New access to the synthetic building block L-aspartic acid β-semialdehyde via Grignard reaction

Article abstract of DOI:10.1016/S0957-4166(00)00487-0

A new, efficient, and inexpensive synthesis of protected L-aspartic acid β-semialdehyde has been developed starting from L-glutamic acid via a substituted L-allylglycine derivative as intermediate. The key step of the reaction sequence was a strongly solvent-dependent Grignard reaction of an L-glutamic acid semiester. The desired regioselective addition to the C-5 ester group was achieved in 1,2-dimethoxyethane while reactions in diethyl ether gave products resulting from additional attack at the carboxylic acid functionality.

Full text of DOI:10.1016/S0957-4166(00)00487-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4965–4973
New access to the synthetic building block
L-aspartic acid
b-semialdehyde via Grignard reaction
Hendrik L u¨ sch and Horst C. Uzar*
Institut f u¨ r Organische Chemie, Universit a¨ t-Gesamthochschule Siegen, Adolf-Reichwein-Straße 2,
D-57068 Siegen, Germany
Received 14 November 2000; accepted 5 December 2000
Abstract
A new, efficient, and inexpensive synthesis of protected
developed starting from -glutamic acid via a substituted -allylglycine derivative as intermediate. The key
step of the reaction sequence was a strongly solvent-dependent Grignard reaction of an -glutamic acid
L
-aspartic acid b-semialdehyde has been
L
L
L
semiester. The desired regioselective addition to the C-5 ester group was achieved in 1,2-dimethoxyethane
while reactions in diethyl ether gave products resulting from additional attack at the carboxylic acid
functionality. © 2001 Elsevier Science Ltd. All rights reserved.
1
. Introduction
L
-Aspartic acid b-semialdehyde (1) is a natural non-proteinogenic amino acid and a key
intermediate in the biosynthesis of the essential amino acids -lysine, -methionine, -threonine,
-isoleucine in higher plants and bacteria. It also represents a relevant synthetic intermedi-
L
L
L
1
and
L
ate. The potential access to a variety of polyfunctional non-proteinogenic and unnatural amino
2
acids using 1 has been demonstrated. Further applications include the total syntheses of
3
4
rhizobitoxin and sinefungin, and also of the phytotoxic agent
D
,
L
-g-hydroxyphosphinothricine
5
via protected, racemic 1.
6
7
An established route to 1 employs ozonolysis of
L
-allylglycine or its derivatives, which in
8
9
10
turn is accessible by malonester syntheses and via glycine-derived or other stable imines
followed by enzyme-catalyzed racemate resolution. Other known methods start from the chiral
pool and proceed through oxidation of -homoserines, which can be prepared from -methion-
-aspartic acid.
However, N-alkoxycarbonyl derivatives of homoserines reportedly have the tendency of lac-
L
L
2
11
12
ine, and by controlled reduction or, preferably, by reduction–oxidation of
L
1
3
tonization. Furthermore, many reducing agents are not compatible with widely-used protecting
*
Corresponding author. Tel: +49-271-740-4244; e-mail: uzar@chemie.uni-siegen.de
0
957-4166/00/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00487-0

4966
H. L u¨ sch, H. C. Uzar / Tetrahedron: Asymmetry 11 (2000) 4965–4973
1
4
groups. Common oxidation methods for the synthesis of some aldehydes have been success-
1
5
16
fully utilized, although they led to unsatisfactory results for other authors. None of these
methods is predominant in the literature.
The need for enantiomerically pure 1 for biochemical and organic-preparative studies
demands an efficient, inexpensive synthetic route of general validity. We describe a method that
combines the strengths of both known approaches using the chiral pool of the biogenic amino
acids and the mild ozonolysis of an
degradation. To avoid stability problems and because of its intended further use in natural
product synthesis, the doubly protected derivative of 1, N-ethoxycarbonyl- -aspartic acid
a-methylester b-semialdehyde 2, had been chosen as a target molecule (see Fig. 1).
L
-allylglycine analogue by an overall Barbier–Wieland
L
CO R
2
R'HN
O
1
2
R=H R'=H
R=Me R'=CO Et
2
Figure 1.
2
. Results and discussion
-Glutamic acid 3 served as starting material. The two acid functions were differentiated by
L
selective esterification of the g-carboxyl group to secure chemoselectivity in later stages in the
synthesis. Esterification and subsequent protection of the amino functionality were carried out
17
analogous to our established method for -aspartic acid. The NMR-spectroscopically pure, yet
L
oily semiester 4 was obtained in high yield. It was further characterized as its dicyclohexylammo-
nium salt 5, which served as a storage compound because of its stability (see Scheme 1).
Scheme 1. (a) MeOH, HCl, 20 h, rt; then NaHCO ; (b) NaHCO , ClCO Et, 16 h, rt; (c) NH(c-C H ) , Et O; (d)
3
3
2
6
11 2
2
NaHCO , Et O; then H SO , Et O
3
2
2
4
2
Grignard reagents are known to add to ester groups but usually not to free acid or carbamate
functionalities, even though we recently observed side products arising from attack at the acid
18
functionality of N-alkoxycarbonyl-
was expected to mainly afford a tertiary alcohol that would dehydrate to a substituted
-allylglycine derivative under mild conditions. Phenylmagnesium bromide was chosen as the
L
-aspartic acid b-methyl ester. Reaction with semiester 4
L
Grignard reagent to favor subsequent acid-catalyzed dehydration because of the stabilizing
effect of the phenyl groups. Four equivalents of Grignard reagent are needed for the reaction:
two equivalents to abstract the acidic protons of the carbamate nitrogen and carboxylic acid
functions, and the other two for the nucleophilic addition onto the ester functionality.

H. L u¨ sch, H. C. Uzar / Tetrahedron: Asymmetry 11 (2000) 4965–4973
4967
Initially, phenylmagnesium bromide was prepared in diethyl ether where quantitative forma-
19
tion of phenylmagnesium bromide was assumed. The Grignard reaction was carried out in the
same solvent by addition of the organometallic compound to semiester 4. Unexpectedly,
hydroxy ketone 6 and diol 7 were the major products while much of the starting material 4
20
remained unreacted. Only minute quantities of the hydroxy acid 8 could be found (see Fig. 2).
Ph
Ph
O
Ph
OH
CO H
2
OH
Ph
OH
Ph
OH
Ph
HN
HN
HN
CO2Et
CO Et
Ph
CO Et
Ph
Ph
2
2
6
7
8
Figure 2.
It was then attempted to increase the selectivity of the Grignard reaction by choosing a
bis-donative solvent such as 1,2-dimethoxyethane (DME) which can slow down the reaction rate
1
9
by chelating the Grignard reagent. Furthermore, chelation of the magnesium cations by the
doubly deprotonated semiester 4 could sterically hinder nucleophilic attack at C-1. Similar
21
complexes with 2,3-dimethoxybutane have been postulated in the literature. Under these
conditions, hydroxy acid 8 was indeed the major product, while hydroxy ketone 6 and diol 7
were not found to have formed. The optimal ratio of bromobenzene to semiester 4 was found
to be 10:1, indicating a low yield in the preparation of phenylmagnesium bromide in DME
2
1
presumably due to coupling reactions. Stronger acidification during the reaction work-up
resulted in the desired dehydration and at 0°C formation of alkenoic acid 9 was favored over
lactonization to compound 10 (3:1) (see Scheme 2). Compound 9 could be purified by
precipitation as its dicyclohexylammonium salt 11 directly from the crude reaction mixture
followed by careful washing with aqueous NaHCO to remove leftover traces of the more polar
3
starting material 4. The 32% overall yield for the last three steps (Grignard reaction, dehydra-
tion, salt precipitation) can still be potentially improved if lactone 10 could be converted into 9.
The method described demonstrates for the first time that alkenoic acid 9 is easily accessible
in enantiomerically pure form. Until now, only a far more complex synthesis of a racemic
22
mixture of the N-acylated 2-amino-5,5-diphenyl-4-pentenoic acid was known.
Esterification of 11 using an H SO /MeOH mixture led to the desired methyl ester 12, but also
2
4
gave lactone 10 as a side product. However, when MeOH and dimethyl sulfate were used, 12
was obtained quantitatively (see Scheme 2). Ozonolysis of 12 in CH Cl /MeOH at −60°C
2
2
followed by reductive work-up with dimethyl sulfide afforded a mixture of semialdehyde 2, its
hydrate 13, and dimethyl acetal 14, in a combined yield of 50% (see Scheme 2), all of which can
potentially be used as building blocks in subsequent synthetic efforts. Reaction of semialdehyde
2
and its hydrate 13 with 2,4-dinitrophenylhydrazine afforded a crystalline derivative that has
been identified unambiguously as hydrazone 15 (see Fig. 3).
3
. Conclusion
A new synthesis of protected -aspartic acid b-semialdehyde 1 was developed in overall yield
L
of ca. 12%. The synthesis is inexpensive since it makes use of the chiral pool, does not require

4968
H. L u¨ sch, H. C. Uzar / Tetrahedron: Asymmetry 11 (2000) 4965–4973
Scheme 2. (a) PhMgBr, DME, 2 h, reflux; then H O; (b) H SO , pH 1.0, 0°C; (c) NH(c-C H ) , Et O; (d) Me SO ,
2
2
4
6
11 2
2
2
4
MeOH, 2 h, steam bath; (e) O , CH Cl /MeOH, −60°C; then Me S, 14 h, rt
3
2
2
2
CO Me
NO2
2
H
N
HN
CO Et
N
2
NO2
15
Figure 3.
costly reagents or possibly harsh oxidizing/reducing conditions, and consists of only a few steps.
It therefore represents a superior alternative to the established methods in the literature.
However, the relatively low pH that is necessary for the dehydration excludes acid-sensitive
N-protecting groups. The key to the success of the synthesis was the control of the regioselectiv-
ity in the reaction of the N-protected semiester 4 with phenylmagnesium bromide, where using
DME as the solvent allowed the nucleophilic addition to be directed successfully towards the
ester group. Exploiting this selective reactivity may enhance the applicability of Grignard
reactions in natural product synthesis.

H. L u¨ sch, H. C. Uzar / Tetrahedron: Asymmetry 11 (2000) 4965–4973
4969
4
. Experimental
.1. General methods
Organic solvents were purified before use. Diethyl ether (Et O) and 1,2-dimethoxyethane
4
2
(
DME) were freed of peroxides by storage over KOH. After subsequent drying over sodium
until positive benzophenone reaction, both ethers were distilled under an inert argon atmo-
sphere. Preparations of phenylmagnesium bromide were also carried out under argon. TLC
analysis was performed using Polygram Sil G/UV254 plates from Macherey–Nagel. The R values
f
of salts given are equivalent to those of the corresponding acids since acidic mobile phases have
been used. Silica gel S (0.032–0.063 mm, 230–400 mesh) from Riedel–de Ha e¨ n was used for flash
chromatography. Melting points were determined on a B u¨ chi 510 apparatus and are uncor-
rected. Optical rotations were measured with the automatic polarimeter AA 1000 from Techno-
1
13
lab. IR spectra were recorded on a Perkin–Elmer FTIR 1750 instrument. H and C NMR
experiments were carried out on a Bruker AC 200 spectrometer operating at 200 and 50 MHz,
respectively, using tetramethylsilane as the internal standard. Mass spectra were obtained on an
HP5988 instrument from Hewlett–Packard, operated in the EI mode at 70 eV. Combustion
analyses were performed by Beller Mikroanalytisches Labor, G o¨ ttingen (Germany).
4
.2. N-Ethoxycarbonyl-
L
-glutamic acid k-methylester 4
L
-Glutamic acid 3 (22.1 g, 150 mmol) was suspended in MeOH (400 mL). Addition of 37%
aqueous HCl (45 mL, 540 mmol) resulted in a colorless solution that was stirred at 25°C for 20
h. H O (120 mL) and NaHCO (46.0 g, 548 mmol) were added, and MeOH was evaporated in
2
3
vacuo. H O was added to give a final volume of 250 mL followed by further NaHCO (33.6 g,
2
3
4
00 mmol). Ethyl chloroformate (32.6 g, 300 mmol) was added dropwise to the solution that
was then stirred for 16 h at 25°C. The solution was washed with Et O (3×50 mL) and the
2
organic phases were discarded. The aqueous solution was cooled using an ice bath and acidified
to pH 2 with cold 50% H SO . The product was extracted with Et O (4×150 mL). The combined
2
4
2
ethereal phases were washed with H O (50 mL), dried over MgSO , and the solvent was
2
4
evaporated to give semiester 4 as a colorless to slightly yellowish oil (24.6 g, 70%): R 0.23
f
1
[
EtOAc/n-hexane/AcOH (30:60:1)]; H NMR (CDCl ) l 1.18 (t, J=7.1 Hz, 3H, OCH CH ),
3
2
3
1
.86–2.08 (m, 1H, CHH%CHN), 2.08–2.30 (m, 1H, CHH%CHN), 2.43 (td, J=7.7, 2.8 Hz, 2H,
CH CO Me), 4.07 (q, J=7.1 Hz, 2H, OCH ), 4.20–4.42 (m, 1H, CH), 5.61 (br d, J=8.1 Hz,
2
2
2
13
0
1
6
.75H, NH), 6.54 (br d, J=7.0 Hz, 0.25H, NH), 10.12 (br s, 1H, CO H); C NMR (CDCl ) l
2
3
4.3 (q, OCH CH ), 27.2 (t, CH CHN), 30.0 (t, CH CO Me), 51.8 (q, OCH ), 52.9 (d, CH),
2
3
2
2
2
3
1.4 (t, OCH ), 156.5 (s, NHCO Et), 173.5 (s, CO Me), 175.3 (s, CO H).
2
2
2
2
4
.3. Dicyclohexylammonium 5-methyl-(S)-N-ethoxycarbonylglutamate 5
Compound 5 was prepared for characterization and storage purposes. Dicyclohexylamine
5.80 g, 32.0 mmol) was added to a solution of semiester 4 (7.46 g, 32.0 mmol) in Et O (100 mL).
(
2
Ammonium salt 5 crystallized overnight in the refrigerator. The colorless crystals were filtered,
washed with cold Et O and dried in vacuo (10.1 g, 76%): R 0.23 [EtOAc/n-hexane/AcOH
2
f
2
0
(
1
30:60:1)]; mp 127–128°C; [h] +11.2 (c 1, MeOH); IR (KBr) w
631, 1547, 1448, 1406, 1374, 1266, 1169, 1075 cm ; H NMR (CDCl ) l 1.03–2.52 (m, 24H, 10
3227, 3000–2400, 1737, 1719,
D
max
−
1 1
3

4970
H. L u¨ sch, H. C. Uzar / Tetrahedron: Asymmetry 11 (2000) 4965–4973
ring-CH , CH CH CO Me), 1.17 (t, J=7.1 Hz, 3H, OCH CH ), 2.81–3.02 (m, 2H, 2 ring-CH),
2
2
2
2
2
3
−
3
8
2
.58 (s, 3H, OCH ), 3.91–4.13 (m, 3H, OCH , NCHCO ), 5.60 (br d, J=6.1 Hz, 1H, NH),
.20–9.70 (br, 2H, N H ); C NMR (CDCl ) l 14.6 (q, OCH CH ), 4×24.7 (t, ring-CH ),
3
2
2
+
13
2
3
2
3
2
×25.0 (t, ring-CH ), 28.9 (t, CH CHN), 4×29.0 (t, ring-CH ), 30.3 (t, CH CO Me), 51.4 (q,
2
2
2
2
2
−
OCH ), 2×52.5 (d, ring-CH), 55.2 (d, NCHCO ), 60.4 (t, OCH ), 156.1 (s, NHCO Et), 174.0 (s,
CO Me), 175.4 (s, CO ). Anal. calcd for C H N O : C 60.85; H 9.24. Found: C, 60.81; H,
3
2
2
2
−
2
2
21 38
2
6
9
.21.
To liberate semiester 4, the ammonium salt 5 (7.50 g, 18.1 mmol) was mixed in a separatory
funnel with an aqueous solution of NaHCO (6.50 g, 77.4 mmol) in H O (70 mL) and Et O (35
3
2
2
mL). NaOH was added until the aqueous phase reached pH 9.5. The ethereal phase was
separated, and the aqueous phase extracted with Et O (2×35 mL) to remove dicyclohexylamine.
2
The aqueous phase was acidified to pH 2 with 50% H SO and extracted with Et O (4×60 mL).
2
4
2
The organic phases were dried over MgSO and the solvent was evaporated to give semiester 4
4
(
3.13 g, 74%).
4
.4. Dicyclohexylammonium (S)-2-(ethoxycarbonylamino)-5,5-diphenyl-4-pentenoate 11
Grignard reactions were carried out in Et O and DME at various stoichiometric ratios and
2
using different reaction work-ups. Reactions in DME using a molar ratio of bromobenzene/
semiester 4 of 10:1 gave the best results. The following procedure proved to be the most efficient.
The Grignard reagent was prepared by dropwise addition of a solution of bromobenzene (35.3
g, 225 mmol) in DME (40 mL) to a slurry of magnesium (5.83 g, 240 mmol) in DME (60 mL).
The reaction started after heating the mixture. To complete the reaction, the mixture was heated
under reflux for an additional 2 h. The Grignard reagent was transferred into a dropping funnel
under an argon atmosphere, while the remaining precipitate and excess magnesium were
removed by this procedure. The Grignard reagent was then added to a solution of semiester 4
(
5.00 g, 21.4 mmol) in DME (75 mL) under vigorous stirring and sonication. The white
suspension was heated under reflux for 2 h and it finally turned yellow. The mixture was
hydrolyzed with H O (100 mL), acidified until pH 1.0 with H SO (50%) under cooling of the
2
2
4
flask with ice. The precipitate dissolved, and the red organic phase was separated. The aqueous,
mixed phase was extracted with Et O (4×100 mL). The extracts were combined with the
2
previously separated organic phase and washed with aqueous NaHCO solution of pH 8.0 (2×25
3
mL) and then further washed with H O (25 mL). The ethereal phase was concentrated to a final
2
volume of 30 mL and dicyclohexylamine (3.88 g, 21.4 mmol) was added. The mixture was
allowed to crystallize overnight in the refrigerator, the precipitated product was then collected
by filtration and recrystallized from CHCl /n-hexane to afford pure 11 (3.54 g, 32% from 4): R
3
f
2
0
0
3
7
.47 [EtOAc/n-hexane/AcOH (30:60:1)]; mp 140–141°C; [h] +36.5 (c 1, MeOH); IR (KBr) w
D
max
422, 3054, 3025, 3000–2400, 1708, 1631, 1595, 1557, 1539, 1495, 1444, 1420, 1397, 1242, 1062,
−
1 1
58, 701 cm ; H NMR (CDCl ) l 1.00–2.03 (m, 23H, 10 ring-CH , CH ), 2.48–3.06 [m, 4H,
3
2
3
+
−
2
CH CHN, N (CH) ], 3.97–4.28 (m, 3H, OCH , NCHCO ), 5.62 (br d, J=7.1 Hz, 1H, NH),
6
2
2
2
+
13
.21 [t, J=7.0 Hz, 1H, CHC(Ph) ], 7.15–7.43 (m, 10H, CH ), 7.90–8.90 (br, 2H, N H );
C
2
ar.
2
NMR (CDCl ) l 14.7 (q, CH ), 4×24.7 (t, ring-CH ), 2×25.0 (t, ring-CH ), 4×29.1 (t, ring-CH ),
3
3
2
2
2
+
−
3
1
4.0 (t, CH CHN), 52.4 [d, N (CH) ], 55.6 (d, NCHCO ), 60.3 (t, OCH ), 126.0 [d, CHC(Ph) ],
26.7, 127.2, 127.9, 128.0, 129.9 (d, 10×CH ), 140.0, 142.8, 143.1 [s, 2×C , C(Ph) ], 155.9 (s,
NHCO Et), 175.6 (s, CO ). Anal. calcd for C H N O : C, 73.81; H, 8.52. Found: C, 73.87; H,
2
2
2
2
2
ipso
ar.
ar.
2
−
2
2
32 44
2
4
8
.42.

H. L u¨ sch, H. C. Uzar / Tetrahedron: Asymmetry 11 (2000) 4965–4973
4971
4
.5. Methyl (S)-2-(ethoxycarbonylamino)-5,5-diphenyl-4-pentenoate 12
A solution of ammonium salt 11 (2.09 g, 4.02 mmol) and dimethyl sulfate (506 mg, 4.02
mmol) in MeOH (20 mL) was heated in a steam bath for 2 h. H O (50 mL) was added and the
2
solution extracted with Et O (4×50 mL). The combined ethereal phases were washed with
2
saturated aqueous NaHCO (50 mL) and then with H O (50 mL). The solvent was evaporated
3
2
to give 12 as an oily, yellowish residue (1.42 g, 100%): R 0.48 [Et O/n-pentane (1:1)]; IR (film)
f
2
wmax 3336, 3056, 3025, 2981, 2953, 1745, 1723, 1599, 1525, 1497, 1444, 1372, 1213, 1178, 1059,
−
1
1
7
62, 702 cm ; H NMR (CDCl ) l 1.14 (t, J=7.1 Hz, 3H, OCH CH ), 2.37–2.72 (m, 2H,
3
2
3
CH CHN), 3.61 (s, 3H, OCH ), 4.02 (q, J=7.1 Hz, 2H, OCH ), 4.32–4.47 (m, 1H, CHN), 5.16
2
3
2
(
br d, J=8.4 Hz, 1H, NH), 5.91 [t, J=7.4 Hz, 1H, CHC(Ph) ], 6.95–7.39 (m, 10H, CH );
2
ar.
1
3
CNMR (CDCl ) l 14.5 (q, OCH CH ), 32.7 (t, CH CHN), 52.3 (q, OCH ), 53.5 (d, CHN),
3
2
3
2
3
6
1
3
1.1 (t, OCH ), 122.6 [d, CHC(Ph) ], 127.2, 127.3, 127.7, 128.1, 128.3, 129.6 (d, 10×CH ),
2
2
ar.
ipso
39.3, 142.0, 145.4 [2×C , C(Ph) ], 155.9 (s, NHCO Et), 172.3 (s, CO Me); MS (EI) m/z (%)
ar.
2
2
2
+
+
53 (2) [M ], 294 (52) [M −CO CH ], 205 (88), 178 (17), 165 (30), 144 (16), 115 (23), 90 (84), 77
’
9), 59 (6) [CO CH ], 29 (56), 28 (100) [C H ].
2
3
+
+
(
2
3
2
4
4
.6. Ozonolysis of methyl (S)-2-(ethoxycarbonylamino)-5,5-diphenyl-4-pentenoate 12
Ester 12 (1.41 g, 3.99 mmol) was dissolved in a mixture of CH Cl /MeOH (2:1) (300 mL) and
2
2
ozonized at −60°C. Dimethyl sulfide (1 mL) was added and the solution stirred at room
temperature overnight. The solvent was removed in vacuo. Flash chromatography of the residue
gave semialdehyde 2, partially hydrated to 13, and its dimethyl acetal 14.
4
.7. Mixture of N-ethoxycarbonyl-
L
-aspartic acid h-methyl ester i-semialdehyde 2 and N-
†
ethoxycarbonyl- -aspartic acid h-methyl ester i-semialdehyde hydrate 13
L
Slightly yellowish oil (250 mg, ca. 31%); R 0.27 [Et O/n-pentane (2:1)]; IR (film) w
982, 2940, 2720, 1740, 1723, 1700, 1531, 1440, 1374, 1221, 1180, 1066 cm ; H NMR (CDCl )
3362,
f
2
max
−
1 1
2
3
for 2: l 1.17 (t, J=7.1 Hz, 3H, OCH CH ), 3.02 (t, J=5.0 Hz, 2H, CH CHN), 3.68 (s, 3H,
2
3
2
OCH ), 4.05 (q, J=7.1 Hz, 2H, OCH ), 4.58 (dt, J=8.4, 5.0 Hz, 1H, CHN), 5.76 (br d, J=8.4
3
2
1
Hz, 1H, NH), 9.66 (s, 1H, CHO); H NMR (CDCl ) for 13: l 1.17 (t, J=7.1 Hz, 3H,
3
OCH CH ), 1.98–2.10 (m, 2H, CH CHN), 3.68 (s, 3H, OCH ), 4.05 (q, J=7.1 Hz, 2H, OCH ),
2
3
2
3
2
1
3
4
.37–4.48 (m, 1H, CHN), 5.20–5.32 [m, 1H, CH(OH) ], 5.65 (br d, J=7.9 Hz, 1H, NH);
C
2
NMR (CDCl ) for 2: l 14.4 (q, OCH CH ), 45.8 (t, CH CHN), 48.8 (d, CHN), 52.8 (q, OCH ),
3
2
3
2
3
13
6
1
9
2
5
1.4 (t, OCH ), 156.1 (s, NHCO Et), 171.2 (s, CO Me), 199.3 (d, CHO); C NMR (CDCl ) for
2
2
2
3
3: l 14.4 (q, OCH CH ), 35.1 (t, CH CHN), 50.5 (d, CHN), 52.5 (q, OCH ), 61.4 (t, OCH ),
2
3
2
3
2
+
8.5 [d, CH(OH) ], 156.1 (s, NHCO Et), 172.5 (s, CO Me); MS (EI) m/z (%) 203 (0.1) [M for
2
2
2
+
], 175 (2), 171 (8), 144 (100) [(M −CO CH ) for 2], 130 (10), 115 (11), 102 (6), 88 (6), 72 (17),
9 (6), 44 (52) [CH ꢀCH-OH ], 29 (25).
2
3
+
’
2
†
NMR signal assignments were made with aid of 2D NMR correlation experiments and published NMR data for
similar compounds.

4972
H. L u¨ sch, H. C. Uzar / Tetrahedron: Asymmetry 11 (2000) 4965–4973
4
.8. Methyl (S)-2-(ethoxycarbonylamino)-4,4-dimethoxybutanoate 14
Slightly yellowish oil (187 mg, 19%); R 0.49 [Et O/n-pentane (2:1)]; IR (film) w
3400, 2980,
f
2
max
−
1 1
2
954, 2820, 1745, 1713, 1542, 1440, 1373, 1224, 1185, 1130–1000 cm ; H NMR (CDCl ) l 1.17
3
(
t, J=7.1 Hz, 3H, OCH CH ), 1.90–2.18 (m, 2H, CH CHN), 3.24 (s, 3H, CH OCHOCH%), 3.27
2
3
2
3
3
(
s, 3H, CH OCHOCH%), 3.67 (s, 3H, CO CH ), 4.05 (q, J=7.1 Hz, 2H, OCH ), 4.28–4.46 (m,
3
3
2
3
2
13
2
3
1
2
2
H, CHCH CH), 5.57 (br d, J=7.9 Hz, 1H, NH); C NMR (CDCl ) l 14.4 (q, OCH CH ),
2
3
2
3
4.8 (t, CH CHN), 50.7 (d, CHN), 52.2, 53.2, 53.6 [q, CO CH , CH(OCH ) ], 61.0 (t, OCH ),
2
2
3
3 2
2
+
02.0 [d, CH(OMe) ], 156.3 (s, NHCO Et), 172.8 (s, CO Me); MS (EI) m/z (%) 249 (0.01) [M ],
18 (2), 190 (5) [M −CO CH ], 161 (4), 158 (9), 129 (33), 88 (6), 75 (100) [CH(OCH ) ], 59 (5),
2
+
2
2
+
2
3
3 2
9 (6).
4
.9. N-Ethoxycarbonyl- -aspartic acid h-methyl ester i-semialdehyde-(2,4-dinitro)phenyl-
L
hydrazone 15
A freshly prepared solution of the mixture of 2 and 13 (100 mg, ca. 479 mmol) in EtOH (1
mL) was added to a solution of 2,4-dinitrophenylhydrazine (400 mg, 2.02 mmol) in concentrated
H SO (2 mL) and H O (25 mL). The resultant precipitate was filtered, washed with H O,
2
4
2
2
recrystallized from EtOAc/n-hexane, and dried in vacuo. Yellow crystals of 15 were obtained
2
0
1
(
20.5 mg, ca. 11%): mp 167–168°C; [h] +40.2 (c 0.5, CHCl ); H NMR (CDCl ) l 1.18 (t,
D
3
3
J=7.1 Hz, 3H, OCH CH ), 2.80–3.06 (m, 2H, CH CHN), 3.73 (s, 3H, OCH ), 4.07 (q, J=7.1
2
3
2
3
Hz, 2H, OCH ), 4.56–4.73 (m, 1H, NCHCO Me), 5.41 (br d, J=8.1 Hz, 1H, NHCO Et), 7.44
2
2
2
(
6)
(
t, J=4.4 Hz, 1H, CHNNH), 7.77 (d, J=9.6 Hz, 1H, CH ), 8.28 (dd, J=9.6, 2.6 Hz, 1H,
CH ), 9.05 (d, J=2.6 Hz, 1H, CH ), 11.0 (s, 1H, NNH); C NMR (CDCl ) l 14.5 (q,
ar.
(
5)
(3)
ar.
13
ar.
3
OCH CH ), 35.4 (t, CH CHN), 51.2 (d, NCHCO Me), 52.9 (q, OCH ), 61.5 (t, OCH ), 116.4
2
3
2
2
3
2
quart.
ar.
quart.
ar.
quart.
(
d, CH ), 123.4 (d, CH ), 129.3 (s, C
), 130.2 (d, CH ), 138.4 (s, C
), 144.9 (s, Car. ),
ar.
ar.
ar.
1
4
46.5 (d, CHNNH), 156.0 (s, NHCO Et), 171.7 (s, CO Me). Anal. calcd for C H N O : C,
3.87; H, 4.47. Found: C, 44.65; H, 4.77.
2
2
14 17
5
8
Acknowledgements
The authors thank the Deutsche Forschungsgemeinschaft and the Fond der Chemischen
Industrie for financial support.
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