Regioselective opening of N-Cbz glutamic and aspartic anhydrides with carbon nucleophiles

Article abstract of DOI:10.1016/j.tetasy.2006.07.039

Depending on the experimental conditions, aspartic and glutamic anhydrides can be opened regioselectively with Grignard reagents, thus giving access to different isomers of chiral amino-ketoesters.

Full text of DOI:10.1016/j.tetasy.2006.07.039

Tetrahedron: Asymmetry 17 (2006) 2120–2125
Regioselective opening of N-Cbz glutamic and aspartic
anhydrides with carbon nucleophiles
*
Geoffrey Deguest, Laurent Bischoff, Corinne Fruit and Francis Marsais
Laboratoire de Chimie Organique Fine et H e´ t e´ rocyclique—IRCOF-INSA Rouen—CNRS UMR 6014—BP 08,
7
6131 Mont-Saint-Aignan Cedex, France
Received 16 June 2006; accepted 27 July 2006
Abstract—Depending on the experimental conditions, aspartic and glutamic anhydrides can be opened regioselectively with Grignard
reagents, thus giving access to different isomers of chiral amino-ketoesters.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
NaBH4 can also reduce regioselectively the a-carbonyl,
providing the corresponding lactone after intramolecular
3
Glutamic and aspartic acid derivatives are both widely
used in synthesis, owing to the possible differentiation
between the two carboxylic acids. Generally, these different
reactivities constitute a valuable tool in selective protec-
tion. This implies that selective activation of a carboxylic
acid moiety is consecutive to the protection of the other
acid, thus generally requiring two or three steps to reach
a suitably protected-activated derivative from the starting
diacid.
esterification.
The literature provides two main methods for the synthesis
of aminoketones from such compounds. On the one hand,
the internal anhydride can be used as a powerful electro-
phile under Friedel–Crafts conditions (i.e., AlCl in the
presence of electron-rich aromatic substances), leading to
3
4
an attack on the side-chain carbonyl. On the other hand,
the reaction of strongly basic organometallics generally
requires protected amino acids, often expensive or time-
consuming, the anhydrides being used as precursors of suit-
ably protected synthons. While nucleophilic additions to
these anhydrides are well-known, reactions involving
organometallics are sparse. Only aspartic anhydride was
reacted with organomagnesiums in refluxing ether, afford-
ing double addition at the a-carbon with low yields of
Herein, we report short and efficient syntheses of amino-
ketoesters starting from N-Cbz glutamic and aspartic
anhydrides. These synthons can lead to regioselective
nucleophilic attack by organometallics, or to rapid trans-
formations which reverse the regioselectivity without prior
monoprotection.
5
the resulting lactones.
2
. Results and discussion
In order to develop very short syntheses of amino-ketoest-
ers from both anhydrides, we examined the reactivities of
different organometallics (Scheme 1). Aryl or alkyllithiums
were first reacted with glutamic anhydride (prepared by
2
.1. Regioselective a-opening
6
In the title anhydrides, the presence of the N-protected
amino group is able to activate the neighboring carbonyl,
thus affording regioselective attack by alcohols or amines
due to an intramolecular hydrogen bond. Furthermore,
dehydration of glutamic acid with acetic anhydride). The
reaction of such organometallics mostly resulted in com-
petitive deprotonation of the carbamate, to give pyro-
glutamic acid 4 (Table 1, entries 1 and 2). Traces of the
desired a-amino-ketoacid 2 were observed with phenyl-
lithium, along with 21% of the isomeric c-aminoketone 3,
presumably obtained by the subsequent opening of lithium
pyroglutamate formed in situ. Each experiment also
1
2
*
Corresponding author. Fax: +33 2 35 52 29 62; e-mail: laurent.bischoff@
insa-rouen.fr
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.039

G. Deguest et al. / Tetrahedron: Asymmetry 17 (2006) 2120–2125
2121
O
O
CbzHN
CbzHN
CbzHN
COOH
Cbz
N
CbzHN
COOH
COOH
O
R
i, ii
O
O
COOH
COOH
R
O
1
2
3
4
5
Scheme 1. Reagents and conditions: (i) 1.6 equiv, R–M, THF; (ii) 0.5 M citric acid.
Table 1. Reaction of different organometallics with glutamic anhydride 1
Table 2. Opening glutamic anhydride with Grignard reagents
a
Entry R–M
Conditions
2
3
4
5
Entry
Organometallic
Compound no.
Yield (%)
(
%) (%) (%) (%)
1
2
3
4
5
PhMgCl
3-(MeO)-C H -MgBr
6 4
2-Thienyl-MgBr
n-BuMgBr
n-Hexyl-MgBr
6a
6b
6c
6d
6e
57
63
58
45
46
1
2
3
4
5
6
PhLi
n-BuLi
ꢀ78 °C, 4 h
ꢀ78 °C, 2 h
6
0
0
0
21
0
0
37
52
65
15
21
18
36
48
35
85
16
39
t-BuMgCl ꢀ78 °C, 4 h
PhZnCl
PhMgCl
ꢀ78 °C, 2 h
ꢀ78 °C, 4 h
0
63
0
a
Isolated yields after column chromatography.
3
Ph MgLi ꢀ78 °C to rt then rt 2 h 17
26
Percentages were estimated by NMR on the crude material spectra.
Cbz pyroglutamic acid was also transformed into diester
. When applying our experimental conditions (i.e.
7
afforded non-negligible amounts of N-Cbz glutamic acid 5,
resulting from hydrolysis of the remaining anhydride or its
salts. Using a more basic alkyllithium reagent, such as
butyllithium, confirmed the predominant formation of
pyroglutamic acid 4 which, however, did not further react
in this case. This was confirmed with t-BuMgCl, which
exhibited a very low nucleophilicity, and also led to the for-
mation of 4 in 65% yield, without further addition. As we
wished to lower the basicity of the organometallic, PhZnCl
was used. No ketone was observed in this experiment and
higher temperatures resulted in degradation.
1.6 M equiv of RMgX in THF, ꢀ78 °C, 4 h), we observed
that arylmagnesium reagents could provide a-amino aryl-
ketones 6a–c in 57–63% isolated yields (entries 1–3). We
also obtained ketone 6b, which can not be synthesized via
Friedel–Crafts acylation, making our method a comple-
mentary tool for such preparations.
Alkylmagnesium halides gave similar aminoketones with
modest yields after subsequent esterification (entries 4
and 5).
In order to broaden the scope of the synthesis of amino-
ketones, we applied this procedure to aspartic anhydride
(Scheme 3). As expected, the same regioselective opening
occurred with comparable yields of a-aminoketones 9a–c
(Table 3). Since this substrate is unable to provide internal
imides by an intramolecular process, the diacid was the
only side product, isolated as its diester derivative 10.
We were pleased to note that the reaction of the organo-
magnesium species (entry 5) led to a regioselective opening
of the anhydride at the a-carbon. Concomitant formation
of pyroglutamic acid 4 and glutamic acid 5 was also ob-
served. Higher temperatures resulted in more pyroglutamic
acid 4, while other solvents such as ether or toluene, made
the addition much slower without increasing the yields. We
7
attempted to use a lithium magnesiate but this led to a
non-regioselective reaction, presumably due to the more
basic character of this reagent.
O
O
CbzHN
CbzHN
CbzHN
COOMe
COOMe
O
R
i, ii
iii
+
We then extended the reactivity of glutamic anhydride to
other Grignard reagents (Scheme 2, Table 2). In order to
avoid difficulties in separating the ketoacid from N-Cbz
glutamic acid 5, the opening was followed by an esterifica-
tion of the crude reaction mixture. Only the keto ester 6a
and N-Cbz-glutamic acid diester 7 were thus obtained, N-
O
COOMe
9a-c
8
10
Scheme 3. Reagents and conditions: (i) 1.6 equiv RMgX, THF, ꢀ 78 °C;
(ii) 0.5 M citric acid; (iii) MeOH, SOCl , overnight.
2
Table 3. Opening aspartic anhydride with Grignard reagents
O
a
O
Entry
Reagent
Compound
Yield (%)
CbzHN
CbzHN
COOMe
CbzHN
i, ii, iii
R
1
2
3
PhMgCl
3-(MeO)-C
n-BuMgBr
9a
9b
9c
54
60
41
O
6 4
H -MgBr
O
COOMe
COOMe
1
a
Isolated yields after column chromatography.
6
a-e
7
Scheme 2. Reagents and conditions: (i) RMgX, ꢀ78 °C, THF; (ii) 0.5 M
citric acid; (iii) MeOH, SOCl , overnight.
In summary, regioselective nucleophilic additions of
organomagnesium compounds on aspartic and glutamic
2

2122
G. Deguest et al. / Tetrahedron: Asymmetry 17 (2006) 2120–2125
anhydrides provide a very expeditious method for the prep-
aration of b-amino-c-ketoesters and particularly c-amino-
d-ketoesters.
Cbz-pyroglutamate 11 (Scheme 5). In addition, Boc O
2
itself is likely to induce dehydration of the diacid, thus
making it suitable for the formation of N-Cbz glutamic
acid internal anhydride 1. This was confirmed by using
N-Cbz glutamic acid in the presence of one more molar
2
.2. Addition onto the side-chain carbonyl
equivalent of Boc O. In this way, side reactions could be
2
In the literature, regioselectivity in favor of the c-amino-
avoided if nucleophilic reagents were further allowed to
react with the resulting material.
ketone is generally obtained by the use of pyroglutamic
8
esters, a method of choice for the preparation of
5
-substituted prolines. These pyroglutamic esters are most
A very short procedure first involved the treatment of N-
classically obtained via treatment of glutamic anhydride
in the presence of dicyclohexylamine. In the present study,
the a-amino-c-ketoacid 3 was obtained using more basic
Cbz glutamic acid with Boc O/DMAP. Subsequent evapo-
2
9
ration afforded clean pyroglutamate 11 which could be
8
treated with Grignard reagents without further purifica-
reagents such as PhLi or Ph MgLi (Table 1). We then tried
tion. Opening 11 with CH MgBr or PhMgCl gave the a-
3
3
to preform the pyroglutamate intermediate in situ by
action of a basic organomagnesium (Scheme 4).
amino-c-ketoesters 12a and 12b in 67% and 70% yields,
respectively (Scheme 5). The enantiomeric excess measured
1
0
for 12a was consistent with that previously reported.
Thus, the reaction of t-BuMgCl, followed by the addition
of PhMgCl gave a 1:10 ratio of a:c-ketones with a global
To the best of our knowledge, this constitutes the shortest
synthesis of N-protected pyroglutamic esters, since these
compounds are generally prepared in three to four steps.
Under our conditions, only one step is required to achieve
at the same time, side-chain activation and a-acid protec-
tion. This preparation can be conducted on a multigram
scale, making it a valuable tool in synthesis of pyrrolidine
precursors.
3
8% conversion, along with 25% unreacted pyroglutamic
acid 4 and 37% glutamic acid 5. This poor conversion can
be explained by the pyroglutamate being a poor electro-
phile, since the latter is formed as its magnesium salt,
which is much less reactive than pyroglutamic esters
themselves.
We thought that the most efficient way of reversing the
regioselectivity was to prevent the hydrogen bond activa-
tion by the carbamate, accounting for the a-regioselecti-
vity. For this purpose, total N-protection as a dicarbamate
With these conditions in hand, we attempted to apply them
to aspartic anhydride, although we believed that its geo-
metry would prevent the intramolecular acylation of the
nitrogen. As depicted in Scheme 6, treatment of N-Cbz
was attempted. Thus, anhydride 1 was treated with Boc O
2
in the presence of 10% DMAP. To our great surprise, these
aspartic acid with Boc O led to the N,N-dicarbamate 13
2
conditions allowed a very clean formation of tert-butyl-N-
instead of the azetidinone.
O
CbzHN
i : PhMgCl
ii : H3O+
COOH
Cbz
N
CbzHN
t-BuMgCl
O
O
COOMgCl
3
1
O
O
Ph
Scheme 4. Attempt at reversing the regioselectivity.
Cbz
N
CbzHN
COOt-Bu
R
2a : R=Me : 67%
2b : R=Ph : 70%
CbzHN
ii
COOH
COOH
i
R-M
O
COOt-Bu
11
O
O
1
1
CbzHN
ii
O
1
O
2
Scheme 5. Reagents and conditions: (i) 2 equiv Boc O, cat DMAP; (ii) 1 equiv Boc
2
O, cat DMAP.
Boc
O
Cbz
O
COOt-Bu
CbzHN
COOH
COOH
N
i
i
N
Cbz
8
0 %
O
13
O
2
Scheme 6. Reagents and conditions: (i) 2 equiv Boc O, cat DMAP.

G. Deguest et al. / Tetrahedron: Asymmetry 17 (2006) 2120–2125
2123
When subjected to reaction with phenylmagnesium chlo-
ride, this anhydride may have led to nucleophilic attack
onto the b-carbon. However, the purification of the result-
ing compound was sluggish and did not allow us to make
reliable conclusions.
(8 mL). After stirring overnight, and subsequent evapora-
tion, the residue was dissolved in anhydrous THF
(20 mL). The Grignard reagent (2.84 mmol) was added at
ꢀ78 °C and stirred for 6 h at this temperature. Quenching
with 0.5 M citric acid (10 mL) and extractive work-up with
diethyl ether afforded a residue, which was chromato-
graphed on silica gel.
Even though the synthetic applications of N,N-diprotected
aspartic anhydride 13 are limited, the straight formation of
pyroglutamate 11 from N-protected glutamic acid makes it
a very useful tool in synthesis.
4.2. Data for new compounds
4.2.1. (4S)-Methyl 4-(benzyloxycarbonylamino)-5-oxo-5-
phenylpentanoate 6a. Following the general procedure
and using commercially available PhMgCl, flash chroma-
tography on silica gel (cyclohexane–ethyl acetate 1:2,
3
. Conclusion
This work shows that the synthetic utility of aspartic and
glutamic anhydrides can be advantageously extended to
ketone synthesis. Chiral amino-ketoesters can be efficiently
synthesized by regioselective nucleophilic addition of
organomagnesiums. The wide range of applications
of chiral amino ketoesters affords an interesting choice of
targets in synthesis.
R = 0.50) provided 6a (383 mg, 57%) as a colorless oil.
f
1
H NMR d 1.69–1.82 (1H, m), 2.27–2.57 (3H, m), 3.66
3H, s), 5.11 (2H, s), 5.45 (1H, td, J 8.3 and 3.0 Hz), 5.85
(
(
7
1H, d, J 8.3 Hz), 7.35 (5H, m), 7.52 (2H, dd, J 7.5 and
13
.2 Hz), 7.61 (1H, t, J 7.2 Hz), 8.04 (2H, d, J 7.5 Hz);
C
NMR d 28.9, 29.5, 51.8, 54.8, 67.1, 128.1, 128.2, 128.6,
28.9, 129.0, 134.0, 134.1, 136.3, 156.3, 173.3, 198.3; IR
1
ꢀ
1
(cm ): 3349, 2951, 1733, 1685, 1596, 1522, 1448, 1353,
4
. Experimental
1261, 1218, 1055, 697; MS-IC(+): 356 (100%), 310, 248,
20
2
22, 205, 73; ½aꢁ ¼ þ29:0 (c 1, CH Cl ). Elemental analy-
D
2
2
4
.1. General experimental
sis calcd for C H NO : C, 67.59; H, 5.96; N, 3.94. Found:
20 21 5
C, 67.55; H, 5.98; N, 3.96.
NMR spectra were recorded on a 300 MHz Bruker
Avance. Unless otherwise indicated, all spectra were
recorded at 300 MHz for H and 75 MHz for C in
4.2.2. (4S)-Methyl 4-(benzyloxycarbonylamino)-5-(3-meth-
oxyphenyl)-5-oxopentanoate 6b. Titration of 3-methoxy-
phenylmagnesium bromide prepared as described above,
gave a concentration of 0.59 mol L . Following the
general procedure, flash chromatography on silica gel (tol-
1
13
CDCl . All chemical shifts are given in ppm. R given for
3
f
ꢀ
1
TLC analyses were measured on silica gel Merck Kieselgel
F254 aluminum plates. Optical rotations were measured on
a Perkin–Elmer 341 polarimeter.
uene–ethyl acetate 4:1, R = 0.57) provided 6b (459 mg,
f
1
63%) as a colorless oil. H NMR d 1.68–1.81 (1H, m),
4
.1.1. Typical procedure for the synthesis of Grignard
2.30–2.41 (2H, m), 2.46–2.59 (1H, m), 3.67 (3H, s), 3.87
(3H, s), 5.11 (2H, s), 5.43 (1H, td, J 8.4 and 2.8 Hz), 5.81
(1H, d, J 7.9 Hz), 7.16 (1H, dd, J 8.1 and 2.4 Hz), 7.35
reagents. Aryl or alkyl halide (8 mmol) was added to a
suspension of magnesium turnings (204 mg, 8.4 mmol) in
THF (1.5 mL). The solution was stirred at 40 °C for 2 h
then diluted with anhydrous THF (6.5 mL). Titration was
carried out with L-(ꢀ)-menthol/1,10-phenanthroline.
13
(6H, m), 7.58 (1H, s), 7.65 (1H, d, J 7.5 Hz); C NMR d
29.1, 29.5, 51.9, 54.9, 55.6, 67.2, 112.9, 120.9, 121.5,
128.2, 128.3, 128.6, 130.1, 135.3, 136.3, 156.3, 160.1,
ꢀ
1
1
73.3, 198.1; IR (cm ): 3338, 2945, 1726, 1684, 1596,
4
.1.2. Typical procedure for 6a–e and 9a–c. To a stirred
solution of N-Cbz-glutamic anhydride (500 mg,
.89 mmol) or commercially available aspartic anhydride
500 mg, 2.00 mmol) in anhydrous THF (20 mL) was
added the Grignard reagent (3.03 mmol) dropwise at
78 °C over a period of 5 min. Stirring was continued
1521, 1435, 1300, 1260, 1248, 1044, 698; MS-IC(+): 386
20
(100%), 342, 282, 250, 152, 73; ½aꢁ ¼ þ23:6 (c 1, CH Cl ).
D
2
2
1
(
Elemental analysis calcd for C H NO : C, 65.44; H, 6.02;
21 23 6
N, 3.63. Found: C, 65.47; H, 6.06; N, 3.54.
ꢀ
4.2.3. (4S)-Methyl 4-(benzyloxycarbonylamino)-5-oxo-
5-(thiophen-2-yl)pentanoate 6c. Titration of 2-thienylmag-
nesium bromide prepared as described above, gave a
for an additional 4 h at this temperature. The reaction
was quenched with 0.5 M citric acid (7 mL), then warmed
to rt and the crude material isolated by extractive work-
up with diethyl ether. The residue was taken-up in 20 mL
absolute methanol, then thionyl chloride (0.14 mL,
ꢀ
1
concentration of 0.56 mol L . Following the general
procedure, flash chromatography on silica gel (toluene–
ethyl acetate 4:1, R = 0.47) provided 6c (395 mg, 58%) as
f
1
1
.89 mmol) was added and the solution stirred overnight.
a brown oil. H NMR d 1.77–1.89 (1H, m), 2.30–2.60
After subsequent evaporation, the residue was chromato-
graphed on silica gel.
(3H, m), 3.69 (3H, s), 5.11 (2H, s), 5.28 (1H, td, J 8.1
and 3.2 Hz), 5.71 (1H, d, J 8.1 Hz), 7.19 (1H, t, J
4
.4 Hz), 7.3 (5H, m), 7.71 (1H, d, J 4.4 Hz), 8.04 (1H, d,
1
3
4
1
.1.3. Procedure for the straight synthesis of ketones 12a and
2b from N-Cbz glutamic acid. To a stirred solution of di-
J 4.4 Hz); C NMR d 29.5, 29.6, 51.9, 55.7, 67.2, 128.2,
128.3, 128.6, 128.8, 128.9, 133.9, 135.4, 136.2, 141.1,
ꢀ1
tert-butyl dicarbonate (776 mg, 3.56 mmol) in anhydrous
THF (4 mL), was added 4-dimethylaminopyridine
156.3, 173.4, 191.1; IR (cm ): 3356, 2922, 1720, 1660,
1513, 1438, 1412, 1357, 1223, 1049, 731, 698; MS-IC(+):
362 (100%), 318, 282, 250, 228, 212, 152, 107, 91;
(
22 mg, 0.18 mmol) immediately followed by N-Cbz glu-
25
tamic acid (500 mg, 1.78 mmol) in anhydrous THF
½aꢁ ¼ ꢀ423 (c 1, CH Cl ). Elemental analysis calcd for
D
2
2

2124
G. Deguest et al. / Tetrahedron: Asymmetry 17 (2006) 2120–2125
C H NO S: C, 59.82; H, 5.30; N, 3.88; S, 8.87. Found: C,
5.3 Hz), 5.93 (d, J 8.5 Hz), 7.12 (1H, dd, J 8.1 and
2.0 Hz), 7.33 (m, 6H), 7.48 (s, 1H), 7.54 (1H, d, J
1
8
19
5
5
9.89; H, 5.16; N, 3.86; S, 8.61.
1
3
7.5 Hz); C NMR d 37.2, 52.2, 52.7, 55.6, 67.3, 112.7,
4
.2.4. (4S)-Methyl 4-(benzyloxycarbonylamino)-5-oxono-
120.8, 121.3, 128.1, 128.3, 128.7, 129.0, 135.7, 136.2,
155.8, 160.1, 171.1, 196.9; MS-IC(+): 372 (100%), 328,
nanoate 6d. Titration of butylmagnesium bromide pre-
pared as described above, gave a concentration of 0.54
mol L . Following the general procedure, flash chroma-
tography on silica gel (cyclohexane–ethyl acetate 1:1,
25
282, 236, 221, 152, 113, 91; ½aꢁ ¼ ꢀ11:6 (c 1, CH Cl ).
D
2
2
ꢀ
1
Elemental analysis calcd for C H NO : C, 64.68; H,
20 21 6
5.70; N, 3.77. Found: C, 64.65; H, 5.62; N, 3.89.
R = 0.74) provided 6d (285 mg, 45%) as a colorless oil.
f
1
H NMR d 0.86–0.91 (3H, m), 1.21–1.35 (2H, m), 1.50–
4.2.8. (4S)-Methyl 4-(benzyloxycarbonylamino)-5-oxooct-
anoate 9c. Titration of butylmagnesium bromide pre-
pared as described above, gave a concentration of 0.54
1
.58 (2H, m), 1.72–1.86 (1H, m), 2.21–2.56 (5H, m), 3.64
(
(
3H, s), 4.42 (1H, td, J 7.6 and 3.8 Hz), 5.07 (2H, s), 5.65
1
3
ꢀ1
1H, d, J 7.6 Hz), 7.33 (5H, m); C NMR d 13.9, 22.3,
mol L . Following the general procedure, flash chroma-
2
1
1
3
5.6, 26.8, 29.6, 39.5, 51.9, 58.9, 67.0, 128.1, 128.3, 128.6,
tography on silica gel (cyclohexane–ethyl acetate 2:1,
ꢀ
1
36.3, 156.1, 173.3, 208.6; IR (cm ): 3348, 2957, 1731,
714, 1519, 1455, 1254, 1175, 1028, 740, 698; MS-IC(+):
R = 0.52) provided 9c (265 mg, 41%) as a colorless oil.
f
1
H NMR d 0.90 (3H, t, J 7.2 Hz), 1.25–1.32 (2H, m),
20
36 (100%), 292, 250, 202, 91; ½aꢁ ¼ þ24:4 (c 1, CH Cl ).
1.52–1.58 (2H, m), 2.52–2.58 (2H, m), 2.73–2.81 (1H, dd,
J 17.1 and 4.3 Hz), 2.97–3.03 (1H, dd, J 17.1 and
4.3 Hz), 3.66 (3H, s), 4.49 (1H, td, J 8.8 and 4.52 Hz),
D
2
2
Elemental analysis calcd for C H NO : C, 64.46; H, 7.51;
N, 4.18. Found: C, 64.31; H, 7.63; N, 4.13.
1
8
25
5
1
3
5.13 (2H, s), 5.88 (1H, d, J 8.8 Hz), 7.36 (5H, m);
C
4
.2.5. (4S)-Methyl 4-(benzyloxycarbonylamino)-5-oxounde-
NMR d 14.0, 22.3, 25.5, 35.7, 38.8, 52.2, 56.4, 67.3,
canoate 6e. Titration of hexylmagnesium bromide pre-
128.2, 128.4, 128.7, 136.2, 156.1, 171.9, 208.6; MS-IC(+):
25
pared as described above, gave a concentration of
336 (100%), 292, 250, 202, 91; ½aꢁ ¼ þ29:3 (c 1, CH Cl ).
D
2
2
ꢀ1
0
.54 mol L . Following the general procedure, flash chro-
Elemental analysis calcd for C H NO : C, 63.54; H, 7.21;
17 23 5
matography on silica gel (cyclohexane–ethyl acetate 2:1,
R = 0.48) provided 6e (316 mg, 46%) as a yellow oil. H
f
N, 4.36. Found: C, 63.24; H, 7.15; N, 4.59.
1
NMR d 0.84–0.88 (3H, m), 1.25 (6H, m), 1.57 (2H, m),
4.2.9. tert-Butyl-N-Cbz pyroglutamate 11. To a stirred
solution of di-tert-butyl dicarbonate (776 mg, 3.56 mmol)
in anhydrous THF (4 mL), was added 4-dimethylamino-
pyridine (22 mg, 0.18 mmol) immediately followed by N-
Cbz glutamic acid (500 mg, 1.78 mmol), diluted in 8 mL
anhydrous THF. After stirring overnight, the reaction mix-
ture was filtrated through Celite, then partitioned between
diethyl ether and brine. The organic layer was dried over
magnesium sulfate and evaporated to give 11 as a light
1
.77 (1H, m), 2.22–2.56 (5H, m), 3.65 (3H, s), 4.42 (1H,
td, J 7.6 and 3.8 Hz), 5.08 (2H, s), 5.61 (1H, d, J 7.6 Hz),
1
3
7
2
1
1
.33 (5H, m); C NMR d 14.1, 22.5, 23.5, 26.9, 28.9,
9.6, 31.6, 39.8, 51.9, 58.9, 67.1, 128.2, 128.3, 128.6,
36.3, 156.2, 173.4, 208.6; IR (cm ): 3344, 2954, 1718,
522, 1454, 1329, 1253, 1051, 698; MS-IC(+): 364
ꢀ
1
20
(
100%), 320, 250, 230, 91; ½aꢁ ¼ þ13:1 (c 1, CH Cl ). Ele-
D
2
2
mental analysis calcd for C H NO : C, 66.09; H, 8.04; N,
20 29 5
1
3
.85. Found: C, 66.07; H, 8.07; N, 3.82.
brown solid (592 mg, 100%). H NMR d 1.31 (9H, s),
1
.90–2.62 (4H, m), 4.49 (1H, dd, J 9.4 and 2.6 Hz), 5.21
1
3
4
4
.2.6. (3S)-Methyl 3-(benzyloxycarbonylamino)-4-oxo-
-phenylbutanoate 9a. Following the general procedure
(2H, dd, J 12.0 and 6.0 Hz), 7.30 (5H, m); C NMR d
22.3, 28.2, 31.4, 59.8, 68.8, 82.9, 128.6, 128.8, 128.9,
2
D
1
and using commercially available PhMgCl, flash chroma-
tography on silica gel (cyclohexane–ethyl acetate 2:1,
135.4, 170.5, 173.6; ½aꢁ ¼ ꢀ39:6 (c 0.05, CHCl3).
R = 0.50) provided 9a (417 mg, 54%) as a colorless oil.
H NMR d 2.75–2.82 (1H, dd, J 16.2 and 5.5 Hz), 2.9–
4.2.10. (2S)-tert-Butyl 2-(benzyloxycarbonylamino)-5-oxo-
10
f
1
hexanoate 12a.
Following the above procedure and
2
.98 (1H, dd, J 16.2 and 5.5 Hz), 3.64 (3H, s), 5.11 (2H,
s), 5.57 (1H, td, J 8.5 and 5.5 Hz), 5.97 (1H, d, J 8.5 Hz),
.33 (5H, m), 7.46 (2H, dd, J 7.5 and 7.4 Hz), 7.59 (1H,
using a commercially available solution of MeMgBr
(3.0 M in Et O), chromatography on silica gel (cyclohex-
2
7
ane–ethyl acetate 4:6, R = 0.61) provided 12a (399 mg,
f
1
3
1
t, J 7.4 Hz), 7.98 (2H, d, J 7.5 Hz); C NMR d 37.1,
67%) as a colorless oil. H NMR d 1.46 (9H, s), 1.84
5
1
2
2.1, 52.5, 67.2, 128.1, 128.3, 128.6, 128.7, 128.9, 133.8,
(1H, m), 2.13 (4H, s), 2.51 (2H, m), 4.22 (1H, m), 5.10
1
3
34.4, 136.2, 155.7, 171.0, 197.1; MS-IC(+): 342 (100%),
(2H, s), 5.40 (1H, d, J 7.9 Hz), 7.35 (m, 5H); C NMR d
207.55, 171.22, 156.09, 136.35, 128.58, 128.48, 128.24,
82.41, 66.98, 53.87, 39.36, 30.06, 28.01, 26.76; MS-IC(+):
2
D
5
98, 236, 208,191, 152, 91; ½aꢁ ¼ ꢀ12:5 (c 1, CH Cl ). Ele-
2
2
mental analysis calcd for C H NO : C, 66.85; H, 5.61; N,
1
9
19
5
20
4
.10. Found: C, 66.80; H, 5.42; N, 4.24.
336, 318, 302, 280, 218; ½aꢁ ¼ þ6:8 (c 0.45, CHCl3).
D
4
.2.7. (3S)-Methyl 3-(benzyloxycarbonylamino)-4-(3-meth-
4.2.11. (2S)-tert-Butyl 2-(benzyloxycarbonylamino)-5-oxo-
5-phenylpentanoate 12b. Following the above procedure
and using a commercially available solution of PhMgCl
(2.0 M in THF), chromatography on silica gel (cyclohex-
oxyphenyl)-4-oxobutanoate 9b. Titration of 3-methoxy-
phenylmagnesium bromide prepared as described above,
gave a concentration of 0.59 mol L . Following the gen-
eral procedure, flash chromatography on silica gel (tolu-
ene–ethyl acetate 4:1, R = 0.55) provided 9b (448 mg,
ꢀ
1
ane–ethyl acetate 4:1, R = 0.39) provided 12b (496 mg,
f
1
70%) as a colorless oil. H NMR d 1.39 (9H, s), 1.97–
f
1
60%) as a colorless oil. H NMR d 2.75–2.82 (1H, dd, J
16.2 and 5.3 Hz), 2.91–2.98 (1H, dd, J 16.2 and 5.3 Hz),
3.65 (s, 3H), 3.83 (s, 3H), 5.12 (s, 2H), 5.55 (td, J 8.5 and
2.07 (1H, m), 2.18–2.29 (1H, m), 3.05 (2H, m), 4.28 (1H,
m), 5.01 (2H, s), 5.41 (1H, d, J 7.9 Hz), 7.27 (5H, m),
7.37 (2H, t, J 7.3 Hz), 7.49 (1H, t, J 7.3 Hz), 7.85 (2H, d,

G. Deguest et al. / Tetrahedron: Asymmetry 17 (2006) 2120–2125
2125
1
3
J 7.3 Hz); C NMR d 27.6, 28.4, 34.9, 54.4, 67.3, 82.8,
References
1
1
3
15.7, 120.7, 128.4, 128.6, 128.9, 129.0, 129.9, 133.6,
36.6, 136.9, 156.5, 171.6, 199.4; MS-IC(+): 398 (100%),
1. Jouin, P.; Castro, B.; Zeggaf, C.; Pantaloni, A.; Senet, J. P.
25
Tetrahedron Lett. 1987, 28, 1665.
80, 342, 296, 246; ½aꢁ ¼ þ9:6 (c 1, CH Cl ). Elemental
D
2
2
2
3
. Huang, X.; Luo, X.; Roupioz, Y.; Keillor, J. J. Org. Chem.
997, 62, 8821, and references cited herein.
. (a) Mc Garvey, G. J.; Hiner, R. N.; Matsubara, Y.; Oh, T.
Tetrahedron Lett. 1983, 24, 2733–2736; (b) Luppi, G.;
Tomasini, C. Synlett 2003, 6, 797–800.
analysis calcd for C H NO : C, 69.50; H, 6.85; N, 3.52.
Found: C, 69.32; H, 6.77; N, 3.68.
2
3
27
5
1
4
.2.12. N-Boc, N-Cbz aspartic anhydride 13. To a stirred
solution of di-tert-butyl dicarbonate (873 mg, 4.0 mmol)
in 4 mL anhydrous THF, was added 4-dimethylaminopyri-
dine (24 mg, 0.2 mmol) immediately followed by N-Cbz
aspartic acid (500 mg, 2.00 mmol), diluted in 8 mL anhy-
drous THF. After stirring overnight, and after filtration
and evaporation the residue was partitioned between
diethyl ether and brine. The organic layer was dried over
4
. (a) Melillo, D. G.; Larsen, R. D.; Mathre, D. J.; Shukis, W.
F.; Wood, A. W.; Colleluori, J. R. J. Org. Chem. 1987, 52,
5143–5150; (b) Yato, M.; Homma, K.; Ishida, A. Hetero-
cycles 1995, 41, 17–20.
5. Brinkmann, T.; Gilg, A.; Hamm, A.; L u¨ scht, H.; Morbach,
G.; Uzar, H. C. Tetrahedron: Asymmetry 2000, 11, 3827–
3
836.
6
7
8
. Furuta, T.; Katayama, M.; Shibasaki, H.; Kasuya, Y. J.
Chem. Soc., Perkin Trans. 1 1992, 1643–1648.
. Hatano, M.; Matsumura, T.; Ishihara, K. . Org. Lett. 2005, 7,
73–576.
. (a) Ohta, T.; Hosoi, A.; Kimura, T.; Nozoe, S. Chem. Lett.
987, 10, 2091–2094; (b) Rudolph, A. C.; Machauer, R.;
magnesium sulfate and then evaporated to give 13
1
(
559 mg, 80%) as a light brown oil. H NMR (DMSO) d
1
.23 (s, 9H), 2.94 (1H, dd, J 18.6 and 6.6 Hz), 3.16 (1H,
5
dd, J 18.6 and 10.4 Hz), 5.18 (2H, s), 5.52 (1H,
1
3
dd, J = 10.4 and 6.6 Hz), 7.31 (5H, m); C NMR (DMSO)
d 27.3, 34.0, 54.3, 69.2, 84.9, 127.9, 128.4, 128.5,
1
Martin, S. F. Tetrahedron Lett. 2004, 45, 4895–4898; (c)
Krelaus, R.; Westermann, B. Tetrahedron Lett. 2004, 45,
5987–5990; (d) Brenneman, J. B.; Martin, S. F. Org. Lett.
2
D
5
1
28.5, 150.1, 152.5, 169.7, 170.8; ½aꢁ ¼ ꢀ37:5 (c 1,
CH Cl ).
2
2
2
004, 6, 1329–1331.
. (a) Dolence, E. K.; Lin, C. E.; Miller, M. J. J. Med. Chem.
991, 34, 956–968; (b) Dolence, E. K.; Minnick, A. A.; Miller,
M. J. J. Med. Chem. 1990, 33, 461–464.
9
Acknowledgements
1
The MENESR (Minist e` re de l’Education Nationale, l’Ens-
eignement Sup e´ rieur et de la Recherche) is gratefully
acknowledged for a grant to Geoffrey Deguest.
10. (a) Mota, A. J.; Chiaroni, A.; Langlois, N. Eur. J. Org. Chem.
2003, 21, 4187–4198; (b) Mota, A. J.; Langlois, N. Tetra-
hedron Lett. 2003, 44, 1141–1143.