Practical asymmetric access to carboxy-differentiated aspartate derivatives via 1,3-dipolar cycloaddition of a nitrone with (R)-4-ethyl-N-vinyloxazolidin-2-one

Article abstract of DOI:10.1016/j.tetasy.2008.08.020

A new practical approach to enantioenriched carboxy-differentiated aspartate derivatives was achieved in three steps via the 1,3-dipolar cycloaddition of N-benzyl-α-carbonyloxyethylnitrone with (R)-4-ethyl-N-vinyloxazolidin-2-one and chemoselective nucleophilic displacement of aspartimide under appropriate conditions (racemization less than 3%).

Full text of DOI:10.1016/j.tetasy.2008.08.020

Tetrahedron: Asymmetry 19 (2008) 2084–2087
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Practical asymmetric access to carboxy-differentiated aspartate
derivatives via 1,3-dipolar cycloaddition of a nitrone with
(R)-4-ethyl-N-vinyloxazolidin-2-one
*
Thanh Binh Nguyen, Thi Minh Ha Vuong, Arnaud Martel, Robert Dhal, Gilles Dujardin
UCO2M UMR 6011 CNRS, Université du Maine, F-72085 Le Mans, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2008
Accepted 20 August 2008
A new practical approach to enantioenriched carboxy-differentiated aspartate derivatives was achieved
in three steps via the 1,3-dipolar cycloaddition of N-benzyl- -carbonyloxyethylnitrone with (R)-4-
ethyl-N-vinyloxazolidin-2-one and chemoselective nucleophilic displacement of aspartimide under
a
appropriate conditions (racemization less than 3%).
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
preparation, circumvented by using trifluoroacetic anhydride in
ethyl acetate.12 Finally, N-Boc
L-aspartic thioanhydride was shown
N-Protected carboxy-differentiated aspartate derivatives are
useful building blocks for the syntheses of many natural products
and pharmaceutical agents,1 including glycoamino acids and glyco-
peptides.2 In this area, aspartate derivatives that are able to under-
go selective manipulation (heteronucleophilic displacements) at
the b-position while retaining their enantiopurity are of specific
to favor b-regioselective ring opening with anilines and L-glyco-
samines, despite moderate yields.13
We have recently disclosed other promising precursors of
aspartate derivatives which allow selective manipulations at the
b-position: the N-dibenzylated aspartimides 4.14 They were effi-
ciently obtained by a high yielding two-step sequence: (i) sol-
vent-free cycloaddition of nitrone 2 to N-vinyloxazolidin-2-one 1
and (ii) isoxazolidine ring opening via N-benzylation of the adducts
3 thus obtained (Scheme 1).
When R = H, we showed that the aspartimide rac-4a could be
easily transformed into racemic carboxy-differentiated aspartate
derivatives rac-5 in high yields by chemocontrolled heteronucleo-
philic attack at the amide center with various reagents (Scheme 2).
Continuing our work toward the asymmetric extension of this
unprecedented sequence, we investigated the use of (R)-4-ethyl-
N-vinyloxazolidin-2-one 1b in order to produce enantioenriched
carboxy-differentiated aspartate derivatives (R) or (S)-5 (Scheme
2). Herein, we report the results of this new approach to enantio-
enriched b-aspartic derivatives starting from the diastereo- and
enantiopure b-aspartimide 4b.
interest. Efficient selective protections of the
a-amino and the
a
-carboxylic acid group have been described by 5-oxazolidinone
formation, using either hexafluoroacetone3 (on aspartic acid itself)
or formaldehyde (on N-protected forms).4 The b-carboxylic group
remains unprotected and can be derivatized regioselectively after
activation. However, in the second case, deprotection requires
highly basic conditions (LiOH 1 N).4 Moreover, simultaneous pro-
tection–activation of L-aspartic acid toward benzylamine has been
reported using dichlorodialkylsilanes5 or boron trifluoride diethyl
etherate6 but gave either opposite chemocontrol5 or low yields.6
As an alternative to the protection, activation, and deprotection
sequence, the use of diacid derivatives was investigated. Enzymatic
aminolysis of aspartate diesters proved to be highly dependent on
N-protection and gave only good b-regiocontrol for N-acetyl sub-
strates.7 Aspartic anhydride proved to be efficient for delivering a
range of unsymmetrical aspartates. Classically, nucleophilic attack
of alcohols,8 amines, and anilines9 proceeds via regioselective
2. Results and discussion
a
-opening of the anhydride. Reversal of this regioselectivity was
The synthesis of the N,N-dibenzyl aspartimide 4b was scaled up
to 13 g following our previously reported procedure. The 1,3-dipo-
lar cycloaddition between nitrone 2 (E:Z ratio = 2:1 in CDCl3 by 1H
NMR analysis) and (R)-4-ethyl-N-vinyloxazolidin-2-one 1b was
carried out under thermal conditions at 110 °C within 10 min.
The adduct was isolated as a mixture of the four possible isomers
of 3b [49(3R,5R):20(3S,5S):20(3R,5S):11(3S,5R)] in 93% yield
(Scheme 3). No attempt was made to separate the individual
reported in some specific cases: (i) with NH4OH,10 (ii) with
anilines, using DMSO as the solvent,8 and (iii) starting from bulky
substrates (N-trityl protection).11 Recent reports have highlighted
the risk of partial racemization of aspartic anhydride during its
* Corresponding author. Tel.: +33 (0)243833344; fax: +33 (0)243833902.
E-mail address: gilles.dujardin@univ-lemans.fr (G. Dujardin).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.08.020

T. B. Nguyen et al. / Tetrahedron: Asymmetry 19 (2008) 2084–2087
2085
CO2Et
CO2Et
CO2Et
NBn2
O
O
O
1. BnBr
BnN
O-
50 °C, 3d
2
NBn
O
N
O
N
N
O
O
O
2. Na2CO3
Δ, [3+2]
solvent free
R
R
R
4a
4b
R = H
R = Et
1
3
Scheme 1.
COOEt
COOEt
NBn2
COOEt
*
NBn2
O
O
CO2Et
O
O
Δ, [3+2]
solvent free
93%
NBn
4b
, R = Et
N
O
O
N
BnN
O-
O
O
N
O
N
O
O
Separation
Et
Et
3b
R
4
Et
2
(R)-1b
diastereomerically pure 4b
99.5% ee
(chiral GC)
1. BnBr
3 equiv
50 °C, 3d
Nu- or
NuH
Nu- or
NuH
R = H
conditions?
rac-4a
2. Na2CO3
COOEt
*
NBn2
COOEt
NBn2
COOEt
NBn2
O
Nu
Nu
O
O
O
N
O
yields?
76-95%
5a-g
ee?
Et
4b
-5a-g
(R)- or (S)
rac-
Flash column
Scheme 2.
chromatography
(gram-scale)
diastereomers. Upon treatment with benzyl bromide (3 equiv), ad-
duct 3b gave the corresponding aspartimides 4b as a nearly equi-
molar mixture.
The large-scale separation of diastereoisomers (R,S)-4b and
(R,R)-4b was carried out by silica gel chromatography with 1%
cyclohexane in dichloromethane. The addition of triethylamine
(0.5%) into the eluent was found to be necessary in order to avoid
the degradation of 4b on SiO2. Compounds (R,S)-4b and (R,R)-4b
were obtained in 40% and 30% yield, respectively, as single
diastereoisomers.
COOEt
COOEt
NBn2
O
O
NBn2
O
N
O
N
O
O
Et
Et
(R,S)-4b
40%
(R,R)-4b
30%
de > 99.5%
de > 99.5%
Product (R,S)-4b was chosen as a starting material for the nucle-
ophilic displacement reactions. Unsurprisingly, (R,S)-4b proved to
be less reactive than its unsubstituted homolog rac-4a, the extent
depending on the nucleophilic reagent used. A comparative reac-
tivity study between the two series (R,S)-4b and rac-4a is summa-
rized in Table 1. The enantiopurities of the aspartate derivatives
(S)-5 thus obtained were determined by chiral HPLC after careful
optimization of the racemic separation conditions applied to the
corresponding rac-5 compound.
For the alcoholysis of (R,S)-4b, racemizing conditions using
alkaline metal alkoxides should be avoided. Starting from (R,S)-
4b, the same conditions for methanolysis of rac-4a in the presence
of sodium azide (10 mol %) as a catalyst15 did not afford the methyl
ester (S)-5a. Indeed, the starting material (R,S)-4b was recovered
unchanged after 40 h of heating at 40 °C. More drastic conditions
were therefore required (excess NaN3, 100 °C, sealed tube, 16 h)
to ensure a good conversion and yield of (S)-5a (Table 1, entry 1).
These conditions were successfully applied to afford benzyl ester
(S)-5b using benzyl alcohol (Table 1, entry 2). However, despite
Scheme 3.
our precautions, slight racemization was observed in both cases
(<3%) which could arise from the prolonged heating.
The saponification of (R,S)-4b was somewhat more difficult
than that of rac-4a, and was achieved only after 4 h at room tem-
perature (Table 1, entry 3). The ee determination for hemiester
(S)-5c could not be carried out by chiral HPLC, but was conve-
niently deduced after transformation into the ethyl methyl ester
(S)-5a by reaction with diazomethane (96% ee).
The aminolysis of (R,S)-4b using n-butylamine was accom-
plished at room temperature within 10 min (Table 1, entry 5),
but required 16 h when benzylamine was used. Nevertheless, the
enantiopurity was excellent in the latter case (99% ee, Table 1, en-
try 4).
To obtain Weinreb’s amide (S)-5f, the presence of a catalyst
such as AlMe3 proved to be necessary.16 As a general trend for

2086
T. B. Nguyen et al. / Tetrahedron: Asymmetry 19 (2008) 2084–2087
Table 1
Attack of nucleophiles on the amide carbonyl
COOEt
O
COOEt
NBn2
COOEt
NBn2
Nu- or NuH
Nu- or NuH
NBn2
O
N
O
Nu
R = H
rac-4a
R = Et
(R,S)-4b
O
Nu
O
R
rac-5a-f
(S)-5a-f
4
Entry
Product
Nu
Conditions for R = H (Ref. 5)
Yielda (%)
Conditions for R = Et
Yielda (%)
ee (%)
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
OMe
OBn
OH
NHBn
NH-n-Bu
MeOH, NaN3, 40 °C, 16 h
BnOLi, THF, rt, 30 min
LiOH, THF/H2O (1:1), rt, 30 min
BnNH2 (10 equiv), rt, 16 h
n-BuNH2 (10 equiv), 10 min
90
76
80
95
90
83
79
MeOH, NaN3, 100 °C, 16 h
BnOH, NaN3, 100 °C, 16 h
LiOH, THF/H2O (1:1), rt, 4 h
BnNH2 (10 equiv), rt 16 h
n-BuNH2 (10 equiv), 10 min
79
72
73
81
78
81
0
94
96
96b
99
95
98
—
NMeOMe
NHGlyOMe
MeONHMeÁHCl, AlMe3, DCM, 0 °C, 30 min
MeONHMeÁHCl, AlMe3, DCM, rt, 3 h
5g
H2NGlyOMeÁHCl, AlMe3, DCM, rt, 30 min
H2NGlyOMeÁHCl, AlMe3, DCM, rt, 30 min
a
Isolated yield.
b
Determined by chiral HPLC analysis of the corresponding methyl ester (S)-5a obtained by the reaction of (S)-5c with diazomethane.
substituted derivative, a longer reaction time was also required.
The absence of basic conditions could help preserve the configura-
tion at stereogenic center (98% ee, Table 1, entry 6).
As a possible limitation of our method, AlMe3-promoted condi-
tions could not be applied to the peptide coupling with glycine
methyl ester, to afford (S)-5g from (R,S)-4b as described in the
racemic series with unsubstituted derivative rac-4a. Forcing the
conditions by increasing the reaction time or/and temperature
resulted in either degradation or recovery of the unchanged start-
ing material.
dried by standard methods when necessary. Commercially
obtained reagents were used without further purification. Com-
pounds 3b, 4b, rac-4a, and rac-5a–g have been prepared according
to our previous report.14 Compounds (R,S)-4b and (R,R)-4b were
isolated in 40% and 30% yield, respectively, from the diastereo-
meric mixture (2 g scale) by flash column chromatography using
pre-treated SiO2 (with 0.5% triethylamine in cyclohexane) and 1%
cyclohexane in dichloromethane as the eluent. Rf (DCM): 0.40 for
(R,S)-4b; 0.20 for (R,R)-4b.
4.2. Procedures for preparation of (S)-5a–f
3. Conclusion
4.2.1. (S)-1-Ethyl 4-methyl 2-(dibenzylamino)succinate (S)-5a
A suspension of NaN3 (20 mg, 0.3 mmol) and (R,S)-4b (44 mg,
0.1 mmol) in methanol (0.5 mL) was heated to 100 °C in a sealed
tube. After 16 h, most of the methanol was removed in vacuo. Col-
umn chromatography (Et2O) provided 5a (28 mg, 79%) as a color-
In conclusion, a range of enantioenriched carboxy-differenti-
ated aspartate derivatives were obtained in high yields and good-
to-excellent ee (94–99%) by chemoselective displacement of the
oxazolidinone moiety in (R,S)-4b, using the appropriate heteronu-
cleophilic reagent under almost non-racemizing conditions. This
[3+2] cycloaddition-based asymmetric approach to carboxy-differ-
entiated aspartates affords N-dibenzylated derivatives and is thus
in complementary way to the previously described diastereo- or
less oil. IR (neat)
m
= 1732 cmÀ1. [
a]D = À76.5 (c 0.39, CHCl3).
ee = 94% (Column OD-R, eluent CH3CN/H2O 50:50, flow
rate = 1 mL/min, Tr(S) = 36.6 min, Tr(R) = 43.3 min). 1H NMR
(400 MHz, CDCl3) d 7.35–7.21 (m, 10H), 4.34–4.17 (m, 2H), 3.87
(dd, J = 7.8, 7.4 Hz, 1H), 3.83 (d, J = 13.6 Hz, 2H), 3.58 (s, 3H), 3.57
(d, JAB = 13.6 Hz, 2H); 2.85 (dd, J = 15.4 Hz, 7.8 Hz, 1H), 2.67 (dd,
J = 15.4 Hz, 7.4 Hz, 1H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3) 171.3, 171.3, 138.9, 128.8, 128.2, 127.1, 61.1,
57.8, 54.6, 51.5, 34.9, 14.4. HRMS (CI+NH3) calcd for C21H26NO4
[M+H+]: 356.1862, found: 356.1862.
enantioselective Mannich-type reactions using a-imino esters with
(thio-)ketene ketals,17 which are restricted to N-sulfinyl, N-acyl, or
N-p-methoxyphenyl substrates.
4. Experimental
4.1. General
4.2.2. (S)-4-Benzyl 1-ethyl 2-(dibenzylamino)succinate (S)-5b
A mixture of NaN3 (35 mg, 0.5 mmol) and (R,S)-4b (44 mg,
0.1 mmol) in benzyl alcohol (108 mg, 1.0 mmol) was heated to
100 °C. After 16 h, most of the benzyl alcohol was removed in a
kugelrohr (0.01 mmHg, 50 °C). (Warning: for large-scale prepara-
tion, prior to distillation, NaN3 must be removed by washing with
water.) Column chromatography (dichloromethane/cyclohex-
ane = 2:1) provided 5b (31 mg, 70%) as a colorless oil. IR (neat)
All reactions were conducted in oven- or flame-dried glassware.
Reactions involving air- and water-sensitive reagents were per-
formed under a dry Ar atmosphere using a standard vacuum line
and Schlenk techniques. NMR spectra were recorded on a Bruker
AC 400 spectrometer (400 MHz). Infrared spectra were recorded
on a Nicolet Avatar 370DTGS spectrometer. Optical rotations were
measured using a Perkin–Elmer 241 polarimeter (c as gram of com-
pound per 100 mL). Flash column chromatography was carried out
using Kieselgel 60 (230–400 mesh Merck). All reactions were mon-
itored by TLC with Macherey-Nagel AlugramÒ G/UV 254 silica gel-
coated plates. The enantiomeric excesses (ee) were determined by
chiral HPLC analysis on Chiralcel OD-R or Chiralcel AD columns
using racemic compounds as references. HRMS was measured by
a Water Micromass GCT Premier. The organic solvents used were
m
= 1732 cmÀ1. [
a]
D = À58.2 (c 0.40, CHCl3). ee = 96% (Column OD-
R, eluent CH3CN/H2O 70:30, flow rate = 1 mL/min, Tr(S) = 13.8 min,
Tr(R) = 15.5 min). 1H NMR (400 MHz, CDCl3) d 7.34–7.20 (m, 15H),
5.13 (d, J = 12.4 Hz, 1H), 4.93 (d, J = 12.4, 1H), 4.30-4.15 (m, 2H),
3.91 (dd, J = 8.1 Hz, 7.1 Hz, 1H), 3.82 (d, J = 13.6 Hz, 2H), 3.57 (d,
J = 13.6 Hz, 2H), 2.92 (dd, J = 15.7 Hz, 8.1 Hz, 1H), 2.71 (dd,
J = 15.7 Hz, J = 7.1 Hz, 1H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3) d 171.4, 170.9, 138.9, 135.7, 128.9, 128. 5,

T. B. Nguyen et al. / Tetrahedron: Asymmetry 19 (2008) 2084–2087
2087
128.3, 128.23, 128.19, 127.1, 66.4, 60.7, 58.0, 54.8, 51.5, 35.2, 14.5.
HRMS (CI+NH3) calcd for C27H30NO4 [M+H+]: 432.2175, found:
432.2160.
hexanes (2 M, 300 lL, 0.6 mmol). The whole mixture was stirred
at room temperature for 4 h. Excess AlMe3 was destroyed by care-
fully adding a saturated aqueous solution of NaHCO3 (1 mL) at 0 °C.
The whole mixture was diluted with saturated brine and extracted
with dichloromethane. The organic layer was dried over MgSO4
and evaporated. The residue was chromatographed on silica gel
(cyclohexane/Et2O = 1:1) to give (S)-5f (31 mg, 81%) as a colorless
4.2.3. (S)-3-(Ethoxycarbonyl)-3-(dibenzylamino)-propanoic
acid (S)-5c
A suspension of (R,S)-4b (44 mg, 0.1 mmol), LiOH (12 mg,
0.5 mmol) in THF (0.5 mL) and H2O (0.5 mL) was stirred at room
oil. IR (neat)
m
= 2927, 1729, 1665 cmÀ1. [
a
]D = À78.2 (c 0.35,
temperature. After 4 h, HCOOH (100
l
L) was added. Work up
CHCl3). ee = 98% (Column AD, eluent isooctane/i-PrOH 95:5, flow
rate = 1 mL/min, Tr(S) = 15.9 min, Tr(R) = 18.6 min). 1H NMR
(400 MHz, CDCl3) d 7.39–7.20 (m, 10H), 4.35–4.17 (m, 2H), 3.94
(dd, J = 9.9 Hz, 5.1 Hz, 1H), 3.84 (d, J = 13.5 Hz, 2H), 3.61 (s, 3H),
3.14–3.01 (m, 1H), 3.10 (s, 3H), 2.64–2.59 (m, 1H), 1.37 (t,
J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) 171.9, 171.8, 139.3,
128.7, 128.2, 127.0, 61.0, 60.5, 57.8, 55.1, 32.7, 14.5. HRMS
(CI+NH3) calcd for C20H24NO4 [M+H+]: 385.2140, found: 385.2140.
(Et2O) and column chromatography (dichloromethane/Et2O = 1:1)
yielded the acid 5c (25 mg, 73%) as a colorless oil. IR (neat)
m
on
= 3433, 1736 cmÀ1. [
a
a]
D = À96.2 (c 0.40, CHCl3). ee = 96% (based
-methyl ester). 1H NMR (400 MHz, CDCl3) d 7.33–7.25 (m,
10H), 4.36–4.22 (m, 2H), 3.94 (d, J = 13.6 Hz, 2H), 3.85 (t,
J = 7.8 Hz, 1H), 3.62 (d, J = 13.6 Hz, 2H); 2.79 (d, J = 7.8, 2H), 1.38
(t, J = 7.1 Hz, 3H). HRMS (CI+NH3) calcd for C20H24NO4 [M+H+]:
342.1699. 13C NMR (100 MHz, CDCl3) d 174.2, 170.2, 137.1, 129.3,
128.6, 127.7, 61.1, 57.0, 54.6, 33.5, 14.4, found: 342.1705.
Acknowledgment
4.2.3.1. General procedure for aminolysis of (S)-5d and
We thank the French Ministry of Research for Nguyen Thanh
Binh’s PhD grant.
(S)-5e.
A solution of (R,S)-4b (44 mg, 0.1 mmol) in amine
(1.0 mmol) was stirred at room temperature. After 16 h with benz-
ylamine and 10 min with n-butylamine, most of the amine was
removed in vacuo (with n-butylamine) or in a kugelrohr (with
benzylamine). Column chromatography (Et2O/cyclohexane = 2:1)
provided (S)-5d (35 mg, 78%) and (S)-5e (31 mg, 78%) as colorless
oils.
References
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4.2.4. (S)-Ethyl 3-(benzylcarbamoyl)-2-(dibenzyl-
amino)propanoate (S)-5d
IR (neat)
CHCl3). ee = 99% (Column AD, eluent isooctane/i-PrOH 95:5, flow
rate
1 mL/min, Tr(S) = 36.9 min, Tr(R) = 55.5 min). 1H NMR
m
= 2918, 2850, 1726, 1650 cmÀ1. [
a]
D = À79.8 (c 0.54,
=
(400 MHz, CDCl3) d 7.37–7.16 (m, 15H), 6.99–6.96 (m, 1H), 4.47
(dd, J = 14.6 Hz, 6.56 Hz, 1H), 4.35–4.19 (m, 2H), 4.07 (dd,
J = 14.6 Hz, 5.05 Hz, 1H), 3.90 (d, J = 13.4 Hz, 2H), 3.83 (dd,
J = 9.4 Hz, 5.3 Hz, 1H), 3.56 (d, J = 13.4 Hz, 2H), 2.76–2.61 (m, 2H),
1.36 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 171.1, 169.9,
138.2, 129.1, 128.6, 128.4, 128.1, 127.40, 127.39, 60.8, 58.0, 54.6,
43.3, 35.5, 14.5. HRMS (CI+NH3) calcd for C27H31N2O3 [M+H+]:
431.2335, found: 431.2341.
4.2.5. (S)-Ethyl 3-(butylcarbamoyl)-2-(dibenzyl-
amino)propanoate (S)-5e
7. Conde, S.; López-Serrano, P. Eur. J. Org. Chem. 2002, 922.
8. (a) Jouin, P.; Castro, B.; Zeggaf, C.; Pantaloni, A.; Senet, J. P. Tetrahedron Lett.
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121.
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Bischoff, L.; Fruit, C.; Marsais, F. Tetrahedron: Asymmetry 2007, 18, 1625 and
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IR (neat)
m
= 2925, 1721, 1632 cmÀ1. [
a]
D = À79.9 (c 0.46 CHCl3).
ee = 95% (Column OD-R, eluent isooctane/i-PrOH 95:5, flow
rate = 0.8 mL/min, Tr(S) = 16.6 min, Tr(R) = 19.1 min). 1H NMR
(400 MHz, CDCl3) d 7.34–7.24 (m, 10H), 6.38 (m, 1H), 4.34–4.19
(m, 2H), 3.91 (d, J = 13.4 Hz, 2H), 3.83 (dd, J = 8.6 Hz, 6.1 Hz, 1H),
3.60 (d, J = 13.4 Hz, 2H), 3.21–3.13 (m, 1H), 3.04–2.96 (m, 1H),
2.69–2.57 (m, 2H), 1.41–1.33 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H),
1.33–1.24 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz,
CDCl3) d 171.3, 170.0, 138.5, 129.1, 128.4, 127.4, 60.7, 58.2, 54.7,
39.0, 35.8, 32.6, 20.1, 14.5, 13.7. HRMS (CI+NH3) calcd for
C
24H33N2O3 [M+H+]: 397.2512, found: 397.2491.
4.2.6. (S)-Ethyl 3-(N-methoxy-N-methylcarbamoyl)-2-
(dibenzylamino)propanoate (S)-5f
To a suspension of CH3NHOCH3ÁHCl (60 mg, 0.6 mmol) in a
solution of (R,S)-4b (44 mg, 0.1 mmol) in dry dichloromethane
(0.5 mL) at 0 °C was added under argon a solution of AlMe3 in
16. (a) Braddock, D. C.; Brown, J. M. Tetrahedron: Asymmetry 2000, 11, 3591; (b) Xu,
Z.; Chen, Z.; Ye, T. Tetrahedron: Asymmetry 2004, 15, 355.
17. (a) Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am.
Chem. Soc. 2003, 125, 2507; (b) Kobayashi, S.; Matsubara, R.; Kitagawa, H. Org.
Lett. 2002, 4, 143; (c) Jacobsen, M. F.; Skrydstrup, T. J. Org. Chem. 2003, 68,
7112; (d) Kobayashi, S.; Akiyama, R.; Kitagawa, H. J. Comb. Chem. 2001, 3, 196.