Access to α-substituted amino acid derivatives via 1,3-dipolar cycloaddition of α-amino ester derived nitrones

Article abstract of DOI:10.1021/jo902107j

(Chemical Equation Presented) Amino acid derived nitrones were conveniently synthesized in good-to-excellent yields by condensation of α-ketoesters with N-benzylhydroxylamine. The cycloaddition reactions of these nitrones with different alkenes were investigated under thermal solvent-free conditions. Considering conversions, yields, and selectivities, alkyl vinyl ethers have proven to be valuable partners to achieve this transformation, which creates a tetrafunctionalized stereogenic quaternary center. Fromthe adducts derived from vinyl ethers, a three-step access to highly functionalized α-substituted amino acid derivatives is described.

Full text of DOI:10.1021/jo902107j

pubs.acs.org/joc
Access to r-Substituted Amino Acid Derivatives via 1,3-Dipolar
Cycloaddition of r-Amino Ester Derived Nitrones
Thanh Binh Nguyen, Alice Beauseigneur, Arnaud Martel, Robert Dhal, Mathieu Laurent,
and Gilles Dujardin*
ꢀ
UCO2M 6011 CNRS, Universite du Maine, 72085 Le Mans, France
gilles.dujardin@univ-lemans.fr
Received October 6, 2009
Amino acid derived nitrones were conveniently synthesized in good-to-excellent yields by condensa-
tion of R-ketoesters with N-benzylhydroxylamine. The cycloaddition reactions of these nitrones with
different alkenes were investigated under thermal solvent-free conditions. Considering conversions,
yields, and selectivities, alkyl vinyl ethers have proven to be valuable partners to achieve this
transformation, which creates a tetrafunctionalized stereogenic quaternary center. From the adducts
derived from vinyl ethers, a three-step access to highly functionalized R-substituted amino acid
derivatives is described.
SCHEME 1. R,R-Disubstituted R-Amino Acid (DAA) Synth-
esis: Nitrone Route
Introduction
Conformationally constrained amino acids are extremely
useful building blocks in synthetic organic chemistry and the
pharmaceutical industry to create novel peptides. Their
incorporation into peptide chains could induce conforma-
tional restrictions and enhance properties with respect to
natural active peptides and proteins. Among these confor-
mational restrictions, the use of R,R-disubstituted amino
acids (DAA) has shown to be one of the most promising
strategies. For this purpose, a range of procedures that
allow the synthesis of the desired DAA in enantiomerically
pure form has been developed.1 However, to our knowledge,
1,3-dipolar cycloaddition (1,3-DC) involving R-amino acid
derived nitrones and alkenes has never been used to afford
such molecules, although isoxazolidine adducts2,3 could be
valuable precursors for DAA derivatives (γ-amino alcohols,
β-amino ketones, aldehydes, and esters) (Scheme 1).4
We have recently revisited5 the one-step preparation of
N-benzyl aspartate nitrones 1 by Michael addition of N-benzyl-
hydroxylamine to dialkylacetylenedicarboxylate 2 and exten-
sively studied their 1,3-DC reaction with alkenes, leading to
high yields under thermal conditions.6 Interestingly, isoxazo-
lidines 3 were obtained with excellent trans selectivities when
vinyl ethers were used as dipolarophiles (X = OR00), especially
in the case of tert-butyl vinyl ether (Scheme 2).
(1) For recent reviews, see: (a) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N.
Eur. J. Org. Chem. 2007, 5969. (b) Cativiela, C.; Dıaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 2007, 18, 569. (c) Vogt, H.; Brase, S. Org. Biomol.
€
Chem. 2007, 5, 406. (d) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005,
5127. (e) Park, K. H.; Kurth, M. J. Tetrahedron 2002, 58, 8629. (f) Cativiela,
C.; Dıaz-de-Villegas, M. D. Tetrahedron 2000, 11, 645. (g) Cativiela, C.;
Dıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517.
(2) For reviews of cycloaddition of nitrones, see: (a) Padwa, A.; Ed. In 1,3-
Dipolar Cycloaddition Chemistry; Wiley-Interscience: New York, 1984; Vols.
1-2. (b) Deshong, P.; Lander, S. W.; Jr.; Leginus, J. M.; Dicken, C. M. In
Advances in Cycloaddition; Curran, D. P.; Ed.; JAI press: Greenwich, CT, 1988;
Vol. 1, pp 87-128. (c) Carruther, W. Cycloaddition Reaction in Organic
Synthesis; Pergamon Press: Oxford, 1990. (d) Little, R. D. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I.; Eds.; Pergamon Press: Oxford,
1991; Vol 5, pp 239-270. (e) Gotheft, K. V.; Jorgensen, K. A. Chem. Rev. 1998,
98, 863–909.
(3) (a) Torsell, K. B. G. Nitrile Oxides, Nitrones and Nitronates in Organic
Syntheses; VCH: New York, 1988; Vol. 20. (b) Frederickson, M. Tetrahedron
1997, 53, 403.
(4) Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Towards Heterocycles and Natural Products; John
Wiley and Sons: Hoboken, NJ, 2003.
(5) Winterfeld, E.; Krohn, W.; Stracke, H. U. Chem. Ber. 1969, 102, 2346.
(6) Nguyen, T. B.; Martel, A.; Dhal, R.; Dujardin, G. Org. Lett. 2008, 10,
4493.
DOI: 10.1021/jo902107j
r
Published on Web 01/08/2010
J. Org. Chem. 2010, 75, 611–620 611
2010 American Chemical Society

Nguyen et al.
JOCArticle
SCHEME 2. Synthesis and 1,3-DC of N-Benzyl Aspartate Nitrones 16
SCHEME 3. Aspartate Nitrones Differentiated at C-4
SCHEME 4. Synthesis of Carboxy-Differentiated Nitrone 4
These results encouraged us (i) to define a general access to
ketone-derived nitrones (Scheme 1) bearing various R0
groups and to reinvestigate the stereochemical outcome of
their 1,3-DC reaction with alkenes, in respect to the nitrone
geometry, and (ii) to explore the ability of isoxazolidines
such as 3 to undergo a ring-opening reaction based on
cleavage of the N-O bond. These two goals are the purpose
of this paper.
As expected, nitrones 4 and 16 displayed similar features:
first, both nitrones exist at rt in CDCl3 solution as the sole
1
1
E-isomer as shown by H NMR (only one set each of H
and 13C NMR was observed, and no NOESY correlation
between CH2Bn and CH2R protons could be observed). The
rationale for the stability of the E-isomer of nitrone 16 is also
valid for 4 as the E-isomer appears to be more stable because
its structure could avoid two unfavorable interactions en-
countered in the Z-isomer (Figure 1).
Results and Discussion
C-4-Differentiated Aspartate Nitrone: Synthesis and 1,3-
Dipolar Cycloaddition with Alkenes. As first extension, start-
ing from the results obtained previously with aspartic nitrone
1,6 we studied the extension of this pathway to aspartate-like
nitrones bearing two differentiated carboxy functions. We
considered that the transformation of the ester function at
C-4 would not deeply alter the electronic nature of the
nitrone moiety (Scheme 3). We decided to replace the ester
function at the C-4 position by a protected form of an
aldehyde function. The dithiolane group7 provides not only
a robust aldehyde protection that could be deprotected by
different methods7,8 but also a versatile functionalizable
center.9
Nitrone 4 was obtained in excellent yield and high purity
by condensing R-ketoester 5 with N-benzylhydroxylamine10 in
an acetate-buffered methanol solution (Scheme 4). R-Ketoester
5 could be conveniently prepared by a one-pot react-
ion between alkoxymethylidenepyruvate 6 and ethane-1,2-
dithiol via an addition/dehydroalkoxylation/cyclization cascade
reaction.
Moreover, compared to nitrone 1,6 the nitrone 4 displayed
similar reactivity under the same thermal uncatalyzed conditions
in 1,3-DC with different acyclic alkenes 7a-i, including
simple alkenes 7a, functional alkenes 7b-d, electron-defi-
cient alkenes 7e,f, and electron-rich alkenes 7g-i (Table 1).
As shown in Table 1, compared to the previously described
isoxazolidines 3,6 the isoxazolidines 8a-i were obtained in
similar yields (88-95%) and with the same degree of regio-
and stereoselectivity. Again, cycloadditions involving elec-
tron-deficient dipolarophiles 7e,f proceeded most rapidly,
leading to completion of the reaction after only 4-16 h at
80 °C (entries 5 and 6). Simple alkene 7a and electron-rich
alkenes 8g-i reacted notably more slowly (entries 1 and
7-9). Compared to its acetate ester 7c (entry 3) or to its
homologue 7d (entry 5), allyl alcohol 7b displayed a notably
high reactivity, leading to a total conversion after only 10 h at
80 °C (entry 2). As previously suggested,6 this enhanced
reactivity is probably due to the hydrogen bonding between
OH group of 7b and ester oxygens of 4 (or 1) in the transition
state that could favor their approach and lower activation
barrier. When the OH group locates further from reaction
site as in 7d, this interaction would be less effective.
(7) (a) Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic Synthesis,
4th ed.; John Wiley & Sons: New York, 2006; pp 482-500. (b) Kocienski, P. J.
Protecting Groups, 3rd ed.; Thieme, Stutgart, 2004; pp 77-93 and references
therein.
(8) (a) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew.
Chem., Int. Ed. 2003, 42, 4077. (b) Liu, J.; Wong, C. H. Tetrahedron Lett.
2002, 43, 4037. (c) Fleming, F. F.; Funk, L.; Altundas, R.; Tu, Y. J. Org.
Chem. 2001, 66, 6502.
Extension to Other r-Substituted r-Nitrone Esters. En-
couraged by the marked trans selectivities of the cycloaddi-
tion with vinyl ethers in both series (1/4), we extended our
study to other R-ester nitrones R-substituted by various alkyl
chains. Different R-substituted ester nitrones 9a-d were
prepared by condensation between N-benzylhydroxylamine
and the corresponding R-keto esters.10 Interestingly, these
new nitrones, obtained in good-to-excellent yields (Table 2),
(9) (a) Smith, A. B. III; Xiang, M. J. Am. Chem. Soc. 2006, 128, 66.
€
(b) Chen, Y.; L.; Leguijt, R.; Redlich, H.; Frohlich, R. Synthesis 2006, 421.
(c) Smith, A. B.; Kim, D. S. Org. Lett. 2004, 6, 1493. (d) Mulzer, J.; Berger,
M. J. Org. Chem. 2004, 69, 891. (e) Sasson, R.; Hagooly, A.; Rozen, S. Org.
Lett. 2003, 5, 3635. (f) Seebach, D.; Wilka, E. M. Synlett 1976, 476.
(10) (a) Hara, J.; Inouye, Y.; Kakisawa, H. Bull. Chem. Soc. Jpn. 1981, 54,
3871. (b) Toy, A.; Thompson, W. J. Tetrahedron Lett. 1984, 25, 3533.
(c) Chiacchio, U.; Piperno, A.; Rescifina, A.; Romeo, G.; Uccella, N.
Tetrahedron 1998, 54, 5695. (d) Nguyen, T. B.; Martel, A.; Dhal, R.;
Dujardin, G. Synthesis 2009, 3174.
612 J. Org. Chem. Vol. 75, No. 3, 2010

Nguyen et al.
JOCArticle
TABLE 1. 1,3-DC of Nitrone 4a with Alkenes 7a-i
entry
alkene
R1
R2
eq of 7/conditions
adduct
diastereomeric ratioa
yield (%)b
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
n-C5H11
CH2OH
CH2OAc
(CH2)2OH
CO2Me
CO2Et
OAc
OEt
O-t-Bu
H
H
H
H
H
10/toluene, 110 °C, 76 h
10/80 °C, 10 h
10/80 °C, 48 h
10/100 °C, 72 h
10/80 °C, 16 h
2/80 °C, 4 h
8a
8b
8c
8d
8e
8f
8g
8h
8i
75:25
61:39
64:36
63:37
62:38
95
93
95
93
88
92
90
91
89
CO2Et
73:27
81c:19
92c:8
H
H
H
2/80 °C, 48 h
10/80 °C, 72 h
3/80 °C, 72 h
>98c:2
aDetermined by 1H NMR of the crude product. bIsolated yield. ctrans configuration assigned for the major adduct.
TABLE 3. 1,3-DC of R-Substituted Ester Nitrones 9a-d with Vinyl
Ethers
a
entry
R0
R00
adduct trans:cis ratio yield (%)b
FIGURE 1. Stability comparison between Z-4 and E-4.
1
2
3
4
5
Me
Et
Bn
Et
Et
Et
10a
10b
10c
10d
10e
75:25
79:21
87:13
91:9
96
97
63
95
85
TABLE 2. Synthesis of R-Substituted Ester Nitrones 9a-d and 1,3-DC
with Vinyl Ethers
CH2CH2CO2Me Et
CH2CH2CO2Me t-Bu
92:8
a10 equiv of ethyl vinyl ether or 3 equiv of tert-butyl vinyl ether.
bYields of isolated adduct.
selectivity increased with the size of the group, from 75:25 for
10a (R = Me, entry 1) to 87:13 for 10c (R = Bn, entry 3). In
contrast, a good trans selectivity was obtained in the glutamic
series (91:9, entry 4), comparable to previous ones. This trans
selectivity was not significantly improved by changing the vinyl
ether (92:8, entry 5).
Transformation of Isoxazolidines 3-10 into DAA Derivatives.
We extensively studied the unprecedented transformation of
adducts 3,10 into DAA derivatives via N-O bond cleavage.
In the case of 5-heterosubstituted isoxazolidines, the direct
reductive cleavage is commonly known as not convenient
since this ring-opening process affords unstable β-amino
aldehydes. As a valuable alternative, the N-quaternization-
mediated ring-opening of 3-monosubstituted 5-heterosub-
stituted isoxazolidines (X = OR, NR2, Scheme 1) has been
described as an effective method to cleave the N-O bond via
β-elimination (disproportionation pathway).13 The thermal
entry
R0
nitrone
yield (%)
1
2
3
4
Me
Et
9a
9b
9c
9d
93
95
83
94
Bn
CH2CH2CO2Me
exhibited an exclusive E configuration as for nitrones 1 and 4
as shown by NMR.11
First, we tested the cycloaddition reactions of dipoles 9a-d
with ethyl vinyl ether, which led to significant trans selectivities
in previous series (92:8 for R = CH2CO2Me and CH2CH-
(SCH2)2).12 In all cases, after 72 h at 80 °C in a sealed tube, the
cycloaddition was found to have proceeded cleanly to give the
desired adducts with total conversion and high yields (Table 3).
Contrary to our expectation based on previous results ob-
served with nitrones 1 and 4, the reaction of these E-nitrones 9
exhibited varied degrees of trans selectivity, depending on the
nature of the R0 group. When R0 is an alkyl group, the trans
(13) (a) DeShong, P.; 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. (e) Nguyen, T. B.;
Martel, A.; Dhal, R.; Dujardin, G. J. Org. Chem. 2008, 73, 2621. (f) Nguyen,
T. B.; Vuong, T. M. H.; Martel, A.; Dhal, R.; Dujardin, G. Tetrahedron:
Asymmetry 2008, 19, 2084.
(11) Only one set of 1H NMR and 13C NMR signals in CDCl3 were
observed for each nitrone. No NOESY correlation corresponding to the
Z-isomer could be seen.
(12) See Scheme 1 (adduct 3) and Table 1, entry 8 (adduct 8h).
J. Org. Chem. Vol. 75, No. 3, 2010 613

Nguyen et al.
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TABLE 4. Selective N-Debenzylation/Reprotection of Isoxazolidines 3a,b and 10d,e
entry
adduct
R0
R00
Et
Et
t-Bu
Et
conditions
product
yield (%)
1
2
3
3
3
3a
3a
3b
10d
10e
CO2Me
CO2Me
CO2Me
CH2CO2Me
CH2CO2Me
H2 (3 atm), Pd (10%)/C, EtOH, rt, 16 h
HCO2H, Pd (10%)/C, MeOH, rt, 16 h
HCO2H, Pd (10%)/C, MeOH, rt, 16 h
HCO2H, Pd (10%)/C, MeOH, rt, 16 h
HCO2H, Pd (10%)/C, MeOH, rt, 16 h
11a
11a
11b
11c
11d
40
91
85
62
76
t-Bu
SCHEME 5. DAA Compounds via Direct Ring-Opening of Iso-
xazolidine 3a
rt and 50 °C (Scheme 5). Unfortunately, all of these condi-
tions resulted in the recovery of the starting adduct.15
Different palladium-catalyzed hydrogenolysis conditions
were next tested. Interestingly, when the reaction was con-
ducted under hydrogen atmosphere (3 bar), the N-benzyl
group was selectively removed without N-O cleavage
despite moderate yield (40%) (Table 4, entry 1). The yield
could be greatly improved (up to 91%) by using formic acid
as hydrogen source (Table 4, entry 2). Product 11a thus
obtained proved to be stable under these conditions and
could be stored at 4 °C for up to 3 months without noticeable
degradation. This selective N-deprotection was successfully
extended to isoxazolidines 3b and 10d,e with good yields
(Table 4, entries 3-5).
procedures using alkylating agents (BnBr, MeI, Me2SO4, ...)
with or without external base added in the reaction med-
ium (DABCO, Et3N, NaH, ...) were previously applied to 5-
oxa-13a-d and 5-aza-isoxazolidines13e,f to afford β-amino
acid esters or β-amino imides respectively in high yields.
Application of these literature procedures to the model
substrate 3a led in all cases to unsatisfactory results, even
after modification. Indeed, the solvent-free conditions using
BnBr in excess, with or without base, at different tempera-
tures (up to 150 °C) resulted in the recovery of the unchanged
starting adduct (Scheme 5). Using a strong alkylating agent
such as BnOTf in chlorinated solvents was also unsuccessful.
Only Me2SO4 could display some reactivity with this sub-
strate. However, in this case, unidentified products were
obtained, presumably due to the formation of quaternary
amine salt and subsequent undesired reactions. The high
steric hindrance on the nitrogen atom due to adjacent bulky
quarternary carbon could prevent attack of the electrophile.
On the basis of these disappointing results, we decided to
reinvestigate the reductive pathway. First, we wondered
whether the reductive cleavage of the N-O bond could be
directly applied in the particular case of the adduct 3a,
considering that bulkiness of the expected aminoaldehyde
around the nitrogen site could avoid side reactions. The first
trials were performed using zinc as reducing agent in differ-
ent acidic media or SmI214 at different temperatures between
This result allowed a N-reprotection of isoxazolidines
11a-d that could conveniently weaken the N-O bond
toward reductive cleavage conditions and that could stabilize
simultaneously the ring-opening product. For this purpose,
an N-acyl protecting group seemed to be a good choice.
Indeed, its electron withdrawing effect could activate it for
reductive cleavage while reducing the nucleophilicity of the
resulting nitrogen site and thus avoiding side reactions with
the aldehyde function. Isoxazolidines 11a-d were converted
cleanly into acetamides 12a-d with a quantitative yield by
treatment with neat Ac2O at rt followed by vacuum evapora-
tion of volatile products. The corresponding trifluoroaceta-
mides 13a,b could be also obtained in quantitative yields
using trifluoroacetic anhydride and NEt3 in THF at rt.
At last, we investigated the access to ring-opening pro-
ducts from these N-acyl derivatives. All our attempts to
reduce the N-O bond by hydrogenolysis were unsuccess-
ful. To our delight, when acetamide 12a was treated with
16
Mo(CO)6 (2 equiv) in wet acetonitrile, the corresponding
(15) Reaction was followed on the basis of the disappearance of the
characteristic blue color of the SmI2 in THF. No color change was observed
after 24 h, and the adduct 3a could be recovered unchanged.
(16) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F. Tetrahe-
dron Lett. 1990, 31, 3351.
(14) (a) Pearson, C. P.; Rinehart, K. L.; Sugano, M.; Costerison, J. R.
Org. Lett. 2000, 2, 2901. (b) Westermann, B.; Walter, A.; Florke, U.;
Altenbach, H. J. Org. Lett. 2001, 3, 1375. (c) Revuelta, J.; Cicchi, S.; Brandi,
A. Tetrahedron Lett. 2004, 31, 3351.
614 J. Org. Chem. Vol. 75, No. 3, 2010

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TABLE 5. DAA Compounds via Ring-Opening of N-Acyl-isoxazolidine 12a-d and 13a,b
R0
R00
Et
Et
Et
Et
Et
t-Bu
t-Bu
t-Bu
t-Bu
Z
conditions
product
Y
yield (%)
1
2
3
4
5
6
7
8
9
12a
12a
12a
12a
12c
12d
13a
13a
13b
CO2Me
CO2Me
CO2Me
CO2Me
CH2CO2Me
CH2CO2Me
CO2Me
CO2Me
CH2CO2Me
Me
Me
Me
Me
Me
Me
CF3
CF3
CF3
Mo(CO)6 (1 equiv), MeCN/H2Oa, reflux, 2 h
Mo(CO)6 (1 equiv), MeCN/H2O, reflux, 16 h
Mo(CO)6 (2 equiv), MeCN/H2O, reflux, 72 h
SmI2 (2 equiv), THF, rt, 10 min
14a
14a
14a
14a
14b
14b
H
H
H
H
H
H
10
40
91
76
60
30
Mo(CO)6 (2 equiv), MeCN/H2O, reflux, 42 hb
Mo(CO)6 (2 equiv), MeCN/H2O, reflux, 96 hc
Mo(CO)6 (2 equiv), MeCN/H2O, reflux, 96 hc
SmI2 (2.5 equiv), THF, rt, 10 min
d
-
15a
15b
Ot-Bu
Ot-Bu
75
81
SmI2 (2.5 equiv), THF, rt, 10 min
a10:3 volume ratio. bComplete conversion of the starting material. cIncomplete conversion of the starting material. dRecovery of starting material.
1,3-amidoaldehyde (()-14a was cleanly obtained in excellent
yield (91%) after extended reaction time (Table 5, entries
1-3). SmI2 could be used instead of Mo(CO)6 with shor-
tened reaction time (10 min), but the product (()-14a was
found to be contaminated by a small amount of unidentified
products (Table 5, entry 4). The 1,3-acetamidoaldehyde (()-
14a displays a fair stability under standard storing condi-
tions. The optimal conditions used to afford (()-14a from
(()-12a were applied successfully to the homologous diester
(()-12c, leading to the acetamidoaldehyde (()-14b in 60%
yield (Table 5, entry 5). The presence of a bulky tert-butoxy
group at the C-5 position decreased significantly the yield of
(()-14b (Table 5, entry 6). SmI2-mediated reactions failed in
our hands when applied to acetamides 12c and 12d. In
contrast to acetamides, trifluoroacetamides 13a and 13b
were found to be unreactive in the presence of Mo(CO)6
(Table 5, entry 7). Surprisingly, SmI2 was efficient to trans-
form these trifluoroacetamides 13a and 13b into the corre-
sponding esters (()-15a and (()-15b. These triesters are of
synthetic interest thanks to the orthogonality of the tert-
butyl ester relative to the methyl ones. Study of the dramatic
influence that the N-acyl substituant displays on the reactiv-
ity toward Mo(CO)6 and on the outcome of the N-O
reaction under SmI2-mediated reactions is currently under
investigation.
substituent R0. The trans-selectivities regularly obtained
with glutamic nitrone 9d (Scheme 1, R0 = -(CH2)2CO2Me),
and with modified or unmodified aspartic based nitrones 4
and 1 (R0 = -CH(SCH2)2 or CH2CO2Me) prompt us to
currently investigate the asymmetric version of these reac-
tions.17 The interest in such 5-oxa-isoxazolidines was exem-
plified by the first examples of their transformation into
densely functionalized R-substituted R-amino acid derivatives
by a three-step sequence N-debenzylation/N-acylation/N-O
bond cleavage. We believe that this pathway via nitrone
cycloaddition could open a new interesting route to new
biologically active molecules containing a polyfunctionalized
quaternary center.
Experimental Section
Ethyl 3-(1,3-Dithiolan-2-yl)-2-oxopropanoate (5). To a stirred
solution of ketoester 618 (3.44 g, 20 mmol) and ethane-1,2-
dithiol (1.88 g, 20 mmol) in toluene (20 mL) was added
p-toluenesulfonic acid (190 mg, 1 mmol) at room temperature.
After 5 min, a white precipitate was formed (this precipitate
could be isolated via filtration and analyzed by 1H and 13C
NMR as 50). The solution was stirred at 40 °C for 16 h, then
cooled to rt, diluted with toluene (80 mL), washed with satu-
rated aqueous NaHCO3 (20 mL), and dried over MgSO4. The
solvent was removed under vacuum to give the product 5 (4.22 g,
96%), suitable for further nitrone formation. Colorless oil. 1H
NMR (400 MHz, CDCl3) δ 4.86 (t, J = 7.1 Hz, 1H), 4.35 (q, J =
7.1 Hz, 2H), 3.43 (d, J = 7.1 Hz, 1H), 3.28-3.22 (m, 4H), 1.37 (t,
J = 7.1 Hz, 3H). 13C NMR 100 MHz (CDCl3) δ 191.2, 159.9,
62.4, 49.6, 45.9, 38.3, 13.7. HRMS (CIþNH3) calcd for
C8H13O3S2 [M þ Hþ]: 221.0306, found 221.0309.
Conclusion
We have reported the high-yielding synthesis of ester
nitrones substituted at the R-position by various func-
tionalized or simple alkyl side chains (R0). This simple and
efficient method allows access to an extended range of
polyfunctional nitrones displaying a common pure E-con-
figuration. The thermal 1,3-dipolar cycloaddition of these
nitrones with different alkenes gave high yields of isoxazo-
lidine adducts up to a multigram scale (20 g). Aspartic mono
ester nitrone 4 gave the same degree of stereoselectivities as
its diester analogue 1, with high trans selectivities observed
when alkyl vinyl ethers were used as dipolarophile (up
to >98:2). For other R-substituted ester nitrones 9a-d,
variable trans selectivities were observed with ethyl vinyl
ether, increasing with the bulkiness and functionality of the
(Z)-Ethyl 4-(2-Mercaptoethylthio)-2-oxobut-3-enoate (50).
Colorless needles from toluene; mp 96 °C (dec). 1H NMR
(200 MHz, CDCl3) δ 5.78 (d, J = 10.4 Hz, 1H), 5.58 (d, J =
10.4 Hz, 1H), 3.44-3.23 (m, 4H), 1.34 (t, J = 7.1 Hz, 3H). 13
C
NMR 100 MHz (CDCl3) δ 191.4, 164.9, 139.0, 113.3, 62.4, 49.6,
45.6, 39.4, 14.0. HRMS (CIþNH3) calcd for C8H13O3S2 [M þ
Hþ]: 221.0306, found 221.0314.
(17) Preliminary results in this field involving 1,3-DC of chiral enol ethers
or alternatively 1,3-DC of chiral aspartic nitrones has been already reported
in this series (see ref 6).
(18) (a) Tietze, L. F.; Meier, H.; Voss, E. Synthesis 1988, 274. (b) Dujardin,
G.; Rossignol, S.; Brown, E. Synthesis 1998, 763.
J. Org. Chem. Vol. 75, No. 3, 2010 615

Nguyen et al.
JOCArticle
(E)-N-(3-(1,3-Dithiolan-2-yl)-1-ethoxy-1-oxopropan-2-ylidene)-
(phenyl)methanamine Oxide (4). A mixture of 5 (11.0 g, 50 mmol),
BnNHOH HCl (8.77 g, 55 mmol), NaOAc 3H2O (8.16 g,
65.3, 61.4, 55.6, 49.4, 42.6, 38.9, 38.3, 37.9, 14.3; 13C NMR
100 MHz (CDCl3) δ 171.5, 137.7, 128.3, 128.2, 127.1, 77.2, 72.4,
62.6, 61.6, 55.3, 49.0, 42.4, 38.5, 38.3, 37.7, 14.2. HRMS
(CIþNH3) calcd for C18H26NO4S2 [M þ Hþ]: 266.1028, found
266.1034.
3
3
60 mmol), and MeOH (100 mL) was stirred at rt for 16 h and
then concentrated under vacuum. The white semisolid residue was
dissolved in a mixture of CH2Cl2 (100 mL) and H2O (20 mL). The
organic phase was separated, washed with H2O (20 mL ꢀ 3), dried
(MgSO4), and concentrated under vacuum to afford a viscous
residue. Purification of this material by column chromatography
on silica gel (300 g) with dichloromethane (Rf = 0.52, CH2Cl2)
Ethyl 3-((1,3-Dithiolan-2-yl)methyl)-5-(acetoxymethyl)-2-
benzylisoxazolidine-3-carboxylate (8c). From 4 and 7c. Purifica-
tion by flash chromatography (30-50% Et2O in cyclohexane)
afforded the title compound as a colorless oil (404 mg, 95%).
Rf = 0.6 (Et2O). Diastereomeric ratio: 64:36. Major adduct: 1H
NMR (400 MHz, CDCl3) δ7.37-7.20 (m, 5H), 4.55 (t, J=6.8Hz,
1H), 4.41-4.35 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.15 (dd, J =
11.6, 7.6 Hz, 1H), 4.11 (d, J = 14.9 Hz, 1H), 4.04 (dd, J = 11.4,
4.0 Hz, 1H), 3.70 (d, J = 14.9 Hz, 1H), 3.32-3.15 (m, 4H), 3.01
(dd, J = 12.4, 8.3 Hz, 1H), 2.61 (dd, J = 14.4, 6.8 Hz, 1H), 2.22
(dd, J = 14.4, 6.8 Hz, 1H), 2.06 (dd, J = 12.4, 6.1 Hz, 1H), 2.01
(s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR 100 MHz (CDCl3) δ
170.9, 170.7, 137.8, 128.1, 127.8, 126.9, 73.6, 72.3, 65.9, 61.4,
1
yielded 15.4 g (95%) of nitrone 4 as a pale yellow oil. H NMR
(400 MHz, CDCl3) δ 7.47-7.45 (m, 2H), 7.37 -7.30 (m, 3H), 5.70
(s, 2H), 5.06 (t, J = 7.6 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H),
3.29-3.18 (m, 6H), 1.33 (t, J = 7.1 Hz, 3H). 13C NMR 100 MHz
(CDCl3) δ 162.0, 138.8, 133.8, 128.6, 128.4, 128.3, 67.6, 61.8, 48.0,
38.2, 38.0, 14.0. HRMS (CIþNH3) calcd for C15H20NO3S2
[M þ Hþ]: 326.0885, found 326.0882.
General Procedure for the Cycloaddition between Nitrone 4
and Alkenes 7a-i. A solution of nitrone 4 (325 mg, 1 mmol) in
alkene (2-10 equiv; see Table 1) under argon in a sealed tube
was stirred at indicated temperature until completion (TLC; for
experimental conditions, see Table 1). The reaction mixture was
then concentrated under vacuum to remove excess alkene. The
crude adducts 8 were purified by column chromatography on
silica gel (Et2O in cyclohexane).
1
55.1, 49.2, 42.6, 39.3, 38.8, 38.4, 20.8, 14.3. Minor adduct: H
NMR (400 MHz, CDCl3) δ7.37-7.20 (m, 5H), 4.58 (t, J=6.8Hz,
1H), 4.27 (q, J = 7.1 Hz, 2H), 4.30-4.25 (m, 2H), 4.20 (dd, J =
11.1, 7.3 Hz, 1H), 4.02 (d, J = 14.7 Hz, 1H), 3.80 (d, J = 14.7 Hz,
1H), 3.32-3.15 (m, 4H), 2.68-2.53 (m, 3H), 2.31 (dd, J = 14.4,
6.8 Hz, 1H), 2.04 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR
100MHz(CDCl3) δ 170.7, 170.3, 137.8, 128.3, 128.1, 127.0, 73.9,
72.3, 64.9, 61.5, 55.4, 49.1, 38.9, 38.8, 38.5, 20.8, 14.2. HRMS
(CIþNH3) calcd for C20H28NO5S2 [M þ Hþ]: 426.1409, found
426.1309.
Ethyl 3-((1,3-Dithiolan-2-yl)methyl)-2-benzyl-5-hexylisoxazo-
lidine-3-carboxylate (8a). From 4 and 7a. Purification by flash
chromatography (Et2O/cyclohexane 1:6) afforded the title com-
pound as a colorless oil (415 mg, 95%). Rf = 0.8 (Et2O).
Diastereomeric ratio: 75:25. Major adduct: 1H NMR (400 MHz,
CDCl3) δ 7.40-7.16 (m, 5H), 4.57 (t, J = 6.8 Hz, 1H), 4.25 (q,
J = 7.1 Hz, 2H), 4.15-4.08 (m, 1H), 4.05 (d, J = 14.7 Hz, 1H),
3.74 (d, J = 14.7 Hz, 1H), 3.32-3.15 (m, 4H), 3.29 (dd, J = 12.1,
8.3 Hz, 1H), 2.62 (dd, J = 14.1, 7.1 Hz, 1H), 2.26 (dd, J = 14.4,
6.6 Hz, 1H), 1.98 (dd, J = 12.1, 5.8 Hz, 1H), 1.72-1.63 (m, 1H),
1.49-1.39 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H), 1.31-1.20 (m, 6H),
0.86 (t, J = 7.1 Hz, 3H); 13C NMR 100 MHz (CDCl3) δ 170.9,
138.4, 128.1, 128.0, 126.7, 76.7, 72.9, 61.2, 55.3, 49.4, 43.1, 42.6,
38.8, 38.4, 36.0, 31.7, 29.1, 26.0, 22.5, 14.3, 14.0. Some char-
acteristic NMR signal of the minor adduct: 1H NMR (400 MHz,
CDCl3) δ 4.16 (t, J = 6.3 Hz, 1H), 4.00 (d, J = 14.4 Hz, 1H),
3.72 (d, J = 14.4 Hz, 1H), 3.32-3.15 (m, 4H), 2.57 (dd, J = 14.4,
6.3 Hz, 1H), 2.51 (dd, J = 12.4, 8.1 Hz, 1H), 1.72-1.63 (m, 1H),
1.49-1.39 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H), 1.31-1.20 (m, 6H),
0.86 (t, J = 7.1 Hz, 3H). 13C NMR 100 MHz (CDCl3) δ 171.5,
138.1, 129.0, 128.1, 126.7, 72.6, 61.2, 55.4, 49.2, 42.9, 42.6, 38.8,
38.5, 29.1, 26.2, 22.5, 14.3, 14.0. HRMS (CIþNH3) calcd for
C18H26NO4S2 [M þ Hþ]: 438.2137, found 438.2129.
Ethyl 3-((1,3-Dithiolan-2-yl)methyl)-2-benzyl-5-(2-hydroxyet-
hyl)isoxazolidine-3-carboxylate (8d). From 4 and 7d. Purifica-
tion by flash chromatography (Et2O/cyclohexane 1:1) afforded
the title compound as a colorless oil (368 mg, 93%). Rf = 0.5
1
(Et2O). Diastereomeric ratio: 63:37. Major adduct: H NMR
(400 MHz, CDCl3) δ 7.40-7.16 (m, 5H), 4.58 (t, J = 6.8 Hz,
1H), 4.28 (q, J = 7.1 Hz, 2H), 4.39-4.31 (m, 1H), 4.08 (d, J =
14.1 Hz, 1H), 3.62 (d, J = 14.1 Hz, 1H), 3.63-3.57 (m, 2H),
3.34-3.15 (m, 4H), 3.05 (dd, J = 12.4, 8.1 Hz, 1H), 2.66 (dd, J =
14.1, 6.8 Hz, 1H), 2.27 (dd, J = 14.1, 6.8 Hz, 1H), 2.10 (dd, J =
12.4, 6.3 Hz, 1H), 1.86 (broadband, 1H), 1.88-1.80 (m, 1H),
1.74-1.67 (m, 1H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR 100 MHz
(CDCl3) δ 170.4, 137.6, 128.5, 127.3, 75.7, 72.6, 61.3, 60.8, 55.8,
49.3, 42.8, 42.6, 38.8, 38.4, 37.9, 14.3.
Minor adduct: 1H NMR (400 MHz, CDCl3) δ 7.40-7.16 (m,
5H), 4.62 (dd, J = 7.1, 6.3 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H),
4.25-4.18 (m, 1H), 4.00 (d, J = 14.4 Hz, 1H), 3.73 (d, J= 14.4 Hz,
1H), 3.73-3.65 (m, 2H), 3.34-3.15 (m, 4H), 2.65 (dd, J = 12.6,
7.1 Hz, 1H), 2.59 (dd, J = 14.7, 6.3 Hz, 1H), 2.57 (dd, J = 12.6,
8.3 Hz, 1H), 2.36 (dd, J = 14.7, 7.1 Hz, 1H), 1.98-1.88 (m, 2H),
1.36 (t, J = 7.1 Hz, 3H), 1.61 (broadband, 1H); 13C NMR
100 MHz (CDCl3) δ 170.4, 137.6, 128.5, 128.3, 127.3, 75.3, 72.5,
61.4, 60.4, 55.6, 49.1, 42.6, 41.7, 38.8, 38.5, 35.7, 14.3. HRMS
(CIþNH3) calcd for C21H32NO5 [M þ Hþ]: 398.1460, found
398.1461.
3-Ethyl 5-Methyl 3-((1,3-dithiolan-2-yl)methyl)-2-benzylisox-
azolidine-3,5-dicarboxylate (8e). From 4 and 7e. Purification by
flash chromatography (30-50% Et2O in cyclohexane) afforded
the title compound as a colorless oil (362 mg, 88%). Rf = 0.6
(Et2O). Diastereomeric ratio: 62:38. 1H NMR (400 MHz,
CDCl3) δ 7.45-7.21 (m, 5H, Ph, both isomers), 4.57-4.53 (m,
2H, both isomers), 4.35-4.20 (m, 2H, both isomers), 4.15 (d,
J = 15.2 Hz, 1H) and 3.73 (d, J = 15.2 Hz, 1H) of the same
isomer, 4.06 (d, J = 14.7 Hz, 1H) and 3.90 (d, J = 14.7 Hz, 1H)
of the same isomer, 3.72 (s, 3H, CO2Me) and 3.74 (s, 3H,
CO2Me), 3,32-3.16 (m, 4H, CH2S), 3.28 (dd, J = 12,6, 3.8
Hz, 1H) and 3.15 (dd, J = 12,9, 5.3 Hz, 1H), 2.78 (dd, J = 12,9,
10.1 Hz, 1H) and 2.63 (dd, J = 12.6, 6.1 Hz, 1H, H3b), 2.62 (dd,
J = 14.4, 7.1 Hz, 1H) and 2.60 (dd, J = 14.1, 7.1 Hz, 1H), 2.26
(dd, J = 6.8, 5.1 Hz, 1H) and 2.23 (dd, J = 6.6, 4.8 Hz, 1H), 1.35
Ethyl 3-((1,3-Dithiolan-2-yl)methyl)-2-benzyl-5-(hydroxymethyl)-
isoxazolidine-3-carboxylate (8b). From 4 and 7b. Purification by
flash chromatography (Et2O/cyclohexane 1:2) afforded the title
compound as a colorless oil (356 mg, 93%). Rf = 0.5 (Et2O).
Diastereomeric ratio: 61:39. Major adduct: 1H NMR (400 MHz,
CDCl3) δ 7.37-7.22 (m, 5H), 4.59 (t, J = 6.8 Hz, 1H), 4.29 (q,
J = 7.1 Hz, 2H), 4.29-4.23 (m, 1H), 4.00 (d, J = 14.4 Hz, 1H),
3.60 (d, J = 14.4 Hz, 1H), 3.62-3.52 (m, 2H), 3.35-3.15 (m,
4H), 2.96 (dd, J = 12.4, 8.3 Hz, 1H), 2.63 (dd, J = 14.1, 7.0 Hz,
1H), 2.25 (dd, J = 14.1, 7.0 Hz, 1H), 2.19 (dd, J = 12.4, 5.8 Hz,
1H), 1.35 (t, J = 7.1 Hz, 3H,); 13C NMR 100 MHz (CDCl3) δ
170.3, 138.0, 128.2, 128.0, 127.1, 76.3, 72.7, 65.3, 61.4, 55.6, 49.4,
42.6, 38.9, 38.3, 37.9, 14.3. Minor adduct: 1H NMR (400 MHz,
CDCl3) δ 7.37-7.22 (m, 5H), 4.63 (t, J = 6.8 Hz, 1H), 4.28 (q,
J = 7.1 Hz, 2H), 4.23-4.17 (m, 1H), 4.11 (d, J = 14.7 Hz, 1H),
3.78 (d, J = 14.7 Hz, 1H), 3.80-3.78 (m, 1H), 3.70-3.64 (m,
1H), 3.35-3.05 (m, 4H), 2.78 (dd, J = 12.9, 6.6 Hz, 1H), 2.62
(dd, J = 14.4, 6.8 Hz, 1H), 2.53 (dd, J = 12.9, 6.8 Hz, 1H), 2.38
(dd, J = 14.4, 6.8 Hz, 1H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR
100 MHz (CDCl3) δ 170.3, 138.0, 128.2, 128.0, 127.1, 76.3, 72.7,
616 J. Org. Chem. Vol. 75, No. 3, 2010

Nguyen et al.
JOCArticle
170.6, 137.9, 128.0, 127.9, 126.7, 100.1, 72.9, 63.7, 61.3, 55.4,
and 1.30 (t, J = 7.1 Hz, 3H, CH3 Et); 13C NMR 100 MHz
(CDCl3) δ 172.7 (CdO), 170.9 (CdO), 170.0 (CdO), 169.9
(CdO), 137.5 (2Cq. Ar), 128.3, 128.1 (CHAr), 128.0 (CHAr),
127.7 (CHAr), 127.1 (CHAr), 126.9 (CHAr), 74.0 and 73.9 (C5),
72.4 and 71.9 (Cq-N), 61.6 and 61.5 (CH2 Et), 55.6 and 55.2 (CH2 Bn),
52.1 (CH3 ester), 49.0 and 49.1 (S-CH-S), 42.6 and 42.5 (CH2),
40.1 and 39.8 (CH2), 38.7 (CH2S), 38.5 (CH2S), 38.4 (CH2S),
38.3 (CH2S), 14.2 and 14.0 (CH3). HRMS (CIþNH3) calcd for
C21H32NO5 [M þ Hþ]: 412.1252, found 412.1238.
1
49.2, 44.0, 42.3, 38.7, 38.3, 15.0, 14.3. Some characteristic H
and 13C NMR signals of the minor adduct (cis): 1H NMR
(400 MHz, CDCl3) δ 4.64 (dd, J = 7.1, 5.8 Hz, 1H), 4.06 (d,
J = 13.6 Hz, 1H), 2.98 (dd, J = 14.0, 3.5 Hz, 1H), 2.75 (dd, J =
14.0, 6.6 Hz, 1H), 2.58 (dd, J = 14.4, 7.1 Hz, 1H), 2.38 (dd, J =
14.4, 5.8 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz,
3H); 13C NMR 100 MHz (CDCl3) δ 169.9, 138.2, 64.0, 56.6,
48.8, 42.5, 38.6, 38.5, 14.9, 13.9. HRMS (CIþNH3) calcd for
C19H28NO4S2 [M þ Hþ]: 398.1460, found 398.1462.
Triethyl 3-((1,3-Dithiolan-2-yl)methyl)-2-benzylisoxazolidine-
3,4,5-tricarboxylate (8f). From 4 and 7f. Purification by flash
chromatography (30-50% Et2O in cyclohexane) afforded the
title compound as a colorless oil (457 mg, 92%). Rf = 0.6 (Et2O).
Diastereomeric ratio: 73:27. Major adduct: 1H NMR (400 MHz,
CDCl3) δ 7.43-7.41 (m, 2H), 7.33-7.29 (m, 2H), 7.25-7.22 (m,
1H), 4.98 (d, J = 5.1 Hz, 1H), 4.77 (dd, J = 6.7, 5.7 Hz, 1H), 4.50
(d, J = 5.1 Hz, 1H), 4.31-4.15 (m, 6H), 4.15 (d, J = 15.4 Hz,
1H), 3.59 (d, J = 15.4 Hz, 1H), 3.30-3.12 (m, 4H), 2.80 (dd, J =
15.7,5.7Hz,1H),2.64(dd,J= 15.7, 6.7 Hz, 1H), 1.30 (t, J=7.1Hz,
3H), 1.27 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR
100 MHz (CDCl3) δ 171.4, 169.2, 168.4, 136.6, 128.1, 127.7,
127.0, 75.6, 74.2, 62.4, 61.5, 61.4, 56.6, 55.6, 48.6, 40.7, 38.7,
38.6, 14.0, 14.1, 14.2. Minor adduct: 1H NMR (400 MHz,
CDCl3) δ 7.43-7.41 (m, 2H), 7.33-7.29 (m, 2H), 7.25-7.22
(m, 1H), 4.92 (d, J = 7.2 Hz, 1H), 4.84 (dd, J = 7.3, 4.5 Hz, 1H),
4.53 (d, J = 7.1 Hz, 1H), 4.31-4.15 (m, 8H), 3.30-3.12 (m, 4H),
2.54 (dd, J = 15.2, 4.5 Hz, 1H), 2.45 (dd, J = 15.2, 7.3 Hz, 1H),
1.32(t,J= 7.1 Hz, 3H), 1.28 (t, J= 7.1 Hz, 3H), 1.24 (t, J=7.1Hz,
3H); 13C NMR 100 MHz (CDCl3) δ 169.8, 169.5, 168.7, 137.1,
128.4, 128.1, 127.1, 78.2, 75.7, 62.3, 61.9, 61.7, 56.6, 56.5, 48.6,
42.0, 38.9, 38.3, 14.1, 14.0, 13.8. HRMS (CIþNH3) calcd for
C23H32NO7S2 [M þ Hþ]: 498.1620, found 498.1608.
Ethyl 3-((1,3-Dithiolan-2-yl)methyl)-2-benzyl-5-tert-butoxyi-
soxazolidine-3-carboxylate (8i). From 4 and 7i. Purification by
flash chromatography (30-50% Et2O in cyclohexane) afforded
the title compound as a colorless oil (378 mg, 89%). Rf = 0.6
(Et2O). Diastereomeric ratio >98:2. Sole detected adduct
(trans): 1H NMR (400 MHz, CDCl3) δ 7.41-7.39 (m, 2H),
7.30-7.26 (m, 2H), 7.23-7.19 (m, 1H), 5.43 (dd, J = 5.6, 4.0 Hz,
1H), 4.55 (dd, J = 7.1, 6.8 Hz, 1H), 4.35-4.18 (m, 2H), 4.11 (d,
J = 14.4 Hz, 1H), 3.65 (d, J = 14.4 Hz, 1H), 3.33-3.12 (m, 5H),
2.62 (dd, J = 14.1, 7.1 Hz, 1H), 2.33 (dd, J = 14.1, 6.8 Hz, 1H),
2.25 (dd, J = 13.1, 4.0 Hz, 1H), 1.35 (t, J = 7.1 Hz, 3H), 1.09 (s,
9H); 13C NMR 100 MHz (CDCl3) δ 170.9, 138.0, 128.5, 127.8,
126.7, 96.1, 74.5, 73.0, 61.2, 55.7, 49.4, 44.9, 42.7, 38.7, 38.3,
28.7, 14.3. HRMS (CIþNH3) calcd for C21H32NO4S2 [M þ Hþ]:
426.1773, found 426.1739.
Nitrone 9a-d. These products were prepared after the pro-
cedure for 4.
(E)-N-(1-Methoxy-1-oxopropan-2-ylidene)(phenyl)methanamine
Oxide (9a). On 10 mmol scale. Purification by flash chromatog-
raphy afforded the title compound as a colorless oil (1.93 g,
93%). 1H NMR (400 MHz, CDCl3) δ 7.51-7.49 (m, 2H),
7.37-7.20 (m, 3H), 5.70 (s, 2H), 3.83 (s, 3H), 3.61 (s, 3H), 2.25
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.7, 137.5, 133.9,
128.6, 128.4, 128.3, 67.0, 52.5, 15.1. HRMS (CIþNH3) calcd for
C11H14NO3 [M þ Hþ]: 208.0974, found 208.0977.
Ethyl 3-((1,3-Dithiolan-2-yl)methyl)-5-acetoxy-2-benzylisox-
azolidine-3-carboxylate (8g). From 4 and 7g. Purification by
flash chromatography (30-50% Et2O in cyclohexane) afforded
the title compound as a colorless oil (370 mg, 90%). Rf = 0.6
(E)-N-(1-Methoxy-1-oxobutan-2-ylidene)(phenyl)methanamine
Oxide (9b). On 10 mmol scale. Purification by flash chromatog-
raphy afforded the title compound as a colorless oil (2.10 g,
95%). 1H NMR (400 MHz, CDCl3) δ 7.51-7.49 (m, 2H),
7.37-7.31 (m, 3H), 5.64 (s, 2H), 3.83 (s, 3H), 2.74 (q, J =
7.3 Hz, 2H), 1.08 (t, J = 7,3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.9, 142.3, 134.0, 128.6, 128.5, 128.3, 67.4, 52.5,
21.9, 8.9. HRMS (CIþNH3) calcd for C12H16NO3 [M þ Hþ]:
222.1130, found 222.1134.
1
(Et2O). Diastereomeric ratio: 81:19. Major adduct (trans): H
NMR (400 MHz, CDCl3) δ 7.38-7.21 (m, 5H), 6.32 (dd, J =
6.3, 3.3 Hz, 1H), 4.56 (t, J = 7.1 Hz, 1H), 4.29 (q, J = 7.1 Hz,
2H), 4.12 (d, J = 15.2 Hz, 1H), 3.71 (d, J = 15.2 Hz, 1H), 3.30
(dd, J = 13.4, 6.6 Hz, 1H), 3.34-3.16 (m, 4H), 2.61 (dd, J =
14.1, 7.1 Hz, 1H), 2.50 (dd, J = 13.4, 3.3 Hz, 1H), 2.29 (dd, J =
14.1, 7.1 Hz, 1H), 2.05 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C
NMR 100 MHz (CDCl3) δ 170.5, 169.8, 137.3, 128.1, 128.0,
127.0, 95.0, 73.9, 61.6, 55.5, 49.0, 43.7, 42.5, 38.5, 38.4, 21.2,
14.2. Minor adduct (cis): 1H NMR (400 MHz, CDCl3) δ
7.38-7.21 (m, 5H), 6.30 (dd, J = 6.6, 3.3 Hz, 1H), 4.57 (t,
J = 7.1 Hz, 1H), 4.13-4.29 (m, 2H), 4.30 (d, J = 14.4 Hz, 1H),
4.04 (d, J = 14.4 Hz, 1H), 3.34-3.16 (m, 4H), 3.06 (dd, J = 14.4,
3.3 Hz, 1H), 2.95 (dd, J = 14.4, 6.6 Hz, 1H), 2.62 (dd, J = 14.1,
7.1 Hz, 1H), 2.41 (dd, J = 14.1, 6.1 Hz, 1H), 2.05 (s, 3H), 1.31 (t,
J = 7.1 Hz, 3H); 13C NMR 100 MHz (CDCl3) δ 170.2, 169.6,
137.5, 128.7, 128.3, 126.9, 95.6, 72.8, 62.0, 56.0, 48.7, 46.1, 42.3,
38.7, 38.5, 21.2, 13.9. HRMS (CIþNH3) calcd for C21H32NO5
[M þ Hþ]: 412.1252, found 412.1242.
(E)-N-(1-Methoxy-1-oxo-3-phenylpropan-2-ylidene)(phenyl)-
methanamine Oxide (9c). On 5 mmol scale. Purification by flash
chromatography afforded the title compound as a colorless oil
1
(1.17 g, 83%). H NMR (400 MHz, CDCl3) δ 7.46-7.24 (m,
10H), 5.71 (s, 2H), 4.07 (s, 2H), 3.82 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.8, 139.7, 136.2, 133.9, 128.82, 128.75, 128.5, 128.4,
128.3, 126.6, 67.8, 52.7, 33.7. HRMS (CIþNH3) calcd for
C17H18NO3 [M þ Hþ]: 284.1287, found 284.1284.
(E)-N-(1,5-Dimethoxy-1,5-dioxopentan-2-ylidene)(phenyl)-
methanamine Oxide (9d). On 10 mmol scale. Purification by
flash chromatography (Et2O/cyclohexane, 1:1) afforded the title
compound as a colorless oil (2.63 g, 94%). 1 H NMR (400 MHz,
CDCl 3) δ 7.47-7.45 (m, 2H), 7.37-7.30 (m, 3H), 5.67 (s, 2H),
3.84(s,3H),3.63(s,3H),3.00(t,J=7.3Hz,2H),2.60(t,J=7.3Hz,
2H); 13 C NMR (100 MHz, CDCl 3) δ 172.9, 162.6, 139.4, 133.9,
128.7, 128.5, 128.4, 67.5, 52.6, 51.6, 28.4, 24.3. HRMS
(CIþNH3) calcd for C14H18NO5 [M þ Hþ]: 280.1185, found
280.1185.
Ethyl 3-((1,3-Dithiolan-2-yl)methyl)-2-benzyl-5-ethoxyisoxa-
zolidine-3-carboxylate (8h). From 4 and 7h. Purification by flash
chromatography (30-50% Et2O in cyclohexane) afforded the
title compound as a colorless oil (361 mg, 91%). Rf = 0.6 (Et2O).
Diastereomeric ratio: 92:8. Major adduct (trans): 1H NMR (400
MHz, CDCl3) δ 7.42-7.39 (m, 2H), 7.31-7.26 (m, 2H),
7.24-7.20 (m, 1H), 5.15 (dd, J = 6.3, 3.5 Hz, 1H), 4.56 (t,
J = 6.8 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.15 (d, J = 14.9 Hz,
1H), 3.68 (d, J = 14.9 Hz, 1H), 3.58 (dq, J = 9.9, 7.1 Hz, 1H),
3.39 (dq, J = 9.9, 7.1 Hz, 1H), 3.29-3.14 (m, 4H), 3.18 (dd, J =
13.1, 6.3 Hz, 1H), 2.60 (dd, J = 14.1, 6.8 Hz, 1H), 2.32 (dd, J =
14.1,6.8Hz,1H),2.32(dd,J= 13.1, 3.5 Hz, 1H), 1.35 (t, J=7.1Hz,
3H), 1.12 (t, J = 7.1 Hz, 3H); 13C NMR 100 MHz (CDCl3) δ
Adducts 10a-e. These products were prepared after the
procedure for 8h.
Methyl 2-Benzyl-5-ethoxy-3-methylisoxazolidine-3-carboxylate
(10a). From 9a (1 mmol) and ethyl vinyl ether. Purification by
flash chromatography (Et2O/cyclohexane, 1:3) afforded the title
compound 10a as a colorless oil (268 mg, 96%). Diastereomeric
J. Org. Chem. Vol. 75, No. 3, 2010 617

Nguyen et al.
JOCArticle
ratio: 75:25. Major adduct (trans): 1H NMR (400 MHz, CDCl3)
δ 7.45-7.41 (m, 2H), 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H),
5.16 (dd, J = 6.3, 3.5 Hz, 1H), 4.12 (d, J = 14.7 Hz, 1H), 3.79 (d,
J = 14.7 Hz, 1H), 3.78 (s, 3H), 3.65-3.57 (m, 1H), 3.44-3.34
(m, 1H), 3.16 (dd, J= 13.4, 6.3 Hz, 1H), 2.16 (dd, J = 13.1, 3.5 Hz,
1H), 1.50 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.8, 138.0, 128.1, 128.0, 126.8, 101.6, 70.1,
63.9, 55.8, 52.0, 46.6, 19.6, 15.0. Minor adduct (cis): 1H NMR
(400 MHz, CDCl3) δ 7.45-7.44 (m, 2H), 7.32-7.29 (m, 2H),
7.25-7.21 (m, 1H), 5.10 (dd, J = 6.3, 3.0 Hz, 1H), 4.19 (d, J =
14.4 Hz, 1H), 3.88 (d, J = 14.4 Hz, 1H), 3.70 (s, 3H), 3.65-3.57
(m, 1H), 3.44-3.34 (m, 1H), 2.86 (dd, J = 13.6, 3.3 Hz, 1H), 2.45
(dd, J = 13.6, 6.3 Hz, 1H), 1.45 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 172.4, 138.0, 128.3, 128.1, 126.8,
100.6, 69.3, 63.6, 55.8, 52.3, 47.3, 19.6, 14.9. HRMS (CIþNH3)
calcd for C15H22NO4 [M þ Hþ]: 280.1549, found 280.1541.
Methyl 2-Benzyl-5-ethoxy-3-ethylisoxazolidine-3-carboxylate
(10b). From 9b (5 mmol) and ethyl vinyl ether. Purification by
flash chromatography (Et2O/cyclohexane, 1:3) afforded the title
compound 10b as a colorless oil (1.42 g, 97%). Diastereomeric
ratio: 79:21. Major adduct (trans): 1H NMR (400 MHz, CDCl3)
δ 7.42-7.40 (m, 2H), 7.32-7.28 (m, 2H), 7.24-7.21 (m, 1H),
5.16 (dd, J = 6.3, 3.5 Hz, 1H), 4.15 (d, J = 14.2 Hz, 1H), 3.79 (s,
3H), 3.73 (d, J = 14.2 Hz, 1H), 3.63-3.55 (m, 1H), 3.43-3.35
(m, 1H), 3.14 (dd, J = 13.4, 6.3 Hz, 1H), 2.12 (dd, J = 13.4,
3.5 Hz, 1H), 2.05-1.96 (m, 1H), 1.76-1.68 (m, 1H), 1.13 (t, J =
7.1 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.0, 138.1, 128.0, 127.9, 126.7, 101.4, 74.9, 63.7,
(d, J = 14.7 Hz, 1H), 3.85 (s, 3H), 3.70 (d, J = 14.7 Hz, 1H),
3.61-3.53 (m, 2H), 3.41-3.34 (m, 1H), 3.07 (dd, J = 13.4, 6.3
Hz, 1H), 2.45-2.38 (m, 2H), 2.30-2.22 (m, 1H), 2.19-2.12
(m, 2H), 1.12 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 172.9, 171.6, 137.8, 127.94, 127.89, 126.8, 100.8, 72.6, 63.6,
55.3, 52.0, 51.6, 44.1, 29.6, 28.1, 14.9. Minor adduct (cis): 13C
NMR (100 MHz, CDCl3) δ 173.2, 170.6, 138.1, 128.3, 127.9,
126.8, 102.8, 72.9, 64.0, 56.7, 52.3, 51.9, 43.1, 29.4, 27.3, 14.8.
HRMS (CIþNH3) calcd for C18H26NO6 [M þ Hþ]: 352.1760,
found 352.1769.
Methyl 2-Benzyl-5-tert-butoxy-3-(3-methoxy-3-oxopropyl)-
isoxazolidine-3-carboxylate (10e). From 9d (10 mmol) and tert-
butyl vinyl ether. Purification by flash chromatography (Et2O/
cyclohexane, 1:1) afforded the title compound 10e as an oil (3.22 g,
85%). Diastereomeric ratio: 92:8. Major adduct (trans): 1H NMR
(400 MHz, CDCl3) δ 7.41-7.38 (m, 2H), 7.30-7.25 (m, 2H),
7.22-7.17 (m, 1H), 5.42 (dd, J = 6.4, 3.7 Hz, 1H), 4.11 (d, J =
14.4 Hz, 1H), 3.78 (s, 3H), 3,66 (d, J = 14.1 Hz, 1H), 3.65 (s, 3H),
3.01 (dd, J = 13.1, 6.6 Hz, 1H), 2.43-2,12 (m, 4H), 2.09 (dd, J =
13.1, 3.7 Hz, 1H), 1.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
172.9, 171.9, 137.9, 128.4, 127.8, 126.7, 93.0, 74.4, 72.8, 55.6, 51.9,
51.6, 44.9, 29.7, 28.6, 26.8. Minor adduct (cis): 1H NMR (400 MHz,
CDCl3) δ 7.41-7.38 (m, 2H), 7.30-7.25 (m, 2H), 7.22-7.17 (m,
1H), 5.42 (m, 1H), 4.24 (d, J = 13.6 Hz, 1H), 3,99 (d, J = 13.6 Hz,
1H), 3.78 (s, 3H), 3.65 (s, 3H), 2.83 (dd, J = 13.8, 4.3 Hz, 1H),
2.49-2,12 (m, 5H), 1.10 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
173.3, 170.8, 138.2, 128.6, 127.8, 126.7, 97.9, 74.7, 73.0, 57.0, 52.1,
51.5, 43.4, 29.4, 28.6, 26.8. HRMS calcd for C20H29NO6 [Mþ]:
379.1995, found 379.2000.
1
55.6, 51.8, 44.1, 26.6, 14.9, 9.6. Minor adduct (cis): H NMR
(400 MHz, CDCl3) δ 7.42-7.40 (m, 2H), 7.32-7.28 (m, 2H),
7.24-7.21 (m, 1H), 5.11 (dd, J = 6.3, 3.5 Hz, 1H), 4.31 (d, J =
14.2 Hz, 1H), 3.97 (s, 3H), 3.71 (d, J = 14.2 Hz, 1H), 3.63-3.55
(m, 1H), 3.43-3.35 (m, 1H), 2.89 (dd, J = 13.9, 3.5 Hz, 1H), 2.55
(dd, J = 13.9, 6.3 Hz, 1H), 2.07-2.00 (m, 1H), 1.83-1.74 (m,
1H), 1.14 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 171.1, 138.1, 128.3, 127.9, 126.7, 102.3,
74.4, 63.8, 56.5, 52.1, 42.0, 26.7, 14.9, 9.6. HRMS (CIþNH3)
calcd for C16H24NO4 [M þ Hþ]: 294.1705, found 294.1696.
Methyl 2,3-Dibenzyl-5-ethoxyisoxazolidine-3-carboxylate (10c).
From 9c (1 mmol) and ethyl vinyl ether. Purification by flash
chromatography (Et2O/cyclohexane, 1:3) afforded the title
compound 10c as a colorless oil (222 mg, 63%). Diastereomeric
ratio: 87:13. Major adduct (trans): 1H NMR (400 MHz, CDCl3)
δ 7.48-7.45 (m, 2H), 7.35-7.31 (m, 2H), 7.29-7.22 (m, 4H),
7.20-7.18 (m, 4H), 5.11 (dd, J = 6.3, 3.8 Hz, 1H), 4.30 (d, J =
14.9 Hz, 1H), 3.82 (d, J = 14.9 Hz, 1H), 3.75 (s, 3H), 3.65-3.56
(m, 1H), 3.43-3.36 (m, 1H), 3.37 (d, J = 12.9 Hz, 1H), 2.96 (d,
J = 12.9 Hz, 1H), 2.87 (dd, J = 13.4, 6.3 Hz, 1H), 2.32 (dd, J =
13.4, 3.8 Hz, 1H), 1.14 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 171.3, 138.0, 136.0, 129.7, 128.4, 128.1, 128.0, 126.9,
126.8, 101.3, 74.9, 63.9, 55.9, 51.9, 44.4, 39.5, 15.0. Minor adduct
(cis): 1H NMR (400 MHz, CDCl3) δ 7.45-7.43 (m, 2H),
7.35-7.18 (m, 6H), 7.29-7.22 (m, 4H), 7.13-7.10 (m, 2H),
5.18 (dd, J = 6.3, 3.8 Hz, 1H), 4.42 (d, J = 13.9 Hz, 1H), 4.05 (d,
J = 13.9 Hz, 1H), 3.68 (s, 3H), 3.65-3.57 (m, 1H), 3.47 (d, J =
13.6 Hz, 1H), 3.43-3.34 (m, 1H), 3.00 (d, J = 13.6 Hz, 1H), 2.77
(dd, J = 14.1, 3.8 Hz, 1H), 2.63 (dd, J = 14.1, 6.3 Hz, 1H), 1.14
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.6, 138.2,
136.2, 130.0, 128.4, 128.1, 128.0, 126.91, 126.85, 102.7, 75.0,
64.1, 56.5, 52.2, 41.1, 39.3, 15.0. HRMS (CIþNH3) calcd for
C21H26NO4 [M þ Hþ]: 356.1862, found 356.1848.
trans-Methyl 5-Ethoxy-3-(2-methoxy-2-oxoethyl)isoxazolid-
ine-3-carboxylate (11a). Under argon, to a stirred solution of
adduct 3a6 (5,00 g, 14.8 mmol) in methanol (10 mL) and Pd/C
(10%, 1 g) was added dropwise formic acid (20 mL). After 16 h
of stirring at rt, the reaction mixture was diluted with AcOEt
(100 mL) and filtered over Celite. The filtrate was concentrated
under reduced pressure. The viscous residue was partitioned
between AcOEt (100 mL) and aqueous saturated NaHCO3 (50
mL). The aqueous phase was separated and extracted with
AcOEt (50 mL ꢀ 2). The combined AcOEt phases were washed
with brine, dried over MgSO4, filtered, and concentrated under
vacuum. Purification of the residue by silica gel chromatogra-
phy (Et2O/cyclohexane, 1:1) (Rf = 0.50 with Et2O) yielded 11a
as a pale yellow oil (3.32 g, 91%). 1H NMR (400 MHz, CDCl3)
δ 6.25 (broadband, 1H), 5.28 (dd, J = 5.6, 1.3 Hz, 1H), 3.78
(s, 3H), 3.70 (s, 3H), 3.78-3.71 (m, 1H), 3.52-3.44 (m, 1H), 3.07
(d, J = 16.9 Hz, 1H), 2.98 (broadband, 1H), 2.88 (d, J = 16.9 Hz,
1H), 2.13 (d, J = 13.6 Hz, 1H), 1.20 (t, J = 7.1 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ 172.7, 170.1, 104.5, 67.1, 63.5, 52.9,
52.0, 45.1, 39.5. HRMS (CIþNH3) calcd for C21H32NO6 [M þ
Hþ]: 248.1134, found 248.1139.
trans-Methyl 5-tert-Butoxy-3-(2-methoxy-2-oxoethyl)isoxaz-
olidine-3-carboxylate (11b). Prepared following the procedure
described for 11a from 3b (2.30 g, 6.3 mmol). Purification of the
residue by silica gel chromatography (Et2O/cyclohexane, 1:1)
yielded 11b as a colorless oil (1.50 g, 85%). 1H NMR (400 MHz,
CDCl3) δ 6.21 (broadband, 1H), 5.58 (dd, J = 5.6, 1.3 Hz, 1H),
3.77 (s, 3H), 3.69 (s, 3H), 3.09 (d, J = 15.9 Hz, 1H), 2.97
(broadband, 1H), 2.87 (d, J = 15.9 Hz, 1H), 2.05 (dd, J = 13.4,
1.1 Hz, 1H), 1.24 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 172.7,
170.0, 99.9, 75.1, 67.3, 52.8, 51.8, 45.8, 39.4, 28.6. HRMS
(CIþNH3) calcd for C12H22NO6 [M þ Hþ]: 276.1447, found
276.1441.
Methyl 2-Benzyl-5-ethoxy-3-(3-methoxy-3-oxopropyl)isoxaz-
olidine-3-carboxylate (10d). From 9d (5 mmol) and ethyl vinyl
ether. Purification by flash chromatography (Et2O/cyclohexane,
1:1) afforded the title compound 10d as a colorless oil (1.67 g,
95%). Diastereomeric ratio: 91:9. Major adduct (trans): 1H
NMR (400 MHz, CDCl3) δ 7.40-7.38 (m, 2H), 7.32-7.28 (m,
2H), 7.24-7.20 (m, 1H), 5.14 (dd, J = 6.3, 3.3 Hz, 1H), 4.14
trans-Methyl 5-Ethoxy-3-(3-methoxy-3-oxopropyl)isoxazoli-
dine-3-carboxylate (11c). Prepared following the procedure
described for 11a from 10d (2.70 g, 7.6 mmol). Purification of
the residue by silica gel chromatography (Et2O/cyclohexane,
1:1) yielded 11c as a colorless oil (1.23 g, 62%). 1H NMR(400 MHz,
CDCl3) δ 5.88 (broadband, 1H), 5.24 (d, J = 4.5 Hz, 1H), 3.77
618 J. Org. Chem. Vol. 75, No. 3, 2010

Nguyen et al.
JOCArticle
(s, 3H), 3.76-3.70 (m, 1H), 3.68 (s, 3H), 3.51-3.43 (m, 1H), 3.00
(dd, J = 13.6, 5.4 Hz, 1H), 2.41-2.36 (m, 2H), 2.28-2.20 (m, 2H),
2.00 (d, J = 13.6 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR
(50 MHz, CDCl3) δ 173.6, 172.6, 104.6, 70.2, 63.5, 52.7, 51.7, 45.6,
30.0, 29.9, 14.9. HRMS (CIþNH3) calcdforC11H20NO6 [Mþ Hþ]:
262.1291, found 262.1295.
trans-Methyl 5-tert-Butoxy-3-(3-methoxy-3-oxopropyl)isoxa-
zolidine-3-carboxylate (11d). Prepared following the procedure
described for 11a from 10e (1.89 g, 5.0 mmol). Purification of the
residue by silica gel chromatography (Et2O/cyclohexane, 1:1)
yielded 11d as a colorless oil (1.1 g, 76%). 1H NMR (400 MHz,
CDCl3) δ 5.86 (broadband, 1H), 5.53 (dd, J = 5.6, 1.6 Hz, 1H),
3.77 (s, 3H), 3.68 (s, 3H), 3.97 (dd, J = 13.4, 5.7, Hz, 1H),
2.46-2.32 (m, 2H), 2.28-2.16 (m, 2H), 1.92 (dd, J = 13.4,
1.5, Hz, 1H), 1,24 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 173.8,
172.7, 99.9, 75.1, 70.4, 52.7, 51.7, 46.6, 30.0, 29.9, 28.7. HRMS
calcd for C13H23NO6 [Mþ]: 289.1525, found 289.1536.
Et3N (0.15 mL, 1.3 mmol) and (CF3CO)2O (0.07 mL,
1.2 mmol), and the mixture was stirred overnight at room
temperature. The reaction was quenched with NH4Cl satd
(5 mL) and extracted with Et2O. The organic phases were
combined, washed with NaCl, dried over MgSO4, filtered,
and concentrated under reduced pressure. The resulting re-
sidue was purified over silica gel chromatography (Et2O/
cyclohexane, 1:1) to afford 13a as a colorless oil (0.33 g,
100%). 1H NMR (400 MHz, CDCl3) δ 5.74 (dd, J = 5.1,
2.5 Hz, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.51 (d, J = 16.1 Hz,
1H), 3.01 (dd, J = 13.4, 2.5 Hz, 1H), 2.97 (d, J = 16.1 Hz, 1H),
2.87 (dd, J = 13.4, 5.1 Hz, 1H), 1.27 (m, 9H). 13C NMR (50 MHz,
CDCl3) δ 170.1, 169.1, 151.7 (q, J = 39.2 Hz), 115.5 (q, J =
284.6 Hz), 99.1, 77.1, 67.1, 53.4, 51.8, 44.0, 37.0, 28.2. HRMS
(CIþNH3) calcd for C14H21NO7F3 [M þ Hþ]: 372.1270,
found 372.1270.
trans-Methyl 5-tert-Butoxy-3-(3-methoxy-3-oxopropyl)-2-(2,
2,2-trifluoroacetyl)isoxazolidine-3-carboxylate (13b). To a solu-
tion of 11d (0.52 g, 1.87 mmol) in THF (2 mL) were added Et3N
(0.39 mL, 2.80 mmol) and (CF3CO)2O (0.37 mL, 2.62 mmol),
and the mixture was stirred overnight at room temperature. The
reaction was quenched with NH4Cl satd (5 mL) and extracted
with Et2O. Organic phases were combined, washed with NaCl,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The resulting residue was purified over silica gel
chromatography (Et2O/cyclohexane, 1:1) to afforded 13b as a
colorless oil (0.72 g, 100%). 1H NMR (400 MHz, CDCl3) δ 5.63
(dd, J = 5.6, 3.2 Hz, 1H), 3.78 (s, 3H), 3.68 (s, 3H), 2.75 (dd, J =
13.3, 5.6 Hz, 1H), 2.67-2.58 (m, 2H), 2.55-2.39 (m, 2H), 2.35
(dd, J = 13.3, 3.1 Hz, 1H), 1.27 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ 173.1, 170.1, 152.9 (q, J = 39.1 Hz), 115.5 (q, J =
286.4 Hz), 98.3, 76.7, 69.2, 53.3, 51.7, 45.1, 28.9, 28.8, 28.3.
HRMS (FD) calcd for C15H22F3NO7 [Mþ]: 385.1348, found
385.1380.
(()-Dimethyl 2-Acetamido-2-(2-oxoethyl)succinate ((()-14a).
A mixture of 12a (289 mg, 1 mmol) and Mo(CO)6 (528 mg,
2 mmol) in CH3CN (10 mL) and H2O (3 mL) was refluxed for 3 d
and then concentrated under vacumm. The residue was parti-
tioned in AcOEt (50 mL) and H2O (10 mL). The aqueous phase
was separated and extracted with AcOEt (50 mL ꢀ 2). The
combined AcOEt phases were dried over MgSO4, filtered, and
concentrated under vacuum. Purification of the residue by silica
gel chromatography with Et2O and then with AcOEt (Rf = 0.10
with Et2O) yielded (()-14a as a pale yellow oil (224 mg, 91%).
1H NMR (400 MHz, CDCl3) δ 9.64 (t, J = 1.3 Hz, 1H), 6.86
(broadband, 1H), 3.82 (dd, J = 17.4, 1.3 Hz, 1H), 3.82 (s, 3H),
3.66 (s, 3H), 3.56 (d, J = 15.7 Hz, 1H), 2.95 (dd, J = 17.4, 1.3 Hz,
1H), 2.84 (d, J = 15.7 Hz, 1H), 1.99 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 198.1, 171.7, 170.0, 169.9, 57.9, 53.3,
51.8, 47.6, 39.5, 23.7. HRMS (CIþNH3) calcd for C10H16NO6
[M þ Hþ]: 246.0978, found 246.0982.
trans-Methyl 2-Acetyl-5-ethoxy-3-(2-methoxy-2-oxoethyl)-
isoxazolidine-3-carboxylate (12a). A solution of11a (1.01 g, 4 mmol)
in Ac2O (3 mL) was stirred at rt for 16 h. The reaction mixture was
then evaporated under reduced pressure (40 °C at 10 mmHg, then
50 °C at 0.01 mmHg) to afford acetamide 12a as a pale yellow oil
(1.16 g, 100%). 1H NMR (400 MHz, CDCl3) δ 5.32 (d, J = 5.1 Hz,
1H), 3.78 (m, 1H), 3.75 (s, 3H), 3.71 (s, 3H), 3.59 (d, J = 16.2 Hz,
1H), 3.57 (m, 1H), 3.11 (dd, J = 13.4 Hz, 1H), 2.90 (d, J = 16.2 Hz,
1H), 2.86 (dd, J = 13.4 Hz, J = 5.1 Hz, 1H), 2.10 (s, 3H), 1.23 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.9, 170.8,
167.4, 101.6, 64.9, 64.3, 53.1, 51.7, 44.8, 37.8, 21.4, 15.0. HRMS
(CIþNH3) calcd for C12H20NO7 [M þ Hþ]: 290.1240, found
290.1242.
trans-Methyl 2-Acetyl-5-tert-butoxy-3-(2-methoxy-2-oxoet-
hyl)isoxazolidine-3-carboxylate (12b). Prepared following the
procedure described for 12a from 11b (0.55 g, 2.0 mmol).
Purification of the residue by silica gel chromatography
(Et2O/cyclohexane, 1:1) yielded 12b as a colorless oil (0.64 g,
100%). 1H NMR (400 MHz, CDCl3) δ 5.62 (dd, J = 5.1, 2.1 Hz,
1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.56 (d, J = 16.1 Hz, 1H), 2.98
(dd, J = 13.3, 2.1 Hz, 1H), 2.90 (d, J = 16.1 Hz, 1H), 2.82 (ddd,
J = 13.3, 5.1, 0.8 Hz, 1H), 2.08 (s, 3H), 1.28 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 170.9, 170.8, 167.4, 97.2, 75.9, 65.1, 52.9,
51.5, 45.2, 37.9, 28.5, 21.2. HRMS (CIþNH3) calcd for
C14H24NO7 [M þ Hþ]: 318.1553, found 318.1556.
trans-Methyl 2-Acetyl-5-ethoxy-3-(3-methoxy-3-oxopropyl)-
isoxazolidine-3-carboxylate (12c). Prepared following the pro-
cedure described for 12a from 11c (0.50 g, 1.9 mmol). Purification
of the residue by silica gel chromatography (Et2O/cyclohexane,
1:1) yielded 12c as a colorless oil (0.57 g, 100%). 1H NMR
(400 MHz, CDCl3) δ 5.22 (dd, J = 5.6, 1.1 Hz, 1H), 3.82-3.77
(m, 1H), 3.75 (s, 3H), 3.66 (s, 3H), 3.61-3.53 (m, 1H), 2.77 (dd,
J = 13.6, 5.6 Hz, 1H), 2.70-2.58 (m, 1H), 2.53-2.41 (m, 1H), 2.41
(dd, J = 13.6, 1.1 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR
(50 MHz, CDCl3) δ173.5, 171.6, 169.2, 100.3, 67.0, 63.9, 52.6, 51.3,
45.6, 29.4, 28.6, 21.5, 14.7. HRMS (CIþNH3) calcd for
C13H22NO7 [M þ Hþ]: 304.1396, found 304.1389.
(()-Dimethyl 2-Acetamido-2-(2-oxoethyl)pentanedioate ((()-
14b). A mixture of 12c (303 mg, 1 mmol) and Mo(CO)6 (528 mg,
2 mmol) in CH3CN (10 mL) and H2O (3 mL) was refluxed for
42 h and then concentrated under vacumm. The residue was
partitioned in AcOEt (50 mL) and H2O (10 mL). The aqueous
phase was separated and extracted with AcOEt (50 mL ꢀ 2).
Combined AcOEt phases were dried over MgSO4, filtered, and
concentrated under vacuum. Purification of the residue by silica
gel chromatography (Et2O/cyclohexane, 1:1) yielded (()-14b as
a pale yellow oil (156 mg, 60%). 1H NMR (400 MHz, CDCl3) δ
9.62 (s, 1H), 6.75 (broadband, 1H), 3.90 (dd, J = 18.3, 1.1 Hz,
1H), 3.76 (s, 3H), 3.65 (s, 3H), 3.05 (d, J = 18.3 Hz, 1H),
2.79-2.71 (m, 1H), 2.37-2.29 (m, 1H), 2.21-2.13 (m, 1H),
2.08-2.00 (m, 1H), 1.98 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
198.7, 172.8, 172.6, 169.6, 57.9, 59.3, 53.1, 51.7, 48.4, 30.2, 28.3,
23.7. HRMS (FI) calcd for C11H18NO6 [M þ Hþ]: 260.1134,
found 260.1135.
trans-Methyl 2-Acetyl-5-tert-butoxy-3-(3-methoxy-3-oxopropy)-
isoxazolidine-3-carboxylate (12d). Prepared following the pro-
cedure described for 12a from 11d (0.64 g, 2.2 mmol). Purificat-
ion of the residue by silica gel chromatography (Et2O/cyclohex-
ane, 1:1) yielded 12d as a colorless oil (0.72 g, 100%). 1H NMR
(400 MHz, CDCl3) δ 5.53 (dd, J = 5.6, 2.2 Hz, 1H), 3.74 (s, 3H),
3.66 (s, 3H), 2.75-2.59 (m, 3H), 2.50-2.41 (m, 2H), 2.33-2.27
(m, 1H), 2.10 (s, 3H), 1.30 (s, 9H). 13C NMR (100 MHz, CDCl3)
δ 173.5, 171.6, 168.8, 96.0, 75.8, 67.0, 52.5, 51.2, 46.2, 29.5, 28.8,
28.4, 21.3. HRMS (FI) calcd for C15H25NO7 [Mþ]: 331.1631,
found 331.1630.
trans-Methyl 5-tert-Butoxy-3-(2-methoxy-2-oxoethyl)-2-(2,2,
2-trifluoroacetyl)isoxazolidine-3-carboxylate (13a). To a solu-
tion of 11b (0.25 g, 0.86 mmol) in THF (1 mL) were added
J. Org. Chem. Vol. 75, No. 3, 2010 619

Nguyen et al.
JOCArticle
(()-1-tert-Butyl 2,3-Dimethyl 2-(2,2,2-trifluoroacetamido)-
propane-1,2,3-tricarboxylate ((()-15a). To a solution of 13a
(100 mg, 0.27 mmol) in THF (1 mL) was added a solution of
SmI2 in THF (4.5 mL, 4.5 mmol) under argon. After color
change of the solution from deep blue to yellow in 10 min,
NH4Cl and Et2O were added, and the aqueous phase was
separated and extracted with Et2O. Combined Et2O phases
were dried over MgSO4, filtered, and concentrated under
vacuum. Purification of the residue by silica gel chromatogra-
phy (Et2O/cyclohexane, 1:1) yielded (()-15a as a pale yellow
oil (75 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 7.77
(broadband, 1H), 3.87 (s, 3H), 3.65 (s, 3H), 3.54 (d, J = 15.8
Hz, 1H), 3.44 (d, J = 15.4 Hz, 1H), 2.93 (d, J = 15.8 Hz, 1H),
2.83 (d, J = 15.4 Hz, 1H), 1.40 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ 170.6, 169.1, 167.6, 156.1 (q, J = 37.3 Hz), 115.3 (q,
J = 286.5 Hz), 82.2, 59.6, 53.7, 52.0, 40.6, 39.1, 27.7. HRMS
(CIþNH3) calcd for C14H21NO7F3 [M þ Hþ]: 372.1270, found
372.1269.
of the solution from deep blue to yellow in 10 min, NH4Cl and
Et2O were added, and the aqueous phase was separated and
extracted with Et2O. Combined Et2O phases were dried over
MgSO4, filtered, and concentrated under vacuum. Purification of
the residue by silica gel chromatography (Et2O/cyclohexane, 1:1)
1
yielded (()-15b as a pale yellow oil (56 mg, 81%). H NMR
(400 MHz, CDCl3) δ 7.58 (broadband, 1H), 3.84 (s, 3H), 3.66
(s, 3H), 3.48 (d, J = 16.5 Hz, 1H), 2.94 (d, J = 16.4 Hz, 1H),
2.80-2.71 (m, 1H), 2.33-2.24 (m, 1H), 2.19-2.11 (m, 2H),1.40
(s, 9H). 13C NMR (100 MHz, CDCl3) δ 172.3, 171.8, 168.4, 155.9
(q, J = 37.3 Hz), 115.3 (q, J = 286.8 Hz), 82.1, 61.7, 53.3, 51.9,
40.5, 29.6, 28.4, 27.8. HRMS (CIþNH3) calcd for C15H23NO7F3
[M þ Hþ]: 386.1427, found 386.1421.
Acknowledgment. We thank the French Ministry of
Research for a Ph.D. grant to T.B.N. We wish to thank
Patricia Gangnery for HRMS spectra.
(()-1-tert-Butyl 2,4-Dimethyl 2-(2,2,2-trifluoroacetamido)-
butane-1,2,4-tricarboxylate ((()-15b). To a solution of 13b
(69 mg, 0.18 mmol) in THF (1 mL) was added a solution of
SmI2 in THF (4.5 mL, 4.5 mmol) under argon. After color change
Supporting Information Available: 1H and 13C NMR spec-
tra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
620 J. Org. Chem. Vol. 75, No. 3, 2010