Asymmetric access to α-substituted functional aspartic acid derivatives by a [3+2] strategy employing a chiral dienophile

Article abstract of DOI:10.1002/ejoc.201301739

Enantiopure vinyl ethers of Stericol underwent diastereoselective thermal 1,3 dipolar cycloadditions with N-benzyl, N-benzhydryl, and N-PMB aspartate ester nitrones. Chemoselective N-debenzylation of the resulting cycloadducts afforded diastereomerically and enantiomerically pure crystalline NH-isoxazolidine, the absolute configuration of which was established by X-ray crystallography. N-Protection and N-O cleavage of this isoxazolidine gave enantioenriched quaternary aspartate derivatives bearing functionalized side chains.

Full text of DOI:10.1002/ejoc.201301739

Job/Unit: O31739
/KAP1
Date: 31-03-14 17:09:22
Pages: 10
FULL PAPER
DOI: 10.1002/ejoc.201301739
Asymmetric Access to α-Substituted Functional Aspartic Acid Derivatives by a
[3+2] Strategy Employing a Chiral Dienophile
Kawther Ben Ayed,[a,b] Anne Beauchard,[a] Jean-François Poisson,[c] Sandrine Py,[c]
Mathieu Y. Laurent,[a] Arnaud Martel,[a] Houcine Ammar,[b] Souhir Abid,[b] and
Gilles Dujardin*[a]
Keywords: Asymmetric synthesis / Cycloaddition / Amino acids / Heterocycles
Enantiopure vinyl ethers of Stericol® underwent diastereo- line NH-isoxazolidine, the absolute configuration of which
selective thermal 1,3 dipolar cycloadditions with N-benzyl,
was established by X-ray crystallography. N-Protection and
N-benzhydryl, and N-PMB aspartate ester nitrones. Chemo- N–O cleavage of this isoxazolidine gave enantioenriched
selective N-debenzylation of the resulting cycloadducts af-
forded diastereomerically and enantiomerically pure crystal-
quaternary aspartate derivatives bearing functionalized side
chains.
Introduction
substituted aspartic acid derivatives such as 2–4 (Figure 1)
is highly valuable.
Despite numerous studies, the asymmetric synthesis of α-
tertiary amines[1] and α,α-disubstituted α-amino acids
(DAAs)[2] still remains a challenge. These classes of com-
pounds have attracted growing interest due to their great
potential in the synthesis of biologically active molecules.
In addition to their ability to induce helix conformation
significantly when present in peptides,[3] their major appli-
cations are the inclusion of DAAs in peptidomimetics[4] and
their use in inhibitor design[5] or as building blocks for the
synthesis of natural products. Moreover, a particularly
interesting feature of this class of amino acids is the chemi-
Figure 1. Asymmetric synthesis of α-substituted aspartate esters:
the nitrone route.
We described in 2010[7] a route to racemic disubstituted
cal, enzymatic, and stereochemical stabilities conferred by aspartic derivatives 3b (RЈЈ = tBu, Pg = COCF3) and 4a
the quaternary C-center. Among compounds of this class, (Pg = Ac) through a strategy based on the selective func-
α-substituted aspartic acid derivatives of type 1 (Figure 1) tional group manipulation of quaternary-center-containing
display a very rich functionality that makes them of par- isoxazolidines 5 (RЈЈ = tBu, PgЈ = Bn), obtained by 1,3-
ticular interest for synthesis, especially when the α-substitu- dipolar cycloaddition involving “aspartic” ketonitrones 6
ent possesses an orthogonal functionality allowing subse- and vinyl ethers.[8] Therefore, an attractive objective was to
quent chemoselective transformations. For instance, a di- achieve an efficient enantioselective version of this synthetic
ester of type 2 (Pg = CO2Me), obtained from (S)-trypto- sequence, based on a key [3+2] cycloaddition that would
phan by stereoselective transformation and final degrad- be asymmetrically controlled by the use either of a chiral
ative oxidation, was fruitfully employed by Crich et al. as auxiliary borne by one cycloreactant or of an enantioselec-
a precursor of (R)-α-methyl aspartic acid.[6] Therefore, the tive catalytic pathway. We report here the preparation of the
development of new methods allowing selective access to α- enantioenriched acid (R)-2b (Pg = COCF3) through facial
and exo-selective [3+2] cycloaddition of nitrones of type 6
with chiral vinyl ethers as dipolarophiles.
[a] LUNAM Université du Maine, IMMM (MSO) UMR 6283
CNRS,
72085 Le Mans, France
E-mail: gilles.dujardin@univ-lemans.fr
Results and Discussion
http://immm.univ-lemans.fr
[b] Université de SFax, Laboratoire de Chimie Appliquée HCGP,
For this study, in addition to the already described N-
Sfax, Tunisie
benzyl aspartic nitrone 6a (Figure 1, PgЈ = Bn),[8] we also
[c] Département de Chimie Moléculaire (SERCO) UMR 5250,
ICMG FR-2607, CNRS-Université Joseph Fourier,
employed the N-benzhydryl and N-p-methoxybenzyl as-
partic nitrones 6b and 6c, conveniently prepared by ad-
dition of the corresponding hydroxylamines to dimethyl
BP 53, 38041 Grenoble Cedex 09, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301739.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1

Job/Unit: O31739
/KAP1
Date: 31-03-14 17:09:22
Pages: 10
G. Dujardin et al.
FULL PAPER
acetylenedicarboxylate (DMAD) (Scheme 1).[9] The two Table 1. Synthesis of O-vinyl-substituted Stericol® derivative 7b.
new aspartic nitrones were tested in order to evaluate alter-
native procedures for the N-deprotection of the isoxazolid-
ine ring after the [3+2] cycloaddition. The hydroxylamine
precursors of 6b and 6c were obtained as oxalate salts, each
in three steps from the corresponding amine.[10] Nitrone
6d[7] was also used in this study to measure the influence of
the C-substitution on the diastereocontrol of the cycload-
Entry Conditions
Yield
7b [%]
dition. The pure E geometry of the crystalline nitrone 6b
(m.p. 97–98 °C) was established by X-ray crystallography
(Figure 2). Importantly, in view of the analogies displayed
in the NMR spectroscopic data, this also confirms the as-
signment of pure E geometry to 6a and to the other N-
benzyl nitrones described previously.[7]
1
2
3
1) KH, ClHCCCl2; 2) nBuLi; H2, Pd/BaSO4
63
42
70
IrCl(cod)2, Na2CO3, toluene, 100 °C, 24 h[14]
AuClPPh3, AgOAc, ethyl vinyl ether, 50 °C,
20 h[15]
4
Pd(OAc)2, DDP, butyl vinyl ether, NEt3,
93
75 °C, 24 h[16]
The nitrones 6a–d and chiral dipolarophiles 7a and 7b
were then subjected to thermal 1,3-DC cycloaddition condi-
tions (toluene, 125 °C, 48 h, Table 2). With N-benzyl
nitrone 6a, cycloadditions occurred in high yields with vinyl
ether 7a in a 86:14 trans selectivity (Table 2, Entry 1), lower
than that previously obtained with ethyl vinyl ether (92:8).[8]
Replacing vinyl ether 7a, originating from 1-phenylethanol
(Table 2, Entry 1), with vinyl ether 7b, derived from Ste-
ricol,® allowed for a noticeable increase in the facial selec-
tivity, from 75:25 up to 90:10 (Table 2, Entries 2–3), as well
as a slight increase in trans selectivity (90:10). As expected,
similar selectivities were observed when N-PMB nitrone 6c
was employed (Table 2, Entry 5). The reaction between the
bulkier N-DPM nitrone 6b and 7b (Table 2, Entry 4) pro-
vided slightly better trans diastereocontrol (95:5 instead of
90:10) but with a simultaneous decrease in facial control
(81:19 instead of 90:10). Suppressing the ester functionality
on the side chain of the nitrone (Entry 6, with alanine-
based nitrone 6d,[7] vs. Entry 2, with aspartic-based nitrone
6a) had a negative influence on both yield and diastereo-
selectivities. For adducts 5a–e, isolation of the major trans
diastereomers as pure products by simple chromatography
on silica gel was found to be impossible. However the
(2ЈR,5S,3R) configuration could later be assigned to the
Scheme 1. Preparation of nitrones 6b and 6c.
Figure 2. X-ray structure of nitrone 6b.
In our previous report, thermal 1,3-dipolar cycload- major isomer of 5b obtained from O-vinyl-substituted Ste-
ditions (1,3-DCs) between nitrone 6a and vinyl ethers de- ricol® derivative (R)-7b (Table 2, Entry 2), after correlation
rived from (–)-menthol, d-(–)-pantolactone, and (R)-methyl deduced from further transformations (vide infra).
mandelate were found to proceed in high yields but with
To obtain the targeted DAA derivatives 2–4 from ad-
low diastereoselectivities.[8] This study was extended to chi- ducts of type 5, the sequence involving N-debenzylation and
ral benzyl vinyl ethers 7a,[11] originating from (R)-1-phen- subsequent N-acylation prior to the removal of the chiral
ylethanol, and 7b, derived from (R)- or (S)-1-(2,4,6-triiso- auxiliary was investigated. Chemoselective N-debenzylation
propylphenyl)ethanol[12] (Stericol®). For the preparation of by Pd/C-catalyzed hydrogenolysis in methanol with formic
O-vinyl ethers 7b, the previously employed two-step method acid as hydrogen source[17] was planned, although applica-
involving the formation of a dichlorovinyl ether[13] (Table 1, tion of these conditions to adducts 5b–e was challenging,
Entry 1) was compared with direct O-vinylation procedures. due to the known sensitivity of the Stericol ethers in acidic
Whereas Ishii’s method[14] employing an IrI catalyst medium.[18] However, to our delight, applying these condi-
(Table 1, Entry 2) gave disappointing results in our hands, tions to the crude cycloadduct 5b led to the desired N-de-
methods employing AuI/AgI[15] or PdII[16] catalysis (Table 1, benzylated isoxazolidine 8 as the major product (Scheme 2).
Entries 3 and 4) were found to improve the yield. The gold- In addition, the major isomer of (+)-8 could be obtained as
catalyzed method proved particularly efficient, producing a white solid (m.p. 182 °C) with a very high diastereomeric
vinyl ether 7b in a high state of purity.
purity after silica gel chromatography and recrystallization,
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31739
/KAP1
Date: 31-03-14 17:09:22
Pages: 10
α-Substituted Functional Aspartic Acid Derivatives
Table 2. 1,3-DC reactions involving chiral benzyl enol ethers 7.[a]
afford the isoxazolidinone 8 are clearly the consequence of
the sensitivity of the Stericol ether moiety under the acidic
conditions used. This prompted us to investigate the exten-
sion of the sequence to the N-PMB nitrone 6c (Table 2, En-
try 5), because it was expected that 6c would allow access
to 8 from an adduct that could be N-deprotected under
non-acidic conditions. Unfortunately, all attempts to re-
move the PMB group from isoxazolidine 5e under oxidative
conditions (DDQ, CAN, NBS) led to oxidative degradation
of the isoxazolidine ring.
Isoxazolidines (+)-8 and (–)-(8) could thus be obtained in
high diastereopurity by starting from (R)- or (S)-Stericol®
(equally available) via the cycloadducts 5b (or 5c) and ent-
5b, respectively. The high levels of enantiopurity of 8 were
unambiguously established by chiral HPLC [Ͼ98% ee, de-
termined on (–)-8]. The relative configuration (2ЈR,5S,3R)
of the diastereomerically pure isoxazolidine (+)-8 could be
established by X-ray crystallography (Figure 3). The same
configuration thus assigned to the major isomer of the ad-
duct 5b is consistent with an exo approach from the Si face
of the E nitrone, as depicted in Figure 4.
Entry Nitrone Chiral
Adduct Yield
5
trans:
cis
dr
[d]
vinyl
ether
[%][b]
(trans)[d]
1
2
3
4
5
6
6a
6a
6a
6b
6c
6d
(R)-7a
(R)-7b
(S)-7b
(S)-7b
(R)-7b
(S)-7b
5a
Ͼ 95/88
Ͼ 95/–[c]
Ͼ 95/–[c]
Ͼ 95/83
–/40
86:14
90:10
90:10
95:5
88:12
85:15
75:25
90:10
90:10
81:19
88:12
72:28
5b
ent-5b
ent-5c
5d
ent-5e
–/62
[a] 1.0 equiv. of 6 and 7, 1 mL of toluene mmol–1. Only the major
diastereoisomer is depicted. [b] Conversion into adduct from crude
product/yield of adduct after silica gel chromatography. [c] No
1
chromatographic purification. [d] Determined by H NMR analy-
sis.
in 50% overall yield (two steps) from starting compounds
6a and (R)-7b. Applying the same procedure to the crude
N-benzhydryl adduct 5c again led mainly to the desired
product (+)-8 (Scheme 2). However, in this case the hydroly-
Figure 3. X-ray structure of (+)-8.
Pure isoxazolidine (–)-(8) was next subjected to N-acetyl-
sis of the acetal moiety during hydrogenolysis proved to be ation, leading to 9 in quantitative yields (Scheme 3). All
significantly more important (Stericol was isolated from the attempts to obtain the amidoaldehyde 4a directly from 9 by
[7]
reaction mixture in 35% yield) than in the N-benzyl series treatment with Mo(CO)6 or SmI2 failed. Removal of the
(20%). N-Deprotected product (+)-8 was obtained after sil- chiral auxiliary could be achieved by acidic cleavage (TFA,
ica gel chromatography in 45% overall yield from starting CH2Cl2), leading to the 5-hydroxyisoxazolidine 10 as a mix-
compounds 6b and (R)-7b (dr: 98:2). The moderate yields ture of C-5 epimers in 81% yield for the two steps and in
obtained for the N-deprotection of adducts 5b and 5c to 30% overall yield from (S)-Stericol® (five steps). Oxidation
Scheme 2. Synthesis of (+)-8.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O31739
/KAP1
Date: 31-03-14 17:09:22
Pages: 10
G. Dujardin et al.
FULL PAPER
Figure 4. Favored approach in the formation of 5b.
of hydroxyisoxazoline 10 under Pinnick conditions[19]
failed, but treatment with TPAP/NMO led to the isoxazol-
idinone (–)-11, a direct precursor of the α-substituted as-
partic acid (S)-2a, in 41% unoptimized yield.
Scheme 4. Synthesis of α-substituted aspartic derivatives (S)-2b.
Conclusions
We report here the first example of high facial selectivity
induced by a chiral vinyl ether as a dipolarophile in [3+2]
cycloaddition reactions involving nitrones as dipoles and
proceeding through an exo approach of the dipolarophile.
This result was achieved thanks to the fixed E geometry of
the α-carboxy ketonitrones and to the strong ability of the
Stericol chiral auxiliary to induce facial recognition. It al-
lowed the preparations of the enantiopure highly functional
α,α-disubstituted amino ester 2b and of valuable cyclic de-
rivatives. The crystalline isoxazolidine 8 acts as a pivotal
intermediate to access different α,α-disubstituted amino
acid derivatives in enantiopure and diastereopure forms. In
addition, N-acyl-5-hydroxyisoxazolidine 10 is a masked
form of a stable N-protected β-aminoaldehyde.[19] To the
best of our knowledge, no N-acyl-5-hydroxyisoxazolidine
bearing a quaternary center has been reported to date, de-
spite their great synthetic potential as α,α-disubstituted α-
amino acid precursors.
Scheme 3. Synthesis of α-substituted aspartic derivatives (S)-2a, 10,
and 11.
In a previous report we had also disclosed another origi-
nal route to acids of type 2, based on the nonclassical SmI2-
mediated ring-opening reaction of an isoxazolidine system
with trifluoroacetyl N-protection.[7] Therefore, we were very
interested in applying this unusual pathway to an enantio-
pure substrate with the aim of delivering an analogue of
(S)-2a with a more labile N-protecting group (Scheme 4).
N-Trifluoroacetylation of (–)-8 proceeded in excellent yield.
Subsequent treatment of (–)-12 with Mo(CO)6 led only to
degradation products, but treatment with SmI2 in THF
pleasingly afforded (–)-3a in good yield. Final acid-medi-
ated removal of the chiral auxiliary by treatment of ester
(–)-3a with TFA led to the pure N-trifluoroacetyl amino
acid (–)-2b in 95% yield.
Experimental Section
(E)-N-(1,4-Dimethoxy-1,4-dioxobut-2-ylidene)diphenylmethan-
amine Oxide (6b): A solution of dimethyl acetylenedicarboxylate
(0.21 g, 1.49 mmol) in methanol (5 mL) was added dropwise at 0 °C
to a suspension of 1-phenylbenzylhydroxylamine dioxalate salt
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31739
/KAP1
Date: 31-03-14 17:09:22
Pages: 10
α-Substituted Functional Aspartic Acid Derivatives
(0.5 g, 1.49 mmol) and NaOAc·3H2O (0.3 g, 2.23 mmol) in meth-
anol (5 mL). After stirring at room temp. for 20 h, the resulting
mixture was concentrated. The residue was dissolved in CH2Cl2
(20 mL), washed twice with water, dried with MgSO4, and filtered,
and the solvents were evaporated. Purification of this material by
column chromatography on silica gel (cyclohexane/AcOEt 9:1) af-
forded nitrone 6b (0.38 g, 75 %), Rf = 0.45 (cyclohexane/AcOEt
70:30), as a white powder (m.p. 97–98 °C). 1H NMR (400 MHz,
CDCl3): δ = 8.30 (s, 1 H), 7.31–7.36 (m, 10 H), 3.84 (s, 3 H), 3.79
(s, 2 H), 3.68 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
168.5, 162.0, 137.0, 135.6, 129.0, 128.4, 128.3, 77.2, 52.9, 52.2,
in anhydrous THF (55 mL). The solution was allowed to warm to
–40 °C and stirred for 10 min, and then saturated aqueous
NaHCO3 (6 mL) and water (6 mL) were added. The solution was
allowed to warm to 0 °C. Pyridine (30 mL) was then added, and
the mixture was hydrogenated (1 atm) over palladium (10% w/w on
BaSO4, 960 mg) at room temperature until IR showed no starting
material remaining (triple bond, ca. 2260 cm–1, 1.5 h). The reaction
mixture was filtered through Celite®, and water was added. The
product was extracted with Et2O, and the combined organic layers
were successively washed with CuSO4(aq), water, and brine, dried
with anhydrous Na2SO4 and filtered, and the filtrate was concen-
trated under vacuum. The residue was purified by flash chromatog-
raphy on silica gel (pretreated with Et3N, 2.5%, v/v, eluent pentane,
100%) to afford vinyl ether (S)-7b (3.2 g, 81%) as a colorless oil.
34.8 ppm. IR (neat): ν = 3021, 2949, 2930, 1732, 1702, 1510, 1434,
˜
1313, 1187, 1118 cm–1. HRMS (CI+, NH3): calcd. for C19H20NO5
[M + H]+ 342.1341; found 342.1336.
Method (b) – From (R)- or (S)-Stericol® by Use of [IrClcod]2: (Chlo-
rocycloocta-1,5-diene)iridium ([IrClcod]2, 0.01 mmol), sodium
carbonate (6 mmol), Stericol (10 mmol), and vinyl acetate
(20 mmol) in toluene (10 mL) were placed in a 100 mL flask
equipped with a condenser. The reaction mixture was maintained
at 100 °C with magnetic stirring and under argon for 24 h. After
the mixture had cooled to room temperature, diethyl ether (2 mL)
was added. The mixture was then filtered through silica and con-
centrated in vacuo to furnish the crude vinyl ether as a colorless
oil.
1,4-Dimethoxy-N-[(4-methoxyphenyl)methyl]-1,4-dioxobutanimine
Oxide (6c): A solution of dimethyl acetylenedicarboxylate (1.42 g,
10 mmol) in methanol (15 mL) was added dropwise at 0 °C to a
suspension of 1-phenylbenzylhydroxylamine dioxalate salt (2.29 g,
10 mmol) and NaOAc·3 H2O (2.44 g, 30 mmol) in methanol
(15 mL). After the end of the addition (1 h 30), the resulting mix-
ture was concentrated. The residue was dissolved in CH2Cl2
(20 mL), washed three times with water, dried with MgSO4, and
filtered, and the solvents were evaporated. Purification of this ma-
terial by column chromatography on silica gel (cyclohexane/AcOEt
9:1) afforded nitrone 6c (1.37 g, 50%). Rf = 0.15 (cyclohexane/Ac-
OEt 70:30, UV). 1H NMR (400 MHz, CDCl3): δ = 7.44 (d, J =
8.0 Hz, 2 H), 6.87 (d, J = 8.0 Hz, 2 H), 5.72 (s, 2 H), 3.84 (s, 3 H),
3.80 (s, 3 H), 3.75 (s, 2 H), 3.67 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 168.5, 161.9, 159.9, 134.3, 130.5, 125.9, 113.9, 67.1,
Method (c) – From (R)- or (S)-Stericol® by Use of Au/Ag: Ethyl
vinyl ether (7.4 mL, 10 equiv.) was added under argon to a screw
cap tube containing AuClPPh3 (69 mg, 2 mol-%) and AgOAc
(23 mg, 2 mol-%). The mixture was stirred at room temp. for
10 min. After addition of (R)- or (S)-Stericol® (1.75 g, 10 mmol),
the mixture was stirred at 50 °C for 16 h, then allowed to cool to
room temp., diluted with AcOEt (20 mL), and filtered through ce-
lite. The solvent was removed under vacuum. Purification by col-
umn chromatography on silica gel (pentane/diethyl ether 95:5), Rf
= 0.75 (pentane/diethyl ether 80:20), afforded the vinyl ether (R)-
(+)- or (S)-(–)-7b (1.46 g, 70%) as a transparent oil, as well as start-
ing alcohol in a second fraction.
55.3, 52.9, 52.2, 34.4 ppm. IR (neat): ν = 1740, 1612, 1033 cm–1.
˜
HRMS (CI+, NH3): calcd. for C14H17NO6 296.1134; found
296.1139.
(R)- and (S)-O-Vinyl-1-(2,4,6-triisopropylphenyl)ethanol (7b)
Method (a): An argon-flushed flask was charged with potassium
hydride (30% suspension in mineral oil, 14.3 g, 107 mmol). The
mineral oil was removed by washing with pentane (3 portions of
ca. 10 mL), and anhydrous THF (60 mL) was then added. A solu-
tion of (S)-1-(2,4,6-triisopropylphenyl)ethanol (Stericol®) (12.0 g,
48.3 mmol) in anhydrous THF (40 mL) was added dropwise at
0 °C. The mixture was stirred at room temperature for 2 h, cooled
to –50 °C, and treated dropwise with a solution of trichloroethylene
(4.8 mL, 53 mmol) in anhydrous THF (20 mL). The reaction mix-
ture was allowed to warm to 0 °C and stirred until TLC (eluent
pentane) showed complete disappearance of starting material. The
mixture was then carefully treated with methanol (6 mL) and water
(12 mL). The crude product was extracted with pentane in the us-
ual way, and the combined extracts were washed with water, dried
with Na2SO4, and concentrated under vacuum at 0 °C. The residue
was purified by flash chromatography on silica gel (pretreated with
triethylamine 2.5%, v/v, eluent pentane) to afford the dichloroenol
ether (13.0 g, 79%) as a white solid: m.p. 38–41 °C. [α]2D0 = –16.2 (c
= 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.05 (s, 2 H),
6.00 (q, J = 6.9 Hz, 1 H), 5.60 (s, 1 H), 3.75–3.15 (br. s, 2 H), 2.90
(sept, J = 6.9 Hz, 1 H), 1.70 (d, J = 6.9 Hz, 3 H), 1.35–1.20 (m, 18
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.5, 142.9, 131.2,
122.1, 98.3, 76.4, 34.1, 29.4, 24.7, 24.5, 23.9, 20.3 ppm. IR (film):
Method (d) – From (R)- or (S)-Stericol® by Use of Pd(OAc)2: Palla-
dium acetate (30.3 mg, 0.135 mmol) and 4,7-diphenylphenanthrol-
ine (44.8 mg, 0.135 mmol) were dissolved in butyl vinyl ether
(27.5 g, 101.8 mmol). After the addition of (R)- or (S)-Stericol
(672 mg, 2.7 mmol) and triethylamine (0.8 mL, 0.2 mmol), the mix-
ture was stirred at 75 °C for 24 h, then allowed to cooled to room
temperature, and filtered through activated charcoal. The solvent
was removed under vacuum. Purification by column chromatog-
raphy on silica gel (pentane/diethyl ether 95:5), Rf = 0.28 (pentane/
diethyl ether 95:5), afforded the vinyl ether (R)-(+)- or (S)-(–)-7b
(0.68 g, 93%) as a transparent oil. For (R)-(+)-7b: [α]2D0 = +22.2 (c
= 1.16, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.00 (s, 2 H),
6.27 (dd, J = 14, 6.5 Hz, 1 H), 5.45 (q, J = 6.8 Hz, 1 H), 4.28 (dd,
J = 14, 1.4 Hz, 1 H), 3.92 (dd, J = 6.5, 1.4 Hz, 1 H), 3.60–3.36 (m,
2 H), 2.90–2.80 (m, 1 H), 1.62 (d, J = 6.8 Hz, 3 H), 1.30–1.20 (m,
18 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.0, 146.7, 134.9,
121.0, 87.5, 73.1, 33.0, 27.9, 23.6, 23.5, 22.9, 21.4 ppm. IR (NaCl):
ν = 2961, 2932, 2869, 1633, 1608, 1460, 1383, 1191, 1079 cm–1. For
˜
(S)-(–)-7b: [α]2D0 = –22.7 (c = 1.15, CHCl3). All attempts to deter-
mine ee by chiral GC or HPLC failed, due to our inability to sepa-
rate the enantiomers from the racemic vinyl ether (Ϯ)-(7b), what-
ever the chromatographic conditions used.
ν = 3086, 1623, 1609, 1078, 1040 cm–1. MS (EI+): m/z = 343 and
˜
341 [M]+, 248, 231 (100). C19H28Cl2O: C 66.47, H 8.22; found C
66.63, H 8.36.
nBuLi (2.5 m in hexanes, 12.8 mL, 32.1 mmol) was added dropwise
General Procedure for Cycloaddition Between Nitrones 6 and Di-
at –78 °C to a solution of the dichloroenol ether (5.0 g, 14.6 mmol)
polarophiles 7: A dipolarophile 7 was added under argon to a sealed
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O31739
/KAP1
Date: 31-03-14 17:09:22
Pages: 10
G. Dujardin et al.
FULL PAPER
tube containing toluene and a nitrone 6. The mixture was stirred
at 125 °C for 48 h and then allowed to cool to room temp. The
reaction mixture was then concentrated under vacuum to remove
toluene.
J = 6.2, 3.7 Hz, 1 H) ppm. IR (NaCl): ν = 2959, 2869, 1743, 1607,
˜
1572, 1497, 1456, 1437, 1361, 1241, 1208, 1099, 1079, 1008, 969,
942, 733, 698 cm–1. HRMS (CI+, NH3): calcd. for C32H46NO6 [M
+ H]+ 540.3325; found 540.3344.
Methyl (3R,5S)-2-Benzyl-3-(2-methoxy-2-oxoethyl)-5-[(R)-1-phenyl-
ethoxy]isoxazolidine-3-carboxylate (5a): This compound was pre-
pared from 6a (40 mg, 0.15 mmol) and (R)-7a (44.4 mg, 0.34 mmol)
in toluene (0.5 mL); purification by flash chromatography (cyclo-
hexane/AcOEt 85:15) afforded the title compound as a colorless oil
(51 mg, 88 %). Rf = 0.15 (cyclohexane/AcOEt 90:10). Dia-
stereomeric ratio: 64.5:21.5:10:4. Major adduct: 1H NMR
(400 MHz, CDCl3): δ = 7.44–7.19 (m, 10 H), 5.04 (dd, J = 6.3,
2.8 Hz, 1 H), 4.60 (q, J = 6.5 Hz, 1 H), 4.08 (d, J = 14.8 Hz, 1 H),
3.74 (s, 3 H), 3.67 (s, 3 H), 3.66 (m, 1 H), 3.29 (dd, J = 13.6, 6.4 Hz,
1 H), 3.14 (d, J = 16.7 Hz, 1 H), 2.81 (d, J = 16.7 Hz, 1 H), 2.28
(dd, J = 13.6, 2.8 Hz, 1 H), 1.36 (d, J = 6.5 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.9, 170.8, 143.2, 137.7, 128.5–
126.3, 98.4, 74.9, 70.4, 55.5, 52.2, 51.9, 45.9, 39.6, 24.2 ppm. Some
characteristic NMR signals of the minor trans adduct: 1H NMR
(400 MHz, CDCl3): δ = 5.42 (dd, J = 6.3, 2.9 Hz, 1 H), 4.67 (q, J
= 6.4 Hz, 1 H), 3.97 (d, J = 14.5 Hz, 1 H), 3.80 (s, 3 H), 3.66 (s, 3
H), 3.56 (d, J = 14.6 Hz, 1 H), 3.41 (dd, J = 13.6, 6.4 Hz, 1 H),
3.08 (d, J = 16.7 Hz, 1 H), 2.74 (d, J = 16.7 Hz, 1 H), 2.30 (dd, J
= 13.6, 3 Hz, 1 H), 1.39 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.3, 169.9, 143.5, 137.4, 125.4, 99, 74.7,
70.5, 55.8, 52.8, 46.2, 39.5, 21.1 ppm. Some characteristic NMR
Methyl (3S,5R)-2-Benzyl-3-(2-methoxy-2-oxoethyl)-5-[(S)-1-(2,4,6-
triisopropylphenyl)ethoxy]isoxazolidine-3-carboxylate (ent-5b): This
adduct was obtained by the same procedure as used for 5b, starting
from (S)-(–)-7b.
Methyl (3S,5R)-2-Benzhydryl-3-(2-methoxy-2-oxoethyl)-5-[(S)-1-
(2,4,6-triisopropylphenyl)ethoxy]isoxazolidine-3-carboxylate (ent-
5c): This compound was prepared from 6b (51 mg, 0.15 mmol) and
(S)-(–)-7b (86 mg, 0.31 mmol) in toluene (0.5 mL); purification by
flash chromatography (cyclohexane/Et2O 85:15) afforded the title
compound as a colorless oil (72 mg, 83%). Rf = 0.55 (cyclohexane/
Et2O 80:20). Diastereomeric ratio: 77:18:5:0. Major adduct 1H
NMR: (400 MHz, CDCl3): δ = 7.58–6.82 (m, 12 H), 5.13 (q, J =
6.9 Hz, 1 H), 4.91 (s, 1 H), 4.83 (dd, J = 6.4, 2.6 Hz, 1 H), 3.88–
3.78 (m, 1 H), 3.60 (s, 3 H), 3.53 (s, 3 H), 3.24 (dd, J = 13.5, 6.4 Hz,
1 H), 2.87–2.76 (m, 1 H), 2.55 (d, J = 16.7 Hz, 1 H), 2.52–2.44 (m,
1 H), 2.37 (d, J = 16.8 Hz, 1 H), 2.25 (dd, J = 13.5, 2.6 Hz, 1 H),
1.61 (d, J = 6.9 Hz, 3 H), 1.33–0.80 (m, 18 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.0, 170.8, 147.5, 143.2, 140.5, 132.1,
128.6, 128.2, 127.9, 127.3, 126.7, 123, 120.5, 96.4, 70.7, 51.9, 51.8,
47.1, 40.9, 30.1–28.3, 23.9, 24.8–24.1, 23.8 ppm. Some characteris-
1
tic NMR signals of the minor trans adduct: H NMR (400 MHz,
1
CDCl3): δ = 5.40 (dd, J = 6.5, 3.2 Hz, 1 H), 5.13 (q, J = 6.9 Hz, 1
H), 4.86 (s, 1 H), 3.58 (s, 3 H), 3.54 (s, 3 H), 3.37 (dd, J = 13.5,
6.5 Hz, 1 H), 2.32 (dd, J = 13.5, 3.2 Hz, 1 H), 1.46 (d, J = 6.8 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.8, 169.7, 148.6,
147.6, 146.9, 141.6, 140.9, 134.9, 99.1, 71.1, 52.1, 51.6, 47.4, 40.6,
34.1, 22.5 ppm. Some characteristic NMR signals of the minor cis I
adduct: 1H NMR (400 MHz, CDCl3): δ = 5.53 (q, J = 6.8 Hz, 1
H), 5.33 (s, 1 H), 4.78 (dd, J = 6.5, 3.3 Hz, 1 H), 4.65 (q, J =
5.2 Hz, 1 H), 2.49 (d, J = 6.6, Hz, 1 H), 3.65 (s, 3 H), 1.50 (d, J =
signals of the minor cis I adduct: H NMR (400 MHz, CDCl3): δ
= 4.96 (dd, J = 6.5, 3.5 Hz, 1 H), 4.34 (d, J = 14 Hz, 1 H), 3.69 (s,
3 H), 3.63 (s, 3 H), 2.75 (d, J = 16.2 Hz, 1 H), 2.60 (dd, J = 14.2,
6.5 Hz, 1 H), 1.50 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 137.8, 75.2, 25.2 ppm. Some characteristic NMR sig-
1
nals of the minor cis II adduct: H NMR (400 MHz, CDCl3): δ =
5.35 (dd, J = 6.6, 3.6 Hz, 1 H), 4.16 (d, J = 14 Hz, 1 H) ppm. IR
(NaCl): ν = 2956, 2923, 2851, 1729, 1643, 1454, 1204 cm–1. HRMS
˜
(CI+, NH3): calcd. for C23H27NO6 [M + H]+ 414.1917; found
414.1913.
6.9 Hz, 1 H) ppm. IR (NaCl): ν = 2958, 2924, 2851, 1741, 1607,
˜
1493, 1455, 1437, 1361, 1205, 1166, 1100, 1079, 997, 972, 742,
705 cm–1. HRMS (CI+, NH3): calcd. for C38H49NO6 [M + H]+
616.3639; found 616.3638.
Methyl (3R,5S)-2-Benzyl-3-(2-methoxy-2-oxoethyl)-5-[(R)-1-(2,4,6-
triisopropylphenyl)ethoxy]isoxazolidine-3-carboxylate (5b): Adduct
5b was obtained from 6a (795 mg, 3 mmol) and (R)-(+)-7b (822 mg,
3 mmol) in toluene (5 mL); the crude adduct was used in the next
step without further purification. Diastereomeric ratio: 81:9:8:2.
Methyl (3R,5S)-2-(4-Methoxybenzyl)-3-(2-methoxy-2-oxoethyl)-5-
[(R)-1-(2,4,6-triisopropylphenyl)ethoxy]isoxazolidine-3-carboxylate
Major adduct: 1H NMR (400 MHz, CDCl3): δ = 7.52–6.87 (m, 7 (5d): This compound was prepared from 6c (112.4 mg, 0.38 mmol)
H), 5.13 (q, J = 7 Hz, 1 H), 4.96 (dd, J = 6.1, 2.2 Hz, 1 H), 4.07
(d, J = 14.5 Hz, 1 H), 3.84–3.75 (m, 2 H), 3.75 (s, 3 H), 3.69 (s, 3
H), 3.62 (d, J = 14.4 Hz, 1 H), 3.27 (dd, J = 13.5, 6.3 Hz, 1 H, 1
H), 3.16 (d, J = 16.8 Hz, 1 H), 2.85 (d, J = 16.9 Hz, 1 H), 2.83 (m,
1 H), 2.23 (dd, J = 13.5, 2.4 Hz, 1 H), 1.44 (d, J = 7 Hz, 3 H),
and (R)-(+)-7b (104.5 mg, 0.38 mmol) in toluene (3.5 mL); purifica-
tion by flash chromatography (cyclohexane/AcOEt 90:10), Rf =
0.21 (cyclohexane/AcOEt 80:20), afforded the title compound
(87.3 mg, 40%). Diastereomeric ratio: 77:11:10:2. Major adduct 1H
NMR: (400 MHz, CDCl3): δ = 7.33 (d, J = 8.6 Hz, 2 H), 7.05–6.95
1.31–1.01 (m, 18 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.0, (m, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 5.13 (q, J = 6.8 Hz, 1 H), 4.96
170.9, 147.4, 138, 132.5, 128.4–127, 123.1, 120.5, 97.9, 70.2, 55.7,
52.1, 51.9, 46, 39.8, 34.0, 31.0, 29.7, 24.4–23.9, 22.8, 21.2 ppm.
Some characteristic NMR signals of the minor trans adduct: 1H
NMR (400 MHz, CDCl3): δ = 5.48 (dd, J = 6.3, 3.1 Hz, 1 H), 5.18
(q, J = 6.6 Hz, 1 H), 4.34 (d, J = 14 Hz, 1 H), 3.80 (s, 3 H), 3.67
(s, 3 H), 3.42 (dd, J = 13.5, 6.3 Hz, 1 H), 3.14 (d, J = 16.1 Hz, 1
H), 3.01 (d, J = 16.8 Hz, 1 H), 2.60 (d, J = 16.9 Hz, 1 H), 1.47 (d,
J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 129.0,
125.3, 69.5, 52.7, 23.9 ppm. Some characteristic NMR signals of
the minor cis I adduct: 1H NMR (400 MHz, CDCl3): δ = 4.91 (dd,
J = 6.5, 3.2 Hz, 1 H), 4.05 (d, J = 13.7 Hz, 1 H), 3.83 (s, 3 H), 3.67
(s, 3 H), 2.54 (dd, J = 13.8, 7.1 Hz, 1 H), 2.24 (d, J = 13.6 Hz, 1 H),
1.48 (d, J = 6.9 Hz, 3 H) ppm. Some characteristic NMR signals of
the minor cis II adduct: 1H NMR (400 MHz, CDCl3): δ = 5.40 (dd,
(dd, J = 2.5, 6.4 Hz, 1 H), 3.99 (d, J = 14.2 Hz, 1 H), 3.90–3.70
(m, 1 H), 3.82 (s, 3 H), 3.74 (s, 3 H), 3.68 (s, 3 H), 3.57 (d, J =
14.2 Hz, 1 H), 3.25 (dd, J = 6.4, 13.7 Hz, 1 H), 3.15 (d, J = 16.6 Hz,
1 H), 2.83 (d, J = 16.6 Hz, 1 H), 2.83 (m, 2 H), 2.21 (dd, J = 2.4,
13.7 Hz, 1 H), 1.44 (d, J = 6.8 Hz, 3 H), 1.22 (d, J = 7.1 Hz, 6 H),
1.0–1.2 (m, 12 H) ppm. Characteristic NMR signals of the minor
adducts (H-5 proton); minor trans adduct: 5.40 (dd, J = 4.2, 6.6 Hz,
1 H); major cis adduct: 4.91 (dd, 1 H, J = 3.2, 6.4 Hz); minor cis
adduct: 5.49 (dd, J = 3.2, 6.3 Hz, 1 H). 13C NMR (100 MHz,
CDCl3): δ = 171.1, 170.9, 158.7, 147.4, 132.5, 130.1, 129.4, 123.0,
120.5, 113.4, 97.2, 70.2, 69.4, 55.3, 52.1, 51.9, 46.0, 39.8, 34.0, 28.9,
28.4, 24.5, 24.1, 23.9, 22.9 ppm. IR (NaCl): ν = 1739, 1616,
˜
1078 cm–1. HRMS (CI+, NH3): calcd. for C33H47NO7 [M + H]+
570.3431; found 570.3406.
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31739
/KAP1
Date: 31-03-14 17:09:22
Pages: 10
α-Substituted Functional Aspartic Acid Derivatives
Methyl (3S,5R)-2-Benzyl-3-methyl-5-[(S)-1-(2,4,6-triisopropylphen-
yl)ethoxy]isoxazolidine-3-carboxylate (ent-5e): This compound was
prepared from 6d (80.7 mg, 0.39 mmol) and (S)-(–)-7b (107 mg,
0.39 mmol) in toluene (0.5 mL); purification by flash chromatog-
raphy (cyclohexane/AcOEt 95:5) afforded the title compound as a
colorless oil (116 mg, 62%). Rf = 0.53 (cyclohexane/AcOEt 80:20).
Diastereomeric ratio: 61:24:9:5. Major adduct: 1H NMR
respectively] as a yellow oil (240 mg, Ͼ95%) that was used in the
next step without further purification. 1H NMR (400 MHz,
CDCl3): δ = 7.05–6.97 (m, 2 H), 5.42 (q, J = 6.9 Hz, 1 H), 5.17 (d,
J = 4.8 Hz, 1 H), 3.73 (s, 3 H), 3.71 (s, 3 H), 3.80–3.65 (m, 1 H),
3.65 (d, J = 16.1 Hz, 1 H), 3.25–3.12 (m, 1 H), 3.1 (d, J = 13.5 Hz,
1 H), 2.98 (d, J = 16.1 Hz, 1 H), 2.90–2.74 (m, 2 H), 2.16 (s, 3 H),
1.58 (d, J = 6.9 Hz, 3 H), 1.28–1.08 (m, 18 H) ppm. 13C NMR
(400 MHz, CDCl3): δ = 7.49–7.22 (m, 5 H), 7.13–6.88 (m, 2 H), (100 MHz, CDCl3): δ = 170.9, 170.7, 167.5, 148.3, 131.0, 123.5,
5.18 (q, J = 6.7 Hz, 1 H), 4.96 (dd, J = 6.2, 3.0 Hz, 1 H, 1 H), 4.19
(d, J = 14.5 Hz, 1 H), 3.86 (d, J = 14.3 Hz, 1 H), 3.71 (s, 3 H),
3.05 (dd, J = 13.2, 6.3 Hz, 1 H), 2.95–2.78 (m, 3 H), 2.16 (dd, J =
120.8, 99.2, 70.7, 65.2, 53.0, 51.7, 45.1, 44.5, 38.0, 34.0, 29.7, 29.3,
26.9, 26.4, 24.3, 23.9, 22.9, 21.5, 20.7 ppm. IR (NaCl): ν = 2988,
˜
2939, 2869, 1642, 1466, 1443, 1374, 1273, 1208, 1104, 1059, 987,
13.1, 3.1 Hz, 1 H), 1.51 (s, 3 H), 1.47 (d, J = 6.9 Hz, 3 H), 1.27– 858, 766, 696 cm–1. HRMS (Cl+NH3CH4): calcd. for C27H42NO7
0.92 (m, 18 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.1,
147.4, 138.6, 132.7, 128.5, 128.2, 128.0, 127.9, 126.8, 123.1, 120.5,
99.1, 70.0, 55.9, 52, 46.7, 34, 29.2, 28.9, 28.4, 26.9, 24.8, 24.5, 24.1,
23.9, 22.9, 20.1 ppm. Some characteristic NMR signals of the
[M + H]+ 492.2961; found 492.2947. For (+)-9: [α]2D5 = +63.2 (c =
0.275, CH2Cl2).
Methyl (3S)-2-Acetyl-5-hydroxy-3-(2-methoxy-2-oxoethyl)isoxazol-
idine-3-carboxylate (10): Isoxazolidine (–)-9 (0.127 g 0.26 mmol)
was dissolved in dichloromethane (6 mL). Trifluoroacetic acid
(350 μL, 0.52 g, 4.6 mmol) was added, and the mixture was stirred
overnight. Water (1 mL) was added. After a few minutes, the mix-
ture was diluted with dichloromethane and treated with a saturated
solution of NaHCO3. The aqueous phase was extracted twice with
dichloromethane. The organic phase was then dried with MgSO4
and concentrated under reduced pressure to give a residue that was
purified by chromatography on silica gel (cyclohexane/AcOEt 9:1,
then pure AcOEt) to give 10 (54.5 mg, 0.21 mmol, 81%) as a color-
1
minor trans adduct: H NMR (400 MHz, CDCl3): δ = 4.88 (dd, J
= 6.2, 2.8 Hz, 1 H), 4.24 (d, J = 14 Hz, 1 H), 3.76 (s, 3 H), 2.31
(dd, J = 13.3, 6.3 Hz, 1 H), 1.47 (d, J = 6.9 Hz, 3 H), 1.39 (s, 3
H) ppm. 13C NMR (100 MHz CDCl3): δ = 172.7, 172.5, 132.5,
126.4, 97.8, 69.4, 55.7, 52.4, 47.3, 34.1, 22.7, 19.9 ppm. Some char-
acteristic NMR signals of the minor cis I adduct: 1H NMR
(400 MHz, CDCl3): δ = 5.45 (dd, J = 6.2, 3.6 Hz, 1 H), 3.98 (d, J
= 14.7 Hz, 1 H), 3.55 (s, 3 H), 3.14 (dd, J = 13.1, 6.3 Hz, 1 H),
1.40 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 100.0, 71.5,
38.0 ppm. Some characteristic NMR signals of the minor cis II ad-
1
1
less oil. Rf 0.19 (cyclohexane/AcOEt 9:1, vanillin detection). H
duct: H NMR (400 MHz, CDCl3): δ = 5.38 (dd, J = 6.2, 3.4 Hz,
NMR (CDCl3, 400 MHz): two anomers (α/β) in a 60:40 ratio: δ =
6.28 (d, J = 10.8 Hz, 1 Hβ), 6.14 (d, J = 12 Hz, 1 Hα), 5.55–5.47
(m, 1 H), 3.85 (s, 3 Hα), 3.77 (s, 3 Hβ), 3.73 (s, 3 Hβ), 3.71 (d, J =
17.8 Hz, 1 Hβ), 3.70 (s, 3 Hα), 3.42 (d, J = 16.6 Hz, 1 Hα), 3.27
(d, J = 17.8 Hz, 1 Hβ), 2.95 (dd, J = 6.1, 14.2 Hz, 1 Hβ), 2.84–
2.80 (m, 2 Hα), 2.76 (d, J = 12.7 Hz, 1 Hβ), 2.72 (d, J = 16.6 Hz,
1 Hα), 2.16 (s, 3 Hβ), 2.14 (s, 3 Hα) ppm. 13C NMR (CDCl3,
100 MHz): Major anomer: δ = 174.0, 170.2, 169.4, 97.8, 64.4, 54.0,
51.9, 47.6, 39.1, 21.2 ppm; minor anomer: 172.5, 171.2, 170.7, 96.2,
1 H), 4.06 (d, J = 14.4 Hz, 1 H), 2.45 (dd, J = 13.3, 6.3 Hz, 1
H) ppm. IR (NaCl): ν = 2960, 2930, 2869, 1731, 1645, 1607, 1456,
˜
1279, 1205, 1140, 1123, 1077, 980, 878, 731, 697 cm–1. HRMS
(Cl+NH3): calcd. for C30H44NO4 [M + H]+ 482.3270; found
482.3236.
Methyl (3R,5S)-3-(2-Methoxy-2-oxoethyl)-5-[(R)-1-(2,4,6-triiso-
propylphenyl)ethoxy]isoxazolidine-3-carboxylate [(+)-8] and Methyl
(3R,5S)-3-(2-Methoxy-2-oxoethyl)-5-[(S)-1-(2,4,6-triisopropylphen-
yl)ethoxy]isoxazolidine-3-carboxylate [(–)-8]: Formic acid (8.6 mL)
was added dropwise under argon to a stirred solution of adduct 5b
(or ent-5b, 1.691 g, 3.13 mol) in MeOH (13 mL) and Pd/C (10%,
644.6 mg). After 16 h of stirring at room temp., the reaction mix-
ture was diluted with AcOEt (10 mL) and filtered through celite.
The filtrate was concentrated under reduced pressure. Recrystalli-
zation of the compound from pentane/AcOEt (2:1) afforded the
title compound (+)-8 [or (–)-8] as a white solid (466 mg, 50%, m.p.
64.9, 53.3, 52.5, 47.3, 37.2, 22.0 ppm. IR (NaCl): ν = 3371, 2956,
˜
1741, 1632, 1438, 1357, 1261, 1204, 1109, 906 cm–1. HRMS (DCI,
NH3, CH4): calcd. for C10H16NO7 262.0927 [M + H]+; found
262.0931.
Methyl (3R)-2-Acetyl-3-(2-methoxy-2-oxoethyl)-5-oxoisoxazolidine-
3-carboxylate [(–)-11]: N-Acetyl-5-OH-isoxazolidine 10 (0.011 g,
0.04 mmol) was dissolved in anhydrous dichloromethane (1 mL)
over molecular sieves (4 Å). NMO (0.0133 g, 0.11 mmol) and TPAP
(2.2 mg, 6.3 μmol, 0.15 equiv.) were added, and the mixture was
stirred at room temperature for 90 min. The mixture was then fil-
tered through a plug of silica gel. The crude product obtained from
washing of this plug of silica with AcOEt was purified by
chromatography on silica gel (cyclohexane/AcOEt 8:2, then pure
AcOEt) to give a colorless oil (4.5 mg, 0.017 mmol, 41 %). Rf
0.10 (cyclohexane/AcOEt 8:2, vanillin detection). [α]2D0 = –48.0 (c =
0.09, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 3.80 (s, 3 H), 3.73
(s, 3 H), 3.58 (d, J = 18.3 Hz, 1 H), 3.33 (d, J = 17.1 Hz, 1 H),
3.29 (d, J = 18.1 Hz, 1 H), 3.25 (d, J = 17.1 Hz, 1 H), 2.20 (s, 3
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 170.8, 169.9, 169.1,
1
181.5–182.5 °C). H NMR (400 MHz, CDCl3): δ = 7.03–7.95 (m,
2 H), 6.40–6.25 (m, 1 H), 5.38 (q, J = 6.7 Hz, 1 H), 5.11 (d, J =
5 Hz, 1 H), 3.80–3.70 (m, 1 H), 3.74 (s, 3 H), 3.72 (s, 3 H), 3.15 (d,
J = 15.9 Hz, 1 H), 3.25–3.10 (m, 1 H), 2.93–2.81 (m, 3 H), 2.11 (d,
J = 13.5 Hz, 1 H), 1.56 (d, J = 6.9 Hz, 3 H), 1.25–1.15 (m, 18
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.0, 131.8, 123,
120.6, 102.1, 69.7, 53.0, 52, 45.2, 39.7, 34, 28.4, 29.5, 24.7, 23.9,
22.9 ppm. IR (neat): ν = 3200, 1732, 1069 cm–1. HRMS (FD):
˜
calcd. for C25H39NO6 [M]+ 449.2777; found 449.2840. For (–)-(8):
[α]2D0 = –153.4 (c = 0.55, CHCl3). Chiral HPLC: ee Ͼ 98%
[Phenomenex Lux Cellulose (2.5 μm), 250ϫ4.6, isooctane/iPrOH
95:5, 1 mLmin–1, 210 nm].
167.7, 66.8, 53.7, 52.2, 39.4, 38.1, 21.7 ppm. IR (NaCl): ν = 3009,
˜
Methyl (3R,5S)-2-Acetyl-3-(2-methoxy-2-oxoethyl)-5-[(R)-1-(2,4,6-
triisopropylphenyl)ethoxy]isoxazolidine-3-carboxylate [(+)-9] and
Methyl (3R,5S)-2-Acetyl-3-(2-methoxy-2-oxoethyl)-5-[(S)-1-(2,4,6-
triisopropylphenyl)ethoxy]isoxazolidine-3-carboxylate [(–)-9]: A
solution of (+)-8 [or (–)-8, 200 mg, 0.44 mmol] in Ac2O (0.8 mL)
was stirred at room temp. for 16 h, and the reaction mixture was
then concentrated under reduced pressure to afford (+)-9 [or (–)-9,
2957, 2852, 1820, 1794, 1689, 1439, 1408, 1370, 1279, 1177, 1083,
1051, 1009, 883, 737 cm–1. HRMS (DCI, NH3CH4): calcd. for
C10H14NO7 [M + H]+ 260.0770; found 260.0770.
Methyl (3S,5R)-3-(2-Methoxy-2-oxoethyl)-2-(2,2,2-trifluoroacetyl)-
5-[(S)-1-(2,4,6-triisopropylphenyl)ethoxy]isoxazolidine-3-carb-
oxylate [(–)-12]: Et3N (0.23 mL) and (CF3CO)2O (0.22 mL,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O31739
/KAP1
Date: 31-03-14 17:09:22
Pages: 10
G. Dujardin et al.
FULL PAPER
1.4 mmol) were added to a solution of (–)-8 (516 mg, 1.15 mmol)
in THF (2.6 mL), and the mixture was stirred overnight at room
temp. The reaction mixture was quenched with NH4Cl and ex-
tracted with EtO2. Organic phases were combined, washed with
NaCl, dried with MgSO4, filtered, and concentrated under reduced
pressure to afford the title compound (610 mg, 97%) as a yellow
oil, which was used in the next step without further purification.
1383, 1327, 1224, 1193, 1162, 1008 cm–1. HRMS (Cl+NH3CH4):
calcd. for C10H13F3NO7 [M + H]+ 316.0644; found 316.0635.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra of all new compounds
and crystallographic data for compounds 6b and (+)-8, as well as
determination of the enantiopurity of acid 2a by chiral HPLC.
1
[α]2D5 = –90.7 (c = 3.08, CH2Cl2). H NMR (400 MHz, CDCl3): δ
= 7.05–6.98 (m, 2 H), 5.46 (q, J = 6.9 Hz, 1 H), 5.26 (d, J = 5.1 Hz,
1 H), 3.76 (s, 3 H), 3.75 (s, 3 H), 3.67 (d, J = 15.8 Hz, 1 H), 3.72–
3.60 (m, 1 H), 3.22–3.13 (m, 2 H), 3.05 (d, J = 15.9 Hz, 1 H), 2.91–
2.81 (m, 2 H), 1.57 (d, J = 6.9 Hz, 3 H), 1.28–1.12 (m, 18 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 170.0, 169.0, 151.8 (q, J =
39.8 Hz, 1 C), 148.5, 147.0, 130.3, 123.4, 120.9, 115.6 (q, J =
286.8 Hz), 100.2, 70.9, 66.9, 53.5, 52.0, 43.5, 36.7, 34.0, 29.1, 28.4,
24.6, 24.3, 24.1, 23.8, 22.4 ppm. 19F NMR (376 MHz, CDCl3): δ =
Acknowledgments
The authors thank the University of Sfax (PhD and Master grants
to K. B. A). Financial support of this study by grants from Agence
Nationale de la Recherche (ANR) (grant number BS07-005-01) is
gratefully acknowledged. The authors thank Pascale Cividino of
the University of Grenoble (DCM-CNRS) for the preparation of
(R)- and (S)-Stericol and Frédéric Legros (IMMM-CNRS) for
technical assistance. Patricia Gangnery and Amélie Durand of the
University of Le Mans (IMMM-CNRS) are thanked for HRMS
and NMR measurements, respectively. The authors thank Karim
Adil and Vincent Maisonneuve of the University of Le Mans
(IMMM-CNRS) for X-ray analysis. Imen Abid is thanked for her
work on the synthesis and N-deprotection of isoxazolidine 5e.
–74.5 ppm. IR (NaCl): ν = 2966, 2871, 1739, 1701, 1608, 1573,
˜
1438, 1363, 1230, 1113, 1072, 1019, 920, 881, 778, 735 cm–1
.
HRMS (Cl+NH3): calcd. for C27H38F3NO7 [M + NH4]+ 563.2944;
found 563.2964.
1,2-Dimethyl 3-[(S)-1-(2,4,6-Triisopropylphenyl)ethyl] (R)-2-(2,2,2-
Trifluoroacetamido)propane-1,2,3-tricarboxylate [(–)-3a]: A solu-
tion of SmI2 in THF (0.1 m, 0.312 mmol, 3.12 mL) was added drop-
wise under argon at 0 °C to a solution of N-(trifluoroacetyl)isox-
azolidine (–)-12 (170 mg, 0.312 mmol) in THF (1.5 mL). After
5 min, TLC showed complete consumption of the starting material.
The reaction was quenched by bubbling air through the solution
until disappearance of its blue color, and aqueous solutions of satd.
NaHCO3 and sodium thiosulfate were then added. The aqueous
phase was extracted three times with AcOEt, and the combined
organic phases were washed with brine, dried with MgSO4, filtered,
and concentrated under vacuum. Purification of the residue by sil-
ica gel chromatography (pentane/AcOEt 9:1) afforded the ester
(–)-3a as a clear oil (102 mg, 60%), Rf 0.3 (pentane/AcOEt 9:1).
[1] J. Clayden, M. Donnard, J. Lefranc, D. J. Tetlow, Chem. Com-
mun. 2011, 47, 4624.
[2] a) P. G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem.
2007, 5969; b) M. Tanaka, Chem. Pharm. Bull. 2007, 55, 349; c)
C. Cativiela, M. D. Díaz-de-Villegas, Tetrahedron: Asymmetry
2007, 18, 569; d) H. Vogt, S. Brase, Org. Biomol. Chem. 2007,
5, 406; e) Y. Ohfune, T. Shinada, Eur. J. Org. Chem. 2005, 5127;
f) K.-H. Park, M. J. Kurth, Tetrahedron 2002, 58, 8629; g) C.
Cativiela, M. D. Dıaz-de-Villegas, Tetrahedron: Asymmetry
2000, 11, 645; h) C. Cativiela, M. D. Dıaz-de-Villegas, Tetrahe-
dron: Asymmetry 1998, 9, 3517; i) S. Cabrera, E. Reyes, J.
Alemán, A. Milelli, S. Kobbelgaard, K. A. Jørgensen, J. Am.
Chem. Soc. 2008, 130, 12031.
[3] a) Y. Demizu, M. Tanaka, M. Doi, M. Kurihara, H. Okuda,
H. Suemune, J. Pept. Sci. 2010, 16, 621; b) G. M. Sambeth,
R. D. Süssmuth, J. Pept. Sci. 2011, 17, 581.
[4] M. C. Evans, A. Pradhan, S. Venkatraman, W. H. Ojala, W. B.
Gleason, R. K. Mishra, R. L. Johnson, J. Med. Chem. 1999,
42, 1441.
[α]2D5 = –64.7 (c = 1.35, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
7.73 (br. s, 1 H), 7.17 (br. s, 2 H), 6.44 (q, J = 6.9 Hz, 1 H), 3.64
(s, 3 H), 3.57 (s, 3 H), 3.52 (d, J = 15.5 Hz, 1 H), 3.50 (d, J =
15.8 Hz, 1 H), 3.35–3.27 (m, 2 H), 2.85 (d, J = 15.8 Hz, 1 H), 2.82–
2.72 (m, 1 H), 2.75 (d, J = 15.5 Hz, 1 H), 1.51 (d, J = 6.9 Hz, 3
H), 1.21–1.13 (m, 18 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
170.6, 169.2, 168.3, 156.4 (q, J = 37.7 Hz), 148.5, 131.5, 129.1,
128.1, 115.4 (q, J = 288.4 Hz), 69.6, 59.8, 53.8, 52.2, 39.8, 39.2,
34.2, 29.5, 24.5, 24.3, 24.1, 24.0, 22.1 ppm. 19F NMR (376 MHz,
CDCl ): δ = –74.5 ppm. IR (neat): ν = 3379, 2959, 2871, 1736,
˜
3
1608, 1526, 1439, 1211, 1164, 1053 cm–1. HRMS (Cl+NH3): calcd.
[5] M. Ilies, L. Di Costanzo, D. P. Dowling, K. J. Thorn, D. W.
Christianson, J. Med. Chem. 2011, 54, 5432.
for C27H39F3NO7 [M + H]+ 546.2600; found 545.2649.
[6] C.-O. Chan, D. Crich, S. Natarajan, Tetrahedron Lett. 1992,
33, 3405.
(S)-5-Methoxy-3-(methoxycarbonyl)-5-oxo-3-(2,2,2-trifluoroacet-
amido)pentanoic Acid [(S)-(–)-2b]: TFA (0.5 mL) was added slowly
to a stirred solution of (–)-3a (125 mg, 0.22 mmol) in CH2Cl2
(6 mL), and the mixture was stirred overnight and then washed
with saturated NaHCO3 solution (10 mLϫ 3). The aqueous layers
were combined, acidified to pH = 2 (10% HCl), and extracted with
CH2Cl2 (10 mLϫ 3). The organic layers were combined, dried with
MgSO4, and filtered, and the solvent was removed in vacuo to yield
the acid (S)-(–)-2b as a colorless oil (66 mg, 95%). [α]2D5 = –17 (c =
[7] T. B. Nguyen, A. Beauseigneur, A. Martel, R. Dhal, M.
Laurent, G. Dujardin, J. Org. Chem. 2010, 75, 611.
[8] T. B. Nguyen, A. Martel, R. Dhal, G. Dujardin, Org. Lett.
2008, 10, 4493.
[9] E. Winterfeldt, W. Krohn, H.-U. Stracke, Chem. Ber. 1969, 102,
2346.
[10] H. Tokuyama, T. Kuboyama, A. Amano, T. Yamashita, T. Fu-
kuyama, Synthesis 2000, 1299.
[11] R. C. Clark, S. S. Pfeiffer, D. L. Boger, J. Am. Chem. Soc. 2006,
128, 2587.
[12] P. Delair, A. M. Kanazawa, M. B. M. de Azevedo, A. E.
Greene, Tetrahedron: Asymmetry 1996, 7, 2707.
[13] B. Darses, A. E. Greene, J.-F. Poisson, Org. Lett. 2010, 12, 3994
and references cited therein.
1
0.065, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 9.52–9.40 (m, 1
H), 7.78 (s, 1 H), 3.87 (s, 3 H), 3.67 (s, 3 H), 3.64 (d, J = 16.3 Hz,
1 H), 3.57 (d, J = 15.7 Hz, 1 H), 3.02 (d, J = 16.3 Hz, 1 H), 2.94
(d, J = 15.7 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173,
170.3, 169.0, 156.5 (q, J = 37.9 Hz), 115.2 (q, J = 288.2 Hz), 59.2,
54.1, 52.3, 39.1, 38.7 ppm. 19F NMR (376 MHz, CDCl3): δ = –77.3
[14] Y. Okimoto, S. Sakaguchi, Y. Ishii, J. Am. Chem. Soc. 2002,
124, 1590.
(s) ppm. IR (NaCl): ν = 3460, 1743, 1717, 1637, 1618, 1560, 1440,
[15] A. Nakamura, M. Tokunaga, Tetrahedron Lett. 2008, 49, 3729.
˜
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O31739
/KAP1
Date: 31-03-14 17:09:22
Pages: 10
α-Substituted Functional Aspartic Acid Derivatives
[16]
[17]
[20] An efficient organocatalytic enantioselective route to N-pro-
tected hydroxyisoxazolines was disclosed by Cordova’s group
from N-protected hydroxylamines and enals.[19] Efficient con-
versions into β-amino alcohols and β-amino acids were already
reported: M. Liu, M. P. Sibi, Tetrahedron 2002, 58, 7991; N.
Sewald, Angew. Chem. Int. Ed. 2003, 42, 5794; T. B. Nguyen,
A. Martel, C. Gaulon, R. Dhal, G. Dujardin, Org. Prep. Pro-
ced. Int. 2010, 42, 387.
M. Bosch, M. Schlaf, J. Org. Chem. 2003, 68, 5225.
U. Chiacchio, A. Corsaro, J. Mates, P. Merino, A. Piperno, A.
Rescifina, G. Romeo, R. Romeo, T. Tejero, Tetrahedron 2003,
59, 4733.
[18] a) J. Ceccon, G. Danoun, A. E. Greene, J.-F. Poisson, Org. Bio-
mol. Chem. 2009, 7, 2029; b) B. Darses, A. E. Greene, S. C.
Coote, J.-F. Poisson, Org. Lett. 2008, 10, 821.
[19] I. Ibrahem, R. Rios, J. Vesely, G.-L. Zhao, A. Córdova, Chem.
Commun. 2007, 849.
Received: November 19, 2013
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O31739
/KAP1
Date: 31-03-14 17:09:22
Pages: 10
G. Dujardin et al.
FULL PAPER
Quaternary Amino Acids
K. Ben Ayed, A. Beauchard, J.-F. Poisson,
S. Py, M. Y. Laurent, A. Martel,
H. Ammar, S. Abid,
G. Dujardin* ................................... 1–10
Enantiopure isoxazolidine (–)-8 is obtained
through the highly diastereoselective [3+2]
cycloaddition of an aspartate-derived
ketonitrone and (S)-Stericol vinyl ether.
Such an isoxazolidine is a direct precursor
of a “superaspartic” acid bearing two dif-
ferentiated side chains.
Asymmetric Access to α-Substituted Func-
tional Aspartic Acid Derivatives by a [3+2]
Strategy Employing a Chiral Dienophile
Keywords: Asymmetric synthesis / Cycload-
dition / Amino acids / Heterocycles
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0