M. J. Am. Chem.
Soc. 1956, 78, 419. (b) Agosta, W. C. J. Org. Chem. 1961, 26, 1724.
(15) For intramolecular related reactions, see: Padwa, A.; Wong, G. S. K.
J. Org. Chem. 1986, 51, 3125.
4494
Org. Lett., Vol. 10, No. 20, 2008

Table 1. Thermal 1,3-Dipolar Cycloaddition Reactions of Nitrones 2c,d with Dipolarophiles 3a-j
entry nitrone
R
alkene
R1
R2
H
R3
equiv alkene/conditions
adduct diastereomeric ratioa yield (%)b
1
2
3
4
5
6
7
8
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2d
2d
2c
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
t-Bu
t-Bu
Me
1
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3i
3j
3k
n-C5H11
-CH2(CH2)2CH2-
H
H
H
H
H
H
10/toluene, 110 °C, 76 h
10/toluene, 110 °C, 120 h
10/80 °C, 10 h
10/80 °C, 48 h
10/100 °C, 72 h
4a
4b
4c
4d
4e
4f
73:27
-
95
0
CH2OH
CH2OAc
(CH2)2OH
COOMe
COOEt
OAc
H
H
H
H
H
H
H
H
H
H
50:50
63:37
62:38
52:48
72:28
80:20
92:8c
98:2c
95:5c
98:2c
-
97
96
93
96
97
89
95
92
99
99
0
10/80 °C, 16 h
COOEt 2/80 °C, 4 h
4g
4h
4i
4j
4k
4l
H
H
H
H
H
H
2/80 °C, 48 h
10/80 °C, 72 h
3/80 °C, 72 h
10/80 °C, 72 h
3/80 °C, 72 h
10/90 °C, 120 h
9
OEt
10
11
12
13
a
O-t-Bu
OEt
O-t-Bu
-O(CH2)2CH2-
4m
Determined by H NMR 400 MHz of the crude product. b Isolated yield c trans configuration assigned to the major isomer.
trans relationship between ethoxy and carbonyloxymethyl
moieties in major adduct 4i.
(-)-menthol, D-(-)-pantolactone, and (R)-methyl mandelate.
Interestingly, in all cases, the cycloaddition gave the desired
adducts in excellent yields (90-96%) and with a good-to-
high trans selectivity and global trans:cis ratios ranging from
5:1 to 19:1.
Possibly resulting from an exo-selective approach of
dipolarophiles 3i,j on E-nitrones 2c,d, the level of trans
stereocontrol observed for adducts 4i-l is notably higher
than any other trans stereocontrol ever obtained in the
uncatalyzed 1,3-dipolar cycloaddition between alkyl vinyl
ethers and activated acyclic nitrones.16,17 Interestingly, this
level of stereocontrol is comparable to those obtained with
(E)-geometry-fixed activated nitrones.18 It must be also
mentioned that such a high trans selectivity was rarely
observed under Lewis acid conditions which could favor the
endo approach of a chelated acyclic (Z)-nitrone: as shown
by Tamura’s group with Eu(fod)3, high trans selectivities
with R-alkoxycarbonylnitrones required the use of a bulky
diphenylmethyl N-protecting group.17
Table 2. Cycloaddition of Nitrone 2c with Alkenes 3l-n
Encouraged by this favorable stereochemical outcome, we
searched for an asymmetric extension (diastereofacially
selective) of such a 1,3-dipolar cycloaddition since it could
represent a promising starting point for the enantioselective
synthesis of highly functionalized derivatives containing a
quaternary stereogenic center.
The first approach was attempted with the achiral nitrone
2a and the chiral vinyl ethers 3l-n (Table 2) derived from
a
Determined by H NMR of the crude product. b Isolated yield.
1
However, a diastereofacial selectivity for the trans adduct
was observed in the sole case of O-vinyl pantolactone 3n,
Figure 2. 2D NOESY correlation for major adduct 4i.
(16) Jensen, K. B.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 1999,
64, 2353.
Org. Lett., Vol. 10, No. 20, 2008
4495

Table 3. Cycloaddition of Nitrones 2e,f with Alkenes 3i,j
diastereomeric ratioa
trans1:trans2:cis1:cis2
yieldb
(%)
entry
nitrone
R1
alkene
R2
Et
adduct
1
2
2e
2e
Me
Me
3i
3j
4q
4r
69:31:0:0
72:28:0:0
96:4:0:0
67:33:0:0
72:28:0:0
99
t-Bu
92c
53d
99
3
4
2f
2f
t-Bu
t-Bu
3i
3j
Et
t-Bu
4s
4t
97
a Determined by 1H NMR of the crude product. b Isolated yield. c Global yield of isolated adduct 4r. d Isolated yield of major adduct 4r after diastereomeric
separation.
with a 4.3:1 ratio (entry 3). Unfortunately, in this critical
case, the major trans adduct 4p could not be separable by
column chromatography.
2, Table 3) to afford the major trans adduct 4r in good
isolated yields.20
In this study, N-protected nitrones 2c-f were synthesized
in excellent yields by a simple addition of N-benzylhydroxy-
lamines to the corresponding dialkyl acetylenedicarboxylates.
Their 1,3-dipolar cycloaddition reactions with alkenes af-
forded a set of original isoxazolidines in excellent yields and
regioselectivities under thermal cycloaddition. These original
cycloadducts 4, obtained in two steps from commercial
sources in 85-97% global yields, could be considered as a
masked form of R,R-disubstituted R-amino acids bearing two
different functionalized side chains. In the cases of alkyl vinyl
ethers, valuable trans selectivities were observed. Asym-
metric versions have been tried with chiral nitrones or chiral
alkyl vinyl ethers, resulting in excellent yields and good to
excellent trans selectivities. If facial control proved to be
never better than moderate, the use of a chiral aspartate
nitrone was found to lead to a first 4-type adduct with high
enantio- and diastereopurity. Further application of these
promising adducts is currently under investigation.
The second approach was made with achiral vinyl ethers
3i,j and chiral nitrones 2e,f bearing a chiral N-protecting
group such as R-methylbenzyl. These nitrones were prepared
in excellent yields in the same manner by addition of (S)-
R-methylbenzylhydroxylamine19 to the corresponding dialkyl
dicarboxylates 1a,b. Interestingly, the thermal 1,3-DC reac-
tion of these nitrones was carried out smoothly at 90 °C and
led to the desired adducts after 3 days with excellent yields
and total trans selectivity. An increase of bulkiness of the
nitrone N-protecting group (Table 1, entries 9-12 vs Table
3, entries 1-4) seems to improve the overall trans selectivity.
This fact is in good agreement with our rationale for the
stability of the E-isomer (Figure 1) and our hypothesis of
an exo-selective approach.
The facial selectivities were found to be moderate, with
an approximate 7:3 ratio whatever the vinyl ether used.
Replacing the methyl group of the ester functions with more
hindered t-Bu did not modify this selectivity. This facial
differentiation could be limited by free rotation around the
C-N bond of the chiral nitrone. However, the mixture of
cycloadducts was separable in the more favored case (entry
Acknowledgment. We thank the French Ministry of
Research for T.B.N.’s PhD grant.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Tamura, O.; Mita, N.; Imai, Y.; Nishimura, T.; Kiyotani, T.;
Yamasaki, M.; Shiro, M.; Morita, N.; Okamoto, I.; Takeya, T.; Ishibashi,
H.; Sakamoto, M. Tetrahedron 2006, 62, 12236.
(18) (a) Tamura, O.; Gotanda, K.; Terashima, R.; Kikuchi, M.;
Miyawaki, T.; Sakamoto, M. Chem. Commun. 1996, 1861. (b) Tamura,
O.; Gotanda, K.; Yoshino, J.; Morita, Y.; Terashima, R.; Kikuchi, M.;
Miyawaki, T.; Mita, N.; Yamashita, M.; Ishibashi, H.; Sakamoto, M. J.
Org. Chem. 2000, 65, 8544.
OL8017243
(19) Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron 1985, 41, 3455.
(20) Absolute configuration not yet determined.
4496
Org. Lett., Vol. 10, No. 20, 2008